DD298507A5 - N-PHENYL ALKYL-SUBSTITUTED ALPHA-AMINO-CARBOXAMIDE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATES CONTAINING THESE COMPOUNDS - Google Patents

Abstract

Described are N-phenylalkyl-substituted a-amino-carboxamide derivatives of the formula wherein R is C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl, furyl, thienyl, pyridyl or unsubstituted or substituted phenyl; A is a (CH 2) m or (CH 2) pX (CH 2) q group, where X is O, S or NR 4; R1, R2, R3, R3, R4, n, m, p and q are as defined herein; and R5 and R6, each independently, are hydrogen or C1-C6 alkyl, as well as the pharmaceutically acceptable salts thereof. These compounds are active against the central nervous system and can be used as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, anti-spastic and / or hypnotic agents for mammals. Also described is the preparation of said compounds. Formula (I) {N-phenylalkyl-substituted a-amino-carboxamide derivatives; Method; manufacture; pharmaceutical preparations}

Description

Field of application of the invention

The invention relates to N-phenylalkyl-substituted a-amino-carboxamide derivatives, processes for their preparation and pharmaceutical compositions containing these compounds.

N-substituted a-amino-carboxamide derivatives having pharmacological properties are already known from GB-PS 1140748. The compounds described therein are useful for the treatment and prophylaxis of such diseases as coronary artery disease and atherosclerosis. They are also useful in the treatment of inflammatory conditions, such as rheumatoid arthritis.

From EP-A-038588 further substituted amino acid derivatives are known, which are enkephalin inhibitors, analgesics and hypotensives.

Further substituted glycine and alanine derivatives are finally described in US-A-4049663. The compounds according to this document are suitable as oral analgesics.

It has now been found that N-phenylalkyl-substituted α-amino-carboxamide derivatives of the general formula (I) as defined herein and the pharmaceutically acceptable salts thereof, as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, anti-spastic and / or hypnotic agents are suitable.

The invention therefore relates to compound of formol (I) as defined herein and the pharmaceutically acceptable salts thereof. The invention further relates to the use of these compounds as anti-epileptic, anti-Parkinson, neuroprotective, anti-depressive, anti-spastic and / or hypnotic agents, as well as pharmaceutical preparations containing said compounds or pharmaceutically acceptable salts thereof. The invention further relates to the use of said compounds of formula (I) and the pharmaceutically acceptable salts thereof for the preparation of pharmaceutical preparations for use as anti-epileptic. anti-Parkinson, neuroprotective, anti-depressive, anti-spastic and / or hypnotic agents

 The compounds of formula (I) have the following general formula:

R is C ₁ -C ₈ alkyl; a Cr-Ce-cycloalkyl, furyl, thionyl or pyridyl ring; or a phenyl ring which is unsubstituted or substituted by 1 to 4 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and trifluoromethyl;

A is a - (CH ₇ ) _m - or - (CH ₂ ) _P -X- (CHj) _q - group, where m is an integer from 1 to 4, one of ρ and q is 0 and the other has the value 0 or an integer from 1 to 4, and X has the meaning -O-, -S- or -NR ₄ -, wherein R "is hydrogen or C, -C ₄ alkyl;

η is 0 or 1;

Ri and R ₂ independently of one another each represent hydrogen or C 1 -C ₄ -alkyl; R _{3 is} hydrogen, C, -C ₄ alkyl, which is unsubstituted or by hydroxy or a phenyl ring, optionally substituted by 1 to 4 substituents. independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and trifluoromethyl; R ' _{3 is} hydrogen; or R ₃ and R ' _{3 taken} together with the adjacent carbon atom form a C ₃ -C ₆ cycloalkyl ring;

R ₆ and R ₈ are each independently hydrogen or C 1 -C ₆ -alkyl; and wherein when R is C ₁ -C ₈ alkyl, then A is a - (CH ₂ ) _p -X- (CH ₂ ) _q - group wherein ρ and q are both 0 and X is as defined above is.

The compounds and their salts are hereinafter referred to as the "active agents" and as the "compounds of the invention".

The present invention includes all possible optical isomers of the compounds of formula (I) and their mixtures as well as the metabolites of the compounds of formula (I). The present invention also includes within its scope the pharmaceutically acceptable bioprecursors and prodrugs of the compounds of formula (I), i. H. Compounds which have a formula different from formula (I), but nevertheless are converted directly or indirectly in vivo into a compound of formula (I) after administration to man.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic acids, e.g. Nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid, or organic acids, e.g. Acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic and salicylic acids.

The alkyl, alkylamino, alkylthio and alkoxy groups may be branched or geradkettigo groups. When both groups Rs and R _{6 are} alkyl groups, then the alkyl group for R ₅ may be the same or different as the alkyl group for R ₆ . A halogen atom is preferably fluorine, chlorine or bromine, in particular fluorine or chlorine.

A C ₁ -C ₆ alkyl group is preferably a C 1 -C ₆ alkyl group.

A C 1 -C ₆ -alkyl group is preferably a C 1 -C ₄ -alkyl group.

A Ct-C ₄ alkyl group is z. For example, methyl, ethyl, propyl, isopropyl, sutyl or tert-butyl, preferably methyl or ethyl.

A Ci-C ₆ alkoxy group is z. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy, preferably methoxy or ethoxy.

A Qj-Cs-cycloalkyl group is preferably a cyclopentyl, cyclohexyl or cycloheptyl group.

A C 1 -C 6 cycloalkyl ring is preferably a cyclopropyl or cyclopentyl ring.

A thienyl ring is z. B. a 2- or 4-thienyl ring.

A pyridyl ring is z. B. a 2-, 3- or 4-, in particular a 3-pyridyl ring.

A furyl ring is z. A 2- or 3-furyl ring.

A substituted-phenyl ring is preferably substituted by one or two substituents independently selected from halogen, C _t -C ₄ alkyl ond trifluoromethyl.

If, in a - (CHj) _n , -, - (CH ₂ ) _P or - (CH ₂ ) _q group, m, ρ and / or q are greater than 1, then such group may be a branched or straight alkylene chain , A - (CH 2) _m - group is z. A -CH (Ru) group, where Ru is hydrogen or Ci-Ca-alkyl, or it is a -CH ₂ -CH ₂ - or -CHr-CH ₂ -CH ₂ -GrUpPe.

A C 1 -C ₄ alkyl group which is substituted by hydroxy is preferably a hydroxymethyl or 1-hydroxyethyl group.

A C 1 -C 4 alkyl group substituted by a phenyl ring is preferably a benzyl or phenethyl group.

m is preferably 1 or 2.

Each of ρ and q is an integer of 1 to 4, preferably 1 or 2.

Preferred compounds of the invention are compounds of formula (I) wherein R is a phenyl ring which is unsubstituted or substituted by one or two substituents independently selected from halo, C 1 -C ₄ alkyl and trifluoromethyl;

A is 6InB- (CH ₂ I _1n - or - (CH ₂ ) _p -X- (CH ₂ ) _q - wherein m is 1 or 2, one of ρ and q is 0 and the other has the value 0.1 or 2, and X has the meaning -O-, -S- or -NH-; η don has value 0 or 1;

Ri and R ₂ are each independently hydrogen or C ₁ -C ₄ -Alk ¹ ,! stand; R _{9 is} hydrogen or C 1 -C ₄ -alkyl which is optionally substituted by hydroxy; FV _{3 is} hydrogen;

R ₆ and Re are each independently hydrogen or C ₁ -C ₄ -A ^ yI, and the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are compounds of formula (I) wherein R is a phenyl ring which is unsubstituted or substituted by halogen; A is a - (CH ₂ ) _m - or - (CH ₂ ) _p -X- (CH ₂ ) _q - group, wherein m is 1 or 2; one of d and q has the value 0 and the other has the value 0 or 1, and X represents -O-, -S- or -NH-;

η has the value 0;

R _{1 is} hydrogen;

R _{2 is} hydrogen or C 1 -C ₄ alkyl;

R _{3 is} hydrogen or C ₁ -C ₂ -alkyl optionally substituted by hydroxy; R ' _{3 is} hydrogen;

R ₆ and Rg are each independently hydrogen or C ₁ -C ₄ alkyl; and the pharmaceutically acceptable salts thereof.

Examples of particularly preferred compounds according to the invention are the following:

2- (4-benzyloxybenzyl) aminopropionamide;

2- [4- (2-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide;

2- (4- (2-chlorobenzyl) oxybenzyl] aminopropionamide;

2- [4- (3-fluorobenzyl) 'oxybenzyl] amino-3-hydroxy-N-methylpropionamide;

2- (4-Benzylaminobenzyl) aminopropionamide;

2- [4- (3-fluorobenzyl) oxybenzyllaminopropionamid;

2- [4- (2-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide;

2- [N- (4-Benzylbenzyl) -N-methyl] aminopropionamide;

2- [4- (3-Chlcrbenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide;

2- (4-benzyloxybenzyl) amino-3-hydroxy-N-methylpropionamide;

2- [4- (3-chlorobenzyl) oxybenzyl] aminopropionamide;

2- [N- [4- (3-chlorobenzyl) oxybenzyl | -N-methyl] aminoacetamide;

2- [4- (3-chlorobenzyl) oxybenzyl] amino-N-methylacetamide;

2- (4-Phenyloxybenzyl) amino-3-hydroxy-N-methylpropionamide;

2- (4-benzylbenzyl) aminopropionamide;

2- (4- (2-phenylethyl) benzyl] aminopropionamide;

2- (4-Phenyloxymethylbenzyl) aminopropionamide;

2- (4-Benzylthiob * nzyl) aminopropionamide;

2-L4- (2-chlorobenzyl) oxybenzyl] amino-N-methylpropionamide;

2- (4-benzyloxybenzyl) amino-N-methylpropionamide;

2- (4- (3-chlorobenzyl) -oxybenzyl] aminoacetamide;

which, if it is the case, are present either as the sole (S) or (R) isomers or as a mixture thereof, as well as the pharmaceutically acceptable salts thereof.

