ZA200907456B - Cinnamide compound - Google Patents
Cinnamide compound Download PDFInfo
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- ZA200907456B ZA200907456B ZA200907456A ZA200907456A ZA200907456B ZA 200907456 B ZA200907456 B ZA 200907456B ZA 200907456 A ZA200907456 A ZA 200907456A ZA 200907456 A ZA200907456 A ZA 200907456A ZA 200907456 B ZA200907456 B ZA 200907456B
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- -1 Cinnamide compound Chemical class 0.000 title claims 5
- 125000001424 substituent group Chemical group 0.000 claims description 73
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 25
- 125000003545 alkoxy group Chemical group 0.000 claims 20
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 16
- 125000000217 alkyl group Chemical group 0.000 claims 16
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 16
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 15
- 125000005133 alkynyloxy group Chemical group 0.000 claims 12
- 125000003118 aryl group Chemical group 0.000 claims 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 11
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims 10
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 10
- 125000004414 alkyl thio group Chemical group 0.000 claims 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims 7
- 150000002430 hydrocarbons Chemical group 0.000 claims 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 6
- 125000003277 amino group Chemical group 0.000 claims 6
- 125000004429 atom Chemical group 0.000 claims 6
- 229910052736 halogen Inorganic materials 0.000 claims 6
- 150000002367 halogens Chemical class 0.000 claims 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 5
- 125000000623 heterocyclic group Chemical group 0.000 claims 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims 4
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 4
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 3
- 125000001153 fluoro group Chemical group F* 0.000 claims 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 238000005859 coupling reaction Methods 0.000 claims 2
- 229910052740 iodine Inorganic materials 0.000 claims 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims 2
- 125000004844 (C1-C6) alkoxyimino group Chemical group 0.000 claims 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 125000000676 alkoxyimino group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims 1
- 125000005149 cycloalkylsulfinyl group Chemical group 0.000 claims 1
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 claims 1
- 125000005366 cycloalkylthio group Chemical group 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 description 14
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 5
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000037259 Amyloid Plaque Diseases 0.000 description 4
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 2
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 2
- 201000010374 Down Syndrome Diseases 0.000 description 2
- 229940121773 Secretase inhibitor Drugs 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical class C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 1
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 1
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 1
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 1
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 102100034004 Gamma-adducin Human genes 0.000 description 1
- 101000799011 Homo sapiens Gamma-adducin Proteins 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000012412 Presenilin-1 Human genes 0.000 description 1
- 108010036933 Presenilin-1 Proteins 0.000 description 1
- 102000012419 Presenilin-2 Human genes 0.000 description 1
- 108010036908 Presenilin-2 Proteins 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000009699 differential effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000015756 familial Alzheimer disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007138 neurofibrillary change Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- APEJMQOBVMLION-VOTSOKGWSA-N trans-cinnamamide Chemical class NC(=O)\C=C\C1=CC=CC=C1 APEJMQOBVMLION-VOTSOKGWSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
oo | W2153 9 / 07456 923/37
BERPITEVL LLL |]
Sr
[0001] I : : The present invention relates to a : : pharmaceutical agent, particularly an agent of reducing amyloid beta (hereinafter referred to as Ap) production, which is effective in the treatment of neurodegenerative diseases caused by AB, such as :
Alzheimer's disease and Down syndrome.
Background Art oo
[0002]
Alzheimer's disease is a disease Co
BN characterized by degeneration and loss of neurons and : also by the formation of senile plaques and neurofibrillary change. Presently, treatment of
Alzheimer's disease is limited to symptomatic therapies : : with a symptom-improving agent represented by an ‘acetylcholinesterase inhibitor, and the basic remedy which prevents progress of the disease has not been developed. A method of controlling the cause of onset : of pathologic conditions needs to be developed for creation of the basic remedy of Alzheimer's disease.
AB protein, which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is
2 | : considered to be greatly involved in degeneration and oo
R loss of neurons as well as onset of demential | : conditions (for example, see Non-Patent Document 1 and
Non-Patent Document 2). The main components of AP protein are AB40 consisting of 40 amino acids and AR42 having two additional amino acids at the C-terminal.
The AP40 and. AB42 tend to aggregate (for example, see
Non-Patent Document 3) and constitute main components oo of senile plaques (for example, Non-Patent Document 3,
Non-Patent Document 4 and Non-Patent Document 5), and furthermore, it is known that mutations of APP and presenelin genes, which is observed in familial
Alzheimer's disease, increase production of AP40 and
AB42 (for example, see Non-Patent Document 6, Non-
Patent Document 7 and Non-Patent Document 8). :
Therefore, compounds which reduce production of AB40 and AP42 are expected as an agent for controlling : : progress of Alzheimer's disease or for preventing the ~~ disease. ~~ These ABs are produced when APP is cleaved by beta secretase and subsequently clipped by gamma : secretase. In consideration of this, creation of inhibitors of y secretase and P secretase has been ‘attempted for the purpose of reducing production of
APs. Many of these secretase inhibitors already known : are peptides or peptidomimetics such as L-685,458 (for example, see Non-Patent Document 9) and LY-411575 (for example, see Non-Patent Document 10, Non-Patent
. Document 11 and Non-Patent Document 12).
Non-Patent Document 1: Klein WL, and seven others, Related Articles, Links Alzheimer's disease- affected brain: presence of oligomeric AR ligands : (ADDLs) suggests a molecular basis for reversible memory loss, Proceeding National Academy of Science : USA, 2003, Sep 2, 100(18), p. 10417-10422; . | Non-Patent Document 2: Nitsch RM, and 16 ‘others, Antibodies against B-amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22, ~ 38(4), p- 547-554; N
Non-Patent Document 3: Jarrett JT, and 2 others, The carboxy terminus of the B amyloid protein is critical for the seeding of amyloid formation: : implications for the pathogenesis of Alzheimer's disease, Biochemistry, 1993, May 11, 32(18), p. 4693- 4697;
Co Non-Patent Document 4: Glenner GG, and : another, Alzheimer's disease: initial report of the purification and characterization of a novel : cerebrovascular amyloid protein, Biochemical. and
Biophysical Research Communications, 1984, May 16, 120(3), p. 885-890;
Non—-Patent Document 5: Masters CL, and six others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, 1985, Jun, 82(12), p. 4245-4249;
Non-Patent Document 6: Gouras GK, and eleven
) rd others, Intraneuronal AB42 accumulation in human brain, N
American Journal of Pathology, 2000, Jan, 156(1), p. 15-20; oo
Non-Patent Document 7: Scheuner D, and twenty others, Secreted amyloid B-protein similar to that in the senile plaques of Alzheimer's disease is increased oo in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature
Medicine, 1996, Aug, 2(8), p. 864-870;
Non-Patent Document 8: Forman MS, and 4 others, Differential effects of the swedish mutant amyloid precursor protein on p-amyloid accumulation and secretion in neurons and nonneuronal cells, Journal of
Biological Chemistry, 1997,. Dec 19, 272 (51), p. 32247- 32253; Co
Non-Patent Document 9: Shearman MS, and nine others, L-685,458, an aspartyl protease transition : state mimic, is a potent inhibitor of amyloid B-protein precursor y-secretase activity, Biochemistry, 2000, Aug 1,39(30), p. 8698-8704;
Non-Patent Document 10: Shearman MS, and six others, Catalytic site-directed y-secretase complex inhibitors do not discriminate pharmacologically : between Notch S3 and P-APP cleavages, Biochemistry, 2003, Jun 24, 42(24), p. 7580-7586; : Non-Patent Document 11: Lanz TA, and three oo others, Studies of AB pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free)
A
; .
Tg2576 mice using the y-secretase inhibitor N2-[(2S)- ] Ny 2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[ (7S) -5- . methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L- alaninamide (LY-411575), Journal of Pharmacology and
Experimental Therapeutics, 2004, Apr, 309(1), p. 49-55;
Non-Patent Document 12: Wong GT, and twelve others, Chronic treatment with the y-secretase inhibitor LY-411,575 inhibits B-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation, Journal of Biological Chemistry, 2004, © Mar 26, 279(13), p. 12876-12882. | oo
Disclosure of the Invention a Problems to be Solved by the Invention -
[0003] oo : : As mentioned above, compounds which prevent "production of AP40 and AP42 from APP are expected as an : : preventive or therapeutic agent for diseases caused by
AP represented by Alzheimer's disease. However, non- peptide compounds which prevent production of AB40 and : AB42 and have an excellent medicinal effect have not been known. Therefore, a novel low molecular compound that inhibits production of AB40 and AP42 is demanded.
Means for Solving the Problems :
[0004] : :
The present inventors have conducted intensive studies and first discovered non-peptidic
) " h 6 Co © cinnamide compounds which inhibit production of AB40 Co and AP42 from APP and discovered preventive or therapeutic agents for diseases caused by AB, _ represented by Alzheimer's disease, thereby completed the present invention. 000s] :
That is, the present invention relates to the followings: | | : 1) ~~ A compound or a pharmacologically acceptable salt thereof represented by Formula (I): :
[0006] oo oT [Formula 1] 1 2 : : : (wherein Ar; represents an imidazolyl group which may be substituted with 1 to 3 substituents selected from -Substituent Group Al shown below; Ar; represents a : pyridinyl group, a pyrimidinyl group, or a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group A2 shown below; Xi " represents (1) -C=C- or (2) -CR?=CR’- (wherein R?® and R! represents a substituent selected from Substituent
Group A3 shown below); and E (1) R! and R? represent groups selected from
Substituent Group A4 shown below or
Rr and R?, together with a nitrogen atom to which they bind, form one of the following groups: : | : (2-1) a 5- to ll-membered non-aromatic heterocyclic group represented by Formula (II): " [Formula 2] (CHa), / N\ oo —N Yo a : : crate (wherein Y; represents (1) _NH-, (2) -0-, (3) -5-, (4) -50-, (5) -SOp-, (6) -CH,-, (7) -CO-, (8) -CONH-, (9) ~ -NHCO-, (10) -CR°=CR®- (wherein R® and R® represent substituents selected from Substituent Group A4 shown below), (11) a single bond or (12) >C=CR*®R'* (wherein. ~~
R'® and R' represent substituents selected from
Substituent Group A4 shown below); and : oo ii and mp represent an integer of 0 to 4) which may be : substituted with 1 to 4 substituents selected from © Substituent Group Ad; (2-2) a 6- to 20-membered non-aromatic heterocyclic group represented by Formula (III): - [Formula 3]
Vaal
RN VAN J 10) (CHM, NCH,)my (wherein Y, represents (1) -NH-, (2) -0-, (3) -S-, (4) : -S0-, (5) -S0,-, (6) -CHy-, (7) -CO-, (8) =-CONH-, (9)
Claims (5)
1. "A process for preparing a compound of formula oo (6a) : ) Co 0 (6a) : R11 : - a oo © wherein Ar; represents an imidazolyl group ‘which may be : ST substituted with 1 to 3 substituents selected from . Substituent Group Al shown below; Ar, represénts a oo pyridinyl group, a pyrimidinyl .group or a phenyl group which may be substituted with 1 %o 3 substituents selected from Substituent Group A2. shown below; and RM . represents a group selected from Substituent Group A3 shown below, which comprises the step of: oo oo a ‘subjecting a compound of formula (5a): - ye oo SE (5a) SI . R11 . oo 8 { wherein I; represents a hydrogen atom, or a leaving } ) group selected from a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a sulfonate, a trialkyltin group, a boronic acid and a boronic acid ester; and Ar, and RY are as defined above, and a compound of formula : (4a) :
. | a 858 wherein Ar; is as defined above, to a coupling reaction, : ~~ Substituent Group Al: (1) a hydrogen atom, (2) a halogen’ : atom, (3) a cyano group, (4) a nitro group, (5) a c3-8 cycloalkyl group, (6) a C2-6 alkenyl. group, (7) a C2-6 alkynyl ‘group, (8) a Cl-6 alkoxy group, (9) a C3-8 : a cycloalkoxy group, (10) a formyl group, (11) a c1-6 alkylcarbonyl group and (12) a Cl1~6 alkyl group wherein the 'C1-6 alkyl group may be substituted with 1 to 3 . substituents selected from the group consisting of a oo Ce So halogen atom, a hydroxyl group p a cyano group, a Cl-6 alkoxy ‘group, a (3-8 ‘cycloalkyl group, and a C1l-6 R alkylcarbonyl group; oo Co Substituent Group A2: (1) a hydrogen atom, (2) a halogen : atom, (3) a hydroxyl group, (4) a cyano group, (5) a Cl- no 6 alkoxy group wherein the Cl-6 alkoxy group may be . substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a Cl- co 6 alkoxy group, a C2-6 alkenyl group, a C2-6 alkynyl group ‘and a C3-8 cycloalkyl group, (6) a 63-8 - 3 cycloalkoxy group, (7) a c2-6 alkenyloxy group, and (8) co oo a C2-6 alkynyloxy group: LL Substituent Group A3: (1) a hydrogen atom, (2) a halogen . . atom, (3) a 5- to l4-membered aromatic heterocyclic group. which may be substituted with 1 to 3 substituents : selected from Substituent Group A4, (4) a C1-6 alkyl group wherein the Cl-6 alkyl group may be substituted ) oo with 1 to 3 substituents "selected from the group consisting of a formyl group, a halogen atom, a hydroxyl : group, a hydroxyl group having a protecting group, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, . a C3-8 cycloalkyl group, a Cl-6 alkoxy group, a Cl-6 . alkylthio group, a Cl1l-6 alkylsulfinyl group, a cl-6 alkylsulfonyl group, .a Cl-6 alkylcarbonyl group, an So amino group wherein the amino group may be substituted
R ’ 859 EE . Bh with a Cl1-6 alkyl group optionally having 1to 5 halogen : atoms, a 6- to l4-membered aromatic - hydrocarbon ring group which may be substituted with 1 to 3 substituents ‘selected from Substituent Group A4, a 5- to l4-membered aromatic heterocyclic group which may be substituted . with 1 to 3 substituents selected from Substituent Group Ad, a 3- to l4-membered non-aromatic hydrocarbon ring 3 group which may be substituted with 1 to 3 substituents selected from Substituent Group Ad, a 5- to l1l4-membered : ‘non-aromatic heterocyclic group which may be substituted F with 1 to 3 substituents selected from Substituent Group A4 and -X-A wherein ‘X represents an imino group, -0- or BB -S—- and A represents a 6~- to 'l14-membered aromatic : Co ©. hydrocarbon ring group or 5- to 1l4-membered aromatic : heterocyclic group which may be substituted with 1 to 3 : substituents selected from Substituent Group A4, and (5) = a Cl-6 alkoxy group; Substituent Group A4: | R ) (1) a hydrogen atom, : BE Ce (2) a halogen atom, : Co } (3) a hydroxyl group, 0 E (4) a cyano group, . : (5) a nitro group, : (6) a €3-8 cycloalkyl group, . (7) a C2-6 alkenyl group, : oo 3 (8) a C2-6 alkynyl group, : : (9) a C3-8 cycloalkoxy group, : (10) a.
C3-8 cycloalkylthio group, | SE (11) a formyl group, : (12) a Cl-6 alkylcarbonyl group, : (13) a C1-6 alkylthio group, (14) a C1-6 alkylsulfinyl group, i (15) a Cl-s6 alkylsulfonyl group, (16) a hydroxyimino group,
(17) a C1-6 alkoxyimino group, So (18) a Cl1l-6 alkyl group wherein the Cl1-6 alkyl group may have 1 to 3 substituents selected from ‘the following . substituent group: : . } Ss } (a) a halogen atom, : - (b) a hydroxyl group p | : oo (c) a cyano group, CL (d) a €3-8 cycloalkyl group, oo : Co (e) a Cl1l-6 alkylthio group, a : (f) a C1-6 alkylsulfinyl group, | oo - (9) a 1-6 alkylsulfonyl group, i Bh : " (h) a Cl-6 alkylcarbonyl group, : Lo (4d) a hydroxyimino group, (3) a Cl-6 alkoxyimino group , - I (k) a Cl1-6 alkoxy group wherein the c1-6 oo - ‘alkoxy group may be substituted with a hydroxyl group, : . (1) a carbamoyl group wherein the carbamoyl Co group may be substituted ‘with 1 to 2 ‘substituents : salected from the group consisting of a C1-6 alkyl group, co | a C2-6 alkenyl group and a C2-6 alkynyl group, © : Co 3 (m) a 6- to l4-membered aromatic ‘hydrocarbon : "ring group (wherein the 6~ to l4-membered aromatic : hydrocarbon ring ‘group may be substituted with 1 to 3. : oo substituents selected from Substituent Group A4-1 ‘shown below, Co : (n) a 3- to l4-membered non-aromatic : hydrocarbon ring group wherein ‘the 3- to 1l4-membered non-aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group : A4-1 shown below, Co CS oo - (0) a 5- to l4-membered aromatic heterocyclic - ) group wherein the 5- to 14-membered aromatic oo ~ heterocyclic group may be substituted. with 1 to 3 substituents selected from Substituent Group A4-1 shown below, oo ] : : g (p) a 5- to 1l4-membered non-aromatic - heterocyclic group wherein the 5- to l4-membered non- aromatic heterocyclic group may be substituted with 1 to 3 substifuénts selected from Substituent Group 2A4-1 shown below, and g : : (q) -X-A wherein X represents an imino group, : © -0- or -S- and A represents a 6- to 14-membered aromatic - hydrocarbon ring. group or 5- to l4-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents. selected from Substituent Group A4-1 shown below, EE to (19) a C1-6 alkoxy group, : : ~ (20) an amino group . wherein the amino group may be substituted: with 1 to 2 substituents selected from the group ‘consisting’ of a ci-6 alkyl group which may be substituted - with a ° 6- to 1l4-membered aromatic hydrocarbon ring group, a C2-6 alkenyl. group and a C2-6 - alkynyl group, ; | : © (21) a carbamoyl group wherein the carbamoyl group may : © bé substituted with 1 to 2 substituents selected from } the group consisting of a C1-6 alkyl group, a C2-6 alkenyl group and a C2-6 alkynyl group, oo : (22) a 6- to l4-membered aromatic hydrocarbon ring group
; . wherein the 6- to 1l4-membered aromatic hydrocarbon ring : - group may be substituted with 1 to 3 substituents Co ) selected from Substituent Group A4-1 shown below, ) (23) a 5- to 14-membered aromatic heterocyclic group . wherein the 5- to 1l4-membered aromatic heterocyclic group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below, Co Co (24) a 3- to l4-membered non-aromatic hydrocarbon ring group wherein the 3- to l4-membered non-aromatic - hydrocarbon ring group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below, - 3 (25) a 5- to l4-membered non-aromatic heterocyclic group . wherein the 5- to l4-membered non-aromatic heterocyclic : ] group may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below, oo oo (26) a C2-6 alkenyloxy group, (27) a €2-6 alkynyloxy group, . (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, oo (30) -X-A wherein X represents an imino group, ~0- or - Co : : S- and A represents a 6- to l4-membered aromatic “hydrocarbon ring group or 5- to 1l4-membered aromatic : heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Group A4-1 shown below, Co oo I. (31) -CO-A wherein A is the same as defined above, and oo (32) =CH-A wherein A is the same as defined above; Substituent Group Ad-1: B o. (1) a halogen atom, oo SEER : (2) a ‘hydroxyl group, - - Co co (3) a eyano group, : : (4) a nitro group, a (5) a c1-6 alkylcarbonyl group, Cr (6) a C1-6 alkylthio group, a. (7) a Cl1-6 alkylsulfinyl group, ! (8) a C1-6 alkylsulfonyl group, 5 (9) a Cl-6 alkoxy group wherein the Cl-6 alkoxy group : may be substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a halogen atom, : . (10) a C2-6 alkenyloxy group, (11) a C2-6 alkynyloxy group, . (12) a Cl-6 alkyl group wherein the C1-6 alkyl group may }
RE 863 =. oo have 1 to 3 substituents selected from the following ~ substituent group: } (i) a halogen atom, | | - Co (ii) a hydroxyl group, a Co © (iii) a C1-6 alkoxy group wherein the Cl-6 : A alkoxy group may be substituted with a C3-8 cycloalkyl group, (iv) a C2-6 alkenyloxy group, (v) a C2-6 alkynyloxy group, : | : : : (vi) a Cl-6 alkylthio group, 0 (vii) a C1-6 alkylsulfinyl group, © (viii) a C1-6 alkylsulfonyl group, EE Co (ix) a 6- to l4-membered aromatic hydrocarbon ring ‘group wherein the 6- to l4-membered aromatic hydrocarbon ring group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a . Cci-6 alkyl GLOTR which may be: substituted with 1 to 3 a halogen atoms, a C2-6 alkenyl group , a C2-6 alkynyl . “group, a Cl-6 alkoxy group which may be substituted with CL 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 Co : alkynyloxy - ‘group, a C1-6 alkylthio group, a Cl-6 } Co alkylsulfinyl group and a c1-6 alkylsulfonyl group, (x) a 3- to 14-membered non-aromatic hydrocarbon ring group wherein the 3- to 1l4-membered non-aromatic hydrocarbon zing group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group which may be oo substituted with 1 to 3 halogen atoms, a C2-6 alkenyl Co group, -a C2-6 alkynyl group, a Cl-6 alkoxy group which may be substituted with 1 to 3 halogen "atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group and a Cl-6 . .alkylsulfonyl group, (xi) a 5- to l4-membered aromatic heterocyclic
Co . 864 oo group wherein the .5- to l4-membered aromatic : : heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a Cl-6 alkyl group which may be substituted with 1 to 3 halogen Co _ atoms, a C2-6 alkenyl group, a C2-6 alkynyl group, a Cl- 6 alkoxy group which may be substituted with 1 to 3 halogen atoms, . a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, ‘a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group and a Cl-6 alkylsulfonyl group, and oo (xii) a 5- to 1l4-membered non-aromatic heterocyclic group wherein the 5- “to 14-membered non- So aromatic heterocyclic group may have 1 to 3 substituents te selected from the group ‘consisting of a halogen atom, a : C1-6 .alkyl group which may be. substituted with 1 to 3 halogen atoms, a C2-6 alkenyl group, a C2-6 alkynyl oo group, a Cl-6 alkoxy group which may be substituted with
Co . 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a -C2-6 : alkynyloxy group, a Cl-6 ‘alkylthio group, a Cl1l-6 alkylsulfinyl group and a Cl-6 alkylsulfonyl group p . : (13) an amino group wherein the amino group may be oo Co substituted with 1 to 2 substituents selected from the - So group consisting of a Cl-6 alkyl group, a | C2-6 alkenyl : group and a c2-6 alkynyl group, : oo - - (14) a 6- to l4-membered aromatic hydrocarbon ring group : Co ‘wherein the 6- to l4-membered aromatic hydrocarbon ring group may be substituted with 1 to 3 substituents _ selected from the group consisting of a halogen atom, a Cl-6 alkyl group , a C2-6 alkenyl group, a C2-6 alkynyl" group, a Cl-6 alkoxy group, a C2~6 alkenyloxy group, a . : C2-6 alkynyloxy group, a Cl-6 alkylthio group, a Cl1-6 alkylsulfinyl group and a Cl-6 alkylsulfonyl group, (15) a 3- to 14-membered non-aromatic hydrocarbon ring group wherein the 3- to l4-membered non-aromatic : hydrocarbon ring group may be substituted with 1 to 3 substituents selected from the group consisting of a Co halogen atom, a Cl-6 alkyl group, a C2-6 alkenyl group, : a C2-6 alkynyl group, a Cl-6 alkoxy group, a C2-6 alkenyloxy group, - a C2-6 alkynyloxy group, a Cl-6 alkylthio group, a Cl-6 alkylsulfinyl group and a Cl-6 alkylsulfonyl group, = oo (16) a 5- to ‘14-membered aromatic ‘heterocyclic group wherein the 5- to l4-membered - aromatic heterocyclic Co group may be ‘substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a Cl-6 alkyl group which may be . substituted with 1 “to 3 hydroxyl groups , a C2-6 alkenyl group, a C2-6 alkynyl group, ‘a Cl-6 alkoxy group which : ‘may be substituted with 1 to 3 halogen atoms, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a Cl-6 alkylthio group, a Cl1l-6 alkylsulfinyl group and a Cl-6 alkylsulfonyl group, : : ) 17) a 5- to l4-membered non-aromatic heterocyclic group Co ~~ wherein the 5- to l4-membered non-aromatic heterocyclic . group may be substituted with 1 to 3 substituents © selected from -the group consisting of a halogen atom, a no © Cl1l-6 alkyl group, a C2-6 alkenyl ‘group, a C2-6 alkynyl - group, a Ccl-6 alkoxy group, a C2-6 alkenyloxy group, a €2~-6 alkynyloxy group, a Cl-6 alkylthio group, a Cl-6 ; alkylsulfinyl group and a C1-6 'alkylsulfonyl group, (18) -X-A wherein X represents an imino group, -O0- or = s- and A reprefents a 6+ to 14-membered aromatic hydrocarbon ring group or 5-~ to ‘14-membered aromatic heterocyclic group which may be substituted with 1 to 3 . halogen atoms, and - : EE (19) ~-CO-A wherein A represents a 6~ to l4-membered : . ~aromatic | hydrocarbon ring group or 5- to 1l4-membered aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms.
yp . 866 LL
2. The ‘process according to claim 1, wherein a compound of formula (II): : Co OCH; ! I a ; wherein IL, is as defined above, and a compound of. . formula (III): : : J NH {1)] : Co =~ + HC ; . So 7 are subjected to the coupling reaction to prepare 3- - methoxy-4- (4-methyl-1H-imidazol~1l-yl)benzaldehyde of a. 3 formula (I): . a. OCH | SA E oo IN Yano -(H iE : H,C | : | oo oo
3. The process according to claim 2, wherein IL, : represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
4. The process according to claim 2, wherein IL, represents a fluorine atom.
5. 3-Methoxy-4- (4-methyl-1H-imidazol-1—~ .. Le oo
4 | : 867 I
. yl)benzaldehyde of formula (I): i E oo OCH; | I SE ee
=~ . . . . HC | | So DATED THIS 23" DAY OF OCTOBER 2009 SPOOR = | | CL APPLICANT'S PATENT ATTORNEYS } Co . : J “ . . . ) | Lr a 0 \ FAS oo J R
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| CN (1) | CN1972916B (en) |
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| CN102180874B (en) * | 2008-07-01 | 2012-09-05 | 韶远化学科技（上海）有限公司 | Synthetic process method for azabicyclo medicinal intermediates |
| US8946426B2 (en) * | 2009-02-06 | 2015-02-03 | Janssen Pharmaceuticals, Inc. | Substituted bicyclic heterocyclic compounds as gamma secretase modulators |
| WO2011007819A1 (en) * | 2009-07-17 | 2011-01-20 | 塩野義製薬株式会社 | Pharmaceutical product containing lactam or benzene sulfonamide compound |
| CN111393660B (en) * | 2020-02-21 | 2022-03-08 | 延安大学 | Nickel metal coordination polymer and preparation method and application thereof |
| CN111533693A (en) * | 2020-05-08 | 2020-08-14 | 张建蒙 | Cinnamic acid amide diazole derivative and application thereof in antifungal drugs |
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| ES2061432T3 (en) * | 1985-10-09 | 1994-12-16 | Shell Int Research | NEW ACRYLIC ACID AMIDES. |
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| JP3176365B2 (en) * | 1990-02-08 | 2001-06-18 | エーザイ株式会社 | Benzenesulfonamide derivative |
| TR199802282T2 (en) * | 1996-05-10 | 1999-03-22 | Icos Corporation | Karbolin térevleri. |
| AU2001254555A1 (en) * | 2000-04-24 | 2001-11-07 | Merck Frosst Canada & Co | Method of treatment using phenyl and biaryl derivatives as prostaglandin E inhibitors and compounds useful therefore |
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| ZA200609845B (en) | 2010-02-24 |
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