JP6449470B2 - N−安息香酸基置換のベンゾピロリン−2−オン誘導体及びその用途 - Google Patents
N−安息香酸基置換のベンゾピロリン−2−オン誘導体及びその用途 Download PDFInfo
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- JP6449470B2 JP6449470B2 JP2017540241A JP2017540241A JP6449470B2 JP 6449470 B2 JP6449470 B2 JP 6449470B2 JP 2017540241 A JP2017540241 A JP 2017540241A JP 2017540241 A JP2017540241 A JP 2017540241A JP 6449470 B2 JP6449470 B2 JP 6449470B2
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 108090000629 orphan nuclear receptors Proteins 0.000 description 1
- 102000004164 orphan nuclear receptors Human genes 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000002165 resonance energy transfer Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 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
- 239000003381 stabilizer Substances 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
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- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 210000004341 tarsal joint Anatomy 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
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Description
Aは五員又は六員のアリール基又はヘテロアリール基であり、
R6はアルキル基、シクロアルキル基、アルコキシ基、アリール基、ハロゲン、トリフルオロメチル基、アミノ基、シアノ基、ヒドロキシ基、カルボキシ基、ハロゲン化アルキル基、ハロゲン化アルコキシ基、アルキルアミノ基、ジアルキルアミノ基、アルキルスルホニル基、アミノスルホニル基、スルホニルアミノ基、アミド基、カルボニル基、アルキルアミノカルボニル基又はジアルキルアミノカルボニル基から選ばれる1つ又は複数であり、
Bはアリール基又はヘテロアリール基であり、
Qはアリール基又はヘテロアリール基であり、前記アリール基又はヘテロアリール基は独立に、ハロゲン、トリフルオロメチル基、アルキル基、シクロアルキル基、アルコキシ基、ヒドロキシ基、アミノ基、シアノ基、ニトロ基、カルボニル基、アリール基、ヘテロアリール基、アルキルアミノ基、ジアルキルアミノ基、アルキルアミノカルボニル基、ジアルキルアミノカルボニル基、アルキルスルホニル基又はアルキルカルボニル基から選ばれる1つ又は複数の基で置換されていてもよい。前記アルキル基、シクロアルキル基、アルコキシ基、アリール基、ヘテロアリール基は、1つ又は複数のハロゲンで置換されていてもよく、
R1は独立に、−C(=O)OH、アルキル基−OC(=O)−、アミド基、5−テトラゾール、HOC(CF3)2、リン酸基、リン酸エステル基、シアノ基、ヒドロキシ基、アミノ基、アルコキシ基、アルキルアミノカルボニル基、アミノスルホニル基、スルホニルアミノ基、アルキルスルホニル基から選ばれてもよく、
R2は水素、ヒドロキシ基、ハロゲン、シアノ基、ニトロ基、(C1−4)アルキル基又は(C1−4)アルコキシ基又は(Cl−3)アルキル基C(=O)O−であり、前記(C1−4)アルキル基、(C1−4)アルコキシ基は1つ又は複数のハロゲンで置換されていてもよく、
mは0、1、2、3又は4であり、
前記複素環基又はヘテロアリール基はN、O及びSから選ばれる1つ又は複数のヘテロ原子を有する。
Aは五員又は六員のアリール基又はヘテロアリール基であり、
R6はアルキル基、シクロアルキル基、アルコキシ基、アリール基、ハロゲン、トリフルオロメチル基、アミノ基、シアノ基、カルボキシ基、ハロゲン化アルキル基、ハロゲン化アルコキシ基、アルキルアミノ基、ジアルキルアミノ基、アルキルスルホニル基、アミノスルホニル基、スルホニルアミノ基、アミド基、カルボニル基、アルキルアミノカルボニル基又はジアルキルアミノカルボニル基から選ばれる1つ又は複数であり、
Bはアリール基又はヘテロアリール基であり、
R1は独立に−C(=O)OH、アルキル基−OC(=O)−、アミド基、5−テトラゾール、HOC(CF3)2、リン酸基、リン酸エステル基、シアノ基、ヒドロキシ基、アミノ基、アルコキシ基、アルキルアミノカルボニル基、アミノスルホニル基、スルホニルアミノ基、アルキルスルホニル基から選ばれてもよく、
R2は水素、ヒドロキシ基、ハロゲン、シアノ基、ニトロ基、(C1−4)アルキル基又は(C1−4)アルコキシ基又は(Cl−3)アルキル基C(=O)O−であり、前記(C1−4)アルキル基、(C1−4)アルコキシ基は1つ又は複数のハロゲンで置換されていてもよく、
R3、R4、R5は独立に、水素、ハロゲン、トリフルオロメチル基、アルキル基、シクロアルキル基、アルコキシ基、ヒドロキシ基、アミノ基、シアノ基、アリール基、ヘテロアリール基、アルキルアミノ基、ジアルキルアミノ基、アルキルスルホニル基又はアルキルカルボニル基から選ばれてもよく、
mは0、1、2、3又は4であり、
nは0、1、2又は3であり、
前記複素環基又はヘテロアリール基はN、O及びSから選ばれる1つ又は複数のヘテロ原子を有する。
Aはフェニル基、ピリジル基、チエニル基、フラニル基又はピリミジニル基であり、
R6はアルキル基、シクロアルキル基、アルコキシ基、アリール基、ハロゲン、トリフルオロメチル基、アミノ基、シアノ基、カルボキシ基、ハロゲン化アルキル基、ハロゲン化アルコキシ基、アルキルアミノ基、ジアルキルアミノ基、アルキルスルホニル基、アミノスルホニル基、スルホニルアミノ基、アミド基、カルボニル基、アルキルアミノカルボニル基又はジアルキルアミノカルボニル基から選ばれる1つ又は複数であり、
R1は独立に、−C(=O)OH、アルキル基−OC(=O)−、アミド基、5−テトラゾール、HOC(CF3)2、リン酸基、リン酸エステル基、シアノ基、ヒドロキシ基、アミノ基、アルコキシ基、アルキルアミノカルボニル基、アミノスルホニル基、スルホニルアミノ基、アルキルスルホニル基から選ばれてもよく、
R2は水素、ヒドロキシ基、ハロゲン、シアノ基、ニトロ基、(C1−4)アルキル基、(C1−4)アルコキシ基又は(Cl−3)アルキル基C(=O)O−であり、前記(C1−4)アルキル基、(C1−4)アルコキシ基は1つ又は複数のハロゲンで置換されていてもよい。
R3、R4、R5は独立に、水素、ハロゲン、トリフルオロメチル基、アルキル基、シクロアルキル基、アルコキシ基、ヒドロキシ基、アミノ基、シアノ基、アリール基、ヘテロアリール基、アルキルアミノ基、ジアルキルアミノ基、アルキルスルホニル基又はアルキルカルボニル基から選ばれてもよく、
mは0、1、2、3又は4であり、
nは0、1、2又は3であり、
前記複素環基又はヘテロアリール基はN、O及びSから選ばれる1つ又は複数のヘテロ原子を有する。
R1は独立に、−C(=O)OH、アルキル基−OC(=O)−、アミド基(例えば、−C(=O)NH2、−C(=O)NHR、−C(=O)NRRaが挙げられ、その中、RとRaはC1−6アルキルから選ばれる)、5−テトラゾール、HOC(CF3)2、リン酸基、リン酸エステル基、シアノ基、ヒドロキシ基、アミノ基、アルコキシ基、アルキルアミノカルボニル基、アミノスルホニル基、スルホニルアミノ基、アルキルスルホニル基から選ばれてもよく、
R2は水素、ヒドロキシ基、ハロゲン、シアノ基、ニトロ基、(C1−4)アルキル基又は(C1−4)アルコキシ基又は(Cl−4)アルキル基C(=O)O−(例えば、(Cl−3)アルキル基C(=O)O−)であり、前記(C1−4)アルキル基、(C1−4)アルコキシ基は1つ又は複数のハロゲンで置換されていてもよく、
R3、R4、R5は独立に、水素、ハロゲン、トリフルオロメチル基、アルキル基、シクロアルキル基、アルコキシ基、ヒドロキシ基、アミノ基、シアノ基、アリール基、ヘテロアリール基、アルキルアミノ基、ジアルキルアミノ基、アルキルスルホニル基又はアルキルカルボニル基から選ばれてもよく、
R6はアルキル基、シクロアルキル基、アルコキシ基、アリール基、ハロゲン、トリフルオロメチル基、アミノ基、シアノ基、カルボキシ基、ハロゲン化アルキル基、ハロゲン化アルコキシ基、アルキルアミノ基、ジアルキルアミノ基、アルキルスルホニル基、アミノスルホニル基、スルホニルアミノ基、アミド基、カルボニル基、アルキルアミノカルボニル基又はジアルキルアミノカルボニル基から選ばれる1つ又は複数であり、
前記複素環基又はヘテロアリール基はN、O及びSから選ばれる1つ又は複数のヘテロ原子を有する。
R2は水素、ヒドロキシ基、ハロゲン、アミノ基、(C1−4)アルキル基、(C1−4)アルコキシ基又は(C1−4)アルキル基C(=O)O−(例えば、(Cl−3)アルキル基C(=O)O−)から選ばれ、前記(C1−4)アルキル基、(C1−4)アルコキシ基は1つ又は複数のハロゲンで置換されていてもよく、
R6は水素、ハロゲン、トリフルオロメチル基、(C1−4)アルキル基、(C1−4)アルコキシ基、(C3−4)シクロアルキル基又はC5−10アリール基から選ばれ、
R3、R4は独立に、ハロゲン(例えば、塩素)、トリフルオロメチル基、(C1−4)アルキル基、(C1−4)アルコキシ基又は(C3−4)シクロアルキル基(例えば、シクロプロピル基)から選ばれてもよく、
さらなる実施形態によれば、式(Id)中、R2は水素、ヒドロキシ基、ハロゲン、アミノ基、(C1−4)アルコキシ基又は(C1−4)アルキル基C(=O)O−から選ばれてもよく、前記(C1−4)アルキル基、(C1−4)アルコキシ基は1つ又は複数のハロゲン原子で置換されていてもよく、R6は水素、ハロゲン、トリフルオロメチル基、(C1−4)アルキル基、(C1−4)アルコキシ基、(C3−4)シクロアルキル基又はC5−10アリール基から選ばれ、R3はハロゲンから選ばれ、且つ、R4は独立に、ハロゲン、トリフルオロメチル基、(C1−4)アルキル基、(C1−4)アルコキシ基又は(C3−4)シクロアルキル基から選ばれてもよい。
(i)哺乳動物において、特にそのような哺乳動物が疾患又は病症に罹患しやすく、まだこの疾患又は病症に罹患していると診断されていない場合、疾患又は病症の出現を予防する。
(ii)疾患又は病症を阻害し、即ちその進展を抑制する。
(iii)疾患又は病症を軽減し、即ちこの疾患又は病症の状態を減退させる。または、
(iv)当該疾患又は病症による症状を軽減する。
本願実施例の化合物は、下記の幾つかのスキームに従って製造することができる。しかしながら、下記の反応スキームは、本願の化合物の調製方法を例示的に説明するものに過ぎない。
1H−NMR(300MHz,DMSO−d6)δ:ppm 7.91(d,J=9.0Hz,1H),7.87(s,1H),7.22−7.31(m,3H),6.95−7.03(m,4H),6.81(d,J=7.8Hz,1H),2.64(s,3H),1.89−1.99(m,1H),0.84−0.87(m,2H),0.64−0.70(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.03(d,2H,J=8.7Hz),7.84(s,1H),7.50(d,2H,J=8.7Hz),7.22(m,3H),6.96(q,2H,J=7.8Hz),6.73(d,1H,J=7.8Hz),2.60(s,3H),1.87(m,1H),0.81(m,2H),0.62(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.03(d,2H,J=8.7Hz),7.84(s,1H),7.50(d,2H,J=8.7Hz),7.22(m,3H),6.96(q,2H,J=7.8Hz),6.73(d,1H,J=7.8Hz),2.60(s,3H),1.87(m,1H),0.81(m,2H),0.62(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 7.92(dd,J=7.5Hz,J=1.2Hz,1H),7.59(s,1H),7.35(t,J=8.1Hz,1H),7.24(t,J=7.8Hz,1H),6.96−7.11(m,5H),6.80(d,J=8.1Hz,1H)3.77(s,3H),2.59(s,3H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 7.91(d,1H,J=8.1Hz),7.70(s,1H),7.52(d,2H,J=7.8Hz),7.36−7.42(m,1H),7.27(t,1H,J=7.8Hz),7.03(d,1H,J=7.8Hz),6.93−6.97(m,2H),6.81(d,1H,J=8.1Hz),2.61(s,3H)
1H−NMR(300MHz,CDCl3)δ:ppm 8.19(d,J=8.4Hz,2H),7.57(s,1H),7.55(d,J=8.1Hz,2H),7.36(d,J=7.8Hz,2H),7.21(t,2H),6.98(d,J=7.8Hz,1H),6.83(d,J=7.8Hz,1H),2.69(s,3H)
1H−NMR(300MHz,CD3OD−d4)δ:ppm 7.95(d,1H,J=8.1Hz),7.69(m,3H),7.46(m,1H),7.21(m,1H),7.00(m,1H),6.86(s,1H),6.77(d,1H,J=7.8Hz),2.59(s,3H)
1H−NMR(300MHz,CDCl3)δ:ppm 7.98(d,1H,J=8.4Hz),7.58(d,2H,J=5.4Hz),7.45(d,1H,J=8.1Hz),7.14−7.25(m,3H),7.00−7.08(m,2H),6.93(d,1H,J=8.1Hz),2.72(s,3H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.06(s,1H),7.91(d,J=9.3Hz,1H),7.21−7.36(m,3H),6.89−6.98(m,4H),6.60(d,J=7.8Hz,1H),4.02(s,3H),1.85−1.94(m,1H),0.85−0.88(m,2H),0.58−0.75(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 7.55(s,1H),7.15−7.33(m,4H),7.03−7.06(m,1H),6.94(d,J=7.8Hz,1H),6.80−6.84(m,2H),6.72(d,J=7.8Hz,1H),2.60(s,3H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 7.89(d,1H,J=8.1Hz),7.77(s,1H),7.22−7.34(m,4H),6.94−7.03(m,3H),6.79(d,1H,J=7.8Hz),2.63(s,3H),2.28(s,3H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 7.85−7.80(m,1H),7.55−7.30(m,5H),6.91−6.78(m,3H),6.57−6.54(m,1H),5.97−5.95(m,1H),4.01(s,3H)
1H−NMR(300MHz,CD3OD−d4)δ:ppm 8.35(s,1H),7.98(d,1H,J=9.0Hz),7.24(m,3H),6.91−7.07(m,4H),6.81(d,1H,J=7.8Hz),2.22(m,1H),1.98(m,1H),1.13(m,2H),0.88(m,4H),0.72(m,1H),0.63(m,1H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.18−8.08(m,2H),7.78−7.14(m,10H),7.02−6.87(m,4H),1.54−1.50(m,1H),1.29−1.17(m,2H),0.85−0.75(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.46−7.94(m,1H),7.79−7.76(m,1H),7.35−7.19(m,4H),7.10−6.79(m,2H),6.76−6.60(m,2H),1.71−1.69(m,1H),1.29−1.23(m,2H),0.88−0.83(m,2H)
1H−NMR(CDCl3)δ:ppm 8.21(d,J=8.4Hz,2H),7.78(d,J=1.5Hz,1H),7.57(d,J=8.7Hz,2H),7.39〜7.35(m,2H),7.31〜7.20(m,2H),6.93〜6.87(m,1H),6.78(d,J=7.8Hz,1H)
1H−NMR(CDCl3)δ:ppm 8.30(d,J=8.4Hz,2H),7.90(s,1H),7.65(d,J=8.7Hz,2H),7.42〜7.38(m,2H),7.32〜7.29(m,1H),7.25〜7.19(m,1H),7.75〜6.65(m,2H)
1H−NMR(300MHz,CDCl3)δ:ppm 8.20(d,2H,J=8.7Hz),8.04(s,1H),7.56(d,2H,J=8.4Hz),7.27(m,2H),7.19(m,1H),6.90(m,2H),6.79(d,1H,J=7.8Hz),1.92(m,1H),0.88(m,3H),0.61(m,1H)
1H−NMR(300MHz,CDCl3)δ:ppm 8.20(d,2H,J=8.7Hz),8.04(s,1H),7.56(d,2H,J=8.4Hz),7.27(m,2H),7.20(d,1H,J=8.1Hz),6.90(m,2H),6.89(d,1H,J=7.8Hz),1.92(m,1H),0.83(m,3H),0.59(m,1H)
1H−NMR(300MHz,CDCl3)δ:ppm 8.30(d,2H,J=8.4Hz),7.88(s,1H),7.62(d,2H,J=8.7Hz),7.21−7.37(m,3H),7.09(t,1H,J=8.7Hz),6.73(d,2H,J=8.1Hz)
1H−NMR(300MHz,CDCl3)δ:ppm 8.22(d,2H,J=8.4Hz),7.76(s,1H),7.56(d,2H,J=8.4Hz),7.22−7.31(m,3H),7.05(t,1H,J=8.7Hz),6.88(t,1H,J=9.0Hz),6.75(d,1H,J=7.8Hz)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.15−8.08(m,2H),7.68−7.66(m,2H),7.60−7.39(m,3H),7.27−6.87(m,3H),6.78−6.73(m,1H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.15−8.08(m,2H),7.69−7.57(m,4H),7.41−6.88(m,4H),6.78−6.73(m,1H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 13.11(brs,1H),8.16−8.13(d,2H),7.90−7.79(m,3H),7.64−7.58(t,1H),7.55−7.52(d,1H),7.45−7.40(m,1H),7.13−7.07(t,1H),6.83−6.80(d,1H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 13.14(brs,1H),8.15−8.13(d,2H),7.93−7.84(m,3H),7.72−7.65(m,3H),7.40−7.33(m,1H),6.83−6.73(m,2H)
1H−NMR(CDCl3)δ:ppm 8.31(d,J=8.4Hz,2H),8.02(s,1H),7.67(d,J=8.7Hz,2H),7.32〜7.27(m,2H),7.23〜7.15(m,2H),6.74(d,J=7.8Hz,1H),6.68〜6.62(m,1H),2.60(t,2H),1.58(m,2H),0.89(t,3H)
1H−NMR(CDCl3)δ:ppm 8.20(d,J=8.4Hz,2H),7.94(s,1H),7.56(d,J=9.0Hz,2H),7.30〜7.27(m,2H),7.25〜7.17(m,2H),6.93〜6.88(m,1H),6.79(d,J=7.8Hz,1H),2.63(t,2H),1.60(m,2H),0.91(t,3H)
1H−NMR(300MHz,CD3OD−d4)δ:ppm 8.02(m,2H),7.35(m,1H),7.24(m,3H),6.95(m,3H),6.82(d,1H,J=8.1Hz),1.92(m,1H),0.91(m,2H),0.74(m,1H),0.65(m,1H)
1H−NMR(300MHz,CD3OD−d4)δ:ppm 8.04(d,1H,J=8.4Hz),8.02(s,1H),7.27(m,3H),7.01−7.19(m,3H),6.93(m,1H),6.76(d,1H,J=7.8Hz),6.69(s,1H),1.83(m,1H),0.90(m,2H),0.67(m,2H)
1H−NMR(300MHz,CD3OD−d4)δ:ppm 8.07(d,1H,J=8.4Hz),7.80(s,1H),7.48(m,2H),7.29−7.41(m,2H),7.10(s,1H),7.05(d,1H,J=8.4Hz),6.69−6.80(m,2H)
1H−NMR(300MHz,CD3OD−d4)δ:ppm 8.01(d,1H,J=8.4Hz),7.76(s,1H),7.44(m,2H),7.35(m,2H),6.97(m,3H),6.82(d,1H,J=7.8Hz)
1H−NMR(300MHz,DMSO−d6)δ:ppm 12.99(brs,1H),8.31−7.78(m,3H),7.70−7.52(m,4H),7.43−7.26(m,3H),6.91−6.81(m,1H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.01−7.79(m,2H),7.64−7.62(m,1H),7.54−7.49(m,1H),7.35−7.22(m,3H),7.05−6.93(m,2H),6.86−6.71(m,1H),1.76−1.71(m,1H),1.26(s,3H),0.87−0.83(m,2H),0.71−0.63(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 8.03(t,1H,J=8.1Hz),7.89(s,1H),7.38−7.46(m,2H),7.22−7.36(m,3H),7.01(dd,2H,J=7.5,18.3Hz),6.86(d,1H,J=7.8Hz),2.64(s,3H),0.83−0.87(m,3H),0.63−0.70(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 11.71(brs,1H),7.98(S,1H),7.90−7.82(m,1H),7.57−7.48(m,2H),7.35−7.25(m,2H),7.19−7.10(m,1H),7.03−6.73(m,3H),5.36(s,1H),1.78−1.73(m,1H),1.49−1.46(m,2H),0.83−0.86(m,2H)
1H−NMR(300MHz,CDCl3)δ:ppm 7.98−8.09(m,2H),7.31−7.37(m,2H),7.10−7.24(m,3H),6.89−6.99(m,3H),6.82−6.84(m,1H),1.89−2.00(m,1H),0.85−0.94(m,3H),0.64−0.76(m,1H)
1H−NMR(300MHz,CDCl3)δ:ppm 8.18(d,2H,J=8.4Hz),7.81(s,1H),7.43(dd,1H,J=8.7Hz,J=1.8Hz),7.16−7.28(m,5H),6.90−7.00(m,3H),2.69(s,3H),1.90−1.95(m,1H),1.35(s,9H),0.80−0.90(m,3H),0.52−0.60(m,1H)
1H−NMR(300MHz,CDCl3)δ:ppm 8.19(d,J=8.4Hz,2H),7.72(s,1H),7.56(d,J=8.4Hz,2H),7.27〜7.15(m,4H),6.98(d,J=7.8Hz,1H),6.84(d,J=7.5Hz,1H),2.69(s,3H),2.34(s,3H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 13.06(brs,1H),8.08−8.06(m,3H),7.55−7.52(d,2H),7.35−7.21(m,3H),6.94−6.90(s,2H),6.58−6.55(d,1H),4.02(s,3H),1.93−1.87(m,1H),0.90−0.84(m,2H),0.73−0.67(m,1H),0.64−0.58(m,1H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 12.99(s,1H),8.11(m,2H),7.84(s,1H),7.69−7.51(m,4H),7.33(m,2H),6.93(d,J=8.4Hz,1H),6.56(d,J=7.8Hz,1H),4.03(s,3H)
1H−NMR(300MHz,CDCl3)δ:ppm 8.18(d,J=8.4Hz,2H),8.61(s,1H),7.56(d,J=8.4Hz,2H),7.24〜7.14(m,2H),7.05(d,J=7.5Hz,1H),6.96(d,J=7.8Hz,1H),6.85〜6.79(m,2H),3.81(s,3H),2.68(s,3H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 7.85−7.78(m,2H),7.31−7.21(m,3H),7.01−6.96(m,2H),6.79−6.77(m,2H),6.52−6.48(m,1H),2.63(s,3H),1.95−1.89(m,1H),0.87−0.83(m,2H),0.69−0.63(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 12.94(brs,1H),8.08−8.05(d,2H),7.77(s,1H),7.54−7.51(d,2H),7.34−7.22(m,4H),7.04−7.02(d,1H),6.79−6.76(d,1H),3.65−3.57(m,1H),2.62(s,3H),2.22−1.99(m,4H),1.92−1.70(m,2H)
1H−NMR(300MHz,DMSO−d6)δ:ppm 7.91−7.89(d,1H),7.76(s,1H),7.32−7.23(m,4H),7.04−6.93(m,3H),6.82−6.80(d,1H),3.62−3.59(m,1H),2.62(s,3H),2.21−1.99(m,4H),1.92−1.70(m,2H)
1H−NMR(300MHz,CDCl3)δ:ppm 7.96(d,1H,J=8.4Hz),7.75(s,1H),7.16−7.31(m,4H),7.09(s,1H),7.00(d,2H,J=8.4Hz),6.91(d,1H,J=8.4Hz),3.29(m 2H),2.61(s,3H),1.15(t,J=7.5Hz,3H)
1H−NMR(300MHz,CD3OD)δ:ppm 7.99(d,1H,J=8.4Hz),7.81(s,1H),7.19−7.27(m,4H),6.99(d,1H,J=8.4Hz),6.89−6.94(m,2H),6.78(d,1H,J=7.8Hz),2.69(s,3H),2.02(s,3H)。
1.インビトロにおける生体活性の選別:TR−FRETによる選別
本発明の化合物は、核内受容体RORγの生体活性を調節(阻害)することができ、この調節(阻害)作用の強さがTR−FRET(時間分解−蛍光共鳴エネルギー転移,Time−Resolved Fluorescence Resonance Energy Transfer)選別システムにより評価することができる。核内受容体コファクター(コアクチベーターとコリプレッサー)は核内受容体との相互作用により、標的遺伝子の転写を調節することができる。リガンド(被験化合物)が核内受容体とコファクターとの相互作用に影響を与えると、このようなリガンド(被験化合物)は対応する遺伝子の転写を調節することができる。
Complete TR−FRET Coregulator Buffer D(以下、単に「コンプリートバッファ(complete buffer)D」と称する)の調製:TR−FRET Coregulator Buffer D(Life Technologies#PV4420)にDTTの最終濃度が5mMになるようにDTT(Life Technologies#P2325)を加えた。
プログラムGraphPad Prismを使用して、TR−FRETの比率であるF520/F490−化合物濃度の対数曲線をプロットし、IC50の値を算出した。この数値が小さいほど、化合物の受容体RORγに対する調節(阻害)作用が強くなることを示す。
5μg/mLのマウスCD3抗体(BDから購入)で96ウェルプレート(37℃、2−6時間)をコートして準備した。CD4+T cell isolation kitII(MACSから購入)でC57マウスリンパ節の初期CD4陽性T細胞を分離し、コート済みの96ウェルプレートに5×105cell/ウェル/100μLで接種した。被験サンプルをRMPI−1640培地(Gibco、22440)を用いて段階希釈し、最終濃度(1μMから、10倍希釈して6つの薬物濃度を設定する)の4倍とした。細胞が接種される実験ウェルに、希釈済みの被験サンプルを1ウェルあたり50μLずつ加えた。陽性対照ウェル及び陰性対照ウェルに、それぞれ、RMPI−1640培地を50μLずつ加えた。実験ウェルと陽性対照ウェルのそれぞれに、さらに、4倍の最終濃度の刺激剤混合液(マウスのCD28に対する抗体(BDから購入)20μg/mL、マウスのIL−4に対する抗体(BDから購入)40μg/mL、マウスのIFNγに対する抗体(BDから購入)40μg/mL、マウスのTGF−β1に対する抗体(R&Dから購入)4ng/mL、マウスのIL−6に対する抗体(R&Dから購入)200ng/mL、マウスのIL−23に対する抗体(R&Dから購入)20ng/mL)を50μLずつ加え、陰性対照ウェルにはRMPI−1640培地を50μL加えた。添加済の96ウェルプレートを37℃、5%CO2のインキュベーターで66時間インキュベーションした後、さらに各ウェルにPMA(Sigmaから購入、作用濃度50ng/mL)とIonomycin(Sigmaから購入、作用濃度1μg/mL)との混合液を50μL加えて、引き続き37℃で6時間インキュベーションした。インキュベーション終了後、細胞培養上澄み液を採取し、マウスIL−17A ELISAキット(達科為社
(2)サンプルの添加:希釈されたCytokine standardを標準物ウェルに100μL/ウェルで加え、サンプルをサンプルウェルに100μL/ウェルで加える。ブランクウェルを設け、サンプルと標準物の代わりに、Dilution buffer R(1×)を使用する。
(3)検出抗体の添加:希釈されたBiotinylated antibodyを50μL/ウェルで加える。均一に混合した後、プレートシーラーでカバーし、37℃で90分間インキュベーションする。
(4)プレートの洗浄:ウェル内の液体を傾瀉除去し、1×washing bufferを300μL/ウェルで加える。1分間を置いてから、ウェル内の液体を捨てる。4回繰り返して、毎回ろ紙上に乾燥まで傾瀉する。
(5)酵素の添加:希釈されたStreptavidin−HRPを100μL/ウェルで加える。プレートシーラーでカバーし、37℃、30分間インキュベーションする。
(6)プレートの洗浄:工程5を繰り返す。
(7)発色:TMBを100μL/ウェルで加え、37℃、遮光で5−30分間インキュベーションし、ウェル内の色の深さ(濃い青)によって反応停止を判断する。通常、10−20分間発色させると良い効果が得られる。
(8)反応停止:Stop solutionを100μL/ウェルで速やかに加えて、反応を停止させる。
プレートの読み取り:停止から10分間以内に、検出波長(measurement wavelength)である450nmで読み取る。
被験動物:Wistarラット、メス、1匹あたりの体重は180−220gの範囲にある。
Claims (14)
- 構造式(Ic)の構造を有することを特徴とする化合物、その立体異性体、互変異性体、薬学的に許容される塩、又は溶媒和物であって、
R2は水素、ヒドロキシ基、アミノ基、メルカプト基、ハロゲン、シアノ基、ニトロ基、(C1−4)アルキル基又は(C1−4)アルコキシ基又は(C1−3)アルキル基C(=O)O−であり、前記(C1−4)アルキル基、(C1−4)アルコキシ基は1つ又は複数のハロゲンで置換されていてもよく、
R3、R4、R5は独立に、水素、ハロゲン、トリフルオロメチル基、アルキル基、シクロアルキル基、アルコキシ基、ヒドロキシ基、アミノ基、シアノ基、アリール基、ヘテロアリール基、アルキルアミノ基、ジアルキルアミノ基、アルキルスルホニル基又はアルキルカルボニル基から選ばれ、
R6は水素、ハロゲン、トリフルオロメチル基、アルキル基、シクロアルキル基、アルコキシ基、アリール基、ヒドロキシ基、アミノ基、シアノ基又はカルボニル基から選ばれる、化合物。 - 式(Ic)において、
R1は−C(=O)OH、−C(=O)NH2、−C(=O)O−C1−6アルキル基、−C(=O)NHR、−C(=O)N(Ra)R(RとRaは、C1−6アルキル基から選ばれる)、5−テトラゾール、HOC(CF3)2、リン酸基、リン酸エステル基、シアノ基、ヒドロキシ基、アミノ基、C1−6アルコキシ基、アミノスルホニル基、スルホニルアミノ基、C1−6アルキルスルホニル基から選ばれ、
R2は水素、ヒドロキシ基、ハロゲン、メルカプト基、アミノ基から選ばれ、
R3はハロゲン、アミノ基、C1−6アルキルアミノ基、ジC1−6アルキルアミノ基、C1−6アルキルスルホニル基、C1−6アルキルカルボニル基から選ばれ、
R4は水素、ハロゲン、トリフルオロメチル基、C1−6アルキル基、C3−6シクロアルキル基又はC1−6アルコキシ基から選ばれ、且つ
R5は水素、C1−6アルキル基、C3−6シクロアルキル基又はC1−6アルコキシ基から選ばれ、
R6はハロゲン、トリフルオロメチル基、C1−6アルキル基、C3−6シクロアルキル基、C1−6アルコキシ基又はC5−10アリール基から選ばれる、請求項1に記載の化合物。 - 前記化合物は(Id)で表されることを特徴とする、請求項1に記載の化合物。
R6は水素、ハロゲン、トリフルオロメチル基、(C1−4)アルキル基、(C1−4)アルコキシ基、(C3−4)シクロアルキル基又はC5−10アリール基から選ばれ、
R3、R4は独立に、ハロゲン、トリフルオロメチル基、(C1−4)アルキル基、(C1−4)アルコキシ基又は(C3−4)シクロアルキル基から選ばれる。 - R2は水素、ヒドロキシ基、ハロゲン、アミノ基、(C1−4)アルキル基、(C1−4)アルコキシ基又は(C1−4)アルキル基C(=O)O−から選ばれ、前記(C1−4)アルキル基、(C1−4)アルコキシ基は1つ又は複数のハロゲン原子で置換されていてもよく、
R6は水素、ハロゲン、トリフルオロメチル基、(C1−4)アルキル基、(C1−4)アルコキシ基、(C3−4)シクロアルキル基又はC5−10アリール基から選ばれ、
R3はハロゲンから選ばれ、且つ、
R4は独立にハロゲン、トリフルオロメチル基、(C1−4)アルキル基、(C1−4)アルコキシ基、(C3−4)シクロアルキル基から選ばれる、請求項3に記載の化合物。 - R2は水素、ヒドロキシ基又はハロゲンであり、
R6はフッ素、メチル基、トリフルオロメチル基又はメトキシ基である、請求項3又は4に記載の化合物。 - R2はヒドロキシ基であり、
R6はフッ素、メチル基又はメトキシ基である、請求項5に記載の化合物。 - R3は塩素である請求項1から請求項6のいずれか1項に記載の化合物。
- R2はヒドロキシ基であり、
R6はメチル基であり、
R3は塩素であり、且つ
R4はシクロプロピル基、トリフルオロメチル基又は塩素である、請求項7に記載の化合物。 - 前記化合物は以下から選択されるものである、請求項1から請求項7のいずれか1項に記載の化合物、その立体異性体、互変異性体、薬学的に許容される塩、又は溶媒和物。
- 請求項1から請求項9のいずれか1項に記載の化合物、その立体異性体、互変異性体、薬学的に許容される塩、又は溶媒和物、及び薬学的に許容される賦形剤を含む医薬組成物。
- 非ステロイド性抗炎症薬、非特異及び特異的なシクロオキシゲナーゼ−2阻害剤、金化合物、コルチコイド、腫瘍壊死因子受容体拮抗薬、サリチル酸エステル又は塩、免疫抑制剤、及びメトトレキサートから選ばれる1種又は複数の種類の抗炎症薬をさらに含む請求項10に記載の医薬組成物。
- RORγ調整剤としての薬剤の調製における請求項1から請求項9のいずれか1項に記載の化合物、その立体異性体、互変異性体、薬学的に許容される塩、又は溶媒和物の使用。
- 自己免疫疾患及び/又は炎症性疾患であるRORγ介在の疾患を予防又は治療するための薬剤の調製における請求項1から請求項9のいずれか1項に記載の化合物、その立体異性体、互変異性体、薬学的に許容される塩、又は溶媒和物の使用。
- 前記疾患が、多発性硬化症、関節リウマチ、乾癬、クローン病、喘息、全身性エリテマトーデス、慢性閉塞性肺疾患、組織移植片拒絶反応及び臓器移植拒絶反応、強皮症、紫斑病、自己免疫性溶血性及び血小板減少性症状、過敏性腸症候群、骨関節炎、川崎病、橋本病、粘膜リーシュマニア症、気管支炎、アレルギー性鼻炎、アトピー性皮膚炎、嚢胞性線維症、肺代謝拒絶反応、若年性関節リウマチ、強直性脊椎炎、膵炎、自己免疫性糖尿病、自己免疫性眼疾患、潰瘍性大腸炎、シェーグレン症候群、視神経炎、糖尿病、視神経脊髄炎、重症筋無力症、ブドウ膜炎、ギラン-バレー症候群、乾癬性関節炎、グレーブス病、及び強膜炎から選ばれる、請求項13に記載の使用。
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