WO1998035960A1

WO1998035960A1 - Prolylendopeptidase inhibitors

Info

Publication number: WO1998035960A1
Application number: PCT/HU1998/000016
Authority: WO
Inventors: Sándor BÁTORI; Judit Bence; Erzsébet FEJÉR; István HERMECZ; ágnes Horváth; Zoltán Kapui; Károly KÁNAI; Zsolt MOLNÁR; Behr Ágnes PAPPNÉ; Judit Sipos; Edit SUSÁN; Zsuzsa SZAMOSVÖLGYI; Gábor SZELECZKY
Original assignee: Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt.
Priority date: 1997-02-14
Filing date: 1998-02-13
Publication date: 1998-08-20
Also published as: HUP9700442A1; HU9700442D0; AU6225198A

Abstract

The present invention relates to new prolylendopeptidase inhibitors of general formula (I).

Description

PROLYLENDOPEPTIDASE INHIBITORS

The present invention relates to new compounds of the general formula (I), to pharmaceutical compositions containing them, and to the process for the preparation of these compounds. A further aspect of our present invention is the use of the new compounds of the general formula I for the treatment of CNS diseases by inhibition of certain enzymes described later on on this page.

Because of the incidence and social consequences of diseases of the central nervous system accompanied with amnesia, dementia and the progressive decline of cognitive and intellectual functioning, for example Alzheimer disease, AIDS dementia, senile dementias of various origin (hypoxia, ischaemia), there are significant demands for new pharmaceuticals for treating and preventing the diseases mentioned above.

Prolyl endopeptidase PE or PEP is a post-proline cleaving enzyme (PPCE). It is widespread in mammalian species and can be found in various organs of the body. The level of the enzyme is the highest in the brain, testis and skeletal muscle (Yoshimoto T., Ogita K., Walter R., Koida M. and Tsuru D.: Biochim. Biophys. Acta, 569, (1979), 184-192).

PEP has some important role in the memory process due to the fact that its substrates are biologically active neuropeptides (substance P, thyrotropin-releasing hormone, Arg -Vasopressin). These neuropeptides exert characteπstic 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., Fujiwara T. and Abe H.: J. Pharm. Exp. Therapeutics, 274, (1995), 1370-1378; Riedel W. and Jolles J.: Drugs & Aging, 8, (1996), 245-274). The neuropeptide sustance P prevents β -amyloid-induced neuronal loss and expression of Alz-50 proteins in cerebral cortex (Kowall N., Beal M.F., Busciglio J. and Duffy L.K.: Proc Natl. Acad. Sci., 88, (1991), 7247-7251). It is well known that in the brain of patients with Alzheimer's disease, the cerebral ACh content is decreased and the cerebral function suffers severe damage (O'Leary R. and O'Connor B.: J. Neurochem., 65, (1995), 953-963). A PEP inhibitor, through increasing the level of TRH, could induce ACh release in the brain which should result in a better cognitive performance. It can be supposed that a highly specific PEP inhibitor proves to be useful in the treatement of disorders of the central nervous system in neurodegenerative illnesses.

The new PEP inhibitor as a new drug would be a

1. nootropic drug having memory enhancing and anti-amnesic effect which could be used in the treatment of age-related cognitive decline;

2. neuroprotective agent 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 are becoming a serious and fastly outgrowing problem of the aging population. A PEP inhibitor could be useful for the general treatment of the above mentioned serious diseases.

We set ourselves the task to prepare new PEP-inhibitors displaying advantageous characteristics which could serve as active ingredients of new drugs. By advantageous characteristics we mean a strong PEP - inhibitory effect, selectivity, easy transfer through the blood-brain barrier, long half-life, good oral resorption, enchanced chemical and biological stability and advantageous therapeutic profile including low toxicity and low probability of side effects.

In the course of the synthesis and biological examination of numerous new compounds we found that new compounds of the general formula (I), wherein A means a mono or multiple substituted or unsubstituted organic cyclic group containing one nitrogen atom with one free valency and optionally one or more further heteroatom, selected from a group consisting of nitrogen atom, sulfuratom or oxigenatom, especially a group having the general formula (1), (la), (2), (2a), (3), (3a), (4a), (4b), (5), (6), (7), (8), (9), (10), (11a), (l ib), (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 hydrogen atom alkyl group of 1-4 carbon atoms or aryl or aralkyl group of 6-12 carbon atoms;

Rl, R2, R3 and R4 mean independently from each other hydrogen atom, halogen atom, hydroxyl group, straight chain or branched chain alkyl- or alkenyl- or alkinyl- or alkoxy- or alkenyloxy- or alkinyloxy groups containing 1-6 carbon atoms, nitro group, amino group, monoalkylamino- or monoacylamino group of 1- 12 carbon atoms, dialkylamino- or diacylamino group of 2-24 carbon atoms - where the acyl group is an alkyl-, aralkyl-, cycloalkyl- or aryl type -, cyano group, 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, isocyanato group, isothiocyanato group, alkylthio group of 1-6 carbon atoms, sulfamino or sulfamoyl group, thiocyanato or cyanato group;

R5 and R^ mean independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1- 4 carbon atoms or R^ and R^ together mean oxo group;

R means hydrogen atom or alkyl group of 1-6 carbon atoms; R8 means hydrogen atom or alkyl group of 1-6 carbon atoms or aralkyl group of 7-10 carbon atoms or alkoxycarbonyl-alkyl group of 3-6 carbon atoms; or aliphatic or aromatic acyl group of 1-7 carbon atoms or difluoro- or trifluoro- or polyfluoro acyl group of 2-6 carbon atom, the dotted line means an optional chemical bond; n is zero 1, 2 or 3;

