MXPA98001190A

MXPA98001190A - Inhibitors of prolil endopeptid

Info

Publication number: MXPA98001190A
Application number: MXPA/A/1998/001190A
Authority: MX
Inventors: Hermecz Istvan; Kanai Karoly; Heja Gergely; Balogh Maria; Erdo Sandor; Szappanos Anrea; Bence Judit; Szvoboda Gyorgyne; Batori Sandor
Original assignee: Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt
Priority date: 1995-08-17
Filing date: 1998-02-12
Publication date: 1998-04-01

Abstract

The present invention relates to new propyl endopeptidase inhibitors of general formula (

Description

INHIBITORS OF PROLIL ENDOPEPTIDASE DESCRIPTION OF THE INVENTION The present invention relates to new compounds of the general formula (I), to pharmaceutical compositions containing them, and to the processes for the preparation of these compounds. A further aspect of our present invention is the use of the novel compounds of the general formula (I) for the treatment of CNS diseases, by inhibition of certain enzymes described later on this page. Because of the incidence and social consequences of diseases of the central nervous system, accompanied by amnesia, dementia and the progressive decline of cognitive and intellectual functioning, for example Alzheimer's disease, AIDS dementia, senile dementias of various origins (hypoxia) , ischemia), there are significant demands for new pharmaceutical compounds to treat and prevent the diseases mentioned above. The prolyl endopeptidase PE or PEP is an enzyme that hydrolyzes post-proline (PPCE). It is widespread in mammalian species, and can be found in various organs of the body. The concentration of the enzyme is highest in the brain, testes and skeletal muscle (Yoshimoto ^ T., Ogita, K__, Walter, R. , Koida., M_ and Tsu.ru., O. Biochim, Biophys, Acta, 569, 184-192 (1979).

PEP has some important role in memory processes, due to the fact that its substrates are biologically active neuropeptides (substance P, hormone that releases thyrotropin, Arg8-Vasopressin). These neuropeptides exert characteristic pharmacological effects on the central nervous system: they are capable of changing the performance of animals and humans in learning and memory tasks (Toide, K., Iwamoto, Z., Fui ara, T., and Abe, H. : J. Pharm, Exp. Therapeutics, 274, 1370-1378 (1995), Riedel, W. and Jolles, J., Drugs &Aging, 8, Z45-274 (.1996)). The neuropeptide substance. P prevents neuronal loss induced by β-amyloid and the expression of Alz-50 proteins in the cerebral cortex (Kowall, N, Beal, M.F., Busciglio, J., and Duffy, L.K.: Proc.

Nati Acad_e., 88, 724.7-7251 (L991)) .. In brains of patients with Alzheimer's disease, it is well known that the content of cerebral Ach decreases, and brain function suffers severe damage (0'learyy R. and O'Connor, B., J. Neurochep, 65. "953-963 (1595)). An in ihidox of PEP, through an increase in the concentration of TRH, could induce Ach release in the brain, which should result in a better cognitive performance. It can be assumed that a highly specific PEP inhibitor could be useful in the treatment of diseases of the central nervous system in neurodegenerative disorders. The new inhibitor of PEP as a new drug would be: 1. a nootropic drug that has an effect of memory improvement and anti-amnestic, and could be used in the treatment of cognitive decline related to aging; 2. an agent neu apratectnr ,. useful in therapy, of a., acute events (ischemia / hypoxia) b., progressive neurodegenerative disorders: - Alzheimer's disease - AIDS dementia - Huntington's disease. Senile dementia and Alzheimer's disease have become a serious problem and are growing rapidly in the aging population, and a PEP inhibitor may be useful for the general treatment of the serious diseases mentioned above. We set ourselves the task of preparing new PEP inhibitors that exhibited advantageous characteristics that could serve as active ingredients of new drugs. By advantages we mean a strong inhibitory effect of PEP, selectivity, easy transfer through the blood brain barrier, a prolonged half-life, good oral resorption, improved chemical and biological stability, and advantageous therapeutic profile, including lower toxicity and low probability of side effects. During the synthesis and biological examination of numerous new compounds, we find that the new compounds of the formula (I), wherein A means an organic cyclic group, substituted once several times, or unsubstituted, containing a nitrogen atom with a free valence, and optionally one or more additional heteroatoms selected from a group consisting of nitrogen atom, sulfur atom or oxygen atom, especially a group having the general formula (1), (a), (2), (2a), (3), (3a), (4), (5) ), (6)., (7), (8), (9), (10), (lia), (llb), (12), (12a), (12b), (13), (13a) , (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22), (23), ( 23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), (29a), (30) , (31), (32), (32a), (33), (34), (35), (36) - wherein R means a hydrogen atom, an alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-12 a-tamas. of carbon; R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, straight or branched chain alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy groups, containing 1 -6 carbon atoms, a nitro group, an amino group, monoalkylamino or onacylamino of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms - wherein the acyl group is one of the alkyl type., aralkyl, cycloalkyl or aryla-, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms carbon, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1 6 carbon atoms, sulfamino or sulfamollo group, thiocyanate group or cyanate, R5 and R6 mean, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together they mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; or A means a group R '-YN = or a group R'-YN (R9) -, where R' means an alkyl group of 1-6 carbon atoms, an aralkyl group of 7-10 carbon atoms, group diphenylmethyl, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or a phenyl or phenoxy or phenylalkyl group containing 7-10 carbon atoms, or a phenylalkyloxy group containing 7-10 carbon atoms, optionally substituted with halogen atoms or alkyl groups of 1-4 carbon atoms, or nitro groups; Y means a chemical bond or an oxo, sulfonyl or sulfinyl group, R9 means a hydrogen atom or an alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X can not mean a group -CH2-, a group -NH-, an oxygen atom or a sulfur atom, and in the case of formulas (30) and (31), X can not mean a group -CH2-, an oxygen atom or a sulfur atom or an amino group; B means a group - (CH2) m-C (0) -, where m is an integer from 1 to 21; or a group -0- (CH2) P-C (O) -, wherein p is an integer from 1 to 3; or a group - n where R9, R10, R11, R12, R13 and R14 independently denote one of the other hydrogen, an alkyl or alkoxy group of 1-6 carbon atoms, halogen, an amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or a phenyl, phenoxy, or arylalkyl group of 7-12 carbon atoms, or an arylalkoxy group of 7-12 carbon atoms, each optionally containing 1, 2, or 3 identical or different substituents, identical to R 1, R2, R3 or R4; or two of R3, R10, Ru, R1¿, R13 and R14 together mean an oxo or epoxy group, or an additional chemical bond, or four of them together signify two additional chemical bonds, and the remaining groups represent hydrogen atoms; or R9, R10, R11, R12, R13 and R14 mean, together with the carbon atoms of the chain, a saturated or unsaturated homocycle, containing 3-8 carbon atoms, or a saturated or unsaturated heterocycle containing 2 or more carbon atoms. -7 carbon atoms and a nitrogen or sulfur atom, to which an aromatic ring of 6-10 carbon atoms is optionally condensed and is zero or 1; C means a prolyl group, or one of the groups of formula (37), (38), (39), £ 40) or (41) - wherein n is zero or 1 or 2, Hlg means a fluorine atom, chlorine, bromine, or iodine; R5 and R6 signify, independently of one another, a hydrogen atom, a hydroxyl group, a phenyl group or an alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R16 means an alkoxy group of 1-4 carbon atoms, or a group -NH-CH2-CN, or a group -NH-CH2-C02R7, wherein R7 is defined above; or the structural unit D or L; or one of the groups of the formula (42) or (43) or (43a) - wherein the dotted line means a chemical bond optionally present-, s is 1, 2 or 3 - or a group of the formula (44 ) - where R15 means an atom of hydrogen, an alkyl group of 1-6 carbon atoms, a phenyl or naphthyl group; or a group of the formula (45) - wherein Z means a group - NH, an oxygen atom or a sulfur atom; D means a covalent chemical bond, or a prolyl or thioprolyl group, or one of the groups of formula (37) or (38), (39), (49) or (41); L represents a pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group, optionally substituted with a halogen atom, or geminally with two halogen atoms; or a group of the formula (46) - wherein R17 signifies a hydrogen atom or a cyano group, n is 0, 1 or 2; or a group of formula (47) or (48) or (49); - and the optical, cis-trans, geometric isomers, epimers, tautomers, salts, prodrugs and human and mammalian metabolites thereof that have a significant inhibitory effect of the prolyl endopeptidase, and show one or more advantages mentioned above. Some preferred groups of compounds of the general formula (I) are as defined and claimed in claims 3, 8 and 9. The meaning of "an organic cyclic group substituted once or many times, or unsubstituted, containing an atom of nitrogen with a free valence, and optionally one or more additional heteroatom (s) selected from the group consisting of of nitrogen atom, sulfur atom or oxygen atom "in the case of A covers all known monocyclic or polycyclic groups that satisfy the definition above In the case of a polycyclic group, the rings may be fused, and / or they may be in a spirocyclic position Some representative examples of the cyclic groups above are represented in formulas (1), (a), (2), (2a), (3), (3a), (4), ( 5), (6), (7), (8), (9), (10), (lia), (llb), (12), (12a), (12b), (13), (13a) , (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22), (23), ( 23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), (29a), (30) , (31), (32), (32a), (33), (34), (35), (36) In the definitions of general formula (I), "alkyl group of 1-6 carbon atoms" means a straight or branched chain alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl The "aryl group of 6-10 atoms xle carbon" means, for example, phenyl, tolyl or naphthyl groups. The "aralkyl group of 6-10 carbon atoms" means for example benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl groups. The alkenyl group of 1-6 carbon atoms means a straight or branched chain alkenyl group