JP2002518469A - 2-fluoro-2-alkylalkanoamide having antispasmodic action - Google Patents

Abstract

(57) [Summary] Formula (I) Α-fluorinated alkanoamides, and pharmaceutical compositions containing them. The compounds and compositions are useful for treating and preventing seizures, such as those associated with epilepsy. The compound of the present invention has a higher therapeutic effect, better pharmacokinetics and pharmacological effect than valproic acid with respect to sedation and teratogenicity.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to 2-fluoro-2-alkylalkanoic amides, to the preparation of such compounds and to their use as antispasmodic agents. The antispasmodic fluorinated amide of the present invention has a higher healing rate in terms of a sedative effect than valproic acid and valpromide, and has a low possibility of teratogenicity. Also, in general, the fluorinated amides of the present invention are more efficacious than the corresponding fluorinated acids. The present invention provides an effective antiepileptic agent having a wider safety margin than valproic acid and valpromide.

[0002]

[Prior art]

About 1% of the world's population suffers from epilepsy. Valproic acid is a drug used to control epileptic seizures. Valproic acid has antispasmodic properties (also called VPA, valproate, or 2-propylpentanoic acid), but its efficacy does not last long. More seriously, VPA has severe side effects such as sedation, sometimes fatal hepatotoxicity, and teratogenicity. Hepatotoxic effects are a problem, especially for young children, especially for children undergoing polytherapy. VPA-induced hepatotoxicity in the latter patient category has been reported to be as high as 1/500 (FE Dreyfus et al., "Neurology Neurology" (1987), 37, 379-385). . Valproic acid has been shown to induce neural tube defects in mice, with an estimated 1-2% risk of developing spina bifida in newborns of women who have consumed VPA during pregnancy ( Centers for Disease C
ontrol, “morbidity and mortality weekly report Morbidity and Morta
"Little Weekly Report" (1983), 32 (33), 438
-439).

[0003]

[Problems to be solved by the invention]

Extensive efforts have been made to find valproic acid analogs with a wide safety margin while retaining their efficacy. For example, H. PCT International Application Publication No. WO 94/06743 by Now et al. And related US Pat. No. 5,786,380 make various adjustments to alkyl valproate chains.

With respect to teratogenicity, the introduction of a triple bond in the tetracoordination of valproic acid greatly increases teratogenicity, but the effect is firstly limited to the S-(−) enantiomer. Have been reported. Teratogenicity was abolished while retaining spasmolytic activity by adding a methyl group to the end of the triple bond (H. Now, RS-Hauk, K. et al.
Ehlers "Pharmacology & Toxicology Pharmacology & Toxicology
y "(1991), 69, 310-321). These results suggest that segregation of teratogenic and antispasmodic effects is possible. Sedative side effects have also been separated from antispasmodic effects in certain analogs (M. Elmatzer, RS Hauk, H. Now, Pharmaceutical Magazine J. Pharm. Sci. (1993), 82, 12).
55-1288). Little is known about α-series carboxylic acids having α-fluorine. P. Crowley et al. In European Patent Application EP 468681 refer to 2-ethyl-2-fluoroptanoic acid as a fungicidal intermediate and a process for its preparation. Takeuchi, in a publication on a method for producing tertiary alkyl fluoride,
Some examples of compounds of this type are given (Y. Takeuchi et al., Organic Chemistry J. J.
Org. Chem. (1993), 58 (13), 3483-3485).

As valproic acid analogs, 2-fluoro-2-propyl-4-pentenoic acid is also
It has been reported. This compound is used as a probe to study the hepatotoxicity and metabolism of valproic acid (W. Tan et al., "Toxicology Chem. Res. T.
oxicol. (1995), 8 (5), 671-682; Julima-Romet et al., "Toxicology" (1996), 112 (1), 69-
85; Tan, F. Abbott “Drug Metab Waste Drug Metab. Disp
os. (1997), 25 (2), 219-227). In the above references, for 2-propyl-4-pentenoic acid, it is reported that the presence of the 2-fluoro substituent reduces hepatotoxicity. No mention is made of the antispasmodic, sedative or teratogenic propensity of fluorine compounds.

As α-fluorinated valproic acid, 2-fluoro-2-propylpentanoic acid is also
(Wey Tan's doctoral dissertation, University of British Columbia, 1
996). The antispasmodic action and pharmacokinetics of this compound were studied, and its potential efficacy as a drug was estimated (F. Abbott, W. Tan, J. Paraty, "Pharmacological First Aid Magazine J. Pharmacol. Exp. Ther." 1997), 282, 116
3-1172). This compound was reported to be less potent than VPA,
No mention is made of hepatotoxicity, sedation or teratogenic tendencies.

[0007] Valproic acid analogs having a terminal trifluoromethyl group have been reported. That is, 5,5,5-trifluoro-2- (3,3,3-trifluoropropyl) pentanoic acid (Yukiharu Yamaguchi, Mikio Yanaka, JP-A-4-21652 (1992)), and
, 5,5-trifluoro-2-n-propylpentanoic acid (Hiroshima et al., "Japanese Psychopharmacology Magazine Japan. J. Psychopharmacol." (1992)
, 12, 427). These compounds are also not as potent as VPA.

