DD216005A5 - PROCESS FOR THE PREPARATION OF PYRROLIDINONE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel pyrrolidinone derivatives for use as medicaments. The aim of the invention is the provision of compounds with increased effectiveness with regard to the improvement of memory performance as well as with a new spectrum of activity including the Antitumoraktivitaet. According to the invention, lactampetides of the formula I are prepared in which R 1 is hydrogen, C 1-4 -alkyl, aryl-lower alkyl or aryl and R 2 is hydrogen, lower-alkyl or aryl, where both R 2 and R 2 have the same meaning, and salts of such compounds having at least one salt-forming group.

Description

Process for the preparation of new pyrrolidinone derivatives

Field of application of the invention

The invention relates to a process for the preparation of novel pyrrolidinone derivatives with valuable pharmacological, e.g. tumor-inhibiting, properties.

The compounds prepared according to the invention are used as medicaments, in particular for the treatment of cerebral performance insufficiency and of sequelae of brain trauma or apoplexy as well as tumor diseases.

Characteristic of the known technical solutions

British Patent No. 1,039,113 describes N-substituted lactams of the general formula

- (ch.) cotf

2 m \

wherein η 3, 4 or 5, m is 0, 1 or 2, R ^{1 is} hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl or aryl and R "is hydrogen or alkyl or R 'and R" together with the nitrogen atom to which they are attached , a heterocyclic ring, for the treatment of motion sickness, hyperkinesia, hypertension and epilepsy. Later, it has been found that these compounds also have central nervous activity and affect memory (see British Patent No. 1,309,692).

German Offenlegungsschrift 2 507 576 describes a process for the preparation of 2-oxo-1-pyrrolidinyl-acetamide which exerts activating, protective and restorative effects on the nerve cells of the cerebral cortex.

Belgian Patent No. 887,487 describes the use of compounds of the formula

^ i -CH ₂ -CO-NHR

(R ₇ ) 2 η

wherein η is 0, 1, 2, 3 or 4, R is hydrogen or -NHCOCH Q, wherein Q is 2-oxo-1-pyrrolidinyl, which is substituted by (R ~), and R is lower alkyl or, if η is 1, OH, or, if R is hydrogen, hydrogen to reduce the undesirable side effects of cytostatics in cancer therapy.

Object of the invention

The aim of the invention is the provision of new PyrroDinonderivate with increased efficacy in terms of improving the memory performance and with a new Wirkungsspek.trum including the antitumor activity.

Explanation of the essence of the invention

The invention has for its object to find new PyrroÜdinonderivate with the desired properties and methods for their preparation.

-Ib-

In accordance with the invention, lactampetides of the formula I are prepared,

. ·. "0 0 0

/ \ Il Il Il

I Ii-CH-C-NH-CH-C-NH-CH-C-NH ₀ (I)

, vi ¹ ir i ^{2 2}

R is hydrogen, C, -alkyl, aryl-lower alkyl or aryl and R "is hydrogen, lower alkyl or aryl, where both radicals

2 R have the same meaning, and salts of such compounds having at least one salt-forming group.

The prefix "lower" here and in the following denotes a radical with 1-7, in particular 1-4 C atoms.

Aryl stands for an unsubstituted or substituted carbocyclic aromatic radical. Aryl in this application primarily stands for unsubstituted or substituted phenyl, but also for unsubstituted or substituted naphthyl.

The following aryl substituents may be mentioned in particular: lower alkyl, halogen and free or functionally modified hydroxy, but also free or esterified carboxy, oxo or unsubstituted or substituted phenyl.

   '. , '- 2 -

Functionally modified hydroxy is esterified or etherified hydroxy. ,,

Esterified hydroxy is preferably by an organic, but also by an inorganic acid esterified hydroxy, especially acyloxy, besides also sulfonyloxy or halogen. Acyloxy is preferably optionally substituted hydrocarbylcarbonyloxy or hydrocarbyloxycarbonyloxy. Optionally substituted hydrocarbyl is here and below in particular an aliphatic radical. 1-21, in particular 1-11, especially 1-7 C atoms, a carbocyclic radical, ie a cycloaliphatic radical having 3-8, in particular 5 or 6, ring members and up to 21, preferably up to 11 C Atoms, or a mono- or bicyclic aromatic radical having 6 or 10 ring members and up to 21, preferably up to 15 C-atoms, or a corresponding carbocyclic-aliphatic radical. The above-mentioned cycloaliphatic or aromatic radicals are preferably unsubstituted or substituted cycloalkyl radicals, in particular unsubstituted or substituted by lower alkyl cycloalkyl radicals, or to phenyl radicals, for example phenyl.

In particular, sulphonyloxy is an aromatic, primarily monocyclic, aromatic, sulfonyloxy having at most 12 carbon atoms, e.g. Toluenesulfonyloxy, or lower aliphatic, preferably lower alkylsulfonyloxy. '.

Etherified hydroxy is especially optionally substituted hydrocarbyloxy.

Esterified carboxy is especially unsubstituted or substituted hydrocarbyloxycarbonyl, especially lower alkoxycarbonyl.

Lower alkyl R is preferably methyl, isopropyl, 1-methyl-propyl

or isobutyl. , \

The configuration of optionally present asymmetry centers in a compound of the formula I can be independent of (D), (L) or (D, L), but is limited to the CR! ² atoms preferably (L).

The general terms used above and below in the context of the present description preferably have the following meanings:

Lower alkyl is especially methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, besides e.g. also sec. Butyl or tert. Butyl, also n-pentyl, neopentyl, n-hexyl or n-heptyl. Halogen is especially fluorine or chlorine, but may also stand for bromine or iodine.

Cycloalkyl is e.g. Cyclohexyl or cyclopentyl.

The invention also relates to the compounds of the formula I which can be used in particular as intermediates and have protected functional groups, in particular protected hydroxy or carboxy.

Protecting groups, their introduction and cleavage are described for example in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974. Characteristic of protective groups is that they are light, ie without unwanted side reactions taking place, e.g. solvolytic, reductive, photolytic or can be cleaved under physiological conditions.

Hydroxy protecting groups are e.g. Acyl radicals, as appropriate, e.g. by halogen, substituted lower alkanoyl, such as 2,2-dichloroacetyl,

or acyl radicals of carbonic monoesters, especially tert-butyloxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxy-carbonyl, furthermore trityl or formyl, or organic silyl or stannyl radicals, furthermore easily cleavable etherifying groups, such as tert-lower alkyl, e.g. tert-butyl, 2-oxa or 2-thia-aliphatic or cycloaliphatic hydrocarbon radicals, primarily 1-lower alkoxy-lower alkyl or 1-lower-alkyl-lower alkyl, e.g. Methoxymethyl, 1-methoxyethyl, 1-ethoxy-ethyl, 1-methylthiomethyl, 1-methylthioethyl or 1-ethylthiqethyl, or 2-oxa- or 2-thiacycloalkyl with 5-6 ring atoms, e.g. Tetrahydrofuryl or 2-tetrahydropyranyl or corresponding Thiaanaloge, and optionally substituted 1-phenyl-lower alkyl, such as optionally substituted benzyl or diphenyl-methyl, wherein as substituents of the phenyl radicals, for example. Halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro come into question.

Carboxyl groups are usually protected in esterified form, with such ester groups being easily cleavable under mild conditions. Carboxyl groups protected in this manner contain, as esterifying groups, lower-alkyl groups branched in the first position or suitably substituted in the 1- or 2-position. Preferred esterified carboxylic groups include i.a. tertiary lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals, these optionally being e.g. by lower alkyl, such as tert-lower alkyl, e.g. tert-butyl, lower alkoxy, such as methoxy, hydroxy, halo, e.g. Chlorine, and / or nitro, mono- or polysubstituted phenyl radicals, as appropriate, e.g. As mentioned above, substituted benzyloxycarbonyl, e.g. 4-methoxybenzyloxycarbonyl, or 4-nitrobenzyloxycarbonyl, or optionally, e.g. as mentioned above, substituted diphenylmethoxycarbonyl, e.g. Diphenylmethoxycarbonyl or di (4-methoxyphenyl) methoxycarbonyl, 1-lower alkoxy-lower alkoxy

carbonyl such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, 1-lower alkylthio-lower alkoxycarbonyl such as 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is optionally substituted, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted) silydethoxycarbonyl, in which the substituents independently of one another each represent an optionally substituted one, for example lower alkyl, lower alkoxy, aryl, halogen, and / or nitro substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical, as appropriate, optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, for example 2-tri-lower alkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

The organic silyl or stannyl radicals mentioned above and below preferably contain lower alkyl, in particular methyl, as

Substituents of the silicon or tin atoms. Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butyl-silyl, or appropriately substituted stannyl, e.g. Tri-n-butylstannyl.

Preferred protected carboxyl groups are tertiary lower alkoxycarbonyl such as tert-butoxycarbonyl, and especially optionally, e.g. As mentioned above, substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, especially 2- (trimethylsilyl) ethoxycarbonyl.

A protected amino group, e.g. in a starting material for the preparation of the compounds of formula I, e.g. in the form of a cleavable acylamino, arylmethylamino, etherified mercaptoamino, ^ -acyl-lower alk-1-en-1-yl-amino, silyl or stannylaminogroup or azido group.

