NO128869B - - Google Patents
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- NO128869B NO128869B NO693770A NO377069A NO128869B NO 128869 B NO128869 B NO 128869B NO 693770 A NO693770 A NO 693770A NO 377069 A NO377069 A NO 377069A NO 128869 B NO128869 B NO 128869B
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- formula
- compound
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- 150000001875 compounds Chemical class 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- YPPZCRZRQHFRBH-UHFFFAOYSA-N 5-hydroxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=C1C=CC=C2O YPPZCRZRQHFRBH-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 3
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims description 2
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical group CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- -1 aspirin Chemical compound 0.000 description 5
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 229940039009 isoproterenol Drugs 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000004593 Epoxy Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000003945 chlorohydrins Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 150000002924 oxiranes Chemical class 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 239000000026 Pentaerythritol tetranitrate Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XENVCRGQTABGKY-ZHACJKMWSA-N chlorohydrin Chemical compound CC#CC#CC#CC#C\C=C\C(Cl)CO XENVCRGQTABGKY-ZHACJKMWSA-N 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000037020 contractile activity Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960004321 pentaerithrityl tetranitrate Drugs 0.000 description 1
- BRBAEHHXGZRCBK-UHFFFAOYSA-N pentrinitrol Chemical compound [O-][N+](=O)OCC(CO)(CO[N+]([O-])=O)CO[N+]([O-])=O BRBAEHHXGZRCBK-UHFFFAOYSA-N 0.000 description 1
- 229950006286 pentrinitrol Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/38—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
- C07D303/26—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds having one or more free hydroxyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av terapeutisk aktive forbindelser med formelen:
hvor R er alkyl med 1-6 karbonatomer, og aminopropanol-sidekjeden er substituert på 5-, 6- eller 7-stillingen i den aromatiske ring, og farmakologisk akseptable syreaddisjonssalter derav.
Innføring av en keto-gruppe forsterker virkningen av den frem-
stilte forbindelse minst 7 ganger sammenlignet med den tilsvarende forbindelse uten keto-gruppe. Dette er beskrevet i en artikkel i J.Med.Chem. vol. 13 (1970), side 684-8, hvor det henvises til av-snittet på side 685 med tittelen "Structure activity relationships",
se særlig linje 8 og 9 efter formelågemaet i høyre spalte.
De nye forbindelser med formel I er funnet å ha fl-adrenerg
blokkerende aktivitet både ved injisering og oral administrering i pattedyr så som hunder, katter, aper og lignende. Den13-
adrenerge blokkerende aktivitet for disse forbindelser bestemmes ved å administrere varierende doser av isoproterenol efter å ha gitt prøvedyret forbindelser med formel I. Det ble funnet at den hjertekontraktile aktivitet og hjertehastighetsreaksjonen overfor isoproterenol blokkeres ved hjelp av disse forbindelser i varierende grad avhergLg av den administrerte dose. Som et eksempel på den IS-adrenerge blokkerende aktivitet for disse forbindelser, ble forbindelsen 5[3-(tert-butylamino) -2-hydroksypropoksy ]tetralon-hydroklorid administrert intravenøst til bedøvede hunder i en dose på 6,7 ^ug/kg. Hundene ble derefter gitt 0,3 /*g/kg isoproterenol. Denne forbindelse var istand til å undertrykke 50%av isoproterenol-virkningene på hundenes hjertehastighet, og synes å være den mest aktive av de nye forbindelser.
Disse forbindelser er nyttige når I3-adrenerge blokkerende midler
som f.eks. propranolol ønskes, f.eks. i slike tilfeller som angina pectoris, hjertearrytmi og andre iskemiske tilstander.
Dosemengden kan varieres alt efter alder, kjønn, kroppsvekt og art av det pattedyr som behandles, og er i området fra ca. 0,1
til ca. 1 mg/kg kroppsvekt, enten oralt eller ved injisering.
I henhold til oppfinnelsen kan forbindelsene med formel I også fremstilles i form av farmasøytisk akseptable syreaddisjonssalter, f.eks. hydroklorider, hydrobromider, fosfater, sulfater eller salter avledet fra organiske syrer så som laktater, salicylater og lignende.
I henhold til oppfinnelsen kan man også fremstille d- eller 1-
optiske isomerer eller den racemiske blanding, såvel som deres salter eller derivater beskrevet ovenfor.
Forbindelsene fremstilt i henhold til oppfinnelsen anvendes hensiktsmessig i preparater som er egnet for oral eller parenteral administrering. De farmasøytiske preparater som er egnet for oral administrering, kan være i form av tabletter, kapsler, vandige eller oljeaktige oppløsninger og lignende, og suspensjoner som lett fremstilles ved kjente metoder. F.eks. kan tabletter lages ved å blande den valgte aktive bestanddel med kjente farmasøytiske eksipienser, så som kalsiumfosfat, laktose eller mannitol, og granulére med slike midler som akasiegummi eller en gelatinopp-løsning, og derefter presse sammen til tabletter. Disse forbindelser kan også gies i en slik form at de gir en forlenget virkning i dyrekroppen. Doseringsformer som er egnet for parenteral administrering, kan lages ved å oppløse eller suspendere den valgte aktive bestanddel i et parenteralt akseptabelt bæremiddel så som sterilt vann, sterilt saltvann, olje og lignende.
For å øke det terapeutiske spektrum kan forbindelsene også blandes med sedativer så som fenobarbital, smertestillende midler så som aspirin, eller kardiovaskulære midler, så som pentaerytritol-tetranitrat, pentaerytritol-trinitrat osv.
I henhold til oppfinnelsen fremstilles forbindelsene med formel I ved at en forbindelse med formelen
hvor OH er i 5-, 6- eller 7-stilling, omsettes med hvor X = halogen så somCl, for å gi henholdsvis
Generelt omsettes utgangsmaterialene II og ill eller II og VI enten under tilbakeløpskjøling uten oppløsningsmiddel, eller de omsettes ved romtemperatur i en alkoholisk oppløsning inneholdende et lite overskudd (1,1 mol) av en base så som natr.iumhydroksyd, kaliumhydroksyd eller natriummetoksyd for å gi mellomprodukter med strukturene V og VI. De således erholdte mellomprodukter V og VI behandles derefter, f.eks. under tilbakeløpskjøling, med det passende amin med formelen NI^R/hvor R har den ovenfor an-gitte betydning. Som egnede oppløsningsmidler for disse omset-ninger kan f.eks. nevnes lavere alifatiske alkoholer så som metanol, etanol og lignende. De ønskede sluttprodukter utvinnes på kjente måter, og eventuelt omdannes de til syreaddisjonssalter.
Utgangsfenolen II erholdes ved behandling av den tilsvarende
eter som er kommersielt tilgjengelige, med hydrogenbromid i eddiksyre.
Det er funnet at under de betingelser som anvendes for fremstilling av de nye forbindelser med formel I, er det ikke mulig å binde sidekjeden til 8-stillingen.
De følgende eksempler, hvor alle temperaturer er gitt i °C, skal tjene til å illustrere oppfinnelsen ytterligere.
EKSEMPEL 1
a) 5-( 2, 3- epok sypropylok sy)- 1- te tralon
En oppløsning av 8,3 g NaOH i 36,5 ml vann fortynnes med 292 ml etanol og derefter tilsettes 28,5 g 5-hydroksy-tetralon og 98 g epiklorhydrin. Blandingen omrøres ved romtemperatur i 16 timer, og får derefter stå to dager. Oppløsningen inndampes derefter, og residuet fordeles mellom 180 ml vann og 250 ml kloroform. Det fraskilte vandige lag ekstraheres med ytterligere 100 ml kloroform. De samlede organiske faser vaskes to ganger med 100 ml vann, tørres og konsentreres for å gi 41 g residuum. Dette opp-løses i 280 ml eter og avkjøles, og 4,5 g krystaller frafiltreres. Filtratet ble strippet for å gi 34 g råprodukt, og dette ble des-tillert ved 136-144°/0,08 mm Hg for å gi 26,1 g. b) 3, 4- dihvdro- 5- r 2- hydroksy- 3-( isopropylamino) propyloksy1- 1( 2H)-naftalenon- hvdroklorid
26,1 g (0,12 mol) epoksydet fra trinn a) og 34,8 g (0,59 mol) isopropylamin i 121 ml 95% etanol tilbakeløpsbehandles i 40 minutter. Reaksjonsblandingen ble inndampet, og residuet ble krystallisert
fra 240 ml cykloheksan for å gi 29,5 g, sm.p. 77-80°. Dette opp-løses i 135 ml kloroform, og HCl-gass bobles inn inntil blandingen er sur. Til denne sure blanding settes 25 ml eter, og omrøring fortsettes inntil fast stoff utfelles. Ytterligere 240 ml eter
tilsettes og omrøring fortsettes en stund, blandingen filtreres, vaskes med eter og tørres for å gi 33 g, sm.p. 195-197,5°. Omkrystallisering fra 320 ml absolutt etanol gir produktet, sm.p. 196,5-198°.
EKSEMPEL 2
a) 3-( tetralon- 5- oksv)- 1, 2- epoksy- propan
3-( tetralon- 5- oksy)- 1- klor- 2- hydroksy- propan
13,8 g 5-hydroksytetralon oppløses i 75 ml epiklorhydrin, og opp-løsningen tilbakeløpsbehandles i 44 timer. Overskudd av epiklorhydrin fjernes i vakuum ved oppvarmning på vannbad, residuet des-tilleres i et kortveis destillasjonsapparat, og det taes 5 frak-sjoner, k.p. 160-2l0°/0,2 mm Hg. Alle har sterk ketonabsorbsjon og de siste to har også sterk hydroksylabsorbsjon. Av tidligere forsøk finner man at lav hydroksylabsorbsjon faller sammen med lave kloranalyser, og høy hydroksylabsorbsjon faller sammen med høye kloranalyser, og man kan derfor slutte seg til at man får en blanding av epoksyforbindelsen og klorhydrinet. Disse frak-sjoner blandes og anvendes til omsetning med aminer. b) 5— r 3 — ( tert- butylamino)- 2- hydroksypropyloksy1tetralon
6 ml av blandingen av epoksy- og klorhydrinforbindelser oppløses
i 100 ml 95% alkohol, og 24 ml t-butylamin tilsettes, og blandingen tilbakeløpsbehandles på dampbad i to timer. Oppløsningsmiddelet avdrives derefter, residuet utgnies med mettet natriumbikarbonat-oppløsning og eter, og 9,2 g av basen frafiltreres. Dette materiale behandles med alkoholisk HCl, og det utfelte NaCl frafiltreres. Oppløsningen strippes, og residuet omkrystalliseres fra acetonitril, sm.p. 170-171°C.
To omkrystalliseringer fra acetonitril gir sm.p. 226-228°C.
EKSEMPEL 3
5- f 2- hydroksy- 3-( isopropylamino) propyloksy1tetralon
7 ml av blandingen av epoksy- og klorhydrinforbindelser fra eksempel 2a) oppløses i 100 ml 95% alkohol, og 28 ml isopropylamin tilsettes, og oppløsningen tilbakeløpsbehandles i to timer.Oppløsningsmiddelet avdrives, og residuet utgnies med mettet natriumbikarbonatoppløsning og ekstraheres med eter som er vasket med vann og tørret. Den beregnede mengde alkoholiskHCl tilsettes for å danne hydrokloridet som frafiltreres (4 g). To omkrystalliseringer fra alkohol gir den analytiske prøve, sm.p. 198,5-199,5°. EKSEMPEL. 4
5— f( 3- tert- butylamino)- 2- hydroksypropyloksy1- 3, 4- dihvdro- 1( 2H)-naftalenon
20,1 g (0,918 mol) epoksyd fremstilt som i eksempel la) og 33 g tert-butylamin i 90 ml 95% etanol tilbakeløpsbehandles i 40 minutter.Reaksjonsblandingen inndampes, og residuet krystalliseres fra 90 ml cykloheksan for å gi 25,8 g, sm.p. 84-86°. Dette opp-løses i 115 ml kloroform, og HCl-gass bobles inn inntil blandingen er sur, blandingen avkjøles og fortynnes med 15 ml eter. Når krystaller utskilles, tilsettes ytterligere 2,5 ml eter, og om-røring fortsettes en stund. Krystallene filtreres, vaskes med eter og tørres for å gi 28 g, sm.p. 223-225°. Omkrystallisering fra absolutt etanol gir sm.p. 223,5-225,5°.
Claims (2)
1. Analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser med formelen
hvor R er alkyl med 1-6 karbonatomer, og aminopropanol-sidekjeden er substituert på 5-, 6- eller 7-stillingen i den aromatiske ring, og farmakologisk akseptable syreaddisjonssalter derav,karakterisert vedat en forbindelse med formelen:
omsettes med en forbindelse med formelen
hvor X er halogen, hvorefter det erholdte reaksjonsprodukt omsettes med en forbindelse med formelen NI^R»hvor R har oven-nevnte betydning, og forbindelsen med formel (I) omdannes eventuelt til et syreaddisjonssalt.
2. Fremgangsmåte ifølge krav 1 for fremstilling av 5-[3-(tert.butylamino)-2-hydroksypropylQksy]tetralon,karakterisert vedat 5-hydroksytetralon omsettes med epiklorhydrin, hvorefter reaksjonsproduktet omsettes med tert.-butylamin.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US76185768A | 1968-09-23 | 1968-09-23 |
Publications (1)
Publication Number | Publication Date |
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NO128869B true NO128869B (no) | 1974-01-21 |
Family
ID=25063434
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO693770A NO128869B (no) | 1968-09-23 | 1969-09-22 |
Country Status (15)
Country | Link |
---|---|
US (1) | US3641152A (no) |
JP (1) | JPS4843734B1 (no) |
BE (1) | BE739195A (no) |
CH (1) | CH525183A (no) |
DE (2) | DE1948144C3 (no) |
DK (2) | DK125588B (no) |
ES (1) | ES371737A1 (no) |
FI (1) | FI51936C (no) |
FR (1) | FR2018626B1 (no) |
GB (1) | GB1223527A (no) |
IT (1) | IT1033032B (no) |
NL (1) | NL139166B (no) |
NO (1) | NO128869B (no) |
SE (1) | SE362414B (no) |
ZA (1) | ZA695648B (no) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE755071A (fr) * | 1969-09-17 | 1971-02-22 | Warner Lambert Pharmaceutical | Procede de resolution de la dl-5-/3-(terbutylamino)-2- hydroxy-propoxy/-3,4-dihydro-1(2h) naphtalenone |
US3959486A (en) * | 1970-05-27 | 1976-05-25 | Imperial Chemical Industries Limited | Method for producing β-adrenergic blockage with alkanolamine derivatives |
DE2130393C3 (de) * | 1970-06-22 | 1981-02-26 | E.R. Squibb & Sons Inc., New York, N.Y. (V.St.A.) | 6,7-Dihydroxy -5,6,7,8-tetrahydronaphthyloxyaminopropanole und ihre Salze mit Säuren sowie ihre Verwendung bei der Bekämpfung von Herzerkrankungen |
FR2119843B1 (no) * | 1970-12-28 | 1974-03-22 | Laroche Navarro Labo | |
JPS5122737Y2 (no) * | 1972-12-30 | 1976-06-11 | ||
US3966749A (en) * | 1975-02-10 | 1976-06-29 | Interx Research Corporation | Novel synthesis of optically active m-acyloxy-α-[(methylamino)methyl]benzyl alcohols, the pharmaceutically acceptable acid addition salts thereof and intermediate useful in the preparation thereof |
GB1493848A (en) * | 1975-07-24 | 1977-11-30 | Beecham Group Ltd | Aryltetralins |
CH621330A5 (no) * | 1976-05-14 | 1981-01-30 | Sandoz Ag | |
DE2810869A1 (de) * | 1977-03-24 | 1978-09-28 | Sandoz Ag | 3-amino-2-hydroxypropoxy-derivate, ihre herstellung und verwendung |
US4176183A (en) * | 1977-05-02 | 1979-11-27 | Merck & Co., Inc. | Novel naphthyridines |
US4270005A (en) * | 1977-11-14 | 1981-05-26 | Pfizer Inc. | 1,9-Dihydroxyoctahydrophenanthrenes and intermediates therefor |
CH641147A5 (de) * | 1979-01-17 | 1984-02-15 | Sandoz Ag | 3-amino-2-hydroxypropoxyaryl-derivat, seine herstellung und dieses enthaltende heilmittel. |
DE2943406A1 (de) * | 1979-10-26 | 1981-05-07 | Basf Ag, 6700 Ludwigshafen | Aminoderivate des 2-methyl-5-(2-hydroxystyryl)-1,3,4-thiadiazols |
FR2507181A1 (fr) | 1981-06-05 | 1982-12-10 | Sanofi Sa | Nouveaux ethers de phenol actifs sur le systeme cardiovasculaire, leur procede de preparation et leur utilisation dans des medicaments |
SE8801518D0 (sv) * | 1988-04-22 | 1988-04-22 | Astra Pharma Prod | A novel process |
US5225565A (en) * | 1988-09-15 | 1993-07-06 | The Upjohn Company | Antibacterial 3-(fused-ring substituted)phenyl-5β-amidomethyloxazolidin-2-ones |
ES2065278B1 (es) * | 1993-06-24 | 1995-09-01 | Medichem Sa | Procedimiento de obtencion enantioselectivo del levobunolol. |
WO2002009760A2 (en) * | 2000-07-27 | 2002-02-07 | Pharmacia Corporation | Epoxy-steroidal aldosterone antagonist and beta-adrenergic antagonist combination therapy for treatment of congestive heart failure |
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GB1023214A (en) * | 1962-12-17 | 1966-03-23 | Ici Ltd | Carbocyclic hydroxyamines |
-
1968
- 1968-09-23 US US761857A patent/US3641152A/en not_active Expired - Lifetime
-
1969
- 1969-08-06 ZA ZA695648A patent/ZA695648B/xx unknown
- 1969-08-22 GB GB41987/69A patent/GB1223527A/en not_active Expired
- 1969-09-11 FR FR696930899A patent/FR2018626B1/fr not_active Expired
- 1969-09-17 NL NL696914077A patent/NL139166B/xx not_active IP Right Cessation
- 1969-09-18 JP JP44073683A patent/JPS4843734B1/ja active Pending
- 1969-09-22 DK DK503669AA patent/DK125588B/da unknown
- 1969-09-22 NO NO693770A patent/NO128869B/no unknown
- 1969-09-22 BE BE739195D patent/BE739195A/xx not_active IP Right Cessation
- 1969-09-22 IT IT22348/69A patent/IT1033032B/it active
- 1969-09-22 ES ES371737A patent/ES371737A1/es not_active Expired
- 1969-09-22 CH CH1430069A patent/CH525183A/de not_active IP Right Cessation
- 1969-09-22 SE SE13017/69A patent/SE362414B/xx unknown
- 1969-09-23 DE DE1948144A patent/DE1948144C3/de not_active Expired
- 1969-09-23 DE DE1967162A patent/DE1967162C3/de not_active Expired
- 1969-09-23 FI FI692717A patent/FI51936C/fi active
-
1971
- 1971-11-12 DK DK556771AA patent/DK128536B/da not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NL139166B (nl) | 1973-06-15 |
US3641152A (en) | 1972-02-08 |
NL6914077A (no) | 1970-03-25 |
JPS4843734B1 (no) | 1973-12-20 |
DE1967162B1 (de) | 1980-07-31 |
DE1948144A1 (de) | 1970-03-26 |
ES371737A1 (es) | 1972-03-16 |
DE1948144B2 (de) | 1979-05-03 |
BE739195A (no) | 1970-03-23 |
FI51936C (fi) | 1977-05-10 |
FR2018626B1 (no) | 1973-06-08 |
CH525183A (de) | 1972-07-15 |
FI51936B (no) | 1977-01-31 |
DK125588B (da) | 1973-03-12 |
FR2018626A1 (no) | 1970-06-26 |
ZA695648B (en) | 1971-03-31 |
DK128536B (da) | 1974-05-20 |
DE1967162C3 (de) | 1981-03-19 |
DE1948144C3 (de) | 1980-01-17 |
SE362414B (no) | 1973-12-10 |
IT1033032B (it) | 1979-07-10 |
GB1223527A (en) | 1971-02-24 |
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