[0008] Valpromide (VPD, amide of valproic acid) is a widely used prodrug of valproic acid. VPD is known to be rapidly transformed in the human body to valproic acid after oral administration (M. Biarrer, International Pharmaceutical Magazine Int.
Pharm. (1985) 23, 25-33). The rate of alteration varies greatly between species, and in mice, for example, it is known that alteration hydrolysis is relatively slow. 2-ethyl-3-methyl-pentanoamide (valnoctamide valno
Certain beta-alkylated analogs, such as ctamide, are resistant to alteration of this pathway. A. Haji-Jehia, M.A. Biarrer et al., "Pharmaceutical Magazine J. Pharm
. Sci. , 79, 719-724 (1990) and references in the dissertation.
Certain substituted cyclopropanecarboxamides have also been found to be sparingly resistant spasmolytics: Biarrer et al., "Pharmaceutical Research Pharm. Res.", 13,
284-289 (1996). The hydrolysis resistance in these compounds is due to the effect of the steric structure.

[0009]

[Means for Solving the Problems]

The present invention relates to 2-fluoro-2-alkyl-alkanoamides, pharmaceutical compositions containing these compounds, and uses for treating or preventing convulsions. The present invention also provides a method for producing these compounds. 2-fluorinated carboxamide as a preferred embodiment of the present invention, compared to valproic acid and valpromide,
Fetotoxicity and teratogenicity are significantly less, the rate of healing in terms of sedation is high, and the effect lasts longer. The 2-fluorinated carboxamides of the present invention surprisingly begin to work faster than the corresponding 2-fluorinated carboxylic acids.

The compounds of the present invention provide compounds of Formula I:

Embedded image Here, R ¹ and R ² are each independently a C3-C5 alkyl group, C3-C5
5, cycloalkyl group, (cyclopropyl) methyl group, 1- (cyclopropyl)
It is selected from the group consisting of an ethyl group, a 2-cyclopropyl (ethyl) group, and a (cyclobutyl) methyl group. Here, the term “alkyl group” refers to a linear or
It shall include both branched-chain alkyl groups.

[0011] The present invention also provides a method for treating seizures caused by various causes by administering at least one of the compounds of the present invention to an individual in need of treatment for seizures in an amount effective for treatment or prevention. And / or a method for treating and / or preventing the disease.

In addition, the compounds of the present invention are useful for treating and / or preventing affective disorders, especially manic states of bipolar depression, and migraine.

One object of the present invention is to provide a mammal with a compound useful for preventing or reducing the onset of seizures.

Another object of the present invention is to provide antispasmodic drug compositions having at least one compound of the present invention.

Yet another object of the present invention is to provide a method of preventing or reducing seizures by administering a pharmaceutical composition of the present invention to an individual in need of a seizure prevention regime.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION

 The present invention provides a compound having the following structure.

Embedded image Here, R ¹ and R ² are each independently a C3-C5 n-alkyl group, C3
A C5 to C5 branched alkyl group, a C3 to C5 cycloalkyl group, a (cyclopropyl) methyl group, a 1- (cyclopropyl) ethyl group, a 2-cyclopropyl (ethyl) group, or a (cyclobutyl) methyl group. Here, the term “alkyl group” includes both straight-chain and branched-chain alkyl groups. In a preferred embodiment, R ¹ and R ² are each independently a C3-C4 alkyl group, a cyclopropyl group, a cyclobutyl group, or a (cyclopropyl) methyl group. In another preferred embodiment, R ¹ is n-propyl, i-propyl, n-butyl, or 1-methylpropyl, and R ² is a C3-C5 alkyl, C3-C5 alkyl.
C5 is a cycloalkyl group, a (cyclopropyl) methyl group, a 1- (cyclopropyl) ethyl group, a 2- (cyclopropyl) ethyl group, or a (cyclobutyl) methyl group. In a more preferred embodiment, R ¹ and R ² are each independently n
-Propyl, i-propyl, n-butyl, or 1-methylpropyl. Most preferably, the compound is 2-fluoro-2-n-propylpentanoamide, 2-fluoro-2-ethyl-3-methylpentanoamide, and 2-fluoro-2- (1-methylpropyl) pentanoamide Selected from the group consisting of

The compounds of the present invention show a surprising advantage over the prior art compounds with regard to their efficacy. VPA and valpromide begin to work quickly but have the sedative and teratogenic side effects described above. Although 2-fluoro-VPA has been found to have no teratogenic effects, it is less effective than VPA and does not show its maximum effect until about 1 hour after administration. In addition, the duration of the effect of 2-fluoro-VPA is relatively short, and the action in vivo is only about 75 minutes (see Table 3).

[0018] Unlike 2-fluoro-VPA, the compounds of the present invention start to work quickly, with a maximum of within 15 minutes, as exemplified by 2-fluoro-2-propylpentanoamide (Example 5). Become active (comparable to VPA and valpromide; Table 3
reference). This is associated with a long half-life of 11.3 hours, as opposed to 1.4 hours for VPA (see below) and 0.84 hours for valpromide (human: M. Biarrer et al., 1985). "International Pharmaceutical Magazine Int. J. Pharm.
, 23, 25-33). Therefore, 2-fluoro-2-propylpentanoamide combines the immediate efficacy of VPA and valpromide with the safety of 2-fluorovalproic acid, and also exhibits a surprising and outstanding long half-life. is there. Such properties are what this kind of antispasmodics has not yet acquired.

