JP6318180B2 - CaMKII阻害剤及びその使用 - Google Patents
CaMKII阻害剤及びその使用 Download PDFInfo
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- JP6318180B2 JP6318180B2 JP2015561594A JP2015561594A JP6318180B2 JP 6318180 B2 JP6318180 B2 JP 6318180B2 JP 2015561594 A JP2015561594 A JP 2015561594A JP 2015561594 A JP2015561594 A JP 2015561594A JP 6318180 B2 JP6318180 B2 JP 6318180B2
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- A—HUMAN NECESSITIES
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Description
特定の実施形態では、例えば以下が提供される:
(項目1)
式Iの化合物:
または、薬剤として許容されるその塩。
(式中、
R 2’ 及びR 3’ の1つは−L 1 −R x であり、他は水素である;
L 1 は共有結合、または線状もしく分枝状C 1−6 脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NR a −または−O−で置換される;
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 4’ 、R 5’ 、及びR 6’ はそれぞれ、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から独立して選択される;
各R a は独立して水素またはC 1−3 脂肪族である;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目2)
式I−a
である項目1に記載の化合物、または薬剤として許容されるその塩。
(式中、
R 2’ 及びR 3’ の1つは−L 1 −R x であり、他は水素である;
L 1 は共有結合、または線状もしく分枝状C 1−6 脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NR a −または−O−で置換される;
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;
各R a は独立して水素またはC 1−3 脂肪族である;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目3)
式II
である項目1に記載の化合物、または薬剤として許容されるその塩。
L 1 は共有結合、または線状もしく分枝状C 1−6 脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NR a −または−O−で置換される;
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;
各R a は独立して水素またはC 1−3 脂肪族である;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目4)
式III
である項目1に記載の化合物、または薬剤として許容されるその塩。
(式中、
L 1 は共有結合、または線状もしく分枝状C 1−6 脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NR a −または−O−で置換される;
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;
各R a は独立して水素またはC 1−3 脂肪族である;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目5)
式IV
である項目3に記載の化合物、または薬剤として許容されるその塩。
(式中、
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;
各R a は独立して水素またはC 1−3 脂肪族である;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目6)
式V
である項目4に記載の化合物、または薬剤として許容されるその塩。
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;
各R a は独立して水素またはC 1−3 脂肪族である;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目7)
式VI
(式中、
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;かつ各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目8)
式VII
である項目4に記載の化合物、または薬剤として許容されるその塩。
(式中、
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目9)
式VIII
である項目3に記載の化合物、または薬剤として許容されるその塩。
(式中、
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目10)
式IX
である項目4に記載の化合物、または薬剤として許容されるその塩。
(式中、
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である。)
(項目11)
前記化合物が以下の構造:
から選択される、項目1に記載の化合物、または薬剤として許容されるその塩。
(項目12)
項目1に記載の化合物または薬剤として許容されるその塩、及び製薬上許容できる担体、補助剤、またはビヒクルを含む医薬組成物。
(項目13)
式I−aの化合物
の合成方法であって、
1)式
の化合物を
(式中、R 6 及びR 7 は上記で定義した通りである)
式
の化合物
(式中、
R 2’ −P及びR 3’ −Pは、任意の第一級アミンである第一級アミン保護基を有する上記R 2’ 及びR 3’ で定義されたものである)
と接触させること
並びに
3)保護基Pを除去すること
(式中、
R 2’ 及びR 3’ の1つはーL 1 −R x であり、他は水素である;
L 1 は共有結合、または線状もしく分枝状C 1−6 脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NR a −または−O−で置換される;
R x はNH 2 、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R 6 及びR 7 はそれぞれ独立して、水素、ハロゲン、−CN、−CF 3 、−OR、−NR 2 、−NO 2 、−COOR、−CONR 2 、及び−Rからなる群から選択される;
各R a は独立して水素またはC 1−3 脂肪族である;かつ
各Rは独立して水素または任意に置換されたC 1−6 脂肪族である;)
からなる、前記式I−aの化合物の合成方法。
(項目14)
必要のある患者に項目12に記載の組成物を投与することを含む、心臓血管病、疾患、もしくは状態、炎症性の病気、疾患もしくは状態、神経系の病気、疾患もしくは状態、
眼の病気、疾患もしくは状態、代謝性の病気、疾患もしくは状態、癌もしくは他の増殖性の病気、疾患もしくは状態、骨の病気、疾患もしくは状態、または中毒性の病気、疾患、もしくは状態の治療方法。
(項目15)
前記心臓血管病、疾患、または状態が心房細動、心室性不整脈、心不全、心臓肥大症、アテローム性動脈硬化症、再狭窄;または薬物療法、心臓発作、虚血再灌流傷害、もしくはカテコールアミン誘発性多形性心室性頻拍から生じる心毒性から選択される、項目14に記載の方法。
(項目16)
前記炎症性の病気、疾患または状態が喘息または関節リウマチである、項目14に記載の方法。
(項目17)
前記神経系の病気、疾患または状態が疼痛または脳卒中である、項目14に記載の方法。
(項目18)
前記代謝性の病気、疾患、または状態が糖尿病である、項目14に記載の方法。
(項目19)
前記癌または他の増殖性の病気、疾患または状態が骨肉腫、黒色腫、または前立腺癌である、項目14に記載の方法。
(項目20)
前記中毒性の病気、疾患、または状態がオピオイド耐性または依存症である、項目14に記載の方法。
ある種の実施形態において、本発明は、CaMKIIの阻害剤を提供する。いくつかの実施形態では、かかる化合物は式Iのもの
(式中、
R2’及びR3’の1つは−L1−Rxであり、他は水素である;
L1は共有結合、または線状もしく分枝状C1−6脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NRa−または−O−で置換される;
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R3、R4、R5、R6、R7、R8、R4’、R5’、及びR6’はそれぞれ、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から独立して選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。)
2.化合物及び定義
3.代表的実施形態の説明
(式中、
R2’及びR3’の1つは−L1−Rxであり、他は水素である;
L1は共有結合、または線状もしく分枝状C1−6脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NRa−または−O−で置換される;
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R3、R4、R5、R6、R7、R8、R4’、R5’、及びR6’はそれぞれ、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から独立して選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。)
(式中、R2’、R3’、R6、及びR7はそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
(式中、L1、Rx、R6、及びR7はそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
(式中、L1、Rx、R6、及びR7はそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
(式中Rx、R6、R7、及びRaはそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
(式中Rx、R6、R7、及びRaはそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
(式中Rx、R6、及びR7はそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
(式中Rx、R6、及びR7はそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
(式中Rx、R6、及びR7はそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
(式中Rx、R6、及びR7はそれぞれ上記で定義され、単独及び組み合わせでの両方で、本明細書内の実施形態に記載されている。)
4.使用、配合物及び投与、並びに製薬上許容できる組成物
化合物及び製薬上許容できる組成物の使用
(実施例1)
(実施例2)
(実施例3)
(実施例4)
化合物9a 12mg(収率20%)を単離した。;1HNMR(500MHz,DMSO−d6)δPPM:11.89(br,1H),8.48(d,1H),7.77(s,1H),7.65−7.68(m,3H),7.53(dd,2H),7.42(t,1H),7.10(d,1H),7.09(t,1H),4.12(s,2H).質量(m/z):274.3(M+H)。
(実施例5)
(実施例6)
(実施例7)
(実施例8)
混合物をセライトに通して濾過し、セライトパッドをEtOAcで洗浄した。混ぜ合わせた濾液を濃縮して乾燥させ、粗生成物をシリカゲル(5% EtOAc/ヘキサン)上で精製して化合物20(500mg、収率23%)をオフホワイト固体として得た。;1HNMR(500MHz,CDCl3)δppm:7.10(t,1H),7.08(s,1H),6.98(d,1H),6.81(d,1H),3.55(t,4H),3.13(t,4H),1.45(s,9H).
(実施例9)
(実施例10)
(実施例11)
(実施例12)
(実施例13)
(実施例14)
(実施例15)
(実施例16)
In vitroCaMKIIδ活性アッセイ
Claims (20)
- 式Iの化合物:
(式中、
R2’及びR3’の1つは−L1−Rxであり、他は水素である;
L1は共有結合、または線状もしく分枝状C1−6脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NRa−または−O−で置換される;
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R3、R4、R5、R6、R7、R8、R4’、R5’、及びR6’はそれぞれ、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から独立して選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式I−a
(式中、
R2’及びR3’の1つは−L1−Rxであり、他は水素である;
L1は共有結合、または線状もしく分枝状C1−6脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NRa−または−O−で置換される;
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式II
L1は共有結合、または線状もしく分枝状C1−6脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NRa−または−O−で置換される;
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式III
(式中、
L1は共有結合、または線状もしく分枝状C1−6脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NRa−または−O−で置換される;
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式IV
(式中、
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式V
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式VI
(式中、
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;かつ各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式VII
(式中、
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式VIII
(式中、
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 式IX
(式中、
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である。) - 前記化合物が以下の構造:
- 請求項1に記載の化合物または薬剤として許容されるその塩、及び製薬上許容できる担体、補助剤、またはビヒクルを含む医薬組成物。
- 式I−aの化合物
1)式
(式中、R6及びR7は上記で定義した通りである)
式
(式中、
R2’−P及びR3’−Pは、任意の第一級アミンである第一級アミン保護基を有する上記R2’及びR3’で定義されたものである)
と接触させること
並びに
2)保護基Pを除去すること
(式中、
R2’及びR3’の1つはーL1−Rxであり、他は水素である;
L1は共有結合、または線状もしく分枝状C1−6脂肪族基であり、ここで1つ以上のメチレン基は独立して、かつ任意に−NRa−または−O−で置換される;
RxはNH2、グアニジノ、窒素、酸素または硫黄から独立して選択される1〜2個のヘテロ原子を有する、任意に置換された4〜7員環飽和複素環、並びに硫黄、窒素及び酸素から独立して選択される1〜2個のヘテロ原子を有する、5〜6員環芳香族複素環からなる群から選択される;
R6及びR7はそれぞれ独立して、水素、ハロゲン、−CN、−CF3、−OR、−NR2、−NO2、−COOR、−CONR2、及び−Rからなる群から選択される;
各Raは独立して水素またはC1−3脂肪族である;かつ
各Rは独立して水素または任意に置換されたC1−6脂肪族である;)
からなる、前記式I−aの化合物の合成方法。 - 心臓血管病、疾患、もしくは状態、炎症性の病気、疾患もしくは状態、神経系の病気、疾患もしくは状態、眼の病気、疾患もしくは状態、代謝性の病気、疾患もしくは状態、癌もしくは他の増殖性の病気、疾患もしくは状態、骨の病気、疾患もしくは状態、または中毒性の病気、疾患、もしくは状態を治療するための、請求項12に記載の医薬組成物であって、前記医薬組成物が、必要のある患者に投与されることを特徴とする、医薬組成物。
- 前記心臓血管病、疾患、または状態が心房細動、心室性不整脈、心不全、心臓肥大症、アテローム性動脈硬化症、再狭窄;または薬物療法、心臓発作、虚血再灌流傷害、もしくはカテコールアミン誘発性多形性心室性頻拍から生じる心毒性から選択される、請求項14に記載の医薬組成物。
- 前記炎症性の病気、疾患または状態が喘息または関節リウマチである、請求項14に記載の医薬組成物。
- 前記神経系の病気、疾患または状態が疼痛または脳卒中である、請求項14に記載の医薬組成物。
- 前記代謝性の病気、疾患、または状態が糖尿病である、請求項14に記載の医薬組成物。
- 前記癌または他の増殖性の病気、疾患または状態が骨肉腫、黒色腫、または前立腺癌である、請求項14に記載の医薬組成物。
- 前記中毒性の病気、疾患、または状態がオピオイド耐性または依存症である、請求項14に記載の医薬組成物。
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