DK165292B - 3-Piperidinecarboxylic acids and 3- tetrahydropyridinecarboxylic acids which are N- substituted by alkyl ethers of oximes, and pharmaceutical preparations which comprise the compounds - Google Patents

Description

in

DK 165292B

The present invention relates to novel 3-piperidinecarboxylic acids or 3-tetrahydropyridinecarboxylic acids, N-substituted with alkyl ethers of oxymers, and salts thereof, which compounds have the general formula I of claim 1. The invention further relates to pharmaceutical compositions containing the compounds of the present invention. In recent years, much pharmacological research has been conducted on 6-amino butyric acid (hereafter referred to as GABA), which is a neurotransmission inhibitor in the manual central nervous system.

Inhibition of the reabsorption of GABA results in increased availability of this neurotransmission inhibitor in the synaptic cleft, resulting in increased GABA activity.

Increased GABA activity may be useful in treating, for example, oxygen deficiency, pain and epilepsy as well as in muscular and movement disorders (see, e.g., Progress in Medicinal Chemistry - 22 (1985) 68 ^ -112 (published by GP Ellis and G: B. West, Elsevier Science Publishers, B «V ~.).

25

A well known and potent inhibitor of the reabsorption of GABA from the synaptic cleft in presynaptic nerve endings and glial cells is, for example, piperidine-3-carboxylic acid (nipecotinic acid). However, it is a relatively polar compound 30 and therefore unable to pass the blood-brain barrier, and therefore piperiden-3-carboxylic acid has no practical utility as a drug. In US Patent Specifications Nos. 4,383,999 and 4,514,414 35 (SmithKline Beckman Corporation) and in Danish patent applications Nos. 1008/87 (which have led to DK 156,398B) and 38/87 (Novo Industri A / S), the claims include aryl and 2

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heteroaryl derivatives of N- (4,4-disubstituted-3-buten-1-yl) azaheterocyclic carboxylic acids as inhibitors of the reabsorption of GABA. Furthermore, it is claimed in Danish Patent Application No. 5280/86 (Warner-Lambert Company) 5 that 1-aryloxyalkylpyridine-3-carboxylic acids are also inhibitors of the reabsorption of GABA.

According to J.Pharm.Exp. Therap. 228 (1984) 109 is, N- (4,4-diphenyl-3-buten-1-yl) nipecotinic acid (designated SK&F 109976A), N- (4,4-diphenyl-3-buten-1-yl) guvacin (designated SK&F 100330A), N- (4,4-diphenyl-3-buten-1-yl] homo-6-proline (designated SK&F 100561) and N- (4-phenyl-4- (2-thienyl) -3-butene -l-yl) nipecotinic acid (designated SK&F 100604J) oral inhibitors of GABA reabsorption.

15 These data are summarized in Epilepsy Res. 1 (1987) 77-93.

Guvacin is 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid and homo-B-proline is pyrrolidine-3-acetic acid.

The present invention relates to novel O-substituted oxymers wherein the O substituent - contains one derivative of piperidine-3-carboxylic acid (nipecotinic acid) of the general formula

II. The compounds of the invention thus differing from the above-mentioned known compounds: in that the piperidine-3-carboxylic acid is substituted with an O-substituted oxime, the general formula I

/ 0- (CH2) n CH (R 3) <CH 2) m -R 4

A = N

(I) where A is R1 ^

35 ° C or 'CH-CH

ΈΓ IT

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Wherein R and R are identical or different and each represents furanyl, imidazolyl, phenyl, pyrazolyl, pyridinyl, pyrrolyl, thienyl or 1,2,4-triazolyl. Each of these may optionally be substituted with one, two, or three substituents selected from the group consisting of lower alkoxy, azido, cyano, halogen, hydroxy, lower alkyl, nitro and 3 trifluoromethyl. R represents hydrogen or lower alkyl 4

and n and m are independently 0, 1 or 2. R represents a cyclic amino acid moiety of general formula 10 II

r6 λΤχ5 -N VR (II) 15 '-' 5 6 wherein R represents hydrogen or hydroxy, R represents hydrogen or R together with R represents an additional 9 9 20 bond, X represents - NH 4 or R, wherein R represents hydroxy or alkoxy, or are pharmaceutically acceptable acid addition salts or, if R is hydroxy, also pharmaceutically acceptable metal salts thereof. The compounds of formula I have a greater lipophilicity - and thus better access to the brain - as well as a significantly higher affinity for the GABA back-absorption sites compared to the amino acids they are derived from (nipecotinic acid and guvacin), and therefore have interesting and useful pharmacological properties.

30

It has been demonstrated that the novel compounds of general formula I exhibit inhibitory properties on the back-absorption of GABA and have useful pharmacological properties associated with the central nervous system, e.g. that they cause a selective increase in GABA activity. Compounds of formula 'I can be used to treat e.g. pain, anxiety, epilepsy and certain muscle and movement 4

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else disorders. They can also be used as sedatives and sleeping agents.