such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl. The group "C 1-6 alkynyl" means a straight or branched chain alkynyl group such as ethynyl, propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl, 5-hexynyl, or -methyl-2-hexynyl The cycloalkyl part of the "acyl group of 1-12 carbon atoms" means for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group These definitions can be used in the case of groups Alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, phenylalkyloxy or alkylamino or acylamino We have examined the inhibitory activity of PEP, and the biological stability of the compounds characterized by the formula (I) by applying the following methods: Measurement of PEP activity on rat brain extract After extraction of the cerebellum, whole brain of male rats (Sprague-Dawley, 180-200 g) was homogenized in a double volume of 0.1 M buffer in Tris-HCl, 1 mM EDTA, pH = 7.5 (buffer solution of PEP). The homogenized material was subjected to centrifugation for 30 minutes at 4 ° C to 4000 g, and the supernatant, which contained the enzyme, was collected. The pellet was resuspended in the same volume of buffer, as in the first case, and subjected again to centrifugation under the same conditions. The two supernatants were combined and stored in aliquots of 1 ml at -70 ° C (for at least 3 months). The supernatant was thawed immediately before the activity measurements, and diluted in a 1:15 ratio with PEP buffer. The activity of the enzyme was measured using the fluorometric method described by JR Atack et al., (Eur. J. Pharmacol., 205, 157-163 (1991) .The reaction of the enzyme was performed at room temperature, for 15 minutes. , in the presence of 62.5 μM Z-glycyl-prolyl-7-amino-4-methyl-coumarin (Bachem Biochem.) as a highly specific synthetic substrate of PEP The inhibitory effect of the compounds was tested under the same conditions, presence of compound at 100 to 0.001 nM The formation of 7-amino-4-methyl-coumarin was detected spectrofluorometrically at an excitation wavelength of 370 nm and emission at 440 nm.The inhibition concentration of 50% of the compounds (IC5o) was calculated by adjusting curves of% inhibition of the enzyme versus inhibitor concentration (M) using the Hill equation.The IC50 values of the compounds of the general formula (I) are in the range of 100. nM - 1 pM Measurement of PEP activity in the brain of pork The prolile endopeptidase from purified pork brain was a kind donation by László Polgár (Enzymology Institute of the Hungarian Acade and of Sciences). The enzyme solution was diluted in the reaction mixture 400,000 times. The measurements were made under the same conditions as in the case of in vitro measurements of the rat brain preparation. It was demonstrated that the compounds of general formula I are also active on PEP activity in pig brain. In vitro metabolism studies The biological stability of prolyl endopeptidase inhibitors was studied in preparations of mouse, rat and human liver microsomes (preparation of the Central Chemistry Institute of the Hungapan Academy of Sciences). Mouse and rat livers were combined and homogenized in 4 times their volume of Tps-HCl buffer solution (pH 7.4) containing 1.15% KCl and 1 mM EDTA. The homogenized materials were subjected to centrifugation for 30 minutes at 10,000 g, and the supernatants were further subjected to ultracentrifugation for 1 hour at 105,000 g. The pellets were homogenized again, and ultracentrifugation was repeated. The pellets were homogenized again, and diluted with buffer to a final volume of 0.5 g of liver / ml. The sample was frozen in 2 ml aliquots at -80 ° C. The preparations were characterized to determine activities of the cytochrome P450 isoenzyme. The new inhibitors of the general formula (I) were tested under the following conditions: the reaction mixture contained 2 mg of the liver microsomal protein, 0.1 M buffer in Tps-HCl (pH = 7.4), 2 mM in NADP, 20 M in disodium salt of glucose-6-phosphate, 10 mM in MgCl2, 5 U of glucose-6-phosphate dehydrogenase, and 50 μM in PEP inhibitors in a final volume of 1.5 ml. After the incubation times of 0, 10, 20, and 40 minutes, the reaction was terminated by the addition of acetonitrile. The samples were subjected to centrifugation at 3000 rpm, for 10 minutes. The supernatant was analyzed by CLAR (Supelcosil C18). The amount of substrate that did not change was determined, and the half-life of the compounds was calculated. Some compounds of the general formula I had half-lives in human liver microsomes of more than 7 hours. Such good biological stability is in favor of an effect of prolonged duration in vivo, and is an advantage over other peptide type inhibitors, which are known to be biologically unstable. Published European Patent Application No. 0 232 849 A2 describes numerous PEP inhibitors, including SUAM-1221 (N- [N- (? -phenyl) butyryl-L-prolyl] pyrrolidine). The compounds of the general formula (I) exert a high inhibitory activity on the prolyl endopeptidase, and this is greater than that of the reference compound SUAM-1221 above, measured in our test system described above: Compounds IC50 (M) in rat brain extract Example 123 2.78 • 10"10 Example 31 3.60 • 10" 10 Example 171 4.51 • 10"10 SUAM-1221 3.12 • 10" 8 The preparation of the compounds of the general formula (I) was carried out by well-known methods