DE1618160B2 - 1 (2 Athynylphenoxy) 2 hydroxy 3 alkylaminopropanes, their physiologically acceptable acid addition salts, processes for their production, as well as drugs containing these compounds - Google Patents
1 (2 Athynylphenoxy) 2 hydroxy 3 alkylaminopropanes, their physiologically acceptable acid addition salts, processes for their production, as well as drugs containing these compoundsInfo
- Publication number
- DE1618160B2 DE1618160B2 DE19671618160 DE1618160A DE1618160B2 DE 1618160 B2 DE1618160 B2 DE 1618160B2 DE 19671618160 DE19671618160 DE 19671618160 DE 1618160 A DE1618160 A DE 1618160A DE 1618160 B2 DE1618160 B2 DE 1618160B2
- Authority
- DE
- Germany
- Prior art keywords
- compounds
- hydroxy
- addition salts
- acid addition
- alkylaminopropanes
- 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
- 239000002253 acid Substances 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 10
- 150000003839 salts Chemical class 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 title description 23
- 238000004519 manufacturing process Methods 0.000 title description 3
- 239000003814 drug Substances 0.000 title description 2
- 229940079593 drug Drugs 0.000 title description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title description 2
- -1 2-Ethynylphenoxy Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- BLUMOGCWKTZKNJ-UHFFFAOYSA-N 1-(tert-butylamino)-3-(2-ethynylphenoxy)propan-2-ol Chemical compound CC(C)(C)NCC(O)COC1=CC=CC=C1C#C BLUMOGCWKTZKNJ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 3
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 3
- 229940039009 isoproterenol Drugs 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- FBRCUUSQZXTNER-UHFFFAOYSA-N 1-(2-ethynylphenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1C#C FBRCUUSQZXTNER-UHFFFAOYSA-N 0.000 description 2
- KTLQDZRFPKXZSB-UHFFFAOYSA-N 2-ethynylphenol Chemical compound OC1=CC=CC=C1C#C KTLQDZRFPKXZSB-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- VLSTXUUYLIALPB-UHFFFAOYSA-N n-propan-2-ylpropan-1-amine Chemical compound CCCNC(C)C VLSTXUUYLIALPB-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- XUJHKPSBHDQIOD-UHFFFAOYSA-N (2-bromo-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)C(Br)C1C2(C)C XUJHKPSBHDQIOD-UHFFFAOYSA-N 0.000 description 1
- KRLZMDKGXUOSON-UHFFFAOYSA-N 1-(butan-2-ylamino)-3-(2-ethynylphenoxy)propan-2-ol Chemical compound CCC(C)NCC(O)COC1=CC=CC=C1C#C KRLZMDKGXUOSON-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- QLWSYRNMJMYSBE-UHFFFAOYSA-N 2-[(2-ethynylphenoxy)methyl]oxirane Chemical compound C#CC1=CC=CC=C1OCC1OC1 QLWSYRNMJMYSBE-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- YIUIVFFUEVPRIU-UHFFFAOYSA-N 8-chlorotheophylline Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21 YIUIVFFUEVPRIU-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000700198 Cavia Species 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
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-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
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical class [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
1515th
OCHj-CHOH-CH2-NHi-R (I)OCHj-CHOH-CH 2 -NHi-R (I)
in der R einen Älkylrest mit 1 bis 4 C-Atomen bedeutet; dadurch gekennzeichnet, daß man in an sich bekannter Weisein R an alkyl radical with 1 to 4 carbon atoms means; characterized in that one in a known manner
a) eine Verbindung der allgemeinen Formela) a compound of the general formula
G=CH
OCH2-ZG = CH
OCH 2 -Z
(II)(II)
in der Z die Gruppe:in the Z the group:
CH2 CH 2
—CHOH—CH5HaI—CHOH — CH 5 HaI
3030th
3535
4040
(Hal = Halogenatom) bedeutet, mit einem Amin der allgemeinen Formel(Hal = halogen atom) means with an amine the general formula
H2N-R (III)H 2 NR (III)
in der R die; obengenannte Bedeutung hat, umsetzt, oder daß man.in the R the; has the above meaning, or that one.
b) l--(2rÄthinylphenoxy)-2-hydroxy-3-aminopropan; der Formelb) 1- (2rethynylphenoxy) -2-hydroxy-3-aminopropane; the formula
45 R1 eine leicht hydrögenolytisch oder hydrolytisch abspaltbare Schutzgruppe bedeutet, die Gruppe R1 durch Wasserstoff ersetzt, oder daß man 45 R 1 denotes a protective group which can be easily split off hydrogenolytically or hydrolytically, the group R 1 is replaced by hydrogen, or that one
d) ein Oxazolidinon der allgemeinen Formel
C=CHd) an oxazolidinone of the general formula
C = CH
OCH2-CH
OOCH 2 -CH
O
CH2 CH 2
N-RNO
(VI)(VI)
in der R die oben angegebene Bedeutung hat, hydrolysiert, oder daß manin which R has the meaning given above, hydrolyzed, or that one
e) ein Harnstoffderivat der allgemeinen Formel C=CHe) a urea derivative of the general formula C = CH
OCH9- CHOH-CH7-N-C-NR7R,OCH 9 - CHOH-CH 7 -NC-NR 7 R,
R OR O
(VII)(VII)
in der R die oben angegebene Bedeutung hat und R2 sowie R3, die gleich oder verschieden sein können, Wasserstoff, Älkylreste, Aralkylreste oder Arylreste, vorzugsweise Phenylreste, bedeuten, mittels starker Basen oder Säuren hydrolysiert und die so erhaltenen Verbindungen gewünschtenfalls in üblicher Weise in ihre physiologisch verträglichen Säureadditiönssälze überführtin which R has the meaning given above and R 2 and R 3 , which can be the same or different, are hydrogen, alkyl radicals, aralkyl radicals or aryl radicals, preferably phenyl radicals, are hydrolyzed by means of strong bases or acids and the compounds obtained in this way, if desired, in the customary manner converted into their physiologically compatible acid addition salts
4. Arzneimittel, enthaltend als Wirkstoff Verbindungen der allgemeinen Formel4. Medicinal products containing compounds as active ingredients the general formula
C=CHC = CH
OCH2-CHOH-CH2-NH-ROCH 2 -CHOH-CH 2 -NH-R
in der R einen Alkylrest mit 1 bis 4 C-Atomen bedeutet, oder deren physiologisch verträgliche Säureadditionssalze in Kombination mit üblichen Hilfs- und/oder Trägerstoffen.in which R is an alkyl radical with 1 to 4 carbon atoms means, or their physiologically acceptable Acid addition salts in combination with usual Auxiliary and / or carrier materials.
OCH2-CHOK-CH2-NH2 (IV)OCH 2 -CHOK-CH 2 -NH 2 (IV)
mit einem üblichen Alkylierungsmittel mit 1 bis 4 C-Atomen umsetzt, oder daß manwith a common alkylating agent with 1 to 4 carbon atoms converts, or that one
c) eine Verbindung der allgemeinen Formel C=CHc) a compound of the general formula C = CH
Die Erfindung betrifft l-(2-Äthmylphenoxy)-2-hydroxy-3-alkylaminopropane und ihre Salze mit interessanten phannäkologischen Eigenschaften bei Warmblütern, Verfahren zu ihrer Herstellung sowie diese Verbindungen enthaltende Arzneimittel. Die neuen Verbindungen entsprechen der allgemeinen FormelThe invention relates to 1- (2-ethylphenoxy) -2-hydroxy-3-alkylaminopropanes and their salts with interesting phannecological properties in warm-blooded animals, Process for their preparation, as well as these Medicines containing compounds. The new compounds correspond to the general formula
6060
C=CHC = CH
OCH2-CHOH-CH2-NH-ROCH 2 -CHOH-CH 2 -NH-R
OCH2-CH-CH2-NH-R (V)OCH 2 -CH-CH 2 -NH-R (V)
OR1 OR 1
in der R die oben angegebene Bedeutung hat und In dieser Formel bedeutet R einen Alkylrest mit bis 4 C-Atomen.in which R has the meaning given above and In this formula, R denotes an alkyl radical with up to 4 carbon atoms.
