CN1033804A - 新的抗心律失常剂及其制备方法 - Google Patents
新的抗心律失常剂及其制备方法 Download PDFInfo
- Publication number
- CN1033804A CN1033804A CN88108941A CN88108941A CN1033804A CN 1033804 A CN1033804 A CN 1033804A CN 88108941 A CN88108941 A CN 88108941A CN 88108941 A CN88108941 A CN 88108941A CN 1033804 A CN1033804 A CN 1033804A
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- China
- Prior art keywords
- propyl group
- compound
- benzonitrile
- amino
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title abstract description 13
- 239000003416 antiarrhythmic agent Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 239000000203 mixture Substances 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 7
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 342
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 87
- -1 propoxy- Chemical class 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
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- 229910052794 bromium Inorganic materials 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 3
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- 125000005905 mesyloxy group Chemical group 0.000 claims description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
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- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 108010010803 Gelatin Proteins 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 6
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- 239000002253 acid Substances 0.000 description 5
- 230000036982 action potential Effects 0.000 description 5
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- 150000001412 amines Chemical class 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
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- JWYAJJXJGHRSJC-UHFFFAOYSA-N 4-[3-(2-hydroxyethylamino)propoxy]benzonitrile Chemical compound OCCNCCCOC1=CC=C(C#N)C=C1 JWYAJJXJGHRSJC-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
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- 230000006793 arrhythmia Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract
本发明提供用于治疗心脏心律不齐的式I化合
物和在适当条件下它的外消旋混合物或立体异构体
形式和其药物上可接受的盐,含这些化合物作为活性
成分的药物组合物和这些化合物以及用于其制备的
中间体的制备方法:
其中n,Y,Z,A如说明书所述定义。
Description
本发明涉及新的有药理活性的化合物及其制备方法。本发明还涉及含有这些化合物的药物组合物及其药理上使用的方法。
本发明的目的是提供用于治疗多种病因的急性以及长期的心脏心律不齐的物质。
GB1433920揭示了下式化合物:
其中R1例如代表烷基或环烷基或芳基,R2例如代表卤,CN或NO2基,A代表2至6个碳原子的亚烷基和X代表-S-,-SO-或-SO2-基。
据报道,这些化合物具有阻断β-肾上腺素能的活性。
GB1457876揭示了其中的下列化合物:
据报道,这些化合物具有阻断β-肾上腺素能的活性。
本发明涉及用于治疗多种病因的急性以及长期的心律不齐的新化合物。
一个目的是提供比现有抗心律不齐药物较少明显副作用的抗心律不齐药。该化合物必须例如没有减弱收缩力的作用和该化合物甚至可以有增强收缩力的作用。该等化合物应能进一步将抗心律不齐效应与中枢神经和胃肠道效应区分开来。
本发明的化合物特征在于通式Ⅰ
并且可适当地以其外消旋混合物或主体异构物组分以及药物上可接受的盐的形式,在式中
n是整数0,1或2
Y是〔CH2〕m,CHOH,CHOCH3,CHNHR或CHF,
m是整数0或1和
R是氢,甲基或乙基,
Z是氢或含1-3个碳原子的饱和或不饱和直链或支链的烷基。
A是下列基团
其中Ra是直链或支链羟烷基或是含1-5个碳原子并被1个或多个氟原子任意取代的烷基,
Rc是含1-4个碳原子并被1个或多个氟原子任意取代的饱和或不饱和,直链或支链的烷基,
Ra′是与Ra相同并与Ra″无关,
Ra″是与Ra相同并与Ra′无关,
p是整数0,1或2,
s是整数2,3,4或5,
在式Ⅰ中卤原子包括氟,氯,溴和碘。
在式Ⅰ中烷基是直链和饱和的,例如是甲基,乙基,正丙基,正丁基。
在式Ⅰ中烷基是直链和不饱和的,例如是乙烯基,烯丙基,丙烯基,-C≡CH,-CH2-C≡CH和-C≡CCH3。
在式Ⅰ中烷基是支链和饱和的,例如是异丙基,仲丁基,异丁基,叔丁基。
在式Ⅰ中烷基是支链和不饱和的,例如是:
在式Ⅰ中烷基是被氟取代的,例如是在该定义的烷基中1-3个H被F取代,它们是直链并饱和的或支链并饱和的例如:CH2CHFCH3,CH2CH2CF3,CH2CF2CH3等。
在式Ⅰ中烷基是被羟基取代的,例如是
本发明化合物的优选基团是当下列情况下得到的即:
n是1
Y是CHOH,CHF或(CH2)m
其中m=1
Z是氢
A是 ,
其中Ra是CH3,C2H5,C3H7,CH2CH2OH,CH2CHOHCH3,
Rc是C2H5,C3H7,CH2CHFCH3,
s是3,4,p是0,1,2。
特别优选的化合物是亚砜,即当p是1。
下列这些基团的化合物是特别优选的化合物,其中
Y是CHOH或(CH2)m,
Ra是C2H5,CH2CH2OH,
s是3,p是1,
Rc是C3H7。
优选的化合物也可以是从上述优选化合物通过在氨基上烷基化得到的季氮化合物。
优选化合物是:
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(甲基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
碘化-3-〔(4-氰苯氧基)-N,N-二乙基-2-氢基-N-〔3-(丙基亚磺酰基)丙基〕-1-丙铵
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2-(S)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-(S)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔4-(乙硫基)丁基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔4-(乙基亚磺酰基)丁基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔2-羟乙基)〔3-丙硫基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-丙基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(丙磺酰基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(甲硫基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔2-羟乙基)〔3-(甲基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔乙基〔3-丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈与盐酸的加成盐,
4-〔3-〔乙基〔3-丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈与联苯-2,2′-二基磷酸氢酯的加成盐,
4-〔3-〔甲基〔3-(2-丙烯基-1-硫)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(2-氟丙基)硫丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-〔(2-氟丙基)亚磺酰基〕丙基〕氨基〕-2-羟氧丙基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-氟丙氧基〕苄腈。
更优选的化合物是:
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
碘化3-(4-氰苯氧基)-N,N-二乙基-2-羟基-N-〔3-(丙基亚磺酰基)丙基〕-1-丙铵,
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(S)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(S)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔4-(乙硫基)丁基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔4-(乙基亚磺酰基)丁基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(丙硫基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(丙基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(丙磺酰基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔乙基〔3-〔(2-氟丙基)硫〕丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-〔(2-氟丙基)亚磺酰基〕丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-丙基亚磺酰基)丙基〕氨基〕-2-氟丙氧基〕苄腈,
最优选的化合物是:
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(R)羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(S)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔4-(乙基亚磺酰基)丁基〕氨基-2-羟丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(丙基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔乙基〔3-〔(2-氟丙基)亚磺酰基〕丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-氟丙氧基〕苄腈,
特别优选的化合物是:
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-丙基亚磺酰基)丙基〕氨基〕-2(S)-羟丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(丙基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈,
在许多情况下式Ⅰ化合物会存在立体异构形式,这些形式是由于例如旋光异构现象,几何异构现象和分子构象所产生的。
本发明的叔胺能用低级烷基季铵化并且该季铵化合物具有如叔胺化合物相同的作用。
本发明的新化合物可以立体化学混合物或以纯的立体化学形式在治疗中使用。
本发明化合物在临床应用时通常以药物制剂形式采用口服,直肠或经注射给药,该药物制剂包括以游离碱或以药物上可接受的无毒性的酸加成盐形式作为活性成分与药物上可接受的载体相结合,该酸加成盐例如是氢溴酸盐,盐酸盐,磷酸盐,硫酸盐,磺酸盐,氨基磺酸盐,柠檬酸盐,乳酸盐,马来酸盐,酒石酸盐,乙酸盐等。因此有关本发明新化合物的术语范围包括游离胺碱类和这些游离碱的酸加成盐,若是在文章中例如在具体实施例中未用到这些术语,则表示与该广义的定义不相一致。
该载体可以是固体,半固体或液体稀释剂或胶囊。这些药物制剂构成本发明的另一方面通常该活性物质将占制剂重量的0.1和99%之间,更具体讲是供注射用的为制剂重量的0.5和20%之间,适于口服给药的为制剂重量的2和50%之间。
为制备供口服给药的单位剂量形式的含本发明化合物的药物制剂,可以将所选的化合物与固体粉末状载体如乳糖、蔗糖、山梨醇、甘露醇,淀粉如马铃薯淀粉、玉米淀粉或支链淀粉,纤维素衍生物,明胶或其它合适的片剂赋形剂和润滑剂如硬脂酸镁、硬脂酸钙、富马酸十八烷基酯钠盐、聚乙二醇蜡等一起混合,然后压制成片剂。如需要包衣片剂,可按上述方法制备片芯,再用常规进行糖包衣或用成膜包衣聚合物进行薄膜包衣。
为在含不同活性物质或含不同量活性化合物之间容易进行区别,可将着色剂加至这些包覆层中。
为制备由明胶和例如甘油构成的明胶软胶囊剂或类似的封闭胶囊,可以将活性物质与植物油一起混合。明胶硬胶囊可以包括活性物质颗粒,并与固体,粉末载体如乳糖、蔗糖、山梨醇、甘露醇、淀粉(如马铃薯淀粉、玉米淀粉或支链淀粉),纤维素衍生物或明胶或其它合适的药物上可接受的成分混配在一起。
供直肠应用的剂量单位可以制备成栓剂形式,包括将活性物质与中性脂肪基质相混合;或制备成明胶直肠胶囊剂,包括将活性物质与植物油或石蜡油相混合。
供口服应用的液体制剂可以是糖浆或悬浮剂的形式,例如制成溶液,可以含有0.2至约20%(重量)本文所述的活性物质,其余部分是糖醇和水,并可任选与乙醇、甘油、丙二醇混合。这些液体制剂可以任选含有着色剂、调味剂、糖精和增稠剂的如羧甲基纤维素、羟丙基甲基纤维素或类似物等。
供肠胃外应用的注射液可制备成该活性物质的水溶性药物上可接受的盐的水溶液,该活性物质的浓度最好是约0.5至约10%(重量)。这些溶液还可以含有稳定剂和/或缓冲剂,并可以方便地制成各种剂量单位的安瓿。
供口服给药的本发明化合物的合适剂量是每日1至4次,每次1-300mg,最好是每日1至4次,每次20-80mg。
本发明化合物可以通过下列任一种方法而制得:
A.式Ⅰ化合物能通过式Ⅱ化合物与式A化合物反应而得到:
在式Ⅰ中A是
并且符号n,Y和Z如上述定义,
其中Ra如上述定义
其中L是离去基,如Br、Cl、I、甲磺酰氧基或甲苯磺酰氧基,s,p和Rc如上述定义。
该反应的典型进行方式是在合适的有机溶剂如乙腈,异丙醇或N,N-二甲基甲酰胺中进行。合适的有机或无机碱(酸接受体)如三乙胺或碳酸钾加至该混合物中。然后将混合物加热至40-100℃范围,直至反应完成,反应后可用常规方法分离和纯化产物。
B.其中p是整数1或2的式Ⅰ化合物可通过将其中p是整数0的式Ⅰ化合物进行氧化而得到。
当作用物是一种胺时,可将它用合适的酸如对甲苯磺酸在溶剂中进行中和,并且所成的盐可溶于乙醇。当制备亚砜(p=1)时,温度必须保持在-20-0℃之间。当制备砜(p=2)时,必须在20-80℃的温度范围。
C.其中n=1,Y=CHOH,Z=H,p=1或2,Ra,Rc和s具有上述定义的式Ⅰ化合物,可通过式Ⅴ化合物和式B化合物反应来制备:
其中Ra,Rc,s和p具有上述定义。
该反应的典型进行方式是在合适溶剂如异丙醇或N,N-二甲基甲酰胺中进行,混合物必须加热至40-100℃的温度范围,直至反应完成,然后可通过常规方法分离产物。
D.其中n=1,Y=CHOH,Z=H,p=0,1,2,Ra,Rc和s具有上述定义的式Ⅰ化合物,可通过式Ⅴ化合物与式C化合物反应来制备:
该反应条件与上述方法C所述者相同。
从上述反应得到下式的产物
然后将其通过常规方法用合适的式Ra-L(其中L是如上述定义的离去基)的烷化基进行烷化,得到如上述定义的式Ⅰ化合物。
当产物中的硫原子是低氧化态(即p=0或1)时,它可以进一步氧化成在上述方法B中叙述的具有高氧化态硫原子的产物(即p=1或2)。
E.其中Ra,Rc,n,p和s具有上述定义的下式化合物能通过式D与式Ⅲ化合物反应来制备:
其中M是甲基或4-甲基苯基残基。
该反应的典型进行方式是在合适的有机溶剂如乙腈或N,N-二甲基甲酰胺中进行。将合适的有机或无机碱如三乙胺或碳酸钾加至该混合物中,然后将混合物加热至90-100℃的温度范围直至反应完成,反应后可用常规方法分离和纯化产物。
中间体:
式Ⅱ化合物是用于通过方法A制备Ⅰ化合物的重要中间体,这些中间体是新的并构成本发明的一部分。
其中n是整数0,1或2
Y是〔CH2〕m,CHOH,CHOCH3,CHNHR或CHF,
m是整数0或1,
R是氢,甲基或乙基,
Z是氢或含有1-3个碳原子的饱和或不饱和,直链或支链的烷基,
Ra是含有1-4个碳原子并被1个或多个氟原子任意取代的直链或支链羟烷基或烷基。
式Ⅱ化合物是通过式E化合物与式Ra-NH2反应制备的:
其中n和Ra具有上述定义。
其它重要的中间体是:
其中Ra,Rc,s和p具有上述定义。
这类中间体一般能通过使用与方法A相似的典型步骤将式A化合物与式H2N-Ra的胺起反应而得到:
其中L是Cl,Br,I,甲磺酰基或甲苯磺酰基。
这类中间体的实例是:
用于通过方法D制备式Ⅰ化合物的其它重要中间体是:
其中Y,Z,Rc,n,s和p具有上述定义。
特别重要的是那些其中s是3和p是0或1的中间体如:
实施例1
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2-羟丙氧基〕苄腈
(a)4-〔3-乙氨基)-2-羟丙氧基〕苄腈
36.0g 4-(环氧乙烷基甲氨基)苄腈溶于250ml乙腈,并与29.7g乙胺在高压釜中混合。混合物于沸水浴中加热过夜,蒸发,剩余物溶于2M盐酸。该酸性水层用乙醚洗二次,以10M氢氧化钠碱化,用二氯甲烷分三次萃取。合并有机物层,用硫酸钠干燥并蒸发,固体剩余物从二异丙醚∶乙腈(9∶1)混合液中重结晶二次,得到57g4-〔3-(乙氨基)-2-羟丙氧基〕苄腈
NMR:13C(CDCl3):
14.88,43.93,51.28,67.60,70.77,104.31,115.26,119.00,133.93,161.93ppm
(b)4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2-羟丙氧基〕苄腈
4.7g 4-〔3-(乙氨基)-2-羟丙氧基〕苄腈,4.5g 1-溴-3-(丙硫基)丙烷和5.8g碳酸钾在50ml异丙醇中混合并回流过夜。混合物过滤并蒸发。剩余的油状物8.3g通过柱色谱法分离,得到4.9g标题化合物。
NMR:13C(CDCl3):
11.44,13.47,22.62,26.84,29.56,34.63,47.44,52.27,56.03,65.81,70.47,103.74,115.08,118.78,133.57,161.87,ppm
实施例2
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈
2.45g 4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2-羟丙氧基〕苄腈和1.4g对甲苯磺酸于50ml乙醇中混合,混合物冷却至-10℃,分小批量加入1.7g间氯过苯甲酸。混合物在-10℃搅拌0.5小时,室温搅拌1小时,然后蒸发,剩余物溶于二氯甲烷,用碳酸钠溶液洗涤三次,水洗涤二次,经硫酸钠干燥,过滤并蒸发,将2.3g黄色油状的剩余物通过柱色谱法纯化得1.4g标题化合物。
NMR:13C(CDCl3):11.21,11.33,13.11,16.02,20.30,20.43,47.41,47.45,49.69,49.95,52.18,52.41,54.29,54.41,56.06,56.09,66.08,70.41,70.49,103.76,115.09,118.83,133.62,
实施例3 161.88ppm
4-〔3-〔乙基〔3-(丙磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈
7.3g 4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2-羟丙氧基〕苄腈与4.2g对甲苯磺酸于75ml乙醇中混合。向该混合物中分小批量加入10.1g间氯过苯甲酸,在添加期间使温度升至45℃。然后将混合物于室温搅拌3小时。反应完成后,蒸发溶剂,剩余物溶于二氯甲烷,用碳酸钠溶液洗涤三次,水洗涤二次。蒸发有机物层,剩余物溶于2M盐酸并用乙醚洗涤三次,水层用1M氢氧化钠溶液碱化,用二氯甲烷萃取。有机溶液经硫酸钠干燥,过滤并蒸发。粗产物通过柱色谱法纯化得3.2g标题化合物。
NMR:13C(CDCl3):
11.41,12.88,15.64,19.57,47.44,50.15,51.88,54.68,56.04,66.19,70.45,104.0,115.2,118.94,133.79,161.91ppm
实施例4
4-〔3-〔乙基〔3-(甲基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈
用与实施例1和2所述的相似方法制备本标题化合物
NMR:13C(CDCl3):
11.16,11.27,20.18,20.31,38.39,38.50,47.40,51.87,52.11,52.17,52.35,56.02,66.09,70.37,70.44,103.68,115.05,118.79,133.58,161.83ppm
实施例5
碘化3-(4-氰苯氧基)-N,N-二乙基-2-羟基-N-〔3-(丙基亚磺酰基)丙基〕-1-丙铵
5.0g 4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈和2.4g乙基碘溶于50ml乙腈并加热回流5小时,再加入另一份2.4g乙基碘,继续回流过夜。蒸发溶液,6.6g剩余的油状物通过柱色谱法分离得4.0g标题化合物。
NMR:13C(D2O):
8.07,13.42,16.75,47.73,53.78,55.53,57.57,60.38,64.41,67.42,70.78,104.00,116.45,120.77,135.39,162.35ppm.
实施例6
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈
(a)(4S)-2,2-二甲基-4-(4-氰苯氧基)甲基-1,3-二氧戊环
4-羟苄腈(55g)的甲醇(100ml)溶液用氢氧化钾(29g)的水(30ml)溶液处理并减压蒸发。剩余的钾盐溶于无水二甲基甲酰胺(75ml),加入(4R)-2,2-二甲基-4-甲磺酰氧甲基-1,3-二氧戊环82.2g。混合物在110℃加热搅拌20小时,使其冷却并于乙醚和水两相之间分配。水相用乙醚萃取三次,合并乙醚相,用10%氢氧化钾水溶液洗三次,水洗二次,经无水硫酸钠干燥并蒸发得77g标题化合物。
NMR:13C(CDCl3):
25.11,26.57,66.35,68.85,73.55,104.30,109.77,115.17,118.83,133.79,161.68ppm.
(b)(2R)-3-(4-氰苯氧基)丙-1,2-二醇
77g(4S)-2,2-二甲基-4-(4-氰苯氧基)甲基-1,3-二氧戊环溶于甲醇(200ml)和水(75ml),加入浓盐酸(0.5ml)。混合物保持50℃过夜,减压蒸发并从水中重结晶,得46g白色叶片状标题化合物,m.p.63-65℃。
NMR:13C(CD3OD)
63.90,70.72,71.44,104.70,116.56,120.07,135.09,163.86ppm.
(c)(2S)-1-(4-氰苯氧基)-3-甲磺酰氧基丙-2-醇
57.2g(2R)-3-(4-氰苯氧基)丙-1,2-二醇溶于无水吡啶(300ml),在-10℃用甲磺酰氯(20.7ml)滴加处理。混合物保持5℃过夜,减压蒸发,倒入冰和2M盐酸混合物中,固体沉淀物从甲醇中重结晶三次,得12.3g标题化合物,m.p.119-121℃〔α〕20 D+9.7°(C1.0,CH3OH)
NMR:13C(CD3OD)
37.26,68.77,69.92,71.76,105.19,116.65,119.99,135.19,163.55ppm.
(d)4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈
11.7g(2S)-1-(4-氰苯氧基)-3-甲磺酰氧基丙-2-醇与乙基(3-丙硫基)丙胺(13.9g),碳酸钾(12.6g)和乙腈(100ml)一起搅拌回流过夜。过滤并蒸发得21.5g粗产物,于乙醚和2M盐酸两相之间分配,水层用二氯甲烷萃取三次,其中以离子对形式存在。蒸发并于乙醚和1M氢氧化钠两相之间分配,在醚层中得到该游离的碱。经二氧化硅色谱法分离,用甲醇-二氯甲烷(5∶95)作流动相,得10.3g无色油状的标题化合物。
〔α〕20 D-24.2°(C1.0,CH3OH)
NMR:13C(CDCl3):
11.53,13.32,22.76,26.92,29.71,34.20,47.56,52.38,56.20,65.82,70.53,103.97,115.17,118.95,133.98,161.95ppm.
实施例7
4-〔3-〔乙基〔3-(丙亚磺酰基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈
按实施例2所述的制备外消旋物的方法,用间氯过苯甲酸将4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈氧化而制得。
〔α〕20 D-18.6°(C1.0,CH3OH)
NMR;13C(CDCl3)
11.35,11.47,13.30,16.24,20.47,20.62,47.59,47.63,49.83,50.12,52.30,52.57,54.53,54.66,56.28,56.31,66.13,70.52,70.60,104.08,115.24,119.02,133.85,162.0ppm.
实施例8
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(S)-羟丙氧基〕苄腈
按实施例6所述的相似方法制备本标题化合物。
〔α〕20 D+24.0°(C1.0,CH3OH)
NMR:13C(CDCl3)
11.52,13.27,22.74,26.93,29.70,34.19,47.58,52.40,56.22,65.85,70.54,103.96,115.16,118.89,133.72,161.95ppm.
实施例9
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(S)-羟丙氧基〕苄腈
按实施例7和实施例2所述的相似方法,制备本标题化合物。
〔α〕20 D+18.0°(C1.0,CH3OH)
NMR:13C(CDCl3):
11.31,11.43,13.26,16.18,20.41,20.57,47.53,47.58,49.8,50.08,52.26,52.53,54.48,54.61,56.22,56.24,66.09,70.48,70.57,104.0,115.20,118.97,133.79,161.96ppm.
实施例10
4-〔3-〔乙基〔4-(乙硫基)丁基〕氨基〕-2-羟丙氧基〕苄腈
2g乙基-〔4-(乙硫基)丁基〕胺和2.17g 4-(环氧乙烷基甲氧基)苄腈在25ml异丙醇中混合,回流过夜。混合物进行蒸发,剩余油状物溶于2M HCl,该酸化的水层用乙醚洗涤三次,然后用二氯甲烷将该产物的HCl-盐以离子对形式萃取三次。将该含离子对的有机物层用2M NaOH碱化,将此含碱形式的该产物的有机物层经硫酸钠干燥并蒸发,通过柱色谱法纯化得3.7g标题化合物。
NMR;13C(CDCl3):
11.67,14.65,25.81,26.31,27.18,31.40,47.57,53.16,56.08,65.69,70.64,104.03,115.20,118.97,133.79,162.01ppm.
实施例11
4-〔3-〔乙基〔4-(乙基亚磺酰基)丁基〕氨基〕-2-羟丙氧基〕苄腈
按实施例2的相似方法,用1.1g间氯过苯甲酸对1.68g 4-〔3-〔乙基〔4-(乙硫基)丁基〕氨基-2-羟丙氧基〕苄腈进行氧化,得到0.7g标题化合物。
NMR:13C(CDCl3)
6.66,11.52,20.41,26.39,45.67,47.75,51.25,53.12,56.24,65.85,70.54,115.24,119.0,133.84,104.0,162.0ppm.
实施例12
4-〔3-〔(2-羟乙基)〕3-(丙硫基)丙基〕氨基〕丙氧基〕苄腈
(a)4-〔3-〔(2-羟乙基)氨基〕丙氧基〕苄腈
3-溴丙氧基苄腈(10g)和乙醇胺(10g)的2-丙醇(150ml)溶液加热回流2小时,放置过夜后,蒸发溶剂,剩余物溶于HCl(2M)水溶液,用乙醚洗涤,该酸性水层用氢氧化钠溶液(10M)碱化,用二氯甲烷萃取并蒸发溶剂,得粗产物(7.2g)。从二异丙醚中重结晶得7.0g标题化合物,m.p.88℃。
NMR:13C(CDCl3)
29.15,46.04,51.09,60.49,66.38,103.55,115.02,119.01,133.74,162.04ppm.
(b)4-〔3-〔(2-羟乙基)〔3-(丙硫基)丙基〕氨基〕丙氧基〕苄腈
4-〔3-〔(2-羟乙基)氨基〕丙氧基〕苄腈(3g),1-溴-3-(丙硫基)丙烷(2.7g)和碳酸钾(3.7g)在2-丙醇(50ml)中的混合物加热回流28小时。蒸发溶剂,剩余物溶于HCl(2M)水溶液,用乙醚萃取。水层用氢氧化钠(10M)碱化,用二氯甲烷萃取,经硫酸钠干燥,蒸发溶剂得粗剩余物,通过柱色谱法纯化得2.6g油状标题化合物。
NMR:13C(CDCl3)
13.13,22.61,26.53,26.73,29.60,31.04,50.11,52.53,55.67,58.66,66.06,103.52,114.92,118.80,133.60,161.92ppm.
实施例13
4-〔3-〔(2-羟乙基)〔3-(丙基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈
按实施例2的相似方法,用间氯过苯甲酸(2.1g)将4g 4-〔3-〔(2-羟乙基)〔3-(丙硫基)丙基〕氨基〕丙氧基〕苄腈进行氧化,经柱色谱法分离后得到2.5g标题化合物。
NMR:13C(CDCl3);13.37,16.28,20.69,26.66,50.03,50.42,52.92,54.65,55.94,59.09,66.29,103.88,115.21,119.12,133.94,162.18ppm.
实施例14
4-〔3-〔(2-羟乙基)〔3-(丙磺酰基)丙基〕氨基〕丙氧基〕苄腈
4-〔3-〔(2-羟乙基)氨基〕丙氧基〕苄腈(1.3g),1-溴-3(丙磺酰基)丙烷(1.3g)和碳酸钾(1.6g)在乙腈(100ml)中的混合物加热回流过夜,按常规方法进行处理(包括色谱法)得到0.5g标题化合物。
NMR:13C(CDCl3)
13.00,15.82,19.53,26.51,50.03,50.20,52.18,54.71,55.84,58.98,66.18,103.75,115.11,119.02,133.87,162.01ppm.
实施例15
4-〔3-〔(2-羟乙基)〔3-(甲硫基)丙基〕氨基〕丙氧基〕苄腈
3g 4-〔3-〔(2-羟乙基)氨基〕丙氧基〕苄腈和2.2g 1-溴-3-(甲硫基)丙烷和3.7g碳酸钾在50ml异丙醇中混合,回流过夜。混合物经过滤和蒸发,剩余物溶于2M盐酸,该酸性水层用乙醚洗二次,用10M氢氧化钠碱化,以二氯甲烷提取三次,合并有机物层并经硫酸钠干燥和蒸发。剩余油状物通过柱色谱法纯化得1.2g标题化合物。
NMR:13C(CDCl3):
15.60,26.50,26.89,32.13,50.47,52.75,55.99,58.84,66.30,104.06,115.18,119.11,133.98,162.17ppm.
实施例16
4-〔3-〔(2-羟乙基)〔3-(甲基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈
按实施例2的相似方法,用0.87g间氯过苯甲酸对1.1g 4-〔3-〔(2-羟乙基)〔3-(甲硫基)丙基〕氨基〕丙氧基〕苄腈进行氧化,得0.7g标题化合物。
NMR:13C(CDCl3):
20.42,26.48,38.56,50.28,52.09,52.74,55.75,58.94,66.08,103.67,115.03,118.98,133.77,161.98ppm.
实施例17
4-〔3-〔甲基〔3-(2-丙烯-1-硫基)丙基〕氨基-2-羟丙氧基〕苄腈
(a)4-〔3-(甲基氨基)-2-羟丙氧基〕苄腈
按与实施例1a所述的相似方法制备标题化合物,m.p.100-102℃。
NMR:13C(CDCl3):
36.18,53.82,67.59,70.88,103.97,115.13,118.92,133.79,161.88.ppm.
(b)1-氯-3(2-丙烯-1-硫基)丙烷
2-丙烯-1-硫醇(6.8g;92mmol),1-溴-3-氯丙烷(14.5g;92mmol)和碳酸钾(20g;145mmol)在乙腈(50ml)中的混合物搅拌并在80℃加热5分钟。过滤和蒸发得油状剩余物,于10mmHg真空蒸馏得到65℃沸点的馏分为7g(51%)无色油状物。
NMR:13C(CDCl3):
27.33,31.74,34.45,43.23,116.76,134.03、ppm.
(C)4-〔3-〔甲基〔3-(2-丙烯-1-硫基)丙基〕氨基〕-2-羟丙氧基〕苄腈
4-〔3-(甲基氨基)-2-羟丙氧基〕苄腈(4.12g;20mmol),1-氯-3(2-丙烯-1-硫基)丙烷(3.5g;23mmol),碘化钠(3.5g;24mmol)和碳酸钾(5g;36mmol)在乙腈(50ml)中的混合物搅拌回流24小时,过滤并蒸发溶剂得剩余物,通过快速色谱法(SiO2;CH2Cl2∶CH3OH(9∶1))纯化得5g(78%)无色油状物。
NMR:13C(CDCl3):
26.62,28.33,34.81,41.97,56.63,59.96,65.82,70.52,104.08,115.22,116.78,119.00,133.84,134.29,161.98.
实施例18
4-〔3-〔乙基〔3-〔(2-氟丙基)硫〕丙基〕氨基〕-2-羟丙基〕苄腈
按常规方法从1-羟基-3-硫丙烷和1-溴-2-氟丙烷制备的1-羟基-3-〔(2-氟丙基)硫〕丙烷(5.5g,36.1mmol)溶液与三乙胺(3.9g,39.7mmol)在二氯甲烷中混合,然后搅拌冷却至0℃,在20分钟内加入甲磺酰氯(4.1g,36.1mmol)。将该溶液过滤并用碳酸氢钠溶液和水洗涤二次,产物为8.2g。将该甲磺酸酯溶于乙腈(100ml)并加入4-〔3-(乙氨基)-2-羟丙氧基〕苄腈(8.7g,39.4mmol),将此溶液回流过夜。蒸发溶剂,剩余物通过硅胶柱色谱法纯化,得5.75g标题化合物。
NMR:13C(CDCl3):
11.46,19.88,20.06,26.87,30.58,37.74,37.92,47.46,52.19,56.07,65.84,70.47,89.52,90.86,103.82,115.11,118.84,133.64,161.90.
实施例19
4-〔3-〔乙基〔3-〔(2-氟丙基)亚磺酰基〕丙基〕氨基〕-2-羟丙氧基〕苄腈
4-〔3-〔乙基〔3-〔(2-氟丙基)硫〕丙基〕氨基〕-2-羟丙氧基〕苄腈(5.1g,14.4mmol)和甲苯基-4-磺酸(2.73g,14.4mmol)在乙醇(10ml)中的溶液搅拌并冷却至-15℃。向混合物中加入3-氯过萃甲酸(4.5g,14.4mmol)的乙醇(10ml)溶液。所得溶液在室温搅拌3小时,加入固体氢氧化钙(2.66g,36mmol),该浆液搅拌15小时,过滤并蒸发得到油状剩余物。剩余物溶于2M盐酸,用乙醚洗涤,该酸性溶液用2M氢氧化钠调节至pH=12,用二氯甲烷萃取,经硫酸钠干燥并蒸发至干,得到油状剩余物,通过硅胶柱色谱法纯化,得到3.2g标题化合物。
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-氟丙氧基〕苄腈
在氢气氛中将三氟化(二乙氨基)硫(2.3g,14.2mmol)溶于二氯甲烷。溶液冷却至-70℃,向此溶液中滴加4-〔3-〔乙基3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈(5.0g,14.2mmol)的二氯甲烷(5ml)溶液。该溶液在-70℃搅拌半小时,在室温搅拌2小时,然后用水(50ml)处理,用氢氧化钠溶液调节至pH=11。分离产生的各液层,水层用二氢甲烷萃取,合并有机物部分,用水洗涤,经硫酸钠干燥。油状剩余物通过硅胶柱色谱法纯化,得1.0g标题化合物。
NMR:13C(CDCl3):
11.69,13.31,16.21,20.45,20.63,22.21,48.31,49.85,49.89,52.96,53.05,53.65,53.69,53.82,53.86,54.49,54.53,104.52,115.08,68.25,68.28,68.44,68.46,89.63,89.70,91.03,91.10,115.25,118.88,133.87,133.94,161.61.ppm
实施例21
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈与盐酸的加成盐
向4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈(1.06g)的二氯甲烷(3ml)溶液里,加入氯化氢在乙醚(3ml)中的饱和溶液,随后再加入乙醚(7ml)。从产生的油状物中倾析出溶剂,油状物用乙醚(3×10ml)洗涤,高真空干燥得1.1g油状物。
NMR:13C(D2O):
8.74,9.17,13.29,16.67,18.23,18.37,18.47,48.01,49.23,49.35,50.97,51.10,51.73,53.32,53.66,55.30,64.77,64.94,70.45,104.01,116.36,120.90,135.36,162.58ppm.
实施例22
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈与联苯-2,2′-二基磷酸氢盐的加成盐
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈(0.35g)和联苯-2,2′-二基磷酸氢盐(0.25g)溶于二氯甲烷(2ml),加入二异丙醚(10ml)得到无色沉淀物。倾析溶剂,固体残余物用乙醚洗涤,得到0.54g(90%)无色结晶体。m.p.147℃。
NMR:13C(CDCl3):
8.68,13.25,16.23,18.14,48.38,48.47,49.44,52.50,54.49,54.57,56.14,64.36,69.96,104.63,115.39,118.93,121.64,124.95,129.42,129.71,133.98,149.89,149.96,161.40ppm.
实施例23
4-〔2-羟基-3-〔〔3(丙硫基)丙基〕氨基丙氧基〕苄腈
4-(环氧乙烷基甲氧基)苄腈(1.32g,75mmol)和3-丙硫基-1-丙氨(1g,7.5mmol)的乙腈(10ml)溶液回流过夜。蒸发溶液,剩余物溶于2M盐酸。该酸性溶液用乙醚洗涤,用10M氢氧化钠碱化,用二氯甲烷萃取。蒸发溶剂,剩余物通过硅胶柱色谱法纯化,得1.1g标题化合物。
NMR:13C(CDCl3)
13.26,22.67,29.26,29.55,34.09,48.43,51.44,67.61,70.63,104.00,115.15,118.87,133.78,161.82.ppm.
实施例24
4-〔2-羟基-3〔〔3(丙基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈
4-〔2-羟基-3〔〔3(丙硫基)丙基〕氨基〕丙氧基〕苄腈(0.9g,2.91mmol)和甲苯基-4-磺酸(0.55g,2.91mmol)的乙醇(20ml)溶液搅拌并冷却至-15℃。在10分钟内,向该溶液中加入3-氯过苯甲酸(0.61g,2.91mmol)的乙醇(10ml)溶液。混合物在-10℃搅拌半小时,再于室温搅拌3小时,加入固体氢氧化钙(0.54g,7.27mmol)并将此浆液搅拌10分钟,过滤及蒸发,得到0.9g无色结晶的标题化合物,m.p.:76-77℃。
NMR:13C(CDCl3):
13.42,16.34,23.44,48.38,48.15,50.19,51.56,54.69,68.68,70.73,104.32,115.34,119.077,133.99,162.01.ppm.
实施例25
N-乙基-N〔(3-丙硫基)丙基〕胺
向1-丙硫醇(228.5g,3mol)和氢氧化钠(0.2g)的溶液里加入乙腈(167.1g,3.15mol),将反应混合物搅拌过夜。加入水(100ml),分离有机物层并用硫酸钠干燥,蒸发得到398g 3-丙硫基-丙腈。将3-丙硫基丙腈(194g,1.5mol)的乙醚(100ml)溶液加至氢化铝锂(60g,1.5mol)的乙醚悬浮液中,按常规方法进行处理得到158g 3-丙硫基丙胺。将全部3-丙硫基丙胺与乙酐(104ml,1.1mol)混合并搅拌1小时,加入水(300ml),用二氯甲烷萃取,接着用硫酸钠干燥并蒸发,得161g 3-丙硫基丙酰胺。将3-丙硫基丙基乙酰胺(133g,1mol)加至氢化铝锂(42g,1.1mol)的乙醚悬浮液中,按常规方法处理,蒸馏(100℃/12mmHg)得113.8g标题化合物。
NMR:13C(CDCl3):
13.34,15.19,22.82,29.87,29.95,34.11,43.98,48.69.ppm.
实施例26
N-乙基-N〔(3-丙基亚磺酰基)丙基〕胺
按实施例2的相似方法,用3-氯过苯甲酸(2.1g,10mmol)将乙基-(3-丙硫基)丙胺(1.61g,10mmol)溶液进行氧化。该标题化合物以其盐酸盐形式从乙酸乙酯中重结晶,得1.7g。
NMR:13C(CDCl3):
12.77,14.68,15.65,22.68,43.28,47.77,49.75,53.84,ppm.
实施例27
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈
4-(环氧乙烷基甲氧基)苄腈(0.2g,1.13mmol)和乙基-(3-丙基亚磺酰基)丙胺(0.2g,1.13mmol)的乙腈(8ml)溶液回流过夜。蒸发溶剂,剩余物溶于盐酸,用乙醚洗涤,接着用氢氧化钠溶液碱化,用二氯甲烷萃取,得0.33g标题化合物。
NMR:13C(CDCl3):
11.31,11.43,13.35,16.30,20.46,20.64,47.71,47.76,49.65,50.15,52.38,52.86,54.65,54.78,56.41,56.45,66.09,70.53,70.61,104.24,115.29,119.04,133.92,162.00,ppm.
药物组合物实施例
由下列实施例阐明本发明的药物组合物的制备。“活性物质”这一名词是代表按本发明的化合物或其盐。
配方A:明胶软胶囊
500g活性物质与500g玉米油混合,随后将混合物装入明胶软胶囊,每粒胶囊含有100mg该混合物(即50mg活性物质)。
配方B:明胶软胶囊
500g活性物质与750g花生油混合,随后将混合物装入明胶软胶囊,每粒胶囊含125mg混合物(即50mg活性物质)。
配方C:片剂
500g活性物质与200g商标为Aerosil的硅酸,450g马铃薯淀粉和500g乳糖同时混合,该混合物用由50g马铃薯淀粉和蒸馏水制备的淀粉糊润湿,随后将该混合物通过筛网制成颗粒。该颗粒经干燥再过筛,将20g硬脂酸镁加入并混合,最后将混合物压制成片,每片重172mg。
配方D:发泡片剂
100g活性物质,140g柠檬酸细粉末,100g碳酸氢钠细粉末,3.5g硬脂酸镁和调味剂(适量)进行混合,将混合物压制成片,每片含100mg活性物质。
配方E:缓释片剂
200g活性物质与50g硬脂酸和50g巴西棕榈蜡一起熔化。将这样得到的混合物冷却并磨碎成为最大直径为1mm的颗粒。这样得到的混合物与5g硬脂酸镁混合,压制成每片重305mg的片剂。于是每片中含200mg活性物质。
配方F:注射液
活性物质 3.0mg
焦亚硫酸钠 0.5mg
乙二胺四乙酸二钠 0.1mg
氯化钠 8.5mg
注射用水 加至1.0ml
配方G:明胶硬胶囊
10g活性物质与400g乳糖混合,最后加入2g硬脂酸镁,然后将混合物装入明胶硬胶囊,每粒胶囊含206mg混合物(即5mg活性成分)。
配方H:片剂
50g活性物质与1500g乳糖,200g微晶纤维素和10g硬脂酸镁混合,最后压制成片芯重176mg,含5mg活性物质的片剂。
药理学测定
据报道,能引起心脏再极化过程延迟并因而能延长心脏不能响应新的刺激的期间(称为有效不应期)的药物,能发挥Ⅲ级抗心律不齐作用(Vaughan Williams,1970,1984)。这个效应可以记录为心肌细胞的作用电位的延长记录,并能用透膜电位记录值来直接测试或用单相作用电位间接测试。属于本发明的那些化合物已用下文的方法进行了研究。
在血液气体控制下,用巴比土酸盐对雄性荷兰豚鼠进行麻醉,用室内空气换气。通过胸廓切开手术暴露心脏并切断迷起神经,从皮肤电极测量标准心电图,用特殊设计的双极电极,将其压在心外膜表面或使用抽压而附接上去,从心室(一般为左侧)的心外膜表面记录单相作用电位(MAP)。还能从该单相作用电位电极范围得到局部的心电图(由表面电极和参比皮肤电极之间测得)。通过一侧股动脉内的动脉导管记录动脉血压,利用静脉血管输注巴比土酸盐和试验物质。由于心脏细胞去极化的持续时间(MAP持续时间)取决于一定的频率,因而必须在恒定的频率条件下进行测定药物作用。为此目的,将一个起搏电极附接在左心房,使心脏能受到在略高于正常窦房节频率的恒定频率的电刺激。
在75%再极化持续期间的单相作用电位是用于初步的筛选。
所有实验是在β-肾上腺受体阻断情况下进行的,通过用0.5mg/kg丙醇预处理来完的。
试验物质是在30秒持续期间并按严格的按期增加剂量的方式通过静脉注射投药,在投药后于严格的期间进行记录,记录时采用Mingograph记录仪和在供后面用常规设计的计算机程序信号分析的记录带。剂量响应曲线是按不同的变量而绘制的,为获得10和20%的延长MAP持续期所需的剂量可以通过内插法求得。增加20%MAP持续期(D20MAP)所用的剂量是用作为药效力的量度指标。
所选化合物在被麻醉以及长时间使用仪器并且有知觉的作了进一步试验,记录其中在前心房和心室上不应性的效果。
表 1
按实施例号的试验物质 D20-MAP VERP
实施例1 6.7 n.t
实施例2 7.3 +
实施例3 6.8 n.t
D20-MAP=在麻醉的荷兰豚鼠上增加20%MAP持续期所给的剂量(摩尔数/千克)的负对数。(参见筛选方法)
在相当于荷兰豚鼠D20-MAP的剂量水平时,对于被麻醉以及有知觉的狗的心室的不应性(VERP)的变化:
+=延长VERP
n.t=未测试
本发明实施的最优选方式
化合物4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈及其盐,制备所述化合物的方法和在治疗中使用所述化合物的方法代表了目前发明人所知的本发明完成的最优选方式。
Claims (22)
2、按权利要求1的化合物,
其中n是1,
Y是CHOH,CHF或(CH2)m,其中m=1,
Z是氢,
A是
其中Ra是CH3,C2H5,C3H7,CH2CH2OH,CH2CHOHCH3,
Rc是C2H5,C3H7,CH2CHFCH3,
s是3,4。
3、按权利要求2的化合物,其中p是1。
4、按权利要求3的化合物
其中Y是CHOH,(CH2)m,其中m=1,
Ra是C2H5,CH2CH2OH,
s是3,
Rc是C3H7。
5、按权利要求4的化合物,其中Y是CHOH,Ra是C2H5。
7、按权利要求1的化合物:
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈,
碘化3-(4-氰苯氧基)-N,N-二乙基-2-羟基-N-〔3-(丙基亚磺酰基)丙基〕-1-丙铵
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(R)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙硫基)丙基〕氨基〕-2(S)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2(S)-羟丙氧基〕苄腈,
4-〔3-〔乙基〔4-(乙硫基)丁基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔4-(乙基亚磺酰基)丁基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(丙硫基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔(2-羟乙基)〔3-(丙基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔(羟乙基)〔3-(丙基亚磺酰基)丙基〕氨基〕丙氧基〕苄腈,
4-〔3-〔乙基〔3-〔(2-氟丙基)硫〕丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-〔2-氟丙基)亚磺酰基〕丙基〕氨基〕-2-羟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-氟丙氧基〕苄腈,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈与盐酸的加成盐,
4-〔3-〔乙基〔3-(丙基亚磺酰基)丙基〕氨基〕-2-羟丙氧基〕苄腈与联苯-2,2′-二基磷酸氢盐的加成盐。
8、一种制备下式化合物或其药物上可接受的盐或立体异构体的方法。
其中n,Y,Z,Ra,s,p和Rc如权利要求1中的定义,该方法包括式Ⅱ化合物与式A化合物反应
其中n,Y,Z,Ra,s,p和Rc如上述定义,L是离去基Br,Cl,I,甲磺酰氧基或甲苯磺酰氧基,随后如有需要,将得到的化合物转化成它的立体异构体或药物上可接受的盐。
9、一种制备权利要求1的并且其中p是1或2的式Ⅰ化合物的方法,该方法包括将权利要求1的其中p是0的式Ⅰ化合物进行氧化。
12、一种制备权利要求1的其中Y=CHOH,Z=H,Ra,Rc,n,s和p具有权利要求1所述定义的式Ⅰ化合物的方法,该方法包括将式D化合物与式Ⅲ化合物反应:
其中M是甲基或4-甲基苯基,Ra,Rc,s和p具有上述的定义。
13、按权利要求8-12中任一项的方法,其特征在于制备按权利要求2-7中任一项的化合物。
14、一种式Ⅱ化合物:
其中x是0,
n是整数0,1或2,
Y是〔CH2〕m,CHOH,CHOCH3,CHNHR或CHF,
m是整数0或1和
R是氢,甲基或乙基,
Z是氢或是含1-3个碳原子的饱和或不饱和,直链或支链烷基,
R是含1-4个碳原子并被1个或多个氟原子任意取代的直链或支链羟烷基或烷基。
16、一种式Ⅳ化合物:
其中Y,Z,Rc,n,s和p具有权利要求1所述定义。
17、一种包括按权利要求1-7中任一项的化合物或其药物上可接受的盐或立体异构体作为活性成分的药物制剂。
18、一种以剂量单位形式的按权利要求1-7的药物制剂。
19、一种按权利要求17-18的药物制剂,包括将活性成分与药物上可接受的载体相结合。
20、一种治疗哺乳动物并包括人类的心脏心律不齐的方法,其特征在于给需要这样治疗的受治疗者施用有效量的按权利要求1-7中任一项的化合物或其药物上可接受的盐。
21、一种用作药物的按权利要求1-7中任一项的化合物。
22、用于制备具有抗心脏心律不齐作用的药剂的按权利要求1-7中任一项化合物的用途。
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SE8705150A SE8705150D0 (sv) | 1987-12-23 | 1987-12-23 | Novel antiarrhythmic agents |
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CN89104335A Pending CN1048214A (zh) | 1987-12-23 | 1989-06-22 | 新的抗心律失常药ii的制备方法 |
CN94105497A Pending CN1097736A (zh) | 1987-12-23 | 1994-05-31 | 新的抗心律失常剂及其制备方法 |
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CN94105497A Pending CN1097736A (zh) | 1987-12-23 | 1994-05-31 | 新的抗心律失常剂及其制备方法 |
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EP (2) | EP0322390B1 (zh) |
JP (2) | JPH0637458B2 (zh) |
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SE8705150D0 (sv) * | 1987-12-23 | 1987-12-23 | Haessle Ab | Novel antiarrhythmic agents |
SE9003902D0 (sv) * | 1990-12-07 | 1990-12-07 | Astra Ab | Solid dosage forms of a drug |
SE8902236D0 (sv) * | 1989-06-20 | 1989-06-20 | Haessle Ab | Novel polystyrenesulfonate |
SE8902235D0 (sv) * | 1989-06-20 | 1989-06-20 | Haessle Ab | Novel cyclodextrin inclusion complexes |
SE8902237D0 (sv) * | 1989-06-20 | 1989-06-20 | Haessle Ab | Novel stereoisomers |
US5084463A (en) * | 1989-12-11 | 1992-01-28 | American Home Products Corporation | N-quinolinyl alkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing class III antiarrhythmic activity |
US5619274A (en) * | 1990-09-10 | 1997-04-08 | Starsight Telecast, Inc. | Television schedule information transmission and utilization system and process |
UA26190C2 (uk) * | 1992-07-28 | 1999-07-19 | Сейфтек Ай Лімітед | Шприц |
US5679706A (en) * | 1994-09-30 | 1997-10-21 | Bristol-Myers Squibb Company | Combination of a potassium channel activator and an antiarrhythmic agent |
US6143569A (en) * | 1998-08-31 | 2000-11-07 | The United States Of America As Represented By The Secretary Of The Navy | Chelators exhibiting triple fluorescence |
GB0123961D0 (en) * | 2001-10-05 | 2001-11-28 | Astrazeneca Ab | Process and intermediates |
WO2004113305A2 (en) | 2003-06-16 | 2004-12-29 | Vertex Pharmaceuticals Incorporated | Diamino substituted quinazoline derivatives as promoters of smn2 |
WO2005007215A2 (en) * | 2003-07-09 | 2005-01-27 | Glucolight Corporation | Method and apparatus for tissue oximetry |
RU2631231C1 (ru) * | 2016-12-01 | 2017-09-19 | Научно-производственная ассоциация "Технопарк Авиационных Технологий" | Способ получения заготовки лопатки газотурбинного двигателя для линейной сварки трением |
CN115417973B (zh) * | 2022-11-03 | 2023-03-24 | 广东粤港澳大湾区黄埔材料研究院 | 抗菌聚氨酯材料及其制备方法和应用 |
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US3149147A (en) * | 1961-03-16 | 1964-09-15 | Smith Kline French Lab | Novel substituted phenylalkylamines |
FR152F (zh) * | 1962-01-24 | |||
GB1069345A (en) * | 1963-07-19 | 1967-05-17 | Ici Ltd | New alkanolamine derivatives |
DE1593771A1 (de) * | 1967-04-06 | 1970-04-30 | Boehringer Sohn Ingelheim | Verfahren zur Herstellung von 1-Phenoxy-2-amino-alkanen |
BE757005A (fr) * | 1969-10-02 | 1971-04-02 | Bristol Myers Co | Phenethanolamines substituees et procede pour leur preparation |
GB1457876A (en) * | 1972-12-15 | 1976-12-08 | Ici Ltd | Alkanolamine derivatives device for use in |
SE404793B (sv) * | 1973-05-25 | 1978-10-30 | Boehringer Sohn Ingelheim | Forfarande for framstellning av vissa angivna nitrilsubstituerade 1-fenoxi-2-hydroxi-3-lagalkylaminopropaner |
GB1433920A (en) * | 1973-10-01 | 1976-04-28 | Ici Ltd | Alkanolamine derivatives |
FR2280376A1 (fr) * | 1974-08-02 | 1976-02-27 | Sogeras | Nouveaux derives du piperidine-4 ethanol |
DE2503222A1 (de) * | 1975-01-27 | 1976-07-29 | Boehringer Sohn Ingelheim | Verfahren zur herstellung von 1-aryl- oxy-3-n-substituierten aminopropanderivaten |
SE421123B (sv) * | 1976-08-25 | 1981-11-30 | Boehringer Sohn Ingelheim | Forfarande for framstellning av vissa angivna nitrilsubstituerade 1-fenoxi-2-hydroxi-3-alkylaminopropaner |
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US4614746A (en) * | 1985-03-21 | 1986-09-30 | American Cyanamid Company | 5-fluorobenzonitrile derivatives for increasing the lean meat to fat ratio and/or enhancing the growth rate of warm-blooded animals |
FI862343A (fi) * | 1985-06-17 | 1986-12-18 | Warner Lambert Co | Foerfarande foer framstaellning av terapeutiskt verkande 1,4-dihydropyridinfoereningar. |
EG18188A (en) * | 1986-05-01 | 1992-09-30 | Pfizer Ltd | Process for preparation anti-arhythmia agents |
SE8705150D0 (sv) * | 1987-12-23 | 1987-12-23 | Haessle Ab | Novel antiarrhythmic agents |
SE8902237D0 (sv) * | 1989-06-20 | 1989-06-20 | Haessle Ab | Novel stereoisomers |
SE8902236D0 (sv) * | 1989-06-20 | 1989-06-20 | Haessle Ab | Novel polystyrenesulfonate |
-
1987
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1988
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1989
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- 1989-08-22 FI FI893937A patent/FI893937A/fi not_active Application Discontinuation
- 1989-08-22 RU SU894614909A patent/RU1836342C/ru active
- 1989-08-23 KR KR1019890701592A patent/KR900700442A/ko not_active Application Discontinuation
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1990
- 1990-02-02 YU YU00196/90A patent/YU19690A/xx unknown
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1991
- 1991-01-18 US US07/643,161 patent/US5155133A/en not_active Expired - Fee Related
- 1991-04-22 RU SU914895329A patent/RU1836343C/ru active
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1992
- 1992-11-12 GR GR920402579T patent/GR3006241T3/el unknown
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1993
- 1993-01-28 GR GR930400159T patent/GR3006912T3/el unknown
- 1993-06-30 LV LV930851A patent/LV10250A/xx unknown
- 1993-12-28 LT LTIP1688A patent/LTIP1688A/xx not_active Application Discontinuation
- 1993-12-28 LT LTIP1687A patent/LTIP1687A/xx not_active Application Discontinuation
- 1993-12-30 LT LTIP1720A patent/LTIP1720A/xx not_active Application Discontinuation
- 1993-12-31 LT LTIP1752A patent/LTIP1752A/xx not_active Application Discontinuation
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1994
- 1994-05-31 CN CN94105497A patent/CN1097736A/zh active Pending
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