CA1129416A - Carbazolyl-(4)-oxypropanolamine derivatives - Google Patents
Carbazolyl-(4)-oxypropanolamine derivativesInfo
- Publication number
- CA1129416A CA1129416A CA324,667A CA324667A CA1129416A CA 1129416 A CA1129416 A CA 1129416A CA 324667 A CA324667 A CA 324667A CA 1129416 A CA1129416 A CA 1129416A
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- Prior art keywords
- oxy
- propan
- carbazolyl
- ethylamino
- process according
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
Abstract
ABSTRACT OF THE DISCLOSURE
New carbazolyl-(4)-oxypropanolamine derivatives and their process of preparation are provided of formula (I):
(I) wherein R1 is a hydrogen atom, a lower alkanoyl radical or an aroyl radical: R2 is a hydrogen atom, a lower alkyl radical or an ar-lower-alkyl radical: R3 is a hydrogen atom or a lower alkyl radical, R4 is a hydrogen atom or a lower alkyl radical or, when X is an oxygen atom, together with R5 can also represent a -CH2-O- radical X is a valency bond. a -CH2- radical or an oxygen or sulphur atom: Ar is a mono-or bicyclic hydrocarbon radical or a pyridyl radical and R5 and R6, which can be the same or different, are selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, aminocarbonyl, lower alkoxy, ar-lower-alkyloxy, lower alkylthio, lower alkylsulphinyl and lower alkylsulphonyl:
or R5 and R6 together represent a methylenedioxy radical:
and the pharmaceutically acceptable, pharmacologically or physiologically compatible acid addition salts thereof with non-toxic physiologically acceptable inorganic or organic acids, the new derivatives show, in pharmacological tests, vasodilatory and .beta.-receptor-blocking actions they are, there-fore, suitable for the treatment of prophylaxis of circulatory and cardiac diseases, for example, of hypertension and angina pectoris.
New carbazolyl-(4)-oxypropanolamine derivatives and their process of preparation are provided of formula (I):
(I) wherein R1 is a hydrogen atom, a lower alkanoyl radical or an aroyl radical: R2 is a hydrogen atom, a lower alkyl radical or an ar-lower-alkyl radical: R3 is a hydrogen atom or a lower alkyl radical, R4 is a hydrogen atom or a lower alkyl radical or, when X is an oxygen atom, together with R5 can also represent a -CH2-O- radical X is a valency bond. a -CH2- radical or an oxygen or sulphur atom: Ar is a mono-or bicyclic hydrocarbon radical or a pyridyl radical and R5 and R6, which can be the same or different, are selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, aminocarbonyl, lower alkoxy, ar-lower-alkyloxy, lower alkylthio, lower alkylsulphinyl and lower alkylsulphonyl:
or R5 and R6 together represent a methylenedioxy radical:
and the pharmaceutically acceptable, pharmacologically or physiologically compatible acid addition salts thereof with non-toxic physiologically acceptable inorganic or organic acids, the new derivatives show, in pharmacological tests, vasodilatory and .beta.-receptor-blocking actions they are, there-fore, suitable for the treatment of prophylaxis of circulatory and cardiac diseases, for example, of hypertension and angina pectoris.
Description
llZ9~6 The present invention is concerned with new carba-zolyl-(4)-oxypropanolamine derivatives and their preparation.
West German Patent 2,240,599, Leinert et al, issued February, 5, 1976, describes carbazole derivatives which block the activity of the ~-receptors of the sympathicus.
The new derivatives of the invention and their physiologically acceptable salts thereof show, in pharma-cological tests, vasodilatory and ~-receptor-blocking actions.
They are, therefore, suitable for the treatment and prophylaxis of circulatory and cardiac diseases, for example, of hyper-tension and angina pectori~.
According to the invention there are provided new carbazolyl-(4)-oxypropanolamine derivatives of formula (I):-, ~ R6 0-CH2-CIH-CH2-N - CH - CH - X -~ Ar J ( I) R2 R3 R4 \~__~ 5 H
wherein Rl is a hydrogen atom, a lower alkanoyl radical or an aroyl radical; R2 i~ a hydrogen atom, a lower alkyl radical or an ar-lower-alkyl radical; R3 is a hydrogen atom or a lower alkyl radical; R4 is a hydrogen atom or a lower alkyl radical or, when X is an oxygen atom, together with R5 can also represent a -CH2-O- radical; X is a valency bond, a -CH2- radical or an oxygen or sulphur atom; Ar is a mono-or bicyclic hydrocarbon radical or a pyridyl radical; and R5 and R6, which can be the same or different, are selected from the group consisting of hydrogen, halogen, hydroxyl, l~Z941~
lower alkyl, aminocarbonyl, lower alkoxy, ar-lower-alkyloxy, lower alkylthio, lower alkylsulphinyl and lower alkylsulphonyl, or R5 and R6 together represent a methylenedioxy radical;
and the pharmaceutically acceptable, pharmacologically or physiologically compatible acid addition salts thereof with non-toxic physiologically acceptable inorganic or organic acids~
The lower alkyl radicals of the substituents R2, R3, R4, R5 and R6 suitably contain 1 to 6 and preferably 1 to 4 carbon atoms and can be straight-chained or branched, Preferred alkyl radicals are the methyl, ethyl, isopropyl, tert.-butyl and n-butyl radicals.
The lower alkanoyl radicals in the definition of R
suitably contain 1 to 6 carbon atoms, preferred alkanoyl radicals being the formyl, acetyl, propionyl and pivaloyl radicals.
The aroyl radicals in the definition of Rl suitably contain 7 to 11 carbons, the preferred radicals being benzoyl and naphthoyl.
The ar-lower-alkyl radicals in the definition of R2 suitably contain 7 to 11 carbon atoms, and preferably contain 1 to 4 carbon atoms, straight chained or branched in the alkyl moiety, preferred radicals include benzyl, phenyl-ethyl and phenylpropyl with the benzyl radical being most preferred.
The halogen atom in the definition of R5 and R6 is to be understood to be a fluorine, chlorine or bromine atom.
The lower-alkoxy, alkylthio, alkylsulphinyl and alkyl-sulphonyl radicals in the definition of R5 and R6 suitably contain l-to 6 and preferably 1 to 4 carbon atoms, the preferred radicals being the methoxy, ethoxy, methylthio, 1~294:16 methylsulphinyl and methylsulphonyl radicals.
The ar-lower-alkyloxy radical in the definition of R5 and R6 suitably contains 7 to 11 carbon atoms, the aryl moiety being phenyl or naphthyl, preferably phenyl, and the alkyl moiety suitably containing 1 to 4 carbon atoms, the benzyloxy radical being preferred.
When Ar is a cyclic mono- or bicyclic hydrocarbon radical, it iR suitably an aryl radical but the ring can also be partly hydrogenated, Suitably Ar will contain 6 to 10 carbon atoms. Preferred radicals include the phenyl, naphthyl, indanyl and tetrahydronaphthyl radicals.
A particular example of a radical in which R4 and R5 together form a -CH2-O- radical, when X is an oxygen atom, is the 1,4-benzodioxanyl-(2)-methyl radical.
In another aspect of the invention there is provided a process for preparing the novel derivatives of formula (I) and their salts, as defined above compriqing:
a) reaction of a compound of the formula (II):-
West German Patent 2,240,599, Leinert et al, issued February, 5, 1976, describes carbazole derivatives which block the activity of the ~-receptors of the sympathicus.
The new derivatives of the invention and their physiologically acceptable salts thereof show, in pharma-cological tests, vasodilatory and ~-receptor-blocking actions.
They are, therefore, suitable for the treatment and prophylaxis of circulatory and cardiac diseases, for example, of hyper-tension and angina pectori~.
According to the invention there are provided new carbazolyl-(4)-oxypropanolamine derivatives of formula (I):-, ~ R6 0-CH2-CIH-CH2-N - CH - CH - X -~ Ar J ( I) R2 R3 R4 \~__~ 5 H
wherein Rl is a hydrogen atom, a lower alkanoyl radical or an aroyl radical; R2 i~ a hydrogen atom, a lower alkyl radical or an ar-lower-alkyl radical; R3 is a hydrogen atom or a lower alkyl radical; R4 is a hydrogen atom or a lower alkyl radical or, when X is an oxygen atom, together with R5 can also represent a -CH2-O- radical; X is a valency bond, a -CH2- radical or an oxygen or sulphur atom; Ar is a mono-or bicyclic hydrocarbon radical or a pyridyl radical; and R5 and R6, which can be the same or different, are selected from the group consisting of hydrogen, halogen, hydroxyl, l~Z941~
lower alkyl, aminocarbonyl, lower alkoxy, ar-lower-alkyloxy, lower alkylthio, lower alkylsulphinyl and lower alkylsulphonyl, or R5 and R6 together represent a methylenedioxy radical;
and the pharmaceutically acceptable, pharmacologically or physiologically compatible acid addition salts thereof with non-toxic physiologically acceptable inorganic or organic acids~
The lower alkyl radicals of the substituents R2, R3, R4, R5 and R6 suitably contain 1 to 6 and preferably 1 to 4 carbon atoms and can be straight-chained or branched, Preferred alkyl radicals are the methyl, ethyl, isopropyl, tert.-butyl and n-butyl radicals.
The lower alkanoyl radicals in the definition of R
suitably contain 1 to 6 carbon atoms, preferred alkanoyl radicals being the formyl, acetyl, propionyl and pivaloyl radicals.
The aroyl radicals in the definition of Rl suitably contain 7 to 11 carbons, the preferred radicals being benzoyl and naphthoyl.
The ar-lower-alkyl radicals in the definition of R2 suitably contain 7 to 11 carbon atoms, and preferably contain 1 to 4 carbon atoms, straight chained or branched in the alkyl moiety, preferred radicals include benzyl, phenyl-ethyl and phenylpropyl with the benzyl radical being most preferred.
The halogen atom in the definition of R5 and R6 is to be understood to be a fluorine, chlorine or bromine atom.
The lower-alkoxy, alkylthio, alkylsulphinyl and alkyl-sulphonyl radicals in the definition of R5 and R6 suitably contain l-to 6 and preferably 1 to 4 carbon atoms, the preferred radicals being the methoxy, ethoxy, methylthio, 1~294:16 methylsulphinyl and methylsulphonyl radicals.
The ar-lower-alkyloxy radical in the definition of R5 and R6 suitably contains 7 to 11 carbon atoms, the aryl moiety being phenyl or naphthyl, preferably phenyl, and the alkyl moiety suitably containing 1 to 4 carbon atoms, the benzyloxy radical being preferred.
When Ar is a cyclic mono- or bicyclic hydrocarbon radical, it iR suitably an aryl radical but the ring can also be partly hydrogenated, Suitably Ar will contain 6 to 10 carbon atoms. Preferred radicals include the phenyl, naphthyl, indanyl and tetrahydronaphthyl radicals.
A particular example of a radical in which R4 and R5 together form a -CH2-O- radical, when X is an oxygen atom, is the 1,4-benzodioxanyl-(2)-methyl radical.
In another aspect of the invention there is provided a process for preparing the novel derivatives of formula (I) and their salts, as defined above compriqing:
a) reaction of a compound of the formula (II):-
2 1 2 ROl' (II) N
wherein Y is a reactive group and Rl' has the same meaning as given above for Rl or Y and Rl' together signify a valency bond, with a compound of the formula (III):-HN - CH - CH - X ~ R6 (III) 1~94~6 wherein R2, R3, R4, X, Ar, R5 and R6 have the same meanings as above; or b) reaction of a compound of formula (IV):-O - CH - CH - CH2 - ~H
~ Rl R2 (IV) wherein Rl and R2 have the same meanings as above, with a compound of the formula (V):-~ 6 Y - CH - IH - X ~ (V) wherein Y, R3, R4, X, Ar, R5 and R6 have the same meanings as above; or c) reduction of a mixture of a compound of formula (IV), as defined above, and of a compound of the formula (VI):-~R6 O = I - CH ~ X ~ R5 (VI) in which R3, R4, X, Ar, R5 and R6 have the same meanings as above, or d) reaction of a compound of formula (IV), as defined above, with a compound of the formula (VII):-1~29416 C - CH - X ~ R6 (VII) in which Y, R4, X, Ar, R5 and R6 have the same meanings as above, and the amide obtained is reduced, whereupon, if desired, the compound thus obtained of formula (I) is con-verted into a different compound of formula (I), and, if desired, a compound of formula (I) obtained is converted into a pharmaceutically acceptable, pharmacologically or physiologically compatible acid addition salt with a non-toxic, physiologically acceptable inorganic or organic acid.
The reactive group Y in the compounds of formulae (II), (V) and (VII) is a leaving group in an SN nucleo-philic substitution reaction displaceable by amino. Suitably Y is an acid residue for.example of a hydrohalic acid or of a sulphonic acid, Suitable radicals Y include chloride, bromide, tosyl, brosyl and mesyl.
Processes a) and b) are suitably carried out in an organic solven`t which is inert under the reaction conditions, for example, toluene, dioxan, ethylene glycol dimethyl ether, isopropanol or dimethylformamide, optionally in the presence .
of an acid-binding agent.
The reaction of an epoxide of formula (II) (Y and R' together represent a valency bond) with an amine of formula (III) can, however, also be accomplished after mixing the reaction components, by leaving the reaction mixture to stand at ambient temperature or by heating, llZ9416 According to process c), an amine of formula (IV) is hydrogenated with a carbonyl compound of formula (VI);
~uitably the process is carried out in an inert solvent, for example, methanol, in the presence of a catalyst, for example, Raney nickel.
The amides obtained according to process d) are preferably reduced by means of complex metal hydrides, for example, lithium aluminium hydride.
Compounds of formula (I) in which Rl is a hydrogen atom can be esterified by reaction with an acid or reactive acid derivative, for example, acid halide or acid anhydride, possibly in the presence of an acid-binding agent, for example, pyridine or triethylamine, and benzyl protective groups possibly present can be removed by catalytic hydro-genation in the presence of noble metal catalysts.
The qtarting compounds employed in the processes of the invention are, as a rule, known from the literature.
The new derivatives can ge~erally be obtained analogously to the processes known for the preparation of the known compounds, Thu~, amines of formula (III) are preferably pre-pared by reacting haloalkyl nitriles with appropriate phenols, naphthols or aryl compounds, for example, chloroacetonitrile and phenol, with subsequent hydrogenation in the presence of ammonia, The amines of formula (IV) can be obtained from the known 4-(2,3-epoxypropoxy)-carbazole (cf. West German Patent No, 2,240,599 Leinert et al, issued February 5, 1976,) by reaction with liquid ammonia.
Reactive compounds of formula (V), for example, E~
toluenesulphonic acid esters, are, as a rule, prepared from the appropriate phenols, naphthols or aryl compounds by reaction ~294~6 with haloalcohols and subsequent esterification with ~-toluenesulphonic acid.
The carbonyl compounds of formula (VI) and acid chlorides of formula (VII) can be obtained from the appropriate phenols, naphthol~ and aryl compound~ by reaction with apprOpriate haloalkyl compounds.
A subsequent conversion of a compound of formula (I) into another compound of formula (I) can take place, for example, by oxidation, for example, conversion of an alkyl-thio radical into an alkylsulphinyl or alkylsulphonyl radical.Hydroxyl group~ can be etherified or esterified according to known methods, ester and ether groups can be converted by known methods into hydroxyl groups and an ar-lower-alkyl group can be removed by hydrogenation, forlexample, when R2 is benzyl it may be hydrogenated to a hydrogen atom R2.
For conversion of derivatives of formula (I) into their pharmaceuticall~ acceptable, pharmacologically or physiologically compatible acid addition salts, the derivatives of formula (I) are reacted, preferably in an organic solvent, with an equivalent amount of a non-toxic inorganic or organic acid, for example, hydrochloric acid, phosphoric acid, sulphuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
In the specification it will be understood that the qualification that the salts be "pharmaceutically accept-able" means that the salts have the necessary physical characteristics, for example, stability, to render them suit-able for formulation into pharmaceutical compositions. The qualification that the salts be "physiologically or pharma-cologically compatible" is to be understood, as extendingto salts of non-toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be un-112~6 suitable for administration to living bodies.
Salts of compounds of formula (I) which are notpharmaceutically acceptable and physiologically or pharma-cologically compatible form a useful aspect of the invention of the novel derivatives, inasmuch as they can be readily converted, by conventional means, to different salts having the required physical and chemical characteristics to make them suitable for admini~tration in pharmaceutical com~
positions to living bodies.
The derivativeq of formula (I) of the invention can be resolved by known methods, via diastereomeric salts, into the optically-active forms. For the resolution of the race-mates, there can be used, for example, tartaric acid, malic acid, camphoric acid or camphorsulphonic acid.
For the preparation of pharmaceuticals, the new compounds (I) of the invention are mixed in the usual manner with appropriate pharmaceutical carrier materials and aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, ~uspended or dissolved in water or in an oil, for example, olive oil.
The new compounds (I) of the invention and the acceptable salts thereof can be administered enterally or parenterally in liquid or solid form. Aq injection medium, it is preferable to uqe water which contains the additives usual in the case of injection solutions, such as stabilising agents, solubilising agents and/or buffers. Additives of this type include, for example, tartrate and citrate buffers, ethanol, complex-forming agents (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (such as liquid polyethylene oxide) 11294~6 for viscosity regulation. Solid carrier materials are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols).
Compositions suitable for oral administration can, if desired, contain flavouring and/or sweetening materials.
The dosages to be administered will, of course, depend on the patient and must be decided by the patient's physician. Convenient unit~ of dosage are dragees contain-ing 25 mg of the compound of the invention; however, the dosage unit may vary from 10 to 300 mg. It i~ recommended that use of the compound of the invention be introduced gradually. For example, in the case of dragees containing 25 mg of active ingredient, an initial treatment with 1 to 4 dragees daily may be suitable and this may be increased to 1 to 4 dragees four times daily in serious cases. Treatment after initial introduction is suitably maintained at 1 dragee two, three or four times daily.
It will be understood that the dosage schedule for blood pressure lowering is entirely dependent on the condition of the patient, e.g., a human or animal mammal, the response of the patient to the treatment and whether or not the patient is ambulatory or hospitalized. The treatment should suitably begin with small doses (100 mg) and increase gradually depending upon the patient's response. The dosage can be increased at 5 to 7 day intervals until an average daily dose of 100 to 300 mg is reached. For maintenance, two to four doses a day are usually required. The dosages for inhibition of adrenergic ~-receptors are substantially the same _ g _ ~ ~29~6 The effectiveness of the compounds (I) of the invention as vaso-dialators and beta-receptor blockina agents is illustrated by the following tests:
A - Vaso Dilator ex~eriments Rabbits were anesthesized with urethane and a catheter implanted in the middle ear artery (A, femoralis) for a continuous measurement of their arterial blo~d pressure.
The blood pressure measurements were effected using an electro-mechanical transducer (Statham P 23 Db)* and were recorded on ,a direct printer and utilized after calibration with a mercury manometer.
After determination of the starting value both jugular arteries (A. carotis) were occluded for two minutes and blood pressure thereby temporarily increased (CSE-reflex). The test compound was then injected at the lowest experimental dosage (0.125 mg/kg) intravenourly and eight minutes later the CSE-reflex was again induced. In intervals of 15 minutes, the test compound was again injected in logarithmically increased dosaae (Factor ~) and the CSE-reflex again induced.
Test compounds which under these conditions moderated the CSE-induced blood pressure increase were demonstrated to be vaso-dilators and the dosage which decreased the CSE-reflex by 30 mm Hg was determined (designated as DE 30mm Hg in the Table below).
B - Beta Receptor Blockina Activity Experiments The heart beat frequency of rabbits was monitored via implanted electrodes and recorded on a frequency counter having a measurement time of 15 seconds. Isoprenalin was then injected intravenously via an ear view, inducing an increase in heart beat frequency of from ca. 200 beats/min. to 330 beats/min. Subsequently, the test compounds were administered *trademark -- 10 _ 11~9~
in increased dosage (as in Experiment A) intravenously and the heart frequency increase after isoprenalin treatment again recorded, The inhibition of isoprenalin tachycardia was taken as a measure of the beta-blockade activity of the test compounds. The dosage which limited the isoprenalin induced heart frequency increase to 250 beats/min. was determined for each test substance and is hereinafter designated DE250.
The results from the above experiments A and B are set forth in Table I below. The determination of the equal effectiveness dosages, i.e., DE_30 mm Hg 250 determined on a logorithmic basis from four to six individual experiments and then the quotient of the vaso dilating dosage (DE 30 mm Hg) to the beta-blockade dosage (DE250) was calculated. A high quotient was taken to indicate test compounds exhibiting ~ubstantially beta-blocking activity, whereas the test compounds with a quotient of about 1 were regarded as exhibiting both beta-blocking and vaso dilating activity, to a comparable degree.
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O d' O ~ O ~; ~ H ~1 1~ ~ 0 ~1 0 ~1--- ~1 ~ r-l a) 1--l ~li lc 11294~6 The results indicate that the inventive compoundsbalance vaso dilating and beta-blocking activity to a much greater extent than do the prior art materials.
The compounds of the invention can be employed in the treatment of hypertension or angina pectoris in the dosages indicated previously. The dosage levels will generally be appropriate, both for achieving a vaso dilating effect, i.e., for reducing blood pressure, and for inhibition of adrenergic beta-receptor activity.
112g416 The following Examples are given for the purpose of illustrating the present invention in particular and preferred embodiments.
It will be understood that different products of the invention will be obtained by appropriate variations of the ~tarting materials.
Example 1, (process a)) l-rCarbazolyl-(4)-oxyl-3-r2-(2-methoxYphenyl)-ethylami propan-2-ol 6.0 g. 4-(2,3-Epoxypropoxy)-carbazole and 7.6 g.
2-(2-methoxyphenyl)-ethylamine are stirred for 20 hours at 70GC. ~he reaction mixture is then triturated with diethyl ether, filtered with suction and recrystallised from ethyl acetate, with the use of active charcoal and fullers' earth. There are obtained 6.0 g. (61% of theory) of the de~ired compound in the form of colourless crystals;
m.p. 135 - 136C.
The following compounds are obtained in an analogous manner: i a) l-rcarbazolx1-54~-oxyl-3- r 2-(3,4-dimethoxv~henvl)-- 20 ethylam-inol-propan-2-ol yield 42% of theory, m.p. 129 - 130C.; acetate m.p. 180 -from 4-(2,3-epoxypropoxy)-carbazole and 2-(3,4-dimethoxy-phenyl)-ethylamine.
b) l-[carbaæolyl-(4)-oxy]-3-[2-(2-pyridyl)-ethylamino]-propan-2-ol yield 32% of theory, m.p. 105 - 107C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-pyridyl)-ethylamine.
- 14 _ ~1294~6 c) l-rcarbazolyl-(4)-o-xy]-3-r2-(4-pyridyl)-ethylamin ~ propan-2-ol yield 24% of theory; m.p. 86 - 88C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(4-pyridyl)-ethylamine.
d) l-rcarbazolyl-(4)-oxy1-3-(3-phenylpropylamino)-propan-2-ol yield 3~/O of theory, succinate m.p. 98 - 99C., from 4-(2,3-epoxypropoxy)-carbazole and 3-phenylpropylamine.
0 e) l-rcarbazolYl-(4)-oxyl-3-r4-phenvlbutyl-(2)-ami propan-2-ol yield 13% of theory; m.p. 124 - 125C., from 4-(2,3-epoxypropoxy)-carbazole and 4-phenylbutyl-(2)-amine.
Example 2 l-rCarbazolYl-(4)-oxyl-3-r2-methoxyphenoxy -ethYlaminol-propan-2-ol 22.6 g. 4-(2,3-Epoxypropoxy)-carbazole and 17.4 g.
2-(2-methoxyphenoxy)-ethylamine in 75 ml. ethylene glycol dimethyl ether are stirred for 25 hours at 50C. The reaction mixture is evaporated to dryness in a Rotavapor and the residue is triturated with diethyl ether and recrystallized from ethyl acetate, with the use of active charcoal. There are obtained 15.1 g. (39% of theory) of the desired compound in the form of colourless crystals, m.p.ll4 - 115C.
The following compounds are obtained in an analogous manner:
- 15 _ a) l-rcarbazolYl-(4)-oxyl-3-(2-phenoxYethYlamino)-propan-2-ol - yield 32% of theory; m,p. 105 - 107C., from 4-(2,3-epoxypropoxy)-carbazole and 2-phenoxyethylamine~
b) l-rcarbazolyl-(4)-oxyl-3-rl-phenoxypropyl-(2)-aminol-propan- 2- ol yield 31% of theory; hydrochloride m.p. 116 - 119C., from 4-(2,3-epoxypropoxy~-carbazole and 1-phenoxypropyl-(2)-amine, c) l-rcarbazolyl-(4)-oxyl-3-rl,4-benzodiox,anYl-(2)-meth aminol-propan-2-ol yield 28% of theory; m,p, 129 - 131C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(aminomethyl)-1,4-benzodioxan.
d) 1- rcarbazolyl-(4)-oxy 1-3- r2-(4-carbamovlphenoxY)-ethylaminol-propan-2-ol yield 13% of theory, m.p. 120 - 122C., from 4-(2,3-epoxypropox~y)-carbazole and 2-(4-carbamoyl-phenoxy)-ethylamine.
Example 3 1- rCarbazolYl-(4)-oxyl-3- r2-(2-ethoxvphenoxY)-ethvlaminol-propan-2-ol 6,0 g, 4-(2,3-Epoxypropoxy)-carbazole and 9.1 g.
2-(2-ethoxyphenoxy)-ethylamine are stirred for 20 hours at 70C, After cooling, the reaction mixture is stirred with diethyl ether, filtered with suction and the residue re-crystallised from ethyl acetate, with the use of active charcoal and fullers' earth. The yield is 4.4 g. (42% of theory) of the desired compound in the form of colourless crystals: m.p. 127.5 to 128.5C.
The following compounds are obtained in an analogous manner:
~12941~
a) l-rcarbazolvl-~4)-oxyl-3-r2-(4-fluorophenoxy)-ethyl-aminol-propan-2-ol yield 56% of theory, m.p. 145 - 146C., ~rom 4-(2,3-epoxypropoxy)-carbazole and 2-(4-fluorophenoxy)-ethylamine.
b) l-rcarbazolYl-(4)-oxyl-3-r2-(4-tert.-butylphenoxy)-ethylaminol-propan-2-ol yield 51% of theory; m,p, 127 - 128C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(4-tert.-butyl-phenoxy)-ethylamine, c) l-rcarbazolYl-(4)-oxYl-3-r2-(2~3-dimethylphenoxy) ethYlaminol-propan-2-ol yield 51% of theory, m.p. 128 - 129C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2,3-dimethyl-phenoxy)-ethylamine.
d) l-rcarbozolyl-(4)-oxYl-3-~2-rindanYl-(5)-oxvl-eth amino~-propan-2-ol yield 54% of theory m.p. 143 - 145C., from 4-(2,3-epoxypropoxy)-carbazole and 2-[indanyl-(5)-oxy]-ethylamine.
e) l-rcarbazoly~-(4)-oxyl-3-r2-rnaPhthY1-(l)-oxyl-ethyl ~ -2-ol yield 64% of theory; m.p. 116 - 119C., from 4-(2,3-epoxypropoxy)-carbazole and 2-[naphthyl-(1)-oxy ]-ethYlamine.
f) l-rcarbazolyl-(4)-oxyl-3-r2-(3,4-methylenedioxy-phenoxy)-ethYlaminol-propan=2-ol yield 32% of theory; m~p. 142 - 143C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(3,4-methylene-dioxyphenoxY)-ethylamine.
l~Z9~6 g) l-rcarbazolx1-(4)-oxyl-3- r-2- ( 2,6-dimethoxyphenoxy)-ethylaminol-propan-2-ol yield 65% of theory; m.p. 136 - 138C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2,6-dimethoxy-phenoxy)-ethylamine.
h) l-rcarbazolyl-(4)-oxyl-3-r2-(2-methox~phenoxy)-~opylaminol-propan-2-ol yield 83% of theory; m.p. 137 - 157C. (crude mixture of the diastereomers), from this, by two recrystallisations from ethyl acetate: 22% of theory, m.p. 173 - 175C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-methoxyphenoxy)-propylamine~
i) l-rcarbazolvl-(4)-oxyl-3-r2-(2-methylthiophenoxy)-ethylaminol-propan-2-ol yield 4~/O of theory; m.p. 83 - 85C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-methylthio-phenoxy)-ethylamine.
j) l-~carbazolYl-(4)-oxyl-3-r2-(2-benzYloyyphenoxy) ethylaminol-~ropan-2-ol yield 56% of theory; m.p. 138 - 139C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-benzyloxy-phenoxy)-ethylamine.
The starting amines employed in Examples 3c, 3d, 3f, 3~ and 31 can be prepared vla the corresponding nitriles by processes analogous to those described in the literature.
2,3-Dimet_ylphenoxyacetonitrile 100 g. 2,3-Dimethylphenol, 57 ml. chloroaceto-nitrile, 110 g. potassium carbonate and 2.0 g. potassium iodide are stirred under reflux for 5 hours in 300 ml. methyl ethyl ketone, The reaction mixture is filtered off with suction, the filtrate is evaporated and the residue is distilled - 18 _ 11~9416 to give 88.0 g. 2,3-dimethylphenoxyacetonitrile in the form of a colourless oil; b.p. 137 - 142C./13 mm.Hg.
In an analogous manner, by the reactions of 5-indanole, 3,4-methylenedioxyphenol and 2-(methylthio)phenol, respectively, with chloroacetonitrile, there are obtained the following compound~:
indanyl-(5)-oxyacetonitrile, b.p. 162-165C./14 mm.Hg.;
wherein Y is a reactive group and Rl' has the same meaning as given above for Rl or Y and Rl' together signify a valency bond, with a compound of the formula (III):-HN - CH - CH - X ~ R6 (III) 1~94~6 wherein R2, R3, R4, X, Ar, R5 and R6 have the same meanings as above; or b) reaction of a compound of formula (IV):-O - CH - CH - CH2 - ~H
~ Rl R2 (IV) wherein Rl and R2 have the same meanings as above, with a compound of the formula (V):-~ 6 Y - CH - IH - X ~ (V) wherein Y, R3, R4, X, Ar, R5 and R6 have the same meanings as above; or c) reduction of a mixture of a compound of formula (IV), as defined above, and of a compound of the formula (VI):-~R6 O = I - CH ~ X ~ R5 (VI) in which R3, R4, X, Ar, R5 and R6 have the same meanings as above, or d) reaction of a compound of formula (IV), as defined above, with a compound of the formula (VII):-1~29416 C - CH - X ~ R6 (VII) in which Y, R4, X, Ar, R5 and R6 have the same meanings as above, and the amide obtained is reduced, whereupon, if desired, the compound thus obtained of formula (I) is con-verted into a different compound of formula (I), and, if desired, a compound of formula (I) obtained is converted into a pharmaceutically acceptable, pharmacologically or physiologically compatible acid addition salt with a non-toxic, physiologically acceptable inorganic or organic acid.
The reactive group Y in the compounds of formulae (II), (V) and (VII) is a leaving group in an SN nucleo-philic substitution reaction displaceable by amino. Suitably Y is an acid residue for.example of a hydrohalic acid or of a sulphonic acid, Suitable radicals Y include chloride, bromide, tosyl, brosyl and mesyl.
Processes a) and b) are suitably carried out in an organic solven`t which is inert under the reaction conditions, for example, toluene, dioxan, ethylene glycol dimethyl ether, isopropanol or dimethylformamide, optionally in the presence .
of an acid-binding agent.
The reaction of an epoxide of formula (II) (Y and R' together represent a valency bond) with an amine of formula (III) can, however, also be accomplished after mixing the reaction components, by leaving the reaction mixture to stand at ambient temperature or by heating, llZ9416 According to process c), an amine of formula (IV) is hydrogenated with a carbonyl compound of formula (VI);
~uitably the process is carried out in an inert solvent, for example, methanol, in the presence of a catalyst, for example, Raney nickel.
The amides obtained according to process d) are preferably reduced by means of complex metal hydrides, for example, lithium aluminium hydride.
Compounds of formula (I) in which Rl is a hydrogen atom can be esterified by reaction with an acid or reactive acid derivative, for example, acid halide or acid anhydride, possibly in the presence of an acid-binding agent, for example, pyridine or triethylamine, and benzyl protective groups possibly present can be removed by catalytic hydro-genation in the presence of noble metal catalysts.
The qtarting compounds employed in the processes of the invention are, as a rule, known from the literature.
The new derivatives can ge~erally be obtained analogously to the processes known for the preparation of the known compounds, Thu~, amines of formula (III) are preferably pre-pared by reacting haloalkyl nitriles with appropriate phenols, naphthols or aryl compounds, for example, chloroacetonitrile and phenol, with subsequent hydrogenation in the presence of ammonia, The amines of formula (IV) can be obtained from the known 4-(2,3-epoxypropoxy)-carbazole (cf. West German Patent No, 2,240,599 Leinert et al, issued February 5, 1976,) by reaction with liquid ammonia.
Reactive compounds of formula (V), for example, E~
toluenesulphonic acid esters, are, as a rule, prepared from the appropriate phenols, naphthols or aryl compounds by reaction ~294~6 with haloalcohols and subsequent esterification with ~-toluenesulphonic acid.
The carbonyl compounds of formula (VI) and acid chlorides of formula (VII) can be obtained from the appropriate phenols, naphthol~ and aryl compound~ by reaction with apprOpriate haloalkyl compounds.
A subsequent conversion of a compound of formula (I) into another compound of formula (I) can take place, for example, by oxidation, for example, conversion of an alkyl-thio radical into an alkylsulphinyl or alkylsulphonyl radical.Hydroxyl group~ can be etherified or esterified according to known methods, ester and ether groups can be converted by known methods into hydroxyl groups and an ar-lower-alkyl group can be removed by hydrogenation, forlexample, when R2 is benzyl it may be hydrogenated to a hydrogen atom R2.
For conversion of derivatives of formula (I) into their pharmaceuticall~ acceptable, pharmacologically or physiologically compatible acid addition salts, the derivatives of formula (I) are reacted, preferably in an organic solvent, with an equivalent amount of a non-toxic inorganic or organic acid, for example, hydrochloric acid, phosphoric acid, sulphuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
In the specification it will be understood that the qualification that the salts be "pharmaceutically accept-able" means that the salts have the necessary physical characteristics, for example, stability, to render them suit-able for formulation into pharmaceutical compositions. The qualification that the salts be "physiologically or pharma-cologically compatible" is to be understood, as extendingto salts of non-toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be un-112~6 suitable for administration to living bodies.
Salts of compounds of formula (I) which are notpharmaceutically acceptable and physiologically or pharma-cologically compatible form a useful aspect of the invention of the novel derivatives, inasmuch as they can be readily converted, by conventional means, to different salts having the required physical and chemical characteristics to make them suitable for admini~tration in pharmaceutical com~
positions to living bodies.
The derivativeq of formula (I) of the invention can be resolved by known methods, via diastereomeric salts, into the optically-active forms. For the resolution of the race-mates, there can be used, for example, tartaric acid, malic acid, camphoric acid or camphorsulphonic acid.
For the preparation of pharmaceuticals, the new compounds (I) of the invention are mixed in the usual manner with appropriate pharmaceutical carrier materials and aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, ~uspended or dissolved in water or in an oil, for example, olive oil.
The new compounds (I) of the invention and the acceptable salts thereof can be administered enterally or parenterally in liquid or solid form. Aq injection medium, it is preferable to uqe water which contains the additives usual in the case of injection solutions, such as stabilising agents, solubilising agents and/or buffers. Additives of this type include, for example, tartrate and citrate buffers, ethanol, complex-forming agents (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (such as liquid polyethylene oxide) 11294~6 for viscosity regulation. Solid carrier materials are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols).
Compositions suitable for oral administration can, if desired, contain flavouring and/or sweetening materials.
The dosages to be administered will, of course, depend on the patient and must be decided by the patient's physician. Convenient unit~ of dosage are dragees contain-ing 25 mg of the compound of the invention; however, the dosage unit may vary from 10 to 300 mg. It i~ recommended that use of the compound of the invention be introduced gradually. For example, in the case of dragees containing 25 mg of active ingredient, an initial treatment with 1 to 4 dragees daily may be suitable and this may be increased to 1 to 4 dragees four times daily in serious cases. Treatment after initial introduction is suitably maintained at 1 dragee two, three or four times daily.
