US20140045900A1 - Administration regime for nitrocatechols - Google Patents

Administration regime for nitrocatechols Download PDF

Info

Publication number
US20140045900A1
US20140045900A1 US13/583,375 US201113583375A US2014045900A1 US 20140045900 A1 US20140045900 A1 US 20140045900A1 US 201113583375 A US201113583375 A US 201113583375A US 2014045900 A1 US2014045900 A1 US 2014045900A1
Authority
US
United States
Prior art keywords
compound
administered
administration
levodopa
oxadiazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/583,375
Other languages
English (en)
Inventor
Patricio Manuel Vieira Araujo Soares Da Silva
Teresa Lucia Silva Pereira NUNES
Lyndon Christopher WRIGHT
Pedro Nuno Leal Palma
David Alexander Learmonth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bial Portela and Cia SA
Original Assignee
Bial Portela and Cia SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bial Portela and Cia SA filed Critical Bial Portela and Cia SA
Priority to US13/583,375 priority Critical patent/US20140045900A1/en
Assigned to BIAL - PORTELA & CA, S.A. reassignment BIAL - PORTELA & CA, S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEARMONTH, DAVID ALEXANDER, NUNES, Teresa Lucia Silva Pereira, SOARES DA SILVA, PATRICIO MANUEL VIEIRA ARAUJO, WRIGHT, Lyndon Christopher, PALMA, PEDRO NUNO LEAL
Publication of US20140045900A1 publication Critical patent/US20140045900A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • This invention relates to the use of substituted nitrocatechols of formula (I) in the treatment of central and peripheral nervous system disorders according to a specified administration (dosing) regimen (regime).
  • COMT inhibition serves to increase the bioavailability of levodopa and the duration of antiparkinsonian action is prolonged with single administrations of levodopa (Nutt, J. G., Lancet, 351:1221-1222, 1998).
  • tolcapone differs from entacapone in that it easily enters the central nervous systems (CNS) and is able to inhibit cerebral COMT as well as peripheral COMT. Shortly after its launch, tolcapone was withdrawn from the market after several cases of hepatotoxicity were reported including three unfortunate deaths from fatal fulminant hepatitis. Today tolcapone can only be used in Parkinsonian patients who are unresponsive to other treatments and only with regular monitoring of liver function, which is expensive and inconvenient for the patient.
  • CNS central nervous systems
  • tolcapone may be reduced metabolically to reactive intermediates and it has been speculated that these may form covalent adducts with hepatic proteins resulting in hepatocellular injury (Smith, K. S. et al, Chem. Res. Toxicol., 16:123-128, 2003).
  • Entacapone on the other hand, although sharing the same nitrocatechol pharmacophore with tolcapone, is not associated with liver toxicity and is generally regarded as a safe drug. Unfortunately, however, entacapone is a significantly less potent COMT inhibitor than tolcapone and has a much shorter in-vivo half-life. This means that entacapone has a very limited duration of effect and as a consequence, the drug must be administered in very high doses with every dose of levodopa taken by the patient. As such, the clinical efficacy of entacapone has been questioned—indeed a recent study (Parashos, S. A. et al., Clin. Neuropharmacol., 27(3): 119-123, 2004) revealed that the principal reason for discontinuation of entacapone treatment in Parkinson's disease patients was a perceived lack of efficacy.
  • COMT inhibitors exhibiting balanced properties of bioactivity, bioavailability and safety.
  • COMT inhibitors having a long in-vivo half-life and, thus, a prolonged action on COMT enabling fewer dosages to obtain the desired therapeutic effect.
  • the present invention is based on a surprisingly advantageous administration regimen for the administration of the compounds of formula (I) which maximises the COMT inhibitory effect of the compounds.
  • the present invention relates to a compound of formula (I)
  • R 1 and R 2 are the same or different and signify hydrogens, groups hydrolysable under physiological conditions, or optionally substituted alkanoyls or aroyls;
  • X signifies a methylene group;
  • Y represents O, S or NH;
  • n represents 0, 1, 2 or 3;
  • m represents 0 or 1;
  • R 3 signifies a pyridine N-oxide group according to the formula A, B, or C, which is connected as indicated by the unmarked bond:
  • R 4 , R 5 , R 6 and R 7 are the same or different, and signify hydrogen, alkyl, thioalkyl, alkoxy, aryloxy, thioaryl, alkanoyl, aroyl, aryl, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, alkylsulphonyl, arylsulphonyl, halogen, haloalkyl, trifluoromethyl, cyano, nitro or heteroaryl; or two or more of R 4 , R 5 , R 6 and R 7 taken together signify aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings;
  • alkyl including its variant ‘alk-’ in terms such as ‘alkoxy’, ‘alkanoyl’ mean carbon residues, straight or branched, containing from one to six carbon atoms;
  • aryl means a phenyl or nap
  • the present invention relates to a compound of formula (I)
  • R 1 and R 2 are the same or different and signify hydrogens, groups hydrolysable under physiological conditions, or optionally substituted alkanoyls or aroyls;
  • X signifies a methylene group;
  • Y represents O, S or NH;
  • n represents 0, 1, 2 or 3;
  • m represents 0 or 1;
  • R 3 signifies a pyridine N-oxide group according to the formula A, B, or C, which is connected as indicated by the unmarked bond:
  • R 4 , R 5 , R 6 and R 7 are the same or different, and signify hydrogen, alkyl, thioalkyl, alkoxy, aryloxy, thioaryl, alkanoyl, aroyl, aryl, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, alkylsulphonyl, arylsulphonyl, halogen, haloalkyl, trifluoromethyl, cyano, nitro or heteroaryl; or two or more of R 4 , R 5 , R 6 and R 7 taken together signify aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings;
  • alkyl including its variant ‘alk-’ in terms such as ‘alkoxy’, ‘alkanoyl’ mean carbon residues, straight or branched, containing from one to six carbon atoms;
  • aryl means a phenyl or nap
  • the invention provides the use of a compound of formula (I) for the manufacture of a medicament for use in the prophylaxis or treatment of a central and peripheral nervous system disorder, wherein said compound is administered without food, between intakes of food, prior to sleep, before bedtime and/or at bedtime.
  • the invention provide a method of prophylaxis or treatment of a central and peripheral nervous system disorder, comprising administering to a patient suffering from said disorder, without food, between intakes of food, prior to sleep, before bedtime and/or at bedtime a therapeutically effective amount of a compound of formula (I).
  • the compounds of formula (I) are advantageously administered to a patient who has a digestive system which is as free from food as possible. Therefore, the compounds of formula (I) should preferably be administered to a patient without food and/or between intakes of food e.g. between meals, prior to sleep, before bedtime or at bedtime. Administering the compound in this manner results in the compounds of formula (I) having better activity e.g. more long lasting and increased inhibition of COMT.
  • the COMT inhibitors of formula (I) are used as an adjunct to catecholamine therapy, so that the metabolism of the catecholamine drug by COMT is decreased.
  • a compound of formula (I) is administered to a patient already taking a catecholamine, such as levodopa (L-DOPA)
  • the effects of the compound of formula (I) are improved if the compound of formula (I) is administered sequentially with the catecholamine.
  • the compound of formula (I) adversely affects the bioavailability of levadopa
  • levadopa adversely affects the bioavailability of the compound of formula (I).
  • the compound of formula (I) is administered prior to sleep, before bedtime or at bedtime, before or after the last daily dose of levodopa has been given to the patient and before the following day's dosage of levodopa is administered. Therefore, the compound of formula (I) and the catecholamine drug are not within the patient's digestive system at the same time and/or not being substantially absorbed at the same time.
  • last daily dose last dose of the day
  • last daily administration last administration of the day
  • FIG. 1 shows mean plasma concentration-time profile of 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol (COMPOUND A) following fasting and fed conditions.
  • FIG. 2 shows mean levodopa plasma concentration-time profiles following single oral administration of Sinemet® (levodopa/carbidopa) 100/25 mg administered alone, administered with 50 mg COMPOUND A separated 1 h and administered concomitantly with 50 mg COMPOUND A.
  • FIG. 3 shows mean S—COMT activity (metanephrine formed, pmol/mg protein/h) profiles from baseline (pre-dose) following single oral administration of Sinemet® 100/25 administered alone, administered with 50 mg COMPOUND A separated 1 h, administered concomitantly with 50 mg COMPOUND A and when COMPOUND A was administered alone.
  • the compounds of formula (I) are extremely potent, they can potentially be administered in a single daily administration.
  • the compounds of formula (I) are preferably administered prior to sleep, before bedtime or at bedtime.
  • the term ‘prior to sleep’ means that the compound of formula (I) is administered shortly before the patient goes to sleep, for example less than 90 minutes prior to sleep, particularly less than one hour prior to sleep, less than 30 minutes prior to sleep or immediately prior to sleep.
  • before bedtime i.e. before going to bed
  • at bedtime means less than 5 minutes before bedtime, for example on going to bed.
  • the compound of formula (I) is taken by the patient before the patient goes to bed (i.e. before bedtime or at bedtime), e.g. less than 90 minutes before bedtime, particularly less than 60 minutes before bedtime, less than 30 minutes before bedtime or less than 5 minutes before bedtime.
  • the term ‘prior to sleep’ or ‘before bedtime’ does not mean any time in the day prior to sleep or going to bed, and in particular does not include, for example, 12 hours before sleep or going to bed. Rather this term means the drug is taken in the period close to the patient going to sleep and probably as part of the patient's bedtime routine.
  • the compound of formula (I) is administered in combination therapy with a catecholamine drug.
  • a catecholamine drug is levodopa.
  • the administration regimen of the compound of formula (I) and the catecholamine drug may differ: each may be administered at the same time or at different times.
  • the compounds of the combination may be administered sequentially (e.g. before or after) or concomitantly, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately). Simultaneously in the same formulation is as a unitary formulation whereas simultaneously in different pharmaceutical formulations is non-unitary.
  • the administration regime of each of the two or more compounds in a combination therapy may also differ with respect to the route of administration.
  • the compounds of formula (I) are administered prior to sleep, before bedtime or at bedtime, before or after the last administration of the day of the catecholamine drug and before the first administration of the next day of the catecholamine drug. This therefore avoids the adverse consequence each drug has on the bioavailability of the other.
  • the COMT inhibitory activity of the compounds of formula I is active prior to administration of the catecholamine drug.
  • the compound of formula (I) is administered from 30 to 150 minutes before or after the last daily administration of the catecholamine drug.
  • the compound of formula (I) is administered at least 30-50 minutes, preferably at least one hour, before or after the last daily administration of the catecholamine drug.
  • the compound of formula (I) is administered at least one hour before or after the last daily administration of the catecholamine drug is administered, and preferably the compound of formula (I) is administered once daily at least one hour before or after the last daily administration of the catecholamine drug. In embodiments of the invention there is a period of at least two, three, four, five or six hours between the administration of the catecholamine and the compounds of formula (I).
  • the subsequent administration of the catecholamine is administered at least two, more preferably at least three, and most preferably at least six hours after administration of the compound of formula (I).
  • the subsequent administration of the catecholamine is administered 12 hours or 23 hours after administration of the compound of formula (I).
  • the subsequent administration of the catecholamine drug is the first daily dose of catecholamine drug of the next day.
  • the administration regime according to the invention involves administration of the compound of formula (I) when the patient has a digestive system free from food.
  • the applicant has discovered that the compounds of formula (I) have improved bioavailability when administered to a patient when the patient does not have food in their digestive system.
  • the compound of formula (I) should be administered to the patient prior to sleep, before bedtime or at bedtime, without food after the patient has had their final meal of the day.
  • a digestive system free from food means that the part of the digestive system where most of the absorption of the compound of formula (I) occurs is free from food, e.g. stomach, small intestine (duodenum, jejunum, ileum).
  • the compound of formula (I) is administered at least one hour after the most recent intake of food and at least one hour before the next intake of food.
  • the compound of formula (I) is administered from 0.25 to 12 hours, preferably from 0.5 to 6 hours, more preferably from 0.75 to 4 hours, after an intake of food. In one embodiment of the invention the compound of formula (I) is administered after 0.25 to 10 hours overnight fasting.
  • the compound of formula (I) is administered from 0.25 to 2 hours, preferably from 0.5 to 1.5 hours, before an intake of food.
  • the compound of formula (I) is administered prior to sleep, and more preferably less than one hour prior to sleep.
  • the compound of formula (I) is administered once daily prior to sleep, before bedtime or at bedtime.
  • the term ‘effective daily dose’ is the effective daily amount of compound administered when administered according to the dosing periodicity.
  • effective daily doses of compounds of general formula (I) are in the range of about 1 to about 1200 mg/day, preferably about 1 to about 900 mg/day, more preferably about 5 to about 400 mg/day, even more preferably about 25 to about 300 mg/day, for example specific daily doses of 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 100 mg, 200 mg, 400 mg, 800 mg or 1200 mg.
  • the term “dosage unit” refers to the amount of compound administered in each dosing periodicity.
  • individual dosage units of compounds of general formula (I) are in the range of about 1 to about 2400 mg, more preferably about 1 to about 1200 mg, even more preferably about 1 to about 800 mg, for example 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 100 mg, 200 mg, 400 mg, 800 mg or 1200 mg.
  • COMT inhibitors are often used as adjuncts to catecholamine compounds because they reduce their metabolic O-methylation.
  • COMT inhibitors are often used as adjuncts to levodopa/aromatic L-amino acid decarboxylase inhibitor (AADCi) therapy because they reduce metabolic O-methylation of levodopa to 3-O-methyl-levodopa (3-OMD).
  • AADCi levodopa/aromatic L-amino acid decarboxylase inhibitor
  • the pathological states treated by the compounds are central and peripheral nervous system-associated disorders of humans which benefit from administration of a COMT inhibitor.
  • the catecholamine drug is administered sequentially or concomitantly with an AADCi, in particular cardidopa or benserazide.
  • the compounds of general formula (I), the catecholamine drug and the AADCi may be administered separately or in any combination. They may be administered concomitantly (for example, simultaneously) or sequentially, and with the same or differing dosing periodicity.
  • the compounds of the general formula (I) can be concomitantly or sequentially administered with the catecholamine drug.
  • the use of the compounds according to the invention is for the propylaxis or treatment of central and peripheral nervous system disorders.
  • the central and peripheral nervous system disorder is, for example, a mood disorder, gastrointestinal disturbance, oedema formation state, hypertension or a movement disorder.
  • the disorders are movement disorders including disorders involving parkinsonism, Parkinson's Disease, and restless leg syndrome.
  • the most preferred central and peripheral nervous system disorder is Parkinson's Disease.
  • treatment and variations such as ‘treat’ or ‘treating’ refer to any regime that can benefit a human or non-human animal.
  • the compounds of formula (I) can be used for prophylaxis (preventative treatment).
  • Treatment may include curative, alleviation or reducing effects, such effects relating to one or more of the symptoms associated with the central and peripheral nervous system-associated disorders.