In consideration of the above-mentioned references of the prior art, it seems to be obvious that some compounds falling within the above general formula (I) are encompassed by the general formulas of some of the cited references, but not specifically mentioned in these documents On the other hand, other compounds of the general formula (I) are not included in the abovementioned publications.

A selected class of active compounds of the formula (I) corresponds to the formula (I a)

ι 9 | 10/11

(CH ₀ ) -NC-CON '

^{2 v} I \ (la)

-C-CON

R ¹ 12

R; for C) -C ₈ -alkyl; a Cs-Ce-cycloalkyl, furyl, thienyl or pyridyl ring; or a phenyl ring which is unsubstituted or substituted by 1 to 4 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and trifluoromethyl;

Z is a - (CHj), or - (CHj), - Y- (CH ₂ ) i group, wherein r is an integer from 1 to 4, one of s and t is 0, and the other is denote Has a value of 0 or is a pure integer from 1 to 4, and Y is -O-, -S- or -NRi ₃ -, wherein R _{13 is} hydrogen or C ₁ -C ₄ -alkyl;

ν has the value 0 or 1;

Re and Rg are each independently hydrogen or C ₁ -C ₄ alkyl; R ₁₀ is hydrogen, C, -C ₄ -alkyl, which is unsubstituted or substituted by hydroxy or a phenyl ring optionally substituted by 1 to 4 substituents independently selected from halogen, C, -C _e alkyl, C ₁ -C ₈ -Aikoxy and trifluoromethyl, substituted, is substituted;

R ', 0 is hydrogen; or R ₁₀ and R _'1O taken together form a C ₃ -C ₆ cycloalkyl ring with the carbon atom angrezenden;

R _n and R, j independently of one another each represent hydrogen or C ₁ -C ₈ -alkyl; and wherein a) when R _{7 is} C ₁ -C ₈ alkyl, then Z is a - (CHj) ₁ -Y- (CHj) ₁ -GrUpPe, wherein both of s and t have the range 0 and Y is as defined above is; and wherein b) when R _{7 is} Ct-Ce-alkyl, and at the same time Z 6ine- (CHj), -Y- (CHj), - group wherein both of s and t are 0, and Y is -O, R _{10 is} hydrogen or C ₁ -C ₄ alkyl. R _'1O is hydrogen, or R ₁₀ and R'io taken together with the adjacent carbon atom, a Cy-Ce-cycloalkyl ring and v, Rg, R ₁₁ and R ₁₂ are as defined above, then R ₈ is C ₁ -C ₄ -AIkYl stands; and wherein c) when Z is a group- (CHj), - Y- (CH ₂ ) _t , wherein s, t and Y are as defined above, and at the same time R _{7 is} a furyl, thienyl or pyridyl ring, or a phenyl ring which is unsubstituted or substituted by 1 or 2 substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C 9 alkoxy and trifluoromethyl, R m is hydrogen or C ₍ C ₄ alkyl R ' _{) 0 is} hydrogen, and v, R ₈ and R _{8 are} as defined above, then at least one of R ₁₁ and R ₁ J has a meaning other than hydrogen, and wherein d) when R _{7 is} phenyl, which is unsubstituted or substituted by 1 to 4 substituents selected from halo and C, -C _e is alkyl, substituted, and at the same time Z is a -CH (R ₁₄₎ = - or - _(CH2), - Y (CH ₂ ), - is group in which R _{14 is} hydrogen or C ₁ -C ₃ alkyl, ^{v is} -O- or -S-, and s and t are both O, R ₈ and R _{9 are} hydrogen , ν has the value O, and R ₁ O, R'io. R ₁₁ and R _{12 are} as defined above, then R ₁ O has a meaning other than hydrogen or unsubstituted C ₁ -C ₄ -alkyl; and the pharmaceutically acceptable salts thereof.

The compounds of formula (Ia) and their pharmaceutically acceptable salts which are novel are also an object of the present invention. Another object of the present invention are pharmaceutical preparations containing as active ingredient a compound of formula (Ia) and a pharmaceutically acceptable salt thereof.

The preferred values or definitions of the substituents R, A, R ₁ , R ₂ , R ₃ , R ₃ ', Rs and Re in connection with the abovementioned formula (I) also apply to the corresponding substituents R ₇ , Z, R ₈ , R ₉ , R ₁₀ , R'io. Ru and R ₁₂ in connection with the formula (I a) to. In a particular analogy, when in a - (CH ₂ ), -, - (CH ₂ ), - or - (CH ₂ ), - group r, s and / or t are greater than 1, then such a group can be a branched or just be Aikylenkette. A- (CH ₂ ), - group is equally 2. B.

a -CH (R ₁₄₎ group, wherein R ₁₄ is as defined above, or a -CH ₂ -CHj- or-CH ₂ -CH ₂ -CHJ group.

Preferred compounds of formula (I a) as defined above, are those in which R ₇ is a phenyl ring which is unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, C _t -C ₄ alkyl and trifluoromethyl; is substituted; Z is a - (CH ₂ ), - or (CH ₂ ', -Y- (CH ₂ ) _t -group, where r is 1 or 2, one of s and t is 0, and · as others have the value 0.1 or 2, and Y has the meaning -O-, -S- or -NH-; v has the value 0 or 1;

R ₈ and Rg, independently of one another, are each hydrogen or C 1 -C ₄ -alkyl; R ₁ O is hydrogen or C ₁ -C ₄ alkyl, optionally substituted by hydroxy; R'io is hydrogen; R ₁₁ and R _{12 are} each independently hydrogen or C ₁ -C ₄ alkyl; and wherein a) when Z is a group - (CHj) ₁ -Y- (CH ₂ ), -, wherein s, t and Y are as defined above, and at the same time R _{7 is} a phonyl ring as defined above, R ₁₀ Is hydrogen or unsubstituted C ₁ -C ₄ alkyl, v, R ₈ and R _{8 are} as defined above, then at least one of R _n and R _{12 has} a meaning other than hydrogen; and wherein b) when R _{7 is} a phenyl ring which is unsubstituted or substituted by 1 or 2 substituents selected from halogen and C ₁ -C ₄ alkyl, and at the same time Z is a -CH (R ₁₄ ) - or - (CH ₂ ), - Y - (CHj) _t - group, wherein R _{14 is} hydrogen or C ₁ -C ₃ alkyl, Y is -O- or -S-, and s and t are both Have a value of 0, R ₈ and Rg are hydrogen, ν is 0, and R ₁₁ and R _{1 are} J as defined above, then R _{10 is} C ₁ -C ₄ alkyl, which is substituted by hydroxy; and the pharmaceutically acceptable salts thereof.

Preferred examples of specific compounds of formula (Ia) are the following:

2- [4- (2-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide;

2-L4- (3-fluorobenzyl) oxybenzyliamino-3-hydroxy-N-methylpropionamide;

2-I4- (2-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide;

2- [N- (4-Benzylbenzyl) -N-methyllaminopropionamid;

2- (4- (3-chlorobenzyl) oxybenzyl) amino-3-hydroxy-N-methylpropionamide;

2- (4-benzyloxybenzyl) amino-3-hydroxy-N-methylpropionamide;

2- [4- (3-chlorobenzyl) oxybenzyl] amino-N-methylacetamide;

2- (4-Pbenyloxybenzyl) amino-3-hydroxy-N-methylpropionamide;

2- [, - (2-phenylethyl) benzyl] aminopropionamide;

2- [4- (2-Ch orbenzyl!) Oxybonzyl] amino-N-methyl) propionamide;

2 - ('3-benzyloxybenzyl) amino-N-methylpropionamide;

which, if it is the case, are present either as the sole (S) or (R) isomers or as a mixture thereof, as well as the pharmaceutically acceptable salts thereof.

None of the compounds of formula (I) specifically provided herein as a single chemical moiety, although encompassed by the general formulas of the prior art references, has ever been specifically described in any of the cited references. These novel chemical compounds and the pharmaceutically acceptable salts thereof are therefore a further object of the present invention.

Examples of such new compounds are the following:

2- (4-Benryloxybenzyi) aminopiopionamid;

2- [4-chlorobenzyl) oxybenzyllaminoproplonamid;

2- (4-Denzylaminobenzyl) aminopropionamide;

2- [4- (3-fluorobenzyl) oxybenzyl) aminoprop onamid!;

2- [4- (3-chlorobenzyl) oxybenzyl] aminoacetamide;

; Amlnoacetamid | 2-LN- [4-i3-chlorobenzyl) oxybenzyl] -N-methyl

2- (4-benzylbenzyl) aminopropionamide;

2- (4-Phenyloxymethylbenzyl) aminopropionamide;

2- (4-O-benzyl Benzylth!)) Aminopropionamide;

which, if it is the case, is present either as sole (S) -or- (R) -isomers or as a mixture thereof, as well as the pharmaceutically acceptable salts thereof.

These nano chemical compounds can be represented by the following general formula (Ib)

in which

R ' _{7 is} a phenyl ring which is unsubstituted or substituted by a halogen atom; Z 'is a - (CH ₂ K or -CH ₂₎ - Y-FCH t group, where r is 1, one of s and t is 0, and the other

has the value 0 or 1, and Y represents -O -, - S or -NH-;

R's is hydrogen;

w has the value 0;

R'g is hydrogen or methyl; R "to stand for hydrogen or methyl; R'11 and R'12 are hydrogen. The compounds of the formula (I b) and the pharmaceutically acceptable salts thereof are a further subject of

present invention.

