JPWO2014092061A1 - ヒダントイン誘導体 - Google Patents
ヒダントイン誘導体 Download PDFInfo
- Publication number
- JPWO2014092061A1 JPWO2014092061A1 JP2014552040A JP2014552040A JPWO2014092061A1 JP WO2014092061 A1 JPWO2014092061 A1 JP WO2014092061A1 JP 2014552040 A JP2014552040 A JP 2014552040A JP 2014552040 A JP2014552040 A JP 2014552040A JP WO2014092061 A1 JPWO2014092061 A1 JP WO2014092061A1
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- dione
- compound
- triazaspiro
- sulfonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001469 hydantoins Chemical class 0.000 title description 11
- 229940053195 antiepileptics hydantoin derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 148
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- -1 3- (trifluoromethyl) phenyl Chemical group 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 31
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 29
- 208000000038 Hypoparathyroidism Diseases 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- 208000001132 Osteoporosis Diseases 0.000 claims description 16
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical group O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims description 16
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 16
- SWHIVSUFNKSRKF-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1C(NC1=O)=NC11CCNCC1 SWHIVSUFNKSRKF-UHFFFAOYSA-N 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
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- 206010043554 thrombocytopenia Diseases 0.000 claims description 12
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- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
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- 125000000217 alkyl group Chemical group 0.000 claims description 8
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- 239000003795 chemical substances by application Substances 0.000 claims description 7
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- OKCOICFERCYLOU-UHFFFAOYSA-N 1-[4-[2-[[2-[4-fluoro-3-(trifluoromethoxy)phenyl]-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1=CC(N2C(C(=O)NC2=O)(C)C)=CC(C)=C1CCS(=O)(=O)N(CC1)CCC1(C(N1)=O)N=C1C1=CC=C(F)C(OC(F)(F)F)=C1 OKCOICFERCYLOU-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- RXZLUBRSOALJMQ-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-4-one Chemical compound FC(F)(F)C1=CC=CC(C=2NC(=O)C3(CCNCC3)N=2)=C1 RXZLUBRSOALJMQ-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 230000003834 intracellular effect Effects 0.000 claims description 4
