HRP20020026A2 - Method of inhibiting amyloid protein aggregation and imaging amyloid deposits - Google Patents

Method of inhibiting amyloid protein aggregation and imaging amyloid deposits Download PDF

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HRP20020026A2
HRP20020026A2 HR20020026A HRP20020026A HRP20020026A2 HR P20020026 A2 HRP20020026 A2 HR P20020026A2 HR 20020026 A HR20020026 A HR 20020026A HR P20020026 A HRP20020026 A HR P20020026A HR P20020026 A2 HRP20020026 A2 HR P20020026A2
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Croatia
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phenylamino
ethyl
acid
dichlorophenyl
benzoic acid
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HR20020026A
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Croatian (hr)
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Corinne Elizab Augelli-Szafran
Takenori Kimura
Yingjie Lai
Annette Theresa Sakkab
Mark James Suto
Lary Craswell Walker
Mark Robert Barvian
Christopher Franklin Bigge
Shelly Ann Glase
Shunichiro Hachiya
John Steven Keil
Tomoyuki Yasunaga
Nian Zhuang
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Warner Lambert Co
Yamanouchi Pharma Co Ltd
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Publication of HRP20020026A2 publication Critical patent/HRP20020026A2/en

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Description

Područje izuma Field of invention

Ovaj izum se odnosi na postupak inhibicije agregacije amiloidnih proteina i vizualizaciju amiloidnih naslaga. Preciznije rečeno, ovaj izum se odnosi na postupak inhibicije agregacije amiloidnih proteina s ciljem tretiranja Alzheimerove bolesti. This invention relates to a method of inhibiting the aggregation of amyloid proteins and visualization of amyloid deposits. More precisely, this invention relates to a method of inhibiting the aggregation of amyloid proteins with the aim of treating Alzheimer's disease.

Pozadina izuma Background of the invention

Amiloidoza je stanje karakterizirano nakupljanjem različitih netopivih vlaknastih proteina u tkivu pacijenta. Vlaknasti proteini koji uključuju nakupine ili naslage nazvani su amiloidni proteini. Prisustvo vlaknaste morfologije i sekundarna struktura s velikom količinom β-listova zajednička je za mnogo tipova amiloida, dok pojedini proteini ili peptidi nađeni u naslagama mogu biti različiti. Amiloidna naslaga nastaje agregacijom amiloidnih proteina te naknadnim spajanjem agregata i/ili amiloidnih proteina. Amyloidosis is a condition characterized by the accumulation of various insoluble fibrous proteins in the patient's tissue. Fibrous proteins that include clumps or deposits are called amyloid proteins. The presence of a fibrous morphology and a secondary structure with a large amount of β-sheets is common to many types of amyloid, while the individual proteins or peptides found in the deposits may be different. Amyloid deposits are formed by aggregation of amyloid proteins and subsequent joining of aggregates and/or amyloid proteins.

Prisustvo amiloidnih naslaga je primijećeno u različitim bolestima, svakom vezanom s karakterističnim proteinom, kao što su Mediteranska groznica, Muckle-Wells sindrom, idiopatetski mielom, amiloidna polineuropatija, amiloidna kardiomiopatija, sistemska senilna amiloidoza, amiloidna polineuropatija, nasljedni izljev krvi u mozak s amiloidozom, Alzheimerova bolest, Downov sindrom, "Scrapie", Creutzfeldt-Jacobova bolest, Kuru, Gerstman-Straussler-Scheinker-ov sindrom, medularni karcinom tiroida, Izolirani atrialni amiloid, β2-mikroglobulinski amiloid u pacijenata na dijalizi, inkluzijski tjelesni miozitis, β2-amiloidne naslage u bolesti propadanja mišića, srpasta anemija, Parkinsonova bolest, i "otočići Langerhansa" dijabetes tipa II inzulinom. The presence of amyloid deposits has been observed in various diseases, each associated with a characteristic protein, such as Mediterranean fever, Muckle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Alzheimer's disease, Down syndrome, "Scrapie", Creutzfeldt-Jacob disease, Kuru, Gerstman-Straussler-Scheinker syndrome, medullary thyroid carcinoma, Isolated atrial amyloid, β2-microglobulin amyloid in dialysis patients, inclusion body myositis, β2-amyloid deposits in muscle wasting disease, sickle cell disease, Parkinson's disease, and "Islets of Langerhans" diabetes type II by insulin.

Alzheimerova bolest je degenerativni poremećaj u mozgu klinički opisan postepenim gubitkom pamćenja, spoznavanja, razumijevanja, prosuđivanja i emocionalne stabilnosti koji postepeno vodi mentalnom propadanju i konačno smrti. Pošto su Alzheimerova bolest i slični degenerativni poremećaji mozga važno medicinsko pitanje kod sve starije populacije, ukazala se potreba za novim metodama dijagnosticiranja i liječenja. Alzheimer's disease is a degenerative brain disorder clinically described by the gradual loss of memory, cognition, understanding, judgment and emotional stability that gradually leads to mental deterioration and finally death. Since Alzheimer's disease and similar degenerative brain disorders are an important medical issue in the aging population, there is a need for new methods of diagnosis and treatment.

Intenzivno se traži jednostavna i neinvazivna metoda za detekciju i kvantitativno određivanje amiloidnih naslaga u pacijenata. Trenutno, detekcija amiloidnih naslaga uključuje histološku analizu materijala s biopsije ili autopsije. Obje metode imaju značajne nedostatke. Na primjer, autopsija se može izvesti samo za dijagnozu poslije smrti. A simple and non-invasive method for the detection and quantitative determination of amyloid deposits in patients is intensively sought. Currently, detection of amyloid deposits involves histological analysis of biopsy or autopsy material. Both methods have significant drawbacks. For example, an autopsy may only be performed for diagnosis after death.

Direktno promatranje amiloidnih naslaga u živom organizmu je teško pošto naslage posjeduju mnogo svojstava sličnih ili istih kao normalno tkivo (npr. gustoća i sadržaj vode). Pokušaji direktnog promatranja amiloidnih naslaga primjenom Magnetske rezonancije (engl. "Magnetic Resonance Imaging", MRI) i Kompjuterizirane aksijalne tomografije (engl. "Computer-Assisted Tomography", CAT) su razočarali, i uspjeli su detektirati amiloidne naslage samo pod određenim povoljnim uvjetima. Uz to, pokušaji označavanja amiloidnih naslaga antitijelima, serumom amiloidnog P proteina, ili drugom probnom molekulom dalo je određenu selektivnost u perifernim tkivima, ali se pokazalo slabim u slučaju unutrašnjih tkiva. Direct observation of amyloid deposits in a living organism is difficult since the deposits have many properties similar or the same as normal tissue (eg density and water content). Attempts to directly observe amyloid deposits using Magnetic Resonance Imaging (MRI) and Computer-Assisted Tomography (CAT) were disappointing, and they managed to detect amyloid deposits only under certain favorable conditions. In addition, attempts to label amyloid deposits with antibodies, serum amyloid P protein, or other probe molecules have yielded some selectivity in peripheral tissues, but proved weak in the case of internal tissues.

Stoga bi bilo korisno imati neagresivnu tehniku za promatranje i kvantitativno određivanje amiloidnih naslaga u pacijentima. Uz to, bilo bi korisno imati spoj koji sprječava agregaciju amiloidnih proteina koji stvaraju amiloidne naslage. Therefore, it would be useful to have a non-invasive technique to observe and quantify amyloid deposits in patients. In addition, it would be useful to have a compound that prevents the aggregation of amyloid proteins that form amyloid deposits.

Bit izuma The essence of invention

Ovaj izum omogućuje metodu liječenja Alzheimerove bolesti, metodu koja obuhvaća davanje, pacijentu koji ima Alzheimerovu bolest, terapeutski efektivnu količinu spoja Formule I The present invention provides a method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of Formula I

[image] [image]

gdje where

Ra je vodik, C1-C6 alkil ili -C(O)C1-C6alkil; R a is hydrogen, C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl;

n je od 0 do uključivo 5; n is from 0 to 5 inclusive;

R1, R2, R3, R4, R5, R6, i R7 su, svaki neovisno, vodik, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkil, NO2, -OC1-C12alkil, -C1-C8 alkil, -CF3, -CN, -OCH2 fenil, -OCH2-supstituirani fenil, -(CH2)m-fenil, -O-fenil, O-supstituirani fenil, -CH=CH-fenil, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkil)(CH2)pNRbRc, [image] ; R1, R2, R3, R4, R5, R6, and R7 are each independently hydrogen, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkyl, NO2, -OC1-C12alkyl, -C1- C8 alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, O-substituted phenyl, -CH=CH-phenyl, -O(CH2)pNRbRc , -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkyl)(CH2)pNRbRc, [image] ;

R8 je COOH, tetrazolil, SO2Rd ili -CONHSO2Rd; R8 is COOH, tetrazolyl, SO2Rd or -CONHSO2Rd;

Rb i Rc su, svaki neovisno, vodik, -C1-C6 alkil, -(CH2)m-fenil ili Rb i Rc uzeti zajedno s dušikom na koji su vezani čine ciklički sustav odabran između slijedećih: piperidinil, pirolil, imidazolil, piperazinil, 4-C1-C6 alkilpiperazinil, morfolino, tiomorfolino, dekahidroizokinolin ili pirazolil; Rb and Rc are each independently hydrogen, -C1-C6 alkyl, -(CH2)m-phenyl or Rb and Rc taken together with the nitrogen to which they are attached form a cyclic system selected from the following: piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-C6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline or pyrazolyl;

Rd je vodik, C1-C6 alkil, -CF3 ili fenil; Rd is hydrogen, C1-C6 alkyl, -CF3 or phenyl;

m je od 0 do uključivo 5; m is from 0 to 5 inclusive;

p je od 1 do uključivo 5; p is from 1 to 5 inclusive;

A je CH ili N; A is CH or N;

R1 i R2, ukoliko su vezani jedan na drugi, mogu biti metilendioksi; R1 and R2, if they are bound to each other, can be methylenedioxy;

ili njihova farmaceutski prihvatljiva sol or a pharmaceutically acceptable salt thereof

U poželjnom ostvarenju [image] skupina je vezana na položaj 4 fenilnog prstena In a preferred embodiment, the [image] group is attached to position 4 of the phenyl ring

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2; i n is 2; and

R3 i R4 su vodici. R3 and R4 are hydrogen.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

R1 je halo; R1 is halo;

R2 je vodik ili halo; R 2 is hydrogen or halo;

R3, R4, R5 i R6 su vodici; i R3, R4, R5 and R6 are hydrogen; and

n je 2 do uključujući 5. n is 2 to 5 inclusive.

U drugom poželjnom ostvarenju metode, u spojevima Formule I In another preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2 ili 3; n is 2 or 3;

R1 je -NRbRc; i R 1 is -NR b R c ; and

R2, R3, R4, R5 i R7 su vodici. R2, R3, R4, R5 and R7 are hydrogen.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2; n is 2;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

R1, R2, i R7 su svaki neovisno, klor, -N(CH2CH3)2, -OH, -CH3, fluor, -CF3, fenil, vodik, -OCH2 fenil, O(CH2)3N(CH3)2, -O fenil, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pirolil, -CH=CH-fenil,[image] ,N[(CH2)3CH3]2, supstituirani fenil, -OCH2-supstituirani fenil, pirazolil, ili -N(fenil)2. R1, R2, and R7 are each independently, chlorine, -N(CH2CH3)2, -OH, -CH3, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl,[image] ,N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl, pyrazolyl, or -N(phenyl)2.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 3, 4, ili 5; n is 3, 4, or 5;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

R1, R2, i R7 su svaki neovisno, klor ili vodik. R 1 , R 2 , and R 7 are each independently chlorine or hydrogen.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2; n is 2;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

R5, R6, i R8 su, svaki neovisno, vodik, -CO2H, -NO2, -OCH3, imidazolil, -SO2CH3, -CN, fluor, -CH3, -CF3, halogen, NH-C1-C6 alkil, -N(C1-C6alkil)2, -NH2 ili pirolil. R5, R6, and R8 are each independently hydrogen, -CO2H, -NO2, -OCH3, imidazolyl, -SO2CH3, -CN, fluorine, -CH3, -CF3, halogen, NH-C1-C6 alkyl, -N( C 1 -C 6 alkyl) 2 , -NH 2 or pyrrolyl.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2; n is 2;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

R5 je -COOH. R 5 is -COOH.

Također, poželjna metoda liječenja Alzheimerove bolesti je metoda koja obuhvaća davanje, pacijentima koji imaju Alzheimerovu bolest, terapeutski efektivnu količinu spoja Formule I Also, a preferred method of treating Alzheimer's disease is a method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of Formula I

[image] [image]

gdje where

Ra je vodik; Ra is hydrogen;

n je 1 do uključujući 5; n is 1 to 5 inclusive;

R3 i R4 su vodici; R3 and R4 are hydrogen;

R1, R7 i R2 su, svaki neovisno, klor, -N(CH2CH3)2, -OH, CH3-, fluor, -CF3, fenil, vodik, -OCH2 fenil, O(CH2)3N(CH3)2, -O fenil, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pirolil, -CH=CH-fenil, N[(CH2)3CH3]2, supstituirani fenil, -OCH2-supstituirani fenil, pirazolil, ili -N(fenil)2; R1, R7 and R2 are each independently chlorine, -N(CH2CH3)2, -OH, CH3-, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl, pyrazolyl, or -N(phenyl )2;

R5 i R6 su, svaki neovisno, vodik, -CO2H, -NO2, -OCH3, imidazolil, -CN, fluor, -CH3, -CF3, ili pirolil; R5 and R6 are each independently hydrogen, -CO2H, -NO2, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl;

ili njegove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.

U poželjnom ostvarenju metode, spojevi Formule I su In a preferred embodiment of the method, the compounds of Formula I are

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[4-(3,4-diklorfenil)etil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-{4-[2-(3,4-dihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dihydroxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4,5-trihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-imidazo-1-il-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoic acid;

2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}benzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}benzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-3,5-dinitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-3,5-dinitrobenzoic acid;

2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-[4-(3,4-diklorbenzil)fenilamino]benzoeva kiselina; 2-[4-(3,4-dichlorobenzyl)phenylamino]benzoic acid;

2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-difluorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-difluorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid;

2-[4-(2-bifenil-4-iletil)fenilamino]-5-nitrobenzoeva kiselina; 2-[4-(2-biphenyl-4-ylethyl)phenylamino]-5-nitrobenzoic acid;

5-nitro-2-(4-fenetilfenilamino)benzoeva kiselina; 5-nitro-2-(4-phenethylphenylamino)benzoic acid;

2-(4-fenetilfenilamino)benzoeva kiselina; 2-(4-phenethylphenylamino)benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metoksibenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methoxybenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}tereftalna kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}terephthalic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methylbenzoic acid;

4-{4-[2-(3,4-diklorfenil)etil]fenilamino}izoftalna kiselina; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}isophthalic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metansulfonilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methanesulfonylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-imidazol-1-il-benzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-imidazol-1-yl-benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-nitrobenzoic acid;

5-cijano-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 5-cyano-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4,6-difluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4,6-difluorobenzoic acid;

6-{4-[2-(3,4-diklorfenil)etil]fenilamino}-2,3-difluorbenzoeva kiselina; 6-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-2,3-difluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-metilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-methylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3,5-difluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3,5-difluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-pirol-1-il-benzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-pyrrol-1-yl-benzoic acid;

2-{4-[2-(4-benziloksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-benzyloxyphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(3-dimetilaminopropoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(3-dimethylaminopropoxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-fenoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-phenoxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-oktiloksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-octyloxyphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(2-etoksi-1-etoksimetiletil)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-ethoxy-1-ethoxymethylethyl)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-pirol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-pyrrol-1-ylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-stirilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-styrylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4'-etilbifenil-4-il)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4'-ethylbiphenyl-4-yl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-oktilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-octylphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[3-(3,5-diklorfenoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[3-(3,5-dichlorophenoxy)phenyl]ethyl}phenylamino)benzoic acid;

2-(4-{2-[4-(2-klor-6-fluorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-chloro-6-fluorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-pirazol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-pyrazol-1-ylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-difenilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-diphenylaminophenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(3,4-diklorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(3,4-dichlorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-aminobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-aminobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-nitrofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-nitrophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-nitrofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-nitrophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-aminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-aminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-aminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-aminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[2-(4-aminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-aminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-dipropilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(4-dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid monohidrat; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride monohydrate;

2-{4-[3-(3-dipropilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dipropylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-dimetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dimethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-etilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-ethylaminophenyl)propyl]phenylamino}benzoic acid;

2-(N-{4-[3-(4-dietilaminofenil)propil]fenil}-N-etilamino)benzoeva kiselina; 2-(N-{4-[3-(4-diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoic acid;

2-{4-[2-(3-dibenzilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-dibenzylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[3-(3-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-diethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[2-(3-aminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-aminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[3-(4-dimetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dimethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[2-(4-acetilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-acetylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3-acetilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-acetylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3-dipropilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(3-dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[2-(3-dibutilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(3-dibutylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[3-(4-acetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-acetylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-acetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-acetylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-dietilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[3-(3-diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[2-(3-piperidin-1-il-fenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(3-piperidin-1-yl-phenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[3-(4-dipropilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dipropylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-dibutilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dibutylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-dibutilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dibutylaminophenyl)propyl]phenylamino}benzoic acid;

2-(4-{3-[4-(1H-pirol-1-il)fenil]propil}fenilamino)benzoeva kiselina; 2-(4-{3-[4-(1H-pyrrol-1-yl)phenyl]propyl}phenylamino)benzoic acid;

2-{4-[3-(4-piperidin-1-ilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-dietilkarbamoilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-diethylcarbamoylphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-karboksifenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-carboxyphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-dietilaminometilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-diethylaminomethylphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-propilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-propylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-propilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-propylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-pirolidin-1-ilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-pyrrolidin-1-ylphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-piperidin-1-il-fenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-piperidin-1-yl-phenyl)propyl]phenylamino}benzoic acid;

2-(4-{3-[4-(2-dietilaminoetilamino)fenil]propil}fenilamino)benzoeva kiselina; 2-(4-{3-[4-(2-diethylaminoethylamino)phenyl]propyl}phenylamino)benzoic acid;

2-(4-{2-[4-(hidroksikarbonilmetilamino)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(hydroxycarbonylmethylamino)phenyl]ethyl}phenylamino)benzoic acid;

2-(4-{2-[4-(2-dietilaminoetilamino)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-diethylaminoethylamino)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[3-(4-morfolinfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-morpholinephenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-piperazinilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-piperazinylphenyl)propyl]phenylamino}benzoic acid;

2-[4-(3,4-diklorfenil)fenilamino]benzoeva kiselina; 2-[4-(3,4-dichlorophenyl)phenylamino]benzoic acid;

Izum također omogućuje prethodne spojeve kod kojih je benzoeva kiselina zamijenjena s piridilkarboksilnom kiselinom, kao npr. 4-[4-(3,4-diklorfenil)fenilamino]-3-hidroksikarbonilpiridin. The invention also provides the foregoing compounds in which the benzoic acid is replaced by a pyridylcarboxylic acid, such as 4-[4-(3,4-dichlorophenyl)phenylamino]-3-hydroxycarbonylpyridine.

Također, omogućena je metoda sprečavanja agregacije amiloidnih proteina koja dovodi do stvaranja amiloidnih naslaga, pri čemu ona obuhvaća davanje, pacijentu kome je potrebno sprečavanje agregacije amiloidnih proteina, dovoljne količine spoja za sprečavanje agregacije amiloidnih proteina pri čemu je isti Formule I Also, a method of preventing the aggregation of amyloid proteins that leads to the formation of amyloid deposits is provided, wherein it comprises administering, to a patient who needs to prevent the aggregation of amyloid proteins, a sufficient amount of a compound to prevent the aggregation of amyloid proteins, wherein the same is Formula I

[image] [image]

gdje where

Ra je vodik, C1-C6 alkil, ili -C(O)C1-C6 alkil; Ra is hydrogen, C1-C6 alkyl, or -C(O)C1-C6 alkyl;

n je 0 do, uključivo, 5; n is 0 to, inclusive, 5;

R1, R2, R3, R4, R5, R6, i R7 su, svaki neovisno, vodik, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6alkil, -NO2, -OC1-C12 alkil, -C1-C8 alkil, -CF3, -CN, -OCH2 fenil, -OCH2-supstituirani fenil, -(CH2)m-fenil, -O-fenil, O-supstituirani fenil, -CH=CH-fenil, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6alkil)(CH2)pNRbRc, [image] ; R1, R2, R3, R4, R5, R6, and R7 are each independently hydrogen, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6alkyl, -NO2, -OC1-C12 alkyl, -C1 -C8 alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, O-substituted phenyl, -CH=CH-phenyl, -O(CH2) pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6alkyl)(CH2)pNRbRc, [image] ;

R8 je COOH, tetrazolil, SO2Rd ili -CONHSO2Rd; R8 is COOH, tetrazolyl, SO2Rd or -CONHSO2Rd;

Rb i Rc su, svaki neovisno, vodik, -C1-C6 alkil, -(CH2)m-fenil ili Rb i Rc uzeti zajedno s dušikom na koji su vezani čine ciklički sustav odabran između slijedećih: piperidinil, pirolil, imidazolil, piperazinil, 4-C1-C6 alkilpiperazinil, morfolino, tiomorfolino, dekahidroizokinolin ili pirazolil; Rb and Rc are each independently hydrogen, -C1-C6 alkyl, -(CH2)m-phenyl or Rb and Rc taken together with the nitrogen to which they are attached form a cyclic system selected from the following: piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-C6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline or pyrazolyl;

Rd je vodik, C1-C6 alkil, -CF3 ili fenil; Rd is hydrogen, C1-C6 alkyl, -CF3 or phenyl;

m je od 0 do uključivo 5; m is from 0 to 5 inclusive;

p je od 1 do uključivo 5; p is from 1 to 5 inclusive;

A je CH ili N; A is CH or N;

R1 i R2, ukoliko su vezani jedan na drugi, mogu biti metilendioksi; R1 and R2, if they are bound to each other, can be methylenedioxy;

ili njegove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2; i n is 2; and

R3 i R4 su vodici. R3 and R4 are hydrogen.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

n je 2 do uključujući 5. n is 2 to 5 inclusive.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2; n is 2;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

R1, R2, i R7 su svaki neovisno, klor, -N(CH2CH3)2, -OH, -CH3, fluor, -CF3, fenil, vodik, -OCH2 fenil, O(CH2)3N(CH3)2, -O fenil, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pirolil, -CH=CH-fenil, [image] ,N[(CH2)3CH3]2, supstituirani fenil, -OCH2-supstituirani fenil, pirazolil, ili -N(fenil)2. R1, R2, and R7 are each independently, chlorine, -N(CH2CH3)2, -OH, -CH3, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, [image] ,N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl, pyrazolyl, or -N(phenyl)2.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 3, 4, ili 5; n is 3, 4, or 5;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

R1, R2, i R7 su svaki neovisno, klor ili vodik. R 1 , R 2 , and R 7 are each independently chlorine or hydrogen.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2; n is 2;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

R5 i R6 su, svaki neovisno, -CO2H, -NO2, -OCH3, imidazolil, -CN, fluor, -CH3, -CF3, halogen, NH-C1-C6 alkil, -N(C1-C6alkil)2, -NH2 ili pirolil. R5 and R6 are each independently -CO2H, -NO2, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, halogen, NH-C1-C6 alkyl, -N(C1-C6alkyl)2, -NH2 or pyrrolyl.

U poželjnom ostvarenju metode, u spojevima Formule I In a preferred embodiment of the method, in the compounds of Formula I

Ra je vodik; Ra is hydrogen;

n je 2; n is 2;

R3 i R4 su vodici; i R3 and R4 are hydrogen; and

R5 je -CO2H. R 5 is -CO 2 H.

Također, omogućena je poželjna metoda sprečavanja agregacije amiloidnih proteina koja dovodi do stvaranja amiloidnih naslaga, pri čemu ona obuhvaća davanje dovoljne količine spoja za sprečavanje agregacije amiloidnih proteina, pacijentu kome je potrebno sprečavanje agregacije amiloidnih proteina, pri čemu je isti Formule I Also, a preferred method of preventing the aggregation of amyloid proteins that leads to the formation of amyloid deposits is provided, wherein it comprises administering a sufficient amount of a compound for preventing the aggregation of amyloid proteins to a patient in need of preventing the aggregation of amyloid proteins, wherein the same is Formula I

[image] [image]

gdje where

Ra je vodik; Ra is hydrogen;

n je 1 do, uključivo, 5; n is 1 to, inclusive, 5;

R3 i R4 su vodici; R3 and R4 are hydrogen;

R1, R7, R2 i su svaki neovisno, klor, -N(CH2CH3)2, -OH, -CH3, fluor, -CF3, fenil, vodik, -OCH2 fenil, O(CH2)3N(CH3)2, -O fenil, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pirolil, -CH=CH-fenil, N[(CH2)3CH3]2, supstituirani fenil, -OCH2-supstituirani fenil, pirazolil, ili -N(fenil)2. R1, R7, R2 are each independently chlorine, -N(CH2CH3)2, -OH, -CH3, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl, pyrazolyl, or -N(phenyl )2.

R5 i R6 su svaki neovisno, vodik, -CO2H, -NO2, -OCH3, imidazolil, -CN, fluor, -CH3, -CF3, ili pirolil; R5 and R6 are each independently hydrogen, -CO2H, -NO2, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl;

R8 je COOH ili tetrazolil; R 8 is COOH or tetrazolyl;

ili njegove farmaceutski prihvatljive soli. or pharmaceutically acceptable salts thereof.

Najpoželjniji spojevi omogućeni ovim izumom su spojevi Formule II The most preferred compounds provided by this invention are compounds of Formula II

[image] [image]

i njihove farmaceutski prihvatljive soli, and their pharmaceutically acceptable salts,

gdje where

R1 je halo; R1 is halo;

R2 je H ili halo; i R 2 is H or halo; and

n i R6 su isti kao ranije definirani u Formuli I. n and R6 are the same as previously defined in Formula I.

Još jedna poželjna grupa spojeva su spojevi Formule III Another preferred group of compounds are the compounds of Formula III

[image] [image]

i njihove farmaceutski prihvatljive soli, and their pharmaceutically acceptable salts,

gdje: where:

R1 je halo; R1 is halo;

R2 je H ili halo; i R 2 is H or halo; and

n i R6 su isti kao ranije definirani u Formuli I. n and R6 are the same as previously defined in Formula I.

Još jedna skupina poželjnih spojeva su spojevi Formule IV Another group of preferred compounds are the compounds of Formula IV

[image] [image]

i njihove farmaceutski prihvatljive soli, and their pharmaceutically acceptable salts,

gdje: where:

R1 je halo; R1 is halo;

R2 je H ili halo; i R 2 is H or halo; and

n i R6 su isti kao ranije definirani u Formuli I. n and R6 are the same as previously defined in Formula I.

U poželjnom ostvarenju postupka, omogućeni su novi spojevi Formule I i to su In a preferred embodiment of the process, new compounds of Formula I are enabled and are

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[4-(3,4-diklorfenil)etil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-{4-[2-(3,4-dihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dihydroxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4,5-trihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-imidazo-1-il-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}benzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}benzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-3,5-dinitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-3,5-dinitrobenzoic acid;

2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-[4-(3,4-diklorbenzil)fenilamino]benzoeva kiselina; 2-[4-(3,4-dichlorobenzyl)phenylamino]benzoic acid;

2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-difluorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-difluorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid;

2-[4-(2-bifenil-4-il-etil)fenilamino]-5-nitrobenzoeva kiselina; 2-[4-(2-biphenyl-4-yl-ethyl)phenylamino]-5-nitrobenzoic acid;

5-nitro-2-(4-fenetilfenilamino)benzoeva kiselina; 5-nitro-2-(4-phenethylphenylamino)benzoic acid;

2-(4-fenetilfenilamino)benzoeva kiselina 2-(4-phenethylphenylamino)benzoic acid

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metoksibenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methoxybenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}tereftalna kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}terephthalic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methylbenzoic acid;

4-{4-[2-(3,4-diklorfenil)etil]fenilamino}izoftalna kiselina; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}isophthalic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metansulfonilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methanesulfonylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-imidazol-1-ilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-imidazol-1-ylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-nitrobenzoic acid;

5-cijano-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 5-cyano-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4,6-difluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4,6-difluorobenzoic acid;

6-{4-[2-(3,4-diklorfenil)etil]fenilamino}-2,3-difluorbenzoeva kiselina; 6-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-2,3-difluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-metilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-methylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3,5-difluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3,5-difluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-pirol-1-ilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-pyrrol-1-ylbenzoic acid;

2-{4-[2-(4-benziloksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-benzyloxyphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(3-dimetilaminopropoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(3-dimethylaminopropoxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-fenoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-phenoxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-oktiloksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-octyloxyphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(2-etoksi-1-etoksimetiletil)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-ethoxy-1-ethoxymethylethyl)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-pirol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-pyrrol-1-ylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-stirilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-styrylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4'-etilbifenil-4-il)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4'-ethylbiphenyl-4-yl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-oktilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-octylphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[3-(3,5-diklorfenoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[3-(3,5-dichlorophenoxy)phenyl]ethyl}phenylamino)benzoic acid;

2-(4-{2-[4-(2-klor-6-fluorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-chloro-6-fluorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-pirazol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-pyrazol-1-ylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-difenilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-diphenylaminophenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(3,4-diklorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(3,4-dichlorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; ili 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid; or

2-[4-(3,4-diklorfenil)fenil]-aminobenzoeva kiselina. 2-[4-(3,4-dichlorophenyl)phenyl]-aminobenzoic acid.

Ovaj izum također omogućuje spojeve: This invention also enables compounds:

2-{4-[4-(3,4-diklorfenil)etil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-{4-[2-(3,4-dihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dihydroxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4,5-trihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-imidazo-1-il-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}benzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}benzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-3,5-dinitrobenzoeva kiselina; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-3,5-dinitrobenzoic acid;

2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;

2-[4-(3,4-diklorbenzil)fenilamino]benzoeva kiselina; 2-[4-(3,4-dichlorobenzyl)phenylamino]benzoic acid;

2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-difluorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-difluorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid;

2-[4-(2-bifenil-4-iletil)fenilamino]-5-nitrobenzoeva kiselina; 2-[4-(2-biphenyl-4-ylethyl)phenylamino]-5-nitrobenzoic acid;

5-nitro-2-(4-fenetilfenilamino)benzoeva kiselina; 5-nitro-2-(4-phenethylphenylamino)benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-aminobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-aminobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)]phenylamino}-5-nitrobenzoic acid;

2-(4-fenetilfenilamino)benzoeva kiselina 2-(4-phenethylphenylamino)benzoic acid

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metoksibenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methoxybenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}tereftalna kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}terephthalic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methylbenzoic acid;

4-{4-[2-(3,4-diklorfenil)etil]fenilamino}izoftalna kiselina; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}isophthalic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metansulfonilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methanesulfonylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-imidazol-1-il-benzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-imidazol-1-yl-benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-nitrobenzoic acid;

5-cijano-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 5-cyano-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4,6-difluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4,6-difluorobenzoic acid;

6-{4-[2-(3,4-diklorfenil)etil]fenilamino}-2,3-difluorbenzoeva kiselina; 6-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-2,3-difluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-metilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-methylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-fluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-fluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3,5-difluorbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3,5-difluorobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-pirol-1-ilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-pyrrol-1-ylbenzoic acid;

2-{4-[2-(4-benziloksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-benzyloxyphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(3-dimetilaminopropoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(3-dimethylaminopropoxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-fenoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-phenoxyphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-oktiloksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-octyloxyphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(2-etoksi-1-etoksimetiletil)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-ethoxy-1-ethoxymethylethyl)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-pirol-1-il-fenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-pyrrol-1-yl-phenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-stirilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-styrylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4'-etilbifenil-4-il)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4'-ethylbiphenyl-4-yl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-oktilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-octylphenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[3-(3,5-diklorfenoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[3-(3,5-dichlorophenoxy)phenyl]ethyl}phenylamino)benzoic acid;

2-(4-{2-[4-(2-klor-6-fluorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-chloro-6-fluorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(4-pirazol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-pyrazol-1-ylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-difenilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-diphenylaminophenyl)ethyl]phenylamino}benzoic acid;

2-(4-{2-[4-(3,4-diklorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(3,4-dichlorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-aminobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-aminobenzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid;

2-{4-[2-(3,4-diklorfenil)]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-nitrofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-nitrophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-nitrofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-nitrophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-aminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-aminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-aminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-aminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[2-(4-aminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-aminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(4-dipropilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(4-dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid monohidrat; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride monohydrate;

2-{4-[3-(3-dipropilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dipropylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-dimetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dimethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-etilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-ethylaminophenyl)propyl]phenylamino}benzoic acid;

2-(N-{4-[3-(4-dietilaminofenil)propil]fenil}-N-etilamino)benzoeva kiselina; 2-(N-{4-[3-(4-diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoic acid;

2-{4-[2-(3-dibenzilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-dibenzylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[3-(3-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-diethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[2-(3-aminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-aminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[3-(4-dimetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dimethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[2-(4-acetilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-acetylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3-acetilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-acetylaminophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3-dipropilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(3-dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[2-(3-dibutilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(3-dibutylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[3-(4-acetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-acetylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-acetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-acetylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-dietilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[3-(3-diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[2-(3-piperidin-1-ilfenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(3-piperidin-1-ylphenyl)ethyl]phenylamino}benzoic acid monohydrochloride;

2-{4-[3-(4-dipropilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dipropylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-dibutilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dibutylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-dibutilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dibutylaminophenyl)propyl]phenylamino}benzoic acid;

2-(4-{3-[4-(1H-pirol-1-il)fenil]propil}fenilamino)benzoeva kiselina; 2-(4-{3-[4-(1H-pyrrol-1-yl)phenyl]propyl}phenylamino)benzoic acid;

2-{4-[3-(4-piperidin-1-ilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-dietilkarbamoilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-diethylcarbamoylphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-karboksifenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-carboxyphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-dietilaminometilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-diethylaminomethylphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-propilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-propylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-propilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-propylaminophenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(4-pirolidin-1-ilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-pyrrolidin-1-ylphenyl)propyl]phenylamino}benzoic acid;

2-{4-[3-(3-piperidin-1-ilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid;

{5-[(1-butil-1,2,3,4-tetrahidro-6-kinolil)metiliden]-4-okso-2-tioksotiazolidin-3-il}octena kiselina; {5-[(1-butyl-1,2,3,4-tetrahydro-6-quinolyl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}acetic acid;

{5-[(1-butil-2,3-dihidro-1-indol-5-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}octena kiselina; {5-[(1-butyl-2,3-dihydro-1-indol-5-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}acetic acid;

3-{5-[(1-butil-1,2,3,4-tetrahidrokinolin-6-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}propanska kiselina; 3-{5-[(1-butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid;

4-{5-[(1-butil-1,2,3,4-tetrahidrokinolin-6-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}butanska kiselina; ili 4-{5-[(1-butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}butanoic acid; or

2-[4-(3,4-diklorfenil)fenil]aminobenzoeva kiselina. 2-[4-(3,4-dichlorophenyl)phenyl]aminobenzoic acid.

Također, omogućeni su spojevi, izvedeni iz prethodno navedenih, u kojima je terminalna fenilalkilna skupina vezana na položaj 2- ili 3- centralnog fenilnog prstena, tj. spojevi Formule Ia Also, compounds derived from the above are possible, in which the terminal phenylalkyl group is attached to the 2- or 3- position of the central phenyl ring, i.e. compounds of Formula Ia

[image] [image]

Tipični 2- i 3- supstituirani spojevi su: Typical 2- and 3-substituted compounds are:

2-{3-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{3-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid;

2-{2-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{2-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid;

2-{3-[3-(4-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{3-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid;

2-{3-[3-(4-di-n-propilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{3-[3-(4-di-n-propylaminophenyl)propyl]phenylamino}benzoic acid;

2-{3-[3-(4-n-propilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{3-[3-(4-n-propylaminophenyl)propyl]phenylamino}benzoic acid;

2-{3-[3-(4-[2-dietilaminoetilamino]fenil)propil]fenilamino}benzoeva kiselina; 2-{3-[3-(4-[2-diethylaminoethylamino]phenyl)propyl]phenylamino}benzoic acid;

2-{2-[3-(4-[hidroksikarbonilmetilamino]fenil)propil]fenilamino}benzoeva kiselina; 2-{2-[3-(4-[hydroxycarbonylmethylamino]phenyl)propyl]phenylamino}benzoic acid;

2-{2-[2-(3-[2-dietilaminoetilamino]fenil)etil]fenilamino}benzoeva kiselina; 2-{2-[2-(3-[2-diethylaminoethylamino]phenyl)ethyl]phenylamino}benzoic acid;

2-{3-[3-(4-morfolinofenil)propil]fenilamino}benzoeva kiselina; 2-{3-[3-(4-morpholinophenyl)propyl]phenylamino}benzoic acid;

2-{3-[3-(4-piperazinilfenil)propil]fenilamino}benzoeva kiselina; 2-{3-[3-(4-piperazinylphenyl)propyl]phenylamino}benzoic acid;

2-{3-[2-(4-klorofenil)etil]fenilamino}benzoeva kiselina; 2-{3-[2-(4-chlorophenyl)ethyl]phenylamino}benzoic acid;

2-{3-[3-(3,4-diklorfenil)propil]fenilamino}benzoeva kiselina; i 2-{3-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid; and

2-(4-{4-[4-(4-metilpiperazinil)fenil]butil}fenilamino)benzoeva kiselina. 2-(4-{4-[4-(4-methylpiperazinyl)phenyl]butyl}phenylamino)benzoic acid.

Farmaceutske formulacije novih spojeva pomiješane s farmaceutski prihvatljivim razrjeđivačem, nosačem ili punilom su također omogućene. Pharmaceutical formulations of the novel compounds admixed with a pharmaceutically acceptable diluent, carrier or excipient are also provided.

Omogućen je i postupak promatranja amiloidnih naslaga koji obuhvaća: The procedure for observing amyloid deposits is also possible, which includes:

a. unošenje u pacijenta dovoljne količine označenog spoja Formule I ili njegove farmaceutski prihvatljive soli koja se u tijelu može otkriti: a. introducing into the patient a sufficient amount of the labeled compound of Formula I or its pharmaceutically acceptable salt that can be detected in the body:

[image] [image]

gdje where

Ra je vodik, C1-C6 alkil ili -C(O)C1-C6alkil; R a is hydrogen, C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl;

n je od 0 do uključivo 5; n is from 0 to 5 inclusive;

R1, R2, R3, R4, R5, R6, i R7 su, svaki neovisno, vodik, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkil, -NO2, -OC1-C12alkil, -C1-C8 alkil, -CF3, -CN, -OCH2 fenil, -OCH2-supstituirani fenil, -(CH2)m-fenil, Ofenil, Osupstituirani fenil, -CH=CH-fenil, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, NH(CH2)pNRbRc, -N(C1-C6alkil)(CH2)pNRbRc, [image] R1, R2, R3, R4, R5, R6, and R7 are each independently hydrogen, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkyl, -NO2, -OC1-C12alkyl, -C1 -C8 alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, Ophenyl, O-substituted phenyl, -CH=CH-phenyl, -O(CH2)pNRbRc, -C( O)NRbRc, -NHC(O)Rb, NH(CH2)pNRbRc, -N(C1-C6alkyl)(CH2)pNRbRc, [image]

R8 je COOH, tetrazolil, SO2Rd ili -CONHSO2Rd; R8 is COOH, tetrazolyl, SO2Rd or -CONHSO2Rd;

Rb i Rc su, svaki neovisno, vodik, -C1-C6 alkil, -(CH2)m-fenil ili Rb i Rc uzeti zajedno s dušikom na koji su vezani čine ciklički sustav odabran između slijedećih: piperidinil, pirolil, imidazolil, piperazinil, 4-C1-C6 alkilpiperazinil, morfolino, tiomorfolino, dekahidroizokinolin ili pirazolil; Rb and Rc are each independently hydrogen, -C1-C6 alkyl, -(CH2)m-phenyl or Rb and Rc taken together with the nitrogen to which they are attached form a cyclic system selected from the following: piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-C6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline or pyrazolyl;

Rd je vodik, C1-C6 alkil, -CF3 ili fenil; Rd is hydrogen, C1-C6 alkyl, -CF3 or phenyl;

m je od 0 do uključivo 5; m is from 0 to 5 inclusive;

p je od 1 do uključivo 5; p is from 1 to 5 inclusive;

A je CH ili N; A is CH or N;

R1 i R2, ukoliko su vezani jedan na drugi, mogu biti metilendioksi; R1 and R2, if they are bound to each other, can be methylenedioxy;

b. ostavljanje dovoljno vremena označenom spoju da se veže s amiloidnim naslagama; i b. allowing enough time for the labeled compound to bind to the amyloid deposits; and

c. detekciju označenog spoja vezanog s amiloidnim naslagama. c. detection of the labeled compound associated with amyloid deposits.

U poželjnom ostvarenju metode, pacijent ima ili se pretpostavlja da ima Alzheimerovu bolest. In a preferred embodiment of the method, the patient has or is suspected of having Alzheimer's disease.

U poželjnom ostvarenju metode, označeni spoj je radioaktivan spoj. In a preferred embodiment of the method, the labeled compound is a radioactive compound.

U poželjnom ostvarenju metode, označeni spoj je detektiran primjenom MRI. In a preferred embodiment of the method, the labeled compound is detected using MRI.

Ovaj izum također omogućuje poželjne spojeve: This invention also provides the preferred compounds:

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid;

2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid;

2-{4-[2-(3,4-diklorfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid;

2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid;

2-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid;

i njihove farmaceutske formulacije. and their pharmaceutical formulations.

Farmaceutski prihvatljive soli nastale adicijom kiselina, amidi i prolijekove prethodno navedenih spojeva su također obuhvaćeni ovim izumom. Pharmaceutically acceptable acid addition salts, amides and prodrugs of the aforementioned compounds are also covered by this invention.

Detaljan opis izuma Detailed description of the invention

Pojam "alkil" podrazumijeva ravni ili razgranati ugljikovodični lanac koji ima 1 do 12 ugljikovih atoma. Reprezentativni primjeri alkilnih skupina su metil, etil, propil, izopropil, izobutil, tert-butil, sec-butil, pentil, heksil, oktil, decil, i 1,1-dimetiloktil. The term "alkyl" refers to a straight or branched hydrocarbon chain having 1 to 12 carbon atoms. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, octyl, decyl, and 1,1-dimethyloctyl.

Poželjne alkilne skupine su C1-C8 alkil, a posebno C1-C6 alkil. Preferred alkyl groups are C1-C8 alkyl, especially C1-C6 alkyl.

Pojam "alkoksi" podrazumijeva alkilnu skupinu vezanu na kisikov atom. Reprezentativni primjeri alkoksi skupina uključuju metoksi, etoksi, tert-butoksi, propoksi, i izobutoksi. Poželjne alkoksi skupine su C1-C12 alkoksi, a posebno C1-C6 alkoksi. "Alkoxy" refers to an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy. Preferred alkoxy groups are C1-C12 alkoxy, and especially C1-C6 alkoxy.

Pojam "halogen" uključuje klor, fluor, brom i jod. The term "halogen" includes chlorine, fluorine, bromine and iodine.

Pojam "supstituiran" podrazumijeva zamjenu jednog ili više vodikovih atoma u molekuli s drugim atomom ili grupom atoma. Na primjer, supstituenti uključuju halogen, posebice klor, -OH, -CF3, -NO2, -NH2, NH(C1C6alkil), -N(C1-C6alkil)2, C1-C6 alkil, -OC1-C6 alkil, -CN, -CF3, -CO2H, i -CO2C1-C6 alkil. The term "substituted" implies the replacement of one or more hydrogen atoms in the molecule by another atom or group of atoms. For example, substituents include halogen, especially chlorine, -OH, -CF3, -NO2, -NH2, NH(C1C6alkyl), -N(C1-C6alkyl)2, C1-C6 alkyl, -OC1-C6 alkyl, -CN, -CF3, -CO2H, and -CO2C1-C6 alkyl.

Pojam "supstituirani fenil" podrazumijeva fenilni prsten u kojem je 1 do 4 vodikovih atoma neovisno zamijenjeni supstituentom, poželjno jednim s gore navedene liste. Tipične "supstituirani fenil" skupine uključuju 4-klorfenil, 3,4-dibromfenil, 3-fluor-4-metilfenil, 3,4-diklorfenil, 3,4-metilendioksifenil, i 4-dimetilaminofenil. The term "substituted phenyl" refers to a phenyl ring in which 1 to 4 hydrogen atoms are independently replaced by a substituent, preferably one from the above list. Typical "substituted phenyl" groups include 4-chlorophenyl, 3,4-dibromophenyl, 3-fluoro-4-methylphenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl, and 4-dimethylaminophenyl.

Simbol "-" podrazumijeva kovalentnu vezu. The symbol "-" implies a covalent bond.

Supstituenti predstavljeni s R1, R3 i R5, na primjer, uključuju amino (NRbRc) i acilamino (NHCORb) skupine. Rb i Rc mogu biti vodik, alkil i fenilalkil i supstituirani fenilalkil, a tipične NRbRc skupine uključuju metilamino, dietilamino, izobutilpropilamino, benzilamino, i 3,4-dimetoksibenzilamino. Primjeri acilamino skupina uključuju formamido, acetamido, 2-fenilacetamido, i 2-(3-nitrofenil)acetamido. R1, R3 i R5 mogu također biti aminoalkoksi (-O(CH2)pNRbRc) kao što su N-metilaminometoksi i 2-(N-benzilamino)etoksi, kao i aminoalkilamino (-NH(CH2)pNRbRc) kao što su 3-(dimetilamino)propilamino) i 2-(N-etil-N-benzil)etilamino. Supstituenti poput R1, R3 i R5 dodatno mogu biti cikličke strukture, na primjer kada je NRbRc dio supstituenta, i Rb i Rc, zajedno s dušikom na koji su vezani, čine neki od slijedećih cikličkih sustava: imidazol, pirol, piperidin, piperazin, 4-C1-C6 alkilpiperazin, morfolin, tiomorfolin, pirazol, i dekahidroizokinolin. Substituents represented by R1, R3 and R5, for example, include amino (NRbRc) and acylamino (NHCORb) groups. Rb and Rc can be hydrogen, alkyl and phenylalkyl and substituted phenylalkyl, and typical NRbRc groups include methylamino, diethylamino, isobutylpropylamino, benzylamino, and 3,4-dimethoxybenzylamino. Examples of acylamino groups include formamido, acetamido, 2-phenylacetamido, and 2-(3-nitrophenyl)acetamido. R 1 , R 3 and R 5 may also be amino alkoxy (-O(CH 2 )pNRbRc) such as N-methylaminomethoxy and 2-(N-benzylamino)ethoxy, as well as aminoalkylamino (-NH(CH 2 )pNRbRc) such as 3-( dimethylamino)propylamino) and 2-(N-ethyl-N-benzyl)ethylamino. Substituents such as R1, R3 and R5 can additionally be cyclic structures, for example when NRbRc is part of the substituent, and Rb and Rc, together with the nitrogen to which they are attached, form one of the following cyclic systems: imidazole, pyrrole, piperidine, piperazine, 4 -C1-C6 alkylpiperazine, morpholine, thiomorpholine, pyrazole, and decahydroisoquinoline.

Supstituenti kao što su R1, R2, R5, R6, i R7 također mogu biti -CH=CH-fenil (tj. stiril), fenoksi, O-supstituirani fenil poput 3-jodfenoksi, 2,4,6-trihidroksifenoksi, 2-fluor-3-nitrofenoksi, kao i -O-benzil i -O-supstituirani benzil poput 2-trifluormetilbenziloksi i 4-aminobenziloksi. Substituents such as R1, R2, R5, R6, and R7 can also be -CH=CH-phenyl (ie, styryl), phenoxy, O-substituted phenyl such as 3-iodophenoxy, 2,4,6-trihydroxyphenoxy, 2- fluoro-3-nitrophenoxy, as well as -O-benzyl and -O-substituted benzyl such as 2-trifluoromethylbenzyloxy and 4-aminobenzyloxy.

Pojam "farmaceutski prihvatljiva sol, ester, amid ili prolijek" kao što je korišteno, odnosi se na one karboksilatne soli, adicijske soli aminokiselina, estere, amide i prolijekove spojeva iz ovog izuma koje se, u okviru prihvaćene liječničke prakse, mogu dovoditi u kontakt s tkivom pacijenta bez neželjene toksičnosti, iritacije, alergijske reakcije i sličnog, posjeduju razuman dobrobit/rizik omjer, i uspješne su u njihovoj predviđenoj upotrebi; kao i unutarnje soli ("zwitterions"), ukoliko su moguće, spojeva iz izuma. Pojam "soli" odnosi se na relativno neotrovne, soli nastale adicijom anorganskih i organskih kiselina iz ovog izuma. Ove soli mogu biti priređene tijekom konačne izolacije i pročišćavanja spoja, ili naknadnom reakcijom pročišćenog spoja u njegovoj formi slobodne baze s pogodnom organskom ili anorganskom kiselinom te izolacijom tako nastale soli. Karakteristični predstavnici soli uključuju hidrobromide, hidrokloride, sulfate, bisulfate, nitrate, acetate, oksalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, laktate, fosfate, tosilate, citrate, maleate, fumarate, sukcinate, tartarate, naftilate, mezilate, glukoheptanoate, laktobionate i laurilsulfonate, i slične. One mogu uključivati katione izvedene iz alkalnih i zemnoalkalnih metala, poput natrija, litija, kalija, kalcija, magnezija i slične, kao i netoksične amonijeve, kvaterne amonijeve i aminske katione uključujući, ali to nije ograničeno na amonij, tetrametilamonij, tetraetilamonij, metilamin, dimetilamin, trimetilamin, trietilamin, etilamin, i slične (Vidjeti npr. Berge S.M., et al., Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977) koji je ovdje uključen putem reference.). The term "pharmaceutically acceptable salt, ester, amide or prodrug" as used refers to those carboxylate salts, addition salts of amino acids, esters, amides and prodrugs of the compounds of this invention which, in the accepted practice of medicine, can be brought into contact with with patient tissue without unwanted toxicity, irritation, allergic reaction and the like, have a reasonable benefit/risk ratio, and are successful in their intended use; as well as internal salts ("zwitterions"), if possible, of the compounds of the invention. The term "salts" refers to relatively non-toxic salts formed by the addition of inorganic and organic acids of this invention. These salts can be prepared during the final isolation and purification of the compound, or by the subsequent reaction of the purified compound in its free base form with a suitable organic or inorganic acid and isolation of the resulting salt. Typical salt representatives include hydrobromides, hydrochlorides, sulfates, bisulfates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laureates, borates, benzoates, lactates, phosphates, tosylates, citrates, maleates, fumarates, succinates, tartrates, naphthylates, mesylates, glucoheptanoates, lactobionates and laurylsulfonates, and the like. These may include cations derived from alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine , trimethylamine, triethylamine, ethylamine, and the like (See, e.g., Berge S.M., et al., Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977) which is incorporated herein by reference.).

Primjeri farmaceutski prihvatljivih, neotrovnih estera spojeva iz izuma uključuju C1-C6 alkilne estere pri čemu je alkilna skupina ravnolančana ili razgranata. Prihvatljivi esteri također uključuju C5-C7 cikloalkilne estere poput, ali nije ograničeno na benzil. Poželjni C1-C4 su alkilni esteri. Esteri spojeva iz ovog izuma mogu biti priređeni primjenom konvencionalnih metoda, npr. reakcijom karboksilne kiseline Formule I s alkoholom poput etanola ili benzilnog alkohola. Examples of pharmaceutically acceptable, non-toxic esters of the compounds of the invention include C1-C6 alkyl esters wherein the alkyl group is straight chain or branched. Acceptable esters also include C5-C7 cycloalkyl esters such as, but not limited to, benzyl. Preferred C1-C4 alkyl esters. Esters of the compounds of this invention can be prepared using conventional methods, for example by reacting a carboxylic acid of Formula I with an alcohol such as ethanol or benzyl alcohol.

Primjeri farmaceutski prihvatljivih, neotrovnih, amida spojeva iz ovoga izuma uključuju amide izvedene iz amonijaka, primarnih C1-C6 alkilamina i sekundarnih C1-C6 dialkilamina u kojima su alkilne skupine ravnolančane ili razgranate. U slučaju sekundarnih amina, amini također mogu biti 5- ili 6-eročlani heterociklički prstenovi koji sadrže jedan dušikov atom. Poželjni su amidi izvedeni iz amonijaka, primarni C1C3 alkil amidi i sekundarni C1-C2 dialkil amidi. Amidi spojeva iz izuma mogu biti pripravljeni primjenom uobičajenih metoda. Examples of pharmaceutically acceptable, non-toxic, amide compounds of this invention include amides derived from ammonia, primary C1-C6 alkylamines and secondary C1-C6 dialkylamines in which the alkyl groups are straight or branched. In the case of secondary amines, the amines may also be 5- or 6-membered heterocyclic rings containing one nitrogen atom. Ammonia derived amides, primary C1C3 alkyl amides and secondary C1-C2 dialkyl amides are preferred. The amides of the compounds of the invention can be prepared using conventional methods.

Pojam "prolijek" se odnosi na spojeve koji se, u organizmu, brzo transformiraju dajući spoj jedne od prije navedenih formula, kao na primjer hidrolizom u krvi. Detaljna rasprava je dostupna u: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S Symposium Series, i u "Bioreversible Carriers in Drug Design", ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, a obje su ovdje uključene putem reference. The term "prodrug" refers to compounds that, in the body, are rapidly transformed to give a compound of one of the above-mentioned formulas, for example by hydrolysis in the blood. A detailed discussion is available in: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S Symposium Series, and in "Bioreversible Carriers in Drug Design", ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

Uz to, spojevi iz ovog izuma mogu postojati u nesolvatiranom kao i u solvatiranom obliku s farmaceutski prihvatljivim otapalima poput vode, etanola i sličnih. Općenito, u svrhe ovog izuma, solvatirani oblici se smatraju jednakima nesolvatiranima. Additionally, the compounds of this invention can exist in unsolvated as well as solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, for the purposes of this invention, solvated forms are considered equal to unsolvated forms.

Spojevi iz ovog izuma mogu postojati u različitim stereoizomernim oblicima uslijed postojanja asimetričnih centara u spojevima. Smatra se da svi stereoizomerni oblici spojeva, kao i njihove smjese, uključujući i racemične smjese, čine dio ovog izuma. The compounds of this invention can exist in different stereoisomeric forms due to the existence of asymmetric centers in the compounds. All stereoisomeric forms of the compounds, as well as mixtures thereof, including racemic mixtures, are considered to form part of this invention.

U prvom koraku ove metode promatranja, označeni spoj Formule I se uvodi u tkivo ili pacijentu u količini koja se može detektirati. Spoj je, tipično, sastavni dio farmaceutske smjese i daje se u tkivo ili pacijentu metodama koje su dobro poznate stručnjacima u području. In the first step of this observation method, a labeled compound of Formula I is introduced into a tissue or patient in a detectable amount. The compound is typically a component of a pharmaceutical composition and is administered to a tissue or patient by methods well known to those skilled in the art.

U metodama iz ovog izuma spoj se može dati ili oralno, rektalno, parenteralno (intravenozno, intramuskularno ili pod kožu), intracisternalno, intravaginalno, intraperitonalno, intravezikalno, lokalno (prašci, masti ili kapi), ili putem spreja u usta ili nos. In the methods of this invention, the compound can be administered either orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, topical (powders, ointments, or drops), or by oral or nasal spray.

Smjese pogodne za parenteralno unošenje mogu obuhvaćati fiziološki prihvatljive sterilne vodene i nevodene otopine, disperzije, suspenzije ili emulzije, te sterilne praške za pripremu sterilnih otopine ili disperzija pogodnih za unošenje. Primjeri pogodnih vodenih i nevodenih nosača, razrijeđivača, otapala ili prijenosnika uključuju vodu, etanol, poliole (propilenglikol, polietilenglikol, glicerol, i slične), njihove pogodne smjese, biljna ulja (poput maslinovog ulja), i unosive organske estere poput etil oleata. Odgovarajuća fluidnost se može održavati primjenom spojeva za presvlačenje površine poput lecitina, održavanjem zahtjevane veličine čestica u slučaju disperzije, te primjenom površinski aktivnih tvari. Mixtures suitable for parenteral administration may include physiologically acceptable sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for the preparation of sterile solutions or dispersions suitable for administration. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and acceptable organic esters such as ethyl oleate. Adequate fluidity can be maintained by applying surface coating compounds such as lecithin, by maintaining the required particle size in the case of dispersion, and by applying surfactants.

Ove smjese mogu također sadržavati pomoćna sredstva poput konzervansa, ovlaživača, emulgatora i sredstva za dispergiranje. Sprečavanje djelovanja mikroorganizama se može ostvariti raznim antibakterijskim i antifugalnim agensima, kao što su, na primjer, parabeni, klorbutanol, fenol, sorbinska kiselina, i slično. Također, može biti poželjno da uključuju izotonične agense, npr. šećere, natrijev klorid, i slično. Do produžene apsorpcije unosivog farmaceutskog oblika može se dovesti primjenom supstanci za odgađanje apsorpcije, npr. aluminijev monostearat i gelatin. These mixtures may also contain auxiliaries such as preservatives, humectants, emulsifiers and dispersants. Preventing the action of microorganisms can be achieved with various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Also, it may be desirable to include isotonic agents, eg sugars, sodium chloride, and the like. Prolonged absorption of the ingestible pharmaceutical form can be achieved by the use of substances to delay absorption, for example, aluminum monostearate and gelatin.

Čvrsti pripravci za oralnu primjenu uključuju kapsule, tablete, pilule, praške i granule. U takvim čvrstim oblicima, aktivni spoj je pomiješan s najmanje jednim inertnim vezivom (ili nosačem) poput natrijevog citrata ili dikalcijevog fosfata ili (a) punila ili produživača, kao na primjer škrob, laktoza, saharoza, glukoza, manitol ili silikatna kiselina; (b) veziva, kao na primjer, karboksimetilceluloza, alginati, gelatin, polivinilpirolidon, saharoza i gumiarabika; (c) sredstva za održavanje vlažnosti, kao na primjer glicerol; (d) sredstva za raspršivanje, kao na primjer, agar-agar, kalcijev karbonat, škrob iz krumpira ili tapioke, alginska kiselina, određeni kompleksni silikati ili natrijev karbonat; (e) supstance za sprečavanje stvaranja otopine, poput parafina; (f) ubrzivači apsorpcije, kao na primjer kvaterni amonijevi spojevi; (g) ovlaživači, kao na primjer, cetilni alkohol ili glicerol monostearat; (h) adsorbensi, kao na primjer kaolin i bentonit; i (i) lubrikanti, kao na primjer, talk, kalcijev stearat, magnezijev stearat, čvrsti polietilenglikoli, natrijev laurilsulfat, ili njihove smjese. U slučaju kapsula, tableta i pilula, oblik za doziranje može također sadržavati i supstance za puferiranje. Solid preparations for oral administration include capsules, tablets, pills, powders and granules. In such solid forms, the active compound is mixed with at least one inert binder (or carrier) such as sodium citrate or dicalcium phosphate or (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol or silicic acid; (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, such as glycerol; (d) dispersing agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates or sodium carbonate; (e) substances to prevent the formation of solution, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) humectants, such as cetyl alcohol or glycerol monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering substances.

Čvrste smjese sličnog tipa mogu također biti primijenjene kao punila u meko ili čvrsto punjenim gelatinskim kapsulama primjenom sredstva za vezanje poput laktoze ili mliječnog šećera kao i polietilenglikola visokih molekulskih masa, i slično. Solid mixtures of a similar type can also be used as fillers in soft or hard filled gelatin capsules using a binding agent such as lactose or milk sugar as well as polyethylene glycol of high molecular weight, and the like.

Čvrsti pripravci kao što su tablete, dražeje, kapsule, pilule i granule mogu biti pipravljene sa slojem inertne supstance ili unutar ljuske, kao što su enterične ljuske (engl. "enteric coatings") i druge dobro poznate u području. One mogu sadržavati sredstvo za zatamnjivanje, a također mogu biti i takvog sastava da usporeno oslobađaju aktivnu supstancu ili supstance u određenom dijelu probavnog trakta. Primjeri uključenih sastojaka koji se mogu koristiti su polimerne supstance i voskovi. Aktivni spojevi mogu također biti u obliku mikrokapsula, ako je potrebno, s jednim od gore navedenih vezivnih supstanci. Solid preparations such as tablets, dragees, capsules, pills and granules may be coated with a layer of inert substance or within a shell, such as enteric coatings and others well known in the art. They can contain a darkening agent, and they can also be of such a composition that they slowly release the active substance or substances in a certain part of the digestive tract. Examples of included ingredients that can be used are polymeric substances and waxes. The active compounds can also be in the form of microcapsules, if necessary, with one of the binding substances mentioned above.

Tekući pripravci za oralnu primjenu uključuju farmaceutski prihvatljive emulzije, otopine, suspenzije, sirupe i eliksire. Uz aktivnu komponentu, tekući pripravci mogu sadržavati uobičajena inertna sredstva za razrijeđivanje, kao što je voda ili druga otapala, sredstva za otapanje i emulgatore, kao što su na primjer etanol, izopropanol, etilkarbonat, etilacetat, benzilni alkohol, benzilbenzoat, propilenglikol, 1,3-butilenglikol, dimetilformamid, ulja, posebno ulje iz sjemena pamuka, ulje kikirikija, ulje iz kukuruznih klica, maslinovo ulje, ricinusovo ulje, sezamovo ulje, glicerol, tetrahidrofurfuril alkohol, polietilenglikoli i esteri masnih kiselina i sorbitana, te smjese ovih supstanci, i slično. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active component, the liquid preparations may contain conventional inert diluents, such as water or other solvents, solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids and sorbitan, and mixtures of these substances, and similar to.

Osim ovih inertnih sredstava za razrijeđivanje, smjesa također uključuje dodatke kao što su sredstva za ovlaživanje, emulgatore, sredstva za pripravu suspenzija, zaslađivače, te pojačivače okusa i mirisa. In addition to these inert diluents, the mixture also includes additives such as wetting agents, emulsifiers, suspending agents, sweeteners, and flavor and aroma enhancers.

Suspenzije, pored aktivnih supstanci, mogu sadržavati sredstva za pripravu suspenzija, kao na primjer etoksilirani izostearil alkohol, polioksietilen sorbitol i sorbitanski esteri, mikrokristalnu celulozu, aluminijev metahidroksid, bentonit, agar-agar, tragakant, ili smjese ovih supstanci, i slično. Suspensions, in addition to active substances, may contain means for preparing suspensions, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, or mixtures of these substances, and the like.

Sastavi za rektalnu primjenu su, poželjno, čepići koji mogu biti pripravljeni mješanjem spojeva iz ovog izuma s pogodnim neiritirajućim vezivnim sredstvomili nosačem, poput maslaca iz kakaa, polietilenglikola ili voska za čepiće, koji su čvrsti na sobnoj temperaturi, ali su tekući pri temperaturi tijela i stoga, tale se u rektumu ili vaginalnoj šupljini te oslobađaju aktivnu komponentu. Compositions for rectal administration are preferably suppositories which may be prepared by mixing the compounds of this invention with a suitable non-irritating binding agent or carrier, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at room temperature but liquid at body temperature and therefore, they melt in the rectum or vaginal cavity and release the active component.

Pripravci za vanjsku primjenu spojeva iz ovog izuma uključuju masti, praške, sprejeve i inhalirajuća sredstva. Aktivna komponenta se izmješa, pri sterilnim uvjetima, s fiziološki prihvatljivim nosačem i nekim konzervansima, puferima ili ubrzivačima ukoliko je to potrebno. Formulacije za oči, masti za oči, prašci i otopine, također se smatraju obuhvaćene ovim izumom. Preparations for external application of the compounds of this invention include ointments, powders, sprays and inhalants. The active component is mixed, under sterile conditions, with a physiologically acceptable carrier and some preservatives, buffers or accelerators if necessary. Eye formulations, eye ointments, powders and solutions are also considered to be encompassed by this invention.

U poželjnom ostvarenju izuma, označeni spoj se unosi u pacijenta u količini koju je moguće detektirati i nakon vremena, dovoljnog za vezanje spoja na amiloidne naslage, označeni spoj se neinvazivno detektira unutar pacijenta. U drugom ostvarenju ovog izuma označeni spoj Formule I se unosi u pacijenta, ostavi se dovoljno vremena za vezanje spoja na amiloidne naslage, a zatim se uzorak tkiva uzme iz pacijenta te se označeni spoj u tkivu detektira izvan pacijenta. U trećem ostvarenju izuma, uzorak tkiva se izvadi iz pacijenta i označeni spoj Formule I se unese u uzorak tkiva. Nakon dovoljnog vremena potrebnog za vezanje spoja na amiloidne naslage, spoj se detektira. In a preferred embodiment of the invention, the labeled compound is introduced into the patient in a detectable amount and after a time, sufficient for the binding of the compound to the amyloid deposits, the labeled compound is non-invasively detected inside the patient. In another embodiment of the present invention, a labeled compound of Formula I is administered to a patient, sufficient time is allowed for the compound to bind to amyloid deposits, and then a tissue sample is taken from the patient and the labeled compound is detected in the tissue outside the patient. In a third embodiment of the invention, a tissue sample is removed from the patient and a labeled compound of Formula I is introduced into the tissue sample. After sufficient time for the compound to bind to the amyloid deposits, the compound is detected.

Davanje označenog spoja pacijentu se može izvršiti jednim od načina općeg ili lokalnog karaktera. Na primjer, označeni spoj se može dati pacijentu tako da zalazi u sve dijelove tijela. Alternativno, označeni spoj se može unijeti u specifični organ ili tkivo. Na primjer, poželjno je locirati i kvantitativno odrediti amiloidne naslage u mozgu s ciljem dijagnosticiranja i praćenja napredovanja Alzheimerove bolesti u pacijentu. Administration of the labeled compound to the patient can be done by one of the methods of a general or local character. For example, a labeled compound can be administered to a patient so that it enters all parts of the body. Alternatively, the labeled compound can be delivered to a specific organ or tissue. For example, it is desirable to locate and quantify amyloid deposits in the brain in order to diagnose and monitor the progression of Alzheimer's disease in a patient.

Pojam "tkivo" podrazumjeva dio tijela pacijenta. Primjeri tkiva uključuju mozak, srce, jetru, krvne sudove i arterije. Količina koju se može detektirati jest ona količina označenog spoja koja je nužna da bi se mogla detektirati odabranom metodom detekcije. Stručnjak iz područja će lako odrediti količinu spoja potrebnu da se unese u pacijenta da bi se omogućila detekcija. Na primjer, količina označenog spoja se može povećavati sve dok se spoj ne detektira odabranom metodom. Spojevi su označeni s ciljem omogućivanja detekcije spoja. The term "tissue" includes a part of the patient's body. Examples of tissues include the brain, heart, liver, blood vessels and arteries. The amount that can be detected is the amount of the labeled compound that is necessary to be able to be detected by the selected detection method. One skilled in the art will readily determine the amount of compound required to be administered to a patient to enable detection. For example, the amount of labeled compound can be increased until the compound is detected by the chosen method. Compounds are labeled to enable compound detection.

Pojam "pacijent" podrazumijeva ljude i druge životinje. Stručnjaci u području su također upoznati s načinom određivanja količine vremena dovoljne spoju za vezanje na amiloidne naslage. Potrebna količina vremena se može lako odrediti unošenjem u pacijenta, za detekciju dovoljne količine označenog spoja Formule I, te naknadnim detektiranjem označenog spoja pri različitim vremenima nakon unošenja. The term "patient" includes humans and other animals. Those skilled in the art are also familiar with how to determine the amount of time sufficient for a compound to bind to amyloid deposits. The required amount of time can be easily determined by administration to the patient, to detect a sufficient amount of the labeled compound of Formula I, and subsequent detection of the labeled compound at various times after administration.

Pojam "vezan" podrazumjeva kemijsku interakciju između označenog spoja i amiloidne naslage. Primjeri vezanja uključuju kovalentne veze, ionske veze, nevezne interakcije tipa hidrofil-hidrofil ili hidrofob-hidrofob te komplekse. The term "bound" implies a chemical interaction between the labeled compound and the amyloid deposit. Examples of bonding include covalent bonds, ionic bonds, non-bonding interactions of the hydrophilic-hydrophilic or hydrophobe-hydrophobe type, and complexes.

Stručnjaci u području su upoznati s različitim načinima detektiranja obilježenih spojeva. Na primjer, Magnetska rezonancija (MRI), pozitronska emisijska tomografija (PET), ili Jednofotonska emisijska računalna tomografija (engl. "single photon emission computed tomography", SPECT) mogu biti primjenjene za detekciju radioaktivno označenih spojeva. Izbor načina označavanja će ovisiti o željenoj metodi detekcije. Na primjer, ukoliko se za detekciju koristi PET, spoj će morati posjedovati atom koji emitira pozitrone, kao što su 11C ili 18F. Experts in the field are familiar with different ways of detecting labeled compounds. For example, Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), or Single Photon Emission Computed Tomography (SPECT) can be used to detect radiolabeled compounds. The choice of marking method will depend on the desired detection method. For example, if PET is used for detection, the compound will need to have a positron-emitting atom, such as 11C or 18F.

Još jedan primjer pogodne oznake u spoju Formule I je atom poput 13C, 15N, ili 19F, koji se može detektirati primjenom magnetske rezonancije (MRI), koja se ponekad zove nuklearna magnetska rezonancija (NMR). Uz to, označeni spoj Formule I se također, može detektirati magnetskom rezonancijom primjenom supstance koja pojačava paramagnetski kontrast. Another example of a suitable label in a compound of Formula I is an atom such as 13C, 15N, or 19F, which can be detected using magnetic resonance imaging (MRI), sometimes called nuclear magnetic resonance (NMR). In addition, the labeled compound of Formula I can also be detected by magnetic resonance using a substance that enhances paramagnetic contrast.

Drugi primjer detekcije je elektronska paramagnetska rezonancija (EPR). U ovom slučaju, mogu biti primjenjene EPR probe dobro poznate stručnjacima u području kao što su nitroksidi. Another example of detection is electron paramagnetic resonance (EPR). In this case, EPR probes well known to those skilled in the art such as nitroxides can be applied.

Promatranje amiloidnih naslaga može biti izvedeno kvantitativno tako da se može odrediti količina amiloidnih naslaga. Observation of amyloid deposits can be carried out quantitatively so that the amount of amyloid deposits can be determined.

Ovaj izum također omogućuje metodu sprečavanja nastajanja amiloidnih naslaga agregacijom amiloidnih proteina, davanjem inhibicijske količine spoja Formule I, pacijentu kome je potrebno sprečavanje agregacije amiloidnih proteina. Stručnjaci u području lako odrede inhibicijsku količinu jednostavno davanjem sve veće količine spoja Formule I pacijentu sve dok se rast amiloidnih naslaga ne smanji ili zaustavi. Brzina rasta se može odrediti korištenjem metoda promatranja ili uzimanjem uzorka tkiva iz pacijenta te promatranjem amiloidnih naslaga u njemu. The present invention also provides a method of preventing the formation of amyloid deposits by amyloid protein aggregation by administering an inhibitory amount of a compound of Formula I to a patient in need of prevention of amyloid protein aggregation. Those skilled in the art readily determine the inhibitory amount simply by administering increasing amounts of a compound of Formula I to a patient until the growth of amyloid deposits is reduced or stopped. The rate of growth can be determined using observational methods or by taking a tissue sample from the patient and observing the amyloid deposits in it.

Pacijent kome je potrebno sprečavanje agregacije amiloidnih proteina je pacijent koji je bolestan ili u stanju u kojem dolazi do agregacije amiloidnih proteina.Primjeri takvih bolesti uključuju Mediteransku groznicu, Muckle-Wells sindrom, idiopatetski mielom, amiloidna polineuropatiju, amiloidna kardiomiopatiju, sistemska senilna amiloidoza, amiloidna polineuropatija, naslijedni izljev krvi u mozak s amiolidozom, Alzheimerovu bolest, Downov sindrom, Scrapie, Creutzfeldt-Jacobova bolest, Kuru, Gerstman-Straussler-Scheinkerov sindrom, medularni karcinom tiroida, Izolirani atrialni amiloid, β2-mikroglobulinski amiloid u pacijenata na dijalizi, inkluzijski tjelesni miozitis, β2-amiloidne naslage u bolesti propadanja mišića, i "otočići Langerhansa" dijabetes tipa II inzulinom. A patient in need of prevention of amyloid protein aggregation is a patient who has a disease or condition in which amyloid protein aggregation occurs. Examples of such diseases include Mediterranean fever, Muckle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyolidosis, Alzheimer's disease, Down syndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstman-Straussler-Scheinker syndrome, medullary thyroid carcinoma, Isolated atrial amyloid, β2-microglobulin amyloid in dialysis patients, inclusion corporal myositis, β2-amyloid deposits in muscle wasting disease, and "Islets of Langerhans" insulin type II diabetes.

Spojevi Formule I, u kojima su jedan ili više atoma u spoju zamjenjeni radioaktivnim izotopom (označeni spoj) su također omogućeni ovim izumom. Radioaktivni izotop može biti bilo koji radioaktivni izotop. Međutim, 3H, 123I, 125I, 131I, 11C i 18F su poželjni. Stručnjaci u području su upoznati s postupcima uvođenja radioaktivnih izotopa u spoj. Na primjer, spoj Formule I u kojem je jedan ugljikov atom 11C ili 14C se jednostavno pripravlja. Compounds of Formula I, in which one or more atoms in the compound are replaced by a radioactive isotope (labeled compound) are also enabled by this invention. The radioactive isotope can be any radioactive isotope. However, 3H, 123I, 125I, 131I, 11C and 18F are preferred. Experts in the field are familiar with the procedures for introducing radioactive isotopes into the compound. For example, a compound of Formula I in which one carbon atom is 11C or 14C is easily prepared.

Spojevi iz ovog izuma mogu se davati pacijentima u dozama od 0,1 do oko 1.000 mg dnevno. Prosječnoj odrasloj osobi težine tijela oko 70 kg, doza od 0,01 do 100 mg po kilogramu tjelesne težine je dovoljna. Primjenjena doza, međutim, može varirati. Na primjer, doza može ovisiti o više faktora uključujući zahtjeve pacijenta, ozbiljnosti stanja koje se liječi i farmakološke aktivnosti primjenjenog spoja. Određivanje optimalne doze je dobro poznato stručnjacima u području. The compounds of this invention can be administered to patients in doses of from 0.1 to about 1,000 mg per day. For an average adult with a body weight of about 70 kg, a dose of 0.01 to 100 mg per kilogram of body weight is sufficient. The dose administered, however, may vary. For example, the dosage may depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound administered. Determining the optimal dose is well known to those skilled in the art.

Slijedeći primjeri su prikazani s namjerom da slikovito prikažu pojedina ostvarenja izuma i ni na koji način ne ograničavaju područje specifikacija uključujući i zahtjeve. The following examples are presented with the intention of graphically illustrating individual embodiments of the invention and in no way limit the scope of the specifications, including the claims.

PRIMJERI EXAMPLES

SINTEZA SYNTHESIS

Spojevi Formule I mogu biti pripravljeni na nekoliko načina kao što je prikazano na Shemama 1 do 6. Sheme 1-5 prikazuju sintetske puteve kojima je moguće dobiti željene polazne amine (IV), (VIII), (XV) i (XXI). Compounds of Formula I can be prepared in several ways as shown in Schemes 1 to 6. Schemes 1-5 show synthetic routes by which the desired starting amines (IV), (VIII), (XV) and (XXI) can be obtained.

U Shemi 1 odgovarajuće supstituirani aldehid (I) i nitrofeniloctena kiselina (II) zagrijavanjem u piperidinu na 150 °C daju olefin (III). Hidrogeniranjem pri standardnim uvjetima, poput Raney nikla, dobije se željeni amin (IV). In Scheme 1, suitably substituted aldehyde (I) and nitrophenylacetic acid (II) give olefin (III) by heating in piperidine at 150 °C. Hydrogenation under standard conditions, such as Raney nickel, gives the desired amine (IV).

Shema 2 prikazuje sintezu amina (VIII) kod kojeg su dvije aromatske podjedinice spojene s trimetilenskim lancom. Kondenzacija aldehida (I) i nitroketona (V) u prisutnosti natrijevog hidroksida daje željeni alfa,beta-nezasićeni keton, koji pri standardnim uvjetima hidrogenacije (Raney-nikal) daje (VII) te naknadnim uvjetima Wolff-Kishner redukcije daje željeni amin (VIII). Scheme 2 shows the synthesis of amine (VIII) in which two aromatic subunits are connected with a trimethylene chain. Condensation of aldehyde (I) and nitroketone (V) in the presence of sodium hydroxide gives the desired alpha,beta-unsaturated ketone, which under standard hydrogenation conditions (Raney-nickel) gives (VII) and subsequent Wolff-Kishner reduction conditions gives the desired amine (VIII) .

Shema 3 je vrlo slična Shemi 2, osim što se aldehid (I) kondenzira sa supstituiranim anilinom (IX). Scheme 3 is very similar to Scheme 2, except that the aldehyde (I) is condensed with a substituted aniline (IX).

Shema 4 prikazuje standardne uvjete Wittig-ove reakcije pri kojima se polazni materijali (XII) i (XIII) dobiju aldolnom kondenzacijom odnosno ilidnom kemijom. Reakcijom aldehida (XII) i bromfosforana (XIII) u prisutnosti baze, kao što je butillitij, dobije se dien (XIV). Standardni uvjeti redukcije (npr. Raney-nikal) spoja (XIV) daju željeni amin (XV). Scheme 4 shows the standard conditions of the Wittig reaction in which starting materials (XII) and (XIII) are obtained by aldol condensation and ylide chemistry, respectively. The reaction of aldehyde (XII) and bromophosphorane (XIII) in the presence of a base, such as butyllithium, yields a diene (XIV). Standard reduction conditions (eg Raney-nickel) of compound (XIV) give the desired amine (XV).

Shema 5 prikazuje sintezu amina (XXI) koji sadrži pentametilenski most. Wittig-ova reakcija bromfosforana (XVII), koji nastaje iz odgovarajućeg supstituiranog bromida (XVI) i nitroaldehida (XIX) dobivenog u Swern-ovoj oksidaciji odgovarajućeg alkohola (XVIII), primjenom baze (npr. LHDMS) daje olefin (XX). Redukcija (XX) pri standardnim uvjetima (Raney-nikal) daje amin (XXI). Scheme 5 shows the synthesis of amine (XXI) containing a pentamethylene bridge. The Wittig reaction of bromophosphorane (XVII), which is formed from the corresponding substituted bromide (XVI) and nitroaldehyde (XIX) obtained in the Swern oxidation of the corresponding alcohol (XVIII), using a base (eg LHDMS) gives the olefin (XX). Reduction of (XX) under standard conditions (Raney-nickel) gives amine (XXI).

Shema 6 prikazuje jedan put priprave spojeva Formule I. Polazeći iz amina poput (IV), (VIII) i (XV), bilo primjenom Buchvald-ove kopulacije (Metoda A) te naknadnom saponifikacijom, bilo Ullman-ovom reakcijom (Metoda B) mogu se izolirati spojevi Formule I. Spojevi Formule I koji sadrže hidroksilnu skupinu, kao što su Primjeri 4 i 6, u zadnjem stupnju sinteze zahtjevaju demetilaciju zaštite hidroksilne skupine reagensima poput bortribromida. Scheme 6 shows one route for the preparation of compounds of Formula I. Starting from amines such as (IV), (VIII) and (XV), either using Buchvald coupling (Method A) and subsequent saponification, or using the Ullman reaction (Method B) can compounds of Formula I can be isolated. Compounds of Formula I containing a hydroxyl group, such as Examples 4 and 6, in the last step of the synthesis require demethylation of the protection of the hydroxyl group with reagents such as boron tribromide.

Zaštitne skupine će također biti korištene kada su prisutne reaktivne funkcionalne skupine, poput amino ili karboksilne skupine, radi izbjegavanja neželjenih nuzreakcija. Karboksilne skupine se, tipično, prevode u estere (npr. tert-butil, benzil), dok se amino skupine aciliraju (npr. acetil ili trimetilsilil). Ove i druge slične zaštitne skupine su dobro poznate organskim kemičarima i potpuno su opisane u Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York (2nd Ed. 1991). Svi citati su ovdje uključeni referencom. Protecting groups will also be used when reactive functional groups, such as amino or carboxyl groups, are present to avoid unwanted side reactions. Carboxyl groups are typically converted to esters (eg tert-butyl, benzyl), while amino groups are acylated (eg acetyl or trimethylsilyl). These and other similar protecting groups are well known to organic chemists and are fully described in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York (2nd Ed. 1991). All quotations are incorporated herein by reference.

Shema 7 prikazuje sintezu spojeva Formule I reakcijom amina, poput (IV), (VIII) i (XXI), s fluornitro međuproduktom (XXIV) u prisutnosti baze (npr. LHMDS, ili trietilamin) dajući ester (XXV). Nastali ester se zatim može saponificirati pri standardnim uvjetima poput natrijevog hidroksida. Scheme 7 shows the synthesis of compounds of Formula I by reaction of amines, such as (IV), (VIII) and (XXI), with a fluoronitro intermediate (XXIV) in the presence of a base (eg LHMDS, or triethylamine) to give the ester (XXV). The resulting ester can then be saponified under standard conditions such as sodium hydroxide.

U Shemi 8, amin (XV) se može spojiti s lako dostupnim fluor- supstituiranim karboksilnim kiselinama [npr. (XXVI) ili (XXVII)] u prisutnosti različitih baza (poput DBU ili trietilamin) dajući spojeve Formule I. In Scheme 8, the amine (XV) can be coupled with readily available fluoro-substituted carboxylic acids [e.g. (XXVI) or (XXVII)] in the presence of various bases (such as DBU or triethylamine) to give compounds of Formula I.

Shema 9 prikazuje spajanje amina (VIII) s lako dostupnim metilnim esterima (XXVIII) u prisutnosti baze, poput imidazola, dajući ester (XXIX). Ovaj ester se može na uobičajeni način saponificirati dajući spojeve Formule I. Scheme 9 shows the coupling of amine (VIII) with readily available methyl esters (XXVIII) in the presence of a base, such as imidazole, to give ester (XXIX). This ester can be saponified in the usual manner to give compounds of Formula I.

Shema 10 prikazuje sintezu fluor- supstituiranog međuprodukta (XXIV) koji se dobije nitracijom lako dospupnog metilnog estera (XXX) dajući (XXVIII). Obradom (XXVIII) s kalijevim cijanidom dobije se (XXIV). Scheme 10 shows the synthesis of a fluoro-substituted intermediate (XXIV) obtained by nitration of a readily available methyl ester (XXX) to give (XXVIII). Treatment of (XXVIII) with potassium cyanide yields (XXIV).

U Shemi 11 prikazana je sinteza spojeva vezanih za Primjer 18. Reakcijom kalijevih soli orto supstituiranih benzojevih kiselina (XXVI) sa supstituiranim anilinima (XXVII) u prisutnosti kalijevog karbonata i bakrovog(II) acetata dobiju se različite jod- supstituirane aminobenzojeve kiseline (XXVIII). Reakcijom (XXVIII) sa supstituiranim bornim kiselinama i paladijevim kloridom dobiju se željene supstituirane aminobenzojeve kiseline (XXX). Scheme 11 shows the synthesis of compounds related to Example 18. The reaction of potassium salts of ortho-substituted benzoic acids (XXVI) with substituted anilines (XXVII) in the presence of potassium carbonate and copper(II) acetate yields various iodine-substituted aminobenzoic acids (XXVIII). By reacting (XXVIII) with substituted boric acids and palladium chloride, the desired substituted aminobenzoic acids (XXX) are obtained.

Treba, naravno, znati da nekoliko spojeva Formule I iz izuma mogu biti pripravljeni iz drugih spojeva definiranih Formulom I primjenom standardnih reakcija u organskoj kemiji kao što su oksidacija, redukcija, alkilacija. kondenzacija, eliminacija i slični dobro poznati sintetski postupci. Na primjer, spojevi Formule I u kojima je Ra vodik, lako se alkiliraju dajući spojeve u kojima je Ra C1-C6 alkil. Spojevi u kojima je R1 NH2 se lako aciliraju u reakciji s kiselinskim halidom ili kiselinskim anhidridom dajući spojeve u kojima je R1 NHCORb. Slično tome, spojevi u kojima je R1 NO2 se lako reduciraju dajući spojeve u kojima je R1 NH2. Benzojeve kiseline (gdje je R8 COOH) lako se prevode rutinskim postupcima u estere i amide, kao i u soli i u druge prolijekove. Na primjer, benzoeva kiselina može reagirati s oksalilkloridom dajući kiselinski klorid, koji zatim lako reagira sa sulfonamidom kao što je metansulfonamid dajući odgovarajući spoj iz izuma u kojem je R8 -CONHSO2CH3. It should, of course, be known that several compounds of Formula I from the invention can be prepared from other compounds defined by Formula I using standard reactions in organic chemistry such as oxidation, reduction, alkylation. condensation, elimination and similar well-known synthetic procedures. For example, compounds of Formula I wherein Ra is hydrogen are readily alkylated to give compounds wherein Ra is C 1 -C 6 alkyl. Compounds in which R1 is NH2 are readily acylated by reaction with an acid halide or acid anhydride to give compounds in which R1 is NHCORb. Similarly, compounds in which R1 is NO2 are readily reduced to compounds in which R1 is NH2. Benzoic acids (where R8 is COOH) are easily converted by routine procedures into esters and amides, as well as salts and other prodrugs. For example, benzoic acid can react with oxalyl chloride to give the acid chloride, which then readily reacts with a sulfonamide such as methanesulfonamide to give the corresponding compound of the invention wherein R 8 is -CONHSO 2 CH 3 .

Nastajanje amina: Formation of amines:

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Postupci spajanja Merger procedures

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R je skupina koja daje ester, poput alkilne ili benzilne. R is an ester yielding group, such as alkyl or benzyl.

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Priprava fluoriranih međuprodukata Preparation of fluorinated intermediates

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PRIMJER 1 EXAMPLE 1

Priprava 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid.

Korak A (Shema 1): Priprava 1,2-diklor-4-[2-(4-nitrofenil)etenil]benzena. Step A (Scheme 1): Preparation of 1,2-dichloro-4-[2-(4-nitrophenyl)ethenyl]benzene.

Smjesa p-nitrofeniloctene kiseline (51,23 g, 0,28 mola) i 3,4-diklorbenzaldehida (49,50 g, 0,28 mola) u piperidinu (50 ml) je zagrijavana na 150-160 °C tijekom 5 sati u atmosferi dušika. Nakon hlađenja reakcijske smjese, talog je obrađen s vrelim metanolom (MeOH) (50 ml) a zatim ohlađen na -5 °C i ostavljen 12 sati. Kristalni talog je odfiltriran, ispran hladnim MeOH, i osušen na sobnoj temperaturi u vakuumskoj peći, preko noći, dajući željeni produkt 22,71 g (0,077 mol, 27 %) u obliku narančaste krutine. T. t. = 190-191 °C. A mixture of p-nitrophenylacetic acid (51.23 g, 0.28 mol) and 3,4-dichlorobenzaldehyde (49.50 g, 0.28 mol) in piperidine (50 mL) was heated at 150-160 °C for 5 h. in a nitrogen atmosphere. After cooling the reaction mixture, the precipitate was treated with hot methanol (MeOH) (50 ml) and then cooled to -5 °C and left for 12 hours. The crystalline precipitate was filtered off, washed with cold MeOH, and dried at room temperature in a vacuum oven overnight to give the desired product 22.71 g (0.077 mol, 27 %) as an orange solid. T.t. = 190-191 °C.

MS: 294,9 (M+) MS: 294.9 (M+)

Korak B (Shema 1): Priprava 4-[2-(3,4-diklorfenil)etil]benzenamina. Step B (Scheme 1): Preparation of 4-[2-(3,4-dichlorophenyl)ethyl]benzenamine.

Uzorak 1,2-diklor-4-[2-(4nitrofenil)etenil]benzena (98,0 g, 0,33 mola) u tetrahidrofuranu (THF) (1,6 l) je reduciran u prisutnosti Raney-nikla (Ra-Ni) (20 g) pri 25 °C do 40 °C (�P = 94,3 kPa) u atmosferi dušika. Reakcijska smjesa je filtrirana , a filtrat je uparen u vakuumu dajući 85,0 g (0,32 mola, 95,8 %) željenog produkta u obliku narančaste krutine. T.t. = 68-70 °C. A sample of 1,2-dichloro-4-[2-(4nitrophenyl)ethenyl]benzene (98.0 g, 0.33 mol) in tetrahydrofuran (THF) (1.6 L) was reduced in the presence of Raney-nickel (Ra- Ni) (20 g) at 25 °C to 40 °C (�P = 94.3 kPa) under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 85.0 g (0.32 mol, 95.8 %) of the desired product as an orange solid. T.t. = 68-70 °C.

MS: 266,1 (M+). MS: 266.1 (M+).

Korak C (Shema 6): Priprava 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzojeve kiseline. Step C (Scheme 6): Preparation of 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid.

Metoda A Method A

Smjesa 4-[2-(3,4-diklorfenil)etil]benzilamina (28,37 g, 106,59 mmola), metil 2-brombenzoata (19,10 g, 88,82 mmola), cezijevog karbonata (40,52 g, 124,35 mmola), tris(dibenzilidenaceton dipaladija(0)) (2,44 g, 2,67 mmola) i (S)-(2,2'-bis(di-p-tolilfosfino-1,1'-binaftil))(98 %, (S)-tol-BINAP) (2,71 g, 4,00 mmola)(Ligand/Pd = 1,5) u bezvodnom toluenu (300 ml) je zagrijavan na 100 °C tijekom 34 sata u atmosferi dušika. Nakon hlađenja na sobnu temperaturu, reakcijska smjesa je razrijeđena s eterom, filtrirana kroz celit i dobro isprana eterom. Filtrat je uparen do suha dajući smeđi ostatak (68 g). Dobiveni ostatak je otopljen u etanolu (EtOH) (50 ml) i THF (100 ml) a zatim je dodana 5N NaOH (vodena otopina) (200 ml), i smjesa je dalje zagrijavana uz refluks tijekom 16 sati. Otapalo je zatim uklonjeno u vakuumu. Ostatak je zakiseljen koncentriranom HCl do pH = 3. Dobiveni talog je odfiltriran, obrađen s vrijućom smjesom MeOH-H2O (4 : 1) i sušen na vakuumu kroz 16 sati, pri sobnoj temperaturi, dajući Primjer 1 (31,95 g, 0,083 mola, 77,6 %) kao narančastu krutinu. T.t. = 175,0-177,0 °C. A mixture of 4-[2-(3,4-dichlorophenyl)ethyl]benzylamine (28.37 g, 106.59 mmol), methyl 2-bromobenzoate (19.10 g, 88.82 mmol), cesium carbonate (40.52 g, 124.35 mmol), tris(dibenzylideneacetone dipalladium(0)) (2.44 g, 2.67 mmol) and (S)-(2,2'-bis(di-p-tolylphosphino-1,1' -binaphthyl))(98%, (S)-tol-BINAP) (2.71 g, 4.00 mmol)(Ligand/Pd = 1.5) in anhydrous toluene (300 mL) was heated at 100 °C during 34 hours in a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ether, filtered through celite and washed well with ether. The filtrate was evaporated to dryness to give a brown residue (68 g). The resulting residue was dissolved in ethanol (EtOH) (50 ml) and THF (100 ml), then 5N NaOH (aq) (200 ml) was added, and the mixture was further heated under reflux for 16 hours. The solvent was then removed in vacuo. The residue was acidified with concentrated HCl to pH = 3. The resulting precipitate was filtered off, treated with a boiling mixture of MeOH-H2O (4:1) and dried under vacuum for 16 hours, at room temperature, giving Example 1 (31.95 g, 0.083 mol , 77.6 %) as an orange solid. T.t. = 175.0-177.0 °C.

Analiza za C21H17NO2Cl2: Rač.: C, 65,30; H, 4,44; N,3,63. Analysis for C21H17NO2Cl2: Sol.: C, 65.30; H, 4.44; N, 3,63.

Nađeno: C, 65,40; H, 4,54; N, 3,50. Found: C, 65.40; H, 4.54; N, 3.50.

Metoda B Method B

Smjesa 2-klorbenzojeve kiseline (5,4 g, 0,034 mola), 4-[2-(3,4-diklorfenil)etil]benzilamina (10,0 g, 0,037 mola), bezvodnog kalijevog karbonata (16,9 g, 0,12 mola), bakra u prahu (4,94 g, 0,077 mola), i bakrovog(I) klorida (0,37 g, 0,0037 mola) u suhom dimetilformamidu (DMF) (85 ml) je zagrijavana pri refluksu otapala tijekom 24 sata na 150 °C. Reakcijska smjesa je isipana u vrelu vodu (150 ml) i zagrijana do 90 °C na vrućoj ploči. Dodan je aktivni ugljen i smjesa je mješana daljnjih 5 minuta pri 90 °C. Topla smeđa smjesa je filtrirana kroz filter papir. Ohlađeni filtrat je zatim zakiseljen koncentriranom kloridnom kiselinom (pH = 1), a talog je odfiltriran, obrađen vrućom smjesom MeOH-voda (1:2) i sušen pri sniženom tlaku pri sobnoj temperaturi slijedećih 16 sati dajući Primjer 1 (2,3 g, 0,006 mola, 17,5 %) kao narančastu krutinu. T.t. 165,0-173,0 °C. A mixture of 2-chlorobenzoic acid (5.4 g, 0.034 mol), 4-[2-(3,4-dichlorophenyl)ethyl]benzylamine (10.0 g, 0.037 mol), anhydrous potassium carbonate (16.9 g, 0 .12 mol), powdered copper (4.94 g, 0.077 mol), and copper(I) chloride (0.37 g, 0.0037 mol) in dry dimethylformamide (DMF) (85 mL) was heated at reflux. for 24 hours at 150 °C. The reaction mixture was poured into hot water (150 ml) and heated to 90 °C on a hot plate. Activated carbon was added and the mixture was stirred for a further 5 minutes at 90 °C. The warm brown mixture was filtered through filter paper. The cooled filtrate was then acidified with conc. 0.006 mol, 17.5 %) as an orange solid. T.t. 165.0-173.0 °C.

Analiza za C21H17NO2Cl2: Rač.: C, 65,30; H, 4,44; N,3,63. Analysis for C21H17NO2Cl2: Sol.: C, 65.30; H, 4.44; N, 3,63.

Nađeno: C, 65,68; H, 4,58; N, 3,60. Found: C, 65.68; H, 4.58; N, 3.60.

PRIMJER 2 EXAMPLE 2

Priprava 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid.

Korak C (Shema 6): Priprava metilnog estera 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzojeve kiseline. Step C (Scheme 6): Preparation of 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid methyl ester.

Smjesa 4-[2-(3,4-diklorfenil)etil]benzilamina (600 mg, 2,25 mmola), metilnog estera 2-brom-5-nitrobenzojeve kiseline (489 mg, 1,88 mmola), cezijevog karbonata (857 mg, 2,62 mmola), tris(dibenzilidenaceton dipaladija(0)) (51 mg, 0,056 mmola) i (S)-(2,2'-bis(di-p-tolilfosfino-1,1'-binaftil))(98 %, (S)-tol-BINAP) (58 mg, 0,085 mmola) (Ligand/Pd = 1,5) u bezvodnom toluenu (16 ml) je zagrijavana na 100 °C tijekom 12 sati u atmosferi dušika. Nakon hlađenja, reakcijska smjesa je razrijeđena s eterom, filtrirana kroz celit i dobro isprana s eterom. Filtrat je uparen do suha, dajući smeđi ostatak. Pročišćavanje "flash" kromatografijom (silikagel, 5 % EtOAc/heksan) daje 540 mg (1,21 mmol, 64 %) željenog produkta. T.t. 107-108 °C. A mixture of 4-[2-(3,4-dichlorophenyl)ethyl]benzylamine (600 mg, 2.25 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (489 mg, 1.88 mmol), cesium carbonate (857 mg, 2.62 mmol), tris(dibenzylideneacetone dipalladium(0)) (51 mg, 0.056 mmol) and (S)-(2,2'-bis(di-p-tolylphosphino-1,1'-binaphthyl)) (98%, (S)-tol-BINAP) (58 mg, 0.085 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (16 ml) was heated at 100 °C for 12 h under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with ether, filtered through celite and washed well with ether. The filtrate was evaporated to dryness, giving a brown residue. Purification by flash chromatography (silica gel, 5% EtOAc/hexane) afforded 540 mg (1.21 mmol, 64%) of the desired product. T.t. 107-108 °C.

Analiza za C22H18N2Cl2O4: Rač.: C, 59,34; H, 4,07; N, 6,29. Analysis for C 22 H 18 N 2 Cl 2 O 4 : Sol.: C, 59.34; H, 4.07; N, 6.29.

Nađeno: C, 59,03; H, 4,04; N, 5,99. Found: C, 59.03; H, 4.04; N, 5.99.

Priprava 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid.

Otopina metilnog estera 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzojeve kiseline (340 mg, 0,76 mmola) i 1N NaOH (vodena otopina)(4,0 ml) u EtOH (4,0 ml) i THF (4,0 ml) je refluksirana tijekom 16 sati. Otapalo je uklonjeno u vakuumu. Ostatak je razrijeđen s H2O i zakiseljen koncentriranom HCl do pH = 1. Smjesa je zatim ekstrahirana s diklormetanom, osušena (Na2SO4), filtrirana i uparena u vakuumu dajući 329 mg (0,76 mmola, 100 %) željenog produkta u obliku žute krutine. T.t. = 214-217 °C. A solution of 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid methyl ester (340 mg, 0.76 mmol) and 1N NaOH (aq) (4.0 mL) in EtOH (4.0 mL) and THF (4.0 mL) was refluxed for 16 h. The solvent was removed in vacuo. The residue was diluted with H 2 O and acidified with concentrated HCl to pH = 1. The mixture was then extracted with dichloromethane, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give 329 mg (0.76 mmol, 100 %) of the desired product as a yellow solid. T.t. = 214-217 °C.

Analiza za C21H16N2Cl2O4: Rač.: C, 58,49; H, 3,74; N, 6,50. Analysis for C21H16N2Cl2O4: Sol.: C, 58.49; H, 3.74; N, 6.50.

Nađeno: C, 58,24; H, 3,81; N, 6,28. Found: C, 58.24; H, 3.81; N, 6.28.

PRIMJER 3 EXAMPLE 3

Priprava 2-{4-[4-(3,4-diklorfenil)etil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline. Preparation of 2-{4-[4-(3,4-dichlorophenyl)ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid.

U ohlađenu (-78 °C) otopinu 4-[2-(3,4-diklorfenil)etil]fenilamina (0,836 g, 3,14 mmola) u THF (20 ml), dokapan je LHDMS (6,28 ml, 1M u THF, 6,28 mmol). Reakcijska smjesa je mješana 10 minuta pri -78 °C. Otopina metilnog estera 2-fluor-4-metoksi-5-nitrobenzojeve kiseline (0,72 g, 3,14 mmola) u THF (30 ml) je polagano dokapana, a zatim je otopina mješana 30 minuta pri -78 °C. Reakcijska smjesa je ostavljena da postepeno postigne sobnu temperaturu, te je mješana još 2 sata u atmosferi dušika. Reakcijska smjesa je razrijeđena s etil acetatom (EtOAc), i zakiseljena s 5N HCl (pH = 3). Organski sloj je osušen (Na2SO4), filtriran i uparen u vakuumu dajući smeđi ostatak. U otopinu ostatka u EtOH (20 ml) i THF (40 ml), dodana je 5N NaOH (50 ml) i smjesa je refluksirana preko noći. Otapalo je upareno u vakuumu, a ostatak je zakiseljen s koncentriranom HCl (pH = 3). Talog je otfiltriran, obrađen s vrelom smjesom MeOH-H2O (1:1), i osušen u vakuumskoj peći tijekom 16 sati. Dobiven je Primjer 3 (0,70 g, 1,51 mmol, 48 %) u obliku narančaste krutine. T.t. = 208-209 °C. To a cooled (-78 °C) solution of 4-[2-(3,4-dichlorophenyl)ethyl]phenylamine (0.836 g, 3.14 mmol) in THF (20 mL), LHDMS (6.28 mL, 1M in THF, 6.28 mmol). The reaction mixture was stirred for 10 minutes at -78 °C. A solution of 2-fluoro-4-methoxy-5-nitrobenzoic acid methyl ester (0.72 g, 3.14 mmol) in THF (30 mL) was slowly added dropwise, and then the solution was stirred for 30 min at -78 °C. The reaction mixture was allowed to gradually reach room temperature and was stirred for another 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (EtOAc), and acidified with 5N HCl (pH = 3). The organic layer was dried (Na2SO4), filtered and evaporated in vacuo to give a brown residue. To a solution of the residue in EtOH (20 mL) and THF (40 mL), 5N NaOH (50 mL) was added and the mixture was refluxed overnight. The solvent was evaporated in vacuo, and the residue was acidified with concentrated HCl (pH = 3). The precipitate was filtered off, treated with a hot mixture of MeOH-H2O (1:1), and dried in a vacuum oven for 16 hours. Example 3 (0.70 g, 1.51 mmol, 48%) was obtained as an orange solid. T.t. = 208-209 °C.

Analiza za C22H18N2O5Cl2: Rač.: C, 57,28; H, 3,93; N, 6,07. Analysis for C22H18N2O5Cl2: Sol.: C, 57.28; H, 3.93; N, 6.07.

Nađeno: C, 57,43; H, 3,69; N, 5,86. Found: C, 57.43; H, 3.69; N, 5.86.

PRIMJER 4 EXAMPLE 4

Priprava 2-{4-[2-(3,4-dihidroksifenil)etil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[2-(3,4-dihydroxyphenyl)ethyl]phenylamino}benzoic acid.

Korak A (Shema 1): Priprava 1,2-dimetoksi-4-[2-(4-nitrofenil)etenil]benzena. Step A (Scheme 1): Preparation of 1,2-dimethoxy-4-[2-(4-nitrophenyl)ethenyl]benzene.

Naslovni spoj je pipravljen iz p-nitrofeniloctene kiseline (25,0 g, 0,14 mola), i 3,4-dimetoksi benzaldehida (21,0 g, 0,14 mola) u piperidinu (5 ml) primjenom postupka opisanog u Primjeru 1, Korak A, dajući 13,4 g (0,047 mola, 34 %) željenog produkta u obliku žute krutine. T.t.= 133-134 °C. The title compound was prepared from p-nitrophenylacetic acid (25.0 g, 0.14 mol) and 3,4-dimethoxy benzaldehyde (21.0 g, 0.14 mol) in piperidine (5 ml) using the procedure described in Example 1, Step A, giving 13.4 g (0.047 mol, 34 %) of the desired product as a yellow solid. T.p.= 133-134 °C.

Analiza za C16H15NO4: Rač.: C, 67,36; H, 5,30; N, 4,91. Analysis for C16H15NO4: Sol.: C, 67.36; H, 5.30; N, 4.91.

Nađeno: C, 66,81; H, 5,27; N, 4,84. Found: C, 66.81; H, 5.27; N, 4.84.

Korak B (Shema 1): Priprava 4-[2-(3,4-dimetoksifenil)etil]fenilamina. Step B (Scheme 1): Preparation of 4-[2-(3,4-dimethoxyphenyl)ethyl]phenylamine.

1,2-Dimetoksi-4-[2-(4-nitrofenil)etenil]benzen (12,1 g, 0,042 mola) je reduciran u prisutnosti 10 % Pd-C (2,0 g) u dimetilformamidu (DMF) (120 ml) pri 25 °C u atmosferi vodika. Reakcijska smjesa je uparena u vakuumu dajući kruti ostatak. Krutina je prekristalizirana iz MeOH (400 ml) dajući 6,8 g. (0,026 mola, 63 %) željenog produkta u obliku bijelih kristala. T.t.= 115-116 °C. 1,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]benzene (12.1 g, 0.042 mol) was reduced in the presence of 10% Pd-C (2.0 g) in dimethylformamide (DMF) (120 ml) at 25 °C in a hydrogen atmosphere. The reaction mixture was evaporated in vacuo to give a solid residue. The solid was recrystallized from MeOH (400 mL) to give 6.8 g (0.026 mol, 63 %) of the desired product as white crystals. T.p.= 115-116 °C.

Analiza za C16H19NO2: Rač.: C, 74,68; H, 7,44; N, 5,44. Analysis for C16H19NO2: Sol.: C, 74.68; H, 7.44; N, 5.44.

Nađeno: C, 74,60; H, 7,39; N, 5,35. Found: C, 74.60; H, 7.39; N, 5.35.

Korak C (Shema 6): Priprava 2-{4-[2-(3,4-dimetoksifenil)etil]fenilamino}benzojeve kiseline. Step C (Scheme 6): Preparation of 2-{4-[2-(3,4-dimethoxyphenyl)ethyl]phenylamino}benzoic acid.

Naslovni spoj je pripravljen iz 4-[2-(3,4-dimetoksifenil)etil]fenilamina (9,25 g, 0,036 mola), 2-klorbenzojeve kiseline (5,2 g, 0,036 mola), bezvodnog kalijevog karbonata (15,0 g, 0,11 mola), bakra u prahu (0,45 g, 0,007 mola) i katalitičke količine bakrovog(I) klorida u suhom DMF-u (75 ml) primjenom postupka opisanog u Primjeru 1, Korak C, Metoda B. Nakon kristalizacije s MeOH/H2O, dobiveno je 4,5 g (0,012 mola, 33 %) željenog produkta. T.t.= 137-139 °C. The title compound was prepared from 4-[2-(3,4-dimethoxyphenyl)ethyl]phenylamine (9.25 g, 0.036 mol), 2-chlorobenzoic acid (5.2 g, 0.036 mol), anhydrous potassium carbonate (15, 0 g, 0.11 mol), powdered copper (0.45 g, 0.007 mol) and a catalytic amount of copper(I) chloride in dry DMF (75 ml) using the procedure described in Example 1, Step C, Method B After crystallization from MeOH/H2O, 4.5 g (0.012 mol, 33 %) of the desired product was obtained. T.p.= 137-139 °C.

Analiza za C23H23NO4: Rač.: C, 73,19; H, 6,14; N, 3,71. Analysis for C23H23NO4: Sol.: C, 73.19; H, 6.14; N, 3.71.

Nađeno: C, 73,47; H, 6,03; N, 3,78. Found: C, 73.47; H, 6.03; N, 3.78.

Korak D: Priprava 2-{4-[2-(3,4-dihidroksifenil)etil]fenilamino}benzojeve kiseline. Step D: Preparation of 2-{4-[2-(3,4-dihydroxyphenyl)ethyl]phenylamino}benzoic acid.

U otopinu 2-{4-[2-(3,4-dimetoksifenil)etil]fenilamino}benzojeve kiseline (0,28 g, 0,74 mola) u CH2Cl2 (20 ml), pri sobnoj temperaturi, u atmosferi dušika dodan je BBr3 (3,5 ml, 1M u CH2Cl2, 3,5 mmola). Reakcijska smjesa je mješana 2 sata pri sobnoj temperaturi, a zatim je isipana u smjesu leda i vode (50 ml). Ova smjesa je ekstrahirana s EtOAc, a organski sloj je ispran dva puta s vodom, osušen (Na2SO4), filtriran i uparen u vakuumu dajući 0,24 g (0,69 mmola, 93 %) željenog produkta. T.t.= 215-217 °C. To a solution of 2-{4-[2-(3,4-dimethoxyphenyl)ethyl]phenylamino}benzoic acid (0.28 g, 0.74 mol) in CH2Cl2 (20 ml), at room temperature, under a nitrogen atmosphere, was added BBr3 (3.5 mL, 1M in CH2Cl2, 3.5 mmol). The reaction mixture was stirred for 2 hours at room temperature and then poured into a mixture of ice and water (50 ml). This mixture was extracted with EtOAc and the organic layer was washed twice with water, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give 0.24 g (0.69 mmol, 93 %) of the desired product. T.p.= 215-217 °C.

Analiza za C21H19NO4: Rač.: C, 72,19; H, 5,48; N, 4,00. Analysis for C21H19NO4: Sol.: C, 72.19; H, 5.48; N, 4.00.

Nađeno: C, 71,80; H, 5,46; N, 3,99. Found: C, 71.80; H, 5.46; N, 3.99.

PRIMJER 5 EXAMPLE 5

Priprava 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid.

Korak A (Shema 1): Priprava 1,1-dibutilamino -4-[2-(4-nitrofenil)etenil]benzena Step A (Scheme 1): Preparation of 1,1-dibutylamino-4-[2-(4-nitrophenyl)ethenyl]benzene

Naslovni spoj je pripravljen iz p-nitrofeniloctene kiseline (9,92 g, 0,055 mola) i 4-dibutilaminobenzaldehida (14,32 g, 0,055 mola) u piperidinu (5 ml) primjenjujući postupak opisan u Primjeru 1, Korak A. Ovaj postupak je dao 4,12 g (0,012 mola, 16 %) željenog produkta u obliku crvene krutine. The title compound was prepared from p-nitrophenylacetic acid (9.92 g, 0.055 mol) and 4-dibutylaminobenzaldehyde (14.32 g, 0.055 mol) in piperidine (5 mL) using the procedure described in Example 1, Step A. This procedure was gave 4.12 g (0.012 mol, 16 %) of the desired product as a red solid.

MS: 352,2 (M+); 353,2 (MH+). MS: 352.2 (M+); 353.2 (MH+).

Korak B (Shema 1): Priprava 4-[2-(4,4-dibutilaminofenil)etil]fenilamina. Step B (Scheme 1): Preparation of 4-[2-(4,4-dibutylaminophenyl)ethyl]phenylamine.

Naslovni spoj je pripravljen iz 1,1-dibutilamino -4-[2-(4-nitrofenil)etenil]benzena (4,10 g, 11,63 mmola) i Ra-Ni (2,0 g) u MeOH (100 ml) pri 21 °C do 32 °C (�P = 25 kPa) u atmosferi vodika primjenjujući postupak opisan u Primjeru 1, Korak B. Ovaj postupak je dao 3,49 g (10,76 mmola, 92,6 %) željenog produkta kao bezbojno ulje. The title compound was prepared from 1,1-dibutylamino-4-[2-(4-nitrophenyl)ethenyl]benzene (4.10 g, 11.63 mmol) and Ra-Ni (2.0 g) in MeOH (100 mL ) at 21 °C to 32 °C (�P = 25 kPa) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure gave 3.49 g (10.76 mmol, 92.6 %) of the desired product as a colorless oil.

MS: 325,3 (MH+). MS: 325.3 (MH+).

Korak C (Shema 6): Priprava 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzojeve kiseline. Step C (Scheme 6): Preparation of 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid.

Naslovni spoj je pripravljen iz 2-klorbenzojeve kiseline (1,46 g, 9,36 mmola), 4-[2-(4,4-dibutilaminofenil)etil]fenilamina (3,31 g, 10,20 mmola), bezvodnog kalijevog karbonata (4,27 g, 30,88 mmola), bakra u prahu (1,25 g, 19,65 mmola) i bakrovog(I) klorida (0,092 g, 0,93 mmola) u suhom DMF (30 ml) primjenjujući postupak opisan u Primjeru 1, Korak C, Metoda B. Ovaj postupak je dao 0,39 g (0,87 mol, 8,6 %) željenog produkta. T.t.= 115-117 °C. The title compound was prepared from 2-chlorobenzoic acid (1.46 g, 9.36 mmol), 4-[2-(4,4-dibutylaminophenyl)ethyl]phenylamine (3.31 g, 10.20 mmol), anhydrous potassium carbonate (4.27 g, 30.88 mmol), copper powder (1.25 g, 19.65 mmol) and copper(I) chloride (0.092 g, 0.93 mmol) in dry DMF (30 ml) using the procedure described in Example 1, Step C, Method B. This procedure gave 0.39 g (0.87 mol, 8.6 %) of the desired product. T.p.= 115-117 °C.

Analiza za C29H36N2O2: Rač.: C, 78,34; H, 8,16; N, 6,30. Analysis for C 29 H 36 N 2 O 2 : Sol.: C, 78.34; H, 8.16; N, 6:30.

Nađeno: C, 78,15; H, 8,07; N, 6,10. Found: C, 78.15; H, 8.07; N, 6,10.

PRIMJER 6 EXAMPLE 6

Priprava 2-{4-[2-(3,4,5-trihidroksifenil)etil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenylamino}benzoic acid.

Korak A (Shema 1): Priprava 1,2,3-trimetoksi-5-[2-(4-nitrofenil)etenil]benzena. Step A (Scheme 1): Preparation of 1,2,3-trimethoxy-5-[2-(4-nitrophenyl)ethenyl]benzene.

Naslovni spoj je pripravljen iz p-nitrofeniloctene kiseline (18,6 g, 0,10 mola), 3,4,5-trimetoksibenzaldehida (19,6 g, 0,10 mola) i piperidina (5 ml) primjenjujući postupak opisaan u Primjeru 1, Korak A. Ovaj postupak daje 13,0 g (0,041 mola, 41 %) krutog željenog produkta. T.t.= 192-195 °C. The title compound was prepared from p-nitrophenylacetic acid (18.6 g, 0.10 mol), 3,4,5-trimethoxybenzaldehyde (19.6 g, 0.10 mol) and piperidine (5 ml) using the procedure described in Example 1, Step A. This procedure afforded 13.0 g (0.041 mol, 41 %) of the solid desired product. T.p.= 192-195 °C.

Korak B (Shema 1) Priprava 4-[2-(3,4,5-trimetoksifenil)etil]fenilamina. Step B (Scheme 1) Preparation of 4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamine.

Naslovni spoj je pripravljen iz 1,2,3-trimetoksi-5-[2-(4-nitrofenil)etenil]benzena (9,5 g, 0,03 mola) The title compound was prepared from 1,2,3-trimethoxy-5-[2-(4-nitrophenyl)ethenyl]benzene (9.5 g, 0.03 mol)

i Ra-Ni (1,0 g) u THF (50 ml) pri 21 °C do 26 °C (�P = 67 kPa) u atmosferi vodika primjenjujući postupak opisan u Primjeru 1, Korak B. Ovaj postupak daje 6,6 g (0,023 mola, 74 %) željenog produkta, kao žutosmeđi prah. T.t.= 91-93 °C. and Ra-Ni (1.0 g) in THF (50 ml) at 21 °C to 26 °C (�P = 67 kPa) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure gave 6.6 g (0.023 mol, 74 %) of the desired product as a tan powder. T.p.= 91-93 °C.

Korak C (Shema 6): Priprava metilnog estera 2-{4-[2-(3,4,5-trimetoksifenil)etil]fenilamino}benzojeve kiseline. Step C (Scheme 6): Preparation of 2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}benzoic acid methyl ester.

Naslovni spoj je pripravljen iz 4-[2-(3,4,5-trimetoksifenil)etil]fenilamina (0,75 g, 2,61 mola), metil 2-brombenzoata (0,47 g, 2,17 mmola), cezijevog karbonata (0,99 g, 3,04 mmola), tris(dibenzilidenaceton dipaladija(0)) (0,06 g, 0,065 mmola) i (S)-(-0-2,2'-bis(di-p-tolilfosfino-1,1'-binaftil))(98 % (S)-tol-BINAP) (0,066 g, 0,098 mmola) (Ligand/Pd = 1,5) u bezvodnom toluenu (100 ml) primjenjujući postupak opisan u Primjeru 1, Korak C, Metoda A dajući 0,69 g (1,63 mmola, 76 %) željenog produka kao žuto ulje. The title compound was prepared from 4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamine (0.75 g, 2.61 mol), methyl 2-bromobenzoate (0.47 g, 2.17 mmol), cesium carbonate (0.99 g, 3.04 mmol), tris(dibenzylideneacetone dipalladium(0)) (0.06 g, 0.065 mmol) and (S)-(-0-2,2'-bis(di-p -tolylphosphino-1,1'-binaphthyl))(98% (S)-tol-BINAP) (0.066 g, 0.098 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (100 ml) using the procedure described in Example 1, Step C, Method A to give 0.69 g (1.63 mmol, 76%) of the desired product as a yellow oil.

Analiza za C25H27NO5: Rač.: C, 71,24; H, 6,46; N, 3,32. Analysis for C25H27NO5: Sol.: C, 71.24; H, 6.46; N, 3.32.

Nađeno: C, 71,53; H, 6,24; N, 3,14. Found: C, 71.53; H, 6.24; N, 3.14.

Priprava 2-{4-[2-(3,4,5-trimetoksifenil)etil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}benzoic acid.

U otopinu metilnog estera 2-{4-[2-(3,4,5-trimetoksifenil)etil]fenilamino}benzojeve kiseline (0,62 g, 1,47 mmol) u THF-EtOH (2:1, 6 ml), dodana je 1N otopina NaOH (4 ml) i reakcijska smjesa je grijana na refluksu otapala tijekom 5 sati. Organska otapala su uklonjena iz reakcijske smjese koncentriranjem u vakuumu. Ostatak je zakiseljen koncentriranom HCl (pH = 3). Nastali talog je filtriran, obrađen vrelom smjesom MeOH-H2O (4:1) i osušen u vakuumu pri sobnoj temperaturi, tijekom 16 sati dajući 0,59 g (1,45 mmola, 98,5 %) željenog produkta kao bijele krutine. T.t.= 146,0-147,0 °C. To a solution of 2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}benzoic acid methyl ester (0.62 g, 1.47 mmol) in THF-EtOH (2:1, 6 ml) , 1N NaOH solution (4 ml) was added and the reaction mixture was heated at solvent reflux for 5 hours. The organic solvents were removed from the reaction mixture by concentration in vacuo. The residue was acidified with concentrated HCl (pH = 3). The resulting precipitate was filtered, treated with hot MeOH-H2O (4:1) and dried in vacuo at room temperature for 16 hours to give 0.59 g (1.45 mmol, 98.5 %) of the desired product as a white solid. T.t.= 146.0-147.0 °C.

Analiza za C24H25NO5: Rač.: C, 70,75; H, 6,18; N, 3,44. Analysis for C24H25NO5: Sol.: C, 70.75; H, 6.18; N, 3.44.

Nađeno: C, 70,54; H, 6,43; N, 3,15. Found: C, 70.54; H, 6.43; N, 3.15.

Korak D: Priprava 2-{4-[2-(3,4,5-trihidroksifenil)etil]fenilamino}benzojeve kiseline. Step D: Preparation of 2-{4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenylamino}benzoic acid.

Naslovni spoj je pripravljen iz 2-{4-[2-(3,4,5-trimetoksifenil)etil]fenilamino}benzojeve kiseline (0,50 g, 1,23 mmola) u CH2Cl2 (40 ml) i BBr3 (10 ml, 1M u CH2Cl2, 10,0 mmola) primjenjujući postupak opisan u Primjeru 4, Korak D. Ovaj postupak daje 0,25 g (0,68 mmola, 65 %) željenog produkta kao zelene krutine. T.t.= 160,0-162,0 °C. The title compound was prepared from 2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}benzoic acid (0.50 g, 1.23 mmol) in CH2Cl2 (40 mL) and BBr3 (10 mL , 1M in CH2Cl2, 10.0 mmol) using the procedure described in Example 4, Step D. This procedure gave 0.25 g (0.68 mmol, 65%) of the desired product as a green solid. T.t.= 160.0-162.0 °C.

Analiza za C21H19NO5 x 1,44 H2O: Rač.: C, 64,46; H, 5,64; N, 3,58. Analysis for C21H19NO5 x 1.44 H2O: Calc.: C, 64.46; H, 5.64; N, 3.58.

Nađeno: C, 64,07; H, 5,27; N, 3,39. Found: C, 64.07; H, 5.27; N, 3.39.

PRIMJER 7 EXAMPLE 7

Priprava 2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline Preparation of 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid

Korak A' (Shema 2): Priprava 3-(3,4-diklorfenil)-1-(4-nitrofenil)propenona. Step A' (Scheme 2): Preparation of 3-(3,4-dichlorophenyl)-1-(4-nitrophenyl)propenone.

Natrijev hidroksid (7,3 g, 0,18 mola) je otopljen u vodi (80 ml) i 95 %-tnom EtOH (80 ml) te ohlađen do 10 °C u ledenoj kupelji. 3,4-diklorbenzaldehid (31,8 g, 0,18 mola) je dodan odjednom. Nakon dodavanja, smjesa je zagrijana do 15 °C. Pri toj temperaturi dodan je 1-(4-nitrofenil)etanon (30,0 g, 0,18 mol) uz snažno miješanje. Nakon mješanja tijekom 5 minuta, reakcijska smjesa je razrijeđena s 95 %-tnim EtOH (300 ml). Dobivena žutosmeđa smjesa je dalje miješana 30 minuta pri sobnoj temperaturi, a zatim je miješana, s ledenom kupelji ispod tikvice, slijedećih 2 sata. Svijetlosmeđa krutina je odfiltrirana, isprana vodom i osušena na zraku. Krutina je otopljena u vrućem THF (1,5 l) i obrađena s aktivnim ugljenom. Dobivena smjesa je odfiltrirana, a filtrat je razrijeđen s 95 %-tnim EtOH (500 ml). Ova otopina je filtrirana i osušena u peći (40 °C) dajući 38,56 g (0,12 mola, 66 %) naslovnog spoja kao svjetlosmeđu krutinu. T.t.= 220 -223 °C. Sodium hydroxide (7.3 g, 0.18 mol) was dissolved in water (80 ml) and 95% EtOH (80 ml) and cooled to 10 °C in an ice bath. 3,4-Dichlorobenzaldehyde (31.8 g, 0.18 mol) was added in one portion. After addition, the mixture was heated to 15 °C. At this temperature, 1-(4-nitrophenyl)ethanone (30.0 g, 0.18 mol) was added with vigorous stirring. After stirring for 5 min, the reaction mixture was diluted with 95% EtOH (300 mL). The resulting tan mixture was further stirred for 30 minutes at room temperature and then stirred, with an ice bath under the flask, for the next 2 hours. The light brown solid was filtered off, washed with water and dried in air. The solid was dissolved in hot THF (1.5 L) and treated with activated carbon. The resulting mixture was filtered, and the filtrate was diluted with 95% EtOH (500 ml). This solution was filtered and dried in an oven (40 °C) to give 38.56 g (0.12 mol, 66 %) of the title compound as a light brown solid. T.p.= 220 -223 °C.

Analiza za C15H9Cl2NO3: Rač.: C, 55,93; H, 2,82; Cl, 22,01; N, 4,35. Analysis for C15H9Cl2NO3: Sol.: C, 55.93; H, 2.82; Cl, 22.01; N, 4.35.

Nađeno: C, 55,79; H, 2,93; Cl, 22,16; N, 4,32. Found: C, 55.79; H, 2.93; Cl, 22.16; N, 4.32.

Korak B' (Shema 2): Priprava 1-(4-aminofenil)-3-(3,4-diklorfenil)propan-1-ona. Step B' (Scheme 2): Preparation of 1-(4-aminophenyl)-3-(3,4-dichlorophenyl)propan-1-one.

3-(3,4-diklorfenil)-1-(4-nitrofenil)propenon (34,56 g, 0,11 mola) je reduciran u prisutnosti Ra-Ni (3,0 g) u THF (250 ml) pri 20 °C do 32 °C (�P = 233 kPa) u atmosferi vodika. Reakcijska smjesa je koncentrirana u vakuumu i rekristralizirana iz MeOH (100 ml) dajući 23,5 g (0,080 mola, 75 %) željenog produkta kao svijetložutih kristala. T.t.= 127 -129 °C. 3-(3,4-Dichlorophenyl)-1-(4-nitrophenyl)propenone (34.56 g, 0.11 mol) was reduced in the presence of Ra-Ni (3.0 g) in THF (250 mL) at 20 °C to 32 °C (�P = 233 kPa) in a hydrogen atmosphere. The reaction mixture was concentrated in vacuo and recrystallized from MeOH (100 mL) to give 23.5 g (0.080 mol, 75 %) of the desired product as pale yellow crystals. T.p.= 127 -129 °C.

Analiza za C15H13Cl2NO: Rač.: C, 61,24; H, 4,45; N, 4,76; Cl, 24,10. Analysis for C15H13Cl2NO: Sol.: C, 61.24; H, 4.45; N, 4.76; Cl, 24,10.

Nađeno: C, 60,91; H, 4,60; N, 4,70; Cl, 23,98. Found: C, 60.91; H, 4.60; N, 4.70; Cl, 23.98.

Korak C' (Shema 2): Priprava 4-[3-(3,4-diklorfenil)propil]fenilamina. Step C' (Scheme 2): Preparation of 4-[3-(3,4-dichlorophenyl)propyl]phenylamine.

Smjesa 1-(4-aminofenil)-3-(3,4-diklorfenil)propan-1-ona (20,0 g, 0,068 mola), NH2NH2-H2O (16 ml) i KOH (85 %, 5,6 g) u etilenglikolu (160 ml) je zagrijavana 16 sati pri refluksu otapala, u atmosferi dušika. Nakon hlađenja na sobnu temperaturu, reakcijska smjesa je isipana u smjesu voda-led i ekstrahirana s CH2Cl2 (2 l). Slojevi su odvojeni, a organski sloj je osušen (Na2SO4) i uparen na vakuumu dajući ulje. Pročišćavanje "flash" kromatografijom (silikagel, CH2Cl2) daje 14,00 g (0,05 mol, 73 %) željenog produkta kao žuto ulje. A mixture of 1-(4-aminophenyl)-3-(3,4-dichlorophenyl)propan-1-one (20.0 g, 0.068 mol), NH2NH2-H2O (16 ml) and KOH (85%, 5.6 g ) in ethylene glycol (160 ml) was heated for 16 hours at solvent reflux, in a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into a water-ice mixture and extracted with CH2Cl2 (2 L). The layers were separated and the organic layer was dried (Na2SO4) and evaporated in vacuo to give an oil. Purification by flash chromatography (silica gel, CH2Cl2) gave 14.00 g (0.05 mol, 73%) of the desired product as a yellow oil.

Analiza za C15H15Cl2N: Rač.: C, 64,30; H, 5,40; N, 4,99; Cl, 25,31. Analysis for C15H15Cl2N: Sol.: C, 64.30; H, 5.40; N, 4.99; Cl, 25,31.

Nađeno: C, 64,21; H, 5,59; N, 5,24; Cl, 24,87. Found: C, 64.21; H, 5.59; N, 5.24; Cl, 24.87.

Priprava metilnog estera 2,4-difluor-5-nitrobenzojeve kiseline. Preparation of 2,4-difluoro-5-nitrobenzoic acid methyl ester.

90 %-tna Dimeća nitratna kiselina (8,5 ml, 0,19 mol) je dodana uz blago miješanje u koncentriranu 98 %-tnu sumpornu kiselinu, u čašu od 1 l. Nakon miješanja u trajanju od 10 minuta pri sobnoj temperaturi, dokapan je metilni ester 2,4-difluorbenzojeve kiseline (21,9 g, 0,127 mola). Nakon dodavanja, reakcijska smjesa je lagano mješana 40 minuta pri sobnoj temperaturi. Reakcijska smjesa je, zatim isipana na smjesu voda-led (1 l) i mješana 10 minuta. Smjesa je ekstrahirana s EtOAc. Slojevi su odvojeni, a organski sloj je ispran susljedno s 1N NaCl, zasićenim NaHCO3, H2O i zasićenom otopinom NaCl, osušen (Na2SO4), filtriran i uparen u vakuumu dajući žuti ostatak. Ovaj ostatak je ispran s 10 % EtOAc/heksan, filtriran i osušen dajući 29,0 (0,133 mola, 82 %) blijedožute krutine. T.t.= 78-80 °C. 90% fuming nitric acid (8.5 ml, 0.19 mol) was added with gentle stirring to concentrated 98% sulfuric acid in a 1 L beaker. After stirring for 10 minutes at room temperature, 2,4-difluorobenzoic acid methyl ester (21.9 g, 0.127 mol) was added dropwise. After the addition, the reaction mixture was gently stirred for 40 minutes at room temperature. The reaction mixture was then poured onto the water-ice mixture (1 l) and stirred for 10 minutes. The mixture was extracted with EtOAc. The layers were separated and the organic layer was washed successively with 1N NaCl, saturated NaHCO 3 , H 2 O and saturated NaCl solution, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give a yellow residue. This residue was washed with 10% EtOAc/hexane, filtered and dried to give 29.0 (0.133 mol, 82%) of a pale yellow solid. T.p.= 78-80 °C.

Analiza za C8H5F2NO4: Rač.: C, 44,25; H, 2,32; N, 6,45. Analysis for C8H5F2NO4: Sol.: C, 44.25; H, 2.32; N, 6.45.

Nađeno: C, 44,18; H, 2,39; N, 6,14. Found: C, 44.18; H, 2.39; N, 6,14.

Priprava metilnog estera 2-fluor-4-metoksi-5-nitrobenzojeve kiseline. Preparation of methyl ester of 2-fluoro-4-methoxy-5-nitrobenzoic acid.

Smjesa metalnog natrija (1,27 g, 0,055 mola) i MeOH (250 ml) je mješana na 0 °C tijekom 10 minuta. Ova otopina je dodana u otopinu metilnog estera 2-fluor-5-nitrobenzojeve kiseline (10,0 g, 0,046 mola) u MeOH (250 ml), te je smjesa miješana 20 minuta pri 0-5 °C. Reakcijska smjesa je zatim ostavljena da postigne sobnu temperaturu te je miješana slijedećih 2 sata. Smjesa je zatim filtrirana dajući sivobijeli talog. Rekristalizacijom iz CHCl3 (70 ml) dobiveno je 1,825 g (0,008 mol, 17 %) naslovnog spoja kao sivobijele kristalne krutine. A mixture of sodium metal (1.27 g, 0.055 mol) and MeOH (250 mL) was stirred at 0 °C for 10 min. This solution was added to a solution of 2-fluoro-5-nitrobenzoic acid methyl ester (10.0 g, 0.046 mol) in MeOH (250 mL), and the mixture was stirred for 20 min at 0-5 °C. The reaction mixture was then allowed to reach room temperature and stirred for the next 2 hours. The mixture was then filtered to give an off-white precipitate. Recrystallization from CHCl3 (70 ml) afforded 1.825 g (0.008 mol, 17 %) of the title compound as an off-white crystalline solid.

Analiza za C9H8FNO5: Rač.: C, 47,17; H, 3,52; N, 6,11. Analysis for C9H8FNO5: Sol.: C, 47.17; H, 3.52; N, 6,11.

Nađeno: C, 47,09; H, 3,47; N, 6,00. Found: C, 47.09; H, 3.47; N, 6.00.

Priprava metilnog estera 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline. Preparation of methyl ester of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid.

Smjesa 4-[3-(3,4-diklorfenil)propil]fenilamina (0,94 g, 3,3 mmola), metilnog estera 2-fluor-4-metoksi-5-nitrobenzojeve kiseline (0,75 g, 3,3 mmola), i Et3N (0,46 ml) u CH3CN (30 ml) je zagrijavana uz refluks otapala 120 sati. Reakcijska smjesa je ohlađena na sobnu temperaturu, razrijeđena s CH2Cl2 i isprana zasićenom otopinom NaHCO3. Organski sloj je osušen (Na2SO4) i uparen dajući kruti ostatak. Rekristalizacijom iz MeOH dobije se 0,67 g (1,37 mmola, 42 %) željenog produkta. A mixture of 4-[3-(3,4-dichlorophenyl)propyl]phenylamine (0.94 g, 3.3 mmol), 2-fluoro-4-methoxy-5-nitrobenzoic acid methyl ester (0.75 g, 3, 3 mmol), and Et3N (0.46 mL) in CH3CN (30 mL) was heated under reflux for 120 h. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 and washed with saturated NaHCO3 solution. The organic layer was dried (Na2SO4) and evaporated to give a solid residue. Recrystallization from MeOH gave 0.67 g (1.37 mmol, 42 %) of the desired product.

Analiza za C24H22N2Cl2O5 x 0,42 H2O: Rač.: C, 58,01; H, 4,63; N, 5,64. Analysis for C 24 H 22 N 2 Cl 2 O 5 x 0.42 H 2 O: Calc.: C, 58.01; H, 4.63; N, 5.64.

Nađeno: C, 57,61; H, 4,51; N, 5,94. Found: C, 57.61; H, 4.51; N, 5.94.

Priprava 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline. Preparation of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid.

U otopinu metilnog estera 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline (0,30 g, 0,061 mola) u THF (5 ml), dodana je 1N NaOH (vodena otopina) (2,5 ml), a smjesa je miješana 36 sati pri sobnoj temperaturi. Otapalo je upareno, a ostatak je zakiseljen koncentriranom HCl do pH 3. Talog je otfiltriran i sušen na vakuumu 16 sati. Rekristalizacijom iz MeOH dobije se 0,21 g (0,043 mol, 70 %) naslovnog spoja u obliku narančaste krutine. T.t.= 200 -201 °C. To a solution of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid methyl ester (0.30 g, 0.061 mol) in THF (5 ml), was added 1N NaOH (aqueous solution) (2.5 ml), and the mixture was stirred for 36 hours at room temperature. The solvent was evaporated, and the residue was acidified with concentrated HCl to pH 3. The precipitate was filtered off and dried under vacuum for 16 hours. Recrystallization from MeOH gave 0.21 g (0.043 mol, 70 %) of the title compound as an orange solid. T.p.= 200 -201 °C.

Analiza za C23H20N2O5Cl2 x 0,2 H2O: Rač.: C, 57,68; H, 4,29; N, 5,85; Cl, 14,81. Analysis for C 23 H 20 N 2 O 5 Cl 2 x 0.2 H 2 O: Calc.: C, 57.68; H, 4.29; N, 5.85; Cl, 14.81.

Nađeno: C, 57,71; H, 4,34; N, 5,58; Cl, 14,56. Found: C, 57.71; H, 4.34; N, 5.58; Cl, 14.56.

PRIMJER 8 EXAMPLE 8

Priprava 2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-imidazol-1-il-5-nitrobenzojeve kiseline. Preparation of 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazol-1-yl-5-nitrobenzoic acid.

Priprava metilnog estera 2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-imidazol-1-il-5-nitrobenzojeve kiseline. Preparation of methyl ester of 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazol-1-yl-5-nitrobenzoic acid.

Smjesa metilnog estera 2,4-difluor-5-nitrobenzojeve kiseline (1,63 g, 7,5 mmola), imidazola (0,56 g, 8,25 mmola), i Et3N (1,14 ml, 8,25 mmola) u CH3CN (50 ml) je mješana 16 sati pri sobnoj temperaturi. U nastalu narančastu otopinu dodani su 4-[3-(3,4-diklorfenil)propil]fenilamin (2,10 g, 7,5 mmola) i trietilamin (Et3N) (1,14 ml, 8,25 mmola), a smjesa je refluksirana preko noći. Reakcijska smjesa je ohlađena i koncentrirana na vakuumu dajući ostatak. Ostatak je razrijeđen s CH2Cl2 i ispran s zasićenom otopinom K2HCO3. Organski sloj je osušen (Na2SO4), filtriran i uparen u vakuumu dajući sirovo ulje. Pročišćavanje "flash" kromatografijom (silikagel, 10 % EtOAc/heksan) daje 1,0 g (1,90 mmola, 25 %) željenog produkta. A mixture of 2,4-difluoro-5-nitrobenzoic acid methyl ester (1.63 g, 7.5 mmol), imidazole (0.56 g, 8.25 mmol), and Et3N (1.14 mL, 8.25 mmol ) in CH3CN (50 ml) was stirred for 16 hours at room temperature. 4-[3-(3,4-dichlorophenyl)propyl]phenylamine (2.10 g, 7.5 mmol) and triethylamine (Et3N) (1.14 ml, 8.25 mmol) were added to the resulting orange solution, and the mixture was refluxed overnight. The reaction mixture was cooled and concentrated in vacuo to give a residue. The residue was diluted with CH2Cl2 and washed with saturated K2HCO3 solution. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo to give a crude oil. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) afforded 1.0 g (1.90 mmol, 25%) of the desired product.

MS: 524,1 (M+) MS: 524.1 (M+)

Priprava 2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-imidazol-1-il-5-nitrobenzojeve kiseline. Preparation of 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazol-1-yl-5-nitrobenzoic acid.

Naslovni spoj je pripravljen iz metilnog estera 2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-imidazol-1-il-5-nitrobenzojeve kiseline (1,0 g, 1,9 mmola) i 1N NaOH (2,0 ml) u THF (30 ml) primjenjujući postupak opisan u Primjeru 8. Ovaj postupak je dao 0,30 g (0,6 mmola, 32 %) željenog produkta u obliku narančaste krutine. The title compound was prepared from 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazol-1-yl-5-nitrobenzoic acid methyl ester (1.0 g, 1.9 mmol) and 1N NaOH (2.0 mL) in THF (30 mL) using the procedure described in Example 8. This procedure afforded 0.30 g (0.6 mmol, 32%) of the desired product as an orange solid.

Analiza za C25H20Cl2N4O4 x 0,2 H2O: Rač.: C, 58,31; H, 3,99; N, 10,88; Cl, 13,89. Analysis for C25H20Cl2N4O4 x 0.2 H2O: Calc.: C, 58.31; H, 3.99; N, 10.88; Cl, 13.89.

Nađeno: C, 58,34; H, 4,07; N, 10,73; Cl, 13,41. Found: C, 58.34; H, 4.07; N, 10.73; Cl, 13,41.

PRIMJER 9 EXAMPLE 9

Priprava 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid.

Priprava metilnog estera 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid methyl ester.

Naslovni spoj je pripravljen iz 4-[3-(3,4-diklorfenil)propil]fenilamina (600 mg, 2,14 mmola), metilnog estera 2-brombenzojeve kiseline (380 mg, 1,78 mmola), cezijevog karbonata (812 mg, 2,49 mmola), tris(dibenzilidenaceton dipaladija(0)) (49 mg, 0,053 mmola) i (S)-(-0-2,2'-bis(di-p-tolilfosfino-1,1'-binaftil))(98 % (S)-tol-BINAP) (54 mg, 0,080 mmola) (Ligand/Pd = 1,5) u bezvodnom toluenu (15 ml) primjenjujući postupak opisan u Primjeru 2, Korak C. Ovaj postupak je dao 0,61 g (1,47 mmol, 69 %) željenog produkta u obliku žutog ulja. The title compound was prepared from 4-[3-(3,4-dichlorophenyl)propyl]phenylamine (600 mg, 2.14 mmol), 2-bromobenzoic acid methyl ester (380 mg, 1.78 mmol), cesium carbonate (812 mg, 2.49 mmol), tris(dibenzylideneacetone dipalladium(0)) (49 mg, 0.053 mmol) and (S)-(-0-2,2'-bis(di-p-tolylphosphino-1,1'- binaphthyl))(98% (S)-tol-BINAP) (54 mg, 0.080 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (15 ml) using the procedure described in Example 2, Step C. This procedure was gave 0.61 g (1.47 mmol, 69%) of the desired product as a yellow oil.

MS: 414 (M+), 416 (MH+) MS: 414 (M+), 416 (MH+)

Analiza za C23H21Cl2O2N x 0,4 H2O: Rač.: C, 65,25; H, 5,23; N, 3,30. Analysis for C23H21Cl2O2N x 0.4 H2O: Sol.: C, 65.25; H, 5.23; N, 3.30.

Nađeno: C, 65,76; H, 5,18; N, 3,10. Found: C, 65.76; H, 5.18; N, 3.10.

Priprava 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid.

Naslovni spoj je pripravljen iz metilnog estera 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzojeve kiseline (0,41 g, 0,99 mmola), 1N NaOH (4,0 ml) u EtOH (4 ml) i THF (4 ml) primjenjujući postupak opisan u Primjeru 2. Ovaj postupak je dao 0,32 g (0,80 mmola, 81 %) željenog produkta u obliku žute krutine. T.t. = 120-126 °C. The title compound was prepared from 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid methyl ester (0.41 g, 0.99 mmol), 1N NaOH (4.0 mL) in EtOH (4 ml) and THF (4 ml) using the procedure described in Example 2. This procedure gave 0.32 g (0.80 mmol, 81%) of the desired product as a yellow solid. T.t. = 120-126 °C.

Analiza za C22H19Cl2O2N x 0,75 H2O: Rač.: C, 64,04; H, 5,00; N, 3,39. Analysis for C 22 H 19 Cl 2 O 2 N x 0.75 H 2 O: Calc.: C, 64.04; H, 5.00; N, 3.39.

Nađeno: C, 64,17; H, 4,69; N, 3,18. Found: C, 64.17; H, 4.69; N, 3.18.

PRIMJER 10 EXAMPLE 10

Priprava 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}benzoic acid.

Priprava trans-3-(3,4-diklorfenil)-2-propenala. Preparation of trans-3-(3,4-dichlorophenyl)-2-propenal.

Smjesa 3,4-diklorbenzaldehida (140,0 g, 0,8 mola) i acetaldehida (300 ml) je ohlađena na 5 °C. Kalijev hidroksid (5,1 g, 0,091 mola) je otopljen u vrućem MeOH (40 ml), a dobivena otopina je dodana u gore navedenu ohlađenu smjesu, održavajući temperaturu smjese između 25 i 30 °C. Smjesa je ostavljena na miješanju u ledenoj kupelji slijedećih 40 minuta, a zatim je obrađena s anhidridom octene kiseline (400 ml). Nakon dodavanja, smjesa je zagrijavana na 100 °C uz miješanje tijekom 30 minuta, a zatim ohlađena na 30 °C. U ovu smjesu dodana je 12N HCl/H2O (102 ml/1,2 l), a rezultirajuća smjesa je zagrijavana pri refluksu 30 minuta te ohlađena na sobnu temperaturu. Ova heterogena smjesa je filtrirana i isprana s H2O dajući smeđu krutinu. Sirovi produkt je otopljen u EtOAc i ispran s H2O, osušen (Na2SO4) te uparen do suha. Rekristalizacija iz smjese heksan/EtOAc (9:1) je dala 76,5 g (0,38 mola, 48 %) naslovnog spoja. T.t. = 91-93 °C. A mixture of 3,4-dichlorobenzaldehyde (140.0 g, 0.8 mol) and acetaldehyde (300 ml) was cooled to 5 °C. Potassium hydroxide (5.1 g, 0.091 mol) was dissolved in hot MeOH (40 mL) and the resulting solution was added to the above cooled mixture, maintaining the temperature of the mixture between 25 and 30 °C. The mixture was left to stir in an ice bath for the next 40 minutes and then treated with acetic anhydride (400 ml). After addition, the mixture was heated to 100 °C with stirring for 30 min and then cooled to 30 °C. 12N HCl/H2O (102 ml/1.2 l) was added to this mixture, and the resulting mixture was heated at reflux for 30 minutes and cooled to room temperature. This heterogeneous mixture was filtered and washed with H2O to give a brown solid. The crude product was dissolved in EtOAc and washed with H2O, dried (Na2SO4) and evaporated to dryness. Recrystallization from hexane/EtOAc (9:1) gave 76.5 g (0.38 mol, 48 %) of the title compound. T.t. = 91-93 °C.

Analiza za C9H6Cl2O: Rač.: C, 53,77; H, 3,01; Cl, 35,27. Analysis for C9H6Cl2O: Sol.: C, 53.77; H, 3.01; Cl, 35,27.

Nađeno: C, 53,75; H, 3,10; Cl, 35,58. Found: C, 53.75; H, 3.10; Cl, 35.58.

Priprava trans,trans-1,2-diklor-4-[4-(4-nitrofenil)-1,3-butadienil]benzena. Preparation of trans,trans-1,2-dichloro-4-[4-(4-nitrophenyl)-1,3-butadienyl]benzene.

Smjesa 4-nitrobenzilbromida (200,0 g, 0,93 mola) i trifenilfosfina (244,0 g, 0,93 mola) u CHCl3 (1,5 l) je refluksirana tijekom noći. Reakcijska smjesa je ohlađena na sobnu temperaturu, uparena u vakuumu da se ukloni CHCl3, a zatim suspendirana u Et2O te snažno mješana. Suspenzija je filtrirana, a sivobijela krutina je isprana s Et2O, sušena na 80 °C tijekom 16 sati dajući 433,0 g (0,91 mola, 98 %) brom[(4-nitrofenil)metil]trifenilfosforana. Otopina brom[(4-nitrofenil)metil]trifenilfosforana (100,0 g, 0,23 mola) u suhom THF (500 ml) je ohlađena na 5 °C. n-Butillitij (n-BuLi) (2,4 M, 96 ml, 0,23 mola) je dokapan uz održavanje temperature između 5 i 10 °C. Kupelj za hlađenje je tada uklonjena, a reakcijska smjesa je ostavljena da postigne sobnu temperaturu. Nakon 4 sata, dokapana je otopina trans-3-(3,4-diklorfenil)-2-propenala (36,2 g, 0,18 mola) u THF (100 ml), a dobivena smjesa je miješana 16 sati pri sobnoj temperaturi. Smjesa je filtrirana, a filtrat je koncentriran u vakuumu dajući ostatak. Pročišćavanjem "flash" kromatografijom (silikagel, 20 % EtOAc/heksan) je dobiveno 16,0 g (0,05 mola, 28 %) željenog produkta. T.t. = 125-135 °C A mixture of 4-nitrobenzyl bromide (200.0 g, 0.93 mol) and triphenylphosphine (244.0 g, 0.93 mol) in CHCl 3 (1.5 L) was refluxed overnight. The reaction mixture was cooled to room temperature, evaporated in vacuo to remove CHCl3, then suspended in Et2O and stirred vigorously. The suspension was filtered and the off-white solid was washed with Et 2 O, dried at 80 °C for 16 h to give 433.0 g (0.91 mol, 98 %) of bromo[(4-nitrophenyl)methyl]triphenylphosphorane. A solution of bromo[(4-nitrophenyl)methyl]triphenylphosphorane (100.0 g, 0.23 mol) in dry THF (500 mL) was cooled to 5 °C. n-Butyllithium (n-BuLi) (2.4 M, 96 ml, 0.23 mol) was added dropwise while maintaining the temperature between 5 and 10 °C. The cooling bath was then removed and the reaction mixture was allowed to reach room temperature. After 4 hours, a solution of trans-3-(3,4-dichlorophenyl)-2-propenal (36.2 g, 0.18 mol) in THF (100 ml) was added dropwise, and the resulting mixture was stirred for 16 hours at room temperature . The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. Purification by flash chromatography (silica gel, 20% EtOAc/hexane) afforded 16.0 g (0.05 mol, 28%) of the desired product. T.t. = 125-135 °C

Analiza za C16H11Cl2NO2: Rač.: C, 60,02; H, 3,46; N, 4,37; Cl, 22,15. Analysis for C16H11Cl2NO2: Sol.: C, 60.02; H, 3.46; N, 4.37; Cl, 22,15.

Nađeno: C, 59,77; H, 3,47; N, 4,40; Cl, 22,39. Found: C, 59.77; H, 3.47; N, 4.40; Cl, 22,39.

Priprava 4-[4-(3,4-diklorfenil)butil]fenilamina. Preparation of 4-[4-(3,4-dichlorophenyl)butyl]phenylamine.

Naslovni spoj je pripravljen iz trans,trans-1,2-diklor-4-[4-(4-nitrofenil)-1,3-butadienil]benzena (15,42 g, 0,048 mola), Ra-Ni (1 g) u THF (75 ml) i MeOH (75 ml) pri 20 °C do 26 °C (�P = 134,8 kPa) u atmosferi vodika primjenjujući postupak opisan u Primjeru 1, Korak B. Ovaj postupak daje 10,97 g (0,037 mola, 78 %) krutog željenog produkta. T.t. = 50-52 °C. The title compound was prepared from trans,trans-1,2-dichloro-4-[4-(4-nitrophenyl)-1,3-butadienyl]benzene (15.42 g, 0.048 mol), Ra-Ni (1 g) in THF (75 ml) and MeOH (75 ml) at 20 °C to 26 °C (�P = 134.8 kPa) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure gave 10.97 g ( 0.037 mol, 78 %) solid desired product. T.t. = 50-52 °C.

Analiza za C16H17N1Cl2: Rač.: C, 65,32; H, 5,82; N, 4,76. Analysis for C16H17N1Cl2: Sol.: C, 65.32; H, 5.82; N, 4.76.

Nađeno: C, 65,43; H, 5,84; N, 4,61. Found: C, 65.43; H, 5.84; N, 4.61.

Priprava 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}benzojeve kiseline. Preparation of 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}benzoic acid.

Naslovni spoj, T.t. = 98-105 °C, je pripravljen iz 4-[4-(3,4-diklorfenil)butil]fenilamina (0,50 g, 1,7 mmola), 2-klorbenzojeve kiseline (0,24 g, 1,56 mmola), bezvodnog kalijevog karbonata (0,71 g, 5,15 mmola), bakra u prahu (0,21 g, 3,28 mmola) i bakrovog(I) klorida (0,015 g, 0,15 mmola) u suhom DMF (5 ml) prema postupku opisanom u Primjeru 1, Korak C, Metoda B. Title compound, T.t. = 98-105 °C, was prepared from 4-[4-(3,4-dichlorophenyl)butyl]phenylamine (0.50 g, 1.7 mmol), 2-chlorobenzoic acid (0.24 g, 1.56 mmol), anhydrous potassium carbonate (0.71 g, 5.15 mmol), powdered copper (0.21 g, 3.28 mmol) and copper(I) chloride (0.015 g, 0.15 mmol) in dry DMF (5 ml) according to the procedure described in Example 1, Step C, Method B.

PRIMJER 11 EXAMPLE 11

Priprava 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-5-nitrobenzoic acid.

Smjesa 2-fluor-5-nitrobenzojeve kiseline (1,85 g, 0,01 mol), 4-[4-(3,4-diklorfenil)butil]fenilamina (2,94 g, 0,01 mola) i Et3N (2,80 ml) u acetonitrilu (110 ml) je refluksirana tijekom 48 sati. Reakcijska smjesa je zatim ohlađena, i uparena u vakuumu. Ostatak je otopljen u CH2Cl2 i ispran s razrijeđenom HCl. Organski sloj je osušen (Na2SO4) i koncentriran u vakuumu dajući sirovu krutinu. Pročišćavanjem "flash" kromatografijom (silikagel, CH2Cl2) dobiveno je 1,40 g (0,003 mola, 30 %) željenog produkta. A mixture of 2-fluoro-5-nitrobenzoic acid (1.85 g, 0.01 mol), 4-[4-(3,4-dichlorophenyl)butyl]phenylamine (2.94 g, 0.01 mol) and Et3N ( 2.80 ml) in acetonitrile (110 ml) was refluxed for 48 hours. The reaction mixture was then cooled, and evaporated in vacuo. The residue was dissolved in CH2Cl2 and washed with dilute HCl. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a crude solid. Purification by "flash" chromatography (silica gel, CH2Cl2) gave 1.40 g (0.003 mol, 30 %) of the desired product.

Analiza za C23H19N2O4Cl2: Rač.: C, 60,27; H, 4,18; N, 6,11; Cl, 14,47. Analysis for C23H19N2O4Cl2: Sol.: C, 60.27; H, 4.18; N, 6.11; Cl, 14,47.

Nađeno: C, 60,16; H, 4,41; N, 6,09; Cl, 15,69. Found: C, 60.16; H, 4.41; N, 6.09; Cl, 15.69.

PRIMJER 12 EXAMPLE 12

Priprava 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-3,5-dinitrobenzojeve kiseline. Preparation of 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-3,5-dinitrobenzoic acid.

U ohlađenu (0 °C) otopinu 4-[4-(3,4-diklorfenil)butil]fenilamina (1,47 g, 5,0 mmola) i DBU (0,75 ml, 7,5 mmola) u acetonitrilu (25 ml), dokapana je otopina 2-fluor-2,5-dinitrobenzojeve kiseline (1,15 g, 5,0 mmola) u acetonitrilu (15 ml). Nakon miješanja tijekom 30 minuta pri 0 °C, reakcijska smjesa je neutralizirana s razrijeđenom HCl i ekstrahirana s EtOAc, osušena (Na2SO4), filtrirana i uparena na vakuumu, pri čemu je dobiven sirovi ostatak. Rekristalizacija iz EtOH je dala 2,06 g (4,1 mmola, 82 %) naslovnog spoja u obliku jarko narančaste krutine. To a cooled (0 °C) solution of 4-[4-(3,4-dichlorophenyl)butyl]phenylamine (1.47 g, 5.0 mmol) and DBU (0.75 mL, 7.5 mmol) in acetonitrile ( 25 ml), a solution of 2-fluoro-2,5-dinitrobenzoic acid (1.15 g, 5.0 mmol) in acetonitrile (15 ml) was added dropwise. After stirring for 30 min at 0 °C, the reaction mixture was neutralized with dilute HCl and extracted with EtOAc, dried (Na 2 SO 4 ), filtered and evaporated in vacuo to give a crude residue. Recrystallization from EtOH gave 2.06 g (4.1 mmol, 82%) of the title compound as a bright orange solid.

Analiza za C23H19Cl2N3O6: Rač.: C, 54,77; H, 3,80; N, 8,33; Cl, 14,06. Analysis for C23H19Cl2N3O6: Sol.: C, 54.77; H, 3.80; N, 8.33; Cl, 14.06.

Nađeno: C, 54,68; H, 4,00; N, 8,12; Cl, 13,81. Found: C, 54.68; H, 4.00; N, 8.12; Cl, 13.81.

PRIMJER 13 EXAMPLE 13

Priprava 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid.

Priprava brom(3,4-diklorfenil)metil]trifenilfosforana. Preparation of bromo(3,4-dichlorophenyl)methyl]triphenylphosphorane.

Smjesa 4-brommetil-1,2-diklorbenzena (2,40 g, 0,01 mol) i trifenilfosfina (5,24 g, 0,02 mol) u toluenu (30 ml) je miješana 16 sati pri sobnoj temperaturi. Krutina je filtrirana, isprana s toluenom i sušena u sušioniku pri sobnoj temperaturi dajući 3,95 g (0,0078 mola, 78 %) željenog produkta u obliku bijelog praha. A mixture of 4-bromomethyl-1,2-dichlorobenzene (2.40 g, 0.01 mol) and triphenylphosphine (5.24 g, 0.02 mol) in toluene (30 mL) was stirred for 16 hours at room temperature. The solid was filtered, washed with toluene and dried in a desiccator at room temperature to give 3.95 g (0.0078 mol, 78 %) of the desired product as a white powder.

1H NMR [dimetilsulfoksid (DMSO): ppm]: 7,89-7,61 (m, 15H), 7,50 (d, J=8,3 Hz, 1H), 7,04 (t, J=2,3 Hz, 1H), 6,97 (m, 1H), 5,20 (d, J=15,9 Hz, 2H). 1H NMR [dimethylsulfoxide (DMSO): ppm]: 7.89-7.61 (m, 15H), 7.50 (d, J=8.3 Hz, 1H), 7.04 (t, J=2, 3 Hz, 1H), 6.97 (m, 1H), 5.20 (d, J=15.9 Hz, 2H).

Priprava 4-(4-nitrofenil)butiraldehida. Preparation of 4-(4-nitrophenyl)butyraldehyde.

U ohlađenu otopinu (-70 °C) oksalil klorida (2,0 M u CH2Cl2, 14,1 ml, 28,2 mmola), dokapan je dimetilsulfoksid (DMSO) (4,40 g, 56,32 mmola) u CH2Cl2. Dobivena reakcijska smjesa je zatim miješana 30 minuta pri -70 °C u atmosferi dušika. Dokapana je otopina 4-(4-nitrofenil)butan-1-ola (5,00 g, 25,6 mmola) u CH2Cl2 (3 ml) te je reakcijska smjesa miješana još 1 sat pri -70 °C. Tada je dodan Et3N (16 ml, 115 mmola), a reakcijska smjesa je ostavljena da postigne sobnu temperaturu i miješana dodatnih 30 minuta. Reakcija je tada zaustavljena s H2O i ekstrahirana s EtOAc. Organski slojevi su isprani s 0,1N otopinom HCl, H2O, zasićenom otopinom NaCl, osušeni (Na2SO4), filtrirani i upareni u vakuumu dajući svijetlosmeđe ulje. Pročišćavanje "flash" kromatografijom (silikagel, 50 % EtOAc/heksan) je dalo 3,20 g (16,56 mmola, 65 %) željenog produkta. To a cooled solution (-70 °C) of oxalyl chloride (2.0 M in CH2Cl2, 14.1 ml, 28.2 mmol), dimethylsulfoxide (DMSO) (4.40 g, 56.32 mmol) in CH2Cl2 was added dropwise. The resulting reaction mixture was then stirred for 30 minutes at -70 °C under a nitrogen atmosphere. A solution of 4-(4-nitrophenyl)butan-1-ol (5.00 g, 25.6 mmol) in CH2Cl2 (3 ml) was added dropwise and the reaction mixture was stirred for another 1 hour at -70 °C. Et3N (16 mL, 115 mmol) was then added and the reaction mixture was allowed to reach room temperature and stirred for an additional 30 min. The reaction was then quenched with H 2 O and extracted with EtOAc. The organic layers were washed with 0.1N HCl, H2O, saturated NaCl, dried (Na2SO4), filtered and evaporated in vacuo to give a light brown oil. Purification by flash chromatography (silica gel, 50% EtOAc/hexane) afforded 3.20 g (16.56 mmol, 65%) of the desired product.

1H NMR (DMSO:ppm): 9,75 (s, 1H), 8,12 (d, J=8,3 Hz, 2H), 7,30 (d, J=8,3 Hz, 2H), 2,72 (t, J=7,7 Hz, 2H), 2,47 (t, J=7,1 Hz, 2H), 1,94 (m, 2H). 1H NMR (DMSO:ppm): 9.75 (s, 1H), 8.12 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 2 .72 (t, J=7.7 Hz, 2H), 2.47 (t, J=7.1 Hz, 2H), 1.94 (m, 2H).

Priprava 1,2-diklor-4-[5-(4-nitrofenil)-1-pentenil]benzena. Preparation of 1,2-dichloro-4-[5-(4-nitrophenyl)-1-pentenyl]benzene.

Otopina brom(3,4-diklorfenil)metil]trifenilfosforana (3,95 g, 7,9 mmola) u suhom THF (20 ml) je ohlađena na 0 °C. LHDMS (1.0 M/THF, 9 ml, 9,0 mmola) je dokapan u otopinu uz održavanje temperature pri 0 °C. Nakon 30 minuta miješanja, dokapana je otopina 4-(4-nitrofenil)butiraldehida (1,45 g, 7,5 mmola) u THF (5 ml), a smjesa je ostavljena da postigne sobnu temperaturu tijekom 2 sata. Reakcija je tada zaustavljena dodavanjem H2O i ekstrahirana s EtOAc. Organski slojevi su isprani s 0,1 N otopinom HCl, H2O, zasićenom otopinom NaCl, osušeni (Na2SO4), filtrirani i upareni u vakuumu dajući svijetlosmeđe ulje. Pročišćavanje "flash" kromatografijom (silikagel, 10 % EtOAc/heksan) je dalo 2,5 g (7,4 mmola, 99 %) željenog produkta. A solution of bromo(3,4-dichlorophenyl)methyl]triphenylphosphorane (3.95 g, 7.9 mmol) in dry THF (20 mL) was cooled to 0 °C. LHDMS (1.0 M/THF, 9 ml, 9.0 mmol) was added dropwise to the solution while maintaining the temperature at 0 °C. After stirring for 30 min, a solution of 4-(4-nitrophenyl)butyraldehyde (1.45 g, 7.5 mmol) in THF (5 mL) was added dropwise, and the mixture was allowed to reach room temperature over 2 h. The reaction was then quenched by addition of H 2 O and extracted with EtOAc. The organic layers were washed with 0.1N HCl, H2O, saturated NaCl, dried (Na2SO4), filtered and evaporated in vacuo to give a light brown oil. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) afforded 2.5 g (7.4 mmol, 99%) of the desired product.

MS: 335 (M+), 337 (MH+). MS: 335 (M + ), 337 (MH + ).

Priprava 4-[5-(3,4-diklorfenil)pentil]fenilamina. Preparation of 4-[5-(3,4-dichlorophenyl)pentyl]phenylamine.

Naslovni spoj je pripravljen iz 1,2-diklor-4-[5-(4-nitrofenil)-1-pentenil]benzena (2,5 g, 7,4 mmola) i Ra-Ni (1 g) u THF (50 ml) pri 25 °C do 40 °C (�P = 69,2 kPa) prema postupku opisanom u Primjeru 1, Korak B. Ovaj postupak je dao 1,06 g (3,4 mmola, 46 %) željenog produkta. The title compound was prepared from 1,2-dichloro-4-[5-(4-nitrophenyl)-1-pentenyl]benzene (2.5 g, 7.4 mmol) and Ra-Ni (1 g) in THF (50 ml) at 25 °C to 40 °C (�P = 69.2 kPa) according to the procedure described in Example 1, Step B. This procedure gave 1.06 g (3.4 mmol, 46 %) of the desired product.

1H NMR (DMSO:ppm): 7,45 (d, J=8,3 Hz, 1H), 7,41 (d, J=2,2 Hz, 1H), 7,12 (m, 1H), 6,74 (d, J=8,3 Hz, 2H), 6,40 (d, J=8,3 Hz, 2H), 4,73 (s, 2H), 2,50 (t, J=7,7 Hz, 2H), 2,31 (t, J=7,6 Hz, 2H), 1,6-1,5 (m, 4H), 1,5-1,4 (m, 2H). 1H NMR (DMSO:ppm): 7.45 (d, J=8.3 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.12 (m, 1H), 6 .74 (d, J=8.3 Hz, 2H), 6.40 (d, J=8.3 Hz, 2H), 4.73 (s, 2H), 2.50 (t, J=7, 7 Hz, 2H), 2.31 (t, J=7.6 Hz, 2H), 1.6-1.5 (m, 4H), 1.5-1.4 (m, 2H).

Priprava 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid.

U ohlađenu otopinu (-78 °C) 4-[5-(3,4-diklorfenil)pentil]fenilamina (0,231 g, 0,75 mmola) u THF (2 ml), dokapan je LHDMS (2,25 ml, 1M u heksanu, 2,25 mmola). Reakcijska smjesa je mješana 10 minuta pri -78 °C. Dokapana je otopina 2-fluor-5-nitrobenzojeve kiseline (0,139 g, 0,75 mmola), a nastala otopina je dalje miješana 30 minuta pri -78 °C. Nakon toga, reakcijska smjesa je ostavljena da postepeno postigne sobnu temperaturu i mješana slijedećih 2 sata u atmosferi dušika. Reakcijska smjesa je razrijeđena s EtOAc, zakiseljena s 1M HCl (pH = 3). Organski sloj je osušen (Na2SO4), filtriran i uparen u vakuumu dajući smeđi ostatak.Pročišćavanjem "flash" kromatografijom (silikagel, 2 % MeOH/CH2Cl2) a zatim rekristalizacijom iz MeOH dobiveno je 265 mg (0,56 mmola, 75 %) željenog produkta. To a cooled solution (-78 °C) of 4-[5-(3,4-dichlorophenyl)pentyl]phenylamine (0.231 g, 0.75 mmol) in THF (2 mL), LHDMS (2.25 mL, 1M in hexane, 2.25 mmol). The reaction mixture was stirred for 10 minutes at -78 °C. A solution of 2-fluoro-5-nitrobenzoic acid (0.139 g, 0.75 mmol) was added dropwise, and the resulting solution was further stirred for 30 minutes at -78 °C. After that, the reaction mixture was allowed to gradually reach room temperature and stirred for the next 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc, acidified with 1M HCl (pH = 3). The organic layer was dried (Na2SO4), filtered and evaporated in vacuo to give a brown residue. Purification by "flash" chromatography (silica gel, 2% MeOH/CH2Cl2) and then recrystallization from MeOH gave 265 mg (0.56 mmol, 75%) of the desired product.

T.t. = 147-148 °C. T.t. = 147-148 °C.

Analiza za C24H22Cl2N2O4 x 0,37 H2O: Rač.: C, 60,05; H, 4,77; N, 5,84. Analysis for C24H22Cl2N2O4 x 0.37 H2O: Sol.: C, 60.05; H, 4.77; N, 5.84.

Nađeno: C, 59,67; H, 4,64; N, 5,51. Found: C, 59.67; H, 4.64; N, 5.51.

PRIMJER 14 EXAMPLE 14

Priprava 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline. Preparation of 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid.

Priprava metilnog estera 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline. Preparation of methyl ester of 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid.

Naslovni spoj je pripravljen iz 4-[5-(3,4-diklorfenil)pentil]fenilamina (231 mg, 0,75 mmola), LHDMS (6,28 ml, 1M u THF, 6,28 mmola) i metilnog estera 2-fluor-4-metoksi-5-nitrobenzojeve kiseline (172 mg, 0,75 mmola) u THF (5 ml) prema postupku opisanom u Primjeru 13. Pročišćavanje "flash" kromatografijom (silikagel, 10 % EtOAc/heksan) je dalo 145 mg (0,28 mmola, 37 %) željenog produkta. The title compound was prepared from 4-[5-(3,4-dichlorophenyl)pentyl]phenylamine (231 mg, 0.75 mmol), LHDMS (6.28 ml, 1M in THF, 6.28 mmol) and methyl ester 2 -fluoro-4-methoxy-5-nitrobenzoic acid (172 mg, 0.75 mmol) in THF (5 ml) according to the procedure described in Example 13. Purification by "flash" chromatography (silica gel, 10% EtOAc/hexane) gave 145 mg (0.28 mmol, 37 %) of the desired product.

MS: 515,2 (M+) 517,2 (MH+). MS: 515.2 (M + ) 517.2 (MH + ).

Priprava 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline. Preparation of 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid.

Naslovni spoj je pripravljen iz metilnog estera 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzojeve kiseline (145 mg, 0,28 mmola) i 1M NaOH (vodena otopina) (0,56 ml) u THF (1,2 ml) prema postupku opisanom u Primjeru 2. Pročišćavanjem "flash" kromatografijom (silikagel, 10 % MeOH/CH2Cl2), a zatim rekristalizacijom iz MeOH dobiveno je 58 mg (0,12 mmola, 41 %) željenog produkta. T.t. = 192-193 °C. The title compound was prepared from 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid methyl ester (145 mg, 0.28 mmol) and 1M NaOH (aq ) (0.56 ml) in THF (1.2 ml) according to the procedure described in Example 2. Purification by "flash" chromatography (silica gel, 10% MeOH/CH2Cl2) and then recrystallization from MeOH gave 58 mg (0.12 mmol, 41 %) of the desired product. T.t. = 192-193 °C.

Analiza za C25H24Cl2N2O5: Rač.: C, 59,65; H, 4,81; N, 5,56. Analysis for C25H24Cl2N2O5: Sol.: C, 59.65; H, 4.81; N, 5.56.

Nađeno: C, 59,29; H, 4,58; N, 5,36. Found: C, 59.29; H, 4.58; N, 5.36.

PRIMJER 15 EXAMPLE 15

Priprava 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid.

Priprava metilnog estera 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of methyl ester of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid.

Naslovni spoj je pripravljen iz 4-[3-(3,4-diklorfenil)propil]fenilamina (420 mg, 1,50 mmola), metilnog estera 2-brombenzojeve kiseline (310 mg, 1,25 mmola), cezijevog karbonata (569 mg, 1,75 mmola), tris(dibenzilidenaceton dipaladija(0)) (34 mg, 0,037 mmola) i (S)-(2,2'-bis(di-p-tolilfosfino-1,1'-binaftil))(98 % (S)-tol-BINAP) (38 mg, 0,056 mmola) (Ligand/Pd = 1,5) u bezvodnom toluenu (15 ml) prema postupku opisanom u Primjeru 2, Korak C. Ovaj postupak je dao 0,51 g (1,11 mmola, 74 %) željenog produkta u obliku narančaste krutine. T.t. = 117-118 °C. The title compound was prepared from 4-[3-(3,4-dichlorophenyl)propyl]phenylamine (420 mg, 1.50 mmol), 2-bromobenzoic acid methyl ester (310 mg, 1.25 mmol), cesium carbonate (569 mg, 1.75 mmol), tris(dibenzylideneacetone dipalladium(0)) (34 mg, 0.037 mmol) and (S)-(2,2'-bis(di-p-tolylphosphino-1,1'-binaphthyl)) (98 % (S)-tol-BINAP) (38 mg, 0.056 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (15 ml) according to the procedure described in Example 2, Step C. This procedure gave 0, 51 g (1.11 mmol, 74 %) of the desired product as an orange solid. T.t. = 117-118 °C.

MS: 457.1 (M+); 459,1 (MH+) MS: 457.1 (M+); 459.1 (MH+)

Priprava 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid.

Naslovni spoj je pripravljen iz metilnog estera 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzojeve kiseline (0,50 g, 1,09 mmola), 2M NaOH (5,0 ml) u EtOH (2 ml) i THF (4 ml) prema postupku opisanom u Primjeru 2. Ovaj postupak je dao 0,49 g (1,10 mmola, 100 %) željenog produkta u obliku narančaste krutine. T.t. = 153-155 °C. The title compound was prepared from 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid methyl ester (0.50 g, 1.09 mmol), 2M NaOH (5.0 ml ) in EtOH (2 ml) and THF (4 ml) according to the procedure described in Example 2. This procedure gave 0.49 g (1.10 mmol, 100%) of the desired product as an orange solid. T.t. = 153-155 °C.

MS: 443.2 (M+); 445,2 (MH+) MS: 443.2 (M+); 445.2 (MH+)

PRIMJER 16 EXAMPLE 16

Priprava 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid.

Priprava metilnog estera 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of methyl ester of 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid.

Naslovni spoj je pripravljen iz 4-[2-(3,4-dimetilfenil)etil]benzenamina (1,0 g, 4,43 mmola), metilnog estera 2-brom-5-nitrobenzojeve kiseline (0,96 g, 3,69 mmola), cezijevog karbonata (1,68 g, 5,17 mmola), tris(dibenzilidenaceton dipaladija(0)) (101 mg, 0,11 mmola) i (S)-(2,2'-bis(di-p-tolilfosfino-1,1'-binaftil))(98 % (S)-tol-BINAP) (113 mg, 0,17 mmola) (Ligand/Pd = 1,5) u bezvodnom toluenu (32 ml) prema postupku opisanom u Primjeru 2, Korak C. Ovaj postupak je dao 1,31 g (3,24 mmol, 73 %) željenog produkta u obliku žute krutine. T.t. = 115-117 °C. The title compound was prepared from 4-[2-(3,4-dimethylphenyl)ethyl]benzenamine (1.0 g, 4.43 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (0.96 g, 3, 69 mmol), cesium carbonate (1.68 g, 5.17 mmol), tris(dibenzylideneacetone dipalladium(0)) (101 mg, 0.11 mmol) and (S)-(2,2'-bis(di- p-tolylphosphino-1,1'-binaphthyl))(98% (S)-tol-BINAP) (113 mg, 0.17 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (32 ml) according to procedure described in Example 2, Step C. This procedure afforded 1.31 g (3.24 mmol, 73%) of the desired product as a yellow solid. T.t. = 115-117 °C.

405 (M+). 405 (M+).

Analiza za C24H24O4N2 x 0,25 H2O: Rač.: C, 71,27; H, 5,98; N, 6,93. Analysis for C24H24O4N2 x 0.25 H2O: Cal.: C, 71.27; H, 5.98; N, 6.93.

Nađeno: C, 70,48; H, 6,03; N, 6,85. Found: C, 70.48; H, 6.03; N, 6.85.

Priprava 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzojeve kiseline. Preparation of 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid.

Naslovni spoj je pripravljen iz metilnog estera 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzojeve kiseline (1,12 g, 2,76 mmola), 1M NaOH (50 ml) u EtOH (50 ml) i THF (50 ml) prema postupku opisanom u Primjeru 2. Ovaj postupak je dao 1,03 g (2,63 mmol, 81 %) željenog produkta u obliku žute krutine. T.t. = 214-216 °C. The title compound was prepared from 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid methyl ester (1.12 g, 2.76 mmol), 1M NaOH (50 ml) in EtOH (50 ml) and THF (50 ml) according to the procedure described in Example 2. This procedure gave 1.03 g (2.63 mmol, 81%) of the desired product as a yellow solid. T.t. = 214-216 °C.

Analiza za C23H22O4N2 x 0,25 H2O: Rač.: C, 69,99; H, 5,74; N, 7,18. Analysis for C23H22O4N2 x 0.25 H2O: Sol.: C, 69.99; H, 5.74; N, 7,18.

Nađeno: C, 69,90; H, 5,82; N, 6,81. Found: C, 69.90; H, 5.82; N, 6.81.

PRIMJER 17 EXAMPLE 17

Priprava 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenil}aminobenzojeve kiseline. Preparation of 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenyl}aminobenzoic acid.

Korak A (Shema 1): Priprava trans-1-klor-2-trifluormetil-4-[2-(4-nitrofenil)etenil]benzena. Step A (Scheme 1): Preparation of trans-1-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene.

Smjesa p-nitrofeniloctene kiseline (51,85 g, 0,29 mola) i 4-klor-3-triflormetilbenzaldehida (47,85 g, 0,23 mola) u piperidinu (19,5 g, 0,23 mola) je zagrijavana 1 sat u atmosferi dušika pri 150-160 °C. Reakcijska smjesa je ohlađena na 80 °C do 100 °C te je dodan i-PrOH (150 ml), prethodno zagrijan do vrenja. Smjesa je dalje hlađena do sobne temperature, a zatim ostavljena 5 sati u hladioniku. Kristalni talog je otfiltriran, ispran hladnim i-PrOH, osušen na sobnoj temperaturi u sušioniku pod vakuumom, preko noći, dajući 22,53 g (68,75 mmola, 30 %) trans-1-klor-2-trifluormetil-4-[2-(4-nitrofenil)etenil]benzena u obliku narančaste krutine. T.t. = 173-174 °C. A mixture of p-nitrophenylacetic acid (51.85 g, 0.29 mol) and 4-chloro-3-trifluoromethylbenzaldehyde (47.85 g, 0.23 mol) in piperidine (19.5 g, 0.23 mol) was heated 1 hour in a nitrogen atmosphere at 150-160 °C. The reaction mixture was cooled to 80 °C to 100 °C and i-PrOH (150 ml), previously heated to boiling, was added. The mixture was further cooled to room temperature and then left for 5 hours in the refrigerator. The crystalline precipitate was filtered off, washed with cold i-PrOH, dried at room temperature in a desiccator under vacuum overnight, yielding 22.53 g (68.75 mmol, 30%) of trans-1-chloro-2-trifluoromethyl-4-[ 2-(4-nitrophenyl)ethenyl]benzene as an orange solid. T.t. = 173-174 °C.

MS: 327,0 (M+). MS: 327.0 (M+).

Korak B (Shema 1): Priprava 4-[2-(4-klor-3-trifluormetilfenil)etil]benzenamina. Step B (Scheme 1): Preparation of 4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]benzenamine.

Naslovni spoj je pripravljen iz trans-1-klor-2-trifluormetil-4-[2-(4-nitrofenil)etenil]benzena (22,53 g, 0,069 mola) i Ra-Ni (22 g) u THF (0,5 l) pri 18 °C do 29 °C (�P = 143,2 kPa) u atmosferi vodika prema postupku opisanom u Primjeru 1, korak B. Ovaj postupak je dao 20,0 g (66,73 mmola, 97 %) željenog produkta u obliku bijele krutine. T.t. = 62-64 °C. The title compound was prepared from trans-1-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene (22.53 g, 0.069 mol) and Ra-Ni (22 g) in THF (0, 5 l) at 18 °C to 29 °C (�P = 143.2 kPa) under a hydrogen atmosphere according to the procedure described in Example 1, step B. This procedure gave 20.0 g (66.73 mmol, 97 %) of the desired product in the form of a white solid. T.t. = 62-64 °C.

MS: 298,1 (M+). MS: 298.1 (M+).

Priprava 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenil}aminobenzojeve kiseline. Preparation of 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenyl}aminobenzoic acid.

U hladnu otopinu 4-[2-(4-klor-3-trifluormetilfenil)etil]benzenamina (4,33 g, 14,45 mmola) u THF (50 ml) pri 78 °C dokapan je LHDMS (43,35 ml, 43,35 mmola) (1M/THF). Reakcijska smjesa je miješana 10 minuta pri 78 °C. Tada je dokapana otopina 2-fluorbenzojeve kiseline (2,02 g, 14,45 mmola) u THF (50 ml). Smjesa je dalje miješana 2 sata pri 78 °C, a zatim je ostavljena da postigne sobnu temperaturu i dodatno miješana 3 sata. Reakcijska smjesa je koncentrirana u vakuumu (40 °C), pri čemu je uklonjeno organsko otapalo. Ostatak je zakiseljen do pH = 3 s 3M HCl (vodena otopina). Talog je otfiltriran, ispran 10 %-tnom HCl (40 ml) i sušen u vakuumu preko noći dajući 4,3 g (10,24 mmola, 70 %) željenog spoja u obliku svjetle krutine. T.t. = 150-152 °C. To a cold solution of 4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]benzenamine (4.33 g, 14.45 mmol) in THF (50 ml) at 78 °C was added LHDMS (43.35 ml, 43.35 mmol) (1M/THF). The reaction mixture was stirred for 10 minutes at 78 °C. A solution of 2-fluorobenzoic acid (2.02 g, 14.45 mmol) in THF (50 ml) was then added dropwise. The mixture was further stirred for 2 hours at 78 °C and then allowed to reach room temperature and stirred for an additional 3 hours. The reaction mixture was concentrated in vacuo (40 °C), removing the organic solvent. The residue was acidified to pH = 3 with 3M HCl (aqueous solution). The precipitate was filtered off, washed with 10% HCl (40 mL) and dried in vacuo overnight to give 4.3 g (10.24 mmol, 70%) of the desired compound as a light solid. T.t. = 150-152 °C.

Analiza za C22H17O2NClF3 x 0,59 H2O: Rač.: C, 61,39; H, 4,26; N, 3,25. Analysis for C 22 H 17 O 2 NClF 3 x 0.59 H 2 O: Calc.: C, 61.39; H, 4.26; N, 3.25.

Nađeno: C, 61,01; H, 4,34; N, 3,30. Found: C, 61.01; H, 4.34; N, 3.30.

PRIMJER 18 EXAMPLE 18

Priprava 2-[4-(3,4-diklorfenil)fenilamino]benzojeve kiseline. Preparation of 2-[4-(3,4-dichlorophenyl)phenylamino]benzoic acid.

Priprava kalijeve soli o-brombenzojeve kiseline Preparation of the potassium salt of o-bromobenzoic acid

U otopinu o-brombenzojeve kiseline (201,03 g, 1,0 mola) u MeOH (500 ml), dodan je K2CO3 (69 g, 1,0 mola). Smjesa je koncentrirana dajući željeni produkt (239,1 g, 1.0 mola, 100 %). To a solution of o-bromobenzoic acid (201.03 g, 1.0 mol) in MeOH (500 mL), K 2 CO 3 (69 g, 1.0 mol) was added. The mixture was concentrated to give the desired product (239.1 g, 1.0 mol, 100 %).

Priprava 2-[(4-jodofenil)amino]benzojeve kiseline. Preparation of 2-[(4-iodophenyl)amino]benzoic acid.

Smjesa kalijeve soli o-brombenzojeve kiseline (47,8 g, 0,2 mola), 4-jodanilina (43,8 g, 0,2 mola), K2CO3 (13,8 g, 0,1 mola) i bakrovog(II) acetata (2,87 g, 6 %) u diglimu (100 ml) je refluksirana 30 minuta. Reakcijska smjesa je razrijeđena s H2O (1,0 l) i filtrirana. Filtrat je zakiseljen s razrijeđenom AcOH. Nastali talog je otfiltriran, ispran s H2O i sušen u vakuumu pri 50 °C tijekom 16 sati. Rekristalizacija iz EtOAc je dala kruti željeni produkt (29,7 g, 0,087 mola, 44 %). T.t. = 205-206 °C. A mixture of the potassium salt of o-bromobenzoic acid (47.8 g, 0.2 mol), 4-iodaniline (43.8 g, 0.2 mol), K2CO3 (13.8 g, 0.1 mol) and copper(II ) of acetate (2.87 g, 6 %) in diglyme (100 ml) was refluxed for 30 minutes. The reaction mixture was diluted with H 2 O (1.0 L) and filtered. The filtrate was acidified with dilute AcOH. The resulting precipitate was filtered off, washed with H2O and dried in vacuum at 50 °C for 16 hours. Recrystallization from EtOAc gave the solid desired product (29.7 g, 0.087 mol, 44 %). T.t. = 205-206 °C.

Analiza za C13H10NO2I: Rač.: C, 45,05; H, 2,97; N, 4,13. Analysis for C13H10NO2I: Sol.: C, 45.05; H, 2.97; N, 4.13.

Nađeno: C, 45,05; H, 2,97; N, 3,92. Found: C, 45.05; H, 2.97; N, 3.92.

Priprava 2-[4-(3,4-diklorfenil)fenilamino]benzojeve kiseline. Preparation of 2-[4-(3,4-dichlorophenyl)phenylamino]benzoic acid.

Smjesa 3,4-diklorfenilborne kiseline (880 mg, 2,3 mmola), 2-[(4-jodofenil)amino]benzojeve kiseline (339 mg, 1 mmol), PdCl2 x dppf x CH2Cl2 [1,1'-bis(difenilfosfino)ferocen paladijev(II) klorid, kompleksiran s diklormetanom (1:1)] (67 mg, 0,082 mmola), K2CO3 (829 mg, 6 mmola) i H2O (2 ml) u dioksanu (15 ml) refluksirana je 1 sat. Reakcijska smjesa je je razrijeđena s EtOAc i filtrirana. Filtrat je obrađen s 1M HCl, ispran s H2O, zasićenom otopinom NaCl, osušen (Na2SO4) i koncentriran u vakumu dajući žutu krutinu. Pročišćavanje "flash" kromatografijom (silikagel, 10 % MeOH/CH2Cl2) dalo je 272 mg (0,76 mmola, 76 %) željenog produkta. T.t. >220 °C. A mixture of 3,4-dichlorophenylboronic acid (880 mg, 2.3 mmol), 2-[(4-iodophenyl)amino]benzoic acid (339 mg, 1 mmol), PdCl2 x dppf x CH2Cl2 [1,1'-bis( diphenylphosphino)ferrocene palladium(II) chloride, complexed with dichloromethane (1:1)] (67 mg, 0.082 mmol), K2CO3 (829 mg, 6 mmol) and H2O (2 ml) in dioxane (15 ml) was refluxed for 1 hour . The reaction mixture was diluted with EtOAc and filtered. The filtrate was treated with 1M HCl, washed with H2O, saturated NaCl solution, dried (Na2SO4) and concentrated in vacuo to give a yellow solid. Purification by flash chromatography (silica gel, 10% MeOH/CH2Cl2) afforded 272 mg (0.76 mmol, 76%) of the desired product. T.t. >220 °C.

Analiza za C19H13O2NCl2: Rač.: C, 63,23; H, 3,71; N, 3,88. Analysis for C19H13O2NCl2: Sol.: C, 63.23; H, 3.71; N, 3.88.

Nađeno: C, 62,95; H, 3,73; N, 3,63. Found: C, 62.95; H, 3.73; N, 3.63.

Primjenom gore opisanih općih postupaka, pripravljeni su slijedeći dodatni spojevi iz izuma: By applying the general procedures described above, the following additional compounds of the invention were prepared:

PRIMJER 19 EXAMPLE 19

2-{4-[3-(4-Dietilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 403 (M+). MS: 403 (M+).

Analiza za C26H30N2O2 x 0,40 mol H2O: Rač.: C, 69,31; H, 6,87; N, 6,12. Analysis for C26H30N2O2 x 0.40 mol H2O: Calc.: C, 69.31; H, 6.87; N, 6,12.

Nađeno: C, 69,29; H, 7,04; N, 6,35. Found: C, 69.29; H, 7.04; N, 6.35.

PRIMJER 20 EXAMPLE 20

2-{4-[3-(4-Nitrofenil)propil]fenilamino}benzoeva kiselina. T.t. 150-153 °C. 2-{4-[3-(4-Nitrophenyl)propyl]phenylamino}benzoic acid. T.t. 150-153 °C.

MS: 376 (M+). MS: 376 (M+).

PRIMJER 21 EXAMPLE 21

2-{4-[3-(3-Nitrofenil)propil]fenilamino}benzoeva kiselina. T.t. 164-167 °C. 2-{4-[3-(3-Nitrophenyl)propyl]phenylamino}benzoic acid. T.t. 164-167 °C.

MS: 376 (M+). MS: 376 (M+).

Analiza za C22H20N2O4 x 2,20 mol H2O: Rač.: C, 63,51; H, 5,91; N, 6,73. Analysis for C22H20N2O4 x 2.20 mol H2O: Calc.: C, 63.51; H, 5.91; N, 6.73.

Nađeno: C, 63,56; H, 5,45; N, 6,46. Found: C, 63.56; H, 5.45; N, 6.46.

PRIMJER 22 EXAMPLE 22

2-{4-[3-(4-Aminofenil)propil]fenilamino}benzoeva kiselina. T.t. 110-112 °C. 2-{4-[3-(4-Aminophenyl)propyl]phenylamino}benzoic acid. T.t. 110-112 °C.

MS: 347 (M+1+). MS: 347 (M+1+).

PRIMJER 23 EXAMPLE 23

2-{4-[3-(3-Aminofenil)propil]fenilamino}benzoeva kiselina. T.t. 109 °C. 2-{4-[3-(3-Aminophenyl)propyl]phenylamino}benzoic acid. T.t. 109 °C.

MS: 333 (M+1+). MS: 333 (M+1+).

PRIMJER 24 EXAMPLE 24

2-{4-[2-(4-Aminofenil)fenilamino}benzoeva kiselina. T.t. 198-201 °C. 2-{4-[2-(4-Aminophenyl)phenylamino}benzoic acid. T.t. 198-201 °C.

MS: 333 (M+1+). MS: 333 (M+1+).

Analiza za C21H20N2O2 x 0,1 mol H2O: Rač.: C, 75,47; H, 6,09; N, 8,38. Analysis for C21H20N2O2 x 0.1 mol H2O: Sol.: C, 75.47; H, 6.09; N, 8.38.

Nađeno: C, 75,32; H, 6,12; N, 8,27. Nađeno: C, 75,32; H, 6,12; N, 8,27. Found: C, 75.32; H, 6.12; N, 8.27. Found: C, 75.32; H, 6.12; N, 8.27.

PRIMJER 25 EXAMPLE 25

2-{4-[2-(4-Dipropilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid. T.t. 176-177 °C. 2-{4-[2-(4-Dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride. T.t. 176-177 °C.

MS: 417 (M+1+). MS: 417 (M+1+).

Analiza za C27H32N2O2: Rač.: C, 71,59; H, 7,34; N, 6,18; Cl, 7,83. Analysis for C27H32N2O2: Sol.: C, 71.59; H, 7.34; N, 6.18; Cl, 7.83.

Nađeno: C, 71,31; H, 7,24; N, 6,19; Cl, 7,74. Found: C, 71.31; H, 7.24; N, 6.19; Cl, 7.74.

PRIMJER 26 EXAMPLE 26

2-{4-[2-(4-Dietilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid monohidrat. 2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride monohydrate.

MS: 389 (M+1+). MS: 389 (M+1+).

Analiza za C25H28N2O2 x HCl x H2O: Rač.: C, 67,78; H, 7,05; N, 6,32; Cl, 8,00. Analysis for C25H28N2O2 x HCl x H2O: Sol.: C, 67.78; H, 7.05; N, 6.32; Cl, 8.00.

Nađeno: C, 67,83; H, 7,01; N, 6,30; Cl, 7,75. Found: C, 67.83; H, 7.01; N, 6.30; Cl, 7.75.

PRIMJER 27 EXAMPLE 27

2-{4-[3-(3-Dipropilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 431 (M+1+). MS: 431 (M+1+).

Analiza za C28H34N2O2 x 0,2 H2O: Rač.: C, 77,46; H, 7,99; N, 6,45. Analysis for C 28 H 34 N 2 O 2 x 0.2 H 2 O: Calc.: C, 77.46; H, 7.99; N, 6.45.

Nađeno: C, 77,43; H, 7,86; N, 6,40. Found: C, 77.43; H, 7.86; N, 6.40.

PRIMJER 28 EXAMPLE 28

2-{4-[3-(3-Dimetilaminofenil)propil]fenilamino}benzoeva kiselina. T.t. 115-117 °C. 2-{4-[3-(3-Dimethylaminophenyl)propyl]phenylamino}benzoic acid. T.t. 115-117 °C.

MS: 374 (M+), 375 (M+1+). MS: 374 (M+), 375 (M+1+).

Analiza za C24H26N2O2 x 0,1 H2O: Rač.: C, 76,61; H, 7,02; N, 7,44. Analysis for C 24 H 26 N 2 O 2 x 0.1 H 2 O: Calc.: C, 76.61; H, 7.02; N, 7.44.

Nađeno: C, 76,57; H, 7,21; N, 7,47. Found: C, 76.57; H, 7.21; N, 7.47.

PRIMJER 29 EXAMPLE 29

2-{4-[3-(4-Etilaminofenil)propil]fenilamino}benzoeva kiselina. T.t. 133 °C. 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoic acid. T.t. 133 °C.

MS: 375 (M+1+). MS: 375 (M+1+).

Analiza za C24H26N2O2 x 0,1 H2O: Rač.: C, 76,61; H, 7,02; N, 7,44. Analysis for C 24 H 26 N 2 O 2 x 0.1 H 2 O: Calc.: C, 76.61; H, 7.02; N, 7.44.

Nađeno: C, 76,62; H, 7,06; N, 7,36. Found: C, 76.62; H, 7.06; N, 7.36.

PRIMJER 30 EXAMPLE 30

2-(N-{4-[3-(4-Dietilaminofenil)propil]fenil}-N-etilamino)benzoeva kiselina. 2-(N-{4-[3-(4-Diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoic acid.

MS: 431 (M+1+). MS: 431 (M+1+).

Analiza za C28H34N2O2: Rač.: C, 78,10; H, 7,96; N, 6,51. Analysis for C28H34N2O2: Sol.: C, 78.10; H, 7.96; N, 6.51.

Nađeno: C, 78,02; H, 8,17; N, 6,50. Found: C, 78.02; H, 8.17; N, 6.50.

PRIMJER 31 EXAMPLE 31

2-{4-[2-(3-Dibenzilaminofenil)etil]fenilamino}benzoeva kiselina. T.t. 95,5-97,5 °C. 2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino}benzoic acid. T.t. 95.5-97.5 °C.

Analiza za C35H32N2O2: Rač.: C, 82,00; H, 6,29; N, 5,46. Analysis for C35H32N2O2: Sol.: C, 82.00; H, 6.29; N, 5.46.

Nađeno: C, 81,81; H, 6,58; N, 5,44. Found: C, 81.81; H, 6.58; N, 5.44.

PRIMJER 32 EXAMPLE 32

2-{4-[3-(3-Dietilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(3-Diethylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 403 (M+1+). MS: 403 (M+1+).

Analiza za C26H30N2O2 x 0,1 H2O: Rač.: C, 77,23; H, 7,53; N, 6,93. Analysis for C26H30N2O2 x 0.1 H2O: Cal.: C, 77.23; H, 7.53; N, 6.93.

Nađeno: C, 77,14; H, 7,82; N, 6,88. Found: C, 77.14; H, 7.82; N, 6.88.

PRIMJER 33 EXAMPLE 33

2-{4-[2-(3-Aminofenil)etil]fenilamino}benzoeva kiselina. T.t. 182-184 °C. 2-{4-[2-(3-Aminophenyl)ethyl]phenylamino}benzoic acid. T.t. 182-184 °C.

MS: 333 (M+1+). MS: 333 (M+1+).

Analiza za C21H20N2O2 x 0,25 H2O: Rač.: C, 74,87; H, 6,13; N, 8,43. Analysis for C21H20N2O2 x 0.25 H2O: Cal.: C, 74.87; H, 6.13; N, 8.43.

Nađeno: C, 74,86; H, 6,16; N, 8,32. Found: C, 74.86; H, 6.16; N, 8.32.

PRIMJER 34 EXAMPLE 34

2-{4-[3-(4-Dimetilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Dimethylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 375 (M+1+). MS: 375 (M+1+).

Analiza za C24H26N2O2 x 0,1 H2O: Rač.: C, 76,61; H, 7,02; N, 7,44. Analysis for C 24 H 26 N 2 O 2 x 0.1 H 2 O: Calc.: C, 76.61; H, 7.02; N, 7.44.

Nađeno: C, 76,52; H, 7,22; N, 7,49. Found: C, 76.52; H, 7.22; N, 7.49.

PRIMJER 35 EXAMPLE 35

2-{4-[2-(4-Acetilaminofenil)etil]fenilamino}benzoeva kiselina. T.t. 224 °C. 2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino}benzoic acid. T.t. 224 °C.

MS: 375 (M+1+). MS: 375 (M+1+).

PRIMJER 36 EXAMPLE 36

2-{4-[2-(3-Acetilaminofenil)etil]fenilamino}benzoeva kiselina. T.t. 213-215 °C. 2-{4-[2-(3-Acetylaminophenyl)ethyl]phenylamino}benzoic acid. T.t. 213-215 °C.

MS: 375 (M+1+). MS: 375 (M+1+).

PRIMJER 37 EXAMPLE 37

2-{4-[2-(3-Dipropilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid. T.t. 189-193 °C. 2-{4-[2-(3-Dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride. T.t. 189-193 °C.

MS: 417 (M+1+). MS: 417 (M+1+).

Analiza za C27H32N2O2 x HCl: Rač.: C, 71,58; H, 7,34; N, 6,18; Cl, 7,83. Analysis for C27H32N2O2 x HCl: Sol.: C, 71.58; H, 7.34; N, 6.18; Cl, 7.83.

Nađeno: C, 71,48; H, 7,35; N, 6,10, Cl, 7,66. Found: C, 71.48; H, 7.35; N, 6.10, Cl, 7.66.

PRIMJER 38 EXAMPLE 38

2-{4-[2-(3-Dibutilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid. T.t. 175-180 °C. 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride. T.t. 175-180 °C.

MS: 445 (M+1+). MS: 445 (M+1+).

Analiza za C29H36N2O2 x HCl: Rač.: C, 72,40; H, 7,75; N, 5,82; Cl, 7,37. Analysis for C29H36N2O2 x HCl: Sol.: C, 72.40; H, 7.75; N, 5.82; Cl, 7.37.

Nađeno: C, 72,61; H, 7,95; N, 5,78, Cl, 7,23. Found: C, 72.61; H, 7.95; N, 5.78, Cl, 7.23.

PRIMJER 39 EXAMPLE 39

2-{4-[3-(4-Acetilaminofenil)propil]fenilamino}benzoeva kiselina. T.t. 176-178 °C. 2-{4-[3-(4-Acetylaminophenyl)propyl]phenylamino}benzoic acid. T.t. 176-178 °C.

MS: 389 (M+1+). MS: 389 (M+1+).

PRIMJER 40 EXAMPLE 40

2-{4-[3-(3-Acetilaminofenil)propil]fenilamino}benzoeva kiselina. T.t. 140-145 °C. 2-{4-[3-(3-Acetylaminophenyl)propyl]phenylamino}benzoic acid. T.t. 140-145 °C.

MS: 389 (M+1+). MS: 389 (M+1+).

PRIMJER 41 EXAMPLE 41

2-{4-[2-(3-Dietilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid. T.t. 166-171 °C. 2-{4-[2-(3-Diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride. T.t. 166-171 °C.

MS: 389 (M+1+). MS: 389 (M+1+).

Analiza za C25H28N2O2 x HCl: Rač.: C, 70,66; H, 6,88; N, 6,59; Cl, 8,34. Analysis for C25H28N2O2 x HCl: Sol.: C, 70.66; H, 6.88; N, 6.59; Cl, 8.34.

Nađeno: C, 70,48; H, 6,89; N, 6,57, Cl, 18,39. Found: C, 70.48; H, 6.89; N, 6.57, Cl, 18.39.

PRIMJER 42 EXAMPLE 42

2-{4-[2-(3-Piperidin-1-ilfenil)etil]fenilamino}benzoeva kiselina monohidroklorid. T.t. 187-193 °C. 2-{4-[2-(3-Piperidin-1-ylphenyl)ethyl]phenylamino}benzoic acid monohydrochloride. T.t. 187-193 °C.

MS: 401 (M+1+). MS: 401 (M+1+).

Analiza za C26H28N2O2 x HCl: Rač.: C, 71,46; H, 6,69; N, 6,41; Cl, 8,11. Analysis for C26H28N2O2 x HCl: Sol.: C, 71.46; H, 6.69; N, 6.41; Cl, 8,11.

Nađeno: C, 71,28; H, 6,73; N, 6,35, Cl, 8,30. Found: C, 71.28; H, 6.73; N, 6.35, Cl, 8.30.

PRIMJER 43 EXAMPLE 43

2-{4-[3-(4-Dipropilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Dipropylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 431 (M+1+). MS: 431 (M+1+).

Analiza za C28H34N2O2: Rač.: C, 78,10; H, 7,96; N, 6,51. Analysis for C28H34N2O2: Sol.: C, 78.10; H, 7.96; N, 6.51.

Nađeno: C, 77,91; H, 8,03; N, 6,43. Found: C, 77.91; H, 8.03; N, 6.43.

PRIMJER 44 EXAMPLE 44

2-{4-[3-(4-Dibutilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Dibutylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 459 (M+1+). MS: 459 (M+1+).

Analiza za C30H38N2O2: Rač.: C, 78,56; H, 8,35; N, 6,11. Analysis for C30H38N2O2: Sol.: C, 78.56; H, 8.35; N, 6,11.

Nađeno: C, 78,40; H, 8,50; N, 6,19. Found: C, 78.40; H, 8.50; N, 6,19.

PRIMJER 45 EXAMPLE 45

2-{4-[3-(3-Dibutilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(3-Dibutylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 459 (M+1+). MS: 459 (M+1+).

Analiza za C30H38N2O2: Rač.: C, 78,56; H, 8,35; N, 6,11. Analysis for C30H38N2O2: Sol.: C, 78.56; H, 8.35; N, 6,11.

Nađeno: C, 78,40; H, 8,43; N, 6,11. Found: C, 78.40; H, 8.43; N, 6,11.

PRIMJER 46 EXAMPLE 46

2-(4-{3-[4-(1H-Pirol-1-il)fenil]propil}fenilamino)benzoeva kiselina. T.t. 131-136 °C. 2-(4-{3-[4-(1H-Pyrrol-1-yl)phenyl]propyl}phenylamino)benzoic acid. T.t. 131-136 °C.

MS: 397 (M+1+). MS: 397 (M+1+).

Analiza za C26H24N2O2 x 0,2 H2O: Rač.: C, 78,05; H, 6,15; N, 7,00. Analysis for C26H24N2O2 x 0.2 H2O: Sol.: C, 78.05; H, 6.15; N, 7.00.

Nađeno: C, 77,95; H, 6,17; N, 7,08. Found: C, 77.95; H, 6.17; N, 7.08.

PRIMJER 47 EXAMPLE 47

2-{4-[3-(4-Piperidin-1-ilfenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid.

MS: 415 (M+1+). MS: 415 (M+1+).

Analiza za C27H30N2O2 x 0,2 H2O: Rač.: C, 77,55; H, 7,33; N, 6,70. Analysis for C27H30N2O2 x 0.2 H2O: Sol.: C, 77.55; H, 7.33; N, 6.70.

Nađeno: C, 77,37; H, 7,35; N, 6,63. Found: C, 77.37; H, 7.35; N, 6.63.

PRIMJER 48 EXAMPLE 48

2-{4-[3-(4-Dietilkarbamoilfenil)propil]fenilamino}benzoeva kiselina. T.t. 57-62 °C. 2-{4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino}benzoic acid. T.t. 57-62 °C.

MS: 431 (M+1+). MS: 431 (M+1+).

Analiza za C27H30N2O3 x 0,3 H2O: Rač.: C, 74,39; H, 7,07; N, 6,43. Analysis for C27H30N2O3 x 0.3 H2O: Cal.: C, 74.39; H, 7.07; N, 6.43.

Nađeno: C, 74,23; H, 6,97; N, 6,27. Found: C, 74.23; H, 6.97; N, 6.27.

PRIMJER 49 EXAMPLE 49

2-{4-[3-(4-Karboksifenil)propil]fenilamino}benzoeva kiselina. T.t. 236-239 °C. 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino}benzoic acid. T.t. 236-239 °C.

MS: 375 (M+). MS: 375 (M+).

PRIMJER 50 EXAMPLE 50

2-{4-[3-(4-Dietilaminometilfenil)propil]fenilamino}benzoeva kiselina. T.t. 137 °C. 2-{4-[3-(4-Diethylaminomethylphenyl)propyl]phenylamino}benzoic acid. T.t. 137 °C.

MS: 417 (M+1+). MS: 417 (M+1+).

PRIMJER 51 EXAMPLE 51

2-{4-[3-(4-Propilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 389 (M+1+). MS: 389 (M+1+).

Analiza za C25H28N2O2 x 0,2 H2O: Rač.: C, 76,58; H, 7,30; N, 7,14. Analysis for C25H28N2O2 x 0.2 H2O: Cal.: C, 76.58; H, 7.30; N, 7,14.

Nađeno: C, 76,61; H, 7,29; N, 7,03. Found: C, 76.61; H, 7.29; N, 7.03.

PRIMJER 52 EXAMPLE 52

2-{4-[3-(3-Propilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(3-Propylaminophenyl)propyl]phenylamino}benzoic acid.

MS: 389 (M+1+). MS: 389 (M+1+).

Analiza za C25H28N2O2 x 0,1 H2O: Rač.: C, 76,93; H, 7,28; N, 7,18. Analysis for C25H28N2O2 x 0.1 H2O: Cal.: C, 76.93; H, 7.28; N, 7,18.

Nađeno: C, 76,85; H, 7,44; N, 7,06. Found: C, 76.85; H, 7.44; N, 7.06.

PRIMJER 53 EXAMPLE 53

2-{4-[3-(4-Pirolidin-1-ilfenil)propil]fenilamino}benzoeva kiselina. T.t. 171-177 °C. 2-{4-[3-(4-Pyrrolidin-1-ylphenyl)propyl]phenylamino}benzoic acid. T.t. 171-177 °C.

MS: 401 (M+1+). MS: 401 (M+1+).

Analiza za C26H28N2O2 x 0,2 H2O: Rač.: C, 77,27; H, 7,08; N, 6,93. Analysis for C26H28N2O2 x 0.2 H2O: Cal.: C, 77.27; H, 7.08; N, 6.93.

Nađeno: C, 77,09; H, 6,97; N, 6,96. Found: C, 77.09; H, 6.97; N, 6.96.

PRIMJER 54 EXAMPLE 54

2-{4-[3-(3-Piperidin-1-ilfenil)propil]fenilamino}benzoeva kiselina. T.t. 59-61 °C. 2-{4-[3-(3-Piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid. T.t. 59-61 °C.

MS: 415 (M+1+). MS: 415 (M+1+).

Analiza za C27H30N2O2 x 0,3 H2O: Rač.: C, 77,22; H, 7,34; N, 6,67. Analysis for C27H30N2O2 x 0.3 H2O: Cal.: C, 77.22; H, 7.34; N, 6.67.

Nađeno: C, 77,18; H, 7,25; N, 6,49. Found: C, 77.18; H, 7.25; N, 6.49.

PRIMJER 55 EXAMPLE 55

{5-[(1-Butil-1,2,3,4-tetrahidro-6-kinolil)metiliden]-4-okso-2-tioksotiazolidin-3-il}octena kiselina. {5-[(1-Butyl-1,2,3,4-tetrahydro-6-quinolyl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}acetic acid.

T.t. 222224 °C. T.t. 222224°C.

MS: 391 (M+1+). MS: 391 (M+1+).

PRIMJER 56 EXAMPLE 56

{5-[(1-Butil-2,3-dihidro-1H-indol-5-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}octena kiselina. {5-[(1-Butyl-2,3-dihydro-1H-indol-5-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}acetic acid.

T.t. > 250 °C. T.t. > 250 °C.

MS: 377 (M+1+). MS: 377 (M+1+).

Analiza za C18H20N2O3S2 x 0,4 H2O: Rač.: C, 56,34; H, 5,46; N, 7,30; S, 16,71. Analysis for C18H20N2O3S2 x 0.4 H2O: Cal.: C, 56.34; H, 5.46; N, 7.30; S, 16.71.

Nađeno: C, 56,27; H, 5,18; N, 7,31; S, 16,74. Found: C, 56.27; H, 5.18; N, 7.31; S, 16.74.

PRIMJER 57 EXAMPLE 57

3-{5-[(1-Butil-1,2,3,4-tetrahidrokinol-6-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}propionska kiselina. 3-{5-[(1-Butyl-1,2,3,4-tetrahydroquinol-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}propionic acid.

T.t. 214215 °C. T.t. 214215 °C.

MS: 405 (M+1+). MS: 405 (M+1+).

PRIMJER 58 EXAMPLE 58

4-{5-[(1-Butil-1,2,3,4-tetrahidrokinol-6-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}butirna kiselina. 4-{5-[(1-Butyl-1,2,3,4-tetrahydroquinol-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}butyric acid.

T.t. 152154 °C. T.t. 152154 °C.

MS: 417 (M-1+), 418 (M+), 419 (M+1+). MS: 417 (M-1+), 418 (M+), 419 (M+1+).

Analiza za C21H26N2O3S2 x 0,2 H2O: Rač.: C, 59,74; H, 6,30; N, 6,64; S, 15,19. Analysis for C 21 H 26 N 2 O 3 S 2 x 0.2 H 2 O: Calc.: C, 59.74; H, 6.30; N, 6.64; S, 15,19.

Nađeno: C, 59,59; H, 6,16; N, 6,52; S, 15,38. Found: C, 59.59; H, 6.16; N, 6.52; S, 15,38.

PRIMJER 59 EXAMPLE 59

2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-5-metilbenzoeva kiselina. T.t. 9899 °C. 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-5-methylbenzoic acid. T.t. 9899 °C.

MS: 414 (M+1+). MS: 414 (M+1+).

PRIMJER 60 EXAMPLE 60

N-(2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzoil)metansulfonamid je pripravljen reakcijom produkta iz Primjera 9 s metansulfonamidom. T.t. 5361 °C. N-(2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoyl)methanesulfonamide was prepared by reacting the product from Example 9 with methanesulfonamide. T.t. 5361 °C.

Analiza za C23H22Cl2N2O3S x 0,13 H2O: Rač.: C, 57,58; H, 4,68; N, 5,84. Analysis for C 23 H 22 Cl 2 N 2 O 3 S x 0.13 H 2 O: Calc.: C, 57.58; H, 4.68; N, 5.84.

Nađeno: C, 57,20; H, 4,66; N, 5,51. Found: C, 57.20; H, 4.66; N, 5.51.

PRIMJER 61 EXAMPLE 61

2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. 214216 °C. 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. 214216 °C.

Analiza za C23H22N2O4 x 0,25 H2O: Rač.: C, 69,99; H, 5,74; N, 7,18. Analysis for C23H22N2O4 x 0.25 H2O: Sol.: C, 69.99; H, 5.74; N, 7,18.

Nađeno: C, 69,90; H, 5,82; N, 6,81. Found: C, 69.90; H, 5.82; N, 6.81.

PRIMJER 62 EXAMPLE 62

2-[4-(2-Bifenil-4-iletil)fenilamino]-5-nitrobenzoeva kiselina. T.t. 239244 °C. 2-[4-(2-Biphenyl-4-ylethyl)phenylamino]-5-nitrobenzoic acid. T.t. 239244 °C.

MS: 439 (MH+). MS: 439 (MH+).

PRIMJER 63 EXAMPLE 63

2-{4-[2-(4-Klor-3-trifluormetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. 207209 °C. 2-{4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. 207209 °C.

Analiza za C22H16ClF3N2O4: Rač.: C, 56,85; H, 3,47; N, 6,03. Analysis for C22H16ClF3N2O4: Sol.: C, 56.85; H, 3.47; N, 6.03.

Nađeno: C, 56,75; H, 3,71; N, 5,83. Found: C, 56.75; H, 3.71; N, 5.83.

PRIMJER 64 EXAMPLE 64

5-Amino-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina je pripravljena reakcijom produkta iz Primjera 2 s plinovitim vodikom u prisutnosti Raney-nikla. T.t. 137142 °C. 5-Amino-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid was prepared by reacting the product from Example 2 with hydrogen gas in the presence of Raney nickel. T.t. 137142 °C.

Analiza za C21H18Cl2N2O2 x 0,96 THF: Rač.: C, 63,94; H, 4,72; N, 6,00. Analysis for C21H18Cl2N2O2 x 0.96 THF: Calc.: C, 63.94; H, 4.72; N, 6.00.

Nađeno: C, 64,33; H, 4,91; N, 6,35. Found: C, 64.33; H, 4.91; N, 6.35.

PRIMJER 65 EXAMPLE 65

5-Nitro-2-(4-fenetilfenilamino)benzoeva kiselina. T.t. 198202 °C. 5-Nitro-2-(4-phenethylphenylamino)benzoic acid. T.t. 198202 °C.

Analiza za C21H18N2O4 x 0,11 H2O: Rač.: C, 69,22; H, 5,04; N, 7,69. Analysis for C21H18N2O4 x 0.11 H2O: Cal.: C, 69.22; H, 5.04; N, 7.69.

Nađeno: C, 69,59; H, 5,27; N, 7,22. Found: C, 69.59; H, 5.27; N, 7.22.

PRIMJER 66 EXAMPLE 66

2-{4-[2-(4-Fluor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina. T.t. 148150 °C. 2-{4-[2-(4-Fluoro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid. T.t. 148150 °C.

Analiza za C22H17F4NO2: Rač.: C, 65,51; H, 4,25; N, 3,47. Analysis for C22H17F4NO2: Sol.: C, 65.51; H, 4.25; N, 3.47.

Nađeno: C, 65,51; H, 4,13; N, 3,46. Found: C, 65.51; H, 4.13; N, 3.46.

PRIMJER 67 EXAMPLE 67

2-{4-[2-(3,4-Difluorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. 203208 °C. 2-{4-[2-(3,4-Difluorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. 203208 °C.

Analiza za C21H16F2N2O4: Rač.: C, 63,32; H, 4,05; N, 7,03. Analysis for C 21 H 16 F 2 N 2 O 4 : Sol.: C, 63.32; H, 4.05; N, 7.03.

Nađeno: C, 62,94; H, 4,37; N, 6,87. Found: C, 62.94; H, 4.37; N, 6.87.

PRIMJER 68 EXAMPLE 68

{4-[2-(3,4-Diklorfenil)etil]fenil}-[2-(1H-tetrazol-5-il)fenil]amin je pripravljen prema postupku opisanom u Primjeru 1, koristeći fluortetrazolni međuprodukt, koji je sintetiziran iz komercijalno dostupnog 2-fluorbenzonitrila i natrijevog azida, pri standardnim reakcijskim uvjetima. T.t. 129 (skuplja se), 152157 °C. {4-[2-(3,4-Dichlorophenyl)ethyl]phenyl}-[2-(1H-tetrazol-5-yl)phenyl]amine was prepared according to the procedure described in Example 1, using the fluorotetrazole intermediate, which was synthesized from of commercially available 2-fluorobenzonitrile and sodium azide, under standard reaction conditions. T.t. 129 (collapsing), 152157 °C.

Analiza za C21H17Cl2N5 x 0,15 EtOAc x 0,15 heksan: Rač.: C, 61,80; H, 4,64; N, 16,12. Analysis for C21H17Cl2N5 x 0.15 EtOAc x 0.15 hexane: Calc.: C, 61.80; H, 4.64; N, 16,12.

Nađeno: C, 61,61; H, 4,28; N, 15,83. Found: C, 61.61; H, 4.28; N, 15.83.

PRIMJER 69 EXAMPLE 69

2-{4-[2-(4-Fluor-3-trifluormetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. 190193 °C. 2-{4-[2-(4-Fluoro-3-trifluoromethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. 190193 °C.

Analiza za C22H16F4N2O4: Rač.: C, 58,93; H, 3,60; N, 6,25. Analysis for C 22 H 16 F 4 N 2 O 4 : Sol.: C, 58.93; H, 3.60; N, 6.25.

Nađeno: C, 58,69; H, 3,42; N, 6,57. Found: C, 58.69; H, 3.42; N, 6.57.

PRIMJER 70 EXAMPLE 70

2-(4-Fenetilfenilamino)benzoeva kiselina. T.t. 173182 °C. 2-(4-Phenethylphenylamino)benzoic acid. T.t. 173182 °C.

Analiza za C21H19NO2: Rač.: C, 79,47; H, 6,03; N, 4,41. Analysis for C21H19NO2: Sol.: C, 79.47; H, 6.03; N, 4.41.

Nađeno: C, 79,42; H, 5,97; N, 4,47; Nađeno: C, 79,59; H, 6,03; N, 4,50. Found: C, 79.42; H, 5.97; N, 4.47; Found: C, 79.59; H, 6.03; N, 4.50.

PRIMJER 71 EXAMPLE 71

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-5-fluorbenzoeva kiselina. T.t. 180182 °C. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-5-fluorobenzoic acid. T.t. 180182 °C.

Analiza za C21H16Cl2FNO2 x 0,06 H2O: Rač.: C, 62,23; H, 4,01; N, 3,46. Analysis for C21H16Cl2FNO2 x 0.06 H2O: Calc.: C, 62.23; H, 4.01; N, 3.46.

Nađeno: C, 61,83; H, 4,04; N, 3,29. Found: C, 61.83; H, 4.04; N, 3.29.

PRIMJER 72 EXAMPLE 72

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}nikotinska kiselina. T.t. 168171 °C. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}nicotinic acid. T.t. 168171 °C.

Analiza za C20H16Cl2N2O2: Rač.: C, 62,03; H, 4,16; N, 7,23. Analysis for C20H16Cl2N2O2: Sol.: C, 62.03; H, 4.16; N, 7.23.

Nađeno: C, 62,11; H, 4,17; N, 7,07. Found: C, 62.11; H, 4.17; N, 7.07.

PRIMJER 73 EXAMPLE 73

2-{4-[2-(3-Klorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. 192,5194,5 °C. 2-{4-[2-(3-Chlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. 192.5194.5 °C.

Analiza za C21H17ClN2O4: Rač.: C, 63,56; H, 4,32; N, 7,06. Analysis for C21H17ClN2O4: Sol.: C, 63.56; H, 4.32; N, 7.06.

Nađeno: C, 63,83; H, 4,62; N, 6,79. Found: C, 63.83; H, 4.62; N, 6.79.

PRIMJER 74 EXAMPLE 74

2-{4-[2-(4-Klorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. 210212 °C. 2-{4-[2-(4-Chlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. 210212 °C.

Analiza za C21H17ClN2O4 x 0,26 H2O: Rač.: C, 62,82; H, 4,40; N, 6,98. Analysis for C21H17ClN2O4 x 0.26 H2O: Calc.: C, 62.82; H, 4.40; N, 6.98.

Nađeno: C, 62,51; H, 4,34; N, 6,58. Found: C, 62.51; H, 4.34; N, 6.58.

PRIMJER 75 EXAMPLE 75

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-5-metilbenzoeva kiselina. T.t. 153160 °C. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-5-methylbenzoic acid. T.t. 153160 °C.

Analiza za C22H19Cl2NO2 x 0,61 H2O: Rač.: C, 64,25; H, 4,96; N, 3,41. Analysis for C22H19Cl2NO2 x 0.61 H2O: Sol.: C, 64.25; H, 4.96; N, 3.41.

Nađeno: C, 63,87; H, 4,64; N, 3,55. Found: C, 63.87; H, 4.64; N, 3.55.

PRIMJER 76 EXAMPLE 76

2-{4-[2-(2-Klorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. 236238 °C. 2-{4-[2-(2-Chlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. 236238 °C.

PRIMJER 77 EXAMPLE 77

2-{4-[2-(2,4-Diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. 200,5202,5 °C. 2-{4-[2-(2,4-Dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. 200.5202.5 °C.

Analiza za C21H16Cl2N2O4: Rač.: C, 58,49; H, 3,74; N, 6,50. Analysis for C21H16Cl2N2O4: Sol.: C, 58.49; H, 3.74; N, 6.50.

Nađeno: C, 58,33; H, 3,67; N, 6,29. Found: C, 58.33; H, 3.67; N, 6.29.

PRIMJER 78 EXAMPLE 78

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-6-trifluormetilbenzoeva kiselina. T.t. 130132 °C. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-6-trifluoromethylbenzoic acid. T.t. 130132 °C.

Analiza za C22H16Cl2F3NO2 x 0,61 H2O: Rač.: C, 58,17; H, 3,55; N, 3,08. Analysis for C22H16Cl2F3NO2 x 0.61 H2O: Calc.: C, 58.17; H, 3.55; N, 3.08.

Nađeno: C, 58,25; H, 3,65; N, 3,05. Found: C, 58.25; H, 3.65; N, 3.05.

PRIMJER 79 EXAMPLE 79

2-{4-[2-(4-Dibutilaminofenil)etil]fenilamino}-5-nitrobenzoeva kiselina. T.t. >260 °C. 2-{4-[2-(4-Dibutylaminophenyl)ethyl]phenylamino}-5-nitrobenzoic acid. T.t. >260 °C.

PRIMJER 80 EXAMPLE 80

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-5-dimetilaminobenzoeva kiselina. T.t. 7580 °C. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-5-dimethylaminobenzoic acid. T.t. 7580 °C.

PRIMJER 81 EXAMPLE 81

2-{4-[2-(3,5-Diklorfenil)etil]fenilamino}benzoeva kiselina. T.t. 191194 °C. 2-{4-[2-(3,5-Dichlorophenyl)ethyl]phenylamino}benzoic acid. T.t. 191194 °C.

Analiza za C21H17Cl2NO2: Rač.: C, 65,30; H, 4,44; N, 3,63. Analysis for C21H17Cl2NO2: Sol.: C, 65.30; H, 4.44; N, 3.63.

Nađeno: C, 65,38; H, 4,29; N, 3,52. Found: C, 65.38; H, 4.29; N, 3.52.

PRIMJER 82 EXAMPLE 82

2-(4-{2-[(4aS,8aR)-4-(Oktahidroizokinolin-2-il)fenil]etil}fenilamino)benzoeva kiselina je pripravljena prema propisu navedenom u Primjeru 1 koristeći dekahidrokinolin aldehid, koji je pripravljen iz trans-dekahidroizokinolina i p-fluorbenzaldehida pri standardnim reakcijskim uvjetima. T.t. 203206 °C. 2-(4-{2-[(4aS,8aR)-4-(Octahydroisoquinolin-2-yl)phenyl]ethyl}phenylamino)benzoic acid was prepared according to the procedure outlined in Example 1 using decahydroquinoline aldehyde, which was prepared from trans- of decahydroisoquinoline and p-fluorobenzaldehyde under standard reaction conditions. T.t. 203206 °C.

Analiza za C30H34N2O2 x 0,12 H2O: Rač.: C, 78,89; H, 7,56; N, 6,13. Analysis for C30H34N2O2 x 0.12 H2O: Cal.: C, 78.89; H, 7.56; N, 6,13.

Nađeno: C, 78,49; H, 7,58; N, 5,90. Found: C, 78.49; H, 7.58; N, 5.90.

Slijedeći primjeri su pripravljeni prema gore navedenim metodama, ili primjenom standardne kombinatorijalne sintetske metodologije, reakcijom estera halo supstituiranih benzojevih kiselina sa supstituiranim anilinom dajući diarilamin, te naknadnom saponifikacijom do benzojeve kiseline Formule I. Reakcije su provedene uz korištenje 0,15 mmola reaktanata prema slijedećem postupku. Otopine svakog halobenzoatnog reaktanta (0,18 M) u toluenu su stavljene u reakcijske bočice od 7,78 grama (2 drama). Svaki anilinski reaktant je otopljen u bezvodnom toluenu na koncentraciju od 0,15 mol dm-3. Distrimanovom pipetom je dodano po 1 ml (0,15 mmola, 1 ekvivalent) otopine svakog halobenzoata u odgovarajuću bočicu koja sadrži 1 ml (0,18 mmola, 1,2 ekvivalenta) anilinskog reaktanta. Otopina katalizatora je pripravljena otapanjem 0,025 M Pd2(dba)3 (dipaladij-tridibenzilidenaceton) i 0,075 M BINAP (2,2'-bis(difenilfosfino)-1,1'-binaftil) u toluenu, a zatim je 0,25 ml otopine dodano u svaku pojedinu reakcijsku bočicu. Baza, najčešće cezijev karbonat (68 mg, 0,21 mmol, 1,40 ekvivalenta) je dodan u svaku reakcijsku bočicu, zatim su bočice zatvorene zatvaračem, i stavljene u peć opremljenu mješalicom te zagrijavane 48 sati pri 100 °C. Reakcijske smjese su tada ohlađene, a otapala su uklonjena uparavanjem. Kruti ostatak je suspendiran u 0,4 ml etil acetata i filtriran, pri čemu je uklonjen sav katalizator. Filtrati su koncentrirani do suha uparavanjem, rezultirajući spojevima Formule I, gdje je benzoatni dio esterificiran (npr. benzilni ili metilni ester). Esteri su otopljeni u 0,5 ml THF/etanol (1:1 volumni omjeri), a zatim je dodano 0,3 ml 5 M natrijevog hidroksida. Otopine su miješane 5 sati pri 60 °C, a zatim ohlađene i uparene do suha dajući željene spojeve Formule I. Tipični spojevi pripravljeni ovom metodom su slijedeći. Struktura spojeva je, uglavnom, potvrđena analizom masenom spektrometrijom. The following examples were prepared according to the methods mentioned above, or by applying standard combinatorial synthetic methodology, by reacting esters of halo-substituted benzoic acids with substituted aniline to give diarylamine, and subsequent saponification to benzoic acid of Formula I. The reactions were carried out using 0.15 mmol of reactants according to the following procedure . Solutions of each halobenzoate reactant (0.18 M) in toluene were placed in 7.78 gram (2 dram) reaction vials. Each aniline reactant was dissolved in anhydrous toluene to a concentration of 0.15 mol dm-3. Using a Distriman pipette, 1 ml (0.15 mmol, 1 equivalent) of each halobenzoate solution was added to the appropriate vial containing 1 ml (0.18 mmol, 1.2 equivalent) of aniline reactant. The catalyst solution was prepared by dissolving 0.025 M Pd2(dba)3 (dipalladium-tridibenzylideneacetone) and 0.075 M BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) in toluene, and then 0.25 ml of the solution added to each individual reaction vial. A base, usually cesium carbonate (68 mg, 0.21 mmol, 1.40 equivalents) was added to each reaction vial, then the vials were closed with a cap, and placed in an oven equipped with a stirrer and heated for 48 hours at 100 °C. The reaction mixtures were then cooled, and the solvents were removed by evaporation. The solid residue was suspended in 0.4 ml ethyl acetate and filtered, removing all catalyst. The filtrates are concentrated to dryness by evaporation, resulting in compounds of Formula I, where the benzoate moiety is esterified (eg, benzyl or methyl ester). The esters were dissolved in 0.5 ml of THF/ethanol (1:1 v/v) and then 0.3 ml of 5 M sodium hydroxide was added. The solutions were stirred for 5 hours at 60 °C, then cooled and evaporated to dryness to give the desired compounds of Formula I. Typical compounds prepared by this method are as follows. The structure of the compounds was mainly confirmed by mass spectrometry analysis.

PRIMJER 83 EXAMPLE 83

2-(3',5'-Diklor-3-metilbifenil-4-ilamino)benzoeva kiselina. 2-(3',5'-Dichloro-3-methylbiphenyl-4-ylamino)benzoic acid.

MS: 371; MW: 372,2495. MS: 371; MW: 372.2495.

PRIMJER 84 EXAMPLE 84

2-(3',5'-Dibrom-3-metilbifenil-4-ilamino)benzoeva kiselina. 2-(3',5'-Dibromo-3-methylbiphenyl-4-ylamino)benzoic acid.

MS: 459; MW: 461,1515. MS: 459; MW: 461.1515.

PRIMJER 85 EXAMPLE 85

2-(4-1,3-Benzodioksol-5-il-2-metilfenilamino)benzoeva kiselina. 2-(4-1,3-Benzodioxol-5-yl-2-methylphenylamino)benzoic acid.

MS: 347; MW: 347,3683. MS: 347; MW: 347.3683.

PRIMJER 86 EXAMPLE 86

2-(2,2',4'-Triklorbifenil-4-ilamino)benzoeva kiselina. 2-(2,2',4'-Trichlorobiphenyl-4-ylamino)benzoic acid.

MS: 391; MW: 392,6678. MS: 391; MW: 392.6678.

PRIMJER 87 EXAMPLE 87

2-(2-Klor-3',4'-difluorbifenil-4-ilamino)benzoeva kiselina. 2-(2-Chloro-3',4'-difluorobiphenyl-4-ylamino)benzoic acid.

MS: 359; MW: 359,7578. MS: 359; MW: 359.7578.

PRIMJER 88 EXAMPLE 88

2-(3'-Brom-2-klorbifenil-4-ilamino)benzoeva kiselina. 2-(3'-Bromo-2-chlorobiphenyl-4-ylamino)benzoic acid.

MS: 401; MW: 402,6737. MS: 401; MW: 402.6737.

PRIMJER 89 EXAMPLE 89

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid.

PRIMJER 90 EXAMPLE 90

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-3-nitrobenzoeva kiselina. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-3-nitrobenzoic acid.

PRIMJER 91 EXAMPLE 91

3-{4-[2-(3,4-Diklorfenil)etil]fenilamino}benzoeva kiselina. 3-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 92 EXAMPLE 92

5-{4-[2-(3,4-Diklorfenil)etil]fenilamino}izoftalna kiselina. 5-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}isophthalic acid.

PRIMJER 93 EXAMPLE 93

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}benzoeva kiselina. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 94 EXAMPLE 94

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-4,5-dimetoksibenzoeva kiselina. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-4,5-dimethoxybenzoic acid.

PRIMJER 95 EXAMPLE 95

2-{4-[2-(3-Klor-4-metilfenil)etil]fenilamino}-3-nitrobenzoeva kiselina. 2-{4-[2-(3-Chloro-4-methylphenyl)ethyl]phenylamino}-3-nitrobenzoic acid.

PRIMJER 96 EXAMPLE 96

3-{4-[2-(3-Klor-4-metilfenil)etil]fenilamino}benzoeva kiselina. 3-{4-[2-(3-Chloro-4-methylphenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 97 EXAMPLE 97

5-{4-[2-(3-Klor-4-metilfenil)etil]fenilamino}izoftalna kiselina. 5-{4-[2-(3-Chloro-4-methylphenyl)ethyl]phenylamino}isophthalic acid.

PRIMJER 98 EXAMPLE 98

2-{4-[2-(3-Klor-4-metilfenil)etil]fenilamino}benzoeva kiselina. 2-{4-[2-(3-Chloro-4-methylphenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 99 EXAMPLE 99

4-(4-{2-[(4aS,8aR)-4-(Oktahidroizokinolin-2-il)fenil]etil}fenilamino)benzoeva kiselina. 4-(4-{2-[(4aS,8aR)-4-(Octahydroisoquinolin-2-yl)phenyl]ethyl}phenylamino)benzoic acid.

PRIMJER 100 EXAMPLE 100

2-{4-[3-(4-Dietilaminofenil)propil]fenilamino}-5-metoksibenzoeva kiselina. 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}-5-methoxybenzoic acid.

PRIMJER 101 EXAMPLE 101

2-{4-[2-(3-Metoksifenil)etil]fenilamino}benzoeva kiselina. 2-{4-[2-(3-Methoxyphenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 102 EXAMPLE 102

2-{4-[2-(3-Bromfenil)etil]fenilamino}benzoeva kiselina. 2-{4-[2-(3-Bromophenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 103 EXAMPLE 103

2-{4-[2-(3-Fluorfenil)etil]fenilamino}benzoeva kiselina. 2-{4-[2-(3-Fluorophenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 104 EXAMPLE 104

4-{4-[2-(3,4-Diklorfenil)etil]fenilamino}nikotinska kiselina. 4-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}nicotinic acid.

PRIMJER 106 EXAMPLE 106

2-[2-(4-Fluor-3-trifluormetilfenil)-2,3-dihidro-1H-izoindol-5-ilamino]benzoeva kiselina. 2-[2-(4-Fluoro-3-trifluoromethylphenyl)-2,3-dihydro-1H-isoindol-5-ylamino]benzoic acid.

PRIMJER 107 EXAMPLE 107

2-{4-[2-(3-Fluor-4-metilfenil)etil]fenilamino}benzoeva kiselina. 2-{4-[2-(3-Fluoro-4-methylphenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 108 EXAMPLE 108

2-{4-[3-(4-Dietilaminofenil)propil]fenilamino}-5-nitrobenzoeva kiselina. 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}-5-nitrobenzoic acid.

PRIMJER 109 EXAMPLE 109

4-{4-[3-(4-Dietilaminofenil)propil]fenilamino}benzoeva kiselina. 4-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid.

PRIMJER 110 EXAMPLE 110

4-{4-[3-(4-Dietilaminofenil)propil]fenilamino}-3-metoksi-6-nitrobenzoeva kiselina. 4-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}-3-methoxy-6-nitrobenzoic acid.

PRIMJER 111 EXAMPLE 111

4-{4-[3-(4-Dietilaminofenil)propil]fenilamino}-3-metoksibenzoeva kiselina. 4-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}-3-methoxybenzoic acid.

PRIMJER 112 EXAMPLE 112

2-{4-[2-(3-Klor-4-metilfenil)etil]fenilamino}-5-metoksibenzoeva kiselina. 2-{4-[2-(3-Chloro-4-methylphenyl)ethyl]phenylamino}-5-methoxybenzoic acid.

PRIMJER 113 EXAMPLE 113

{4-[2-(3-Klor-4-metilfenil)etil]fenilamino}-2-metoksi-5-nitrofenilamin. {4-[2-(3-Chloro-4-methylphenyl)ethyl]phenylamino}-2-methoxy-5-nitrophenylamine.

PRIMJER 114 EXAMPLE 114

2-{4-[3-(4-Dietilaminofenil)propil]fenilamino}-3-nitrobenzoeva kiselina. 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}-3-nitrobenzoic acid.

PRIMJER 115 EXAMPLE 115

3-{4-[3-(4-Dietilaminofenil)propil]fenilamino}benzoeva kiselina. 3-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid.

PRIMJER 116 EXAMPLE 116

2-{4-[2-(3,4-Dimetoksifenil)etil]fenilamino}benzoeva kiselina. T.t. 159-161 °C. 2-{4-[2-(3,4-Dimethoxyphenyl)ethyl]phenylamino}benzoic acid. T.t. 159-161 °C.

PRIMJER 117 EXAMPLE 117

Mononatrijev 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoat. T.t. 107-108 °C. Monosodium 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoate. T.t. 107-108 °C.

PRIMJER 118 EXAMPLE 118

Monokalijev 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoat. T.t. >220 °C. Monopotassium 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoate. T.t. >220 °C.

PRIMJER 119 EXAMPLE 119

Kalcijev 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoat (1:1). T.t. >220 °C. Calcium 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoate (1:1). T.t. >220 °C.

PRIMJER 120 EXAMPLE 120

2-Hidroksi-1,1-bishidroksimetiletilamonijev 2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}benzoat. T.t. 185-187 °C. 2-Hydroxy-1,1-bishydroxymethylethylammonium 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}benzoate. T.t. 185-187 °C.

PRIMJER 121 EXAMPLE 121

2-{4-[4-(3,4-Diklorfenil)butil]fenilamino}-5-metoksibenzoeva kiselina. T.t. 155-158 °C. 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}-5-methoxybenzoic acid. T.t. 155-158 °C.

PRIMJER 122 EXAMPLE 122

2-{4-[2-(3,4-Difluorfenil)etil]fenilamino}benzoeva kiselina. T.t. 184-185 °C. 2-{4-[2-(3,4-Difluorophenyl)ethyl]phenylamino}benzoic acid. T.t. 184-185 °C.

PRIMJER 123 EXAMPLE 123

2-{3-[2-(4-Klorfenil)etil]fenilamino}benzoeva kiselina. T.t. 155-157 °C. 2-{3-[2-(4-Chlorophenyl)ethyl]phenylamino}benzoic acid. T.t. 155-157 °C.

PRIMJER 124 EXAMPLE 124

2-{3-[2-(3,4-Dimetilfenil)etil]fenilamino}benzoeva kiselina. T.t. 182-184 °C. 2-{3-[2-(3,4-Dimethylphenyl)ethyl]phenylamino}benzoic acid. T.t. 182-184 °C.

PRIMJER 125 EXAMPLE 125

2-{4-[2-(2,4-Dimetoksifenil)etil]fenilamino}benzoeva kiselina. T.t. 180-181 °C. 2-{4-[2-(2,4-Dimethoxyphenyl)ethyl]phenylamino}benzoic acid. T.t. 180-181 °C.

PRIMJER 126 EXAMPLE 126

2-{4-[2-(2-Klorfenil)etil]fenilamino}benzoeva kiselina. T.t. 140-143 °C. 2-{4-[2-(2-Chlorophenyl)ethyl]phenylamino}benzoic acid. T.t. 140-143 °C.

PRIMJER 127 EXAMPLE 127

2-{4-[2-(2-Hidroksifenil)etil]fenilamino}benzoeva kiselina. T.t. 218-219 °C. 2-{4-[2-(2-Hydroxyphenyl)ethyl]phenylamino}benzoic acid. T.t. 218-219 °C.

PRIMJER 128 EXAMPLE 128

2-{4-[2-(3-Klorfenil)etil]fenilamino}benzoeva kiselina. T.t. 152-154 °C. 2-{4-[2-(3-Chlorophenyl)ethyl]phenylamino}benzoic acid. T.t. 152-154 °C.

PRIMJER 129 EXAMPLE 129

2-[4-(2-Bifenil-4-iletil)fenilamino]benzoeva kiselina. T.t. 200-202 °C. 2-[4-(2-Biphenyl-4-ylethyl)phenylamino]benzoic acid. T.t. 200-202 °C.

PRIMJER 130 EXAMPLE 130

2-{4-[2-(2,4-Diklorfenil)etil]fenilamino}benzoeva kiselina. T.t. 181-183 °C. 2-{4-[2-(2,4-Dichlorophenyl)ethyl]phenylamino}benzoic acid. T.t. 181-183 °C.

PRIMJER 131 EXAMPLE 131

3-{4-[2-(3,4-Diklorfenil)etil]fenilamino}benzoeva kiselina. T.t. 137-138 °C. 3-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}benzoic acid. T.t. 137-138 °C.

PRIMJER 132 EXAMPLE 132

4-{4-[2-(3,4-Diklorfenil)etil]fenilamino}benzoeva kiselina. T.t. 214-215 °C. 4-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}benzoic acid. T.t. 214-215 °C.

PRIMJER 133 EXAMPLE 133

2-{4-[2-(3,4,5-Trimetoksifenil)etil]fenilamino}benzoeva kiselina. T.t. 146-147 °C. 2-{4-[2-(3,4,5-Trimethoxyphenyl)ethyl]phenylamino}benzoic acid. T.t. 146-147 °C.

PRIMJER 134 EXAMPLE 134

2-{4-[2-(4-Fenoksifenil)etil]fenilamino}benzoeva kiselina. T.t. 153-154 °C. 2-{4-[2-(4-Phenoxyphenyl)ethyl]phenylamino}benzoic acid. T.t. 153-154 °C.

PRIMJER 135 EXAMPLE 135

2-{4-[5-(3,4-Diklorfenil)pentil]fenilamino}benzoeva kiselina. T.t. 106-108 °C. 2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}benzoic acid. T.t. 106-108 °C.

PRIMJER 136 EXAMPLE 136

2-(4-{2-[4-(2-Hidroksikarbonilfenilamino)fenil]etil}fenilamino)benzoeva kiselina. MS: 451 (M-1). 2-(4-{2-[4-(2-Hydroxycarbonylphenylamino)phenyl]ethyl}phenylamino)benzoic acid. MS: 451 (M-1).

PRIMJER 137 EXAMPLE 137

2-(3',5'-Diklorbifenil-4-ilamino)benzoeva kiselina. T.t. >220 °C. 2-(3',5'-Dichlorobiphenyl-4-ylamino)benzoic acid. T.t. >220 °C.

PRIMJER 138 EXAMPLE 138

4-{4-[3-(3,4-Diklorfenil)propil]fenilamino}-2-metoksi-5-nitrobenzoeva kiselina. T.t. 74-78 °C. 4-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-2-methoxy-5-nitrobenzoic acid. T.t. 74-78 °C.

PRIMJER 139 EXAMPLE 139

2-{4-[3-(3,4-Diklorfenil)propil]fenilamino}-5-fluorbenzoeva kiselina. T.t. 122-123 °C. 2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-fluorobenzoic acid. T.t. 122-123 °C.

PRIMJER 140 EXAMPLE 140

5-Amino-2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}benzoeva kiselina. T.t. 182-184 °C. 5-Amino-2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}benzoic acid. T.t. 182-184 °C.

PRIMJER 141 EXAMPLE 141

N-(2-{4-[3-(3,4-Diklorfenil)propil]fenilamino}benzoil)-C,C,C-trifluormetansulfonamid. MS: 531 (M-). N-(2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}benzoyl)-C,C,C-trifluoromethanesulfonamide. MS: 531 (M-).

PRIMJER 142 EXAMPLE 142

N-(2-{4-[3-(3,4-Diklorfenil)propil]fenilamino}benzoil)benzensulfonamid. MS: 539. N-(2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}benzoyl)benzenesulfonamide. MS: 539.

PRIMJER 143 EXAMPLE 143

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina. T.t. 190-192 °C; MS: 453 (M-1) 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid. T.t. 190-192 °C; MS: 453 (M-1)

PRIMJER 144 EXAMPLE 144

4-{4-[2-(3,4-Diklorfenil)etil]fenilamino}izoftalna kiselina. T.t. 264-266 °C. 4-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}isophthalic acid. T.t. 264-266 °C.

PRIMJER 145 EXAMPLE 145

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-4-trifluormetilbenzoeva kiselina. T.t. 134-136 °C; MS: 454 (M+). 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-4-trifluoromethylbenzoic acid. T.t. 134-136 °C; MS: 454 (M+).

PRIMJER 146 EXAMPLE 146

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-3-trifluormetilbenzoeva kiselina. MS: 454 (M+). 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-3-trifluoromethylbenzoic acid. MS: 454 (M+).

PRIMJER 147 EXAMPLE 147

2-({4-[2-(3,4-Diklorfenil)etil]fenil}metilamino)-5-dimetilaminobenzoeva kiselina. T.t. 128-131 °C. 2-({4-[2-(3,4-Dichlorophenyl)ethyl]phenyl}methylamino)-5-dimethylaminobenzoic acid. T.t. 128-131 °C.

PRIMJER 148 EXAMPLE 148

2-({4-[2-(3,4-Diklorfenil)etil]fenil}metilamino)benzoeva kiselina. MS: 400 (M+). 2-({4-[2-(3,4-Dichlorophenyl)ethyl]phenyl}methylamino)benzoic acid. MS: 400 (M+).

PRIMJER 149 EXAMPLE 149

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-5-dipropilaminobenzoeva kiselina. MS: 485 (M+). 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-5-dipropylaminobenzoic acid. MS: 485 (M+).

PRIMJER 150 EXAMPLE 150

5-Dibutilamino-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina. MS: 513 (M+). 5-Dibutylamino-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid. MS: 513 (M+).

PRIMJER 151 EXAMPLE 151

2-{4-[2-(3,4-Diklorfenil)etil]fenilamino}-5-dietilaminobenzoeva kiselina. T.t. 106-110 °C. 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-5-diethylaminobenzoic acid. T.t. 106-110 °C.

PRIMJER 152 EXAMPLE 152

2,2'-[Etan-1,2-diilbis(4,1-fenilenimino)]bisbenzoeva kiselina. 2,2'-[Ethane-1,2-diylbis(4,1-phenyleneimino)]bisbenzoic acid.

PRIMJER 153 EXAMPLE 153

4-{3-[4-(Dietilamino)fenil]propil}-N-(2-metoksi-5-nitrofenil)benzilamin. 4-{3-[4-(Diethylamino)phenyl]propyl}-N-(2-methoxy-5-nitrophenyl)benzylamine.

PRIMJER 154 EXAMPLE 154

2-{3-[2-(4-Klorfenil)etil]fenilamino}benzoeva kiselina. 2-{3-[2-(4-Chlorophenyl)ethyl]phenylamino}benzoic acid.

PRIMJER 155 EXAMPLE 155

2-{3-[3-(3,4-Diklorfenil)propil]fenilamino}benzoeva kiselina. 2-{3-[3-(3,4-Dichlorophenyl)propyl]phenylamino}benzoic acid.

PRIMJER 156 EXAMPLE 156

2-{3-[3-(3,4-Dietilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{3-[3-(3,4-Diethylaminophenyl)propyl]phenylamino}benzoic acid.

PRIMJER 157 EXAMPLE 157

2-{3-[3-(4-Di-n-propilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{3-[3-(4-Di-n-propylaminophenyl)propyl]phenylamino}benzoic acid.

Idući Primjeri 158-163 prikazuju primjenu spojeva iz izuma kao polaznih materijala u sintezi drugih spojeva iz izuma i njihovih derivata. Primjeri prikazuju redukciju nitro skupine u amino skupinu, alkilaciju amino skupine i esterifikaciju karboksilne skupine. Ove reakcije su prikazane u slijedećoj poopćenoj Shemi 12. The following Examples 158-163 show the use of compounds from the invention as starting materials in the synthesis of other compounds from the invention and their derivatives. Examples show reduction of a nitro group to an amino group, alkylation of an amino group, and esterification of a carboxyl group. These reactions are shown in the following generalized Scheme 12.

[image] [image]

gdje su Rb i Rc definirani ranije, dok je E skupina koja sudjeluje u nastajanju estera kao što su C1-C6 alkil (npr. metil, 2,2,2-trikloretil), benzil, difenilmetil, ili slične. where Rb and Rc are defined earlier, while E is a group that participates in the formation of esters such as C1-C6 alkyl (eg methyl, 2,2,2-trichloroethyl), benzyl, diphenylmethyl, or the like.

PRIMJER 158 EXAMPLE 158

2-{4-[3-(4-Nitrofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Nitrophenyl)propyl]phenylamino}benzoic acid.

U gustu smjesu 4-[3-(4-nitrofenil)propil]anilina (4,08 g, 15,9 mmola) i 2-brombenzojeve kiseline (3,52 g, 17,5 mmola) u i-PrOH (100 ml) dodani su Cu(OAc)2 (87 mg, 0,478 mmola) i KOAc (3,44 g, 35,0 mmola) pri sobnoj temperaturi. Nastala smjesa je zagrijavana 23 sata uz refluks, a zatim ohlađena na sobnu temperaturu. Nakon uklanjanja otapala pri sniženom tlaku, ostatak je razrijeđen s vodom (100 ml) i zalužen 1,0 M vodenom otopinom NaOH do pH 9,0. Vodeni sloj je ispran s Et2O (20 ml, dva puta), a zatim zakiseljen s 1,0 M vodenom otopinom HCl do pH 3,0. Nastali talog je odsisan i osušen pri 60 °C u vakuumu, dajući naslovni spoj u obliku žućkastosive krutine (5,75 g, 96 % prinos). T.t. 150-153 °C. MS (Fab): 376 (MH+). To a thick mixture of 4-[3-(4-nitrophenyl)propyl]aniline (4.08 g, 15.9 mmol) and 2-bromobenzoic acid (3.52 g, 17.5 mmol) in i-PrOH (100 ml ) were added Cu(OAc)2 (87 mg, 0.478 mmol) and KOAc (3.44 g, 35.0 mmol) at room temperature. The resulting mixture was heated for 23 hours under reflux and then cooled to room temperature. After removal of the solvent under reduced pressure, the residue was diluted with water (100 ml) and basified with 1.0 M aqueous NaOH to pH 9.0. The aqueous layer was washed with Et2O (20 mL, twice) and then acidified with 1.0 M aqueous HCl to pH 3.0. The resulting precipitate was filtered off with suction and dried at 60 °C in vacuo to give the title compound as a yellowish gray solid (5.75 g, 96% yield). T.t. 150-153 °C. MS (Fab): 376 (MH+).

PRIMJER 159 EXAMPLE 159

2-{4-[3-(4-Aminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Aminophenyl)propyl]phenylamino}benzoic acid.

U otopinu 2-{4-[3-(4-nitrofenil)propil]fenilamino}benzojeve kiseline. (Primjer 158) (3,0 g, 7,97 mmola) u DMF (40 ml) dodan je, 10 %-tni Pd-C (300 mg) pri sobnoj temperaturi, u atmosferi argona. U tikvicu je uveden plinoviti vodik (101,33 kPa) i smjesa je miješana 14 sati pri sobnoj temperaturi. Reakcijska smjesa je filtrirana kroz sloj Celita radi uklanjanja Pd-C, te je koncentrirana pri sniženom tlaku. Ostatak je razrijeđen s MeOH (ca. 50 ml) i uparen u vakuumu. Ovaj postupak je ponovljen 3 puta radi uklanjanja tragova DMF-a. Ostatak je ponovno razrijeđen s MeOH, a netopljivi dio je otfiltriran. Uparavanjem otapala iz filtrata zaostaje ulje koje je razrijeđeno s CH3CN (50 ml), a zatim je u otopinu polagano dokapana voda (100 ml). Nastali talog je otfiltriran i osušen pri 60 °C u vakuumu dajući naslovni spoj kao bijelu krutinu (2,34 g, 85 % prinos). T.t. 110-112 °C. MS (Fab): 347 (MH+). In a solution of 2-{4-[3-(4-nitrophenyl)propyl]phenylamino}benzoic acid. (Example 158) (3.0 g, 7.97 mmol) in DMF (40 mL) was added 10% Pd-C (300 mg) at room temperature under an argon atmosphere. Hydrogen gas (101.33 kPa) was introduced into the flask and the mixture was stirred for 14 hours at room temperature. The reaction mixture was filtered through a layer of Celite to remove Pd-C, and was concentrated under reduced pressure. The residue was diluted with MeOH (ca. 50 ml) and evaporated in vacuo. This procedure was repeated 3 times to remove traces of DMF. The residue was diluted again with MeOH, and the insoluble part was filtered off. After evaporating the solvent from the filtrate, an oil remains, which is diluted with CH3CN (50 ml), and then water (100 ml) is slowly added to the solution. The resulting precipitate was filtered off and dried at 60 °C in vacuo to give the title compound as a white solid (2.34 g, 85% yield). T.t. 110-112 °C. MS (Fab): 347 (MH+).

PRIMJER 160 EXAMPLE 160

Metilni ester 2-{4-[3-(4-aminofenil)propil]fenilamino}benzojeve kiseline. 2-{4-[3-(4-aminophenyl)propyl]phenylamino}benzoic acid methyl ester.

U otopinu 2-{4-[3-(4-aminofenil)propil]fenilamino}benzojeve kiseline (Primjer 159) (2,34 g, 6,75 mmola) u MeOH (50 ml) dodana je koncentrirana H2SO4 (1,0 ml) pri sobnoj temperaturi. Smjesa je mješana pri refluksu otapala 3,0 dana. Reakcija je prekinuta dodatkom Et3N (10 ml) pri 5 °C, a otapalo je uklonjeno pri sniženom tlaku. Ostatak je razrijeđen vodom (20 ml) i ekstrahiran s Et2O (20 ml, 4 puta). Spojeni eterski slojevi su isprani vodom (10 ml) i zasićenom otopinom NaCl (10 ml), te sušeni na bezvodnom Na2SO4. Otapalo je upareno u vakuumu, a pročišćavanjem kolonskom kromatografijom dobiven je naslovni spoj u obliku žutog amorfnog materijala (2,59 g). Ovaj materijal je dalje korišten bez dodatnog pročišćavanja. To a solution of 2-{4-[3-(4-aminophenyl)propyl]phenylamino}benzoic acid (Example 159) (2.34 g, 6.75 mmol) in MeOH (50 ml) was added conc. ml) at room temperature. The mixture was stirred at solvent reflux for 3.0 days. The reaction was quenched by the addition of Et 3 N (10 ml) at 5 °C, and the solvent was removed under reduced pressure. The residue was diluted with water (20 ml) and extracted with Et 2 O (20 ml, 4 times). The combined ether layers were washed with water (10 ml) and saturated NaCl solution (10 ml), and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and purification by column chromatography afforded the title compound as a yellow amorphous material (2.59 g). This material was further used without further purification.

PRIMJER 161 EXAMPLE 161

Metilni ester 2-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzojeve kiseline i 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid methyl ester and

metilni ester 2-{4-[3-(4-etilaminofenil)propil]fenilamino}benzojeve kiseline. 2-{4-[3-(4-ethylaminophenyl)propyl]phenylamino}benzoic acid methyl ester.

U otopinu sirovog estera opisanog gore (2,59 g, ~ 6,75 mmola) i CH3CHO (2,0 ml, 35,1 mmol) u CH3CN (50 ml) dodan je NaBH3CN (1,70 g, 27,0 mmola) pri 5 °C te je nastala suspenzija miješana 30 minuta. Tijekom tog vremena praćen je pH i dodavanjem 1.0 M vodene otopine HCl reakcijska smjesa je održavana u blago kiselom području (pH 3,0-4,0). Reakcijska smjesa se ostavi da postigne sobnu temperaturu tijekom jednog sata, a zatim zaluži s 1,0 M vodenom otopinom NaOH do pH 9,0. Reakcijska smjesa je uparena pri sniženom tlaku da se ukloni CH3CN, a dobivena vodena otopina je zakiseljena s 1,0 M vodenom otopinom HCl do pH 3,0. Vodena otopina je zatim ekstrahirana s CHCl3 (20 ml, 3 puta), a spojeni ekstrakti su isprani s zasićenom otopinom NaCl (5 ml). Nakon sušenja na bezvodnom Na2SO4, otapalo je upareno na vakuumu, a ostatak je pročišćen kolonskom kromatografijom (silikagel 60 N, n-heksan/CHCl3/Et3N 50:98:2). Prvi eluat je dialkilirani produkt, izoliran u obliku žutog amorfnog materijala (1,07 g, 38 %). To a solution of the crude ester described above (2.59 g, ~6.75 mmol) and CH3CHO (2.0 mL, 35.1 mmol) in CH3CN (50 mL) was added NaBH3CN (1.70 g, 27.0 mmol ) at 5 °C and the resulting suspension was stirred for 30 minutes. During this time, the pH was monitored and by adding 1.0 M aqueous HCl solution, the reaction mixture was maintained in a slightly acidic range (pH 3.0-4.0). The reaction mixture was allowed to reach room temperature for one hour and then basified with 1.0 M aqueous NaOH to pH 9.0. The reaction mixture was evaporated under reduced pressure to remove CH 3 CN and the resulting aqueous solution was acidified with 1.0 M aqueous HCl to pH 3.0. The aqueous solution was then extracted with CHCl 3 (20 ml, 3 times) and the combined extracts were washed with saturated NaCl solution (5 ml). After drying over anhydrous Na2SO4, the solvent was evaporated under vacuum, and the residue was purified by column chromatography (silica gel 60 N, n-hexane/CHCl3/Et3N 50:98:2). The first eluate is the dialkylated product, isolated as a yellow amorphous material (1.07 g, 38 %).

MS (Fab): 417 (MH+). MS (Fab): 417 (MH+).

Slijedeći eluat je monoalkilirani produkt, izoliran u obliku žutog amorfnog materijala (0,79 g, 30 %). The next eluate is the monoalkylated product, isolated as a yellow amorphous material (0.79 g, 30 %).

MS (Fab): 389 (MH+). MS (Fab): 389 (MH + ).

PRIMJER 162 EXAMPLE 162

2-{4-[3-(4-Dietilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid.

U emulziju metilnog estera 2-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzojeve kiseline (1,68 g, 4,03 mmola) u EtOH (50 ml) dodana je 3 M vodena otopina KOH (4,0 ml, 12,0 mmola) pri sobnoj temperaturi, a zatim je smjesa zagrijavana 40 minuta pri refluksu otapala. Reakcijska smjesa je ohlađena na sobnu temperaturu i neutralizirana s 1,0 M vodenom otopinom HCl do pH 9.0. Smjesa je koncentrirana u vakuumu da se ukloni EtOH, a nastala vodena otopina je ekstrahirana s CHCl3 (50 ml, 3 puta). Spojeni ekstrakti su isprani s zasićenom otopinom NaCl (10 ml), i osušeni na bezvodnom Na2SO4. Nakon uparavanja otapala pri sniženom tlaku, pročišćavanjem ostatka kolonskom kromatografijom (silikagel 60N, konc. NH4OH/MeOH/CHCl3 0,2:2:100 do 0,5:5:100) dobiveno je žuto ulje. Dobiveno ulje je razrijeđeno je acetonom, adobivena otopina je uparena u vakuumu pri sobnoj temperaturi dajući naslovni spoj u obliku amorfne krutine (1,62 g, 99 % za 0,2 hidrat). To an emulsion of 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid methyl ester (1.68 g, 4.03 mmol) in EtOH (50 mL) was added 3 M aqueous KOH (4, 0 ml, 12.0 mmol) at room temperature, and then the mixture was heated for 40 minutes at solvent reflux. The reaction mixture was cooled to room temperature and neutralized with 1.0 M aqueous HCl solution to pH 9.0. The mixture was concentrated in vacuo to remove EtOH, and the resulting aqueous solution was extracted with CHCl 3 (50 mL, 3 times). The combined extracts were washed with saturated NaCl solution (10 ml), and dried over anhydrous Na2SO4. After evaporation of the solvent under reduced pressure, purification of the residue by column chromatography (silica gel 60N, conc. NH4OH/MeOH/CHCl3 0.2:2:100 to 0.5:5:100) yielded a yellow oil. The resulting oil was diluted with acetone, the resulting solution was evaporated in vacuo at room temperature to give the title compound as an amorphous solid (1.62 g, 99% for 0.2 hydrate).

MS (Fab): 403 (MH+). MS (Fab): 403 (MH+).

Analiza za C26H30N2O2 x 0,20 H2O: Rač.: C, 76,89; H, 7,54; N, 6,90. Analysis for C 26 H 30 N 2 O 2 x 0.20 H 2 O: Calc.: C, 76.89; H, 7.54; N, 6.90.

Nađeno: C, 76,73; H, 7,67; N, 7,10. Found: C, 76.73; H, 7.67; N, 7,10.

PRIMJER 163 EXAMPLE 163

2-{4-[3-(4-Etilaminofenil)propil]fenilamino}benzoeva kiselina. 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoic acid.

Naslovni spoj je pripravljen iz metilnog estera 2-{4-[3-(4-etilaminofenil)propil]fenilamino}benzojeve kiseline (iz Primjera 161), EtOH (10 ml) i 3 M otopine KOH (1,0 ml) primjenjujući postupak opisan u Primjeru 162. Ovaj postupak je dao 253 mg željenog produkta (90 % za 0,1 hidrat), u obliku žute krutine. The title compound was prepared from 2-{4-[3-(4-ethylaminophenyl)propyl]phenylamino}benzoic acid methyl ester (from Example 161), EtOH (10 ml) and 3 M KOH solution (1.0 ml) using the procedure described in Example 162. This procedure gave 253 mg of the desired product (90% for 0.1 hydrate), as a yellow solid.

MS (Fab): 375 (MH+). MS (Fab): 375 (MH+).

Analiza za C24H26N2O2 x 0,10 H2O: Rač.: C, 76,61; H, 7,02; N, 7,44. Analysis for C24H26N2O2 x 0.10 H2O: Calc.: C, 76.61; H, 7.02; N, 7.44.

Nađeno: C, 76,62; H, 7,06; N, 7,36. Found: C, 76.62; H, 7.06; N, 7.36.

BIOLOŠKI PRIMJERI BIOLOGICAL EXAMPLES

Reprezentativni spojevi Formule I su ocijenjeni u nekoliko in vitro i in vivo testova koji su prihvaćeni kao pokazatelji kliničke korisnosti u liječenju Alzheimerove bolesti. Representative compounds of Formula I have been evaluated in several in vitro and in vivo assays that have been accepted as indicators of clinical utility in the treatment of Alzheimer's disease.

TESTOVI NA AMILOIDE AMYLOID TESTS

BASSR ( Radiotest samoaktivirajućih beta-amiloida, "Beta-Amyloid Self-Seeding Radioassay") BASSR (Beta-Amyloid Self-Seeding Radioassay)

Test za inhibitore rasta samoaktivirajućih amiloidnih vlakana. Assay for growth inhibitors of self-activating amyloid fibrils.

Materijali: Materials:

Pripremljene otopine: Prepared solutions:

Testni pufer - 50 mM natrijev fosfat, pH 7,5, 100 mM NaCl, 0,02 % NaN3, 1 M urea (profiltrirati i pohraniti pri 4 °C). Assay buffer - 50 mM sodium phosphate, pH 7.5, 100 mM NaCl, 0.02 % NaN3, 1 M urea (filter and store at 4 °C).

Topivi Aβ(1-40) peptid (Bachem, Torrance, CA) - 2,2 mg/ml u deioniziranoj H2O (pohranjeno u alikvotima pri 20 °C, nakon odmrzavanja držati na ledu) će se sam aktivirati nakon 1 tjedna stajanja. Tipično, otopina treba biti pohranjena sve dok ne prestane stvaranje zaostale faze u testu. Soluble Aβ(1-40) peptide (Bachem, Torrance, CA) - 2.2 mg/ml in deionized H2O (stored in aliquots at 20 °C, keep on ice after thawing) will self-activate after 1 week of standing. Typically, the solution should be stored until no residual phase has formed in the test.

125I-označeni Aβ(1-40) - 150K - 350K cpm/μl u 100 % acetonitrilu - 0,1 % trifloroctena kiselina (TFA) - 1 % βmerkaptoetanol (alikvoti pohranjeni na -20 °C). 125I-označeni Aβ(1-40) se može pripraviti prema postupku kojeg je opisao H. LeVine, III u "Neurobiol. Aging", 16, 755, (1995), koji je ovdje uključen referencom, ili se ovaj reagens može kupiti od Amersham, Arlington Heights, Illinois. 125I-labeled Aβ(1-40) - 150K - 350K cpm/μl in 100% acetonitrile - 0.1% trifluoroacetic acid (TFA) - 1% βmercaptoethanol (aliquots stored at -20 °C). 125I-labeled Aβ(1-40) can be prepared according to the procedure described by H. LeVine, III in "Neurobiol. Aging", 16, 755, (1995), which is incorporated herein by reference, or this reagent can be purchased from Amersham, Arlington Heights, Illinois.

Konačni uvjeti testa: 30 μM topivog Aβ(1-40) u deioniziranoj vodi u testnom puferu + 20K - 50K cpm 125I-označenog Aβ(1-40) po testu. Testirani spoj je otopljen u dimetilsulfoksidu (DMSO), tipično u 5 - 50 mM količinama, tako da je konačna koncentracija DMSO < 1 % (volumni) pri testu. Final assay conditions: 30 μM soluble Aβ(1-40) in deionized water in assay buffer + 20K - 50K cpm 125I-labeled Aβ(1-40) per assay. The test compound is dissolved in dimethylsulfoxide (DMSO), typically in 5 - 50 mM amounts, so that the final concentration of DMSO is < 1% (volume) in the test.

Test: Reakcijska smjesa za 50 testova (na ledu) obuhvaća 0,1 do 0,2 μl 125I-označenog A125I-označenog Aβ(1-40) + 1 μl topivog Aβ(1-40) + 13,5 μl testnog pufera po testu. U daljnjem tekstu su navedene količine komponenti reakcijske smjese dovoljne za 50 testnih uzoraka. Assay: The reaction mixture for 50 tests (on ice) comprises 0.1 to 0.2 μl of 125I-labeled A125I-labeled Aβ(1-40) + 1 μl of soluble Aβ(1-40) + 13.5 μl of assay buffer per the test. In the following text, the amounts of the components of the reaction mixture are sufficient for 50 test samples.

5-10 μl 125I-označenog Aβ(1-40) osušenog do suha 5-10 μl of 125I-labeled Aβ(1-40) dried to dryness

675 μl testnog pufera 675 μl of assay buffer

50 μl topivog Aβ(1-40). 50 μl of soluble Aβ(1-40).

Testna metoda: Test method:

1) Pripraviti gore navedenu reakcijsku smjesu miješanjem komponenti i pohranjivanjem na ledu. 1) Prepare the above reaction mixture by mixing the components and storing on ice.

2) Pipetirati 14,5 μl reakcijske smjese u svaku od 50 jažica na polipropilenskoj mikrotiter pločici, U - oblika, s 96 jažica (Costar 3794). 2) Pipette 14.5 μl of the reaction mixture into each of the 50 wells on a polypropylene microtiter plate, U-shaped, with 96 wells (Costar 3794).

3) Dodati 1,7 μl razrijeđenog testnog spoja u svaku jažicu, u koloni po 8, uključujući i kontrolni uzorak s otapalom. Serijsko trostruko razrijeđivanje od 1 mM (100 μM konačno), u testnom puferu - urea = 7 razrijeđenja + nula. Stoga se na svaku pločicu s 96 jažica može smjestiti 11 uzoraka + Kongo crveno kontrola (0,039 -5 μM konačno u dvostrukim koracima). 3) Add 1.7 μl of diluted test compound to each well, in a column of 8, including the solvent control sample. Serial 3-fold dilution of 1 mM (100 μM final), in assay buffer - urea = 7 dilutions + zero. Therefore, each 96-well plate can accommodate 11 samples + Congo red control (0.039 -5 μM final in duplicate steps).

4) Zatvoriti pločicu s aluminijskim filmom (Beckman 538619) i inkubirati 10 minuta na ledu. 4) Close the plate with aluminum film (Beckman 538619) and incubate for 10 minutes on ice.

5) Povisiti temperaturu do 37 °C i inkubirati 3 do 5 sati (ovisno o količini peptida). 5) Raise the temperature to 37 °C and incubate for 3 to 5 hours (depending on the amount of peptide).

6) Ukloniti aluminijski film i dodati 200 μl/jažica ledeno hladnog testnog pufera s ureom, skupljajući radioaktivno označena vlakanca vakuum filtracijom kroz GVWP filtere s porama veličine 0,2 μm, u pločice s 96 jažica (Millipore MAGV N22, Bedford, MA). Odrediti radioaktivnost filtera korištenjem standardnih metoda dobro poznatima stručnjaku u području. 6) Remove aluminum foil and add 200 μl/well of ice-cold urea assay buffer, collecting radiolabeled fibers by vacuum filtration through 0.2 μm pore size GVWP filters into 96-well plates (Millipore MAGV N22, Bedford, MA). Determine the radioactivity of the filter using standard methods well known to those skilled in the art.

BASST (Samoaktiviranje beta amiloida, Tioflavin T) BASST (Self-activation of beta amyloid, Thioflavin T)

Test za inhibitore rasta samoaktivirajućih amiloidnih vlakana. Assay for growth inhibitors of self-activating amyloid fibrils.

METODE: METHODS:

Materijali: Materials:

Pripremljene otopine: Prepared solutions:

Testni pufer - 50 mM natrijev fosfat, pH 7,5, 100 mM NaCl, 0,02 % NaN3, 1 M urea (profiltrirati i pohraniti pri 4 °C). Assay buffer - 50 mM sodium phosphate, pH 7.5, 100 mM NaCl, 0.02 % NaN3, 1 M urea (filter and store at 4 °C).

Topivi Aβ(1-40) peptid - 2,2 mg/ml u deioniziranoj H2O (pohranjeno u alikvotima pri -20 °C, nakon odmrzavanja držati na ledu) će se sam aktivirati nakon 1 tjedna stajanja. Tipično, otopina treba biti pohranjena sve dok ne prestane stvaranje zaostale faze u testu. Soluble Aβ(1-40) peptide - 2.2 mg/ml in deionized H2O (stored in aliquots at -20 °C, keep on ice after thawing) will self-activate after 1 week of standing. Typically, the solution should be stored until no residual phase has formed in the test.

Konačni uvjeti testa: 30 μM topivog Aβ(1-40) u deioniziranoj vodi u testnom puferu. Testirani spoj je otopljen u dimetilsulfoksidu (DMSO), tipično u 5 - 50 mM količinama, tako da je konačna koncentracija DMSO < 1 % (volumni) pri testu. Final assay conditions: 30 μM soluble Aβ(1-40) in deionized water in assay buffer. The test compound is dissolved in dimethylsulfoxide (DMSO), typically in 5 - 50 mM amounts, so that the final concentration of DMSO is < 1% (volume) in the test.

Test: Reakcijska smjesa za 50 testova (na ledu) obuhvaća 1 μl topivog Aβ(1-40) + 13,5 μl testnog pufera po testu. U daljnjem tekstu su navedene količine komponenti reakcijske smjese koja se dobije u svakom od 50 testnih jažica. Assay: The reaction mixture for 50 tests (on ice) includes 1 μl of soluble Aβ(1-40) + 13.5 μl of assay buffer per test. In the following text, the quantities of the components of the reaction mixture obtained in each of the 50 test wells are listed.

50 μl topivog Aβ(1-40) 50 μl of soluble Aβ(1-40)

675 μl testnog pufera 675 μl of assay buffer

Testna metoda: Test method:

1) Pripraviti gore navedenu reakcijsku smjesu miješanjem komponenti i pohranjivanjem na ledu. 1) Prepare the above reaction mixture by mixing the components and storing on ice.

2) Pipetirati 14,5 μl reakcijske smjese u svaku od 50 jažica na polistirenskoj mikrotiter pločici, U - oblika, s 96 jažica (Corning 25881-96) na ledu. 2) Pipette 14.5 μl of the reaction mixture into each of 50 wells on a U-shaped, 96-well polystyrene microtiter plate (Corning 25881-96) on ice.

3) Dodati 1,7 μl razrijeđenog testnog spoja u svaku jažicu, u koloni po 8, uključujući i kontrolni uzorak s otapalom. Serijsko trostruko razrijeđivanje od 1 mM (100 μM konačno), u testnom puferu - urea = 7 razrijeđenja + nula. Stoga se na svaku pločicu s 96 jažica može smjestiti 11 uzoraka + Kongo crveno kontrola (0,039 -5 μM konačno u dvostrukim koracima). 3) Add 1.7 μl of diluted test compound to each well, in a column of 8, including the solvent control sample. Serial 3-fold dilution of 1 mM (100 μM final), in assay buffer - urea = 7 dilutions + zero. Therefore, each 96-well plate can accommodate 11 samples + Congo red control (0.039 -5 μM final in duplicate steps).

4) Zatvoriti pločicu s aluminijskim filmom i inkubirati 10 minuta na ledu. 4) Close the plate with aluminum film and incubate for 10 minutes on ice.

5) Povisiti temperaturu do 37 °C i inkubirati 3 do 5 sati (ovisno o količini peptida). 5) Raise the temperature to 37 °C and incubate for 3 to 5 hours (depending on the amount of peptide).

6) Ukloniti aluminijski film i dodati 250 μl/jažica otopine 5 μM tioflavina T (ThT) [T-3516, Sigma-Aldrich] u 50 mM glicin-NaOH, pH 8,5. Očitavati fluorescenciju na čitaču pločica (ex = 440 nm / 20 nm; em = 485 nm / 20 nm) tijekom 5 minuta. 6) Remove the aluminum film and add 250 μl/well of a solution of 5 μM thioflavin T (ThT) [T-3516, Sigma-Aldrich] in 50 mM glycine-NaOH, pH 8.5. Read the fluorescence on a plate reader (ex = 440 nm / 20 nm; em = 485 nm / 20 nm) for 5 minutes.

BAPA (Agregacija beta-amiloidnih peptida) BAPA (beta-amyloid peptide aggregation)

Ovaj test je primjenjen radi mjerenja inhibicije agregacije beta amiloidnog peptida spojem. This test was applied to measure the inhibition of beta amyloid peptide aggregation by the compound.

Svrha ovog testa je omogućiti metodu testiranja većih volumena na količinu agregacije beta amiloida koristeći test na završetak agregacije baziran na filtraciji. U ovom testu, heksafluorizopropanol (HFIP) je primjenjen radi razgradnje početnog amiloidnog peptida u monomerne jedinice i korištena je koncentracija od 33 μM koja je dovoljna da agregacija počne pri pH 6,0 u roku od nekoliko sati. The purpose of this assay is to provide a method of testing larger volumes for the amount of beta amyloid aggregation using a filtration-based aggregation termination assay. In this assay, hexafluoroisopropanol (HFIP) was used to degrade the starting amyloid peptide into monomeric units and a concentration of 33 μM was used, which is sufficient to initiate aggregation at pH 6.0 within a few hours.

METODE: METHODS:

Agregacija β-amiloida, pH 6,0 (BAPA) β-amyloid aggregation, pH 6.0 (BAPA)

Na pločicu s 96 jažica (Costar 3794) doda se 25 μl 50 mM fosfatnog pufera, pH 6,0, 10 μl 0,5 mg/ml Aβ(1-40) peptida u 20 % HFIP + 0,1 ml/test radiojodiranog 125I Aβ(1-40) [125I Aβ(1-40)], i 1 μl testiranog spoja polazeći od 50 mM s koncentracijom DMSO < 1%. Zatim slijedi inkubacija u vremenu od 2 do 4 sata pri sobnoj temperaturi. Reakcija se zaustavi s 200 μl 50 mM fosfatnog pufera, pH 6,0 i filtrira kroz 0,2 μm filter pločicu s 96 jažica (Millipore MAGU N22). Filter pločica se ispere s 100 μl istog fosfatnog pufera. Agregacija je detektirana na Mikrobeta brojaču nakon impregniranja filtera s Meltilex (1450-441) i korigirana na šum mjerenja. To a 96-well plate (Costar 3794) add 25 μl of 50 mM phosphate buffer, pH 6.0, 10 μl of 0.5 mg/ml Aβ(1-40) peptide in 20% HFIP + 0.1 ml/test radioiodinated 125I Aβ(1-40) [125I Aβ(1-40)], and 1 μl of the tested compound starting at 50 mM with a DMSO concentration < 1%. This is followed by incubation for 2 to 4 hours at room temperature. The reaction was stopped with 200 μl of 50 mM phosphate buffer, pH 6.0 and filtered through a 0.2 μm 96-well filter plate (Millipore MAGU N22). The filter plate is washed with 100 μl of the same phosphate buffer. Aggregation was detected on a Microbeta counter after impregnating the filter with Meltilex (1450-441) and corrected for measurement noise.

BATYM TEST BATYM TEST

METODE: METHODS:

Nužni Aβ(1-42) (California Peptide) je osušen od heksafluorizopropanolne otopine za čuvanje. Aβ(1-42) je otopljen u dimetilsulfoksidu (DMSO) i zatim pomješan s fosfatno puferiranom salinom (engl. PBS) (pH 7,4). Izmješana Aβ(1-42) otopina je filtrirana kroz 0,2 μm Omnipore membranski filter za injekcije (Millipore, Bedford, MA). Testirani spoj u DMSO (50 puta koncentriran je stavljen u svaku jažicu (0,5 μl/jažica) pločice s 96 jažica. Otopina Aβ(1-42) je dodana u svaku jažicu (24,5 μl/jažica). Pločica je centrifugirana pri 1,000 g 5 minuta i inkubirana pri 37 °C 1 dan (Aβ 1-42; konačna koncentracija 100 μM). The essential Aβ(1-42) (California Peptide) was dried from hexafluoroisopropanol storage solution. Aβ(1-42) was dissolved in dimethyl sulfoxide (DMSO) and then mixed with phosphate-buffered saline (PBS) (pH 7.4). The mixed Aβ(1-42) solution was filtered through a 0.2 μm Omnipore injection membrane filter (Millipore, Bedford, MA). Test compound in DMSO (50-fold concentrated) was added to each well (0.5 μl/well) of a 96-well plate. Aβ(1-42) solution was added to each well (24.5 μl/well). The plate was centrifuged at 1,000 g for 5 minutes and incubated at 37 °C for 1 day (Aβ 1-42; final concentration 100 μM).

Nakon inkubacije, otopina Tioflavina T (ThT) (30 μM) u puferu glicin - NaOH (pH 8,5, 50 mM) je dodana u svaku jažicu (250 μl/jažica) i mjerena je fluorescencija (ex = 440 nm / 20 nm; em = 485 nm / 20 nm) korištenjem čitača fluorescencije pločice. Aktivnost inhibitora je računata kao smanjenje fluorescencije prema slijedećoj formuli: After incubation, a solution of Thioflavin T (ThT) (30 μM) in glycine - NaOH buffer (pH 8.5, 50 mM) was added to each well (250 μl/well) and fluorescence was measured (ex = 440 nm / 20 nm ; em = 485 nm / 20 nm) using a plate fluorescence reader. Inhibitor activity was calculated as a decrease in fluorescence according to the following formula:

Inhibicija (%) = {F(Aβ)-F(Aβ+spoj)}/{F(Aβ)-F(otapalo+spoj)} x 100 Inhibition (%) = {F(Aβ)-F(Aβ+compound)}/{F(Aβ)-F(solvent+compound)} x 100

IC50 su izračunati s programom za fitanje krivulja koristeći slijedeće jednadžbe. Podaci su dobiveni iz dva različita eksperimenta provedenih po tri puta. IC50s were calculated with a curve fitting program using the following equations. Data were obtained from two different experiments performed three times each.

Inhibicija(x) = 100 - 100/{1+(x/IC50)n}, Inhibition(x) = 100 - 100/{1+(x/IC50)n},

x = koncentracija testnog spoja (M), x = concentration of the test compound (M),

IC50 = (M), IC50 = (M),

n= Hill-ov koeficijent. n= Hill's coefficient.

Reprezentativni spojevi Formule I pokazuju inhibicijsku aktivnost (IC50) u području od 0,1 μM do više od 100 μM u prethodnim testovima. Representative compounds of Formula I exhibit inhibitory activity (IC 50 ) in the range of 0.1 μM to greater than 100 μM in the foregoing assays.

Rezultati ovih testova za specifične i reprezentativne spojeve iz ovog izuma prikazani su dalje u Tablici 1. The results of these tests for specific and representative compounds of this invention are shown below in Table 1.

Tablica 1. Aktivnost Spojeva Formule I kao inhibitora β-amiloida Table 1. Activity of Compounds of Formula I as β-amyloid inhibitors

[image] [image] [image] [image] [image] [image]

Slovo u zagradama nakon određene vrijednosti ukazuje na određeni sintetizirani pripravak testiranog spoja. Oznake "P", "Q", "R", "S", "T" i "Z" označavaju različite pripravke istog spoja. Na primjer, 10 (P) indicira da je testirani uzorak pripremljen u Sintezi P. Ukoliko nije specificirano, podrazumjeva se da je uzorak iz Sinteze P. A letter in parentheses after a specific value indicates a specific synthesized preparation of the tested compound. The designations "P", "Q", "R", "S", "T" and "Z" indicate different preparations of the same compound. For example, 10 (P) indicates that the tested sample was prepared in Synthesis P. If not specified, it is assumed that the sample is from Synthesis P.

Skraćenica "ppt" označava talog i ukazuje na nastajanje taloga pri navedenoj koncentraciji. Nadalje, "u V obliku" označava primjećenu inhibiciju s naknadnim taloženjem. The abbreviation "ppt" stands for precipitate and indicates the formation of a precipitate at the specified concentration. Furthermore, "V-shaped" refers to the observed inhibition with subsequent deposition.

Vrijednost nakon koje slijedi neki broj i "x" (npr. 4x) označava da je spoj bio testiran 4 puta uz isti rezultat svakog mjerenja. A value followed by a number and an "x" (eg 4x) indicates that the compound was tested 4 times with the same result each time.

Spojevi iz izuma su također pokazali dobru aktivnost u standardnim testovima u živom organizmu (lat. in vivo), često korištenima za ocjenjivanjeagenasa za liječenje bolesti vezanih za agregaciju amiloidnih proteina, naročito Alzheimerove bolesti, i drugih amiloidoza. U jednom testu, amiloidni protein je potaknut u slezeni miševa davanjem injekcije srebro nitrata i Freundovog potpunog pomagala, pod kožu, te intravenoznom injekcijom faktora amiloidnog pojačavanja. Srebro nitrat je davan svaki dan do Dana 11. Testni spojevi su davani miševima svakog dana počevši od Dana 1 do Dana 11. Na Dan 12. životinje su žrtvovane, a slezena je uklonjena, histološki pripremljena, obojana Kongo crvenim, a postotak površine slezene pokriven birefraktivnim obojenim amiloidom kvantitativno određen mikroskopom. Spojevi iz ovog izuma, ispitani u ovom testu inhibirali su stvaranje amiloidnih naslaga u slezeni do 70 % u odnosu na neliječeni kontrolni eksperiment. The compounds of the invention also showed good activity in standard tests in a living organism (lat. in vivo), often used to evaluate agents for the treatment of diseases related to the aggregation of amyloid proteins, especially Alzheimer's disease, and other amyloidoses. In one test, amyloid protein was induced in the spleen of mice by injecting silver nitrate and Freund's complete medium under the skin, and by intravenously injecting amyloid-enhancing factor. Silver nitrate was administered daily until Day 11. Test compounds were administered to mice daily beginning on Day 1 through Day 11. On Day 12, the animals were sacrificed, and the spleen was removed, histologically prepared, stained with Congo red, and the percentage of spleen surface area covered birefringent stained amyloid quantitatively determined by microscope. The compounds of this invention tested in this test inhibited the formation of amyloid deposits in the spleen by up to 70% compared to the untreated control experiment.

Drugi in vivo test u kojem su spojevi iz izuma ispitani na transgenskim miševima, Miševi imaju transgen humanog β-amiloidnog proteina s prionskim promotorom što su opisali Hsiao et al., "Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice", Science 1966, 274, 99-102. Ovi transgenski miševi razvijaju β-amiloidne naslage pri ~ 9 mjeseci starosti. S 15 mjeseci, znaci difuzne i kompaktne senilnosti su zastupljeni, primarno u neokorteksu, olfaktornom mjehuru i hipokampusu. Spojevi iz izuma su davani oralno miševima od starosti 8 mjeseci (neposredno pred početak stvaranja amiloidnih naslaga), i davanje je nastavljeno nekoliko mjeseci (do starosti 14-18 mjeseci). Životinje su tada žrtvovane, a mozgovi uklonjeni. Količina amiloida u mozgu je kvantitativno određena i histološkim i biokemijskim putem. Spojevi iz izuma, ispitani u ovom modelu, imaju svojstvo inhibicije nakupljanja amiloida u moždanoj kori i hipokampusu do 49 % u odnosu na neliječeni kontrolni eksperiment. Another in vivo test in which the compounds of the invention were tested in transgenic mice, Mice having a human β-amyloid protein transgene with a prion promoter as described by Hsiao et al., "Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice", Science 1966, 274, 99-102. These transgenic mice develop β-amyloid deposits at ~9 months of age. At 15 months, signs of diffuse and compact senility are present, primarily in the neocortex, olfactory bulb and hippocampus. The compounds of the invention were administered orally to mice from the age of 8 months (immediately before the beginning of the formation of amyloid deposits), and the administration was continued for several months (up to the age of 14-18 months). The animals were then sacrificed and the brains removed. The amount of amyloid in the brain was quantitatively determined both histologically and biochemically. The compounds of the invention, tested in this model, have the property of inhibiting the accumulation of amyloid in the cerebral cortex and hippocampus by up to 49% compared to the untreated control experiment.

Gore navedeni podaci pokazuju da reprezentativni spojevi iz izuma su aktivni u standardnim testovima korištenim za mjerenje inhibicije agregacije proteina. Spojevi pokazuju visoku specifičnost, na primjer, kao što je pokazano u BASST testu kao i u BATYM i BAPA testovima. Stoga su ovi spojevi korisni u kliničkom sprečavanju agregacije amiloidnih proteina i za promatranje amiloidnih naslaga u dijagnostičke svrhe. Spojevi će biti u obliku farmaceutskih formulacija, a slijedeći primjeri prikazuju tipične sastave. The above data show that representative compounds of the invention are active in standard assays used to measure inhibition of protein aggregation. The compounds show high specificity, for example, as demonstrated in the BASST assay as well as in the BATYM and BAPA assays. Therefore, these compounds are useful in the clinical prevention of amyloid protein aggregation and for the observation of amyloid deposits for diagnostic purposes. The compounds will be in the form of pharmaceutical formulations, and the following examples show typical compositions.

PRIMJER 164 EXAMPLE 164

Formulacija tablete Tablet formulation

[image] [image]

Spoj iz Primjera 1 je pomješan s laktozom i kukuruznim škrobom (za smjesu) i izmješan dok nije postao homogen. Kukuruzni škrob (za pastu) je suspendiran u 6 ml vode i zagrijan dok ne nastane pasta. Pasta je dodana u izmješani prah, i sve zajedno je granulirano. Vlažne granule su propuštene kroz teški zaslon Br. 8 i sušene pri 50 °C. Smjesa je nauljena s 1 % magnezijevim stearatom i komprimirana u tabletu. Tablete se daju pacijentima 1 do 4 na dan radi prevencije agregacije amiloidnih proteina i liječenja Alzheimerove bolesti. The compound from Example 1 was mixed with lactose and corn starch (for the mixture) and mixed until it became homogeneous. Corn starch (for paste) is suspended in 6 ml of water and heated until a paste forms. The paste was added to the mixed powder, and everything was granulated together. The wet granules were passed through a heavy screen No. 8 and dried at 50 °C. The mixture is oiled with 1% magnesium stearate and compressed into a tablet. Tablets are given to patients 1 to 4 a day to prevent the aggregation of amyloid proteins and treat Alzheimer's disease.

PRIMJER 165 EXAMPLE 165

Parenteralna otopina Parenteral solution

U otopinu od 700 ml propilen glikola i 200 ml vode za injekcije, dodano je 20,0 g Spoja Br. 19 (Primjer 19). Smjesa je miješana, a pH je podešen na 5,5 s klorovodičnom kiselinom. Otopina se dopuni do 1000 ml s vodom za injekcije. Otopina je sterilizirana, napunjena u ampule od 5,0 ml s po 2,0 ml otopine u svaku ampulu (40 mg Spoja Br. 19), i zataljena u atmosferi dušika. Otopina se daje pacijentu koji boluje od medularnog karcinoma tiroida i potrebno mu je liječenje. In a solution of 700 ml of propylene glycol and 200 ml of water for injections, 20.0 g of Compound No. 19 (Example 19). The mixture was stirred and the pH was adjusted to 5.5 with hydrochloric acid. The solution is made up to 1000 ml with water for injections. The solution was sterilized, filled into 5.0 ml ampoules with 2.0 ml of solution in each ampoule (40 mg of Compound No. 19), and sealed under a nitrogen atmosphere. The solution is given to a patient suffering from medullary thyroid cancer and in need of treatment.

PRIMJER 166 EXAMPLE 166

Formulacija obloga Coating formulation

Deset miligrama 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzojeve kiseline je pomiješano s 1 ml propilen glikola i 2 mg ljepila baziranog na poliakrilu koje sadrži agens s smolastim unakrsnim vezivom. Smjesa je nanešena na nepromočiv nosač (30 cm2) te primjenjena na gornji dio leđa pacijenta u svrhu liječenja amiloidne polineuropatije postupnim oslobađanjem aktivne supstance. Ten milligrams of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid was mixed with 1 ml of propylene glycol and 2 mg of a polyacrylic-based adhesive containing a resinous cross-linking agent. The mixture was applied to a waterproof carrier (30 cm2) and applied to the patient's upper back for the purpose of treating amyloid polyneuropathy by gradual release of the active substance.

Izum i način i postupak dobivanja i korištenja su sada opisani takvim potpunim, jasnim, sažetim i točnim pojmovima da omogućuju bilo kojoj osobi stručnoj u području na koje se odnosi, da pripremi i koristi isti. Podrazumijeva se da prethodni tekst opisuje poželjne primjere ovog izuma i da modifikacije mogu biti izvedene bez bitnog odstupanja od duha ili opsega ovog izuma kao što je pokazano u zahtjevima. Da posebno istaknemo i jasno zahtijevamo predmet smatran izumom, slijedeći zahtjevi zaključuju specifikaciju. The invention and the method and process of obtaining and using it are now described in such complete, clear, concise and accurate terms as to enable any person skilled in the field to which it relates to prepare and use the same. It is to be understood that the foregoing text describes preferred embodiments of the present invention and that modifications may be made without substantially departing from the spirit or scope of the present invention as set forth in the claims. To specifically highlight and clearly claim the subject matter considered as an invention, the following claims conclude the specification.

Claims (43)

1. Postupak liječenja Alzheimerove bolesti, naznačen time, da obuhvaća davanje, pacijentu koji ima Alzheimerovu bolest, terapeutski efektivne količine spoja Formule I [image] gdje Ra jest vodik, C1-C6 alkil ili -C(O)C1-C6alkil; n jest 0 do uključivo 5; R1, R2, R3, R4, R5, R6, i R7 jesu, svaki neovisno, vodik, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkil, -NO2, -OC1-C12alkil, -C1-C8 alkil, -CF3, -CN, -OCH2 fenil, -OCH2-supstituirani fenil, -(CH2)m-fenil, -O-fenil, -O-supstituirani fenil, -CH=CH-fenil, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkil)(CH2)pNRbRc, [image] ; R8 jest COOH, tetrazolil, SO2Rd ili -CONHSO2Rd; Rb i Rc jesu, svaki neovisno, vodik, -C1-C6 alkil, -(CH2)m-fenil ili Rb i Rc uzeti zajedno s dušikom na koji su vezani čine ciklički sustav odabran između slijedećih: piperidinil, pirolil, imidazolil, piperazinil, 4-C1-C6 alkilpiperazinil, morfolino, tiomorfolino, dekahidroizokinolin ili pirazolil; Rd jest vodik, C1-C6 alkil, -CF3 ili fenil; m jest 0 do uključivo 5; p jest 1 do uključivo 5; A jest CH ili N; R1 i R2, ukoliko su vezani jedan na drugi, mogu biti metilendioksi; ili njihova farmaceutski prihvatljiva sol.1. A method of treating Alzheimer's disease, characterized in that it comprises administering to a patient suffering from Alzheimer's disease, a therapeutically effective amount of a compound of Formula I [image] where R a is hydrogen, C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl; n is 0 to 5 inclusive; R1, R2, R3, R4, R5, R6, and R7 are, each independently, hydrogen, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkyl, -NO2, -OC1-C12alkyl, -C1-C8 alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, - O-substituted phenyl, -CH=CH-phenyl, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkyl)(CH2)pNRbRc, [image] ; R8 is COOH, tetrazolyl, SO2Rd or -CONHSO2Rd; Rb and Rc are, each independently, hydrogen, -C1-C6 alkyl, -(CH2)m-phenyl or Rb and Rc taken together with the nitrogen to which bound form a cyclic system selected from the following: piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-C6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline or pyrazolyl; Rd is hydrogen, C1-C6 alkyl, -CF3 or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R1 and R2, if they are bound to each other, can be methylenedioxy; or a pharmaceutically acceptable salt thereof. 2. Postupak prema zahtjevu 1, naznačen time, da: Ra jest vodik; n jest 2; i R3 i R4 jesu vodici.2. The procedure according to claim 1, characterized in that: Ra is hydrogen; n is 2; and R3 and R4 are leads. 3. Postupak prema zahtjevu 1, naznačen time, da: Ra jest vodik; R3 i R4 jesu vodici; i n jest 2 do uključivo 5.3. The procedure according to claim 1, characterized in that: Ra is hydrogen; R3 and R4 are hydrogen; and n is 2 to 5 inclusive. 4. Postupak prema zahtjevu 1, naznačen time, da: Ra jest vodik; n jest 2; R3 i R4 jesu vodici; i R1, R2, i R7 jesu svaki neovisno, klor, -N(CH2CH3)2, -OH, -CH3, fluor, -CF3, fenil, vodik, -OCH2 fenil, O(CH2)3N(CH3)2, -O fenil, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pirolil, -CH=CH-fenil, [image] , N[(CH2)3CH3]2, supstituirani fenil, -OCH2-supstituirani fenil, pirazolil, ili -N(fenil)2.4. The procedure according to claim 1, characterized in that: Ra is hydrogen; n is 2; R3 and R4 are hydrogen; and R1, R2, and R7 are each independently, chlorine, -N(CH2CH3)2, -OH, -CH3, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, [image] , N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl, pyrazolyl, or -N(phenyl)2. 5. Postupak prema zahtjevu 1, naznačen time, da: Ra jest vodik; n jesu 3, 4 ili 5; R3 i R4 jesu vodici; i R1, R2, i R7 jesu svaki neovisno, klor ili vodik.5. The procedure according to claim 1, characterized in that: Ra is hydrogen; n is 3, 4 or 5; R3 and R4 are hydrogen; and R 1 , R 2 , and R 7 are each independently chlorine or hydrogen. 6. Postupak prema zahtjevu 1, naznačen time, da: Ra jest vodik; n jest 2; R3 i R4 jesu vodici; i R5, R6, i R8 jesu, svaki neovisno, -CO2H, -NO2, -OCH3, imidazolil, -CN, fluor, -CH3, -CF3, halogen, NH-C1-C6 alkil, -N(C1-C6alkil)2, -NH2 ili pirolil.6. The procedure according to claim 1, characterized in that: Ra is hydrogen; n is 2; R3 and R4 are hydrogen; and R5, R6, and R8 are, each independently, -CO2H, -NO2, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, halogen, NH-C1-C6 alkyl, -N(C1-C6alkyl)2, -NH2 or pyrrolyl. 7. Postupak prema zahtjevu 1, naznačen time, da: Ra jest vodik; n jest 2; R3 i R4 su vodici; i R5 je -COOH.7. The procedure according to claim 1, characterized in that: Ra is hydrogen; n is 2; R3 and R4 are hydrogen; and R 5 is -COOH. 8. Postupak liječenja Alzheimorove bolesti, naznačen time, da obuhvaća davanje, pacijentu koji ima Alzheimerovu bolest, terapeutski efektivne količine spoja Formule I [image] gdje Ra jest vodik; n jest 1 do uključivo 5; R3 i R4 jesu vodici; i R1, R7 i R2 jesu, svaki neovisno, klor, -N(CH2CH3)2, -OH, CH3-, fluor, -CF3, fenil, vodik, -OCH2 fenil, O(CH2)3N(CH3)2, -O fenil, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pirolil, -CH=CH-fenil, N[(CH2)3CH3]2, supstituirani fenil, -OCH2-supstituirani fenil, pirazolil, ili -N(fenil)2; R5 i R6 jesu, svaki neovisno, vodik, -CO2H, -NO2, -OCH3, imidazolil, -CN, fluor, -CH3, -CF3, ili pirolil; R8 jest COOH ili tetrazolil; ili njegove farmaceutski prihvatljive soli.8. A method of treating Alzheimer's disease, characterized in that it comprises administering to a patient suffering from Alzheimer's disease, a therapeutically effective amount of a compound of Formula I [image] where Ra is hydrogen; n is 1 to 5 inclusive; R3 and R4 are hydrogen; and R1, R7 and R2 are, each independently, chlorine, -N(CH2CH3)2, -OH, CH3-, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, N[(CH2)3CH3]2, substituted phenyl, - OCH2-substituted phenyl, pyrazolyl, or -N(phenyl)2; R5 and R6 are, each independently, hydrogen, -CO2H, -NO2, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; R 8 is COOH or tetrazolyl; or pharmaceutically acceptable salts thereof. 9. Postupak prema zahtjevu 1, naznačen time, da: spoj Formule I jest: 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)etil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4,5-trihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-imidazo-1-il-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}benzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-3,5-dinitrobenzoeva kiselina; 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-[4-(3,4-diklorbenzil)fenilamino]benzoeva kiselina; 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-difluorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-[4-(2-bifenil-4-iletil)fenilamino]-5-nitrobenzoeva kiselina; 5-nitro-2-(4-fenetilfenilamino)benzoeva kiselina; 2-(4-fenetilfenilamino)benzoeva kiselina 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metoksibenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}tereftalna kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metilbenzoeva kiselina; 4-{4-[2-(3,4-diklorfenil)etil]fenilamino}izoftalna kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metansulfonilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-imidazol-1-il-benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-nitrobenzoeva kiselina; 5-cijano-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4,6-difluorbenzoeva kiselina; 6-{4-[2-(3,4-diklorfenil)etil]fenilamino}-2,3-difluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-metilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3,5-difluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-pirol-1-ilbenzoeva kiselina; 2-{4-[2-(4-benziloksifenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(3-dimetilaminopropoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-fenoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-oktiloksifenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(2-etoksi-1-etoksimetiletil)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-pirol-1-il-fenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-stirilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4'-etilbifenil-4-il)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-oktilfenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[3-(3,5-diklorfenoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-klor-6-fluorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-pirazol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-difenilaminofenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(3,4-diklorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-aminobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; ili 2-[4-(3,4-diklorfenil)fenil]aminobenzoeva kiselina.9. The method according to claim 1, characterized in that: the compound of Formula I is: 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[4-(3,4-dichlorophenyl)ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-{4-[2-(3,4-dihydroxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}benzoic acid; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-3,5-dinitrobenzoic acid; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-[4-(3,4-dichlorobenzyl)phenylamino]benzoic acid; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-difluorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid; 2-[4-(2-biphenyl-4-ylethyl)phenylamino]-5-nitrobenzoic acid; 5-nitro-2-(4-phenethylphenylamino)benzoic acid; 2-(4-phenethylphenylamino)benzoic acid 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methoxybenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}terephthalic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methylbenzoic acid; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}isophthalic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methanesulfonylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-imidazol-1-yl-benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-nitrobenzoic acid; 5-cyano-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4,6-difluorobenzoic acid; 6-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-2,3-difluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-methylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3,5-difluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-pyrrol-1-ylbenzoic acid; 2-{4-[2-(4-benzyloxyphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(3-dimethylaminopropoxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-phenoxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-octyloxyphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(2-ethoxy-1-ethoxymethylethyl)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-pyrrol-1-yl-phenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-styrylphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4'-ethylbiphenyl-4-yl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-octylphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[3-(3,5-dichlorophenoxy)phenyl]ethyl}phenylamino)benzoic acid; 2-(4-{2-[4-(2-chloro-6-fluorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-pyrazol-1-ylphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-diphenylaminophenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(3,4-dichlorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-aminobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)]phenylamino}-5-nitrobenzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid; or 2-[4-(3,4-dichlorophenyl)phenyl]aminobenzoic acid. 10. Postupak sprečavanja agregacije amiloidnih proteina što dovodi do stvaranja amiloidnih naslaga, naznačen time, da obuhvaća davanje, pacijentu kome je potrebno spriječiti agregaciju amiloidnih proteina, dovoljne količine spoja za sprečavanje agregacije amiloidnih proteina pri čemu spoj ima Formulu I [image] gdje Ra jest vodik, C1-C6 alkil ili -C(O)C1-C6alkil; n jest 0 do uključivo 5; R1, R2, R3, R4, R5, R6, i R7 jesu, svaki neovisno, vodik, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkil, -NO2, -OC1-C12alkil, -C1-C8 alkil, -CF3, -CN, -OCH2 fenil, -OCH2-supstituirani fenil, -(CH2)m-fenil, -O-fenil, -O-supstituirani fenil, -CH=CH-fenil, -O(CH2)pNRbRc, -C(O)NRbRc, NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkil)(CH2)pNRbRc, [image] ; R8 jest COOH, tetrazolil, SO2Rd ili -CONHSO2Rd; Rb i Rc jesu, svaki neovisno, vodik, -C1-C6 alkil, -(CH2)m-fenil ili Rb i Rc uzeti zajedno s dušikom na koji su vezani čine ciklički sustav odabran između slijedećih: piperidinil, pirolil, imidazolil, piperazinil, 4-C1-C6 alkilpiperazinil, morfolino, tiomorfolino, dekahidroizokinolin ili pirazolil; Rd jest vodik, C1-C6 alkil, -CF3 ili fenil; m jest 0 do uključivo 5; p jest 1 do uključivo 5; A jest CH ili N; R1 i R2, ukoliko su vezani jedan na drugi, mogu biti metilendioksi; ili njihova farmaceutski prihvatljiva sol.10. A method of preventing the aggregation of amyloid proteins that leads to the formation of amyloid deposits, indicated by the fact that it comprises administering to a patient who needs to prevent the aggregation of amyloid proteins, a sufficient amount of a compound to prevent the aggregation of amyloid proteins, wherein the compound has Formula I [image] where R a is hydrogen, C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl; n is 0 to 5 inclusive; R1, R2, R3, R4, R5, R6, and R7 are, each independently, hydrogen, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkyl, -NO2, -OC1-C12alkyl, -C1-C8 alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, - O-substituted phenyl, -CH=CH-phenyl, -O(CH2)pNRbRc, -C(O)NRbRc, NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkyl)(CH2) pNRbRc, [image] ; R8 is COOH, tetrazolyl, SO2Rd or -CONHSO2Rd; Rb and Rc are, each independently, hydrogen, -C1-C6 alkyl, -(CH2)m-phenyl or Rb and Rc taken together with the nitrogen to which bound form a cyclic system selected from the following: piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-C6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline or pyrazolyl; Rd is hydrogen, C1-C6 alkyl, -CF3 or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R1 and R2, if they are bound to each other, can be methylenedioxy; or a pharmaceutically acceptable salt thereof. 11. Postupak prema zahtjevu 10, naznačen time, da: Ra jest vodik; n jest 2; i R3 i R4 jesu vodici.11. The procedure according to claim 10, characterized in that: Ra is hydrogen; n is 2; and R3 and R4 are leads. 12. Postupak prema zahtjevu 10, naznačen time, da: Ra jest vodik; R3 i R4 jesu vodici; i n jest 2 do uključivo 5.12. The procedure according to claim 10, characterized in that: Ra is hydrogen; R3 and R4 are hydrogen; and n is 2 to 5 inclusive. 13. Postupak prema zahtjevu 10, naznačen time, da: Ra jest vodik; n jest 2; R3 i R4 jesu vodik; i R1, R2, i R7 jesu svaki neovisno, klor, -N(CH2CH3)2, -OH, -CH3, fluor, -CF3, fenil, vodik, -OCH2 fenil, O(CH2)3N(CH3)2, -O fenil, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pirolil, -CH=CH-fenil, [image] N[(CH2)3CH3]2, supstituirani fenil, -OCH2-supstituirani fenil, pirazolil, ili -N(fenil)2.13. The procedure according to claim 10, characterized in that: Ra is hydrogen; n is 2; R3 and R4 are hydrogen; and R1, R2, and R7 are each independently, chlorine, -N(CH2CH3)2, -OH, -CH3, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, [image] N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl, pyrazolyl, or -N(phenyl)2. 14. Postupak prema zahtjevu 10, naznačen time, da: Ra jest vodik; n jesu 3, 4 ili 5; R3 i R4 jesu vodik; i R1, R2, i R7 jesu svaki neovisno, klor ili vodik.14. The procedure according to claim 10, characterized in that: Ra is hydrogen; n is 3, 4 or 5; R3 and R4 are hydrogen; and R 1 , R 2 , and R 7 are each independently chlorine or hydrogen. 15. Postupak prema zahtjevu 10, naznačen time, da: Ra jest vodik; n jest 2; R3 i R4 jesu vodik; i R5 i R6 jesu, svaki neovisno, -CO2H, -NO2, -OCH3, imidazolil, -CN, fluor, -CH3, -CF3, halogen, NH-C1-C6 alkil, -N(C1-C6alkil)2, -NH2 ili pirolil.15. The method according to claim 10, characterized in that: Ra is hydrogen; n is 2; R3 and R4 are hydrogen; and R5 and R6 are, each independently, -CO2H, -NO2, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, halogen, NH-C1-C6 alkyl, -N(C1-C6alkyl)2, -NH2 or pyrrolyl. 16. Postupak prema zahtjevu 10, naznačen time, da: Ra jest vodik; n jest 2; R3 i R4 jesu vodik; i R8 je -COOH.16. The procedure according to claim 10, characterized in that: Ra is hydrogen; n is 2; R3 and R4 are hydrogen; and R 8 is -COOH. 17. Postupak sprečavanja agregacije amiloidnih proteina što dovodi do stvaranja amiloidnih naslaga, naznačen time, da metoda obuhvaća davanje, pacijentu kome je potrebno spriječiti agregaciju amiloidnih proteina, dovoljne količine spoja za sprečavanje agregacije amiloidnih proteina pri čemu spoj ima Formulu I [image] gdje Ra jest vodik; n jest 1 do uključivo 5; R3 i R4 jesu vodici; i R1, R7 i R2 jesu, svaki neovisno, klor, -N(CH2CH3)2, -OH, CH3-, fluor, -CF3, fenil, vodik, -OCH2 fenil, O(CH2)3N(CH3)2, -O fenil, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pirolil, -CH=CH-fenil, N[(CH2)3CH3]2, supstituirani fenil, -OCH2-supstituirani fenil, pirazolil, ili -N(fenil)2; R5 i R6 jesu, svaki neovisno, vodik, -CO2H, -NO2, -OCH3, imidazolil, -CN, fluor, -CH3, -CF3, ili pirolil; R8 jest COOH ili tetrazolil; A jest CH ili N; R1 i R2, ukoliko su vezani jedan na drugi, mogu biti metilendioksi; ili njegova farmaceutski prihvatljiva sol.17. A method of preventing the aggregation of amyloid proteins that leads to the formation of amyloid deposits, indicated by the fact that the method comprises administering, to a patient who needs to prevent the aggregation of amyloid proteins, a sufficient amount of a compound to prevent the aggregation of amyloid proteins, wherein the compound has Formula I [image] where Ra is hydrogen; n is 1 to 5 inclusive; R3 and R4 are hydrogen; and R1, R7 and R2 are, each independently, chlorine, -N(CH2CH3)2, -OH, CH3-, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, N[(CH2)3CH3]2, substituted phenyl, - OCH2-substituted phenyl, pyrazolyl, or -N(phenyl)2; R5 and R6 are, each independently, hydrogen, -CO2H, -NO2, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; R 8 is COOH or tetrazolyl; A is CH or N; R1 and R2, if they are bound to each other, can be methylenedioxy; or a pharmaceutically acceptable salt thereof. 18. Postupak prema zahtjevu 1, naznačen time, da spoj Formule I jest: 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)etil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4,5-trihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-imidazo-1-il-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}benzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-3,5-dinitrobenzoeva kiselina; 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-[4-(3,4-diklorbenzil)fenilamino]benzoeva kiselina; 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-difluorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-[4-(2-bifenil-4-iletil)fenilamino]-5-nitrobenzoeva kiselina; 5-nitro-2-(4-fenetilfenilamino)benzoeva kiselina; 2-(4-fenetilfenilamino)benzoeva kiselina 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metoksibenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}tereftalna kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metilbenzoeva kiselina; 4-{4-[2-(3,4-diklorfenil)etil]fenilamino}izoftalna kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metansulfonilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-imidazol-1-il-benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-nitrobenzoeva kiselina; 5-cijano-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4,6-difluorbenzoeva kiselina; 6-{4-[2-(3,4-diklorfenil)etil]fenilamino}-2,3-difluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-metilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3,5-difluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-pirol-1-ilbenzoeva kiselina; 2-{4-[2-(4-benziloksifenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(3-dimetilaminopropoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-fenoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-oktiloksifenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(2-etoksi-1-etoksimetiletil)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-pirol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-stirilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4'-etilbifenil-4-il)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-oktilfenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[3-(3,5-diklorfenoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-klor-6-fluorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-pirazol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-difenilaminofenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(3,4-diklorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; ili 2-[4-(3,4-diklorfenil)fenil]aminobenzoeva kiselina.18. The method according to claim 1, characterized in that the compound of Formula I is: 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[4-(3,4-dichlorophenyl)ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-{4-[2-(3,4-dihydroxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}benzoic acid; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-3,5-dinitrobenzoic acid; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-[4-(3,4-dichlorobenzyl)phenylamino]benzoic acid; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-difluorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid; 2-[4-(2-biphenyl-4-ylethyl)phenylamino]-5-nitrobenzoic acid; 5-nitro-2-(4-phenethylphenylamino)benzoic acid; 2-(4-phenethylphenylamino)benzoic acid 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methoxybenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}terephthalic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methylbenzoic acid; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}isophthalic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methanesulfonylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-imidazol-1-yl-benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-nitrobenzoic acid; 5-cyano-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4,6-difluorobenzoic acid; 6-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-2,3-difluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-methylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3,5-difluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-pyrrol-1-ylbenzoic acid; 2-{4-[2-(4-benzyloxyphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(3-dimethylaminopropoxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-phenoxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-octyloxyphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(2-ethoxy-1-ethoxymethylethyl)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-pyrrol-1-ylphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-styrylphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4'-ethylbiphenyl-4-yl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-octylphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[3-(3,5-dichlorophenoxy)phenyl]ethyl}phenylamino)benzoic acid; 2-(4-{2-[4-(2-chloro-6-fluorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-pyrazol-1-ylphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-diphenylaminophenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(3,4-dichlorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid; or 2-[4-(3,4-dichlorophenyl)phenyl]aminobenzoic acid. 19. Spojevi, naznačeni time, da su: 2-{4-[4-(3,4-diklorfenil)etil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4,5-trihidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-4-imidazo-1-il-5-nitrobenzoeva kiselina; ili 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}benzoeva kiselina.19. Compounds, indicated by the fact that they are: 2-{4-[4-(3,4-dichlorophenyl)ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-{4-[2-(3,4-dihydroxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4,5-trihydroxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoic acid; or 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}benzoic acid. 20. Spojevi, naznačeni time, da su: 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-3,5-dinitrobenzoeva kiselina; 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}-4-metoksi-5-nitrobenzoeva kiselina; 2-[4-(3,4-diklorbenzil)fenilamino]benzoeva kiselina; 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-difluorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-[4-(2-bifenil-4-iletil)fenilamino]-5-nitrobenzoeva kiselina; 5-nitro-2-(4-fenetilfenilamino)benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-aminobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; ili 2-{4-[2-(3,4-diklorfenil)]fenilamino}-5-nitrobenzoeva kiselina.20. Compounds, indicated by the fact that they are: 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-3,5-dinitrobenzoic acid; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-[4-(3,4-dichlorobenzyl)phenylamino]benzoic acid; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-difluorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid; 2-[4-(2-biphenyl-4-ylethyl)phenylamino]-5-nitrobenzoic acid; 5-nitro-2-(4-phenethylphenylamino)benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-aminobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid; or 2-{4-[2-(3,4-dichlorophenyl)]phenylamino}-5-nitrobenzoic acid. 21. Spojevi, naznačeni time, da su: 2-(4-fenetilfenilamino)benzoeva kiselina 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metoksibenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}tereftalna kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metilbenzoeva kiselina; 4-{4-[2-(3,4-diklorfenil)etil]fenilamino}izoftalna kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metansulfonilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-imidazol-1-ilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-nitrobenzoeva kiselina; ili 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-nitrobenzoeva kiselina.21. Compounds, indicated by the fact that they are: 2-(4-phenethylphenylamino)benzoic acid 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methoxybenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}terephthalic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methylbenzoic acid; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}isophthalic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methanesulfonylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-imidazol-1-ylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-nitrobenzoic acid; or 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-nitrobenzoic acid. 22. Spojevi, naznačeni time, da su: 5-cijano-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4,6-difluorbenzoeva kiselina; 6-{4-[2-(3,4-diklorfenil)etil]fenilamino}-2,3-difluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-metilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3,5-difluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-trifluormetilbenzoeva kiselina; 2-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-nitrofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-nitrofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-aminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-aminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-aminofenil)]fenilamino}benzoeva kiselina; 2-{4-[2-(4-dipropilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid monohidrat; 2-{4-[3-(3-dipropilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dimetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-etilaminofenil)propil]fenilamino}benzoeva kiselina; 2-(N-{4-[3-(4-dietilaminofenil)propil]fenil}-N-etilamino)benzoeva kiselina; 2-{4-[2-(3-dibenzilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-aminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dimetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-acetilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-acetilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-dipropilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(3-dibutilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[3-(4-acetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-acetilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-dietilaminofenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[2-(3-piperidin-1-ilfenil)etil]fenilamino}benzoeva kiselina monohidroklorid; 2-{4-[3-(4-dipropilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dibutilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-dibutilaminofenil)propil]fenilamino}benzoeva kiselina; 2-(4-{3-[4-(1H-pirol-1-il)fenil]propil}fenilamino)benzoeva kiselina; 2-{4-[3-(4-piperidin-1-ilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dietilkarbamoilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-karboksifenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-dietilaminometilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-propilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-propilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(4-pirolidin-1-ilfenil)propil]fenilamino}benzoeva kiselina; 2-{4-[3-(3-piperidin-1-ilfenil)propil]fenilamino}benzoeva kiselina; {5-[(1-butil-1,2,3,4-tetrahidro-6-kinolil)metiliden]-4-okso-2-tioksotiazolidin-3-il}octena kiselina; {5-[(1-butil-2,3-dihidro-1H-indol-5-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}octena kiselina; 3-{5-[(1-butil-1,2,3,4-tetrahidrokinolin-6-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}propanska kiselina; 4-{5-[(1-butil-1,2,3,4-tetrahidrokinolin-6-il)metiliden]-4-okso-2-tioksotiazolidin-3-il}butanska kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-5-metilbenzoeva kiselina; N-(2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzoilmetansulfonamin; 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-[4-(2-bifenil-4-iletil)fenilamino]-5-nitrobenzoeva kiselina; 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 5-amino-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 5-nitro-2-(4-fenetilfenilamino)benzoeva kiselina; 2-{4-[2-(4-fluor-3-trifluormetilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-difluorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; {4-[2-(3,4-diklorfenil)etil]fenil}-[2-(1H-tetrazol-5-il)fenil]amin; 2-{4-[2-(4-fluor-3-trifluormetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-(4-fenetilfenilamino)benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-fluorbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}nikotinska kiselina; 2-{4-[2-(3-klorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(4-klorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metilbenzoeva kiselina; 2-{4-[2-(2-klorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(2,4-diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-6-trifluormetilbenzoeva kiselina; 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-dimetilaminobenzoeva kiselina; 2-{4-[2-(3,5-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[(4aS,8aR)-4-(oktahidroizokinolin-2-il)fenil]etil}fenilamino)benzoeva kiselina; 2-(3',5'-diklor-3-metilbifenil-4-ilamino)benzoeva kiselina; 2-(3',5'-dibrom-3-metilbifenil-4-ilamino)benzoeva kiselina; 2-(4-1,3-benzodioksol-5-il-2-metilfenilamino)benzoeva kiselina; 2-(2,2',4'-triklorbifenil-4-ilamino)benzoeva kiselina; 2-(2-klor-3',4'-difluorbifenil-4-ilamino)benzoeva kiselina; 2-(3'-brom-2-klorbifenil-4-ilamino)benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; 3-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 5-{4-[2-(3,4-diklorfenil)etil]fenilamino}izoftalna kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4,5-dimetoksibenzoeva kiselina; 2-{4-[2-(3-klor-4-metilfenil)etil]fenilamino}-3-nitrobenzoeva kiselina; 3-{4-[2-(3-klor-4-metilfenil)etil]fenilamino}benzoeva kiselina; 5-{4-[2-(3-klor-4-metilfenil)etil]fenilamino}izoftalna kiselina; 2-{4-[2-(3-klor-4-metilfenil)etil]fenilamino}benzoeva kiselina; 4-(4-{2-[(4aS,8aR)-4-(oktahidroizokinolin-2-il)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[3-(4-dietilaminofenil)propil]fenilamino}-5-metoksibenzoeva kiselina; 2-{4-[2-(3-metoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-bromfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-fluorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-metoksibenzoeva kiselina; 4-{4-[2-(3,4-diklorfenil)etil]fenilamino}nikotinska kiselina; 2-[2-(4-fluor-3-trifluormetilfenil)-2,3-dihidro-1H-izoindol-5-ilamino]benzoeva kiselina; ili 2-{4-[2-(3-fluor-4-metilfenil)etil]fenilamino}benzoeva kiselina.22. Compounds, indicated by the fact that they are: 5-cyano-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4,6-difluorobenzoic acid; 6-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-2,3-difluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-methylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3,5-difluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-trifluoromethylbenzoic acid; 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-nitrophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-nitrophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-aminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-aminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(4-aminophenyl)]phenylamino}benzoic acid; 2-{4-[2-(4-dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride monohydrate; 2-{4-[3-(3-dipropylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-dimethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-ethylaminophenyl)propyl]phenylamino}benzoic acid; 2-(N-{4-[3-(4-diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoic acid; 2-{4-[2-(3-dibenzylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[3-(3-diethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(3-aminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[3-(4-dimethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(4-acetylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3-acetylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3-dipropylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[2-(3-dibutylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[3-(4-acetylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-acetylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(3-diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[2-(3-piperidin-1-ylphenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[3-(4-dipropylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-dibutylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-dibutylaminophenyl)propyl]phenylamino}benzoic acid; 2-(4-{3-[4-(1H-pyrrol-1-yl)phenyl]propyl}phenylamino)benzoic acid; 2-{4-[3-(4-piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-diethylcarbamoylphenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-carboxyphenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-diethylaminomethylphenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-propylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-propylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-pyrrolidin-1-ylphenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(3-piperidin-1-ylphenyl)propyl]phenylamino}benzoic acid; {5-[(1-butyl-1,2,3,4-tetrahydro-6-quinolyl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}acetic acid; {5-[(1-Butyl-2,3-dihydro-1H-indol-5-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}acetic acid; 3-{5-[(1-butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid; 4-{5-[(1-butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}butanoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-5-methylbenzoic acid; N-(2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoylmethanesulfonamine; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-[4-(2-biphenyl-4-ylethyl)phenylamino]-5-nitrobenzoic acid; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 5-amino-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 5-nitro-2-(4-phenethylphenylamino)benzoic acid; 2-{4-[2-(4-fluoro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-difluorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; {4-[2-(3,4-dichlorophenyl)ethyl]phenyl}-[2-(1H-tetrazol-5-yl)phenyl]amine; 2-{4-[2-(4-fluoro-3-trifluoromethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-(4-phenethylphenylamino)benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-fluorobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}nicotinic acid; 2-{4-[2-(3-chlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(4-chlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methylbenzoic acid; 2-{4-[2-(2-chlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(2,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-6-trifluoromethylbenzoic acid; 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}5-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-dimethylaminobenzoic acid; 2-{4-[2-(3,5-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[(4aS,8aR)-4-(octahydroisoquinolin-2-yl)phenyl]ethyl}phenylamino)benzoic acid; 2-(3',5'-dichloro-3-methylbiphenyl-4-ylamino)benzoic acid; 2-(3',5'-dibromo-3-methylbiphenyl-4-ylamino)benzoic acid; 2-(4-1,3-benzodioxol-5-yl-2-methylphenylamino)benzoic acid; 2-(2,2',4'-trichlorobiphenyl-4-ylamino)benzoic acid; 2-(2-chloro-3',4'-difluorobiphenyl-4-ylamino)benzoic acid; 2-(3'-bromo-2-chlorobiphenyl-4-ylamino)benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 3-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 5-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}isophthalic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4,5-dimethoxybenzoic acid; 2-{4-[2-(3-chloro-4-methylphenyl)ethyl]phenylamino}-3-nitrobenzoic acid; 3-{4-[2-(3-chloro-4-methylphenyl)ethyl]phenylamino}benzoic acid; 5-{4-[2-(3-chloro-4-methylphenyl)ethyl]phenylamino}isophthalic acid; 2-{4-[2-(3-chloro-4-methylphenyl)ethyl]phenylamino}benzoic acid; 4-(4-{2-[(4aS,8aR)-4-(octahydroisoquinolin-2-yl)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}-5-methoxybenzoic acid; 2-{4-[2-(3-methoxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3-bromophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3-fluorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-methoxybenzoic acid; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}nicotinic acid; 2-[2-(4-fluoro-3-trifluoromethylphenyl)-2,3-dihydro-1H-isoindol-5-ylamino]benzoic acid; or 2-{4-[2-(3-fluoro-4-methylphenyl)ethyl]phenylamino}benzoic acid. 23. Spojevi, naznačeni time, da su: 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-pirol-1-ilbenzoeva kiselina; 2-{4-[2-(4-benziloksifenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(3-dimetilaminopropoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-dietilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-fenoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-oktiloksifenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(2-etoksi-1-etoksimetiletil)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-pirol-1-ilfenil)etil]fenilamino}benzoeva kiselina; ili 2-{4-[2-(4-stirilfenil)etil]fenilamino}benzoeva kiselina.23. Compounds, indicated by the fact that they are: 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-pyrrol-1-ylbenzoic acid; 2-{4-[2-(4-benzyloxyphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(3-dimethylaminopropoxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-diethylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-phenoxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-octyloxyphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(2-ethoxy-1-ethoxymethylethyl)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-pyrrol-1-ylphenyl)ethyl]phenylamino}benzoic acid; or 2-{4-[2-(4-styrylphenyl)ethyl]phenylamino}benzoic acid. 24. Spojevi, naznačeni time, da su: 2-{4-[2-(4-dibutilaminofenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4'-etilbifenil-4-il)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-oktilfenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[3-(3,5-diklorfenoksi)fenil]etil}fenilamino)benzoeva kiselina; 2-(4-{2-[4-(2-klor-6-fluorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(4-pirazol-1-ilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-difenilaminofenil)etil]fenilamino}benzoeva kiselina; 2-(4-{2-[4-(3,4-diklorbenziloksi)fenil]etil}fenilamino)benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-aminobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)propil]fenilamino}-5-nitrobenzoeva kiselina; 2-{4-[2-(3,4-dimetilfenil)etil]fenilamino}-5-nitrobenzoeva kiselina; ili 2-[4-(3,4-diklorfenil)fenil]aminobenzoeva kiselina.24. Compounds, indicated by the fact that they are: 2-{4-[2-(4-dibutylaminophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4'-ethylbiphenyl-4-yl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-octylphenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[3-(3,5-dichlorophenoxy)phenyl]ethyl}phenylamino)benzoic acid; 2-(4-{2-[4-(2-chloro-6-fluorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(4-pyrazol-1-ylphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-diphenylaminophenyl)ethyl]phenylamino}benzoic acid; 2-(4-{2-[4-(3,4-dichlorobenzyloxy)phenyl]ethyl}phenylamino)benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-aminobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-dimethylphenyl)ethyl]phenylamino}-5-nitrobenzoic acid; or 2-[4-(3,4-dichlorophenyl)phenyl]aminobenzoic acid. 25. Spoj, naznačen time, da je: 2-{4-[2-(3,4-diklorfenil)etil]fenil}aminobenzoeva kiselina ili njena farmaceutski prihvatljiva sol.25. Compound, characterized in that: 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenyl}aminobenzoic acid or a pharmaceutically acceptable salt thereof. 26. Spoj, naznačen time, da je: 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzoeva kiselina ili njena farmaceutski prihvatljiva sol.26. Compound, characterized by the fact that: 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid or a pharmaceutically acceptable salt thereof. 27. Spoj, naznačen time, da je odabran od: 2-{4-[3-(4-dietilaminofenil)propil]fenilamino}-5-nitrobenzoeva kiselina; 4-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 4-{4-[3-(4-dietilaminofenil)propil]fenilamino}-3-metoksibenzoeva kiselina; 2-{4-[2-(3-klor-4-metilfenil)etil]fenilamino}-5-metoksibenzoeva kiselina; {4-[2-(3-klor-4-metilfenil)etil]fenil}-(2-metoksi-5-nitrofenil)amin; 2-{4-[3-(4-dietilaminofenil)propil]fenilamino}-3-nitrobenzoeva kiselina; 3-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-dimetoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina, mononatrijeva sol; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina, monokalijeva sol; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina, kalcijeva sol (1:1); 2-hidroksi-1,1-bis(hidroksimetil)etilamonijev 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoat; 2-{4-[4-(3,4-diklorfenil)butil]fenilamino}-5-metoksibenzoeva kiselina; 2-{4-[2-(3,4-difluorfenil)etil]fenilamino}benzoeva kiselina; 2-{3-[2-(4-klorfenil)etil]fenilamino}benzoeva kiselina; 2-{3-[2-(3,4-dimetilfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(2,4-dimetoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(2-klorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(2-hidroksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3-klorfenil)etil]fenilamino}benzoeva kiselina; 2-[4-(2-bifenil-4-iletil)fenilamino]benzoeva kiselina; 2-{4-[2-(2,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 3-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 4-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4,5-trimetoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(4-fenoksifenil)etil]fenilamino}benzoeva kiselina; 2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}benzoeva kiselina; 2-(3',5'-diklorbifenil-4-ilamino)benzoeva kiselina; 4-{4-[3-(3,4-diklorfenil)propil]fenilamino}-2-metoksi-5-nitrobenzoeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}-5-fluorbenzoeva kiselina; 5-amino-2-{4-[5-(3,4-diklorfenil)pentil]fenilamino}benzoeva kiselina; N-(2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzoil)-C,C,C-trifluormetansulfonamid; N-(2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzoil)benzensulfonamid; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-trifluormetilbenzoeva kiselina; 4-{4-[2-(3,4-diklorfenil)etil]fenilamino}izoftalna kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-4-trifluormetilbenzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-3-trifluormetilbenzoeva kiselina; 2-({4-[2-(3,4-diklorfenil)etil]fenil}metilamino)-5-dimetilaminobenzoeva kiselina; 2-({4-[2-(3,4-diklorfenil)etil]fenil}metilamino)benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-dipropilaminobenzoeva kiselina; 5-dibutilamino-2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzoeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-dietilaminobenzoeva kiselina; 2,2'-[1,2-etandiilbis(4,1-fenilenimino)bisbenzoeva kiselina; i 4-{3-[4-(dietilamino)fenil]propil}-N-(2-metoksi-5-nitrofenil)benzenamin.27. A compound, characterized in that it is selected from: 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}-5-nitrobenzoic acid; 4-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid; 4-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}-3-methoxybenzoic acid; 2-{4-[2-(3-chloro-4-methylphenyl)ethyl]phenylamino}-5-methoxybenzoic acid; {4-[2-(3-chloro-4-methylphenyl)ethyl]phenyl}(2-methoxy-5-nitrophenyl)amine; 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}-3-nitrobenzoic acid; 3-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dimethoxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid, monosodium salt; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid, monopotassium salt; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid, calcium salt (1:1); 2-hydroxy-1,1-bis(hydroxymethyl)ethylammonium 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoate; 2-{4-[4-(3,4-dichlorophenyl)butyl]phenylamino}-5-methoxybenzoic acid; 2-{4-[2-(3,4-difluorophenyl)ethyl]phenylamino}benzoic acid; 2-{3-[2-(4-chlorophenyl)ethyl]phenylamino}benzoic acid; 2-{3-[2-(3,4-dimethylphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(2,4-dimethoxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(2-chlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(2-hydroxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3-chlorophenyl)ethyl]phenylamino}benzoic acid; 2-[4-(2-biphenyl-4-ylethyl)phenylamino]benzoic acid; 2-{4-[2-(2,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 3-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(4-phenoxyphenyl)ethyl]phenylamino}benzoic acid; 2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}benzoic acid; 2-(3',5'-dichlorobiphenyl-4-ylamino)benzoic acid; 4-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-2-methoxy-5-nitrobenzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-5-fluorobenzoic acid; 5-amino-2-{4-[5-(3,4-dichlorophenyl)pentyl]phenylamino}benzoic acid; N-(2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoyl)-C,C,C-trifluoromethanesulfonamide; N-(2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoyl)benzenesulfonamide; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-trifluoromethylbenzoic acid; 4-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}isophthalic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-4-trifluoromethylbenzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-3-trifluoromethylbenzoic acid; 2-({4-[2-(3,4-dichlorophenyl)ethyl]phenyl}methylamino)-5-dimethylaminobenzoic acid; 2-({4-[2-(3,4-dichlorophenyl)ethyl]phenyl}methylamino)benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-dipropylaminobenzoic acid; 5-dibutylamino-2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-diethylaminobenzoic acid; 2,2'-[1,2-ethanediylbis(4,1-phenyleneimino)bisbenzoic acid; and 4-{3-[4-(diethylamino)phenyl]propyl}-N-(2-methoxy-5-nitrophenyl)benzenamine. 28. Postupak vizualizacije amiloidnih naslaga, naznačen time, da isti obuhvaća slijedeće korake: a. unošenje, u pacijenta, minimalne mjerljive količine označenog spoja Formule I, ili njegove farmaceutski prihvatljive soli. [image] gdje Ra jest vodik, C1-C6 alkil ili -C(O)C1-C6alkil; n jest 0 do uključivo 5; R1, R2, R3, R4, R5, R6, i R7 jesu, svaki neovisno, vodik, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkil, -NO2, -OC1-C12alkil, -C1-C8 alkil, -CF3, -CN, -OCH2 fenil, -OCH2-supstituirani fenil, -(CH2)m-fenil, -O-fenil, -O-supstituirani fenil, -CH=CH-fenil, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkil)(CH2)pNRbRc, [image] ; R8 jest COOH, tetrazolil, SO2Rd ili -CONHSO2Rd; Rb i Rc jesu, svaki neovisno, vodik, -C1-C6 alkil, -(CH2)m-fenil ili Rb i Rc uzeti zajedno s dušikom na koji su vezani čine ciklički sustav odabran između slijedećih: piperidinil, pirolil, imidazolil, piperazinil, 4-C1-C6 alkilpiperazinil, morfolino, tiomorfolino, dekahidroizokinolin ili pirazolil; Rd jest vodik, C1-C6 alkil, -CF3 ili fenil; m jest 0 do uključivo 5; p jest 1 do uključivo 5; A jest CH ili N; R1 i R2, ukoliko su vezani jedan na drugi, mogu biti metilendioksi; ili njihova farmaceutski prihvatljiva sol; b. ostavljanje dovoljno vremena da se označeni spoj veže na amiloidne naslage; i c. detektiranje označenog spoja vezanog na amiloidne naslage.28. The procedure for visualizing amyloid deposits, characterized by the fact that it includes the following steps: a. introducing, into the patient, a minimum measurable amount of the indicated compound of Formula I, or its pharmaceutically acceptable salt. [image] where R a is hydrogen, C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl; n is 0 to 5 inclusive; R1, R2, R3, R4, R5, R6, and R7 are, each independently, hydrogen, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkyl, -NO2, -OC1-C12alkyl, -C1-C8 alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkyl)(CH2)pNRbRc, [image] ; R8 is COOH, tetrazolyl, SO2Rd or -CONHSO2Rd; Rb and Rc are, each independently, hydrogen, -C1-C6 alkyl, -(CH2)m-phenyl or Rb and Rc taken together with the nitrogen to which they are attached form a cyclic system selected from the following: piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-C6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline or pyrazolyl; Rd is hydrogen, C1-C6 alkyl, -CF3 or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R1 and R2, if they are bound to each other, can be methylenedioxy; or a pharmaceutically acceptable salt thereof; b. allowing enough time for the labeled compound to bind to the amyloid deposits; and c. detection of the labeled compound bound to amyloid deposits. 29. Postupak prema zahtjevu 28, naznačen time, da pacijent ima ili se pretpostavlja da ima ili Alzheimerovu bolest.29. The method according to claim 28, characterized in that the patient has or is assumed to have Alzheimer's disease. 30. Postupak prema zahtjevu 28, naznačen time, da označeni spoj jest radioaktivno označeni spoj.30. The method according to claim 28, characterized in that the labeled compound is a radioactively labeled compound. 31. Postupak prema zahtjevu 28, naznačen time, da označeni spoj jest detektiran primjenom MRI.31. The method according to claim 28, characterized in that the labeled compound is detected using MRI. 32. Spojevi, naznačeni time, da su: 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}benzojeva kiselina; 2-{4-[2-(3,4-diklorfenil)etil]fenilamino}-5-nitrobenzojeva kiselina; 2-{4-[3-(3,4-diklorfenil)propil]fenilamino}benzojeva kiselina; 2-{4-[2-(4-klor-3-trifluormetilfenil)etil]fenilamino}benzojeva kiselina; i 2-{4-[3-(4-dietilaminofenil)propil]fenilamino}benzojeva kiselina.32. Compounds, indicated by the fact that they are: 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}benzoic acid; 2-{4-[2-(3,4-dichlorophenyl)ethyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid; 2-{4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]phenylamino}benzoic acid; and 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}benzoic acid. 33. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 19 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.33. Pharmaceutical preparation, characterized in that it comprises the compound of claim 19 mixed with a pharmaceutically acceptable diluent, binder or carrier. 34. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 20 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.34. Pharmaceutical preparation, characterized in that it comprises the compound of claim 20 mixed with a pharmaceutically acceptable diluent, binder or carrier. 35. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 21 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.35. Pharmaceutical preparation, characterized in that it comprises the compound of claim 21 mixed with a pharmaceutically acceptable diluent, binder or carrier. 36. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 22 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.36. Pharmaceutical preparation, characterized in that it comprises the compound of claim 22 mixed with a pharmaceutically acceptable diluent, binder or carrier. 37. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 23 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.37. Pharmaceutical preparation, characterized in that it comprises the compound of claim 23 mixed with a pharmaceutically acceptable diluent, binder or carrier. 38. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 24 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.38. Pharmaceutical composition, characterized in that it comprises the compound of claim 24 mixed with a pharmaceutically acceptable diluent, binder or carrier. 39. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 25 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.39. Pharmaceutical preparation, characterized in that it comprises the compound of claim 25 mixed with a pharmaceutically acceptable diluent, binder or carrier. 40. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 26 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.40. Pharmaceutical preparation, characterized in that it comprises the compound of claim 26 mixed with a pharmaceutically acceptable diluent, binder or carrier. 41. Farmaceutski pripravak, naznačen time, da obuhvaća spoj iz zahtjeva 32 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.41. Pharmaceutical preparation, characterized in that it comprises the compound of claim 32 mixed with a pharmaceutically acceptable diluent, binder or carrier. 42. Spoj formule I [image] naznačen time, da: Ra jest vodik, C1-C6 alkil ili -C(O)C1-C6alkil; n jest 0 do uključivo 5; R1, R2, R3, R4, R5, R6, i R7 jesu, svaki neovisno, vodik, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkil, -NO2, -OC1-C12alkil, -C1-C8 alkil, -CF3, -CN, -OCH2 fenil, -OCH2-supstituirani fenil, -(CH2)m-fenil, -O-fenil, -O-supstituirani fenil, -CH=CH-fenil, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkil)(CH2)pNRbRc, [image] ; R8 jest COOH, tetrazolil, SO2Rd ili -CONHSO2Rd; Rb i Rc jesu, svaki neovisno, vodik, -C1-C6 alkil, -(CH2)m-fenil ili Rb i Rc uzeti zajedno s dušikom na koji su vezani čine ciklički sustav odabran između slijedećih: piperidinil, pirolil, imidazolil, piperazinil, 4-C1-C6 alkilpiperazinil, morfolino, tiomorfolino, dekahidroizokinolin ili pirazolil; Rd jest vodik, C1-C6 alkil, -CF3 ili fenil; m jest 0 do uključivo 5; p jest 1 do uključivo 5; A jest CH ili N; R1 i R2, ukoliko su vezani jedan na drugi, mogu biti metilendioksi; ili njihova farmaceutski prihvatljiva sol.42. Compound of formula I [image] indicated that: R a is hydrogen, C 1 -C 6 alkyl or -C(O)C 1 -C 6 alkyl; n is 0 to 5 inclusive; R1, R2, R3, R4, R5, R6, and R7 are, each independently, hydrogen, halogen, -OH, NH2, -NRbRc, -CO2H, -CO2C1-C6 alkyl, -NO2, -OC1-C12alkyl, -C1-C8 alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, -O(CH2)pNRbRc, -C(O)NRbRc, -NHC(O)Rb, -NH(CH2)pNRbRc, -N(C1-C6 alkyl)(CH2)pNRbRc, [image] ; R8 is COOH, tetrazolyl, SO2Rd or -CONHSO2Rd; Rb and Rc are, each independently, hydrogen, -C1-C6 alkyl, -(CH2)m-phenyl or Rb and Rc taken together with the nitrogen to which they are attached form a cyclic system selected from the following: piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-C6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline or pyrazolyl; Rd is hydrogen, C1-C6 alkyl, -CF3 or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R1 and R2, if they are bound to each other, can be methylenedioxy; or a pharmaceutically acceptable salt thereof. 43. Farmaceutski pripravak, naznačena time, da obuhvaća spoj iz zahtjeva 42 pomješan s farmaceutski prihvatljivim razrijeđivačem, vezivom ili nosačem.43. Pharmaceutical composition, characterized in that it comprises the compound of claim 42 mixed with a pharmaceutically acceptable diluent, binder or carrier.
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