GB2151612A - 2-Amino-1-(methoxyphenyl)-1-ethanol derivatives as medicaments - Google Patents
2-Amino-1-(methoxyphenyl)-1-ethanol derivatives as medicaments Download PDFInfo
- Publication number
- GB2151612A GB2151612A GB08429340A GB8429340A GB2151612A GB 2151612 A GB2151612 A GB 2151612A GB 08429340 A GB08429340 A GB 08429340A GB 8429340 A GB8429340 A GB 8429340A GB 2151612 A GB2151612 A GB 2151612A
- Authority
- GB
- United Kingdom
- Prior art keywords
- methoxyphenyl
- addition salts
- amino
- ethanol
- ethanols
- 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.)
- Granted
Links
- ILFKFOKAPPGUOP-UHFFFAOYSA-N 2-amino-1-(2-methoxyphenyl)ethanol Chemical class COC1=CC=CC=C1C(O)CN ILFKFOKAPPGUOP-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title claims description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- DJNXSGUDJKUXMC-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-(4-methylpentan-2-ylamino)ethanol Chemical class COC1=CC=C(C(O)CNC(C)CC(C)C)C=C1 DJNXSGUDJKUXMC-UHFFFAOYSA-N 0.000 claims description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- AWWLGRLLSSADJD-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-(3-methylbutylamino)ethanol Chemical class COC1=CC=C(C(O)CNCCC(C)C)C=C1 AWWLGRLLSSADJD-UHFFFAOYSA-N 0.000 claims 1
- 230000001430 anti-depressive effect Effects 0.000 abstract description 3
- 230000001624 sedative effect Effects 0.000 abstract description 3
- 239000003071 vasodilator agent Substances 0.000 abstract description 3
- 239000004215 Carbon black (E152) Substances 0.000 abstract 1
- 239000000935 antidepressant agent Substances 0.000 abstract 1
- 229940005513 antidepressants Drugs 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- 150000002430 hydrocarbons Chemical group 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- -1 monomethoxyphenyl Chemical class 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 230000000304 vasodilatating effect Effects 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 4
- 230000001077 hypotensive effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229940105631 nembutal Drugs 0.000 description 3
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 2
- 229960004046 apomorphine Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 2
- JIQNWFBLYKVZFY-UHFFFAOYSA-N methoxycyclohexatriene Chemical compound COC1=C[C]=CC=C1 JIQNWFBLYKVZFY-UHFFFAOYSA-N 0.000 description 2
- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical class NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 description 2
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 2
- 229960003147 reserpine Drugs 0.000 description 2
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006313 (C5-C8) alkyl group Chemical group 0.000 description 1
- HPTDZDPYAJHSGA-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-(4-methylpentan-2-ylamino)ethanone Chemical compound COC1=CC=C(C(=O)CNC(C)CC(C)C)C=C1 HPTDZDPYAJHSGA-UHFFFAOYSA-N 0.000 description 1
- OPRJBPJGNFQUHQ-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-(4-methylpentan-2-ylamino)ethanone;hydrochloride Chemical compound Cl.COC1=CC=C(C(=O)CNC(C)CC(C)C)C=C1 OPRJBPJGNFQUHQ-UHFFFAOYSA-N 0.000 description 1
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 1
- ZGLBYKQSLSVZRD-UHFFFAOYSA-N 2-amino-2-methoxy-1-phenylethanone Chemical compound COC(N)C(=O)C1=CC=CC=C1 ZGLBYKQSLSVZRD-UHFFFAOYSA-N 0.000 description 1
- XQJAHBHCLXUGEP-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(=O)CBr)C=C1 XQJAHBHCLXUGEP-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical class [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002686 anti-diuretic effect Effects 0.000 description 1
- 239000003160 antidiuretic agent Substances 0.000 description 1
- 229940124538 antidiuretic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 239000012442 inert solvent 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
- 229960001317 isoprenaline Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical class COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000024883 vasodilation Effects 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
-
- 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
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
2-Amino-1 -(methoxyphenyl)-1 -ethanol derivatives of the formula <IMAGE> (wherein Z is C4-C8-alkyl or hydroxyalkyl group having a branched hydrocarbon chain) and their addition salts, are useful as vasodilating agents. Some exhibit antidepressant and sedative effects also.
Description
SPECIFICATION
Medicaments belonging to the family of 2-amino-i -(methoxyphenyl)-1 -ethanol derivatives
This invention relates to the use of new medicaments, which belong to the 2-amino-1-phenyl-1ethanols family, namely 2-amino-1-(methoxyphenyl)-1-ethanol derivatives which are useful in therapeutics as agents acting on the central nervous system (CNS) and on the cardiovascular system.
It is known from FR-A-2 460 668 that 2-amino-l-phenyl-l -ethanol derivatives of the general formula
Wherein R is H, CH3, OCH3; R1 is in particular C1-C4-alkyl; and R2 is C5-C8-alkyl and may represent in certain conditions CH(CH3)2 or C(CH3)3] have been recommended as substances useful in therapeutics. However FR-A-2 460 668 neither discloses nor suggests the interest, from a therapeutical point of view, of the methoxy compounds (R = OCH3).
It is known that the 1-(2-,3- and 4-methoxyphenyl)-2-tertiobutylamino-1-ethanols have been disclosed in GB-A-1 043 519 as intermediate compounds in the synthesis of anti-diuretic substances, namely the N-methyl-N-tertiobutyl- 1-(2-, 3- and 4-methoxyphenyl)-1 -ethanols.
Moreover dimethoxyphenyl compounds, which are structurally different from the monomethoxyphenyl derivatives according to the invention, were already disclosed in the past.
In particular FR-A-1 372 742 recommends the 1-(3,4-dimethoxyphenyl)-2-tertiobutylamino-1ethanol as an agent which inhibits fi-adrenergic receptors, and FR-M-2864 recommends 1-(2,5 dimethoxyphenyl)-2-alkylamino-1-propanols as cardiac antiarythmia agents.
It has been found now that some 2-amino-1-(methoxyphenyl)-1-ethanol derivatives which can be included within the definition of the above formula lo, but without being specifically disclosed as medicaments, exhibit beneficial therapeutical properties which are particularly interesting with respect to certain diseases of the CNS and mainly to diseases of the cardiovascular system.
According to the invention are recommended as drugs, 2-amino-1-(methoxyphenyl)-1-ethanol derivatives of the formula
wherein Z is a C4-C8-alkyl group with a branched hydrocarbon chain, or a C4-C8-hydroxyalkyl group with a branched hydrocarbon chain, said drugs which are new, being characterized in that they are selected from the group consisting of::
a) the 1 -(2-methoxyphenyl), 1 -(3-methoxyphenyl)- and 1 (4-methoxyphenyl)-2-tertiobutylam- ino-1-ethanols and their addition salts,
b) the 1 -(2-methoxyphenyl), 1 -(3-methoxyphenyl)- and 1 (4-methoxyphenyl)-2-[( 1 , 3-dimethyl- butyl)-amino]-1-ethanols and their addition salts,
c) the 1 -(2-methoxyphenyl), 1 -(3-methoxyphenyl)- and 1 -(4-methoxyphenyl)-2-[ur, a-d i methyl-P- hydroxyethyl)-amino]-1-ethanols and their addition salts,
d) the 1 -(2-methoxyphenyl), 1 -(3-methoxyphenyl)- and 1 -(4-methoxyphenyl-2-isoamylamino- 1 - ethanols and their addition salts,
e) the 1-(2-methoxyphenyl, 1 -(3-methoxyphenyl)- and 1 (4-methoxyphenyl)-2-[( 1 , 1 3, 3-tetram- ethylbutyl)-amino]-1-ethanols and their addition salts, and
f) the 1 -(2-methoxyphenyl), 1 -(3-methoxyphenyl)- and 1 -(4-methoxyphenyl)-2-[( 1 -isopropyl-2 methylpropyl)-amino]-1-ethanols and their addition salts.
The expression "addition salts" is understood here as meaning firstly the acid addition salts obtained by reacting one of the above-mentioned free bases with an inorganic or organic acid, and secondly the ammonium salts. Hydrochloric, hydrobromic, acetic, formic, proprionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic. tartaric, aspartic, glutamic.
methanesulfonic and p-toluenesulfonic acids may be mentioned in particular among the acids which can be used to salify the abovementioned free bases. CH3l and CH3CI may be mentioned in particular among the compounds making it possible to obtain ammonium salts. In general terms. the acid addition salts are preferred to the ammonium salts.
A number of compounds useful as drugs according to the invention have been collated in
Table I below without in any way implying a limitation. The most interesting compounds, from a therapeutical point of view, are the CRL 40 832 (example 5), CRL 40 774 (exampie 1),
CRL 40 819 (example 4), the preferred one being the said CRL 40 832.
TABLE I
Product Code No A Z Melting Point Ex 1 (a) CRL 40 774 4-OCH3 C(CH3)3 215 C Ex 2 (a) CRL 40 798 4-OCH3 C(CH3)2CH2 OR 18200 Ex 3 (a) CRL 40 800 4-OCH3 CH(CH3)CH2CH(CH3)2 177 C Ex 4 (a) CRL 40 819 2-OCH3 C(CH3)3 174 C Ex 5 (b) CRL 40 832 3-OCH3 C(CH3)3 151 C Ex 6 (a) CRL 40 832 A 3-OCH3 C(CH3)3 184 C Ex 7 (a) - 3-OCH3 C(CH3)2CH2C(CH3)3 Ex 8 (a) - 3-OCH3 CH[CH(CH3)2]2 - Ex 9 (a) - 2-OCH3 C(CH3)2CH2OH Ex 10 (a) - 4-OCH3 CH2CH2CH(CH3)2 - Notes (a) : hydrochloride (h) : methanesulfonate
The compounds according to the invention can be prepared according to a method known per se by application of classical reaction mechanisms.The method which is recommended here comprises subjecting a N-(methoxyphenyl)-amine derivative to a reduction reaction with NaBH4 or KBH4, according to the following reaction:
This reaction is carried out in an inert solvent selected from C1-C2-alcohols, at a temperature comprised between - 5'C and 0 C (for at least 0.30 h), in a proportion of 1 to 1.3 mol of borohydride selected from NaBH4 and KBH4 for 1 mol of N-(methoxyphenacyl)-amine of the formula II.
Compounds of the formula II, used here as starting material, can be prepared according the method given in French patent application No 83 1 8868 of the Applicant.
All the compounds according to the invention act as vasodilating agents, some of them exhibit interesting effect on the CNS. In particular (i) CRL 40-832 (example 5) has at a lower dose antidepressant effects (antagonism of the hypothermiae induced by the apomorphine, reserpine and oxotremorine), exhibits at a higher dose sedative effects, and decreases the intergroup aggressiveness of male mice from the dose of 1 mg/kg l.P., and, (ii) CRL40819 (example 4) decreases the intergroup aggressiveness of male mice at the dose of 8 mg/kg l.P.
According to the invention a therapeutical composition is provided which comprises, in association with a physiologically acceptable excipient, at least a 2-amino-1-(methoxyphneyl)-1ethanol or one of its addition salts, as the active ingredient.
Of course, in a composition of this type the active ingredient which is selected from the group consisting of 2-amino-1-(methoxyphenyl)-1-ethanol derivatives and non-toxic addition salts thereof is present in a pharmaceutially effective amount.
Further advantages and characteristics of the invention will be understood more clearly on reading the following description of preparative examples and results of pharmacological assays; these data as a whole do not imply a limitation but are given by way of illustration.
PREPARATION I
Obtention of I -(4-methoxyphenyl)-%f( 1, 3-dimethylbutyl)aminol- 1-ethanol
(Example 3; Code No: CRL 40 800)
26.1 g (0.0914 Mol) of N-(4-methoxyphenacyl)-1,3-dimethylbutylamine hydrochloride (Code
No: CRL 40 799; MP = 1 90"C with decomposition) are dissolved in water. NaCO3 is added up to a pH of 11. The mixture thus obtained is extracted with 500 ml of diethylether, the ethereal phase is washed with H20, dried over MgSO4 and filtered in order to recover the filtrate which contain the N-(4-methoxyphenacyl)-1 ,3-dimethylbutylamine.
The filtrate is evaporated to dryness and the evaporation residue is taken up with 280 ml of CH3OH then cooled at - 5"C before addition of 3.5g (0.0914 mol) of NaBH4. The reaction mixture is left to evolve until disappearing of the phenacyl derivative as checked on TLC (eluent: CH3C6H-CH3COCH3-NH40H(30 :70:2) v/v; support: silica gel plate; revelation: U.V. radiation + Draggendorf reagent]. After addition of acetic acid, the reaction mixture is evaporated to dryness; the evaporation residue is taken up with 500 ml of water, adjusted to pH 11 and extracted with diethylether.
The ethereal phase is washed with water, dried over MgSO4 and filtered in order to recover the filtrate. From the filtrate the expected hydrochloride salt is precipitated by means of a 15 ml solution of HCI 7N in ethanol. Recrystallization from an acetone-ethanol (1:1) v/v mixture gives 7 g (yield: 26%) of CRL 40 800. M.P. = 177'C.
% N measured = 4.86 % Analysis % N theoretical = 4.86 % PREPARATION II Obtention of 1 -(4-meThoxyphenyl)-2-U', tr-dimethyl- - h ydroxyethyl)-amino]- 1- ethanol hydrochloride, alternative nomenclature: 1-(4-methoxyphenyl)-2-[2-(2-hydroxymethyl- propyl)-amino]-1-ethanol.
(Example 2; Code No: CRL 40 798)
50 g (0.218 mol) of 4-methoxyphenacyl bromide (in solution in 200 ml of chloroform) are poured into a solution of 77.6 g (0.872 mol) of 2-(2-hydroxymethyl-propyl)-amine in 100 ml of methanol. The reaction mixture is heated under reflux for 2 h, cdoled, evaporated to dryness, and the evaporation residue is taken up with 500 ml of water and extracted with ethyl acetate.
The ethyl acetate phase is washed with water and extracted by a mixture consisting of 500 ml of water and 22 ml of concentrated hydrochloric acid (d = 1.19). The aqueous phase is washed with CH3CO2C2H5 alcalinized up to pH 11 with K,CO,. extracted with CH3CO2C2H5. The organic phase is washed with water, dried over MgSO4 and filtered. The filtrate which comprises the N (4-methoxyphenacyl)-N-2-(2-hydroxymethyl-propyl)amine of the formula
is evaporated to dryness.
The evaporation residue is dissolved in 680 ml of methanol, cooled at - 5'C and 9.1 g (0.24 mol) of NaBH, are added. The reaction is left to evolve until total disappearing of the phenacyl compound as checked on TLC (as indicated above in Preparation I), then 14.5 ml of acetic acid are added and the resulting mixture is evaporated to dryness. The evaporation residue is taken up with 300 ml of water. After extraction with CH3CO2C2H5, washing the ester phase with water, drying over MgSO4 and filtration for removing MgSO4, the expected hydrochloride salt is obtained by means of a 31 ml solution of HO 7N in ethanol.Recrystallization from an acetonemethanol (1:1) v/v mixture gives 5 g (overall yieid: 8%) of CRL 40 798 M.P. = 182"C.
% N measured = 5.00 % Analysis % N theoretical = 5.08 % PREPARATION III Obtention of 1 (3-methoxyphenyl)-2-tertiobutylamino- methanol methanesulfonate.
(Example 5; Code No = CRL40 832)
NaBH4 (0.12 mol) is introduced at - 5"C into a solution of 0.10 mol of N-(3-methoxyphenacyl)-tertiobutylamine in methanol. The reaction is left to evolve until total disappearing of the phenacyl compound as checked on TLC (as indicated above in Preparation I), then acetic is added and the resulting mixture is evaporated to dryness. The evaporation residue is taken up with H20; after extraction with either, washing the ethereal phase with water, drying over
MgSO4 and filtration in order to discard MgS04, the expected methanesulfonate salt is obtained by addition of methanesulfonic acid. Recrystallization from an acetone-methanol (1 )v/v mixture CRL40832 with a yieid of 35% M.P. = 151 C.
Results of assays, which have been carried out, are summed up hereinafter.
A-CRL 40 774 (Example 1)
On nembutal anesthetized dog, it is observed that CRL 40 774 administered by l.V. route exhibits a femoral vasodilating action at a dose of 10 mg/kg (+ 36%). As from 1 mg/kg
CRL 40 74 presents an important bradycardial effect, and as from 5 mg/kg an hypotensive action. It seems that CRL 40 774 possesses a fli action, since, besides its own effect, it highly decreases the isoprenaline ss-stimulating action; moreover its femoral vasodilating action seems to be of the ss2+ type.
On awake normotensive dogs CRL40774 has a slight hypotensive effect (- 18%) at a dose of 10 mg/kg per os.
On awake and spontaneously hypertensive rats, the minimal hypotensive dose of CRL 40 774 per os is 5 mg/kg.
B--CRL 40 798 (Example 2)
CRL 40 798 exhibits on the nembutal anesthetized dog a femoral vasodilating effect. It seems to present a ssl- effect.
C-CRL 40 800 (Example 3)
CRL 40 800 exhibits a femoral vasodilating action as from the dose of 1 mg/kg. It seems to present a ss+ effect.
D-CRL 40 819 (Example 4)
CRL 40 819 administered intraduodenally to nembutal anesthetized dogs. It exhibits an important hypotensive action as from the dose of 20 mg/kg. This product seems to have a fl effect. Moreover it decreases aggressiveness as from 8 mg/kg l.P. on male mice according to the intergroup aggressiveness test.
E-CRL 40 832 (Example 5)
CRL 40 832 exhibits, on one hand, at lower doses, effects of the antidepressive type (antagonism of hypothermia induced by apomorphine, reserpine or oxotremorine), and, on the other hand, at higher doses, effects the sedative type which can explain only partially the clear decrease of aggressiveness.
Moreover, CRL 40 832 administered intraduodenally to anesthetized dogs at doses from 0.1 to 20 mg/kg exhibits a femoral vasodilating activity as from 0.1 mg/kg. the effect is proportionnal to the dose used and has a duration higher than 1 hour. It is also observed that, at lower doses, the compound induces tachycardia and vertebral vasodilatation which are both moderate. It seems that CRL 40 832 has a ssl~ effect. This product is useful in particular as periphereal vasodilating agent.
Claims (9)
1. A medicament belonging to the group of the 2-amino-1-(methoxyphenyl)-1-ethanols of the formula
wherein Z is a C4-C8-alkyl group with a branched hydrocarbon chain, said medicament being characterized in that it is selected from the group consisting of:
a) the 1 -(2-methoxyphenyl), 1-(3-methoxyphenyl)- and 1 -(4-methoxyphenyl)-2-tertiobutylamino-1-ethanols and their addition salts,
b) the 1 -(2-methoxyphenyl), 1 (3-methoxyphenyl)- and 1 -(4-methoxyphenyl)-2-[( 1,3-dimethyl- butyl)-amino]-1-ethanols and their addition salts,
c) the 1 -(2-methoxyphenyl), 1 -(3-methoxyphenyl)- and 1-(4-methoxyphenyl)-2-[α,α;-dimethyl-ss- hydroxyethyl)-amino]-1-ethanols and their addition salts,
d) the 1 -(2-methoxyphenyl), 1 -(3-methoxyphenyl)- and 1 -(4-methoxyphenyl)-2-isoamylamino-1 - ethanols and their addition salts,
e) the 1 -(2-methoxyphenyl), 1-(3-methoxyphenyl)-and 1 -(4-methoxyphenyl)-2-[1 , 1,3,3-tetram- ethylbutyl)-amino]-1-ethanois and their addition salts, and
f) the 1 -(2-methoxyphenyl), 1 -(3-methoxyphenyl)- and 1 -(4-methoxyphenyl)-2-( 1 -isopropyl-2- methylpropyl)-amino]-1-ethanols and their addition salts.
2. A medicament according to claim 1, characterized in that it is selected from the group consisting of the 1-(4-methoxyphenyl)-2-tertiobutylamino-1-ethanol and its addition salts.
3. A medicament acording to claim 1, characterized in that it is selected rom the group consisting of the 1-(4-methoxyphenyl)-2-[(α,α-dimethyl-ss-hydroxyethyl)-amino]-1-ethanol and its addition salts.
4. A medicament according to claim 1, characterized in that it is selected from the group consisting of the 1-(4-methoxyphenyl)-2-[(1,3-dimethylbutyl)-amino]-1-ethanol and its addition salts.
5. A medicament according to claim 1, characterized in that it is selected from the group consisting of the 1-(2-methoxyphenyl)-2-tertiobutylamino-1-ethanol and its addition salts.
6. A medicament according to claim 1, characterized in that it is selected from the group consisting of the 1-(3-methoxyphenyl)-2-tertiobutylamino-1-ethanol and its addition salts.
7. A medicament according to claim 1 which is 1-(3-methoxyphenyl)-2-tertiobutylamino-1ethanol methanesulfonate.
8. A therapeutical composition characterized in that it comprises, in association with a physiologically acceptable excipient, at least a 2-amino-1-(methoxyphenyl)-1-ethanol derivative or one of its addition salts according to any one of claim 1 to 7.
9. A medicament substantially as hereinbefore described in any one of the preparative
Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8318869A FR2555574B2 (en) | 1979-07-13 | 1983-11-25 | 2-AMINO-1- (METHOXYPHENYL) -1-ETHANOL DERIVATIVES USEFUL AS MEDICAMENTS |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8429340D0 GB8429340D0 (en) | 1985-01-03 |
| GB2151612A true GB2151612A (en) | 1985-07-24 |
| GB2151612B GB2151612B (en) | 1988-08-03 |
Family
ID=9294555
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08429340A Expired GB2151612B (en) | 1983-11-25 | 1984-11-21 | The use of the family of 2-amino-1-(methoxyphenyl)-1- ethanol derivatives for the manufacture of a medicament for use as a vasodilating agent |
Country Status (5)
| Country | Link |
|---|---|
| BE (1) | BE901127A (en) |
| CH (1) | CH660728A5 (en) |
| GB (1) | GB2151612B (en) |
| IT (1) | IT1179828B (en) |
| ZA (1) | ZA849158B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017014524A (en) * | 2011-07-28 | 2017-01-19 | アンガス ケミカル カンパニー | Amino alcohol compound and use thereof as zero or low voc additive for paint and coating |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2460668A1 (en) * | 1979-07-13 | 1981-01-30 | Lafon Labor | 2-Amino-1-phenyl-1-ethanol cpds. - use as medicaments, i.e. as CNS and/or cardiovascular agents |
-
1984
- 1984-11-21 GB GB08429340A patent/GB2151612B/en not_active Expired
- 1984-11-23 IT IT68172/84A patent/IT1179828B/en active
- 1984-11-23 CH CH5613/84A patent/CH660728A5/en not_active IP Right Cessation
- 1984-11-23 ZA ZA849158A patent/ZA849158B/en unknown
- 1984-11-23 BE BE6/48035A patent/BE901127A/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2460668A1 (en) * | 1979-07-13 | 1981-01-30 | Lafon Labor | 2-Amino-1-phenyl-1-ethanol cpds. - use as medicaments, i.e. as CNS and/or cardiovascular agents |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017014524A (en) * | 2011-07-28 | 2017-01-19 | アンガス ケミカル カンパニー | Amino alcohol compound and use thereof as zero or low voc additive for paint and coating |
| 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 |
|---|---|
| IT8468172A1 (en) | 1986-05-23 |
| CH660728A5 (en) | 1987-06-15 |
| IT8468172A0 (en) | 1984-11-23 |
| GB2151612B (en) | 1988-08-03 |
| ZA849158B (en) | 1985-07-31 |
| BE901127A (en) | 1985-03-15 |
| GB8429340D0 (en) | 1985-01-03 |
| IT1179828B (en) | 1987-09-16 |
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| PCNP | Patent ceased through non-payment of renewal fee |