For example, in a corresponding acylamino group, acyl is the acyl radical of an organic carboxylic acid with e.g. up to 18 carbon atoms, especially an optionally, e.g. by halogen or aryl, substituted alkanecarboxylic acid or optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic monoester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl, or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, in particular 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2, 2-trichloroacetyl, optionally, for example; halo, lower alkoxy or nitro substituted benzoyl, e.g. Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, in particular tert-lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals, preferably optionally, e.g. lower alkyl, especially tert.-lower alkyl, such as tert.butyl, lower alkoxy, such as methoxy, hydroxy, halo, e.g. Chlorine, and / or nitro, mono- or polysubstituted phenyl, such as optionally substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, e.g. Benzhydryloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is preferably optionally substituted, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted Silyd-ethoxycarbonyl, in which the substituents independently of one another each represent an optionally substituted, for example substituted by lower alkyl, lower alkoxy, aryl, halogen or nitro, aliphatic, Araliphatic, cycloaliphatic or aromatic hydrocarbon radical having, for example, up to 15 carbon atoms, such as corresponding, optionally substituted lower alkyl, phenyl, alkyl, cycloalkyl or phenyl, for example 2-Triniederalkylsilylethoxycaifbonyl, such as 2-trimethylsilylethoxycarbonyl or 2- (Di

: -r ' ^: . - 7 - ': -: -

n-butyl-methyl-silyD-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

Other acyl radicals which may be used as amino-protecting groups are also corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as diloweralkylphosphoryl, e.g. Dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, e.g. Dicyclohexylphosphoryl, optionally substituted diphenylphosphoryl, e.g. Diphenylphosphoryl, optionally, e.g. nitro-substituted di- (phenyl-lower alkyl) -phosphoryl, e.g. Dibenzylphosphoryl or di- (4-nitrobenzyl) -phosphoryl, optionally substituted phenyloxy-phenyl-phosphonyl, e.g. Phenyloxyphenyl phosphonyl, dilower alkyl phosphinyl, e.g. Diethylphosphinyl, or optionally substituted diphenylphosphinyl, e.g. Diphenylphosphinyl.

In an arylmethylamino group which represents a mono-, di- or in particular triarylmethylamino, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups include, for example, benzyl, diphenylmethyl and especially tritylamine.

An etherified mercapto group in an amino group protected with such a radical is primarily arylthio or aryl-lower alkylthio, wherein aryl is especially optionally, e.g. is phenyl substituted by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro. A corresponding amino protecting group is e.g. 4-nitrophenylthio.

In a 2-acyl-lower alk-1-enyl radical useful as an amino-protecting group, acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, an optionally, e.g. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro substituted benzoic acid, or in particular a carbonic monoester, such as a carbonic acid lower alkyl.

Corresponding protecting groups are primarily 1-lower alkanoylprop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, e.g. l-ethoxycarbonyl-prop-l-en-2-yl.

An amino group can also be protected in protonated form; suitable anions are primarily those of strong inorganic acids, such as hydrohalic acids, e.g. the chlorine or Bromanionj or of organic sulfonic acids, such as p-toluenesulfonic acid in question.

Preferred amino protecting groups are acyl radicals of carbonic monoesters, especially tert-butyloxycarbonyl, optionally, e.g. as indicated, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-loweralkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, furthermore trityl or formyl.

Salts of the compounds of the invention having salt-forming groups are primarily pharmaceutically acceptable non-toxic salts, such as those of compounds of formula I having acidic groups, e.g. with a free carboxyl group. Such salts are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, wherein primarily aliphatic cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the Salt formation come into question, such as lower alkylamines, eg Triethylamine, hydroxy-lower alkylamides, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine, 2-hydroxyethyldiethylamine or tri (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. A-aminobenzoic acid, ^ -diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. Ν, Ν'-dibenzylethylenediamine, also pyridine-type bases, for example * pyridine, collidine or chiriolin.

, - 9 -, ν

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred. , ;

The compounds of the formula I, wherein the fuftktionellen groups in! more free, i. are not in protected form, but where carboxyl and hydroxyl groups are optionally present in physiologically cleavable, esterified form, and their pharmaceutically acceptable non-toxic salts are valuable, pharmacologically active substances. In particular, they provide protection against the amnesiogenic effect of cerebral electroshock and an improvement in memory performance. Findings of this kind can be determined in the following learning tests:

One of these learning tests is a so-called two-compartment passive avoidance test, modified by Jarvik and Koop, Psychol. Rep. TX, 221-224 (1967). \

The test device consists of a large box (35 χ 20.x 10 cm), which is connected by a sliding door to a small box (10 χ 10 χ 18 cm). While the small box is lit up by a 100 watt lamp from above, the big box is dark. The bottom of both compartments consists of an electrically conductive grate whose bars (6 mm diameter) are arranged at a distance of 13 mm. For training groups of 10 male mice with a body weight of 20-22 g individually placed in the brightly lit little box. Since mice have a spontaneous preference for darkness, most go into the dark compartment within 30 seconds. Once you have entered this completely, the sliding door is closed and a foot shock (1 mA, 50 Hz, 5 seconds) administered. The animals are immediately removed from the experimental apparatus.

In order to test the learning effect (retest), the mice are again individually placed in the bright compartment after 24 hours and the period until they '

are completely in the dark compartment, measured. Of course, most animals stay over the entire observation time: 150 seconds in the light compartment. The learning effect is largely abolished or the memory of the foot shock is at least partially wiped out if, as amnesiogenic treatment immediately following the foot shock of the learning period, a temporal electroshock treatment is connected. Electro-shock parameters: 50 mA, 0.4 seconds, 50 Hz, 0.6 milliseconds (pulse duration).

To test and compare their protective effect against the amnesiogenic effect of the electric shock, the test substances will be dosed at 0.1 mg / kg, 1 mg / kg, 10 mg / kg and 100 mg / kg (for each dose) at 30 minutes prior to the learn session 10 mice used) as a solution in physiological NaCl solution or saline alone (= placebo) administered intraperitoneally and subjected the animals immediately after learning the electroshock treatment. 24 hours later, based on the length of stay in the illuminated box. measured the extent of the remaining learning effect and compared with that of the other test substances as well as of control animals with sole administration of the particular solvent used and training without, as well as those with subsequent electric shock treatment. A placebo-treated group without electroshock is used to control learning in the avoidance test, a second placebo-treated control group followed by electroshock is used to monitor the extent of the amnesiogenic effect of the electric shock.

The above-mentioned effects can be, for example, after intraperitoneal administration of N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl-glycinamide in one. Dose range from 0.1 to 100 mg / kg

 To directly measure memory improvement, another passive avoidance test is used (Psychopharmacol., 63, 297-300 [1979]):

The test device consists of a daylight normally illuminated box (50 χ 50 χ 50 cm) with an electrically conductive <grid, whose bars (6 mm diameter) are arranged at a distance of 13 mm. In the middle of the grid is a wooden platform (10 mm high, 67 mm in diameter), which is surrounded by a plastic tube (20 cm high, 68 mm internal diameter). For training purposes, groups of 30 male mice each weighing 2O-22g are used by placing one animal on the platform surrounded by the plastic tube, removing the plastic tube after 10 seconds, and measuring the amount of time the animal has spent needed to descend and touch the grid with all 4 paws. When all 4 paws touch the grid, a foot shock (1 mA, 50 Hz, 1 second) is given. Within 10 seconds of administration of the foot shock, the test substances are dosed at 3 mg / kg, 10 mg / kg and 30 mg / kg (30 mice are used for each dose) as a solution in physiological NaCl solution or its solvent (physiological sodium chloride solution = Placebo) intraperitoneally. Twenty-four hours later, the amount of improvement or deterioration of the learning effect compared to the animals to which only the solvent had been applied was determined on the basis of the length of stay of each individual animal on the platform. Thus, an improvement in memory performance, for example, after i.p. Administration of 10 mg / kg N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl-glycinamide.

Because of these properties, the novel compounds are useful in the treatment of cerebral insufficiency, in particular, memory disorders of various etiologies, such as senile dementia, multi-infarct dementia, or dementia of the Alzheimer's type, as well as sequelae of brain trauma or apoplexy.

   . -. - 12 - ': ·.: /

The new compounds also have a pronounced tumorhemme'nde effect. They not only inhibit the growth of tumors and reduce the number of tumors, but they also increase the survival time. Two advantages of the compounds according to the invention over conventional cytostatic or cytotoxic drugs are their good tolerability and their reasoning that they do not reduce the quality of life of the tumor patients as nootropics but, on the contrary, help these patients to overcome their psychological problems. The compounds according to the invention can thus also be used for the therapy of tumor diseases, e.g. respiratory tract, used in warm-blooded animals, including humans.

The anti-tumor activity of the new compounds may be e.g. be shown by the following experiment:

In Syrian hamsters, the administration of diethylnitrosamine to the stomach produces papillary, epidermoid, and adenocarcinomatous tumors of the larynx, trachea, and lungs [G. Papadopoulo and K.H. Schmidt-Ruppin, Oncology J ^ 3, 40-43 (1976 /].) A portion of these tumorous hamsters are treated with a compound of formula I (eg twice a day for 5 days, 5 days a week in a single dose of 20) The remaining part of the hamsters are treated with a placebo Three to four days after the end of the treatment all hamsters are killed The respiratory tract is excised and, after appropriate preparation, microscopically examined for size, number and type of tumors It is found that the size and number of tumors in the hamsters treated with a compound of formula I are significantly lower compared to the untreated hamsters.

- 13 -

In particular, the invention relates to compounds of formula I wherein R is hydrogen, C 1-6 alkyl, lower alkyl substituted by an unsubstituted or substituted phenyl or naphthyl radical, or an unsubstituted or substituted phenyl radical;

2 '"R is hydrogen, lower alkyl or a phenyl radical, and SaI; of such compounds having at least one salt-forming group.

