Patent Evaluation: 17 β-Aminobenzoyl-4-aza-5α-andro-1-en-3-ones for the treatment of benign prostatic hypertrophy

Summary

Novelty: 17β-Aminobenzoyl-4-aza-5α-androst-1-en-3-ones and related compounds are claimed for the treatment of hyperandrogenic conditions including prostatic hypertrophy.

Biology: No biological data are presented.

Chemistry: Six compounds are specifically claimed including 17β(4-dimethylaminophenyl-carbonyl)-4-aza-5α-androst-1-en-3-one; synthesis from a steroid ester is described.

Structure:     

Patent Evaluation: Guanidine-like Anti-arrhythmic Agents

Summary

Novelty: Novel aryl-fused and hetaryl-fused 2,4-diazepines, benzodiazocines and benzodiazepines are said to possess anti-arrhythmic activity. Some novel intermediates which are used in the preparation of the inventive compounds are also disclosed.

Biology: Anti-arrhythmic activity was demonstrated using electrophysiological techniques in guinea pigs. In an assay to assess the dose which causes a 20% increase in the effective refrectory period (ERP). The most active compounds had ED₂₀ values of 0.01 to 0.05 mg/kg.

Chemistry: (R)-(+)-4,5-Dihydro-4-methyl-1-phenyl-3-(2-phenylethyl)-1H-2,4-benzodiazepine is one of eleven specifically claimed compounds.

Structure:      

Congestive Heart Failure/β-Adrenergic Antagonist: Novel Pyridazinones with Combined β-Adrenergic and PDE III Activity for the Treatment of Congestive Heart Failure

Summary

Novelty: Novel pyridazinones, which are both positive inotropes and β-adrenergic blocking agents, are disclosed. As such, they are considered useful in the treatment of congestive heart failure.

Biology: A rat aorta relaxation screen identified PDE inhibitors. The IC₅₀ for the preferred compound is 0.34 μM. Inotropic activity is demonstrated in the anaesthetised dog (ED₅₀ = 0.11 μg/kg), and is not blocked by atenolol. Inotropic activity is also shown in a guinea pig left atrial test (ED₅₀ = 9μM). A pIC₅₀ of 7.57 was reported in a β-adrenoceptor binding assay.

Chemistry: The patent is exemplified by the synthesis of fifty final compounds using standard procedures. The preferred compound is 6-(4-[N-[2-[3-phenoxy-2-hydroxypropylamino]ethyl]-carbamoylmethoxy]-3-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone.     

Patent Evaluation: Novel Prodrugs for the Treatment of PCP

Summary

Novelty: Novel water-soluble derivatives of antibiotic lipopeptides are disclosed. The compounds are potentially useful as antimycotic agents and for the prevention or treatment of Pneumocystis carinii.

Biology: The compounds are evaluated in a Pneumocystis carinii rat infection assay (ED₉₀=0.6 mg/kg). Evaluation against Candida species in vitro is also recorded (MIC=0.5–16 μg/ml).

Chemistry: 1- [4[Hydroxy-N2-(10,12-dimethyl-1-oxotetradecyl)-ornithine]-4-[3-hydroxy-4′-O-phosphonyl-homotyrosine]-S-[3-hydroxyglutamine]-6-[3-hydroxyproline] eichinocandin B disodium salt is one two specifically claimed compounds.

Structure:     

Patent Evaluation: Heterocyclic sulphonylureas as antitumour agents

Summary

Novelty: Heterocyclic sulphonylureas are claimed to possess broad-spectrum antitumour activity.

Biology: Antitumour activity is demonstrated against transplantable solid murine tumours in vivo, in particular lymphosarcoma 6C3HED borne by C3H mice. The compounds, administered at a dose of 300 mg/kg po, show almost total inhibition of tumour growth and an improvement in mortality in comparison with control.

