NO840311L - SUBSTITUTED PYRROLIDINO DERIVATIVES AND PROCEDURES FOR THEIR PREPARATION. - Google Patents

Abstract

Process for the preparation of lactam peptides with. formula I and their salts. wherein Z i.a. may mean trimethylene or 2-hydroxy-trimethylene, R 1, R ", R 4 and R 12 may mean, inter alia, hydrogen, X may, inter alia, denote the group NH, W may mean a residue of the formulas III or IV. .a. may mean hydrogen or methyl, and R7 may be hydrogen, and R may mean, inter alia, hydrogen or C1-4alkyl, whereby the configuration at CR, when R represents methyl, may be large (D) or (L). treatment of celebral performance insufficiency.

Description

The invention relates to lactam peptides of the formula I,

where Z means an alkylene residue, which is unsubstituted or substituted with free or functionally converted hydroxy and/or with aryl and together with the amide group forms a 5-membered ring,

R"<*>" is hydrogen, lower alkyl or aryl which is unsubstituted or substituted with aryl or with free or functionally converted hydroxy,

X is oxygen or the group NR 2 , in which R 2 stands for hydrogen or lower alkyl,

R^ is hydrogen, or lower alkyl or aryl which is unsubstituted or substituted with free or functionally converted hydroxy, aryl, aminocarbonyl, mercapto, methylthio, free, alkylated or acylated amino, guanidino, free, esterified or amidated carboxy or imidazole-4- yl, or R 2 and R"^ together form trimethylene which is unsubstituted or substituted with free or functionally converted hydroxy,

R 4 is hydrogen or lower alkyl,

W is a residue of formulas III, IV, V or VI,

which with the carbonyl C atom is bound to the residue of formula

II,

where R^, R^ and R"^ independently of each other stand for hydrogen

5 7 9 11

or lower alkyl, R , R , R and R independently represent hydrogen, unsubstituted or with free or functionally converted hydroxy, aryl, aminocarbony1, mercapto, methylthio, free, alkylated or acylated amino, guanidino,

free, esterified or amidated carboxy or imidazole-4-

4 5

yl substituted lower alkyl, or aryl or R and R co-

6 7 89 1011 but, R and R together, R and R together and/or R and R-together independently of each other stand for unsubstituted or with free or functionally converted hydroxy substituted 12 13

trimethylene, and R- and R independently of each other mean hydro-12 13

gen or lower alkyl or R and R together mean tetra- or pentamethylene, 3-oxa-1,5-pentylene or unsubstituted or with oxo or methyl substituted 3-aza-3-methyl-1,5-pentylene, and salts of such compounds, with at least one salt-forming base, with the exception of such compounds of formula I, where

Z means unsubstituted alkylene with 3 C atoms and at the same time

R"*" means hydrogen, unsubstituted alkyl with 1-4 C atoms,

aryl or aryl lower alkyl,

C means the residue NH,

R 3 means aryl, unsubstituted alkyl or hydrogen,

4

R means hydrogen,

W means a residue of formula III, where R^ has a meaning identical to the residue R"^, and

12 13

R and R mean hydrogen,

and of salts of the latter compounds with at least one salt-forming group.

Processes 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 unsubstituted alkylene residue Z has at least 3 and preferably no more than 17 C atoms and is trimethylene or trimethylene, which is substituted with at least 1 and up to 4, but preferably only 1 or 2, alkyl groups, and this preferably in the 1-position, 1,1-position, or 3-position, whereby the 1-position in the trimethylene residue denotes the end that is bound to the nitrogen atom.

Functionally converted hydroxy is esterified or etherified hydroxy.

Esterified hydroxy is preferably hydroxy which is esterified with an organic, but also with an inorganic acid, above all acyloxy, also sulphonyloxy or halogen. Acyloxy is preferably optionally substituted hydrocarbyl carbonyloxy or hydrocarbyloxy carbonyloxy. Optionally substituted hydrocarbyl stands here and in the following in particular for an aliphatic residue with 1-21, primarily 1-11, above all 1-7 C atoms, a carbocyclic residue, i.e. a cycloaliphatic residue with 3-8, in particular 5 or 6, ring members, and up to 21, preferably up to 11 C atoms, or a mono- or dicyclic, aromatic residue with 6 or 10 ring members and up to 21, preferably up to 15 C atoms, or a corresponding carbocyclic -aliphatic residue. The above-mentioned cycloaliphatic, respectively aromatic residues are preferably unsubstituted or substituted cycloalkyl residues, especially unsubstituted or lower alkyl substituted cycloalkyl residues, respectively about phenyl residues, e.g. phenyl.

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

lower alkylsulfonyloxy.

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

The etherified hydroxy is especially optionally substituted, preferably, although not in the case of aryloxy, unsubstituted hydrocarbyloxy.

Aryl stands for an unsubstituted or substituted carbocyclic aromatic residue. In the first row, aryl is in the residues r\

R"^ and W for unsubstituted or substituted phenyl, in the remainder

Z, furthermore also for unsubstituted or substituted naphthyl.

The following are mainly to be mentioned as aryl substituents:

lower alkyl, halogen and free or functionally converted hydroxy, also free or esterified carboxy, oxo or unsubstituted or substituted phenyl. Aryl as a substituent in the alkylene residue C carries as substituents especially halogen, above all fluorine or halogenophenoxy, above all 4-chloro-phenoxy.

Alkylated amino is primarily di-lower alkylamino, but also mono-lower alkylamino.

Acylated amino is unsubstituted or substituted hydrocarbyl carbonylamino, especially lower alkanoylamino.

Esterified carboxy is in particular unsubstituted or substituted hydrocarbyloxycarbonyl, above all lower alkoxycarbonyl.

Amidated carboxy is primarily carbamoyl, and also carboxy which is amidated with an amino acid, e.g. an α-amino-lower alkanecarboxylic acid, or with mono- or di-lower alkylamino.

Unsubstituted lower alkyl R 3 , R 5 , R 7 , R 9 or R 11 is preferably methyl, isopropyl, 1-methyl-propyl or isobutyl. 3 5 7 9 11 Substituted lower alkyl R , R , R , R or R is preferably phenylmethyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, carbamoylmethyl, 2-carboxyethyl, 2-carbamoylethyl or 4-amino -butyl, furthermore also 3-guanidino-propyl, 4-imidazolyl-methyl, 4-hydroxyphenyl-methyl, mercaptomethyl or 2-methylthio-ethyl. 3-aza-3-methyl-1,5-pentylene is substituted with oxo preferably in the 1-, 1- and 2- or 1- and 4-position or with methyl preferably in the 1- and 5-position.

The configuration of any asymmetry centers present

in a compound of formula I, may independently be (D), (L) or (D,L), however, preferably (L)

in the amino acid residues.

The general terms used in the foregoing

and in the following, within the scope of the present description preferably has the following meanings: Lower alkyl is above all methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, moreover, e.g. also sec. butyl or tert.butyl, further n-pentyl, neopentyl, n-hexyl or n-heptyl.

Halogen is especially fluorine or chlorine, but can also stand for bromine or iodine.

Cycloalkyl is e.g. cyclohexyl or cyclopentyl.

Di-lower alkylamino is e.g. dimethylamino or diethylamino.

Mono lower alkylamino is e.g. methylamino or ethylamino. Lower alkanoylamino is e.g. acetylamino or propionylamino. Lower alkoxycarbony1 is e.g. methoxy or ethoxycarbonyl.

The invention also applies to those compounds of formula I with protected, functional groups, especially protected hydroxy, carboxy or amino, which are particularly useful as intermediates.

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

Hydroxy protecting groups are e.g. acyl residues, such as lower alkanoyl which is optionally substituted with e.g. halogen,

such as 2,2-dichloroacetyl, or acyl residues of carbonic acid half-esters, especially tert-butyloxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halogen-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, further trityl or formyl, or organic silyl or stannyl residues, further easily cleavable etherified groups, such as tert.-lower alkyl , e.g. tert-butyl, 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon residues, primarily 1-lower alkoxy lower 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-thiacycloalkyl with 5-6 ring atoms, e.g. tetrahydro-furyl or 2-tetrahydropyrranyl or corresponding thianalogues, as well as optionally substituted 1-phenyl-lower alkyl, such as optionally substituted benzyl or diphenylmethyl, whereby the substituents in the phenyl residue come into question e.g. halogen, such as chlorine, lower alkoxy, such as methoxy and/or nitro.

Carboxyl groups are usually protected in esterified form, whereby such ester groupings are easily cleavable under gentle conditions. Carboxyl groups that are protected in this way contain, as esterifying groups, primarily in the 1-position branched or in the 1- or 2-position suitably substituted lower alkyl groups. Preferred carboxyl groups present in esterified form are i.a. tert.-lower alkoxy carbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl with 1 or 2 aryl residues, whereby these optionally consist of phenyl residues which are mono- or poly-substituted, e.g. with lower alkyl, such as tert.-lower alkyl, e.g. tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. chlorine and/or nitro, as possibly, e.g. as mentioned above, substituted benzyloxycarbonyl, e.g. 4-methoxybenzyloxycarbonyl, or 4-nitrobenzyloxycarbonyl, or optionally, e.g. as above, substituted diphenylmethoxycarbonyl, e.g. diphenylmethoxycarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl, 1-lower alkoxy lower alkoxycarbonyl, such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl1, 1-lower alkylthio-lower methoxycarbonyl, such as 1-methylthiomethoxycarbonyl1 or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl1, where the aroyl group is possibly made up of benzoyl which is substituted e.g. with halogen, such as bromine, e.g. phenazyloxycarbonyl, 2-halogen lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl, in which 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, as corresponding, optionally substituted lower alkyl, phenyl lower alkyl, cycloalkyl or phenyl, e.g. 2-tri lower alkylsilylethoxycarbonyl, such as 2-trimethyl-silylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl1.

The organic silyl or stanyl residues mentioned above and in the following preferably contain lower alkyl, especially methyl, as substituents for the silicon or tin atoms. Corresponding silyl or stanyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butyl-silyl, or similarly substituted stanyl, e.g. tri-n-butylstannyl.

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

A protected amino group can e.g. available in the form of

an easily cleavable acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl lower alk-1-en-1-yl-amino, silyl or stannylamino group or as an azido group.

In a corresponding 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, halogen lower alkanoyl, such as 2-halogenacety1, 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-methoxybenzoyl or 4-nitrobenzoyl, or in the 1-position of the lower alkyl radical branched or in the 1- or 2-position suitably substituted lower alkoxycarbonyl, especially tert.-lower alkoxycarbonyl, e.g. tert-butyl-oxycarbonyl, arylmethoxycarbonyl with 1 or 2 aryl residues, which preferably optionally consists of phenyl which is mono- or poly-substituted with e.g. lower alkyl, especially tert.-lower alkyl, such as tert.-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. chlorine, and/or nitro,

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 is preferably optionally constituted by benzoyl which is substituted, e.g. with halogen, such as bromine, e.g. phenazyloxycarbonyl, 2-halo-lower alkoxycarbonyl, 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, as corresponding, optionally substituted lower alkyl, phenyl lower alkyl, cycloalkyl or phenyl, e.g. 2-tri-lower alkylsilylethoxycarbonyl, such as 2-trimethyl silylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-tri-phenylsilylethoxycarbonyl.

Further acyl residues that come into question as amino protecting groups are also corresponding residues of organic phosphoric, phosphonic or phosphinic acids, such as lower alkyl phosphoryl, e.g. dimethylphosphoryl, diethylphosphory1, di-n-propylphospho-

ryl 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. dibenzyl-phosphoryl or di-(4-nitrobenzyl)-phosphoryl, eventually

alternatively substituted phenyloxy-phenyl-phosphonyl, e.g. phenyloxy-phenyl-phosphonyl, di-lower alkylphosphinyl, e.g. diethylphosphinyl, or optionally substituted diphenylphosphinyl, e.g. diphenyl-phosphinyl.

In an arylmethylamino group which consists of a mono-, di- or especially triarylmethylamino group, the aryl residues are in particular optionally substituted phenyl residues. Such groups are, for example, benzyl, diphenylmethyl and especially tritylamino. An etherified mercapto group in an amino group that is protected with such a residue is, in the first row, arylthio or aryl lower alkylthio, where aryl is especially possibly phenyl which is substituted, e.g. with 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-en-1-yl residue that can be used as an amino protecting group, acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, a benzoic acid which is optionally substituted, e.g. with lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, or especially a carbonic acid half-ester, such as a carbonic-lower alkyl half-ester. Corresponding protecting groups are primarily 1-lower alkanoyl-prop-1-ene-2-

howl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, e.g. 1-ethoxycarbonyl-prop-1-en-2-yl.

An amino group can also be protected in protonated form. Corresponding anions are primarily those of strong inorganic acids, such as halogenated acids, e.g. chlorine or bromine anions, or of organic sulphonic acids, such as p-toluenesulphonic acid, in question.

Preferred amino protecting groups are acyl residues of carbonic acid half-esters, especially tert-butyloxycarbonyl, possibly e.g. as indicated, substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halogen-lower alkoxycarbonyl, 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 and sulfo 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, as well as ammonium salts with ammonia or suitable organic amines, whereby primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic binary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases come into question for the salt formation, such as lower alkylamines, e.g. triethylamine, hydroxy lower alkylamines, 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 amino, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. dicyclohexylamine, or benzylamines, e.g. N,N'-dibenzylethylenediamine, further bases of the pyridine type, e.g. pyridine, collidine or quinoline. Compounds of formula I with at least one basic group can form acid addition salts, e.g. with inorganic acids,

such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. trifluoroacetic acid, as well as with amino acids, such as arginine and lycine. In case of weathering of several acidic or basic groups, mono- or poly-salts can be formed. Compounds of formula I with an acid, e.g. free carboxyl group, and a free basic, e.g.

an amino group, can also exist in the form of internal salts, i.e. in zwitterionic form, or part of the molecule can exist as an internal salt, and another part as a normal salt.

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

The compounds of formula I, where the functional groups are present in free form, i.e. in unprotected form, whereby however the 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 effect a protection against the amnesiogenic effect of cerebral electroshock and an improvement of memory performance. Findings of the aforementioned nature can be determined using the following learning tests: One of these learning tests is a passive avoidance test, the so-called "two-compartment passive avoidance test", modified by Jarvik and Koop, Psychol. Rep. 21, 221-224 (1967). The test device consists of a large box (35 x 20 x 10 cm), which is connected to a small box (10 x 10 x 18 cm) with a sliding door. While the small box is illuminated from above with a 100 W lamp, the large box is dark. The bottom of both compartments consists of an electrically conductive grid, whose grid rods (6 mm diameter) are arranged at a distance of 13 mm. For training, groups of 10 male mice each with a body weight of 20-22 g are placed individually in the lighted, small box. Since the mice have a spontaneous preference for darkness,

most people enter the dark department 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 immediately removed from the experimental apparatus.

To investigate the learning effect ("retest"), after 24 hours, put the mice back individually into the light compartment, and the time is measured until they are completely in the dark compartment. Usually, most of the animals now stay in the bright compartment for the entire monitoring time of 150 seconds. The learning effect is largely nullified, or the memory of the foot shock is at least partially erased, when a temporal electroshock treatment is added as an amnesiogenic treatment immediately after the foot shock in the learning process. Electroshock parameter: 50 mA, 0.4 seconds, 50 Hz, 0.6 milliseconds

(pulse duration).

For testing and for comparing their protective effect against the amnesiogenic effect of the electric shock, the test substances are administered 30 minutes before the learning process in doses of 0.1 mg/kg, 1 mg/kg, 10 mg/kg and 100 mg/kg (for each dose is used 10 mice) as a solution in physiological NaCl solution or physiological saline solution alone (= Placebo) intraperitoneally and the animals are subjected to the electroshock treatment immediately after the learning process. 24 hours later, in connection with the duration of stay in the illuminated box, the extent of the still remaining learning effect is measured and compared with that of the other test substances as well as

of control animals with the exclusive addition of the used solvent and training without, as well as those with subsequent electroshock treatment. A group treated with Placebo without electroshock treatment serves as a control of learning in the avoidance test, another control group treated with Placebo with subsequent electroshock treatment serves to monitor the extent of the amnesiogenic effect of electroshock.

The effects mentioned above can be demonstrated, for example

after intraperitoneal administration of N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-(L)-alanine amide in a dose range from 0.1 to 100 mg/kg. For the immediate measurement of the improvement of the memory disorder, another passive avoidance test ("step down passive avoidance test", Psychopharmacol. 63, 297-300 (1979)) is used: The device consists of a box (50 x 50 x 50 cm) which is normally illuminated by daylight, with an electrically conductive grid, whose grid rods (6 mm diameter) are arranged at a distance of 13 mm. A wooden platform (10 mm height, 67 mm diameter) is placed in the middle of the grating, which is surrounded by a plastic channel (20 cm high, 68 mm inner diameter). For carrying out the training, groups of 30 each are used

male mice with a body weight of 20-22 g, each time an animal is placed on the platform surrounded by the plastic channel, after 10 seconds the plastic channel is removed and the time required for the animal to step down and touch the grating with all four paws is measured. When all four paws touch the grating, a foot shock is delivered ((1 mA, 50 Hz, 1 second). Within 10 seconds after the delivery of the foot shock, the test substances are delivered in doses of 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 their solvent (physiological sodium chloride solution (= Placebo) intraperitoneally. 24 hours later, the extent of the improvement or deterioration is determined on the basis of the duration of stay for each individual animal on the platform the reduction of the learning effect compared to the animals that only had solvent added as a control. Thus, it is possible to demonstrate an improvement in memory performance, for example, already after intraperitoneal administration of 10 mg/kg of N-[(2-oxo-l-pyrrolidinyl)-acetyl]- glycyl-(L)-alanine amide.

Because of these properties, the new compounds show

suitable for the treatment of cerebral performance insufficiency, especially of memory disorders of various origins, such as senile dementia, multi-infarct dementia, or dementia of the Alzheimer type, further of the after-effects of brain damage or apoplexy.

The new compounds also have a distinct tumor-inhibiting effect. They not only inhibit the growth of the tumors and reduce the tumor number, but they also increase the survival time. There are two advantages of the compounds according to the invention over ordinary cytostatic or cytotoxic medicines in the good tolerability and the reason for that, that as nootropics they do not reduce the quality of life of tumor patients, but on the other hand 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. in the respiratory tract, in warm-blooded people including humans.

The tumor-inhibiting effect of the new compounds can e.g. is shown by the following experiments: In Syrian hamsters, application of diethylnitrosamine in the stomach produces papillary, epidermoid and adenocarcinomatous tumors in the larynx, trachea and lungs (G. Papadopoulo and K.H. Schmidt-Ruppin, Oncology 33, 40-43 (1976) ). Part of these sick hamsters with tumors treated with a compound of formula I (eg for 4 weeks twice a day for 5 days per week in a single dose of 20 mg/kg each time), the rest of the hamsters with a Placebo . 3 or 4 days after the end of treatment, all hamsters are killed. The respiratory tract is cut out and, after suitable preparation, the tumors contained are examined microscopically for size, number and type. Thereby it is found that the size and number of tumors in hamsters treated with a compound of formula I is significantly smaller compared to untreated hamsters.

In particular, the invention relates to compounds of formula I,

where Z means an alkylene radical with 3-17 C atoms, which is unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy and/or a phenyl or naphthyl radical which is unsubstituted or substituted by halogen, lower alkyl, halophenoxy, hydroxy or lower alkoxy, and which together with the amide grouping forms a 5-membered ring,

R"<*>" means hydrogen, lower alkyl or phenyl which is unsubstituted or substituted with a phenyl residue, hydroxy, lower alkoxy or lower alkanoyloxy, X oxygen or the group

2 2

NR , where R stands for hydrogen or lower alkyl,

R^ means hydrogen, unsubstituted or with hydroxy, lower alkanoyloxy, a phenyl residue, aminocarbonyl, mercapto, methylthio, amino, di- or mono lower alkylamino, lower alkanoylamino, guanidino, carboxy, lower alkoxycarbonyl or imidazol-4-yl substituted lower alkyl or a phenyl radical, or R 2 and R 3 together means trimethylene which is unsubstituted or substituted with hydroxy, lower alkoxy or lower alka-

noyloxy,

4

R means hydrogen or lower alkyl,

W means a residue of the formulas III, IV, V or VI, which is bound by the carbonyl C atom to the residue of the formula II, where R^, R^ and R"*"^ independently of each other stand for hydrogen or lower alkyl ,

R^, R<7>, R<9> and R"'""'" independently represent hydrogen, unsubstituted or with hydroxy, lower alkoxy, lower alkanoyloxy, a phenyl residue, aminocarbonyl, mercapto, methylthio, amino, di - or mono-lower alkylamino, lower alkanoylamino, guanidino, carboxy, lower alkoxycarbonyl or imidazol-4-yl substituted lower alkyl or a phenyl residue,

4 5 6 7 8 9

or R and R together, R and R together, R and R together, or R"^ and R"^ together independently represent trimethylene which is unsubstituted or substituted by hydroxy, lower alkoxy or lower alkanoyloxy, and

12 13

R and R independently of each other mean hydrogen or lower alkyl or

12 13

R and R together mean tetra- or penta-methylene, 3-oxa-1,5-pentylene or unsubstituted or oxo- or methyl-substituted 3-aza-3-methyl-1,5-pentylene, and salts of such compounds with at least one salt-forming group, with the exception of the already excluded compounds of formula I, which are not the subject of the present invention.

Primarily, the present invention applies to compounds of formula I, where Z means an alkylene residue with 3-14 C atoms, which is unsubstituted or substituted with hydroxy, lower alkanoyloxy and/or naphthyl or a phenyl residue which is unsubstituted or substituted with halogen or halogenophenoxy , and which together with the amide group forms a 5-membered ring, R<1>means hydrogen or unsubstituted or with hydroxy

or lower alkanoyloxy substituted lower alkyl,

X means oxygen or the group NR 2 , where R<2> stands for hydrogen or C,_-alkyl,

R 3 means hydrogen, lower alkyl which is unsubstituted or substituted by hydroxy, lower alkanoyloxy, phenyl, 4-hydroxy-phenyl, aminocarbonyl, amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or imidazol-4-yl, or phenyl, or

R 2 and R 3 together mean trimethylene which is unsubstituted or substituted with hydroxy,

R 4 means hydrogen or C^_^-alkyl,

W a residue of the formulas III, IV, V, or VI, which is bound by the carbonyl C atom to the residue of the formula II, where

R^, R^ and R"*"^ independently of each other mean hydrogen or C -alkyl,

R , R , R and R independently represent hydrogen, lower alkyl which is unsubstituted or substituted by hydroxy, lower alkanoyloxy, phenyl, 4-hydroxyphenyl, aminocarbonyl, amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or imidazol-4-y1 , or phenyl, or R^ and R^ together, R^ and R<7>together, R^ and R^ together, and/or R"<*>"^ and R^^ together independently represent trimethylene which is unsubstituted or substituted with hydroxy or lower alkanoyloxy, and

12 13

R and R independently of each other mean hydrogen or lower

12 13

alkyl, or R and R together means tetra- or penta-methylene, 3-oxa-1,5-pentylene or 3-aza-3-methyl-1,5-pentylene which is unsubstituted or substituted by oxo or methyl, and salts of such compounds with at least one salt-forming group.

Mainly, the invention relates to compounds of formula

In, where

Z represents a residue of formula VII,

which is bound to the nitrogen atom by the C(R 14 ) atom, and where

14 15

R and R independently of each other mean hydrogen or

C1-4-alkyl,

C<l6> means hydrogen, naphthyl, phenyl which is unsubstituted or substituted by fluorine, chlorine, fluorophenoxy or chlorophenoxy, hydroxy or lower alkanoyloxy and

R"*"7 means hydrogen, hydroxy or lower alkanoyloxy,

R^" means hydrogen, unsubstituted or hydroxy-substituted C, .-alkyl,

X means oxygen or the group NR<2>, where R<2> stands for hydrogen or linear C, _-.-alkyl,

R 3 means hydrogen or lower alkyl which is unsubstituted or substituted by hydroxy, phenyl, p-hydroxy-phenyl, aminocarbonyl or imidazol-4-yl,

R 4 means hydrogen or linear C^_^-alkyl,

W means a residue of the formulas III, IV, V or VI, which is bonded with the carbonyl C atom to the residue of the formula II,

R^, R^ and R"^ independently of each other represent hydrogen or linear C 1-6 alkyl,

5 7 9 11

R , R , R and R independently represent hydrogen or lower alkyl which is unsubstituted or substituted by hydroxy, phenyl, 4-hydroxy-phenyl, aminocarbonyl or imidazol-4-yl, or, when W represents formula III, means R and R together, or when W stands for formula IV, means R and R<7> together, or, when W stands for formula V, means R<8> and R 9 together, or, when W stands for formula VI , R<10>and R"'""'" together mean a trimethylene residue which is unsubstituted or substituted with hydroxy or lower alkanoyloxy, and

12 13

R- and R independently of each other mean hydrogen or C, .-alkyl or

12 13

R= and R together mean 3-oxa-1,5-pentylene or 3-aza-3-methyl-1,5-pentylene, and salts of such compounds with at least one salt-forming group.

Above all, the invention relates to compounds of formula

I, where Z means a residue of formula VII which is bound to

14 14 15 the nitrogen atom with the C(R ) atom, where R and R independently mean hydrogen or C^_^-alkyl, R"*"^ means hydrogen, naphthyl, 4-fluoro-phenyl, 4-chloro-phenoxyphenyl or

17

hydroxy, and R means hydrogen,

R"*" means hydrogen,

X means oxygen or the group NH,

R 1 means hydrogen or C 1-6 alkyl,

4

R means hydrogen,

W means a residue with the formulas III, IV, V or VI, where R^, R7, R<9> and R^^ independently of each other stand for hydrogen or C, .-alkyl,

_6 „8 -.10 _ .. _10 _,11

R , R and R stand for hydrogen or R and R together stand for trimethylene, R<12> means hydrogen and R<13> means C1-C4-alkyl.

In particular, the invention relates to the above-mentioned compounds of formula V, where X means the group NH and/or W means a residue

7 9 11

with the formulas III or IV and/or R , R and R , moreover also R 5 , independently of each other means hydrogen or C,_.-2368 10 in 1 ^ alkyl, and/or R , R , R , R and R means hydrogen .

In particular, the invention relates to compounds of formula I, where Z means trimethylene or 2-hydroxy-trimethylene,

13 4 12

R , R , R and R hydrogen, X the group NH, W a residue of formulas III or IV, in which R 5 stands for hydrogen or

6 7» 13

methyl and R and R stand for hydrogen, and R means hydrogen or C,,-alkyl, whereby the configuration at C-R^, when R 5 stands for methyl, can be (D) or (L), especially all the above-mentioned compounds, where Z means trimethylene, and salts of such compounds with at least one salt-forming group, above all compounds of formula I, where Z 1 2 2 means trimethylene, R means hydrogen, X the group NR , R 3 2 3-4

and R hydrogen or R and R together trimethylene, R hydrogen, W a residue of formulas III, IV, V or VI, where

5 4 5

R stands for hydrogen or C^_^-alkyl or R and R together stand for trimethylene, R , R , R , R9, R~^ and R"'""'" stand for hydrogen or R^ and R<7> together stand for trimethylene,

12 13

R means hydrogen or C^_^-alkyl and R means hydrogen.

In the very first place, the invention concerns the compounds described in the examples, above all N-[(2-oxo-1-pyrrolidiny1)-acetyl]-L-prolyl-glycyl-glycinamide, but also N-[(2-oxo- 1-pyrrolidinyl)-acetyl]-glycyl-(L)-alanine amide and N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-(L)-alanine-N-monoethylamide.

