CN1306503A - 2-fluoro-2-alkyl alkanoamides with anticonvulsant activity - Google Patents
2-fluoro-2-alkyl alkanoamides with anticonvulsant activity Download PDFInfo
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Abstract
Alpha-fluorinated alkanoamides of formula (I), and pharmaceutical compositions containing them, are provided. The compounds and compositions are useful for the treatment and prevention of seizures such as are associated with epilepsy. The compounds of the invention exhibit an improved therapeutic ratio, relative to valproic acid, with regard to sedation and teratogenic potential, and exhibit improved pharmacokinetics and pharmacodynamics.
Description
Invention field
The present invention relates to the preparation of 2-fluoro-2-alkyl alkanoamides, these compounds and as the purposes of anticonvulsion therapeutical agent.Compare with third amylamine with valproic acid, the treatment ratio of anticonvulsant fluorinated amide of the present invention on sedation effect improves, and reduced ter possibility.Generally speaking, fluorinated amide of the present invention is faster than corresponding fluorinated, acid onset.The invention provides a kind of effective Anti-epileptics, its safety coefficient is greater than the valproic acid and third amylamine.
Background of invention
There is 1% people to suffer from epilepsy in the world approximately.The medicine that is used for the Taking Control of Epilepsy onset is a valproic acid.Valproic acid (being also referred to as VPA, valproate or 2-propane valeric acid) is a kind of effective anticonvulsive agent, but the time of its continuous action is very short.More seriously, VPA has a series of side effect, sedative effect, the fatal hepatotoxicity of potential is wherein arranged and cause deformity.For the child, children's hepatotoxicity of particularly accepting multiple treatment is a serious problem.It is reported, in the latter's patient, VPA inductive liver lethality rate be 1/500 (F.E.Dreifuss etc., Neurology (1987), 37,379-385).Valproic acid has shown can induce the mouse neural tube defect, and according to estimates, the danger of taking the neonatal spina bifida that the women bears of VPA in the pregnancy period is 1-2% (Center for Disease Control, Morbidity and Mortality Weekly Report (1983), 32 (33), 438-439).
People make a considerable effort to find a kind of and valproic acid equivalence but the higher valproic acid analogue of safety coefficient.For example, H.Nau etc., PCT application WO94/06743 and relevant U.S.Patent 5,786,380 have wherein done various modifications to the alkyl chain of valproic acid.
About teratogenesis shape, it is reported that 4 ethynylations at valproic acid can increase teratogenesis shape greatly, but this effect only is confined to S-(-) enantiomorph.Add that at the triple-linked end methyl can eliminate teratogenesis shape, and keep anti-convulsant activity (H.Nau, R.-S.Hauck, K.Ehlers, Pharmacology ﹠amp; Toxicology (1991), 69,301-321.).These results show that teratogenesis shape and separating of anticonvulsion property are feasible.In some analogues, also the side effect of calmness can be separated with anti-convulsant activity (M.Elmazar, R.-S.Hauck, H.Nau, J.Pharm.Sci. (1993), 82,1255-1288).
People know little about it to the α branched carboxylic acids with α-fluorine.P.Crowley etc. disclose 2-ethyl-2-fluorine butyric acid as the mycocide intermediate and preparation method thereof in European patent application EP 468681.Takeuchi in the article that relates to tertiary alkyl fluorochemical preparation method, mentioned this compounds several examples (Y.Takeuchi etc., J.Org.Chem. (1993), 58 (13), 3483-3485).
The 2-fluoro-2-propyl group-4-pentenoic acid of valproic acid analogue also has report.Compound is used for hepatotoxicity and metabolic research (W.Tang etc., Chem.Res.Toxical. (1995), 8 (5), the 671-682 of valproic acid as probe; M.Jurima-Romet etc., Toxicology (1996), 112 (1), 69-85; W.Tang and F.abbott, Drug Metab.Dispos (1997), 25 (2), 219-227).According to above-mentioned reference, for 2-propyl group-4-pentenoic acid, the existence of 2-fluorine substituent can reduce hepatotoxicity.The anticonvulsion property of fluorizated compound, calm or teratogenesis shape characteristic is still unexposed.
α-fluorizated valproic acid: the existing report of 2-fluoro-2-Valproic acid (Ph.D.thesus of Wei Tang, University of British Columbia 1996).Studied the anti-convulsant activity and the pharmacokinetics of this compound, and infer its medicine potential (F.Abbott, W.Tang, J.Palety, J.Pharmacol.Exp.Ther. (1997), 282,1163-1172).It is reported that the drug effect of this compound is worse than VPA, and hepatotoxicity, calmness or teratogenesis shape characteristic there is not report as yet.
The existing report of valproic acid analogue with latter end trifluoromethyl: 5,5,5-three fluoro-2-(3,3, the 3-trifluoro propyl) valeric acid (K.Yamaguchi and M.Taninaka, Japanese patent application 4-21552 (1992) and 5,5,5-three fluoro-2-n-propyl valeric acids (Hiroshima etc., Japan.J.Psychopharmacol. (1992) 12, and 427). the effect of these compounds is poorer than VPA.
Valpromide (VPD, the acid amides of valproic acid) is widely used valproic acid precursor.The oral back of known VPD in human body rapidly metabolism be valproic acid (M.Bialer, Int.J.Pharm. (1985) 23 25-33).Variation is sizable between the kind of accretion rate; For example, the metabolism hydrolytic action in the known mouse is relatively slow.Specific β-alkylation analogue, for example 2-ethyl-3-methyl-valeramide (val-vanium) this pathways metabolism capable of blocking.Referring to A.Hai-Yehia, M.Bialer etc., J.Pharm.Sci., 79,719-724 (1990) and reference wherein.Found that the cyclopropane carboxamide of specific replacement has the anticonvulsion property of metabolic stability: Pharm.Res. such as M.Bialer, 13,284-289 (1996).Blocking-up to hydrolytic action in these compounds should be owing to steric effect.
