Title of Invention	ADAMANTANE AND AZABICYCLO-OCTANE AND NONANE DERIVATIVES
Abstract	The invention relates to new compounds of the general formula (I), which are strong DPP-IV enzyme inhibitors.

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ADAMANTANE AND AZABICYCLO-OCTANE AND NONANE DERIVATIVES The present invention relates to the novel compounds of the general formula (I) possessing dipeptidyl peptidase IV enzyme inhibitory activity, as well as their salts, solvates and isomers, to the pharmaceutical compositions containing them, to the therapeutic application of the compounds of the general formula (I), to the process of preparation of the compounds of the general formula (I) and to the new intermediates of the general formulae (II), (IV), (V), (VII), (VIII) and (IX). The enzyme, dipeptidyl peptidase IV (DPP-IV), which is identical with the lymphocyte surface glycoprotein CD26, a polypeptide with the molecular mass of 110 k Dalton, is formed in the tissues and organs of mammals. This enzyme can be found, among others, in the liver, in the Langerhans islands, in the renal cortex, in the lungs, and in certain tissues of the prostate and small intestine. Significant DPP-IV activity can be observed furthermore in the body liquors (as for instance in the plasma, serum and urine). DPP-IV is a serine protease type enzyme, which has the unique specificity to cleave dipeptides from the N-terminals of the peptides, where the pre-terminal dipeptide is prolyl- alanine, or hydroxy-proline. DPP-IV enzyme is responsible for the decomposition of the glucagon-like peptides, peptide-1 (GLP-1) and peptide-2 (GLP-2) in the body. The enzyme GLP-1 strongly stimulates the insuline production of the pancrease, thus it has a direct, favourable effect on the glucose homeostasis, therefore DPP-IV inhibitors are suitable for the treatment of non- insuline dependent diabetes mellitus (NIDDM) and for the treatment or prophylaxis of other diseases connected to the DPP-IV enzyme activity, including but not limited to diabetes, obesity, hyperlipidemia, dermatological or mucous membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as encephalomyelitis, complement metiated disorders such as glomerulonephritis, lipodystrohy and tissue damage, psychosomatic, depressive and neuropsychiatric disease such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasm and chronic pain, HTV infection, allergies, inflammation, arthritis, transplant rejection, high 6/ood pressure, congestive heart failure, tumors and stress-induced abortions. There are a number of DPP- IV inhibitors known in the literature, but they have disadvantages as regards their activity, toxicity, physico-chemical properties, stability and duration of action. Our aim was to prepare new, effective and safe DPP-IV inhibitors having advantageous physico-chemical and biological properties. We have found that the compounds of the general formula (I) - wherein R represents: - a nitrogen-containing mono- or bicyclic aromatic moiety, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazinyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono- or disubstituted independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - Phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, rihalogenomethyl group, methylthio group, nitro group, cyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - R1,-CH2-group, where the meaning of R1, is hydrogen, C1-4 alkyl group, pheny, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl group, substituted ndependently by one or more C1-4 alkyl, C1-4 alkoxy, alkylenedioxy group, halogen atom, trihalogenomethyl, nitro or cyano group; or - R1aR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, fenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, halogeno, trihalogenomethyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C1-4 alkyl, -alkoxy, - alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and - R2 represents hydrogen or methyl group; or - R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, halogeno, trihalogenomethyl, nitro, or cyano group, or an amino group, or a heterocyclic group, preferably pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl group; or -p-toluenesulphonyl group; B represents a group of formula (1), (2), (3), (4) or (5); and isomers, salts, solvates of the above compounds, as well as solvates of their salts, possess remarkable advantages in their activity, stability and toxicity. In accordance with the accepted terminology, the configuration of the carbon atom next to the nitrogen atom of the 5-membered-ring-pentacycle is favourably S if Z stands for formula (A), (B), (C), or (E), whereas it is favourably R if Z stands for formula (D). In the present description the term "C1-4 alkyl" means a straight-chain or branched chain alkyl group with 1-4 carbon atoms as for example methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl or isobutyl. The term "C1-4 alkoxy" means a straight-chain or branched chain alkoxy group with 1-4 carbon atom as for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy or isobutoxy. The term "C2-5 alkoxy carbonyl" means a straight or branched chain alkoxy carbonyl group with 2-5 carbon atom as for example methoxy carbonyl, ethoxy carbonyl, popoxy carbonyl, isopropoxy carbonyl, butoxy carbonyl, sec.-butoxy carbonyl, isobutoxy carbonyl. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "C1-4 alkylenedioxy" means a straight-chain or branched chain alkylcnedioxy group with 1-4 carbon atoms as for example methylencdioxy, ethylenedioxy, propxylenedioxy, butylenedioxy. The term "C2-5 alkylcarbonyl" menas a straight-chain or branched chain alkylcarbonyl group with 2-5 carbon atoms as for example methyl-carbonyl, ethylcarbonyl, propylcarbonyl, isopropyl carbonyl or butyl carbonyl, sec.-butyl carbonyl or isobutyl carbonyl. A large group of compounds of the general formula (I) are - wherein the meaning of R is the same as defined earlier, B represents a group of formula (1), (2), (4) or (5) and Z represents a group of formula (A), (B) or (D). Such compounds from this large group are for instance (25)-4,4-difluoro-1 - {N-[3-(pyrimidin-2-ylamino)-1 -adamantyljglycyl} pyrrolidine-2- carbonitrile (25)-4,4-difluoro-1 -(N- {3-[(3-nitrobenzyI)aminoJ-1 -adamantyl} glycyl) pyrrolidine-2- carbonitrile N-{3- {[2-(2-cyano-(25)-4,4-difluoropyrrolidin-1 -yl)-2-oxoethyl]amino} -1 -adamantyl)-4- methoxybenzamide (25)-4,4-difluoro-1-[N-(3-pyTimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)exo- aminoacetyl]pyrrolidine-2-carbonitrile (2S)-4,4-difluoro-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)endo- aminoacetyl]pyrrolidine-2-carbonitrile (2S)-4,4-difluoro-1-[N-(3-methyI-8-pyrimidin-2-yl-8-azabicyclo[3.2.1 ]oct-3-yl) exo- aminoacetyl]pyrrolidine-2-carbonitrile (25,45)-4-fluoro-1-{N-[3-(pyTimidin-2-yIamino)-1-adamantyljglycyl} pyrrolidine-2- carbonitrile (4R)-3-{N-[3-(pyrimidin-2-ylamino)-1-adamantyl]glycyl}-l,3-thia2olidine-4-carbonitrile (4S)-3- {M[3-(pyrimidin-2-ylamino)-1 -adamantyl]glycyl} -1,3-oxazolidine-4-carbonitrile (2S)-4,4-difluoro-1-{N-[3-( 1,2,4-triazin-3-ylamino)-1-adamantyl]glycyl} pyrrohdine-2- carbonitrile (25)-4,4-difluoro-1 - {N-[3-(pyrazin-2-ylamino)-1 -adamantyljglycyl} pyrrolidine-2- carbonitrile (2S)-1-(N- (3- [(4-cyanopbenyl)amino]-1 -adamantyl} glycyl)-4,4-difluoropyrrolidine-2- carbonitrile 6-[(3-{[2-(2-cyano-(25)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino}-1- adamantyl)amino] nicotinonitrile (2S)-4,4-difluoro-1-[N-(3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1- adamantyl)glycyl]pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[N-(3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1- adamantyl)glycylJpyrrolidine-2-carbonitrile (25)-4,4-difluoro-1-{N-[3-(1,3-thiazol-2-ylamino)-1-adamanty]]glycyl} pyrrolidine-2- carbonitrile (25)-1 -(N- {3-[( 1 -ethyl- 1H-pyrazol-5-yl)amino]-1 -adamantyl} glycyl)-4,4 difluoropyrrolidine-2-carbonitrile (2S)-4,4-difluoro-1-(N-{3-[(5-methylisoxazol-3-yl)amino]-1-adamantyl}glycyl) pyrrolidine-2-carbonitrile (2S)-4,4-difluoro-1- {N-[3-(quinolin-2-ylammo)-1-adamantyl]glycyl} pyrrolidine-2- carbonitrile (2S,4S}-4-fluoro-1-{N-[3-(quinolin-2-ylamino)-1-adamantyl]glycyl} pyrrolidine-2- carbonitrile (25)-4,4-difluoro-1-{N-[3-{[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1- adamantyl]glycyl} pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1- {N-[3-([ 1,2,4]triazolo[ 1,5-a]pyridin-2-ylamino)-1 - adamantyljglycyl} pyrrolidine-2-carbonitrile (4R)-3- {N-[3-([ 1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1 -adamantyljglycyl} -1,3- thiazolidine-4-carbonitrile (2S)- 1 -(N- {3-[(4-cyanobenzyl)amino]-1 -adamantyl} glycyl)-4,4-difluoropyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1 -[N-(3- {[4-(trifluoromethyl)benzyl]amino} -1 -adamantyl) glycyl]pyrrolidine-2-carbonitrile (25)-4,4-difluoro-1 -(N- {3-[(3-fluorobcnzyl)amino]-1 -adamantyl} glycyl) pyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1-(N-{3-[(3,4,5-trimethoxybenzyl)amino]-1-adamantyl} glycyl)pyrrolidine-2-carbonitrile (25)-4,4-difluoro-1-(N-{3-[(pyridin-3-ylmethyl)amino]-1-adamantyl}glycyl)pyrrolidine-2- carbonitrile (2S)-4,4-difIuoro-1 -(N- {3-[(pyridazin-3-ylmethyl)amino]-1 -adamantyl} glycyl) pyrrolidine- 2-carbonitrile (2S)-4,4-difluoro-1 -(N- {3-[(1,3-thiazol-2-ylmethyl)amino]-1 -adamantyl} glycyl) pyrrolidine-2-carbonitrile 4-chloro-N-(3-{[2-(2-cyano-(25)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl] amino}-1- adamantyl)benzamide N-(3- {[2-(2-cyano-(2,S)-4,4-difluoropyrrolidin-1 -yl)-2-oxoethyl]amino) -1 -adamantyl)-3- fluorobenzamide (2E)-N-(3- {[2-(2-cyano-(2S}-4,4-(difluoropyrrolidin-1 -yl)-2-oxoethyl]amino} -1 - adamantyl)-3-phenylacrylamide N-(3- {[2-(2-cyano-(25)-4,4-difluoropyrrolidin-1 -yl)-2-oxoethyl]amino} -1 - adamantyl)thiophene-2-carboxamide (25)-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)endo-amino-acetyl]pyrrolidine-2- carbonitrile (25)-4,4-difluoro-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.3.1]non-9-yl)glycyl] pyrrolidine- 2-carbonitrile 6-(9- {[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino} -3- azabicyclo[3.3.1]non-3-yl)pyridazine-3-carbonitrile (2S)-1-[N-3-pyrirnidin-2-yl-3-azabicyclo[3.3.1]non-9-yl)glycyl]pyrrolidine-2-carbonitrile The compounds of the general formula (I) according to our invention - wherein the meanings of R, B and Z are as defined above- can be prepared by alkylation of the cyclic primary amines of the general formula (II) with the chloroacetyl derivatives of general formula (III) wherein the meaning of Z is as defined above - and, if desired, the resulting compounds are transformed into their salts or solvates (Scheme 1). In the course of the alkylation the cyclic primary amines of the general formula (II) are applied in equivalent amount or in slight excess, and the resulting hydrogen chloride is bound by various acid binding agents, preferably by a base, such as for instance triethylamine, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or scavenger resin, polimer bound 2-tert-butylimino-2-diemylamino-1,3-dimethyl-perhydro- 1,3,2-diazaphosphorine (PBEMP), polimer bound diethylamine (PS-DIEA). The reaction is generally performed at a temperature between 25 and 75 °C in acetonitrile, alcoholes, tetrahydrofuran or dioxane. The primary amines of the general formula (II) - if moiety B stands for formula (2), (3), (4) or (5) - are prepared in a two-step synthesis (Scheme 2). In the first step the starting cyclic secondary amines containing the acylamido side-chain -the compound of the general formula (IV) wherein Y stands for acetyl or tert-butoxycarbonyl group- is reacted with the compound containing the group R, forming thus the compunds of general formula (V). If R means aryl or hetaryl group, aryl or hetaryl halogenides, preferably aryl- or hetaryl bromides or aryl- or hetaryl chlorides are used for the arylation reaction. The arylation is performed in a polar, protic or aprotic solvent between 70 and 140 °C, generally in an alcohol (ethanol, n-butanol, n-pentanol), or in microwave oven without solvent, using excess amine or DBU as acid binder. The arylation is also performed in an aprotic or polar solvent, at a temperature between 25 and 110°C, preferably in toluene or in dimethoxyethane, using sodium alcoholates as acid binders and palladium complexes as catalysts (J. Org. Chem. 2000, 65, 1158). In the cases when R stands for R1aR2-CH- or R1b-CO group, the compounds of the general formula (TV) - wherein Y means an acetyl or tert-butoxycarbonyl group - are reacted with the derivatives of general formula R1aR2-CHX or Rlb-COX - wherein X means a leaving group (preferably a chloro- or bromo atom) - generally at a temperature around 0°C, using an inorganic or organic base, preferably triethylamine, as acid binder. The compounds of the general formula (IV), by literature analogy, are prepared in several steps. If moiety (B) stands for the group of formula (2) or (3), the starting material is the 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (N-benzylcamphidin-8-one; J. Med. Chem. 1994, 37, 2831). From that, the desired compound is prepared in four steps. The isomeric products obtained in the second step are separated by coloumn chromatography for the exo and endo products, which further on are reacted in the same way: (i) NH2OHxHCl; (ii) Na/n-pentanol; (iii) Boc2O; (iv) H2/Pd-C; If moiety (B) stands for the group of formula (4), the starting material is the 3- benzyl-3-azabicyclo[3.3.1]nonan-9-one (J. Med. Chem. 1994, 37, 2831). Following the above reaction sequence, we did not succeed at any stage to separate the exo/endo products, and at the end of the synthesis the resulting product always contained the two isomers: If moiety (B) stands for the group of formula (5), the starting material is the 8- benzyl-8-azabicyclo[3.2.1]octan-3-one (J.C.S. Perkin I. 1997, 1307). From that in regioselective Grignard reaction the 8-benzyl-3-methyl-8-azabicyclo[3.2.1]octan-3-exo-ol is formed, from which, on literature analogy, the exo-acetamido derivative can be obtained in Ritter reaction (Tetrahedron Lett. 1996, 37, 1297), which, following debenzylation results the desired compound: From the resulting compounds of the general formula (V), if moiety (B) stands for the group of formula (2), (3), (4) or (5) - the Y protecting group is cleaved under acidic conditions, arriving thus to the compounds of the general formula (II). Hydrolysis is preferably carried out by trifluoroacetic acid in dichloromethane solution at a temperature between 0 -30°C, or in aqueous hydrochloric acid solution or in ethanolic hydrogen chloride solution at a temperature between 25-78 °C. If moiety (B) stands for the group of formula (1), the compounds of the general formula (II) can be prepared from two different starting materials. One is the 3-hydroxy-1- aminoadamantane, (Pharm. Chem. J. (Engl. Trans.) 1990, 24, 35) from which after protecting the amino group a tert-butoxycarbonyl derivative is prepared, then treating the hydroxy group with mezyl chloride, the mezyloxy derivative is obtained. Utilising the excellent leaving capability of the leaving group, the compound is reacted with 2-amino- heterocycles - preferably in aprotic solvents or without solvent at 100-140°C - resulting the compounds of the general formula (IV), which following treatment with trifluoroacetic acid in dichloromethane at 0 -30°C, give the compounds of general formula (II): The other starting material is the 1,3-diaminoadamantane (Ber. 1941, 74, 1769), which after acylation, alkylation or by Schiff base formation and reduction gives the compounds of general formula (II): The chloroacetyl compounds of the general formula (III) - wherein Z stands for the group of formulae (A), (B), (C), (D) or (E) - are prepared in a four-step synthesis (Scheme 3). The starting compounds are the N-containing pentacyclic carboxylic acids with the nitrogen protected with tert-butoxycarbonyl group - compounds of the general formula (VI) wherein the meaning of Z is as defined above. (2S)-1-(tert-butoxycarbonyl)proline (Z = moiety (C)) and (4R)-3-(tert-butoxycarbonyl)-l,3-thia2olidine-4-carboxylic acid (Z = moiety (D)) can be purchased, (25)-1-(tert-butoxycarbonyl)-4,4-difluoroproline (Z = moiety (A)), (2S,4S)-1-tert-butoxycarbonyl)-4-fluoroproline (Z = moiety (B)) and (4S)-3- (tert-butoxycarbonyl)-l,3-oxazolidine-4-carboxylic acid (Z = moiety (E)) can be prepared (Tetrahedron Lett. 1998, 39, 1169 and Tetrahedron 1994,50, 13493). In the first step a mixed anhydride is prepared with pivaloyl or ethoxycarbonyl chloride, then the carbamoyl derivatives of the general formula (VII) - wherein the meaning of Z is the same as defined above - are formed with aqueous ammonia. The reaction is preferably carried out in a halogenated solvent (CHCl3, CH2Cl2) at 15°C. In the second step the tert-butoxycarbonyl group is cleaved by ethanolic hydrogen chloride solution. Hydrolysis takes place at 0 - 25°C and the hydrochlorides of the carboxamides of the general formula (VIII) - wherein the meaning of Z is the same as defined above -. are obtained. The resulting pcntacyclic saturated carboxamides of the general formula (VIII) are in the third step acylated with chloroacetyl chloride, preferably at 0°C in a halogenated solvent (CHCl3, CH2Cl2) to obtain the chloroacetylcarboxamide derivatives of the general formula (IX) -wherein the meaning of Z is the same as defined above. In the fourth step the chloroacetylcarboxamide derivatives of the general formula (IX) - wherein the meaning of Z is as defined above - are dehydrated to yield the chloroacetylcyano derivatives of the general formula (III). Dehydratation is generally carried out with phosphoryl chloride in dichloromethane at reflux temperature, or with oxalyl chloride in the presence of DMF, at a temperature lower than 0°C. Biological investigations DPP-IV enzyme inhibitory activtics of the compounds with the general formula (I) were determined by the following method: Applied conditions of the assay: DPP-IV. source: solubilized crude extractum from CaCo/Tc-7 cells content: 0.8-lug/assay Substrate: H-Gly-Pro-AMC (Bachem) Reaction: 1 hour preincubation with samples at 37 °C , 30 min reaction time at 37 C° Stop solution: 1M Na-acetate buffer (pH=4.2) Reaction mixture: 10 µl enzyme solution 10 µl test compound or assay buffer 55µl assay buffer 25µl substrate 300µl stop solution Measurement: spectrofluorometric determination by Tecan plate reader (Ex: 360nm Em: 465nm) The reaction of the DPP-IV enzyme and the H-Gly-Pro-AMC substrate is recorded by the liberation of AMC (7-amino-4-methylcoumarin) at 37 °C in 100 mM Tris-HCl, pH=7.5 (assay buffer). Standard curve of AMC is linear up to 31.25 µM concentration, therefore we used the relative fluorescence unit (RFU) of the AMC formed. It is detected using 360 nm excitation and 465 emmission filters (integration time 30 µs, Gain 25, No. of Flashes 50) by Tecan Spectrofluor Plus plate reader. Under these conditions enzyme reaction is linear for at least 30 min, and the enzyme dependence is linear up to 2.5 µg protein (up to 700 RFU). Using 1-0.8 µg of extracted protein Km for H-Gly-Pro-AMC is 50 uM. Higher than 500 µM substrate concentration caused fluorescent detection problems (inner filter effect) that can be solved by dilution of the samples. The assay is designed to detect as efficiently as possible the active inhibitors using a 60 min preincubation time at 37 °C. The assay is conducted by adding 0.8-1 µg protein extract in 10 µl enzyme sulution (using assay buffer: 100 mM Tris-HCl, pH=7.5) to the wells containing the test compounds in 10 µl volume and the 55 µl assay buffer (65µl assay buffer in the case of contrails). After the preincubation period, the reaction is started by the addition of 25 µl ImM H-Gly-Pro-AMC substrate solution (250µM final concentration). The final test volume is 100 µl and the test solution contains 1% DMSO coming from the test compounds solution. Reaction time is 30 min at 37 °C, and the reaction is stopped by adding 300 µl 1M Na-acetate buffer, pH= 4.2. The fluorescence (RFU) of AMC formed is detected using 360 nm excitation and 465 emission filters in Tecan spectrofluor Plus plate reader (30 µs integration time, Gain 25 No. of Flashes 50). Inhibition % are calculated using the RFU of control and RFU of blank. The IC50 values are characteristic for the enzyme inhibitory effect of the compounds of the general formula (I) according to the invention. The compounds of the general formula (I) exhibit low IC50 values, generally below 100 nM. For example the endproduct of (2S)-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)glycyl]pyrrolidine- 2-carbonitrile (Example 40) shows IC50 value of 30 nM, endproduct of (4S)-3-N-[3- (pyrimidin-2-ylamino)-1-adamantyl]glycyl}-l,3-oxazolidine-4-carbonitrile (Example 9) shows IC50 value of 21 nM and endproduct of (2S)-1-(N-{3-[(4-cyanobenzyl)amino]-1- adamantyl}glycyl)-4,4-difluoropyrrolidine-2-carbonitrile (Example 27) shows IC50 value of 16 nM. Their duration of action and their activity are therapeutically favourable. The compounds of the general formula (I) and their solvates, isomers, salts and solvates of their salts can be formulated to orally or parenterally applicable pharmaceutical compositions by methods known per se, by mixing them with one or more pharmaceutically accepted support material or diluent and can be administered as a unitary dosage form.. The appropriate unitary dosage form comprise the oral forms, such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions or suspensions, the sublingual, buccal, intratracheal, intraocular, intranasal forms, by inhalation, the topical, transdermal, sub-cutaneous, intramuscular or intra-venous forms, the rectal forms and the implants. For the toical application, the compounds of the invention may be used as creams, gels, ointments of lotions. As an example, a unitary dosage form for a compound according to the invention, in the form of a tablet, can comprise the following ingredients: A compound of the general formula (I) 50.0 mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Maize starch 30.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg The daily dose of the compounds of the general formula (I) depends on several factors, thus on the nature and severeness of the disease of the patient, on the mode of application and on the compound itself. The following examples illustrate the preparation of the compounds of the general formula (I) but not at all limit the scope of the invention. Example 1. (25)-4,4-difluoro-1-{N-13-(pyrimidin-2-ylamino)-1-adamantyl]glycyl} pyrrolidine-2- carbonitrile dihydrochloride monoriydrate In general formula (I) R stands for pyrirnidin-2-yl group, B stands for the group of formula (1), Z stands for the group of formula (A). a.) tert-Butvl [3-(pyrimidin-2-ylamino)-1-adamantyl]carbamate In general formula (V) the meaning of R and B are as defined above, Y represents tert- butoxycarbonyl group. (i) tert-Butyl (3 -hydroxy-1-adamanty)carbamate 2.51 g (15 mmole) of 3-hydroxy- 1-aminoadamantane (Pharm. Chem. J. (Engl. Trans.) 1990,24, 35) are dissolved in the mixture of 15 ml of dioxane, 15 ml of water and 15 ml of IN sodium hydroxide solution, then under cooling and stirring 4.91 g (22.5 mmole) of di- fer/-butyl dicarbonate are added. The mixture is stirred at room temperature for 16 hours, the solution is evaporated, and the residue is dissolved in the mixture of 50 ml of ethyl acetate and 50 ml of water. Following extraction and separation of the phases, the organic phase is dried over sodium sulphate. After evaporation the white crystalline residue is treated with n-hexane, to obtain 2.61 g (65%) of product. M.p.: 131-132°C. 'H-NMR.: (DMSO-d6): 1.36 (s, 9H), 1.41 (s, 2H), 1.48 (d, 4H), 1.70 (d, 6H), 2.10 (bs, 2H), 4.43 (s, 1H), 6.41 (s, 1H). (ii) 3-[(tert-Butoxycarbonyl)amino]-1-adamantyl methanesulphonate 5.6 g (21 mmole) of tert-butyl (3-hydroxy-1-adamantyl)carbamate are dissolved in 80 ml of dichloromethane, 4.4 ml (31.5 mmole) of triethylamine are added to it. The mixture is cooled to 0°C and 1.82 ml (23.5 mmole) of methanesulphonyl chloride is added to it dropwise. The reaction mixture is stirred at that temperature for 45 minutes, then washed consecutively with water and saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate, evaporated, the residue is purified by column chromatography (n-hexane - ethyl acetate - chloroform 2:1:1) and crystallised from n- hexane, to obtain 2.9 g (40%) of product: Mp.: 100-102°C. 1H-NMR (DMSO-d6): 1.37 (s, 9H), 1.48 (s, 2H), 1.77 (q, 4H), 2.05 (t, 4H), 2.17 (d, 2H), 3.10 (s, 3H), 6.66 (s, 1H). (iii) tert-Butyl [3-(pyrimidin-2-ylamino)-1-adamantyl]carbamate The mixture of 1.04 g (3 mmole) of 3-[(tert-butoxycarbonyl)amino]-1-adamantyl methanesulphonate and 1.0 g (10.5 mmole) 2-aminopyrimidine are melted at 140°C. After 15 minutes of stirring the melt is cooled down and purified by column chromatography («- hexane - ethyl acetate - chloroform 2:1:1). The product is white crystalline material, 0.7 g (68%). Mp.: 163-165°C. 1H-NMR (DMSO-d6): 1.36 (s, 9H), 1.52 (s, 2H), 1.71 (d, 2H), 1.86 (d, 4H), 2.07 (m, 4H), 2.25 (m, 2H), 6.38 (s, 1H), 6.49 (t, 3H), 6.58 (s, 1H), 8.22 (d, 2H). b.) N-pyrimidin-2-yladamantane-1,3-diamine dihydrochloride In general formula (II) the meaning of R and B is as defined above. 700 mg (2 mmole) of tert-butyl [3-(pyrimidin-2-ylamino) -1-adamantyl] carbamate are dissolved in 25 ml of 20% ethanolic hydrogen chloride solution. The mixture is stirred at room temperature for 24 hours, evaporated to dryness; the residue is treated with acetone to obtain white crystalline material: 453 mg (68%). M.p.: 301-304°C. 1H-NMR (DMSO- d6): 1.56 (q, 2H), 1.78 (s, 4H), 2.00 (q, 4H), 2.24 (s, 4H), 6.78 (t, 1H), 8.21 (br, 3H), 7.85 (br, lH),8.46(d,2H). c) tert-Butyl (2S)-2-(aminocarbonyl)-4.4-difluoropyrrolidine-1-carboxylate In general formula (VII) Z stands for the group of formula (A) 5.7 g (22.7 mmole) of (2S)-1-(tert-butoxycarbonyl)-4,4-difluoroproline (Tetrahedron Lett. 1998, 39, 1169) are dissolved in 57 ml of dichloromethane and to the solution 3.8 ml (27.2 mmole) of triethylamine are added. To the resulting mixture at -15°C 3 ml (25 mmole) of pivaloyl chloride is added, the reaction mixture is stirred at that temperature for 1 hour, then 7 ml of 25 % aqueous ammonia solution is added to it drop wise and stirring is continued for an additional hour. The reaction mixture is washed with water, with 1 N sodium hydroxide solution, and with water, dried over sodium sulphate and evaporated. The product is crystallised from diethyl ether to obtain 3.94 g (69%) of the title product. M.p.: 136-138°C. 1H-NMR (CDCl3): 1.48 (s, 9H); 2.3-2.9 (m, 3- CH2), 3.69 (br, minor) + 3.86 (m, major)(5-CH2), 4.53 (br, 2-CH), 6.0 (br, major) + 6.81 (br, minor)(NH2). d.) (2S)-4.4-Difluoroprolinamide hydrochloride In general formula (VIII) Z stands for the group of formula (A). 3.93 g (15.7 mmole) of tert-butyl (2S)-2-(aminocarbonyl)-4,4-difluoro-pyrrolidine- 1 -carboxylate are dissolved in 75 ml of 25% ethanolic hydrogen chloride solution and stirred at room temperature for 4 hours. To the resulting suspension 150 ml of diethyl ether is added and the white crystalline material is filtered off, to obtain 2.55 g (87 %) title product M.p.: 232-233°C. 1H-NMR (DMSO-d6): 2.43-2.51 (m, minor) + 2.81-3.05(m, major)(3-CH2), 3.71 (t, 2H, 5-CH2), 4.46 (t, 1H, 2-CH), 7.81 (s, 1H.) + 8.12(s, 1HXNH2), 10.12 (br.2H.NH24) e.) (2S)-1 -(Chloroacetyl)-4.4-difluoroprolinamide In general formula (IX) Z stands for the group of formula (A). 2.54 g (13.6 mmole) of (2S)-4,4-difIuoroprolinamide hydrochloride are suspended in 25 ml of dichloromethane, 4.1 ml (29.3 mmole) of triethylamine is added to it, and to the mixture, below -10°C, the solution of 1.2 ml (15 mmole) of chloroacetyl chloride in 20 ml dichloromethane are added dropwise. After 1 hour of stirring the suspension is poured onto 450 ml of ethyl acetate, the precipitated triethylamine hydrochloride is filtered off. The filtrate is evaporated and purified by chromatography using chloroform-methanol 4:1 mixture as eluent. 3.0 g (97%) colourless oil is obtained, which is crystallised after a few days of standing. M.p.: 118-121°C. 1H-NMR (DMSO-d6): 2.34-2.52 (m, 1H) + 2.66- 2.83(m, 1H)(3-CH2), 4.07-4.29 (m, 2H, 5-CH2), 4.40(qv, 2H, CH2C1), 4.71 (m, 1H, 2-CH), 7.17 (br, 1H) + 7.42(d, 1H)(NH2). f.) (2S)-1 -(Chloroacetyl)-4.4-difluoropyrrolidine-2-carbonitrile In general formula (III) Z stands for the group of formula (A). 10.4 g (40 mmole) of (2iS)-1-(Chloroacetyl)-4,4-difluoroprolinamide are dissolved in 230 ml of dichloromethane and to the solution 13 ml (140 mmole) of phosphorus oxychloride are added. The mixture is heated under reflux for 24 hours. In the course of the heating the solution turns into yellow and a small amount of dark resin also precipitates. The solution is transferred into a larger container, 50 g of potassium carbonate is added to it and stirred for 1 hour. The solid salts are filtered off; the filtrate is evaporated to obtain yellow oil, which crystallises from n-hexane. The crude product is treated with 70 ml of diethyl ether to obtain 6.0 g (56%) white crystalline material. M.p.: 86-87°C. 1H-NMR (CDCl3): 2.76-2.98 (m, 2H, 3-CH2), 3.92-4.26 (m, 2H, 5-CH2), 4.46(q, 2H, CH2CI), 5.11 (m, 1H, 2-CH). g.) (2S)-4.4-difIuoro-1 - W-[3-(pyrimidin-2-ylamino)-1 -adamantyllglycyl) pvrrolidine- 2-carbonitrile dihydrochloride monohydrate 424 mg (1.3 mmole) of N-pyrimidin-2-yladamantane-l,3-diamine dihydrochloride are suspended in 10 ml of dichloromethane and extracted with 10 ml of saturated sodium carbonate solution. The organic phase is dried over sodium sulphate and evaporated. The residue is dissolved in 10 ml of acetonitrile, to the solution 229 mg (1.1 mmole) of (2S)-1- (chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile and 0.42 ml (3 mmol) of triethylamine are added. The mixture is stirred at room temperature for 40 hours, evaporated. The residue is dissolved in 30 ml of dichloromethane, washed with water, dried over sodium sulpfate and evaporated. The yellowish-coloured residue is purified by column chromatography (chloroform-methanol 6:1), the product is obtained in the form of an oil, which gives dihydrochloride salt with ethereal hydrochloric acid: 160 mg (29%), m.p.: 209-212°C. 1H-NMR (DMSO-d6): 1.50 (d, 1H), 1.60 (d, 1H), 1.88 (m, 6H), 2.11 (m, 2H), 2.31 (s, 4H), 2.84-2.93 (m, 2H), 4.00 (m, 1H), 4.01-4.17 (m, 2H), 4.32 (m, 1H), 5.18 (dd, 1H), 6.72 (t, 1H), 7.61 (b, 1H), 8.40 (d, 2H), 9.10 (s, 2H). Example 2. (2S)-4,4-dinuoro-1-(N-{3-[(3-nitrobenzyl)aminol-1-adamantyl} glycyl)pyrrolidine-2-carbonitrile trihydrochloride In general formula (I) R stands for 3-nitrobenzyl group, B stands for the group of formula (1), Z stands for the group of formula (A). a.) N-(3-Nitrobenzyl)adamantane-1,3-diamine In general formula (II) the meaning of R and B is as defined above. 287 mg (1.2 mmole) of 1,3-diamino-adamantane dihydrochloride (Chem. Ber. 1941, 1769) are suspended in 30 ml of dichloromethane and extracted with 30 ml of saturated sodium carbonate solution. The organic phase is dried over sodium sulphate and evaporated. The residue is dissolved in 30 ml of toluene, to the solution 90 mg (0.6 mmole) of 3-nitrobenzaldehyde and 10 mg p-toluenesulfonic acid monohydrate are added. The mixture is reluxed for 2 hours, and then evaporated, the residue is dissolved in 30 ml methanol, to the solution 114 mg (3 mmole) sodium borohydride are added. After 16 hours of stirring at room temperature solution is evaporated, the residue is dissolved in dichloromethane and washes with water. The organic layer was dried over sodium sulphate, evaporated and purified by column chromatography (chloroform-methanol- 25 % aqueous ammonia solution 9:1:0.05). The product is obtained in the form of thick oil, which is crystallized after standing: 93 mg (26%). 1H-NMR (DMSO-d6): 1.40 (m, 10H), 1.46 (s, 2H), 2.08 (s, 2H), 3.80 (s, 2H), 7.56 (t, 1H), 7.78 (d, 1H), 8.05 (d, 1H), 8.23 (s, 1H). b.) (2S)-4,4-difluoro-1-(N-(3-[(3-nitrobenzynaminol-1-adamantyl) glycyl)pyrrolidine- 2-carbonitrile trihydrochloride 90 mg (0.3 mmole) of N-(3-nitrobenzyl)adamantane-1,3-diamine and 50 mg (0.24 mmole) of (2S)-1-(chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile are dissolved in acetonitrile, to the solution 300 mg (0.75 mmole) of polimer bound 2-tert-butylimino-2- diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (PBEMP) are added. The mixture is sirred at 70°C for 4 hours, then at room temperature for 20 hours. The scavanger resin is fitered off and the filtrate is evapotared, the residue is purified by column chromatography (chloroform-methanol 6:1). After acidification of the formed oil with ethereal hydrochloride acide the title compound is obtained: 41 mg (29%), m.p.: 226- 229°C. 1H-NMR (DMSO-d*): 1.57 (s, 2H), 1.95 (d, 8H), 2.45 (d, 4H), 2.91 (m, 2H), 4.14 (m, 2H), 4.33 (m, 4H), 5.21 (m, 1H), 7.74 (t, 1H), 8.15 (t, 1H), 8.27 (dd, 1H), 8.58 (s, 1H), 9.41 (b,2H), 9.77 (b,2H). Example 3. N-(3-{]2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyll amino}-1- adamantyl)-4-methoxybenzamide dihydrochloride monohydrate In general formula (I) R stands for 4-methoxybenzoyl group, B stands for the group of formula (1), Z stands for the group of formula (A). a.) N-(3-Amino-1 -adamantyl)-4-methoxvbenzamide In general formula (II) the meaning of R and B is as defined above. Free base is prepared from 487 mg (2 mmole) of 1,3-diamino-adamantane dihydrochloride, as described in Example 2/a.). It is dissolved in 20 ml of dichlorometane, to the solution 253 mg (2.1 mmole) polimer-bound dietilamine (PS-DIEA) are added, and to the mixture at 0°C the solution of 119 mg (0.7 mmole) of p-anisoyl chloride in 20 ml of dichloromethane are added dropwise. After stirring 24 hours the solid materials are filtered off and the filtrate is evaporated. The residue is purified by column chromatography (chloroform-methanol-25 % aqueous ammonia solution 9:1:0.1): 132 mg (63%) 1H-NMR (DMSO-d6): 1.41 (m, 6H), 1.89 (d, 6H), 2.11 (s, 2H), 3.80 (s, 3H), 6.96 (d, 2H), 7.47 (s, 1H), 7.76 (d, 2H). b.) N-(3-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl] amino}-1- adamantyl)-4-methoxybenzamide dihydrochloride monohydrate 132 mg (0.45 mmole) of N-(3-Amino-1-adamantyl)-4-methoxybenzarnide are reacted with 87 mg (0.42 mmole) of (2S)-1-(chloroacetyl)-4,4-difluoro-pyrrolidine-2- carbonitrile in the presence 340 mg (1.32 mmole) PS-DIEA in 25 ml acetonitrile, as described in Example 2/b.). After work-up and chromatographic purification (chloroform- methanol-25 % aqueous ammonia solution 9:1:0.1) and acidification ethereal hydrochloride acide the title compound is obtained: 90 mg (46%). M.p.: 160-161°C. 1H- NMR (DMSO-d6): 1.60 (dd, 2H), 1.85 (m, 6H), 2.14 (m, 2H), 2.30 (m, 2H), 2.38 (m, 2H), 2.87 (m, 2H), 3.79 (s, 3H), 4.17 (m, 2H), 4.26 (m, 1H), 4.47 (m, 1H), 5.21 (m, 1H), 6.95 (d, 2H), 7.71 (s, 1H), 7.77 (d, 2H), 9.41 (b, 2H), 9.02 (b, 2H). Example 4. (2S)-4,4-dinuoro-1-(N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)ciro- amlnoacetyl]pyrrolidine-2-carbonitrile In general formula (I) R stands for pyrimidin-2-yl group, B stands for the group of formula (3), Z stands for the group of formula (A) a.) tert-Butyl (3-pyrimidin-2-yl-3-azabicyclo[3.2,1]oct-8-yl)-exo-carbamate In general formula (V) the meaning of R and B are as defined above, Y represents tert- butoxycarbonyl group. (i) 3-Benzyl-3-azabicvclor3.2.11octan-8-one oxime The mixture of 19 g (88 mmole) of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (J. Med. Chem. 1994, 37, 2831), 200 ml of ethanol, 8.78 g (126.4 mmole) of hydroxylamine hydrochloride and 13 ml of pyridine are heated and stirred on a 100ºC oil-bath, then the mixture is evaporated. To the residue 65 ml of 2.5 N sodium hydroxide solution is added, the resulting solution is extracted with 3x120 ml of ethyl acetate. The extractum is dried over sodium sulphate and evaporated. The resulting oil is purified by column chromatography (n-hexane - ethyl acetate from 9:1 to 1:1) to obtain 11.05 g (54%) of white, crystalline material. M.p.: 92-95°C. (MH+) = 231. (ii) 3-Benzyl-3-azabicyclo[3.2.1]octan-8-exo-amine and 3-benzyl-3-azabi- cyclo[3.2.1]octan-8-endo-amine 11.05 g (48 mmole) of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one oxime are dissolved at room temperature in 300 ml of n-pentanol. To the boiling solution under nitrogen stream and intensive stirring, in several portions 12 g (52 mmole) of sodium metal is added in small peaces. At the end of the addition the raction mixture is heated under reflux for an additional half an hour. After cooling the mixture is poured onto 250 ml of cold water. The phases are separated; the organic phase is washed with 100 ml of cold water and extracted with 3x100 ml of 2N hydrochloric acid. Carefully, under cooling, the acidic solution is made alkaline (pH=13) with solid potassium hydroxide and the mixture is extracted with dichloromethane. The extract is dried over sodium sulphate and evaporated. The residue is purified by column chromatography (dichloromethane - methanol from 95:5 to 4:1) to obtain separately 4.52 g (44%) of the exo-isomer (m.p. 61-63°C) and 1.07 g (10%) of the endo-isomer (m.p. 70-72°C). (MH+) = 217. 4.50 g (21 mmole) of 3-benzyl-3-azabicyclo[3.2.1]octan-8-exo-amine are dissolved in 10 ml of dichoromethane and to the solution 5.71 g (26 mmole) of di-tert-butyl dicarbonate in 10 ml of dichoromethane are added under cooling. The mixture is stirred at room temperature for 2 hours, evaporated and crystallized from n-hexane, to obtain: 5.47 g (83%). M.p.: 118-119°C. 1H-NMR (DMSO-d6): 1.40 (s, 9H), 1.58-1.67 (m, 4H), 2.00 (s, 2H), 2.28 (dd, 2H), 2.45 (d, 2H), 3.37 (d, 1H), 3.46 (d, 2H), 6,83 (s, 1H), 7.19-7.30 (m, 5H).(MHV317. (iv-) tert-Butyl 3-azabicyclo[3.2.1]oct-8-yl-exo-carbamate 5.4 g (17 mmole) of tert-Butyl (3-benzyl-3-azabicyclo[3.2.1]oct-8-yl)-exo- carbamate are dissolved in 50 ml of methanol, to the solution 1.8 g of 10% palladium on charcoal are added and the mixture is hydrogenated under small pressure (3-5 atm). The catalyst is filtered off, the filtrate is evaporated, the residue is crystallised from the mixture of diethyl ether and p-hexane to obtain 3.85 g (96%) of product. M.p.: 93-94°C. (MH+) = (v)tert-Butyl (3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)-exo-carbamate The mixture of 2.32 g (10 mmole) of tert-butyl 3-azabicyclo[3.2.1]oct-8-yl-axo- carbamate, 1.15 g (10 mmole) of 2-chloropyrimidine, 1.8 ml (12 mmole) of DBU and 20 ml of acetonitrile are stirred at room temperature for 24 hours. The reaction mixture is evaporated, after addition of 20 ml of water to the residue, it is extracted with 3x 10 ml of dichloromethane. The extract is dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with dichloromethane eluent, to obtain 1.91 g (61%) of white, crystalline product. M.p.: 145-146°C. (MH+) = 305. b.) 3-Pyrimidin-2-yl-3-azabicyclo[3.2.1]octan-8-exo-amine In general formula (II) the meaning of R and B are as defined above To the solution of 2.1 g (6.9 mmole) of tert-butyl (3-pyrimidin-2-yl-3- azabicyclo[3.2.1]oct-8-yl)-exo-carbamate in 35 ml of dichloromethane, 16.1 ml of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature, then evaporated. The pH is adjusted pH=9 with saturated sodium carbonate solution, under cooling; the mixture is then extracted with dichloromethane. The organic layer is dried over sodium-sulphate and evaporated. The residue is suspended in n-hexane, after cooling the solid material is filtered off, dried, to obtain 0.63 g (45%) of white crystals. M.p.: 105- 107°C.'(MH+) = 205. c.) (2S)-4.4-difluoro- 1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)exo- aminoacetyl]pyrrolidine-2-carbonitrile 204 mg (1.0 mmole) of 3-pyrimidin-2-yl-3-azabicyclo[3.2.1]octan-8-exo-amine and 208 mg (1 mmole) of (25)-1-(chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile and 0.25 ml (1.8 mmole) of triethylamine are reacted in acetonitrile as described in Example 1/g). After purification by column chromatography (dichloromethane - methanol 9:1) and treatment with n-hexane, white crystalline product is obtained: 200 mg (53%). M.p.: 50- 52°C. 1H-NMR (DMSO-d6): 1.44 (td, 2H), 1.67 (m, 2H), 2.18 (s, 2H), 2.42 (br, 1H), 2.81 (m 3H), 3.31 (m, 2H), 3.47 (m, 2H), 3.98 (m, 3H), 4.18 (m, 1H), 5.08 (dd, 1H), 6.56 (t, 1H), 8.32 (d, 2H). (MH+) = 377. Example 5. (2S)-4,4-difluoro-1-[N-{3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)endo- aminoacetyl]pyrrolidine-2-carbonitriledihydrochloride In general formula (I) R stands for pyrimidin-2-yl group, B stands for the group of formula (2), Z stands for the group of formula (A). a.) tert-Buryl(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)-endo-carbamate In general formula (V) the meaning of R and B are as defined above, Y represents tert- butoxycarbonyl group. From 1.0 g (4.6 mmole) of 3-benzyl-3-azabicyclo[3.2.1]octan-8-endo-amine obtained in step 2/a./(ii) with di-tert-butyl dicarbonate, according to step 2/a7(iii) 1.02 g (70%) of the title product is obtained. M.p.: 127-129°C. 1H-NMR (DMSO-d6): 1.37 (s, 9H), 1.53-1.57 (m, 2H), 1.70 (m, 2H), 2.03 (s, 2H), 2.07 (d, 2H), 2.58 (dd, 2H), 3.24 (d, 1H), 3.44 (d, 2H), 6.60 (s, 1H), 7.12-7.32 (m, 5H). (MH+) = 317 (ii) tert-Butyl 3-azabicyclo[3.2.1]oct-8-yl-endo-carbamate Following the method described in step 4/a7(iv), from 1.0 g (3.2 mmole) of tert- Butyl (3-benzyl-3-azabicyclo[3.2.1]oct-8-yl)-endo-carbamate after debenzylation 0.71 g (98%) of title product is obtained. (MH+) = 227. (iii) tert-Buryl(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)-endo-carbamate Following the method described in step 4/a./(v) from 0.7 g (3.1 mmole) of tert- butyl 3-azabicyclo[3.2.1]oct-8-yl-endo-carbamate with 2-chloropyrimidine 0.87 g (92 %) of title product is obtained in the form of an oil. (MH+) = 305. b.) 3-(Pyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-endo-amine In general formula (II) the meaning of R and B are as defined above. Following the method described in step 4/b.) starting from 0.87 g (2.9 mmole) of tert-butyl (3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl}-endo-carbamate, after hydrolysis 0.49 g (83%) of title product is obtained. (MH+) = 205. c.) (2S)-4.4-difluoro-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl) endo- aminoacetyl]pyrrolidine-2-carbontrile dihydrochloride Following the method described in step 4/c.) from 204 mg (1.0 mmole) of 3- (pyrimidin-2-yl)-3-azabicyclo[3.2.1]octan-8-endo-amine and 208 mg (1 mmole) (2S)-1- (chloro-acetyl)-4,4-difluoropyrrolidine-2-carbonitrile the title product is obtained in the form of hydrochloride salt. Yield: 152 mg (34%), m.p. > 300°C. 'H-NMR (DMSO-d6): 1.44 (d, 2H), 1.98 (m, 2H), 2.67 (s, 2H), 2.86-3.00 (m 4H), 4.09-4.21 (m, 4H), 4.38-4.48 (m, 3H), 5.21 (dd, 1H), 6.71 (t, 1H), 8.39 (d, 2H), 9.11 (d,2H). (MH+) = 377. Example 6. (25)-4,4-difluoro-1-[N-(3-methyl-8-pyrimidin-2-yl-8-azabicyclo [3.2.1] oct-3- yl)exo-aminoacetyl] py rrolidine-2-carbonltrile dihydrochloride In general formula (I) R stands for pyrimidin-2-yl group, B stands for the group of formula (5), Z stands for the group of formula (A). In general formula (V) the meaning of R and B are as defined above, Y represents acetyl group. To the solution of 16.00 g (74 mmole) of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (J.C.S. Perkin I. 1997, 1307) in 270 ml of dry tetrahydrofurane, under nitrogen atmosphere are dropped 38 ml (330 mmole) of methyl magnesium bromide, at -20 °C with syringe. The reaction mixture is stirred at -20°C for 30 minutes, and then allowed to warm up to room temperature and stirring is continued for 16 hours. To the mixture 900 ml of saturated ammonium chloride solution and 300 ml of diethyl ether are added. After mixing and separation the aqueous phase is extracted with 3x 100 ml of dichloromethane, the dichloromethane phase is washed with 100 ml of saturated sodium chloride. The combined organic phase is dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel (chloroform). The product is 5.95 g (35%) oily material. (MH+) = 232. 3.0 g (13 mmole) of 8-benzyl-3-methyl-8-azabicyclo[3.2.1]octan-3-endo-ol are dissolved in 15 ml of acetonitrile. To the solution, carefully, under cooling and stirring, 12.2 ml of concentrated sulphuric acid (t room temperature for 16 hours. The reaction mixture is poured onto 100 g of ice. The pH of the solution is adjusted to pH=10 with 50% potassium hydroxide. The mixture is extracted with dichloromethane; the extract is washed with concentrated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is crystallised from the mixture of n-hexane and ether, to obtain 2.11 g (59%) of white crystalline material. M.p.: 151-155°C. (MH+) = 273. 2.10 g (7.7 mmole) of N-(8-benzyl-3-methyl-8-azabicyclo[3.2.1]oct-3-endo- yl)acetamide are hydrogenated as described in step 4/a./(iv). After debeneylation 1.20 g (86%) of the title product is obtained. M.p.: 63-65 °C. (MH+) = 183. (iv) N-(3-methyl-8-pyrimidin-2-yl-8-azabicyclo[3.2.1]oct-3-exo-yl)acetamide 1.20 g (6.6 mmole) of (3-methyl-8-azabicyclo[3.2.1]oct-3-exo-yl)acetamide, 0.76 g (6.6 mmole) of 2-chloropyrimidine and 1.18 ml (7.9 mmole) of DBU are heated in n- pentanol under reflux conditions for 8 hours. The reaction mixture is worked-up as described in step 4/a./(v) to obtain 0.89 g (52%) of white crystalline material. M.p.: 175- 176°C.(MH+) = 261. b.) 3-Methyl-8-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-3-exo-amine In general formula (II) the meaning of R and B are as defined above. 0.89 g (3.4 mmole) of N-(3-methyl-8-pyrimidin-2-yl-8-azabicyclo[3.2.1] oct-3-exo- yl)acetamide are refluxed in 35 ml of 2N hydrochloric acid for 16 hours. After cooling the reaction mixture is made alkaline (pH=11) with 20 % sodium hydroxide solution and extrated with 20 ml of dichloromethane. The extract is dried over sodium sulphate and evaporated. The residue is suspended in diethyl ether, filtered; the mother liquor is evaporated, to obtain 130 mg (18%) of the product in the form of pale-yellow oil. (MH+) = 219. c.) (2S)-4.4-difluoro-1-[N-(3-methyl-8-pyrimidin-2-yl-8-azabicyclo[3.2.1]oct- 3-yl)exo-aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride Following the method described in step 4/c), from 110 mg (0.5 mmole) of 3- methyl-8-pyrimidin-2-yl-8-azabicyclo[3.2.1]oct-3-yl-exo-amine and 104 mg (0.5 mmole) of (25)-1-(chloroacetyl)-4,4-difluoropyrrolidine-2-carbonitrile 59 mg (30%) of white, crystalline product is isolated. M.p.: 169-172°C. 1H-NMR (400 MHz, DMSO-d6): d 0.81 (s, 3H), 1.62-1.73 (m, 5H), 1.80 (m, 2H), 2.18 (d, 2H), 2.79- (m, 2H), 3.37-3.45 (m, 2H), 4.04 (ddd, 1H), 4.30 (ddd, 1H), 4.55 (m, 2H), 5.09 (dd, 1H), 6.57 (t, 1H), 8.32 (d, 2H). (MH+) = 391. The following compounds of general formula (I) are prepared according to example 1-6 in the Table 1. Following procedures outlined for Examples 1/a.) the compounds of the general formula (V) - wherein B is a group of formula (1) - listed in the Table 2 were prepared. Following procedures outlined for Examples 1/b.), 2/a.) and 3/a.) the compounds of the general formula (II) - wherein B is a group of formula (1) - listed in the Table 3 were prepared. WE CLAIM: 1. Adamantane and azabicyclo-octane and nonane derivatives of the general formula (I) - wherein R represents: - a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono or disubstituted independently by one or two of the following groups or atoms: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - a phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, trihalogenomethyl group, methylthio group, nitro group, eyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - a R1a-CH2-group, where the meaning of R1a is hydrogen, C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl group, substituted independently by one or more halogen atom, C1-4 alkyl, C1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano group; or - an R1aR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group, substituted independently with one or more halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, trihalogenomethyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C1-4 alkyl, - alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and R2 represents hydrogen or methyl group; or - an R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy group, halogen atom, trihalogenomethyl, nitro, or cyano group, or an amino group, or a pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl group; or -P-toluenesulphonyl group; - B represents a group of formula (1), (2), (4) or (5); 2. The compounds of the general formula (I) as claimed in claim 1 - wherein R represents: - a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazinyl, tetrazolyl, triazinyl quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono- or disubstituted independently by one or two of the following groups or atoms: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - a phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, trihalogenomethyl group, methylthio group, nitro group, cyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - a R1a-CH2- group, where the meaning of R1a is hydrogen, C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl group, substituted independently by one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano group; or - an RlaR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group, substituted independently with one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, trihalogenomethyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C1- 4 alkyl, - alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and R2 represents hydrogen or methyl group; or - an R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy group, halogen atom, trihalogenomethyl, nitro, or cyano group, or an amino group, or a pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl group; - B represents a group of formula (1), (2), (4) or (5); - Z represents a group of formula (A); and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 3. The compounds of the general formula (I) as claimed in claim 1 - wherein R represents: - a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono- or disubstituted independently by one or two of the following groups or atoms: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - a phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, trihalogenomethyl group, methylthio group, nitro group, cyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - a R1a-CH2- group, where the meaning of R1a is hydrogen, C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl orp-tolylsulphonyl group, substituted independently by one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano group; or - an R1aR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group, substituted independently with one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, trihalogeno- methyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C1-4 alkyl, - alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and R2 represents hydrogen or methyl group; or - an R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy group, halogen atom, trihalogenomethyl, nitro, or cyano group, or an amino group, or a pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl group; - B represents a group of formula (1), (2), (4) or (5); - Z represents a group of formula (B); and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 4. The compounds of the general formula (I) as claimed in claim 1 - wherein R represents: - a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazinyl, tetrazolyl, triazinyl quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxal-inyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono- or disubstituted independently by one or two of the following groups or atoms: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - a phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, trihalogenomethyl group, methylthio group, nitro group, cyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - a R1a-CH2-group, where the meaning of R1a is hydrogen, C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl group, substituted independently by one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano group; or - an R1aR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyil, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group, substituted independently with one or more halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, trihalogenomethyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C1-4 alkyl, - alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and R2 represents hydrogen or methyl group; or - an R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy group, halogen atom, trihalogenomethyl, nitro, or cyano group, or an amino group, or a pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl group; - B represents a group of formula (1), (2), (4) or (5); - Z represents a group of formula (D), and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 5. The compounds of the general formula (I) as claimed in claim 1 - wherein R represents: - a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazinyl, tetrazolyl, triazinyl quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono- or disubstituted independently by one or two of the following groups or atoms: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - a phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, trihalogenomethyl group, methylthio group, nitro group, cyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - a R1a-CH2-group, where the meaning of R1a is hydrogen, C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl group, substituted independently by one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano group; or - an R1aR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group, substituted independently with one or more halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, trihalogenomethyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C1-4 alkyl,- alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and R2 represents hydrogen or methyl group; or - an R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy group, halogen atom, trihalogenomethyl, nitro, or cyano group, or an amino group, or a pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl group; - B represents a group of formula (1); - Z represents a group of formula (A), (B), or (D); and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 6. The compounds of the general formula (I) as claimed in claim 1 - wherein R represents: - a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazinyl, tetrazolyl, triazinyl quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono- or disubstituted independently by one or two of the following groups or atoms: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - a phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, trihalogenomethyl group, methylthio group, nitro group, cyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - a R1a-CH2-group, where the meaning of R1a is hydrogen, C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl group, substituted independently by one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano group; or - an R1aR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group,substituted independently with one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, trihalogenomethyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C1-4 alkyl, - alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and R2 represents hydrogen or methyl group; or - an R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy group, halogen atom, trihalogenomethyl, nitro, or cyano group, or an amino group, or a heterocyclic group, preferably pyrrolidine, piperidino, piperazino, morpholino, thienyl or furyl group; - B represents a group of formula (2); - Z represents a group of formula (A), (B), or (D); and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 7. The compounds of the general formula (I) as claimed in claim 1 - wherein R represents: - a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazinyl, tetrazolyl, triazinyl quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono- or disubstituted independently by one or two of the following groups or atoms: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - a phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, trihalogenomethyl group, methylthio group, nitro group, cyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - a R1a-CH2 -group, where the meaning of R1a is hydrogen, C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl group, substituted independently by one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano group; or - an R1aR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group, substituted independently with one or more halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, trihalogenomethyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C1-4 alkyl, - alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and R2 represents hydrogen or methyl group; or - an R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy group, halogen atom, trihalogenomethyl, nitro, or cyano group, or an amino group, or a pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl group; - B represents a group of formula (4); - Z represents a group of formula (A), (B), or (D); and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 8. The compounds of the general formula (I) as claimed in claim 1 - wherein R represents: - a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazinyl, tetrazolyl, triazinyl quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl moiety; optionally mono- or disubstituted independently by one or two of the following groups or atoms: C1-4 alkyl group, C1-4 alkoxy group, C2-5 alkoxycarbonyl group, halogen atom, trihalogenomethyl group, methylthio group, nitro group, carboxamido group, cyano group; or - a phenyl group, which is mono- or disubstituted, independently by one or two of the following groups: C1-4 alkyl group, C1-4 alkoxy group, C1-4 alkylenedioxy group, trihalogenomethyl group, methylthio group, nitro group, cyano group, C2-5 alkylcarbonyl group, C2-5 alkoxycarbonyl group, C2-8 dialkylamino group; or - a R1a-CH2-group, where the meaning of R1a is hydrogen, C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, furyl or p-tolylsulphonyl group, substituted independently by one or more halogenatom, C1-4 alkyl, C1-4 alkoxy, alkylenedioxy, trihalogenomethyl, nitro or cyano group; or - an R1aR2-CH group, where - the meaning of R1a is C1-4 alkyl group, phenyl, benzyl, phenylethyl, phenylethenyl, phenylpropyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl, thienyl, or furyl group, substituted independently with one or more halogen atom, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy, trihalogenomethyl, nitro, amino or cyano group, or a phenylcarbonyl moiety, substituted independently with one or more, C 1-4 alkyl, - alkoxy, -alkylenedioxy halogeno, trihalogenomethyl, nitro-, amino- or cyano group, and R2 represents hydrogen or methyl group; or - an R1b-CO group, where - the meaning of R1b is C1-4 alkyl group, or a phenyl, benzyl, phenylethyl, phenylethenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinazolinyl, quinoxalinyl moiety, substituted independently with one or more C1-4 alkyl, C1-4 alkoxy, C1-4 alkylenedioxy group, halogen atom, trihalogenomethyl, nitro, or cyano group, or an amino group, or a pyrrolidino, piperidino, piperazino, morpholino, thienyl or furyl group; - B represents a group of formula (5); - Z represents a group of formula (A), (B), or (D); and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 9. The compounds of the general formula (I) as claimed in claim 1 - wherein R has the same meaning as in claim 1, B represents a group of formula (1), (2), (4) or (5); Z represents a group of formula (A), (B) or (D) - and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 10. The compounds of the general formula (I) as claimed in claim 1 - wherein R has the same meaning as in claim 1, B represents a group of formula (1); Z represents a group of formula (A), (B) or (D) - and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 11. The compounds of the general formula (I) as claimed in claim 1 - wherein R has the same meaning as claimed in claim 1, B represents a group of formula (2) or (4); Z represents a group of formula (A) - and isomers, salts, solvates of the above compounds, as well as solvates of their salts. 12. The following compounds of the general formula (I) as claimed in claim 1: (2S)-4,4-difluoro-1-{N-[3-(pyrimidin-2-ylamino)-1-adamantyl]glycyl} pyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1 -(N-(3-[(3-nitrobenzyl)amino] -1 -adamantyl)glycyl) pyrrolidine-2- carbonitrile N-(3- {[2-(2-cyano-(25)-4,4-difluoropyrrolidin-1 -yl)-2-oxoethyl] amino)-1 -adamantyl)-4- methoxybenzamide (2S)-4,4-difluoro-1-(N-(3-pyrimidin-2-yl-3-azabicyclo[3.2.1]oct-8-yl)endo-aminoacetyl] pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-{N-[3-(pyrimidin-2-ylamino)-1-adamantyl]glycyl} pyrrolidine-2- carbonitrile (4R)-3-{N-[3-(pyrimidin-2-ylamino)-1-adamantyl]glycyl}-l,3-thiazolidine-4-carbonitrile (25)-4,4-difluoro-1-{N-[3-(l ,2,4-triazin-3-ylamino)-1-adamantyl]glycyl} pyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1 -{N-[3-(pyrazin-2-ylamino)-1 -adamantyl]glycyl} pyrrolidine-2-carbonitrile (2S)-1-(N-{3-[(4-cyanophenyl)amino]-1-adamantyl}glycyl)-4,4-difluoropyrrolidine-2- carbonitrile 6-[(3- {[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino}-1-adamantyl)amino] nicotinonitrile (2S)-4,4-difluoro-1-[N-(3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1-adamantyl)glycyl] pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1-[N-(3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1-adamantyl)glycyl] pyrrolidine-2-carbonitrile (25)-4,4-difluoro-1-{N[3-(l,3-thiazol-2-ylamino)-1-adamantyl]glycyl} pyrrolidine-2- carbonitrile (2S)-1 -(N- { 3 - [(1 -ethyl-1H-pyrazol-5 -yl)amino] -1 -adamantyl} glycyl)-4,4-difluoropyrrolidine- 2-carbonitrile (2S)-4,4-difluoro-1-(N-{3-[(5-methylisoxazol-3-yl)amino]-1-adamantyl}glycyl)pyrrolidine-2- carbonitrile (25)-4,4-difluoro-1 -{N-[3-(quinolin-2-ylamino)-1 -adamantyl]glycyl} pyrrolidine-2- carbonitrile (2S,4S)-4-fluoro-1 -{N-[3-(quinolin-2-ylamino)-1 -adamantyl] glycyl} pyrrolidine-2-carbonitrile (2S)-4,4-difluoro-1 -{N-[3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1 -adamantyl] glycyl} pyrrolidine-2-carbonitrile (2S,4S)-4-fluoro-1- {N-[3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1 -adamantyl] glycyl} pyrrolidine-2-carbonitrile (4S)-3-{N-[3-([l,2,4]triazolo[l,5-a]pyridin-2-ylamino)-1-adamantyl]glycyl}-1,3-thiazolidine- 4-carbonitrile (2S)-1-(N-{3-[(4-cyanobenzyl)amino]-1-adamantyl} glycyl)-4,4-difluoropyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1-[N-(3- {[4-(trifluoromethyl)benzyl]amino}-1-adamantyl) glycyl] pyrrolidine-2-carbonitrile (2S)-4,4-difluoro-1-(N-{3-[(3-fluorobenzyl)amino]-1-adamantyl}glycyl)pyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1-(N{3-[(3,4,5-trimethoxybenzyl)amino]-1-adamantyl} glycyl)pyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1 -(N-{3-[(pyridin-3-ylmethyl)amino]-1 -adamantyl} glycyl) pyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1-(N-3-[(pyridazin-3-ylmethyl)amino]-1-adamantyl)glycyl)pyrrolidine-2- carbonitrile (2S)-4,4-difluoro-1 -(N- { 3-[(1,3-thiazol-2-ylmethyl)amino]-1 -adamantyl} glycyl) pyrrolidine- 2-carbonitrile 4-chloro-N-(3-{[2-(2-cyano-(25)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl] amino}-1- adamantyl)benzamide N-(3 - {[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1 -yl)-2-oxoethyl] amino} -1 -adamantyl)-3 - fluorobenzamide (2S)-N-(3- {[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1 -yl)-2-oxoethyl]amino} -1 -adamantyl)-3- phenylacrylamide N-(3-{[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino }-1-adamantyl) thiophene-2-carboxamide (2S)-4,4-difluoro-1-[N-(3-pyrimidin-2-yl-3-azabicyclo[3.3.1]non-9-yl)glycyl]pyrrolidine-2- carbonitrile 6-(9- {[2-(2-cyano-(2S)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]amino} -3-azabicyclo[3.3.1] non-3-yl)pyridazine-3-carbonitrile and their salts, solvates as well as solvates of their salts. 13. Pharmaceutical composition wherein, it contains a compound of the general formula (I) -wherein the meanings of R, B and Z are as defined in Claim 1 - or the isomers or solvates thereof, in the form of the free compound or of its salt, and at least one pharmaceutically accepted excipient or diluent. 14. Process for the preparation of the compounds of the general formula (I) - wherein the meanings of R, B and Z are as defined in Claim 1 - wherein, a compound of the general formula (II) R-B-NH2 (II) - wherein the meaning of R and B are as defined above - is reacted with a compound of the general formula (III) - wherein the meaning Z is as defined above - and isolating the resulting compound of the general formula (I) or its salt from the reaction mixture. 15. A process for the preparation of compound of the general formula (I) - wherein the meanings of R and Z are as defined in claim 1 and B means a group of the formula (1) - wherein, the used compounds of the general formula (II) - wherein R is as defined in Claim 1 and B means a group of the formula (1) - is prepared starting from 3-hydroxy-1-amino-adamantane using the reaction route described in page 11 of this specification. 16. A compound of the general formula (I) - wherein the meanings of R, B and Z are as defined in Claim 1 - for the preparation of a pharmaceutical composition suitable to inhibit DPP-IV enzyme activity, thus suitable to treat diseases related with the DPP-IV enzyme concentration. The invention relates to new compounds of the general formula (I), which are strong DPP-IV enzyme inhibitors.

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637-KOLNP-2006-CORRESPONDENCE 1.1.pdf

637-KOLNP-2006-CORRESPONDENCE.pdf

637-KOLNP-2006-FORM 27 1.1.pdf

637-KOLNP-2006-FORM 27.pdf

637-kolnp-2006-granted-abstract.pdf

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637-kolnp-2006-granted-claims.pdf

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637-kolnp-2006-granted-form 1.pdf

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