WO2003063872A1 - Derives d'acide barbiturique non sedatifs - Google Patents

Derives d'acide barbiturique non sedatifs Download PDF

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Publication number
WO2003063872A1
WO2003063872A1 PCT/US2003/002638 US0302638W WO03063872A1 WO 2003063872 A1 WO2003063872 A1 WO 2003063872A1 US 0302638 W US0302638 W US 0302638W WO 03063872 A1 WO03063872 A1 WO 03063872A1
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Prior art keywords
lower alkyl
phenyl
substituted
benzyl
aryl
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PCT/US2003/002638
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English (en)
Inventor
Dainel A. Moros
Daniella Gutman
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Taro Pharmaceutical Industries Ltd.
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Priority to EP03735068A priority Critical patent/EP1485101A4/fr
Priority to JP2003563562A priority patent/JP2005516052A/ja
Priority to CA2471436A priority patent/CA2471436C/fr
Publication of WO2003063872A1 publication Critical patent/WO2003063872A1/fr
Priority to IL163168A priority patent/IL163168A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/62—Barbituric acids
    • C07D239/64—Salts of organic bases; Organic double compounds
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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

Definitions

  • the present invention relates to novel non-sedating barbituric acid derivatives, pharmaceutical compositions containing them and methods of neuroprotection in cases of cerebral ischemia, head trauma and other acute neurologic injuries, and prevention of resulting neuronal damage.
  • the invention also relates to the use of non-sedating barbituric acid derivatives given in a manner and dosage effective to produce blood levels and brain levels of these drugs and/or their active metabolites sufficient to provide a therapeutic effect.
  • Barbituric acid and its derivatives have been known since the turn of the century to possess pharmacological properties and some of them serve as active ingredients in widely used drags.
  • Barbituric acid derivatives are known to act mainly as sedatives, hypnotics and anaesthetics. Certain derivatives also have an anticonvulsive effect and are therefore employed in the treatment of epilepsy.
  • pharmaceutical compositions containing 5-ethyl-5-phenyl barbituric acid (phenobarbital) are at present most widely used as drags employed in the treatment of epilepsy.
  • phenobarbital has sedative and hypnotic effects, which are a disadvantage in the treatment of epilepsy. Therefore, a great effort has been devoted to the search for compounds which have anticonvulsant properties and at the same time are devoid of sedative and hypnotic effects.
  • a known derivative of barbituric acid is 5,5-diphenyl barbituric acid, which was disclosed by S.M. McElvain in J. Am. Chem. Soc. 57, 1303 (1935), which is incorporated herein by reference in its entirety.
  • the compound was found to be effective only in very large doses and therefore no pharmacological application was suggested.
  • Raines et al. reported in Epilepsia 20, 105 (1979), which is incorporated herein by reference in its entirety, that 5,5- diphenyl barbituric acid has an anticonvulsant effect on rodents but with the disadvantage of relatively short term activity.
  • non-sedating barbituric acid derivatives have been disclosed in Levitt, U.S. Patent No.
  • Ischemia stroke is the third leading cause of death in the United
  • barbiturates prevent neuronal injury in ischemia is that they inhibit the ischemia-induced uncontrolled release of neurotransmitters, which can attain high, neurotoxic concentrations that cause neuronal death (Bhardwaj A, Brannan T, Weinberger J, J Neural Transom 1990, 82: 111-117).
  • the literature regarding the neuroprotective effects of anesthetic barbiturates is over two decades old, but the clinical use of barbiturates has been severely limited because of toxicity. The dosages and blood and brain levels necessary to confer neuroprotection are toxic and cause lethargy, stupor, and coma.
  • 4,628,056 describes non-sedating oxopyrimidine derivatives and their use as anticonvulsants, anti-anxiety and muscle relaxant agents.
  • the literature does not suggest the use of such compounds as neuroprotectant agents. Indeed, even in published studies about using sedative barbiturates for neuroprotection there is no reference to non-sedating barbiturate compounds. It is generally believed that the anticonvulsant and neuroprotective effects of barbiturates are linked to their sedative/hypnotic effects. For example, Lightfoote et al. suggested that the protective effects of pentobarbital are due to the duration of the barbiturate-induced anesthesia (Lightfoote WE II, Molinari GF, Chase TN, Stroke 1977, 8:627-628).
  • Non-sedating barbituric acid derivatives having a long acting neurological activity and being devoid of any significant hypnotic and sedative effects.
  • Neurological activity may include neuroprotective, anti-stress and anti-strain, anticonvulsant, anti-seizure, muscle relaxant, anti-nervous strain, and anti-anxiety.
  • Non-sedating barbituric acid derivatives, also termed non-sedative barbiturates, of the present invention have the general Formula I
  • R and R may be the same or different and are independently hydrogen; lower alkyl, optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms; phenyl;
  • R 3 and R 4 may be the same or different and are independently hydrogen; aryl optionally containing one or more heteroatoms selected from the group consisting of N, S and O; lower acyloxy; phenyl; phenyl substituted with a halogen, lower alkyl group, lower acyl group or derivative thereof or acetamido; benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O and S; lower alkyl; or lower alkyl substituted with an aromatic moiety. At least one of R 3 and R 4 is an aromatic ring or an aromatic ring containing moiety.
  • lower alkyl refers to a branched or straight chain alkyl group having eight or fewer carbons.
  • Alkyl also includes hydrocarbon groups having one or two double or triple bonds in the chain.
  • the present invention also includes salts of the aforementioned compounds. In the compounds and salts of the present invention,
  • R 1 and/or R 2 is methoxymethyl
  • R 3 and R 4 are not both phenyl, are not both phenyl substituted by lower alkyl, and are not both phenyl substituted by halogen
  • R 3 and R 4 when one of R 3 and R 4 is phenyl or benzyl, the other of R 3 and R is not ethyl;
  • l-methyl-5-(l-phenylethyl)-5-propionyloxy-barbituric acid a) l,3-diphenyl-5,5-(dibenzyl) barbituric acid, c) 1,3,5-triphenyl barbituric acid, and d) 5-benzyl-l,3-dimethyl barbituric acid.
  • R 1 and R 2 is lower alkyl substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms; phenyl; CH 2 SR 5 , wherein R 5 is lower alkyl, aryl, alkylaryl or benzyl; C(S)XR 6 , wherein X is S or O and R 6 is lower alkyl or aryl; CSR 7 , wherein R 7 is hydrogen, lower alkyl or aryl; and CH(SR 8 ) 2 , wherein R 8 is a lower alkyl group.
  • At least one of R 3 and R 4 is lower acyloxy; phenyl substituted with a lower acyl group or derivative thereof or acetamide; and cycloalkyl of which the ring optionally contains one or more heteroatoms selected from the group consisting of N, O and S.
  • the ring optionally contains one or more heteroatoms selected from the group consisting of N, O and S.
  • R and R are different and are individually selected from butyl, benzyl, thiophenylmethyl, cyclopropylmethyl, 3,3,3-trifluoropropyl, benzyloxymethyl, and alkoxymethyl.
  • R 1 and R 2 are the same and are selected from butyl, benzyl, thiophenylmethyl, cyclopropylmethyl, 3,3,3-trifluoropropyl, benzyloxymethyl, and alkoxymethyl.
  • one of R 1 and R 2 is hydrogen and the other of R 1 and R is selected from alkoxymethyl, butyl, benzyl, thiophenylmethyl, cyclopropylmethyl, 3,3,3-trifluoropropyl, and benzyloxymethyl.
  • R 3 and R 4 are methoxymethyl.
  • R 3 and R 4 are both aromatic rings or aromatic ring containing moieties.
  • R 3 and R 4 are the same or different and are independently phenyl; phenyl substituted with a halogen or lower alkyl group; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O and S; benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; lower alkyl; or lower alkyl substituted with an aromatic moiety, provided that at least one of R 3 and R 4 is phenyl or substituted phenyl.
  • At least one of R 3 and R 4 are selected from the group consisting of phenyl, benzyl, fluorophenyl and tolyl. [0017] In other exemplary embodiments, at least one of R 3 and R 4 is [0018] selected from:
  • R and R may be the same or different.
  • Non-sedating barbituric acid derivatives according to the invention may be administered to treat mammals for strain and stress conditions and nervous dysfunctions such as convulsions, seizure, muscle stiffness, nervous strain and anxiety.
  • Non-sedating barbituric acid derivatives according to the invention may also be administered to achieve a neuroprotective effect.
  • the present invention also encompasses pharmaceutical compositions having a compound of Formula I as the active ingredient together with a pharmaceutically acceptable carrier.
  • the invention further provides an article of manufacture comprising a container comprising a pharmaceutical composition and a label with indications for use as a treatment for strain and stress conditions; nervous dysfunctions such as convulsions, seizure, muscle stiffness, nervous strain and anxiety, and/or as a neuroprotectant, the pharmaceutical composition comprising a non-sedating barbiturate compound in a pharmacologically effective amount together with a pharmaceutically acceptable ca ⁇ ier or excipient.
  • 4,628,056 describes non-sedating oxopyrimidine derivatives and their use as anticonvulsants, anti-anxiety and muscle relaxant agents.
  • Levitt further describes the preparation of some 1,3- disubstituted-5,5-diphenyl barbituric acid derivatives. The diphenyl substituents of Levitt may be further substituted by lower alkyl or halogen.
  • Gutman et al. U.S. Patent No. 6,093,820, describes methods of N-alkylating ureides that are useful for preparing mono- and di-N substituted barbituric acid derivatives. The methods disclosed can be useful in preparing compounds useful in the present invention.
  • Gutman et al., WO 02/007729 Al incorporated herein by reference in its entirety, describes the use of non-sedating barbiturate compounds as neuroprotective agents.
  • non-sedative barbituric acid derivatives encompasses the family of barbituric acid anticonvulsant compounds and derivatives and structural analogs having the general Formula I, and salts thereof
  • R 1 and R 2 may be the same or different and are independently hydrogen; lower alkyl, optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms; phenyl; CH 2 XR 5 , wherein X is S or O and R 5 is lower alkyl, aryl, or alkylaryl (e.g., benzyl);
  • R 3 and R 4 may be the same or different and are independently hydrogen; aryl optionally containing one or more heteroatoms selected from the group consisting of N, S and O; lower acyloxy; phenyl; phenyl substituted with a halogen, lower alkyl group, lower acyl group or derivative thereof or acetamido; benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O and S; lower alkyl; or lower alkyl substituted with an aromatic moiety. At least one of R 3 and R 4 is an aromatic ring or an aromatic ring containing moiety.
  • lower alkyl refers to a branched or straight chain alkyl group having eight or fewer carbons.
  • Alkyl also includes hydrocarbon groups having one or two double or triple bonds in the chain.
  • the present invention also includes salts of the aforementioned compounds. For new compounds and salts of the present invention,
  • R 1 and/or R 2 is methoxymethyl
  • R 3 and R 4 are not both phenyl, are not both phenyl substituted by lower alkyl, and are not both phenyl substituted by halogen
  • R 3 and R 4 when one of R 3 and R 4 is phenyl or benzyl, the other of R 3 and R 4 is not ethyl;
  • R 1 and R 2 is lower alkyl substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms; phenyl; CH 2 SR 5 , wherein R 5 is lower alkyl, aryl, alkylaryl or benzyl; C(S)XR 6 , wherein X is S or O and R 6 is lower alkyl or aryl; CSR 7 , wherein R 7 is hydrogen, lower alkyl or aryl; and CH(SR 8 ) 2 , wherein R 8 is a lower alkyl group.
  • R 3 and R 4 is lower acyloxy; phenyl substituted with a lower acyl group or derivative thereof or acetamide; and cycloalkyl of which the ring optionally contains one or more heteroatoms selected from the group consisting of N, O and S.
  • the substituents R 1 and R 2 are different and are individually selected from butyl, benzyl, thiophenylmethyl, cyclopropylmethyl, 3,3,3-trifluoropropyl, benzyloxymethyl, and alkoxymethyl.
  • R 1 and R 2 are the same and are selected from butyl, benzyl, thiophenylmethyl, cyclopropylmethyl, 3,3,3-trifluoropropyl, benzyloxymethyl, and alkoxymethyl.
  • one of R 1 and R 2 is hydrogen and the other of R 1 and R is selected from alkoxymethyl, butyl, benzyl, thiophenylmethyl, cyclopropylmethyl, 3,3,3-trifluoropropyl, and benzyloxymethyl.
  • one of R 1 and R 2 is hydrogen, and the other of R 1 and R 2 is selected from: -CH 2 -O-(CH 2 ) n -CH 3 with n > 0;
  • R 1 and R 2 are methoxymethyl.
  • R 3 and R 4 are both aromatic rings or aromatic ring containing moieties.
  • R 3 and R 4 are the same or different and are independently phenyl; phenyl substituted with a halogen or lower alkyl group; cycloalkyl, which optionally comprises one or more heteroatoms selected from the group consisting of N, O and S; benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; lower alkyl; or lower alkyl substituted with an aromatic moiety, provided that at least one of R and R 4 is phenyl or substituted phenyl.
  • At least one of R 3 and R 4 are selected from the group consisting of phenyl, benzyl, fluorophenyl and tolyl.
  • At least one of R 3 and R 4 is selected from:
  • R ,3 and R may be the same or different.
  • R 1 and R 2 may function as non-toxic leaving groups capable of being removed in a biological system to give rise to a pharmacologically active species. The relatively slow loss of R 1 and/or R 2 results in an extension of the metabolic half-life of the pharmacologically active species in mammals.
  • R and R 4 may be chosen so that the resultant pharmacologically active compound avoids the sedative properties normally associated with barbituric acid derivatives.
  • a modified version of the test described in Example 3 could serve as a test method for identifying compounds which do not have the sedative properties normally associated with barbituric acid derivatives.
  • the compound may be understood as having sedative properties.
  • R 3 and R 4 substituents compounds not having the sedative properties normally associated with barbituric acid derivatives can be identified.
  • N,N'-dimethoxymethyl- 5,5-diphenyl barbituric acid degrades metabolically to form diphenyl barbituric acid (DPB). It has also been learned that the degradation mechanism involves formation of the monomethoxymethyl intermediate.
  • the N-substituted R'/R 2 groups may be cleaved metabolically to produce the R 3 /R 4 substituted compounds with mono or no N substitution or the R*/R 2 groups may remain bound in an active compound.
  • Preferred compounds are those without adverse side effects.
  • Examples of adverse side effects are toxicity, which can be assessed by the method of Example 2, and sedation, which can be assessed by the method of Example 3, as described above.
  • Placement of the 1 and 3 substituents to prepare 1,3- bis(substituted)-5,5-disubstituted barbituric acids according to the invention may be accomplished by reacting an appropriate 5,5-di(substituted) barbituric acid with an alkali hydride to form the co ⁇ esponding barbiturate salt which is then reacted with a moiety having a leaving group in a process similar to that described by Samour et al. in J. Med. Chem. 14, 187 (1971).
  • mono- and di-substituted compounds may be prepared according to the process described in U.S. Patent No. 6,093,820 and modifications thereof.
  • a 5,5- disubstituted barbituric acid derivative is reacted with excess base.
  • the dianion formed is then reacted with one equivalent of an alkylating agent if the monosubstituted derivative is desired, or two equivalents of alkylating agent, if the disubstituted derivative is desired.
  • Substituents at the 5-position may be prepared by reacting alloxan with an appropriate starting material in a manner similar to the preparation of diphenyl barbituric acid described by McElvain, referenced above. These substituents may also be placed on a l,3-bis(substituted)-barbituric acid by oxidation of the acid to the co ⁇ esponding 1,3-dialkyl alloxan, which is then reacted with an appropriate compound in a similar way to yield the desired product.
  • treatment is intended to encompass administration of compounds according to the invention prophylactically to prevent or suppress an undesired condition, and therapeutically to eliminate or reduce the extent or symptoms of the condition.
  • Treatment according to the invention is given to a human or other mammal having a disease or condition creating a need of such treatment. Treatment also includes application of the compound to cells or organs in vitro.
  • the non-sedative barbituric acid derivatives of the present invention may be formulated into "pharmaceutical compositions" with appropriate pharmaceutically acceptable carriers, excipients or diluents. If appropriate, pharmaceutical compositions may be formulated into preparations including, but not limited to, solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols, in the usual ways for their respective route of administration.
  • An effective amount is the amount of active ingredient administered in a single dose or multiple doses necessary to achieve the desired pharmacological effect.
  • Neurological disorders include strain and stress conditions and nervous dysfunctions such as convulsions, seizure, muscle stiffness, nervous strain and anxiety.
  • the compounds of the present invention may be used as anticonvulsive agents and can therefore be employed in the treatment of epilepsy.
  • the compounds of the present invention may also be used as neuroprotective agents for the treatment of cerebral ischemia, head trauma and other acute neurologic injuries, and in the prevention of resulting neuronal damage.
  • the compounds may be used in individuals undergoing cardiac surgery or carotid endarterectomy, and individuals at risk for atrial fibrillation, transient ischemic attacks (TIAs), cerebral ischemia, bacterial endocarditis, strokes, or subarachnoid hemo ⁇ hage due to a cerebral aneurysm.
  • TIAs transient ischemic attacks
  • the compounds can also be used after an acute event.
  • the useful doses of the non-sedative barbiturate useful for neuroprotective purposes may exceed the minimum anticonvulsant dosage of the barbiturate.
  • the useful dose of the non-sedative barbiturate is in the range of from about 2 times to about 5 times the anticonvulsant dosage.
  • the effective dose of the non-sedative barbiturate for neuroprotective purposes is in the range of from about 5 times to about 10 times the anticonvulsant dosage of the non-sedative, or even higher so long as the dose is clinically acceptable.
  • the useful doses may exceed the dose of a sedative barbiturate, such as Phenobarbital, at which sedation occurs and may exceed the doses at which coma or death would occur for Phenobarbital.
  • the neuroprotective effect of the present methods can be used to mitigate the effect of cerebral ischemia.
  • the non-sedating barbiturate can be administered orally, intravenously, transdermally, in combination with an adjuvant, or transpulmonarily by means of a particulate or aerosol inhalant.
  • the non-sedating barbiturate can be administered preventively, prophylactically or therapeutically, at a clinically acceptable dose.
  • the compound may be administered prophylactically before evident neuronal damage, or therapeutically after onset of neuronal damage.
  • the neuroprotective effect diminishes, or protects the subject from neuronal damage caused by head trauma or cerebral ischemia.
  • the compound may be administered in conjunction with cardiac surgery or carotid endarterectomy.
  • the mammalian subject may have or be at risk for atrial fibrillation, a transient ischemic attack (TIA), bacterial endocarditis, a stroke, head trauma, or subarachnoid hemo ⁇ hage.
  • TIA transient ischemic attack
  • the non-sedating barbiturate is administered in a dose sufficient to obtain blood concentrations of at least about 30 ⁇ g/ml of barbiturate or of an active metabolite thereof, preferably at least about 100 ⁇ g/ml, more preferably at least about 250 ⁇ g/ml, and possibly as high as 200- 300 ⁇ g/ml, or even higher.
  • the reported therapeutic range for phenobarbital is lower, 10-30 ⁇ g/ml blood levels.
  • preferred ranges are at or above about 25, 30, 50, 75, 100, 200, 250, or 300 ⁇ g/ml. Similar doses are suitable for the other pharmaceutical effects described herein.
  • the invention includes a pharmaceutical composition comprising a non-sedating barbiturate administered in an amount effective to have a neurological effect.
  • the non-sedating barbiturate is administered in oral doses in the range of from about 25 to about 1,500 mg/kg/day body weight.
  • the dose is greater than about 50 mg/kg/day, or greater than about 100 mg/kg/day, or greater than 250 mg/kg/day.
  • a prefe ⁇ ed dose is one that is pharmacologically equivalent to a dose of about 1000 mg/kg/day in the rat.
  • dosage forms may be sufficient individually or in multiple doses to provide a dose equal to or above about 1, 5, 10, 15, 20, 25, 50, 70, 100, 250, 500, 1000, or 1500 mg/kg body weight per day.
  • lower doses are suitable in the range of over or about 0.1, 0.5, 1, 5, or 10 mg/kg body weight per day and other doses as are well known in respect to barbiturates.
  • the inventive barbituric acid derivatives have prolonged half-life in humans making it possible to achieve substantial blood levels with lower oral dosages. Blood levels of non-sedating barbiturates greater than 100 ⁇ g/ml may be achieved with, for example, dosages between about 40 and about 100 mg/kg/day, and are within the scope of the invention. With parenteral administration of non- sedating barbiturates, similar blood concentrations are obtained with daily dosages of less than 25 mg/kg/day. However, first day loading dosages may still need initial dosages of greater than 25 mg/kg. [0048] It is generally believed that the neurological, e.g. anticonvulsant and neuroprotective, effects of barbiturates are linked to their sedative/hypnotic effects.
  • the invention also provides for pharmaceutical compositions comprising as active material a compound of the above general Formula I or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable ca ⁇ iers, excipients or diluents. Any conventional technique may be used for the preparation of pharmaceutical formulations according to the invention.
  • the active ingredient may be contained in a formulation that provides quick release, sustained release or delayed release after administration to the patient.
  • Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, parenteral and topical administration. Other contemplated formulations include nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.
  • compositions described herein may be prepared by any method known or hereafter developed. In general, preparation includes bringing the active ingredient into association with a carrier or one or more other additional components, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
  • Prolonged activity is a valuable attribute of drags in general and of anticonvulsant drags in particular. Aside from allowing infrequent administration, it also improves patients' compliance with the drag. Furthermore, seram and tissue levels, which are crucial for maintaining therapeutic effectiveness, are more stable with a long acting compound. Moreover, stable serum levels reduce the incidence of break-through seizures and possible other adverse effects.
  • additional components include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; pharmaceutically acceptable polymeric or hydrophobic materials as well as other components.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan, based on this disclosure, that such compositions are generally suitable for administration to any mammal. Preparation of compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modifications with routine experimentation based on pharmaceutical compositions for administration to humans.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient in each unit dose is generally equal to the total amount of the active ingredient which would be administered or a convenient fraction of a total dosage amount such as, for example, one-half or one-third of such a dosage.
  • a formulation of a pharmaceutical composition of the invention suitable for oral administration may be in the form of a discrete solid dosage unit.
  • Solid dosage units include, for example, a tablet, a caplet, a hard or soft capsule, a cachet, a troche, or a lozenge.
  • Each solid dosage unit contains a predetermined amount of the active ingredient, for example a unit dose or fraction thereof.
  • Other formulations suitable for administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion.
  • an "oily" liquid is one which comprises a carbon or silicon based liquid thatis less polar than water.
  • a tablet comprising the active ingredient may be made, for example, by compressing or molding the active ingredient, optionally containing one or more additional components.
  • Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, a glidant, an excipient, a surface active agent, and a dispersing agent.
  • Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.
  • Tablets may be non-coated or they may be coated using methods known in the art or methods to be developed.
  • Coated tablets may be formulated for delayed disintegration in the gastrointestinal tract of a subject, for example, by use of an enteric coating, thereby providing sustained release and absorption of the active ingredient. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide pharmaceutically elegant and palatable preparation.
  • Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional components including, for example, an inert solid diluent.
  • Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin.
  • Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium.
  • Liquid formulations of a pharmaceutical composition of the invention which are suitable for administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.
  • Liquid suspensions, in which the active ingredient is dispersed in an aqueous or oily vehicle, and liquid solutions, in which the active ingredient is dissolved in an aqueous or oily vehicle may be prepared using conventional methods or methods to be developed.
  • Liquid suspension of the active ingredient may be in an aqueous or oily vehicle and may further include one or more additional components such as, for example, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Liquid solutions of the active ingredient may be in an aqueous or oily vehicle and may further include one or more additional components such as, for example, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents.
  • Powdered and granular formulations according to the invention may be prepared using known methods or methods to be developed. Such formulations may be administered directly to a subject, or used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Powdered or granular formulations may further comprise one or more of a dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.
  • a pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. Such compositions may further comprise one or more emulsifying agents. These emulsions may also contain additional components including, for example, sweetening or flavoring agents.
  • Compounds of Formula I can be prepared by N-alkylation of an appropriately substituted barbituric acid derivative (Formula II). Suitable exemplary methods for N-alkylation of barbituric acids are given below in Examples 8a, 8b, 9a, 9b, 10, 11, and 12. Other known methods will be known to persons skilled in the art and may also be used.
  • the required barbituric acid derivatives of Formula II can be prepared by condensation of urea with a suitable substituted malonic ester (Formula III).
  • the barbituric acid derivatives of Formula I can be prepared by reacting a substituted urea (Formula IV) with a suitably substituted malonic ester (III).
  • the anticonvulsant activity of the barbituric acid derivatives of the invention may be demonstrated or tested by evaluating the protection against a maximal electro shock seizure (MES) in treated rats.
  • MES tests are widely used for the assessment of anticonvulsant properties of chemical compounds, mainly due to the good correlation between the test results and the clinical finding of efficacy in patients suffering from epilepsy.
  • corneal electrodes are employed, a cu ⁇ ent of about 150 milliamperes is used and a 60 hertz stimulus applied for about 200 milliseconds.
  • Rats are tested on the day prior to drug administration so as to eliminate from the study any animals failing to respond with a complete tonic convulsion including tonic hind-limb extension (THE), which serves as the basis for the assessment of the efficacy of the active material employed. Animals protected from THE are regarded as protected in the MES tests.
  • TEE tonic hind-limb extension
  • test composition is dissolved in warm polyethylene glycol 400 or other suitable solvent and the solution administered in an initial dose of about 500 mg/kg by stomach tube to, for example, Sprague-Dawley rats.
  • MES electro shock seizure
  • EXAMPLE 2 The non-toxicity of barbituric acid derivatives of the invention can be tested by repeated administration of a high dosage, as follows: [0070] The test compound suspended in warm polyethylene glycol 400 or other suitable solvent is administered in an initial dose of about 1500 mg/kg by gastric tube to, for example, Sprague Dawley rats. A similar dose is administered to same rats after 24 hours and again 48 hours after the first administration. Animals are examined for several hours after administration, again prior to the next dosing, and through an additional 3 days after the last administration. The toxic effects of administration are monitored as well as behavioral effects such as, for example, locomotion, escape behavior, feeding or any other observable effect.
  • the test composition in alkalinized saline may be administered intraperitoneally to, for example, Swiss Webster mice.
  • the time required for animals receiving various doses to exhibit particular motor and behavioral effects is noted. Effects monitored may include, for example, muscle hypotonia, motor activity, quietness and escape behavior. Toxic effects are also noted.
  • the efficacy of the composition can be evaluated relative to known centrally acting skeletal muscle relaxants and/or tranquilizing drugs. The combination of the tranquilizing effect without impairing the capacity of the animal to react to its environment is highly desirable in agents used for the treatment of anxiety. Hypnotic activity or depression of the central nervous system is preferably not exhibited by the compositions of the invention.
  • the non-sedative barbituric acid derivatives of the invention may be tested in rats exposed to either reversible or irreversible ischemia. Varying doses of drag are administered. The neuroprotective effect is compared to a negative control (placebo) and a positive control, pentobarbital, a known neuroprotective but sedative barbiturate, given at doses known to reduce infarct volume in cerebral ischemia.
  • Animals are sacrificed several days after the onset of the ischemic insult and the brains examined to determine the volume of brain infarction as an outcome measure of the drug's reduction of ischemic brain damage.
  • MCA middle cerebral artery
  • Negative control via nasogastric (NG) tube;
  • IP intraperitoneal
  • NSB compound DMMDPB (or a compound being tested for its utility in the present invention) via NG tube at doses between 500 mg/kg and 1500 mg/kg for 7 days prior to experimental infarctions. The results are compared.
  • Irreversible MCA occlusion is produced by ligating the carotid artery and then inserting a filament into the origin of the MCA with the animal maintained under halothane anesthesia. Blood flow in the MCA is measured by laser doppler and those animals in which a significant drop in blood flow occu ⁇ ed are considered to have experienced cerebral ischemia, and to be at risk for subsequent damage (i.e., a stroke). No clinical strokes are expected in animals that do not experience a precipitous drop in MCA blood flow. All animals showing a drop in MCA blood flow are expected to experience strokes. [0079] Animals at risk are then followed behaviorally and scored by clinical findings using the Bederson grading scale as either: 0 no evidence of stroke
  • Rats are pretreated as in Example 4 (above) and a similar procedure is performed except that the filament occluding the MCA is removed after 30 to 60 minutes, restoring blood flow through the MCA. Rats are then followed clinically for three days, graded for their degree of stroke and then sacrificed as in Example 5. The brains are removed and examined as described above.
  • Rats are pretreated as in Example 4 (above) and then, during ether anesthesia, the rats' vertebral arteries are electrocauterized through the alar foramina of the first cervical vertebra. Reversible clamps are then placed loosely around the common carotid arteries. After 24 hours, working with awake rats, the carotid clamps are tightened to produce 4-vessel occlusion. Following 10-30 minutes of 4-vessel occlusion, the clamps are removed and 72 hours later the animals sacrificed by perfusion fixation. Untreated rats routinely demonstrate ischemic neuronal damage after 20 or 30 minutes of 4-vessel occlusion. Multiple areas of the forebrain, including the HI and paramedian hippocampus, sfriatum, and posterior neocortex are evaluated. The NSBs are shown to be neuroprotective under these circumstances.
  • EXAMPLE 8a Preparation of Mono and Bis N-alkylated barbituric acids [0083] A compound of Formula II is dissolved with potassium hydroxide in ethanol. An alkyl halide, R'X, is dissolved in the solution; the solutes react.
  • a compound of Formula II is dissolved with potassium hydroxide in ethanol.
  • An alkyl tosylate, R'O Ts, is dissolved in the solution; the solutes react.
  • a urea substituted with an alkyl group at one or both amides is used as a starting material (Formula IV). If disubstituted, the alkyl grouping may be the same or different, i.e., the first alkyl group may be R', and the second alkyl group may be R' or R", where R' and R" are different.
  • the substituted urea is then reacted with a malonic ester (Formula III), e.g., diethyl malonate, and sodium ethoxide in ethanol.
  • a range of alkyl groups having cycloalkyl, acyl, acyloxy, aryl, aryloxy, alkoxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, or halogen groups can be substituted for R 1 and R 2 of Formula I using methods similar to those described in Examples 8a, 8b, and 8c.
  • EXAMPLE 9a Preparation of N-alkoxyalkylated compounds
  • Dialkoxymethane R'OCH 2 OR'
  • the temperature of the solution is raised to 25 °C and the components allowed to react for 2 hours.
  • the resultant solution is then added gradually over 45 minutes to a mixture of a suitably substituted barbituric acid (Formula II) and sodium hydride (as a 60% dispersion in mineral oil) in dry dimethylformamide.
  • the resultant reaction mixture is sti ⁇ ed for about 15 minutes and then diluted with hydrochloric acid, followed by dilution with ethyl acetate.
  • 1 9 consists of material of Formula I with one of R and R being substituted as CH 2 OR' and the other being substituted with hydrogen.
  • EXAMPLE 9b Alternative Preparation of N-alkoxyalkylated compounds
  • a suitable barbituric acid (Formula II) is dissolved in dimethylformamide. Once the solution has cooled, sodium hydride is added and the mixture stirred for 30 minutes. An appropriate chloromethyl alkyl ether is added to the mixture over a period of about 30 minutes. The reaction mixture is then stirred for 1 hour, then poured into ice water. The solid precipitate is filtered, washed with water, and crystallized from ethanol. (U.S. Pat No. 4,628,056)
  • R 3 and R 4 groups may be varied.
  • Different alkoxides can be substituted as R 1 and R 2 by using different chlorinated ethers.
  • Alkylthio groups can be substituted as R 1 and R 2 by using chlorinated thioethers.
  • a compound of Formula II is dissolved with an alkyl chloroformate in a solution containing sodium hydroxide.
  • EXAMPLE 11 Preparation of N-acyl substituted barbituric acids [0096]
  • a compound of Formula II is dissolved with an acid chloride of the formula ClC(O)R', where R' is hydrogen, alkyl, or aryl and allowed to react over an aqueous solution of sodium hydroxide.
  • EXAMPLE 12a Preparation of N-acetal substituted barbituric acids [0097] A compound having Formula II is dissolved in dimethylformamide. Sodium hydride is added to the solution. A chlorinated diether having the general formula, ClCH(OR') 2 , wherein R' is alkyl, is added to the solution. The reactant product is then purified. The product has Formula I with (Loudon GM, Organic Chemistry, Addison- Wesley (1984), pp. 1062-1064) EXAMPLE 12b - Preparation of N-arylmethyl substituted barbituric acid [0098] A compound of Formula II is dissolved with potassium hydroxide in ethanol.
  • a halomethyl substituted aromatic compound, ArCH 2 X, wherein X is halogen, is dissolved in the solution.
  • This synthesis method can also be conducted with benzyl chloride substituted on the benzene ring with sulfur hydride, SH.
  • EXAMPLE 13 Preparation of 5 -aryl substituted barbituric acid derivatives
  • the inert solvent can be selected from the group consisting of diethylether, dimethoxymethane, tert-butylmethylether, tetrahydropyran, diisopropylether, toluene, and mesitylene and can be a mixture of these solvents. Including either 1,2-dibromomethane or diethylether can be beneficial.
  • an arylmethylhalide is added to the solution.
  • the aryl group may be a heteroaromatic group containing nitrogen in the ring and optionally containing carbon, oxygen, or sulfur in the ring.
  • the solution can also contain tri-n-butylamine.
  • Ethanol is then distilled from the solution.
  • the solution is neutralized with hydrochloric acid.
  • the organic layer is then separated, dried, and concentrated in vacuum to yield a diethyl arylmalonate.
  • the diethyl arylmalonate is then dissolved with urea and sodium ethoxide in ethanol.
  • the reaction product has Formula I with one of R 3 and R 4 being aryl, and the other of R 3 and R 4 being hydrogen.
  • a halogen-substituted benzene e.g., fluorobenzene
  • an alkyl-substituted benzene e.g., ethylbenzene
  • R' is alkyl.
  • EXAMPLE 14b- Preparation of 5-aryl substituted barbituric acid derivatives
  • a solution of magnesium, dimethoxymethane, and dibromomethane is made.
  • a halomethyl substituted aromatic compound in dimethoxymethane is added and allowed to react.
  • Cold diethoxycarbonate is added to the solution.
  • the solution is then neutralized with hydrochloric acid.
  • the organic layer is separated and concentrated by distillation.
  • Sodium ethylate is added to the concentrated organic layer.
  • Dimethoxymethane and ethanol are distilled from the solution.
  • the solution is neutralized with hydrochloric acid and the organic layer separated, dried with magnesium sulfate, and concentrated in vacuum.
  • the resultant product is an aromatic substituted diethyl malonate.
  • the diethyl malonate is then dissolved with urea and sodium ethoxide in ethanol and reacts.
  • the reaction product has Formula I with one of R and R 4 being aromatic and the other of R 3 and R 4 being hydrogen.
  • This synthesis method can also be conducted with chloromethylphenyl dithiane as the halomethyl substituted aromatic compound.
  • Diethyl malonate is dissolved with a bromomethyl substituted aromatic compound, having formula ArCH 2 X, where Ar is aryl and X is halogen, and sodium ethoxide in ethanol.
  • the product is a mono-arylmethylmalonate ester of formula ArCH 2 CH(CO 2 Et) 2 .
  • the monoarylmethylmalonate ester is then dissolved with urea and sodium ethoxide in ethanol and reacts.
  • the aromatic compound can be further substituted in the ring with, e.g., a halogen or an alkyl group.
  • EXAMPLE 15b Preparation of 5,5-bis(arylmethyl) substituted barbituric acid derivatives
  • Diethyl malonate is dissolved with a bromomethyl substituted aromatic compound, having formula ArCH 2 X, where Ar is aryl and X is halogen, and sodium ethoxide in ethanol.
  • the product is a mono-arylmethylmalonate ester of formula ArCH 2 CH(CO 2 Et) 2 .
  • the mono-arylmethylmalonate ester is separated from the solution.
  • the separated mono-arlymethylmalonate ester is then dissolved with an iodomethyl substituted aromatic compound, having formula Ar'CH 2 I, where Ar' is aryl and Ar and Ar' may be the same or different, and sodium ethoxide in ethanol.
  • the product is a diarylmethyl-malonate ester of formula (ArCH 2 )(Ar'CH 2 )C(CO 2 Et) 2 .
  • aromatic ring of either compound can be substituted with, e.g., a halogen or an alkyl group.
  • EXAMPLE 16a Preparation of 5,5-dialkyl substituted barbituric acid derivatives
  • EXAMPLE 16b- Preparation of 5 -alkyl substituted barbituric acid derivatives Diethyl malonate is dissolved with an alkyl bromide, having formula R'Br, wherein R' is alkyl, and sodium ethoxide in ethanol.
  • the product is a mono-alkylmalonate ester of formula R'CH(CO 2 Et) 2 .
  • the mono- alkylmalonate ester is then dissolved with urea and sodium ethoxide in ethanol and reacts.
  • the reaction product has Formula I with one of R 3 and R 4 being R', and the other of R 3 and R 4 being hydrogen. (Loudon GM, Organic Chemistry, Addison- Wesley (1984), pp. 1086-1088)
  • the alkyl, R' may be substituted; e.g., the alkyl, R', may be substituted with an aromatic group.
  • EXAMPLE 16c Preparation of 5,5-dialkyl substituted barbituric acid derivatives
  • Diethyl malonate is dissolved with an alkyl bromide, having formula R'Br, wherein R' is alkyl, and sodium ethoxide in ethanol.
  • the product is a mono-alkylmalonate ester of general formula R'CH(CO 2 Et) 2 .
  • the mono- alkylmalonate ester is separated from the solution.
  • the separated mono- alkylmalonate ester is then dissolved with an alkyl iodide, having formula R"I, wherein R" is alkyl and may be the same as or different from R', and sodium ethoxide in ethanol.
  • the product is a di-alkylmalonate ester of formula R"R'C(CO 2 Et) 2 .
  • the di-alkylmalonate ester is then dissolved with urea and sodium ethoxide in ethanol.
  • the reaction product has Formula II with one of R 3 and R 4 being R', and the other of R 3 and R 4 being R".
  • R' and R" may be the same or different alkyls. (Loudon GM, Organic Chemistry, Addison- Wesley (1984), pp. 1086-1088)
  • the alkyls, R' and R" may be substituted; e.g., the R' and R" alkyls may each be substituted with an aromatic group.

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Abstract

L'invention se rapporte à des nouveaux dérivés d'acide barbiturique non sédatifs, à des compositions pharmaceutiques contenant ces dérivés et à des procédés de neuroprotection dans des cas d'ischémie cérébrale, de traumatisme crânien et d'autres troubles neurologiques aigus, ainsi qu'à des procédés de prévention des lésions neuronales qui en résultent. L'invention se rapporte également à l'utilisation de dérivés d'acide barbiturique non sédatifs administrés à une dose efficace pour produire des concentrations sanguines et des concentrations cérébrales de ces médicaments et/ou de leurs métabolites actifs suffisantes pour obtenir un effet thérapeutique.
PCT/US2003/002638 2002-01-30 2003-01-30 Derives d'acide barbiturique non sedatifs WO2003063872A1 (fr)

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EP03735068A EP1485101A4 (fr) 2002-01-30 2003-01-30 Derives d'acide barbiturique non sedatifs
JP2003563562A JP2005516052A (ja) 2002-01-30 2003-01-30 非鎮静性バルビツール酸誘導体
CA2471436A CA2471436C (fr) 2002-01-30 2003-01-30 Derives d'acide barbiturique non sedatifs
IL163168A IL163168A (en) 2002-01-30 2004-07-22 Non-sedative barbiturate which provides a neuroprotective effect for protection from a neurological damage

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1625848A1 (fr) * 2004-08-10 2006-02-15 Taro Pharmaceuticals North America, Inc. Composition et procédé pour améliorer l'administration de l'acide 5,5-diphénylbarbiturique
US7166610B2 (en) 2002-12-11 2007-01-23 Taro Pharmaceuticals U.S.A., Inc. Method of treating movement disorders using barbituric acid derivatives
US7683071B2 (en) 2000-07-26 2010-03-23 Taro Pharmaceuticals Industries Ltd. Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid
US7723346B2 (en) 2000-07-26 2010-05-25 Taro Pharmaceutical Industries Ltd. Non-sedating barbiturate compounds as neuroprotective agents
WO2013038153A1 (fr) 2011-09-14 2013-03-21 The University Court Of The University Of Aberdeen Composés barbituriques marqués au 18f, convenant comme agents d'imagerie par émission de positrons

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JP2015092251A (ja) * 2010-10-07 2015-05-14 富士フイルム株式会社 偏光板保護フィルム、偏光板および液晶表示装置

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Cited By (9)

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Publication number Priority date Publication date Assignee Title
US7683071B2 (en) 2000-07-26 2010-03-23 Taro Pharmaceuticals Industries Ltd. Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid
US7723346B2 (en) 2000-07-26 2010-05-25 Taro Pharmaceutical Industries Ltd. Non-sedating barbiturate compounds as neuroprotective agents
US8076346B2 (en) 2000-07-26 2011-12-13 Taro Pharamaceutical Industries Ltd. Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid
US8158639B2 (en) 2000-07-26 2012-04-17 Taro Pharmaceutical Industries Ltd. Non-sedating barbiturate compounds as neuroprotective agents
US7166610B2 (en) 2002-12-11 2007-01-23 Taro Pharmaceuticals U.S.A., Inc. Method of treating movement disorders using barbituric acid derivatives
US7776871B2 (en) 2002-12-11 2010-08-17 Taro Pharmaceutical Industries Ltd. Method of treating movement disorders using barbituric acid derivatives
US8314115B2 (en) 2002-12-11 2012-11-20 Taro Pharmaceutical Industries Limited Method of treating movement disorders using barbituric acid derivatives
EP1625848A1 (fr) * 2004-08-10 2006-02-15 Taro Pharmaceuticals North America, Inc. Composition et procédé pour améliorer l'administration de l'acide 5,5-diphénylbarbiturique
WO2013038153A1 (fr) 2011-09-14 2013-03-21 The University Court Of The University Of Aberdeen Composés barbituriques marqués au 18f, convenant comme agents d'imagerie par émission de positrons

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CA2471436C (fr) 2011-10-11
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CA2471436A1 (fr) 2003-08-07
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JP2005516052A (ja) 2005-06-02
CN1896084A (zh) 2007-01-17
IL163168A (en) 2012-01-31
CN1625401A (zh) 2005-06-08

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