  • One particular embodiment of the invention is a compound of formula (I), particularly 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and its pharmacologically acceptable salts, esters, carbamates and phosphates, for use in combination with a catecholamine drug, particularly levodopa, for the prophylaxis or treatment of central and peripheral nervous system disorder, particularly a movement disorder such as Parkinson's disease, wherein the compound of formula (I) is administered orally once daily at least one hour before or after the last daily dose of the catecholamine drug and prior to sleep, before bedtime or at bedtime and/or without food and/or between intakes of food and/or at least one hour after the most recent intake of food and at least one hour before the next intake of food.
  • a catecholamine drug particularly levodopa
  • a movement disorder such as Parkinson
  • a method of treating at least one pathological state in a patient in need thereof comprising administering, without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug, a pharmacologically effective dose of a compound of general formula (I) as defined above to the patient.
  • a method for inhibiting COMT in a subject comprising administering, without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug, an effective dose of a compound of general formula (I) as defined above to the subject.
  • a method for increasing levels of levodopa in the brain of a subject being treated with levodopa comprising administering, without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug, an effective dose of a compound of general formula (I) as defined above to the subject.
  • a method for increasing levels of levodopa in the plasma of a subject being treated with levodopa comprising administering, without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug, an effective dose of a compound of general formula (I) as defined above to the subject.
  • a method for decreasing levels of 3-O-methyl-levodopa (3-OMD) in the brain of a subject being treated with levodopa comprising administering, without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug, an effective dose of a compound of general formula (I) as defined above to the subject.
  • a method for decreasing levels of 3-OMD in the plasma of a subject being treated with levodopa comprising administering, without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug, an effective dose of a compound of general formula (I) as defined above to the subject.
  • a method for increasing bioavailability of levodopa in the brain of a subject being treated with levodopa comprising administering, without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug, an effective dose of a compound of general formula (I) as defined above to the subject.
  • a method for increasing bioavailability of levodopa in the plasma of a subject being treated with levodopa comprising administering, without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug, an effective dose of a compound of general formula (I) as defined above to the subject.
  • the present invention also relates to a package comprising a pharmaceutical composition of a compound of the general formula (I) in combination with instructions to administer said formulation without food and/or between intakes of food and/or prior to sleep and/or before bedtime and/or at bedtime and/or before or after administration of a catecholamine drug.
  • Groups hydrolysable under physiological conditions represent groups cleavable in vivo, at physiological conditions of pH and temperature.
  • the pH values for tissue fluids are indicated.
  • groups hydrolysable under physiological conditions for the —OH functional group are esters, carbamates and phosphates.
  • Further examples of groups hydrolysable under physiological conditions for the —OH functional group are well known to the skilled in the art and can be found for example on pages 101-103 from Korolkovas in Essentials of Medicinal Chemistry, 2 nd edn., 1988, eds. John Wiley & Sons and on page 426 of Krogsgaard-larsen et al in Textbook of Drug Design and Discovery, 3 rd edn., 2002, eds. Taylor & Francis.
  • R 4 , R 5 , R 6 and R 7 independently from each other represent hydrogen, C 1 -C 6 -alkyl, C 6 -C 12 aryl, C 1 -C 6 -thioalkyl, C 1 -C 6 -alkoxy, C 6 -C 10 -aryloxy, C 6 -C 10 -thioaryl, C 1 -C 6 -alkanoyl, C 7 -C 11 -aroyl, amino, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 3 -C 12 -cycloalkylamino, C 4 -C 8 -heterocycloalkylamino, C 1 -C 6 -alkylsulphonyl, C 6 -C 10 -arylsulphonyl, halogen, C 1 -C 6 -haloalkyl, trifluoromethyl, cyano, nitro or hetero
  • R 4 , R 5 , R 6 and/or R 7 represent C 1 -C 6 -alkyl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, or hexyl.
  • R 4 , R 5 , R 6 and/or R 7 represent C 6 -C 12 -aryl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent phenyl or naphthyl.
  • R 4 , R 5 , R 6 and/or R 7 represent C 1 -C 6 -thioalkyl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent thiomethyl, thioethyl, thio-n-propyl, thio-isopropyl, thio-n-butyl, thio-n-pentyl, or thio-n-hexyl.
  • R 4 , R 5 , R 6 and/or R 7 represent C 1 -C 6 -alkoxy residues, preferably R 4 , R 5 , R 6 and/or R 7 represent methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy.
  • R 4 , R 5 , R 6 and/or R 7 represent C 6 -C 10 -aryloxy residues, preferably R 4 , R 5 , R 6 and/or R 7 represent phenoxy or naphthoxy.
  • R 4 , R 5 , R 6 and/or R 7 represent C 6 -C 10 -thioaryl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent thiophenyl or thionaphthyl.
  • R 4 , R 5 , R 6 and/or R 7 represent C 1 -C 6 -alkanoyl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent methanoyl, ethanoyl, propanoyl or butanoyl.
  • R 4 , R 5 , R 6 and/or R 7 represent C 7 -C 11 -aroyl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent benzoyl or naphthoyl.
  • R 4 , R 5 , R 6 and/or R 7 represent C 1 -C 6 -alkylamino residues, preferably R 4 , R 5 , R 6 and/or R 7 represent methylamino, ethylamino, n-propylamino, isopropylamino or n-butylamino.
  • R 4 , R 5 , R 6 and/or R 7 represent di-C 1 -C 6 -alkylamino residues, preferably R 4 , R 5 , R 6 and/or R 7 represent dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, di-isopropylamino, methylethylamino, methylpropylamino or ethylpropylamino.
  • R 4 , R 5 , R 6 and/or R 7 represent C 3 -C 12 -cycloalkylamino residues, preferably R 4 , R 5 , R 6 and/or R 7 represent pyrrolidino, piperidino, cyclohexylamino or dicyclohexylamino.
  • R 4 , R 5 , R 6 and/or R 7 represent C 4 -C 8 -heterocycloalkylamino residues, preferably R 4 , R 5 , R 6 and/or R 7 represent morpholino, 2,6-dimethylmorpholino, 3,5-dimethylmorpholino, piperazino, N-methylpiperazino or N-ethylpiperazino.
  • R 4 , R 5 , R 6 and/or R 7 represent C 1 -C 6 -alkylsulphonyl or C 6 -C 10 -arylsulphonyl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent methylsulfonyl, ethylsulfonyl, phenylsulfonyl, or tolylsulfonyl.
  • R 4 , R 5 , R 6 and/or R 7 represent halogen residues, preferably R 4 , R 5 , R 6 and/or R 7 represent chloro, bromo, iodo or fluoro.
  • R 4 , R 5 , R 6 and/or R 7 represent C 1 -C 6 -haloalkyl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl or trifluoromethyl.
  • R 4 , R 5 , R 6 and/or R 7 represent heteroaryl residues, preferably R 4 , R 5 , R 6 and/or R 7 represent pyridyl, pyrimidyl, isoxazolyl, oxazolyl, isoxadiazolyl, oxadiazolyl, triazolyl or tetrazolyl.
  • residues R 4 , R 5 , R 6 and R 7 taken together represent aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings
  • the two or more residues preferably represent aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings.
  • Preferred combined residues are indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, naphthyridinyl, isoquinolyl and quinolyl.
  • R 4 , R 5 , R 6 and R 7 may optionally be substituted one or more times by hydroxy, alkoxy or halogen groups.
  • the most preferred example of a compound according to the general formula (I) is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, henceforth designated as compound A, and its pharmacologically acceptable salts, esters, carbamates and phosphates.
  • compound A is 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, henceforth designated as compound A, and its pharmacologically acceptable salts, esters, carbamates and phosphates.
  • the half life of compound A is relatively short given its long duration of action.
  • the compounds of general formula (I) may also be present in the form of pharmacologically acceptable salts, esters, carbamates or phosphates thereof.
  • Suitable pharmaceutically acceptable counter ions are known to the art.
  • prodrugs of compounds of the general formula (I) in order to alter the therapeutic profile of the active compound.
