JP4425906B2 - ４−ヒドロキシカルバモイルフェニル）−カルバミン酸（６−ジエチルアミノメチル−ナフタレン−２−イル）エステルの塩酸一水和物 - Google Patents
４−ヒドロキシカルバモイルフェニル）−カルバミン酸（６−ジエチルアミノメチル−ナフタレン−２−イル）エステルの塩酸一水和物 Download PDFInfo
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- diethylaminomethyl
- naphthalen
- hydroxycarbamoylphenyl
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- hydrochloric acid
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- -1 4-hydroxycarbamoylphenyl Chemical group 0.000 title claims description 5
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 title claims description 4
- 150000002148 esters Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 8
- ANKMYKYGSGDNSG-UHFFFAOYSA-N [4-(hydroxycarbamoyl)phenyl]carbamic acid Chemical compound ONC(=O)C1=CC=C(NC(O)=O)C=C1 ANKMYKYGSGDNSG-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 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
- 239000002904 solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 2
- NCHVNKHIEHGHEU-UHFFFAOYSA-N 4-[[6-(diethylaminomethyl)naphthalen-2-yl]methoxycarbonylamino]benzoic acid Chemical compound C1=CC2=CC(CN(CC)CC)=CC=C2C=C1COC(=O)NC1=CC=C(C(O)=O)C=C1 NCHVNKHIEHGHEU-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- QKSGNWJOQMSBEP-UHFFFAOYSA-N diethyl-[[6-[[4-(hydroxycarbamoyl)phenyl]carbamoyloxymethyl]naphthalen-2-yl]methyl]azanium;chloride Chemical compound [Cl-].C1=CC2=CC(C[NH+](CC)CC)=CC=C2C=C1COC(=O)NC1=CC=C(C(=O)NO)C=C1 QKSGNWJOQMSBEP-UHFFFAOYSA-N 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000947 anti-immunosuppressive effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000007416 differential thermogravimetric analysis Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、抗炎症活性を有するヒドロキサム酸の誘導体に関する。
従来技術
（４−ヒドロキシカルバモイルフェニル）−カルバミン酸の（６−ジエチルアミノメチル−ナフタレン−２−イル）−メチルエステルの塩酸塩（ＩＩ）
（４−ヒドロキシカルバモイルフェニル）−カルバミン酸の（６−ジエチルアミノメチル−ナフタレン−２−イル）−メチルエステルの塩酸塩（ＩＩ）
は、恐らく前炎症性サイトカインの生産を阻害するそれらの能力により抗炎症および免疫抑制活性を有するヒドロキサム酸の誘導体として特許文献１に記載された。この化合物は上記特許明細書の実施例１２に従い、取り扱いが難しい無水の、非晶質、吸湿性、潮解性固体として得られる。
[参考文献]
[参考文献]
発明の提示
本発明の主題は、結晶状の（４−ヒドロキシカルバモイルフェニル）−カルバミン酸の（６−ジエチルアミノメチル−ナフタレン−２−イル）−メチルエステルの塩酸一水和物（Ｉ）である。
本発明の主題は、結晶状の（４−ヒドロキシカルバモイルフェニル）−カルバミン酸の（６−ジエチルアミノメチル−ナフタレン−２−イル）−メチルエステルの塩酸一水和物（Ｉ）である。
この形態は上記の無水かつ非晶質形よりも安定で、しかも取り扱いが簡単であるので、工業的観点から特に有利である。
一水和物（Ｉ）は以下の工程を含んでなる方法により得られる：
ａ）４−（６−ジエチルアミノメチル−ナフタレン−２−イルメトキシカルボニルアミノ）安息香酸と塩化チオニルを、溶媒としてテトラヒドロフラン中で反応させて対応する酸クロライドを提供し；
ｂ）酸クロライドを、溶媒としてテトラヒドロフラン中のヒドロキシルアミン水溶液と反応させ、そして塩酸を加えることにより塩酸塩を沈殿させ；
ｃ）前記工程で得られた塩酸塩を重炭酸ナトリウムの溶液に溶解し；
ｄ）溶液をテトラヒドロフランおよび酢酸エチルの混合物で抽出し；
ｅ）３７％ＨＣｌの添加により塩酸一水和物を沈殿させる。
ａ）４−（６−ジエチルアミノメチル−ナフタレン−２−イルメトキシカルボニルアミノ）安息香酸と塩化チオニルを、溶媒としてテトラヒドロフラン中で反応させて対応する酸クロライドを提供し；
ｂ）酸クロライドを、溶媒としてテトラヒドロフラン中のヒドロキシルアミン水溶液と反応させ、そして塩酸を加えることにより塩酸塩を沈殿させ；
ｃ）前記工程で得られた塩酸塩を重炭酸ナトリウムの溶液に溶解し；
ｄ）溶液をテトラヒドロフランおよび酢酸エチルの混合物で抽出し；
ｅ）３７％ＨＣｌの添加により塩酸一水和物を沈殿させる。
溶媒和水の存在はＤＳＣ分析により確認され、この分析は８０から１２０℃の間に脱溶媒和の吸熱を示し（図１）、そして熱重量分析により（図２）、４０から１２０℃の間の温度で結晶化溶媒の損失による３．３％の損失を示す。この生成物の結晶形はＸ−線分析により確認される（図３）。
本発明はさらに式（Ｉ）の化合物を含む製薬学的組成物に関する；これらの組成物はカプセル、ピル、コートピル、クリーム、軟膏または経口、筋肉内もしくは静脈内投与用のバイアルの形態であることができる。
式（Ｉ）の化合物は単独で、または通常の担体もしくは賦形剤、例えばレミングトンの製薬科学ハンドブック（Ｒｅｍｉｎｇｔｏｎ’ｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅｓ Ｈａｎｄｂｏｏｋ）、第ＸＶＩＩ版、メルク出版、ニューヨーク、米国に記載されているものとの混合物で含まれる。
これから本発明を以下の実施例を参照にしてさらに詳細に説明する。
材料および方法
示差走査熱量分析（ＤＳＣ）および熱重量分析（ＴＧＡ）は、セルＤＳＣ８２１／７００を備えたＭｅｔｔｌｅｒ ＴＡ８０００装置を用い、そしてＴＧ５０サーモバランスにより以下の条件下で行った：
−ガス：窒素２０〜３０ｍｌ／分；
−容器：アルミニウム製の開放カプセル；
−加熱速度：１０℃／分；
−「スターシステム（Ｓｔａｒ Ｓｙｓｔｅｍ）」ソフトウェアによる熱反応の評価。
示差走査熱量分析（ＤＳＣ）および熱重量分析（ＴＧＡ）は、セルＤＳＣ８２１／７００を備えたＭｅｔｔｌｅｒ ＴＡ８０００装置を用い、そしてＴＧ５０サーモバランスにより以下の条件下で行った：
−ガス：窒素２０〜３０ｍｌ／分；
−容器：アルミニウム製の開放カプセル；
−加熱速度：１０℃／分；
−「スターシステム（Ｓｔａｒ Ｓｙｓｔｅｍ）」ソフトウェアによる熱反応の評価。
４−（６−ジエチルアミノメチル−ナフタレン−２−イルメトキシカルボニルアミノ）安息香酸は、米国特許第６，０３４，０９６号明細書の実施例１２、ポイントＣに記載されているように調製することができる。
酸（１．２２ｋｇ、３モル）をＴＨＦ（１９リットル）に懸濁し、そして混合物を窒素下で周辺温度にて一晩、撹拌した。次いで混合物を０℃に冷却し、そして塩化チオニル（０．６５７リットル、９モル）をさらに窒素下でゆっくりと加え、温度を１０℃未満に維持した。反応混合物を６０分間、加熱還流し、ＤＭＦ（２６ｍｌ）を加え、そして混合物をさらに６０分間、加熱還流した。
溶媒は真空下で蒸発させ、残渣にトルエンを加え、そして蒸発させた。この操作を２回繰り返し、次いで残渣をＴＨＦ（１１．５リットル）に懸濁し、そして混合物を０℃に冷却した。
次いで混合物を５．７リットルの水中のヒドロキシルアミンの冷溶液（５０％水性、１．６リットル、２６４モル）に注いだ。次いで混合物を周囲温度に冷却し、そして３０分間撹拌した。６Ｍ ＨＣｌをｐＨ２に達するまで加え、そしてほとんどのＴＨＦを排除するために混合物を真空下で部分的に蒸発させた。固体を濾過し、水で繰り返し洗浄し、そして重炭酸ナトリウムの溶液（２．５％、１２．２リットル）に溶解した。溶液はＴＨＦおよび酢酸エチルの１８．６リットルの混合物（２：１容量／容量）で抽出した。（４−ヒドロキシカルバモイル−フェニル）−カルバミン酸の（６−ジエチルアミノメチル−ナフタレン−２−イル）−メチルエステル塩酸塩の一水和物を沈殿させるために、３７％ＨＣｌ（１３０ｍｌ）を有機層に加えた。必要ならば、この操作を数回繰り返して元の酸の残渣を除去することができる。
最終的に固体を真空下で乾燥させて（約３０ｍｂａｒ、５０℃）、０．８５ｋｇ（６０％）の化合物（Ｉ）を得た。
ＨＰＬＣ純度：９９．５％；水分含量（カールフィッシャー法）：３．８％；（銀）アッセイ：９９．８％。
Claims (2)
- 結晶状の式（Ｉ）
- 請求項１に記載の化合物を含む製薬学的組成物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000063A ITMI20030063A1 (it) | 2003-01-17 | 2003-01-17 | Cloridrato monoidrato dell'estere (6-dietilamminometil-naftalen-2-il)metilico dell'acido (4-idrossicarbammoil-fenil)carbammico. |
| PCT/IT2004/000003 WO2004065355A1 (en) | 2003-01-17 | 2004-01-08 | Monohydrate hydrochloride of the 4-hydroxycarbamoyl-phenyl)-carbamic acid (6-diethylaminomethyl-naphtalen-2-yl) ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2006515028A JP2006515028A (ja) | 2006-05-18 |
| JP4425906B2 true JP4425906B2 (ja) | 2010-03-03 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2006500386A Expired - Lifetime JP4425906B2 (ja) | 2003-01-17 | 2004-01-08 | ４−ヒドロキシカルバモイルフェニル）−カルバミン酸（６−ジエチルアミノメチル−ナフタレン−２−イル）エステルの塩酸一水和物 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US7329689B2 (ja) |
| EP (1) | EP1583737B1 (ja) |
| JP (1) | JP4425906B2 (ja) |
| ES (1) | ES2372280T3 (ja) |
| IT (1) | ITMI20030063A1 (ja) |
| WO (1) | WO2004065355A1 (ja) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| IT1392908B1 (it) * | 2008-09-29 | 2012-04-02 | Italfarmaco Spa | Uso degli inibitori delle istone-deacetilasi per la cura di sindromi mieloproliferative philadelphia-negative |
| IT1396915B1 (it) | 2009-10-23 | 2012-12-20 | Italfarmaco Spa | Dietil-[6-(4-idrossicarbamoil-fenil-carbamoilossimetil)-naftalen-2-il-metil]-ammonio cloruro ed altri derivati della n-idrossi-benzammide per l'uso nel trattamento di infezioni da hiv. |
| IT1397912B1 (it) * | 2010-01-28 | 2013-02-04 | Chemi Spa | Nuovo polimorfo dell'estere 6-dietilamminometil-2-naftilico dell'acido 4-idrossicarbamoil-fenil-carbammico cloridrato. |
| US8217079B2 (en) | 2010-03-26 | 2012-07-10 | Italfarmaco Spa | Method for treating Philadelphia-negative myeloproliferative syndromes |
| CN104093403A (zh) | 2012-02-03 | 2014-10-08 | 意大发马克股份公司 | 用于治疗肌肉萎缩症的二乙基-[6-(4-羟基氨基甲酰基-苯基-氨基甲酰氧基-甲基)-萘-2-基-甲基]-氯化铵 |
| ITUB20155193A1 (it) * | 2015-11-03 | 2017-05-03 | Italfarmaco Spa | Sospensioni orali di Givinostat fisicamente e chimicamente stabili |
| WO2018054960A1 (en) | 2016-09-21 | 2018-03-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting and treating resistance to chemotherapy in npm-alk(+) alcl |
| IT201900003281A1 (it) * | 2019-03-06 | 2020-09-06 | Chemi Spa | Processo per preparare {6-[(dietilammino)metil]naftalen-2-il}metil [4-(idrossicarbamoil)fenil]carbammato ad elevata purezza |
| WO2022088047A1 (zh) * | 2020-10-30 | 2022-05-05 | 中国科学院深圳先进技术研究院 | Itf2357在制备预防和治疗冠状病毒的药物中的应用 |
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|---|---|---|---|---|
| IT1283637B1 (it) * | 1996-05-14 | 1998-04-23 | Italfarmaco Spa | Composti ad attivita' antinfiammatoria ed immunosoppressiva |
-
2003
- 2003-01-17 IT IT000063A patent/ITMI20030063A1/it unknown
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2004
- 2004-01-08 ES ES04700754T patent/ES2372280T3/es not_active Expired - Lifetime
- 2004-01-08 EP EP04700754A patent/EP1583737B1/en not_active Expired - Lifetime
- 2004-01-08 WO PCT/IT2004/000003 patent/WO2004065355A1/en active Application Filing
- 2004-01-08 JP JP2006500386A patent/JP4425906B2/ja not_active Expired - Lifetime
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2005
- 2005-06-10 US US11/149,548 patent/US7329689B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US20050245604A1 (en) | 2005-11-03 |
| EP1583737A1 (en) | 2005-10-12 |
| WO2004065355A1 (en) | 2004-08-05 |
| EP1583737B1 (en) | 2011-08-24 |
| JP2006515028A (ja) | 2006-05-18 |
| ITMI20030063A1 (it) | 2004-07-18 |
| ES2372280T3 (es) | 2012-01-18 |
| US7329689B2 (en) | 2008-02-12 |
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