X means-CH.2-group, -NH-group, carbon atom, hydrogen atom, oxygen atom or amino group; or R⁹

A means an R - Y - N = group or R -Y-N- group - wherein R' means alkyl group of 1-6 carbon atoms, aralkyl group of 7-10 carbon atoms, diphenylmethyl group, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or phenyl- or phenoxy- or phenylalkyl group containing 7-10 carbon atoms or 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 chemical bond or oxo-, sulfonyl- or sulfinyl group, R⁹ means hydrogen atom or alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X cannot mean

- CH2- group, - NH- group, oxygen atom or sulfur atom and in the case of formulas (30) and (31) X cannot mean - CH2- group, oxygen atom or sulfur atom or amino group;

B means -(CH₂)_m - C - group - wherein m is an integer of 1 to 21; or O R^s

- (CH₂)_m - N - C -group O

- wherein R means the same substituents as defined above, or -O-(CH₂)_p - C - group wherein p is an integer of 1 to 3; or

O

group - wherein R⁹, R¹⁰, R^{1 1}, R¹², R¹³ and R¹⁴ mean independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl group of 1-6 carbonatoms; or phenyl, phenoxy, aryl-alkyl group of 7-12 carbon atoms or aryl-alkoxy group of 7- 12 carbon atoms each of them optionally containing 1, 2 or 3 of the same or different substituents identical to R¹, R², R³ or R⁴; or two of R⁹, R¹⁰, R¹¹, R¹²', R¹³ and R¹⁴ mean together an oxo or epoxy group or further chemical bond, or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or

R⁹, R¹⁰, R¹¹, R¹²', R¹³ and R¹⁴ mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is o condensed; R means the same substituents as defined above, and w is zero or 1 ; C means prolyl group or one of the groups of formula (37), (38), (39), (40) or (41)

- where n is zero or 1 or 2, Hlg means fluoro, chloro, bromo, or iodo atom;

R and R mean independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1-4 carbonatoms or R⁵ and R⁶ together mean oxo- group; Rl6 means an alkoxy group of 1-4 carbon atoms, or -NH- CFf? -CN group, or - NH-CH2-CO2R group - where R^ is defined as above; or D or L structural unit; or one of the groups of the formula (42) or (43) or (43a)

- where the dotted line means a chemical bond optionally present-, s is 1, 2 or 3 - or a group of the formula (44) -wherein R 5 means hydrogen atom, alkyl group of 1-6 carbon atoms, phenyl or naphthyl group; or a group of the formula (45) - wherein Z means NH - group, oxygen atom or sulfur atom;

D means a covalent chemical bond or prolyl- or thioprolyl group, or one of the groups of formula (37) or (38), (39), (40) or (41);

L means pyrrolidino or 2-cyanopyrrolidino, thiazolidino or 2-cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - wherein Rl means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49); or a group of formula (46) - wherein

R¹⁷ means - CF₂H group or a group of the formula (50) or formula (51) - wherein

R means hydrogen atom, halogen atom, l,3-dioxolan-2-yl group or -OR group wherein R stands for hydrogen atom or alkyl group of 1-6 carbon atom or phenyl group optionally substituted by one or two alkoxy group of 1-4 carbon atom or alkyl group of 1-4 carbon atom or nitro groups; n is 0, 1 or 2

R¹⁹ means hydrogen atom halogen atom l,3-dioxolan-2-yl group or - OR group

71 wherein R stands for alkyl group of 1-6 carbon atoms or phenyl group optionally substituted by one or two alkoxy group of 1-4 carbon atoms or alkyl group of 1-4 carbon atoms or nitro groups, or

R¹⁸ and R¹ form together an oxo-group;

70 77

R means a - (CH₂)_t - T - R group - wherein t is 0, 1 or 2, T is an oxygen or sulphur

O

I atom, = S = O; - S - or II O

77

- NH- group or a chemical bond and R means hydrogen atom, phenyl, 2- thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyrrolyl, thienyl, 2-benzothiazolyl, 2- benzoxazolyl, 2- benzimidazolyl, 2-indolyl, 2-thiazolo[5,4-b]pyridinyl, 2- oxazolo[4,5-b]pyridinyl, 2-imidazolo[4,5-b]pyridinyl, 5-thiazolyl, 2-thiazolinyl,

2-pyridinyl, 3-pyridinyl, 5- pyrimidinyl, 2-pyrazinyl, 2-triazolyl, 2-pyrazolyl ring optionally substituted by one or two alkyl group of 1-6 carbon atoms, alkoxy group of 1-6 carbon atoms or phenoxy group, or R²² means a - CF₂ - C - R²³ group -

O wherein R means hydroxy group, alkoxy group of 1-6 carbon atoms or - NR

7 74 7

R -group - wherein R is alkyl group of 1-6 carbon atoms, R is alkyl group of 1- 6 carbon atoms or R and R form together a alkylene group of 1-5 carbon atoms with the proviso that if a.) B means -(CH₂)_m - C - group - wherein m is an integer of 1 to 21; or

O -O-(CH₂)_p - C - group wherein p is an integer of 1 to 3; or O

Rl3 and R¹⁴ mean

independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or phenyl group, phenoxy group, aryl-alkyl group of 7-12 carbon atoms or aryl-alkoxy group of 7-12 carbon atoms each of them optionally containing 1, 2 or 3 of the same or different substituents identical to R ,

R², R³ or R⁴; or two of R , R , R , R ', R and R mean together an oxo or epoxy group or further chemical bond, or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or

R , R , R , R ', R and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; and w is zero or 1 ;