Die neuen Verbindungen können in folgender Weise hergestellt werden:The new connections can be made in the following ways:
a) Umsetzung einer Verbindung der allgemeinen Formel IIa) Implementation of a compound of the general formula II
(II)(II)
OGH2-ZOGH 2 -Z
e) Hydrolyse eines Harnstoffderivats der allgemeinen Formele) hydrolysis of a urea derivative of the general formula
C=CH
/~~S—OCH2-CH1OH- CH2-N-C- NR2R3 C = CH
/ ~~ S-OCH 2 -CH 1 OH-CH 2 -NC-NR 2 R 3
in der Z die Gruppein the Z the group
R OR O
(VII)(VII)
-CH-CH
CH2 CH 2
-CHOH-CH2HaI-CHOH-CH 2 HaI
(Hai = Halogenatom) bedeutet, mit einem Amin der allgemeinen Formel(Hal = halogen atom) means with an amine of the general formula
H,N—RH, N-R
(III)(III)
OCH2-CH-CH2-NH-R (V) OR1 OCH 2 -CH-CH 2 -NH-R (V) OR 1
in der R die oben angegebene Bedeutung hat und R1 eine leicht hydrögeöölytisch oder hydrolytisch abspaltbare Schutzgruppe (beispielsweise eine Acyl- oder Acetylgrüppe) bedeutet, in für derartige Reaktionen üblicherweise.in which R has the meaning given above and R 1 denotes a protective group which can be easily split off hydrodynamically or hydrolytically (for example an acyl or acetyl group), usually for such reactions.
d) Hydrolyse^ eines Oxäzolidinoris der allgemeinen Formeld) Hydrolysis ^ of an Oxazolidinoris of the general formula
C=CHC = CH
OCH7-CHOCH 7 -CH
CH2 Ν—RCH 2 Ν-R
(VI)(VI)
C OC O
in der R die oben angegebene Bedeutung hat und R2 sowie R3, die gleich oder verschieden sein können, Wasserstoff, Alkylreste, Aralkylreste oder Arylreste, vorzugsweise Phenylreste, bedeuten, z. B. mittels starker Basen oder Säuren wie NaOH oder HCl.in which R has the meaning given above and R 2 and R 3 , which can be identical or different, denote hydrogen, alkyl radicals, aralkyl radicals or aryl radicals, preferably phenyl radicals, e.g. B. by means of strong bases or acids such as NaOH or HCl.
Die Ausgangsverbindungen der Verfahren a) bis e) sind zum Teil bereits bekannt, zum Teil können sie nach bekannten Verfahren gewonnen werden, wobei man dann meistens von Verbindungen der Formel II oder von den Verbindungen der FormelSome of the starting compounds for processes a) to e) are already known, and some can can be obtained by known processes, in which case compounds of the formula II or of the compounds of the formula
C=CHC = CH
in der R die oben angegebene Bedeutung hat, in für derartige Reaktionen üblicher Weise.in which R has the meaning given above, in a manner customary for such reactions.
b) Einführung des Restes R in das primäre Amin der Formelb) Introduction of the radical R into the primary amine of the formula
C=CHC = CH
/~\-OCH2—CHOH—CH2-NH2 (IV)/ ~ \ -OCH 2 -CHOH-CH 2 -NH 2 (IV)
beispielsweise mittels Alkylhalogeniden mit 1 bis 4 C-Atomen, in für derartige Reaktionen üblicher Weise.for example by means of alkyl halides having 1 to 4 carbon atoms, which is more common for such reactions Way.
c) Abspaltung einer leicht entfernbaren Schutzgruppe aus Verbindungen der allgemeinen Formelc) Cleavage of an easily removable protective group from compounds of the general formula
40 C=CH 40 C = CH
in der R die oben angegebene Bedeutung hat, in üblicher Weise, z. B. mit KOH.in which R has the meaning given above, in the usual way Way, e.g. B. with KOH.
