CA1119600A - (2-oxo-pyrrolidine-1) and (2-oxo-piperidine-1) carboxylic-acid derivatives, a method for producing them and pharmaceutical preparations containing them - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to new (2-oxo-pyrrolidine-1)-carboxylic-acid hydrazides, (2-oxo-piperidine-1)-carboxylic-acid hydrazides, (2-oxo-pyrrolidine-1) carboxylic-acid esters, and (2-oxo-piperidine-1)-carboxylic-acid esters, and to pharmaceutically compatible salts thereof. The new compounds exhibit superior pharmacological effectiveness and, at the same time, extremely low toxicity. They act, for example, as psychopharmaca, against retrograde and anterograde amnesia, ischemias of various origins and also have a nootropic action.

Description

The invention relates to new (2-oxo-pyrrolidine-1)-carboxylic-acid hydraæides, (2-oxo-piperidine-1)-carboxylic-acid hydrazides, (2-oxo-pyrrolidine-1)-carboxylic-acid esters, and (2-oxo-piperidine-1)-carboxylic-acid esters, and to pharmaceutically compatible salts thereof. The new compounds exhibit superior pharmacological effectiveness and, at the same time, extremely low toxicity. They act, for example, as psychopharmaca, against retrograde and anterograde amnesia, ischemias of various origins and also have a nootropic action.
In recent times (2-oxo-pyrrolidine-1)-acetamide has been used, under the generic name "piracetam", as a medication ~or travel sickness, for the treatment of senile involution (A.J. STEGINK, Arzneimittelforshcung 22, 1972, No. 6, pages 975-977), and as a nootropic agent for improving learning ability (W. STREHL, A. BROSSWITZ, Therapiewoche 36, 1972, page 2975).
As compared with piracetam, the compounds aeeording to the invention are not only definitely superior as regards improving learning ability, but also exhibit additional-favourable effeets upon cerebral funetions. The invention relates mainly to new hydrazides of the general formula (I): -Rl ~H2)m (I), -CH~2)n - C~ R3 mb~
,: .

-:' - : : ' ~ .
.

oo wherein Rl and R2 signify, independently of e~ch other, hydrogcn or Cl-C4-alkyl, n signifies zero or a whole number between 1 and 4, _ signifies the number 1 or 2, and R3 signifies hydrogen or a residue of the formula (II):

(CH2)m N ) ¦ (II), R2 CH(CH2)nC~

wherein Rl, R2, n and _ have the meanings given above and C1-C4-alkyl, in particular signify methyl, ethyl, propyl, isopropyl and butyl.
The invention does not relate to the compounds according to claim 1 of German Offenlegungschrift 2 444 633, i.e. l2-oxo-pyrrolidine-1)-acetic-acid hydrazide and 1,2-bis-(2-oxo-pyrrolidine-1)-acetic-acid hydrazide.
The effect of substituent Rl in the heterocyclic rings may be that the C atoms carrying these substituents become centres of asymmetry, the substance according to the invention being then present as a mixture of diastereomers.
For example, in the preferred compound according to the invention N,N'-bis-t5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide of the formula:

H3C ~ ~ ~ ~ ~ ~ C13 CM2-c-NIl-NH-c-cEl2 O O

mb/ 2 -- ' .
.
' ~ , .~ ' .

-the effect of the two methyl substituents in 5- and5l-position is to make this compound available in the form of a mixture of diastereomers, consisting of a racemate and a mesoform.
For the purpose of producing the pure isomer, the preliminary products, already present as racemates, are preferably separated and further processed. To this end, for example, 5-methyl-pyrrolidinone-(2)-1-acetic-acid hydrazide may be divided conventionally into its d and 1 forms, while the other reaction components, i.e. 5-methyl-5-oxo-pyrrolidine-1-acetic-acid methyl ester are pre-ferably first saponified, after which the acid thus obtained is separated into the isomers in the conventional way. It then becomes possible to convert the optic-isomeric acids back into optically homogeneous esters.
Thereafter, for example, the d-hydrazide may be reacted, with the d-ester, according to Example 3, to N,N9-bis-(d-5-methyl-pyrrolidinone(2)-1-acetic-acid)-hydrazide.
End-products of the formula (I), which may be present in the form of a mixture of isomers, may be separated into individual isomers by known methods, e.g. by fractionated distillation, crystallization and/or chromotography. For example, the racemates obtained may be broken down into their optically-active d- and l-forms by recrystallization out of optically-active solvents, or by treatin~ the :racemic mixture with an optically-aetive aeid, preferably in the presenee of a suLtable solvent. Example= of suitable optieally-active acids are: d- and l-tartarie aeids, optieally-aetive forms of malie aeid, mandelie aeid, and other optieally-aetive aeids.
Compounds of the ~ormula (I) may be produeed as follows by methods ~nown per se:

mb/ - 3 ' .
.. . ~
-, .
. ~ ~
, 1. by reacting possibl.y substituted (2-oxo-pyrrolidine-l)- and (2-oxo-piperidine-1)-carboxylic acid derivatives of the formula:

~ (CH2)m Rl _ ¦
~ N ~ o R2-CH (Cl'12) ll-X

wherein X is a reactive, activated carboxyl group, Rl, R2, m and n have the meaning given above, with a hydrazine derivative of the formula:

wherein R3 signifies hydrogen or the group:

t--(CH ) t Nl ) .

A reactive carboxyl group X is, for example, the -COY group, wherein Y signifies a halogen or the -OR group, R representing a Cl-C4 alkyl residue.
If the new compounds contain only one heterocyclic ring, they may preferably be obtained by reacting esters of the general formula (IIIl:

r-- (C~ 2)m R~ o 7 (III) R2 -CH(CH2)n-COOR
.

