NO840310L - PYRROLIDINON DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION. - Google Patents

Description

The invention relates to lactam peptides of formula I,

where R 1 means hydrogen, C 1-4 alkyl, aryl lower alkyl or aryl and

R 2 means hydrogen, lower alkyl or aryl, being both

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

methods and new intermediates for the preparation of these compounds, pharmaceutical preparations containing these compounds, and their use for the preparation of pharmaceutical preparations or as pharmacologically active compounds.

The prefix "lower" here and in what follows denotes one

residue with 1-7, especially 1-4 C atoms.

Aryl stands for an unsubstituted or substituted carbocyclic aromatic residue. In this application, aryl primarily stands for unsubstituted or substituted phenyl, and also for unsubstituted or substituted naphthyl.

As aryl substituents, the following should mainly be mentioned: lower alkyl, halogen and free or functionally converted hydroxy, also free or esterified carboxy, oxo or unsubstituted or substituted phenyl.

Functionally converted hydroxy is esterified or etherified hydroxy.

Esterified hydroxy is preferably with an organic, but also with an inorganic acid esterified hydroxy, above all acyloxy, furthermore also sulfonyloxy or halogen. Acyloxy is preferably optionally substituted hydrocarbylcarbonyloxy or hydrocarbyloxycarbonyloxy. Optionally substituted hydrocarbyl stands here and in the following in particular for an aliphatic residue with 1-21, preferably 1-11, preferably 1 to 7 C atoms, a carbocyclic residue, i.e. a cycloaliphatic residue with 3-8, especially 5 or 6, members in the ring and up to 21, preferably up to 11 C atoms, or a mono- or bicyclic aromatic residue with 6 or 10 ring members and up to 21, preferably up to 15 C atoms, or a corresponding carbocyclic-aliphatic rest. With the above-mentioned cycloaliphatic or the aromatic residues are preferably unsubstituted or substituted cycloalkyl residues, especially unsubstituted or lower alkyl substituted cycloalkyl residues, or

about phenyl residues, e.g. phenyl.

Sulfonyloxy is particularly aromatic, preferably monocyclic aromatic, sulfonyloxy with no more than 12 carbon atoms, e.g. toluenesulfonyloxy, or lower aliphatic, preferably lower alkylsulfonyloxy.

Etherated hydroxy is particularly optionally substituted hydrocarbyloxy.

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

Lower alkyl R 2 is preferably methyl, isopropyl, 1-methyl-propyl or isobutyl.

The configuration at possibly present asymmetry centers in a compound of formula I can independently be (D), (L), or (D,L), with the C-R<2-> atoms, however, it is preferably (L).

The general terms used above and below have, within the scope of the present description, preferential

show the following meanings:

Lower alkyl is primarily methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, also e.g. also

Sec. butyl or tert. butyl, further n-pentyl, neopentyl, n-hexyl or n-heptyl.

Halogen is particularly fluorine or chlorine, but can however

also stand for bromine or iodine.

Cycloalkyl is e.g. cyclohexyl or cyclopentyl.

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

Protective groups, their introduction and removal are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in "Methoden der organischen Chemie", Houben-Weyl, 4. Auflage, vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974. Characteristic of protecting groups is that they are easily cleavable, e.g. solvolytic, reductive, photolytic or also under physiological conditions, i.e. without unwanted side reactions taking place.

Hydroxy protecting groups are e.g. acyl residues, which optionally, e.g. with halogen, substituted lower alkanoyl, such as 2,2-dichloroacetyl, or acyl residues of carboxylic acid half-esters, especially tert-butyloxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halogen lower oxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, further trityl or formyl, or organic silyl or stanyl residues, further easily cleavable ether-forming groups, such as tertiary lower alkyl, e.g. . tert-butyl, 2-oxa-or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residues, primarily 1-lower oxylower alkyl or 1-lower alkylthio-lower alkyl, e.g. methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cycloalkyl with 5 to 6 ring atoms, e.g. tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogs, as well as optionally substituted 1-phenyl-lower alkyl,

as optionally substituted benzyl or diphenylmethyl, as substituents on the phenyl residue include e.g. halogen, such as chlorine, lower alkoxy, such as methoxy and/or nitro.

Carboxyl groups are normally protected in esterified form, as such ester groupings are easily cleavable under gentle conditions. Carboxyl groups protected by this technique contain, as ester-forming groups, primarily branched in the 1-position or suitably substituted lower alkyl groups in the 1- or 2-position. Preferred carboxyl groups which are present in esterified form are, among other things, tertiary lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl with one or two aryl residues, as these optionally form with e.g. lower alkyl, such as tertiary lower alkyl, e.g. tertiary butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro, mono- or polysubstituted phenyl residues, which optionally e.g. as mentioned above, substituted benzyloxycarbonyl, e.g. 4-methoxybenzyloxycarbonyl, or 4-nitro-benzyloxycarbonyl, or optionally, e.g. as mentioned above, substituted diphenylmethoxycarbonyl, e.g. diphenylmethoxycarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl, 1-lower methoxycarbonyl, such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, 1-lower alkylthiolower oxycarbonyl, such as 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, where the aroyl group optionally constitutes e.g. with halogen, such as bromine, substituted benzoyl, e.g. phenacyloxycarbonyl, 2-halolower oxycarbonyl,

e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl, where the substituents independently of each other mean an optionally substituted, e.g. with lower alkyl, lower alkoxy, aryl, halogen, and/or nitro substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon residue, which suitably means optionally substituted lower alkyl, phenyl lower alkyl, cycloalkyl or phenyl, e.g. 2-trilower 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 residues mentioned above and below preferably contain lower alkyl, especially methyl, as substituents on the silicon or tin atoms. Suitable silyl or stannyl groups are primarily trilower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butylsilyl, or similarly substituted stannyl, e.g. tri-n-butylstannyl.

Preferred protected carboxyl groups are tert.-lower oxycarbonyl, such as tert.-butoxycarbonyl, and primarily possibly e.g. as mentioned above, substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, preferably 2-(trimethylsilyl)ethoxycarbonyl.

A protected amino group, e.g. in a starting material for the preparation of compounds of formula I, can e.g. present in the form of an easily cleavable acylamino-, arylmethylamino-, etherified mercaptoamino-, 2-acylvarealk-1-en-1-yl-amino-, silyl- or stannylamino group or as an azido group.

In a suitable acylamino group, acyl is, for example, the acyl residue of an organic carboxylic acid, with e.g. up to 18 carbon atoms, especially one optionally, e.g. with halogen or aryl, substituted alkanecarboxylic acid or optionally, e.g. with halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic acid half-ester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl, or propionyl, halolower alkanoyl, such as 2-haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2, 2-trichloroacetyl, optionally, e.g. with halogen, lower alkoxy or nitro substituted benzoyl, e.g. benzoyl, 4-chlorobenzoyl, 4-methoxy benzoyl or 4-nitrobenzoyl, or in the 1-position to the lower alkyl radical branched or in the 1- or 2-position suitably substituted lower alkoxycarbonyl, especially tert.-lower oxycarbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl with one or two aryl residues, which preferably constitute, if necessary, e.g. with lower alkyl, especially tert.lower alkyl, such as tert.butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as 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, where the aroyl group preferably makes up e.g. with halogen, such as bromine, substituted benzoyl, e.g. phenacyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl, where the substituents independently of each other mean an optionally substituted, e.g. with lower alkyl, lower alkoxy, aryl, halogen or nitro substituted aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon residue with e.g. up to 15 C atoms, which suitably means, optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, e.g. 2-trilower alkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl, or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

Further acyl residues that come into question as amino-protecting groups are also suitable residues of organic phosphoric, phosphonic or phosphinic acids, such as dilaverealkyl-phosphoryl, e.g. dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, e.g. dicyclohexylphosphoryl, optionally substituted diphenylphosphoryl, e.g. diphenylphosphoryl, optionally, e.g. with nitro substituted di-(phenyl lower alkyl)-phosphoryl e.g. dibenzylphosphoryl or di-(4-nitrobenzyl)-phosphoryl, optionally substituted phenyloxy-phenyl-phosphonyl, e.g. phenyloxyphenyl-phosphonyl, dilaverealkylphosphinyl, e.g. diethylphosphinyl, or optionally substituted diphenylphosphinyl, e.g. diphenylphosphinyl.

In an arylmethylamino group which constitutes a mono-, di- or especially triarylmethylamino, the aryl residue is particularly optionally substituted phenyl residues. Such groups are, for example, benzyl, diphenylmethyl and especially tritylamino.

An etherified mercapto group in an amino group protected by such a residue is primarily arylthio or aryllower alkylthio, where aryl is particularly optional, e.g. with lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, substituted phenyl. A suitable amino protecting group is e.g. 4-nitrophenylthio.

In a 2-acyl-lower-alk-l-en-l-yl residue that can be used as an amino protecting group, acyl is e.g. the corresponding residue of a lower alkane carboxylic acid, an optionally, e.g. with 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 carboxylic acid half-ester, such as a carboxylic acid lower alkyl half-ester.

Suitable protecting groups are primarily t21-lower alkanoyl-prop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower oxycarbonyl-prop-1-en-2-yl, e.g. 1-Ethoxycarbonyl-1-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 bromine ion, or of organic sulphonic acids, such as p-toluenesulphonic acid, in question.

Preferred amino protecting groups are acyl residues of carboxylic acid half-esters, especially tert-butyloxycarbonyl, optionally benzyloxycarbonyl such as e.g. is substituted as indicated, e.g. 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower oxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, further trityl or formyl.

Salts of compounds according to the invention with salt-forming groups are primarily pharmaceutically usable, non-toxic salts, such as those of compounds of formula I with acidic groups, e.g. with a free carboxyl group.

Such salts are primarily metal or ammonium salts, such as alkali metal or alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, also ammonium salts with ammonia or suitable organic amines, the formation of the salt primarily involving aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases, such as lower alkylamine, e.g. triethylamine, hydroxyl lower alkylamine, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, 2-hydroxyethyldiethylamine or tri-(2,-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethylaminoethyl ester, lower alkylene amine, e.g. 1-ethylpiperidine, cycloalkylamine, e.g. dicyclohexylamine, or benzylamine, e.g. N,N'-dibenzylethylenediamine, further bases of the pyridine type, e.g. pyridine, collidine or quinoline.

Pharmaceutically unsuitable salts can also be used for isolation or purification. For therapeutic use, only the pharmaceutically usable, non-toxic salts are sufficient, which are therefore preferred.

The compounds of formula I, where the functional groups are free, i.e. not in protected form, since, however, carboxyl and hydroxyl groups are possibly present in physiologically cleavable, esterified form, and their pharmaceutically usable, 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. Results of the aforementioned type can be examined in the following learning tests: One of these 3-point tests is a so-called "two-compartment passive avoidance test", modified by Jarvik und Koop, Psychol. Rep. 21, 221-224 (1967).

The test device consists of a large box (35 x 20 x 10 cm), which is connected by a sliding door to a small box (10 x 10 x 18 cm). While the small box is illuminated clearly from above with a 100 watt lamp, the large box is dark. The floor in both parts consists of an electrically conductive grid, where the grid bars (6 mm diameter) are arranged at a distance of 13 mm from each other. For training, groups of 10 male mice each with a body weight of 20-22 g are placed one by one in the brightly lit small box. As mice have a spontaneous preference for darkness, most enter the dark section within 30 seconds. As soon as they have fully entered this, the sliding door is closed and a foot shock is given (1 mA, 50 Hz, 5 seconds). The animals are then removed eye-

visible from the experimental apparatus.

To investigate the learning effect (re-test), after 24 hours, the mice are placed again one by one in the light compartment and the time until they are completely inside the dark compartment is measured. Usually, most of the animals now remain in the bright part for the entire observation time. The learning effect is enhanced to a large extent, respectively. the memory of the foot shock is triggered at least partially, when a temporary electroshock treatment is immediately added to the foot shock during the learning process as an amnesiogenic treatment. Electroshock parameters: 50 mA, 0.4 seconds, 50 Hz, 0.6 milliseconds (pulse duration).

For investigation of and for comparison of their protective effect against the amnesiogenic effect of the electric shock, the test substances are administered 30 minutes before the teacher review in doses of 0.1 mg/kg, 1 mg/kg, 10 mg/kc and 100 mg/kg (for each dose use there 10 mice) as a solution in physiological NaCl solution, or physiological saline solution alone (=placebo), intraperitoneally and the animals are removed immediately after the learning review with electroshock treatment. 24 hours later, the extent of the sustained learning effect still obtained is measured using the duration of stay in the illuminated box and compared with the equivalent for other test compounds,

as well as in control animals with administration of the possibly used solvent and with exercise, as well as those with connected electroshock treatment. A group treated with placebo and without electroshock treatment serves as a control of the learning in the avoidance test, another control group treated with placebo and with connected electroshock treatment serves to monitor the extent of the amnesiogenic effect of the electroshock.

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

For immediate measurement of the improvement in memory performance, another passive avoidance test ("step down passive avoidance test", Psychopharmacol. 63, 297-300 [1979]) is used: The test device consists of a box (50 x 50 x 550 cm) normally lit by daylight with an electrically conductive grid, where the grid bars (6 mm in diameter) are arranged at a distance of 13 mm from each other. A wooden platform (10 mm thickness, 67 mm in diameter) is placed in the middle of the grating, which is surrounded by a plastic pipe (20 cm height, 68 mm inner diameter). To carry out the training, groups of 30 male mice each with a body weight of 20 -2 2 g, as an animal is placed each time on the platform surrounded by the plastic tube, after 10 seconds the plastic tube is removed and the time the animal needs to dismount and touch the grating with all 4 paws is measured. When all 4 paws touches the grating, a footshock is given (1 mA, 50 Hz, 1 second). Within 10 seconds after the administration of the footshock, the test substances were given in doses of 3 mg/kg, 10 mg/kg and 30 mg/kg (for each dose 30 mice) were used as a solution in physiological NaCl solution, or its solvent (physiological sodium chloride solution = placebo), intraperitoneally. 24 hours later, the extent of improvement or deterioration of the learning effect was examined using the length of stay for each individual animals on the platform when comparing the animals with those that had been given the solvent alone as a control. In this way, an improvement in memory performance can be demonstrated, for example already after intraperitoneal administration of 10 mg/kg N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide.

Because of these properties, the new compounds prove to be suitable for the treatment of cerebral performance insufficiency, in particular of memory disorders of various origins, such as senile dementia, multi-infarct dementia or dementia of the Alzheimer type, further of secondary phenomena of brain trauma or apoplexy .

The new compounds also have a distinct tumor-inhibiting effect. They not only inhibit the growth of the tumor and reduce the tumor number, but they also increase the survival time. Moreover, two advantages of the compound according to the invention over traditional cytostatic or cytotoxic drugs lie in the good compatibility and in the proof that they, as nootropics, do not reduce the quality of life of the tumor patients, but on the contrary help these patients in overcoming their psychological problems. The compounds can therefore also be used for the therapy of tumor diseases, e.g. in the respiratory tract, in warm-blooded animals including humans.

The tumor-inhibiting effect of the new compounds can e.g. is demonstrated through the following experiments: In Syrian hamsters, when diethylnitrosamine is placed in the stomach, papillary, epidermoid and adenocarcinoma tumors are produced in the larynx, trachea and lungs

[G.Papadopoulo and K.H. Schmidt-Ruppin, Oncology 33_, 40-43

(1976)]. A proportion of these hamsters which have become ill with tumors are treated with a compound of formula I (e.g.

for 4 weeks twice a day for 5 days per week with single doses of 20 mg/kg each), the remaining part of the hamsters are treated with a placebo. Three or four days after the end of the treatment, all hamsters are killed. The respiratory system is excised and, after appropriate preparation, the size, number and type of the tumors contained therein are examined microscopically. Thereby, it is found that the size and number of tumors in the hamsters treated with a compound of formula I is significantly smaller compared to the untreated hamsters.

The invention relates in particular to compounds of formula I, where R"*" means hydrogen, C-4-alkyl, lower alkyl which is substituted with an unsubstituted or substituted phenyl radical or naphthyl radical or an unsubstituted or substituted phenyl radical, and R 2 means hydrogen, lower alkyl or a phenyl radical , and salts of such compounds with at least one salt-forming group.

Primarily, the invention relates to compounds with

formula I, where R''" means hydrogen, unsubstituted or phenyl-substituted C-4-alkyl or phenyl and

R<2> means hydrogen, C1-4~alkyl, phenyl or 4-hydroxy-phenyl.

Mainly, the invention relates to compounds of formula

1 2

I, where R and R are independently hydrogen

or C 1-4 alkyl.

Above all, the invention relates to compounds of formula I, where R"'" means hydrogen or C, -alkyl and

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

The invention relates in particular to the above-mentioned compounds of formula I, where R means hydrogen and the asymmetrically substituted C-R 2 atoms have the (L) configuration.

First and foremost, the invention relates to N-[(2-oxo-1-pyrrolidinyl)-acetyl]-(L)-alanyl-(L)-alanine amide and in particular to N-[(2-oxo-1-pyrrolidinyl)-acetyl] -glycyl-glycinamide.

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

Compounds of formula I and salts of such compounds which contain at least one salt-forming group are prepared, for example, by

a) ring-closes a compound of formula II,

where Y means a nucleophilic, leaving group and the other substituents have the meanings mentioned above, with the additional stipulation that in the residues R and R any functional groups present are optionally protected with easily cleavable protective groups, intramolecularly while forming the pyrrolidone ring, or b) ring-closes a compound of formula III,

where R 3 means a carboxyl group or an activated derivative thereof and where also the amino groups that participate in the reaction can be present in activated form and the other substituents have the meanings mentioned above, with the til-1 2 stipulation that in the residues R and R any functional groups present are optionally protected with easily cleavable protective groups, intramolecularly while forming the pyrrolidone ring, or c) reacts 2-oxo-pyrrolidine with formula IV

or a reactive form of this compound with

a compound of formula V

where Y means a nucleophilic, leaving group and the other substituents have the meanings mentioned above, 1 2 with the additional stipulation that in the residues R and R, functional groups present are optionally protected with easily removable protective groups, or d) reacts a compound of formula VI where n and p independently of each other mean the numbers 0 or 1, and the other substituents have the meanings mentioned above, with the additional provision that any functional groups present in the residues R 1 and R<2> are possibly protected with easily removable protective groups, or a reactive carboxylic acid derivative of the compound of formula VI, with a compound of formula VII,

where q and r independently stand for the number 0

or 1, with the additional stipulation that r and q both stand for 1 when p in the reaction participant with formula VI stands for 0,

or that r stands for 1 and q stands for 0, when p stands for 1 and n stands for 0, or that r stands for 0 when p and n both stand for 1, and where the other substituents have the meanings mentioned above, with the additional provision that in the residue R 2 any functional groups present are optionally protected with easily cleavable protective groups, or a derivative of the compound of formula VII, where one of the NH groups is present in a reactive form, or e) transfers the cyano group in a compound of formula VIII,

where all the substituents have the meanings mentioned above, in an amide group, or f) transfers the oxime group in a compound of formula IX

where the substituents have the meanings mentioned above, by a Beckmann rearrangement in an amide group, or

g) esterifies or etherifies free hydroxy or esterifies free carboxy in a connection with formula I

which has at least one free hydroxy or carboxy group, and

after carrying out the procedures described under a) to f), any protective groups present cleave off

and, if desired, separating obtained stereoisomer mixtures, and, if desired, transferring an obtained compound with at least one salt-forming group into a salt or an obtained salt into 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 sulfonate, such as mesylate or tosylate, preferably halogen, such as bromine or iodine, but especially chlorine.

The reaction is carried out with the aid of a base, preferably using equimolar amounts of this base. As bases, e.g. metal hydroxide,

carbonate or alcoholate, such as alkali metal or alkaline earth metal hydroxide or alcoholate, e.g. sodium or potassium hydroxide or sodium tert.-butylate, or alkali metal carbonate or salts, especially alkali metal salts, secondary amides, e.g. 2-oxo-pyrrolidine sodium, or strongly basic ion exchangers, e.g. "Dowex 1"

(registered trademark), also hydrides or amides, e.g. alkali metal hydride or amides, such as sodium hydride or amide or lithium diisopropylamide.

The cyclization reaction is preferably carried out in an inert organic solvent, if desired or necessary, under cooling or heating, e.g. in a temperature range from approx. -80°C to approx. +150°C, mainly between 0°C and 100°C.

In general, the reaction conditions are chosen so that the intramolecular ring closure reaction is favored over intermolecular reactions of the same reaction type that would lead to the formation of dimers or the like.

For this purpose, one can, for example, when necessary, work in greater dilution.

The activation by means of the base can occur at it

same or a different temperature as the actual ring-closing reaction.

Especially when using a very strong base, e.g. lithium diisopropylamide, the activation with the base ("metallization") occurs at a lower temperature (e.g. -80°C)

than the loop conclusion. In this case, one can e.g. allow the reaction container to be heated slowly after metallization has taken place.

When choosing a solvent, the type of base used must also be taken into account. Reactions using alkali metal hydroxides are preferably carried out in dimethylsulfoxide or in alcohols, such as lower alkanols, e.g. anhydrous ethanol at the boiling point 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-oxo-pyrrolidine sodium is carried out i.a. 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 according to the invention using an ion exchanger is carried out in particular in an alcohol, e.g. lower alkanol, e.g. ethanol, at room temperature.

The starting compounds of formula II can be prepared according to

procedures known per se, e.g. by acylation of the free amino group in a peptide amide of formula X,

where the substituents have the meanings mentioned above, with the additional stipulation that free functional groups, which are present, if desired are available in protected form, with an acid chloride of formula XI,

where Y has the meaning mentioned above, e.g. stands for Y

for chlorine, and then subsequent cleavage of the protecting groups.

Method b) (intramolecular cyclization of a compound of formula III): Activated carboxylic acid derivatives of a compound of formula III are primarily reactive activated ester or reactive anhydride, further reactive cyclic amide; furthermore, reactive derivatives of acids of formula III can be formed in situ.

Activated esters of acids are particularly unsaturated esters at the linking carbon atom of the esterified residue, e.g. of the vinyl ester type, such as the actual vinyl ester (which can, for example, be obtained by transesterification of a suitable ester with vinyl acetate; process with activated vinyl esters), carbamoyl vinyl ester (which can, for example, be obtained by treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower oxyvinyl ester (which can be obtained, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or amidino-type ester, such as N,N'-disubstituted amidino ester (which can be obtained, for example, by treating the corresponding acid with a suitable N,N'-disubstituted carbodiimide, e.g. N,N'-dicyclohexylcarbodiimide; carbodiimide -method), or N,N-disubstituted amidino ester (which can be obtained, for example, by treating the corresponding acid with an N,N-disubstituted cyanamide; cyanamide method), suitable aryl esters, especially in the case of phenyl esters which are substituted with suitable electron-withdrawing substt uenter (as one e.g. can be obtained by treating the corresponding acid with a suitably substituted phenol, e.g. 4-nitrophenol, 4-methylsulfonyl-phenyl, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent, such as N,N<1-> dicyclohexyl carbodiimide; method with activated aryl ester), cyanomethyl ester (which can, for example, be obtained by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester method), thioester, especially phenyl thioester which is optionally substituted, e.g. with nitro (which can be obtained, e.g. by treating the corresponding acid with thiophenols, which are optionally substituted, e.g. with nitro, e.g. by means of the anhydride or carbodiimide method; method with activated thiol ester), or amino or amido ester (which can be obtained, for example, by treating the corresponding acid with an N-hydroxy-amino or N-hydroxy-amido compound, e.g. N-hydroxy-succinimide , N-hydroxy-piperidine, N-hydroxy-phthalimide or 1-hydroxy-benztriazole, e.g. by the anhydride or carbodiimide method; method with activated N-hydroxy ester) or silyl esters (which can be obtained e.g. by treatment of the corresponding acid with a silylating agent, e.g. hexamethyldisilazane).

Anhydrides of acids of formula III can be symmetrical or preferably mixed anhydrides, such as e.g. anhydrides with inorganic acids, such as acid halides, especially acid chlorides (which can 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 over the corresponding hydrazide and treatment of this with nitric acidification; acid method), anhydrides of carboxylic acid half-ester derivatives, which of corresponding esters, e.g. carboxylic acid lower alkyl half-esters (such as

can be obtained by treating the corresponding acid with halo-, such as chloroformic acid-lower alkyl esters or of a 1-lower alkylcarbonyl-2-lower alkyloxy-1,2-dihydro-quinoline, e.g. 1-lower oxycarbonyl-2-ethoxy-1,2-dihydroquinoline; method with mixed O-alkyl carboxylic acid anhydrides), or anhydrides of dihalogenated, especially dichlorinated phosphoric acid (which can be obtained, for example, by treating the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), or anhydrides of organic acids, such as mixed anhydrides of organic carboxylic acids (which can be obtained, for example, by treating the corresponding acid with an optionally substituted lower alkane or phenylalkane carboxylic acid halide,

e.g. phenylacetic acid, pivalic acid or trifluoroacetic acid chloride; method with mixed carboxylic acid anhydrides) or with organic sulfonic acids (which can be obtained, for example, by treating a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic^sulfonic acid halide, such as lower alkane or aryl, e.g. e.g. methane or p-toluenesulfonic acid chloride; method with mixed sulfonic anhydrides), also symmetrical anhydrides (which can be obtained, for example, by condensation of the corresponding acid in the presence of a carbodiimide or from 1-diethylaminopropyne; method with symmetrical anhydrides).

Suitable cyclic amides are particularly amides with a 5-membered di-azacyclic aromatic character, such as amides with imidazoles, e.g. imidazole (which can be obtained, for example, by treating the corresponding acid with N,N<1->carbonyldiimidazole; imidazolide method), or pyrazoles, e.g. 3,5-dimethyl-pyrazole (which can be obtained, e.g. from the acid hydrazide by treatment with acetylacetone; pyrazolid method).

The amino group in a starting material with formula III which participates in the reaction is preferably present in free form, particularly when the carboxy group that reacts with it is present in a reactive form, however, it can also itself be derivatized, i.e. activated, e.g. by reaction with a phosphite, such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite.

Protective groups for any functional groups present are e.g. the above-mentioned ownership groups.

The cyclization reaction can be carried out in a manner known per se, as the reaction conditions primarily depend on whether and how the carboxyl group participating in the reaction is activated, usually in the presence of a suitable solvent or diluent or a mixture thereof and, if necessary, in presence of a condensation agent, which, when the carboxyl group participating in the reaction is present as an anhydride, also e.g. can be an acid binding agent, during cooling or heating, e.g. in a temperature range from approx. -30°C to approx. +200°C,

in a closed reaction container and/or in an inert gas atmosphere, e.g. nitrogen.

In general, the reaction conditions are chosen so that the intramolecularly proceeding ring closure reaction is favored over intermolecular reactions of similar reaction types, which would possibly lead to the formation of dimers or the like. For this purpose, when necessary, e.g. work in greater dilution, The reaction can e.g. is carried out by heating a compound of formula III, where R 3 means a non-activated carboxyl group, and the other residues which are possibly present in protected form have the meanings mentioned above, possibly in the presence of a water-removing agent, e.g.

an N,N'-disubstituted carbodiimide, such as dicyclohexylcarbodiimide, and optionally thereto in the presence of an N-hydroxyamine or N-hydroxyamide, e.g. N-hydroxy-succinimide, in an anhydrous inert solvent, e.g. to 50°C-180°C.

Compounds of formula III, where R 3 means an activated carboxyl group react in an anhydrous solvent already at lower temperatures, e.g. -20° to +50°C, forming the 2-oxo-pyrrolidine ring. Preferably, one starts from such activated carboxylic acid compounds with formula III, where the neighboring amino group of the C-R^ atom is present in a protected form and releases the amino group in situ, after which the ring closure occurs.

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

The compounds of formula III, where the carboxyl group R<3> is present in protected form, i.e. as residue R^3, e.g. as

a 2-trimethylsilylethylcarbonyl, can e.g. is prepared by N-alkylation of a compound of formula X or a suitable derivative thereof, e.g. an azomethine or alkali metal salt of a benzenesulfonamide, with a compound of formula XII,

where R a3 means a protected carboxyl group and Y has the meaning mentioned above.

Method c) (N-alkylation of 2-oxo-pyrrolidine with formula IV):

A reactive form of a compound of formula IV

is in particular a metal compound, primarily an alkali metal compound, e.g. a sodium, potassium or lithium

connection of this, which can be produced e.g. by impact of a corresponding, suitable base, e.g. an alkali metal hydroxide, e.g. sodium hydroxide, an alkali metal alcoholate, e.g. -lower alkanolate, such as -methylate, -ethylate or -tert.butylate, a -hydride, -amide, e.g. sodium hydride, sodium amide, or lithium diisopropylamide, or an alkali metal hydrocarbon compound, e.g. butyllithium.

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

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

The starting compounds of formula V are available by acylation of a compound of formula VII, where q and r are both 1, with an acylating agent of formula XIII

where Y and R"<*>" have the above-mentioned meaning, with the additional stipulation that in the residue R"*" there are present free, functional groups, if necessary, in protected form, and then subsequent cleavage of the protective group(s) .

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

Method d) (formation of a peptide bond): Reactive carboxylic acid derivatives of a compound of formula VI are reactive esters, anhydrides or amides

analogously to those mentioned under method b).

As discussed under b), derivatives of acids with formula VI

also formed in situ. Thus, one can e.g. form the N,N'-disubstituted amidino ester 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 N,N'-disubstituted carbodiimide, e.g. N,N<1->dicyclohexylcarbodiimide. Furthermore, one can form amino- or amido-

ester of acids of formula VI in the presence of the starting material of formula VII which is thus acylated, reacting the mixture of the corresponding acid and amino starting material in the presence of an N,N<1->disubstituted carbodiimide, e.g. N,N<1->dicyclohexylcarbodiimide, and an N-hydroxyamine or N-hydroxyamide, e.g. N-hydroxy-succinimide optionally in the presence of a suitable base, e.g. 4-dimethylamino-pyridine.

A derivative of a compound of formula VII, where the amino group that participates in the reaction is present in a reactive form, can be prepared, e.g. by reaction of a phosphite, e.g. one of those mentioned under procedure b).

A reactive form of a compound of formula VII

is e.g. also a carbamic acid halide or an isocyanate, the amino group in a compound of formula VII which participates in the reaction is bound to halocarbonyl, e.g. chlorcarbhoyl, respectively present as an isocyanate group. A reactive form of a compound of formula VII, where r stands for 0 is e.g. urea.

For example, by heating equimolar amounts of urea and a free acid of formula VI, the compounds of formula I are obtained

in good profit.

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, as the reaction conditions primarily depend on the type of acylating agent used, usually in in the presence of a suitable solvent or diluent, or a mixture thereof, and if necessary in the presence of a condensing agent, such as e.g.

when using an anhydride as an acylating agent, it may also be an acid-binding agent, during cooling or heating, e.g. in a temperature range from approx. -30°C to approx. +150°C, in a closed reaction container and/or in an inert gas atmosphere, e.g. nitrogen.

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

Method d) also includes the embodiment whereby, firstly, a carboxylic acid of formula VI, where no and p stand for 1, is reacted with a compound of formula VII, where r stands for 0, forming an ammonium salt

of the carboxylic acid of formula VI, and thermally dehydrates the ammonium salt thus obtained or otherwise to form a compound of formula I, e.g. analogous to the technique described in G.B. patent document no. 1. 309. 692 .

Process e) (amide preparation from a nitrile): The transfer of a nitrile to an amide can take place by partial hydrolysis or via carboxylic acid ester imide salt. The conditions for hydrolysis of a compound of formula VIII must be chosen so that the reaction can be stopped at the amide stage, so that the free carboxylic acid is not formed. In general, the best suited for this purpose is the hydrolysis with acids, since, depending on the substituents present in a compound of formula VIII, one can choose between 80% sulfuric acid (under heating), polyphosphoric acid (at 110-150°C), hydrogen bromide/glacial acetic acid (room temperature ), formic acid (without solvent), hydrogen chloride gas in ether solution followed by the addition of water or aqueous hydrochloric acid, or boron halides/1 equivalent of water.

