Patent Grant
8853424
The present invention relates to a protein cross-linking inhibitor comprising a boron compound. Furthermore, the present invention relates to a novel boron compound useful for use thereof.
Calcium ion is essential for the body, and the concentration of intracellular Ca2+ constituting the body is as extremely low as 10−7M, which is 1 to 10,000 relative to the extracellular concentration. When the cell is stimulated, intracellular Ca2+ increases to generate Ca2+ wave that produces slow intracellular Ca2+ oscillation, and induces physiological function.
SOCE (store-operated calcium entry) is also called capacitive calcium entry, which is a mechanism that causes extracellular influx of Ca2+ for replenishment of depleted intracellular Ca2+ stores, and important for long-term sustainability of intracellular Ca2+ signals.
SOCE is measured as Icrac (calcium release-activated calcium-selective current). It has been clarified that SOCE and Icrac channel are defective in the T cells of patients with severe combined immunodeficiency (SCID). Furthermore, it has also been clarified that a protein called STIM (stromal interaction molecule) senses depletion of Ca2+ in the endoplasmic reticulum, passes the information to the cellular membrane, and activates CRACM (calcium release-activated calcium modulator) (Orai) located in the cellular membrane and forms Icrac channel pore.
Extracellular stimulus is recognized by a receptor on the cellular membrane, the information thereof activates PLC (phospholipase C) via G protein and hydrolyzes PIP2 (phosphatidylinositol bisphosphate), which is an inositolphospholipid in the cellular membrane, and produces diacylglycerol and IP3 (inositol trisphosphate). Diacylglycerol activates protein kinase C and phosphorylates protein, causing various physiological phenomena. IP3 acts on IP3 receptor to cause release of Ca2+. The present inventors have found an IP3 receptor molecule in mutant mouse, and successfully determined all base sequences of the membrane protein (non-patent document 1). In addition, they have clarified that the IP3 receptor localizes in the endoplasmic reticulum, and this is the calcium channel (non-patent documents 1-5). Furthermore, the present inventors have clarified that the IP3 receptor is the molecule involved in development and differentiation, neural plasticity and various signal transduction (non-patent documents 6-11). In addition, they have clarified that the IP3 receptor is also bound to the Ca2+ channel on the cell membrane surface (non-patent document 12).
2-Aminoethyl diphenylborinate (2-APB: C6H5B (OCH2CH2NH2)C6H5) has been internationally recognized as an IP3 receptor inhibitor, and is sold from Sigma. It decreases intracellular calcium concentration by inhibiting SOCE. The present inventors have synthesized and found compounds that control intracellular calcium concentration (patent document 1, patent document 2, Japanese patent application No. 2008-028152).
It has been clarified that the causes of intractable diseases such as Alzheimer's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis, congenital hemostatic disorder and the like are based on the abnormal cross-linking reaction of proteins (non-patent document 13, non-patent document 14). In addition, it has also been clarified that the cause of Huntington's disease is abnormal aggregation of polyglutamine (non-patent document 15).
Transglutaminase is an enzyme activated by the presence of Ca2+, and its involvement in neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and the like has recently been known. Therefore, novel inhibitors thereof are considered to be effective as therapeutic drugs for the diseases (non-patent document 16, non-patent document 17). A reaction forming an isopeptide bond by deammoniation of an amide group of glutamine and an amino group of lysine is the main reaction of protein cross-linking. The mechanism by which an inhibitor of enzyme transglutaminase causing the reaction is effective for the aforementioned neurological diseases has been clarified (non-patent document 19). As a basis, while many studies have been made based on the above to develop inhibitors of transglutaminase as therapeutic drugs for intractable diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease and the like (non-patent documents 17-23), a boron compound having a transglutaminase inhibitory activity has not been reported heretofore.
The present invention aims to develop a prophylaxis and/or therapeutic drug for diseases caused by cross-linking abnormality of protein (Alzheimer's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis, congenital hemostatic disorder etc.).
The present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that a series of boron compounds, particularly the compounds represented by the following formulas (1)-(13) (hereinafter to be also simply referred to as compounds (1)-(13)), inhibit cross-linking of protein, and the compounds can be used as prophylactic and/or therapeutic drugs for diseases caused by abnormal cross-linking of proteins.
Accordingly, the present invention provides the following.
[1] A compound represented by any of the following formulas (1)-(13) or a pharmaceutically acceptable salt thereof;
R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (1)
R3—[—X—B(ZR1)—Y—]n—R4 (2)
R3—[—B(ZR1)—Y—B(ZR2)—W—]n—R4 (3)
R3—[—X—B(ZR1)—]n—R4 (4)
R3—[—B(ZR2)—W—]n—R4 (5)
R3—X—B(ZR1)-T[B(ZR2)—W—R4]2 (6)
R3—B(OH)2 (7)
R3—B(ZR1)—X—B(ZR2)—R4 (8)
R3—B(R1)—O—B(R2)—R4 (9)
R3—[—X—B(ZR1)—Y—B(ZR2)—]n—R4 (10)
R3—[—X—B(ZR1)—Y—B(ZR2)—W-Q-]n—R4 (11)
R3—[—O—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (12)
[R3—X—B(ZR1)—Y]2B(ZR2) (13)
wherein B is a boron atom,
Z is O or S,
R1 and R2 are independently a group selected from H, —(CH2)m—NR5R6, —CO—(CH2)m—NR7R9, —COCH(NH2)—R9, —CH2CH(NH2)—R10, —CHR11R12, —COCH(—NR13R14)—R15, —COCH(NH2)—(CH2)mNHCR18NH2, —COCH(NH2)—(CH2)m—COR19, —COR20, —(CH2)m—R22, —O(CH2)mNH2, —COCH(NH2)—(CH2)m—R23, —(CH2CH2NH)2—R23,
and heterocyclylalkyl, or when R1 and R2 are present in plurality, R1 may be bonded to R1, R2 may be bonded to R2, or R1 may be bonded to R2, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R19, R20 and R22 are independently H, or each is a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, amino, aminoalkylcarbonyl, hydroxy, aromatic group or heterocyclylalkyl,
R18 is oxo or ═NH,
Q is a group represented by —R16—O—R17—, —R21—O— or —O— (wherein R16, R17 and R21 mean a single bond or lower alkylene),
R23 is a fluorescence group,
m is an integer of 1 to 5,
R3 and R4 are H, OH, CH2OH, CH2OCH2OCH3, cyano or aryloxy, or each is a substituted or unsubstituted alkyl or aryl,
T is a substituted or unsubstituted aryl,
X, Y and W are independently groups containing aromatic series or fatty series, and
n is an integer of 1 to 100.
[2] A compound represented by any of the following formulas (1)-(13) or a pharmaceutically acceptable salt thereof;
R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (1)
R3—[—X—B(ZR1)—Y—]n—R4 (2)
R3—[—B(ZR1)—Y—B(ZR2)—W—]n—R4 (3)
R3—[—X—B(ZR1)—]n—R4 (4)
R3—[—B(ZR2)—W—]n—R4 (5)
R3—X—B(ZR1)-T[B(ZR2)—W—R4]2 (6)
R3—B(OH)2 (7)
R3—B(ZR1)—X—B(ZR2)—R4 (8)
R3—B(R1)—O—B(R2)—R4 (9)
R3—[—X—B(ZR1)—Y—B(ZR2)—]n—R4 (10)
R3—[—X—B(ZR1)—Y—B(ZR2)—W-Q-]n—R4 (11)
R3—[—O—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (12)
[R3—X—B(ZR1)—Y]2B(ZR2) (13)
wherein B is a boron atom,
Z is O or S,
R1 and R2 are independently a group selected from H, —(CH2)m—NR5R6, —CO—(CH2)mNR7R8, —COCH(NH2)—R9, —CH2CH(NH2)—R10, —CHR11R12, —COCH(—NR13R14)—R15, —COCH(NH2)— (CH2)mNHCR18NH2, —COCH(NH2)—(CH2)m—COR19, —COR20, —(CH2)m—R22, —O(CH2)mNH2, —COCH(NH2)—(CH2)m—R23, —(CH2CH2NH)2—R23,
and heterocyclylalkyl, or when R1 and R2 are present in plurality, R1 may be bonded to R1, R2 may be bonded to R2, or R1 may be bonded to R2, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R19, R20 and R22 are independently H, or each is a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, amino, aminoalkylcarbonyl, hydroxy, aromatic group or heterocyclylalkyl, R18 is oxo or ═NH,
Q is a group represented by —R16—O—R11—, —R21—O—, or —O— (wherein R16, R17 and R21 mean a single bond or lower alkylene),
R23 is a fluorescence group,
m is an integer of 1 to 5,
R3 and R4 are H, OH, CH2OH, CH2OCH2OCH3, cyano or aryloxy, or each is a substituted or unsubstituted alkyl or aryl,
T is a substituted or unsubstituted aryl,
X, Y and W are independently groups containing aromatic series or fatty series, and
n is an integer of 1 to 100,
excluding a compound represented by the following formula (Ia)
wherein
B is a boron atom,
B is an oxygen or sulfur atom,
J1 and J3 are each independently a monocyclic aromatic group, a polycyclic aromatic group, or a heterocyclic group containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom,
J2 is a hydrogen atom; —(CH2)D—NJ4J5 wherein D is an integer of 1-4,
J4 and J5 are independently a hydrogen atom, or C1-4 alkyl substituted or unsubstituted by an amino group, a mono or di-C1-4 alkylamino group or a phenyl group, or J4 and J5 form, together with the nitrogen atom bonded thereto, a 5- or 6-membered cyclo ring); —CO—(CH2)D—NJ4J5 wherein D, J4 and J5 are as defined above; —COCH(NH2)J6 wherein J6 is an amino acid residue, or —(CH2)D′NH2 wherein D′ is an integer of 1 to 3; —CHJ7J8 wherein J7 and J8 are independently an amino group, C1-4 alkyl substituted or unsubstituted by a mono or di(C1-4 alkyl substituted or unsubstituted by an amino group)amino group or phenyl group, or phenyl substituted by pyridyl or a C1-3 alkoxy group; —CH2CH(NH2)-J6 wherein J9 is phenyl, or C1-4 alkyl substituted by phenyl; quinolyl or isoquinolyl substituted by a alkyl group; or C1-4 alkyl substituted by a pyridyl group, a piperidino group or a pyrrolidinyl group, and
U is a monocyclic aromatic group, a polycyclic aromatic group or a heterocyclic group, which is the same as or different from J1 and J3, or a bifunctional group having a monocyclic aromatic group, a polycyclic aromatic group or a heterocyclic group bonded to both sides thereof via a group selected from the group consisting of a single bond, O, CH2, S, SO2, CH2OCH2, OCH2, OCH2CH2OCH2, OCH2OCH2CH2 and CH2OCH2CH2, and a compound represented by the following formula (Ib)
wherein J10 is
(1) a hydrogen atom,
(2) —(CH2)D″NJ11J12 wherein D″ is an integer of 1 to 3, J11 and J12 are each independently a hydrogen atom, C1-4 alkyl, C5-6 monocyclic carbocycle, C1-4 alkyl substituted by C5-6 monocyclic carbocycle, or 5- or 6-membered monocyclic heterocycle,
the carbon atom in —(CH2)D″— is optionally substituted by 1 or 2 J13, and further, said carbocycle and heterocycle are optionally substituted by 1 or 2 J16,
J13 is (a) C1-8 alkyl, (b) carboxyl, (c) C1-4 alkoxycarbonyl, (d) keto, (e) C5-6 monocyclic carbocycle, (f) guanidino(C1-2)alkyl, (g) C1-6 alkyl substituted by C5-6 monocyclic carbocycle, (h) C1-2 alkyl substituted by 4-chlorophenoxy, or (i) C1-4 alkyl substituted by di(C1-4 alkylamino,
(3) C1-6 alkyl or C2-6 alkenyl substituted by C5-6 monocyclic carbocycle, wherein said carbocycle is optionally substituted by 1 to 5 J16, and further, said C1-6 alkyl or C2-6 alkenyl is optionally substituted by 1 or 2 J19,
(4) C1-6 alkyl or C2-6 alkenyl substituted by 5- or 6-membered monocyclic heterocycle, wherein said heterocycle is optionally substituted by 1 to 5 J16, and further, said C1-6 alkyl or C2-6 alkenyl is optionally substituted by 1 or 2 J19, and
J19 is C1-4 alkyl or C2-4 alkenyl,
(5) a —CHJ14J15 group wherein J14 and J15 are each independently
(i) C5-6 monocyclic carbocycle,
(ii) 5- or 6-membered monocyclic heterocycle,
(iii) C1-6 alkyl or C2-6 alkenyl substituted by C5-6 monocyclic carbocycle, or
(iv) C1-6 alkyl or C2-6 alkenyl substituted by 5- or 6-membered monocyclic heterocycle, wherein said carbocycle and heterocycle are optionally substituted by 1 to 5 J16, or
(6) 5,6,7,8-tetrahydroquinolin-8-yl,
J16 is (a) C1-4 alkyl, (b) C1-4 alkoxy, (c) a halogen atom, (d) —CF3, (e) nitro, (f) C5-6 monocyclic carbocycle, (g) C1-4 alkyl substituted by C5-6 monocyclic carbocycle, (h) amino, (i) —NHCO(C1-4 alkyl), or (j) C1-4 alkoxycarbonyl,
G is Cyc1 or hydroxy, Cyc1 is C5-10 monocyclic or bicyclic carbocycle, or 5- to 10-membered monocyclic or bicyclic heterocycle, wherein said carbocycle and heterocycle are optionally substituted by 1 to 5 J17,
Cyc2 is C5-10 monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heterocycle, wherein said carbocycle and heterocycle are optionally substituted by 1 to 5 J18, J17 and J18 are each independently
carbocycle, phenyl, Cyc1 and Cyc2 in J17 and J18 are optionally substituted by 1 or 2 J18, or J17 and J18 in combination optionally show —O—, and J18 and J19 in combination optionally show a single bond,
d′1 is an integer of 1 to 4,
d′2 is an integer of 1 to 4,
d′3 is an integer of 1 to 4, and
E is a single bond or C1-4 alkylene substituted or unsubstituted by C5-6 monocyclic carbocycle.
[3] The compound of [2] represented by the following formula (4′) or (8′)
R3′—[X′—B(ZR1′)—]n—R4′ (4′)
R3′—B(ZR1′)—X′—B(ZR2′)—R4′ (8′)
wherein B is a boron atom,
Z is O or S,
R1′ and R2′ are H, —(CH2)m—NR5′R6′, —COCH(NH2)—(CH2)mNHCONH2 or —COCH(NH2)—(CH2)m—COR19′, wherein R5′, R6′, R11′, R12′ and R19′ are independently H, or each is a substituted or unsubstituted amino, heterocyclyl or aryloxy,
R3′ and R4′ are H, aryl or heterocyclyl,
X′ is a substituted or unsubstituted aromatic group,
m is an integer of 1 to 5, and
n is an integer of 1 to 100, or a pharmaceutically acceptable salt thereof.
[4] The compound of [2] or [3], which is any of
wherein n is an integer of 1 to 100, or a pharmaceutically acceptable salt thereof.
[5] A protein cross-linking inhibitor comprising the compound of [2] to [4] or a pharmaceutically acceptable salt thereof.
[6] The inhibitor of [5], wherein the compound is represented by the formula (1) or (8)
R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (1)
R3—B(ZR1)—X—B(ZR2)—R4 (8)
wherein each symbol is as defined in [2].
[7] A prophylactic and/or therapeutic drug for a disease caused by cross-linking of protein, comprising the compound of [2] to [4] or a pharmaceutically acceptable salt thereof.
[8] The prophylactic and/or therapeutic drug of [7], wherein the compound is represented by the formula (1) or (8)
R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (1)
R3—B(ZR1)—X—B(ZR2)—R4 (8)
wherein each symbol is as defined in [2].
[9] The prophylactic and/or therapeutic drug of [7] or [8], wherein the disease caused by cross-linking of protein is selected from Alzheimer's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis and congenital hemostatic disorder.
[10] A method of preventing and/or treating a disease caused by cross-linking of protein, comprising administering an effective amount of the compound of [2] to [4] or a pharmaceutically acceptable salt thereof to a subject.
[11] The method of [10], wherein the compound is represented by the formula (1) or (8)
R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (1)
R3—B(ZR1)—X—B(ZR2)—R4 (8)
wherein each symbol is as defined in [2].
[12] The method of [10] or [11], wherein the disease caused by cross-linking of protein is selected from Alzheimer's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis and congenital hemostatic disorder.
[13] The compound of [2] to [4] to be used for the prophylaxis and/or treatment of disease caused by cross-linking of protein, or pharmaceutically acceptable salts thereof.
[14] The compound of [13] which is represented by the formula (1) or (8)
R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (1)
R3—B(ZR1)—X—B(ZR2)—R4 (8)
wherein each symbol is as defined in [2], or a pharmaceutically acceptable salt thereof.
[15] The compound of [13] or [14], wherein the disease caused by cross-linking of protein is selected from Alzheimer's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis and congenital hemostatic disorder, or a pharmaceutically acceptable salt thereof.
The present invention can provide a prophylactic and/or therapeutic drug for the diseases based on an abnormal cross-linking reaction of protein such as Alzheimer's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis, congenital hemostatic disorder and the like.
In the present invention, the cross-linking of protein means the state where a new bond of protein chain is formed in a molecule or between molecules (covalent bond, ionic bond, coordinate bond, hydrogen bond etc.), and a bridge is built.
In addition, polyglutamine aggregation means formation of assembly of polyglutamine (polymerization and/or specific aggregate).
Abnormal aggregation of polyglutamine is one example of cross-linking abnormalities of protein. An abnormal cross-linking of protein occurs due to abnormal transglutaminase activity that depends on calcium concentration.
The present invention relates to a protein cross-linking inhibitor containing a compound represented by any of the following formulas (1)-(13).
R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (1)
R3—[—X—B(ZR1)—Y—]n—R4 (2)
R3—[—B(ZR1)—Y—B(ZR2)—W—]n—R4 (3)
R3—[—X—B(ZR1)—]n—R4 (4)
R3—[—B(ZR2)—W—]n—R4 (5)
R3—X—B(ZR1)-T[B(ZR2)—W—R4]2 (6)
R3—B(OH)2 (7)
R3—B(ZR1)—X—B(ZR2)—R4 (8)
R3—B(R1)—O—B(R2)—R4 (9)
R3—[—X—B(ZR1)—Y—B(ZR2)—]n—R4 (10)
R3—[—X—B(ZR1)—Y—B(ZR2)—W-Q-]n—R4 (11)
R3—[—O—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (12)
[R3—X—B(ZR1)—Y]2B(ZR2) (13)
In the formula.
B is a boron atom,
Z is O or S,
R1 and R2 are independently a group selected from H, —(CH2)m—NR5R6, —CO—(CH2)m—NR7R8, —COCH(NH2)—R9, —CH2CH(NH2)—R10, —CHR11R12, —COCH(—NR13R14)—R15, —COCH(NH2)—(CH2)mNHCR18NH2, —COCH(NH2)—(CH2)m—COR19, —COR20, —(CH2)m—R22, —O(CH2)mNH2, —COCH(NH2)—(CH2)m—R23, —(CH2CH2NH)2—R23,
and heterocyclylalkyl, or when R1 and R2 are present in plurality, R1 may be bonded to R1, R2 may be bonded to R2, or R1 may be bonded to R2, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R19, R20 and R22 are independently H, or each is a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, amino, aminoalkylcarbonyl, hydroxy, aromatic group or heterocyclylalkyl,
R18 is oxo or ═NH,
Q is a group represented by —R16—O—R17—, —R21—O— or —O— (wherein R16, R17 and R21 mean a single bond or lower alkylene),
R23 is a fluorescence group,
m is an integer of 1 to 5,
R3 and R4 are H, OH, CH2OH, CH2OCH2OCH3, cyano or aryloxy, or each is a substituted or unsubstituted alkyl or aryl,
T is a substituted or unsubstituted aryl,
X, Y and W are independently groups containing aromatic series or fatty series, and
n is an integer of 1 to 100.
R1 and R2 are preferably independently a group selected from H, —(CH2)m—NR5R6, —CH2CH(NH2)—R10, —CHR11R12, —COCH(NH2)—(CH2)m—COR19, —COR20, —(CH2)m—R22, —COCH(NH2)—(CH2)m—R23 and heterocyclylalkyl.
R3 and R4 are preferably independently H, or a substituted or unsubstituted aryl.
When n is 2 to 100, repeat units may be bonded to each other at both ends, and may be bonded by R1 and R2.
In the present specification, preferable examples of alkyl include methyl, ethyl, propyl, butyl and isomers thereof.
In the present specification, “heterocyclyl” means 5- to 10-membered saturated or unsaturated monocycle containing 1 to 4 hetero atoms (a nitrogen atom, a sulfur atom, an oxygen atom) or a fused ring thereof. For example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, piperidine, piperazine, pyrrolidine, pyrimidine, pyridazine, furan, pyran, thiophene, thiin, oxazole, isoxazole, thiazole, isothiazole, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, benzooxazole, benzothiazole, benzoimidazole, chromene, indoline, isoindoline, dihydrobenzofuran, dihydrobenzothiophene, dihydroindazole, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroquinoxaline, tetrahydroquinazoline, tetrahydrocinnoline and the like can be mentioned.
Here, heterocyclylalkyl means the aforementioned alkyl moiety substituted by the aforementioned heterocyclyl moiety. Preferable examples of heterocyclylalkyl include 2-pyridylmethyl.
In the present specification, preferable examples of alkenyl include ethenyl, propenyl, butenyl, and isomers thereof and the like.
In the present specification, preferable examples of alkynyl include ethynyl, propynyl, butynyl, and isomers thereof and the like.
In the present specification, “cycloalkyl” means cyclic saturated hydrocarbon. Examples of cycloalkyl include 3- to 10-membered, preferably 5- or 6-membered, cycloalkyl such as cyclopentyl and cyclohexyl.
In the present specification, the “cycloalkenyl” means cyclic unsaturated hydrocarbon having 1 or 2 carbon-carbon double bonds.
Preferable examples of cycloalkenyl include 5- or 6-membered cycloalkenyl, for example, cyclopentenyl, cyclohexenyl and the like.
In the present specification, “aryl” means an atomic group obtained by removing one hydrogen atom from aromatic hydrocarbon. Examples of aryl include a substituted or unsubstituted phenyl, naphthyl, anthryl and the like.
In the present specification, “arylalkyl” means the aforementioned alkyl moiety substituted by 1 or plural aforementioned aryl moieties. Preferable examples of arylalkyl include benzyl and phenylethyl.
In the present specification, aryl of the “aryloxy” is as defined above. Preferable examples of aryloxy include phenoxy.
The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, aryloxy, heterocyclyl and heterocyclylalkyl may have substituent(s) at substitutable position(s). While the number of the substituents is not particularly limited, it is preferably 1 to 3. Specific examples of the substituent include halogen (e.g., fluorine, chlorine), optionally substituted hydroxy (e.g., hydroxy, alkoxy (e.g., methoxy, ethoxy)), optionally substituted methyl (e.g., methyl, trifluoromethyl), optionally substituted amino, carboxyl, optionally substituted phenyl (e.g., phenyl, naphthyl), thiol, optionally substituted amide (e.g., carbonamide), aminoalkylcarbonyl (e.g., aminoethylcarbonyl), thioalkyl (e.g., thiomethyl), and cyano. The optionally substituted amino may have substituent(s) at substitutable position(s). Specific examples of the substituent include aminoalkyl.
In the present specification, “lower alkylene” means straight chain or branched alkylene having a carbon number of 1 to 6, preferably 1 to 4, and preferably includes methylene, ethylene and propylene.
In the present specification, “aminoalkyl” means alkyl having an amino group, preferably aminoethyl.
In the present specification, the “fluorescence group” includes fluorescein such as fluorescein isothiocyanate (FITC) and the like, tetramethylrhodamine (TMeRH), cyanine (Cy2, Cy3, Cy5, Cy7 etc.), fluorescamine and the like. Particularly, FITC and TMeRH are preferable.
In the present specification, the aromatic group is a group derived from aromatic hydrocarbon and heterocycle showing aromatic property, and means a group derived from monocyclic aromatic series (monocyclic aromatic group) and a group derived from polycyclic aromatic series (polycyclic aromatic group). The monocyclic aromatic group means a substituted or unsubstituted phenyl or phenylene group. The phenylene group includes o-, m- and p-phenylene. Examples of the substituent include at least one substituent selected from the group consisting of halogen (e.g., fluorine, chlorine), halogenated C1-C4 alkyl, cyano, hydroxy, hydroxy C1-C4 alkyl, sulfanyl, amino, nitro, mono or di C1-C4 alkylamino, carboxyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, cycloalkyl (as defined above), cycloalkenyl (as defined above), C1-C4 alkylthio, C1-C4 alkoxy, aryl (as defined above), aryloxy (as defined above), amide and C1-C4 alkylamide, thiol and carbamoyl.
In the aforementioned groups, the C1-C4 alkyl moiety means a linear or branched alkyl group having a carbon number of 1 to 4 (e.g., methyl, ethyl, propyl, butyl).
In the aforementioned group, the C1-C4 alkoxy moiety means a linear or branched alkoxy group having a carbon number of 1 to 4 (e.g., methoxy, ethoxy).
In the aforementioned group, the C2-C4 alkenyl moiety means a linear or branched alkenyl group having a carbon number of 1 to 4 (e.g., ethenyl, propenyl, butenyl).
In the aforementioned group, the C2-C4 alkynyl moiety means a linear or branched alkynyl group having a carbon number of 1 to 4 (e.g., ethynyl, propynyl, butynyl).
In the aforementioned group, the aryl moiety is as defined above.
In the aforementioned group, examples of the substituted phenyl include, but are not limited to, mono, di or trifluorophenyl, methoxyphenyl, tolyl, xylyl, o-chlorotolyl, trifluoromethylphenyl, methoxyphenyl, tolyl, xylyl, o-chlorotolyl, trifluoromethylphenyl, 2-methoxy-5-fluorophenyl, hydroxymethylphenyl, phenoxyphenyl and the like. Examples of the substituted phenylene include, but are not limited to, 5-methyl-m-phenylene, 5-methyl-p-phenylene and the like. The polycyclic aromatic group means a fused polycyclic hydrocarbon group comprised of a fused ring of 2 to 6, preferably 2 or 3, of 5-membered and/or 6-membered monocyclic carbocycles. Examples include, but are not limited to, substituted or unsubstituted naphthyl, anthryl, phenanthryl, indenyl, fluorenyl and the like. Here, examples of the substituent include the same substituents as recited above. Examples of the aromatic heterocyclic group include a 5-membered ring containing one hetero atom such as a furanyl group, a thiophenyl group, a pyrrolyl group and the like, a 6-membered ring containing one hetero atom such as a pyridinyl group and the like, a 5-membered ring containing two hetero atoms such as an oxazolyl group, a thiazolyl group and the like, a 6-membered ring containing two hetero atoms such as a pyridazinyl group, a pyrimidinyl group and the like, and a 5- to 7-membered ring containing at least one hetero atom, a bicyclic condensed hetero group containing one hetero atom such as an indolyl group, a quinolinyl group and the like, a bicyclic condensed hetero group containing two hetero atoms such as a quinoxalinyl group and the like, a tricyclic condensed hetero group containing one hetero atom such as an acrydinyl group and the like, a bicyclic condensed hetero group containing two hetero atoms such as an indazolyl group and the like, and a polycyclic condensed hetero group containing at least one hetero atom, and the like.
In the present specification, a group of aliphatic series (aliphatic group) is a group derived from saturated hydrocarbon (alkane) and unsaturated hydrocarbon (alkene, alkyne).
Particularly preferably, X, Y and W are groups containing aromatic series or aliphatic series, monocyclic aromatic groups, such as
condensed aromatic groups having two or more rings, such as
aromatic groups wherein two aromatic groups are directly bonded, such as
substituted or unsubstituted aromatic groups wherein two aromatic groups are bonded via O, CH2, S, SO2, CH2OCH2, OCH2, OCH2CH2OCH2, OCH2OCH2CH2, CH2OCH2CH2, CH2OCH2CH2OCH2 and the like, such as
and substituted or unsubstituted aliphatic groups such as (CH2)4 can be mentioned.
More preferably, as X, Y, W, monocyclic aromatic groups, such as
condensed aromatic groups having two or more rings, such as
aromatic groups wherein two aromatic groups are directly bonded, such as
substituted or unsubstituted aromatic groups wherein an aromatic group is bonded via O, CH2O, CH2OCH2 and the like, such as
can be mentioned.
However the compound of the present invention excludes a compound represented by the following formula (Ia)
and a compound represented by the following formula (Ib)
In the formula (Ia), B is a boron atom, and V is an oxygen or sulfur atom. J1 and J3 are each independently a monocyclic aromatic group, a polycyclic aromatic group, or a heterocyclic group containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom.
J2 is a hydrogen atom; —(CH2)D—NJ4J5 wherein D is an integer of 1-4, J4 and J5 are independently a hydrogen atom, or C1-4 alkyl substituted or unsubstituted by an amino group, a mono or di-C1-4 alkylamino group or a phenyl group, or J4 and J5 form, together with a nitrogen atom bonded thereto, a 5-membered or 6-membered cyclo ring); —CO—(CH2)J5 wherein D, J4 and J5 are as defined above); —COCH(NH2)J6 wherein J6 is an amino acid residue, or —(CH2)D′NH2 wherein D′ is an integer of 1-3; —CHJ7J6 wherein J7 and J8 are independently an amino group, C1-4 alkyl substituted or unsubstituted by a mono or di(C1-4 alkyl substituted or unsubstituted by an amino group)amino group or phenyl group, or phenyl substituted by pyridyl or C1-3 alkoxy group; —CH2CH(NH2)-J9 wherein J9 is C1-4 alkyl substituted by phenyl or phenyl); quinolyl or isoquinolyl substituted by a C1-4 alkyl group; or C1-4 alkyl substituted by a pyridyl group, a piperidino group or a pyrrolidinyl group.
U is a monocyclic aromatic group, a polycyclic aromatic group or a heterocyclic group, which is the same as or different from J1 and J3, or a bifunctional group having a monocyclic aromatic group, a polycyclic aromatic group or a heterocyclic group bonded to both sides thereof via a group selected from the group consisting of a single bond, O, CH2, S, SO2, CH2OCH2, OCH2, OCH2CH2OCH2, OCH2OCH2CH2 and CH2OCH2CH2.
A compound represented by the formula (Ia) to be excluded from the compound of the present invention corresponds to a compound represented by the formula (I) disclosed in WO2007/061074. Therefore, the definition of each substituent (functional group) in the formula (Ia) follows the definition described in the publication.
In the formula (Ib), J10 is any of the following (1)-(6).
(1) a hydrogen atom.
(2) —(CH2)D″—NJ11J12.
In the group, D″ is an integer of 1-3, J11 and J12 are each independently a hydrogen atom, C1-4 alkyl, C5-6 monocyclic carbocycle, C1-4 alkyl substituted by C5-6 monocyclic carbocycle, or 5- or 6-membered monocyclic heterocycle.
The carbon atom in —(CH2)D″— is optionally substituted by 1 or 2 J13, and the carbocycle and heterocycle are optionally substituted by 1 or 2 J16. J13 is (a) C1-8 alkyl, (b) carboxyl, (c) alkoxycarbonyl, (d) keto, (e) C5-6 monocyclic carbocycle, (f) guanidino(C1-2)alkyl, (g) C1-6 alkyl substituted by C5-6 monocyclic carbocycle, (h) C1-2 alkyl substituted by 4-chlorophenoxy, or (i) C1-4 alkyl substituted by di(C1-4 alkylamino.
(3) C1-6 alkyl or C2-6 alkenyl substituted by C5-6 monocyclic carbo cycle.
The carbocycle is optionally substituted by 1 to 5 J16, and the C1-6 alkyl or C2-6 alkenyl is optionally substituted by 1 or 2 J19.
(4) C1-6 alkyl or C2-6 alkenyl substituted by 5- or 6-membered monocyclic heterocycle.
The heterocycle is optionally substituted by 1 to 5 J16, and the C1-6 alkyl and C2-6 alkenyl are optionally substituted by 1 or 2 J19. J19 is C1-4 alkyl or C2-4 alkenyl.
(5) —CHJ14J15.
In the group, J14 and J15 are each independently
(i) C5-6 monocyclic carbocycle,
(ii) 5- or 6-membered monocyclic heterocycle,
(iii) C1-6 alkyl or C2-6 alkenyl substituted by C5-6 monocyclic carbocycle, or
(iv) C1-6 alkyl or C2-6 alkenyl substituted by 5- or 6-membered monocyclic heterocycle.
Moreover, the carbocycle and heterocycle are optionally substituted by 1 to 5 J16.
(6) 5,6,7,8-tetrahydroquinolin-8-yl.
J16 is (a) C1-4 alkyl, (b) C1-4 alkoxy, (c) a halogen atom, (d) —CF3, (e) nitro, (f) C5-6 monocyclic carbocycle, (g) C1-4 alkyl substituted by C5-6 monocyclic carbocycle, (h) amino, (i) —NHCO(C1-4 alkyl), or (j) C1-4 alkoxycarbonyl.
G is Cyc1 or hydroxy.
Cyc1 is C5-10 monocyclic or bicyclic carbocycle, or 5- to 10-membered monocyclic or bicyclic heterocycle, the carbocycle and heterocycle are optionally substituted by 1 to 5 J17.
Cyc2 is C5-10 monocyclic or bicyclic heterocycle, or 5- to 10-membered monocyclic or bicyclic heterocycle. The carbocycle and heterocycle are optionally substituted by 1 to 5 Jn.
J17 and J18 are each independently
The carbocycle, phenyl, Cyc1 and Cyc2 in J17 and J18 are optionally substituted by 1 or 2 J16, or J17 and J18 optionally show —O—, and further, J18 and J19 optionally show a single bond.
d′1 is an integer of 1-4, d′2 is an integer of 1-4, and d′3 is an integer of 1-4. E is a single bond or C1-4 alkylene substituted or unsubstituted by C5-6 monocyclic carbocycle.
A compound represented by the formula (Ib) to be excluded from the compound of the present invention corresponds to a compound represented by the formula (I) disclosed in WO03/033002. Therefore, the definition of each substituent (functional group) in the formula (Ib) follows the definition described in the publication.
The compounds of the aforementioned (1)-(13) in the present invention specifically include the following.
The present invention also relates to the compounds represented by the following formula (4′) or (8′) or a pharmaceutically acceptable salt thereof.
R3′—[—X′—B(ZR1′)—]n—R4′ (4′)
R3′—B(ZR1′)—X′—B(ZR2′)—R4′ (8′)
In the formulas, B is a boron atom, Z is O or S, R1′ and R2′ are H, —(CH2)m—NR5′R6′, —CHR11′R12′, —COCH(NH2)—(CH2)mNHCONH2 or —COCH(NH2)—(CH2)m—COR19′. Here, R5′, R6′, R11′, R12′ and R19′ are independently H, or amino or heterocyclyl, each of which is substituted or unsubstituted. R3′ and R4′ are H, aryl or heterocyclyl, X′ is substituted or unsubstituted aromatic group, m is an integer of 1-5, and n is an integer of 1-100.
The “amino”, “heterocyclyl”, “aryl” and “aromatic group” are as defined above.
Specifically, the following compound can be mentioned:
The compounds (1)-(13) in the present invention can be converted to pharmaceutically acceptable non-toxic salts by a known method. The non-toxic salts include, for example, alkali metal salts, alkaline earth metal salts, amine salts, acid addition salts, solvates (including hydrates) and the like. In general, water-soluble ones are preferable.
Suitable non-toxic salts are salts with alkali metal such as potassium, sodium and the like; salts with alkaline earth metal such as calcium, magnesium and the like; and salts with organic amine such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine and the like, preferably, alkali metal salts.
Moreover, as suitable acid addition salts, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, and organic acid salts such as acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate and gluconate can be mentioned.
The compound of the present invention also includes solvates. Solvate is a conjugate, particularly in a crystal form, of the aforementioned compound of the present invention and a pharmaceutically acceptable solvent (for example, water, organic solvent) at a stoichiometrical or non-stoichiometrical ratio.
The present invention relates to a prophylactic and/or therapeutic drug for a disease caused by protein cross-linking, which contains the aforementioned protein cross-linking inhibitor.
As the disease caused by abnormal protein cross-linking, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis and congenital hemostatic disorder can be mentioned. Particularly, it is desirably used as prophylactic and/or therapeutic drug for Alzheimer's disease.
The compound of the present invention can be synthesized by the methods described in WO03/033002 and WO2007/061074 or a method analogous thereto. In addition, the compound of the present invention can be synthesized by the following method or a method analogous thereto.
The main starting materials for the production of the compound of the present invention are monobromo compound, dibromo compound and alkoxyborane. A bromo compound is reacted with alkyl lithium to give a lithium compound R3—Li (formula (17)). A dibromo compound (Br—X—Br or Br—Y—Br) is reacted with alkyl lithium to give a dilithium compound (Li—X—Li or Li—Y—Li) (formula (14) and formula (15)). Alternatively, magnesium is reacted to give a Grignard reagent (formula (16)). These metal compounds are reacted with trialkoxyborane to give dialkoxyborane R3—B(OAlk)2 (formula (19)). R3—B(OAlk)2 is reacted with Li—X—Li to give R3—B(OAlk)-X—B—(OAlk)-R3 (formula (20)) (Alk is an alkyl group having 1 to 4 carbon atoms). A dilithium compound (Li—X—Li) is reacted with R3—B(OAlk)-X—B—(OAlk)-R3 to give (—B(OAlk)-X—)n. The resultant product is treated with acidic water to give (—B(OH)—X—), (formula (22)). R3—Li, R4—Li, (OAlk)2B—X—B(OAlk)2 and Li—Y—Li are reacted to give R3—(—Y—B(OAlk)-X—B(OAlk)-)n—R4 and this is treated with acidic water to give R3—(—Y—B(OH)—X—B(OH)—)n—R4 (formula (23)). Li—X—Li is reacted with (OAlk)2B—Y—B(OAlk)2 to give (—X—B(OAlk)-Y—B(OAlk-)n, which is treated with acidic water to give (—X—B(OH)—Y—B(OH)—)n (formula (24)). These two bifunctional compounds are reacted to give various borinic acids. Borinic acid is reacted with desired HZR wherein R is R1 or R2 used in the formulas (1)-(13)) to give the object compound (formulas (25) and (26)).
By a reaction with diphenylborinic acid using amino acid and β aminothiol instead of β amino alcohol, a dehydrating reaction occurs and a desired compound can be obtained (formula (27), formula (28)).
C6H5B(OH)C6H5+HOOC6CHRNH2→C6H5B(OCOCHRNH2)C6H5 (27)
C6H5B(OH)C6H5+HSCH2CH2NH2→C6H5B(SCH2CH2NH2)C6H5 (28)
As for a part of the compounds (1)-(13) of the present invention, according to the aforementioned schemes (14)-(26), borinic acid is synthesized from a bromine compound and bromobenzene by a similar method, which is reacted with amino alcohol, amino acid or aminothiol to synthesize a desired compound.
In addition, a compound represented by the formula (4′) or (8′) can be synthesized according to the formulas (20), (29), (30) and (31).
In the following, the compounds represented by the formulas (1)-(13) (including compounds represented by the formulas (4′) and (8′)) are also referred to as the compound of the present invention.
In the present invention, the enzyme (transglutaminase (TGase)) inhibitory action is determined by measuring the enzyme activity by an appropriately-modified method based on Lorand et al. (Lorand, L. et al. (1971), Anal Biochem. 1971 November; 44(1):221-31.). For example, the method described in the Example can be performed.
In the present invention, the polyglutamine aggregation inhibitory activity (x-Fold) can be measured, for example, by the method described in the Example.
The SOC (store operated calcium channel)-suppressive action can be measured by the method described in the Example and using, for example, FDSS 3000.
The compound of the present invention (i.e., active substance or active ingredient) is administered systemically or topically in an oral or parenteral dosage form to a test subject (mammal inclusive of human, preferably human). The parenteral administration includes intravenous administration, intraarterial administration, intramuscular administration, subcutaneous administration, intradermal administration, intraperitoneal administration, intrarectal administration, intradural administration, vaginal administration, transmucosal administration and the like.
While the dose varies depending on the kind of the compound to be administered, age, body weight and symptom of the subject of administration, treatment effect, administration method and the like, generally, for example, 10 μg-1000 mg is orally administered to one adult (body weight about 60 kg) once to several times per day or, for example, 1 μg-100 mg is parenterally administered to one adult (body weight about 60 kg) once to several times per day.
The administration preparation of the compound of the present invention includes, but are not limited to, tablet, pill, suspension, solution, capsule, syrup, elixir, granule, powder and the like for oral administration, injection, external preparation, suppository, external liquid, ointment, embrocation, inhalant, spray, pessary for vaginal administration and the like for parenteral administration.
The aforementioned preparation can contain a pharmacologically acceptable carrier (excipient, diluent and the like) or an additive in combination with the compound of the present invention as an active ingredient.
As the aforementioned excipient and additive, those conventionally used in the field of medicaments can be used. For example, the agents and formulation methods described in Remington: The Science and Practice of Pharmacy 9th ed. (1995) MACK PUBLISHING COMPANY (US) can be referred to.
Examples of the excipient include lactose, mannitol, glucose, microcrystalline cellulose, starch and the like.
Examples of the additive include binders (hydroxypropylcellulose, polyvinylpyrrolidone, magnesium alumino metasilicate etc.), disintegrants (calcium cellulose glycolate etc.), lubricants (magnesium stearate etc.), stabilizers, solubilizing agents (glutamic acid, aspartic acid etc.) and the like.
The preparation of the present invention may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulosephthalate etc.), or may be coated with two or more layers. By applying such coating, the forms of control release preparation, enteric preparation and the like can be provided. Further, a capsule of absorbable substances such as gelatin is also encompassed.
In a liquid for oral administration, one or more of the activity substances are dissolved, suspended or emulsified in a generally-used diluent (purified water, ethanol, buffer, or a mixed solution thereof etc.). Further, the liquid may contain a wetting agent, a suspending agent, an emulsifier, a stabilizer, a sweetening agent, a flavoring agent, an aromatic, a preservative, a buffering agent and the like.
The injection for parenteral administration includes a solution, a suspension, an emulsion and an injection obtained by dissolving or suspending in a solvent when in use. An injection can be obtained by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, saline, vegetable oil, alcohols such as propylene glycol, polyethylene glycol and ethanol and a combination thereof are used. Furthermore, the injection may contain a stabilizer (amino acid such as lysine, methionine and the like, sugar such as trehalose and the like), a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark) etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative and the like. These injections are sterilized in the final step or produced and prepared by an aseptic operation method. In addition, an aseptic solid agent, for example, a freeze-dried product may be produced, and dissolved in sterilized or aseptic distilled water for injection or other solvent and used.
A spray may contain, besides a generally-used diluent, a stabilizer such as sodium bisulfite and a buffering agent that achieves isotonicity, for example, an isotonic agent such as sodium chloride, sodium citrate and citric acid.
In the present specification, when the terminal group is a hydroxyl group, a chemical formula omitting a hydroxyl group is sometimes described. The number after the compound name is the compound No.
The compound of the present invention (10 mM, 1 μL) was taken in a 96-well plate (Nunc, 96 Well Black Plate with Clear Bottom), an enzyme reaction solution (100 mM HEPES-NaOH, pH 7.5, 1 mM CaCl2, 20 μM monodansyl cadaverine, 0.05 mg/mL N,N-dimethylcasein, 5 μg/mL TGase) (0.1 ml) was added and the mixture was sufficiently mixed without making foams. The mixture was set on a fluorescence drug screening system FDSS 3000 (Hamamatsu Photonics K.K.), and changes in the fluorescence wavelength per unit time at 340 nm were measured, based on which the TGase inhibitory activity of the compound of the present invention was calculated. As a control, change in the fluorescence when 1 μL of DMSO (dimethyl sulfoxide) was added instead of the compound of the present invention was taken as 100, and TG50 was when the activity decreased to half due to the compound of the present invention. The results are shown in the following.
Truncated N-terminal huntington 150 Q-EGFP-Neuron 2a cells (prepared according to Wang, G. H., Nukina, N et al, Neuroreport, 10, 2435-2438 (1999)) were cultured for one day in a 96-well plate, 1 μM ponasterone A (2 μL) and 5 μM dibutyl cyclic AMP (2 μL) were added such that the concentration of the compound of the present invention became 20 μM, and the mixture was cultured for 20 hr. The cells were fixed with 4% para-formaldehyde and, 30 min later, the cells were washed with PBS and stained with Hoechst 33342. The number of the aggregated cells, and the total number of cells were counted by Array Scan V T1 (manufactured by Cellomics, Pittuburg, USA), and the ratio of the aggregated cells to the total number of cells was determined (x-Fold). Without the compound of the present invention, the respective numbers of cells were almost the same, and the number of the aggregated cells to the total number of cells was almost 1. A smaller value shows a stronger polyglutamine aggregation inhibitory activity. The results are shown in the following.
CHO cell culture medium was replaced with a BSS solution which is an extracellular fluidfree of calcium, the compound of the present invention was added 1 min later, and 1 μM thapsigargin was allowed to act thereon 2 min later to deplete intracellular calcium store. After 9 min, to the extracellular fluid was added calcium chloride at the final concentration of 2 mM, and an influence of each compound on the degree of increase in the intracellular calcium concentration after addition was estimated, based on which SOC suppressive action (IC50) was determined. The results are shown in the following.
TG 28, x-Fold 0.95
TG 28, x-Fold 0.82, SOC IC50 0.2 μM
TG −20, x-Fold 0.49, SOC IC50 0.5 μM
TG 109, x-Fold 0.80, SOC IC50 5 μM
TG −4, x-Fold 0.60, SOC IC50 0.15 μM
TG 23, x-Fold 1.01, SOC IC50 0.2 μM
TG 14, x-Fold 1.03, SOC IC50 0.2 μM
TG 24, x-Fold 1.1, SOC IC50 0.2 μM
TG 12, x-Fold 0.87, SOC IC50 0.5 μM
TG 7, x-Fold 0.92, SOC IC50 0.5 μM
TG 36, x-Fold 0.99
TG 91, x-Fold 1.04
TG 100, x-Fold 1.11
4,4′-p-brombenzyl ether (90 mg) was dissolved in ether (4 ml), and the mixture was cooled to −78° C. 1N sec-Butyllithium (0.75 mL) was added and the mixture was stirred for 60 min (SOLUTION A). 4,4′-parabromophenyl ether (90 mg) was dissolved in ether (4 ml), and the mixture was cooled to −78° C. Thereto was added 1N sec-butyllithium (0.7 mL) and the mixture was stirred for 30 min. Triisopropoxyborane (188 mg) was added and the mixture was stirred to −65° C. (SOLUTION B). SOLUTION A and SOLUTION B were mixed, and the mixture was gradually warmed and stirred at room temperature for 15 hr. The mixture was acidified with 1N hydrochloric acid, and the organic layer was washed with water, dried, and concentrated to give the title compound (154 mg).
TG 85, x-Fold 1.03
Poly(1,4-phenylenemethyleneoxymethylene 1,4-phenylene hydroxyborane) (34 mg) obtained in Example 13 was dissolved in a mixture of ethanol (0.5 mL) and ether (0.5 mL) and the mixture was stirred at 50° C. for 1 hr. After concentration, ether (1 mL) was added to produce the title compound (15 mg) as a white precipitate.
TG 91, x-Fold 0.90
TG 86, x-Fold 0.95
TG 111, x-Fold 0.65
4,4′-Dibromodiphenylether (328 mg) was dissolved in ether (10 ml), sec-butyllithium (2 ml) was added at −95° C. and the mixture was warmed to −78° C. 30 min later. Thereto was added triisopropoxyborane (188 mg) and the mixture was stirred for 1 hr. The mixture was gradually warmed and stirred at room temperature for 15 hr. The mixture was acidified with 1N hydrochloric acid, and the organic layer was washed with water, dried, concentrated, and subjected to silica gel column chromatography to give the title compound (112 mg).
TG −17, x-Fold 0.84, SOC IC50 1.5 μM
TG 47, x-Fold 0.86
TG 54, x-Fold 0.63, SOC IC50 4 μM
TG 111, x-Fold 0.72
TG 30, x-Fold 0.62
TG 114, x-Fold 0.62
4,4′-p-bromophenyl p-brombenzyl ether (171 mg) was dissolved in ether (8 ml), and the mixture was cooled to −100° C. Thereto was added 1N sec-butyllithium (1 mL) and the mixture was stirred for 30 min to −78° C. (SOLUTION A). p-bromophenyl p-brombenzyl ether (171 mg) was dissolved in ether (10 ml), and the mixture was cooled to −78° C. Thereto was added 1N sec-butyllithium (1 ml) and the mixture was stirred for 30 min. Triisopropoxyborane (188 mg) was added and the mixture was stirred to −65° C. (SOLUTION B). SOLUTION A and SOLUTION B were mixed, and the mixture was gradually warmed and stirred at room temperature for 15 hr. The mixture was acidified with 1N hydrochloric acid, and the organic layer was washed with water, dried, and concentrated to give the title compound (161 mg).
TG 96, x-Fold 0.78
TG 12, x-Fold 0.69
TG 116, x-Fold 0.78
TG 45, x-Fold 0.86, SOC IC50 5 μM
The title compound (189 mg) was obtained from bis(4-bromobenzyl)ether (178 mg) and parabromophenyl parabrombenzyl ether (171 mg).
TG 94, x-Fold 0.72
TG 52, x-Fold 0.83
TG 107, x-Fold 1.02
TG 127, x-Fold 0.95
TG 12, x-Fold 1.02, SOC IC50 1 μM
di(3-Chloro-4-methylphenyl)borinic acid (44 mg) and 2-aminoethanethiol (35 mg) were reacted in ethanol (1 mL) to give the title compound (52 mg).
TG 51, x-Fold 0.92
Paradibromobenzene (353.85 mg) was dissolved in ether (10 mL), and sec-butyllithium (3 mL) was added at −95° C. 30 min later, triisoproxyborane (552 μL) was added at −78° C. and the mixture was stirred for 1 hr (SOLUTION A). 2,5-Dimethoxy-1,4-dibromobenzene (443.35 mg) was dissolved in ether (10 μL), sec-butyllithium (3 ml) was added at −95° C. and the mixture was stirred for 30 min (SOLUTION B). SOLUTION A and SOLUTION B were mixed at −78° C., and the mixture was gradually warmed to room temperature and stirred overnight. Thereto was added hydrochloric acid solution to give the title compound (4.9 mg).
TG 39, x-Fold 1.01
TG 14, x-Fold 0.98
TG 6, x-Fold 0.65, SOC IC50 3 4M
4,4′-Dibromobiphenyl (312 mg) was dissolved in ether (10 mL), and the mixture was cooled to −100° C. Thereto was added 1N sec-butyllithium (2.1 mL) and the mixture was stirred for 30 min to −78° C. (SOLUTION A). 4,4′-Dibromodiphenylether (328 mg) was dissolved in ether (10 ml), and the mixture was cooled to −78° C. Thereto was added 1N sec-butyllithium (2.1 ml) and the mixture was stirred for 30 min. Triisopropoxyborane (376 mg) was added and the mixture was stirred to −65° C. (SOLUTION B). SOLUTION A and SOLUTION B were mixed, and the mixture was gradually warmed and stirred at room temperature for 15 hr. The mixture was acidified with 1N hydrochloric acid, and the organic layer was washed with water, dried, and concentrated to give the title compound (114 mg).
TG −22, x-Fold 0.73
TG 79, x-Fold 0.71
TG 99, x-Fold 1.04
TG 26, x-Fold 0.52
TG 54, x-Fold 0.63, SOC IC50 2 μM
TG 8, x-Fold 0.53, SOC IC50 2 μM
TG 13, x-Fold 0.73, SOC IC50 3 μM
TG 12, x-Fold 0.54, SOC IC50 4 μM
TG 99, x-Fold 0.52
TG 93, x-Fold 0.50
TG 106, x-Fold 0.58
TG 102, x-Fold 0.59
TG 89, x-Fold 0.96
TG 112, x-Fold 0.59
TG 13, x-Fold 0.43
TG 73, x-Fold 0.69
TG 113, x-Fold 0.74
TG 112, x-Fold 0.67
TG 151, x-Fold 0.71
TG 74, x-Fold 0.71
TG 5.98, x-Fold 0.67, SOC IC50 μM
TG 45, x-Fold 0.62
TG 107, x-Fold 0.72
TG 24, x-Fold 0.73
TG 100, x-Fold 0.99
4,4′-Dibromodibenzyl ether (96 mg) was dissolved in ether (6 ml), 1M sec-butyllithium (0.7 mL) was added and the mixture was stirred for 30 min. Triisoproxyborane (240 μL) was added at −78° C. and the mixture was stirred for 1 hr (SOLUTION A). 4,4′-Dibromodiphenyl ether (82.7 mg) was dissolved in ether (5 ml), 1N sec-butyllithium (0.7 mL) was added at −78° C. and the mixture was stirred (SOLUTION B). SOLUTION A and SOLUTION B were mixed at −78° C., and the mixture was gradually warmed to room temperature and stirred overnight. 1N Hydrochloric acid was added, and the ether layer was washed with saturated brine, dried, and concentrated to give the title compound (150 mg).
TG 94, x-Fold 0.95
TG 63, x-Fold 1.04
TG 11, x-Fold 0.95
TG 115, x-Fold 1.02, SOC IC50 7 μM
TG 120, x-Fold 1.18, SOC IC50 >20 μM
TG 122, x-Fold 0.87
4,4′-Parabrombenzyl ether (180 mg) was dissolved in ether (10 mL), and the mixture was cooled to −78° C. 1.57N tert-Butyllithium (0.7 mL) was added and the mixture was stirred for 60 min (SOLUTION A). 1,4-Dibromobenzene (118 mg) was dissolved in ether (10 mL), and the mixture was cooled to −78° C. 1.57N tert-Butyllithium (0.7 mL) was added and the mixture was stirred for 30 min. Triisopropoxyborane (188 mg) was added and the mixture was stirred to −65° C. (SOLUTION B). SOLUTION A and SOLUTION B were mixed, and the mixture was gradually warmed to room temperature and stirred for 15 hr. The mixture was acidified with 1N hydrochloric acid, and the organic layer was washed with water, dried, and concentrated to give the title compound (184 mg).
TG 119, x-Fold 1.04
1,4-Tetramethylenedibromide (262 mg) was dissolved in ether (10 ml), and reacted with magnesium (Mg) (58 mg). Trimethoxyboroxin (60 μL) was added and the mixture was stirred overnight. Hydrochloric acid was added and the ether layer was concentrated to give the title compound (43.8 mg).
TG 76, x-Fold 1.02
TG 13, x-Fold 0.73, SOC IC50 0.3 μM
TG 51, x-Fold 0.97, SOC IC50 1 μM
TG 41, x-Fold 1.02, SOC IC50 0.5 μM
TG 35, x-Fold 0.85, SOC IC50 1.2 μM
TG 41, x-Fold 0.95, SOC IC50 1 μM
TG 97, x-Fold 0.88
TG 117, x-Fold 0.78
TG 98, x-Fold 0.91
TG 104, x-Fold 1.02
TG 97, x-Fold 0.88
TG 93, x-Fold 0.90
TG 97, x-Fold 0.92
TG 103, x-Fold 0.95
TG 101, x-Fold 0.92
TG 91, x-Fold 0.92
TG 128, x-Fold 0.79
4,4′-Dibromodiphenyl (234 mg) was dissolved in ether (10 ml), and 1.5N tert-butyllithium (1.3 mL) was added at −95° C. 30 min later, triisoproxyborane (345 μL) was added at −78° C. and the mixture was stirred for 1 hr (SOLUTION A). 4,4′-Dibromodiphenyl (234 mg) was dissolved in ether (10 mL), 1.5N tert-butyllithium (1.3 mL) was added at −95° C. and the mixture was stirred (SOLUTION B). SOLUTION A and SOLUTION B were mixed at −78° C., and the mixture was gradually warmed to room temperature and stirred overnight. 1N Hydrochloric acid solution was added and the ether layer was with washed with saturated brine and dried and concentrated to give the title compound (155 mg).
TG 103, x-Fold 0.99
TG 91, x-Fold 1.02
TG 82, x-Fold 0.83
TG 80, x-Fold 0.94
TG 93, x-Fold 0.81
TG 107, x-Fold 0.99
TG 106, x-Fold 1.00
TG 117, x-Fold 0.93
TG 114, x-Fold 0.95
TG 114, x-Fold 0.88
TG 124, x-Fold 0.86
TG 122, x-Fold 0.72
TG 111, x-Fold 0.95
TG 109, x-Fold 0.73
TG 119, x-Fold 0.97
TG 122, x-Fold 1.02
TG 72, x-Fold 1.10
TG 114, x-Fold 0.89
TG 94, x-Fold 1.16
TG 92, x-Fold 1.05
TG 23, x-Fold 0.92
TG 111, x-Fold 0.98
TG 111, x-Fold 1.00
TG 108, x-Fold 1.02, SOC IC50 >10 μM
TG 115, x-Fold 1.02, SOC IC50 >10 μM
TG 121, x-Fold 1.02
TG 123, x-Fold 0.99
TG 112, x-Fold 0.99
TG 120, x-Fold 0.99, SOC IC50 2 μM
TG 101, x-Fold 1.07
TG 108, x-Fold 1.02
TG 108, x-Fold 0.06, SOC IC50 1.5 μM
TG 93, x-Fold 0.97, SOC IC50 2 μM
TG 101, x-Fold 0.84, SOC IC50 >20 μM
TG 88, x-Fold 1.08
TG 121, x-Fold 0.94
TG 93, x-Fold 0.98, SOC IC50 7 μM
Arginine (82 mg) and 2-aminoethyldiphenylborinate (112 mg) were stirred in ethanol (0.4 ml), water (1.5 ml) and acetic acid (0.9 ml) at 110° C. for 3 hr to give the title compound (17 mg).
The present compound were also obtained by heating arginine hydrochloride (211 mg) and sodium tetraphenylborate (342 mg) in water (5 mL) at 100° C. for 3 hr.
TG 98, x-Fold 0.84, SOC IC50 1 μM
TG 90, x-Fold 0.96
TG 113, SOC IC50 10 μM
TG 81, x-Fold 1.04
TG 109, x-Fold 0.70
TG 143, x-Fold 0.93
TG 101, x-Fold 0.78
TG 116, x-Fold 0.85
TG 16, x-Fold 1.1, SOC IC50 0.3 μM
TG 88, x-Fold 0.95
TG 106, x-Fold 1.00
TG 94, x-Fold 0.92
TG 99, x-Fold 1.03
TG 96, x-Fold 0.98
TG 14, x-Fold 0.99, SOC IC50 0.3 μM
TG 96, x-Fold 0.99
TG 122, x-Fold 0.88
TG −72, x-Fold 0.85
TG 97, x-Fold 0.92
TG 88, x-Fold 0.24
TG 118, x-Fold 0.90
TG 99, x-Fold 0.87
TG 97, x-Fold 0.91
TG 91, x-Fold 1.02
TG 101, x-Fold 0.87, SOC IC50 20 μM
TG 68, x-Fold 1.00
TG 96, x-Fold 0.99
TG 2, x-Fold 0
TG 33, x-Fold 0.87
TG54, x-Fold 1.07
TG 65, x-Fold 0.79
TG 105, x-Fold 0.96-
TG 100, x-Fold 1.02
TG 91, x-Fold 1.08
TG 96, x-Fold 0.73
TG 12, x-Fold 0.69
TG 102, x-Fold 0.96
TG 88, x-Fold 1.02
TG 6, x-Fold 0.99
NHS-Florescein (Pierce: catalog No. 46100) (4.73 mg) was dissolved in DMF (100 μL), TEAB (pH 7.5) (100 μL) and diphenyl 2-aminoethylaminoethoxyborane (2.68 mg) were added, and the mixture was stirred at room temperature for 3 hr and applied to DEAE cellulose column for purification, whereby the title compound (8.1 mg) was obtained.
TG −2, x-Fold 0.85
TG 109, x-Fold 1.00
TG 94, x-Fold 0.67
TG 120, x-Fold 0.99
TG 74, x-Fold 0.70
TG 21, x-Fold 0.71
TG 35, x-Fold 0.72
TG 101, x-Fold 0.78
TG 96, x-Fold 0.96
TG 98, x-Fold 0.71
TG 69, x-Fold 1.22
TG 122, x-Fold 1.06
TG 103, x-Fold 0.99
TG 5, x-Fold 0.89
TG 47, x-Fold 1.06
TG 28, x-Fold 1.00
TG 142, x-Fold 0.89
TG 127, x-Fold 0.99
TG 35, x-Fold 0.98
TG 54, x-Fold 0.69
TG 137, x-Fold 1.01
Di(3-chloro-4-methylphenyl)borinic acid (32 mg) and glutamine (15 mg) were reacted in ethanol (0.6 mL) at 90° C. for 2 hr to give the title compound (34 mg).
TG 91, x-Fold 1.02
TG 94, x-Fold 0.95
TG 130, x-Fold 0.94, SOC IC50 >20 μM
Aminoethyldiphenylborinate (112 mg) and piperazinecarboxylic acid (102 mg) were reacted in ethanol (0.6 mL) and acetic acid (30 mL) at 80° C. for 5 hr to give the title compound (36 mg).
TG 81, x-Fold 0.98
TG 106, x-Fold 0.97
TG 91, x-Fold 0.98
TG 119, x-Fold 0.94
TG 99, x-Fold 1.05
TG 85, x-Fold 1.04
TG 102, x-Fold 0.95
TG 92, x-Fold 1.03
Aminoethyldiphenylborinate (112 mg) and pyrazine 2,3-dicarboxylic acid monoamide (83 mg) were reacted in ethanol (0.5 mL) and acetic acid (30 mg) to give the title compound (40 mg).
TG 106, x-Fold 1.03
The title compound (35 mg) was obtained from diphenylborinic acid (61 mg) and methionine (50 mg).
TG 115, x-Fold 0.77
TG 117, x-Fold 0.90
TG 99, x-Fold 1.02
TG 28, x-Fold 0.8
TG 3, x-Fold 0.90
TG 100, x-Fold 0.92
TG 99, x-Fold 0.57
TG 91, x-Fold 0.94
TG 97, x-Fold 0.97
TG 61, x-Fold 0.79
TG 47, x-Fold 0.80
TG 34, x-Fold 1.14
TG 83, x-Fold 0.91
TG −7, x-Fold 0.67
TG 1, x-Fold 0.98
TG 27, x-Fold 0.98, SOC IC50 2 μM
TG 86, x-Fold 0.99, SOC IC50 1 μM
TG 115, x-Fold 0.75
TG 117, x-Fold 1.00
TG −7, x-Fold 0.90, SOC IC50 2 μM
TG 69, x-Fold 1.03, SOC IC50 2 μM
TG 17, x-Fold 1.03, SOC IC50 0.6 μM
TG 118, x-Fold 0.94
TG 90, x-Fold 0.97
TG 91, x-Fold 0.88
TG 26, x-Fold 0.50, SOC IC50 0.5 μM
TG 73, x-Fold 0.94
TG 122, x-Fold 0.86
Compound 7142 (Example 478) (53.3 mg) and glutamine (44 mg) were reacted in ethanol (2 ml) at 80° C. for 24 hr to give the title compound (14 mg).
NMR (DMSO) 1.95 (m, 2H), 2.0 (m, m, 2H), 2.23 (m, 2H), 3.35 (m, 4H), 7.4-8.1 (m, 8H)
TG 116, x-Fold 1.02
Compound 4144 (Example 235) (41.3 mg) and glutamine (36 mg) were reacted in ethanol (2 ml) at 80° C. for 24 hr to give the title compound (75 mg).
NMR (DMSO) 1.95 (m, 2H), 2.05 (m, 2H), 2.25 (m, 2H), 3.40 (m, 4H), 6.8-7.7 (m, 8H)
TG 112, x-Fold 0.89
TG 109, x-Fold 1.03, SOC IC50 0.5 μM
TG 97, x-Fold 0.94
TG 110, x-Fold 0.99
TG 99, x-Fold 0.98
TG 40, x-Fold 1.09, SOC IC50 0.5 μM
TG 108, x-Fold 1.03
TG 94, x-Fold 1.01
TG 108, x-Fold 1.10
TG 112, x-Fold 1.12
TG 98, x-Fold 1.07, SOC IC50 0.5 μM
TG 80, x-Fold 1.03
TG 87, x-Fold 1.10
TG 88, x-Fold 1.15
TG 87, x-Fold 1.07
TG 126, x-Fold 0.94
TG 25, x-Fold 0.99, SOC IC50 0.08 μM
TG 67, x-Fold 1.10
TG 98, x-Fold 1.17
TG 106, x-Fold 0.73
TG 74, x-Fold 0.76, SOC IC50 1 μM
TG 94, x-Fold 0.91
TG 94, x-Fold 0.67
TG 99, x-Fold 0.91, SOC IC50 0.7 μM
TG 103, x-Fold 0.87
TG 25, x-Fold 0.74, SOC IC50 0.3 μM
TG 125, x-Fold 0.86
TG 121, x-Fold 0.83
TG 93, x-Fold 0.95, SOC IC50 0.5 μM
TG 92, x-Fold 1.11
TG 101, x-Fold 0.95
TG 113, x-Fold 0.94, SOC IC50 0.5 μM
TG 112, x-Fold 0.67, SOC IC50 1.5 μM
Diphenylborinic acid (78 mg) and sodium glutamate (73 mg) were stirred with heating in ethanol, water 1:1 mixture (1 mL) at 70° C. for 1 hr to give the title compound (120 mg).
TG 103, x-Fold 0.98
Diphenylborinic acid (50 mg) and aspartic acid (25 mg) were stirred with heating in ethanol, water 1:1 mixture (1 mL) at 70° C. for 1 hr to give the title compound (6 mg).
TG 110, SOC IC50 5 μM
Diphenylborinic acid (50 mg) and L-alanine (25 mg) were stirred with heating in ethanol, water 1:1 mixture (1 mL) at 70° C. for 1 hr to give the title compound (6 mg).
TG 67, x-Fold 0.97, SOC IC50 2.5 μM
Diphenylborinic acid (47 mg) and phenylalanine (43 mg) were stirred with heating in ethanol, water 1:1 mixture (1 mL) at 70° C. for 16 hr to give the title compound (10 mg).
TG 106, x-Fold 0.89
Diphenylborinic acid (46 mg) and tryptophan (52 mg) were stirred with heating in ethanol, water 1:1 mixture (1 mL) at 70° C. for 1 hr to give the title compound (15 mg).
TG 109, x-Fold 0.89
Diphenylborinic acid (46 mg) and leucine (33 mg) were stirred with heating in ethanol, water 1:1 mixture (1 ml) at 70° C. for 1 hr to give the title compound (10 mg).
TG 115, x-Fold 0.97
Diphenylborinic acid (52 mg) and isoleucine (37 mg) were stirred with heating in ethanol, water 1:1 mixture (1 mL) at 70° C. for 1 hr to give the title compound (10 mg).
TG 146, x-Fold 0.89, SOC IC50 3 μM
Sodium tetraphenylborate (342 mg) and 2,4-diaminobutyric acid-hydrochloride (191 mg) were stirred with heating in water (7 ml) at 80° C. for 1 hr to give the title compound (160 mg).
TG 109, x-Fold 1.00, SOC IC50 5 μM
Diphenylborinic acid (57 mg) and tyrosine (57 mg) were stirred with heating in ethanol, water 1:1 mixture (1 ml) at 70° C. for 1 hr to give the title compound (24 mg).
TG 112, x-Fold 0.94
Diphenylborinic acid (42 mg) and threonine (28 mg) were stirred with heating in ethanol, water 1:1 mixture (0.5 mL) at 70° C. for 1 hr to give the title compound (20 mg).
TG 84, x-Fold 0.87, SOC IC50 3 μM
Diphenylborinic acid (31 mg) and cysteine (21 mg) were stirred with heating in ethanol, water 1:1 mixture (0.5 mL) at 70° C. for 1 hr to give the title compound (20 mg).
TG 82, x-Fold 0.60, SOC IC50 3 μM
Diphenylborinic acid (32 mg) and histidine hydrochloride (36 mg) were stirred with heating in ethanol, water 1:1 mixture (0.5 mL) at 70° C. for 1 hr to give the title compound (6 mg).
TG 103, x-Fold 0.96, SOC IC50 5 μM
Diphenylborinic acid (41 mg) and hydroxyproline (30 mg) were stirred with heating in ethanol, water 1:1 mixture (0.5 ml) at 70° C. for 1 hr to give the title compound (5 mg).
TG 95, x-Fold 1.01, SOC IC50 3 μM
Diphenyl 2-aminoethylborinate (112 mg) and glutamine (74 mg) were stirred with heating in a mixture of ethanol (0.4 mL), water (1.5 ml) and acetic acid (0.03 ml) at 100° C. for 10 min to give the title compound (21 mg).
TG 111, x-Fold 0.54, SOC IC50 0.7 μM
Diphenylborinic acid (182 mg) and asparagine (32 mg) were stirred with heating in ethanol, water 3:1 mixture (1 mL) at 70° C. for 1 hr to give the title compound (14 mg).
TG 109, x-Fold 1.07, SOC IC50 0.5 μM
Diphenylborinic acid (49 mg) and lysine hydrochloride (49 mg) were stirred with heating in a mixture of ethanol (1.5 ml) and water (0.5 mL) at 80° C. for 1 hr to give the title compound (44 mg).
TG 83, x-Fold 0.09, SOC IC50 0.3 μM
Sodium tetraphenylborate (342 mg) and 2,4-diaminopropionic acid•hydrochloride (141 mg) were stirred with heating in water (5.5 ml) at 80° C. for 2 hr to give the title compound (203 mg).
TG 83, x-Fold 0.56, SOC IC50 0.25 μM
Bis(4,4′-(phenylhydroxyboryl)phenyl)ether (22 mg) and glutamine (19 mg) were heated in ethanol (2 mL) at 60° C. for 1 hr to give the title compound (8 mg).
TG 56, x-Fold 0.59, SOC IC50 0.3 μM
Bis(4,4′-(phenylhydroxyboryl)phenyl)ether (20 mg) and asparagine (14 mg) were stirred with heating in ethanol (3 mL) at 60° C. for 1 hr to give the title compound (7 mg).
TG 117, x-Fold 0.67, SOC IC50 0.3 μM
4-(Phenyl-hydroxyboryl)phenyl)-4′-(hydroxymethylphenyl-hydroxyboryl)phenyl)ether (27 mg) and sodium glutamate (22.3 mg) were reacted in ethanol (0.5 mL) to give the title compound (23 mg).
TG 105, x-Fold 0.8
Diphenylborinic acid (39 mg) and glutamine (3.7 mg) were reacted in ethanol (0.6 mL) at 60° C. for 1 hr to give the title compound (10 mg).
TG 105, x-Fold 0.98, SOC IC50 0.3 μM
Diphenylborinic acid (47 mg) and proline (2.7 mg) were reacted in ethanol (0.6 ml) at 60° C. for 1 hr to give the title compound (10 mg).
TG 2, x-Fold 1.08, SOC IC50 0.3 μM
Using 3-bromobenzyl-3′-phenoxybenzylether (1173 mg), bromobenzene (400 mg) and triisopropoxyborane (560 mg) as main starting materials, hydroxybromo compound was synthesized, and reacted with ethanolamine at room temperature to give the title compound (700 mg).
NMR (CDCl3), 2.73 (m, 2H), 3.72 (t, 2H), 4.14 (m, 4H), 4.49 (s, 2H), 6.8-7.3 (m, 18H)
TG 103, x-Fold 0.98
TG 98, x-Fold 0.88
Aminoethyldiphenylborinate (112 mg) and 2,4-diaminobutyric acid•hydrochloride (35 mg) were reacted in ethanol (0.5 ml) and acetic acid (30 mg) to give the title compound (139 mg).
TG 77, x-Fold 0.94
TG 112, x-Fold 0.95, SOC IC50 0.3 μM
Di(3-chloro-4-methyl)phenylborinic acid (82 mg) and asparagine (81 mg) were reacted in ethanol (0.6 mL) to give the title compound (37 mg).
TG 12, x-Fold 0.83, SOC IC50 0.9 μM
Di(3-chloro-4-methyl)phenylborinic acid (47 mg) and dimethylaminoethanethiol (17 mg) were stirred in ether (1 ml) overnight, ether (2 ml) was added to give the title compound (17 mg) as a white precipitate.
TG 89, x-Fold 1.03
TG 51, x-Fold 0.99, SOC IC50 2 μM
TG 104, x-Fold 0.93
TG 146, x-Fold 1.00
TG 106, x-Fold 1.02
TG 94, x-Fold 1.08, SOC IC50 0.3 μM
TG 113, x-Fold 1.05
TG 50, x-Fold 1.02, SOC IC50 0.5 μM
TG 146, x-Fold 1.00, SOC IC50 1 μM
TG 116, x-Fold 0.91
TG 114, x-Fold 0.96, SOC IC50 2 μM
1N Sodium hydroxide (0.28 mL) was added to dimethylaminoethylthiol hydrochloride (40 mg) and the mixture was extracted with ether. Diphenylborinic acid (44 mg) was added and the mixture was dried to solidness, ethanol (1 mL) was added and the mixture was stirred for 15 hr, dried to solidness and washed with ether to give the title compound (2 mg).
TG 107, x-Fold 0.92, SOC IC50 0.8 μM
TG 97, x-Fold 0.74
TG 89, x-Fold 0.69
1,2-Dibromobenzene (236 mg) was reacted with 1N sec-BuLi (2.1 mL) at −98° C. (SOLUTION A). Bromobenzene was reacted with sec-BuLi and triisopropoxyborane (460 μL) (SOLUTION B). SOLUTION A and SOLUTION B were reacted to give the title compound (95 mg) as a candy-like substance.
TG 101, x-Fold 1.01
TG 118, x-Fold 1.13
Poly(2,5-dimethylphenyl hydroxyborane) (34 mg) and glutamine (40 mg) were stirred in ethanol at 80° C. for 12 hr to give the title compound (7 mg).
NMR (DMSO) 1.95 (m, 2H), 2.0 (m, 2H), 2.1 (m, 6H), 3.2 (m, 4H), 7.2-8.0 (m, 2H)
TG 95, x-Fold 0.80, SOC IC50 5 μM
TG 108, x-Fold 0.84
TG 103, x-Fold 0.94
TG 103, x-Fold 0.91
TG 47, x-Fold 0.90
Compound 8013 (Example 406) (24 mg) and glutamine (19 mg) were stirred in ethanol at 80° C. for 12 hr to give the title compound (16 mg).
NMR (DMSO) 1.90 (m, 2H), 1.95 (m, 2H), 2.10 (m, 4H), 2.30 (m, 4H), 7.0-8.0 (m, 12H)
TG 94, x-Fold 0.98
TG 90, x-Fold 0.98
TG 54, x-Fold 1.06, SOC IC50 0.5 μM
TG 27, x-Fold 1.05, SOC IC50 0.5 μM
TG 109, x-Fold 0.93
TG 114, x-Fold 1.02
2,5-Dimethyl-1,5-dibromobenzene (263 mg) was dissolved in ether (10 mL) at −78° C., sec-butyllithium (2 ml) was added and the mixture was stirred for 1 hr. Triisopropoxyborane (220 μL) was added and the mixture was gradually warmed to room temperature and treated with hydrochloric acid to give the title compound (74.5 mg).
NMR (CDCl3) 2.38 (s, 6H), 7.4 (m, 2H)
TG 111, x-Fold 1.00
TG 98, x-Fold 1.00
TG 107, x-Fold 0.98
TG 104, x-Fold 0.93
4,4′-parabrombenzylether (90 mg) was dissolved in ether (4 mL), and 1N sec-butyllithium (0.75 mL) cooled to −78° C. was added and the mixture was stirred for 60 min (SOLUTION A). 4,4′-parabromophenylether (90 mg) was dissolved in ether (4 mL) and the mixture was cooled to −78° C. 1N sec-Butyllithium (0.7 mL) was added and the mixture was stirred for 30 min. Triisopropoxyborane (188 mg) was added and the mixture was stirred to −65° C. (SOLUTION B). SOLUTION A and SOLUTION B were mixed and the mixture was gradually warmed and stirred at room temperature for 15 hr. The mixture was acidified with 1N hydrochloric acid, and the organic layer was washed with water, dried, and concentrated to give the title compound (154 mg).
TG 102, x-Fold 0.92
TG 72, x-Fold 1.11
TG 107, x-Fold 0.99
TG 81, x-Fold 1.02
TG 108, x-Fold 1.04
TG 100, x-Fold 0.78, SOC IC50 5 μM
Poly(4,4′-biphenylborinic acid) (38 mg) was dissolved in ether (0.5 mL), ethanolamine (13 mg) was added and the mixture was stirred for 10 hr. Ether (1 mL) was added to give the title compound (12 mg) as a precipitate.
TG 116, x-Fold 0.78
TG 98, x-Fold 0.32, SOC IC50 0.2 μM
TG 111, x-Fold 0.82
Paradibromobenzene (148 mg) was dissolved in ether (10 ml), sec-butyllithium (1.5 mL) was added at −95° C. and the mixture was stirred for 30 min. Triisoproxyborane (276 μL) was added at −78° C. and the mixture was stirred for 1 hr (SOLUTION A). Paradibromobenzene (148 mg) was dissolved in ether (10 mL), sec-butyllithium (1.5 ml) was added at −95° C. and the mixture was stirred for 30 min (SOLUTION B). SOLUTION A and SOLUTION B were mixed at −78° C., and the mixture was gradually warmed to room temperature and stirred overnight. Hydrochloric acid solution was added, and the mixture was applied to column chromatography to give the title compound (110 mg).
x-Fold 0.76
TG 92, x-Fold 0.99, SOC IC50 4 μM
TG 103, x-Fold 1.09
Compound 7051 (Example 310) (34 mg) and ethanolamine (17 mg) were reacted at room temperature for 4 hr to give the title compound (8.7 mg).
NMR (CDCl3) 2.34 (s, 6H), 2.62 (m, 2H), 2.95 (m, 2H), 3.65 (m, 2H), 7.2-7.8 (m, 2H)
TG 14, x-Fold 1.07
Compound 7051 (Example 310) (32 mg) and aminoethanethiol (20 mg) were reacted at room temperature for 4 hr to give the title compound (28 mg).
NMR (CDCl3) 1.8-2.0 (br, 2H), 2.31 (m, 6H), 2.76 (m, 2H), 3.01 (m, 2H)
TG 100, x-Fold 1.04
TG 81, SOC IC50 0.2 μM
TG 89, x-Fold 0.90
TG 101, x-Fold 0.98, SOC IC50 1 μM
TG 21, x-Fold 0.98, SOC IC50 0.2 μM
TG 107, x-Fold 1.09
TG 21, x-Fold 1.02, SOC IC50 0.3 μM
TG 91, x-Fold 1.02
TG 101, x-Fold 1.02
TG 102, x-Fold 0.98
TG 110, x-Fold 0.83
TG 115, x-Fold 0.91
TG 63, x-Fold 1.01
TG 107, x-Fold 1.04
TG 114, x-Fold 1.02
TG 55, x-Fold 1.02
TG 91, x-Fold 0.93
TG 95, x-Fold 0.92
TG 101, x-Fold 0.81
TG 104, x-Fold 0.90
TG 104, x-Fold 0.80
TG 105, x-Fold 0.92
TG 103, x-Fold 1.00
TG 97, x-Fold 1.02
TG 115, x-Fold 0.85
TG 113, x-Fold 1.09
TG 91, x-Fold 1.09
TG 51, x-Fold 1.06
TG 89, x-Fold 1.03
TG 112, x-Fold 0.91
TG 139, x-Fold 0.96
TG 88, x-Fold 1.05
TG 100, x-Fold 0.88, SOC IC50 >20 μM
TG 108, x-Fold 1.08
TG 97, x-Fold 0.92
TG 44, x-Fold 0.82
TG 118, x-Fold 0.91
TG 108, x-Fold 0.93
Compound 7051 (Example 310) (7.2 mg) and 2-pyridylmethanol (6 mg) were reacted in ethanol at room temperature for 4 hr to give the title compound (4 mg).
NMR (CDCl3) 3.45 (m, 6H), 4.72 (m, 2H), 7.2-8.5 (m, 6H)
TG 113, x-Fold 0.73
TG 52, x-Fold 1.03
TG 105, x-Fold 1.10
TG 39, x-Fold 0.76, SOC IC50 2 μM
TG 16, x-Fold 0.85, SOC IC50 2 μM
TG −18, x-Fold 0.86, SOC IC50 1 μM
TG 1, x-Fold 0.84, SOC IC50 2 μM
TG 17, x-Fold 1.14
TG 44, x-Fold 1.05
TG 75, x-Fold 0.93
TG 70, x-Fold 0.75, SOC IC50 >20 μM
TG 88, x-Fold 0.79
TG 92, x-Fold 0.74
TG 92, x-Fold 0.67
TG 55, x-Fold 0.80
TG 76, x-Fold 0.80
TG 103, x-Fold 0.92
TG 60, x-Fold 1.05
TG 116, x-Fold 0.78
TG 10, x-Fold 0.98, SOC IC50 0.5 μM
TG 96, x-Fold 0.73
2,8-Dibromodibenzothiophene (242 mg) was dissolved in ether (7 mL), and the mixture was cooled to −78° C. Secondary butyllithium (2 mL) was added and the mixture was stirred for 1 hr. Further, isopropoxyborane (460 μL) was added and the mixture was stirred for 1 hr (SOLUTION A). In a separate flask, bromobenzene (211 mg) was dissolved in ether (10 ml), secondary butyllithium (2 mL) was added and the mixture was stirred for 1 hr (SOLUTION B). SOLUTION A and SOLUTION B were mixed, and the mixture was gradually warmed to room temperature. The mixture was treated with hydrochloric acid the next morning to give the title compound (150 mg).
NMR (CDCl3) 4.3 (s, 2H), 6.8-8.2 (m, 16H)
TG 41, x-Fold 0.67, SOC IC50 0.5 μM
TG 81, x-Fold 0.83
Compound 8012 (Example 387) (25 mg) and 2-pyrrolidinemethanol (18 mg) were stirred in ethanol at room temperature for 5 hr to give the title compound (4.9 mg).
NMR (CDCl3) 1.6-1.8 (m, 8H), 3.42-4 (m, 4H), 4.64 (m, 4H), 7.0-7.8 (m, 12H)
TG 56, x-Fold 0.59
TG 15, x-Fold 0.32, SOC IC50 0.5 μM
TG 83, x-Fold 0.91
TG 117, x-Fold 0.56
TG 41, x-Fold 0.44, SOC IC50 1.5 μM
TG 116, x-Fold 0.86
TG 3, x-Fold 0.58, SOC IC50 1.2 μM
TG 70, x-Fold 0.59
TG −17, x-Fold 0.88
TG 53, x-Fold 0.96
TG 52, x-Fold 1.01
TG 121, x-Fold 0.95
TG −12, x-Fold 0.57
TG 67, x-Fold 1.14, SOC IC50 2 μM
TG 105, x-Fold 1.07, SOC IC50 4 μM
TG −3, x-Fold 0.86, SOC IC50 0.5 μM
TG 61, x-Fold 0.85
2,8-Dibromodibenzothiophene (242 mg) was lithiated, and reacted with triisopropoxyborane (499 mg) (SOLUTION A). Bromothiophene (326 mg) was lithiated (SOLUTION B). SOLUTION A and SOLUTION B were mixed at −78° C., and the mixture was gradually warmed to room temperature to synthesize the title compound (230 mg).
NMR (DMSO) 3.45 (m, 2H), 7.5-8.1 (m, 12H)
TG 77, x-Fold 1.02
TG 108, x-Fold 0.92
Compound 8012 (Example 387) (30 mg) and 2-aminoethanol (7.4 mg) were synthesized by stirring at room temperature for 5 hr to give the title compound (6.3 mg).
NMR (CDCl3), 2.60 (m, 4H), 3.50 (m, 4H), 3.98 (m, 4H) 7.2-8.0 (m, 16H)
TG 29, x-Fold 0.86, SOC IC50 1.5 μM
TG 130, x-Fold 0.90, SOC IC50 2 μM
TG 138, x-Fold 0.90
TG 65, x-Fold 0.89, SOC IC50 2 μM
TG 28, x-Fold 0.81, SOC IC50 0.8 μM
TG 128, x-Fold 0.90
TG 130, x-Fold 0.90
TG 114, x-Fold 0.92
TG 91, x-Fold 1.01
TG 45, x-Fold 1.02
TG 140, x-Fold 0.90
TG −3, x-Fold 0.81, SOC IC50 1.2 μM
TG −1, x-Fold 1.03, SOC IC50 1.2 μM
TG 13, x-Fold 0.95, SOC IC50 1.2 μM
TG 27, x-Fold 0.76, SOC IC50 1.2 μM
TG 22, x-Fold 1.03, SOC IC50 1.2 μM
TG 130, x-Fold 0.9, SOC IC50 0.5 μM
Bis(4,4′-(p-trifluoromethylphenyl-hydroxyboryl)benzyl)ether (85 mg) and asparagine (48 mg) were reacted in ethanol (0.7 mL) to give the title compound (8 mg).
TG 19, x-Fold 0.93, SOC IC50 1.2 μM
TG 20, x-Fold 0.73, SOC IC50 0.8 μM
TG 53, x-Fold 0.82, SOC IC50 1.5 μM
TG 102, x-Fold 0.81, SOC IC50 0.7 μM
TG 106, x-Fold 1.03
TG 118, x-Fold 1.02
TG 60, x-Fold 0.71, SOC IC50 0.3 μM
TG −5, x-Fold 0.71, SOC IC50 0.5 μM
TG 43, x-Fold 0.60, SOC IC50 0.4 μM
TG 26, x-Fold 0.84, SOC IC50 2 μM
TG 104, x-Fold 0.85
TG 119, x-Fold 0.85
TG 29, x-Fold 0.67, SOC IC50 2 μM
TG 33, x-Fold 0.54
TG 63, x-Fold 0.69
TG −1, x-Fold 0.58
TG 102, x-Fold 0.58
TG 84, x-Fold 0.63, SOC IC50 3 μM
TG 20, x-Fold 0.65, SOC IC50 1.4 μM
TG 108, x-Fold 0.49
TG 73, x-Fold 0.85
TG 97, x-Fold 0.49
TG 112, x-Fold 0.95
Di(3-chloro-4-methylphenyl)borinic acid (45.8 mg) and asparagine (19 mg) were reacted in ethanol (1 mL) at 90° C. for 1 hr to give the title compound (24 mg).
TG 92, x-Fold 0.89
TG 53, x-Fold 0.49
TG 6, x-Fold 0.91, SOC IC50 1.4 μM
TG 29, x-Fold 0.96, SOC IC50 0.5 μM
TG 113, x-Fold 1.04
TG 15, x-Fold 0.97, SOC IC50 0.5 μM
TG 23, x-Fold 1.04, SOC IC50 0.5 μM
TG 29, x-Fold 0.87, SOC IC50 0.5 μM
TG 30, x-Fold 1.10, SOC IC50 0.6 μM
TG 31, x-Fold 1.10, SOC IC50 0.5 μM
TG 80, x-Fold 1.03
TG 26, x-Fold 0.95, SOC IC50 0.4 μM
TG 30, x-Fold 0.85
TG 31, x-Fold 0.92, SOC IC50 0.3 μM
TG 24, x-Fold 0.92, SOC IC50 0.3 μM
TG 41, x-Fold 0.76, SOC IC50 0.8
TG 18, x-Fold 1.06, SOC IC50 0.2 μM
TG 71, x-Fold 1.04
TG 60, x-Fold 0.98, SOC IC50 0.25 μM
TG 35, x-Fold 0.98, SOC IC50 0.3 μM
TG 15, x-Fold 0.94, SOC IC50 0.25 μM
TG 19, x-Fold 1.02, SOC IC50 0.3 μM
TG 52, x-Fold 1.04, SOC IC50 0.6 μM
TG 47, x-Fold 0.95, SOC IC50 1 μM
TG-4, x-Fold 0.96, SOC IC50 0.5 μM
TG 145, x-Fold 1.04, SOC IC50 0.5 μM
TG 21, x-Fold 1.01, SOC IC50 0.6 μM
TG 103, x-Fold 0.95, SOC IC50 1.5 μM
TG 97, x-Fold 1.02
TG 121
4,4′-Dibromodiphenylether (28 mg) was lithiated using isobutyllithium and reacted with triisopropoxyborane to give the title compound (150 mg).
NMR (CDCl3) 3.45 (br, 1H), 6.7-8.0 (m, 8H)
TG 54, x-Fold 1.00, SOC IC50 1.5 μM
TG 59, x-Fold 0.66, SOC IC50 1.5 μM
TG 48, x-Fold 0.80, SOC IC50 1.5 μM
TG 114, x-Fold 1.08
Compound 8012 (Example 387) (40 mg) and glutamine (31 mg) were reacted at 80° C. to give the title compound (15 mg).
NMR (DMSO) 2.2 (m, 2H), 2.5 (m, 4H), 3.3 (m, 10H), 7.0-7.8 (m, 16H)
TG 107, x-Fold 0.73
The title compound (37 mg) was obtained from compound 8013 (Example 406) (30 mg) and 2-pyrrolidinemethanol (16 mg).
NMR (DMSO) 1.05 (m, 4H), 1.7 (m, 4H), 3.3-3.5 (m, 4H), 7.7-8.0 (m, 16H)
TG 82, x-Fold 0.78
The title compound (30 mg) was obtained from compound 8012 (Example 387) (24 mg) and arginine (32 mg).
NMR (DMSO) 1.06 (m, 2H), 2.60 (m, 4H), 3.3 (m, 6H), 7.1-7.8 (m, 16H)
TG 76, x-Fold 0.98
The title compound (6.4 mg) was obtained from compound 8013 (Example 406) (42 mg) and ethanolamine (14 mg).
NMR (CDCl3) 2.41 (4H), 2.65 (m, 4H), 3.65 (m, 4H), 7.0-7.9 (m, 12H)
TG 52, x-Fold 1.04, SOC IC50 0.5 μM
TG 90, x-Fold 0.64, SOC IC50 3 μM
TG 108, x-Fold 1.01, SOC IC50 4 μM
TG 118, x-Fold 0.80
TG 111, x-Fold 0.94
TG 106, x-Fold 0.84
TG 106, x-Fold 1.03
The effects of 162AE (bis(3,3′-(phenylaminoethoxyboryl)benzyl)ether described in Example 8) and 163AE (bis(4,4′-(phenylaminoethoxyboryl)benzyl)ether described in Example 131) for ICRAC, whose molecular entity as one of SOCE has been clarified, were investigated using an electrophysiological method. STIM1 and Orail (CRACM1) were forcibly expressed in HEK293 cells, and whole cell records were taken by the Patch clamp technique. BAPTA (20 mM), which is a calcium chelator, and IP3 (20 μM) that depletes intracellular calcium store were added to a recording electrode internal solution (120 mM Cs-glutamate, 10 mM HEPES, 3 mM MgCl2), 10 mM calcium was added to an extracellular solution to facilitate observation of calcium electric current, and a ramp command from −150 mV to +150 mV was input at 0.5 Hz to obtain a current-voltage curve. For quantification of SOCE, the size of the inward current at −80 mV was used as an index. After the start of the whole cell recording, time was taken to sufficiently activate SOCE (ICRAC), and compounds 162AE and 163AE as inhibitors were administered to the cells. As a result of the experiment, these inhibitors highly strongly inhibited SOCE (ICRAC) and the IC50 thereof was 0.086 μM, 0.17 μM (for 162AE, 163AE, respectively), thus exhibiting a strong inhibitory effect. Moreover, since SOCE (ICRAC) reconstituted by STIM1 and Orail (CRACM1) is indispensible for the immune response of T cells, it is considered possible to suppress excess immune response that occurs in autoimmune diseases, by utilizing the inhibitor, and treat the disease or mitigate the symptoms.
According to the present invention, a drug for the prophylaxis and/or treatment of a disease based on abnormal protein cross-linking reaction, such as Alzheimer's disease, Parkinson's disease, Celiac disease, cataract, mad cow disease, congenital lamellar ichthyosis, congenital hemostatic disorder and the like can be provided.
This application is based on a patent application No. 2008-207315 filed in Japan (filing date: Aug. 11, 2008), the contents of which are incorporated in full herein by this reference.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2008-207315 | Aug 2008 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2009/064206 | 8/11/2009 | WO | 00 | 5/10/2011 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2010/018837 | 2/18/2010 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 8017809 | Mikoshiba et al. | Sep 2011 | B2 |
| 20040259842 | Mikoshiba et al. | Dec 2004 | A1 |
| 20060009422 | Perry et al. | Jan 2006 | A1 |
| 20060014723 | Bellinger-Kawahara et al. | Jan 2006 | A1 |
| 20060019927 | Bellinger-Kawahara et al. | Jan 2006 | A1 |
| Number | Date | Country |
|---|---|---|
| 1 961 756 | Aug 2008 | EP |
| 2008-502694 | Jan 2008 | JP |
| 2008-502702 | Jan 2008 | JP |
| 2009-184988 | Aug 2009 | JP |
| WO 9740859 | Nov 1997 | WO |
| WO 0244184 | Jun 2002 | WO |
| WO 03033002 | Apr 2003 | WO |
| WO 2006074419 | Jul 2006 | WO |
| WO 2007056341 | May 2007 | WO |
| WO 2007061074 | May 2007 | WO |
| WO 2007098418 | Aug 2007 | WO |
| WO 2007125351 | Nov 2007 | WO |
| WO 2007146965 | Dec 2007 | WO |
| WO 2008055068 | May 2008 | WO |
| Entry |
|---|
| CAPLUS 1970:531065. |
| Dean, H. et al, J. Biol. Chem. 2008, vol. 283, pp. 16790-16800. |
| International Search Report, dated Jan. 12, 2010, issued in PCT/JP2009/064206. |
| Number | Date | Country | |
|---|---|---|---|
| 20110212919 A1 | Sep 2011 | US |