L cannot mean pyrrolidino- or 2-cyanopyrrolidino, thiazolidino or 2- cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R¹^ means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49); or if b.) L means pyrrolidino- or 2-cyanopyrrolidino, thiazolidino or 2- cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R^{1 #}7 means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49);

B cannot mean -(CH₂)_m - C - group - wherein m is an integer of 1 to 21; or

O

-O-(CH₂)₀ - C - group wherein p is an integer of 1 to 3; or

II O

C- group - wherein R⁹, R10, RU , R12, R¹³ and R¹⁴ mean II

O independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl groups of 1-6 carbon atoms; or phenyl group, phenoxy group, aryl-alkyl group of

7-12 carbon atoms or aryl-alkoxy group of 7-12 carbon atoms each of them optionally containing 1, 2 or 3 of the same or different substituents identical to R¹, R², R³ or R⁴; or two of R , R , R , R ', R and R mean together an oxo or epoxy group or further chemical bond, or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or

R , R , R , R ', R and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; and w is zero or 1; - and optical , cis-trans, geometric isomers , epimers, tautomers, salts, prodrugs and human and mammalian metabolites of them having significant prolylendopeptidase inhibiting effect and they show one or more of the advantages mentioned above. The meaning of „mono or multiple substituted or unsubstituted organic cyclic group containing one nitrogen atom with one free valency and optionally one or more further heteroatom(s) selected from a group consisting of nitrogen atom, sulfuratom or oxigen atom" in case of A covers all known monocyclic or polycyclic groups satisfying the above definition. In case of a polycyclic group the rings may be condensed and/or may be in spirocyclic position. Some representatives of the above cyclic moieties are depicted in formulas (1), (la), (2), (2a), (3), (3a), (4a), (4b), (5), (6), (7), (8), (9), (10), (1 la), (l ib), (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 chain or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. The „aryl group of 6-10 carbon atoms" 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 chain or branched alkenyl group such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl-, 4-pentenyl-, 2-hexenyl-, 5-hexenyl. The „alkinyl group of 1-6 carbon atoms" means a straight-chain or branched alkinyl group such as ethynyl, propargyl, 2-butynyl-, 3-butynyl, 2-pentynyl, 4-pentynyl, 2- hexynyl 5-hexynyl 4-methyl-2-hexynyl. The cycloalkyl part of the „acyl group of 1-12 carbonatoms" means for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group. These definitions may be used in the cases of alkyloxy, alkenyloxy-, alkinyloxy, aryloxy,aralkyloxy, phenylalkyloxy or alkylamino or acylamino groups. Halogen atom means fluoro, chloro, brom or iodo atom, preferably fluoro atom. Acyl group means acetyl, formyl, benzoyl group, difluoro- trifluoro- or polyfluoro acyl group e.g. trifluoroacetyl group or pentafluoropropionyl group.

We have examined the PEP - inhibitory activity and the biological stability of the compounds characterised by formula (I) applying the following methods:

PEP activity measurement on rat brain extract:

After removal of the cerebellum whole brain of male (Sprague-Dawley,180-200g) rats was homogenized in a double volume of 0.1 M Tris-HCl, lrnM EDTA buffer, pH=7.5 (PEP buffer). The homogenate was centrifuged for 30 min. at 4°C at 40000 g and the supernatant, containing the enzyme, was collected. The pellet was re- suspended in the same volume of buffer as in the first case and centrifuged again under the same conditions. The two supernatants were pooled and stored in 1ml aliquots at -70°C (for at least 3 months). The supernatant was thawn just before activity measurement and diluted in a 1 :15 ratio with PEP buffer. The enzyme activity was measured by using fluorometric method described by J. R. Atack et al. (Eur J. Pharmacol., 205, (1991), 157-163). Enzyme reaction 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 the PEP. The inhibitory effect of the compounds was tested under the same conditions in the presence of 100 to 0.001 nM of the compound. The formation of 7-amino-4-methyl-coumarin was detected spectrofluorometrically at 370 nm exitation and 440 nm emission wavelength. The 50% inhibition concentration values of the compounds (IC₅₀) were calculated by curve fitting of the % inhibition of the enzyme versus inhibitor concentration (M) using Hill- equation. IC₅₀ values of the compounds of the general formula (I) are in the range of lOOnM - lpM.

Pig brain PEP activity measurement

Purified pig brain prolyl endopeptidase was a kind gift from Laszlό Polgar (Enzymology Institute of the Hungarian Academy of Sciences). Enzyme solution was diluted in the reaction mixture 400000 times. Measurements were performed under the same conditions as in the case of the in vitro measurements on rat brain preparation. The compounds of the general Formula I were shown to be active also on pig brain PEP activity test.

In vitro metabolism studies

The biological stability of prolyl endopeptidase inhibitors was studied in mouse, rat and human (preparation of the Central Chemistry Institute of The Hungarian Academy of Sciences) liver microsomal preparation. Mouse and rat livers were pooled and homogenized in 4-fold volume Tris-HCl buffer (pH 7.4) containing 1.15% KC1 and lmM EDTA The homogenates were centrifuged for 30 minutes at 10000 g, the supernatants were further ultracentrifuged for 1 hour at 105000 g. Pellets were rehomogenized and ultracentrifiigation was repeated. The pellets were re-homogenized again and were diluted with buffer to a final volume of 0.5 g liver/ml. Samples were frozen in 2ml aliquots at -80 °C. Preparations were characterized for cytochrome P450 isoenzyme activities.

New inhibitors of the general formula (I) were tested under the following conditions: The reaction mixture contained 2mg of liver microsomal protein, 0. IM of Tris-HCl buffer (pH=7.4), of NADP, 20mM of glucose-6-phosphate disodium salt, 10 mM of MgCl₂ 5 TJ glucose-6-phosphate dehydrogenase and 50 μM of PEP inhibitors in a final volume of 1.5 ml. After 0, 10, 20. 40 min incubation times, reaction was terminated by addition of acetonitrile. Samples were centrifuged at 3000 rpm for 10 minutes. The supernatant was analyzed by HPLC (Supelcosil C18). The unchanged substrate amount was determined and half-life of the compounds were calculated.

Some compounds of the general (I) had half-life on human liver microsomes of more than 7 hours. Such good biological stabilities favour an long lasting effect in vivo and are an advantage over other peptidic-type PEP-inhibitors which are known to be biologically unstable. The published European Patent Application No 0 232 849 A2 describes numerous PEP-inhibitors including SUAM-1221 (N-[N-(γ-phenyl)butyryl-L- prolyl]pyrrolidine).

The compounds of the general formula (I) exert high inhibition activity on prolyl endopeptidase their effect is greater than that of the above reference compound, SUAM- 1221 , measured in our test-system described above.

The preparation of compounds of the general formula (I) is carried out by methods well known from the literature or by obvious chemical equivalents thereof related to the synthesis of peptide type substances. The A and B units of compounds of the general formula A - B - C - D - L (I) - where 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 arnine, yielding compounds of the general formula (II) - where the meanings of A and B are as described above. The coupling of units C and D happens likewise by coupling the appropriate activated acid derivative e.g. acid anhydride and an amine. The coupling of units CD and L to yield compounds of the general formula (III) - where the meanings of CD and L are as described above - is carried out by reacting the appropriate mixed anhydride and amine resp. ester and metallo - organic compound. The starting compounds corresponding to units A, B, C, D, and L are commercially available or readily producible by known transformations of them or as described in Chem. Pharm. Bulletin 41 (9) p 1583-1588 (1993.) The compound (IV) can be prepared from the commercially available /-proline by a known route according to the process described by Azami et. al. (Bioorg.Med. Chem.Letters 1995, 5, 2199. The compounds of formula (III) can be prepared from (IV) by one of the reaction routes shown below. All the abbreviations have the same meaning as defined previously.

(X)

(XIII) _(XIV)

The epoxide compound (V) is obtained from the protected /-prolinal (IV) by a conventional method described by Corey and Chaykovsky (J. Am. Chem. Soc.

1962, 84, 3782.

The compound of the formula (VI) may be obtained by treating the epoxide (V) with an appropriate phenolic compound in the presence of a base such as sodium methoxide at reflux temperature in methanol. The keto derivatives (IX) or (XII) could be obtained by treating the compound (VI) or (XI) separately with an oxidizing agent, preferable oxalyl chloride and dimethyl- sulfoxide in the presence of triethylamine at a temperature between 0°C and -60°C. The N-protected prolinal (IV) is reacted with heterocycles in the presence of a strong base (butyllithium or the like) in an inert solvent, such as THF, at -75°C to yield a compound of the general formula (XI).

The free alcohol function of the (V) or (XI) is protected as Tosyl or Mesyl derivatives (S.R.Sandler and W. Karo Organic Functional Group Preparations Vol. I. p633- Academic Press 1983. Second Edition) and then treated with spray-dried KF in a suitable solvent such as ethylene glycol at 80 °C to give compound (VIII) or (XIII) respectively. These compounds of the formula (VI) or (XI) when treated directly with DAST in benzene or dichloromethane also resueted in formation of mono fluoro compounds such as formulas (VIII) or (XIII).

A compound of the formula (IX) or (XII) is reacted with DAST [(diethylamino)sulfur trifluoride] in a suitable solvent such as benzene at the room temperature to give compound (X) or (XIV) respectively. Removal of R in (IX), (X) or (XI) by cerium ammonium nitrate in aqueous acetonitrile-pyridine mixture preferable at room temperature could give useful intermediate to the compound of formula (III) as well.

We have prepared the compounds of general formula (I) by reacting activated derivatives of compounds of the general formula (II) with compounds of the general formula (III) under conditions of amide coupling usual in peptide chemistry. The activated derivatives of compounds having general formula (II) were e.g. acid chlorides, which can be synthesized by applying halogenating agents (e.g. thionyl chloride). Active esters can be produced by 1-hydroxybenzotriazole in the presence of N,N'-dicyclohexylcarbodiimid (Chem. Ber. 103, 788/1970/). Mixed anhydrides can be produced by alkyl chloroformates or by pivaloyl chloride (Methoden der Organischen Chemie (Houben-Weyl) Band XV/2 Synthese von Peptiden, Georg Thieme Verlag, Stuttgart, 1974).

The coupling reaction can favourably be carried out in organic solvents (preferably at a temperature between - 25°C and the boiling point of the reaction mixture). Use of acid binding agents e.g. organic amines is favourable during the reaction. A compound of formula (I) can also be prepared by other condensation method. According to this an amine component (III) is coupled to an isocyanate formed in situ from an acid (II) via a modified Curtius degradation [Eaton et.al. J.Org.Chem. 1984, 49, 185.] to give (I) in very good yield. Diphenyl phosphorazidate is a commonly used reagent in this proccess. Preferable solvents for this reaction are toluene, xylene, THF or DMF. The reaction temperature may vary from room temperature to 120°C, preferably a range from 80 to 120°C is applied.

The compounds of the general formula (I) can be purified, if appropriate, by a conventional purification technique, its isomers, if desired, may be separated by a conventional separation technique, and they are converted, if necessary, to their addition salts with a pharmaceutically acceptable acid. Pharmaceutically acceptable acids may be for example hydrochloric, sulfuric, tartaric, fumaric, methanesulfonic acid and the like.

Another subject of the present invention is pharmaceutical compositions containing, as active principle, at least one compound of general formula (I) or one of its addition salts with a pharmaceutically acceptable acid, alone or in combination with one or more inert and nontoxic excipients or vehicles. Mention may more particularly be made, among pharmaceutical compositions according to the invention, of those which are suitable for oral, parenteral, rectal or nasal administration, simple or sugar-coated tablets, sublingual tablets, injectable compositions, infusions, packets, 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 the severity of the ailment and on the administration route. The latter can be oral, nasal, rectal or parenteral. The unit dose generally varies between 0,1 and 50 mg/body weight kg 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 process description in case of the example 3. Other embodiments of the invention will be apparent to the person skilled in the art from a consideration of this specification or practice of the invention disclosed herein. Example 1

Description of the preparation of compound depicted as Example 1 (Table 1.)

A mixture of 1.1 g of 3-phthalimido-propionic acid and 6 ml thionyl chloride was refluxed for 1 hour. The reaction mixture was cooled to room temperature and evaporated. The residue was dissolved in 5 ml of dichloromethane and reacted with 1.3 g of 2-(3-hydroxy-l-oxopropyl)-l-pyrrolidinyl-carbonyl-l-pyrrolidine dissolved in a mixture of 10 mL of dichloromethane and 1,5 mL of triethylamine. The reaction mixture was stirred at room temperature for 4 hours, then it was washed successively with water, 30 % cc. citric acid solution, saturated aqueous sodium bicarbonate solution, water and sodium chloride solution. The organic phase was dried on calcinated magnesium sulfate and it was evaporated. The residue was purified by silica gel chromatography (eluent: chloroform-methanol) to give the title compound (1.3g, 53%) as a waxy solid.

Η-NMR (DMSO-d₆) δ 1.7-2.2 (8H, M), 2.6 (2H, m), 3.4-3.75 (total 6H, m), 4.1-

5.2 (5H, m), 7.8-7.9 (4H, m)

R_f= 0.27 (chloroform-methanol 20-1)

Example 2

Description of the preparation of compound depicted as Example 2 (Table 1.)

To a solution prepared by dissolving 2,21 g (10,0 mM) 3-phthalimido-propionic acid and 1,12 g (11,0 mM) triethylamine in 30 mL chloroform 1,22 g (10,0 mM) pivaloil chloride were dropped at -15 °C under stirring. The reaction mixture was stirred for 1 hour at the above temperature and then a solution prepared by dissolving 5,53 g (10,0 mM) 2-(4-methoxyphenoxyacetyl)-pyrrolidinyl-carbonyl- pyrrolidine acid salt in a mixture of 10 mL chloroform and 3 mL (2,2 g, 22 mM) triethylamine was dropwise added to it. The reaction mixture was stirred at room temperature for 4 hours, then it was washed successively with water, 30% cc. citric acid solution, saturated aqueous sodium hydrogene carbonate solution, water and finally with saturated sodium chloride solution. The organic phase was dried on calcinated magnesium sulphate and it was evaporated. The residue was purified by silica gel chromatography (eluent chloroform-methanol) to give the title compound (2,9 g, 59%) as a white waxy solid.

'-HMR (DMSO-d₆) δ 1.7-2.25 (total 8H, m), 2.6-2.7 (2H, m), 3.2 (3H, s), 3.3-3.8 (total 6H, m), 4,5-4.9 (total 4H, m), 6.8-6.85 (4H, m), 7.8-7.9 (4H, m)

R_f = 0.38 (chloroform-methanol 20:1)

The compounds of the general formula (I) were synthesised by the method as explained above starting from the corresponding compounds having general formulae (II) and (III).

Structures of several novel compounds of the general Formula (I) are listed in Table 1.

It should be noted that the present invention is not limited to the example and Compounds 1-10 shown in Table 1 are also encompassed in the present invention. These representatives were prepared as described in the experimental part.

Comp. Comp.

No. No.

4.

5.

7.

10.

Claims

1.) Compounds of the general formula (I) wherein A means an mono of multiple substituted or unsubstituted organic cyclic group containing one nitrogen atom with one free valency and optionally one or more further heteroatom selected from a group consisting of nitrogen atom, sulfuratom or oxigenatom, especially one of the groups having the general formula (1), (la), (2), (2a), (3), (3a), (4a), (4b), (5), (6), (7), (8), (9), (10), (11a), (l ib), (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 hydrogen atom, alkyl group of 1-4 carbon atoms or aryl or aralkyl group of 6-12 carbon atoms; R1 , R², R3 and R⁴ mean independently from each other hydrogen atom, halogen atom, hydroxyl group, straight chain or branched chain alkyl- or alkenyl- or alkynyl- or alkoxy- or alkenyloxy- or alkynyloxy groups containing 1-6 carbon atoms, nitro-group, amino group, monoalkylamino- or monoacylamino group of 1- 12 carbon atoms, dialkylamino- or diacylamino group of 2-24 carbon atoms - where the acyl group is an alkyl-, aralkyl-, cycloalkyl- or aryl type -, cyano group, 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 group, benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanato group, isothiocyanato group, alkylthio group of 1-6 carbon atoms, sulfamino or sulfamoyl group, thiocyanato or cyanato group;

R means hydrogen atom or alkyl group of 1-6 carbon atoms; R8 means hydrogen atom or alkyl group of 1-6 carbon atoms or aralkyl group of 7-10 carbon atoms, or alkoxycarbonyl-alkyl group of 3-6 carbon atoms, or aliphatic or aromatic acyl group of 1-7 carbon atoms or difluoro- or trifmoroacyl or polyfluoroacyl group of 2-6 cabon atoms, the dotted line means an optional chemical bond; n is zero 1, 2 or 3;

X means-CH2-group, -NH-group, carbon atom, hydrogen atom, oxygen atom or amino group; or

R⁹ I A means an R - Y - N = group or R -Y-N- group - wherein R' means alkyl group of

1-6 carbon atoms, aralkyl group of 7-10 carbon atoms, diphenylmethyl group, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or phenyl- or phenoxy or phenylalkyl group containing 7-10 carbon atoms or 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 chemical bond or oxo-, sulfonyl- or sulfinyl group, R⁹ means hydrogen atom or alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X cannot mean - CH2- group, - NH- group, oxygen atom or sulfur atom and in the case of formulas (30) and (31) X cannot mean - CH2- group, oxygen atom or sulfur atom or amino group; Bjneans -(CH₂)_m - C - group - wherein m is an integer of 1 .0 21 ; or O

R^a

- (CH₂)_m - N - C -group

O

- wherein R means the same substituents as defined above

-0-(CH₂)_p - C - group wherein p is an integer of 1 to 3; or O

group - wherein R⁹, R¹⁰, R¹ *, R¹², R¹³ and R¹⁴ mean independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl group of 1-6 carbon atoms; or phenyl, phenoxy, aryl-alkyl group of 7-12 carbon atoms or aryl-alkoxy group of 7- 12 carbon atoms each of them optionally containing 1, 2 or 3 of the same or different substituents identical to R¹, R², R³ or R⁴; or two of R , R , R , R ', R and R mean together an oxo or epoxy group or further chemical bond, or four of them mean together two f rther chemical bonds and the remaining groups stand for hydrogen atoms; or R , R , R , R ', R and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; R means the same substituens as defined above; and w is zero or 1 ;

C means prolyl group or one of the moieties of formula (37), (38), (39), (40) or

(41)

- where n is zero or 1 or 2, Hlg means fluoro, chloro, bromo, or iodo atom;

R and R mean independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1-4 carbon atoms or R and R together mean oxo- group;

Rl6 means an alkoxy group of 1-4 carbon atoms, or -NH- CH2 -CN group, or -

NH-CH2-CO2 group - where R^ is defined as above; or

D or L structural unit; or one of the groups of the formula (42) or (43) or (43 a) - where the dotted line means a chemical bond optionally present-, s is 1 , 2 or 3 - or a group of the formula (44) -wherein R¹^ means hydrogen atom, alkyl group of

1-6 carbon atoms, phenyl or naphthyl group; or a group of the formula (45) - wherein Z means NH - group, oxygen atom or sulfur atom;

L means pyrrolidino- or 2-cyanopyrrolidino, thiazolidino or 2-cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R¹^ means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49); - or a group of formula (46) - wherein

17

R means - CF₂H group or a group of the formula (50) or formula (51) wherein R means hydrogen atom, halogen atom, 1,3 -dioxolan-2-yl groups or - OR group

71 wherein R stands for hydrogen atom alkyl group of 1-6 carbon atoms or phenyl group optionally substituted by one or two alkoxy group of 1-4 carbon atoms or alkyl group of 1-4 carbon atoms or nitro groups; n is 0, 1 or 2 R¹⁹ means hydrogen atom halogen atom l,3-dioxolan-2-yl group or - OR²¹ group

71 wherein R stands for alkyl group of 1-6 carbon atoms or phenyl group optionally substituted by one or two alkoxy group of 1-4 carbon atoms or alkyl group of 1-4 carbon atoms or nitro groups, or R and R form together an oxo-group; and

70 77

O

II atom, = S = O; - S - or

II O

- NH- group or a chemical bond and R²² means hydrogen atom, phenyl, 2- thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyrrolyl, thienyl, 2-benzothiazolyl, 2- benzoxazolyl, 2- benzimidazolyl, 2-indolyl, 2-thiazolo[5,4-b]pyridinyl, 2- oxazolo[4,5-b]pyridinyl, 2-imidazolo[4,5-b]pyridinyl, 5-thiazolyl, 2-thiazolinyl, 2-pyridinyl, 3-pyridinyl, 5- pyrimidinyl, 2- pyrazinyl, 2-triazolyl, 2-pyrazolyl ring optionally substituted by one or two alkyl group of 1 -6 carbon atoms, alkoxy group of 1-6 carbon atoms or phenoxy group, or R²² means a - CF₂ - C - R group -

O wherein R²³ means hydroxy group, alkoxy group of 1-6 carbon atoms or - NR R²⁵-group - wherein R is alkyl group of 1-6 carbon atoms, R ⁵ is alkyl group of 1- 6 carbon atoms or R and R form together an alkylene group of 1 -5 carbon atoms with the proviso that if a.) B means -(CH₂)_m - C - group - wherein m is an integer of 1 to 21; or

II

O -O-(CH₂)_p - C - group wherein p is an integer of 1 to 3; or O

group - wherein R⁹, RlO, R1 1, R12_{> R}13 _and R*⁴ mean

independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl group of 1-6 carbon atoms; or phenyl, phenoxy, aryl-alkyl group of 7-12 carbonatoms or aryl-alkoxy group of 7-12 carbon atoms each of them optionally containing 1, 2 or 3 of the same or different substituents identical to R¹, R², R³ or R⁴; or two of R , R , R , R ', R and R mean together an oxo or epoxy group or further chemical bond, or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or

L cannot mean pyrrolidino- or 2-cyanopyrrolidino, thiazolidino or 2-cyano- thiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R¹^ means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49); or if b.) L means pyrrolidino- or 2-cyanopyrrolidino, thiazolidino or 2- cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R¹^ means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49); B cannot mean -(CH₂)_m - C - group - wherein m is an integer of 1 to 21; or

O

-0-(CH₂)_p - C - group wherein p is an integer of 1 to 3; or

Ii O

- group - wherein R⁹, RlO, R^π, Rl2, Rl3 and R¹⁴ mean

independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbonatoms, halogen atom, amino group optionally substituted with one or two alkyl group of 1-6 carbonatoms; or phenyl, phenoxy, aryl-alkyl group of 7-12 carbonatoms or aryl-alkoxy group of 7-12 carbon atoms each of them optionally

1 7 ^ containing 1, 2 or 3 of the same or different substituents identical to R , R , R or R⁴; or two of R , R , R , R ', R and R mean together an oxo or epoxy group or further chemical bond, or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or

R , R , R , R ', R and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; and w is zero or 1 ; -

and optical , cis-trans, geometric isomers , epimers, 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 general formula (1), (la), (2), (2a), (3), (3a), (4a), (4b), (5), (6), (7), (8), (9), (10), (11a), (l ib), (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 hydrogen atom alkyl group of 1-4 carbon atoms or aryl or aralkyl group of 6-12 carbon atoms,

R¹, R2, R3 and R⁴ mean independently from each other hydrogen atom, halogen atom, hydroxyl group, straight chain or branched chain alkyl or alkenyl- or alkinyl or alkoxy- or alkenyloxy- or alkinyloxy groups containing 1-6 carbon atoms, nitro group, amino group, monoalkylamino or monoacylamino group of 1- 12 carbon atoms, dialkylamino- or diacylamino group of 2-24 carbon atoms - where the acyl group is an alkyl, aralkyl, cycloalkyl or aryl type -, cyano group, 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, isocyanato group, isothiocyanato group, alkylthio group of 1-6 carbon atoms, sulfamino or sulfamoyl group, thiocyanato or cyanato group; R5 and R^ mean independently from each other hydrogen atom, hydroxyl group, phenyl group or alkyl group of 1- 4 carbon atoms or R^ and R > together mean oxo group;

R7 means hydrogen atom or alkyl group of 1-6 carbon atoms; R8 means hydrogen atom or alkyl group of 1-6 carbon atoms or aralkyl group of 7-10 carbon atoms, or alkoxycarbonyl-alkyl of 3-6 carbon atoms; or aliphatic or aromatic acyl group of 1-7 carbon atoms or difluoro- or trifluoro- or polyfluoro acyl group of 2-6 carbon atoms, the dotted line means an optional chemical bond; n is zero, 1, 2 or 3; X means-CH2-group, -NH-group, carbon atom, hydrogen atom, oxygen atom or amino group; or

1-6 carbon atoms, aralkyl group of 7-10 carbon atoms, diphenylmethyl group, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or phenyl- or phenoxy or phenylalkyl group containing 7-10 carbon atoms or phenylalkyloxy group containing 7-10 carbon atoms optionally substituted with halogen atoms or alkyl groups of 1-4 carbon atoms or nitro gioups; Y means chemical bond or oxo-, sulfonyl- or sulfinyl group, R⁹ means hydrogen atom or alkyl group of 1-4 carbon atoms; - with the proviso that in the case of formulas (20) and (33) X cannot mean

B means -(CH₂)_m - C - group - wherein m is an integer of 1 to 21; or

II O

R⁸ I

- (CH₂)_m - N - C -group

O

- wherein R means the same substituents as defined above

- O - (CH₂)_p - C - group wherein p is an integer of 1 to 3; or O

group - wherein R , R , R^{1 1}, , R^l and R mean independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbonatoms, halogen atom,, amino group optionally substituted with one or two alkyl group of 1-6 carbonatoms; or phenyl, phenoxy, aryl-alkyl group of 7-12 carbon atoms or aryl-alkoxy group of 7-

12 carbon atoms each of them optionally containing 1, 2 or 3 of thesame or different substituents identical to R , R , R or R ; or two of R , R¹ , R^u, R¹ , R and R mean together an oxo or epoxy group or further chemical bond, or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or

R⁹, R¹⁰, R¹ R¹²', R¹³ and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; R⁸ means the same substituents as defined above, and w is zero or 1 ;

C means prolyl group or one of the groups of formula (37), (38), (39), (40) or (41) - where n is zero or 1 or 2, Hlg means fluoro, chloro, bromo, or iodo atom;

R⁵ and R mean independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1-4 carbon atoms or R⁵ and R⁶ together mean oxo- group; Rl6 means an alkoxy group of 1-4 carbon atoms, or -NH- CH2 -CN group, or - NH-CH2-CO2R group - where R? is defined as above; or D or L structural unit; or one of the group of the formula (42) or (43) or (43a)

- where the dotted line means a chemical bond optionally present-, s is 1, 2 or 3 or a group of the formula (44) -wherein R¹^ means hydrogen atom, alkyl group of 1-6 carbon atoms, phenyl or naphthyl group; or a group of the formula (45) - wherein Z means NH - group, oxygen atom or sulfur atom;

D means a covalent chemical bond or prolyl or thioprolyl group, or one of the groups of formula (37) or (38), (39), (40) or (41); L means pyrrolidino- or 2- cyanopyrrolidino, thiazolidino or 2-cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - wherein Rl means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49), - or a group of formula (46) - wherein

R means - CF₂H group or a group of the formula (50) or formula (51) wherein

18 71

R means hydrogen atom, halogen atom, l,3-dioxolan-2-yl groups or - OR group

21 wherein R stands for hydrogen atom, alkyl group of 1-6 carbon atoms or phenyl group optionally substituted by one or two alkoxy group of 1-4 carbon atoms or alkyl group of 1-4 carbon atoms or nitro groups; n is 0, 1 or 2