It will be understood that the dosage schedule for blood pressure lowering is entirely dependent on the condition of the patient, e.g., a human or animal mammal, the response of the patient to the treatment and whether or not the patient is ambulatory or hospitalized. The treatment should suitably begin with small doses (100 mg) and increase gradually depending upon the patient's response. The dosage can be increased at 5 to 7 day intervals until an average daily dose of 100 to 300 mg is reached. For maintenance, two to four doses a day are usually required. The dosages for inhibition of adrenergic ~-receptors are substantially the same _ g _ ~ ~29~6 The effectiveness of the compounds (I) of the invention as vaso-dialators and beta-receptor blockina agents is illustrated by the following tests:
A - Vaso Dilator ex~eriments Rabbits were anesthesized with urethane and a catheter implanted in the middle ear artery (A, femoralis) for a continuous measurement of their arterial blo~d pressure.
The blood pressure measurements were effected using an electro-mechanical transducer (Statham P 23 Db)* and were recorded on ,a direct printer and utilized after calibration with a mercury manometer.
After determination of the starting value both jugular arteries (A. carotis) were occluded for two minutes and blood pressure thereby temporarily increased (CSE-reflex). The test compound was then injected at the lowest experimental dosage (0.125 mg/kg) intravenourly and eight minutes later the CSE-reflex was again induced. In intervals of 15 minutes, the test compound was again injected in logarithmically increased dosaae (Factor ~) and the CSE-reflex again induced.
Test compounds which under these conditions moderated the CSE-induced blood pressure increase were demonstrated to be vaso-dilators and the dosage which decreased the CSE-reflex by 30 mm Hg was determined (designated as DE 30mm Hg in the Table below).
B - Beta Receptor Blockina Activity Experiments The heart beat frequency of rabbits was monitored via implanted electrodes and recorded on a frequency counter having a measurement time of 15 seconds. Isoprenalin was then injected intravenously via an ear view, inducing an increase in heart beat frequency of from ca. 200 beats/min. to 330 beats/min. Subsequently, the test compounds were administered *trademark -- 10 _ 11~9~
in increased dosage (as in Experiment A) intravenously and the heart frequency increase after isoprenalin treatment again recorded, The inhibition of isoprenalin tachycardia was taken as a measure of the beta-blockade activity of the test compounds. The dosage which limited the isoprenalin induced heart frequency increase to 250 beats/min. was determined for each test substance and is hereinafter designated DE250.
The results from the above experiments A and B are set forth in Table I below. The determination of the equal effectiveness dosages, i.e., DE_30 mm Hg 250 determined on a logorithmic basis from four to six individual experiments and then the quotient of the vaso dilating dosage (DE 30 mm Hg) to the beta-blockade dosage (DE250) was calculated. A high quotient was taken to indicate test compounds exhibiting ~ubstantially beta-blocking activity, whereas the test compounds with a quotient of about 1 were regarded as exhibiting both beta-blocking and vaso dilating activity, to a comparable degree.
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O d' O ~ O ~; ~ H ~1 1~ ~ 0 ~1 0 ~1--- ~1 ~ r-l a) 1--l ~li lc 11294~6 The results indicate that the inventive compoundsbalance vaso dilating and beta-blocking activity to a much greater extent than do the prior art materials.
The compounds of the invention can be employed in the treatment of hypertension or angina pectoris in the dosages indicated previously. The dosage levels will generally be appropriate, both for achieving a vaso dilating effect, i.e., for reducing blood pressure, and for inhibition of adrenergic beta-receptor activity.
112g416 The following Examples are given for the purpose of illustrating the present invention in particular and preferred embodiments.
It will be understood that different products of the invention will be obtained by appropriate variations of the ~tarting materials.
Example 1, (process a)) l-rCarbazolyl-(4)-oxyl-3-r2-(2-methoxYphenyl)-ethylami propan-2-ol 6.0 g. 4-(2,3-Epoxypropoxy)-carbazole and 7.6 g.
2-(2-methoxyphenyl)-ethylamine are stirred for 20 hours at 70GC. ~he reaction mixture is then triturated with diethyl ether, filtered with suction and recrystallised from ethyl acetate, with the use of active charcoal and fullers' earth. There are obtained 6.0 g. (61% of theory) of the de~ired compound in the form of colourless crystals;
m.p. 135 - 136C.
The following compounds are obtained in an analogous manner: i a) l-rcarbazolx1-54~-oxyl-3- r 2-(3,4-dimethoxv~henvl)-- 20 ethylam-inol-propan-2-ol yield 42% of theory, m.p. 129 - 130C.; acetate m.p. 180 -from 4-(2,3-epoxypropoxy)-carbazole and 2-(3,4-dimethoxy-phenyl)-ethylamine.
b) l-[carbaæolyl-(4)-oxy]-3-[2-(2-pyridyl)-ethylamino]-propan-2-ol yield 32% of theory, m.p. 105 - 107C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-pyridyl)-ethylamine.
- 14 _ ~1294~6 c) l-rcarbazolyl-(4)-o-xy]-3-r2-(4-pyridyl)-ethylamin ~ propan-2-ol yield 24% of theory; m.p. 86 - 88C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(4-pyridyl)-ethylamine.
d) l-rcarbazolyl-(4)-oxy1-3-(3-phenylpropylamino)-propan-2-ol yield 3~/O of theory, succinate m.p. 98 - 99C., from 4-(2,3-epoxypropoxy)-carbazole and 3-phenylpropylamine.
0 e) l-rcarbazolYl-(4)-oxyl-3-r4-phenvlbutyl-(2)-ami propan-2-ol yield 13% of theory; m.p. 124 - 125C., from 4-(2,3-epoxypropoxy)-carbazole and 4-phenylbutyl-(2)-amine.
Example 2 l-rCarbazolYl-(4)-oxyl-3-r2-methoxyphenoxy -ethYlaminol-propan-2-ol 22.6 g. 4-(2,3-Epoxypropoxy)-carbazole and 17.4 g.
2-(2-methoxyphenoxy)-ethylamine in 75 ml. ethylene glycol dimethyl ether are stirred for 25 hours at 50C. The reaction mixture is evaporated to dryness in a Rotavapor and the residue is triturated with diethyl ether and recrystallized from ethyl acetate, with the use of active charcoal. There are obtained 15.1 g. (39% of theory) of the desired compound in the form of colourless crystals, m.p.ll4 - 115C.
The following compounds are obtained in an analogous manner:
- 15 _ a) l-rcarbazolYl-(4)-oxyl-3-(2-phenoxYethYlamino)-propan-2-ol - yield 32% of theory; m,p. 105 - 107C., from 4-(2,3-epoxypropoxy)-carbazole and 2-phenoxyethylamine~
b) l-rcarbazolyl-(4)-oxyl-3-rl-phenoxypropyl-(2)-aminol-propan- 2- ol yield 31% of theory; hydrochloride m.p. 116 - 119C., from 4-(2,3-epoxypropoxy~-carbazole and 1-phenoxypropyl-(2)-amine, c) l-rcarbazolyl-(4)-oxyl-3-rl,4-benzodiox,anYl-(2)-meth aminol-propan-2-ol yield 28% of theory; m,p, 129 - 131C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(aminomethyl)-1,4-benzodioxan.
d) 1- rcarbazolyl-(4)-oxy 1-3- r2-(4-carbamovlphenoxY)-ethylaminol-propan-2-ol yield 13% of theory, m.p. 120 - 122C., from 4-(2,3-epoxypropox~y)-carbazole and 2-(4-carbamoyl-phenoxy)-ethylamine.
Example 3 1- rCarbazolYl-(4)-oxyl-3- r2-(2-ethoxvphenoxY)-ethvlaminol-propan-2-ol 6,0 g, 4-(2,3-Epoxypropoxy)-carbazole and 9.1 g.
2-(2-ethoxyphenoxy)-ethylamine are stirred for 20 hours at 70C, After cooling, the reaction mixture is stirred with diethyl ether, filtered with suction and the residue re-crystallised from ethyl acetate, with the use of active charcoal and fullers' earth. The yield is 4.4 g. (42% of theory) of the desired compound in the form of colourless crystals: m.p. 127.5 to 128.5C.
The following compounds are obtained in an analogous manner:
~12941~
a) l-rcarbazolvl-~4)-oxyl-3-r2-(4-fluorophenoxy)-ethyl-aminol-propan-2-ol yield 56% of theory, m.p. 145 - 146C., ~rom 4-(2,3-epoxypropoxy)-carbazole and 2-(4-fluorophenoxy)-ethylamine.
b) l-rcarbazolYl-(4)-oxyl-3-r2-(4-tert.-butylphenoxy)-ethylaminol-propan-2-ol yield 51% of theory; m,p, 127 - 128C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(4-tert.-butyl-phenoxy)-ethylamine, c) l-rcarbazolYl-(4)-oxYl-3-r2-(2~3-dimethylphenoxy) ethYlaminol-propan-2-ol yield 51% of theory, m.p. 128 - 129C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2,3-dimethyl-phenoxy)-ethylamine.
d) l-rcarbozolyl-(4)-oxYl-3-~2-rindanYl-(5)-oxvl-eth amino~-propan-2-ol yield 54% of theory m.p. 143 - 145C., from 4-(2,3-epoxypropoxy)-carbazole and 2-[indanyl-(5)-oxy]-ethylamine.
e) l-rcarbazoly~-(4)-oxyl-3-r2-rnaPhthY1-(l)-oxyl-ethyl ~ -2-ol yield 64% of theory; m.p. 116 - 119C., from 4-(2,3-epoxypropoxy)-carbazole and 2-[naphthyl-(1)-oxy ]-ethYlamine.
f) l-rcarbazolyl-(4)-oxyl-3-r2-(3,4-methylenedioxy-phenoxy)-ethYlaminol-propan=2-ol yield 32% of theory; m~p. 142 - 143C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(3,4-methylene-dioxyphenoxY)-ethylamine.
l~Z9~6 g) l-rcarbazolx1-(4)-oxyl-3- r-2- ( 2,6-dimethoxyphenoxy)-ethylaminol-propan-2-ol yield 65% of theory; m.p. 136 - 138C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2,6-dimethoxy-phenoxy)-ethylamine.
h) l-rcarbazolyl-(4)-oxyl-3-r2-(2-methox~phenoxy)-~opylaminol-propan-2-ol yield 83% of theory; m.p. 137 - 157C. (crude mixture of the diastereomers), from this, by two recrystallisations from ethyl acetate: 22% of theory, m.p. 173 - 175C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-methoxyphenoxy)-propylamine~
i) l-rcarbazolvl-(4)-oxyl-3-r2-(2-methylthiophenoxy)-ethylaminol-propan-2-ol yield 4~/O of theory; m.p. 83 - 85C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-methylthio-phenoxy)-ethylamine.
j) l-~carbazolYl-(4)-oxyl-3-r2-(2-benzYloyyphenoxy) ethylaminol-~ropan-2-ol yield 56% of theory; m.p. 138 - 139C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-benzyloxy-phenoxy)-ethylamine.
The starting amines employed in Examples 3c, 3d, 3f, 3~ and 31 can be prepared vla the corresponding nitriles by processes analogous to those described in the literature.
2,3-Dimet_ylphenoxyacetonitrile 100 g. 2,3-Dimethylphenol, 57 ml. chloroaceto-nitrile, 110 g. potassium carbonate and 2.0 g. potassium iodide are stirred under reflux for 5 hours in 300 ml. methyl ethyl ketone, The reaction mixture is filtered off with suction, the filtrate is evaporated and the residue is distilled - 18 _ 11~9416 to give 88.0 g. 2,3-dimethylphenoxyacetonitrile in the form of a colourless oil; b.p. 137 - 142C./13 mm.Hg.
In an analogous manner, by the reactions of 5-indanole, 3,4-methylenedioxyphenol and 2-(methylthio)phenol, respectively, with chloroacetonitrile, there are obtained the following compound~:
indanyl-(5)-oxyacetonitrile, b.p. 162-165C./14 mm.Hg.;
3,4-methylenedioxyphenoxyacetonitrile b.p. 170-175C./
12 mm.Hg.;
2-methylenethiophenoxyacetonitrile, m.p. 56-58C.; b.p.
173 - 176C./12 mm.Hg.
2-rindanyl-(5)-oxyl-ethylamine.