In the first place, the invention relates to compounds of the formula I, wherein R is hydrogen, unsubstituted or substituted by phenyl C. Alkyl or phenyl and

R is hydrogen, C, alkyl, phenyl or 4-hydroxy-phenyl.

Mainly the invention relates to compounds of the formula I in which

12 R and R are independently hydrogen or C-alkyl.

Above all, the invention relates to compounds of the formula I, wherein R is hydrogen or C, -alkyl and

R is hydrogen, methyl, ethyl, 2-propyl, 2-butyl or 2-methyl-propyl.

In particular, the invention relates to the abovementioned compounds of the formula I, in which

1 2

¹ R is hydrogen and have the (L) configuration of asymmetrically substituted QR atoms.

First and foremost, the invention relates to N - [(2-oxo-1-pyrrolidinyl) acetyl] (L) -alanyl- (L) -alanineamide and especially to N ^ [(2-oxo-1-pyrrolidinyl) -acetyl]. glycyl-glycinamide. >

The compounds according to the invention of formula I and salts of such compounds having at least one salt-forming group are obtained by processes known per se.

 · ... -. , - 14 - ^; , '

Compounds of formula I and salts of such compounds containing at least one salt-forming group are prepared, for example, by reacting c ^!

a) eM.ne compound of the formula II,

0 0 0 0

N Jl Il Il

Y-CH-CH-CH-C-NH-CH-C-M-CH-C-CH-C-NH (II)

¹ * * 'II? '2

RR

in which Y is a nucleophilic leaving group "'and the remaining substituents have the abovementioned meanings, with the proviso that

1 2 that in the radicals R and R optionally existing functional groups. Are protected if necessary by easily cleavable protective groups, cyclized intramolecularly to form the pyrrolidone ring, or

b) a compound of the formula III,

0 0 0

3 Il Il Il

R - <3H _o H: H _o -CH-NH-CH-C-HiH-CH-C-CH-CHJH- (III)

^{2 2 2} Il 12 «2

R R R

3 \ '. .-.

wherein R represents a carboxyl group or an activated derivative thereof and also the amino group participating in the reaction may be present in activated form and the remaining substituents have the abovementioned meanings, with the proviso that in the radicals

12

R and R optionally functional groups are optionally protected by readily cleavable protecting groups, cyclized intramolecularly to form the pyrrolidone ring or

c) 2-oxo-pyrrolidine of the formula IV

- 15 -

(IV)

or a reactive form of this compound with a compound of the formula V,

0 0 ο

Il II Il Y-CH-C-NH-CH-C-NH-CH-C- ^ IH-

1-1 '2' 2 ² RRR

(V)

wherein Y represents a nucleophilic leaving group and the other substituents have the abovementioned meanings, with the proviso that

1 2 functional groups present in the radicals R and R are optionally protected by easily removable protective groups,

d) a compound of the formula VI *

0 0 0 / OV η Il ί-CH Il H / Il / \ Il -C- NH-CH-C 1 NH-CH-C- ί) R V '2 / R > R •

OH

wherein η and ρ independently of one another denote the number 0 or 1, and the other substituents have the abovementioned meanings, with

1 2

with the proviso that any functional groups present in the radicals R and R are optionally protected by readily cleavable protective groups, or a reactive carboxylic acid derivative of the compound of the formula VI with a compound of the formula VII,

- 16 -

H-

NH-CH-C

^ ^ ²

O is NH-CH-C-

(VII)

wherein q and r independently represent the number O or 1, with the proviso that r and q are each 1, if in the reactant of the formula VI ρ is 0, or that r is 1 and q is 0, if ρ is 1 and η is 0, or that r is when ρ and η are each 1, and in which the other substituents have the abovementioned meanings, with the proviso that

optionally present in the radical R functional groups are protected by readily cleavable protecting groups, or a derivative of the compound of formula VII in which one of the NH groups is present in a reactive form, or

e) the cyano group in a compound of the formula VIII,

0 M

/ \ Il I> -CH-C-NH-CH-C-NH-CH-GN

(VIII)

wherein all substituents have the abovementioned meanings, converted into an amide group, or

f) the oxime group in a compound of the formula IX,

O Il

0 II

HI

I V-T-CH-C-NH-CH-C-NH-CH-C == N-OH

\ / Il

'2

(IX)

wherein the substituents have the abovementioned meanings, converted by a Beckmann rearrangement in an amide group, or

I - 17 -

g) in a compound of the formula I which has at least one free hydroxy or carboxy group, free esterified or etherified hydroxy or esterified free carboxy and, after carrying out the process described under a) to f) optionally splits off existing protective groups and, if desired, obtained Stereoisomerengemisehe separated, and, if desired, a compound obtained having at least one salt-forming group in a salt or a salt obtained in the free compound. '

Process a) (intramolecular cyclization of a compound of formula II): A nucleophilic leaving group Y is in particular a hydroxy group esterified with suitable acids, e.g. a sulphonate, such as mesylate or tosylate, especially halogen, such as bromine or iodine, but especially chlorine.

The reaction is carried out with the aid of a base, using preferably equimolar amounts of this base. As bases, in particular, e.g. Metal hydroxides, carbonates or alcoholates such as alkali metal or alkaline earth metal hydroxides or alcoholates, e.g. Sodium or potassium hydroxide or sodium tert-butoxide, or alkali metal carbonates or salts, especially alkali metal salts, secondary amides, e.g. 2-oxopyrrolidine sodium, or strong base ion exchangers, e.g. Dowex 1 (Registered Trade Mark), as well as hydrides or amides, e.g. Alkali metal hydrides or amides, such as sodium hydride or amide or lithium diisopropylamide. .

The ring closure reaction is preferably conducted in an inert organic solvent, if desired or necessary, carried out under cooling or heating, for example in a temperature range of about -80 ^c C to about +150 ⁰ C, especially between 0 ° C and 100 ⁰ C.

In general, the reaction conditions should be selected so that the intramolecular ring-closure reaction is carried out in comparison to intermolecular

Reactions of the same type of reaction, which would lead to the formation of dimers or the like, favored. For this purpose one can, for example, work in greater dilution, if necessary.

The activation with the aid of the base can be carried out at the same or a different temperature than the actual ring-closing reaction.

In particular, when using a very strong base, for example Lithiuradiisopropylamid, the activation with the base ("metallation") at a lower temperature (eg -8O ⁰ C) than the ring closure. In this case, for example, it is possible to slowly warm up the reaction vessel after the metalization has taken place.

When choosing the solvent must also the type of to be used

Base to be considered. Reactions using alkali metal hydroxides are preferably in dimethyl sulfoxide or in alcohols such as lower alkanols, e.g. Anhydrous ethanol at boiling temperature, reactions using alcoholates are preferably carried out in ethers, especially cyclic ethers, using sodium tert-butylate, e.g. in dioxane at room temperature.

Ring closure reactions with e.g. 2-oxopyrrolidine sodium is inter alia dispersed in a mixture of a cyclic ether and an aromatic hydrocarbon, e.g. a dioxane-toluene mixture, at a temperature between room temperature and 60 ° C.

The cyclization with the aid of an ion exchanger according to the invention is carried out in particular in an alcohol, e.g. Lower alkanol, e.g. Ethanol, at room temperature.

- 19 -

The starting materials of the formula II can be prepared by methods known per se, e.g. by acylation of the free amino group of a peptide amide of the formula X,

0 0 0

Il II Il H ₀ N-CH-C-NH-CH-C-NH-CH-C-NH ₀ (X)

² I ₁ I ₂ I ₂ ² RRR

in which the substituents have the abovementioned meanings, with the proviso that free functional groups present therein, if

desires to be present in protected form with an acid chloride of the formula XI,

Y-CH- ™ -CH D

^{1 lz} \ (Χι)

Cl

wherein Y has the abovementioned meaning, e.g. Y is chlorine, and subsequent deprotection.

Process b) (intramolecular cyclization of a compound of the formula III):

Activated carboxylic acid derivatives of a compound of formula III are primarily reactive activated esters or reactive anhydrides, further reactive cyclic amides; In this case, reactive derivatives of acids of the formula III can also be formed in situ.

Activated esters of acids, especially at the linking carbon atom of the esterifying radical, are unsaturated esters, e.g. Vihylester type, such as actual vinyl esters (which can be obtained, for example, by transesterification of a corresponding ester with vinyl acetate, activated vinyl ester method), carbamoylvinyl esters (which can be obtained, for example, by

- 20 -

Treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl ester (which can be obtained, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or amidino-type esters, such as N, N'-disubstituted amidinoesters ( which can be obtained, for example, by treating the corresponding acid with a suitable Ν, Ν'-disubstituted carbodiimide, for example Ν, Ν'-dicyclohexylcarbodiimide, carbodiimide method), or N, N-disubstituted amidinoesters (which can be obtained, for example, by treating the corresponding Cyanamide method), suitable aryl esters, in particular by electron-attracting substituents suitably substituted phenyl (which, for example, by treating the corresponding acid with an appropriately substituted phenol, for example 4-nitrophenol, 4-Methylsülfonyl -phenol, 2,4,5-trifluorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as N, N'-dicyclohexyl-c arbodiimide, can be obtained; Method of activated aryl esters), Cyanmethylester (which can be obtained, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base, cyanomethyl ester method), thioesters, in particular optionally substituted, for example by nitro, phenyl thioester (which, for example, by treating the corresponding acid with optionally substituted, for example by nitro, substituted thiophenols, inter alia with the aid of the anhydride or carbodiimide method, method of activated thiol esters), or amino or amido esters (which, for example, by treating the corresponding acid with an N- Hydroxy-amino or N-hydroxy-amido compound, for example, N-hydroxy-succinimide, N-hydroxy-piperidine, N-hydroxyphthalimide or 1-hydroxy-benzotriazole, for example by the anhydride or carbodiimide method, can be obtained; Activated N-hydroxy ester method) ^or silyl ester (which can be obtained, for example, by treating the corresponding acid with a silylation cleavage, eg, hexane-ethyldisilazane). .

- 21.-

Anhydrides of acids of formula III may be symmetrical or preferably mixed anhydrides of these acids, for example anhydrides with inorganic acids such as acid halides, in particular acid chlorides (which may be obtained, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride, acid chloride method), azides (which can be obtained, for example, from a corresponding acid ester via the corresponding hydrazide and its treatment with nitrous acid, azide method), anhydrides with carbonic acid half derivatives, such as with corresponding esters, ¹ Z..B · · carbonic acid lower alkyl half esters (which, for example, by treating the corresponding acid with halo, such as lower alkyl chloroformate or with a l-lower alkoxycarbonyl-Z-lower alkoxy-l ^ -dihydro-quinoline, for example, l-N'i'ederalkoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline; Mixed O-alkyl-carbonic anhydride method), or dihalogenated anhydrides, in particular e dichlorinated phosphoric acid (which can be obtained, for example, by treating the corresponding acid with phosphorus oxychloride; Phosphoroxychloridmethode), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (which can be obtained, for example, by treating the corresponding acid with an optionally substituted lower alkane or Phenylalkancarbonsäurehalogenid, eg Phenylessigsäure-, Pivalinsäure- or Trifluoressigsäurechlorid, mixed carboxylic acid anhydrides method or with organic sulfonic acids (which can, for example, can, for example methane- or p-Toluolsülfonsäurechlorid obtained by treatment of a salt, alkali metal wie.eines ¹ salt, the corresponding acid with a suitable organic sulfonic acid halide, such as lower alkane- or aryl-,;. method the mixed sulfonic anhydrides), as well as symmetrical anhydrides (which can be obtained, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne; symmetrical anhydride method).

Suitable cyclic amides are in particular amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, e.g.

Λ: ¹ ; · '- .- .; ':. -, - '- 22 -: -. ·. _; , , '·.

Imidazo! (e.g., by treating the corresponding acid with Ν, Ν'-carbonyldiimidazole, imidazolide method), or pyrazoles, e.g. 3,5-dimethyl-pyrazole (which can be obtained, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).

The amino group participating in the reaction in a starting material of formula III is preferably in free form, especially when the carboxy group reacting therewith is in a reactive form, but it may also be derivatized itself, i. e.g. by reaction with a phosphite such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite

Protecting groups of optionally present functional groups are e.g. the above-mentioned protecting groups. .

The ring closure reaction can be carried out in manner known per se, the reaction conditions depend primarily on whether and how the person participating in the reaction, the carboxyl group is activated, usually in the presence of a suitable solvent - or encryption _{(dünnungsmittels} or a mixture of such and, if necessary, in the presence of a condensation agent which, for example, if that is present in the reaction participating carboxyl group as the anhydride, may also be an acid-binding agent, with cooling or heating, for example in a temperature range of about -30 ⁰ C to about +200 ⁰ C, gases in a closed reaction vessel and / or in the atmosphere of an inert ^1, for example nitrogen.

In general, the reaction conditions should be selected so that the intramolecular ring-closing reaction is favored over intermolecular reactions of the same type of reaction which would lead to the formation of dimers or the like. For this purpose one can, for example, work in greater dilution, if necessary.

- 23 -

The reaction can e.g. be done by connecting

of formula III, wherein R represents an inactivated carboxyl group, and the remaining radicals optionally in protected form have the abovementioned meanings, if appropriate in the presence of a dehydrating agent, e.g. a Ν, Ν'-disubstituted carbodiimide, such as dicyclohexylcarbodiimide, and optionally additionally in the presence of an N-hydroxyamine or N-hydroxyamide, e.g. N-hydroxy-succinimide, heated in an anhydrous inert solvent, e.g. to 5O ° C-18O ° C.

3 Compounds of formula III, wherein R is an activated carboxyl group, react in an anhydrous solvent even at lower temperatures, for example -20 ° to +50 ⁰ C, to form the 2-oxo-pyrrolidine ring. Preferably, such activated carboxylic acid compounds of formula III are used, wherein the amino group adjacent to the CR atom is in protected form and then releases the amino group in situ, followed by cyclization.

A preferred embodiment of process b) is the heating of a carboxylic acid of formula III in hexamethyldisilazane.

3 The compounds of the formula III in which the carboxyl group R in protected

3 ter form, ie as the radical R ^, for example as 2-trimethylsilylethyl ^ carbonyl, for example, by N-alkylation of a compound of formula X or a suitable derivative thereof, for example an azomethine or the alkali metal salt einejs benzenesulfonamide, with a compound of Formula XII,

(XII) called meaning to be produced.

₂₂₂ ^ wherein R ^ is a protected carboxyl group, and Y is the obengeVerfahren c) (N-alkylation of the 2-oxo-pyrrolidine of formula IV):

A reactive form of a compound of formula IV is especially a metal compound, primarily an alkali metal compound, e.g. a sodium, potassium or lithium compound of the

, - ... :. -. ; 'V. ·; '· - 24> ·. ^; , . ' , , ;

same, which is e.g. by the action of a suitable base, e.g. an alkali metal hydroxides, e.g. Sodium hydroxide, an alkahmetalalcoholate, e.g. lower alkanolate, such as -methylate, -ethylate or tert -butylate, an -hydride, -amide, e.g. Sodium hydride, sodium amide or lithium diisopropylamide, or an alkali metal hydrocarbon compound, e.g. Butyllithium, can produce.

The nucleophilic leaving group Y corresponds to the group Y mentioned in process a) and is especially chlorine or bromine.

The reaction is preferably carried out in an anhydrous or, depending on the base used, aprotic solvent at temperatures between about -80 ° C and + 150 ° C and similar to method a).

The starting compounds of the formula V are obtained by acylation of a compound of the formula VII, in which q and r are both 1, with an acylating agent of the formula XIII,

Y-CH- C ^/ (XIII)

i \ ^

wherein Y and R have the abovementioned meaning, with the proviso that in the radical R existing free functional groups, if necessary, are in protected form, and subsequent cleavage of the protective group (s) accessible. .

The starting compound of formula IV is known and may be e.g. by cyclization of 4-amino-butyric acid by heating to 200-250 ° C without solvent and Kugelrohr distillation can be obtained.

Method d) (formation of a peptide bond):

Reactive carboxylic acid derivatives of a compound of formula VI are reactive esters, anhydrides or amides analogous to those mentioned in process b).

- 25 -

As mentioned in b) derivatives of acids of the formula VI can also be formed in situ. So you can, for example Form Ν, Ν'-disubstituted amidinoesters in situ by reacting the mixture of the starting material of formula VII and the acid of formula VI in the presence of a suitable Ν, Ν'-disubstituted carbodiimide, e.g. Ν, Ν'-Dicyclohexylcarbodiimid, brings to reaction. Further, one can form amino or amido esters of acids of formula VI in the presence of the starting material of formula VII to be acylated by reacting the mixture of the corresponding acid and amino starting materials in the presence of a Ν, Ν'-disubstituted carbodiimide, e.g. N, N'-dicyclohexyl-carbodi-, imide, and an N-hydroxy-amine or N-hydroxy-amide, e.g. N-hydroxysuccinimide, optionally in the presence of a suitable base, e.g. 4-dimethylamino-pyridine.

The derivative of a compound of formula VII wherein the amino group participating in the reaction is in reactive form may be e.g. by reaction with a phosphite, e.g. one of those mentioned in process b) are produced. A reactive form of a compound of formula VII is e.g. also a carbamic acid halide or an isocyanate, wherein the amino group participating in the reaction in a compound of formula VII on halogenocarbonyl, e.g. Chlorocarbonyl, is bound, or present as an isocyanato group. A reactive form of a compound of formula VII wherein r is O is e.g. also urea.

For example, when heating equimolar amounts of urea and a free acid of the formula VI, the compounds of the formula I are obtained in good yield. ^

The acylation of a compound of formula VII or a reactive derivative thereof with a compound of formula VI or a reactive acid derivative thereof can be carried out in a manner known per se, the reaction conditions depending primarily on the type of acylating agent used, usually in the presence of a suitable solvent or diluent or a mixture of such, and, if necessary, in the presence

- 26 -

     · '.

a condensing agent, which may also be an acid-binding agent, for example when using an anhydride as the acylating agent, with cooling or heating, for example in a temperature range from about -30 ⁰ C to about +150 ⁰ C, in a closed reaction vessel and / or in the atmosphere of an inert gas, eg nitrogen.

The starting materials of formulas VI and VII are known or may be prepared by methods known per se, e.g. analogous to the methods described in this application.

Process d) also encompasses the embodiment in which first a carboxylic acid of the formula VI in which η and ρ is 1 is reacted with a compound of the formula VII in which r is 0 to give an ammonium salt of the carboxylic acid of the formula VI, and the ammonium salt obtained in this or another way thermally dehydrated to form a compound of formula I, eg analogous to that described in British Patent 1 309 692.