There are two reasons for using the prodrug form. It is for improving the absorption / distribution and / or for maintaining the pharmacological effect longer. Prodrug forms generally have a slower, or at most similar, effect on the parent drug, as they must be metabolically converted to a pharmaceutically activated form.

Surprisingly, it has been found that the α-fluorocarboxamides described herein, even in the absence of steric effects, appear to be significantly more potent than the corresponding carboxylic acids. Because this effect is observed with parenteral administration, it is not due to faster absorption from the gastrointestinal tract. Also, the compounds are more potent and have longer lasting effects than the corresponding acids.

Therefore, it seems that the 2-fluorocarboxamide of the present invention certainly has an essential antispasmodic effect. These compounds are not only prodrugs of fluorinated carboxylic acids, but also have their own medicinal properties. Accordingly, the present invention is directed to an α-fluorinated carboxamide which is effective in treating or preventing seizures and is non-teratogenic and, upon substance replacement, produces a non-teratogenic metabolite which is itself an antispasmodic. I will provide a.

The compounds of the present invention can be prepared by applying other methods well known in the art for the preparation of α-fluorocarboxylic acids, followed by conversion to an amide. For example, 2-hydroxy-2-alkylalkanoic acid ester is converted to diethylaminosulfur trifluoride (DAST).
Fluoride), and the corresponding α-fluoroester obtained is hydrolyzed to give the acid (P. Crowley et al., 1992, European Patent Application EP 468681).
issue). Alternatively, a 2-amino-2-alkylalkanoic acid may be mixed with a fluoride ion, subjected to a diazotization treatment, and subjected to a deamination-fluorination treatment (J. Barber, R. Keck, J. Lith " Tetrahedron Lett
ers "(1982), 23, 1549-1552). In order to introduce a 2-alkyl group, a 2-bromo-2-fluoroalkanoic acid ester can be subjected to a reformatosky reaction (Y. Takeuchi et al., J. Org. Chem.
(1993), 58 (13), 3483-3485). In one preferred embodiment for laboratory-level synthesis, an enolate ester or silyl enol ether of a 2-alkylalkanoic acid is used with a source of "positive fluorine" such as N-fluoropyridinium salts or N-fluoroamides or N-fluoroimides, It can also be fluorinated (see, for example, E. Differing, G. Lug "Tetrahedral Tetrahed."
ron Letters "(1991), 32, 3815-3818). In a specific embodiment exemplified below, a lithium enolate of a methyl 2-propylpentanoate group is fluorinated with N-fluorobenzenesulfonimide, but is not intended to exclude other synthesis methods from the scope of the present invention. And

[0023] The starting ester of the exemplary process is often commercially available, or, alternatively, is a method known in the art, for example, M.P. Elmatzer, R.A. -S. Hauk, H .;
Now, "Pharmaceutical Magazine J. Pharm. Sci." (1993), 82, 1255-1.
288, obtained by malonic ester synthesis. Also, H
. See PCT International Application WO 94/06743 by Now et al. And US Patent Application Serial No. 08 / 344,810. A well-known modification of malonate synthesis by acetoacetate can also be applied. In the examples below, direct alkylation of a linear ester enolate is used. Other synthetic methods will be apparent to those skilled in the art, and the invention is not limited to the specific synthetic methods illustrated herein.

Generally speaking, the present invention provides a method for preparing a compound having structure I, comprising the following steps. A) R ¹ is defined above, R ³ is a lower alkyl group (preferably a C ₁ -C ₄ alkyl group) or a benzyl group, and R ⁴ is a lower alkyl group (preferably a C ₁ alkyl group -C _4), junior alkoxy group _(preferably, in the case of the alkoxy group), or a benzyloxy group of C 1 -C _4,

Embedded image A compound having the structure of formula (I) wherein X is an appropriate residue and R ² is as defined above.

Embedded image An alkylating reagent having the structure of

Embedded image And (b) when R ⁴ is a lower alkoxy group or a benzyloxy group, hydrolysis, decarboxylation, and re-esterification of compound IV, if necessary. Or when R ⁴ is a lower alkyl group, by subjecting compound IV to a deacylation treatment,

Embedded image (D) enolizing the compound V with an appropriate base in an inert solvent, and (e) adding a fluorinating reagent,

Embedded image (F) hydrolyzing the ester moiety; and (g) converting the carboxylic acid to carboxamide.

Properly identifying the group R ⁴ will be straightforward to a person skilled in the art. Preferred R ⁴ groups include alkoxy groups that are easily saponified, such as methoxy and ethoxy groups, and other carboxylic acid protecting groups that can be easily removed by other means, such as t-butoxy and benzyloxy. Term that step (b) and used in (f) "hydrolysis", the nature of ^{R 4} suitable, non-protective (Deprotec
ting) action, for example, saponification treatment in the case of a lower alkoxy group, acid decomposition treatment in the case of a t-butoxy group, or hydrogenolysis treatment in the case of a benzyloxy group. And Similar considerations there than true of groups R ^3, R ³ is preferably is a junior alkyl group such as a methyl group or an ethyl group, another carboxy-protecting group, for example, t- butyl group, a benzyl group, etc. It may be. In step (b), since R ³ are reintroduced later removed, practitioner, if you so desired, it is found to have the opportunity to become entirely changing the R ^3.

When R ⁴ is an alkyl group, preferred groups are those which enable the COR ⁴ group to be deacylated, in which case the most preferred R ⁴ is a methyl group. Deacylation, for example, besides treating with sodium hydroxide or ammonia,
It can be performed by a method known in the art.

Suitable residues X can be selected from, but not limited to, halogens of chlorine, bromine or iodine, or sulfonic acid ester groups such as methanesulfonyloxy or toluenesulfonyloxy. is not. Suitable bases of step (a) are alkali metal alkoxides, calcium and magnesium alkoxides,
It can be selected from alkali metal hydrides and the like, but is not limited thereto.

For the appropriate base in step (d), several processes for enolizing the ester have been published and will be apparent to those skilled in the art. The base is preferably one which does not react with the functional group of compound V because it has _a pKa high enough to substantially deprotonate compound V. Examples include, but are not limited to, lithium or sodium salts of inhibitory disubstituted amines, such as lithium diisopropylamide and lithium hexamethyldisyl azide.

As an alternative, the compounds of formula (I) can be prepared by a method comprising the following steps: A) when R ¹ is defined above and R ³ is a lower alkyl group or a benzyl group,

Embedded image Wherein X is an appropriate residue as described above and R ² is as defined above,

Embedded image An alkylating reagent having the structure of

Embedded image (B) enolizing the compound V with an appropriate base in an inert solvent, and (c) adding a fluorinating reagent,

Embedded image (D) hydrolyzing the ester moiety; and (e) converting the carboxylic acid to carboxamide.

It will be apparent to those skilled in the art that modifications can be made to the above exemplary process. For example, an inert solvent other than THF, such as dioxane, di-alkyl ether, dimethoxyethane and other polyethers, toluene and heptane, may be used. For the fluorination reaction, an additive such as hexamethylphosphoramide, tetramethylethylenediamine, or tetramethylurea can be used.For deprotonation, an alkali metal hydride, an alkoxide, or a hexamethyldisilazide salt, Other bases can be used. Without departing from the scope of the present invention, such changes can be made, for example, by increasing yields or reducing production costs, to determine the most desirable conditions for a given reaction. The experiment is a routine task for a skilled technician in the art.

As an example, the conversion treatment of carboxylic acid to carboxamide is also described below. The carboxamides of the present invention can be condensed with the ammonia or ammonium salts, or the corresponding esters, by the methods provided herein, or in 2-carbo-2-alkylalkanoic acids, in carbodiimide or other condensing reagents. It can be prepared by any of various methods, such as by thermal decomposition. Such methods are well known to those skilled in the art, and it is not intended that the invention be limited to the illustrated synthetic means.

Here, by the method provided, the following compounds of the invention can be prepared from the appropriate starting materials: Example No. Compound 1 2-Fluoro-2-ethylpentanoamide 22 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 13 2-fluoro-2-cyclopropylpentanoamide 14 2-fluoro-2-cyclopropylhexanoamide 15 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 232 -Fluoro-2-cyclobutylhexanoamide 24 2-fluoro- -Cyclobutyl-3-methylpentanoamide 25 2-fluoro-2-cyclobutylheptanoamide 26 2- (cyclopropyl) methyl-2-fluoropentanoamide 27 2- (cyclopropyl) methyl-2-fluorohexano Amide 28 2- (cyclopropyl) methyl-2-fluoro-3-methylpentanoamide 29 2- (cyclopropyl) methyl-2-fluoroheptanoamide 30 2,2-bis (cyclopropyl) -2-fluoroa Cetamide 31 2-cyclobutyl-2-cyclopropyl-2-fluoroacetamide 32 2-fluoro-2-i-propyl-3-methylbutanoamide 33 2-fluoro-2-i-propyl-4-methylpenta Noamide 34 2-Fluoro-2-i-propyl-3,3-dimethylbutanoamide 35 2 Fluoro-2-i-propyl-3-methylhexanoamide 36 2-Fluoro-2-i-propyl-4-methylhexanoamide 37 2-Fluoro-2-i-propyl-5-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-methylbuta Noamide 41 2,3-bis (cyclopropyl) -2-fluoropropionamide 42 2-cyclobutyl-2-fluoro-3-methylbutanoamide 43 2-cyclopentyl-2-fluoro-3-methylbutanoamide 442 -(Cyclobutylmethyl) -2-fluoro-3-methylbutanoamide 45 2- (1-cyclopropylethyl)- -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- (1-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-methylpentanoamide 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-fluoro Pentanoamide

The above compounds are provided by way of example only and are not intended to limit the scope of the invention.

