DK163665B - Beta-methylen-furan-ethanaminer - Google Patents
Beta-methylen-furan-ethanaminer Download PDFInfo
- Publication number
- DK163665B DK163665B DK607685A DK607685A DK163665B DK 163665 B DK163665 B DK 163665B DK 607685 A DK607685 A DK 607685A DK 607685 A DK607685 A DK 607685A DK 163665 B DK163665 B DK 163665B
- Authority
- DK
- Denmark
- Prior art keywords
- methylene
- furanethanamine
- dbh
- beta
- furan
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 17
- 102100033156 Dopamine beta-hydroxylase Human genes 0.000 abstract description 14
- 239000003112 inhibitor Substances 0.000 abstract description 9
- DAKOVWLRNPFXDL-UHFFFAOYSA-N 2-(furan-2-yl)prop-2-en-1-amine Chemical class NCC(=C)C1=CC=CO1 DAKOVWLRNPFXDL-UHFFFAOYSA-N 0.000 abstract description 3
- 108010015720 Dopamine beta-Hydroxylase Proteins 0.000 abstract description 3
- 229940030600 antihypertensive agent Drugs 0.000 abstract description 2
- 239000002220 antihypertensive agent Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 101000927562 Homo sapiens Dopamine beta-hydroxylase Proteins 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000003276 anti-hypertensive effect Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- -1 3-methylene-furanethanamines Chemical class 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 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
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 150000003943 catecholamines Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007788 liquid Substances 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
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- VESLRNDUOCLYDT-UHFFFAOYSA-N 1-phenylprop-2-en-1-amine Chemical compound C=CC(N)C1=CC=CC=C1 VESLRNDUOCLYDT-UHFFFAOYSA-N 0.000 description 1
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 1
- OBBIFUJGKFYOGT-UHFFFAOYSA-N 2-(furan-3-yl)prop-2-en-1-amine Chemical compound NCC(=C)C=1C=COC=1 OBBIFUJGKFYOGT-UHFFFAOYSA-N 0.000 description 1
- IEMMBWWQXVXBEU-UHFFFAOYSA-N 2-acetylfuran Chemical compound CC(=O)C1=CC=CO1 IEMMBWWQXVXBEU-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- XESZUVZBAMCAEJ-UHFFFAOYSA-N 4-tert-butylcatechol Chemical compound CC(C)(C)C1=CC=C(O)C(O)=C1 XESZUVZBAMCAEJ-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 238000005642 Gabriel synthesis reaction Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 238000003747 Grignard reaction Methods 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
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- YWWZCHLUQSHMCL-UHFFFAOYSA-N diphenyl diselenide Chemical compound C=1C=CC=CC=1[Se][Se]C1=CC=CC=C1 YWWZCHLUQSHMCL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 108700006189 dopamine beta hydroxylase deficiency Proteins 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cephalosporin Compounds (AREA)
- Lubricants (AREA)
- Paper (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Non-Silver Salt Photosensitive Materials And Non-Silver Salt Photography (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Description
DK 163665 B
Den foreliggende opfindelse angår hidtil ukendte /3-methylen-furan-ethanaminer som udviser dopamin-/3-hydroxy-lase-inhiberende virkning og er anvendelige til behandling af hypertension.
5 Det er kendt, at β-methylen-phenylethanamin udviser dopamin-/3-hydroxylase-inhiberende (DBH-inhiberende) virkning, jf. S.W. May, P.W. Mueller, S.R. Padgette, H.H. Herman og R.S. Philips, Biochem. Biophys. Res. Commun. 110. 161 (1983).
Det har nu vist sig, at de tilsvarende furylforbin-10 delser udviser en overraskende forbedret DBH-inhiberende virkning i forhold til denne kendte forbindelse.
Opfindelsen angår således /3-methylen-furanethanaminer med formlen I
15 _ CH2 (1^ jj—c-ch2nh2 20 nemlig j8-methylen-2-furanethanamin og /3-methylen-3-furan-ethanamin, og de ugiftige farmaceutisk acceptable syreadditionssalte deraf.
25 Repræsentative salte er sådanne salte, som er dannet med ugiftige organiske eller uorganiske syrer, f.eks. salte dannet ud fra de følgende syrer: saltsyre, hydrogenbromid-syre, sulfonsyre, svovlsyre, phosphorsyre, salpetersyre, maleinsyre, fumarsyre, benzoesyre, ascorbinsyre, ravsyre, 30 methansulfonsyre, eddikesyre, propionsyre, vinsyre, citronsyre, mælkesyre, æblesyre, mandelsyre, kanelsyre, palmitin-syre, itaconsyre og benzensulfonsyre.
De her omhandlede forbindelser med formlen (I) kan let fremstilles ved en række reaktioner illustreret ved det 35 følgende reaktionsskema:
O
2
DK 163665 B
H
5
II III IV
. O-C-* OrCpJ — ·
V VI
I det væsentlige viser reaktionsskemaet ovenfor omdan-15 nelsen af 2- eller 3-acetyl-derivater af furan til de tilsvarende 2- eller 3-isopropyliden-derivater ved reaktioner med methylmagnesiumbromid med efterfølgende dehydrering ifølge standard-Grignard-reaktionsbetingelser. Isopropyliden-deriva-terne med formlen (IV) underkastes allyl-chlorering ifølge 20 standard-betingelser, og råprodukterne med formlen (V) omdannes (via phthalimid-derivater med foralen (VI)) ved den velkendte Gabriel-syntese til dannelse af de ønskede forbindelser med formlen I. De frie baser kan omdannes til syreadditions-saltene/ eller syreadditionssaltene kan omdannes til de frie 25 baser/ ved konventionel kemisk metodik.
Det ovennævnte reaktionsskema illustreres ved det følgende specifikke eksempel.
Eksempel 30 B-Methylen-2-furanethanamin-hydrochlorid
Trin A; 2-(1-Methyl)-ethenylfuran
En opløsning af 55/06 g (0,5 mol) 2-acetylfuran i 100 ml vandfri ether sættes dråbevis under i løbet af 1,5 35 timer til 211 ml 2,85 M methylmagnesiumbromid/ether (0,6 mol), medens reaktionsblandingen omrøres i et isbad. Temperaturen holdes under 30°C ved regulering af tilsætningshastig- 3
DK 163665 B
O
heden. Der dannes et gråt bundfald. Blandingen får lov til at opvarme til 25°C i 1 time, hvorpå den igen afkøles i et isbad, medens der forsigtigt tilsættes 100 ml mættet NaHCO^-ropløsning. Den fremkomne masse opløses i ca. 1 liter vand, 5 og den vandige fase ekstraheres to gange med ether. De kombinerede etheropløsninger ekstraheres med mættet NaCl-opløs-ning, tørres over l^CO^, filtreres og koncentreres ved atmosfærisk tryk til en gul olie. Til denne rå alkohol sættes 5,0 g KHSO4 og ca. 0,1 g 4-tert.butylcatechol (inhibitor), 10 og blandingen destilleres ved 1 atm. En blanding af det ønskede produkt og vand destillerer over ved ca. 90°C. Vandet fraskilles, og produktet tørres over I^CO^, hvorpå det filtreres til dannelse af 8,5 g farveløs olie. På lignende måde fremstilles 3-(1-methyl)-ethenylfuran.
15
Trin B; N-2-(2-Furanyl)-propenylphthalimid
Til en opløsning af 8,35 g (0,077 mol) af olefinen i trin A i 310 ml DMF sættes 12,37 g (0,093 mol) N-chlorsucci-nimid og 1,46 g (0,0047 mol) diphenyldiselenid. Efter 3 timer 20 ved stuetemperatur fordeles blandingen mellem 500 ml hexan og 1000 ml 5%'s ^2820^. Hexanet afdestilleres ved atmosfærisk tryk, og remanensen opløses i 200 ml DMF, der tilsættes 9,49 g (0,051 mol) kaliumphthalimid, og blandingen opvarmes til 90°C under Efter 45 minutter hældes den afkølede reak-25 tionsblanding i vand, og det udfældede produkt frafiltreres og omkrystalliseres fra ethylacetat/2-propanol, hvilket giver 3,57 g farveløse krystaller med smp. 136-137°C.
Analyse for C15H11N02S: C% H% N% 30 Beregnet: 66,90 4,12 5,20
Fundet: 66,82 4,30 4,97 På lignende måde fremstilles N-2-(3-furanyl)-propenylphthalimid.
35
O
4
DK 163665 B
Trin C? 6-Methylen-2-furanethanamin-HCl
Til en magnetisk omrørt suspension af 3,50 g (13,83 mmol) af phthalimidet fremstillet i trin B sættes 1,34 g (27,64 mmol) hydrazinhydrat og 400 ml ethanol, og blandingen 5 tilbagesvales under Nj i 1 time, og i løbet af denne tid dannes et tykt bundfald. Den afkølede blanding destilleres med 1 Μ KOH til opløsning af bundfaldet, hvorpå den ekstraheres med ether. Etherlaget vaskes med 1 M KOH og ekstraheres derpå med 1 M HCl. Det sure lag gøres basisk med 5 N NaOH, hvorpå 10 det mættes med NaCl og ekstraheres med ether. Etherfasen tørres over K2C03 °9 koncentreres til en gul olie. Destillation giver 1,23 g farveløs væske med kp. 40°C ved 0,5 mm Hg. Aminen optages i ether og afkøles i et isbad, og en mættet opløsning af vandfrit HCl i ether tilsættes dråbevis, indtil der ikke 15 dannes mere bundfald. De flygtige bestanddele fjernes under vakuum, og remanensen omkrystalliseres fra ethano1/ethylace-tat til dannelse af 1,2 g farveløse krystaller med smp. 150-151°C.
Analyse for C^HgNO*HCl: 20 C% H% N%
Beregnet: 52,68 6,31 8,78
Fundet: 52,48 6,43 8,61
De her omhandlede allylaminer er dopamin-β-hydroxylase-25 (DBH) -inhibitorer på en mekanisme-baseret måde; idet inaktiveringen er tids- og koncentrations-afhængig. Forbindelserne. med formlen I forventes derfor at være værdifulde terapeutiske midler, som er nyttige ved behandling af hypertension.
De dopamin-p-hydroxylase-inhiberende egenskaber af de 3Q her omhandlede forbindelser kan let bestemmes ved velkendte standard-procedurer, f.eks. procedurerne beskrevet i US patentskrift nr. 4.415.591. F.eks. eksemplificeres bestemmelse af, hvorvidt DBH-inhiberingen tillader tidsafhængig kinetik, ved en procedure, ved hvilken enzymatisk oxygenering med DBH be-35 stemmes i vandig opløsning i nærværelse af molekylært oxygen, en elektrondonor, såsom ascorbat, og de nødvendige co-fak-torer for enzymet ved en pH-værdi på 5 og en temperatur på
O
DK 163665 B
5 20-40°C, fortrinsvis 37°C. Forsøgsforbindelsen tilsættes i den ønskede koncentration, og systemet inkuberes. Portioner tages ved forskellige tidsintervaller, og DBH-aktiviteten måles ved anvendelse af tyramin som substrat, og reaktionen 5 følges ved måling af oxygenoptagelsen ved anvendelse af en polarografisk elektrode og en oxygen-monitor ved metoden i-følge S. May et a., J. Biol. Chem. 256, 2258 (1981). Inhi-beringskonstanterne for inaktiveringen af DBH med hver forbindelse bestemmes ved konventionelle procedurer, såsom me-10 toden ifølge Kitz og Wilson, J. Biol. Chem. 237, 3245 (1962) .
Når forbindelsen vist i tabel I testes ifølge den ovenfor beskrevne procedure, forøges den DBH-inhiberende aktivitet som en funktion af inkubationstiden. Begyndelseshastigheden af aktivitetsnedsættelsen forøges med stigende koncentration 15 af inhibitor. Resultaterne i tabel I viser, at B-methylen-2--furanethanamin er aktivt som illustreret ved den hurtige inaktiveringshastighed (K. = . ) og lave inhiberingskonstant lliaCL · (κχ).
20 Tabel I
DBH-inhiberende aktivitet - in vitro
Forbindelse K^. (mM) iSinact tøfl*1"'*') 25 3-Methylen-2-furanethanamin 8 0,004
Tabel II
Antihypertensiv virkning - in vivo
Dosis Maksimumsændring i % af 30 Forbindelse mg/kg gennemsnitsblodtryk B-Methylen-2-furanethan- amin 10 (ip) 18 30 (ip) 32 35
DK 163665 B
6
De her omhandlede forbindelsers evne til at sænke blod-; trykket kan bestemmes in vivo ved anvendelse af hypertensive rotter ifølge velkendte standard-procedurer. Forsøgsforbindelsen indgives intraperitonealt (ip) eller oralt (po) til 5 rotter/ og blodtrykket måles uafbrudt. Da DBH er et hovedenzym ved syntesevejen for catecholaminer, forventes det/ at nærværelsen af en inhibitor vil formindske mængden af fremstillede catecholaminer og derved have en antihypertensiv virkning. Resultaterne af testningen af denne antihyperten- 10 sive virkning er vist i tabel II.
Ved en anden test som beskrevet af Barger et al. (Communications to the Editor/ J. Med. Chem. 29., 315-317 (1986)) undersøges β-methylen-2-furanethanamin og /3-methy-len-3-furanethanamin og sammenlignes med /3-methylen-phenyl- 15 ethanamin in vitro for deres dopamin-jø-hydroxylase-inhibe-rende egenskaber med følgende resultater:
TABEL III
20 Kinetiske konstanter for dopamin-fi-hvdroxylase-inhibitorer.
Forbindelse3 KIf/iM kcat/ min"1 kcat/Kx, M"1 min"1 25 I 410 0,130 317 II 230 0,077 334 III 13000 0,04 3 30 a) Forbindelse I - j3-Methylen-2- fur anethanamin II - /3-Methylen-3-furanethanamin III - /3-Methylen-phenylethanamin 35 Man kan af tabel ill konkludere ud fra beregningerne
DK 163665 B
7 af kcat/KI' som nærmer sig DBH-inhiberingsraten ved koncentrationer af inhibitor meget mindre end Kj, at /9-methy-len-2-furanethanamin og β-methylen-3-furanethanamin hver især er over 100 gange mere virksomme som inhibitorer af 5 dopamin-/3-hydroxylase in vitro end /3-methylen-phenylethan-axnin.
Baseret på disse og andre standard-laboratoriemetoder/ som kendes til bedømmelse af dopamin-B-hydroxylase-inhibito-rer ved standard-toksicitetsforsøg og ved standard-farmakolo-10 giforsøg til bestemmelse af antihypertensiv virkning hos pattedyr og ved sammenligning af disse resultater med resultaterne med kendte antihypertensive midler, kan den effektive antihypertensive dosis af de her omhandlede forbindelser således let bestemmes. Sædvanligvis kan effektive antihyper-15 tensive resultater opnås ved en dosis på ca. 5 til ca. 100 mg pr. kg legemsvægt pr. dag. Naturligvis vil den specifikke begyndelses- og fortsatte dosis for hver patient variere i-følge naturen og alvoren af hypertensionen, som bestemt af den pågældende diagnostiker.
20 I deres funktion som terapeutisk anvendelige forbindel ser er det fordelagtigt at indgive forbindelserne til værtsdyret i blanding med en acceptabel farmaceutisk bærer, som egner sig til enterisk eller parenteral indgivelse, idet den nævnte bærer udgør en større del af blandingen. Sådanne præ-25 parater kan være i form af f.eks. tabletter, kapsler og suppositorier, eller i flydende former, f.eks. eliksirer, emulsioner, sprøjtevæsker og injektionsopløsninger. Ved formuleringen af farmaceutiske præparater kan der anvendes sådanne stoffer, som ikke reagerer med aktivt stof, f.eks. vand, 30 gelatine, lactose, stivelse, magnesiumstearat, talkum, vegetabilske olier, benzylalkoholer, gummier, polyalkylenglycoler, vaseline og lignende. Den aktive bestanddel af sådanne farmaceutiske præparater er fortrinsvis til stede i præparatet i sådanne vægtforhold, at vægtforholdet af den aktive bestand-del, som skal indgives, ligger mellem 0,1 og 50%.
Claims (2)
- 2. Forbindelse ifølge krav 1, kendetegnet ved, at den er j8-methylen-2-furanethanamin.
- 3. Forbindelse ifølge krav 1,kendetegnet ved, at den er /3-methylen-3-furanethanamin. 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68762784A | 1984-12-31 | 1984-12-31 | |
| US68762784 | 1984-12-31 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK607685D0 DK607685D0 (da) | 1985-12-30 |
| DK607685A DK607685A (da) | 1986-07-01 |
| DK163665B true DK163665B (da) | 1992-03-23 |
| DK163665C DK163665C (da) | 1992-09-07 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK607685A DK163665C (da) | 1984-12-31 | 1985-12-30 | Beta-methylen-furan-ethanaminer |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0186915B1 (da) |
| JP (1) | JPS61161275A (da) |
| KR (1) | KR900003398B1 (da) |
| CN (1) | CN1007247B (da) |
| AT (1) | ATE55379T1 (da) |
| AU (1) | AU585922B2 (da) |
| CA (1) | CA1245228A (da) |
| DE (1) | DE3579143D1 (da) |
| DK (1) | DK163665C (da) |
| ES (1) | ES8701744A1 (da) |
| FI (1) | FI84822C (da) |
| GR (1) | GR853147B (da) |
| HU (1) | HU193620B (da) |
| IE (1) | IE58188B1 (da) |
| NO (1) | NO168580C (da) |
| NZ (1) | NZ214697A (da) |
| PH (1) | PH21981A (da) |
| PT (1) | PT81771B (da) |
| ZA (1) | ZA859890B (da) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1293511C (en) * | 1986-12-23 | 1991-12-24 | James R. Mccarthy | Allenyl amines |
| US4847288A (en) * | 1986-12-23 | 1989-07-11 | Merrell Dow Pharmaceuticals Inc. | Allenyl amines |
| CA1309719C (en) * | 1987-02-26 | 1992-11-03 | Thomas M. Bargar | Heterocycly1-2-propyn-1-amines |
| CN112441934B (zh) * | 2020-11-25 | 2022-04-22 | 华南理工大学 | 一种卤代氧杂烯丙基胺类化合物及其制备方法和应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4454158A (en) * | 1981-06-01 | 1984-06-12 | Merrell Toraude Et Compagnie | Allyl amine MAO inhibitors |
| CA1309719C (en) * | 1987-02-26 | 1992-11-03 | Thomas M. Bargar | Heterocycly1-2-propyn-1-amines |
-
1985
- 1985-12-23 NZ NZ214697A patent/NZ214697A/xx unknown
- 1985-12-27 JP JP60293323A patent/JPS61161275A/ja active Pending
- 1985-12-27 PH PH33244A patent/PH21981A/en unknown
- 1985-12-27 GR GR853147A patent/GR853147B/el unknown
- 1985-12-27 FI FI855159A patent/FI84822C/fi not_active IP Right Cessation
- 1985-12-28 HU HU855007A patent/HU193620B/hu not_active IP Right Cessation
- 1985-12-30 IE IE332785A patent/IE58188B1/en not_active IP Right Cessation
- 1985-12-30 CN CN85109441A patent/CN1007247B/zh not_active Expired
- 1985-12-30 CA CA000498782A patent/CA1245228A/en not_active Expired
- 1985-12-30 NO NO855352A patent/NO168580C/no unknown
- 1985-12-30 AU AU51726/85A patent/AU585922B2/en not_active Ceased
- 1985-12-30 ZA ZA859890A patent/ZA859890B/xx unknown
- 1985-12-30 EP EP85116657A patent/EP0186915B1/en not_active Expired - Lifetime
- 1985-12-30 PT PT81771A patent/PT81771B/pt not_active IP Right Cessation
- 1985-12-30 KR KR1019850009967A patent/KR900003398B1/ko not_active Expired
- 1985-12-30 ES ES550569A patent/ES8701744A1/es not_active Expired
- 1985-12-30 DE DE8585116657T patent/DE3579143D1/de not_active Expired - Fee Related
- 1985-12-30 DK DK607685A patent/DK163665C/da not_active IP Right Cessation
- 1985-12-30 AT AT85116657T patent/ATE55379T1/de active
Also Published As
| Publication number | Publication date |
|---|---|
| CN85109441A (zh) | 1986-08-13 |
| HU193620B (en) | 1987-11-30 |
| NO855352L (no) | 1986-07-01 |
| DK163665C (da) | 1992-09-07 |
| FI84822C (fi) | 1992-01-27 |
| EP0186915A3 (en) | 1987-03-25 |
| ES8701744A1 (es) | 1986-12-01 |
| FI855159A0 (fi) | 1985-12-27 |
| PT81771A (en) | 1986-01-02 |
| PT81771B (pt) | 1987-11-11 |
| AU585922B2 (en) | 1989-06-29 |
| DE3579143D1 (en) | 1990-09-13 |
| ZA859890B (en) | 1987-06-24 |
| EP0186915A2 (en) | 1986-07-09 |
| IE853327L (en) | 1986-06-30 |
| KR900003398B1 (ko) | 1990-05-18 |
| PH21981A (en) | 1988-05-02 |
| GR853147B (da) | 1986-04-29 |
| NO168580B (no) | 1991-12-02 |
| CN1007247B (zh) | 1990-03-21 |
| DK607685A (da) | 1986-07-01 |
| FI84822B (fi) | 1991-10-15 |
| AU5172685A (en) | 1986-07-10 |
| IE58188B1 (en) | 1993-07-28 |
| DK607685D0 (da) | 1985-12-30 |
| CA1245228A (en) | 1988-11-22 |
| HUT40093A (en) | 1986-11-28 |
| KR860004852A (ko) | 1986-07-14 |
| NZ214697A (en) | 1988-10-28 |
| ES550569A0 (es) | 1986-12-01 |
| JPS61161275A (ja) | 1986-07-21 |
| NO168580C (no) | 1992-03-11 |
| EP0186915B1 (en) | 1990-08-08 |
| FI855159L (fi) | 1986-07-01 |
| ATE55379T1 (de) | 1990-08-15 |
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