of the literature, or by obvious chemical equivalents thereof, which are related to the synthesis of peptide-type substances. Units A and B of the compounds of the general formula ABCDL (I) - wherein the meanings of A, B, C, D, and L are as described above - are coupled by the reaction of the appropriate acid anhydride or other activated acid derivative and an amine, providing compounds of the general formula (II) - wherein the meanings of A and B are as described above. Coupling of units C and D also occurs by coupling the appropriate activated acid derivative, for example an acid anhydride and an amine. The coupling of the CD and L units to provide compounds of the general formula (III) - wherein the meanings of CD and L are as described above - is carried out by reacting the appropriate mixed anhydride and resp. ester and metallo-organic compound. The starting compounds corresponding to units A, B, C, D, and L are commercially available, or they can be easily produced by a known transformation of them, as described in Chem. Pharm. Bulletin, 41 (9), 1583-1588 (1993). We have prepared the compounds of general formula (I) by reacting activated derivatives of compounds of general formula (I) with compounds of the general formula (III) under the amide coupling conditions customary in peptide chemistry. The activated derivatives of the compounds having the general formula (II) could be, for example, acid chlorides, which can be synthesized by applying halogenating agents (for example thionyl chloride). The active esters can be produced by 1-hydroxy-benzotriazole, in the presence of N, N '-dicyclohexylcarbodyl ida (Chem. Ber., 103, 788, 1970). The mixed anhydrides can be produced by chloroformic acid ester or pivaloyl chloride (Methoden der Organischen Chemie (Houben-Weyl) Band XV / 2, Synthese von Peptiden, Georg Thieme Verlag, Stuttgart, 1974). The coupling reaction can favorably be carried out preferably in an organic solvent, (at a temperature between -25 ° C and the boiling point of the reaction mixture). The use of agents that take up acid, for example organic amines, is favorable during the reaction. The compounds of the general formula (I) can be purified, if appropriate, by a conventional purification technique, the isomers from which they are separated, if 1 you want, by a conventional separation technique, and are converted, if necessary, to their addition salts with a pharmaceutically acceptable acid. The pharmaceutically acceptable acids may be, for example, hydrochloric, sulfuric, tartaric, fumaric, methanesulfonic, and the like. Another object of the present invention are pharmaceutical compositions containing, as an active ingredient, at least one compound of the general formula (I), or one of its addition salts with a pharmacologically acceptable acid, alone or in combination with one or more excipients or inert and non-toxic vehicles. More particularly, mention may be made, among the pharmaceutical compositions according to the invention, of those which are suitable for oral, parenteral, rectal or nasal administration, as simple or sugar-coated tablets, sublingual tablets, injectable compositions, infusions, concentrates , gelatin capsules, suppositories, creams, ointments, dermal gels, and the like. The dose varies according to the age and weight of the patient, the nature and severity of the disorder, and the route of administration. The latter can be oral, nasal, rectal or parenteral. The unit dose usually varies between 0.1 and 50 mg / kilo of 1 body weight, for a treatment taken 1 to 3 times per 24 hours. The invention will be further clarified by the following tabular, non-limiting examples, in greater detail, and by a detailed description of the process in the case of Example 4. Other embodiments of the invention will be apparent to the person skilled in the art of a consideration of this specification, or the practice of the invention described herein. EXAMPLES Description of the preparation of the compound represented in Example 4 (Table 1) To a solution prepared by dissolving 1.17 g (5.0 mM) of 4-phthalimidobutyric acid and 0.56 g (5.5 mM) of triethylamine in 20 ml of chloroform, they added dropwise 0.61 g (5.0 mM) of pivaloyl chloride at -15 ° C under agitation. The reaction mixture was stirred for 1 hour at the temperature mentioned above, and then a solution prepared by dissolving 1.03 g (5.0 mM) of L-prolyl pyrrolidine hydrochloride salt in a mixture of sodium hydroxide was added thereto dropwise. ml of chloroform and 1.5 ml (1.1 g, 11.0 mM) of triethylamine. The reaction mixture was stirred at room temperature for 4 hours, then washed successively with water, with 30% citric acid solution, with saturated aqueous sodium bicarbonate solution, with water and with saturated sodium chloride solution. The organic phase dried over calcined magnesium sulfate, and evaporated. Crystallization of the residue from a mixture of 5 ml of chloroform and "10 ml of petroleum ether gave 1.1 g (53%) of N- (4-phthalimido-butanoyl) -L-prolyl-pyrrolidine, which melted at 148 ° C. 149 ° C. The compounds of the general formula I were synthesized by the method described above, starting from the corresponding compounds having the general formula (II) and (III) The structures and physical constants of several new compounds of the Formula general (I) are listed in Table 1.

