CA2335598A1 - 2-fluoro-2-alkyl alkanoamides with anticonvulsant activity - Google Patents

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

TITLE

FIELD OF THE INVENTION
This invention relates to 2-fluoro-2-alkyl alkanoic acid amides, to the preparation of these compounds, and to the use thereof as anti-convulsive therapeutic agents.
The anticonvulsant fluorinated amides of the invention have an improved therapeutic ratio compared to valproic acid and valpromide with respect to sedative effects, and have reduced teratogenic potential. In general, the fluorinated amides of this invention also exhibit a more rapid onset of action than the corresponding fluorinated acids. The invention provides effective anti-epileptic agents with a greater margin of safety than either valproic acid or valpromide.
BACKGROUND OF THE INVENTION
Epilepsy affects roughly 1 % of the world's population. Among the drugs employed for control of epileptic seizures is valproic acid. Valproic acid (also referred to as VPA, valproate, or 2-propylpentanoic acid) is an effective anticonvulsant, but it has a short duration of action.
More seriously, VPA suffers from serious side effects, among them sedation, potentially fatal hepatotoxicity, and teratogenicity. Hepatotoxicity is particularly a problem in young children, especially children on polytherapy. The VPA-induced hepatic fatality rate among the latter patient category is reported to be 1/500 (F. E. Dreifuss et al., Neurolo~v (1987), 37, 379-385).
Valproic acid has been shown to induce neural tube defects in mice, and it is estimated that the risk of spina bifida among newborns of women taking VPA during pregnancy is 1-2% (Centers for Disease Control, Morbidit~and Mortality Weekly Report (1983), 32(33), 438-439).
There has been a considerable effort to discover analogues of valproic acid that are equally effective, but that have a greater margin of safety. See, for example, H. Nau et al., PCT
application WO 94/06743, wherein a variety of modifications to the alkyl chains of valproic acid are made, and the related U.S. Patent 5,786,380.
With regard to teratogenicity, it has been reported that introduction of a triple bond into the 4-position of valproic acid greatly increases teratogenicity, but that this effect is largely confined to the S-(-) enantiomer. Addition of a methyl group to the end of the triple bond abolished teratogenicity, while maintaining anticonvulsant activity (H. Nau, R.-S. Hauck, K.
Ehlers, Pharmacologr~& Toxicology (1991), 69, 310-321.) These results indicated that separation of teratogenicity and anticonvulsive activity was possible.
Sedative side effects were 475049 f also separated from anticonvulsant activity in some analogues (M. Elmazar, R.-S. Hauck, H.
Nau, J. Pharm. Sci. (1993), 82, 1255-1288.) Alpha-branched carboxylic acids with an alpha-fluorine are little known. P.
Crowley et al., in European patent application EP 468681, refers to 2-ethyl-2-fluorobutanoic acid as a fungicide intermediate, and a method for its preparation. Takeuchi refers to several examples of this class of compound in a publication relating to methods of preparing tertiary alkyl fluorides (Y. Takeuchi et al., J. Org. Chem. (1993), 58(13), 3483-3485).
The valproic acid analogue 2-fluoro-2-propyl-4-pentenoic acid has also been reported.
The compound was used as a probe for studies of valproic acid hepatotoxicity and metabolism.
(W. Tang et al., Chem. Res. Toxicol. (1995), 8(5), 671-G82; M. Jurima-Romet et al., Toxicolo~v (1996), 112(1), 69-85; W. Tang and F. Abbott, Drue Metab. Dispos.
(1997), 25(2), 219-227.} In the above references, the presence of the 2-fluoro substituent was reported to reduce hepatotoxicity relative to 2-propyl-4-pentenoic acid. Anticonvulsant, sedative or teratogenic properties of the fluorinated compound were not disclosed.
Alpha-fluorinated valproic acid, 2-fluoro-2-propylpentanoic acid, has also been reported (Ph.D. thesis of Wei Tang, University of British Columbia, 1996). The anticonvulsant activity and pharmacokinetics of this compound were studied, and its pharmaceutical potential was speculated upon (F. Abbott, W. Tang, J. Palaty, J. Pharmacol. Ex~ Ther.
(1997), 282, 1163-1172). The compound was reported to be less potent than VPA, and the hepatotoxic, sedative, or teratogenic properties were not disclosed.
Valproic acid analogues with terminal trifluoromethyl groups have been reported: 5,5,5-trifluoro-2-(3,3,3-trifluoropropyl) pentanoic acid (K. Yamaguchi and M.
Taninaka, Japanese patent Application 4-21652 (1992), and 5,5,5-trifluoro-2-n-propyl pentanoic acid (Hiroshima et al., Japan J. Psychopharmacol. (1992) 12, 427). These compounds, too, are less potent than VPA.
Valpromide (VPD, the amide of valproic acid) is a widely-used prodrug of valproic acid. VPD is known to be rapidly metabolized in humans to valproic acid after oral administration (M. Bialer, Int. J. Pharm. (1985) 23 25-33). Interspecies variations in the rate of metabolism are considerable; in mice, for example, metabolic hydrolysis is known to be relatively slow. Certain beta-alkylated analogues such as 2-ethyl-3-methyl-pentanoamide (valnoctamide) are resistant to this route of metabolism. See A. Haj-Yehia, M.
Bialer et al., J.
Pharm. Sci., 79, 719-724 (1990), and references therein. Certain substituted cyclopropane carboxamides have also been found to be metabolically stable anticonvulsants:
M. Bialer et al., Pharm. Res., 13, 284-289 (1996). The resistance to hydrolysis among these compounds is attributed to steric effects.
SUMMARY OF THE INVENTION
This invention relates to 2-fluoro-2-alkyl alkanoamides, pharmaceutical compositions containing these compounds, and their use to treat or prevent convulsions.
This invention also provides processes for the preparation of these compounds. The preferred 2-fluorinated carboxamides of the invention exhibit greatly reduced embryotoxicity and teratogenicity, an improved therapeutic ratio with respect to sedation, and a longer duration of activity, when compared to valproic acid or valpromide. The 2-fluorinated carboxamides of this invention unexpectedly provide a more rapid onset of activity than do the corresponding 2-fluorinated carboxylic acids.
The invention provides compounds of formula I below:

(I) wherein R' and RZ are independently chosen from the group consisting of C3 to CS alkyl, C3 to CS cycloalkyl, (cyclopropyl)methyl, 1-(cyclopropyl)ethyl, 2-cyclopropyl(ethyl), and (cyclobutyl)methyl. The term "alkyl" as used herein is intended to include both straight-chain and branched alkyl groups.
The invention also provides a method for treating and/or preventing convulsions due to a variety of causes, by administering to an individual in need of such treatment a therapeutically or prophylactically effective amount of at least one of the compounds of this invention.
In addition the compounds of this invention may be useful for treating and/or preventing affective disorders, especially the mania phase of bipolar depression; and migraine.
An object of this invention is to provide compounds useful for preventing or reducing seizure activity in a mammal.
Another object of this invention is to provide anti-convulsant pharmaceutical compositions comprising at least one compound of this invention.
Yet another object of this invention is to provide methods of preventing or reducing seizure activity by administering to an individual in need of such treatment a pharmaceutical composition of this invention.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Dose-effect curves of valproic acid and several 2-alkyl alkanoamides and 2-fluoro-2-alkyl alkanoamides.
3Me-VPD = 3-methyl valpromide, 3-methyl-2-propylpentanoic acid;
2F-VCD = 2-fluoro valnoctamide, 2-ethyl-2-fluoro-3-methylpentanoic acid;
VCD = valnoctaamide, 2-ethyl-3-methylpentanoic acid;
2F-VPD = 2-fluorovalpromide, 2-fluoro-2-propylpentanoamide;
VPD = valpromide, 2-propylpentanoamide;
VPA = valproic acid, 2-propylpentanoic acid.
I O Figure 2: Representative example of synthesis of compounds of the invention:
2-fluoro-valnoctamide.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides compounds having the following structure:
CONHZ
CI) ~F
15 where R~ and RZ are independently C3 to CS n-alkyl, C3 to CS branched alkyl, C3 to CS
cycloalkyl, (cyclopropyl)methyl, 1-(cyclopropyl)ethyl, 2-cyclopropyl(ethyl), or (cyclobutyl)methyl. The term "alkyl" as used herein is intended to include both straight-chain and branched alkyl groups. In a preferred embodiment, Rl and RZ are independently C3 to C4 alkyl, cyclopropyl, cyclobutyl, or (cyclopropyl)methyl. In another preferred embodiment, R~ is 20 n-propyl, i-propyl, n-butyl, or 1-methylpropyl; and RZ is C3 to CS alkyl, C3 to CS cycloalkyl, (cyclopropyl)methyl, 1-(cyclopropyl)ethyl, 2-cyclopropyl(ethyl), or (cyclobutyl)methyl. In a more preferred embodiment, R~ and Rz are independently n-propyl, i-propyl, n-butyl, or 1-methylpropyl. Most preferably, the compound is selected from the group consisting of 2-fluoro-2-n-propylpentanoamide, 2-fluoro-2-ethyl-3-methylpentanoamide, and 2-fluoro-2-(1-25 methylpropyl)pentanoamide.
The compounds of this invention exhibit unexpected advantages over the compounds of the prior art with respect to their pharmacodynamics. While VPA and valpromide have a very rapid onset of activity, they suffer from the above-mentioned side effects of sedation and teratogenicity. While 2-fluoro-VPA has been found to be free of teratogenic effects, it is much 30 less potent than VPA, and it does not reach maximal activity until about one hour after administration. Also, the duration of activity of 2-fluoro-VPA is relatively short, with in vfvo activity lasting for only about 75 minutes (see Table 3).
In contrast to 2-fluoro-VPA, the compounds of this invention, as exemplified by 2-fluoro-2-propylpentanoarnide (example 5) exhibit a rapid onset, reaching maximal activity within 15 minutes (comparable to that of VPA and valpromide; see Table 3).
This is combined with a long half life of 11.3 hours, versus 1.4 hours for VPA (see below), and 0.84 hours for valpromide (in humans: M. Bialer et al., 1985, Int. J. Pharm., 23, 25-33).
Thus, 2-fluoro-2-propylpentanoamide combines the rapid onset of VPA and valpromide with the safety of 2-fluorovalproic acid, and additionally has a remarkably and surprisingly long half life. Such properties have not been previously obtained with anti-convulsants of this class.
There are two major reasons for employing a pro-drug form, which are to improve absorption/distribution properties, and/or to provide more prolonged pharmacological effects.
Pro-drug forms must undergo metabolic conversion to their pharmacologically active forms, hence pro-drug forms will generally exhibit either a delayed onset of activity relative to the parent drug, or at best an onset of action comparable to that of the parent drug.
Unexpectedly, the alpha-fluoro carboxamides described herein have been found to exhibit a significantly faster onset of action than the corresponding carboxylic acids, even in the absence of steric effects. This effect is observed upon parenteral administration, and therefore it is not due to more rapid absorption from the gastrointestinal tract. The compounds are also more potent than the corresponding acids, and have a longer duration of activity.
The 2-fluoro carboxamides of this invention thus appear to possess intrinsic anti-convulsant activity. These compounds are not merely pro-drugs for the fluorinated carboxylic acids, but possess their own uniaue pharmacology. Accordingly, this invention provides alpha-fluorinated carboxamides, which are useful for treating or preventing seizures, which are not teratogenic, and which upon metabolism generate non-teratogenic metabolites which are themselves anticonvulsants.
The compounds of the invention can be prepared by methods known in the art for the preparation of other alpha-fluoro carboxylic acids, followed by conversion to the amide. For example, treatment of a 2-hydroxy-2-alkyl alkanoate ester with diethylaminosulfur trifluoride (DAST} provides the corresponding alpha-fluoro ester, which upon hydrolysis provides the acid (P. Crowley et al., 1992, European patent application EP 468681).
Alternatively, a 2-amino-2-alkyl alkanoic acid can be subjected to diazotization in the presence of fluoride ion, to effect a deaminative fluorination (J. Barber, R. Keck, J. Retey, Tetrahedron Letters (1982), 23, 1549-1552). The Reformatsky reaction can be carried out on a 2-bromo-2-fluoroalkanoate ester (Y.
Takeuchi et al., J. Org. Chem. (1993), 58(13), 3483-3485) to introduce a 2-alkyl group. In one embodiment that is preferred for laboratory-scale synthesis, an ester enolate or silyl enol ether of a 2-alkyl alkanoic acid is fluorinated with a "positive fluorine" source, such as an N-fluoro pyridinium salt, N-fluoro amide, or N-fluoro imide (see, e.g., E. Differding, G. Ruegg, Tetrahedron Letters (1991), 32, 3815-3818). In the particular embodiment exemplified below, the lithium enolate of methyl 2-propylpentanoate is fluorinated with N-fluoro benzenesulfonimide, but it will be understood that other methods of synthesis are within the scope of this invention.
The starting esters for the exemplified process are in many cases commercially available; alternatively they may be obtained by methods known in the art, for example the malonic ester synthesis described in M. Elmazar, R.-S. Hauck, H. Nau, J.
Pharm. Sci. (1993), 82, 1255-1288. See also H. Nau et al., 1994, PCT International Application, publication No.
WO 94/06743, and US patent application serial No. 08/344,810. The well-known acetoacetate variation of the malonic ester synthesis is also applicable. In the example below, direct alkylation of a straight-chain ester enolate is employed. Other methods of synthesis will be apparent to those skilled in the art, and this invention is not limited by the particular synthetic method exemplified herein.
In general terms, this invention provides a process for preparation of compounds of structure I, which comprises the steps of:
a) alkylating a compound of structure COORS
R1 H (II) wherein R~ is as defined above and R3 is lower alkyl (preferably C, to Ca alkyl) or benzyl, and R4 is lower alkyl (preferably C, to Ca alkyl), lower alkoxy (preferably C~ to C4 alkoxy), or benzyloxy, with an alkylating reagent of structure Rz X (III) wherein X is a suitable leaving group, and wherein RZ is as defined above, in the presence of a suitable base, so as to obtain a compound of structure COORS
R1 R2 C IV) (b) in the cases where R4 is lower alkoxy or benzyloxy, hydrolysis, decarboxylation, and re-esterification if necessary of compound IV; or in cases where R4 is lower alkyl, deacylation S of compound IV, so as to obtain a compound of structure COORS
R1 R2 (V) H
(d) enolization of compound V with a suitable base, in an inert solvent;
(e) addition of a fluorinating reagent, so as to obtain a compound of structure COORS
R1 R2 (VI) F
(f) hydrolysis of the ester moiety, and (g) conversion of the carboxylic acid to a carboxamide.
Suitable identities of group R'' will be apparent to those skilled in the art.
Preferred R4 groups are alkoxy groups which are readily saponified, such as methoxy or ethoxy, or other carboxylic acid protecting groups which are readily removed by other means, such as tert-butoxy, benzyloxy, and the like. It will be appreciated that the term "hydrolysis" as used in steps (b) and (f) is intended to encompass the deprotecting operations appropriate to the nature of R4, for example saponification in the case of lower alkoxy groups, acidolysis in the case of tert-butoxy groups or hydrogenolysis in the case of benzyloxy groups. Similar considerations apply to the group R3, which is preferably lower alkyl such as methyl or ethyl but which may be another carboxy-protecting group, such as for example, tert-butyl, benzyl, and the like. It will be apparent that in step (b), where R3 is removed and then re-introduced, the practitioner will have the opportunity to change the identity of R3 if it is desired to do so.
Where R4 is alkyl, the preferred groups are those which lend themselves to deacylation _g_ of the group COR4; in these cases R4 is most preferably methyl. Deacylation may be accomplished by treatment with, for example, sodium hydroxide or ammonia, or other methods known in the art.
Suitable leaving groups X may be selected from, but are not limited to, the halogens chlorine, bromine, or iodine, or sulfonate ester groups such as methanesulfonyloxy or toluenesulfonyloxy. Suitable bases for step (a) may be chosen from, but are not limited to, alkali metal alkoxides, calcium and magnesium alkoxides, alkali metal hydrides, and the like.
Suitable bases for step (d) will be apparent to those skilled in the art, since a number of procedures for enolizing esters have been published. Preferred bases will be those with a sufficiently high pKa to substantially deprotonate the compound V, and which are also non-reactive with the functional groups of the compound V. Examples may be chosen from, but are not limited to, the lithium or sodium salts of hindered disubstituted amines, such as lithium diisopropylamide or lithium hexamethyldisilazide.
In an alternative process, compounds of formula (I) may be prepared by the process I S comprising the steps of:
a) alkylating a compound of structure COORS
R1 H (VII) H
wherein R~ is as defined above, and R3 is lower alkyl or benzyl, with an alkylating reagent of structure RZ X (III) wherein X is a suitable leaving group as described above, and wherein Rz is as defined above, in the presence of a suitable base, so as to obtain a compound of structure COORS
R1 Rz (V) H
(b) enolization of compound V with a suitable base, in an inert solvent;
(c) addition of a fluorinating reagent, so as to obtain a compound of structure COORS
R1 Rz (VI) F

(d) hydrolysis of the ester moiety, and (e) conversion of the carboxylic acid to the carboxamide.
It will be apparent to those skilled in the art that modifications to the exemplified procedure can be made. For example, inert solvents other than THF may be employed, such as dioxane, di-alkyl ethers, dimethoxyethane and other polyethers, toluene, heptane, and the like.
Additives such as hexamethylphosphoramide, tetramethylethylenediamine, or tetramethylurea can be employed in the fluorination reaction, and other bases such as alkali metal hydrides, alkoxides, or hexamethyldisilazide salts can be employed in the deprotonation reactions. Such modifications could be made for any reason, for example to improve the yield or to reduce process costs, without departing from the scope of this invention, and experimentation to determine the most desirable conditions for any given reaction would be a routine matter to those skilled in the art.
By way of example, a procedure for conversion of the carboxylic acid to the carboxamide is also provided below. The carboxamides of this invention may be prepared by the method provided, or by any of a variety of methods, such as condensation of 2-fluoro-2-alkyl alkanoic acids with ammonia or ammonium salts in the presence of a carbodiimide or other condensation reagent, or by ammonolysis of the corresponding esters.
Such methods will be apparent to those skilled in the art, and it will be understood that this invention is not limited by the exemplified means of synthesis.
By the methods provided herein, the following compounds of this invention may be prepared from the appropriate starting materials;
Example No. Compound 1 2-fluoro-2-ethylpentanoamide 2 2-fluoro-2-ethylhexanoamide 3 2-fluoro-2-ethyl-3-methylpentanoamide 4 2-fluoro-2-ethylheptanoamide 5 2-fluoro-2-n-propylpentanoamide 6 2-fluoro-2-n-propylhexanoamide 7 2-fluoro-2-n-propyl-3-methylpentanoamide 8 2-fluoro-2-n-propylheptanoamide 9 2-fluoro-2-i-propylpentanoamide 10 2-fluoro-2-i-propylhexanoamide 11 2-fluoro-2-i-propyl-3-methylpentanoamide 12 2-fluoro-2-i-propylheptanoamide i 3 2-fluoro-2-cyclopropylpentanoamide 14 2-fluoro-2-cyclopropylhexanoamide S 1 S 2-fluoro-2-cyclopropyl-3-methylpentanoamide 16 2-fluoro-2-cyclopropylheptanoamide 17 2-fluoro-2-n-butylhexanoamide 18 2-fluoro-2-(1-methylpropyl)pentanoamide 19 2-fluoro-2-(1-methylpropyl)hexanoamide 20 2-fluoro-2-(1-methylpropyl)-3-methylpentanoamide 21 2-fluoro-2-(1-methylpropyl)heptanoamide 22 2-fluoro-2-cyclobutylpentanoamide 23 2-fluoro-2-cyclobutylhexanoamide 24 2-fluoro-2-cyclobutyl-3-methylpentanoamide 1S 2S 2-fluoro-2-cyclobutylheptanoamide 26 2-(cyclopropyl)methyl-2-fluoropentanoamide 27 2-(cyclopropyl)methyl-2-fluorohexanoamide 28 2-(cyclopropyl)methyl-2-fluoro-3-methylpentanoamide 29 2-(cyclopropyl)methyl-2-fluoroheptanoamide 30 2,2-bis(cyclopropyl)-2-fluoroacetamide 31 2-cyclobutyl-2-cyclopropyl-2-fluoroacetamide 32 2-fluoro-2-i-propyl-3-methylbutanoamide 33 2-fluoro-2-i-propyl-4-methylpentanoamide 34 2-fluoro-2-i-propyl-3,3-dimethylbutanoamide 3S 2-fluoro-2-i-propyl-3-methylhexanoamide 36 2-fluoro-2-i-propyl-4-methylhexanoamide 37 2-fluoro-2-i-propyl-S-methylhexanoamide 38 2-fluoro-2-i-propyl-3,3-dimethylpentanoamide 39 2-fluoro-2-i-propyl-4,4-dimethylpentanoamide 40 2-cyclopropyl-2-fluoro-3-methylbutanoamide 41 2,3-bis(cyclopropyl)-2-fluoropropionamide 42 2-cyclobutyl-2-fluoro-3-methylbutanoamide 43 2-cyclopentyl-2-fluoro-3-methylbutanoamide 44 2-(cyclobutylmethyl)-2-fluoro-3-methylbutanoamide 45 2-(1-cyclopropylethyl)-2-fluoro-2-(i-propyl)butanoamide 46 2-(cyclopropylmethyl)-2-fluoro-3-methylbutanoamide 47 2-fluoro-2-(1-methylpropyl)-4-methylpentanoamide 48 2-fluoro-2-(1,1-dimethylethyl)-3-methylbutanoamide 49 2-fluoro-2-(1-methylpropyl)-3-methylhexanoamide 50 2-fluoro-2-(1-methylpropyl)-4-methylhexanoamide 51 2-fluoro-2-( I -methylpropyl)-5-methylhexanoamide 52 2-fluoro-3,3-dimethyl-2-(1-methylpropyl)pentanoamide 53 2-fluoro-4,4-dimethyl-2-(1-methylpropyl)pentanoamide 54 2-cyclopropyl-2-fluoro-3-methylpentanaamide 55 2-cyclobutyl-2-fluoro-3-methylpentanoamide 56 2-cyclopentyl-2-fluoro-3-methylpentanoamide 57 2-(cyclobutylmethyl)-2-fluoro-3-methylpentanoamide 58 2-(1-cyclopropylethyl)-2-fluoro-3-methylpentanoamide 59 2-(cyclopropylmethyl)-2-fluoro-3-methylpentanoamide 60 3-ethyl-2-fluoro-2-(1-methylpropyl)pentanoamide 61 3-ethyl-2-( 1-ethylpropyl)-2-fluoropentanoamide 62 3-ethyl-2-(1-ethylbutyl)-2-fluoropentanoamide The above compounds are presented merely by way of example, and are not intended to limit the scope of the invention.
It will be apparent to those skilled in the art that most of the compounds of this invention may exist in enantiomeric and diastereomeric forms. Pure enantiomers may be resolved from the racemate by methods well-known in the art, for example by fractional recrystallization of diastereomeric amine salts of the corresponding 2-fluoro-2-alkyl alkanoic acids, by chromatography of diastereomeric derivatives, or by chiral column chromatography.
Alternatively, enantiomeric forms may be prepared by chiral synthesis, for example by alkylation or fluorination of chiral hydrazones (R.-S. Hauck, H. Nau, 1989, Toxicology Letters, 49, 41-48) or by alkylation or fluorination of chiral oxazolidinone derivatives (H. Nau et al., 1994, PCT International Application, publication No. WO 94/06743, US patent application serial No. 08/344,810). Chiral starting materials may also be employed in the synthesis of the compounds of this invention. Individual diastereomers, R and S enantiomers, racemates, and non-racemic mixtures of enantiomers or diastereomers of structure I are all contemplated to be within the scope of this invention.
Another object of this invention is to provide a method of treating individuals with epilepsy, or others in need of anticonvulsant therapy, with compounds of formula I. Mammals, and in particular humans, who would benefit from this method of treatment include those exhibiting, or at risk for exhibiting, any type of seizure. For example, the methods of this invention are useful for treating individuals with idiopathic generalized seizures such as absence, myoclonic and tonic-clonic seizures and partial seizures. Individuals suffering from epilepsy, in particular, are expected to benefit from administration of the compounds of this invention. The method of the invention comprises administering to an individual a therapeutically effective amount of at least one compound of formula I or a salt or prodrug thereof, which is sufficient to reduce or prevent seizure activity.
The dose of the compound used in the treatment of such disease will vary in the usual way with the seriousness of the disorder, the weight and metabolic health of the sufferer, and the relative efficacy of the compound employed. The preferred initial dose for the general patient population will be determined by routine dose-ranging studies, as are conducted for example during clinical trials. Therapeutically effective doses for individual patients may be determined by titrating the amount of drug given to the individual to arrive at the desired therapeutic or prophylactic effect while minimizing untoward side effects, as is currently done with valproic acid. Dosages may be similar to those used with VPA, however they may be adjusted appropriately, based on the potencies and kinetic parameters disclosed herein or as determined by routine methods.
For example, the compound 2-fluoro-2-n-propylpentanoamide would be expected to be useful at dosages which are about 25% of those used for VPA. A preferred initial dose for this compound, accordingly, may be estimated to be between about 1 and 60 mg/kg/day, more preferably between S and 15 mg/kg/day. The initial dose may be varied so as to obtain the optimum therapeutic effect in the patient, and may be provided as a daily dose or in a divided dose regimen. In general, the compounds of this invention will be provided in doses of between 1 and 150 mg/kg/day.
Administration of the compounds of this invention may be by any method used for administering therapeutics, such as for example oral, parenteral, intravenous, intramuscular, subcutaneous, or rectal administration.
This invention also provides pharmaceutical compositions useful for providing anticonvulsant activity, which comprise at least one compound of the invention. In addition to comprising at least one of the compounds described by formula I, the pharmaceutical composition may also comprise additives such as preservatives, excipients, fillers, wetting agents, binders, disintegrants, buffers, and/or carriers. Suitable additives may be for example magnesium and calcium carbonates, carboxymethylcellulose, starches, sugars, gums, S magnesium or calcium stearate, coloring or flavoring agents, and the like.
There exists a wide variety of pharmaceutically acceptable additives for pharmaceutical dosage forms, and selection of appropriate additives is a routine matter for those skilled in art of pharmaceutical formulation.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose. Unit dose forms for oral administration may be tablets, capsules, and the like, and may contain conventional excipients such as binding agents, for 1 S example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; and carriers or fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine.
Additives may include disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; preservatives, and pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
In addition to unit dose forms, mufti-dosage forms are also contemplated to be within the scope of the invention. Delayed-release compositions, for example those prepared by employing slow-release coatings, micro-encapsulation, and/or slowly-dissolving polymer carriers, will also be apparent to those skilled in the art, and are contemplated to be within the scope of the invention.
The solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
Such operations are conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, for example with an enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats;
emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil or fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavoring or coloring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile Garner, and, depending on the concentration used, can be either suspended or dissolved in the Garner. In preparing solutions the compound can be dissolved in water or saline for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, additives such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. Suitable buffering agents are, for example, phosphate and citrate salts. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially 1 S the same manner, except that the compound is suspended in the carrier instead or being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by conventional means, for example by exposure to radiation or ethylene oxide, before being suspended in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
EXAMPLES
A. Preparation of the compounds.
Example 3: Synthesis of 2-fluoro-valnoctamide. Ethyl diethyl malonate (32.3 g, 0.172 mol) was dropped into a suspension of 7 g sodium hydride (60% in oil) in 200 ml dry N,N-dimethylformamide (DMF). After complete deprotonation 28.8 ml (0.25 mol) 2-iodobutane was added and the mixture was warmed up to 153° for 12 h.
The cooled mixture was poured into ice/water and extracted with ether. The combined organic layers were washed several times with water and dried over sodium sulfate. The solvent was evaporated and distillation of the crude product yielded 16.5 g colorless liquid, boiling point 68°C at 1 mbar.
The resulting dialkyl malonic ester (16.5 g) and potassium hydroxide (12 g) were heated to reflux in 30 ml water and 60 ml ethanol for 75 h. Ethanol was evaporated, the residue was diluted with water and extracted with ether. The water layer was then acidified with concentrated HCl and again extracted with ether. After drying and evaporation of the solvent the crude product (13.9 g yellow oil} was heated to 175°C for decarboxylation for 2 h.
Subsequent distillation yielded 7.2 g valnoctic acid as a colorless liquid, boiling point 66-68°C
at 0.9 mbar.
Valnoctic acid (6.7 g) was warmed up to reflux with 100 ml methanol and 5 ml concentrated sulfuric acid for 5 h. Methanol was distilled, the residue was diluted with ether, the phases were separated and the organic layer was washed with water and dried over sodium sulfate. The ester was distilled carefully and the crude product distilled under reduced pressure to provide methyl valnoctate as a colorless liquid (4.5 g), boiling point 46°C at 8 mbar.
At 4°C a solution of 0.0313 mol lithium diisopropyl amide (LDA) in 100 ml dry THF
was prepared from 4.4 ml diisopropylamine and 20 ml butyl lithium ( 1.5 M in hexane). This solution was cooled to -78°C and 4.Sg (0.0285 mol) valnoctic acid methyl ester was dropped in.
The mixture was allowed to warm up to -20°C to make deprotonation complete and then cooled again to -78°C. lOg (l.l.equivalents) N-fluoro-benzenesulfonimide in 50 ml THF was added and the stirred mixture was allowed to warm to room temperature over night.
After quenching 1 S with 100 ml water the layers were separated, the water layer was extracted with either, the organic layers were washed with aqueous sodium hydrogen carbonate and saturated sodium chloride, and dried over sodium sulfate. After careful evaporation of the solvent the crude product was distilled to provide 2-fluoro-valnoctic acid methyl ester (3.7 g) as a colorless liquid, boiling point 69-73°C at 8 mbar.
2-Fluoro-valnoctic acid methyl ester (3.7 g) was stirred with 1 g lithium hydroxide (one mole crystal water) in 80 ml methanol/water (3:1 ) at room temperature over night. Methanol was evaporated, the residue was diluted with water and extracted with ether.
The water layer was acidified with concentrated HC1 and extracted with ether. After drying and evaporation of the solvent 2.3 g crude acid were warmed in 10 ml thionyl chloride. Excess thionyl chloride was removed by distillation and the crude acid chloride was dropped with stirnng into a cooled solution of ammonia in water. The precipitate was filtered off and recrystallized from ethanol/water to provide 2-fluoro-valnoctamide ( 1.3 g} as colorless crystals, melting point 110°C. ~H-NMR (CDCL3: 8=0.92 (9HM m, 3 x CH3), 1.2 (1H, m, CH), 1.86 (4H, m, 2 x CHZ), 5.75 and 6.34 (2H, broad, COHNz).
Example 5: 2-fluoro-2-n-propvlpentanoamide. A solution of 0.055 mol of lithium diisopropylamide in 100 ml THF was cooled to -78°C under an inert atmosphere, and 0.050 mol of methyl 2-propylpentanoate in THF was added dropwise with stirring. The mixture was allowed to warm to -20°C, then cooled again to -78°C. A solution of N-fluoro benzenesulfonimide (16 g) in THF (SO ml) was added dropwise. The mixture was allowed to warm to room temperature overnight, and was quenched with saturated ammonium chloride solution. Aqueous 6N HCl (100 ml) was added, and the product extracted with ethyl ether, dried with anhydrous sodium sulfate, concentrated, and distilled in vacuo to provide 7.3 g S (83%) methyl 2-fluoro-2-propylpentanoate as an oil, by 73°C/8mbar.
The methyl ester (7.3 g, 0.041 mol) was saponified by dissolving it in 60 ml of methanol, adding 20 ml of water and 0.042 mol of lithium hydroxide, and stirring at room temperature for 24 hours. The methanol was removed in vacuo, and the residue diluted with water and extracted twice with ethyl ether. The aqueous solution was then acidified with hydrochloric acid and extracted again with ether. The ether extract was worked up as above, and after evaporation of solvent the crude 2-fluoro-2-propylpentanoic acid was used as is for the next step. The acid could be chromatographed on silica gel with 3:1 hexane-ethyl acetate to provide the title compound as an oil. The physical and spectroscopic properties were as reported (Ph.D. thesis of Wei Tang, University of British Columbia, 1996).
To 2-fluoro-2-n-propylpentanoic acid (7.0 g, .043 mol) was added thionyl chloride (25 ml). The solution was warmed gently and maintained at 60°C until the evolution of hydrogen chloride ceased. Excess thionyl chloride was removed by distillation, and the product was distilled in vacuo to provide 7.3 g (94%) 2-fluoro-2-propylpropionyl chloride, by 83°C/12 mbar, as an oil.
The acid chloride (7.3 g, 0.04 mol) was added dropwise with stirring to 25%
aqueous ammonium hydroxide solution ( 100 ml), while maintaining the temperature below 0°C with an ice/salt bath. The resulting precipitate was collected and recrystallized from ethanol/water, to provide the title compound (S.0 g, 77%) as a colorless crystalline solid, mp 131°C. 'H NMR
(CDCl3): b 0.92 (6H, t, 3=7 Hz), 1.2-2.4 (8H, m), 5.44 (1H, broad s) and 6.32 (1H, broad s).
Example 8: 2-fluoro-2-n-nroRvlheptanoamide. By the method described above, methyl 2-propylheptanoate was converted into the title compound (37% overall), a colorless crystalline solid, mp 128°C. 'H NMR (CDC13}: b 0.9 (6H, 2t, 2CH3), 1.2-2.02 (12H, m, 6CHz), 5.79 (1H, broad s, CONH) and 6.36 (1H, broad s, CONH).
Example 18: 2-fluoro-3-meth~lvalpromide. By either of the methods described above, the title compound could be obtained as a colorless solid. 'H NMR (CDC13): 8 0.94 (9H, m, 3CH3), 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. Biological activities of the compounds.
The anti-convulsive activity of the compounds of the invention was determined by the PTZ convulsion test (E. Swinyard et al., 1969, "Laboratory Evaluation of Antiepileptic Drugs, Review of Laboratory Methods," Epilepsia 10, 107-119; E. Swinyard, J.
Woodhead, in Antiepileptic Drugs, 2nd ed., D. Woodbury, J. Penry, C. Pippenger, eds., Raven Press, New York, 1982, 111-126). The compounds were suspended before administration in a 25%
aqueous solution of the castor oil-ethylene oxide derivative marketed under the trade name CREMOPHOR EL. Briefly, animals were dosed intraperitoneally with a suspension of the compound to be tested, and then challenged after 15 minutes with a subcutaneous injection of pentylenetetrazole (65 mg/kg). The number of animals that exhibited tonic seizures lasting at least five seconds was noted over the course of 30 minutes. Test groups of six mice were used at each dose level, and five dosages were used to calculate the EDSO values.
The calculated EDSo values (the dose that protects 50% of animals form seizures) are presented in Table 1 as "Anticonvulsant Activity". The percentage of animals that were protected from seizures is reported in Table 2 as "Anticonvulsant Activity %".
The sedative activity of the compounds was determined by the "Rotorod" test (Dunham, Miya, 1957, J. Am. Pharm. Assoc., 46, 208-209). Groups of six animals were dosed at five dosage levels as above with a suspension of the compound to be tested, and after 15 minutes they were placed on the ROTOROD apparatus (Rotorod, Ugobasile, Italy). The percentage of animals that fell from the rod was recorded as "Sedative Activity %". The TDso values (the "Toxic Dose" at which 50% of animals fall from the Rotorod) was calculated as above, and is reported as "Sedative Activity TDSO" in Table 1 and as "Sedation TDSO" in Table 2.
The teratogenic potential of the compounds was determined by injecting pregnant animals on day 8 of gestation with a suspension of the compound to be tested, and by examining the fetuses on day 18 of gestation (H. Nau, 1985, Toxicol. Appl.
Pharmacol., 80, 243-250; H. Nau, W. Loscher, 1986, Fund. Appl. Toxicol., 6, 669). The percent of fetuses exhibiting exencephaiy is reported as "Teratogenic Activity %" in Table 1.
C. Pharmacokinetics Anticonvulsant activity was measured as described above, with PTZ being injected at 15, 30, 45, 60, and 75 minutes after dosing with either VPA, valpromide, 2-fluoro-VPA, or 2-fluoro-2-propylpentanoamide. The results are presented in Table 3.

Pharmacodynamics were also studied in pregnant mice. Mice were injected with 3.0 mmol/kg of 2-fluoro-2-propylpentanoamide (Example 5) on day 8 of gestation.
Blood samples were taken at 0.25, 0.5, l, 2, 4, 6, 8, 12, and 24 hours after injection. Drug concentrations in plasma were determined by GC-MS analysis after treatment with N-methyl-N-(t-butyldimethylsilyl) trifluoroacetamide. Maximum drug concentration (57 t 15 pg/ml) was reached after 1 hour. The half life was 11.3 hours (vs. 1.4 hours for VPA).
The maximum concentration of the metabolite 2-fluoro-2-propylpentanoic acid was 6.5 t 3.6 pg/ml. Embryo tissue concentrations were 60-70% of the maternal plasma concentrations (vs.
100% for VPA).
All in vivo assays with valproic acid (.VPA) were conducted similarly, except that a solution of the sodium salt of VPA was used for injections.
D. Results Alpha-fluorination consistently reduced the sedative side-effect of the carboxamides, and in most cases increased the anticonvulsant potency as well. Therefore, the 2-fluorinated carboxamides of the invention generally show improved anticonvulsant properties, EDso-values, and therapeutic ratios when compared to their non-fluorinated analogues. In addition, they exhibit greatly reduced teratogenic potential, a faster onset of action, and a longer half life.
While the examples presented herein describe a number of embodiments of this invention, it is apparent that the compounds, compositions, and methods of this invention can be altered to provide alternative embodiments which nonetheless utilize the methods of this invention. That such alternative embodiments may not have been expressly presented is not to be considered a disclaimer of those alternative embodiments. Therefore, it will be appreciated that the scope of this invention is not limited to the specific embodiments which have been presented above by way of example, and that such alternative embodiments will be within the literal scope of the claims or will be equivalent thereto.

Table 1.
Anti-convulsive activity, sedation, therapeutic ratio, and teratogenic potential.
i ANTICONVULSIVE SEDATIVE THERAPEUTIC TERATOGENIC

COMPOUND ACTIVITY ACTIVITY RATIO ACTIVITY, ~ (EXAMPLE EDSO, mmol/kg TDso, mmollkg(TDso/EDso) (dose, mmol/kg) NO.) 2-Fluoro- 0.12 0.54 4.5 0 (3.0) Valnoctamide (Example 3) 2-Fluoro- 0.16 0.57 3.6 0 (3.0) Valpromide (Example 5) 0.12 0.45 3.8 0 (3.0) 2-Fluoro-3-Methyl Valpromide (Example 18) Valproic 0.61 1.83 3.0 37 (3.0) acid Valpromide 0.29 0.72 2.5 6.5 (3.0) n.d. : not determined Table 2.
(see text for definition of % activity) Substance Structure Dose Activity EDso Sedation Therapeutic TDso mmollkg (%) mmollkg ratio mmollkg Valpromide 0.25 16.7 CONH2 0.28 33.3 0.29 0.72 2.5 0.3 66.7 0.4 100 2-Fluoro- 0.06 16.7 Valpromide CONH2 0.12 16.7 0.16 0.57 3.6 (Example S) 0.20 50.0 F 0.26 83.3 0.52 100 V alnoctamide 0.1 20 CONHZ p,15 20 0.17 0.68 4.1 a 0.2 60 0.4 100 2-Fluoro- 0.1 16.6 Valnoctamide CONHZ 0,12 66.6 0.12 0.54 4.5 (Example 3) Ylu 0.14 100 IF
0.175 83.3 0.2 100 3-Methyl 0.05 0 Valpromide CONH2 O,Og 33.3 0:10 0.51 5.1 a ~ 0.1 66.6 0.2 83.3 0.3 100 2-Fluoro- CONH
3-methyl 2 0.12 0.45 3.8 V alpromide (Example 18) F
2-Fluoro-2-propyl- CONHZ 0.2 33.3 ~ 0,4 n.d. n.d.
heptanoamide 0.3 33.3 (Example 8) F 0.4 50 Valproic acid 0.5 16.7 COOH 0.63 50 0.61 1.83 3.0 0.75 83.3 1.0 100 n.d. : not determined Table 3.
Anticonvulsant activity at various times after administration % OF
ANIMALS
PROTECTED

COMPOUND DOSE at times (minutes) post-dosing ) (mmol/k EXAMPLE NO ) . g ( 15 30 45 60 75 min min min min min Valproic acid 1.5 100 100 (VPA) 2-Fluoro-VPA 1.5 0 40 80 0 Valpromide 1.5 100 2-Fluoro-Valpromide (Example 5) 1.5 100 2-Fluoro-Valpromide (Example 5) 1.0 80 60 40

Claims (15)

We claim:

1. A compound of formula wherein R1 and R2 are independently chosen from the group consisting of C3 to C5 n-alkyl, C3 to C5 branched alkyl, C3 to C5 cycloalkyl, (cyclopropyl)methyl, 1-(cyclopropyl)ethyl, 2-cyclopropyl(ethyl), and (cyclobutyl)methyl.

2. A compound of claim 1, wherein R1 and R2 are independently chosen from the group consisting of C3 to C4 n-alkyl, C3 to C4 branched alkyl, cyclopropyl, cyclobutyl, and (cyclopropyl)methyl.

3. A compound of claim 1, wherein R1 is chosen from the group consisting of n-propyl, i-propyl, n-butyl, and 1-methylpropyl; and R2 is chosen from the group consisting of C3 to C5 n-alkyl, C3 to C5 branched alkyl, C3 to C5 cycloalkyl, (cyclopropyl)methyl, 1-(cyclopropyl)ethyl, 2-cyclopropyl(ethyl), and (cyclobutyl)methyl.

4. A compound of claim 1, wherein R1 and R2 are independently chosen from the group consisting of n-propyl, i-propyl, n-butyl, and 1-methylpropyl.

5. A compound selected from the group consisting of:
2-fluoro-2-n-propylpentanoamide, 2-fluoro-2-ethyl-3-methylpentanoamide, and 2-fluoro-2-(1-methylpropyl)pentanoamide.

6. A method of reducing seizure activity in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.

7. A method of reducing seizure activity in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 2.

8. A method of reducing seizure activity in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 3.

9. A method of reducing seizure activity in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 4.

10. A method of reducing seizure activity in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 5.

11. A pharmaceutical composition comprising at least one compound of claim 1, in combination with at least one pharmaceutically acceptable additive.

12. A pharmaceutical composition comprising at least one compound of claim 2, in combination with at least one pharmaceutically acceptable additive.

13. A pharmaceutical composition comprising at least one compound of claim 3, in combination with at least one pharmaceutically acceptable additive.

14. A pharmaceutical composition comprising at least one compound of claim 4, in combination with at least one pharmaceutically acceptable additive.

15. A pharmaceutical composition comprising at least one compound of claim 5, in combination with at least one pharmaceutically acceptable additive.