DK144064B - Analogifremgangsmaade til fremstilling af n-(3!-p-hydroxy-fenyltiopropyl)-3,3-difenylpropylamin eller salte deraf - Google Patents
Analogifremgangsmaade til fremstilling af n-(3!-p-hydroxy-fenyltiopropyl)-3,3-difenylpropylamin eller salte deraf Download PDFInfo
- Publication number
- DK144064B DK144064B DK269278AA DK269278A DK144064B DK 144064 B DK144064 B DK 144064B DK 269278A A DK269278A A DK 269278AA DK 269278 A DK269278 A DK 269278A DK 144064 B DK144064 B DK 144064B
- Authority
- DK
- Denmark
- Prior art keywords
- salts
- diphenylpropylamine
- hydroxy
- preparation
- compound
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000003839 salts Chemical class 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- KHLFAZWSFALWCN-UHFFFAOYSA-N 4-[3-(3,3-diphenylpropylamino)propylsulfanyl]phenol Chemical compound C1=CC(O)=CC=C1SCCCNCCC(C=1C=CC=CC=1)C1=CC=CC=C1 KHLFAZWSFALWCN-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000000203 mixture Substances 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- -1 alkali metal salt Chemical class 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 208000025865 Ulcer Diseases 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000026 anti-ulcerogenic effect Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000036269 ulceration Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ABQYEFLQXKNEFL-UHFFFAOYSA-N 4-[3-(3,3-diphenylpropylamino)propylsulfanyl]phenol;hydrochloride Chemical compound Cl.C1=CC(O)=CC=C1SCCCNCCC(C=1C=CC=CC=1)C1=CC=CC=C1 ABQYEFLQXKNEFL-UHFFFAOYSA-N 0.000 description 2
- BXAVKNRWVKUTLY-UHFFFAOYSA-N 4-sulfanylphenol Chemical compound OC1=CC=C(S)C=C1 BXAVKNRWVKUTLY-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
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000001663 anti-spastic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229960002895 phenylbutazone Drugs 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- SLHSRCBFPHCSGL-UHFFFAOYSA-N (3-bromo-1-phenylpropyl)benzene Chemical compound C=1C=CC=CC=1C(CCBr)C1=CC=CC=C1 SLHSRCBFPHCSGL-UHFFFAOYSA-N 0.000 description 1
- NUWWGCMQIKROIJ-UHFFFAOYSA-N 3,3-diphenyl-n-(3-phenylsulfanylpropyl)propan-1-amine Chemical compound C=1C=CC=CC=1SCCCNCCC(C=1C=CC=CC=1)C1=CC=CC=C1 NUWWGCMQIKROIJ-UHFFFAOYSA-N 0.000 description 1
- SFYVRUBKBDKDBR-UHFFFAOYSA-N 3,3-diphenylpropyl(3-phenylsulfanylpropyl)azanium;chloride Chemical compound Cl.C=1C=CC=CC=1SCCCNCCC(C=1C=CC=CC=1)C1=CC=CC=C1 SFYVRUBKBDKDBR-UHFFFAOYSA-N 0.000 description 1
- IHPRVZKJZGXTBQ-UHFFFAOYSA-N 3-chloropropan-1-amine;hydron;chloride Chemical compound Cl.NCCCCl IHPRVZKJZGXTBQ-UHFFFAOYSA-N 0.000 description 1
- YRJNRIPTEYAKDD-UHFFFAOYSA-N 4-(3-aminopropylsulfanyl)phenol Chemical compound NCCCSC1=CC=C(O)C=C1 YRJNRIPTEYAKDD-UHFFFAOYSA-N 0.000 description 1
- AQNOLWMUYSZMJS-UHFFFAOYSA-N 4-(3-aminopropylsulfanyl)phenol;hydrochloride Chemical compound Cl.NCCCSC1=CC=C(O)C=C1 AQNOLWMUYSZMJS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 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
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 241001481796 Rattus exulans Species 0.000 description 1
- IDSGSDWHRMTENJ-UHFFFAOYSA-N SC1=CC=C(C=C1)O.[Na] Chemical compound SC1=CC=C(C=C1)O.[Na] IDSGSDWHRMTENJ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 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
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940117955 isoamyl acetate Drugs 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- CTYRPMDGLDAWRQ-UHFFFAOYSA-N phenyl hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=CC=C1 CTYRPMDGLDAWRQ-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940076788 pyruvate Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(19) DANMARK \Ra> /^ir
|j| (12) FREMLÆGGELSESSKRIFT (n) 144064 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENET
(21) Ansøgning nr. 2692/78 (51) IntCI» C 07 C 1A9/A2 (22) indleveringsdag 15· jun. 1978 (24) Løbedag 15· jun. 1978 (41) Aim. tilgængelig 18. dec. 1978 (44) Fremlagt 50. nov. 1981 (86) International ansøgning nr. ~ (86) International indleveringsdag -(85) Videreførelsesdag “ (62) Stamansøgning nr. “
(30) Prioritet 17· jun. 1977, IT
(71) Ansøger ALFA FARMACEUTICI S.P.A., 40153 Bologna, IT.
(72) Opfinder Valerio Borzatta, IT.
(74) Fuldmægtig Kontor for Industriel Eneret v. Svend Sehønning.
(54) Analogifremgangsmåde til fremstil·* ling af N-(5‘ -p-hydroxy-fenyltio= propyl)-5,3-difenylpropylamin el= ler salte deraf.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af en hidtil ukendt forbindelse, N-tø (3'-p-hydroxy-fenyltiopropyl)-3,3-difenyl-propylamin, med
formlen CD
3 ΓΛ \. /\ ---
CH-(CH,J--N-(CH.,),-S-<^ -OH
s ry/ i \—/ 2 144064 eller salte deraf med organiske eller uorganiske, farmaceutisk acceptable syrer. Den omhandlede forbindelse og salte deraf har antiulcerogen, antispastisk og spasmolytisk virkning.
Fra OS-PS 3.884.938 er det kendt at N-(3'fenyltiopro-pyl)-3,3-difenylpropylamin og farmaceutisk acceptable salte deraf har en god antiulcerogen virkning.
Den omhandlede forbindelse eller dens salte kan ifølge opfindelsen vindes ved at man a) omsætter en primær amin med formlen eller det tilsvarende hydroklorid med et halogenderivat med den almene formel
^ CH- (CH2} 2~X
hvor X er et halogenatom, eller b) omsætter et halogenderivat med den almene formel
Ck
.CH-(CH2)2-NH-(CH2)3-Y
cx 3 1U064 hvor Y er et halogenatom, med 4-merkaptofenol med formlen
HS- -OH
eller med et alkalimetalsalt deraf, hvorefter man om ønsket omdanner den vundne forbindelse til et syréadditionssalt deraf eller frigør den frie base fra et vundet syreadditionssalt.
Med udtrykket "salte af farmaceutisk acceptably syrer" menes her salte af det omhandlede produkt med en ikke-toxisk anion.
Eksempler på sådanne salte er hydroklortdet, brpmidpt, sulfatet, fosfatet, nitratet, acetatet, propionatet, succinatet, adipatet, glykolatet, laktatet, malatet, askorbatet, pyruvatet, tartratet, raaleatet, citratet, bikarbonatet, palmoatet, fenylace-tatet, benzoatet, salicylatet, alkylsulfatet, ajrylsulfatet, glukuronatet, samt salte med metionin, tryptgfan, lysin og arginin.
Det foretrukne salt er hydrokloridet»
De ifølge opfindelsen fremstillede produkter har vist en god farmakologisk virkning hvilket gør dem velegnede til at blive anvendt som antiulcerogene, antispastiske og/eller gpasmolytiske lægemidler.
N-(3'-p-Hydroxyfenyltiopropyl)-3,3-difenylprppylamin, navnlig som hydrokloridet, har en kraftig antiulcerpgen virkning kombineret med en lav toxicitet. Dette produkt har mod ulcere fremkaldt hos rotter med fenylbutazon vist inhiberingsværdier på henholdsvis 50% og 80% i doser på 10 og 50 mg/kg givet i.p., mens det har vist sig at LD^g-værdien er >1000 og 150 mg/kg henholsvis p.o. og i.p.
Opfindelsen belyses nærmere i det følgende ved hjælp af nogle eksempler. Tyndtlagskromatografi (TLC) er gennemført på silika- (r) gelplader Merck GF254'som elueringgmiddel er der anvendt en blanding af isoamylacetat/metanol/vand/myresyre i rumfangsforholdet 60:20:6:5.
144064 4
Eksempel 1 N-(3-p-Hydroxyfenyltiopropyl)-3,3-difenylpropylamin-hydroklorid Til 3,8 g (0,012 mol) 3,3-difeny1-3'-hydroxydipropylamin-hydroklorid (vundet ved behandling af den frie base i ætanol med hydrogenkloridgas efterfulgt af krystallisation af den vundne olie først fra ætylacetat og derpå fra n-butanol) i 40 ml vandfri benzen sættes 0,37 ml (0,004 mol) PBr^. Efter 1 time ved stuetemperatur koges blandingen under tilbagesvaling i 1 time, afkøles og udhældes i en kold opløsning af 10% natriumbikarbonat.
Benzenlaget vaskes to gange med vand, tørres og inddampes.
Den rå 3,3-difenyl-3,-bromdipropylamin vindes som en olie (3,2 g,
Rf = 0,9) og kan anvendes direkte i den efterfølgende reaktion.
Til 2,49 g (0,019 mol) 4-merkaptofenol opløst i 20 ml metanol sættes under omrøring ved 40°C en opløsning af 0,22 g (0,0096 mol) natrium i 8 ml metanol. Blandingen koges under tilbagesvaling, der tilsættes en opløsning af 6,4 g (0,019 mol) 3,3-difeny1-3'-bromdipropylamin i 10 ml metanol og koges atter under tilbagesvaling i 24 timer. Efter afkøling afdampes opløsningsmidlet under vakuum. Remanensen opløses i kloroform og vaskes to gange med 6N saltsyre. Kloroformen afdampes under vakuum og remanensen krystalliseres først fra ætylacetat og derpå fra en blanding af n-butanol og ætylæter. Der vindes 3,64 g N-(3-p-hydroxyfenyltiopropyl)-3,3 difenylpropylamin-hydroklorid, smp. 146-148°C, Rf = 0,35.
Eksempel 2 N-(31-p-Hydroxyfenyltiopropyl)-3,3-difenylpropylamin-hydroklorid Til 6,3 g (0,05 mol) 4-merkaptofenyl i 20 ml metanol sættes under omrøring ved 40°C en opløsning af 1,15 g (0,05 mol) natrium i 20 ml metanol. Opløsningen omrøres i 90 minutter ved 40-50°C. Til 6,45 g (0,05 mol) 3-klorpropylamin-hydroklorid i 20 ml metanol sættes i kulden og under omrøring en opløsning af 1,15 g (0,05 mol) natrium i 20 ml metanol.
Efter fraomrøring af det dannede natriumklorid tilsættes gradvist den tidligere fremstillede opløsning af 4-merkaptofenols natriumsalt. Efter 150 minutter ved 60°C filtreres det faste stof fra, opløsningen inddampes og remanensen opløses i en blanding af metylenklorid og vand i rumfangsforholdet 1:1.
5 144064
Det faste stof som består af rå 3-p-hydroxyfenyltiopropyl-amin filtreres, opløses i ætanol mættet med hydrogenklorid og der tilsættes ætylacetat for at udfælde hydrokloridet. Der vindes 4,6 g produkt med smp. 174-175°C.
Til en opløsning af 4,38 g (0,02 mol) 3-p-hydroxyfenyltio-propylamin-hydroklorid i 30 ml vandfri ætanol sættes en opløsning af 0,46 g (0,02 mol) natrium i 10 ml vandfri ætanol. Efter omrøring i kulden i 30 minutter bringes blandingen til tilbagesvaling.
Der tilsættes gradvist 2,75 g (0,01 mol) 3,3-difenylpropyl-bromid i 20 ml vandfri ætanol og blandingen koges under tilbagesvaling i 24 timer. Efter afkøling afdampes opløsningsmidlet under vakuum. Remanensen opløses i kloroform og opløsningen vaskes to gange med 10% natriumhydroxyd og 2 gange med 6N saltsyre.
Det organiske lag skilles fra, opløsningsmidlet afdampes og remanensen opløses i ætylacetat og omkrystalliseres fra en blanding af n-butanol og ætylæter. Der vindes 2,0 g af det i overskriften angivne hydroklorid med smp. 146-149°C.
6 144064
Biologisk forsøgsrapport
Der er foretaget en biologisk sammenligning mellem den ifølge opfindelsen fremstillede forbindelse N-(3’-p-hydroxy-fenyltiopropy1)-3,3-difeny1-propylamin-hydroklorid, betegnet A, og den fra OS patentskrift nr. 3.884.939 kendte forbindelse N-(3'-fenyltiopropyl)-3,3-difenyl-propylamin-hydroklorid, betegnet B.
Disse forbindelser undersøgtes hos rotter, hvori der var fremkaldt gastriske ulcerationer, dvs. mavesår, ved indgift af en passende mængde af et kendt antiflogistisk lægemiddel, nemlig fenylbutazon, som også er kendt for at besidde ulcerogene egenskaber, jfr. Burger, Medicinal Chemistry, 3. udgave, side 959-960, Wiley Interscience, 1979.
Resultaterne fremgår af følgende tabel.
Tabel
Forbindelse Dosis mg/kg % Inhibering af LD5Q mg/kg rotte i.p. rotte gastriske ulcerationer p.o. i.p.
A 10 50 >2000 150 50 80 B 10 40 >1000 39,5 50 50
Det fremgår af de vundne resultater at den ifølge opfindelsen fremstillede forbindelse, forbindelse A, har en større aktivitet med hensyn til at inhibere gastriske ulcerationer sammenlignet med den kendte forbindelse, forbindelse B. Desuden er forbindelse A mindre toxisk end forbindelse B.
Claims (2)
144064 7 Analogifremgangsmåde til fremstilling af N-(3'-p-hydroxy-fenyltiopropyl)-3,3-difenyl-propylamin med formlen ^CH-(CH9)0-N-(CH0)--S-<^ \-0H ry/ ί V-/ eller salte deraf med organiske eller uorganiske, farmaceutisk acceptable syrer, kendetegnet ved at man a) omsætter en primær amin med formlen eller det tilsvarende hydroklorid med et halogenderivat med den almene formel GK CH-(CH2)2-X GK hvor X er et halogenatom, eller b) omsætter et halogenderivat med den almene formel GK x /Cn~ (CH2)
2-NH~ (CH2) 3~y GK
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT347477 | 1977-06-17 | ||
| IT03474/77A IT1080455B (it) | 1977-06-17 | 1977-06-17 | N 3 feniltiopropil 3.3 difenil propilammine sostituite dotate di attivita farmacologia |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK269278A DK269278A (da) | 1978-12-18 |
| DK144064B true DK144064B (da) | 1981-11-30 |
| DK144064C DK144064C (da) | 1982-06-21 |
Family
ID=11108046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK269278A DK144064C (da) | 1977-06-17 | 1978-06-15 | Analogifremgangsmaade til fremstilling af n-(3'-p-hydroxy-fenyltiopropyl)-3,3-difenylpropylamin eller salte deraf |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5430142A (da) |
| AT (1) | AT357141B (da) |
| BE (1) | BE867570A (da) |
| DE (1) | DE2825447A1 (da) |
| DK (1) | DK144064C (da) |
| ES (1) | ES470845A1 (da) |
| FR (1) | FR2394527A1 (da) |
| GB (1) | GB1561679A (da) |
| GR (1) | GR73140B (da) |
| IT (1) | IT1080455B (da) |
| NL (1) | NL7805617A (da) |
| NO (1) | NO145097C (da) |
| PT (1) | PT68122A (da) |
| SE (1) | SE7806945L (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2015197C (en) * | 1990-04-23 | 1999-08-24 | Kowichi Jimbow | Phenolic amine depigmenting and antimelanoma agents |
| US5395611A (en) * | 1990-04-24 | 1995-03-07 | The Governors Of The University Of Alberta | Phenolic amine depigmenting and antimelanoma agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO134800C (da) * | 1971-07-15 | 1976-12-15 | Alfa Farmaceutici Spa |
-
1977
- 1977-06-17 IT IT03474/77A patent/IT1080455B/it active
-
1978
- 1978-05-24 NL NL7805617A patent/NL7805617A/xx not_active Application Discontinuation
- 1978-05-25 GB GB22681/78A patent/GB1561679A/en not_active Expired
- 1978-05-29 BE BE2057020A patent/BE867570A/xx unknown
- 1978-05-31 PT PT68122A patent/PT68122A/pt unknown
- 1978-06-09 DE DE19782825447 patent/DE2825447A1/de not_active Withdrawn
- 1978-06-13 AT AT430078A patent/AT357141B/de not_active IP Right Cessation
- 1978-06-13 FR FR7817593A patent/FR2394527A1/fr active Granted
- 1978-06-15 DK DK269278A patent/DK144064C/da active
- 1978-06-16 SE SE7806945A patent/SE7806945L/xx unknown
- 1978-06-16 NO NO782101A patent/NO145097C/no unknown
- 1978-06-16 GR GR56534A patent/GR73140B/el unknown
- 1978-06-16 JP JP7310378A patent/JPS5430142A/ja active Pending
- 1978-06-16 ES ES470845A patent/ES470845A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AT357141B (de) | 1980-06-25 |
| BE867570A (fr) | 1978-09-18 |
| JPS5430142A (en) | 1979-03-06 |
| FR2394527B1 (da) | 1980-06-20 |
| GB1561679A (en) | 1980-02-27 |
| NL7805617A (nl) | 1978-12-19 |
| NO782101L (no) | 1978-12-19 |
| ES470845A1 (es) | 1979-09-01 |
| DE2825447A1 (de) | 1979-01-04 |
| GR73140B (da) | 1984-02-08 |
| DK269278A (da) | 1978-12-18 |
| ATA430078A (de) | 1979-11-15 |
| NO145097C (no) | 1982-01-13 |
| IT1080455B (it) | 1985-05-16 |
| PT68122A (en) | 1978-06-01 |
| NO145097B (no) | 1981-10-05 |
| FR2394527A1 (fr) | 1979-01-12 |
| DK144064C (da) | 1982-06-21 |
| SE7806945L (sv) | 1978-12-18 |
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