JP7393348B2 - (1-(3-フルオロ-2(トリフルオロメチル)イソニコチニル)ピぺリジン―4-オン)を作製するためのプロセス及び中間体 - Google Patents
(1-(3-フルオロ-2(トリフルオロメチル)イソニコチニル)ピぺリジン―4-オン)を作製するためのプロセス及び中間体 Download PDFInfo
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- JP7393348B2 JP7393348B2 JP2020562089A JP2020562089A JP7393348B2 JP 7393348 B2 JP7393348 B2 JP 7393348B2 JP 2020562089 A JP2020562089 A JP 2020562089A JP 2020562089 A JP2020562089 A JP 2020562089A JP 7393348 B2 JP7393348 B2 JP 7393348B2
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- 229940049954 penicillin Drugs 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical compound Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000007112 pro inflammatory response Effects 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 208000005631 pseudoachondroplasia Diseases 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 235000009736 ragweed Nutrition 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000009996 subepithelial mucinous corneal dystrophy Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000004489 tear production Effects 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
式中、Z1はHまたは保護基である。
本発明は、とりわけ、式Iの化合物を作製するためのプロセス及び中間体を提供する。したがって、一態様において、式IIIの化合物:
式中、Z1はHまたは保護基である。
式中、Z1はHまたは保護基である。
式Iの化合物である{1-{1-[3-フルオロ-2-(トリフルオロメチル)イソニコチノイル]ピペリジン-4-イル}-3-[4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)-1H-ピラゾール-1-イル]アゼチジン-3-イル}アセトニトリルは、JAK(例えばJAK1、JAK2)の阻害物質である。JAK阻害物質は、様々なJAK関連の疾患または障害の治療において有用である。JAK関連疾患の例としては、例えば移植臓器拒絶(例えば同種異系移植片拒絶及び移植片対宿主病)を包含する、免疫系に関与する疾患が挙げられる。JAK関連疾患のさらなる例としては、多発性硬化症、関節リウマチ、若年性関節炎、乾癬性関節炎、1型糖尿病、狼瘡、乾癬、炎症性大腸疾患、潰瘍性大腸炎、クローン病、重症筋無力症、免疫グロブリンA腎症、心筋炎、自己免疫性甲状腺疾患、慢性閉塞性肺疾患(COPD)、及び同種のもの等の自己免疫疾患が挙げられる。いくつかの実施形態において、自己免疫疾患は、尋常性天疱瘡(PV)または水疱性類天疱瘡(BP)等の自己免疫性水疱性皮膚障害である。
スキームI
スキームII
スキームIII
スキームIV
スキームV
スキームVI
スキームVII
スキームVIII
スキームIX
式Iの化合物を、Park et al.,Analytical Biochemistry 1999,269,94-104中で記載される以下のインビトロアッセイに従って、JAK標的の阻害活性について試験した。N末端Hisタグを備えたヒトJAK1(アミノ酸837~1142)及びJAK2(アミノ酸828~1132)の触媒ドメインを、昆虫細胞中でバキュロウイルスを使用して発現させ、精製した。JAK1及びJAK2の触媒活性を、ビオチン化ペプチドのリン酸化の測定によってアッセイした。リン酸化ペプチドを均一系時間分解蛍光(HTRF)によって検出した。100mMのNaCl、5mMのDTT及び0.1mg/mL(0.01%)のBSAを含む50mMのトリス(pH7.8)バッファー中の、酵素、ATP及び500nMのペプチドを含む40μLの反応物において、各々のキナーゼについて化合物のIC50を測定した。1mMのIC50測定について、反応中のATP濃度は1mMであった。反応を室温で1時間実行し、次いで20μLのアッセイバッファー(Perkin Elmer、Boston、MA)中の、45mMのEDTA、300nMのSA-APC、6nMのEu-Py20により停止した。ユウロピウム標識抗体への結合を40分間行い、HTRFシグナルをFusionプレートリーダー(Perkin Elmer、Boston、MA)上で測定した。式Iの化合物及びアジピン酸塩は≦5nMのJAK1でIC50を有し(1mMのATPで測定した)、>10のJAK2/JAK1比であった(1mMのATPで測定した)。
増殖についてサイトカイン及びしたがってJAK/STATシグナル形質導入に依存する癌細胞株は、RPMI 1640、10%のFBS、及び1nG/mLの適切なサイトカイン中で1ウェル(96ウェルプレートフォーマット)あたり6000細胞でプレーティングすることができる。化合物をDMSO/培地(0.2%のDMSOの最終濃度)中で細胞へ添加し、37℃、5%のCO2で72時間インキュベーションすることができる。細胞生存率に対する化合物の効果を、CellTiter-Glo Luminescent Cell Viability Assay(Promega)、続いてTopCount(Perkin Elmer、Boston、MA)の定量を使用して査定する。化合物の可能性のあるオフターゲット効果を、非JAK駆動性の細胞株を使用して、同じアッセイのリードアウトにより並列して測定する。すべての実験を典型的には二重で遂行する。
本明細書における化合物は、免疫不全マウス中のヒト腫瘍異種移植モデルにおいて評価することができる。例えば、INA-6形質細胞腫細胞株の腫瘍形成性バリアントを使用して、SCIDマウスに皮下接種することができる(Burger,R.,et al.Hematol J.2:42-53,2001)。次いで担がん動物を薬物処置群またはベヒクル処置群へと無作為化し、異なる用量の化合物を、経口、腹腔内、または植込み可能なポンプを使用する連続点滴を含む、いくつかの通常の経路によって投与することができる。腫瘍増殖を、キャリパーを使用して経時的に追跡する。さらに、上で記載されるような分析(実施例B)のために、腫瘍サンプルを処理の開始後の任意の時間で収穫して、JAK活性及び下流のシグナル経路に対する化合物効果を評価することができる。加えて、化合物(複数可)の選択性を、他の公知のキナーゼ(例えばBcr-Abl)によって駆動される、K562腫瘍モデル等の異種移植腫瘍モデルを使用して査定することができる。
本明細書における化合物を、T細胞駆動性のマウスの遅延型過敏性の試験モデルにおける(JAK標的の阻害の)有効性についても試験することができる。マウスの皮膚接触遅延型過敏性(DTH)応答は、臨床的な接触性皮膚炎、及び乾癬等の他のTリンパ球媒介性の皮膚の免疫障害の有効なモデルであるとみなされている(Immunol Today.1998 Jan;19(1):37-44)。マウスのDTHは、免疫浸潤、炎症性サイトカインの付随する増加、及びケラチノサイト過剰増殖を含む、複数の特徴を乾癬と共有している。さらに、クリニックでの乾癬の治療において有効な多くのクラスの薬剤が、マウスにおけるDTH応答の有効な阻害物質でもある(Agents Actions.1993 Jan;38(1-2):116-21)。
本明細書における化合物は、単一または複雑な炎症応答を再現するように設計された齧歯動物モデルまたは非齧歯動物モデルにおいて評価することができる。例えば、関節炎の齧歯類モデルを使用して、予防的にまたは治療的に投薬した化合物の処置可能性を評価することができる。これらのモデルとしては、マウスまたはラットのコラーゲン誘発関節炎、ラットのアジュバント誘発関節炎、及びコラーゲン抗体誘発関節炎が挙げられるがこれらに限定されない。多発性硬化症、1型糖尿病、ぶどう膜網膜炎、甲状腺炎、重症筋無力症、免疫グロブリン腎症、心筋炎、気道感作(喘息)、狼瘡または大腸炎が挙げられるがこれらに限定されない自己免疫疾患を使用して、本明細書における化合物の治療可能性を評価することができる。これらのモデルは研究コミュニティーにおいて十分に確立されており、当業者は精通している(Current Protocols in Immunology,Vol 3.,Coligan,J.E.et al,Wiley Press.、Methods in Molecular Biology:Vol.225,Inflammation Protocols.,Winyard,P.G.and Willoughby,D.A.,Humana Press,2003.)。
薬剤は、ウサギのコンカナバリンA(ConA)涙腺モデル、マウスのスコポラミンモデル(皮下または経皮)、マウスのBotulinumn涙腺モデル、または眼腺機能不全をもたらすいくつかの自然発生する齧歯類自己免疫モデル(例えばNOD-SCID、MRL/lprまたはNZB/NZW)のいずれかが挙げられるがこれらに限定されない、1つまたは複数の当業者に公知のドライアイの前臨床モデルにおいて評価することができる(Barabino et al.,Experimental Eye Research 2004,79,613-621及びSchrader et al.,Developmental Opthalmology,Karger 2008,41,298-312、その各々の全体は参照により本明細書に援用される)。これらのモデルにおけるエンドポイントとしては、眼腺及び眼(角膜など)の組織病理学、ならびに場合によっては涙液産生を測定する古典的Schirmer試験またはその修飾バージョン(Barabino et al.)が挙げられ得る。活性は、複数の投与経路(例えば全身的または局所的)を経由して投薬することによって査定することができ、それは測定可能な疾患が存在する前またはその後に開始することができる。
化合物は、骨減少症、骨粗鬆症、または当業者に公知の骨吸収の様々な前臨床モデルにおいて評価することができる。例えば、卵巣切除歯動物を使用して、化合物が骨の再形成及び/または密度の徴候及びマーカーに影響する能力を評価することができる(W.S.S.Jee and W.Yao,J Musculoskel.Nueron.Interact.,2001,1(3),193-207、その全体は参照により本明細書に援用される)。あるいは、骨の密度及び構造を、コントロールまたは化合物により処置した、治療(例えばグルココルチコイド)誘発骨減少症のモデルにおける齧歯動物で評価することができる(Yao,et al.Arthritis and Rheumatism,2008,58(6),3485-3497、及び同上58(11),1674-1686、その両方の全体は参照することによって本明細書に援用される)。加えて、骨の吸収及び密度に対する化合物の効果は、上で考察された関節炎の齧歯類のモデル(実施例E)において評価することができる。これらのすべてのモデルについてのエンドポイントは、変化し得るが、多くの場合、組織学的査定及び放射線学的査定に加えて、骨再形成の免疫組織学及び適切な生化学的マーカーを含み得る。
Claims (27)
- 式IIIの化合物:
- 前記4-ヒドロキシピペリジンとの反応が、塩基の存在下において遂行される、請求項1に記載のプロセス。
- 前記塩基が第三級アミンである、請求項2に記載のプロセス。
- 前記第三級アミンがN,N-ジイソプロピルエチルアミンである、請求項3に記載のプロセス。
- 前記4-ヒドロキシピペリジンとの反応が、ジクロロメタンを含む溶媒構成要素中で遂行される、請求項1~4のいずれか1項に記載のプロセス。
- 前記4-ヒドロキシピペリジンとの反応が25℃~35℃の温度で遂行される、請求項1~5のいずれか1項に記載のプロセス。
- 前記式IIIの化合物が、式IIの化合物:
- 前記塩化オキサリルとの前記式IIの化合物の反応が、触媒量のジメチルホルムアミド(DMF)の存在下において遂行される、請求項7に記載のプロセス。
- 前記塩化オキサリルとの前記式IIの化合物の反応が、ジクロロメタンを含む溶媒構成要素中で遂行される、請求項7または8のプロセス。
- 前記塩化オキサリルとの前記式IIの化合物の反応が、15℃~25℃の温度で遂行される、請求項7~9のいずれか1項に記載のプロセス。
- 前記式IVの化合物またはその塩を酸化条件下で反応させて、式Vの化合物:
- 前記酸化条件が第1の酸化剤を含む、請求項11に記載のプロセス。
- 前記酸化条件が第2の酸化剤を含む、請求項12に記載のプロセス。
- 前記第1の酸化剤がトリクロロイソシアヌル酸(TCIC)である、請求項12または13に記載のプロセス。
- 前記TCICが、前記式IVの化合物に関して、0.5~0.7モル当量の間で存在する、請求項14に記載のプロセス。
- 前記第2の酸化剤が2,2,6,6-テトラメチル-1-ピペリジニルオキシ(TEMPO)である、請求項13~15のいずれか1項に記載のプロセス。
- 前記TEMPOが、前記式IVの化合物に関して、0.015~0.025モル当量の間で存在する、請求項16に記載のプロセス。
- 前記酸化条件下での前記式IVの化合物の反応が、重炭酸ナトリウム、炭酸ナトリウム及び臭化ナトリウムのうちの1つまたは複数をさらに含む、請求項11~17のいずれか1項に記載のプロセス。
- 前記酸化条件下での前記式IVの化合物の反応が、ジクロロメタンを含む溶媒構成要素をさらに含む、請求項11~18のいずれか1項に記載のプロセス。
- 前記溶媒構成要素が水をさらに含む、請求項19に記載のプロセス。
- 前記酸化条件が、トリクロロイソシアヌル酸を、前記式IVの化合物及びTEMPOを含む溶液へ0℃~5℃の温度で添加することを含む、請求項11に記載のプロセス。
- 前記トリクロロイソシアヌル酸の添加が、少なくとも2つの小分けでトリクロロイソシアヌル酸を添加することを含む、請求項21に記載のプロセス。
- 前記溶液が、前記添加後に0℃~5℃の温度で30分間撹拌される、請求項21または22に記載のプロセス。
- 前記撹拌後に、前記溶液を20℃~25℃の温度へ1時間~2時間の時間で暖めることをさらに含む、請求項23に記載のプロセス。
- 還元剤の存在下において、前記式Vの化合物を、式VIの化合物:
式中、Z1はHまたは保護基である、
請求項11~24のいずれか1項に記載のプロセス。 - Z1がHである、請求項25に記載のプロセス。
- 前記還元剤が、水素化シアノホウ素ナトリウムまたは水素化トリアセトキシホウ素ナトリウムである、請求項25または26に記載のプロセス。
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