In Formula I, at least one of the groups R and R is selected which are identical or different and which may be optionally substituted, preferably from the group consisting of furanyl, phenyl, pyrazolyl, pyrrolyl, thienyl and 1,2,4-triazolyl. more preferably from the group consisting of phenyl, pyrrolyl and thienyl.

In the definition of R and R, furanyl is 2-furanyl or 3-furanyl; imidazolyl is 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; pyrazolyl is 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl; pyridyl is 2-pyridyl, 3-pyridyl or 4-15 pyridyl; pyrrolyl is 2-pyrrolyl; thienyl is 2-thienyl or 3- [thienyl] and 1,2,4-triazolyl is 1,2,4-triazol-3-yl or 1,2,4-triazol-5-yl.

in

The substituents that. optionally selected for the archipelago. R and / or 20 or R are preferably lower, alkoxy, azido, cyano, halogen, hydroxy, lower alkyl or trifluoromethyl, preferably lower alkoxy, halogen or lower alkyl. The term halogen in this connection means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, and most preferably fluorine and chlorine.

Preferably, 3 R is hydrogen, methyl or ethyl, more preferably 3 is R hydrogen.

Preferably, n + m = 0, 1 or 2, preferably n + m = 1.

Preferably, R is hydrogen or together with g R ° further represents a bond.

R 5 is hydrogen or represents together with R .....

another bond.

9 5

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X is preferably R.

R 9 is hydroxy or alkoxy, preferably R is hydroxy, g methoxy or ethoxy; most preferably R is hydroxy.

5

In the definition of the compounds of formula I, the term lower alkyl when used alone - unless otherwise indicated - represents an alkyl group having at most 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, cyclopropyl or tert-butyl, where the preferred groups are are methyl, ethyl and cyclopropyl. Used in combinations such as alkoxy, alkylthio and alkylamino, the term "lower alkyl" also denotes an alkyl group having no more than 4 carbon atoms, preferably methyl and ethyl, such that the preferred combinations are methoxy, ethoxy, methylthio, ethylthio, methylamino and ethylamino, respectively.

Examples of specific and preferred compounds of formula I are as follows; (R) -Diphenylmethanone O [2- (3-carboxypiperidin-1-yl) ethyl] oxime (1) (R) - (2-Methylphenyl) - (3-methyl-2-thienyl) methanone O [ 2- (3-25 carboxypiperidin-1-yl) ethyl] oxime hydrochloride (2) (R) -Bis (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride (3) (R) - (2-Ethylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride (4) < R) - (3-Methyl-2-thienyl) - (2-thienyl) methanone O- [2- (3'-carboxypiperidin-1-yl) ethyl] oxime (5) (R) - (2-Methylphenyl ) - {3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride (10) 6

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Diphenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride (25) (2-Methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-car-5) boxypiperidin-1-yl) ethyl] oxime hydrochloride (26)

Diphenylmethanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime (45) (2-Methylphenyl) phenylmethanone O- [2- (3-carboxylic acid) 1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride (50) (3-Fluorophenyl) - (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridine-1 yl) ethyl] oxime hydrochloride (51) (R) -Bis (4-fluoro-2-methylphenyl) methanone O- [2- (3-carboxy-piperidin-1-yl) ethyl] oxime hydrochloride (53) 2; 4 (Dichlorophenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride (58):

Bis (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride (64) (2-Chlorophenyl) phenylmethanone - [2- (3-ethoxycarbonyl-1,2.5,6-tetrahydropylidin-1-yl) ethyl] oxime hydrochloride (76) and pharmaceutically acceptable acid addition salts or metal salts thereof.

The compounds of formula I may appear as geometric bg optical isomers and all isomers and mixtures thereof are included herein. Isomeric forms can be separated using standard methods such as chromatographic methods or

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7 fractional crystallization of salts with optically active acids or bases.

Pharmaceutically acceptable acid addition salts of compounds of formula I include those derived from inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, maleic, phthalic and fumaric.

The compounds of general formula I can be prepared by the following conventional methods:

Method A: 15 '/ OH 0- (CH2) nCH (R3) (CH) R4

A — N + Y (CH2) nCH (RJ) (CH2) BR4 -> A «» K

· (V) (VI) (I) 25 One oxime of formula V, wherein A is as defined above, is reacted with a compound of formula VI, 34 where R, R, n and m are as defined above and Y is a suitable leaving group such as halogen or p-toluene sulphonate. This reaction can be carried out in a polar, inert solvent, e.g. acetone, ethanol or N, N-dimethylformamide in the presence of a base, e.g. potassium carbonate or sodium hydride at a temperature up to reflux temperature over 1 to 72 hours.

35

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8

Method B:

5 µm 30, CH2) nCH (R1) (CH2) mZ

A = ~ N + Y (CH_) CH (R; (CH_) z - *> A * /

Z Π Z O

(V) (VII) (Vin) 10 S2H.0- (CH2) nCH (R1) (CH2) iR2 - »A = N (I)

An oxylm of formula V, wherein A is as defined above, is alkylated with a compound of formula VII wherein Y is a suitable reactive leaving group such as bromine or toluene sulfonate and Z is a less labile group, e.g.

20 is chlorine (or alternatively a group such as hydroxy which can be converted to a reactive leaving group) and R, n and m are as defined above. This reaction can be carried out in a suitable solvent, e.g. acetone, ethanol, or N, N-dimethylformamide in the presence of a base, e.g. potassium carbonate or sodium hydride at a temperature up to reflux temperature over 1 to 72 hours.

The product VIII from this reaction where A, R, n, m and Z

2, as defined above, is reacted with R H, 4 wherein R is an amino acid or an amino acid derivative as specified above. This alkylation reaction can be carried out in an inert solvent such as acetone in the presence of a base e.g. potassium carbonate and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature over 1 to 95 hours.

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9

Method C: .0- (CH2) CH (R3) (CH2) R4 / z n z m

At — O + H2N

(IX) (x)

O- (CH2) nCH (R3) (CH2) mR4 A

10 (I)

A ketone of formula IX, wherein A is defined as above, is reacted with an alkyl hydroxylamine of formula X where R, R, n and m are defined as above in an inert solvent, e.g. ethanol or pyridine or a combination of solvents at a temperature up to reflux temperature for 1/2 - 12 hours.

In certain circumstances, it may be necessary to protect the intermediate products used in the above-mentioned methods (eg R Η, V or VI) with suitable protecting groups. In cases where A contains an amino group, this can be protected by acylation, and in cases where A and / or R 25 contains a hydroxy group, this can be protected, for example, by acylation or by ether formation. For example, the carboxylic acid groups in R can be esterified. Introduction and removal of such group is described in "Protective Groups in Organic Chemistry" J.F.W. McOrnie 30th ed. (New York, 1973).

If esters are prepared according to methods AC, compounds of formula I wherein X is OH can be prepared by hydrolysis of the ester group, preferably at room temperature 35 in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for about 1/2 to 6 hours. hours.

10

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♦

Compounds of formula V can be prepared by reacting the corresponding ketone or aldehyde with hydroxylamine (or hydrochloride) in a solvent such as ethanol or pyridine (see, e.g., W.E. Bachmann, Orq.Syn., (1967) 70; W.G.

Honey et al., J.Pharm.Sci., 66 (1977) 1602-1606; S. Rossi et al., Farm. Ed ♦ Sci., 24 (1969) 685-703 or P.L. Huerta et al., J.Pharm. Sci. 66 (1977) 1120-4.

Compounds of formula VI may be prepared by reaction 4 of the corresponding amino acid (R H) protected, for example, as the ethyl ester with a 2-haloethanol e.g. 2-bromethanol in the presence of a base, e.g. triethylamine or an alkali metal carbonate. A suitable solvent may be ethanol, acetone, methyl ethyl ketone or Ν, Ν-dimethylformamide. This is followed by halogenation with a suitable halogenating agent in an inert solvent at reflux temperature over 1/2 to 24 hours. A suitable solvent may be toluene and the halogenating agent may be, for example, thionyl chloride.

20.

Compounds of formula X can be prepared by O-alkylating e.g. acetone oxime with compound VI in a suitable solvent such as benzene, pyridine or ethanol in the presence of a base, e.g. an alkali metal carbonate, e.g. at reflux temperature over 1/2 - 24 hours.

This is followed by hydrolysis of the product under acidic conditions, for example using 10% hydrochloric acid as a solvent at reflux temperature for 1/2 to 24 hours (see FJ Villiani et al., J.Pharm.Sci. 58 (1969) 138-141. ; G.

Aichinger et al., Arznem.Forsch., 19 (1969) 838-845).

35 3

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11

Pharmacological methods

The in vitro inhibition of [H] -GABA absorption was assessed mainly by Fjailand's method (Acta Pharmacol. Toxi-5 col »42 (1978) 73-76). Wistar male rat cerebral tissue was easily homogenized manually using a glass teflon homogenizer in 10 volumes of 0.32 M sucrose. Incubation was performed in a 40 mM Tris HCl buffer (pH 7.5 at 30 ° C) containing 120 nM NaCl, 9.2 nM KCl, 4 mM MgSO4, 2.3 mM CaCl3, and 10 mM glucose, for 60 minutes. at 30 ° C. The ligand concentration was 0.2 nM.

Values for inhibiting GABA absorption for some representative compounds of the invention as well as for compounds of the prior art are shown in Tables 1 and 1a below.

20 25 30 35 12

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13

Notes to Table 1 (1) A are R1 ^

R2 / C

(2) A is rI

^ CH-CH

R2 and 10 5 6 (3) R and R form a bond Table 1a 3 15 Inhibition of [H] -GABA uptake for some known nipecotinic acid derivatives:

Reference IC50 in vitro 20 - USP 4,383,999, Example 18 (A) 465 USP 4,383,999, Example 1 (B) 353 DK-ans. 5280/86, Example VII (C) 1439 DK-ans. 5280/86, Example VIII (D) 312 (A) is 1 - [(E / Z) -4-phenyl-4- (2-thienyl) -3-butenyl] -3-piperidinecarboxylic acid, HCl (B) is 1- (4,4-diphenyl-3-butenyl) -3-piperidinecarboxylic acid, HCl (C); 1- [3- (diphenylmethoxy) propyl] -3-piperidinecarboxylic acid, HCl (D) is 1- [2- [bis (4-chlorophenyl) methoxy] ethyl] -3-piperidine carboxylic acid, HCl

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14

Compounds of formula I are useful because they have pharmacological activity in humans as inhibitors of GABA absorption.

