US3410944A - Pharmaceutical composition containing 1-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propanol and salts thereof - Google Patents
Pharmaceutical composition containing 1-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propanol and salts thereof Download PDFInfo
- Publication number
- US3410944A US3410944A US435344A US43534465A US3410944A US 3410944 A US3410944 A US 3410944A US 435344 A US435344 A US 435344A US 43534465 A US43534465 A US 43534465A US 3410944 A US3410944 A US 3410944A
- Authority
- US
- United States
- Prior art keywords
- hydroxyphenyl
- ethylamino
- formula
- propanol
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000003839 salts Chemical class 0.000 title description 17
- IOVGROKTTNBUGK-UHFFFAOYSA-N 4-[2-[[1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]phenol Chemical compound C=1C=C(O)C=CC=1C(O)C(C)NCCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-UHFFFAOYSA-N 0.000 title description 4
- 239000008194 pharmaceutical composition Substances 0.000 title description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 150000001875 compounds Chemical class 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 230000003000 nontoxic effect Effects 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- -1 benzyloxy- Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 4
- 230000001077 hypotensive effect Effects 0.000 description 4
- 229910052727 yttrium Inorganic materials 0.000 description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- LSQLSCUJBXFBRB-UHFFFAOYSA-N 2-bromo-1-(4-phenylmethoxyphenyl)propan-1-one Chemical compound C1=CC(C(=O)C(Br)C)=CC=C1OCC1=CC=CC=C1 LSQLSCUJBXFBRB-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- LTPVSOCPYWDIFU-UHFFFAOYSA-N 4-methoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1 LTPVSOCPYWDIFU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000000468 ketone group Chemical group 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
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 238000005932 reductive alkylation reaction Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JLTCWSBVQSZVLT-CDIPANDDSA-N (2s)-n-[(2s)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]-1-[(4r,7s,10s,13s,16s,19r)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-benzyl-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosan Chemical compound NCCCC[C@@H](C(=O)NCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](N)CSSC1.C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 JLTCWSBVQSZVLT-CDIPANDDSA-N 0.000 description 1
- WNCXDNZVUJLFPD-UHFFFAOYSA-N 1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propan-1-one Chemical compound C=1C=C(O)C=CC=1C(=O)C(C)NCCC1=CC=C(O)C=C1 WNCXDNZVUJLFPD-UHFFFAOYSA-N 0.000 description 1
- MKKMZZXGIORPMU-UHFFFAOYSA-N 2-(4-phenylmethoxyphenyl)ethanamine Chemical compound C1=CC(CCN)=CC=C1OCC1=CC=CC=C1 MKKMZZXGIORPMU-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 206010000242 Abortion threatened Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229910000761 Aluminium amalgam Inorganic materials 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
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 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
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- CLJHABUMMDMAFA-UHFFFAOYSA-N Nylidrin hydrochloride Chemical compound [Cl-].C=1C=C(O)C=CC=1C(O)C(C)[NH2+]C(C)CCC1=CC=CC=C1 CLJHABUMMDMAFA-UHFFFAOYSA-N 0.000 description 1
- 102000005320 Posterior Pituitary Hormones Human genes 0.000 description 1
- 108010070873 Posterior Pituitary Hormones Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000005985 Threatened Abortion Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000001813 broncholytic effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 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
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- XOVSRHHCHKUFKM-UHFFFAOYSA-N s-methylthiohydroxylamine Chemical compound CSN XOVSRHHCHKUFKM-UHFFFAOYSA-N 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003506 spasmogen Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/10—Mercury compounds
Definitions
- the invention relates to a new compound of the FormulaI and salts thereof.
- the compound and its salts are to be considered in particular to be used, after being brought in a therapeutic form of administration known per se, in the treatment of pregnant women with threatened abortion and in the treatment of dysmenorrhea.
- the uterospasmolytic activity was found inter alia in experiments in which the influence on the spasms, pro prised in the uteri of rats by the administration of pituitrin as a spasmogen, of the compound according to the invention was compared with that of that compound of Formula II in which R is an isobutyl group, which compound is the active constituent of a therapeutic which is known under the name of Dilatol. In this case it appeared that for reaching the same spasmolytic effect as with the known compound, only half of the quantity of the new compound is necessary.
- hypotensive action between the two compounds was found in experiments in which cats were used as experimental animals. It was found that the known compound has a hypotensive effect which is approximately twice as large as the compound according to the invention.
- a particularly suitable method is that in which a ketone of the Formula III or a salt thereof, in which formula Y and Y are possibly etherified or esterified hydroxy groups, is converted into the alcohol of the Formula I by reduction if required followed by hydrolysis or hydroge'nolysis of esterified or etherified hydroxy groups Y and/ or Y'.
- the aminoketones of the Formula IH can be prepared, for example, by reaction of an amine of the Formula IV with a halogenide of the Formula V
- etherified hydroxy groups Y and/or Y are to be considered preferably ar-alkoxy groups, for example, benzyloxy-, diphenyl-, methoxyor triphenylmethoxy groups.
- esterified hydroxy groups Y and/or Y" are to be considered, for example, hydroxy groups esterified with lower fatty acids, for example, acetic acid, or with toluenesulphonic acid.
- the reduction of the keto group to the carbinol group may be carried out in any manner known for this type of reduction, for example, by catalytic hydrogenation by means of Ni, Pt or 'Pd as a catalyst, or by reduction with aluminum amalgam. Very good results are obtained also when this reduction is carried out by means of a complex metal hydride, for example, with LiAlH, or with NaBH.
- the compounds according to the invention may be prepared by reaction of a. compound of the Formula VI with a compound of the Formula VII where Y and Y have the above indicated meanings and Z and X are groups which, during the coupling reaction,
- the reduction of the intermediately formed acid amide to the secondary amide is preferably carried out by means of a complex metal hydride or metal alkyl hydride, for example, LiAlH or diisobutylaluminiumhydride.
- a complex metal hydride or metal alkyl hydride for example, LiAlH or diisobutylaluminiumhydride.
- racemates are obtained, these may be separated by commonly used methods, by fractional crystallisation. Also by methods known per se the separate optical antipodes may be prepared, either by resolution of the racemates, or by choice of optically active starting substances during the synthesis.
- Both the free base and salts of the compound according to the invention can be used for the preparation of new pharmaceutical compositions.
- salts are to be considered, for example, acid addition salts of the base of the Formula I with hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, sul-famic acid, tartaric acid, citric acid and acetic acid.
- the pharmacologically active substances may be processed in any known manner to pharmaceutical compositions by mixing with or dissolving in solid or liquid carrier materials commonly used in pharmacy, for example, starch, talcum powder, lactose, gelatin, sodium carboxy methyl cellulose, magnesium stearate and/or mixtures thereof as solid carrier materials and, for example, water rendered isotonic with blood by means of salt, or water mixed with, for example, glycerin as liquid carrier.
- solid or liquid carrier materials commonly used in pharmacy, for example, starch, talcum powder, lactose, gelatin, sodium carboxy methyl cellulose, magnesium stearate and/or mixtures thereof as solid carrier materials and, for example, water rendered isotonic with blood by means of salt, or water mixed with, for example, glycerin as liquid carrier.
- new pharmaceutical compositions such as injection liquids, powders and solid pharmaceutical dosage unit forms, such as tablets, coated tablets and suppositories, are obtained which are characterized by a content of the new compound of the
- the resulting residue which consisted of the hydrochloride of 4-hydroxy-2- ⁇ 2-(4-methoxyphenyl)ethylamino ⁇ propiophenone, was mixed with 30 ml. of a 48% hydrobromic acid solution and the mixture was boiled until no methylbromide developed any more, which was the case after approximately 45 minutes. Then the reaction mixture was stored in the refrigerator, after which the hydrobromide of 4'-hydroxy-2- ⁇ 2-(4-hydroxyphenyl)- ethylamino ⁇ propiophenone crystallized.
- Example II A solution of 12.76 g. of 2-bromo-4' benzyloxypropiophenone, 9.08 g. of 2-(4-benzyloxyphenyl)ethylamine and 4.44 g. of thiethylamine in 40 ml. of ethanol was boiled for three hours. The solution was partially evaporated as a result of which some substance crystallized out. To the mixture were added ml. of water and 3 ml. of ether and the non-dissolved substance (hydrobromide of the reaction product) was removed by filtration. The two layers of the filtrate were separated, the ether layer was washed once again with water and then mixed with an excess of 4 N hydrochloric acid. After all the hydrochloride of the.
- reaction product had crystallized, it was sucked 01f, washed with water and ether and dried in vacuo over KOH.
- the yield was 10.3 g. of hydrochloride of 4'-benzyloxy-2- ⁇ 2- 4-benzyloxyphenyl ethylamino ⁇ propiophenone with melting point 202204
- a solution of 2.00 g. of this product in 60 ml. of 80% ethanol was hydrogenated until the two benzyl groups had been removed hydrogenolytically, which appeared from a considerable decrease of the hydrogenation rate.
- the catalyst was filtered off and the alcohol removed from the filtrate for the greater part by distilling it off the vacuo.
- the resulting concentrate was diluted with water and again hydrogenated until no hydrogen was taken up any longer.
- Example 111 3.45 g. of sodium borohydride were dissolved in a mixture of 75 ml. of ethanol and 1.5 ml. of 2 N sodium hydroxide solution. To this solution was added a solution of g. of hydrochloride of 4'-benzyloxy-2- ⁇ 2-(4- benzyloxyphenyl)ethylamino ⁇ propiophen0ne (Example II) in 450 ml. of methanol, to which 1.2 g. of sodium hydroxide (in a few mls. of water) had been added. The mixture was boiled for three hours and then evaporated in vacuo to approximately 300 g. of residue. Then again 300 ml.
- a liquid uterospasmolytic composition containing a compound selected from the group consisting of 1-(4- hydroxyphenyl -2- ⁇ 2- (4-hydroxyphenyl) ethylamino ⁇ propanol and the physiologically non-toxic acid addition salts thereof and a liquid non-toxic pharmaceutical carner.
- a solid uterospasmolytic composition containing a compound selected from the group consisting of 1-(4- hydroxyphenyl -2- ⁇ 2- (4-hydroxyphenyl) ethylamino ⁇ propanol and the physiologically non-toxic acid addition salts thereof and a solid non-toxic pharmaceutical carrier.
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL6401871A NL6401871A (uk) | 1964-02-27 | 1964-02-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3410944A true US3410944A (en) | 1968-11-12 |
Family
ID=19789406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US435344A Expired - Lifetime US3410944A (en) | 1964-02-27 | 1965-02-25 | Pharmaceutical composition containing 1-(4-hydroxyphenyl)-2-{2-(4-hydroxyphenyl)ethylamino}-propanol and salts thereof |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US3410944A (uk) |
| AT (4) | AT264502B (uk) |
| BE (1) | BE660244A (uk) |
| BR (1) | BR6567446D0 (uk) |
| CH (3) | CH539604A (uk) |
| DE (1) | DE1293782B (uk) |
| DK (2) | DK118827B (uk) |
| ES (1) | ES309809A1 (uk) |
| FR (2) | FR1483718A (uk) |
| GB (1) | GB1111451A (uk) |
| NL (1) | NL6401871A (uk) |
| SE (1) | SE339481B (uk) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966814A (en) * | 1969-12-12 | 1976-06-29 | Boehringer Ingelheim Gmbh | 1-Phenyl-2-(Naphthylalkyl-amino)-ethanols and salts thereof |
| US4704407A (en) * | 1984-12-20 | 1987-11-03 | Eli Lilly And Company | Soluble dobutamine salts |
| EP1095932A1 (en) * | 1998-07-08 | 2001-05-02 | Kissei Pharmaceutical Co., Ltd. | Phenoxyacetic acid derivatives and medicinal compositions containing the same |
| CN102060716A (zh) * | 2009-11-15 | 2011-05-18 | 海南中化联合制药工业股份有限公司 | 一种盐酸利托君的制备方法 |
| ITMI20100740A1 (it) * | 2010-04-29 | 2011-10-30 | Lundbeck Pharmaceuticals Italy S Pa | Processo di preparazione di ritodrina cloridrato |
| CN102976959A (zh) * | 2012-12-07 | 2013-03-20 | 许学农 | 利托君的制备方法 |
| US10288602B2 (en) | 2013-01-08 | 2019-05-14 | Atrogi Ab | Screening method, a kit, a method of treatment and a compound for use in a method of treatement |
| US11357757B2 (en) | 2017-09-13 | 2022-06-14 | Atrogi Ab | Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia |
| US11427539B2 (en) | 2017-09-13 | 2022-08-30 | Atrogi Ab | Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia |
| US11648216B2 (en) | 2017-09-13 | 2023-05-16 | Atrogi Ab | Fluorophenyl beta-hydroxyethylamines and their use in the treatment of hyperglycaemia |
| US11793774B2 (en) | 2017-09-13 | 2023-10-24 | Atrogi Ab | Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB202205895D0 (en) | 2022-04-22 | 2022-06-08 | Atrogi Ab | New medical uses |
| WO2024153813A1 (en) | 2023-01-20 | 2024-07-25 | Atrogi Ab | Beta 2-adrenergic receptor agonists for treatment or prevention of muscle wasting |
| GB202302225D0 (en) | 2023-02-16 | 2023-04-05 | Atrogi Ab | New medical uses |
| GB202303229D0 (en) | 2023-03-06 | 2023-04-19 | Atrogi Ab | New medical uses |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL86359C (uk) * | ||||
| US2661373A (en) * | 1953-03-02 | 1953-12-01 | Kulz Ida | Certain amino alcohols and ketones |
| CA623286A (en) * | 1961-07-04 | N.V. Philips Gloeilampenfabrieken | Production of optically active 1-(3',4'-dihydroxyphenyl)-2-amino ethanols | |
| AT228786B (de) * | 1961-01-23 | 1963-08-12 | Philips Nv | Verfahren zur Herstellung des neuen (-)-Enantiomeren des 1-(p-Hydroxyphenyl)-2-(α-methyl- γ-phenyl-propylamino)-propanols-(1) und seiner Säureadditionssalze |
| US3211792A (en) * | 1963-01-24 | 1965-10-12 | Hoffmann La Roche | 1-(phenyl)-or 1-(alkyl-substitutedphenyl)-5-(substituted-phenyl)-3-aza penta-(1)-ols and salts thereof |
| US3250803A (en) * | 1961-07-06 | 1966-05-10 | Philips Corp | Method of manufacturing the individual racemates of n-(p-hydroxyphenylisopropyl) arterenol and products |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE612995A (fr) * | 1961-01-23 | 1962-07-23 | Philips Nv | Procédé de préparation d'un nouveau composé à activité optique |
-
1964
- 1964-02-27 NL NL6401871A patent/NL6401871A/xx unknown
-
1965
- 1965-02-24 CH CH1410468A patent/CH539604A/de not_active IP Right Cessation
- 1965-02-24 CH CH1410368A patent/CH503692A/de not_active IP Right Cessation
- 1965-02-24 AT AT783767A patent/AT264502B/de active
- 1965-02-24 CH CH249665A patent/CH472368A/de not_active IP Right Cessation
- 1965-02-24 SE SE02385/65A patent/SE339481B/xx unknown
- 1965-02-24 AT AT922766A patent/AT270618B/de active
- 1965-02-24 AT AT161165A patent/AT261590B/de active
- 1965-02-24 BR BR167446/65A patent/BR6567446D0/pt unknown
- 1965-02-24 DK DK95865AA patent/DK118827B/da unknown
- 1965-02-24 AT AT783867A patent/AT268252B/de active
- 1965-02-24 DE DEN26270A patent/DE1293782B/de active Pending
- 1965-02-25 ES ES0309809A patent/ES309809A1/es not_active Expired
- 1965-02-25 BE BE660244A patent/BE660244A/xx unknown
- 1965-02-25 GB GB8153/65A patent/GB1111451A/en not_active Expired
- 1965-02-25 US US435344A patent/US3410944A/en not_active Expired - Lifetime
- 1965-02-26 FR FR7240A patent/FR1483718A/fr not_active Expired
- 1965-05-24 FR FR18183A patent/FR4404M/fr not_active Expired
-
1966
- 1966-11-30 DK DK619266AA patent/DK116740B/da unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL86359C (uk) * | ||||
| CA623286A (en) * | 1961-07-04 | N.V. Philips Gloeilampenfabrieken | Production of optically active 1-(3',4'-dihydroxyphenyl)-2-amino ethanols | |
| US2661373A (en) * | 1953-03-02 | 1953-12-01 | Kulz Ida | Certain amino alcohols and ketones |
| AT228786B (de) * | 1961-01-23 | 1963-08-12 | Philips Nv | Verfahren zur Herstellung des neuen (-)-Enantiomeren des 1-(p-Hydroxyphenyl)-2-(α-methyl- γ-phenyl-propylamino)-propanols-(1) und seiner Säureadditionssalze |
| US3250803A (en) * | 1961-07-06 | 1966-05-10 | Philips Corp | Method of manufacturing the individual racemates of n-(p-hydroxyphenylisopropyl) arterenol and products |
| US3211792A (en) * | 1963-01-24 | 1965-10-12 | Hoffmann La Roche | 1-(phenyl)-or 1-(alkyl-substitutedphenyl)-5-(substituted-phenyl)-3-aza penta-(1)-ols and salts thereof |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966814A (en) * | 1969-12-12 | 1976-06-29 | Boehringer Ingelheim Gmbh | 1-Phenyl-2-(Naphthylalkyl-amino)-ethanols and salts thereof |
| US4704407A (en) * | 1984-12-20 | 1987-11-03 | Eli Lilly And Company | Soluble dobutamine salts |
| EP1095932A1 (en) * | 1998-07-08 | 2001-05-02 | Kissei Pharmaceutical Co., Ltd. | Phenoxyacetic acid derivatives and medicinal compositions containing the same |
| EP1095932A4 (en) * | 1998-07-08 | 2002-10-16 | Kissei Pharmaceutical | PHENOXYACETIC ACID COMPOUNDS AND MEDICAL COMPOSITIONS CONTAINING THEM |
| US6538152B1 (en) | 1998-07-08 | 2003-03-25 | Kissei Pharmaceutical Co., Ltd. | Phenoxyacetic acid derivatives and medicinal compositions containing the same |
| CN102060716A (zh) * | 2009-11-15 | 2011-05-18 | 海南中化联合制药工业股份有限公司 | 一种盐酸利托君的制备方法 |
| WO2011134724A3 (en) * | 2010-04-29 | 2012-03-15 | Lundbeck Pharmaceuticals Italy S.P.A. | Method for preparing ritodrine hydrochloride |
| WO2011134724A2 (en) | 2010-04-29 | 2011-11-03 | Lundbeck Pharmaceuticals Italy S.P.A. | Method for preparing ritodrine hydrochloride |
| ITMI20100740A1 (it) * | 2010-04-29 | 2011-10-30 | Lundbeck Pharmaceuticals Italy S Pa | Processo di preparazione di ritodrina cloridrato |
| US8912360B2 (en) | 2010-04-29 | 2014-12-16 | Lundbeck Pharmaceuticals Italy S.P.A. | Methods for preparing ritodrine hydrochloride |
| CN102976959A (zh) * | 2012-12-07 | 2013-03-20 | 许学农 | 利托君的制备方法 |
| CN102976959B (zh) * | 2012-12-07 | 2014-06-04 | 许学农 | 利托君的制备方法 |
| US10288602B2 (en) | 2013-01-08 | 2019-05-14 | Atrogi Ab | Screening method, a kit, a method of treatment and a compound for use in a method of treatement |
| US11357757B2 (en) | 2017-09-13 | 2022-06-14 | Atrogi Ab | Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia |
| US11427539B2 (en) | 2017-09-13 | 2022-08-30 | Atrogi Ab | Beta-hydroxy heterocyclic amines and their use in the treatment of hyperglycaemia |
| US11648216B2 (en) | 2017-09-13 | 2023-05-16 | Atrogi Ab | Fluorophenyl beta-hydroxyethylamines and their use in the treatment of hyperglycaemia |
| US11793774B2 (en) | 2017-09-13 | 2023-10-24 | Atrogi Ab | Chiral beta-hydroxyethylamines and their use in the treatment of hyperglycemia |
| US12036210B2 (en) | 2017-09-13 | 2024-07-16 | Atrogi Ab | Heteroaryl substituted beta-hydroxyethylamines for use in treating hyperglycaemia |
Also Published As
| Publication number | Publication date |
|---|---|
| GB1111451A (en) | 1968-04-24 |
| ES309809A1 (es) | 1965-07-01 |
| DK118827B (da) | 1970-10-12 |
| AT268252B (de) | 1969-02-10 |
| BR6567446D0 (pt) | 1973-08-02 |
| AT264502B (de) | 1968-09-10 |
| FR4404M (uk) | 1966-10-10 |
| NL6401871A (uk) | 1965-08-30 |
| DK116740B (da) | 1970-02-09 |
| DE1293782B (de) | 1969-04-30 |
| BE660244A (uk) | 1965-08-25 |
| AT270618B (de) | 1969-05-12 |
| AT261590B (de) | 1968-05-10 |
| SE339481B (uk) | 1971-10-11 |
| FR1483718A (fr) | 1967-06-09 |
| CH472368A (de) | 1969-05-15 |
| CH503692A (de) | 1971-02-28 |
| CH539604A (de) | 1973-07-31 |
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