R means hydrogen atom halogen atom l,3-dioxolan-2-yl group or - OR group

71 wherein R stands for alkyl group of 1-6 carbon atoms or phenyl group optionally substituted by one or two alkoxy group of 1-4 carbon atoms or alkyl group of 1-4 carbon atoms or nitro groups, or R¹⁸ and R¹⁹ form together an oxo-group; and

R²⁰ means a - (CH₂)_t - T - R²² group - wherein t is 0, 1 or 2, T is an oxygen or sulphur O

II atom, = S = O; - S - or

Ii O - NH- group or a chemical bond and R²² means hydrogen atom, phenyl, 2- thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyrrolyl, thienyl, 2-benzothiazolyl, 2- benzoxazolyl, 2- benzimidazolyl, 2-indolyl, 2-thiazolo[5,4-b]pyridinyl, 2- oxazolo[4,5-b]pyridinyl, 2-imidazolo[4,5-b]pyridinyl, 5-thiazolyl, 2-thiazolinyl, 2-pyridinyl, 3-pyridinyl, 5- pyrimidinyl, 2- pyrazinyl, 2-triazolyl, 2-pyrazolyl ring optionally substituted by one or two alkyl group of 1-6 carbon atoms, alkoxy group

77 " of 1-6 carbon atoms or phenoxy group, or R means a - CF₂ - C - R grou -

O

7"^ " A wherein R means hydroxy group, alkoxy group of 1-6 carbon atoms or - NR

7^ 74 7^

R -group - wherein R is alkyl group of 1-6 carbon atoms, R is alkyl group of 1-6 carbon atoms or R ⁴ and R²⁵ form together a alkylene group of 1-5 carbon atoms with the proviso that if a.) B means -(CH₂)_m - C - group - wherein m is an integer of 1 to 21; or

O

-O-(CH₂)_p - C - group wherein p is an integer of 1 to 3; or

II O

- group - wherein R⁹, R¹⁰, R¹1, R¹², R¹³ and R¹⁴ mean

independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen, amino group optionally substituted with one or two alkyl group of 1-6 carbon atoms; or phenyl, phenoxy, aryl-alkyl group of 7-12 carbonatoms or aryl-alboxy group of 7-12 carbonatoms each of them optionally containing 1, 2 or 3 of thesame or different substituents identical to R¹, R², R³ or R⁴; or two of R , R , R¹ , R ', R¹³ and R¹⁴ mean together an oxo or epoxy group or further chemical bond, or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or

R⁹, R , R , R ', R and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or w is zero or 1;

L cannot mean pyrrolidino- or 2- cyanopyrrolidino, thiazolidino or 2-cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R¹^ means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49); or if b.) L means pyrrolidino- or 2-cyanopyrrolidino, thiazolidino or 2- cyanothiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula (46) - where R¹^ means hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula (47) or (48) or (49);

B cannot mean -(CH₂)_ra - C - group - wherein m is an integer of 1 to 21; or

O -O-(CH₂)₀ - C - group wherein p is an integer of 1 to 3; or

II O

group - wherein R⁹, RlO, R1 1, Rl2, R13 _and RI⁴ mean

independently from each other hydrogen atom, alkyl or alkoxy group of 1-6 carbon atoms, halogen atom, amino group optionally substituted with one or two alkyl group of 1-6 carbonatoms; or phenyl, phenoxy, aryl-alkyl group of 7-12 carbonatoms or aryl-alkoxy group of 7-12 carbonatoms each of them optionally containing 1, 2 or 3 of the same or different substituents identical to R¹, R², R or R⁴; or two of R , R , R , R ', R and R mean together an oxo or epoxy group or further chemical bond,or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or R⁹, R¹⁰, R¹¹, R¹²', R¹ and R mean together with the chain carbon atoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; and w is zero or 1; and optical, cis-trans, geometric isomers, epimers, tautomers, salts, prodrugs and human and mammalian metabolites of them.

3.) Pharmaceutical composition containing one or more compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claim 1 or 2 - and/or optical, cis-trans, geometric isomers, epimers, tautomers, salts, prodrugs and human and mammalian metabolites of them, alone or together with usual carrier and/or auxiliary materials applied in the pharmaceutical industry.

4.) 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 1 or 2 - and 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 ) - where the meanings of A and B are as given in claim 1 or 2 - is transformed to an acid halide, or an active ester, or to a mixed acid anhydride or to a carbodiimide, and the resulted compound is reacted with a racemic or optically active compound or their salt of the general formula (III), - where the meanings of C, D and L are as given in claim 1 - and the resulted compound of the general formula (I) - where the meanings of A, B, C, D, and L are as given in claim 1 or 2 - optionally is separated into the their optical, cis-trans, geometric isomers, epimers or tautomers or a salt of compounds of general formula ( I ) is formed, or the compounds of general formula (I) are liberated from their salts.

5.) Use of the compounds of the general formula (I) defined in claim 1 or 2 for inhibition of prolyl-endopeptidase enzyme in mammals including man.

6.) A process according to claim 4 characterized in that, a reactive mixed anhydride is formed starting from a compound of the general formula (II) and pivaloyl chloride is applied.

7.) A process according to claim 4 characterized in that, the reaction is carried out in an organic solvent.

8.) A process according to claim 4 characterized in that, the reaction is carried out at a temperature between - 25 °C and the boiling point of the reaction mixture.

9.) A process according to claim 4 characterized in that, the reaction is carried out in the presence of an acid binding agent.

10.) Compounds according to claim 1 substantially as hereinbefore described.