6~)~
wh~rein R, Rl, R2 m and n have the meaning given above, with hy~razine. If the new compounds of the formula (I) contain two heterocycli~ rings, they may be obtained by reacting hydrazides of the formula (I), wherein R3 signifies hydrogen, with esters of the general formula (III).
In reacting esters of the formula (III) with hydrazine, approximately molar ratios are required to form the hydrazides, i.e. 1 mol of ester to 1 mol of hydrazine.
It is desirable, however, to operate with a slight excess of hydrazine, for example with 1.1 or 1.2 mols of hydrazine to 1 mol of ester. Usual, commercially obtainable, hydrazine-hydrate may be used with this method. If solvents containing small amounts of water, and/or hydrazine-hydrate, are used, the water is first of all expelled quite easily by azeotropic distillation, so that it does not interfere.
Hydrazides o-E the formula (I), wherein R3 has the meaning of a group of the formula (II), are generally produced at above 50C, preferably at between 100 and 180C, with only small amounts of solvent, or no solvent at all, and ~ith a corresponding excess of esterls).
Because of their pharmacological activity, special preference is given to bis-pyrrolidones of the formula:

O

R2-CH (CE12) nCONHNEICO (CH2) nCHR2 mb/ ~ 5 ~

' .

wherein Rl, R2, m and n have the me~ning given above. Of special interest is the compound of the formula (I) wherein Rl signifies methyl in 5- and 5'-position, R2 signifies hydrogen, and n signifies zero;

2. by reacting possibly substituted lactones of the formula IIV~ with monoamino- and diamino-alkane acid hydrazides of the formula ~V):

tCH2)m 7H2 ~ I /

+ R2_cH(cH2)n_ll_NHNH_Icl_(cH2)n_cH_R2 ~s (I), O O O

(IV) (V) wherein Rl, R2, _ and _ have the meaning given above and R4 or R5 s.ignify hydrogen or, in conjunction with the nitrogen atom as -NR4R5, the residue:

R ~ jC 2)m N ~

As lactones of the formula tIV), consideration may be given to possibly substituted butyrolactones or valero-lactones. Depending upon whether one or two 2-oxo-pyrrolidine residues or 2-oxo-piperidine residues are introduced, one or two mols of the lactone of the formula (IV) are used.
In this reaction, temperatures of between 100 and :

200C, for example, preferably between 120 and 200C, and the following high-bolling-point solvents, weFe found desirable:

mb/ - 6 -- , .

~.~19~

high-boiling-point hydrocarbons, for example, iso-octane, toluene, x~lcne, tetrahydronaphthalene; high-boiling-point aliphatics, ~or example benzenes and ligroines; and ethers, for example methyl-glycol ether, ethyl-glycol ether, butyl.glycol ether, methyl digl~ycol, ethyl diglycol, and triethyleneglycol dimethyl ether;

3. by ring-closure reaction of possibly substituted monoamino- or diamino alkane-acid hydrazides of the formula (VI):

. H2C -- (CH2)m Rl~ ¦

H2l COY R'4 R 5 NH N
R2-C`H- (CH2) n-C-NH-NH-C- (CH2) n~CH~R2 o O

(VI) .

~herein Rl, R2, m, n and Y have the meaning given above, R'4 :
and R'5, or R'4 and R'5, in conjunction with the nitrogen atom as -NR4R5, have the meaning give above~ In the case of the ester, ring closure is achieved by heating to a temperature of between 100 and 200C, whereas in the case of an acid halide, ring closure may be carried out even at room temperature (with :
the addition of bases). The bases used may be, for example, organic or inorganic, for example triethylamine. Alkaline- or alkaline-earth-hydroxides may be used as inorganic bases.
. The initial compounds for this method may be obtained for example, by reacting monoamino- or diamino-alkane acid hydrazide oE the formula (VII): :
: ' bm:
... .. ,~. .. ~ :
~ , OO

~4 R 5 CII2--C\-l2 H2N-C~I-(C~2)n-C-NII-M~I-C-(CH2)n-~1-N ~ 2 R~ C ~

(VII) with one or two mols of laevulinic-acid derivatives, the Schiff's base obtained as the condensation product, preferably in the form of a Cl-C4-alkyl ester or an acid halide, for example, acid chloride, being subjected to reductlon. For example, hydration of the double bond may be carried out catalytically with the aid of palladium activated charcoal.

4. According to another method, compounds of the formula (I) are obtained in that, in compounds of the formula (VIII): :

2 (CH2)m R

NH N
R2-CH-(CH2)n-C-N H-NH-l-(cH2)n-cH-R2 - :
(VIII) O

wherein Rl and R2 have the meaning given above, Y signifies a halogen atom, more particularly chlorine or bromine, R6 signifies a 4-halogen-butyl residue of the formula:

R~

/~C~

R7 signifies hydrogen, or R6 and R7, in conjunction with the :~

nitrogen atom as -NR6R7~ signify the residue:
'. ~
- 8 - :
bm: .

