JP7373804B2 - 精子の受精機能増強剤 - Google Patents
精子の受精機能増強剤 Download PDFInfo
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- JP7373804B2 JP7373804B2 JP2020523109A JP2020523109A JP7373804B2 JP 7373804 B2 JP7373804 B2 JP 7373804B2 JP 2020523109 A JP2020523109 A JP 2020523109A JP 2020523109 A JP2020523109 A JP 2020523109A JP 7373804 B2 JP7373804 B2 JP 7373804B2
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 87
- 238000000034 method Methods 0.000 claims description 69
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 239000007864 aqueous solution Substances 0.000 claims description 30
- 230000002708 enhancing effect Effects 0.000 claims description 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 22
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- ATOYWPVEKTUJHE-UHFFFAOYSA-N methyl 3-(2-methoxy-2-oxoethyl)indole-1-carboxylate Chemical compound C1=CC=C2C(CC(=O)OC)=CN(C(=O)OC)C2=C1 ATOYWPVEKTUJHE-UHFFFAOYSA-N 0.000 description 17
- KTHADMDGDNYQRX-UHFFFAOYSA-N 3-indoleacetic acid methyl ester Natural products C1=CC=C2C(CC(=O)OC)=CNC2=C1 KTHADMDGDNYQRX-UHFFFAOYSA-N 0.000 description 15
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 150000004672 propanoic acids Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 235000012045 salad Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000005368 silicate glass Substances 0.000 description 1
- 150000003384 small molecules Chemical group 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- 229960001005 tuberculin Drugs 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000004061 uncoupling agent Substances 0.000 description 1
- 238000005292 vacuum distillation 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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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D209/12—Radicals substituted by oxygen atoms
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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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Description
〔1〕以下の一般式(I0)、一般式(II)、及び一般式(III)で表される化合物、並びに、R3がOHのときそれらの生理学的に許容される塩からなる群から選択される1種又は2種以上の化合物を含む、哺乳類精子の受精機能増強剤。
〔2〕化合物が、以下の式(I-2)で表される化合物若しくはその生理学的に許容される塩である、上記〔1〕に記載の受精機能増強剤。
式(I-2);
〔4〕化合物が、以下の式(I-2)で表される化合物若しくはその生理学的に許容される塩である、上記〔3〕に記載の増強方法。
式(I-2);
〔6〕採取された少なくとも1つの哺乳類精子と、採取された少なくとも1つの哺乳類卵子とを、以下の一般式(I0)、一般式(II)、及び一般式(III)で表される化合物、並びに、R3がOHのときそれらの生理学的に許容される塩からなる群から選択される1種又は2種以上の化合物を含む培養液中で培養する工程(b-2)を含む、哺乳類受精卵の作製方法。
〔7〕化合物が、以下の式(I-2)で表される化合物若しくはその生理学的に許容される塩である、上記〔6〕に記載の作製方法。
式(I-2);
以下に示す化合物の合成方法に用いる合成原料、反応試薬等は一般的な市販品である。また、反応溶媒、反応温度に関して特に記載のない場合は、通常その反応に利用される溶媒、温度で反応が行われる。また、反応は、アルゴン若しくは乾燥させた窒素雰囲気下で行われる。
4-フェニル-2-(4-クロロ-1H-インドール-3-イル)-4-オキソ-ブタン(化合物#1)は、インドールの代わりに4-クロロインドールを用いて、後述する化合物#20の合成方法により合成した。
4-(4-クロロフェニル)-2-(1H-インドール-3-イル)-4-オキソ-ブタン酸(化合物#2)及び3-(1H-インドール-3-イル)-1-オキソ-1-フェニル-ブタン(化合物#3)は、Sayed,G. H. et al, “Synthesis and reactions of some β-aroyl-α-(indol-3-yl)propionic acids” Journal of the Chemical Society of Pakistan,7(4), 263-72; 1985の記載の方法に従って合成した。
トランス-4-(4-フルオロフェニル)-4-オキソ-2-ブテン酸
トランス-4-(2,4-ジフルオロフェニル)-4-オキソ-2-ブテン酸
for 330.0942 (C18H14F2NO3).
トランス-4-(2,4-ジメチルフェニル)-4-オキソ-2-ブテン酸
インドール-3-酢酸(2.00g,11.42mmol)をメタノール(40ml)に溶かし、そこに塩化アセチル(0.5ml,6.688mmol)を一滴ずつ滴下し、室温で2時間撹拌した。TLCで反応終了を確認した後、飽和重曹水溶液を加え、反応を停止させ、酢酸エチル(50ml)で3回抽出した。有機層を飽和食塩水で2回洗浄し、無水硫酸ナトリウムで脱水した。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3)で精製し、インドール-3-酢酸 メチルエステルを得た。(2.14g,収率99%):1H NMR(400MHz,CDCl3):δ 8.13(s,1H),6.97(s,1H),7.59(d,J=7.7Hz,1H),7.23(d,J=7.9Hz,1H),7.10-7.19(m,2H),3.67(s,3H),3.76(s,2H);13C NMR(100MHz,CDCl3):δ 172.3,136.0,127.1,123.2,122.0,119.5,118.6,111.2,108.0,51.9,31.0;IR(neat):3410,1730,1458,1435,1337,1164,1095,1011cm-1;EI-MS m/z 189 [M]+.
インドール-3-酢酸メチル(2.00g,10.57mmol)をジクロロメタン(30ml)に溶かし、そこにヨウ化テトラブチルアンモニウム(TBAI,30.0mg,0.081mmol)、30%水酸化ナトリウム水溶液(24ml)を加え、0℃に冷却した。反応液に塩化ギ酸メチル(1.96g,20.73mmol)を加え、0℃で2時間撹拌した。TLCで反応終了を確認した後、6N塩酸を加え、反応を停止させた。水(50ml)を加え、クロロホルム(50ml)で3回抽出し、有機層を飽和食塩水で2回洗浄し、無水硫酸ナトリウムで脱水した。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=8:2)で精製し、N-メトキシカルボニルインドール-3-酢酸メチルを得た。(2.26g,収率87%):1H NMR(400MHz,CDCl3):δ 8.18(d,J=7.0Hz,1H),7.59(s,1H),7.53(d,J=7.7Hz,1H),7.35(t,J=7.5Hz,1H),7.27(t,J=7.4Hz,1H),4.00(s,3H),3.72(s,3H),3.71(s,2H);13C NMR(100MHz,CDCl3):δ 171.1,151.1,135.2,129.9,124.6,123.8,122.8,118.9,115.0,113.8,53.5,51.9,30.6;IR(neat):1746,1455,1382,1258,1164,1089,1018cm-1;EI-MS: m/z 247 [M]+.
2-(N-tert-ブトキシカルボニル-4-ピペリジニル)エタノール
α-4-アミノブチル-N-メトキシカルボニル-3-インドール酢酸 メチルエステル
(m,2H);13C NMR(100MHz,CDCl3):δ 173.8,171.0,170.8,151.1,135.3,129.2,124.6,122.9,122.8,119.2,119.1,115.0,59.4,53.6,51.9,48.1,42.3,38.9,31.5,29.0,27.2,24.8,24.7,22.3;FAB-MS:m/z 458[M+H]+.
α-[2-(2-アミノエトキシ)-エチル]-N-メトキシカルボニル-3-インドール酢酸 メチルエステル
α-(N-tert-ブトキシカルボニル-6-アミノ-1-ヘキシル)-α-(1-ナフチル)-酢酸 メチルエステル
N-tert-ブトキシカルボニル-6-アミノ-1-ヘキサノール
8.19(d,J=6.3Hz,1H),7.52(d,J=7.9Hz,1H),7.48(s,1H),7.32(t,J=7.5Hz,1H),7.21(t,J=7.5Hz,1H),4.54(s,1H),4.03(s,3H),3.62(s,3H),3.06(m,2H),2.04-2.12(m,2H),1.61(s,3H),1.17-1.43(m,17H);13C NMR(100MHz,CDCl3):δ 176.3,155.9,151.3,135.8,128.6,124.9,124.5,122.8,122.0,120.0,115.2,78.9,53.7,52.1,45.5,40.4,37.2,29.9,29.5,28.3,26.5,24.2,22.5;FAB-MS:m/z 460[M]+.
2-(N-tert-ブトキシカルボニル-2-アミノエトキシ)-エタノール
N-tert-ブトキシカルボニル-4-アミノ-1-ブタノール
2-エチル-1-ヨードブタン
3-メチル-1-ヨードペンタン
2-メチル-1-ヨードペンタン
4-フェニル-2-(1H-インドール-3-イル)-4-オキソ-ブタン酸
(化合物#20)
IR:(neat):3400,3055,1711,1677,1453cm-1;HRFAB-MS found m/z 294.1143[M+H]+, calcd for 294.1130(C18H16NO3).
4,4,5,5,5-ペンタフルオロ-1-ヨードペンタン
3-(2-ヒドロキシ-1-エチル)-1,1’-ビフェニル
355[M]+.
α-(2-フェニル-1-エチル)-1-メトキシカルボニル-3-インドール酢酸 メチルエステル
2-シクロペンチル-1-ヨードエタン
シクロペンチルヨードメタン
に記載の方法に従って合成した。
N-メチル-3-インドール酢酸 メチルエステル
N-エチル-3-インドール酢酸 メチルエステル
N-プロピル-3-インドール酢酸 メチルエステル
N-ブチル-3-インドール酢酸 メチルエステル
N-ヘキシル-3-インドール酢酸 メチルエステル
N-ヘプチル-3-インドール酢酸 メチルエステル
α-(7-ブトキシ-1-ナフタレニル)-酢酸 エチルエステル
認した後、6N塩酸を加え酸性(pH=3~4)にし、溶媒を減圧留去した。水(5ml)を加え、酢酸エチル(10ml)で3回抽出した。有機層を飽和食塩水で2回洗浄し、無水硫酸ナトリウムで脱水した。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=9:1)で精製しα-(7-ブトキシ-1-ナフタレニル)-酢酸(化合物#33)を得た。(67mg,収率98%):融点102~104℃;1H NMR(400MHz,CDCl3):δ 7.75(d,J=8.9Hz,1H),7.71(d,J=8.1Hz,1H),7.34(d,J=6.9Hz,1H),7.26(dd,J=8.1,6.9Hz,1H),7.23(d,J=2.0Hz,1H),7.16(q,J=8.9,2.0Hz,1H),4.05(t,J=6.5Hz,2H),4.00(s,2H),1.51(m,2H),1.80(m,2H),0.98(t,J=7.4Hz,3H);13C NMR(100MHz,CDCl3):δ 177.6,157.6,133.2,130.2,129.1,128.6,127.9(2C),123.0,118.7,103.1,67.7,39.2,31.2,19.3,13.8;IR(neat):3021,2931,1699,1457,1138cm-1;HREI-MS found m/z 258.1268[M]+,calcd for 258.1256(C16H18O3).
α-(7-ペントキシ-1-ナフタレニル)-酢酸 エチルエステル
5-(3,5-ジメトキシベンジルオキシ)-3-インドール酢酸 メチルエステル
5-メトキシ-3-インドール酢酸 メチルエステル
5-エトキシ-3-インドール酢酸 メチルエステル
5-(1-プロポキシ)-3-インドール酢酸 メチルエステル
5-(1-ブトキシ)-3-インドール酢酸 メチルエステル
1H-NMR(400MHz, CDCl3) δ 10.31 (s, 1H), 8.01 (m, 1H), 7.47 (dd, J=8.8, 5.2, 1H),7.34 (d, J=2.0, 2H), 7.12-7.20 (m, 3H), 6.92 (td, J=9.6, 2.4, 1H), 4.54 (dd, J=10.4, 4.0, 1H), 4.01 (ddd, J=18.8, 10.8, 3.2, 1H), 3.38 (td, J=18.8, 3.2, 1H);
13C-NMR (100MHz, CDCl3) δ 195.18, 174.85, 166.28 JC-F(dd, 254, 13 Hz), 163.42 JC-F (dd, 254, 13 Hz), 161.74, 159.4, 137.54 JC-F (d, 13 Hz), 133.47 JC-F(dd, 11,3 Hz), 123.35 JC-F(d, 4Hz), 123.02 JC-F (dd, 13, 4 Hz), 120.97 JC-F (d, 11 Hz), 113.51, 112.94 JC-F (dd, 10, 2 Hz) , 108.27 JC-F (d, 24 Hz), 105.59 JC-F (t, 27 Hz), 98.27 JC-F (d, 26 Hz), 46.68 JC-F (d, 7Hz) ,38.47;
FAB-MS m/z = 348 [M+H]+
1H-NMR(400MHz, acetone-d6) δ10.34 (s, 1H), 8.02 (m, 1H), 7.47 (dd, J=10.4, 2.8,1H), 7.39-7.43 (m, 2H), 7.13-7.21 (m, 2H), 6.93 (td, J=9.2 , 2.8, 1H), 4.52 (dd, J=10.4, 3.6, 1H), 4.03 (ddd, 18.4, 10.8, 3.6, 1H), 3.40 (td, 18.4, 3.6, 1H); 13C-NMR (100MHz, acetone-d6) δ 195.17, 174.86, 166.52 JC-F(dd, 254, 13 Hz), 163.58 JC-F(dd, 254, 13 Hz), 159.52, 157.21, 134.25, 133.46 JC-F (dd, 11, 4 Hz), 127.66 JC-F(d, 11 Hz), 123.01 JC-F (dd, 10, 4 Hz), 113.42 JC-F (d, 5 Hz), 113.28 JC-F(d, 10 Hz), 113.51 JC-F (dd, 21, 4 Hz), 110.56 JC-F(d, 27 Hz), 105.61 JC-F (t, 27 Hz), 104.65 JC-F (d, 24 Hz), 46.68 JC-F (d, 8Hz), 38.48;
FAB-MS m/z = 348 [M+H]+
1H-NMR(400MHz, acetone-d6) δ10.55 (s, 1H), 8.01 (m, 1H), 7.75 (d, J=8.4, 1H), 7.45 (d, J=2.8, 1H), 7.06-7.14 (m, 4H), 7.08 (t. J=7.6, 1H), 4.57 (dd, J=10.4 , 3.6, 1H), 4.03 (ddd, 18.4, 10.8, 3.6, 1H), 3.41 (td, 18.4, 3.6, 1H);
13C-NMR(100MHz, acetone-d6) δ195.06, 74.67, 166.53, JC-F(dd, 252, 12 Hz), 163.63 JC-F(dd, 252, 12 Hz), 134.45, 133.46 JC-F(dd, 11, 5 Hz), 129.25, 124.97, 122.98 JC-F(dd, 13, 4 Hz), 121.91, 120.84, 119.03, 117.22, 114.73, 112.99 JC-F(dd, 21, 3 Hz), 105.61 JC-F(t, 27 Hz), 46.71 JC-F (d, 8 Hz) , 38.50;
FAB-MS m/z = 364 [M+H]+
1H-NMR(400MHz, acetone-d6) δ10.45 (s, 1H), 8.02 (q, J=8.3, 1H), 7.80 (d, J=1.6,1H), 7.44 (m, 2H), 7.11-7.22 (m, 3H), 4.54 (dd, J=10.4, 3.8, 1H), 4.01 (ddd, J=18.7, 10.7, 3.2, 1H), 3.41 (td, J=18.7, 3.2, 1H);
13C-NMR (100MHz, acetone-d6) δ195.10, 174.76, 166.52 JC-F(dd, 253, 12Hz), 163.62 JC-F(dd, 253, 12 Hz), 136.06, 133.44 JC-F(dd, 12, 4 Hz), 128.47, 125.62, 122.96 JC-F(dd, 13, 4 Hz), 122.48, 119.33, 113.77, 113.12, 112.96 JC-F(dd, 22, 3 Hz), 105.61 JC-F(t, 27 Hz), 46.72 JC-F (d, 8 Hz), 38.35;
FAB-MS m/z = 364 [M+H]+
1H-NMR(400MHz, acetone-d6) δ10.24 (s, 1H), 8.01 (m, 1H), 7.77 (d, J=8.4, 1H), 7.42 (d, J=8.0, 1H), 7.21~7.03 (m, 4H), 4.57 (dd, J=10.8, 3.6, 1H), 4.03 (ddd 18.8, 10.8, 3.2, 1H), 3.38 (td, 18.8, 3.2, 1H);
13C-NMR (100MHz, acetone-d6) δ195.28, 174.97, 166.55 JC-F(dd, 254, 12 Hz), 163.62 JC-F(dd, 254, 12 Hz), 137.646, 137.49, 133.46 JC-F (dd, 11, 4 Hz), 127.37, 123.70, 123.54, 123.05 JC-F(dd, 13, 4 Hz), 122.39, 119.88, 119.79, 112.95 JC-F(dd, 22, 4 Hz), 105.58 JC-F (t, 26 Hz), 46.95 JC-F (d, 8 Hz), 38.47;
FAB-MS m/z = 364 [M+H]+
1H-NMR(400MHz, acetone-d6) δ10.10 (s, 1H), 8.01 (m, 1H), 7.54 (s, 1H), 7.20-7.31 (m, 2H), 7.13-7.20 (m, 1H), 7.96 (d, J=6.8, 1H), 4.53 (dd, J=10.6, 3.6, 1H), 4.01 (ddd 18.8, 10.6, 3.2, 1H), 3.36 (td, 18.8, 3.2, 1H), 2.40 (s, 3H);
13C-NMR (100MHz, acetone-d6) δ195.33, 175.08, 166.54 JC-F(dd, 254, 12 Hz), 163.49 JC-F(dd, 254, 12 Hz), 136.01, 133.45 JC-F(dd, 11, 4 Hz), 128.59, 127.63, 124.02, 123.72, 123.05 JC-F (dd, 13, 4 Hz), 119.43, 112.94 JC-F(dd, 22, 4 Hz), 112.74, 112.03, 105.59 JC-F(t, 26 Hz), 47.01 JC-F(d, 7 Hz), 38.45, 21.64;
FAB-MS m/z = 344 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 8.00 (m, 1H), 7.75 (d, J=7.6, 1H) , 7.37 (d, J=8.4, 1H), 7.12-7.22 (m, 4H), 7.07 (t, J=7.6, 1H), 4.54 (dd, J=10.8, 3.6, 1H), 4.00 (ddd, 18.8, 10.4, 3.6, 1H), 3.79 (s, 3H), 3.36 (td, 18.8, 3.6, 1H);
13C-NMR (100MHz, acetone-d6) δ195.22, 174.94, 166.52 JC-F(dd, 253, 13 Hz), 163.57 JC-F(dd, 253, 13 Hz), 138.08, 133.46 JC-F(dd, 11, 4 Hz), 128.00, 127.79, 123.03 JC-F(dd, 13, 4 Hz), 122.36, 120.07, 119.72, 112.94 JC-F(d, 22, 4 Hz), 112.33, 110.32, 105.60 JC-F(t, 27 Hz), 47.01 JC-F(d, 8 Hz), 38.36, 32.72;
FAB-MS m/z = 344 [M+H]+
1H-NMR(400MHz, acetone-d6) δ10.26 (s, 1H), 8.01 (m, 1H), 7.35 (d, J=8.0, 1H),7.28 (d, J=2.8, 1H), 7.12-7.20 (m, 2H), 6.98 (t, J=7.8, 1H), 6.67 (d, J=7.8, 1H),4.54 (dd, J=10.8, 3.6, 1H), 4.03 (ddd 18.8, 10.6, 3.3, 1H), 3.92 (s, 3H), 3.36(td, 18.6, 3.2, 1H);
13C-NMR (100MHz, acetone-d6) δ1195.28, 174.98, 166.54 JC-F(dd, 252, 12 Hz), 163.48 JC-F(dd, 252, 12 Hz), 147.35, 133.44 JC-F(dd, 11, 4 Hz), 128.81, 127.83, 123.22, 123.05 JC-F (dd, 13, 4 Hz) , 120.43, 113.76, 112.94 JC-F(dd, 22, 4 Hz), 112.7, 105.59 JC-F(t, 27 Hz), 102.52, 55.52, 46.97 JC-F(d, 8 Hz) , 38.59;
FAB-MS m/z = 360 [M+H]+
1H-NMR(400MHz, acetone-d6) δ10.09 (s, 1H), 8.02 (m, 1H), 7.27-7.31 (m, 3H), 7.13-7.20 (m, 2H), 6.79 (dd, J=8.8, 2.4, 1H), 4.52 (dd, J=10.8, 3.6, 1H), 4.00 (ddd, 18.8, 10.4, 3.4, 1H), 3.80 (s, 3H), 3.38 (td, 18.6, 3.4, 1H;
13C-NMR (100MHz, acetone-d6) δ195.35, 175.03, 166.53, JC-F(dd, 253, 12 Hz), 163.61 JC-F(dd, 253, 12 Hz), 154.84, 133.45 JC-F(dd, 11, 4 Hz), 132.72, 127.78, 124.22, 123.04 JC-F (dd, 12, 4 Hz), 112.95 JC-F (dd, 22, 4 Hz), 112.96, 112.68, 105.61 JC-F (t, 26 Hz), 101.58, 55.79, 46.9 JC-F(d, 8 Hz), 38.67;
FAB-MS m/z = 360 [M+H]+
1H-NMR(400MHz, acetone-d6) δ 10.0 4(s, 1H), 8.01 (m, 1H), 7.65 (d, J=8.8, 1H), 7.48 (d, J-7.6, 2H), 7.38 (t, J=7.2, 2H), 7.31 (m, 1H), 7.13-7.20 (m, 3H), 7.03 (d, J=2.0, 1H), 6.83 (dd, J=8.4 , 2.0, 1H), 4.51 (dd, J=10.4 , 3.6, 1H), 4.01 (ddd, 18.1, 10.4, 3.3, 1H), 3.36 (td, 18.1, 3.3, 1H);
13C-NMR (100MHz, acetone-d6) δ195.29, 175.00, 166.54 JC-F(dd, 254, 12 Hz), 163.52 JC-F(dd, 254, 12 Hz), 156.33, 138.85, 138.45, 133.45, JC-F (dd, 11, 4 Hz), 129.17, 128.37, 128.23, 123.01 JC-F(dd, 13, 4 Hz), 122.49, 121.97, 120.54, 113.24,113.06 JC-F (dd, 21, 4 Hz), 110.73, 105.59 JC-F(t, 27 Hz), 96.89, 70.70, 46.94 JC-F(d, 8 Hz), 38.57;
FAB-MS m/z = 436 [M+H]+
(E)-4-(2,4-ジフルオロフェニル)-4-オキソ-2-ブテン酸
1H-NMR(400MHz, acetone-d6) δ 7.98 (m, 1H), 7.72 (dd, J=15.6 , 3.6, 1H), 7.20-7.28 (m, 2H), 6.75 (d, J=15.6, 2H);
13C-NMR(100MHz, acetone-d6) δ187.13, 166.86 JC-F(dd, 254, 12 Hz), 166.35, 163.33 JC-F(dd, 254, 12 Hz), 139.95 JC-F(d, 7 Hz), 133.98 JC-F (dd, 66, 59 Hz), 132.91, 123.22 JC-F(d, 9 Hz), 113.33 JC-F(dd, 22 , 3 Hz), 105.76, JC-F (t, 22 Hz)
実施例1で合成した本件化合物群(化合物#5)を用い、以下に示す方法に従って、哺乳類精子の受精機能増強効果を確認した。なお、精子の前培養及び媒精は、5%CO2/20%O2、37℃条件下で行った。
〔1〕メスのC57/B6マウスに、妊馬血清性腺刺激ホルモン(PMSG;pregnant mare serum gonadotropin)を腹腔内投与し、PMSG投与48時間後にヒト絨毛性性腺刺激ホルモン(hCG;Human chorionic gonadotropin)することにより過排卵を誘起した。hCG投与5~17時間後にマウスを安楽死させ、卵管を回収した。
〔2〕オスのC57/B6マウスを安楽死させた後、精巣上体の尾部を摘出し、回収した。
〔3〕100μLの4種類の培養液(0.0001%のDMSOを含む媒精用培養液[TYH培養液、LSIメディエンス社製]、及び1μMの化合物#5を含むTYH培養液、並びに、10μMのFCCP(Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone)を含むTYH培養液、及び10μMのFCCPと1μMの化合物#5とを含むTYH培養液)からなる滴(ドロップ)をそれぞれ調製し、その上をミネラルオイル(シグマ-アルドリッチ社製)で覆った。上記回収した精巣上体の尾部を、上記ミネラルオイル中に移し、ピンセットで把持した状態で1mLの26G針付きツベルクリン用シリンジ(ニプロ社製)にて精巣上体管に傷をつけ、得られた精子塊を、ミネラルオイル中の上記4種類の培養液中にそれぞれ移し、媒精前の培養(前培養)を1時間行った。
〔4〕上記4種類の培養液中で前培養した精子3μLを、マイクロピペッター(エッペンドルフ社製、ドイツ)を用いて、卵丘細胞-卵子複合体(COC;cumulus oocyte complex)を含むTYH培養液のドロップ200μL中にそれぞれ移し、その上をミネラルオイル(シグマ-アルドリッチ社製)で覆い、媒精を行った。
〔5〕媒精24~28時間後に2細胞期卵の有無を観察し、2細胞期卵が観察された場合、受精したと評価し、受精率を測定した。
化合物#5の溶媒であるDMSOを含むTYH培養液、すなわち、化合物#5不含の培養液中で前培養した精子を用いて媒精を行うと、受精率40%であったのに対して、化合物#5含有培養液中で前培養した精子を用いて媒精を行うと、受精率は100%であった(表1参照)。
この結果は、本件化合物群(化合物#5)は、精子の受精機能を賦活化(増強)する作用を有することを示している。
この結果は、本件化合物群(化合物#5)は、低下した精子の受精機能(例えば、ATPを利用した前進運動)を改善する作用を有することを示している。
Claims (7)
- 以下の一般式(I0 )、及び、R3がOHのときそれらの生理学的に許容される塩からなる群から選択される1種又は2種以上の化合物を含む、哺乳類精子の受精機能増強剤。
- 採取された少なくとも1つの哺乳類精子を、以下の一般式(I0 )、及び、R3がOHのときそれらの生理学的に許容される塩からなる群から選択される1種又は2種以上の化合物を含む生理的水溶液中に移す工程(a)を含む、哺乳類精子の受精機能の増強方法。
- 請求項3又は4に記載の増強方法により得られた哺乳類精子を、採取された少なくとも1つの哺乳類卵子を含む培養液中で培養する工程(b-1)を含む、哺乳類受精卵の作製方法。
- 採取された少なくとも1つの哺乳類精子と、採取された少なくとも1つの哺乳類卵子とを、以下の一般式(I0 )、及び、R3がOHのときそれらの生理学的に許容される塩からなる群から選択される1種又は2種以上の化合物を含む培養液中で培養する工程(b-2)を含む、哺乳類受精卵の作製方法。
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WO2014080640A1 (ja) | 2012-11-26 | 2014-05-30 | 国立大学法人東北大学 | エリスロポエチン発現増強剤 |
WO2017072984A1 (ja) | 2015-10-29 | 2017-05-04 | 株式会社東北テクノアーチ | 筋萎縮性疾患治療剤 |
WO2017072816A1 (ja) | 2015-10-29 | 2017-05-04 | 国立大学法人東北大学 | 臓器線維化疾患の治療剤 |
WO2017073060A1 (ja) | 2015-10-29 | 2017-05-04 | 国立大学法人東北大学 | コラーゲン産生抑制剤 |
JP2018076274A (ja) | 2016-11-11 | 2018-05-17 | 国立大学法人東北大学 | ライソゾーム病の予防又は改善剤 |
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WO2014080640A1 (ja) | 2012-11-26 | 2014-05-30 | 国立大学法人東北大学 | エリスロポエチン発現増強剤 |
WO2017072984A1 (ja) | 2015-10-29 | 2017-05-04 | 株式会社東北テクノアーチ | 筋萎縮性疾患治療剤 |
WO2017072816A1 (ja) | 2015-10-29 | 2017-05-04 | 国立大学法人東北大学 | 臓器線維化疾患の治療剤 |
WO2017073060A1 (ja) | 2015-10-29 | 2017-05-04 | 国立大学法人東北大学 | コラーゲン産生抑制剤 |
JP2018076274A (ja) | 2016-11-11 | 2018-05-17 | 国立大学法人東北大学 | ライソゾーム病の予防又は改善剤 |
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