JP2011521928A - 3,4−ジヒドロピリミジンtrpa1アンタゴニスト - Google Patents
3,4−ジヒドロピリミジンtrpa1アンタゴニスト Download PDFInfo
- Publication number
- JP2011521928A JP2011521928A JP2011511021A JP2011511021A JP2011521928A JP 2011521928 A JP2011521928 A JP 2011521928A JP 2011511021 A JP2011511021 A JP 2011511021A JP 2011511021 A JP2011511021 A JP 2011511021A JP 2011521928 A JP2011521928 A JP 2011521928A
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- Prior art keywords
- alkyl
- compound
- mmol
- hydrogen
- alkyloxy
- Prior art date
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- Granted
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- OKGNMRKOGWTADH-UHFFFAOYSA-N 1,4-dihydropyrimidine Chemical compound C1C=CNC=N1 OKGNMRKOGWTADH-UHFFFAOYSA-N 0.000 title abstract description 4
- 229940123524 TRPA1 antagonist Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 127
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- -1 hydroxy, cyano, amino Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- SSGGNFYQMRDXFH-UHFFFAOYSA-N sulfanylurea Chemical compound NC(=O)NS SSGGNFYQMRDXFH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 14
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- 201000010099 disease Diseases 0.000 abstract description 11
- 101000764872 Homo sapiens Transient receptor potential cation channel subfamily A member 1 Proteins 0.000 abstract description 4
- 241001465754 Metazoa Species 0.000 abstract description 4
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- 230000003042 antagnostic effect Effects 0.000 abstract description 3
- 238000012824 chemical production Methods 0.000 abstract description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- 239000000203 mixture Substances 0.000 description 59
- 239000011541 reaction mixture Substances 0.000 description 46
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 46
- 239000000047 product Substances 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 239000000543 intermediate Substances 0.000 description 28
- 239000012071 phase Substances 0.000 description 28
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 27
- 239000002244 precipitate Substances 0.000 description 27
- UHKAJLSKXBADFT-UHFFFAOYSA-N 1,3-indandione Chemical compound C1=CC=C2C(=O)CC(=O)C2=C1 UHKAJLSKXBADFT-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- MDKCFLQDBWCQCV-UHFFFAOYSA-N benzyl isothiocyanate Chemical compound S=C=NCC1=CC=CC=C1 MDKCFLQDBWCQCV-UHFFFAOYSA-N 0.000 description 8
- 229910052796 boron Inorganic materials 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
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- 235000019441 ethanol Nutrition 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 238000004808 supercritical fluid chromatography Methods 0.000 description 7
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 235000019634 flavors Nutrition 0.000 description 6
- 235000003599 food sweetener Nutrition 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- RNCCOSMXJQOWRS-UHFFFAOYSA-N methyl 11h-benzo[c][1]benzazepine-10-carboxylate Chemical compound C1=NC2=CC=CC=C2CC2=C1C=CC=C2C(=O)OC RNCCOSMXJQOWRS-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 108090000862 Ion Channels Proteins 0.000 description 5
- 102000004310 Ion Channels Human genes 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- QAADZYUXQLUXFX-UHFFFAOYSA-N N-phenylmethylthioformamide Natural products S=CNCC1=CC=CC=C1 QAADZYUXQLUXFX-UHFFFAOYSA-N 0.000 description 4
- 229940123223 TRPA1 agonist Drugs 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
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- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 2
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- 201000004624 Dermatitis Diseases 0.000 description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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Classifications
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Abstract
Description
A1及びA2は両方ともCR5であるか、あるいはA1又はA2の1つはNであり、他はCR5であり、ここで各R5は独立して水素、ハロ、C1−6アルキル、C1−6アルキルオキシ、ポリハロC1−6アルキル又はポリハロC1−6アルキルオキシから選ばれ;B1、B2、B3及びB4はすべてCHであるか、又はB1、B2、B3及びB4の1つはNであり、他はCHであり;
XはO又はSであり;
R1はハロ、ヒドロキシ、シアノ、アミノ、C1−6アルキル、ヒドロキシC1−6アルキル、C1−6アルキルオキシ、ポリハロC1−6アルキルオキシ、アリール、アリールオキシ又はOR6であり、ここでR6はヒドロキシ、C1−4アルキルオキシ、アリール、アリールオキシ、C1−4アルキルカルボニル、C1−4アルキルカルボニルオキシ又はNR7R8で置換されたC1−6アルキルであり、ここでR7及びR8はそれぞれ独立して水素又はC1−4アルキルから選ばれ;
R2は水素、フルオロ、C1−4アルキル又はC1−4アルキルオキシであり;
且つR1及びR2は一緒になって−O−CH2−O−又は−O−CH2−CH2−O−基を形成することができ;
R3は水素、C1−4アルキル又はアリールC1−2アルキルであり;
R4は水素、C1−4アルキル又はアリールC1−2アルキルであり;
各アリールは互いに独立して、水素、ハロ、ヒドロキシ、C1−4アルキル、ポリハロC1−4アルキル、C1−4アルキルオキシ、ポリハロC1−4アルキルオキシ、シアノ、ニトロ、アミノ又はモノ−もしくはジ−(C1−4アルキル)アミノからそれぞれ独立して選ばれる1、2又は3個の置換基で置換されたフェニルから選ばれ;
但し、XがOであり、且つA1及びA2が両方ともCR5であり、ここでR5が水素であり、且つR2が水素又はC1−4アルキルオキシであり、且つR3及びR4が水素である場合、R1はハロ、C1−6アルキル又はC1−6アルキルオキシではない]
の新規な化合物あるいはその製薬学的に許容され得る酸付加塩又はその溶媒和物又はそのN−オキシドに関する。
−ハロはフルオロ、クロロ、ブロモ及びヨードの総称であり;
−C1−4アルキルは、1〜4個の炭素原子を有する直鎖状及び分枝鎖状飽和炭化水素基、例えばメチル、エチル、プロピル、ブチル、1−メチルエチル、2−メチルプロピルなどを定義し;
−C1−6アルキルは、C1−4アルキル及び5〜6個の炭素原子を有するその高級同族体、例えば2−メチルブチル、ペンチル、ヘキシルなどを含むものとし;
−ポリハロC1−4アルキルは、ポリハロ置換されたC1−4アルキル、特に2〜6個のハロゲン原子で置換された(上記で定義されたような)C1−4アルキル、例えばジフルオロメチル、トリフルオロメチル、トリフルオロエチルなどとして定義され;
−ポリハロC1−6アルキルは、ポリハロ置換されたC1−6アルキル、特に2〜6個のハロゲン原子で置換された(上記で定義されたような)C1−6アルキル、例えばジフルオロメチル、トリフルオロメチル、トリフルオロエチルなどとして定義される。
a)A1及びA2が両方ともCR5であり、ここで各R5は独立して水素又はハロから選ばれるか;あるいは
b)A1及びA2の1つがCR5であり、ここでR5は水素又はハロであり、そしてA1及びA2の他がNであるか;あるいは
c)B1、B2、B3及びB4がすべてCHであるか;あるいは
d)R2が水素又はC1−4アルキルオキシであるか;あるいは
e)R1及びR2が一緒になって−O−CH2−O−を形成することができるか;あるいは
f)R3が水素又はメチルであるか;あるいは
g)R4が水素、メチル又はフェニルメチルであるか;あるいは
h)アリールがフェニル又はハロ、トリフルオロメチル、シアノもしくはC1−4アルキルオキシで置換されたフェニルであるか;あるいは
i)C*におけるステレオジェン中心がR−立体配置を有する。
一般に、1,3−ジカルボニル化合物(III)、アルデヒド(IV)及び(チオ)ウレア(V)の間の多成分縮合反応を介して式(I)の化合物を合成することができる。
ッテルビウムトリフレート、塩化セリウム(III)、塩化ジルコニウム(IV)、オキシ塩化ジルコニウム(IV)、リチウムブロミド、フェニルピルビン酸、塩化カルシウム、ポリリン酸エステル又は固体クレー酸触媒(clay acid catalyst)、例えばモントモリロナイトKSFクレーあるいはこれらの触媒の組み合わせである。
ような適した塩基の存在下に、例えば2−プロパノン、1,4−ジオキサン、ジメチルホルムアミド又はTHFのような反応に不活性な溶媒中でアルキル化して、中間体(IX)及び/又は(X)を与えることにより製造することができる。熱的又はマイクロ波補助加熱下でTFAを用いて中間体(IX)又は(X)を処理すると、それぞれ式(I−d)及び(I−e)の化合物が得られる。
ともでき、但し、反応は立体特異的に起こる。好ましくは、特定の立体異性体が望まれる場合、該化合物は立体特異的製造方法により合成されるであろう。これらの方法は、有利にはエナンチオマー的に純粋な出発材料を用いるであろう。
sensitivity)、かゆみ過敏症(itching sensitivity)、皮膚刺激、術後痛、ガン痛、ニューロパシー痛、炎症痛、片頭痛、糖尿病性ニューロパシー、乾癬、湿疹、皮膚炎、ヘルペス後神経痛、尿失禁、膵臓炎、変形性関節症、慢性関節リウマチ、口内粘膜炎(oral mucositis)、毛髪成長の阻害又は刺激、涙液分泌、眼の損傷、眼瞼痙攣及び肺の刺激(咳)ならびに創傷治癒の刺激である。
性成分の溶解性を向上させるための他の成分が含まれることができる。例えば食塩水、グルコース溶液又は両者の混合物を含んでなる製薬学的担体を用いることにより、注入可能な溶液を調製することができる。適した液体担体、懸濁化剤などを用いることにより、注入可能な懸濁剤を調製することもできる。経皮的投与に適した組成物において、製薬学的担体は場合により浸透促進剤及び/又は適した湿潤剤を含んでなることができ、それらは場合により皮膚に有意な悪影響を引き起こさない小さい割合の適した添加剤と組み合わされていることができる。該添加剤は、皮膚への活性成分の投与を促進するように及び/又は所望の組成物の調製の助けとなるように選ばれることができる。これらの局所用組成物を種々の方法で、例えば経皮パッチ、スポット−オン又は軟膏として投与することができる。式(I)の化合物の付加塩は、対応する塩基形態より向上したそれらの水溶性のために、水性組成物の調製において明らかにより適している。
甘味料は、約10%〜約35%、好ましくは約10%〜15%(重量/容量)の範囲の比較的高い濃度で有効に用いられ得る。
Cool)、ファンタジー(Fantasy)などが必要であり得る。各風味料は、約0.05%〜1%(重量/容量)の範囲の濃度で、最終的な組成物中に存在することができる。該強い風味料の組み合わせは、有利に用いられる。好ましくは、調剤の環境下で味及び/又は色の変化又は喪失を経ない風味料が用いられる。
「DIPE」はジイソプロピルエーテルとして定義され、「DMF」はN,N−ジメチルホルムアミドとして定義され、「DMSO」はジメチルスルホキシドとして定義され、「DCM」又は「CH2Cl2」はジクロロメタンとして定義され、「THF」はテトラヒドロフランとして定義される。「CH3CN」という用語はアセトニトリルを意味し、「K2CO3」という用語は炭酸カリウムを意味し、「CH3OH」という用語はメタノールを意味し、「MgSO4」という用語は硫酸マグネシウムを意味し、「NaH」という用語は水素化ナトリウムを意味し、「EtOH」という用語はエタノールを意味し、「TFA」という用語はトリフルオロ酢酸を意味し、「EtOAc」という用語は酢酸エチルを意味する。
−精製法A
生成物を逆相高性能液体クロマトグラフィー(Shandon Hyperprep(R) C18 BDS(塩基不活性化シリカ)8μm,250g,内径 5cm)により精製した。3種の移動相を用いる勾配を適用した(相A:水中の0.25%NH4HCO3溶液;相B:CH3OH;相C:CH3CN)。所望の画分を集め、仕上げた。
−精製法B
生成物を逆相高性能液体クロマトグラフィー(Shandon Hyperprep(R) C18 BDS(塩基不活性化シリカ)8μm,250g,内径 5cm)により精製した。3種の移動相を用いる勾配を適用した(相A:水中の0.5%NH4OAc溶液の90%+10% CH3CN;相B:CH3OH;相C:CH3CN)。所望の画分を集め、仕上げた。
実施例A.1
実施例A.2
実施例A.3
実施例A.4
実施例A.5
/0から97/3)。所望の生成物画分を集め、溶媒を蒸発させ、1.65gの中間体(5)を与えた。
実施例A.6
実施例B.1
実施例B.2
実施例B.3
実施例B.4
リモル)の混合物を、室温で撹拌した。濃HCl(15滴)を加え、反応混合物をマイクロ波オーブン中で110℃において22分間加熱した。反応混合物を濾過し、赤色の沈殿をアセトニトリルで洗浄し、真空中で乾燥した。この画分をメタノール及びいくらかの2−プロパノン下で磨砕し、濾過し、乾燥し、0.6gの化合物(5)を与えた。
実施例B.5
実施例B.6
実施例B.7
デン−1,3(2H)−ジオン(7.5ミリモル)及びチオウレア(5ミリモル)の混合物に濃HCl(15滴)を加えた。得られる反応混合物をマイクロ波オーブン中で110℃において25分間加熱した。沈殿が生成し、それを濾過し、アセトニトリルで洗浄し、350mgの化合物(8)を与えた。
実施例B.8
実施例B.9
実施例B.10
熱時に濾過し、アセトニトリルで洗浄した。得られる画分をメタノール(10ml)下に80℃で2時間磨砕した。沈殿を濾過し、乾燥し、0.73gの化合物(11)を与えた。
実施例B.11
実施例B.12
実施例B.13
モル)、インデン−1,3(2H)−ジオン(7.5ミリモル)及びチオウレア(5ミリモル)の混合物を室温で撹拌した。濃HCl(15滴)を加え、反応混合物をマイクロ波オーブン中で110℃において22分間加熱した。次いで反応混合物を、マイクロ波オーブンの外で80℃においてさらに2時間撹拌した。室温でさらに24時間撹拌した後、黄オレンジ色の沈殿が生成し、それを濾過し、アセトニトリルで洗浄した。この生成物画分をメタノール下で磨砕し、濾過し、乾燥し、0.200gの化合物(14)を与えた。
実施例B.14
実施例B.15
実施例B.16
拌した。濃HCl(7滴)を加え、反応混合物をマイクロ波オーブン中で110℃において30分間加熱した。次いで反応混合物を、マイクロ波オーブンの外で80℃において終夜撹拌した。黄色の沈殿を濾過し、アセトニトリルで洗浄し、真空中で乾燥し、0.180gの化合物(17)を与えた。
実施例B.17
実施例B.18
実施例B.19
実施例B.20
実施例B.21
実施例B.22
実施例B.23
実施例B.24
実施例B.25
実施例B.26
実施例B.27
実施例B.28
生成物を逆相高性能液体クロマトグラフィー(Shandon Hyperprep(R) C18 BDS(塩基不活性化シリカ)8μm,250g,内径 5cm)により精製した。3種の移動相を用いた(相A:水中の0.5%NH4OAc溶液の90%+10% CH3CN;相B:CH3OH;相C:CH3CN)。最初に、40ml/分の流
量を用いて75%A及び25%Bを0.5分間保持した。次いで80ml/分の流量を用いて、41分内に50%B及び50%Cへの勾配を適用した。次いで80ml/分の流量を用いて20分内に100%Cへの勾配を適用し、4分間保持した。
HPLC方法B
生成物を逆相高性能液体クロマトグラフィー(Shandon Hyperprep(R) C18 BDS(塩基不活性化シリカ)8μm,250g,内径 5cm)により精製した。3種の移動相を用いた(相A:水中の0.25%NH4HCO3溶液;相B:CH3OH;相C:CH3CN)。最初に40ml/分の流量を用いて、75%A及び25%Bを0.5分間保持した。次いで80ml/分の流量を用いて、41分内に50%B及び50%Cへの勾配を適用した。次いで80ml/分の流量を用いて20分内に100%Cへの勾配を適用し、4分間保持した。
HPLC方法C
生成物を逆相高性能液体クロマトグラフィー(Shandon Hyperprep(R) C18 BDS(塩基不活性化シリカ)8μm,250g,内径 5cm)により精製した。3種の移動相を用いた(相A:水中の0.25%NH4HCO3溶液;相B:CH3OH;相C:CH3CN)。最初に40ml/分の流量を用いて、75%A及び25%Bを0.5分間保持した。次いで80ml/分の流量を用いて、41分内に100%Bへの勾配を適用した。次いで80ml/分の流量を用いて20分内に100%Cへの勾配を適用し、4分間保持した。
C.1.LC−MS 一般的方法1
LC測定は、バイナリーポンプ、サンプルオルガナイザー、カラムヒーター(55℃に設定)、ダイオードアレー検出器(DAD)及び下記のそれぞれの方法において特定されるカラムを含んでなるAcquity UPLC(Waters)システムを用いて行なわれた。カラムからの流れはMS分光計に分けられた。MS検出器は、エレクトロスプレーイオン化源を用いて形成された。0.02秒の滞留時間を用いて0.18秒内に100から1000まで走査することにより、質量スペクトルを取得した。毛管針電圧は3.5kVであり、源温度は140℃に保たれた。ネブライザーガスとして窒素を用いた。Waters−Micromass MassLynx−Openlynxデータシステムを用いてデータ取得を行なった。
複数の化合物に関し、DSC823e(Mettler−Toledo)を用いて融点(m.p.)を決定した。30℃/分の温度勾配を用いて融点を測定した。報告される値はピーク値である。最高温度は400℃であった。値は、この分析法に通常伴う実験的な不確かさを以て得られる。
Perkin Elmer 341偏光計を用いて旋光度を測定した。[α]D 20は、20℃*の温度でナトリウムのD−線の波長(589nm)における光を用いて測定される旋光度を示す。セルの路長は10cmである。実際の値の後に、旋光度の測定に用いられた溶液の濃度及び溶媒を挙げる。
細胞及び培養
ヒトTRPA1遺伝子をpT−REx−Dest30誘導可能ベクター(inducible vector)中にクローニングし、後にT−RexTM−293細胞(Invitrogen,Merelbeke,Belgiumから購入した)中に安定にトランスフェクションした。持続的なTRPA1発現の故の培養細胞におけるCa2+過剰負荷(overload)を妨げるために、このテトラサイクリン誘導hTRPA1発現系を用いた。hTRPA1/TREx−HEK293細胞(以下の文中ではhTRPA1細胞と言う)を標準的な無菌の細胞培養条件下に保持した。hTRPA1−HEK細胞のための培地は、0.5g/lのジェネテシン(geneticin)(Gibco)、5mg/lのブラスチシジン(blasticidin)(invitrogen)、14.6g/lのL−グルタミン(200mM;Gibco)、5g/lのペニシリン/ストレプトマイシン(5.10−6IU/l,Gibco)、5.5g/lのピルビン酸(Gibco)及び10%の胎児ウシ血清(Hyclone,Logan UT,USA)が補足されたDMEM(Gibco BRL,Invitrogen,Merelbeke,Belgium)であった。
TRPA1イオン−チャンネルへのアゴニストの結合はイオン−チャンネルを活性化して開き、それは細胞内Ca2+濃度を大きく増加させる(cause a robust
increase)。細胞内Ca2+濃度の検出及び測定のために、細胞にCa2+−感受性染料を負荷した。細胞内のCa2+濃度における変化に対応する細胞内の蛍光における変化を、FDSS測定器(Hamamatsu)を用いて速度論的に監視することができ、それはTRPA1イオンチャンネルに向かうアゴニズムを示しており、これをTRPA1−受容体アンタゴニストにより減少させることができる。
g/mlのテトラサイクリンを加え、hTRPA1発現を誘導した。
Claims (9)
- 立体化学的異性体を含む式(I)
A1及びA2は両方ともCR5であるか、あるいはA1又はA2の1つはNであり、他はCR5であり、ここで各R5は独立して水素、ハロ、C1−6アルキル、C1−6アルキルオキシ、ポリハロC1−6アルキル又はポリハロC1−6アルキルオキシから選ばれ;B1、B2、B3及びB4はすべてCHであるか、又はB1、B2、B3及びB4の1つはNであり、他はCHであり;
XはO又はSであり;
R1はハロ、ヒドロキシ、シアノ、アミノ、C1−6アルキル、ヒドロキシC1−6アルキル、C1−6アルキルオキシ、ポリハロC1−6アルキルオキシ、アリール、アリールオキシ又はOR6であり、ここでR6はヒドロキシ、C1−4アルキルオキシ、アリール、アリールオキシ、C1−4アルキルカルボニル、C1−4アルキルカルボニルオキシ又はNR7R8で置換されたC1−6アルキルであり、ここでR7及びR8はそれぞれ独立して水素又はC1−4アルキルから選ばれ;
R2は水素、フルオロ、C1−4アルキル又はC1−4アルキルオキシであり;
且つR1及びR2は一緒になって−O−CH2−O−又は−O−CH2−CH2−O−基を形成することができ;
R3は水素、C1−4アルキル又はアリールC1−2アルキルであり;
R4は水素、C1−4アルキル又はアリールC1−2アルキルであり;
各アリールは互いに独立して、水素、ハロ、ヒドロキシ、C1−4アルキル、ポリハロC1−4アルキル、C1−4アルキルオキシ、ポリハロC1−4アルキルオキシ、シアノ、ニトロ、アミノ又はモノ−もしくはジ−(C1−4アルキル)アミノからそれぞれ独立して選ばれる1、2又は3個の置換基で置換されたフェニルから選ばれ;
但し、XがOであり、且つA1及びA2が両方ともCR5であり、ここでR5が水素であり、且つR2が水素又はC1−4アルキルオキシであり、且つR3及びR4が水素である場合、R1はハロ、C1−6アルキル又はC1−6アルキルオキシではない]
の化合物あるいはその製薬学的に許容され得る酸付加塩又はその溶媒和物又はそのN−オキシド。 - B1、B2、B3及びB4がすべてCHである請求項1に記載の化合物。
- XがSである請求項1に記載の化合物。
- A1及びA2が両方ともCR5であり、ここで各R5は独立して水素又はハロから選ばれる請求項1に記載の化合物。
- 少なくとも1種の製薬学的に許容され得る担体及び請求項1〜5のいずれかに従う化合物の治療的に活性な量を含んでなる製薬学的組成物。
- 請求項1〜5のいずれかに従う化合物の治療的に活性な量を製薬学的に許容され得る担体と緊密に混合する請求項6に従う製薬学的組成物の調製方法。
- 薬剤として使用するための請求項1〜5のいずれかに従う化合物。
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EP08157398 | 2008-06-02 | ||
PCT/EP2009/056593 WO2009147079A1 (en) | 2008-06-02 | 2009-05-29 | 3,4-dihydropyrimidine trpa1 antagonists |
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CN (1) | CN102046608B (ja) |
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JP2015520756A (ja) * | 2012-05-25 | 2015-07-23 | ザ プロクター アンド ギャンブルカンパニー | Trpa1及びtrpv1感覚を軽減するための組成物 |
JP2016511240A (ja) * | 2013-02-06 | 2016-04-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 置換二環式ジヒドロピリミジノン及び好中球エラスターゼ活性の阻害薬としてのそれらの使用 |
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US8530487B1 (en) | 2009-01-29 | 2013-09-10 | Hydra Biosciences, Inc. | Compounds useful for treating disorders related to TRPA1 |
EP2520566A1 (en) | 2011-05-06 | 2012-11-07 | Orion Corporation | New Pharmaceutical Compounds |
BR112013032025A2 (pt) | 2011-06-13 | 2016-12-20 | Glenmark Pharmaceutical S A | antagonistas trpa1, compostos ou seus sais farmaceuticamente aceitáveis, métodos para reduzir a quantidade de eosinófilos ou neutrófilos e/ou aumentar fev1 em indivíduo com distúrbio respiratório, para tratar distúrbio respiratório em indivíduo e/ou para identificar antagonista trpa1, usos de quantidade eficaz de antagonista trpa1, e composição farmacêutica para administração por inalação |
JP6226991B2 (ja) | 2012-10-01 | 2017-11-08 | オリオン コーポレーション | N−プロプ−2−インイルカルボキサミド誘導体およびtrpa1アンタゴニストとしてのそれらの使用 |
JP6626454B2 (ja) | 2014-01-06 | 2019-12-25 | アルゴメディクス インコーポレイテッド | Trpa1モジュレーター |
WO2017060488A1 (en) | 2015-10-09 | 2017-04-13 | Almirall, S.A. | New trpa1 antagonists |
WO2017064068A1 (en) | 2015-10-14 | 2017-04-20 | Almirall, S.A. | New trpa1 antagonists |
CN106243096B (zh) * | 2016-07-29 | 2019-11-29 | 上海璃道医药科技有限公司 | 三环类药物的新用途 |
CA3037098C (en) | 2016-10-25 | 2023-01-17 | The Procter & Gamble Company | Differential pillow height fibrous structures |
US11198972B2 (en) | 2016-10-25 | 2021-12-14 | The Procter & Gamble Company | Fibrous structures |
FI3891145T3 (fi) * | 2018-12-06 | 2023-07-18 | Constellation Pharmaceuticals Inc | TREX1:n MODULAATTORIT |
IT202100015098A1 (it) | 2021-06-09 | 2022-12-09 | Flonext S R L | Composto antagonista del canale trpa1 per uso in patologie degenerative della retina |
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Cited By (2)
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JP2015520756A (ja) * | 2012-05-25 | 2015-07-23 | ザ プロクター アンド ギャンブルカンパニー | Trpa1及びtrpv1感覚を軽減するための組成物 |
JP2016511240A (ja) * | 2013-02-06 | 2016-04-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 置換二環式ジヒドロピリミジノン及び好中球エラスターゼ活性の阻害薬としてのそれらの使用 |
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AU2009253978B2 (en) | 2014-01-30 |
ES2409262T3 (es) | 2013-06-26 |
CA2724878A1 (en) | 2009-12-10 |
CN102046608B (zh) | 2014-04-02 |
US20110124666A1 (en) | 2011-05-26 |
JP5559156B2 (ja) | 2014-07-23 |
CN102046608A (zh) | 2011-05-04 |
CA2724878C (en) | 2016-09-13 |
EP2300440B1 (en) | 2013-02-27 |
EP2300440A1 (en) | 2011-03-30 |
KR101606778B1 (ko) | 2016-03-28 |
AU2009253978A1 (en) | 2009-12-10 |
WO2009147079A1 (en) | 2009-12-10 |
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