(C~12)m R~- _ ¦
~NJ ., the ring is closed into a possibly substituted oxo-pyrrolidone or oxo-piperidine. This ring closure is carried out, for example, at a temperature of between 0 and 150C, preferably between 20 and 100C, in the presence of an inorganic or organic base, for example alkaline- or alkaline-earth-hydroxides or carbonates or pyridine.
Ring closure may also be achieved by hydrolytic separation by the phase-transfer method, with a carboxylate, in an aqueous medium, in the presence of a phase-transfer càtalyst and an inorganic base. The term carboxylate is intended to mean the salt of an organic carboxylic acid, the said salts being mainly metal salts such as alkaline or alkaline-earth metal salts, also ammonium salts of such acids of corresponding aliphatic and aromatic carboxylic acids, such as lower-alkane carboxylic acids, for example acetic and propionic acid, and benzoic acid. It is preerable to use alkaline metals, such as sodium or potassium, also calcium ~ ;
alkanoates with 1-3 carbon atoms, including corresponding `::
-formiates and -acetates, chiefly sodium- or potassium-formiate or -acetate.
The phase-transfer catalysts used may be, for example, onium salts, more particularly ammonium and phosphonium salts, for example tetra-alkylammonium salts or phosphonium ~
salts, especially corresponding halides such as tetra-n- ~ ;
butylammonium chloride or ~bromide, or tetra-alkylphosphonium ~;
chloride or tetra-~alkylphosphonium bromide, ethyl _ g _ ~ ~ bm: ~

{)o trioctylphosphonium chloride, or alkyltrioc-tylphosphonium bromide, or aryl-lower-alkyl, tri-lower-alkylammonium salts in special corresponding halides, for example benzyltriethyl-ammonium chloride.
Similarly, it is also possible to use corresponding arsonium- and sulphonium-salts (cf E.V. DEHMLOV, Applied Chemistry, Vol. 8, pages 521 - 533) For neutralizing the acid corresponding to the carboxylate reagent, which arises as an intermediate product of the hydrolysis, and in order to accelerate this hydrolysis, a base is added. Use is normally made of inorganic bases such as corresponding metal bases, for example alkaline-metal or alkaline-earth-metal bases, more particularly corresponding hydroxides, hydrogen carbonates, or preferably carbonates, for example sodium or potassium hydroxide or - hydrogen carbonate and preferably sodium- or potassium hydrogen carbonate.
Similarly it is also possible to use the corresponding hydroxides, hydrogen-carbonates of calcium or magnesiumr preference being given, possibly to CaC03 as a not-easily- ~ ;
soluble carbonate.
The reaction is usually carried out in a two-phase system consisting of an aqueous and an organic phase, the - latter being formed from the organic initial product.
- The initial compounds of the formula VIII may be produced, for example, according to the following reaction diagram, by reacting 2 mols of a protective amino acid of ` the formula: - ;

RX-~lH-f~l (CH2) n-COX - ,~
R2 ' ' - 1 0 - . ~;
bm:

o~

wherein Rx signifies a protective amino group, wi.th a hydrazine, to a bisaminoalkane-acid hydrazicle:

RX-N}~-c~-(cl~2)n~ll_N~_NH_~-(cH2)n-c~l-NH
O Rx which, by solvolytic fission, is converted into a compound of the formula IX:

H2N-FH- (CH2) n-lcl-NH-NH-lcl- (CH2) n-fH-NH2 (IX) This is reacted with a possibly substituted halo-carboxylic-aeid derivative of the formula:

~CH2)m ' H2C , X

.
wherein X is a halogen and Y has the meaning given above.
A protective amino group is mainly an acyl group, :~
: such as aeyl of an aliphatlc, aromatic, or araliphatie earboxylie aeid, more part1eularly lower alkanoyl~ far example acetyl, propionyl, or aroyl, for example benæoyl, or aeyl of formie aeid or of a semi-derivative of earbonie aeid, for :
: ::
example of an -ester, sueh as formyl, lower alkoxy earbonyl~

bm for example ethoxy carbonyl or tert.-butyloxy carbonyl~ or aryl loweralkoxy carbonyl, for example benzyloxy carbonyl.
The splitting off of an acyl residue, used as a protective amino group Rx, is carried out in a manner known per se, for example by solvolysis, mainly by alcoholysis, also by hydrolysis. Alcoholytic splitting off of an acyl residue Rx may be carried out, for example, in the presence of a highly basic agent, at an increasêd temperature, for example between about 50 and about 120C. In this case, use is made, in particular, of a lower alkanol, for example n-butanol or ethanol, the strong base being an alkaline-metal-, for example a sodium- or potassium-lower-alkanolate, for example -n-butylate or - ethylate, or an alkaline-metal-, for example a sodium- o~ potassium-hydroxide.
Protective amino groups Rx, for example lower-alkoxy carbonyl groups such as tert.-butyloxycarbonyl, may be split off acidolytically, for example by treatment with trifluoracetic acid, with very little detriment.
Another protective amino group which can be split off with very little~detriment, is an ethoxy carbonyl group which carries, in ~-position~ a silyl group substituted with three hydrocarbon radicals such as a triphenyl- silyl-, dimethyl-butyl-silyl- or, above all, a trimethyl-silyl group, Such a ~-(tri-lower-alkyl--silyl)-ethoxy carbonyl group forms, with the amino group to be protected, a corresponding ~-tri-lower-alkyl-silyl-ethoxy carbonyl amino group~ which can be split off under mild conditions by the action o fluoride ions. Reagents releasing fluoride ions may be~ for example~
fluorides of quaternary organic bases such as tetraethyl bm:

:,: . ~ .

ammoniumEluoride.
In this con~ection, it should be noted that the only protective amino groups Rx that can be used are those which can be split off selectively while retaining the structure of the compounds of the general formula (IX).

5. According to another method, it is possible to obtain compounds of the formula (I) by reacting 2-oxo-pyrrolidine or 2-oxo-piperidine with mono- or b:is-alkane-acid hydrazides of the formula (X) in a manner known per se:

Xl-lH-(CH2~n-C-NH-NH-C~-(CH2)n-CH-X

(X) wherein Xl signifies halogen or the residue:

H2C ( 2)m `

O--'` CH2 : -- ~ ~
N .~.

however, one of the two substituents Xl must be a halogen atom.

The initial compound of the formula (X) is obtained, for example, by reàcting a halogen alkane-acid halide of the :~

~ formula~

: ~ X-fH-(CH2)m-C-X :;:

R

in single molar volume, with a hydrazine of the formula bm ~
:
:

NH2N~IR3, wherein R3 has the meaning given above, or in double molar volume with hydrazine.
Depending upon the conditions of the method and the initial substances, the final products of methods 1 to 5 described above are obtained in the free form or in the form of their salts, also included in the invention.
The following examples 1-7 e~xplain method variant 1.
Example 1 5-methyl-2-oxo-pyrrolidine-1-acetic-acid methyl ester. -99 g (1 mol) of 5-methyl-2-oxo-pyrrolidine are dripped at 30-40C, under nitrogen, into a suspension of 43 g - 14 - .

bm:

: - -: -- ~

~1.2 mols) of sodium amide in 1200 ml of toluene (dry).
The ammonia is then expelled with a flow of nitrogen~
whereupon a solution of 114 g (1.2 mols) of chloroacetic-acid methyl ester, or 184 g (1.2 mols) of bromoacetic-acid methyl ester, in 150 ml of toluene, is dripped in, at 50 - 60C, uniformly over a period of 3 hours, Heating is continued for three more hours after this addition, after which the salt and some resin are drawn off cold.
This is followed by washing with some toluene. The solvent is distilled out of the combined filtrates, and the distillation residue is passed to a high vacuum. Boiling point 0.05 : 114 - 5C.
The following esters were synthesized according to the method of Example l;

. .

1:

;; ` ' ' ' ' : . bm:

d~'q ' ' ~ ~;

1) 2-Oxo-p~rrolidme-1-(2-~ropionic acid ~ethylester);
2) 5-Methyl-2-oxo-pyrrolidine-1-(3-propionic acid methylester) (112& /0,2 mm);
3) 5-Methyl-2-oxo-pyrrolidine-1-(2 propionic acid methylester) (111& /0,22 mm);
4) 3-Methyl-2-oxo-pyrrolidine-1-(3-propionic acid methylester);
5) 3-Methyl-2-oxo-pyrr~lidine-1-acetic acid methylester;

6) 4-Methyl-2-oxo-pyrrolidine-1-acetic acid methylester;

7) 3,5-Dimethyl-2-oxo-pyrrolidine-1-acetic acid methylester;

8) 4,4-Dimethyl-2-oxo-pyrrolidine-1-acetic acid methylester;

9) 3,4-Dimethyl-2-oxo-pyrrolidine-1-acetic acid methylester;

10~ 5-Ethyl-2-o~xo-pyrrolidine-1-acetic acid methylester;

11) 5-Methyl-2-oxo-pyrrolidine-1-(4-butyric acid methylester);

12) 5-~ethyl-2-oxo-pyrr~lidine-1-(2-butyric acid methy:lester);

13) 2-Oxo-piperidine-l-acetic acid methylester;

14) 6-Methyl-2-oxo-piperidine-1-acetic acid methylester;

15) 2-Oxo-piperidine-1-(3-propionic acid methylester);

16) 2 ~xo-piperidine-1-(4-butyric acid methylester);

17~ 2-Oxo-piperidine-1-(2-butyric acid methylester);

18) 6-~ethyl-2-oxo-piperidine-1-(4-butyric acid methylester);

.
~ ~' :::

-~ - 16 -: i ~ .

:: . : ~ . :., 3~
Example 2.
5-methyl-pyrrolidinone-(2)-1-acetic-acid hydrazide.
C7H13N3O2 171 ~ (1 mol) of 5-methylpyrrolidinone-(2)-1-acetic-acid methyl ester are dripped at 50C into a solution of 60g (1.2 mols) of 100% hydrazine hydrate in 200 ml of isopropanol.
The mixture is then heated for 4 hours in reflux. The solvent is then distilled off in vacuo, for the purpose of simultaneously removing both the water and the exc:ess hydrazine-hydrate. In order to complete the dehydration, 200 ml of sec~ butyl alcohol are again added and again distilled off in vacuo. The distillation residue is finally recrystallized out of 200 ml of sec. butyl alcohol.
- Melting point: 98 - 99C.
Example 3.
N,N-bis-(5-methyl-pyrrolidinone-(2)-1-acetic-acid)-hydrazide . C14H22N44 Molecular weight 310.3 A mixture of 171 g of 5-methyl-pyrrolidinone-(2)-1-acetic-acid hydrazide and 171 g of 5-methyl-pyrrolidinone-(2)-l-acetic-acid-methyl ester is heated at 130 - 140C for 24 hours, ~ ;
with stirring. The reaction mixture is then allowed to cool.
400 ml of isopropanol are added, followed by boiling for 30 minutes, after which the mixture is cooled with stirring.
The reaction product is drawn off, washed in the suction filter with isopropanol, and dried at 50C.
Melting point 181C, C 54,17 found 54.11; N 18,05 ~ound 18,1 ' bm ~

. ~

0~
Example ~.
N--(pyrrolidinone-(2)-1-acetic-acid-N'-(5-methyl-pyrrolidinone-(2)-1-acetic-acid)-hydrazide.

13 20 4 4 Molecular weight 296.3 A mixture of 171 g of 5-me~hyl-pyrrolidinone-(2)-1-acetic-acid-hydrazide and 157 g of pyrrolidinone-(2)-1-acetic-acid methyl ester is heated at 130 - 140~C for 24 hours under stirring. The reaction mixture is allowed to cool. 400 ml of isopropanol are added. The mixture is then boiled for 30 min.
and finally cooled with stirring. The reaction product is drawn off, washed in the suction filter with isopropanol, and dried at 50C.