For the above indications, the dose will vary depending on the compound of formula I used, the method of administration and the treatment desired. However, generally satisfactory results are obtained with a dose of from about 0.5 mg to approx. 1000 mg, preferably from ca. 1 10 mg to approx. 500 mg of compounds of formula I, conveniently given from 1 to 5 times daily, optionally with delayed release. Usually, doses suitable for oral administration comprise from ca. 0.5 mg to approx. 1000 mg, preferably from ca. 1 mg to approx. 500 mg of the compounds of formula 15 I, mixed with a pharmaceutical carrier or diluent. No toxic effects have been identified.

The compounds of formula I may be administered in the form of pharmaceutically acceptable acid addition salt or, where possible, as a metal or a lower alkylammonium salt. Such salts exhibit approximately the same degree of activity as the free bases.

The invention also relates to pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof. These compositions also contain a pharmaceutical carrier or diluent. The compositions may be prepared by conventional techniques or in conventional forms, for example, capsules 30 or tablets.

The pharmaceutical carrier used may be a conventional, solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc 35, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.

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15

Also, the carrier or diluent may comprise any known delayed release material such as glyceryl monostearate or glyceryl distearate alone or mixed with a wax.

5

If a solid carrier is used for oral administration, the composition may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troika or lozenge. The amount of solid carrier may vary a portion, but will preferably be from ca. 25 mg to approx. If a liquid carrier is used, the composition may be in the form of a mixture, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension.

15

The pharmaceutical compositions may be prepared according to the conventional techniques of the pharmaceutical industry which involve mixing, granulating and compressing, or variously mixing and dissolving the ingredients to give the desired final product.

The route of administration can be anyone who effectively transports the active compound to the right or desired site, such as oral or parenteral, with the oral being preferred.

25

The characteristics described in the present description with examples and claims, both separately and in any combination thereof, may be essential for the practice of the present invention in its various embodiments.

30

The process for preparing the compounds of formula I and compositions containing them is further described in the following examples; The examples illustrate some preferred embodiments. In the following, tic denotes thin layer chromatography, THF tetrahydrofuran, DMF is Ν, Ν-dimethylformamide, and m.p. is

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16 melting point. The structure of the compounds is verified by NMR and elemental analysis. Where melting points are stated, these are uncorrected. All temperatures are given in ° C. The compounds used as starting materials are either known compounds or compounds which can be readily prepared by methods known per se. Column chromatography was performed using that of W.C. Still et al. J. J. Org.Chem., 43 (1978) 2923-2925 on Merck silica gel 60 (Art. 9385) silica gel.

10 ......

15 20 25 30 35

Example 1 (Method A):

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17 (H) -Diphenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime 5 - (R) -enantiomer of ethylene nipecotate (100 g, 0.64 mol) (AM Akkerman et al., Rec Trav. Chim., 70 (1951), 899; G. Bettoni et al., Gazz. Chim. In Nos. 102 (1972) 189) were mixed in dry acetone (300 ml) with 2-bromoethanol (84.98 0, 0.68 mol), dried, powdered potassium carbonate (176.91 g, 1.28 mol) and potassium iodide (21.58 g, 0.13 mol). The reaction mixture was stirred at room temperature for 18 hours and at reflux temperature for 24 hours. Filtration and evaporation of the filtrate gave an oil which was purified by distillation in vacuo (110-115 ° C, 0.1 mmHg), yield 72.17 g (56%). Tc rf 0.20 (SiO 2; dichloromethane / methanol 19/1).

The above alcohol (19.86 g, 0.099 mol) was dissolved in 20 toluene (125 ml). A solution of thionyl chloride (14.16 g, 0.119 mol) in toluene (50 ml) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. Cooling in an ice bath followed by filtration produced the (R) -N- (2-chloroethyl) nipecotinic acid ethyl ester as a solid. A sample was recrystallized from 2-propanol, m.p.

187.5 to 194.5 ° C.

To the hydrochloride of the above ester (2.56 g, 10 mmol) was added dried, powdered potassium carbonate (5.53 g, 40 mmol), acetone (200 ml) and benzophenone oxime (3.94 g, 20 mmol). The suspension was heated at reflux for 96 hours, cooled and filtered. The solvent was removed from the filtrate in vacuo leaving a residue. Water (100 ml) and ethyl acetate (100 ml) were added. The aqueous layer was separated and further extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give a brim oil (6; 2 g). This oil

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18 was purified by flash chromatography eluting with cyclohexane / ethyl acetate (5/1) to give (R) -diphenyl methanone O- [2- (3-ethoxycarbonylpiperidin-1-yl) ethyl] oxime (2.66 g, 70%) as a rubber, tic rf 0.067 (SiO 2, cyclohex-5 an / ethyl acetate 5/1).