Process e) (Amide Preparation from a Nitrile): The conversion of a nitrile into an amide can be carried out by partial hydrolysis or by way of carboxylic acid ester imide salts. The conditions for the hydrolysis of a compound of formula VIII must be chosen so that the reaction at the stage of the amide can be stopped and not the free carboxylic acid is formed. Suitable for this purpose at the most general, the hydrolysis with acids, it being possible to choose according to the present in a compound of formula VIII substituent ¹ between 80% sulfuric acid (with heating), polyphosphoric acid (at 110-150 °), Bromw ^ sserstoff Glacial acetic acid (room temperature), formic acid (without solvent), hydrogen chloride gas in ethereal solution followed by addition of water or aqueous hydrochloric acid, or boron halides / 1 equivalent of water.

In some cases, the alkaline hydrolysis succeeds, but the method Von Radziszewski with hydrogen peroxide in the presence of alkalis at moderate temperature is usually more successful.

- 27 -

Preferably, one uses an ion exchange resin, e.g. Lewatite ^ M 504 (see German Offenlegungsschrift 2 507 576) or Amberlite ^ IRA-400.

The carboxylic acid esterimides are e.g. produced by acid-catalyzed addition of alcohols to the nitriles of the formula VIII. From the esterimides, the amides are obtained in the sense of a Pinner cleavage. Instead of using a strong acid, one can also catalyze with mercury (II) nitrate and then reduce it with sodium borohydride.

Nitriles of the formula VIII can be prepared, for example, by a Kolbe synthesis from the corresponding primary halides with cyanide ions in the:

Sense of nucleophilic substitution. It is preferable to use e.g. a primary halide with copper cyanide in dioxane (see German Offenlegungsschrift 2 507 576). from the primary alcohols by means of thionyl chloride (see German Offenlegungsschrift 2 507 576). preferably,

Compound 2 gives the nitriles of formula VIII wherein R is hydrogen by reaction of a compound of formula VI wherein ρ is 1, η is

and R is hydrogen, with aminoacetonitrile, which is commercially available

- Is available, according to the methods described for method d).

Method f) (Beckmann rearrangement):

The rearrangement of compounds of formula IX can be carried out under the known conditions of Beckmann rearrangement of aldoximes, most preferably with polyphosphoric acid or boron trifluoride.

The oximes of the formula IX are prepared by methods known per se, e.g. accessible by reaction of the corresponding aldehydes with hydroxylamine. *.

Method g) (transformations within the definition of the end products):

The compounds of the formula (I) obtainable according to the invention can be converted in a manner known per se into other compounds of the formula (I).

- 28 -

In the compounds of formula (I) which have at least one free hydroxyl group, this can be etherified or esterified (acylated) by methods known per se. Free carboxy can be esterified.

Suitable agents for etherifying a hydroxyl group or esterifying a carboxyl group are, for example, corresponding diazo compounds. such as optionally substituted diazo-lower alkanes, e.g. Diazomethane, diazoethane, diazo-n-butane or diphenyldiazomethane. These reagents are reacted in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. Methylene chloride, or an ether such as a di-lower alkyl ether, e.g. Diethyl ether, or a cyclic ether, e.g. Tetrahydrofuran or dioxane, or a solvent mixture, and, depending on the diazo reagent, with cooling, at room temperature or with gentle heating, further, if necessary, in a sealed vessel and / or

under an inert gas, eg. _:

Nitrogen atmosphere, to be used

Further suitable agents for etherification of a hydroxyl group or for esterification of a carboxyl group in a compound of formula I are esters of corresponding alcohols, primarily those with strong inorganic or organic acids, such as mineral acids, for example hydrogen halides, such as hydrochloric, hydrobromic or hydriodic acid, furthermore sulfuric acid, or halogenosulfuric acid, eg Fluorosulfuric acid, or strong organic sulfonic acids, as appropriate, e.g. by halogen, such as fluorine, substituted lower alkanesulphonic acids, or aromatic sulphonic acids, e.g. optionally benzenesulfonic acids substituted by lower alkyl, such as methyl, halo, such as bromo, and / or nitro, e.g. Methanesulfone, trifluoromethane

- 29 -

sulfonic or p-toluenesulfonic acid. Such esters include lower alkyl halides, di-lower alkyl sulfates such as dimethyl sulfate, fluoro, sulfonic acid esters such as lower alkyl esters, eg, fluorosulfonic acid methyl ester, or optionally halo-substituted methanesulfonic acid lower alkyl esters, eg, methyl trifluoromethanesulfonate. They are usually used in the presence of an inert solvent, such as an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, for example methylene chloride, an ether, such as dioxane or tetrahydrofuran, or a mixture. In this case, it is preferable to use suitable condensing agents, such as alkali metal carbonates or bicarbonates, for example sodium or potassium carbonate or bicarbonate (usually together with a sulfate), or organic bases, such as. Usually hindered Triniederalkylamine, eg, Ν, Ν-diisopropyl-N-ethyl amine (preferably together with halosulfonic acid lower alkyl or optionally halogen-substituted methanesulfonic lower alkyl), with cooling, at room temperature or with heating, for example at temperatures of about -20 ° C to about 50 ⁰ C and, if necessary, in a closed vessel and / or in an inert gas, eg nitrogen atmosphere, is worked.

By phase transfer catalysis [see, e.g. Dehmlow, Angewandte Chemie, 86, 187 (1974)], the etherification reaction described above can be significantly accelerated. As phase transfer catalysts, quaternary phosphonium salts, and especially quaternary ammonium salts, such as optionally substituted tetraalkylammonium halides, e.g. Tetrabutylammonium chloride, bromide or iodide, or benzyl triethylammonium chloride, can be used in catalytic or up to equimolar amounts. The organic phase may be any of the water-immiscible solvents, for example one of the optionally halogenated, such as chlorinated, lower aliphatic, cycloaliphatic or aromatic hydrocarbons, such as tri- or tetrachlorethylene, tetrachloroethane, carbon tetrachloride.

- 30 -

fabric, chlorobenzene, toluene or xylene. The alkali metal carbonates or bicarbonates suitable as condensing agents, e.g. Potassium or sodium carbonate or bicarbonate, alkali metal phosphates, e.g. Potassium phosphate, and alkali metal hydroxides, e.g. Sodium hydroxide may be added titrimetrically to base-sensitive compounds of the reaction mixture, e.g. by means of a titration machine so that the pH value during the etherification remains between about 7 and about 8.5.

Further agents for etherifying a hydroxyl group or esterifying a carboxyl group in a compound of the formula I are corresponding trisubstituted oxonium salts (so-called seaweed salts), or disubstituted carbenium or halonium salts in which the substituents are the etherifying radicals, for example tri-lower alkyloxonium salts and di-lower alkoxycarbeniuin or di-lower alkyl halonium salts. in particular the corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates, or hexachloroantimonates. Such reagents are, for example, trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachloroantimonate, hexafluorophosphate or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbroronohexafluoroantimonate. It is preferable to use these etherifying agents in an inert solvent such as an ether or a halogenated hydrocarbon such as diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture thereof, if necessary, in the presence of a base such as an organic base, for example one, preferably sterically hindered Triniederalkylamins, eg Ν, Ν-diisopropyl-N-ethyl-amine, and with cooling, at room temperature or with gentle heating, for example at about -20 ^e C to about. 50 ⁰ C, if necessary, in a closed vessel and / or in an inert gas, eg nitrogen atmosphere.

- 31 -

Further suitable etherifying agents are finally corresponding 1-substituted 3-aryl triazene compounds in which the substituent is the etherifying radical, and aryl is preferably optionally substituted phenyl, for example lower alkylphenyl, such as 4-methylphenyl. Such triazene compounds are 3-aryl-1-lower alkyl triazery, eg 3- (4-methylphenyl) -1-methyl-triazene, 3- (4-methylphenyl) -1-ethyl-triazene or 3- (4-methylphenyl) -l isopropyl-triazene. These reagents are usually in the presence of inert solvents, such as optionally halogenated hydrocarbons or ethers, for example benzene, or solvent mixtures, and with cooling, at room temperature and preferably at elevated temperature, for example at about 20 ⁰ C to about ^ 100 ⁰ C, if necessary in a closed vessel and / or in an inert gas, eg nitrogen atmosphere used. ;

The conversion of free carboxyl in a compound of formula (I) into esterified carboxyl may be further effected, for example, by reacting a compound of formula (I) wherein other optional functional groups are optionally in protected form or a reactive functional carboxy derivative , including a salt thereof, with an appropriate alcohol or a reactive functional derivative thereof.

The esterification of free carboxyl with the desired alcohol is carried out in the presence of a suitable condensing agent. Typical condensing agents are, for example, carbodiimides, for example Ν, Ν'-diethyl, N, N'-dipropyl, Ν, Ν'-dicyclohexyl or N-ethyl-N '- (3-dimethylaninopropyl) carbodiimide, suitable carbonyl compounds, for example, carbonyldiimidazole, or 1,2-oxazolium compounds, for example, 2-ethyl-5-phenyl-l, 2-oxazolium-3 ^1- sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or

- 32 -

Diluent, e.g. Methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran and, if necessary, carried out under cooling or heating and / or in an inert gas atmosphere.

Suitable reactive functional derivatives of the carboxyl compounds of formula (I) to be esterified are e.g. Anhydrides, especially mixed anhydrides, and activated esters.