  • the compound of formula (I) is administered as a pharmaceutical composition.
  • inert pharmaceutically acceptable carriers are admixed with the active compounds.
  • the pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, dispersible granules and capsules.
  • a solid carrier can be one or more substances which may also act as diluent, flavouring agent, solubiliser, lubricant, suspending agent, binder, glidant, or disintegrant; it may also be an encapsulating material.
  • the pharmaceutical composition is in unit dosage form, e.g. a packaged preparation, the package containing discrete quantities of the preparation, for example packaged tablets, capsules and powders in vials or ampoules.
  • the compound of formula (I) is administered orally.
  • the compound of formula (I) typically is administered from once a day to about once weekly.
  • the compound of formula (I) is administered with a periodicity lower than once a day (e.g. once weekly), it is understood that it will be administered prior to sleep, before bedtime or at bedtime, before or after the last daily dose of levodopa of the day(s) of the week where compound (I) should be administered and not every day, as levodopa.
  • a periodicity lower than once a day e.g. once weekly
  • the next administration will occur on the first day of week two, prior to sleep, before bedtime or at bedtime, before or after the last daily dose of levodopa of that day and so on. Throughout this period levodopa is administered every day (in several doses).
  • the compound of formula (I) is typically administered from once a day to about once weekly.
  • compositions are prepared as follows:
  • Compound A 15.0% Lactose monohydrate 43.0% Microcrystalline cellulose 30.0% Povidone 4.0% Croscarmellose sodium 5.0% Talc 2.0% Magnesium stearate 1.0%
  • Compound A 15.0% Microcrystalline cellulose 72.5% Ethylcellulose 5.0% Sodium starch glycolate 6.0% Colloidal Silicon Dioxide 0.5% Magnesium stearate 1.0%
  • Compound A 20.0% Microcrystalline cellulose 25.0% Calcium Phosphate, dibasic dihydrate 40.0% Povidone 6.0% Croscarmellose sodium 6.0% Talc 2.0% Magnesium stearate 1.0%
  • This study was an open-label, randomized, single administration, 2-period, 2-sequence, crossover study in 12 healthy male subjects aimed to assess the effects of food on the pharmacokinetic (PK) profile of COMPOUND A and its metabolites.
  • PK pharmacokinetic
  • COMPOUND A pharmacokinetic parameters following fasting and fed conditions are presented in Table 1. Summary of PK main results of COMPOUND A following fasting and fed conditions.
  • This study was a single-centre, open-label, randomized, gender-balanced, crossover study with four consecutive single-administration treatment periods to assess the PK-PD interaction when standard release 25/100 mg carbidopa/levodopa is administered concomitantly with a 50 mg COMPOUND A dose or 1 hour thereafter. Eighteen (18) subjects completed 2 treatment periods, 17 subjects completed 3 treatment periods and 16 subjects completed all 4 treatment periods. A total of 18 male [10 (55.6%)] and female [8 (44.4%)] subjects were enrolled in this study.
  • Treatment consisted of four single-administration periods.
  • Single-administration of 50 mg COMPOUND A was constituted by 2 capsules of 25 mg.
  • Single-administration of immediate/standard release 25 mg carbidopa/100 mg levodopa was constituted of 1 tablet of Sinemet® 100/25.
  • subjects were administered COMPOUND A and Sinemet® 100/25 concomitantly in one period, Sinemet® 100/25 1 h after the COMPOUND A administration in another period, COMPOUND A alone in another period, and Sinemet® 100/25 alone in the remaining period.
  • the washout period between administrations was at least 3 weeks.
  • COMPOUND A and Sinemet® 100/25 were to be administered concomitantly; in another treatment period, Sinemet® 100/25 was to be administered 1 h after the COMPOUND A administration; in another treatment period, COMPOUND A was to be administered alone; in the remaining treatment period, Sinemet® 100/25 was to be administered alone.
  • C max of 3-OMD was lower when Sinemet® 100/25 was administered 1 h after 50 mg COMPOUND A than when Sinemet® 100/25 was administered concomitantly with 50 mg COMPOUND A.
  • C max and AUC of carbidopa were similar when Sinemet® 100/25 was administered alone and when administered with 50 mg COMPOUND A separated 1 h.
  • the increase in carbidopa C max ranged from 5.33% when Sinemet® 100/25 was administered 1 h after 50 mg COMPOUND A to 5.86% when Sinemet® 100/25 was administered concomitantly with 50 mg COMPOUND A.
  • the increase in carbidopa AUC 0- ⁇ ranged from 5.42% when Sinemet® 100/25 was administered 1 h after 50 mg COMPOUND A to 9.20% when Sinemet® 100/25 was administered concomitantly with 50 mg COMPOUND A.
  • This study was a three-center, double-blind, randomised, placebo-controlled, cross-over study to investigate the tolerability and effect a single administration of three dosages of COMPOUND A (25, 50 and 100 mg) on the levodopa pharmacokinetics, motor response, and erythrocyte soluble catechol-O-methyltransferase activity in 10 Parkinson's Disease patients concomitantly treated with levodopa/dopa-decarboxylase inhibitor.
  • Subjects were eligible if they presented: a diagnosis of PD according to the UK PDS Brain Bank diagnostic criteria; predictable signs of end-of-dose deterioration despite “optimal” levodopa/AADCi therapy; being treated with a stable regimen of 3 to 8 doses of standard release levodopa/AADCi 100/25 mg per day within at least 1 week prior to randomisation; modified Hoehn and Yahr stage of less than 5 in the off-state; and/or mean duration of OFF stage ⁇ 1.5 h during waking hours.
  • Concomitant anti-Parkinsonian medication (other than apomorphine, entacapone or tolcapone) was allowed in stable doses for at least 4 weeks prior to randomisation.
  • levodopa/AADCi therapy is the levodopa/AADCi dosage and administration regime, which produces the best motor response in a patient, i.e. absence or reduction to a minimum of end-of-dose deterioration (wearing-off) and/or motor complications.
  • the study consisted of four consecutive treatment periods, corresponding to the 4 different treatment options (Compound A 25 mg, 50 mg, 100 mg or placebo).
  • subjects were to be admitted to the study site 2 days prior to receiving the administration of Compound A/Placebo (Day 1) and were to remain hospitalized (“in-patient”) until 48 h after receiving the administration of Compound A/Placebo.
  • the washout period between administrations was to be at least 10 days.
  • a follow-up visit was to occur approximately 2 weeks after the last treatment administration or early discontinuation.
  • the COMPOUND A/Placebo capsules were to be co-administered with the morning dose of levodopa/carbidopa 100/25 mg (1 tablet of Sinemet® 25/100) or levodopa/benserazide 100/25 mg (1 tablet of Madopar®/Restex® 125) on Day 3.
  • the mean ( ⁇ SD) age, height and weight were 58.40 ⁇ 10.24 (range: 42-70) years, 1.69 ⁇ 0.14 (1.52-1.95) m, 71.5 ⁇ 15.06 (50-100) kg, respectively.
  • Compound A is tested as the research therapy and entacapone and placebo as the reference therapies.
  • Compound A is available in capsules of 5 mg, 25 mg and 50 mg. Entacapone tablets of 200 mg are used.
  • the placebo capsules are prepared by filling identical capsules with filler (also used as back-filling). All placebo capsules contain, on average, 1 mg riboflavin to mimic the urinary discoloration seen as a harmless side effect of entacapone
  • subjects take 1 capsule of treatment concomitantly with each daytime levodopa/AADCi administration (3 to 8 daily administrations).
  • An additional treatment (‘before bedtime’ or ‘prior to sleep’ administration) is administered at least 1 hour after the last administration of the day of levodopa/AADCi.
  • the treatment administration is as follows:
  • the treatment administration is as follows:
  • patients with Parkinson's disease maintained on levodopa/AADCi are treated as follows. Patients take either the placebo or compound A (25 mg or 50 mg) in the evening at least one hour after the last dose of the day of levodopa/AADCi therapy (the bedtime dose (administration)).
  • Subjects are required to fast for 1 hour before and for at least 1 hour after intake of the treatment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Psychology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Saccharide Compounds (AREA)
US13/583,375 2011-02-11 2011-10-12 Administration regime for nitrocatechols Abandoned US20140045900A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/583,375 US20140045900A1 (en) 2011-02-11 2011-10-12 Administration regime for nitrocatechols

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201161441988P 2011-02-11 2011-02-11
US13/583,375 US20140045900A1 (en) 2011-02-11 2011-10-12 Administration regime for nitrocatechols
PCT/GB2011/052056 WO2012107708A1 (en) 2011-02-11 2011-10-21 Administration regime for nitrocatechols

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2011/052056 A-371-Of-International WO2012107708A1 (en) 2011-02-11 2011-10-21 Administration regime for nitrocatechols

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/963,621 Continuation US10065944B2 (en) 2011-02-11 2013-08-09 Administration regime for nitrocatechols

Publications (1)

Publication Number Publication Date
US20140045900A1 true US20140045900A1 (en) 2014-02-13

Family

ID=44999798

Family Applications (3)

Application Number Title Priority Date Filing Date
US13/583,375 Abandoned US20140045900A1 (en) 2011-02-11 2011-10-12 Administration regime for nitrocatechols
US13/963,621 Active 2032-07-20 US10065944B2 (en) 2011-02-11 2013-08-09 Administration regime for nitrocatechols
US16/114,430 Pending US20190144436A1 (en) 2011-02-11 2018-08-28 Administration regime for nitrocatechols

Family Applications After (2)

Application Number Title Priority Date Filing Date
US13/963,621 Active 2032-07-20 US10065944B2 (en) 2011-02-11 2013-08-09 Administration regime for nitrocatechols
US16/114,430 Pending US20190144436A1 (en) 2011-02-11 2018-08-28 Administration regime for nitrocatechols

Country Status (18)

