Patent Application
20220281835
The present invention relates to the field of pharmaceutical compounds, in particular phenol derivatives, also for use as antimicrobial, antibacterial, bactericide.
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:
exhibiting high killing rates, synergism with gentamicin, and a low probability of resistance selection, in a C. elegans-MRSA killing assay against MRSA strain MW2 and activity against a panel of clinical S. aureus and Enterococcus faecium strains, but not against Gram-negative species.
WO9801132 and WO0156563 disclose adamantyl containing retinoid compounds used as anticancer agents.
International patent application N. WO2017053778 specifically discloses the following compounds: 6-(4-hydroxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic 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-yl)-2-propenoic acid, 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-glucanpyranosato-S-(triethyl-phosphine)gold,
useful in treating bacterial infections such as a bacterial infection.
International patent application N. WO2018213609 discloses the preparation of the following compounds:
and their antibacterial activity in particular against Cutibacterium (Propionibacterium) acnes bacteria.
International patent application, publication n. WO01/56554 discloses retinoid-type molecules for preparing compositions for preventive or curative treatment of bacterial colonisation, deterioration in pathological conditions caused by said colonisation and secondary skin infections induced by said bacteria and more particularly by the Staphylococcus aureus. WO01/56554 Specifically discloses the following compounds:
Also WO2018213609 and EP3301085 disclose retinoid-type antibacterial compounds.
Bacterial resistance to antimicrobial drugs might become one of the biggest threats to human health in our times. The increasing occurrence of infections with multi-drug-resistant pathogens is associated with high mortality and morbidity (H. W. Boucher et al. Clin. Infect. Dis., 2013, 56, 1685-1694) and the prevailing lack of new efficient antimicrobial drugs for treatment of these infections has led to serious concerns.
Bacterial resistance includes the modification or overexpression of the antibiotics target, the decrease of the intracellular antibiotic concentration, by either expression of efflux systems actively transporting the drug out of the cell or by mechanism that reduce their influx, and the expression of enzymes able to deactivate the antibiotic.
It is therefore clear that the need for novel antimicrobial drugs is a continuous one in order to counteract the development of bacterial resistance.
The technical problem is solved by providing the compounds of formula (I)
wherein
A is absent or is CW═CZ
B is C3-C12 cycloakyl, or phenyl, or a C3-C13 heterocycle containing S, N, O
R1 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl, linear or branched, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl linear or branched, or with a C3-C13 heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S or C3-C13 and optionally substituted with OH, NH2
R2 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl, linear or branched, (CH2)n—R7, (CH2)nO(CH2)mO—(CH2)p—R8, (CH2O)n CH3, CO—R8, CO—R9, (CH2)n—R10, monosaccharide residue, glycosyl, glucuronate, (SO2) OH
R7 is OH, COOH, CONHO—R8, (CH2)nO(CH2)mO—R8, CN, NH2,
R8 is H, C1-C18 alkyl, C1-C18 alkenyl, C1-C18 alkynyl, linear or branched, optionally substituted with NH2, cycloalkyl optionally substituted with NH2
R9 is aryl, C1-C5 alkyl-aryl,
R10 is a heterocycle containing at least one N, amidine, guanidine
R3 is H, OH or (CH2)nNH2, (CH2)nOH, CHO, NHCO—R18, NHCONH—R18 or
R2 and R3 are linked to form a cycle with the oxygen atom on the phenyl ring, said cycle comprising at least one atom of O and/or N
R4 is H
R5 is H, CH3, OH, C1-C5 alkyl C1-C5 alkenyl, C1-C5 alkynyl, linear or branched, (CH2)n—R11, CHO, CH═NOH, CH═NO—R14, CH═NO—(CH2)n—COOH, CH═NO—(CH2)n—NH2, CH═NO—(CH2)n—OH, (CH2)nNHCO—R14, (CH2)n—R15, CH═NO—R14, CH2OH, COCH3, COOH, (CH2)nNH—R17, (CH2)nN(R17)2,
R11 is OH, NH2, N—R12R13,
R12 and R13, the same or different are, H, C1-C5 alkyl C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C(═NH)NH2
R15 is an heterocycle containing N, O, S
R6 is CH2OH, CHO, CH═NOH, COOH, CONHOH, (CH2)nCOOH, (CH2)nCONHOH, (CH2)nNHOH, (CH2)nCH═NOH, CX═CY—CHO═CHCOOH, ═CHCOOR14, CX═CYCOOH, CX═CYCN, CX═CY-tetrazolyl, CX═CYCOO—R14, CX═CYCONH2, CX═CY—CONH—R14, CX═CYCONHOH, CX═CYCH2OH, CX═CY—P(═O) (O—R14)2, C≡CCOOH C≡C-tetrazolyl, C≡CCH2OH, C≡CC(alkyl)2OH, C≡CCOO—R14, C≡CCONH2, C≡CONH—R14, C≡CCONH-aryl, C≡CCONHOH, COO-glycosyl, CX═CYCOO-glycosyl, C≡CCOO-glycosyl,
X and Y, the same or different, are H, C2-C4 alkyl linear or branched, halogen, CN, or
X and Y together form an C3-C6 cycloalkyl or a C3-C6 heterocycle containing N, O, S
R14 is C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl, linear or branched, C3-C12 cycloakyl, aryl, C1-C3 arylalkyl, C(═NH) NH2
R17 is C2-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl linear or branched
R18 is C2-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl linear or branched
W and Z, the same or different, are H, C2-C4 alkyl linear or branched, halogen, CN,
n is an integer from 1 to 15
m is an integer from 1 to 15
p is an integer from 1 to 15
with the proviso that
when A is CW═CZ R2 is hydrogen and R1 and R5 are not hydrogen
optionally when A is CW═CZ and B is phenyl, A can form a heterocyclic ring containing O, N, S with the phenolic ring
optionally when A is absent R4 and R5 can be joined together to form CH═CH, CO, O, S, SO, SO2
or a pharmaceutically acceptable salt thereof, for use as antimicrobial and/or antibacterial and/or bactericide.
With the intent of solving the technical problem new compounds have been synthesized.
Another object of the present invention are compounds of formula (II) (named as compounds of class A)
wherein
B is C3-C12 cycloakyl, or phenyl, or a C3-C13 heterocycle containing S, N, O
R1 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl, linear or branched, heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S, optionally substituted with OH, NH2
R2 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched, (CH2)n—R7, (CH2)nO(CH2)mO—(CH2)p-R8, (CH2O)n CH3, CO—R8, (CH2)n—R10, D-mannosyl, glucuronate, (SO2) OH
R7 is OH, COOH, CONHO—R8, (CH2)nO(CH2)mO—R8, CN, NH2,
R8 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched
R10 is NH2, N-containing heterocycle, amidine, guanidine
R3 is H, OH, CHO or
R2 and R3 are linked to form a cycle comprising at least one atom of O and/or N
R4 is H
R5 is CH═NO—R14, CH═NO—(CH2)n—NH2, (CH2)nNHCO—R14,
R14 is H, C1-C5 alkyl C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C3-C12 cycloakyl, aryl, C1-C3 arylalkyl, (CH2)n—COOH
R4 and R5 can be joined together to form CH═CH or CO or O or S or SO or SO2
R6 is ═CHCOOH, (CH2)nCH═NOH, ═CHCOOR16, CX═CYCOOH, CX═CYCN, CX═CYCOO—R16, CX═CY-tetrazolyl, CX═CYCONH2, CX═CY—CONH—R16, CX═CYCONH-aryl, CX═CYCONHOH, CX═CYCH2OH, C≡CCOOH, C≡CCH2OH, C≡CCOO—R16, C≡CCONH2, C≡CONH—R16, C≡CCONH-aryl, C≡CCONHOH, CX═CYCOO glycosyl, C≡CCOO glycosyl,
R16 is H, C2-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl linear or branched, C3-C12 cycloalkyl, aryl, C1-C3 arylalkyl, (CH2)n—COOH
X and Y, the same or different, are H, C2-C4 alkyl linear or branched, halogen, CN,
n is an integer from 1 to 8
with the proviso that when R14 is H, CH3, tert-butyl or (CH2)COOH, R6 is not CH═CH—COOH
or a pharmaceutically acceptable salt thereof.
Another object of the present invention are compound of formula (II) (named compounds of class B)
wherein B is C3-C12 cycloalkyl, or phenyl, or a C3-C13 heterocycle containing S, N, O
R1 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl linear or branched, heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S, optionally substituted with OH, NH2
R2 is C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched, (CH2)n—R7, (CH2)nO(CH2)mO—(CH2)p-R8, (CH2O)nCH3, CO—R8, (CH2)n—R10, D-mannosyl, glucuronate, (SO2) OH
R7 is OH, COOH, CONHO—R8, (CH2)nO(CH2)mO—R8, CN, NH2,
R8 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched
R10 is NH2, N-containing heterocycle, amidine, guanidine
R3 is H, OH CHO or
R2 and R3 are linked to form a cycle wherein said cycle comprises at least one atom of O and/or N
R4 is H
R5 is H, OH, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, (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 is OH, NH2, N—R12R13,
R12 and R13, the same or different are, H, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C(═NH)NH2
R15 is an heterocycle containing N, O, S
R6 is C≡CCOOH, C≡CCH2OH, C≡C—CH═NOH, C≡C—C(R17)2OH, C≡CCOO—R14, C≡CCONH2, C≡C(CH3)2OH, C≡CONH—R14, C≡CCONHOH, C≡C-tetrazolyl C≡CCOO glycosyl
R14 is C2-C5 alkyl C2-C5 alkenyl, C2-C5 alkynyl linear or branched, C3-C12 cycloakyl, aryl, C1-C3 arylalkyl
R17 is C2-C5 alkyl linear or branched saturated or unsaturated
n is an integer from 1 to 15
m is an integer from 1 to 15
p is an integer from 1 to 15
with the proviso that when R6 is C≡CCOOH or C≡CCOOCH3 and R1 is H or adamantly and R2 is H or CH3, R3 and R5 are not both H
or a pharmaceutically acceptable salt thereof.
Another object of the present invention are compounds of formula (II) (named compounds of class C):
wherein
B is C3-C12 cycloakyl, or phenyl, or a C3-C13 heterocycle containing S, N, O
R1 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl, linear or branched, heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S, optionally substituted with OH, NH2
R2 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched, (CH2)n—R7, (CH2)nO(CH2)mO—(CH2)p-R8, (CH2O)nCH3, CO—R8, (CH2)n—R10, D-mannosyl, glucuronate, (SO2) OH
R7 is OH, COOH, CONHO—R8, (CH2)nO(CH2)mO—R8, CN, NH2,
R8 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched
R10 is NH2, N-containing heterocycle, amidine, guanidine
R3 is H, OH CHO or
R2 and R3 are linked to form a cycle comprising at least one atom of O and/or N
R4 is H
R5 is H, OH, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, (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 is OH, NH2, N—R12R13,
R12 and R13, the same or different are, H, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C(═NH)NH2
R14 is H, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C3-C12 cycloakyl, 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 is 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═CYCOO glycosyl,
X is H, C2-C4 alkyl linear or branched, halogen, CN
Y is H, C2-C4 alkyl linear or branched, halogen, CN
n is an integer from 1 to 15
m is an integer from 1 to 15
p is an integer from 1 to 15
with the proviso that when R1 is adamantyl and R5 is hydrogen, R6 is not CX═CY—COOH or CX═CY—COOCH3 or CX═CY—COOCH2CH3
or a pharmaceutically acceptable salt thereof.
Are also object of the present invention, compounds belonging to groups A, B and C for use as a medicament and compounds belonging to groups A, B and C for use as antimicrobial and/or antibacterial and/or bactericide.
Object of the present invention are also the method used for the preparation of compounds belonging to groups A, B and C.
Object of the invention are pharmaceutical compositions comprising at least one compound of formula (I) and/or (II) belonging to groups A, B and C as active ingredient and pharmaceutically acceptable adjuvants and/or vehicles and/or excipients.
Within the meaning of the present invention antibacterial or bactericide means any compounds able to kill bacteria or suppresses their growth or their ability to reproduce.
Within the meaning of the present invention bacteria can be gram-positive bacteria and/or gram-negative bacteria, such as Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Streptococcus thermophilus.
Within the meaning of the present invention antimicrobial means any compound being germicides, antibiotics, antibacterials, antivirals, antifungals, antiprotozoals and antiparasites.
Within the meaning of the present invention alkyl means to linear or branched alkyl groups having from 1 to 18 carbon atoms or from 1 to 12 carbon atoms or from 1 to 5 carbon atoms or from 1 to 4 carbon atoms or from 2 to 5 carbon atoms.
Within the meaning of the present invention cycloalkyl means saturated carbocyclic group of 3 to 12 carbon atoms or of 3 to 6 carbon atoms, optionally substituted with C1-C4 alkyl or OH or NH2. An aromatic group is not intended. The cycloalkyl group can comprise a single ring or multiple condensed rings.
Within the meaning of the present invention heterocycle means a saturated or partially unsaturated, but not aromatic, C3-C13 or C3-C12 ring or multiple condensed ring containing at least one heteroatom selected from the group consisting of N, O, S and optionally substituted with OH, NH2.
Within the meaning of the present invention aryl means aromatic ring, for example phenyl, optionally substituted with C1-C3 alkyl or C1-C4 alkyl, OH, NH2.
Within the meaning of the present invention monosaccharide residue means simple sugar of general formula CnH2nOn such as triose, tetrose, pentose, hexose, heptose etc.
Within the meaning of the present invention glycosyl means a radical from a saccharide by removal of hydroxyl group.
The compounds of formula (I):
wherein
A is absent or is CW═CZ
B is C3-C12 cycloakyl, or phenyl, or a C3-C13 heterocycle containing S, N, O
R1 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl linear or branched, or with a C3-C13 heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S or C3-C13 optionally substituted with OH, NH2
R2 is H, C1-C12 alkyl, C1-C12 alkenyl, C1-C12 alkynyl linear or branched, (CH2)n—R7, (CH2)nO(CH2)mO—(CH2)p—R8, (CH2O)n CH3, CO—R8, CO—R9, (CH2)n—R10, monosaccharide residue, glycosyl, glucuronate, (SO2) OH
R7 is OH, COOH, CONHO—R8, (CH2)nO(CH2)mO—R8, CN, NH2,
R8 is H, C1-C18 alkyl, C1-C18 alkenyl, C1-C18 alkynyl linear or branched optionally substituted with NH2, cycloalkyl optionally substituted with NH2
R9 is aryl, C1-C5 alkyl-aryl,
R10 is a heterocycle containing at least one N, amidine, guanidine
R3 is H, OH or (CH2), NH2, (CH2)nOH, CHO, NHCO—R18, NHCONH—R18 or
R2 and R3 are linked to form a cycle with the oxygen atom on the phenyl ring, said cycle comprising at least one atom of O and/or N
R4 is H
R5 is H, CH3, OH, C1-C5 alkyl C1-C5 alkenyl, C1-C5 alkynyl linear or branched, (CH2)n—R11, CHO, CH═NOH, CH═NO—R14, CH═NO—(CH2)n—COOH, CH═NO—(CH2)n—NH2, CH═NO—(CH2)n—OH, (CH2)nNHCO—R14, (CH2)n—R15, CH═NO—R14, CH2OH, COCH3, COOH, (CH2)nNH—R17, (CH2)nN(R17) 2,
R11 is OH, NH2, N—R12R13,
R12 and R13, the same or different are, H, C1-C5 alkyl C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C(═NH)NH2
R15 is an heterocycle containing N, O, S
R6 is CH2OH, CHO, CH═NOH, COOH, CONHOH, (CH2)nCOOH, (CH2)nCONHOH, (CH2)nNHOH, (CH2)nCH═NOH, CX═CY—CHO, ═CHCOOH, ═CHCOOR14, CX═CYCOOH, CX═CYCN, CX═CY-tetrazolyl, CX═CYCOO—R14, CX═CYCONH2, CX═CY—CONH—R14, CX═CYCONHOH, CX═CYCH2OH, CX═CY—P(═O) (O—R14)2, C≡CCOOH, C≡C-tetrazolyl, C≡CCH2OH, C≡CC(alkyl)2OH, C≡CCOO—R14, C≡CCONH2, C≡CONH—R14, C≡CCONH-aryl, C≡CCONHOH, COO-glycosyl, CX═CYCOO-glycosyl, C≡CCOO-glycosyl,
X and Y, the same or different, are H, C2-C4 alkyl linear or branched, halogen, CN, or
X and Y together form an C3-C6 cycloalkyl or a C3-C6 heterocycle containing N, O, S
R14 is C1-C12 alkyl linear or branched saturated or unsaturated, C3-C12 cycloakyl, aryl, C1-C3 arylalkyl, C(═NH) NH2
R17 is C2-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl linear or branched
R18 is C2-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl linear or branched, aryl
W and Z, the same or different, are H, C2-C4 alkyl linear or branched, halogen, CN,
n is an integer from 1 to 15
m is an integer from 1 to 15
p is an integer from 1 to 15
with the proviso that
when A is CX═CY R2 is hydrogen and R1 and R5 are not hydrogen
optionally when A is CX═CY and B is phenyl, A can form a heterocyclic ring containing O, N, S with the phenolic ring
optionally when A is absent R4 and R5 can be joined together to form CH═CH, CO, O, S, SO, SO2
or a pharmaceutically acceptable salt thereof, for use as antimicrobial and/or antibacterial and/or bactericide.
Preferably A is absent.
Preferably B is selected from the group consisting of phenyl, dihydroindene, dihydronaphthalene, tetrahydronaphtalene, thiophene, indole, benzothiophene, benzofuran.
Preferably R1 is C6-C12 cycloalkyl, optionally substituted with C1-C4 alkyl or OH.
More preferably R1 is selected from the group consisting of 1-methyl-cyclododecane, 1-methyl-cyclohexane, phenyl.
Preferably R1 is tert-butyl.
Preferably R1 is adamantyl.
Preferably B is phenyl.
Preferably R2 is H.
Preferably R3 is H, OH, CH2NH2, CHO Preferably R4 is H.
Preferably R5 is H, CH3, (CH2)nNH2, CH═NO—R14 CH2OH, COCH3, COOH, COH, CH2NHCO-Aryl, (CH2)nNH—R17, (CH2)nN(R17)2, CHO, CH═NOH, (CH2)nNHCO—R17, (CH2)nNHCO Aryl, (CH2)n—R15,
Preferably R6 is C≡CCOOH, C≡CCH2OH, C≡CCOO-alkyl, C≡CCONH2, C≡CONH-alkyl, C≡CCONH-aryl, CX≡CYCONHOH, CX═CYCOOH, CX═CYCH2OH, CH═CH—P(═O) (O—R14)2, CH═C(CH3)COOH, C(CH3)═CHCOOH, CH═CHCN, CH═CH—CH═NOH.
Preferably when X and Y, the same or different are halogen are selected from the group consisting of: F, Cl, Br, I.
More preferably R6 is C≡CCOOH, CH═CH—P(═O) (O—R14)2, CH═C(CH3) COOH, C(CH3)═CHCOOH, CH═CYCOOH where Y is F, Cl, Br, I, C≡CCOOH, CH═CHCN, CH═CH—CH═NOH.
More preferably when A is absent, R1 is adamantyl, R2 is H or methyl, B is phenyl, R5 is H, R6 is, C≡CCH2OH, C≡CCONH2, C≡CONH alkyl, C≡CCONH aryl, CX≡CYCONHOH.
More preferably when A is absent, R1 is adamantyl, R2 is H, B is phenyl, R5 is H, R6 is CX═CYCH2OH, X and Y, the same or different, are, C1—C alkyl linear or branched, halogen, CN.
More preferably when A is absent, R1 is adamantyl, R2 is H, B is phenyl, R5 is (CH2)nNH2, (CH2)nNHR17, (CH2)nN(R17)2, CHO, CH═NOH, CH═NOR17, (CH2)nNHCOR17, (CH2)nNHCO Aryl, (CH2)n—R15, R15 is an heterocycle containing N, R6 is CX═CYCOOH or CX═CYCH2OH, X is H and Y is C1—C alkyl linear or branched, halogen, CN.
Preferably are antibacterial and/or bactericide against S. Aureus, Enterococcus faecalis, E. coli, S. thermophiles.
Preferably the compounds of formula (I) are selected from the group consisting of:
New synthesised compounds belonging to group A are of formula (II)
wherein
B is C3-C12 cycloalkyl, or phenyl, or a C3-C13 heterocycle containing S, N, O
R1 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl, linear or branched, heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S, optionally substituted with OH, NH2
R2 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched, (CH2)n—R7, (CH2)nO(CH2)mO—(CH2)p—R8, (CH2O)n CH3, CO—R8, (CH2)n—R10, D-mannosyl, glucuronate, (SO2) OH
R7 is OH, COOH, CONHO—R8, (CH2)nO(CH2)mO—R8, CN, NH2,
R8 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched
R10 is NH2, N-containing heterocycle, amidine, guanidine
R3 is H, OH, CHO or
R2 and R3 are linked to form a cycle comprising at least one atom of O and/or N
R4 is H
R5 is CH═NO—R14, CH═NO—(CH2)n—NH2, (CH2)nNHCO—R14,
R14 is H, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C3-C12 cycloakyl, aryl, C1-C3 arylalkyl, (CH2)n—COOH
R4 and R5 can be joined together to form CH═CH or CO or O or S or SO or SO2
R6 is ═CHCOOH, (CH2)nCH═NOH, ═CHCOOR16, CX═CYCOOH, CX═CYCN, CX═CYCOO—R16, CX═CY-tetrazolyl, CX═CYCONH2, CX═CY—CONH—R16, CX═CYCONH-aryl, CX≡CYCONHOH, CX═CYCH2OH, C≡CCOOH, C≡CCH2OH, C≡CCOO—R16, C≡CCONH2, C≡CONH—R16, C≡CCONH-aryl, C≡CCONHOH, CX═CYCOO glycosyl, C≡CCOO glycosyl,
R16 is H, C2-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl linear or branched, C3-C12 cycloakyl, aryl, C1-C3 arylalkyl, (CH2)n—COOH
X and Y, the same or different, are H, C2-C4 alkyl linear or branched, halogen, CN,
n is an integer from 1 to 8
with the proviso that when R14 is H, CH3, tert-butyl or (CH2)COOH, R6 is not CH═CH—COOH
or a pharmaceutically acceptable salt thereof.
Preferably B is phenyl.
Preferably R1 is adamantyl, benzyl.
Preferably R2 is H.
Preferably R3 is H.
Preferably R5 is CH═NO—C(CH3)3, CH═NO-aryl; CH2-1,4-Oxazinane
Preferably R6 is C≡CCOOH, C≡CC—CH2OH, CH═CHCOOH, CH═CH—CH2OH
More preferably the compounds belonging to group A are selected from the group consisting of:
New synthesised compounds belonging to group B are of formula (II)
wherein B is C3-C12 cycloalkyl, or phenyl, or a C3-C13 heterocycle containing S, N, O
R1 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl linear or branched, heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S, optionally substituted with OH, NH2
R2 is C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched, (CH2)n—R7, (CH2)nO(CH2)mO—(CH2)p-R8, (CH2O)nCH3, CO—R8, (CH2)n—R10, D-mannosyl, glucuronate, (SO2) OH
R7 is OH, COOH, CONHO—R8, (CH2)nO(CH2)mO—R8, CN, NH2,
R8 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched
R10 is NH2, N-containing heterocycle, amidine, guanidine
R3 is H, OH CHO or
R2 and R3 are linked to form a cycle wherein said cycle comprises at least one atom of O and/or N
R4 is H
R5 is H, OH, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, (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 is OH, NH2, N—R12R13,
R12 and R13, the same or different are, H, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C(═NH)NH2
R15 is an heterocycle containing N, O, S
R6 is C≡CCOOH, C≡CCH2OH, C≡C—CH═NOH, C≡C—C(R17)2OH, C≡CCOO—R14, C≡CCONH2, C≡C(CH3)2OH, C≡CONH—R14, C≡CCONHOH, C≡C-tetrazolyl C≡CCOO glycosyl
R14 is C2-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl linear or branched, C3-C12 cycloakyl, aryl, C1-C3 arylalkyl
R17 is C2-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl linear or branched.
n is an integer from 1 to 15
m is an integer from 1 to 15
p is an integer from 1 to 15
with the proviso that when R6 is C≡CCOOH or C≡CCOOCH3 and R1 is H or adamantly and R2 is H or CH3, R3 and R5 are not both H
or a pharmaceutically acceptable salt thereof.
Preferably B is phenyl.
Preferably R1 is adamantyl, benzyl, 1-methylcyclohexyl.
Preferably R2 is C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched, D-mannosyl, PEG
Preferably R3 is H.
Preferably R5 is H.
Preferably R6 is C≡CCH2OH, C≡CCOOH C≡C(CH3)2OH, C≡CONH—R14, C≡CCONHOH
More preferably compounds of group (B) are selected from the group consisting of:
New synthesised compounds belonging to group C are of formula (II)
wherein
B is C3-C12 cycloakyl, or phenyl, or a C3-C13 heterocycle containing S, N, O
R1 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched, C3-C12 cycloalkyl optionally substituted with C1-C4 alkyl or OH, C1-C3 arylalkyl, phenyl, optionally substituted with C1-C4 alkyl, linear or branched, heterocycle containing at least one heteroatom selected from the group consisting of: N, O, S, optionally substituted with OH, NH2
R2 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched, (CH2)n—R7, (CH2)nO(CH2)mO—(CH2)p-R8, (CH2O)nCH3, CO—R8, (CH2)n—R10, D-mannosyl, glucuronate, (SO2) OH
R7 is OH, COOH, CONHO—R8, (CH2)nO(CH2)mO—R8, CN, NH2,
R8 is H, C1-C12 alkyl C1-C12 alkenyl, C1-C12 alkynyl linear or branched
R10 is NH2, N-containing heterocycle, amidine, guanidine
R3 is H, OH CHO or
R2 and R3 are linked to form a cycle comprising at least one atom of O and/or N
R4 is H
R5 is H, OH, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, (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 is OH, NH2, N—R12R13,
R12 and R13, the same or different are, H, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, C(═NH)NH2
R14 is H, C1-C5 alkyl, C1-C5 alkenyl, C1-C5 alkynyl linear or branched, 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 is 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═CYCOO glycosyl,
X is H, C2-C4 alkyl linear or branched, halogen, CN
Y is H, C2-C4 alkyl linear or branched, halogen, CN
n is an integer from 1 to 15
m is an integer from 1 to 15
p is an integer from 1 to 15
with the proviso that when R1 is adamantyl and R5 is hydrogen, R6 is not CX═CY—COOH or CX═CY—COOMe or CX═CY—COOEt
or a pharmaceutically acceptable salt thereof.
Preferably B is phenyl.
Preferably R1 is adamantyl, benzyl, 1-methylcyclohexyl.
Preferably R2 is H.
Preferably R3 is H.
Preferably R4 is H.
Preferably R5 is H.
Preferably R6 is CX═CYCOOH, CX═CYCN, CX═CYCOO—R14, CX═CYCONH2, CX═CY—CONH—R14, CX≡CYCONHOH, CX═CYCH2OH, Preferably X is H.
Preferably Y is C2-C4 alkyl linear or branched, halogen, CN.
More preferably compounds of group (C) are selected from the group consisting of:
The pharmaceutical acceptable salts of the compound of formula (I) and (II) belonging to the group A or B or C are included in the scope of the invention.
Pharmaceutical acceptable salts are salts which retain the biological activity of the base and are derived from such known pharmacologically acceptable acids such as, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, fumaric, succinic, oxalic, malic, tartaric, maleic, citric, methanesulfonic or benzoic acid and others commonly used in the art, and their corresponding basis.
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 out hereinafter.
Another object of the present invention is a pharmaceutical composition containing at least one compound of formula (I) and/or (II) of group A or B or C as an active ingredient, in an amount such as to produce a significant therapeutic effect, together with pharmaceutically acceptable vehicle and/or excipients.
The pharmaceutical compositions can be prepared by conventional methods and techniques which are common practice in the pharmaceutical industry, such as, for example, those illustrated in Remington's Pharmaceutical Science Handbook, Mack Pub. N.Y.—last edition.
The compositions according to the present invention contain, along with the active ingredient, at least one pharmaceutically acceptable vehicle or excipient. These may be particularly useful formulation coadjuvants, e.g. solubilising agents, dispersing agents, suspension agents, and emulsifying agents.
The Synthetized compounds from 1 to 15, are herein listed:
2-(Adamantan-1-yl)-4-(4-bromophenyl)phenol. A finely pulverized 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 mixture of 9:1 AcOH/H2SO4. After 4 days at room temperature addition of ice/water and filtration gave 100% of the title compound, mp 140-143° C., lit. 148-149° C. 1H NMR (CDCl3) δ: 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).
(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) of acrylonitrile, 8.78 mg (0.0391 mmol) of Pd(OAc)2, and 23.80 mg (0.00782 mmol) of tri-o-tolylphosphine 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, 2 N 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. (E/Z isomers, 2:1). Yield 45%. 1H NMR (CDCl3), E, δ: 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). 1H NMR (CDCl3), Z, δ: 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)
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 at 60° C. for 20 h. Evaporation, taking up with water and ice, addition of 2 N HCl, extraction with ethyl acetate and filtration of the exacts and evaporation, gave 2.47 g of the crude compound. The product was purified by flash chromatography (hexane/ethyl acetate from 90:10 to 70:30) to give 347 mg of the title compound of the product. (19%). M.P. 200° C. 1H NMR (CDCl3), δ: 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).
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. Then 3.7 mL of a 2 M 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 were added. The mixture was refluxed for 2 h in a stream of nitrogen. It was then cooled, taken up with ethyl acetate, and washed with a NaCl saturated solution. The phases were separated, the organic layer was filtered, dried over Na2SO4, and filtered, the solvent was 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) E-2-Methyl-3-[3′-(adamantan-1-yl)-4′-hydroxybiphenyl-4-yl]acrylic Acid (3). Under a stream of nitrogen 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 was 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 was stirred at room temperature for 2 days. After evaporation of THF, the aqueous phase was acidified with 3 mL of 1 M HCl and extracted with AcOEt. Drying, filtration and evaporation of the solvent afforded 312 mg of crude product, which was purified by flash chromatography (hexane/ethyl acetate, 2:1 and then 3:2) to obtain 69 mg of the title compound as a white solid, mp 200° C. 1H NMR (600 MHz) (DMSO-d6) δ 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).
A suspension of 3′-(Adamantan-1-yl)-4′-tert-butyldimethylsilyloxybiphenyl-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) was heated at 50° C. for 4 h. The solvent was evaporated and the yellow residue was taken up with CH2Cl2 (25 ml). The solution was 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′-tetrbutyldimethylsilyloxy-[1,1′-biphenyl]-4-yl)-2-cyanoacrylate M.p. 185° C.
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 was 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 reverse phase flash chromatography (MeOH:H2O 3:1) gave 26 mg of the title compound. M.p 228° C. 1H NMR (acetone-d6), δ: 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).
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 anhydrous 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., an amount of 200 mg (0.448 mmol) of 3′-(adamantan-1-yl)-4′-tert-butyldimethylsilyloxybiphenyl-4-aldehyde (see example 3) dissolved in 0.5 mL of THF was dropped, and the solution was slowly brought to room temperature (3 h). After acidification with 6 mL of 2 N HCl the aqueous phase was extracted with AcOEt. The organic layers were washed with brine, dried, filtered, and evaporated to afford 280 mg of a crude product. Purification by flash chromatography (hexane/ethyl acetate, 95:5) gave 180 mg (75%) of the ethyl ester of the tertbutyldimethylsilyl derivative 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 was evaporated and the remaining aqueous phase was washed with hexane, then acidified with 0.5 mL of 2 N HCl. The light-yellow precipitate was filtered and dried to afford 55 mg of the title compound. Yield 77%, mp 202° C. 1H NMR (acetone-d6): δ 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-3-(3′-tert-Butyl-4′-hydroxybiphenyl-4-yl) acrylic acid (6). To a solution of CH3COOH/conc. H2SO4, 9:1 (2 mL), an amount of 500 mg (2.01 mmol) of 4-(4′-bromophenyl)-phenol was added. Then an amount of 0.192 mL (2.01 mmol) of tert-butyl alcohol was added dropwise. The mixture was stirred at room temperature for 2 weeks. CH3COOH was evaporated, and water and ice were added. The white solid was filtered and washed with water. The crude 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. Water and ice were added, 2 N 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 (dichloromethane/hexane, 95:5), to give 121 mg of methyl E-3-(3′-tert-butyl-4′-hydroxybiphenyl-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 was stirred overnight at room temperature in the dark. THF was evaporated. The aqueous phase was washed with hexane and Et2O and then acidified with 2 N HCl (0.6 mL). The white solid was filtered and dried to give 54 mg of pure product. Yield 81%, mp 218° C. 1H NMR (DMSO-d6) δ 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).
A) Methyl 4-(3-(1-adamantyl)-4-methoxyphenyl)propiolate. 301 mg (1.26 mmol) of methyl 4-bromophenylpropiolate were dissolved in 2.5 ml of toluene, 1.34 ml of an aqueous solution of 2M Na2CO3, then 43.7 mg of Pd-tetrakistriphenylphosphine, and finally 398 mg (1.39 mmol) of 3-(1-adamantyl)-4-methoxyphenylboronic acid were added, and the mixture refluxed for 3 hours. The crude product was taken up in ethyl ether, the organic phase washed with 15 a saturated NaCl solution, dried over Na2SO4, evaporated to dryness to give 570 mg of crude product. Flash chromatography on silica gel (Merck) with hexane:ethyl acetate 2:1 as eluent gave 15 mg of pure product. M.p. 175° C. 1H-NMR (CDCl3) δ: 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) 4-(3-(1-adamantyl)-4-methoxyphenyl)propiolic acid (7) 15 mg (0.0374 mmol) of methyl E-4-(3-(1-adamantyl)-4-methoxyphenyl)propiolate were dissolved in 2.14 ml of 0.7N NaOH in methanol, and the mixture refluxed for 1 hour. Methanol was evaporated, the residue taken up in water, acidified with 6N HCl, and extracted with ethyl ether. After drying over Na2SO4 and having evaporated 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) 1H-NMR (DMSO-d6) δ: 1.70 (s, 6H), 2.10 (s, 9H), 3.85 (s, 3H, OCH3), 7.05 (d, 1H, J=8.4, H-6′), 7.40 (d, 1H, J=2, H-2′), 7.45-7.60 (3H arom.), 7.65 (2H arom.)
To a suspension of 3-(3′-adamantan-1-yl-4′-hydroxy-biphenyl-4-yl)-acrylic acid (0.53 mmol) in dry DMF (8.3 mL) HOBt (86 mg, 0.64 mmol) and WSC (132 mg, 0.69 mmol) were added. 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 addition of water, a precipitate formed, which was filtered and dried to obtain the desired hydroxamic acid. The crude precipitate was purified by flash chromatography with CH30H/H2O 75:25 v/v on RP-18 silica gel. Yield: 54%. M.p. 184° C. 1H NMR (DMSO-d6) δ: 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). 13C NMR (DMSO-d6) δ: 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.
A) 3-(3′-Adamantan-1-yl-4′-ethoxycarbonylmethoxy-biphenyl-4-yl)-acrylic acid tert-butyl ester. A mixture of 3-(3′-adamantan-1-yl-4′-hydroxy-biphenyl-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 of DMF was heated at 80° C. for 1 h. K2CO3 was filtered, DMF evaporated and the residue was taken up with water. The solid precipitated was filtered and crystallized from diethyl ether to give 2.09 g (97%) of product as white solid, m.p. 175° C., Rf (petroleum ether/ethyl acetate 90:10) 0.31. 1H-NMR (300 MHz, CDCl3) δ: 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). 13C-NMR (75 MHz, CDCl3) δ: 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) 3-(3′-Adamantan-1-yl-4′-carboxymethoxy-biphenyl-4-yl)-acrylic acid tert-butyl ester. To a solution of 3-(3′-Adamantan-1-yl-4′-ethoxycarbonylmethoxy-biphenyl-4-yl)-acrylic acid tert-butyl ester (2.08 g, 4.02 mmol) in 125 ml of aq. 50% THF was added with 843 mg (20.1 mmol) of LiOH.H2O and left overnight at rt. Evaporation, taking up with EtOAc, washing with 60 ml of 1N KHSO4, extraction with EtOAc, drying 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 (300 MHz, DMSO-d6) δ: 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). 13C-NMR (75 MHz, DMSO-d6) δ: 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 the overlap with solvent, 37.1, 37.9, 28.9 (×3C), 28.3 (×3C).
C) 3-{3′-Adamantan-1-yl-4′-[(tetrahydropyran-2-yloxycarbamoyl)-methoxy]-biphenyl-4-yl}-acrylic acid tert-butyl ester. Into an ice-cooled suspension of 3-(3′-Adamantan-1-yl-4′-carboxymethoxy-biphenyl-4-yl)-acrylic acid tert-butyl ester (1.25 g, 2.56 mmol) in 26 ml of dry DMF, under nitrogen, HBTU (0.971 g, 2.56 mmol) and DIPEA (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 was left overnight at rt. DMF was evaporated, the residue was taken up with water and the white solid filtered. Purification by flash chromatography on silica gel with petroleum ether/EtOAc 7:3 gave 1.23 g of the product, white solid, m.p. 193° C., Rf (AcOEt/petroleum ether 3:7) 0.31. 1H-NMR (300 MHz, CDCl3) δ: 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). 13C-NMR (75 MHz, CDCl3) δ: 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) (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) was added portionwise 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 was filtered, the solid was washed with water until neutral pH to give 175 mg (92%) of desired compound as white solid, m.p. 265° C., Rf (CH2Cl2/MeOH 18:2) 0.49. 1H-NMR (300 MHz, CDCl3+TFA) δ: 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). 13C-NMR (75 MHz, DMSO-d6) δ: 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 the overlap with signal solvent), 37.1, 36.9, 28.9 (×3C).
A) (E)-3-(3′-adamantan-1-yl)-4′-((1-ethoxy-1-oxopropan-2-yl)oxy)-[1,1′-biphenyl]-4-yl)acrylic acid tert-butyl ester
To a solution of 3-(3′-adamantan-1-yl-4′-hydroxy-biphenyl-4-yl)-acrylic acid tert-butyl ester (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), were added under nitrogen. The mixture was heated 5 h to reflux. K2CO3 was filtered, and the solvent removed in vacuo. The crude was triturated with hexane:diethyl ether 5:1, the precipitate was filtered to give 340 mg of title compound. Yield: 55%. m.p. 88° C., Rf (petroleum ether/ethyl acetate 92.5:7.5) 0.30. 1H-NMR (300 MHz, CDCl3) δ: 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).
B) (E)-3-(3′-adamantan-1-yl)-4′-(1-carboxyethoxy)-[1,1′-biphenyl]-4-yl)acrylic acid tert-butyl ester
To a solution of (E)-3-(3′-adamantan-1-yl)-4′-((1-ethoxy-1-oxopropan-2-yl)oxy)-[1,1′-biphenyl]-4-yl)acrylic acid tert-butyl ester (500 mg, 0.94 mmol) in aq. 50% THF (30 mL), LiOH.H2O (198 mg, 4.71 mmol) was added. The solution was stirred overnight at rt. The solvent was 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 title compound (white solid), m.p. 206° C., Rf (CH2Cl2/MeOH 193:7) 0.23. 1H-NMR (300 MHz, DMSO-d6) δ: 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).
C) (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 acid tert-butyl ester
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 nitrogen atmosphere. The solution was stirred 30 min at 0° C. then 0-(tetrahydropyran-2-yl)-hydroxylamine (93 mg, 079 mmol) was added and the reaction was stirred overnight at rt. The solvent was removed in vacuo, 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 title compound. Yield: 84%, Rf (hexane:ethyl acetate 7:3) 0.32. 1H-NMR (300 MHz, CDCl3) δ: mixture of stereoisomer 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).
D) (E)-3-(3′-adamantan-1-yl)-4′-((1-(hydroxyamino)-1-oxopropan-2-yl)oxy)-[1,1′-biphenyl]-4-yl)acrylic acid
To a solution of (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 acid tert-butyl ester (1.35 g, 2.20 mmol) in dry CH2Cl2 (22 mL) at 0° C., TFA (22 mL) was dropwise under nitrogen. The solution was stirred at 0° C. for 4 h. The mixture was evaporated and treated with toluene to remove TFA, the solid obtained was triturated in CH2Cl2 and filtrated to give 646 mg of title compound. Yield: 64%, Rf (CH2Cl2/MeOH/H2O 18:2:0.2) 0.35. 1H-NMR (300 MHz, CDCl3+TFA) δ: 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).
A) 3-[4′-(4-Acetoxy-butoxy)-3′-adamantan-1-yl-biphenyl-4-yl]-acrylic acid methyl ester A mixture of 3-(3′-adamantan-1-yl-4′-hydroxy-biphenyl-4-yl)-acrylic acid methyl ester (100 mg, 0.26 mmol), 4-bromobutyl acetate (67.4 mg, 0.34 mmol), K2CO3 (102 mg, 0.74 mmol) in DMF (4.50 mL) was heated 2 h at 80° C. Then, K2CO3 was 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 white solid, m.p. 157° C., Rf (petroleum ether/EtOAc 80:20) 0.50. 1H-NMR (300 MHz, DMSO-d6) δ: 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 missing due to the overlap with signal solvent; 2.20-1.98 (9H, m); 1.84-1.65 (6H, m); 1.47 (7H, S).
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 0.7 N NaOH in was refluxed for 10 h. After removal of methanol, the residue was treated with cold water, acidified with 1M HCl, and the precipitate was filtered. Crystallization from isopropyl ether gave 10 mg (37%) of the pure product as white solid, m.p. 208° C., Rf (petroleum ether/EtOAc 50:50) 0.15. 1H-NMR (300 MHz, DMSO-d6) δ: 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).
A) Methyl 3-[3′-adamantan-1-yl-4′-(tert-butyl-dimethyl-silanyloxy)-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 0-tertbutylhydroxylamine hydrochloride, and refluxed for 1 hour. Evaporation gave a crude that was used for the next step without further purification.
B) 3-[3′-Adamantan-1-yl-4′-hydroxy-2-tert-butoxyiminomethyl-biphenyl-4-yl]-acrylic acid. 100 mg (0.18 mmol) of methyl 3-[3′-adamantan-1-yl-4′-(tert-butyl-dimethyl-silanyloxy)-2-tert-butoxyiminomethyl-biphenyl-4-yl]-acrylate are dissolved in 6 ml of a solution 1N of NaOH in methanol and the mixture refluxed for 5 hours. Evaporation, taking up with water, cooling with ice, slow addition of HCl 1N to acid pH, filtration, and drying gives 65 mg of a yellowish product, m.p. 239° C. 1H-NMR (300 MHz, CDCl3) δ: 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).
A) Methyl 3-[3′-adamantan-1-yl-4′-(tert-butyl-dimethyl-silanyloxy)-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 is added with 1.4 ml of pyridine and 52 mg (0.62 mmol) of O-methylhydroxylamine hydrochloride, and refluxed 1 hour. Evaporation gave a crude that was used for the next step without further purification.
B) 3-[3′-Adamantan-1-yl-4′-hydroxy-2-methoxyimino-methyl-biphenyl-4-yl]-acrylic acid 85 mg (0.15 mmol) of methyl 3-[3′-adamantan-1-yl-4′-(tert-butyl-dimethyl-silanyloxy)-2-methoxyimino-methyl-biphenyl-4-yl]-acrylate are dissolved in 5 ml of a solution 1N of NaOH in methanol and the mixture refluxed for 5 hours. Evaporation, taking up with water, cooling with ice, slow addition of HCl 1N to acid pH, filtration, and drying give a yellowish product, 55 mg, m.p. 224° C. 1H-NMR (300 MHz, CDCl3) δ: 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).
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 is treated with 1 eq of pyridine, then with 20 mg of aminooxyacetic acid and left at room T for 24 hrs. Evaporation and column chromatography with CH2Cl2:MeOH 4:1 give 65 mg of the product, m.p. 108-110° C. (dec). 1H-NMR (300 MHz, DMSO-d6) δ: 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) 3-(3′-Adamantan-1-yl-2-(ditertbutoxycarbonylguanidino)methyl)-4′-hydroxy-biphenyl-4-yl)-acrylic acid A suspension of 113 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 is 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″-trifluoromethanesulfonyl-guanidine and another eq. of triethylamine, and left under a nitrogen atmosphere and in the dark for 12 hours. Taking up with 15 ml of dichloromethane, washing with a solution 2M of NaHSO4, washing with water, drying over Na2SO4, and evaporation gives 133 mg of a crude product. Crystallization from dichloromethane/methanol (5 ml: 0.25 ml) gives 30 mg of pure product, whereas chromatography of the mother liquid with dichloromethane/methanol gives further 70 mg, m.p. 280° C. 1H-NMR (300 MHz, MeOD) δ: 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).
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 is slowly added under nitrogen atmosphere, 1.1. ml of trifluoroacetic acid, and left 12 hours in the dark. Evaporation and chromatography with silica gel with CH2Cl2/MeOH/TFA 18:2:0.2 as an eluent gives a hygroscopic product, (67 mg, m.p. 163° C.). 1H-NMR (300 MHz, MeOD) δ: 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).
3-{4-[8-(Adamantan-1-yl)-2,3-dihydro-benzo[1,4]-dioxin-6-yl]-phenyl}-acrylic acid (16). Suzuki one-pot condensation between 200 mg (0.573 mmol) of 4-bromo-1,2-ethylenedioxybenzene with methyl 4-bromocinnamate was carried out as described in R. Cincinelli et al./Bioorg. Med. Chem. 15 (2007) 4863-4875. The residue was purified by flash chromatography (dichloromethane/hexane 1.1) to give 124 mg (50%) of 3-{4-[8-(adamantan-1-yl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-phenyl}-acrylic acid methyl ester, mp 209° C. 1H NMR (300 MHz, CDCl3) δ: 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). The above ester (70 mg, 0.163 mmol) was hydrolysed with LiOH to afford 62 mg (91%) of the pure product, mp 288° C. 1H NMR (300 MHz, DMSO-d6) δ: 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).
A) N-[5-Bromo-2-hydroxy-3-(adamantan-1-yl)-benzyl] acetamide. A finely pulverized mixture of 2-(1-adamantanyl)-4-bromophenol (500 mg, 163 mmol) and N-(hydroxymethyl)acetamide (145 mg, 1.63 mmol) was added portionwise, at 10° C. while stirring, to 1.63 mL of a solution of CH3COOH/H2SO4 9:1. After the mixture was stirred at room temperature for 5 days, ice was added and the yellow solid was filtered and washed with water. Purification by flash chromatography (hexane/ethyl acetate 60:40) gave 225 mg (37%) of the pure product, mp 216° C. 1H NMR (300 MHz, CDCl3) δ: 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.
B) E-3-[3′-(Acetylaminomethyl)-4′-hydroxy-5′-(adamantan-1-yl)biphenyl-4-yl]-acrylic acid (17). An amount of 195 mg (0.516 mmol) of N-[5-Bromo-2-hydroxy-3-(adamantan-1-yl)-benzyl]acetamide was reacted with methyl p-bromocinnamate 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) afforded 103 mg (43%) of 3-[3′-(acetylaminomethyl)-4′-hydroxy-5′-(adamantan-1-yl)biphenyl-4-yl]-acrylic acid methyl ester, mp 163° C. 1H NMR (300 MHz, CDCl3) δ: 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). The above ester (100 mg, 0.218 mmol) was hydrolyzed 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. 1H NMR (300 MHz, acetone-d6) δ: 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).
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 μl). The mixture was stirred 5 days at room temperature. The solvent was evaporated and water (2 ml) was added, followed by 2N HCl (100 μl). The yellow solid formed was filtered and dried (Yield 80%). 1H NMR (300 MHz, DMSO-d6) δ: 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).
3-(3′-Adamantan-1-yl-4′-hydroxybiphenyl-4-yl)propionic Acid (19). Methyl E-3-(3′-Adamantan-1-yl-4′-hydroxybiphenyl-4-yl)acrylate (80 mg) was dissolved in 40 mL of AcOEt, an amount of 30 mg of PtO2 was added, and the mixture was hydrogenated for 40 min. After filtration of the catalyst, the solvent was evaporated to obtain 80 mg (100%) of methyl 3-(3′-adamantan-1-yl-40-hydroxybiphenyl-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 was evaporated, and the remaining aqueous layer was washed with hexane and then acidified with 1M HCl to pH 2 to obtain, after filtration, 57 mg of a white solid. Yield 74%, mp 197-200° C. 1H NMR (acetone-d6) δ: 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 (2H, d, 2Ar, J=8.34 Hz), 8.45 (1H, brs, OH).
To a solution of (E)-3-(30-Adamantan-1-yl-40-hydroxybiphenyl-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 were added 208 mg (0.696 mmol) of linoleoyl chloride. After stirring overnight at room temperature the reaction mixture was poured into iced water and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with 1 N HCl, water and dried over Na2SO4. Flash chromatography of the reaction mixture (hexane/ethyl acetate 95:5) gave 210 mg of (E)-octadeca-9,12-dienoic acid 3-adamantan-1-yl-40-(2-tert-butoxycarbonylvinyl)-biphenyl-4-yl ester as a colourless oil. Yield 65%, 1H-MNMR (300 MHz, DMSO-d6) δ 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).
(E)-Octadeca-9,12-dienoic acid 3-adamantan-1-yl-40-(2-tertbutoxycarbonylvinyl)-biphenyl-4-yl 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. under stirring. After 30 min at 0° C. the solvent was evaporated to give 100 mg of title compound as a white solid. Yield 99%. 1H NMR (300 MHz, DMSO-d6) δ 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).
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 over 10 min under a nitrogen atmosphere. A pale yellow precipitate was formed. The mixture was allowed 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 additional 10 min, then heated at 90-95° C. for 7 h. After having cooled at room temperature, 30 mL of water and 6 mL of HCl 1 M were added. The aqueous phase was extracted with ethyl acetate, the extract washed with brine, dried over Na2SO4, and evaporated. The crude product was purified by flash chromatography (hexane/ethyl acetate 95:5) to give 1.3 g (60%) of the title compound, mp 189° C. 1H NMR (300 MHz, CDCl3) δ: 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).
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 general procedure reported in R. Cincinelli et al./Bioorg. Med. Chem. 15 (2007) 4863-4875. The 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 diisopropylether. Yield 66%, mp 245° C. 1H NMR (300 MHz, CDCl3) δ: 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 hydrolysed as described in general procedure reported in R. Cincinelli et al./Bioorg. Med. Chem. 15 (2007) 4863-4875 to obtain the corresponding acid, yield 83%, mp>300° C. 1H NMR (300 MHz, DMSO-d6) δ: 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).
Determination of Minimal Inhibitory Concentration (MIC), Minimal Bactericidal Concentration (MBC), bactericidal curves and killing rate on Gram positive and Gram negative bacteria strains, for the evaluation of the bactericidal activity of compounds of example 1 (n. 1 to 14).
Sensitivity tests have been performed in broth-dilution (micromethod) with the purpose to test the possible bacteriostatic and/or bactericidal power in different compounds, in accordance with CLSI guidelines (Clinical and Laboratory Standards Institute). In details, phenotypic methods based on in vitro MIC and MBC determination have been performed on previously isolated bacterial strains, identified and characterized at the level of their antibiotic susceptibility profile. According to MIC and MBC data, the Killing Rate was calculated as the ratio between MBC and MIC on which basis it is possible to define the compounds tested as bactericides (killing rate=1-4), or bacteriostatic (killing rate >4).
Preparation of the solution containing molecules: for each molecule to be tested, solutions were made as DMSO Stock, 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 μg/ml. The scalar dilutions were prepared directly on plates by using Mueller Hinton Broth (MHB) as a solvent.
Bacterial suspension preparation: cryostrains preserved at −80° C. were recovered by incubation in growth medium (Brain Heart Infusion Broth, BHI) for 24-48 hours at 37° C. followed by passages in agar growth medium (Columbia Blood Agar). Colonies with less than 30 hours are suspended in MHB with the purpose to prepare a bacterial suspension with a turbidity of 0.5 MF, containing approximately 1.5×108 cfu/ml. This injection is additionally diluted in MHB until reaching a final concentration of 5×105 cfu/ml (range 3-7×105 cfu/ml). Identical volumes of this bacterial suspension are added on a plate, for each well containing drug scalar dilutions, to obtain a final concentration between 512 a 0.25 μg/ml. The set up of bacterial suspensions as well as the passage on slate has always been performed within 30 minutes, in order not to alter the concentration of the bacterial suspension. Simultaneously, check in broth-microdilution only with solvent (in order to exclude that the effect of growth inhibition might be due to the drug solution solvent), positive growth control in absence of DMSO and drug, and negative purity control only with injection broth are performed. As a consequence the slate is incubated at 37° C. for 24 and 48 hours in aerobes. The 24 hours MIC is considered as the minimum drug concentration able to inhibit bacterial growth, which makes it possible to observe the absence of bacterial growth and the absence of turbidity. The same observations are valid to evaluate 48 hours MIC. After the incubation, an equal volume of bacterial suspension from each well is plated on agar growth medium and incubated for 24-48 hours at a temperature of 37° C. in aerobes, in order to define the MBC after the incubation. The MBC is evaluated as the minimum concentration of drug able to kill the 99,9% of the initial bacterial population.
Time-killing curves: evaluation of the number of survivors after 2, 6 and 24 hours drug exposition. The bacterial culture at an exponential growth phase is diluted in fresh broth until reaching a concentration between 106 and 107 cfu/ml. Starting from this suspension, the control in drug absence and the solution containing the drug at a concentration of four times the MIC are set up. In order to evaluate the initial bacterial charge, after a sampling at 0 time, other samplings are performed to count the survivors at the end of 2, 6 and 24 incubation hours.
The dilution of bacterial suspension is realized from samplings, in order to make the bacterial count possible.
Bacterial strains: the bactericidal and/or bacteriostatic power of the synthesized compounds can be determined by using standard reference strains such as:
The results of antibacterial activity are reported in the following table 1.
S.
AUREUS
S.
AUREUS
S.
AUREUS
E.
FAECALIS
E.
E.
FAECALIS
FAECALIS
A.
P.
E.
COLI
BAUMANNII
AERUGINOSA
| Number | Date | Country | Kind |
|---|---|---|---|
| 102019000003343 | Mar 2019 | IT | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/054717 | 2/24/2020 | WO |