Mixed anhydrides are e.g. those with inorganic acids, such as hydrohalic acids, i. the corresponding acid halides, e.g. chlorides or bromides, also hydrazoic acids, i. the corresponding acid azides, as well as phosphorus-containing acids, e.g. Phosphoric acid, diethylphosphoric acid or phosphorous acid, or sulphurous acids, e.g. Sulfuric acid, or hydrogen cyanide. Mixed anhydrides are further e.g. those with organic carboxylic acids, such as with optionally, e.g. halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, e.g. Pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl halides of carbonic acid, such as ethyl or isobutyl halides of carbonic acid, or with organic, in particular aliphatic or aromatic sulfonic acids, e.g. p-toluene sulfonic acid.

Activated esters suitable for reaction with an alcohol of a compound of formula I having at least one carboxyl group are e.g. Esters with vinylogous alcohols (ie enols), such as vinylogous lower alkenols, or iminomethyl ester halides, such as dimethyliminomethyl ester chloride (prepared from the carboxylic acid and dimethylchloromethylidene iminium dichloride of the formula [(CH 2) .N = CHCl] ClJ, or aryl esters, such as pentachlorophenyl, 4-nitrophenyl or 2,3-dinitrophenyl esters, heteroaromatic esters, such as benzotriazole, eg 1-benztriazole ester, or diacylimino esters, such as succinylimino or phthalylimino esters.

The reaction between such an acid derivative of formula I, such as an anhydride, especially an acid halide, and an alcohol is preferably carried out in the presence of an acid-binding agent, for example an organic base, such as an organic amine, e.g. a tertiary amine such as tri-lower alkylamine, e.g. Trimethylamine, triethylamine or ethyldiisopropylamine, or Ν, Ν-di-lower alkylaniline, e.g. Ν, Ν-dimethylaniline, or a cyclic tertiary amine such as an N-lower alkylated morpholine, such as, N-methylmorpholine, or a pyridine-type base, e.g. Pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonates or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide. , · '<

A reactive functional derivative of the esterifying alcohol is primarily a corresponding ester, preferably with a strong inorganic or organic acid, and in particular provides a corresponding halide, e.g. Chloride, bromide or

Iodide, or a corresponding lower alkyl or aryl, such as methyl or 4-methylphenylsulfonyloxy compound.

Such a reactive ester of an alcohol can be reacted with the free carboxy compound of formula (I) or a salt thereof such as an alkali metal or ammonium salt, preferably using the acid in the presence of an acid-binding agent.

The above esterification reactions are carried out in an inert, usually anhydrous solvent or solvent mixture, for example in a carboxylic acid amia, such as a formamide, e.g. Dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. Acetone, an ester, e.g. Ethyl acetate, or

a nitrile, ζ.B. acetonitrile, or mixtures thereof, if necessary with cooling or heating, for example in a temperature range of about -40 ⁰ C to about + 100 ⁰ C, preferably at about -1O ⁰ C to about + 4O ⁰ C, and / or in an inert gas, eg nitrogen atmosphere.

Further, if desired, the acid derivative may be formed in situ . Thus, for example, a mixed anhydride is obtained by treating the carboxylic acid compound with appropriately protected functional groups or a suitable salt thereof, such as an ammonium salt, eg with an organic amine such as piperidine or 4-methylmorpholine, or a metal, eg alkali metal, salt with a suitable acid derivative such as the corresponding acid halide of an optionally substituted lower alkanecarboxylic acid, eg trichloroacetyl chloride, with a half ester of a carbonic acid halohydogen, eg chloroformate or isobutyl ester, or with a halide of a di-lower alkyl phosphoric acid, eg diethyl phosphor bromide, and uses the thus obtained mixed anhydride without isolation.

For the esterification (acylation) of a hydroxy group in a compound of the formula I, the starting material of the formula (I) is treated with an acylating agent which leads to the desired acyl radical of an organic carboxylic acid. In this case, one uses the corresponding carboxylic acid or a reactive derivative thereof, in particular an anhydride, including a mixed or internal anhydride of such an acid. Mixed anhydrides are e.g. those with hydrohalic acids, i. the corresponding acid halides, especially chlorides, further with hydrocyanic acid, or then those with suitable carbonic acid half derivatives, such as corresponding half-esters (such as the mixed anhydrides formed, for example, with a halo-formic acid, such as ethyl chloroformate or isobutyl ester, or with optionally substituted, eg Halogen, such as chlorine, containing lower alkanecarboxylic acids (such as those with pivalin

- 35 -

acid chloride or trichloroacetic acid chloride formed mixed anhydrides). Internal anhydrides are, for example, those of organic carboxylic acids, i. Ketenes, such as ketene or diketene, or those of carbamic or thiocarbamic acids, i. Isocyanates or isothiocyanates. Other reactive derivatives of organic carboxylic acids useful as acylating agents are activated esters such as suitably substituted lower alkyl, e.g. Cyanomethyl, or suitably substituted phenyl, e.g. Pentachlorophenyl or 4-Nitrophenylester. The esterification may, if necessary, in the presence of suitable condensing agents, using free carboxylic acids, e.g. in the presence of carbodiimide compounds such as dicyclohexylcarbodiimide or carbonyl compounds such as diimidazolylcarbonyl, and when using reactive acid derivatives e.g. in the presence of basic agents, such as tri-lower alkylamines, e.g. Triethylamine, or heterocyclic bases, e.g. Pyridine, be carried out. The acylation reaction may take place in the absence or in the presence of a solvent or solvent mixture, with cooling, at room temperature or with heating, and if necessary in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere, are performed. Suitable solvents are e.g. optionally substituted, especially optionally chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as benzene or toluene, it also being possible to use suitable esterification reagents, such as acetic anhydride, as diluents.

One by an organic sulfonic acid, e.g. Lower alkanesulfonic acid, such as methanesulfonic acid, or an aromatic sulfonic acid, such as p-toluenesulfonic acid, esterified hydroxy group may preferably be prepared by treating the starting material of formula (I) with a reactive sulfonic acid derivative, such as a corresponding halide, e.g. Chloride, if necessary, in the presence of an acid-neutralizing basic agent, e.g. an inorganic or organic base, e.g. in an analogous manner as the corresponding esters with organic carboxylic acids.

The starting materials required for carrying out the processes a) to g) described above are known or can be prepared by processes ZiB. be prepared according to or analog de'n described in this application.

Functional groups in starting materials can be protected with the same protective groups as are mentioned for corresponding functional groups in the end-products of the formula I in this application. The introduction and removal of these protective groups can also take place in the manner described in the cited references. : '. _ '' '.

In an obtained compound of the formula (I) wherein one or more functional groups are protected, these, e.g. protected carboxyl and / or hydroxy groups, in a manner known per se, by means of solvolysis, in particular hydrolysis,

Alcoholysis or acidolysis, or in some cases by careful reduction, optionally in stages or released simultaneously. Silyl protecting groups are advantageously treated with fluorides, e.g. Tetraethylammonium fluoride, split off.

Salts of compounds of formula (I) having salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of formula (I) with acidic groups, e.g. by treating with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of α-ethyl-caproic acid, or with inorganic alkali or alkaline earth metal salts, e.g. Sodium bicarbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.

- 37 -

Salts can be converted to the free compounds in the usual way, e.g. by treatment with suitable acids.

Mixtures of isomers may be prepared in a manner known per se, e.g. be fractionated by fractional crystallization, ChromatQgraphie etc. into the individual isomers.

Racemates can be prepared in a manner known per se, e.g. after conversion of the optical antipodes into diastereomers, for example by reaction with optically active acids or bases, are cleaved.

The invention also relates to those embodiments

the process starting from an intermediate obtainable at any stage and performing the missing steps, or the process at any stage. breaks off or one obtains a compound obtainable by the process according to the invention under the process conditions and further processed in situ.

Novel starting materials and / or intermediates and processes for their preparation are also the subject of the present invention. Preferably, such starting materials are used and the reaction conditions are chosen so as to arrive at the compounds listed in this application as being particularly preferred.

The pharmacologically useful compounds of the present invention For example, they can be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients.

The pharmaceutical preparations according to the invention are those for enteral, such as oral or rectal as well as parenteral, such as intraperitoneal, intramuscular or intravenous administration to warm-blooded animals, which contain the pharmacological active ingredient alone or together with a pharmaceutically acceptable carrier material.

- 38 -

The dosage of the active ingredient depends on the species of warm-blooded animals, body weight, age and individual condition, the disease to be treated and the mode of administration.

The dosage is between about 0.1 and about 100 mg / kg daily, preferably between about 0.1 and about 40 mg / kg daily, e.g. at about

10 mg / kg daily. ^

Those on warm-blooded animals, e.g. Humans doses of about 70 kg body weight are between about 10 mg and about 10 g, preferably between about 100 mg and 2 g, e.g. at 600 mg, per warm-blooded animal per day, distributed up to about 12, preferably 2 to 4, e.g. 3, single doses, e.g. can be the same size. The dosage in enteral and parenteral administration is essentially the same. The dependence of the dosage on the body weight is not linear, but rather weak; so that the above-mentioned dosage can also be used in warm-blooded animals with a bodyweight lower or higher than 70 kg,

'' f .. · ' ¹

e.g. 35 kg or 100 kg, can apply. Usually, however, children receive half the adult dose.

The novel pharmaceutical compositions contain a significant amount, especially from about 1% to about 99%, mainly from about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient. Pharmaceutical preparations according to the invention may e.g. in unit dosage form such as dragees, tablets, capsules, suppositories or ampoules.

The pharmaceutical preparations of the present invention are prepared in a manner known per se, e.g. by conventional mixing, granulation, coating, solution or lyophilization process. Pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers,

optionally granulating a mixture obtained and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, into tablets or dragee cores. They can also be incorporated into plastic carriers, which deliver the active ingredients dosed or diffused.