Summary of the invention
The present invention relates to the purposes of 2-fluoro-2-alkyl alkanoamides, the pharmaceutical composition that contains these compounds and treatment thereof or prevention convulsions disease.The present invention also discloses the method for preparing these compounds.Compare with valproic acid or valpromide, preferred 2-fluoridizes carboxylic acid amides and greatly shows the minimizing of embryotoxicity and hepatotoxicity, the raising of relevant sedation treatment ratio and the growth of active duration among the present invention.To fluoridize the relevant 2-fluorinated carboxylic of the onset specific activity of carboxylic acid amides rapid unexpectedly for 2-among the present invention.
The invention provides the compound of following formula I:
R wherein
1And R
2Independently be selected from C respectively
3-C
5Alkyl, C
3-C
5Cycloalkyl, (cyclopropyl) methyl, 1-(cyclopropyl) ethyl, 2-cyclopropyl (ethyl) and (cyclobutyl) methyl.Term used herein " alkyl " comprises the alkyl of straight chain and side chain.
The present invention also discloses by making the individuality that needs this treatment take the compound at least a of the present invention that significant quantity was gone up or prevented to go up in treatment, to treat and/or prevent the method for the convulsions disease that is caused by a variety of causes.
Compound of the present invention in addition also can be used for treating and/or preventing the emotion disease, particularly in the manic stage of bipolar cell depression (mania phase of bipolar depression); And migraine.
An object of the present invention is to provide a kind of compound that can be used for prevention or reduce Mammals epileptic seizures activity (seizure activity).
Another object of the present invention provides a kind of anticonvulsive pharmaceutical composition that contains at least a The compounds of this invention.
A further object of the present invention provides and a kind ofly needs the individuality of this treatment to take pharmaceutical composition of the present invention by making, with prevention or reduce the active method of epileptic seizures.
Brief description of drawings
Fig. 1: the consumption effect curve of valproic acid and several 2-alkyl alkanoamides and 2-fluoro-2-alkyl alkanoamides.
3Me-VPD=3-methyl-prop valeramide, 3-methyl-2-Valproic acid;
2F-VCD=2-fluorine val-vanium, 2-ethyl-2-fluoro-3 methylvaleric acid;
VCD=val-vanium, 2-ethyl-3 methylvaleric acid;
2F-VPD=2-fluorine valpromide, 2-fluoro-dipramide;
VPA=valpromide, dipramide;
The VPA=valproic acid, the 2-Valproic acid.
Fig. 2: synthetic compound of the present invention: the exemplary embodiments of 2-fluorine val-vanium.Detailed Description Of The Invention
The invention provides the compound with following structure:
R wherein1And R2Respectively C3-C
5Straight chained alkyl, C3-C
5Branched alkyl, C3-C
5Cycloalkyl, (cyclopropyl) methyl, 1-(cyclopropyl) ethyl, 2-cyclopropyl (ethyl) or (cyclobutyl) methyl. Term used herein " alkyl " comprises the alkyl of straight chain and side chain. In preferred embodiments, R1And R2Respectively C3-C
4Alkyl, cyclopropyl, cyclobutyl or (cyclopropyl) methyl. In a further preferred embodiment, R1N-pro-pyl, isopropyl, normal-butyl or 1-methyl-propyl; And R2C3-C
5Alkyl, C3-C
5Cycloalkyl, (cyclopropyl) methyl, 1-(cyclopropyl) ethyl, 2-cyclopropyl (ethyl) or (cyclobutyl) methyl. In another more preferred, R1And R2Respectively n-pro-pyl, isopropyl, normal-butyl or 1-methyl-propyl. Most preferably, compound is selected from 2-fluoro-2-n-pro-pyl pentanamide, 2-fluoro-2-ethyl-3-methylpent acid amides and 2-fluoro-2-(1-methyl-propyl) amylene acid amides.
With the Compound Phase ratio of prior art, compound of the present invention has the advantage of beyond thought pharmacokinetics. When the active rapidly onset of VPA and valpromide, they cause above-mentioned calmness and the side effect of hepatotoxicity. And find that 2-fluoro-VPA without the teratogenic while, finds that also its drug effect is more far short of what is expected than VPA, and take after one hour and just can reach maximum activity. Equally, 2-fluoro-VPA active duration is also relatively short, and activity can only continue about 75 minutes (seeing Table 3) in vivo.
VPA is different from the 2-fluoro-, compound of the present invention-(embodiment 5) rapidly onset as an example of 2-fluoro-dipramide example, and in 15 minutes, reach maximum activity and (compare with valpromide with VPA; See Table 3). Simultaneously, its long half time of 11.3 hours that has in 1.4 hours of VPA (below seeing) and valpromide 0.84 hour (in human body: M.Bialer etc., 1985, Int. J. Pharm., 23,25-33). Therefore, 2-fluoro-dipramide combines the characteristic of VPA and the rapid onset of valpromide and the security of 2-fluorine valproic acid, has again simultaneously significantly and other people is taken aback the long half-lift. Do not expect that before obtaining the anticonvulsion compound of this class they have this specific character.
Use the form of pro-drug that two main causes are arranged, namely improve absorption/partition characteristic, and/or longer pharmacological effect is provided. Prodrug form must change their pharmacological activity forms into through metabolism, so prodrug form generally can be with respect to parent drug, the delay of the active onset that shows, or at most identical with parent drug.
Unexpectedly, find herein α-the fluorine carboxylic acid amides is obviously faster than corresponding carboxylic acid onset, or even not during the Existential Space effect. This effect can be observed when parenterai administration, so be not because stomach and intestine absorb faster cause. Compound is also more effective than corresponding acid, and the active duration is also longer.
2-fluorine carboxylic acid amides of the present invention shows itself to have anti-convulsant activity. It is the pro-drug that simple carboxylic acid is fluoridized that these compounds have more than, but has the materia medica characteristic of self uniqueness. Therefore, the invention provides α that anti-convulsant activity is arranged-fluorine carboxylic acid amides itself, can be used for treatment or prevention epileptic attack, do not produce deformity and can produce not teratogenic metabolite (itself has antiepileptic activity) by metabolism.
