DK149952B - Analogifremgangsmaade til fremstilling af et aminoalkylfuranderivat - Google Patents
Analogifremgangsmaade til fremstilling af et aminoalkylfuranderivat Download PDFInfo
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- DK149952B DK149952B DK416384A DK416384A DK149952B DK 149952 B DK149952 B DK 149952B DK 416384 A DK416384 A DK 416384A DK 416384 A DK416384 A DK 416384A DK 149952 B DK149952 B DK 149952B
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- Prior art keywords
- methyl
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- compound
- preparation
- aminoal
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- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000001816 cooling Methods 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000011928 denatured alcohol Substances 0.000 claims 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 34
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 14
- 241000700159 Rattus Species 0.000 description 7
- 230000009858 acid secretion Effects 0.000 description 7
- 229960001340 histamine Drugs 0.000 description 7
- 230000010412 perfusion Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 210000001015 abdomen Anatomy 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- -1 aminoalkyl furan derivative Chemical class 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- IDEZECZCLMOIJN-ONEGZZNKSA-N (2e)-2-(nitromethylidene)-1,3-thiazolidine Chemical compound [O-][N+](=O)\C=C1/NCCS1 IDEZECZCLMOIJN-ONEGZZNKSA-N 0.000 description 3
- SPCAMUHZAISWDN-UHFFFAOYSA-N 2-[[1-(methylamino)-2-nitroethyl]amino]ethanethiol Chemical compound SCCNC(C[N+](=O)[O-])NC SPCAMUHZAISWDN-UHFFFAOYSA-N 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
- 230000000694 effects Effects 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 210000001187 pylorus Anatomy 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000003710 Histamine H2 Receptors Human genes 0.000 description 2
- 108090000050 Histamine H2 Receptors Proteins 0.000 description 2
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 2
- 102000000543 Histamine Receptors Human genes 0.000 description 2
- 108010002059 Histamine Receptors Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960001380 cimetidine Drugs 0.000 description 2
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 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
- 239000006210 lotion Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 2
- 229960000582 mepyramine Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- NXGHEDHQXXXTTP-UHFFFAOYSA-N 1,1-bis(methylsulfanyl)-2-nitroethene Chemical compound CSC(SC)=C[N+]([O-])=O NXGHEDHQXXXTTP-UHFFFAOYSA-N 0.000 description 1
- VFIAOIVGTFADLM-UHFFFAOYSA-N 1-(furan-2-yl)-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CO1 VFIAOIVGTFADLM-UHFFFAOYSA-N 0.000 description 1
- PKHXOTCCTRHUFQ-UHFFFAOYSA-N 1-nitropropane-2,2-diamine Chemical compound CC(N)(N)C[N+]([O-])=O PKHXOTCCTRHUFQ-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- FPBPLBWLMYGIQR-UHFFFAOYSA-N Metiamide Chemical compound CNC(=S)NCCSCC=1N=CNC=1C FPBPLBWLMYGIQR-UHFFFAOYSA-N 0.000 description 1
- VMXUWOKSQNHOCA-UHFFFAOYSA-N N1'-[2-[[5-[(dimethylamino)methyl]-2-furanyl]methylthio]ethyl]-N1-methyl-2-nitroethene-1,1-diamine Chemical compound [O-][N+](=O)C=C(NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 229920005439 Perspex® Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000000138 effect on histamine Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000004185 liver Anatomy 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, 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
-
- 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
-
- 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
- C07D307/56—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 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
- C07D307/64—Sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
149952
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af et hidtil ukendt aminoalkylfuranderivat eller salte deraf med syrer, hvilke forbindelser har selektiv virkning på histamin receptorer, hvorfor der med disse forbindelser kan fremstilles farmaceutiske 5 præparater.
En underinddeling af histaminreceptorer (H-receptorer) i to grupper, der betegnes som H^- og receptorer, er blevet foreslået af Ash og Schild (Brit. J. Pharmacol. Chemother., 1966, 27, s. 427) og Black et al. (Nature, 1972, 236, s. 385). Stimulation af den bløde muskula-10 tur i bronchial- og gastrointestinal-området formidles af H.|-receptorer, og virkningen deraf kan forhindres med sædvanlige histaminantagonister såsom mepyramin. Stimulation af mavesyresekretion og hjertefrekvens formidles af receptorer; disse virkninger modificeres ikke af mepyramin, men forhindres eller ophæves af h^-antago-15 nister såsom metiamid. Histamin stimulerer H^- og l·^-receptorer.
Det har vist sig, at det her omhandlede, hidtil ukendte aminoalkylfuranderivat er en selektiv H2_antagonist, hvilket vil sige, at det inhiberer sekretionen af mavesyre, når denne stimuleres via histamin -H2~receptorer (Ash og Schild loc. cit.). Dets evne til at forhin-20 dre sekretion af mavesyre, når denne stimuleres via histamin-Hj-re-ceptorer, kan demonstreres på en perfuseret rottemave under anvendelse af den af Ghosh og Schild (Brit. J. Pharmacol., 1958, 13, s.
54) beskrevne metode, modificeret på den nedenfor beskrevne måde, og på vågne hunde, der er udstyret med Heidenhain-lommer under 25 anvendelse af samme metode som beskrevet af Black et al. (Nature, 1972, 236, s. 385). Den ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede forbindelse modificerer ikke histamin-inducerede kontraktioner i isoleret blød muskulatur fra gastrointestinalområdet.
En forbindelse med histamin-H2_blokerende virkning kan anvendes til 30 behandling af tilstande, hvor der er hypersekretion af mavesyre, fx ved gastrisk og peptisk ulceration, og til behandling af allergiske tilstande, hvor histamin er en kendt mediator. Forbindelsen kan anvendes enten alene eller i kombination med andre aktive stoffer til behandling af allergiske og inflammatoriske tilstande, fx urticaria.
149952 2
Den foreliggende opfindelse bygger på denne erkendelse og angår en analogifremgangsmåde til fremstilling af N-[2-[[[5-(dimethylamino)me-thyl-2-furanyl]methyi]thio] ethyl]-N'-methyl-2-nitro-1,1-ethendiamin med formlen I
CH3 \ f/-^ HCN°2 5 N_CH2 -CH2S (CH2} 2NH<2NHCH3 '
eller fysiologisk tolerable salte deraf, hvilken fremgangsmåde er ejendommelig ved, at en forbindelse med den almene formel IV
CH3\ ri 7 —ch2or' iv ca3 0
hvor betegner hydrogen eller acyl, omsættes med thiolen med form-10 len V
HS(CH,).NHCNHCH.
\\ V
hcno2 hvorefter, til fremstilling af fysiologisk tolerable salte, forbindelsen med formlen I behandles med en fysiologisk tolerabel uorganisk eller organisk syre, eller et vundet salt omdannes til et andet salt deraf 15 med en fysiologisk tolerabel syre.
Forbindelsen med formlen I har den fordel, at den let kan fremstilles ud fra let tilgængelige udgangsmaterialer.
149952 3
Forbindelsen med formlen I kan udvise tautomeri, og formlen skal dække alle de tautomere.
Forbindelsen med formlen I danner let fysiologisk tolerable salte.
Sådanne salte omfatter salte med uorganiske og organiske syrer såsom 5 hydrochlorider, hydrobromider og sulfater. Særlig værdifulde salte af organiske syrer dannes med aliphatiske mono- eller di-carboxylsyrer.
Eksempler på sådanne salte er acetater, maleater og fumarater.
Forbindelsen med formlen I administreres oralt, topisk eller parente-ralt eller som suppositorier, og den foretrukne administrationsvej er 10 den orale. Den kan anvendes i form af basen eller som fysiologisk tolerabelt salt. Forbindelsen blandes sædvanligvis med et farmaceutisk tolerabelt bærestof eller en diluent til dannelse af et farmaceutisk præparat.
Forbindelsen med formlen I kan administreres i kombination med andre 15 aktive bestanddele, om nødvendigt fx sædvanlige antihistaminer. Til oral administration kan det farmaceutiske præparat være i form af kapsler eller tabletter, der kan være tabletter med langsom frigivelse.
Præparatet kan også have form af en dragée eller kan være i sirupform. Egnede topiske præparater omfatter salver, lotioner, cremer, 20 pulvere og spraymidler.
En bekvem daglig dosis til oral administration ligger i området mellem 100 mg og 1,2 g/dag i form af dosisenheder indeholdende mellem 20 og 200 mg pr. dosisenhed. En bekvem kur i tilfælde af anvendelse af tabletter med langsom frigivelse kan være administration to eller tre 25 gange daglig.
Parenteral administration kan udføres ved injektioner med mellemrum eller som kontinuerlig infusion. Injektionsopløsninger kan indeholde 10-100 mg/ml aktivstof.
Til topisk applikation kan anvendes en spray, salve, creme eller 30 lotion. Disse præparater kan indeholde en virksom mængde af den aktive bestanddel, fx i størrelsesordenen 1 1/2 - 2 vægtprocent af det totale præparat.
149952 4
Ved fremgangsmåden fremstilles forbindelsen ud fra et udgangsmateriale med den almene formel IV
“3\ J L 7
N-CH2——CHjOR IV
æ3 ° hvor R^ er hydrogen eller acyl såsom acetyl eller p-nitrobenzoyl.
5 De ovenfor anførte forbindelser IV omsættes med thiolen med formlen V
HS(CH-)-NHCNHCH, 2 2 II 3 v hcno2
Reaktionen udføres fortrinsvis ved 0°C i koncentreret saltsyre.
Forbindelsen med formlen I adskiller sig strukturelt fra de i britisk 10 patentskrift nr. 1.307.539, 1.338.169, 1.397.436 og 1.421.792 beskrevne forbindelser ved at være aminoalkylfuranderivater og ikke forbindelser indeholdende en nitrogenholdig heterocyclisk ring. De kendte forbindelser, som på trods heraf må siges at være forbindelse I nærmestliggende, er beskrevet i britisk patentskrift nr. 1.338.169 15 og 1.421.792 og har den almene formel ch3 . —CH2S(CH2)2NH^ /nhch3 hn. n 9 149952 5
Forbindelsen cimetidin (X = NCN) og det tilsvarende nitrovinylderivat deraf (X = CHNOj) har dog langt større ED^-værdier end forbindelse I, hvilket indicerer svagere virkning.
Ved fremgangsmåden fås forbindelsen med formlen I som nævnt ved 5 omsætning af en forbindelse med formlen IV med thiolen med formlen V. Forbindelsen med formlen V kan fremstilles ud fra et thiazolidin-mellemprodukt med formlen XVI
ΛΛ
S NH
γ xvi :hno2
ved omsætning med methylamin. Thiazolidinen med formlen XVI kan 10 fremstilles ud fra cysteamin og en bis-methylthioforbindelse med formlen XVII
CH-SCSCH, II 3 xvn CHN02
Forbindelsen med formlen I har som nævnt vist sig at inhibere mave-syresekretion, der induceres af histamin. Dette er påvist på rotter 15 under anvendelse af en modifikation af den fremgangsmåde, der er beskrevet af M.N. Ghosh og H.O. Schild i British Journal of Pharmacology, 1958, 13, s. 54.
Hunrotter med en vægt på ca. 150 g suites natten over og gives derefter 8% saccharose i normalt saltvand i stedet for drikkevand.
20 Rotterne anæstetiseres ved en enkelt intraperitoneal injektion af en 25 vægt/volumenprocents urethanopløsning (0,5 ml/100 g), og der lægges kanyler i trachea og halsvenerne.
149952 6
Der lægges et midtlinjesnit i abdomenvæggen for at blotlægge maven, som skilles fra leveren og milten ved overskæring af bindevævet. En lille åbning laves i fundusregionen i maven, og maven vaskes med en 5%'s dextroseopløsning. Oesophagus drænes med en gummislange, og 5 oesophagus og vagi overskæres derefter over kanylen.
Der laves derefter en lille åbning i pylorusregionen. Der anbringes en stor perspex-kanyle via åbningen i fundusregionen på en sådan måde, at indgangsenden af kanylen går ud af maven gennem åbningen i pylorusområdet. Kanylen er af en sådan form, at den reducerer det 10 effektive rumfang i maven, og at der fremkaldes en turbulent strøm i perfusionsvæsken hen over slimhindeoverfladen. Der indlægges derefter en drænkanyle gennem åbningen i fundusregionen i maven. Begge kanyler holdes på plads af ligaturer rundt om maven anbragt således, at hovedblodårerne undgås. Der stikkes huller i væggen, og kanyler-15 ne stikkes igennem. Maven perfuseres gennem oesophagus- og pylo-rus-kanylerne med 5%’s dextroseopløsning ved 39°C med en hastighed på 1,5 ml/minut i hver kanyle. Effluenten ledes igennem en microflow pH-elektrode og måles via et pH-meter og en "flat-bed"-recorder.
Den basale mængde syresekretion fra maven bestemmes ved måling af 20 pH-værdien i perfusionseffluenten, og derefter induceres forøget syresekretion ved fortsat intravenøs infusion af en submaksimal histamindosis; dette fremkalder et stabilt højt niveau af syresekretion, og pH-værdien i perfusionseffluenten bestemmes, når denne tilstand er nået.
25 Forsøgsforbindelsen administreres derefter til rotten ved intravenøs injektion, og ændringen i "mavesyre"-sekretion bestemmes ved måling af ændringen i pH-værdien i perfusionseffluenten.
Ud fra ændringen i pH-værdien i perfusionseffluenten beregnes forskellen i syresekretion imellem den basale mængde og det histaminsti-30 mulerede niveau som hydrogen ion koncentration i mol/L. Reduktionen af syresekretion fremkaldt ved administration af forsøgsforbindelsen beregnes også som ændringen i hydrogenionkoncentration i mol/L ud fra forskellen i pH-værdien i perfusionseffluenten. Den procentvise 149952 7 reduktion af syresekretion, der fremkaldes ved administration af forsøgsforbindelsen, kan derefter beregnes ud fra de to vundne værdier.
EDsQ-Værdier for inhibering af syresekretion bestemmes ved at admi-5 nistrere én dosis af forsøgsforbindelsen til én rotte og gentage dette på mindst 4 rotter for hvert af tre eller flere dosisniveauer. De vundne resultater anvendes derefter til at beregne ED^-værdien ved de mindste kvadraters metode, som anvendes for hver dosis-responslinje.
10 Under anvendelse af den ovenfor beskrevne teknik er der opnået en EDjjQ-værdi på 0,18 mg/kg.
Under de samme forsøgsbetingelser er der for den i britisk patentskrift nr. 1.338.169 nævnte forbindelse cimetidin opnået en ED^g-værdi på 1,12 mg/kg, og for det tilsvarende nitrovinylderivat, som 15 falder inden for omfanget af britisk patentskrift nr. 1.421.792, er der opnået en ED^g-værdi på 1,75 mg/kg. Da en lav ED^g-værdi angiver et mere aktivt produkt, er den ifølge opfindelsen fremstillede forbindelse virkningsmæssigt de tidligere beskrevne forbindelser overlegen.
Fremgangsmåden ifølge opfindelsen belyses nærmere i nedenstående 20 eksempel 2 og 3, og fremstillingen af mellemprodukter belyses i eksempel 1.
EKSEMPEL 1 2-Nitromethylen-thiazolidin
En blanding af 11,36 g cysteamin-hydrochlorid, 5,61 g kaliumhydroxid 25 og 16,52 g 1,1-bis(methylthio)-2-nitroethen i 30 ml vand og 100 ml ethanol opvarmes til kogning under tilbagesvaling i 1 time. Suspensionen inddampes til tørhed, remanensen suspenderes i vand og filtreres, og remanensen krystalliseres af methanol, hvorved der fås 9,2 g 2-nitromethylen-thiazolidin, smeltepunkt 141-142°C.
149952 8
Analyse:
Beregnet for C4HgN202S: C 32,87 H 4,14 N 19,17
Fundet: C 32,91 H 4,13 N 19,10.
N-(2-Mercaptoethyl)-N'-methyl-2-nitro-1,1-ethendiamin 5 En opløsning af 5 g 2-nitromethylen-thiazolidin i en opløsning af 33% methylamin i 40 ml ethanol holdes ved stuetemperatur i 65 timer. Det udskilte faste stof frafiltreres, vaskes med ethanol og tørres, hvorved der fås 4,98 g N-(2-mercaptoethyl)-N’-methyl-2-nitro-1,1-ethendiamin, smeltepunkt 174-175°C, sønderdeling ved 209-211°C.
10 Analyse:
Beregnet for 05Η1ΊΝ3025: C 33,88 H 6,26 N 23,71
Fundet: C 34,05 H 5,87 N 23,85.
EKSEMPEL 2 N-[2-[[[5-(DimethyIamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-15. methy!-2-nitro-l,1-ethendiamin 125 mg N,N-dimethyl-2-furanmethanamin opløses i 1 ml iseddike, og der tilsættes 30 mg paraformaldehyd. En opløsning af 354 mg N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethendiamin i 1 ml koncentreret saltsyre og 1 ml iseddike tilsættes dråbevis, og blandingen lades 20 henstå ved stuetemperatur i 5 dage. Opløsningen fortyndes med 30 ml vand, mættes med kaliumcarbonat og ekstraheres med ethylacetat. De samlede ekstrakter renses ved præparativ tyndtlagschromatografi, hvorved der fås 89 mg af den i overskriften nævnte forbindelse. Tyndtlagschromatografi på siliciumdioxid med ethylacetat:ethanol:0,88% 25 ammoniakvand (10:1:1) giver en R^-værdi på 0,64.
Claims (2)
149952 EKSEMPEL 3 N-[2-[[[5-(Dimethylamino)methyl-2-fu ranylj methyl] thio] ethyl]-N'-me-thyl-2-nitro-l,1-ethendiamin-hydrochlorid 50 g (0,16 mol) N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]-5 thio]ethyl]-N'-methyl-2-nitro-l,1-ethendiamin opløses i 200 ml industrielt, denatureret sprit, 74° (indeholdende mere alkohol end normalt), indeholdende 0,16 ækvivalent hydrogenchlorid. 200 ml ethylace-tat sættes langsomt til opløsningen. Hydrochloridet krystalliserer og frafiltreres, vaskes med en blandning af 50 ml af det ovenfor be-' 10 skrevne denaturerede sprit og 50 ml ethylacetat og tørres ved 50°C. Der fås 50 g produkt i form af et off-white fast stof, smeltepunkt 133-134°C.
1. Analogifremgangsmåde til fremstilling af et aminoalkylfuranderivat 15 med formlen I °H3\ _jT\ T2 ^>N“CH2 \0/ -CH2s (CH2) 2nhcnhch3 1 eller fysiologisk tolerable salte deraf med syrer, kendetegnet ved, at en forbindelse med den almene formel IV “3\ J L 7 20 /N-ch2-< >—CH2OR |v ch3 w
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3246576 | 1976-08-04 | ||
| GB32465/76A GB1565966A (en) | 1976-08-04 | 1976-08-04 | Aminoalkyl furan derivatives |
| GB5068576 | 1976-12-06 | ||
| GB5068576 | 1976-12-06 | ||
| GB2018777 | 1977-05-13 | ||
| GB2018777 | 1977-05-13 | ||
| KR770001808 | 1977-08-04 | ||
| KR7701808A KR810000355B1 (ko) | 1977-05-13 | 1977-08-04 | 아미노 알킬푸란 유도체의 제조방법 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK416384A DK416384A (da) | 1984-08-30 |
| DK416384D0 DK416384D0 (da) | 1984-08-30 |
| DK149952B true DK149952B (da) | 1986-11-03 |
| DK149952C DK149952C (da) | 1987-07-06 |
Family
ID=27448487
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK337977A DK148258C (da) | 1976-08-04 | 1977-07-26 | Analogifremgangsmaade til fremstilling af et aminoalkylfuranderivat |
| DK416384A DK149952C (da) | 1976-08-04 | 1984-08-30 | Analogifremgangsmaade til fremstilling af et aminoalkylfuranderivat |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK337977A DK148258C (da) | 1976-08-04 | 1977-07-26 | Analogifremgangsmaade til fremstilling af et aminoalkylfuranderivat |
Country Status (16)
| Country | Link |
|---|---|
| AT (1) | AT375931B (da) |
| CH (2) | CH642072A5 (da) |
| CY (1) | CY1077A (da) |
| DE (2) | DE2759959C2 (da) |
| DK (2) | DK148258C (da) |
| ES (2) | ES461334A1 (da) |
| FI (1) | FI72318C (da) |
| HK (1) | HK55780A (da) |
| IE (1) | IE45456B1 (da) |
| IT (2) | IT1126759B (da) |
| KE (1) | KE3080A (da) |
| NZ (2) | NZ184759A (da) |
| PH (1) | PH13540A (da) |
| PT (1) | PT66874B (da) |
| SE (3) | SE437373B (da) |
| YU (2) | YU40006B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4203909A (en) * | 1978-09-26 | 1980-05-20 | Bristol-Myers Company | Furan compounds |
| YU52598A (sh) * | 1998-11-19 | 2001-05-28 | D.D. Zdravlje- sektor za istraživanje i razvoj | POSTUPAK ZA sintezu N-[2[[[5=[(DIALKILAMINO)METIL]-2= FURANIL]METIL]TIO]ETIL]-N'-ALKIL-2-NITRO 1,1 ALKENDIAMINA I NJIHOVIH HIDROHLORIDA |
-
1977
- 1977-07-22 FI FI772264A patent/FI72318C/fi not_active IP Right Cessation
- 1977-07-22 CY CY1277A patent/CY1077A/xx unknown
- 1977-07-25 SE SE7708521A patent/SE437373B/xx not_active IP Right Cessation
- 1977-07-25 IE IE1536/77A patent/IE45456B1/en not_active IP Right Cessation
- 1977-07-26 DK DK337977A patent/DK148258C/da not_active IP Right Cessation
- 1977-07-27 NZ NZ184759A patent/NZ184759A/en unknown
- 1977-07-27 NZ NZ191383A patent/NZ191383A/xx unknown
- 1977-07-28 DE DE2759959A patent/DE2759959C2/de not_active Expired
- 1977-07-28 DE DE2760097A patent/DE2760097C2/de not_active Expired
- 1977-07-29 CH CH938077A patent/CH642072A5/de not_active IP Right Cessation
- 1977-08-01 PT PT66874A patent/PT66874B/pt unknown
- 1977-08-02 PH PH20057A patent/PH13540A/en unknown
- 1977-08-03 IT IT50551/77A patent/IT1126759B/it active Protection Beyond IP Right Term
- 1977-08-03 YU YU1911/77A patent/YU40006B/xx unknown
- 1977-08-03 ES ES461334A patent/ES461334A1/es not_active Expired
- 1977-08-04 AT AT0574077A patent/AT375931B/de not_active IP Right Cessation
-
1978
- 1978-06-15 ES ES470836A patent/ES470836A1/es not_active Expired
-
1980
- 1980-08-30 KE KE3080A patent/KE3080A/xx unknown
- 1980-10-02 HK HK557/80A patent/HK55780A/xx unknown
-
1982
- 1982-08-27 CH CH509282A patent/CH641176A5/de not_active IP Right Cessation
- 1982-09-03 YU YU2000/82A patent/YU40088B/xx unknown
- 1982-09-28 SE SE8205533A patent/SE454882B/sv not_active IP Right Cessation
- 1982-11-17 SE SE8206556A patent/SE454883B/sv not_active IP Right Cessation
-
1984
- 1984-08-30 DK DK416384A patent/DK149952C/da not_active IP Right Cessation
-
1985
- 1985-08-01 IT IT48437/85A patent/IT1221058B/it active
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