109 g. Indanyl-(5)-oxyacetonitrile are hydrogenated in the present of Raney nickel in 700 ml. ethanol and 180 ml.
liquid ammonia at 110 ats. and 90C. After distillation of the reaction mixture, there are obtained 86 g. 2-[indanyl-(5)-oxy]-ethylamine in the form of a colourle~s oil; b.p.
' 154 - 156C./12 mm.Hg.
' In an analogous manner, by hydrogenating 2,3-di-m~ethylphenoxyacetonitrile or 3,4-methylenedioxyphenoxy-a~etonitrile, there are obtained the following compounds:
2-(2,3-dimethylphenoxy)-ethylamine; b.p. 129 - 132C./
12 mm.Hg.
2-(3,4-methylenedioxyphenoxy)-ethylamine; b.p. 162 - 164C./
13 mm.Hg.
2-(2-methylthiophenoxy)-ethylamine 26.7 g. (2-Methylthiophenoxy)-acetonitrile are reduced with 8.5 g. lithium aluminium hydride in 1.3 liters diethyl ether by heating under reflux for 4 hours. After working up the reaction mixture in the usual manner and distilling, there are obtained 21.0 g. 2-(2-methylthiophenoxy)-l~Z9416 ethylam~ne in the form of a colourless oil, b.p. 117 - 120C./
0.1 mm.Hg.
In an analogous manner, by the reduction of 2,6-- - dimethoxyphenoxyacetonitrile, there is obtained the following compound:
2-(2,6-dimethoxyphenoxy)-ethylamine, b.p. 160 - 162C./
12 mm.Hg.
Example 4 1 rc arbazolvl-(4)-oxvl-3-r2-(2-methYlPhenoxy)-ethylami 10 propan-2-ol 6.0 g. 4-(2,3-Epoxypropoxy)-carbazole and 7.6 g.
2-(2-methylphenoxy)-ethylamine are stirred for 20 hours at 70C. The reaction mixture is then dissolved in methylene chloride and the mixture separated by chromatography on a silica gel column (500 ml.) with the elution agents methylene chloride, methylene chloride-ethyl acetate (9:1 v/v and 7:3 v/v), ethyl acetate and ethyl acetate-methanol (9:1 v/v).
The sequence of the elution is: tertiary amine, secondary amine and primary starting amine. After trituration with diethyl ether and recry3tallisation from ethyl acetate, with the use of active charcoal and fullers' earth, there are obtained 5.2 g. (S3% of theory) of the desired compound in the form of colourless crystals, m.p. 125 - 126C.
The following compounds are obtained in an analogous manner:
a~ l-rcarbazolyl-(4)-oxyl-3-r2-~3-methylphenoxy~--eth aminol-propan-2-ol yield 43% of theory, m.p. 129 - 130C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(3-methylphenoxy)-ethylamine.
- llZ9~16 b) 1- rcarbazolYl-(4)-oxyl-3-r2-(2-chlorophenoxy)-ethyl-aminol-propan-2-ol yield 26% of theory; m.p. 111 - 112C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-chlorophenoxy)-ethylamine.
c) l-rcarbazolyl-(4)-oxyl-3-r2-(3-methoxyphenoxy)-ethyl-aminol-propan-2-ol yield 22% of theory; m.p. 111 - 113C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(3-methoxyphenoxy)-ethylamine, d) 1- rcarbazolYl-(4)-oxyl-3- r2-(4-methoxYphenoxy)-ethyl-aminol-propan-2-ol yield 48% of theory; m.p. 106 - 108C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(4-methoxy-phenoxy)-ethylamine.
e) 1- rcarbazolYl-(4)-oxyl-3- r2-(2-methoxyphenvlthio)-ethylaminol-propan-2-ol yield 15% of theory; m.p. 108 - 109C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-methylphenyl-thio)-ethylamine.
f) 1- rcarbazolYl-(4)-oxyl-3- r 1 ( 2-methoxyphenoxy~-propyl-2-aminol-propan-2-ol yield 85% of theory; m.p. 112 - 125C, (crude mixture of the diastereomers), and from this, by recrystallisation from ethanol, ethyl acetate and toluene-isopropanol, colourless crystals (m.p. 140 - 141C.) and from the mother liquor a further product (m.p. 121.5 - 122.5C.), from 4-(2,3-epoxy-propoxy)-carbazole and l-(2-methoxyphenoxy)-propyl-2-amine.
g) 1- rcarbazolyl-(4)-~-3- r2-methylsulphinylphenOxy) ethYlaminol-Propan-2-ol yield 25% of theory; oxalate decomposes above 126C., 1~29416 from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-methylsulphinyl-phenoxy)-ethylamine.
The compound is also obtained by the oxidation of 1- [carbazolyl-(4)-oxy]-3- [2-(2-methylthiophenoxy)-ethylamino]-propan-2-ol (cf. Example 3i) with the equivalent amount of hydrogen peroxide in acetic acid at allibient temperature.
The starting amines used in Examples 4e, 4~ and 4g can be prepared by reactions analogous to those described in the literature as follows:
10 2-(2-methoxYphenvlthio~- hylamine by the reaction of o-(2-chloroethylthio)-anisole in liquid ammonia for 8 hours at 120C., oil, b.p. 118 - 122C./0.05 mm.Hg., hydroch~oride m.p. 163 - 167C.
1-(2-methoxyphenoxY)-propyl-2-amine by the hydrogenation of 2-methoxyphenoxyacetone in ammonia-ethanol at 120 ats. and 90C.; oil, b.p. 144 - 146C./
13 mm.Hg.; oxalate m.p. 199 - 200C. (decomP~);
2-(2-methYlsulphinylPhenoxv)-ethvlamine by the oxidation of 2-(2-methylthio)-ethylamine with 20 one equivalent of perhydrol (30YO) in acetic acid at anibient temperature, oil, oxalate m.p. 174 - 175C.
Example 5 1- rCarbazolyl-(4)-oxyl-3- rN-benzyl-2- 5 2-methoxYphenoxY ) -ethylaminol-propan-2-ol 15.1 g. 4-(2,3-Epoxypropoxy)-carbazole and 16.2 g.
N-[2-(2-methoxyphenoxy)-ethyl]-benzylamine in 50 ml. ethylene glycol dimethyl ether are heated under reflux for 24 hours.
The reaction mixture is evaporated to dryness, the residue is purified over a silica gel column with the elution agents 30 methylene chloride, methylene chloride-ethyl acetate (9:1 v/~ and 7:3 v/v and ethyl acetate and the residue obtained by evaporation of the main fraction is triturated with diethyl ~1~9416 ether. There are obtained 25.0 g. ( 8~/o of theory) of the desired compound in the form of colourless crystals, m.p.
- 97 - 99C.
The following compounds are obtained in ~n analogous manner:
a) l-Lcarbazolyl- ( 4 ) ~oxy 1-3- rN-methyl-2- ( 2-methoxyphenoxY ) ~
eth~laminol-propan-2-ol yield 22% of theory; colourless oil; hydrochloride m.p. 109C.
(slight evolution of gas), from 4~ ( 2 ~ 3-epoxypropoxy)-carbazole and N-methyl-2-(2-methoxyphenoxy)-ethylamine, b) l-rcarbazolvl-(4)-oxYl-3-rN-butyl-2-(2-methoxYPhenoxy) ethylaminol-propan-2-ol yield 84% of theory, colourless oil; hydrochloride m.p.
169 - 170C., from 4-(2,3-epoxypropoxy)-carbazole and N-[2-(2-methoxy-phenoxy)-ethyl]-butylamine, ! c) l-rcarbazolyl-(4)-oxyl-3-rN-benzyl-2-(5-carbamoyl-2 pyridyloxy~-ethvlaminol-propan-2-ol yield 80% of theory; m.p. 165 - 167C, from 4-(2,3-epoxypropoxy)-carbazole and N-[2-(5-carbamoyl-2-pyridyloxy)-ethyl]-benzylamine.
Example 6 l-rCarbazolvl-(4)-oxy1-2-formYloxy-3-rN-benzyl-2-(2-methoxy-phenoxy)-eth~_aminol-propane hydrochloride A formic acid-acetic acid anhydride mixture prepared from 3 ml, formic acid and 6 ml, acetic anhydride is allowed to act for 2,5 days at ambient temperature on 7,9 g. 1-rcarbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxyphenoxy)-ethyl-amino]-propan-2-ol, (see Example 5). The reaction mixture is then poured into ice water, neutralised with an aqueous 1129~16 solution of sodium bicarbonate, extracted with methylene chloride and the desired hydrochloride then precipitated out from an ethereal solution of the extraction residue. The yield is 8.1 g. (91% of theory) of colourless crystals which sinter above 85C. and form bubb~es above 120C.
Example 7 l-rCarbazolyl-(4)-oxyl-2-pivaloyloxy-3-rN-benzyl-2-(2-methoxy-phe~n ~laminol-propane hydrochloride 1.9 rrl. pivalic acid chloride is introduced into a solution of 7.0 g. 1- [carbazolyl-(4)-oxy]-3- [N-benzyl~
2-(2-methoxyphenoxy)-ethylamino]-propan-2-ol, (see Example 5), in 35 ml. pyridine. After standing overnight, the re-action mixture is poured into water, extracted with methylene chloride, purified chromatographically with a silica gel column and the hydrochloride precipitated out from an ethereal solution of the ba~e. The yield i~3 6.6 g. (77YO of theory) of colourless crystais which sinter above 102C. and melt at 120C., with a slight evolution of gas.
The following compound i9 prepared in an analogous 20 manner by benzoylation of 1-[carbazolyl-(4)-oxy]-3-[N-benzyl 2-(2-methoxyphenoxy)-ethylamir~-propan-2-ol wi~h benzoyl chloride:
1- rcarbazolyl-(4¦-oxyl-2-benzoyloxy-3-rN-benzvl-2-(2-methoxy-phenoxy)-ethylaminol-propane hYdrochloride yield 70/O of theory; m.p. 113C. with slight evolution of gas.
Example 8 1- rCarbazolyl-(4)-oxyl-2-formyloxy-3-r2-(2-met~
ethvlaminol-pro~ane hydrochloride 2.2 g. 1- rCarbazolyl-(4)-oxy]-2-formyloxy-3-[N-benzyl-30 2-(2-methoxyphenoxy)-ethylamino]-propane hydrochloride (see Example 6), are hydrogenated in 40 ml. anhydrous tetrahydrofuran :1129416 in the presence of 0.3 g~ l~/o palladium~charcoal at atmospheric pressure. After filtering with suction and evaporating the filtrate, the residue obtained is worked up with diethyl ether and crystallises. The yield of the desired product i~ 1.3 g.
(7~/O of theory) in the form of colourless crystal~; m.p. 62C., with bubble formation.
The following compounds are obtained in an analogous manner:
a) l-rcarbazolYl-(4)-oxYl-2-pivaloyloxY--3-r2-(2-meth phenoxy)-ethYlaminol-propane hydrochloride yield 85% of theory; m.p. 199 - 201C., with slight evolution of gas;
by the hydrogenolysis of l-[carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propane hydro-chloride (see Example 7).
b) l-rcarbazolYl-(4)-oxYl-2-benzovloxY-3-r2-(2-meth phenoxy)-ethYlaminol-Dropane hYdrochloride yield 84% of theory; m.p. 102C., with evolution of gas; by hydrogenolysis of l-Ccarbazolyl-(4)-oxy~-2-benzoyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propane hydrochloride, (see Example 7).
c) 1-rcarb ~ xYl-3-r2-~5-carbamov~-2-pYridyloxy)-ethy~-ProDan-2 -ol by hydrogenolysis of l-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(5-carbamoyl-2-pyridyloxy)-ethylamino]-propan-2-ol, (see Example 5c), d) l-rcarbazolYl-~4)-oxYl-3-r2-(2-hYdroxyphenoxy)-ethylamin propan-2-ol yield 77% of theory, hydrochloride m.p. 214 - 215C.,; by hydrogenolysis of 1-[carbazolyl-(4)-oxy]-3-[2-(2-benzyloxy-phenoxy)-ethylamino]-propan-2-ol, (see Example 3j).