- 208000024891 symptom Diseases 0.000 claims description 4
- VFTAIOPRNOYJLT-UHFFFAOYSA-N 1-[4-[2-[[2-(2,2-difluoro-1,3-benzodioxol-5-yl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione Chemical compound C=1C(C)=C(CCS(=O)(=O)N2CCC3(CC2)C(NC(=N3)C=2C=C3OC(F)(F)OC3=CC=2)=O)C(C)=CC=1N1C(=O)NC(=O)C1(C)C VFTAIOPRNOYJLT-UHFFFAOYSA-N 0.000 claims description 3
- WOQJOOBZXXVDGR-UHFFFAOYSA-N 1-[4-[2-[[2-[3-fluoro-4-(trifluoromethoxy)phenyl]-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1=CC(N2C(C(=O)NC2=O)(C)C)=CC(C)=C1CCS(=O)(=O)N(CC1)CCC1(C(N1)=O)N=C1C1=CC=C(OC(F)(F)F)C(F)=C1 WOQJOOBZXXVDGR-UHFFFAOYSA-N 0.000 claims description 3
- KWYWOGBBXZGMPQ-UHFFFAOYSA-N 1-[4-[2-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]-3,5-dimethylphenyl]-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1=CC(N2C(C(=O)NC2=O)(C)C)=CC(C)=C1CCS(=O)(=O)N(CC1)CCC1(C(N1)=O)N=C1C1=CC=C(F)C(C(F)(F)F)=C1 KWYWOGBBXZGMPQ-UHFFFAOYSA-N 0.000 claims description 3
- MOAUWOUSPNAMTP-UHFFFAOYSA-N 4-[3,5-dimethyl-4-[2-[[4-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-4,6-diazaspiro[2.4]heptane-5,7-dione Chemical compound CC1=CC(N2C3(CC3)C(=O)NC2=O)=CC(C)=C1CCS(=O)(=O)N(CC1)CCC1(C(N1)=O)N=C1C1=CC=C(OC(F)(F)F)C=C1 MOAUWOUSPNAMTP-UHFFFAOYSA-N 0.000 claims description 3
- STUYIOKFRHRZHA-UHFFFAOYSA-N BrC=1C=C(C=CC1)C1=NC2(C(N1)=O)CCN(CC2)S(=O)(=O)CCC2=C(C=C(C=C2C)N2C(NC(C2(C)C)=O)=O)C Chemical compound BrC=1C=C(C=CC1)C1=NC2(C(N1)=O)CCN(CC2)S(=O)(=O)CCC2=C(C=C(C=C2C)N2C(NC(C2(C)C)=O)=O)C STUYIOKFRHRZHA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 230000001483 mobilizing effect Effects 0.000 claims 2
- 235000008733 Citrus aurantifolia Nutrition 0.000 claims 1
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- 239000004571 lime Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000011575 calcium Substances 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 26
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 108700020797 Parathyroid Hormone-Related Proteins 0.000 description 21
- 102000043299 Parathyroid hormone-related Human genes 0.000 description 21
- 241000700159 Rattus Species 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
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- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 12
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- NGNNFDYHJKDHJN-UHFFFAOYSA-N 5-aminoimidazole-2,4-dione Chemical class N=C1NC(=O)NC1=O NGNNFDYHJKDHJN-UHFFFAOYSA-N 0.000 description 6
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 239000008399 tap water Substances 0.000 description 1
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- 150000003892 tartrate salts Chemical class 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- 229940116362 tragacanth Drugs 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
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
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- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
Description
その他、骨折、無形成骨症、軟骨無形成症、軟骨低形成症、骨軟化症、変形性関節症、関節炎、血小板減少症、高リン血症、腫瘍状石灰沈着症などの疾患の治療においても、PTH様作用を有し、かつ非侵襲的に投与できる薬剤が望まれる。
が、PTH様作用をもつ化合物、好ましくはPTH1Rアゴニスト、として有用であり、骨粗鬆症、骨折、骨軟化症、関節炎、血小板減少症、副甲状腺機能低下症、高リン血症、または腫瘍状石灰沈着症などの予防および/または治療、あるいは幹細胞動員に有用であることを見出して、先に特許出願をした(特許文献1)。
R1およびR2は、R1とR2が共に水素原子ではないとの条件の下、それぞれ独立して
1)水素原子、
2)ハロゲン原子、
3)1〜5個のフッ素原子で置換されていてもよい炭素数1〜2個のアルキル基、または
4)1〜5個のフッ素原子で置換されていてもよい炭素数1〜2個のアルコキシ基
であるか;または、
R1およびR2は、互いに結合して形成される下記式:
かつ、R3およびR4は、それぞれ独立して1〜3個のフッ素原子で置換されていてもよいメチル基であるか;または、
R3およびR4は、それらが結合する炭素原子と一緒になって炭素数3〜6の環(ここで、環を形成する炭素原子のうち一つは酸素原子;硫黄原子;またはメチル基で置換されていてもよい窒素原子で置換されていてもよい。)を形成する。〕。
1)R1が水素原子、またはハロゲン原子であり、かつR2が水素原子、トリフルオロメチル基、またはトリフルオロメトキシ基である(但し、R1とR2が共に水素原子となる場合を除く);
2)R1がトリフルオロメチル基、またはトリフルオロメトキシ基であり、かつR2が水素原子、またはハロゲン原子である;
3)R1およびR2が互いに結合して形成される下記式:
かつ、R3およびR4は、メチル基であるか;または、
R3およびR4はそれらが結合する炭素原子と一緒になって以下から選択される環:
1)R1がトリフルオロメトキシ基であり、かつR2がフッ素原子である;
2)R1が臭素原子であり、かつR2が水素原子である;
3)R1がトリフルオロメチル基であり、かつR2がフッ素原子である;
4)R1がフッ素原子であり、かつR2がトリフルオロメトキシ基である;
5)R1がトリフルオロメチル基であり、かつR2が水素原子である;
6)R1が水素原子であり、かつR2がトリフルオロメトキシ基である;
7)R1、R2は互いに結合して形成される下記式:
かつ、R3およびR4はメチル基であるか;または、
R3およびR4はそれらが結合する炭素原子と一緒になって以下から選択される環:
〔1〕記載の化合物またはその薬理学的に許容される塩。
1−(4−(2−((2−(4−フルオロ−3−(トリフルオロメトキシ)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(4−(2−((2−(3−ブロモフェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン:
1−(4−(2−((2−(4−フルオロ−3−(トリフルオロメチル)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(4−(2−((2−(3−フルオロ−4−(トリフルオロメトキシ)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(4−(2−((2−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(3−(トリフルオロメチル)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン):
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−1,3−ジアザスピロ[4.4]ノナン−2,4−ジオン;
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−8−メチル−1,3,8−トリアザスピロ[4.5]デカン−2,4−ジオン;
5−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−2−オキサ−5,7−ジアザスピロ[3.4]オクタン−6,8−ジオン;および
4−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−4,6−ジアザスピロ[2.4]ヘプタン−5,7−ジオン。
また、本発明においては、置換基の数は特に断りのない限り限定されないが、たとえば、置換基の数は、1〜5個、1〜4個、1〜3個、1〜2個あるいは1個などである場合が挙げられる。
本明細書における「PTH様作用」とは、PTH受容体に作用して、あるいはPTH受容体を介したシグナル伝達系に作用して、細胞内cAMP(cAMP:環状アデノシン一リン酸)を産生させる活性を意味する。
式中、R1およびR2が以下の組み合わせから選択され:
1)R1が水素原子、またはハロゲン原子であり、かつR2が水素原子、トリフルオロメチル基、またはトリフルオロメトキシ基である(但し、R1とR2が共に水素原子となる場合を除く);
2)R1がトリフルオロメチル基、またはトリフルオロメトキシ基であり、かつR2が水素原子、またはハロゲン原子である;
3)R1およびR2が互いに結合して形成される下記式:
かつ、R3およびR4は、メチル基であるか;
またはR3およびR4はそれらが結合する炭素原子と一緒になって以下から選択される環:
式中、R1、R2は以下の組み合わせから選択され:
1)R1がトリフルオロメトキシ基であり、かつR2がフッ素原子である;
2)R1が臭素原子であり、かつR2が水素原子である;
3)R1がトリフルオロメチル基であり、かつR2がフッ素原子である;
4)R1がフッ素原子であり、かつR2がトリフルオロメトキシ基である;
5)R1がトリフルオロメチル基であり、かつR2が水素原子である;
6)R1が水素原子であり、かつR2がトリフルオロメトキシ基である;
7)R1、R2は互いに結合して形成される下記式:
かつ、R3およびR4はメチル基であるか;
またはR3およびR4はそれらが結合する炭素原子と一緒になって以下から選択される環:
化合物1:1−(4−(2−((2−(4−フルオロ−3−(トリフルオロメトキシ)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン、
化合物2:1−(4−(2−((2−(3−ブロモフェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン、
化合物3:1−(4−(2−((2−(4−フルオロ−3−(トリフルオロメチル)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン、
化合物4:1−(4−(2−((2−(3−フルオロ−4−(トリフルオロメトキシ)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン、
化合物5:1−(4−(2−((2−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン、
化合物6:1−(3,5−ジメチル−4−(2−((4−オキソ−2−(3−(トリフルオロメチル)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン、
化合物7:1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン、
化合物8:1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−1,3−ジアザスピロ[4.4]ノナン−2,4−ジオン、
化合物9:1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−8−メチル−1,3,8−トリアザスピロ[4.5]デカン−2,4−ジオン、
化合物10:5−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−2−オキサ−5,7−ジアザスピロ[3.4]オクタン−6,8−ジオン、および
化合物11:4−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−4,6−ジアザスピロ[2.4]ヘプタン−5,7−ジオン。
これらの化合物1〜11のなかでは、化合物6、7、8がより好適である。
本発明の化合物は様々な方法によって合成することができるが、その一部を以下のスキームで説明する。スキームは例示であり、本発明は、明示された化学反応および条件だけで制限されない。以下のスキームでは、明解にするために一部の置換基が除外されているが、これらはスキームの開示の制限を意図するものではない。本発明の代表的化合物は、適切な中間体、公知の化合物、および、試薬を用いて合成することができる。下記一般的合成法中の式におけるR1、R2、R3、R4は、前記一般式(1)で表される化合物(下記一般的合成法中では式1で表される化合物)のR1、R2、R3、R4と同意義である。
なお、本明細書において引用された全ての先行技術文献は、参照として本明細書に組み入れられる。
1−(4−(2−((2−(4−フルオロ−3−(トリフルオロメトキシ)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン(化合物1)
反応混合物にMeOH(52ml)と5N水酸化ナトリウム水溶液(52ml,260mmol)を室温にて加えた後、この混合物を75度Cにて1.5時間加熱攪拌した。反応混合物を冷却後、水を加え、1N硫酸水素カリウム水溶液でpH5とし、酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸マグネシウムで乾燥、濃縮し、2−((4−ブロモ−3,5−ジメチルフェニル)アミノ)−2−メチルプロパン酸を粗生成物として得た(5.79g)。
MS(ESI) m/z = 286, 288 (M+H)+
MS(ESI) m/z = 311, 313 (M+H)+
MS(ESI) m/z = 464 (M+H)+
MS(ESI) m/z = 420 (M+H)+
1H-NMR (300MHz, DMSO-d6) δ: 1.3 (6H, s), 1.7 (2H, m), 2.0 (2H, m), 2.3 (6H, s), 2.7 (2H, s), 2.9 (2H, m), 3.4 (2H, m), 6.9 (1H, d, J = 15.9 Hz), 7.1 (2H, s), 7.4 (1H, d, J = 15.9 Hz), 11.2 (1H, brs)
MS(ESI) m/z = 464 (M+H)+
MS(ESI) m/z = 466 (M+H)+
MS(ESI) m/z = 672 (M+H)+
MS(ESI) m/z = 654 (M+H)+。1H-NMR (400MHz, CD3OD) δ: 1.40 (6H, s), 1.71-1.80 (2H, m), 2.00-2.08 (2H, m), 2.43 (6H, s), 3.22 (4H, s), 3.47-3.57 (2H, m), 3.80-3.88 (2H, m), 7.01 (2H, s), 7.50-7.57 (1H, m), 7.97-8.04 (1H, m), 8.05-8.12 (1H, m)
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(3−(トリフルオロメチル)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン(化合物6)
MS(ESI) m/z = 618 (M+H)+。
MS(ESI) m/z = 620 (M+H)+。1H-NMR (400MHz, CD3OD) δ: 1.40 (6H, s), 1.72-1.81 (2H, m), 2.00-2.10 (2H, m), 2.44 (6H, s), 3.22 (4H, s), 3.50-3.58 (2H, m), 3.80-3.88 (2H, m), 7.01 (2H, s), 7.72-7.79 (1H, m), 7.88-7.94 (1H, m), 8.16-8.23 (1H, m), 8.31 (1H, s)
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン(化合物7)
MS(ESI) m/z = 636 (M+H)+。1H-NMR (400MHz, CDCl3) δ: 1.47 (6H, s), 1.70-1.78 (2H, m), 2.10-2.19 (2H, m), 2.40 (6H, s), 3.00-3.07 (2H, m), 3.19-3.25 (2H, m), 3.45-3.53 (2H, m), 3.81-3.88 (2H, m), 6.94 (2H, s), 7.35 (2H, d, J = 8.0 Hz), 7.73 (1H, brs), 7.93 (2H, d, J = 8.0 Hz), 9.37 (1H, brs)
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−1,3−ジアザスピロ[4.4]ノナン−2,4−ジオン(化合物8)
1H-NMR (400MHz, CDCl3) δ: 1.83-1.92 (4H, m), 2.07-2.15 (2H, m), 2.33-2.42 (2H, m), 2.37 (6H, m), 3.71 (1H, brs), 6.56 (2H, s)
反応混合液に、トリエチルアミン(0.103ml,0.742mmol)、水(0.045ml)およびメタノール(0.10ml)を順次加えた後、混合物を窒素気流下、1.5時間加熱還流した。反応混合物を冷却後、水で希釈し、1N塩酸水溶液でpH5とした後、ジクロロメタンで抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥、減圧下濃縮し1−(4−ブロモ−3,5−ジメチルフェニル)−4−イミノ−1,3−ジアザスピロ[4.4]ノナン−2−オンを粗生成物として得た。
MS(ESI) m/z = 336, 338 (M+H)+。
MS(ESI) m/z = 337, 339 (M+H)+。
MS(ESI) m/z = 662 (M+H)+。1H-NMR (400MHz, DMSO-d6) δ: 1.36-1.44 (2H, m), 1.60-1.70 (4H. m), 1.82-1.91 (2H, m), 1.91-2.06 (4H, m), 2.38 (6H, s), 3.01-3.09 (2H, m), 3.22-3.30 (2H, m), 3.30-3.42 (2H, m), 3.70-3.77 (2H, m), 7.03 (2H, s), 7.57 (2H, d, J = 8.4 Hz), 8.14 (2H, d, J = 8.4 Hz)
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−8−メチル−1,3,8−トリアザスピロ[4.5]デカン−2,4−ジオン(化合物9)
MS(ESI) m/z = 777 (M+H)+。
MS(ESI) m/z = 677 (M+H)+。
MS(ESI) m/z = 691 (M+H)+。1H-NMR (400MHz, CD3OD) δ: 1.76-1.84 (2H, m), 1.92-2.02 (2H, m), 2.02-2.12 (4H, m), 2.38 (3H, s), 2.46 (6H, s), 2.81-2.88 (2H, m), 2.92-3.02 (2H, m), 3.23 (4H, s), 3.51-3.60 (2H, m), 3.72-3.80 (2H, m), 7.01 (2H, s), 7.48 (2H, d, J = 8.0 Hz), 8.10 (2H, d, J = 8.0 Hz)
5−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−2−オキサ−5,7−ジアザスピロ[3.4]オクタン−6,8−ジオン(化合物10)
MS(ESI) m/z = 650 (M+H)+。1H-NMR (400MHz, CDCl3) δ: 1.69-1.77 (2H, m), 2.12-2.22 (2H, m), 2.45 (6H, s), 3.03-3.11 (2H, m), 3.22-3.29 (2H, m), 3.46-3.53 (2H, m), 3.84-3.91 (2H, m), 4.86 (2H, d, J = 7.2 Hz), 5.03 (2H, d, J = 7.2 Hz), 7.07 (2H, s), 7.35 (2H, d, J = 8.4 Hz), 7.98 (2H, d, J = 8.4 Hz), 8.56 (1H, s), 10.34 (1H, s)
4−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−4,6−ジアザスピロ[2.4]ヘプタン−5,7−ジオン(化合物11)
MS(ESI) m/z = 284, 286 (M+H)+。
MS(ESI) m/z = 309, 311 (M+H)+。
MS(ESI) m/z = 634 (M+H)+。1H-NMR (400MHz, DMSO-d6) δ: 0.99-1.03 (2H, m), 1.19-1.27 (4H, m), 1.58-1.64 (2H, m), 1.81-1.90 (2H, m), 2.35 (6H, s), 2.99-3.04 (2H, m), 3.22-3.29 (2H, m), 3.67-3.73 (2H, m), 6.95 (2H, s), 7.56 (2H, d, J = 8.4 Hz), 8.12 (2H, d, J = 8.4 Hz)
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(3−(トリフルオロメチル)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−1,3−ジアザスピロ[4.4]ノナン−2,4−ジオン(化合物12)
MS(ESI) m/z = 646 (M+H)+。1H-NMR (400MHz, DMSO-d6) δ: 1.40-1.48 (2H, m), 1.62-1.71 (4H, m), 1.88-1.97 (2H, m), 1.97-2.08 (4H, m), 2.41 (6H, s), 3.03-3.10 (2H, m), 2.29-3.34 (2H, m), 3.38-3.47 (2H, m), 3.72-3.79 (2H, m), 7.06 (2H, s), 7.84 (1H, dd, J = 7.6, 7.6 Hz), 8.02 (1H, d, J = 7.6 Hz), 8.33 (1H, d, J = 7.6 Hz), 8.38 (1H, s)
本発明の化合物について、ヒトPTH1Rを介するcAMP産生能、ラット受容体を介するcAMP産生能、ヒト肝ミクロソームを用いた代謝安定性、ラット肝細胞を用いた代謝安定性、TPTXラットモデルでの血清Ca濃度上昇作用、に対する各試験結果を試験例1〜5に示す。尚、比較化合物として、表2に示すWO2010/126030A1に記載の化合物を用いた。
(ペプチド)
ヒトPTH(1−34)およびカルシトニンはペプチド研究所(日本、大阪)より購入して、10mM酢酸に溶解して1mMとし、−80℃冷凍庫で保存した。
(細胞培養)
細胞は、10%ウシ胎児血清(Hyclone)、100単位/mlペニシリンG、および100μg/ml硫酸ストレプトマイシン(Invitrogen Corp)を添加したダルベッコ改変イーグル培地(DMEM)中で、5%CO2含有加湿雰囲気下、37℃で培養した。
PTH1Rを発現していないLLC−PK1細胞、および、LLC−PK1の1細胞あたり9.5×105個のヒトPTH1Rを過剰発現するHKRK−B7を、cAMPシグナル伝達分析に用いた(Takasu et al., J. Bone. Miner. Res. 14:11-20, 1999)。
(cAMP刺激)
HKRK−B7またはLLC−PK1細胞を1X105細胞/ウェルで96ウェルプレートに播種し、一晩インキュベーションした。翌日、次にヒトPTH(1−34)または化合物を含む50μlのcAMPアッセイ緩衝液(DMEM、2mM IBMX、0.2mg/mlウシ血清アルブミン、35mM Hepes−NaOH、pH7.4)を加え、37℃のインキュベーター中に置き、20分間インキュベーションした。培地を除去した後、細胞を100μlのcAMPアッセイ緩衝液で1回洗浄した。細胞を凍結させるためにプレートをドライアイス粉末上に置き、その後ドライアイスから取り出した。40μlの50mM HClを用いて細胞を融解させ、ドライアイス上で再度凍結させた。市販のcAMP EIAキット(Biotrack cAMP EIA system, GE health care)を用いて細胞内cAMPの産生量を測定した。
可変勾配によるS字形用量反応式を用いて解析し、100nMでのヒトPTH(1−34)のcAMPシグナル活性を100%として、各化合物が20%もしくは50%のcAMPシグナル活性を示す濃度をEC20もしくはEC50として算出した。
HKRK−B7細胞における結果を表3に示す。
なお、LLC−PK1細胞においてのcAMP応答の程度はHKRK−B7細胞での程度に比べ低いものであった。
HKRK−B7細胞の代わりに中外製薬で樹立したラットPTH1Rを過剰発現するLLC−PK46_RATO_PTH1R細胞を用いて試験例1と同様に測定を行った。
LLC−PK46_RATO_PTH1R細胞を用いた結果を表4に示す。
ラットPTH1受容体におけるインビトロcAMPシグナル活性のEC20値は、ヒトPTH1RにおけるインビトロcAMPシグナル活性のEC20値と良好な相関関係にあった。EC50値についても、ラットとヒトの間で良好な相関関係にあった。
0.1Mリン酸緩衝液(pH7.4)中、ヒト肝ミクロゾームと化合物あるいは比較例をNADPH共存下37℃で所定の時間インキュベーションした。各反応時間における親化合物濃度をLC/MS/MSを用いて測定し、反応時間に対する残存率の傾きから固有クリアランス(μL/min/mg protein)を算出した。
化合物濃度: 1μM
ミクロゾーム: 0.5mg/mL
NADPH: 1mM
反応時間: 0、5、15および30分
ラット(SD、♀)の肝臓からコラゲナーゼ還流法により肝細胞を調製した。実施例化合物あるいは比較例を添加して37℃で所定の時間インキュベーションした後反応停止液を添加した。各反応時間における親化合物濃度をLC/MS/MSを用いて測定し、反応時間に対する残存率の傾きから固有クリアランス(μL/106cells/min)を算出した。
細胞濃度: 1×106cells/mL
化合物濃度: 1μM
培地: Williams' medium E
反応時間: 0、15、30、60、120および240分
反応停止液: アセトニトリル/2−プロパノール(4/6、v/v)
4週齢の雌性Crl:CD(SD)ラットを日本チャールス・リバー株式会社(厚木飼育センター)より入手し、20〜26℃、湿度35〜75%の標準実験室条件下で1週間順化させた。ラットには、水道水ならびに1.1%カルシウム、1.0%リン酸および250IU/100gのビタミンD3を含む標準げっ歯動物飼料(CE−2)(日本クレア株式会社)を自由に摂取させた。
5週齢のラットにTPTXを実施した。一部の個体には、偽手術(Sham)を実施した。使用するためのTPTXラットは、手術4日後の血清Ca濃度が8mg/dL未満の個体を選択した。手術5日後に、手術4日後に測定した血清Ca濃度と体重に基づき、各群5匹ずつ8つのTPTX群と1つのSham群に振り分けた。Sham群およびTPTX−Vehicle群には、溶媒のみを10mL/kgの用量で経口投与した。TPTX−各検体群には、各検体30 mg/10mL/kgの用量で溶媒に溶解させてそれぞれ経口投与した。溶媒の組成は、10%ジメチルスルホキシド(和光純薬工業株式会社)、10%クレモフォールEL(シグマ アルドリッチ ジャパン合同会社)、20%ヒドロキシプロピル‐β‐シクロデキストリン(日本食品化工株式会社)、グリシン(和光純薬工業株式会社)によりpH10に調製したものを使用した。各々の投与直前にPre採血をし、投与2、6、10および24時間後にも採血を実施して血清Ca濃度を測定した。各血液採取はイソフルラン吸入麻酔下にて頸静脈から行った。
Claims (16)
- 下記一般式(1)で表される化合物またはその薬理学的に許容される塩;
R1およびR2は、R1とR2が共に水素ではないとの条件の下、それぞれ独立して
1)水素、
2)ハロゲン原子、
3)1〜5個のフッ素原子で置換されていてもよい炭素数1〜2個のアルキル基、または
4)1〜5個のフッ素原子で置換されていてもよい炭素数1〜2個のアルコキシ基
であるか;または、
R1およびR2は、互いに結合して形成される下記式:
かつ、R3およびR4は、それぞれ独立して1〜3個のフッ素原子で置換されていてもよいメチル基であるか;または、
R3およびR4は、それらが結合する炭素原子と一緒になって炭素数3〜6の環(ここで、環を形成する炭素原子のうち一つは酸素原子;硫黄原子;またはメチル基で置換されていてもよい窒素原子で置換されていてもよい。)を形成する。〕。 - R1およびR2は以下の組み合わせから選択され:
1)R1が水素原子、またはハロゲン原子であり、かつR2が水素原子、トリフルオロメチル基、またはトリフルオロメトキシ基である(但し、R1とR2が共に水素原子となる場合を除く);
2)R1がトリフルオロメチル基、またはトリフルオロメトキシ基であり、かつR2が水素原子、またはハロゲン原子である;
3)R1およびR2が互いに結合して形成される下記式:
かつ、R3およびR4は、メチル基であるか;または、
R3およびR4はそれらが結合する炭素原子と一緒になって以下から選択される環:
- R1、R2は以下の組み合わせから選択され:
1)R1がトリフルオロメトキシ基であり、かつR2がフッ素原子である;
2)R1が臭素原子であり、かつR2が水素原子である;
3)R1がトリフルオロメチル基であり、かつR2がフッ素原子である;
4)R1がフッ素原子であり、かつR2がトリフルオロメトキシ基である;
5)R1がトリフルオロメチル基であり、かつR2が水素原子である;
6)R1が水素原子であり、かつR2がトリフルオロメトキシ基である;
7)R1、R2は互いに結合して形成される下記式:
かつ、R3およびR4はメチル基であるか;または、
R3およびR4はそれらが結合する炭素原子と一緒になって以下から選択される環:
請求項1記載の化合物またはその薬理学的に許容される塩。 - R3およびR4がメチル基である、請求項1に記載の化合物またはその薬理学的に許容される塩。
- 化合物が以下からなる群より選択される、請求項1記載の化合物またはその薬理学的に許容される塩:
1−(4−(2−((2−(4−フルオロ−3−(トリフルオロメトキシ)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(4−(2−((2−(3−ブロモフェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン:
1−(4−(2−((2−(4−フルオロ−3−(トリフルオロメチル)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(4−(2−((2−(3−フルオロ−4−(トリフルオロメトキシ)フェニル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(4−(2−((2−(2,2−ジフルオロベンゾ[d][1,3]ジオキソール−5−イル)−4−オキソ−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)−3,5−ジメチルフェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(3−(トリフルオロメチル)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン;
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオン):
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−1,3−ジアザスピロ[4.4]ノナン−2,4−ジオン;
1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−8−メチル−1,3,8−トリアザスピロ[4.5]デカン−2,4−ジオン;
5−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−2−オキサ−5,7−ジアザスピロ[3.4]オクタン−6,8−ジオン;および
4−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−4,6−ジアザスピロ[2.4]ヘプタン−5,7−ジオン。 - 化合物が1−(3,5−ジメチル−4−(2−((4−オキソ−2−(3−(トリフルオロメチル)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオンである、請求項1記載の化合物またはその薬理学的に許容される塩。
- 化合物が1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−5,5−ジメチルイミダゾリジン−2,4−ジオンである、請求項1記載の化合物またはその薬理学的に許容される塩。
- 化合物が1−(3,5−ジメチル−4−(2−((4−オキソ−2−(4−(トリフルオロメトキシ)フェニル)−1,3,8−トリアザスピロ[4.5]デカ−1−エン−8−イル)スルホニル)エチル)フェニル)−1,3−ジアザスピロ[4.4]ノナン−2,4−ジオンである、請求項1記載の化合物またはその薬理学的に許容される塩。
- 請求項1〜9のいずれかに記載の化合物またはその薬理学的に許容される塩を有効成分として含有する、医薬組成物。
- 医薬組成物が経口投与用である、請求項10に記載の医薬組成物。
- 請求項1〜9のいずれかに記載の化合物またはその薬理学的に許容される塩を有効成分として含有する、細胞内cAMP応答を活性化するための医薬組成物。
- 請求項1〜9のいずれかに記載の化合物またはその薬理学的に許容される塩を有効成分として含有する、骨粗鬆症、骨折、無形成骨症、軟骨無形成症、軟骨低形成症、骨軟化症、変形性関節症、関節炎、血小板減少症、副甲状腺機能低下症、高リン血症、または腫瘍状石灰沈着症の予防剤もしくは治療剤、または幹細胞動員剤。
- 請求項1〜9のいずれかに記載の化合物またはその薬理学的に許容される塩を含有する組成物の医薬的に有効な量を、骨粗鬆症、骨折、無形成骨症、軟骨無形成症、軟骨低形成症、骨軟化症、変形性関節症、関節炎、血小板減少症、副甲状腺機能低下症、高リン血症、または腫瘍状石灰沈着症の予防もしくは治療、または幹細胞動員を必要とする患者に投与することからなる、該疾患の予防もしくは治療、または幹細胞動員方法。
- 骨粗鬆症骨粗鬆症、骨折、無形成骨症、軟骨無形成症、軟骨低形成症、骨軟化症、変形性関節症、関節炎、血小板減少症、副甲状腺機能低下症、高リン血症、または腫瘍状石灰沈着症の予防剤もしくは治療剤、または幹細胞動員剤の製造のための、請求項1〜9のいずれかに記載の化合物またはその薬理学的に許容される塩の使用。
- 骨粗鬆症、骨折、無形成骨症、軟骨無形成症、軟骨低形成症、骨軟化症、変形性関節症、関節炎、血小板減少症、副甲状腺機能低下症、高リン血症、または腫瘍状石灰沈着症の治療もしくは予防、または幹細胞動員のための、請求項1〜9のいずれかに記載の化合物またはその薬理学的に許容される塩。
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2017
- 2017-01-11 CL CL2017000069A patent/CL2017000069A1/es unknown
- 2017-12-20 US US15/848,267 patent/US20180237436A1/en not_active Abandoned
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2018
- 2018-04-24 HR HRP20180647TT patent/HRP20180647T1/hr unknown
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2020
- 2020-02-28 US US16/805,204 patent/US20210024524A1/en not_active Abandoned
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2021
- 2021-05-25 US US17/330,200 patent/US20220162208A1/en active Pending
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