In some cases the alkaline hydrolysis is also successful, however the method of Radziszewski with hydrogen peroxide in the presence of alkalis at a moderate temperature is the most successful.

An ion exchange resin is preferably used, e.g. "Lewatite" ^ M 504 (according to BRD official document no. 2,507,576 or "Amberlite" ® IRA-400.

The carboxylic acid ester imides are prepared, e.g. by acid-catalyzed addition of alcohols to nitriles of formula VIII. From the ester imides, the amides are obtained using

a Pinner cleavage. Instead of using a strong acid, you can also catalyze with mercury(II) nitrate and additionally reduce with sodium borohydride.

Nitriles with formula VIII can be prepared, for example

through a "flask" synthesis from the corresponding primary halides with cyanide ions by means of a nucleophilic substitution. Preferably, you convert e.g. a primary halide with copper cyanide in dioxane (compare BRD official document no. 2,507,576). The primary halides are obtained e.g. from the primary alcohols using thionyl chloride (compare BRD official document no. 2,507,576). Preferably receives

2

the nitrile of formula VIII, where R stands for hydrogen, by reacting a compound of formula VI, where p stands for 1, n stands for 0 and R 2 stands for hydrogen, with commercially available aminoacetonitrile, according to the procedure d) described procedure.

Procedure f) (Beckmann rearrangement):

The rearrangement of compounds of formula IX can be carried out under the known conditions for the Beckman rearrangement of alkoximes, preferably with polyphosphoric acid or boron trifluoride.

The oximes of formula IX are available by methods known per se, e.g. by reacting the corresponding aldehyde with hydroxylamine.

Method g) (conversions within definitions of the final compound): The compounds of formula (I) which can be obtained according to the invention can be transferred in a manner known per se into other compounds of formula (I).

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

Suitable agents for etherification of a hydroxyl group or esterification of a carboxyl group are, for example, corresponding diazo compounds, such as optionally substituted diazolaveralkane, e.g. diazomethane, diazoethane, diazo-n-butane or diphenyldiazomethane. These reagents are used 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 dilower 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, under cooling, at room temperature or under slight heating, further if necessary, in a closed container and/or under an inert gas, e.g. nitrogen atmosphere.

Further suitable agents for forming a hydroxyl group or for esterifying 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, e.g. hydrohalide acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid, or halosulphuric acid, e.g. fluorosulphuric acid, or strong organic sulphonic acids, which may e.g. with halogen, such as fluorine-substituted lower alkanesulphonic acids, or aromatic sulphonic acids, such as e.g. optionally with lower alkyl, such as methyl, halogen, such as bromine, and/or nitro substituted benzenesulfonic acids, e.g. methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid. Such esters are e.g. lower alkyl halides, dilower alkyl sulfates, such as dimethyl sulfate, further fluorosulfonic acid esters, such as lower alkyl esters, e.g. fluorosulfonic acid ester, or optionally halogen-substituted methanesulfonic acid lower alkyl esters, e.g. trifluoromethanesulfonic acid methyl ester. They are usually used in the presence of an inert solvent, such as an optionally halogenated, such as chlorinated, aliphatic, cyclo-aliphatic or aromatic hydrocarbon, e.g. methylene chloride, an ether, such as dioxane or tetrahydrofuran, or a mixture. In addition, suitable condensation agents are preferably used, such as alkali metal carbonates or hydrogen carbonates, e.g. sodium or potassium carbonates or

-hydrogen carbonate (usually together with a sulfate), or organic bases, which are usually sterically hindered tri-lower alkylamines, e.g. N,N-diisopropyl-N-ethylamine (preferably together with halosulfonic acid lower alkyl esters or optionally halogen-substituted methanesulfonic acid lower alkyl esters), working under cooling, at room temperature or under heating, e.g. at temperatures from approx. -20°C to approx. 50°C and, if necessary, in a closed container and/or in an inert gas, e.g. nitrogen atmosphere. The etherification reaction described above can be significantly accelerated by phase transfer catalysis [see e.g. Dehmlow, Angewandte Chemie, 86, 187 (1974)]. Quaternary phosphonium salts and particularly quaternary ammonium salts can be used as vase transfer catalysts, such as optionally substituted tetraalkylammonium halides, e.g. tetrabutylammonium chloride, bromide or iodide, or also benzyl triethyl ammonium chloride, in catalytic or up to equimolar amounts. As an organic phase, one or another solvent that is not miscible with water can be used, for example one of the optionally halogenated, such as chlorinated, lower aliphatic, cycloaliphatic or aromatic hydrocarbons, such as tri- or tetrachloroethylene, tetrachloroethane, carbon tetrachloride, chlorobenzene, toluene or xylene. Alkali metal carbonates or hydrogen carbonates suitable as condensation agents, e.g. potassium or sodium carbonate or hydrogen carbonate, alkali metal phosphates, e.g. potassium phosphate, and alkali metal hydroxides, e.g. sodium hydroxide, can be added to base-sensitive compounds in the reaction mixture titrimetrically, e.g. by means of an automatic titrator, whereby the pH value remains between approx. 7 and approx. 8.5 during the exercise.

Further agents for etherification of a hydroxyl group or for esterification of a carboxyl group in a compound of formula I are suitable trisubstituted oxonium salts (so-called Meerwein salts), or disubstituted carbenium or halonium salts, where the substituents are the etherified residues, for example trilower alkyl oxonium salts, such as dilavereal oxycarbenium or dilave alkylhaldnium salts, in particular the corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates, or hexachloroantimonates. Such reagents are e.g. trimethyloxonium or triethyloxonium hexafluoroantimonate, -hexachloroantimonate,

-hexafluorophosphate or -tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbromonium hexafluoro-

antimonate. These etherification agents are preferably used in an inert solvent, such as an ether or a halogenated hydrocarbon, e.g. diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture thereof, if necessary, in the presence of a base, such as an organic base, e.g. a preferably sterically hindered tri-lower alkylamine, e.g. N,N-diisopropyl-N-ethylamine, and under cooling, at room temperature or under slight heating, e.g. at approx. -20°C to approx. 50°C, if necessary, in a closed container and/or in an inert gas, e.g. nitrogen atmosphere.

Further suitable etherifying agents are finally suitable 1-substituted 3-aryltriazene compounds, where the substituent means the ether-forming residue, and aryl preferably means optionally substituted phenyl, e.g. lower alkylphenyl, such as 4-methylphenyl. Such triazene compounds are 3-aryl-1-lower alkyl triazene, e.g. 3-(4-methylphenyl)-1-methyl-triazene, 3-(4-methylphenyl)-1-ethyl-triazene or 3-(4-methylphenyl)-1-isopropyl-triazene. These reagents are usually used in the presence of an inert solvent, such as optionally halogenated hydrocarbons or ethers, e.g. benzene, or solvent mixtures, and under cooling, at room temperature and preferably at elevated temperature, e.g. at approx. 20°C to approx. 100°C, if necessary in a closed container and/or in an inert gas, e.g. nitrogen atmosphere.

The conversion of free carboxyl in a compound of formula (I) to esterified carboxyl can, for example, take place as follows

one reacts a compound of formula (I), where other, possibly present, functional groups are optionally present in protected form, or reacts a reactive functional carboxy derivative, including a salt thereof, with a suitable 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 condensation agent. Common condensation agents are e.g. carbodiimides, for example N,N'-diethyl-, N,N<1->dipropyl-, N,N'-dicyclohexyl- or N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, e.g. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, e.g. 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 diluent, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran and, if necessary, under cooling or heating and/or in an inert gas atmosphere.

Suitable reactive functional derivatives for the esterification of carboxyl compounds of formula (I) are e.g. anhydrides, especially mixed anhydrides, and activated esters.

Mixed anhydrides are e.g. those of inorganic acids, such as hydrohalic acids, i.e. the corresponding acid halides, e.g. chlorides or bromides, further hydrogen nitrogen acids, i.e. the corresponding acid azides, furthermore phosphorus-containing acids, e.g. phosphoric acid, diethylphosphoric acid or phosphoric acid, or sulphurous acids, e.g. sulfuric acid,

or hydrocyanic acid. Mixed anhydrides are further e.g. those of organic carboxylic acids, such as of any, e.g. with halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, e.g. pivalic acid or trichloroacetic acid, or of half-esters, especially lower alkyl half-esters of carboxylic acid, such as ethyl or isobutyl half-esters of carboxylic acid, or of organic, especially aliphatic or aromatic sulphonic acids, e.g. p-toluenesulfonic acid.