Meltin~ point: 159-160C.
C 52.69 found 52.87%
N 18.91 found 18.73%
Example 5.
Pyrrolidinone-(2)-1-(3-propionic-acid) hydra~ide.

7 13 3 2 Molecular weight: 171 2 185 g tl mol) of pyrrolidinone-(2)-1-(3-propionic-acid ethyl ester) are dripped, at 50C, into a solution of 60 g (1.2 mol) of 100~ hydrazinehydrate in 200 ml of isopropanol.
The mixture is then heated for 4 hours under reflu~. The solvent is then distilled off in vacuo, in order to remove simultaneously both the water and the excess hydrazine hydrate.
In order to complete the dehydration, another 200 ml of isopropanol are added, and this is again distilled off in vacuo.
Finally, the distillation residue is dissolved hot in 70 ml of isopropanol, and the resulting solution is cooled with stirring.
This causes the pxoduct to crystallize out in the form of colourless crystals~ It is drawn off, washed with isopropanol, and dried.
Melting point: 106 - 107C. -~ 18-B~ bm:

.~. ~ .. - .

EX~ le 6 N,M'-bis-(pyrrolidinone-(2)-1-(3-propionic-acid)-hydrazlde.

14~22N~4 Molecular weight: 310.3 ~ mixture of pyrrolidinone-(2)-1-(3-propionic-acid hydrazide) and pyrrolidinone-~2)-1-(3-propionic-acid meth~l ester) is heated to 130 - 140 C
for 24 hours with stirrin~. The mlxture is then allowed to cool. 400 ml of isopropanol are added, the whole is boilecl for 30 minutes, and is finally cooled with stirring. The reaction product is drawn off, washed in the suction filter with isopropanol, and dried at 50C.

(~ith decomposition). ~elting point: 228&

C 54.17 found 54.03 N 18.05 found 17.98 The follownng mono- and bis-hydrazides were synthesized according to Examples 2-6.
Monohydrazide 1) 2-Oxo-pyrrolidine-1-(2-propionic acid hydrazidR);
2) 5-Methyl-2-oxo-pyrrolidine-1-(3-propionic acid hydrazide);
3) 5-~thyl-2-oxo-pyrrolidine-1-(2-propionic acid hydrazide);
4) 3-1~ethyl-2-oxo-pyrrolidine-1-(3-propionic acid hydrazide);

5) 3-Methyl-2-oxo-pyrrolidine-1-acetic acid hydrazide;

6) 4-MRthyl-2-oxo-pyrrolidine-1-acetic acid hydrazide;
7) 3,5-Di~ethyl-2-oxo-py~rolidine-1-acetic acid hydrazide;

.. . .

~ ' ., ' . ', . -' .

OQ

8) 4,4-Dimethyl-2-oxo-pyrrolidine-1-acetic acid hydrazide;
9) 3,9-Dimethyl-2-oxo--pyrroli.dine-1-acetic acid hydrazide;
10) 5-Ethyl-2--oxo-pyrrolidine-1-ace-ti.c acid hyclrazide; "
11) 5-Methyl-2-oxo-pyrrolidine-1-1~-blltyric acid hy~razidé);
12) 5-Methyl-2-oxo-pyrrolidine-1-(2-buty-i.c acid llydrazide);
13) 2-Oxo-piperidine-l-acetic acid hydrazide;
14) 6-~thyl-2-oxo-piperidine-1-acetic acid hy~razide;
15) 2-Oxo-piperidine-1-(3-propionic acid hydrazide);
16) 2-Oxo-piperidine-1-(4-butyric acid hydrazide);
17) 2-Oxo-piperidine-1-(2-butyric acid hydrazide);
N,~ ishydrazide 18) N,N'-Bis-[2-oxo-pyrrolidine-1-(2-propionic acid)]-hydrazide;

19) N,N'-Bis-[5-Methyl-2-oxo-pyrrolidine-1-(4-butyric acid)]-hydrazide;

20) N,N'-Bis-~5-Methyl-2-oxo-pyrrolidine-1-(2-propionic acid)]-hydrazide;

21) N,N'-Bis-[5-Ethyl-2-oxo-pyrrolidine-1-acetic acid]-hvdrazide;

22) N,N'-Bis-[2-oxo-piperidine-1-acetic acid]-hydrazide;

23) N,M'-Bis-[6-methyl-2-oxo-piperidine-1-14-butyric acid)]-hydrazide;

24) N-~2-oxo-pyrrolidine-1-acetic acid-M'-[2-oxo-pyrrolidine-1-(3-propionic acid)~-hydrazide;

25) N-~2-oxo-pyrrolidine-1-acetic acid]-N'-~2-oxo-piperidine-1-acetic acid]-hydrazide;

., . . - . . . . .

- , , O~

26) N-[5-Ethyl-2-o~o-pyrro]icline-1-acetic acid]-N'-[5-m~thyl-2-oxo-pyrrolidine-l-acetic acid]-hydrazide;

27) ~1-[2-Oxo-piperidine-l-acetic acid]-N'-[6-methyl-2-oxo- piperidine-1-acetic acid]-hydrazide;

28) N-[3-Methyl-2-oxo-~yrrolidine-1-acetic acid]-N'-[6-methyl-2-oxo-piperidine-l-acetic acid]-hydrazide;
The following exa~ples illustrate the production of the compound N,N'-bis-(5-methyl-pyrrolidin~ne-(2)-1-acetic acid) -hydrazide.

Exa~ple 7 (method variant 1).