It will be well known to those skilled in the art that most of the compounds of the present invention can exist in enantiomeric and diastereomeric forms. The pure enantiomer may be obtained by methods known in the art, for example, by fractional recrystallization of the corresponding diastereomeric amine salt of a 2-fluoro-2-alkylalkanoic acid, or by diastereomeric separation. The derivative can be separated from the racemate by chromatography or chiral column chromatography. Alternatively, enantiomeric forms may be prepared by chiral synthesis, for example, by alkylating or fluorinating a chiral hydrazone (R.-S. Hauk, H. Now,
1989, "Toxicology Letters", 49, 41.
-48) or by alkylating or fluorinating a chiral oxazolidinone derivative (H. Now et al., 1994, PCT International Application Publication No. WO 94/0).
No. 6743, U.S. Patent Application Serial No. 08 / 344,810). Chiral starting materials can also be used in synthesizing compounds of the present invention. The individual diastereomers, R and S enantiomers, racemates, and non-racemic mixtures of enantiomers or diastereomers having structure I are all considered to be within the scope of the invention.

Another object of the present invention is to treat an individual in need of an antispasmodic treatment, such as having epilepsy, with the formula (I)
) May be provided. Mammals, particularly humans, that would benefit from this method of treatment include those who have, or are at risk for, having any type of seizure. For example, the method of the present invention
It is useful for treating individuals with sudden systemic seizures, such as muscle-clonic or tonic-clonic seizures, and localized seizures. Individuals suffering from epilepsy are expected to benefit, inter alia, from administering the compounds of the present invention. The method of the present invention comprises administering at least one compound of formula (I), or a salt or prodrug thereof, to an individual in a therapeutically effective amount, ie, sufficient to reduce or prevent seizure action. Consists of

The dose of a compound used in the treatment of such a disease will usually vary depending on the severity of the disease, the weight and metabolic integrity of the patient, and the relative potency of the compound used. Come. Preferred initial doses for the general patient population include, for example,
It will be determined by daily dose range studies performed during clinical trials.
A therapeutically effective dose for an individual patient will be administered to the individual to achieve the desired therapeutic or prophylactic effect and to minimize unwanted side effects, as is currently done with valproic acid. Can be determined by titrating the amount of the drug. Dosages may not differ significantly from those used in VPA, but need to be adjusted appropriately based on the indications and kinetic variables described herein or on a routine basis. is there.

For example, the compound 2-fluoro-2-n-propylpentanoamide is expected to be effective at about 25% of the dose used in VPA. A preferred initial dose of the compound can therefore be estimated to be about 1-60 mg / kg / day, more preferably 5-15 mg / kg / day. This initial dose can be varied to achieve the optimal therapeutic effect for the patient, and can be taken once daily or in scheduled doses. Generally, the compounds of the present invention comprise 1-15
It is expected that a dose of 0 mg / kg / day will be administered.

The administration of the compound of the present invention may be performed by any method used for drug therapy, for example, oral, parenteral, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration and the like.

The present invention also provides a pharmaceutical composition which has an antispasmodic effect and comprises at least one compound of the present invention. In addition to having at least one compound represented by Formula (I), the pharmaceutical composition comprises a preservative, excipient, excipient, wetting agent,
Additives such as binders, disintegrants, buffers, and carriers can also be included. As the additive, for example, magnesium carbonate and calcium carbonate, carboxymethylcellulose, starches, sugars, gums, magnesium stearate and calcium stearate, a coloring agent or a flavor are preferable. There are a wide variety of pharmaceutically acceptable excipients in pharmaceutical dosage forms, and the selection of appropriate excipients
It is a routine task for skilled technicians in the field of dispensing.

The compositions may take the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral drenches or suspensions. it can.

In order to keep the dosage constant, the composition of the present invention is preferably in the form of a single dosage unit. Dosage forms for oral administration include tablets and capsules, and binders such as syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone, and carriers and excipients, such as lactose, sugar. , Excipients such as corn starch, calcium phosphate, sorbitol, or glycine. As additives, disintegrants,
For example, starch, polyvinylpyrrolidone, sodium starch glycolate, or microcrystalline cellulose, and preservatives, and pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.

In addition to dosage unit forms, multiple dosage forms are also contemplated as being within the scope of this invention. Slow release compositions, such as those prepared using sustained release coatings, microcapsules, and / or slow dissolving polymeric carriers, are also well known to those skilled in the art, It is considered within the range.

Solid oral compositions can be manufactured by conventional methods, such as mixing, excipient addition, tableting, and the like. An iterative mixing process is used to disperse the actives in excipient-intensive compositions. Such processing belongs to the related art in the relevant field. The tablets may be coated with methods well known in normal pharmaceutical practice, for example, with an enteric coating.

Liquid dosage forms for oral use can take the form of, for example, emulsions, syrups or elixirs, or are provided as solids, and are reconstituted with water or other suitable excipient before use. You may do so. Such liquid preparations include suspending agents, such as sorbitol syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fat, and emulsifiers such as lecithin, monooleic acid. Sorbitan, or acacia, as well as water-insoluble excipients (which may include edible fats), such as tonsil oil or coconut oil, oily esters such as glycerin esters, propylene glycol esters and ethyl alcohol esters, For example, conventional additives such as methyl or propyl p-hydroxybenzoate, or sorbic acid, and, if desired, conventional flavors and colorants can be included.

For parenteral administration, liquid dosage units are prepared using the compound and a sterile carrier, which, depending on the concentration employed, can be suspended or dissolved in the carrier. You can also do. When 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, preservatives and buffering agents can be dissolved in the vehicle. Suitable buffers include, for example, phosphates and citrates. To improve the stability, the composition may be frozen after being poured into a vial and water-removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle without dissolution and cannot be sterilized by filtration. The compounds can be sterilized by conventional means, for example, by exposure to radiation or ethylene oxide, before suspension in a sterile vehicle. Conveniently, the composition contains surfactants and wetting agents that help the compound to be dispersed evenly.

Example A. Compound Preparation Example 3: Synthesis of 2-fluoro-barnoctamide. Diethyl ethyl malonate (3
(2.3 g, 0.172 mol) was added dropwise to a suspension of 7 g of sodium hydride (60% in oil) in 200 ml of dry N, N-dimethylformamide (DMF).
After complete deprotonation, 28.8 ml (0.25 mol) of 2-iodobutane was added and the resulting mixture was warmed to 153 degrees in 12 hours. 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 is distilled and the crude product is distilled and extracted, bp 68 ° C,
16.5 g of a colorless liquid of 1 mbar were produced.

The resulting dialkylmalonate (16.5 g) and potassium hydroxide (12 g) were heated to reflux in 30 ml of water and 60 ml of ethanol for 75 hours. The ethanol was distilled, the residue was diluted with water and extracted with ether. Thereafter, the aqueous layer is acidified with concentrated HCl and extracted again with ether. After drying and distillation of the solvent, the crude product (13.9 g of yellow oil) was heated to 175 ° C. for 2 hours to decarboxylate. Next, by performing distillation, the boiling point 66
Yield 7.2 g of barnoctic acid as a colorless liquid at -68 ° C, 0.9 mbar.

The barnoctic acid (6.7 g) was warmed and refluxed with 100 ml of methanol and 5 ml of concentrated sulfuric acid for 5 hours. The methanol was distilled, the residue was diluted with ether, the phases were separated, the organic layer was washed with water and dried over sodium sulfate. The ester is carefully distilled and the crude product is distilled under reduced pressure to produce methyl barnoctoate as a colorless liquid (4.5 g), bp 46 ° C., 8 mbar.

At 4 ° C., 0.0313 mol of lithium diisopropylamide (LDA)
A 0 ml dry THF solution was prepared from 4.4 ml diisopropylamine and 20 ml butyllithium (1.5M in hexane). The solution was cooled to −78 ° C., and 4.5 g (0.0285 mol) of barnoctic acid methyl ester was added dropwise. The mixture was allowed to warm to −20 ° C. to complete the deprotonation and was cooled again to −78 ° C. 10 g (1.1. Equivalents) in 50 ml of THF
Of N-fluoro-benzenesulfonimide was added and the stirred mixture was allowed to warm to room temperature overnight. After pouring with 100 ml of water, the layers were separated, the aqueous layer was extracted with ether, the organic layer was washed with aqueous sodium hydrogen carbonate and saturated sodium chloride and dried over sodium sulfate. After careful distillation of the solution, the crude product was distilled to yield 2-fluoro-barnocic acid methyl ester (3.7 g) as a colorless liquid with a boiling point of 69-73 ° C. and 8 mbar.

Stir the 2-fluoro-barnocic acid methyl ester (3.7 g) overnight at room temperature with 1 g lithium hydroxide (1 molar water of crystallization) in 80 ml methanol / water (3: 1). did. The methanol was distilled and the residue was diluted with water and extracted with ether. The aqueous layer was acidified with concentrated HCl and extracted with ether. After drying and distillation of the solution, 2.3 g of crude product was warmed in 10 ml of thionyl chloride. Excess thionyl chloride was removed by distillation, and crude hydrochloric acid was added dropwise and stirred to obtain a cooled ammonia solution in water. The precipitate is filtered and recrystallized from ethanol / water, mp 110 ° C.
Yielded 2-fluoro-barnoctamide as colorless crystals of (1.3 g). ¹ H-NMR (CDCL ₃ : δ = 0.92 (9HM, m, 3 × CH ₃ ), 1.2 (
1H, m, CH), 1.86 (4H, m, 2 × CH 2), 5.75 and 6.34
_{(2H, broad, COHN 2)} .

Example 5: 2-Fluoro-2-n-propylpentanoamide. 0.055mol
Of lithium diisopropylamide in 100 ml of THF under an inert gas
After cooling to 8 ° C., 0.050 mol of methyl 2-propylpentanoate in THF was added dropwise with stirring. The mixture was allowed to warm to −20 ° C. and then cooled again to −78 ° C. A solution of N-fluorobenzenesulfonimide (16 g) in THF (50 ml) was added dropwise. The mixture was allowed to warm to room temperature overnight and quenched with saturated ammonium chloride solution. Aqueous 6 N HCl (
100 ml), the product is extracted with ethyl ether, dried over anhydrous sodium sulphate, concentrated and distilled in vacuo to give 2-fluoro-2 with a boiling point of 73 ° C./8 mbar.
7.3 g (83%) of methyl propylpentanoate were produced as an oil.

The methyl ester (7.3 g, 0.041 mol) was dissolved in 60 ml of methanol, and 20 ml of water and 0.042 mol of lithium hydroxide were added.
It was saponified by stirring for hours. The methanol was removed under vacuum, the residue was diluted with water and extracted twice with ethyl ether. The aqueous solution was then acidified with hydrochloric acid and extracted again with ether. An ether extract was generated as described above, and after distillation of the solution, crude 2-fluoro-2-propylpentanoic acid was used as used in the next step. The acid can be chromatographed on silica gel with 3: 1 hexane-ethyl acetate to give the title compound as an oil. Its physical and spectral properties have been reported (Doctoral Dissertation by Wey Tan, University of British Columbia, 1996).

To 2-fluoro-2-n-propylpentanoic acid (7.0 g, 0.03 mol)
Thionyl chloride (25 ml) was added. The solution was gradually warmed and maintained at 60 ° C. until the evolution of hydrogen chloride ceased. The excess thionyl chloride was distilled off and the resulting product was distilled in vacuo to give 2-fluoro-2 having a boiling point of 83 ° C./12 mbar.
7.3 g (94%) of propylpropionyl chloride were produced as an oil.

While maintaining the temperature at 0 ° C. in an ice / salt bath, add hydrochloric acid (7.3 g, 0.04 mol)
While stirring, it was added dropwise to a 25% aqueous ammonium hydroxide solution (100 ml).
. The resulting precipitate is collected, recrystallized from ethanol / water,
The title compound (5.0 g, 77%) was obtained as colorless crystals with a melting point of 131 ° C. ¹ HNMR (CDCl₃: Δ = 0.92 (6H, t, J = 7 Hz), 1.2-2
. 4 (8H, m), 5.44 (1H, broad s) and 6.32 (1H, b
load s).

Example 8: 2-Fluoro-2-n-propylheptanoamide. Methyl 2-propylheptanoate was converted to the title compound (37% overall) as colorless crystals with a melting point of 128 ° C. by the method described above. ¹ H NMR (CDCl ₃ : δ 0.9 (6H
_{, 2t, 2CH 3), 1.2-2.02} (12H, m, 6CH 2), 5.79 (
1H, broads, CONH) and 6.36 (1H, broads, COH).
NH).

Example 18: 2-Fluoro-3-methylvalpromide. The title compound was obtained as a colorless solid by any of the methods described above. ¹ H NMR (CDCl ₃ : δ0
. _{94 (9H, m, 3CH 3} ), 1.08-1.64 (4H, m), 1.64-
2.0 (3H, m), 5.98 (1H, broads, CONH) and 6.3.
6 (1H, broads, CONH).

B. Biological Action of Compounds The antispasmodic action of the compounds of the present invention was evaluated by the PTZ spasm test (E. Swinyard et al., 19
69, <Experimental evaluation of epilepsy drug, reconsideration of experimental method>, "Epilepti Epilepsy
a "10, 107-119; Swinyard, J.M. Woodhead, Antiepileptic Drugs, 2nd edition, D.C. Woodbury, J
. Penley, C.I. Pippinger Co., Raven Press, New York, 1982, 111-126). The compound is administered prior to administration.
Brand name CREMOPHOR EL. Oil-a 25% aqueous solution of an ethylene oxide derivative sold under the trade name Briefly, a suspension of the test compound was administered intraperitoneally to the animal, and 15 minutes later, pentylenetetrazole (65 mg / kg) was administered.
) By subcutaneous injection. The number of animals that developed tonic seizures and lasted for at least 5 seconds was noted down over the 30 minute process. A test group of 6 mice was used for each dose level and 5 to generate an ED ₅₀ value.
Three doses were used. The ED ₅₀ values produced (the dose at which 50% of the animals escaped seizures) are reported in Table 1 as "spasmolytic effect". The percentage of animals in which seizures were prevented is reported in Table 2 as "% spasmolytic effect".

The sedative effect of this compound was determined by the “Rotating rod rod” test (Danham, Mi
Ya, 1957, "American Pharmaceutical Society Journal J. Am. Pharm. Assoc."
46, 208-209). Targeted for testing in groups of 6 animals
15 minutes after the administration of the suspension of the compound, a ROTOROD device (Rotorod, c)
-Gobasile, Italy). For the percentage of animals that fell from the stick,
The percentage of sedation was recorded in Table 1. TD₅₀Value (50% of the animals are Roto
The "toxic dose" falling from the rod is calculated as described above and the "sedative TD ₅₀ In Table 1 and “Sedative TD₅₀"Is reported in Table 2.

The teratogenic potential of the compound was determined by injecting an animal at 8 days of gestation with a suspension of the test compound and examining the fetus at 18 days of gestation (H. Now, 1985, "Toxicol. Appl. Pharmac.
ol. H., 80, 243-250; Now, W.S. Rosher, 1986, "Basic Applied Toxicology Fund. Appl. Toxicol.", 6, 669). The percentage of fetuses that developed cerebral aneurysms are reported in Table 1 as "% teratogenic effects".

C. The pharmacokinetic antispasmodic action is, as described above, VPA, valpromide, 2-fluoro-VPA,
Or after administration of either 2-fluoro-2-propylpentanoamide,
At 5, 30, 45, 60, and 75 minutes, PTZ was injected and measured.
The results are shown in Table 3.

The pharmacokinetics were also investigated in pregnant mice. Mice on day 8 of pregnancy were injected with 3.0 mmol / kg of 2-fluoro-propylpentanoamide (Example 5). Blood samples were taken 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after injection. Drug concentrations in plasma were measured by GC-MS analysis after treatment with N-methyl-N- (t-butyldimethylsilyl) trifluoroacetamide. The maximum drug concentration (57 ± 15 μg / ml) was reached after 1 hour. The half-life was 11.3 hours (versus 1.4 hours for VPA). The maximum drug concentration of 2-fluoro-2-propylpentanoic acid as a metabolite was 6.5 ± 3.6 μg / ml. The concentration in fetal tissue is (VPA
Was 60-70% of the maternal plasma concentration (as opposed to 100%).

[0062] All biopsy tests showed that, even with valproic acid (VPA),
The procedure was the same except that it was a sodium salt solution of A.

D. RESULTS The α-fluorination treatment uniformly reduces the sedative side effects of carboxamide and also often improves the spasmolytic efficacy. Therefore, 2 of the present invention
-Fluorinated carboxamides are generally spasmolytic,
The ED ₅₀ value and the cure rate are improved. In addition, the teratogenic potential is greatly reduced, the effect is faster and the half-life is longer.

While the above examples describe some of the embodiments of the present invention,
It is evident that the compounds, compositions, and methods of the invention can be modified to provide alternative, but nonetheless, embodiments that utilize the methods of the invention.
Such an alternative embodiment should not be deemed to be a waiver of that alternative embodiment unless explicitly provided. Accordingly, the scope of the present invention is not limited to the specific embodiments described and illustrated by way of example,
Such alternative embodiments will be understood to be within the literal scope of the claims or equivalents thereof.

[0065]

[Table 1]

[0066]

[Table 2]

[0067]

[Table 3]

[Brief description of the drawings]

FIG. 1 is a dosing effect curve of valproic acid and some 2-alkylalkanoamides and 2-fluoro-2-alkylalkanoamides. 3Me-VPD = 3-methylvalpromide, 3-methyl-2-propylpentanoic acid, 2F-VCD = 2-fluorobarnoctamide, 2-ethyl-2-fluoro-3
-Methylpentanoic acid VCD = valnoctamide, 2-ethyl-2-fluoro-3-methylpentanoic acid 2F-VPD = 2-fluorovalpromide, 2-fluoro-2-propylpentanoamide, VPD = valpromide, 2-propylpentano Amides, VPA = valproic acid, 2-propylpentanoic acid.

FIG. 2 Representative example of synthesis of compounds of the invention: 2-fluoro-barnoctamide.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY , CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW

Claims (15)

[Claims] 1. R ¹ and R ² each independently represent a C3-C5 n-alkyl group, a C3-C5 branched alkyl group, a C3-C5 cycloalkyl group, a (cyclopropyl) methyl group, A formula selected from the group consisting of-(cyclopropyl) ethyl, 2-cyclopropyl (ethyl), and (cyclobutyl) methyl Compound. 2. R ¹ and R ² each independently represent a C3-C4 n-alkyl group, a C3-C4 branched alkyl group, a cyclopropyl group, a cyclobutyl group,
And a compound selected from the group consisting of and (cyclopropyl) methyl groups. 3. R ¹ is selected from the group consisting of n-propyl, i-propyl, n-butyl, and 1-methylpropyl, and R ² is a C3-C5 n-alkyl, C3 -C5 branched alkyl group, C3-C5 cycloalkyl group, (cyclopropyl) methyl group, 1- (cyclopropyl) ethyl group, 2-cyclopropyl (ethyl) group, and (cyclobutyl) methyl group The compound of claim 1, selected from: 4. The compound of claim ^1, wherein R ¹ and R ² are each independently selected from the group consisting of n-propyl, i-propyl, n-butyl, and 1-methylpropyl. . 5. A method for producing 2-fluoro-2-n-propylpentanoamide, 2-fluoro-2-ethyl-3-methylpentanoamide, and 2-fluoro-2- (1-
A compound selected from the group consisting of methylpropyl) pentanoamide. 6. A method for suppressing a seizure effect in a mammal, comprising administering to the mammal a compound of claim 1 in a therapeutically effective amount. 7. A method for suppressing a seizure effect in a mammal, comprising administering to the mammal the compound of claim 2 in a therapeutically effective amount. 8. A method for suppressing a seizure effect in a mammal, comprising administering to the mammal a compound of claim 3 in a therapeutically effective amount. 9. A method for suppressing a seizure effect in a mammal, comprising administering to the mammal a compound of claim 4 in a therapeutically effective amount. 10. A method for suppressing a seizure effect in a mammal, comprising:
A method comprising administering a therapeutically effective amount of a compound of claim 5. 11. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable additive. 12. A pharmaceutical composition comprising at least one compound of claim 2 and at least one pharmaceutically acceptable additive. 13. A pharmaceutical composition comprising at least one compound of claim 3 and at least one pharmaceutically acceptable additive. 14. A pharmaceutical composition comprising at least one compound of claim 4 and at least one pharmaceutically acceptable additive. 15. A pharmaceutical composition comprising at least one compound of claim 5 and at least one pharmaceutically acceptable additive.