CN1625401A

CN1625401A - Non-sedating barbituric acid derivatives

Info

Publication number: CN1625401A
Application number: CNA038029898A
Authority: CN
Inventors: 戴尼尔·A·莫罗斯; 丹尼拉·吉特曼
Original assignee: Taro Pharmaceutical Industries Ltd
Current assignee: Taro Pharmaceutical Industries Ltd
Priority date: 2002-01-30
Filing date: 2003-01-30
Publication date: 2005-06-08
Anticipated expiration: 2023-01-30
Also published as: CN1291720C; EP1485101A4; CN1896084A; IL163168A; CA2471436C; WO2003063872A1; EP1485101A1; CA2471436A1; JP2005516052A

Abstract

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.

Description

Non-sedating barbituric acid derivatives

Background of invention

The present invention relates to new non-sedating barbituric acid derivatives, comprise their pharmaceutical composition, and under the situation of cerebral ischemia, head trauma and other acute nerve injury the method for neuroprotective, and the neuronal damage that produced of prevention.The invention still further relates to the purposes of non-sedating barbituric acid derivatives, it gives effective dose in some way, makes these medicines and/or the enough concentration of their active metabolite generation in blood and the brain, so that therapeutical effect to be provided.

Since 19th century not since 20 beginnings of the century, barbituric acid and its derivant have a pharmacological property with regard to known, and some in them are used as active component in many medicines.Known barbituric acid derivatives is mainly as tranquilizer, sleeping pill and anesthetis.Some derivant also has anticonvulsant action, therefore is used for the treatment of epilepsy.Therefore, at present, the pharmaceutical composition that contains 5-ethyl-5-phenyl barbituric acid (phenobarbital) is widely used in treating the medicine of epilepsy.But as other barbituric acid derivatives, phenobarbital also has calmness and syngignoscism, and this is a shortcoming in the epilepsy treatment.Therefore, people make great efforts to seek such chemical compound, and it has anticonvulsant properties and does not have calmness and syngignoscism simultaneously.

For example, a kind of known barbituric acid derivatives be S.M.McElvain at J.Am.Chem.Soc.57, disclosed 5 in 1303 (1935), the 5-5,5-Diphenylbarbituric acid, this piece document is this whole being incorporated herein by reference.Find that this chemical compound only is only effectively, does not therefore mention that the pharmacology uses in very heavy dose of.People such as Raines are report in Epilepsia 20,105 (1979): 5, and the 5-5,5-Diphenylbarbituric acid has anticonvulsant action to Rodents, is relative short-term but shortcoming is an activity, and this piece document is this whole being incorporated herein by reference.Other non-sedating barbituric acid derivatives has been disclosed in the US4 of Levitt, 628,056 and people such as Gutman on January 31st, 2002 disclosed WO 02/007729Al, wherein each piece document is this whole being incorporated herein by reference.

In the U.S., ischemia (apoplexy) is to cause dead the third-largest main cause.When the blood of supplying with brain is reduced to a certain threshold limit value when following, a series of biochemical events take place, cause irreversible damage of neuron and cerebral infarction.People have carried out research widely to treatment and prevention ischemia, but unfortunately, also rest on foundation phase at present, still there is not suitable Therapeutic Method (StrokeTherapy:Basic clinical and pre-clinical directions in practice, Leonard P.Miller, ed. (Wiley1999)).

The barbital (barbiturates) that has proved high concentration has neuroprotective to the cerebral ischemia of Rodents and primates, can reduce the degree of ischemic cerebral infarction, and prevention or minimizing brain injury (Hoff JT, Smith AL, Hankinson HL, Nielsen SL, Stroke 1975,6:28-33; Levy DE, BrierleyJB.Delayed pentobarbital administration limits ischemia brain damage in gerbils; Lightfoote WE II, Molinari GF, Chase TN, Stroke 1977,8:627-628; Corkill G, Chikovani OK, McLeish I, McDonald LW, Youmans JR, Surg.Neurol.1976,147-149).How to prevent a kind of theory of neuronal damage to be about barbital under ischemic situation: their suppress the uncontrolled property release of the neurotransmitter that brought out by ischemia, it can reach high, neurotoxic concentration, this concentration can cause neuronal death (Bhardwaj A, Brannan T, Weinberger J, J Neural Transom 1990,82:111-117).

Document about the neuroprotective of narcoticness barbital existed before 20 years, but because its toxicity uses barbital to be subjected to strictly limiting clinically.The concentration that gives in the required dosage of neuroprotective and blood and the brain is toxic, causes lethargy, numb and stupor.May more effective more high dose be fatal (Hoff JT, Smith AL, Hankinson HL, Nielsen SL, Stroke 1975,6:28-33; Levy DE, Brierley JB.Delayed pentobarbital administration limitsischemia brain damage in gerbils; Lightfoote WE II, Molinari GF, Chase TN, Stroke 1977,8:627-628; Corkill G, Chikovani OK, McLeish I, McDonald LW, Youmans JR, Surg.Neurol.1976,147-149; Masuda Y, Utsui Y, Shiraishi Y, Karasawa T, Yoshida K, Shimizu M., Epilepsia 1979,20:623-633.), make barbital not be suitable for treating ischemia (Hoff JT, Smith AL, Hankinson HL, Nielsen SL, Stroke 1975,6:28-33).These toxic and side effects are set up a kind of " function maximum " on the dosage of barbital, it has hindered further research to use narcoticness/calmness barbital to prevent ischemia.

People such as Levitt are at U.S.4, have described non-sedating oxo pyrimidine derivatives and they purposes as anticonvulsant, antianxiety drugs and muscle relaxant in 628,056.The document does not hint uses such chemical compound as the neuroprotective medicament.Really, even do not mention non-sedating barbital chemical compound about the research of using the calmness barbital to be used for neuroprotective disclosed yet.People generally believe: the convulsion of barbital and neuroprotective and their sedative/hypnotic effect link together.For example, people such as Lightfoote mention: the protective effect of pentobarbital be because the continuing of the inductive anesthesia of barbital (Lightfoote WE II, Molinari GF, Chase TN, Stroke 1977,8:627-628).This viewpoint is proved by the Biochemical Research of cell receptor level, and all these effects are relevant with the effect on the GABA receptor.Therefore, because their toxicity, prior art is not instructed and is used the calmness barbital to be used for neuroprotective, because they do not have calmness or anesthesia character, prior art is not instructed yet and used the non-sedating barbital as neuroprotective.

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

For example, U.S.6,093,820, it has described N this whole being incorporated herein by reference, N-dimethoxy-methyl-5, synthetic (formula I, the R of 5-5,5-Diphenylbarbituric acid ¹=R ²=CH ₂OMe and R ³=R ⁴=Ph).U.S.4,628,056, it has described the another kind of synthetic method of this chemical compound this whole being incorporated herein by reference.

Summary of the invention

Therefore, the purpose of this invention is to provide and new have long-acting neural activity and without any the non-sedating barbituric acid derivatives of hypnosis and sedation significantly.Neural activity can comprise neuroprotective, anti-stress and antitonic, convulsion, epilepsy outbreak, of flaccid muscles, anti-nervous and anxiety.

Non-sedating barbituric acid derivatives of the present invention is also referred to as the non-sedating barbital, has the structure of following general formula I

R wherein ¹And R ²Can be identical or different, and be hydrogen independently;

Low alkyl group optional is replaced by low-grade cycloalkyl, acyl group, acyloxy, aryl, aryloxy group, lower alkoxy, alkylthio group or arylthio, amino, alkyl amino, dialkyl amido or one or more halogen atom;

Phenyl;

CH ₂XR ⁵, wherein X is S or O, R ⁵Be low alkyl group, aryl or alkaryl (for example benzyl);

C (O) XR ⁶, wherein X as defined above, R ⁶Be low alkyl group or aryl;

CXR ⁷, wherein X as defined above, R ⁷Be hydrogen, low alkyl group or aryl; With

CH (XR ⁸) ₂, wherein X as defined above, R ⁸Be low alkyl group, condition is R ¹And R ²In at least one be not hydrogen.

R ³And R ⁴Can be identical or different, and be hydrogen independently; Optional one or more N of being selected from, S and the heteroatomic aryl of O of containing; Low-grade acyloxy; Phenyl; By the phenyl of halogen, low alkyl group, lower acyl or derivatives thereof or acetamido replacement; Benzyl; On the ring by one or more halogens, low alkyl group or benzyl that both replace; Optional one or more N of being selected from, O and the heteroatomic cycloalkyl of S of containing; Low alkyl group; Or the low alkyl group that is replaced by aromatics part.R ³And R ⁴In at least one be aromatic ring or the part that contains aromatic ring (an aromatic ring containing moiety).Low alkyl group is meant and has 8 or the branched-chain or straight-chain alkyl of carbon still less as used herein.Alkyl also is included in has one or two pair key or triple-linked alkyl in the carbochain.The present invention also comprises the salt of above-claimed cpd.In chemical compound of the present invention and salt,

1. work as R ¹And/or R ²When being methoxy, R ³And R ⁴Not all be phenyl, the phenyl that is not all replaced by low alkyl group and the phenyl that is not all replaced by halogen; With

2. work as R ³And R ⁴One of when being phenyl or benzyl, R ³And R ⁴In another be not ethyl; With

3. work as R ¹And R ²In at least one when being benzyl, work as R so ³And R ⁴One of when being phenyl, R ³And R ⁴In another be not pi-allyl; With

4. work as R ¹And R ²In one be methyl and another when being hydrogen, work as R so ³And R ⁴One of when being phenyl, R ³And R ⁴In another be not unsubstituted low alkyl group; With

5. work as R ¹=R ²=R ^aThe time, R wherein ^aBe alkoxy methyl or (acyloxy) methyl, work as R so ³And R ⁴One of when being the 1-phenethyl, R ³And R ⁴In another be not propionyloxy.

In addition, about combination, following compounds is not included in the scope of the present invention, but can use in the method for the invention.

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

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

C) 1,3,5-triphenyl barbituric acid and

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

In some exemplary embodiments, R ¹And R ²In at least one low alkyl group that is replaced by low-grade cycloalkyl, acyl group, acyloxy, aryl, aryloxy group, alkylthio group or arylthio, amino, alkyl amino, dialkyl amido or one or more halogen atom; Phenyl; CH ₂SR ⁵, R wherein ⁵Be low alkyl group, aryl, alkaryl or benzyl; C (S) XR ⁶, wherein X is S or O and R ⁶Be low alkyl group or aryl; CSR ⁷, R wherein ⁷Be hydrogen, low alkyl group or aryl; And CH (SR ⁸) ₂, R wherein ⁸It is low alkyl group.

In other exemplary embodiment, R ³And R ⁴In at least one be low-grade acyloxy; By the phenyl of lower acyl or derivatives thereof or acetamide replacement; And optional one or more N of being selected from, O and the heteroatomic cycloalkyl of S of containing of ring.

In some exemplary embodiment of the present invention, substituent R ¹And R ²Be different and be selected from butyl, benzyl, thiophenyl methyl, cyclopropyl methyl, 3,3,3-trifluoro propyl, benzyloxymethyl and alkoxy methyl respectively.In other exemplary embodiment, R ¹And R ²Be identical and be selected from butyl, benzyl, thiophenyl methyl, cyclopropyl methyl, 3,3,3-trifluoro propyl, benzyloxymethyl and alkoxy methyl.In other exemplary embodiment, R ¹And R ²One of be hydrogen, R ¹And R ²In another be selected from alkoxy methyl, butyl, benzyl, thiophenyl methyl, cyclopropyl methyl, 3,3,3-trifluoro propyl and benzyloxymethyl.

In other exemplary embodiment, R ¹And R ²In at least one be methoxy.In other exemplary embodiment, R ³And R ⁴Two all is aromatic ring or the part that contains aromatic ring.

In some exemplary embodiment, R ³And R ⁴Be identical or different and be phenyl independently; By the phenyl of halogen or low alkyl group replacement; Optional one or more N of being selected from, S and the heteroatomic cycloalkyl of O of containing; Benzyl; On the ring by one or more halogens, low alkyl group or benzyl that both replace; Low alkyl group; Or the low alkyl group that is replaced by aromatics part, condition is R ³And R ⁴In at least one be the phenyl of phenyl or replacement.

In other exemplary embodiment, R ³And R ⁴In at least one be selected from phenyl, benzyl, fluorophenyl and tolyl.

In other exemplary embodiment, R ³And R ⁴In at least one be selected from:

With

R ³And R ⁴Can be identical or different.

Non-sedating barbituric acid derivatives of the present invention can be delivered medicine to mammal, be used for the treatment of nervous and stress disease and delayed ischemic neurological deficits for example convulsions, epilepsy, muscle rigidity, nervous and anxiety.Give non-sedating barbituric acid derivatives of the present invention and can also obtain neuroprotective.

The present invention also comprises pharmaceutical composition, and it contains as the formula I chemical compound of active component and pharmaceutically acceptable carrier.

The present invention further provides a kind of goods, it comprises the container that contains pharmaceutical composition, and indication is used for the treatment of nervous and stress disease; Delayed ischemic neurological deficits is convulsions, epilepsy, muscle rigidity, nervous and anxiety for example; and/or as the label of neuroprotective, this pharmaceutical composition comprises non-sedating barbital chemical compound and pharmaceutically acceptable carrier or the excipient that the pharmacology goes up effective dose.

Detailed description of the invention

In the embodiment that the present invention describes, for the sake of clarity, use special term.Yet the present invention is not subjected to the restriction of selected buzzword.Should be appreciated that each proper name comprises all technical coordinates, it is operated in a similar manner to obtain similar purpose.Without departing from the invention, persons skilled in the art are according to above-mentioned instruction, can modify or change above-mentioned embodiment of the present invention, and add or leave out key element.Here every piece of list of references quoting all is incorporated herein by reference respectively.

People such as Levitt are at U.S.4, have described non-sedating oxo pyrimidine derivatives and they purposes as anticonvulsant, antianxiety drugs and muscle relaxant in 628,056.Levitt also described some 1,3-two replaces-5, the preparation of 5-5,5-Diphenylbarbituric acid derivant.The diphenyl substituent group of Levitt can further be replaced by low alkyl group or halogen.People such as Gutman are at U.S.6, have described N-alkylation uride in 093,820 and have been used to prepare single-and the method for the barbituric acid derivatives that replaces of two-N.The method of the disclosure can be used to prepare the chemical compound that uses in the present invention.People such as Gutman are in WO 02/007729 Al, and it has described use non-sedating barbital chemical compound as neuroprotective this whole being incorporated herein by reference.

Term " non-sedating barbituric acid derivatives " comprises barbituric acid convulsion chemical compound and derivant and analog and its salt with following general formula I as used herein,

R wherein ¹And R ²Can be hydrogen identical or different and independently;

Phenyl;

C (O) XR ⁶, wherein X as defined above, R ⁶Be low alkyl group or aryl;

R ³And R ⁴Can be hydrogen identical or different and independently; Optional one or more N of being selected from, S and the heteroatomic aryl of O of containing; Low-grade acyloxy; Phenyl; By the phenyl of halogen, low alkyl group, lower acyl or derivatives thereof or acetamido replacement; Benzyl; On the ring by one or more halogens, low alkyl group or benzyl that both replace; Optional one or more N of being selected from, O and the heteroatomic cycloalkyl of S of containing; Low alkyl group; Or the low alkyl group that is replaced by aromatics part.R ³And R ⁴In at least one be aromatic ring or the part that contains aromatic ring.Low alkyl group is meant and has 8 or the branched-chain or straight-chain alkyl of carbon still less as used herein.Alkyl also is included in has one or two pair key or triple-linked alkyl in the carbochain.The present invention also comprises the salt of above-claimed cpd.For noval chemical compound of the present invention and salt,

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

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

C) 1,3,5-triphenyl barbituric acid and

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

In some exemplary embodiment of the present invention, substituent R ¹And R ²Be different and be selected from butyl, benzyl, thiophenyl methyl, cyclopropyl methyl, 3,3,3-trifluoro propyl, benzyloxymethyl and alkoxy methyl respectively.In other exemplary embodiment, R ¹And R ²Be identical and be selected from butyl, benzyl, thiophenyl methyl, cyclopropyl methyl, 3,3,3-trifluoro propyl, benzyloxymethyl and alkoxy methyl.In other exemplary embodiment, R ¹And R ²One of be hydrogen, R ¹And R ²In another be selected from alkoxy methyl, butyl, benzyl, thiophenyl methyl, cyclopropyl methyl, 3,3,3-trifluoro propyl and benzyloxymethyl.In other words, R ¹And R ²One of be hydrogen, R ¹And R ²In another be selected from:

-CH ₂-O-(CH ₂) _n-CH ₃，n≥0；

-CH ₂-CH ₂-CF ₃With

In some exemplary embodiment, R ³And R ⁴Be identical or different and be phenyl independently; By the phenyl of halogen or low alkyl group replacement; Optional one or more N of being selected from, S and the heteroatomic cycloalkyl of O of comprising; Benzyl; On the ring by one or more halogens, low alkyl group or benzyl that both replace; Low alkyl group; Or the low alkyl group that is replaced by aromatics part, condition is R ³And R ⁴In at least one be the phenyl of phenyl or replacement.

In other exemplary embodiment, R ³And R ⁴In at least one be selected from:

With

R ³And R ⁴Can be identical or different.

R ¹And R ²Can be used as nontoxic leaving group, they can be removed in biosystem to produce pharmacological active substance.Lose R relatively lentamente ¹And/or R ², make the metabolic half-life of pharmacological active substance in mammal prolong.To R ³And R ⁴Select, so that the pharmacologically active chemical compounds of gained does not have the sedative properties relevant with barbituric acid derivatives usually.The modified model of the test described in embodiment 3 can be used as test method and is used to differentiate that those do not have the chemical compound of relevant with barbituric acid derivatives usually sedative properties.For example, if give the experimental animal of chemical compound the stimulation that major part applies is not reacted, this chemical compound can be understood that to have sedative properties so.Has specific R by test ³And R ⁴Substituent chemical compound can be differentiated the chemical compound with relevant with barbituric acid derivatives usually sedative properties.

Report (Rains A, Moros D et al., J.Exp.Biol. (Abstracts) 1996,895; Epilepsia 1996, and 37:Suppl.5): N, N '-dimethoxy-methyl-5,5-5,5-Diphenylbarbituric acid metabolic degradation are 5,5-Diphenylbarbituric acid (DPB).Learn that also mechanism of degradation comprises generation mono methoxy methyl intermediate.According to the present invention, the R that N-replaces ¹/ R ²Group can split in metabolism, produces R ³/ R ⁴The chemical compound or the R that have list or do not have N to replace that replace ¹/ R ²Group can remain attached in the reactive compound.

Those chemical compounds that do not have adverse side effect are preferred.The example of adverse side effect is a toxicity, and it can be estimated by the method for embodiment 2, and sedation, and it can be estimated by the method for aforesaid embodiment 3.

By following reaction: with suitable 5, two (replacement) barbituric acids of 5-and alkali metal hydride reaction are to prepare corresponding barbital, then with this barbital with the part with leaving group according to people such as Samour at J.Med.Chem.14, the similar approach of describing in 187 (1971) is reacted, displacement 1 and 3 substituent groups, thereby can prepare of the present invention 1, two (replacements)-5 of 3-, 5-two replacement barbituric acids.In method more generally, single-and two-chemical compound of replacing can be according to U.S.6, and 093,820 and its method preparation of describing in revising.Usually, 5, dibasic barbituric acid derivatives of 5-and excessive alkali react.If required then is mono-substituted derivant, the dianion of formation and 1 normal alkylating reagent react, if required be that dianion and the 2 normal alkylating reagents that dibasic derivant forms so react.

Substituent group on 5 can be by being prepared alloxan and suitable starting material according to the mode that is similar to the preparation 5,5-Diphenylbarbituric acid that above-mentioned McElvain describes.These substituent groups can also be positioned at 1, on two (the replacements)-barbituric acids of 3-, and by acid oxidase being become corresponding 1,3-dialkyl group alloxan, itself and suitable compound are reacted the product that obtains needs in a similar manner then.

The chemical compound that exists with free acid form can be translated into for example last acceptable salt of sodium, potassium or other pharmacology of salt by persons skilled in the art technique known.

Persons skilled in the art can easily be selected suitable synthetic method, perhaps by the known normal experiment of those of ordinary skill in the synthetic field of organic chemistry, can easily derive out.Noval chemical compound of the present invention is not subjected to the restriction of their preparation method, but can be prepared by method described here, known other method of persons skilled in the art or the method that awaits to develop.

Term " treatment " comprises and prophylactically gives chemical compound of the present invention with prevention or suppress undesirable disease as used herein, and therapeutic ground gives chemical compound of the present invention to eliminate or the degree or the symptom of minimizing disease.Treatment of the present invention suffers from human or other mammal of this treatment of needs of disease or disease.Treatment also comprises chemical compound is applied to cell in vitro or organ.Treatment can be general or topical.

Non-sedating barbituric acid derivatives of the present invention can be mixed with " pharmaceutical composition " with suitable pharmaceutically acceptable carrier, excipient or diluent.If it is suitable, pharmaceutical composition can be mixed with preparation and include but not limited to solid, semisolid, liquid or gas form, for example tablet, capsule, powder, granule, unguentum, liquor, suppository, injection, inhalant and aerosol are used for their route of administration separately in common mode.

Effective dose is in order to reach the quantity of the required active component that gives with single dose or multiple dose of ideal pharmacotoxicological effect.For individual patient, skilled doctor can determine and the optimization effective dose, perhaps treats individual disease by skilled doctor known normal experiment and titration.Depend on whether compositions gives with other medicines, or depend on the difference of the pharmacokinetics, disposition of drug and the metabolism aspect that exist between individuality, actual dose and drug dosage schedule table can change.Similarly, the quantity of external application also can change.Persons skilled in the art can be regulated dosage by needs as the case may be, do not need over-drastic experiment.Dosage range disclosed herein is not got rid of the component of using higher or lower dosage, can go through to use when concrete the application.

Sacred disease comprises nervous and stress disease and delayed ischemic neurological deficits for example convulsions, epilepsy, muscle rigidity, nervous and anxiety.Chemical compound of the present invention can be used as anticonvulsant, so it can use in the treatment of epilepsy.Chemical compound of the present invention can also be used for the treatment of cerebral ischemia, head trauma and other acute nerve injury as neuroprotective, and the neuronal damage that produced of prevention.These chemical compounds can the individuality that carries out operation on heart or carotid endarterectomy and since being in the individuality among auricular fibrillation, transient ischemic attack (TIA) (TIA), cerebral ischemia, bacterial endocarditis, apoplexy or the subarachnoid hemorrhage danger of causing of cerebral aneurysm use.Chemical compound can also use after the generation acute events.

The doses available that is used for the non-sedating barbital of neuroprotective purpose can exceed the minimum anticonvulsant dosage of barbital.In some embodiments of the present invention, the doses available of non-sedating barbital anticonvulsant dosage about 2 times to about 5 times scope.But in other context, if mammal needs, the effective dose that is used for the non-sedating barbital of neuroprotective purpose is about 5 times to about 10 times of anticonvulsant dosage, or even higher, needing only dosage is acceptable clinically.Especially, doses available can exceed the barbital dosage of phenobarbital for example that produces sedation, and can exceed the dosage that produces stupor or the phenobarbital when dead.

The neuroprotective of this method can be used for alleviating the influence that cerebral ischemia causes.The non-sedating barbital can perhaps pass through microgranule or aerosol inhalant through the lung administration with the adjuvant per os, by intravenous, through the skin administration.In addition, within the scope of the invention, can be prophylactically or therapeutic ground give the non-sedating barbital with acceptable dosage clinically.Before significantly neuronal damage occurs, can prophylactically give this chemical compound, perhaps after beginning, neuronal damage can give to therapeutic this chemical compound.Neuroprotective reduces, and perhaps protects the patient to avoid by head trauma or the caused neuronal damage of cerebral ischemia.Can in operation on heart or carotid endarterectomy, give this chemical compound.Mammalian subject may have or be in the risk of auricular fibrillation, transient ischemic attack (TIA) (TIA), bacterial endocarditis, apoplexy, head trauma or subarachnoid hemorrhage.

Usually; in order to obtain neuroprotective; give the non-sedating barbital of sufficient dosage; the haemoconcentration that makes barbital or its active metabolite 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 can be up to 200-300 μ g/ml, or even it is higher.By contrast, the therapeutic domain of the phenobarbital of having reported is lower, and its haemoconcentration is 10-30 μ g/ml.Therefore, preferred range is for being equal to or greater than about 25,30,50,75,100,200,250 or 300 μ g/ml.Similarly dosage is suitable for other medicines effect described here.

The present invention includes a kind of pharmaceutical composition, it comprises the non-sedating barbital, and it has the neurological effect when giving this non-sedating barbital with effective dose.Preferably, the dosage of orally give non-sedating barbital is about 1 at about 25-, in the scope of 500mg/kg/ days body weight.Preferably, dosage is greater than about 50mg/kg/day, perhaps greater than about 100mg/kg/ days, perhaps greater than 250mg/kg/day.Preferred dosage be with about 1000mg/kg/ days dosage in mouse on the pharmacology quite.Therefore, dosage form can be single dose or multiple dose, so that dosage is equal to or greater than about 1,5,10,15,20,25,50,70,100,250,500,1000 or 1500mg/kg body weight every day.As for other therapeutic use, greater than about 0.1,0.5,1,5 or 10mg/kg body weight scope every day in be suitable than low dosage, be well-known about other dosage of barbital.

Barbituric acid derivatives of the present invention has the half-life that has prolonged in the mankind, make that lower oral dose just can obtain appreciable haemoconcentration.For example, about 40 to about 100mg/kg/ days dosage can make the haemoconcentration of non-sedating barbital reach greater than 100 μ g/ml, and within the scope of the invention.Give the non-sedating barbital with daily dose parenteral, obtain similar haemoconcentration less than 25mg/kg/ days.But first day loading dose still need be greater than the predose of 25mg/kg.

People generally believe the neurological effect of barbital, for example convulsion and neuroprotective, with their sedative/hypnotic effect be associated.For example, people such as Lightfoote are at Stroke 8, and 627-628 mentions in (1977): the protective effect of pentobarbital is because the result of the inductive anesthetic action continuity of barbital.This viewpoint is proved by the Biochemical Research of cell receptor level, and all these influence with relevant to the effect of GABA receptor.Therefore, because their toxicity, prior art is not instructed and is used the calmness barbital to be used for neuroprotective, because they do not have calmness or anesthesia character, prior art is not instructed yet and used the non-sedating barbital as neuroprotective.

The present invention also provides pharmaceutical composition, and it comprises as the chemical compound of the above-mentioned general formula I of active substance or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, excipient or diluent.Any routine techniques can be used to prepare pharmaceutical preparation of the present invention.After active component can be included in and deliver medicine to the patient, can provide rapid release, continue to discharge or postpone in the preparation of release.

Useful in the method for the invention pharmaceutical composition can be to be suitable for per os, formulation preparation, packing or sale through parenteral and local administering mode.The preparation of other consideration comprises nanoparticle, Liposomal formulation, contain the erythrocyte that reseals of active component and based on the preparation of immunity.

The preparation of pharmaceutical composition described here can be by any method preparation known or exploitation in the future.Usually, preparation comprises active component and carrier or one or more other supplementary elements mixed, if necessary or needs, and with product shaping or be packaged in the required single dose or multiple dose unit.

Usually, for medicine anticonvulsant drug particularly, prolonging activity is a kind of important properties.Except that allowing uncommon administration, it can also improve the compliance of patient to medicine.In addition, the serum of long-acting chemical compound and tissue concentration, it is crucial for keeping curative effect, and is more stable.In addition, stable serum-concentration has reduced the incidence rate of sudden (break-through) epilepsy invasion rate and possible other side effect.

" supplementary element " includes but are not limited to as used herein, the material below one or more: excipient; Surfactant; Dispersant; Inert diluent; Granulating agent and disintegrating agent; Binding agent; Lubricant; Sweeting agent; Flavoring agent; Coloring agent; Antiseptic; Degradable compositions gelatin for example on the physiology; Aqueous excipient and solvent; Oil-containing excipient and solvent; Suspending agent; Dispersant or wetting agent; Emulsifying agent; Demulcen (demulcents); Buffer agent; Salt; Thickening agent; Filler; Emulsifying agent; Antioxidant; Antibiotic; Antifungal agent; Stabilizing agent; Pharmaceutically acceptable polymeric or hydrophobic material and other component.

Though the description at this pharmaceutical composition that provides mainly is meant the pharmaceutical composition that is suitable for human administration, persons skilled in the art should be understood that based on this open, such compositions and also are suitable for giving any mammal usually.The preparation of compositions that is fit to give various animals is fine understanding, and based on giving human pharmaceutical composition, by normal experiment, the veterinary pharmacology man of ordinary skill can design and carry out this change.

Pharmaceutical composition of the present invention can be with form preparation, packing or the sale of single unit dose or a plurality of single unit dose." unit dose " is the discrete amount that comprises the pharmaceutical composition of the active component that pre-determines quantity as used herein.In per unit dosage, the quantity of active component is generally equal to and will or equals the appropriate fraction of accumulated dose by the total amount of the active component of administration, for example half of this dosage or three/

The preparation that is suitable for peroral administration pharmaceutical composition of the present invention can exist with the form of separating (discrete) solid dosage unit.Solid dosage unit for example comprises tablet, Caplet (caplet), hard or soft capsule, cachet, lozenge or lozenge.Each solid dosage unit contains the active component that pre-determines quantity, for example unit dose or its mark.Other preparation that is suitable for administration includes but are not limited to, powder or granular preparation, moisture or contain oil suspension, moisture or oil-containing solutions or Emulsion." oily liq " is meant that it contains polarity the liquid based on carbon or silicon littler than water as used herein.

The tablet that contains active component for example can make by compression or the molded optional active component that contains one or more annexing ingredients.Tabletting can make by compressing in suitable device, and active component is with a kind of form of free-flow shape for example powder or granular preparation, optional and one or more binding agents, lubricant, fluidizer, excipient, surfactant and dispersant.Molded tablet can make by molded mixture in suitable device, and this mixture is active component, pharmaceutically acceptable carrier and the enough at least mixtures of liquids that are used for wet mix.

Tablet can be not coating or they can use known in the art maybe with the exploitation method carry out coating.In order to delay the disintegrate in experimenter's gastrointestinal tract, for example can use enteric coating to be mixed with coated tablet, obtain the lasting release and the absorption of active component thus.In order to obtain pharmaceutically exquisite and good to eat preparation, tablet can also comprise sweeting agent, flavoring agent, coloring agent, antiseptic or these some combinations.

Can use degradable compositions on the physiology for example the gelatin preparation contain the hard capsule of active component.This hard capsule comprises active component, and can comprise annexing ingredient and for example comprise inert solid diluent.Can use degradable compositions on the physiology for example the gelatin preparation contain the soft capsule of active component.This soft capsule comprises active component, and it can mix with water or oily medium.

The liquid preparation that is suitable for the pharmaceutical composition of the present invention of administration can be with form preparation, packing and the sale of liquid form or dryed product, and wherein dryed product is prepared again with water or another kind of suitable excipient before use.

Liquid suspension, wherein active component be dispersed in moisture or the oil-containing excipient in, and liquid solution, wherein active component be dissolved in moisture or the oil-containing excipient in, can use the method preparation of conventional method or exploitation in the future.The liquid suspension of active component can be in moisture or butyraceous excipient, and may further include one or more annexing ingredients for example suspending agent, dispersant or wetting agent, emulsifying agent, demulcen, antiseptic, buffer agent, salt, flavoring agent, coloring agent and sweeting agent.Contain oil suspension and can further comprise thickening agent.The liquid solution of active component can be in moisture or oil-containing excipient, and may further include one or more annexing ingredients for example antiseptic, buffer agent, salt, flavoring agent, coloring agent and sweeting agent.

Powder of the present invention and granular preparation can use known in the art maybe with the exploitation method be prepared.Such preparation can directly give the experimenter, perhaps for example forms tablet, is filled in the capsule or by to wherein adding moisture or the oil-containing excipient, is prepared into moisture or contains oil suspension or solution gives the experimenter again.Powder or granular preparation can further comprise one or more dispersants or wetting agent, suspending agent and antiseptic.Other excipient for example filler and sweeting agent, flavoring agent or coloring agent also can join in these preparations.

Pharmaceutical composition of the present invention can be with form preparation, packing or the sale of oil-in-water emulsion or water-in-oil emulsion.Such compositions can further comprise one or more emulsifying agents.The component that these Emulsions can also contain other for example comprises sweeting agent or flavoring agent.

For example can set forth among the following non-limiting Examples 1-3 by convulsions, epilepsy, muscle rigidity, effect nervous and anxiety about nervous and pressure disease and delayed ischemic neurological deficits for The compounds of this invention.Similarly, the neuroprotective ability of chemical compound for example can be by testing with reference to the conventional method of non-limiting example 5-7 elaboration in the non-limiting example 4 and specifically.Other is known maybe can be used for testing chemical compound of the present invention similarly with the method that is developed.

Chemical compound of the present invention can use normally methods known in the art or its improvement to be prepared by two general synthetic routes, and it does not need undue experimentation just can be obtained at an easy rate by the common those skilled in the art in this area.The exemplary method of various steps for example can be at Loudon, G.M., OrganicChemistry, Addison-Wesley, 1984; People's such as Levitt (1986) U.S.4,628,056; People's such as Gutman (2000) U.S.6,093,820; EP 1,083 172 Al of Ashkinazi (2001); With people's (1998) such as Krummel U.S.5, find in 750,766, each of these documents is this whole being incorporated herein by reference.Scheme 1 is the retrosynthetic analysis general introduction route of The compounds of this invention.

The chemical compound of formula I can be by suitable replacement the N-alkylation preparation of barbituric acid derivatives (formula II).The alkylating suitable exemplary method of the N-of barbituric acid provides among embodiment 8a, 8b, 9a, the 9b, 10,11 and 12 below.Other known method is that persons skilled in the art are known and also can be used.The required barbituric acid derivatives of formula II can be by urea and suitable replacement the condensation reaction preparation of malonate (formula III).In the synthetic route (referring to embodiment 8c) of a kind of selectivity, the barbituric acid derivatives of formula I can be by the urea (formula IV) of replacement and malonate (III) prepared in reaction of suitable replacement.The preparation of the urea that replaces is known.The method for preparing the formula III chemical compound also is known in the art.The suitable exemplary method for preparing them, wherein R ³And/or R ⁴Can be substituted, in embodiment 13-16, provide.Other method is that persons skilled in the art are known and also can be used.

Scheme I

Embodiment 1

Prevent maximal electroshock seizure (MES) by the mouse of estimating treatment, can prove or test the anti-convulsant activity of barbituric acid derivatives of the present invention.Mainly be that the MES test extensively is used to the anticonvulsant properties of assessing compound because have good dependency between the clinical discovery of effect in test result and the trouble epilepsy patients.In a typical MES test, wherein use Corneal electrode, the stimulation of about 150 milliamperes electric current and 60 hertz applies about 200 milliseconds, estimates the anticonvulsant properties of barbituric acid derivatives of the present invention.Administration Pretesting mouse, so that eliminating is any from research tonic convulsion is completely comprised the animal that THE (THE) is not reacted, it uses the basis of the effect of the used active substance that judges.It is shielded that the animal that protected by THE is considered in the MES test.

Test composition is dissolved in warm PEG400 or other the suitable solvent, and this solution for example gives the Sprague-Dawley mouse with the initial dose of about 500mg/Kg by stomach tube.The scheduled time of these animals after administration, for example after the administration about 6 and 23 hours, test maximal electroshock seizure (MES).Before being accepted research, all animals all show complete maximum epilepsy to electricity irritation.

Embodiment 2

The avirulence of barbituric acid derivatives of the present invention can be tested by high dose administration repeatedly, and is as follows:

Test compounds is suspended in warm PEG400 or other the suitable solvent, for example gives the Sprague-Dawley mouse by stomach tube with the initial dose of about 1500mg/kg.Take similar dosage for after 24 hours identical mouse, administration for the first time took similar dosage for once more identical mouse after 48 hours.Animal is checked in administration after several hours, check animal before the next administration once more, to the last after the administration again through checking animal in 3 days.Monitor poisonous influence and for example motion of behavior effect, escape behavior, feed or any other observable effect of administration.

Embodiment 3

By monitoring behavior and the motion effect of treatment mouse, can prove the calm and muscle relaxant properties of barbituric acid derivatives of the present invention.

For example, can give test composition in the alkalization of the Swiss Webster mouse for example saline to intraperitoneal.Write down the required time of the various dosage of animals received to show specific motion and behavior effect.The supervision effect for example can comprise that muscle tone goes down, motor activity, peace and quiet and escape behavior.Toxic effect also is recorded.

The effect of compositions can mainly be estimated as skeletal muscle relaxant and/or calm medicine with respect to known.Calm effect and not damage in the medicament that being combined in of ability that animal reacts to its environment be used for treating anxiety be very ideal.Compositions of the present invention does not preferably show central nervous system's hypnotic activity or depression.

Embodiment 4Measure the general design of treatment ischemia effect

Non-sedating barbituric acid derivatives of the present invention (NSB) can be tested the mouse that is under the reversible or irreversible ischemia condition.Mouse is given the medicine of various dose.Neuroprotective is compared with the positive control pentobarbital with negative control (placebo), but wherein pentobarbital is a kind of barbital of known neuroprotective calmness, reduces infarct volume under known dose in cerebral ischemia.

Ischemic injury morbidity back several days, kill animals checks that brain to measure the volume of infarction of brain, reduces the measurement result of ischemic brain injury as medicine.Check animal clinically and before killing, carry out grade after determining ischemic " apoplexy ", whether medicine has given any wholesome effect to relevant function.

Preferred four neuroprotectives that experimental model is used to test the NSB medicine.Referring to GinsbergMD, " Animal Models of Global and Focal Cerebral Ischemia, " Chapter 34 inWelsh KMA et al., Primer on Cerebrovascular Diseases, Academic Press, NewYork, 1997; And Pulsinelli WA, Brierley JB, A new model of bilateralhemispheric ischemia in the unanesthetized rat, Stroke 1979, May-June10 (3): 267-72.These lists of references are hereby incorporated by.

1. stop up the irreversible ischemia that causes by middle cerebral artery (MCA);

2. stop up the reversible ischemia that causes by MCA;

3. by the temporary global ischemia that causes at the interval cross-clamp aorta of determining; And

4. by burning vertebral artery and reversibly vising the temporary full ischemia that common carotid artery causes.

In each experimental model, each is organized mouse and treats with following scheme:

1. give negative control thing (placebo) by nose stomach (NG) pipe;

2. positive control: intraperitoneal (IP), the pentobarbital of 70mg/kg dosage; Or

3. in experimental infarction preceding 7 days,, give NSB Compound D MMDPB (perhaps the tested chemical compound of its practicality) in the present invention with the dosage of 500mg/kg to 1500mg/kg by the NG pipe.

The result of Huo Deing relatively.

Embodiment 5The irreversibility cerebral ischemia

Cause that by ligation carotid artery irreversibility MCA stops up, animal is inserted into filament the root of MCA under halothane anesthesia then.Use the blood flow among Laser Doppler Velocimeter (laser Doppler) the mensuration MCA, significantly reduced those animals of blood flow are considered to suffer cerebral ischemia, and have the risk (being apoplexy) of damage subsequently.Those MCA blood flows do not suffer precipitate animal, just clinical apoplexy can not take place.All animals all show: the MCA blood flow reduces and will indicate and suffer apoplexy.

Then, observe the behavior that is in the animal in the danger, score by clinical discovery with Bederson evaluation yardstick:

0 does not have the evidence of apoplexy

1 minor stroke

2 moderate apoplexy

3 serious apoplexy

Kill the animal that those were survived three days, check their brain.Give for example chloral hydrate (35mg/kg IP, their brain be by 0.9% saline of intracardiac perfusion heparinization, then pours into 10% buffered formalin and fix) of the animal that will kill.Brain is shifted out from calvarium carefully, intactly keep arachnoidea and following intracranial vessel.For example under 80 ℃, that fixed brain is freezing.In cryostat, under-20 ℃, the coronal section that 20 μ m are thick cuts with the interval of 400 μ m, dries on 60 ℃ hot plate then, and photographic fixing in 90% ethanol (fix) 10 minutes is with hematoxylin and eosin (7) dyeing.Compare with the remainder of brain, the brain of infarction is pale.Determine the amount of infarction brain by the microexamination brain sections, and with mm ³Calculate Infarction volume.

Embodiment 6The reversibility cerebral ischemic model

The mode of mouse such as top embodiment 4 is carried out pretreatment,, blood flow is flow through beyond the MCA again, carry out similar method except removing the filament of inaccessible MCA after 30-60 minute.Then, mouse was observed three days clinically, the degree of their apoplexy of grade is killed mouse then as embodiment 5.Remove brain, check like that as mentioned above.

Embodiment 7

Mouse carries out pretreatment in the mode of top embodiment 4, then during etherization, by the axil hole of the atlas vertebral artery of mouse of fulgerizing.Then, reversible pincers are placed on loosely Carotid around.After 24 hours, handle the mouse that wakes, tight with carotid artery pincers pincers, cause the 4-blood vessel blockage.After the 4-blood vessel blockage 10-30 minute, remove pincers, by pouring into fixedly kill animals.Usually, untreated mouse shows the ischemic neuronal damage in 4-blood vessel blockage 20 or after 30 minutes.To a plurality of zones of forebrain, comprise H1 and other Hippocampus, striatum and the rear portion neopallium of hitting exactly, estimate.In these situations, NSB is proved to be to have neuroprotective.

Embodiment 8aThe preparation of single and two alkylating barbituric acids of N-

The chemical compound of formula II is dissolved in alcoholic acid potassium hydroxide solution.With alkyl halide R ' X, be dissolved in this solution and react.Obtain the product of formula I, wherein R ¹=R ²=R '.(Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，p.1194)

Embodiment 8bThe preparation of single and two alkylating barbituric acids of N-

The chemical compound of formula II is dissolved in alcoholic acid potassium hydroxide solution.With alkyl tosylate R ' OTs, be dissolved in this solution and react.Obtain the product of formula I, wherein R ¹=R ²=R '.(LoudonGM，Organic?Chemistry，Addison-Wesley(1984)，p.1194)

Embodiment 8cCondensation reaction by urea and malonate prepares single and two alkylating barbituric acid of N-

The urea that is replaced by alkyl on one or two amide is used as starting material (formula IV).If two replace, alkyl can be identical or different, and promptly first alkyl can be R ', and second alkyl can be R ' or R ", wherein R ' and R " be different.Then, for example diethyl malonate and Sodium ethylate react in ethanol for the urea of replacement and malonate (formula III).Obtain the product of formula I, wherein R ¹=R ' and R ²=H, R ' or R ".(Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，p.1087；Euro.Pat.Applic.No.1083?172Al)

Use and be described in similar methods among embodiment 8a, 8b and the 8c, can replace the R of formula I with alkyl with cycloalkyl, acyl group, acyloxy, aryl, aryloxy group, alkoxyl, alkylthio group, arylthio, amino, alkyl amino, dialkyl amido or halogen ¹And R ²

Embodiment 9aThe chemical compound of preparation N-alkoxyalkylization

Under 0 ℃, with dialkoxy methane (R ' OCH ₂OR ') joins in the acetyl methanesulfonates.The temperature of solution is risen to 25 ℃, and reaction was carried out 2 hours.Then, in 45 minutes, gained solution is joined gradually in the mixture of dry dimethyl formamide of the barbituric acid (formula II) of suitable replacement and sodium hydride (being dispersed in the mineral oil) with 60%.With gained reactant mixture stir about 15 minutes, with the hydrochloric acid dilution, then dilute then with ethyl acetate.Be separated, ethyl acetate is washed with aqueous sodium hydroxide washes then with the saturated sodium-chloride water solution washing.Then, ethyl acetate filters and is concentrated into dried through anhydrous sodium sulfate drying.Then, with the toluene crystallization of exsiccant product, obtain the chemical compound of formula I structure, wherein R ¹=R ²=CH ₂OR.(U.S.Pat.No.6,093,820)

By using different barbituric acid derivatives, can change R as starting material ³And R ⁴Group.

By using excessive sodium hydride and 1 normal alkylating reagent, help forming single product that replaces, therefore most of product is made up of formula I, wherein R ¹And R ²One of be substituted by CH ₂OR ', R ¹And R ²Another replaced by hydrogen.

Embodiment 9bSelectivity prepares the chemical compound of N-alkoxyalkylization

(formula II) is dissolved in the dimethyl formamide with suitable barbituric acid.Solution is cooling in a single day, to wherein adding sodium hydride, then mixture is stirred 30 minutes.In about 30 minutes, in mixture, add suitable chloromethyl alkyl ether.Then, reactant mixture was stirred 1 hour, be poured in the frozen water then.Filter solid precipitation, wash with water, and carry out crystallization with ethanol.(U.S.Pat?No.4,628,056)

By using different chlorinated ether, R ¹And R ²Can replace with different alkoxide.For example, can generate R ¹=R ²=CH ₂The group of OR ', wherein R ' is alkyl, aryl, alkaryl or benzyl.By using chlorination thioether, R ¹And R ²Can replace with alkylthio group.For example, can generate R ¹=R ²=CH ₂The group of SR ', wherein R ' is alkyl, aryl, alkaryl or benzyl.

Embodiment 10The preparation of the barbituric acid that single and two N-acyloxy replace

Chemical compound and the alkyl chloroformate of formula II are dissolved in the solution that contains sodium hydroxide together.Obtain the product of formula I, wherein R ¹=R ²=C (O) OR ', wherein R ' is an alkyl.

The chemical compound of through type II and chloro-carbonic acid aryl ester react in containing the solution of sodium hydroxide, obtain the product of formula I, wherein R ¹=R ²=C (O) OR ', wherein R ' is an aryl.(Loudon，pp.1061-1064)

The chemical compound of the chemical compound of through type I and formula ClC (O) SR ', wherein R ' is an alkyl or aryl, reacts, and obtains the product of formula I, wherein R ¹=R ²=C (O) SR ', wherein R ' is an alkyl or aryl.

Embodiment 11The preparation of the barbituric acid of N-acyl substituted

The chemical compound of formula II dissolves with the acid chloride of formula ClC (O) R ', and wherein R ' is hydrogen, alkyl or aryl, is allowed to condition in the sodium hydrate aqueous solution then and reacts.Obtain the product of formula I, wherein R ¹=R ²=C (O) R '.(Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，pp.1062-1064)

Embodiment 12aThe preparation of the barbituric acid that the N-acetal replaces

With the compound dissolution of formula II in dimethyl formamide.In this solution, add sodium hydride.Adding general formula ClCH in this solution (OR ') ₂The chlorination diether, wherein R ' is an alkyl.Then, purified reaction product.Product has the structure of formula I, wherein R ¹=R ²=C (OR ') ₂(Loudon?GM，OrganicChemistry，Addison-Wesley(1984)，pp.1062-1064)

Embodiment 12bThe preparation of the barbituric acid that the N-arylmethyl replaces

The chemical compound of formula II is dissolved in the ethanol with potassium hydroxide.Aromatic compounds ArCH with the halomethyl replacement ₂X, wherein X is a halogen, is dissolved in this solution.Obtain the product of formula I, wherein R ¹=R ²=CH ₂Ar.(Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，p.1194)

This synthetic method can also be reacted with the benzyl chloride that hydrogen SH replaces that cures on the phenyl ring.

Embodiment 12cThe preparation of the barbituric acid that the N-arylthio replaces

The chemical compound of formula II is dissolved in the ethanol with potassium hydroxide.With sulfo-halogenated aryl alkyl compound R ' ArSX, wherein X is that halogen and R ' are H or alkyl, is dissolved in this solution.Obtain the product of formula I, wherein R ¹=R ²=SArR '.

Embodiment 13The preparation of the barbituric acid derivatives that the 5-aryl replaces

The solution of preparation magnesium in atent solvent.Atent solvent can be selected from ether, dimethoxymethane, t-butyl methyl ether, Pentamethylene oxide., diisopropyl ether, toluene and mesitylene and can be the mixture of these solvents.Wherein 1,2-methylene bromide or ether are favourable.In the first step, in solution, add aryl methyl halogenation thing.Aryl can be the nitrogenous and optional heteroatom group that contains carbon, oxygen or sulfur in the ring.Can also contain tri-n-butylamine in this solution.

Then, in solution, add diethyl carbonate, then neutralize with hydrochloric acid.Then, organic layer is separated.

Add Sodium ethylate in the organic layer after concentrating.Then, ethanol is removed in distillation from solution.Solution neutralizes with hydrochloric acid.Separate organic layer then, drying concentrates in a vacuum, obtains the aryl diethyl malonate.

Then, the aryl diethyl malonate is dissolved in the ethanol with urea and Sodium ethylate.Product has the structure of formula I, wherein R ³And R ⁴One of be aryl, R ³And R ⁴Another be hydrogen.(U.S.Pat.No.5,750,766；Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，p.1087)

Embodiment 14aThe preparation of the barbituric acid derivatives that the 5-aryl replaces

With an alloxan monohydrate (formula I, wherein R ³=R ⁴=OH) in the vitriolization.Add aromatic compounds (Ar-H), heat this solution then, solution is reacted.Then, reaction mixture is separated sulfuric acid layer.Sulfuric acid layer is poured in the cold water, separated out product.The product that filtration is separated out, washing refilters, and drying if necessary, is carried out chromatograph and is purified, and obtains the product of pure formula I, wherein R ³=R ⁴=Ar.(U.S.Pat?No.4,628,056)

Make in this way, the benzene that can use halogen to replace, for example fluorobenzene obtains formula I product, wherein R ³=R ⁴=PhX, wherein X is a halogen.(U.S.Pat?No.4,628,056)

Perhaps, the benzene that can use alkyl to replace, for example ethylbenzene obtains formula I product, wherein R ³=R ⁴=PhR ', wherein R ' is an alkyl.(U.S.Pat?No.4,628,056)

In another kind changed, the benzene of acyl substituted can be used for obtaining the product of formula I, wherein R ³=R ⁴=PhC (O) R ', wherein R ' is an alkyl; Perhaps, the benzyl Methanamide can be used for obtaining the product of formula I, wherein R ³=R ⁴=PhCH ₂C (O) NH ₂, perhaps, the benzene with dithiane replacement of following structure can be used for obtaining the product of formula I, wherein R ³=R ⁴=Ph-dithiane.

Embodiment 14bThe preparation of the barbituric acid derivatives that the 5-aryl replaces

The solution of preparation magnesium, dimethoxymethane and methylene bromide.In the solution of the aromatic compounds that the halomethyl that wherein adds dimethoxymethane replaces, it is reacted.In this solution, add cold diethoxy carbonic ester.Then, solution neutralizes with hydrochloric acid.Separate organic layer, concentrate by distillation.

Add Sodium ethylate in the organic layer after concentrating.Then, dimethoxymethane and ethanol are removed in distillation from solution.Solution neutralizes with hydrochloric acid, separates organic layer, uses dried over mgso, concentrates in a vacuum.Products therefrom is the diethyl malonate that aromatics replaces.

Then, be dissolved in ethanol with urea and Sodium ethylate diethyl malonate and react.Product has the structure of formula I, wherein R ³And R ⁴One of be aromatics, R ³And R ⁴Another be hydrogen.(U.S.Pat.No.5,750,766；Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，p.1087)

In order to obtain the product of formula I, wherein R ³And R ⁴One of be the aromatic group that replaces, R ³And R ⁴Another be hydrogen; those of ordinary skills can make in this way or it changes form; by the synthetic barbituric acid derivatives of aromatic compound that halomethyl replaces, wherein aromatic compound has other substituent group for example halogen, alkyl, acyl group, acyl derivative or acetamido on ring.

This synthetic method can also be reacted with the chloromethyl phenyl dithiane of the aromatic compounds that replaces as halomethyl.

Embodiment 15aThe preparation of the barbituric acid derivatives that the 5-arylmethyl replaces

The aromatic compounds ArCH of diethyl malonate and Bromomethyl Substituted ₂X, wherein Ar is that aryl and X are that halogen and Sodium ethylate are dissolved in the ethanol together.Product is formula ArCH ₂CH (CO ₂Et) ₂List-aryl methyl malonate.Then, be dissolved in ethanol with urea and Sodium ethylate single aryl methyl malonate and react.Product has the structure of formula I, wherein R ¹=R ²=H, R ³And R ⁴One of be CH ₂Ar, R ³And R ⁴Another be hydrogen.(Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，pp.617，1086-1088)

Aromatic compounds can further for example be replaced by halogen or alkyl on ring.

Embodiment 15b5, the preparation of the barbituric acid derivatives that 5-two (arylmethyl) replaces

Aromatic compounds ArCH with diethyl malonate and Bromomethyl Substituted ₂X, wherein Ar is that aryl and X are that halogen and Sodium ethylate are dissolved in the ethanol together.Product is formula ArCH ₂CH (CO ₂Et) ₂List-aryl methyl malonate.From solution, separate single aryl methyl malonate.Then, the aromatic compounds Ar ' CH that isolating single aryl methyl malonate and iodomethyl are replaced ₂I, wherein Ar ' be aryl and Ar and Ar ' can be identical or different and Sodium ethylate be dissolved in the ethanol.Product is formula (ArCH ₂) (Ar ' CH ₂) C (CO ₂Et) ₂The diaryl dimethyl malonic ester.

Then, be dissolved in ethanol with urea and Sodium ethylate the diaryl dimethyl malonic ester and react.Obtain the product of formula I, wherein R ³=CH ₂Ar; R ⁴=CH ₂Ar '.(Loudon?GM，OrganicChemistry，Addison-Wesley(1984)，pp.617，1086-1088)

For example, the aromatic ring of chemical compound or can be replaced by halogen or can be replaced by alkyl.

Embodiment 16a5, the preparation of the barbituric acid derivatives that the 5-dialkyl group replaces

The chemical compound of formula I, wherein R ³=R ⁴=OH is dissolved in the pyridine with paratoluensulfonyl chloride, replaces hydroxyl with tosyl.The tosylate that obtains is separated, with formula R ' ₂Cu ^-Li ⁺Dialkyl group copper acid lithium (lithium dialkylcuprate), wherein R '=alkyl is dissolved in the ether together again.Obtain the product of formula I, wherein R ³=R ⁴=R '.(Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，pp.721-722)

Embodiment 16bThe preparation of the barbituric acid derivatives that the 5-alkyl replaces

With the alkyl bromide of diethyl malonate and formula R ' Br, wherein R ' is that alkyl and Sodium ethylate are dissolved in the ethanol together.Product is formula R ' CH (CO ₂Et) ₂The monoalkyl malonate.Then, be dissolved in ethanol with urea and Sodium ethylate the monoalkyl malonate and react.Product has the structure of formula I, wherein R ³And R ⁴One of be R ', R ³And R ⁴Another be hydrogen.(Loudon?GM，OrganicChemistry，Addison-Wesley(1984)，pp.1086-1088)

Alkyl R ' can be substituted; For example alkyl R ' can be replaced by aryl.

Embodiment 16c5, the preparation of the barbituric acid derivatives that the 5-dialkyl group replaces

With the alkyl bromide of diethyl malonate and formula R ' Br, wherein R ' is that alkyl and Sodium ethylate are dissolved in the ethanol together.Product is a general formula R ' CH (CO ₂Et) ₂The monoalkyl malonate.From solution, separate the monoalkyl malonate.Then, with monoalkyl malonate and the formula R after separating " alkyl iodide of I, wherein R " be alkyl and can be with R ' identical or different and Sodium ethylate be dissolved in the ethanol together.Product is formula R " R ' C (CO ₂Et) ₂The dialkyl group malonate.

Then, be dissolved in ethanol with urea and Sodium ethylate the dialkyl group malonate and react.Product has the structure of formula II, wherein R ³And R ⁴One of be R ', R ³And R ⁴Another be R ".R ' and R " can be identical or different alkyl.(Loudon?GM，Organic?Chemistry，Addison-Wesley(1984)，pp.1086-1088)

Alkyl R ' and R " can be substituted; For example alkyl R ' and R " each can be replaced by aryl.

The embodiment that illustrates in this manual and discuss only is in order to instruct the optimum implementation known to persons skilled in the art inventor, with preparation with utilize the present invention.Any content in this manual should not be considered to limit the scope of the invention.At these all embodiment that provide all is representational and nonrestrictive.Without departing from the spirit and scope of the present invention, persons skilled in the art are according to above-mentioned instruction, can modify or change above-mentioned embodiment of the present invention.Therefore, should be appreciated that, in the scope of the coordinate of claim and they, the practice of the present invention can with description in specifically described different.

Claims

1. method of protecting mammal to avoid nerve injury comprises non-sedating barbital and its salt of the following structure that gives described mammal doses,

It is enough to provide neuroprotective, and described non-sedating barbital is non-sedating and non-hypnotic under described dosage, wherein

R ¹And R ²Can be identical or different and independently

Hydrogen;

Phenyl;

CH ₂XR ⁵, wherein X is S or O, R ⁵Be low alkyl group, aryl, alkaryl or benzyl;

C (O) XR ⁶, wherein X as defined above, R ⁶Be low alkyl group or aryl;

CH (XR ⁸) ₂, wherein X as defined above, R ⁸Be low alkyl group, condition is R ¹And R ²In at least one be not hydrogen; With

Wherein

R ³And R ⁴Can be identical or different and independently

Hydrogen;

Optional one or more N of being selected from, S and the heteroatomic aryl of O of containing;

Low-grade acyloxy;

Phenyl;

By the phenyl of halogen, low alkyl group, lower acyl or derivatives thereof or acetamide replacement;

Benzyl; On the ring by one or more halogens, low alkyl group or benzyl that both replace; Optional one or more N of being selected from, O and the heteroatomic cycloalkyl of S of containing;

Low alkyl group; Or the low alkyl group that is replaced by aromatics part;

Condition is R ³And R ⁴In at least one be aromatic ring or the part that contains aromatic ring.

2. the method for claim 1, condition is to work as R ¹And/or R ²When being methoxy, R ³And R ⁴Not all be phenyl, the phenyl that is not all replaced by low alkyl group and the phenyl that is not all replaced by halogen; With

Work as R ³And R ⁴One of when being phenyl or benzyl, R ³And R ⁴Another be not ethyl; With

Work as R ¹And R ²In at least one when being benzyl, work as R so ³And R ⁴One of when being phenyl, R ³And R ⁴In another be not pi-allyl; With

Work as R ¹And R ²In one be methyl and another when being hydrogen, work as R so ³And R ⁴One of when being phenyl, R ³And R ⁴In another be not unsubstituted low alkyl group; With

Work as R ¹=R ²=R ^aThe time, R wherein ^aBe alkoxy methyl or (acyloxy) methyl, work as R so ³And R ⁴One of when being the 1-phenethyl, R ³And R ⁴In another be not propionyloxy; With

Chemical compound is not

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

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

C) 1,3,5-triphenyl barbituric acid and

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

3. the process of claim 1 wherein

(a) R ¹And R ²In at least one is

By the low alkyl group of low-grade cycloalkyl, acyl group, acyloxy, aryl, aryloxy group, alkylthio group or arylthio, amino, alkyl amino, dialkyl amido or the replacement of one or more halogen atom;

Phenyl;

CH ₂SR ⁵, R wherein ⁵Be low alkyl group, aryl, alkaryl or benzyl;

C (S) XR ⁶, wherein X is S or O and R ⁶Be low alkyl group or aryl;

CSR ⁷, R wherein ⁷Be hydrogen, low alkyl group or aryl; With

CH (SR ⁸) ₂, R wherein ⁸It is low alkyl group; Perhaps

(b) R ³And R ⁴In at least one is a low-grade acyloxy;

By the phenyl of lower acyl or derivatives thereof or acetamide replacement; With

Optional one or more N of being selected from, O and the heteroatomic cycloalkyl of S of containing of ring.

4. the method for claim 3, condition is to work as R ¹And/or R ²When being methoxy, R ³And R ⁴Not all be phenyl, the phenyl that is not all replaced by low alkyl group and the phenyl that is not all replaced by halogen; With

Chemical compound is not

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

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

C) 1,3,5-triphenyl barbituric acid.

5. the process of claim 1 wherein R ¹And R ²Be identical or different and be selected from hydrogen, butyl, benzyl, thiophenyl methyl, cyclopropyl methyl, 3,3,3-trifluoro propyl, benzyloxymethyl and alkoxy methyl.

6. the method for claim 2, wherein R ¹And R ²In at least one be methoxy.

7. the process of claim 1 wherein R ³And R ⁴All be aromatic ring or the part that contains aromatic ring.

8. the process of claim 1 wherein R ³And R ⁴Be identical or different, and be phenyl independently; By the phenyl of halogen or low alkyl group replacement; Optional one or more N of being selected from, O or the heteroatomic cycloalkyl of S of comprising; Benzyl; On ring by one or more halogens, low alkyl group or benzyl that both replace; Low alkyl group; Or the low alkyl group that is replaced with aromatics part, condition is R ³And R ⁴In at least one is the phenyl of phenyl or replacement.

9. the process of claim 1 wherein R ³And R ⁴In at least one be selected from phenyl, benzyl, fluorophenyl and tolyl.

10. the process of claim 1 wherein R ³And R ⁴In at least one be selected from

With

11. the process of claim 1 wherein that described dosage is greater than about 25mg/kg body weight.

12. the process of claim 1 wherein that described non-sedating barbital gives with enough dosage, make the haemoconcentration of described non-sedating barbital or its active metabolite be at least 30 μ g/ml.

13. the method for claim 12, wherein in described administration after at least 12 hours, the described haemoconcentration of described non-sedating barbital or its active metabolite is at least 30 μ g/ml.

14. the process of claim 1 wherein that described non-sedating barbital is to give greater than the dosage more than the anticonvulsant dosage twice.

15. the process of claim 1 wherein that described non-sedating barbital gives with oral or intravenous form.

16. the process of claim 1 wherein that described non-sedating barbital prophylactically gave or gives to therapeutic after the neuronal damage morbidity begins before obvious neuronal damage occurring.

17. the process of claim 1 wherein and in operation on heart or carotid endarterectomy, give described non-sedating barbital.

18. the method for claim 1; wherein said neuroprotective reduces, and perhaps protects the patient to avoid the neuronal damage that is caused by auricular fibrillation, transient ischemic attack (TIA) (TIA), cerebral ischemia, bacterial endocarditis, apoplexy, head trauma, subarachnoid hemorrhage or other polarity nerve injury.

19. the method for claim 1; wherein give described non-sedating barbital, describedly have or be in mammal in auricular fibrillation, transient ischemic attack (TIA) (TIA), cerebral ischemia, bacterial endocarditis, apoplexy, head trauma, subarachnoid hemorrhage or other polarity nerve injury to protect.

20. a pharmaceutical composition comprises non-sedating barbital and its salt as active substance, and pharmaceutically acceptable carrier; when giving with dosage with neuroprotective; said composition is non-sedating and non-hypnotic, and barbital has following array structure

Wherein

R ¹And R ²Can be identical or different, and be independently

Hydrogen;

Phenyl;

C (O) XR ⁶, wherein X as defined above, R ⁶Be low alkyl group or aryl;

CH (XR ⁸) ₂, wherein X as defined above, R ⁸Be low alkyl group, condition is R ¹And R ²In at least one be not hydrogen; And wherein

R ³And R ⁴Can be identical or different, and be independently

Hydrogen;

Low-grade acyloxy;

Phenyl;

By the phenyl of halogen, low alkyl group, lower acyl or derivatives thereof or acetamido replacement;

Benzyl; On ring by one or more halogens, low alkyl group or benzyl that both replace; Optional one or more N of being selected from, O and the heteroatomic cycloalkyl of S of containing;

Low alkyl group; Or the low alkyl group that is replaced by aromatics part;

Condition is R ³And R ⁴In at least one be aromatic ring or the part that contains aromatic ring,

Condition is to work as R ¹And/or R ²When being methoxy, R ³And R ⁴Not all be phenyl, the phenyl that is not all replaced by low alkyl group and the phenyl that is not all replaced by halogen; With

Chemical compound is not

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

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

C) 1,3,5-triphenyl barbituric acid and

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

21. the compositions of claim 20, wherein

(a) R ¹And R ²In at least one is

Phenyl;

CH ₂SR ⁵, R wherein ⁵Be low alkyl group, aryl, alkaryl or benzyl;

C (S) XR ⁶, wherein X is S or O and R ⁶Be low alkyl group or aryl;

CSR ⁷, R wherein ⁷Be hydrogen, low alkyl group or aryl; With

CH (SR ⁸) ₂, R wherein ⁸It is low alkyl group; Perhaps

(b) R ³And R ⁴In at least one is

Low-grade acyloxy;

22. the pharmaceutical composition of claim 20, wherein R ¹And R ²Be identical or different and be selected from hydrogen, butyl, benzyl, thiophenyl methyl, cyclopropyl methyl, 3,3,3-trifluoro propyl, benzyloxymethyl and alkoxy methyl.

23. the pharmaceutical composition of claim 20, wherein R ¹And R ²In at least one be methoxy.

24. the pharmaceutical composition of claim 20, wherein R ³And R ⁴All be aromatic ring or the part that contains aromatic ring.

25. the pharmaceutical composition of claim 20, wherein R ³And R ⁴Be identical or different, and be phenyl independently; By the phenyl of halogen or low alkyl group replacement; Optional one or more N of being selected from, O or the heteroatomic cycloalkyl of S of comprising; Benzyl; On ring by one or more halogens, low alkyl group or benzyl that both replace; Low alkyl group; Or the low alkyl group that is replaced by aromatics part, condition is R ³And R ⁴In at least one is the phenyl of phenyl or replacement.

26. the pharmaceutical composition of claim 20, wherein R ³And R ⁴In at least one be selected from phenyl, benzyl, fluorophenyl and tolyl.

27. the pharmaceutical composition of claim 20, wherein R ³And R ⁴In at least one be selected from

With

28. the pharmaceutical composition of claim 20, wherein said dosage is greater than about 25mg/kg body weight.

29. the pharmaceutical composition of claim 20, wherein said non-sedating barbital or its give with enough dosage, make the haemoconcentration of described non-sedating barbital or its active metabolite be at least 30 μ g/ml.

30. the pharmaceutical composition of claim 20, wherein administration is after at least 12 hours, and the haemoconcentration of described non-sedating barbital or its active metabolite is at least 30 μ g/ml.

31. the pharmaceutical composition of claim 20, wherein said non-sedating barbital is to give greater than the dosage more than the anticonvulsant dosage twice.

32. a method for the treatment of sacred disease comprises the compositions that gives claim 20.

33. the method that neuroprotective is provided comprises

(a) identify the mammal that needs the cerebral nerve protection;

(b) pharmaceutical composition of a kind of claim 20 of selection; With

(c) give the described pharmaceutical composition of the effective neuroprotective dosage of described mammal, described neuroprotective is provided thus.

34. the method for claim, wherein

(a) R ¹And R ²In at least one is

Phenyl;

CH ₂SR ⁵, R wherein ⁵Be low alkyl group, aryl, alkaryl or benzyl;

C (S) XR ⁶, wherein X is S or O and R ⁶Be low alkyl group or aryl;

CSR ⁷, R wherein ⁷Be hydrogen, low alkyl group or aryl;

And CH (SR ⁸) ₂, R wherein ⁸It is low alkyl group; Or

(b) R ³And R ⁴In at least one is

Low-grade acyloxy;