A solution of 18 g of l,l-carbonyl-diimidazole in 100 ml of abs.

chloroform is dripped,' under ice-coolin~, into a solution of 15.7 g of 5-methyl-2-oxo-pyrrolidine-1-acetic acid in 200 ml of chloroform.
After 5 hours, this is stirred again at rocm temperature and is then mixed with 17.2 g of 5-methyl-2-oxo-pyrrolidine-l~acetic acid-hydrazide. The mixture is thoroughly stirred overnight, is heated for a short time under reflux, the solvent is distilled off in vacuo, the distillation residue is taken up in 100 ml of hot isopro~anol, and the solution is finally allowed to cool to rocm te~perature. A colourless crystalline material is obtained,' with a meltin~ point of 180 - 181C. :

21 - ' - - . : , :
. ~ .
, Exa~le ~ (method variant 2) A solution consisting o~ 100 ~ of 5-methyl-2 oxo-tetrahydrofurane and 228.3 g o~ N-(5-methyl-2-oxo-pyrrolidine-l-ace~ic acid)-hydrazide in 500 ml of triethylene-glycol-dimethylether is heated under nitrogen for 12 hours at about 190 - 200C.
As much as possible of the solvent is distilled off in vacuo, the distillation residue is extracted with 500 ml of hexane, and the remaining extraction residue is recrystallized out of 250 ml of hot isopropanol, also using activated charcoal.
The melting point of the product obtained is 175 - 180C.
After a second recrystallization, the melting point of the product obtained is 179 - 181C.
Example 9 (method variant 3), 125 g of thionyl chloride are dripped, over a period of 30 minutes, into a mixture of 209 g of N,N'-bis-[N-(l-carboxybutyl-(3))-aminoacetic acid]-hydrazide and 1000 ml of abs. chloroform. This followed by heating under reflux until no more gas is released. The solvent is then distilled off i~
in vacuo and the distillation residue is introduced into an ice-cold solution of 220 g of triethylamine in 1000 ml of chloroform. The mixture is stirred overnight at room temperature, after which the solvent is distilled off in vacuo and the resid~e is recrystallized repeatedly out of isopropanol, until a melting point of 180 - 181C is obtained.
The initial material required for the reaction, namely N,N'-bis-[N-(l-carboxybutyl-~3))-aminoacetic acid]-hydrazide-dichloride, may be obtained by condensing laevulinic acid with N,N'-bis-(aminoacetic acid)-hydrazide and then hydrating the double bond with a Pd/C catalyst.

d5~7 bm:

o~
Example 10 (method variant ~) 118 g oE N,N'-bis-(aminoacetic acid)-hydrazide are mixed, in 1500 ml of chloroform and 19~ g of pyridine, under ice-coolin~, with a solution of 371 g of ~-bromobutyryl chloride in 1000 ml of chloroform. Stirrin~ is continued for 12 hours.
The pyridine hydrochloride is converted to the aqueous phase by the addition of 200 ml of water, and the solvent is then di~tilled out of the chloroform phase. The residue is taken up in 2000 ml of acetone, 250 g of potash are added, and the mixture is heated for 48 hours under reflux. The salts are then filtered out, the acetone is distilled off in vacuo, and the remaining residue is recrystallized repeatedly out of isopropanol. The product obtained has a melting point of 179 - 1~1C.
Example 11 (method variant 5).
A solution of 198 g of 5-methyl-pyrrolidone in 600 ml of toluene is dripped, under nitrogen, into a suspension of 80 g of sodium amide in 2000 ml of toluene.
Thereafter, nitrogen is passed through the mixture at 40 - 50C until the ammonia has been expelled. 203 g of N,N'-bis-(chloroacetic-acid)-hydrazide is then introduced, at 50 - 60 C, batchwise, through a metering device, after which the reaction mixture is stirred for a further 7 hours at the same temperature. All of the solvent is then distilled off in vacuo, the distillation residue is treated hot with 2000 ~1 of isopropanol r the sodium chloride is drawn off, the solution is concentrated and, after inoculation, the concentrate is allowed to stand in the refrigerating chamber for a few days.
The product gradually crystallizes out. It is drawn - 23 - :
~7 bm:
.

~: ~ ~ : . . . ..

- . . ~ . . .

off, again recrystallized out of isopropanol~ and the produc-t i.s dried at 50C. The product thus obtained has a melti.ng point of 179 - 180C.
m e present invention also covers pharmaceutical preparations containing, in addition to non-toxic, inert pharmaceutically appropriate carrier substances, the active substances according to the invention, together with methods for producing these preparations.
m e present invention also co~ers pharmaceutical preparations in dosage units. This means that the preparation is available in the form of tablets, dragées (sugar-coated pills), capsules, or pills, the amount of active substance contained therein being a fraction, or a multiple, of a single dose. For example, the units may contain 1,2,3 or 4 single doses, or 1/2, 1/3 or 1/4 of a single dose A single dose preferably contains the amount of active substance administered in one application, which usually corresponds to the whole of the daily dose, or to one-half, one-third, or one-quarter thereof.
Non-toxic, inert, pharmaceutically appropriate carrier substances are to be understood as solid, semi-solid or liquid diluents, fillers, or aids to formulation of all kinds.
Preferred pharmaceutical preparations are tablets, drasées, capsules, pills, granular materials, solutions, suspensions! emulsions and powders. . .
Tablets, drage'es! capsules, pills and granular materials may contain the active substance in addition to conventional carrier substances, for example fillers~ extenders, bonding agents, moisture-retaining agents, bursting agents, solution retarders~ resorption accelerators, wetting -agents,-adsorption agents, luhricants, or mixtures of these substances Tablets, drageJes, capsules~ pills and granular materials may be provided with conventional coatings and sheaths~ if necessary containing opaqying agents~

,~ hn: ' ' ' - . . .

