JPH029895A - Nucleoside analog compound and antitumor agent - Google Patents
Nucleoside analog compound and antitumor agentInfo
- Publication number
- JPH029895A JPH029895A JP16040388A JP16040388A JPH029895A JP H029895 A JPH029895 A JP H029895A JP 16040388 A JP16040388 A JP 16040388A JP 16040388 A JP16040388 A JP 16040388A JP H029895 A JPH029895 A JP H029895A
- Authority
- JP
- Japan
- Prior art keywords
- group
- antitumor agent
- compound
- acid
- substituted
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 14
- 239000002777 nucleoside Substances 0.000 title claims description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 title claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- -1 5-substituted-1H-pyrazolo[3,4-b]pyrazine Chemical class 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 5
- HMFHBZSHGGEWLO-TXICZTDVSA-N beta-D-ribose Chemical class OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-TXICZTDVSA-N 0.000 abstract description 4
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- USDIRSJFHPHMAS-UHFFFAOYSA-N ClC1=NC=C(C=2C1=NC=CN=2)F Chemical class ClC1=NC=C(C=2C1=NC=CN=2)F USDIRSJFHPHMAS-UHFFFAOYSA-N 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
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- 238000006243 chemical reaction Methods 0.000 description 3
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- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229940127073 nucleoside analogue Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
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- 229920002261 Corn starch Polymers 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000014121 butter Nutrition 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
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- 230000010261 cell growth Effects 0.000 description 2
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- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
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- 238000001035 drying Methods 0.000 description 2
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- 235000011852 gelatine desserts Nutrition 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
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- 238000002844 melting Methods 0.000 description 2
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- 238000000034 method Methods 0.000 description 2
- 239000010446 mirabilite Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
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- 239000000843 powder Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- DDZGQYREBDXECY-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyrazine Chemical compound C1=CN=C2C=NNC2=N1 DDZGQYREBDXECY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 150000000845 D-ribose derivatives Chemical class 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
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- 229920001615 Tragacanth Polymers 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
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- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、下記一般式（１）
（ここで、Ｒはハロゲン原子、Ｒ′−〇−基又はＲ’−
ＮＨ−基を示し、Ｒ′はアルキル基、ベンジル基、フェ
ニル基又はフェニル基の１つ以上の水素原子がハロゲン
原子、アルキル基もしくはアルコキシ基で置換されたフ
ェニル基である。）で示されるヌクレオシド類似化合物
又はその塩。Detailed Description of the Invention [Industrial Application Field] The present invention relates to the following general formula (1) (where R is a halogen atom, an R'-〇- group, or an R'-
It represents an NH- group, and R' is an alkyl group, a benzyl group, a phenyl group, or a phenyl group in which one or more hydrogen atoms of the phenyl group are substituted with a halogen atom, an alkyl group, or an alkoxy group. ) or a salt thereof.
２、請求項１記載のヌクレオシド類似化合物又はその塩
を有効成分として官有する抗腫瘍剤。2. An antitumor agent containing the nucleoside analog compound or its salt according to claim 1 as an active ingredient.
（ここで、Ｒはハロゲン原子、Ｒ’−０−基又はＲ’−
ＮＨ−基を示し、Ｒ′はアルキル基、ベンジル基、フェ
ニル基又はフェニル基の１つ以上の水素原子がハロゲン
原子、アルキル基もしくはアルコキシ基で置換されたフ
ェニル基である。）で示される新規ヌクレオシド類似化
合物又はその塩及びこれらの化合物を有効成分とする抗
腫瘍剤に関する。(Here, R is a halogen atom, R'-0- group, or R'-
It represents an NH- group, and R' is an alkyl group, a benzyl group, a phenyl group, or a phenyl group in which one or more hydrogen atoms of the phenyl group are substituted with a halogen atom, an alkyl group, or an alkoxy group. ) and antitumor agents containing these compounds as active ingredients.
〔従来の技術及び発明が解決しようとする課題〕従来、
ＩＨ−ピラゾロ（３，４−ｂ）ピラジン誘導体のある種
のものが抗腫瘍作用を有し、これらが抗腫瘍剤として有
用であることが知られている（特開昭５８−１３５８８
７、特開昭５８−１８０４８５、特開昭５８−１８０４
８６、特開昭５９−６２５９２、特開昭６０−５６９８
１゜特開昭６０−１８１０１６、特開昭６０−１８１０
１７、特開昭６２−２７３９７９、特開昭６３−１７８
８２号公報）。[Problems to be solved by conventional techniques and inventions] Conventionally,
It is known that certain IH-pyrazolo(3,4-b) pyrazine derivatives have antitumor effects and are useful as antitumor agents (Japanese Patent Laid-Open No. 58-13588).
7, JP-A-58-180485, JP-A-58-1804
86, JP-A-59-62592, JP-A-60-5698
1゜Japanese Patent Publication No. 60-181016, Japanese Patent Application Publication No. 60-1810
17, JP-A-62-273979, JP-A-63-178
Publication No. 82).
しかし、優れた抗腫瘍活性を持ち、安全性が高く、抗腫
瘍剤として有効に使用できる物質の開発が更に要望され
ている。However, there is a further need for the development of substances that have excellent antitumor activity, are highly safe, and can be effectively used as antitumor agents.
〔課題を解決するための手段及び作用〕本発明者らは、
上記要望に応えるべく更に検討を続けた結果、５−置換
−ＩＨ−ピラゾロ〔３，４−ｂ）ピラジン誘導体にβ−
Ｄ−リボース誘導体を反応させることにより得られる物
質が抗腫瘍剤として有効であることを見い出した。[Means and effects for solving the problem] The present inventors,
As a result of further studies to meet the above request, we found that β-substituted -IH-pyrazolo[3,4-b) pyrazine derivatives
It has been found that a substance obtained by reacting a D-ribose derivative is effective as an antitumor agent.
即ち、下記一般式（２）
（ここで、Ｒはハロゲン原子、Ｒ′−〇−基又はＲ’−
ＮＨ−基を示し、Ｒ′はアルキル基、ベンジル基、フェ
ニル基又はフェニル基の１つ以上の水素原子がハロゲン
原子、アルキル基もしくはアルコキシ基で置換されたフ
ェニル基である。）で示される５−置換−ＩＨ−ピラゾ
ロＣ３，４−ｂ）ピラジン誘導体とβ−Ｄ−リボース誘
導体とを反応させることにより、下記一般式（１）（但
し、Ｒは上記と同じ意味を示す）
で示される新規ヌクレオシド類似化合物又はその塩が得
られると共に、この新規物質は後述する実施例に示した
ように優れた抗腫瘍作用を示し、しかもＬＤ、。も高く
、抗腫瘍剤として有効に使用し得ることを知見し、本発
明をなすに至ったものである。That is, the following general formula (2) (where R is a halogen atom, R'-〇- group, or R'-
It represents an NH- group, and R' is an alkyl group, a benzyl group, a phenyl group, or a phenyl group in which one or more hydrogen atoms of the phenyl group are substituted with a halogen atom, an alkyl group, or an alkoxy group. ) By reacting the 5-substituted-IH-pyrazoloC3,4-b) pyrazine derivative with the β-D-ribose derivative, the following general formula (1) (where R has the same meaning as above) can be obtained. ) A novel nucleoside-like compound or a salt thereof is obtained, and this new substance exhibits excellent antitumor activity as shown in the Examples below, and furthermore, LD. The present invention was based on the discovery that the compound has a high tumor resistance and can be effectively used as an antitumor agent.
以下、本発明につき更に詳しく説明する。The present invention will be explained in more detail below.
本発明に係る新規ヌクレオシド類似化合物は上述した（
１）式で示されるものである。ここで、（１）式におい
て、Ｒのハロゲン原子としては塩素原子、臭素原子など
が挙げられ、Ｒ′のアルキル基、アルコキシ基としては
炭素数１〜８のものなどが挙げられる。The novel nucleoside analogues of the present invention are as described above (
1) is shown by the formula. Here, in formula (1), examples of the halogen atom of R include a chlorine atom and a bromine atom, and examples of the alkyl group and alkoxy group of R' include those having 1 to 8 carbon atoms.
また、その塩としては、塩酸、硫酸等の無機塩。In addition, its salts include inorganic salts such as hydrochloric acid and sulfuric acid.
酢酸、クエン酸等の有機酸とで形成される塩が挙げられ
る。Examples include salts formed with organic acids such as acetic acid and citric acid.
上記のヌクレオシド類似化合物は、上述した（２）式の
５−＠換−ＩＨ−ピラゾロＣ３，４−ｂ〕ピラジン誘導
体にβ−Ｄ−リボース誘導体を化学的又は酵素的に縮合
反応させることにより合成することができる。The above nucleoside analogue compound is synthesized by chemically or enzymatically condensing a β-D-ribose derivative with the 5-@substituted-IH-pyrazoloC3,4-b] pyrazine derivative of the above-mentioned formula (2). can do.
この場合、β−Ｄ−リボース誘導体としては、例えば１
−酢酸−２，３，５−三安息香酸一β−Ｄ−リボフラノ
ース、１，２，３．５−四酢酸一β−Ｄ−リボフラノー
ス、１−臭化−２，３，５−三酢酸−β−Ｄ−リボフラ
ノースなどを用いることができ、このようにβ−Ｄ−リ
ボフラノールの水酸基が保護されたものを使用した場合
は、縮合反応後、水酸基の保護基を脱保護することがで
きる。In this case, as the β-D-ribose derivative, for example, 1
-2,3,5-tribenzoic acid monoβ-D-ribofuranose, 1,2,3,5-tetraacetic acid monoβ-D-ribofuranose, 1-2,3,5-tribromide Acetic acid-β-D-ribofuranose etc. can be used, and when β-D-ribofuranol with a protected hydroxyl group is used, the protecting group of the hydroxyl group must be deprotected after the condensation reaction. I can do it.
ここで、縮合反応は例えば以下の手順で行なうことがで
きる。Here, the condensation reaction can be carried out, for example, by the following procedure.
（１）５−置換−ＩＨ−ピラゾロ（３，４−ｂ）ピラジ
ン誘導体と２，４−ジニトロフェノールを反応容器内で
混合する。(1) A 5-substituted-IH-pyrazolo(3,4-b) pyrazine derivative and 2,4-dinitrophenol are mixed in a reaction vessel.
（２）上記混合物を１４０〜１４５℃の油浴を使って加
熱溶融する（時間は２０〜３０分程度）。(2) The above mixture is heated and melted using an oil bath at 140 to 145°C (for about 20 to 30 minutes).
（３） この混合物を油浴より取り出し放冷する（通
常、加熱溶融した混合物は固化する）。(3) This mixture is taken out of the oil bath and allowed to cool (usually, a heated and molten mixture solidifies).
（４）該混合物に所定量の１−酢酸−２，３，５三安息
香酸−β−Ｄ−リボフラノース等を加え。(4) Add a predetermined amount of 1-acetic acid-2,3,5-tribenzoic acid-β-D-ribofuranose, etc. to the mixture.
１４０〜１４５°Ｃの油浴中で２〜４時間撹拌下に加熱
し、縮合反応を行なう。The condensation reaction is carried out by heating in an oil bath at 140-145° C. for 2-4 hours with stirring.
（５）所定時間撹拌下に加熱反応させたものを放冷後、
クロロホルムに溶解し、クロロホルム層を５％Ｎ ａ
ＨＣ○、水溶液、飽和ＮａＣＱ水溶液で洗浄後、芒硝で
乾燥し、クロロホルムを減圧留去し、生成物を得る。(5) After heating and reacting with stirring for a predetermined period of time and cooling,
Dissolve in chloroform and add 5% Na to the chloroform layer.
After washing with HC○, aqueous solution, and saturated NaCQ aqueous solution, drying with Glauber's salt, and chloroform was distilled off under reduced pressure to obtain a product.
また、上記脱保護は常法に従って行なうことができ、塩
形成も常法に従うことができる。Moreover, the above-mentioned deprotection can be carried out according to a conventional method, and salt formation can also be carried out according to a conventional method.
本発明の新規ヌクレオシド類似化合物は優れた抗腫瘍活
性を有し、抗腫瘍剤として使用することができる。The novel nucleoside analogues of the present invention have excellent antitumor activity and can be used as antitumor agents.
この場合、この新規ヌクレオシド類似化合物を有効成分
とする抗腫瘍剤は、これを単独で又は必要により他の医
薬成分と併用して静脈内注射、皮下注射、筋肉内注射、
経口投与、廃剤による直腸投与等の方法で投与される。In this case, the antitumor agent containing this new nucleoside analog compound as an active ingredient can be administered by intravenous injection, subcutaneous injection, intramuscular injection, alone or in combination with other pharmaceutical ingredients if necessary.
It is administered by oral administration, rectal administration using waste medicine, etc.
その投与量は投与経路、投与回数等により異なり、また
症状の軽重などに依存して広範囲に変えることができる
が、−般には治療的有効投与量は１日当たり約１〜１０
■である。The dosage varies depending on the route of administration, the number of times of administration, etc., and can be varied over a wide range depending on the severity of the symptoms, etc., but in general, the therapeutically effective dosage is about 1 to 100 mg per day.
■It is.
本発明に係る抗腫瘍剤は、その製剤化に当たり、新規ヌ
クレオシド類似化合物の有効量に適当量の無毒性担体を
配合し、任意慣用の製剤方法を用いて投与用に調製する
ことができる。即ち、経口投与用に調製する場合は、軟
カプセル、硬カプセル、錠剤、顆粒剤、細粒剤、散剤、
有効成分持続的解放剤、液剤、懸濁剤等に調製され、非
経口投与する場合は、注射剤、点滴剤、座薬等に調製さ
れる。The antitumor agent according to the present invention can be formulated for administration by combining an effective amount of the novel nucleoside analog compound with an appropriate amount of non-toxic carrier and using any conventional formulation method. That is, when preparing for oral administration, soft capsules, hard capsules, tablets, granules, fine granules, powders,
The active ingredient is prepared into sustained release agents, solutions, suspensions, etc. For parenteral administration, it is prepared into injections, drips, suppositories, etc.
この場合、製剤化するに際しては、無毒性担体、例えば
アルコール、エステル類、ポリエチレングリコール誘導
体、ソルビタン脂肪酸エステル類、硫酸化脂肪アルコー
ル類等の界面活性剤、アラビヤガム、ゼラチン、ソルビ
ット、トラガカントガム、ポリビニルピロリドン等の結
合剤、蔗糖、乳糖、デンプン、結晶セルロース、マンニ
ット、軽質無水ケイ酸、アルミン酸マグネシウム、メタ
ケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウ
ム、炭酸カルシウム、炭酸水素ナトリウム。In this case, when formulating, non-toxic carriers such as alcohols, esters, polyethylene glycol derivatives, sorbitan fatty acid esters, surfactants such as sulfated fatty alcohols, gum arabic, gelatin, sorbitol, gum tragacanth, polyvinylpyrrolidone, etc. binder, sucrose, lactose, starch, crystalline cellulose, mannitol, light silicic anhydride, magnesium aluminate, magnesium aluminate metasilicate, synthetic aluminum silicate, calcium carbonate, sodium bicarbonate.
リン酸水素カルシウム、カルボキシメチルセルロースカ
ルシウム等の賦形剤、ステアリン酸マグネシウム、タル
ク、硬化油等の滑沢剤、食塩、サッカリン、オレンジ油
、カンゾウエキス、クエン酸。Excipients such as calcium hydrogen phosphate and calcium carboxymethyl cellulose, lubricants such as magnesium stearate, talc, and hydrogenated oil, salt, saccharin, orange oil, licorice extract, and citric acid.
ブドウ糖、メントール、ユーカリ油、リンゴ酸等の矯味
剤、矯臭剤、ココナツツ油、オリーブ油。Flavoring agents such as glucose, menthol, eucalyptus oil, malic acid, flavoring agents, coconut oil, and olive oil.
ゴマ油、落花生油、乳酸カルシウム、ベニバナ油。Sesame oil, peanut oil, calcium lactate, safflower oil.
大豆リン脂質等の懸濁剤、湿潤剤、酢酸フタル酸セルロ
ース（ＣＡＰ）などのセルロース、糖類等の炭水化物誘
導体、アクリル酸メチル・メタアクリル酸共重合体、メ
タアクリル酸メチル・メタアクリル酸共重合体などのア
クリル酸系共重合体、二塩基酸モノエステル類等のポリ
ビニル誘導体その他の皮膜形成剤、コーティング助剤な
どの成分を用いて慣用の方法で調製され、使用に供され
る。Suspending agents such as soybean phospholipids, wetting agents, cellulose such as cellulose acetate phthalate (CAP), carbohydrate derivatives such as sugars, methyl acrylate/methacrylic acid copolymer, methyl methacrylate/methacrylic acid copolymer It is prepared by a conventional method using components such as acrylic acid copolymers such as polymers, polyvinyl derivatives such as dibasic acid monoesters, other film forming agents, and coating aids, and is used.
なお、粘膜適用の製剤、特に廃剤を調製する場合には、
基剤としてカカオ脂、ラウリン脂、ポリエチレングリコ
ール、グリセロゼラチン、ステアリン酸ナトリウム又は
それらの混合物が用いられる。In addition, when preparing preparations for mucosal application, especially waste preparations,
Cocoa butter, lauric butter, polyethylene glycol, glycerogelatin, sodium stearate or mixtures thereof are used as bases.
更に、注射剤も慣用の方法によって調製されるが、注射
用蒸留水に懸濁或いは乳化させる方法を採用する場合は
、懸濁化剤として、ソルビットシロップ、メチルセルロ
ース、ゼラチン、ヒドロキシエチルセルロース、ステア
リン酸アルミニウムゲル等が使用でき、また乳化剤とし
てモノオレイン酸ソルビタン、ポリオキシエチレン硬化
ヒマシ油、レシチン等を使用できる。Furthermore, injections can be prepared by conventional methods, but when suspending or emulsifying in distilled water for injection is used, suspending agents such as sorbitol syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, and aluminum stearate may be used. Gels and the like can be used, and sorbitan monooleate, polyoxyethylene hydrogenated castor oil, lecithin, etc. can be used as emulsifiers.
本発明に係る新規ヌクレオシド類似化合物は、癌化細胞
の増殖を効果的に抑制し、優れた抗腫瘍作用を有するの
で、抗腫瘍剤として有用であり、この新規化合物を有効
成分とする抗腫瘍剤は、優れた抗腫瘍活性を有する上、
比較的低毒性であり、固型癌に対しても有効である。The novel nucleoside-like compound according to the present invention effectively suppresses the proliferation of cancerous cells and has excellent antitumor effects, and therefore is useful as an antitumor agent, and an antitumor agent containing this new compound as an active ingredient has excellent antitumor activity and
It has relatively low toxicity and is effective against solid cancers.
以下、実施例により本発明を更に具体的に説明する。Hereinafter, the present invention will be explained in more detail with reference to Examples.
ｌ１町
上記反応式に従い、第１表に示すＲ基を有する５−置換
−１°Ｈ−［：３．４−ｂ］ピラジン誘導体（２）に、
２，４−ジニトロフェノールの存在下、１−酢酸−２，
３，５−三安息香酸一β−Ｄ−リボフラノース（３）を
縮合反応させ、次いで、脱保護反応して、第１表に示す
目的物質（１）を合成した。According to the above reaction formula, to the 5-substituted-1°H-[:3.4-b] pyrazine derivative (2) having the R group shown in Table 1,
In the presence of 2,4-dinitrophenol, 1-acetic acid-2,
3,5-Tribenzoic acid monoβ-D-ribofuranose (3) was subjected to a condensation reaction and then deprotected to synthesize the target substance (1) shown in Table 1.
より具体的にその製造法を示すと、製造例１にあっては
下記の通りである。More specifically, the manufacturing method for Manufacturing Example 1 is as follows.
２．４−ジニトロフェノール９．１ｇに原料５−エトキ
シ−ＩＨ・ピラゾロ（３，４−ｂ）ピラジン１．６２ｇ
を加え、１４０〜１４５℃の油浴で加熱溶融する。この
混合物を冷却固化した後、該混合物に１＝酢酸−２，３
，５−三安息香酸一β−Ｄ−リボフラノース４．４ｇを
加え、１４０〜１４５℃の油浴で３時間撹拌下に加熱す
る。9.1 g of 2.4-dinitrophenol and 1.62 g of raw material 5-ethoxy-IH pyrazolo(3,4-b) pyrazine
and melt by heating in an oil bath at 140-145°C. After cooling and solidifying this mixture, 1=acetic acid-2,3
, 4.4 g of 5-tribenzoic acid monoβ-D-ribofuranose are added and heated in an oil bath at 140 to 145° C. for 3 hours with stirring.
冷却後、反応固化物をＣＨＣαユに溶解させ、ＣＨＣＩ
Ｉ、ｌを５％ＮａＨＣＯ３水溶液、飽和ＮａＣＱ水溶液
で洗浄し、芒硝で乾燥した後、ＣＨＣＱ３を減圧留去し
、粗生成物を得る。After cooling, the reaction solidified product was dissolved in CHCl
After washing I and I with a 5% aqueous NaHCO3 solution and a saturated aqueous NaCQ solution and drying over Glauber's salt, CHCQ3 is distilled off under reduced pressure to obtain a crude product.
本粗生成物をシリカゲルカラムクロマトグラフィで精製
し、５−エトキシ−１−（２，３，５−三安息香酸−β
−Ｄ−リボフラノシル）−１Ｈ−ピラゾロ（３，４−ｂ
〕ピラジンを得る（収量＝２．１ｇ）。This crude product was purified by silica gel column chromatography, and 5-ethoxy-1-(2,3,5-tribenzoic acid-β
-D-ribofuranosyl)-1H-pyrazolo(3,4-b
] Pyrazine is obtained (yield=2.1 g).
次に、この精製化合物１．０８ｇに無水メタノール５Ｉ
ｄを添加して溶解し、これに２８％ＣＨ。Next, 1.08 g of this purified compound was added with 5I of anhydrous methanol.
Add and dissolve d, and add 28% CH to this.
ＯＮ ａ ／ ＣＨ３０Ｈ０，３４ｇを無水メタノール
３ｄで希釈したものを添加し、室温で十分に撹拌して脱
保護反応を行なう。脱保護完了後、適当量のクロマトグ
ラフィ用シリカゲルを添加し、メタノールを減圧下に留
去する。残渣をシリカゲルカラムクロマトグラフィで精
製し、目的物５−エトキシ−１−（β−Ｄ−リボフラノ
シル）−ＬＨ−ピラゾロ（３，４−ｂ）ピラジンを得る
（収量：０．４５ｇ、収率：８５％；融点：１３０〜１
３１℃；無色粉末状結晶、アセトン−水より結晶化）。34 g of ON a / CH30H0 diluted with 3 d of anhydrous methanol is added, and the mixture is sufficiently stirred at room temperature to carry out a deprotection reaction. After completion of deprotection, an appropriate amount of chromatographic silica gel is added, and methanol is distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target product 5-ethoxy-1-(β-D-ribofuranosyl)-LH-pyrazolo(3,4-b)pyrazine (yield: 0.45 g, yield: 85% ; Melting point: 130-1
31°C; colorless powder crystals, crystallized from acetone-water).
また、他の目的物質も上記と同様の方法で合成を行なっ
た。In addition, other target substances were synthesized in the same manner as above.
第１表に得られた目的化合物とその収率、形態。Table 1 shows the target compounds obtained, their yields, and forms.
融点を示し、第２表に各目的化合物のＮＭＲ。Melting points are shown, and Table 2 shows NMR of each target compound.
ＩＲの測定結果を示す。IR measurement results are shown.
腫 効 及びＬＤ、の」−
培養液として１０％の牛の胎児血清と５０１！ｇ／−の
カナマイシンを含むＲＰＭニー１６４０を用い、これに
１．０Ｘ１０”個／＋ｄのマウス白血病癌細胞Ｌ１．２
１０を添加したものにサンプル（製造例１〜１４の化合
物）を１００Ａ／−になるように加え、５％炭酸ガスを
含む空気中で４８時間培養した後、生存癌細胞数を測定
し、コントロールと比較して下記式より各サンプルの癌
細胞増殖抑制率を調べた。なお、コントロールはサンプ
ル無添加の結果である。Tumor effect and LD, - 10% fetal bovine serum as culture medium and 501! Using RPM Nee 1640 containing g/- of kanamycin, 1.0 x 10''/+d mouse leukemia cancer cells L1.2 were added.
Samples (compounds of Preparation Examples 1 to 14) were added to 100A/- to a sample containing 100A/-, and after culturing in air containing 5% carbon dioxide for 48 hours, the number of viable cancer cells was measured, and the control The cancer cell growth inhibition rate of each sample was investigated using the following formula. Note that the control is the result with no sample added.
また、上記製造例１〜１４の化合物につき、マウス（ｉ
ｐ）におけるＬＤ、。値を調べた。In addition, for the compounds of Production Examples 1 to 14 above, mouse (i
LD in p). I checked the value.
結果を第３表に示す。The results are shown in Table 3.
癌細胞増殖抑制率（％）＝へ二ｕｘ１ｏ。Cancer cell growth inhibition rate (%)=He2ux1o.
Ａ：コントロールの平均生存細胞数
Ｂ：試験群の平均生存細胞数
第
表
（１）錠剤
製造例３の化合物 ２００ｇトウモロコシデ
ンプン １５０ｇタルク
８０ｇステアリン酸マグネシウム ３０ｇ上記
各成分を混和し、６ｏメツシユの金網を通過せしめて粒
度を調整した後、打錠機を用いて１０００個の錠剤を製
造する（１日当たり１〜３錠を経口的に投与する）。A: Average number of viable cells in control B: Average number of viable cells in test group Table (1) Compound of Tablet Production Example 3 200g corn starch 150g talc
80g Magnesium stearate 30g The above ingredients are mixed and passed through a 6O mesh wire gauze to adjust the particle size, and then 1000 tablets are manufactured using a tablet press (1 to 3 tablets are taken orally per day). Administer).
（２）カプセル剤
製造例５の化合物 ２００ｇ乳糖
５０ｇ
トウモロコシデンプン ３０ｇステアリン酸マ
グネシウム ５ｇ上記成分を混和し、６ｏメツシ
ユの金網を通過せしめて粒度を調整した後、１０００個
のゼラチンカプセルに充填する（１日当たり１〜３カプ
セルを経口的に投与する）。(2) Compound of Capsule Production Example 5 200g lactose
50g corn starch 30g magnesium stearate 5g The above ingredients are mixed and passed through a 6o mesh wire mesh to adjust the particle size, then filled into 1000 gelatin capsules (1 to 3 capsules are administered orally per day). .
（３）カプセル剤
製造例７の化合物 １８０ｇ無水ケイ酸
６０ｇステアリン酸マグネシウム
５ｇ製造例７の化合物をアセトンに溶解し、無水ケ
イ酸を加えて分散した後、アセトンを留去し、粒状化す
る。この粒子にステアリン酸マグネシウムを加えて十分
に混合して滑らかにし、６０メツシユの金網を通過せし
めて粒度を調整した後、１０００個のゼラチンカプセル
に充填する。(3) Compound of Capsule Production Example 7 180g silicic anhydride
60g magnesium stearate
5g of the compound of Production Example 7 is dissolved in acetone, silicic anhydride is added and dispersed, and then the acetone is distilled off and granulated. Magnesium stearate is added to the particles, thoroughly mixed to make them smooth, passed through a 60-mesh wire gauze to adjust the particle size, and then filled into 1000 gelatin capsules.
（４）原剤
製造例１３の化合物 １４０ｇカカオ脂
１２００ｇカカオ脂を５０℃に加熱して溶
解し、これに製造例１３の化合物を添加して均一にし、
次いでコンテナーの中に流し込み、冷却固化させて原剤
１０ｏＯ個を製造する。(4) Compound of Raw Material Production Example 13 140g cacao butter
1200g of cocoa butter was heated to 50°C and dissolved, and the compound of Production Example 13 was added thereto to make it homogeneous.
Then, the mixture is poured into a container and cooled and solidified to produce 10000 pieces of the raw material.
（５）注射剤
製造例１の化合物 ４０ｇ
標準生理食塩水 全量１０Ａ
上記比率に従って常法により注射剤を調製し、１アンプ
ル２−ずつ充填する。(5) Compound of Injection Preparation Example 1 40g Standard physiological saline Total amount 10A An injection is prepared by a conventional method according to the above ratio, and 2 ampules are filled into each ampoule.
（６）注射剤
製造例１ｏの化合物 ４０ｇポリオキシ
エチレン硬化ヒマシ油 ５Ｑｇ注射用蒸留水
全量１０Ｑ上記の処方に従い、常法により注
射剤を調製し、１アンプル２ｍＱずつ充填する。(6) Compound of Injection Production Example 1o 40g polyoxyethylene hydrogenated castor oil 5Qg distilled water for injection
Total amount: 10Q In accordance with the above prescription, prepare an injection by a conventional method and fill each ampoule with 2 mQ.
Claims (1)
ＮＨ−基を示し、Ｒ’はアルキル基、ベンジル基、フェ
ニル基又はフェニル基の１つ以上の水素原子がハロゲン
原子、アルキル基もしくはアルコキシ基で置換されたフ
ェニル基である。）で示されるヌクレオシド類似化合物
又はその塩。 ２、請求項１記載のヌクレオシド類似化合物又はその塩
を有効成分として含有する抗腫瘍剤。[Claims] 1. General formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼... (1) (Here, R is a halogen atom, an R'-O- group, or an R'-
It represents an NH- group, and R' is an alkyl group, a benzyl group, a phenyl group, or a phenyl group in which one or more hydrogen atoms of the phenyl group are substituted with a halogen atom, an alkyl group, or an alkoxy group. ) or a salt thereof. 2. An antitumor agent containing the nucleoside analog compound or its salt according to claim 1 as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16040388A JPH029895A (en) | 1988-06-28 | 1988-06-28 | Nucleoside analog compound and antitumor agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16040388A JPH029895A (en) | 1988-06-28 | 1988-06-28 | Nucleoside analog compound and antitumor agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH029895A true JPH029895A (en) | 1990-01-12 |
Family
ID=15714186
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16040388A Pending JPH029895A (en) | 1988-06-28 | 1988-06-28 | Nucleoside analog compound and antitumor agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH029895A (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06126362A (en) * | 1992-10-15 | 1994-05-10 | Hiraoka Kinzoku Kogyo Kk | Device for supporting reinforcing bar cage |
| US5617376A (en) * | 1992-12-02 | 1997-04-01 | Seiko Epson Corporation | Gear train structure of an electronic watch |
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| US9801889B2 (en) | 2015-02-20 | 2017-10-31 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US9890156B2 (en) | 2015-02-20 | 2018-02-13 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US10040790B2 (en) | 2013-04-19 | 2018-08-07 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
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| US10611762B2 (en) | 2017-05-26 | 2020-04-07 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
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| US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
| US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
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-
1988
- 1988-06-28 JP JP16040388A patent/JPH029895A/en active Pending
Cited By (34)
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|---|---|---|---|---|
| JPH06126362A (en) * | 1992-10-15 | 1994-05-10 | Hiraoka Kinzoku Kogyo Kk | Device for supporting reinforcing bar cage |
| US5617376A (en) * | 1992-12-02 | 1997-04-01 | Seiko Epson Corporation | Gear train structure of an electronic watch |
| US10813930B2 (en) | 2010-12-22 | 2020-10-27 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
| US10213427B2 (en) | 2010-12-22 | 2019-02-26 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
| US11053246B2 (en) | 2012-06-13 | 2021-07-06 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
| US10131667B2 (en) | 2012-06-13 | 2018-11-20 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
| US11840534B2 (en) | 2012-06-13 | 2023-12-12 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
| US9611267B2 (en) | 2012-06-13 | 2017-04-04 | Incyte Holdings Corporation | Substituted tricyclic compounds as FGFR inhibitors |
| US9745311B2 (en) | 2012-08-10 | 2017-08-29 | Incyte Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
| US11530214B2 (en) | 2013-04-19 | 2022-12-20 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
| US10947230B2 (en) | 2013-04-19 | 2021-03-16 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| US10040790B2 (en) | 2013-04-19 | 2018-08-07 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
| US10450313B2 (en) | 2013-04-19 | 2019-10-22 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US10738048B2 (en) | 2015-02-20 | 2020-08-11 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US9801889B2 (en) | 2015-02-20 | 2017-10-31 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US9708318B2 (en) | 2015-02-20 | 2017-07-18 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
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| US11014923B2 (en) | 2015-02-20 | 2021-05-25 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US9890156B2 (en) | 2015-02-20 | 2018-02-13 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US11173162B2 (en) | 2015-02-20 | 2021-11-16 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US11667635B2 (en) | 2015-02-20 | 2023-06-06 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US10632126B2 (en) | 2015-02-20 | 2020-04-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| US11472801B2 (en) | 2017-05-26 | 2022-10-18 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
| US10611762B2 (en) | 2017-05-26 | 2020-04-07 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
| US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
| US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
| US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
| US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| US11407750B2 (en) | 2019-12-04 | 2022-08-09 | Incyte Corporation | Derivatives of an FGFR inhibitor |
| US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
| US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
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