Compound of the present invention can prepare other α-carboxylic acid fluoride by prior art, then is converted into the method preparation of acid amides. For example, processing 2-hydroxyl-2-alkyl chain alkanoic acid ester with trifluoro diethyl sulfuration ammonia (DAST) obtains corresponding α-fluorine ester, then obtains acid (P.Crowly etc., 1992, European patent application EP 468681) by hydrolysis. Perhaps, can be to 2-ammonia-2-alkyl chain alkanoic acid diazotising in the presence of fluorine ion, obtain deaminizating fluoride (J.Barber, R.Keck, J.Retey, Tetrahedron Letters (1982), 23,1549-1552). Reform (reformatsky) reaction can 2-bromo-2-fluorine alkanoate (Y Takeuchi etc., J.Org.Chem. (1993), 58 (13), 3483-3485) have lower carrying out, thereby introducing 2-alkyl group. Following embodiment is preferred for laboratory scale synthetic: use " just (positive) fluorine " source, for example N-fluorine pyridiniujm, N-flutolanil or N-fluorine acid imide, enol ester or the monosilane enol ether of 2-alkyl chain alkanoic acid are fluoridized (referring to, for example, E.Differding, G.Ruegg, Tetrahedron Letters (1991), 32,3815-3818). In the embodiment of following example, the enol lithium of valproic acid methyl esters is used for fluoridizing N-fluorobenzene thionyl imide, but should be understood to other synthetic method still within the scope of the invention.
The ester raw material that uses in the method for example can be bought from market, or obtains by the method for prior art. For example, M.Elmazar, R-S.Hauck, H.Nau, J.Pharm.Sci. (1993), the malonic acid ester synthesis of describing among 82, the 1255-1288. Also can be referring to H.Nau etc., 1994, PCT international application No.WO/94/06743, and US patent application series number No.08/344,810. Also can use the synthetic acetoacetate of known malonate to change. Following examples have adopted the direct alkylation of straight chain enol ester. Other synthetic method is apparent for those skilled in the art, and the present invention is not limited by the special synthetic method of this paper example.
Generally speaking, the invention provides the preparation method of the compound of formula I, it may further comprise the steps: a) in the presence of suitable alkali, use the alkylating reagent R of formula III
2-X (III)
Wherein X is the leavings group that is fit to, R
2Definition is as above with the alkylation of formula II,
R wherein
1Define as above, and R
3Be low alkyl group (preferred C
1-C
4Alkyl) or benzyl, and
R
4Be low alkyl group (preferred C
1-C
4Alkyl), lower alkoxy (preferred C
1-C
4Alkoxyl group)
Or benzyloxy, obtain the compound of formula IV
B) at R
4When being lower alkoxy or benzyloxy, with formula IV compound hydrolysis, decarboxylation and esterification again when needed; Or at R
4When being low alkyl group, formula IV compound is taken off acetyl, obtain formula V compound
D) in inert solvent, use suitable alkali with compound V enolization; E) add fluorination reagent, obtain the compound of formula VI
F) part of ester hydrolysis, and g) carboxylic acid is transformed into carboxylic acid amides.
R
4Proper group be conspicuous for those skilled in the art.Preferred R
4Be easy saponified alkoxyl group, methoxy or ethoxy for example, or other carboxylic acid protective group who removes with other method easily, for example tert.-butoxy, benzyloxy etc.Be to be understood that step (b) and the term " hydrolysis " that (f) uses comprise that the protection operation is to become R
4Itself, for example the saponification under the lower alkoxy situation, under the tert.-butoxy situation acid hydrolysis or the hydrolytic action under the benzyloxy situation.For same consideration, R
3Be preferably low alkyl group, for example methyl or ethyl, but also can be other carboxy protective group, for example tertiary butyl, benzyl etc.Obviously, in step (b), R
3Be removed and introduce again subsequently, if desired, the operator has an opportunity to change R
3Definition.
Work as R
4When being alkyl, preferred group is that those participate in COR
4The group of deacetylation; At R
4When being most preferred methyl, by using, for example sodium hydroxide or ammoniacal liquor, or the method for other prior art is finished deacetylation.
Suitable leavings group X can be selected from but be not limited to halogen-chlorine, bromine or iodine, or sulphonate, for example mesyloxy or tosyloxy.The suitable alkali that is used for step (a) can be selected from but be not limited to the alkoxide of alkali metal alcoholates, calcium and magnesium and alkalimetal hydride etc.
Suitable alkali is conspicuous for those skilled in the art in the step (d), because existing many methods with the ester enolization are disclosed.Preferred those have sufficiently high pKa value, can be with the abundant deprotonation of compound V, not with the alkali of the functional group reactions of compound V.For example can be selected from but be not limited to the lithium salts or the sodium salt of back resistance bis substituted amine, for example diisopropyl amide lithium or hexamethyl two silicon nitrine lithiums (lithium hexamethyldisilazide).
In selectable method, the compound of formula I can prepare by the method that comprises the following steps: a) in the presence of suitable alkali, use the alkylating reagent of formula III, R
2-X (III)
Wherein X is the above-mentioned leavings group that is fit to, and R
2Define the same, with the alkylation of formula VII,
R wherein
1Define as above, and R
3Be low alkyl group or benzyl, obtain the compound of formula V
B) in inert solvent, use suitable alkali with compound V enolization; C) add fluorination reagent, obtain the compound of formula VI
D) part of ester hydrolysis, and e) carboxylic acid is converted into carboxylic acid amides.
It will be apparent to one skilled in the art that can be with the method modification of example.For example, can use the inert solvent except that THF, for example dioxane, dialkyl ether, glycol dimethyl ether and other polyethers, toluene and heptane etc.Can use additive in fluoridation, for example hexamethylphosphoramide, Tetramethyl Ethylene Diamine or tetramethyl-urea also can use other alkali, for example alkali-metal hydride, alkoxide or hexamethyl two silicon azide salts in hydrogenation reaction.Described modification has several reasons, for example improves yield or reduce the technology cost in not departing from the scope of the present invention, and to those skilled in the art, determines that the experiment of the ideal conditions of given reaction is known.
The method that carboxylic acid is converted into carboxylic acid amides is provided by the following examples.Carboxylic acid amides of the present invention can provide prepared in various methods with the preparation of the method that provides, for example in the presence of carbodiimide or other condensation reagent,, or prepares by the ammonolysis of corresponding ester the condensation of 2-fluoro-2-alkyl chain alkanoic acid with ammoniacal liquor or ammonium salt.These methods it will be apparent to those skilled in the art that and the present invention is not limited to the synthetic method of example.
Adopt method provided herein, below compound of the present invention can prepare by proper raw material:
Embodiment No. compound
1 2-fluoro-2-ethyl valeramide
2 2-fluoro-2-ethyl hexanoyl amine
3 2-fluoro-2-ethyl-3-methylpent acid amides
4 2-fluoro-2-ethyl heptamides
5 2-fluoro-2-n-propyl valeramides
6 2-fluoro-2-n-propyl hexanamides
7 2-fluoro-2-n-propyl-3-methylpent acid amides
8 2-fluoro-2-n-propyl heptamides
9 2-fluoro-2-sec.-propyl valeramides
10 2-fluoro-2-sec.-propyl hexanamides
11 2-fluoro-2-sec.-propyl-3-methylpent acid amides
12 2-fluoro-2-sec.-propyl heptamides
13 2-fluoro-2-cyclopropyl valeramides
14 2-fluoro-2-cyclopropyl hexanamides
15 2-fluoro-2-cyclopropyl-3-methylpent acid amides
16 2-fluoro-2-cyclopropyl heptamides
17 2-fluoro-2-normal-butyl hexanamides
18 2-fluoro-2-(1-methyl-propyl) valeramides
19 2-fluoro-2-(1-methyl-propyl) hexanamides
20 2-fluoro-2-(1-methyl-propyl)-3-methylpent acid amides
21 2-fluoro-2-(1-methyl-propyl) heptamides
22 2-fluoro-2-cyclobutyl valeramides
23 2-fluoro-2-cyclobutyl hexanamides
24 2-fluoro-2-cyclobutyl-3-methylpent acid amides
25 2-fluoro-2-cyclobutyl heptamides
26 2-(cyclopropyl) methyl-2-fluorine valeramide
27 2-(cyclopropyl) methyl-2-fluorine hexanamide
28 2-(cyclopropyl) methyl-2-fluoro-3-methylpent acid amides
29 2-(cyclopropyl) methyl-2-fluorine heptamide
30 2,2-two (cyclopropyl)-2-monofluoroacetamide
31 2-cyclobutyl-2-cyclopropyl-2-monofluoroacetamide
32 2-fluoro-2-sec.-propyl-3-methylbutyryl amine
33 2-fluoro-2-sec.-propyl-4-methylbutyryl amine
34 2-fluoro-2-sec.-propyls-3, the 3-amide dimethyl butyrate
35 2-fluoro-2-sec.-propyl-3-methyl hexanamides
36 2-fluoro-2-sec.-propyl-4-methyl hexanamides
37 2-fluoro-2-sec.-propyl-5-methyl hexanamides
38 2-fluoro-2-sec.-propyls-3,3-dimethyl-penten acid amides
39 2-fluoro-2-sec.-propyls-4,4-dimethyl-penten acid amides
40 2-cyclopropyl-2-fluoro-3-methylbutyryl amine
41 2,3-two (cyclopropyl)-2-fluoroalanine
42 2-cyclobutyl-2-fluoro-3-methylbutyryl amine
43 2-cyclopentyl-2-fluoro-3-methylbutyryl amine
44 2-(cyclobutylmethyl)-2-fluoro-3-methylbutyryl amine
45 2-(1-cyclopropyl ethyl)-2-fluoro-2-(sec.-propyl) butyryl
Amine
46 2-(cyclopropyl methyl)-2-fluoro-3-methylbutyryl amine
47 2-fluoro-2-(1-methyl-propyl)-4-methylpent acid amides
48 2-fluoro-2-(1, the 1-dimethyl ethyl)-3-methylbutyryl amine
49 2-fluoro-2-(1-methyl-propyl)-3-methyl hexanamides
50 2-fluoro-2-(1-methyl-propyl)-4-methyl hexanamides
51 2-fluoro-2-(1-methyl-propyl)-5-methyl hexanamides
52 2-fluoro-3,3-dimethyl-2-(1-methyl-propyl) valeramide
53 2-fluoro-4,4-dimethyl-2-(1-methyl-propyl) valeramide
54 2-cyclopropyl-2-fluoro-3-methylpent acid amides
55 2-cyclobutyl-2-fluoro-3-methylpent acid amides
56 2-cyclopentyl-2-fluoro-3-methylpent acid amides
57 2-(cyclobutylmethyl)-2-fluoro-3-methylpent acid amides
58 2-(1-cyclopropyl ethyl)-2-fluoro-3-methylpent acid amides
59 2-(cyclopropyl methyl)-2-fluoro-3-methylpent acid amides
60 3-ethyl-2-fluoro-2-(1-methyl-propyl) valeramide
61 3-ethyl-2-(1-ethyl propyl)-2-fluorine valeramide
62 3-ethyl-2-(1-ethyl-butyl)-2-fluorine valeramide
Above-claimed cpd only is for example, does not limit the scope of the invention.
To those skilled in the art, most compounds of the present invention obviously can exist with mapping or diastereomeric form.Pure enantiomorph can be resolved from racemic modification by the method for prior art, for example the fractional recrystallization of the diastereomer amine salt by corresponding 2-fluoro-2-alkyl chain alkanoic acid, by the chromatography of non-enantiomer derivative or by the chiral column chromatogram.Also can prepare mapping shape by chirality synthetic method, for example pass through alkylation or fluorination process (R.-S.Hauck, H.Nau, 1989 of chirality hydrazone, Toxicology Letters, 49,41-48) or alkylation or fluorination process (H.Nau etc., 1994 of adopting the chiral oxazolidinone derivative, the PCT international application, publication number No.WO94/06473, US patent application series number No.08/344,810).Chiral raw material also can be used for the synthetic of compound of the present invention.The enantiomorph of discrete diastereomer, R and S enantiomorph, racemoid and formula I or the non--racemic mixture of diastereomer all fall within the scope of the present invention.
Another object of the present invention provides a kind of the individual of formula I compounds for treating trouble purplish or white patches on the skin epilepsy disease or other used needs the patient's of anticonvulsion treatment method.Mammals, those showed epileptic seizures or the patient who shows epileptic seizures danger were arranged particularly human comprising of can being benefited from this methods of treatment.For example, method of the present invention can be used for treatment and suffers from spontaneous whole body epileptic seizures, the individuality of for example inattentive, myoclonus and tetanic property clonic spasm epileptic seizures and local epileptic seizures.Special expection suffers from the individuality of purplish or white patches on the skin epilepsy disease and is benefited from take compound of the present invention.Method of the present invention comprises at least a formula I compound or its salt or the prodrug of taking the treatment significant quantity to individuality, and described significant quantity is enough to reduce or prevent the activity of epileptic seizures.
The dosage that is used for the treatment of the compound of described disease changes as usual with the relative effectiveness of the compound of severity of disease, patient's body weight and metabolism healthy state and use.General patient's preferred initial can be according to the mode of embodiment in the clinical trial, the research method decision of the dosage range by routine.The treatment significant quantity of individual patient can be according to the method for present use valproic acid, gives the method decision of amount of the medicine of required treatment of reaching of patient or preventive effect side effect simultaneously minimum by titration.Consumption may be the same when using VPA, but can do suitable adjustment according to effect disclosed herein and kinetic parameter, or determine by ordinary method.
For example, but the expection consumption VPA consumption of compound 2-fluoro-2-n-propyl valeramide about 25%.Therefore, the preferred initial content of estimating this compound is 1-60mg/kg/ days, more preferably 5-15mg/kg/ days.Initial consumption also can change, obtaining the best result of treatment of patient, and can daily dose or the mode of divided dose provide.Generally speaking, the consumption of compound is 1-150mg/kg/ days among the present invention.
The instructions of taking of compound can be any method that treatment is adopted among the present invention, and is for example oral, enteron aisle outer, the administering mode of intravenously, intramuscular, subcutaneous or rectum.
The present invention also provides pharmaceutical composition anti-anti-convulsant activity, that comprise at least a The compounds of this invention.Except comprising at least a formula I compound, pharmaceutical composition also can comprise additive, for example sanitas, vehicle, weighting agent, wetting agent, tackiness agent, disintegrating agent, buffer reagent and/or carrier.Suitable additive can be as magnesiumcarbonate or lime carbonate, carboxymethyl cellulose, starch, sucrose, natural gum, Magnesium Stearate or calcium, tinting material or seasonings etc.There is a lot of the variation in the medicine acceptable additive that is used for pharmaceutical dosage forms, and the selection of suitable additive is routine operation for those skilled in the art.
Composition can be tablet, capsule, powder, granula, lozenge, suppository, renewable powder or liquid preparation, for example oral or the sterilization non-enteron aisle solution or suspension.
For the consistence that obtains to take, compound of the present invention preferably exists with the form of unitary dose.Oral unit dosage form can be tablet and capsule etc., also can comprise conventional vehicle, as tackiness agent, and for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth or polyvinylpyrrolidone; Carrier or weighting agent, for example lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol or glycine.Conditioning agent can comprise disintegrating agent, for example starch, polyvinylpyrrolidone, sodium starch glycol or Microcrystalline Cellulose; The acceptable wetting agent of sanitas and medicine, for example Sodium Lauryl Sulphate BP/USP.
Except unit dosage form, the multiple doses form also within the scope of the present invention.The composition that postpones release, for example the composition of those employing sustained release coatings, microcapsule and/or slow dissolved polymers preparing carriers is conspicuous for those skilled in the art, is also included within the scope of the present invention.
Solid oral composition can be by the ordinary method preparation of mixing, filling or compressing tablet etc.The blended operation can be used for distributing promoting agent at a large amount of compositions of weighting agent that use repeatedly.This operation is conventional technology.Can for example use enteric coatings according to known conventional dose operation with the tablet dressing.
Oral liquid preparation can be, example emulsion, syrup or elixir, or have water or other suitable excipient regeneration before use with the dryed product form.Such liquid preparation can contain conventional additive, such as suspension agent, and for example sorbitol syrups, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel and hydrogenant edible-fat; Emulsifying agent, for example Yelkin TTS, anhydro sorbitol monooleate or gum arabic; Non-water excipient (can comprise edible oil), for example Prunus amygdalus oil or fractionated theobroma oil; Oily ester, for example glyceryl ester, propylene glycol ester or alcoholic acid ester; Sanitas, for example methyl p-hydroxybenzoate or ethyl ester or Sorbic Acid; Also can contain conventional seasonings or tinting material if desired.
Can utilize compound and sterilization preparing carriers fluid units consumption, be used for the enteron aisle external administration, and, can suspend or be dissolved in the carrier according to the concentration of using.During solution, compound can be dissolved in water or the injection salt solution in preparation, and before pack into suitable bottle or ampoule and sealing filtration sterilization.Preferable additives is dissolved in the excipient as local anesthetic, sanitas and buffer reagent.Suitable reducing is, for example phosphoric acid salt or Citrate trianion.For enhanced stability, composition can be behind the bottle of packing into freezing and vacuum remove and anhydrate.Except compound is to be suspended in the excipient rather than at dissolved state, and can not be accomplished by filtration outside the sterilization, the outer suspension of enteron aisle can adopt essentially identical mode to prepare.Compound can be sterilized with ordinary method, for example it is suspended in the disinfectant excipient it, preceding compound is exposed under ray or the oxyethane.Also contain tensio-active agent or wetting agent in the preferred composition, to promote the uniform distribution of compound.
Embodiment A. the preparation of compound
Synthesizing of embodiment 3:2-fluoro-valpromide.(32.3g 0.172mol) splashes into and is suspended in the 200ml that contains 7g sodium hydride (60% in oil) and does N, in the suspension of dinethylformamide (DMF) with ethyl diethylmalonate.After complete deprotonation, add 28.8ml (0.25mo1) sec.-butyl iodide, and mixture was heated 12 hours at the highest 153 ℃.With in the refrigerative mixture impouring ice/water and use extracted with diethyl ether.Wash for several times and use the organic layer that merges with water dried over sodium sulfate.Evaporating solvent, and distill thick product and obtain the 16.5g colourless liquid, boiling point is 68 ℃ under 1mbar.
In 30ml water and 60ml ethanol, with the dialkyl malonate (16.5g) that obtains and potassium hydroxide (12g) reflux 75 hours.Ethanol evaporation is with residue diluted with water and use extracted with diethyl ether.With water layer with dense HCl acidifying and reuse extracted with diethyl ether.Behind evaporation and dry solvent, the thick product (13.9g yellow oil) that obtains was heated to 175 ℃ of decarboxylation 2 hours.Distillation obtains 7.2g colourless liquid valproic acid subsequently, and boiling point is 66-68 ℃ under 0.91mbar.
With valproic acid (6.7g) and 100ml methyl alcohol and 5ml vitriol oil reflux 5 hours.Distillating carbinol, resistates dilutes with ether, is separated, and water cleans organic layer and uses dried over sodium sulfate.Carefully distill ester and the thick product of underpressure distillation, obtain the valproic acid methyl esters (4.5g) of colourless liquid, boiling point is 46 ℃ under 8mbar.
At 4 ℃, with the dried THF solution of 100ml of 4.4ml diisopropyl amide and 20ml butyllithium (hexane solution of 1.5M) preparation 0.0313mol LDA (LDA).This solution is cooled to-78 ℃, and drips the valproic acid methyl esters of 4.5g (0.0285mol).Mixture is warmed to the highest-20 ℃, makes deprotonation complete, be cooled to-78 ℃ subsequently once more.Add the 50ml THF solution of 10g (1.1. equivalent) N-fluoro-benzenesulfonamide and spend the night being up under the room temperature mixture stirred.Be separated after with the quencher of 100ml water, the extracted with diethyl ether water layer washs organic layer and uses dried over sodium sulfate with sodium bicarbonate aqueous solution and saturated sodium-chloride.Solvent is being evaporated carefully the back at the thick product of distillation, can obtain the 2-fluoro-valproic acid methyl esters (3.7 gram) of colourless liquid, boiling point is 8mbar 69-73 ℃.
With 80ml methanol (3: the 1) solution of 2-fluoro-valproic acid methyl esters (3.7g) and 1g lithium hydroxide (1 mole of crystal water) in stirred overnight at room temperature.Evaporation methyl alcohol, the dilute with water resistates is also used extracted with diethyl ether.With dense HCl with the water layer acidifying and use extracted with diethyl ether.After with solvent evaporation and drying, the thick product of 2.3g is heated up with the 10ml thionyl chloride.Remove excessive thionyl chloride by distillation, and thick sour muriate is added drop-wise in the cold ammonia soln while stirring.The filtering precipitation is also used the ethanol/water recrystallization, obtains colourless 2-fluorine valpromide crystal (1.3g), and fusing point is 110 ℃.
1H-NMR (CDCL
3: δ=0.92 (9HM m, 3xCH
3), 1.2 (1H, m, CH), 1.86 (4H, m, 2xCH
2), 5.75 and 6.34 (2H, broad, COHN
2).
Embodiment 5:2-fluoro-2-n-propyl valeramide.In inert atmosphere, the 100mlTHF solution of 0.055mol diisopropyl amide is cooled to-78 ℃, under agitation drip the THF solution of 0.050mol2-Valproic acid methyl esters.Mixture heating up is arrived-20 ℃, and then be cooled to-78 ℃.Drip the THF solution (50ml) of N-fluorobenzene sulphonamide (16g).Mixture heating up to ambient temperature overnight, is used saturated ammonium chloride solution cancellation subsequently.Add the 6N HCl aqueous solution (100ml), product with extracted with diethyl ether and with anhydrous sodium sulfate drying, concentrated and vacuum distilling, is obtained 7.3g (83%) oily 2-fluoro-2-Valproic acid methyl esters, bp73 ℃/8mbar.
(7.3g 0.041mol) is dissolved in the 60ml methyl alcohol, adds 20ml water and 0.042mol lithium hydroxide, and carries out saponification in 24 hours in stirring at room with methyl esters.Vacuum is removed methyl alcohol, and the dilute with water resistates is also used twice of extracted with diethyl ether.Then with the hcl acidifying aqueous solution and use extracted with diethyl ether.The extracted with diethyl ether method is the same.After solvent evaporation, obtain being used for the thick 2-fluoro-2-Valproic acid of next step.Available 3: the 1 hexane-ethyl acetate of acid is carried out the tripoli gel chromatography, obtains the buttery title compound.The existing report of its physics and spectroscope characteristic (Ph.D.thesis of Wei Tang, University ofBritish Columbia).
With thionyl chloride (25ml) add 2-fluoro-2-n-propyl valeric acid (7.0g .043mol) in.With the solution mild heat and remain on 60 ℃, up to stopping to produce hydrogenchloride.Excessive thionyl chloride is removed in distillation, and the vacuum distilling product obtains 7.3g oily (94%) 2-fluoro-2-propyl group propionyl chloride, bp83 ℃/12mbar.
Under agitation, with the muriate of acid (7.3,0.04mol) be added drop-wise to (100ml) in 25% ammonium hydroxide aqueous solution, keep temperature to be lower than 0 ℃ with ice/salt bath simultaneously.The precipitation that collection obtains, and use the ethanol/water recrystallization, obtain the title compound (5.0 gram g, 77%) of colourless crystalline solid, mp131 ℃.
1HNMR (CDCl
3): δ 0.92 (6H, t, J=7Hz), 1.2-2.4 (8H, m), 5.44 (1H, broad s) and 6.32 (1H, broad s).
Embodiment 8:2-fluoro-2-n-propyl heptamide.Adopt above-mentioned method, 2-propylheptanoic acid methyl esters is converted into the title compound (amount to 37%) of colourless crystalline solid, mp128 ℃.
1HNMR (CDCl
3): δ 0.9 (6H, 2t, 2CH
3), 1.2-2.02 (12H, m, 6 CH
2), 5.79 (1H, broad s, CONH) and 6.36 (1H, broad s, CONH).
Embodiment 18:2-fluoro-3-methyl-prop valeramide.With any above-mentioned method, obtain the title compound of colorless solid.
1HNMR (CDCl
3): δ 0.94 (9H, m, 3CH
3), 1.08-1.64 (4H, m), 1.64-2.0 (3H, m), 5.98 (1H, broad s, CONH) and 6.36 (1H, broad s, CONH).B. the biological activity of compound
The anti-convulsant activity of The compounds of this invention can with PTZ faint from fear test (E.Swinyard etc., 1969, " antiepileptic drug laboratory evaluation, laboratory method summary ", Epilepsia 10,107-119; E.Swinyard, J.Woodhead, in Antieplieptic Drugs, 2nd ed., D.Woodbury, J.Penry, C.Pippenger, eds., Raven Press, New York, 1982,111-126) detect.Before taking, compound is suspended in Viscotrol C-epoxyethane derivative (trade mark is called CREMOPHOR EL) aqueous solution of 25%.The suspension of testing compound to the instantaneous administration of animal intraperitoneal, was carried out subcutaneous injection pentetrazole (65mg/kg) subsequently after 15 minutes.Recorder reveals the number that tonic seizures continues the animal in 5 seconds at least in whole 30 minutes process.The test group consumption difference of six rats, 5 consumptions are used to calculate ED
50Value.The ED that calculates
50Value (making 50% animal not show the consumption of epileptic seizures) in table 1 with " anti-convulsant activity " expression.The per-cent of the animal that does not show effect is represented with " anti-convulsant activity % " in table 2.
" Rotorod " test of the sedative activity of compound (Dunham, Miya, 1957, J.Am.Pharm.Assoc., 46,208-209) determine.The suspension of the testing compound of above-mentioned 5 kinds of consumption levels is taken by the group of six animals, be placed in 15 minutes on the ROTOROD device (Rotorod, Ugobasile, Italy).The per-cent of the animal of landing is with " sedative activity % " record from the scale.TD
50The method of calculation of value (50% animal goes up " toxic dose " of landing from Rotorod) are the same, use " sedative activity TD in table 1
50" expression, in table 2, use " calm TD
50" expression.
By the suspension of giving 8 days animal of gestation injection testing compound and the potential teratogenesis shape of checking the method test compounds of 18 days fetus of gestation, (H.Nau, 1985, Toxicol.Appl.Pharmacol., 80,243-250; H.Nau, W.Loscher, 1986, Fund.Appl.Toxicol., 6,669) decision.The per-cent of fetus demonstration exencephaly is represented with " the active % of teratogenesis shape " in table 1.C. pharmacokinetics
Use VPA, valpromide, 2-fluoro-VPA or 2-fluoro-dipramide any respectively administration inject PTZ after 15,30,60 and 75 minutes, adopt aforesaid method to measure anti-convulsant activity.The results are shown in Table shown in 3.
The rat of same use gestation is studied pharmacokinetics.To 8 days rat of gestation injection 2-fluoro-dipramide 3.0mmol/kg (embodiment 5).Take blood sample in injection after 0.25,0.5,1,2,4,6,8,12 and 24 hour.After handling, determine drug level in the blood plasma with the GC-MS analytical procedure with N-methyl-N-(t-butyldimethylsilyl) trifluoroacetamide.After 1 hour, reach peak concentration (57 ± 15 μ g/ml).Transformation period is 11.3 hours (relatively, VPA is 1.4 hours).The peak concentration of metabolite 2-fluoro-2-Valproic acid is 6.5 ± 3.6 μ g/ml.Embryonic tissue concentration is the 60-70% (relatively, VPA is 100%) of mother's plasma concentration.
According to similar methods intravital all valproic acids (VPA) are analyzed, except the sodium salt solution with VPA is used for injection.D. result
The fluorination of α position can always reduce the calm side effect of carboxylic acid amides, and has in most of the cases also increased anticonvulsant effect.So, comparing with their nonfluorinated analogue, 2-of the present invention fluoridizes carboxylic acid amides and shows anticonvulsion characteristic, the ED that has improved usually
50Value and treatment ratio.In addition, they also show potential deforming remarkable reduction, onset is rapider and the transformation period is longer.
When the embodiment of this paper describes many embodiment of the present invention, thereby compound of the present invention obviously, composition and method can change the embodiment that provides variable but still used the inventive method.The phenomenon that this variable embodiment may clearly not expressed should not regarded abandoning those variable embodiments as.So, will be understood that scope of the present invention is not limited to the particular with embodiment statement, and this variable embodiment should fall in the literal scope of claim or is equal to it.
Table 1 anti-convulsant activity, calmness, treatment ratio and potential teratogenesis shape
| Compound (embodiment number) | Anti-convulsant activity ED 50,mmol/kg | Sedative activity TD 50,mmol/kg | Treatment ratio (TD 50/ED 50) | Teratogenesis shape activity (dosage, mmol/kg) |
| 2-fluoro-val-vanium (embodiment 3) | ?????0.12 | ?????0.54 | ?????4.5 | ??????0(3.0) |
| 2-fluoro-valpromide (embodiment 5) | ?????0.16 | ?????0.57 | ?????3.6 | ??????0(3.0) |
| 2-fluoro-3-methyl-prop valeramide (embodiment 3) | ?????0.12 | ?????0.45 | ?????3.8 | ??????0(3.0) |
| Valproic acid | ?????0.61 | ?????1.83 | ?????3.0 | ??????37(3.0) |
| Valpromide | ?????0.29 | ?????0.72 | ?????2.5 | ??????6.5(3.0) |
N.d.: do not measure.
Table 2 (seeing that original text is about the active definition of %)
N.d.: do not detect
The anti-convulsant activity of different time after table 3 administration
| Compound (embodiment number) | Dosage (mmol/kg) | Time after the % administration of protected animal (minute) | ||||
| 15 minutes | 30 minutes | 45 | 60 minutes | 75 minutes | ||
| Valproic acid (VPA) | ?????1.5 | ??100 | ??100 | |||
| 2-fluoro-VPA | ?????1.5 | ???0 | ???40 | ???80 | ???0 | |
| Valpromide | ?????1.5 | ??100 | ||||
| 2-fluoro-valpromide (embodiment 5) | ?????1.5 | ??100 | ||||
| 2-fluoro-valpromide (embodiment 5) | ?????1.0 | ???80 | ???60 | ???40 | ||
Claims (15)
1. formula I compound:
R wherein
1And R
2Independently be selected from C respectively
3-C
5Straight chained alkyl, C
3-C
5Branched-chain alkyl, C
3-C
5Cycloalkyl, (cyclopropyl) methyl, 1-(cyclopropyl) ethyl, 2-cyclopropyl (ethyl) and (cyclobutyl) methyl.
2. the compound of claim 1, wherein R
1And R
2Independently be selected from C respectively
3-C
4Straight chained alkyl, C
3-C
4Branched-chain alkyl, cyclopropyl, cyclobutyl and (cyclopropyl) methyl.
3. the compound of claim 1, wherein R
1Be selected from n-propyl, sec.-propyl, normal-butyl and 1-methyl-propyl; And R
2Be C
3-C
5Positive alkyl, C
3-C
5Branched-chain alkyl, C
3-C
5Cycloalkyl, (cyclopropyl) methyl, 1-(cyclopropyl) ethyl, 2-cyclopropyl (ethyl) and (cyclobutyl) methyl.
4. the compound of claim 1, wherein R
1And R
2Independently be selected from n-propyl, sec.-propyl, normal-butyl and 1-methyl-propyl respectively.
5. be selected from the compound of 2-fluoro-2-n-propyl valeramide, 2-fluoro-2-ethyl-3-methylpent acid amides and 2-fluoro-2-(1-methyl-propyl) valeramide.
6. one kind is reduced the active method of Mammals epileptic seizures, comprises the compound of taking the claim 1 of treatment significant quantity to described Mammals.
7. one kind is reduced the active method of Mammals epileptic seizures, comprises the compound of taking the claim 2 of treatment significant quantity to described Mammals.
8. one kind is reduced the active method of Mammals epileptic seizures, comprises the compound of taking the claim 3 of treatment significant quantity to described Mammals.
9. one kind is reduced the active method of Mammals epileptic seizures, comprises the compound of taking the claim 4 of treatment significant quantity to described Mammals.
10. one kind is reduced the active method of Mammals epileptic seizures, comprises the compound of taking the claim 5 of treatment significant quantity to described Mammals.
11. a pharmaceutical composition, the compound that comprises at least a claim 1 can be accepted additive with at least a medicine and combine.
12. a pharmaceutical composition comprises that the compound of at least a claim 2 combines with at least a medicine acceptable additive.
13. a pharmaceutical composition comprises that the compound of at least a claim 3 combines with at least a medicine acceptable additive.
14. a pharmaceutical composition comprises that the compound of at least a claim 4 combines with at least a medicine acceptable additive.
15. a pharmaceutical composition comprises that the compound of at least a claim 5 combines with at least a medicine acceptable additive.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9028498P | 1998-06-22 | 1998-06-22 | |
| US60/090,284 | 1998-06-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1306503A true CN1306503A (en) | 2001-08-01 |
Family
ID=22222110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99807600A Pending CN1306503A (en) | 1998-06-22 | 1999-06-22 | 2-fluoro-2-alkyl alkanoamides with anticonvulsant activity |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1089962A1 (en) |
| JP (1) | JP2002518469A (en) |
| CN (1) | CN1306503A (en) |
| AU (1) | AU4701399A (en) |
| CA (1) | CA2335598A1 (en) |
| WO (1) | WO1999067199A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060004098A1 (en) | 2003-07-28 | 2006-01-05 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compounds useful for treating neurological disorders |
-
1999
- 1999-06-22 JP JP2000555855A patent/JP2002518469A/en active Pending
- 1999-06-22 CA CA002335598A patent/CA2335598A1/en not_active Withdrawn
- 1999-06-22 EP EP99930479A patent/EP1089962A1/en not_active Withdrawn
- 1999-06-22 AU AU47013/99A patent/AU4701399A/en not_active Abandoned
- 1999-06-22 WO PCT/US1999/013941 patent/WO1999067199A1/en not_active Application Discontinuation
- 1999-06-22 CN CN99807600A patent/CN1306503A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999067199A1 (en) | 1999-12-29 |
| EP1089962A1 (en) | 2001-04-11 |
| AU4701399A (en) | 2000-01-10 |
| CA2335598A1 (en) | 1999-12-29 |
| JP2002518469A (en) | 2002-06-25 |
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