- 39 -

Suitable carriers are, in particular, fillers, such as sugars, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes using e.g. maize, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinyl pyrrolidone, Agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee kernels are provided with suitable, optionally enteric coatings, which include i.a. concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance.

The preparation of the injection preparations takes place in

usual way under ant imikrobiel len conditions, as well as the filling in ampoules or vials and the closure of the container.

To prepare the injectable preparations, it is preferable to use solutions of the active ingredient, as well as suspensions, in particular isotonic, aqueous solutions or suspensions, these being e.g. in lyophilized preparations containing the. Active substance alone or together with a carrier material, e.g. Mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or

- 40 -

Adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the ostnotic pressure and / or buffers, and are prepared in a manner known per se, e.g. by conventional solution or lyophilization. The solutions or suspensions mentioned may viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin! contain.

embodiments

The following examples serve to illustrate the invention. Temperatures are given in degrees centigrade. R. values are determined on silica gel thin-layer plates (Merck, Darmstadt, Germany) unless otherwise stated.

- 41 -

Example 1: At 15.degree., 15.64 g (0.4 mol) of 2- (2-oxo-1-pyrrolidinyl) -acetic acid, o-chloro-phenyl-ester, 6.68 g (0.4 mol) of glycyl-glycinamide are added hydrochloride in 108 ml of dimethylformamide (DMF) at once with 6 ml of triethylamine, whereupon the temperature rises spontaneously to 25 °. Thereafter, the mixture is heated to 60 ° with stirring within 30 minutes and stirred for 1 hour at 60-65 °. It is cooled to 20 °, mixed with 200 ml of ether, the solid components are filtered off with suction and washed with ether. To remove accompanying triethylammonium chloride, the solid obtained is stirred in 40 ml of methanol and 40 ml of ethanol, filtered off with suction and washed with ethanol and ethyl ether. The residue is dissolved in 320 ml of methanol in the heat, the solution is decolorized with animal charcoal, filtered and washed with 100 ml of hot methanol. The filtrate is concentrated on a rotary evaporator, finally at 6O ° / 13 Torr, to 70 ml and cooled in an ice bath. The crystals of N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl-glycinamide, obtained after filtration with suction and washing with absolute ethanol, melt at 169-170 °, solidify again at 171 ° and melt again at 189 °. 190 °.

C ₁ H NO (256,26) Ber. C 46.87 H 6.29 N 21.86 IU Ib η it

Gef. C 46.71 H 6.28 N 21.56

The activated ester used as the starting product is prepared as follows:

To 14.3 g (0.1 mol) of 2- (2-oxo-1-pyrrolidinyl) acetic acid, and 29.3 g

(0.11 mol) of pentachlorophenol in 100 ml of methylene chloride are added with stirring at room temperature 22.7 g (0.11 mol) of solid dicyclohexylcarbodiimide in 5 portions, the initially thin suspension is always viscous and slightly warmed. After completion of the addition of dicyclohexylcarbodiimide is boiled for 6 hours under reflux, then cooled to 10 °, sucks the dicyclohexylurea formed and washed three times with methylene chloride. The filtrate is concentrated to the viscosity and admixed with 100 ml of diethyl ether and 100 ml of pentane. The crystallized product with melting point 125-131 ° is dissolved in 1.5 l of diethyl ether, concentrated and concentrated with petroleum ether.

100 mg 15 mg 2 mg ⁶ / mg 1 me

ether. After the crystallized substance has been filtered off with suction, washing and drying, 2- (2-oxo-1-pyrrolidinyl) -acetic acid-pentachlorophenyl ester having a melting point of 137-138 ° is obtained.

Example 2; Analogously, as described in this application, N- [2- (2-oxo-1-pyrrolidinyl) -butyryl] -glycyl-glycinamide and N- [2- (2-oxo-1-pyrrolidinyl-D-propionyl ] glycyl-glycinamide.

Example 3: Recipe for a tablet:

N - [(2-oxo-l-pyrrolidinyl) acetyl] -glycyl-glycinamide

Strength

Polyvinylpyrrolidone talcum * magnesium stearate

Example 4 Preparation of 1000 Tablets Each Containing 100 mg of N - [(2-Oxo-1-Pyrrolidinyl) -acetyl] -glycyl-glycinamide

composition

N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl-glycinamide 100 g lactose, 100 g

Potato starch 70 g

Gelatin 1.6 g

Talc '12 g

Magnesium stearate. , 2g

Silica (fumed) 4g

Ethanol q.s.

The active ingredient is mixed with the lactose and 60 g of potato starch, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. After drying, the remainder of the potato starch, talc, magnesium stearate and fumed silica are mixed and the mixture is compressed into 289j6 mg tablets each having the above stated active ingredient content which may be provided with partial scores for finer dosage adjustment.

- 43 -

Example 5: In 100 ml of dimethylformamide 12.6 g (D ₅ L) -2- butyric acid and 5.0 g of pentachlorophenyl stirred (30 mmol) (2-0xo-l-pyrrolidinyl) glycyl glycinamide hydrochloride. Under nitrogen atmosphere is stirred at 40 ⁰ C for 18 hours. The resulting slightly brown suspension is cooled to 10 ⁰ C and filtered. On the filter remain 3.3 g of triethylamine hydrochloride, mp. 254-6 °. The filtrate is evaporated at 8O ° / 13 Torr. The residue, 20 g of brown oil, is chromatographed on 300 g of silica gel (Merck, Kieselgel'60, 70-230 mesh). The fractions are eluted with ethanol. The first fractions contain pentachlorophenol. The following fractions are combined, freed of ethanol and crystallized from methanol-ethane, whereupon (D, L) -N- [2- (2-oxo-1-pyrrolidinyl) -butyryl] -glycylglycine-amide of melting point 146-149 ° receives.

^C 12 ^H 2 O ^N 4 ° 4 ^{(284 '32) Ber} · ^{c 5 O} ' ^{7 H 7} > ^r N 19.7

Gef. C 50 * 8 H 7.2 N 19.5

The starting material is obtained as follows:

To a solution of 29.3 g (0.11 mol) of pentachlorophenol and 17.1 g (0.10 mol) of (D, L) -2- (2-oxo-1-pyrrolidinyl) -butyric acid in 370 ml of tetrahydrofuran 22.7 g (0.11 mol) of Ν, Ν-dicyclohexylcarbodiimide, dissolved in 30 ml of tetrahydrofuran are added dropwise at 10 ° C within 30 minutes. After 58 hours of stirring at 40 °, the white suspension is filtered off with suction. The clear, slightly pink colored filtrate is evaporated to dryness and crystallized from ether-petroleum ether at ^{0 0} C. Recrystallization from acetone-hexane gives 33.1 g of (D, L) -2- (2-oxo-1-pyrrolidinyl) -butyric acid pentachlorophenyl ester of melting point 107-109 °.

C ₁₄ H ₁₂ Cl ₅ NO ₃ (419.52) Ber. C 40.08 H 2.88 N 3.34

Gef. C 40.2 H 3.0 N 3.6

- 44 -

Example 6; 2.74 g (0.01 mol) of N- (3-carboxy-propyl) -glycyl-glycylglycinamid be suspended in 20 ml of hexamethyldisilazane and heated to boiling with stirring. After a short time, a clear solution is formed. The mixture is refluxed for 24 hours and then the crude reaction mixture is evaporated under high vacuum. The residue is dissolved in 30 ml of methanol and stirred at room temperature, after a short time the N - [_ (2-0xo-1-pyrrole idinyl) -acetylj-glycyl-glycinamide described in Example 1 precipitates. This is filtered off with suction and washed with a little cold methanol.

The starting material is prepared as follows.

10.3 g (0.10 mol) of 3-amino-butyric acid, 28 g (0.20 mol) of potassium carbonate and 1.2.5 g (0.05 mol) of N- (bromo-acetyl) -glycyl-glycinamide

¹ 'S

are stirred in 200 ml of ethanol for 8 hours at 50 °. Then it is carefully neutralized with 2N hydrochloric acid and then evaporated in a water-jet vacuum. The residue is mixed with 250 ml of isopropanol and heated to boiling. The insoluble salts are filtered off with suction and the filtrate is concentrated on a rotary evaporator until incipient crystallization, whereupon N- (3-carboxy-propyl) -glycyl-glycyl-glycinatnid is obtained, which is processed further directly.

i

Example 7 : 2.92 g (0.01 mol) of N- (4-chlorobutyryl) -glycylglycylglycine amide and 1.5 g (0.011 mol) of potassium carbonate are heated to boiling with stirring in 100 ml of ethanol for 5 hours. The mixture is then evaporated on a rotary evaporator, the residue is digested in 200 ml of boiling isopropanol, filtered from the insoluble inorganic salts and concentrated in a water-jet vacuum until incipient crystallization, wherein the N-ε described in Example 1 (2-0xo-1-pyrrolidinyl ) -acetylJ-glycyl-glycinamide precipitated, which is filtered off with suction and washed with a little Isopröpanol.

- 45 The starting material is prepared as follows:

To a mixture of 2.1 g (0.01 mol) of glycyl-glycyl-glycinamidhydrochlorid and 2.0 g (0.02 mol) of triethylamine in 50 ml of dimethylformamide is allowed to stir at a reaction temperature of 5 "1.5 g ( After completion of the addition, the mixture is left to react for 1 hour at 5 ° -20 ° C. Then the dimethylformamide is distilled off in a high vacuum The residue is then sliced with 200 ml of ethanol and the insoluble N- (100 μl) is added. A-Ch-IOrbutyryl) -glycyl-glycinamide.