Suitable activated esters of a compound of formula I with at least one carboxyl group for reaction with an alcohol are e.g. esters of vinyl-containing alcohols (ie enols),

as vinyl-containing lower alkenols, or iminomethyl ester halides, such as dimethyliminomethyl ester chloride (prepared from the carboxylic acid and dimethylchloromethylideneiminium-

the chloride with the formula [(CH3)2N=CHC1]<®>C1<9>), or aryl esters, such as pentachlorophenyl-, 4-nitrophenyl- or 2,3-dinitrophenyl-ester, heteroaromatic esters, such as benztriazole-, e.g. . 1-benztriazole esters, or diacyl imino esters, such as succinyl imino or phthalyl imino esters.

The reaction between such an acid derivative of formula I, which

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 trilower alkylamine, e.g. trimethylamine, triethylamine or ethyldiisopropylamine, or N,N-dilaverealkylaniline, e.g. N,N-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, carbonate or hydrogen carbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

A reactive functional derivative of the ester-forming alcohol is primarily a corresponding ester, preferably with a strong inorganic or organic acid and consists in particular of 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 carboxyl compound of formula (I) or a salt, such as an alkali metal or ammonium salt, thereof, working using the free acid, preferably in the presence of an acid-binding agent.

The above-mentioned esterification reactions are carried out in an inert, usually anhydrous solvent or solvent mixture, for example in a carboxylic acid amide, 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. acetic acid ethyl ester, or a nitrile, e.g. acetonitrile, or mixtures thereof, if necessary during cooling or heating, e.g. in a temperature range from approx. -40°C

to approx. +100°C, preferably at approx. -10°C to approx. +40°C, and/or in an inert gas, e.g. nitrogen atmosphere.

Furthermore, the acid derivative can, if desired, be formed in situ. Thus, one obtains e.g. a mixed anhydride by treating the carboxylic acid compound with suitable protected functional groups or a suitable salt thereof, such as an ammonium salt, e.g. with an organic amine, such as piperidine or 4-methylmorpholine, or a metal, e.g. alkali metal salt with a suitable acid derivative, such as the corresponding acid halide of an optionally substituted lower alkane carboxylic acid, e.g. trichloroacetyl chloride, with a half-ester of a carboxylic acid half-halide, e.g. chloroformic acid half ester or isobutyl ester, or with a halide of a dilave alkyl phosphoric acid, e.g. diethyl phosphorous bromide, and uses the thus obtainable mixed anhydride without isolation.

For the esterification (acylation) of a hydroxy group in a compound of formula I, the starting material of formula (I) is treated with an acylating agent which introduces the desired acyl residue of an organic carboxylic acid. For this, the corresponding carboxylic acid or a reactive derivative thereof, in particular an anhydride, including a mixed or internal anhydride of such an acid, is used. Mixed anhydrides are e.g. those with hydrohalic acids, i.e.

the corresponding acid halides, especially the -chlorides,

further with prussic acid, or those with suitable carboxylic acid half-derivatives, as suitable -half-esters (such as the mixed anhydrides formed, for example, with a halogen-formic acid-lower alkyl, such as chloroformic acid ethyl ester or -isobutyl ester) or with optionally substituted, e.g. e.g. halogen, such as chlorine, containing lower alkane carboxylic acids (such as the mixed anhydrides formed with pivalic acid chloride or trichloroacetic acid chloride). Internal anhydrides are e.g. those of organic carboxylic acids, e.g. ketenes, such as ketene or diketene, or those of carbamic or thiocarbamic acids, i.e. isocyanates or isothiocyanates. Further reactive derivatives of organic carboxylic acids that can be used as acylating agents are activated esters, which are suitably substituted lower alkyl, e.g. cyanomethyl ester, or suitably substituted phenyl-, e.g. pentachlorophenyl or 4-nitrophenyl esters. The esterification can, if necessary, be carried out in the presence of suitable condensation agents, using free carboxylic acids, e.g. in the presence of carbodiimide compounds, such as dicyclohexylcarbodiimide, or carbonyl compounds, such as diimidazolylcarbonyl, and using reactive acid derivatives, e.g. in the presence of basic agents, such as trilower alkylamines, e.g. triethylamine, or heterocyclic bases, e.g. e.g. pyridine The acylation reaction can be carried out in the absence or in the presence of a solvent or solvent mixture, under cooling, at room temperature or under heating and, if necessary, in a closed container and/or in an inert gas, e.g. nitrogen atmosphere Suitable solvents are, for example, optionally substituted, especially optionally chlorinated, aliphatic cycloaliphatic or aromatic hydrocarbons, such as benzene or toluene, as suitable esterification reagents, such as acetic anhydride, can also be used as a diluent.

A hydroxy group which is esterified with an organic sulphonic acid, e.g. lower alkanesulfonic acid, such as methanesulfonic acid, or an aromatic sulfonic acid, such as p-toluenesulfonic acid,

can preferably be formed by treating starting material of formula (I) with a reactive sulphonic acid derivative, such as a suitable halide, e.g. chloride, if necessary, in the presence of an antacid basic agent, e.g. an inorganic or organic base, e.g. in an analogous manner to the corresponding ester with organic carboxylic acids.

Those for carrying out the methods described above

a) to g) necessary starting compounds are known or can be produced according to methods known per se,

e.g. according to or analogous to those described in this application.

Functional groups in starting compounds can be protected with the same protecting groups as those mentioned in this application for corresponding functional groups in the final compounds of formula I. Also the introduction and removal of these protecting groups can take place on

the way described in the cited literature.

In an obtained compound of formula (I), where one or

several functional groups are protected, these can, e.g. protected carboxy and/or hydroxy groups, are released, possibly step by step, or simultaneously, in a manner known per se, by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or in some cases also by means of careful reduction. Silyl protecting groups are preferably cleaved with fluorides, e.g. tetraethylammonium fluoride.

Salts of compounds of formula (I) with salt-forming groups can be prepared in a manner known per se. Thus, one can form salts of compounds of formula (I) with acidic groups, e.g. by treatment 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.

Salts can normally be transferred in the free compounds, e.g. by treatment with suitable acids.

Mixtures of isomers can be separated into the individual isomers in a manner known per se, e.g. by fractional crystallization, chromatography, etc.

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

The invention also relates to the embodiments of the methods whereby one starts from a compound that can be obtained as an intermediate in one or another step, and performs the missing steps, or one interrupts the method at one or the other step, or one produces a compound which can be obtained by the process according to the invention, under the process conditions and processes it further in situ.

New starting materials and/or intermediate products as well as methods for their production are also subject to the present invention. Such starting compounds are preferably used and reaction conditions are chosen so that the compounds which are listed as preferred in this application are obtained.

The pharmacologically usable compounds according to the present invention can be used e.g. for the production of pharmaceutical preparations containing an effective amount of the active compound together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers.

As pharmaceutical preparations according to the invention revolve

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 pharmacologically active compound alone or together with a pharmaceutically usable carrier material.

The dosage of the active compound depends on the species

of the were-blooded animal, body weight, age and individual condition, the disease to be treated as well as the method of application.

The dosage is between approx. 0.1 and approx. 100 mg/kg daily, preferably between approx. 0.1 and approx. 40 mg/kg daily, e.g. at approx. 10 mg/kg daily.

The dose for administration in warm-blooded animals, e.g. people with approx. 70 kg body weight, lies between approx. 10 mg and approx. 10 g, preferably between approx. 100 mg and 2 g, e.g. at 600 mg, per warm-blooded animal and day, divided into up to approx.

12, preferably 2 to 4, e.g. 3, single doses, such as e.g. can be the same size. The dosages for enteral or parenteral application are essentially the same. The dependence of the dosage on body weight is not linear, but rather not pronounced, so that the above-mentioned dosage can also be used in warm-blooded animals with a body weight lower and higher than 70 kg, e.g. respectively 35 and 100 kg. Usually, however, children receive half the wax dose.