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

Of course, also with all the above-mentioned compound groups is the initially mentioned compound group of formula I, where Z means unsubstituted alkylene with 3 C atoms and likewise R means hydrogen, unsubstituted alkyl with 1-

4 C atoms, aryl or aryl lower alkyl, X means the residue

3 4 NH, R means aryl, unsubstituted alkyl or hydrogen, R means hydrogen, W means a residue of formula III, where R^ 3 12

has a meaning identical to the residue R, and R

and R"*"^ means hydrogen, and salts of compounds of this compound group unless a salt-forming group is excluded, i.e. the invention does not apply to the latter compounds.

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

a) a compound of formula VIII,

where Y means a nucleophilic leaving group and the other substituents have the above-mentioned meanings, with the proviso that any functional groups present in the residues Z, R 1 , R 3 or W are possibly protected with easy cleavage-

only protecting groups, are ring-closed intramolecularly to form a pyrrolidone ring, or

b) a compound of formula IX,

19

where R 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 above-mentioned meanings, with the proviso that any functional groups present in the residues Z,

3

R , R or W are optionally protected with easily cleavable protective groups, are ring-closed intramolecularly to form the pyrrolidine ring or

c) a compound of formula X,

where Z has the above meaning, with the proviso that functional groups present therein are optionally protected by means of easily cleavable protective groups, or a reactive form of this compound is reacted with a compound of formula XI,

where Y means a nucleophilic leaving group and the other substituents

tuents have the above-mentioned meanings, with the proviso that functional groups present in the residues Z, r\

R or W is possibly protected by means of easily cleavable protective groups, or

d) a compound of formula XII,

where n and p independently mean the number 0 or

1 and A means the residue W or W Sl , whereby W El means a residue with the formulas III, IV or V, and the other substituents have the above-mentioned meanings, with the proviso that functional groups which are possibly present in the residues Z, 3 R , R and A are optionally protected with easily removable protective groups, or a reactive carboxylic acid derivative of compounds of formula XII, is reacted with a compound of formula

where E stands for the remainder with the formula -N-W- or for the remainder

R<4>

W, b , which is defined in such a way that when connecting W a and ^ W, the remainder W is obtained, and q and r independently of each other stand for the number 0 or 1, with the assumption that r and q stand for 1 and E for the remainder -N-W-, when p stands for 0 in reaction R<4>

the partner with formula XII, or that r stands for E, q for 0

and E for the rest

p stands for E and n stands for 0, rather that r stands for 1, q for 0 and E for , when p stands for 1, n for 1 and A for Wcl, or that r stands for 0, when p and n stands for 1 and A stands for W, and where the other substituents have the above-mentioned meanings, with the proviso that functional groups that may be present in the residues R and E are possibly protected by means of easily removable protective groups, or a derivative of the compounds with formula XIII, where the group H-X-, H-E- or

is available

in reactive form, or

e) a compound of formula I, where at least one of the residues R^, R4, R^, R^, R~^, R"^ and R"^ represents hydrogen and the

the other substituents have the above-mentioned compounds, under the condition that functional groups present in a compound of formula I, with the exception of the reactive amide group, are optionally protected with easily cleavable protective groups, or a reactive derivative of this compound is reacted with an alkylating agent which T.2 „4 „6 n8 „10 ^12 introduces the above-mentioned residues R , R , R , R , R , R and/or R"^, or f) in a compound of formula I, where Z stands for a residue with the formula VX or XVI attached to the nitrogen atom

14

with the C(R ) atom,

whereby all substituents have the above-mentioned meanings, with the proviso that any functional

functional groups in the residues R"*", R~^, W, R"*"^ and R"*"7 are optionally protected with easily cleavable protecting groups, the keto group in the formulas XV or XVI is transferred with a regio-selective reducing agent to a hydroxy group, or

g) the cyano group in a compound of formula XVII,

where U means a residue of the formula XVIII, XIX, XX or XXI

where all substituents have the above-mentioned meanings, are transferred to an amide group or

h) the oxime group in a compound of formula XXII,

where the substituents have the above-mentioned meanings, are transferred by a Beckmann rearrangement to an amide group, or

i) in a compound of formula I, which exhibits at least one free hydroxy, carboxy or amino group, esterified or etherified free hydroxy, esterifies or amidates free carboxy or alkylates or acylates free amino and after carrying out the methods described under a )

to h) any protective groups present are removed and, if desired, stereoisomer mixtures obtained are resolved, and, if desired, a compound obtained with at least one salt-forming group is transferred to a salt or a salt obtained to the free compound.

Method a) (intramolecular cyclization of a compound of formula VIII): a nucleophilic leaving group Y is in particular a hydroxy group which is esterified with suitable acids, e.g. a sulfonate, such as mesylate or tosylate, above all halogen, such as bromine or iodine, but especially chlorine.

The reaction is carried out using a base, whereby equimolar amounts of this base are preferably used.

As bases, 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.-butylate, or alkali metal carbonates or salts, especially alkali metal salts, secondary amides, e.g. 2-oxo-pyrrolidine sodium, or strongly basic ion exchangers, e.g. "Dowex 1" (including trademark), also hydrides or amides, e.g. alkali metal hydrides 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 to approx. +150°C, mainly between 0 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, which would lead to the formation of dimers etc. For this purpose, if necessary, work can be done in greater dilution.

The activation using the base can take place at the same or a different temperature than the actual cyclization reaction.

Especially when using a strong base, e.g. lithium diisopropylamide, the activation with the base ("metallation") takes place at a lower temperature (e.g. -80°C) than ring closure. In this case, e.g. Allow the reaction vessel to warm up slowly after metallization has been completed. When choosing a solvent, consideration must also be given to the nature of the base used. The reaction using alkali metal hydroxides is preferably carried out in dimethyl sulphoxide 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,

when 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 substances with formula VIII can be prepared according to i

and known methods, e.g. by acylation of the free amino group in a peptide amide of the formula XXIII,

where the substituents have the above-mentioned meanings, under the condition that free, functional groups present therein are, if desired, in protected form, with an acid chloride of the formula XXIV,

where Y and Z have the meanings mentioned above, e.g. Y stands for chlorine, under the condition that free, functional groups present in the residue Z are optionally protected with easily removable protective groups, and subsequent removal of the protective groups.

Process b) (intramolecular cyclization of a compound of formula IX): Activated carboxylic acid derivatives of a compound of formula IX are primarily reactive, activated esters or reactive anhydrides, further reactive cyclic amides. Thereby, reactive derivatives of acids with formula IX can also be formed in situ.

Activated esters of acids are especially esters which are unsaturated at the connecting carbon atom of the esterifying residue, e.g. of the vinyl ester type, as actual vinyl esters (which can for example be obtained by transesterification of a corresponding ester with vinyl acetate. The method for the activated vinyl ester) > carbamoyl vinyl ester (which can for example be obtained by treating the corresponding acid with es isoxazolium reagent; 1,2 -oxazolium or the Woodvard method), or 1-lower alkoxy-vinyl esters (which can for example be obtained by treating the corresponding acid with a lower alkoxyacetylene; the ethoxy-acetylene method), or esters of the amidino type, such as N,N'- disubstituted amidino esters (which can, for example, be obtained by treating the corresponding acid with a suitable, large N,N<1->disubstituted carbodiimide, e.g. N,N<1->dicyclohexyl carbodiimide. The carbodiimide method), or N, N-disubstituted amidino esters (which can for example be obtained by treating the corresponding acid with a large N,N-disubstituted cyanamide; the cyanamide method), suitable aryl esters, especially phenyl esters which are suitably substituted with electron-withdrawing substituents ent (which can, for example, be obtained by treating the corresponding acid with a suitable substituted phenol, e.g. 4-nitrophenyl, 4-methylsulphonyl phenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol,

in the presence of a condensing agent, such as N,N'-dicyclohexylcarbodiimide; the activated aryl ester method), cyanomethyl esters which can for example be obtained by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester method), thioesters, especially phenyl thioesters which are optionally substituted, e.g. with nitro, (which can, for example, be obtained 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. The activated thiol ester method), amino- or amido esters (which can, for example, be obtained 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; the activated N-hydroxy-ester method) or silyl esters (which can for example be obtained by treating the corresponding acid with a silylating agent, e.g. . hexamethyldisilazane).

Anhydrides of acids with formula IX can be symmetrical or preferably mixed anhydrides of these acids, thus e.g. anhydrides with organic acids, such as acid halides, especially acid chlorides (which can for example be obtained by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride. Acid chloride method), azides

(which can for example be obtained from a corresponding acid ester over the corresponding hydrazide and its treatment with nitrous oxide; the azide method), anhydrides with carbonic acid half-derivatives, which with corresponding esters, e.g. carbonic acid lower alkyl half-esters (which can, for example, be obtained by treating the corresponding acid with halogen-, such as chloroformic acid-lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower-alkoxy-1,2-dihydro-quinoline, e.g. 1 -lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; the mixed O-alkyl carbonic anhydride method), or anhydrides with dihalogenated, especially dichlorinated phosphoric acid (which can for example be obtained by treating the corresponding acid with phosphorus oxychloride; the phosphorus oxychloride method ), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (which can for example be obtained by treating the corresponding acid with an optionally substituted lower alkane or phenyl-alkane carboxylic acid halide, e.g. phenylacetic acid, pivalic acid or trifluoroacetic acid chloride; the the mixed carboxylic acid anhydride method (or with organic sulphonic acids) which can for example be obtained 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. methane or p-toluenesulfonic acid chloride. The mixed sulfonic anhydride method), as well as symmetrical anhydrides (which can for example be obtained by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne; the symmetrical anhydride method).

Suitable cyclic amides are in particular amides with 5-membered thiazaries of an aromatic character, such as amides with imidazoles, e.g. imidazole (which can for example be obtained by treating the corresponding acid with N,N'-carbonyldiimidazole; the imidazolide method), or pyrazoles, e.g. 3,5-dimethyl-pyrazole (which, for example, can be obtained over the acid hydrazide by treatment with acetylacetone; the pyrazolid method).

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

Protective groups of possibly present functional groups are e.g. the above-mentioned protective groups.

The cyclization reaction can be carried out in a manner known per se, whereby 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 of such, and whether necessary, in the presence of a condensing agent, such as, for example, when the carboxyl group that participates in the reaction is present as an anhydride, can also be an acid binding agent, during cooling or heating, e.g. in a temperature range from approx. -30 to approx. +200°C, in a closed reaction vessel and/or in an inert gas atmosphere, e.g. nitrogen.

In general, the reaction conditions can be chosen such that the intramolecularly proceeding cyclization reaction is favored over intermolecular reactions of the same reaction type, which would lead to the formation of dimers or the like.

For this purpose, it can e.g. when necessary, work in greater dilution.

The reaction can e.g. is carried out by a connection

19

with the formula IX, where R means an unactivated carboxyl group, and the other residues which are possibly present in protected form have the above-mentioned meanings, possibly in the presence of a water-extending agent, e.g. an N,N'-disubstituted carbodiimide, such as dicyclohexylcarbodiimide, and optionally additionally in the presence of a large N-hydroxy-amine or N-hydroxy-

amide, e.g. N-hydroxy-succinimide, is heated in an anhydrous, inert solvent, e.g. to 50-180°C.

19

Compounds of formula IX, where R 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. It is preferably started with such activated carboxylic acid compounds of formula IX, where the amino group neighboring the residue Z is in a protected form, and the amino group is released

then in situ, whereupon the ring closure occurs.

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

19 The compounds of formula IX, where the carboxyl group R fore-19

lies in protected form, i.e. as residue R , e.g. like 2-

a

trimethylsilyl-ethyl-carbonyl, can e.g. is produced by N-alkylation of a compound of formula XXIII or a suitable derivative thereof, e.g. an azomethine or alkali metal salt of a benzenesulfonamide, with a compound of formula

XXV,

19

where R means a protected carboxyl group and Z and Y have

a

the above meanings.

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

A reactive form of a compound of formula X

is in particular a metal compound, primarily an alkali metal compound, e.g. a sodium, potassium or lithium compound of the same, which can for example be produced by the action 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, 1-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 above all 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 and +150°C and in a similar way as in method a) or e).

The starting compounds of formula XI are available by acylation of a compound of formula XXIII, where q and r are both 1, with an acylating agent of formula XXVI,

where Y and R"*" have the above-mentioned meaning, under the condition that free, functional groups present in the residue'R"<*>", if necessary, are present in protected form, and if desired, subsequent removal of the protective groups. The starting compounds of formula X are known or can be obtained e.g. by cyclization of a compound of formula XXVII or an activated carboxylic acid derivative thereof,

where Z has the above-mentioned meaning, under the condition that free, functional groups present there are, if necessary, protected, analogous to procedure b) and split-

ning of the protective groups.

The cyclization of a free acid of formula XXVII succeeds in many cases by heating to 200-250°C without solvent and bubble tube distillation.

Method d) (linking of a peptide - or ester bond): Reactive carboxylic acid derivatives of a compound of formula XII are reactive esters, anhydrides or amides analogous to those mentioned in method d).

As mentioned under b), derivatives of acids with the formula XII can also be formed in situ. Thus, for example, N,N<1->disubstituted amidinoesters can be formed in situ, the mixture of the starting material with formula XIII and the acid with formula XII being reacted in the presence of a suitable, large N,N'-disubstituted carbodiimide, e.g. e.g. N,N'-dicyclohexyl carbodiimide. Furthermore, amino or amido esters of acids of formula XII can be formed in the presence of the starting material of formula XIII to be acylated, the mixture of the corresponding acid and amino starting materials being reacted in the presence of an N,N'-disubstituted carbodiimide , e.g. N,N'-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 the compound of formula XIII, where the amino group that participates in the reaction is present in a reactive form, can e.g. produced by reaction with a phosphite, e.g. one of those mentioned in procedure b). A reactive form of a compound of formula XIII is e.g. also a carbamic acid halide or an isocyanate, whereby the amino group in a compound of formula XIII that participates in the reaction is bound to halogencarbony1, e.g. chloro-carbonyl, respectively exists as an isocyanato group, where in the latter case only compounds of formula I are available, which have a hydrogen atom at the nitrogen atom in the amide group formed by the reaction. A further reactive form of a compound of formula XIII, where r stands for 0, is e.g. a urea with formula

XXVIII,

12 13

where R and R have the above meanings, or dimethylformamide when R and R 13 mean methyl.

For example, the compounds of formula I are obtained in good yield by heating equimolar amounts of such urea substances and the free acids of formula XII.

The acylation of a compound of formula XIII or a reactive derivative thereof with a compound of formula XII or a reactive acid derivative thereof can be carried out in a manner known per se, whereby the reaction conditions primarily depend on the nature of the acylating agent used, usually 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, possibly also an acid-binding agent, during cooling or heating, e.g. in a temperature range from approx. -30 to approx. +150°C,

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

The starting substances with the formulas XII and XIII are known or

can be produced using methods known per se, e.g. analogous to the methods described in this application.

Method d) also includes the embodiment, where first a carboxylic acid of formula XII, where n and p stand for 1, is reacted with a compound of formula XIII, where r stands for 0, forming an ammonium salt of the carboxylic acid of formula XII, and the ammonium salt obtained in this way or in another way is thermally dehydrated to form a compound of formula I, e.g. analogous to the method described in GB-PS 1,309,692.

Method e) (N-alkylation of a compound of formula

I) :

An alkylating agent which introduces the residues R^, R<4>, R^, R^,

10 12 13

R , R or R , is particularly a compound, wherein a

of these residues is bound to the above-mentioned nucleophilic leaving group Y.

The compound of formula I is usually first brought into a reactive form by means of a base. Preferably, equimolar amounts of base are used, e.g. one of the bases mentioned in method a). As a rule, it is unnecessary, but stronger bases can also be used, e.g. metal hydrocarbyl compounds, such as alkali metal lower alkyl compounds, e.g. butyllithium, or the activation can be carried out with the aid of weaker bases under phase transfer conditions or in the presence of suitable complex formers for the base cation, such as throne ethers, e.g. 18-krona-6.

The reaction is preferably carried out in an inert, organic solvent, if desired or necessary, during cooling or heating, e.g. in a temperature range from approx.

-80 to approx. +150°C, mainly between 0 and 100°C.

When choosing a solvent, special consideration must be given to the nature of the base used. Reactions using alkali metal hydroxides are preferably carried out in dimethylsulfoxide or in alcohols, such as lower alkanols, e.g. anhydrous ethanol with a 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. Alkylation reactions using e.g. 2-oxo-pyrrolidine sodium can i.a. is carried out in a mixture of a cyclic ether and an aromatic hydrocarbon, e.g. a dioxane-toluene mixture

ing, at a temperature between room temperature and 60°C. The actual alkylation reaction can take place at the same or a different temperature than the activation with the base. Speci-

or when using very strong bases, such as lithium diisopropylamide or butyllithium, the activation of the starting compound of formula I with the base ("metalation") takes place at a lower temperature (e.g. -80°C) than the actual alkyler -

Eng. In this case, the alkylating agent can be added to the reaction pair only after metallization has been completed and allowed to heat up slowly. Such metallization reactions with very strong bases are carried out in an inert, aprotic solvent and under protective gas, for example in a hydrocarbon, e.g. hexane, benzene, toluene or xylene,

a weakly polar ether, e.g. diethyl ether, tetrahydrofuran or dioxane, or an acid amide, e.g. hexamethylphosphorus

acid triamide, or mixtures thereof. The reaction temperature is between approx. -80° and approx. room temperature, mainly depending on the melting point of the solvent or solvent mixture and on the reactivity of the metallization reagent in the chosen solvent, but also on the solubility and reactivity of the substrate.

The amide group -CO-NH- in a compound of formula I, which does not

is to be alkylated, can be protected in a manner known per se,

e.g. in the form of N-diphenyl-methyl derivatives or an N-methoxy-benzyl derivative, e.g. a 2,4-dimethoxy or 2,4,6-tri-methoxy-benzyl deriv.

Further details for the implementation of metallization

and alkylation reactions, which are analogous to those above

described, are e.g. described in Houben-Weyl, Methoden der Organischen Chemie, Volume XIII/I, Thieme Verlag, Stuttgart 1970.

Method f) (reduction of a keto group in the residue Z): Such regioselective reducing agents can be used, which under the reaction conditions reduce an isolated keto group sufficiently faster than amide groups.

In the first place, mention must be made of many borohydrides, such as alkali metal borohydrides, especially sodium borohydride, lithium borohydride or sodium cyanoborohydride, or some aluminum hydrides, which are sterically hindered alkali metal lower alkoxy aluminum hydrides, e.g. lithium-tris-tert.butoxy-aluminum hydride.

The reduction can also be carried out with hydrogen in the presence

of certain heavy metal catalysts, e.g. Raney nickel, platinum or palladium catalysts, or after Meerwein-Ponndorf-Verley by means of aluminum alkanolates, preferably aluminum 2-propanolate or -ethanolate.

The reduction is preferably carried out with stoichiometric amounts or, when due to unwanted side reactions, e.g. with the solvent, is necessary, with an accurately measured excess of the reducing agent in an inert solvent at temperatures between -80 and +180°C, preferably between -20 and +100°C, if necessary, under protective gas, e.g. argon.

The starting compounds can be produced using methods known per se, e.g. those described in this application. Thereby, the 2,3- or 2,4-dioxo-pyrrolidine ring can e.g. is produced by a Dieckmann condensation starting from a compound of formula XXXI, respectively XXXII,

20 where R means a residue with the formula XXXIII

or a suitable, completed part thereof, and all other substituents have the above meanings.

When R"*"4 and R"*"^ stand for hydrogen, a suitable fully formed part of a residue of formula XXXIII is preferably ethoxycarbonylmethyl.

Method g) (transfer of a cyano group to amide): The transfer can take place by partial hydrolysis, as a Graf-Ritter reaction or via the carboxylic acid ester imide salt. The conditions for the hydrolysis of a compound of formula XVII must be chosen so that the reaction can be stopped at the amide stage and that the free carboxylic acid is not formed. For this purpose, the hydrolysis with acids is generally best suited, whereby it depends on the substituents present in a compound of formula XVIII can be chosen between 80% sulfuric acid (under heating), polyphosphoric acid (at 110-150°C), hydrogen bromide /glacial vinegar (room temperature), formic acid (without solvent), chlorine hydrogen gas in ether solution followed by the addition of water or aqueous hydrochloric acid, or boron halides/

1 equivalent of water.

Preferably, an ion exchange resin is used, e.g.

Lewatite ® M 504 (comp. DE-off.skrift 2.507.576) or Amberlite ® IRA-400.

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

Using the Graf-Ritter reaction, it is possible to prepare N-substituted amides from nitriles with the formula XVII.

To achieve this, the nitriles are reacted in the presence of a strong acid, preferably 85-90% sulfuric acid, or also polyphosphoric acid, formic acid, boron trifluoride or other Lewis acids,

however not aluminum chloride, with compounds which can form carbenium ions in the acidic medium, i.e. e.g. with olefins or alcohols.

Instead of using a strong acid, it can also be catalysed with mercury(II) nitrate and then reduced with sodium borohydride.

Carboxylic acid ester imides are obtained, e.g. by acid-catalyzed addition of alcohols to the nitriles. From the ester imides, the amides are obtained by means of a Pinner cleavage.

Nitriles with formula XVII can, for example, be prepared by

a Kolbe synthesis from the corresponding primary halides with cyanide ions in the form of a nucleophilic substitution.

Preferably, e.g. a primary halide with copper cyanide in dioxane (cf. DE-Off.skrift 2,507,576). The primary halides are obtained, e.g. from the primary alcohols by means of thionyl chloride (cf. DE-Off.skrift 2,507,576). Preferably, nitriles of formula XVII with a terminal cyanomethylene group are obtained by reaction between a compound of formula XII, where p stands for 1 and, if n also stands for 1, A means the residue Wcl, and aminoacetonitrile, which can be obtained commercially, according to the methods described for procedure d).

Procedure h) (Beckmann rearrangement):

13 The rearrangement of compounds of formula XXII, in which R means lower alkyl, can be carried out under the known conditions of the Beckmann rearrangement, e.g. with concentrated sulfuric acid, halogen hydrogens, polyphosphoric acid, thionyl chloride, formic acid, tosyl chloride in pyridine, copper, alkali metal chlorides, iron (III) or aluminum chloride, trifluoroacetic acid or "Japanese acid earth". However, it is preferably started from oximes where R is in the trans position to the hydroxy group in the oxime grouping, and catalysts are used in this case, which cause as little isomerization as possible, such as phosphorus (V) chloride in ether or benzene at low temperature.

13 The rearrangement of compounds of formula XXII, where R be-

tyr hydrogen, is best carried out using polyphosphoric acid or boron trifluoride. In this case, the configuration of the oxime does not matter.

The oximes of formula XXII are available by means of i

and known methods, e.g. by reacting the corresponding aldehyde or ketone with hydroxylamines.

Process i) (transformations within the definition of the final compounds): The compounds of formula (I) which can be obtained according to the invention can be transferred to other compounds of formula (I)

in a manner known per se.

In the compounds of formula (I), which have at least one free hydroxyl group, this can be etherified or esterified (acylated) in a manner known per se. Free carboxy can be esterified or amidated. Free amino can be alkylated or acylated, whereby the alkylation is carried out analogously to the etherification and the acylation analogously to the esterification of a hydroxyl group.

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

Other suitable agents for etherifying 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 acid, e.g. hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, further sulfuric acid, or halosulphuric acid, e.g. fluorosulphuric acid, or strong, organic sulphonic acids, such as benzenesulphonic acids which, for example, are optionally substituted with lower alkyl, such as methyl, halogen, such as bromine, and/or nitro, e.g. methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid. Such esters are i.a. lower alkyl halides, di-lower alkyl sulfates, such as dimethyl sulfate, further fluorosulfonic acid esters, such as -lower alkyl esters, e.g. fluorosulfonic acid methyl esters, or optionally halogen-substituted methanesulfonic acid lower alkyl esters, e.g. trifluoromethane sulfonic acid methyl esters.

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. Thereby, suitable condensation agents are preferably used,

such as alkali metal carbonates or hydrogen carbonates, e.g. sodium or potassium carbonate or bicarbonate (usually together with a sulphate), or organic bases, which are usually sterically hindered tri-lower alkylamines, e.g. N,N-diisopropyl-N-ethylamine (preferably together with halogen-sulfonic acid-lower alkyl esters or optionally halogen-substituted methanesulfonic acid-lower alkyl esters), whereby it worked under cooling, at room temperature or under heating, e.g. at temperatures from approx. -20 to approx.

50°C and, if necessary, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

By phase-transfer catalysis (see, for example, Dehmlow, Angewandte Chemie, 86, 187 (1974)), the above-described etherification reaction can be significantly accelerated. Quaternary phosphonium salts and especially quaternary ammonium salts can be used as phase transfer catalysts, such as optionally substituted tetra-alkylammonium halides, e.g. tetrabutylammonium chloride, bromide or iodide, or also benzyltriethylammonium chloride, in catalytic or up to equimolar quantities. Any solvent that is not miscible with water can serve as the organic phase, for example one of the possibly halogenated, such as chlorinated, lower aliphatic, cycloaliphatic or aromatic hydrocarbons, such as tri- or tetrachloroethylene, tetrachloroethane, carbon tetrachloride, chlorobenzene, toluene or xylene . The alkali metal carbonates or

- hydrogen carbonates which are 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, for base-sensitive compounds can be added to the reaction mixture titrimetrically, e.g. using a titration machine, so that the pH value

during the treatment will lie between approx. 7 and approx. 8.5.

Other agents for etherifying a hydroxyl group or

for the etherification of a carboxyl group in a compound of formula I, are corresponding trisubstituted oxonium salts (so-called Meerwein salts), or disubstituted carbenium or halogenium salts, where the substituents are the etherifying residues, for example tri-lower alkyl oxonium salts, as well as di-lower alkoxycarbenium - or di-lower alkylhalogenium salts, especially 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 hexafluoroantimonate. These esterification 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 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 to approx. 50°C, if necessary, in a closed vessel and/or in an inert gas, e.g. nitrogen atmosphere.

Other suitable etherifying agents are finally corresponding 1-substituted 3-aryltriazen compounds, where the substituent means the etherifying residue, and aryl preferably means optionally substituted phenyl, e.g. lower alkylphenyl, such as 4-methylphenyl. Such triazene compounds are 3-aryl-1-lower alkyltriazenes, 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 inert solvents, such as optionally halogenated hydrocarbons or ethers, e.g. benzene, or solvent mixtures, and under cooling, at room temperature and preferably at an elevated temperature, e.g. at approx. 20 to approx. 100°C, if necessary, in a closed vessel 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 further, for example, take place by a compound of formula (I), where other, possibly present functional groups are possibly present in protected form, or a reactive, functional carboxy derivative, including a salt thereof, is reacted with a corresponding 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'-dipropyl-, N,N<1->dicyclohexy1- or N-ethyl-N<1->(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 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 halogenated acids, e.g. the corresponding acid halides, e.g. -chlorides or -bromides, further nitrogen-

hydrogen acids, i.e. the corresponding acid azides, as well as 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. such with organic carboxylic acids, as with lower alkane carboxylic acids, such as e.g. is substituted with halogen, such as fluorine or chlorine, e.g. pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters of carbonic acid, such as ethyl or isobutyl half-esters of carbonic acid, or with organic, especially aliphatic or aromatic sulphonic acids, e.g. p-toluenesulfonic acid.

Activated esters of a compound of formula I with at least

a carboxyl group suitable for reaction with an alcohol is e.g. esters with vinylogenic alcohols (ie enols),

as vinylogenic lower alkenols, or iminomethyl ester halides, such as dimethyliminomethyl ester chloride (prepared from the carboxylic acid and dimethylchloromethylideneiminium chloride with the formula [ (CH3 ) 2N=CHC1]®C1®), or aryl esters, such as pentachlorophenyl-, 4-nitrophenyl- or 2 ,3-dinitrophenyl esters, heteroaromatic esters, such as benztriazole-, e.g. 1-benz-triazole esters, or diacylimino 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 are 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 ethyl-diisopropylamine, or N,N-di-lower alkyl-aniline, 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 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 alcohol to be esterified is primarily a corresponding ester, preferably with a strong, inorganic or organic acid and is especially 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, whereby when using the free acid it preferably works 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 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 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 be formed in situ if desired. Thus, e.g. a mixed anhydride by treating the carboxylic acid compound with correspondingly 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 carbonic acid half-halide, e.g. chloroformic acid half-ester or isobutyl ester, or with a halide of a di-lower alkyl phosphoric acid, e.g. diethyl phosphorous bromide, and the thus obtainable mixed anhydride is used without isolation.

For esterification (acylation) of a hydroxy group in a compound of formula I, treat the starting material of formula (I) with an acylating agent which introduces the desired acyl residue of an organic carboxylic acid. Thereby, the corresponding carboxylic acid or a reactive derivative thereof is used, especially an anhydride, including a mixed or internal anhydride of such an acid. Mixed anhydrides are e.g. those with hydrohalic acids, i.e. the corresponding acid halides, specilet chlorides, further with hydrocyanic acid, or also those with suitable carbonic acid half-derivatives,

as corresponding -half-esters (such as the mixed anhydrides which, for example, are formed with a halogen-formic acid-lower alkyl,

such as chloroformic acid ethyl ester or isobutyl ester), or with optionally substituted, e.g. halogen, such as chlorine, containing lower alkane carboxylic acids (such as mixed anhydrides formed with pivalic acid chloride or trichloroacetic acid chloride). Internal anhydrides are e.g. those of organic carboxylic acids, i.e. ketenes, such as ketene or diketene, or those of carbamic or thiocarbamic acids, i.e. isocyanates or isothiocyanates. Other reactive derivatives of organic carboxylic acids which are useful as acylating agents are activated esters, which are suitably substituted lower alkyl, e.g. cyanomethyl esters, or suitably substituted phenyl-, e.g. pentachlorophenyl 1-, or 4-nitro-phenyl esters. If necessary, the esterification can 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 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. The acylation reaction can be carried out

in the absence or in the presence of a solvent or solvent mixture, during cooling, at room temperature or during heating, and if necessary, in a suitable closed vessel and/or in an inert gas, e.g. nitrogen atmosphere. Suitable solvents are e.g. optionally substituted, especially optionally chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as benzene or toluene, whereby suitable esterification reagents, such as acetic anhydride, can also be used as diluents.

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 the starting material of formula (I) with a reactive sulphonic acid derivative,

as a corresponding 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 esters with organic carboxylic acids.

In a compound of formula I, which has at least one carboxyl group or a reactive derivative thereof, this can be amidated with an amine analogous to that described in method d) for the acids of formula XII or their acid derivatives.

The starting materials which are necessary for carrying out the methods a) to i) described above are known or can be produced using methods known per se, e.g. according to or analogous to those described in this application.

Functional groups in the starting materials can be protected with

the same protective groups, as those mentioned for corresponding functional groups in the final substances with formula I in this application. The introduction and separation of these protective groups can also take place in the manner described in the cited literature references.

In an obtained compound of formula (I), where one or more functional groups are protected, these can, e.g. protected carboxyl and/or hydroxy groups are released on

in a manner known per se, by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or in some cases also by means of careful reduction, possibly stepwise or simultaneously. Silyl protecting groups are advantageously 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. Salts can thus be formed 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 hydrogen carbonate, or with ammonia or a suitable organic amine, whereby stoichiometric amounts or only a small excess of the salt-forming agent are preferably used. Acid addition salts of compounds of formula (I) with at least one basic group, e.g. a free amino group, is obtained in the usual way, e.g. by treatment with an acid or a suitable ion exchange reagent. Internal salts of compounds of formula (I), such as e.g. contains a free carboxyl group and a free amino group, can e.g. is formed by neutralization of salts, such as acid addition salts, at the isoelectric point, e.g. with weak bases, or when treated with liquid ion exchangers.

Salts can normally be transferred to the free compounds, metal and ammonium salts, e.g. by treatment with suitable acids, and acid addition salts, e.g. by treatment with a suitable basic agent.

Mixtures of isomers can in a manner known per se, e.g. by fractional crystallization, chromatography, etc., are divided

in the individual isomers.

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 such embodiments of the method, in which an obtainable compound at any step is assumed as an intermediate product, and the multi-length steps are carried out or the method is interrupted at any step or a compound that can be obtained by means of the process according to the invention, is formed under the process conditions and further processed in situ.

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

The pharmacologically usable compounds in the present invention can e.g. is used for the production of pharmaceutical preparations, which contain an effective amount of the active substance together with or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers.

As far as the pharmaceutical preparations are concerned, it matters

whether such for enteral, such as oral or rectal, as well as parenteral, such as intraperitoneal, intramuscular or intravenous, supply to warm-blooded animals, which contain the pharmacologically active substance alone or together with a pharmaceutically usable carrier material. The dosage of the active substance depends on the type of warm-blooded, body weight, age and the individual

dual condition of the disease to be treated, as well as of the method of administration.

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 doses to be administered to warm-blooded animals, e.g. people, of 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 and day, divided into up to approx. 12, preferably 2-4, e.g. 3, single doses, such as e.g. can be the same size. The dosage for enteral and parenteral application is essentially the same. The dependence of the dosage on body weight is not linear, but rather weakly pronounced, so that the above-mentioned dosage can also be used with a lower or higher body weight than 70 kg, e.g. 35 kg and 100 kg respectively. However, children usually receive half the growing dose.

The new pharmaceutical preparations contain a significant 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 substance. Pharmaceutical preparations can e.g. present in dosage unit form, such as dragees, tablets, capsules, suppositories or ampoules.

The pharmaceutical preparations 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 substance with solid carriers, a resulting mixture possibly being granulated and the mixture or the granulate, if desired or necessary after the addition of suitable excipients, processed to

tablets or dragé cores. Thereby, they can also be built into plastic carriers, which release the active substances in dosed form

or allows them to diffuse.

Suitable carriers are especially 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,

as starch pastes using e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or, if desired, explosives, 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 control and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof,

such as magnesium or calcium stearate, and/or polyethylene glycol. Dragé cores are equipped with suitable, possibly gastric juice-resistant covers, whereby it i.a. concentrated sugar solutions are used, which possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solutions in suitable organic solvents or solvent 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 have dyes or pigments added, e.g. for identification or to characterize different doses of the active substances.

The preparation of the injection preparations takes place in the usual way under anti-microbial conditions, as does the filling in ampoules or vials, as well as the closing of the containers.

For the preparation of the injection preparations, solutions of the active substances are preferably used, also suspensions, and especially isotonic, aqueous solutions or suspensions, whereby these e.g. in the case of lyophilized preparations, which contain 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 contain excipients, e.g. preservatives, stabilisers, cross-linking and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffers, and are produced in a manner known per se, e.g. using conventional solution or lyophilization methods. The aforementioned solutions or suspensions may contain viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

The following examples serve to illustrate the invention. Temperatures are given in °C, R^ values are determined, unless otherwise stated, on silica gel thin-layer plates (Merck, Darm-stadt, Germany).

Example 1.

36 g (0.088 mol) 2-(4-hydroxy-2-oxo-1-pyrrolidinyl)-acetic acid pentachlorophenyl ester and 14.7 g (0.088 mol) glycyl glycinamide hydrochloride are stirred into 250 ml of dimethylformamide and 13 ml (0.088 moles) of triethylamine. The suspension is stirred for 20 hours at room temperature and then suctioned off. The clear filtrate is stirred with 1.5 liters of ethyl ether, whereupon an oil precipitates, which crystallizes after stirring for 1 hour. The crystals are suctioned off, dissolved in 100 ml of water and then placed on a column with 400 g of "Amberlite" IR 120 (H+<-> form, strongly acidic cation exchanger). The aqueous eluate is evaporated on a rotary evaporator (60°/12 min.) The semi-solid residue is dissolved in 300

ml of hot ethanol, filtered and allowed to crystallize in an ice bath.

The crude product with a melting point of 133-9° is crystallized once more from ethanol, filtered off with suction and dried in a desiccator at 120°/

12 Torr, whereupon N-[(4-hydroxy-2-oxo-1-pyrrolidinyl)-acetyl]-glycy1-glycinamide with m.p. 138-141°C.

The ester used as starting product is obtained in the following way: 4.0 g (0.034 mol) of 4-amino-3-hydroxybutyric acid is melted at 200-250°C. The mixture is distilled at 180°C/0.02 Torr in a ball tube.

The distillate is dissolved in hot ethanol, cooled and ethyl ether is added. The obtained crystals of 4-hydroxy-2-oxo-pyrrolidine are suctioned off and washed with ethyl ether, after which they melt at 118-120°C.

1.0 g (0.01 mol) 4-hydroxy-2-oxo-pyrrolidine and 1.1 g (0.015 mol) ethyl vinyl ether in 6 ml chloroform are stirred at room temperature. A small spatula tip (approx. 30 mg) of trichloroacetic acid is added to this suspension. The suspension is heated for 10 minutes at 50°C, after which a clear solution is formed, which is stirred at room temperature for 18 hours.

The reaction mixture is extracted with 10 ml of saturated aqueous sodium bicarbonate solution. The chloroform phase is washed with saturated, aqueous sodium chloride solution, dried over sodium sulfate, evaporated and distilled in a bubble tube, whereupon 4-(1-ethoxyethoxy)-2-oxo-pyrrolidine is obtained as a clear, colorless oil with R^= 0.40 (Toluene :ethanol = 8:2, silica gel).

1.1 g (0.0064 mol) 4-(1-ethoxy-ethoxy)-2-oxo-pyrrolidine in 10 ml toluene and 0.3 g of a 50% suspension of sodium hydride in mineral oil, stirred for 1 hour at room temperature .

Then it is added drop by drop while cooling in an ice bath and stirring in the barrel

of 10 minutes a solution of 2.5 g (0.0064 mol) bromoacetic acid pentachlorophenyl ester in 5 ml of toluene. The reaction mixture is stirred for 18 hours at room temperature. The brownish suspension is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and

is evaporated at 65°/12 Torr, after which a viscous oil is obtained, which is added to 20 ml of methanol and filtered.

The filtrate containing 2-[4-(1-ethoxy-ethoxy)-2-oxo-1-pyrrolidinyl]-acetic acid pentachlorophenyl ester is added to 0.2

g p-toluenesulfonic acid monohydrate and let stand for 30 minutes at room temperature. It is then evaporated and the solid obtained is boiled with hexane to free it from mineral oil. The part which is insoluble in hexane is recrystallized from ethyl acetate, after which 2-(4-hydroxy-2-oxo-1-pyrrolidinyl)-acetic acid pentachlorophenyl ester with m.p. 182-186°C is achieved.

The bromoacetic acid ester used is obtained in the following way:

14.0 g (0.1 mol) of bromoacetic acid and 32 g (0.12 mol) of pentachlorophenol are dissolved in 250 ml of absolute tetrahydrofuran. The yellowish solution is stirred in an ice bath and a solution of 22.7 g (0.11 mol) of dicyclohexylcarbodiimide in 75 ml of absolute tetrahydrofuran is added dropwise, whereby the temperature is kept below 10°. Then stir for another 1 hour in an ice bath and 2 hours at room temperature.

The precipitated dicyclohexylurea is suctioned off, and the filtrate is evaporated at 60°/12 Torr. The residue is dissolved in 500 ml of ethyl ether and filtered. The clear filtrate is extracted with 50 ml of cold IN sodium hydroxide solution, washed with sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The solid residue is recrystallized from hexane, whereupon bromoacetic acid pentachlorophenyl ester with m.p. 113-115°C.

Example 2.

9.0 g (0.04 mol) glycyl-glycyl-glycinamide hydrochloride and

9.6 g (0.04 mol) of 2-(2-oxo-1-pyrrolidinyl)-acetic acid-N-hydroxy-succinimide ester are stirred into 400 ml of absolute DMF

and 1 ml of triethylamine is added. The reaction mixture is stirred at room temperature for 24 hours. The largest part of DMF is distilled off on a rotary evaporator at 12 Torr and 70°. The remainder is added to absolute ethanol and suctioned off. The product obtained is dissolved in 100 ml of water to remove triethylammonium chloride and washed through a column with 60 ml of "Amberlite" IR-120 (strongly acidic cation exchanger, H+<-> form). The aqueous eluate is evaporated on a rotary evaporator, dissolved in 20-

22 ml of water, add 100 ml of ethanol and place in a refrigerator (5°). The formed colorless crystals of N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycyl-glycinamide have a melting point of 230-232° after suction and removal of the solvent at 80°/13 Torr.

The starting products used are obtained as follows:

A solution of 14 g (0.08 mol) of N-tert-butyloxycarbonyl-1-glycine (obtained from the company Fluka) in 240 ml of DMF is first added to 22 ml (0.16 mol) of triethylamine, then 10.4 ml (0. 08 mol) chloroformate isobutyl ester. After stirring for 30 minutes at room temperature, 13.4 g (0.08 mol) of solid glycyl-glycyl-glycinamide hydrochloride and 10.4 ml (0.08 mol) of triethylamine are added and the mixture is stirred for 18 hours at room temperature. The solution is deacidified with 6N alcoholic hydrochloric acid until the color of the indicator turns Congo red and it is evaporated on a rotary evaporator at 60°/12 Torr. The residue is boiled in 300 ml of ethanol and the solid contained therein is suctioned off. This solid is dissolved in 400 ml of water, the solution is filtered, diluted with 1000 ml of ethanol and placed in a refrigerator. The separated crystals of glycy1-glycyl-glycinamine hydrochloride have, after suction and removal of the solvent at 100°/12 Torr, a m.p. at 240-243°.

To a suspension of 25.6 g (0.18 mol) 2-(2-oxo-1-pyrrolidinyl)-acetic acid and 20.6 g (0.18 mol) N-hydroxysuccinimide in 450 ml dioxane, 37.6 g are stirred (0.18 mol) of dicyclohexylcarbodiimide in portions while cooling with ice water. It is then stirred for 18 hours at room temperature and the precipitated dicyclohexylurea is suctioned off. The filtrate is evaporated on a rotary evaporator at 60°/12 Torr. The residue is crystallized from ethyl acetate/diethyl ether. The obtained 2-(2-oxo-1-pyrrolidinyl)-acetic acid-N-hydroxy-succinimide ester melts at 128-130°.

Example 3.

6.6 g (0.02 mol) 2-(4-[4-fluorophenyl]-2-oxo-1-pyrrolidinyl)-acetic acid-N-hydroxysuccinimide ester and 3.35 g (0.02 mol) glycyl-glycinamide- hydrochloride is stirred into 400 ml of absolute DMF, after which 6.11 ml of triethylamine is added during

of 10 minutes while stirring. The suspension is stirred for 20 hours at room temperature and then evaporated in a vacuum (water jet pump). The yellowish, solid residue is stirred with 200 ml of water, cooled in an ice water bath and suctioned off. The still moist, colorless filter residue is dissolved in 140 ml of water at 90°. The solution is filtered and placed in an ice bath, whereupon N-{.(4-[4-fluoro-phenyl]-2-oxo-1-pyrrolidinyl)-acetyl-glycyl-glycinamide with a melting point of 200-202° crystallizes out.

The starting materials used are obtained as follows: In a solution of 35.6 g (0.15 mol) 2-(4-[4-fluorophenyl]-2-oxo-1-pyrrolidinyl)-acetic acid and 17.25 g (0. 15 mol) of N-hydroxysuccinimide in 570 ml of dioxane is stirred in portions

in the course of 10 minutes 31.5 g of dicyclohexylcarbodiimide, whereby the reaction temperature is kept below 30° by cooling with ice water. After stirring for 18 hours at room temperature, the obtained dicyclohexylurea is filtered off with suction and the clear filtrate is evaporated to dryness. The oil-active residue is taken up in 200 ml of ethyl acetate and hexane is added until the solution becomes cloudy, whereupon colorless 4-(4-fluorophenyl)-2-oxo-pyrrolidinyl-acetic acid-N-hydroxysuccinimide ester with melting point 120-123° crystallizes out.

Example 4.

To a solution of 4.9 g (0.031 mol) of 5-methyl-2-oxo-pyrrolidinyl-acetic acid in 75 ml of DMF (purissimum), 4.4 ml of triethylamine is added while stirring at 10°. It cools to -

15° and 4.23 g (0.031 mol) chloroformic acid isobutyl ester is added dropwise while stirring. After stirring for 20 minutes, 5.2 g (0.034 mol) glycy1-glycinamide hydrochloride and then 4.4 ml (0.035 mol) triethylamine are first added at -10°. It is stirred for 1 hour at 0-5° and 22 hours at 20°, whereby a suspension is formed. The reaction solution is diluted with 250 ml of ether and the crystalline crude product is filtered off with suction,

which is then stirred into 120 ml of absolute ethanol, to wash out triethylammonium chloride. It is filtered off with suction, washed with diethyl ether, the filter residue is dissolved in 200 ml of methanol in the heat, the previously filtered solution is evaporated to 50 ml, filtered off, washed with ethanol and ether and the filter residue obtained as N-[(5-methyl-2-oxo- 1-pyrrolidinyl)-acetyl]-glycyl-glycinamide with m.p. 197-198° is dried.

Example 5.

Dissolve 6.0 g (0.042 mol) of 2-oxo-pyrrolidine-1-acetic acid and 5.3 ml (0.042 mol) of N-ethylmorpholine in 100 ml of dimethylformamide and add at -15° 5.5 ml (0.042 mol) of chloroformic acid isobutyl ester. After 10 minutes at -15°, a solution of 7.8 g (0.051 mol) glycyl-alaminconide hydrochloride and 5.3 ml of N-ethylmorpholine in 200 ml of dimethylformamide is added dropwise in such a way that the temperature does not exceed -10° .

After a further 1 hour at -10° and 10 hours at 20°, the reaction mixture is evaporated, the residue is taken up in water and passed through a column of strongly basic ion exchanger (in free form, i.e. with free dialkylamino groups (Merck III). The eluate is evaporated and the residue is recrystallized from methanol-ether, whereupon N-[(2-oxo-1-pyrrolidiny1)-acetyl]-glycyl-(L)-alanine amide is obtained with m.p. 196-198° [a] = -22° (c = 1.204 , water) and R f = 0.40 (eluent system A, i.e. n-butanol/pyridine/acetic acid/water = 42/24/4/30).

Analogues are obtained:

N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-(D)-alanamide

with m.p. 195-196°, "[a = +24 (c = 0.873 , water) and Rf = 0.40 ('system A) ,

N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-(L)-alanine-N-ethyl-amide with m.p. 195-196°, [a] 2 0= -35° (c = 0.858, water) and Rf = 0.48 /system A),

N-[(2-oxo-1-pyrrolidinyl)-acetyl J-glycyl-(D)-alanine-N-ethyl-amide with m.p. 202-203°, [a] 2 0= +38° (c = 0.916, water) and Rf = 0.48 ('system A), as well as

N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-(L)-alanine-N,N-diethyl-amide and

N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-(D)-alanine-N,N-diethyl-amide, both as oil and with R^ = 0.52 /system A).

The peptide glycyl-(L)-alanine amide hydrochloride used

as starting substance, is obtained in the following way:

To 13.51 g (0.065 mol) N-benzyloxycarbonylglycine, 8.0

g (0.0645 mol) alaninamide hydrochloride and 8.15 ml (0.068

mol) of N-ethylmorpholine in 200 ml of dimethylformamide is added at 0° 14.65 g (0.071 mol) of dicyclohexylcarbodiimide and 10.88

g (0.08 mol) of 1-hydroxybenzotriazole. After 15 hours at 20° it is filtered, the filtrate is evaporated, the residue is taken up in ethyl acetate and this solution is washed with 0.5N aqueous citric acid solution, 0.5N aqueous sodium bicarbonate solution and water, the organic phase is dried over sodium sulfate and evaporated. After recrystallization of the residue from methanol/ether, N-benzyloxycarbonyl-glycyl-(L)-alanine amide is obtained with m.p. 181-182° and [o]^°= -10° (c = 0.781 methanol).

Analogously, this is achieved:

N-benzyloxycarbonyl-glycyl-(D)-alanine amide with m.p. 182-

2 0

183° and [a] = +12° (c = 1.283, methanol),

N-benzyloxycarbonyl-gylcyl-(L)-alanine-N-ethylamide with m.p.

2 n

134-136° and [a] = -27° (c = 1.126, methanol),

N-benzyloxycarbonyl-gylcyl-(D)-alanine-N-ethylamide with m.p.

2 0

138-140° and [a] = +29° (c = 0.896, methanol),

N-benzyloxycarbonyl 1-gylcyl - (L)-alanine-N, N-die ty lami d me^d m.p. 92-93° and [a] 2 0= -9° (c = 1.627, chloroform) as well as

N-benzyloxycarbonyl-glyely-(D)-alanine-N,N-diethylamide with m.p. 90-92° and = +9° (c = 1.724, chloroform).

A solution of 11.7 g (0.042 mol) of N-berzyloxycarbonyl-glycyl-alanine amide in 400 ml of methanol and 41.9 ml of 1.0N hydrochloric acid is hydrated in the presence of 1.2 g of palladium charcoal, (10% Pd) at 22 °/840 Torr, whereby the CO^ that arises is absorbed in a second hydration vessel with IN, aqueous potassium hydroxide solution. After completion of hydrogen uptake (approx. 40 minutes), the catalyst is filtered off and the filtrate is evaporated.

In an analogous way, the benzyloxycarbonyl protecting group in the other above-mentioned peptides is cleaved off.

The obtained glycyl-alanine amine hydrochlorides are used directly for the reaction described at the beginning of this: example.

Example 6.

4.4 g (0.011 mol) 4-(4-chlorophenoxy)-phenyl-2-oxo-pyrrolidinyl-acetic acid-N-hydroxy-succinimide ester and 1.7 g (0.01 mol) glycyl-glycinamide hydrochloride in 100 ml DMF is added to 2.8 ml of triethylamine and stirred for 20 hours at room temperature. The solid residue that remains after evaporation on a rotary evaporator is stirred with 500 ml of water, sucked off and washed with 10 ml of water. The solid filter residue, which melts after drying at 204-208°, is boiled in 200 ml of water, allowed to stand at room temperature for 3 hours, suctioned off and dried.

The obtained N-{(4-[4-chlorophenoxy]-phenyl-2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycinamide melts at 211-213°.

The succinimide ester used as starting substance is obtained in the following way: 38.5 g (0.111 mol) 4-(4-chlorophenoxy)-phenyl-2-oxo-pyrrolidinyl-acetic acid 12.7 g (0.111 mol) N-hydroxy-succinimide and 25.1 g (0.122 mol) of dicyclohexylcarbodiimide in 1500 ml of dioxane are stirred for 20 hours at room temperature. The dicyclohexylurea formed is suctioned off and the filtrate is evaporated to dryness. The amorphous solid residue is crystallized from ethyl acetate-diethyl ether. After suction and drying, 4-(4-chlorophenoxy)-phenyl-2-oxo-pyrrolidinyl-acetic acid-N-hydroxy-succinimide ester with m.p. 132-134°.

Example 7.

7.2 (0.027 mol) 2-(5,5-dimethyl-2-oxo-1-pyrrolidinyl)-acetic acid-(2,5-dioxo-1-pyrrolidinyl)-ester, 4.5 g (0.027 mol) glycyl -glycinamide hydrochloride and 7 ml of triethylamine are stirred in 90 ml of absolute dimethylformamide for 48 hours at room temperature.

The precipitated triethylamine hydrochloride is suctioned off and the filtrate is evaporated to dryness at 70°/14 Torr. The residue which precipitates as a viscous oil is chromatographed over 200 g of silica gel 6C (Merck A.G.) The desired substance is eluted with methanol, the eluate is evaporated and crystallized from ethanol-ether, whereupon N-[(5,5-dimethyl-2-oxo -1-pyrrolidinyl)-acetyl]-glycyl-glycinamide with m.p. 138-140°.

The succinimide ester used as starting product is obtained in the following way: 27.8 g (0.162 mol) 2-(5,5-dimethyl-2-oxo-1-pyrrolidinyl)-acetic acid and 18.6 g (0.162 mol) N- hydroxysuccinimide is dissolved in 400 ml of dioxane and 34 g (0.162 mol) of N,N'-dicyclohexylcarbodiimide are added in portions. Temperatures are kept at 27-30°. After stirring for 20 hours at room temperature, the obtained dicyclohexylurea is filtered off with suction. The filtrate is evaporated at 60°/14 Torr. The yellow, viscous oil which is obtained as a residue is dissolved in 100 ml. ethyl acetate and 100 ml of ether are added. In an ice bath, 2-(5,5-dimethyl-2-oxo-1-pyrrolidinyl)-acetic acid-(2,5-dioxo-1-pyrrolidinyl)-ester crystallizes with m.p. 100-105°.

The starting material is obtained in the following way:

53.2 g (0.287 mol) of 2-(5,5-dimethyl-2-oxo-1-pyrrolidinyl)-acetic acid ethyl ester are boiled with 19 g (0.287 mol) of 85% aqueous potassium hydroxide solution in 300 ml of methanol for 2 hours under backflow. The reaction mixture is evaporated to dryness at 60°/14 Torr. The residue is dissolved in 500 ml of water, adjusted to pH 4 with concentrated hydrochloric acid and evaporated. The residue is stirred in 200 ml of ethanol. It is filtered off and the filtrate is evaporated to dryness, dissolved in 100 ml of ethanol and diluted with 400 ml of ether. On standing in an ice bath, 2-(5,5-dimethyl-2-oxo-1-pyrrolidinyl)-acetic acid crystallizes with m.p. 128-130°.

The starting material is obtained in the following way:

A sodium methanolate solution is prepared from 11.5 g (0.5 gram atoms) of sodium with 350 ml of methanol. 56.5 g (0.5 mol) of 5,5-dimethyl-2-pyrrolidone (Org. Synthesis IV, 357 (1963)) are stirred into this solution. After 3 hours, the reaction mixture is evaporated to dryness. The dry sodium salt of pyrrolidone is suspended in 250 ml of toluene and 53 ml of bromoacetic acid methyl ester in 50 ml of toluene is added dropwise. The suspension is stirred at room temperature for 20 hours.

The reaction mixture is extracted with 200 ml of water. The organic layer is dried over sodium sulphate, filtered and evaporated. The remainder is fractionated in high vacuum. The fraction with boiling point 104°/0.005 Torr consists of 2-(5,5-dimethyl-2-oxo-1-pyrrolidinyl)-acetic acid ethyl ester.

Example 8.

A mixture of 14.6 g (0.04 mol) of 2-[4-(1-naphthyl)-2-oxo-l-pyrrolidinyl]-acetic acid-(2,5-dioxo-l-pyrrolidinyl)-ester, 6 .7 g (0.04 mol) of glycyl glycinamide hydrochloride and 8.1 g (11 ml) of triethylamine in 150 ml of dimethylformamide are stirred at 50°C for 20 hours. The largest part of the formed triethylamine hydrochloride is suctioned off. The clear filtrate is evaporated at 70°/14 Torr. The oily residue is stirred into 50 ml of water and allowed to stand for 20 hours at 5°C. The crystalline precipitate is filtered off and recrystallized 3 times from dimethylformamide/ether, after which N-[[4-(1-naphthyl)-2-oxo-1-pyrrolidinyl]-acetyl}-glycly-glycinamide with m.p. 206-208° is obtained.

The succinimide ester used as starting product is obtained

in the following way:

A mixture of 11.5 g (0.043 mol) of 2-[4-(1-naphthyl)-2-oxo-1-pyrrolidinyl]-acetic acid, 4.9 g (0.043 mol) of N-hydroxysuccinimide and 8.9 g (0.043 mol) of dicyclohexylcarbodiimide is stirred in 200 ml of absolute dioxane at room temperature for 20 hours.

The secreted dicyclohexy1 urea is aspirated. The clear filtrate is evaporated at 60°/14 Torr, whereupon 2-[4-(1-naphthyl)-2-oxo-1-pyrrolidinyl]-acetic acid-(2,5-dioxo-1-pyrrolidinytester) is obtained in the form of an oil, which is used directly further.