Example 8: To a solution of 1.70 g (0.02 mol) of 2-oxo-pyrrolidine in 30 ml of dimethylformamide is added with stirring and Stickstoffätmosphäre 0.86 g (0.02 mol) of a 57prozentigen dispersion of sodium hydride in mineral oil, wherein a strong evolution of hydrogen gas takes place. The mixture is allowed to react for 30 minutes at room temperature and then admixed with 5.0 g (0.02 mol) of N- (bromo-acetyl) -glycyl-glycinamide. The reaction mixture is stirred for 15 hours at room temperature. For workup, the dimethylformamide is evaporated under high vacuum and the residue is digested in 250 ml of hot ethanol. It is filtered off from the insoluble inorganic salts and concentrated the filtrate in a water-jet vacuum until the onset of crystallization. The precipitated, described in Example 1 N- ε (2-0xo-l-pyrrolidinyl) acetyl ^ glycylglycinamid is filtered off with suction and washed with a little ethanol;

Example 9 ; 2.0 g (0.01 mol) of N - [(2-oxo-1-pyrrolidinyl) acetyl] glycine and 1.1 g (0.01 mol) of glycinamide hydrochloride are dissolved in 20 ml of dimethylformamide with stirring and Nitrogen atmosphere in succession with 1.1 g (0.011 mol) of triethylamine and 3.26 g (0.0105 mol) of triphenyl phosphite. Then the reaction mixture is heated for hours to 85-90 °, with a clear solution ensteht. Then it is cooled to 5 ° and treated with 30 ml of diethyl ether. The precipitate is filtered off with suction and used to separate triethylamine

hydrochloric acid slurried in 20 ml of ethanol and sucked off again, to obtain the N- ε (2-oxo-1-pyrrolidinyl) -acetyl ^ -glycyl-glycinamide described in Example 1.

Example 10 : 2.7 g (0.01 mol) of N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl-glycine-methyl ester are dissolved in 100 ml of methanol and ammonia gas is introduced with stirring. It is allowed to react for a total of 15 hours at room temperature, then the precipitated, described in Example 1 N- (2-0xo-l-pyrrolidinyl) -acetyl ^ -glycylglycinamid from and crystallized from this methanol.

Example 11 : Into a 2.5 cm diameter chromatography vessel

Add 50 ml of wet slurried AMBERLITE IRA-400 (strong base anion exchange resin based on polystyrene) in chloride form and cover with a mixture of 20 ml of triethylamine, 20 ml of ethanol and 60 ml of water. The mixture is passed dropwise and then rinsed with distilled water until the eluate is neutral.

® The activated and washed Amberlite IRA-400

is transferred to a round bottom flask and the water is decanted off.

An aqueous solution (100 ml) of 2.38 g (0.01 mol) of N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycine-N-cyanomethyl-amide is stirred with the activated anion exchanger with magnetic stirring for 5 hours. cooked under reflux for a long time. At room temperature, the ion exchanger is filtered off with suction on a suction filter and the clear aqueous filtrate is evaporated to dryness at 60/14 torr. The remaining in the residue, described in Example 1 N- ε (2-0xo-lpyrrolidinyl) acetylj-glycyl-glycinamide is purified by recrystallization from methanol. ','

The starting material is obtained from N - [(2-oxo-1-pyrrolidinyl) acetyl] -glycine and aminoacetonitrile.

  , - 47 - '

'Example 12: In an analogous manner, as described in this application, one obtains

N - [[(2-0xo-1-pyrrole-idinyl) -acetyl]] - (L) -alanyl- (L) -alanine-amide, R ,. = 0.35 (chloroform: methanol = 4: 1), N - [(2-oxo-1-pyrrolidinyl) acetyl] - (D, L) -phenylglycyl (D, L) -

phenylglycinamide, R _f = 0.45 (chloroform: methanol = 4: 1) i

(D, L) -N- £ 2- (2-oxo-1-pyrrolidinyl) -2-benzyl-acetyl] -glycyl-glycinamide, R = 0.40 (chloroform: methanol = 4: 1), and

(D, L) -N- [2- (2-Oxo-1-pyrrolidinyl) -2-phenyl-acetyl-3-glycyl-glycinamide, R. = 0.41 (chloroform: methanol = 4: 1).

Claims (8)

"'.- 48 - Claim of invention . , ... , '1. Process for the preparation of a lactain peptide of the formula I. Il. • 0 0 0 ^XX .11 Il Il ^ -CH- C-NH-CH-C-NH-CH-C-NH _n '(I) I ₁ Ίο '. U. 2 wherein R is hydrogen, C _{1 l} -alkyl, aryl-lower alkyl or aryl end 2. ' R is hydrogen, lower alkyl or aryl, where both radicals R have the same meaning, or a salt of such a compound having at least one salt-forming group, characterized in that, one (a) a compound of formula II,. · 0 0 ^.: '. Ji II (II) · il_ "~ \" (* t _ '' I ^ iNCTvii V ^ .K *. \ -iii ν * '^ i * i. L · i ti wherein Y is a nucleophilic leaving group and the remaining 3ub stituenten, have the abovementioned meanings, with the proviso that optionally present in the catches R ¹ and R ² functional groups are protected by readily cleavable protecting groups, intramolecularly to form the Pyrrolidonri.igas / cyclonic, or. ·. ' b) a compound of the formula III, wherein R is a carboxyl group or an activated derivative thereof  3 n.   - 49 -. _ and also the amino group participating in the reaction can be present in activated form and the other substituents have the abovementioned meanings, with the proviso that in the radicals 12 R and R optionally functional groups are optionally protected by readily cleavable protecting groups, cyclized intramolecularly to form the pyrrolidone ring or c) 2-oxo-pyrrolidine of the formula IV II. (IV) or a reactive form of this compound with a compound of the formula V, 0 0 ο ! II! Il
Y-CH-C-NH-CH-C-NH-CH-C-NH .. wherein Y represents a nucleophilic leaving group and the other substituents have the abovementioned meanings, with the proviso that 12 '' in the radicals R and R existing functional groups are optionally protected by readily cleavable protecting groups, reacting, or d) a compound of the formula VI, Il I! -NH-CH- C- I? R " NH-CH OH (VI) " ¹ p in which η and ρ independently of one another denote the number 0 or 1, and the remaining substituents have the abovementioned meanings, with - 50 - the proviso that the radicals R and R yn existing functional groups are optionally protected if necessary by readily removable protecting groups, or a reactive Carbonsäurederivät the compound of formula VI with- a compound of formula VII. H-' NH-CH-C NH, (VII) wherein q and r independently represent the number 0 or 1, with the proviso that r and q are each 1, when in the reac-; , where ρ is 1 and η is 0, or that r is 0 if ρ and η are each 1, and in which the other substituents have the abovementioned meanings, with the proviso that *   2 '' optionally functional groups which are optionally protected by light, removable protective groups in the radical R 1, or a derivative of the compound of the formula VII in which one of the NH groups is in reactive form, or js.) The cyano group in a compound of formula VIII ,. Η-C-NH-CH-HZ-NTi-CH-CN I ₂ '2 ¹ R · R (VIII) wherein all substituents have the abovementioned meanings, converted into an amide group, or ^; '. - 51 - f) the qxim group in a compound of the formula IX, (IX) /. II wherein the subscituents have the abovementioned meanings, by a Beckmann rearrangement in an amide group. convicted, or g) in a compound of formula I which has at least one free hydroxy or carboxy esterified or etherified free hydroxy or esterified free.Carboxy and after execution of the process described under a) to f) optionally existing Schutzgrup groups splits off and, if desired , separating sterea isomeric genicres, and, if desired, converting a compound obtained having at least one salt-forming group into a salt or a salt obtained in the free compound. 2. The method according to item 1, characterized in that the ι starting materials are selected so that a compound of formula I, wherein R is hydrogen, C, alkyl, by a unsubstituted or substituted phenyl or naphthyl radical substituted lower alkyl or '·' · '' 2 an unsubstituted or substituted phenyl radical and R is hydrogen, lower alkyl or an unsubstituted or substituted phenyl radical, or a salt of such a compound having 'at least one salt-forming group. 3. The method according to item 1, characterized in that one selects the starting materials so that a compound of formula I, wherein R "is hydrogen, unsubstituted or substituted by phenyl 2 - ' C ₁ alkyl or phenyl and R is hydrogen, C _{1 7} alkyl, phenyl or 4-hydroxy-phenyl mean. - 52 - 4. Process according to item 1, characterized in that the starting materials are chosen such that a compound of the formula I 1 2 in which $ and R independently of one another are hydrogen or C-alkyl. 5. The method according to item 1, characterized in that one selects the starting materials so that one obtains a compound of formula I, 1 2 wherein R is hydrogen or C, -alkyl and R is hydrogen, methyl, ethyl, 2-propyl, 2-butyl or 2-methyl-propyl. 6. Method according to one of the items 1 to 5, characterized by that you choose the starting materials so that you can connect the       1 '' '' 'Formula I, worm R is hydrogen and the asymmetric 2
substituted--R atoms having the (L) configuration. 7. The method according to any one of items 1 to 5, characterized in that one chooses the source materials so that one can  ''. '...' · '.' '. 2 A compound of the formula I which has the (L) -configuration on asymmetrically substituted CHR atoms or a salt of such a compound with at least one salt-forming group. 8. The method according to item 1, characterized in that one selects the starting materials so as to obtain N - [(2-0xo-l-pyrrolidinyl) -acetyl] -glycyl-glycinamide.