Table 1 Secondary Factor Factor Point No. Structural Formula of CO Compound Retention Fusion and c a, b, o, d Assignment of epimeros, can be reversed Abbreviations of eluents: A CM201 Chloroform: methanol = 20: 1 B BM 41 Benzene: methanol = 4: 1 C CM 41 Chloroform: methanol = 4: 1 D DM101 Dichloromethane: methanol = 10: 1 E CM955 Chloroform: methanol = 95: 5 F CM 91 Chloroform: methanol = 9: 1 G DM 91 Dichloromethane: methanol = 9: 1 I HA 21 n-Hexane: acetone = 2: 1 J HA 31 n-Hexane: acetone = 3: 1 K CA 101 Chloroform: acetone = 10: 1 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

CLAIMS 1. Compounds of general formula (I), wherein A is an organic cyclic group, monosubstituted or polysubstituted or unsubstituted, containing a nitrogen atom with a free valence, and optionally one or more additional heteroatoms, selected from a group consisting of nitrogen atom / sulfur atom or oxygen atom, especially a group having the general formula (1), (a), (2), (2a), (3), (3a) , (4), (5), (6), (7), (8), (9), (10), (lia), (llb), (12), (12a), (12b), ( 13), (13a), (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22) , (23), (23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), ( 29a), (30), (31), (32), (32a), (33), (34), (35), (36) - wherein R means a hydrogen atom, an alkyl group of 1 4 carbon atoms, or an aryl or aralkyl group of 6-12 carbon atoms; R1, R2, R3 and R4 independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, alkyl groups or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy straight or branched chain, containing 1 -6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino group or ino diacila 2-24 carbon atoms - where the acyl group is one of alkyl type, aralkyl, cycloalkyl or aryl-, a cyano group, a group mercapto, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group , anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1-6 carbon atoms, sulfamoyl group or sulfo ino, thiocyanato or cyanato group, R5 and R6 independently of each other, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; or A means a group R '-YN = or a group R'-YN (R9) -, where R' means an alkyl group of 1-6 carbon atoms, an aralkyl group of 7-10 carbon atoms, group diphenylmethyl, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or a phenyl or phenoxy or phenylalkyl group which contains from 7-10 carbon atoms, or a phenylalkyloxy group containing from 7-10 carbon atoms, optionally substituted with halogen atoms or alkyl groups of 1-4 carbon atoms, or nitro groups; Y means a chemical bond or an oxo, sulfonyl or sulfinyl group, R9 means a hydrogen atom or an alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X can not mean a group -CH2-, a group -NH-, an oxygen atom or a sulfur atom, and in the case of formulas (30) and (31), X can not mean a group -CH2-, an oxygen atom or a sulfur atom or an amino group; B means a group - (CH2) m-C (O) -, where m is an integer from 1 to 21; or a group -O- (CH2) P-C (O) -, wherein p is an integer from 1 to 3; or a group

R14 1 -where R9, R: A R'Y R, R13 and R14 C- C- ¿? independently denote one of the other hydrogen, an alkyl or alkoxy group of 1-6 carbon atoms, halogen, an amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or a phenyl, phenoxy, or arylalkyl group of 7-12 carbon atoms, or an arylalkoxy group of 7-12 carbon atoms, each one of them optionally containing 1, 2 or 3 substituents, identical or different, identical to R1, R2, R3 or R4; or two of R9, R10, R11, R12, R13 and R14 together mean an oxo or epoxy group, or an additional chemical bond, or four of them together signify two additional chemical bonds, and the remaining groups represent hydrogen atoms; or R9, R10, R11, R12, R13 and R14 mean, together with the carbon atoms of the chain, a saturated or unsaturated homocycle, containing 3-8 carbon atoms, or a saturated or unsaturated heterocycle containing 2 or more carbon atoms. -7 carbon atoms and a nitrogen or sulfur atom, to which an aromatic ring of 6-10 carbon atoms is optionally condensed; and w is zero or 1; C means a prolyl group, or one of the groups of formula (37), (38), (39), (40) or (41) - wherein n is zero or 1 or 2, Hlg means a fluorine atom, chlorine, bromine, or iodine; R5 and R6 signify, independently of one another, a hydrogen atom, a hydroxyl group, a phenyl group or an alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R16 means an alkoxy group of 1-4 carbon atoms, or a group -NH-CH2-CN, or a group -NH-CH2-C02R7, wherein R7 is defined above; or the structural unit D or L; or one of the groups in formula (42) or (43) or (43a) - where the dotted line means a optionally present chemical bond -, s is 1, 2 or 3 - or a group of the formula (44) - wherein Rx5 means a hydrogen atom, an alkyl group of 1-6 carbon atoms, a phenyl or naphthyl group; or a group of the formula (45) - wherein Z means a group -NH, an oxygen atom or a sulfur atom; D means a covalent chemical bond, or a prolyl or thioprolyl group, or one of the groups of formula (37) or (38), (39), (49) or (41); L represents a pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group, optionally substituted with a halogen atom, or geminally with two halogen atoms; or a group of the formula (46) - wherein R17 signifies a hydrogen atom or a cyano group, n is 0, 1 or 2; or a group of formula (47) or (48) or (49); - and the optical isomers, cis-trans, geometrical, epimeros, tautomers, salts, prodrugs and human and mammalian metabolites of them.
