CN1085548A - 特殊的1，4-二氢吡啶-3，5-二羧酸酯及其制备方法以及其药用用途 - Google Patents
特殊的1，4-二氢吡啶-3，5-二羧酸酯及其制备方法以及其药用用途 Download PDFInfo
- Publication number
- CN1085548A CN1085548A CN93108711A CN93108711A CN1085548A CN 1085548 A CN1085548 A CN 1085548A CN 93108711 A CN93108711 A CN 93108711A CN 93108711 A CN93108711 A CN 93108711A CN 1085548 A CN1085548 A CN 1085548A
- Authority
- CN
- China
- Prior art keywords
- chloro
- cyclopropyl
- dihydropyridine
- dimethyl
- trifluoromethyl
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- -1 1,4-dihydropyridine-3,5-dicarboxylic ester Chemical class 0.000 title claims description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 230000004089 microcirculation Effects 0.000 claims abstract description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 6
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 150000003935 benzaldehydes Chemical class 0.000 claims description 5
- SIIJRCRHAIMFNT-UHFFFAOYSA-N cyclopropanamine;hydrochloride Chemical compound Cl.NC1CC1 SIIJRCRHAIMFNT-UHFFFAOYSA-N 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 239000012752 auxiliary agent Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 208000023589 ischemic disease Diseases 0.000 abstract description 5
- 230000036772 blood pressure Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 6
- 206010003497 Asphyxia Diseases 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SYHPGXUWPYJXOO-UHFFFAOYSA-N 1,4-dihydropyridine-2,3-dicarboxylic acid Chemical class OC(=O)C1=C(C(O)=O)NC=CC1 SYHPGXUWPYJXOO-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 101150048270 DHPS gene Proteins 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000001720 action spectrum Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229910001038 basic metal oxide Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及新的4-(4-氯-3-二氟甲基苯基)
-1-环丙基-2，6-二甲基-1，4-二氢吡啶-3，5-二羧
酸二甲酯、其制备方法以及其作为药物在与微循环障
碍有关的局部缺血性疾病方面的用途。该作用在外
周和脑血管系统均有。
Description
本发明涉及新的4-（4-氯-3-三氟甲基苯基）-1-环丙基-2，6-二甲基-1，4-二氢吡啶-3，5-二羧酸二甲酯、它的制备方法以及其作为药物在与微循环障碍有关的局部缺血性疾病方面的用途。该作用在外周和脑血管系统均有。
人们已经知道1，4-二氢吡啶二羧酸酯具钙拮抗或钙激动作用，因此可用作影响血管和循环的药剂（参见美国专利3773773）。
欧洲专利240828（美国专利4975440）也描述了具有血液流变特性的降压药1，4-二氢吡啶。
本发明涉及式新的式（Ⅰ）4-（4-氯-3-三氟甲基苯基）-1-环丙基-2，6-二甲基-1，4-二氢吡啶-3，5-二羧酸二甲酯：
令人吃惊的是，该化合物具较强的血液流变作用并能改善循环，特别是改善微循环而且同时对血压没有影响。因此，它特别适用于急性和慢性缺血性疾病的控制。
本发明式（Ⅰ）化合物可按常规方法制备，例如按下述方法制备：[A]在惰性溶剂中或无溶剂条件下、必要时在碱/酸存在下，式（Ⅱ）（4-氯-3-三氟甲基亚苄基）乙酰乙酸甲酯直接与3-环丙基氨基巴豆酸甲酯反应，或者与乙酰乙酸甲酯和盐酸环丙胺反应;式（Ⅱ）结构如下：
或
[B]式（Ⅲ）4-氯-3-三氟甲基苯甲醛与乙酰乙酸甲酯和盐酸环丙胺或与环丙胺和盐酸吡啶分别在吡啶中反应;式（Ⅲ）结构如下：
或
[C]首先在保护气体气氛中将3-环丙基氨基巴豆酸甲酯与路易斯酸最好是四氯化钛在惰性溶剂中用碱最好是哌啶处理，然后再加入式（Ⅲ）4-氯-3-三氟甲基苯甲醛。
本发明的方法可用以下反应路线为例如加以说明：
合适的溶剂是在反应条件下不发生改变的水或有机溶剂。优选的溶剂包括醇类例如甲醇、乙醇、丙醇、异丙醇、丁醇、醚类例如乙醚、二噁烷、四氢呋喃、乙二醇-甲醚或乙二醇二甲醚，或酰胺类例如二甲基甲酰胺、二甲基乙酰胺或六甲基磷酰胺，或冰乙酸，二甲亚砜，乙腈或吡啶。1，2-二甲氧基乙烷、丁醇和吡啶为佳。
依照各自的操作步骤，可以使用的碱为氢化物象氢化钠，碱金属或碱土金属氢氧化物例如氢氧化钠或氢氧化钾，醇盐例如叔丁醇钾，或吡啶。以氢化钠和吡啶为佳。
所用的酸一般是盐酸或硫酸。
反应温度可以在相对较宽的范围内变动。一般来说，反应在+10℃～150℃间进行，最好是在+20℃～120℃间、特别是在各自溶剂的沸点进行。
反应可在常压下进行，但也可以在加压或减压的条件下进行。一般来说，反应在常压下进行。
在实施本发明不同的A、B和C方法时，参与反应的物质的用量可以是任何需要的比率。然而一般来说，反应由摩尔量反应物来完成。本发明物质最好通过真空蒸馏除去溶剂并将残留物重结晶分离和纯化，只在冰冷却后可从适宜的溶剂中以结晶的形式获得。在某些情况下可能有必要用层析方法纯化本发明化合物。
式（Ⅱ）和式（Ⅲ）化合物是已知的。
本发明新的化合物显示出意想不到的有效的药理作用谱。它在剂量范围达到至少静注10mg/Kg和口服30mg/Kg时对血管和血压没有影响，通过影响红细胞的可变形性和抑制白细胞的活化和粘连而使循环、特别是微循环加快。
不影响血压的作用在以下用于二氢吡啶的典型的模型中测定：用SH大鼠;口服给药后在尾动脉测定（Riva Rocci法）以及用麻碎的Wistar大鼠，静注给药后测定。测定通过在颈动脉中的导管来进行。由于该化合物在给定的剂量下在两个实验模型中均未降低血压，因此可以说该化合物对血压没有影响。治疗剂量和血压作用间至少差100倍。
因此本发明化合物可以用来生产药物以治疗急性和慢性局部缺血性疾病，例如间歇跛行，心肌梗塞、大脑柱塞并且也治疗再灌注损伤和休克。
下列体外和体内实验显示了经特别挑选的本发明化合物的使人感兴趣的作用。
Ⅰ）红细胞功能
红细胞的可变形性在急性或慢性局部缺血性疾病的发生和发展过程中起着重要的作用。它们决定着血液的粘度因而决定其在微循环中分布。检测各种测定量的实验：
实验a）检测该物质的溶血作用（ED50，mol/l）在该实验中，在高切应力下通过小孔给载钙红细胞加压以使血红蛋白释放并且测定血红蛋白作为它们溶血作用的表征。所测得的值是血红蛋释放的减少。
实验b）在玻璃毛细管（直径25μm）中在施于狭窄后的管区的低切应力下检测红细胞悬浮液的粘度。增加细胞外的钙会增加粘度。
a）在红细胞中的抗溶血作用
在高切应力下正常的红细胞成为溶血的。载钙细胞的溶血现象尤其明显。这个力学稳定性的测量被用来表示物质的特征。所测得的值是在介质中游离血红蛋白的浓度。MEC为5×10-7mol/l。
b）在玻璃毛细管中的粘度
与循环有关的戏细胞的生物物理相互作用可在玻璃毛细管（直径20-30μm）中进行试验。得到的粘度取决于这些细胞的状态在。载钙的情况下粘度增加。在0.7帕压力下测得了相对于受损但未经处理的对照的粘度增加的百分数。实验剂量是10-8g/ml。
表Ⅰ：
实施例序号 效应（%）
本发明化合物（Ⅰ） 72
Ⅱ白细胞功能
微循环可以在仓鼠颊囊模型中直接观察到。所测得的值是白细胞粘连，也是脉管直径和红细胞沉降速度。在局部缺血和非局部缺血的实验条件下来对粘连进行定量。在非局部缺血条件下，在小的小静脉区域内对粘连进行定量，而在局部缺血条件下（循环阻塞10分钟）在小的小动脉内。将对照实验的结果调到100%。所选择的实验剂量在每种情况下均为0.1mg/Kg（静注），结果是对照降低百分数。令人吃惊的是，似乎在局部缺血条件下静注0.1mg/Kg时该物质也仍然有效。这对于期望的适应症特别有利。
表Ⅱ：
实施例序号 外局部缺血 局部缺血
对照=100% 对照=100%
本发明化合物(I) 50% 49%
Ⅲ）血压
临床知识表明，二氢吡啶的抗局部缺血作用常为血管舒张所掩盖。因此目的是要发现血压稳定的（即血液流变作用和低血压作用间的差≥10）DHPs。下表显示口服给药（SH大鼠）或静注给药（麻醉的Wistar大鼠）使血压降低的剂量。
表Ⅲ：
实施例序号 口服(mg/kg) 静注(mg/kg)
本发明化合物(I) >90 >10
与模型Ⅱ相比较，该表显示出治疗作用和血压作用间之差至少为100。
该新活性物质可按已知方法用惰性、无毒、药学上适用的赋形剂或溶剂转变成常规制剂，例如片剂、包衣片剂、丸剂、颗粒剂、气雾剂、糖浆、乳剂、混悬剂和溶液。如果这样，在每种制剂中该治疗活性化合物的浓度都应为混合物总重量的约0.5-90%，即足以达到指示的剂量范围的量。
这些制剂例如可以通过将活性物质与溶剂和/或赋形剂混合来生产，必要时可使用乳化剂和/或分散剂，例如当用水作稀释剂时，可任选有机溶剂作助溶剂。
使用方法按常规，口服或肠道外给药尤其是经舌给药或静注为佳。
业已证明，一般来说静注用药量约0.001-1mg/Kg体重最好约为0.01-0.5mg/Kg体重时有利于取得有效的结果，而口服时剂量约为0.01-20mg/Kg体重。以0.1-10mg/Kg体重为佳。
尽管这样，有时还需要偏离上述的剂量，确切地讲是根据体重或给药途径的类型、对药物的个体反应、药物制剂的形式以及药药时间或给药间隔。因此，在某些情况下，用量低于上述最低剂量时可能足够，而在另外一些情况下则必须超出上述的最高限。在给药量相对较大时，最好将其分成每天若干单剂服用。
制备实施例
实施例1
4-（4-氯-3-三氟甲基苯基）-1-环丙基-2，6-二甲基-1，4-二氢吡啶-3，5-羧酸二甲酯
方法A
将23.3g（0.15mol）3-环丙基氨基-巴豆酸甲酯、46.0g（0.15mol）（4-氯-3-三氟甲基亚苄基）乙酰乙酸甲酯和17.7g（0.15mol）盐酸吡啶于100ml吡啶中的溶液回流搅拌7.5小时。真空蒸发后，将残留物在120ml二氯甲烷和150ml水中进行分配，有机相径蒸发后得树脂状粗产物，将其用100ml环己烷重结晶。
熔点：131-135℃
产量：35.0g（收率为52.6%）
方法B
将4.17g（0.02mmol）4-氯-3-三氟甲基苯甲醛、4.65g（0.04mol）乙酰乙酸甲酯和1.96g（0.021mol）盐酸环丙胺于20ml吡啶中的溶液回流搅拌4小时。蒸发后将残留物在40ml二氯甲烷和50ml水中进行分配。有机相径蒸发得油状粗产物，将具用环己环和正戊烷结晶。
熔点：131-134℃
产量：3.33g（收率为37.5%）
Claims (5)
1、4-(4-氯-3-三氟甲基苯基)-1-环丙基-2，6-二甲基-1，4-二氢吡啶-3，5-二羧酸二甲酯。
2、4-（4-氯-3-三氟甲基苯基）-1-环丙基-2，6-二甲基-1，4-二氢吡啶-3，5-二羧酸二甲酯的制备方法，其特征在于：[A]在惰性溶剂中或无溶剂条件下、必要时在碱/酸存在下，式（Ⅱ）（4-氯-3-三氟甲基亚苄基）乙酰乙酸甲酯直接与3-环丙基氨基巴豆酸甲酯反应，或者与乙酰乙酸甲酯和盐酸环丙胺反应;式（Ⅱ）结构如下：
或
[B]式（Ⅲ）4-氯-3-三氟甲基苯甲醛与乙酰乙酸甲酯和盐酸环丙胺或与环丙胺和盐酸吡啶分别在吡啶中反应;式（Ⅲ）结构如下：
或
[C]首先在保护气体气氛中将3-环丙基氨基巴豆酸甲酯与路易斯酸最好是四氯化钛在惰性溶剂中用碱最好是哌啶处理，然后再加入式（Ⅲ）4-氯-3-三氟甲基苯甲醛。
3、含权利要求1化合物的药物。
4、药物的生产方法，其特征在于：将权利要求1的化合物转化成适宜的给药形式，必要时通过加入常规助剂和赋形剂来完成这一转化。
5、权利要求1的化合物治疗微循环障碍的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4223867A DE4223867A1 (de) | 1992-07-20 | 1992-07-20 | Spezieller 1,4-Dihydropyridin-3,5-dicarbonsäureester, Verfahren zu seiner Herstellung und seine pharmazeutische Verwendung |
| DEP4223867.6 | 1992-07-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1085548A true CN1085548A (zh) | 1994-04-20 |
Family
ID=6463655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93108711A Pending CN1085548A (zh) | 1992-07-20 | 1993-07-20 | 特殊的1，4-二氢吡啶-3，5-二羧酸酯及其制备方法以及其药用用途 |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5559139A (zh) |
| EP (1) | EP0581079A1 (zh) |
| JP (1) | JPH06179654A (zh) |
| KR (1) | KR940002223A (zh) |
| CN (1) | CN1085548A (zh) |
| AU (1) | AU4164693A (zh) |
| CA (1) | CA2100707A1 (zh) |
| CZ (1) | CZ141593A3 (zh) |
| DE (1) | DE4223867A1 (zh) |
| FI (1) | FI933255A (zh) |
| HU (1) | HU9302077D0 (zh) |
| IL (1) | IL106369A0 (zh) |
| MX (1) | MX9304119A (zh) |
| PL (1) | PL299713A1 (zh) |
| SK (1) | SK76293A3 (zh) |
| ZA (1) | ZA935191B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044316A (zh) * | 2013-01-23 | 2013-04-17 | 石家庄学院 | 一种以咪唑离子液体为催化剂制备1,4-二氢吡啶的方法 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3883543A (en) * | 1969-05-10 | 1975-05-13 | Bayer Ag | N-alkyl-1,4-dihydropyridines |
| DE1923990C3 (de) * | 1969-05-10 | 1978-11-23 | Bayer Ag | Verfahren zur Herstellung von N-substituierten M-Dihydropyridin-S.S-dicarbonsäureestern |
| DE2210667A1 (de) * | 1972-03-06 | 1973-09-20 | Bayer Ag | Kondensiert aromatisch substituierte 1,4-dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| US3956341A (en) * | 1974-02-21 | 1976-05-11 | Smithkline Corporation | 1,3,5-Tricarbo-1,4-dihydropyridines |
| US4975440A (en) * | 1984-09-28 | 1990-12-04 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Optically-active 1,4-dihydropyridine |
| US4780538A (en) * | 1986-02-12 | 1988-10-25 | Merck & Co., Inc. | Process for 1,4-dihydropyridine compounds using a titanamine catalyst |
| DE4011695A1 (de) * | 1990-04-11 | 1991-10-17 | Bayer Ag | Verwendung von n-alkylierten 1,4-dihydropyridindicarbonsaeureestern als arzneimittel, neue verbindungen und verfahren zu ihrer herstellung |
| DE4200714A1 (de) * | 1992-01-14 | 1993-07-15 | Bayer Ag | Spezieller 1,4-dihydropyridin-3,5-dicarbonsaeureester, verfahren zu seiner herstellung und seine pharmazeutische verwendung |
-
1992
- 1992-07-20 DE DE4223867A patent/DE4223867A1/de not_active Withdrawn
-
1993
- 1993-06-30 AU AU41646/93A patent/AU4164693A/en not_active Abandoned
- 1993-07-08 EP EP93110936A patent/EP0581079A1/de not_active Ceased
- 1993-07-08 MX MX9304119A patent/MX9304119A/es unknown
- 1993-07-13 US US08/090,722 patent/US5559139A/en not_active Expired - Fee Related
- 1993-07-15 CZ CZ931415A patent/CZ141593A3/cs unknown
- 1993-07-16 FI FI933255A patent/FI933255A/fi not_active Application Discontinuation
- 1993-07-16 CA CA002100707A patent/CA2100707A1/en not_active Abandoned
- 1993-07-16 IL IL106369A patent/IL106369A0/xx unknown
- 1993-07-16 PL PL93299713A patent/PL299713A1/xx unknown
- 1993-07-19 KR KR1019930013536A patent/KR940002223A/ko not_active Application Discontinuation
- 1993-07-19 ZA ZA935191A patent/ZA935191B/xx unknown
- 1993-07-19 HU HU9302077A patent/HU9302077D0/hu unknown
- 1993-07-19 JP JP5198759A patent/JPH06179654A/ja active Pending
- 1993-07-19 SK SK762-93A patent/SK76293A3/sk unknown
- 1993-07-20 CN CN93108711A patent/CN1085548A/zh active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044316A (zh) * | 2013-01-23 | 2013-04-17 | 石家庄学院 | 一种以咪唑离子液体为催化剂制备1,4-二氢吡啶的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| IL106369A0 (en) | 1993-11-15 |
| DE4223867A1 (de) | 1994-01-27 |
| KR940002223A (ko) | 1994-02-16 |
| PL299713A1 (en) | 1994-03-21 |
| AU4164693A (en) | 1994-01-27 |
| JPH06179654A (ja) | 1994-06-28 |
| CZ141593A3 (en) | 1994-03-16 |
| FI933255A0 (fi) | 1993-07-16 |
| MX9304119A (es) | 1994-02-28 |
| CA2100707A1 (en) | 1994-01-21 |
| ZA935191B (en) | 1994-03-02 |
| FI933255A (fi) | 1994-01-21 |
| EP0581079A1 (de) | 1994-02-02 |
| SK76293A3 (en) | 1994-07-06 |
| HU9302077D0 (en) | 1993-10-28 |
| US5559139A (en) | 1996-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1272319C (zh) | 制备氨氯地平马来酸盐的工艺、所制得的氨氯地平马来酸盐、其药物组合物和用途 | |
| JP3021719B2 (ja) | 酸化窒素生合成の抑制剤 | |
| EP0109020B1 (de) | Neue Derivate tricyclischer Aminosäuren, Verfahren zu ihrer Herstellung, diese enthaltende Mittel und deren Verwendung, sowie neue bicyclische Aminosäuren als Zwischenstufen und Verfahren zu deren Herstellung | |
| WO2014198195A1 (zh) | 联芳基取代的4-氨基丁酸衍生物及其制备方法和用途 | |
| US6514986B2 (en) | Chiral fluoroquinolone arginine salt forms | |
| WO2005121123A1 (fr) | Composes utilises comme antagonistes de ccr5 | |
| US20170267687A1 (en) | Dihydroetorphines and Their Preparation | |
| US6518288B2 (en) | Amlodipine fumarate | |
| CN1085548A (zh) | 特殊的1，4-二氢吡啶-3，5-二羧酸酯及其制备方法以及其药用用途 | |
| JPH0526782B2 (zh) | ||
| EP0220653B1 (en) | 3-aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid compounds, process for preparation and use thereof, and pharmaceutical composition containing the same | |
| CN1777586A (zh) | 稳定的无定形樟脑磺酸氨氯地平、其制备工艺以及其口服给药的组合物 | |
| JPH075530B2 (ja) | カルボキシアルキルカルボニルアミノ酸エンドペプチダーゼ阻害剤 | |
| CN1075141A (zh) | 1，4-二氢吡啶-3，5-二甲酸酯的制备及用途 | |
| EP0118565B1 (en) | 1,4-methano-2-benzazepine derivatives | |
| EP1619185A1 (en) | 4,4-difluoro-1,2,3,4-tetrahydro-5h-1-benzazepine derivative or salt thereof | |
| US20220227722A1 (en) | Sphingosine 1 phosphate receptor modulator | |
| JPH0686436B2 (ja) | 新規ヒダントイン誘導体及び該化合物を含有する医薬組成物 | |
| CN1128999A (zh) | 杂环化合物 | |
| CN1266429A (zh) | 新的季戊四醇衍生物、其制备与应用以及合成该衍生物的中间体产物 | |
| WO2008056059A2 (fr) | Derives de 4-azasteroles, leurs procedes de synthese et leur utilisation a titre de medicament | |
| CN1006383B (zh) | 新的噻吩取代的烯丙基胺类的制备方法 | |
| CN1450064A (zh) | 5－苯甲酰氨基－1，3－二氧环类化合物及其制备方法以及在制备蛋白激酶c抑制剂药物中的应用 | |
| WO2024059331A1 (en) | Erythritol ester of phenyl butyric acid | |
| SE441447B (sv) | 2-hydroxi-5-/1-hydroxi-2-/4-(2-oxo-1-bensimidazolinyl)-piperidino/etyl/bensoesyraderivat och sett att framstella dessa |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |