JP2017528503A - 新規化合物αvβ6インテグリンアンタゴニスト - Google Patents
新規化合物αvβ6インテグリンアンタゴニスト Download PDFInfo
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- JP2017528503A JP2017528503A JP2017516365A JP2017516365A JP2017528503A JP 2017528503 A JP2017528503 A JP 2017528503A JP 2017516365 A JP2017516365 A JP 2017516365A JP 2017516365 A JP2017516365 A JP 2017516365A JP 2017528503 A JP2017528503 A JP 2017528503A
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- Prior art keywords
- compound
- fluoro
- mmol
- acid
- pharmaceutically acceptable
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- 229940123038 Integrin antagonist Drugs 0.000 title description 8
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- -1 3-Fluoro-3- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) pyrrolidin-1-yl Chemical group 0.000 claims description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
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- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- NOJNFULGOQGBKB-UHFFFAOYSA-M sodium;3-[3-tert-butylsulfanyl-1-[[4-(6-ethoxypyridin-3-yl)phenyl]methyl]-5-[(5-methylpyridin-2-yl)methoxy]indol-2-yl]-2,2-dimethylpropanoate Chemical compound [Na+].C1=NC(OCC)=CC=C1C(C=C1)=CC=C1CN1C2=CC=C(OCC=3N=CC(C)=CC=3)C=C2C(SC(C)(C)C)=C1CC(C)(C)C([O-])=O NOJNFULGOQGBKB-UHFFFAOYSA-M 0.000 description 1
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository 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
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229920001187 thermosetting polymer Polymers 0.000 description 1
- 239000004634 thermosetting polymer Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000009974 thixotropic effect Effects 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000002750 tryptase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229960004258 umeclidinium Drugs 0.000 description 1
- 201000007954 uterine fibroid Diseases 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 210000001260 vocal cord Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
本発明の第1の態様では、式(I)の化合物またはその塩、より詳しくは、式(I)の化合物またはその薬学上許容可能な塩:
が提供される。
本発明の第1の態様では、式(I)の化合物またはその塩:
が提供される。
本発明の化合物は、標準的な化学作用を含む様々な方法によって製造することができる。従前に定義された変項はいずれも、そうではないことが示されない限り、従前に定義された意味を有し続ける。一般合成法の実例を以下に示し、次いで、具体的な本発明の化合物を、実施例において調製する。
の化合物の第1の脱保護、すなわち、エステル基の切断、続いて、塩への変換を伴う工程によって製造され得る。
の化合物から、構造式(IV):
のボロン酸化合物との反応により得られ得る。
の化合物と、ジクロロメタンなどの溶媒中、N,N−ジイソプロピルエチルアミン(「DIPEA」)などの有機塩基および好適なパラジウム系触媒、例えば、ジクロロメタンとの錯体としてのPdCl2(dppf)−CH2Cl2[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)の存在下で反応させることにより得ることができる。式(V)の化合物は親化合物として使用することができ、または第三級アミン塩基の存在下、二塩酸塩などの塩からin situで生成させることもできる。
式(I)の化合物およびその塩は、αvインテグリンアンタゴニスト活性、特に、αvβ6受容体活性を有すると考えられ、従って、αvβ6アンタゴニストが指示される疾患または病態の治療において潜在的有用性を有する。
療法において使用するために、式(I)の化合物ならびにその薬学上許容可能な塩を、そのままの化学物質として投与してもよいが、有効成分を医薬組成物として提供することが一般的である。
以下のリストは、本明細書で使用される特定の略語の定義を示す。このリストは排他的ではなく、本明細書の下記で定義されていない略語の意味は当業者には容易に分かることが認識されるであろう。
BCECF−AM(2’,7’−ビス−(2−カルボキシエチル)−5−(および−6)−カルボキシフルオレセインアセトキシメチルエステル)
BEH(エチレン架橋ハイブリッド技術)
Bu(ブチル)
CBZ(カルボキシベンジル)
CHAPS(3−[(3−コラミドプロピル)ジメチルアンモニオ]−1−プロパンスルホネート)
Chiralcel OD−H(5μmシリカゲル上のセルローストリス(3,5−ジメチルフェニルカルバメート)コーティング)
Chiralpak AD−H(5μmシリカゲル上のアミローストリス(3,5−ジメチルフェニルカルバメート)コーティング)
Chiralpak ID(5μmシリカゲル上に固定されたアミローストリス(3−クロロフェニルカルバメート))
Chiralpak AS(5μmシリカゲル上のアミローストリス((S)−α−メチルベンジルカルバメート)コーティング)
CDI(カルボニルジイミダゾール)
CSH(表面チャージハイブリッド技術)
CV(カラム体積)
DCM(ジクロロメタン)
DIPEA(ジイソプロピルエチルアミン)
DMF(N,N−ジメチルホルムアミド)
DMSO(ジメチルスルホキシド)
DSC(示差操作比色法)
Et(エチル)
EtOH(エタノール)
EtOAc(酢酸エチル)
h(時間)
HCl(塩酸)
HEPES(4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸)
LCMS(液体クロマトグラフィー質量分析)
M(モル)
MDAP(質量分析自動分取HPLC)
MDCK(Madin−Darbyイヌ腎臓)
Me(メチル)
MeCN(アセトニトリル)
MeI(ヨウ化メチル)
MeOH(メタノール)
min(分)
MS(質量スペクトル)
PdCl2(dppf)−CH2Cl2 [1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II),ジクロロメタンとの錯体
Ph(フェニル)
iPr(イソプロピル)
(R)−BINAP (R)−(+)−2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフタレン
[Rh(COD)Cl]2(クロロ(1,5−シクロオクタジエン)ロジウム(I)二量体)
SPE(固相抽出)
TBME(tert−ブチルメチルエーテル)
TEA(トリエチルアミン)
TFA(トリフルオロ酢酸)
TGA(熱重量分析)
TGA−IR(赤外線インターフェース熱重量分析装置)
THF(テトラヒドロフラン)
TLC(薄層クロマトグラフィー)
UPLC(超高速液体クロマトグラフィー)
XRPD(X線粉末回折)
分析的LCMS
分析的LCMSを、次のシステムAまたはB1つで行った。
カラム: 50mm×2.1mm ID、1.7μm Acquity UPLC BEH C18カラム
流速: 1mL/分
温度: 40℃
溶媒: A:アンモニア溶液でpH10に調整した水中10mM重炭酸アンモニウム
B:アセトニトリル
勾配: 時間(分) A% B%
0 99 1
1.5 3 97
1.9 3 97
2.0 99 1
カラム: 50mm×2.1mm ID、1.7μm Acquity UPLC BEH C18カラム
流速: 1mL/分
温度: 40℃
溶媒: A:水中0.1%v/vギ酸溶液
B:アセトニトリル中0.1%v/vギ酸溶液
勾配: 時間(分) A% B%
0 97 3
1.5 0 100
1.9 0 100
2.0 97 3
カラム: 50mm×2.1mm ID、1.7μm Acquity UPLC CSH C18カラム
流速: 1mL/分
温度: 40℃
溶媒: A:アンモニア溶液でpH10に調整した水中10mM重炭酸アンモニウム
B:アセトニトリル
勾配: 時間(分) A% B%
0 97 3
1.5 5 95
1.9 5 95
2.0 97 3
異性体1:わら色のガム(123.4mg、31%);LCMS (システムA) RT=1.28分, 95%, ES+ve m/z 382 (M+H)+および
異性体2:わら色のガム(121.5mg、31%);LCMS (システムA) RT=1.22分, 91%, ES+ve m/z 382 (M+H)+
総収量=244.9mg、62.5%。
実施例1:(S)−4−((S)−3−フルオロ−3−(2−(5,6,7,8−テトラヒドロ−1,8−ナフチリジン−2−イル)エチル)ピロリジン−1−イル)−3−(3−モルホリノフェニル)ブタン酸
MeCN(0.2mL)を(S)−4−(S)−(3−フルオロ−3−(2−(5,6,7,8−テトラヒドロ−1,8−ナフチリジン−2−イル)エチル)ピロリジン−1−イル)−3−(3−モルホリノフェニル)ブタン酸(製造については実施例1を参照)(19.8mg)に加え、次いで、マレイン酸(水中3M溶液、0.0133mL)を加えた。この溶液の温度を48時間40℃と5℃の間で循環させ、各サイクル間を1時間保持した。結晶性固体を、0.45μmフィルターを取り付けた遠心フィルターチューブを用いて単離し、結晶性マレイン酸塩を得た。
MeCN(0.2mL)を(S)−4−(S)−(3−フルオロ−3−(2−(5,6,7,8−テトラヒドロ−1,8−ナフチリジン−2−イル)エチル)ピロリジン−1−イル)−3−(3−モルホリノフェニル)ブタン酸(製造については実施例1を参照)(19.7mg)に加え、次いで、フマル酸(EtOH中0.2M溶液、198.3μL)を加えた。この溶液の温度を48時間40℃と5℃の間で循環させ、各サイクル間を1時間保持した。溶媒を減圧下で蒸発させ、MeCN(0.2mL)を加えた。この生成物の温度を一晩(約16時間)40℃と5℃の間で循環させ、各サイクル間を1時間保持したところ、ガムとなった。マレイン酸塩のシード(製造については実施例3を参照)をこのガムに加え、懸濁液を室温で一晩撹拌したところ、ガムと結晶性固体の混合物が得られた。
(S)−4−((S)−3−フルオロ−3−(2−(5,6,7,8−テトラヒドロ−1,8−ナフチリジン−2−イル)エチル)ピロリジン−1−イル)−3−(3−モルホリノフェニル)ブタン酸(製造については実施例1を参照)(1.24g、2.50mmol)にEtOH(1.8mL)を加えた。この撹拌油性溶液にEtOH中0.2Mフマル酸(12.48mL、2.5mmol)および結晶性フマル酸塩(製造については上記を参照)を加え、橙色溶液およびガムを得た。これを1時間40℃に加熱した。白色固体が1時間かけて沈殿した。この懸濁液を氷/水浴で冷却し、1時間撹拌した。次に、この懸濁液を室温で18時間撹拌した。固体を濾取し、エタノールで洗浄した(2mL)。固体を真空乾燥させ、標題化合物(1.34g、88%)を白色固体として得た:1H NMR (DMSO-d6, 600MHz) 7.13 (1H, t, CH), 7.08 (1H, d, CH), 6.82 (1H, t, CH), 6.78 (1H, br.s, NH), 6.75ppm (1H, dd, CH), 6.69 (1H, br.d, CH), 6.61 (2H, s, CH [フマル酸塩]), 6.31 (1H, d, CH), 3.72 (4H, br.t, 2xCH2), 3.25 (2H, br.t, CH2), 3.13 (1H, m, CH), 3.08 (4H, br.t, 2xCH2), 2.85-2.69 (5H, m, CH2+3x 1/2 CH2), 2.61 (2H, t, CH2), 2.58-2.48 (4H, m, CH2+2x1/2CH2), 2.41 (1H, dd, CH), 2.03-1.85 (4H, m, 2xCH2), 1.75 (2H, m, CH2)。
MeCN(0.2mL)を(S)−4−((S)−3−フルオロ−3−(2−(5,6,7,8−テトラヒドロ−1,8−ナフチリジン−2−イル)エチル)ピロリジン−1−イル)−3−(3−モルホリノフェニル)ブタン酸(製造については実施例1を参照)(20.4mg)に加え、次いで、クエン酸(THF中1M溶液、41.1μL)を加え、ガムを得た。このガム残渣の温度を48時間40℃と5℃の間で循環させ、各サイクル間を1時間保持した。溶媒を減圧下で蒸発させ、MeCN(0.2mL)を加えた。得られた生成物の温度を一晩(約16時間)40℃と5℃の間で循環させ、各サイクル間を1時間保持し、結晶性クエン酸塩を得た。
細胞間接着アッセイ
使用した試薬および方法は記載の通りであり[Ludbrook et al, Biochem. J. 2003, 369, 311およびにαvβ8関してはMacdonald et al. ACS MedChemLett 2014, 5, 1207-1212)、以下に明瞭化の点を示す。以下の細胞株を使用し、括弧内にリガンドを示す:、K562−αvβ3(LAP−b1)、K562−αvβ5(ビトロネクチン)、K562−αvβ6(LAP−b1)、K562−αvβ8(LAP−b1)、A549−αvβ1(LAP−b1)。接着を促進するために使用した二価陽イオンは2mM MgCl2であった。接着を、蛍光色素BCECF−AM(Life TecHnologies)での細胞標識によって定量化し、その際、3×106細胞/mLの細胞懸濁液を、0.33μL/mLの30mM BCECF−AMとともに37℃で10分間インキュベートし、その後、50μL/ウェルを96ウェルアッセイプレートに分注した。アッセイの終了時に、接着した細胞を、H2O中0.5%Triton X−100を50μL/ウェルで使用して溶解し、蛍光を放出させた。蛍光強度を、Envision(登録商標)プレートリーダー(Perkin Elmer)を使用して検出した。このアッセイにおいて活性なアンタゴニストについて、IC50決定のために、データを4パラメーターロジスティック方程式にフィットさせた。
実施例1、実施例2および実施例5(総て両性イオンとして)の受動的膜透過性を、Madin−Darbyイヌ腎臓−多剤耐性1(MDCKII−MDR1)細胞においてpH7.4、強力なP−糖タンパク質阻害剤GF120918の存在下で決定した。各化合物を、各試験の場合で3・Mの濃度にて2反復でインキュベートした。このアッセイにおいて、実施例1の受動的な見掛けの透過性(Papp)は68nm/秒(試験回数n=2)であり、実施例2は20nm/秒(試験回数n=1)であった。実施例5 Pappは90nm/秒(±26nm/秒;試験回数n=3)であった。
3−フルオロピロリジン不斉中心の絶対立体配置の同定
目的分子(IA)の合成は、それぞれ構造式(IX)の中間体の各鏡像異性体で開始した。この材料はWuxi App Tecから3−フルオロ−3−(ヒドロキシメチル)ピロリジン−1−カルボン酸(+)−ベンジルまたは3−フルオロ−3−(ヒドロキシメチル)ピロリジン−1−カルボン酸(−)−ベンジルとして購入し、それぞれのものは(IA)の主要ジアステレオ異性体を提供し、これは副ジアステレオ異性体よりも強力であった。3−フルオロ−3−(ヒドロキシメチル)ピロリジン−1−カルボン酸ベンジル(IX)の鏡像異性体のそれぞれの絶対立体配置は未知であり、それらの立体配置を確定するためにスキーム3に概略を示す以下の実験を行った。
実施例1のベンジル不斉中心の絶対立体配置は、スキームIVで示す分解実験によって得られた。従って、実施例1をDCM中、ヨウ化メチルで、室温にて一晩処理してピロリジン窒素を第四級化した後、炭酸カリウムを加え、マイクロ波反応器内で1時間120℃に加熱し、(S)−4−(3−モルホリノフェニル)ジヒドロフラン−2(3H)−オン(化合物XXIII)を得た。この分解生成物を、古典的な林の不斉反応(T. Hayashi et. al. Tetrahedron Asymmetry, 1999, 10, 4047-4056)を用い、触媒としてのビス(ノルボルナジエン)ロジウム(I)テトラフルオロボレートおよびキラル配位子としての(R)−BINAPを用いて、(3−モルホリノフェニル)ボロン酸をフラン−2(5H)−オンを付加することによって製造した真正な(R)−4−(3−モルホリノフェニル)ジヒドロフラン−2(3H)−オン(化合物XXIV)と比較し、分解生成物の鏡像異性体であることを示し、従って、そのベンジル中心における実施例1の立体配置を(S)と確定した。
実施例1は、構造式(IA2)の化合物(S)−4−((S)−3−フルオロ−3−(2−(5,6,7,8−テトラヒドロ−1,8−ナフチリジン−2−イル)エチル)ピロリジン−1−イル)−3−(3−モルホリノフェニル)ブタン酸であり、実施例2は、構造式(IA3)の化合物(S)−4−(R)−(3−フルオロ−3−(2−(5,6,7,8−テトラヒドロ−1,8−ナフチリジン−2−イル)エチル)ピロリジン−1−イル)−3−(3−モルホリノフェニル)ブタン酸である。
3−フルオロ−3−(((R)−1−フェニルエチル)カルバモイル)ピロリジン−1−カルボン酸(S)−tert−ブチル(化合物XVIII)および3−フルオロ−3−(((R)−1−フェニルエチル)カルバモイル)ピロリジン−1−カルボン酸(R)−tert−ブチル(化合物XIX)
THF(70mL)中、(±)−1−(tert−ブトキシカルボニル)−3−フルオロピロリジン−3−カルボン酸(化合物XVII[Chemical Abstracts登録番号1001754−59−1](Wuxi App Tecから入手可能)(3.00g、12.9mmol)の溶液を、室温にて固体CDI(2.5g、15.4mmol)で処理した後、この混合物を1.5時間80℃に加熱した。(R)−(+)−α−メチルベンジルアミン(Flukaから入手可能)(1.6g、13.2mmol)をこの温度で加えた後、この混合物をさらに1.5時間80℃で加熱した。この混合物を酢酸エチルで希釈し、希HCl、NaHCO3、ブラインで洗浄し、乾燥させ(MgSO4)、濾過し、室温でゆっくり蒸発さえた。この混合物は、固体が析出しなかったので最終的に減圧下で濃縮した。残渣を40分かけて0〜25%EtOAc−シクロヘキサンで溶出するシリカ(2×100g)カートリッジでのクロマトグラフィーにより精製した。最初に溶出する化合物は白色泡沫として得られた(1.54g、36%):LCMS (システムA) RT=1.17分, ES+ve m/z 337 (M+H)+; 1H NMR (500 MHz, CDCl3) 1.43-1.49 (m, 9H), 1.54 (d, J=7.0 Hz, 3H), 2.08-2.19 (m, 1H), 2.37-2.62 (m, 1H), 3.43-3.56 (m, 1H), 3.61-3.93 (m, 3H), 5.14 (quin, J=7.1 Hz, 1H), 6.71-6.76 (m, 1H), 7.27-7.39 (m, 5H)、約10%の極性の高いジアステレオ異性体を含有する;[α]D 20+61(MeOH中c=1.27);分析的キラルHPLC 10%EtOH−ヘプタンで溶出し、流速=1mL/分、215nmで検出するChiralpak ADカラム(250mm×4.6mm)で、RT=7.58分、90%、およびRT=9.53分、10%。50mg部のこのサンプルを20分かけて0〜25%EtOAc−シクロヘキサンで溶出するシリカカートリッジ(20g)でさらに精製した。適当な画分を減圧下で蒸発させ、3−フルオロ−3−(((R)−1−フェニルエチル)カルバモイル)ピロリジン−1−カルボン酸(R)−tert−ブチル(化合物XIX)の分析上純粋なサンプル(30mg)を得たLCMS (システムC) RT=1.16分, ES+ve m/z 337 (M+H)+および(M+NH4)+ならびにES-ve m/z 335 (M-H)- ; [α]D 20 +63 (MeOH 中c=0.933)。
化合物(IX)の(−)−異性体である(−)−N−CBZ−3−フルオロ−3−(ヒドロキシメチル)ピロリジン(Wuxi App Tecから入手可能)(4.0g、15.8mmol)の溶液を、エタノール(150mL)中、10%Pd/C(400mg)上で一晩水素化した。触媒をセライトで濾去し、エタノールで洗浄した。濾液および洗液を減圧下で蒸発させ、標題化合物(2.0gm、106%、NMRによればいくらかのエタノールを含有)を黄色油状物として得、これは固化して蝋状固体となった:LCMS (システムC) RT=0.22分, ES+ve m/z 120 (M+H)+およびES-ve m/z 118 (M-H)-。生成物をさらにブローダウンユニットに窒素下、40℃で乾燥させた。1H NMR (500 MHz, CDCl3) 3.82 (dd, J=18.7, 12.5 Hz, 1H), 3.73 (dd, J=22.0, 12.2 Hz, 1H), 3.22-3.15 (m, 1H), 3.23-3.14 (m, 1H), 2.99-2.92 (m, 1H), 2.91 (dd, J=29.1, 13.2 Hz, 1H), 2.66 (br s, 2H), 2.10-1.98 (m, 1H), 1.94-1.81 (m, 1H);[α]D 20=-4 (EtOH中c=1.19)。
DCM(15mL)およびジイソプロピルエチルアミン(4.13mL、23.7mmol)中、(R)−(3−フルオロピロリジン−3−イル)メタノール(化合物XX)(1.88g、15.8mmol)の溶液を二炭酸ジ−tert−ブチル(3.79g、17mmol)で処理し、混合物を20℃で3時間撹拌した。この混合物を2M HClとDCMとで分液し、相分離カートリッジで分離した。有機層を減圧下で濃縮し、残渣を40分で0〜50%EtOAc−シクロヘキサンの勾配で溶出するシリカカートリッジ(70g)でのクロマトグラフィーにより精製した。画分をシリカでのTLC(50%EtOAc−シクロヘキサン)により確認し、KMnO4溶液で染色した。適当な画分を合わせ、減圧下で蒸発させ、標題化合物(2.73g、79%)を無色の油状物として得た:LCMS (システムC) RT=0.79分, ES+ve m/z 220 (M+H)+ and 439 (2M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 9H), 1.96-2.14 (m, 2H), 3.32-3.41 (m, 2H), 3.42-3.50 (m, 2H), 3.54-3.61 (m, 1H), 3.62-3.69 (m, H), 4.90 (t, J=5.8 Hz, 1H); [α]D 20 = -28 (CHCl3中c=3.51)。
MeCN(1mL)および水(1mL)中、3−フルオロ−3−(ヒドロキシメチル)ピロリジン−1−カルボン酸(−)−tert−ブチル(化合物XXI)(200mg、0.9mmol)の溶液をRuCl3(9.5mg、0.05mmol)および過ヨウ素酸ナトリウム(976mg、4.5mmol)で処理し、この混合物を20℃で16時間撹拌した。この混合物を1M HCl(5mL)で酸性化し、DCMで分液した。水相をDCMで2回再抽出し、相分離カートリッジで相を分離した。有機溶液をブローダウンユニットで蒸発させ、(R)−1−(tert−ブトキシカルボニル)−3−フルオロピロリジン−3−カルボン酸(化合物XXII)(125mg、59%)を得た:MS ES-ve m/z 232 (M-H)-。この酸(125mg、0.54mmol)を酢酸エチル(10mL)に溶かし、CDI(360mg、2.2mmol)で処理し、この混合物を室温で1時間撹拌した後、50℃で0.5時間加熱した。この混合物をブローダウンユニットで濃縮し、残渣をTHF(6mL)に溶かし、(R)−(+)−α−メチルベンジルアミン(200mg、1.9mmol)で処理し、20℃で1.5時間撹拌した。この混合物を酢酸エチルで希釈し、2M HCl溶液で2回、次いで、ブラインで洗浄した。有機溶液を乾燥させ(MgSO4)、減圧下で蒸発させ、灰色の固体を得た(290mg)。この残渣をMeOH−DMSO(1:1;3mL)に溶かし、周囲温度で、30〜85%(アンモニア水溶液でpH10に調整した水中10mM重炭酸アンモニウム−アセトニトリル)の勾配で溶出し、30分流動し、254nmで検出し、RT=17.4分のピークで回収するXSELECT CSH C18カラム(150mm×30mm i.d.充填径5μm)でのMDAPにより精製したES+ve m/z 337(M+H)+。この画分を45℃、窒素下、ブローダウンユニットで濃縮し、残った懸濁液をEtOAcで抽出した。有機溶液を2M HClで2回、次いで、ブラインで洗浄し、乾燥させ(MgSO4)、減圧下で蒸発させ、黄色ガムを得た(35mg)。このガムを、周囲温度で、アンモニア水溶液でpH10に調整した水中10mM重炭酸アンモニウム−アセトニトリル)の勾配で溶出し、25分流動し、254nmで検出し、最初の画分(RT=10分)を回収するXBridge C18カラム(100mm×19mm i.d.充填径5μm)でのMDAPにより再精製した。溶媒をブローダウンユニットにて窒素下、45℃で除去し、標題化合物(16mg、5%)を無色のガムとして得た:LCMS (システムC) RT=1.16分, ES+ve m/z 337 (M+H)+, 354 (M+NH4)+;分析的キラルHPLC 10%EtOH−ヘプタンで溶出し、流速=1mL/分、215nmで検出するChiralpak ADカラム(250mm×4.6mm)でRT=7.58分、97.7%;[α]D 20+63(MeOH中c=1.15)。1H NMRスペクトル(500MHz、CDCl3)ならびに旋光度およびキラルHPLC RTは総て、3−フルオロ−3−(((R)−1−フェニルエチル)カルバモイル)ピロリジン−1−カルボン酸(R)−tert−ブチル(化合物XIX)のものと一致する。
室温で、DCM(8mL)中、(S)−4−((S)−3−フルオロ−3−(2−(5,6,7,8−テトラヒドロ−1,8−ナフチリジン−2−イル)エチル)ピロリジン−1−イル)−3−(3−モルホリノフェニル)ブタン酸(実施例1)(100mg、0.201mmol)の溶液をヨードメタン(0.195mL、3.13mmol)で処理し、18時間撹拌した。この反応物を真空濃縮した(過剰なヨードメタンを除去するため)。残渣をDCM(5mL)中に再溶解させ、炭酸カリウム(122mg、0.884mmol)を加えた。この反応物をマイクロ波反応器内、120℃で1時間加熱した。溶液を濾過し、真空濃縮した。残った油状物をシクロヘキサン中0〜100%TBMEの勾配で溶出するシリカ(10g)でのカラムクロマトグラフィーにより精製した。関連画分を真空濃縮し、(S)−4−(3−モルホリノフェニル)ジヒドロフラン−2(3H)−オン(化合物XXIII)(32mg、64%)を白色固体として得た:LCMS (システムC) RT=0.82分, 100%, ES+ve m/z 247 (M+H)+; 1H NMR (400MHz, CDCl3) 7.32-7.26 (m, 1H), 6.89-6.84 (m, 1H), 6.79-6.73 (m, 2H), 4.67 (dd, J=9, 8 Hz, 1H), 4.30 (dd, J=9.06, 7.5 Hz, 1H), 3.92-3.85 (m, 4H), 3.76 (quin, J=8.31 Hz, 1H), 3.21-3.17 (m, 4H), 2.93 (dd, J=17.5, 8.7 Hz, 1H), 2.93 (dd, J=17.5, 8.7 Hz, 1H), 2.70 (dd, J =17.5, 8.7 Hz, 1H); [a]D 22 = +37.1 (c = 1.40 in CHCl3);キラルHPLC 20%イソプロパノール−ヘプタンで溶出し、流速1mL/分、215nmで検出するChiralpak IDカラム(25cm×4.6mm)でRT=25.4分。化合物XXIIIの一部を緩慢な結晶化によりクロロホルムから再結晶化させ、X線回折試験に好適な結晶を得た。
1,4−ジオキサン(10mL)中、テトラフルオロホウ酸ビス(ノルボルナジエン)ロジウム(I)(Aldrichから入手可能)(18.70mg、0.05mmol)および(3−モルホリノフェニル)ボロン酸(1035mg、5.00mmol)の溶液をフラン−2(5H)−オン(0.142mL、2.0mmol)およびKOH溶液(3.8M、1.053mL、4.00mmol)で処理した。得られた溶液をマイクロ波反応器にて1時間100℃に加熱した。この反応物を放冷し、真空濃縮し、褐色油状物を得た。残渣を45分でシクロヘキサン中0〜50%EtOAcの勾配で溶出するクロマトグラフィー(50g KPNHカートリッジ)により精製した。関連画分を真空濃縮し、(R)−4−(3−モルホリノフェニル)ジヒドロフラン−2(3H)−オン(化合物XXIV)(132mg、27%)を白色固体として得た:LCMS (システムC) RT= 0.82分, 100%, ES+ve m/z 248 (M+H)+; [a]D 22 = -28.3 (CHCl3中c = 1.70); キラルHPLC 20%イソプロパノール−ヘプタンで溶出し、流速1mL/分、215nmで検出するChiralpak IDカラム(25cm×4.6mm)でRT=23.4分、94%、RT=25.4分 6%。
Claims (17)
- 式(I):
の化合物またはその塩。 - 式(IA):
- 式(IA2):
- 式(IB):
- 式(IB2):
- 治療において使用するための、請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容される塩。
- αvβ6受容体アンタゴニストが指示される疾患または病態の治療において使用するための、請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容される塩。
- 特発性肺線維症の治療において使用するための、請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容される塩。
- ヒトにおけるαvβ6受容体の拮抗作用が有益である障害の治療のための方法であって、それを必要とするヒトに治療上有効な量の請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容可能な塩を投与することを含んでなる、方法。
- ヒトにおけるαvβ6受容体の拮抗作用が有益である障害の予防のための方法であって、それを必要とするヒトに治療上有効な量の請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容可能な塩を投与することを含んでなる、方法。
- ヒトにおける線維性疾患の治療のための方法であって、それを必要とするヒトに治療上有効な量の請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容可能な塩を投与することを含んでなる、方法。
- ヒトにおける線維性疾患の予防のための方法であって、それを必要とするヒトに治療上有効な量の請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容可能な塩を投与することを含んでなる、方法。
- ヒトにおける特発性肺線維症の治療のための方法であって、それを必要とするヒトに治療上有効な量の請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容可能な塩を投与することを含んでなる、方法。
- ヒトにおける特発性肺線維症の予防のための方法であって、それを必要とするヒトに治療上有効な量の請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容可能な塩を投与することを含んでなる、方法。
- 請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容可能な塩と、1種以上の薬学上許容可能な担体、希釈剤または賦形剤とを含んでなる医薬組成物。
- 経口投与に適合した形態の請求項15に記載の医薬組成物。
- αvβ6受容体アンタゴニストが指示される疾患または病態の治療のための医薬の製造における、請求項1〜5のいずれか一項に記載の化合物またはその薬学上許容可能な塩の使用。
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EP (1) | EP3197893B1 (ja) |
JP (1) | JP6665169B2 (ja) |
KR (1) | KR20170063590A (ja) |
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Cited By (1)
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JP2022511029A (ja) * | 2018-12-04 | 2022-01-28 | スミトモ ダイニッポン ファーマ オンコロジー, インコーポレイテッド | がんの処置のための薬剤としての使用のためのcdk9インヒビターおよびその多形 |
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GB201305668D0 (en) | 2013-03-28 | 2013-05-15 | Glaxosmithkline Ip Dev Ltd | Avs6 Integrin Antagonists |
GB201417002D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compound |
GB201417094D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
GB201417018D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
GB201604680D0 (en) * | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
GB201604681D0 (en) * | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
WO2018089358A1 (en) | 2016-11-08 | 2018-05-17 | Bristol-Myers Squibb Company | Azole amides and amines as alpha v integrin inhibitors |
CA3042714A1 (en) | 2016-11-08 | 2018-05-17 | Bristol-Myers Squibb Company | Indazole derivatives as a .alpha.v integrin antagonists |
EA038164B1 (ru) | 2016-11-08 | 2021-07-16 | Бристол-Маерс Сквибб Компани | 3-замещенные пропановые кислоты в качестве ингибиторов интегрина v |
WO2018089355A1 (en) | 2016-11-08 | 2018-05-17 | Bristol-Myers Squibb Company | Cyclobutane- and azetidine-containing mono and spirocyclic compounds as alpha v integrin inhibitors |
CA3042693A1 (en) | 2016-11-08 | 2018-05-17 | Bristol-Myers Squibb Company | Pyrrole amides as .alpha.v integrin inhibitors |
WO2018119087A1 (en) | 2016-12-23 | 2018-06-28 | Pliant Therapeutics, Inc. | Amino acid compounds and methods of use |
JP7092784B2 (ja) | 2017-02-28 | 2022-06-28 | モーフィック セラピューティック,インコーポレイテッド | αvβ6インテグリン阻害剤 |
EP4147698A1 (en) | 2017-02-28 | 2023-03-15 | Morphic Therapeutic, Inc. | Inhibitors of (alpha-v)(beta-6) integrin |
CN107823208A (zh) * | 2017-10-25 | 2018-03-23 | 南京多宝生物科技有限公司 | 吗啉类化合物在制备治疗和预防肾纤维化药物中的应用 |
SG11202004077WA (en) | 2017-11-07 | 2020-05-28 | Bristol Myers Squibb Co | Pyrrolopyrazine derivatives as alpha v integrin inhibitors |
CN108208177A (zh) * | 2017-11-28 | 2018-06-29 | 上海交通大学医学院附属新华医院 | 含丁酸类化合物的组合物及其应用 |
JP2021535141A (ja) | 2018-08-29 | 2021-12-16 | モーフィック セラピューティック,インコーポレイテッド | αvβ6インテグリンの阻害 |
AR116036A1 (es) | 2018-08-29 | 2021-03-25 | Morphic Therapeutic Inc | DERIVADOS DE NAFTIRIDINA COMO INHIBIDORES DE INTEGRINA avb6 |
TW202028179A (zh) | 2018-10-08 | 2020-08-01 | 美商普萊恩醫療公司 | 胺基酸化合物及使用方法 |
JP2022512648A (ja) * | 2018-10-09 | 2022-02-07 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 心筋線維化の処置のためのαV-インテグリン(CD51)阻害剤の使用 |
WO2023225119A1 (en) * | 2022-05-18 | 2023-11-23 | Pliant Therapeutics, Inc. | Stabilization of integrin inhibitors |
WO2024129931A1 (en) | 2022-12-14 | 2024-06-20 | Alnylam Pharmaceuticals, Inc. | ALPHA-V BETA-6(ανβ6) INTEGRIN LIGANDS FOR EXTRAHEPATIC DELIVERY |
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GB201305668D0 (en) | 2013-03-28 | 2013-05-15 | Glaxosmithkline Ip Dev Ltd | Avs6 Integrin Antagonists |
WO2015048819A1 (en) | 2013-09-30 | 2015-04-02 | The Regents Of The University Of California | Anti-alphavbeta1 integrin compounds and methods |
GB201417002D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compound |
GB201417018D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
GB201417094D0 (en) | 2014-09-26 | 2014-11-12 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
TWI736529B (zh) | 2015-02-19 | 2021-08-21 | 美商賽氟洛生命科學公司 | 氟化之四氫啶基壬酸衍生物及其用途 |
JP2018515424A (ja) | 2015-03-10 | 2018-06-14 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 抗アルファvベータ1インテグリン阻害剤及び使用方法 |
GB201604589D0 (en) | 2016-03-18 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical compound |
GB201604680D0 (en) | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
GB201604681D0 (en) | 2016-03-21 | 2016-05-04 | Glaxosmithkline Ip Dev Ltd | Chemical Compounds |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022511029A (ja) * | 2018-12-04 | 2022-01-28 | スミトモ ダイニッポン ファーマ オンコロジー, インコーポレイテッド | がんの処置のための薬剤としての使用のためのcdk9インヒビターおよびその多形 |
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ES2704525T3 (es) | 2019-03-18 |
TW201629057A (zh) | 2016-08-16 |
BR112017006253A2 (pt) | 2017-12-12 |
GB201417011D0 (en) | 2014-11-12 |
UY36315A (es) | 2016-04-29 |
RU2017114346A (ru) | 2018-11-02 |
AR101995A1 (es) | 2017-01-25 |
EP3197893A1 (en) | 2017-08-02 |
CA2962326A1 (en) | 2016-03-31 |
KR20170063590A (ko) | 2017-06-08 |
EP3197893B1 (en) | 2018-10-24 |
WO2016046226A1 (en) | 2016-03-31 |
US10000489B2 (en) | 2018-06-19 |
CN107074849A (zh) | 2017-08-18 |
JP6665169B2 (ja) | 2020-03-13 |
US20170298063A1 (en) | 2017-10-19 |
AU2015320859A1 (en) | 2017-03-09 |
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