The new pharmaceutical preparations contain a certain amount, especially from approx. 1% to approx. 99%, mainly from approx. 10% to approx. 95%, preferably from approx. 20% to approx. 90% of the active compound. Pharmaceutical preparations according to the invention may be available, e.g. in dosage unit form, such as dragees,

tablets, capsules, suppositories or ampoules.

The pharmaceutical preparations according to the present invention are prepared in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. Pharmaceutical preparations for oral use can be obtained by combining the active compound with solid carriers, possibly granulating a resulting mixture and processing the mixture or the granulate, when desirable or necessary after the addition of suitable excipients, into tablets or dragon cores. In addition, they can also be built into a plastic carrier, which emits the active compound in a dosed manner or allows it to diffuse.

Suitable carriers are especially fillers, such as sugar,

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 glue when using e.g. of corn, wheat, rice

or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or if desired, wetting agents, such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone,

agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow regulating and lubricating agents, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragon cores are supplied with suitable, possibly gastric juice-resistant coatings, using, among other things, concentrated sugar solutions, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solutions in suitable organic solvents or solvents

agent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragé coatings can be added with dyes or pigments, e.g. for identification or to characterize different doses of active compound.

The production of injection preparations takes place in the usual way

manner under antimicrobial conditions, as well as the filling into ampoules or bottles and the sealing of the container.

For the production of injection preparations, solutions of the active compound are preferably used,

moreover also suspensions, and especially isotonic aqueous solutions or suspensions, as these can be prepared before use, e.g. in the case of lyophilized preparations containing the active compound alone or together with a carrier material, e.g. mannite. The pharmaceutical preparations may be sterilized and/or contain excipients,

e.g. preservation- , . _ stabilizing agent and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffer, are prepared according to methods known per se, e.g. using conventional dissolution or lyophilization methods. The aforementioned solutions or suspensions may contain viscosity-increasing compounds, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius. R₂ values are examined, unless otherwise indicated, on silicon dioxide gel thin-layer plates (Merck, Darmstadt, BRD).

Example 1

At 15°, 15.64 g (0.4 mol) 2-(2-oxo-1-pyrrolidinyl)-acetic acid pentachloro-phenyl ester, 6.68 g (0.4 mol) glycyl-glycinamide are added -hydrochloride in 108 ml of dimethylformamide

(DMF) at once 6 ml of triethylamine, whereby the temperature rises instantly to 25°. The mixture is then heated to 60° during 30 minutes with stirring and stirred for a further 1 hour at 60-65°. Cool to 20°, add 200 ml of ether, suck off the solid components and wash with ether. For removal of accompanying triethylam-1. ammonium chloride, the solid obtained is stirred in 40 ml of methanol, filtered off with suction and washed with ethanol and ethyl ether. The residue is dissolved in 320 ml of methanol while heating, the solution is decoloured with bone charcoal, filtered and washed with 100 ml of hot methanol. The filtrate is evaporated on a rotary evaporator, finally at 60°/13 Torr, to 70 ml and cooled in an ice bath.

The crystals of N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide obtained after suction and washing with absolute ethanol melt at 169-170°, become solid again at 171° and melt again at 189- 190°.

C10H16N4°4 <256'26) Calculated C 46.87 H 6.29 N 21.86

Found C 46.71 H 6.28 N 21.56.

The activated ester used as starting product is prepared as follows: To 14.3 l g (0.1 mol) of 2-(2-oxo-1-pyrrolidinyl)-acetic acid and 29.3 g (0.11 mol) of pentachlorophenol in 22.7 g (0.11 mol) of solid dicyclohexylcarbodiimide are added in 5 portions to 100 ml of methylene chloride while stirring at room temperature, whereby the initially thin suspension becomes increasingly viscous and is heated somewhat. After the complete addition of dicyclohexylcarbodiimide is boiled for 6 hours under reflux, then cooled to 10°, the dicyclohexylurea formed is sucked off and washed three times with methylene chloride. The filtrate is evaporated until it becomes viscous and 100 ml of diethyl ether and 100 ml of pentane are added. The crystallized product with a melting point of 125-131° is dissolved in 1.5 1 of diethyl ether, evaporated and petroleum ether is added. After suctioning off the crystallized substance, washing and drying, 2-(2-oxo-1-pyrrolidinyl)-acetic acid pentachlorophenyl ester with a melting point of 137-138° is obtained.

Example 2

In an analogous manner to what is described in this application, one obtains N-[2-(2-oxo-1-pyrrolidinyl)-butyryl]-glycyl-glycinamide and N-[2-(2-oxo-1-pyrrolidinyl)- propionyl]-glycyl-glycinamide.

Example 3

Recipe for one tablet:

Example 4

Preparation of 1000 tablets, each containing 100 mg of N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide:

Composition

The active compound is mixed with the lactose and 60 g of potato starch, the mixture is moistened with an alcohol solution of the gelatin and granulated through a sieve. After drying, the rest of the potato starch, the talc, the magnesium stearate and the highly dispersed silicon dioxide are mixed in and the mixture is pressed into tablets each weighing 289.6 mg and the above-mentioned content of active compound, which can be provided with dividing notches for finer adjustment of the dosage if desired .

Example.. 5.

12.6 g (30 mmol) (D,L)-2-(2-oxo-1-pyrrolidinyl)-butyric acid pentachlorophenyl ester and 5.0 g glycyl-glycinamide hydrochloride are stirred into 100 ml of dimethylformamide. It is stirred under a nitrogen atmosphere at 40°C for 18 hours. The slightly brown suspension formed is cooled to 10°C and filtered. 3.3 g of triethylamine hydrochloride, m.p. 254-256°. The filtrate is evaporated at 80°/13 torr. The residue, 20 g of brown oil, is chromatographed on 300 g of silicon dioxide gel (Merck, silica gel 60, 70-230 mesh). The fractions are eluted with ethanol. The first fractions contain pentachlorophenol. The following fractions are combined, freed from ethanol and crystallized from methanol-ether, thereby obtaining (D,L)-N-[2-(2-oxo-1-pyrrolidinyl)-butyryl]-glycyl-glycinamide with melting point 14 6-14 9°.

C12H20<N>4°4 (<2>84'32> Calculated C 50,] H 7.1 N 19.7

Found C 50.8 H7.2 N 19.5.

The output connection is obtained in the following way:

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 N,N-dicyclohexylcarbodiimide, dissolved in 30 ml of tetrahydrofuran, are added dropwise at 10°C over the course of 30 minutes. After 58 hours of stirring at 40°, the white suspension is filtered. The clear, slightly pink colored filtrate is evaporated to dryness and crystallized from ether-petroleum ether at 0°C. After recrystallization from acetone-hexane, 3 3.1 g is obtained

(D,L)-2-(2-oxo-1-pyrrolidinyl)-butyric acid pentachlorophenyl ester with melting point 107-109°.

C14<H>12C15N03(419.52) Calculated: C 40.08 H 2.88 N 3.34

Found: C 40.2 H3.0 N3.6

Example 6

2.74 g (0.01 mol) of N-(3-carboxy-propyl)-glycyl-glycyl-glycinamide are suspended in 20 ml of hexamethyldisilazane and heated to boiling with stirring. After a short time, a clear solution is formed. The mixture is heated under reflux for 24 hours and the crude reaction mixture is then evaporated under high vacuum. The residue is dissolved in 30 ml of methanol and stirred at room temperature, whereby the N-[(2-oxo-1-pyrrolidinylIsacetyl]-glycyl-glycinamide described in example 1 precipitates out after a short time. This is removed and washed with a little cold methanol.

The starting material is produced in the following way.

10.3 g (0.10 mol) 3-amino-butyric acid, 28 g (0.20 mol) potassium carbonate and 12.5 g (0.05 mol) N-(bromo-acetyl)-glycyl-glycinamide are stirred in 200 ml of ethanol for 8 hours at 50°. It is then carefully neutralized with 2N hydrochloric acid and then evaporated under a water jet vacuum. 250 ml isopropanol is added to the residue and heated to the boiling point.

The insoluble salts are removed and the filtrate is evaporated on a rotary evaporator until crystallization begins, whereby N-(3-carboxy-propyl)-glycyl-glycyl-glycinamide is obtained, which is further processed directly.