11294~6 Example 9 (proceRs_~
l-rCarbazolvl-(4)-oxyl-3-r2-(5-fluoro-2-methoxyphenoxy)-ethYlaminol-propan-2-ol 7.0 g. 1-Amino-3-[carbazolyl-(4)-oxy]-propan-2-ol, 9,2 g. 2-(5-fluoro-2-methoxyphenoxy)-ethyl E~toluene-sulphonate and 3.8 ml. triethylamine are stirred in 20 ml. dimethyl-formamide for 20 hours at 70C. The reaction mixture is then poured into a dilute aqueous solution of sodium hydroxide, extracted with methylene chloride, dried and purified chromato-graphically in the manner describedin Example 4. After re-crystallisation from ethyl acetate with the use of active charcoal and fullers' earth, there are obtained 2 7 g. (23%
of theory) of the desired product in the form of colourless crystals; m.p. 146 - 147C.
The starting materials can be prepared in the follow-ing manner:
l-amino-3-~carbazolyl-(4)-oxYl-propan-2-ol 40 g. 4-(2,3-Epoxypropoxy)-carbazole are stirred with 500 ml. liquid ammonia in 2 litres methanol for 24 hours at 50C. in an autoclave, After evaporating the reaction mixture and recrystallising the residue from ethanol, there are obtained 31 g~ of the desired product in the form of colourless crystals; m.p. 141 - 143C.
2-t5-fluoro-2-methoxy~henoxy)-ethvl P-toluenesulPhonate 40.4 g 5-Fluoro-2-methoxyphenol, 24.6 ml. 2-chloro-ethanol and 20.7 g. potassium hydroxide are stirred in 100 ml.
,dimethylformamide for 2 hours at 70C, The reaction mixture is poured into water, extracted with methylene chloride, evaporated and the residue distilled in a high vacuum to give 11.3 g. 2-(5-fluoro-2-methoxyphenoxy)-ethanol in the form of a colourless oil which solidifies upon standing, m.p. 43 - 45C.
llZ941~
The further reaction thereof with p-toluenesulphonic acid chloride gives the desired tosylate, m.p. 66 - 68C., re-crystallised from ethanol.
Example 10 (process c)) 1-rCarbazolyl-(4)-oxyl-3-rl-t2-methoxyphenoxy)-propyl-2-aminol-propan-2-ol A mixture of 8.1 g. 1-amino-3-[carbazolyl-(4)-oxy]-propan-2-ol and 6.0 g. (2-methoxyphenoxy)-acetone in 250 ml.
methanol is hydrogenated in the presence of 1.0 g. l~/o palladium charcoal at 5 ats pressure and 38C. and the crude product obtained i9 purified chromatographically in the manner described in Example 4. After triturating the residue obtained by evaporation of the main fraction, there are obtained 5.5 g. (41% of theory) of the desired product in the form of colourless crystals (m.p. 113 - 117C.) which is a crude diastereomeric mixture. By recrystallisation from ethyl acetate and from ethanol, there is obtained there-from a product with a constant melting point of 140 - 141C.
Example 11 (process d)) l-rCarbazolyl-(4~-oxyl-3-L3-(2-methoxyphenyl)-propylamin propan-2-ol A solution of 4.4 g. 3-(2-methoxyphenyl)-propionic acid chloride in 50 ml. methylene chloride is added dropwise, with stirring, to a solution of 6.0 g. 1-amino-3-[carbazolyl-
12 mm.Hg.;
2-methylenethiophenoxyacetonitrile, m.p. 56-58C.; b.p.
173 - 176C./12 mm.Hg.
2-rindanyl-(5)-oxyl-ethylamine.
109 g. Indanyl-(5)-oxyacetonitrile are hydrogenated in the present of Raney nickel in 700 ml. ethanol and 180 ml.
liquid ammonia at 110 ats. and 90C. After distillation of the reaction mixture, there are obtained 86 g. 2-[indanyl-(5)-oxy]-ethylamine in the form of a colourle~s oil; b.p.
' 154 - 156C./12 mm.Hg.
' In an analogous manner, by hydrogenating 2,3-di-m~ethylphenoxyacetonitrile or 3,4-methylenedioxyphenoxy-a~etonitrile, there are obtained the following compounds:
2-(2,3-dimethylphenoxy)-ethylamine; b.p. 129 - 132C./
12 mm.Hg.
2-(3,4-methylenedioxyphenoxy)-ethylamine; b.p. 162 - 164C./
13 mm.Hg.
2-(2-methylthiophenoxy)-ethylamine 26.7 g. (2-Methylthiophenoxy)-acetonitrile are reduced with 8.5 g. lithium aluminium hydride in 1.3 liters diethyl ether by heating under reflux for 4 hours. After working up the reaction mixture in the usual manner and distilling, there are obtained 21.0 g. 2-(2-methylthiophenoxy)-l~Z9416 ethylam~ne in the form of a colourless oil, b.p. 117 - 120C./
0.1 mm.Hg.
In an analogous manner, by the reduction of 2,6-- - dimethoxyphenoxyacetonitrile, there is obtained the following compound:
2-(2,6-dimethoxyphenoxy)-ethylamine, b.p. 160 - 162C./
12 mm.Hg.
Example 4 1 rc arbazolvl-(4)-oxvl-3-r2-(2-methYlPhenoxy)-ethylami 10 propan-2-ol 6.0 g. 4-(2,3-Epoxypropoxy)-carbazole and 7.6 g.
2-(2-methylphenoxy)-ethylamine are stirred for 20 hours at 70C. The reaction mixture is then dissolved in methylene chloride and the mixture separated by chromatography on a silica gel column (500 ml.) with the elution agents methylene chloride, methylene chloride-ethyl acetate (9:1 v/v and 7:3 v/v), ethyl acetate and ethyl acetate-methanol (9:1 v/v).
The sequence of the elution is: tertiary amine, secondary amine and primary starting amine. After trituration with diethyl ether and recry3tallisation from ethyl acetate, with the use of active charcoal and fullers' earth, there are obtained 5.2 g. (S3% of theory) of the desired compound in the form of colourless crystals, m.p. 125 - 126C.
The following compounds are obtained in an analogous manner:
a~ l-rcarbazolyl-(4)-oxyl-3-r2-~3-methylphenoxy~--eth aminol-propan-2-ol yield 43% of theory, m.p. 129 - 130C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(3-methylphenoxy)-ethylamine.
- llZ9~16 b) 1- rcarbazolYl-(4)-oxyl-3-r2-(2-chlorophenoxy)-ethyl-aminol-propan-2-ol yield 26% of theory; m.p. 111 - 112C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-chlorophenoxy)-ethylamine.
c) l-rcarbazolyl-(4)-oxyl-3-r2-(3-methoxyphenoxy)-ethyl-aminol-propan-2-ol yield 22% of theory; m.p. 111 - 113C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(3-methoxyphenoxy)-ethylamine, d) 1- rcarbazolYl-(4)-oxyl-3- r2-(4-methoxYphenoxy)-ethyl-aminol-propan-2-ol yield 48% of theory; m.p. 106 - 108C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(4-methoxy-phenoxy)-ethylamine.
e) 1- rcarbazolYl-(4)-oxyl-3- r2-(2-methoxyphenvlthio)-ethylaminol-propan-2-ol yield 15% of theory; m.p. 108 - 109C., from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-methylphenyl-thio)-ethylamine.
f) 1- rcarbazolYl-(4)-oxyl-3- r 1 ( 2-methoxyphenoxy~-propyl-2-aminol-propan-2-ol yield 85% of theory; m.p. 112 - 125C, (crude mixture of the diastereomers), and from this, by recrystallisation from ethanol, ethyl acetate and toluene-isopropanol, colourless crystals (m.p. 140 - 141C.) and from the mother liquor a further product (m.p. 121.5 - 122.5C.), from 4-(2,3-epoxy-propoxy)-carbazole and l-(2-methoxyphenoxy)-propyl-2-amine.
g) 1- rcarbazolyl-(4)-~-3- r2-methylsulphinylphenOxy) ethYlaminol-Propan-2-ol yield 25% of theory; oxalate decomposes above 126C., 1~29416 from 4-(2,3-epoxypropoxy)-carbazole and 2-(2-methylsulphinyl-phenoxy)-ethylamine.
The compound is also obtained by the oxidation of 1- [carbazolyl-(4)-oxy]-3- [2-(2-methylthiophenoxy)-ethylamino]-propan-2-ol (cf. Example 3i) with the equivalent amount of hydrogen peroxide in acetic acid at allibient temperature.
The starting amines used in Examples 4e, 4~ and 4g can be prepared by reactions analogous to those described in the literature as follows:
10 2-(2-methoxYphenvlthio~- hylamine by the reaction of o-(2-chloroethylthio)-anisole in liquid ammonia for 8 hours at 120C., oil, b.p. 118 - 122C./0.05 mm.Hg., hydroch~oride m.p. 163 - 167C.
1-(2-methoxyphenoxY)-propyl-2-amine by the hydrogenation of 2-methoxyphenoxyacetone in ammonia-ethanol at 120 ats. and 90C.; oil, b.p. 144 - 146C./
13 mm.Hg.; oxalate m.p. 199 - 200C. (decomP~);
2-(2-methYlsulphinylPhenoxv)-ethvlamine by the oxidation of 2-(2-methylthio)-ethylamine with 20 one equivalent of perhydrol (30YO) in acetic acid at anibient temperature, oil, oxalate m.p. 174 - 175C.
Example 5 1- rCarbazolyl-(4)-oxyl-3- rN-benzyl-2- 5 2-methoxYphenoxY ) -ethylaminol-propan-2-ol 15.1 g. 4-(2,3-Epoxypropoxy)-carbazole and 16.2 g.
N-[2-(2-methoxyphenoxy)-ethyl]-benzylamine in 50 ml. ethylene glycol dimethyl ether are heated under reflux for 24 hours.
The reaction mixture is evaporated to dryness, the residue is purified over a silica gel column with the elution agents 30 methylene chloride, methylene chloride-ethyl acetate (9:1 v/~ and 7:3 v/v and ethyl acetate and the residue obtained by evaporation of the main fraction is triturated with diethyl ~1~9416 ether. There are obtained 25.0 g. ( 8~/o of theory) of the desired compound in the form of colourless crystals, m.p.
- 97 - 99C.
The following compounds are obtained in ~n analogous manner:
a) l-Lcarbazolyl- ( 4 ) ~oxy 1-3- rN-methyl-2- ( 2-methoxyphenoxY ) ~
eth~laminol-propan-2-ol yield 22% of theory; colourless oil; hydrochloride m.p. 109C.
(slight evolution of gas), from 4~ ( 2 ~ 3-epoxypropoxy)-carbazole and N-methyl-2-(2-methoxyphenoxy)-ethylamine, b) l-rcarbazolvl-(4)-oxYl-3-rN-butyl-2-(2-methoxYPhenoxy) ethylaminol-propan-2-ol yield 84% of theory, colourless oil; hydrochloride m.p.
169 - 170C., from 4-(2,3-epoxypropoxy)-carbazole and N-[2-(2-methoxy-phenoxy)-ethyl]-butylamine, ! c) l-rcarbazolyl-(4)-oxyl-3-rN-benzyl-2-(5-carbamoyl-2 pyridyloxy~-ethvlaminol-propan-2-ol yield 80% of theory; m.p. 165 - 167C, from 4-(2,3-epoxypropoxy)-carbazole and N-[2-(5-carbamoyl-2-pyridyloxy)-ethyl]-benzylamine.
Example 6 l-rCarbazolvl-(4)-oxy1-2-formYloxy-3-rN-benzyl-2-(2-methoxy-phenoxy)-eth~_aminol-propane hydrochloride A formic acid-acetic acid anhydride mixture prepared from 3 ml, formic acid and 6 ml, acetic anhydride is allowed to act for 2,5 days at ambient temperature on 7,9 g. 1-rcarbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxyphenoxy)-ethyl-amino]-propan-2-ol, (see Example 5). The reaction mixture is then poured into ice water, neutralised with an aqueous 1129~16 solution of sodium bicarbonate, extracted with methylene chloride and the desired hydrochloride then precipitated out from an ethereal solution of the extraction residue. The yield is 8.1 g. (91% of theory) of colourless crystals which sinter above 85C. and form bubb~es above 120C.
Example 7 l-rCarbazolyl-(4)-oxyl-2-pivaloyloxy-3-rN-benzyl-2-(2-methoxy-phe~n ~laminol-propane hydrochloride 1.9 rrl. pivalic acid chloride is introduced into a solution of 7.0 g. 1- [carbazolyl-(4)-oxy]-3- [N-benzyl~
2-(2-methoxyphenoxy)-ethylamino]-propan-2-ol, (see Example 5), in 35 ml. pyridine. After standing overnight, the re-action mixture is poured into water, extracted with methylene chloride, purified chromatographically with a silica gel column and the hydrochloride precipitated out from an ethereal solution of the ba~e. The yield i~3 6.6 g. (77YO of theory) of colourless crystais which sinter above 102C. and melt at 120C., with a slight evolution of gas.