2. Compounds of the general formula (I), - wherein A means one of the groups having the general formula (1), (a), (2), (2a), (3), (3a), (4) , (5), (6), (7), (8), (9), (10), (lia), (llb), (12), (12a), (12b), (13), ( 13a), (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22), (23) , (23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), (29a), (30), (31), (32), (32a), (33), (34), (35), (36) - where R means an atom of hydrogen, an alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-12 carbon atoms; R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, straight or branched chain alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy groups, containing 1 -6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms - wherein the acyl group is one of the alkyl, aralkyl type , cycloalkyl or aryl-, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1-6 carbon atoms, sulfa or sulfamoyl group, thiocyanate group or cyanate, R5 and R6 mean, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; Rb means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH; -, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; or A means a group R '-YN = or a group R'-YN (R9) -, where R' means an alkyl group of 1-6 carbon atoms, an aralkyl group of 7-10 carbon atoms, group diphenylmethyl, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or a phenyl or phenoxy or phenylalkyl group containing 7-10 carbon atoms, or a phenylalkyloxy group containing 7-10 carbon atoms, optionally substituted with halogen atoms or alkyl groups of 1-4 carbon atoms, or nitro groups; Y means a chemical bond or an oxo, sulfonyl or sulfinyl group, R9 means a hydrogen atom or an alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X can not mean a group -CH2-, a group -NH-, an oxygen atom or a sulfur atom, and in the case of formulas (30) and (31), X can not mean a group -CH2-, an oxygen atom or a sulfur atom or an amino group; B means a group - (CH2) m-C (0) -, where m is an integer from 1 to 21; or a group -0- (CH2) P-C (0) -, where p is an integer from 1 to 3; or a group independently denote one of the other hydrogen, an alkyl or alkoxy group of 1-6 carbon atoms, halogen, an amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or a phenyl, phenoxy, or arylalkyl group of 7-12 carbon atoms, or an arylalkoxy group of 7-12 carbon atoms, each optionally containing 1, 2 or 3 substituents, identical or different, identical to R 1, R2, R3 or R4; or two of R9, R10, R11, R12, R13 and R14 together mean an oxo or epoxy group, or an additional chemical bond, or four of them together signify two additional chemical bonds, and the remaining groups represent hydrogen atoms; or R9, R10, Ru, R12, R13 and R14 mean, together with the carbon atoms of the chain, a saturated or unsaturated homocycle, containing 3-8 carbon atoms, or a saturated or unsaturated heterocycle containing 2 or -7 carbon atoms and a nitrogen or sulfur atom, to which an aromatic ring of 6-10 carbon atoms is optionally condensed; Y w is zero or 1; C means a prolyl group, or one of the groups of formula (37), (38), (39), (40) or (41) - wherein n is zero or 1 or 2, Hlg means a fluorine atom, chlorine, bromine, or iodine; R5 and R6 signify, independently of one another, a hydrogen atom, a hydroxyl group, a phenyl group or an alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R16 means an alkoxy group of 1-4 carbon atoms, or a group -NH-CH2-CN, or a group -NH-CH2-C02R7, wherein R7 is defined above; or the structural unit D or L; or one of the groups in the formula (42) or (43) or (43a) - wherein the dotted line means an optionally present chemical bond-, s is 1, 2 or 3 - or a group of the formula (44) - wherein R15 signifies an atom of hydrogen, an alkyl group of 1-6 carbon atoms, a phenyl or naphthyl group; or a group of the formula (45) - where Z means a group -NH, an oxygen atom or a sulfur atom; D means a covalent chemical bond, or a prolyl or thioprolyl group, or one of the groups of formula (37) or (38), (39), (49) or (41); L means a pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group, optionally substituted with a halogen atom, or geminally with two halogen atoms; or a group of the formula (46) - wherein R17 signifies a hydrogen atom or a cyano group, n is 0, 1 or 2; or a group of formula (47) or (48) or (49); - and the optical isomers, cis-trans, geometrical, epimeros, tautomers, salts, prodrugs and human and mammalian metabolites of them.
3. Compounds according to claim 2, characterized in that A means a group of the general formula (20a) or (23a) - wherein R means a hydrogen atom, an alkyl group of 1-4 carbon atoms, or an aryl group or aralkyl of 6-12 carbon atoms; R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, straight or branched chain alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy groups, containing 1 -6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms - wherein the acyl group is one of the alkyl, aralkyl type , cycloalkyl or aryl-, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group from 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1-6 carbon atoms, sulfamino or sulfamollo group, thiocyanate group or cyanate, R5 and Rb signify, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or Rb and R ° together mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; B means a group - (CH2) m-C (O) -, where m is 2 or 3; C means a prolyl group, or a group of general formula (38) or (41) - wherein n is 1 or 2; D means a covalent chemical bond; L means a pyrrolidino or thiazolidino group - and the optical isomers, cis-trans, geometrical, epi-eros, tautomers, salts, prodrugs and human and mammalian metabolites thereof.
4. Pharmaceutical composition characterized in that it contains one or more compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claims 1 and 2 - and / or the optical isomers, cis-trans, geometrical, epimeros, tautomers, salts, prodrugs and human and mammalian metabolites thereof, alone or together with carriers and / or usual auxiliary materials applied in the pharmaceutical industry.