(VIII)(VIII)
in der Kt Wasserstoff oder ein Kation (beispielsweise eine Alkalimetällion) bedeutet, ausgeht. Die Epoxide der Formel II lassen sich dabei aus Verbindungen der Formel VIII durch Reaktion mit Epichlorhydrin herstellen. Die Verbindungen der Formel VIII sind beispielsweise nach der in Bull. ehem. Soc (Japan) 29, (1956), S. 471 (zitiert in CA. 51 (1957), Sp. 8705 b, beschriebenen Methode herstellbar.in which Kt is hydrogen or a cation (for example an alkali metal ion), goes out. the Epoxides of the formula II can be prepared from compounds of the formula VIII by reaction with epichlorohydrin produce. The compounds of the formula VIII are, for example, according to the in Bull. Former Soc (Japan) 29, (1956), p. 471 (cited in CA. 51 (1957), col. 8705 b, described method can be produced.
Bezüglich der Herstellung der Ausgangsverbindungen der Verfahren a) bis e) wird zusätzlich auf folgende Literaturstellen verwiesen:With regard to the preparation of the starting compounds of processes a) to e), the following is additionally made References referenced:
Journal of Pharm. iried. Chem. Bd. 5,Journal of Pharm. Iried. Chem. Vol. 5,
S. 69 bis 76 (1952),
Journal Pharm. Pharmacol. Bd. 5,Pp. 69 to 76 (1952),
Journal Pharm. Pharmacol. Vol. 5,
S. 359 bis 369 (1953),
Journal Pharm. Pharmacol. Bd. 9,Pp. 359 to 369 (1953),
Journal Pharm. Pharmacol. Vol. 9,
S. 10 bis 19 (1957),
britische Patentschrift 984189,
belgische Patentschrift 641133,
Chemical Abstracts Bd. 58, Sp. 3337 e (1962)Pp. 10 to 19 (1957),
British Patent 984189,
Belgian patent 641133,
Chemical Abstracts Vol. 58, Sp. 3337 e (1962)
sowie
Houben—Weyl, Methoden der Organischenas
Houben-Weyl, Methods of the Organic
Chemie, 1. und 2. Auflage;Chemistry, 1st and 2nd edition;
Die Verbindungen der allgemeinen Formel I besitzen aft der — CH OH-Gruppierung ein asymmetrisches C-Atom und kommen daher in Form von Räeenrtaten wie auch von optisch aktiven Antipoden vor. Die optisch aktiven Verbindungen können erhalten werden, indem man entweder von optisch aktiven Ausgangsverbindungen ausgeht oder die erhaltenen Racemäte auf übliche Weise, beispielsweise mittels Dibenzöylweinsäure oder Bromcamphersülfonsäure, in ihre optischen Antipoden spaltet.The compounds of general formula I have aft of the - CH OH group an asymmetric one C-atom and therefore come in the form of deeds as well as optically active antipodes. The optically active compounds can be obtained be by either optically active Starting compounds runs out or the obtained Racemates in the usual way, for example by means of dibenzoyltartaric acid or bromocamphorsulfonic acid, splits into their optical antipodes.
Die nach den Verfahren a) bis e) erhaltenen Verbindungen der allgemeinen Formel I können gewünschtenfalls in üblicher Weise in ihre physiologisch verträglichen Säureädditionssalze übergeführt werden. Für die Salzbildung geeignete Säuren sind beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Methansulfonsäüre, Maleinsäure, Essigsäure, Oxalsäure, Milchsäure, Weinsäure oder 8-Chlortheophyllin.The compounds obtained by processes a) to e) of the general formula I can, if desired, in the usual manner in their physiological compatible acid addition salts are transferred. Acids suitable for salt formation are, for example Hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid, Lactic acid, tartaric acid, or 8-chlorotheophylline.
Die Verbindungen der allgemeinen Formel I bzw. deren physiologisch verträgliche Säureadditionssalze haben wertvolle therapeutische, insbesondere /5-adrenolytische Eigenschaften und können daher beispielsweise zur Behandlung oder Prophylaxe von Erkrankungen der Herzkranzgefäße und zur Behandlung von Herzarrhythmien, insbesondere von Tachycardien, an Menschen eingesetzt werden. Auch die blutdrucksenkenden Eigenschaften der Verbindungen sind therapeutisch interessant. Als wertvoll haben sich dabei insbesondere solche Verbindungen der allgemeinen Formel I herausgestellt, bei denen R den Isopropyl- oder t-Butylrest bedeutet, also die Verbindungen l-(2-Äthinylphenoxy) - 2 - hydroxy - 3 - isopropylaminopropan und 1 - (2 -Äthinylphenoxy) - 2 - hydroxy - 3 - tert.butylaminopropan. The compounds of general formula I or their physiologically acceptable acid addition salts have valuable therapeutic, especially / 5-adrenolytic Properties and can therefore be used, for example, for the treatment or prophylaxis of diseases coronary arteries and for the treatment of cardiac arrhythmias, especially tachycardias, used on people. The antihypertensive properties of the compounds are also therapeutic Interesting. Compounds of the general formula in particular have proven to be of value here I highlighted, in which R is the isopropyl or t-butyl radical, i.e. the compounds l- (2-ethynylphenoxy) - 2 - hydroxy - 3 - isopropylaminopropane and 1 - (2 -ethynylphenoxy) - 2 - hydroxy - 3 - tert-butylaminopropane.
Die Einzeldosis der erfindungsgemäßen Verbindungen bzw. ihrer Säureadditionssalze liegt bei I bis 300 mg, (0,016 bis 5 mg/kg) vorzugsweise bei 15 bis 100 mg (0,25 bis 1,66 mg/kg) für die orale Anwendung bzw. bei 0,1 bis 25 mg (0,002 bis 0,40 mg/kg) für die parenterale Anwendung am Menschen.The single dose of the compounds according to the invention or their acid addition salts is from 1 to 300 mg, (0.016 to 5 mg / kg) preferably at 15 to 100 mg (0.25 to 1.66 mg / kg) for oral use or at 0.1 to 25 mg (0.002 to 0.40 mg / kg) for parenteral use in humans.
Die galenische Verarbeitung der Verbindungen der allgemeinen Formel I zu den üblichen Anwendungsformen wie Lösungen, Emulsionen, Tabletten, Dragees oder Depotformen kann in bekannter Weise unter Heranziehung der gebräuchlichen galenischen Hilfsstoffe erfolgen. Die erfindungsgemäßen Verbindungen können auch in Kombination mit anderen pharmazeutischen Wirkstoffen, beispielsweise herz- oder kreislaufwirksamen Sympathicomimetica oder Coronardilatatoren, angewendet werden.The pharmaceutical processing of the compounds of general formula I into the customary application forms such as solutions, emulsions, tablets, coated tablets or depot forms can be used in a known manner using the usual galenic Auxiliary materials take place. The compounds according to the invention can also be used in combination with others pharmaceutical active ingredients, for example cardiac or circulatory sympathicomimetics or Coronary dilators.
Die folgenden Beispiele erläutern die Erfindung:The following examples illustrate the invention:
A. VerfahrensbeispieleA. Process examples
l-(2-Äthinylphenoxy)-2-hydroxy-3-isopropylaminopropan · HCl1- (2-Ethynylphenoxy) -2-hydroxy-3-isopropylaminopropane · HCl
12,8 g l-(2-Äthinylphenoxy)-2,3-epoxypropan, durch Reaktion von 8,9 g (0,075 Mol) 2-Athinylphenol mit 7,65 g(0,08 Mol) Epichlorhydrin in verdünntem NaOH gewonnen, werden in 120 ml Methanol gelöst und 17,7 g (0,3 Mol) Isopropylamin zugegeben. Nach mehrstündigem Stehen bei Raumtemperatur wird 2,5 Stunden auf 60 bis 70° C erwärmt, sodann werden die flüchtigen Anteile unter vermindertem Druck abdestilliert. Der verbleibende Rückstand wird aus Essigester unter Zugabe von Petroläther umkristallisiert. Die Base wird in verdünntem HCl gelöst, über Kohle filtriert und nach Zugabe von NaOH die ausfallende feste Base abgesaugt. Sie wird nochmals aus Essigester/ Petroläther umkristallisiert. Ausbeute 9,6 g, Fp.: 93 bis 95° C.12.8 g of 1- (2-ethynylphenoxy) -2,3-epoxypropane, by reacting 8.9 g (0.075 mol) of 2-ethynylphenol with 7.65 g (0.08 mol) of epichlorohydrin obtained in dilute NaOH are dissolved in 120 ml of methanol and 17.7 g (0.3 mol) of isopropylamine were added. After several hours Standing at room temperature is heated to 60 to 70 ° C for 2.5 hours, then the volatile Portions distilled off under reduced pressure. The remaining residue is taken from ethyl acetate Recrystallized addition of petroleum ether. The base is dissolved in dilute HCl and filtered through charcoal and after the addition of NaOH, the precipitated solid base is filtered off with suction. It is again made from ethyl acetate / Recrystallized petroleum ether. Yield 9.6 g, m.p .: 93 to 95 ° C.
Durch Lösen der Base in Acetonitril und Zugabe von ätherischer HCl wird das kristalline Hydrochlorid gewonnen, dessen Schmelzpunkt bei 143 bis 1450C liegt.By dissolving the base in acetonitrile and adding ethereal HCl, the crystalline hydrochloride is obtained, the melting point of which is 143 to 145 ° C.
l-(2-Äthinylphenoxy)-2-hydroxy-3-tert.butylaminopropan · HCl1- (2-Ethynylphenoxy) -2-hydroxy-3-tert-butylaminopropane · HCl
12 g (0,07MoI) l-(2-Äthinylphenoxy)-2-hydroxy-3-tert.butylaminopropan werden in 100 ml Methanol gelöst und 18 g (0,025 Mol) tert.Butylamin zugegeben, über Nacht wird bei Raumtemperatur stehengelassen, sodann 2 Stunden auf etwa 600C erwärmt. Nach dem Abdestillieren des Lösungsmittels unter vermindertem Druck wird der verbleibende Rückstand in verdünntem HCl gelöst und über Aktivkohle filtriert. Die klare wäßrige Lösung wird dann mit NaOH alkylisch gestellt. Die ausfallenden basischen Anteile werden in Äther aufgenommen, die ätherische Phase wird über MgSO4 getrocknet und der Äther abdestilliert. Der verbleibende ölige Rückstand wird in Äthanol gelöst und durch Zugabe von ätherischer HCl das Hydrochlorid ausgefällt. Nach der Isolierung des Kristallisats wird noch zweimal aus Äthanol unter Zugabe von Äther umkristallisiert, Fp: 172 bis 174° C.12 g (0.07 mol) 1- (2-ethynylphenoxy) -2-hydroxy-3-tert-butylaminopropane are dissolved in 100 ml methanol and 18 g (0.025 mol) tert-butylamine are added, the mixture is left to stand overnight at room temperature, then Heated to about 60 ° C. for 2 hours. After the solvent has been distilled off under reduced pressure, the residue that remains is dissolved in dilute HCl and filtered through activated charcoal. The clear aqueous solution is then made alkyl with NaOH. The precipitating basic components are taken up in ether, the ethereal phase is dried over MgSO 4 and the ether is distilled off. The remaining oily residue is dissolved in ethanol and the hydrochloride is precipitated by adding ethereal HCl. After the isolation of the crystals, it is recrystallized twice more from ethanol with the addition of ether, melting point: 172 to 174 ° C.
B ei s ρ i e 1 3B ei s ρ i e 1 3
l-(2-Äthinylphenoxy)-2-hydroxy-3-sek.butylaminopropan · HCl1- (2-Ethynylphenoxy) -2-hydroxy-3-sec-butylaminopropane · HCl
Das aus 10,4 g (0,088 Mol) 2-Äthinylphenol und 8,8 g (0,095 Mol) Epichlorhydrin gewonnene rohe l-(2-Äthinylphenoxy)-2,3-epoxypropan (13,8 g) wird in 120 ml Äthanol mit 22 g (0,3 Mol) sek.Butylamin durch zweistündiges Erhitzen umgesetzt. Nach dem Abdestillieren der Lösungsmittel im Vakuum wird der Rückstand mit verdünnter HCl verrührt, mit Äther extrahiert und die wäßrige Phase mit NaOH alkalisch gestellt. Die ausfallende ölige Base wird in Äther aufgenommen, mit H2O gewaschen, über MgSO4 getrocknet und der Äther abdestilliert. Der feste Rückstand wird aus Essigester und Petroläther umkristallisiert. Die Base wird sodann in Äthanol gelöst, mit ätherischer HCl angesäuert und das ausfallende Hydrochlorid isoliert. Ausbeute 7,4 g, Fp: 149 bis 151°C.The crude l- (2-ethynylphenoxy) -2,3-epoxypropane (13.8 g) obtained from 10.4 g (0.088 mol) of 2-ethynylphenol and 8.8 g (0.095 mol) of epichlorohydrin is dissolved in 120 ml of ethanol with 22 g (0.3 mol) of sec-butylamine reacted by heating for two hours. After the solvents have been distilled off in vacuo, the residue is stirred with dilute HCl, extracted with ether and the aqueous phase is made alkaline with NaOH. The precipitated oily base is taken up in ether, washed with H 2 O, dried over MgSO 4 and the ether is distilled off. The solid residue is recrystallized from ethyl acetate and petroleum ether. The base is then dissolved in ethanol, acidified with ethereal HCl and the precipitating hydrochloride is isolated. Yield 7.4 g, m.p .: 149-151 ° C.
B. FormulierungsbeispieleB. Formulation Examples
1. Depotdragees Kern1. Depot dragees core
1 -(2-Äthiny lphenoxy)-2-hydroxy-1 - (2-ethynylphenoxy) -2-hydroxy-
3-isopropylaminopropan ■ HCl .. 40,0 g3-isopropylaminopropane ■ HCl .. 40.0 g
Carboxymethylcellulose (CMC) ... 300,0 gCarboxymethyl cellulose (CMC) ... 300.0 g
Stearinsäure 20,0 gStearic acid 20.0 g
Celluloseacetatphthalat (CAP) 40,0 g Cellulose acetate phthalate (CAP) 40.0 g
400,0 g400.0 g
Herstellung der DrageesProduction of the coated tablets
Der Wirkstoff, die CMC und die Stearinsäure werden intensiv gemischt und die Mischung in üblicher Weise granuliert, wobei man eine Lösung des CAP in 200 ml eines Gemisches aus Äthanol/Äthylacetat verwendet. Das Granulat wird dann zu 380-mg-Kernen verpreßt, die in üblicher Weise mit einer zuckerhaltigen 5% igen Lösung von Polyvinylpyrrolidon in Wasser überzogen werden. Jedes Dragee enthält 25 mg Wirkstoff. The active ingredient, the CMC and the stearic acid are mixed intensively and the mixture in the usual way Granulated way, a solution of the CAP in 200 ml of a mixture of ethanol / ethyl acetate used. The granules are then compressed into 380 mg cores, which are then mixed with a sugary one in the usual way 5% solution of polyvinylpyrrolidone in water. Each coated tablet contains 25 mg of active ingredient.
2. Injektionslösung2. Solution for injection
Die Lösung wird aus folgenden Bestandteilen hergestellt: The solution is made from the following components:
1 -(2-Äthinylphenoxy)-2-hydroxy-3-tert.butylaminopropan ·1 - (2-Ethynylphenoxy) -2-hydroxy-3-tert-butylaminopropane ·
HCl 2,5 TeileHCl 2.5 parts
Natriumsalz der EDTAEDTA sodium salt
(Äthylendiamintetra-(Ethylenediamine tetra-
essigsäure) 0,2 Teileacetic acid) 0.2 parts
Destilliertes Wasser. 100,0TeileDistilled water. 100.0 parts
HerstellungManufacturing
Der Wirkstoff und das EDTA-SaIz werden in genügend Wasser gelöst und mit Wasser auf das gewünschte Volumen aufgefüllt. Die Lösung wird frei von suspendierten Partikeln filtriert und in 1-ccm-Ampullen unter aseptischen Bedingungen abgefüllt. Zuletzt werden die Ampullen sterilisiert und verschlossen. Jede Ampulle enthält 25 mg Wirkstoff.The active ingredient and the EDTA salt are in sufficient Dissolved water and made up to the desired volume with water. The solution becomes free filtered of suspended particles and filled into 1 cc ampoules under aseptic conditions. Last the ampoules are sterilized and sealed. Each ampoule contains 25 mg of active ingredient.
VergleichsversuchComparative experiment
Die wertvollen Eigenschaften der erfindungsgemäßen Substanzen wurden durch Messung der Herzfrequenz an lebenden Meerschweinchen in Urethan-Narkose bestimmt. Die jeweils geprüfte Dosis wurde intravenös injiziert. Dann wurde 1 y/kg des eine Tachycardie verursachenden Sympathicomimeticums Isoproterenol injiziert und die maximale Änderung der Herzfrequenzen beobachtet. (Bestimmung der sogenannten Isoproterenol - antagonistischen Wirkung). Die Prüfung der erfindungsgemäßen Substanz erfolgte beginnend bei 0,1 g/kg nacheinander in 5 ansteigenden Dosen am gleichen Tier. Jede Substanz wurde auf diese Weise an vier verschiedenen Tieren geprüft. Als Standardsubstanz diente das bekannte /i-Adrenolyticum 3,4-Dichlorisoproterenol (DCI), dessen Wirkung gleich 1 gesetzt wurde.The valuable properties of the substances according to the invention were determined by measuring the heart rate determined on live guinea pigs under urethane anesthesia. The dose tested in each case was injected intravenously. Then 1 y / kg of one became tachycardia causative sympathicomimetic isoproterenol injected and the maximum change in Heart rates observed. (Determination of the so-called isoproterenol - antagonistic effect). The substance according to the invention was tested, starting at 0.1 g / kg, in 5 increasing steps one after the other Cans on the same animal. Each substance was tested in this way on four different animals. as The standard substance was the well-known / i-Adrenolyticum 3,4-dichloroisoproterenol (DCI), the effect of which was set equal to 1.
Wirkungantagonistic
effect
309 537/541309 537/541
Claims (3)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19671618160 DE1618160C3 (en) | 1967-05-18 | 1967-05-18 | 1- (2-Ethynylphenoxy) -2-hydroxy-3alkylaminopropanes, their physiologically acceptable acid addition salts, processes for their preparation, and pharmaceuticals containing these compounds |
| AT479468A AT297681B (en) | 1967-05-18 | 1968-05-17 | Process for the preparation of new äthinyl-substituted 1-phenoxy-2-hydroxy-3-butylaminopropanes, their optically active isomers and acid addition salts |
| AT953970A AT297683B (en) | 1967-05-18 | 1968-05-17 | Process for the preparation of new äthinyl-substituted 1-phenoxy-2-hydroxy-3-alkylaminopropanes, their optically active isomers and acid addition salts |
| AT953870A AT297682B (en) | 1967-05-18 | 1968-05-17 | Process for the preparation of new äthinyl-substituted 1-phenoxy-2-hydroxy-3-alkylaminopropanes, their optically active isomers and acid addition salts |
| AT954070A AT297684B (en) | 1967-05-18 | 1968-05-17 | Process for the preparation of new äthinyl-substituted 1-phenoxy-2-hydroxy-3-alkylaminopropanes, their optically active isomers and acid addition salts |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19671618160 DE1618160C3 (en) | 1967-05-18 | 1967-05-18 | 1- (2-Ethynylphenoxy) -2-hydroxy-3alkylaminopropanes, their physiologically acceptable acid addition salts, processes for their preparation, and pharmaceuticals containing these compounds |
| DEB0092594 | 1967-05-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1618160A1 DE1618160A1 (en) | 1972-04-13 |
| DE1618160B2 true DE1618160B2 (en) | 1973-09-13 |
| DE1618160C3 DE1618160C3 (en) | 1974-04-25 |
Family
ID=25753761
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19671618160 Expired DE1618160C3 (en) | 1967-05-18 | 1967-05-18 | 1- (2-Ethynylphenoxy) -2-hydroxy-3alkylaminopropanes, their physiologically acceptable acid addition salts, processes for their preparation, and pharmaceuticals containing these compounds |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1618160C3 (en) |
-
1967
- 1967-05-18 DE DE19671618160 patent/DE1618160C3/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE1618160A1 (en) | 1972-04-13 |
| DE1618160C3 (en) | 1974-04-25 |
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