Chemistry: Syntheses of the compounds are by conventional methods, outlined in a multi-step preparative scheme and forming a subsidiary part of the claim. Twenty-three compounds are exemplified, and several are specifically claimed including N-[[(4-chlorophenyl)amino]-carbonyl]-4,5-dimethyl-2-thiophenesulphonamide.

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: 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: Quinolinyl-Benzoheterobicyclic Derivatives as LTD4 Antagonists

Summary

Novelty: Quinoline-containing compounds are disclosed as leukotriene (LT) antagonists, especially against LTD₄. The compounds also show lipoxygenase (LO) inhibitory activity. This spectrum of activity is potentially useful in the treatment of inflammatory and allergic conditions.

Biology: LT antagonism is examined in a guinea pig lung strips assay, in competition binding experiments in lung tissue membranes and by inhibition of mediator release from sensitized mast cells. However, no specific data are provided.

Chemistry: Synthesis of the compounds is by a multistep procedure from the parent heterocycle, exemplified in sixty-seven cases. Twenty-four specifically claimed compounds include 5-[6-[3-[2-quinolinylmethyloxy]phenoxymethyl]benzoxazol-2-yl]tetrazole.     

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: Dual ACE and Endopeptidase Inhibitors in the Treatment of Cardiovascular Disease

Summary

Novelty: Novel cycloalkyl-substituted glutaramides and their prodrugs are claimed along with processes for their preparation. The compounds inhibit the enzymes atriopeptidase and ACE and are therefore potentially useful in the treatment of various forms of hypertension and associated cardiovascular disorders.

Biology: Protocols for various tests used to establish the above activities are given but no results are disclosed.

Chemistry: Sixty-eight compounds are exemplified by synthesis. N-[1-(2(S)-Carboxy-4-(2-methoxyethoxy)pentyl)-1-cyclopentanecarbonyl]-(S)-tyrosine is one of four specifically claimed compounds.     

Patent Evaluation: Novel Imidazol[2,1-b]thiazole Derivatives as Anti-ulcer Agents

Summary

Novelty: Novel imidazol[2,1-b]thiazole derivatives, said to exhibit gastric acid secretion inhibiting activity, are disclosed. The compounds are potentially useful as anti-ulcer agents and possess very low toxicity.

Biology: The compounds were evaluated for anti-ulcer activity against the following models: aspirin-induced, water-immersion, stress-induced and ethanol induced, and rodent ulcer. The compounds were also evaluated for their gastric juice secretion inhibition activity and for their toxicity. A selected compound gave inhibition rates of over 40% in all ulcer models.

Chemistry: 5-(1-Hydroxybutyl)-6-methylimidazo[2,1-b]-thiazole is one of three 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: Class III Anti-Arrhythmic Agents with Positive Inotropic Activity

Summary

Novelty: Pyrimidinedione derivatives which are claimed to be effective in the treatment of cardiac arrhythmias are disclosed.

Biology: Myocardial action potential duration time (APD₇₅) effects are measured in an assay using hybrid adult dog heart as described previously (results are tabulated).

Chemistry: The synthesis is by standard techniques. Fifteen compounds are exemplified by synthesis. 1,3-Dimethyl-6-[4-(2-hydroxy-4-phenylbutyl)piperazin-1-yl]-2,4-(1H,3H)-pyrimidinedione hydrochloride is the preferred compound.

Structure:     

Patent Evaluation: Novel N-benzylpiperidino-Substituted Tricyclic Amines for the Treatment of Memory Disorders

Summary

Novelty: A diverse group of tricyclic-based compounds are disclosed. The compounds show activity as acetylcholinesterase (AChE) inhibitors, potentially useful in the treatment of the memory deficits of dementias such as Alzheimer's disease.

Biology: An in vitro assay for AChE inhibition is discussed. No specific data are provided.

Chemistry: Synthesis of the compounds forms a subsidiary part of the claim, outlined in nine synthetic schemes and exemplified by eighty-seven compounds. 2,3-Dihydro-2-[[1-(phenylmethyl)-4-piperidinyl]methylene]-1H-pyrrolo[1,2-a]indole-1-one is specifically claimed.     