Country Link
US (3) US20140045900A1 (tr)
EP (2) EP3831382A1 (tr)
JP (4) JP6148985B2 (tr)
AU (1) AU2011358842B2 (tr)
BR (2) BR112013020424A2 (tr)
CA (1) CA2826080C (tr)
CY (1) CY1124022T1 (tr)
DK (1) DK2672973T3 (tr)
ES (1) ES2855162T3 (tr)
HR (1) HRP20210474T1 (tr)
HU (1) HUE054072T2 (tr)
LT (1) LT2672973T (tr)
PL (1) PL2672973T3 (tr)
PT (1) PT2672973T (tr)
RS (1) RS61643B1 (tr)
RU (1) RU2639131C2 (tr)
SI (1) SI2672973T1 (tr)
WO (1) WO2012107708A1 (tr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8907099B2 (en) 2005-07-26 2014-12-09 Bial-Portela & Ca, S.A. Nitrocatechol derivatives as COMT inhibitors
US9126988B2 (en) 2011-12-13 2015-09-08 Bial—Portela & Ca, S.A. Intermediate for preparing a catechol-O-methyltransferase inhibitor
US9446012B2 (en) 2006-04-10 2016-09-20 Bial—Portela & Ca, S.A. Pharmaceutical compounds
WO2017060870A1 (en) 2015-10-09 2017-04-13 Hermann Russ Combination of deuterated levodopa with carbidopa and opicapone for the treatment of parkinson`s disease
US9745290B2 (en) 2007-01-31 2017-08-29 Bial—Portela & Ca, S.A. Dosage regimen for COMT inhibitors
US9845316B2 (en) 2008-03-17 2017-12-19 BIAL—Portela & CA., S.A. Crystal forms of 5-[3-(2,5-dichloro-4, 6-dimethyl-1-oxy-pyridine-3-yl)[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol
US10065944B2 (en) 2011-02-11 2018-09-04 Bial-Portela & Ca, S.A. Administration regime for nitrocatechols
US10071085B2 (en) 2009-04-01 2018-09-11 Bial—Portela & Ca, S.A. Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making thereof
US10357468B2 (en) 2014-11-28 2019-07-23 Bial—Portela & Ca, S.A. Medicaments for slowing Parkinson's disease
US10672179B2 (en) * 2015-12-30 2020-06-02 Wuhan United Imaging Healthcare Co., Ltd. Systems and methods for data rendering

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020072886A1 (en) 2018-10-05 2020-04-09 Neurocrine Biosciences, Inc. Methods for the administration of comt inhibitors
CA3112994A1 (en) 2018-10-05 2020-04-09 Neurocrine Biosciences, Inc. Methods for the administration of comt inhibitors
JP2020023540A (ja) * 2019-10-11 2020-02-13 ノヴィファーマ，エス．アー． パーキンソン病を遅延させるための医薬
JP7251026B2 (ja) 2019-11-14 2023-04-04 国立大学法人九州大学 ポリマー化合物およびコーティング組成物

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6500867B1 (en) * 1999-06-30 2002-12-31 Orion Corporation Pharmaceutical composition comprising entacapone, levodopa, and carbidopa
WO2010014025A1 (en) * 2008-07-29 2010-02-04 Bial - Portela & Ca., S.A. Administration regime for nitrocatechols
US20100113529A1 (en) * 2007-01-31 2010-05-06 Bial-Portela & Ca., S.A. Dosage regimen for comt inhibitors
US20100256194A1 (en) * 2009-04-01 2010-10-07 Bial - Portela & Ca, S.A. Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making the same
US20100266193A1 (en) * 2009-04-21 2010-10-21 Samsung Techwin Co., Ltd. Electronic part recognition apparatus and chip mounter having the same
WO2011107653A2 (en) * 2010-03-04 2011-09-09 Orion Corporation Method for treating parkinson's disease
US20120196904A1 (en) * 2005-07-26 2012-08-02 David Alexander Learmonth Nitrocatechol derivatives as comt inhibitors
US20140024682A1 (en) * 2006-04-10 2014-01-23 Bial - Portela & Ca, S.A. Pharmaceutical compounds

Family Cites Families (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1532178A (en) 1921-07-25 1925-04-07 Louis A Godbold Lubricator
FR1260080A (fr) 1960-03-22 1961-05-05 Materiel De Forage Soc De Fab Trépan à molettes étanche
IL31990A (en) 1968-04-26 1974-05-16 Chinoin Gyogyszer Es Vegyeszet Pyridyl 1,2,4-oxadiazole derivatives,process for the preparation thereof and pharmaceutical compositions containing same
US4022901A (en) 1975-03-05 1977-05-10 E. R. Squibb & Sons, Inc. 3-Pyridinyl-5-isothiocyanophenyl oxadiazoles
US4264573A (en) 1979-05-21 1981-04-28 Rowell Laboratories, Inc. Pharmaceutical formulation for slow release via controlled surface erosion
US4386668A (en) 1980-09-19 1983-06-07 Hughes Tool Company Sealed lubricated and air cooled rock bit bearing
US5236952A (en) 1986-03-11 1993-08-17 Hoffmann-La Roche Inc. Catechol derivatives
DK175069B1 (da) 1986-03-11 2004-05-24 Hoffmann La Roche Pyrocatecholderivater
YU213587A (en) 1986-11-28 1989-06-30 Orion Yhtymae Oy Process for obtaining new pharmacologic active cateholic derivatives
DE3840954A1 (de) 1988-12-05 1990-06-07 Shell Int Research Herstellung von 2-chlornicotinsaeureestern
EP0462639A1 (en) 1990-06-05 1991-12-27 Shell Internationale Researchmaatschappij B.V. Preparation of 2-chloropyridine derivatives
ES2066092T3 (es) 1990-11-29 1995-03-01 Wei Ming Pharmaceutical Mfg Co Coadyuvante para la formacion directa de comprimidos.
AU3171493A (en) 1991-12-31 1993-07-28 Fujisawa Pharmaceutical Co., Ltd. Oxadiazole derivatives having acetylcholinesterase-inhibitory and muscarinic agonist activity
DE19628617A1 (de) 1996-07-16 1998-01-22 Basf Ag Direkttablettierhilfsmittel
US6206110B1 (en) 1996-09-09 2001-03-27 Smith International, Inc. Protected lubricant reservoir with pressure control for sealed bearing earth boring drill bit
US5788987A (en) * 1997-01-29 1998-08-04 Poli Industria Chimica Spa Methods for treating early morning pathologies
WO2000017175A1 (en) 1998-09-18 2000-03-30 Vertex Pharmaceuticals Incorporated INHIBITORS OF p38
GB2344819A (en) 1998-12-18 2000-06-21 Portela & Ca Sa 2-Phenyl-1-(3,4-dihydroxy-5-nitrophenyl)-1-ethanones
CA2381975A1 (en) 1999-08-19 2001-02-22 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US6660753B2 (en) 1999-08-19 2003-12-09 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
FI20000635A0 (fi) 2000-03-17 2000-03-17 Orion Yhtymae Oyj COMT-inhibiittoreiden käyttö analgeettina
SE0001438D0 (sv) 2000-04-18 2000-04-18 Axon Chemicals Bv New chemical compounds and their use in therapy
DE10029201A1 (de) 2000-06-19 2001-12-20 Basf Ag Verfahren zur Herstellung fester oraler Darreichungsformen mit retardierender Wirkstoffreisetzung
GB2363792A (en) 2000-06-21 2002-01-09 Portela & Ca Sa Nitrocatechols
CN1166626C (zh) 2000-08-30 2004-09-15 李凌松 三或四取代苯基化合物、其制备方法及应用
PT1356046E (pt) 2000-11-28 2010-03-09 Zymogenetics L L C Receptor de citocina zcytor19
CA2436739A1 (en) 2000-12-26 2002-07-04 Takeda Chemical Industries, Ltd. Combination agent
US20040097555A1 (en) 2000-12-26 2004-05-20 Shinegori Ohkawa Concomitant drugs
EP1679313A3 (en) 2001-02-21 2006-08-16 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US20030208067A1 (en) 2001-05-30 2003-11-06 Cao Sheldon Xiaodong Inhibitors of protein kinase for the treatment of disease
IL159086A0 (en) 2001-06-08 2004-05-12 Cytovia Inc 3-aryl-5-aryl- [1, 2, 4] -oxadiazole derivatives and pharmaceutical compositions containing the same
DK1408964T3 (da) 2001-07-26 2007-05-21 Merck Patent Gmbh Hidtil ukendt anvendelse af 2-5-(4-fluorphenyl)-3-pyridylmethylaminomethyl-chroman og fysiologisk acceptable salte deraf
JP4379853B2 (ja) 2001-10-05 2009-12-09 惠民製藥股▲分▼有限公司 直接錠剤化用調合物および補助剤の調合方法
US7144876B2 (en) 2002-12-18 2006-12-05 Cytovia, Inc. 3,5-Disubstituted-[1,2,4]-oxadiazoles and analogs as activators of caspases and inducers of apoptosis and the use thereof
DE60334406D1 (de) 2002-12-23 2010-11-11 Merck Frosst Company Pharmazeutische zusammensetzungen und verfahren zur behandlung von morbus parkinson
WO2005006945A2 (en) 2003-07-03 2005-01-27 The Salk Institute For Biological Studies Methods for treating neural disorders and compounds useful therefor
ATE455546T1 (de) 2003-08-06 2010-02-15 Vertex Pharma Aminotriazol-verbindungen als proteinkinase- hemmer
DE10338174A1 (de) 2003-08-20 2005-03-24 Lts Lohmann Therapie-Systeme Ag Transdermale Arzneimittelzubereitungen mit Wirkstoffkombinationen zur Behandlung der Parkinson-Krankheit
US7300406B2 (en) 2003-09-30 2007-11-27 Carter Vandette B Medical examination apparatus
GB0325956D0 (en) 2003-11-06 2003-12-10 Addex Pharmaceuticals Sa Novel compounds
EP1751133B1 (en) 2004-04-28 2010-04-14 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of rock and other protein kinases
GB0510143D0 (en) 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds A1
WO2006051154A1 (en) 2004-11-10 2006-05-18 Orion Corporation Treatment of restless legs syndrome
EP1827453A1 (en) 2004-12-06 2007-09-05 Themis Laboratories Private Limited Sulfonylurea compositions and a process for its preparation
CN101090895A (zh) 2004-12-28 2007-12-19 阿斯利康(瑞典)有限公司 芳基磺酰胺调节剂
US20080051441A1 (en) 2004-12-28 2008-02-28 Astrazeneca Ab Aryl Sulphonamide Modulators
WO2006114400A1 (en) 2005-04-26 2006-11-02 Neurosearch A/S Novel oxadiazole derivatives and their medical use
US20060257473A1 (en) 2005-05-11 2006-11-16 Porranee Puranajoti Extended release tablet
GB0510139D0 (en) 2005-05-18 2005-06-22 Addex Pharmaceuticals Sa Novel compounds B1
ATE530519T1 (de) 2005-06-03 2011-11-15 Abbott Lab Cyclobutylaminderivate
JP2007024970A (ja) 2005-07-12 2007-02-01 Miyakawa:Kk 液晶表示装置の開口効率を上昇させるための樹脂レンズ製造法及びその製造装置
US20090000437A1 (en) 2005-07-14 2009-01-01 Provo Craft And Novelty, Inc. Methods for Cutting
FR2889525A1 (fr) 2005-08-04 2007-02-09 Palumed Sa Nouveaux derives de polyquinoleines et leur utilisation therapeutique.
US20070048384A1 (en) 2005-08-26 2007-03-01 Joerg Rosenberg Pharmaceutical compositions
EP1948153A2 (en) 2005-09-21 2008-07-30 Orion Corporation Treatment of symptoms of parkinson`s disease
WO2007061862A2 (en) 2005-11-18 2007-05-31 Janssen Pharmaceutica N.V. 2-keto-oxazoles as modulators of fatty acid amide hydrolase
JP4738419B2 (ja) 2005-11-30 2011-08-03 富士フイルムＲｉファーマ株式会社 アミロイドの凝集及び／又は沈着に起因する疾患の診断薬及び治療薬
GB0606774D0 (en) 2006-04-03 2006-05-10 Novartis Ag Organic compounds
PE20080906A1 (es) 2006-08-17 2008-07-05 Kemia Inc Derivados heteroarilo como inhibidores de citocina
US20080167286A1 (en) 2006-12-12 2008-07-10 Abbott Laboratories Pharmaceutical compositions and their methods of use
US8486979B2 (en) 2006-12-12 2013-07-16 Abbvie Inc. 1,2,4 oxadiazole compounds and methods of use thereof
WO2009029632A1 (en) 2007-08-27 2009-03-05 Helicon Therapeutics, Inc. Therapeutic isoxazole compounds
CN101959504A (zh) 2008-02-28 2011-01-26 比艾尔-坡特拉有限公司 用于难溶性药物的药物组合物
US8975410B2 (en) 2008-03-17 2015-03-10 BIAL—Portela & CA., S.A. Crystal forms of 5-[3-(2,5-dichloro-4, 6-dimethyl-1-oxy-pyridine-3-yl)[1,2,4] oxadiazol-5-yl]-3-nitrobenzene-1,2-diol
CN105878242A (zh) * 2009-04-01 2016-08-24 巴尔-波特拉及康邦亚股份有限公司 包括硝基儿茶酚衍生物的药物制剂及其制备方法
US20140045900A1 (en) * 2011-02-11 2014-02-13 Bial-Portela & Ca, S.A. Administration regime for nitrocatechols
BR112014014341A2 (pt) 2011-12-13 2017-08-22 Bial Portela & Ca Sa Intermediário metilado, seu método de preparação e seus usos, e composição farmacêutica

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6500867B1 (en) * 1999-06-30 2002-12-31 Orion Corporation Pharmaceutical composition comprising entacapone, levodopa, and carbidopa
US20120196904A1 (en) * 2005-07-26 2012-08-02 David Alexander Learmonth Nitrocatechol derivatives as comt inhibitors
US20140024682A1 (en) * 2006-04-10 2014-01-23 Bial - Portela & Ca, S.A. Pharmaceutical compounds
US20100113529A1 (en) * 2007-01-31 2010-05-06 Bial-Portela & Ca., S.A. Dosage regimen for comt inhibitors
US8524746B2 (en) * 2007-01-31 2013-09-03 Bial-Portela & Ca., S.A. Dosage regimen for COMT inhibitors
US20130331416A1 (en) * 2007-01-31 2013-12-12 Bial - Portela & Ca, S.A. Dosage regimen for comt inhibitors
WO2010014025A1 (en) * 2008-07-29 2010-02-04 Bial - Portela & Ca., S.A. Administration regime for nitrocatechols
US20100256194A1 (en) * 2009-04-01 2010-10-07 Bial - Portela & Ca, S.A. Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making the same
US20100266193A1 (en) * 2009-04-21 2010-10-21 Samsung Techwin Co., Ltd. Electronic part recognition apparatus and chip mounter having the same
WO2011107653A2 (en) * 2010-03-04 2011-09-09 Orion Corporation Method for treating parkinson's disease

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8907099B2 (en) 2005-07-26 2014-12-09 Bial-Portela & Ca, S.A. Nitrocatechol derivatives as COMT inhibitors
US10336740B2 (en) 2005-07-26 2019-07-02 Bial—Portela & Ca, S.A. Nitrocatechol derivatives as COMT inhibitors
US9550759B2 (en) 2005-07-26 2017-01-24 Bial—Portela & Ca, S.A. Nitrocatechol derivatives as COMT inhibitors
US9446012B2 (en) 2006-04-10 2016-09-20 Bial—Portela & Ca, S.A. Pharmaceutical compounds
US9745290B2 (en) 2007-01-31 2017-08-29 Bial—Portela & Ca, S.A. Dosage regimen for COMT inhibitors
US9845316B2 (en) 2008-03-17 2017-12-19 BIAL—Portela & CA., S.A. Crystal forms of 5-[3-(2,5-dichloro-4, 6-dimethyl-1-oxy-pyridine-3-yl)[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol
US10071085B2 (en) 2009-04-01 2018-09-11 Bial—Portela & Ca, S.A. Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making thereof
US10583130B2 (en) 2009-04-01 2020-03-10 Bial-Portela & Ca, S.A. Pharmaceutical formulations compromising nitrocatechol derivatives and methods of making thereof
US10065944B2 (en) 2011-02-11 2018-09-04 Bial-Portela & Ca, S.A. Administration regime for nitrocatechols
US9630955B2 (en) 2011-12-13 2017-04-25 BIAL—Portela & Cª., S.A Chemical compound useful as intermediate for preparing a catechol-O-methyltransferase inhibitor
US9126988B2 (en) 2011-12-13 2015-09-08 Bial—Portela & Ca, S.A. Intermediate for preparing a catechol-O-methyltransferase inhibitor
US10357468B2 (en) 2014-11-28 2019-07-23 Bial—Portela & Ca, S.A. Medicaments for slowing Parkinson's disease
WO2017060870A1 (en) 2015-10-09 2017-04-13 Hermann Russ Combination of deuterated levodopa with carbidopa and opicapone for the treatment of parkinson`s disease
US10672179B2 (en) * 2015-12-30 2020-06-02 Wuhan United Imaging Healthcare Co., Ltd. Systems and methods for data rendering

Also Published As

Publication number Publication date
AU2011358842B2 (en) 2017-02-02
EP2672973B1 (en) 2020-12-30
LT2672973T (lt) 2021-04-26
SI2672973T1 (sl) 2021-07-30
CY1124022T1 (el) 2022-05-27
PT2672973T (pt) 2021-03-30
ES2855162T8 (es) 2022-01-04
JP2014505096A (ja) 2014-02-27
US20190144436A1 (en) 2019-05-16
WO2012107708A1 (en) 2012-08-16
HRP20210474T1 (hr) 2021-08-06
CA2826080C (en) 2020-08-18
AU2011358842A1 (en) 2013-08-15
EP3831382A1 (en) 2021-06-09
ES2855162T3 (es) 2021-09-23
JP2018197262A (ja) 2018-12-13
PL2672973T3 (pl) 2021-06-28
JP6568274B2 (ja) 2019-08-28
JP6843930B2 (ja) 2021-03-17
RS61643B1 (sr) 2021-04-29
BR112013007380A2 (pt) 2018-11-21
BR112013020424A2 (pt) 2021-04-13
US20130324578A1 (en) 2013-12-05
JP6148985B2 (ja) 2017-06-14
JP2019206567A (ja) 2019-12-05
US10065944B2 (en) 2018-09-04
JP6389498B2 (ja) 2018-09-12
JP2017071619A (ja) 2017-04-13
EP2672973A1 (en) 2013-12-18
WO2012107708A9 (en) 2013-02-14
DK2672973T3 (da) 2021-03-29
RU2639131C2 (ru) 2017-12-19
RU2013139414A (ru) 2015-03-20
HUE054072T2 (hu) 2021-08-30
CA2826080A1 (en) 2012-08-16

Similar Documents

Publication Publication Date Title
US20190144436A1 (en) Administration regime for nitrocatechols
US10016426B2 (en) Pharmaceutical compositions for substituted quinazolinones
EP2307020B1 (en) Administration regime for nitrocatechols
JP6889231B2 (ja) レボドパ、ドーパミン脱炭酸酵素阻害薬およびｃｏｍｔ阻害薬を含む医薬組成物ならびにその投与方法
US8524746B2 (en) Dosage regimen for COMT inhibitors
JP2014505096A5 (tr)
WO2005117853A1 (ja) 高脂血症治療剤及び糖尿病治療剤

Legal Events

Date Code Title Description
AS Assignment

Owner name: BIAL - PORTELA & CA, S.A., PORTUGAL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SOARES DA SILVA, PATRICIO MANUEL VIEIRA ARAUJO;NUNES, TERESA LUCIA SILVA PEREIRA;WRIGHT, LYNDON CHRISTOPHER;AND OTHERS;SIGNING DATES FROM 20121011 TO 20121212;REEL/FRAME:029772/0397

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION