IE50485B1 - Novel substituted 2-phenylamino-imidazolines-(2),the acid addition salts thereof,pharmaceuticals containing same and processes for the preparation thereof - Google Patents
Novel substituted 2-phenylamino-imidazolines-(2),the acid addition salts thereof,pharmaceuticals containing same and processes for the preparation thereofInfo
- Publication number
- IE50485B1 IE50485B1 IE2555/80A IE255580A IE50485B1 IE 50485 B1 IE50485 B1 IE 50485B1 IE 2555/80 A IE2555/80 A IE 2555/80A IE 255580 A IE255580 A IE 255580A IE 50485 B1 IE50485 B1 IE 50485B1
- Authority
- IE
- Ireland
- Prior art keywords
- acid addition
- addition salts
- group
- general formula
- imidazolines
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims abstract description 28
- 150000003839 salts Chemical class 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 6
- 239000003814 drug Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims abstract description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 3
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 150000004820 halides Chemical class 0.000 claims abstract description 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- DZHUQIOYWZHKQP-UHFFFAOYSA-N n-(2,6-dibromo-4-methylphenyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound BrC1=CC(C)=CC(Br)=C1N=C1NCCN1 DZHUQIOYWZHKQP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims abstract 3
- 125000005394 methallyl group Chemical group 0.000 claims abstract 3
- 229910052799 carbon Inorganic materials 0.000 claims abstract 2
- 239000007795 chemical reaction product Substances 0.000 claims abstract 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical class N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
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- 239000000843 powder Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
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- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 230000000747 cardiac effect Effects 0.000 claims 1
- 230000003111 delayed effect Effects 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
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- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000000059 bradycardiac effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UFQDKRWQSFLPQY-UHFFFAOYSA-N 4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound Cl.C1CN=CN1 UFQDKRWQSFLPQY-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- YIUIVFFUEVPRIU-UHFFFAOYSA-N 8-chlorotheophylline Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21 YIUIVFFUEVPRIU-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 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
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 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
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000010309 melting process Methods 0.000 description 1
- -1 methallyl radical Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 229940005605 valeric acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole 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
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
1. Claims for the Contracting state : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Substituted 2-phenylamino-imidazolines-(2) of general formula (I) see diagramm : EP0030616,P7,F1 wherein R represents an n-propyl, cyclopropylmethyl, cyclopentylmethyl, allyl or methallyl group, and the physiologically acceptable acid addition salts thereof. 1. Claims for the Contracting state : AT Process for preparing substituted 2-phenylamino-imidazolines-(2) of general formula (I) see diagramm : EP0030616,P8,F1 wherein R represents an n-propyl, cyclopropylmethyl, cyclopentylmethyl, allyl or methallyl group, and the physiologically acceptable acid addition salts thereof, characterised in that a) 2-(2,6-dibromo-4-methylphenyl-imino)-imidazolidine of formula II see diagramm : EP0030616,P8,F2 is reacted with a halide of general formula III Hal-R wherein Hal represents a chlorine, bromine or iodine atom and R is as hereinbefore defined, at 40 degrees C to 150 degrees C, or b) a compound of general formula IV see diagramm : EP0030616,P8,F3 wherein R is as hereinbefore defined and A represents a cyano group or the group see diagramm : EP0030616,P8,F4 wherein Y represents an alkoxy or alkylthio group with up to 4 carbon atoms or a mercapto group or an amino group, is reacted with ethylenediamine or the acid addition salts thereof at 60 to 180 degrees C, and the end product obtained according to one of these processes is optionally converted into a corresponding acid addition salt.
Description
DE-A- 25 23 103, DE-A- 26 36 732, DE-A- 19 57 722 and DE-A- 22 59 160 disclose substituted 2-phenylamino-imidazolines-(2) which exhibit therapeutic properties. The compounds disclosed in tnese references especially possess analgesic, blood-pressure decreasing, sedative and secretion inhibiting properties.
According to the present invention novel substituted 2-phenylaminoimidazolines of the general formula (I) Br Br (I) and the physiologically acceptable acid addition salts thereof are 10 provided which also have valuable therapeutic properties, especially bradycardiac activity.
In formula I R represents a n-propyl, cyclopropyl-methyl, cyclopentyl rnothyl, the allyl or methallyl radical.
According to a further aspect of the present invention we provide a 15 process for the preparation of 2-pheny1amino-imidazolines-(2) of fonnula I (as defined above) and addition salts thereof which process 50488 comprises at least one of the following steps:(a) react ing 2-(2,6-dibromo-4-methylphenyl-imino)imidazolidine with a halideof formula III Hal-R (HI) (wherein Hal represents a chlorine, bromine or iodine atom and R is as defined above); (b) reacting a compound of formula IV (wherein R is as defined above and A represents a cyano group or a group of formula ;NH -c [wherein- Y represents an alkoxy or alkylthio group with up to 4 carbon atoms, a sulfhydril group or an amino group]) with ethylene diamine or an acid addition salt thereof; and (c) converting a 2-phenylamino-imidazoline-(2) of formula I (wherein R is as defined above) into an acid addition salt thereof.
The reaction according to process (a) may be effected by heating the reactants - preferably in the presence of a polar or apolar solvent - to temperatures from 40 to 150°C.
To a great extent the specific reaction conditions employed depend upon the reactivity of the reagents.
It is recommended that during alkylation the halide of general formula III is employed in excess and also that the reaction is carried out in the presence of an acid-binding agent.
With process (b) it is normally necessary to work at elevated temperature, appropriately between 60° and 180°C. Solvents are not necessary, but they may if desired be used.
The starting compounds of formulae II and IV are known from the literature (vide, for example, Belgian Patent No. 623 305, Chem. Ber. 107, 2644 (1974) and Liebigs Ann. Chem. 751, 159 (1971)).
Compounds of formula III may be produced by halogenation of the basic alcohols.
The acid addition salts of compounds of formula 50483 X are preferably physiologically acceptable acid addition salts. Other acid addition salts may however be useful in the preparation of the 2-phenylaminoimidazolines-(2) of formula I or of physiologically acceptable acid addition salts thereof and are therefore included within the scope of the invention. Compounds of formula I can be converted in the conventional way into their physiologically acceptable acid addition salts. Acids suitable for the preparation of physiologically acceptable acid addition salts include, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, .succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid and 8-chlorotheophylline.
The novel compounds of general formula I and their physiologically acceptable acid addition salts possess a very strong bradycardiac action and are, therefore, suitable for treatment of coronary diseases and ailments. Their influence on the heart rate has been tested in rabbits and pithed rats as well as intact, narcotized rats.
According to a further aspect of the present invention we provide pharmaceutical compositions comprising at least one compound of formula I or physiologically acceptable acid addition salt thereof together with a carrier and/or excipient.
The pharmaceutical compositions of the invention are advantageously in forms suitable for oral, rectal or parenteral administration and preferably are in dosage unit form. Pharmaceutical compositions of the invention in dosage unit form conveniently contain 0.1 to 80 mg, preferably from 1 to 30 mg, of the compound of formula I or addition salt thereof.
The pharmaceutical compositions of the present invention optionally may contain active substances other than the compounds of the invention.
Suitable galenic dosage forms are, for example, tablets, capsules, suppositories, solutions or powders; for their production may be used the conventional galenic excipients, carriers, disintegrants or lubricants or substances for obtaining sustained release.' According to a yet further aspect of the present invention we provide a method of treatment of the human or animal body to control heart or coronary diseases or ailments thereof which method comprises administering to the said body an effective amount of a compound of formula I or a physiologically acceptable acid addition salt thereof.
The following Examples are provided to illustrate the present invention without restricting the scope of protection sought therefor:6 S048S Example 1 Preparation of 2[N-(cyclopropylmethyl)-N-(2,6-dibromo4-methyl-phenyl)amino]-2-imidazoline hydrochloride 4.2 g (0.013 mol) of 2-[(2,6-dibromo-4-methyl5 phenyl)-imino]-imidazolidine are refluxed together with 1.7 g (150%) of ehloromethylcyclopropane in 25 ml of acetonitrile for 42 hours while stirring. Thereafter, the reaction mixture is evaporated in vacuo and the remaining residue is dissolved in approx.
IN HCI. The hydrochloric acid solution is extracted twice with ether (these ether extracts being abandoned) and subsequently extracted with ether at increasing pH-values in fractions (alkalizing with 2 N NaOH) .
Out of the 12 ether fractions obtained, the uniform ones are united (control by thin-layer chromatogram), dried over magnesium sulfate and admixed with etheric hydrochloric acid up to the congo-acid reaction.
In doing so the novel imidazoline hydrochloride precipitates. It is sucked off, washed with ether and dr ied.
Yield: 1.9 g (corresponding to 36.5% of theory).
Melting point: 140°C.
Analogously to the preceding Example the foil owing 5 compounds of formula 1 were produced: Example No. R Yield Melting Process % of theory Point °C -CH. 57.7 152-153 (base) -^3^7 ΰ a 77.5 280 (hydrobromide) -CH. 9.3 92-93 (base) -CH2-CH = CH2 a 80.7 272-274 (hydrohromide) Example A: Sugar-coated Tablets Active ingredient according to the present invention 5 mg lactose 65 mg corn starch 130 mg sec. calcium phosphate 40 mg soluble starch 3 mg magnesium stearate 3 mg colloidal silicic acid 4 mq total 250 mg The active ingredient is admixed with part of the excipients, kneaded thoroughly with an aqueous solution of the soluble starch and granulated in the conventional way with the aid of a screen.
The granulate is admixed with the remaining excipients and pressed to tablet-cores of 250 ma weight; the cores being coated in the conventional way with sugar, talcum and gum arabic.
Example B: Ampoules Active ingredient according to the present invention 1.0 mg sodium chloride 18.0 mg distilled water ad 2.0 ml The active ingredient and sodium chloride are dissolved in water and filled under nitrogen into glass ampoules. . 50485 Ε χam ηle C: Drops \ctiv? ingredient according to the present invention 0.02 g methyl-p-hydroxy-benzoate 0.07 g prooy1-D-hydroxy-benzoate 0.03 g demineralized water ad 100.00 ml The active ingredient and the p-hydroxybenzoates are dissolved in the demineralized water.
Claims (9)
1. Substituted 2-phenylamino-imidazolines-(2) of general formula (I) wherein R represents an n-propyl, cyclopropylmethyl, 5 cyclopentylmethyl, allyl or methallyl group, and the physiologically acceptable acid addition salts thereof.
2. Process for preparing substituted 2-phenylamino-imidazolines as claimed in claim 1, wherein a) 2-(2,6-dibromo-4-methylphenyl-imino)-imidazoline of 10 formula (II) is reacted with a halide of general formula III Hal - R (III) wherein Hal represents a chlorine, bromine or iodine atom and 15 R is as hereinbefore defined, at 40°C to 150°C, or b) a compound of general formula IV wherein R is as hereinbefore defined and A represents a cyano group or the group wherein Y represents an alkoxy or alkylthio group with up to 4 carbon atoms or a mercapto group or an amino group, is reacted with ethylenediamine or the acid addition salts thereof at 60 to 180°C, and the end product obtained according to one of these methods is optionally 10 converted into a corresponding acid addition salt.
3. Pharmaceutical preparations, which contain, as active substance, one or more compounds as claimed in claim 1.
4. Process for preparing pharmaceutical compositions as claimed in claim 3, wherein one or more compounds as claimed in claim 1 are 15 combined with conventional galenic excipients, carriers, disintegrants or lubricants or substances for obtaining delayed release, to form tablets, capsules, suppositories, solutions or powders.
5. Compounds of general formula I or the physiologically acceptable acid addition salts thereof as claimed in claim 1 for use in combatting cardiac and coronary diseases.
6. Substituted 2-phenylamino-imidazolines -(2) of formula I 5 as claimed in claim 1 or physiologically acceptable acid addition salts thereof substantially as described herein with reference to Examples 1 to 5.
7. Pharmaceutical preparations containing as active compound a compound of formula I as claimed in claim 1 or physiologically 10 acceptable acid addition salts thereof substantially as described herein with reference to Examples A to C.
8. A process for the preparation of a compound of formula I as claimed in claim 1, or physiologically acceptable acid addition salts thereof, substantially as described herein with reference to 15 Examples 1 to 5.
9. Substituted 2-phenylamino-imidazolines -(2) of general formula I as claimed in claim 1 or physiologically acceptable acid addition salts thereof whenever prepared by a process as claimed in claim 2 or claim 8.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792949287 DE2949287A1 (en) | 1979-12-07 | 1979-12-07 | NEW SUBSTITUTED 2-PHENYLAMINO-IMIDAZOLINE (2), THE ACID ADDITION SALTS THEREOF, THE MEDICINAL PRODUCTS CONTAINING THE SAME AND METHOD FOR THE PRODUCTION THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE802555L IE802555L (en) | 1981-06-07 |
| IE50485B1 true IE50485B1 (en) | 1986-04-30 |
Family
ID=6087857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2555/80A IE50485B1 (en) | 1979-12-07 | 1980-12-05 | Novel substituted 2-phenylamino-imidazolines-(2),the acid addition salts thereof,pharmaceuticals containing same and processes for the preparation thereof |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0030616B1 (en) |
| JP (1) | JPS5692274A (en) |
| AT (1) | ATE5818T1 (en) |
| AU (1) | AU533756B2 (en) |
| DE (2) | DE2949287A1 (en) |
| DK (1) | DK521680A (en) |
| ES (1) | ES497480A0 (en) |
| FI (1) | FI69068C (en) |
| IE (1) | IE50485B1 (en) |
| IL (1) | IL61637A (en) |
| NO (1) | NO151412C (en) |
| ZA (1) | ZA807611B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4644007A (en) * | 1981-11-20 | 1987-02-17 | Alcon Laboratories, Inc. | 3-chloro-4-(4,5-dihydro-1H-imidazo-2-yl)-amino-5-alkylbenzoic acids, esters, salts, compositions and methods |
| US4515800A (en) * | 1981-11-20 | 1985-05-07 | Icilio Cavero | Method of lowering intraocular pressure using phenylimino-imidazoles |
| US4461904A (en) * | 1981-11-20 | 1984-07-24 | Alcon Laboratories, Inc. | 2-(Trisubstituted phenylimino)-imidazolines |
| US4517199A (en) * | 1981-11-20 | 1985-05-14 | Alcon Laboratories, Inc. | Method for lowering intraocular pressure using phenylimino-imidazoles |
| HU192986B (en) * | 1984-05-23 | 1987-08-28 | Egyt Gyogyszervegyeszeti Gyar | Process for production of imidasodiline derivatives |
| DE19514579A1 (en) | 1995-04-20 | 1996-10-24 | Boehringer Ingelheim Kg | Use of alpha-1-olone agonists for the treatment of urinary incontinence |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT285599B (en) * | 1968-06-21 | 1970-11-10 | Boehringer Sohn Ingelheim | Process for the preparation of new trisubstituted 2-arylaminoimidazolines and their salts |
| BE759048A (en) * | 1969-11-17 | 1971-05-17 | Boehringer Sohn Ingelheim | NEW N-AMINOALCOYL-ARYLAMINO-IMIDAZOLINES- (2) SUBSTITUTES AND METHODS FOR MAKING THEM |
| DE2259160A1 (en) * | 1972-12-02 | 1974-06-06 | Boehringer Sohn Ingelheim | NEW SUBSTITUTED 2-PHENYLAMINOIMIDAZOLINE, THEIR ACID-ADDITIONAL SALTS AND METHOD FOR MANUFACTURING THE SAME AND THEIR USE AS A MEDICINAL PRODUCT |
| DE2523103C3 (en) * | 1975-05-24 | 1979-11-29 | C.H. Boehringer Sohn, 6507 Ingelheim | Substituted 2- [N-Progargyl-N- (2-chlorophenyl) amino] -imidazoline- ^), their acid addition salts, processes for their preparation and their use |
| DE2636732A1 (en) * | 1976-08-14 | 1978-02-16 | Boehringer Sohn Ingelheim | NEW SUBSTITUTED 2-PHENYLAMINO IMIDAZOLINE (2), THE ACID ADDITION SALTS THEREOF, THE MEDICINAL PRODUCTS CONTAINING THE SAME AND METHOD FOR THE PRODUCTION THEREOF |
-
1979
- 1979-12-07 DE DE19792949287 patent/DE2949287A1/en not_active Withdrawn
-
1980
- 1980-11-03 AT AT80106725T patent/ATE5818T1/en not_active IP Right Cessation
- 1980-11-03 DE DE8080106725T patent/DE3066104D1/en not_active Expired
- 1980-11-03 EP EP80106725A patent/EP0030616B1/en not_active Expired
- 1980-12-05 ZA ZA00807611A patent/ZA807611B/en unknown
- 1980-12-05 IE IE2555/80A patent/IE50485B1/en unknown
- 1980-12-05 ES ES497480A patent/ES497480A0/en active Granted
- 1980-12-05 AU AU65136/80A patent/AU533756B2/en not_active Ceased
- 1980-12-05 FI FI803799A patent/FI69068C/en not_active IP Right Cessation
- 1980-12-05 JP JP17196380A patent/JPS5692274A/en active Pending
- 1980-12-05 NO NO803682A patent/NO151412C/en unknown
- 1980-12-05 DK DK521680A patent/DK521680A/en not_active Application Discontinuation
- 1980-12-05 IL IL61637A patent/IL61637A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2949287A1 (en) | 1981-06-11 |
| FI803799L (en) | 1981-06-08 |
| NO803682L (en) | 1981-06-09 |
| EP0030616B1 (en) | 1984-01-11 |
| JPS5692274A (en) | 1981-07-25 |
| AU533756B2 (en) | 1983-12-08 |
| NO151412B (en) | 1984-12-27 |
| FI69068B (en) | 1985-08-30 |
| IE802555L (en) | 1981-06-07 |
| ZA807611B (en) | 1982-08-25 |
| ATE5818T1 (en) | 1984-01-15 |
| DE3066104D1 (en) | 1984-02-16 |
| FI69068C (en) | 1985-12-10 |
| EP0030616A1 (en) | 1981-06-24 |
| DK521680A (en) | 1981-06-08 |
| IL61637A (en) | 1984-11-30 |
| ES8201978A1 (en) | 1982-01-01 |
| ES497480A0 (en) | 1982-01-01 |
| NO151412C (en) | 1985-04-10 |
| AU6513680A (en) | 1981-06-18 |
| IL61637A0 (en) | 1981-01-30 |
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