Another object of the present invention are pharmaceutical preparations containing as active ingredient a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, in particular a compound selected from

following group:

2- (4-benzyloxybenzyl) aminopropionamide;

2- [4- (2-chlorobenzyl) oxybenzyl] aminopropionamide;

2- (4-Benzylaminobenzyl) aminopropionamide;

2- [4- (3-fluorobenzyl) oxybenzyl] aminopropionamide;

2- [4- (3-chlorobenzyl) oxybenzyl] aminopropionam d!;

2- (N- [4- (3-chlorobenzyl) o; <ybenzyll-N-rrtethyl] arninoacet &mid;

2- [4- (3-chlorobenzyl) oxybenzyl) aminoacetamide;

2- (4-8enzylbenzyl) aminopropionamide;

2- (4-Phenyloxymethylbenzyl) to \ inopropionamid;

2- (4-Banzylthiobenzy)) aminopropionamide;

which, if present, are present either as the sole (S) or (R) isomers or as a mixture thereof, as well as the pharmaceutically acceptable salts thereof.

The N-phenylalkyl-substituted a-amino-carboxamide derivatives of the formula (I) can be represented by the following Analogy methods are produced. The derivatives of formula (Ia) can be prepared in the same manner using the Starting compounds (Ha) to (IXa), (X) and (Xl) are prepared, wherein the symbols R ₇ to R ₁₂ , R'io> Z and ν are the symbols R, Replace Ri to Ra, R5, Rg, Rs, A and η in the compounds (II) to (IX). D! E Derivatives of the formula (I b) can also according to the

same way, using the Ausgangsverbindungon (Hb) and (IVb) to (IXb), (X) and (Xl) are prepared, wherein the

Symbols R ' ₇ to R'g, R " ₁₀ , R' _n , R ' ₍₂ , Z' and w are the symbols R, R) to R ₃ , R ₆ , R ₆ , A and η in the compounds (II ) and (IV) to (IX)

replace, and the R ' ₃ corresponding symbol H is. The analogy method for preparing the derivatives of formula (I) comprises the steps of:

a) reaction of a compound of the formula (II) or (III)

R-A L J ^ O R-A

(III)

wherein R, R ₁ and A are as defined above, with a compound of the formula (IV)

R ₂ R3

I i

HN-C-CON

R ₅

(IV)

wherein R ₂ , R j and R ' _{3 are} as defined above, and R ₆ and R _{6 are} as defined above but not both a C 1 -C ₆ alkyl group to give a compound of the invention wherein η is 0 or 1 and R ₅ and Re are as defined above but are not both C 1 -C ₆ alkyl; or b) reacting a compound of formula (V) or an alkyl ester thereof

R.

R-A

CH- (CH _n) -NC ⁿ -COOH

wherein R, A, R ₁ , R ₂ , R ₃ , R ' ₃ and η are as defined above, with an amine of formula (Vl) HN

wherein Rg and Re are as defined above; or c) reaction of a compound of the formula (VII)

R-A

R.

H- (CH _n ) -NH 2 η

wherein R, A, Ri, η and R _{2 are} as defined above, with a compound of the formula (VIII)

(V)

(Vl) (VII)

W-CH ₂ -CON

(VIII)

wherein W is a halogen atom, and R ₆ and R _{6 are} as defined above; to obtain a compound of the invention wherein R ₃ and R ' _{3 are} both hydrogen; or

d) reaction of a compound of the formula (IX)

R ₁ HR ₃

IN THE .

CH- (CH ₂ ) _n -NC-CON

(IX)

wherein R, A, R ₁ , n, R ₃ , R ' ₃ , R ₅ and R _{8 are} as defined above, with a compound of formula (X) or (XI)

R " ₉ -W (X) R'VCHO (XI)

wherein W is a halogen atom; R " _{e is} C ₁ -C ₄ -A ^ yl and R '" _{8 is} hydrogen or C ₁ -C ₃ -alkyl, to give a compound of the invention wherein R _{2 is} C ₁ -C ₄ alkyl ; and, if desired,

Conversion of a compound according to the invention into another compound according to the invention and / or

if desired, converting a compound of the invention into a pharmaceutically acceptable salt and / or, if desired, converting a salt to a free compound and / or, if desired, separating one

Mixture of isomers of the compounds of the invention in the single isomers. All of the above methods are ancillary methods and can be well known in organic chemistry Procedures are performed. The reaction of a compound of formula (II) or (III) with a compound of formula (IV) is a reductive Amination reaction, which can be carried out by well-known methods. According to a preferred Embodiment of the invention, it can be carried out under a nitrogen atmosphere, in a suitable organic solvent,

like an alcohol, eg. B. a lower alkanol, in particular methanol, or in acetonitrile, be carried out at a temperature ranging from about ⁰ ° C to about 4O ⁰ C, and in the presence of a reducing agent, the most appropriate Eder reducing agent is sodium cyanoborohydride. Occasionally, molecular sieves may be added to the reaction mixture to facilitate the reaction.

An alkyl ester of a compound of formula (V) is z. As a C ^ Cj-alkyl esters, such as a Ci-C ^ alkyl ester, and, in particular, a Methyl, ethyl or propyl ester, which may be unsubstituted or substituted by a phenyl ring, which in turn

optionally substituted by a nitro group.

Preferably, an alkyl ester of a compound of formula (V) is used. The reaction of a compound of general formula (V) or an alkyl ester thereof, with an amine of formula (VI),

may be by use of an excess of the amine, and possibly in the presence of water or of an organic

Solvents, such as dimethylformamide, are performed. The reaction temperature may range from about 20 ° C to about

100 ⁰ C lie.

In a compound of formula (VIII), W is preferably bromine or chlorine. The reaction of a compound of the general Formula (VII) with a compound of general formula (VIII) may be dissolved in a suitable organic solvent, such as

an alcohol, eg. As ethanol, or in dimethylformamide, at a temperature in the range before, about 4O ⁰ C to about 14O ⁰ C and in

Presence of a suitable acid acceptor, e.g. be carried out of anhydrous potassium carbonate. In a compound of the formula (X), the halogen W is preferably iodine. The alkylation reaction of a compound of Formula (IX) with a compound of formula (X) may be dissolved in a suitable organic solvent such as an alcohol, e.g. B. Methanol, ethanol or isopropanol, especially methanol, at a temperature in the range of about ⁰ ° C to about 50 ° C

d - '^ be led.

The alkylation reaction of a compound of the formula (IX) with an aldehyde of the formula (XI) can be carried out in a suitable

organic solvents such as an alcohol, e.g. As methanol, or acetonitrile in the presence of a suitable

Reducing agent, such as sodium cyanoborohydride, at a temperature ranging from about 0 ° C to about 3O ⁰ C performed

become.

A compound according to the invention can, as indicated above, be known in another compound according to the invention Methods are converted. The above process variant d) can be used as an example of an optional conversion of a

Compound of the invention are considered in another compound of the invention.

Also, the optional salt formation of a compound of the invention, as well as the conversion of a salt into the free compound

and the separation of a mixture of isomers into the individual isomers can be carried out by conventional methods.

The compounds of formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (X) and (XI) are known compounds, or they may be prepared according to

known methods are obtained from known compounds.

Thus, for example, the carboxylic acids of formula (V) and their ο alkyl ester as described in GB-A-1140748

(Derwent 30027 F). An acid of the formula (V) in which η is 0 or 1 can also be obtained by reacting a compound of the formula (II) or (III) as defined above with a compound of the formula (XII)

R ₂ R 3, 2, 3

HN-C-COOH (XII),

R ^! 3

wherein Rj, R3 and R'3 are as defined above.

The reaction of a compound of formula (XII) with a compound of formula (II) or (III) may be followed by the same Procedure be experienced, as described above as process variant a). The connections of the Formula (IX) are compounds of the invention in which R _{2 is} hydrogen, and they can be characterized by the herein

described process variants a) and b) are obtained.

The compounds of the formula (XII) are known compounds or can be obtained by known methods. When in the compounds according to the invention and in their intermediates there are groups which are protected

before they are subjected to the above reactions, then they can, after, in the organic

Chemistry well-known, methods are protected from the implementation. After the reaction then the protecting groups

split off again.

The intermediates used in the processes described herein for the preparation of the compounds of the invention

may be present either in the form of a single isomer or as a mixture thereof. Preferably, they are in the form of a single isomer.

pharmacology

The compounds of the invention and selected classes thereof, of formulas (I a) and (I b) as defined herein, are active against the central nervous system (CNS) and may be used in therapy, for example, as antiepileptic drugs in the treatment of Parkinson's disease and as neuroprotective agents in degenerative procedures with the normal

Aging or associated with pathological conditions, such as brain chemistry, are used. They can also be used as antidepressants, hypnotics and antispastic agents.

The activity of the compounds according to the invention against the CNS was determined on the basis of pharmacological methods, for example the antagonism of convulsions and lethality, induced by intravenous injection of bicuculin into mice (Ar.tiepileptic Drug, DM Woodbury et al., Ed. Raven Press, New York, 1982), or the antagonism of convulsions induced in mice by subcutaneous injection of 3-mercaptopropionic acid (W. Löscher, Biochem. Pharmacol., 28; 1397-1407, 1979). Accordingly, in Tables 1 and 2 below, the doses representing 50% of the mice (ie, ED ₆₀ ) before lethality and tonic convulsions induced by bicuclinic or 3-mercaptopropionic acid, respectively, are given for a representative group of compounds of the invention.

Table 1 Antagonism of bicuculin-induced lethality in mice. The Wii substances were administered orally 1 h before bicuculin

(0.6 mg / kg, i.v.)

R-A-

-CH ₀ -A-iH-

»Ill *» -

internal R-A- R ₂ Ra Rs * ED ₆₀ code m-chlorobenzyloxy H H H (FCE) m-chlorobenzyloxy H CH ₃ H R mg / kg, ρ. ο. 25989 benzyloxy H CH ₂ OH CH ₃ S 190 26312 m-chlorobenzyloxy H CH ₂ OH CH ₃ S 50 26358 o-chlorobenzyloxy H CH ₂ OH CH ₃ S 16 26359 benzyloxy H CH ₃ H S 29 26502 o-fluorobenzyloxy H CH ₂ OH CH ₃ S 27 26550 m-fluorobenzyloxy H CH ₂ OH CH ₃ S 15 26649 o-chlorobenzyloxy H CH ₃ H S 12 26650 benzyl H CH ₃ H S. 25 26700 m-fluorobenzyloxy H CH ₃ H S 17 26723 benzylamino H CH ₃ H S 16 26743 benzyl CH ₃ CH ₃ H S 29 267 (9 valproate 9 26762 54 401

'absolute configuration

Table 2 Antagonism to 3-mercaptopropionic acid (MPA) -induced tonic convulsions in mice; the Drugs were administered orally 1 h before MPA (60 mg / kg s.c.)

Internal code ED ₆₀ (mg / kg, po) FCE25989 28 FCE 26312 10 FCE 26358 43 FCE 26359 29 FCE26502 16 FCE 26550 13 valproate 302

The indicated in Tables 1 and 2 ED ₆₀ -WeHe show that the compounds of the invention as anti-epileptic very

are active. In fact, it has been found that the ED ₆₀ values determined for the compounds of the invention are much higher than those of valproate, which is a recognized good antiepileptic drug.

The internal FCE code designations of Tables 1 and 2 denote the following connections (in brackets is the

internal FCE code specified):

[25989] 2- [4- (3-chlorobenzyl) oxybenzylaminoacetamide;

[26550] (S) -2- (4-benzyloxybenzyl) aminopropionamide;

[26,502] (S) -2- [4- (2-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide; [26700] (S) -2- [4- (2-chlorobenzyl) oxybenzyl] aminopropionamide;

[266501 (S) -2- [4- (3-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methyl-propionamide; [26749] (S) -2- (4-benzylaminobenzyl) aminopropionamide;

[26743] (S) -2- [4- (3-fluorobenzyl) oxybenzyl] aminopropionamide;

[26649] (S) -2- [4- (2-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide; [26762] (S) -2- [N- (4-benzylbenzyl) -N-methyl ] arninopropionamid;

[26359] (SJ-Z-H-O-chlorobenzyl-oxybenzylamino-S-hydroxy-N-methyl-propionamide;

[26,358] (S) -2- (4-Benzyloxybenzyl) amino-3-hydroxy-N-methyl-propionamide; [26312] (R) -2- [4- (3-chlorobenzyl) oxybenzyl] aminopropionamide; and

[26723] (S) -2- (4-Benzylbenzyl) aminopropionamide.

The inventive compounds are tested potent Hemmerder monoamine oxidase! MAO), Thus, for example when using rat liver mitochondria as the source of MAO and 2-phenylethylamine as substrate, a ICFO value of 2 x 10 ^"7 M against MAO type B for found the compound FCE 25989. It has been shown that the activity of brain MAO B is increased in aging as well as in degenerative disorders (see M.Strolin Benedetti and P. Dostert, Biochem.

Pharmacol. 38: 555 to 561.1988). It has also been shown that the compounds of the invention increase levels of serotonin (5-HT) and its major metabolite, 5-hydroxy-indole-3-acetic acid (5-HIAA) in various brain areas. For example, it has been found that administration (200mg / kg, p.o.) of compound FCE 25989 to mice resulted in an elevation of 5-HT (48%) i and 5-HIAA (37%) in the frontal cortex. It has been shown that the administration of L-tryptophan, the natural bioprecursor of 5-HT and 5-HIAA, is effective in the treatment of mood disorders and mild to moderate insomnia (see B.Boman, Aust. New Zealand J Psychiatry 22 : 83 to 97.1988).

The toxicity of the compounds of the present invention is negligible so that they can be safely used in therapy The toxicity was determined as follows: Mice which had been excluded from food for 9 hours were orally treated with increasing doses in a single administration and then confined and normal fed.The orienting acute toxicity (LD _M ) was determined on the 7th day after the treatment.

The compounds of the present invention may be administered in a variety of dosage forms such as orally, in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions; rectally, in the form of suppositories; parenteral, e.g. by intramuscular or by intravenous injection or infusion.

The therapeutic administration pattern for the various clinical syndromes must be adapted to the type of pathology, as usual including the route of administration, the form in which the compound is administered and the age, weight and condition of the patient.

The oral route is generally preferred for all conditions requiring such compounds. In emergency situations, intravenous injection is preferred.

For these purposes, the compounds of the invention may be administered orally at doses ranging from about 50 to about 1500 mg / day. Naturally, these dose patterns may be adjusted to obtain an optimal therapeutic response.

The nature of the pharmaceutical preparations containing the compounds of the invention together with pharmaceutically acceptable carriers or diluents naturally depends on the desired route of administration.

The preparations may be formulated conventionally using the usual ingredients. Thus, for example, the compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions of tablets, pills, gelatin capsules, syrups, drops or suppositories.

For orala administration, the pharmaceutical compositions containing the compounds of the invention are preferably tablets, pills or gelatin capsules containing the active ingredient together with diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; Lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols. They may also contain binders such as starches, gelatin, methyl cellulose, carboxymethyl cellulose, gum arabic, tragacanth gum, polyvinylpyrrolidone; Disintegrants, wiu starches, alginic acid, alginates, sodium starch glycolate; foaming mixtures; dyes; sweeteners; Humectants, such as lecithin, polysorbates, lauryl sulfates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations can be prepared in a known manner, for example, by mixing, granulating, tableting, coating with sugar, or by film coating.

The liquid dispersions for oral administration may, for. As syrups, emulsions and suspensions.

The syrups can be used as a carrier z. As sucrose or sucrose with glycerol and / or mannitol and / or sorbitol. The suspensions and the emulsions can be used as a carrier z. A natural gum, agar, sodium alginate, pectin, methyl cellulose, carboxymethyl cellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injection may, together with the active ingredient, be a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. Propylene glycol, and, if desired, an appropriate amount of lidocaine hydrochloride.

The solutions for intravenous injection or infusion may contain as carriers, for example, sterile water, or they may preferably be in the form of sterile aqueous isotonic saline solutions. The suppositories may contain, together with the active ingredient, a pharmaceutically acceptable carrier, e.g. Cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid starter or lecithin.

The invention therefore furthermore relates to a pharmaceutical preparation, which is characterized in that it contains as active ingredient a compound of the formula (Ia) or (B), as defined above, together with a suitable carrier and / or diluent.

The invention is illustrated in the examples.

example 1

22.4 g (0.203 mol) of glycinamide hydrochloride are suspended in 1000 ml of dry methanol and treated with 10.2 g (0.162 mol) Nariumcyano-borohydride with stirring under nitrogen. After dissolution of the mixture, 50 g (0.203 mol) of 3-chlorobenxyloxybenzaldehyde are added in a single part. The reaction mixture is stirred for 8 hours at room temperature and then allowed to stand for 16 hours. The solution is filtered and evaporated, taken up with water and extracted three times with methylene chloride. After drying and evaporation, the crude residue on silica gel chromatographies (eluent: chloroform / methanol / conc NH ₄ OH; 97/3 / 0.3) to give 2- [4- (3-chlorobenzyl) oxybenzyl) aminoacetamide which is converted to its hydrochloride by reaction with the stoichiometric amount of gaseous HCl in ethanol (32.1 g, 46.3%, mp: 225-230 ° C).

In an analogous manner, starting from the corresponding aldehyde or ketone and the appropriate a-aminoamide and, if so, a suitable acidic agent, the following compounds can be obtained:

(4-benzyloxybenzyl) aminoacetamide, hydrochloric), m.p .: 25O ⁰ C;

^ • ß-Chlorbenzyloxyl-a-methyl-benzyljaminoacetamid, hydrochloride, m.p .: 199.5 to 202 ⁰ C; (R 1 -MO-chlorobenzyoxybenzylamino-S-hydroxy-propionamide, m.p .: 110-110.5 ° C; (S) -2- [4- {3-chlorobenzyl) oxybenzylamino-3-hydroxy-propionamide, m.p .: 111-113 ° C; 2- [4- (3-chlorobenzyl) oxybenzyl] -amino-N-methylacetamide, hydrochloride, m.p .: 226-228 ° C; (Si ^ - ^ - O-ChlorobenzyDoxybenzyllamino-N-methylpropionamide, hydrochloride; mp: 176, & 178.5 ° C; {S) -2- [4- (3-chlorobenzyl) oxybenzyl] amino-3-hydroxy N-methyl-propionamide, m.p .: 128-130 ° C; (S) -2- [4- (3-chlorobenzyl) oxybenzyl] aminopropionamide, m.p .: 198, S ⁰ C; (S) -2- (4-benzyloxybenzyl) amino-N-methylpropionamide, mp .: 189 to 191.5 ⁰ C; (S) -2- (4-benzyloxybenzyl) amino-3-hydroxy-N-methylpropionamide, mp .: 102-104 ⁰ C; (R) -2- [4- (3-chlorobenzyl) oxybenzyl) aminopropionamide, hydrochloride, m.p .: 198.5 to 200 ⁰ C; (R) -2- (4-benzyloxybenzyl) amino-3-hydroxy-N-methylpropionamide, mp .: 100-103 ⁰ C; (S) -2- [4- (3-Methoxybenzyl) oxybenzyl) amino-3-hydroxy-N-methyl-propionamide, mp .: 83-87 ⁰ C; (S) -2- [4- (2-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N-methyl-propionamide, mp .: 131-134 ⁰ C; (S) -2- (4- (4-Chlorbonzyl) oxybenzyl] amino-3-hydroxy-N-methyl-proplonamid, m.p .: 139-141 ⁰ C; 1 - [(4-Benzyloxybenzyl) amino] cyclopentane-1 -N-methylcarboxamide, hydrochloride, m.p .: 218-221 ⁰ C; 2- (4-benzyloxybenzyl) amino-N-methylacetamide, hydrochloride, m.p .: 238-242 ⁰ C 1 - [(4-benzyloxybenzyl) amino] cyclopropane 1-N-methylcarboxamide, hydrochloride, mp .: 194-200 (dec.) C ^0; 1-I (4-benzyloxybenzyl) amino] cyclopentane-1-carboxamide, hydrochloride, m.p .: 229-234 ⁰ C; (S ) -2- (4-benzyloxybenzyl) aminopropionamide, mp .: 229-232 ⁰ C; (S) -2- (4-benzyloxybenzyl) amino-3-methyl-N-rnethylbutanamid, hydrochloride, m.p .: 160-163 ° C; (R) -2- (4-benzyloxybenzyl) amino-3-methyl-N-methylbutanamide, 161-165 ⁰ C hydrochloride, m.p .:; (R) -2- (4-benzyloxybenzyl) amino-3-phenyl -N-methyl-propionamide, m.p .: 222.5 to 227.5 ⁰ C; 1 - [(4-Benzyloxybenzvi) aminc] cyclopropane-1-carboxamide, methanesulfonate, m.p .: 219-228 (dec.) C ⁰ ( R) -2- (4-benzyloxybenzyl) amincpropionamid, hydrochloride, m.p .: 228-231 ⁰ C; (2R, 3S) -2- (4-benzyloxybenzyl) aTuno-3-hydroxy-N-methyl-buta Namid, hydrochloride, m.p .: 187.5 to 191 ⁰ C; (2S, 3R) -2- (4-benzyloxybenzyl) arnino-3-hydroxy-N-methyl-butanamide, hydrochloride, m.p .: 187-191 ⁰ C; (S) -2- (4-benzyloxybenzyl) amino-4-methyl-N-methylpentanamide, hydrochloride, m.p .: 141-144 ⁰ C; (S) -2- (4-benzyloxybenzyl) amino-3-hydroxy-propionamide, mp .: 128,5-13O ⁰ C; (R) -2- (4-benzyloxybenzyl) amino-3-hydroxy-propionamide, mp .: 117-122 ⁰ C; (S) -2- [4- (2-methylbenzyl) oxybenzyl] amino-3-hydroxy- N-methyl-propionamide, methanesulfonate, mp .: 170-172 ⁰ C; (S) -2-I4- (3-methylbenzyl) oxybenzyliamino-3-hydroxy-N-methyl-propionamide, methanesulfonate, mp .: 80-82 ⁰ C (water 0.57%); (S) -2- [4- (3-trifluoro-methylbenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide, methanesulfonate, m.p .: 120.5 to 124 ⁰ C; (S) -2- (4- (2-trifluoromethylbenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide, methanesulfonate, m.p .: 60-7O ⁰ C (water 1.39%);

(S) -2-I4- (2-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide, methanesulfonate, m.p .: 137-14O ⁰ C; (S) -2- (4- (3-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide, methanesulfonate, m.p .: 135-138 ° C; (S) -2-I4- (2-chlorobenzyl) oxybenzyl] aminopropionamide, methanesulfonate, m.p .: 219-22O ⁰ C, (S) -2-l4- (2-chlorobenzyl) oxybenzylamino-N-methylpropionamide, methanesulfonate, m.p .: 80-90 (water 1.21%) ⁰ C, (R) -2- [4- (2-chlorobenzyl) oxybenzyl] amino-N-methylpropionamide, methanesulfonate, m.p. 13C-134 ° C; (R) -2- [4- (2-chlorobenzyl) oxybenzyl ] amlnopropionamid, methanesulfonate m.p .: 218-221 ⁰ C; (R) -2- (4-benzyloxybenzyl) amino-N-methylpropionamide, methanesulfonate, m.p .: 134.5 to 138.5 ⁰ C; (S) -2 - (4-Phenyloxybenzyl) aminopropionamide, methanesulfonate, mp .: 210-213 ⁰ C; (S) -2- (4-Phenyloxybenzyl) amino-3-hydroxy-N-met iylpropionarnid, methanesulfonate, m.p .: 112-116! ⁰ C; (S) -2- (4-Benzylbenzyl) aminopropionamide, methanesulfonate, mp .: 182-185 ⁰ C; (S) -2-I4- (2-phenylethyl) benzyl) aminopropionamide, methanesulfonate, mp .: 235 -238 ⁰ C; (S) -2 - ('1-Benzylbenzyl) amino-3-hydroxy-N-methylpropionamide, methanesulfonate, m.p .: 126-128 ° C; (S) -2- (4-Phenylethyloxybenzyl) aminoprr lionamid, methanesulfonate, m.p .: 178-181 ⁰ C; (S) -2- (4-Benzylthiobenzyl) aminopropionamide, methanesulfonate, m.p .: 250 ° C;

(S) -2- (4-Benzylthiobenzyl) amino-3-hydroxy-N-methylpropionamide, methanesulfonate, m.p .: 151-155 ° C; (S) -2- (4-phenylethylbenzyl) amino-3-hydroxy-N-methyl-propionamide, methanesulfonate, m.p .: 143-146 ° C; (S) -2- [4- (2-Phenylethyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide, methanesulfonate, mp .: 108-110 ⁰ C; (S) -2- (4-Phenyloxymethylbenzyl) aminopropionamide, methanesulfonate, mp .: 212-217 ⁰ C; (S) -2- [4- (2-fluorobenzyl) oxybenzyl] aminopropionamide, mp .: 237-241 ⁰ C; (S) -2- [4- (3-fluorobenzyl) oxybenzyllaminopropionamid, m.p .: 208-212 ⁰ C; (S) - (+) - 2- (4-Phenyloxymethylbenzyl) amino-3-hydroxy-N-methyl-propionamide, methanesulfonate, mp .: 125-128 ⁰ C; (S) -2- (4-Benzylaminobenzyl) amino-3-hydroxy-N-methyl-propionamide, dihydrochloride, m.p .: 193-195 ° C; (S) -2- (4-Benzylaminobenzyl) aminopropionamide, dihydrochloride, m.p .: 173 ⁰ C; (S) -2- (4-benzyloxyphenetyl) aminopropionamide, methanesulfonate; (S) -2- [4- (2-chlorobenzyl) oxyphenetyl] aminopropionamide, methanesulfonate; 2- [4- (3-chlorobenzyloxy) -a-methylbenzyl] aminopropionamide, methanesulfonate; (S) -2- [4- (3-phenylpropyl) oxybenzylaminopropionamide, methanesulfonate; 2 - [(4-benzyl) -a-methylbenzyl) aminopropionamide, methanesulfonate; (R) -2- (4-Benzyloxybenzyl) aminobutanamide, methanesulfonate; (S) -2- (4-benzyloxybenzyl) aminobutanamide, methanesulfonate; (S) -2- (2-benzyloxybenzyl) aminopropionamide, methanesulfonate; (S) -2- (3-benzyloxybenzyl) aminopropionamide, methanesulfonate; (S) -2- (4-cyclohexylmetylaminobenzyl) aminopropionamide, dihydrochloride; (S) -2- (4-cyclopropylmethylaminobenzyl) aminopropionamide, dihydrochloride;

(S) -2- (4-phenylaminomethylbenzyl) aminopropionamide, dihydrochloride; (S) -2- (4-Benzylaminomethylbenzyl) aminopropionamide, dihydrochloride; (S) -2- [4- (3-furfuryl) oxybenzyl] aminopropionamide, methanesulfonate; (S) -2- [4- (2-furfuryl) oxybenzyl] aminopropionamide, methanesulfonate; (S) -2- [4- (3-pyridyl) methyloxybenzyl] aminopropionamide, methanesulfonate; (Si-2- [4- (2-pyridyl) methyloxybenzyl] aminopropionamide, methanesulfonate; (S) -2- [4- (4-pyridyl) methyloxybenzyl) aminopropionamide, methanesulfonate; (S) -2- [4- (3-thenyl) oxybenzyl] aminopropionamide, methanesulfonate; and (S) -2- [4- (2-thenyl) oxybenzyl] aminopropionamide, methanesulfonate.

Example 2

0.8 g (0.00298 mol) of (S) - (+) - 2- (4-benzylbenzyl) aminopropionamide are dissolved in 45 ml of acetonitrile under a stream of nitrogen. 2.98 ml (0.0149 mol) of 37% formaldehyde and 0.27 g (0.00432 mol) are added to this mixture.

Sodium cyanoborohydride added at room temperature. After 40min. Glacial acetic acid is added dropwise until the solution is neutral. The mixture is evaporated to dryness and treated with 40ml 2 N KOH. After extraction with ethyl acetate, wash with N / 2 KOH and then with water and brine, the solution is dried over Na ₂ SO ₄ , then filtered and evaporated,

whereby a crude oil is obtained, which is chromatographed on silica gel (eluent: CHCl ₃ / MeOH / conc NH ₄ OH, 200/3 / 0.2). In this way, 0.58 g (69%) of a colorless oil is obtained. The product is dissolved in methanol and reacted oxalic acid having equimolar amount, thereby aminopropionamide white crystals of (S) -2- [N- (4-Benzylbenzyl) -N-methyl], oxalate (m.p .: 58-64 ⁰ C.) become.

In an analogous manner, starting from the corresponding secondary amine, the following compounds can be obtained

become:

(R) -2- [N- (4-benzyloxybenzyl) -N-methyl] amino-3-hydroxy-N-methyl-propionamide, mp .: 73-77 ⁰ C; (S) -2- [N- ( 4-Phenyloxymethylbenzyl) -N-methyl] aminopropionamide;

(S) -2- [N- (4-Benzylethylbsnzyl) -N-methyl] aminopropionamide;

(S) -2- [N- (4-benzylbenzyl) -N-methyl)] amino-3-hydroxy-N-methylprnpionamide; (S) -2- (N- (4-benzylthiobenzyl) -N-methyl] aminopropionamide:

(S) -2- [N- (4-Benzylaminobenzyl) -N-methyllaminopropionamid; (NMR: δ (CDCl ₃ ): 1.05 (d, 3H, Me) 2.02 (s, 3H, N-Me) 3.55 (q, 1H,

CH-CONH2) 4.20 (s, 2H, ArCH2NMe) 4.28 (s, 2H, ArCH2NHAr) 6.55-7.30 (m, 11H, arom. + CONH2);

(S) -2- [N- (4- (2-chlorobenzyl) oxybenzyl) -N-methyl] amino-3-hydroxy-N-methylpropionamide, methanesulfonate; (S) -2- [N- (4- (3 Fluorobenzyl) oxybenzyl) -N-methyl) amino-3-hydroxy-N-methylpropionic acid, methanesulfonate; (S) -2- [N- (4- (2-fluorobenzyl) oxybenzyl) -N-methyl] amino-3- hydroxy-N-methylpropionamide, methanesulfonate; (S) -2- [N- (4- (3-fluobibenzyl) oxybenzyl) -N-methyl] aminopropionamide, methanesulfonate; and (S) -2- [N- (4- (2-chlorobenzyl) oxybenzyl) -N-methyl] aminopropionamide, methanesulfonate.

Example 3

33.5 g (0.149 mol) of N-benzylidene-tyramine are added to a mixture of 4.45 g (0.193 mol) of sodium in 400 mL of anhydrous ethanol. After cooling to 0-5 ⁰ C., a solution of 3-chlorobenzyl chloride is (28,8g; 0.193 mol) in dry ethanol (160ml) was added dropwise. After stirring at room temperature for 6 hours, the residue is boiled. The hot mixture is filtered and the solution is concentrated to dryness. The residue is washed with 10% HCl (170ml) and heated for 1 hour at 70-75 ⁰ C. The white solid precipitate is filtered and washed with η-hexane. After recrystallization from ethanol, 31 g of 4- (3-chlorobenzyl) oxyphenetylamine hydrochloride are obtained. Mp .: 195-200 (Zers.). 31 g (0.104 mol) of 4- (3-chlorobenzyloxy) phenetylamine hydrochloride are suspended in 450 ml of anhydrous ethanol. To this mixture are added 9.7 g (0.104 mol) of chloroacetamide and 28.8 g (0.208 mol) of anhydrous potassium carbonate. After heating to reflux is stirred for a further 40h. The hot mixture is filtered, then evaporated to dryness, and the crude residue is chromatographed on silica gel (eluant CHClA / MeOH / conc NH ₄ OH, 97/3 / 0.3). The resulting free compound (20.2 g, 60.7%) is treated with lavish HCl in ethanol to give a quantitative yield of the corresponding [4- (3-chlorobenzyl) -oxyphe.-1-ethyl-aminoacetamide hydrochloride, m.p .: 248-251 ° C is obtained. In analogous manner, the following compound can, starting from the corresponding primary amine are obtained: HO-Chlorbenzyloxyl-a-methyl-benzyllaminoacetamid, hydrochloride, m.p .: 199.5 to 202 ⁰ C; 2 - ((4-benzylpherylethyl) aminoacetamide; and 2- [2- (4-benzylamino) phenylethyl] aminoacetamide;

Example 4

7.07 g (0.066 mol) of glycinothyl ester hydrochloride are diluted in 200 mL of dry methanol and washed with 3.32 g (0.053 mol)

Sodium cyanoborohydride with stirring under nitrogen. To this solution are added 15g (0.0608 mol)

Added 3-chlorobenzyloxybenzaldehyde in a single portion. Stirring is continued for 18 hours at room temperature and the mixture is evaporated to dryness. The crude residue is chromatographed on silica gel (eluant:

Cyclohexane / ethyl acetate; 60/40). It will be 6.8 g (34%) of [4- (3-chlorobenzyl) oxybenzyl] amino acetic acid ethyl ester (mp .: 114-115 ⁰ C as hydrochloride).

3 g (0.0090 mol) of the above ester (free base) are heated in 70 ml of dimethylamine at 60 ° C for 7 h. The solution is over

Allowed to stand overnight at room temperature, then evaporated, and the residue is purified on silica gel (eluant: Chloroform / methanol / 30% NH ₄ OH; 95/5 / 0.5). In this way, 0.7 g (23%) of (4- (3-chlorobenzyl) oxybenzyl] amino-N, N-

Dimethylacetarnid hydrochloride (mp.: 120-125 ⁰ C).

In an analogous manner, starting from the corresponding ethyl esters, the following compounds can be obtained:

2- (4-benzyloxybenzyl) amino-N, N-dimethylacetamide; 2- (4-benzyloxybenzyl) amino-3-hydroxy-N, N-dimethyl-propionamide; 2- (4-Benzylbenzyl) amino-N, N-dimethylacetamide; 2- (4-Benzylaminobenzyl) amino-N, N-dimethylacetamide;

(S) -2- [4- (2-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N, N-dimethylpropionamide, methanesulfonate; (S) -2- [4- (3-fluorobenzyl) oxybenzylamino-3-hydroxy-N, N-dimethylpropionamide, methanesulfonate; (S) -2- [4- (2-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N, N-dimethylpropionamide, methanesulfonate; (S) -2- (4- (3-fluorobenzyl) oxybenzyl] amino-N, N-dimethylpropionamide, methanesulfonate; (S) -2- [4- (2-chlorobenzyl) oxybenzylamino-N, N-dimethylpropionamide, methanesulfonate; (S) -2- [4- (2-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N, N-dir. -Ethyl-propionamide, methanesulfonate, and (S) -2- (4-banzyloxybenzyl) -amino-N, N-dimethylpropionamide, methanesulfonate.

Example 5

8g (0.026 mol) of [4- (3-chloroboncyl) oxybenzyl] aminoacetamide are dissolved in methanol (100 ml) and to the solution is added 3.6g (0.026 mol) of anhydrous potassium carbonate. Methyl iodide (3 ml, 0.050 mol) is dropped into the mixture, which is stirred for 2 hours at room temperature and then evaporated to dryness. The crude residue is chromatographed on silica gel (eluent: chloroform / methanol: 95/5).

In this manner, 4.25 g (51.3%) of 2- | N- (4- (3-chlorobenzyl) oxybenzyl) -N-methyl] aminoacetamide (mp .: 108-111 ⁰ C). In an analogous manner, the following compounds can be obtained and, if necessary, converted into the salt with a suitable acidic agent:

(S) -2- [N- (4-Benzyloxy-benzyl) -N-methyl-amino-N-methyl-propionamide: mp: 80-82.5 ° C; (S) -2- [N- (4- (3-Chloibenzyl) oxybenzyl) -N-methyl] amino-3-hydroxy-N-methylpropionamide, fumarate, m.p .: 87.5 to 95 ⁰ C (dec.) ; (S) -2- (N- (4-Benzyloxybenzyl) -N-methyl] amino-3-hydroxy-N-methyl-propionamide; mp: 75-78 ° C; (S) -2- [N- (4-) (3-chlorobenzyl) oxybenzyl) -N-methyl] amino-N-methylpropionamide, oxalate, m.p .: 75-85 ⁰ C (water 1.54%); (S) -N - [(4-benzyloxybenzyl) -N methyl] aminopropionamide, mp .: 102-104 ⁰ C; and (S) -2-IN- (4- (3-chlorobenzyl) oxybenzyl) -N-methyl] aminopropionamide, Fp.:81-84°C.

Example β

Tablets each weighing 300 mg and containing 100 mg of the active ingredient can be prepared as follows:

Compositions: (for 5000 tablets)

[4- (3-Chlorobenzyl) oxybenzyl] aminoacetamide hydrochloride 500g

Lactose 710g

Corn starch 237.5 g

Talcum powder 37.5 g

Magnesium Stearate 15g

The 2- [4- (3-chlorobenzyl) oxybenzyl] aminoacotamide hydrochloride, the lactose and half the corn starch are mixed. The mixture is then forced through a sieve with 0.5 mm openings. The corn starch (18g) is suspended in warm water (180ml).

The resulting paste is used to granulate the powder. The granules are dried, triturated on a sieve with a sieve size of 1.4 mm, and then the remaining amount of starch, talc and magnesium stearate is added. The whole thing is mixed thoroughly and made into tablets.

Example 7

Tablets, each weighing 300 mg and having an active substance content of 100 mg, can be prepared as follows:

Compositions: (for 500 tablets)

(S) -2- (4-Benzylbenzyl) aminopropionamide,

Methanesulfonate 500 g

Lactose 710g

Corn starch 237.5 g

Talcum powder 37.5 g

Magnesium Stearate 15g

The (S) -2- (4-benzylbenzyl) aminopropionamide, methanesulfonate, lactose and half of the corn starch are mixed. The mixture is then forced through a sieve with 0.5 mm openings. The corn starch (18g) is suspended in warm water (180ml).

The resulting paste is used to granulate the powder. The granules are dried, triturated on a sieve with a sieve size of 1.4 mm and then added with the remaining amount of starch, talc and magnesium stearate. The whole is mixed thoroughly and pressed into tablets.

Claims (2)

R _{7 is} C ₁ -C ₈ alkyl; a C ₃ -C ₈ -cycloalkyl, furyl, thienyl or pyridyl ring; or a phenyl ring which is unsubstituted or substituted by 1 to 4 substituents independently selected from halogen, C ₁ -C ₈ alkyl, C ₁ -C ₆ alkoxy and trifluoromethyl; Z is a - (CH ₂ ) _r or - (CH ₂ ) _s -Y- (CH ₂ ) _t group, wherein r is an integer from 1 to 4, one of s and t is 0, and other is 0 or an integer from 1 to 4, and Y is -0-, -S- or -NR ₁₃ -, wherein R _{13 is} hydrogen or C ₁ -C ₄ alkyl; ν has the value O or 1; R ₈ and R ₉ are each independently hydrogen or C ₁ -C ₄ -alkoxy; R is hydrogen, C ₁ -C ₄ alkyl which is unsubstituted, or hydroxy or a phenyl ring optionally substituted by 1 to 4 substituents independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and trifluoromethyl is substituted; R'io is hydrogen; or R ₁₀ and RSo taken together with the adjacent carbon atom form a Cs-Ce-cycloalkyl ring; R ₁₁ and R ₁₂ are each independently hydrogen or C ₁ -C ₆ alkyl; and wherein a) when R _{7 is} C ₁ -C ₈ alkyl, then Z is a - (CH 2) _s -Y- (CH 2) t group wherein both of s and t are O and Y is as defined above is; and wherein b) when R _{7 has} the meaning Ci-C ₈ -alkyl, and at the same time Z is a - (CH ₂ ) SY- (CH ₂ K-GrUpPe, wherein both of s and t have the value O, and YO-, R ₁₀ is hydrogen or C ₁ -C ₄ -alkyl, R 'is _1O is hydrogen, or R ₀ and R' _1O taken together form a Cs-Ce-cycloalkyl ring with the adjacent carbon atom, and v, Rg, Rn and R _{12 are} as defined above, then [. _{8 is} C 1 -C ₄ alkyl; and wherein c) when Z is a group- (CH ₂ ) ₈ -Y- (CH ₂ ) wherein s, t and Y are as are defined above and at the same time R _{7 is} a furyl, thienyl or pyridyl ring, or a phenyl ring which is unsubstituted or a phenyl ring which is unsubstituted, or by 1 or 2 substituents selected from halogen, C C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and trifluoromethyl, R _{10 is} hydrogen or C ₁ -C ₁ -alkyl, R ' _{1O is} hydrogen, and v, R ₈ and R _{9 are} as defined above , then at least one of the groups R ₁₁ and R ₁₂ another Bede wherein d) when R _{7 is} phenyl which is unsubstituted or substituted by 1 to 4 substituents selected from halogen and C ₁ -C ₆ -alkyl, and at the same time Z is a -CH (R ₁₄ ) - or- (CH ₂ ) ₅ -Y- (CH ₂ ) t-group, wherein R _{14 is} hydrogen or C ₁ -C ₃ -alkyl, Υ-0 or -S-, and s and t are both have the value O, R ₈ and R _{9 are} hydrogen, ν has the value O, and R ₁ O, R'io, ru and R _{12 are} as defined above, then R _{10 has} a meaning other than hydrogen or unsubstituted C ₁ - C ₄ alkyl has; and the pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, characterized in that in the formula (I a) R _{7 is} a phenyl ring which is unsubstituted, or by 1 or 2 substituents independently selected from halogen, C ₁ -C ₄ alkyl and trifluoromethyl, is substituted; Z is a - (CH ₂ ) _r - or - (CH ₂ ) ₈ -Y- (CH ₂ ) _t group, wherein r is 1 or 2, one of s and t is O, and the other has the value 0.1 or 2, and Y is -O-, -S- or -NH-; ν has the value O or 1; R ₈ and R ₉ , independently of one another, are each hydrogen or C 1 -C ₄ -alkyl; R _{10 is} hydrogen or C ₁ -C ₄ alkyl, optionally substituted by hydroxy; R ' _{1O is} hydrogen; Rn and R ₁₂ , each independently, are hydrogen or C ₁ -C ₄ alkyl; and wherein a) when Z is a group - (CH ₂ ) _s -Y- (CH ₂ ) _t -, wherein s, t and Y are as defined above, and at the same time R _{7 is} a phenyl ring as defined above, R _{10 is} hydrogen or unsubstituted C ₁ -C ₄ alkyl, v, R ₈ and R _{9 are} as defined above, then at least one of R ₁₁ and R _{12 has} a meaning other than hydrogen; and b) when R _{7 is} a phenyl ring which is unsubstituted or by 1 or 2 substituents selected from halogen and C ₁ -C ₄ -alkyl, and at the same time Z is a -CH (Ru) - or - (CH ₂ ) _t group, wherein Ri _{4 is} hydrogen or C ₁ -C ₃ -alkyl, Y is -O- or -S- and s and t are both 0, R ₈ and R _{9 are} hydrogen, ν is 0, and Rn and Ri _{2 are} as defined above, then Ri _{0 is} C 1 -C ₄ alkyl substituted by hydroxy is, stands.
3. Process for the preparation of a compound of formula (I a) fgfio (CH J-N-C-CON 11 C-CON R ' "ίο R _{7 is} Ci-Ce-alkyl; a Cj-C ₈ cycloalkyl, furyl, thionyl or pyridyl ring; or a phenyl ring which is unsubstituted or substituted by 1 to 4 substituents independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and trifluoromethyl; Z is a - (CH ₂ Jr or - (CH ₂ ) ₈ -Y- (CH ₂ ) _t - group, where n is an integer from 1 to 4, one of s and t is 0, and the other is dei, value 0 has or is an integer of from .1 to 4 and Y is-O -, - S-or-NRi3-hat where R ^ is hydrogen or Ci-C ₄ alkyl; ν is 0 or 1 ; R ₈ and R ₉ are each independently hydrogen or C 1 -C ₄ -alkyl; R _{1 is} hydrogen, C ₁ -C ₄ alkyl which is unsubstituted or substituted by hydroxy or a phenyl ring optionally substituted by 1 to 4 substituents independently selected from halogen, C ₁ -C ₆ alkoxy and trifluoromethyl, stands; R ' _{1O is} hydrogen; or Ri ₀ and R _'1O taken together with the adjacent carbon atom form a C3-C ₆ cycloalkyl ring; Rn and Ri ₂ independently of one another each represent hydrogen or C ₁ -C ₆ -alkyl; and wherein a) when R _{7 is} C 1 -C ₈ -alkyl, then Z is a - (CH ₂ ) ₈ -Y- (CH ₂ ) _t -group, wherein both of s and t are 0 and Y is as above is defined; and wherein b) when R _{7 has} the meaning Ci-C ₈ -alkyl, and at the same time Z is a - (CH ₂ ) "- Y- (CH ₂ ), - group, wherein both of s and t is the value 0 and Y is O, Ri _{0 is} hydrogen, or R i ₀ and R'io taken together with the adjacent carbon atom form a C 3 -C ₆ cycloalkyl ring, and v, Rg, R ₁₁ and R _{12 are} as defined above, then Ra is C 1 -C ₄ -alkyl; and wherein c) when Z is a group - (CH ₂ ) _S -Y- (CH ₂ ), wherein s, t and Y are as defined above, and at the same time R _{7 is} a furyl, thionyl or pyridyl ring or a phenyl ring which is unsubstituted or substituted by 1 or 2 substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and trifluoromethyl, R i _{0 is} hydrogen or C ₁ -C ₄ al kyl is, R'io is hydrogen, and v, R ₈ and R _{9 are} as defined above, then at least one of R ₁₁ and Ri _{2 has} a meaning other than hydrogen, and wherein d) when R _{7 is} phenyl, the is unsubstituted or substituted by 1 to 4 substituents selected from halogen and C ₁ -C ₆ alkyl, "d at the same time Z is a -CH (R ₁₄ ) - or - (CH ₂ ) _s -Y- (CH ₂ ) _t group wherein R _{14 is} hydrogen or C ₁ -C ₃ alkyl, Υ-0 or -S-, and s and t are both 0, R ₈ and R _{9 are} hydrogen , ν is 0, and R ₁₀ , R'10, R ₁₁ and Ri _{2 are} as defined above, then R ₁ O has a meaning other than hydrogen or unsubstituted C ₁ -C ₄ -AlkYl; and the pharmaceutically acceptable salts thereof; characterized in that one a) a compound of the formula (Ha) or (IIIa), (Ha) (IH) wherein R ₇ , R ₈ and Z are as defined above, with a compound of formula (IVa): R ₉ R ₁₀
HN-C-CON -R ₁₁ (IVa) 10 ^R 12 wherein R ₉ , R ₁₀ , Rn and R _{12 are} as defined above, and both R ₁₁ and R _{12 are} not a C ₁ -C ₆ alkyl group to give a compound of formula (Ia) wherein ν is the value 0 or 1, and R ₁₁ and R _{12 are} as defined above, and are not both C ₁ -C ₆ alkyl, are reacted; or b) a compound of the formula (Va) or an alkyl ester thereof: 10 H- (CH ₂ ) _v -NC-COOH (Va) R. ¹ 10 wherein R ₇ , Z, R ₈ , Rg, R ₁ O, R'io and ν are as defined above, with an amine of formula (Vl a): (Via) wherein R ₁₁ and R _{12 are} as defined above; or
c) a compound of the formula (Vila) R (Vila) wherein R ₇ , Z, R ₈ , ν and R _{9 are} as defined above, with a compound of the formula (Villa): W-CH ₂ - (Villa) wherein W is a halogen atom and R ₁ I and R _{12 are} as defined above; to obtain a compound of formula (I a) reacting, in which R ₁₀ and R _'1O are both hydrogen; or d) a compound of the formula (IXa) ^R 8 Γ Γ "/" π H- (CH ₀₎ -NC-CON 2 ν, ^R lo Λ 2 (IXa) in which R ₇ , Z, R ₈ , v, R ₁₀ , RSo, R ₁₁ and R _{12 are} as defined above, with a compound of the formula (X) or (XI) R ₉ "-W R ₉ "'- CHO (XI) wherein W is a halogen atom; R ₉ "is C ₁ -C ₄ -AIRyI and R ₉ "'is hydrogen or C ₁ -C ₃ -AIRyI to give a compound of formula (I a) wherein R _{9 is} C ₁ -C ₄ -AIRyI stands, converts; and, if desired, converts a compound of formula (Ia) into another compound of formula (Ia) and / or, if desired, converts a compound of formula (Ia) into a pharmaceutically acceptable salt and / or, if desired, a salt in a free compound converts and / or, if desired, a mixture of isomers of the compounds of formula (Ia) separates into the individual isomers. 4. Compound of formula (Ib) * 8 fgf'io .CH- (CH.) -N-CH- 11 12 (Ib) FT _{7 is} a phenyl ring which is unsubstituted or substituted by a halogen atom; Z 'is a - (CH ₂ ) _r - or - (CH ₂ ) _s -Y- (CH ₂ h group wherein r is 1, one of s and t is 0, and the other is the value 0 or 1, and Y is -O-, -S- or -NH-; R'a is hydrogen;
w has the value 0; R'g is hydrogen or methyl; R 'io is hydrogen or methyl, R'n and R' _{12 are} hydrogen, and the pharmaceutically acceptable salts thereof, 5. Process for the preparation of a compound of formula (I b) r 'r "| 9 | 10 ) -N-CH-CONi 11 "12 (Ib) R ' _{7 is} a phenyl ring which is unsubstituted or substituted by a halogen atom; Z 'is a - (CH ₂ ) _r - or - (CH ₂ ) sY- (CH ₂ ) t group, where r is 1, one of s and t is 0, and the other is 0 or 1 and Y is -O-, -S- or -NH-; R ' _{8 is} hydrogen; w has the value 0; R ' _{9 is} hydrogen or methyl; R _{10 is} hydrogen or methyl, R 1 and R _{12 are} hydrogen, and the pharmaceutically acceptable salts thereof, characterized in that a) a compound of the formula (Hb) (Hb) wherein R ' ₇ , R'e and Z are as defined above, with a compound of formula (IVb): R' ₉ R " ₁₀ R ¹ (IVb) NH-CH-CON 12 wherein R'9, R "io / R'n and R _{'12 are} as defined above, or;
b) a compound of formula (Vb) or an alkyl ester thereof I 9 VOO H (CH) -N-CH-COOH (L ι * * (Vb) in which R ' _{7 (} Z', R ' _{8 (} R'g, R "io / and W are as defined above) with an amine of the formula (Vl b)
R ' 11 (VIb) wherein R'n and R _{'12 are} as defined above; or
c) a compound of the formula (VIIb) f f ^; CH- (CH J ^ -NH (VIIb) wherein R ' _{7 /} Z', R ' ₈ , w and R' _{9 are} as defined above, with a compound of formula (VIII b) (VIIIb) wherein W is a halogen atom and R'n and R _{'12 are} as defined in claim 9, to give a compound of formula (Ib) wherein R "io is hydrogen;
d) a compound of the formula (IXb) R.H.R. 10 ¹ Il H- (CH _n) -NC-CON: 2 w 1 (IXb) 12 wherein R ' ₇ , Z', R ' ₈ , w, R " ₁₀ , R'n and R' _{12 are} as defined in claim 9, with a compound of formula (X) or (XI) R ₉ "-W (X) R ₉ "'- CHO (XI) wherein W is a halogen atom; R " _{9 is} C ₁ -C ₄ alkyl and R '" _{9 is} hydrogen or C ₁ -C ₃ -AIRyl, to give a compound of formula (I b) wherein R' _{9 is} C ₁ -C ₄ -alkyl is reacted;
and, if desired, converting a compound of formula (Ib) into another compound of formula (Ib) and / or, if desired, converting a compound of formula (Ib) into a pharmaceutically acceptable salt and / or, if desired Salt in a free compound
converts and / or, if desired, a mixture of isomers of compounds of formula (I b) separates into the individual isomers. 6. A compound according to claim 1 or 2, characterized in that the compound of formula (Ia) consists of: 2- (4- (2-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N-methyl-propionamide; 2- [4- (3-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methyl-propionamide; 2-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide; 2- [N- (4-benzylbenzyl) -N-methyl] aminopropionamide;
2- [4- (3-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropion8mid; 2- (4-benzyloxybenzyl) amino-3-hydroxy-N-methylpropionamide; 2- [4- (3-chlorobenzyl) oxybenzyl] amino-N-methylacetamide; 2- (4-Phenyloxvbenzyl) amino-3-hydroxy-N-methylpropionamide; 2- [4- (2-phenylethyl) benzyllaminopropionamid;
2- [4- (2-chlorobenzyl) oxybenzyl] amino-N-methylpropionamide; 2- (4-benzyloxybenzyl) amino-N-methylpropionamide; which, if present, is present either as the sole (S) or (R) isomers or as a mixture thereof, and the pharmaceutically acceptable salts thereof. 7. A compound according to claim 4, characterized in that the compound of formula (I b) of: 2- (4-benzyloxybenzyl) aminopropionamide;
2- [4-chlorobenzyl) oxybenzyl] aminopropionamide;
2- (4-Benzylaminobenzyl) aminopropionamide;
2- (4- (3-fluoro-benzyl) oxybenzylJaminopropionamid;
2- [4- (3-chlorobenzyl) oxybenzyl] aminoacetamide;
2- [N- [4- (3-chlorobenzyl) oxybenzyl] -N-methyl] aminoacetarnid; 2- (4-benzylbenzyl) aminopropionamide;
2- (4-Phenyloxymethylbenzy!) Aminopropionamide;
2- (4-Benzylthiobenzyl)) aminopropionamide; which, if present, is present either as the sole (S) or (R) isomers or as a mixture thereof, and the pharmaceutically acceptable salts thereof. 8. Pharmaceutical preparation, characterized in that it comprises a compound of formula (Ia) or (I b) according to claims 1 to 2,4, and 6 to 7 or a pharmaceutically acceptable salt thereof, together with a suitable carrier and / or Contains diluent. 9. Use of a compound of the formula (I) R_R _n / R- , CH- (CH ₂ ) _n -Ni-CON / _(|) R-A-fl-I * x R is C ₁ -C ₈ alkyl; a C 1 -C 6 cycloalkyl, furyl, thienyl or pyridyl ring; or a phenyl ring which is unsubstituted or substituted by 1 to 4 substituents independently selected from halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and trifluoromethyl; A is a - (CH ₂ ) H ₁ - or - (CH ₂ ) _p -X- (CH ₂ ) _q - group, wherein m is an integer from 1 to 4, one of ρ and q is 0 and the other is 0 or an integer from 1 to 4, and X is -O-, -S- OdOR-NR ₄ -, in which R _{4 is} hydrogen or C 1 -C ₄ -alkyl: η has the value O or 1; Ri and R ₂ are each independently hydrogen, O-C ₁ -C ₄ -alkyl; R _{3 is} hydrogen, C ₁ -C ₄ -alkyl which is unsubstituted or substituted by hydroxy or a phenyl ring which is optionally substituted by 1 to 4 substituents independently of halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and Trifluoromethyl substituted, substituted; R ' _{3 is} hydrogen; or R ₃ and R ' _{3 taken} together with the adjacent carbon atom form a Cy-Ce-cycloalkyl ring; R ₆ and R ₆ are each independently hydrogen or C, -C ₆ alkyl; and wherein, when R is C ₁ -C ₈ alkyl, then A is a - (CH ₂ ) _p -X- (CH ₂ ) _q - group, wherein ρ and q are both O and X is as defined above is; or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical preparation for use as an anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, anti-spastic and / or hypnotic agent. 10. Use according to claim 9, characterized in that R is a phenyl ring which is unsubstituted or substituted by 1 or 2 substituents independently selected from halogen, C 1 -C ₄ alkyl and trifluoromethyl; A is a - (CH ₂ ) _m - or - (CH ₂ ) pX- (CH?) _Q - group, where m e'en value has 1 or 2, one of ρ and q has the value 0 and the other the Has a value of 0.1 or 2, and X is -O-, -S- or -NH-; η is 0 or 1; R ₁ and R ₂ , independently of one another, are each hydrogen or C ₁ -C ₄ -alkyl; R _{3 is} hydrogen or C ₁ -C ₄ alkyl, optionally substituted by hydroxy; R ' _{3 is} hydrogen; and R ₅ and R ₆ , each independently, are hydrogen or C ₁ -C ₄ -A ^ yI. 11. Use according to claim 9, characterized in that R is a phenyl ring which is unsubstituted or substituted by halogen; A-fibrino- (CH ₂ ) _m -or- (CH ₂ ) p X- (CH ₂ ) q- group in which _{m is} 1 or ₂ ; one of ρ and q has the value 0 and the other has the value 0 or 1, and X represents -O-, -S- or -NH-; η has the value 0; R _{1 is} hydrogen; R _{2 is} hydrogen or C ₁ -C ₄ alkyl; R _{3 is} hydrogen or C ₁ -C ₂ alkyl, optionally substituted by hydroxy; R ' _{3 is} hydrogen; and R ₅ and R ₆ , independently of one another, are each hydrogen or C ₁ -C ₄ -alkyl. 12. Use according to claim 9, characterized in that said compound is selected from: 2- (4-benzyloxybenzyl) aminopropionamide; 2-L4- (2-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide; 2- [4- (2-chlorobenzyl) oxybenzyl] aminopropionamide;
2- [4- (3-Fluorbenzy!) Oxybenzyl] amino-3-hydroxy-N-methylpropionamide; 2- (4-Benzylaminobenzyl) aminopropionamide;
2- [4- (3-fluorobenzyl) oxybenzyl] aminopropionamide;
2- [4- (2-fluorobenzyl) oxybenzyl] amino-3-hydroxy-N-methylpropionamide; 2- [N- (4-Benzylbenzyl) -N-methyl) aminopropionamide;
2-L4- (3-chlorobenzyl) oxybenzyl] amino-3-hydroxy-N-methyl-propionamide; 2- (4-benzyloxybenzyl) amino-3-hydroxy-N-methylpropionamide; 2- [4- (3-chlorobenzyl) oxybenzyl] aminopropionamide;
2- [N- [4- (3-chlorobenzyl) oxybenzyl] -N-methyl] aminoacetamide; 2- [4- (3-chlorobenzyl) oxybenzyl] amino-N-methylacetarnid;
2- (4-Phenyloxybenzyl) amino-3-hydroxy-N-methylpropionamide; 2- (4-benzylbenzyl) aminopropionamide;
2- [4- (2-phenylethyl) benzyl] aminopropionamide;
2- (4-Phenyloxymethylbenzyl) aminopropionamide;
2- (4-Benzylthiobenzyl) aminopropionamide;
2- [4- (2-chlorobenzyl) oxybenzyl] amino-N-methylpropionamide; 2- (4-benzyloxybenzyl) amino-N-methylpropionamide; and
2- [4- (3-chlorobenzyl) -oxybenzyl] aminoacetamide; which, if it is the case, are present either as sole (S) or (R) isomers or as a mixture thereof.