The above ester (2.66 g, 6.99 mmol) was dissolved in ethanol (100 ml) and 10 N sodium hydroxide solution (6.99 ml) was added. After 2 hours at room temperature, the solution was cooled in an ice bath and the pH was adjusted to 3 with 4N hydrochloric acid. Extraction with dichloromethane (3 x 50 ml), drying (MgSO 4) of the total fractions and evaporation gave the title compound as hydrochloride hydrate (1.3 g, 53%) m.p. 241-242 ° C.

15

According to the above general procedure, the following oxime derivatives were prepared:

Example 2 (R) - (2-Methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic rf O> 30 (SiO2 , dichloromethane / methanol 1/1).

Example 3 (R) -Bis (3-methyl-2-thienyl) methanone O- [2- (3-carboxy-piperidin-1-yl) ethyl] oxime hydrochloride

Mp. 45 ° C.

(R) - (2-Ethylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

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Example 4 19

Mp. 202-203 ° C (acetone).

Example 5 (R) - (3-Methyl-2-thienyl) - (2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime m.p. 210-216 ° C.

Example 6 (R) - (3-Methoxyphenyl) - (3-methyl-2-thienyl) with male O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Tic rf 0.3 (SiO 2, dichloromethane / methanol 1/1) Example 7 (R) - (2-Methylphenyl) - (1-methyl-2-pyrrolyl) methanone O- [2- (3-carboxypiperidine-1 - yl) ethyl] oxime 30

Tc rf 0.29 (SiO 2, dichloromethane / methanol 1/1).

(R) - (1-Methyl-2-pyrrolyl) phenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Example 8 20

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Mp. 221.5 to 225 ° C.

Example 9 (R) - (3-Methoxyphenyl) - (4-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic, rf 0.31 (SiO2 , dichloromethane / methanol 1/1).

Example 10 (R) - (2-Methylpyrenyl) - (3-methyl-2-thienyl) methanori-O- [-2 - (- 3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Tic, rf 0.32 (SiO 2, dichloromethane / methanol 1/1).

Example 11 (R) - (2-Methyl-1,2,4-triazol-3-yl) - (2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Tic, rf 0.90 (reverse phase, Whatman KC1 8F, methanol / water 4/1).

(R) - (3-Azidophenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

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Example 12 21

Tc, rf 0.20 (SiO 2, methanol).

Example 13 10 (R) - (2-Methylphenyl 1) - (3-methyl-2-thienyl) methanone O- [2- (3-ethoxycarbonylpiperidin-1-yl) ethyl] oxime Tic, rf 0, (SiO2, cyclohexane / ethyl acetate 1/1).

Example 14 (R) - (2-Azidophenyl) phenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Tic, rf 0.14 (SiO 2, dichloromethane / methanol 1/1).

Example 15 (S) -Diphenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic, rf 0.38 (SiO 2, dichloromethane / methanol 1/1).

(R) -Bis (3-ethyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloricl 5 ---

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Example 16 22

Tic, rf 0.30 (S1O2, dichloromethane / methanol 1/1).

Example 17 (R) - (2,4-Dichlorophenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic, rf 0.52 (S1O2, dichloromethane / methanol 1/1).

Example 18 (R) -t (3-Methoxyphenyl) phenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Snip. 180-185 ° C.

Example 19 (R) - (3-Methoxyphenyl) - (2-methoxyphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride m.p. 185-190 ° C.

(R) -Bis (4-chloro-2-methylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

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Example 20 23

Mp. 230-232 ° C.

Example 21 (R) - (2-Methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-ethoxycarbonylpiperidin-1-yl) ethyl] oxime hydrochloride

Mp. 124 to 125.5 ° C.

Example 22 (R) - (4-Chloro-2-methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Mp. 170-175 ° C.

Example 23 (R) -Bis (2-methylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride 30

Tlc> rf. 0.49 (SiO 2, dichloromethane / methanol 1/1).

Using (R, S) -N- (2-chloroethyl) nipecotinic acid ethyl ester as starting material, the following (R, S) -35 enantiomeric mixtures were prepared (according to method A, Example 1):

Example 24 24

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Diphenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride 5 = -

Mp. 234-235 ° C.

Example 25 10 (2-Methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic rf. 0.30 (SiO 2, dichloromethane / methanol 1/1).

Example 26 (1-Methyl-2-imidazolyl) phenylmethanone O- [2- (3-carboxy-piperidin-1-yl) ethyl] oxime

Tc rf 0.07 (SiO 2; methanol / dichloromethane 1/1).

Example 27

Phenyl (2-pyridyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Mp. 61-63 ° C.

35

Phenyl- (2-pyrrolyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride 5-

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Example 28 25

Mp. 172.5 to 176 ° C.

Example 29 10

Bis (4-chlorophenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic rf 0.25 (SiO 2, dichloromethane / methanol 1/1).

Example 30 (3 - Az idopheny 1) phenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Tic, rf. 0.30 (SiO 2, methanol).

Example 31 (4-Fluorophenyl) phenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic, rf. 0.35 (SiO 2, dichloromethane / methanol 1/1).

(2-Chlorophenyl) phenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride 5 -: -

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Example 32 26 - Tic, rf. 0.35 (SiO 2, dichloromethane / methanol 1/1).

Example 33 10 (4-Chloro-2-methylphenyl) - (2-methylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic, rf. 0.33 (SiO 2, dichloromethane / methanol 1/1).

Example 34 (3-Azidophenyl) phenylmethanone Or [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Tic, rf. 0.30 (SiO 2, methanol).

Example 35 (3-Nitrophenyl) phenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic, rf. 0.30 (SXO 2, methanol).

35

Bis (2-hydroxyphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Example 36 27

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"\

Mp. 215-220 ° C (not recrystallized).

Example 37 10

Bis (3-methoxyphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride 4 Tic, rf. 0.31 (SiO 2, dichloromethane / methanol 1/1).

Example 38 (2,4-Dichlorophenyl) τ (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Tic, rf. 0.30 (SiO 2, dichloromethane / methanol 1/1).

Example 39 (2-Chlorophenyl) - (2-methylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride Tic, rf 0.57 (SiO 2, dichloromethane / methanol 1/1) .

(2-Methylphenyl) - (3-methylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride 5 ----

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Example 40 28

Mp. 174-176 ° C.

Example 41 (2-Methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl oxime hydrochloride m.p. 209-211 ° C.

Example 42 (3-Hydroxyphenyl) phenylmethanone O- [2- (3-carboxypiperidin-20-din-1-yl) ethyl] oxime hydrochloride

Tic, rf. 0.40 (SiO 2, methanol).

Example 43 25

Bis (2-methylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) -1-methylethyl] oxime hemihydrochloride Tic, rf. 0.52 (reverse phase, Whatman KC1 8F, methanol / water 4/1).

35

Example 44 (Method B): 29

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Diphenylmethanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxylmethyl

Benzophenone oxime (3.94 g, 20 mmol), 1-bromo-2-chloroethane (28.7 g, 200 mmol) and dried, powdered potassium carbonate (5.53 g, 80 mmol) in acetone (60 ml) were heated under re-flux for 72 hours. The reaction mixture was cooled and filtered and the filtrate was evaporated to an oily residue which was purified by flash chromatography (eluted with heptane / ethyl acetate 19/1) to give diphenylmethanone O- (2-chloroethyl) oxime (3.82 g, 73%) as an oil, tic rf 0.36 (SiO 2, heptane / ethyl acetate 9/1).

The above chloroethyloxime (1.309 g, 5 mmol) was dissolved in acetone (25 ml) and guvacin methyl ester hydrochloride (1.776 g, 10 mmol) powdered, dried potassium carbonate 20 (2.073 g, 15 mmol) and potassium iodide (0.75 g, 5 mmol) was added. The reaction mixture was heated under reflux for 18 hours and cooled. Filtration and evaporation of the filtrate gave an oil which was purified by flash chromatography on silica gel, fumigation with cyclohexane / ethyl acetate (2/1) to give diphenylmethanone O- [2- (3-methoxycarbonyl-1,2, 6-tetrahydropyridin-1-yl) ethyl] oxime (0.87 g, 48%) as a rubber, tic rf 0.30 (SiO 2 / heptane / ethyl acetate 1/1). Some of the diphenylmethanone 0- (2-haloethyl) oxime (0.66 g, 50%) used as the starting material was also isolated.

30

The above methyl ester (0.81 g, 2.39 mmol) was dissolved in ethanol (25 ml) and 10 N sodium hydroxide solution (2.39 ml) was added. The solution is stirred at room temperature for 4 hours and acidified to pH 2 with 2N hydrochloric acid. The liquid was extracted with dichloromethane (3 x 50 ml) and the combined organic extracts were dried (MgSO4). Evaporation of the solvent gift rubber, which was freeze-dried, 30

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to give the title compound (0.825 g, 89%) as a hemi hydrochloride. Tc rf 0.40 (SiO 2, dichloromethane / methanol 1/1). Found: C, 65.6; H, 6.3; N, 7.05; Cl, 4.9.

C21H22N2 ° 3 * 21101 ^ ¾0 requires cr 65.2; H, 6.4; N, 7.2; Cl, 4.6%.

In the above general procedure (Example 45,

Method B) the following oxime derivatives were prepared: 10

Example 45

Bis (3-methyl-2-thienyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 79-80 ° C.

Example 46 (S) -Bis (3-methyl-2-thienyl) methanone O- [2- (3-carboxy-piperidin-1-yl) ethyl] oxime hydrochloride m.p. 168-169 ° C.

Example 47 (S) - (2-Methylphenyl) - (3-methyl-2-thienyl) methanone.

O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Tic-rf 0.30 (SiO 2, dichloromethane / methanol 1/1).

35 -

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Example 48 31 (3-Methyl-2-thienyl) - (2-thienyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride 5 -

Tic rf 0.8 (reverse phase, Whatman KC18F, methanol / water (4/1)).

Example 49 (2-Methylphenyl) phenylmethanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Tic, rf. 0.49 (SiO 2, dichloromethane / methanol 1/1).

Example 50 (3-Fluorophenyl) - (2-methylphenyl) methanone-O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 219-223 ° C.

Example 51 (R) -Bis (4-fluoro-2-methylphenyl) methanone O- [2- (3-ethoxycarbonylpiperidin-1-yl) ethyl] oxime hydrochloride

Mp. 102-103 ° C.

(R) -Bis (4-fluoro-2-methylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride 5 - = -

Example 52 32

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Mp. 181-182 ° C.

Example 53 (2-Methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-ethoxycarbonyl-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Srnpi 116-117 ° C.

Example 54 (2-Methylphenyl) - (- 3-methyl-2-thienyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride m.p. 204-207 ° C.

Example 55

Bis (4-fluoro-2-methylphenyl) methanone O- [2- (3-ethoxycarbonyl-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 157-159 ° C.

35

Bis (4-fluoro-2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride 5 - - - - -

Example 56 33

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Mp. 241-244 ° C.

Example 57 (2,4-Dichlorophenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Tic, rf. 0.76 (reverse phase, Whatman KC1 8F, methanol / water 4/1).

Example 58 (2-Chlorophenyl) - (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride m.p. 152-155 ° C.

Example 59 (2-Methylphenyl) - (3-trifluoromethylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 205-207 ° C.

(R) - (2-Methylphenyl) - (3-trifluoromethylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride 5 ---

Example 60 34

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Mp. 156-158 ° C.

Example 61 E / Z-2- (2-Methylphenyl) -2- (2-methyl-4-trifluoromethylphenyl) acetaldehyde O- [2- (3-carboxy-1,2,5,5-tetrahydro-pyridine) 1-yl) ethyl] oxime hydrochloride 15

Mp. 195-200 ° C.

Example 62 (S) - (2-Methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-ethoxycarbonylpiperidin-1-yl) ethyl] oxime hydrochloride Tic, rf. 0.35 (SK 2, cyclohexane / ethyl acetate 1/1).

Example 63

Bis (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 214 to 218.5 ° C.

(S) -Bis (2-methylphenyl) methanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride

Example 64 35

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-s

Tic, rf. 0.39 (S1O2, dichloromethane / methanol 1/1).

Example 65 10

Diphenylmethanone 0- [2- (3-aminocarbonylpiperidin-1-yl) -ethyl] oxime Tic, rf. 0.41 (S1O2, dichloromethane / methanol 9/1).

Example 66 (4-Chloro-2-methylphenyl) - (2-methylphenyl) methanone O- (2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Tic, rf. 0.45 (S1O2, dichloromethane / methanol 1/1).

Example 67 (2-Chlorophenyl) phenylmethanone O- (2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 198.5 to 200 ° C.

(2-Thienyl) phenylmethanone O- [2 (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride 5 -: -: -

Example 68 36

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Tic, rf. 0.63 (SiO 2, dichloromethane / methanol 1/1).

Example 69 (3-Chlorophenyl) - (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride m.p. 223 ° C (decomp.).

Example 70 (3'-Methoxyphenyl 1) phenylmethanone O- [2- (3-carboxy-1,2,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 140-145 ° C.

Example 71 (3-Methoxyphenyl) - (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 190-195 ° C.

35

Example 72

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37 (4-Fluoro-2-methylphenyl) - (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 205-2l3 ° C.

Example 73

Diphenylmethanone O-C 2- (3-ethoxycarbonyl-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 110-116 ° C (toluene / cyclohexane).

Example 74 (2-Fluorophenyl) - (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 195-196 ° C (decomp.).

Example 75 (2-Chlorophenyl) phenylmethanone O- [2- (3-ethoxycarbonyl-1,2.5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride 30

Tic; rf. 0> 25 (SXO2 / cyclohexane / ethyl acetate 1/1).

35

Example 76 38

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Bis (2-methylphenyl) methanone O- [2- (3-ethoxycarbonyl-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 163-164.5 ° C (toluene / cyclohexane).

Example 77 (4-Chloro-2-methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxy-1,2,5,6 -1 ether ahydropyridin-1-yl) ) ethyl] oxime hydrochloride 15

Mp. 213-216 ° C.

Example 78 (4-Fluoro-2-methylphenyl) - (3-methyl-2-thienyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride m.p. 165-169 ° C.

Example 79 (3,4-Dichlorophenyl) - (2-methylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride

Mp. 258-260 ° C.

35

Bis (2-ethylphenyl) methanone O- [2- (3-carboxy-1,2,5,6-tetrahydropyridin-1-yl) ethyl] oxime hydrochloride 5-

Example 80

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39

Mp. 130-135 ° C.

Example 81 (Method A) 10 (R, S) -Diphenylmethanone O- [3- (3-carboxypiperidin-1-yl) propyl] oxime hydrochloride 15 (R, S) -ethylnipecotate (15.72 g, 100 mmol) was mixed in dry acetone (120 ml) with 3-bromo-1-propanol (20.85 g, 150 mmol) and dried, powdered potassium carbonate (20.73 g, 150 mmol). The reaction mixture was heated under reflux for 3 hours, cooled and filtered. The filtrate was evaporated to give an oil (32.8 g) which was dissolved in dichloromethane. To this solution, phosphorus tribromide (30.45 g, 112.5 mmol) was added dropwise while maintaining reflux during the addition, and when complete, reflux was continued for 2 1/2 hours. After cooling, dry methanol (30 ml) was added and the mixture was poured into a mixture of saturated sodium bicarbonate solution (250 ml) and water (250 ml). The dichloromethane layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 150 ml). The combined organic extracts were dried (MgSO4) and evaporated to an oil which was purified by flash chromatography. Elution with cyclohexane / tetrahydrofuran 3/1 gave N- (3-bromopropyl) nipecotinic acid ethyl ester (7.85 g, 28%) as a waxy solid.

Found C, 47.3; 7.9; N, 4.7. C ^^^ BrtK ^ O, ^ H ^ 0 required C; -46.9; H, 7.2; N, 4.95%. · 35 ............

This compound was used for the alkylation of benzopene nonoxime, as set forth in Example 1, and the resulting

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ester was hydrolyzed to give the title compound as a gummy solid (0.5 g, 52% from N- (3-bromopropyl) nipecotinic acid ethyl ester). Tic rf 0.70 (reverse phase, Whatman KC 18F, methanol / water 8/2).

5

Using (R) -N- (2-bromethyl] nipecotinic acid ethyl ester hydrobromide and a 2,2-diarylacetaldehyde oxime as starting material, the following compounds were prepared (according to Method A, Example 1).

10

Example 82 E / z- (R) -2,2-Diphenylacetaldehyde O- [2- (3-carboxy-piperidin-1-yl) ethyl] oxime hydrochloride 15 - rf. 0; 34 (SiO 2, dichloromethane / methanol 1/1) • -. . · *

Example 83 E / Z- (R) -2- (2-Methylpheryl) -2-phenyl'acetaldehyde 'O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime hydrochloride' 25 rf. 0.40 (SiO 2, dichloromethane / methanol 1/1).

Example 84 E / Z- (R) -2- (2-Methylphenyl) -2- (2-methyl-4-trifluoromethyl-phenyl) -acetaldehyde O- [2- (3-carboxy-piperidin-1-yl) ethyl] - oxime hydrochloride

Mp. 190-200 ° C.

35

Example 85

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41

Preparation of capsules 5

Ingredients mg per capsule (R) -diphenylmethanone 0- [2- (3-carboxypiperidin-1-yl) ethyl] oxime 10 Magnesium stearate 0.15

Lactose 15

The above ingredients are thoroughly mixed and placed in 15 hard gelatin capsules. Such capsules are administered orally 1 to 5 times daily to patients requiring treatment. Example 86

Preparation of Tablets 20

Ingredients mg per tablet (R) -diphenylmethanone O- [2- (3-carboxypiperidin-1-yl) ethyl] oxime 200

Corn starch 50

Polyvinyl pyrrolidone 15

Magnesium stearate 1 30

The oxime is thoroughly mixed with 2/3 of the corn starch and granulated. The resulting granules are dried, mixed with the remaining ingredients and turned into tablets.

The capsules or tablets thus prepared are administered orally. Similarly, other oximes of formula I may be used. ......

Claims (9)

Compounds according to claim 1, wherein R and R are independently furanyl, phenyl, pyrazolyl, pyrrolyl, thienyl or 1,2,4-triazolyl, preferably phenyl, pyrrolyl or thienyl, each ring being optionally substituted by one, two or three substituents selected from the group 10 consisting of lower alkoxy, azido, cyano, fluoro, chloro, bromo, iodo, hydroxy and lower alkyl, preferably lower alkoxy, fluoro, chloro and lower alkyl. 4 3 Compounds according to claim 1 or claim 2, wherein R represents hydrogen, methyl or ethyl, preferably hydrogen or methyl. Compounds according to any one of the preceding claims, wherein n is 0 or 1. 20 Compounds according to any one of the preceding claims, wherein m is 0 or 1. Compounds according to any one of the preceding claims, wherein R is hydroxy, methoxy or ethoxy. Pharmaceutical composition, characterized in that it contains as an active component a compound according to any one of claims 1-6. Pharmaceutical composition according to claim 7, characterized in that it contains between 0.5 mg and 1000 mg, preferably between 1 mg and 500 mg of the compound of the general formula I per unit dose. DK 165292B A pharmaceutical composition for treating a symptom related to GABA activity in the central nervous system, characterized in that it contains as one active ingredient a compound according to claims 1-6. 5 A pharmaceutical composition for the treatment of epilepsy, characterized in that it contains as an active ingredient a compound according to claims 1-6. 10 15 20 25 30 35