3~
If necessary, the active substance may also be present, with one or more of the above-men-tioned carrler substances, in the micro-encapsulatcd form.
m e therapeutically active ccn~ounds are to be present in the above-mentioned pharmaceutical preparations, preferably in concentrations of about 1.9 to 99.5, more particularly 0.5 to 95% of the weight of the entire mixture.
In addition to the active substancê according -to the invention, the above-mentioned pharmaceutical preparations may contain other pharma-ceutically active substances.
m e above~mentioned pharmaceutical preparations may be producedin known fashion by known methods, e.g. by mixing the active substance, or substances, with the carrier substance, or substances.
m e present invention also covers the use of the active substance according to the invention, and of pharmaceutical preparations which contain the active substance according to the invention, in human and veterinary medicine, for the prevention, alleviation, and/or curing of diseases which may occ~ in the cerebral-function area, for example:
chronic cerebal dysfunctions such as cerebal sclerosis, reduced me ry after interruptions in blood supply as a result of alcoholism or the effects of trauma.
Generally speaking, it has been found advantageous to administer the active substance according to the invention in total amounts of about 1.2 to about 2.4 g per 24 hours, if necessary in the fonm of repeated small doses, in order to achieve the desired results. A single dose preferably contains betwee 100 and 500 mg, more particularly between 200 and 400 mg, of the active substance according to the invention. It may, hcwever, be necessary to vary these amounts, depending on the type and body weight of the patient and the nature and gravity of the disease.

m~
~, ':

: . ~ . . ~ . -. : - .-~
: ::

Claims (26)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for preparing a compound of Formula (I), their diasterecmeric compounds, and pharmaceutically acceptable salts thereof:

(I) wherein R1 and R2 are each hydrogen or C1 to C4-alkyl, n is zero or a whole number from 1 to 4, m is 1 or 2, and R3 is hydrogen or the radical of Formula (II) (II) wherein R1, R2, m and n are as defined above; which comprises a process selected from the following processes:
(1) reacting a (2-oxo-pyrrolidine-1-) or (2-oxo-piperidine-1)-carboxylic acid derivative of the formula wherein R1, R2, m and n are as defined above and X is a reactive, activated carboxyl group, with a hydrazine derivative of the formula H2NNHR3 wherein R3 is hydrogen or the group wherein R1, R2, m and n are as defined above, and if desired separating the product thus obtained into individual diastereomeric forms;
(2) reacting a lactone of Formula (IV) (IV) wherein R1 and m are as defined above, with a monoamino- or diamino-alkane-acid hydrazide of Formula (V):

(V) wherein R2 and n are as defined above and R4 and R5 are hydrogen or in con-junction with the N-atom form the radical wherein R1 and m are as defined above, at temperatures of about 100°C to 200°C
in the presence of high-boiling-point solvents, and if desired separating the product thus obtained into individual diastereomeric forms;
(3) ring-closure of a monoamino- or diamino-alkane acid hydrazide of Formula (VI):

(VI) wherein R1, R2, R4, R5, m and n are as defined above and Y is a halogen or -OR with R being C1 to C4-alkyl, and if desired separating the product thus obtained into individual diastereomeric forms;
(4) ring-closure of a compound of Formula (VIII) wherein R1, R2, m and n are as defined above, Y' is a halogen atom, R6 is a 4-halobutyryl or 5-halovaleryl radical of the formula in which Y is a halogen, and R7 is hydrogen or an conjunction with R6 and the N-atom the radical wherein R1 and m are as defined above; and if desired separating the product thus obtained into individual diastereomeric forms; and (5) reacting 2-oxo-pyrrolidine or 2-oxo-piperidine with a mono- or bis-alkane acid hydrazide of the formula (X):
wherein R2 and n are as defined above and X1 is a halogen or the group with the proviso that one X1 must be a halogen and R1 and m are as defined above; and if desired separating the product thus obtained into individual diastereomeric forms.

2. The process defined in claim 1, including the step of preparing a pharmaceutically acceptable salt of the product thus obtained.

3. A method for preparing compounds of Formula (I), their diastereomeric compounds, and pharmaceutically acceptable salts thereof:

wherein R1 and R2 are each hydrogen or C1 to C4-alkyl, n is zero or a whole number from 1 to 4, m is 1 or 2, and R3 is hydrogen or the group wherein R1, R2, m and n are as defined above; which comprises reacting a (2-oxo-pyrrolidine-1)-or (2-oxo-piperidine-1)-carboxylic acid derivative of the formula wherein R1, R2, m and n are as defined above and x is a reactive, activated carboxyl group, with a hydrazine derivative of the formula H2N NHR3 wherein R3 is hydrogen or the group wherein R1, R2, m and n are as defined above, and if desired separating the product thus obtained into individual diastereomeric forms.

4. The process defined in claim 3 including the step of preparing a pharmaceutically acceptable salt of the product thus obtained.

5. A method of preparing compounds of Formula (I), their diastereomeric compounds, and pharmaceutically acceptable salts thereof.

wherein R1 and R2 are each hydrogen or C1 to C4-alkyl, n is zero or a whole number from 1 to 4, m is 1 or 2, and R3 is hydrogen or the group wherein R1, R2, m and n are as defined above; which comprises reacting a lactone of Formula (IV) wherein R1 and m are as defined above, with a monoamino- or diamino-alkane-acid hydrazice of Formula (V):

(V) where R2 and n are as defined above and R4 and R5 are each hydrogen or in conjunction with the N-atom form the group wherein R1 and m are as defined above, at temperatures of about 100°C to 200°C
in the presence of high-boiling point solvents, and if desired separating the product thus obtained into individual diastereomeric forms.

