HK1103298A - Non-sedating barbituric acid derivatives - Google Patents

Description

Non-sedating barbituric acid derivatives

This application is a divisional application based on the invention patent application entitled "non-sedating barbituric acid derivatives" with application number 03802989.8 filed on 30/1/2003.

Background

The present invention relates to novel non-sedating barbituric acid derivatives, pharmaceutical compositions containing them, and methods of neuroprotection in the event of cerebral ischemia, head trauma, and other acute nerve injuries, and prevention of resultant neuronal damage. The invention also relates to the use of non-sedating barbituric acid derivatives in a manner that provides an effective dose to produce a sufficient concentration of these drugs and/or their active metabolites in the blood and brain to provide a therapeutic effect.

Barbituric acid and its derivatives have been known to have pharmacological properties since the beginning of the 20 th century, some of them being used as active ingredients in many drugs. Barbituric acid derivatives are known to be mainly used as sedatives, hypnotics and anesthetics. Certain derivatives also have anticonvulsant effects and are therefore useful in the treatment of epilepsy. Therefore, at present, a pharmaceutical composition containing 5-ethyl-5-phenylbarbituric acid (phenobarbital) is widely used as a medicament for treating epilepsy. However, like other barbituric acid derivatives, phenobarbital also has sedative and hypnotic effects, which is a disadvantage in the treatment of epilepsy. Accordingly, efforts have been made to find compounds that have anticonvulsant properties and at the same time have no sedative and hypnotic effects.

For example, one known barbituric acid derivative is 5, 5-diphenyl barbituric acid disclosed in j.am.chem.soc.57, 1303(1935) by s.m.mcelvain, which is incorporated herein by reference in its entirety. The compound was found to be effective only at very large doses and therefore no pharmacological use was mentioned. Raines et al reported in Epilepsia 20, 105 (1979): 5, 5-Diphenyl barbituric acid has an anticonvulsant effect on rodents, but has the disadvantage that the activity is relatively short-lived, which is incorporated herein by reference in its entirety. Other non-sedating barbituric acid derivatives have been disclosed in U.S. Pat. No.4,628,056 to Levitt and WO 02/007729A 1 to Gutman et al, 2002, 1/31, each of which is incorporated herein by reference in its entirety.

Ischemia (stroke) is the third leading cause of death in the united states. When blood supply to the brain falls below a certain critical threshold, a series of biochemical events occur, resulting in irreversible damage to neurons and cerebral infarction. Extensive research has been carried out on the treatment and prevention of ischemia, but unfortunately, it is still at its Basic stage and no suitable treatment is available in practice (Stroke therapy: Basic clinical and pre-clinical directions, Leonard P.Miller, ed. (Wiley 1999)).

It has been demonstrated that barbiturates (barbiturates) in high concentrations have a neuroprotective effect on rodent and primate cerebral ischemia, reducing the extent of ischemic cerebral infarction and preventing or reducing brain damage (Hoff JT, Smith AL, Hankinson HL, Nielsen SL, Stroke 1975, 6: 28-33; Levy DE, brierley jb. delayed pentabal administration limits ischemia brazilian large in gels; lightfocus WE II, mollinari GF, Chase TN, Stroke 1977, 8: 627-. One theory on how barbiturate prevents neuronal damage in the case of ischemia is: they inhibit the ischemia-induced uncontrolled release of neurotransmitters, which can reach high, neurotoxic concentrations that can lead to neuronal death (Bhardwaj A, Brannan T, Weinberger J, J Neural Transom 1990, 82: 111-.

Literature on the neuroprotective effects of narcotic barbiturates has existed for twenty years ago, but clinical use of barbiturates has been severely limited due to their toxicity. The doses required for neuroprotection and blood and brain concentrations are toxic, causing lethargy, stupor and coma. Higher doses, which may be more effective, are lethal (Hoff JT, Smith AL, Hankinson HL, Nielsen SL, Stroke 1975, 6: 28-33; Levy DE, Brierley JB. Delayed pendibal administration Limitation limitsischia braine dam in gels; Lightfoote WE II, Molinari GF, Chase TN, Stroke 1977, 8: 627 628; Corkill G, Chikovani OK, McLeish I, McDonald LW, Yous JR, Surge. Neurol.1976, 147-. These toxic side effects establish a "functional ceiling" on the dose of barbiturate, which precludes further studies on the use of narcotic/sedating barbiturates to prevent ischemia.

Levitt et al, U.S.4,628,056, describe non-sedating oxopyrimidine derivatives and their use as anticonvulsants, anxiolytics, and muscle relaxants. The document does not suggest the use of such compounds as neuroprotective agents. Indeed, no non-sedating barbiturate compounds are mentioned even in published studies on the use of sedating barbiturates for neuroprotection. It is generally believed that: the anticonvulsant and neuroprotective effects of barbiturates and their sedative/hypnotic effects are linked. For example, lightfocus et al mention: the protective effect of pentobarbital is due to persistence of barbital-induced anesthesia (Lightfoote WEII, Molinari GF, Chase TN, Stroke 1977, 8: 627-. This view has been confirmed by biochemical studies at the cellular receptor level, all of which are related to effects on GABA receptors. Thus, the prior art does not teach the use of sedative barbiturates for neuroprotection due to their toxicity, nor does the prior art teach the use of non-sedative barbiturates as neuroprotective agents due to their lack of sedative or anesthetic properties.

Some barbituric acid derivatives of formula I and processes for their preparation are known.

For example, U.S. Pat. No. 6,093,820, which is incorporated herein in its entirety by reference, describes the synthesis of N, N-dimethoxymethyl-5, 5-diphenyl barbituric acid (formula I, R)¹＝R²＝CH₂OMe and R³＝R⁴Ph). U.S.4,628,056, which is incorporated herein by reference in its entirety, describes another synthetic method for this compound.

Summary of The Invention

It is therefore an object of the present invention to provide novel non-sedating barbituric acid derivatives with long-lasting neural activity and without any significant hypnotic and sedative effects. The neurological activity may include neuroprotection, anti-stress and anti-stress, anti-convulsive, anti-seizure, muscle relaxation, anti-nervous and anti-anxiety.

The non-sedating barbituric acid derivative, also called non-sedating barbiturate, of the present invention has the structure of the following general formula I

Wherein R is¹And R²May be the same or different and independently are

Hydrogen;

lower alkyl optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, alkylthio or arylthio, amino, alkylamino, dialkylamino or one or more halogen atoms;

a phenyl group;

CH₂XR⁵wherein X is S or O, R⁵Is lower alkyl, aryl or alkylaryl (e.g. benzyl);

C(O)XR⁶wherein X is as defined above, R⁶Is lower alkyl or aryl;

CXR⁷wherein X is as defined above, R⁷Is hydrogen, lower alkyl or aryl; and

CH(XR⁸)₂wherein X is as defined above, R⁸Is lower alkyl, provided that R¹And R²Is not hydrogen.

R³And R⁴May be the same or different and are independently hydrogen; aryl optionally containing one or more heteroatoms selected from N, S and O; a lower acyloxy group; a phenyl group; phenyl substituted by halogen, lower alkyl, lower acyl or derivatives thereof or acetamido; a benzyl group; benzyl substituted on the ring by one or more halogen, lower alkyl or both; cycloalkyl optionally containing one or more heteroatoms selected from N, O and S; a lower alkyl group; or lower alkyl substituted with an aromatic moiety. R³And R⁴At least one of which is an aromatic ring containing moiety. Lower alkyl as used herein refers to a branched or straight chain alkyl group having 8 or fewer carbons. Alkyl also includes hydrocarbyl groups having one or two double or triple bonds in the carbon chain. The invention also includes salts of the above compounds. In the compounds and salts of the present invention,

1. when R is¹And/or R²When it is methoxymethyl, R³And R⁴Not all phenyl groups, not all phenyl groups substituted with lower alkyl groups and not all phenyl groups substituted with halogen; and

2. when R is³And R⁴When one is phenyl or benzyl, R³And R⁴Is not ethyl; and

3. when R is¹And R²When at least one of is benzyl, then when R is³And R⁴When one is phenyl, R³And R⁴Is not allyl; and

4. when R is¹And R²One of which is methyl and the other is hydrogen, then when R is³And R⁴When one is phenyl, R³And R⁴Is not unsubstituted lower alkyl; and

5. when R is¹＝R²＝R^aIn which R is^aIs alkoxymethyl or (acyloxy) methyl, then when R is³And R⁴When one is 1-phenylethyl, R³And R⁴Is not propionyloxy.

In addition, with respect to the combination, the following compounds are not included in the scope of the present invention, but may be used in the method of the present invention.

a) 1-methyl-5- (1-phenethyl) -5-propionyloxy-barbituric acid,

b)1, 3-diphenyl-5, 5- (dibenzyl) barbituric acid,

c)1, 3, 5-triphenylbarbituric acid, and

d) 5-benzyl-1, 3-dimethyl barbituric acid.

In some exemplary embodiments, R¹And R²Is lower alkyl substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, alkylthio or arylthio, amino, alkylamino, dialkylamino, or one or more halogen atoms; a phenyl group; CH (CH)₂SR⁵Wherein R is⁵Is lower alkyl, aryl, alkaryl or benzyl; c (S) XR⁶Wherein X is S or O and R⁶Is lower alkyl or aryl; CSR⁷Wherein R is⁷Is hydrogen, lower alkyl or aryl; and CH (SR)⁸)₂Wherein R is⁸Is a lower alkyl group.

In other exemplary embodiments, R³And R⁴At least one of which is a lower acyloxy group; phenyl substituted with lower acyl or a derivative thereof or acetamide; and cycloalkyl optionally containing one or more heteroatoms selected from N, O and S.

In certain exemplary embodiments of the invention, the substituent R¹And R²Are different and are each selected from the group consisting of butyl, benzyl, phenylthiomethyl, cyclopropylmethyl, 3, 3, 3-trifluoropropyl, benzyloxymethyl and alkoxymethyl. In other exemplary embodimentsIn the embodiment, R¹And R²Are the same and are selected from the group consisting of butyl, benzyl, phenylthiomethyl, cyclopropylmethyl, 3, 3, 3-trifluoropropyl, benzyloxymethyl and alkoxymethyl. In other exemplary embodiments, R¹And R²One of which is hydrogen, R¹And R²Is selected from the group consisting of alkoxymethyl, butyl, benzyl, phenylthiomethyl, cyclopropylmethyl, 3, 3, 3-trifluoropropyl and benzyloxymethyl.

In other exemplary embodiments, R¹And R²At least one of which is methoxymethyl. In other exemplary embodiments, R³And R⁴Both of which are aromatic rings or aromatic ring-containing moieties.

In certain exemplary embodiments, R³And R⁴Are the same or different and are independently phenyl; phenyl substituted by halogen or lower alkyl; cycloalkyl optionally containing one or more heteroatoms selected from N, S and O; a benzyl group; benzyl substituted on the ring by one or more halogen, lower alkyl or both; a lower alkyl group; or lower alkyl substituted by an aromatic moiety, with the proviso that R³And R⁴At least one of which is phenyl or substituted phenyl.

In other exemplary embodiments, R³And R⁴At least one of which is selected from phenyl, benzyl, fluorophenyl, and tolyl.

In other exemplary embodiments, R³And R⁴At least one of which is selected from:

R³and R⁴May be the same or different.

The non-sedating barbituric acid derivatives of the invention may be administered to a mammal for the treatment of stress and stress disorders and neurological dysfunctions such as convulsions, seizures, muscle stiffness, nervousness and anxiety. Neuroprotective effects can also be obtained by administering the non-sedating barbituric acid derivatives of the present invention.

The invention also includes pharmaceutical compositions comprising as an active ingredient a compound of formula I and a pharmaceutically acceptable carrier.

The invention further provides an article of manufacture comprising a container containing a pharmaceutical composition and instructions for use in the treatment of stress and stress conditions; neurological disorders such as convulsions, seizures, muscle stiffness, nervousness and anxiety, and/or as a label for neuroprotective agents, comprising a pharmacologically effective amount of a non-sedating barbiturate compound and a pharmaceutically acceptable carrier or excipient.

Detailed description of the invention

In describing embodiments of the invention, specific terminology is employed for the sake of clarity. However, the invention is not limited by the specific terminology selected. It is to be understood that each specific term includes all technical equivalents which operate in a similar manner to accomplish a similar purpose. Modifications or variations may be made to the above-described embodiments of the invention, and elements may be added or deleted by those skilled in the art in light of the above teachings without departing from the present invention. Each of the references cited herein is individually incorporated by reference.

Levitt et al, U.S.4,628,056, describe non-sedating oxopyrimidine derivatives and their use as anticonvulsants, anxiolytics, and muscle relaxants. Levitt also describes the preparation of certain 1, 3-disubstituted-5, 5-diphenyl barbituric acid derivatives. The diphenyl substituent of Levitt may be further substituted with lower alkyl or halogen. Gutman et al, U.S. Pat. No. 6,093,820, describe the use of N-alkylated ureides for the preparation of mono-and di-N substituted barbituric acid derivatives. The disclosed methods may be used to prepare compounds for use in the present invention. Gutman et al, in WO 02/007729A 1, which is incorporated herein by reference in its entirety, describe the use of non-sedating barbiturate compounds as neuroprotective agents.

The term "non-sedating barbituric acid derivatives" as used herein includes the barbituric acid anticonvulsant compounds and derivatives and structural analogs and salts thereof having the following general formula I,

wherein R is¹And R²May be the same or different and independently

Hydrogen;

lower alkyl optionally substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, lower alkoxy, alkylthio or arylthio, amino, alkylamino, dialkylamino or one or more halogen atoms;

a phenyl group;

CH₂XR⁵wherein X is S or O, R⁵Is lower alkyl, aryl or alkylaryl (e.g. benzyl);

C(O)XR⁶wherein X is as defined above, R⁶Is lower alkyl or aryl;

CXR⁷wherein X is as defined above, R⁷Is hydrogen, lower alkyl or aryl; and

CH(XR⁸)₂wherein X is as defined above, R⁸Is lower alkyl, provided that R¹And R²Is not hydrogen.

R³And R⁴May be the same or different and independently hydrogen; aryl optionally containing one or more heteroatoms selected from N, S and O; a lower acyloxy group; a phenyl group; phenyl substituted by halogen, lower alkyl, lower acyl or derivatives thereof or acetamido; a benzyl group; benzyl substituted on the ring by one or more halogen, lower alkyl or both; optionally containing one or more hetero-atoms selected from N, O and SCycloalkyl groups of the subgroups; a lower alkyl group; or lower alkyl substituted with an aromatic moiety. R³And R⁴At least one of which is an aromatic ring or an aromatic ring-containing moiety. Lower alkyl as used herein refers to a branched or straight chain alkyl group having 8 or fewer carbons. Alkyl also includes hydrocarbyl groups having one or two double or triple bonds in the carbon chain. The invention also includes salts of the above compounds. With respect to the novel compounds and salts of the present invention,

1. when R is¹And/or R²When it is methoxymethyl, R³And R⁴Not all phenyl groups, not all phenyl groups substituted with lower alkyl groups and not all phenyl groups substituted with halogen; and

2. when R is³And R⁴When one is phenyl or benzyl, R³And R⁴Is not ethyl; and

3. when R is¹And R²When at least one of is benzyl, then when R is³And R⁴When one is phenyl, R³And R⁴Is not allyl; and

4. when R is¹And R²One of which is methyl and the other is hydrogen, then when R is³And R⁴When one is phenyl, R³And R⁴Is not unsubstituted lower alkyl; and

5. when R is¹＝R^a＝R^aIn which R is^aIs alkoxymethyl or (acyloxy) methyl, then when R is³And R⁴When one is 1-phenylethyl, R³And R⁴Is not propionyloxy.

In addition, with respect to the combination, the following compounds are not included in the scope of the present invention, but may be used in the method of the present invention.

a) 1-methyl-5- (1-phenethyl) -5-propionyloxy-barbituric acid,

b)1, 3-diphenyl-5, 5- (dibenzyl) barbituric acid,

c)1, 3, 5-triphenylbarbituric acid, and

d) 5-benzyl-1, 3-dimethyl barbituric acid

In some exemplary embodiments, R¹And R²Is lower alkyl substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, alkylthio or arylthio, amino, alkylamino, dialkylamino, or one or more halogen atoms; a phenyl group; CH (CH)₂SR⁵Wherein R is⁵Is lower alkyl, aryl, alkaryl or benzyl; c (S) R⁶Wherein X is S or O and R⁶Is lower alkyl or aryl; CSR⁷Wherein R is⁷Is hydrogen, lower alkyl or aryl; and CH (SR)⁸)₂Wherein R is⁸Is a lower alkyl group.

In other exemplary embodiments, R³And R⁴At least one of which is a lower acyloxy group; phenyl substituted with lower acyl or a derivative thereof or acetamide; and cycloalkyl optionally containing one or more heteroatoms selected from N, O and S.

In certain exemplary embodiments of the invention, the substituent R¹And R²Are different and are each selected from butylBenzyl, phenylthiomethyl, cyclopropylmethyl, 3, 3, 3-trifluoropropyl, benzyloxymethyl and alkoxymethyl. In other exemplary embodiments, R¹And R²Are the same and are selected from the group consisting of butyl, benzyl, phenylthiomethyl, cyclopropylmethyl, 3, 3, 3-trifluoropropyl, benzyloxymethyl and alkoxymethyl. In other exemplary embodiments, R¹And R²One of which is hydrogen, R¹And R²Is selected from the group consisting of alkoxymethyl, butyl, benzyl, phenylthiomethyl, cyclopropylmethyl, 3, 3, 3-trifluoropropyl and benzyloxymethyl. In other words, R¹And R²One of which is hydrogen, R¹And R²The other of which is selected from:

-CH₂-O-(CH₂)_n-CH₃，n≥0；

in other exemplary embodiments, R¹And R²At least one of which is methoxymethyl. In other exemplary embodiments, R³And R⁴Both of which are aromatic rings or aromatic ring-containing moieties.

In certain exemplary embodiments, R³And R⁴Are the same or different and are independently phenyl; phenyl substituted by halogen or lower alkyl; cycloalkyl optionally containing one or more heteroatoms selected from N, S and O; a benzyl group; benzyl substituted on the ring by one or more halogen, lower alkyl or both; a lower alkyl group; or lower alkyl substituted by an aromatic moiety, with the proviso that R³And R⁴At least one of which is phenyl or substituted phenyl.

In other exemplary embodiments, R³And R⁴At least one of which is selected from phenyl, benzyl, fluorophenyl, and tolyl.

In other placesIn exemplary embodiments, R³And R⁴At least one of which is selected from:

R³and R⁴May be the same or different.

R¹And R²Can be used as non-toxic leaving groups which can be removed in biological systems to produce pharmacologically active substances. Loss of R relatively slowly¹And/or R²Resulting in an extended metabolic half-life of the pharmacologically active agent in the mammal. To R³And R⁴The choice is made so that the resulting pharmacologically active compound does not have the sedative properties normally associated with barbituric acid derivatives. An improvement of the assay described in example 3 can be used as an assay to identify compounds that do not have the sedative properties normally associated with barbituric acid derivatives. For example, a compound may be understood to have sedative properties if the test animal to which it is administered does not respond to a majority of the applied stimuli. By testing for having a specific R³And R⁴Compounds with substituents, compounds that do not have the sedative properties normally associated with barbituric acid derivatives can be identified.

It has been reported (Rains A, Moros D et al., J.Exp.biol. (Abstracts)1996, 895; Epilepsia 1996, 37: Supp1.5): the metabolic degradation of N, N' -dimethoxymethyl-5, 5-diphenyl barbituric acid into diphenyl barbituric acid (DPB). It is also known that the degradation mechanism involves the formation of monomethoxymethyl intermediates. According to the invention, N-substituted R¹/R²The group can be metabolically cleaved to yield R³/R⁴Substituted compounds with mono or non N substitution or R¹/R²The groups may remain attached in the active compound.

Those compounds which do not have adverse side effects are preferred. Examples of adverse side effects are toxicity, which can be evaluated by the method of example 2, and sedation, which can be evaluated by the method of example 3 as described above.

By the following reaction: 1, 3-bis (substituted) -5, 5-disubstituted barbituric acids of the present invention may be prepared by reacting the appropriate 5, 5-bis (substituted) barbituric acid with an alkali metal hydride to prepare the corresponding barbiturate, and then reacting the barbiturate with a moiety having a leaving group in a manner similar to that described by Samour et al, J.Med.chem.14, 187(1971), substituting the 1 and 3 substituents. In a more general approach, mono-and di-substituted compounds may be prepared according to the methods described in U.S.6,093,820 and modifications thereof. Typically, a 5, 5-disubstituted barbituric acid derivative is reacted with an excess of a base. The resulting dianion is then reacted with 1 equivalent of alkylating agent if a monosubstituted derivative is desired and with 2 equivalents of alkylating agent if a disubstituted derivative is desired.

The substituent in position 5 may be prepared by reacting the ureide with the appropriate starting materials in a manner analogous to that described for the preparation of diphenylbarbituric acid by McElvain, supra. These substituents can also be located on the 1, 3-bis (substituted) -barbituric acid by oxidizing the acid to the corresponding 1, 3-dialkyl ureide, which is then reacted with the appropriate compound in a similar manner to give the desired product.

The compounds in the free acid form may be converted to salts such as sodium, potassium or other pharmacologically acceptable salts by techniques well known to those of ordinary skill in the art.

Suitable synthetic methods can be readily selected by one of ordinary skill in the art or can be readily derived by routine experimentation known to those of ordinary skill in the art of organic chemical synthesis. The novel compounds of the present invention are not limited by their method of preparation, but may be prepared by the methods described herein, other methods known to those of ordinary skill in the art, or methods yet to be developed.

The term "treating" as used herein includes prophylactic administration of a compound of the invention to prevent or inhibit an undesired condition, as well as therapeutic administration of a compound of the invention to eliminate or reduce the extent or symptoms of a condition. The treatment of the present invention is administered to a human or other mammal suffering from a disease or condition in need of such treatment. Treatment also includes application of the compound to cells or organs in vitro. The treatment may be systemic or local administration.

The non-sedating barbituric acid derivatives of the present invention may be formulated into a "pharmaceutical composition" together with a suitable pharmaceutically acceptable carrier, excipient or diluent. If appropriate, the pharmaceutical compositions may be formulated in preparations including, but not limited to, solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, liquids, suppositories, injections, inhalants and aerosols, for their respective routes of administration in a usual manner.

An effective amount is the amount of active ingredient that is administered in a single dose or multiple doses required to achieve the desired pharmacological effect. Effective dosages can be determined and optimized by the skilled practitioner for the individual patient, or the individual condition can be treated by routine experimentation and titration as is well known to the skilled practitioner. The actual dosage and schedule of administration may vary depending on whether the composition is administered with other drugs or depending on the differences in pharmacokinetics, drug disposition and metabolism that exist between individuals. Similarly, the number of in vitro applications may also vary. One of ordinary skill in the art can adjust the dosage as needed for a particular situation without undue experimentation. The dosage ranges disclosed herein do not preclude the use of higher or lower dosages of the components, which may be approved for use in a particular application.

Neurological disorders include stress and stress disorders and neurological dysfunctions such as convulsions, seizures, muscle stiffness, nerve tension and anxiety. The compounds of the invention are useful as anticonvulsants and therefore may be used in the treatment of epilepsy. The compounds of the invention may also be used as neuroprotective agents for the treatment of cerebral ischemia, head trauma and other acute nerve injuries, and for the prevention of resulting neuronal damage. These compounds may be used in individuals undergoing cardiac surgery or carotid endarterectomy, as well as in individuals at risk for atrial fibrillation, transient ischemic attack (TLA'), cerebral ischemia, bacterial endocarditis, stroke, or subarachnoid hemorrhage due to a cerebral aneurysm. The compounds may also be administered after an acute event has occurred.

The available dose of non-sedating barbiturate for neuroprotective purposes may exceed the minimum anticonvulsant dose of barbiturate. In some embodiments of the invention, the useful dose of non-sedating barbiturate is in the range of about 2-fold to about 5-fold the dose of the anticonvulsant. In other contexts, however, an effective dose of non-sedating barbiturate for neuroprotective purposes will be about 5-fold to about 10-fold, or even higher, than the dose of the anticonvulsant agent, if the mammal so desires, so long as the dose is clinically acceptable. In particular, the available dose may exceed the dose of barbiturates that produce sedation, such as phenobarbital, and may exceed the dose of phenobarbital that produces coma or death.

The neuroprotective effect of the present method can be used to alleviate the effects of cerebral ischemia. The non-sedating barbiturate may be administered orally, intravenously, transdermally, or pulmonarily by microparticle or aerosol inhalation, together with an adjuvant. Additionally, within the scope of the present invention, non-sedating barbiturates may be administered prophylactically or therapeutically at clinically acceptable doses. The compound can be administered prophylactically before significant neuronal damage occurs, or the compound can be administered therapeutically after the onset of neuronal damage. Neuroprotection is reduced or the patient is protected from neuronal damage caused by head trauma or cerebral ischemia. The compounds may be administered in cardiac surgery or carotid endarterectomy. A mammalian subject may have or be at risk of atrial fibrillation, transient ischemic attack (TLA), bacterial endocarditis, stroke, head trauma, or subarachnoid hemorrhage.

Typically, to achieve neuroprotective effects, a sufficient dose of non-sedating barbiturate is administered such that the blood concentration of barbiturate or its active metabolites is at least about 30 μ g/ml, preferably at least about 100 μ g/ml, more preferably at least about 250 μ g/ml, and may be as high as 200 μ g/ml or even higher, 300 μ g/ml. In contrast, the reported therapeutic range of phenobarbital is low, with blood concentrations of 10-30 μ g/ml. Thus, preferred ranges are equal to or greater than about 25, 30, 50, 75, 100, 200, 250, or 300 μ g/ml. Similar dosages are appropriate for the other drug effects described herein.

The present invention includes a pharmaceutical composition comprising non-sedating barbiturate which has a neurological effect when administered in an effective amount. Preferably, the non-sedating barbiturate is administered orally in a dose ranging from about 25 to about 1,500 mg/kg/day of body weight. Preferably, the dosage is greater than about 50mg/kg/day, alternatively greater than about 100 mg/kg/day, alternatively greater than 250 mg/kg/day. The preferred dose is pharmacologically equivalent to a dose of about 1000 mg/kg/day in mice. Thus, the dosage form may be in a single dose or in multiple doses, such that the dose is equal to or greater than about 1,5, 10, 15, 20, 25, 50, 70, 100, 250, 500, 1000, or 1500mg/kg body weight per day. For other therapeutic uses, lower doses in the daily range of greater than or about 0.1, 0.5, 1,5 or 10mg/kg body weight are suitable, other doses for barbital being well known.

The barbituric acid derivatives of the present invention have an extended half-life in humans, allowing for relatively low oral doses to achieve appreciable blood concentrations. For example, a dose of about 40 to about 100 mg/kg/day may achieve a blood concentration of non-sedating barbiturate of greater than 100 μ g/ml and is within the scope of the present invention. Similar blood concentrations were obtained with parenteral administration of non-sedating barbiturate at daily doses of less than 25 mg/kg/day. However, the loading dose on the first day still requires an initial dose of more than 25 mg/kg.

It is generally accepted that the neurological effects of barbiturates, such as anticonvulsant and neuroprotective effects, are linked to their sedative/hypnotic effects. For example, Lightfoote et al, Stroke 8, 627-: the protective effect of pentobarbital is due to the extended anesthetic effect induced by barbital. This view has been confirmed by biochemical studies at the cellular receptor level, and all of these effects are related to the effects on GABA receptors. Thus, the prior art does not teach the use of sedative barbiturates for neuroprotection due to their toxicity, nor does the prior art teach the use of non-sedative barbiturates as neuroprotective agents due to their lack of sedative or anesthetic properties.

The present invention also provides a pharmaceutical composition comprising as active substance a compound of formula I as described above or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers, excipients or diluents. Any conventional technique may be used to prepare the pharmaceutical formulations of the present invention. The active ingredient may be included in a formulation that provides rapid release, sustained release, or delayed release following administration to a patient.

Pharmaceutical compositions 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 formulations, resealed red blood cells containing active ingredients, and immune-based formulations.

The formulations of the pharmaceutical compositions described herein may be prepared by any method known or developed in the future. Generally, preparation involves mixing the active ingredient with the carrier or one or more other additional ingredients, and forming or packaging the product into the desired single or multiple dosage units, as necessary or desired.

In general, prolonged activity is an important property for drugs, particularly anticonvulsants. In addition to allowing unusual drug administration, it may also improve patient compliance with the drug. In addition, serum and tissue concentrations of long acting compounds, which are critical to maintaining efficacy, are more stable. In addition, stable serum concentrations reduce the incidence of paroxysmal (breakthrough-through) epilepsy and possible incidence of other side effects.

As used herein, "additional ingredients" include, but are not limited to, one or more of the following: an excipient; a surfactant; a dispersant; an inert diluent; granulating and disintegrating agents; a binder; a lubricant; a sweetener; a flavoring agent; a colorant; a preservative; physiologically degradable compositions such as gelatin; aqueous excipients and solvents; oily excipients and solvents; a suspending agent; a dispersing or wetting agent; an emulsifier; demulcents (demucients); a buffering agent; salt; a thickener; a filler; an emulsifier; an antioxidant; (ii) an antibiotic; an antifungal agent; a stabilizer; pharmaceutically acceptable polymeric or hydrophobic materials, and other components.

While the description of pharmaceutical compositions provided herein refers primarily to pharmaceutical compositions suitable for administration to humans, it will be appreciated by those of ordinary skill in the art, based on this disclosure, that such compositions are also generally suitable for administration to any mammal. The preparation of compositions suitable for administration to various animals is well understood and based on the pharmaceutical compositions for administration to humans, such changes can be designed and made by the veterinarian of ordinary skill through routine experimentation.

The pharmaceutical compositions of the present invention may be prepared, packaged or sold in a single unit dose or in multiple single unit doses. As used herein, a "unit dose" is an individual amount of a pharmaceutical composition that contains a predetermined amount of an active ingredient. The amount of active ingredient in each unit dose is generally equal to the total amount of active ingredient to be administered or to a suitable fraction of the total dose, for example half or one third of such dose.

Formulations of the pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete (discrete) solid dosage units. Solid dosage units include, for example, tablets, caplets, hard or soft capsules, cachets, lozenges, or troches. Each solid dosage unit contains a predetermined quantity of active ingredient, for example a unit dose or a fraction thereof. Other formulations suitable for administration include, but are not limited to, powder or granular formulations, aqueous or oily suspensions, aqueous or oily solutions, or emulsions. As used herein, "oil-containing liquid" refers to a carbon or silicon-based liquid that contains less polar than water.

Tablets containing the active ingredient may be prepared, for example, by compressing or molding the active ingredient, optionally with one or more additional components. Compressed tablets may be prepared by compressing, in a suitable apparatus, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with one or more binders, lubricants, glidants, excipients, surfactants and dispersants. Molded tablets may be made by molding, in a suitable apparatus, a mixture of the active ingredient, the pharmaceutically acceptable carrier, and at least sufficient liquid to wet the mixture.

The tablets may be uncoated or they may be coated using methods known in the art or to be developed. In order to delay disintegration in the gastrointestinal tract of a subject, coated tablets may be formulated, for example, using an enteric coating, whereby sustained release and absorption of the active ingredient is achieved. To obtain pharmaceutically elegant and palatable preparations, the tablets may also contain sweetening agents, flavoring agents, coloring agents, preserving agents or some combination of these.

Hard capsules containing the active ingredient can be prepared using physiologically degradable compositions such as gelatin. Such hard capsules comprise the active ingredient and may also comprise additional components including, for example, inert solid diluents. Soft capsules containing the active ingredient can be prepared using physiologically degradable compositions such as gelatin. Such soft capsules contain the active ingredient, which may be mixed with water or an oil medium.

Liquid formulations of the pharmaceutical compositions of the invention suitable for administration may be prepared, packaged and sold in liquid form or as a dry product which is reconstituted with water or another suitable excipient 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 developed in the future. Liquid suspensions of the active ingredients may be in an aqueous or oily vehicle, and may further include one or more additional components such as suspending agents, dispersing or wetting agents, emulsifying agents, wetting agents, preservatives, buffering agents, salts, flavoring agents, coloring agents and sweetening agents. The oily suspension may further comprise a thickening agent. The liquid solutions of the active ingredients may be in aqueous or oily vehicles and may further include one or more additional components such as preservatives, buffers, salts, flavouring agents, colouring agents and sweetening agents.

The powders and granule formulations of the present invention may be prepared using methods known or to be developed in the art. Such formulations may be administered directly to the subject, or prepared as an aqueous or oily suspension or solution for administration to the subject, for example, by forming a tablet, filling into a capsule, or by adding thereto an aqueous or oily excipient. The powder or granule formulation may further comprise one or more dispersing or wetting agents, suspending agents and preservatives. Other excipients, for example fillers and sweeteners, flavouring or colouring agents, may also be added to these formulations.

The pharmaceutical compositions of the present invention may be prepared, packaged or sold in the form of oil-in-water emulsions or water-in-oil emulsions. Such compositions may further comprise one or more emulsifiers. These emulsions may also contain other ingredients including, for example, sweetening or flavoring agents.

The efficacy of the compounds of the present invention with respect to stress and stress conditions and neurological disorders such as convulsions, seizures, muscle stiffness, nervousness and anxiety may be illustrated in the following non-limiting examples 1-3. Similarly, the neuroprotective ability of a compound can be tested, for example, by the general method set forth in non-limiting example 4 and with specific reference to non-limiting examples 5-7. Other known or yet to be developed methods may similarly be used to test the compounds of the invention.

The compounds of the present invention may be prepared by two general synthetic routes using methods generally known in the art or modifications thereof which can be readily obtained by one of ordinary skill in the art without undue experimentation. Exemplary methods of various steps can be found, for example, in Loudon, g.m., organic chemistry, Addison-Wesley, 1984; U.S.4,628,056 to Levitt et al (1986); U.S.6,093,820 to Gutman et al (2000); EP 1083172A 1 to Ashkinazi (2001); and Krummel et al (1998), U.S. Pat. No.5,750,766, each of which is incorporated herein by reference in its entirety. Scheme 1 is a retrosynthetic analytical summary of the compounds of the invention.

The compounds of formula I may be prepared by N-alkylation of a suitably substituted barbituric acid derivative (formula II). Suitable exemplary methods for N-alkylation of barbituric acid are given in examples 8a, 8b, 9a, 9b, 10, 11 and 12 below. Other known methods are known to those of ordinary skill in the art and may also be used. The desired barbituric acid derivatives of formula II may be prepared by condensation of urea with a suitably substituted malonate (formula III). In an alternative synthetic route (see example 8c), barbituric acid derivatives of formula I may be prepared by reacting a substituted urea (formula IV) with a suitably substituted malonate (III). The preparation of substituted ureas is well known. Methods for preparing compounds of formula III are also known in the art. Suitable exemplary methods for preparing them, wherein R³and/R⁴Can be substituted, are given in examples 13 to 16. Other methods are known to those of ordinary skill in the art and may also be used.

Scheme I

Example 1

The anticonvulsant activity of the barbituric acid derivatives of the invention can be demonstrated or tested by evaluating treated mice to prevent Maximal Electroshock Seizures (MES). Mainly because of the good correlation between the test results and clinical findings of efficacy in patients with epilepsy, the MES test is widely used to evaluate the anticonvulsant properties of compounds. In a typical MES test, wherein a corneal electrode is used, a current of about 150 milliamps and a 60 hertz stimulus is applied for about 200 milliseconds, the anticonvulsant properties of the barbituric acid derivatives of the invention are evaluated. Mice were tested prior to dosing in order to exclude from THE study any animals that did not respond to complete tonic convulsions, including hind limb tonic extension (tee), which served as a basis for evaluating THE efficacy of THE active substances used. THE animals protected by THE tee were considered protected in THE MES test.

The test compositions are dissolved in warmed polyethylene glycol 400 or other suitable solvent and the solution is administered at a first dose of about 500mg/kg through a gastric tube, for example to Sprague-Dawley rats. These animals were tested for maximal electrical shock seizures (MES) at predetermined times after dosing, e.g., about 6 and 23 hours after dosing. All animals showed full maximal seizures to the electrical stimulation before being subjected to the study.

Example 2

The non-toxicity of the barbituric acid derivatives of the invention can be tested by repeated high dose administration as follows:

test compounds are suspended in warmed polyethylene glycol 400 or other suitable solvent and administered at a first dose of about 1500mg/kg through a gastric tube, for example to Sprague-Dawley rats. Similar doses were given to the same mice 24 hours later and again 48 hours after the first administration. Animals were checked a few hours after dosing and again before the next dose until a further 3 days after the last dose. The toxic effects of the administration are monitored as well as behavioral effects such as exercise, escape behavior, eating, or any other observable effect.

Example 3

The calming and muscle-relaxing properties of the barbituric acid derivatives of the invention can be demonstrated by monitoring the behavioural and motor effects of treated mice.

For example, test compositions in alkalized saline, e.g., Swiss Webster mice, can be administered intraperitoneally. The time required for the animals to receive each dose was recorded to show specific motor and behavioral effects. Monitoring effects may include, for example, hypotonia, motor activity, peace and evasive behavior. Toxic effects were also recorded.

The efficacy of the composition can be assessed relative to known uses primarily as a skeletal muscle relaxant and/or a tranquilizer. The combination of sedation and the ability to not impair the animal's ability to respond to its environment is highly desirable in agents used to treat anxiety. The composition of the present invention preferably does not exhibit hypnotic activity or depression of the central nervous system.

Example 4 general design for determining efficacy of treatment of ischemia

The non-sedating barbituric acid derivatives (NSB) of the present invention may be tested on mice under reversible or irreversible ischemic conditions. The mice were given different doses of the drug. Neuroprotective effect compared to negative control (placebo) and positive control pentobarbital, a known neuroprotective but sedative barbital, at known doses in cerebral ischemia reduced infarct volume.

Several days after the onset of ischemic injury, animals were sacrificed and the brain was examined to determine the volume of cerebral infarction as a measure of the reduction of ischemic brain injury by the drug. Animals are clinically examined and graded prior to killing to determine if the drug imparts any beneficial effect on the relevant function following ischemic "stroke".

Four experimental models are preferred for testing the neuroprotective effects of NSB drugs. See GinsbergMD, "Animal Models of Global and Focal cellular Ischemia," Chapter 34 inWelsh KMA et al, Primer on cellular Diseases, Academic Press, New York, 1997; and Pulsellli WA, Brierley JB, A new model of bipolar hemipathological ischemia in the unanested rat, Stroke 1979, May-June10 (3): 267-72. These references are incorporated herein by reference.

1. Irreversible ischemia caused by blockage of the Middle Cerebral Artery (MCA);

2. reversible ischemia caused by MCA occlusion;

3. transient global ischemia caused by crossing the clamped aorta at defined intervals; and

4. transient global ischemia caused by cauterizing the vertebral arteries and reversibly clamping the common carotid artery.

In each experimental model, groups of mice were treated with the following protocol:

1. negative control (placebo) was given via Nasogastric (NG) tube;

2. positive control: intraperitoneal (IP), pentobarbital at a dose of 70 mg/kg; or

3. The NSB compound DMMDPB (or a compound whose utility is tested in the present invention) was administered at a dose of 500mg/kg to 1500mg/kg through an NG tube 7 days before the experimental infarction. The obtained results were compared.

Example 5 irreversible cerebral ischemia

Irreversible MCA occlusion was caused by ligation of the carotid artery, and then the animals were under halothane anesthesia with a filament inserted into the root cause of MCA. Blood flow in the MCA was measured using a laser Doppler velocimeter (laser Doppler), and those animals with significantly reduced blood flow were considered to have suffered cerebral ischemia and were at risk of subsequent injury (i.e., stroke). Those animals that did not suffer a sharp decrease in MCA blood flow did not experience a clinical stroke. All animals showed: a decrease in MCA blood flow would be indicative of stroke.

The animals at risk were then observed for behavior and scored by clinical findings using a bererson rating scale:

0 No evidence of Stroke

1 mild stroke

2 moderate apoplexy

3 severe stroke

Those animals that survived for three days were sacrificed and their brains were examined. Animals to be killed are given, for example, chloral hydrate (35mg/kg IP, their brains are fixed by intracardiac infusion of heparinized 0.9% saline followed by infusion of 10% buffered formalin). The brain is carefully removed from the cranial apex, leaving the arachnoid and underlying intracranial blood vessels intact. For example, the fixed brain is frozen at 80 ℃. Crown-like sections 20 μm thick were cut at 400 μm intervals in a cryostat at-20 ℃ and then dried on a hot plate at 60 ℃ and fixed (fix) in 90% ethanol for 10 minutes, stained with hematoxylin and eosin (7). The infarcted brain is bloodless than the rest of the brain. Determining the amount of infarcted brain by microscopic examination of brain sections and in mm³Calculating the infarct volume.

Example 6 reversible cerebral ischemia model

Mice were pretreated as described above in example 4, except that the filaments occluding the MCA were removed after 30-60 minutes, and blood flow was allowed to re-flow through the MCA, in a similar manner. Then, the mice were clinically observed for three days, grade their extent of stroke, and then killed as in example 5. The brain is removed and the examination is performed as described above.

Example 7

The mice were pretreated in the manner of example 4 above, and then the spinal arteries of the mice were electrically burned through the axillary pores of the first cervical vertebra during ether anesthesia. The reversible forceps are then placed loosely around the common carotid artery. After 24 hours, the awake rats were treated and clamped with carotid artery clamps to cause 4-vessel occlusion. 4-10-30 minutes after vessel occlusion, the clamp was removed and the animals were sacrificed by perfusion fixation. Typically, untreated mice exhibited ischemic neuronal damage 20 or 30 minutes after 4-vessel occlusion. Multiple regions of the forebrain, including H1 and the paraspinal hippocampus, striatum, and posterior neocortex were evaluated. In these cases, NSB has been shown to have a neuroprotective effect.

EXAMPLE 8a preparation of mono-and bis-N-alkylated barbituric acid

The compound of formula II was dissolved in a solution of ethanol in potassium hydroxide. The reaction is carried out by dissolving the alkyl halide R' X in the solution. To give a product of the formula I, in which R¹＝R²＝R’。(Loudon GM，Organic Chemistry，Addison-Wesley(1984)，p.1194)

EXAMPLE 8b preparation of mono-and bis-N-alkylated barbituric acid

The compound of formula II was dissolved in a solution of ethanol in potassium hydroxide. The reaction was carried out by dissolving alkyl p-toluenesulfonate R' OTs in the solution. To give a product of the formula I, in which R¹＝R²＝R’。(LoudonGM，Organic Chemistry，Addison-Wesley(1984)，p.1194)

Example 8c preparation of mono-and bis-N-alkylated barbituric acids by condensation of urea and malonic ester

Urea substituted with alkyl groups on one or both amides was used as the starting material (formula IV). If disubstituted, the alkyl groups 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 ", wherein R ' and R" are different. The substituted urea is then reacted with a malonate (formula III) such as diethyl malonate and sodium ethoxide in ethanol. To give a reaction product of the formula I, in which R¹R' and R²H, R' or R ". (Loudon GM, Organic Chemistry, Addison-Wesley (1984), p.1087; Euro.Pat.Applic.No.1083172A 1)

Using a similar procedure to that described in examples 8a, 8b and 8c, an alkyl group having a cycloalkyl, acyl, acyloxy, aryl, aryloxy, alkoxy, alkylthio, arylthio, amino, alkylamino, dialkylamino or halogen may be used in place of R of formula I¹And R²。

EXAMPLE 9a preparation of N-alkoxyalkyl Compounds

At 0 deg.C, reacting dialkoxymethane (R' OCH)₂OR') is added to the acetyl methanesulfonate. The temperature of the solution was raised to 25 ℃ and the reaction was carried out for 2 hours. The resulting solution was then gradually added to a mixture of suitably substituted barbituric acid (formula II) and sodium hydride (dispersed at 60% in mineral oil) in dry dimethylformamide over 45 minutes. The resulting reaction mixture was stirred for about 15 minutes, then diluted with hydrochloric acid, followed by ethyl acetate. The phases were separated and the ethyl acetate phase was washed with saturated aqueous sodium chloride solution and then with aqueous sodium hydroxide solution. The ethyl acetate phase was then dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The dried product is then crystallized from toluene to provide a compound of formula I, wherein R is¹＝R²＝CH₂OR。(U.S.Pat.No.6,093,820)

By using different barbituric acid derivatives as starting materials, R can be varied³And R⁴A group.

By using an excess of sodium hydride and 1 equivalent of alkylating agent, the formation of mono-substituted products is favoured, and therefore the majority of the product consists of formula I, wherein R¹And R²One of which is substituted with CH₂OR’，R¹And R²Is substituted by hydrogen.

EXAMPLE 9b Selective preparation of N-Alkoxyalkylated Compounds

The appropriate barbituric acid (formula II) is dissolved in dimethylformamide. Once the solution was cooled, sodium hydride was added thereto, and then the mixture was stirred for 30 minutes. The appropriate chloromethyl alkyl ether was added to the mixture over about 30 minutes. Then, the reaction mixture was stirred for 1 hour and then poured into ice water. The solid precipitate was filtered, washed with water, and crystallized from ethanol. (U.S. Pat. No.4,628,056)

By using different barbituric acid derivatives as starting materials, R can be varied³And R⁴A group.

By using different chlorinated ethers, R¹And R²Different alkoxides may be used for substitution. For example, R can be generated¹＝R²＝CH₂OR 'wherein R' is alkyl, aryl, alkaryl OR benzyl. By using chlorinated thioethers, R¹And R²May be substituted with alkylthio. For example, R can be generated¹＝R²＝CH₂The group of SR ', wherein R' is alkyl, aryl, alkaryl or benzyl.

EXAMPLE 10 preparation of mono-and bis-N-acyloxy substituted barbituric acids

The compound of formula II is dissolved in a solution containing sodium hydroxide together with an alkyl chloroformate. To give a product of the formula I, wherein R¹＝R²(o) OR ', wherein R' is alkyl.

By reacting a compound of formula II with an aryl chloroformate in a solution containing sodium hydroxide, a product of formula I is obtained, wherein R¹＝R²OR ', wherein R' is aryl. (Loudon, pp.1061-1064)

By reacting a compound of formula I with a compound of formula ClC (O) SR ', wherein R' is alkyl or aryl, to give a product of formula I, wherein R is¹＝R²(o) SR ', wherein R' is alkyl or aryl.

EXAMPLE 11 preparation of N-acyl substituted barbituric acid

The compound of formula II is dissolved with an acid chloride of formula ClC (O) R ', wherein R' is hydrogen, alkyl or aryl, and then allowed to react in aqueous sodium hydroxide. To obtain the product of the formula I,wherein R is¹＝R²＝C(O)R’。(Loudon GM，Organic Chemistry，Addison-Wesley(1984)，pp.1062-1064)

EXAMPLE 12a N preparation of acetal-substituted barbituric acid

The compound of formula II was dissolved in dimethylformamide. To this solution was added sodium hydride. To this solution was added a solution of the general formula ClCH (OR')₂Wherein R' is alkyl. Then, the reaction product is purified. The product has the structure of formula I, wherein R¹＝R²＝CH(OR’)₂。(Loudon GM，OrganicChemistry，Addison-Wesley(1984)，pp.1062-1064)

EXAMPLE 12b N preparation of arylmethyl-substituted barbituric acid

The compound of formula II was dissolved in ethanol together with potassium hydroxide. By substitution of halomethyl-substituted aromatic compounds ArCH₂X, wherein X is a halogen, is dissolved in the solution. To give a reaction product of the formula I, in which R¹＝R²＝CH₂Ar。(Loudon GM，Organic Chemistry，Addison-Wesley(1984)，p.1194)

The synthesis process can also be reacted with benzyl chloride substituted by hydrogen sulfide SH on the benzene ring.

EXAMPLE 12c N preparation of arylthio-substituted barbituric acid

The compound of formula II was dissolved in ethanol together with potassium hydroxide. A thiohaloarylalkyl compound, R 'ArSX, where X is halogen and R' is H or alkyl, is dissolved in the solution. To give a reaction product of the formula I, in which R¹＝R²＝SArR’。

EXAMPLE 135 preparation of aryl-substituted barbituric acid derivatives

A solution of magnesium is prepared in an inert solvent. The inert solvent may be selected from the group consisting of diethyl ether, dimethoxymethane, t-butyl methyl ether, tetrahydropyran, diisopropyl ether, toluene and mesitylene and may be a mixture of these solvents. Of these, 1, 2-dibromomethane or diethyl ether is advantageous. In the first step, an arylmethyl halide is added to the solution. The aryl group may be a heteroatom group containing nitrogen in the ring and optionally containing carbon, oxygen, or sulfur. The solution may also contain tributylamine.

Then, diethyl carbonate was added to the solution, followed by neutralization with hydrochloric acid. Then, the organic layer was separated.

Sodium ethoxide was added to the concentrated organic layer. Then, ethanol was distilled off from the solution. The solution was neutralized with hydrochloric acid. The organic layer was then separated, dried and concentrated in vacuo to afford diethyl arylmalonate.

Then, diethyl arylmalonate was dissolved in ethanol together with urea and sodium ethoxide. The reaction product has the structure of formula I, wherein R³And R⁴One of which is aryl, R³And R⁴Is hydrogen. (U.S. Pat.No.5,750, 766; Loudon GM, Organic Chemistry, Addison-Wesley (1984), p.1087)

EXAMPLE 14a preparation of 5-aryl-substituted barbituric acid derivatives

Mixing monohydrated ureide (formula I, wherein R³＝R⁴OH) was dissolved in sulfuric acid. An aromatic compound (Ar-H) is added, and then the solution is heated to react the solution. Then, the reaction mixture was cooled, and the sulfuric acid layer was separated. Pouring the sulfuric acid layer into cold water to separate out the product. The precipitated product is filtered, washed, filtered again, dried and, if necessary, chromatographed to give the pure product of formula I, wherein R is³＝R⁴＝Ar。(U.S.Pat No.4,628,056)

Using this method, halogen-substituted benzenes, such as fluorobenzene, can be used to give the product of formula I, wherein R³＝R⁴PhX, wherein X is halogen. (U.S. Pat. No.4,628,056)

Alternatively, alkyl substituted benzenes, such as ethylbenzene, may be used to provide a product of formula I wherein R³＝R⁴PhR', itWherein R' is an alkyl group. (U.S. Pat. No.4,628,056)

In another variation, acyl-substituted benzenes may be used to obtain a product of formula I wherein R³＝R⁴(ii) phc (o) R ', wherein R' is alkyl; alternatively, benzylformamides may be used to obtain products of formula I, wherein R³＝R⁴＝PhCH₂C(O)NH₂Alternatively, dithiane substituted benzenes having the structure wherein R is³＝R⁴Ph-dithiane.

EXAMPLE 14b preparation of 5-aryl-substituted barbituric acid derivatives

A solution of magnesium, dimethoxymethane and dibromomethane is prepared. To this was added a solution of dimethoxymethane in a halomethyl-substituted aromatic compound, and the reaction was carried out. To this solution was added cold diethoxy carbonate. The solution was then neutralized with hydrochloric acid. The organic layer was separated and concentrated by distillation.

Sodium ethoxide was added to the concentrated organic layer. Then, dimethoxymethane and ethanol were distilled off from the solution. The solution was neutralized with hydrochloric acid, the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The resulting product is an aromatic substituted diethyl malonate.

Then, diethyl malonate was dissolved in ethanol together with urea and sodium ethoxide and reacted. The reaction product has the structure of formula I, wherein R³And R⁴One of which is aromatic, R³And R⁴Is hydrogen. (U.S. Pat.No.5,750, 766; Loudon GM, Organic Chemistry, Addison-Wesley (1984), p.1087)

In order to obtain a product of the formula I, wherein R³And R⁴One of which is a substituted aromatic radical, R³And R⁴Is hydrogen, is artOne of ordinary skill can use this method or a variation thereof to synthesize barbituric acid derivatives from halomethyl-substituted aromatic compounds having additional substituents on the ring such as halogen, alkyl, acyl derivatives, or acetamido groups.

This synthesis can also be reacted with chloromethylphenyldithiane as the halomethyl-substituted aromatic compound.

EXAMPLE 15a preparation of 5-Arylmethy-substituted barbituric acid derivatives

Malonic acid diethyl ester and bromomethyl substituted aromatic compound ArCH₂X, wherein Ar is aryl and X is halogen, is dissolved in ethanol together with sodium ethoxide. The product is of the formula ArCH₂CH(CO₂Et)₂Mono-arylmethylmalonic acid esters of (i). Then, the monoarylmethylmalonate was dissolved in ethanol together with urea and sodium ethoxide and reacted. The reaction product has the structure of formula I, wherein R¹＝R²＝H，R³And R⁴One is CH₂Ar，R³And R⁴Is hydrogen. (Loudon GM, Organic Chemistry, Addison-Wesley (1984), pp.617, 1086-1088)

The aromatic compounds may be further substituted on the ring, for example by halogen or alkyl.

Example 15b preparation of 5, 5-bis (arylmethyl) substituted barbituric acid derivatives

Reacting diethyl malonate with bromomethyl-substituted aromatic compound ArCH₂X, wherein Ar is aryl and X is halogen, is dissolved in ethanol together with sodium ethoxide. The product is of the formula ArCH₂CH(CO₂Et)₂Mono-arylmethylmalonic acid esters of (i). Separating the monoarylmethylmalonate from the solution. Then, the isolated monoarylmethylmalonate is reacted with an iodomethyl-substituted aromatic compound Ar' CH₂I, wherein Ar 'is an aryl group and Ar' may be the same or different, and sodium ethoxide is dissolved in ethanol. The product is of formula (ArCH)₂)(Ar’CH₂)C(CO₂Et)₂Is a diarylmethylmalonate.

Then, the diarylmethylmalonate together with urea and sodium ethoxide is dissolved in ethanol and reacted. To give a reaction product of the formula I, in which R³＝CH₂Ar；R⁴＝CH₂Ar’。(Loudon GM，OrganicChemistry，Addison-Wesley(1984)，pp.617，1086-1088)

For example, the aromatic ring of the compound may be substituted with either halogen or alkyl.

EXAMPLE 16a preparation of 5, 5-dialkyl-substituted barbituric acid derivatives

A compound of formula I, wherein R³＝R⁴OH, dissolved in pyridine along with p-toluenesulfonyl chloride, replacing the hydroxyl group with tosyl. Separating the resulting tosylate from the compound of formula R'₂Cu-Li⁺Lithium dialkylcopprate (lithium dialylcuprate) in which R ═ alkyl groups, were redissolved together in ether. To give a product of the formula I, in which R³＝R⁴＝R’。(Loudon GM，Organic Chemistry，Addison-Wesley(1984)，pp.721-722)

EXAMPLE 16b preparation of 5-alkyl-substituted barbituric acid derivatives

Diethyl malonate is dissolved in ethanol with an alkyl bromide of the formula R 'Br, wherein R' is an alkyl group, together with sodium ethoxide. The product is of the formula R' CH (CO)₂Et)₂A monoalkylmalonic acid ester of (a). Then, the monoalkylmalonate together with urea and sodium ethoxide was dissolved in ethanol and reacted. The reaction product has the structure of formula I, wherein R³And R⁴One of which is R', R³And R⁴Is hydrogen. (Loudon GM, organic chemistry, Addison-Wesley (1984), pp.1086-1088)

The alkyl group R' may be substituted; for example, the alkyl group R' may be substituted with an aryl group.

EXAMPLE 16c preparation of 5, 5-dialkyl-substituted barbituric acid derivatives

Diethyl malonate is dissolved in ethanol with an alkyl bromide of the formula R 'Br, wherein R' is an alkyl group, together with sodium ethoxide. The product is of the formula R' CH (CO)₂Et)₂A monoalkylmalonic acid ester of (a). Separating the monoalkylmalonate from the solution. The separated monoalkylmalonate is then dissolved in ethanol with an alkyl iodide of the formula R "I, wherein R" is an alkyl group and may be the same or different from R', together with sodium ethoxide. The product is of the formula R 'R' C (CO)₂Et)₂A dialkyl malonate.

Then, the dialkyl malonate is dissolved in ethanol together with urea and sodium ethoxide and reacted. The reaction product has the structure of formula II, wherein R³And R⁴One of which is R', R³And R⁴Is R ". R' and R "may be the same or different alkyl groups. (Loudon GM, Organic Chemistry, Addison-Wesley (1984), pp.1086-1088)

The alkyl groups R 'and R' may be substituted; for example, the alkyl groups R 'and R' may each be substituted with an aryl group.

The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best embodiments known to the inventors to make and use the invention. Nothing in this specification should be taken as limiting the scope of the invention. All examples provided herein are representative and non-limiting. Modifications and variations of the above-described embodiments of the invention are possible in light of the above teachings, to those skilled in the art, without departing from the spirit and scope of the invention. It is, therefore, to be understood that within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described in the specification.

Claims (23)

1. Use of non-sedating barbiturate and salts thereof in the manufacture of a medicament for protecting a mammal from neurological damage, the non-sedating barbiturate having the structure:

wherein

R¹And R²May be the same or different and independently

CH₂OR′、CH₂SR′、C(O)OR′、C(O)SR′、C(O)R′、CH(OR′)₂、CH₂Ar, SArR ', wherein R' is selected from hydrogen, alkyl, aryl, alkaryl, or benzyl;

and wherein

R³And R⁴May be the same or different and independently: hydrogen; an aryl group; PhX, wherein X is halogen; PhR ', PhC (O) R', PhCH₂C(O)NH₂Ph-dithiane, wherein Ph is benzene and R' is alkyl; CH (CH)₂Ar or CH₂Ar ', wherein Ar and Ar ' are alkyl groups, and Ar ' may be the same or different.

2. Use according to claim 1, wherein R¹And R²Is CH₂O-alkyl, and R³Is hydrogen, and R⁴Is an aryl group.

3. Use according to claim 1, wherein R¹And R²Is alkyl, and R³Is hydrogen or aryl, and R⁴Is an aryl group.

4. Use according to claim 1, wherein R¹And R²Is CH₂OR′、CH₂S R ', R' is selected from hydrogen, alkyl, aryl, alkaryl, or benzyl.

5. Use according to claim 1, wherein R¹And R²Is C (O) OR ', C (O) SR ', R ' is alkyl OR aryl.

6. Use according to claim 1, wherein R¹And R²Is C (O) R 'OR CH (OR')₂Or CH₂Ar and R' are hydrogen, alkyl or aryl.

7. Use according to claim 1, wherein R¹And R²Is SArR ', wherein R' is hydrogen or alkyl.

8. Use according to claim 1, wherein R³And R⁴In contrast, one is aryl and the other is hydrogen.

9. Use according to claim 1, wherein R³And R⁴Is PhX, PhR ', PhC (O) R', PhCH₂C(O)NH₂And X is halogen and R' is alkyl.

10. Use according to claim 1, wherein R³＝CH₂Ar；R⁴＝CH₂Ar ', wherein Ar and Ar ' are aryl groups, and Ar ' may be the same or different.

11. The use according to claim 1, wherein the medicament is formulated for oral or intravenous administration.

12. The use of claim 1, wherein the medicament for protecting a mammal from nerve damage is a medicament for protecting a mammal from neuronal damage caused by atrial fibrillation, transient ischemic attack, cerebral ischemia, bacterial endocarditis, stroke, head trauma, subarachnoid hemorrhage, or other polar nerve damage.

13. A pharmaceutical composition comprising as an active ingredient a non-sedating barbiturate having the structure

Wherein

R¹And R²May be the same or different and independently

CH₂OR′、CH₂SR′、C(O)OR′、C(O)SR′、C(O)R′、CH(OR′)₂、CH₂Ar, SArR ', wherein R' is selected from hydrogen, alkyl, aryl, alkaryl, or benzyl;

and wherein

R³And R⁴May be the same or different and independently: hydrogen; an aryl group; PhX, wherein X is halogen; PhR ', PhC (O) R', PhCH₂C(O)NH₂Ph-dithiane, wherein Ph is benzene and R' is alkyl; CH (CH)₂Ar or CH₂Ar ', wherein Ar and Ar ' are alkyl groups, and Ar ' may be the same or different.

14. The composition of claim 13, wherein the pharmaceutical composition is formulated in solid, semi-solid, liquid, or gaseous form.

15. The composition of claim 13, wherein the solid, semi-solid, liquid, or gaseous form is a tablet, capsule, powder, granule, paste, liquid, suppository, injection, inhalation, or aerosol.

16. The composition of claim 13, further comprising one or more pharmaceutically acceptable excipients or diluents.

17. The composition of claim 13, further comprising one or more additional ingredients comprising: an excipient; a surfactant; a dispersant; an inert diluent; granulating and disintegrating agents; a binder; a lubricant; a sweetener; a flavoring agent; a colorant; a preservative; physiologically degradable compositions such as gelatin; aqueous excipients and solvents; oily excipients and solvents; a suspending agent; a dispersing or wetting agent; an emulsifier; moistening the medicinal herbs; a buffering agent; salt; a thickener; a filler; an antioxidant; (ii) an antibiotic; an antifungal agent; a stabilizer; a pharmaceutically acceptable polymeric or hydrophobic material.

18. The composition of claim 13, wherein the pharmaceutical composition is formulated as a powder or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion.

19. The composition of claim 14, wherein the solid form comprises a tablet, caplet, hard or soft capsule, cachet, lozenge or troche.

20. The composition of claim 18, wherein the aqueous or oily suspension is made of the active ingredient non-sedating barbiturate and an aqueous or oily vehicle, and a liquid solution in which the active ingredient is dissolved in the aqueous or oily vehicle.

21. The composition of claim 20, further comprising suspending, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavoring, coloring and sweetening agents.

22. The composition according to claim 13, wherein the composition is prepared and packaged in the form of an oil-in-water emulsion or a water-in-oil emulsion.

23. Use of a pharmaceutical composition according to claim 13 in the manufacture of a medicament for providing neuroprotection.