Patent Evaluation: Hydrogenated Rapamycin Derivatives as Antifungal Agents

Summary

Novelty: Hydrogenated derivatives of rapamycin are disclosed as antifungal agents.

Biology: Data are presented which show that both claimed compounds are less active against five strains of Candida albicans than the parent rapamycin. 1,2-Dihydrorapamycin is significantly less active, whereas the 1,2,3,4-tetrahydro derivative was generally only half as effective (MIC = 0.006 μg/ml, compared with 0.003 μg/ml). However, Candida albicans 3669 was more sensitive to the tetrahydroderivative (MIC = 0.0125 μg/ml) than rapamycin (MIC = 0.025 μg/ml). Both new derivatives were relatively inactive in in vitro LAF and in vivo PLN tests and hence lack the immunosuppresive activity associated with rapamycin.

Chemistry: 1,2-Dihydro and 1,2,3,4-tetrahydro rapamycin were prepared by high pressure hydrogenation of rapamycin, which employs tris(triphenylphosphine)rhodium(I)chloride as a catalyst.     

Patent Evaluation: Novel Azole Derivatives as Anxiolytic Agents

Summary

Novelty: Omega azole derivatives are disclosed. They are said to be more effective in treating cognitive disorders, senile dementia, Alzheimer's disease and related disorders that the anxiolytic benzodiazepines.

Biology: Cognition amelioration activity was shown by the preferred compound in a light/dark box test according to the method of Barnes et al. (Pharmacol. Biochem. Behav. (1990) 35:955-962). The reversal of the learning period produced by scopolamine was totally blocked. Antidepressive activity was demonstrated by immobility times in the test according to Porsolt et al. (Arch. Int. Pharmacodyn. (1977) 229:327-336). Results show the specified compound had activity from immobility times of 87, 58 and 32 seconds for control, compound and Imipramine, respectively. Doses were 1 and 30mg/kg, ip for the compound and Imipramine.

Chemistry: Five syntheses by standard techniques are described, together with three examples of preparation of the compounds. Characterization is by mp, IR and NMR. The specified compound is 1H-pyrazole-4-chloro-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl] dihydrochloride.

Structure:      

Patent Evaluation: Novel Oxamide Derivatives as TNF Inhibitors

Summary

Novelty: Novel oxamide derivatives and a process for their preparation are disclosed. These compounds are said to inhibit the production of TNF and are potentially useful for the treatment of disease states mediated or exacerbated by TNF production. The compounds are also said to inhibit PDE(IV).

Biology: In vitro TNF production by human monocytes showed IC₅₀ values in the range of 0.01-<3.0. The inhibition of TNF production in a mammal is also demonstrated. Also reported is the phosphodiesterase inhibitory activity, IC50 values range from 0.05 μM to 40μM.

Chemistry: Preferred novel compounds have the generic structure below. Nine compounds are specifically claimed. Representative of these is N-[2-(3-cyclopentyloxy-4-methoxyphenyl)-ethyl]-N-methyl oxamide, which is prepared by a multistep process. The preparation of oxamide derivatives and intermediates are illustrated in forty-seven examples.

Structure:      

Patent Evaluation: Novel Naphthyridine and Pyridopyrazine Derivatives as Anti-Allergy Agents

Summary

Novelty: Anti-inflammatory and anti-allergic properties as well as cytoprotective properties are claimed for new 1-substituted naphthyridines and pyridopyrazines.

Biology: The anti-allergic potential of the compounds is demonstrated in a guinea pig anaphylactic bronchospasm assay. The compound below shows 79% inhibition at 2 mg/kg, po. Some details are also given of activity in the passive Arthus response, anti-ulcer, mouse ear oedema and graft vs host reaction assays.

Chemistry: There are five synthetic examples and several formulations. The preferred compound is 3-(2-hydroxyethyl)-1-(3-chlorophenyl)-1,8-naphthyridin-2(1H)-one.     

Patent Evaluation: Novel 3-Indolyl Thioacetate Derivatives as NMDA Receptor Antagonists

Summary

Novelty: New 3-indolylthioacetate derivatives are disclosed as NMDA antagonists. The compounds are claimed to be useful in treating convulsions, ischaemia, hypoxic or hypoglycaemic conditions and neurodegenerative diseases. They also have an anxiolytic effect.

