RS8504A - Novi cikloheksil sulfoni - Google Patents

Novi cikloheksil sulfoni

Info

Publication number
RS8504A
RS8504A YUP-85/04A YUP8504A RS8504A RS 8504 A RS8504 A RS 8504A YU P8504 A YUP8504 A YU P8504A RS 8504 A RS8504 A RS 8504A
Authority
RS
Serbia
Prior art keywords
compound
pharmaceutically acceptable
halogen
acceptable salt
alkyl
Prior art date
Application number
YUP-85/04A
Other languages
English (en)
Inventor
Ian Churcher
Kevin Dinnell
Timothy Harrison
Sonia Kerrad
Alan John Nadin
Paul Joseph Oakley
Duncan Edward Shaw
Martin Richard Teall
Brian John Williams
Susannah Williams
Original Assignee
Merck Sharp & Dohme Limited,
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/GB2001/003741 external-priority patent/WO2002081435A1/en
Application filed by Merck Sharp & Dohme Limited, filed Critical Merck Sharp & Dohme Limited,
Priority claimed from PCT/GB2002/003806 external-priority patent/WO2003018543A1/en
Publication of RS8504A publication Critical patent/RS8504A/sr
Publication of RS51296B publication Critical patent/RS51296B/sr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/12—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/20—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/30—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

Novi cikloheksil sulfoni Izloženi su novi sulfoni formule I: Jedinjenja menjaju stvaranje amiloidnog prekursornog proteina gama-sekretazom i time su korisna u lečenju ili prevenciji Alchajmerove bolesti.

Description

NOVI CIKLOHEKSIL SULFONI
Ovaj pronalazak se odnosi na novu grupu jedinjenja, njihove soli, farmaceutske smeše koje ih sadrže, na postupke njihove izrade i njihovu upotrebu u lečenju ljudskog organizma. Posebno, pronalazak se odnosi na nove sulfone, koji menjaju stvaranje APP-a y-sekretazom i zbog toga su korisni u lečenju ili prevenciji Alchajmerove bolesti.
Alchajmerova bolest (AD) je najrasprostranjeniji oblik demencije, lako je prvenstveno bolest starijih, koja pogađa do 10% populacije preko 65 godina, AD, takođe, napada značajan broj mlađih pacijenata sa genetskom predispozicijom. To je neurodegenerativni poremećaj, koji se klinički karakteriše progresivnim gubitkom memorije i kognitivne funkcije, a patološki se karakteriše odlaganjem ekstracelularnih proteinoznih plakova u kortikalnim i asocijativnim regionima mozga jedinki koje pate od ove bolesti. Ovi plakovi uglavnom sadrže fibrilarne agregate (3-amiloidnog peptida (Ap). Uloga sekretaza, uključujući navedenu y-sekretazu, u stvaranju amiloidnog prekursornog proteina (APP) kako bi se obrazovao Ap\ dobro je dokumentovana u literaturi i izložena je, na primer, u WO 01/70677.
U literaturi postoji samo nekoliko izveštaja o jedinjenjima sa inhibitornom aktivnošću prema y-sekretazi, mereno testovima baziranim na nivou ćelije. Oni su prikazani u WO 01/70677. Mnoga od bitnih jedinjenja su peptidi ili peptidni derivati.
Ovaj pronalazak obezbeđuje novu klasu ne-peptidnih jedinjenja, koja su korisna u lečenju ili prevenciji AD, menjajući stvaranje APP-a navedenom y-sekretazom, zaustavljajući na taj način proizvodnju Ap\
Ovaj pronalazak obezbeđuje jedinjenje formule I:
u kome je:
m 0 ili 1;
Z predstavlja CN, OR2a,C02R<2a>ili CON(R<2a>)2;
R<1b>predstavlja H, CV4alkil ili OH;
R<1>c predstavlja H ili C^alkil;
Ar<1>predstavlja fenil ili piridil, od kojih oba nose 0-3 supstituenta, nezavisno odabrana od: halogena, CN, N02, CF3, OH, OCF3, C^alkoksi ili C..4alkila, koji opciono nosi supstituent, koji je odabran od: halogena, CN, N02, CF3, OH i C^alkoksi;
Ar<2>predstavlja fenil, koji je supstituisan na 2- j 5- položajima sa halogenom;
R2a predstavlja: H, C^alkil, C3.6cikloalkil, C3.6cikloalkilC-,.6alkil, C2.6alkenil, od kojih svaki opciono nosi supstituent, koji je odabran od: halogena, CN, N02, CF3, OR<25>, C02R<2b>, N(R<2b>)2, CON(R<2b>)2, Ar i COAr; ili R<2a>predstavlja Ar; ili dve R<2a>grupe, zajedno sa atomom azota za koji su međusobno vezane, mogu obrazovati N-heterociklil grupu, koja nosi 0-4 supstituenta, koji su nezavisno odabrani od: =0, =S, halogena, C,.4alkila, CN, N0?, CF„ OH. C^alkoksi, C^alkoksikarbonila, C02H, amino, C^alkilamino,d\( C,_4alkil)amino, karbamoila, Ar i COAr;
R? predstavlja: H, CV6alkil, C3.6cikloalkil, Cg.gCikloalkilC^alkil, C2.6aikenil, od kojih svaki opciono nosi supstituent, koji je odabran od halogena, CN, N02, CF3, OH, C^alkoksi, C1.4alkoksikarbonila, C02H, amino, C^alkilamino, di(C1.4alkil)amino, karbamoila, Ar i COAr; ili R2" predstavlja Ar; ili dve R2" grupe, zajedno sa atomom azota, na koji su međusobno vezane, mogu obrazovati N-heterociklil grupu, koja nosi 0-4 supstituenta, koji su nezavisno odabrani od: =0, =S, halogena, C^alkila, CN, N02, CF3, OH, C^alkoksi, C^alkoksikarbonila, C02H, amino, C^alkilamino, di(C1.4alkil)amino, karbamoila, Ar i COAr;
Ar predstavlja fenil ili heteroaril, koji nose 0-3 supstituenta, odabrana od: halogena, CMalkila, CN, N02, CF3, OH, C^alkoksi, C^alkoksikarbonila, amino, C^alkilamino, di(C1.4alkil)amino, karbamoila, C^alkilkarbamoila i dKC^aikilJkarbamoila;
ili njegovu farmaceutski prihvatljivu so.
Kada se u formuli I ili u njenom supstituentu promenljiva javlja više od jednog puta, pojedinačna pojavljivanja te promenljive su nezavisna jedno od drugog, ukoliko nije drugačije navedeno.
Kao što je ovde korišćen, izraz "C^alkir, u kom je x ceo broj veći od 1, odnosi se na ravnolančane ili razgranate alkil grupe, u kojima je broj konstitutivnih atoma ugljenika u rasponu od 1 do x. Posebne alkil grupe uključuju: metil, etil, n-propii, izopropil i t-butil. Analogno treba protumačiti izvedene izraze kao što su: "C2.6alkenil", "hidroksiC^alkil", "heteroariP'C,.8alkil, "C2.6alkinil" i "C^alkoksf.
Izraz "C3.6cikloalkil", kao što je ovde korišćen, odnosi se na nearomatične monocikličke ili spojene biciklične sisteme ugljovodoničnih prstenova, koji sadrže od 3 od 6 atoma u prstenu. Primeri uključuju: ciklopropil, ciklobutil, ciklopentil, cikloheksil i cikloheksenil.
Izraz "Ca^cikloalkilC^ealkil", kao što je ovde korišćen, uključuje: ciklopropilmetil, ciklobutilmetil, ciklopentilmetil i cikloheksilmetil.
Izraz "N-heterociklil", kao što je ovde korišćen, označava ciklični ili policiklični sistem od do 10 atoma u prstenu, odabranih od: C, N, O i S, u kome nijedan od konstitutivnih prstenova nije aromatični i u kome je najmanje jedan atom prstena azot, a vezivanje je preko navedenog azota prstena. Poželjne N-heterociklil grupe su monociklični sistemi od 4-6 članova, kao što su: azetidinil, pirolidinil, piperidinil, piperazinil, morfolinil, tiomorfolinil, imidazolidinil, oksazolidinil i tiazolidinii.
Izraz "heteroarir, kao što je ovde korišćen, označava ciklični ili policiklični sistem od do 10 atoma u prstenu, odabranih od: C, N, O i S, u kome je najmanje jedan od konstituitvnih prstenova aromatični i sadrži najmanje jedan atom prstena koji nije ugljenik. Poželjne heteroaril grupe su monociklični sistemi od 5 ili 6 članova, kao što su: piridinil, piridazinil, pirimidinil, pirazinil, pirolil, furil, tienil, pirazolil, oksazolil, izoksazolil, tiazolil, izotiazolil, imidazolil, oksadiazoli!, triazolil i tiadiazolil grupe. Sledeći primeri heteroaril grupa uključuju: tetrazol, 1,2,4-triazin i 1,3,5-triazin.
Izraz "halogen", kao što je ovde korišćen, uključuje: fluor, nlor, brom i jod, od kojih su poželjni fluor i hior.
Za upotrebu u medicini, jedinjenja formule I mogu pogodno biti u obliku farmaceutski prihvatljivih soli. ali druge soli mogu biti korisne u izradi navedenih jedinjenja ili njihovih farmaceutski prihvatljivih soli. Pogodne farmaceutski prihvatljive soli jedinjenja ovog pronalaska uključuju soli koje se obrazuju dodatkom kiseline, kao što su one soli, koje se obrazuju sa hlorovodoničnom, sumpornom, metansulfonskom, fumarnom, maleinskom, ćilibarnom, sirćetnom, benzojevom, oksalnom, limunskom, vinskom, ugljenom ili fosfornom kiselinom i, kada jedinjenja pronalaska nose kiseli deo, soli natrijuma, kalijuma, kalcijuma ili magnezijuma i soli, koje se obrazuju sa pogodnim organskim ligandima, npr., kvaternerne amonijum soli ili piridinijum soli.
Kada jedinjenja u skladu sa pronalaskom imaju najmanje jedan asimetrični centar ona mogu, zbog toga, postojati kao enantiomeri. Kada jedinjenja u skladu sa pronalaskom poseduju dva ili više asimetričnih centara, ona dodatno, mogu postojati kao dijastereoizomeri. Treba shvatiti da su svi takvi izomeri i njihove mešavine u bilo kom odnosu uključeni unutar okvira ovog pronalaska.
Bez obzira na prisustvo ili odsustvo asimetričnih centara, određena jedinjenja u skladu sa pronalaskom mogu postojati kao enantiomeri na osnovu asimetrije molekula kao ceiine. Treba shvatiti da su,
u takvim slučajevima, oba enantiomera i njihove mešavine u bilo kom odnosu, uključeni unutar okvira ovog pronalaska, i da će strukturne formule,
koje oslikavaju molekule ovog tipa, biti reprezent oba moguća enantiomera, ukoliko nije drugačije naznačeno.
U jedinjenjima formule I, Ar<1>predstavlja opciono supstituisani fenil
ili piridil, naročito, opciono supstituisani fenil ili 3-piridil. Ar<1>je poželjno odabran od fenil grupa, supstituisanih na 4-položaju sa halogenom. metilom ili trifluorometilom i od fenil grupa, supstituisanih na 3- i 4- položajima sa halogenom,
Ar<?>je poželjno 2,5-difiuorofenii.
' U posebnim ostvarenjima, Ar<1>je 4-hlorofenil ili 4-trifluorometilfenil, a Ar<2>je 2,5-difluorofenil.
R,<b>obično predstavlja: H, metil ili OH, poželjno H.
R<1c>obično predstavlja H ili metil, poželjno H.
Kada je m 1, oba iR1bi R<1c>poželjno ne predstavljaju C,.4alkil.
Naročite vrednosti R<2a>uklj<uč>uju: H, fenil, piridil, C3.6cikloalkil (kao što su: ciklopropil, ciklobutil i ciklopentil), C3.6cikloalkilC1^alkil (kao što je ciklopropilmetil), C^alkenil (kao što je alil) i linearni ili razgranati C^alkil, koji je opciono supstituisan sa: CF3, Ar, OR<2b>, N(R<2b>)2, 0O2<R2b>ili CON(R2b)2.
Primeri N-heterociklil grupa, predstavljenih sa N(R<2a>)2, uključuju: piperidin-1-il (opciono supstituisan sa: OH, C02H, C02C1w,alkilom, Me ili Ph), piperazin-1-il (opciono supstituisan sa Me ili Ph), morfolin-4-il, tiomorfolin-4-il, 1,1-diokso-tiomorfolin-4-il, 2-okso-imidazolidin-1-il, 5,5-dirneti!-2,2-diokso-oksazolidin-3-il, 2,5-diokso-imidazolidin-1-il, 2-okso-oksazolidin-3-il, 2-okso-piridin-1-il i 2-okso-pirolidin-1-il.
R<2b>obično predstavlja H ili Cv4alkil.
Kada Z predstavljaOR2a, R<2a>pogodno predstavlja H, Ar (posebno piridil), alki! (kao što je: metil, etil, propil ili butil) ili supstituisani alkil (posebno CKAr, kao što je benzil ili piridilmetil).
Kada Z predstavlja C02R<2a>, R<2>a pogodno predstavlja H ili alkil (kao što je: metil, etil, propil ili butil).
Kada Z predstavlja C0N(R2a)2,R2a grupe nezavisno predstavljaju H ili opciono supstituisani: alkil, cikloalkil, cikloalkilalkil ili alkenil, ili zajedno kompletiraju N-heterociklil grupu. Veoma pogodno, jedan R<2a>predstavlja H, a drugi predstavlja: H. alkil (kao što je: metil, etil, n-propii, izopropil, n-butii, sek-butiL terc-butil ili 1-etilpropii), alkenil (kao što je alil), cikioalkii (kao što je ciklopropil, cikiobutil ili ciklopentil), cikloalkilalkil (kao što je ciklopropilmetil) ili supstituisani alkil (kao što je alkil, supstituisan sa Ar, posebno 2-piridiletilom, 3-(imidazol-1-il)propilom ili 2-feniletilom; ili alkilom, supstituisanim sa: CF3, COžR<2b>ili CON(R<2b>)2:posebno 2,2,2-trifluoroetilom, metoksikarbonilmetilom ili karbamoilmetilom). Alternativno, dve R<2a>grupe kompletiraju N-heterociklil grupu, kao što je: morfolin, tiomorfolin, tiomorfolin-1,1-dioksid, 4-metilpiperazin, 4-fenilpiperazin, piperidin, 4-hidroksipiperidin ili piperidin, koji je supstituisan na 3- ili 4- položaju sa CC^R2*5 i/ili C^alkilom, posebno 3- ili 4-karboksipiperidinom, 3- ili 4-etoksikarbonilpiperidinom, 3-karboksi-3-metilpiperidinom i 3-etoksikarbonil-3-metilpiperidinom.
Primeri pojedinačnih jedinjenja u skladu sa formulom I dati su u odlomku Primeri, dodatom ovde.
Jedinjenja formule I imaju aktivnost kao modulatori stvaranja APP-a posredstvom y-sekretaze.
Pronalazak, takođe, obezbeđuje farmaceutske smeše, koje sadrže jedno ili više jedinjenja formule I ili njihove farmaceutski prihvatljive soli i farmaceutski prihvatljiv nosač. Poželjno, ove smeše su u obliku doznih jedinica, kao što su: tablete, pilule, kapsule, prašci, granule, sterilni parenteralni rastvori ili suspenzije, aerosol sa meračem ili tečni sprejevi, kapi, ampule, transdermalni flasteri, auto-injekcioni uređaji ili supozitorije; za oralnu, parenteralnu, intranazalnu, sublingvalnu ili rektalnu primenu, ili za primenu putem inhalacije ili insuflacije. Za izradu čvrstih smeša, kao što su tablete, glavni aktivni sastojak je izmešan sa farmaceutskim nosačem, kao što su konvencionalni sastojci za tabletiranje, poznati stručnom licu u ovoj oblasti, npr., kao što je opisano u WO 01/70677 i obrazovan u forme jedinične doze. Uobičajeni oblici jediničnih doza sadrže od 0.1 do 500 mg, na primer: 1, 2, 5, 10, 25, 50, 100 iii 200 mg aktivnog sastojka. Tablete ili piiule nove smeše mogu biti presvučene ili na drugi način sjedinjene da bi se obezbedio dozni oblik, koji pruža prednost produženog delovanja, kao što je opisano, primera radi, u WO 01/70677.
Tečni oblici, u koje nove smeše ovog pronalaska mogu biti ugrađene, za primenu oralno ili putem injekcija, uključuju: vodene rastvore, sirupe pogodnog ukusa, vodene iii uljane suspenzije i emulzije sa jestivim uljima i aromom, kao što je opisano u WO 01/70677.
Ovaj pronalazak, takođe, obezbeđuje jedinjenje formule I ili njegovu farmaceutski prihvatljivu so za korišćenje u postupku lečenja ljudskog organizma. Poželjno, lečenje se odnosi na stanje, koje je udruženo sa odlaganjem [3-amiloida. Poželjno, stanje je neurološka bolest, koja ima pridruženo odlaganje (3-amiloida, kao što je Alchajmerova bolest.
Ovaj pronalazak dalje obezbeđuje upotrebu jedinjenja formule I ili njegove farmaceutski prihvatljive soli u proizvodnji leka za lečenje ili prevenciju Alchajmerove bolesti.
Takođe, izložen je posiupak lečenja jedinke, koja pati od ili ima sklonost ka Alchajmerovoj bolesti, a koji obuhvata primenu toj jedinki, delotvorne količine jedinjenja u skladu sa formulom I ili njegove farmaceutski prihvatljive soli.
Za lečenje ili prevenciju Alchajmerove bolesti, pogodni nivo doziranja je oko 0.01 do 250 mg/kg dnevno, poželjno oko 0.05 do 100 mg/kg dnevno, a posebno oko 0.1 do 50 mg/kg telesne težine dnevno. Jedinjenja mogu biti primenjena u režimu 1 do 4 puta dnevno, U nekim slučajevima, međutim, može biti upotrebljeno doziranje izvan ovih granica.
Jedinjenja formule I, u kojima je m 0, a Z je C02R<2a>ili CON(R<2a>)2mogu biti pripremljena kuplovanjem karboksilne kiseline (1) sa (pojedinačno) R<2a>OH ili HN(R<2a>)2,
gde Ar1, Ar<2>,R1ci R<2>a i<m>aju ista značenja kao prethodno. Može biti upotrebljena bilo koja od standardnih tehnika kuplovanja, uključujući upotrebu kuplujućih agenasa, kao što su dimetilaminopiridin, hidroksibenzotriazol, dicikloheksilkarbodiimid, karbonildiimidazol i slični. U jednom poželjnom postupku, kiselina se prevodi u odgovarajući kiseli hlorid (npr., obradom sa oksalil hloridom u DMF rastvoru) i reaguje direktno sa željenim nukleofilom. U drugom poželjnom postupku, kiselina se prevodi u aktivni derivat estra, kao što je pentafluorofenol estar (npr., kuplovanjem sa fenolom u prisustvu dicikloheksil karbodiimida), a ovaj intermedijer reaguje sa željenim nukleofilom.
Kiseline (1) su dostupne hidrolizom estara (2), obično pod alkalnim uslovima, kao što je obrada sa LiOH u etanolnom rastvoru:
gde R<2>predstavlja alkil, kao što je metil ili etil, a Ar<1>Ar<2>i R<1c>imaju ista značenja kao prethodno.
Estri (2) su dostupni redukcijom alkiliden derivata (3), posle koje opciono sledi alkilacija sa (C^alkiO-L, gde je L odlazeća grupa (posebno bromid ili jodid), kada R1c nije H:
gde Ar1, Ar<2>i R<2>imaju ista značenja kao prethodno. Redukcija se može izvesti korišćenjem natrijum borohidrida i nikl(ll)hlorida u etanolu, dok opciona alkilacija može biti izvedena obradom estra (2, R<1c>=H) sa jakom bazom (npr. natrijum bis(trimetilsilil)amid) u neprotonskom rastvaraču, na niskoj temperaturi, posle čega sledi obrada sa (CMalkil)-L i zagrevanje do sobne temperature.
Ukoiiko se želi, nezasićeni estri (3) se mogu hidroiizovati u odgovarajuće kiseline i konvertovati u amide reakcijom sa HN(R<2a>)2, pre redukcije olefinske veze.
Nezasićeni estri (3) su dostupni iz kondenzacije ketona (4) sa Ph3P=CHC02R<2>: gde Ar<1>, Ar<2>i R<2>imaju ista značenja kao prethodno, dok su ketoni (4) dostupni dekarboksilacijom enola (5), koji se redom obrazuju reakcijom sulfona (6) sa najmanje dva ekvivalenta akrilata (7):
gde Ar\ Ar<2>i R<2>imaju ista značenja kao prethodno. Dekarboksilacija može biti izvršena zagrevanjem na 150°C u DMSO, u prisustvu natrijum hlorida i vode, dok se reakcija jedinjenja (6) sa jedinjenjem (7) može izvesti na temperaturi sredine, u inertnom rastvaraču, kao što je THF, u prisustvu jake baze, kao što je kalijum t-butoksid.
Sulfoni (6) su pripremljeni oksidacijom tioetara A^-CH^SAr<1>(8), koji se redom obrazuju reakcijom tiola Ar<1>SH (9) sa benzil derivatima Ar<2>CH2-L (10), gde je L odlazeća grupa, kao što je hlorid ili bromid, a Ar<1>i Ar<2>imaju ista značenja kao prethodno. Reakcija između jedinjenja (9) i (10) odvija se u inertnom rastvaraču, kao što je dihiorometan, u prisustvu baze, kao što je trietilamin, dok se oksidacija (8) u (6) konvencionalno odvija pomoću m-hloroperoksibenzojeve kiseline, takođe, u inertnom rastvaraču, kao što je dihiorometan.
Jedinjenja formule I, u kojima je m 0, a Z je CN ili OR<2a>se mogu dobiti reakcijom sulfonat estra (11) sa (pojedinačno) cijanidnim jonom ili R<2a>OH:
gde L<1>predstavlja sulfonatnu odlazeću grupu (kao što je mezilat, tozilat ili triflai), a Ar1, Ar<2>,R1c i R<2a>i<m>aju ista značenja kao prethodno. Reakcija izrnene se može izvesti u DMF-u, na povišenoj temperaturi, npr. oko 80°C.
Kada je nukleofil R<2a>OH, pogodno je da se proizvede odgovarajući anjon, obradom sa natrijum hidridom, pre reakcije sa (11).
Suifonati (11) su pripremljeni reakcijom alkohola (12) sa odgovarajućim sulfonil hloridom (npr. pod bezvodnim uslovima, na niskoj temperaturi, u prisustvu tercijernog amina).
Alkoholi (12) su dostupni iz hidroboracije alkena (13):
gde Ar1, Ar<2>i R<lc>imaju ista značenja kao prethodno. Postupak obično obuhvata reakciju sa borom u THF, na sobnoj temperaturi, koju sledi obrada sa alkalnim vodonik peroksidom i razdvajanje željenogc/ sizomera hromatografijom. Alkeni (13) su dostupni iz ketona (4), kondenzacijom sa Ph3P=CHR<1c>, gde R<1c>ima isto značenje kao prethodno.
Alternativni put do alkohola (12), u kojima jeR1<c>H, obuhvata redukciju ketona (4) (npr. korišćenjem borohidrida) do odgovarajućeg sekundarnog alkohola (14), prevodeći navedeni alkohol (14) u odgovarajući mezilat (ili ekvivalentnu odlazeću grupu), izvodeći nukleofilnu izmenu sa jonom cijanida, uz hidrolizu nastalog nitrila u odgovarajuću karboksilnu kiselinu, posle čega sledi redukcija u primarni alkohol. Hidroliza se obično izvodi pod kiseiim uslovima (npr. u mešavini sirćetne kiseline i conc. HCI, na 110°C), a redukcija se pogodno izvodi narednom obradom sa izobutil hloroformatom i borohidridom u THF.
Jedinjenja formule I, u kojima je m 1, a R<1b>je H ili C^alkil, mogu se dobiti putem oksidacije alkohola (12) do odgovarajućeg aldehida ili ketona, i obradom njihove karbonilne grupe, na način opisan prethodno u vezi sa prevođenjem ketona (4) u jedinjenja sa formulom I, u kojima je m 0. Na primer, oksidacija alkohola (12) u kojima je R<1c>H, obezbeđuje odgovarajuće cikloheksankarboksaldehide, koji se mogu kondenzovati sa Ph3P=C02Et, da bi se dobili etil estri 2-cikloheksilpropenskih kiselina. Oni redom mogu biti hidrogenizovani u odgovarajuće 2-cikloheksilpropanoate, koji, opciono, mogu biti podvrgnuti alkilaciji i/ili hidrolizi u odgovarajuće kiseline i/ili mogu biti konvertovani u brojne amide ili alternativne estarske derivate.
Kada oni sami nisu komercijalno dostupni, polazni materijali i reagensi, koji su uključeni u gore opisane sintetske šeme, mogu se dobiti primenom standardnih tehnika organske sinteze na komercijalno dostupne materijale.
Može se proceniti da mnoge od gore-opisanih sintetskih šema mogu dovesti do stvaranja mešavina steroizomera. Posebno, određeni proizvodi se mogu obrazovati kao mešavinec/ sitransizomera, u kojima je određeni supstituent prstena na istoj ili suprotnoj strani prstena kao arilsulfonil grupa. Takve mešavine mogu biti izdvojene konvencionalnim sredstvima, kao što je frakciona kristalizacija i preparativna hromatografija.
Određena jedinjenja u skladu sa pronalaskom mogu postojati kao optički izomeri zahvaljujući prisustvu jednog ili više hiralnih centara ili zbog ukupne asimetrije molekula. Takva jedinjenja mogu biti pripremljena u racemskom obliku ili pojedini enantiomeri mogu biti pripremljeni bilo enantiospecifičnom sintezom bilo razdvajanjem, Nova jedinjenja mogu, na primer, biti razdvojena u njihove enantiomerne komponente standardnim tehnikama, kao što je preparativna HPLC, ili obrazovanjem parova dijastereomera putem formiranja soli sa optički aktivnom kiselinom, kao što je (-)-di-p-toluoil-d-tartarna kiselina i/ili (+)-di-p-to!uoil-i-tartarna kiselina, posle čega sledi frakciona kristalizacija i regenerisanje slobodne baze. Nova jedinjenja mogu, takođe, biti razdvojena obrazovanjem estara ili amida dijastereomera, posle čega sledi hromatografsko izdvajanje i uklanjanje hiralnih pomoćnih sredstava.
Tokom bilo kog od prethodnih sintetskih delova, može biti neophodno i/ili poželjno da se osetijive ili reaktivne grupe na bilo kom od dotičnih molekula zaštite. Ovo se može postići pomoću konvencionalnih zaštitnih grupa, kao što su one, koje su opisane u Protective Groups in Organic Chemistrv, ed. J.F.VV McOmie, Plenum Press, 1973; i T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Svnthesis, John Wiley & Sons, 1991. Zaštitne grupe mogu biti uklonjene u prikladnom narednom koraku upotrebom postupaka, poznatih u ovoj oblasti.
Pogodni postupci testiranja nivoa aktivnosti jedinjenja ovog pronalaska prema y-sekretazi izložene su u WO 01/70677 i uBiochemistry,2000, 39(30), 8698-8704.
Primeri ovog pronalaska, svi su imali vrednost ED50manju od 10 U.M, poželjno manju od 1 uM, a najpoželjnije manju od 100 nM u barem jednom od gore izloženih testova.
Primer, koji slede, iiustruju ovaj pronalazak.
PRIMERI
Intermedijer 1
4-hlorotiofenol (3.6g,0.025mol) u dihiorometanu (100ml) je obrađen sa 2,5-difluorobenzil bromidom (5.17g,0.025mol) i trietilaminom (3.9ml,0.028mol), reakciona smeša je mešana tokom 2 sata, a zatim je razblažena dihlorometanom (250ml) i isprana vodom (100ml) i slanom vodom (100ml). Izdvojeni organski sloj je osušen (MgS04) i uparen do suvog. Proizvod je prečišćen propuštanjem kroz sloj silikata, eluirajući sa heksan-etil acetatnim mešavinama. 5.12g.<1>H NMR CDCl37.23 (4H,s),6.69-6.86 (3H,m) i 4.04 (2H,S).
Ovaj tioetar (5.12g,0.018mol) je rastvoren u dihiorometanu (100 ml), obrađen m-hioroperoksibenzojevom kiselinom (14.3g,0.042mol (50%tež/tež)) i mešan tokom 2 sata. Reakciona smeša je zatim isprana sa Na2S205(5%-tni rastvor, 100ml) i slanom vodom (50ml), osušena (MgSOJ i uparena do suvog. Sulfonski proizvod je prečišćen na silikatu, eluirajući sa heksan-etil acetatnim mešavinama, 3.6g. 'H NMR CDCI37.61 (2H,d,J=8.6Hz), 7.45 (2H,d,J=8.6Hz), 7.13-7.03 (1H,m), 7.05-7.01 (1H,m), 7.05-7.00 (1H,m), 6.99-6.87 (1H,m) i 4.36 (2h,s).
i ntermedijer 2
Pripremljen je kao Intermedijer 1, uz korišćenje 4-trifiuorometiltiofenola, i dobijen u vidu čvrste mase.<!>H NMR (360MHz, cdci3) 5 7.85-7.83 (2H,m), 7.76-7.74 (2H,m), 7.15-7.10 (1H,m), 7.06-7.0 (1H,m), 6.92-6.86 (1H,m) i 4.46 (2H,s).
Izrada 1
Intermedijer 1 (1g,3.31mmol) i metil akrilat (0.84ml,9.27mmoi) u tetrahidrofurahu (30ml) su obrađeni, kap po kap, sa kalijum 'butoksidom (3.64ml 1M rastvora u tetrahidrofuranu, 3.64mmol). Reakciona smeša je mešana tokom 2 sata, razblažena etil acetatom (100ml) i isprana vodom (50ml) i slanom vodom (50ml). Organska faza je izdvojena, osušena (MgS04) i uparena do suvog, a proizvod je prečišćen na silikatu, eluirajući sa mešavinama heksan-etil acetata. (1.0g). 'H NMR CDCI312.0(1H,s), 7.41 (4H,S), 7.06-7.0 (2H,m), 6.87-6.81 (1H,s), 3.31 (3H,s), 3.38 (1H,dd,J=3.2,15.8Hz), 3.02-2.92 (2H,m), 2.52 (1 H,dd,J=5.7,18.5Hz), 2.3-2.2 (1H,m) i 2.2-2.1 (IH.m).
Izrada 2
Estar iz Izrade 1 (1.0g,2.25mmoi) u dimetilsulfoksidu (10m!) je obrađen sa NaCI (0.3g,4.96mmol) i vodom (0.9ml,4.96mmol) i zagrevan na 150°C tokom 2 sata. Ohlađena reakciona mešavina je razblažena etil acetatom (100ml) i isprana zasićenim NH4CI (100mi), a organska faza je izdvojena, osušena (MgS04) i uparena do suvog. Proizvod je prečišćen na silikatu, eluirajući mešavinama heksan-etil acetata, 0.5g.<1>HNMRcdci37.43-7.37 (4H,m), 7.22-7.1 (2H,m), 6.97-6.9 (1H,m), 3.05-2.98 (2H,m) i 2.61-2.53 (2H,m).
Izrada 3
Pripremljen je postupcima iz Izrada 1 i 2 upotrebom Intermedijera 2, da bi se dobio proizvod u vidu čvrste mase. (0.3g)<1>HNMR (360MHz, CDCI3) 5 7.71-7.69 (2H,d,J=7.5Hz), 6.62-6.60 (2H,d,J=7.4Hz), 7.22-7.11 (2H,m), 6.95-6.88 (1H,m), 3.02-2.99 (2H,m), 2.63-2.54 (4H,m) i 2.25-2.16 (2H,m).
Izrada 4
Etil (dietoksifosfinil)acetat (5.16mL,26mmol) je dodat, kap po kap, žitkoj masi natrijum hidrida (60%-tna disperzija u mineralnom ulju, 988mg,24.7mmol) u tetrahidrofuranu (60mL) i smeša je mešana na sobnoj temperaturi tokom 1h. Keton iz Izrade 2 (5g,13mmo!) u tetrahidrofuranu (50mL) dodavan je, kap po kap, tokom 20 minuta i reakciona smeša je mešana na sobnoj temperaturi tokom 18h. Dodata je voda i smeša je ekstrahovana etil acetatom. Sjedinjene organske frakcije su isprane vodom i osušene (MgSOJ, a rastvarač je uparen pod smanjenim pritiskom. Ostatak je prečišćen flash hromatografijom na koloni, na silika gelu, eluirajući sa izoheksan:EtOAc (85:15), da bi se dobio proizvod u vidu čvrste mase bele boje (5.2g,88%).<1>HNMR(400MHz, CDCI3) 6 7.41-7.36 (4H,m), 7.18-7.13 (1H,m), 7.11-7.05 (1H,m), 6.93-6.86 (1H,m), 5.64 (1H,S), 4.14-4.10 (2H,m), 3.99-3.96 (1H,m), 2.91-2.80 (2H,m), 2.42-2.38 (1H,m), 2.31-2.04 (3H,m), 1.89-1.78 (1H,m), 1.28-1.24 (3H,m).
Izrada 5
Keton iz Izrade 2, (0.1g,0.26mmol) u metanolu (2ml) je obrađen sa NaBH4(0.098g,0.26mmol) i mešan tokom 1 sata. Reakcija je ugašena sa HCI (1N,10ml) i razblažena etil acetatom (20ml), a zatim je organska faza izdvojena, osušena (MgS04) i uparena do suvog.C/ sitransproizvodi su prečišćeni na silikatu, eluirajući sa mešavinama heksan-etil acetata. (a){ trans)0.052g.<1>H NMR CDCI37.39-7.33 (4H,m), 7.11-7.02 (2H,m), 6.88-6.82 (1H,m), 3.80-3.73 (1H,m), 2.80-2.60 (2H,m), 2.22-2.16 (2H,m), 2.08-2.04 (2H,m), 1.53 (1H,br) i 1.27-1.13 (2H,m). (b)(C/S)<1>H NMR (CDC!3) 7.40 (4H,s), 7.16-7.03 (2H,m), 6.90-6.83 (1H,m), 3.97-3.95 (1H,m), 3.77-3.68 (1H,m), 3.51-3.49 (1H,m), 2.61-2.53 (2H,m), 1.91-1.83 (2H,m) i 1.50-1.42 (2H,m).
Izrada 6
Transcikloheksanol iz Izrade 5 (2.7g, 6.9mmol) i trietilamin (1.45mL,10.3mmol) u dihiorometanu (50mL) su obrađeni sa metan sulfonil hloridom (0.645mL,8.9mmol) na -30°C. Posle 30 minuta smeša je isprana vodom (20mL), 10%-tnom vodenom limunskom kiselinom (20ml_) i zasićenim vodenim natrijum hidrogen karbonatom (50ml_), osušena (MgS04) i uparena do suvog. Čvrsta masa je usitnjena sa etrom kako bi se dobio mezilat (2.6g)<1>H NMR (CDCI3) 7.40-7.37 (4H,m), 7.12-7.07 (2H,m), 6.92-6.83 (1H,m), 4.78-4.65 (1H,m), 2.96 (3H,s), 2.88-2.52 (2H,m), 2.29-2.21 (4H,m) i 1.59-1.47 (2H,m).
Izrada 7
Transmezilat iz Izrade 6 (103mg,0.22mmol) je rastvoren u toluenu (20ml) i dodat je pre-azeotropnom uzorku tetrabutiiamonijum cijanida (354mg,1.32mmol) i mešavina je zagrejana do 70°C tokom 18 sati, a zatim ohlađena do sobne t. Rastvor je razblažen vodom (10ml) i ispran etil acetatom (2x50ml). Organska faza je isprana slanom vodom (10ml), osušena (MgSOJ i uparena. Dobijeno bistro ulje je prečišćeno hromatografijom na koloni, na silika gelu, eluirajući sa 10-20%-tnim etil acetatom u heksanima, da bi se dobio cijanid.<1>H NMR (CDCl3)7.42-7.36 (4H,s), 7.10-7.05 (2H,m), 6.89-6.84 (1H,m), 2.88-2.86 (1H,m), 2.76-2.72 (2H,m), 2.52-2.45 (1H,m), 2.12-2.07 (1H,m) i 1.56-1.49 (1H,m).
Izrada 8
Cijanid iz Izrade 7 (143mg,0.36mmol) je rastvoren/suspendovan u mešavini ledene sirćetne kiseline (10ml) i conc.HCI (6ml) i zagrevan je na 110°C u toku 15 sati. Smeša je ohlađena, razblažena etil acetatom, isprana vodom (x3), osušena (MgS04) i uparena do suvog. Ovaj sirovi ostatak (153mg) je prečišćen preparativnom tlc (5% metanol u dihlorometanu/1% sirćetnoj kiselini).<1>H NMR (CDCI3) 7.38-7.35 (4H,s), 7.08-7.06(2H,m), 6.90-6.84 (1H,m), 2.65-2.58 (2H,m), 2.38-2.33 (3H,m) i 1.75-1.49 (4H,m).
Izrada 9
Cijanid iz Izrade 8 (50mg,0.12mmol) je rastvoren u mešavini tetrahidrofurana (4.5ml) i vode (0.5ml) i mešan je na 20°C. Smeša je obrađena vodonik peroksidom (20ml,0.6mmol), a zatim litijum hidroksidom (6mg,0.25mmol) tokom 2 sata. Dodat je vodonik peroksid (20ml.0.6mmol), a zatim litijum hidroksid (6mg,0.25mmol) i smeša je mešana na sobnoj t tokom 72 sata. Smeša je ohlađena, razblažena etil acetatom, isprana vodom (x2) i zas. natrijum bisulfitom, osušena (MgS04) i uparena do suvog. Ovaj sirovi ostatak (51 mg) je prečišćen preparativnom tlc (20% etil acetat u heksanima)<1>H NMR (CDCi3) 7.37(4H,s), 7.10-7.02 (2H,m), 6.90-6.84 (1H,m), 5.57 (2H,brs), 2.54-2.48 (3H,m), 2.43-2.39 (1H.m), 2.19-2.15 (2H,m) i 1.62-1.50 (3H,m).
Primer 1
Natrijum borohidrid (313mg,8.23mmol) je dodat mešavini nezasićenog estra iz Izrade 4 (3.74g.8.23mmol) i nikl(ll)hlorida (2.67g, 20.6mmol) u etanolu (100mL). Smeša je mešana na sobnoj temperaturi tokom 20 minuta, a zatim je dodana voda (100mL). Smeša je filtrirana kroz Hyflo™, uz ispiranje sa etanolom i etil acetatom. Rastvarač je uparen pod smanjenim pritiskom, a ostatak je raspodeljen između etil acetata i vode. Organski sloj je sakupljen i osušen (MgSOJ, a rastvarač je uparen pod smanjenim pritiskom. Ostatak je prečišćen flash hromatografijom na koloni, na silika gelu, uz eluaciju sa izoheksan:EtOAc (85:15), da bi se dobioc/s-izomer,koji brže prolazi, u vidu ulja (1.36g, 36%), 'H NMR (400MHz,CDCI3) 5 7 37-7.30 (4H,m), 7.09-7.00 (2H,m), 6.86-6.79 (1H,m), 4.14 (2H,q,J=7.1Hz), 2.47 (2H,d,J=7.6Hz), 2.46-2.38 (2H,m), 2.19-2.14 (1H,m), 1.76-1.71 (2H,m), 1.57-1.48 (4H,m), 1.27 (3H,t,J 7.1Hz);
i isto takotrans-\ zomer,koji sporije prolazi, u vidu ulja (200mg, 5.3%).
Primer 2
Litijum hidroksid (350mg,14.57mmol) je dodat rastvoruc/s-estraiz Primera 1 (1.33g,2.91mmol) u etanolu (40mL). Smeša je oslobođena gasa i mešana na sobnoj temperaturi pod gasom azota tokom 5 h. Smeša je ulivena u vodenu hlorovodoničnu kiselinu (1M) i ekstrahovana je etil acetatom. Organski ekstrakt je osušen (MgSOJ, a rastvarač je uparen pod smanjenim pritiskom, da bi se dobila bela čvrsta masa, koja se zatim iskristališe iz IPA, da bi se dobio proizvod u vidu bele čvrste mase (950mg,76%).<1>H NMR (400MHz,CD3OD) 5 7.51-7.49 (2H,m), 7.40-7.37 (2H,m), 7.19-7.10 (2H,m), 7.00-6.94 (1H,m), 2.51-2.35 (6H,m), 2.13-2.10 (1H,m), 1.78-1.74 (2H,m), 1.57-1.50 (2H,m).
Primer 3
Kiselina iz Primera 2 (50mg,0.117mmol), morfolin (30ui_,0.351mmol), 1-hidroksibenzotriazol (24mg,0.176mmol) i trietilamin (65uJ_,0.468mmol) su mešani u tetrahidrofuranu na sobnoj temperaturi pod gasom azota tokom 10 minuta. Mešavini je dodat 1-(3-dimetilaminopropil)-3-etilkarbodiimid hidrohlorid (45mg,0.234mmol) i smeša je mešana tokom 24h. Smeša je izručena u vodeni natrijum hidroksid (1M) i ekstrahovana etil acetatom. Organski ekstrakti su osušeni (MgSG4) i rastvarač uparen pod sniženim pritiskom. Ostatak je prečišćen flash hromatografijom na koloni silika gela, eluirajući sa 5 do 10% metanolom u dihiorometanu kako bi se dobio proizvod u vidu bele pene (50mg, 86%). 'H NMR (400MHz,CD3OD) 5 7.50 (2H,cW 8.6Hz), 7.37 (2H,d,J 8.6Hz), 7.19-7.09 (2H,m), 7.00-6.93 (1H,m), 3.69-3.63 (4H,m), 3.59-3.56 (4H,m), 2.55 (2H,cW 7.4Hz), 2.47-2.39 (4H,m), 2.16-2.07 (1H,m), 1.78-1.74 (2H,m), 1.58-1.51 (2H,m). m/z (ES<+>) (M+1) 498+500.
Primeri 4- 15
Sledeća jedinjenja su proizvedena prema postupku iz Primera 3, upotrebom odgovarajućeg amina umesto morfolina.
Primeri 16- 33
Ovi Primeri su pripremljeni sledećom metodom, koristeći pogodnu slobodnu bazu amina ili so amina, uz prethodnu neutralizaciju.
Izmešanoj suspenzijic/ s4-(4-hlorobenzensuifonil)-4-(2,5-difluorofenil)cikloheksansirćetne kiseline (Primer 2, 0.15g.0.35mmol) u dihiorometanu (5ml) dodati su oksalil hlorid (0.05ml,0.57mmol) i dimetilformamid (1kap). Posle 30 minuta rastvor je uparen na mali volumen, a rastvoru ostatka u dihiorometanu (5ml) dodat je željeni amin (1.75mmol). Posle mešanja rastvora tokom 20 minuta, rastvarač je uklonjenin vacuo,a ostatak je prečišćen hromatografijom na silika gelu, uz eluiranje sa rastućim koncentracijama etil acetata u izoheksanu (25%, 50%). Frakcije, koje sadrže proizvod su uparene da bi se dobio proizvod amid. Hromatografsko prečišćavanje je izvedeno na silika gelu, uz korišćenje pogodnih koncentracija etil acetata u izoheksanu, etil acetata ili metanola u etil acetatu, kada je to pogodno. Primer 33
Rastvoruc/ samida iz Izrade 9 (46mg) i piridina (0.053ml) u tetrahidrofuranu (1ml) dodat je trifluorosirćetni anhidrid (0.056ml). Rastvor je mešan na sobnoj temperaturi tokom 2 sata, kada su dodati 0.5M-HCI (vodeni) i etil acetat. Organska faza je osušena (MgS04), uparena na mali volumen i prečišćena hromatografijom na silika gelu, uz eiuaciju sa izoheksan:etil acetatom (5:1) da bi se dobio željeni proizvod u vidu bezbojne čvrste mase.<1>H NMR (360MHz, CDCl3) 5 1.61-1.70 (2H,m), 1.86-1.94 (2H,m), 2.03-2.10 (1H.m), 2.42-2.45 (4H,m), 2.51 (2H,d J 8.0Hz), 6.8 (1H,m), 7.02-7.09 (2H,m), 7.30 (2H,d J 8.6Hz), 7.36 (2H,d J 8 7Hz).
Primer 34
Kiselina iz Izrade 8 (153mg) je rastvorena u suvom THF-u (10ml) i ohlađena do 0°C, pod azotom. Dodati su trietilamin (61 ul, 0.43mmol) i izobutilhloroformat (57u,L,0.43mmol) i smeša je mešana na 0°C tokom jednog sata. Talog, koji se obrazovao, uklonjen je filtracijom i ispran sa daljih 5ml suvog THF. Sjedinjeni THF slojevi su ponovo ohlađeni do 0°C i dodat je sa penušanjem natrijum borohidrid (70mg,1.84mmol) kao rastvor u vodi (2ml). Posle mešanja od 30 minuta na 0°C, reakciona smeša je razblažena etil acetatom, isprana rastvorom amonijum hlorida, rastvorom natrijum bikarbonata i slanom vodom, a zatim je osušena (MgSOJ i uparena do suvog. Ostatak je prečišćen hromatografijom na koloni, uz eluaciju sa etil acetat:heksanom (1:3) da bi se dobio željeni alkohol (75mg).<1>HNMR (CDCl3) 7.39-7.31(4H,m), 7.10-7.01(2H,m), 6.88-6.81 (1H,m), 3.71 (2H,d,J=7.5Hz), 2.46-2.32 (4H,m), 1.90-1.85 (2H,m), 1.78-1.74 (1H,m) i 1.54-1.44 (2H,m). m/z=423 [MNa]<+>
Primer 35
Korak ( 1)
Rastvoru kiseline iz Primera 2 (1g) u DCM (50ml) i etil acetatu (30ml) je dodat pentafluorofenol (1.5 ekviv.) i DCC (1.5 ekviv.) i mešano je na sobnoj temperaturi tokom 1h. Reakciona mešavina je uparena in vacuo, pokupljena etil acetatom i filtrirana. Filtrat je uparen in vacuo, da bi se dobio pentafluorofenolni estar dovoljne čistoće za korišćenje u narednim reakcijama.
Korak ( 2)
Pentafluorofenolni estar, pripremljen u Koraku (1) (155mg, 0.25mmol) je rastvoren u DMF-u (3ml) i pod azotom su dodati glicin metil estar hidrohlorid (125mg,1 .Ommol) i trietilamin (0.15ml). Posle 2h, reakciona mešavina je razblažena vodom, ekstrahovana etil acetatom (x3), isprana vodom i slanom vodom, osušena (MgSOJ, filtrirana i uparena. Prečišćena je flash hromatografijom na koloni (1:1 'heksan/etil acetat do 9:1 etil acetat/metanol) da bi se dobila bela čvrsta masa (55mg).<1>H NMR (CDCI3) 1.08-1.16 (1H,m), 1.3C-1.37 (1H,m), 1.67-1.71 (1H,m), 1.75-1.79 (2H,m), 1.91-1.95 (1H,m), 2.20-2.25 (1H,m), 2.41 (4H,d,J=7.8Hz), 3.77 (3H,s), 4.05 (2H,d,J=5.1Hz), 6.19 (1H,br), 6.79-6.85 (1H,m), 7.00-7.07 (2H,m), 7.30-7.37 (4H,m).
Primer 36
Glicinski estar, pripremljen u Primeru 35 (50mg,0.1mmol) u zapečaćenoj epruveti i rastvoren u 2M rastvoru amonijaka u rastvoru metanola (3ml) zagrevan je do 50°C, tokom 3h. Posle hlađenja do sobne temperature, reakciona mešavina je ukoncentrisana i prečišćena usitnjavanjem sa etrom da bi se dobila bela čvrsta masa (28mg). MS(El+): 485 (MH+)
Primer 37
Alkohol iz Primera 34 (4g,10mmol) je rastvoren u dihiorometanu (280ml) i obrađen sa Dess Martin perjodinanom (4.66g, 11mmol) i mešavina je mešana tokom 45 minuta pre dodavanja zasićenog vodenog natrijum bisulfita (lOOml), a posle 5 minuta smeša je izdvojena, a organska faza je isprana zasićenim vodenim natrijum bikarbonatom (100ml), osušena (MgSOJ i uparena do suvog. Sirovi ostatak (4g) je rastvoren u suvom dihiorometanu (100m!) i obrađen sa metil trifenilfosfinoacetatom (4.7g 14mmol), uz mešanje na sobnoj t. tokom 16 sati. Rastvarač je uparen, a ostatak je prečišćen hromatografijom na koloni, na silika gelu, uz eluaciju sa 10-20% etil acetatom u heksanima, da bi se dobio proizvod.<1>H NMR (CDCl3) 7.37-7.36 (4H,m), 7.10-7.02 (3H,m), 6.87-6.83 (1H,m), 5.91 (1H,d.J=16Hz), 3.77 (3H,s), 2.55-2.45 (3H,m), 2.40-2.38 (2H,m), 1.95-1.90 (2H,m) i 1.65-1.52 (2H,m).
Primer 38
Alken iz Primera 37 (3.6g,9mmol) je rastvoren u etil acetatu (350ml). Iz balona je uklonjen gas, a zatim je dodat 10% paladijum na ugljeniku (400mg) i smeša je mešana pod atmosferom vodonika tokom 45 minuta. Rastvor je filtriran kroz Celite™ i uparen. Dobijeno bistro uiie je prečišćeno preparativnom tlc, uz eluaciju sa 5% etil acetatom u heksanima. Dobijeno ulje je zatim dalje prečišćeno hromatografijom na koloni na silika gelu, uz eluaciju sa 5-10% etil acetatom u heksanu da biSe dobio proiZVOd.<1>H NMR (CDCI3) 7.37-7.34 (4H,m), 7.08-7.00 (2H,m), 6.85-6.81 (1H,m), 3.67 (3H,s), 2.45-2.39 (4H,m), 2.33 (2H,t,J=8.4Hz), 1.81 (2H,q,J=8.4Hz), 1.72-1.68 (2H,m) i 1.60-1.43 (3H,m).
Primer 39
Estar iz Primera 38 (104rng,0.23mmol) je rastvoren u mešavini etanola (lOml) i vode (3m!) i mešan na 20°C. iz balona je uklonjen gas, a zatim je dodat litijum hidroksid (27mg,1.15mmol). Smeša je mešana tokom 3 sata na sobnoj temperaturi. Zatim je dodata 1N hlorovodonična kiselina i mešavina je isprana etil acetatom (2x50ml). Organska faza je isprana slanom vodom (50ml), osušena (MgSOJ i uparena. Dobijeno ulje je zatim dalje prečišćeno preparativnom tlc eluirajući sa etil acetatom da bi se dobila kiselina. 'H NMR (CDCIJ 7.37-7.30 (4H,m). 7.09-6.99 (2H,m). 6.85-6.79 (1H,m), 2.42-2.36 (6H.m), 1.85-1.79 (2H,m), 1.73-1.69 (2H,m), 1.63-1.58 (1H,m) i 1.53-1.45 (2H,m).
Primer 40
Kiselina iz Primera 39 (52mg,0.118mmol) u dihiorometanu (2ml) je obrađena sa oksalil hloridom (88uJ, 2M rastvor u dihiorometanu, 0.176mmol). Dodata je kap N,N-dimetilformamida i rastvor je ostavljen da se meša tokom 2 sata. Posle ovog vremena, rastvarač je uklonjenin vacuo,a ostatak je ponovo rastvoren u dihiorometanu (1ml). Ovaj rastvor je ukapan u metanolni amonijak (2M, 2ml). Reakciona smeša je uparenain vacuo,a ostatak je podvrgnut hromatografiji na silikatu, uz eluaciju sa 80% etil acetatom u heksanima. Nastali materijal je dalje prečišćen preparativnom t.l.c, uz eluaciju sa 100% etil acetatom, posle čega je sledila rekristalizacija iz vrućeg heksana da bi se dobio proizvod (7.4mg, 14%).<1>H NMR (360MHz, CDCI3), 1.45-1.53 (2H,m). 1.57-1.65 (1H,br), 1.70-1.75 (2H,m), 1.78-1.84 (2H,rn), 2.32 (2H,t,J=15.3Hz), 2.38-2.44 (4H,br), 2.95 (3H,s), 3.02 (3H,s), 6.79-6.86 (1H,m), 7.00-7.09 (2H,m), 7.31-7.37 (4H,m); ms. (ES4), 470 (M<+>1), 294 (M<+>175).
Primer 41
C/s-estar iz Primera 1 (669mg,1.467mmoi) u tetrahidrofuranu (14ml) je ohlađen na -78°C, obrađen sa natrijum bis(trimetilsilil)amidom (2.20ml, 1M rastvor u tetrahidrofuranu, 2.20mmol) i mešan, dok se zagreva do sobne temperature u toku 2 sata. Metil jodid (457uJ, 7.36mmol) je zatim dodat mešavini na -20°C, nastavljeno je mešanje i ponovo zagrevanje do sobne temperature tokom 2 sata. Reakciona smeša je ugašena ledenom sirćetnom kiselinom (132u.l,2.20mmol), razblažena amonijum hloridom (50%aq.,80ml) i ekstrahovana etil acetatom (3x100ml). Sjedinjeni organski delovi su, zatim, isprani slanim rastvorom (zasićen, 200ml), osušeni (MgS04) i upareniin vacuoda bi se dobio sirovi proizvod (670mg). Ovaj materijal je podvrgnut hromatografiji na silikatu, uz eluaciju sa 8% etil acetatom u heksanima, da bi se dobio proizvod (272mg,40%).<1>HNMR (400MHz, CDCI3), 1.16 (3H,d,J=6.9Hz), 1.28 (3H,t,J=7.1Hz);1.45-1.51 (2H,m), 1.71-1.77 (2H,m), 1.89-1.94 (1H,m), 2.28-2.48 (3H,br), 2.54-2.60 (1H,br), 2.70-2.74 (1H,m), 4.09-4.18 (2H,m), 6.77-6.84 (1H,m), 6.99-7.08 (2H,m), 7.26-7.36 (4H,m).
Primer 42
Pripremljen je iz ketona iz Izrade 3, sledeći postupke iz Izrade 4 i Primera 112.^ NMR (360MHz, CDCI3) 1.52-1.61 (2H,m), 1.76-1.81 (2H,m). 2.20-2.26 (1H,m), 2.39 (2H,d,J=7.6Hz), 2.40-2.50 (4H,m), 5.37 (1H,br), 5.51 (1H,br), 5.75-6.83 (1H,m), 7.01-7.08 (2H,m), 7.51 (2H,d,J=8.3Hz) i 7.64 (2H,d,J=8.3Hz).
Primer 43
Pripremljen je iz kiseline Primera 42 postupkom iz Primera 35, koristeći amonijak u drugom koraku. MS MH+462(463).
Primer 44
Pripremljen je iz ketona iz Izrade 3, sledeći postupke iz Izrada 5-8 i Primera 34, 37, 38 i 39.
<1>H NMR (360MHz,CDCI3) 5 10.1 (1H,m), 7.64 (2H,dJ=8.3Hz), 7.53 (2H,d,J=8.3Hz), 7.09-7.00 (2H,m), 6.83-6.76 (1H,m), 2.50-2.37 (6H,m), 1.85-1.81 (2H,q,J=7.4Hz), 1.75-1.70 (2H,m), 1.63-1.59 (1H,m), 1.55-1.45 (2H,m).
MS(EI<+>) 477 (MH<+>).

Claims (14)

1. Jedinjenjeformule I: naznačeno t i m e što je: m 0 ili 1; Z predstavlja: CN, OR<2a>, C02R<2a>ili CON(R<2a>)2; R<1b>predstavlja: H, C^aikil ili OH;R1c predstavlja H ili C^alkil: Ar<1>predstavlja fenil ili piridil, od kojih oba nose 0-3 supstituenta, nezavisno odabrana od: halogena, CN, N02, CF3, OH, OCF3, C^alkoksi ili C^aikila, koji opciono nosi supstituent, koji je odabran od: halogena, CN, N02, CF3, OH i C^alkoksi; Ar<2>predstavlja fenil, koji je supstituisan na 2- i 5- položajima sa halogenom; R2a predstavlja: H, C^alkil, C3.6cikloalkil, C3.ecikloalkilC1.6alkil, C2.6alkenil, od kojih svaki opciono nosi supstituent, koji je odabran od: halogena, CN, N02, CF3, OR<2b>, C02R<2b>, N(R<2b>)2, CON(R<2b>)2, Ar i COAr; iliR2apredstavlja Ar; ili dve R<2a>grupe, zajedno sa atomom azota na koji su međusobnoi vezane, mogu obrazovati N-heterociklil grupu, koja nosi 0-4 supstituenta, koji su nezavisno odabrani od: =0, =S, halogena, C^alkila, CN, N02, CF3, OH, C,.4alkoksi, C1.4alkoksikarbonila, C02h, aminc, C^aikiiamino, di(C,.4aikil)amino, karbamoila, Ar i COAr: R<2b>predstavlja: H, CV6alkil, G^cikloalkil, C3^cikloalkilCV6alkil, C2.6alkenil, od kojih svaki opciono nosi supstituent, koji je odabran od: halogena, CN, N02, CF3, OH, C^alkoksi, C^alkoksikarbonila, C02H, amino, C1.4alkilamino, dKC^alkiOamino, karbamoila, Ar i COAr; ili R<2b>predstavija Ar; ili dve R2" grupe, zajedno sa atomom azota na koji su zajednički vezane, mogu obrazovati N-heterociklil grupu, koja nosi 0-4 supstituenta, koji su nezavisno odabrani od: =0, =S, halogena, C,_4alkila, CN, N02, CF3, OH, C.,.4alkoksi, C^alkoksikarbonila, C02H, amino, C^alkilamino, di(C1^alkil)amino, karbamoila, Ar i COAr; Ar predstavlja fenil ili heteroaril, koji nose 0-3 supstituenta, odabrana od: halogena, C^alkila, CN, N02, CF3, OH, C^alkoksi, C^alkoksikarbonila, amino, C^alkilamino, di(C1.4alkil)amino, karbamoila, C^aikilkarbamoila i di(C1.4alkil)karbamoila; ili njegova farmaceutski prihvatljiva so.
2. Jedinjenje, kao u Patentnom zahtevu 1, naznačeno t i m e što je Ar<1>odabran od fenil grupa, supstituisanih na 4-položaju sa halogenom, metilom ili trifluorometilom i fenil grupa, supstituisanih na 3- i 4-položajima halogenom.
3. Jedinjenje, kao u Patentnom zahtevu 1 ili Patentnom zahtevu 2, n a z n a č e n o t i m e što je Ar<1>4-hlorofenil ili 4-trifluorometilfenil, a Ar<2>je 2,5-difluorofenil.
4. Jedinjenje, kao u bilo kom od Patentnih zahteva 1-3, naznačeno time što Z predstavlja C02R<2a>, a R<2a>predstavlja H ili C^alkil.
5. Jedinjenje, kao u Patentnom zahtevu 1, naznačeno t i m e što je m 1, Ar<1>predstavlja 4-hlorofenil, Ar<2>predstavlja 2,5-difluorofenil, oba iR1bi R<1>c predstavljaju H, a Z predstavlja C02H ili njegova farmaceutski prihvatljiva so.
6. Jedinjenje, kao u Patentnom zahtevu 1, naznačeno time što je m 1, Ar<1>predstavlja 4-trifluorometilfenil, Ar<2>predstavlja 2,5-difluorofenil, oba, i R1biR1c predstavljaju H, a Z predstavlja C02H ili njegova farmaceutski prihvatljiva so.
7. Jedinjenje, kao u Patentnom zahtevu 1, naznačeno t i m e što je m 0, Ar<1>predstavlja 4-hlorofenil, Ar<2>predstavlja 2,5-difluorofenil, R<1c>predstavlja H, a Z predstavlja CONH2, ili njegova farmaceutski prihvatljiva so.
8. Jedinjenje, kao u Patentnom zahtevu 1, naznačeno time što je m 0, Ar' predstavlja 4-trifluorometilfenil, Ar2 predstavlja 2,5-difluorofenil, R<1c>predstavlja H, a Z predstavlja CONH2, ili njegova farmaceutski prihvatljiva so.
9. Jedinjenje, kao u Patentnom zahtevu 1, naznačeno time što je m 0, Ar<1>predstavlja 4-hlorofenil, Ar<2>predstavlja 2,5-difluorofenil, R<1c>predstavlja H, a Z predstavlja CONHCH2CH3, ili njegova farmaceutski prihvatljiva so.
10. Jedinjenje, kao u Patentnom zahtevu 1, naznačeno t i m e što je m 0, Ar<1>predstavlja 4-hlorofenil, Ar<2>predstavlja 2,5-difluorofenil, R<1c>predstavlja H, a Z predstavlja CN, ili njegova farmaceutski prihvatljiva so.
11. Farmaceutska smeša, naznačena ti me što sadrži jedinjenje, kao u bilo kom od Patentnih zahteva 1-10 ili njegovu farmaceutski prihvatljivu so i farmaceutski prihvatljiv nosač.
12. Jedinjenje, kao u bilo kom od Patentnih zahteva 1-10, ili njegova farmaceutski prihvatljiva so, naznačeno t i m e što se koristi u postupku lečenja ljudskog organizma.
13. Upotreba jedinjenja, kao u bilo kom od Patentnih zahteva 1-10, ili njegove farmaceutski prihvatljive soli, naznačena time što se koristi u proizvodnji leka za lečenje ili prevenciju Alchajmerove bolesti.
14. Postupak lečenja jedinke, koja pati ili ima sklonost ka Alchajmerovoj bolesti, naznačen time što obuhvata primenu tom ispitaniku delotvorne količine jedinjenja formule I, kako je definisano u Patentnom zahtevu 1, ili njegove farmaceutski prihvatljive soli.
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