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Bisboron compound

Foreign code F110003825
File No. I018P007WO
Posted date Jul 5, 2011
Country United States of America
Application number 09496806
Gazette No. 20100087645
Gazette No. 8017809
Date of filing Nov 24, 2006
Gazette Date Apr 8, 2010
Gazette Date Sep 13, 2011
International application number JP2006323492
International publication number WO2007061074
Date of international filing Nov 24, 2006
Date of international publication May 31, 2007
Priority data
  • P2005-340864 (Nov 25, 2005) JP
  • 2006WO-JP323492 (Nov 24, 2006) WO
Title Bisboron compound
Abstract (US8017809)
A bisboron compound represented by the general formula (I): wherein B represents a boron atom, Y represents an oxygen or sulfur atom, R1 and R2 independently represent a monocyclic aromatic group, a polycyclic aromatic group, or a heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur atoms, R3 represents a hydrogen atom; —(CH2)m—NR4R5; —CO—(CH2)m—NR4R5; —COCH(NH2)R6; —CHR7R8; —CH2CH(NH2)—R9; quinolyl substituted with C1-C4 alkyl group; or C1-C4 alkyl substituted with pyridyl, piperidino or pyrrolidinyl group, and X represents a monocyclic aromatic group, a polycyclic aromatic group or a heterocyclic group, which may be the same as or different from R1 and R2, or a bifunctional group having a monocyclic aromatic group, polycyclic aromatic group or heterocyclic group bonded to each side of a group selected from the group consisting of a single bond, O, CH2, S, SO2, CH2OCH2, OCH2, OCH2CH2OCH2, OCH2OCH2CH2 and CH2OCH2CH2, or a salt thereof, and a composition for controlling the intracellular calcium concentration, which comprises the compound or salt thereof as an active ingredient.
Scope of claims [claim1]
1. A bisboron compound having activity to control the intracellular calcium concentration represented by the general formula (I):
wherein B represents a boron atom,
Y represents an oxygen or sulfur atom,
R1 and R2 independently represent a monocyclic aromatic group, a polycyclic aromatic group, or a heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur atoms,
R3 represents a hydrogen atom; -- (CH2)2 -- NR4R5, wherein R4 and R5 independently represent a hydrogen atom, or C1-C4 alkyl substituted or unsubstituted with amino, mono- or di-C1-C4 alkylamino or phenyl group, or R4 and R5 are taken together with the nitrogen atom to which they are bonded to form a 5- or 6-membered cyclic ring; -- CO -- (CH2)m -- NR4R5, wherein m represents an integer of 1 to 4, and R4 and R5 are as defined above; -- COCH(NH2)R6, wherein R6 represents an amino acid residue or -- (CH2)nNH2, wherein n represents an integer of 1 to 3; -- CHR7R8, wherein R7 and R8 independently represent C1-C4 alkyl substituted or unsubstituted with amino, mono- or di-(amino group-substituted or unsubstituted C1-C4 alkyl)amino or phenyl group, pyridyl, or phenyl substituted with C1-C3 alkoxy group; -- CH2CH(NH2) -- R9, wherein R9 represents phenyl, or C1-C4 alkyl substituted with phenyl group; quinolyl or isoquinolyl substituted with C1-C4 alkyl group; or C1-C4 alkyl substituted with pyridyl, piperidino or pyrrolidinyl group, and
X represents a bifunctional group having a monocyclic aromatic group, polycyclic aromatic group or heterocyclic group bonded to each side of a group selected from CH2OCH2, and CH2OCH2CH2,
or a salt thereof,
provided that bis[2-(hydroxyphenylboryl)benzyl]ether, 1,4-bis(4-(hydroxyphenylboryl)phenoxy)butane, bis[4-(hydroxyphenylboryl)benzyl]ether, bis[2-[(2-aminoethoxy)phenylboryl]benzyl]ether, bis[4-((2-aminoethoxy)phenylboryl)benzyl]ether, [4-[(2-aminoethoxy)phenylboryl]benzyl][2-[4-[(2-aminoethoxy)phenylboryl]phenyl]ethyl]ether, [2-[(2-aminoethoxy)phenylboryl]benzyl][2-[4-[(2-aminoethoxy)phenylboryl]phenyl]ethyl]ether and salts thereof are excluded.
[claim2]
2. The bisboron compound or salt thereof according to claim 1, wherein the monocyclic aromatic group or polycyclic aromatic group is an aromatic group substituted or unsubstituted with at least one substituent selected from the group consisting of halogen, halogenated C1-C4 alkyl, cyano, hydroxy, sulfanyl, amino, nitro, mono- or di-C1-C4 alkylamino, carboxyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, C2-C4 alkenyl, C2-C4 alkynyl, cycloalkyl, cycloalkenyl, C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxy, aryl, amide and C1-C4 alkylamide.
[claim3]
3. The bisboron compound or salt thereof according to claim 1, wherein the heterocyclic group is a 5- to 15-membered heterocyclic group substituted or unsubstituted with at least one substituent selected from the group consisting of halogen, cyano, hydroxy, sulfanyl,amino, nitro, mono- or di-C1-C4 alkylamino, carboxyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, C2-C4 alkenyl, C2-C4 alkynyl, cycloalkyl, cycloalkenyl, C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxy, aryl, amide and C1-C4 alkylamide.
[claim4]
4. The bisboron compound or salt thereof according to claim 1, wherein the X is a group selected from the group consisting of the following groups
[claim5]
5. The bisboron compound or salt thereof according to claim 1, wherein the X is substituted or unsubstituted, dibenzyl ether, or benzyl phenethyl ether having a meta-meta, ortho-ortho, para-para, meta-para, meta-ortho or ortho-para orientation.
[claim6]
6. The bisboron compound or salt thereof according to claim 5, wherein the X is dibenzyl ether having any of meta-meta, ortho-para, ortho-meta and meta-para orientations.
[claim7]
7. The bisboron compound or salt thereof according to claim 6, wherein the X is dibenzyl ether having a meta-meta orientation.
[claim8]
8. The bisboron compound or salt thereof according to claim 5, wherein the X is benzyl phenethyl ether having any of meta-meta, ortho-ortho, ortho-meta and meta-para orientations.
[claim9]
9. The bisboron compound or salt thereof according to claim 8, wherein the X is benzyl phenethyl ether having a meta-meta or ortho-ortho orientation.
[claim10]
10. The bisboron compound or salt thereof according to claim 1, wherein the R1 and R2 are independently a substituted or unsubstituted phenyl or phenylene group.
[claim11]
11. The bisboron compound or salt thereof according to claim 1, wherein the R3 is a hydrogen atom or a 2-aminoethyl group.
[claim12]
12. The bisboron compound or salt thereof according to claim 1, wherein the Y is an oxygen atom.
[claim13]
13. The bisboron compound according to claim 1, wherein the compound is selected from the group consisting of: bis(4,4'-(3-chloro-4-methylphenylhydroxyboryl)benzyl) ether;
bis(3,3'-(phenylhydroxyboryl)benzyl) ether;
bis(3,3'-(phenylaminoethoxyboryl)benzyl) ether;
bis(4-(4-trifluoromethylphenylhydroxyboryl)benzyl) ether;
bis(4-(1-naphthylhydroxyboryl)benzyl) ether;
bis(4-(fluorophenylhydroxyboryl)benzyl) ether;
bis(3-(4-methoxyphenylhydroxyboryl)benzyl) ether;
(3-(phenylhydroxyboryl)benzyl) (4-(phenylhydroxyboryl)benzyl) ether;
(2-(phenylhydroxyboryl)benzyl) (3-(phenylhydroxyboryl)benzyl) ether;
(2-(phenylhydroxyboryl)benzyl) (4-(phenylhydroxyboryl)benzyl) ether;
(3-(phenylaminoethoxyboryl)benzyl) (4-(phenylaminoethoxyboryl)benzyl) ether;
bis(3-(3-chloro-4-methylphenylhydroxyboryl)benzyl) ether;
(2-(phenylaminoethoxyboryl)benzyl) (3-(phenylaminoethoxyboryl)benzyl) ether;
2-(phenylaminoethoxyboryl)benzyl) (4-(phenylaminoethoxyboryl)benzyl) ether;
bis(3-(4-fluorophenylhydroxyboryl)benzyl) ether;
bis(3-(4-fluorophenylaminoethoxyboryl)benzyl) ether;
bis(4-(4-chloro-3-methyl-phenylhydroxyboryl)benzyl) ether;
bis(4-(4-chloro-3-methyl-phenylaminoethoxyboryl)benzyl) ether;
bis(3-(3',4'-methylenedioxy-phenylhydroxyboryl)benzyl) ether;
(3-(3-chloro-4-methylphenylhydroxyboryl)benzyl) (4-(3-chloro-4-methylphenylhydroxyboryl)benzyl) ether;
(3-(3',4',5'-trifluorophenylhydroxyboryl)benzyl) (4-(3',4',5'-trifluorophenylhydroxyboryl)benzyl) ether;
bis(3-(4-methoxyphenylaminoethoxyboryl)benzyl) ether;
(3-(4-chloro-3-methylphenylhydroxyboryl)benzyl) (2-(4-chloro-3-methylphenylhydroxyboryl)benzyl) ether;
bis(3-(4-cyanophenylhydroxyboryl)benzyl) ether;
bis(3-(2'-thiophenylhydroxyboryl)benzyl) ether;
bis(3-(1'-naphthylhydroxyboryl)benzyl) ether;
bis(3-(2'-thiophenylhydroxyboryl)benzyl) ether;
bis(4-(2-methoxy-5-fluorophenylhydroxyboryl)benzyl) ether;
bis(4-(3,4-difluorophenylhydroxyboryl)benzyl) ether;
bis(4-(3,4-difluorophenylaminoethoxyboryl)benzyl) ether;
bis(4-(4-methylphenylhydroxyboryl)benzyl) ether;
bis(4-(4-methylphenylaminoethoxyboryl)benzyl) ether;
(2-(phenylhydroxyboryl)phenethyl) ((2-phenylhydroxyboryl)benzyl) ether;
(2-(phenylhydroxyboryl)phenethyl) ((2-phenylaminoethoxyboryl)benzyl) ether;
bis(3-(1-naphthylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-N,N-dimethylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-N-aminoethylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-N-methylaminoethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-N,N-dimethylaminoethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-asparagineboryl)benzyl) ether;
bis(3,3'-(phenyl-aminothioethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-2-pyridylmethoxyboryl)benzyl) ether;
bis(4,4'-(p-trifluoromethylphenyl-hydroxyboryl)benzyl) ether;
bis(4,4'-(3-chloro-4-methylphenyl-hydroxyboryl)benzyl) ether;
bis(4,4'-(phenyl-lysineboryl)benzyl) ether;
bis(4,4'-(p-methoxymethyl-phenyl-hydroxyboryl)benzyl) ether;
bis(4,4'-(3,4-difluorophenyl-hydroxyboryl)benzyl) ether;
bis(4,4'-(p-methoxyphenyl-aminoethoxyboryl)benzyl) ether;
bis(4,4'-(p-methoxyphenyl-N-methylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(p-methoxyphenyl-N,N-dimethylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(p-methoxyphenyl-2,4-diaminobutyric acid boryl)benzyl) ether;
bis(4,4'-(3,4-difluorophenyl-aminoethoxyboryl)benzyl) ether;
bis(4,4'-(3,4-difluorophenyl-N-methylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(3,4-difluorophenyl-N,N-dimethylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(3,4-difluorophenyl-N-aminoethylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(3-chloro-4-methylphenyl-aminoethoxyboryl)benzyl) ether;
bis(4,4'-(3-chloro-4-methylphenyl-N-methylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(3-chloro-4-methylphenyl-N,N-dimethylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(3-chloro-4-methylphenyl-2-piperidylmethyloxyboryl)benzyl) ether;
bis(4,4'-(p-trifluoromethylphenyl-N,N-dimethylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(p-trifluoromethylphenyl-asparagineboryl)benzyl) ether;
bis(4,4'-(p-trifluoromethylphenyl-aminoethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-2-amino-1-phenylethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-aminothioethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-2-pyrrolidinemethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-2,4-diaminobutyric acid boryl)benzyl) ether;
bis(4,4'-(phenyl-butylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-phenylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-benzylaminoethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-N-methylpiperidine-methoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-1-methyl-2-aminoethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-1-piperidylethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-2-pyrrolidinomethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-aminothioethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-2-phenyl-2-aminoethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-2-piperazylmethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-dimethylaminoethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-1-methyl-2-aminoethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-2-piperidylethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-2-pyridylmethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-2-amino-1-phenylethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-N-methylethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-N-aminoethyl-1-methyl-3-aminopropoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-glutamineboryl)benzyl) ether;
bis(3,3'-(phenyl-2,4-diaminobutyric acid boryl)benzyl) ether;
bis(3,3'-(phenyl-N-butylaminoethylboryl)benzyl) ether;
bis(3,3'-(phenyl-asparagineboryl)benzyl) ether;
bis(3,3'-(phenyl-lysineboryl)benzyl) ether;
bis(3,3'-(phenyl-ornithineboryl)benzyl) ether;
bis(4,4'-(phenyl-2-benzyl-2-amino-ethoxyboryl)benzyl) ether;
bis(3,3'-(phenyl-2-benzyl-2-amino-ethoxyboryl)benzyl) ether;
bis(4,4'-(phenyl-2-phenyl-2-amino-ethoxyboryl)benzyl) ether; and salts thereof.
[claim14]
14. A composition comprising the bisboron compound or salt thereof according to claim 1.
[claim15]
15. A method for alleviation or treatment of a disease associated with an increase in intracellular calcium concentration comprising administering a therapeutically effective amount of the composition of claim 14, to a subject in need thereof.
[claim16]
16. A method for reducing release of endogenous calcium and/or entry of capacitative calcium comprising administering an effective amount of the composition according to claim 14, to reduce release of endogenous calcium and/or entry of capacitative calcium.
[claim17]
17. The method according to claim 15, wherein the disease is selected from the group consisting of ischemic heart or brain disease, cardiac hypertrophy, renal disease, hypertension, cerebral vasospasm, pancreatitis,asthma, immunodeficiency, allergic disease, and Alzheimer's disease.
  • Inventor, and Inventor/Applicant
  • MIKOSHIBA KATSUHIKO
  • OZAKI SHOICHIRO
  • SUZUKI AKINOBU
  • NAKAMURA TAKESHI
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
IPC(International Patent Classification)
U.S. Cl./(Sub)
  • C07F005/02C
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