Biology: Anticonvulsant properties are assessed in vivo by inhibition of quinolinic acid-induced seizures in mice, where the control group has a statistically higher seizure rate than mice administered intracerebroventricularly with the test compound. Anti-epileptic activity is assessed by inhibition of audiogenic convulsion (one hundred and ten decibels for thirty seconds) in mice with similiar results. The anxiolytic effect is measured by blocking the ultrasonic vocalization in rat pups in vivo when removed from the litter, again the two groups show statistical differences.

Chemistry: Synthesis, by conventional methods, of the starting material, the 3,5-dichlorophenylhydrazone of ethyl pyruvate, and of eleven compounds is presented. Characterization is by Mp, IR and NMR. The preferred compound is 2-carboxyethyl-4,6-dichloroindole. A large number of compounds are claimed.     

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 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 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: Novel LHRH Antagonists

Summary

Novelty: Novel analogues of LHRH are disclosed and are said to be antagonists of LHRH, potentially useful for the treatment of cancerous tumours.

Biology: Receptor binding affinities for human breast cancer cell membranes was demonstrated using labelled LHRH as desribed by Kadar et al. (Proc. Natl. Acad. Sci. USA (1988)

B5:890-894) Affinity constants range from 4.08-48.28 nM. In tests on the growth of Dunning R3327 prostate cancer in rats, compounds of the claim reduced the volume of the tumours by up to half after 7 weeks at 25 μg/day.

Chemistry: Seven synthetic schemes for production of the peptides are presented and twentysix compounds are exemplified; none is specifically claimed. A typical peptide is Ac-DNal(2)D-Phe(4Cl)-D-Pa1(3)Ser-Arg-D-Lys[A₂pr(Car)2]-Leu-Arg-Pro-D-Ala-NH₂, where Ac=acetyl, Na1(2)=3-(2-naphthyl)alanine, Phe(4Cl)4-chlorophenylalanine, Pal(3)=3-(3-pyridyl)-alanine and A₂pr=2,3-diaminopropinic acid.     

Patent Evaluation: Novel Antibody-Autoantigen Conjugates

Summary

Novelty: Diseases which are attributable to a predominantly cell-mediated immune response, notably autoimmune diseases, are said to be suppressed by administering a novel conjugate of an appropriate antigen, notably an autoantigen, with an antibody to an appropriate B cell surface molecule, such as IgD.

Biology: It appears that autoantigens supplied as antibody-autoantigen conjugates, cause the autoantigen to be presented to T-cells by B-cells (because the anti-IgD binds to the IgD on the B cells surface). This mode of presentation induces the T-cells to produce IL-4 and IL-10 on subsequent encounter with the body's endogenous autoantigen. These lymphokines then suppress the action of potentially harmful T-cells, that are otherwise responsible for the tissue damage associated with autoimmunity.     

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: Novel Antifungal Agents

Summary

Novelty: Novel fungicidal compositions comprising a pyranyl ester and a β-lactone are disclosed. A method for controlling mycotic infections is also given.

Biology: The MIC against Candida albicans was determined to be 3.1μg/ml for β-lactone dienoic acid and 2μg/ml for the pyranyl glycine ester.

Chemistry: The pyranyl glycine esters are either (2,3,4,5)-tetrahydro-4-methoxy-5-methyl-2-(1-methyl-1,3,5-nonatrienyl)-2-pyran-3-yl glycine or (2,3,4,5)-tetarahydro-4-methoxy-5-methyl-2-(1-methyl-1,3,5-nonatrienyl)-2-pyran-3-yl-N,N-dimethylglycine. The preferred β-lactone is 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-7-methyl-2,4-undecadienoic acid.

Structure:      

Patent Evaluation: Novel Self-Assembling Proteins

Summary

Novelty: A novel gene construct has been generated which is designed for the co-expression, in a host cell, of a self-assembling protein moiety which will form a protein core and a membrane-bound protein. The nascent protein core will bud off from the cell, in the process acquiring a membrane envelope with which the membrane-bound protein component will be associated.

Biology: In one example, the HIV gag 1 coding sequence was excized from an existing plasmid vector as a BamH1 cassette and cloned into pAcRP23. This baculovirus expression vector consisted of the sequence encoding the polyhedrin gene of the Autographa californica nuclear polyhedrosis virus ligated into a high copy number bacterial plasmid and modified to generate a unique cloning site. On introduction of the recombinant plasmid into Spodoptera frugiperda, the p55^gag polypeptide was found to accumulate in the culture supernatant, indicating that the recombinant protein is released from the cell. Electron microscopy indicated that the p55^gag polypeptide was associated with particles which budded off the cell surface. Cells expressing the gag sequence were co-infected with a recombinant baculovirus expressing the haemagglutinin gene from influenza virus. On co-expression of the gag the haemagglutinin genes, extracellular particles were obtained which encapsulated the gag polypeptide while having haemagglutinin associated with the particle surface.     

Patent Evaluation: Moranoline Derivatives as Antiviral Agents

Summary

Novelty: A novel series of moranoline derivatives are disclosed. These compounds are claimed to have antiviral activity and are potentially useful for the treatment of viral diseases, such as HIV.

Biology: The cell degeneration effect (CPE) observed in cells to which the drug was added was compared to controls (N-n-butylmoranoline and N-ethylmoranoline) and expressed as an MIC (the amount of drug whereby 50% of CPE was produced). Two specific compounds had MICs of 1 μg/ml compared with > 100 for the controls and demonstrated anti-HIV activity with IC₅₀s of 0.1 and 0.3 μg/ml compared with 40.8 μg/ml for moranoline. Both compounds had LD₅₀s (ip) > 300 mg/kg (po) > 5000 mg/kg in mice.

Chemistry: No experimental details are included but 207 compounds are exemplified. The preferred compounds are N-[4-(4-phenoxyphenyl)-3-pentenyl]moranoline (115) and N-[4-(4-chlorophenoxy)butyl]moranoline (141).

Structure:     

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: Novel Angiotensin II Antagonists

Summary

Novelty: New imidazole derivatives are disclosed as antihypertensives. They contain an imidazole substituted in all positions, except for one nitrogen.

Biology: An in vitro assay is described using rat liver membranes treated with radiolabeled [¹²⁵I] angiotensin II (A II) at 30 μM (IC₅₀ values in the 0.5 nM range). An additional assay using portal vein rings of male Wistar rats treated with 30nM A II indicates IC₅₀ values in the order of 0.1 nM. In vivo, an assay to measure arterial diastolic pressure in pentobarbital anaesthetized male Sprague-Dawley rats indicates IC₅₀ values of 22 μg/kg.

Chemistry: One hundred and forty-three examples are given using conventional methods for the preparation of the compounds. Characterization is by mp, ir, NMR and elemental analysis. The preferred compound is 2-butyl-4-(methylthio) 1-[[2′-(1H-tetrazol-5-yl) (1,1′-biphenyl)-4-yl]methyl] 1H-imidazole-5-carboxylic acid.     

Patent Evaluation: Novel Potassium Channel Openers

Summary

Novelty: Methods for the enantiomer-selective preparation of (+)-N-(2-ethoxyphenyl)-N',N'-(1,2,2-trimethylpropyl)-2-nitroethene-1,1-diamine a known K⁺ channel antagonist and smooth muscle relaxant, are disclosed. The use of this enantiomer as an antihypertensive and anti-asthmatic agent forms a further part of the claim.

Biology: The superior potency of the (+) enantiomer was demonstrated by inhibition of K^+- induced contractions in rat aortic rings; the IC₅₀ value of the (+) enantiomer was 15.5 nM compared with 248.0 nM for the (-) enantiomer.

Chemistry: The preparative process comprizes the reaction of 1-[(1-ethoxy)phenylamino]-1-methylthio-2-nitroethene with 1,2,2-trimethylpropylamine in organic solvent at a temperature between 50-160°C to form the final product. Enantiomer-selectivity is achieved by either using a single enantiomer of the 1,2,2-trimethylpropylamine, or by employing sophisticated hplc methods. Two preparative examples are given. Methods for the preparation and use of N-(2-ethoxyphenyl)-N',N'-(1,2,2-trimethylpropyl)-2-nitroethene-1,1-diamine have been previously disclosed.

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: