HRP20030048A2 - Imidazole derivatives - Google Patents

Imidazole derivatives Download PDF

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HRP20030048A2
HRP20030048A2 HR20030048A HRP20030048A HRP20030048A2 HR P20030048 A2 HRP20030048 A2 HR P20030048A2 HR 20030048 A HR20030048 A HR 20030048A HR P20030048 A HRP20030048 A HR P20030048A HR P20030048 A2 HRP20030048 A2 HR P20030048A2
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imidazol
cyclobutyl
cis
acetylamino
naphthalen
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HR20030048A
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Croatian (hr)
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Michael Kirk Ahlijanian
Christopher Blair Cooper
Cristopher John Helal
Lit-Fui Lau
Frank Samuel Menniti
Mark Allen Sanner
Patricia Ann Seymour
Anabella Villalobos
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Pfizer Prod Inc
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Description

Područje izuma Field of invention

Predmet ovog izuma odnosi se na derivate imidazola, farmaceutske pripravke koji sadrže te derivate i postupke upotrebe takvih derivata prilikom tretmana nenormalnog rasta stanica i određenih bolesti i stanja centralnog živčanog sustava. Spojevi prema ovom izumu djeluju kao inhibitori enzima o ciklinu ovisne proteinske kinaze cdk5 (o ciklinu ovisna proteinska kinaza 5) i cdk2 (o ciklinu ovisna proteinska kinaza 2). Spojevi prema ovom izumu također inhibiraju i enzim GSK-3 (glikogen sintetaze kinaza 3). The subject of this invention relates to imidazole derivatives, pharmaceutical preparations containing these derivatives and methods of using such derivatives in the treatment of abnormal cell growth and certain diseases and conditions of the central nervous system. The compounds of the present invention act as inhibitors of the cyclin-dependent protein kinase enzymes cdk5 (cyclin-dependent protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). The compounds of this invention also inhibit the enzyme GSK-3 (glycogen synthetase kinase 3).

Pozadina izuma Background of the invention

Serin/treonin kinaza cdk5, kao i njezin kofaktor p25 (ili njezin duži kofaktor p35) povezani su s neurodegenerativnim poremećajima, pa su prema tome inhibitori cdk5/p25 (ili cdk5/p35) korisni u tretmanu neurodegenerativnih poremećaja kao što su to Alzheimerova bolest, Parkinsonova bolest, udar ili Huntingtonova bolest. Otkriće da je cdk5 uključen u fosforilaciju tau proteina (J. Biochem, 117, 741-749 (1995)) dodatno potvrđuje ispravnost korištenja cdk5 inhibitora prilikom tretmana takvih neurodegenerativnih poremećaja. Nadalje, cdk5 provodi fosforilaciju fosfoproteina reguliranog dopaminom i cikličkim AMP (DARPP-32) na treoninu 75, čime se ukazuje na njegovu ulogu u dopaminergijskoj neurotransmisiji (Nature, 402, 669-671 (1999)). The serine/threonine kinase cdk5, as well as its cofactor p25 (or its longer cofactor p35) are associated with neurodegenerative disorders, therefore cdk5/p25 (or cdk5/p35) inhibitors are useful in the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, stroke or Huntington's disease. The discovery that cdk5 is involved in tau protein phosphorylation (J. Biochem, 117, 741-749 (1995)) further confirms the correctness of using cdk5 inhibitors in the treatment of such neurodegenerative disorders. Furthermore, cdk5 phosphorylates the dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32) at threonine 75, indicating its role in dopaminergic neurotransmission (Nature, 402, 669-671 (1999)).

Serin/treonin kinaza cdk2 esencijalna je za normalan stanični ciklus, te predstavlja kritičan faktor u poremećajima koji su posljedica nenormalnog staničnog ciklusa, što je zajednička karakteristika mnogih onkoloških poremećaja. Prema tome, inhibitori cdk2 su korisni tijekom tretmana različitih tipova raka i drugih bolesti ili stanja povezanih s nenormalnim rastom stanica (Meijer et al., Properties and Potential-applications of Chemical Inhibitors of Cyclin-dependent Kinsases, Pharmacology & therapeutics, 82 (2-3), 279-284 (1999); Sausville et al., Cyclin-dependent Kinases: Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology & therapeutics, 82 (2-3) 285-292 (1999)). The serine/threonine kinase cdk2 is essential for a normal cell cycle, and is a critical factor in disorders resulting from an abnormal cell cycle, which is a common characteristic of many oncological disorders. Therefore, cdk2 inhibitors are useful during the treatment of various types of cancer and other diseases or conditions associated with abnormal cell growth (Meijer et al., Properties and Potential-applications of Chemical Inhibitors of Cyclin-dependent Kinases, Pharmacology & therapeutics, 82 (2- 3), 279-284 (1999); Sausville et al., Cyclin-dependent Kinases: Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology & therapeutics, 82 (2-3) 285-292 (1999)).

GSK-3 jest serin/treonin proteinska kinaza. To je jedan od nekoliko protein kinaza koje provode fosforilaciju glikogen sintetaze (Embi et al., Eur. J. Biochem. 107:519-527 (1980); Hemmings et al., Eur. J. Biochem., 119:443-451 (1982)). Postoje dvije izoforme GSK-3 u kralježnjaka, α i β, za koje je pronađeno da se odlikuju monomernom strukturom 49 kD (α) i 47 kD (β). Obje izoforme fosforiliraju glikogen sintetazu u mišićima (Cross et al., Biochemical Journal 303: 21-26 (1994)). Slijed aminokiselina unutar katalitičke domene istovjetan je u iznosu većem od 98 % za GSK-3 homologe dobivene iz različitih vrsta (Plyte et al., Biochim. Biophys. Acta 1114: 147-162 (1992)). Uslijed izvanredno visokog stupnja očuvanja unutar filogenetskog spektra, pretpostavlja se fundamentalna uloga GSK-3 u staničnim procesima. GSK-3 is a serine/threonine protein kinase. It is one of several protein kinases that phosphorylate glycogen synthetase (Embi et al., Eur. J. Biochem. 107:519-527 (1980); Hemmings et al., Eur. J. Biochem., 119:443-451 (1982)). There are two isoforms of GSK-3 in vertebrates, α and β, which have been found to be characterized by monomeric structures of 49 kD (α) and 47 kD (β). Both isoforms phosphorylate glycogen synthetase in muscle (Cross et al., Biochemical Journal 303: 21-26 (1994)). The amino acid sequence within the catalytic domain is greater than 98% identical for GSK-3 homologs obtained from different species (Plyte et al., Biochim. Biophys. Acta 1114: 147-162 (1992)). Due to the extraordinarily high degree of conservation within the phylogenetic spectrum, a fundamental role of GSK-3 in cellular processes is assumed.

GSK-3 je povezan s brojnim različitim bolestima i stanjima. Na primjer, Chen et al., Diabetes 43: 1234-1241 (1994) je predložio da povećanje aktivnosti GSK-3 može biti važno u slučaju diabetesa tipa 2. Smatra se da povećana ekspresija GSK-3 u dijabetičnih mišića doprinosi slabljenju aktivnosti glikogen sintetaze i rezistenciji skeletnih mišića spram inzulina, što su pojave koje prate tip 2 diabetesa (Nikoulina et al., Diabetes 49: 263-271 (2000)). Nadalje, visoka aktivnost proteinske fosfataze tipa 1, koja je zabilježena u nepokretnih spermija, povezuje se s povećanom aktivnošću GSK-3, te se smatra odgovornom za nepokretnost spermija (Vijayaraghavan et al., Biology of Reproduction 54: 709-718 (1996)). Vijayaraghavan je predložio da ovi podatci pokazuju biokemijsku osnovu razvoja i regulacije pokretljivosti spermija i moguću fiziološku ulogu sustava proteinska fosfataza 1/inhibitor 2/GSK-3. Aktivnost GSK-3 je također povezana s Alzheimerovom bolešću i poremećajima ponašanja kao što je to bipolarni poremećaj (WO 97/41854). Između drugih stanja, GSK-3 je povezan s gubitkom kose, shizofrenijom i neurodegenerativnim procesima, uključujući kronične neurodegenerativne bolesti (kao što je to gore spomenuta Alzheimerova bolest) i neurotraume, na primjer udar, traumatičnu povredu mozga i traumu kralješnične moždine. GSK-3 is associated with a number of different diseases and conditions. For example, Chen et al., Diabetes 43: 1234-1241 (1994) proposed that increased GSK-3 activity may be important in type 2 diabetes. Increased expression of GSK-3 in diabetic muscle is thought to contribute to the attenuation of glycogen synthetase activity. and skeletal muscle insulin resistance, which are phenomena accompanying type 2 diabetes (Nikoulina et al., Diabetes 49: 263-271 (2000)). Furthermore, the high activity of protein phosphatase type 1, which has been reported in immotile sperm, is associated with increased GSK-3 activity, and is considered responsible for sperm motility (Vijayaraghavan et al., Biology of Reproduction 54: 709-718 (1996)) . Vijayaraghavan proposed that these data indicate a biochemical basis for the development and regulation of sperm motility and a possible physiological role for the protein phosphatase 1/inhibitor 2/GSK-3 system. GSK-3 activity is also associated with Alzheimer's disease and behavioral disorders such as bipolar disorder (WO 97/41854). Among other conditions, GSK-3 is associated with hair loss, schizophrenia, and neurodegenerative processes, including chronic neurodegenerative diseases (such as the aforementioned Alzheimer's disease) and neurotrauma, for example, stroke, traumatic brain injury, and spinal cord trauma.

Bit izuma The essence of invention

Ovaj izum omogućava spojeve formule The present invention provides compounds of the formula

[image] [image]

gdje R1 jest ravnolančani ili razgranati (C1-C8)alkil, ravnolančani ili razgranati (C2-C8)alkenil, ravnolančani ili razgranati (C2-C8)alkinil, (C3-C8)cikloalkil, (C4-C8)cikloalkenil, (3-8 člani) heterocikloalkil, (C5-C11)bicikloalkil, (C7-C11)bicikloalkenil, (5-11 člani) heterobicikloalkil, (C6-C14)aril ili (5-14 člani) heteroaril; i gdje je R1 opcijski supstituiran s jednim do šest supstituenata R5 neovisno odabranih između F, Cl, Br, I, nitro, cijano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, -O-S(=O)2R7, -N3 i R7; where R1 is straight or branched (C1-C8)alkyl, straight or branched (C2-C8)alkenyl, straight or branched (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3- 8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl or (5-14 membered) heteroaryl; and wherein R1 is optionally substituted with one to six R5 substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, - NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7 , -S(=O)2NR7R8, -O-S(=O)2R7, -N3 and R7;

R2 jest H, F, CH3, CN ili C(=O)OR7; R 2 is H, F, CH 3 , CN or C(=O)OR 7 ;

R3 jest -C(=O)NR9-, -C(=O)O-, -C(=O)(CR10R11)n- ili –(CR10R11)n-; R3 is -C(=O)NR9-, -C(=O)O-, -C(=O)(CR10R11)n- or -(CR10R11)n-;

R4 jest ravnolančani ili razgranati (C1-C8)alkil, ravnolančani ili razgranati (C2-C8)alkenil, ravnolančani ili razgranati (C2-C8)alkinil, (C3-C8)cikloalkil, (C4-C8)cikloalkenil, (3-8 člani) heterocikloalkil, (C5-C11)bicikloalkil, (C7-C11)bicikloalkenil, (5-11 člani) heterobicikloalkil, (C6-C14)aril ili (5-14 člani) heteroaril; i gdje je R4 opcijski supstituiran s jednim do tri supstituenata R6 neovisno odabranih između F, Cl, Br, I, nitro, cijano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8 ili R7; R4 is straight-chain or branched (C1-C8)alkyl, straight-chain or branched (C2-C8)alkenyl, straight-chain or branched (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 members) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl or (5-14 membered) heteroaryl; and wherein R4 is optionally substituted with one to three R6 substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, - NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7 , -S(=O)2NR7R8 or R7;

svaki R7, R8 i R9 neovisno je odabran između H, ravnolančanog ili razgranatog (C1-C8)alkila, ravnolančanog ili razgranatog (C2-C8)alkenila, ravnolančanog ili razgranatog (C2-C8)alkinila, (C3-C8)cikloalkila, (C4-C8)cikloalkenila, (3-8 članog) heterocikloalkila, (C5-C11)bicikloalkila, (C7-C11)bicikloalkenila, (5-11 članog) heterobicikloalkila, (C6-C14)arila i (5-14 članog) heteroarila; i gdje je svaki od R7, R8 i R9 neovisno opcijski supstituiran s jednim do šest supstituenata neovisno odabranih između F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10, -OC(=O)NR10R11, -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -C(=O)OR10, -C(=O)NR10R11 i R10; each R 7 , R 8 and R 9 is independently selected from H, straight or branched (C 1 -C 8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, straight or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, ( C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl and (5-14 membered) heteroaryl ; and wherein each of R7, R8 and R9 is independently optionally substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C (=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10, - OC(=O)NR10R11, -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -C(=O)OR 10 , -C(=O)NR 10 R 11 and R 10 ;

ili ukoliko R7 i R8 jesu oblika NR7R8, tada mogu opcijski biti povezani, te zajedno s dušikovim atomom iz NR7R8 na koji su vezani tvoriti heterocikloalkilni dio koji se sastoji od prstena s tri do sedam članova, gdje rečeni heterocikloalkilni dio opcijski može sadržavati i jedan ili dva dodatna heteroatoma neovisno odabrana između N, O i S; or if R7 and R8 are of the form NR7R8, then they can optionally be connected, and together with the nitrogen atom from NR7R8 to which they are connected, form a heterocycloalkyl part consisting of a ring with three to seven members, where said heterocycloalkyl part can optionally contain one or two additional heteroatoms independently selected from N, O and S;

svaki R10, R11 i R12 neovisno je odabran između H, ravnolančanog ili razgranatog (C1-C8)alkila, ravnolančanog ili razgranatog (C2-C8)alkenila, ravnolančanog ili razgranatog (C2-C8)alkinila, (C3-C8)cikloalkila, (C4-C8)cikloalkenila, (3-8 članog) heterocikloalkila, (C5-C11)bicikloalkila, (C7-C11)bicikloalkenila, (5-11 članog) heterobicikloalkila, (C6-C14)arila i (5-14 članog) heteroarila; i gdje je svaki od R10, R11 i R12 neovisno opcijski supstituiran s jednim do šest supstituenata neovisno odabranih između F, Cl, Br, I, NO2, -CN, -CF3, -NR13R14, -NR13C(=O)R14, -NR13C(=O)OR14, -NR13C(=O)NR14R15, -NR13S(=O)2R14, -NR13S(=O)2NR14R15, -OR13, -OC(=O)R13, -OC(=O)OR13, -OC(=O)NR13R14, -OC(=O)SR13, -SR13, -S(=O)R13, -S(=O)2R13, -S(=O)2NR13R14, -C(=O)R13, -C(=O)OR13, -C(=O)NR13R14 i R13; each R 10 , R 11 and R 12 is independently selected from H, straight or branched (C 1 -C 8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, straight or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, ( C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl and (5-14 membered) heteroaryl ; and wherein each of R10, R11 and R12 is independently optionally substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR13R14, -NR13C(=O)R14, -NR13C (=O)OR14, -NR13C(=O)NR14R15, -NR13S(=O)2R14, -NR13S(=O)2NR14R15, -OR13, -OC(=O)R13, -OC(=O)OR13, - OC(=O)NR13R14, -OC(=O)SR13, -SR13, -S(=O)R13, -S(=O)2R13, -S(=O)2NR13R14, -C(=O)R13, -C(=O)OR 13 , -C(=O)NR 13 R 14 and R 13 ;

svaki R13, R14 i R15 neovisno je odabran između H, ravnolančanog ili razgranatog (C1-C8)alkila, ravnolančanog ili razgranatog (C2-C8)alkenila, ravnolančanog ili razgranatog (C2-C8)alkinila, (C3-C8)cikloalkila, (C4-C8)cikloalkenila, (3-8 članog) heterocikloalkila, (C5-C11)bicikloalkila, (C7-C11)bicikloalkenila, (5-11 članog) heterobicikloalkila, (C6-C14)arila i (5-14 članog) heteroarila; i gdje je svaki od R13, R14 i R15 neovisno opcijski supstituiran s jednim do šest supstituenata neovisno odabranih između F, Cl, Br, I, NO2, -CN, -CF3, -NR16R17, -NR16C(=O)R17, -NR16C(=O)OR17, -NR16C(=O)NR17R18, -NR16S(=O)2R17, -NR16S(=O)2NR17R18, -OR16, -OC(=O)R16, -OC(=O)OR16, -OC(=O)NR16R17, -OC(=O)SR16, -SR16, -S(=O)R16, -S(=O)2R16, -S(=O)2NR16R17, -C(=O)R16, -C(=O)OR16, -C(=O)NR16R17 i R16; each R 13 , R 14 and R 15 is independently selected from H, straight or branched (C 1 -C 8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, straight or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, ( C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl and (5-14 membered) heteroaryl ; and wherein each of R13, R14 and R15 is independently optionally substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR16R17, -NR16C(=O)R17, -NR16C (=O)OR17, -NR16C(=O)NR17R18, -NR16S(=O)2R17, -NR16S(=O)2NR17R18, -OR16, -OC(=O)R16, -OC(=O)OR16, - OC(=O)NR16R17, -OC(=O)SR16, -SR16, -S(=O)R16, -S(=O)2R16, -S(=O)2NR16R17, -C(=O)R16, -C(=O)OR 16 , -C(=O)NR 16 R 17 and R 16 ;

svaki R16, R17 i R18 neovisno je odabran između H, ravnolančanog ili razgranatog (C1-C8)alkila, ravnolančanog ili razgranatog (C2-C8)alkenila, ravnolančanog ili razgranatog (C2-C8)alkinila, (C3-C8)cikloalkila, (C4-C8)cikloalkenila, (3-8 članog) heterocikloalkila, (C5-C11)bicikloalkila, (C7-C11)bicikloalkenila, (5-11 članog) heterobicikloalkila, (C6-C14)arila i (5-14 članog) heteroarila; each R 16 , R 17 and R 18 is independently selected from H, straight or branched (C 1 -C 8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, straight or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, ( C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl and (5-14 membered) heteroaryl ;

n jest 0, 1, 2 ili 3; n is 0, 1, 2 or 3;

gdje R10 i R11 u –C(=O)(CR10R11)n- i -(CR10R11)n- za svaku vrijednost n jesu neovisno definirani na gore opisani način; where R10 and R11 in –C(=O)(CR10R11)n- and -(CR10R11)n- for each value of n are independently defined as described above;

te njegove farmaceutski prihvatljive soli. and its pharmaceutically acceptable salts.

Spojevi formule 1 prema ovom izumu inhibitori su serin/treonin kinaza, a posebno o ciklinu ovisnih kinaza kao što su to cdk5 i cdk2, te su korisni u tretmanu neurodegenerativnih poremećaja i drugih CNS poremećaja, te nenormalnog rasta stanica, uključujući i kancer. Spojevi formule 1 naročito su korisni za inhibiciju cdk5. Spojevi formule 1 također su korisni i kao inhibitori GSK-3. The compounds of formula 1 according to this invention are inhibitors of serine/threonine kinases, and especially of cyclin-dependent kinases such as cdk5 and cdk2, and are useful in the treatment of neurodegenerative disorders and other CNS disorders, as well as abnormal cell growth, including cancer. Compounds of formula 1 are particularly useful for cdk5 inhibition. The compounds of formula 1 are also useful as GSK-3 inhibitors.

Pojam “alkil”, kako je ovdje korišten, osim ukoliko nije navedeno drugačije, obuhvaća zasićene jednovalentne ugljikovodične radikale koji se odlikuju ravnolančanim ili pak razgranatim dijelom molekule. U primjere alkila uključuju se, ne ograničavajući se pri tome samo na navedene, metil, etil, propil, izopropil i t-butil. The term "alkyl", as used herein, unless otherwise stated, includes saturated monovalent hydrocarbon radicals characterized by a straight-chain or branched part of the molecule. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl and t-butyl.

Pojam “alkenil”, kako je ovdje korišten, osim ukoliko nije navedeno drugačije, uključuje alkilne dijelove molekula koji sadrže barem jednu ugljik-ugljik dvostruku vezu, gdje alkil jest kako je to gore definirano. U primjere alkenila uključuju se, ne ograničavajući se pri tome samo na navedene, etenil i propenil. The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl moieties of molecules containing at least one carbon-carbon double bond, where alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

Pojam “alkinil”, kako je ovdje korišten, osim ukoliko nije navedeno drugačije, uključuje alkilne dijelove molekula koji sadrže barem jednu ugljik-ugljik trostruku vezu, gdje alkil jest kako je to gore definirano. U primjere alkenila uključuju se, ne ograničavajući se pri tome samo na navedene, etinil i 2-propinil. The term "alkynyl", as used herein, unless otherwise specified, includes alkyl moieties of molecules containing at least one carbon-carbon triple bond, where alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethynyl and 2-propynyl.

Pojam “cikloalkil”, kako je ovdje korišten, osim ukoliko nije navedeno drugačije, uključuje nearomatske zasićene cikloalkilne dijelove molekula, gdje alkil jest kako je to gore definirano. U primjere cikloalkila uključuju se, ne ograničavajući se pri tome samo na navedene, ciklopropil, ciklobutil, ciklopentil, cikloheksil i cikloheptil. “Bicikloalkilne” skupine su nearomatske zasićene karbocikličke skupine koje se sastoje od dva prstena, gdje rečeni prsteni dijele jedan ili dva zajednička atoma ugljika. Za svrhe ovoga izuma i ukoliko nije drugačije navedeno, bicikličke skupine uključuju spiro skupine i skupine kondenziranih prstena. U primjere bicikloalkilnih skupina uključuju se, ne ograničavajući se pri tome samo na navedene, biciklo-[3.1.0]-heksil, norbornil, spiro[4.5]decil, spiro[4.4]nonil, spiro[4.3]oktil i spiro[4.2]heptil. Pojmovi “cikloalkenil” i “bicikloalkenil” odnose se na već gore definirane nearomatske karbocikličke cikloalkilne i bicikloalkilne dijelove molekula koje sadrže jednu ili više ugljik-ugljik dvostrukih veza koje povezuju ugljike prstena (“endociklička” dvostruka veza) i/ili jednu ili više ugljik-ugljik dvostrukih veza koje povezuju ugljikov atom iz prstena i susjedni atom ugljika koji se ne nalazi u prstenu (“egzociklička” dvostruka veza). U primjere cikloalkenilnih skupina uključuju se, ne ograničavajući se pri tome samo na navedene, ciklopentenil i ciklobutenil, dok je primjer za bicikloalkenilnu skupinu, ne ograničavajući se pri tome samo na navedenu, norbornenil. Cikloalkilne, cikloalkenilne, bicikloalkilne i bicikloalkenilne skupine također uključuju i skupine koje su supstituirane s jednim ili više okso skupina. U primjere takvih skupina uključuju se oksociklopentil, oksociklobutil, oksociklopentenil i norkamforil. The term "cycloalkyl", as used herein, unless otherwise specified, includes non-aromatic saturated cycloalkyl moieties of the molecule, where alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. "Bicycloalkyl" groups are non-aromatic saturated carbocyclic groups consisting of two rings, wherein said rings share one or two carbon atoms in common. For the purposes of this invention and unless otherwise stated, bicyclic groups include spiro groups and fused ring groups. Examples of bicycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]hexyl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, and spiro[4.2] heptyl. The terms "cycloalkenyl" and "bicycloalkenyl" refer to the previously defined non-aromatic carbocyclic cycloalkyl and bicycloalkyl parts of molecules containing one or more carbon-carbon double bonds connecting the ring carbons ("endocyclic" double bond) and/or one or more carbon- carbon double bonds that connect a carbon atom from the ring and an adjacent carbon atom that is not in the ring ("exocyclic" double bond). Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclobutenyl, while an example of a bicycloalkenyl group is, but not limited to, norbornenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl and bicycloalkenyl groups also include groups substituted with one or more oxo groups. Examples of such groups include oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl and norcamphoryl.

Pojam “aril”, kako je ovdje korišten, osim ukoliko nije navedeno drugačije, uključuje organske radikale dobivene iz aromatskih ugljikovodika uklanjanjem jednog vodika kao što su to fenil, naftil, indenil i fluorenil. The term "aryl", as used herein, unless otherwise specified, includes organic radicals derived from aromatic hydrocarbons by removal of one hydrogen such as phenyl, naphthyl, indenyl and fluorenyl.

Pojmovi “heterociklički”, “heterocikloalkil” i slični pojmovi, kako su ovdje korišteni, odnose se na nearomatične cikličke skupine koje sadrže jedan ili više heteroatoma, poželjno je od jednog do četiri heteroatoma, od kojih je svaki odabran između O, S i N. “Heterobicikloalkilne” skupine su nearomatske skupine koje se sastoje od dva prstena, gdje rečeni prsteni dijele jedan ili dva atoma i gdje barem jedan prsten sadrži heteroatom (O, S ili N). Heterobicikloalkilne skupine za svrhe ovog izuma i ukoliko nije drugačije navedeno uključuju spiro skupine i skupine kondenziranih prstena. U jednom uobličenju svaki prsten heterobicikloalkila sadrži do četiri heteroatoma (tj. od nula do četiri heteroatoma, uz uvjet da barem jedan prsten sadrži barem jedan heteroatom). Heterocikličke skupine prema ovom izumu mogu također sadržavati prstenasti sustav supstituiran s jednim ili više okso skupina. U primjere nearomatskih heterocikličkih skupina uključuju se aziridinil, azetidinil, pirolidinil, piperidinil, azepinil, piperazinil, 1,2,3,6-tetrahidropiridinil, oksiranil, oksetanil, tetrahidrofuranil, tetrahidrotienil, tetrahidropiranil, tetrahidrotiopiranil, morfolino, tiomorfolino, tioksanil, pirolinil, indolinil, 2H-piranil, 4H-piranil, dioksanil, 1,3-dioksolanil, pirazolinil, dihidropiranil, dihidrotienil, dihidrofuranil, pirazolidinil, imidazolinil, imidazolidinil, 3-azabiciklo[3.1.0]heksanil, 3-azabiciklo[4.1.0]heptanil, kinolizinil, kvinuklidinil, 1,4-dioksaspiro[4.5]decil, 1,4-dioksaspiro[4.4]nonil, 1,4-dioksaspiro[4.3]oktil i 1,4-dioksaspiro[4.2]heptil. The terms "heterocyclic", "heterocycloalkyl" and similar terms, as used herein, refer to non-aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each of which is selected from O, S and N. "Heterobicycloalkyl" groups are non-aromatic groups consisting of two rings, where said rings share one or two atoms and where at least one ring contains a heteroatom (O, S or N). Heterobicycloalkyl groups for the purposes of this invention and unless otherwise specified include spiro groups and fused ring groups. In one embodiment, each heterobicycloalkyl ring contains up to four heteroatoms (ie, from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). Heterocyclic groups according to the present invention may also contain a ring system substituted with one or more oxo groups. Examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl. , 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl , quinolizinyl, quinuclidinyl, 1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyl, 1,4-dioxaspiro[4.3]octyl and 1,4-dioxaspiro[4.2]heptyl.

Pojam “heteroaril”, kako je ovdje korišten, odnosi se na aromatske skupine koje sadrže jedan ili više heteroatoma (O, S ili N), poželjno je od jednog do četiri heteroatoma. Policiklička skupina koja sadrži jedan ili više heteroatoma uz uvjet da je barem jedan prsten aromatski naziva se “heteroaril”. Heteroarilne skupine prema ovom izumu mogu također uključivati i sustave prstena supstituirane s jednom ili više okso skupina. Primjeri heteroarilnih skupina su piridinil, piridazinil, imidazolil, pirimidinil, pirazolil, triazolil, pirazinil, kinolil, izokinolil, tetrazolil, furil, tienil, izoksazolil, tiazolil, oksazolil, izotiazolil, pirolil, indolil, benzimidazolil, benzofuranil, cinolinil, indazolil, indolizinil, ftalazinil, triazinil, izoindolil, purinil, oksadiazolil, tiadiazolil, furazinil, benzofurazanil, benzotiofenil, benzotriazolil, benzotiazolil, benzoksazolil, kinazolinil, kinoksalinil, naftiridinil, dihidrokinolil, tetrahidrokinolil, dihidroizokinolil, tetrahidroizokinolil, benzofuril, furopiridinil, pirolopirimidinil i azaindolil. The term "heteroaryl" as used herein refers to aromatic groups containing one or more heteroatoms (O, S or N), preferably from one to four heteroatoms. A polycyclic group containing one or more heteroatoms with the condition that at least one ring is aromatic is called "heteroaryl". Heteroaryl groups according to this invention may also include ring systems substituted with one or more oxo groups. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazinyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl, and azaindolyl.

Navedene skupine, dobivene iz gore navedenih spojeva, mogu ukoliko je to moguće biti vezane preko C atoma ili pak preko N atoma. Na primjer, skupina dobivena iz pirola može biti pirol-1-il (N povezana skupina) ili pak pirol-3-il (C povezana skupina). Pojmovi koji se odnose na skupine također uključuju i sve moguće tautomere. The mentioned groups, obtained from the above-mentioned compounds, can, if possible, be linked via C atoms or via N atoms. For example, a group derived from pyrrole can be pyrrole-1-yl (N linked group) or pyrrole-3-yl (C linked group). Terms relating to groups also include all possible tautomers.

U jednom svojem uobličenju, ovaj izum omogućuje spojeve formule 1, gdje R3 jest –C(=O)NR9– ili –C(=O)(CR10 R11)n–. U drugom uobličenju R10 i R11 iz skupine –C(=O)(CR10 R11)n– su vodici za svaku vrijednost n. U slijedećem uobličenju R9 iz skupine –C(=O)NR9 – jest vodik. U narednom uobličenju R3 iz –C(=O)NR9- ili –C(=O)(CR10 R11)n–, te R2 jesu vodik. In one embodiment, this invention provides compounds of formula 1, where R3 is –C(=O)NR9– or –C(=O)(CR10 R11)n–. In another embodiment, R10 and R11 from the group –C(=O)(CR10 R11)n– are hydrogens for each value of n. In the following embodiment, R9 from the group –C(=O)NR9 – is hydrogen. In the following embodiment, R3 from –C(=O)NR9- or –C(=O)(CR10 R11)n–, and R2 are hydrogen.

U drugom uobličenju ovog izuma omogućen je spoj formule 1 u kojem R1 jest opcijski supstituiran (C3-C8)cikloalkil ili je pak opcijski supstituiran (C5-C11)bicikloalkil. Poželjno uobličenje jest ono u kojem R1 jest ciklopropil, ciklobutil, ciklopentil, cikloheksil ili norbornil, gdje su svaki opcijski supstituirani kako je to već gore navedeno (tj. opcijski s jednim do šest supstituenata R5 neovisno odabranih između F, Cl, Br, I, nitro, cijano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8 i R7). Još je poželjnije uobličenje u kojem R1 jest (C3-C8)cikloalkil ili je pak opcijski supstituiran (C5-C11)bicikloalkil, na primjer ciklopropil, ciklobutil, ciklopentil, cikloheksil ili norbornil, te je opcijski supstituiran s jednim do tri supstituenata neovisno odabranih između F, Cl, Br, I, nitro, cijano, -CF3, -NR7R8, -NR7C(=O)R8, -OR7, -C(=O)OR7, -C(=O)R7 i R7. Još je poželjnije uobličenje u kojem R1 jest (C3-C8)cikloalkil ili je pak opcijski supstituiran (C5-C11)bicikloalkil, na primjer ciklopropil, ciklobutil, ciklopentil, cikloheksil ili norbornil i gdje je R1 supstituiran s -NR7C(=O)R8, (C6-C14)arilom, (3-8 članim)heterocikloalkilom ili pak s (5-14 članim)heteroarilom i gdje su rečeni aril, heterocikloalkil i heteroaril svaki opcijski supstituiran s jednim do šest supstituenata neovisno odabranih između F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10, -OC(=O)NR10R11, -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -C(=O)OR10, -C(=O)NR10R11 i R10. U narednom uobličenju ovog izuma R1 jest biciklo-[3.1.0]-heksil koji je opcijski supstituiran kako je to već gore opisano (tj. opcijski supstituiran s jednim do šest supstituenata R5 neovisno odabranih između F, Cl, Br, I, nitro, cijano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8 i R7). In another embodiment of this invention, a compound of formula 1 is provided in which R1 is optionally substituted (C3-C8)cycloalkyl or is optionally substituted (C5-C11)bicycloalkyl. A preferred embodiment is that in which R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, each optionally substituted as set forth above (ie, optionally with one to six R 5 substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8 , -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8 and R7). Even more preferred is an embodiment in which R 1 is (C 3 -C 8 )cycloalkyl or is optionally substituted (C 5 -C 11 )bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, and is optionally substituted with one to three substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -OR7, -C(=O)OR7, -C(=O)R7 and R7. Even more preferred is an embodiment in which R1 is (C3-C8)cycloalkyl or optionally substituted (C5-C11)bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl and where R1 is substituted with -NR7C(=O)R8 , (C6-C14)aryl, (3-8 membered)heterocycloalkyl or else with (5-14 membered)heteroaryl and where said aryl, heterocycloalkyl and heteroaryl are each optionally substituted with one to six substituents independently selected from F, Cl, Br , I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(= O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10, -OC(=O)NR10R11, -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -C(=O)OR10, -C(=O)NR10R11 and R10. In a further embodiment of the present invention R1 is bicyclo-[3.1.0]-hexyl optionally substituted as described above (ie optionally substituted with one to six R5 substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7 , -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, - OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8 and R7).

U slijedećem uobličenju ovog izuma omogućen je spoj formule 1 u kojem R1 jest opcijski supstituiran ravnolančani ili razgranati (C1-C8)alkil ili opcijski supstituiran ravnolančani ili razgranati (C2-C8)alkenil. In the following embodiment of this invention, a compound of formula 1 is provided in which R1 is optionally substituted straight chain or branched (C1-C8)alkyl or optionally substituted straight chain or branched (C2-C8)alkenyl.

U slijedećem uobličenju ovog izuma omogućen je spoj formule 1 u kojem R2 jest vodik. U još jednom uobličenju ovog izuma R2 jest vodik i R1 jest kako je to dodatno definirano u prethodnom poglavlju. In the following embodiment of this invention, a compound of formula 1 in which R2 is hydrogen is provided. In another embodiment of the present invention, R 2 is hydrogen and R 1 is as further defined in the previous chapter.

U slijedećem uobličenju ovog izuma omogućen je spoj formule 1 u kojem R4 jest (C6-C14)aril ili (5-14 člani)heteroaril, gdje je svaki opcijski supstituiran. U poželjnom uobličenju R4 jest opcijski supstituiran fenil ili opcijski supstituiran piridil. U narednom poželjnom uobličenju R4 jest naftil, kinolil ili izokinolil, gdje je svaki opcijski supstituiran. U narednom uobličenju R4 jest naftil, kinolil ili izokinolil, gdje su svi nesupstituirani. In the following embodiment of this invention, a compound of formula 1 is provided in which R4 is (C6-C14)aryl or (5-14 membered)heteroaryl, where each is optionally substituted. In a preferred embodiment R 4 is optionally substituted phenyl or optionally substituted pyridyl. In a further preferred embodiment, R 4 is naphthyl, quinolyl or isoquinolyl, each optionally substituted. In the following embodiment, R 4 is naphthyl, quinolyl or isoquinolyl, all of which are unsubstituted.

U još jednom svojem uobličenju omogućen je spoj formule 1 u kojem R2 jest vodik i R4 jest kako je to dodatno definirano u prethodnom poglavlju. In yet another embodiment, the compound of formula 1 is possible in which R2 is hydrogen and R4 is as further defined in the previous chapter.

Primjeri poželjnih spojeva formule 1 su: Examples of preferred compounds of formula 1 are:

N-(1-ciklobutil-1H-imidazol-4-il)-2-kinolin-6-il-acetamid; N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide;

N-(1-ciklopentil-1H-imidazol-4-il)-2-(4-metoksi-fenil)-acetamid; N-(1-cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxy-phenyl)-acetamide;

N-[1-(cis-3-fenil-ciklobutil)-1H-imidazol-4-il]-2-kinolin-6-il-acetamid; N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-yl-acetamide;

(1-ciklobutil-1H-imidazol-4-il)-karbamske kiseline fenil ester; (1-Cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester;

1-(1-ciklobutil-1H-imidazol-4-il)-3-izokinolin-5-il-urea; 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea;

N-[1-(cis-3-amino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamid; N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide;

6-metil-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 6-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

1H-imidazol-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 1H-imidazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

6-hidroksi-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 6-hydroxy-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

3-metil-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 3-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

2-piridin-3-il-tiazol-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 2-pyridin-3-yl-thiazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

6-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutilkarbamoil}-nikotinske kiseline metil ester; 6-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}-nicotinic acid methyl ester;

pirazin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-benzamid; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide;

5-metil-pirazin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 5-methyl-pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-izobutiramid; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-isobutyramide;

6-klor-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 6-chloro-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

kinolin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; quinoline-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

1H-pirol-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 1H-pyrrole-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-2-m-tolil-acetamid; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-2-m-tolyl-acetamide;

piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;

2-(3-hidroksi-fenil)-N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-acetamid; 2-(3-hydroxy-phenyl)-N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-acetamide;

piperidin-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid klorovodik; Piperidine-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide hydrochloride;

N-[1-(cis-3-acetilamino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-2-il-acetamid; N-[1-(cis-3-acetylamino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-yl-acetamide;

N-{cis-3-[4-(2-izokinolin-5-il-acetilamino)-imidazol-1-il]-ciklobutil}-benzamid i N-{cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide and

piridin-2-karboksilne kiseline {cis-3-[4-(2-izokinolin-5-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid i pyridine-2-carboxylic acid {cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide and

farmaceutski prihvatljive soli gore navedenih spojeva. pharmaceutically acceptable salts of the above-mentioned compounds.

Primjeri drugih spojeva formule 1 prema ovom izumu su: Examples of other compounds of formula 1 according to the present invention are:

cis-N-(1-biciklo[3.1.0]heks-3-il-1H-imidazol-4-il)-2-kinolin-6-il-acetamid; cis-N-(1-bicyclo[3.1.0]hex-3-yl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide;

cis-N-{1-[trans-6-(piridin-2-karbonil)-biciklo[3.1.0]heks-3-il]-1H-imidazol-4-il}-2-kinolin-6-il-acetamid; cis-N-{1-[trans-6-(pyridin-2-carbonyl)-bicyclo[3.1.0]hex-3-yl]-1H-imidazol-4-yl}-2-quinolin-6-yl- acetamide;

N-{1-[cis-3-(2-metoksi-fenil)-ciklobutil]-1H-imidazol-4-il}-2-kinolin-6-il-acetamid; N-{1-[cis-3-(2-methoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl-acetamide;

N-{1-[cis-3-(2-fluor-fenil)-ciklobutil]-1H-imidazol-4-il}-2-kinolin-6-il-acetamid; N-{1-[cis-3-(2-fluoro-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl-acetamide;

N-{1-[cis-3-(4-metoksi-fenil)-ciklobutil]-1H-imidazol-4-il}-2-kinolin-6-il-acetamid; N-{1-[cis-3-(4-methoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl-acetamide;

2-kinolin-6-il-N-[1-(cis-3-p-tolil-ciklobutil)-1H-imidazol-4-il]-acetamid; 2-quinolin-6-yl-N-[1-(cis-3-p-tolyl-cyclobutyl)-1H-imidazol-4-yl]-acetamide;

N-{1-[cis-3-(2-etoksi-fenil)-ciklobutil]-1H-imidazol-4-il}-2-kinolin-6-il-acetamid; N-{1-[cis-3-(2-ethoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl-acetamide;

N-{1-[cis-3-(3-metoksi-fenil)-ciklobutil]-1H-imidazol-4-il}-2-kinolin-6-il-acetamid i N-{1-[cis-3-(3-methoxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-quinolin-6-yl-acetamide and

farmaceutski prihvatljive soli gore navedenih spojeva. pharmaceutically acceptable salts of the above-mentioned compounds.

Naredni primjeri spojeva formule 1 su: Further examples of compounds of formula 1 are:

N-{1-[3-(2-hidroksi-fenil)-ciklobutil]-1H-imidazol-4-il}-2-(4-metoksi-fenil)-acetamid; N-{1-[3-(2-hydroxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{1-[3-(3-hidroksi-fenil)-ciklobutil]-1H-imidazol-4-il}-2-(4-metoksi-fenil)-acetamid; N-{1-[3-(3-hydroxy-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{1-[3-(2-amino-fenil)-ciklobutil]-1H-imidazol-4-il}-2-(4-metoksi-fenil)-acetamid; N-{1-[3-(2-amino-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{1-[3-(3-amino-fenil)-ciklobutil]-1H-imidazol-4-il}-2-(4-metoksi-fenil)-acetamid; N-{1-[3-(3-amino-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{1-[3-(3-aminometil-fenil)-ciklobutil]-1H-imidazol-4-il}-2-(4-metoksi-fenil)-acetamid; N-{1-[3-(3-aminomethyl-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-(4-methoxy-phenyl)-acetamide;

N-{1-[3-(3-dimetilaminometil-fenil)-ciklobutil]-1H-imidazol-4-il}-2-(4-metoksi-fenil)-acetamid; N-{1-[3-(3-dimethylaminomethyl-phenyl)-cyclobutyl]-1H-imidazol-4-yl}-2-(4-methoxy-phenyl)-acetamide;

2-(4-metoksi-fenil)-N-{1-[3-(1-metil-1H-pirazol-3-il)-ciklobutil]-1H-imidazol-4-il}-acetamid i 2-(4-methoxy-phenyl)-N-{1-[3-(1-methyl-1H-pyrazol-3-yl)-cyclobutyl]-1H-imidazol-4-yl}-acetamide and

farmaceutski prihvatljive soli gore navedenih spojeva. pharmaceutically acceptable salts of the above-mentioned compounds.

Soli spojeva formule 1 mogu se prirediti iz kiselih ili baznih skupina prisutnih na spoju formule 1. Primjeri farmaceutski prihvatljivih soli spojeva formule 1 su soli dobivene pomoću kloridne, p-toluensulfonske, fumarne, limunske, sukcinatne, salicilne, oksalne, bromidne, fosforne, metansulfonske, vinske, maleinske, di-p-toluoil vinske, octene, sumporne, jodidne i fenilglikolne kiseline, te iz natrijeve, kalijeve, magnezijeve, kalcijeve i litijeve baze. Salts of compounds of formula 1 can be prepared from acidic or basic groups present on the compound of formula 1. Examples of pharmaceutically acceptable salts of compounds of formula 1 are salts obtained using chloride, p-toluenesulfonic, fumaric, citric, succinate, salicylic, oxalic, bromide, phosphoric, methanesulfonic , tartaric, maleic, di-p-toluoyl tartaric, acetic, sulfuric, iodide and phenylglycolic acids, and from sodium, potassium, magnesium, calcium and lithium bases.

Spojevi formule 1 mogu imati optičke centre, pa se prema tome mogu pojaviti u različitim enantiomernim i drugim stereoizomernim konfiguracijama. Izum obuhvaća sve enantiomere, diastereomere i druge stereoizomere takvih spojeva formule 1, a također i njihove racemične i druge smjese. Compounds of formula 1 may have optical centers, and therefore may occur in various enantiomeric and other stereoisomeric configurations. The invention includes all enantiomers, diastereomers and other stereoisomers of such compounds of formula 1, as well as their racemic and other mixtures.

Predmet ovog izuma također uključuje i izotopno označene spojeve koji su istovjetni gore navedenima za spojeve formule 1, uz razliku da je jedan ili više atoma u takvom spoju zamijenjeno s atomom čija se atomska masa ili maseni broj razlikuje od atomske mase ili masenog broja atoma uobičajeno prisutnog u prirodi. Primjeri izotopa koji se mogu ugraditi u spojeve prema ovom izumu uključuju izotope vodika, ugljika, dušika, kisika, fosfora, fluora, joda i klora kao što su to 3H, 11C, 14C, 18F, 123I i 125I. Spojevi ovog izuma i farmaceutski prihvatljive soli tih spojeva koji sadrže gore navedene izotope i/ili izotope drugih atoma obuhvaćeni su ovim izumom. Izotopno označeni spojevi ovog izuma, na primjer oni u kojima se nalaze radioaktivni izotopi kao što su to 3H i 14C, korisni su prilikom ispitivanja raspodjele lijekova i/ili supstrata u tkivima. Izotopi tricij, tj. 3H, i ugljik-14, tj. 14C, naročito su poželjni zbog lakoće njihove pripreme i detekcije. 11C i 18F izotopi naročito su korisni za PET (tomografija pozitronske emisije), a 125I je naročito koristan za SPECT (emisijska kompjutorizirana tomografija), što su tehnike korisne za prikaz slike (imaging) mozga. Nadalje, supstitucija s težim izotopima kao što je to deuterij, tj. 2H, može rezultirati određenim terapijskim poboljšanjima koja su posljedica veće metaboličke stabilnosti, na primjer povećati vrijeme poluraspada in vivo ili smanjiti potrebnu dozu, što u određenim slučajevima može biti poželjno. Izotopno označeni spojevi formule 1 prema ovom izumu mogu se općenito prirediti postupcima prikazanima u dolje danim shemama i/ili primjerima, supstitucijom neizotopnog reagensa s izotopno označenim reagensom. The subject of this invention also includes isotopically labeled compounds which are identical to those mentioned above for compounds of formula 1, with the difference that one or more atoms in such a compound are replaced with an atom whose atomic mass or mass number differs from the atomic mass or mass number of atoms normally present in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine such as 3H, 11C, 14C, 18F, 123I and 125I. The compounds of this invention and pharmaceutically acceptable salts of these compounds containing the above-mentioned isotopes and/or isotopes of other atoms are covered by this invention. Isotopically labeled compounds of the present invention, for example those containing radioactive isotopes such as 3H and 14C, are useful when examining tissue distribution of drugs and/or substrates. The isotopes of tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly desirable due to the ease of their preparation and detection. 11C and 18F isotopes are particularly useful for PET (positron emission tomography), and 125I is particularly useful for SPECT (emission computed tomography), which are techniques useful for brain imaging. Furthermore, substitution with heavier isotopes such as deuterium, i.e. 2H, may result in certain therapeutic improvements resulting from greater metabolic stability, for example increasing the half-life in vivo or reducing the required dose, which may be desirable in certain cases. The isotopically labeled compounds of formula 1 according to the present invention can generally be prepared by the procedures shown in the schemes and/or examples below, by substituting the non-isotopically labeled reagent with an isotopically labeled reagent.

Ovaj izum također omogućuje farmaceutske pripravke namijenjene tretmanu bolesti ili stanja u sisavaca koja su praćena nenormalnim rastom stanica, a koji sadrže spoj formule 1 u količini učinkovitoj za inhibiciju nenormalnog rasta stanica i farmaceutski prihvatljivog nositelja. The present invention also provides pharmaceutical compositions intended for the treatment of diseases or conditions in mammals that are accompanied by abnormal cell growth, which contain a compound of formula 1 in an amount effective to inhibit abnormal cell growth and a pharmaceutically acceptable carrier.

Ovaj izum također omogućuje farmaceutske pripravke namijenjene tretmanu bolesti ili stanja u sisavaca koja su praćena nenormalnim rastom stanica, a koji sadrže spoj formule 1 u količini učinkovitoj za inhibiciju aktivnosti cdk2 i farmaceutski prihvatljivog nositelja. The present invention also provides pharmaceutical compositions intended for the treatment of diseases or conditions in mammals that are accompanied by abnormal cell growth, comprising a compound of formula 1 in an amount effective to inhibit cdk2 activity and a pharmaceutically acceptable carrier.

Ovaj izum također omogućuje postupak tretmana bolesti ili stanja u sisavaca koja su praćena nenormalnim rastom stanica, a koji uključuje davanje spoja formule 1 rečenom sisavcu u količini učinkovitoj za inhibiciju nenormalnog rasta stanica. The present invention also provides a method of treating a disease or condition in a mammal that is accompanied by abnormal cell growth, comprising administering to said mammal a compound of formula 1 in an amount effective to inhibit the abnormal cell growth.

Ovaj izum također omogućuje postupak tretmana bolesti ili stanja u sisavaca koja su praćena nenormalnim rastom stanica, a koji uključuje davanje spoja formule 1 rečenom sisavcu u količini učinkovitoj za inhibiciju aktivnosti cdk2. The present invention also provides a method of treating a disease or condition in a mammal characterized by abnormal cell growth, comprising administering to said mammal a compound of formula 1 in an amount effective to inhibit cdk2 activity.

S obzirom na farmaceutske pripravke i postupke tretmana bolesti i stanja koja uključuju nenormalni rast stanica prema ovom izumu u jednom svojem uobličenju bolest ili stanje praćeno nenormalnim rastom stanica jest kancer. Kancer može biti karcinom, na primjer karcinom mokraćnog mjehura, dojke, crijeva, bubrega, jetre, pluća, na primjer rak malih stanica pluća, ezofagusa, žučnog mjehura, jajnika, pankreasa, trbuha, cerviksa, štitnjače, prostate ili kože, na primjer karcinom pločastih stanica; hematopoetski tumor limfocitnog sustava, na primjer leukemija, akutna limfatična leukemija, limfom B stanica, limfom T stanica, Hodgkinsov limfom, ne-Hodgkinsov limfom, limfom vlasastih stanica ili Burkettov limfom; hematopoetski tumor mijeloičnog sustava, na primjer akutna i kronična mijeloična leukemija, mijelodisplastični sindrom ili promijeloična leukemija; tumor mezenhimnog porijekla, na primjer fibrosarkom ili rabdomiosarkom; tumor centralnog ili perifernog živčanog sustava, na primjer astrocitom, neuroblastom, gliom ili neurilemom; melanom; seminom; teratokarcinom, osteosarkom; kseroderma pigmentna; keratoakantom; folikulski karcinom štitnjače ili Kaposiev sarkom. With regard to pharmaceutical preparations and procedures for the treatment of diseases and conditions involving abnormal cell growth according to this invention, in one embodiment, the disease or condition accompanied by abnormal cell growth is cancer. Cancer can be cancer, for example cancer of the bladder, breast, bowel, kidney, liver, lung, for example small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate or skin, for example cancer squamous cells; a hematopoietic tumor of the lymphocytic system, for example leukemia, acute lymphocytic leukemia, B cell lymphoma, T cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma or Burkett's lymphoma; hematopoietic tumor of the myeloid system, for example acute and chronic myeloid leukemia, myelodysplastic syndrome or promyeloid leukemia; a tumor of mesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or neurilemma; melanoma; seminoma; teratocarcinoma, osteosarcoma; xeroderma pigmentosum; keratoacanthoma; follicular thyroid cancer or Kaposi's sarcoma.

U narednom uobličenju bolesti i stanja povezana s nenormalnim rastom stanica su benigna. U takve se bolesti i stanja uključuju benigna hiperplazija prostate, familijarna adenomatoza polipoza, neurofibromatoza, ateroskleroza, pulmonarna fibroza, artritis, psorijaza, glomerulonefritis, restenoza, keloidni ožiljci, upalna bolest crijeva, odbacivanje transplantanata, gljivične infekcije i endotoksični šok. In the following embodiment, diseases and conditions associated with abnormal cell growth are benign. Such diseases and conditions include benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, keloid scars, inflammatory bowel disease, transplant rejection, fungal infections, and endotoxic shock.

Ovaj izum omogućuje i farmaceutski pripravak namijenjen tretmanu neurodegenerativnih bolesti ili stanja u sisavaca, a koji sadrži spoj formule 1 u količini učinkovitoj za tretman rečenih bolesti ili stanja i farmaceutski prihvatljivog nositelja. This invention also enables a pharmaceutical preparation intended for the treatment of neurodegenerative diseases or conditions in mammals, which contains the compound of formula 1 in an amount effective for the treatment of said diseases or conditions and a pharmaceutically acceptable carrier.

Ovaj izum omogućuje i farmaceutski pripravak namijenjen tretmanu neurodegenerativnih bolesti ili stanja u sisavaca, a koji sadrži spoj formule 1 u količini učinkovitoj za inhibiciju aktivnosti cdk5 i farmaceutski prihvatljivog nositelja. This invention also provides a pharmaceutical preparation intended for the treatment of neurodegenerative diseases or conditions in mammals, which contains the compound of formula 1 in an amount effective for inhibiting cdk5 activity and a pharmaceutically acceptable carrier.

Ovaj izum omogućuje i postupak tretmana neurodegenerativnih bolesti ili stanja u sisavaca, a koji uključuje davanje spoja formule 1 rečenom sisavcu u količini učinkovitoj za inhibiciju aktivnosti cdk5. The present invention also provides a method of treating neurodegenerative diseases or conditions in mammals, which includes administering a compound of formula 1 to said mammal in an amount effective to inhibit cdk5 activity.

Ovaj izum omogućuje i postupak tretmana neurodegenerativnih bolesti ili stanja u sisavaca, a koji uključuje davanje spoja formule 1 rečenom sisavcu u količini učinkovitoj za tretman rečenih bolesti ili stanja. This invention also provides a method of treating neurodegenerative diseases or conditions in mammals, which includes administering a compound of formula 1 to said mammal in an amount effective for the treatment of said diseases or conditions.

U jednom uobličenju ovog izuma neurodegenerativne bolesti ili stanja koja se tretiraju odabiru se između Huntingtonove bolesti, udara, traume kralješnične moždine, traumatske povrede mozga, multi-infarktne demencije, epilepsije, amiotrofične lateralne skleroze, bola, demecije izazvane virusnim putem, na primjer demencija uzrokovana AIDSom, neurodegeneracije uzrokovane bakterijskom infekcijom, migrene, hipoglikemije, urinarne inkontinencije, ishemije mozga, multiple skleroze, Alzheimerove bolesti, senilne demencije Alzheimerova tipa, blagog kognitivnog poremećaja, kognitivnog poremećaja povezanog sa starošću, povraćanja, kortikobazalne degeneracije, demencije pugilistica, Downovog sindroma, miotonične distrofije, Niemann-Pickove bolesti, Pickove bolesti, prionska bolest s plakovima, progresivna supranuklearna paraliza, donja lateralna skleroze i subakutnog sklerozantnog leukoencefalitisa (panencefalitis). In one embodiment of the present invention, the neurodegenerative disease or condition to be treated is selected from Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, virally induced dementia, for example dementia caused by AIDS, neurodegeneration caused by bacterial infection, migraine, hypoglycemia, urinary incontinence, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive impairment, age-related cognitive impairment, vomiting, corticobasal degeneration, dementia pugilistica, Down's syndrome, myotonic dystrophy, Niemann-Pick disease, Pick disease, prion disease with plaques, progressive supranuclear palsy, inferior lateral sclerosis and subacute sclerosing leukoencephalitis (panencephalitis).

Ovaj izum omogućuje i farmaceutski pripravak namijenjen tretmanu onih bolesti ili stanja na koja se može utjecati ili ih olakšati promjenom dopaminom posredovane neurotransmisije u sisavaca, a koji sadrži inhibitor aktivnosti cdk5 u količini učinkovitoj za tretman rečenih bolesti ili stanja i farmaceutski prihvatljivog nositelja. This invention also provides a pharmaceutical preparation intended for the treatment of those diseases or conditions that can be affected or alleviated by changing dopamine-mediated neurotransmission in mammals, and which contains an inhibitor of cdk5 activity in an amount effective for the treatment of said diseases or conditions and a pharmaceutically acceptable carrier.

Ovaj izum omogućuje i farmaceutski pripravak namijenjen tretmanu onih bolesti ili stanja na koja se može utjecati ili ih olakšati promjenom dopaminom posredovane neurotransmisije u sisavaca, a koji sadrži inhibitor aktivnosti cdk5 u količini učinkovitoj za inhibiciju cdk5 i farmaceutski prihvatljivog nositelja. This invention also provides a pharmaceutical composition intended for the treatment of those diseases or conditions that can be affected or alleviated by altering dopamine-mediated neurotransmission in mammals, and which contains an inhibitor of cdk5 activity in an amount effective for cdk5 inhibition and a pharmaceutically acceptable carrier.

Ovaj izum omogućuje i postupak tretmana onih bolesti ili stanja na koja se može utjecati ili ih olakšati promjenom dopaminom posredovane neurotransmisije u sisavaca, a koji uključuje davanje inhibitora aktivnosti cdk5 rečenom sisavcu u količini učinkovitoj za inhibiciju cdk5. This invention also provides a method of treating those diseases or conditions that can be affected or alleviated by altering dopamine-mediated neurotransmission in mammals, which includes administering an inhibitor of cdk5 activity to said mammal in an amount effective to inhibit cdk5.

Ovaj izum omogućuje i postupak tretmana onih bolesti ili stanja na koja se može utjecati ili ih olakšati promjenom dopaminom posredovane neurotransmisije u sisavaca, a koji uključuje davanje inhibitora aktivnosti cdk5 rečenom sisavcu u količini učinkovitoj za tretman rečenih bolesti. This invention also provides a method of treating those diseases or conditions that can be affected or alleviated by altering dopamine-mediated neurotransmission in mammals, which includes administering an inhibitor of cdk5 activity to said mammal in an amount effective for the treatment of said diseases.

U jednom uobličenju ovog izuma bolesti ili stanja na koja se može utjecati ili ih olakšati promjenom dopaminom posredovane neurotransmisije odabiru se između Parkinsonove bolesti, shizofrenije, shizofrenog poremećaja, shizoafektivnog poremećaja, na primjer paranoidnog oblika ili depresivnog oblika, paranoidnog poremećaja, psihotičnih poremećaja uzrokovanih zlouporabom supstancija, na primjer psihoze uzrokovane alkoholom, amfetaminima, kanabisom, kokainom, halucinogenima, inhalantima, opijatima ili fenciklidinima; poremećaja ličnosti paranoidnog oblika, poremećaja ličnosti shizoidnog oblika, ovisnosti, uključujući ovisnost o narkotiku (npr. heroin, opijum i morfij), ovisnosti o kokainu i alkoholu; stanja uzrokovanih prestankom uzimanja lijekova, uključujući prestanak uzimanja narkotika, kokaina i alkohola; opsesivno kompulzivnog poremećaja, Touretteovog sindroma, depresija, depresivnih epizoda, maničnih epizoda ili epizoda promjenjivog raspoloženja, epizoda hipomaničnih raspoloženja, depresivnih epizoda s netipičnim obilježjima ili s melankoličnim obilježjima ili pak s katatonim obilježjima, epizoda poslijeporođajne osjetljivosti, depresije nakon udara, teškog depresivnog poremećaja, distimije, blagog depresivnog poremećaja, predmenstruacijskog sindroma, shizofrenog post-psihotičnog depresivnog poremećaja, teškog depresivnog poremećaja nadograđenog na psihotički poremećaj kao što je to paranoidni poremećaj ili shizofrenija, bipolarnog poremećaja, na primjer bipolarnog poremećaja I, bipolarnog poremećaja II, ciklotimije, aksioznosti, poremećaja smanjene pažnje i hiperaktivnosti, te poremećaja smanjenja pažnje. In one embodiment of the present invention, the diseases or conditions that can be affected or alleviated by altering dopamine-mediated neurotransmission are selected from Parkinson's disease, schizophrenia, schizophrenic disorder, schizoaffective disorder, for example paranoid form or depressive form, paranoid disorder, psychotic disorders caused by substance abuse , for example psychoses caused by alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, opiates or phencyclidines; paranoid personality disorder, schizoid personality disorder, addiction, including drug addiction (eg heroin, opium and morphine), addiction to cocaine and alcohol; conditions caused by drug withdrawal, including withdrawal from narcotics, cocaine, and alcohol; obsessive compulsive disorder, Tourette's syndrome, depression, depressive episodes, manic episodes or episodes of mood swings, episodes of hypomanic moods, depressive episodes with atypical features or with melancholic features or with catatonic features, episode of postpartum sensitivity, post-stroke depression, major depressive disorder, dysthymia, mild depressive disorder, premenstrual syndrome, schizophrenic post-psychotic depressive disorder, major depressive disorder superimposed on a psychotic disorder such as paranoid disorder or schizophrenia, bipolar disorder, for example bipolar I disorder, bipolar II disorder, cyclothymia, anxiety, reduced attention and hyperactivity, and attention deficit disorders.

U odnosu na postupak ili pripravak namijenjen tretmanu bolesti ili stanja na koja se može utjecati ili ih olakšati promjenom dopaminom posredovane neurotransmisije u jednom svojem uobličenju inhibitor aktivnosti cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. In relation to a procedure or a preparation intended for the treatment of diseases or conditions that can be influenced or alleviated by changing dopamine-mediated neurotransmission, in one embodiment, the inhibitor of cdk5 activity is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum također omogućuje farmaceutski pripravak namijenjen tretmanu bolesti ili stanja koja se mogu olakšati inhibicijom aktivnosti cdk5 u sisavaca, a koji sadrži spoj formule 1 u količini učinkovitoj za inhibiciju aktivnosti cdk5 i farmaceutski prihvatljivog nositelja. The present invention also provides a pharmaceutical composition for the treatment of diseases or conditions that can be alleviated by inhibition of cdk5 activity in mammals, comprising a compound of formula 1 in an amount effective to inhibit cdk5 activity and a pharmaceutically acceptable carrier.

Ovaj izum također omogućuje i postupak tretmana bolesti ili stanja koja se mogu olakšati inhibicijom aktivnosti cdk5 u sisavaca, a koji uključuje davanje spoja formule 1 rečenom sisavcu u količini učinkovitoj za inhibiciju aktivnosti cdk5. The present invention also provides a method of treating a disease or condition that can be alleviated by inhibiting cdk5 activity in a mammal, which comprises administering a compound of formula 1 to said mammal in an amount effective to inhibit cdk5 activity.

Otkrili smo da se spojevi formule 1 također odlikuju inhibicijskim učinkom spram GSK-3. Prema tome, može se očekivati da su spojevi formule 1 korisni prilikom tretmana bolesti ili stanja na koja se može utjecati ili ih olakšati inhibicijom aktivnosti GSK-3. U bolesti ili stanja na koja se može utjecati ili ih olakšati inhibicijom aktivnosti GSK-3 uključuju se neurodegenerativne bolesti i stanja. Neurodegenerativne bolesti i stanja već su prije navedena, te uključuju, ali se pri tome ne ograničavaju samo na navedene i na primjer Alzheimerovu bolest, Parkinsonovu bolest, Huntingtonovu bolest, amiotrofičnu lateralnu sklerozu, multiplu sklerozu, udar, cerebralnu ishemiju, demenciju povezanu s AIDSom, neurodegeneraciju povezanu s bakterijskom infekcijom, multi-infarktnu demenciju, traumatsku povredu mozga i povredu kralješnične moždine. Prema tome, spojevi formule 1 učinkoviti su prilikom tretmana neurodegenerativnih bolesti i stanja koja se baziraju na aktivnosti i cdk5 i GSK-3. We found that the compounds of formula 1 are also characterized by an inhibitory effect against GSK-3. Accordingly, the compounds of formula 1 may be expected to be useful in the treatment of diseases or conditions that can be affected or alleviated by inhibition of GSK-3 activity. Diseases or conditions that may be affected or alleviated by inhibition of GSK-3 activity include neurodegenerative diseases and conditions. Neurodegenerative diseases and conditions have been previously mentioned and include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, cerebral ischemia, AIDS-related dementia, bacterial infection-related neurodegeneration, multi-infarct dementia, traumatic brain injury and spinal cord injury. Therefore, the compounds of formula 1 are effective in the treatment of neurodegenerative diseases and conditions based on the activity of both cdk5 and GSK-3.

U ostale bolesti i stanja na koja je moguće utjecati ili ih olakšati inhibicijom GSK-3 uključuju se psihotički poremećaji i stanja, na primjer shizofrenija, shizofreni poremećaj; shizoafektivni poremećaj, na primjer paranoidnog tipa ili depresivnog tipa; paranoidni poremećaj; psihotički poremećaji uzrokovani uzimanjem supstancija, na primjer psihoze uzrokovane alkoholom, amfetaminom, kanabisom, kokainom, halucinogenima, inhalantima, opijatima ili fenciklidinom; poremećaji ličnosti paranoidnog tipa; poremećaji ličnosti shizoidnog oblika. Na tretman takvih bolesti i stanja moguće je utjecati ili ga pak olakšati i mijenjanjem dopaminom posredovane neurotransmisije. Prema tome, spojevi formule 1 učinkoviti su prilikom tretmana takvih poremećaja i stanja koja se baziraju na aktivnosti i cdk5 i GSK-3. Other diseases and conditions that can be affected or alleviated by GSK-3 inhibition include psychotic disorders and conditions, for example schizophrenia, schizophrenic disorder; schizoaffective disorder, for example paranoid type or depressive type; paranoid disorder; psychotic disorders caused by substance use, for example psychosis caused by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opiates or phencyclidine; personality disorders of the paranoid type; schizoid personality disorders. The treatment of such diseases and conditions can be influenced or facilitated by changing dopamine-mediated neurotransmission. Therefore, the compounds of formula 1 are effective in the treatment of such disorders and conditions that are based on the activity of both cdk5 and GSK-3.

U ostale poremećaje i stanja na koja je moguće utjecati ili ih olakšati inhibicijom GSK-3 uključuju se poremećaji raspoloženja i epizode raspoloženja, na primjer, teške depresivne epizode, manične epizode ili epizode promjenjivog ponašanja, epizode hipomaničnog ponašanja, depresivne epizode s netipičnim obilježjima ili s melankoličnim obilježjima ili pak s katatonim obilježjima, epizode poslijeporođajne osjetljivosti, depresije nakon udara, teški depresivni poremećaj, distimija, blagi depresivni poremećaj, predmenstruacijski sindrom, shizofreni post-psihotični depresivni poremećaj, teški depresivni poremećaj nadograđen na psihotički poremećaj, kao što je to paranoidni poremećaj ili shizofrenija, bipolarni poremećaj, na primjer bipolarni poremećaj I, bipolarni poremećaj II i ciklotimija. Na tretman takvih epizoda i poremećaja raspoloženja, kao što je to depresija, moguće je utjecati ili ga pak olakšati mijenjanjem dopaminom posredovane neurotransmisije. Prema tome, spojevi formule 1 učinkoviti su prilikom tretmana određenih epizoda i poremećaja raspoloženja, a koja se baziraju na aktivnosti i cdk5 i GSK-3. Other disorders and conditions that may be affected or alleviated by GSK-3 inhibition include mood disorders and mood episodes, for example, major depressive episodes, manic episodes or fluctuating behavior episodes, hypomanic behavior episodes, depressive episodes with atypical features or with with melancholic features or with catatonic features, episodes of postpartum sensitivity, post-stroke depression, major depressive disorder, dysthymia, mild depressive disorder, premenstrual syndrome, schizophrenia, post-psychotic depressive disorder, major depressive disorder superimposed on a psychotic disorder, such as paranoid disorder or schizophrenia, bipolar disorder, for example bipolar I disorder, bipolar II disorder and cyclothymia. Treatment of such episodes and mood disorders, such as depression, can be influenced or facilitated by altering dopamine-mediated neurotransmission. Therefore, the compounds of formula 1 are effective in the treatment of certain episodes and mood disorders, which are based on the activity of both cdk5 and GSK-3.

U ostale bolesti i stanja na koja je moguće utjecati ili ih olakšati inhibicijom GSK-3 uključuju se muška neplodnost i poremećaj pokretljivosti spermija; diabetes melitus; smanjenje tolerancije spram glukoze; metabolički sindrom ili sindrom X; sindrom policističkog jajnika; lipogeneza i pretilost; miogeneza i tjelesna slabost, na primjer opadanje fizičkih sposobnosti povezano sa starenjem; akutna atrofija, na primjer atrofija mišića i/ili kaheksija povezana s opekotinama, ležanjem u krevetu, imobilizacijom udova ili s obimnim operacijama prsnog koša, abdomena i/ili ortopedskim operacijama; sepsa; povreda kralješnične moždine; opadanje kose, stanjivanje kose i ćelavost; imunodeficijencija i kancer. Other diseases and conditions that can be affected or alleviated by GSK-3 inhibition include male infertility and sperm motility disorders; diabetes mellitus; reduction of glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; myogenesis and physical weakness, for example age-related decline in physical abilities; acute atrophy, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; spinal cord injury; hair loss, hair thinning and baldness; immunodeficiency and cancer.

Prema tome, ovaj izum također omogućuje farmaceutski pripravak namijenjen tretmanu bolesti i stanja u sisavaca, uključujući i ljude, gdje su rečene bolesti i stanja odabrane između muške neplodnosti i poremećaja pokretljivosti spermija; diabetes melitusa; poremećene regulacije glukoze; metaboličkog sindroma ili sindroma X; sindroma policističkog jajnika; lipogeneze i pretilosti; miogeneze i tjelesne slabosti, na primjer opadanja fizičkih sposobnosti povezanog sa starenjem; akutne atrofije, na primjer atrofije mišića i/ili kaheksije povezane s opekotinama, ležanjem u krevetu, imobilizacijom udova ili s obimnim operacijama prsnog koša, abdomena i/ili ortopedskim operacijama; sepse; opadanja kose, stanjivanja kose i ćelavosti; imunodeficijencije, gdje rečeni pripravak sadrži farmaceutski prihvatljivog nositelja i spoj formule 1 u količini učinkovitoj za tretman rečenih bolesti i stanja. Accordingly, the present invention also provides a pharmaceutical composition for the treatment of diseases and conditions in mammals, including humans, wherein said diseases and conditions are selected from male infertility and sperm motility disorders; diabetes mellitus; impaired glucose regulation; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; myogenesis and physical weakness, for example the decline of physical abilities associated with aging; acute atrophy, for example muscle atrophy and/or cachexia associated with burns, bed rest, immobilization of limbs or extensive thoracic, abdominal and/or orthopedic surgery; sepsis; hair loss, hair thinning and baldness; immunodeficiency, where said preparation contains a pharmaceutically acceptable carrier and a compound of formula 1 in an amount effective for the treatment of said diseases and conditions.

Ovaj izum, nadalje, omogućuje farmaceutski pripravak namijenjen tretmanu bolesti i stanja u sisavaca, uključujući i ljude, gdje su rečene bolesti i stanja odabrani između muške neplodnosti i poremećaja pokretljivosti spermija; diabetes melitusa; poremećene regulacije glukoze; metaboličkog sindroma ili sindroma X; sindroma policističkog jajnika; lipogeneze i pretilosti; miogeneze i tjelesne slabosti, na primjer opadanja fizičkih sposobnosti povezanog sa starenjem, akutne atrofije, na primjer atrofije mišića i/ili kaheksije povezana s opekotinama, ležanjem u krevetu, imobilizacijom udova ili s obimnim operacijama prsnog koša, abdomena i/ili ortopedskim operacijama; sepse; opadanja kose, stanjivanja kose i ćelavosti; te imunodeficijencije, gdje rečeni pripravak sadrži farmaceutski prihvatljivog nositelja i spoj formule 1 u količini učinkovitoj za inhibiciju GSK-3. The present invention further provides a pharmaceutical composition for the treatment of diseases and conditions in mammals, including humans, wherein said diseases and conditions are selected from male infertility and sperm motility disorders; diabetes mellitus; impaired glucose regulation; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; myogenesis and physical weakness, for example age-related decline in physical abilities, acute atrophy, for example muscle atrophy and/or cachexia associated with burns, bed rest, immobilization of limbs or extensive thoracic, abdominal and/or orthopedic surgery; sepsis; hair loss, hair thinning and baldness; and immunodeficiency, where said preparation contains a pharmaceutically acceptable carrier and a compound of formula 1 in an amount effective for inhibiting GSK-3.

Ovaj izum, također, omogućuje i postupak tretmana bolesti i stanja u sisavaca, uključujući i ljude, gdje su rečene bolesti i stanja odabrane između muške neplodnosti i poremećaja pokretljivosti spermija; diabetes melitusa; poremećene regulacije glukoze; metaboličkog sindroma ili sindroma X; sindroma policističkog jajnika; lipogeneze i pretilosti; miogeneze i tjelesne slabosti, na primjer opadanja fizičkih sposobnosti povezanog sa starenjem; akutne atrofije, na primjer atrofije mišića i/ili kaheksije povezane s opekotinama, ležanjem u krevetu, imobilizacijom udova ili s obimnim operacijama prsnog koša, abdomena i/ili ortopedskim operacijama; sepse; opadanja kose, stanjivanja kose i ćelavosti; te imunodeficijencije, gdje rečeni postupak uključuje davanje spoja formule 1 rečenom sisavcu u količini učinkovitoj za tretman rečenih bolesti i stanja. This invention also provides a method of treating diseases and conditions in mammals, including humans, where said diseases and conditions are selected from male infertility and sperm motility disorders; diabetes mellitus; impaired glucose regulation; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; myogenesis and physical weakness, for example the decline of physical abilities associated with aging; acute atrophy, for example muscle atrophy and/or cachexia associated with burns, bed rest, immobilization of limbs or extensive thoracic, abdominal and/or orthopedic surgery; sepsis; hair loss, hair thinning and baldness; and immunodeficiency, wherein said method includes administering a compound of formula 1 to said mammal in an amount effective for the treatment of said diseases and conditions.

Ovaj izum, također, omogućuje i postupak tretmana bolesti i stanja u sisavaca, uključujući i ljude, gdje su rečene bolesti i stanja odabrane između muške neplodnosti i poremećaja pokretljivosti spermija; diabetes melitusa; poremećene regulacije glukoze; metaboličkog sindroma ili sindroma X; sindroma policističkog jajnika; lipogeneze i pretilosti; miogeneze i tjelesne slabosti, na primjer opadanja fizičkih sposobnosti povezanog sa starenjem; akutne atrofije, na primjer atrofije mišića i/ili kaheksije povezane s opekotinama, ležanjem u krevetu, imobilizacijom udova ili s obimnim operacijama prsnog koša, abdomena i/ili ortopedskim operacijama; sepse; opadanja kose, stanjivanja kose i ćelavosti, te imunodeficijencije, gdje rečeni postupak uključuje davanje spoja formule 1 rečenom sisavcu u količini učinkovitoj za inhibiciju GSK-3. This invention also provides a method of treating diseases and conditions in mammals, including humans, where said diseases and conditions are selected from male infertility and sperm motility disorders; diabetes mellitus; impaired glucose regulation; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; myogenesis and physical weakness, for example the decline of physical abilities associated with aging; acute atrophy, for example muscle atrophy and/or cachexia associated with burns, bed rest, immobilization of limbs or extensive thoracic, abdominal and/or orthopedic surgery; sepsis; hair loss, hair thinning and baldness, and immunodeficiency, wherein said method comprises administering a compound of formula 1 to said mammal in an amount effective to inhibit GSK-3.

Ovaj izum, također, omogućuje i postupak za inhibiciju GSK-3 u sisavaca, uključujući i ljude, gdje rečeni postupak uključuje davanje spoja formule 1 rečenom sisavcu u količini učinkovitoj za inhibiciju GSK-3. The present invention also provides a method for inhibiting GSK-3 in a mammal, including humans, wherein said method comprises administering to said mammal a compound of formula 1 in an amount effective to inhibit GSK-3.

Ovaj izum, nadalje, omogućuje i farmaceutski pripravak namijenjen tretmanu poremećaja u sisavaca, gdje su rečeni poremećaji odabrani između Alzheimerove bolesti, blagog kognitivnog poremećaja i kognitivnog poremećaja povezanog sa starošću, gdje rečeni pripravak sadrži inhibitore aktivnosti cdk5 i COX-II u količinama učinkovitima za tretman rečenih poremećaja i farmaceutski prihvatljivog nositelja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. The present invention further provides a pharmaceutical composition intended for the treatment of disorders in mammals, wherein said disorders are selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitive impairment, wherein said composition contains inhibitors of cdk5 and COX-II activity in amounts effective for treatment said disorders and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana poremećaja u sisavaca, gdje su rečeni poremećaji odabrani između Alzheimerove bolesti, blagog kognitivnog poremećaja i kognitivnog poremećaja povezanog sa starošću, gdje rečeni postupak uključuje davanje inhibitora aktivnosti cdk5 i COX-II rečenom sisavcu u količinama učinkovitima za tretman rečenih poremećaja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitori cdk5 i COX-II mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, ti se inhibitori mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. The present invention further provides a method of treating disorders in mammals, wherein said disorders are selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitive impairment, wherein said method comprises administering to said mammal an inhibitor of cdk5 and COX-II activity in amounts effective for treatment of said disorders. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 and COX-II inhibitors can be administered to the mammal simultaneously and/or separately. Additionally, these inhibitors can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Nadalje, inhibitor cdk5, na primjer spoj formule 1 prema ovom izumu ili njegova farmaceutski prihvatljiva sol, mogu se prirediti ili uzimati u obliku farmaceutskog pripravka koji sadrži i jednu ili više antidepresivnih tvari ili pak anksiolitika namijenjenih tretmanu ili prevenciji depresija i/ili anksioznosti. Furthermore, a cdk5 inhibitor, for example a compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof, can be prepared or taken in the form of a pharmaceutical preparation containing one or more antidepressant substances or anxiolytics intended for the treatment or prevention of depression and/or anxiety.

Prema tome, ovaj izum omogućuje i farmaceutski pripravak namijenjen tretmanu depresije ili anksioznosti u sisavaca, gdje rečeni pripravak sadrži inhibitor cdk5 i antagonista receptora NK-1 u količinama učinkovitima za tretman depresije ili anksioznosti i farmaceutski prihvatljivog nositelja. U jednom uobličenju cdk5 inhibitor jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Therefore, this invention also provides a pharmaceutical preparation intended for the treatment of depression or anxiety in mammals, where said preparation contains a cdk5 inhibitor and an NK-1 receptor antagonist in amounts effective for the treatment of depression or anxiety and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana depresije ili anksioznosti u sisavaca, gdje rečeni postupak uključuje davanje inhibitora cdk5 i antagonista receptora NK-1 rečenom sisavcu u količinama učinkovitima za tretman depresije ili anksioznosti. U jednom uobličenju cdk5 inhibitor jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitori cdk5 i antagonist receptora NK-1 mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, ti se inhibitori mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. This invention further provides a method of treating depression or anxiety in a mammal, wherein said method includes administering a cdk5 inhibitor and an NK-1 receptor antagonist to said mammal in amounts effective for treating depression or anxiety. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitors and the NK-1 receptor antagonist can be administered to the mammal simultaneously and/or separately. Additionally, these inhibitors can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Ovaj izum omogućuje i farmaceutski pripravak namijenjen tretmanu depresije ili anksioznosti u sisavaca, gdje rečeni pripravak sadrži inhibitore cdk5 i antagonista receptora 5HT1D u količinama učinkovitima za tretman depresije ili anksioznosti i farmaceutski prihvatljivog nositelja. U jednom uobličenju cdk5 inhibitor jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. This invention also provides a pharmaceutical preparation intended for the treatment of depression or anxiety in mammals, where said preparation contains cdk5 inhibitors and 5HT1D receptor antagonists in amounts effective for the treatment of depression or anxiety and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana depresije ili anksioznosti u sisavaca, gdje rečeni postupak uključuje davanje inhibitora cdk5 i antagonista receptora 5HT1D rečenom sisavcu u količinama učinkovitima za tretman depresije ili anksioznosti. U jednom uobličenju cdk5 inhibitor jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitori cdk5 i antagonist receptora 5HT1D mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, ti se inhibitori mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. This invention further provides a method of treating depression or anxiety in a mammal, wherein said method includes administering a cdk5 inhibitor and a 5HT1D receptor antagonist to said mammal in amounts effective for treating depression or anxiety. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitors and the 5HT1D receptor antagonist can be administered to the mammal simultaneously and/or separately. Additionally, these inhibitors can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Ovaj izum omogućuje i farmaceutski pripravak namijenjen tretmanu depresije ili anksioznosti u sisavaca, gdje rečeni pripravak sadrži inhibitor cdk5 i SSRI u količinama učinkovitima za tretman depresije ili anksioznosti i farmaceutski prihvatljivog nositelja. U jednom uobličenju cdk5 inhibitor jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. This invention also provides a pharmaceutical preparation intended for the treatment of depression or anxiety in mammals, where said preparation contains a cdk5 inhibitor and an SSRI in amounts effective for the treatment of depression or anxiety and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana depresije ili anksioznosti u sisavaca, gdje rečeni postupak uključuje davanje inhibitora cdk5 i SSRI rečenom sisavcu u količinama učinkovitima za tretman depresije ili anksioznosti. U jednom uobličenju cdk5 inhibitor jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitor cdk5 i SSRI mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, ti se inhibitori mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. This invention further provides a method of treating depression or anxiety in a mammal, wherein said method includes administering a cdk5 inhibitor and an SSRI to said mammal in amounts effective to treat depression or anxiety. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and SSRI can be administered to the mammal simultaneously and/or separately. Additionally, these inhibitors can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Ovaj izum također omogućuje i farmaceutski pripravak namijenjen tretmanu shizofrenije u sisavaca, gdje rečeni pripravak sadrži inhibitor cdk5 i antipsihotik odabran između ziprazidona, olanzapina, risperidona, L-745870, sonepiprazola, RP 62203, NGD 941, balaperidona, flezinoksana i gepirona u količinama učinkovitima za tretman shizofrenije i farmaceutski prihvatljivog nositelja. U jednom uobličenju cdk5 inhibitor jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. This invention also provides a pharmaceutical composition intended for the treatment of schizophrenia in mammals, wherein said composition contains a cdk5 inhibitor and an antipsychotic selected from ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan and gepirone in amounts effective for treatment of schizophrenia and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum također omogućuje i postrupak tretmana shizofrenije u sisavaca, gdje rečeni postupak uključuje davanje, rečenom sisavcu, inhibitora cdk5 i antipsihotika odabranog između ziprazidona, olanzapina, risperidona, L-745870, sonepiprazola, RP 62203, NGD 941, balaperidona, flezinoksana i gepirona u količinama učinkovitima za tretman shizofrenije. U jednom uobličenju cdk5 inhibitor jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitor cdk5 i antipsihotik mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, te se tvari mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. The present invention also provides a method of treating schizophrenia in a mammal, wherein said method includes administering to said mammal a cdk5 inhibitor and an antipsychotic selected from ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxan and gepirone in in amounts effective for the treatment of schizophrenia. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the antipsychotic can be administered to the mammal simultaneously and/or separately. Additionally, these substances can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Ovaj izum, nadalje, omogućuje i farmaceutski pripravak namijenjen tretmanu poremećaja u sisavaca, gdje su rečeni poremećaji odabrani između Alzheimerove bolesti, blagog kognitivnog poremećaja kognitivnog poremećaja povezanog sa starošću, gdje rečeni pripravak sadrži inhibitore aktivnosti cdk5 i acetilkolinesteraze u količinama učinkovitima za tretman rečenih poremećaja i farmaceutski prihvatljivog nositelja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. This invention further provides a pharmaceutical composition intended for the treatment of disorders in mammals, where said disorders are selected from Alzheimer's disease, mild cognitive impairment, age-related cognitive disorder, wherein said composition contains inhibitors of cdk5 and acetylcholinesterase activity in amounts effective for the treatment of said disorders and pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana poremećaja u sisavaca, gdje su rečeni poremećaji odabrani između Alzheimerove bolesti, blagog kognitivnog poremećaja i kognitivnog poremećaja povezanog sa starošću, gdje rečeni postupak uključuje davanje inhibitora aktivnosti cdk5 i acetilkolinesteraze rečenom sisavcu u količinama učinkovitima za tretman rečenih poremećaja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitori cdk5 i acetilkolinesteraze mogu se davati sisavcu istovremeno i/ili odvojeno. This invention further provides a method of treating disorders in mammals, wherein said disorders are selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitive impairment, wherein said method includes administering to said mammal an inhibitor of cdk5 and acetylcholinesterase activity in amounts effective to treat said disorders. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 and acetylcholinesterase inhibitors can be administered to the mammal simultaneously and/or separately.

Ovaj izum također omogućuje i farmaceutski pripravak namijenjen tretmanu bolesti i stanja u sisavaca, gdje su rečene bolesti i stanja odabrane između udara, povrede kralješnične moždine, traumatske povrede mozga, multi-infarktne demencije, epilepsije, bola, Alzheimerove bolesti, senilne demencije, gdje rečeni pripravak sadrži inhibitor aktivnosti cdk5 i TPA (aktivator tkivnog plazminogena, na primjer ACTIVASE) u količinama učinkovitima za tretman rečenih bolesti ili stanja i farmaceutski prihvatljivog nositelja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. This invention also provides a pharmaceutical composition intended for the treatment of diseases and conditions in mammals, where said diseases and conditions are selected from stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, senile dementia, where said the composition contains an inhibitor of cdk5 activity and TPA (tissue plasminogen activator, for example ACTIVASE) in amounts effective for the treatment of said diseases or conditions and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana bolesti ili stanja u sisavaca, gdje su rečene bolesti i stanja odabrane između udara, povrede kralješnične moždine, traumatske povrede mozga, multi-infarktne demencije, epilepsije, bola, Alzheimerove bolesti, senilne demencije, gdje rečeni postupak uključuje davanje inhibitora aktivnosti cdk5 i TPA rečenom sisavcu u količinama učinkovitima za tretman rečenih poremećaja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitor cdk5 i TPA mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, te se tvari mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. This invention, furthermore, enables a method of treating diseases or conditions in mammals, where said diseases and conditions are selected from stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, senile dementia, where said the method includes administering an inhibitor of cdk5 activity and TPA to said mammal in amounts effective to treat said disorders. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and TPA can be administered to the mammal simultaneously and/or separately. Additionally, these substances can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Ovaj izum, također, omogućuje i farmaceutski pripravak namijenjen tretmanu bolesti ili stanja u sisavaca, gdje su rečene bolesti ili stanja odabrane između udara, povrede kralješnične moždine, traumatske povrede mozga, multi-infarktne demencije, epilepsije, bola, Alzheimerove bolesti, senilne demencije, gdje rečeni pripravak sadrži inhibitor aktivnosti cdk5 i NIF (inhibicijski faktor neutrofila) u količinama učinkovitima za tretman rečenih bolesti ili stanja i farmaceutski prihvatljivog nositelja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. This invention also provides a pharmaceutical preparation intended for the treatment of diseases or conditions in mammals, where said diseases or conditions are selected from among stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, senile dementia, wherein said preparation contains an inhibitor of cdk5 activity and NIF (neutrophil inhibitory factor) in amounts effective for the treatment of said diseases or conditions and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana bolesti ili stanja u sisavaca, gdje su rečene bolesti ili stanja odabrane između udara, povrede kralješnične moždine, traumatske povrede mozga, multi-infarktne demencije, epilepsije, bola, Alzheimerove bolesti, senilne demencije, gdje rečeni postupak uključuje davanje inhibitora aktivnosti cdk5 i NIF rečenom sisavcu u količinama učinkovitima za tretman rečenih bolesti ili stanja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitor cdk5 i NIF mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, te se tvari mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. This invention also provides a method of treating diseases or conditions in mammals, where said diseases or conditions are selected from stroke, spinal cord injury, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease, senile dementia, where said the method includes administering an inhibitor of cdk5 and NIF activity to said mammal in amounts effective to treat said diseases or conditions. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and NIF can be administered to the mammal simultaneously and/or separately. Additionally, these substances can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Ovaj izum, također, omogućuje i farmaceutski pripravak namijenjen tretmanu bolesti i stanja u sisavaca, gdje su rečene bolesti i stanja odabrani između Huntingtonove bolesti, udara, traume kralješnične moždine, trumatske povrede mozga, multi-infarktne demencije, epilepsije, amiotrofične lateralne skleroze, bola, demecije izazvane virusnim putem, na primjer demencija uzrokovana AIDSom, migrene, hipoglikemije, urinarne inkontinencije, ishemije mozga, multiple skleroze, Alzheimerove bolesti, senilne demencije Alzheimerova tipa, blagog kognitivnog poremećaja, kognitivnog poremećaja povezanog sa starošću, povraćanja, kortikobazalne degeneracije, demencije pugilistica, Downovog sindroma, miotonične distrofije, Niemann-Pickove bolesti, Pickove bolesti, prionske bolesti s plakovima, progresivne supranuklearne paralize, donje lateralne skleroze i subakutnog sklerozantnog leukoencefalitisa, gdje rečeni pripravak sadrži inhibitor aktivnosti cdk5 i antogonista NMDA receptora u količinama učinkovitima za tretman rečenih poremećaja i farmaceutski prihvatljivog nositelja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. This invention also provides a pharmaceutical composition intended for the treatment of diseases and conditions in mammals, where said diseases and conditions are selected from Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain , virally induced dementias, for example AIDS dementia, migraines, hypoglycemia, urinary incontinence, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive impairment, age-related cognitive impairment, vomiting, corticobasal degeneration, dementia pugilistica , Down syndrome, myotonic dystrophy, Niemann-Pick disease, Pick disease, prion disease with plaques, progressive supranuclear palsy, inferior lateral sclerosis and subacute sclerosing leukoencephalitis, where said preparation contains an inhibitor of cdk5 activity and an NMDA receptor antagonist in effective amounts has a pharmaceutically acceptable carrier for the treatment of said disorders. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana bolesti ili stanja u sisavaca, gdje su rečene bolesti ili stanja odabrani između Huntingtonove bolesti, udara, traume kralješnične moždine, trumatske povrede mozga, multi-infarktne demencije, epilepsije, amiotrofične lateralne skleroze, bola, demencije izazvane virusnim putem, na primjer demencija uzrokovana AIDSom, migrene, hipoglikemije, urinarne inkontinencije, ishemije mozga, multiple skleroze, Alzheimerove bolesti, senilne demencije Alzheimerova tipa, blagog kognitivnog poremećaja, kognitivnog poremećaja povezanog sa starošću, povraćanja, kortikobazalne degeneracije, demencije pugilistica, Downovog sindroma, miotonične distrofije, Niemann-Pickove bolesti, Pickove bolesti, prionske bolesti s plakovima, progresivne supranuklearne paralize, donje lateralne skleroze i subakutnog sklerozantnog leukoencefalitisa, gdje rečeni postupak uključuje davanje inhibitora aktivnosti cdk5 i antagonista NMDA receptora rečenom sisavcu u količinama učinkovitima za tretman rečenih bolesti ili stanja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitor cdk5 i antagonist NMDA receptora mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, te se tvari mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. This invention further provides a method of treating a disease or condition in a mammal, wherein said disease or condition is selected from Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, dementia caused by a virus, for example dementia caused by AIDS, migraine, hypoglycemia, urinary incontinence, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive impairment, age-related cognitive impairment, vomiting, corticobasal degeneration, dementia pugilistica, Down's syndrome, myotonic dystrophy, Niemann-Pick disease, Pick disease, prion disease with plaques, progressive supranuclear palsy, inferior lateral sclerosis and subacute sclerosing leukoencephalitis, wherein said method comprises administering to said mammal an inhibitor of cdk5 activity and an NMDA receptor antagonist in amounts of effective for the treatment of said diseases or conditions. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the NMDA receptor antagonist can be administered to the mammal simultaneously and/or separately. Additionally, these substances can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Ovaj izum, također, omogućuje i farmaceutski pripravak namijenjen tretmanu bolesti ili stanja u sisavaca, gdje su rečene bolesti ili stanja odabrani između udara, traume kralješnične moždine, trumatske povrede mozga, multi-infarktne demencije, epilepsije, bola, Alzheimerove bolesti i senilne demencije, gdje rečeni pripravak sadrži inhibitor aktivnosti cdk5 i modulator kalijevih kanala u količinama učinkovitima za tretman rečenih poremećaja i farmaceutski prihvatljivog nositelja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. This invention also provides a pharmaceutical composition intended for the treatment of a disease or condition in a mammal, wherein said disease or condition is selected from stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia, wherein said preparation contains an inhibitor of cdk5 activity and a potassium channel modulator in amounts effective for the treatment of said disorders and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Ovaj izum, nadalje, omogućuje i postupak tretmana bolesti ili stanja u sisavaca, gdje su rečene bolesti ili stanja odabrani između udara, traume kralješnične moždine, trumatske povrede mozga, multi-infarktne demencije, epilepsije, bola, Alzheimerove bolesti i senilne demencije, gdje rečeni postupak uključuje davanje inhibitora aktivnosti cdk5 i modulatora kalijevih kanala rečenom sisavcu u količinama učinkovitima za tretman rečenih bolesti ili stanja. U jednom uobličenju inhibitor cdk5 jest spoj formule 1 ili njegova farmaceutski prihvatljiva sol. Inhibitor cdk5 i modulator kalijevih kanala mogu se davati sisavcu istovremeno i/ili odvojeno. Dodatno, te se tvari mogu uzeti u obliku jedinstvenog farmaceutskog pripravka ili pak u obliku odvojenih farmaceutskih pripravaka. This invention further provides a method of treating diseases or conditions in mammals, where said diseases or conditions are selected from among stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia, where said the method includes administering an inhibitor of cdk5 activity and a potassium channel modulator to said mammal in amounts effective to treat said diseases or conditions. In one embodiment, the cdk5 inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the potassium channel modulator can be administered to the mammal simultaneously and/or separately. Additionally, these substances can be taken in the form of a single pharmaceutical preparation or in the form of separate pharmaceutical preparations.

Pojmovi “tretman”, “tretirati” i sl. odnose se na izlječenje, ublažavanje ili usporavanje napredovanja onih bolesti ili stanja ili pak jednog ili više simptoma tih bolesti ili stanja na koja se ti pojmovi odnose. Ovi pojmovi, kako su ovdje korišteni, ovisno o stanju pacijenta također uključuju i sprječavanje pojave bolesti ili stanja ili pak simptoma povezanih s tom bolesti ili stanjem, uključujući smanjenje težine bolesti ili stanja ili pak s njima povezanih simptoma prije razvoja rečene bolesti ili stanja. Ovakva prevencija ili smanjenje težine prije razvoja bolesti odnosi se na davanje spoja prema ovom izumu subjektu u kojeg u vrijeme uzimanja spoja nije još došlo do razvoja bolesti ili stanja. Pojam “prevencija” također uključuje i prevenciju ponovnog izbijanja bolesti ili stanja ili pak s njima povezanih simptoma. The terms "treatment", "treat", etc. refer to curing, alleviating or slowing down the progress of those diseases or conditions or one or more symptoms of those diseases or conditions to which these terms refer. These terms, as used herein, depending on the patient's condition, also include preventing the onset of a disease or condition or symptoms associated with that disease or condition, including reducing the severity of the disease or condition or associated symptoms prior to the development of said disease or condition. Such prevention or weight reduction before the development of a disease refers to the administration of the compound according to the present invention to a subject in whom the disease or condition has not yet developed at the time of taking the compound. The term "prevention" also includes the prevention of the recurrence of a disease or condition or the symptoms associated with them.

Pojam “sisavac”, kako je ovdje korišten i ukoliko nije drugačije navedeno, odnosi se na bilo kojeg sisavca. U pojam “sisavca” uključuju se, na primjer i bez ograničenja samo na navedene, psi, mačke i ljudi. The term "mammal", as used herein and unless otherwise specified, refers to any mammal. The term "mammal" includes, for example and without limitation, dogs, cats and humans.

Pojam “nenormalni rast stanica”, kako je ovdje korišten, odnosi se na rast stanica koji je neovisan o uobičajenom mehanizmu kontrole rasta (npr. gubitak kontaktne inhibicije) i uključuje maligni rast (npr. kao kod kancera) ili benigni rast. Primjeri benignih proliferatnih bolesti su psorijaza, benigna hipertrofija prostate, humani papilo virus (HPV) i restenoza. The term "abnormal cell growth", as used herein, refers to cell growth that is independent of normal growth control mechanisms (eg, loss of contact inhibition) and includes malignant growth (eg, as in cancer) or benign growth. Examples of benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papillomavirus (HPV) and restenosis.

Pojam “neurodegenerativne bolesti i stanja”, kako je ovdje korišten, odnosi se na bolesti i stanja povezana s degeneracijom neurona. Stanja i bolesti koja su u svojoj osnovi neurodegenerativna općenito su poznata stručnjaku na području. The term "neurodegenerative diseases and conditions", as used herein, refers to diseases and conditions associated with the degeneration of neurons. Conditions and diseases that are neurodegenerative in nature are generally known to a person skilled in the art.

U odnosu na bolesti i stanja, pojam “tretman na koji se može utjecati ili ga poboljšati promjenom neurotransmisije posredovane dopaminom” odnosi se na bolesti ili stanja koja su barem djelomice uzrokovana dopaminskom neurotransmisijom, ili pak na stanja ili bolesti koja uzrokuju nenormalnu dopaminsku neurotransmisiju, čime ova pojava doprinosi simptomima i ispoljavanju bolesti ili stanja. In relation to diseases and conditions, the term "treatment that can be affected or improved by altering dopamine-mediated neurotransmission" refers to diseases or conditions that are at least partially caused by dopamine neurotransmission, or to conditions or diseases that cause abnormal dopamine neurotransmission, thereby this phenomenon contributes to the symptoms and manifestation of the disease or condition.

U odnosu na bolesti i stanja, pojam “tretman na koji se može utjecati ili ga poboljšati smanjenjem aktivnosti cdk5” odnosi se na bolesti ili stanja koja su barem djelomice uzrokovana aktivnošću cdk5, ili pak na stanja ili bolesti koja uzrokuju nenormalnu aktivnost cdk5, čime ova pojava doprinosi simptomima i ispoljavanju bolesti ili stanja. In relation to diseases and conditions, the term "treatment that can be affected or improved by reducing cdk5 activity" refers to diseases or conditions that are at least partially caused by cdk5 activity, or to conditions or diseases that cause abnormal cdk5 activity, whereby this occurrence contributes to the symptoms and manifestation of the disease or condition.

Pojam “količina učinkovita za inhibiciju aktivnosti cdk5”, kako je ovdje korišten, odnosi se na količinu spoja dostatnu za vezanje spoja na enzim cdk5, čime se smanjuje aktivnost cdk5. The term "amount effective to inhibit cdk5 activity", as used herein, refers to an amount of a compound sufficient to bind the compound to the cdk5 enzyme, thereby reducing cdk5 activity.

Pojam “količina učinkovita za inhibiciju aktivnosti cdk2”, kako je ovdje korišten, odnosi se na količinu spoja dostatnu za vezanje spoja na enzim cdk2, čime se smanjuje aktivnost cdk2. The term "amount effective to inhibit cdk2 activity", as used herein, refers to an amount of a compound sufficient to bind the compound to the cdk2 enzyme, thereby reducing cdk2 activity.

Detaljan opis izuma Detailed description of the invention

Gore opisani spojevi formule 1 i njihove farmaceutski prihvatljive soli mogu se prirediti na načine opisane u dolje danim shemama i raspravi. Osim ukoliko nije drugačije navedeno R1, R2, R3 i R4 jesu kako je to gore definirano. Izolacija i pročišćavanje produkata provodi se uobičajenim postupcima poznatima prosječno obrazovanom kemičaru. The compounds of formula 1 described above and their pharmaceutically acceptable salts can be prepared by the methods described in the schemes and discussion below. Unless otherwise stated R1, R2, R3 and R4 are as defined above. Isolation and purification of the products is carried out by the usual procedures known to an average educated chemist.

Kako je ovdje korišten, pojam “inertno reakcijsko otapalo” odnosi se na sustav otapala u kojem komponente ne reagiraju s polaznim materijalom, reagensima ili međuproduktima na način koji bi bespovratno utjecao na iskorištenje željenog produkta. As used herein, the term "inert reaction solvent" refers to a solvent system in which the components do not react with the starting material, reagents or intermediates in a manner that would irreversibly affect the recovery of the desired product.

Tijekom bilo kojeg, dolje navedenog, sintetskog koraka može biti potrebno i/ili poželjno zaštititi osjetljive ili reaktivne skupine na bilo kojoj molekuli. To se može postići upotrebom uobičajenih zaštitnih skupina, kao što su to one opisane u T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; i T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991. During any synthetic step listed below, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule. This can be accomplished by using conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991.

Shema 1 prikazuje pogodne postupke priprave spojeva formule 1 za koje R3 jest –C(=O)NH–, –C(=O)O– ili –C(=O)(CR10R11)n–. Prema shemi 1 reakcijom 1,4-dinitroimidazola (J. Phys. Chem. (1995) Vol. 99, str. 5009-5015) i primarnog alkila ili aril amina u dimetilsulfoksidu (DMSO), sustavu otapala piridin-voda, vodi, sustavu otapala acetonitril-voda, alkoholu ili sustavu otapala alkohol-voda, poželjno je da to bude niži alkohol kao što je to metanol, pri temperaturi od oko –20 °C do oko 50 °C, dok je poželjno da to bude od oko –5 °C do 35 °C, dobivaju se 1-N-supstituiran-4-nitroimidazoli formule 2. 1,4-dinitroimidazol je visoko energetska, nestabilna tvar, te treba biti pohranjen u hladnjaku sve dok se ne koristi. Termodinamička mjerenja pokazala su da ovaj spoj pri 35 °C uz adijabatske uvjete može razviti dovoljno topline da dođe do žestoke eksplozije. Prilikom korištenja ovog spoja potrebna je izuzetna pažnja. Redukcija nitro spoja formule 2 u amin formule 3 može se postići izlaganjem smjese spoja formule 2 i katalizatora plemenitog metala atmosferi vodika pri tlaku od oko 1 do 100 atmosfera, gdje je poželjan tlak vodika od jedne do oko deset atmosfera, u otapalu kao što je to etil acetat, tetrahidrofuran, dioksan ili njihove smjese. Poželjan katalizator je paladijev katalizator. Metal se uobičajeno može suspendirati na inertnom krutom nositelju kao što je to ugljen. Nakon što je završena reakcija spoja formule 2, smjesa se filtrira, a dobiveni amin formule 3 se odmah podvrgne reakciji s kiselinskim kloridom ClC(=O)(CR10R11)nR4, anhidridom (R4(CR10R11)nC(=O))2O ili pak s aktiviranim derivatom karboksilne kiseline XC(=O)(CR10R11)nR4 uz prisustvo baze kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, pri temperaturi od oko –78 °C do 40 °C. Poželjna kombinacija jest ciklički anhidrid propanfosfonske kiseline i trietilamin. Aktivirani derivat karboksilne kiseline priređuje se iz karboksilne kiseline HOC(=O)(CR10R11)nR4 i poznatih aktivirajućih reagensa kao što su to dicikloheksil karbodiimid, 1-(3-dimetilaminopropil)-3-etilkarbodiimid klorid, karbonil diimidazol, 1-ciklički anhidrid propanfosfonske kiseline, alkil ili aril kloroformat, bi(2-okso-3-oksazolidinil)fosfinoil klorid, benzotriazol-1-iloksi-tris(dimetilamino)fosfonijev heksafluorofosfat ili pak bilo koji drugi uobičajeni literaturni reagens. Ovim se postupkom dobiva spoj formule 1B, gdje R3 jest –C(=O)(CR10R11)n–. Scheme 1 shows convenient procedures for the preparation of compounds of formula 1 for which R3 is –C(=O)NH–, –C(=O)O– or –C(=O)(CR10R11)n–. According to Scheme 1 by the reaction of 1,4-dinitroimidazole (J. Phys. Chem. (1995) Vol. 99, pp. 5009-5015) and a primary alkyl or aryl amine in dimethylsulfoxide (DMSO), a pyridine-water solvent system, water, acetonitrile-water solvent, alcohol or an alcohol-water solvent system, preferably a lower alcohol such as methanol, at a temperature of about -20 °C to about 50 °C, while it is preferable that it be from about -5 °C to 35 °C, 1-N-substituted-4-nitroimidazoles of formula 2 are obtained. 1,4-dinitroimidazole is a highly energetic, unstable substance, and should be stored in a refrigerator until it is not used. Thermodynamic measurements have shown that this compound at 35 °C under adiabatic conditions can develop enough heat to cause a violent explosion. Extreme caution is required when using this compound. Reduction of a nitro compound of formula 2 to an amine of formula 3 can be accomplished by exposing a mixture of a compound of formula 2 and a noble metal catalyst to a hydrogen atmosphere at a pressure of about 1 to 100 atmospheres, where a hydrogen pressure of from one to about ten atmospheres is preferred, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or their mixtures. A preferred catalyst is a palladium catalyst. The metal can usually be suspended on an inert solid support such as coal. After the reaction of the compound of formula 2 is completed, the mixture is filtered, and the resulting amine of formula 3 is immediately subjected to a reaction with acid chloride ClC(=O)(CR10R11)nR4, anhydride (R4(CR10R11)nC(=O))2O or with an activated carboxylic acid derivative XC(=O)(CR10R11)nR4 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-dimethylpyridine, at a temperature of about -78 °C to 40 °C. The preferred combination is cyclic anhydride of propanephosphonic acid and triethylamine. The activated carboxylic acid derivative is prepared from the carboxylic acid HOC(=O)(CR10R11)nR4 and known activating reagents such as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide chloride, carbonyl diimidazole, 1-cyclic propanephosphonic anhydride acids, alkyl or aryl chloroformate, bi(2-oxo-3-oxazolidinyl)phosphinoyl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or any other common literature reagent. This procedure gives a compound of formula 1B, where R3 is –C(=O)(CR10R11)n–.

Dodatno, nakon filtracije, amin formule 3 može se podvrgnuti reakciji s alkil- ili aril- kloroformatom uz prisustvo baze kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin pri temperaturi od oko –78 °C do 40 °C, dok je poželjno da to bude –78 °C do –40 °C, čime se dobiva spoj formule 1A, gdje R3 jest –C(=O)O– i R4 je fenil. Poželjna kombinacija je diizopropiletilamin i fenil kloroformat. Dodatnom reakcijom fenil karbamata formule 1A s primarnim ili sekundarnim aminom u otapalu kao što je to dioksan, dimetilformamid ili acetonitril pri temperaturi od oko 40 °C do 90 °C, dobiva se odgovarajući produkt uree 1C, gdje R3 jest –C(=O)NR9– i R4 je fenil ili heteroaril. Poželjno je korištenje 1:1 smjese dioksan-dimetilformamid pri temperaturi od 70 °C. Additionally, after filtration, the amine of formula 3 can be reacted with an alkyl or aryl chloroformate in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-dimethylpyridine at a temperature of about -78°C to 40°C, while it is preferable that it be -78 °C to -40 °C, thereby obtaining the compound of formula 1A, where R3 is -C(=O)O- and R4 is phenyl. The preferred combination is diisopropylethylamine and phenyl chloroformate. Additional reaction of the phenyl carbamate of formula 1A with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile at a temperature of about 40 °C to 90 °C gives the corresponding urea product 1C, where R3 is –C(=O) NR9– and R4 is phenyl or heteroaryl. It is preferable to use a 1:1 dioxane-dimethylformamide mixture at a temperature of 70 °C.

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Postupak dobivanja spojeva formule 1 u kojima je R1 supstituiran s R5 i R5 jest NHC(=O)R8 prikazan je na shemi 2. Reakcijom spoja formule 4, gdje R5 jest OH, s alkil- ili aril-sulfonil kloridom, gdje se prednost daje p-toluensulfonil kloridu (TosCl), u inertnom reakcijskom otapalu, kao što je to tetrahidrofuran, metilen klorid ili kloroform, gdje se prednost daje metilen kloridu, pri temperaturi od oko –10°C do oko 30 °C uz prisustvo baze amina kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, dok je poželjno da to bude trietilamin, te katalitičke količine 4-N,N-dimetilaminopiridina, dobiva se spoj formule 5, gdje R5 jest CH3(C6H4)SO3 (TosO). Reakcijom ovako dobivenog tosilata s azidnom soli alkalijskog metala, gdje se prednost daje natrijevu azidu, u polarnom otapalu kao što je to dimetilformamid, dimetilsulfoksid, niži alkohol, voda ili pak smjesa ovih otapala, gdje se prednost daje smjesi etanol-voda, pri temperaturi od oko 20 °C do 130 °C, gdje se prednost daje temperaturama od 90 °C do 110 °C, dobiva se spoj formule 6, gdje R5 jest N3. The procedure for obtaining compounds of formula 1 in which R1 is substituted by R5 and R5 is NHC(=O)R8 is shown in scheme 2. By reacting the compound of formula 4, where R5 is OH, with an alkyl- or aryl-sulfonyl chloride, where preference is given p-toluenesulfonyl chloride (TosCl), in an inert reaction solvent, such as tetrahydrofuran, methylene chloride or chloroform, where methylene chloride is preferred, at a temperature of about -10°C to about 30°C in the presence of an amine base such as is triethylamine, diisopropylethylamine, pyridine or 2,6-dimethylpyridine, while it is preferable that it be triethylamine, and catalytic amounts of 4-N,N-dimethylaminopyridine, the compound of formula 5 is obtained, where R5 is CH3(C6H4)SO3 (TosO) . By reacting the tosylate thus obtained with an alkali metal azide salt, preferably sodium azide, in a polar solvent such as dimethylformamide, dimethylsulfoxide, lower alcohol, water or a mixture of these solvents, preferably an ethanol-water mixture, at a temperature of about 20 °C to 130 °C, with temperatures from 90 °C to 110 °C being preferred, the compound of formula 6 is obtained, where R5 is N3.

Podvrgavanjem azida selektivnim redukcijskim uvjetima, kao što su to trialkil- ili triarilfosfin i voda, gdje se prednost daje trifenilfosfinu, u otapalu kao što je to tetrahidrofuran, dioksan, acetonitril ili pak njihova smjesa, gdje se prednost daje tetrahidrofuranu, dobiva se spoj formule 7, gdje R5 jest NH2. Primarna amino skupina na ovako dobivenom spoju formule 7 (R5 = NH2) može se prevesti u svoje derivate reakcijom s kloroformatom, izocijanatom, karbamoil kloridom, kiselinskim kloridom, anhidridom ili pak aktiviranim derivatom karboksilne kiseline. Aktivirani derivat karboksilne kiseline priređuje se iz karboksilne kiseline iz poznatih aktivirajućih reagensa, kao što su to dicikloheksil karbodiimid, 1-(3-dimetilaminopropil)-3-etilkarbodiimid, karbonil diimidazol, 1-ciklički anhidrid propanfosfonske kiseline, alkil kloroformat, bi(2-okso-3-oksazolidinil)fosfinoil klorid, benzotriazol-1-iloksi-tris(dimetilamino)fosfonijev heksafluorofosfat ili pak bilo kojeg drugog uobičajenog literaturnog reagensa uz prisustvo baze amina kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, dok je poželjno da to bude 1-(3-dimetilaminopropil)-3-etilkarbodiimid klorid, pri temperaturi od oko –78 °C do 80 °C, dok se prednost daje temperaturama od 0 °C do 40 °C. Poželjna otapala su tetrahidrofuran i metilen klorid. By subjecting the azide to selective reducing conditions, such as trialkyl- or triarylphosphine and water, where triphenylphosphine is preferred, in a solvent such as tetrahydrofuran, dioxane, acetonitrile or their mixture, where tetrahydrofuran is preferred, the compound of formula 7 is obtained , where R 5 is NH 2 . The primary amino group on the thus obtained compound of formula 7 (R5 = NH2) can be converted into its derivatives by reaction with chloroformate, isocyanate, carbamoyl chloride, acid chloride, anhydride or an activated carboxylic acid derivative. The activated carboxylic acid derivative is prepared from the carboxylic acid from known activating reagents, such as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyl diimidazole, 1-cyclic propanephosphonic anhydride, alkyl chloroformate, bi(2- oxo-3-oxazolidinyl)phosphinoyl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or any other common literature reagent with the presence of an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-dimethylpyridine, while is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide chloride, at a temperature of about -78°C to 80°C, while temperatures of 0°C to 40°C are preferred. Preferred solvents are tetrahydrofuran and methylene chloride.

Prevođenje ovako dobivenog spoja formule 8, gdje R5 jest –NHC(=O)R8 u spoj formule 1D (R5 jest NHC(=O)R8; R3 jest C(=O)(CR10R11)nR4) može se postići izlaganjem smjese spoja formule 8 i katalizatora plemenitog metala atmosferi vodika pri tlaku od oko 1 do 100 atmosfera, gdje je poželjan tlak vodika od jedne do oko deset atmosfera, u otapalu kao što je to etil acetat, tetrahidrofuran, dioksan ili pak njihova smjesa, gdje je poželjan katalizator paladijev katalizator i gdje se metal uobičajeno može suspendirati na inertnom krutom nositelju kao što je to ugljen. Nakon što je završena reakcija spoja formule 8, smjesa se filtrira, a dobiveni amin se odmah podvrgne reakciji acilacije s kiselinskim kloridom, anhidridom ili pak s aktiviranim derivatom karboksilne kiseline uz prisustvo baze kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, gdje se prednost daje cikličkom anhidridu 1-propanefosfonske kiseline i trietilaminu, pri temperaturi od oko –78 °C do oko 40 °C, te se dobiva N-acilirani produkt formule 1D. Aktivirani derivat karboksilne kiseline priređuje se iz karboksilne kiseline pomoću poznatih aktivirajućih reagensa, kao što su to dicikloheksil karbodiimid, 1-(3-dimetilaminopropil)-3-etilkarbodiimid, karbonil diimidazol, 1-ciklički anhidrid propanfosfonske kiseline, alkil kloroformat, bi(2-okso-3-oksazolidinil)fosfinoil klorid, benzotriazol-1-iloksi-tris(dimetilamino)fosfonijev heksafluorofosfat, ili pak pomoću bilo kojeg drugog uobičajenog literaturnog reagensa. The conversion of the thus obtained compound of formula 8, where R5 is –NHC(=O)R8 into the compound of formula 1D (R5 is NHC(=O)R8; R3 is C(=O)(CR10R11)nR4) can be achieved by exposure to a mixture of compounds of the formula 8 and a noble metal catalyst to a hydrogen atmosphere at a pressure of about 1 to 100 atmospheres, where a hydrogen pressure of one to about ten atmospheres is preferred, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof, where a palladium catalyst is preferred catalyst and where the metal can usually be suspended on an inert solid support such as coal. After the reaction of the compound of formula 8 is completed, the mixture is filtered, and the resulting amine is immediately subjected to an acylation reaction with an acid chloride, an anhydride or with an activated carboxylic acid derivative in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6- dimethylpyridine, where preference is given to the cyclic anhydride of 1-propanephosphonic acid and triethylamine, at a temperature of about -78 °C to about 40 °C, and the N-acylated product of formula 1D is obtained. The activated carboxylic acid derivative is prepared from the carboxylic acid using known activating reagents, such as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyl diimidazole, 1-cyclic propanephosphonic anhydride, alkyl chloroformate, bi(2- oxo-3-oxazolidinyl)phosphinoyl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or using any other common literature reagent.

Ukoliko se u gornjoj reakciji acilacije umjesto kiselinskog klorida, anhidrida ili pak aktiviranog derivata karboksilne kiseline koristi kloroformat ili heteroaril kloroformat dobiva se arilni karbamat 1E. Dobiveni aril karbamat 1E (R3 jest C(=O)O- i R4 jest aril ili heteroaril) može se podvrgnuti reakciji s aminom u otapalu kao što je to dioksan, dimetilformamid ili acetonitril, gdje se prednost daje 1:1 smjesi dioksan-dimetilformamid, pri temperaturi od oko 40 °C do 90 °C, dok se prednost daje temperaturi od 70 °C, te se dobiva odgovarajući produkt uree formule 1F (R3 jest -C(=O)NR9-, R4 jest aril ili heteroaril). If chloroformate or heteroaryl chloroformate is used instead of acid chloride, anhydride or an activated carboxylic acid derivative in the above acylation reaction, aryl carbamate 1E is obtained. The resulting aryl carbamate 1E (R3 is C(=O)O- and R4 is aryl or heteroaryl) can be reacted with an amine in a solvent such as dioxane, dimethylformamide or acetonitrile, where a 1:1 dioxane-dimethylformamide mixture is preferred , at a temperature of about 40 °C to 90 °C, while preference is given to a temperature of 70 °C, and the corresponding urea product of formula 1F is obtained (R3 is -C(=O)NR9-, R4 is aryl or heteroaryl).

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Dodatni postupak priprave spojeva formule 1 u kojima R5 jest -NHC(=O)R8 prikazan je na shemi 3. Reakcijom spoja formule 4, gdje R5 jest OH, s alkil- ili aril-sulfonil kloridom, gdje se prednost daje p-toluensulfonil kloridu (TosCl), u inertnom reakcijskom otapalu kao što je to tetrahidrofuran, metilen klorid ili kloroform, gdje se prednost daje metilen kloridu, pri temperaturi od oko –10°C do oko 30 °C uz prisustvo baze amina, kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, te 4-N,N-dimetilaminopiridina, dobiva se spoj formule 5, gdje R5 jest CH3(C6H4)SO3 (TosO). Poželjno je da se kao aminska baza koristi trietilamin. Prevođenje ovako dobivenog spoja formule 5 (R5 jest TosO) u spoj formule 1G (R5 jest TosO; R3 jest C(=O)(CR10R11)nR4) može se postići izlaganjem smjese spoja formule 5 (R5 jest TosO) i katalizatora plemenitog metala atmosferi vodika pri tlaku od oko 1 do 100 atmosfera, gdje je poželjan tlak vodika od jedne do oko deset atmosfera, u otapalu kao što je to etil acetat, tetrahidrofuran, dioksan ili njihova smjesa. Poželjan katalizator jest paladijev katalizator. Uobičajeno, metal se može suspendirati na inertnom krutom nositelju kao što je to ugljen. Nakon što je završena reakcija spoja 5, smjesa se filtrira, a dobiveni amin se odmah podvrgne reakciji s kiselinskim kloridom, anhidridom ili pak s aktiviranim derivatom karboksilne kiseline uz prisustvo, ukoliko je to poželjno, baze amina, kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, gdje se prednost daje kombinaciji cikličkog anhidrida 1-propanfosfonske kiselina i trietilamina, pri temperaturi od oko –78 °C do oko 40 °C, te se dobiva N-acilirani produkt formule 1G. Aktivirani derivat karboksilne kiseline priređuje se iz karboksilne kiseline iz poznatih aktivirajućih reagensa, kao što su to dicikloheksil karbodiimid, 1-(3-dimetilaminopropil)-3-etilkarbodiimid, karbonil diimidazol, ciklički anhidrid 1-propanfosfonske kiseline, alkil kloroformat, bi(2-okso-3-oksazolidinil)fosfinoil klorid, benzotriazol-1-iloksi-tris(dimetilamino)fosfonijev heksafluorofosfat ili pak bilo kojeg drugog uobičajenog literaturnog reagensa. An additional procedure for the preparation of compounds of formula 1 in which R5 is -NHC(=O)R8 is shown in scheme 3. By reacting the compound of formula 4, where R5 is OH, with alkyl- or aryl-sulfonyl chloride, where p-toluenesulfonyl chloride is preferred (TosCl), in an inert reaction solvent such as tetrahydrofuran, methylene chloride or chloroform, where methylene chloride is preferred, at a temperature of about -10°C to about 30°C in the presence of an amine base, such as triethylamine, diisopropylethylamine, pyridine or 2,6-dimethylpyridine, and 4-N,N-dimethylaminopyridine, the compound of formula 5 is obtained, where R5 is CH3(C6H4)SO3 (TosO). It is preferable to use triethylamine as the amine base. The conversion of the thus obtained compound of formula 5 (R5 is TosO) into the compound of formula 1G (R5 is TosO; R3 is C(=O)(CR10R11)nR4) can be achieved by exposing the mixture of the compound of formula 5 (R5 is TosO) and the noble metal catalyst to the atmosphere of hydrogen at a pressure of from about 1 to 100 atmospheres, where a hydrogen pressure of from one to about ten atmospheres is preferred, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof. A preferred catalyst is a palladium catalyst. Typically, the metal can be suspended on an inert solid support such as coal. After the reaction of compound 5 is completed, the mixture is filtered, and the resulting amine is immediately subjected to a reaction with an acid chloride, an anhydride or with an activated carboxylic acid derivative in the presence, if desired, of an amine base, such as triethylamine, diisopropylethylamine, pyridine or 2,6-dimethylpyridine, where preference is given to the combination of the cyclic anhydride of 1-propanephosphonic acid and triethylamine, at a temperature of about -78 °C to about 40 °C, and the N-acylated product of formula 1G is obtained. The activated carboxylic acid derivative is prepared from the carboxylic acid from known activating reagents, such as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyl diimidazole, cyclic 1-propanephosphonic anhydride, alkyl chloroformate, bi(2- oxo-3-oxazolidinyl)phosphinoyl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or any other common literature reagent.

Reakcijom ovako dobivenog spoja formule 1G (R5 jest TosO; R3 jest -C(=O)(CR10R11)n- s azidnom soli alkalijskog metala, gdje se prednost daje natrijevu azidu, u polarnom otapalu kao što je to dimetilformamid, dimetilsulfoksid, niži alkohol, voda ili pak smjesa ovih otapala, gdje se prednost daje smjesi etanol-voda, pri temperaturi od oko 20 °C do 130 °C, gdje se prednost daje temperaturama od 90 °C do 110 °C, dobiva se spoj formule 1H u kojem R5 jest N3. Potom se redukcija azida formule 1H (R5 jest N3) može provesti izlaganjem smjese spoja formule 1H (R5 jest N3) i katalizatora plemenitog metala, gdje poželjan katalizator jest paladijev katalizator, te se uobičajeno metal može suspendirati na inertnom krutom nositelju kao što je to ugljen, atmosferi vodika pri tlaku od oko 1 do 100 atmosfera, gdje je poželjan tlak vodika od jedne do oko deset atmosfera, u otapalu kao što je to etil acetat, tetrahidrofuran, dioksan ili njihova smjesa. By reacting the thus obtained compound of formula 1G (R5 is TosO; R3 is -C(=O)(CR10R11)n- with an alkali metal azide salt, where preference is given to sodium azide, in a polar solvent such as dimethylformamide, dimethylsulfoxide, lower alcohol , water or a mixture of these solvents, where preference is given to the ethanol-water mixture, at a temperature of about 20 °C to 130 °C, where preference is given to temperatures of 90 °C to 110 °C, a compound of formula 1H is obtained in which R5 is N3. Then the reduction of the azide of formula 1H (R5 is N3) can be carried out by exposing a mixture of the compound of formula 1H (R5 is N3) and a noble metal catalyst, where the preferred catalyst is a palladium catalyst, and usually the metal can be suspended on an inert solid support as which is coal, to a hydrogen atmosphere at a pressure of about 1 to 100 atmospheres, where a hydrogen pressure of from one to about ten atmospheres is preferred, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or a mixture thereof.

Dodatno, redukcija azida formule 1H (R5 jest N3) može se provesti reakcijom s trialkil- ili triarilfosfinom i vodom, gdje se prednost daje trifenilfosfinu, u otapalu kao što je to tetrahidrofuran, dioksan ili acetonitril, gdje se prednost daje tetrahidrofuranu. Primarna amino skupina na ovako dobivenom spoju formule 1I (R5 = NH2) može se prevesti u svoje derivate reakcijom s kloroformatom, izocijanatom, karbamoil kloridom, kiselinskim kloridom, anhidridom ili pak aktiviranim derivatom karboksilne kiseline. Aktivirani derivat karboksilne kiseline priređuje se iz karboksilne kiseline iz poznatih aktivirajućih reagensa kao što su to dicikloheksil karbodiimid, 1-(3-dimetilaminopropil)-3-etilkarbodiimid, karbonil diimidazol, ciklički anhidrid 1-propanfosfonske kiseline, alkil kloroformat, bi(2-okso-3-oksazolidinil)fosfinoil klorid, benzotriazol-1-iloksi-tris(dimetilamino)fosfonijev heksafluorofosfat ili pak bilo kojeg drugog uobičajenog literaturnog reagensa uz prisustvo, ukoliko je to potrebno, baze amina kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, dok je poželjno da to bude 1-(3-dimetilaminopropil)-3-etilkarbodiimid klorid, pri temperaturi od oko –78 °C do 80 °C, dok se prednost daje temperaturama od 0 °C do 40 °C. Poželjna otapala su tetrahidrofuran i metilen klorid. Additionally, reduction of azides of formula 1H (R5 is N3) can be carried out by reaction with trialkyl- or triarylphosphine and water, preferably triphenylphosphine, in a solvent such as tetrahydrofuran, dioxane or acetonitrile, preferably tetrahydrofuran. The primary amino group on the thus obtained compound of formula 1I (R5 = NH2) can be converted into its derivatives by reaction with chloroformate, isocyanate, carbamoyl chloride, acid chloride, anhydride or an activated carboxylic acid derivative. The activated carboxylic acid derivative is prepared from the carboxylic acid from known activating reagents such as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyl diimidazole, 1-propanephosphonic acid cyclic anhydride, alkyl chloroformate, bi(2-oxo -3-oxazolidinyl)phosphinoyl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or any other common literature reagent with the presence, if necessary, of an amine base such as triethylamine, diisopropylethylamine, pyridine or 2, 6-dimethylpyridine, while preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide chloride, at a temperature of about -78 °C to 80 °C, while temperatures of 0 °C to 40 °C are preferred. Preferred solvents are tetrahydrofuran and methylene chloride.

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Dobivanje spojeva formule 1, gdje R3 jest –(CR10R11)n–, može se provesti u skladu sa shemom 4. Prema shemi 4, reakcijom otopine 4-bromimidazola s bazom kao što je to natrijev hidrid, kalijev hidrid, litijev hidrid, cezijev karbonat, natrijev hidroksid, kalijev hidroksid, cezijev hidroksid, litijev diizopropil amid, natrijev amid, kalijev heksametildisilazid, natrijev heksametildisilazid, natrijev terc-butoksid ili kalijev terc-butoksid, u inertnom reakcijskom otapalu kao što je to tetrahidrofuran, 1,4-dioksan, N,N-dimetilformamid, dimetilsulfoksid ili toluen, pri temperaturi od oko –20 °C do 150 °C, gdje se prednost daje temperaturama od 20 °C do 100 °C, uz prisustvo ili odsustvo katalizatora faznog prijelaza (phase transfer), kao što je to tetra-n-butilamonijev klorid, tetra-n-butilamonijev bromid, tetra-n-butilamonijev jodid, benziltrimetil amonijev klorid, benziltrimetil amonijev bromid, ili benziltrimetil amonijev fluorid, iza čega slijedi dodatak alkila, alila ili benzil klorida, bromida, jodida, alkil sulfonata, aril sulfonata ili triflata, dobiva se smjesa 1-supstituiran-4-bromimidazola (9) i 1-supstituiran-5-bromimidazola (10), koji se mogu odvojiti postupcima poznatima stručnjaku s područja. Obtaining compounds of formula 1, where R3 is –(CR10R11)n–, can be carried out in accordance with scheme 4. According to scheme 4, by reacting a solution of 4-bromoimidazole with a base such as sodium hydride, potassium hydride, lithium hydride, cesium carbonate , sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium diisopropyl amide, sodium amide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium tert-butoxide or potassium tert-butoxide, in an inert reaction solvent such as tetrahydrofuran, 1,4-dioxane, N ,N-dimethylformamide, dimethylsulfoxide or toluene, at a temperature of about -20 °C to 150 °C, where preference is given to temperatures of 20 °C to 100 °C, with the presence or absence of a phase transfer catalyst, such as is tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, or benzyltrimethylammonium fluoride, followed by addition of alkyl, allyl, or benzyl chloride, bromide, iodide, alkyl sulfonate, aryl sulfonate or triflate, a mixture of 1-substituted-4-bromoimidazole (9) and 1-substituted-5-bromoimidazole (10) is obtained, which can be separated by methods known to the expert in the field.

Dodatno, reakcijom 4-bromimidazola s alil fluoridom, kloridom, bromidom, jodidom, acetatom ili karbonatom, gdje se prednost daje alil karbonatu, u inertnom reakcijskom otapalu kao što je to tetrahidrofuran, 1,2-dikloretan, 1,4-dioksan, dimetilsulfoksid ili N,N-dimetilformamid, gdje se prednost daje tetrahidrofuranu, uz prisustvo paladijeva katalizatora, kao što je to paladij (0) tetrakis(trifenilfosfin), paladijev (II) acetat, dimer alil paladijeva klorida, tris(dibenzilidenaceton)dipaladij (0), adukt tris(dibenzilidenaceton)dipaladij (0) kloroform, paladijev (II) klorid, gdje se prednost daje paladijevu tetrakis(trifenilfosfinu) ili paladijevu (II) acetatu, uz prisustvo ili odsustvo liganda fosfina kao što je to trifenilfosfin, tri-o-tolilfosfin, tri-terc-butilfosfin, 1,2-bis(difenilfosfino)etan ili 1,3-bis(difenilfosfino)propan, pri temperaturi od oko 0 °C do 100 °C, gdje se prednost daje temperaturama od 50 °C do 80 °C, dobiva se smjesa 1-supstituiran-4-bromimidazola (9) i 1-supstituiran-5-bromimidazola (10). Additionally, by reacting 4-bromoimidazole with allyl fluoride, chloride, bromide, iodide, acetate or carbonate, where allyl carbonate is preferred, in an inert reaction solvent such as tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, dimethylsulfoxide or N,N-dimethylformamide, where preference is given to tetrahydrofuran, in the presence of a palladium catalyst, such as palladium (0) tetrakis(triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris(dibenzylideneacetone)dipalladium (0) , adduct tris(dibenzylideneacetone)dipalladium (0) chloroform, palladium (II) chloride, where preference is given to palladium tetrakis(triphenylphosphine) or palladium (II) acetate, with the presence or absence of a phosphine ligand such as triphenylphosphine, tri-o- tolylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphino)ethane or 1,3-bis(diphenylphosphino)propane, at a temperature of about 0 °C to 100 °C, with temperatures of 50 °C to 80 °C, a mixture of 1-substituted-4-bromoimidazole (9) and 1-substituted uran-5-bromoimidazole (10).

Reakcijom 1-supstituiran-4-bromimidazola (9) s međuproduktom formule –NH2(CR10R11)nR4 i paladijevim katalizatorom, kao što je to paladijev (II) acetat, dimer alil paladijeva klorida, tris(dibenzilidenaceton)dipaladij (0), adukt tris(dibenzilidenaceton)dipaladij (0) kloroform ili paladijev (II) klorid, gdje se prednost daje paladijevu (II) acetatu, tris(dibenzilidenaceton)dipaladiju (0), aduktu tris(dibenzilidenaceton)dipaladij (0) kloroformu, uz prisustvo liganda fosfina kao što je to BINAP, 2-bifenil dicikloheksilfosfin, 2-bifenil di-terc-butilfosfin ili 2-N,N-dimetilamino-2ʹ-difenilfosfino bifenil, gdje se prednost daje 2-N,N-dimetilamino-2ʹ-difenilfosfino bifenilu, te uz prisustvo baze kao što je to natrijev terc-butoksid, cezijev karbonat ili kalijev fosfat (K3PO4), gdje se prednost daje kalijevu fosfatu, u inertnom reakcijskom otapalu kao što je to toluen, 1,4-dioksan ili tetrahidrofuran, pri temperaturi od oko 0 °C do 150 °C, gdje se prednost daje temperaturama od 20 °C do 110 °C, dobiva se produkt 1. By the reaction of 1-substituted-4-bromoimidazole (9) with an intermediate of the formula –NH2(CR10R11)nR4 and a palladium catalyst, such as palladium (II) acetate, dimer allyl palladium chloride, tris(dibenzylideneacetone)dipalladium (0), adduct tris (dibenzylideneacetone)dipalladium (0) chloroform or palladium (II) chloride, where preference is given to palladium (II) acetate, tris(dibenzylideneacetone)dipalladium (0), adduct tris(dibenzylideneacetone)dipalladium (0) chloroform, with the presence of a phosphine ligand as which is BINAP, 2-biphenyl dicyclohexylphosphine, 2-biphenyl di-tert-butylphosphine or 2-N,N-dimethylamino-2'-diphenylphosphino biphenyl, where 2-N,N-dimethylamino-2'-diphenylphosphino biphenyl is preferred, and in the presence of a base such as sodium tert-butoxide, cesium carbonate or potassium phosphate (K3PO4), where potassium phosphate is preferred, in an inert reaction solvent such as toluene, 1,4-dioxane or tetrahydrofuran, at a temperature of about 0 °C to 150 °C, where temperatures from 20 °C to 110 °C are preferred , product 1 is obtained.

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Dodatni postupak sinteze spojeva formule 1, gdje R3 jest –C(=O)(CR10R11)n–, prikazan je dolje danom shemom 5. Reakcijom etil-2-izocijano-3-N,N-dimetilamino akrilata (11) s primarnim aminom R1-NH2, u otapalu kao što je to n-butanol, n-propanol, l-propanol ili etanol ili pak u odsustvu otapala, gdje se prednost daje n-propanolu ili pak reakciji bez otapala, pri temperaturi od oko 23 °C do oko 200 °C, gdje se prednost daje temperaturama od oko 60 °C do oko 150 °C, dobivaju se imidazoli formule 12. Reakcijom N,O-dimetil hidroksil amin klorida s trimetilaluminijem u 1,2-dikloretanu, iza čega slijedi dodatak spoja 12 i grijanjem pri oko 30 °C do oko 80 °C, gdje se prednost daje temperaturi od oko 50 °C, dobiva se imidazol 13. Dodatkom organometalnog reagensa M-(CR10R11)nR4, gdje M može biti ili litijev ili pak magnezijev halid, gdje se prednost daje magnezijevu halidu, u otopinu spoja 13 u otapalu kao što je to tetrahidrofuran, metilen klorid ili dietil eter, pri temperaturama od oko -50 °C do oko 30 °C, gdje se prednost daje temperaturama od oko -20 °C do oko 0 °C, dobiva se spoj 14. Dodatkom spoja 14 u smjesu hidroksil amin klorida i kalijeva acetata uz niži alkohol kao otapalo, gdje se prednost daje etanolu, pri temperaturi od oko 23 °C, dobiva se oksim 15 u obliku smjese izomera. Reakcijom otopine oksima 15 u acetonu s vodenom otopinom natrijeva hidroksida i paratoluensulfonil klorida pri 0 °C dobiva se smjesa O-sulfonil spojeva koja se potom ekstrahira. Otapanjem sirovog produkta u nepolarnom otapalu kao što je to benzen, heksan ili toluen, gdje se prednost daje benzenu, te primjenom kromatografije na koloni aluminijeva oksida uz eluaciju sa smjesom kloroform-metanol (oko 10:1) tijekom oko 5 minuta, dobiva se spoj 1B i regioizomer nastao Beckmanovom pregradnjom. An additional procedure for the synthesis of compounds of formula 1, where R3 is –C(=O)(CR10R11)n–, is shown below in scheme 5. Reaction of ethyl-2-isocyano-3-N,N-dimethylamino acrylate (11) with a primary amine R1-NH2, in a solvent such as n-butanol, n-propanol, l-propanol or ethanol or in the absence of a solvent, where preference is given to n-propanol or the reaction without a solvent, at a temperature of about 23 °C to about 200 °C, with temperatures from about 60 °C to about 150 °C being preferred, imidazoles of formula 12 are obtained. Reaction of N,O-dimethyl hydroxyl amine chloride with trimethylaluminum in 1,2-dichloroethane, followed by addition of the compound 12 and by heating at about 30 °C to about 80 °C, where preference is given to a temperature of about 50 °C, imidazole 13 is obtained. By adding the organometallic reagent M-(CR10R11)nR4, where M can be either lithium or magnesium halide , where magnesium halide is preferred, in a solution of compound 13 in a solvent such as tetrahydrofuran, methylene chloride or diethyl ether, at temperatures of about -50 °C to about 30 °C, where the temperature from about -20 °C to about 0 °C is preferred, compound 14 is obtained. By adding compound 14 to a mixture of hydroxyl amine chloride and potassium acetate with a lower alcohol as solvent, where ethanol is preferred , at a temperature of about 23 °C, oxime 15 is obtained in the form of a mixture of isomers. By reacting a solution of oxime 15 in acetone with an aqueous solution of sodium hydroxide and paratoluenesulfonyl chloride at 0 °C, a mixture of O-sulfonyl compounds is obtained, which is then extracted. By dissolving the crude product in a non-polar solvent such as benzene, hexane or toluene, where benzene is preferred, and applying chromatography on an aluminum oxide column with elution with a chloroform-methanol mixture (about 10:1) for about 5 minutes, the compound is obtained 1B and the regioisomer formed by Beckman rearrangement.

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Spojevi formule 1J mogu se također prirediti postupkom prikazanim na dolje danoj shemi 6. Ključni polazni materijal za ovu sintezu jest spoj koji sadrži dvostruku vezu (spoj formule X) i koji je supstituiran sa skupinom ER5 i s jednom do tri skupina odabranih između R5 (X), gdje ER5 jest elektron akceptorska skupina odabrana između C(=O)R7, C(=O)OR7, C(=O)NR7R8, S(=O)2R7, S(=O)2NR7R8, S(=O)2OR7, cijano i heteroarilne skupine. Dodatno, spojevi formule X mogu biti i oni u kojima je ER5 skupina povezana na jednu od R5 skupina ili je pak neposredno vezana na ugljik-ugljik dvostruku vezu te tvori prsten, pa su prema tome uključeni i spojevi kao što su to 2-ciklopenten-1-on i 2-cikloheksen-1-on. Dodatno, kao polazni materijal mogu se koristiti i spojevi formule X u kojima je L definiran kao Cl, Br, I, OC(=O)2R7 iliOS(=O)2R7; primjeri ovakvih spojeva su 3-klor-1-ciklopentanon, 3-acetoksi-1-ciklobutanon. Prema tome, u skladu sa shemom 6, reakcijom (5)-nitroimidazolne soli 4, gdje se radi o natrijevoj, kalijevoj, cezijevoj, 1,8-diazabiciklo[5.4.0]undek-7-en (DBU) ili tetraalkil amonijevoj soli i gdje se prednost daje n-butilamonijevoj ili DBU soli, s međuproduktima 16 ili 17 u otapalu kao što je to acetonitril, metilen klorid, 1,2-dikloretan ili kloroform, gdje se prednost daje acetonitrilu, pri temperaturi od oko -60 °C do 50 °C, gdje se prednost daje temperaturama od -20 °C do 23 °C, dobiva se produkt formule 2A. Redukcija nitro spoja formule 2A može se postići izlaganjem smjese spoja formule 2 i katalizatora plemenitog metala atmosferi vodika pri tlaku od oko 1 do 100 atmosfera, gdje je poželjan tlak vodika od jedne do oko deset atmosfera, u otapalu kao što je to etil acetat, tetrahidrofuran, dioksan ili pak neka od njihovih smjesa, gdje je poželjan katalizator paladijev katalizator i gdje se metal uobičajeno može suspendirati na inertnom krutom nositelju kao što je to ugljen. Nakon što je završena reakcija spoja 2A, smjesa se filtrira, a dobiveni amin se odmah podvrgne reakciji s kiselinskim kloridom ClC(=O)(CR10R11)nR4, anhidridom (R4(CR10R11)nC(=O))2O ili pak s aktiviranim derivatom karboksilne kiseline XC(=O)(CR10R11)nR4, uz prisustvo baze kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, gdje se prednost daje kombinaciji cikličkog anhidrida propanfosfonske kiseline i trietilamina, pri temperaturi od oko –78 °C do 40 °C, te se dobiva spoj 1J. Aktivirani derivat karboksilne kiseline priređuje se iz karboksilne kiseline HOC(=O)(CR10R11)nR4 i poznatih aktivirajućih reagensa kao što su to dicikloheksil karbodiimid, 1-(3-dimetilaminopropil)-3-etilkarbodiimid, karbonil diimidazol, ciklički anhidrid 1-propanfosfonske kiseline, alkil ili aril kloroformat, bi(2-okso-3-oksazolidinil)fosfinoil klorid, benzotriazol-1-iloksi-tris(dimetilamino)fosfonijev heksafluorofosfat ili pak bilo koji drugi uobičajeni literaturni reagens. Compounds of formula 1J can also be prepared by the procedure shown in Scheme 6 below. The key starting material for this synthesis is a compound containing a double bond (compound of formula X) and substituted with the group ER5 and with one to three groups selected from R5 (X) , where ER5 is an electron acceptor group selected from C(=O)R7, C(=O)OR7, C(=O)NR7R8, S(=O)2R7, S(=O)2NR7R8, S(=O)2OR7 , cyano and heteroaryl groups. Additionally, the compounds of formula X can also be those in which the ER5 group is connected to one of the R5 groups or is directly connected to a carbon-carbon double bond and forms a ring, so compounds such as 2-cyclopentene- 1-one and 2-cyclohexen-1-one. Additionally, compounds of formula X in which L is defined as Cl, Br, I, OC(=O)2R7 or OS(=O)2R7 can also be used as starting material; examples of such compounds are 3-chloro-1-cyclopentanone, 3-acetoxy-1-cyclobutanone. Therefore, according to scheme 6, the reaction of (5)-nitroimidazole salt 4, where it is a sodium, potassium, cesium, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or tetraalkyl ammonium salt and preferably the n-butylammonium or DBU salt, with intermediates 16 or 17 in a solvent such as acetonitrile, methylene chloride, 1,2-dichloroethane or chloroform, preferably acetonitrile, at a temperature of about -60 °C to 50 °C, where preference is given to temperatures from -20 °C to 23 °C, the product of formula 2A is obtained. Reduction of the nitro compound of formula 2A can be achieved by exposing a mixture of the compound of formula 2 and a noble metal catalyst to an atmosphere of hydrogen at a pressure of from about 1 to 100 atmospheres, where a hydrogen pressure of from one to about ten atmospheres is preferred, in a solvent such as ethyl acetate, tetrahydrofuran , dioxane or some of their mixtures, where the preferred catalyst is a palladium catalyst and where the metal can usually be suspended on an inert solid support such as coal. After the reaction of compound 2A is completed, the mixture is filtered, and the obtained amine is immediately subjected to a reaction with acid chloride ClC(=O)(CR10R11)nR4, anhydride (R4(CR10R11)nC(=O))2O or with an activated derivative carboxylic acid XC(=O)(CR10R11)nR4, with the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-dimethylpyridine, where preference is given to the combination of the cyclic anhydride of propanephosphonic acid and triethylamine, at a temperature of about -78 ° C to 40 °C, and compound 1J is obtained. Activated carboxylic acid derivative is prepared from carboxylic acid HOC(=O)(CR10R11)nR4 and known activating reagents such as dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyl diimidazole, cyclic anhydride of 1-propanephosphonic acid , alkyl or aryl chloroformate, bi(2-oxo-3-oxazolidinyl)phosphinoyl chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate or any other common literature reagent.

Dodatno, nakon filtracije, amin međuprodukt može se podvrgnuti reakciji s alkil- ili aril- kloroformatom uz prisustvo baze kao što je to trietilamin, diizopropiletilamin, piridin ili 2,6-dimetilpiridin, gdje se prednost daje kombinaciji diizopropiletilamina i fenil kloroformata, pri temperaturi od oko –78 °C do 40 °C, dok se prednost daje temperaturama od oko –78 °C do oko -40 °C, čime se dobiva spoj formule 1K. Additionally, after filtration, the amine intermediate can be reacted with alkyl- or aryl-chloroformate in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-dimethylpyridine, where preference is given to the combination of diisopropylethylamine and phenyl chloroformate, at a temperature of about -78 °C to about -40 °C, while temperatures from about -78 °C to about -40 °C are preferred, which gives the compound of formula 1K.

Dodatnom reakcijom spoja formule 1K s primarnim ili sekundarnim aminom u otapalu kao što je to dioksan, dimetilformamid ili acetonitril, gdje se prednost daje 1:1 smjesi dioksan-dimetilformamid, pri temperaturi od oko 40 °C do 90 °C, gdje se prednost daje temperaturi od oko 70 °C, dobiva se odgovarajući produkt uree 1L. By further reacting a compound of formula 1K with a primary or secondary amine in a solvent such as dioxane, dimethylformamide or acetonitrile, preferably a 1:1 dioxane-dimethylformamide mixture, at a temperature of about 40°C to 90°C, preferably at a temperature of about 70 °C, the corresponding urea product 1L is obtained.

Koristeći se postupcima poznatima na području, spojevi 2A, 1J, 1K i 1L mogu se prevesti u druge, u ovoj prijavi već opisane spojeve formule 1. Using methods known in the field, compounds 2A, 1J, 1K and 1L can be converted into other compounds of formula 1 already described in this application.

Ovdje opisani spojevi formule 1 u kojima R2 jest različit od vodika mogu se prirediti postupcima dobro poznatima na području iz ovdje već opisanih spojeva formule 1 u kojima R2 jest vodik. Na primjer, spojevi formule 1 u kojima R2 jest F mogu se prirediti reakcijom spojeva formule 1 u kojima R2 jest vodik, na primjer spojevi formule 1A, 1B i 1C iz prije dane sheme 1, s N-fluorbenzensulfonimid u toluenu, ksilenu ili dioksanu, pri temperaturi od sobne do oko 150 °C, dok se prednost daje temperaturama od oko 100 °C do oko 120 °C. The compounds of formula 1 described here in which R 2 is different from hydrogen can be prepared by methods well known in the field from the compounds of formula 1 already described here in which R 2 is hydrogen. For example, compounds of formula 1 in which R 2 is F can be prepared by reacting compounds of formula 1 in which R 2 is hydrogen, for example compounds of formula 1A, 1B and 1C of Scheme 1 above, with N-fluorobenzenesulfonimide in toluene, xylene or dioxane, at room temperature to about 150 °C, while temperatures from about 100 °C to about 120 °C are preferred.

[image] [image]

Farmaceutski prihvatljive soli spoja formule 1 mogu se prirediti na uobičajeni način reakcijom otopine ili suspenzije odgovarajuće slobodne baze ili kiseline s jednim kemijskim ekvivalentom farmaceutski prihvatljive kiseline ili baze. Za izolaciju soli mogu se koristiti uobičajene tehnike koncentriranja ili kristalizacije. Primjeri pogodnih kiselina su octena, mliječna, sukcinska, maleinska, vinska, limunska, glukonska, askorbinska, benzojeva, 3-fenil propanska, fumarna, sumporna, fosforna, kloridna, bromidna, jodidna, aminosulfonska, sulfonska kiselina kao što je to metansulfonska, benzen sulfonska, p-toluensulfonska i slične kiseline. Primjeri baza su natrijeva, kalijeva i kalcijeva baza. Pharmaceutically acceptable salts of the compound of formula 1 can be prepared in the usual way by reacting a solution or suspension of a suitable free base or acid with one chemical equivalent of a pharmaceutically acceptable acid or base. Common techniques of concentration or crystallization can be used to isolate the salt. Examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, 3-phenyl propanoic, fumaric, sulfuric, phosphoric, chloride, bromide, iodide, aminosulfonic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic and similar acids. Examples of bases are sodium, potassium and calcium bases.

Spoj prema ovom izumu može se uzimati samostalno ili u kombinaciji s farmaceutski prihvatljivim nositeljima, bilo u obliku pojedinačne ili višekratne doze. Pogodni farmaceutski nositelji uključuju inertne krute tvari za razrjeđivanje ili punila, sterilne vodene otopine i različita organska otapala. Farmaceutski pripravci spoja formule 1 ili njegove farmaceutski prihvatljive soli mogu se uzimati pomoću brojnih doznih oblika kao što su to tablete, prašci, lozenge, sirupi, otopine za injekcije i sl. Ovakvi farmaceutski pripravci mogu, ukoliko je to potrebno, sadržavati i dodatne sastojke kao što su to sredstva za poboljšanje okusa, vezivne tvari, dodatne tvari i sl. Prema tome, za oralnu se upotrebu mogu koristiti tablete koje sadrže različite dodatne tvari kao što su to natrijev citrat, kalcijev karbonat i kalcijev fosfat, te različite tvari za raspadanje kao što su to brašno, metilceluloza, alginska kiselina i određeni kompleksi silikata, zajedno s vezivnim tvarima kao što su to polivinilpirolidon, sukroza, želatina i akacija. Dodatno, tvari za vlaženje, kao što su to magnezijev stearat, natrijev dodecilsulfat i talk, često su korisne tijekom izrade tableta. Kruti pripravci sličnog sadržaja mogu se također koristiti kao punila za meke i tvrde želatinske kapsule. U poželjne materijale namijenjene takvoj svrsi uključuju se laktoza ili mliječni šećer, te polietilen glikoli velike molekulske mase. Ukoliko se za oralnu upotrebu žele koristiti suspenzije ili eliksiri, tada se aktivna tvar može kombinirati s različitim sladilima ili tvarima za poboljšanje okusa, bojama i, ukoliko je potrebno, tvarima za suspendiranje ili emulgatorima, zajedno sa sredstvima za razrjeđivanje kao što je to voda, etanol, propilen glikol, glicerin ili njihovim kombinacijama. A compound of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers, either in single or multiple dose form. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Pharmaceutical preparations of the compound of formula 1 or its pharmaceutically acceptable salts can be taken using numerous dosage forms such as tablets, powders, lozenges, syrups, solutions for injections, etc. Such pharmaceutical preparations can, if necessary, also contain additional ingredients such as which are flavor enhancers, binders, additives, etc. Therefore, for oral use, tablets can be used that contain various additives such as sodium citrate, calcium carbonate and calcium phosphate, and various disintegrants such as which are flour, methylcellulose, alginic acid and certain silicate complexes, together with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, wetting agents such as magnesium stearate, sodium dodecyl sulfate, and talc are often useful during tablet formulation. Solid preparations of similar content can also be used as fillers for soft and hard gelatin capsules. Preferred materials for this purpose include lactose or milk sugar, and high molecular weight polyethylene glycols. If suspensions or elixirs are to be used for oral use, then the active substance can be combined with various sweeteners or flavor enhancers, colors and, if necessary, suspending agents or emulsifiers, together with diluents such as water, ethanol, propylene glycol, glycerin or their combinations.

Za parenteralnu upotrebu može se koristiti otopina spoja prema ovom izumu ili njegove farmaceutski prihvatljive soli u ulju sezama ili kikirikija, vodenoj otopini propilen glikola ili pak u obliku sterilne vodene otopine. Ukoliko je to potrebno, u takve vodene otopine može se dodati pufer, a tekuće sredstvo za razrjeđivanje se dodatkom soli ili glukoze podesi u oblik izotinične otopine. Ovakve vodene otopine naročito su pogodne za intravenozno, intramuskularno, supkutano i intraperitonealno davanje. Sterilizacija korištenog vodenog medija može se provesti uobičajenim načinima poznatima na području. For parenteral use, a solution of the compound according to the present invention or its pharmaceutically acceptable salts in sesame or peanut oil, an aqueous solution of propylene glycol, or in the form of a sterile aqueous solution can be used. If necessary, a buffer can be added to such aqueous solutions, and the liquid diluent is adjusted to the form of an isotonic solution by adding salt or glucose. Such aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Sterilization of the used aqueous medium can be carried out by conventional means known in the field.

Spoj formule 1 ili njegova farmaceutski prihvatljiva sol može se uzimati oralno, transdermalno (npr. pomoću sustava flastera), parenteralno (npr. intravenozno), rektalno ili topikalno. U općenitom će slučaju dnevna doza za tretman neurodegenerativnih bolesti ili stanja ili pak bolesti ili stanja na koja se može utjecati promjenom neurotransmisije posredovane dopaminom varirati od oko 0,0001 do oko 10,0 mg/kg tjelesne mase tretiranog pacijenta. Dnevna doza namijenjena tretmanu kancera ili pak bolesti ili stanja koja uključuju nenormalni rast stanica benignog tipa, varirati će od oko 0,0001 do oko 500 mg/kg tjelesne mase tretiranog pacijenta. Na primjer, prilikom tretmana neurodegenerativnog poremećaja u odrasle osobe prosječne mase (oko 70 kg) spoj formule 1 ili njegova farmaceutski prihvatljiva sol može se uzimati u dozi od oko 0,01 mg do oko 1000 mg dnevno, gdje se prednost daje dozi od oko 0,1 do oko 500 mg dnevno, u obliku pojedinačne ili višekratne doze. Prilikom tretmana dijabetesa, poremećaja pokretljivosti spermija, opadanja kose ili druge bolesti ili stanja koja se mogu tretirati inhibicijom GSK-3, dnevna će doza u općenitom slučaju varirati od oko 0,0001 do oko 10,0 mg/kg tjelesne mase pacijenta. Potrebne varijacije doze, temeljene na gore spomenutim dozama, odredit će liječnik uzimajući u obzir poznate činjenice kao što su to težina, starost i stanje tretiranog pacijenta, te težina stanja i način uzimanja pripravka. A compound of formula 1 or a pharmaceutically acceptable salt thereof may be administered orally, transdermally (eg by means of a patch system), parenterally (eg intravenously), rectally or topically. In general, the daily dose for the treatment of neurodegenerative diseases or conditions or diseases or conditions that can be influenced by altering dopamine-mediated neurotransmission will vary from about 0.0001 to about 10.0 mg/kg body weight of the treated patient. The daily dose intended for the treatment of cancer or diseases or conditions involving the abnormal growth of cells of the benign type will vary from about 0.0001 to about 500 mg/kg of body weight of the treated patient. For example, in the treatment of a neurodegenerative disorder in adults of average weight (about 70 kg), a compound of formula 1 or a pharmaceutically acceptable salt thereof may be administered at a dose of from about 0.01 mg to about 1000 mg per day, with a dose of about 0 ,1 to about 500 mg per day, in the form of a single or multiple dose. When treating diabetes, sperm motility disorders, hair loss, or other diseases or conditions that can be treated with GSK-3 inhibition, the daily dose will generally vary from about 0.0001 to about 10.0 mg/kg of patient body weight. The necessary dose variations, based on the above-mentioned doses, will be determined by the doctor taking into account known facts such as the weight, age and condition of the treated patient, as well as the severity of the condition and the way of taking the preparation.

Spoj formule 1 ili njegova farmaceutski prihvatljiva sol može se uzimati ili prirediti u farmaceutski pripravak uz prisustvo jedne ili više tvari odabranih između inhibitora angiogeneze, inhibitora prijenosa impulsa i antiproliferatnih tvari u količini učinkovitoj za inhibiciju nenormalnog rasta stanica. The compound of formula 1 or its pharmaceutically acceptable salt can be taken or prepared into a pharmaceutical preparation in the presence of one or more substances selected from angiogenesis inhibitors, impulse transmission inhibitors and antiproliferative substances in an amount effective to inhibit abnormal cell growth.

Za ovdje opisane postupke i farmaceutske pripravke namijenjene tretmanu nenormalnog rasta stanica, uključujući i kancer, a koji uključuju spoj formule 1 i upravo navedene dodatne tvari, mogu se koristiti inhibitori angiogeneze kao što je to inhibitor MMP-2 (matriks-metaloproteinaze 2), MMP-9 (matriks-metaloproteinaze 9) i inhibitor COX-II (ciklooksigenaze II). U primjere korisnih inhibitora COX-II uključuju se CELEBREX™ (celecoxib), valdecoxib i rofecoxib. Primjeri korisnih inhibitora matriks metaloproteinaze opisani su u WO 96/33172 (objavljeno 24. listopada 1996), WO 96/27583 (objavljeno 7. ožujka 1996), European Patent Application No. 97304971.1 (podnesena 8. srpnja 1997), European Patent Application No. 99308617.2 (podnesena 29. listopada 1999), WO 98/07697 (objavljeno 26. veljače 1998), WO 98/03516 (objavljeno 29. siječnja 1998), WO 98/34918 (objavljeno 13. kolovoza 1998), WO 98/34915 (objavljeno 13. kolovoza 1998), WO 98/33768 (objavljeno 6. kolovoza 1998), WO 98/30566 (objavljeno 16. srpnja 1998), European Patent Publication 606,046 (objavljeno 13. srpnja 1994), European Patent Publication 931,788 (objavljeno 28. srpnja 1999), WO 90/05719 (objavljeno 31. svibnja 1990), WO 99/52910 (objavljeno 21. listopada 1999), WO 99/52889 (objavljeno 21. listopada 1999), WO 99/29667 (objavljeno 17. lipnja 1999), PCT Interanational Application No. PCT/IB98/01113 (podneseno 21. srpnja 1998), European Patent Application No. 99302232.1 (podneseno 25. ožujka 1999), Great Britain patent application number 9912961.1 (podneseno 3. Lipnja 1999), United States Provisional Application No. 60/148,464 (podneseno 12. kolovoza 1999), United States Patent 5,863,949 (izdano 26. siječnja 1999), United States Patent 5,861,510 (izdano 19. siječnja 1999) i European Patent Publication 780,386 (objavljeno 25. lipnja 1997), gdje su svi primjeri ovdje u cijelosti dani u obliku literaturnog navoda. U poželjne inhibitore MMP-2 i MMP-9 uključuju se oni s malenom ili nikakvom aktivnošću inhibiranja MMP-1. Još su poželjniji oni koji u odnosu na druge matriks-metaloproteinaze (tj. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 i MMP-13) selektivno inhibiraju MMP-2 i/ili MMP-9. For the procedures described here and the pharmaceutical preparations intended for the treatment of abnormal cell growth, including cancer, and which include the compound of formula 1 and the aforementioned additional substances, angiogenesis inhibitors such as MMP-2 (matrix-metalloproteinase 2) inhibitor, MMP -9 (matrix-metalloproteinase 9) and COX-II (cyclooxygenase II) inhibitor. Examples of useful COX-II inhibitors include CELEBREX™ (celecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 ( published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published 28 .July 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999 1999), PCT International Application No. PCT/IB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain patent application number 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed Aug. 12, 1999), United States Patent 5,863,949 (issued Jan. 26, 1999), United States Patent 5,861,510 (issued Jan. 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which examples given here in full in the form of literature citations. Preferred MMP-2 and MMP-9 inhibitors include those with little or no MMP-1 inhibitory activity. Even more preferred are those that compared to other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12 and MMP-13) selectively inhibit MMP-2 and/or MMP-9.

Određeni primjeri inhibitora MMP korisnih u ovom izumu su AG-3340, RO 32-3555, RS 13-0830, te dolje navedeni spojevi: Certain examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds listed below:

3-[[4-(4-fluor-fenoksi)-benzensulfonil]-(1-hidroksikarbamoil-ciklopentil)-amino]-propanska kiselina; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propanoic acid;

3-egzo-3-[4-(4-fluor-fenoksi)-benzensulfonilamino]-8-oksa-biciklo[3.2.1]oktan-3-karboksilne kiseline hidroksi amid; 3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxy amide;

(2R,3R)-1-[4-(2-klor-4-fluor-benziloksi)-benzensulfonil]-3-hidroksi-3-metil-piperidin-2-karboksilne kiseline hidroksiamid; (2R,3R)-1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

4-[4-(4-fluor-fenoksi)-benzensulfonilamino]-tetrahidro-piran-4-karboksilne kiseline hidroksiamid; 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide;

3-[[4-(4-fluor-fenoksi)-benzensulfonil]-(1-hidroksikarbamoil-ciklobutil)-amino]-propanska kiselina; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propanoic acid;

4-[4-(4-klor-fenoksi)-benzensulfonilamino]-tetrahidro-piran-4-karboksilne kiseline hidroksiamid; 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide;

(R)-3-[4-(4-klor-fenoksi)-benzensulfonilamino]-tetrahidro-piran-4-karboksilne kiseline hidroksiamid; (R)-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide;

(2R, 3R)-1-[4-(4-fluor-2-metil-benziloksi)-benzensulfonil]-3-hidroksi-3-metil-piperidin-2-karboksilne kiseline hidroksiamid; (2R, 3R)-1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

3-[[4-(4-fluor-fenoksi)-benzensulfonil]-(1-hidroksikarbamoil-1-metil-etil)-amino]-propanska kiselina; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propanoic acid;

3-[[4-(4-fluor-fenoksi)-benzensulfonil]-(4-hidroksikarbamoil-tetrahidro-piran-4-il)-amino]-propanska kiselina; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propanoic acid;

3-egzo-3-[4-(4-klor-fenoksi)-benzensulfonilamino]-8-oksa-biciklo[3.2.1]oktan-3-karboksilne kiseline hidroksi amid; 3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxy amide;

3-endo-3-[4-(4-fluor-fenoksi)-benzensulfonilamino]-8-oksa-biciklo[3.2.1]oktan-3-karboksilne kiseline hidroksi amid i 3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxy amide and

(R)-3-[4-(4-fluor-fenoksi)-benzensulfonilamino]-tetrahidro-furan-3-karboksilne kiseline hidroksiamid (R)-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide

i farmaceutski prihvatljive soli i solvati rečenih spojeva. and pharmaceutically acceptable salts and solvates of said compounds.

Za ovaj je izum moguće koristiti i druge inhibitore angiogeneze, uključujući i druge COX-II inhibitore i druge MMP inhibitore. It is possible to use other angiogenesis inhibitors for this invention, including other COX-II inhibitors and other MMP inhibitors.

Učinkovitu količinu inhibitora COX-II u kombinaciji s inhibitorom cdk5, a koji za primjer može biti spoj formule 1, u općenitom slučaju će odrediti stručnjak na području. Kao prijedlog može se navesti da će učinkovita dnevna doza inhibitora COX-II u kombinaciji s inhibitorom cdk5 iznositi od oko 0,1 do oko 25 mg/kg tjelesne mase. U općenitom slučaju učinkovita dnevna doza inhibitora cdk5 će iznositi od oko 0,0001 do oko 10 mg/kg tjelesne mase. U ponekim slučajevima kombiniranog uzimanja moguće je da učinkovita količina inhibitora COX-II i/ili inhibitora cdk5 potrebna za postizanje željenog učinka inhibicije nenormalnog rasta stanice bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. The effective amount of the COX-II inhibitor in combination with the cdk5 inhibitor, which may for example be a compound of formula 1, will generally be determined by one skilled in the art. As a suggestion, it can be stated that the effective daily dose of the COX-II inhibitor in combination with the cdk5 inhibitor will be from about 0.1 to about 25 mg/kg of body weight. In general, an effective daily dose of a cdk5 inhibitor will be from about 0.0001 to about 10 mg/kg of body weight. In some cases of combined intake, it is possible that the effective amount of COX-II inhibitor and/or cdk5 inhibitor needed to achieve the desired effect of inhibiting abnormal cell growth may be less than the amount needed when they are taken individually.

Spoj formule 1 može se također koristiti i u kombinaciji s inhibitorima prijenosa impulsa, kao što su to inhibitori EGFR (receptor epidermalnog faktora rasta), kao što su to antitijela EGFR, antitijela EGF i molekule koje su inhibitori EGFR; inhibitori VEGF (faktor rasta vaskularnog endotela); te inhibitori receptora erbB2, kao što su to organske molekule ili antitijela koja se vežu na erbB2 receptor, na primjer HERCEPTINTM (Genentech, Inc. of South San Francisco, California, USA). Kako je to ovdje već opisano ovakve kombinacije korisne su prilikom tretmana i prevencije nenormalnog rasta stanica, uključujući i kancer. The compound of formula 1 can also be used in combination with impulse transmission inhibitors, such as EGFR (epidermal growth factor receptor) inhibitors, such as EGFR antibodies, EGF antibodies and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example HERCEPTINTM (Genentech, Inc. of South San Francisco, California, USA). As already described here, such combinations are useful in the treatment and prevention of abnormal cell growth, including cancer.

Inhibitori EGFR su opisani na primjer u WO 95/19970 (objavljeno 27. srpnja 1995), WO 98/14451 (objavljeno 9. travnja 1998), WO 98/02434 (objavljeno 22. siječnja 1998) i u United States Patent 5,747,498 (izdano 5. svibnja 1998), te se takve tvari mogu koristiti u ovom izumu na već opisani način. U inhibitore EGFR uključuju se, ali se pri tome ne ograničava samo na navedene, monoklona antitijela C225 i ANTI-egfr 22Mab (ImClone Systems Incorporated of New York, New York USA), spoj ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA) i OLX-103 (Merck & Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) i EGF fuzijski toksin (Seragen Inc. of Hopkinton, Massachusettes). Ovi i drugi inhibitori EGFR mogu se koristiti u ovom izumu na već opisani način. EGFR inhibitors are described for example in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998) and in United States Patent 5,747,498 (issued 5 . May 1998), and such substances can be used in the present invention in the manner already described. EGFR inhibitors include, but are not limited to, monoclonal antibodies C225 and ANTI-egfr 22Mab (ImClone Systems Incorporated of New York, New York USA), compound ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA) and OLX-103 (Merck & Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusetts). These and other EGFR inhibitors can be used in the present invention in the manner already described.

Inhibitori VEGF, na primjer SU-5416 i SU-6668 (Sugen Inc. of South San Francisco, California, USA), također se mogu kombinirati sa spojem formule 1. Inhibitori VEGF su opisani na primjer u WO 99/24440 (objavljeno 20. svibnja 1999), PCT International Application PCT/IB99/00797 (podneseno 3. svibnja 1999), WO 95/21613 (objavljeno 17. kolovoza 1995), WO 99/61422 (objavljeno 2. prosinca 1999), United States Patent 5,834,504 (izdano 10. studenog 1998), WO 98/50356 (objavljeno 12. studenog 1998), United States Patent 5,883,113 (izdano 16. ožujka 1999), United States Patent 5,886,020 (izdano 23. ožujka 1999), United States Patent 5,792,783 (izdano 11. kolovoza 1998), WO 99/10349 (objavljeno 4. ožujka 1999), WO 97/32856 (objavljeno 12. rujna 1997), WO 97/22596 (objavljeno 26. lipnja 1997), WO 98/54093 (objavljeno 3. prosinca 1998), WO 98/02438 (objavljeno 22. siječnja 1998), WO 99/16755 (objavljeno 8. travnja 1999) i WO 98/02437 (objavljeno 22. siječnja 1998) ovdje dani u cijelosti u obliku literaturnih navoda. Drugi primjeri određenih specifičnih inhibitora VEGF korisnih za ovaj izum su IM862 (Cytran Inc. of Kirkland, Washington, USA), monoklonsko antitijelo anti-VEGF proizvođača Genentech, Inc. of South San Francisco, California, te angiozim - sintetski ribozim proizvođača Ribozyme (Boulder, Colorado) i Chiron (Emeryville, California). Ovi i drugi inhibitori VEGF mogu se koristiti u ovom izumu na već opisani način. VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, California, USA), can also be combined with the compound of formula 1. VEGF inhibitors are described for example in WO 99/24440 (published 20 May 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued March 11, 1999). August 1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998 ), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998) incorporated herein by reference in their entirety. factual allegations. Other examples of certain specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Washington, USA), an anti-VEGF monoclonal antibody manufactured by Genentech, Inc. of South San Francisco, California, and angiozyme - a synthetic ribozyme manufactured by Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). These and other VEGF inhibitors can be used in the present invention in the manner already described.

Sa spojem formule 1 mogu se kombinirati i inhibitori receptora erbB2, kao što je to GW-282974 (Glaxo Wellcome plc.), te monoklona antitijela AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) i 2B-1 (Chiron), opisani na primjer u WO 98/02434 (objavljeno 22. siječnja 1998), WO 99/35146 (objavljeno 15. srpnja 1999), WO 99/35132 (objavljeno 15. srpnja 1999), WO 98/02437 (objavljeno 22. siječnja 1998), WO 97/13760 (objavljeno 17. travnja 1997), WO 95/19970 (objavljeno 27. srpnja 1995), United States Patent 5,587,458 (izdano 24. prosinca 1996) i United States Patent 5,877,305 (izdano 2. ožujka 1999) ovdje dani u cijelosti u obliku literaturnih navoda. Inhibitori receptora erbB2 korisni za ovaj izum opisani su također i u United States Provisional Application No. 60/117,341 (podneseno 27. siječnja 1999), te u United States Provisional Application No. 60/117,346 (podneseno 27. siječnja 1999) koji su ovdje dani u cijelosti u obliku literaturnih navoda. erbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc.), and monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 ( Chiron), described for example in WO 98/02434 (published 22 January 1998), WO 99/35146 (published 15 July 1999), WO 99/35132 (published 15 July 1999), WO 98/02437 (published 22 .January 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1996 1999) given here in full in the form of literature references. Inhibitors of the erbB2 receptor useful in the present invention are also described in United States Provisional Application No. 60/117,341 (filed January 27, 1999), and in United States Provisional Application No. 60/117,346 (filed Jan. 27, 1999) which are incorporated herein by reference in their entirety.

Spojevi i tvari opisani u gore navedenim PCT prijavama, U.S. patentima i U.S. Provisional prijavama, a koji su inhibitori receptora erbB2, a također i drugi spojevi i tvari koji inhibiraju receptor erbB2, mogu se koristiti u kombinaciji sa spojem formule 1 u skladu s ovim izumom. The compounds and substances described in the aforementioned PCT applications, U.S. patents and U.S. Provisional applications, which are inhibitors of the erbB2 receptor, and also other compounds and substances that inhibit the erbB2 receptor, can be used in combination with the compound of formula 1 in accordance with the present invention.

Spoj formule 1 može se također koristiti u kombinaciji s drugim tvarima korisnim prilikom tretmana nenormalnog rasta stanica ili kancera, a u koje se ubrajaju, ali se pri tome ne ograničava samo na navedene i tvari za pojačanje protutumornog imuno odgovora, kao što su to antitijela CTLA4 (citotoksičkog limfocita antigen 4) i druge tvari koje blokiraju CTLA4, te antiproliferatne tvari kao što su to inhibitori farnezil protein transferaze. U specifična antitijela CTLA4 koja se mogu koristiti u ovom izumu uključuju se ona opisana u United States Provisional Application No. 60/113,647 (podneseno 23. prosinca 1998) koji je ovdje dan u cijelosti u obliku literaturnog navoda, a također i druga antitijela CTLA4. The compound of formula 1 can also be used in combination with other substances useful in the treatment of abnormal cell growth or cancer, which include, but are not limited to, substances for enhancing the antitumor immune response, such as CTLA4 antibodies ( cytotoxic lymphocyte antigen 4) and other substances that block CTLA4, and antiproliferative substances such as farnesyl protein transferase inhibitors. Specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application No. 60/113,647 (filed Dec. 23, 1998) which is incorporated herein by reference in its entirety, as well as other CTLA4 antibodies.

Spojevi formule 1 mogu se uzimati kao dio postupka za inhibiciju nenormalnog rasta stanica u sisavaca u kombinaciji s terapijom pomoću zračenja. Postupci primanja terapije zračenja poznati su na području, te se takvi postupci mogu koristiti u ovdje opisanoj kombiniranoj terapiji. Uzimanje spoja prema ovom izumu u takvoj kombiniranoj terapiji može se odrediti kako je to ovdje opisano. The compounds of formula 1 may be administered as part of a procedure for inhibiting abnormal cell growth in mammals in combination with radiation therapy. Procedures for receiving radiation therapy are known in the art, and such procedures may be used in the combination therapy described herein. Administration of a compound of the present invention in such combination therapy may be determined as described herein.

Inhibitori cdk5, kao što je to spoj formule 1, mogu se također uzimati i u kombinaciji s inhibitorom COX-II za tretman Alzheimerove bolesti, blagog kognitivnog poremećaja ili kognitivnog poremećaja povezanog sa starošću. Određeni primjeri inhibitora COX-II korisni u ovom vidu ovog izuma već su prije navedeni u dijelu gdje je opisana upotreba inhibitora COX-II u kombinaciji sa spojem formule 1 prilikom tretmana nenormalnog rasta stanica. Učinkovitu količinu inhibitora COX-II u kombinaciji s inhibitorom cdk5, a koji na primjer može biti spoj formule 1, u općenitom slučaju će odrediti stručnjak na području. Kao prijedlog može se navesti da će učinkovita dnevna doza inhibitora COX-II u kombinaciji s inhibitorom cdk5 iznositi od oko 0,1 do oko 25 mg/kg tjelesne mase. U općenitom slučaju učinkovita dnevna doza inhibitora cdk5 će iznositi od oko 0,0001 do oko 10 mg/kg tjelesne mase. U ponekim slučajevima kombiniranog uzimanja moguće je da učinkovita količina inhibitora COX-II i/ili inhibitora cdk5 potrebna za postizanje željenog učinka prilikom tretmana Alzheimerove bolesti, blagog kognitivnog poremećaja ili kognitivnog poremećaja povezanog sa starošću bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. Cdk5 inhibitors, such as the compound of formula 1, can also be taken in combination with a COX-II inhibitor for the treatment of Alzheimer's disease, mild cognitive impairment or age-related cognitive impairment. Certain examples of COX-II inhibitors useful in this aspect of this invention have already been previously mentioned in the section where the use of COX-II inhibitors in combination with the compound of formula 1 in the treatment of abnormal cell growth is described. The effective amount of the COX-II inhibitor in combination with the cdk5 inhibitor, which may for example be a compound of formula 1, will generally be determined by one skilled in the art. As a suggestion, it can be stated that the effective daily dose of the COX-II inhibitor in combination with the cdk5 inhibitor will be from about 0.1 to about 25 mg/kg of body weight. In general, an effective daily dose of a cdk5 inhibitor will be from about 0.0001 to about 10 mg/kg of body weight. In some cases of combined intake, it is possible that the effective amount of COX-II inhibitors and/or cdk5 inhibitors needed to achieve the desired effect in the treatment of Alzheimer's disease, mild cognitive impairment or age-related cognitive impairment may be less than the amount needed when they are taken individually. .

Inhibitori cdk5, kao što je to spoj formule 1 može se također uzimati i u kombinaciji s antagonistom receptora NK-1 za tretman depresija ili anksioznosti. Antagonist receptora NK-1 jest tvar koja je sposobna antagonizirati receptore NK-1, pa prema tome inhibirati odgovore posredovane tahikininom, kao što su to odgovori posredovani s tvari P. Na području su poznati različiti antagonisti receptora NK-1, te se prema ovom izumu bilo koji takav antagonist može koristiti u kombinaciji s inhibitorom cdk5, na primjer spojem formule 1. Antagonisti receptora NK-1 opisani su na primjer u United States Patent 5,716,965 (izdano 10. veljače 1998), United States Patent 5,852,038 (izdano 22. prosinca 1998), WO 90/05729 (s nadnevkom međunarodne objave od 31. svibnja 1990), United States Patent 5,807,867 (izdano 15. rujna 1998), United States Patent 5,886,009 (izdano 23. ožujka 1999), United States Patent 5,939,433 (izdano 17. kolovoza 1999), United States Patent 5,773,450 (izdano 30. lipnja 1998), United States Patent 5,744,480 (izdano 28. travnja 1998), United States Patent 5,232,929 (izdano 3. kolovoza 1993), United States Patent 5,332,817 (izdano 26. srpnja 1994), United States Patent 5,122,525 (izdano 16. lipnja 1992), United States Patent 5,843,966 (izdano 1. prosinca 1998), United States Patent 5,703,240 (izdano 30. prosinca 1997), United States Patent 5,719,147 (izdano 17. veljače 1998) i United States Patent 5,637,699 (izdano 10. lipnja 1997). Svaki od gore navedenih U.S. patenata i objavljenih PCT prijava ovdje je dan u cijelosti u obliku literaturnog navoda. Spojevi opisani u tim navodima, a koji se odlikuju antagonističkim učinkom spram receptora NK-1, mogu se koristiti u ovom izumu. U ovom se izumu mogu koristiti i drugi antagonisti receptora NK-1. Cdk5 inhibitors, such as the compound of formula 1, can also be taken in combination with an NK-1 receptor antagonist for the treatment of depression or anxiety. An NK-1 receptor antagonist is a substance capable of antagonizing NK-1 receptors, thus inhibiting responses mediated by tachykinin, such as responses mediated by substance P. Various NK-1 receptor antagonists are known in the field, and according to this invention any such antagonist can be used in combination with a cdk5 inhibitor, for example a compound of formula 1. NK-1 receptor antagonists are described for example in United States Patent 5,716,965 (issued February 10, 1998), United States Patent 5,852,038 (issued December 22, 1998 ), WO 90/05729 (with international publication date of May 31, 1990), United States Patent 5,807,867 (issued September 15, 1998), United States Patent 5,886,009 (issued March 23, 1999), United States Patent 5,939,433 (issued September 17, 1998). August 1999), United States Patent 5,773,450 (issued June 30, 1998), United States Patent 5,744,480 (issued April 28, 1998), United States Patent 5,232,929 (issued August 3, 1993), United States Patent 5,332,817 (issued April 26, 1998). July 1994), United States Patent 5,122,525 (issued June 16, 1992), United States Patent 5,843,966 (issued December 1, 1998), United States Patent 5,703,240 (issued December 30, 1997), United States Patent 5,719,147 (issued February 17, 1998 ) and United States Patent 5,637,699 (issued June 10, 1997). Each of the above U.S. patents and published PCT applications are given here in full in the form of a literature citation. The compounds described in these claims, which are characterized by an antagonistic effect against the NK-1 receptor, can be used in the present invention. Other NK-1 receptor antagonists may be used in this invention.

Učinkovitu količinu antagonista receptora NK-1 u kombinaciji s inhibitorom cdk5, a koji na primjer može biti spoj formule 1, u općenitom slučaju će odrediti stručnjak na području. Kao prijedlog može se navesti da će učinkovita dnevna doza antagonista receptora NK-1 u kombinaciji s inhibitorom cdk5 iznositi od oko 0,07 do oko 21 mg/kg tjelesne mase. U općenitom slučaju učinkovita dnevna doza inhibitora cdk5 će iznositi od oko 0,0001 do oko 10 mg/kg tjelesne mase. U ponekim slučajevima kombiniranog uzimanja moguće je da učinkovita količina antagonista receptora NK-1 i/ili inhibitora cdk5 potrebna za postizanje željenog učinka prilikom tretmana depresije ili anksioznosti bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. The effective amount of the NK-1 receptor antagonist in combination with the cdk5 inhibitor, which may for example be a compound of formula 1, will generally be determined by one skilled in the art. As a suggestion, it can be stated that the effective daily dose of the NK-1 receptor antagonist in combination with the cdk5 inhibitor will be from about 0.07 to about 21 mg/kg of body weight. In general, an effective daily dose of a cdk5 inhibitor will be from about 0.0001 to about 10 mg/kg of body weight. In some cases of combined intake, it is possible that the effective amount of NK-1 receptor antagonist and/or cdk5 inhibitor needed to achieve the desired effect in the treatment of depression or anxiety may be less than the amount needed when they are taken individually.

Predmet ovog izuma jest također i kombinacija inhibitora cdk5, kao što je to spoj formule 1, s antagonistom receptora 5HT1D prilikom tretmana depresije ili anksioznosti. Antagonist receptora 5HT1D jest tvar koja antagonizira 5HT1D podvrstu receptora serotonina. Prema ovom izumu, bilo koja takva tvar može se koristiti u kombinaciji s inhibitorom cdk5 kao što je to spoj formule 1. Stručnjak na području lako može odrediti da li se tvar odlikuje aktivnošću antagoniziranja receptora 5HT1D. Na primjer, antagonisti receptora 5HT1D opisani su u WO 98/14433 (s nadnevkom međunarodne objave od 9. travnja 1998), WO 97/36867 (s nadnevkom međunarodne objave od 9. listopada 1997), WO 94/21619 (s nadnevkom međunarodne objave od 29. rujna 1994), United States Patent 5,510,350 (izdano 23. travnja 1996), United States Patent 5,358,948 (izdano 25. listopada 1994) i u GB 2276162 A (objavljeno 21. rujna 1994). Ovi antagonisti receptora 5HT1D, a također i drugi, mogu se koristiti u skladu s ovim izumom. Gore navedene objavljene patentne prijave i patenti ovdje su dani u cijelosti u obliku literaturnih navoda. The subject of this invention is also the combination of a cdk5 inhibitor, such as the compound of formula 1, with a 5HT1D receptor antagonist in the treatment of depression or anxiety. A 5HT1D receptor antagonist is a substance that antagonizes the 5HT1D subtype of serotonin receptors. According to the present invention, any such substance can be used in combination with a cdk5 inhibitor such as a compound of formula 1. One skilled in the art can readily determine whether the substance exhibits 5HT1D receptor antagonizing activity. For example, 5HT1D receptor antagonists are described in WO 98/14433 (international publication date Apr. 9, 1998), WO 97/36867 (international publication date Oct. 9, 1997), WO 94/21619 (international publication date dated September 29, 1994), United States Patent 5,510,350 (issued April 23, 1996), United States Patent 5,358,948 (issued October 25, 1994) and in GB 2276162 A (published September 21, 1994). These 5HT1D receptor antagonists, as well as others, can be used in accordance with the present invention. The above published patent applications and patents are hereby incorporated by reference in their entirety.

Učinkovitu količinu antagonista receptora 5HT1D u kombinaciji s inhibitorom cdk5, a koji na primjer može biti spoj formule 1, u općenitom slučaju će odrediti stručnjak na području. Kao prijedlog može se navesti da će učinkovita dnevna doza antagonista receptora 5HT1D u kombinaciji s inhibitorom cdk5 iznositi od oko 0,01 do oko 40 mg/kg tjelesne mase. U općenitom slučaju učinkovita dnevna doza inhibitora cdk5 će iznositi od oko 0,0001 do oko 10 mg/kg tjelesne mase. U ponekim slučajevima kombiniranog uzimanja moguće je da učinkovita količina antagonista receptora 5HT1D i/ili inhibitora cdk5 potrebna za postizanje željenog učinka prilikom tretmana depresije ili anksioznosti bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. The effective amount of the 5HT1D receptor antagonist in combination with the cdk5 inhibitor, which may for example be a compound of formula 1, will generally be determined by one skilled in the art. As a suggestion, it can be stated that the effective daily dose of the 5HT1D receptor antagonist in combination with the cdk5 inhibitor will be from about 0.01 to about 40 mg/kg of body weight. In general, an effective daily dose of a cdk5 inhibitor will be from about 0.0001 to about 10 mg/kg of body weight. In some cases of combined intake, it is possible that the effective amount of 5HT1D receptor antagonists and/or cdk5 inhibitors needed to achieve the desired effect in the treatment of depression or anxiety may be less than the amount needed when they are taken individually.

Ovaj izum, također, omogućuje farmaceutski pripravak i postupak tretmana depresije ili anksioznosti u sisavaca, a koji uključuju inhibitor cdk5, na primjer spoj formule 1, i SSRI. U primjere SSRI koji se mogu kombinirati s inhibitorom cdk5, na primjer spojevima formule 1 i njihovim farmaceutski prihvatljivim solima, u farmaceutski pripravak ili postupak, uključuju se, ali se pri tome ne ograničava samo na navedene, fluoksetin, paroksetin, sertralin i fuvoksamin. I drugi SSRI mogu se kombinirati ili uzimati u kombinaciji s inhibitorom cdk5, na primjer sa spojevima formule 1 ili njihovim farmaceutski prihvatljivim solima. U ostale antidepresive ili anksiolitike koji se mogu kombinirati ili uzimati u kombinaciji s inhibitorom cdk5, na primjer spojevima formule 1 i njihovim farmaceutski prihvatljivim solima, uključuju se WELLBUTRIN, SERZON i EFFEXOR. The present invention also provides a pharmaceutical composition and method of treating depression or anxiety in a mammal comprising a cdk5 inhibitor, for example a compound of formula 1, and an SSRI. Examples of SSRIs that can be combined with a cdk5 inhibitor, for example compounds of formula 1 and their pharmaceutically acceptable salts, in a pharmaceutical preparation or process include, but are not limited to, fluoxetine, paroxetine, sertraline and fuvoxamine. Other SSRIs can also be combined or taken in combination with a cdk5 inhibitor, for example with compounds of formula 1 or their pharmaceutically acceptable salts. Other antidepressants or anxiolytics that can be combined or taken in combination with a cdk5 inhibitor, for example the compounds of formula 1 and their pharmaceutically acceptable salts, include WELLBUTRIN, SERZON and EFFEXOR.

Učinkovitu količinu SSRI u kombinaciji s inhibitorom cdk5, a koji na primjer može biti spoj formule 1, u općenitom slučaju će odrediti stručnjak na području. Kao prijedlog može se navesti da će učinkovita dnevna doza SSRI u kombinaciji s inhibitorom cdk5 iznositi od oko 0,01 do oko 500 mg/kg tjelesne mase. U općenitom slučaju učinkovita dnevna doza inhibitora cdk5 će iznositi od oko 0,0001 do oko 10 mg/kg tjelesne mase. U ponekim slučajevima kombiniranog uzimanja moguće je da učinkovita količina SSRI i/ili inhibitora cdk5 potrebna za postizanje željenog učinka prilikom tretmana depresije ili anksioznosti bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. An effective amount of an SSRI in combination with a cdk5 inhibitor, which may for example be a compound of formula 1, will generally be determined by one skilled in the art. As a suggestion, it can be stated that the effective daily dose of an SSRI in combination with a cdk5 inhibitor will be from about 0.01 to about 500 mg/kg of body weight. In general, an effective daily dose of a cdk5 inhibitor will be from about 0.0001 to about 10 mg/kg of body weight. In some cases of combined intake, it is possible that the effective amount of SSRI and/or cdk5 inhibitor needed to achieve the desired effect in the treatment of depression or anxiety may be less than the amount needed when they are taken individually.

Inhibitor cdk5, na primjer spoj formule 1 ili njegova farmaceutski prihvatljiva sol, može se također kombinirati i sa jednim ili više antipsihotika, na primjer s dopaminergijskom tvari, prilikom tretmana bolesti ili stanja na koja se može utjecati ili ih poboljšati promjenom neurotransmisije posredovane dopaminom, kao što je to shizofrenija. U primjere antipsihotika s kojima se spoj prema ovom izumu može kombinirati uključuju se ziprazidon (5-(2-(4-(1,2-benzizotiazol-3-il)-1-piperazinil)etil)-6-klor-1,3-dihidro-2H-indol-2-on, U.S. Patent 4,831,031 i U.S. Patent 5,312,925); olanzapin (2-metil-4-(4-metil-1-piperazinil-10H-tien (2,3b) (1,5)benzodiazepin; U.S. Patent 4,115,574 i U.S. Patent 5,229,382); risperidon (3-[2-[4-(6-fluor-1,2-benzizoksazol-3-il)-1-piperidinil]etil]-6,7,8,9-tetrahidro-2-metil-4H-pirido[1,2-a]pirimidin-4-on; U.S. Patent 4,804,663); L-745870 (3-(4-(4-klorfenil)piperazin-1-il)metil-1H-pirolo(2,3-b)piridin; U.S. Patent 5,432,177); sonepiprazol (S-4-(4-(2-(izokroman-1-il)etil)piperazin-1-il)benzensulfonamid; U.S. Patent 5,877,317); RP 62203 (fananserin, 2-(3-(4-(4-(fluorfenil)-1-piperazinil)propil)nafto(1,8-c,d)izotiazol-1,1-dioksid; U.S. Patent 5,021,420); NGD 941 (U.S. Patent 5,633,376 i U.S. Patent 5,428,165); balaperidon ((1α,5α,6α)-3-(2-(6-(4-fluorfenil)-3-azabiciklo(3.2.0)hept-3-il)etil)-2,4-(1H,3H)-kinazolindion, U.S. Patent 5,475,105); flezinoksan ((+)-4-fluor-N-[2-[4-5-(2-hidroksimetil-1,4-benzodioksanil)]-1-piperazinil]etil]benzamid; U.S. Patent 4,833,142) i gepiron (4,4-dimetil-1-(4-(4-(2-pirimidinil)-1-piperazinil)butil)-2,6-piperidindion, U.S. Patent 4,423,049). Patenti navedeni u gornjem paragrafu, ovdje su dani cijelosti u obliku literaturnih navoda. U općenitom slučaju učinkovita dnevna doza inhibitora cdk5 će iznositi od oko 0,0001 do oko 10 mg/kg tjelesne mase. Količina bilo kojeg gore navedenog antipsihotika namijenjenog kombiniranju s inhibitorom cdk5, kao što je to na primjer spoj formule 1, u općenitom će slučaju biti ona količina za koju je na području poznato da je korisna u tretmanu psihičkih poremećaja. Pa ipak, u ponekim slučajevima kombiniranog uzimanja moguće je da učinkovita količina antipsihotika i/ili inhibitora cdk5 potrebna za postizanje željenog učinka prilikom tretmana depresije ili anksioznosti bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. Nadalje, podrazumijeva se da ovaj izum također obuhvaća i kombinacije inhibitora cdk5, kao što je to na primjer spoj formule 1, s antipsihoticima ili dopaminergijskim tvarima koje su različite od gore navedenih. A cdk5 inhibitor, for example a compound of formula 1 or a pharmaceutically acceptable salt thereof, can also be combined with one or more antipsychotics, for example a dopaminergic substance, in the treatment of diseases or conditions that can be affected or improved by altering dopamine-mediated neurotransmission, such as what is schizophrenia. Examples of antipsychotics with which a compound of the present invention can be combined include ziprasidone (5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3 -dihydro-2H-indol-2-one, U.S. Patent 4,831,031 and U.S. Patent 5,312,925); olanzapine (2-methyl-4-(4-methyl-1-piperazinyl-10H-thiene (2,3b) (1,5)benzodiazepine; U.S. Patent 4,115,574 and U.S. Patent 5,229,382); risperidone (3-[2-[4 -(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidine- 4-one; U.S. Patent 4,804,663); L-745870 (3-(4-(4-chlorophenyl)piperazin-1-yl)methyl-1H-pyrrolo(2,3-b)pyridine; U.S. Patent 5,432,177); sonepiprazole ( S-4-(4-(2-(isochroman-1-yl)ethyl)piperazin-1-yl)benzenesulfonamide; U.S. Patent 5,877,317); RP 62203 (phananserin, 2-(3-(4-(4-(fluorophenyl) )-1-piperazinyl)propyl)naphtho(1,8-c,d)isothiazole-1,1-dioxide; U.S. Patent 5,021,420); NGD 941 (U.S. Patent 5,633,376 and U.S. Patent 5,428,165); balaperidone ((1α,5α, 6α)-3-(2-(6-(4-fluorophenyl)-3-azabicyclo(3.2.0)hept-3-yl)ethyl)-2,4-(1H,3H)-quinazolindione, U.S. Patent 5,475,105) ; flesinoxane ((+)-4-fluoro-N-[2-[4-5-(2-hydroxymethyl-1,4-benzodioxanyl)]-1-piperazinyl]ethyl]benzamide; U.S. Patent 4,833,142 and gepirone (4 ,4-dimethyl-1-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-p iperidindione, U.S. Patent 4,423,049). The patents mentioned in the above paragraph are given here in their entirety in the form of literature references. In general, an effective daily dose of a cdk5 inhibitor will be from about 0.0001 to about 10 mg/kg of body weight. The amount of any of the above antipsychotics intended to be combined with a cdk5 inhibitor, such as for example a compound of formula 1, will generally be that amount known in the art to be useful in the treatment of psychiatric disorders. And yet, in some cases of combined intake, it is possible that the effective amount of antipsychotics and/or cdk5 inhibitors needed to achieve the desired effect in the treatment of depression or anxiety may be less than the amount needed when they are taken individually. Furthermore, it is understood that the present invention also encompasses combinations of cdk5 inhibitors, such as for example the compound of formula 1, with antipsychotics or dopaminergic agents other than those mentioned above.

Predložena količina sonepiprazola u gore opisanim kombinacijama s inhibitorom cdk5, kao što je to na primjer spoj formule 1, iznosi od oko 0,005 do oko 50 mg/kg tjelesne mase pacijenta dnevno. Predložena količina RP 62203 u takvim kombinacijama iznosi od oko 0,20 do oko 6 mg/kg tjelesne mase pacijenta dnevno. Predložena količina NGD 941 u takvim kombinacijama iznosi od oko 0,1 do oko 140 mg/kg tjelesne mase pacijenta dnevno. Predložena količina balaperidona u takvim kombinacijama iznosi od oko 1 do oko 100 mg/kg tjelesne mase pacijenta dnevno. Predložena količina flezinoksana u takvim kombinacijama iznosi od oko 0,02 do oko 1,6 mg/kg tjelesne mase pacijenta dnevno. Predložena količina gepirona u takvim kombinacijama iznosi od oko 0,01 do oko 2 mg/kg tjelesne mase pacijenta dnevno. Predložena količina L-745870 u takvim kombinacijama iznosi od oko 0,01 do oko 250 mg/kg tjelesne mase pacijenta dnevno, dok se prednost daje količini od oko 0,05 do oko 100 mg/kg tjelesne mase dnevno. Predložena količina risperidona u takvim kombinacijama iznosi od oko 0,05 do oko 50 mg/kg tjelesne mase pacijenta dnevno. Predložena količina olanzapina u takvim kombinacijama iznosi od oko 0,0005 do oko 0,6 mg/kg tjelesne mase pacijenta dnevno. Predložena količina ziprazidona u takvim kombinacijama iznosi od oko 0,05 do oko 10 mg/kg tjelesne mase pacijenta dnevno. U ponekim slučajevima bilo kojeg gore navedenog kombiniranog uzimanja moguće je da učinkovita količina bilo koje tvari u kombinaciji potrebna za postizanje željenog učinka prilikom tretmana psihičkog stanja bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. The suggested amount of sonepiprazole in the combinations described above with the cdk5 inhibitor, such as for example the compound of formula 1, is from about 0.005 to about 50 mg/kg of the patient's body weight per day. The suggested amount of RP 62203 in such combinations is from about 0.20 to about 6 mg/kg of the patient's body weight per day. The suggested amount of NGD 941 in such combinations is from about 0.1 to about 140 mg/kg of the patient's body weight per day. The suggested amount of balaperidone in such combinations is from about 1 to about 100 mg/kg of the patient's body weight per day. The suggested amount of flesinoxan in such combinations is from about 0.02 to about 1.6 mg/kg of the patient's body weight per day. The suggested amount of gepirone in such combinations is from about 0.01 to about 2 mg/kg of the patient's body weight per day. The suggested amount of L-745870 in such combinations is from about 0.01 to about 250 mg/kg body weight of the patient per day, while an amount of from about 0.05 to about 100 mg/kg body weight per day is preferred. The suggested amount of risperidone in such combinations is from about 0.05 to about 50 mg/kg of the patient's body weight per day. The suggested amount of olanzapine in such combinations is from about 0.0005 to about 0.6 mg/kg of the patient's body weight per day. The suggested amount of ziprasidone in such combinations is from about 0.05 to about 10 mg/kg of the patient's body weight per day. In some cases of any of the above-mentioned combined intakes, it is possible that the effective amount of any substance in combination required to achieve the desired effect when treating a psychological condition may be less than the amount needed when they are taken individually.

Ovaj izum, također, omogućuje farmaceutski pripravak i postupak tretmana Alzheimerove bolesti, blagog kognitivnog poremećaja ili kognitivnog poremećaja povezanog sa starošću, a koji uključuju inhibitor cdk5, na primjer spoj formule 1, i inhibitor acetilkolinesteraze. Inhibitori acetilkolinesteraze poznati su na području, te se bilo koji inhibitor acetilkolinesteraze može koristiti za gore opisane farmaceutske pripravke ili postupke. U primjere inhibitora acetilkolinesteraze koji se mogu koristiti u ovom izumu uključuju se ARIECEPT (donepezil, U.S. Patent 4,895,841); EXELON (rivastigmin ((S)-[N-etil-3-[1-(dimetilamino)etil]fenil karbamat), U.S. Patent 5,603,176 i U.S. Patent 4,948,807); metrifonat ((2,2,2-triklor-1-hidroksietil)fosfonske kiseline dimetil ester, U.S. Patent 2,701,225 i U.S. Patent 4,950,658); galantamin (U.S. Patent 4,663,318); fizostigmin (Forest, USA); takrin (1,2,3,4-tetrahidro-9-akridinamin, U.S. Patent 4,816,456); huperzin A (5R-(5α,9β,11E))-5-amino-11-etiliden-5,6,9,10-tetrahidro-7-metil-5,9-metanciklookta(b)piridin-2-(1H)-on) i ikopezil (5,7-dihidro-3-(2-(1-(fenilmetil)-4-piperidinil)etil)-6H-pirolo(3,2-f)-1,2-benzizoksazol-6-on, U.S. Patent 5,750,542 i WO 92/17475). Gore navedeni patenti i patentne prijave ovdje su dani u cijelosti u obliku literaturnog navoda. The present invention also provides a pharmaceutical composition and method of treating Alzheimer's disease, mild cognitive impairment or age-related cognitive impairment, comprising a cdk5 inhibitor, for example a compound of formula 1, and an acetylcholinesterase inhibitor. Acetylcholinesterase inhibitors are known in the art, and any acetylcholinesterase inhibitor can be used for the pharmaceutical compositions or methods described above. Examples of acetylcholinesterase inhibitors that can be used in the present invention include ARIECEPT (donepezil, U.S. Patent 4,895,841); EXELON (rivastigmine ((S)-[N-ethyl-3-[1-(dimethylamino)ethyl]phenyl carbamate), U.S. Patent 5,603,176 and U.S. Patent 4,948,807); metrifonate ((2,2,2-trichloro-1-hydroxyethyl)phosphonic acid dimethyl ester, U.S. Patent 2,701,225 and U.S. Patent 4,950,658); galantamine (U.S. Patent 4,663,318); physostigmine (Forest, USA); tacrine (1,2,3,4-tetrahydro-9-acridinamine, U.S. Patent 4,816,456); huperzine A (5R-(5α,9β,11E))-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanecycloocta(b)pyridine-2-(1H )-one) and icopezil (5,7-dihydro-3-(2-(1-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2-f)-1,2-benzisoxazole-6 -on, U.S. Patent 5,750,542 and WO 92/17475). The above-mentioned patents and patent applications are provided herein in their entirety by way of reference.

Učinkovitu količinu inhibitora acetilkolinesteraze u kombinaciji s inhibitorom cdk5, a koji na primjer može biti spoj formule 1, u općenitom slučaju će odrediti stručnjak na području. Kao prijedlog može se navesti da će učinkovita dnevna doza inhibitora acetilkolinesteraze u kombinaciji s inhibitorom cdk5 iznositi od oko 0,01 do oko 10 mg/kg tjelesne mase. U općenitom slučaju učinkovita dnevna doza inhibitora cdk5 će iznositi od oko 0,0001 do oko 10 mg/kg tjelesne mase. U ponekim slučajevima kombiniranog uzimanja moguće je da učinkovita količina inhibitora acetilkolinesteraze i/ili inhibitora cdk5 potrebna za postizanje željenog učinka prilikom tretmana Alzheimerove bolesti, blagog kognitivnog poremećaja ili kognitivnog poremećaja povezanog sa starošću bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. The effective amount of an acetylcholinesterase inhibitor in combination with a cdk5 inhibitor, which may for example be a compound of formula 1, will generally be determined by one skilled in the art. As a suggestion, it can be stated that the effective daily dose of an acetylcholinesterase inhibitor in combination with a cdk5 inhibitor will be from about 0.01 to about 10 mg/kg of body weight. In general, an effective daily dose of a cdk5 inhibitor will be from about 0.0001 to about 10 mg/kg of body weight. In some cases of combined intake, it is possible that the effective amount of acetylcholinesterase inhibitors and/or cdk5 inhibitors required to achieve the desired effect in the treatment of Alzheimer's disease, mild cognitive impairment or age-related cognitive impairment may be less than the amount required when they are taken individually.

Ovaj izum, također, omogućuje kombinaciju inhibitora cdk5 i neuroprotektivne tvari, na primjer antagonista receptora NMDA, namijenjenu tretmanu Huntingtonove bolesti, udara, traume kralješnične moždine, traumatske povrede mozga, multi-infarktna demencija, epilepsije, amiotrofične lateralne skleroze, bola, demecije izazvane virusnim putem, na primjer demencija uzrokovana AIDSom, migrene, hipoglikemije, urinarne inkontinencije, ishemije mozga, multiple skleroze, Alzheimerove bolesti, senilne demencije Alzheimerova tipa, blagog kognitivnog poremećaja, kognitivnog poremećaja povezanog sa starošću, povraćanja, kortikobazalne degeneracije, demencije pugilistica, Downovog sindroma, miotinične distrofije, Niemann-Pickove bolesti, Pickove bolesti, prionske bolesti s plakovima, progresivne supranuklearne paralize, donje lateralne skleroze ili subakutnog sklerozantnog leukoencefalitisa. U primjere antagonista receptora NMDA koji se mogu koristiti u skladu s ovim izumom uključuju se (1S,2S)-1-(4-hidroksifenil)-2-(4-hidroksi-4-fenilpiperidin-1-il)-1-propanol (U.S. Patent 5,272,160), eliprodil (U.S. Patent 4,690,931) i gavestenel (U.S. Patent 5,373,018). Ostali antagonisti receptora NMDA, koji se mogu koristiti u skladu s ovim izumom, opisani su u U.S. Patent 5,373,018, U.S. Patent 4,690,931, U.S. Patent 5,272,160, U.S. Patent 5,185,343, U.S. Patent 5,356,905, U.S. Patent 5,744,483, WO 97/23216, WO 97/23215, WO 97/23214, WO 96/37222, WO 96/06081, WO 97/23458, WO 97/32581, WO 98/18793, WO 97/23202 i u U.S. Serial No. 08/292,651 (podneseno 18. kolovoza 1994). Gore navedeni patenti i patentne prijave ovdje su dani u cijelosti u obliku literaturnog navoda. This invention also provides a combination of a cdk5 inhibitor and a neuroprotective substance, for example an NMDA receptor antagonist, intended for the treatment of Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral-induced dementia by, for example, AIDS-related dementia, migraine, hypoglycemia, urinary incontinence, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer type, mild cognitive impairment, age-related cognitive impairment, vomiting, corticobasal degeneration, dementia pugilistica, Down syndrome, myotinic dystrophy, Niemann-Pick disease, Pick disease, prion disease with plaques, progressive supranuclear palsy, inferior lateral sclerosis or subacute sclerosing leukoencephalitis. Examples of NMDA receptor antagonists that may be used in accordance with the present invention include (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol ( U.S. Patent 5,272,160), eliprodil (U.S. Patent 4,690,931) and gavestenel (U.S. Patent 5,373,018). Other NMDA receptor antagonists that may be used in accordance with the present invention are described in U.S. Pat. U.S. Patent 5,373,018 U.S. Patent 4,690,931 U.S. Patent 5,272,160 U.S. Patent 5,185,343 U.S. Patent 5,356,905 Patent 5,744,483, WO 97/23216, WO 97/23215, WO 97/23214, WO 96/37222, WO 96/06081, WO 97/23458, WO 97/32581, WO 98/18793, WO 97/23202 and in the U.S. Serial no. 08/292,651 (filed Aug. 18, 1994). The above-mentioned patents and patent applications are provided herein in their entirety by way of reference.

U općenitom će slučaju učinkovita dnevna doza inhibitora cdk5 u kombinaciji s antagonistom receptora NMDA iznositi od oko 0,0001 do oko 10 mg/kg tjelesne mase. Učinkovita dnevna doza antagonista receptora NMDA u kombinaciji s inhibitorom cdk5, kao što je to na primjer spoj formule 1, namijenjena tretmanu bilo koje gore navedene bolesti, na primjer Alzheimerove bolesti, u općenitom će slučaju iznositi od oko 0,02 mg/kg/dan do oko 10 mg/kg/dan. U ponekim slučajevima kombiniranog uzimanja moguće je da učinkovita količina antagonista receptora NMDA i/ili inhibitora cdk5 potrebna za postizanje željenog učinka prilikom tretmana rečenih poremećaja bude i manja od količine koja je potrebna prilikom njihova pojedinačnog uzimanja. In general, the effective daily dose of a cdk5 inhibitor in combination with an NMDA receptor antagonist will be from about 0.0001 to about 10 mg/kg of body weight. An effective daily dose of an NMDA receptor antagonist in combination with a cdk5 inhibitor, such as for example a compound of formula 1, for the treatment of any of the above diseases, for example Alzheimer's disease, will generally be about 0.02 mg/kg/day up to about 10 mg/kg/day. In some cases of combined intake, it is possible that the effective amount of NMDA receptor antagonist and/or cdk5 inhibitor needed to achieve the desired effect in the treatment of said disorders may be less than the amount needed when they are taken individually.

Predmet ovog izuma jest i omogućavanje kombinacija inhibitora cdk5 i tvari korisnih prilikom tretmana udara ili traumatske povrede mozga, kao što su to TPA, NIF ili modulatori kalijevih kanala, na primjer BMS-204352. Ovakve kombinacije korisne su prilikom tretmana neurodegenerativnih poremećaja kao što su to na primjer udar, trauma kralješnične moždine, trumatska povreda mozga, multi-infarktna demencija, epilepsija, bol, Alzheimerova bolest i senilna demencija. The object of this invention is to enable combinations of cdk5 inhibitors and substances useful in the treatment of stroke or traumatic brain injury, such as TPA, NIF or potassium channel modulators, for example BMS-204352. Such combinations are useful in the treatment of neurodegenerative disorders such as stroke, spinal cord trauma, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer's disease and senile dementia.

U slučaju gore opisanih kombiniranih terapija i farmaceutskih pripravaka, učinkovitu količinu spoja prema ovom izumu i drugih tvari utvrdit će stručnjak na području temeljem ovdje opisanih učinkovitih količina i količina opisanih ili poznatih na području kao što su to one opisane na primjer u gore danim patentima i patentnim prijavama. Načini priprave i uzimanja takvih pripravaka, te provedba takvih terapija može se odrediti temeljem ovdje danih informacija o pripravcima i terapijama koje uključuju spoj prema ovom izumu kao pojedinačnu aktivnu tvar, te temeljem dostupnih informacija za druge tvari u slučaju kombiniranja s upravo navedenim. In the case of the combination therapies and pharmaceutical preparations described above, the effective amount of the compound according to the present invention and other substances will be determined by one skilled in the art based on the effective amounts described herein and the amounts described or known in the art such as those described for example in the above patents and patent applications. The methods of preparing and taking such preparations, and the implementation of such therapies can be determined on the basis of the information provided here on preparations and therapies that include the compound according to this invention as an individual active substance, and on the basis of available information for other substances in case of combination with the ones just mentioned.

Koristeći se biološkim istraživanjima, kao što su to u nastavku opisani biološki opiti, a koji su poznati stručnjaku na području, moguće je utvrditi točno određene spojeve formule 1 koji inhibiraju cdk2, cdk5 ili pak GSK-3. Using biological research, such as the biological tests described below, which are known to the expert in the field, it is possible to determine the exact compounds of formula 1 that inhibit cdk2, cdk5 or GSK-3.

Specifična inhibicijska aktivnost spoja formule 1 spram cdk5 ili cdk2 može se odrediti, na primjer, slijedećim opitima pomoću materijala lako dostupnih stručnjaku na području. The specific inhibitory activity of a compound of formula 1 against cdk5 or cdk2 can be determined, for example, by the following assays using materials readily available to one skilled in the art.

Enzimska aktivnost može se odrediti mjerenjem zračenja dobivenog od gama fosfata [33P] iz [33P]ATP (Amersham, kataloški br. AH-9968) vezanog na biotinirani peptidni supstrat PKTPKKAKKL. U ovakvom opitu reakcija se provodi u puferu koji sadrži: 50 mM Tris-HCl, pH 8,0, 10 mM MgCl2, 0,1 mM Na3VO4 i 1 mM DTT. Konačna koncentracija ATP je oko 0,5 μM (konačne specifične radioaktivnosti 4 μCi/nmol), a konačna koncentracija supstrata je 0,75 μM. Reakcija započinje ili dodatkom cdk5 i aktivatorskog proteina p25 ili pak dodatkom cdk2 i aktivatorskog ciklina E, te se provodi pri sobnoj temperaturi tijekom oko 60 minuta. Reakcija se zaustavlja dodatkom 0,6 volumena pufera koji sadrži (konačne koncentracije): 2,5 mM EDTA, 0,05 % Triton-X 100, 100 μM ATP i 1,25 mg/ml SPA nositelja obloženog sa streptavidinom (Amersham, kataloški br. RPNQ0007). Radioaktivnost nositelja mjeri se pomoću scintilacijskog brojača. Enzyme activity can be determined by measuring the radiation derived from [33P] gamma phosphate from [33P]ATP (Amersham, Catalog No. AH-9968) bound to the biotinylated peptide substrate PKTPKKAKKL. In this experiment, the reaction is carried out in a buffer containing: 50 mM Tris-HCl, pH 8.0, 10 mM MgCl2, 0.1 mM Na3VO4 and 1 mM DTT. The final ATP concentration is about 0.5 μM (final specific radioactivity 4 μCi/nmol), and the final substrate concentration is 0.75 μM. The reaction starts either with the addition of cdk5 and the activator protein p25, or with the addition of cdk2 and the activator cyclin E, and is carried out at room temperature for about 60 minutes. The reaction is stopped by the addition of 0.6 volumes of buffer containing (final concentrations): 2.5 mM EDTA, 0.05% Triton-X 100, 100 μM ATP and 1.25 mg/ml streptavidin-coated SPA carrier (Amersham, catalog No. RPNQ0007). The radioactivity of the carrier is measured using a scintillation counter.

Specifična inhibicijska aktivnost spoja formule 1 spram GSK-3 može se odrediti pomoću u literaturi već opisanih opita (vidjeti na primjer WO 99/65897) uz prisustvo ili pak odsustvo stanica. Opit bez stanica općenito se može provesti inkubacijom GSK-3 s peptidnim supstratom, radioaktivnim ATP (kao što je to na primjer γ33P- ili γ32P-ATP, oba komercijalno dostupna od Amersham, Arlington Heights, Illinois), magnezijevim ionima i ispitivanim spojem. Smjesa se inkubira tijekom vremenskog perioda dovoljnog za vezanje radioaktivnog fosfora na peptidni supstrat. Zatim se reakcijska smjesa ispere radi uklanjanja neizreagiranog radioaktivnog ATP što se uobičajeno provodi prebacivanjem cjelokupne enzimske reakcijske smjese ili pak dijela te smjese u udubine koje sadrže istovjetnu količinu liganda sposobnog da se veže na peptidni supstrat. Nakon ispiranja određuje se količina zaostalog 33P ili 32P u udubinama čime se može odrediti količina radioaktivnog fosfora vezanog na peptidni supstrat. Inhibicijska aktivnost se dakle određuje kao smanjenje, u odnosu na kontrolni uzorak, količine vezanog radioaktivnog fosfora na peptidni supstrat. U primjer pogodnog GSK-3 peptidnog supstrata uključuje se SGSG-vezani CREB peptidni slijed, dobiven iz CREB DNA vezivnog proteina kako je to opisano u Wang et al., Anal. Biochem., 220:397-402 (1994). Pročišćeni GSK-3 može se dobiti pomoću na primjer stanica transfektiranih s humanim GSK-3β ekspresijskim plazmidom kako je to opisano u Stambolic et al., Current Biology 6:1664-68 (1996). WO 99/65897, Wang et al., i Stambolic et al. ovdje su dani u cijelosti u obliku literaturnih navoda. The specific inhibitory activity of the compound of formula 1 against GSK-3 can be determined by means of tests already described in the literature (see for example WO 99/65897) with the presence or absence of cells. A cell-free assay can generally be performed by incubating GSK-3 with a peptide substrate, radioactive ATP (such as, for example, γ33P- or γ32P-ATP, both commercially available from Amersham, Arlington Heights, Illinois), magnesium ions, and the test compound. The mixture is incubated for a period of time sufficient for the binding of radioactive phosphorus to the peptide substrate. Then, the reaction mixture is washed to remove unreacted radioactive ATP, which is usually carried out by transferring the entire enzymatic reaction mixture or a part of that mixture into wells containing the same amount of ligand capable of binding to the peptide substrate. After washing, the amount of residual 33P or 32P in the wells is determined, which can determine the amount of radioactive phosphorus bound to the peptide substrate. The inhibitory activity is therefore determined as a decrease, in relation to the control sample, of the amount of bound radioactive phosphorus to the peptide substrate. An example of a suitable GSK-3 peptide substrate includes the SGSG-linked CREB peptide sequence, derived from the CREB DNA binding protein as described in Wang et al., Anal. Biochem., 220:397-402 (1994). Purified GSK-3 can be obtained using, for example, cells transfected with a human GSK-3β expression plasmid as described in Stambolic et al., Current Biology 6:1664-68 (1996). WO 99/65897, Wang et al., and Stambolic et al. they are given here in full in the form of literature references.

Drugi primjer GSK-3 opita, sličan upravo opisanom, jest kako slijedi: enzimska aktivnost se određuje mjerenjem zračenja dobivenog od gama fosfata [33P] iz [33P]ATP (Amersham, kataloški br. AH-9968) vezanog na biotinirani peptidni supstrat PKTPKKAKKL. U ovakvom opitu reakcija se provodi u puferu koji sadrži: 50 mM Tris-HCl, pH 8,0, 10 mM MgCl2, 0,1 mM Na3VO4 i 1 mM DTT. Konačna koncentracija ATP je oko 0,5 μM (konačne specifične radioaktivnosti 4 μCi/nmol), a konačna koncentracija supstrata je 0,75 μM. Reakcija započinje dodatkom enzima, te se provodi pri sobnoj temperaturi tijekom oko 60 minuta. Reakcija se zaustavlja dodatkom 0,6 volumena pufera koji sadrži (konačne koncentracije): 2,5 mM EDTA, 0,05 % Triton-X 100, 100 μM ATP i 1,25 mg/ml SPA nositelja obloženog sa streptavidinom (Amersham, kataloški br. RPNQ0007). Radioaktivnost nositelja mjeri se pomoću scintilacijskog brojača. Another example of a GSK-3 assay, similar to the one just described, is as follows: enzyme activity is determined by measuring radiation derived from gamma phosphate [33P] from [33P]ATP (Amersham, catalog no. AH-9968) bound to the biotinylated peptide substrate PKTPKKAKKL. In this experiment, the reaction is carried out in a buffer containing: 50 mM Tris-HCl, pH 8.0, 10 mM MgCl2, 0.1 mM Na3VO4 and 1 mM DTT. The final ATP concentration is about 0.5 μM (final specific radioactivity 4 μCi/nmol), and the final substrate concentration is 0.75 μM. The reaction starts with the addition of an enzyme and is carried out at room temperature for about 60 minutes. The reaction is stopped by the addition of 0.6 volumes of buffer containing (final concentrations): 2.5 mM EDTA, 0.05% Triton-X 100, 100 μM ATP and 1.25 mg/ml streptavidin-coated SPA carrier (Amersham, catalog No. RPNQ0007). The radioactivity of the carrier is measured using a scintillation counter.

Gore opisanim opitom s cdk5 određeno je da su se svi naslovni spojevi iz u nastavku danih primjera odlikovali s IC50 vrijednošću manjom od oko 50 μM za inhibiciju procesa fosforilacije peptidnog supstrata. In the cdk5 experiment described above, it was determined that all of the title compounds of the following examples exhibited an IC50 value of less than about 50 μM for the inhibition of the peptide substrate phosphorylation process.

Nekoliko naslovnih spojeva iz u nastavku danih primjera ispitivano je s obzirom na inhibiciju GSK-3, te je pomoću gore opisanog opita određeno da su se svi ispitivani spojevi odlikovali s IC50 vrijednošću manjom od oko 50 μM za inhibiciju GSK-3β. Several of the title compounds from the examples below were tested for GSK-3 inhibition, and it was determined by the assay described above that all test compounds exhibited an IC50 value of less than about 50 μM for GSK-3β inhibition.

U nastavku dani primjeri opisuju ovaj izum. Jasno je da ovi primjeri niti na koji način ne ograničavaju izum koji je ovdje u potpunosti opisan, te ponovno definiran u zahtjevima. The following examples illustrate this invention. It is clear that these examples do not in any way limit the invention which is fully described herein and redefined in the claims.

PRIMJERI EXAMPLES

Priprema 1 Preparation 1

1-ciklobutil-4-nitro-1H-imidazol 1-cyclobutyl-4-nitro-1H-imidazole

1,4-dinitroimidazol (237 mg, 1,5 mmol, J. Phys. Chem. 1995, 99, 5009-5015) dodan je otopini ciklobutilamina (107 mg, 1,5 mmol) u metanolu (10 ml) pri 23 °C. Reakcijska smjesa je miješana tijekom 16 sati, te je potom otapalo uklonjeno in vacuo, a dobiveni zaostatak je pročišćen kromatografijom na silikagelu (1:1 heksan-etil acetat), te je dobiveno 230 mg (iskorištenje 92 %) 1-ciklobutil-4-nitro-1H-imidazola. 1H NMR (400 MHz, CDCl3) δ 7,81 (s, 1H), 7,45 (s, 1H), 4,64 (m, 1H), 2,6 (m, 2H), 2,4 (m, 2H), 2,0 (m, 2H); MS (AP/Cl) 168,2 (M+H)+. Pažnja: 1,4-dinitroimidazol je visoko energetska, nestabilna tvar, te treba biti pohranjen u hladnjaku sve dok se ne koristi. Termodinamička mjerenja pokazala su da ovaj spoj pri 35 °C uz adijabatske uvjete može razviti dovoljno topline da dođe do žestoke eksplozije. Prilikom korištenja ovog spoja potrebna je izuzetna pažnja. 1,4-Dinitroimidazole (237 mg, 1.5 mmol, J. Phys. Chem. 1995, 99, 5009-5015) was added to a solution of cyclobutylamine (107 mg, 1.5 mmol) in methanol (10 mL) at 23 °C. C. The reaction mixture was stirred for 16 hours, and then the solvent was removed in vacuo, and the obtained residue was purified by chromatography on silica gel (1:1 hexane-ethyl acetate), and 230 mg (yield 92%) of 1-cyclobutyl-4- nitro-1H-imidazole. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.45 (s, 1H), 4.64 (m, 1H), 2.6 (m, 2H), 2.4 (m , 2H), 2.0 (m, 2H); MS (AP/Cl) 168.2 (M+H) + . Attention: 1,4-dinitroimidazole is a highly energetic, unstable substance, and should be stored in the refrigerator until it is not used. Thermodynamic measurements have shown that this compound at 35 °C under adiabatic conditions can develop enough heat to cause a violent explosion. Extreme caution is required when using this compound.

Priprema 2 Preparation 2

1-ciklopentil-4-nitro-1H-imidazol 1-cyclopentyl-4-nitro-1H-imidazole

Ova je reakcija provedena postupkom opisanim u pripremi 1 uz ciklopentil amin i 1,4-dinitroimidazol, te je dobiveno 205 mg (iskorištenje 75 %) 1-ciklopentil-4-nitro-1H-imidazola. 1H NMR (400 MHz, CDCl3) δ 7,77 (s, 1H), 7,45 (s, 1H), 4,49 (m, 1H), 2,25 (m, 2H), 2,0-1,7 (m, 6H); MS (AP/Cl) 182,2 (M+H)+. This reaction was carried out by the procedure described in preparation 1 with cyclopentyl amine and 1,4-dinitroimidazole, and 205 mg (yield 75%) of 1-cyclopentyl-4-nitro-1H-imidazole was obtained. 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.45 (s, 1H), 4.49 (m, 1H), 2.25 (m, 2H), 2.0-1 .7 (m, 6H); MS (AP/Cl) 182.2 (M+H) + .

Priprema 3 Preparation 3

4-nitro-1-(cis-3-fenil-ciklobutil)-1H-imidazol 4-nitro-1-(cis-3-phenyl-cyclobutyl)-1H-imidazole

Ova je reakcija provedena postupkom opisanim u pripremi 1 uz cis-3-fenilciklobutilamin (J. Med. Pharm. Chem. 1960, 2, 687-691, ACIEE 1981, 20, 879-880) i 1,4-dinitroimidazol, te je dobiveno 46 mg (iskorištenje 46 %) 4-nitro-1-(cis-3-fenil-ciklobutil)-1H-imidazola. 1H NMR (300 MHz, CDCl3) δ 7,9 (s, 1H), 7,55 (s, 1H), 7,4-7,2 (m, 5H), 4,73 (m, 1H), 3,48 (m, 1H), 3,12 (m, 2H), 2,54 (m, 2H); MS (AP/Cl) 244 (M+H)+. This reaction was carried out by the procedure described in preparation 1 with cis-3-phenylcyclobutylamine (J. Med. Pharm. Chem. 1960, 2, 687-691, ACIEE 1981, 20, 879-880) and 1,4-dinitroimidazole, and was obtained 46 mg (yield 46%) of 4-nitro-1-(cis-3-phenyl-cyclobutyl)-1H-imidazole. 1H NMR (300 MHz, CDCl3) δ 7.9 (s, 1H), 7.55 (s, 1H), 7.4-7.2 (m, 5H), 4.73 (m, 1H), 3 .48 (m, 1H), 3.12 (m, 2H), 2.54 (m, 2H); MS (AP/Cl) 244 (M+H) + .

Primjer 1 Example 1

N-(1-ciklobutil-1H-imidazol-4-il)-2-kinolin-6-il-acetamid N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide

U bocu za hidrogenaciju Parr dodan je 1-ciklobutil-4-nitro-1H-imidazol (priprema 1, 150 mg, 0,9 mmol) i etil acetat (10 ml), a potom i 10 % Pd na ugljenu (250 mg). Reakcijska smjesa je smještena u Parrovu aparaturu za hidrogenaciju, te je tijekom 6 sati podvrgnuta tlaku od 50 psi H2 pri 23 °C. Sadržaj boce je filtriran na celite filteru, ispran suhim metilen kloridom (25 ml), te prenesen u plamenom sušenu bocu pod dušikom. Zatim je dodan Et3N (626 μL, 4,5 mmol), te je reakcijska smjesa ohlađena na –10 °C. Potom su dodani 6-kinoliloctena kiselina (168 mg, 0,9 mmol) i tripropilfosfonijev anhidrid (530 μL, 1,7 M otopina u etil acetatu), te je smjesa miješana pri –10 °C tijekom 2 sata. Otopina je razrijeđena s metilen kloridom (50 mL), te isprana s vodom (2x). Vodeni sloj je ekstrahiran s metilen kloridom (3x), te su organski slojevi spojeni i isprani sa zasićenom vodenom otopinom soli (1x). Otapalo je uklonjeno in vacuo, a zaostatak je adsorbiran na silikagelu, te podvrgnut kromatografiji pomoću Biotage Flash 12 sustava uz SIM nastavak (40:1 metilen klorid-metanol), te je dobiveno 130 mg (iskorištenje 47 %) N-(1-ciklobutil-1H-imidazol-4-il)-2-kinolin-6-il-acetamida (naslovni spoj). 1H NMR (300 MHz, CDCl3) δ 9,48 (s, 1H), 8,87 (dd, J = 1,6, 4,3 Hz, 1H), 8,11 (m, 2H), 7,76 (d, J = 1,8 Hz, 1H), 7,67 (dd, J = 2,0, 8,7 Hz, 1H), 7,44 (d, J = 1,6 Hz, 1H), 7,38 (m, 1H), 7,25 (d, J = 1,6 Hz, 1H), 4,5 (m, 1H), 3,90 (s, 2H), 2,4 (m, 2H), 2,3 (m, 2H), 1,85 (m, 2H); MS (AP/Cl) 307,1 (M+H)+. 1-cyclobutyl-4-nitro-1H-imidazole (preparation 1, 150 mg, 0.9 mmol) and ethyl acetate (10 ml) were added to a Parr hydrogenation flask, followed by 10% Pd on charcoal (250 mg) . The reaction mixture was placed in a Parr hydrogenation apparatus and subjected to a pressure of 50 psi H2 at 23 °C for 6 hours. The contents of the bottle were filtered on a celite filter, washed with dry methylene chloride (25 ml), and transferred to a flame-dried bottle under nitrogen. Et3N (626 μL, 4.5 mmol) was then added, and the reaction mixture was cooled to –10 °C. Then 6-quinolylacetic acid (168 mg, 0.9 mmol) and tripropylphosphonic anhydride (530 μL, 1.7 M solution in ethyl acetate) were added, and the mixture was stirred at -10 °C for 2 hours. The solution was diluted with methylene chloride (50 mL) and washed with water (2x). The aqueous layer was extracted with methylene chloride (3x), and the organic layers were combined and washed with saturated aqueous salt solution (1x). The solvent was removed in vacuo, and the residue was adsorbed on silica gel and subjected to chromatography using a Biotage Flash 12 system with a SIM extension (40:1 methylene chloride-methanol), and 130 mg (yield 47%) of N-(1-cyclobutyl) was obtained -1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide (title compound). 1H NMR (300 MHz, CDCl3) δ 9.48 (s, 1H), 8.87 (dd, J = 1.6, 4.3 Hz, 1H), 8.11 (m, 2H), 7.76 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 2.0, 8.7 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7 .38 (m, 1H), 7.25 (d, J = 1.6 Hz, 1H), 4.5 (m, 1H), 3.90 (s, 2H), 2.4 (m, 2H) , 2.3 (m, 2H), 1.85 (m, 2H); MS (AP/Cl) 307.1 (M+H) + .

Primjer 2 Example 2

N-(1-ciklopentil-1H-imidazol-4-il)-2-(4-metoksi-fenil)-acetamid N-(1-cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxy-phenyl)-acetamide

Ova je reakcija provedena postupkom opisanim u primjeru 1 uz p-metoksi-feniloctenu kiselinu i 1-ciklopentil-4-nitro-1H-imidazol (priprema 2), te je priređen N-(1-ciklopentil-1H-imidazol-4-il)-2-(4-metoksi-fenil)-acetamid uz iskorištenje od 32 % (26,5 mg). 1H NMR (400 MHz, CDCl3) δ 8,54 (s, 1H), 7,35 (s, 1H), 7,24 (m, 2H), 6,87 (d, J =1,7 Hz), 4,36 (m, 1H), 3,78 (s, 3H), 3,64 (s, 2H), 2,1 (m, 2H), 1,8 (m, 4H), 1,6 (m, 2H); MS (AP/Cl) 300,3 (M+H)+. This reaction was carried out by the procedure described in example 1 with p-methoxy-phenylacetic acid and 1-cyclopentyl-4-nitro-1H-imidazole (preparation 2), and N-(1-cyclopentyl-1H-imidazol-4-yl) was prepared )-2-(4-methoxy-phenyl)-acetamide with a yield of 32% (26.5 mg). 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.35 (s, 1H), 7.24 (m, 2H), 6.87 (d, J =1.7 Hz), 4.36 (m, 1H), 3.78 (s, 3H), 3.64 (s, 2H), 2.1 (m, 2H), 1.8 (m, 4H), 1.6 (m , 2H); MS (AP/Cl) 300.3 (M+H) + .

Primjer 3 Example 3

N-[1-(cis-3-fenil-ciklobutil)-1H-imidazol-4-il]-2-kinolin-6-il-acetamid N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-yl-acetamide

Ova je reakcija provedena postupkom opisanim u primjeru 1 uz 6-kinoliloctenu kiselinu i 4-nitro-1-(cis-3-fenilciklobutil)-1H-imidazol (priprema 3), te je priređen N-[1-(cis-3-fenil-ciklobutil)-1H-imidazol-4-il]-2-kinolin-6-il-acetamid uz iskorištenje od 38 %. 1H NMR (300 MHz, CDCl3) δ 8,93 (m, 1H), 8,12 (m, 2H), 7,79 (d, J =1,5 Hz, 1H), 7,71 (m, 1H), 7,55 (d, J = 1,5 Hz, 1H), 7,41 (dd, J =4,3, 8,4 Hz, 1H), 7,37-7,22 (m, 5H), 4,57 (m, 1H), 3,96 (s, 2H), 3,33 (m, 1H), 2,95 (m, 2H), 2,49 (m, 2H); MS (AP/Cl) 383,0 (M+H)+. This reaction was carried out by the procedure described in example 1 with 6-quinolylacetic acid and 4-nitro-1-(cis-3-phenylcyclobutyl)-1H-imidazole (preparation 3), and N-[1-(cis-3- phenyl-cyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-yl-acetamide with a yield of 38%. 1H NMR (300 MHz, CDCl3) δ 8.93 (m, 1H), 8.12 (m, 2H), 7.79 (d, J =1.5 Hz, 1H), 7.71 (m, 1H ), 7.55 (d, J = 1.5 Hz, 1H), 7.41 (dd, J =4.3, 8.4 Hz, 1H), 7.37-7.22 (m, 5H) , 4.57 (m, 1H), 3.96 (s, 2H), 3.33 (m, 1H), 2.95 (m, 2H), 2.49 (m, 2H); MS (AP/Cl) 383.0 (M+H) + .

Primjer 4 Example 4

(1-ciklobutil-1H-imidazol-4-il)-karbamske kiseline fenil ester (1-Cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester

U bocu za hidrogenaciju Parr dodani su 1-ciklobutil-4-nitro-1H-imidazol (priprema 1, 3 g, 18 mmol) i etil acetat (70 ml), a potom i 10 % Pd na ugljenu (1,2 g) u atmosferi dušika. Reakcijska smjesa je podvrgnuta tlaku od 50 psi H2 pri 23 °C tijekom 6 sati. Sadržaj boce je profiltriran na celite filteru, prethodno ispranom sa suhim metilen kloridom (140 ml), te prenesen u plamenom sušenu bocu. Reakcijska smjesa je ohlađena na –78 °C, te je dodan diizopropiletilamin (2,3 g, 18 mmol), a potom i kap po kap fenilkloroformat (2,5 g, 16,2 mmol). Nakon 30 minuta dodan je metanol (9 ml) u kojem se nalazila i octena kiselina (1,8 mmol). Reakcijska smjesa je prenesena u tikvicu za odvajanje, razrijeđena je dodatkom etil acetata (200 ml), te je isprana s vodom (2x). Vodeni slojevi su ekstrahirani s etil acetatom (2x10 ml). Organski slojevi su spojeni, isprani sa zasićenom vodenom otopinom soli (2x), sušeni (MgSO4), filtrirani i koncentrirani in vacuo. Sirovi produkt je adsorbiran na silikagelu, te je pročišćen kromatografijom (1:1 heksan-etil acetat), te je dobiveno 3 g (iskorištenje 65 %) (1-ciklobutil-1H-imidazol-4-il)-karbamske kiseline fenil estera. 1H NMR (400 MHz, CDCl3) δ 7,4-7,3 (m, 2H), 7,22-7,18 (m, 3H), 4,5 (m, 1H), 2,46-2,30 (m, 4H), 1,83 (m, 2H); MS (AP/Cl) 258,2 (M+H)+. 1-cyclobutyl-4-nitro-1H-imidazole (preparation 1.3 g, 18 mmol) and ethyl acetate (70 ml) were added to the Parr hydrogenation flask, followed by 10% Pd on charcoal (1.2 g) in a nitrogen atmosphere. The reaction mixture was pressurized with 50 psi H 2 at 23 °C for 6 hours. The contents of the bottle were filtered on a celite filter, previously washed with dry methylene chloride (140 ml), and transferred to a flame-dried bottle. The reaction mixture was cooled to -78 °C, and diisopropylethylamine (2.3 g, 18 mmol) was added, followed by phenylchloroformate (2.5 g, 16.2 mmol) dropwise. After 30 minutes, methanol (9 ml) containing acetic acid (1.8 mmol) was added. The reaction mixture was transferred to a separation flask, diluted with the addition of ethyl acetate (200 ml), and washed with water (2x). The aqueous layers were extracted with ethyl acetate (2x10 ml). The organic layers were combined, washed with saturated aqueous salt solution (2x), dried (MgSO4), filtered and concentrated in vacuo. The crude product was adsorbed on silica gel and purified by chromatography (1:1 hexane-ethyl acetate), and 3 g (yield 65%) of (1-cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester were obtained. 1H NMR (400 MHz, CDCl3) δ 7.4-7.3 (m, 2H), 7.22-7.18 (m, 3H), 4.5 (m, 1H), 2.46-2, 30 (m, 4H), 1.83 (m, 2H); MS (AP/Cl) 258.2 (M+H) + .

Primjer 5 Example 5

1-(1-ciklobutil-1H-imidazol-4-il)-3-izokinolin-5-il-urea 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea

U 1 dram vijalu opremljenu s čepom sa navojem i otvorom za dokapavanje dodani su (1-ciklobutil-1H-imidazol-4-il)-karbamske kiseline fenil ester (primjer 4, 50 mg, 0,19 mmol), 5-aminoizokinolin (30 mg, 0,21 mmol) i 1:1 dioksan-DMF (1 ml). Reakcijska smjesa je grijana pri 70 °C tijekom 2 sata. Smjesa je potom adsorbirana na silikagelu, te je pročišćena kromatografijom (40:1 kloroform-metanol), te je dobiveno 30 mg (iskorištenje 52 %) 1-(1-ciklobutil-1H-imidazol-4-il)-3-izokinolin-5-il-uree. 1H NMR (400 MHz, CD3OD) δ 9,21 (d, J = 1,7 Hz, 1H), 8,45 (d, J = 6,2 Hz, 1H), 8,24 (d, J = 7,5 Hz, 1H), 7,98 (d, J = 5,4 Hz, 1H), 7,84 (dd, J = 2,3, 8,3 Hz, 1H), 7,66 (m, 1H), 7,54 (s, 1H), 7,12 (brs, 1H), 4,66 (m, 1H), 2,5-2,3 (m, 4H), 1,9 (m, 2H); MS (AP/Cl) 308,0 (M+H)+. (1-Cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester (Example 4, 50 mg, 0.19 mmol), 5-aminoisoquinoline ( 30 mg, 0.21 mmol) and 1:1 dioxane-DMF (1 ml). The reaction mixture was heated at 70 °C for 2 hours. The mixture was then adsorbed on silica gel and purified by chromatography (40:1 chloroform-methanol), and 30 mg (yield 52%) of 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinoline- 5-yl-urea. 1H NMR (400 MHz, CD3OD) δ 9.21 (d, J = 1.7 Hz, 1H), 8.45 (d, J = 6.2 Hz, 1H), 8.24 (d, J = 7 .5 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.84 (dd, J = 2.3, 8.3 Hz, 1H), 7.66 (m, 1H ), 7.54 (s, 1H), 7.12 (brs, 1H), 4.66 (m, 1H), 2.5-2.3 (m, 4H), 1.9 (m, 2H) ; MS (AP/Cl) 308.0 (M+H) + .

Priprema 4 Preparation 4

N-[1-(cis-3-azido-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamid N-[1-(cis-3-azido-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide

Korak 1 Step 1

3-benziloksiciklobutilamin (43,4 g, 245 mmol, Chem. Ber. 1957, 90, 1424-1432) otopljen je u otopini klorovodika u metanolu (zasićena otopina, 450 ml), te je potom dodan 10 % Pd na ugljenu (4 g). Smjesa je podvrgnuta hidrogenaciji pri 50 psi H2 tijekom 6 sati. Zatim je reakcijska smjesa filtrirana i koncentrirana in vacuo, te je dobiveno oko 35 g ulja. Ulje je preneseno u metanol (600 ml), ohlađeno na 0 °C, te je dodan kalijev hidroksid (13,7 g, 245 mmol) do pH = 10. Potom je dodana otopina 1,4-dinitroimidazola (42,7 g, 270 mmol) u metanolu (200 ml) (priređena otapanjem 1,4-dinitroimidazola u metanolu pri 0 °C). (Pažnja: 1,4-dinitroimidazol je visoko energetska, nestabilna tvar, te treba biti pohranjen u hladnjaku sve dok se ne koristi. Termodinamička mjerenja pokazala su da ovaj spoj pri 35 °C uz adijabatske uvjete može razviti dovoljno topline da dođe do žestoke eksplozije. Prilikom korištenja ovog spoja potrebna je izuzetna pažnja). Dobivena narančasta suspenzija je ostavljena da se zagrije na 23 °C tijekom noći. Otapalo je uklonjeno in vacuo, a dobiveni zaostatak je pročišćen na velikoj količini silikagela (20:1 kloroform-metanol), te je dobiveno 19 g (iskorištenje 42 %) 3-(4-nitro-imidazol-1-il)-ciklobutanola u obliku 1:1 smjese cis-trans izomera. 1H NMR (400 MHz, CD3OD) δ 8,29 (s, 1H), 8,27 (s, 1H), 7,84 (s, 1H), 7,81 (s, 1H), 5,02 (m, 1H), 4,53 (m, 1H), 4,37 (m, 1H), 4,10 (m, 1H), 2,95 (m, 2H), 2,7 (m, 2H), 2,5 (m, 2H), 2,3 (m, 2H); MS (AP/Cl) 184,0 (M+H)+. 3-Benzyloxycyclobutylamine (43.4 g, 245 mmol, Chem. Ber. 1957, 90, 1424-1432) was dissolved in a solution of hydrogen chloride in methanol (saturated solution, 450 ml), and then 10% Pd on carbon (4 Mr). The mixture was hydrogenated at 50 psi H2 for 6 hours. Then the reaction mixture was filtered and concentrated in vacuo, and about 35 g of oil was obtained. The oil was transferred to methanol (600 ml), cooled to 0 °C, and potassium hydroxide (13.7 g, 245 mmol) was added to pH = 10. Then a solution of 1,4-dinitroimidazole (42.7 g, 270 mmol) in methanol (200 ml) (prepared by dissolving 1,4-dinitroimidazole in methanol at 0 °C). (Caution: 1,4-dinitroimidazole is a highly energetic, unstable substance and should be stored in a refrigerator until use. Thermodynamic measurements have shown that this compound at 35 °C under adiabatic conditions can develop enough heat to cause a violent explosion (Extreme care is required when using this compound). The resulting orange suspension was allowed to warm to 23 °C overnight. The solvent was removed in vacuo, and the obtained residue was purified on a large amount of silica gel (20:1 chloroform-methanol), and 19 g (yield 42 %) of 3-(4-nitro-imidazol-1-yl)-cyclobutanol were obtained in in the form of a 1:1 mixture of cis-trans isomers. 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 5.02 (m , 1H), 4.53 (m, 1H), 4.37 (m, 1H), 4.10 (m, 1H), 2.95 (m, 2H), 2.7 (m, 2H), 2 .5 (m, 2H), 2.3 (m, 2H); MS (AP/Cl) 184.0 (M+H) + .

Korak 2 Step 2

U otopinu 3-(4-nitro-imidazol-1-il)-ciklobutanola (priprema 4, korak 1, 4 g, 22 mmol) u metilen kloridu (150 ml) dodan je Et3N (7,7 ml, 55 mmol), a potom i p-toluensulfonil klorid (TsCl) (5 g, 26,4 mmol) i 4-N,N-dimetilaminopiridin (DMAP) (268 mg, 2,2 mmol). Dobivena smjesa je miješana pri sobnoj temperaturi tijekom 24 sata. Analiza tankoslojnom kromatografijom pokazala je dvije nove mrlje. Otopina je razrijeđena s metilen kloridom, te isprana s vodom (1x) i sa zasićenom vodenom otopinom soli (1x). Organski sloj je sušen (MgSO4), filtriran i koncentriran in vacuo. Cis i trans diastereoizomeri su odvojeni kromatografijom na silikagelu (1:1 do 2:1 heksan-etil acetat). Prvo se izeluirao (velika Rf vrijednost) trans-izomer, trans-toluen-4-sulfonske kiseline 3-(4-nitro-imidazol-1-il)-ciklobutil ester (2,7 g, iskorištenje 37 %). 1H NMR (400 MHz, CDCl3) δ 7,79 (s, 1H), 7,77 (m, 2H), 7,44 (d, J = 1,7 Hz, 1H), 7,36 (dd, J = 0,5, 8,0 Hz, 2H), 5,034 (m, 1H), 4,94 (m, 1H), 2,9 (m, 2H), 2,7 (m, 2H); MS (AP/Cl) 338,1 (M+H)+. Zatim se izeluirao cis-izomer, cis-toluen-4-sulfonske kiseline 3-(4-nitro-imidazol-1-il)-ciklobutil ester (2,9 g, iskorištenje 39 %). 1H NMR (400 MHz, CDCl3) δ 7,8 (m, 3H), 7,43 (d, J = 1,4 Hz, 1H), 7,36 (dd, J = 0,6, 8,5 Hz, 2H), 4,74 (m, 1H), 4,30 (m, 1H), 3,05 (m, 2H), 2,6-2,5 (m, 2H), 2,45 (s, 3H); MS (AP/Cl) 338,1 (M+H)+. Relativna konfiguracija određena je mjerenjem nuklearnog Overhauser efekta. To a solution of 3-(4-nitro-imidazol-1-yl)-cyclobutanol (preparation 4, step 1, 4 g, 22 mmol) in methylene chloride (150 ml) was added Et3N (7.7 ml, 55 mmol), and then p-toluenesulfonyl chloride (TsCl) (5 g, 26.4 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (268 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 24 hours. Analysis by thin layer chromatography showed two new spots. The solution was diluted with methylene chloride, and washed with water (1x) and with saturated aqueous salt solution (1x). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Cis and trans diastereoisomers were separated by chromatography on silica gel (1:1 to 2:1 hexane-ethyl acetate). First, the trans-isomer, trans-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.7 g, yield 37%) was eluted (high Rf value). 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.77 (m, 2H), 7.44 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 0.5, 8.0 Hz, 2H), 5.034 (m, 1H), 4.94 (m, 1H), 2.9 (m, 2H), 2.7 (m, 2H); MS (AP/Cl) 338.1 (M+H) + . Then the cis-isomer, cis-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.9 g, yield 39%) was eluted. 1H NMR (400 MHz, CDCl3) δ 7.8 (m, 3H), 7.43 (d, J = 1.4 Hz, 1H), 7.36 (dd, J = 0.6, 8.5 Hz , 2H), 4.74 (m, 1H), 4.30 (m, 1H), 3.05 (m, 2H), 2.6-2.5 (m, 2H), 2.45 (s, 3H); MS (AP/Cl) 338.1 (M+H) + . The relative configuration was determined by measuring the nuclear Overhauser effect.

Korak 3 Step 3

Trans-toluen-4-sulfonske kiseline 3-(4-nitro-imidazol-1-il)-ciklobutil ester (priprema 4, korak 2, 590 mg, 1,75 mmol) pomiješan je s 10 % Pd na ugljenu (500 mg) i etil acetatom (30 ml). Reakcijska smjesa je podvrgnuta tlaku od 50 psi H2 tijekom 6 sati. Potom je smjesa profiltrirana na celite filteru, te prenesena u plamenom sušenu bocu u atmosferi dušika. Zatim je dodan Et3N (1,22 mL, 8,75 mmol), a potom i 1-naftiloctena kiselina (326 mg, 1,75 mmol) i tripropilfosfonski anhidrid (1,1 mL, 1,7 M otopina u etil acetatu, 1,75 mmol). Smjesa je miješana pri sobnoj temperaturi tijekom 1 sata, te je razrijeđena s etil acetatom i isprana s vodom i sa zasićenom vodenom otopinom soli. Organski sloj je sušen (MgSO4), filtriran i koncentriran in vacuo. Dobiveni zaostatak je pročišćen kromatografijom na silikagelu (50:1 kloroform-metanol), te je dobiveno 600 mg (iskorištenje 72 %) trans-toluen-4-sulfonske kiseline 3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil estera. 1H NMR (400 MHz, CDCl3) δ 7,9 (m, 2H), 7,85 (m, 2H), 7,76 (d, J = 8,3 Hz, 2H), 7,48 (m, 2H), 7,42 (m, 2H), 7,33 (m, 2H), 7,04 (s, 1H), 4,96 (m, 1H), 4,73 (m, 1H), 2,7 (m, 4H), 2,44 (s, 3H); MS (AP/Cl) 476,2 (M+H)+. Trans-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (Preparation 4, step 2, 590 mg, 1.75 mmol) was mixed with 10% Pd on carbon (500 mg ) and ethyl acetate (30 ml). The reaction mixture was pressurized with 50 psi H2 for 6 hours. The mixture was then filtered on a celite filter and transferred into a flame-dried bottle in a nitrogen atmosphere. Et3N (1.22 mL, 8.75 mmol) was then added, followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonic anhydride (1.1 mL, a 1.7 M solution in ethyl acetate, 1.75 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and washed with water and saturated aqueous salt solution. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The obtained residue was purified by chromatography on silica gel (50:1 chloroform-methanol), and 600 mg (yield 72%) of trans-toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-yl-acetylamino) was obtained. -imidazol-1-yl]-cyclobutyl ester. 1H NMR (400 MHz, CDCl3) δ 7.9 (m, 2H), 7.85 (m, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.48 (m, 2H ), 7.42 (m, 2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS (AP/Cl) 476.2 (M+H) + .

Korak 4 Step 4

Trans-toluen-4-sulfonske kiseline 3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil ester (priprema 4, korak 3, 593 mg, 1,25 mmol) pomiješan je s natrijevim azidom (813 mg, 12,5 mmol) u smjesi etanola (15 ml), vode (5 ml) i kloroforma (5 ml). Smjesa je grijana i miješana uz refluks tijekom 96 sati. Otapalo je uklonjeno in vacuo, a zaostatak je razrijeđen s vodom, te ekstrahiran s metilen kloridom. Organski sloj je sušen (MgSO4), filtriran i koncentriran in vacuo. Pročišćavanjem pomoću kromatografije na silikagelu (50:1 kloroform-metanol) dobiveno je 340 mg (iskorištenje 79 %) N-[1-(cis-3-azido-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamid. 1H NMR (400 MHz, CDCl3) δ 8,41 (s, 1H), 7,98 (d, J = 6,4 Hz, 1H), 7,87 (m, 1H), 7,82 (m, 1H), 7,5 (m, 2H), 7,45 (m, 3H), 7,08 (d, J = 1,7 Hz, 1H), 4,2 (m, 3H), 3,75 (m, 1H), 2,85 (m, 2H), 2,35 (m, 2H); MS (AP/Cl) 347,2 (M+H)+. Trans-toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl ester (Preparation 4, step 3, 593 mg, 1.25 mmol) mixed is with sodium azide (813 mg, 12.5 mmol) in a mixture of ethanol (15 ml), water (5 ml) and chloroform (5 ml). The mixture was heated and stirred under reflux for 96 hours. The solvent was removed in vacuo, and the residue was diluted with water and extracted with methylene chloride. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel (50:1 chloroform-methanol) yielded 340 mg (yield 79%) of N-[1-(cis-3-azido-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalene- 1-yl-acetamide. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.87 (m, 1H), 7.82 (m, 1H ), 7.5 (m, 2H), 7.45 (m, 3H), 7.08 (d, J = 1.7 Hz, 1H), 4.2 (m, 3H), 3.75 (m , 1H), 2.85 (m, 2H), 2.35 (m, 2H); MS (AP/Cl) 347.2 (M+H) + .

Primjer 6 Example 6

N-[1-(cis-3-amino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamid N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide

N-[1-(cis-3-azido-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamid (priprema 4, korak 4, 330 mg, 0,95 mmol) pomiješan je s trifenilfosfinom (301 mg, 1,15 mmol) u tetrahidrofuranu (10 ml) i s vodom (1 ml) pri 23 °C. Otopina je miješana pri sobnoj temperaturi tijekom 18 sati. Otapalo je uklonjeno in vacuo, a dobiveni zaostatak je pročišćen kromatografijom na silikagelu (20:1:0,5 kloroform-metanol-amonijev hidroksid), te je dobiveno 289 mg (iskorištenje 95 %) N-[1-(cis-3-amino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamida. 1H NMR (400 MHz, CD3OD) δ 8,05 (d, J = 7,5 Hz, 1H), 7,87 (d, J = 7,9 Hz, 1H), 7,79 (d, J = 9,0 Hz, 1H), 7,45 (m, 5H), 7,35 (s, 1H), 4,26 (m, 1H), 4,16 (s, 2H), 3,29 (m, 2H), 3,16 (m, 1H), 2,75 (m, 2H), 2,1 (m, 2H); MS (AP/Cl) 321,3 (M+H)+. N-[1-(cis-3-azido-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Preparation 4, step 4, 330 mg, 0.95 mmol) was mixed with triphenylphosphine (301 mg, 1.15 mmol) in tetrahydrofuran (10 ml) and water (1 ml) at 23 °C. The solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the obtained residue was purified by chromatography on silica gel (20:1:0.5 chloroform-methanol-ammonium hydroxide), and 289 mg (yield 95%) of N-[1-(cis-3- amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide. 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 9 ,0 Hz, 1H), 7.45 (m, 5H), 7.35 (s, 1H), 4.26 (m, 1H), 4.16 (s, 2H), 3.29 (m, 2H ), 3.16 (m, 1H), 2.75 (m, 2H), 2.1 (m, 2H); MS (AP/Cl) 321.3 (M+H) + .

Primjer 7a Example 7a

6-metil-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid 6-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

U otopinu 6-metilpikolinske kiseline (9,4 mg, 0,07 mmol) u metilen kloridu dodani su 1-(3-dimetilaminopropil)-3-etilkarbodiimid klorovodik (84 mg) i DMAP (2 mg) pri 23 °C. Nakon miješanja tijekom 10 minuta dodan je N-[1-(cis-3-amino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamida (primjer 6, 20 mg, 0,06 mmol). Dobivena smjesa je potom miješana tijekom 3 sata. Dodana je voda, otopina je neutralizirana dodatkom vodene otopine NaOH, te je ekstrahirana s etil acetatom. Organski sloj je sušen (MgSO4), filtriran i koncentriran in vacuo. Pročišćavanjem pomoću kromatografije na silikagelu (20:1 CHCl3-MeOH) dobiveno je 26 mg (iskorištenje 95 %) 6-metil-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amida. 1H NMR (400 MHz, CDCl3) δ 9,15 (s, 1H), 8,28 (d, J = 8,3 Hz, 1H), 8,01 (d, J = 7,5 Hz, 1H), 7,96 (d, J = 7,5 Hz, 1H), 7,97 (d, J = 7,5 Hz, 1H), 7,81 (dd, J = 2,4, 6,6 Hz, 1H), 7,72 (m, 1H), 7,5 (m, 5H), 7,2 (m, 1H), 7,16 (s, 1H), 4,45 (m, 1H), 4,25 (m, 1H), 4,18 (s, 2H), 2,98 (m, 2H), 2,60 (s, 3H), 2,40 (m, 2H); MS (AP/Cl) 440,3 (M+H)+. To a solution of 6-methylpicolinic acid (9.4 mg, 0.07 mmol) in methylene chloride was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg) and DMAP (2 mg) at 23 °C. After stirring for 10 minutes, N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Example 6, 20 mg, 0.06 mmol). The resulting mixture was then stirred for 3 hours. Water was added, the solution was neutralized by the addition of aqueous NaOH solution, and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel (20:1 CHCl3-MeOH) yielded 26 mg (95% yield) of 6-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino) )-imidazol-1-yl]-cyclobutyl}-amide. 1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.81 (dd, J = 2.4, 6.6 Hz, 1H ), 7.72 (m, 1H), 7.5 (m, 5H), 7.2 (m, 1H), 7.16 (s, 1H), 4.45 (m, 1H), 4.25 (m, 1H), 4.18 (s, 2H), 2.98 (m, 2H), 2.60 (s, 3H), 2.40 (m, 2H); MS (AP/Cl) 440.3 (M+H) + .

Primjer 7b Example 7b

1H-imidazol-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid 1H-imidazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 8,06 (d, J = 7,9 Hz, 1H), 7,87 (m, 1H), 7,80 (d, J = 7,5 Hz, 1H), 7,7 (s, 1H), 7,64 (s, 1H), 7,5 (m, 6H), 4,44 (m, 1H), 4,32 (m, 1H), 4,18 (s, 2H), 2,9 (m, 2H), 2,45 (m, 2H); MS (AP/Cl) 415,3 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 7.9 Hz, 1H), 7.87 (m, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.7 (s, 1H), 7.64 (s, 1H), 7.5 (m, 6H), 4.44 (m, 1H), 4.32 (m, 1H), 4.18 (s , 2H), 2.9 (m, 2H), 2.45 (m, 2H); MS (AP/Cl) 415.3 (M+H) + .

Primjer 7c Example 7c

6-hidroksi-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid 6-hydroxy-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 8,02 (d, J = 7,9 Hz, 1H), 7,84 (d, J = 7,9 Hz, 1H), 7,79 (d, J = 7,5 Hz, 1H), 7,65 (s, 1H), 7,60 (m, 1H), 7,45 (m, 6H), 7,14 (brs, 1H), 6,71 (d, J = 8,7 Hz, 1H), 4,4 (m, 1H), 4,32 (m, 1H), 4,17 (s, 2H), 2,93 (m, 2H), 2,5 (m, 2H); MS (AP/Cl) 442,3 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 8.02 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7 .5 Hz, 1H), 7.65 (s, 1H), 7.60 (m, 1H), 7.45 (m, 6H), 7.14 (brs, 1H), 6.71 (d, J = 8.7 Hz, 1H), 4.4 (m, 1H), 4.32 (m, 1H), 4.17 (s, 2H), 2.93 (m, 2H), 2.5 (m , 2H); MS (AP/Cl) 442.3 (M+H) + .

Primjer 7d Example 7d

3-metil-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid 3-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 8,39 (d, J = 4,2 Hz, 1H), 8,06 (d, J = 8,3 Hz, 1H), 7,87 (d, J = 7,5 Hz, 1H), 7,80 (d, J = 7,5 Hz, 1H), 7,69 (d, J = 7,9 Hz, 1H), 7,5 (m, 7H), 4,5 (m, 1H), 4,3 (m, 1H), 4,17 (s, 2H), 2,92 (m, 2H), 2,54 (s, 3H), 2,46 (m, 2H); MS (AP/Cl) 440,3 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 8.39 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7 ,5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.5 (m, 7H), 4, 5 (m, 1H), 4.3 (m, 1H), 4.17 (s, 2H), 2.92 (m, 2H), 2.54 (s, 3H), 2.46 (m, 2H ); MS (AP/Cl) 440.3 (M+H) + .

Primjer 7e Example 7e

2-piridin-3-il-tiazol-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid 2-pyridin-3-yl-thiazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 9,21 (d, J = 2,5 Hz, 1H), 8,61 (d, J = 5,0 Hz, 1H), 8,41 (dd, J = 1,7, 7,9 Hz, 1H), 8,26 (s, 1H), 8,06 (d, J = 7,9 Hz, 1H), 7,86 (d, J = 7,5 Hz, 1H), 7,79 (d, J = 7,9 Hz, 1H), 7,5 (m, 7H), 4,44 (m, 2H), 4,17 (s, 2H), 2,9 (m, 2H), 2,6 (m, 2H); MS (AP/Cl) 509,3 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 9.21 (d, J = 2.5 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.41 (dd, J = 1 .7, 7.9 Hz, 1H), 8.26 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H ), 7.79 (d, J = 7.9 Hz, 1H), 7.5 (m, 7H), 4.44 (m, 2H), 4.17 (s, 2H), 2.9 (m , 2H), 2.6 (m, 2H); MS (AP/Cl) 509.3 (M+H) + .

Primjer 7f Example 7f

6-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutilkarbamoil}-nikotinske kiseline metil ester 6-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}-nicotinic acid methyl ester

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD/CDCl3) δ 9,15 (d, J = 1,6 Hz, 1H), 9,12 (d, J = 8,0 Hz, 1H), 8,45 (dd, J = 2,0, 8,4 Hz, 1H), 8,16 (d, J = 8,0 Hz, 1H), 8,02 (d, J = 8,4 Hz, 1H), 7,85 (d, J = 8,0 Hz, 1H), 7,80 (d, J = 7,8 Hz, 1H), 7,48 (m, 6H), 4,45 (m, 2H), 3,96 (s, 3H), 2,94 (m, 2H), 2,58 (m, 2H); MS (AP/Cl) 484,3 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD/CDCl3) δ 9.15 (d, J = 1.6 Hz, 1H), 9.12 (d, J = 8.0 Hz, 1H), 8.45 (dd, J = 2.0, 8.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 (d , J = 8.0 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.48 (m, 6H), 4.45 (m, 2H), 3.96 (s , 3H), 2.94 (m, 2H), 2.58 (m, 2H); MS (AP/Cl) 484.3 (M+H) + .

Primjer 7g Example 7g

pirazin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 9,23 (d, J = 2,0 Hz, 1H), 9,03 (d, J = 8,0 Hz, 1H), 8,73 (d, J = 2,4 Hz, 1H), 8,63 (d, J = 1,6, 2,4 Hz, 1H), 8,02 (d, J = 8,4 Hz, 1H), 7,85 (d, J = 8,0 Hz, 1H), 7,79 (d, J = 8,0 Hz, 1H), 7,49 (m, 6H), 4,44 (m, 2H), 4,16 (s, 2H), 2,95 (m, 2H), 2,56 (m, 2H); MS (AP/Cl) 427,3 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 9.23 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.73 (d, J = 2 ,4 Hz, 1H), 8.63 (d, J = 1.6, 2.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.49 (m, 6H), 4.44 (m, 2H), 4.16 (s, 2H ), 2.95 (m, 2H), 2.56 (m, 2H); MS (AP/Cl) 427.3 (M+H) + .

Primjer 7h Example 7h

N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-benzamid N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 8,05 (d, J = 8,3 Hz, 2H), 7,99 (d, J = 7,1 Hz, 1H), 7,86 (d, J = 7,5 Hz, 1H), 7,80 (J = 7,1 Hz, 2H), 7,45 (m, 8H), 4,47 (m, 1H), 4,37 (m, 1H), 4,17 (s, 2H), 2,90 (m, 2H), 2,47 (m, 2H); MS (AP/Cl) 425,0 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 7 ,5 Hz, 1H), 7.80 (J = 7.1 Hz, 2H), 7.45 (m, 8H), 4.47 (m, 1H), 4.37 (m, 1H), 4, 17 (s, 2H), 2.90 (m, 2H), 2.47 (m, 2H); MS (AP/Cl) 425.0 (M+H) + .

Primjer 7i Example 7i

5-metil-pirazin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid 5-methyl-pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 9,07 (d, J = 1,2 Hz, 1H), 8,5 (d, J = 0,8 Hz, 1H), 8,02 (d, J = 8,0 Hz, 1H), 7,85 (d, J = 7,6 Hz, 1H), 7,79 (d, J = 7,6 Hz, 1H), 7,45 (m, 6H), 4,40 (m, 2H), 4,16 (s, 2H), 2,93 (m, 2H), 2,61 (s, 3H), 2,54 (m, 2H); MS (AP/Cl) 441,3 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 9.07 (d, J = 1.2 Hz, 1H), 8.5 (d, J = 0.8 Hz, 1H), 8.02 (d, J = 8 ,0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.45 (m, 6H), 4, 40 (m, 2H), 4.16 (s, 2H), 2.93 (m, 2H), 2.61 (s, 3H), 2.54 (m, 2H); MS (AP/Cl) 441.3 (M+H) + .

Primjer 7j Example 7j

N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-izobutiramid N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-isobutyramide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 8,01 (d, J = 7,9 Hz, 1H), 7,84 (d, J = 7,5 Hz, 1H), 7,78 (d, J = 7,5 Hz, 2H), 7,45 (m, 6H), 4,35 (m, 1H), 4,15 (s, 2H), 4,11 (m, 1H), 2,84 (m, 2H), 2,35 (m, 1H), 2,28 (m, 2H), 1,06 (d, J = 6,6 Hz, 6H); MS (AP/Cl) 391,1 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7 .5 Hz, 2H), 7.45 (m, 6H), 4.35 (m, 1H), 4.15 (s, 2H), 4.11 (m, 1H), 2.84 (m, 2H ), 2.35 (m, 1H), 2.28 (m, 2H), 1.06 (d, J = 6.6 Hz, 6H); MS (AP/Cl) 391.1 (M+H) + .

Primjer 7k Example 7k

6-klor-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid 6-chloro-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Naslovni spoj je priređen postupkom istovjetnim primjeru 7a. 1H NMR (400 MHz, CD3OD) δ 8,07 (d, J = 7,9 Hz, 1H), 8,03 (d, J = 7,5 Hz, 1H), 7,94 (m, 1H), 7,87 (d, J = 7,9 Hz, 1H), 7,81 (d, J = 7,9 Hz, 1H), 7,61 (d, J = 7,1 Hz, 1H), 7,58 (s, 1H), 7,5 (m, 5H), 4,45 (m, 1H), 4,39 (m, 1H), 4,18 (s, 2H), 2,89 (m, 2H), 2,63 (m, 2H); MS (AP/Cl): 460,2, 462,2 (M+H)+. The title compound was prepared by a procedure identical to Example 7a. 1H NMR (400 MHz, CD3OD) δ 8.07 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.94 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7, 58 (s, 1H), 7.5 (m, 5H), 4.45 (m, 1H), 4.39 (m, 1H), 4.18 (s, 2H), 2.89 (m, 2H ), 2.63 (m, 2H); MS (AP/Cl): 460.2, 462.2 (M+H) + .

Primjer 8 Example 8

Acilacija N-[1-(cis-3-amino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamida (primjer 6) s različitim karboksilnim kiselinama, te pročišćavanje produkta provedeno je na slijedeći način: u 1 dram vijale s navojem dodana je karboksilna kiselina (RCO2H, 1 ekvivalent, 0,075 mmol), a potom i otopina N-[1-(cis-3-amino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamida (0,33 ekvivalenta, 8 mg, 0,025 mmol) u metilen kloridu (1 mL). Zatim je dodan PS-karbodiimid (Argonaut Technologies, 0,5 ekvivalenta, 39 mg, 0,038 mmol, 1 mmol/g). Smjesa je protresana tijekom 24 sata pri 23 °C. Pažnja: ukoliko se koristila kiselina netopiva u metilen kloridu, dodavao se N,N-dimetilformamid (0,5 mL). Svaka reakcijska smjesa je prenesena pomoću metilen klorida (0,5 mL) u 3 mL SPE sustav (s pločicom za filtriranje veličine pora 20 μm) opremljen s 2 dram vijalom radi prikupljanja otapala. Otapalo je propušteno kroz pločicu za filtriranje, a polimer je ispran s THF (0,5 mL), metilen kloridom (0,5 mL), THF (0,5 mL) i s metilen kloridom (0,5 mL). Otopine su koncentrirane u struji dušika, te je sirovi produkt podvrgnut LCMS analizi (kolona: 3,9 x 150 mm Waters Symmetry C18, 5 μM, protok = 1,0 ml/min, sustav otapala: A = 0,1 % vodena otopina TFA, B = acetonitril, gradijenta 10-100 % B tijekom 10 min). Ukoliko je dobiven željeni ion (M+H), sirova smjesa je pročišćena preparativnom HPLC (kolona: 30 x 150 mm Waters Symmetry C18, 5 μM, protok = 20 mL/min, sustav otapala: A = 0,1 % vodena otopina TFA, B = acetonitril, gradijenta 0-100 % B tijekom 15 min), te su odgovarajuće frakcije određene masenom spektrometrijom. Čistoća kromatografiranih spojeva određena je s analitičkom HPLC (kolona: 2,1 x 150 mm Waters Symmetry C18, 5 μM, protok = 0,5 mL/min, sustav otapala: A = 0,1 % vodena otopina TFA, B = acetonitril, gradijenta 0-100 % B tijekom 10 min) pomoću UV: 254 nM uz detekciju diodama. Acylation of N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Example 6) with different carboxylic acids, and purification of the product was carried out as follows method: carboxylic acid (RCO2H, 1 equivalent, 0.075 mmol) was added to 1 dram of a threaded vial, followed by a solution of N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]- of 2-naphthalen-1-yl-acetamide (0.33 equiv, 8 mg, 0.025 mmol) in methylene chloride (1 mL). PS-carbodiimide (Argonaut Technologies, 0.5 equivalent, 39 mg, 0.038 mmol, 1 mmol/g) was then added. The mixture was shaken for 24 hours at 23 °C. Attention: if an acid insoluble in methylene chloride was used, N,N-dimethylformamide (0.5 mL) was added. Each reaction mixture was transferred using methylene chloride (0.5 mL) to a 3 mL SPE system (with a 20 μm pore size filter plate) equipped with a 2 dram vial to collect the solvent. The solvent was passed through a filter pad and the polymer was washed with THF (0.5 mL), methylene chloride (0.5 mL), THF (0.5 mL), and methylene chloride (0.5 mL). The solutions were concentrated in a stream of nitrogen, and the crude product was subjected to LCMS analysis (column: 3.9 x 150 mm Waters Symmetry C18, 5 μM, flow = 1.0 ml/min, solvent system: A = 0.1 % aqueous solution TFA, B = acetonitrile, gradient 10-100% B over 10 min). If the desired ion (M+H) was obtained, the crude mixture was purified by preparative HPLC (column: 30 x 150 mm Waters Symmetry C18, 5 μM, flow rate = 20 mL/min, solvent system: A = 0.1 % aqueous TFA solution , B = acetonitrile, gradient 0-100% B for 15 min), and the corresponding fractions were determined by mass spectrometry. The purity of the chromatographed compounds was determined by analytical HPLC (column: 2.1 x 150 mm Waters Symmetry C18, 5 μM, flow = 0.5 mL/min, solvent system: A = 0.1% aqueous TFA solution, B = acetonitrile, gradient 0-100 % B for 10 min) using UV: 254 nM with diode detection.

Gore opisanim postupkom priređeni su slijedeći spojevi. Podatci dobiveni iz njihovih masenih spektara, te vremena zadržavanja prikazani su u tablici 1: The following compounds were prepared by the procedure described above. The data obtained from their mass spectra and retention times are shown in table 1:

Primjer 8a: Example 8a:

Kinolin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid Quinoline-2-carboxylic acids {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Primjer 8b: Example 8b:

1H-pirol-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid 1H-pyrrole-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Primjer 8c: Example 8c:

N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-2-m-tolil-acetamid N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-2-m-tolyl-acetamide

Primjer 8d: Example 8d:

piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Primjer 8e: Example 8e:

2-(3-hidroksi-fenil)-N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-acetamid 2-(3-hydroxy-phenyl)-N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-acetamide

Tablica 1. Table 1.

Acilirani produkti, njihova vremena zadržavanja i podatci iz masenog spektra Acylated products, their retention times and mass spectrum data

[image] [image]

Priprema 5 Preparation 5

4-{3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutilkarbamoil}-piperidin-1-karboksilne kiseline 9H-fluoren-9-ilmetil ester 4-{3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}-piperidin-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

Korak 1 Step 1

4-piperidin karboksilna kiselina (129 mg, 1 mmol) pomiješana je s natrijevim hidroksidom (80 mg, 2 mmol) u smjesi voda/dioksan (1:1, 10 mL). Nakon miješanja tijekom 30 minuta pri sobnoj temperaturi dodana je kap po kap otopina 9-fluorenilmetil kloroformata (259 mg, 1 mmol) u dioksanu (2 mL), te je reakcijska otopina miješana tijekom 4 sata. Otapalo je uklonjeno in vacuo, te je dodana voda. Dodatkom HCl (1 N) pH otopine je podešen na 1, te je vodena otopina ekstrahirana s etil acetatom. Organski sloj je sušen (MgSO4), filtriran i koncentriran in vacuo. Pročišćavanjem s kromatografijom na silikagelu (50:1:0,5 kloroform-metanol-octena kiselina) dobiveno je 340 mg (iskorištenje 97 %) N-1-(fluorenilmetiloksikarbonil)-4-piperidinilkarboksilne kiseline. 1H NMR (400 MHz, CDCl3) δ 7,75 (d, J = 7,1 Hz, 2H), 7,55 (d, J = 7,5 Hz, 2H), 7,39 (m, 2H), 7,30 (m, 2H), 4,4 (brs, 2H), 4,23 (t, J = 6,5 Hz, 1H), 3,9 (brd, 2H), 2,9 (brs, 2H), 2,52 (m, 1H), 1,90 (brs, 2H), 1,62 (brs, 2H); MS (AP/Cl) 352,0 (M+H)+. 4-piperidine carboxylic acid (129 mg, 1 mmol) was mixed with sodium hydroxide (80 mg, 2 mmol) in water/dioxane (1:1, 10 mL). After stirring for 30 minutes at room temperature, a solution of 9-fluorenylmethyl chloroformate (259 mg, 1 mmol) in dioxane (2 mL) was added dropwise, and the reaction solution was stirred for 4 hours. The solvent was removed in vacuo, and water was added. By adding HCl (1 N), the pH of the solution was adjusted to 1, and the aqueous solution was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel (50:1:0.5 chloroform-methanol-acetic acid) yielded 340 mg (yield 97%) of N-1-(fluorenylmethyloxycarbonyl)-4-piperidinylcarboxylic acid. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.1 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.39 (m, 2H), 7.30 (m, 2H), 4.4 (brs, 2H), 4.23 (t, J = 6.5 Hz, 1H), 3.9 (brd, 2H), 2.9 (brs, 2H ), 2.52 (m, 1H), 1.90 (brs, 2H), 1.62 (brs, 2H); MS (AP/Cl) 352.0 (M+H) + .

Korak 2 Step 2

Otopini N-1-(fluorenilmetiloksikarbonil)-4-piperidinilkarboksilne kiseline (priprema 5, korak 1, 77 mg) u metilen kloridu dodani su 1-(3-dimetilaminopropil)-3-etilkarbodiimid klorovodik (84 mg) i DMAP (5 mg). Nakon miješanja tijekom 30 minuta dodan je N-[1-(cis-3-amino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamid (primjer 6). Dobivena smjesa je potom miješana tijekom 4 sata. Dodana je voda, otopina je neutralizirana i ekstrahirana s etil acetatom. Organski sloj je sušen (MgSO4), filtriran i koncentriran in vacuo. Pročišćavanjem s kromatografijom na silikagelu (20:1 kloroform-metanol) dobiveno je 101 mg (iskorištenje 77 %) 4-{3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutilkarbamoil}-piperidin-1-karboksilne kiseline 9H-fluoren-9-ilmetil estera. 1H NMR (400 MHz, CD3OD) δ 8,0 (d, J = 8,3 Hz, 1H), 7,83 (m, 1H), 7,78 (dd, J = 2,07, 7,5 Hz, 1H), 7,73 (d, J = 7,5 Hz, 2H), 7,53 (d, J = 6,6 Hz, 2H), 7,44 (m, 5H), 7,35 (m, 3H), 7,27 (m, 2H), 4,4 (brs, 2H), 4,2 (m, 1H), 4,15 (m, 5H), 2,85 (m, 4H), 2,25 (m, 3H), 1,7 (brs, 2H), 1,5 (brs, 2H); MS (AP/Cl) 654,8 (M+H)+. To a solution of N-1-(fluorenylmethyloxycarbonyl)-4-piperidinylcarboxylic acid (Preparation 5, step 1, 77 mg) in methylene chloride was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg) and DMAP (5 mg). . After stirring for 30 minutes, N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Example 6) was added. The resulting mixture was then stirred for 4 hours. Water was added, the solution was neutralized and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel (20:1 chloroform-methanol) yielded 101 mg (yield 77%) of 4-{3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl }-piperidin-1-carboxylic acid 9H-fluoren-9-ylmethyl ester. 1H NMR (400 MHz, CD3OD) δ 8.0 (d, J = 8.3 Hz, 1H), 7.83 (m, 1H), 7.78 (dd, J = 2.07, 7.5 Hz , 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 6.6 Hz, 2H), 7.44 (m, 5H), 7.35 (m , 3H), 7.27 (m, 2H), 4.4 (brs, 2H), 4.2 (m, 1H), 4.15 (m, 5H), 2.85 (m, 4H), 2 .25 (m, 3H), 1.7 (brs, 2H), 1.5 (brs, 2H); MS (AP/Cl) 654.8 (M+H) + .

Primjer 9 Example 9

piperidin-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid klorovodik Piperidine-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide hydrochloride

4-{3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutilkarbamoil}-piperidin-1-karboksilne kiseline 9H-fluoren-9-ilmetil ester (priprema 5, 100 mg, 0,15 mmol) u DMF (5 mL) pomiješan je s piperidinom (0,5 mL), te je reakcijska smjesa miješana tijekom 2 sata pri sobnoj temperaturi. Otapalo je uklonjeno in vacuo, a zaostatak je pročišćen kromatografijom na silikagelu (4:1:0,08 kloroform-metanol-amonijev hidroksid), te je dobivena slobodna baza. Slobodna baza je potom otopljena u dietil eteru, te je dodana 1 N HCl u metanolu, čime je dobivena HCl sol (64 mg, iskorištenje 91 %) piperidin-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid klorovodik. 1H NMR (400 MHz, CD3OD) δ 8,01 (d, J = 8,0 Hz, 1H), 7,84 (d, J = 8,2 Hz, 1H), 7,78 (d, J = 7,8 Hz, 1H), 7,43 (m, 4H), 7,36 (s, 2H), 4,34 (m, 1H), 4,15 (s, 2H), 4,10 (m, 1H), 3,03 (m, 2H), 2,83 (m, 2H), 2,54 (m, 2H), 2,24 (m, 3H), 1,69 (m, 2H), 1,55 (m, 2H); MS (AP/Cl) 432 (M+H)+. 4-{3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}-piperidin-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (preparation 5, 100 mg , 0.15 mmol) in DMF (5 mL) was mixed with piperidine (0.5 mL), and the reaction mixture was stirred for 2 hours at room temperature. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (4:1:0.08 chloroform-methanol-ammonium hydroxide), and the free base was obtained. The free base was then dissolved in diethyl ether, and 1 N HCl in methanol was added, which gave the HCl salt (64 mg, yield 91 %) of piperidine-4-carboxylic acid {cis-3-[4-(2-naphthalene- 1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 7 .8 Hz, 1H), 7.43 (m, 4H), 7.36 (s, 2H), 4.34 (m, 1H), 4.15 (s, 2H), 4.10 (m, 1H ), 3.03 (m, 2H), 2.83 (m, 2H), 2.54 (m, 2H), 2.24 (m, 3H), 1.69 (m, 2H), 1.55 (m, 2H); MS (AP/Cl) 432 (M+H) + .

Priprema 6 Preparation 6

Izokinolin-5-il-octena kiselina Isoquinolin-5-yl-acetic acid

Korak 1 Step 1

5-aminoizokinolin (5,0 g, 34,7 mmol) miješan je s 48 % vodenom otopinom HBr (65 mL) pri –78 °C tijekom 15 minuta. Potom je kap po kap dodan natrijev nitrit (3,1 g, 45 mmol) u vodi (6 mL). Nakon miješanja tijekom 15 minuta pri –78 °C smjesa je zagrijana na 0 °C. Zatim je polagano, da se izbjegne prekomjerno pjenjenje, dodan bakrov prah (0,3 g). Po cjelokupnom dodatku na reakcijsku tikvicu je stavljen kondenzator, te je smjesa grijana pri 100 °C tijekom 4 sata uz refluks. Smjesa je prenesena na led (oko 200 g) i zalužena (pH = 10) dodatkom KOH. Vodena smjesa je ekstrahirana s etil acetatom, a spojeni organski slojevi su isprani sa zasićenom vodenom otopinom soli, sušeni (MgSO4), filtrirani i koncentrirani in vacuo. Pročišćavanjem pomoću kromatografije na silikagelu (10:1 heksan-etil acetat) dobiveno je 3,8 g (iskorištenje 53 %) 5-bromizokinolina. 1H NMR (400 MHz, CD3OD) δ 9,25 (s, 1H), 8,57 (d, J = 6,2 Hz, 1H), 8,1 (m, 3H), 7,60 (m, 1H); MS (AP/Cl) 208,0, 210,0 (M+H)+. 5-Aminoisoquinoline (5.0 g, 34.7 mmol) was stirred with 48% aqueous HBr (65 mL) at -78 °C for 15 min. Sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was then added dropwise. After stirring for 15 minutes at –78 °C, the mixture was heated to 0 °C. Then, to avoid excessive foaming, copper powder (0.3 g) was added slowly. After the entire addition, a condenser was placed on the reaction flask, and the mixture was heated at 100 °C for 4 hours under reflux. The mixture was transferred to ice (about 200 g) and made alkaline (pH = 10) by adding KOH. The aqueous mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous salt solution, dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel (10:1 hexane-ethyl acetate) yielded 3.8 g (yield 53%) of 5-bromoisoquinoline. 1H NMR (400 MHz, CD3OD) δ 9.25 (s, 1H), 8.57 (d, J = 6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H ); MS (AP/Cl) 208.0, 210.0 (M+H) + .

Korak 2 Step 2

5-bromizokinolin (priprema 6, korak 1, 1,04 g, 5,0 mmol) pomiješan je u atmosferi dušika s aliltributilkositrom (1,7 mL, 5,5 mmol) i diklorpaladijevim bis(trifenilfosfinom) (176 mg, 0,25 mmol) u toluenu (20 mL). Smjesa je grijana uz refluks tijekom 16 sati. Nakon hlađenja na sobnu temperaturu dodana je uz miješanje zasićena vodena otopina kalijeva fluorida (20 mL), te je dobiven precipitat. Nakon dodatnih 15 minuta miješanja, smjesa je filtrirana, organski je sloj odvojen od vodenog i koncentriran in vacuo, te je pročišćavanjem pomoću kromatografije na silikagelu (6:1 heksan-etil acetat) dobiveno 778 mg (iskorištenje 92 %) 5-alilizokinolina. 1H NMR (400 MHz, CDCl3) δ 9,25 (s, 1H), 8,54 (d, J = 5,8 Hz, 1H), 7,85 (m, 1H), 7,79 (d, J = 5,8 Hz, 1H), 7,56 (m, 2H), 6,1 (m, 1H), 5,15 (m, 1H), 5,05 (m, 1H), 3,81 (d, J = 6,2 Hz, 2H); MS (AP/Cl) 170,1 (M+H)+. 5-Bromoisoquinoline (Preparation 6, Step 1, 1.04 g, 5.0 mmol) was mixed under a nitrogen atmosphere with allyltributyltin (1.7 mL, 5.5 mmol) and dichloropalladium bis(triphenylphosphine) (176 mg, 0, 25 mmol) in toluene (20 mL). The mixture was heated under reflux for 16 hours. After cooling to room temperature, a saturated aqueous solution of potassium fluoride (20 mL) was added with stirring, and a precipitate was obtained. After an additional 15 minutes of stirring, the mixture was filtered, the organic layer was separated from the aqueous layer and concentrated in vacuo, and purification using silica gel chromatography (6:1 hexane-ethyl acetate) yielded 778 mg (yield 92%) of 5-allylisoquinoline. 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.54 (d, J = 5.8 Hz, 1H), 7.85 (m, 1H), 7.79 (d, J = 5.8 Hz, 1H), 7.56 (m, 2H), 6.1 (m, 1H), 5.15 (m, 1H), 5.05 (m, 1H), 3.81 (d , J = 6.2 Hz, 2H); MS (AP/Cl) 170.1 (M+H) + .

Korak 3 Step 3

U smjesu 5-alilizokinolina (priprema 6, korak 2, 169 mg, 1,0 mmol), metilen klorida (2 mL), octene kiseline (0,5 mL) i vode (0,5 mL) dodan je dimetil polietilen glikol (prosječne brojčane mase oko 500, 95 μL, 100 mg, 0,2 mmol) u metilen kloridu (1 mL) pri 23 °C. Smjesa je ohlađena na 0 °C, te je u obrocima dodan KMnO4 u prahu (521 mg, 3,3 mmol) uz održavanje temperature ispod 30 °C. Nakon žestokog miješanja tijekom 18 sati otapalo je uklonjeno in vacuo, te je dodan klorovodik u metanolu (10 mL, 1 N), a smjesa je držana pod refluksom tijekom 4 sata. Metanol je uklonjen in vacuo, zaostatak je razrijeđen s vodom, a smjesa je zalužena dodatkom Na2CO3 (pH = 9). Potom je smjesa ekstrahirana s etil acetatom, a dobiveni organski sloj je ispran sa zasićenom vodenom otopinom soli, sušen (MgSO4), filtriran i koncentriran in vacuo. Pročišćavanjem pomoću kromatografije na silikagelu (2:1 heksan-etil acetat) dobiven je izokinolin-5-il-octene kiseline metil ester. 1H NMR (400 MHz, CDCl3) δ 9,28 (brs, 1H), 8,58 (d, J = 6,2 Hz, 1H), 7,95 (d, J = 7,9 Hz, 1H), 7,80 (d, J = 5,8 Hz, 1H), 7,66 (d, J = 5,8 Hz, 1H), 7,59 (t, J = 7,6 Hz, 1H), 4,06 (s, 2H), 3,70 (s, 3H); MS (AP/Cl) 202,1 (M+H)+. Pažnja: Nakon kromatografije na silikagelu ostalo je oko 20 % nečistoće 5-izokinolilkarboksaldehida. Dimethyl polyethylene glycol ( average numerical mass about 500, 95 μL, 100 mg, 0.2 mmol) in methylene chloride (1 mL) at 23 °C. The mixture was cooled to 0 °C, and powdered KMnO4 (521 mg, 3.3 mmol) was added in portions while maintaining the temperature below 30 °C. After vigorous stirring for 18 hours, the solvent was removed in vacuo, hydrogen chloride in methanol (10 mL, 1 N) was added, and the mixture was refluxed for 4 hours. Methanol was removed in vacuo, the residue was diluted with water, and the mixture was made alkaline by adding Na2CO3 (pH = 9). The mixture was then extracted with ethyl acetate, and the resulting organic layer was washed with saturated aqueous salt solution, dried (MgSO4), filtered and concentrated in vacuo. Isoquinolin-5-yl-acetic acid methyl ester was obtained by purification using chromatography on silica gel (2:1 hexane-ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 9.28 (brs, 1H), 8.58 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 5.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 4, 06 (s, 2H), 3.70 (s, 3H); MS (AP/Cl) 202.1 (M+H) + . Attention: After chromatography on silica gel, about 20% of the impurity of 5-isoquinolylcarboxaldehyde remained.

Korak 4 Step 4

Izokinolin-5-il-octene kiseline metil ester (priprema 6, korak 3, 90 mg, 0,448 mmol) otopljen je u vodenoj otopini natrijeva hidroksida (4 N, 3 mL), te je otopina grijana tijekom 4 sata pri 50 °C. Zatim je otopina ohlađena na 0 °C, te je kap po kap dodana octena kiselina (2 mL), čime je dobiven precipitat. Smjesa je držana na 0 °C tijekom noći (oko 15 sati), precipitat je uklonjen filtracijom i ispran s vodom. Krutina je sušena na zraku, te je dobiveno 35 mg (47 % iskorištenja) izokinolin-5-il-octene kiseline. 1H NMR (400 MHz, CD3OD) δ 9,24 (s, 1H), 8,47 (d, J = 6,2 Hz, 1H), 8,04 (d, J = 7,9 Hz, 1H), 7,96 (d, J = 6,2 Hz, 1H), 7,74 (d, J = 6,6 Hz, 1H), 7,66 (t, J = 7,6 Hz, 1H), 4,11 (s, 2H); MS (AP/Cl) 188,3 (M+H)+. Isoquinolin-5-yl-acetic acid methyl ester (Preparation 6, step 3, 90 mg, 0.448 mmol) was dissolved in aqueous sodium hydroxide solution (4 N, 3 mL), and the solution was heated for 4 hours at 50 °C. Then the solution was cooled to 0 °C, and acetic acid (2 mL) was added drop by drop, resulting in a precipitate. The mixture was kept at 0 °C overnight (about 15 hours), the precipitate was removed by filtration and washed with water. The solid was dried in air, and 35 mg (47% yield) of isoquinolin-5-yl-acetic acid was obtained. 1H NMR (400 MHz, CD3OD) δ 9.24 (s, 1H), 8.47 (d, J = 6.2 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.74 (d, J = 6.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 4, 11 (s, 2H); MS (AP/Cl) 188.3 (M+H) + .

Priprema 7 Preparation 7

N-[cis-3-(4-nitro-imidazol-1H-il)ciklobutil]acetamid N-[cis-3-(4-nitro-imidazol-1H-yl)cyclobutyl]acetamide

Korak 1 Step 1

Trans-toluen-4-sulfonske kiseline 3-(4-nitro-imidazol-1-il)-ciklobutil ester (priprema 4, korak 2, 3,6 g, 10,7 mmol) pomiješan je s natrijevim azidom (7 g, 107 mmol) u etanolu (100 mL), s vodom (35 mL) i kloroformom (20 mL). Potom je smjesa grijana uz refluks tijekom 24 sata. Etanol i kloroform su uklonjeni in vacuo, a dobivena smjesa je razrijeđena s vodom i ekstrahirana s etil acetatom. Organski sloj je ispran sa zasićenom vodenom otopinom soli, sušen (MgSO4), filtriran i koncentriran in vacuo. Pročišćavanjem pomoću kromatografije na silikagelu (1:1 do 3:1 etil acetat-heksan) dobiveno je 2,2 g (99 %) 1-(3-cis-azido-ciklobutil)-4-nitro-1H-imidazol. 1H NMR (400 MHz, CDCl3) δ 7,85 (s, 1H), 7,49 (s, 1H), 4,42 (m, 1H), 3,91 (m, 1H), 3,07 (m, 2H), 2,43 (m, 1H); MS (AP/Cl) 208,5 (M+H)+. Trans-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (Preparation 4, step 2, 3.6 g, 10.7 mmol) was mixed with sodium azide (7 g, 107 mmol) in ethanol (100 mL), with water (35 mL) and chloroform (20 mL). The mixture was then heated under reflux for 24 hours. Ethanol and chloroform were removed in vacuo, and the resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography on silica gel (1:1 to 3:1 ethyl acetate-hexane) yielded 2.2 g (99%) of 1-(3-cis-azido-cyclobutyl)-4-nitro-1H-imidazole. 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.49 (s, 1H), 4.42 (m, 1H), 3.91 (m, 1H), 3.07 (m , 2H), 2.43 (m, 1H); MS (AP/Cl) 208.5 (M+H) + .

Korak 2 Step 2

1-(3-cis-azido-ciklobutil)-4-nitro-1H-imidazol (priprema 7, korak 1, 2,2 g, 10,7 mmol) u THF (100 mL) pomiješan je s trifenilfosfinom (3,36 g, 12,8 mmol) i vodom (10 mL). Otopina je miješana pri sobnoj temperaturi tijekom 18 sati. Otapalo je uklonjeno in vacuo, a zaostatak je pročišćen kromatografijom na silikagelu (20:1:0,4 kloroform-metanol-amonijev hidroksid), te je dobiveno 1,95 g (iskorištenje 100 %) 1-(3-cis-amino-ciklobutil)-4-nitro-1H-imidazola. 1H NMR (400 MHz, CD3OD) δ 8,32 (s, 1H), 7,81 (s, 1H), 4,46 (m, 1H), 3,29 (m, 1H), 2,87 (m, 2H), 2,17 (m, 2H); MS (AP/Cl) 183,1 (M+H)+. 1-(3-cis-azido-cyclobutyl)-4-nitro-1H-imidazole (Preparation 7, step 1, 2.2 g, 10.7 mmol) in THF (100 mL) was mixed with triphenylphosphine (3.36 g, 12.8 mmol) and water (10 mL). The solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (20:1:0.4 chloroform-methanol-ammonium hydroxide), and 1.95 g (yield 100%) of 1-(3-cis-amino- cyclobutyl)-4-nitro-1H-imidazole. 1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.81 (s, 1H), 4.46 (m, 1H), 3.29 (m, 1H), 2.87 (m , 2H), 2.17 (m, 2H); MS (AP/Cl) 183.1 (M+H) + .

Korak 3 Step 3

1-(3-cis-amino-ciklobutil)-4-nitro-1H-imidazol (priprema 7, korak 2, 500 mg, 2,75 mmol) podvrgnut je reakciji s octenom kiselinom, te je pročišćavanjem kao u primjeru 7 dobiveno 594 mg (iskorištenje 96 %) N-[cis-3-(4-nitro-imidazol-1H-il)ciklobutil]acetamida. 1H NMR (400 MHz, CD3OD) δ 8,30 (s, 1H), 7,82 (s, 1H), 4,58 (m, 1H), 4,17 (m, 1H), 2,95 (m, 2H), 2,39 (m, 2H), 1,93 (s, 3H); MS (AP/Cl) 225,1 (M+H)+. 1-(3-cis-amino-cyclobutyl)-4-nitro-1H-imidazole (preparation 7, step 2, 500 mg, 2.75 mmol) was subjected to a reaction with acetic acid, and purification as in example 7 gave 594 mg (yield 96%) of N-[cis-3-(4-nitro-imidazol-1H-yl)cyclobutyl]acetamide. 1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 7.82 (s, 1H), 4.58 (m, 1H), 4.17 (m, 1H), 2.95 (m , 2H), 2.39 (m, 2H), 1.93 (s, 3H); MS (AP/Cl) 225.1 (M+H) + .

Priprema 8 Preparation 8

N-[cis-3-(4-nitro-imidazol-1-il)-ciklobutil]-benzamid N-[cis-3-(4-nitro-imidazol-1-yl)-cyclobutyl]-benzamide

N-[cis-3-(4-nitro-imidazol-1-il)-ciklobutil]-benzamid je priređen postupkom sukladnim dobivanju produkta pripreme 7. 1H NMR (400 MHz, CD3OD) δ 8,36 (s, 1H), 7,85 (m, 3H), 7,55 (m, 1H), 7,47 (m, 2H), 4,65 (m, 1H), 4,44 (m, 1H), 3,05 (m, 2H), 2,60 (m, 2H); MS (AP/Cl) 287,3 (M+H)+. N-[cis-3-(4-nitro-imidazol-1-yl)-cyclobutyl]-benzamide was prepared by the procedure corresponding to the preparation product 7. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.85 (m, 3H), 7.55 (m, 1H), 7.47 (m, 2H), 4.65 (m, 1H), 4.44 (m, 1H), 3.05 (m , 2H), 2.60 (m, 2H); MS (AP/Cl) 287.3 (M+H) + .

Priprema 9 Preparation 9

Piridin-2-karboksilne kiseline [cis-3-(4-nitro-imidazol-1-il)-ciklobutil]-amid Pyridine-2-carboxylic acid [cis-3-(4-nitro-imidazol-1-yl)-cyclobutyl]-amide

Piridin-2-karboksilne kiseline [cis-3-(4-nitro-imidazol-1-il)-ciklobutil]-amid je priređen postupkom sukladnim dobivanju produkta pripreme 7. 1H NMR (400 MHz, CDCl3) δ 8,55 (m, 1H), 8,35 (d, J = 7,0 Hz, 1H), 8,19 (d, J = 7,9 Hz, 1H), 8,01 (s, 1H), 7,88 (td, J = 1,65, 7,9 Hz, 1H), 7,57 (s, 1H), 7,47 (m, 1H), 4,5 (m, 2H), 3,17 (m, 2H), 2,72 (m, 2H); MS (AP/Cl) 288,1 (M+H)+. Pyridine-2-carboxylic acid [cis-3-(4-nitro-imidazol-1-yl)-cyclobutyl]-amide was prepared by the procedure corresponding to the preparation product 7. 1H NMR (400 MHz, CDCl3) δ 8.55 (m , 1H), 8.35 (d, J = 7.0 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 7.88 (td , J = 1.65, 7.9 Hz, 1H), 7.57 (s, 1H), 7.47 (m, 1H), 4.5 (m, 2H), 3.17 (m, 2H) , 2.72 (m, 2H); MS (AP/Cl) 288.1 (M+H) + .

Primjer 9a Example 9a

N-[1-(cis-3-acetilamino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-2-il-acetamid N-[1-(cis-3-acetylamino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-yl-acetamide

N-[cis-3-(4-nitro-imidazol-1H-il)ciklobutil]acetamid (priprema 7, 50 mg, 0,22 mmol) podvrgnut je hidrogenaciji i acilaciji s 2-naftil octenom kiselinom sukladno postupku opisanom u primjeru 1, te je dobiveno 35 mg (iskorištenje 44 %) N-[1-(cis-3-acetilamino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-2-il-acetamida. 1H NMR (400 MHz, CD3OD) δ 8,05 (d, J = 8,0 Hz, 1H), 7,87 (d, J = 7,6 Hz, 1H), 7,81 (d, J = 6,4 Hz, 1H), 7,46 (m, 5H), 7,37 (s, 1H), 4,41 (m, 1H), 4,17 (s, 2H), 4,12 (m, 1H), 2,84 (m, 2H), 2,27 (m, 2H), 1,89 (s, 3H); MS (AP/Cl) 363,3 (M+H)+. N-[cis-3-(4-nitro-imidazol-1H-yl)cyclobutyl]acetamide (preparation 7, 50 mg, 0.22 mmol) was subjected to hydrogenation and acylation with 2-naphthyl acetic acid according to the procedure described in example 1 , and 35 mg (yield 44%) of N-[1-(cis-3-acetylamino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-yl-acetamide were obtained. 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 6 ,4 Hz, 1H), 7.46 (m, 5H), 7.37 (s, 1H), 4.41 (m, 1H), 4.17 (s, 2H), 4.12 (m, 1H ), 2.84 (m, 2H), 2.27 (m, 2H), 1.89 (s, 3H); MS (AP/Cl) 363.3 (M+H) + .

Primjer 9b Example 9b

N-{cis-3-[4-(2-izokinolin-5-il-acetilamino)- imidazol-1-il]-ciklobutil}-benzamid N-{cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide

Naslovni spoj je priređen postupkom sukladnim primjeru 9a, iz produkta pripreme 8 i izokinolin-5-il octene kiseline (priprema 6). 1H NMR (400 MHz, CD3OD) δ 9,24 (s, 1H), 8,45 (d, J = 6,2 Hz, 1H), 8,05 (d, J = 7,9 Hz, 1H), 8,02 (J = 6,2 Hz, 1H), 7,82 (m, 3H), 7,67 (m, 1H), 7,52 (m, 2H), 7,45 (m, 3H), 4,5 (m, 1H), 4,4 (m, 1H), 4,21 (s, 2H), 2,95 (m, 2H), 2,50 (m, 2H); MS (AP/Cl) 426,3 (M+H)+. The title compound was prepared by the procedure according to example 9a, from the product of preparation 8 and isoquinolin-5-yl acetic acid (preparation 6). 1H NMR (400 MHz, CD3OD) δ 9.24 (s, 1H), 8.45 (d, J = 6.2 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 8.02 (J = 6.2 Hz, 1H), 7.82 (m, 3H), 7.67 (m, 1H), 7.52 (m, 2H), 7.45 (m, 3H), 4.5 (m, 1H), 4.4 (m, 1H), 4.21 (s, 2H), 2.95 (m, 2H), 2.50 (m, 2H); MS (AP/Cl) 426.3 (M+H) + .

Primjer 9c Example 9c

Piridin-2-karboksilne kiseline {cis-3-[4-(2-izokinolin-5-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid Pyridine-2-carboxylic acid {cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide

Naslovni spoj je priređen postupkom sukladnim primjeru 9a, iz produkta pripreme 9 i izokinolin-5-il octene kiseline (priprema 6). 1H NMR (400 MHz, CD3OD) δ 9,23 (s, 1H), 8,60 (m, 1H), 8,44 (d, J = 5,8 Hz, 1H), 8,03 (m, 3H), 7,92 (dt, J = 1,7, 7,5 Hz, 1H), 7,78 (d, J = 7,1 Hz, 1H), 7,66 (m, 1H), 7,58 (s, 1H), 7,5 (m, 1H), 7,46 (s, 1H), 4,45 (m, 1H), 4,40 (m, 1H), 4,20 (s, 2H), 2,85 (m, 2H), 2,6 (m, 2H); MS (AP/Cl) 427,2 (M+H)+. The title compound was prepared by the procedure according to example 9a, from the product of preparation 9 and isoquinolin-5-yl acetic acid (preparation 6). 1H NMR (400 MHz, CD3OD) δ 9.23 (s, 1H), 8.60 (m, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.03 (m, 3H ), 7.92 (dt, J = 1.7, 7.5 Hz, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.66 (m, 1H), 7.58 (s, 1H), 7.5 (m, 1H), 7.46 (s, 1H), 4.45 (m, 1H), 4.40 (m, 1H), 4.20 (s, 2H) , 2.85 (m, 2H), 2.6 (m, 2H); MS (AP/Cl) 427.2 (M+H) + .

Primjer 10 Example 10

N-{cis-3-[4-(3-naftalen-1-il-ureido)-imidazol-1-il]-ciklobutil}-acetamid N-{cis-3-[4-(3-naphthalen-1-yl-ureido)-imidazol-1-yl]-cyclobutyl}-acetamide

N-[cis-3-(4-nitro-imidazol-1H-il)ciklobutil]acetamid (priprema 7, 50 mg, 0,22 mmol) podvrgnut je reakciji s fenil kloroformatom kako je to opisano u primjeru 4. Na ovaj je način dobivena neodjeljiva smjesa mono i bi-fenil karbamata koja je podvrgnuta kromatografiji na silikagelu (20:1:0,2 kloroform-metanol-amonijev hidroksid), te je međuprodukt otopljen u 1:1 smjesi DMF/dioksan (500 μL). Potom je dodan 1-naftilamin (31 mg, 0,22 mmol), te je smjesa grijana pri 70 °C tijekom 16 sati. Produkt je pročišćen dva puta kromatografijom na silikagelu (20:1:0,02 kloroform-metanol-amonijev hidroksid), te je dobiveno 4,4 mg (iskorištenje 5 %) N-{cis-3-[4-(3-naftalen-1-il-ureido)-imidazol-1-il]-ciklobutil}-acetamida. 1H NMR (400 MHz, CD3OD) δ 8,06 (d, J = 8,0 Hz, 1H), 7,97 (d, J = 8,8 Hz, 1H), 7,83 (d, J = 7,6 Hz, 1H), 7,66 (d, J = 8,4 Hz, 1H), 7,51 (m, 4H), 7,16 (s, 1H), 4,46 (m, 1H), 4,15 (m, 1H), 2,89 (m, 2H), 2,33 (m, 2H), 1,92 (s, 3H); MS (AP/Cl) 364,0 (M+H)+. N-[cis-3-(4-nitro-imidazol-1H-yl)cyclobutyl]acetamide (Preparation 7, 50 mg, 0.22 mmol) was reacted with phenyl chloroformate as described in Example 4. method obtained an inseparable mixture of mono and bi-phenyl carbamate which was subjected to chromatography on silica gel (20:1:0.2 chloroform-methanol-ammonium hydroxide), and the intermediate product was dissolved in a 1:1 mixture of DMF/dioxane (500 μL). Then 1-naphthylamine (31 mg, 0.22 mmol) was added, and the mixture was heated at 70 °C for 16 hours. The product was purified twice by chromatography on silica gel (20:1:0.02 chloroform-methanol-ammonium hydroxide), and 4.4 mg (yield 5%) of N-{cis-3-[4-(3-naphthalene) were obtained -1-yl-ureido)-imidazol-1-yl]-cyclobutyl}-acetamide. 1H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 7 .6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.51 (m, 4H), 7.16 (s, 1H), 4.46 (m, 1H), 4.15 (m, 1H), 2.89 (m, 2H), 2.33 (m, 2H), 1.92 (s, 3H); MS (AP/Cl) 364.0 (M+H) + .

Claims (13)

1. Spoj, naznačen time, da je isti formule: [image] gdje R1 jest ravnolančani ili razgranati (C1-C8)alkil, ravnolančani ili razgranati (C2-C8)alkenil, ravnolančani ili razgranati (C2-C8)alkinil, (C3-C8)cikloalkil, (C4-C8)cikloalkenil, (3-8 člani) heterocikloalkil, (C5-C11)bicikloalkil, (C7-C11)bicikloalkenil, (5-11 člani) heterobicikloalkil, (C6-C14)aril ili (5-14 člani) heteroaril; i gdje je R1 opcijski supstituiran s jednim do šest supstituenata R5 neovisno odabranih između F, Cl, Br, I, nitro, cijano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8, -O-S(=O)2R7, -N3 i R7; R2 jest H, F, -CH3, -CN ili -C(=O)OR7; R3 jest -C(=O)NR9-, -C(=O)O-, -C(=O)(CR10R11)n- ili –(CR10R11)n-; R4 jest ravnolančani ili razgranati (C1-C8)alkil, ravnolančani ili razgranati (C2-C8)alkenil, ravnolančani ili razgranati (C2-C8)alkinil, (C3-C8)cikloalkil, (C4-C8)cikloalkenil, (3-8 člani) heterocikloalkil, (C5-C11)bicikloalkil, (C7-C11)bicikloalkenil, (5-11 člani) heterobicikloalkil, (C6-C14)aril ili (5-14 člani) heteroaril; i gdje je R4 opcijski supstituiran s jednim do tri supstituenata R6 neovisno odabranih između F, Cl, Br, I, nitro, cijano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7, -S(=O)2NR7R8 ili R7; svaki R7, R8 i R9 neovisno je odabran između H, ravnolančanog ili razgranatog (C1-C8)alkila, ravnolančanog ili razgranatog (C2-C8)alkenila, ravnolančanog ili razgranatog (C2-C8)alkinila, (C3-C8)cikloalkila, (C4-C8)cikloalkenila, (3-8 članog) heterocikloalkila, (C5-C11)bicikloalkila, (C7-C11)bicikloalkenila, (5-11 članog) heterobicikloalkila, (C6-C14)arila i (5-14 članog) heteroarila; i gdje je svaki od R7, R8 i R9 neovisno opcijski supstituiran s jednim do šest supstituenata neovisno odabranih između F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C(=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10, -OC(=O)NR10R11, -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -C(=O)OR10, -C(=O)NR10R11 i R10; ili ukoliko R7 i R8 jesu oblika NR7R8, tada mogu opcijski biti povezani, te zajedno s dušikovim atomom iz NR7R8 na koji su vezani tvoriti heterocikloalkilni dio koji se sastoji od prstena s tri do sedam članova, gdje rečeni heterocikloalkilni dio opcijski može sadržavati i jedan ili dva dodatna heteroatoma neovisno odabrana između N, O i S; svaki R10, R11 i R12 neovisno je odabran između H, ravnolančanog ili razgranatog (C1-C8)alkila, ravnolančanog ili razgranatog (C2-C8)alkenila, ravnolančanog ili razgranatog (C2-C8)alkinila, (C3-C8)cikloalkila, (C4-C8)cikloalkenila, (3-8 članog) heterocikloalkila, (C5-C11)bicikloalkila, (C7-C11)bicikloalkenila, (5-11 članog) heterobicikloalkila, (C6-C14)arila i (5-14 članog) heteroarila; i gdje je svaki od R10, R11 i R12 neovisno opcijski supstituiran s jednim do šest supstituenata neovisno odabranih između F, Cl, Br, I, -NO2, -CN, -CF3, -NR13R14, -NR13C(=O)R14, -NR13C(=O)OR14, -NR13C(=O)NR14R15, -NR13S(=O)2R14, -NR13S(=O)2NR14R15, -OR13, -OC(=O)R13, -OC(=O)OR13, -OC(=O)NR13R14, -OC(=O)SR13, -SR13, -S(=O)R13, -S(=O)2R13, -S(=O)2NR13R14, -C(=O)R13, -C(=O)OR13, -C(=O)NR13R14 i R13; svaki R13, R14 i R15 neovisno je odabran između H, ravnolančanog ili razgranatog (C1-C8)alkila, ravnolančanog ili razgranatog (C2-C8)alkenila, ravnolančanog ili razgranatog (C2-C8)alkinila, (C3-C8)cikloalkila, (C4-C8)cikloalkenila, (3-8 članog) heterocikloalkila, (C5-C11)bicikloalkila, (C7-C11)bicikloalkenila, (5-11 članog) heterobicikloalkila, (C6-C14)arila i (5-14 članog) heteroarila; i gdje je svaki od R13, R14 i R15 neovisno opcijski supstituiran s jednim do šest supstituenata neovisno odabranih između F, Cl, Br, I, -NO2, -CN, -CF3, -NR16R17, -NR16C(=O)R17, -NR16C(=O)OR17, -NR16C(=O)NR17R18, -NR16S(=O)2R17, -NR16S(=O)2NR17R18, -OR16, -OC(=O)R16, -OC(=O)OR16, -OC(=O)NR16R17, -OC(=O)SR16, -SR16, -S(=O)R16, -S(=O)2R16, -S(=O)2NR16R17, -C(=O)R16, -C(=O)OR16, -C(=O)NR16R17 i R16; svaki R16, R17 i R18 neovisno je odabran između H, ravnolančanog ili razgranatog (C1-C8)alkila, ravnolančanog ili razgranatog (C2-C8)alkenila, ravnolančanog ili razgranatog (C2-C8)alkinila, (C3-C8)cikloalkila, (C4-C8)cikloalkenila, (3-8 članog) heterocikloalkila, (C5-C11)bicikloalkila, (C7-C11)bicikloalkenila, (5-11 članog) heterobicikloalkila, (C6-C13)arila i (5-12 članog) heteroarila; n jest 0, 1, 2 ili 3; gdje R10 i R11 u –C(=O)(CR10R11)n- i -(CR10R11)n- za svaku vrijednost n jesu neovisno definirani na gore opisani način; ili njegove farmaceutski prihvatljive soli.1. A compound, indicated by the fact that it has the same formula: [image] where R1 is straight or branched (C1-C8)alkyl, straight or branched (C2-C8)alkenyl, straight or branched (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3- 8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl or (5-14 membered) heteroaryl; and wherein R1 is optionally substituted with one to six R5 substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, - NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7 , -S(=O)2NR7R8, -O-S(=O)2R7, -N3 and R7; R2 is H, F, -CH3, -CN or -C(=O)OR7; R3 is -C(=O)NR9-, -C(=O)O-, -C(=O)(CR10R11)n- or -(CR10R11)n-; R4 is straight-chain or branched (C1-C8)alkyl, straight-chain or branched (C2-C8)alkenyl, straight-chain or branched (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (3-8 members) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl or (5-14 membered) heteroaryl; and wherein R4 is optionally substituted with one to three R6 substituents independently selected from F, Cl, Br, I, nitro, cyano, -CF3, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, - NR7C(=O)NR8R9, -NR7S(=O)2R8, -NR7S(=O)2NR8R9, -OR7, -OC(=O)R7, -OC(=O)OR7, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -OC(=O)NR7R8, -OC(=O)SR7, -SR7, -S(=O)R7, -S(=O)2R7 , -S(=O)2NR7R8 or R7; each R 7 , R 8 and R 9 is independently selected from H, straight or branched (C 1 -C 8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, straight or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, ( C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl and (5-14 membered) heteroaryl ; and wherein each of R7, R8 and R9 is independently optionally substituted with one to six substituents independently selected from F, Cl, Br, I, NO2, -CN, -CF3, -NR10R11, -NR10C(=O)R11, -NR10C (=O)OR11, -NR10C(=O)NR11R12, -NR10S(=O)2R11, -NR10S(=O)2NR11R12, -OR10, -OC(=O)R10, -OC(=O)OR10, - OC(=O)NR10R11, -OC(=O)SR10, -SR10, -S(=O)R10, -S(=O)2R10, -S(=O)2NR10R11, -C(=O)R10, -C(=O)OR 10 , -C(=O)NR 10 R 11 and R 10 ; or if R7 and R8 are of the form NR7R8, then they can optionally be connected, and together with the nitrogen atom from NR7R8 to which they are connected, form a heterocycloalkyl part consisting of a ring with three to seven members, where said heterocycloalkyl part can optionally contain one or two additional heteroatoms independently selected from N, O and S; each R 10 , R 11 and R 12 is independently selected from H, straight or branched (C 1 -C 8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, straight or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, ( C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl and (5-14 membered) heteroaryl ; and wherein each of R10, R11 and R12 is independently optionally substituted with one to six substituents independently selected from F, Cl, Br, I, -NO2, -CN, -CF3, -NR13R14, -NR13C(=O)R14, - NR13C(=O)OR14, -NR13C(=O)NR14R15, -NR13S(=O)2R14, -NR13S(=O)2NR14R15, -OR13, -OC(=O)R13, -OC(=O)OR13, -OC(=O)NR13R14, -OC(=O)SR13, -SR13, -S(=O)R13, -S(=O)2R13, -S(=O)2NR13R14, -C(=O)R13 , -C(=O)OR 13 , -C(=O)NR 13 R 14 and R 13 ; each R 13 , R 14 and R 15 is independently selected from H, straight or branched (C 1 -C 8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, straight or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, ( C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C14)aryl and (5-14 membered) heteroaryl ; and wherein each of R13, R14 and R15 is independently optionally substituted with one to six substituents independently selected from F, Cl, Br, I, -NO2, -CN, -CF3, -NR16R17, -NR16C(=O)R17, - NR16C(=O)OR17, -NR16C(=O)NR17R18, -NR16S(=O)2R17, -NR16S(=O)2NR17R18, -OR16, -OC(=O)R16, -OC(=O)OR16, -OC(=O)NR16R17, -OC(=O)SR16, -SR16, -S(=O)R16, -S(=O)2R16, -S(=O)2NR16R17, -C(=O)R16 , -C(=O)OR 16 , -C(=O)NR 16 R 17 and R 16 ; each R 16 , R 17 and R 18 is independently selected from H, straight or branched (C 1 -C 8 )alkyl, straight or branched (C 2 -C 8 )alkenyl, straight or branched (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, ( C4-C8)cycloalkenyl, (3-8 membered) heterocycloalkyl, (C5-C11)bicycloalkyl, (C7-C11)bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C6-C13)aryl and (5-12 membered) heteroaryl ; n is 0, 1, 2 or 3; where R10 and R11 in –C(=O)(CR10R11)n- and -(CR10R11)n- for each value of n are independently defined as described above; or pharmaceutically acceptable salts thereof. 2. Spoj prema zahtjevu 1, naznačen time, da R3 jest –C(=O)NH– ili –C(=O)(CR10 R11)n– skupina.2. Compound according to claim 1, characterized in that R3 is –C(=O)NH– or –C(=O)(CR10 R11)n– group. 3. Spoj prema zahtjevu 1, naznačen time, da R1 jest opcijski supstituiran (C3-C8)cikloalkil ili opcijski supstituiran (C5-C11)bicikloalkil.3. A compound according to claim 1, characterized in that R1 is optionally substituted (C3-C8)cycloalkyl or optionally substituted (C5-C11)bicycloalkyl. 4. Spoj prema zahtjevu 4, naznačen time, da R1 jest ciklopropil, ciklobutil, ciklopentil, cikloheksil, norbornil ili biciklo-[3.1.0]-heksil, gdje je svaki opcijski supstituiran.4. A compound according to claim 4, characterized in that R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl or bicyclo-[3.1.0]-hexyl, where each is optionally substituted. 5. Spoj prema zahtjevu 1, naznačen time, da R1 jest opcijski supstituiran ravnolančani ili razgranati (C1-C8)alkil ili opcijski supstituiran ravnolančani ili razgranati (C2-C8)alkenil.5. A compound according to claim 1, characterized in that R1 is optionally substituted straight-chain or branched (C1-C8)alkyl or optionally substituted straight-chain or branched (C2-C8)alkenyl. 6. Spoj prema zahtjevu 1, naznačen time, da R4 jest (C6-C14)aril ili (5-14 člani)heteroaril, gdje je svaki opcijski supstituiran.6. A compound according to claim 1, characterized in that R4 is (C6-C14)aryl or (5-14 membered)heteroaryl, where each is optionally substituted. 7. Spoj prema zahtjevu 6, naznačen time, da R4 jest fenil, piridil, naftil, kinolil ili izokinolil, gdje je svaki opcijski supstituiran.7. A compound according to claim 6, characterized in that R4 is phenyl, pyridyl, naphthyl, quinolyl or isoquinolyl, where each is optionally substituted. 8. Spoj prema bilo kojem zahtjevu 1-7, naznačen time, da R2 jest vodik.8. A compound according to any of claims 1-7, characterized in that R2 is hydrogen. 9. Spoj prema zahtjevu 1, naznačen time, da je isti odabran iz grupe koju čine: N-(1-ciklobutil-1H-imidazol-4-il)-2-kinolin-6-il-acetamid; N-(1-ciklopentil-1H-imidazol-4-il)-2-(4-metoksi-fenil)-acetamid; N-[1-(cis-3-fenil-ciklobutil)-1H-imidazol-4-il]-2-kinolin-6-il-acetamid; (1-ciklobutil-1H-imidazol-4-il)-karbamske kiseline fenil ester; 1-(1-ciklobutil-1H-imidazol-4-il)-3-izokinolin-5-il-urea; N-[1-(cis-3-amino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-1-il-acetamid; 6-metil-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 1H-imidazol-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 6-hidroksi-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 3-metil-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 2-piridin-3-il-tiazol-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 6-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutilkarbamoil}-nikotinske kiseline metil ester; pirazin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-benzamid; 5-metil-pirazin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-izobutiramid; 6-klor-piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; kinolin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 1H-pirol-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-2-m-tolil-acetamid; piridin-2-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid; 2-(3-hidroksi-fenil)-N-{cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-acetamid; piperidin-4-karboksilne kiseline {cis-3-[4-(2-naftalen-1-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid klorovodik; N-[1-(cis-3-acetilamino-ciklobutil)-1H-imidazol-4-il]-2-naftalen-2-il-acetamid; N-{cis-3-[4-(2-izokinolin-5-il-acetilamino)-imidazol-1-il]-ciklobutil}-benzamid i piridin-2-karboksilne kiseline {cis-3-[4-(2-izokinolin-5-il-acetilamino)-imidazol-1-il]-ciklobutil}-amid, te farmaceutski prihvatljive soli gore navedenih spojeva. 9. The compound according to claim 1, characterized in that it is selected from the group consisting of: N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide; N-(1-cyclopentyl-1H-imidazol-4-yl)-2-(4-methoxy-phenyl)-acetamide; N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-yl-acetamide; (1-Cyclobutyl-1H-imidazol-4-yl)-carbamic acid phenyl ester; 1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea; N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide; 6-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 1H-imidazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 6-hydroxy-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 3-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 2-pyridin-3-yl-thiazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 6-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}-nicotinic acid methyl ester; pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide; 5-methyl-pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-isobutyramide; 6-chloro-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; quinoline-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 1H-pyrrole-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-2-m-tolyl-acetamide; pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; 2-(3-hydroxy-phenyl)-N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-acetamide; Piperidine-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide hydrochloride; N-[1-(cis-3-acetylamino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-2-yl-acetamide; N-{cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide and pyridine-2-carboxylic acid {cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide, and pharmaceutically acceptable salts of the above-mentioned compounds. 10. Farmaceutski pripravak namijenjen tretmanu bolesti ili stanja koja su praćena nenormalnim rastom stanica ili pak neurodegenerativnih bolesti ili stanja u sisavaca, naznačen time, da sadrži spoj prema zahtjevu 1 u količini učinkovitoj za tretman rečenih bolesti ili stanja, te farmaceutski prihvatljivog nositelja.10. Pharmaceutical preparation intended for the treatment of diseases or conditions that are accompanied by abnormal cell growth or neurodegenerative diseases or conditions in mammals, characterized in that it contains the compound according to claim 1 in an amount effective for the treatment of said diseases or conditions, and a pharmaceutically acceptable carrier. 11. Farmaceutski pripravak namijenjen tretmanu onih bolesti ili stanja u sisavaca na koja se može utjecati ili ih olakšati promjenom neurotransmisije posredovane dopaminom, naznačen time, da sadrži inhibitor aktivnosti cdk5 u količini učinkovitoj za tretman rečenih bolesti ili stanja ili pak u količini dostatnoj za inhibiciju aktivnosti cdk5, te farmaceutski prihvatljivog nositelja.11. A pharmaceutical preparation intended for the treatment of those diseases or conditions in mammals that can be affected or alleviated by changing dopamine-mediated neurotransmission, characterized in that it contains an inhibitor of cdk5 activity in an amount effective for the treatment of said diseases or conditions or in an amount sufficient to inhibit the activity cdk5, and a pharmaceutically acceptable carrier. 12. Farmaceutski pripravak namijenjen tretmanu bolesti ili stanja u sisavaca odabranih između muške neplodnosti i poremećaja pokretljivosti spermija; diabetes melitusa; poremećene regulacije glukoze; metaboličkog sindroma ili sindroma X; sindroma policističkog jajnika; lipogeneze i pretilosti; miogeneze i tjelesne slabosti, na primjer opadanja fizičkih sposobnosti povezanog sa starenjem; akutne atrofije, na primjer atrofije mišića i/ili kaheksije povezane s opekotinama, ležanjem u krevetu, imobilizacijom udova ili s obimnim operacijama prsnog koša, abdomena i/ili ortopedskim operacijama; sepse; opadanja kose, stanjivanja kose i ćelavosti; te imunodeficijencije, naznačen time, da sadrži spoj prema zahtjevu 1 u količini učinkovitoj za tretman rečenih bolesti ili stanja, te farmaceutski prihvatljivog nositelja.12. Pharmaceutical preparation intended for the treatment of diseases or conditions in mammals selected from male infertility and sperm motility disorders; diabetes mellitus; impaired glucose regulation; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; myogenesis and physical weakness, for example the decline of physical abilities associated with aging; acute atrophy, for example muscle atrophy and/or cachexia associated with burns, bed rest, immobilization of limbs or extensive thoracic, abdominal and/or orthopedic surgery; sepsis; hair loss, hair thinning and baldness; and immunodeficiencies, characterized in that it contains the compound according to claim 1 in an amount effective for the treatment of said diseases or conditions, and a pharmaceutically acceptable carrier. 13. Farmaceutski pripravak, naznačen time, da isti sadrži inhibitor cdk5 i drugu tvar odabranu iz grupe koju čine SSRI, antagonist receptora NK-1, antagonist 5HT1D, ziprazidon, olanzapin, risperidon, L-745870, sonepiprazol, RP 62203, NGD 941, balaperidon, flezinoksan, gepiron, inhibitor acetilkolinesteraze, TPA, NIF, modulator kalijevih kanala kao što je to BMS-204352, te antagonist receptora NMDA, te farmaceutski prihvatljivog nositelja, gdje su inhibitor cdk5 i rečena druga tvar zajedno prisutne u učinkovitoj količini. 13. Pharmaceutical preparation, characterized in that it contains a cdk5 inhibitor and another substance selected from the group consisting of SSRI, NK-1 receptor antagonist, 5HT1D antagonist, ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxane, gepirone, acetylcholinesterase inhibitor, TPA, NIF, potassium channel modulator such as BMS-204352, and NMDA receptor antagonist, and a pharmaceutically acceptable carrier, where the cdk5 inhibitor and said second substance are present together in an effective amount.
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