JP5508256B2 - 神経変性疾患の治療のためのヘテロアリールアミド置換ピリミドン誘導体 - Google Patents
神経変性疾患の治療のためのヘテロアリールアミド置換ピリミドン誘導体 Download PDFInfo
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- JP5508256B2 JP5508256B2 JP2010508002A JP2010508002A JP5508256B2 JP 5508256 B2 JP5508256 B2 JP 5508256B2 JP 2010508002 A JP2010508002 A JP 2010508002A JP 2010508002 A JP2010508002 A JP 2010508002A JP 5508256 B2 JP5508256 B2 JP 5508256B2
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- bipyrimidinyl
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- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- DFWRZHZPJJAJMX-UHFFFAOYSA-N propanimidamide;hydrochloride Chemical compound Cl.CCC(N)=N DFWRZHZPJJAJMX-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000026938 proteasomal ubiquitin-dependent protein catabolic process Effects 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- ARYJURLFRJCKLP-UHFFFAOYSA-N pyrazino[2,3-d]triazine Chemical compound N1=NN=CC2=NC=CN=C21 ARYJURLFRJCKLP-UHFFFAOYSA-N 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- MHOZZUICEDXVGD-UHFFFAOYSA-N pyrrolo[2,3-d]imidazole Chemical compound C1=NC2=CC=NC2=N1 MHOZZUICEDXVGD-UHFFFAOYSA-N 0.000 description 1
- QEIQICVPDMCDHG-UHFFFAOYSA-N pyrrolo[2,3-d]triazole Chemical compound N1=NC2=CC=NC2=N1 QEIQICVPDMCDHG-UHFFFAOYSA-N 0.000 description 1
- RQGPLDBZHMVWCH-UHFFFAOYSA-N pyrrolo[3,2-b]pyrrole Chemical compound C1=NC2=CC=NC2=C1 RQGPLDBZHMVWCH-UHFFFAOYSA-N 0.000 description 1
- GZTPJDLYPMPRDF-UHFFFAOYSA-N pyrrolo[3,2-c]pyrazole Chemical compound N1=NC2=CC=NC2=C1 GZTPJDLYPMPRDF-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 108010061506 tau-protein kinase Proteins 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- URGSAXLBDOVRJJ-UHFFFAOYSA-N thiadiazolo[5,4-c]pyridazine Chemical compound N1=NC=CC2=C1SN=N2 URGSAXLBDOVRJJ-UHFFFAOYSA-N 0.000 description 1
- 150000008634 thiazolopyrimidines Chemical class 0.000 description 1
- VJYJJHQEVLEOFL-UHFFFAOYSA-N thieno[3,2-b]thiophene Chemical compound S1C=CC2=C1C=CS2 VJYJJHQEVLEOFL-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- AFWHQLQLEUKQAH-UHFFFAOYSA-N triazolo[4,5-d]triazole Chemical compound N1=NC2=NN=NC2=N1 AFWHQLQLEUKQAH-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
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Description
Xは、水素原子2個、硫黄原子、酸素原子またはC1−2アルキル基および水素原子を表し、
Zは、結合、酸素原子、窒素原子(水素原子またはC1−3アルキル基で置換されている。)、硫黄原子、メチレン基(C1−6アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2過ハロゲン化アルキル基またはアミノ基から選択される1または2つの基で場合によって置換されている。)を表し、
R1は、2、4もしくは5−ピリミジン環または4−ピリジン環を表し、これらの環は、C1−6アルキル基、C1−6アルコキシ基またはハロゲン原子で場合によって置換されており、
R2は、4−15員の複素環式基を表し、この基は、C1−6アルキル基、ハロゲン原子、C1−2過ハロゲン化アルキル基、C1−6ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2過ハロゲン化アルコキシ基、C1−6ハロゲン化アルコキシ基、ニトロ、シアノ、アミノ、C1−6モノアルキルアミノ基、C2−12ジアルキルアミノ基、S−(C1−6−アルキル)基、複素環式基、アリール基、ヘテロアリール基、O−アリール基またはS−アリール基(上述の基は、C1−6アルキル基、ハロゲン原子、C1−6アルコキシ基、C(O)O(C1−6−アルキル)またはC(O)O(アリール)基(このアリールは、C1−6アルキル基、ハロゲン原子、C1−6アルコキシ基から選択される1から4つの置換基で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されており、
R3は、水素原子、C1−6アルキル基またはハロゲン原子を表し、
R4は、水素原子またはC1−6アルキル基を表し、
R5は、水素原子、C1−6アルキル基を表し、
R6は、水素原子、C1−6アルキル基を表し、
R7は、水素原子またはC1−6アルキル基を表し、
nは、0から3を表し、mは、0を表す。)。
(1)R1は、4−もしくは5−ピリミジン環または4−ピリジン環を表し、この環は、C1−2アルキル基、C1−2アルコキシ基またはハロゲン原子で場合によって置換されている、および/または
(2)R2は、6−10員の複素環式基を表し、この基は、C1−6アルキル基、ハロゲン原子、C1−2過ハロゲン化アルキル基、C1−6ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2過ハロゲン化アルコキシ基、C1−6ハロゲン化アルコキシ基、ニトロ、シアノ、アミノ、C1−6モノアルキルアミノ基、C2−12ジアルキルアミノ基、S−(C1−6−アルキル)基、複素環式基、アリール基、ヘテロアリール基、O−アリール基もしくはS−アリール基(上述の基は、C1−6アルキル基、ハロゲン原子、C1−6アルコキシ基、C(O)O(C1−6−アルキル)またはC(O)O(フェニル)基(このフェニルはC1−6アルキル基、ハロゲン原子、C1−6アルコキシ基から選択される1から4つの置換基で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されている、
(3)R3は、水素原子、C1−6アルキル基もしくはハロゲン原子を表す、および/または
(4)R4は、水素原子もしくはC1−6アルキル基を表す、および/または
(5)R5は、水素原子、C1−6アルキル基を表す、および/または
(6)R6は、水素原子、C1−6アルキル基を表す、および/または
(7)R7は、水素原子もしくはC1−6アルキル基を表す、および/または
(8)Xは、水素原子2個、酸素原子、もしくはC1−2アルキル基および水素原子を表す、および/または
(9)Zは、結合、酸素原子、窒素原子(水素原子またはC1−3アルキル基で置換されている。)、メチレン基(C1−3アルキル基、ヒドロキシル基、C1−3アルコキシ基、C1−2過ハロゲン化アルキル基もしくはアミノ基から選択される1または2つの基で場合によって置換されている。)を表す、および/または
(10)nは、0から3を表す。
(1)R1は、非置換4−ピリミジン環を表す、および/または
(2)R2は、ベンゾジオキシン環、ピリミジン環、ピリダジン環、ナフチリジン環、ピリジン環、ジヒドロベンゾジオキシン、ベンゾフラン、ジヒドロベンゾフラン環、ベンゾチアゾール環、ベンゾチオフェン環、ベンゾジオキソール、ジヒドロベンゾジオキソール環、イミダゾピリジン環を表し、これらの環は、場合によって部分的もしくは完全に飽和しており、および/またはヒドロキシル基、アミノ、C1−6アルキル基、S−(C1−6アルキル)基、ハロゲン原子、C1−2過ハロゲン化アルキル基、C1−6アルコキシ基、C1−2過ハロゲン化アルコキシ基またはアリール基(ハロゲン原子で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されている、および/または
(3)R3は、水素原子を表す、および/または
(4)R4は、メチルを表す、および/または
(5)R5は、水素原子もしくはメチルを表す、および/または
(6)R6は、水素原子を表す、および/または
(7)R7は、水素原子を表す、および/または
(8)Xは、酸素原子を表す、および/または
(9)Zは、結合もしくは水素原子で置換された窒素原子を表す、および/または
(10)nおよびmは、0を表す。
1.8−アミノ−7−クロロ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
2.5−クロロ−2−メチルスルファニル−ピリミジン−4−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
3.3,6−ジメトキシ−ピリダジン−4−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
4.[1,5]ナフチリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
5.2−メトキシ−N−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−ニコチンアミド
6.ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
7.6−フルオロ−4H−ベンゾ[1,3]ジオキシン−8−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
8.[1,6]ナフチリジン−5−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
9.N−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−ニコチンアミド
10.6−クロロ−ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
11.2,3−ジヒドロ−ベンゾフラン−7−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
12.2,2−ジメチル−2,3−ジヒドロ−ベンゾフラン−7−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
13.5−ブロモ−ベンゾフラン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
14.ベンゾチアゾール−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
15.ベンゾ[b]チオフェン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
16.2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−4−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
17.(+/−)[1,5]ナフチリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
18.3−ヒドロキシ−ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
19.(+/−)6−クロロ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
20.(+/−)5−クロロ−2−メチルスルファニル−ピリミジン−4−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
21.4−メトキシ−ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
22.(+/−)ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
23.(+/−)6−(2−フルオロ−フェニル)−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
24.(+/−)3−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
25.(+/−)2−メトキシ−N−[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−ニコチンアミド
26.(+/−)ベンゾ[b]チオフェン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
27.3H−イミダゾ[4,5−b]ピリジン−6−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
28.(+/−)4−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
29.(+)−4−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
30.(−)−4−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
31.6−フルオロ−4H−ベンゾ[1,3]ジオキシン−8−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
32.8−アミノ−7−クロロ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
33.5−ブロモ−2−メチルスルファニル−ピリミジン−4−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
34.(+)−2−メトキシ−N−[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−ニコチンアミド
35.(−)−2−メトキシ−N−[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−ニコチンアミド
36.2,6−ジメトキシ−N−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−ニコチンアミド
さらなる目的として、本発明はまた、上述の式(I)により表されるピリミドン化合物を調製するための方法にも関する。
上述の式(I)により表されるピリミドン化合物は、スキーム1に記載されている方法に従い調製し得る。
2−メトキシ−N−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−ニコチンアミド
1.1 2−メチル−1H−[4,4’]ビピリミジニル−6−オン
アセトアミジン塩酸塩200g(2.11モル)(1:1)のエタノール1.2L中懸濁液に、水酸化ナトリウム84g(2.11モル)およびエチル3−(4−ピリミジニル)−3−オキソプロピオネート410g(2.11モル)(特許DE2705582号明細書に記載されている方法と類似の方法により調製した。)を加えた。生成した混合物を、還流下で12時間攪拌した。冷却した溶液を蒸発させて溶媒を取り除いた。この混合物を水で処理し、沈殿物を濾過し、ジエチルエーテルおよび酢酸エチルで洗浄した。沈殿物を2/1比のエタノール/水の混合物中で30分間攪拌し、所望の化合物200g(50%)を茶色粉末として得た。
Mp:320−322℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):12.70(br s,1H);9.30(s,1H);9.00(d,1H);8.20(d,1H);7.15(s,1H);2.40(s,3H)。
2−メチル−1H−[4,4’]ビピリミジニル−6−オン96g(0.51モル)の無水ジメチルホルムアミド480mL中懸濁液に、炭酸カリウム77.55g(0.56モル)を加えた。生成した混合物を室温で15分間攪拌させ、0℃で冷却し、ヨウ化メチル31.78mL(0.51モル)を滴加した。
Mp:179−181℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.30(s,1H);9.00(d,1H);8.25(d,1H);7.20(s,1H);3.55(s,3H);2.60(s,3H)。
1,2−ジメチル−1H−[4,4’]ビピリミジニル−6−オン17g(0.084モル)の水45mL中懸濁液に、硫酸8.5mL、四塩化炭素25mLおよびアイオダイド9.6g(0.037モル)を加えた。生成した混合物を還流させ、過酸化水素(35%水溶液)16.38mLを滴加した。この混合物を還流下で5時間攪拌し、室温で冷却し、塩化アンモニウムの飽和水溶液100mLおよびクロロホルム100mLを加えた。生成した沈殿物を濾別し、濾液をクロロホルムで抽出し、乾燥蒸発させることによって、生成物13.6が得られ、これをそのまま次のステップで使用した。
2−ヨードメチル−1−メチル−1H−[4,4’]ビピリミジニル−6−オン14.80g(45.11mmol)の無水ジメチルホルムアミド30ml中溶液に、フタルイミドカリウム16.71g(90.21mmol)を加えた。生成した混合物を130℃で3時間攪拌した。冷却後、水を加え、生成した混合物を0℃で12時間攪拌した。この沈殿物を濾過し、酢酸エチル中で加熱し、沈殿物を濾過した。生成物を乾燥することによって、純粋な化合物5.3g(30%)を茶色固体として得た。
Mp:273−275℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.40(s,1H);8.85(d,1H);8.20(m,4H);7.50(d,1H);7.40(s,1H);5.35(s,2H);3.80(s,3H)。
2−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−イソインドール−1,3−ジオン5.3g(15.26mmol)のエタノール40ml中溶液に、ヒドラジン水化物2.37mL(76.30mmol)を加え、生成した混合物を還流下で3時間加熱した。この混合物を濾過し、得た固体を24時間ジクロロメタンで粉末化し、濾過し、生成した濾液を蒸発乾燥させ、残留物をジエチルエーテルで粉末化し、濾過することによって、純粋な化合物1.8gを固体として得た。
Mp:153−155℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.40(s,1H);9.10(d,1H);8.50(d,1H);7.30(s,1H);3.95(s,2H);3.50(s,3H);2.15(br d,2H)。
2−アミノメチル−1−メチル−1H−[4,4’]ビピリミジニル−6−オン0.08g(0.37mmol)のジメチルホルムアミド7.37mL中溶液に、2−メトキシ−ニコチン酸0.056g(0.37mmol)およびシアノホスホン酸ジエチル(DEPC)70μL(0.44mmol)を加えた。生成した混合物を0℃で冷却し、トリエチルアミン60μL(0.41mmol)を加えた。この反応混合物を室温で1時間攪拌した。
Mp:269−271℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.35(s,1H);9.10(m,2H);8.50−8.20(m,3H);7.35(s,1H);7.20(m,1H);4.80(d,2H);4.10(s,3H);3.60(s,3H)。
(+/−)6−クロロ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
2.1 2−エチル−1H−[4,4’]ビピリミジニル−6−オン
実施例1(ステップ1.1)に記載されている方法と類似の方法により、アセトアミジン塩酸塩(1:1)の代わりにプロピオンアミジン塩酸塩(1:1)を用いて、この化合物を茶色粉末として得た。
Mp.:227−229℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.30(s,1H);9.10(d,1H);8.30(d,1H);7.15(s,1H);3.50(brs,1H);2.70(q,2H);1.35(t,3H)。
実施例1(ステップ1.2)に記載されている方法と類似の方法により、1,2−ジメチル−1H−[4,4’]ビピリミジニル−6−オンの代わりに2−エチル1H−[4,4’]ビピリミジニル−6−オンを用いて、この化合物を茶色粉末として得た。
Mp.:150−152℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.40(s,1H);9.10(d,1H);8.40(d,1H);7.30(s,1H);3.60(s,3H);3.00(q,2H);1.40(t,3H)。
実施例1(ステップ1.3)に記載されている方法と類似の方法により、1,2−ジメチル−1H−[4,4’]ビピリミジニル−6−オンの代わりに2−エチル1−メチル−1H−[4,4’]ビピリミジニル−6−オンを用いて、この化合物をそのまま次のステップで使用した。
実施例1(ステップ1.4)に記載されている方法と類似の方法により、2−ヨードメチル−1−メチル−1H−[4,4’]ビピリミジニル−6−オンの代わりに(+/−)2−(1−ヨード−エチル)−1−メチル−1H−[4,4’]ビピリミジニル−6−オンを用いて、この化合物をそのまま次のステップで使用した。
実施例1(ステップ1.5)に記載されている方法と類似の方法により、2−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−イソインドール−1,3−ジオンの代わりに(+/−)2−[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−イソインドール−1,3−ジオンを用いて、この化合物を茶色粉末として得た。
Mp.:158−160℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.40(s,1H);9.20(d,1H);8.70(d,1H);8.50(brs,2H);7.35(s,1H);4.90(m,1H);3.60(s,3H);1.55(d,3H)。
実施例1(ステップ1.6)に記載されている方法と類似の方法により、2−アミノメチル−1−メチル−1H−[4,4’]ビピリミジニル−6−オンの代わりに(+/−)2−(1−アミノ−エチル)−1−メチル−1H−[4,4’]ビピリミジニル−6−オンを用いて、この化合物を白色粉末として得た。
Mp.:254−256℃
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.50(d,1H);9.40(s,1H);9.10(d,1H);8.50(m,1H);8.10(m,2H);7.80(m,1H);7.30(s,1H);5.40(m,1H);3.60(s,3H);1.60(d,3H)。
(+)−4−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
(+/−)−4−メトキシ−ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド0.147g(0.40mmol)(表1の化合物28)を、割合30/70比のイソプロパノール/n−ヘプタン混合物で溶出するキラル分取HPLC(Daicel CHIRALCEL OD−H 20μm50×220)で分離することによって、純粋な生成物0.052gを遊離塩基の形態で得た。
tR:29.65分
Mp.:178.2℃。[α]D 20=+39.02°(c=0.174、DMSO)。
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.35(d,1H);9.08(d,1H);9.04(d,1H);8.42(d,1H);8.22(d,1H);7.60(m,1H);7.50(m,1H);7.30(s,1H);5.42(m,1H);3.85(s,3H);3.62(s,3H)。1.60(s,3H)。
(−)−4−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
(+/−)−4−メトキシ−ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド(表1の化合物28)0.147g(0.40mmol)を、30/70比のイソプロパノール/n−ヘプタン混合物で溶出するキラル分取HPLC(Daicel CHIRALCEL OD−H2Oμm50×220)で分離することによって、純粋な生成物0.058gを遊離塩基の形態で得た。
tR:43.18分
Mp.:176.2℃。[α]D 20=−44.96°(c=0.224、DMSO)。
RMN 1H(DMSO−d6;200MHz)
δ(ppm):9.35(d,1H);9.08(d,1H);9.04(d,1H);8.42(d,1H);8.22(d,1H);7.60(m,1H);7.50(m,1H);7.30(s,1H);5.42(m,1H);3.85(s,3H);3.62(s,3H)。1.60(s,3H)。
2つの異なるプロトコルを使用することができる。
NH2−YRRAAVPPSPSLSRHSSPHQS(P)EDEE−COOH(Woodgett,J.R.(1989年)、Analytical Biochemistry、180、237−241頁。
(1)錠剤
以下の成分を通常方法で混合し、従来の装置を用いて圧縮した。
実施例1の化合物 30mg
結晶性セルロース 60mg
コーンスターチ 100mg
乳糖 200mg
ステアリン酸マグネシウム 4mg
以下の成分を通常の方法で混合し、軟カプセル剤に充填した。
実施例1の化合物 30mg
オリーブ油 300mg
レシチン 20mg
以下の成分を通常の方法で混合し、1mlアンプル中に含有される注射剤を調製した。
実施例1の化合物 3mg
塩化ナトリウム 4mg
注射用蒸留水 1ml
Claims (18)
- 式(I)で表される、遊離塩基または酸との付加塩の形態での、ピリミドン誘導体もしくはその塩、またはその溶媒和化合物もしくはその水和物
Xは、水素原子2個、硫黄原子、酸素原子またはC1−2アルキル基および水素原子を表し、
Zは、結合、酸素原子、窒素原子(水素原子またはC1−3アルキル基で置換されている。)、硫黄原子、メチレン基(C1−6アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2過ハロゲン化アルキル基またはアミノ基から選択される、1または2つの基で場合によって置換されている。)を表し、
R1は、2、4もしくは5−ピリミジン環または4−ピリジン環を表し、これらの環は、C1−6アルキル基、C1−6アルコキシ基またはハロゲン原子で場合によって置換されており、
R2は、4−15員の複素環式基を表し、この基は、C1−6アルキル基、ハロゲン原子、C1−2過ハロゲン化アルキル基、C1−6ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2過ハロゲン化アルコキシ基、C1−6ハロゲン化アルコキシ基、ニトロ、シアノ、アミノ、C1−6モノアルキルアミノ基、C2−12ジアルキルアミノ基、S−(C1−6−アルキル)基、複素環式基、アリール基、ヘテロアリール基、O−アリール基またはS−アリール基(上述の基は、C1−6アルキル基、ハロゲン原子、C1−6アルコキシ基、C(O)O(C1−6−アルキル)またはC(O)O(アリール)基(このアリールは、C1−6アルキル基、ハロゲン原子、C1−6アルコキシ基から選択される1から4つの置換基で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されており、
R3は、水素原子、C1−6アルキル基またはハロゲン原子を表し、
R4は、水素原子またはC1−6アルキル基を表し、
R5は、水素原子、C1−6アルキル基を表し、
R6は、水素原子、C1−6アルキル基を表し、
R7は、水素原子またはC1−6アルキル基を表し、および
nは、0から3を表し、mは、0を表す。)。 - R1が、非置換4−ピリミジン環を表す、請求項1に記載のピリミドン誘導体もしくはその塩、またはその溶媒和化合物もしくはその水和物。
- R1が、4−もしくは5−ピリミジン環または4−ピリジン環を表し、これら環が、C1−2アルキル基、C1−2アルコキシ基またはハロゲン原子で場合によって置換されており、および/または
R2が、6−10員の複素環式基を表し、この基は、C1−6アルキル基、ハロゲン原子、C1−2過ハロゲン化アルキル基、C1−6ハロゲン化アルキル基、ヒドロキシル基、C1−6アルコキシ基、C1−2過ハロゲン化アルコキシ基、C1−6ハロゲン化アルコキシ基、ニトロ、シアノ、アミノ、C1−6モノアルキルアミノ基、C2−12ジアルキルアミノ基、S−(C1−6−アルキル)基、複素環式基、アリール基、ヘテロアリール基、O−アリール基またはS−アリール基(上述の基は、C1−6アルキル基、ハロゲン原子、C1−6アルコキシ基、C(O)O(C1−6−アルキル)またはC(O)O(フェニル)基(このフェニルは、C1−6アルキル基、ハロゲン原子、C1−6アルコキシ基から選択される1から4つの置換基で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されており、
R3が、水素原子、C1−6アルキル基もしくはハロゲン原子を表し、および/または
R4が、水素原子もしくはC1−6アルキル基を表し、および/または
R5が、水素原子、C1−6アルキル基を表し、および/または
R6が、水素原子、C1−6アルキル基を表し、および/または
R7が、水素原子もしくはC1−6アルキル基を表し、および/または
Xが、水素原子2個、酸素原子、もしくはC1−2アルキル基および水素原子を表し、および/または
Zが、結合、酸素原子、窒素原子(水素原子またはC1−3アルキル基で置換されている。)、メチレン基(C1−3アルキル基、ヒドロキシル基、C1−3アルコキシ基、C1−2過ハロゲン化アルキル基もしくはアミノ基から選択される1もしくは2つの基で場合によって置換されている。)を表し、および/または
nが、0から3を表す、
遊離塩基または酸との付加塩の形態での、請求項1に記載のピリミドン誘導体もしくはその塩、またはその溶媒和化合物もしくはその水和物。 - R1が、非置換4−ピリミジン環を表し、および/または
R2が、ベンゾジオキシン環、ピリミジン環、ピリダジン環、ナフチリジン環、ピリジン環、ジヒドロベンゾジオキシン、ベンゾフラン、ジヒドロベンゾフラン環、ベンゾチアゾール環、ベンゾチオフェン環、ベンゾジオキソール、ジヒドロベンゾジオキソール環、イミダゾピリジン環を表し、これらの環は、場合によって部分的もしくは完全に飽和しており、および/またはヒドロキシル基、アミノ、C1−6アルキル基、S−(C1−6アルキル)基、ハロゲン原子、C1−2過ハロゲン化アルキル基、C1−6アルコキシ基、C1−2過ハロゲン化アルコキシ基もしくはアリール基(ハロゲン原子で場合によって置換されている。)から選択される1から4つの置換基で場合によって置換されており、および/または
R3が、水素原子を表し、および/または
R4が、メチルを表し、および/または
R5が、水素原子もしくはメチルを表し、および/または
R6が、水素原子を表し、および/または
R7が、水素原子を表し、および/または
Xが、酸素原子を表し、および/または
Zが、結合、もしくは水素原子で置換された窒素原子を表し、および/または
nおよびmが、0を表す、
遊離塩基または酸との付加塩の形態での、請求項1に記載のピリミドン誘導体もしくはその塩、またはその溶媒和化合物もしくはその水和物。 - 以下からなる群から選択される、請求項1に記載のピリミドン誘導体もしくはその塩、またはその溶媒和化合物もしくはその水和物:
・8−アミノ−7−クロロ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・5−クロロ−2−メチルスルファニル−ピリミジン−4−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・3,6−ジメトキシ−ピリダジン−4−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・[1,5]ナフチリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・2−メトキシ−N−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−ニコチンアミド
・ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・6−フルオロ−4H−ベンゾ[1,3]ジオキシン−8−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・[1,6]ナフチリジン−5−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・N−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−ニコチンアミド
・6−クロロ−ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・2,3−ジヒドロ−ベンゾフラン−7−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・2,2−ジメチル−2,3−ジヒドロ−ベンゾフラン−7−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・5−ブロモ−ベンゾフラン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・ベンゾチアゾール−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・ベンゾ[b]チオフェン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・2,2−ジフルオロ−ベンゾ[1,3]ジオキソール−4−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・(+/−)[1,5]ナフチリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・3−ヒドロキシ−ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・(+/−)6−クロロ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・(+/−)5−クロロ−2−メチルスルファニル−ピリミジン−4−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・4−メトキシ−ピリジン−2−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・(+/−)ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・(+/−)6−(2−フルオロ−フェニル)−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・(+/−)3−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・(+/−)2−メトキシ−N−[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−ニコチンアミド
・(+/−)ベンゾ[b]チオフェン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・3H−イミダゾ[4,5−b]ピリジン−6−カルボン酸(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−アミド
・(+/−)4−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・(+)−4−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・(−)−4−メトキシ−ピリジン−2−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・6−フルオロ−4H−ベンゾ[1,3]ジオキシン−8−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・8−アミノ−7−クロロ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・5−ブロモ−2−メチルスルファニル−ピリミジン−4−カルボン酸[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−アミド
・(+)−2−メトキシ−N−[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−ニコチンアミド
・(−)−2−メトキシ−N−[1−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イル)−エチル]−ニコチンアミド
・2,6−ジメトキシ−N−(1−メチル−6−オキソ−1,6−ジヒドロ−[4,4’]ビピリミジニル−2−イルメチル)−ニコチンアミド。 - 請求項1から5のいずれか一項に記載の式(I)で表されるピリミドン誘導体もしくはその塩、またはその溶媒和化合物もしくはその水和物からなる群から選択される物質を活性成分として含む薬剤。
- 請求項1に記載の式(I)で表されるピリミドン誘導体もしくはその塩、またはその溶媒和化合物もしくは水和物の群から選択されるGSK3β阻害剤。
- GSK3βの異常活性によって引き起こされる疾患の予防的および/または治療的処置のための、請求項1から5のいずれか一項に記載の化合物。
- 神経変性疾患の予防的および/または治療的処置のための、請求項1から5のいずれか一項に記載の化合物。
- 神経変性疾患が、アルツハイマー病、パーキンソン病、タウオパチー、脳血管性認知症、急性脳卒中、外傷性障害、脳血管障害、脳損傷(brain cord trauma)、脊髄損傷、末梢神経障害、網膜症または緑内障からなる群から選択される、請求項9に記載の化合物。
- インスリン非依存性糖尿病、肥満、躁うつ病、統合失調症、脱毛症、癌、腎実質性疾患または筋萎縮の予防的および/または治療的処置のための、請求項1から5のいずれか一項に記載の化合物。
- 癌が、乳癌、肺非小細胞癌、甲状腺癌、T細胞白血病もしくはB−細胞白血病またはウイルス誘発性腫瘍である、請求項11に記載の化合物。
- マラリアの予防的および/または治療的処置のための、請求項1から5のいずれか一項に記載の化合物。
- 骨疾患の予防的および/または治療的処置のための、請求項1から5のいずれか一項に記載の化合物。
- 尋常性天疱瘡の予防的および/または治療的処置のための、請求項1から5のいずれか一項に記載の化合物。
- 癌化学療法で誘発される好中球減少症の予防的および/または治療的処置のための、請求項1から5のいずれか一項に記載の化合物。
- 認知欠陥および記憶欠損を特徴とする疾患の治療的処置のための、請求項1から5のいずれか一項に記載の化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07290627.4 | 2007-05-16 | ||
EP07290627A EP1992621A1 (en) | 2007-05-16 | 2007-05-16 | Heteroarylamide-substituted pyrimidone derivatives for the treatment of neurodegenerative diseases |
PCT/IB2008/002429 WO2008155666A2 (en) | 2007-05-16 | 2008-05-14 | Heteroarylamide-substituted pyrimidone derivatives for the treatment of neurodegenerative diseases |
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JP2010526864A JP2010526864A (ja) | 2010-08-05 |
JP5508256B2 true JP5508256B2 (ja) | 2014-05-28 |
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JP2010508002A Active JP5508256B2 (ja) | 2007-05-16 | 2008-05-14 | 神経変性疾患の治療のためのヘテロアリールアミド置換ピリミドン誘導体 |
Country Status (15)
Country | Link |
---|---|
US (1) | US8598175B2 (ja) |
EP (2) | EP1992621A1 (ja) |
JP (1) | JP5508256B2 (ja) |
KR (1) | KR20100016510A (ja) |
CN (1) | CN101679306B (ja) |
AR (1) | AR066605A1 (ja) |
AU (1) | AU2008264898A1 (ja) |
BR (1) | BRPI0811094A2 (ja) |
CA (1) | CA2687255A1 (ja) |
EA (1) | EA200971060A1 (ja) |
IL (1) | IL201449A0 (ja) |
MX (1) | MX2009012376A (ja) |
NZ (1) | NZ581162A (ja) |
TW (1) | TW200906803A (ja) |
WO (1) | WO2008155666A2 (ja) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009132051A1 (en) | 2008-04-21 | 2009-10-29 | Signum Biosciences, Inc. | Compounds, compositions and methods for making the same |
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
CA2945263A1 (en) | 2014-04-09 | 2015-10-15 | Christopher Rudd | Use of gsk-3 inhibitors or activators which modulate pd-1 or t-bet expression to modulate t cell immunity |
MA49014A (fr) * | 2017-03-21 | 2020-02-05 | Arbutus Biopharma Corp | Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US4145423A (en) | 1976-02-10 | 1979-03-20 | Rhone-Poulenc Industries | Pyrimidinyl-1,2-dithiole compounds and anti-bilharzia compositions thereof |
US5629322A (en) | 1994-11-15 | 1997-05-13 | Merck & Co., Inc. | Cyclic amidine analogs as inhibitors of nitric oxide synthase |
JP4533534B2 (ja) | 1998-06-19 | 2010-09-01 | ノバルティス バクシンズ アンド ダイアグノスティックス,インコーポレーテッド | グリコーゲンシンターゼキナーゼ3のインヒビター |
AR023052A1 (es) | 1998-09-25 | 2002-09-04 | Mitsuharu Yoshimura Milton | Derivados de pirimidona |
AU2002342798C1 (en) * | 2001-09-21 | 2008-09-25 | Mitsubishi Pharma Corporation | Substituted 2-pyrimidinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyrimidinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives for neurodegenerative disorders |
EA009027B1 (ru) | 2002-12-16 | 2007-10-26 | Мицубиси Фарма Корпорейшн | Производные 3-замещенного-4-пиримидона |
EP1454909B1 (en) * | 2003-03-07 | 2008-08-20 | Sanofi Aventis | 8'-pyridinyl-dihydrospiro (cycloalkyl) -pyrimido (1,2-a) pyrimidin-6-one and 8'-pyrimidinyl-dihydrospiro (cycloalkyl) pyrimido (1,2-a) pyrimidin-6 derivatives -one and their use against neurodegenerative diseases |
BRPI0408186A (pt) * | 2003-03-07 | 2006-04-04 | Sanofi Aventis | derivados de 2-(diaza-biciclo-alquil)-pirimidona substituìdos |
EP1790649A1 (en) | 2005-11-21 | 2007-05-30 | Sanofi-Aventis | Substituted bicyclic pyrimidone derivatives |
-
2007
- 2007-05-16 EP EP07290627A patent/EP1992621A1/en not_active Withdrawn
-
2008
- 2008-05-14 EP EP08807106.3A patent/EP2162443B1/en not_active Not-in-force
- 2008-05-14 AU AU2008264898A patent/AU2008264898A1/en not_active Abandoned
- 2008-05-14 EA EA200971060A patent/EA200971060A1/ru unknown
- 2008-05-14 NZ NZ581162A patent/NZ581162A/en not_active IP Right Cessation
- 2008-05-14 JP JP2010508002A patent/JP5508256B2/ja active Active
- 2008-05-14 KR KR1020097023694A patent/KR20100016510A/ko not_active Application Discontinuation
- 2008-05-14 WO PCT/IB2008/002429 patent/WO2008155666A2/en active Application Filing
- 2008-05-14 CA CA002687255A patent/CA2687255A1/en not_active Abandoned
- 2008-05-14 CN CN2008800160643A patent/CN101679306B/zh not_active Expired - Fee Related
- 2008-05-14 MX MX2009012376A patent/MX2009012376A/es not_active Application Discontinuation
- 2008-05-14 BR BRPI0811094-8A2A patent/BRPI0811094A2/pt not_active IP Right Cessation
- 2008-05-16 AR ARP080102086A patent/AR066605A1/es unknown
- 2008-05-16 TW TW097118184A patent/TW200906803A/zh unknown
-
2009
- 2009-10-11 IL IL201449A patent/IL201449A0/en unknown
- 2009-10-27 US US12/606,669 patent/US8598175B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
EP2162443A2 (en) | 2010-03-17 |
AU2008264898A1 (en) | 2008-12-24 |
EP2162443B1 (en) | 2013-07-31 |
AR066605A1 (es) | 2009-09-02 |
US8598175B2 (en) | 2013-12-03 |
JP2010526864A (ja) | 2010-08-05 |
CA2687255A1 (en) | 2008-12-24 |
WO2008155666A2 (en) | 2008-12-24 |
WO2008155666A3 (en) | 2009-04-09 |
US20100081677A1 (en) | 2010-04-01 |
CN101679306B (zh) | 2011-12-28 |
BRPI0811094A2 (pt) | 2014-12-09 |
NZ581162A (en) | 2011-10-28 |
MX2009012376A (es) | 2009-12-03 |
IL201449A0 (en) | 2010-05-31 |
EP1992621A1 (en) | 2008-11-19 |
EA200971060A1 (ru) | 2010-04-30 |
KR20100016510A (ko) | 2010-02-12 |
TW200906803A (en) | 2009-02-16 |
CN101679306A (zh) | 2010-03-24 |
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