JP7490781B2 - Sarm1の阻害剤 - Google Patents
Sarm1の阻害剤 Download PDFInfo
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- JP7490781B2 JP7490781B2 JP2022541796A JP2022541796A JP7490781B2 JP 7490781 B2 JP7490781 B2 JP 7490781B2 JP 2022541796 A JP2022541796 A JP 2022541796A JP 2022541796 A JP2022541796 A JP 2022541796A JP 7490781 B2 JP7490781 B2 JP 7490781B2
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
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- 239000008174 sterile solution Substances 0.000 description 1
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- 239000003206 sterilizing agent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
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- 206010043207 temporal arteritis Diseases 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 230000003685 thermal hair damage Effects 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 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
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 201000006397 traumatic glaucoma Diseases 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 208000006961 tropical spastic paraparesis Diseases 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
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Description
本出願は、2020年1月7日に出願された米国仮特許出願第62/958,178号および2020年8月14日に出願された米国仮特許出願第63/065,736号の利益を主張し、それらの全体が参照により本明細書に組み込まれる。
本出願は、ASCIIフォーマットで電子的に提出された配列表を含んでおり、その全体が参照により本明細書に組み込まれる。2020年12月22日に作成されたASCIIコピーは、2012800-0069_SL.txtという名前であり、サイズは8,857バイトである。
環Aが、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R1が、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環から選択される任意に置換された基、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rxが、独立して、ハロゲン、シアノ、OR、SR、N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個または2個の炭素原子が、-O-、-N(R)-、-S-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-から独立して選択される基、および二価の3~5員の単環式、二環式、もしくは架橋二環式炭素環によって任意に置き換えられており、
各Rが、独立して、水素、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
2つのR基が、それらが結合している窒素原子と一緒になって、酸素、窒素、および硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成し、
R2が、水素、ハロゲン、N(R)2、OR、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的に不飽和、もしくはアリール炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和もしくは部分的に不飽和の複素環式環、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
nが、0、1、または2である。
環Aが、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R1が、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環から選択される任意に置換された基、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rxが、独立して、ハロゲン、シアノ、OR、SR、N(R)2、S(O)2N(R)2、C(O)OR、C(O)N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個または2個の炭素原子が、-O-、-N(R)-、-S-、-S(O)2-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-から独立して選択される基、および二価の3~5員の単環式、二環式、もしくは架橋二環式炭素環によって任意に置き換えられており、
各Rが、独立して、水素、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
2つのR基が、それらが結合している窒素原子と一緒になって、酸素、窒素、および硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成し、
R2が、水素、ハロゲン、N(R)2、OR、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的に不飽和、もしくはアリール炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和もしくは部分的に不飽和の複素環式環、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
nが、0、1、または2である。
脂肪族:「脂肪族」という用語は、完全に飽和しているか、もしくは1つ以上の不飽和の単位を含有する、直鎖(すなわち、非分岐)もしくは分岐、置換もしくは非置換の炭化水素鎖、または完全に飽和しているか、もしくは1つ以上の不飽和の単位を含有するが、芳香族ではなく(本明細書において「「炭化水素」または「脂環式」」とも呼ばれる)、分子の残りの部分への単一の結合点を有する、単環式炭化水素または二環式炭化水素を指す。特に明記しない限り、脂肪族基は、1~6個の脂肪族炭素原子を含有する。いくつかの実施形態において、脂肪族基は、1~5個の脂肪族炭素原子を含有する。他の実施形態において、脂肪族基は、1~4個の脂肪族炭素原子を含有する。さらに他の実施形態において、脂肪族基は、1~3個の脂肪族炭素原子を含有し、さらに他の実施形態において、脂肪族基は、1~2個の脂肪族炭素原子を含有する。いくつかの実施形態において、「脂環式」(または「炭素環」)は、完全に飽和しているか、または1つ以上の不飽和の単位を含有するが、芳香族ではない、単環式C3~C8炭化水素または二環式C7~C10炭化水素を指す。好適な脂肪族基は、直鎖または分岐鎖、置換または非置換のアルキル、アルケニル、アルキニル、アルキレン、アルケニレン、アルキニレン基、およびそれらのハイブリッドが含まれるが、これらに限定されない。
プログラムされた軸索変性およびSARM1
軸索変性は、限定されないが、アルツハイマー病、パーキンソン病、ALS、多発性硬化症、糖尿病性末梢神経障害、化学療法誘発性末梢神経障害、遺伝性神経障害、外傷性脳損傷、および/または緑内障などの神経疾患の主要な病理学的特性である。損傷した軸索または不健康な軸索は、ウォーラー変性として知られるアポトーシスのような従来の細胞死経路とは異なる固有の自己破壊プログラムによって排除される。(Gerdts,J.,et al.,Neuron,2016,89,449-460;Whitmore,A.V.et al.,Cell Death Differ.,2003,10,260-261)。ウォーラー変性の際、末梢神経は損傷の遠位にある軸索セグメントの選択的分解を受けるが、一方、近位軸索セグメントおよび細胞体は無傷のままである。この変性は、最初にニコチンアミドモノヌクレオチドアデニルトランスフェラーゼ(NMNAT)の枯渇、続いてニコチンアミドアデニンジヌクレオチド(NAD+)の喪失、アデノシン三リン酸(ATP)の喪失、ニューロフィラメントタンパク質分解、および損傷の約8~24時間後の軸索分解を特徴とする。(Gerdts,J.,et al.,Neuron,2016,89,449-460)。
いくつかの実施形態において、本開示は、式Iの化合物、
環Aが、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R1が、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環から選択される任意に置換された基、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rxが、独立して、ハロゲン、シアノ、OR、SR、N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個または2個の炭素原子が、-O-、-N(R)-、-S-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-から独立して選択される基、および二価の3~5員の単環式、二環式、もしくは架橋二環式炭素環式環によって任意に置き換えられており、
各Rが、独立して、水素、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
2つのR基が、それらが結合している窒素原子と一緒になって、酸素、窒素、および硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成し、
R2が、水素、ハロゲン、N(R)2、OR、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的に不飽和、もしくはアリール炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和もしくは部分的に不飽和の複素環式環、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
nが、0、1、または2である。
環Aが、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R1が、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環から選択される任意に置換された基、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rxが、独立して、ハロゲン、シアノ、OR、SR、N(R)2、S(O)2N(R)2、C(O)OR、C(O)N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個または2個の炭素原子が、-O-、-N(R)-、-S-、-S(O)2-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-から独立して選択される基、および二価の3~5員の単環式、二環式、もしくは架橋二環式炭素環式環によって任意に置き換えられており、
各Rが、独立して、水素、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
2つのR基が、それらが結合している窒素原子と一緒になって、酸素、窒素、および硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成し、
R2が、水素、ハロゲン、N(R)2、OR、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的に不飽和、もしくはアリール炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和もしくは部分的に不飽和の複素環式環、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
nが、0、1、または2である。
窒素原子上のRxが、C1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
炭素原子上のRxが、ハロゲン、シアノ、OR、SR、N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択される。
環Aが、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R1が、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環から選択される任意に置換された基、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rxが、独立して、ハロゲン、シアノ、OR、SR、N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個または2個の炭素原子が、-O-、-N(R)-、-S-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-から独立して選択される基、および二価の3~5員の単環式、二環式、もしくは架橋二環式炭素環によって任意に置き換えられており、
各Rが、独立して、水素、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
2つのR基が、それらが結合している窒素原子と一緒になって、酸素、窒素、および硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環を形成し、
R2が、水素、ハロゲン、N(R)2、OR、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的に不飽和、もしくはアリール炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和もしくは部分的に不飽和の複素環、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
nが、0、1、または2である、化合物。
窒素原子上のRxが、C1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
炭素原子上のRxが、ハロゲン、シアノ、OR、SR、N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択される、実施形態1に記載の化合物。
(i)軸索変性を特徴とする状態を有するか、または(ii)軸索変性を特徴とする状態を発症するリスクがある対象に、実施形態1~91aのいずれか1つに記載の化合物を投与するステップを含む、方法。
環Aが、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
R1が、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環から選択される任意に置換された基、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であり、
各Rxが、独立して、ハロゲン、シアノ、OR、SR、N(R)2、S(O)2N(R)2、C(O)OR、C(O)N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
Lが、任意に置換されたC1-4脂肪族鎖であり、脂肪族鎖中の1個または2個の炭素原子が、-O-、-N(R)-、-S-、-S(O)2-、-C(O)-、-C(O)N(R)-、-N(R)C(O)-、-C(O)O-、-OC(O)-、-S(O)2N(R)-、-N(R)S(O)2-から独立して選択される基、および二価の3~5員の単環式、二環式、もしくは架橋二環式炭素環式環によって任意に置き換えられており、
各Rが、独立して、水素、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環であるか、あるいは
2つのR基が、それらが結合している窒素原子と一緒になって、酸素、窒素、および硫黄から独立して選択される0~2個の追加のヘテロ原子を有する任意に置換された3~7員の単環式複素環式環を形成し、
R2が、水素、ハロゲン、N(R)2、OR、またはC1-6脂肪族から選択される任意に置換された基、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、8~10員の二環式飽和、部分的に不飽和、もしくはアリール炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式飽和もしくは部分的に不飽和の複素環式環、または酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する8~10員の二環式ヘテロアリール環であり、
nが、0、1、または2である、化合物。
窒素原子上のRxが、C1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択され、
炭素原子上のRxが、ハロゲン、シアノ、OR、SR、N(R)2、またはC1-4脂肪族から選択される任意に置換された基、3~7員の飽和もしくは部分的に不飽和の炭素環式環、酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する3~7員の飽和もしくは部分的に不飽和の複素環式環、フェニル、ならびに酸素、窒素、および硫黄から独立して選択される1~3個のヘテロ原子を有する5~6員のヘテロアリール環、から選択される、実施形態96に記載の化合物。
(i)軸索変性を特徴とする状態を有するか、または(ii)軸索変性を特徴とする状態を発症するリスクがある対象に、実施形態96~211のいずれか1つに記載の化合物を投与するステップを含む、方法。
いくつかの実施形態において、式Iまたは式I’の化合物は、組成物において、例えば、1つ以上の他の成分との組み合わせ(例えば、混合物)で提供され得る。
とりわけ、本開示は、本明細書に記載される化合物および/または組成物の同定および/または特性評価のための様々な技術を提供する。例えば、本開示は、SARM1阻害活性を評価するための、特に、SARM1阻害活性を評価するための様々なアッセイを提供する。
いくつかの実施形態において、SARM1阻害剤を同定する方法は、a)i)SARM1の変異体またはフラグメント、ii)NAD+、およびiii)候補阻害剤を含む混合物を提供することであって、変異体またはフラグメントは、構成的活性を有する、提供することと、b)混合物をインキュベートすることと、c)インキュベーション後の混合物中のNAD+を定量化することと、d)NAD+の量が、候補阻害剤を含有しない対照混合物の量よりも多い場合、候補阻害剤化合物を阻害剤として同定することと、を含む。
いくつかの実施形態において、提供されるSARM1阻害剤の有効性は、例えば、2018年3月29日に公開されたWO2018/057989に記載されたアッセイに従って決定することができ、参照によりその全体が本明細書に組み込まれる。いくつかの実施形態において、提供されるSARM1阻害剤は、SARM1またはそのフラグメントを含有する溶液に適用することができる。いくつかの実施形態において、提供されるSARM1阻害剤は、インビトロシステムに適用することができる。いくつかの実施形態において、提供されるSARM1阻害剤は、インビボで適用することができる。いくつかの実施形態において、提供されるSARM1阻害剤は、患者に適用することができる。いくつかの実施形態において、SARM1阻害剤は、エピトープタグで標識されたSARM1またはそのフラグメントと混合することができる。いくつかの実施形態において、結合されたSARM1阻害剤の量は、結合されていないSARM1阻害剤の量と比較され得、SARM1阻害剤に対する親和性をもたらす。
いくつかの実施形態において、SARM1-TIRドメインは、例えば、精製において有用であり得る様々なタンパク質またはエピトープ、タグで操作することができる。いくつかの実施形態において、本開示はまた、ニコチンアミドリボシドキナーゼ1(NRK1)で形質転換されたHEK293T細胞を含むNRK1-HEK293T細胞株を提供する。いくつかの実施形態において、HEK293T細胞は、ニコチンアミドリボシドキナーゼ1(NRK1)をコードするDNA配列で形質転換またはトランスフェクトされた。いくつかの実施形態において、NRK1をコードするDNAは、ゲノムまたはcDNAであり得る。いくつかの実施形態において、HEK293T細胞は、宿主細胞に対して外因性の供給源からNRK1をコードするDNAで安定的または一時的にトランスフェクトされる。いくつかの実施形態において、HEK293T細胞は、細胞が対照細胞と比較して高いレベルでNRK1を発現するように、NRK1をコードするDNAで安定的または一時的にトランスフェクトされる。いくつかの実施形態において、NRK1をコードするDNAは、プロモーター、エンハンサー、またはそれらの組み合わせなどの1つ以上の外因性調節DNA配列の制御下にある。いくつかの実施形態において、NRK1をコードするDNA配列と調節配列との組み合わせは、天然に存在しない組み合わせである。いくつかの実施形態において、NRK1をコードするDNAは、ゲノムまたはcDNAのいずれかであり、FCIV発現ベクターなどの発現ベクターを含む。いくつかの実施形態において、NRK1をコードするDNAは、脊椎動物または無脊椎動物種、例えば、これらに限定されないが、ヒト、マウス、ゼブラフィッシュ、またはショウジョウバエからのゲノムDNAまたはcDNAに由来する。いくつかの構成において、NRK1 DNAは、ヒトNRK1 DNAである。
本開示は、例えば、本明細書に記載されるそれらの活性および/または特徴の見地から、本明細書に記載される化合物および/または組成物の様々な使用および用途を提供する。いくつかの実施形態において、かかる使用は、治療的および/または診断的使用を含み得る。代替的に、いくつかの実施形態において、かかる使用は、研究、生産、および/または他の技術的使用を含み得る。
いくつかの実施形態において、本明細書に記載される化合物および/または組成物は、1つ以上の疾患、障害、または状態に罹患している対象に投与することができる。いくつかの実施形態において、1つ以上の疾患、障害、または状態は、SARM1によって媒介される。
いくつかの実施形態において、本明細書に記載される化合物および/または組成物は、本明細書に記載の疾患、障害もしくは状態に罹患している、または罹患しやすい対象に投与される。いくつかの実施形態において、かかる疾患、障害、または状態は、本明細書で言及される状態の1つなどの軸索変性を特徴とする。
当業者は、いくつかの実施形態において、本明細書に記載されるような薬学的組成物もしくはレジメンの投与に含まれるおよび/または投与によって送達される特定の化合物の正確な量が、医師によって選択され得、例えば、対象の1つ以上の種、年齢、および一般的な状態、および/または特定の化合物もしくは組成物の同一性、その投与方法などを考慮して、異なる対象に対して異なっていてもよいことを理解するであろう。代替的に、いくつかの実施形態において、本明細書に記載されるような薬学的組成物またはレジメンの投与に含まれるおよび/または投与される特定の化合物の量は、関連する患者集団(例えば、すべての患者、特定の年齢もしくは疾患のすべての患者、または特定のバイオマーカーを発現しているすべての患者など)にわたって標準化され得る。
本明細書に記載のいくつかの方法および組成物は、当業者に周知の実験技術を利用し、実験マニュアルに認めることができ、Sambrook,J.,et al.,Molecular Cloning:A Laboratory Manual,3rd ed.Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,2001、Methods In Molecular Biology,ed.Richard,Humana Press,NJ,1995、Spector,D.L.et al.,Cells:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1998、およびHarlow,E.,Using Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1999などが挙げられる。医薬品の投与方法および投与レジームは、標準的な参照テキストによって提供される方法を使用して、薬理学の標準的な原則に従って決定することができ、Remington:the Science and Practice of Pharmacy(Alfonso R.Gennaro ed.19th ed.1995)、Hardman,J.G.,et al.,Goodman & Gilman’s The Pharmacological Basis of Therapeutics,Ninth Edition,McGraw-Hill,1996、およびRowe,R.C.,et al.,Handbook of Pharmaceutical Excipients,Fourth Edition,Pharmaceutical Press,2003などが挙げられる。
一般的な合成方法
本発明による化合物およびそれらの中間体は、当業者に知られており、有機合成の文献に記載されている合成方法を使用して得られ得る。好ましくは、化合物は、特に実験のセクションに記載されるように、以下により完全に説明される調製方法に類似した方法で得られる。場合によっては、反応ステップを実行する順序は、変更され得る。当業者には知られているが、ここでは詳細に説明されていない反応方法の変種も使用され得る。
a)Waters Xbridge C18 10μm 30×100mmカラム
b)Waters Sunfire C18 10μm 30×100mmカラム
c)Waters Xbridge C18 3.5μm 50×4.6mmカラム
d)HALO C18 2.7μm 30×4.6mmカラム
e)Waters Sunfire C18 3.5μm 50×4.6mmカラム
本明細書に開示される化合物を調製するために使用されるカルボン酸は、市販されているか、当業者によって容易に調製することができるか、または以下の方法のうちの1つを使用して調製することができる。本明細書に開示される化合物を調製するために使用される酸塩化物は、塩化オキサリルおよび塩化スルホニルなどの試薬によって、カルボン酸から当業者によって容易に調製することができる。
本発明の最終化合物を調製するために使用されるアミンは、市販されているか、当業者によって容易に調製することができるか、または以下の方法のうちの1つを使用して調製することができる。
方法F:実施例17の合成
実施例117(95mg、0.30mmol)をメタノール/アセトニトリルの混合物に溶解し、Chiralpak OD-H、10×250mm、15mL/分の流速で、CO2中の0%~15%のメタノールの勾配で溶出する5μmカラムでの超臨界流体クロマトグラフィーにより精製して、表題の化合物を得た。
実施例109(226mg、0.67mmol)をメタノール、アセトニトリル、IPA、およびギ酸の混合物に溶解し、Chiralpak OD-H、20×250mm、9mL/分の流量で、メタノールで溶出する5μmカラムでのフラッシュカラムクロマトグラフィーにより精製して、表題化合物を得た。
実施例131(82mg、0.257mmol)をメタノール、IPA、およびギ酸の混合物に溶解し、Chiralpak AD-H、20×250mm、9mL/分の流量で、メタノールで溶出する5μmカラムでのフラッシュカラムクロマトグラフィーにより精製して、表題化合物を得た。
実施例132(21mg、0.063mmol)をメタノールおよびIPAの混合物に溶解し、Chiralpak AD-H、20×250mm、9mL/分の流量で、メタノールで溶出する5μmカラムでのフラッシュカラムクロマトグラフィーにより精製して、表題化合物を得た。
LCMS方法:
分析LC/MS分析方法A:
ESI+/-イオンモード150-850Da
カラム:Phenomenex Kinetix-XB C18、品番00D-4498-AN、2.1×100mm、1.7μm
温度:40℃
勾配:
ESI+/-イオンモード150-850Da
カラム:Phenomenex Gemini-NX C18、品番00D-4453-B0、2.0×100mm、3.0μm
温度:40℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:Waters UPLC(登録商標)BEH(商標)C18、品番186002352、2.1×100mm、1.7μm
温度:40℃
勾配:
ESI+/-イオンモード100-1000Da
カラム:Waters UPLC(登録商標)BEH(商標)C18、品番186005297、1.7μm 2.1×50mmカラム
温度:40℃
勾配:
この実施例は、ARM-SAM-TIR NADアーゼ活性のアッセイ、およびSARM1媒介NAD+切断をブロックするための式Iまたは式I’の化合物の有効性を測定するためのこのアッセイの使用を説明する。このアッセイは、SARM1活性を阻害する式Iまたは式I’の化合物の有効性を特徴付け、各化合物のIC50値を計算するように最適化されている。このアッセイは、ARM、SAM、およびTIRドメインを含む全長のSARM1を使用する。本明細書に示されるように、自己阻害性N-末端ドメインなしでのこのフラグメントの発現は、NAD+を切断する構成的に活性な酵素を生成する。
NRK1-HEK293T細胞を、150cm2のプレート上に20×106細胞/プレートで播種した。翌日、細胞を15μgのARM-SAM-TIR発現プラスミド、配列番号1でトランスフェクトした。
GCGATCGCGGCTCCCGACATCTTGGACCATTAGCTCCACAGGTATCTTCTTCCCTCTAGTGGTCATAACAGCAGCTTCAGCTACCTCTCAATTCAAAAAACCCCTCAAGACCCGTTTAGAGGCCCCAAGGGGTTATGCTATCAATCGTTGCGTTACACACACAAAAAACCAACACACATCCATCTTCGATGGATAGCGATTTTATTATCTAACTGCTGATCGAGTGTAGCCAGATCTAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGCTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCAGATCTTTGTCGATCCTACCATCCACTCGACACACCCGCCAGCGGCCGCTGCCAAGCTTCCGAGCTCTCGAATTCAAAGGAGGTACCCACcatgGCCATGCATCACCACCACCATCATAGCTCCGGCGTCGACCTCGGCACCGAGAATTTATATTTCCAAAGCGGCCTCAATGATATCTTCGAGGCCCAGAAGATCGAGTGGCACGAGGGCAGCTCCGACCTCGCCGTGCCCGGTCCCGATGGAGGCGGAGGCACTGGTCCTTGGTGGGCTGCTGGCGGCAGAGGCCCTAGAGAAGTGAGCCCCGGTGCTGGCACCGAGGTGCAAGACGCTCTGGAGAGGGCTCTGCCCGAACTGCAGCAAGCTCTGTCCGCTTTAAAGCAAGCTGGAGGAGCTAGAGCCGTCGGCGCCGGACTGGCCGAAGTGTTCCAGCTCGTGGAGGAAGCTTGGTTATTACCCGCTGTGGGAAGAGAGGTCGCCCAAGGTCTGTGTGACGCCATTCGTCTGGACGGAGGTTTAGACTTATTACTGAGGCTGCTGCAAGCTCCCGAACTGGAGACAAGGGTCCAAGCTGCTCGTCTGCTGGAGCAGATCCTCGTGGCCGAGAATCGTGACAGAGTGGCTAGAATCGGTTTAGGCGTCATCCTCAATTTAGCCAAAGAGAGGGAGCCCGTTGAGCTGGCCAGAAGCGTCGCTGGCATCCTCGAGCACATGTTCAAGCATTCCGAGGAGACTTGTCAGAGACTGGTCGCCGCCGGAGGACTCGATGCTGTTTTATACTGGTGCAGAAGGACAGACCCCGCTTTACTGAGGCATTGTGCTCTGGCCCTCGGCAATTGCGCTTTACATGGAGGCCAAGCCGTCCAGAGAAGGATGGTGGAGAAAAGAGCCGCCGAGTGGCTGTTCCCTTTAGCCTTCTCCAAAGAAGACGAACTGTTACGTCTGCATGCTTGTCTCGCTGTCGCTGTTTTAGCCACCAACAAGGAGGTGGAAAGGGAAGTGGAAAGAAGCGGAACACTGGCTTTAGTCGAACCTCTGGTGGCTTCTTTAGATCCCGGAAGGTTTGCCAGATGTCTGGTCGACGCCAGCGATACCTCCCAAGGAAGAGGCCCCGACGATCTCCAGAGACTGGTGCCTCTGCTGGACAGCAATCGTCTGGAGGCCCAATGTATTGGCGCCTTCTATCTCTGCGCCGAAGCCGCCATCAAGTCTTTACAAGGTAAGACCAAGGTGTTCTCCGACATTGGAGCCATCCAATCTTTAAAGAGGCTGGTGAGCTATTCCACCAACGGCACAAAAAGCGCTTTAGCCAAAAGAGCTTTAAGACTGCTGGGCGAAGAGGTGCCTAGGCCCATTTTACCTTCCGTGCCTAGCTGGAAGGAGGCCGAGGTGCAGACTTGGCTGCAGCAGATCGGCTTTAGCAAATATTGCGAATCCTTTAGGGAGCAGCAAGTTGACGGCGATTTATTATTAAGGCTGACCGAGGAAGAGCTCCAGACAGATTTAGGCATGAAAAGCGGCATCACTCGTAAGAGGTTCTTTCGTGAGCTCACCGAACTGAAGACCTTCGCCAACTACTCCACTTGTGATCGTAGCAATTTAGCTGATTGGCTCGGATCCCTCGATCCCAGATTTCGTCAGTACACCTATGGACTCGTCTCTTGTGGACTGGACAGATCTTTACTGCATCGTGTGAGCGAGCAACAGCTGCTGGAAGATTGCGGCATCCATTTAGGAGTGCACAGAGCCAGAATTCTGACCGCCGCTAGAGAGATGCTGCATTCCCCTCTCCCTTGTACCGGAGGCAAGCCTAGCGGAGACACCCCCGACGTGTTCATCAGCTATCGTAGAAACAGCGGAAGCCAGCTGGCCTCTTTACTGAAGGTCCATTTACAGCTGCACGGATTTAGCGTCTTCATCGACGTGGAGAAACTGGAGGCTGGCAAGTTCGAGGACAAGCTGATCCAGTCCGTGATGGGCGCTAGGAATTTCGTTTTAGTGCTCAGCCCCGGCGCTCTGGATAAATGCATGCAAGATCATGACTGTAAGGACTGGGTCCACAAGGAAATCGTGACCGCTCTGTCTTGTGGCAAGAACATCGTCCCCATCATCGACGGCTTCGAATGGCCCGAGCCTCAAGTTCTCCCCGAAGATATGCAAGCTGTTTTAACCTTCAATGGAATCAAGTGGAGCCACGAGTACCAAGAAGCCACAATCGAGAAGATCATTCGTTTTCTGCAAGGTAGATCCTCCAGAGATTCCTCCGCTGGCAGCGACACATCTTTAGAGGGCGCCGCCCCTATGGGTCCTACCTAATAATctagAAGTTGTCTCCTCCTGCACTGACTGACTGATACAATCGATTTCTGGATCCGCAGGCCTCTGCTAGCTTGACTGACTGAGATACAGCGTACCTTCAGCTCACAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAAAGCAAGTAAAACCTCTACAAATGTGGTATTGGCCCATCTCTATCGGTATCGTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGTGCCCCTCGGGCCGGATTGCTATCTACCGGCATTGGCGCAGAAAAAAATGCCTGATGCGACGCTGCGCGTCTTATACTCCCACATATGCCAGATTCAGCAACGGATACGGCTTCCCCAACTTGCCCACTTCCATACGTGTCCTCCTTACCAGAAATTTATCCTTAAGGTCGTCAGCTATCCTGCAGGCGATCTCTCGATTTCGATCAAGACATTCCTTTAATGGTCTTTTCTGGACACCACTAGGGGTCAGAAGTAGTTCATCAAACTTTCTTCCCTCCCTAATCTCATTGGTTACCTTGGGCTATCGAAACTTAATTAACCAGTCAAGTCAGCTACTTGGCGAGATCGACTTGTCTGGGTTTCGACTACGCTCAGAATTGCGTCAGTCAAGTTCGATCTGGTCCTTGCTATTGCACCCGTTCTCCGATTACGAGTTTCATTTAAATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCATTTAAATTTCCGAACTCTCCAAGGCCCTCGTCGGAAAATCTTCAAACCTTTCGTCCGATCCATCTTGCAGGCTACCTCTCGAACGAACTATCGCAAGTCTCTTGGCCGGCCTTGCGCCTTGGCTATTGCTTGGCAGCGCCTATCGCCAGGTATTACTCCAATCCCGAATATCCGAGATCGGGATCACCCGAGAGAAGTTCAACCTACATCCTCAATCCCGATCTATCCGAGATCCGAGGAATATCGAAATCGGGGCGCG
CCTGGTGTACCGAGAACGATCCTCTCAGTGCGAGTCTCGACGATCCATATCGTTGCTTGGCAGTCAGCCAGTCGGAATCCAGCTTGGGACCCAGGAAGTCCAATCGTCAGATATTGTACTCAAGCCTGGTCACGGCAGCGTACCGATCTGTTTAAACCTAGATATTGATAGTCTGATCGGTCAACGTATAATCGAGTCCTAGCTTTTGCAAACATCTATCAAGAGACAGGATCAGCAGGAGGCTTTCGCATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTGCGCGAGTGGGTTACATCGAACTGGATCTCAACAGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGCTTTCCAATGATGAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTATTGACGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTATTCACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAACGATTGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGTAGCAATGGCAACAACCTTGCGTAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAGTTGATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACCGATTCTAGGTGCATTGGCGCAGAAAAAAATGCCTGATGCGACGCTGCGCGTCTTATACTCCCACATATGCCAGATTCAGCAACGGATACGGCTTCCCCAACTTGCCCACTTCCATACGTGTCCTCCTTACCAGAAATTTATCCTTAAGATCCCGAATCGTTTAAACTCGACTCTGGCTCTATCGAATCTCCGTCGTTTCGAGCTTACGCGAACAGCCGTGGCGCTCATTTGCTCGTCGGGCATCGAATCTCGTCAGCTATCGTCAGCTTACCTTTTTGGCA(SEQ ID NO:1).
式Iまたは式I’の化合物のARM-SAM-TIR IC50アッセイ。
この実施例は、式Iまたは式I’の化合物を特徴付けるために使用されるインビトロ軸索変性アッセイを示す。このアッセイは、マウス後根神経節(DRG)落下培養における軸索変性を予防するための式Iまたは式I’の化合物の有効性を試験するために使用された。
Claims (11)
- R2が、任意に置換されたフェニルである、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。
- R2が、ピリジニルまたはピリミジニルから選択される任意に置換された基である、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。
- 請求項1~6のいずれか一項に記載の化合物またはその薬学的に許容される塩と、薬学的に許容される担体と、を含む、薬学的組成物。
- 請求項1~6のいずれか一項に記載の化合物またはその薬学的に許容される塩を含む、軸索変性を特徴とする状態を治療または予防するための薬学的組成物。
- 請求項1~6のいずれか一項に記載の化合物またはその薬学的に許容される塩を含む、軸索変性を治療または予防するための薬学的組成物。
- 請求項1~6のいずれか一項に記載の化合物またはその薬学的に許容される塩を含む、SARM1を阻害するための薬学的組成物。
- 請求項1~6のいずれか一項に記載の化合物またはその薬学的に許容される塩を含む、筋萎縮性側索硬化症、多発性硬化症、糖尿病性末梢神経障害、および化学療法誘発性神経障害から選択される疾患または障害を治療または予防するための薬学的組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3897670A4 (en) | 2018-12-19 | 2022-09-07 | Disarm Therapeutics, Inc. | MRSA1 INHIBITORS IN COMBINATION WITH NEUROPROTECTIVE AGENTS |
EP4192828A1 (en) | 2020-08-04 | 2023-06-14 | Nura Bio, Inc. | Substituted pyridine derivatives as sarm1 inhibitors |
TWI786777B (zh) | 2020-08-24 | 2022-12-11 | 美商達薩瑪治療公司 | Sarm1之抑制劑 |
EP4214197A1 (en) | 2020-09-16 | 2023-07-26 | Nura Bio, Inc. | Substituted pyridine derivatives as sarm1 inhibitors |
EP4376840A1 (en) | 2021-07-28 | 2024-06-05 | Nura Bio, Inc. | Substituted pyridine derivatives as sarm1 inhibitors |
WO2024125624A1 (en) * | 2022-12-15 | 2024-06-20 | Sironax Ltd. | Sarm1 modulators, preparations, and uses thereof |
WO2024158775A1 (en) | 2023-01-24 | 2024-08-02 | Disarm Therapeutics, Inc. | Pyridazines as sarm1 inhibitors |
WO2024158607A1 (en) | 2023-01-24 | 2024-08-02 | Disarm Therapeutics, Inc. | Substituted 1h-pyrazole-4-carboxamides as sarm1 inhibitors |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040157861A1 (en) | 2003-01-02 | 2004-08-12 | Millennium Pharmaceuticals, Inc. | Compositions and methods for inhibiting TGF-beta |
JP2004532235A (ja) | 2001-04-30 | 2004-10-21 | ザ プロクター アンド ギャンブル カンパニー | 望ましくないサイトカイン活性に関連する疾患を治療するのに有用なトリアゾール化合物 |
JP2006514684A (ja) | 2002-10-30 | 2006-05-11 | バーテックス ファーマシューティカルズ インコーポレイテッド | Rockおよび他のプロテインキナーゼとして有用な組成物 |
JP2006525266A (ja) | 2003-05-02 | 2006-11-09 | ノバルティス アクチエンゲゼルシャフト | ホスファチジルイノシトール3−キナーゼの阻害剤 |
JP2007523168A (ja) | 2004-02-18 | 2007-08-16 | アストラゼネカ アクチボラグ | 追加の複素多環式化合物及びそれらの代謝調節型グルタミン酸受容体アンタゴニストとしての使用 |
JP2007535551A (ja) | 2004-04-28 | 2007-12-06 | バーテックス ファーマシューティカルズ インコーポレイテッド | Rockおよび他のプロテインキナーゼの阻害剤として有用な組成物 |
WO2008001930A1 (fr) | 2006-06-28 | 2008-01-03 | Aska Pharmaceutical Co., Ltd. | Dérivé de pyridylisoxazole |
JP2008524233A (ja) | 2004-12-16 | 2008-07-10 | バーテックス ファーマシューティカルズ インコーポレイテッド | 炎症性疾患、増殖性疾患および免疫介在性疾患の治療のためのtecファミリータンパク質キナーゼのインヒビターとして有用なピリド−2−オン |
JP2010504295A (ja) | 2006-09-21 | 2010-02-12 | ノバルティス アーゲー | サイトカイン介在疾患の処置に有用なピロール誘導体 |
WO2010093849A2 (en) | 2009-02-13 | 2010-08-19 | Amgen Inc. | Phenylalanine amide derivatives useful for treating insulin-related diseases and conditions |
JP2011506563A (ja) | 2007-12-20 | 2011-03-03 | ノバルティス アーゲー | ビスチアゾール誘導体、その製造方法および医薬品としてのその使用 |
JP2011506560A (ja) | 2007-12-20 | 2011-03-03 | ノバルティス アーゲー | Pi3キナーゼ阻害剤として用いられるチアゾール誘導体 |
WO2018107056A1 (en) | 2016-12-09 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | 1,3-substitued pyrazole compounds useful for reduction of very long chain fatty acic levels |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1732164A (zh) * | 2002-10-30 | 2006-02-08 | 沃泰克斯药物股份有限公司 | 可用作rock及其他蛋白质激酶抑制剂的组合物 |
CN101111479A (zh) * | 2004-12-16 | 2008-01-23 | 沃泰克斯药物股份有限公司 | 可用作激酶抑制剂的吡啶酮 |
EP2219646A4 (en) * | 2007-12-21 | 2010-12-22 | Univ Rochester | METHOD FOR MODIFYING THE LIFETIME OF EUKARYOTIC ORGANISMS |
RU2570907C2 (ru) * | 2013-10-21 | 2015-12-20 | Автономная Некоммерческая Организация "Научно-Исследовательский Центр Биотехнологии Антибиотиков И Других Биологически Активных Веществ "Биоан" | Производные 3-ациламинопиридин-2(1h)-она, применимые как ингибиторы серин-треониновой протеинкиназы gsk3b в качестве лекарственных препаратов для лечения диабета ii типа. |
WO2015112847A1 (en) * | 2014-01-24 | 2015-07-30 | Confluence Life Sciences, Inc. | Arylpyridinone itk inhibitors for treating inflammation and cancer |
US10392402B2 (en) * | 2015-05-18 | 2019-08-27 | Translational Drug Development, Llc | Heterocyclic compounds as kinase inhibitors |
CN110545804A (zh) | 2016-09-24 | 2019-12-06 | 华盛顿大学 | Sarm1 nad酶活性抑制剂及其用途 |
MA52812A (fr) * | 2018-06-07 | 2021-04-14 | Disarm Therapeutics Inc | Inhibiteurs de sarm1 |
CN111253333A (zh) * | 2018-11-30 | 2020-06-09 | 青岛清原化合物有限公司 | N-(1,3,4-噁二唑-2-基)芳基甲酰胺类或其盐、制备方法、除草组合物和应用 |
EP4192828A1 (en) * | 2020-08-04 | 2023-06-14 | Nura Bio, Inc. | Substituted pyridine derivatives as sarm1 inhibitors |
-
2021
- 2021-01-06 KR KR1020227027204A patent/KR20220164471A/ko unknown
- 2021-01-06 TW TW110100350A patent/TW202140437A/zh unknown
- 2021-01-06 EP EP21703092.3A patent/EP4087838A1/en active Pending
- 2021-01-06 CN CN202180019643.9A patent/CN115175900A/zh active Pending
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- 2021-08-17 US US17/404,523 patent/US20230008433A1/en active Pending
-
2022
- 2022-07-05 CL CL2022001825A patent/CL2022001825A1/es unknown
- 2022-07-05 DO DO2022000141A patent/DOP2022000141A/es unknown
- 2022-07-06 CO CONC2022/0009514A patent/CO2022009514A2/es unknown
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-
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- 2024-02-06 AU AU2024200703A patent/AU2024200703A1/en active Pending
- 2024-05-15 JP JP2024079079A patent/JP2024119812A/ja active Pending
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004532235A (ja) | 2001-04-30 | 2004-10-21 | ザ プロクター アンド ギャンブル カンパニー | 望ましくないサイトカイン活性に関連する疾患を治療するのに有用なトリアゾール化合物 |
JP2006514684A (ja) | 2002-10-30 | 2006-05-11 | バーテックス ファーマシューティカルズ インコーポレイテッド | Rockおよび他のプロテインキナーゼとして有用な組成物 |
US20040157861A1 (en) | 2003-01-02 | 2004-08-12 | Millennium Pharmaceuticals, Inc. | Compositions and methods for inhibiting TGF-beta |
JP2006525266A (ja) | 2003-05-02 | 2006-11-09 | ノバルティス アクチエンゲゼルシャフト | ホスファチジルイノシトール3−キナーゼの阻害剤 |
JP2007523168A (ja) | 2004-02-18 | 2007-08-16 | アストラゼネカ アクチボラグ | 追加の複素多環式化合物及びそれらの代謝調節型グルタミン酸受容体アンタゴニストとしての使用 |
JP2007535551A (ja) | 2004-04-28 | 2007-12-06 | バーテックス ファーマシューティカルズ インコーポレイテッド | Rockおよび他のプロテインキナーゼの阻害剤として有用な組成物 |
JP2008524233A (ja) | 2004-12-16 | 2008-07-10 | バーテックス ファーマシューティカルズ インコーポレイテッド | 炎症性疾患、増殖性疾患および免疫介在性疾患の治療のためのtecファミリータンパク質キナーゼのインヒビターとして有用なピリド−2−オン |
WO2008001930A1 (fr) | 2006-06-28 | 2008-01-03 | Aska Pharmaceutical Co., Ltd. | Dérivé de pyridylisoxazole |
JP2010504295A (ja) | 2006-09-21 | 2010-02-12 | ノバルティス アーゲー | サイトカイン介在疾患の処置に有用なピロール誘導体 |
JP2011506563A (ja) | 2007-12-20 | 2011-03-03 | ノバルティス アーゲー | ビスチアゾール誘導体、その製造方法および医薬品としてのその使用 |
JP2011506560A (ja) | 2007-12-20 | 2011-03-03 | ノバルティス アーゲー | Pi3キナーゼ阻害剤として用いられるチアゾール誘導体 |
WO2010093849A2 (en) | 2009-02-13 | 2010-08-19 | Amgen Inc. | Phenylalanine amide derivatives useful for treating insulin-related diseases and conditions |
WO2018107056A1 (en) | 2016-12-09 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | 1,3-substitued pyrazole compounds useful for reduction of very long chain fatty acic levels |
Non-Patent Citations (3)
Title |
---|
Journal of Medicinal Chemistry,2015年,58(12),5028-5037 |
REGISTRY STN online,2023年08月21日,CAS登録番号 1345729-47-6, 1344686-21-0, 1339145-34-4, 1339108-74-5, 1338956-60-7, 1301765-55-8, 1268820-66-1, 1346660-89-6, 1404213-99-5, 1346509-22-5, 1298034-16-8 |
REGISTRY STN online,2023年09月05日,CAS登録番号 329710-13-6, 714211-34-4, 874588-00-8, 1241262-29-2, 1268815-25-3 |
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ECSP22053394A (es) | 2022-11-30 |
US20230008433A1 (en) | 2023-01-12 |
CO2022009514A2 (es) | 2022-10-21 |
AU2024200703A1 (en) | 2024-02-29 |
BR112022013388A2 (pt) | 2022-09-20 |
MX2022008395A (es) | 2022-09-26 |
JP2024119812A (ja) | 2024-09-03 |
JP2023510743A (ja) | 2023-03-15 |
PE20230165A1 (es) | 2023-02-01 |
EP4087838A1 (en) | 2022-11-16 |
CN115175900A (zh) | 2022-10-11 |
CL2022001825A1 (es) | 2023-06-02 |
KR20220164471A (ko) | 2022-12-13 |
AU2021206651B2 (en) | 2024-02-22 |
DOP2022000141A (es) | 2022-10-16 |
CR20220375A (es) | 2022-09-22 |
WO2021142006A1 (en) | 2021-07-15 |
TW202140437A (zh) | 2021-11-01 |
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