Patent Evaluation: Acridine Multidrug Resistance Inhibitiors

Summary

Novelty: A novel group of compounds which sensitize multidrug resistant (MDR) cancer cells to chemotherapy is disclosed. In contrast to similar known agents, the claimed compounds are non-toxic at their effective dose levels.

Biology: The efficacy of compounds as inhibitors of MDR is evaluated in the CHO cell line CH^RC5, treated with doxorubicin (5 mg/ml). EC₅₀ data (0.018 ? 0.72 mM) refer to cell viability relative to doxorubicin-treated controls. The EC₅₀ for the known agent verapamil was 3mM. Oral toxicity in mice is said to be negligible at 300mg/kg.

Chemistry: Procedures are outlined for the synthesis of one hundred and thirty-seven named examples of which thirty-six are specifically claimed, including 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-diethoxy-2-isoquinolinyl)ethyl]phenyl]-4-acridinecarboxamide. Thirteen novel compounds are amongst 101 named intermediates.

Structure:     

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: Novel Piperidines as Leukotriene Antagonists

Summary

Novelty: 4-Diarylmethoxypiperidines which bear an N-linked alkoxyaryl moiety and are potentially useful for the treatment of allergic conditions, such as urticaria, eczema and asthma, are disclosed.

Biology: Histamine (10^–5 M)- and leukotriene (10-⁸ M)-induced contractions in guinea pig ileum were antagonized at a concentration of 10^–7 M of test compound.

Chemistry: Five schemes are presented for preparation of the compounds which employ standard techniques and are exemplified in seventy cases. Several compounds are specifically claimed, including 1-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)propyl]-4-[(4-chloro)-phen-yl-2-pyridylmethoxy]piperidine.

Structure:     

Patent Evaluation: Novel class III anti-arrhythmics

Summary

Novelty: Novel carbostyril analogues are claimed to possess anti-arrhythmic activity.

Biology: Data are provided for two compounds in an in vitro assay using guinea pig heart muscle (increase in VERP) and in vivo in guinea pig (effect on cardiac electrical activity). The compounds are effective in all tests. The two preferred compounds have ED₃₀ VERP values of 1.15 and 2.20 mg/kg. Toxicity data are also provided (rat, iv and po). No gross pathological or histopathological abnormalities can be detected at 7.5 mg/kg/day.

Chemistry: There are seven synthetic examples and fifteen preparations detailed. S(-)-3,4-Dihydro-5-[2-hydroxy-3-(4-(isobutyloxycarbonylamino)-1-piperidyl)-propoxy]carbostyril is one of two preferred compounds.

Structure:     

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:     

Patent Update: Lipoxygenase Inhibitors and Leukotriene Antagonists as Therapeutic Agents

Summary

Novelty: N-dimethoxy phenyl alkyl-N′-imidazolylphenylamidine derivatives and processes for their preparation are disclosed. These derivatives are potentially useful anti-ulcer agents.

Biology: Data are provided on inhibition of gastric secretion, inhibition of acid output and inhibition of indomethacin-induced gastric ulcers by the novel derivatives as compared with known compounds (mifentidine, famotidine, cimetidine and ranitidine). Comparable or better results than the standards are obtained.

Chemistry: The novel comopunds have the generic structure illustrated below. Specifically claimed are N-[2-(3,4-dimethoxy phenyl)ethyl]-N′-[4-(imidazol-4-yl)phenyl]formamidine (shown below) and N-[2-(3,4-dimethoxy phenyl)ethyl]-N′-[5-methyl-4-(imidazol)-4-yl) phenyl]-3,4-dimethoxy phenyl acetamidine. Seven examples illustrate the preparation of novel compounds. One method of preparation comprises reacting an N-cyano-N′-[4-(imidazol-4-yl) phenyl]amidine with a 3,4-dimethoxyphenylalkyl amine.

Structure: