IT202000029906A1 - PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE. - Google Patents

PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE. Download PDF

Info

Publication number
IT202000029906A1
IT202000029906A1 IT102020000029906A IT202000029906A IT202000029906A1 IT 202000029906 A1 IT202000029906 A1 IT 202000029906A1 IT 102020000029906 A IT102020000029906 A IT 102020000029906A IT 202000029906 A IT202000029906 A IT 202000029906A IT 202000029906 A1 IT202000029906 A1 IT 202000029906A1
Authority
IT
Italy
Prior art keywords
adamantan
mmol
biphenyl
alkyl
linear
Prior art date
Application number
IT102020000029906A
Other languages
Italian (it)
Inventor
Claudio Pisano
Massimiliano Florio
Claudio Camponeschi
Sabrina Dallavalle
Original Assignee
Special Product’S Line S P A
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Special Product’S Line S P A filed Critical Special Product’S Line S P A
Priority to IT102020000029906A priority Critical patent/IT202000029906A1/en
Publication of IT202000029906A1 publication Critical patent/IT202000029906A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/04—Phenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Description

Descrizione della domanda di brevetto per industriale dal titolo: Derivati fenolici per uso come antimicrobici, antibatterici, battericidi. Description of the industrial patent application entitled: Phenolic derivatives for use as antimicrobials, antibacterials, bactericides.

Campo dell'invenzione Field of invention

La presente invenzione riguarda il campo dei composti farmaceutici, in particolare derivati fenolici, anche per uso come antimicrobici, batterici, battericidi. The present invention relates to the field of pharmaceutical compounds, in particular phenolic derivatives, also for use as antimicrobials, bacteria, bactericides.

Stato dell'arte State of art

La pubblicazione scientifica Nature Wooseong Kim et al., 2018, A new class of synthetic retinoid antibiotics effective against bacterial persisters, 556, 103-107 doi:10.1038/nature26157, divulga i seguenti composti: The scientific publication Nature Wooseong Kim et al., 2018, A new class of synthetic retinoid antibiotics effective against bacterial persisters, 556, 103-107 doi:10.1038/nature26157, discloses the following compounds:

che presentano elevati tassi di uccisione, sinergia con gentamicina, e una bassa probabilit? di selezione della resistenza, in un saggio di uccisione di C. elegans-MRSA contro il ceppo di MRSA MW2 e l?attivit? contro un gruppo di ceppi clinici di S. aureus ed Enterococcus faecium, ma non contro specie Gram-negative. which have high kill rates, synergy with gentamicin, and a low probability? of resistance selection, in a C. elegans-MRSA kill assay against MRSA strain MW2 and the activity? against a group of clinical strains of S. aureus and Enterococcus faecium, but not against Gram-negative species.

WO9801132 e WO0156563 divulgano composti retinoidi contenenti adamantile usati come agenti antitumorali. WO9801132 and WO0156563 disclose adamantyl-containing retinoid compounds used as anticancer agents.

La domanda di brevetto internazionale n. WO2017053778 divulga specificamente i seguenti composti: The international patent application n. WO2017053778 specifically discloses the following compounds:

acido 6-(4-idrossi-3-triciclo[3,3,1,13,7]dec-1-ilfenil)-2-naftalencarbossilico, acido 4-(6-idrossi-7-triciclo[3,3,1,13,7]dec-1-il-2-naftalenil)-benzoico, acido (2E)-3-(4'-Idrossi-3'-triciclo[3,3,1,13,7]dec-1-il[1,1'-bifenil]-4-i1)-2-propenoico, piridin-2-ilmetil 9-fluoro-3-metil-10-(4-metilpiperazin-l-il)-7-osso-3,7-diidro-2H-[1,4]ossazino[2,3,4-ij] chinolina-6-carbossilato, 2,3,4,6-tetra-o-acetil-1-tio-D-glucanpiranosato-S-(trietil-fosfina)oro, 6-(4-Hydroxy-3-tricyclo[3,3,1,13,7]dec-1-ylphenyl)-2-naphthalencarboxylic acid, 4-(6-hydroxy-7-tricyclo[3,3,1 ,13,7]dec-1-yl-2-naphthalenyl)-benzoic acid, (2E)-3-(4'-Hydroxy-3'-tricyclo[3,3,1,13,7]dec-1- yl[1,1'-biphenyl]-4-i1)-2-propenoic, pyridin-2-ylmethyl 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3, 7-Dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate, 2,3,4,6-tetra-o-acetyl-1-thio-D-glucanpyranosate-S -(triethyl-phosphine)gold,

utili nel trattamento di infezioni batteriche come un'infezione batterica. useful in treating bacterial infections such as a bacterial infection.

La domanda di brevetto internazionale n. WO2018213609 divulga la preparazione dei seguenti composti: The international patent application n. WO2018213609 discloses the preparation of the following compounds:

Metil 6-(3-(adamantan-1-il)-4-idrossifenil)-2-naftoato Methyl 6-(3-(adamantan-1-yl)-4-hydroxyphenyl)-2-naphthoate

2-(adamantan-l-il)-4-(6-(idrossimetil)naftalen-2-il)fenolo 6-(3-(adamantan-l-il)-4-idrossifenil)-2-naftammide 2-(adamantan-1-yl)-4-(6-(hydroxymethyl)naphthalene-2-yl)phenol 6-(3-(adamantan-1-yl)-4-hydroxyphenyl)-2-naphthamide

6-(3-(adamantan-l-il)-4-idrossifenil)-N-etil-2-naftammide 6-(3-(adamantan-1-yl)-4-hydroxyphenyl)-N-ethyl-2-naphthamide

Metil 6-(3-(adamantan-l-il)-4-metossifenil)-2-naftoato Methyl 6-(3-(adamantan-1-yl)-4-methoxyphenyl)-2-naphthoate

(6-(3-(adamantan-l-il)-4-metossifenil)naftalen-2-il)metanolo (6-(3-(adamantan-1-yl)-4-methoxyphenyl)naphthalene-2-yl)methanol

6-(3-(adamantan-l-il)-4-metossifenil)-2-naftammide 6-(3-(adamantan-1-yl)-4-methoxyphenyl)-2-naphthamide

6-(3-(adamantan-l-il)-4-metossifenil)-N-etil-2-naftammide 6-(3-(adamantan-1-yl)-4-methoxyphenyl)-N-ethyl-2-naphthamide

acido 6-(3-benzil-4-idrossifenil)-2-naftoico 6-(3-benzyl-4-hydroxyphenyl)-2-naphthoic acid

acido 6-(5-(adamantan-1-il)-2-idrossifenil)-2-naftoico 6-(5-(adamantan-1-yl)-2-hydroxyphenyl)-2-naphthoic acid

acido 6-(3-(adamantan-1-il)-4-idrossifenil)-4-idrossi-2-naftoico 6-(3-(adamantan-1-yl)-4-hydroxyphenyl)-4-hydroxy-2-naphthoic acid

acido 6-(3-benzil-4-idrossifenil)-4-idrossi-2-naftoico 6-(3-benzyl-4-hydroxyphenyl)-4-hydroxy-2-naphthoic acid

acido 6-(5-(adamantan-1-il)-2-idrossifenil)-4-idrossi-2-naftoico 6-(5-(adamantan-1-yl)-2-hydroxyphenyl)-4-hydroxy-2-naphthoic acid

acido 6-(3-(adamantan-l-il)-4-idrossifenil)-4,8-diidrossi-2-naftoico 6-(3-(adamantan-1-yl)-4-hydroxyphenyl)-4,8-dihydroxy-2-naphthoic acid

acido 6-(3-benzil-4-idrossifenil)-4,8-diidrossi-2-naftoico 6-(3-benzyl-4-hydroxyphenyl)-4,8-dihydroxy-2-naphthoic acid

acido 6-(5-(adamantan-1-il)-2-idrossifenil)-4,8-diidrossi-2-naftoico 6-(5-(adamantan-1-yl)-2-hydroxyphenyl)-4,8-dihydroxy-2-naphthoic acid

e la loro attivit? antibatterica in particolare contro il batterio dell?acne Cutibacterium (Propionibacterium). and their activity? antibacterial in particular against the acne bacterium Cutibacterium (Propionibacterium).

La domanda di brevetto internazionale n. WO01/56554 divulga molecole di tipo retinoide per la preparazione di composizioni per il trattamento preventivo o curativo della colonizzazione batterica, del deterioramento in condizioni patologiche causate da detta colonizzazione e delle infezioni cutanee secondarie indotte da detto batterio e pi? in particolare dallo Staphylococcus aureus. WO01/56554 Divulga specificamente i seguenti composti: The international patent application n. WO01/56554 discloses molecules of the retinoid type for the preparation of compositions for the preventive or curative treatment of bacterial colonization, deterioration in pathological conditions caused by said colonization and secondary skin infections induced by said bacterium and more especially from Staphylococcus aureus. WO01/56554 Specifically discloses the following compounds:

acido 4-[4-(4'-Propil-bifenil-2-il)-but-3-en-1-inil] benzoico 4-[4-(4'-Propyl-biphenyl-2-yl)-but-3-en-1-ynyl]benzoic acid

acido 2-Idrossi-4-(3,5,5,8,8-pentametil)-5,6,7,8-tetraidronaftalen-2-ilselaniletinil) benzoico 2-Hydroxy-4-(3,5,5,8,8-pentamethyl)-5,6,7,8-tetrahydronaphthalene-2-ylselanylethynyl)benzoic acid

2'-(3-Metossi-5,5,8,8-tetrametil-5,6,7,8-tetraidronaftalen-2-il)-[1,1',4',11-terfenil]-4-carbossilico 2'-(3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-[1,1',4',11-terphenyl]-4-carboxylic acid

acido 6-[Butossi-(5,5,8,8-tetrametil-5,6,7,8-tetraidro-naftalen-2-il)-metil]-naftalen-2-carbossilico 6-[Butoxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-yl)-methyl]-naphthalene-2-carboxylic acid

acido 4-[3-(1,1-Dimetil-decil)-4-metossi-benzoilammino] benzoico 4-[3-(1,1-Dimethyl-decyl)-4-methoxy-benzoylamino]benzoic acid

acido 4-(3-Adamantan-1-il-4-esilossi-benzoilammino) benzoico 4-(3-Adamantan-1-yl-4-hexyloxy-benzoylamino) benzoic acid

643-(1-adamantil)-4-idrossifenil]-2-naftilmetanolo 643-(1-adamantyl)-4-hydroxyphenyl]-2-naphthylmethanol

acido 2-Idrossi-4-(5,5,8,8-tetrametil-5,6,7,8-tetraidroantracen-2-il)-benzico 2-Hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroanthracene-2-yl)-benzic acid

acido 2-(3-Adamantan-1-il-4-idrossi-fenil)-benzofuran-5-carbossilico 2-(3-Adamantan-1-yl-4-hydroxy-phenyl)-benzofuran-5-carboxylic acid

acido 446-metossietossimetossi-7-(1-adamantil)-2-naftil] salicilico 446-Methoxyethoxymethoxy-7-(1-adamantyl)-2-naphthyl]salicylic acid

acido (E)-444-(5-Metossimetossi-4'-metil-bifenil-2-il)-but-3-en-1-il] benzoico (E)-444-(5-Methoxymethoxy-4'-methyl-biphenyl-2-yl)-but-3-en-1-yl]benzoic acid

acido 4-[4-(3-Metossi-4'-metil-bifenil-2-il-but-3-en-1-inil]-benzico 4-[4-(3-Methoxy-4'-methyl-biphenyl-2-yl-but-3-en-1-ynyl]-benzic acid

acido 4-(3,5,5,8,8-Pentametil)-5,6,7,8-tetraidro-naftalen-2-ilselaniletinil)-benzico 4-(3,5,5,8,8-Pentamethyl)-5,6,7,8-tetrahydro-naphthalene-2-ylselanylethynyl)-benzic acid

2-Metossimetossi-2'-(5,5,8,8-tetrametil-5,6,7,8-tetraidronaftalen-2-il)-[1,1',4',1"]terfenil-4"-carbossilico 2-Methoxymethoxy-2'-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-[1,1',4',1"]terphenyl-4"- carboxyl

acido 2-Idrossi-1-(5,5,8,8-tetrametil-5,6,7,8-tetraidronaftalen-2-il)-[1,1',4',1"]terfenil-4-carbossilico 2-Hydroxy-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-[1,1',4',1"]terphenyl-4-carboxylic acid

acido 4-[(Z)-2-(5,6,7,8-tetraidro-5,5,8,8-tetrametil-2-naftil)-2-undecenammido] benzoico 4-[(Z)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido]benzoic acid

acido 444-(4'-Mmetil-bifenil-2-il)-but-3-en-1-inil] benzoico 444-(4'-Mmethyl-biphenyl-2-yl)-but-3-en-1-ynyl]benzoic acid

acido 21-Propossi-5'-(5,5,8,8-tetrametano)-5,6,7,8-tetraidronaftalen-2-il)-bifenil-4-carbossilico 21-Propoxy-5'-(5,5,8,8-tetramethane)-5,6,7,8-tetrahydronaphthalene-2-yl)-biphenyl-4-carboxylic acid

acido 4 [2-Eptilossiimmino-2-(5,5,8,8-tetrametil)-5,6,7,8-tetraidronaftalen-2-il)acetilammino] benzoicoammide di acido 6-(5,5,8,8-Tetrametil)-5,6,7,8-tetraidro-naftalen-2-ilossi)-naftalen-2-carbossilico 4 [2-Heptyloxyimino-2-(5,5,8,8-tetramethyl)-5,6,7,8-tetrahydronaphthalene-2-yl)acetylamino]benzoicamide acid 6-(5,5,8,8) -Tetramethyl)-5,6,7,8-tetrahydro-naphthalene-2-yloxy)-naphthalene-2-carboxylic acid

(2-dimetilammino-etil)-ammide di acido 6-(3-Adamantan-1-il-4-metossi-fenil)-naftalen-2-carbossilico 6-(3-Adamantan-1-yl-4-methoxy-phenyl)-naphthalene-2-carboxylic acid (2-dimethylamino-ethyl)-amide

acido 2-Idrossi-4-(5,5,8,8-tetrametil-5,6,7,8-tetraidronaftalen-2-ilselaniletinil) benzoico 2-Hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-ylselanylethynyl)benzoic acid

2'-(3-Metossimetossi-5,5,8,8-tetrametil-5,6,7,8-tetraidronaftalen-2-il)-[1,1',4',1"]terfenil-4"-carbossilico 2'-(3-Methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-[1,1',4',1"]terphenyl-4"- carboxyl

acido 3-Idrossi-2'-(5,5,8,8-tetrametil-5,6,7,8-tetraidronaftalen-2-il)-[1,1',4',1"]terfenil-4-carbossilico 3-Hydroxy-2'-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-[1,1',4',1"]terphenyl-4- acid carboxyl

acido 3-(5'-Adamantan-1-il-4'-metossi-21-metil-bifenil-3-il)-acrilico 3-(5'-Adamantan-1-yl-4'-methoxy-21-methyl-biphenyl-3-yl)-acrylic acid

Problema tecnico Technical problem

La resistenza batterica ai farmaci antimicrobici pu? diventare una delle minacce pi? grandi per la salute umana ai nostri tempi. L'insorgenza crescente di infezioni con patogeni multifarmacoresistenti ? associata a mortalit? e morbilit? elevate (H.W. Boucher et al. Clin. Infect. Dis., 2013, 56, 1685? 1694) e la mancanza prevalente di nuovi farmaci antimicrobici efficienti per il trattamento di queste infezioni ha portato a seri problemi. Can bacterial resistance to antimicrobial drugs become one of the threats great for human health in our time. The increasing occurrence of infections with multidrug-resistant pathogens ? associated with mortality and morbidity? high (H.W. Boucher et al. Clin. Infect. Dis., 2013, 56, 1685? 1694) and the prevailing lack of new efficient antimicrobial drugs for the treatment of these infections has led to serious problems.

La resistenza batterica include la modifica o sovraespressione degli antibiotici, la diminuzione della concentrazione antibiotica cellulare, mediante espressione di sistemi di efflusso che trasportano attivamente il farmaco fuori dalla cellula o mediante meccanismo che riduce il loro afflusso, e l'espressione degli enzimi in grado di disattivare l'antibiotico. Bacterial resistance includes modification or overexpression of antibiotics, decrease in cellular antibiotic concentration, either by expression of efflux systems that actively transport drug out of the cell or by mechanisms that reduce their influx, and expression of enzymes capable of deactivate the antibiotic.

? pertanto chiaro che la necessit? di nuovi farmaci antimicrobici sia una necessit? continua al fine di contrastare lo sviluppo della resistenza batterica. ? therefore clear that the need? of new antimicrobial drugs is a necessity? continues in order to counteract the development of bacterial resistance.

Obiettivo dell'invenzione Objective of the invention

Il problema tecnico ? risolto fornendo i composti di formula (II) (denominati composti di classe C): The technical problem? solved by giving the compounds of formula (II) (called compounds of class C):

in cui in which

B ? C3-C12 cicloalchile, o fenile, o un eterociclo C3-C13 contenente S, N, O B ? C3-C12 cycloalkyl, or phenyl, or a C3-C13 heterocycle containing S, N, O

R1 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo, C3-C12 cicloalchile sostituito facoltativamente con C1-C4 alchile o OH, C1-C3 arilalchile, fenile, sostituito facoltativamente con C1-C4 alchile lineare o ramificato, l?eterociclo contenendo almeno un eteroatomo selezionato dal gruppo costituito da: N, O, S, sostituito facoltativamente con OH, NH2R1 ? H, C1-C12 linear or branched saturated or unsaturated alkyl, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 linear or branched alkyl, the heterocycle containing at least a heteroatom selected from the group consisting of: N, O, S, optionally replaced by OH, NH2

R2 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo, (CH2)n-R7, (CH2)nO(CH2)mO-(CH2)p-R8, (CH2O)nCH3, CO-R8, (CH2)n-R10, D-mannosile, glucuronato (SO2)OH R2 ? H, C1-C12 saturated or unsaturated linear or branched alkyl, (CH2)n-R7, (CH2)nO(CH2)mO-(CH2)p-R8, (CH2O)nCH3, CO-R8, (CH2)n- R10, D-mannosil, glucuronate (SO2)OH

R7 ? OH, COOH, CONHO-R8, (CH2)nO(CH2)mO-R8, CN, NH2, R7 ? OH, COOH, CONHO-R8, (CH2)nO(CH2)mO-R8, CN, NH2,

R8 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo R8 ? H,C1-C12 linear or branched saturated or unsaturated alkyl

R10 ? NH2, eterociclo contenente N, ammidina, guanidina R10 ? NH2, N-containing heterocycle, amidine, guanidine

R3 ? H, OH, CHO o R3 ? H, OH, CHO or

R2 e R3 sono legati a formare un ciclo comprendente almeno un atomo di O e/o N R2 and R3 are bonded to form a cycle comprising at least one O and/or N atom

R4 ? H R4 ? h

R5 ? H, OH, C1-C5 alchile lineare o ramificato saturo insaturo, (CH2)-R11, CHO, CH=NOH, CH=NO-R14, CH=NO-(CH2)n-COOH, CH=NO-(CH2)n-NH2, (CH2)nNHCO-R14, (CH2)n-R15 R5 ? H, OH, C1-C5 saturated unsaturated straight or branched alkyl, (CH2)-R11, CHO, CH=NOH, CH=NO-R14, CH=NO-(CH2)n-COOH, CH=NO-(CH2) n-NH2, (CH2)nNHCO-R14, (CH2)n-R15

R11 ? OH, NH2, N-R12R13, R11 ? OH, NH2, N-R12R13,

R12 e R13, uguali o diversi sono H, C1-C5 alchile lineare o ramificato saturo o insaturo, C(=NH)NH2R12 and R13, equal or different are H, C1-C5 saturated or unsaturated linear or branched alkyl, C(=NH)NH2

R14 ? H, ? C1-C5 alchile lineare o ramificato saturo o insaturo, C3-C12 cicloalchile, arile, C1-C3 arilalchile, R14 ? H, ? C1-C5 linear or branched saturated or unsaturated alkyl, C3-C12 cycloalkyl, aryl, C1-C3 arylalkyl,

Facoltativamente R4 e R5 possono essere uniti insieme per formare CH=CH o CO o O o S o SO o SO2Optionally R4 and R5 can be joined together to form CH=CH or CO or O or S or SO or SO2

R6 ? CX=CYCOOH, CX=CYCN, CX=CYCH=NOH, CX=CYCOO-R14, CX=CYCONH2, CX=CY-CONH-R14, CX=CYCONHOH, CX=CY-tetrazolile, CX=CYCH2OH, CX=CY-P(=O)(O-R14)2, CX=CYCOOglicosile, R6 ? CX=CYCOOH, CX=CYCN, CX=CYCH=NOH, CX=CYCOO-R14, CX=CYCONH2, CX=CY-CONH-R14, CX=CYCONHOH, CX=CY-tetrazolyl, CX=CYCH2OH, CX=CY- P(=O)(O-R14)2, CX=CYCOOglycosyl,

X ? H, C2-C4 alchile lineare o ramificato, alogeno, CN X ? H, C2-C4 straight or branched alkyl, halogen, CN

Y ? H, C2-C4 alchile lineare o ramificato, alogeno, CN Y ? H, C2-C4 straight or branched alkyl, halogen, CN

n ? un numero intero da 1 a 15 n ? an integer from 1 to 15

m ? un numero intero da 1 a 15 m ? an integer from 1 to 15

p ? un numero intero da 1 a 15 p ? an integer from 1 to 15

a condizione che quando R1 ? adamantile e R5 ? idrogeno, R6 non sia CX=CY-COOH o CX=CY-COOCH3 o CX=CY-COOCH2CH3provided that when R1 ? adamantyl and R5 ? hydrogen, R6 is not CX=CY-COOH or CX=CY-COOCH3 or CX=CY-COOCH2CH3

o un suo sale farmaceuticamente accettabile. or a pharmaceutically acceptable salt thereof.

Sono anche oggetto della presente invenzione composti appartenenti al gruppoC per uso come medicinale e composti appartenenti al gruppo C per uso come antimicrobici e/o antibatterici e/o battericidi. Also object of the present invention are compounds belonging to group C for use as a medicine and compounds belonging to group C for use as antimicrobials and/or antibacterials and/or bactericides.

Oggetto della presente invenzione ? anche il metodo usato per la preparazione di composti appartenenti al gruppo C. Object of the present invention ? also the method used for the preparation of compounds belonging to group C.

Oggetto dell'invenzione sono composizioni farmaceutiche comprendenti almeno un composto di formula (II) appartenente al gruppo C come principio attivo e adiuvanti e/o veicoli e/o eccipienti farmaceuticamente accettabili. Object of the invention are pharmaceutical compositions comprising at least one compound of formula (II) belonging to group C as active ingredient and pharmaceutically acceptable adjuvants and/or carriers and/or excipients.

Descrizione dettagliata dell'invenzione Detailed description of the invention

Definizioni Definitions

Nel contesto della presente invenzione, antibatterico o battericida significa qualsiasi composto in grado di uccidere i batteri o sopprimere la loro crescita o la loro capacit? di riprodursi. In the context of the present invention, antibacterial or bactericide means any compound capable of killing bacteria or suppressing their growth or ability to absorb bacteria. to reproduce.

Nel contesto della presente invenzione i batteri possono essere batteri gram-positivi e/o batteri gram-negativi, come Staphilococcus aureus, Enterococcus faecalis, Escherichia coli, Streptococcus thermophilus. In the context of the present invention the bacteria can be gram-positive bacteria and/or gram-negative bacteria, such as Staphilococcus aureus, Enterococcus faecalis, Escherichia coli, Streptococcus thermophilus.

Nel contesto della presente invenzione, antimicrobico indica qualsiasi composto che sono germicidi, antibiotici, antibatterici, antivirali, antifungini, antiprotozoari e antiparassitari. In the context of the present invention, antimicrobial means any compounds that are germicidal, antibiotic, antibacterial, antiviral, antifungal, antiprotozoal, and antiparasitic.

Nel contesto della presente invenzione, alchile indica gruppi alchile lineare o ramificato aventi da 1 a 18 atomi di carbonio o da 1 a 12 atomi di carbonio o da 1 a 5 atomi di carbonio o da 1 a 4 atomi di carbonio o da 2 a 5 atomi di carbonio. In the context of the present invention, alkyl means linear or branched alkyl groups having 1 to 18 carbon atoms or 1 to 12 carbon atoms or 1 to 5 carbon atoms or 1 to 4 carbon atoms or 2 to 5 carbon atoms.

Nel contesto della presente invenzione, cicloalchile indica un gruppo carbociclico saturo o parzialmente insaturo di 3-12 atomi di carbonio o di 3-6 atomi di carbonio, sostituito facoltativamente con C1-C4 alchile o OH o NH2. Un gruppo aromatico non ? previsto. Il gruppo cicloalchile pu? comprendere un singolo anello o molteplici anelli condensati. In the context of the present invention, cycloalkyl means a saturated or partially unsaturated carbocyclic group of 3-12 carbon atoms or 3-6 carbon atoms, optionally substituted with C1-C4 alkyl or OH or NH2. An aromatic group, isn't it? expected. The cycloalkyl group can comprise a single ring or multiple condensed rings.

Nel contesto della presente invenzione eterociclo indica un anello C3-C13 o C3-C12 saturo o parzialmente insaturo, ma non aromatico o un anello condensato multiplo contenente almeno un eteroatomo selezionato dal gruppo costituito da N, O, S e sostituito facoltativamente con OH, NH2. In the context of the present invention heterocycle means a saturated or partially unsaturated, but non-aromatic C3-C13 or C3-C12 ring or a multiple condensed ring containing at least one heteroatom selected from the group consisting of N, O, S and optionally replaced by OH, NH2 .

Nel contesto della presente invenzione, arile indica un anello aromatico, per esempio fenile, sostituito facoltativamente con C1-C3 alchile o C1-C4 alchile, OH, NH2. In the context of the present invention, aryl means an aromatic ring, for example phenyl, optionally substituted with C1-C3 alkyl or C1-C4 alkyl, OH, NH2.

Nel contesto della presente invenzione, residuo monosaccaridico indica uno zucchero semplice di formula generale CnH2nOn come trioso, tetroso, pentoso, esoso, eptoso ecc. In the context of the present invention, monosaccharide residue means a simple sugar of general formula CnH2nOn such as triose, tetrose, pentose, hexose, heptose, etc.

Nel contesto della presente invenzione, glicosile indica un radicale derivato da un saccaride mediante rimozione del gruppo idrossile. In the context of the present invention, glycosyl means a radical derived from a saccharide by removal of the hydroxyl group.

I nuovi composti sintetizzati appartenenti al gruppo C sono di formula (II) The new synthesized compounds belonging to group C are of formula (II)

in cui in which

B ? C3-C12 cicloalchile, o fenile, o un eterociclo C3-C13 contenente S, N, O B ? C3-C12 cycloalkyl, or phenyl, or a C3-C13 heterocycle containing S, N, O

R1 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo, C3-C12 cicloalchile sostituito facoltativamente con C1-C4 alchile o OH, C1-C3 arilalchile, fenile, sostituito facoltativamente con C1-C4 alchile lineare o ramificato, l?eterociclo contenendo almeno un eteroatomo selezionato dal gruppo costituito da: N, O, S, sostituito facoltativamente con OH, NH2R1 ? H, C1-C12 linear or branched saturated or unsaturated alkyl, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 linear or branched alkyl, the heterocycle containing at least a heteroatom selected from the group consisting of: N, O, S, optionally replaced by OH, NH2

R2 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo, (CH2)n-R7, (CH2)nO(CH2)mO-(CH2)p-R8, (CH2O)nCH3, CO-R8, (CH2)n-R10, D-mannosile, glucuronato (SO2)OH R2 ? H, C1-C12 saturated or unsaturated linear or branched alkyl, (CH2)n-R7, (CH2)nO(CH2)mO-(CH2)p-R8, (CH2O)nCH3, CO-R8, (CH2)n- R10, D-mannosil, glucuronate (SO2)OH

R7 ? OH, COOH, CONHO-R8, (CH2)nO(CH2)mO-R8, CN, NH2, R7 ? OH, COOH, CONHO-R8, (CH2)nO(CH2)mO-R8, CN, NH2,

R8 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo R8 ? H,C1-C12 linear or branched saturated or unsaturated alkyl

R10 ? NH2, eterociclo contenente N, ammidina, guanidina R10 ? NH2, N-containing heterocycle, amidine, guanidine

R3 ? H, OH, CHO o R3 ? H, OH, CHO or

R2 e R3 sono legati a formare un ciclo comprendente almeno un atomo di O e/o N R2 and R3 are bonded to form a cycle comprising at least one O and/or N atom

R4 ? H R4 ? h

R5 ? H, OH, C1-C5 alchile lineare o ramificato saturo insaturo, (CH2)-R11, CHO, CH=NOH, CH=NO-R14, CH=NO-(CH2)n-COOH, CH=NO-(CH2)n-NH2, (CH2)nNHCO-R14, (CH2)n-R15 R5 ? H, OH, C1-C5 saturated unsaturated straight or branched alkyl, (CH2)-R11, CHO, CH=NOH, CH=NO-R14, CH=NO-(CH2)n-COOH, CH=NO-(CH2) n-NH2, (CH2)nNHCO-R14, (CH2)n-R15

R11 ? OH, NH2, N-R12R13, R11 ? OH, NH2, N-R12R13,

R12 e R13, uguali o diversi sono H, C1-C5 alchile lineare o ramificato saturo o insaturo, C(=NH)NH2R12 and R13, equal or different are H, C1-C5 saturated or unsaturated linear or branched alkyl, C(=NH)NH2

R14 ? H, ? C1-C5 alchile lineare o ramificato saturo o insaturo, C3-C12 cicloalchile, arile, C1-C3 arilalchile, R14 ? H, ? C1-C5 linear or branched saturated or unsaturated alkyl, C3-C12 cycloalkyl, aryl, C1-C3 arylalkyl,

Facoltativamente R4 e R5 possono essere uniti insieme per formare CH=CH o CO o O o S o SO o SO2Optionally R4 and R5 can be joined together to form CH=CH or CO or O or S or SO or SO2

R6 ? CX=CYCOOH, CX=CYCN, CX=CYCH=NOH, CX=CYCOO-R14, CX=CYCONH2, CX=CY-CONH-R14, CX=CYCONHOH, CX=CY-tetrazolile, CX=CYCH2OH, CX=CY-P(=O)(O-R14)2, CX=CYCOOglicosile, R6 ? CX=CYCOOH, CX=CYCN, CX=CYCH=NOH, CX=CYCOO-R14, CX=CYCONH2, CX=CY-CONH-R14, CX=CYCONHOH, CX=CY-tetrazolyl, CX=CYCH2OH, CX=CY- P(=O)(O-R14)2, CX=CYCOOglycosyl,

X ? H, C2-C4 alchile lineare o ramificato, alogeno, CN X ? H, C2-C4 straight or branched alkyl, halogen, CN

Y ? H, C2-C4 alchile lineare o ramificato, alogeno, CN Y ? H, C2-C4 straight or branched alkyl, halogen, CN

n ? un numero intero da 1 a 15 n ? an integer from 1 to 15

m ? un numero intero da 1 a 15 m ? an integer from 1 to 15

p ? un numero intero da 1 a 15 p ? an integer from 1 to 15

a condizione che quando R1 ? adamantile e R5 ? idrogeno, R6 non sia CX=CY-COOH o CX=CY-COOMe o CX=CY-COOEt provided that when R1 ? adamantyl and R5 ? hydrogen, R6 is not CX=CY-COOH or CX=CY-COOMe or CX=CY-COOEt

o un suo sale farmaceuticamente accettabile. or a pharmaceutically acceptable salt thereof.

Preferibilmente B ? fenile. Preferably B? phenyl.

Preferibilmente R1 ? adamantile, benzile, 1-metilcicloesile. Preferably R1 ? adamantyl, benzyl, 1-methylcyclohexyl.

Preferibilmente R2 ? H. Preferably R2 ? h.

Preferibilmente R3 ? H. Preferably R3? h.

Preferibilmente R4 ? H. Preferably R4? h.

Preferibilmente R5 ? H. Preferably R5? h.

Preferibilmente R6 ? CX=CYCOOH, CX=CYCN, CX=CYCOO-R14, CX=CYCONH2, CX=CY-CONH-R14, CX=CYCONHOH, CX=CYCH2OH, Preferably R6 ? CX=CYCOOH, CX=CYCN, CX=CYCOO-R14, CX=CYCONH2, CX=CY-CONH-R14, CX=CYCONHOH, CX=CYCH2OH,

Preferibilmente X ? H. Preferably X ? h.

Preferibilmente Y ? C2-C4 alchile lineare o ramificato, alogeno, CN. Preferably Y? C2-C4 linear or branched alkyl, halogen, CN.

Pi? preferibilmente i composti del gruppo (C) sono selezionati dal gruppo costituito da: Pi? preferably the compounds of group (C) are selected from the group consisting of:

?Alk? = Alch ?alk? = Alch

?amide? = ammide ?amide? = amide

?guanidine? = guanidina ?guanidine? = guanidine

I sali farmaceuticamente accettabili del composto di formula (II) appartenenti al gruppo C sono inclusi nella portata dell'invenzione. The pharmaceutically acceptable salts of the compound of formula (II) belonging to group C are included in the scope of the invention.

Sali farmaceuticamente accettabili sono sali che mantengono l'attivit? biologica della base e sono derivati da tali acidi farmacologicamente accettabili noti come, per esempio, acido cloridrico, bromidrico, solforico, fosforico, nitrico, fumarico, succinico, ossalico, malico, tartarico, maleico, citrico, metansolfonico o benzoico e altri comunemente usati nell'arte, e la loro base corrispondente. Pharmaceutically acceptable salts are salts that retain the activity? biological base and are derived from such pharmacologically acceptable acids known as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, fumaric, succinic, oxalic, malic, tartaric, maleic, citric, methanesulfonic, or benzoic acid and others commonly used in art, and their corresponding basis.

I composti della presente invenzione possono essere sintetizzati mediante molti metodi disponibili ai tecnici del ramo della chimica organica. Esempi di composti della presente invenzione sono riportati nella sezione degli intermedi e degli esempi esposta di seguito. The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry. Examples of compounds of the present invention are given in the intermediates and examples section set forth below.

Un altro oggetto della presente invenzione ? una composizione farmaceutica contenente almeno un composto di formula (II) del gruppo C come principio attivo, in una quantit? tale da produrre un effetto terapeutico significativo, insieme a un veicolo e/o eccipienti farmaceuticamente accettabili. Another object of the present invention ? a pharmaceutical composition containing at least one compound of formula (II) of group C as active ingredient, in an amount such as to produce a significant therapeutic effect, together with a pharmaceutically acceptable vehicle and/or excipients.

Le composizioni farmaceutiche possono essere preparate mediante metodi e tecniche convenzionali che sono pratica comune nell'industria farmaceutica, come, per esempio, quelli illustrati in Remington's Pharmaceutical Science Handbook, Mack Pub. N.Y. - ultima edizione. The pharmaceutical compositions can be prepared by conventional methods and techniques which are common practice in the pharmaceutical industry, such as, for example, those disclosed in Remington's Pharmaceutical Science Handbook, Mack Pub. N.Y. - latest edition.

Le composizioni secondo la presente invenzione contengono, insieme al principio attivo, almeno un veicolo o eccipiente farmaceuticamente accettabile. Questi possono essere coadiuvanti di formulazione particolarmente utile, ad esempio agenti solubilizzanti, agenti di dispersione, agenti di sospensione e agenti emulsionanti. The compositions according to the present invention contain, together with the active ingredient, at least one pharmaceutically acceptable carrier or excipient. These can be particularly useful formulation aids, for example solubilizing agents, dispersing agents, suspending agents and emulsifying agents.

ESEMPI EXAMPLES

I Composti sintetizzati da 1 a 15 sono elencati nel presente documento: The Synthesized Compounds 1 to 15 are listed in this document:

Esempio 1: sintesi di (E/Z)-3-(3'-(Adamantan-1-il-4'-idrossibifenil-4-il)-acrilonitrile (1) Example 1: Synthesis of (E/Z)-3-(3'-(Adamantan-1-yl-4'-hydroxybiphenyl-4-yl)-acrylonitrile (1)

2-(Adamantan-1-il)-4-(4-bromofenil)fenolo. Una miscela finemente polverizzata di 4-(4-bromofenil)fenolo (200 mg, 0,8 mmol) e adamantan-1-olo (122 mg, 0,8 mmol) ? stata aggiunta in porzioni e con agitazione a 0,8 mL di una miscela di 9:1 AcOH/H2 SO4. Dopo 4 giorni a temperatura ambiente l'aggiunta di ghiaccio/acqua e la filtrazione hanno dato il 100% del composto del titolo, pf 140-143 ?C, lit. 148-149 ?C. <1>H NMR (CDCl3) ?: 1,75 (6H, s, 6Ad), 2,03(3H, s, 3Ad), 2,12 (6H, s, 6Ad), 6,70 (2H, d, 1Ar, J = 8,56 Hz),7,85 (1H, d, 1Ar, J = 8,56 Hz), 7,25 (1H, m, 1Ar), 7,30-7,42(3H, m, 3Ar), 7,45 (2H, m, 2Ar). 2-(Adamantan-1-yl)-4-(4-bromophenyl)phenol. A finely powdered mixture of 4-(4-bromophenyl)phenol (200 mg, 0.8 mmol) and adamantan-1-ol (122 mg, 0.8 mmol) ? was added in portions and with stirring to 0.8 mL of a 9:1 AcOH/H2 SO4 mixture. After 4 days at room temperature the addition of ice/water and filtration gave 100% of the title compound, mp 140-143 ?C, lit. 148-149?C. <1>H NMR (CDCl3) ?: 1.75 (6H, s, 6Ad), 2.03(3H, s, 3Ad), 2.12 (6H, s, 6Ad), 6.70 (2H, d , 1Ar, J = 8.56Hz), 7.85 (1H, d, 1Ar, J = 8.56Hz), 7.25 (1H, m, 1Ar), 7.30-7.42(3H, m, 3Ar), 7.45 (2H, m, 2Ar).

(E/Z)-3-(3'-(Adamantan-1-il-4'-idrossi-bifenil-4-il)-acrilonitrile (1). 2-(Adamantan-1-il)-4-(4-bromofenil)fenolo. (300 mg, 0,782 mmol), 66,4 mg (1,25 mmol) di acrilonitrile, 8,78 mg (0,0391 mmol) di Pd(OAc)2, e 23,80 mg (0,00782 mmol) di tri-otolilfosfina in 0,600 mL di Et3N sono stati miscelati in un pallone rotondo e riscaldati a 100 ?C per 8 h. Sono stati aggiunti acqua e ghiaccio, ? stato aggiunto HCl 2N, e la fase acquosa ? stata estratta con etil acetato. La fase organica ? stata essiccata su Na2SO4, filtrata e fatta evaporare. Il prodotto grezzo ? stato purificato mediante cromatografia flash (esano/etil acetato, 80:20) a dare 124 mg del prodotto. (Isomeri E/Z, 2:1). Resa 45%. <1>H NMR (CDCl3), E, ?: 1,78 (6H, s), 2,13 (3H, s), 2,17 (3H, s), 4,9 (1H, bs, OH), 5,87 (1H, d, J = 16,5 Hz), 6,72 (1H, d, J = 8,50 Hz), 7,30 (1H, dd, J = 8,50 Hz, J = 2,30 Hz), 7,41 (1H, d, J = 16,50 Hz), 7,45 (1H, d, J = 2,30 Hz), 7,47 (2H, d, J = 8,60 Hz), 7,58 (2H, d, J= 8,60 Hz). MS (EI) m/z: 355 (56, M+), 97 (100). <1>H NMR (CDCl3), Z, ?: 1,78 (6H, s), 2,13 (3H, s), 2,17 (6H, s), 4,9 (1H, bs, OH), 5,40 (1H, d, J = 11,3 Hz), 6,72 (1H, d, J = 8,50 Hz), 7,13 (1H, d, J = 11,3 Hz), 7,33 (1H, dd, J = 8,50 Hz, J = 2,30 Hz), 7,48 (1H, d, J = 2,30 Hz), 7,62 (2H, d, J = 8,50 Hz), 7,85 (2H, d, J =8,50 Hz) (E/Z)-3-(3'-(Adamantan-1-yl-4'-hydroxy-biphenyl-4-yl)-acrylonitrile (1). 2-(Adamantan-1-yl)-4-(4 -bromophenyl)phenol (300 mg, 0.782 mmol), 66.4 mg (1.25 mmol) acrylonitrile, 8.78 mg (0.0391 mmol) Pd(OAc)2, and 23.80 mg (0 0.00782 mmol) of tri-otolylphosphine in 0.600 mL of Et3N were mixed in a round flask and heated at 100 °C for 8 h Water and ice were added, 2N HCl was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 80:20) to give 124 mg of the product. (Isomers E/Z, 2:1).Yield 45%.<1>H NMR (CDCl3), E, ?: 1.78 (6H, s), 2.13 (3H, s), 2.17 (3H, s), 4 ,9 (1H, bs, OH), 5.87 (1H, d, J = 16.5 Hz), 6.72 (1H, d, J = 8.50 Hz), 7.30 (1H, d, J = 8.50Hz, J = 2.30Hz), 7.41 (1H, d, J = 16.50Hz), 7.45 (1H, d, J = 2.30Hz), 7.47 (2H, d, J = 8.60 Hz), 7.58 (2H, d, J= 8.60 Hz).MS (EI) m/z: 355 (5 6, M+), 97 (100). <1>H NMR (CDCl3), Z, ?: 1.78 (6H, s), 2.13 (3H, s), 2.17 (6H, s), 4.9 (1H, bs, OH) , 5.40 (1H, d, J = 11.3 Hz), 6.72 (1H, d, J = 8.50 Hz), 7.13 (1H, d, J = 11.3 Hz), 7 .33 (1H, dd, J = 8.50 Hz, J = 2.30 Hz), 7.48 (1H, d, J = 2.30 Hz), 7.62 (2H, d, J = 8, 50Hz), 7.85 (2H, d, J =8.50Hz)

Esempio 2: sintesi di 3-(adamantan-1-il)-4'-(3-idrossiprop-1-in-1-il)-[1,1'-bifenil]-4-olo (2) Example 2: Synthesis of 3-(adamantan-1-yl)-4'-(3-hydroxyprop-1-in-1-yl)-[1,1'-biphenyl]-4-ol (2)

2-(Adamantan-1-il)-4-(4-bromofenil)fenolo (2 g, 5,22 mmol), ? stato aggiunto a una miscela di CuI (0,017 g, 0,089 mmol), PdCl2(Ph3P)2 (0,037 g, 0,052 mmol, diisopropilammina (14,4 mol) e TEA (3,48 ml). La miscela risultante ? stata agitata per 30 min a temperatura ambiente, addizionata con alcol propargilico (0,33 g, 5,74 mmol), riscaldata a 60 ?C per 20 h. Evaporazione, ripresa con acqua e ghiaccio, aggiunta di HCl 2N, estrazione con etil acetato e filtrazione degli estratti ed evaporazione, hanno dato 2,47 g del composto grezzo. Il prodotto ? stato purificato mediante cromatografia flash (esano/etil acetato da 90:10 a 70:30) a dare 347 mg del composto del titolo del prodotto. 2-(Adamantan-1-yl)-4-(4-bromophenyl)phenol (2 g, 5.22 mmol), ? was added to a mixture of CuI (0.017 g, 0.089 mmol), PdCl2(Ph3P)2 (0.037 g, 0.052 mmol, diisopropylamine (14.4 mol) and TEA (3.48 mL). The resulting mixture was stirred for 30 min at room temperature, added with propargyl alcohol (0.33 g, 5.74 mmol), heated to 60 ?C for 20 h Evaporated, taken up with water and ice, added 2N HCl, extracted with ethyl acetate and filtered of the extracts and evaporation, gave 2.47 g of the crude compound The product was purified by flash chromatography (hexane/ethyl acetate 90:10 to 70:30) to give 347 mg of the title compound of the product.

(19%). P.F. 200 ?C. <1>H NMR (CDCl3), ?: 1,80 (6H, s), 2,13 (3H, s), 2,17 (6H, s), 4,50 (1H, s), 5,40 (1H, d, J = 11,3 Hz), 6,69 (1H, d, J = 7,8 Hz), 7,27 (1H, dd, J = 7,8 Hz, J = 2,6 Hz), 7,37-7,55 (5H, m). (19%). M.P. 200?C. <1>H NMR (CDCl3), ?: 1.80 (6H, s), 2.13 (3H, s), 2.17 (6H, s), 4.50 (1H, s), 5.40 (1H, d, J = 11.3Hz), 6.69 (1H, d, J = 7.8Hz), 7.27 (1H, dd, J = 7.8Hz, J = 2.6Hz ), 7.37-7.55 (5H, m).

Esempio 3: sintesi di acido E-2-metil-3-[3'-(adamantan-1-il)-4'-idrossibifenil-4-il]acrilico (3) Example 3: Synthesis of E-2-methyl-3-[3'-(adamantan-1-yl)-4'-hydroxybiphenyl-4-yl]acrylic acid (3)

A) 3'-(Adamantan-1-il)-4'-terz-butildimetilsililossibifenil-4-aldeide. 3-(Adamantan-1-il)-4-(terzbutildimetilsililossi)bromobenzene (1,56 g, 3,70 mmol)? stato disciolto in 7,5 mL di toluene. Dopodich?, 3,7 mL di una soluzione acquosa 2M di Na2CO3 , 0,128 g (0,11 mmol) of tetrakistrifenilfosfina-palladio, ed ? stata aggiunta una soluzione di 610 mg (4,07 mmol) di acido 4-formilbenzenboronico in 1,73 mL di etanolo. La miscela ? stata posta a riflusso per 2 h in una corrente di azoto. ? stata poi raffreddata, ripresa con etil acetato, e lavata con una soluzione satura di NaCl. Le fasi sono state separate, lo strato organico ? stato filtrato, essiccato su Na2SO4 e filtrato, il solvente ? stato fatto evaporare, e il residuo ? stato sottoposto a cromatografia flash (esano/etil acetato, 3:1)a dare 1,09 g del composto del titolo, pf 158 ?C. A) 3'-(Adamantan-1-yl)-4'-tert-butyldimethylsilyloxybiphenyl-4-aldehyde. 3-(Adamantan-1-yl)-4-(tert-butyldimethylsilyloxy)bromobenzene (1.56 g, 3.70 mmol)? was dissolved in 7.5 mL of toluene. After that, 3.7 mL of a 2M aqueous solution of Na2CO3 , 0.128 g (0.11 mmol) of tetrakistriphenylphosphine-palladium, and ? A solution of 610 mg (4.07 mmol) of 4-formylbenzeneboronic acid in 1.73 mL of ethanol was added. The mixture ? was refluxed for 2 h in a stream of nitrogen. ? was then cooled, taken up with ethyl acetate, and washed with a saturated solution of NaCl. The phases have been separated, the organic layer? been filtered, dried on Na2SO4 and filtered, the solvent ? been evaporated, and the residue ? was subjected to flash chromatography (hexane/ethyl acetate, 3:1) to give 1.09 g of the title compound, mp 158 ?C.

B) Acido E-2-metil-3-[3'-(adamantan-1-il)-4'-idrossibifenil-4-il]acrilico (3). Sotto una corrente di azoto 200 mg (0,448 mmol) di 3'-(adamantan-1-il)-4'-terz-butildimetilsililossibifenil-4-aldeide e 167 mg (0,448 mmol) di Ph3Pd C(CH3)-COOEt sono stati disciolti in 2,3 mL di CHCl3, e la soluzione risultante ? stata posta a riflusso per 21 h. Il solvente ? stato fatto evaporare, e l'estere grezzo ottenuto ? stato usato senza ulteriore purificazione. Questo composto (390 mg, 0,714 mmol) ? stato aggiunto a 90 mg (2,14 mmol) di LiOH. H2O disciolta in 30 mL di THF/H2O, 1:1. La soluzione ? stata agitata a temperatura ambiente per 2 giorni. Dopo evaporazione di THF, la fase acquosa ? stata acidificata con 3 mL di HCl 1M ed estratta con AcOEt. B) E-2-methyl-3-[3'-(adamantan-1-yl)-4'-hydroxybiphenyl-4-yl]acrylic acid (3). Under a nitrogen stream 200 mg (0.448 mmol) of 3'-(adamantan-1-yl)-4'-tert-butyldimethylsilyloxybiphenyl-4-aldehyde and 167 mg (0.448 mmol) of Ph3Pd C(CH3)-COOEt were dissolved in 2.3 mL of CHCl3, and the resulting solution? was refluxed for 21 h. The solvent? been evaporated, and the crude ester obtained ? was used without further purification. This compound (390 mg, 0.714 mmol) ? was added to 90 mg (2.14 mmol) of LiOH. H2O dissolved in 30 mL of THF/H2O, 1:1. The solution ? stirred at room temperature for 2 days. After evaporation of THF, the aqueous phase? was acidified with 3 mL of 1M HCl and extracted with AcOEt.

Essiccazione, filtrazione ed evaporazione del solvente hanno dato 312 mg di prodotto grezzo, che ? stato purificato mediante cromatografia flash (esano/etil acetato, 2:1 e poi 3:2) per ottenere 69 mg del composto del titolo come solido bianco, pf 200?C. <1>H NMR (600 MHz) (DMSO-d6) ? 1,73-1,76 (6H, s, 6Ad), 2,04-2,06 (3H, m, 3Ad), 2,08 (Me, d, J = 1,59 Hz), 2,12-2,94 (6H, m, Ad), 6,86 (1H, d, H-5?, J = 8,27 Hz), 7,36 (1H, dd, H-6?, J = 2,38 Hz, J = 8,27 Hz), 7,38 (1H, d, H-2?, J = 2,38 Hz), 7,51 (2H, d, H-3 and H-5, J =8,42 Hz), 7,60 (1H, br s, CH), 7,63 (2H, d, H-2 and H-6, d, J = 8,42 Hz) 9,50 (1H, s, OH), 12,4 (1H, s, COOH). MS (m/z): 388 (M+, 100), 267 (40), 178 (40), 79 (60). Drying, filtration and evaporation of the solvent gave 312 mg of crude product, which ? was purified by flash chromatography (hexane/ethyl acetate, 2:1 then 3:2) to give 69 mg of the title compound as a white solid, mp 200°C. <1>H NMR (600 MHz) (DMSO-d6) ? 1.73-1.76 (6H, s, 6Ad), 2.04-2.06 (3H, m, 3Ad), 2.08 (Me, d, J = 1.59Hz), 2.12- 2.94 (6H, m, Ad), 6.86 (1H, d, H-5?, J = 8.27 Hz), 7.36 (1H, dd, H-6?, J = 2.38 Hz, J = 8.27 Hz), 7.38 (1H, d, H-2?, J = 2.38 Hz), 7.51 (2H, d, H-3 and H-5, J =8 .42 Hz), 7.60 (1H, br s, CH), 7.63 (2H, d, H-2 and H-6, d, J = 8.42 Hz) 9.50 (1H, s, OH), 12.4 (1H, s, COOH). MS (m/z): 388 (M+, 100), 267 (40), 178 (40), 79 (60).

Esempio 4: sintesi di acido 3-(3'-adamantan-1-il)-4'-idrossi-[1,1'-bifenil]-4-il)-2-cianoacrilico (4) Example 4: Synthesis of 3-(3'-adamantan-1-yl)-4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-cyanoacrylic acid (4)

Una sospensione di 3'-(Adamantan-1-il)-4'-terzbutildimetilsilossibifenil-4-aldeide (Cincinelli et al J. Med. Chem. 2005, 48, 4931-4946) (150 mg, 0,34 mmol), metil cianoacetato (1 g, 10,1 mmol) e beta-alanina (119 mg, 1,34 mmol) in etanolo (26 ml) ? stata riscaldata a 50 ?C per 4 h. Il solvente ? stato fatto evaporare e il residuo giallo ? stato ripreso con CH2Cl2 (25 ml). La soluzione ? stata lavata tre volte con acqua (35 ml), essiccata e fatta evaporare. Il solido risultante ? stato lavato con etanolo per dissolvere il cianoacetato di partenza a dare 151 mg (85%) di Metil 3-(3'-adamantan-1-il)-4'-terzbutildimetilsililossi-[1,1'-bifenil]-4-il)-2-cianoacrilato P.f. 185 ?C. A suspension of 3'-(Adamantan-1-yl)-4'-tert-butyldimethylsiloxybiphenyl-4-aldehyde (Cincinelli et al J. Med. Chem. 2005, 48, 4931-4946) (150 mg, 0.34 mmol), methyl cyanoacetate (1 g, 10.1 mmol) and beta-alanine (119 mg, 1.34 mmol) in ethanol (26 mL) ? been heated at 50 ?C for 4 h. The solvent? been evaporated and the yellow residue ? was taken up with CH2Cl2 (25 ml). The solution ? washed three times with water (35 ml), dried and evaporated. The resulting solid was washed with ethanol to dissolve the starting cyanoacetate to give 151 mg (85%) of Methyl 3-(3'-adamantan-1-yl)-4'-tert-butyldimethylsilyloxy-[1,1'-biphenyl]-4-yl )-2-cyanoacrylate M.p. 185?C.

Il composto di cui sopra (100 mg, 0,19 mmol) ? stato aggiunto a una soluzione (THF: H2O 1:1, 7,7 ml) di LiOH.H2O (40 mg, 0,95 mmol). La miscela ? stata agitata per 72 h a temperatura ambiente. THF ? stato fatto evaporare. La fase acquosa rimanente ? stata estratta con esano, poi acidificata con HCl 1N fino a pH 2 e filtrata a dare 57 mg di un composto grezzo. Purificazione mediante cromatografia flash su fase inversa (MeOH: H2O 3:1) ha dato 26 mg del composto del titolo. P.f 228 ?C <1>H NMR (acetoned6), ?: 1,78 (6H, s), 2,13 (3H, s), 2,17 (6H, s), 6,95-7,05 (1H, m), 7,40-7,50 (1H, m), 7,65-7,55 (1H, m), 7,77-7,90 (2H, m), 8,07-8,22 (2H, m),8,32 (1H, s),10,06 (1H, s). The above compound (100 mg, 0.19 mmol) ? was added to a solution (THF: H2O 1:1, 7.7 mL) of LiOH.H2O (40 mg, 0.95 mmol). The mixture ? was stirred for 72 h at room temperature. THF ? been evaporated. The remaining aqueous phase ? was extracted with hexane, then acidified with 1N HCl to pH 2 and filtered to give 57 mg of a crude compound. Purification by reversed phase flash chromatography (MeOH: H2O 3:1) gave 26 mg of the title compound. M.p 228 ?C <1>H NMR (acetoned6), ?: 1.78 (6H, s), 2.13 (3H, s), 2.17 (6H, s), 6.95-7.05 ( 1H, m), 7.40-7.50 (1H, m), 7.65-7.55 (1H, m), 7.77-7.90 (2H, m), 8.07-8, 22 (2H, m), 8.32 (1H, s), 10.06 (1H, s).

Esempio 5: sintesi di acido E-2-Fluoro-3-[3'-(adamantan-1-il)-4'-idrossibifenil-4-il]-acrilico (5) Example 5: Synthesis of E-2-Fluoro-3-[3'-(adamantan-1-yl)-4'-hydroxybiphenyl-4-yl]-acrylic acid (5)

Acido E-2-fluoro-3-[3'-(adamantan-1-il)-4'-idrossibifenil-4-il]-acrilico (5). EtOOC-CH(F)-PO(OEt)2 (124 mg, 0,493 mmol) ? stato disciolto in 1 mL di THF anidro, raffreddato a -78 ?C, e trattato con una soluzione di BuLi 1,6 M in esano (0,364 mL). Dopo agitazione per 30 min a -78 ?C, una quantit? di 200 mg (0,448 mmol) di 3'-(adamantan-1-il)-4'-terzbutildimetilsilossibifenil-4-aldeide (si veda l'esempio 3) disciolta in 0,5 mL di THF ? stata fatta gocciolare, e la soluzione ? stata lentamente portata a temperatura ambiente (3 h). Dopo acidificazione con 6 mL di HCl 2N, la fase acquosa ? stata estratta con AcOEt. Gli strati organici sono stati lavati con salamoia, essiccati, filtrati, e fatti evaporare a dare 280 mg di un prodotto grezzo. La purificazione mediante cromatografia flash (esano/etil acetato, 95:5) ha dato 180 mg (75%) dell'etil estere del derivato di terzbutildimetilsilile del composto del titolo come olio. Questo composto (97 mg, 0,181 mmol) ? stato sospeso in una soluzione di 38 mg (0,905 mmol) di LiOH. H2O in 7,4 mL di THF/H2O, 1:1, e agitato per tutta la notte a temperatura ambiente al buio. THF ? stato fatto evaporare e la fase acquosa rimanente ? stata lavata con esano, poi acidificata con 0,5 mL di HCl 2N. Il precipitato giallo chiaro ? stato filtrato ed essiccato a dare 55 mg del composto del titolo. Resa 77%, pf 202 ?C. <1>H NMR (acetone-d6): ? 1,8 (8H, s, 8 Ad), 2,2 (6H, s, 6 Ad), 6,90 (1H, d, J = 8,5 Hz), 7,00 (1H, d, JH,F = 23,9 Hz), 7,36 (1H, dd, J = 8,5 and 2,6 Hz), 7,50 (1H, d, J = 2,6 Hz), 7,60 (2H, d, J = 8,8 Hz), 7,71 (2H, d, J ) 8,8 Hz). MS (EI) m/z: 392 (M+, 100). E-2-fluoro-3-[3'-(adamantan-1-yl)-4'-hydroxybiphenyl-4-yl]-acrylic acid (5). EtOOC-CH(F)-PO(OEt)2 (124 mg, 0.493 mmol) ? was dissolved in 1 mL of dry THF, cooled to -78 ?C, and treated with a solution of 1.6 M BuLi in hexane (0.364 mL). After stirring for 30 min at -78 ?C, a quantity? of 200 mg (0.448 mmol) of 3'-(adamantan-1-yl)-4'-tert-butyldimethylsiloxybiphenyl-4-aldehyde (see example 3) dissolved in 0.5 mL of THF ? been dripped, and the solution ? was slowly brought to room temperature (3 h). After acidification with 6 mL of 2N HCl, the aqueous phase is was extracted with AcOEt. The organic layers were washed with brine, dried, filtered, and evaporated to give 280 mg of crude product. Purification by flash chromatography (hexane/ethyl acetate, 95:5) gave 180 mg (75%) of the tert-butyldimethylsilyl derivative ethyl ester of the title compound as an oil. This compound (97 mg, 0.181 mmol) ? was suspended in a solution of 38 mg (0.905 mmol) of LiOH. H2O in 7.4 mL of THF/H2O, 1:1, and stirred overnight at room temperature in the dark. THF ? been evaporated and the remaining aqueous phase? was washed with hexane, then acidified with 0.5 mL of 2N HCl. The light yellow precipitate ? was filtered and dried to give 55 mg of the title compound. Yield 77%, mp 202 ?C. <1>H NMR (acetone-d6): ? 1.8 (8H, s, 8 Ad), 2.2 (6H, s, 6 Ad), 6.90 (1H, d, J = 8.5 Hz), 7.00 (1H, d, JH, F = 23.9 Hz), 7.36 (1H, dd, J = 8.5 and 2.6 Hz), 7.50 (1H, d, J = 2.6 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.71 (2H, d, J ) 8.8 Hz). MS (EI) m/z: 392 (M+, 100).

Esempio 6: sintesi di acido E-3-(3'-terz-butil-4'-idrossibifenil-4-il) acrilico (6) Example 6: Synthesis of E-3-(3'-tert-butyl-4'-hydroxybiphenyl-4-yl)acrylic acid (6)

Acido E-3-(3'-terz-butil-4'-idrossibifenil-4-il) acrilico (6). A una soluzione di CH3COOH/conc. H2SO4, 9:1 (2 mL), ? stata aggiunta una quantit? di 500 mg (2,01 mmol) di 4-(4'-bromofenil)-fenolo. Poi una quantit? di 0,192 mL (2,01 mmol)di alcol terz-butilico ? stata aggiunta goccia a goccia. La miscela ? stata agitata a temperatura ambiente per 2 settimane. CH3COOH ? stato fatto evaporare, e sono stati aggiunti acqua e ghiaccio. Il solido bianco ? stato filtrato e lavato con acqua. Il prodotto grezzo ? stato purificato mediante cromatografia flash (esano/etil acetato, 85: 15) a dare 163 mg di 2-terz-butil-4-(4'-bromofenil)fenolo. Resa 27%, pf 114-116 ?C. Il composto di cui sopra (160 mg, 0,524 mmol), 72 mg (0,838 mmol) di metil acrilato, 5 mg (0,0223 mmol) di Pd(OAc)2, e 27 mg (0,0887 mmol) di tri-o-tolilfosfina in 0,243 mL di Et3N sono stati miscelati in un pallone rotondo e riscaldati a 100 ?C per 4 h. Sono stati aggiunti acqua e ghiaccio, ? stato aggiunto HCl 2N, e la fase acquosa ? stata estratta con etil acetato. La fase organica ? stata essiccata su Na2SO4, filtrata e fatta evaporare. Il prodotto grezzo ? stato purificato mediante cromatografia flash (diclorometano/esano, 95:5), a dare 121 mg di metil E-3-(3'-terz-butil-4'-idrossifenil-4-il) acrilato. Resa 74%, pf 182 ?C. Il composto di cui sopra (70 mg, 0,226 mmol) ? stato disciolto in una soluzione di 47,4 mg (1,13 mmol) di LiOH. H2O in 9,30 mL di THF/H2O, 1:1, e la soluzione ? stata agitata per tutta la notte a temperatura ambiente al buio. THF ? stato fatto evaporare. La fase acquosa ? stata lavata con esano ed Et2O e poi acidificata con HCl 2N (0,6 mL). Il solido bianco ? stato filtrato ed essiccato a dare 54 mg di prodotto puro. Resa 81%, pf 218 ?C. <1>H NMR (DMSO-d6) ? 1,34 (9H, s, 3CH3), 6,47 (1H, d, CH, J = 16,38 Hz), 6,83 (1H, d, 1Ar, J = 8,19 Hz), 7,34 (1H, dd, 1Ar, J = 8,19 Hz, J = 2,23 Hz), 7,40 (1H, d, 1Ar, J = 2,23 Hz), 7,55 (1H, d, CH, J = 16,38 Hz), 7,58 (2H, d, 2Ar, J = 8,25 Hz), 7,68 (2H, d, 2Ar, J = 8,25 Hz), 9,63 (1H, s, OH). MS (EI) m/z: 296 (97, M+), 281 (100), 253 (64). E-3-(3'-tert-butyl-4'-hydroxybiphenyl-4-yl)acrylic acid (6). To a solution of CH3COOH/conc. H2SO4, 9:1 (2 mL), ? was added a quantity? of 500 mg (2.01 mmol) of 4-(4'-bromophenyl)-phenol. Then a quantity? of 0.192 mL (2.01 mmol) tert-butyl alcohol ? been added drop by drop. The mixture ? stirred at room temperature for 2 weeks. CH3COOH ? evaporated, and water and ice were added. The white solid? was filtered and washed with water. The raw product? was purified by flash chromatography (hexane/ethyl acetate, 85: 15) to give 163 mg of 2-tert-butyl-4-(4'-bromophenyl)phenol. Yield 27%, mp 114-116 ?C. The above compound (160 mg, 0.524 mmol), 72 mg (0.838 mmol) of methyl acrylate, 5 mg (0.0223 mmol) of Pd(OAc)2, and 27 mg (0.0887 mmol) of tri- o-tolylphosphine in 0.243 mL of Et3N were mixed in a round flask and heated at 100 ?C for 4 h. Have water and ice been added, ? been added 2N HCl, and the aqueous phase ? was extracted with ethyl acetate. The organic phase? was dried over Na2SO4, filtered and evaporated. The raw product? was purified by flash chromatography (dichloromethane/hexane, 95:5), to give 121 mg of methyl E-3-(3'-tert-butyl-4'-hydroxyphenyl-4-yl) acrylate. Yield 74%, mp 182 ?C. The above compound (70 mg, 0.226 mmol) ? was dissolved in a solution of 47.4 mg (1.13 mmol) of LiOH. H2O in 9.30 mL of THF/H2O, 1:1, and the solution ? stirred overnight at room temperature in the dark. THF ? been evaporated. The aqueous phase? was washed with hexane and Et2O and then acidified with 2N HCl (0.6 mL). The white solid? was filtered and dried to give 54 mg of pure product. Yield 81%, mp 218 ?C. <1>H NMR (DMSO-d6) ? 1.34 (9H, s, 3CH3), 6.47 (1H, d, CH, J = 16.38 Hz), 6.83 (1H, d, 1Ar, J = 8.19 Hz), 7.34 (1H, dd, 1Ar, J = 8.19 Hz, J = 2.23 Hz), 7.40 (1H, d, 1Ar, J = 2.23 Hz), 7.55 (1H, d, CH, J = 16.38Hz), 7.58 (2H, d, 2Ar, J = 8.25Hz), 7.68 (2H, d, 2Ar, J = 8.25Hz), 9.63 (1H, s, oh). MS (EI) m/z: 296 (97, M+), 281 (100), 253 (64).

Esempio 7: sintesi di acido 4-(3-(1-adamantil)-4-metossifenil)propiolico (7) Example 7: Synthesis of 4-(3-(1-adamantyl)-4-methoxyphenyl)propiolic acid (7)

A)Metil 4-(3-(1-adamantil)-4-metossifenil)propiolato. 301 mg (1,26 mmol) di metil 4-bromofenilpropiolato sono stati disciolti in 2,5 ml di toluene, sono stati aggiunti 1,34 ml di una soluzione acquosa di 2M Na2C03, poi 43,7 mg di Pdtetrakistrifenilfosfina, e infine 398 mg (1,39 mmol) di acido 3-(l-adamantil)-4-metossifenilboronico, e la miscela ? stata posta a riflusso per 3 ore. Il prodotto grezzo ? stato ripreso in etil etere, la fase organica ? stata lavata con 15 una soluzione satura di NaCl, essiccata su Na2SO4, fatta evaporare fino a essiccamento a dare 570 mg di prodotto grezzo. La cromatografia flash su gel di silice (Merck) con esano:etil acetato 2:1 come eluente ha dato 15 mg di prodotto puro. P.f. 175?C. <1>H-NMR (CDCl3) ?: 3,86 (s, 3H, OCH3), 3,90 (s, 3H, OCH3), 6,96 (d, 1H, J = 8,5), 7,43 (dd, 1H, J = 2,2, 8,5), 7,47 (d, 1H, J = 2,2), 7,55,7,70 (4H arom.). A) Methyl 4-(3-(1-adamantyl)-4-methoxyphenyl)propiolate. 301 mg (1.26 mmol) of methyl 4-bromophenylpropiolate was dissolved in 2.5 ml of toluene, 1.34 ml of an aqueous solution of 2M Na2CO3 was added, then 43.7 mg of Pdtetrakistriphenylphosphine, and finally 398 mg (1.39 mmol) of 3-(1-adamantyl)-4-methoxyphenylboronic acid, and the mixture is ? refluxed for 3 hours. The raw product? been taken up in ethyl ether, the organic phase ? a saturated NaCl solution was washed with 15, dried over Na2SO4, evaporated to dryness to give 570 mg of crude product. Flash chromatography on silica gel (Merck) with 2:1 hexane:ethyl acetate as eluent gave 15 mg of pure product. P.f. 175?C. <1>H-NMR (CDCl3) ?: 3.86 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.96 (d, 1H, J = 8.5), 7, 43 (dd, 1H, J = 2.2, 8.5), 7.47 (d, 1H, J = 2.2), 7.55,7,70 (4H arom.).

B) Acido 4-(3-(1-adamantil)-4-metossifenil)propiolico (7) 15 mg (0,0374 mmol) di metil E-4-(3-(1-adamantil)-4-metossifenil)propiolato sono stati disciolti in 2,14 ml di NaOH 0,7 N in metanolo, e la miscela ? stata posta a riflusso per 1 ora. Il metanolo ? stato fatto evaporare, il residuo ripreso in acqua, acidificato con HCl 6 N, ed estratto con etil etere. Dopo essiccamento su Na2S04 ed evaporazione del solvente, il residuo ? stato lavato con esano, da cui dopo filtrazione sono stati ottenuti 10 mg di prodotto P.f. 156?C. Rf= 0,41 (gel di silice Merck 6OF254, EtOAc/MeOH 2/1) <1>H-NMR (DMSO-d6) ?: 1,70 (s, 6?), 2,10 (s, 9?), 3,85 (s, 3?, OCH3), 7,05 (d, 1?, J =8,4, ?-6'), 7,40 (d, 1?, J = 2, ?-2'), 7,45-7,60 (3? arom.), 7,65 (2? arom.) B) 4-(3-(1-adamantyl)-4-methoxyphenyl)propiolic acid (7) 15 mg (0.0374 mmol) methyl E-4-(3-(1-adamantyl)-4-methoxyphenyl)propiolate have been dissolved in 2.14 ml of NaOH 0.7 N in methanol, and the mixture ? refluxed for 1 hour. The methanol ? evaporated, the residue taken up in water, acidified with 6N HCl, and extracted with ethyl ether. After drying on Na2SO4 and evaporation of the solvent, the residue? was washed with hexane, from which, after filtration, 10 mg of product were obtained M.p. 156?C. Rf= 0.41 (Merck silica gel 6OF254, EtOAc/MeOH 2/1) <1>H-NMR (DMSO-d6) ?: 1.70 (s, 6?), 2.10 (s, 9? ), 3.85 (s, 3?, OCH3), 7.05 (d, 1?, J =8.4, ?-6'), 7.40 (d, 1?, J = 2, ?- 2'), 7.45-7.60 (3? arom.), 7.65 (2? arom.)

Esempio 8: sintesi di 3-(3'-Adamantan-1-il-4-idrossibifenil-4-il)-N-idrossiacrilammide (8) Example 8: Synthesis of 3-(3'-Adamantan-1-yl-4-hydroxybiphenyl-4-yl)-N-hydroxyacrylamide (8)

A una sospensione di acido 3-(3'-adamantan-1-il-4'-idrossibifenil-4-il)-acrilico (0,53 mmol) in DMF secca sono stati aggiunti (8,3 mL), HOBt (86 mg, 0,64 mmol) e WSC(132 mg, 0,69 mmol). La miscela ? stata agitata a temperatura ambiente sotto azoto per 3 h, poi sono stati aggiunti NH2OH.HCl (185 mg, 2,66 mmol) e TEA (368 mL, 2,66 mmol). La reazione ? stata agitata a temperatura ambiente per 4 h. Dopo l'aggiunta di acqua, si ? formato un precipitato che ? stato filtrato ed essiccato per ottenere l'acido idrossamico desiderato. Il precipitato grezzo ? stato purificato mediante cromatografia flash con CH3OH/H2O 75:25 v/v su gel di silice RP-18. Resa: 54%. P.f. 184?C. <1>H NMR (DMSO-d6) ?: 10,70 (1H, brs); 9,50 (1H, s); 9,01 (1H,brs); 7,65e7,50 (4H, m); 7,45 (1H, d, J = 16,2 Hz); 7,35e7,25 (2H, m); 6,82 (1H, d, J = 8,8 Hz); 6,45 (1H, d, J = 16,2 Hz); 2,12 (6H, s); 2,04 (3H, s); 1,72 (6H, s). <13>C NMR (DMSO-d6) ?: 162,9, 156,4, 141,9, 138,1, 136,0, 132,7, 129,9, 128,1, 126,4, 124,9, 124,7, 118,3, 117,0, 38,7, 36,7, 36,3, 28,4. To a suspension of 3-(3'-adamantan-1-yl-4'-hydroxybiphenyl-4-yl)-acrylic acid (0.53 mmol) in dry DMF was added (8.3 mL), HOBt (86 mg, 0.64 mmol) and WSC (132 mg, 0.69 mmol). The mixture ? was stirred at room temperature under nitrogen for 3 h, then NH2OH.HCl (185 mg, 2.66 mmol) and TEA (368 mL, 2.66 mmol) were added. The reaction ? was stirred at room temperature for 4 h. After adding water, yes ? formed a precipitate that ? filtered and dried to obtain the desired hydroxamic acid. The crude precipitate ? was purified by flash chromatography with CH3OH/H2O 75:25 v/v on RP-18 silica gel. Yield: 54%. P.f. 184?C. <1>H NMR (DMSO-d6) ?: 10.70 (1H, brs); 9.50 (1H, s); 9.01 (1H,brs); 7.65e7.50 (4H, m); 7.45 (1H, d, J = 16.2Hz); 7.35e7.25 (2H, m); 6.82 (1H, d, J = 8.8Hz); 6.45 (1H, d, J = 16.2Hz); 2.12 (6H, s); 2.04 (3H, s); 1.72 (6H, s). <13>C NMR (DMSO-d6) ?: 162.9, 156.4, 141.9, 138.1, 136.0, 132.7, 129.9, 128.1, 126.4, 124, 9, 124.7, 118.3, 117.0, 38.7, 36.7, 36.3, 28.4.

Esempio 9: sintesi di acido (E)-3-(3'-adamantan-1-il)-4'-(2-(idrossiammino)-2-ossoetossi)-[1,1'-bifenil]-4-il) acrilico (9) A) Terz-butil estere di acido 3-(3'-Adamantan-1-il-4'-etossicarbonilmetossi-bifenil-4-il)-acrilico. Una miscela di terz-butil estere di acido 3-(3'-adamantan-1-il-4'-idrossibifenil-4-il)-acrilico (2,00 g, 4,64 mmol), etil bromoacetato (1,58 g, 9,28 mmol), K2CO3 (2,57 g, 18,6 mmol) in 40 ml di DMF ? stata riscaldata a 80 ?C per 1 h. K2CO3 ? stato filtrato, DMF fatta evaporare e il residuo ? stato ripreso con acqua. Il solido precipitato ? stato filtrato e cristallizzato da dietil etere a dare 2,09 g (97%) di prodotto come solido bianco, p.f. Example 9: Synthesis of (E)-3-(3'-adamantan-1-yl)-4'-(2-(hydroxyamino)-2-oxoethoxy)-[1,1'-biphenyl]-4-yl acid )acrylic (9)A) Tert-butyl 3-(3'-Adamantan-1-yl-4'-ethoxycarbonylmethoxy-biphenyl-4-yl)-acrylic acid ester. A mixture of 3-(3'-adamantan-1-yl-4'-hydroxybiphenyl-4-yl)-acrylic acid tert-butyl ester (2.00 g, 4.64 mmol), ethyl bromoacetate (1.58 g, 9.28 mmol), K2CO3 (2.57 g, 18.6 mmol) in 40 ml DMF ? been heated to 80 ?C for 1 h. K2CO3 ? been filtered, DMF evaporated and the residue? was taken up with water. The solid precipitate? was filtered and crystallized from diethyl ether to give 2.09 g (97%) of product as a white solid, m.p.

175?C, Rf (etere di petrolio/etil acetato 90:10) 0,31. <1>H-NMR (300 MHz, CDCl3) ?: 7,61 (1H, d, J= 15,9 Hz), 7,58-7,53 (4H, m), 7,50 (1H, d, J= 2,35 Hz), 7,39 (1H, dd, J= 8,39 Hz, J= 2,35 Hz), 6,79 (1H, d, J= 8,39 Hz), 6,38 (1H, d, J= 15,9 Hz), 4,67 (2H, s), 4,31 (2H, q, J= 7,16 Hz), 2,23-2,07 (9H, m), 1,88-1,74 (6H, m), 1,54 ( 9H, s), 1,32 (3H, t, J= 7,16 Hz). <13>C-NMR (75 MHz, CDCl3)?: 168,7, 166,4, 156,7, 143,2, 142,9, 139,2, 133,2, 132,9, 128,4 (? 2C), 127,1 (? 2C), 126,0, 125,2, 119,6, 112,2, 80,4, 65,4, 61,3, 40,5 (? 3C), 37,2, 37,0 (? 3C), 29,1 (? 3C), 28,2 (? 3C), 14,2. 175?C, Rf (petroleum ether/ethyl acetate 90:10) 0.31. <1>H-NMR (300 MHz, CDCl3) ?: 7.61 (1H, d, J= 15.9 Hz), 7.58-7.53 (4H, m), 7.50 (1H, d , J= 2.35Hz), 7.39 (1H, dd, J= 8.39Hz, J= 2.35Hz), 6.79 (1H, d, J= 8.39Hz), 6, 38 (1H, d, J= 15.9 Hz), 4.67 (2H, s), 4.31 (2H, q, J= 7.16 Hz), 2.23-2.07 (9H, m ), 1.88-1.74 (6H, m), 1.54 ( 9H, s), 1.32 (3H, t, J= 7.16 Hz). <13>C-NMR (75 MHz, CDCl3)?: 168.7, 166.4, 156.7, 143.2, 142.9, 139.2, 133.2, 132.9, 128.4 ( ?2C), 127.1 (?2C), 126.0, 125.2, 119.6, 112.2, 80.4, 65.4, 61.3, 40.5 (?3C), 37, 2, 37.0 (? 3C), 29.1 (? 3C), 28.2 (? 3C), 14.2.

B) Terz-butil estere di acido 3-(3'-Adamantan-1-il-4'-carbossimetossi-bifenil-4-il)-acrilico. Una soluzione di terzbutil estere di acido 3-(3'-Adamantan-1-il-4'-etossicarbonilmetossi-bifenil-4-il)-acrilico (2,08 g, 4,02 mmol) in 125 ml di THF al 50% acq. ? stata addizionata con 843 mg (20,1 mmol) di LiOH.H2O e lasciata per tutta la notte a temperatura ambiente. Evaporazione, ripresa con EtOAc, lavaggio con 60 ml di KHSO4 1N, estrazione con EtOAc, essiccamento degli estratti con Na2SO4, filtrazione ed evaporazione hanno dato 1,92 g (98%) del prodotto, solido bianco, p.f. > 300?C, Rf (CH2Cl2/MeOH 19: 1) 0,23. 1H-NMR (300MHz, DMSO-d6)?: 7,75-7,60 (4H, m), 7,56 (1H, d, J= 15,8 Hz), 7,48 (1H, dd, J= 8,51 Hz, J= 2,36 Hz), 7,43 (1H, d, J= 2,36 Hz), 6,93 (1H, d, J= 8,51 Hz), 6,51 (1H, d, J= 15,8 Hz), 4,70 (2H, s), 2,19-1,98 (9H, m), 1,83-1,66 (6H, m), 1,48 (9H, s). <13>C-NMR (75MHz, DMSO-d6)?: 170,4, 166,1, 157,2,143,7, 142,5, 138,6, 132,9, 132,1, 129,3 (? 2C), 127,0 (? 2C), 125,5, 125,2, 119,7, 113,5, 80,3, 65,3, mancano alcuni segnali a causa della sovrapposizione con il solvente, 37,1, 37,9, 28,9 (? 3C), 28,3 (? 3C). B) Tert-butyl ester of 3-(3'-Adamantan-1-yl-4'-carboxymethoxy-biphenyl-4-yl)-acrylic acid. A solution of 3-(3'-Adamantan-1-yl-4'-ethoxycarbonylmethoxy-biphenyl-4-yl)-acrylic acid tertbutyl ester (2.08 g, 4.02 mmol) in 125 ml THF 50 % aq. ? was added with 843 mg (20.1 mmol) of LiOH.H2O and left overnight at room temperature. Evaporation, resumption with EtOAc, washing with 60 ml of 1N KHSO4, extraction with EtOAc, drying of the extracts with Na2SO4, filtration and evaporation gave 1.92 g (98%) of the product, white solid, m.p. > 300°C, Rf (CH2Cl2/MeOH 19: 1) 0.23. 1H-NMR (300MHz, DMSO-d6)?: 7.75-7.60 (4H, m), 7.56 (1H, d, J= 15.8 Hz), 7.48 (1H, dd, J = 8.51Hz, J= 2.36Hz), 7.43 (1H, d, J= 2.36Hz), 6.93 (1H, d, J= 8.51Hz), 6.51 ( 1H, d, J= 15.8Hz), 4.70 (2H, s), 2.19-1.98 (9H, m), 1.83-1.66 (6H, m), 1.48 (9H, s). <13>C-NMR (75MHz, DMSO-d6)?: 170.4, 166.1, 157.2,143.7, 142.5, 138.6, 132.9, 132.1, 129.3 (? 2C), 127.0 (? 2C), 125.5, 125.2, 119.7, 113.5, 80.3, 65.3, some signals are missing due to solvent overlap, 37.1, 37.9, 28.9 (? 3C), 28.3 (? 3C).

C) Terz-butil estere di acido 3-{3'-Adamantan-1-il-4'-[(tetraidropiran-2-ilossicarbamoil)-metossi]-bifenil-4-il}-acrilico. In una sospensione raffreddata con ghiaccio di terzbutil estere di acido 3-(3'-Adamantan-1-il-4'-carbossimetossibifenil-4-il)-acrilico (1,25 g, 2,56 mmol) in 26 ml di DMF secca, sotto azoto, sono stati aggiunti HBTU (0,971 g, 2,56 mmol) e DIPEPEA (0,993 g, 7,68 mmol). Dopo due minuti sono stati aggiunti 0,312 g (2,56 mmol) di O-(tetraidro-piran-2-il)-idrossilammina e la miscela ? stata lasciata per tutta la notte a temperatura ambiente. DMF ? stato fatto evaporare, il residuo ? stato ripreso con acqua e il solido bianco filtrato. La purificazione mediante cromatografia flash su gel di silice con etere di petrolio/EtOAc 7:3 ha dato 1,23 g del prodotto, solido bianco, p.f. 193 ?C, Rf (AcOEt/etere di petrolio 3:7) 0,31. <1>H-NMR (300 MHz, CDCl3)?: 9,13 (1H, s), 7,61 (1H, d, J= 16,0 Hz), 7,58-7,54 (4H, m), 7,51 (1H, d, J= 2,24 Hz), 7,43 (1H, dd, J= 8,53 Hz, J= 2,24 Hz), 6,91 (1H, d, J= 8,53 Hz), 6,39 (1H, d, J= 16,0 Hz), 5,07-5,02 (1H, m), 4,68 (2H, s), 4,00-3,90 (1H, m), 3,67-3,57 (1H, m), 2,18-2,11 (9H, m), 1,92-1,78 (8H, m), 1,70-1,58 (4H, m), 1,54 (9H, s). <13>C-NMR (75 MHz, CDCl3)?: 166,4, 165,1, 156,1, 143,1, 142,5, 138,8, 134,2, 133,2, 128,4 (? 2C), 127,1 (? 2C), 126,2, 125,6, 119,8, 113,4, 102,8, 80,5, 67,6, 62,5, 41,1 (? 3C), 37,1, 37,0 (? 3C), 28,9 (? 3C), 28,2 (? 3C), 27,9, 24,9, 18,5. C) Tert-butyl ester of 3-{3'-Adamantan-1-yl-4'-[(tetrahydropyran-2-yloxycarbamoyl)-methoxy]-biphenyl-4-yl}-acrylic acid. In an ice-cooled suspension of 3-(3'-Adamantan-1-yl-4'-carboxymethibiphenyl-4-yl)-acrylic acid tertbutyl ester (1.25 g, 2.56 mmol) in 26 ml DMF dried, under nitrogen, HBTU (0.971 g, 2.56 mmol) and DIPEPEA (0.993 g, 7.68 mmol) were added. After two minutes 0.312 g (2.56 mmol) of O-(tetrahydro-pyran-2-yl)-hydroxylamine were added and the mixture ? been left overnight at room temperature. DMF ? been evaporated, the residue ? was taken up with water and the white solid filtered. Purification by silica gel flash chromatography with petroleum ether/EtOAc 7:3 gave 1.23 g of the product, white solid, m.p. 193 ?C, Rf (AcOEt/petroleum 3:7) 0.31. <1>H-NMR (300 MHz, CDCl3)?: 9.13 (1H, s), 7.61 (1H, d, J= 16.0 Hz), 7.58-7.54 (4H, m ), 7.51 (1H, d, J= 2.24 Hz), 7.43 (1H, dd, J= 8.53 Hz, J= 2.24 Hz), 6.91 (1H, d, J = 8.53Hz), 6.39 (1H, d, J= 16.0Hz), 5.07-5.02 (1H, m), 4.68 (2H, s), 4.00-3 .90 (1H, m), 3.67-3.57 (1H, m), 2.18-2.11 (9H, m), 1.92-1.78 (8H, m), 1.70 -1.58 (4H, m), 1.54 (9H, s). <13>C-NMR (75 MHz, CDCl3)?: 166.4, 165.1, 156.1, 143.1, 142.5, 138.8, 134.2, 133.2, 128.4 ( ?2C), 127.1 (?2C), 126.2, 125.6, 119.8, 113.4, 102.8, 80.5, 67.6, 62.5, 41.1 (?3C ), 37.1, 37.0 (? 3C), 28.9 (? 3C), 28.2 (? 3C), 27.9, 24.9, 18.5.

D) Acido (E)-3-(3'-adamantan-1-il)-4'-(2-(idrossiammino)-2-ossoetossi)-[1,1'-bifenil]-4-il)acrilico. Terz-butil estere di acido 3-{3'-Adamantan-1-il-4'-[(tetraidropiran-2-ilossicarbamoil)-metossi]-bifenil-4-il}-acrilico (250 mg, 0,425 mmol) ? stato aggiunto in porzioni a 3,5 ml di TFA a 0?C sotto azoto e la miscela ? stata agitata a 0 ?C per 1 h. La sospensione rosa ? stata filtrata, il solido ? stato lavato con acqua fino a pH neutro a dare 175 mg (92%) di composto desiderato come solido bianco, p.f. 265 ?C, Rf (CH2Cl2/MeOH 18:2) 0,49. <1>H-NMR (300 MHz, CDCl3 +TFA)?: 7,91 (1H, d, J = 16,0 Hz), 7,67-7,59 (4H, m), 7,55 (1H, d, J = 2,22 Hz), 7,47 (1H, dd, J= 8,30 Hz, J= 2,22 Hz), 6,90 (1H, d, J= 8,30 Hz), 6,49 (1H, d, J= 16,0 Hz), 4,78 (2H, s), 2,20-2,10 (9H, m), 1,91-1,72 (6H, m). D) (E)-3-(3'-adamantan-1-yl)-4'-(2-(hydroxyamino)-2-oxoethoxy)-[1,1'-biphenyl]-4-yl)acrylic acid. 3-{3'-Adamantan-1-yl-4'-[(tetrahydropyran-2-yloxycarbamoyl)-methoxy]-biphenyl-4-yl}-acrylic acid tert-Butyl ester (250 mg, 0.425 mmol) ? been added in portions to 3.5 ml of TFA at 0?C under nitrogen and the mixture ? was stirred at 0 ?C for 1 h. The pink suspension? been filtered, the solid ? was washed with water to neutral pH to give 175 mg (92%) of the desired compound as a white solid, m.p. 265 ?C, Rf (CH2Cl2/MeOH 18:2) 0.49. <1>H-NMR (300 MHz, CDCl3 +TFA)?: 7.91 (1H, d, J = 16.0 Hz), 7.67-7.59 (4H, m), 7.55 (1H , d, J = 2.22Hz), 7.47 (1H, dd, J= 8.30Hz, J= 2.22Hz), 6.90 (1H, d, J= 8.30Hz), 6.49 (1H, d, J= 16.0 Hz), 4.78 (2H, s), 2.20-2.10 (9H, m), 1.91-1.72 (6H, m) .

<13>C-NMR (75 MHz, DMSO-d6)<?>: 168,1, 164,8, 157,7, 144,0, 142,5, 138,8, 133,0, 132,3, 129,2 (? 2 C), 127,1 (? 2C), 125,6, 125,2, 119,1, 114,0, 66,4, (5C mancante a causa della sovrapposizione con il solvente segnale), 37,1, 36,9, 28,9 (? 3C). <13>C-NMR (75MHz, DMSO-d6)<?>: 168.1, 164.8, 157.7, 144.0, 142.5, 138.8, 133.0, 132.3, 129.2 (?2C), 127.1 (?2C), 125.6, 125.2, 119.1, 114.0, 66.4, (5C missing due to overlap with signal solvent), 37.1, 36.9, 28.9 (? 3C).

Esempio 10: sintesi di acido (E)-3-(3'-adamantan-1-il)-4'-((1-(idrossiammino)-1-ossopropan-2-il)ossi)-[1,1'-bifenil]-4-il)acrilico (10) Example 10: Synthesis of (E)-3-(3'-adamantan-1-yl)-4'-((1-(hydroxyamino)-1-oxopropan-2-yl)oxy)-[1,1' acid -biphenyl]-4-yl)acrylic (10)

A) terz-butil estere di acido (E)-3-(3'-adamantan-1-il)-4'-((1-etossi-1-ossopropan-2-il)ossi)-[1,1'-bifenil]-4-il)acrilico A) tert-butyl acid (E)-3-(3'-adamantan-1-yl)-4'-((1-ethoxy-1-oxopropan-2-yl)oxy)-[1,1' -biphenyl]-4-yl)acrylic

A una soluzione di terz-butil estere di acido 3-(3'-adamantan-1-il-4'-idrossi-bifenil-4-il)-acrilico sono stati aggiunti sotto azoto (500 mg, 1,16 mmol) in acetone secco (7 mL), K2CO3 (641 mg, 4,64 mmol), KI (13 mg, 0,08 mmol) ed etil estere di acido 2-bromopropionico (180 ?L, 1,39 mmol). La miscela ? stata riscaldata 5 h a riflusso. K2CO3 ? stato filtrato, e il solvente rimosso sottovuoto. Il grezzo ? stato triturato con esano: dietil etere 5:1, il precipitato ? stato filtrato a dare 340 mg del composto del titolo. Resa: 55%; p.f. 88?C, Rf (etere di petrolio/etil acetato 92,5:7,5) 0,30. To a solution of 3-(3'-adamantan-1-yl-4'-hydroxy-biphenyl-4-yl)-acrylic acid tert-butyl ester was added under nitrogen (500 mg, 1.16 mmol) in dry acetone (7 mL), K2CO3 (641 mg, 4.64 mmol), KI (13 mg, 0.08 mmol), and 2-bromopropionic acid ethyl ester (180 µL, 1.39 mmol). The mixture ? heated to reflux for 5 h. K2CO3 ? was filtered, and the solvent removed in vacuo. The crude ? been triturated with hexane: diethyl ether 5:1, the precipitate ? was filtered to give 340 mg of the title compound. Yield: 55%; m.p. 88?C, Rf (petroleum ether/ethyl acetate 92.5:7.5) 0.30.

<1>H-NMR (300 MHz, CDCl3)? : 7,61 (1H, d, J = 15,7 Hz), 7,57-7,52 (4H, m), 7,49 (1H, d, J = 2,3 Hz), 7,35 (1H, dd, J = 2,3, 8,4 Hz), 6,71 (1H, d, J = 8,4 Hz), 6,38 (1H, d, J = 15,7 Hz), 4,88 (1H, q, J = 6,6 Hz), 4,22 (2H, q, J = 7,1 Hz), 2,31-2,14 (6H, m), 2,13-2,04 (3H, m), 1,84-1,74 (6H, m), 1,71 (3H, d, J = 6,6 Hz), 1,54 (9H, s), 1,25 (3H, t, J = 7,1 Hz). <1>H-NMR (300 MHz, CDCl3)? : 7.61 (1H, d, J = 15.7 Hz), 7.57-7.52 (4H, m), 7.49 (1H, d, J = 2.3 Hz), 7.35 ( 1H, dd, J = 2.3, 8.4 Hz), 6.71 (1H, d, J = 8.4 Hz), 6.38 (1H, d, J = 15.7 Hz), 4, 88 (1H, q, J = 6.6Hz), 4.22 (2H, q, J = 7.1Hz), 2.31-2.14 (6H, m), 2.13-2.04 (3H, m), 1.84-1.74 (6H, m), 1.71 (3H, d, J = 6.6 Hz), 1.54 (9H, s), 1.25 (3H, t, J = 7.1Hz).

B) terz-butil estere di acido (E)-3-(3'-adamantan-1-il)-4'-(1-carbossietossi)-[1,1'-bifenil]-4-il)acrilico B) (E)-3-(3'-adamantan-1-yl)-4'-(1-carboxyethoxy)-[1,1'-biphenyl]-4-yl)acrylic acid tert-butyl ester

A una soluzione di terz-butil estere di acido (E)-3-(3'-adamantan-1-il)-4'-((1-etossi-1-ossopropan-2-il)ossi)-[1,1'-bifenil]-4-il)acrilico (500 mg, 0,94 mmol) in THF al 50% acq. (30 mL), ? stato aggiunto LiOH.H2O (198 mg, 4,71 mmol). La soluzione ? stata agitata per tutta la notte a temperatura ambiente. Il solvente ? stato fatto evaporare, il grezzo ? stato diluito in KHSO4 1N ed estratto con EtOAc. Gli estratti organici combinati sono stati lavati con salamoia, essiccati su Na2SO4 anidro e concentrati sottovuoto, a dare 462 mg (98%) del composto del titolo (solido bianco), p.f. 206?C, Rf (CH2Cl2/MeOH 193: 7) 0,23. <1>H-NMR (300MHz, DMSO-d6) ?: 7,76-7,60 (m, 4H), 7,56 (d, 1H, J = 15,9 Hz), 7,47 (dd, 1H, J = 2,0, 8,4 Hz), 7,43 (d, 1H, J = 2,0 Hz), 6,80 (d, 1H, J = 8,4 Hz), 6,51 (d, 1H, J = 15,9 Hz), 4,91 (q, 1H, J = 6,5 Hz), 2,24 ? 2,00 (m, 9H), 1,79-1,66 (m, 6H), 1,57 (d, 3H, J = 6,5 Hz), 1,47 (9H, s). To a solution of (E)-3-(3'-adamantan-1-yl)-4'-((1-ethoxy-1-oxopropan-2-yl)oxy)-[1, 1'-Biphenyl]-4-yl)acrylic (500 mg, 0.94 mmol) in 50% THF aq. (30mL), ? LiOH.H2O (198 mg, 4.71 mmol) was added. The solution ? stirred overnight at room temperature. The solvent? been evaporated, the crude ? was diluted in 1N KHSO4 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give 462 mg (98%) of the title compound (white solid), m.p. 206?C, Rf (CH2Cl2/MeOH 193:7) 0.23. <1>H-NMR (300MHz, DMSO-d6) ?: 7.76-7.60 (m, 4H), 7.56 (d, 1H, J = 15.9Hz), 7.47 (dd, 1H, J = 2.0, 8.4Hz), 7.43 (d, 1H, J = 2.0Hz), 6.80 (d, 1H, J = 8.4Hz), 6.51 ( d, 1H, J = 15.9Hz), 4.91 (q, 1H, J = 6.5Hz), 2.24 ? 2.00 (m, 9H), 1.79-1.66 (m, 6H), 1.57 (d, 3H, J = 6.5Hz), 1.47 (9H, s).

C) terz-butil estere di acido (E)-3-(3'-adamantan-1-il)-4'-((1-osso-1-(((tetraidro-2H-piran-2-il)ossi)ammino)propan-2-il)ossi)-[1,1'-bifenil]-4-il)acrilico C) acid tert-butyl ester (E)-3-(3'-adamantan-1-yl)-4'-((1-oxo-1-(((tetrahydro-2H-pyran-2-yl)oxy )amino)propan-2-yl)oxy)-[1,1'-biphenyl]-4-yl)acrylic

A una soluzione di terz-butil estere di acido (E)-3-(3'-adamantan-1-yl)-4'-(1-carbossietossi)-[1,1'-bifenil]-4-yl)acrilico (400 mg, 0,79 mmol) in DMF secca (6 mL), HBTU (302 mg, 0,79 mmol) e DIPEA (423 ?L, 2,38 mmol) sono stati aggiunti a 0?C sotto atmosfera di azoto. La soluzione ? stata agitata 30 min a 0?C, poi ? stata aggiunta O-(tetraidropiran-2-il)-idrossilammina (93 mg, 079 mmol) e la reazione ? stata agitata per tutta la notte a temperatura ambiente. Il solvente ? stato rimosso sottovuoto, il residuo ? stato triturato con acqua e filtrato. Il grezzo ? stato purificato mediante cromatografia flash su colonna in esano:etil acetato 3: 1 a dare 400 mg del composto del titolo. Resa: 84%, Rf (esano: etil acetato 7: 3) 0,32. <1>H-NMR (300 MHz, CDCl3) ?: miscela di stereoisomero 8,98 (1H, s), 8,87 (1H, s), 7,61 (2H, d, J = 15,8 Hz), 7,57-7,53 (8H, m), 7,51 (2H, d, J = 2,3 Hz), 7,45-7,35 (2H, m), 6,91-6,83 (2H, m), 6,38 (2H, d, J = 15,9 Hz), 5,03-4,81 (4H, m), 3,90-3,76 (2H, m), 3,64-3,54 (1H, m), 3,50-3,38 (1H, m), 2,26-2,07 (18H, m), 1,84-1,76 (12H, m), 1,69-1,74 (6H, m), 1,54 (18H, s). To a solution of (E)-3-(3'-adamantan-1-yl)-4'-(1-carboxyethoxy)-[1,1'-biphenyl]-4-yl)acrylic acid tert-butyl ester (400 mg, 0.79 mmol) in dry DMF (6 mL), HBTU (302 mg, 0.79 mmol), and DIPEA (423 µL, 2.38 mmol) were added at 0 °C under a nitrogen atmosphere . The solution ? been stirred for 30 min at 0?C, then ? O-(tetrahydropyran-2-yl)-hydroxylamine (93 mg, 079 mmol) was added and the reaction ? stirred overnight at room temperature. The solvent? been removed under vacuum, the residue ? was triturated with water and filtered. The crude ? was purified by flash column chromatography in hexane:ethyl acetate 3:1 to give 400 mg of the title compound. Yield: 84%, Rf (hexane: ethyl acetate 7: 3) 0.32. <1>H-NMR (300 MHz, CDCl3) ?: stereoisomer mixture 8.98 (1H, s), 8.87 (1H, s), 7.61 (2H, d, J = 15.8 Hz) , 7.57-7.53 (8H, m), 7.51 (2H, d, J = 2.3Hz), 7.45-7.35 (2H, m), 6.91-6.83 (2H, m), 6.38 (2H, d, J = 15.9 Hz), 5.03-4.81 (4H, m), 3.90-3.76 (2H, m), 3, 64-3.54 (1H, m), 3.50-3.38 (1H, m), 2.26-2.07 (18H, m), 1.84-1.76 (12H, m), 1.69-1.74 (6H, m), 1.54 (18H, s).

D) Acido (E)-3-(3'-adamantan-1-il)-4'-((1-(idrossiammino)-1-ossopropan-2-il)ossi)-[1,1'-bifenil]-4-il)acrilico D) (E)-3-(3'-adamantan-1-yl)-4'-((1-(hydroxyamino)-1-oxopropan-2-yl)oxy)-[1,1'-biphenyl] acid -4-il)acrylic

A una soluzione di terz-butil estere di acido (E)-3-(3'-adamantan-1-il)-4'-((1-osso-1-(((tetraidro-2H-piran-2-il)ossi)ammino)propan-2-il)ossi)-[1,1'-bifenil]-4-il)acrilico sono stati aggiunti goccia a goccia (1, 35 g, 2,20 mmol) in CH2Cl2 secco (22 mL) a 0 ?C, TFA (22 mL) sotto azoto. La soluzione ? stata agitata a 0 ?C per 4 h. La miscela ? stata fatta evaporare e trattata con toluene per rimuovere TFA, il solido ottenuto ? stato triturato in CH2Cl2 e filtrato a dare 646 mg del composto del titolo. Resa: 64%., Rf (CH2Cl2/MeOH/H2O 18: 2: 0,2) 0,35. <1>H-NMR (300 MHz, CDCl3+TFA) ?: 7,92 (1H, d, J = 15,9 Hz), 7,68-7,59 (4H, m), 7,57 (1H, d, J = 2,2 Hz), 7,44 (1H, dd, J = 2,2 Hz, 8,3 Hz), 6,80 (1H, d, J = 8,3 Hz), 6,49 (1H, d, J = 15,9 Hz), 5,10-4,95 (1H, m), 2,28-2,03 (9H, m), 1,91-1,68 (9H, m). To a solution of tert-butyl acid (E)-3-(3'-adamantan-1-yl)-4'-((1-oxo-1-(((tetrahydro-2H-pyran-2-yl )oxy)amino)propan-2-yl)oxy)-[1,1'-biphenyl]-4-yl)acrylic were added dropwise (1.35 g, 2.20 mmol) in dry CH2Cl2 (22 mL) at 0 ?C, TFA (22 mL) under nitrogen. The solution ? was stirred at 0 ?C for 4 h. The mixture ? been evaporated and treated with toluene to remove TFA, the solid obtained ? was triturated in CH2Cl2 and filtered to give 646 mg of the title compound. Yield: 64%., Rf (CH2Cl2/MeOH/H2O 18: 2: 0.2) 0.35. <1>H-NMR (300 MHz, CDCl3+TFA) ?: 7.92 (1H, d, J = 15.9 Hz), 7.68-7.59 (4H, m), 7.57 (1H , d, J = 2.2 Hz), 7.44 (1H, dd, J = 2.2 Hz, 8.3 Hz), 6.80 (1H, d, J = 8.3 Hz), 6, 49 (1H, d, J = 15.9 Hz), 5.10-4.95 (1H, m), 2.28-2.03 (9H, m), 1.91-1.68 (9H, m).

Esempio 11: sintesi di acido 3-[3'-Adamantan-1-il-4'-(idrossibutossi)-bifenil-4-il]-acrilico (11) Example 11: Synthesis of 3-[3'-Adamantan-1-yl-4'-(hydroxybutoxy)-biphenyl-4-yl]-acrylic acid (11)

A) estere di acido 3-[4'-(4-Acetossi-butossi)-3'-adamantan-1-ilbifenil-4-il]-acrilico Una miscela di metil estere di acido 3-(3'-adamantan-1-il-4'-idrossi-bifenil-4-il)-acrilico (100 mg, 0,26 mmol), 4-bromobutil acetato (67,4 mg, 0,34 mmol), K2CO3 (102 mg, 0,74 mmol) in DMF (4,50 mL) ? stata riscaldata per 2 h a 80 ?C. Dopodich?, K2CO3 ? stato filtrato, DMF fatto evaporare e il residuo ? stato diluito con etil acetato e lavato con HCl 1M, acqua e salamoia. La fase organica ? stata essiccata su Na2SO4 anidro e il solvente fatto evaporare. La purificazione mediante cromatografia flash (etere di petrolio/etil acetato 80: 20) ha dato 98 mg (75%) di prodotto come solido bianco, p.f. 157 ?C, Rf (etere di petrolio/EtOAc 80:20) 0,50. <1>H-NMR (300 MHz, DMSO-d6) ?: 7,76-7,60 (4H, m); 7,56 (1H, d, J =16,5 Hz); 7,48 (1H, dd, J = 8,50, 2,14 Hz); 7,43 (1H, d, J = 2,14 Hz); 6,95 (1H, d, J = 8,50 Hz); 6,51 (1H, d, J = 16,5 Hz); 4,84 (2H, s); 3,73 (3H, s); 4H mancante a causa della sovrapposizione con il solvente segnale; 2,20-1,98 (9H, m); 1,84-1,65 (6H, m); 1,47 (7H, s). A) 3-[4'-(4-Acetoxy-butoxy)-3'-adamantan-1-ylbiphenyl-4-yl]-acrylic acid ester A mixture of 3-(3'-adamantan-1 acid methyl ester -yl-4'-hydroxy-biphenyl-4-yl)-acrylic (100 mg, 0.26 mmol), 4-bromobutyl acetate (67.4 mg, 0.34 mmol), K2CO3 (102 mg, 0.74 mmol) to DMF (4.50 mL) ? been heated for 2 h at 80 ?C. After that, K2CO3 ? been filtered, DMF evaporated and the residue ? was diluted with ethyl acetate and washed with 1M HCl, water and brine. The organic phase? was dried over anhydrous Na2SO4 and the solvent evaporated. Purification by flash chromatography (petroleum ether/ethyl acetate 80:20) gave 98 mg (75%) of product as a white solid, m.p. 157 ?C, Rf (light petroleum/EtOAc 80:20) 0.50. <1>H-NMR (300 MHz, DMSO-d6) ?: 7.76-7.60 (4H, m); 7.56 (1H, d, J = 16.5Hz); 7.48 (1H, dd, J = 8.50, 2.14Hz); 7.43 (1H, d, J = 2.14Hz); 6.95 (1H, d, J = 8.50Hz); 6.51 (1H, d, J = 16.5Hz); 4.84 (2H, s); 3.73 (3H, s); 4H missing due to signal solvent overlap; 2.20-1.98 (9H, m); 1.84-1.65 (6H, m); 1.47 (7H, s).

B) Acido 3-[3'-Adamantan-1-il-4'-(idrossi-butossi)-bifenil-4-il]-acrilico. Una sospensione agitata di metil estere di acido 3-[4'-(4-Acetossi-butossi)-3'-adamantan-1-il-bifenil-4-il]-acrilico (30 mg, 0,06 mmol) in NaOH 0,7 N ? stata posta a riflusso per 10 h. Dopo la rimozione di metanolo, il residuo ? stato trattato con acqua fredda, acidificato con HCl 1M, e il precipitato ? stato filtrato. La cristallizzazione da isopropil etere ha dato 10 mg (37%) del prodotto puro come solido bianco, p.f. 208?C, Rf (etere di petrolio/EtOAc 50:50) 0,15. <1>H-NMR (300 MHz, DMSO-d6) ?: 7,74-7,61 (4H, m); 7,59 (1H, d, J = 16,5 Hz); 7,49 (1H, dd, J = 8,80, 2,11 Hz); 7,41 (1H, d, J = 2,11 Hz); 7,03 (1H, d, J = 8,80 Hz); 6,51 (1H, d, J = 16,5 Hz); 4,49 (1H, brs); 4,02 (2H, t, J = 6,38 Hz); 3,48 (2H, t, J = 6,38 Hz); 2,16-2,20 (9H, m); 1,90-1,78 (2H, m); 1,77-1,59 (8H, m). B) 3-[3'-Adamantan-1-yl-4'-(hydroxy-butoxy)-biphenyl-4-yl]-acrylic acid. A stirred suspension of 3-[4'-(4-Acetoxy-butoxy)-3'-adamantan-1-yl-biphenyl-4-yl]-acrylic acid methyl ester (30 mg, 0.06 mmol) in NaOH 0.7N? was refluxed for 10 h. After the removal of methanol, the residue ? been treated with cold water, acidified with 1M HCl, and the precipitate ? been filtered. Crystallization from isopropyl ether gave 10 mg (37%) of the pure product as a white solid, m.p. 208?C, Rf (petrol ether/EtOAc 50:50) 0.15. <1>H-NMR (300 MHz, DMSO-d6) ?: 7.74-7.61 (4H, m); 7.59 (1H, d, J = 16.5Hz); 7.49 (1H, dd, J = 8.80, 2.11Hz); 7.41 (1H, d, J = 2.11Hz); 7.03 (1H, d, J = 8.80Hz); 6.51 (1H, d, J = 16.5Hz); 4.49 (1H, brs); 4.02 (2H, t, J = 6.38Hz); 3.48 (2H, t, J = 6.38Hz); 2.16-2.20 (9H, m); 1.90-1.78 (2H, m); 1.77-1.59 (8H, m).

Esempio 12: sintesi di acido 3-[3'-Adamantan-1-il-4'idrossi-2-terz-butossiimminometilmetil-bifenil-4-il]-acrilico (12) Example 12: Synthesis of 3-[3'-Adamantan-1-yl-4'hydroxy-2-tert-butoxyiminomethylmethyl-biphenyl-4-yl]-acrylic acid (12)

A) Metil 3-[3'-adamantan-1-il-4'-(terz-butil-dimetilsilanilossi)-2-terz-butossiimminometil-bifenil-4-il]-acrilato. Una soluzione di 100 mg (0,19 mmol) di metil 3-[3'-adamantan-1-il-4'-(terz-butil-dimetil-silanilossi)-2-formil-bifenil-4-il]-acrilato (R. Cincinelli et al. Journal of Medicinal Chemistry, 2005, 48, (4931-4946) in 9 ml di etanolo ? addizionata con 1,4 ml di piridina e 78 mg (0,62 mmol) di O-tertbutilidrossilammina cloridrato, e posta a riflusso per 1 ora. L'evaporazione ha dato un grezzo che ? stato usato per la fase successiva senza ulteriore purificazione. A) Methyl 3-[3'-adamantan-1-yl-4'-(tert-butyl-dimethylsilaniloxy)-2-tert-butoxyiminomethyl-biphenyl-4-yl]-acrylate. A solution of 100 mg (0.19 mmol) of methyl 3-[3'-adamantan-1-yl-4'-(tert-butyl-dimethyl-silanyloxy)-2-formyl-biphenyl-4-yl]-acrylate (R. Cincinelli et al. Journal of Medicinal Chemistry, 2005, 48, (4931-4946) in 9 ml of ethanol is added with 1.4 ml of pyridine and 78 mg (0.62 mmol) of O-tertbutylhydroxylamine hydrochloride, and refluxed for 1 hour.The evaporation gave a crude which was used for the next step without further purification.

B) Acido 3-[3'-Adamantan-1-il-4'- idrossi-2-terzbutossiimminometilmetil-bifenil-4-il]-acrilico. 100 mg (0,18 mmol) di metil 3-[3'-adamantan-1-il-4'-(terz-butil-dimetilsilanilossi)-2-terz-butossiimminometilmetil-bifenil-4-il]-acrilato vengono disciolti in 6 ml di una soluzione 1N di NaOH in metanolo e la miscela posta a riflusso per 5 ore. Evaporazione, assorbimento con acqua, raffreddamento con ghiaccio, lenta aggiunta di HCl 1N a pH acido, filtrazione ed essiccamento danno 65 mg di un prodotto giallastro, p.f. 239?C. B) 3-[3'-Adamantan-1-yl-4'- hydroxy-2-tertbutoxyiminomethylmethyl-biphenyl-4-yl]-acrylic acid. 100 mg (0.18 mmol) of methyl 3-[3'-adamantan-1-yl-4'-(tert-butyl-dimethylsilanyloxy)-2-tert-butoxyiminomethylmethyl-biphenyl-4-yl]-acrylate are dissolved in 6 ml of a 1N solution of NaOH in methanol and the mixture refluxed for 5 hours. Evaporation, absorption with water, cooling with ice, slow addition of 1N HCl at acidic pH, filtration and drying give 65 mg of a yellowish product, m.p. 239?C.

<1>H-NMR (300 MHz, CDCl3) ?: 8,12 (1H, s); 8,06 (1H, s); 7,87 (1H, d, J = 16,2 Hz); 7,59 (1H, dd, J = 8,2, 1,5 Hz); 7,38 (1H, d, J = 8,2 Hz); 7,18 (1H, d, J = 1,8 Hz); 7,05 (1H, dd, J = 8,2, 1,8 Hz); 6,73 (1H, d, J = 8,2 Hz); 6,54 (1H, d, J = 16,2 Hz); 2,19-2,05 (9H, m), 1,80 (6H, s); 1,45 (9H, s). <1>H-NMR (300 MHz, CDCl3) ?: 8.12 (1H, s); 8.06 (1H, s); 7.87 (1H, d, J = 16.2Hz); 7.59 (1H, dd, J = 8.2, 1.5Hz); 7.38 (1H, d, J = 8.2Hz); 7.18 (1H, d, J = 1.8Hz); 7.05 (1H, dd, J = 8.2, 1.8Hz); 6.73 (1H, d, J = 8.2Hz); 6.54 (1H, d, J = 16.2Hz); 2.19-2.05 (9H, m), 1.80 (6H, s); 1.45 (9H, s).

Esempio 13: sintesi di acido 3-[3'-Adamantan-1-il-4'-idrossi-2-metossiimmino-metil-bifenil-4-il]-acrilico (13) Example 13: Synthesis of 3-[3'-Adamantan-1-yl-4'-hydroxy-2-methoxyimino-methyl-biphenyl-4-yl]-acrylic acid (13)

A) Metil 3-[3'-adamantan-1-il-4'-(terz-butil-dimetilsilanilossi)-2-metossiimminometil-bifenil-4-il]-acrilato. Una soluzione di 100 mg (0,19 mmol) di metil 3-[3'-adamantan-1-il-4'-(terz-butil-dimetil-silanilossi)-2-formil-bifenil-4-il]-acrilato (R. Cincinelli et al. Journal of Medicinal Chemistry (2005), 48,4931-4946) in 9 ml di etanolo ? addizionata con 1,4 ml di piridina e 52 mg (0,62 mmol) di O-metilidrossilammina cloridrato e posta a riflusso per 1 ora. L'evaporazione ha dato un grezzo che ? stato usato per la fase successiva senza ulteriore purificazione. A) Methyl 3-[3'-adamantan-1-yl-4'-(tert-butyl-dimethylsilanyloxy)-2-methoxyiminomethyl-biphenyl-4-yl]-acrylate. A solution of 100 mg (0.19 mmol) of methyl 3-[3'-adamantan-1-yl-4'-(tert-butyl-dimethyl-silanyloxy)-2-formyl-biphenyl-4-yl]-acrylate (R. Cincinelli et al. Journal of Medicinal Chemistry (2005), 48,4931-4946) in 9 ml of ethanol ? added with 1.4 ml of pyridine and 52 mg (0.62 mmol) of O-methylhydroxylamine hydrochloride and refluxed for 1 hour. The evaporation has given a rough that ? was used for the next step without further purification.

B) Acido 3-[3'-Adamantan-1-il-4'-idrossi-2-metossiimminometil-bifenil-4-il]-acrilico B) 3-[3'-Adamantan-1-yl-4'-hydroxy-2-methoxyiminomethyl-biphenyl-4-yl]-acrylic acid

85 mg (0,15 mmol) di metil 3-[3'-adamantan-1-il-4'-(terz-butildimetil-silanilossi)-2-metossimmino-metil-bifenil-4-il]-acrilato vengono disciolti in 5 ml di una soluzione 1N di NaOH in metanolo e la miscela posta a riflusso per 5 ore. Evaporazione, assorbimento con acqua, raffreddamento con ghiaccio, lenta aggiunta di HCl 1N a pH acido, filtrazione ed essiccamento danno un prodotto giallastro, 55 mg, p.f. 224?C. <1>H-NMR (300 MHz, CDCl3) ?: 8,13 (1H, s); 8,07 (1H, s); 7,85 (1H, d, J = 16,2 Hz); 7,60 (1H, dd, J = 8,2, 1,8 Hz); 7,40 (1H, d, J = 8,2 Hz); 7,18 (1H, d, J = 2,1 Hz); 7,03 (1H, dd, J = 8,2, 2,1 Hz) 6,74 (1H, d, J = 8,2 Hz); 6,55 (1H, d, J = 16,2 Hz); 4,00 (3H, s); 2,21-2,06 (9H, m), 1,80 (6H, s). 85 mg (0.15 mmol) of methyl 3-[3'-adamantan-1-yl-4'-(tert-butyldimethyl-silanyloxy)-2-methoxymino-methyl-biphenyl-4-yl]-acrylate are dissolved in 5 ml of a 1N solution of NaOH in methanol and the mixture refluxed for 5 hours. Evaporation, absorption with water, cooling with ice, slow addition of 1N HCl at acidic pH, filtration and drying give a yellowish product, 55 mg, m.p. 224?C. <1>H-NMR (300 MHz, CDCl3) ?: 8.13 (1H, s); 8.07 (1H, s); 7.85 (1H, d, J = 16.2Hz); 7.60 (1H, dd, J = 8.2, 1.8Hz); 7.40 (1H, d, J = 8.2Hz); 7.18 (1H, d, J = 2.1Hz); 7.03 (1H, dd, J = 8.2, 2.1 Hz) 6.74 (1H, d, J = 8.2 Hz); 6.55 (1H, d, J = 16.2Hz); 4.00 (3H, s); 2.21-2.06 (9H, m), 1.80 (6H, s).

Esempio 14: sintesi di acido 3-[3'-Adamant-1-il-4'-idrossi-2-carbossimetossiimminometil-bifenil-4-il]-acrilico. (14) Example 14: synthesis of 3-[3'-Adamant-1-yl-4'-hydroxy-2-carboxymethoxyiminomethyl-biphenyl-4-yl]-acrylic acid. (14)

Una soluzione di 70 mg di acido metil 3-[3'-adamantan-1-il-4'-idrossi-2-(formil)-bifenil-4-il]-acrilico in 4 ml di etanolo ? trattata con 1 eq di piridina, poi con 20 mg di acido amminossiacetico e lasciata a T ambiente per 24 ore. Evaporazione e cromatografia su colonna con CH2Cl2:MeOH 4:1 danno 65 mg del prodotto, p.f. 108-110?C (dec). <1>H-NMR (300 MHz, DMSO-d6) ?: 9,68 (1H,s); 8,07 (1H, s); 7,93 (1H, d, J= 1,53 Hz); 7,82 (1H, dd, J= 8,24 Hz, 1,53 Hz); 7,64 (1H, d, J= 16,2 Hz); 7,43 (1H, d, J= 8,24 Hz); 7,06-6,99 (2H, m); 6,88 (1H, d, J= 8,24 Hz); 6,54 (1H, d, J= 16,2 Hz); 4,66 (2H, s); 2,14-1,99 (9H, m); 1,72 (6H, s). A solution of 70 mg of methyl 3-[3'-adamantan-1-yl-4'-hydroxy-2-(formyl)-biphenyl-4-yl]-acrylic acid in 4 ml of ethanol? treated with 1 eq of pyridine, then with 20 mg of aminoxyacetic acid and left at room temperature for 24 hours. Evaporation and column chromatography with CH2Cl2:MeOH 4:1 give 65 mg of the product, m.p. 108-110?C (dec.). <1>H-NMR (300 MHz, DMSO-d6) ?: 9.68 (1H,s); 8.07 (1H, s); 7.93 (1H, d, J= 1.53Hz); 7.82 (1H, dd, J= 8.24Hz, 1.53Hz); 7.64 (1H, d, J= 16.2Hz); 7.43 (1H, d, J= 8.24Hz); 7.06-6.99 (2H, m); 6.88 (1H, d, J= 8.24Hz); 6.54 (1H, d, J= 16.2Hz); 4.66 (2H, s); 2.14-1.99 (9H, m); 1.72 (6H, s).

Esempio 15: sintesi di trifluoroacetato di acido 3-(3'-Adamantan-1-il-2-guanidinometil-4'-idrossi-bifenil-4-il)-acrilico (15). Example 15: Synthesis of 3-(3'-Adamantan-1-yl-2-guanidinomethyl-4'-hydroxy-biphenyl-4-yl)-acrylic acid trifluoroacetate (15).

A) Acido 3-(3'-Adamantan-1-il-2-(diterzbutossicarbonilguanidino)metil)-4'-idrossi-bifenil-4-il)-acrilico A) 3-(3'-Adamantan-1-yl-2-(ditertbutoxycarbonylguanidino)methyl)-4'-hydroxy-biphenyl-4-yl)-acrylic acid

Una sospensione di 133 mg (0,22 mmol) di trifluoroacetato di acido 3-(3'-adamantan-1-il-2-amminometil-4'-idrossi-bifenil-4-il)-acrilico in 2,2 ml di diclorometano ? addizionata con 60 ?l (2 eq.) di trietilammina, poi, dopo 5 minuti, addizionata con 94 mg (0,24 mmol) di N, N'-Di-Boc-N"-trifluorometansolfonilguanidina e un altro eq. di trietilammina, e lasciata sotto un'atmosfera di azoto e al buio per 12 ore. Ripresa con 15 ml di diclorometano, lavaggio con una soluzione 2M di NaHSO4,lavaggio con acqua, essiccamento su Na2SO4, ed evaporazione danno 133 mg di un prodotto grezzo. La cristallizzazione da diclorometano/metanolo (5 ml: 0,25 ml) d? 30 mg di prodotto puro, mentre la cromatografia del liquido madre con diclorometano/metanolo d? ulteriori 70 mg, p.f. 280?C. <1>H-NMR (300 MHz, MeOD) ?: 7,73-7,64 (m, 2H), 7,58 (dd, J = 8,2, 1,8 Hz, 1H), 7,31 (d, J = 8,2 Hz, 1H), 7,04 (d, J = 2,1 Hz, 1H), 6,96 (dd, J = 8,2, 2,1 Hz, 1H), 6,76 (d, J = 8,2 Hz, 1H), 6,50 (d, J = 16,2 Hz, 1H), 4,31 (s, 2H), 2,15-1,94 (m, 9H), 1,77 (s, 6H), 1,46 (s, 9H), 1,42 (s, 9H). A suspension of 133 mg (0.22 mmol) of 3-(3'-adamantan-1-yl-2-aminomethyl-4'-hydroxy-biphenyl-4-yl)-acrylic acid trifluoroacetate in 2.2 mL of dichloromethane ? added with 60 µl (2 eq.) of triethylamine, then after 5 minutes added with 94 mg (0.24 mmol) of N,N'-Di-Boc-N"-trifluoromethanesulfonylguanidine and another eq. of triethylamine , and left under a nitrogen atmosphere in the dark for 12 hours.Recovery with 15 ml of dichloromethane, washing with a 2M NaHSO4 solution, washing with water, drying over Na2SO4, and evaporating to give 133 mg of a crude product. crystallization from dichloromethane/methanol (5 ml: 0.25 ml) gives 30 mg of pure product, while chromatography of the mother liquid with dichloromethane/methanol gives an additional 70 mg, m.p. 280?C. <1>H-NMR ( 300 MHz, MeOD) ?: 7.73-7.64 (m, 2H), 7.58 (dd, J = 8.2, 1.8 Hz, 1H), 7.31 (d, J = 8, 2 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.2, 2.1 Hz, 1H), 6.76 (d, J = 8.2Hz, 1H), 6.50 (d, J = 16.2Hz, 1H), 4.31 (s, 2H), 2.15-1.94 (m, 9H), 1.77 ( s, 6H), 1.46 (s, 9H), 1.42 (s, 9H).

B) Trifluoroacetato di acido 3-(3'-Adamantan-1-il-2-guanidinometil-4'-idrossi-bifenil-4-il)-acrilico. Una soluzione di 70 mg (0,11 mmol) di acido 3-(3'-adamantan-1-il-2-(diterzbutossicarbonilguanidino)metil)-4'-idrossi-bifenil-4-il)-acrilico in 1,1 ml di diclorometano ? lentamente aggiunta sotto atmosfera di azoto, 1,1 ml di acido trifluoroacetico, e lasciata 12 ore al buio. Evaporazione e cromatografia con gel di silice con CH2Cl2/MeOH/TFA 18:2:0,2 come eluente danno un prodotto igroscopico (67 mg, p.f. 163?C). <1>H-NMR (300 MHz, MeOD) ?: 7,69 (d, J = 16,2 Hz, 1H), 7,64-7,58 (m, 2H), 7,32 (d, J = 8,2 Hz, 1H), 7,08 (d, J = 1,5 Hz, 1H), 6,97 (dd, J = 8,2, 1,5 Hz, 1H), 6,78 (d, J = 8,2 Hz, 1H), 6,50 (d, J = 16,2 Hz, 1H), 4,27 (s, 2H), 2,20-1,96 (m, 9H), 1,78 (s, 6H). B) 3-(3'-Adamantan-1-yl-2-guanidinomethyl-4'-hydroxy-biphenyl-4-yl)-acrylic acid trifluoroacetate. A solution of 70 mg (0.11 mmol) of 3-(3'-adamantan-1-yl-2-(ditertbutoxycarbonylguanidino)methyl)-4'-hydroxy-biphenyl-4-yl)-acrylic acid in 1.1 ml of dichloromethane ? slowly adding 1.1 ml of trifluoroacetic acid under a nitrogen atmosphere and left in the dark for 12 hours. Evaporation and silica gel chromatography with CH2Cl2/MeOH/TFA 18:2:0.2 as eluent gives a hygroscopic product (67 mg, m.p. 163?C). <1>H-NMR (300 MHz, MeOD) ?: 7.69 (d, J = 16.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.32 (d, J = 8.2Hz, 1H), 7.08 (d, J = 1.5Hz, 1H), 6.97 (dd, J = 8.2, 1.5Hz, 1H), 6.78 (d , J = 8.2Hz, 1H), 6.50 (d, J = 16.2Hz, 1H), 4.27 (s, 2H), 2.20-1.96 (m, 9H), 1 .78 (s, 6H).

Esempio 16: sintesi di acido 3-{4-[8-(Adamantan-1-il)-2,3-diidro-benzo[1,4]-diossin-6-il]-fenil}-acrilico (16). Example 16: Synthesis of 3-{4-[8-(Adamantan-1-yl)-2,3-dihydro-benzo[1,4]-dioxin-6-yl]-phenyl}-acrylic acid (16).

Acido 3-{4-[8-(Adamantan-1-il)-2,3-diidro-benzo[1,4]-diossin-6-il]-fenil}-acrilico (16). La condensazione one-pot di Suzuki tra 200 mg (0,573 mmol) di 4-bromo-1,2-etilendiossibenzene con metil 4-bromocinnamato ? stata eseguita come descritto in R. Cincinelli et al. /Bioorg. Med. Chem. 15 (2007) 4863-4875. Il residuo ? stato purificato mediante cromatografia flash (diclorometano/esano 1,1) a dare 124 mg (50%) di metil estere di acido 3-{4-[8-(adamantan-1-il)-2,3-diidro-benzo[1,4]diossin-6-il]-fenil}-acrilico, pf 209 ?C. <1>H NMR (300 MHz, CDCl3)?: 1,78 (6H, s, 6Ad), 2,08 (3H, s, 3Ad), 2,13 (6H, s, 6Ad), 3,83 (3H, s, OMe), 4,33 (4H, s, OCH2), 6,45 (1H, d, CH=, J = 16,0 Hz), 7,00 (1H, d, 1Ar, J = 2,3 Hz), 7,05 (1H, d, 1Ar, J = 2,3 Hz), 7,50? 7,63 (4H, m, 4Ar), 7,70 (1H, d, CH=, J = 16,0 Hz). L'estere di cui sopra (70 mg, 0,163 mmol) ? stato idrolizzato con LiOH a dare 62 mg (91%) del prodotto puro, pf 288 ?C. <1>H NMR (300 MHz, DMSO-d6)?: 1,71 (6H, s, 6Ad), 2,02 (3H, s, 3Ad), 2,08 (6H, s, 6Ad), 4,25 (4H, s, OCH2), 6,50 (1H, d, CH@, J = 15,6 Hz), 6,97 (1H, d, 1Ar, J = 1,9 Hz), 7,02 (1H, d, 1Ar, J = 1,9 Hz), 7,56 (1H, d, CH@, J = 15,6 Hz), 7,58 (2H, d, 2Ar, J = 8,25 Hz), 7,69 (2H, d, 2Ar, J = 8,3 Hz). 3-{4-[8-(Adamantan-1-yl)-2,3-dihydro-benzo[1,4]-dioxin-6-yl]-phenyl}-acrylic acid (16). Suzuki's one-pot condensation of 200 mg (0.573 mmol) of 4-bromo-1,2-ethylenedioxybenzene with methyl 4-bromocinnamate ? was performed as described in R. Cincinelli et al. /bioorg. Med. Chem. 15 (2007) 4863-4875 . The residue? was purified by flash chromatography (dichloromethane/1,1 hexane) to give 124 mg (50%) of 3-{4-[8-(adamantan-1-yl)-2,3-dihydro-benzo[ acid methyl ester 1,4]dioxin-6-yl]-phenyl}-acrylic, mp 209 ?C. <1>H NMR (300 MHz, CDCl3)?: 1.78 (6H, s, 6Ad), 2.08 (3H, s, 3Ad), 2.13 (6H, s, 6Ad), 3.83 ( 3H, s, OMe), 4.33 (4H, s, OCH2), 6.45 (1H, d, CH=, J = 16.0 Hz), 7.00 (1H, d, 1Ar, J = 2 .3Hz), 7.05 (1H, d, 1Ar, J = 2.3Hz), 7.50? 7.63 (4H, m, 4Ar), 7.70 (1H, d, CH=, J = 16.0 Hz). The above ester (70 mg, 0.163 mmol) ? was hydrolyzed with LiOH to give 62 mg (91%) of the pure product, mp 288 ?C. <1>H NMR (300 MHz, DMSO-d6)?: 1.71 (6H, s, 6Ad), 2.02 (3H, s, 3Ad), 2.08 (6H, s, 6Ad), 4, 25 (4H, s, OCH2), 6.50 (1H, d, CH@, J = 15.6 Hz), 6.97 (1H, d, 1Ar, J = 1.9 Hz), 7.02 ( 1H, d, 1Ar, J = 1.9 Hz), 7.56 (1H, d, CH@, J = 15.6 Hz), 7.58 (2H, d, 2Ar, J = 8.25 Hz) , 7.69 (2H, d, 2Ar, J = 8.3Hz).

Esempio 17: sintesi di acido E-3-[3'-(Acetilamminometil)-4'-idrossi-5'-(adamantan-1-il)bifenil-4-il]-acrilico (17). Example 17: Synthesis of E-3-[3'-(Acetylaminomethyl)-4'-hydroxy-5'-(adamantan-1-yl)biphenyl-4-yl]-acrylic acid (17).

A) N-[5-Bromo-2-idrossi-3-(adamantan-1-il)-benzil]acetammide. Una miscela finemente polverizzata di 2-(1-adamantanil)-4-bromofenolo (500 mg, 163 mmol) e N-(idrossimetil)acetammide (145 mg, 1,63 mmol) ? stata aggiunta in porzioni, a 10 ?C durante agitazione, a 1,63 mL di una soluzione di CH3COOH/H2SO4 9:1. Dopo che la miscela ? stata agitata a temperatura ambiente per 5 giorni, ? stato aggiunto ghiaccio e il solido giallo ? stato filtrato e lavato con acqua. La purificazione mediante cromatografia flash (esano/etil acetato 60:40) ha dato 225 mg (37%) del prodotto puro, pf 216 ?C <1>H NMR (300 MHz, CDCl3) d: 1,77 (6H, s, 6Ad), 2,04 (3H, s, 3Ad), 2,05(3H, s, CH3), 2,10 (6H, s, 6Ad), 4,25 (2H, d, CH2N, J = 6,8 Hz), 6,28 (1H, t, NH, J = 6,8 Hz), 7,05 (1H, d, 1Ar, J = 2,6 Hz), 7,23 (1H, d, 1Ar, J = 2,6 Hz). 6,4,10. A) N-[5-Bromo-2-hydroxy-3-(adamantan-1-yl)-benzyl]acetamide. A finely powdered mixture of 2-(1-adamantanyl)-4-bromophenol (500 mg, 163 mmol) and N-(hydroxymethyl)acetamide (145 mg, 1.63 mmol) ? was added in portions, at 10°C while stirring, to 1.63 mL of a 9:1 CH3COOH/H2SO4 solution. After the mixture ? been stirred at room temperature for 5 days, ? been added ice and the yellow solid? was filtered and washed with water. Purification by flash chromatography (hexane/ethyl acetate 60:40) gave 225 mg (37%) of pure product, mp 216 ?C <1>H NMR (300 MHz, CDCl3) d: 1.77 (6H, s , 6Ad), 2.04 (3H, s, 3Ad), 2.05(3H, s, CH3), 2.10 (6H, s, 6Ad), 4.25 (2H, d, CH2N, J = 6 .8 Hz), 6.28 (1H, t, NH, J = 6.8 Hz), 7.05 (1H, d, 1Ar, J = 2.6 Hz), 7.23 (1H, d, 1Ar , J = 2.6Hz). 6,4,10.

B) Acido E-3-[3'-(Acetilamminometil)-4'-idrossi-5'-(adamantan- B) E-3-[3'-(Acetylaminomethyl)-4'-hydroxy-5'-(adamantan-

1-il)bifenil-4-il]-acrilico (17). Una quantit? di 195 mg (0,516 mmol) di N-[5-Bromo-2-idrossi-3-(adamantan-1-il)-benzil]acetammide ? stata fatta reagire con metil pbromocinnamato secondo la procedura generale descritta in R. Cincinelli et al. /Bioorg. Med. Chem. 15 (2007) 4863-4875. La purificazione mediante cromatografia flash (etil acetato/diclorometano 9:1) ha dato 103 mg (43%) di metil estere di acido 3-[3'-(acetilamminometil)-4'-idrossi-5'-(adamantan-1-il)bifenil-4-il]-acrilico, pf 163 ?C. <1>H NMR (300 MHz, CDCl<3>)?: 1,80 (6H, s, 6Ad), 2,05(3H, s, OAc), 2,08 (3H, s, 3Ad), 2,20 (6H, s, 6Ad),3,80 (3H, s, OMe), 4,40 (2H, d, CH2N, J = 6,0 Hz),6,32 (1H, t, NH, J = 6,0 Hz), 6,69 (1H, d, CH=,J = 15,8 Hz), 7,19 (1H, d, 1Ar, J = 2,6 Hz), 7,44 (1H, d, 1Ar, J = 2,6 Hz), 7,54?7,58 (4H, m, 4Ar), 7,72 (1H,d, CH=, J = 15,8 Hz). L'estere di cui sopra (100 mg, 0,218 mmol) ? stato idrolizzato 1-yl)biphenyl-4-yl]-acrylic (17). A quantity? of 195 mg (0.516 mmol) of N-[5-Bromo-2-hydroxy-3-(adamantan-1-yl)-benzyl]acetamide ? was reacted with methyl pbromocinnamate according to the general procedure described in R. Cincinelli et al. /bioorg. Med. Chem. 15 (2007) 4863-4875 . Purification by flash chromatography (ethyl acetate/dichloromethane 9:1) gave 103 mg (43%) of 3-[3'-(acetylaminomethyl)-4'-hydroxy-5'-(adamantan-1- yl)biphenyl-4-yl]-acrylic, mp 163 ?C. <1>H NMR (300 MHz, CDCl<3>)?: 1.80 (6H, s, 6Ad), 2.05(3H, s, OAc), 2.08 (3H, s, 3Ad), 2 ,20 (6H, s, 6Ad),3.80 (3H, s, OMe), 4.40 (2H, d, CH2N, J = 6.0 Hz),6.32 (1H, t, NH, J = 6.0 Hz), 6.69 (1H, d, CH=,J = 15.8 Hz), 7.19 (1H, d, 1Ar, J = 2.6 Hz), 7.44 (1H, d, 1Ar, J = 2.6Hz), 7.54?7.58 (4H, m, 4Ar), 7.72 (1H,d, CH=, J = 15.8Hz). The above ester (100 mg, 0.218 mmol) ? been hydrolysed

come descritto nella procedura generale descritta in R. Cincinelli et al. /Bioorg. Med. Chem. 15 (2007) 4863?4875, per ottenere 70 mg (72%) del prodotto puro, pf 264 ?C. <1>H NMR (300 MHz, acetone-d6)?: 1,83 (6H, s, 6Ad), 2,10 (3H, s, Ac), 2,07 (3H, s, 3Ad), 2,25 (6H, s, 6Ad), 4,36 (2H, d, CH2N, J = 6,0 Hz), 6,53 (1H, d, CH=, J = 15,8 Hz), 7,40 (1H, d, 1Ar, J = 2,3 Hz), 7,48 (1H, d, 1Ar, J = 2,3 Hz), 7,64 (2H, d, 2Ar, J = 8,3 Hz), 7,69 (1H, d, CH=, J = 15,8 Hz), 7,73 (2H, d, 2Ar, J = 8,3 Hz), 8,37 (1H, t, NH, J = 6,0 Hz), 10,41 (1H, s). as described in the general procedure described in R. Cincinelli et al. /bioorg. Med. Chem. 15 (2007) 4863?4875, to obtain 70 mg (72%) of the pure product, mp 264?C. <1>H NMR (300 MHz, acetone-d6)?: 1.83 (6H, s, 6Ad), 2.10 (3H, s, Ac), 2.07 (3H, s, 3Ad), 2, 25 (6H, s, 6Ad), 4.36 (2H, d, CH2N, J = 6.0 Hz), 6.53 (1H, d, CH=, J = 15.8 Hz), 7.40 ( 1H, d, 1Ar, J = 2.3Hz), 7.48 (1H, d, 1Ar, J = 2.3Hz), 7.64 (2H, d, 2Ar, J = 8.3Hz), 7.69 (1H, d, CH=, J = 15.8 Hz), 7.73 (2H, d, 2Ar, J = 8.3 Hz), 8.37 (1H, t, NH, J = 6 .0Hz), 10.41 (1H, s).

Esempio 18: sintesi di acido (E)-3-(3'-adamantan-1-il)-4'-idrossi-5'-((3-fenilureido)metil)-[1,1'-bifenil]-4-il)acrilico (18) Example 18: Synthesis of (E)-3-(3'-adamantan-1-yl)-4'-hydroxy-5'-((3-phenylureido)methyl)-[1,1'-biphenyl]-4 acid -il)acrylic (18)

A una sospensione di 33 mg di acido E-3-{3'-[(2-Cloroacetilammino)-metil]-4'-idrossi-5'-(adamantan-1-il)bifenil-4-il}-acrilico (R. Cincinelli et al. /Bioorg. Med. Chem. 15 (2007) 4863?4875) in TEA (4 ml), sono stati aggiunti DMF (2 ml) e DMSO (0,2 ml), seguiti da fenilisocianato (30 ?l). La miscela ? stata agitata per 5 giorni a temperatura ambiente. Il solvente ? stato fatto evaporare ed ? stata aggiunta acqua (2 ml), seguita da HCl 2N (100 ?l). Il solido giallo formato ? stato filtrato ed essiccato (resa 80%). <1>H NMR (300 MHz, DMSO-d6) ?: 1,80 (6H, s, 6Ad), 2,07 (3H, s, 3Ad), 2,21 (6H, s, 6Ad), 4,31 (2H, d, CH2N, J = 6,0 Hz), 6,50 (1H, d, CH=, J = 16,0 Hz), 6,90-7,80 (12H, m), 8,05 (1H, m), 8,90 (1H, s), 10,05 (1H, s). To a suspension of 33 mg of E-3-{3'-[(2-Chloroacetylamino)-methyl]-4'-hydroxy-5'-(adamantan-1-yl)biphenyl-4-yl}-acrylic acid ( R. Cincinelli et al. /Bioorg. Med. Chem. 15 (2007) 4863?4875) in TEA (4 ml), DMF (2 ml) and DMSO (0.2 ml) were added, followed by phenylisocyanate (30 ?L). The mixture ? stirred for 5 days at room temperature. The solvent? been evaporated and ? water (2 ml) was added, followed by 2N HCl (100 µl). The yellow solid formed ? filtered and dried (80% yield). <1>H NMR (300 MHz, DMSO-d6) ?: 1.80 (6H, s, 6Ad), 2.07 (3H, s, 3Ad), 2.21 (6H, s, 6Ad), 4, 31 (2H, d, CH2N, J = 6.0Hz), 6.50 (1H, d, CH=, J = 16.0Hz), 6.90-7.80 (12H, m), 8, 05 (1H, m), 8.90 (1H, s), 10.05 (1H, s).

Esempio 19: sintesi di acido 3-(3'-Adamantan-1-il-4'-idrossifenil-4-il) propionico (19). Example 19: synthesis of 3-(3'-Adamantan-1-yl-4'-hydroxyphenyl-4-yl) propionic acid (19).

Acido 3-(3'-Adamantan-1-il-4'-idrossifenil-4-il) propionico (19). Metil E-3-(3'-Adamantan-1-il-4'-idrossifenil-4-il)acrilato (80 mg) ? stato disciolto in 40 mL di AcOEt, ? stata aggiunta una quantit? di 30 mg di PtO2, e la miscela ? stata idrogenata per 40 min. Dopo la filtrazione del catalizzatore, il solvente ? stato fatto evaporare per ottenere 80 mg (100%) di metil 3-(3'-adamantan-1-il-4-idrossifenil-4-il)propionato, pf 150 ?C. Una soluzione di 43 mg (1,03 mmol) di LiOH.H2O e 80 mg (0,205 mmol) dell'estere di cui sopra in 8,4 mL di THF/H2O, 1:1, ? stata agitata a temperatura ambiente per 1,5 h. THF ? stato fatto evaporare, e lo strato acquoso rimanente ? stato lavato con esano e poi acidificato con HCl 1M a pH 2 per ottenere, dopo filtrazione, 57 mg di un solido bianco. Resa 74%, pf 197-200 ?C. 3-(3'-Adamantan-1-yl-4'-hydroxyphenyl-4-yl) propionic acid (19). Methyl E-3-(3'-Adamantan-1-yl-4'-hydroxyphenyl-4-yl)acrylate (80 mg) ? been dissolved in 40 mL of AcOEt, ? was added a quantity? of 30 mg of PtO2, and the mixture ? was hydrogenated for 40 min. After the filtration of the catalyst, the solvent ? was evaporated to obtain 80 mg (100%) of methyl 3-(3'-adamantan-1-yl-4-hydroxyphenyl-4-yl)propionate, mp 150 ?C. A solution of 43 mg (1.03 mmol) of LiOH.H2O and 80 mg (0.205 mmol) of the above ester in 8.4 mL of THF/H2O, 1:1, ? was stirred at room temperature for 1.5 h. THF ? been evaporated, and the remaining aqueous layer? was washed with hexane and then acidified with 1M HCl at pH 2 to obtain, after filtration, 57 mg of a white solid. Yield 74%, mp 197-200 ?C.

<1>H NMR (acetone-d6)?: 1,80 (6H, s, 6Ad), 2,10 (3H, s, 3Ad), 2,25 (6H, s, 6Ad), 2,65 (2H, t, -CH2-, J = 7,72 Hz), 2,95(2H, t, -CH2-, J = 7,72 Hz), 6,90 (1H, d, 1Ar, J = 8,09 Hz), <1>H NMR (acetone-d6)?: 1.80 (6H, s, 6Ad), 2.10 (3H, s, 3Ad), 2.25 (6H, s, 6Ad), 2.65 (2H , t, -CH2-, J = 7.72 Hz), 2.95(2H, t, -CH2-, J = 7.72 Hz), 6.90 (1H, d, 1Ar, J = 8.09 Hz),

7,25-7,35 (3H, m, 3Ar), 7,42 (1H, d, 1 Ar, J = 2,21 Hz), 7,50 7.25-7.35 (3H, m, 3Ar), 7.42 (1H, d, 1Ar, J = 2.21Hz), 7.50

(2H, d, 2Ar, J = 8,34 Hz), 8,45 (1H, brs, OH). (2H, d, 2Ar, J = 8.34Hz), 8.45 (1H, brs, OH).

Esempio 20: sintesi di 3-adamantan-1-il-40-(2-carbossivinil)-bifenil-4-il estere di acido (E)-Ottadeca-9,12-dienoico (20) Example 20: Synthesis of 3-adamantan-1-yl-40-(2-carboxyvinyl)-biphenyl-4-yl ester of (E)-Octadeca-9,12-dienoic acid (20)

A una soluzione di terz-butil estere di acido (E)-3-(30-Adamantan-1-il-40-idrossifenil-4-il)acrilico (200 mg, 0,464 mmol) e pochi cristalli di DMAP in 2,19 mL di piridina secca sono stati aggiunti 208 mg (0,696 mmol) di linoleoil cloruro. Dopo agitazione per tutta la notte a temperatura ambiente, la miscela di reazione ? stata versata in acqua ghiacciata e lo strato acquoso ? stato estratto due volte con etil acetato. Gli strati organici combinati sono stati lavati due volte con HC1 1N, acqua ed essiccati su Na2SO4. La cromatografia flash della miscela di reazione (esano/etil acetato 95:5) ha dato 210 mg di 3-adamantan-1-il-40-(2-terz-butossicarbonilvinil)-bifenil-4-il estere di acido (E)-ottadeca-9,12-dienoico come olio incolore. Resa 65%, <1>H-MNMR (300 MHz, DMSO-d6) ? 7,81?7,65 (m, 4H), 7,64? 7,53 (m, 3H), 7,10 (d, J = 8,5 Hz, 1H), 6,56 (d, J = 16,0 Hz, 1H), 5,43?5,24 (m, 4H), 2,73 (t, J = 2,25 Hz, 2H), 2,67 (t, J = 3,75 Hz, 2H), 2,10?1,93 (m, 13H), 1,80?1,60 (m, 8H), 1,50 (s, 9H), 1,43?1,21 (m, 14H), 0,85 (t, J = 3,0 Hz, 3H). To a solution of (E)-3-(30-Adamantan-1-yl-40-hydroxyphenyl-4-yl)acrylic acid tert-butyl ester (200 mg, 0.464 mmol) and a few crystals of DMAP in 2.19 mL of dry pyridine was added with 208 mg (0.696 mmol) of linoleoyl chloride. After stirring overnight at room temperature, the reaction mixture been poured into ice water and the watery layer ? was extracted twice with ethyl acetate. The combined organic layers were washed twice with 1N HC1, water and dried over Na2SO4. Flash chromatography of the reaction mixture (hexane/ethyl acetate 95:5) gave 210 mg of 3-adamantan-1-yl-40-(2-tert-butoxycarbonylvinyl)-biphenyl-4-yl acid ester (E) -octadeca-9,12-dienoic as a colorless oil. Yield 65%, <1>H-MNMR (300 MHz, DMSO-d6) ? 7.81?7.65 (m, 4H), 7.64? 7.53 (m, 3H), 7.10 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 16.0 Hz, 1H), 5.43?5.24 (m , 4H), 2.73 (t, J = 2.25 Hz, 2H), 2.67 (t, J = 3.75 Hz, 2H), 2.10?1.93 (m, 13H), 1 .80?1.60 (m, 8H), 1.50 (s, 9H), 1.43?1.21 (m, 14H), 0.85 (t, J = 3.0 Hz, 3H).

3-adamantan-1-il-40-(2-terzbutossicarbonilvinil)-bifenil-4-il estere di acido (E)-Ottadeca-9,12-dienoico (110 mg, 0,159 mmol) ? stato disciolto in metilen cloruro secco (1,59 mL) e trattato con TFA (1,59 mL) a 0 ?C sotto agitazione. Dopo 30 min a 0 ?C il solvente ? stato fatto evaporare a dare 100 mg del composto del titolo come solido bianco. Resa 99%. <1>H NMR (300 MHz, DMSO-d6) ? 7,84?7,68 (m, 4H), 7,62 (d, J = 15,0 Hz, 1H), 7,58?7,50 (m, 2H), 7,10 (d, J = 8,5 Hz, 1H), 6,58 (d, J = 16,0 Hz, 1H), 5,40?5,22 (m, 4H), 2,76 (t, J = 2,25 Hz, 2H), 2,70 (t, J = 2,65 Hz, 2H), 2,10?1,90 (m, 13H), 1,80?1,67 (m, 8H), 1,45?1,16 (m, 14H), 0,86 (t, J = 3,0 Hz, 3H). 3-adamantan-1-yl-40-(2-tert-butoxycarbonylvinyl)-biphenyl-4-yl (E)-Octadeca-9,12-dienoic acid ester (110 mg, 0.159 mmol) ? was dissolved in dry methylene chloride (1.59 mL) and treated with TFA (1.59 mL) at 0°C with stirring. After 30 min at 0 ?C the solvent ? was evaporated to give 100 mg of the title compound as a white solid. Yield 99%. <1>H NMR (300 MHz, DMSO-d6) ? 7.84?7.68 (m, 4H), 7.62 (d, J = 15.0 Hz, 1H), 7.58?7.50 (m, 2H), 7.10 (d, J = 8.5Hz, 1H), 6.58 (d, J = 16.0Hz, 1H), 5.40?5.22 (m, 4H), 2.76 (t, J = 2.25Hz, 2H), 2.70 (t, J = 2.65 Hz, 2H), 2.10?1.90 (m, 13H), 1.80?1.67 (m, 8H), 1.45?1 .16 (m, 14H), 0.86 (t, J = 3.0Hz, 3H).

Esempio 21: sintesi di acido E-3-[3'-Formil-4'-idrossi-5'-(adamantan-1-il)-bifenil-4-il]-acrilico (21). Example 21: Synthesis of E-3-[3'-Formyl-4'-hydroxy-5'-(adamantan-1-yl)-biphenyl-4-yl]-acrylic acid (21).

A) 4'-Bromo-4-idrossi-5-(adamantan-1-il)bifenil-3-carbaldeide. A una soluzione di 2 g (5,22 mmol) di 4-(4'-bromofenil)-2-(adamantan-1-il)-fenolo e 1,12 g (1,22 mL, 10,44 mmol) di 2,6-lutidina in 11 mL di toluene appena distillato, 0,68 g (2,61 mmol, 0,3 mL) di SnCl4 sono stati aggiunti per 10 min sotto un'atmosfera di azoto. Si ? formato un precipitato giallo chiaro. La miscela ? stata lasciata agitare a temperatura ambiente per 20 min, poi ? stata aggiunta paraformaldeide solida (0,626 g, 20,88 mmol) in una porzione e la miscela di reazione ? stata agitata per altri 10 min, poi riscaldata a 90?95 ?C per 7 h. Una volta raffreddata a temperatura ambiente, sono stati aggiunti 30 mL di acqua e 6 mL di HCl 1M. La fase acquosa ? stata estratta con etil acetato, l'estratto lavato con salamoia, essiccato su Na2SO4, e fatto evaporare. Il prodotto grezzo ? stato purificato mediante cromatografia flash (esano/etil acetato 95:5) a dare 1,3 g (60%) del composto del titolo, pf 189 ?C. <1>H NMR (300 MHz, CDCl3) d: 1,8 (6H, s, Ad), 1,65 (3H, s, Ad), 2,19 (6H, s, Ad), 7,40 (2H, d, 2Ar, J = 8,3 Hz), 7,54 (2H, d, 2Ar, J = 8,3 Hz), 7,56 (1H, d, 1Ar, J = 2,3 Hz), 7,64 (1H, d, 1Ar, J = 2,3 Hz), 9,94 (1H, s, OH), 11,8 (1H, s, CHO). A) 4'-Bromo-4-hydroxy-5-(adamantan-1-yl)biphenyl-3-carbaldehyde. To a solution of 2 g (5.22 mmol) of 4-(4'-bromophenyl)-2-(adamantan-1-yl)-phenol and 1.12 g (1.22 mL, 10.44 mmol) of 2,6-lutidine in 11 mL of freshly distilled toluene, 0.68 g (2.61 mmol, 0.3 mL) of SnCl4 was added for 10 min under a nitrogen atmosphere. Yup ? formed a pale yellow precipitate. The mixture ? been left to stir at room temperature for 20 min, then ? solid paraformaldehyde (0.626 g, 20.88 mmol) was added in one portion and the reaction mixture ? was stirred for another 10 min, then heated at 90?95?C for 7 h. Once cooled to room temperature, 30 mL of water and 6 mL of 1M HCl were added. The aqueous phase? was extracted with ethyl acetate, the extract washed with brine, dried over Na2SO4, and evaporated. The raw product? was purified by flash chromatography (hexane/ethyl acetate 95:5) to give 1.3 g (60%) of the title compound, mp 189 ?C. <1>H NMR (300 MHz, CDCl3) d: 1.8 (6H, s, Ad), 1.65 (3H, s, Ad), 2.19 (6H, s, Ad), 7.40 ( 2H, d, 2Ar, J = 8.3Hz), 7.54 (2H, d, 2Ar, J = 8.3Hz), 7.56 (1H, d, 1Ar, J = 2.3Hz), 7.64 (1H, d, 1Ar, J = 2.3 Hz), 9.94 (1H, s, OH), 11.8 (1H, s, CHO).

B) Acido E-3-[3'-Formil-4'-idrossi-5'-(adamantan-1-il)-bifenil-4-il]-acrilico (21). 4'-Bromo-4-idrossi-5-(adamantan-1-il) bifenil-3-carbaldeide ? stata sottoposta a condensazione di Heck come descritto nella procedura generale riportata in R. Cincinelli et al. /Bioorg. Med. Chem. 15 (2007) 4863-4875. Il metil estere di acido 3-(3'-formil-4'-idrossi-5'-(adamantan-1-il)bifenil-4-il)-acrilicopuro ? stato ottenuto dopo purificazione mediante cromatografia flash (esano/etil acetato 3:7) e cristallizzazione da diisopropiletere. Resa 66%, pf 245 ?C. <1>H NMR (300 MHz, CDCl3) d: 1,56 (6H, s, Ad), 2,07 (3H, s, Ad), 2,20 (6H, s, Ad), 3,58 (3H, s, OMe), 6,46 (1H, d, CH=, J = 15,0 Hz), 7,59 (m, 4H, 4Ar), 7,60 (1H, d, 1Ar, J = 2,3 Hz), 7,70 (1H, d, 1Ar, J = 2,3 Hz), 7,73 (1H, d, CH=, J = 15,0 Hz), 9,95 (1H, s, OH), 11,9 (1H, s, CHO). L'estere di cui sopra ? stato idrolizzato come descritto nella procedura B) E-3-[3'-Formyl-4'-hydroxy-5'-(adamantan-1-yl)-biphenyl-4-yl]-acrylic acid (21). 4'-Bromo-4-hydroxy-5-(adamantan-1-yl) biphenyl-3-carbaldehyde ? was subjected to Heck condensation as described in the general procedure reported in R. Cincinelli et al. /bioorg. Med. Chem. 15 (2007) 4863-4875 . Pure 3-(3'-formyl-4'-hydroxy-5'-(adamantan-1-yl)biphenyl-4-yl)-acrylic acid methyl ester ? was obtained after purification by flash chromatography (hexane/ethyl acetate 3:7) and crystallization from diisopropyl ether. Yield 66%, mp 245 ?C. <1>H NMR (300 MHz, CDCl3) d: 1.56 (6H, s, Ad), 2.07 (3H, s, Ad), 2.20 (6H, s, Ad), 3.58 ( 3H, s, OMe), 6.46 (1H, d, CH=, J = 15.0 Hz), 7.59 (m, 4H, 4Ar), 7.60 (1H, d, 1Ar, J = 2 .3 Hz), 7.70 (1H, d, 1Ar, J = 2.3 Hz), 7.73 (1H, d, CH=, J = 15.0 Hz), 9.95 (1H, s, OH), 11.9 (1H, s, CHO). The above ester ? was hydrolyzed as described in the procedure

generale riportata in R. Cincinelli et al. /Bioorg. Med. Chem. reported in R. Cincinelli et al. /bioorg. Med. Chem.

15 (2007) 4863?4875 per ottenere l'acido corrispondente, resa 15 (2007) 4863?4875 to obtain the corresponding acid, yield

83%, pf > 300 ?C. <1>H NMR (300 MHz, DMSO-d6)?: 1,54 (6H, s, Ad), 2,08 (3H, s, Ad), 2,16 (6H, s, Ad), 6,55 (1H, d, CH=, J = 16,0 Hz), 7,59 (1H, d, CH=, J = 16,0 Hz), 7,66?8,18 (5H, m, 5Ar), 8,03 (1H, d, 1Ar, J = 2,3 Hz), 10,05 (1H, s, CHO), 12,05 (1H, s, 83%, mp > 300 ?C. <1>H NMR (300 MHz, DMSO-d6)?: 1.54 (6H, s, Ad), 2.08 (3H, s, Ad), 2.16 (6H, s, Ad), 6, 55 (1H, d, CH=, J = 16.0 Hz), 7.59 (1H, d, CH=, J = 16.0 Hz), 7.66?8.18 (5H, m, 5Ar) , 8.03 (1H, d, 1Ar, J = 2.3 Hz), 10.05 (1H, s, CHO), 12.05 (1H, s,

OH). OH).

Esempio 22: Attivit? antimicrobica Example 22: Activity? antimicrobial

Determinazione della concentrazione minima inibitoria (MIC), della concentrazione minima battericida (MBC), delle curve battericide e del tasso di uccisione su ceppi Gram positivi e Gram negativi, per la valutazione dell'attivit? battericida dei composti dell'esempio 1 (n. da 1 a 14). Determination of the minimum inhibitory concentration (MIC), of the minimum bactericidal concentration (MBC), of the bactericidal curves and of the killing rate on Gram positive and Gram negative strains, for the evaluation of the activity bactericide of the compounds of example 1 (n. from 1 to 14).

Test di sensibilit? sono stati eseguiti nel micrometodo della diluizione in brodo allo scopo di testare il possibile potere batteriostatico e/o battericida in composti differenti, secondo le linee guida CLSI (Clinical and Laboratory Standards Institute). In dettaglio, metodi fenotipici basati sulla determinazione in vitro di MIC e MBC sono stati eseguiti su ceppi batterici precedentemente isolati, identificati e caratterizzati a livello del loro profilo di suscettibilit? agli antibiotici. Secondo i dati di MIC e MBC, il tasso di uccisione ? stato calcolato come il rapporto tra MBC e MIC sulla base di cui ? possibile definire i composti testati come battericidi (tasso di uccisione = 1-4), o batteriostatici (tasso di uccisione > 4). Sensitivity test? were performed in the micromethod of broth dilution in order to test the possible bacteriostatic and/or bactericidal power in different compounds, according to the CLSI (Clinical and Laboratory Standards Institute) guidelines. In detail, phenotypic methods based on the in vitro determination of MIC and MBC were performed on bacterial strains previously isolated, identified and characterized at the level of their susceptibility profile. to antibiotics. According to MIC and MBC data, the killing rate ? been calculated as the ratio between MBC and MIC on the basis of which ? It is possible to define the compounds tested as bactericidal (killing rate = 1-4), or bacteriostatic (killing rate > 4).

Preparazione della soluzione contenente molecole: per ciascuna molecola da testare, sono state realizzate soluzioni come soluzione madre di DMSO, con una concentrazione di 2,560 mg/ml, usata per testare diluizioni 12 con le seguenti concentrazioni scalari di farmaco: 512-256-128-64-32-16-8-4-2-1-0,5-0,25 ?g/ml. Le diluizioni scalari sono state preparate direttamente su piastre usando brodo Mueller Hinton (MHB) come solvente. Preparation of the solution containing molecules: For each molecule to be tested, solutions were made as a stock solution of DMSO, with a concentration of 2,560 mg/ml, used to test 12 dilutions with the following scalar drug concentrations: 512-256-128- 64-32-16-8-4-2-1-0.5-0.25 ?g/ml. Stepwise dilutions were prepared directly on plates using Mueller Hinton Broth (MHB) as solvent.

Preparazione della sospensione batterica: i crioceppi conservati a -80?C sono stati recuperati mediante incubazione in terreno di coltura (Brain Heart Infusion Broth, BHI) per 24-48 ore a 37 ?C seguita da fasi in terreno di coltura agar (Columbia Blood Agar). Colonie con meno di 30 ore sono sospese in MHB allo scopo di preparare una sospensione batterica con una torbidit? di 0,5 MF, contenente circa 1,5 x 10<8 >cfu/ml. Questa iniezione viene diluita in aggiunta in MHB fino al raggiungimento di una concentrazione finale di 5 x 10<5 >cfu/ml (intervallo 3-7 x 10<5 >cfu/ml). Volumi identici di questa sospensione batterica vengono aggiunti su una piastra, per ciascun pozzetto contenente diluizioni scalari di farmaco, per ottenere una concentrazione finale tra 512 e 0,25 ?g/ml. La preparazione di sospensioni batteriche nonch? la fase su lastra sono sempre state eseguite entro 30 minuti, al fine di non alterare la concentrazione della sospensione batterica. Simultaneamente, sono eseguiti il controllo della microdiluizione in brodo unicamente con solvente (al fine di escludere che l'effetto dell'inibizione della crescita possa essere dovuto al solvente della soluzione di farmaco), il controllo di crescita positivo in assenza di DMSO e farmaco, e il controllo di purezza negativo unicamente con brodo di iniezione. Di conseguenza la lastra viene incubata a 37 ?C per 24 e 48 ore in aerobi. La MIC dopo 24 ore ? considerata la concentrazione minima di farmaco in grado di inibire la crescita batterica, il che rende possibile osservare l'assenza di crescita batterica e l'assenza di torbidit?. Le stesse osservazioni sono valide per valutare la MIC dopo 48 ore. Dopo l'incubazione, un uguale volume di sospensione batterica da ciascun pozzetto viene piastrato su terreno di coltura agar e incubato per 24-48 ore a una temperatura di 37 ?C in aerobi, al fine di definire la MBC dopo l'incubazione. La MBC viene valutata come la concentrazione minima di farmaco in grado di uccidere il 99,9% della popolazione batterica iniziale. Preparation of the bacterial suspension: Cryo strains stored at -80°C were recovered by incubation in culture medium (Brain Heart Infusion Broth, BHI) for 24-48 hours at 37°C followed by phases in culture medium agar (Columbia Blood Agar). Colonies less than 30 hours old are suspended in MHB in order to prepare a bacterial suspension with a turbidity of 0.5 MF, containing approximately 1.5 x 10<8 >cfu/ml. This injection is additionally diluted in MHB to a final concentration of 5 x 10<5 >cfu/ml (range 3-7 x 10<5 >cfu/ml). Identical volumes of this bacterial suspension are added to a plate, for each well containing stepwise dilutions of drug, to obtain a final concentration between 512 and 0.25 µg/ml. The preparation of bacterial suspensions as well as? the phase on the plate were always carried out within 30 minutes, in order not to alter the concentration of the bacterial suspension. Simultaneously, the broth microdilution control with solvent only (in order to exclude that the growth inhibition effect could be due to the drug solution solvent), the positive growth control in the absence of DMSO and drug, and the negative purity control with injection broth only. Consequently the plate is incubated at 37 ?C for 24 and 48 hours in aerobes. The MIC after 24 hours? considered the minimum concentration of drug capable of inhibiting bacterial growth, which makes it possible to observe the absence of bacterial growth and the absence of turbidity. The same observations are valid for evaluating the MIC after 48 hours. After incubation, an equal volume of bacterial suspension from each well is plated on agar culture medium and incubated for 24-48 hours at 37°C in an aerobe to define the MBC after incubation. MBC is evaluated as the lowest drug concentration capable of killing 99.9% of the initial bacterial population.

Curve di uccisione temporali: valutazione del numero di sopravvissuti dopo esposizione al farmaco di 2, 6 e 24 ore. La coltura batterica in una fase di crescita esponenziale viene diluita in brodo fresco fino al raggiungimento di una concentrazione tra 10<6 >e 10<7 >cfu/ml. A partire da questa sospensione, vengono preparati il controllo in assenza di farmaco e la soluzione contenente il farmaco a una concentrazione quattro volte la MIC. Al fine di valutare la carica batterica iniziale, dopo un campionamento in corrispondenza del tempo 0, sono eseguiti altri campionamenti per contare i sopravvissuti al termine di 2, 6 e 24 ore di incubazione. Temporal killing curves: evaluation of the number of survivors after drug exposure of 2, 6 and 24 hours. The bacterial culture in an exponential growth phase is diluted in fresh broth until a concentration between 10<6> and 10<7>cfu/ml is reached. From this suspension, the no-drug control and solution containing drug at a concentration four times the MIC are prepared. In order to evaluate the initial bacterial load, after a sampling at time 0, other samplings are performed to count the survivors at the end of 2, 6 and 24 hours of incubation.

La diluizione di sospensione batterica ? realizzata a partire da campionamenti, al fine di rendere possibile la conta batterica. The dilution of bacterial suspension ? made starting from samplings, in order to make bacterial counts possible.

Ceppi batterici: il potere battericida e/o batteriostatico dei composti sintetizzati pu? essere determinato usando ceppi di riferimento standard come: Bacterial strains: the bactericidal and/or bacteriostatic power of the synthesized compounds can be determined using standard reference strains such as:

1. S. Aureus ATCC 25923 res kan, tob, res streptogramina (sgasgb, efflusso), res mupirocina (a basso livello), res trimetoprim; 1. S. Aureus ATCC 25923 res kan, tob, res streptogramin (sgasgb, efflux), res mupirocin (low level), res trimethoprim;

2. S. Aureus ceppo 1 (raccolta) mec a , res kan tob gen, res chinoloni, lincosamidi, res streptogramina (sga-sgb), costituente mlsb+sa, costituente mlsb, res mupirocina (basso livello), res trimetoprim; 2. S. Aureus strain 1 (collection) mec a , res kan tob gen, res quinolones, lincosamides, res streptogramin (sga-sgb), mlsb+sa constituent, mlsb constituent, res mupirocin (low level), res trimethoprim;

3. S. Aureus ceppo 2 (raccolta) penicillinasi acquisita, res kan tob, res streptogramina (sga-sgb, efflusso), res mupirocina (basso livello), res trimetoprim; 3. S. Aureus strain 2 (collection) acquired penicillinase, res kan tob, res streptogramin (sga-sgb, efflux), res mupirocin (low level), res trimethoprim;

4. Enterococcus faecalis ATCC 51299 (str gen res a livello elevato, mlsb res, simil van b res); 4. Enterococcus faecalis ATCC 51299 (str gen res at high level, mlsb res, similar van b res);

5. Enterococcus faecalis ceppo 1 (raccolta) (str+ kan res a livello elevato str res a livello elevato tetraciclina res); 5. Enterococcus faecalis strain 1 (collection) (str+ kan res at high level str res at high level tetracycline res);

6. Enterococcus faecalis ceppo 2 (raccolta) (kan res a livello elevato); 6. Enterococcus faecalis strain 2 (collection) (kan res at high level);

7. E. coli della Raccolta: RESISTENTE ad ampicillina, amox ac clav, ampicillinr sulbactam, cefalexina, cefuroxima, cefuroxima axetil, cefixima, cefpodoxima, cefotaxima, ceftazidima, ceftriaxone, netilmicina, tobramicina, ciprofloxacina, trim/sulfametox, esbl pos, SENSIBILE a meropenem e gentamicina, INTERMEDIO rispetto ad amikacina; 7. E. coli from Collection: RESISTANT to ampicillin, amox ac clav, ampicillinr sulbactam, cefalexin, cefuroxime, cefuroxime axetil, cefixime, cefpodoxime, cefotaxime, ceftazidime, ceftriaxone, netilmicin, tobramycin, ciprofloxacin, trim/sulfamethox, esbl pos, SENSITIVE to meropenem and gentamicin, INTERMEDIATE to amikacin;

8. 8. A. baumannii della raccolta: RESISTENTE a cefotaxima, ertapenem, imipenem, meropenem, gentamicina, ciprofloxacina, fosfomicina, nitrofurantoina, trim/sulf; SENSIBILE a colistina, INTERMEDIO rispetto ad amikacina; 9. P. Aeruginosa della raccolta: RESISTENTE ad amox ac clav, cefotaxima, ertapenem, tigeciclina, fosfomicina, trimetoprim/slf SENSIBILE a piperacillina/tazobactam, ceftazidima, cefepima, imipenem, meropenem, amikacina, gentamicina, ciprofloxacina, colistina. 8. 8. A. baumannii from the collection: RESISTANT to cefotaxime, ertapenem, imipenem, meropenem, gentamicin, ciprofloxacin, phosphomycin, nitrofurantoin, trim/sulf; SENSITIVE to colistin, INTERMEDIATE to amikacin; 9. P. Aeruginosa from the collection: RESISTANT to amox ac clav, cefotaxime, ertapenem, tigecycline, phosphomycin, trimethoprim/slf SENSITIVE to piperacillin/tazobactam, ceftazidime, cefepime, imipenem, meropenem, amikacin, gentamicin, ciprofloxacin, colistin.

I risultati dell'attivit? antibatterica sono riportati nella seguente tabella 1. The results of the activity? antibacterial are shown in the following table 1.

Tabella 1 Table 1

in cui* il valore di MIC si legge a 48 ore where* the MIC value is read at 48 hours

Claims (4)

RIVENDICAZIONI 1) Composti di formula (II) CLAIMS 1) Compounds of formula (II) in cui B ? C3-C12 cicloalchile, o fenile, o un eterociclo C3-C13 contenente S, N, O R1 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo, C3-C12 cicloalchile sostituito facoltativamente con C1-C4 alchile o OH, C1-C3 arilalchile, fenile, sostituito facoltativamente con C1-c4 alchile, lineare o ramificato, l?eterociclo contenendo almeno un eteroatomo selezionato dal gruppo costituito da: N, O, S, sostituito facoltativamente con OH, NH2 R2 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo, (CH2)n-R7, (CH2)nO(CH2)mO-(CH2)p-R8, (CH2O)nCH3, CO-R8, (CH2)n-R10, D-mannosile, glucuronato, (SO2)OH R7 ? OH, COOH, CONHO-R8, (CH2)nO(CH2)mO-R8, CN, NH2, R8 ? H, C1-C12 alchile lineare o ramificato saturo o insaturo R10 ? NH2, eterociclo contenente N, ammidina, guanidina R3 ? H, OH, CHO o R2 e R3 sono legati a formare un ciclo comprendente almeno un atomo di O e/o N R4 ? H R5 ? H, OH, C1-C5 alchile lineare o ramificato saturo o insaturo, (CH2)-R11, CHO, CH=NOH, CH=NO-R14, CH=NO-(CH2)n-COOH, CH=NO-(CH2)n-NH2, (CH2)nNHCO-R14, (CH2)nNHCO-Arile, (CH2)-R15 R11 ? OH, NH2, N-R12R13, R12 e R13, uguali o diversi sono H, C1-C5 alchile lineare o ramificato saturo o insaturo, C(=NH)NH2 R14 ? H, C1-C5 alchile lineare o ramificato saturo o insaturo, C3-C12 cicloalchile, arile, C1-C3 arilalchile, Facoltativamente, R4 e R5 possono essere uniti insieme per formare CH=CH o CO o O o S o SO o SO2 R6 ? CX=CYCOOH, CX=CYCN, CX=CYCH=NOH, CX=CYCOO-R14, CX=CYCONH2, CX=CY-CONH-R14, CX=CYCONHOH, CX=CYtetrazolile, CX=CYCH2OH, CX=CY-P(=O)(O-R14)2, CX=CYCOOglicosile, X ? H, C2-C4 alchile lineare o ramificato, alogeno, CN Y ? H, C2-C4 alchile lineare o ramificato, alogeno, CN n ? un numero intero da 1 a 15 m ? un numero intero da 1 a 15 p ? un numero intero da 1 a 15 a condizione che quando R1 ? adamantile e R5 ? idrogeno, R6 non sia CX=CY-COOH o CX=CY-COOCH3 o CX=CY-COOCH2CH3 o un suo sale farmaceuticamente accettabile. in which B ? C3-C12 cycloalkyl, or phenyl, or a C3-C13 heterocycle containing S, N, O R1 ? H, C1-C12 linear or branched saturated or unsaturated alkyl, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl, linear or branched, the heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S, optionally replaced by OH, NH2 R2 ? H, C1-C12 saturated or unsaturated linear or branched alkyl, (CH2)n-R7, (CH2)nO(CH2)mO-(CH2)p-R8, (CH2O)nCH3, CO-R8, (CH2)n- R10, D-mannosil, glucuronate, (SO2)OH R7 ? OH, COOH, CONHO-R8, (CH2)nO(CH2)mO-R8, CN, NH2, R8 ? H, C1-C12 linear or branched saturated or unsaturated alkyl R10 ? NH2, N-containing heterocycle, amidine, guanidine R3 ? H, OH, CHO or R2 and R3 are bonded to form a cycle comprising at least one O and/or N atom R4 ? h R5 ? H, OH, C1-C5 saturated or unsaturated linear or branched alkyl, (CH2)-R11, CHO, CH=NOH, CH=NO-R14, CH=NO-(CH2)n-COOH, CH=NO-(CH2 )n-NH2, (CH2)nNHCO-R14, (CH2)nNHCO-Aryl, (CH2)-R15 R11 ? OH, NH2, N-R12R13, R12 and R13, equal or different are H, C1-C5 saturated or unsaturated linear or branched alkyl, C(=NH)NH2 R14 ? H, C1-C5 linear or branched saturated or unsaturated alkyl, C3-C12 cycloalkyl, aryl, C1-C3 arylalkyl, Optionally, R4 and R5 can be joined together to form CH=CH or CO or O or S or SO or SO2 R6 ? CX=CYCOOH, CX=CYCN, CX=CYCH=NOH, CX=CYCOO-R14, CX=CYCONH2, CX=CY-CONH-R14, CX=CYCONHOH, CX=CYtetrazolyl, CX=CYCH2OH, CX=CY-P( =O)(O-R14)2, CX=CYCOOglycosyl, X ? H, C2-C4 straight or branched alkyl, halogen, CN Y ? H, C2-C4 straight or branched alkyl, halogen, CN n ? an integer from 1 to 15 m ? an integer from 1 to 15 p ? an integer from 1 to 15 provided that when R1 ? adamantyl and R5 ? hydrogen, R6 is not CX=CY-COOH or CX=CY-COOCH3 or CX=CY-COOCH2CH3 or a pharmaceutically acceptable salt thereof. 2) Composti della rivendicazione 1 per uso come medicinale. 2) Compounds of claim 1 for use as a medicine. 3) Composti della rivendicazione 1 per uso come antimicrobici e/o antibatterici e/o battericidi. 3. Compounds of claim 1 for use as antimicrobials and/or antibacterials and/or bactericides. 4) Composizione farmaceutica comprendente almeno un composto della rivendicazione 1 come principio attivo e adiuvanti e/o veicoli e/o eccipienti farmaceuticamente accettabili. 4) Pharmaceutical composition comprising at least one compound of claim 1 as active ingredient and pharmaceutically acceptable adjuvants and/or carriers and/or excipients.
IT102020000029906A 2020-12-04 2020-12-04 PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE. IT202000029906A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
IT102020000029906A IT202000029906A1 (en) 2020-12-04 2020-12-04 PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IT102020000029906A IT202000029906A1 (en) 2020-12-04 2020-12-04 PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE.

Publications (1)

Publication Number Publication Date
IT202000029906A1 true IT202000029906A1 (en) 2022-06-04

Family

ID=74759307

Family Applications (1)

Application Number Title Priority Date Filing Date
IT102020000029906A IT202000029906A1 (en) 2020-12-04 2020-12-04 PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE.

Country Status (1)

Country Link
IT (1) IT202000029906A1 (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001132A1 (en) 1996-07-08 1998-01-15 Centre International De Recherches Dermatologiques Galderma Apoptosis inducing adamantyl derivatives and their usage as anti-cancer agents
WO2001056563A1 (en) 2000-02-04 2001-08-09 Galderma Research & Development, S.N.C. Adamantyl derivatives as anti-cancer agents
WO2001056554A2 (en) 2000-01-31 2001-08-09 Galderma Research & Development Use of retinoid-type compounds as antibacterial agents
WO2003011808A1 (en) * 2001-07-31 2003-02-13 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Retinoid derivatives with antiangiogenic, antitumoral and proapoptotic activities
WO2017053778A1 (en) 2015-09-25 2017-03-30 Fuchs Helen Burgwyn Antibacterial and antifungal compounds
EP3301085A1 (en) * 2016-09-29 2018-04-04 Biogem S.Ca.R.L. Retinoid derivatives with antitumor activity
WO2018213609A1 (en) 2017-05-17 2018-11-22 Ausubel Frederick M Antibiotic compounds

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998001132A1 (en) 1996-07-08 1998-01-15 Centre International De Recherches Dermatologiques Galderma Apoptosis inducing adamantyl derivatives and their usage as anti-cancer agents
WO2001056554A2 (en) 2000-01-31 2001-08-09 Galderma Research & Development Use of retinoid-type compounds as antibacterial agents
WO2001056563A1 (en) 2000-02-04 2001-08-09 Galderma Research & Development, S.N.C. Adamantyl derivatives as anti-cancer agents
WO2003011808A1 (en) * 2001-07-31 2003-02-13 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Retinoid derivatives with antiangiogenic, antitumoral and proapoptotic activities
WO2017053778A1 (en) 2015-09-25 2017-03-30 Fuchs Helen Burgwyn Antibacterial and antifungal compounds
EP3301085A1 (en) * 2016-09-29 2018-04-04 Biogem S.Ca.R.L. Retinoid derivatives with antitumor activity
WO2018213609A1 (en) 2017-05-17 2018-11-22 Ausubel Frederick M Antibiotic compounds

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
CINCINELLI RAFFAELLA ET AL: "Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 48, no. 15, 1 July 2005 (2005-07-01), pages 4931 - 4946, XP009100315, ISSN: 0022-2623, DOI: 10.1021/JM049440H *
CINTINELLI ET AL., MED. CHEM., vol. 48, 2005, pages 4931 - 4946
FRANKE A ET AL: "Synthetische Juvenilhormone. 1. p-Substituierte beta-Methyl-Zimtsäurederivate", HELVETICA CHIMICA ACTA, VERLAG HELVETICA CHIMICA ACTA, vol. 58, no. 1, 29 January 1975 (1975-01-29), pages 268 - 278, XP002142990, ISSN: 0018-019X, DOI: 10.1002/HLCA.19750580133 *
GARATTINI E ET AL: "ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 1103, no. 1, 1 January 2004 (2004-01-01), pages 194 - 207, XP002498487, ISSN: 0006-4971, [retrieved on 20030904], DOI: 10.1182/BLOOD-2003-05-1577 *
H.W. BOUCHER ET AL., CLIN. INFECT. DIS., vol. 56, 2013, pages 1685 - 1694
JOCHEN C. DAAB ET AL: "Total Syntheses of the Alkaloids Ipalbidinium and Clathryimine B", MONATSHEFTE FÜR CHEMIE / CHEMICAL MONTHLY, vol. 134, no. 4, 1 March 2003 (2003-03-01), Vienna, pages 573 - 583, XP055666467, ISSN: 0026-9247, DOI: 10.1007/s00706-002-0540-5 *
R. CINTINELLI ET AL., BIOORG. MED. CHEM., vol. 15, 2007, pages 4863 - 4875
R. CINTINELLI ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, 2005, pages 4931 - 4946
WOOSEONG KIM ET AL.: "A new class of synthetic retinoid antibiotics effective against bacterial persisters", NATURE, vol. 556, 2018, pages 103 - 107
XIA ZEBIN ET AL: "Heteroatom-Substituted Analogues of Orphan Nuclear Receptor Small Heterodimer Partner Ligand and Apoptosis Inducer ( E )-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic Acid", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 11, 9 June 2011 (2011-06-09), US, pages 3793 - 3816, XP055794238, ISSN: 0022-2623, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/jm200051z> DOI: 10.1021/jm200051z *
ZEBIN XIA ET AL: "Analogues of Orphan Nuclear Receptor Small Heterodimer Partner Ligand and Apoptosis Inducer ( E )-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic Acid. 2. Impact of 3-Chloro Group Replacement on Inhibition of Proliferation and Induction of Apoptosis of Leukemia and Cancer Cell Lines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 1, 2 December 2011 (2011-12-02), US, pages 233 - 249, XP055351225, ISSN: 0022-2623, DOI: 10.1021/jm2011436 *

Similar Documents

Publication Publication Date Title
US8314268B2 (en) 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases
TWI519508B (en) Antibacterial agents
BG106494A (en) Novel derivatives of dicarboxylic acid having pharmaceutical properties
EA012136B1 (en) Substituted tetracycline compounds, pharmaceutical composition and method of treatment tetracycline compound-responsive states in a subject
FR2651497A1 (en) NOVEL BIVALENT METAL SALTS OF N, N-DI (CARBOXYMETHYL) AMINO-2-CYANO-3-CARBOXYMETHYL-CARBOXY-5 THIOPHENE ACID, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME.
IT201900003343A1 (en) Phenolic derivatives for use as antimicrobials, antibacterials, bactericides
WO2004048309A1 (en) Vitamin d receptor modulators
EP1687258A2 (en) Vitamin d receptor modulators
CA3090833A1 (en) Compound acting as antibiotics
IT202000029906A1 (en) PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE.
IT202000029882A1 (en) PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE
IT202000029912A1 (en) PHENOLIC DERIVATIVES FOR USE AS ANTIMICROBIAL, ANTIBACTERIAL, BACTERICIDE
IL183655A (en) Vitamin d receptor modulators, pharmaceutical formulations comprising them and use thereof in the manufacture of medicaments for treating osteoporosis
SK55093A3 (en) Cyclopentane-beta-amino acids and cyclopentene-beta-amino acids
EP1692123A1 (en) Phenyl-furan compounds as vitamin d receptor modulators
ITMI991330A1 (en) PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE FUNGICIDES CONSTITUTED BY N-ACYL DERIVED FROM METHYL N- (2,6-DIMETHYLPHENYL) -D-ALANINATE
AU2003294861B2 (en) Indenoncarboxylic acids derivatives and their use for the treatment of and preventing diabetes and dyslipidaemia
WO2004073705A1 (en) 1-phenyl-2- monoalkyl carboxylic acid derivatives for the treatment of neurodegenerative diseases
US5929098A (en) Fungicidically active N-acetonylbenzamide compounds
CZ65098A3 (en) Novel benzoxazindione derivatives, process of their preparation and their use
ZA200506614B (en) 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases
CA2863221C (en) Compounds having antibacterial activity, process for their preparation and pharmaceutical compositions comprising them
Curran et al. The Total Synthesis of Nocardicin A
Peretto et al. Raveglia et al.(45) Date of Patent: Nov. 20, 2012