5. A process for the preparation of compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claims 1 and 2 - and / or the optical isomers, cis- trans, geometrical, epimerous, tautomeric, and their salts, characterized in that a racemic or optically active carboxylic acid of the general formula (II) - wherein the meanings of A and B are as given in claims 1 and 2 - is transformed to an acid halide, or an active ester, or a mixed acid anhydride, or a carbodiimide, and the resulting compound is reacted with a racemic or optically active compound, or its salt of the general formula (III), - in where the meanings of C, D and L are as given in claim 1 - and the resulting compound of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in Claims 1 and 2 - optionally separated into its optical isomers, cis-trans, or geometries, epimers or tautomers, or a salt is formed of the compounds of general formula (I), or the compounds of the general formula (I) are liberated from their salts.
6. Use of the compounds of the general formula (I) according to claim 1 or 2, characterized in that it is for the inhibition of the prolyl-endopeptidase enzyme in mammals, including man.
7. Compounds of the general formula (I), characterized in that A means, one of the groups having the general formula (1), (2), (2a), (3) and (3a), (4), (5) , (6), (7), (8), (9), (10), (lia), (llb), (12), (12a), (13), (13a), (14), ( 15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (25a), (26) , (27), (28), (28a), (29), (30), (31), (32), (32a), (33), (34), (35), (36) - en where R means a hydrogen atom, an alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-10 carbon atoms; R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, a hydroxyl group, straight or branched chain alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or alkynyloxy groups, containing 1 -6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms carbon - wherein the acyl group is one of the alkyl, aralkyl, cycloalkyl or aryl type -, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms carbon, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1 6 carbon atoms, sulfamino or sulfamoyl group, thiocyanato group or cyanate, R5 and Rb signify, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together they mean an oxo group; R 'means an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom ^ or a hydrogen atom, an oxygen atom or an amino group; or A means a group R '-Y-N = or a group R'-Y-N (R9) -, where R' means an alkyl group of 1-6 carbon atoms, an aralkyl group of 7-10 carbon atoms, group diphenylmethyl, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or a phenyl or phenoxy or phenylalkyl group containing 7-10 carbon atoms, or a phenylalkyloxy group containing 7-10 carbon atoms, optionally substituted with halogen atoms or alkyl groups of 1-4 carbon atoms, or nitro groups; Y means a chemical bond or an oxo, sulfonyl or sulfinyl group, R9 means a hydrogen atom or an alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X can not mean a group -CH2-, a group -NH-, an oxygen atom or a sulfur atom, and in the case of formulas (30) and (31), X can not mean a group -CH2-, an oxygen atom or a sulfur atom or an amino group; B means a group - (CH2) m-C (O) -, where m is an integer from 1 to 21; or a group -O- (CH_2) P-C (O) -, wherein p is an integer from 1 to 3; or a group -where R9, R10, Rn, R12, R13 and R14 independently denote one of the other hydrogen, an alkyl or alkoxy group of 1-6 carbon atoms, halogen, an amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or a phenyl, phenoxy, or arylalkyl group of 7-12 carbon atoms, or an arylalkoxy group of 7-12 carbon atoms, each ring thereof optionally containing 1, 2 or 3 substituents, identical or different, identical to R1, R2 , R3 or R4; or two of R9, R10, R11, R12, R13 and R14 together mean an oxo or epoxy group, or an additional chemical bond, or four of them together signify two additional chemical bonds, and the remaining groups represent hydrogen atoms; or R9, R10, R11, R12, R13 and R14 mean, together with the carbon atoms of the chain, a saturated or unsaturated homocycle, containing 3-8 carbon atoms, or a saturated or unsaturated heterocycle containing 2 or more carbon atoms. -7 carbon atoms and a nitrogen or sulfur atom, to which an aromatic ring of 6-10 carbon atoms is optionally condensed; and w is zero or 1; C means a prolyl group, or one of the groups of formula (37), (38), (39), (40) or (41) - wherein n is zero or 1 or 2, Hlg means a fluorine atom, chlorine, bromine, or iodine; R5 and R6 signify, independently of one another, a hydrogen atom, a hydroxyl group, a phenyl group or an alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; Rld means an alkoxy group of 1-4 carbon atoms, or a group -NH-CH2-CN, or a group -NH-CH2-C02R7, wherein R7 is defined above; or the structural unit D or L; or one of the groups of the formula (42) or (43) - wherein the dotted line means an optionally present chemical bond, or a group of the formula (44) -. wherein R 5 represents a hydrogen atom, alkyl group of 1-6 carbon atoms, a phenyl or naphthyl group; or a group of the formula (45) - wherein Z means a group -NH, an oxygen atom or a sulfur atom; D means a covalent chemical bond, or a prolyl or thioprolyl group, or one of the groups of formula (37) or (38), (39), (49) or (41); L represents a pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group, optionally substituted with a halogen atom, or geminally with two halogen atoms; or a group of the formula (46) - wherein R17 signifies a hydrogen atom or a cyano group, n is 0, 1 or 2; or a group of the formula (47) or (48); and the optical, cis-trans, geometric isomers, epimers, tautomers, salts, prodrugs and human and mammalian metabolites thereof. (priority: August 1, 1995)
8. Compounds in accordance with the claim 7, characterized in that A means a group of the general formula (1) or (9) u (lia) u (llb) or (13) or (22) - wherein R means a hydrogen atom, an alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-10 carbon atoms; R1, R2, R3 and R4 mean, independently of each other, a hydrogen atom, a halogen atom, a hydroxyl group, alkyl or alkenyl or alkynyl or alkoxy or alkenyloxy or straight or branched chain alkynyloxy groups, containing 1-6 carbon atoms, a nitro group, an amino group , monoalkylamino or monoacylamino of 1-12 carbon atoms, a dialkylamino or diacylamino group of 2-24 carbon atoms - where the acyl group is one of the alkyl, aralkyl, cycloalkyl or aryl type -, a cyano group, a group mercapto, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group , anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1-6 carbon atoms, sulfamino or sulphamoyl group, thiocyanate group or cyanate, R5 and R6 mean, independently of each other, atom of hydrogen, gr ux hydroxyl, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; Rd means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; B means a group - (CH2) m-C (O) -, where m is 2 or 3; C means a prolyl group, or a group of the general formula (38) or (41) - wherein n is zero or 1 or 2; D means a covalent chemical bond; means a pyrrolidino group - and the optical, cis-trans, geometric isomers, epimers, tautomers, salts, prodrugs and human and mammalian metabolites thereof. (Priority: August 17, 1995)
9. Compounds according to claim 7, characterized in that: A means a group of the general formula (1) or (4) or (9) u (Ha) u (llb) - wherein R means a hydrogen atom., A alkyl group of 1-4 carbon atoms, or an aryl or aralkyl group of 6-10 carbon atoms, * R1, R2, R3 and R4 signify, independently of one another, a hydrogen atom, a halogen atom, an hydroxyl group, alkyl or alkenyl or alkynyl or alkoxy groups or straight or branched chain alkenyloxy or alkynyloxy, containing from 1-6 carbon atoms, a nitro group, an amino, monoalkylamino or monoacylamino group of 1-12 carbon atoms, a dialkylamino or diacyla ino group of 2-24 carbon atoms carbon - wherein the acyl group is one of the alkyl, aralkyl, cycloalkyl or aryl type -, a cyano group, a mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms carbon, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanate group, isothiocyanate group, alkylthio group of 1- 6 carbon atoms, sulfamino or sulphamoyl group, thiocyanate group or cyanate, R5 and R6 mean, independently of one another, hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1-4 carbon atoms, or R5 and R6 together they mean an oxo group; R7 is an alkyl group of 1-6 carbon atoms; R8 means a hydrogen atom or an alkyl group of 1-6 carbon atoms, or an aralkyl group of 7-10 carbon atoms; dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means a group -CH2-, a group -NH-, a carbon atom, or a hydrogen atom, an oxygen atom or an amino group; B means a group - (CH mC (0) -, where m is 2 or 3, C means a prolyl group, or a group of the general formula (38) or (41) - where n is zero or 1 or 2; D means a covalent chemical bond; L means a pyrrolidone or thiazolidino group - and the optical, cis-trans, geometric, epimer, tautomer, salt, prodrug, and human and mammalian metabolites thereof (Priority: August 17 of 1995)
10. Pharmaceutical composition characterized in that it contains one or more compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claim 7 - and / or the optical isomers, cis- trans, geometrical, epimeros, tautomers, salts, prodrugs and human and mammalian metabolites thereof, alone or together with carriers and / or usual auxiliary materials applied in the pharmaceutical industry. (Priority: August 17, 1995)
11. A process for the preparation of compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claim 7 - and the optical, cis-trans, geometric isomers, epimers, tautomers, and their salts, characterized in that a racemic or optically active carboxylic acid of the general formula (II) - wherein the meanings of A and B are as given in claim 7 - is transformed to an acid halide, or an active ester, or a mixed acid anhydride, or a carbodiimide, and the resulting compound is reacted with a racemic or optically active compound, or its salt of the general formula (III), - wherein the meanings of C, D and L are as given in claim 7. - and the resulting compound of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claim 7 - optionally separated into their optical isomers, cis-trans, or geometries, epimers or tautomers, or a salt is formed of the compounds of general formula (I), or the compounds of the general formula (I) are liberated from their salts. (Priority: August 17, 1995)
12. A process according to claim 11, characterized in that an acid addition salt of the compound of general formula (III) is used. (Priority: August 17, 1995)
13. A process according to claim 11, characterized in that a reactive mixed anhydride is formed by starting from a compound of the general formula (II), and applying pivaloyl chloride. (Priority: August 17, 1995)
14. A process according to claim 11, characterized in that the reaction is carried out in an organic solvent. (.Priority: August 17, 1995)
15. A process according to claim 11, characterized in that the reaction is carried out at a temperature between -25 ° C and the boiling point of the reaction mixture. (Priority: August 17, 1995)
16. A process according to claim 11, characterized in that the reaction is carried out in the presence of an agent that captures acid. (Priority: August 17, 1995)
17. Use of the compounds of the general formula (I) according to claim 6, characterized in that it is for the inhibition of the prolyl-endopeptidase enzyme in mammals, including man. (Priority: August 17, 1995)
18. Compounds according to claim 1 or claim 7, characterized in that they are substantially as described above.