IE43798B1 - An ester of an indole-derived aminoalcohol - Google Patents
An ester of an indole-derived aminoalcoholInfo
- Publication number
- IE43798B1 IE43798B1 IE2297/79A IE229779A IE43798B1 IE 43798 B1 IE43798 B1 IE 43798B1 IE 2297/79 A IE2297/79 A IE 2297/79A IE 229779 A IE229779 A IE 229779A IE 43798 B1 IE43798 B1 IE 43798B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- indole
- ester
- addition salt
- Prior art date
Links
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 title 1
- 150000002148 esters Chemical class 0.000 title 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 150000003839 salts Chemical group 0.000 claims description 8
- 239000012458 free base Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 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 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229940039009 isoproterenol Drugs 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-M malonate(1-) Chemical compound OC(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000001800 adrenalinergic effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000004116 glycogenolysis Effects 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 230000004130 lipolysis Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- UUOJIACWOAYWEZ-UHFFFAOYSA-N 1-(tert-butylamino)-3-[(2-methyl-1H-indol-4-yl)oxy]propan-2-yl benzoate Chemical compound C1=CC=C2NC(C)=CC2=C1OCC(CNC(C)(C)C)OC(=O)C1=CC=CC=C1 UUOJIACWOAYWEZ-UHFFFAOYSA-N 0.000 description 1
- AYILGIIGTGQSTA-UHFFFAOYSA-N 2-methyl-3-propoxy-1H-indole Chemical class O(CCC)C1=C(NC2=CC=CC=C12)C AYILGIIGTGQSTA-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- -1 3-aminopropoxy Chemical class 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010058177 Hyperkinetic heart syndrome Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000001871 Tachycardia Diseases 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
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000001834 epinephrinelike Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 208000009157 neurocirculatory asthenia Diseases 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 206010042431 subvalvular aortic stenosis Diseases 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
The present invention relates to a 3-amino-. propoxy-2-methyl-indole derivative.
British patent specification No. 1'-35G'31O 5 discloses and claims a class of 3-aminopropoxy~indole derivatives having a blocking effect on the adrenergic p-receptors.
The present invention provides 4-(2-benzoyloxy-3-tert butylaminopropoxy)-2-methyl-indole of formula I, -la43798 - 2 not specifically described in British patent specification No. l'356'31O which has now been found to have more benefi cial effects than would have been expected for such a compound, i.e. exceptionally good tolerability and parti5 cularly high and long lasting activity having regard to the generality of the compounds specifically disclosed and claimed in British patent specification No. 1'356*310.
The present invention also provides a process for the production of the compound of formula I as defined above, which comprises esterifying the compound of formula II, The present process may for example be effected in conventional manner as described in the Example and in our copending application No. 1791/76 (patent specification No. 43797) for analogous compounds.
The compound of formula II is known.
The compound of formula I can, by virtue of the asymmetric carbon atom in the position p to the oxygen atom bound to the indole nucleus, exist in the form of optically active isomers or as a racemate.
The process of the invention does not alter the configuration of the asymmetrically substituted carbon atom. Accordingly, when a racemic starting material is employed, a racemic final product of formula I is ob25 tained, and when an optically active starting material is employed^corresponding optically active final product - 3 is obtained.
The resulting compound of formula I may be isolated and purified using conventional techniques.
The free base form of the compound of formula I 5 may be converted Into acid addition salt forms and vice-versa in conventional manner.
In the following non-limitative Example , all temperatures are indicated in degrees Centigrade and are uncorrected.
EXAMPLE; 4- (2-benzoyloxy~3-tert.butylamlnopropoxy)26 g of henzoic acid are dissolved, while heating, in 50 cc of hexamethylphosphoric acid triamide and 3.5 g of l-tert.butylamino-3-(2-methyl-indole-4yloxy)-2-propanol are added. After cooling, 3.0 g of benzoic acid anhydride are added and stirring is effected for 20 hours at room temperature. The resulting clear, yellow solution is poured onto ice, 0.5 litres of ether are added and stirring is effected for 2 hours. After making the liquid alkaline with concentrated ammonia, the ether phase le separated, shaken out with tartaric acid, made alkaline with caustic soda solution while cooling with ice and extracted with methylene chloride. After evaporating the solvent, the residue is crystallised with 1 mol of fumaric acid from methanol and acetone. M.p. of hydrogen fumarate form: 189-191°.
In analogous manner, but employing appropriate, optically active starting material in approximately equivalent amounts, the compound of formula I can be obtained in (S) form (M.P. of the hydrogen malonate 95°) and in (R) form (M.P. of the hydrogen malonate 95°) .
The compound of formula I exhibits pharmacological activity. In particular, the compound exhibits a blocking effect on the adrenergic p receptors (a p-blocking effect) as indicated in standard tests, for example, by an inhibition of the positive inotropic - 5 adrenaline effect in the spontaneously beating guineapig atrium and by an inhibition of the tachycardia and hypotension induced by isoproterenol in anaesthetized cats in the infusion test.
Additionally, the compound exhibits an antiarrhythmic affect as indicated in standard tests, for example, as demonstrated in mice according to the method of Lawson, J.W., J. Pharmac. Exp. Ther. 160 (1968) 22-31.
Furthermore, the compound of formula I inhibits lipolysis induced by isoproterenol as indicated by standard tests. For example, in vitro, the inhibition of lipolysis can be observed in isolated fat cells-taken from the epidymal fat tissue of rats, the cells having been isolated in accordance with the method of M. Rodbell [J.Biol, Chem. 239 (1964} 375-380].
In addition, the compound inhibits isoproterenol-induced glycogenolysis as indicated by standard tests, for example by an inhibition of glycogenolysis stimulated by isoproterenol in vivo in rats.
The compound is therefore indicated for use as a p-blocking agent. Such agents are indicated for use inter alia in the prophylaxis and therapy of coronary diseases, especially in the treatment of Angina pectoris, in the treatment of the hyperkinetic heart syndrome and the conditions resulting from a muscular hypertrophic subvalvular aortic stenosis. - 6 An indicated daily dose is from about 1 to 10 mg; it may be administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 5 mg, or in sustained release form.
The (S)-enantiomer of the compound of formula I and acid salt forms thereof are more active than the corresponding (R)-enantiomers, and accordingly the compound is preferably in racemic Or S enantiomeric form.
The compound of formula 1 may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the Game order of activity as the free base form and are readily prepared in conventional manner. Representative acid addi15 tion salt forms include the fumarate, hydrogen fumarate and hydrogen malonate.
The present invention also provides a pharmaceutical composition comprising the compound of formula X, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be in the form of, for example, a solution or a capsule.
Claims (9)
1. A process for the production of the compound 5 which comprises esterifying the compound of formula II,
2. A process for the production of the compound of formula I, stated in Claim 1, substantially as hereinbefore described with reference to the Example. 10
3. The compound of formula I, whenever produced by a process according to Claim 1 or 2.
4. The compound of formula I, as defined in Claim 1.
5. , The compound of claims 3 or 4, In the form of a racemate. 15
6. The compound of claims 3 or 4, in (S) enantiomeric form.
7. The compound of any one of claims 3 to 6, in free base form.
8. The compound of any o ne of claims 3 to 6, in acid addition salt form.
9. A pharmaceutical composition comprising a compound according to any one of claims 3 to 6 in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutically acceptable carrier or diluent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1071475 | 1975-08-15 | ||
| IE1791/76A IE43797B1 (en) | 1975-08-15 | 1976-08-13 | Esters of indole-derived amino alcohols |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE43798L IE43798L (en) | 1977-02-15 |
| IE43798B1 true IE43798B1 (en) | 1981-06-03 |
Family
ID=25707119
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2297/79A IE43798B1 (en) | 1975-08-15 | 1976-08-13 | An ester of an indole-derived aminoalcohol |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE43798B1 (en) |
-
1976
- 1976-08-13 IE IE2297/79A patent/IE43798B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE43798L (en) | 1977-02-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed | ||
| HK2 | Errata: patent lapsed |