JP2017500304A - IL−12、IL−23および/またはIFNα応答のモジュレーターとして有用なイミダゾピリダジン化合物 - Google Patents
IL−12、IL−23および/またはIFNα応答のモジュレーターとして有用なイミダゾピリダジン化合物 Download PDFInfo
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- JP2017500304A JP2017500304A JP2016538025A JP2016538025A JP2017500304A JP 2017500304 A JP2017500304 A JP 2017500304A JP 2016538025 A JP2016538025 A JP 2016538025A JP 2016538025 A JP2016538025 A JP 2016538025A JP 2017500304 A JP2017500304 A JP 2017500304A
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- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N trimethylmethane Natural products CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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Abstract
Description
本出願は、米国仮出願番号61/914,102(2013年12月10日出願)に基づく利益を主張し、引用によりその開示の全体を本明細書に包含させる。
本発明は、Tyk−2に作用してシグナル伝達阻害を引き起こすことにより、IL−12、IL−23および/またはIFNαの調節に有用な化合物に関する。ここに提供されるのは、イミダゾピリダジン(imidazopyradazine)化合物、そのような化合物を含む組成物およびその使用法である。本発明は、さらに、哺乳動物におけるIL−12、IL−23および/またはIFNαの調節と関係する状態の処置に有用な、本発明の化合物の少なくとも1個を含む医薬組成物に関する。
共通p40サブユニットを有するヘテロ二量体サイトカインインターロイキン(IL)−12およびIL−23は、活性化抗原提示細胞により産生され、自己免疫において鍵となる役割を有する2種のエフェクターT細胞系譜であるTh1細胞およびTh17細胞の分化および増殖に重要である。IL−23は、p40サブユニットおよび独特なp19サブユニットからなる。IL−23は、IL−23RおよびIL−12Rβ1からなるヘテロ二量体受容体を介して作用し、IL−17A、IL−17F、IL−6およびTNF−αのような炎症誘発性サイトカインを産生するTh17細胞の生存および増殖に必須である(McGeachy, M.J. et al., “The link between IL-23 and Th17 cell-mediated immune pathologies”, Semin. Immunol., 19:372-376 (2007))。これらのサイトカインは、リウマチ性関節炎、多発性硬化症、炎症性腸疾患および狼瘡を含む多数の自己免疫性疾患の病理生物学との関わりにおいて重要である。IL−12は、IL−23と共通するp40サブユニットに加えて、p35サブユニットを含み、IL−12Rβ1およびIL−12Rβ2からなるヘテロ二量体受容体を介して作用する。IL−12はTh1細胞の発達と、MHC発現刺激、B細胞のIgGサブクラスへのクラススイッチングおよびマクロファージの活性化により免疫に重要な役割を有するサイトカインであるIFNγ分泌に必須である(Gracie, J.A. et al., “Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass”, Eur. J. Immunol., 26:1217-1221 (1996); Schroder, K. et al., “Interferon-gamma: an overview of signals, mechanisms and functions”, J. Leukoc. Biol., 75(2):163-189 (2004))。
本発明は、Tyk2介在シグナル伝達阻害によりIL−12、IL−23および/またはIFNαのモジュレーターとして有用である、下記式Iの化合物に関する。
ここに提供されるのは、式I
R1はHまたは−NHR5であり;
R2はH、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい6〜10員単環式もしくは二環式アリールまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R3はH、ハロ、場合により置換されていてよいC1−C6アルキルまたは場合により置換されていてよいC2−C6アルキニルであるかまたは
R1およびR3は、それらが結合している炭素と一体となって4〜8員環を形成でき;
R4はH、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよい6〜10員単環式または二環式アリール、場合により置換されていてよい4〜10員単環式または二環式ヘテロシクロまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロアリールであり、各ヘテロシクロまたはヘテロアリールはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R5は場合により置換されていてよいC1−C4アルキルであり;
XはCHまたはNであり;
Yは
ZはCHまたはNである。〕
の化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグから選択される、少なくとも1個の化学物質である。
R1はHまたはNHR5であり、ここで、R5はC1−C4アルキルであり;
R2はH、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい6〜10員単環式もしくは二環式アリールまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R3はHまたはハロであり;
R4はH、場合により置換されていてよい4〜10員単環式または二環式ヘテロアリール、C1−C6アルキル、フェニル、3〜10員単環式もしくは二環式シクロアルキルまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロアリールまたはヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含む。〕
の化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグが提供される。
R5はC1−C4アルキルであり;
R2はH、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい6〜10員アリールまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R3はハロであり;
R4は、各々N、OおよびSから選択される1〜3個のヘテロ原子を含む。〕
を有する式Iの化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグが提供される。
R2はHであるか;または
R2は
R2は、場合によりC1−C4アルコキシ、ハロ、OH、CNまたは場合によりヒドロキシ−C1−C4−アルキルで置換されていてよい3〜10員シクロアルキルから選択される1個、2個または3個の置換基で置換されていてよいC1−C6アルキルであるか;または
R2はフェニルであるか;あるいは
R2は
R3はHまたはハロであり;
R4はHまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロアリールであり、各ヘテロアリールはN、OおよびSから選択される1〜3個のヘテロ原子を含む。〕
を有する、式Iの化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグが提供される。
R1はHまたはNHCH3であり;
R2はH、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい6〜10員単環式もしくは二環式アリールまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R3はH、FまたはClであり;
R4はHであるか;または
R4は
R4はCH3、i−C3H7または
R4は場合によりハロ、ジハロ−C1−C4−アルキル、トリハロ−C1−C4−アルキル、ヒドロキシ−C1−C4−アルキル、CNまたはN、OおよびSから選択される1〜3個のヘテロ原子を含む4〜10員単環式ヘテロシクロで置換されていてよいフェニルもしくはC1−C4アルキルスルホニルであるか;または
R4は
R4は
を有する式Iの化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグが提供される。
R2は
R3は
R4は
を有する式Iの化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグが提供される。
N−((1R,2S)−2−フルオロシクロプロピル)−8−(メチルアミノ)−6−(2−オキソ−1−(ピリジン−2−イル)−1,2−ジヒドロピリジン−3−イルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;
6−{[5−フルオロ−1−(6−メチルピリダジン−3−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル]アミノ}−N−[(1R,2S)−2−フルオロシクロプロピル]−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;
N−[(1R,2S)−2−フルオロシクロプロピル]−8−(メチルアミノ)−6−{[1−(6−メチルピリジン−2−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル]アミノ}イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;
N−[(1R,2S)−2−フルオロシクロプロピル]−6−{[1−(6−メトキシピリダジン−3−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル]アミノ}−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;および
6−{[1−(1,5−ジメチル−1H−ピラゾール−3−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル]アミノ}−N−[(1R,2S)−2−フルオロシクロプロピル]−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;
である化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体が提供される。
以下に、本明細書および添付する特許請求の範囲において使用する用語の定義を記載する。ここである基または用語について規定した最初の定義は、特に断らない限り、本明細書および特許請求の範囲を通して、独立してまたは他の基の一部として、その基または用語に適用される。
a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985);
b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991);および
c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992)
を参照のこと。
本発明の化合物は、遺伝子転写を含む、IL−23刺激およびIFNα刺激細胞機能を調節する。本発明の化合物により調節され得る他のタイプの細胞機能は、IL−12刺激応答を含むが、これに限定されない。
プローブ変位アッセイ
プローブ変位アッセイを、次のとおり行う。385ウェルプレートにおいて、試験化合物を、ヒトTyk2のアミノ酸575〜869(配列下記)に対応する組み換えにより発現される2.5nMHisタグ付タンパク質、40nM ((R)−N−(1−(3−(8−メチル−5−(メチルアミノ)−8H−イミダゾ[4,5−d]チアゾロ[5,4−b]ピリジン−2−イル)フェニル)エチル)−2−([3H]メチルスルホニル)ベンズアミド)(製造は下記)および80μg/mL 銅His−Tagシンチレーションプロキシミティアッセイビーズ(Perkin Elmer, Catalog #RPNQ0095)と共に、100μg/mL ウシ血清アルブミンおよび5%DMSOを含む50mM HEPES、pH7.5中、30分、室温でインキュベートした。Tyk2に結合した放射標識プローブ(製造は下記)をシンチレーション計数により計数し、阻害剤不含(0%阻害)またはTyk2不含(100%阻害)のウェルとの比較により、試験化合物による阻害を計算した。IC50値を、放射標識プローブ結合を50%阻害するのに必要な試験化合物濃度と定義する。
2−([3H]メチルスルホニル)安息香酸:2−メルカプト安息香酸(2.3mg、0.015mmol)および炭酸セシウム(2mg、0.006mmol)を、5mL丸底フラスコに添加した。フラスコを開口したガラス真空ラインに接続し、無水DMF(0.5mL)を磁気撹拌しながら導入した。1アンプルのトリチウム標識ヨウ化メチル(200mCi、Perkin-Elmer lot 3643419)を反応フラスコに添加し、撹拌をrtで3時間維持した。放射測定検出を伴うインプロセスHPLC分析は、標品との比較により所望の生成物への80%変換を示した。精製せずに、粗製生成物をCH2Cl2(1mL)に予め溶解したmCPBA(10mg、0.058mmol)と室温で撹拌しながら反応させた。反応物を7時間撹拌し、さらなるmCPBA(10mg、0.058mmol)を添加した。反応物を約24時間撹拌し、HPLC分析は、所望のスルホン酸塩生成物への35〜40%変換を示した。粗製生成物を半分取HPLC(Luna 5um C18(10×250cm);A:MeOH/H2O=15/85(0.1%TFA);B:MeOH;270nm;0〜8分0%B 1ml/分;8〜10分0%B 1〜3ml/分;10〜55分0%B 3ml/分;55〜65分0〜10%B 3ml/分;65〜75分10〜50%B 3ml/分;75〜80分50〜100%B 3ml/分)で精製して、標品とのHPLC共溶出により同定した、81mCi(40%放射化学的収率)の2−([3H]メチルスルホニル)安息香酸生成物を得た。放射化学的純度は、HPLCで99%と測定された(Luna 5u C18(4.6×150cm);A:H2O(0.1%TFA);B:MeOH;1.2ml/分;270nm;0〜10分20%B;10〜15分20〜100%B;15〜25分100%B。生成物を無水アセトニトリルに溶解して、5.8mCi/mLの最終溶液活性を得た。
安定に統合されたSTAT依存性ルシフェラーゼレポーターを有するKit225 T細胞を、10%熱不活性化FBS(GIBCO)および100U/mL PenStrep(GIBCO)含有RPMI(GIBCO)に播種した。次いで細胞を20ng/mL ヒト組み換えIL−23または200U/mL ヒト組み換えIFNα(PBL InterferonSource)のいずれかで、5〜6時間刺激した。ルシフェラーゼ発現を、製造業者の指示に従いSTEADY-GLO(登録商標)Luciferase Assay System(PROMEGA(登録商標))を使用して測定した。阻害データを、阻害剤不含対照ウェルの0%阻害および非刺激対象ウェルの100%阻害と比較して計算した。用量応答曲線を作成して、非線形回帰分析により導かれる細胞応答の50%阻害に必要な濃度(IC50)を決定した。
本発明の化合物を、有機化学の当業者に利用可能な多くの方法により合成し得る。本発明の化合物の製造のための一般的合成スキームを下に記載する。これらのスキームは説明的であり、ここに開示する化合物の製造のために当業者が使用し得る可能な方法を制限する意図はない。本発明の化合物を製造する異なる方法が当業者には明らかである。さらに、これらの合成における種々の方法を、所望の化合物または化合物を得るために別の順番で実施し得る。
NaHCO3(水性)=飽和重炭酸ナトリウム水溶液
塩水=飽和塩化ナトリウム水溶液
DCM=ジクロロメタン
DIEA=N,N−ジイソプロピルエチルアミン
DMAP=4−(N,N−ジメチルアミノ)ピリジン
DMF=N,N−ジメチルホルムアミド
DMSO=ジメチルスルホキシド
EDC=N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩
EtOAc=酢酸エチル
HOAT=1−ヒドロキシ−7−アザベンゾトリアゾール
HOBT=1−ヒドロキシベンゾトリアゾール水和物
rt=周囲の室温(一般に約20〜25℃)
TEA=トリエチルアミン
TFA=トリフルオロ酢酸
THF=テトラヒドロフラン
6−クロロ−N−(1−シアノシクロプロピル)−8−((4−メトキシベンジル)(メチル)アミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
6−クロロ−N−(trans−2−フルオロシクロプロピル)−8−((4−メトキシベンジル)(メチル)アミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
tert−ブチル(trans−2−フルオロシクロプロピル)カルバメート(0.123g、0.702mmol)のジクロロメタン(2mL)溶液に、0℃でTFA(2mL、26.0mmol)を添加した。混合物をrtで1時間撹拌した。揮発物を減圧下除去して、所望の生成物であるtrans−2−フルオロシクロプロパンアミン、TFA(0.132g、0.698mmol、99%収率)を蝋状固体として得た。
6−クロロ−N−(3−ヒドロキシ−2−(ヒドロキシメチル)−2−メチルプロピル)−8−((4−メトキシベンジル)(メチル)アミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
3−アミノ−5−フルオロ−1−メチルピリジン−2(1H)−オン
3−アミノ−5−フルオロ−1−(2−フルオロエチル)ピリジン−2(1H)−オン
3−アミノ−5−フルオロ−1−(2−ヒドロキシ−2−メチルプロピル)ピリジン−2(1H)−オン
3−アミノ−1−シクロヘキシルピリジン−2(1H)−オン
3−アミノ−1−(4−フルオロフェニル)ピリジン−2(1H)−オン
3−アミノ−1−シクロプロピルピリジン−2(1H)−オン
3−アミノ−1−シクロプロピル−5−フルオロピリジン−2(1H)−オン
3−アミノ−3’−フルオロ−2H−[1,2’−ビピリジン]−2−オン
3−アミノ−2H−[1,2’−ビピリジン]−2−オン
3−アミノ−6’−(メチルアミノ)−2H−[1,3’−ビピリジン]−2−オン
3−アミノ−1−(6−メチルピリダジン−3−イル)ピリジン−2(1H)−オン
3−アミノ−1−(チアゾール−2−イル)ピリジン−2(1H)−オン
3−アミノ−5−フルオロ−1−(6−メチルピリダジン−3−イル)ピリジン−2(1H)−オン
5−アミノ−3−(ピリジン−2−イル)ピリミジン−4(3H)−オン
3−アミノ−1−(5−フルオロ−4−メチルピリミジン−2−イル)ピリジン−2(1H)−オン
3−アミノ−1−(1,5−ジメチル−1H−ピラゾール−3−イル)ピリジン−2(1H)−オン
3−アミノ−1−(4−ヒドロキシシクロヘキシル)ピリジン−2(1H)−オン
3−アミノ−1−(4−(1−ヒドロキシエチル)フェニル)ピリジン−2(1H)−オン
4−アミノ−2−フェニルピリダジン−3(2H)−オン
6−((1−メチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)アミノ)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボン酸、2HCl
N−(1−シアノシクロプロピル)−6−(1−メチル−2−オキソ−1,2−ジヒドロピリジン−3−イルアミノ)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
6−((1−(4−シアノフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−イル)アミノ)−N−シクロプロピル−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
N−((1R,2S)−2−フルオロシクロプロピル)−8−(メチルアミノ)−6−(2−オキソ−1−(ピリジン−2−イル)−1,2−ジヒドロピリジン−3−イルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
N−(1−クロロ−3−ヒドロキシプロパン−2−イル)−8−(メチルアミノ)−6−(2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−イルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
N−シクロブチル−8−(メチルアミノ)−6−((2−オキソ−1−(4−(トリフルオロメチル)ピリミジン−2−イル)−1,2−ジヒドロピリジン−3−イル)アミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
N−(3−ヒドロキシ−2,2−ジメチルプロピル)−8−(メチルアミノ)−6−((1−(5−メチルピラジン−2−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル)アミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
(R)−8−(メチルアミノ)−6−((2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−イル)アミノ)−N−(テトラヒドロフラン−3−イル)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
N−シクロブチル−8−(メチルアミノ)−6−((3−オキソ−2−フェニル−2,3−ジヒドロピリダジン−4−イル)アミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
N−(3−ヒドロキシ−2,2−ジメチルプロピル)−6−((1−メチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)アミノ)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
N−シクロブチル−6−((2−オキソ−2H−[1,2’−ビピリジン]−3−イル)アミノ)−9,10−ジヒドロ−8H−イミダゾ[1’,2’:1,6]ピリダジノ[4,5−b][1,4]オキサジン−3−カルボキサミド
6−((2−オキソ−2H−[1,2’−ビピリジン]−3−イル)アミノ)−9,10−ジヒドロ−8H−イミダゾ[1’,2’:1,6]ピリダジノ[4,5−b][1,4]オキサジン−3−カルボン酸、3HCl(0.0346g、0.064mmol)およびシクロブタンアミン(9.08mg、0.128mmol)のDMF(1.5mL)中のやや不均質な、無色溶液に、BOP(0.056g、0.128mmol)およびDIPEA(0.067mL、0.383mmol)を添加した。反応物を密閉し、50℃に加熱した。1時間後、反応物を室温に冷却した。水(10mL)を添加し、溶液を15分撹拌し、濾過し、水で洗浄して、残渣を得た。これをCH2Cl2で摩砕し、濾過し、一夜、50℃で乾燥して、N−シクロブチル−6−((2−オキソ−2H−[1,2’−ビピリジン]−3−イル)アミノ)−9,10−ジヒドロ−8H−イミダゾ[1’,2’:1,6]ピリダジノ[4,5−b][1,4]オキサジン−3−カルボキサミドを白色固体として得た。LCMS (M + H)+ = 459.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (1 H, dt, J=3.91, 1.02 Hz), 8.53 (1 H, d, J=7.92 Hz), 8.23 (1 H, s), 8.17 (1 H, dd, J=7.26, 1.76 Hz), 8.05 (1 H, td, J=7.81, 1.98 Hz), 7.89 (1 H, s), 7.87 (1 H, s), 7.60 (1 H, dd, J=7.15, 1.65 Hz), 7.51 - 7.58 (2 H, m), 6.48 (1 H, t, J=7.15 Hz), 4.47 - 4.61 (1 H, m), 4.35 (2 H, t, J=3.96 Hz), 3.56 (2 H, d, J=2.64 Hz), 2.26 - 2.43 (2 H, m), 1.96-2.09 (2 H, m), 1.71-1.81 (2 H, m)
5−クロロ−3−ニトロピリジン−2−オール(0.200g、1.146mmol)、ヨードエタン(0.137mL、1.719mmol)および炭酸カリウム(0.348g、2.52mmol)のDMF(5mL)の混合物を室温で4時間撹拌した。LC−MSは、所望の生成物塊への完全な変換を示した。反応混合物を減圧下濃縮し、酢酸エチルで希釈し、塩水で洗浄した。酢酸エチル抽出物を硫酸ナトリウムで乾燥し、濾過し、濃縮した。濃縮物を30%酢酸エチル:70%ヘキサンで溶出するシリカゲル上のクロマトグラフィーに付して、5−クロロ−1−エチル−3−ニトロ−1,2−ジヒドロピリジン−2−オール(0.144g、0.704mmol、61%収率)を黄色固体として得た。LC-MS m+1 203.2; 205.2
N−((1R,2S)−2−フルオロシクロプロピル)−6−((1−(5−(2−ヒドロキシプロパン−2−イル)ピラジン−2−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル)アミノ)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
6−クロロ−N−((1R,2S)−2−フルオロシクロプロピル)−8−((4−メトキシベンジル)(メチル)アミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド(4u、60mg、0.149mmol)、3−アミノ−1−(5−(2−ヒドロキシプロパン−2−イル)ピラジン−2−イル)ピリジン−2(1H)−オン(45.7mg、0.186mmol)、酢酸パラジウム(II)(6.67mg、0.030mmol)、BrettPhose(15.95mg、0.030mmol)および炭酸カリウム(30.8mg、0.223mmol)の1,4−ジオキサン(1.5mL)中の混合物を、80℃で2.5時間加熱した。反応混合物を酢酸エチル(5mL)で希釈し、セライトで濾過した。濾液を酢酸エチル(80mL)で希釈し、水(2×25mL)および塩水(25mL)で洗浄し、無水MgSO4で乾燥した。溶媒を減圧下除去した。残渣をジクロロメタン(8mL)に溶解した。この溶液に、rtで1,4−ジオキサン中の塩酸(8.0mL、32.00mmol)。混合物をrtで30分撹拌し、減圧下濃縮した。残渣をDMSO(1.5mL)およびMeOH(4.5mL)で希釈し、3分割し、分取HPLCに注入した。目的とするフラクションを合併し、減圧下濃縮し、1.5M K2HPO4溶液でpH9に塩基性化し、ジクロロメタン(4×40mL)で抽出した。合わせた抽出物を無水Na2SO4で乾燥した。減圧下の溶媒の除去により、所望の生成物であるN−((1R,2S)−2−フルオロシクロプロピル)−6−((1−(5−(2−ヒドロキシプロパン−2−イル)ピラジン−2−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル)アミノ)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド(28.2mg、0.056mmol、37.7%収率)を白色固体として得た。LCMS (M + H)+ = 494.2. 1H NMR (400MHz, DMSO-d6) δ 9.08 (d, J=1.5 Hz, 1H), 8.93 (d, J=1.5 Hz, 1H), 8.69 (s, 1H), 8.64 (d, J=4.0 Hz, 1H), 8.04 (dd, J=7.4, 1.7 Hz, 1H), 7.92 (s, 1H), 7.58 (dd, J=7.1, 1.7 Hz, 1H), 7.52 (q, J=4.6 Hz, 1H), 6.47 (t, J=7.2 Hz, 1H), 6.42 (s, 1H), 5.62 (s, 1H), 5.04 - 4.75 (m, 1H), 3.07 - 2.95 (m, 1H), 2.88 (d, J=4.8 Hz, 3H), 1.55 (s, 6H), 1.34 - 1.18 (m, 1H), 1.07 - 0.92 (m, 1H)
6−((1−(5−(ジメチルカルバモイル)ピラジン−2−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル)アミノ)−N−((1R,2S)−2−フルオロシクロプロピル)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
6−クロロ−N−((1R,2S)−2−フルオロシクロプロピル)−8−((4−メトキシベンジル)(メチル)アミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド(4u、50mg、0.124mmol)、5−(3−アミノ−2−オキソピリジン−1(2H)−イル)−N,N−ジメチルピラジン−2−カルボキサミド(40.1mg、0.155mmol)、酢酸パラジウム(II)(5.56mg、0.025mmol)、BrettPhose(13.29mg、0.025mmol)および炭酸カリウム(25.7mg、0.186mmol)の1,4−ジオキサン(1.5mL)中の混合物を、80℃で2.5時間加熱した。反応混合物を酢酸エチル(5mL)で希釈し、セライトで濾過した。濾液を酢酸エチル(80mL)で希釈し、水(2×25mL)および塩水(25mL)で洗浄し、無水MgSO4で乾燥した。溶媒を減圧下除去した。残渣をジクロロメタン(8mL)に溶解した。この溶液に、rtで1,4−ジオキサン中の塩酸(8.0mL、32.00mmol)。混合物をrtで30分撹拌し、減圧下濃縮した。残渣をDMSO(1.5mL)およびMeOH(4.5mL)で希釈し、3分割し、分取HPLCに注入した。目的とするフラクションを合併し、減圧下濃縮し、1.5M K2HPO4溶液でpH9に塩基性化し、ジクロロメタン(4×40mL)で抽出した。合わせた抽出物を無水Na2SO4で乾燥した。減圧下の溶媒の除去により、所望の生成物である6−((1−(5−(ジメチルカルバモイル)ピラジン−2−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル)アミノ)−N−((1R,2S)−2−フルオロシクロプロピル)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド(17.9mg、0.035mmol、28.3%収率)を黄色固体として得た。LCMS (M + 1) = 507.1. 1H NMR (400MHz, DMSO-d6) δ 9.23 (d, J=1.3 Hz, 1H), 8.92 (d, J=1.5 Hz, 1H), 8.73 (s, 1H), 8.63 (d, J=4.2 Hz, 1H), 8.05 (dd, J=7.3, 1.6 Hz, 1H), 7.93 (s, 1H), 7.62 (dd, J=7.1, 1.7 Hz, 1H), 7.52 (q, J=4.6 Hz, 1H), 6.50 (t, J=7.2 Hz, 1H), 6.42 (s, 1H), 5.02 - 4.75 (m, 1H), 3.08 (s, 3H), 3.06 (s, 3H), 3.04 - 2.95 (m, 1H), 2.88 (d, J=4.8 Hz, 3H), 1.33 - 1.18 (m, 1H), 1.09 - 0.90 (m, 1H)
6−((5’−(ジメチルカルバモイル)−2−オキソ−2H−[1,2’−ビピリジン]−3−イル)アミノ)−N−((1R,2S)−2−フルオロシクロプロピル)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド
3−((3−(((1R,2S)−2−フルオロシクロプロピル)カルバモイル)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−6−イル)アミノ)−2−オキソ−2H−[1,2’−ビピリジン]−5’−カルボン酸、2HCl(40mg、0.073mmol)、THF中のジメチルアミン(0.073mL、0.145mmol)、BOP(40.1mg、0.091mmol)およびN,N−ジイソプロピルエチルアミン(0.063mL、0.363mmol)のDMF(0.5mL)を中の混合物を50℃で2時間加熱した。反応は明確に完了した。混合物をDMF(1.5mL)で希釈し、精製のためにSCPグループに提供して、所望の生成物である6−((5’−(ジメチルカルバモイル)−2−オキソ−2H−[1,2’−ビピリジン]−3−イル)アミノ)−N−((1R,2S)−2−フルオロシクロプロピル)−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド、2HCl(27.8mg、0.048mmol、65.6%収率)を得た。LCMS (M + H)+ = 506.1. 1H NMR (500MHz, DMSO-d6) δ 8.71 - 8.65 (m, 3H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 8.00 (d, J=6.8 Hz, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J=6.1 Hz, 1H), 7.51 (d, J=4.7 Hz, 1H), 6.44 (t, J=7.2 Hz, 1H), 6.38 (s, 1H), 4.98 - 4.78 (m, 1H), 3.05 (s, 3H), 3.02 - 2.98 (m, 4H), 2.88 (d, J=4.7 Hz, 3H), 1.31 - 1.19 (m, 1H), 1.05 - 0.92 (m, 1H)
Claims (14)
- 式
R1はHまたは−NHR5であり;
R2はH、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい6〜10員単環式もしくは二環式アリールまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R3はH、ハロ、場合により置換されていてよいC1−C6アルキルまたは場合により置換されていてよいC2−C6アルキニルであるかまたは
R1およびR3は、それらが結合している炭素と一体となって4〜8員環を形成でき;
R4はH、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよい6〜10員単環式または二環式アリール、場合により置換されていてよい4〜10員単環式または二環式ヘテロシクロまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロアリールであり、各ヘテロシクロまたはヘテロアリールはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R5は場合により置換されていてよいC1−C4アルキルであり;
XはCHまたはNであり;
Yは
ZはCHまたはNである。〕
を有する化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体。 - 式
R1はHまたはNHR5であり、ここで、R5はC1−C4アルキルであり;
R2はH、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい6〜10員単環式もしくは二環式アリールまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R3はHまたはハロであり;
R4はH、場合により置換されていてよい4〜10員単環式または二環式ヘテロアリール、C1−C6アルキル、フェニル、3〜10員単環式もしくは二環式シクロアルキルまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロアリールまたはヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含む。〕
を有する、請求項1に記載の化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体。 - 式
R5はC1−C4アルキルであり;
R2はH、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい6〜10員アリールまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R3はハロであり;
R4は、各々N、OおよびSから選択される1〜3個のヘテロ原子を含む。〕
を有する、請求項2に記載の化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体。 - 式
R2はHであるか;または
R2は
R2は、場合によりC1−C4アルコキシ、ハロ、OH、CNまたは場合によりヒドロキシ−C1−C4−アルキルで置換されていてよい3〜10員シクロアルキルから選択される1個、2個または3個の置換基で置換されていてよいC1−C6アルキルであるか;または
R2はフェニルであるか;
R2は
R3はHまたはハロであり;
R4はHまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロアリールであり、各ヘテロアリールはN、OおよびSから選択される1〜3個のヘテロ原子を含む。〕
を有する、請求項2に記載の化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体。 - R3がHまたはハロである、請求項2に記載の化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体。
- 式
R1はHまたはNHCH3であり;
R2はH、場合により置換されていてよい3〜10員単環式または二環式シクロアルキル、場合により置換されていてよいC1−C6アルキル、場合により置換されていてよい6〜10員単環式もしくは二環式アリールまたは場合により置換されていてよい4〜10員単環式もしくは二環式ヘテロシクロであり、各ヘテロシクロはN、OおよびSから選択される1〜3個のヘテロ原子を含み;
R3はH、FまたはClであり;
R4はHであるか;または
R4は
R4はCH3、i−C3H7または
R4は場合によりハロ、ジハロ−C1−C4−アルキル、トリハロ−C1−C4−アルキル、ヒドロキシ−C1−C4−アルキル、CNまたはN、OおよびSから選択される1〜3個のヘテロ原子を含む4〜10員単環式ヘテロシクロで置換されていてよいフェニルもしくはC1−C4アルキルスルホニルであるか;または
R4は
R4は
を有する、請求項2に記載の化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体。 - 式
R2は
R3は
R4は
を有する、請求項6に記載の化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体。 - N−((1R,2S)−2−フルオロシクロプロピル)−8−(メチルアミノ)−6−(2−オキソ−1−(ピリジン−2−イル)−1,2−ジヒドロピリジン−3−イルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;
6−{[5−フルオロ−1−(6−メチルピリダジン−3−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル]アミノ}−N−[(1R,2S)−2−フルオロシクロプロピル]−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;
N−[(1R,2S)−2−フルオロシクロプロピル]−8−(メチルアミノ)−6−{[1−(6−メチルピリジン−2−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル]アミノ}イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;
N−[(1R,2S)−2−フルオロシクロプロピル]−6−{[1−(6−メトキシピリダジン−3−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル]アミノ}−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;または
6−{[1−(1,5−ジメチル−1H−ピラゾール−3−イル)−2−オキソ−1,2−ジヒドロピリジン−3−イル]アミノ}−N−[(1R,2S)−2−フルオロシクロプロピル]−8−(メチルアミノ)イミダゾ[1,2−b]ピリダジン−3−カルボキサミド;
である、請求項1に記載の化合物またはその薬学的に許容される塩、互変異性体もしくは立体異性体。 - 請求項1に記載の化合物の1個以上および薬学的に許容される担体または希釈剤を含む、医薬組成物。
- 疾患を処置する方法であって、そのような処置を必要とする患者に請求項1に記載の化合物の治療有効量を投与することを含み、該疾患が炎症性疾患または自己免疫性疾患である、方法。
- 疾患が炎症性疾患である、請求項10に記載の方法。
- 疾患が自己免疫性疾患である、請求項10に記載の方法。
- 疾患が全身性エリテマトーデス(SLE)、ループス腎炎、皮膚ループス、クローン病、潰瘍性大腸炎、1型糖尿病、乾癬、リウマチ性関節炎、全身型若年性特発性関節炎、強直性脊椎炎または多発性硬化症である、請求項10に記載の方法。
- 疾患が全身性エリテマトーデス(SLE)である、請求項13に記載の方法。
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EP3080131A1 (en) | 2016-10-19 |
US10273237B2 (en) | 2019-04-30 |
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CN105992768B (zh) | 2018-04-20 |
CN105992768A (zh) | 2016-10-05 |
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