Example 7

2.92 g (0.01 mol) of N-(4-chloro-butyryl)-glycyl-glycyl-glycinamide and 1.5 g (0.011 mol) of potassium carbonate are heated with stirring in 100 ml of ethanol for 5 hours. It is then evaporated in a rotary evaporator, the residue decomposed in 200 ml of boiling isopropanol, filtered from the insoluble inorganic

the salts and evaporates under a water jet vacuum until crystallization begins, whereby the N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide described in example 1 precipitates out, it is removed and washed with a little isopropanol.

The starting material is produced in the following way:

A mixture of 2.1 g (0.01 mol) glycyl-glycyl-glycinamide hydrochloride and 2.0 g (0.02 mol) triethylamine in 50 ml of dimethylformamide is allowed to stir at a reaction temperature of 5° 1 .5 g (0.011 mol) of 4-chlorobutyric acid chloride is added dropwise. After the addition is complete, it is left to react for another hour at 5-20°. The dimethylformamide is then distilled off under high vacuum. The residue is slurried with 200 ml of ethanol and the insoluble N-(4-chloro-butyryl)-glycyl-glycinamide is removed.

Example 8

To a solution of 1.70 g (0.02 mol) of 2-oxo-pyrrolidine

in 30 ml of dimethylformamide, 0.86 g (0.02 mol) of a 57 percent dispersion of sodium hydride in mineral oil is added with stirring and a nitrogen atmosphere, whereby a strong evolution of hydrogen gas takes place. It is allowed to react for 30 minutes at room temperature and then 5.0 g (0.02 mol) N-(bromo-acetyl)-glycyl-glycinamide is added. The reaction mixture is stirred for 15 hours at room temperature. For work-up, the dimethylformamide is evaporated under high vacuum and the residue decomposed in 250 ml of hot ethanol. The insoluble inorganic salts are removed and the filtrate is evaporated under a water jet vacuum until crystallization begins. The N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide described in example 1 which precipitates, is removed and washed with a little ethanol.

Example 9

2.0 g (0.01 mol) N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycine and 1.1 g (0.01 mol) glycinamide hydrochloride are added to 20 ml

dimethylformamide under stirring and nitrogen atmosphere 1.1 g (0.011 mol) of triethylamine and 3.26 g (0.0105 mol) of triphenyl phosphite successively. The reaction mixture is then heated for 3 hours at 85-90°, whereby a clear solution is formed. It is then cooled to 5° and 30 ml of diethyl ether is added. The precipitate is removed and suspended in 20 ml of ethanol for separation from triethylamine hydrochloride and removed again, thereby obtaining the N-[(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 added while stirring. It is allowed to react for 15 hours at room temperature, then the precipitated N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide described in example 1 is removed and this is recrystallized from methanol.

Example 11

50 ml of moist slurry "Amberlite" IRA-400 (strongly basic polystyrene-based anion exchange resin) in chloride form is introduced into a chromatography vessel with a diameter of 2.5 cm and a mixture of 20 ml of triethylamine, 20 ml of ethanol and 60 ml of water is added. The mixture is added dropwise and then rinsed with distilled water until the eluate is neutral.

The thus activated and washed "Amberlite" IRA-400 is transferred into a round bottom flask and the water is decanted off.

An aqueous solution (100 ml) of 2.38 g (0.01 mol) N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycine-N-cyanomethyl-amide is boiled with the activated anion exchanger under magnetic stirring in 5 hours under reflux. The ion exchanger is filtered off at room temperature on a Nutsch and the clear aqueous filtrate is evaporated to dryness at 60°/14 torr. The N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide described in example 1 which remains in the residue is purified by

recrystallization from methanol.

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

Example 12

In an analogous manner as described in this application, one obtains N-[(2-oxo-1-pyrrolidinyl)-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^= 0.45 (chloroform: methanol = 4:1 ), (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]-glycyl-glycinamide, Rf = 0.41 (chloroform: methanol = 4:1).

Claims (8)

1. Process for the production of a lactam peptide of formula I where R"'" means hydrogen, C -alkyl, aryl lower alkyl or aryl 2 1 and R means hydrogen, lower alkyl or aryl, both residues R 2 having the same meaning, or a salt of such a compound with at least one salt-forming group, characterized by that you a) ring-closes a compound of formula II, where Y means a nucleophilic leaving group and the other substituents have the meanings mentioned above, with the 1 2 additional provision that in the residues R and R any functional groups present are optionally substituted with easily cleavable protective groups, intramolecularly while forming the pyrrolidone ring, orb) ring-closing a compound of formula III, where R 3 means a carboxyl group or an activated derivative thereof and also the amino group that participates in the reaction can be present in activated form, and the other substituents have the meanings mentioned above, with the additional stipulation that in the residues R 1 and R 2 are optionally present functional groups optionally protected with easily cleavable protective groups, intramolecularly while forming the pyrrolidone ring, orc) reacts 2-oxo-pyrrolidine with formula IV or a reactive form of this compound with a compound of formula V, where Y means a nucleophilic leaving group and the other substituents have the meanings mentioned above, with the 1 2 additional provision that in the residues R and R are present being functional groups optionally protected with easily cleavable protective groups, ord) reacts with a compound of formula VI where n and p independently mean the numbers 0 or 1, and the other substituents have the meanings mentioned above, with the additional stipulation that in the residues R 1 and R <2> any functional groups present are optionally protected with easily removable protective groups, or a reactive carboxylic acid derivative of the compound of formula VI, with a compound of formula VII, where q and r independently stand for the numbers 0 or 1, with the additional provision that r and q always stand for 1 when p in the reaction participant with formula VI stands for 0, or that r stands for 1 and q stands for 0 when p stands for 1 and n stand for 0, or that r stands for 0 when p and n both stand for 1, and where the other substituents have the meanings mentioned above, with the additional stipulation that in the residue R 2 any functional groups present are optionally protected with light cleavable protecting groups, or a derivative of the compound of formula VII, where one of the NH groups is present in a reactive form, or) transfers the cyano group in a compound of formula VIII, where all the substituents have the above meanings, in an amide group, orf) transfers the oxime group in a compound of formula IX where the substituents have the above-mentioned meanings by a Beckmann rearrangement in an amide group, or g) esterifies--.or etherifies free hydroxy- or esterifies free carboxy in a compound of formula I which has at least one free hydroxy or carboxy group, and after carrying out the procedures described under a) to f) cleaves off any protective groups present and, if desired, separate stereoisomer mixtures obtained and, if desired, transfer a compound obtained with at least one salt-forming group into a salt or obtained salt in the free compound. 2. Method according to claim 1, characterized in that the starting compound is selected so that a compound of formula I is obtained, where R" <*> " means hydrogen, C 4 -alkyl, with an unsubstituted or substituted phenyl or naphthyl residue substituted lower alkyl or an unsubstituted or substituted phenyl radical and R 2 means hydrogen, lower alkyl or an unsubstituted or substituted phenyl radical, or a salt of such a compound with at least one salt-forming group. 3. Method according to claim 1, characterized in that the starting compound is chosen so that a compound of formula I is obtained, where R means hydrogen, unsubstituted or phenyl substituted C,.-alkyl or phenyl, and R 2 means hydrogen, C-^ _4-alkyl, 14-phenyl or 4-hydroxy-phenyl. 4. Method according to claim 1, characterized in that the starting compound is selected so that 1 2 obtains a compound of formula I, where R and R independently of each other mean hydrogen or C 1 -4 alkyl. 5. Method according to claim 1, characterized in that the starting compound is chosen so that a compound of formula I is obtained, where R"*" means hydrogen or C-1-4-alkyl and R<2> means hydrogen, methyl, ethyl, 2- propyl, 2-butyl or 2-methyl-propyl. 6. Method according to one of claims 1 to 5, characterized by choosing the starting compound so that a compound of formula I is obtained, where R" <*> " means hydrogen and which, in the case of asymmetrically substituted C-R 2 atoms, has (L ) configuration. 7. Method according to one of claims 1 to 5, characterized in that the starting compound is selected so that a compound of formula I is obtained, which in the case of asymmetrically substituted C-R 2 atoms has the (L) configuration, or a salt of such a compound with at least one salt-forming group. 8. Method according to claim 1, characterized in that the starting compound is selected so that N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide is obtained.