6. The process defined in claim 5, including the step of preparing a pharmaceutically acceptable salt of the product thus obtained.

7. A method of preparing compounds of Formula (I), their diastereomeric compounds, and pharmaceutically acceptable salts thereof.

wherein R1 and R2 are each hydrogen or C1 to C4-alkyl, n is zero or a whole number from 1 to 4, m is 1 or 2, and R3 is hydrogen or the group wherein R1, R2, m and n are as defined above; which comprises ring-closing a monoamino-or diamino-alkane acid hydrazide of Formula (VI):

wherein R1, R2, m and n are as defined above, Y is a halogen or -OR with R being C1 to C4-alkyl, and R4 and R5 are each hydrogen or in conjunction with the N-atom form the radical wherein R1 and m are as defined above; and if desired separating the product thus obtained into individual diastereomeric forms.

8. The process defined in claim 7, including the step of preparing a pharmaceutically acceptable salt of the product thus obtained.

9. A method of preparing compounds of Formula (I), their diastereomeric compounds, and pharmaceutically acceptable salts thereof:

wherein R1 and R2 are each hydrogen or C1 to C4-alkyl, n is zero or a whole number from 1 to 4, m is 1 or 2, and R3 is hydrogen or the group wherein R1, R2, m and n are as defined above; which comprises ring-closing a compound of Formula (VIII) wherein R1, R2, m and n are as defined above, Y' is a halogen atom, R6 is a 4-halobutyryl or 5-halovaleryl radical, and R7 is hydrogen or in conjunction with R6 and the N-atom the radical wherein R1 and m are as defined above; and if desired separating the product thus obtained into individual diastereomeric forms.

10. The process defined in claim 9, including the step of preparing a pharmaceutically acceptable salt of the product thus obtained.

11. A method of preparing compounds of Formula (I), their diastereomeric compounds, and pharmaceutically acceptable salts thereof:
wherein R1 and R2 are each hydrogen or C1 to C4-alkyl, n is zero or a whole number from 1 to 4, m is 1 or 2, and R3 is hydrogen or the group wherein R1, R2, m and n are as defined above; which comprises reacting 2-oxo-pyrrolidine or 2-oxo-piperidine with a mono- or bis-alkane acid hydrazide of the formula (X):

wherein R2 and n are as defined above and X1 is a halogen or the group with the proviso that one X1 must be halogen and R1 and m are as defined above; and if desired separating the product thus obtained into individual diastereomeric forms.

12. The process defined in claim 11, including the step of preparing a pharmaceutically acceptable salt of the product thus obtained.

13. A process for the preparation of 5-methyl-pyrrolidinone-(2)-1-acetic acid hydrazide which comprises reacting 5-methylpyrrolidinone-(2)-1-acetic acid methyl ester with hydrazine.

14. A process for the preparation of N,N-bis-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide which comprises reacting 5-methyl-pyrrolidinone-(2)-1-acetic acid hydrazide with 5-methyl-pyrrolidinone-(2)-1-acetic acid methyl ester.

15. A process for the preparation of N-(pyrrolidinone-(2)-1-acetic acid)-N-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide which comprises reacting 5-methyl-pyrrolidinone-(2)-1-acetic acid hydrazide with pyrrolidinone-(2)-1-acetic acid methyl ester.

16. A process for the preparation of pyrrolidinone-(2)-1-(3-propionic acid)-hydrazide whirh comprises reacting pyrrolidinone-(2)-1-(3-propionic-acid) ethyl ester with hydrazine.

17. A process for the preparation of N,N'-bis-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide which comprises reacting 5-methyl-2-oxo-tetra-hydrofurane with N-(5-methyl-2-oxo-pyrrolidine-1-acetic acid)-hydrazide in triethylene-glycol-dimethylether.

18. A process for the preparation of N,N'-bis-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide which comprises refluxing N,N'-bis-[N-(1-carboxybutyl-(3))-aminoacetic acid]-hydrazide with thionyl chloride to effect ring closure.

19. A process for the preparation of N,N'-bis-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide which comprises reacting N,N'-bis-(aminoacetic acid)-hydrazide with 4-bromobutyryl chloride and refluxing the product in an organic solvant in the presence of a base to effect ring closure.

20. A process for the preparation of N,N'-bis-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide which comprises reacting 5-methyl-pyrrolidinone-(2)-with sodium amide and then reacting the product thus obtained with N,N'-bis-(chloro-acetic acid)-hydrazide.

21. A compound of the Formula (I), diastereomeric forms thereof and pharmaceutically acceptable salts thereof:
wherein R1, R2, X, m and n are as defined in claim 1, whenever prepared or produced by the process defined in claim 1 or 2 or by the obvious chemical equivalent.

22. 5-Methyl-pyrrolidinone-(2)-1-acetic acid hydrazide, whenever prepared or produced by the process defined in claim 13 or by the obvious chemical equivalent.

23. N,N'-bis-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide, whenever prepared or produced by the process defined in claim 14 or 17 or by the obvious chemical equivalent.

24. N,N'-bis-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide, whenever prepared or produced by the process defined in claim 18, 19 or 20 or by the obvious chemical equivalent.

25. N-(pyrrolidinone-(2)-1-acetic acid-N'-(5-methyl-pyrrolidinone-(2)-1-acetic acid)-hydrazide, whenever prepared or produced by the process defined in claim 15 or by the obvious chemical equivalent.

26. Pyrrolidinone-(2)-1-(3-propionic acid)hydrazide, whenever prepared or produced by the process defined in claim 16 or by the obvious chemical equivalent.