The starting material is obtained in the following way:

19.2 g (0.065 mol) of 2-[4-(1-naphthyl)-2-oxo-1-pyrrolidinyl]-acetic acid ethyl ester are dissolved in 100 ml of methanol and 65 ml of aqueous 1N caustic soda are added. The mixture is stirred for 20 hours at room temperature and then evaporated to dryness at 60°/14 Torr. The residue is taken up in 100 ml of water and adjusted to pH 1 with 6N HC1. The precipitated 2-[4-(1-naphthyl)-2-oxo-1-pyrrolidinyl]-acetic acid crystallizes out in an ice bath and is suctioned off.

After recrystallization from 350 ml of methanol, it melts at 212-214°.

The starting material is obtained in the following way:

42.4 g (0.2 mol) of 4-(1-naphthyl)-2-oxo-pyrrolidine are dissolved in 300 ml of dimethylformamide and 8.8 g (0.2 mol) of a 55% suspension are added in portions at room temperature of sodium hydride in mineral oil. After the addition is complete, stir for a further 2 hours at room temperature.

A solution of 22.4 ml (0.2

mol) of bromoacetic acid ethyl ester in 120 ml of toluene during 20 minutes at 15°C. The reaction mixture is stirred for 18 h

hours at room temperature and 8 hours at 80°.

The reaction mixture is freed from toluene and dimethylformamide

at 70°/14 Torr. The oily residue is diluted with ethyl acetate and washed with saturated sodium chloride solution. After drying over sodium sulphate and evaporation, the oily residue is stirred twice with 50 ml of hexane to remove the mineral oil. The residue is distilled under high vacuum. The fraction at 190°/0.005 Torr is a yellowish clear oil consisting of 2-[4-(1-naphthyl)-2-oxo-1-pyrrolidinyl]-acetic acid ethyl ester.

Example 9.

11.7 g (30 mmol) of 2-(2-oxo-1-pyrrolidinyl)-acetic acid pentachlorophenyl ester and 10.2 g (30 mmol) of glycy1-glycyl-glycyl-glycyl-glycinamide hydrochloride are stirred into 300 ml of dry dimethylformamide and 4.6 ml (33 mmol) of triethylamine are then added. The suspension is heated to 70°C within 30 minutes and stirred for 1 hour at this temperature. The white suspension is cooled to 10° and suctioned off at 13 Torr. The filter material is washed with ethanol and ether and recrystallized 2 times from each time 300 ml of boiling water, whereupon N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycyl-glycyl-glycyl-glycinamide with cleavage region is obtained >300°.

The starting product is obtained as follows:

To a solution of 23.2 g (0.1 mol) of N-tert.-butyloxycarbonyl-glycyl-glycine with 14 ml of triethylamine in 700 ml of dimethylformamide is added dropwise at -10°C 13.7 g (0.1 mol) chloroformic acid isobutyl ester. After the addition is finished, stir for a further 10 minutes and then stir in 22.5 g (0.1 mol) glycyl-glycyl-glycinamide hydrochloride at an unchanged temperature (-10°C). After adding 14 ml of triethylamine, it is slowly heated to room temperature and then stirred for 18 hours at 40°C.

To remove the protective group, 20 ml of 21% ethanolic hydrochloric acid solution and 1 ml of water are now added, and the mixture is stirred for 1 hour at 40°C. The reaction mixture is evaporated to dryness at 70°/14 Torr. The residue is boiled in 600 ml of ethanol and suctioned hot. The filter residue is heated in 250 ml of water to 90°. Aqueous 2N hydrochloric acid is added to the turning point for the Congo blue indicator (pH <4), treated with activated charcoal and 700 ml of ethanol is added to the filtrate. In an ice bath, glycy1-glycy1-glycyl-glycyl-glycinamide hydrochloride crystallizes with a cleavage range >300°.

Example 10.

A mixture of 5.6 g (0.02 mol) glycyl-glycyl-glycyl-glycinamide hydrochloride, 3.1 ml (0.022 mol) triethylamine and 11.7

g (0.02 mol) of 2-(2-oxo-1-pyrrolidinyl)-acetic acid pentachlorophenyl ester is stirred in 400 ml of dimethylformamide under a nitrogen atmosphere at 60° for 15 hours. The reaction mixture is cooled to 15° and filtered off. The crystalline mass on the filter is stirred with 96% ethanol, suctioned off and washed with ether. The filter residue is dissolved in 100 ml of water at 90°. The slightly cloudy solution is filtered and cooled slowly to room temperature. The precipitated product is filtered off with suction and washed with ethanol and ether, after which N-[(2-oxo-1-pyrrolidinyl)-acetyl]-glycyl-glycyl-glycyl-glycinamide with cleavage range 268-272° is obtained.

The starting material is produced as follows:

23.2 g (0.1 mol) of N-tert-butyloxy-carbonyl-glycy1-glycine are stirred into 700 ml of dimethylformamide. The solution is cooled to

-10°C and 14 ml (0.1 mol) triethylamine is added. At -10°, 13.7 g (0.1 mol) of chloroformic acid isobutyl ester are added dropwise. After 10 minutes of stirring, a further 14 ml is added

(0.1 mol) triethylamine, and then 16.8 g (0.1 mol) glycyl glycinamide hydrochloride is added as a solid. The reaction mixture is stirred for 40 hours at room temperature.

To remove the protective group, the cloudy, yellowish suspension is added to 1 ml of water and adjusted to pH 1 with ethanolic hydrochloric acid (21% strength). The reaction mixture is evaporated to dryness at 60°/14 Torr. The solid obtained is dissolved in 200 ml of water at 80°, treated with activated carbon and suctioned off. The clear filtrate is diluted with 700 ml of ethanol and stirred in an ice bath. The product that falls out is filtered off, dissolved in 100 ml of water at 80° and 500 ml of ethanol is added to the solution. After suction and drying, glycyl-glycyl-glycyl-glycinamide hydrochloride is obtained in crystalline form, which melts above 280°.

Example 11.

3.3 g (0.01 mol) of N-tert.-butyloxycarbonyl-L-prolyl-glycyl-glycinamide is stirred in 10 ml of 1N HCl for 2 hours at 80°. The clear solution is evaporated at 70°/13 Torr and further evaporated

2 times with each time 50 ml of toluene. The rest are admitted in 60

ml of dimethylformamide, and 3.91 g (10 mmol) of 2-(2-oxo-pyrrolidine-1-y1)-acetic acid pentachlorophenyl ester and 1.4 ml (10 mmol) of triethylamine are added. The reaction mixture is stirred for 20 hours at 50°C and then evaporated to dryness at 70°/13 torr. The viscous residue is stirred in the heat with 50 ml of acetic acid ethyl ester. The ethyl acetate layer contains pentachlorophenol.

The glassy residue is chromatographed on 100 g of silica gel ("Kieselgel" 60, 70-230 mesh, Merck AG). The fractions eluted with chloroform/methanol = 20/1 are combined. The crude product obtained after evaporation of the solvent is taken up in 25 ml of water and washed through a short column with 10 g of "Dowex" 50 (cation exchanger, H+<-> form). The aqueous eluate is evaporated to dryness, whereupon N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-glycy1-glycinamide is obtained in the form of an amorphous solid.

100 MHz-<1>H-NMR (dimethylsulfoxide-dg):<5 = 1.7-2.4 (8H), 3.3-3.6(4H), 3.8 (4H), 4.1 (2H), 4.35 (1H), 6.7 (1H), 6.95 (1H), 7.9 (1H) and 8.6 (1H).

The intermediate product is produced in the following way:

A mixture of 23.2 g (0.05 mol) N-tert-butyloxycarbonyl-L-proline pentachlorophenyl ester (m.p. 113-115°), 5.8 g (0.05 mol) glycyl glycinamide hydrochloride and 7 ml (0.05 mol) of triethylamine in 250 ml of dimethylformamide is stirred at 60° under a nitrogen atmosphere. After stirring for 15 hours, the reaction mixture is evaporated to 80 ml at 70°/13 Torr and stirred again for 20 hours at 80°. After cooling to room temperature, the secreted triethylamine hydrochloride is suctioned off. The filtrate is evaporated to dryness at 70°/15 Torr. The viscous oil obtained is stirred with 100 ml of toluene and 100 ml of ether. After 90 minutes of stirring, an amorphous solid is obtained, which is soluble in hot dioxane and is crystallized from dioxane/ethyl acetate/ether = 7/10/10, after which N-tert.-butyloxycarbonyl-L-prolyl-glycyl-glycinamide is obtained with m.p. 171-172°.

Example 12.

In an analogous manner as described in this application, N-[4-hydroxy-2-(2-oxo-1-pyrrolidinyl)-butyryl]-glycyl-glycinamide is obtained.

Example 13.

Prescription for one tablet:

Example 14.

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

Composition:

The active substance is mixed with the lactose and 60 g of potato starch, the mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying, the rest of the potato starch, talc, magnesium stearate and the highly dispersed silicon dioxide are mixed in, and the mixture is pressed into tablets of 289.6 mg weight each and the above-mentioned content of active substance, which in humans can be adapted to finer adjustment of the dosage by be equipped with a distribution line.

Example 15.

20.7 g (0.1 mol) 2-(5,5-dimethyl-2-oxo-1-pyrrolidinyl)-propionic acid sodium salt (described in DE-Official 2,747,369)

and 16.8 g (0.1 mol) glycyl-glycinamide hydrochloride are stirred for 10 minutes in 150 ml of dimethylformamide and then 32.1

g (0.105 mol) of triphenyl phosphite. It is then heated under a nitrogen atmosphere and stirred for 2 hours to 90-95°, whereby a yellow suspension is formed. For work-up, cool to 5° and add 300 ml of diethyl ether. The precipitated crude product is suctioned off, heated in isopropanol, freed by filtration from insoluble, inorganic salts and then evaporated

to incipient crystallization. The crystallized N-[2-(5,5-dimethyl-2-oxo-1-pyrrolidinyl)-propionyl]-glycyl-glycinamide is filtered off with suction and dried in a vacuum at 80°, m.p. 218-220°.

Example 16.

3.17 g (0.01 mol) N-(3-carboxy-propyl)-glycyl-L-prolyl-glycyl-glycinamide in 25 ml of hexamethyldisilazane and heated with stirring to boiling. After a short time, a clear solution is formed. It is heated for 24 hours under reflux 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. The precipitated N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-glycyl-glycinamide, which is described in example 11, is suctioned off and washed with a little cold methanol.

The starting material is produced as follows:

10.3 g (0.10 mol) of 4-aminobutyric acid, 28 g (0.20 mol) of potassium carbonate and 17.2 g (0.05 mol) of N-bromoacetyl-L-prolyl-glycyl-glycinamide are stirred at 300 ml of ethanol for 8 hours at 50°. It is then carefully neutralized with 2N hydrochloric acid and then carefully evaporated in a water jet vacuum. Add 250 ml of isopropanol to the residue and heat to boiling. The insoluble salts are suctioned off and the filtrate is evaporated until initial crystallization on a rotary evaporator. Thus, crude N-(3-carboxy-propyl)-glycyl-L-prolyl-glycyl-glycinamide is obtained, which is further processed directly.

Example 17.

3.9 g (0.01 mol) of N-(4-chloro-butyryl)-glycyl-L-prolyl-glycyl-glycinamide and 1.5 g (0.011 mol) of potassium carbonate are heated with stirring in 120 ml of ethanol for 5 hours to cooking. It is then evaporated in a rotary evaporator, the residue is digested in 200 ml of boiling isopropanol, filtered off from the insoluble inorganic salts and evaporated until crystallization begins in a water jet vacuum. The precipitated N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-glycyl-glycinamide, which is described in example 11, is suctioned off and washed with a little isopropanol.

The starting material is produced as follows:

To a mixture of 3.1 g (0.01 mol) glycy1-L-proly1-glycyl-glycinamide hydrochloride and 2.0 g (0.02 mol) triethylamine in 50 ml dimethylformamide is added dropwise while stirring at a reaction temperature of 5° 1.5 g (0.011 mol) of 4-chlorobutyric acid chloride. After the addition of the mixture is complete, react for a further 1 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-chlorobutyryl)-glycyl-L-prolyl-glycyl-glycinamide is suctioned off.

Example 18.

To a solution of 1.7 g (0.02 mol) 2-oxo-pyrrolidinium 50

ml of dimethylformamide is added under stirring and nitrogen atmosphere to 0.86 g (0.02 mol) of a 57% dispersion of sodium hydride in mineral oil, whereby a strong evolution of hydrogen gas takes place. The mixture is allowed to react for 30 minutes at room temperature and 6.94 g (0.02 mol) of N-(bromoacetyl)-L-prolyl-glycyl-glycinamide are then added. The reaction mixture is then stirred for 15 hours at room temperature. For work-up, the dimethylformamide is evaporated under high vacuum and the residue is digested in 250 ml of hot ethanol. The soluble, inorganic salts are sucked off and the filtrate is evaporated in a water jet

vacuum until incipient crystallization. The precipitated N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-glycyl-glycinamide, which is described in example 11, is suctioned off and washed with a little ethanol.

Example 19.

2.97 g (0.01 mol) N-[(2-oxo-1-pyrrolidiny1)-acetyl]-L-prolyl-glycine and 1.1 g (0.01 mol) glycinamide hydrochloride are added in 50 ml of dimethylformamide under stirring and nitrogen atmosphere successively 1.1 g (0.011 mol) of triethylamine and 3.26 g (0.0105 mol) of triphenylphosphite. The reaction mixture is then heated for 3 hours to 85-90°, whereby a clear solution is formed. Then cool to 5° and add 30

ml of diethyl ether. The precipitate is filtered off with suction, slurried in 20 ml of ethanol to separate out triethylamine hydrochloride and then filtered off again, whereupon N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-glycyl-glycinamide is obtained, which is described in example 11.

Example 20.

3.67 g (0.01 mol) of N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-glycyl-glycine methyl ester are dissolved in 150 ml of methanol and ammonia gas is introduced while stirring. The mixture is allowed to react for a total of 15 hours at room temperature, then the precipitated N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-glycyl-glycinamide described in example 11 is filtered off with suction, and this is recrystallized from methanol .

Example 21.

Into a chromatography vessel of 2.5 cm diameter, 50 ml of wet-slurry "Amberlite" IRA 400 (strongly basic polystyrene-based ion exchange resin) in chloride form is introduced and screened over with a mixture of 20 ml of triethylamine, 20 ml ethanol and 60 ml of water. The mixture is passed through drop by drop and then flushed with distilled water until the effluent is neutral.

The thus activated and washed "Amberlite" IRA 400 is transferred to a round bottom flask and the water is decanted off. An aqueous solution (150 ml) of 3.35 g (0.01 mol) N-[(2-oxo-l-pyrrolidinyl)-acetyl]-L-prolyl-glycine-N-cyanomethylamide is boiled with the activated anion exchanger under magnetic stirring for 5 hours under reflux. At room temperature, the ion exchangers are sucked off on a filter and the clear, aqueous filtrate is evaporated to dryness at 60°/14 Torr. The remaining N-[(2-oxo-1-pyrrolidiny1)-acetyl]-L-prolyl-glycyl-glycinamide described in example 11 is purified by recrystallization

from methanol.

Example 22.

8.6 g (20.2 mol) of N-tert.-butyloxycarbonyl-L-prolyl-L-prolyl-glycyl-glycinamide are stirred for 2 hours at 60° in 20.2 ml of 1N aqueous hydrochloric acid. The solution is evaporated to dryness at 80°/14 Torr, evaporated twice with 20 ml absolute ethanol and dried overnight at 90°/14 Torr over calcium chloride.

The glassy residue is added to 100 ml of dimethylformamide

(DMF) and 2.82 ml of triethylamine and stirred at 40° until a clear solution occurs. A solution of 9.0 g (23 mmol) 2-(2-oxo-1-pyrrolidinyl)-acetic acid pentachlorophenyl ester in 60 ml DMF is added dropwise to this solution. The addition lasts 3 hours at an internal temperature of 50°. The solvent is distilled off at 60°/l Torr. The residue is distributed between 50 ml of water and 50 ml of diethyl ether and the aqueous layer is washed again twice with diethyl ether to remove all pentachlorophenol. The aqueous layer is removed with activated charcoal and filtered. The clear, colorless, aqueous solution is allowed to acylate through a column of 20 ml of neutrally washed "Dowex 50" (cation exchanger), H+<->form, and is then washed with 50 ml of water. The aqueous eluate is evaporated to dryness at 60°/14 Torr.

After a longer period of time at room temperature (20°), spontaneous crystallization takes place. The crystals are covered with diethyl ether, driven off and suctioned off, whereupon N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-L-prolyl-glycyl-glycinamide is obtained with m.p. 135-138° (water loss at 98-120°).

The starting material, N-tert.butyloxycarbonyl-L-prolyl-L-prolyl-glycyl-glycinamide is obtained from 19.3 g (34 mmol)

N-tert-butyloxycarbonyl-L-prolyl-L-prolyl-pentachlorophenyl ester (m.p. 153-154°) and 3.9 g (34 mmol) glycyl glycinamide hydrochloride in 150 ml DMF in the presence of 4.7 ml ( 34 mmol) triethylamine .

Claims (10)

1. Process for the production of lactam peptides of formula I where Z means an alkylene residue, which is unsubstituted or substituted with free or functionally converted hydroxy and/or with aryl and which together with the amide grouping forms a five-membered ring, R''' means hydrogen, unsubstituted or with aryl or with free or functionally converted hydroxy substituted lower alkyl or aryl, X means oxygen or the group NR <2> , where R <2> stands for hydrogen or lower alkyl, R 3 means hydrogen, unsubstituted or with free or functionally converted hydroxy, aryl, aminocarbonyl, mercapto, methylthio, free, alkylated or acylated amino, guanidino, free, esterified or amidated carboxy or imidazol-4-2 3 yl substituted lower alkyl or aryl , or R and R together mean unsubstituted or with free or functionally converted hydroxy substituted trimethylene, R 4 means hydrogen or lower alkyl, W means one with the carbony1-C atom of the residue of formula II bonded residue of formulas III, IV, V or VI, where R^, R^ and R"^ independently represent hydrogen 5 7 9 11 or lower alkyl, R , R , R and R independently represent hydrogen, unsubstituted or with free or functionally converted hydroxy, aryl, aminocarbony1 , mercapto, methylthio, free, alkylated or acylated amino, guanidino, free, esterified or amidated carboxy or imidazol-4-yl substituted lower alkyl, or aryl or R 4 and R 5 together, 67 89 1011 R and R together, R and R together and/or R and R together independently stand for unsubstituted or with free highly functionally converted hydroxy substituted trimethylene, 12 13 and R and R independently of each other mean hydrogen or 12 13 lower alkyl, or R and R together mean tetra- or pentamethylene, 3-oxa-1,5-pentylene or unsubstituted or oxo- or methyl-substituted 3-aza-3-methyl-1,5-pentylene, and of salts of such compounds, which contain at least one salt-forming group, with the exception of such compounds of formula I, where Z means unsubstituted alkylene with 3 C atoms and at the same time R <1> means hydrogen, unsubstituted alkyl with 1-4 C atoms, aryl or aryl lower alkyl, X means the residue NH, R^ means aryl, unsubstituted alkyl or hydrogen, 4 R means hydrogen, W means a residue of formula III, where R~ <*> has a meaning identical to the residue R^, and „12 „13 .. , , R and R mean hydrogen, and of salts of these compounds with at least one salt-forming group, characterized by ata) a compound of formula VIII, where Y means a nucleophilic leaving group and the other substituents have the above meanings, with the proviso that any functional groups present 1 3 in the residues Z, R , R or W are possibly protected with easily cleavable protective groups, are ring-closed intramolecularly to form the pyrrolidone ring, orb) a compound of formula IX, 19 where R 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 above-mentioned meanings, with the proviso that functional groups that may be present in the residues Z, r\ R ^ or W is optionally protected with easily cleavable protective groups, is ring-closed intramolecularly to form the pyrrolidone ring, orc) a compound of formula X, where Z has the above-mentioned meaning, with the proviso that functional groups present therein are optionally protected with easily cleavable protective groups, or a reactive form of this compound is reacted with a compound of formula XI, where Y means a nucleophilic leaving group and the other substituents have the above-mentioned meanings, with the proviso that functional groups present in the residues Z, R"*", R^ or W are possibly protected with easily removable protective groups, ord) a compound of formula XII, where n and p independently of each other mean the number o or 1 and A means the residue W or W a , whereby W means a residue with the formulas III, IV or V, and the other substituents have the meanings mentioned above, with the proviso that functional groups which is optionally present in the residues Z, R , R <3> and A is optionally protected with easily cleavable protective groups, or a reactive carboxylic acid derivative of the compound of formula XII is reacted with a compound of formula XIII, where E stands for the remainder with the formula or for the rest Wtø , which is defined so that when combining W a and WD, the remainder W is obtained, and k and r independently of each other stand for the numbers 0 or 1, with the assumption that r and q stand for 1 and E stand for the rest when p stands for 0 in reaction the partner with formula XII, or that r stands for 1, q stands for for 0 and E for the rest when p stands for 1 and n stands for for 0, or that r stands for 1, q stands for 0 and E stands for Wtø, when p stands for 1, n for 1 and A for Wa, or that r stands for 0, when p and n stand for 1 and A stands for W, and where the other substituents have the above-mentioned meanings, with the proviso that functional groups that may be present in the residues R <3> and E are optionally protected with easily removable protective groups, or a derivative of the compound of formula XIII, in which the groups H-X-, H-E- or is available in a reactive form, e.g e) a compound of formula I, where at least one of the residues R 2 , R 4 , R 6 , R 8 , R 10 , R 12 and R <13> stands for hydrogen and the other substituents have the meanings mentioned above, with the proviso that functional groups present in a compound of formula I with the exception of the reacting amide group(s) are possibly protected with easily cleavable protective groups, or a reactive derivative of this compound is reacted with an alkylating agent which introduces the above-mentioned residues R 2, R <4> , R <6> , R <8> , R10, R12 and R<13> , or f) for the preparation of a compound of formula I, where Z means 1- or 2-hydroxy-1,3-alkylene, in a compound of formula I, where Z stands for a residue of formula XV or XVI which is bound to the nitrogen atom by the C(R 14 ) atom, whereby all substituents have the meanings mentioned above, with the proviso that functional groups which are possibly present in the residues R"*", R3, W, R~^ and R"*"7 are optionally protected with easily cleavable protective groups, are transferred the keto group of formulas XV or XVI, with a regioselective reducing agent to a hydroxy group, or g) the cyano group in a compound of formula XVII, where U means a residue of the formula XVIII, XIX, XX or XXI, and where all substituents have the above meanings, are transferred to an amide group, or h) for the preparation of a compound of formula I, where R 12 stands for hydrogen, the oxime group is transferred in a compound else with formula XXII, where the substituents have the above meanings, to an amide group by means of a Beckmann rearrangement, or i) in a compound of formula I, which exhibits at least one free hydroxy, carboxy or amino group, free hydroxy is esterified or etherified, free carboxy is esterified or amidated or free amino is alkylated or acylated and after carrying out the methods described under a ) to h) any protective groups present are cleaved off and, if desired, stereoisomer mixtures obtained are separated, and, if desired, an obtained compound with at least one salt-forming group is transferred to a salt or an obtained salt is transferred to the free compound. 2. Method according to claim 1, characterized in that the starting substances are selected as follows, that a compound of formula I is obtained, where Z means an alkylene radical with 3-14 C atoms, which is unsubstituted or substituted with hydroxy, lower alkanoyloxy and/or naphthyl or with a phenyl radical which is unsubstituted or substituted with halogen or halophenoxy, and which, together with the amide group, forms a 5-membered ring, R" <*> " means hydrogen or unsubstituted or with hydroxy or lower alkanoyloxy substituted lower alkyl, 2 2 X means oxygen or the group NR , where R stands for hydrogen or C1 _4~ alkyl, R <3> means hydrogen, unsubstituted or with hydroxy, lower alkanoyloxy, phenyl, 4-hydroxy-phenyl, aminocarbonyl, amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or imidazol-4-yl substituted lower alkyl bearing phenyl, or R 2 and R 3 together means unsubstituted or hydroxy-substituted trimethylene, R 4 means hydrogen or C 2 -alkyl, W one with the carbonyl C atom of the residue of formula II bonded residue of formulas III, IV, V or VI, wherein R <6> , R <8> and R <10> independently of each other represent hydrogen or C^ _4~ alkyl, R^, R7, R9 and R^ independently of each other represent hydrogen, unsubstituted or with hydroxy, lower alkanoyloxy , phenyl, 4-hydroxyphenyl, aminocarbonyl, amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or imidazol-4-yl substituted lower alkyl or phenyl, or R <4> and R~ <*> together, R^ and R <7> together, R <8> and R <9> together and/or R "^ and R ^ together independently represent unsubstituted or hydroxy or lower alkanoyloxy substituted trimethylene, and 12 13 R and R independently of each other mean hydrogen or lower 12 13 alkyl, or R and R together mean tetra- or pentamethylene, 3-oxa-1,5-pentylene or unsubstituted or oxo- or methyl-substituted 3-aza-3-methyl-1,5-pentylene, or a salt of such connection with at least one salt-forming group. 3. Method according to one of the claims 1-2, characterized in that the starting materials are selected such that a compound of formula I is obtained, where X means the group NH, or a salt of such a compound with at least one salt-forming group. 4. Method according to one of the claims 1-3, characterized in that the starting materials are selected such that a compound of formula I is obtained, where R<5> means hydrogen or C 1 -4~ alkyl, or a salt of such a compound with at least one salt-forming group. 5. Process according to one of the claims 1-4, characterized in that the starting substances are chosen such that a compound of formula I is obtained, where, when W stands for a residue of formula IV, R7, when W stands for a residue of formula V , R <7> and R <9> , and, now r W stands for a remainder 7 9 11 with formula VI, R , R , and R independently of each other mean hydrogen or C 1 -4 alkyl, or a salt of such a compound with at least one salt-forming group. 6. Method according to one of the claims 1-5, characterized in that the starting materials are chosen such that a compound of formula I is obtained, which at an asymmetrically substituted C-R <3-> atom and at all centers of asymmetry in the residue W exhibits the (L) configuration, at the C-R 5 atom alternatively also ° exhibits the (D) configuration, or a salt of such a compound with at least one salt-forming group. 7. Method according to claim 1, characterized in that the starting materials are selected as follows, that a compound of formula I is obtained, where Z means trimethylene or 2-hydroxy-trimethylene, R1, R, R4 and R means hydrogen, X means the group NH, W means a residue of formulas III or IV, where R~* stands for hydrogen or 6 7= 13 methyl and R and R stand for hydrogen, and R stands for hydrogen or C. __.-alkyl, whereby the configuration at C-R" <*> , when R stands for methyl, can be (D) or (L). 8. Method according to one of claims 1-7, characterized in that the starting materials are selected such that a compound of formula I is obtained, where Z means trimethylene, or a salt of such a compound with at least one salt-forming group. 9. Method according to claim 1, characterized in that the starting substances are selected as follows, that a compound of formula I is obtained, where Z means 1 2 2 trimethylene, R means hydrogen, X means the group NR , R 3 2 3 and R means hydrogen or R and R together means trimethylene, R<4> means hydrogen, W means a residue of formulas III, IV, V or VI, where R^ stands for hydrogen or C-^^ -alkyl or R4 and R^ together stand for trimethylene, R^, R7, R8, R9, R"^ and R 11 stand for hydrogen or R <6 > and R <7> together stand for 12 13 trimethylene, R means hydrogen or C-^^-alkyl and R means hydrogen. 10. Process according to claim 1, characterized in that the starting materials are selected so that N-[(2-oxo-1-pyrrolidinyl)-acetyl]-L-prolyl-glycyl-glycinamide is obtained.