HU0200849A2 - N-aminoacetyl-2-cyano-pyrrolidine derivatives, and pharmaceutical compositions containing these compounds preparation process - Google Patents

N-aminoacetyl-2-cyano-pyrrolidine derivatives, and pharmaceutical compositions containing these compounds preparation process Download PDF

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HU0200849A2
HU0200849A2 HU0200849A HU0200849A HU0200849A2 HU 0200849 A2 HU0200849 A2 HU 0200849A2 HU 0200849 A HU0200849 A HU 0200849A HU 0200849 A HU0200849 A HU 0200849A HU 0200849 A2 HU0200849 A2 HU 0200849A2
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cyano
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Imre Bata
Éva Boronkay
Sándor Bátori
Katalin Urbán-Szabó
Zoltán Kapui
Edit Susán
Márton Varga
Péter Arányi
Tibor Szabó
NAGY Lajos T.
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Sanofi-Synthelabo
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Abstract

A találmány tárgyát az új (I) általános képletű 1-szubsztituált-acetil-2-ciano-4,4'-difluoro-pirrolidinek és analógjaik képezik,melyek a dipeptidil peptidáz IV enzim aktivitását erősen gátolják. The invention provides (I) a substituted-1-acetyl-2-cyano-4,4-difluoro-pyrrolidines and their analogues of general formula, which are potent inhibitors of dipeptidyl peptidase IV enzyme activity. Az(I) általános képletben R1 nitrogénatomot tartalmazó egy- vagy kéttagúaromás gyűrű; mono- or kéttagúaromás ring containing a nitrogen atom, R1 in formula (I); tienil- vagy furilcsoport; thienyl or furyl; p- toluolszulfonilcsoportvagy R1a-CO-csoport R2 hidrogén vagy fluoratom; p- toluolszulfonilcsoportvagy R1a-CO-R2 group is hydrogen or fluorine; R3 fluoratom; R3 is fluoro; Bjelentése (1), (2), (3), (4) vagy (5) általános képletű csoport. B is (1), (2), (3), (4) or (5) a group of formula. Ó HE

Description

PÉLDÁNY COPIES

2002/4 2002/4

Új vegyületek new compounds

Bejelentő: Sanofí-Synthelabo, Párizs, Franciaország Applicant: Sanofi-Synthelabo, Paris, France

Képviselő: CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Rt. Owner: CHINOIN Pharmaceutical and Chemical Works Plc.

Feltalálók: inventors:

Arányi Péter és társai nem egyenlő arányban Arányi Peter and others are not equally

Bejelentés napja: 2002. 03. 06. Report date: 03 2002 06th

• · • ·

Jelen találmány tárgyát az (I) általános képletű dipeptidil-peptidáz-IV enzim inhibitor hatású vegyületek ezek sói, szolvátjai és izomerjei, az azokat tartalmazó gyógyszerkészítmények, az (I) általános képletű vegyületek terápiás alkalmazása, az (I) általános képletű vegyületek előállítási eljárása és a (II), (III), (V), (VII), (VIII) és (IX) általános képletű új intermedierek képezik. The present invention provides a dipeptidyl peptidase-IV enzyme in the formula (I) inhibitor compounds and their salts, solvates and isomers, to the pharmaceutical compositions containing them for therapeutic use of the compounds of formula (I), process for preparing the compounds of formula (I) and (II), (III), (V), (VII), (VIII) and (IX) are novel intermediates of the formula.

A dipeptidil-peptidáz-IV enzim (DPP-IV), mely azonos a CD26 jelű limfocita felszíni glikoproteinnel, egy 11 Ok Dalton molekulatömegű polipeptid, mely az emlősök szöveteiben és szerveiben képződik. Dipeptidyl peptidase-IV enzyme (DPP-IV), which, is formed in the mammalian tissues and organs of the same sign lymphocyte surface glycoprotein CD26, a 11 Dalton polypeptide Cause. Ez az enzim többek között megtalálható a májban, a hasnyálmirigy szigeteiben, a vesekéregben, a tüdőben, a prosztata és a vékonybél egyes szöveteiben. This enzyme can be found, inter alia, the liver, pancreatic islets, renal cortex, in the lungs, the prostate and small intestine in certain tissues. Továbbá jelentős mértékű DPP-IV aktivitás figyelhető meg a testfolyadékokban (például plazma, szérum, vizelet). Also significant DPP-IV activity is observed in body fluids (e.g., plasma, serum, urine).

A DPP-IV egy szerin proteáz típusú enzim, mely egyedi specifitással rendelkezik, dipeptideket hasít le olyan peptidek N-terminálisáról, ahol az utolsó előtti aminosav elsősorban prolin, másodsorban alanin. DPP-IV is a serine protease type enzyme, which has a unique specificity to cleave dipeptides described peptides N-terminus of which the penultimate amino acid is primarily proline, alanine secondarily.

A DPP-IV enzim felelős a glucagonszerű 1-es peptid (GLP-1) és 2-es peptid (GLP-2) lebontásáért a szervezetben. The DPP-IV enzyme is responsible for the glucagonszerű peptide 1 (GLP-1) and peptide 2 (GLP-2) degradation in the body. A GLP-1 a hasnyálmirigy inzulintermelését erőteljesen serkenti, és így közvetlenül előnyös hatással van a glükóz homeosztázisra, ezért a DPP-IV inhibitorok alkalmasak a nem-inzulinfuggő diabetes mellitus (NIDDM) kezelésére. GLP-1 in the pancreas to produce insulin is a powerful stimulus, and thus directly affects the preferred glucose homeostasis, therefore DPP-IV inhibitors are suitable for the treatment of non-insulin dependent diabetes mellitus (NIDDM).

Célul tűztük ki, új, hatékony és biztonságos DPP-IV inhibitorok előállítását. Our aim was the preparation of new, effective and safe DPP-IV inhibitors.

Azt találtuk, hogy az (I) általános képletű vegyületek ahol R 1 jelentése It has been found that the compounds of formula (I) wherein R 1 is

- nitrogénatomot tartalmazó egy- vagy kéttagú aromás gyűrű, előnyösen piridil, piridazinil, pirimidinil, pirazinil, imidazolil, pirazolil, tiazolil, isotiazolil, oxazolil, izoxazolil, oxadiazolil, kinolinil, izokinolinil, cinnolinil, ftalazinil, kinazolinil, kinoxalinil, benzimidazolil, indazolil, benzotiazolil, benzoizotiazolil, benzoxazolíl és benzizoxazolil csoport, mely adott esetben egymástól függetlenül mono- vagy diszubsztituált, a következő csoportok egy vagy két képviselőjével: 1-4 szénatomos alkil csoport, 1-4 szénatomos alkoxi-csoport, halogénatom, trihalogén-metil-csoport, metiltio-csoport, nitro-csoport, és ciano-csoport; - one or two-member aromatic ring, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isotiazolil, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl nitrogen containing , benzoisothiazolyl, benzoxazolyl and benzisoxazolyl group which is optionally independently mono- or di-substituted, the group consisting of one or two representative: C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalogenomethyl group, methylthio alkyl, nitro and cyano; vagy or

- tienil vagy furil csoport, vagy - thienyl or furyl group, or

- p-toluolszulfonil csoport, vagy - p-toluenesulfonyl group, or

- Rn-CO acilcsoport, ahol R ]a 1-4 szénatomos alkil csoport, fenil, egy vagy több alkilés/vagy alkoxi csoporttal, nitro-csoporttal, vagy halogénatommal helyettesített fenil, piridil, fenil-eténil, alkiléndioxi csoporttal helyettesített fenil-eténil vagy feniletil csoport, vagy piperidin-l-il, 4-(metil)piperazin-l-il, pirrolidin-1 -il csoport; - Rn-CO acyl group, wherein R] a C1-4 alkyl group, phenyl, one or more alkyl and / or alkoxy, nitro, or halogen substituted phenyl, pyridyl or phenylethenyl substituted alkylenedioxy group phenylethenyl or phenylethyl groups, or piperidin-l-yl, 4- (methyl) piperazin-l-yl, pyrrolidin-1-yl group;

B jelentése B is

- az (1) vagy (2) vagy (3) képletű csoport; - (1) or R (2) or (3); vagy or

- a (4) képletű csoport ahol m értéke 2 vagy 3; - a group of formula (4) wherein m is 2 or 3; vagy or

- az (5) képletű csoport - ahol R 4 jelentése hidrogénatom vagy 1-4 szénatomos egyenes vagy elágazó szénláncú alkilcsoport, n értéke 2 vagy 3; - the group of formula (5) - wherein R4 is hydrogen or C1-4 straight or branched alkyl group, n is 2 or 3;

R jelentése hidrogénatom vagy fluoratom; R is hydrogen or fluorine;

R 3 jelentése fluoratom valamint sóik, izomerjeik és szolvátjaik • · · • · R 3 is a fluorine atom and their salts, isomers and solvates • • · · ·

- és e vegyületek sói, izomerjei és szolvátjai jelentős előnyökkel rendelkeznek hatékonyság, stabilitás és toxicitás tekintetében. - and salts, isomers and solvates of these compounds have significant advantages efficiency, stability and toxicity regard. Összhangban az elfogadott terminológiával, a fluoro-pirrolidin 2-es szénatomjának konfigurációja előnyösen S, a In accordance with the terminology adopted by the fluorouracil pyrrolidin-2 carbon atom of S configuration, preferably, the

4-es szénatomé pedig S vagy R. 4-carbon atom is S or R.

Különösen előnyösek az R 1 helyén pirazin-2-il és az 5-cianopiridin-2-il csoportot tartalmazó vegyületek, ahol R 2 valamint R 3 egyaránt fluoratom, B jelentése pedig piperidin-4-il, ilyenek például az l-{[l-(pirazin-2-il)piperidin-4-il]amino}acetil-2-(S)ciano-4,4'-difluoropirrolidin és az l-{[l-(5-cianopiridin-2-il)piperidin-4-il]amino} acetil-2-(S)-ciano-4,4'-difluoro pirrolidin. Particularly preferred are compounds in which R 1 contains pyrazin-2-yl and 5-cyanopyridine-2-yl group, wherein R 2 and R 3 are both fluorine atoms, B is piperidin-4-yl, for example the l - {[l - (pyrazin-2-yl) piperidin-4-yl] amino} acetyl-2- (S) cyano-4,4'-difluoropirrolidin and l - {[l- (5-cyanopyridine-2-yl) piperidine 4-yl] amino} acetyl-2 (S) -cyano-4,4'-difluoro pyrrolidine.

Találmányunk szerinti (I) általános képletű vegyületek előállításakor úgy járunk el, hogy a (II) általános képletű primer aminokat - ahol R 1 és B jelentése a fent megadott alkilezzük a (III) általános képletű - ahol R és R jelentése a fent megadott klóracetil származékokkal, majd a kapott vegyületeket kívánt esetben sóvá vagy szolváttá alakítjuk (1. ábra). Preparation of the compounds of formula The invention compound (I) are prepared by the general formula (II) primary amines - where R1 and B are as defined above is alkylated with a (III): - wherein R and R are as defined above chloroacetyl derivatives and if desired converting the compounds obtained into a salt or solvate (Figure 1).

Alkilezésnél a (III) általános képletű klóracetil vegyületeket feleslegben használjuk, a képződő sósavat különféle savmegkötő anyagok, előnyösen erős bázisok, például 1,8diazabiciklo[5.4.0]undec-7-én (DBU) ill. Alkylation the chloroacetyl compound of formula (III) in an excess of HCl produced by various acid binding agents, preferably a strong base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), respectively. a szuperbázisként ismert, gyantához kötött known as super base resin bound

2-terc-butilimino-2-dietilamino-1,3-dimetil-perhidro-1,3,2-diazafoszforin (PBEMP) segítségével kötjük meg. 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (PBEMP) to cohere. A reakciót előnyösen 25 és 55 °C között végezzük. The reaction is preferably conducted between 25 and 55 ° C.

A (II) általános képletű primer aminokat kétlépéses reakcióban állítjuk elő (2. ábra). The primary amine (II) amine in two steps (Figure 2). Először a kiindulási anyagként (IV) általános képletű - ahol Y jelentése hidrogénatom, acetil, vagy terc-butoxikarbonil csoport - ciklusos szekunder aminokat arilezzük előnyösen a (X) képletű — ahol R 1 jelentése a fent megadott, X jelentése halogénatom- arilhalogenidekkel: az arilezést az R 1 jelentésének fiiggvényében poláros, protikus vagy aprotikus oldószerekben végezzük 25 és 150 °C között, előnyösen alkoholokban (etanol, w-butanol, o-pentanol), vagy mikrohullámú készülékben oldószer nélkül, savmegkötőként az amin feleslegét vagy DBU-t alkalmazva. First, the starting materials (IV) - wherein Y is hydrogen, acetyl or tert-butoxycarbonyl group - a cyclic secondary amine arylation is preferably a (X) - wherein R1 is as defined above, X is halo arilhalogenidekkel means arylation versus hold the R 1 is carried out in a polar, protic or aprotic solvents, between 25 and 150 ° C, preferably without solvent, acid binding agent, using an excess or DBU in alcohols (ethanol, w-butanol, o-pentanol), or microwave for the amine.

Kiindulási anyagként irodalomból ismert (IV) általános képletű szabad aminokat, vagy védett ciklusos szekunder aminokat használjuk 4-acetamino-piperidint B = (1) képlet, Y = COCH 3 ) (Chem. Abstr. 1996, 64, 6664); As a starting material known in the art (IV) of the free amine of formula, or a protected cyclic secondary amine used in of 4-acetamino-piperidine B = formula (1), Y = COCH 3) (Chemical Abstracts 1996, 64, 6664)..; 4-tercbutoxikarbonilamino-piperidint B = (1) képlet, Y = COOC(CH 3 ) 3 (J. Med. Chem. 1999, 42, 2706); 4-tert-butoxycarbonylamino-piperidine B = formula (1), Y = COOC (CH3) 3 (J. Med Chem 1999, 42, 2706th.); 3-(S)-z*erc-butoxikarbonilamino-piperidint B = (2) képlet és 3-(S)terc-butoxikarbonil-amino-pirrolidint B = (3) képlet (Synth. Comm. 1998, 28, 3919); 3- (S) -z * tert-butoxycarbonylamino-piperidine B = formula (2) and 3- (S) tert-butoxycarbonylamino-pyrrolidine B = formula (3) (Synth Comm 1998, 28, 3919th.); (Y = COOC(CH 3 ) 3 ) az utóbbi két esetben); (Y = COOC (CH3) 3) in the latter two cases);

3-exo-[(Zerc-butoxikarbonil)amino]-8-azabiciklo[3.2.1]oktánt, 3-era/o-[(fércbutoxikarbonil)amino]-8-azabiciklo[3.2.1]oktánt (B = (4) képlet, m = 2 (J. Med. Chem. 1991, 34, 656), valamint 3-exo-[(ierc-butoxikarbonil)amino]-9azabiciklo[3.3.1 jnonánt és 3-e«e/o-[(terc-butoxikarbonil)amino]-9-azabiciklo[3.3.1]nonánt B = (4) képlet, m = 3 (J. Med. Chem. 1993, 36, 3720) (Y = COOC(CH 3 ) 3 ); 3-exo - [(Zerc-butoxycarbonyl) amino] -8-azabicyclo [3.2.1] octane, 3-era / p - [(fércbutoxikarbonil) amino] -8-azabicyclo [3.2.1] octane (= B (4 ) wherein m = 2 (J Med Chem 1991, 34, 656) and 3-exo -.. [(tert-butoxycarbonyl) amino] -9-azabicyclo [3.3.1 jnonánt and 3-e 'e / o [ (tert-butoxycarbonyl) amino] -9-azabicyclo [3.3.1] nonane = B (4) wherein, m = 3 (J. Med. Chem. 1993, 36, 3720) (Y = COOC (CH3) 3) ;

diaminoetánt (Β = (5) képlet, ahol R 4 = Η, n = 2, Y = H); diaminoethane (Β = formula (5) wherein R 4 = Η, n = 2, Y = H); diaminopropánt (B = (5) képlet, ahol R 4 = Η, n = 3, Y = H); diaminopropane (B = formula (5) wherein R 4 = Η, n = 3, Y = H); 7V-metil-V'-(férc-butoxikarbonil)-diaminoetánt (B = (5) képlet, ahol R 4 = Me, n = 2, Y = COOC(CH3)3) (J. Med. Chem. 1990, 33, 97); 7V-methyl-V '- (t-butoxycarbonyl) diaminoethane (B = formula (5) wherein R 4 = Me, n = 2, Y = COOC (CH3) 3) (J. Med Chem 1990, 33rd. , 97); jV-metil-A'-(/erc-butoxikarbonil)-diaminopropánt (B = (5) képlet, ahol R 4 =Me, n = 3, Y = COOC(CH3) 3 ); JV-methyl-N - (/ tert-butoxycarbonyl) -diaminopropánt (B = formula (5) wherein R 4 = Me, n = 3, Y = COOC (CH3) 3); (Org. Lett. 2000, 2, 2117). (Org. Lett. 2000, 2, 2117).

A második lépésben az (V) általános képletű - ahol R 1 és B jelentése a fent megadott - arilezett aminokról savas hidrolízissel eltávolítjuk az Y védőcsoportot. Wherein R 1 and B are as defined above - - arylated amine on the Y protecting group is removed by acid hydrolysis. The second step of the general formula (V) A reakció vizes sósavban, vagy sósavas etanolban 25-78 °C között lejátszódik és így kapjuk a (II) általános képletű - ahol R 1 és B jelentése a fent megadott - alifás és ciklusos primer aminokat. The reaction in aqueous hydrochloric acid or hydrochloric acid in ethanol proceeds to give the (II) of formula from 25 to 78 ° C - where R1 and B are as defined above -, and cyclic aliphatic primary amines.

Amennyiben az R 1 csoport jelentése Ria-CO acilcsoport, akkor a (IV) általános képletű vegyületeket, - ahol Y jelentése Zerc-butoxikarbonil csoport - reagáltatjuk R la -COZ általános képletű savszármazékokkal, ahol Z jelentése egy kilépőcsoport (előnyösen klóratom), előnyösen 0°C körüli hőmérsékleten, savmegkötőként valamilyen szervetlen vagy szerves bázist, - előnyösen trietilamint - alkalmazva. Where the group R1 is Ria-CO acyl group, the compound of formula (IV): - wherein Y is Zerc-butoxycarbonyl group - is reacted with acid derivatives of formula Rla COZ, wherein Z is a leaving group (preferably chlorine atom), preferably 0 temperature in the region C, an inorganic or organic base as an acid scavenger - applying - preferably triethylamine. A kapott (V) általános képletű vegyületekről az Y védőcsoportot savas körülmények között lehasítjuk, előnyösen trifluorecetsav diklórmetános oldatát alkalmazva 0 -30°C között, és így jutunk a (II) általános képletű aminokhoz, amelyeknél RÍ jelentése Rla-CO csoport. Compounds of formula (V) Y is deprotected under acidic conditions, preferably using trifluoroacetic acid in dichloromethane solution at 0 to -30 ° C, to give the amines of general formula (II) in which R j is Rla-CO group.

A (III) általános képletű klóracetil-ciano vegyületeket - ahol R“ és R jelentése a fent megadott - négylépéses reakcióban állítjuk elő (3. ábra). The chloroacetyl-cyano compound of formula (III) - wherein R "and R are as defined above - prepared by the four step reaction (Figure 3).

• · »7 ·»······ • · »· 7» ······

A kiindulási vegyületek olyan (VI) általános képletü fluoro-prolin előnyösen L-fluoro-prolin származékok, ahol R és R jelentése a fent megadott, s amelyek nitrogénje terc-butoxikarbonil csoporttal védett. The starting compounds (VI) Formula fluoro-proline is preferably L-proline-fluoro derivatives, wherein R and R are as defined above, and which protected nitrogen of t-butoxycarbonyl groups. Ezek a vegyületek irodalmi módszerrel előállíthatok (Tetrahedron Lett. 1998, 39, 1169). literature method, these compounds can be prepared (Tetrahedron Lett. 1998, 39, 1169). Az első lépésben pivaloil kloriddal vegyes anhidridet képzünk, majd vizes ammóniával kialakítjuk a (VII) általános képletü - ahol R 2 és R 3 jelentése a fent megadott - karbamoil-származékokat. Pivaloyl chloride in the first step a mixed anhydride, and then with aqueous ammonia to form the formula (VII) - wherein R 2 and R 3 are as defined above - carbamoyl derivatives. A reakciót előnyösen halogénezett oldószerben (CHCI3, CH 2 C1 2 ), 0-25 °C-on végezzük. The reaction is preferably conducted in a halogenated solvent (CHCl 3, CH 2 C1 2), 0-25 ° C.

A második lépésben a terc-butoxikarbonil csoportot sósavas etanolban távolítjuk el. In the second step the tert-butoxycarbonyl group is removed with hydrogen chloride in ethanol. A hidrolízis 0-25°C-on megy végbe és a (VIII) általános képletü - ahol R 2 és R 3 jelentése a fent megadott - karboxamidok hidrokloridja képződik. The hydrolysis is carried out 0-25 ° C, and general formula (VIII) - wherein R 2 and R 3 are as defined above - carboxamides hydrochloride formed.

Az így kapott (VIII) általános képletü fluoro-pirrolidin-karboxamidokat a harmadik lépésben klóracetilkloriddal acilezzük, előnyösen 0°C-on, halogénezett oldószerben (CHC1 3 , CH 2 C1 2 ). The resulting formula fluoro-pyrrolidine-carboxamide (VIII) is acylated with chloroacetyl chloride in the third step, preferably at 0 ° C, a halogenated solvent (CHC1 3, CH 2 C1 2). Ekkor a (IX) általános képletü - ahol R 2 és R 3 jelentése a fent megadott - klóracetil-karbamoil származékok képződnek. Then the formula (IX) - wherein R 2 and R 3 are as defined above - chloroacetyl-carbamoyl derivatives of formula XVIII.

A negyedik lépésben a (IX) általános képletü klóracetil-karbamoilszármazékokat dehidratálva jutunk a (III) általános képletü - ahol R és R jelentése a fent megadott - klóracetil-ciano vegyületekhez. In the fourth step of the general formula (IX) are dehydrated to give a chloroacetyl karbamoilszármazékokat the general Formula (III) - wherein R and R are as defined above - chloroacetyl-cyano compounds. A dehidratálást előnyösen oxalil-klorid és DMF jelenlétében végezzük acetonitrilben 0 °C alatt. The dehydration is preferably carried out with oxalyl chloride and DMF in the presence of acetonitrile at 0 ° C.

C0C1 C0C1

ο ο

3. ábra • · Figure 3 • ·

...... ......

Biológiai vizsgálatok biological tests

DPP-IV enzyme inhibitory activties of the compounds with the generál formula (I) were determined by the following method: DPP-IV enzyme inhibitory activties of the compounds with the general formula (I) Were Determined by the Following method:

Applied conditions of the assay: Applied Conditions of the assay:

DPP-IV. DPP-IV. source: source: solubilized crude extractum from CaCo/Tc-7 cells Solubilized Crude extractum from CaCo / Tc-7 cells
Substrate: Substrate: content: 0.8-lpg/assay H-Gly-Pro-AMC (Bachem) content: 0.8-lpg / assay H-Gly-Pro-AMC (Bachem)
Reaction: Reaction: 1 hour preincubation with samples at 37 °C , 30 min reaction time at 37 C° 1 hour preincubation with samples at 37 ° C, 30 min reaction time at 37 ° C
Stop solution: Stop solution: 1M Na-acetate buffer (pH=4.2) 1M Na-acetate buffer (pH 4.2)
Reaction mixture: Reaction Mixture: 10 μΐ enzyme solution 10 μΐ enzyme solution
Measurement: Measurement: 1 Ομί test compound or assay buffer 55μ1 assay buffer 25μ1 substrate 300μ1 stop solution spectrofiuorometric determination by Tecan plate reader (Ex: 360nm Em: 465nm) Ομί body 1 as compound or assay buffer assay buffer 55μ1 25μ1 300μ1 Substrate Stop Solution spectrofiuorometric 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-methyl coumarin) at 37 °C in π The reaction of the DPP-IV enzyme and the H-Gly-Pro-AMC substrate is Recorded by the liberation of AMC (7-amino-4-methyl coumarin) at 37 ° C in π

• · · • · ·

100 mM Tris-HCl, pH=7.5 (assay buffer). 100 mM Tris-HCl, pH 7.5 (assay buffer). Standard curve of AMC is linear up to 31.25 μΜ concentration, that is why we used the relatíve fluorescence unit ( Standard curve of AMC is linear up to 31.25 μΜ concentration, thatis why we Used the relative fluorescence units (

RFU) of AMC formed. RFU) of AMC shape. It is detected using 360 nm excitation and 465 emmission filters (30 ps integration time, Gain 25, No. of Flashes 50) by Tecan It is detected using 360 nm excitation and emmission filters 465 (30 ps integration time, Gain 25, No. of Flashes 50) by Tecan

Spectrofluor Plus plate reader. Spectrofluor Plus plate reader. Under these conditions enzyme reaction is linear fór at least 30 min, and the enzyme dependence is linear up to 2.5 pg protein ( up to 700 RFU). Under These Conditions enzyme reaction is linear for at Least 30 min, and the enzyme dependence is linear up to 5.2 pg of protein (up to 700 RFU). Using 1-0.8 pg of extracted protein K m fór H-Gly-Pro-AMC is 50 pM. Using 1-0.8 pg of Extracted protein K m for H-Gly-Pro-AMC is 50 pM. Higher than 500 pM substrate concentration caused fluorescent detection problems (inner filter effect) that can be solved by dilution of the samples. Higher than 500 pM substrate concentration causa fluorescent detection Problems (inner filter effect) that can be solved by dilution of the samples.

The assay is designed to detect as effíciently as possible the active inhibitors using a 60 min preincubation time at 37 °C. The assay is designed to detect as effíciently as possible the active inhibitors using the 60 min preincubation time at 37 ° C. The assay is conducted by adding The assay is by adding Conducta

0.8-1 pg protein extract in 10 pl enzyme sulution (using assay buffer: 100 mM 0.8-1 pg of protein extract in 10 ul enzyme sulution (using assay buffer: 100 mM

Tris-HCl, pH=7.5) to the wells containing the test compounds in 10 pl volume and the 55 pl assay buffer (65pl assay buffer in the case of controlls ). Tris-HCl, pH = 5.7) to the wells containing the test compounds in 10 l volume and the 55 pl assay buffer (65pl assay buffer in the case of controlls). After the preincubation period, the reaction is started by the addition of 25 pl ImM After the preincubation period, the reaction is started by the Addition of 25 l lmM

H-Gly-Pro-AMC substrate solution (250 pM final concentration). H-Gly-Pro-AMC substrate solution (250 pM final concentration). The final test volume is 100 pl and the test solution contains 1% DMSO comming from the test compounds solution . The final test volume is 100 l and the test solution contains 1% DMSO comming from the test compounds solution. Reaction time is 30 min at 37 °C, and the reaction is stopped by adding 300 pl 1M Na-acetate buffer, pH- 4.2. Reaction time is 30 min at 37 ° C, and the reaction is stopped by adding 300 pl of 1 M Na-acetate buffer, pH 4.2. The fluorescence (RFU) of AMC formed is detected using 360 nm excitation and 465 emmission filters in Tecan spectrofluor Plus plate reader (30 ps integration time, Gain 25 The fluorescence (RFU) of AMC format is detected using 360 nm excitation and emmission filters in Tecan spectrofluor 465 Plus plate reader (30 ps integration time, Gain 25

No. of Flashes 50). No. of Flashes 50).

Inhibition % are calculated using the RFU of control and RFU of blank. Inhibition% CALCULATED are using the RFU of control and RFU of blank.

A találmányunk szerinti (I) általános képletű vegyületek enzim inhibitor hatására jellemző IC 50 értékek 100 nM alattiak. Of the potency of the enzyme of the present invention compounds of formula (I) inhibitor IC 50 values below 100 nM. Az (I) általános képletű vegyületek, sóik, szolvátjaik, izomerjeik önmagában ismert módszerekkel orálisan vagy parenterálisan alkalmazható gyógyszerkészítménnyé alakíthatók egy vagy több gyógyszerészetileg elfogadható hordozó vagy segédanyaggal keverve. known methods of the compounds (I) of the formula, their salts, solvates, isomers, orally or parenterally applicable pharmaceutical preparations can be converted into one or more pharmaceutically acceptable carriers, or in admixture with excipients.

Az (I) általános képletű vegyületek napi dózisa számos tényezőtől függ, így a kezelendő személy betegségének természetéből és súlyosságától, az alkalmazás módjától és a konkrét vegyülettől. The daily dose of the compounds of formula (I) depends on several factors including the subject being treated and the severity of disease in nature, mode of administration and the particular compound.

Találmányunk további részleteit a következő példákban mutatjuk be anélkül, hogy oltalmi igényünket ezekben leírtakra korlátoznánk. Further details of the following examples without being understood that it is not limited to those described.

1. Példa: Example 1:

- {Γ1 -(Pirazin-2-il)piperidin-4-il1amino ] acetil-2-( S)-ciano-4,4 x -difluoropirrolidin - {Γ1 - (pyrazin-2-yl) piperidin-4-il1amino] acetyl-2- (S) -cyano-4,4 x -difluoropirrolidin

Az (I) általános képletben R 1 jelentése pirazin-2-il csoport, B jelentése piperidin-4-il csoport (1) képlet, R 2 és R 3 jelentése fluoratom. In formula (I), R1 represents pyrazin-2-yl group, B is piperidin-4-yl group of formula (1), R 2 and R 3 is fluoro.

a. the. ) l-(Pirazin-2-il)-4-acetamino-piperidin (V) általános képlet - ahol Y = ) L- (pyrazin-2-yl) -4-acetamino-piperidine (V) general formula - where Y =

COCPE, B jelentése (1) képletű csoport. COCPE, B is a group of formula (1).

0,45 ml (5 mmól) klórpirazin 15 ml 72-pentanollal készült oldatához adunk 1,6 g (10 mmól) 4-acetamidopiperidin monohidrátot. 0.45 ml (5 mmol) in 15 ml of 72 chloropyrazin-pentanol were added 1.6 g (10 mmol) of 4-acetamidopiperidin monohydrate. Az elegyet 14 órán át forraljuk, majd bepároljuk. The mixture was refluxed for 14 hours and then evaporated. A maradékot etilacetát-metanol-25%-os vizes ammónia 17:3:1 arányú elegyével oszlopkromatográfiásan tisztítva 0,81 g (76 %) fenti terméket kapunk. The residue from ethyl acetate-methanol-25% aqueous ammonia 17: 3: 1 mixture of column chromatography to give 0.81 g (76%) of the above product. Op: 158-160 °C. Mp: 158-160 ° C. 'H-NMR (DMSO-d 6 ): δ 1.34 (dq, 2H), 1.78 (m, 2H), 3.03 (dt, 2H), 3.74-3.89 (m,lH), 4.21 (td, 2H), 7.77 (d, ¹H-NMR (DMSO-d6): δ 1:34 (dq, 2H), 1.78 (m, 2H), 3:03 (dt, 2H), 3.74-3.89 (m, IH), 4.21 (td, 2H), 7.77 (d,

1H, 3'-H), 7.80 (s, 1H, NH), 8.05 (dd, 1H, 5'-H), 8.31 (d, 1H, 6'-H). 1H, 3'-H), 7.80 (s, 1H, NH), 8:05 (dd, 1H, 5'-H), 8.31 (d, 1H, 6'-H).

b. b. ) l-(Pirazin-2-il)-4-amino-piperidin (II) általános képlet - ahol R 1 és B jelentése a fenti ) Wherein l- (pyrazin-2-yl) -4-aminopiperidine (II) - wherein R1 and B are as defined above

697 mg (3,2 mmól) l-(pirazin-2-il)-4-acetamino-piperidint 15 ml 2N sósavban oldunk és 8 órán át forralunk. 697 mg (3.2 mmol) of l- (pyrazin-2-yl) -4-acetamino-piperidine dissolved in 15 ml of 2N hydrochloric acid and heated under reflux for 8 hours. Az elegyet ezután lehűtjük, 20 %-os NaOH oldattal lúgosítjuk és 4 x 20 ml diklórmetánnal extraháljuk. The mixture was cooled, basified with 20% NaOH solution and extracted with 4 x 20 ml dichloromethane. Az • · · egyesített szerves fázist nátrium-szulfáton szárítjuk, bepárlás után a terméket sárga, kristályos anyagként kapjuk: 292 mg (52 %). • · The combined organic layer was dried over sodium sulfate and evaporated to give the product as a yellow crystalline solid: 292 mg (52%). Op.: 113-115°C. M.p .: 113-115 ° C. *H-NMR (DMSO-d 6 -CDCl 3 ): δ 1.09-1.36 (m, 2H), 1.78 (d, 2H), 2.78-3.31 (m, 4H), 3.54 (m, III), 7.76 (d, 1H, 3'-H), 8.03 (dd, 1H, 5'-H), 8.29 (d, 1H, 6'-H). H-NMR (DMSO-d 6 -CDCl 3): δ 1:09 to 1:36 (m, 2H), 1.78 (d, 2H), 2.78-3.31 (m, 4H), 3:54 (m, lH), 7.76 (d , 1H, 3'-H), 8:03 (dd, 1H, 5'-H), 8.29 (d, 1H, 6'-H).

A fenti termékhez juthatunk úgy is, ha 0,71 ml (8 mmól) klórpirazint és The above product was obtained also when 0.71 ml (8 mmol) and klórpirazint

1,4 g (7 mmól) 4-terc-butoxikarbonilamino-piperidint és 1,27 ml (8,5 mmól) 4-tert-butoxycarbonylamino-piperidine and 1.27 ml (8.5 mmol) 1.4 g (7 mmol) of

DBU-t forralunk 40 ml «-pentanolban 18 órán át. DBU was refluxed in 40 ml of «pentanol 18 hours. Az oldatot bepároljuk és The solution is evaporated and

EtOAc-«-hexán-kloroform 3:1:1 arányú elegyével oszlopkromatográfiásan tisztítva 1,10 g l-(pirazin-2-il)-4-terc-butoxikarbonilamino-piperidint (V) általános képlet, ahol Y = COOC(CH 3 ) 3 kapunk. EtOAc - «- hexane-chloroform 3: 1: column chromatography to obtain 1.10 g of l- (pyrazin-2-yl) wherein 4-tert-butoxycarbonylamino-piperidine (V) wherein Y = COOC (CH 3 1 mixture of ) 3 was obtained. Op: 132-133 °C. Mp: 132-133 ° C. Ezt 20 ml sósavas etanolban 4 órán át kevertetjük szobahőn, az oldatból kivált termék 0,5 g (70 %) l-(pirazin-2-il)-4-amino-piperidin hidroklorid, melyből lúgosítással 390 mg (80 %) fent leírt termék képződik. This was stirred at room temperature for 4 hours in 20 ml of hydrogen chloride in ethanol, the precipitated product (0.5 g, 70%) of l- (pyrazin-2-yl) -4-amino-piperidine hydrochloride, which basification 390 mg (80%) of the above-described product formed.

c.) l-(ígrc-Butoxikarbonil)-2-(S)-karbamoil-4,4'-difluoro-pirrolidin (VII) általános képlet - ahol R és R jelentése fluoratom c) l- (ígrc-Butoxycarbonyl) -2 (S) -carbamoyl-4,4-difluoro-pyrrolidine (VII): wherein -. wherein R and R is fluoro

5,7 g (22,7 mmól) l-(Zerc-butoxikarbonil)-4,4'-difluoro-2-(S)-prolint feloldunk 57 ml diklórmetánban és 3,8 ml (27,2 mmól) trietilamint adunk hozzá. 5.7 g (22.7 mmol) of l- (Zerc-butoxycarbonyl) -4,4-difluoro-2- (S) -proline are dissolved in 57 ml of dichloromethane and triethylamine (3.8 ml, 27.2 mmol) was added . A kapott elegyhez -15 °C-on becsepegtetünk 3 ml (25 mmól) pivaloilkloridot, ezen a hőfokon kevertetjük további 1 órán át, majd becsepegtettünk 7 ml 25 %-os vizes ammónia-oldatot és további 1 órát kevertetjük. To the resulting mixture at -15 DEG C. dropwise with 3 ml (25 mmol) of pivaloyl chloride and stirred at this temperature for 1 hour and then added dropwise to 7 ml of 25% aqueous ammonia solution is stirred for additional 1 hour. A rekcióelegyet vízzel, 1 N NaOH oldattal, majd újra vízzel mossuk, nátriumszulfáton szárítjuk és bepároljuk. Time the reaction was washed with water, 1N NaOH and again with water, dried over sodium sulfate and evaporated. Dietiléterből 3,94 g (69%) fenti termék kristályosodik ki. Diethyl ether provided 3.94 g (69%) of the above product crystallized. Op: 136-138 °C. Mp: 136-138 ° C. 1 H-NMR (CDC1 3 ): δ 1.48 (s, 9H); 1 H NMR (CDC1 3): δ 1:48 (s, 9H); 2.3-2.9 (m, 3-CH 2 ), 3.69 (br, minor) + 3.86 (m, major)(5-CH 2 ), 4.53 (br, 2-CH). 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)(NH 2 ). 6.0 (br, major) + 6.81 (br, minor) (NH2).

d. d. ) 4,4 > -Difluoro-pirrolidin-2-(S)-karboxamid hidroklorid (VIII) általános képlet - ahol R és R jelentése fluoratom ) 4.4> difluorobiphenyl-pyrrolidin-2- (S) -carboxamide hydrochloride (VIII): wherein - R and R is fluoro

3,93 g (15,7 mmól) l-/erc-butoxikarbonil-2-(S)-karbamoil-4.4'difluoro-pirrolidint feloldunk 75 ml 25%-os sósavas etanolban és 4 órán át szobahőmérsékleten kevertetjük. 3.93 g (15.7 mmol) of l- / tert-butoxycarbonyl-2- (S) -carbamoyl-pyrrolidine-4.4'difluoro dissolved in 75 ml of 25% ethanolic hydrogen chloride solution and stirred for 4 hours at room temperature. A kapott szuszpenzióhoz 150 ml dietilétert adunk, majd a fehér kristályos anyagot kiszűrjük. To this slurry was added 150 mL of ether and the white crystals were filtered off. így 2,55 g (87 %) fenti terméket kapunk. to give 2.55 g (87%) of the above product. Op: 232-233 °C. Mp: 232-233 ° C. 'H-NMR (DMSO-d 6 ): δ 2.43-2.51 (m, minor) + 2.81-3.05(m, major)(3-CH 2 ), 3.71 (t, 2H, 5-CH 2 ), 4.46 (t, 1H, 2-CH), 7.81 (s, 1H,) + 8.12(s, 1H)(NH 2 ), 10.12 (br, 2H, NH 2 + ). ¹H-NMR (DMSO-d6): δ 2:43 to 2:51 (m, minor) + 2.81-3.05 (m, major) (3-CH 2), 3.71 (t, 2H, 5-CH2), 4:46 ( t, 1H, 2-CH), 7.81 (s, 1H,) + 8.12 (s, 1H) (NH 2), 12.10 (br, 2H, NH2 +).

e. e. ) 1 -Klóracetil-2-(S)-karbamoil-4,4 , -difluoro-pirrolidin (IX) általános képlet - ahol R 2 és R 5 jelentése fluoratom ) Carbamoyl-4,4-Difluoro-pyrrolidine (IX) wherein one -Klóracetil-2- (S) - wherein R 2 and R 5 is fluoro

2.54 g (13.6 mmól) 4,4'-difluoro-pirrolidin-2-(S)-karboxamid hidrokloridot elszuszpendálunk 25 ml diklórmetánban, majd 4,1 ml (29,3 mmól) trietilamint és 4 mg (0,03 mmól) 4-dimetilaminopiridint adunk hozzá. (6.13 mmol) of 4,4'-difluoro-pyrrolidine-2 2:54 g of (S) -carboxamide hydrochloride are suspended in 25 ml of dichloromethane and 4.1 ml (29.3 mmol) of triethylamine and 4 mg (0.03 mmol) of 4 -dimetilaminopiridint added. A kapott elegyhez -10 °C alatt becsepegtetünk 1,2 ml (15 mmól) klóracetilklorid 20 ml diklórmetánnal készült oldatát. added dropwise 1.2 mL (15 mmol) of chloroacetyl chloride in 20 ml of dichloromethane is added over the resulting mixture at -10 ° C. Kevertetés 1 órán át, majd a szuszpenziót 450 ml etilacetátra öntjük, a kivált trietilamin hidrokloridot kiszűrjük, a szűrletet bepároljuk és kloroform-metanol 4:1 arányú elegy ével kromatográfiásan tisztítjuk. Stirring for 1 hour, then the suspension was poured into 450 ml of ethyl acetate, the precipitated triethylamine hydrochloride was filtered off, the filtrate was concentrated, and chloroform-methanol 4: 1 mixture is purified by chromatography. így 3.0 g (97%) színtelen olajként kapjuk a fenti terméket. to give the above product (3.0 g, 97%) as a colorless oil. 'H-NMR (DMSO-d 6 ): δ 2.34-2.52 (m, 1H) + 2.66-2.83(m, 1H)(3CH 2 ), 4.07-4.29 (m, 2H, 5-CH 2 ), 4.40(qv, 2H, CH 2 C1), 4.71 (m, 1H, 2-CH), ¹H-NMR (DMSO-d6): δ 2:34 to 2:52 (m, 1H) + 2.66-2.83 (m, 1H) (3-CH2), 4:07 to 4:29 (m, 2H, 5-CH2), 4:40 ( qv, 2H, CH 2 C1), 4.71 (m, 1H, 2-CH);

7.17 (br, 1H, ) + 7.42(d, 1H)(NH 2 ). 7.17 (br, 1H, +) 7:42 (d, 1H) (NH2).

f.) 1 -Klóracetil-2-(S)-ciano-4,4' -difluoro-pirrolidin (III) általános képlet ahol R 2 és R 3 jelentése fluoratom f.) 1 -Klóracetil-2- (S) -cyano-4,4'-difluorobiphenyl-pyrrolidine of formula (III) wherein R 2 and R 3 is fluorine

340 mg (1,5 mmól) l-klóracetil-2-(S)-karbamoil-4,4'-difluoropirrolidint feloldunk 10 ml acetonitrilben és hozzáadunk 0,15 ml dimetilformamidot. (1.5 mmol) of l-chloroacetyl-2- (S) -carbamoyl-4,4 difluoropirrolidint 340 mg dissolved in 10 ml of acetonitrile was added 0.15 ml of dimethylformamide. Az elegyet - 25 °C-ra hűtjük és becsepegtetjük 0,15 ml (1,73 mmól) oxalilklorid 2 ml acetonitrillel készült oldatát. The mixture was - cooled to 25 ° C and a solution of oxalyl chloride (0.15 mL, 1.73 mmol) in 2 mL of acetonitrile. Az elegyet szobahőmérsékleten 2 órán át kevertetjük, majd bepároljuk. The mixture was stirred at room temperature for 2 hours and then evaporated. A maradékot diklórmetánban oldjuk és telített nátrum-hidrogén-karbonát oldattal mossuk. The residue was dissolved in dichloromethane and saturated with sodium hydrogen carbonate solution. A szerves fázist nátrium-szulfáton szárítjuk és bepároljuk. The organic layer was dried over sodium sulfate and evaporated. A maradékot CHC1 3 MeOH 9:1 arányú elegyével kromatográfiásan tisztítjuk. The residue CHC1 3 MeOH 9: 1 mixture of chromatography. így 209 mg (67 %) sárga olajként kapjuk a kívánt terméket. to give the desired product as a yellow oil (209 mg, 67%). 1 H-NMR (CDClj): δ 2.76-2.98 (m, 2H, 1H-NMR (CDCl₃): δ 2.76-2.98 (m, 2H,

3-CH 2 ), 3.92-4.26 (m, 2H, 5-CH 2 ), 4.46(qv, 2H, CH 2 C1), 5.11 (m, 1H, 2-CH). 3-CH2), 3.92-4.26 (m, 2H, 5-CH2), 4:46 (qv, 2H, CH 2 C1), 5.11 (m, 1H, 2-CH).

g.) 1 -1Γ1 -(Pirazin-2-il)piperidin-4-inamino)acetil-2-( S)-ciano-4.4' difluoro-pirrolidin dihidroklorid mg (0,32 mmól) l-(pirazin-2-il)-4-amino-piperidint és 65 mg (0,32 mmól) l-klóracetil-2-(S)-ciano-4,4'-difluoro-pirrolidin feloldunk 20 ml acetonitrilben és hozzáadunk 285 mg (0,73 mmól) PBEMP-t. g) 1 -1Γ1. - (pyrazin-2-yl) piperidin-4-inamino) acetyl-2- (S) -cyano-4,4 'difluoro-pyrrolidine dihydrochloride mg (0.32 mmol) of l- (pyrazin-2- yl) -4-aminopiperidine and 65 mg (0.32 mmol) of l-chloroacetyl-2- (S) -cyano-4,4'-difluoro-pyrrolidine are dissolved in 20 ml of acetonitrile was added 285 mg (0.73 mmol ) was PBEMP. Az elegyet 8 órán • · át 55 °C-on kevertetjük, majd a gyantát kiszűrjük, a szűrletet bepároljuk. The mixture was stirred at 55 ° C for 8 hr · • and then the resin was filtered off, the filtrate was concentrated. A maradékot CHCf-MeOH 9:1 arányú elegyével kromatográfiásan tisztítjuk. The residue readings CHCf-MeOH 9: 1 mixture of chromatography. A fenti terméket 72 mg (60 %) színtelen olajként lapjuk, melyből sósavas éterrel dihidroklorid sót képzünk. The above product as a colorless oil (72 mg, 60%) of their hand, which form a dihydrochloride salt with ethereal HCl. Op: 146-147 °C. Mp: 146-147 ° C. 1 H-NMR (DMSO-dő): δ 1.54 (m, 2H), 2.15 (m, 2H), 2.80-2.95 (m, 4H), 4.20-4.25 (m, 4H), 4.55 (d, 2H,), 5.20 (t, 1H), 7.00 (d, 1H), 7.87 (dd, 1H), 8.50 (d, 1H); 1H-NMR (DMSO-d): δ 1.54 (m, 2H), 2.15 (m, 2H), 2.80-2.95 (m, 4H), 4:20 to 4:25 (m, 4H), 4.55 (d, 2H,) 5.20 (t, 1H), 7:00 (d, 1H), 7.87 (dd, 1H), 8:50 (d, 1H); 9.38 (br, 2H). 9:38 (br, 2H).

2. Példa: Example 2:

- {[ 1 -(5-Cianopiridin-2-il')piperidin-4-illamino} acetil-2-( S)-ciano-4,4 5 difluoro-pirrolidin dihidroklorid - {[1 - (5-Cyanopyridin-2-yl ') illamino} piperidin-4-acetyl-2- (S) -cyano-4,4'-difluoro-5 DIHYDROCHLORIDE

Az (I) általános képletben R 1 jelentése 5-cianopiridin-2-il csoport, B jelentése az (1) képletű csoport, R ésR jelentése fluoroatom. In formula (I), R1 is 5-cyanopyridine-2-yl group, B represents a group of formula (1), R or R represents fluoroatom.

Az 1. példában leírtak alapján állítottuk elő a fenti vegyületet úgy, hogy klórpirazin helyett 5-ciano-2-klórpiridint alkalmazunk. was prepared as described in Example 1, the above compound was prepared by employing 5-cyano-2-chloropyridine instead of chloropyrazine. A kívánt címszerinti vegyületet fehér kristályok alakjában kapjuk az 1. példában leírthoz hasonló hozammal. The title compound were obtained as white crystals in a similar manner to that described in Example 1 yield. Op: 146-147 °C. Mp: 146-147 ° C. 'H-NMR (DMSO-d 6 ): δ 1.56 (m, 2H), 2.15 (d, 2H), 2.92 (m, 4H), 4.20 (m, 4H), 4.55 (d, 2H), 5.20 (t, 2H), 7.01 (d, 1H), 7.88 (d, 1H), 8.49 (dd, 1H), 9.38 (d, 1H). ¹H-NMR (DMSO-d6): δ 1:56 (m, 2H), 2.15 (d, 2H), 2.92 (m, 4H), 4.20 (m, 4H), 4:55 (d, 2H), 5.20 (t , 2H) 7.01 (d, 1H), 7.88 (d, 1H), 8:49 (dd, 1H), 9:38 (d, 1H).

3. példa EXAMPLE 3

- {Γ 8-(Pirazin-2-iB-8-azabiciklo[3.2.1 loktán-3-ín-exo-amino ) acetil-2-f S)ciano-4,4' -difluoro-pirrolidin - {Γ 8- (pyrazin-2-iB-8-azabicyclo [3.2.1 octane-3-yl-exo-amino) acetyl-2-f S) cyano-4,4'-difluorobiphenyl-pyrrolidin

Az (I) általános képletben R 1 jelentése pirazin-2-il csoport, B jelentése az (5) képletű csoport - ahol m értéke 2, R 2 és R 3 jelentése fluoratom. In formula (I), R1 represents pyrazin-2-yl group, B represents a group of formula (5), - wherein a fluorine atom, m is 2, R2 and R3.

a. the. ) 3-exo-r(/erc-Butoxikarbonil)aminol-8-(pirazin-2-ilJ-8-azabicikloF3.2.11oktán (VJ általános képlet - ahol B jelentése (5) képletű csoport - ahol m értéke 2, Y jelentése -COOC(CHfh csoport ) 3-exo-r (/ tert-Butoxycarbonyl) amino-8- (pyrazin-2-yl-8-azabicikloF3.2.11oktán (VJ formula - wherein B is a group of formula (5) - wherein m is 2, Y is COOC (CHfh group

0,54 ml (6 mmól) klórpirazin, 1,13 g (6 mmól) 3-exo-[(/ercbutoxikarbonil)amino]-8-azabiciklo[3.2.1]oktán és 0,97 ml (6.5 mmól) diazabiciklo[5.4.0]undecén 40 ml n-pentanollal készült odatát 50 órán át forraljuk. 0.54 ml (6 mmol) of chloropyrazine, 1.13 g (6 mmol) of 3-exo - 8-azabicyclo [3.2.1] [(/ ercbutoxikarbonil) amino] octane and 0.97 ml (6.5 mmol) of diazabicyclo [ 5.4.0] undecene ode in 40 ml of n-pentanol was heated for 50 hours. A kapott elegyet vákuumban bepároljuk, a maradékot diklórmetánban oldjuk, vízzel mossuk és nátriumszulfáton szárítjuk. The resulting mixture was concentrated in vacuo and the residue dissolved in dichloromethane, washed with water and dried over sodium sulfate. Kromatográfiás tisztítás után (etilacetát-n-hexán-kloroform 3:1:1) 0,55 g (36 %) fent nevezett anyagot kapunk. Chromatography (ethyl acetate: n-hexane-chloroform 3: 1: 1) 0.55 g (36%) of the aforesaid material. Op.: 122-123 °C. M.p .: 122-123 ° C. ^-NMR (DMSO-d 6 ): 5 1.34 (s, 9H); H NMR (DMSO-d6): 5 1:34 (s, 9H); 1.441.66 (m; 2H), 1.67-1.99 (m, 6H), 3.88 (m, 1H), 4.56 (bs, 2H), 6.59 (d, 1H), 7.77 (d, 1H), 8.07 (dd, 1H), 8.17 (d, 1H). 1.441.66 (m, 2H), 1.67-1.99 (m, 6H), 3.88 (m, 1H), 4:56 (bs, 2H), 6:59 (d, 1H), 7.77 (d, 1H), 8:07 (dd, 1H), 8.17 (d, 1H).

b. b. ) 3-exo-Amino-8-(pirazin-2-il)-8-azabiciklol3.2.1 loktán (II) általános képlet - ahol R 1 és B jelentése a fenti a.) lépésben megadott ) 3-exo-amino-8- (pyrazin-2-yl) -8-azabiciklol3.2.1 octane (II) general formula - where R 1 and B are as defined above in step a).

..· : .·.· * .. ·. · *.

385 mg (1.26 mmól) 3-exo-[(/erc-butoxikarbonil)amino]-8-(pirazin-2il)-8-azabiciklo[3.2.1]oktánt 20 ml 12%-os sósavas etanollal kevertetjük szobahőmérsékleten 3 órán át. 385 mg (1.26 mmol) of 3-exo - [(/ tert-butoxycarbonyl) amino] -8- (pyrazin-2-yl) -8-azabicyclo [3.2.1] octane in 20 ml of 12% at room temperature for 3 hours ethanolic hydrogen chloride . A kapott fehér szuszpenzióhoz 20 ml vizet adva oldatot kapunk, melyet pH>10 értékig lúgosítunk 40%-os káliumhidroxid oldattal, majd ezt diklórmetánnal extraháljuk. 20 ml of water were added to the resulting white suspension was obtained which was a pH> basified with 40% potassium hydroxide solution up to 10, and then extracted with dichloromethane. A szerves fázist nátriumszulfáton szárítjuk, bepároljuk. The organic layer was dried over sodium sulfate and evaporated. A maradékot oszlopkromatográfiás úton (etilacetát-metanol-25%-os vizes ammónia 7:3:1) tisztítva 167 mg (65%) olajos anyagként kapjuk a fenti terméket. The residue was purified by column chromatography (ethyl acetate-methanol-25% aqueous ammonia 7: 3: 1) to give the above product as an oil (167 mg, 65%). 'H-NMR (DMSO-d 6 ): δ 1.29 (t, 2H), 1.621.83 (m, 4H), 1,84-2,00 (m, 2H), 3.12 (sp, 1H), 4.57 (dd, 2H), 7.74 (d, 1H), ¹H-NMR (DMSO-d6): δ 1.29 (t, 2H), 1.621.83 (m, 4H), 1.84-2.00 (m, 2H), 3.12 (sp, 1H), 4:57 ( dd, 2H), 7.74 (d, 1H);

8.05 (dd, 1H), 8.15 (d, 1H). 8:05 (dd, 1H), 8.15 (d, 1H).

c.) l-{r8-(Pirazin-2-il)-8-azabiciklol3.2.11oktan-3-il1-exo-amino)acetil-2(S)-ciano-4,4'-difluoro-pirrolidin dihidroklorid c.) 8- {l- (pyrazin-2-yl) -8-azabiciklol3.2.11oktan-3-yl-1-exo-amino) acetyl-2 (S) -cyano-4,4'-difluoro-pyrrolidine dihydrochloride

167 mg (0,82 mmól) 3-exo-amino-8-(pirazin-2-il)-8-azabiciklo[3.2.1] oktánt és 170 mg (0,815 mmól) l-klóracetil-2-(S)-ciano-4,4'-difluoropirrolidint feloldunk 20 ml acetonitrilben és hozzáadunk 600 mg (1,6 mmól) PBEMP-t. 3-exo-amino-8- (pyrazin-2-yl) -8-azabicyclo [3.2.1] octane (167 mg, 0.82 mmol) and 170 mg (0.815 mmol) of l-chloroacetyl-2- (S) - cyano-4,4'-difluoropirrolidint dissolved in 20 ml of acetonitrile was added PBEMP-t (600 mg, 1.6 mmol). Az elegyet 16 órán át 55 °C-on kevertetjük, majd a takarító gyantát kiszűrjük, a szűrletet bepároljuk. The mixture was stirred at 55 ° C for 16 hours and then the cleaning resin was filtered off, the filtrate was concentrated. A maradékot CHCl 3 -MeOH 9:1 arányú elegyével kromatográfiásan tisztítjuk. The residue CHCl3 -MeOH 9: 1 mixture of chromatography. Sósavas etanollal történő savanyítás és dietiléteres kicsapás után sárga kristályos anyagként kapjuk a fenti terméket: 88 mg (24 %), op: 238-240 °C. After acidification with ethanolic hydrogen chloride and ether precipitation a yellow crystalline solid to give the above product: 88 mg (24%), mp: 238-240 ° C. 1 H-NMR (DMSO-d6): δ 1.70-1.82 (m, 4H), 1H-NMR (DMSO-d6): δ 1.70-1.82 (m, 4H);

1.95-2.15 (m, 4H), 2.79-3.01 (m, 2H), 3.94-4.27 (m, 5H), 4.68 (s, 2H), 5.15 (m, 1H), 7.87 (d, 1H), 8.15 (dd, 1H), 8.29 (d, 1H), 9.01 (bs, 2H). 1.95-2.15 (m, 4H), 2.79-3.01 (m, 2H), 3.94-4.27 (m, 5H), 4.68 (s, 2H), 5.15 (m, 1H), 7.87 (d, 1H), 8.15 ( dd, 1H), 8.29 (d, 1H), 9:01 (bs, 2H).

2002/4 2002/4

Claims (3)

Szabadalmi igénypontok
1. igénypontban megadott - és izomerjeik. as defined in claim 1 - and their isomers.
A Bejelentő helyett a Meghatalmazott: Instead of reporting the Nominee:
Ρ02 00849 KÖZZÉTÉTELI Ρ02 00 849 DISCLOSURE
Új vegyületek PÉLDÁNY New compounds COPIES
Bejelentő: Sanofi-Synthelabo, Párizs, Franciaország 3/1 ;,uiíü'.r tvnf'icifjöo , ', » J......| Applicant: Sanofi-Synthelabo, Paris, France 3/1,, uiíü'.r tvnf'icifjöo ',' J ...... | HtLUANY HtLUANY
Ρ0 2 008 4¾ Ρ0 2008 4¾
Új vegyületek new compounds
Bejelentő: Sanofí-Synthelabo, Párizs, Franciaország Applicant: Sanofi-Synthelabo, Paris, France
2002/4 2002/4
1. igénypontban megadott - és izomerjeik és sóik. as defined in claim 1 - and their isomers and salts.
15. A (IX) általános képletü vegyületek - ahol R 2 és R 3 jelentése az 15. The compound (IX) - wherein R 2 and R 3 represents the
1. igénypontban megadott - és izomerjeik. as defined in claim 1 - and their isomers.
14. A (VIII) általános képletü vegyületek - ahol R 2 és R 3 jelentése az 14. Compounds of formula (VIII) - wherein R 2 and R 3 represents the
1. igénypontban megadott - alkalmazása gyógyszerkészítmény előállítására, mely alkalmas DPP-IV enzim aktivitásának gátlására, és így DPP-IV enzim koncentrációjával kapcsolatos betegségek kezelésére. As defined in claim 1 - a pharmaceutical preparation, which is suitable for DPPIV enzyme activity of inhibiting and therefore treat diseases related to DPP-IV enzyme concentration.
9. Eljárás DPP-IV enzim gátlására, illetve DPP-IV enzim koncentrációjával kapcsolatos betegségek kezelésére, azzal jellemezve, hogy egy, az 1. igénypont szerinti (I) általános képletü vegyületet alkalmazunk terápiásán hatékony mennyiségben szabad formájában vagy sói alakjában. 9. A method for treating diseases associated with inhibition of DPP-IV enzyme or DPP-IV enzyme concentration, characterized by using a compound as claimed in claim 1 (I), a compound of formula therapeutically effective amount of a free form or in salt form.
10. A (II) általános képletü vegyületek - ahol R 1 és B jelentése az 1. igénypontban megadott - és izomerjeik és sóik. 10. The compounds (II) - wherein R1 and B are as defined in claim 1 - and their isomers and salts.
Λ Λ
11. A'í (II) általános képletü vegyületek - ahol R és R jelentése az 1. igénypontban megadott és izomerjeik. Compounds of formula 11 A'í (II) - wherein R and R are as defined in Claim 1, and isomers thereof.
12. Az (V) általános képletü vegyületek - ahol R 1 és B jelentése az 1. igénypontban megadott, - Y jelentése acetil vagy ferc-butoxikarbonil-csoport és izomerjeik és sóik. 12. The compound (V) - wherein R1 and B are as defined in claim 1, - Y is acetyl or tert-butoxycarbonyl and isomers and salts thereof.
13. A (VII) általános képletü vegyületek - ahol R 2 és R 3 jelentése az 13 (VII) - wherein R 2 and R 3 represents the
1. Az (I) általános képletű vegyületek - ahol 1. The compounds of formula (I) - wherein
R 1 jelentése R 1 is
- nitrogénatomot tartalmazó egy- vagy kéttagú aromás gyűrű, előnyösen piridil, piridazinil, pirimidinil, pirazinil, imidazolil, pirazolil, tiazolil, isotiazolil, oxazolil, izoxazolil, oxadiazolil, kinolinil, izokinolinil, cinnolinil, ftalazinil, kinazolinil, kinoxalinil, benzimidazolil, indazolil, benzotiazolil, benzoizotiazolil, benzoxazolil és benzizoxazolil csoport, mely adott esetben egymástól függetlenül mono- vagy diszubsztituált, a következő csoportok egy vagy két képviselőjével: 1-4 szénatomos alkil csoport, 1-4 szénatomos alkoxicsoport, halogénatom, trihalogén-metil-csoport, metiltio-csoport, nitro-csoport, és ciano-csoport; - one or two-member aromatic ring, preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isotiazolil, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl nitrogen containing , benzoisothiazolyl, benzoxazolyl and benzisoxazolyl group which is optionally independently mono- or di-substituted, the group consisting of one or two representative: C1-4 alkyl, C1-4 alkoxy, a halogen atom, a trihalomethyl group, a methylthio group; , nitro, and cyano; vagy or
- tienil vagy füril csoport, vagy - thienyl or furyl or
- p-toluolszulfonil csoport, vagy - p-toluenesulfonyl group, or
- R la -CO acilcsoport, ahol R la 1-4 szénatomos alkil csoport, fenil, egy vagy több alkil- és/vagy alkoxi csoporttal, nitro-csoporttal, vagy halogénatommal helyettesített fenil, piridil, fenil-eténil, alkiléndioxi csoporttal helyettesített fenil-eténil vagy feniletil csoport, vagy piperidin- 1-il, 4-(metil)piperazin-l-il, pirrolidin-1-il csoport; - Rla-CO acyl group, wherein R la C1-4 alkyl, phenyl, one or more alkyl and / or alkoxy, nitro, or halogen substituted phenyl, pyridyl or phenylethenyl substituted alkylenedioxy group, phenyl ethenylene or phenylethyl group, or piperidin-1-yl, 4- (methyl) piperazin-l-yl, pyrrolidin-1-yl group;
Bjelentése b is
- az (1) vagy (2) vagy (3) képletű csoport; - (1) or R (2) or (3); vagy *· or * ·
- a (4) képletü csoport ahol m értéke 2 vagy 3; - group where m is 2 or 3 (4) formula; vagy or
- az (5) képletü csoport - ahol R 4 jelentése hidrogénatom vagy 1-4 szénatomos egyenes vagy elágazó szénláncú alkilcsoport, n értéke 2 vagy 3; - the group (5) - wherein R4 is hydrogen or C1-4 straight or branched alkyl group, n is 2 or 3;
R jelentése hidrogénatom vagy fluoratom; R is hydrogen or fluorine;
R 3 jelentése fluoratom valamint sóik, izomerjeik és szolvátjaik. R 3 is a fluorine atom and their salts, isomers and solvates.
2. Az 1. igénypont szerinti (I) általános képletü vegyületek - ahol R 1 jelentése pirazin-2-il vagy ciano-csoporttal szubsztituált piridil-csoport, B jelentése piperidin-4-il csoport, R 2 és R 3 jelentése fluoratom - valamint sóik, izomerjeik és szolvátjaik. 2. Compounds of formula I according to claim 1 (I) - wherein R1 represents pyrazin-2-yl or cyano substituted pyridyl, B is piperidin-4-yl group, R 2 and R 3 is a fluorine atom - and their salts, isomers and solvates.
3. l-{[l-(Pirazin-2-il)piperidin-4-il]amino}acetil-2-(S)-ciano-4,4'difluoro-pirrolidin. 3. l - {[l- (pyrazin-2-yl) piperidin-4-yl] amino} acetyl-2 (S) -cyano-pyrrolidine-4,4'difluoro.
4. l-{[l-(5-Cianopiridin-2-il)piperidin-4-il]amino}acetil-2-(S)-ciano-4,4'difluoro-pirrolidin. 4. l - {[l- (5-Cyanopyridin-2-yl) piperidin-4-yl] amino} acetyl-2 (S) -cyano-pyrrolidine-4,4'difluoro.
5. l-{8-[Pirazin-2-il)-8-azabicíklo[3.2.1]oktán-3-il]-exo-amino}acetil-2(S)-ciano-4,4'-difluoro-pirrolidin. 5. 8- {l- [pyrazin-2-yl) -8-azabicyclo [3.2.1] octan-3-yl] exo-amino} acetyl-2 (S) -cyano-4,4'-difluoro pyrrolidine.
6. Gyógyszerkészítmény, azzal jellemezve, hogy egy (I) általános képletü ahol R 1 , B, R 2 és R 3 jelentése az 1. igénypontban megadott - vegyületet, vagy izomerjét, vagy szolvátját tartalmazza szabad formában vagy sója alakjában legalább egy gyógyszerészetileg elfogadható hordozóanyaggal vagy hígítóanyaggal együtt. 6. A pharmaceutical composition characterized in that (I) wherein R 1, B, R 2 and R 3 are as defined in Claim 1 - a compound or isomer, or solvate thereof, in free form or salt form at least one pharmaceutically acceptable carrier or diluents.
7. Eljárás az (I) általános képletü - ahol R 1 , B, R 2 és R 3 jelentése az 1. igénypontban megadott - vegyületek előállítására , azzal jellemezve, hogy valamely (II) általános képletü - ahol R 1 és B jelentése a fent megadott vegyületek valamely (III) általános képletü — ahol R és R jelentése a fent megadott - vegyülettel reagáltatunk és a kapott (I) általános képletü vegyületet vagy sóját kinyerjük a reakcióelegyből. 7. A method for the general formula (I) - for preparing compounds characterized by the formula (II) general formula - - wherein R 1, B, R 2 and R 3 are as defined in claim 1 wherein R 1 and B are as defined above (III) a compound of formula as defined - in which R and R are as defined above - with a compound of formula and a compound or salt of formula (I) is recovered from the reaction mixture.
8. Egy (I) általános képletü vegyület - ahol R , B, R és R jelentése az 8. A (I), a compound of formula - wherein R, B, R and R are
3/2 3/2
< f π\·'“Ί*: »·», no'a-Svtt'.hílak;f \ · " 'Ί *:" · ", no'a-Svtt'.hílak; j (tvi)' (VII) (X) \ j (tvi) '(VII) (X) \
Ρ02 00849 00 849 Ρ02 • · · · »·· · ««1 • · ·· · ·· • · · · »· ··« «1 · • · ·· ·· Új vegyületek new compounds KÖZZÉTÉTELI PÉLDÁNY PUBLICATION COPIES 2002/4 2002/4 Bejelentő: Sanofi-Synthelabo, Párizs, Franciaország Applicant: Sanofi-Synthelabo, Paris, France 3/3 3/3 fi'J* I -SVhV. fi'J * I -SVhV. SCÍÍ...V Scii V ... /' / ' L öa/v L Ö / v - (1) (1) Gk- Gk- (2) (2) o He (3) (3) — N—-A - SO (4) (4) R 4 | R 4 | — N —(CH 2 ) n - N - (CH2) n - (5) (5)
ι> ι>
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