The following compound i9 prepared in an analogous 20 manner by benzoylation of 1-[carbazolyl-(4)-oxy]-3-[N-benzyl 2-(2-methoxyphenoxy)-ethylamir~-propan-2-ol wi~h benzoyl chloride:
1- rcarbazolyl-(4¦-oxyl-2-benzoyloxy-3-rN-benzvl-2-(2-methoxy-phenoxy)-ethylaminol-propane hYdrochloride yield 70/O of theory; m.p. 113C. with slight evolution of gas.
Example 8 1- rCarbazolyl-(4)-oxyl-2-formyloxy-3-r2-(2-met~
ethvlaminol-pro~ane hydrochloride 2.2 g. 1- rCarbazolyl-(4)-oxy]-2-formyloxy-3-[N-benzyl-30 2-(2-methoxyphenoxy)-ethylamino]-propane hydrochloride (see Example 6), are hydrogenated in 40 ml. anhydrous tetrahydrofuran :1129416 in the presence of 0.3 g~ l~/o palladium~charcoal at atmospheric pressure. After filtering with suction and evaporating the filtrate, the residue obtained is worked up with diethyl ether and crystallises. The yield of the desired product i~ 1.3 g.
(7~/O of theory) in the form of colourless crystal~; m.p. 62C., with bubble formation.
The following compounds are obtained in an analogous manner:
a) l-rcarbazolYl-(4)-oxYl-2-pivaloyloxY--3-r2-(2-meth phenoxy)-ethYlaminol-propane hydrochloride yield 85% of theory; m.p. 199 - 201C., with slight evolution of gas;
by the hydrogenolysis of l-[carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propane hydro-chloride (see Example 7).
b) l-rcarbazolYl-(4)-oxYl-2-benzovloxY-3-r2-(2-meth phenoxy)-ethYlaminol-Dropane hYdrochloride yield 84% of theory; m.p. 102C., with evolution of gas; by hydrogenolysis of l-Ccarbazolyl-(4)-oxy~-2-benzoyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propane hydrochloride, (see Example 7).
c) 1-rcarb ~ xYl-3-r2-~5-carbamov~-2-pYridyloxy)-ethy~-ProDan-2 -ol by hydrogenolysis of l-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(5-carbamoyl-2-pyridyloxy)-ethylamino]-propan-2-ol, (see Example 5c), d) l-rcarbazolYl-~4)-oxYl-3-r2-(2-hYdroxyphenoxy)-ethylamin propan-2-ol yield 77% of theory, hydrochloride m.p. 214 - 215C.,; by hydrogenolysis of 1-[carbazolyl-(4)-oxy]-3-[2-(2-benzyloxy-phenoxy)-ethylamino]-propan-2-ol, (see Example 3j).
11294~6 Example 9 (proceRs_~
l-rCarbazolvl-(4)-oxyl-3-r2-(5-fluoro-2-methoxyphenoxy)-ethYlaminol-propan-2-ol 7.0 g. 1-Amino-3-[carbazolyl-(4)-oxy]-propan-2-ol, 9,2 g. 2-(5-fluoro-2-methoxyphenoxy)-ethyl E~toluene-sulphonate and 3.8 ml. triethylamine are stirred in 20 ml. dimethyl-formamide for 20 hours at 70C. The reaction mixture is then poured into a dilute aqueous solution of sodium hydroxide, extracted with methylene chloride, dried and purified chromato-graphically in the manner describedin Example 4. After re-crystallisation from ethyl acetate with the use of active charcoal and fullers' earth, there are obtained 2 7 g. (23%
of theory) of the desired product in the form of colourless crystals; m.p. 146 - 147C.
The starting materials can be prepared in the follow-ing manner:
l-amino-3-~carbazolyl-(4)-oxYl-propan-2-ol 40 g. 4-(2,3-Epoxypropoxy)-carbazole are stirred with 500 ml. liquid ammonia in 2 litres methanol for 24 hours at 50C. in an autoclave, After evaporating the reaction mixture and recrystallising the residue from ethanol, there are obtained 31 g~ of the desired product in the form of colourless crystals; m.p. 141 - 143C.
2-t5-fluoro-2-methoxy~henoxy)-ethvl P-toluenesulPhonate 40.4 g 5-Fluoro-2-methoxyphenol, 24.6 ml. 2-chloro-ethanol and 20.7 g. potassium hydroxide are stirred in 100 ml.
,dimethylformamide for 2 hours at 70C, The reaction mixture is poured into water, extracted with methylene chloride, evaporated and the residue distilled in a high vacuum to give 11.3 g. 2-(5-fluoro-2-methoxyphenoxy)-ethanol in the form of a colourless oil which solidifies upon standing, m.p. 43 - 45C.
llZ941~
The further reaction thereof with p-toluenesulphonic acid chloride gives the desired tosylate, m.p. 66 - 68C., re-crystallised from ethanol.
Example 10 (process c)) 1-rCarbazolyl-(4)-oxyl-3-rl-t2-methoxyphenoxy)-propyl-2-aminol-propan-2-ol A mixture of 8.1 g. 1-amino-3-[carbazolyl-(4)-oxy]-propan-2-ol and 6.0 g. (2-methoxyphenoxy)-acetone in 250 ml.
methanol is hydrogenated in the presence of 1.0 g. l~/o palladium charcoal at 5 ats pressure and 38C. and the crude product obtained i9 purified chromatographically in the manner described in Example 4. After triturating the residue obtained by evaporation of the main fraction, there are obtained 5.5 g. (41% of theory) of the desired product in the form of colourless crystals (m.p. 113 - 117C.) which is a crude diastereomeric mixture. By recrystallisation from ethyl acetate and from ethanol, there is obtained there-from a product with a constant melting point of 140 - 141C.
Example 11 (process d)) l-rCarbazolyl-(4~-oxyl-3-L3-(2-methoxyphenyl)-propylamin propan-2-ol A solution of 4.4 g. 3-(2-methoxyphenyl)-propionic acid chloride in 50 ml. methylene chloride is added dropwise, with stirring, to a solution of 6.0 g. 1-amino-3-[carbazolyl-
(4)-oxy]-propan-2-ol and 3.3 ml. triethylamine in 50 ml.
methylene chloride at ambient temperature. After standing overnight, the reaction mixture is shaken with water and the organic phase is dried, evaporated and the residue is stirred with diethyl ether to give 8.2 g, (84% of theory) l-[carbazolyl-(4)-oxy]-3-r3-(2-methoxyphenyl)-propionylamino~-propan-2-ol, m.p. 142 - 144C. 7.7 g. of this intermediate product are reduced with 1.5 g. lithium aluminium hydride in 100 ml.
~1294~6 anhydrous tetrahydrofuran by boiling under reflux for 20 hours.
After working up in the usual manner the oil obtained, it is purified chromatographically with a silica gel column in the manner described in Example 4, By recrystallisation form toluene, with the use of active charcoal and fullers' earth, there are obtained 2.1 g, (28% of theory) of the desired product in the form of colourless crystals; m~p. 102 - 104C~
_ 28 -
methylene chloride at ambient temperature. After standing overnight, the reaction mixture is shaken with water and the organic phase is dried, evaporated and the residue is stirred with diethyl ether to give 8.2 g, (84% of theory) l-[carbazolyl-(4)-oxy]-3-r3-(2-methoxyphenyl)-propionylamino~-propan-2-ol, m.p. 142 - 144C. 7.7 g. of this intermediate product are reduced with 1.5 g. lithium aluminium hydride in 100 ml.
~1294~6 anhydrous tetrahydrofuran by boiling under reflux for 20 hours.
After working up in the usual manner the oil obtained, it is purified chromatographically with a silica gel column in the manner described in Example 4, By recrystallisation form toluene, with the use of active charcoal and fullers' earth, there are obtained 2.1 g, (28% of theory) of the desired product in the form of colourless crystals; m~p. 102 - 104C~
_ 28 -
Claims (103)
1. A process for the preparation of a carbazolyl-(4)-oxypropanolamine derivative of the formula (I):- (I) in which R1 is a hydrogen atom, an alkanoyl radical of 1 to 6 carbon atoms or an aroyl radical of 7 to 11 carbon atoms; R2 is a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms or a phenylalkyl radical of 7 to 11 carbon atoms, R3 is a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms; R4 is a hydro-gen atom or an alkyl radical of 1 to 6 carbon atoms; X is a valency bond, a -CH2- radical or an oxygen or sulphur atom, Ar is a mono- or bicyclic hydrocarbon radical of 6 to 10 carbon atoms or a pyridyl radical, and R5 and R6, which can be the same or different, are selected from the group consisting of hydro-gen, halogen, hydroxyl, lower alkyl of 1 to 6 carbon atoms, carbamoyl, lower alkoxy of 1 to 6 carbon atoms, ar-alkoxy of 7 to 11 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkyl-sulphinyl of 1 to 6 carbon atoms, or alkylsulphonyl of 1 to 6 carbon atom radicals, or R5 and R6 together represent a methy-lenedioxy radical and, when X is an oxygen atom, R4 and R5 together can also represent a -CH2-0- radical, and the pharma-ceutically acceptable, physiologically or pharmacologically compatible acid addition salts thereof, comprising a) reacting a compound of the formula (II):- (II) in which Y is a reactive group and R1 has the same meaning as R1 above or Y and R1' together represent a valency bond, with a compound of the formula (III):- (III) in which R2, R3, R4, X, Ar, R5 and R6 are as defined above, or b) reacting a compound of the formula (IV):- (IV) in which R1 and R2 are as defined above, with a compound of the formula (V):- (V) in which Y, R3, R4, X, Ar, R5 and R6 are as defined above, or c) reducing a mixture of a compound of formula (IV), as defined above, and of a compound of the formula (VI):- (VI) in which R3, R4, X, Ar, R5 and R6 are as defined above, or d) reacting a compound of formula (IV), as defined above, with a compound of the formula (VII):- (VII) in which Y, R4, X, Ar, R5 and R6 are as defined above, and reducing the amide obtained whereafter, if desired, the com-pound obtained of formula (I) is converted into another com-pound of formula (I) in a process selected from:
i) oxidizing a compound obtained of formula (I) in which at least one of R5 and R6 is an alkylthio radical to produce an alkylsulphinyl or alkyl-sulphonyl radical, ii) esterifying or etherifying a hydroxyl group in a compound of formula (I), iii) converting an ester or ether group into a hydroxyl group, and iv) hydrogenating a ar-lower-alkyl group, and, if desired, a compound obtained is converted into a pharmaceutically acceptable, physiologically or pharma-cologically compatible acid addition salt.
i) oxidizing a compound obtained of formula (I) in which at least one of R5 and R6 is an alkylthio radical to produce an alkylsulphinyl or alkyl-sulphonyl radical, ii) esterifying or etherifying a hydroxyl group in a compound of formula (I), iii) converting an ester or ether group into a hydroxyl group, and iv) hydrogenating a ar-lower-alkyl group, and, if desired, a compound obtained is converted into a pharmaceutically acceptable, physiologically or pharma-cologically compatible acid addition salt.
2. A process according to claim 1, comprising reacting said compound of formula (II) with said compound of formula (III).
3. A process according to claim 1, comprising reacting said compound of formula (IV) with said compound of formula (V) .
4. A process according to claim 1, comprising reducing said mixture of said compound of formula (IV) with said com-pound of formula (VI).
5. A process according to claim 1, comprising reacting said compound of formula (IV) with said compound of formula (VII).
6. A process according to claim 1, including the step of reacting a free base obtained of formula (I) with a non-toxic, inorganic or organic acid to form a corresponding pharmaceutically acceptable, physiologically or pharma-cologically compatible acid addition salt thereof.
7. A process according to claim 1, in which R1 is a hydrogen atom, formyl, acetyl, propionyl, pivalolyl, benzoyl or naphthoyl, R2 is a hydrogen, atom, alkyl of 1 to 4 carbon atoms, benzyl, phenylethyl or phenylpropyl;
R3 and R4 are hydrogen or alkyl of 1 to 4 carbon atoms.
R3 and R4 are hydrogen or alkyl of 1 to 4 carbon atoms.
8. A process according to claim 1, in which R5 and R6 can be the same or different and are selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, alkyl of 1 to 4 carbon atoms, carbamoyl, methoxy, ethoxy, methylthio, methylsulphinyl, methylsulphonyl and benzyloxy, and Ar is phenyl, naphthyl, indanyl, tetrahydronaphthyl or pyridyl.
9. A process according to claim 1, in which Y is a leaving group in an SN nucleophilic substitution reaction displaceable by amino.
10. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(2-methoxyphenyl)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-methoxyphenyl)-ethylamine.
11. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(3,4-dimethoxyphenyl)-ethylamine,
12. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(2-pyridyl)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-pyridyl)-ethylamine.
13. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(4-pyridyl)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(4-pyridyl)-ethylamine.
14. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-(3-phenylpropylamino)-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 3-phenylpropyl-amine.
15. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[4-phenylbutyl-(2)-amino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 4-phenylbutyl-(2)-amine.
16. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-methoxyphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-methoxyphenoxy)-ethylamine.
17. A process according to claim 2, for preparing l-[car-bazolyl-(4)-oxy]-3-(2-phenoxyethylamino)-propan-2-ol, com-prising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-phenoxyethylamine.
18. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[1-phenoxypropyl-(2)-amino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 1-phenoxypropyl-(2)-amine,
19. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[1,4-benzodioxanyl-(2)-methylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(aminomethyl)-1,4-benzodioxan.
20. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(4-carbamoylphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(4-carbamoylphenoxy)-ethylamine.
21. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(2-ethoxyphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-ethoxyphenoxy)-ethylamine.
22. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(4-fluorophenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(4-fluorophenoxy)-ethylamine.
23. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(4-tert.-butylphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(4-tert.-butylphenoxy)-ethylamine.
24. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(2,3-dimethylphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2,3-dimethylphenoxy)-ethylamine,
25. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-{2-[indanyl-(5)-oxy]-ethylamino}-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-[indanyl-(5)-oxy]-ethylamine.
26. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-{2-[naphthyl-(1)-oxy]-ethylamino}-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-[naphthyl-(1)-oxy]-ethylamine.
27. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(3,4-methylenedioxyphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carba-zole with 2-(3,4-methylenedioxyphenoxy)-ethylamine.
28. A process according to claim 2, for preparing l-[car-bazolyl-(4)-oxy]-3-[2-(2,6-dimethoxyphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carba-zole with 2-(2,6-dimethoxyphenoxy)-ethylamine.
29. A process according to claim 2, for preparing 1-[car-bazolyl-(4)-oxy]-3-[2-(2-methoxyphenoxy)-propylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-methoxyphenoxy)-propylamine.
30. A process according to claim 2, for preparing l-[car-bazolyl-(4)-oxy]-3-[2-(2-methylthiophenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-methylthiophenoxy)-ethylamine.
31. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(2-benzyloxyphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-benzyloxyphenoxy)-ethylamine.
32. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(2-methylphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-methylphenoxy)-ethylamine.
33. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(3-methylphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(3-methylphenoxy)-ethylamine.
34. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(2-chlorophenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-chlorophenoxy)-ethylamine.
35. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(3-methoxyphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carba-zole and 2-(3-methoxyphenoxy)-ethylamine.
36. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(4-methoxyphenoxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carba-zole with 2-(4-methoxyphenoxy)-ethylamine.
37. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(2-methoxyphenylthio)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with 2-(2-methylphenylthio)ethylamine.
38. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[1-(2-methoxyphenoxy)-propyl-2-amino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carba-zole with 1-(2-methoxyphenoxy)-propyl-2-amine.
39. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-methylsulphinylphenoxy)-ethylamino]-propan-2-ol, comprising reacting4-(2,3-epoxypropoxy)-carba-zole with 2-(2-methylsulphinylphenoxy)-ethylamine.
40. A process according to claim 8, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-methylsulphinylphenoxy)-ethylamino]-propan-2-ol, comprising oxidizing 1-[carbazolyl-(4)-oxy]-3-[2-(2-methylthiophenoxy)-ethylamino]-propan-2-ol.
41. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxyphenoxy)-ethyl-amino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with N-[2-(2-methoxyphenoxy)-ethyl]-benzylamine,
42. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[N-methyl-2-(2-methoxyphenoxy)-ethyl-amino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with N-methyl-2-(2-methoxyphenoxy)-ethylamine.
43. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[N-butyl-2-(2-methoxyphenoxy)-ethyl-amino]-propan-2-ol, comprising reacting 4-(2,3-epoxypropoxy)-carbazole with N-[2-(2-methoxyphenoxy)-ethyl]-butylamine.
44. A process according to claim 2, for preparing 1-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(5-carbamoyl-2-pyridyloxy)-ethylamino]-propan-2-ol, comprising reacting 4-(2,3-epoxy-propoxy)-carbazole with N-[2-(5-carbamoyl-2-pyridyloxy)-ethyl]-benzylamlne.
45. A process according to claim 8, for preparing 1-[carbazolyl-(4)-oxy]-2-formyloxy-3-[N-benzyl-2-(2-methoxy-phenoxy)-ethylamino]-propane, comprising esteri-fying l-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol with formic acid
46. A process according to claim 8, for preparing 1-[carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[N-benzyl-2-(2-methoxy-phenoxy)-ethylamino]-propane comprising esteri-fying l-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol with pivalic acid chloride.
47. A process according to claim 8, for preparing 1-[carbazolyl-(4)-oxy]-2-benzoyloxy-3-[N-benzyl-2-(2-methoxy-phenoxy)-ethylamino]-propae,comprising benzoylating 1-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxyphenoxy)-ethyl-amino]-propan-2-ol.
48. A process according to claim 8, for preparing 1-[carbazolyl-(4)-oxy]-2-formyloxy-3-[2-(2-methoxyphenoxy)-ethylamino]-propane, comprising hydrogenating 1-[carbazolyl-(4)-oxy]-2-formyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethyl-amino]-propane.
49. A process according to claim 8, for preparing 1-[carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[2-(2-methoxyphenoxy)-ethylamino]-propane hydrochloride comprising hydrogenolysing 1-[carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propane hydrochloride,
50. A process according to claim 8, for preparing 1-rcarbazolyl-(4)-oxy]-2-benzoyloxy-3-[2-(2-methoxyphenoxy)-ethylamino]-propane hydrochloride, comprising hydrogenolysing l-[carbazolyl-(4)-oxy]-2-benzoyloxy-3-[N-benzyl-2-(2-methoxy-phenoxy)-ethylamino]-propane hydrochloride.
51. A process according to claim 8, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(5-carbamoyl-2-pyridyloxy)-ethyl-amino]-propan-2-ol, comprising hydrogenolysing 1-[carbazolyl-(4)-oxy]-3-[N-benzyl-2-(5-carbamoyl-2-pyridyloxy)-ethyl-amino]-propan-2-ol,
52. A process according to claim 8, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(2-hydroxyphenoxy)-ethylamino)]-propan-2-ol, comprising hydrogenolysing 1-[carbazolyl-(4)-oxy]-3-[2-(2-benzyloxyphenoxy)-ethylamino]-propan-2-ol.
53. A process according to claim 3, for preparing 1-[carbazolyl-(4)-oxy]-3-[2-(5-fluoro-2-methoxyphenoxy)-ethyl-amino]-propan-2-ol, comprising reacting 1-amino-3-[carbazolyl-(4)-oxy]-propan-2-ol with 2-(5-fluoro-2-methoxyphenoxy)-ethyl p-toluenesulphonate.
54. A process according to claim 4, for preparing 1-[carbazolyl-(4)-oxy]-3-[1-(2-methoxyphenoxy)-propyl-2-amino]-propan-2-ol, comprising reducing a mixture of 1-amino-3-[carba-zolyl-(4)-oxy]-propan-2-ol and (2-methoxyphenoxy)-acetone.
55. A process according to claim 54, wherein said reduction comprises hydrogenation over a catalyst.
56. A process according to claim 5, for preparing 1-[carbazolyl-(4)-oxy]-3-[3-(2-methoxyphenyl)-propylamino]-propan-2-ol comprising reacting 3-(2-methoxyphenyl)-propionic acid chloride with 1-amino-3-[carbazolyl-(4)-oxy]-propan-2-ol. and reducing the resulting 1-[carbazolyl-(4)-oxy]-3-[3-(2-methoxyphenyl)-propionylamino]-propan-2-ol.
57. A carbazolyl-(4)-oxypropanolamine derivative of the formula (I):- (I) wherein R1, R2, R3, R4, R5, R6, X and Ar are as defined in claim 1, and the pharmaceutically acceptable, physiologically or pharmacologically compatible acid addition salts thereof, whenever prepared by the process of claim 1, 2 or 3, or by an obvious chemical equivalent.
58. A pharmaceutically acceptable, physiologically or pharmacologically compatible acid addition salt of a carbazolyl-(4)-oxypropanolamine derivative of formula (I) as defined in claim 1, whenever prepared by the process of claim 6, or by an obvious chemical equivalent.
59. 1-[Carbazoly1-(4)-oxy]-3-[2-(2-methoxyphenyl)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 10, or by an obvious chemical equivalent.
60. 1-[Carbazolyl-(4)-oxy]-3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 11, or by an obvious chemical equivalent.
61. 1-[Carbazolyl-(4)-oxy]-3-[2-(2-pyridyl)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 12, or by an obvious chemical equivalent.
62. 1-[Carbazolyl-(4)-oxy]-3-[2-(4-pyridyl)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 13, or by an obvious chemical equivalent.
63. 1-[Carbazolyl-(4)-oxy]-3-(3-phenylpropylamino)-propan-2-ol, whenever prepared by the process of claim 14, or by an obvious chemical equivalent.
64. 1-[Carbazolyl-(4)-oxy]-3-[4-phenylbutyl-(2)-amino]-propan-2-ol, whenever prepared by the process of claim 15, or by an obvious chemical equivalent.
65. 1-[Carbazolyl-(4)-oxy]-3-[2-methoxyphenoxy)-ethyl-amino]-propan-2-ol, whenever prepared by the process of claim 16, or by an obvious chemical equivalent.
66. 1-[Carbazolyl-(4)-oxy]-3-(2-phenoxyethylamino)-propan-2-ol, whenever prepared by the process of claim 17, or by an obvious chemical equivalent.
67. 1-[Carbazolyl-(4)-oxy]-3-[1-phenoxypropyl-(2)-amino]-propan-2-ol, whenever prepared by the process of claim 18, or by an obvious chemical equivalent.
68. 1-[Carbazolyl-(4)-oxy]-3-[1,4-benzodioxanyl-(2)-methylamino]-propan-2-ol, whenever prepared by the process of claim 19, or by an obvious chemical equivalent.
69, 1-[Carbazolyl-(4)-oxy]-3-[2-(4-carbamoylphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 20, or by an obvious chemical equivalent.
70. 1-[Carbazolyl-(4)-oxy]-3-[2-(2-ethoxyphenoxy)-ethyl-amino]-propan-2-ol, whenever prepared by the process of claim 21, or by an obvious chemical equivalent.
71. 1-[Carbazolyl-(4)-oxy]-3-[2-(4-fluorophenoxy)ethyl amino]-propan-2-ol, whenever prepared by the process of claim 22, or by an obvious chemical equivalent.
72. 1-[Carbazolyl-(4)-oxy]-3-[2-(4-tert.-butylphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 23, or by an obvious chemical equivalent.
73. 1-[Carbazolyl-(4)-oxy]-3-[2-(2,3-dimethylphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 24, or by an obvious chemical equivalent.
74. 1-[Carbazolyl-(4)-oxy]-3-{2-[indanyl-(5)-oxy]-ethyl amino}-propan-2-ol, whenever prepared by the process of claim 25, or by an obvious chemical equivalent.
75. 1-[Carbazolyl-(4)-oxy]-3-{2-[naphthyl-(1)-oxy]-ethylamino}-propan-2-ol, whenever prepared by the process of claim 26, or by an obvious chemical equivalent.
76. 1-[Carbazolyl-(4)-oxy]-3-[2-(3,4-methylendioxy-phenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 27, or by an obvious chemical equivalent.
77. 1-[Carbazolyl-(4)-oxy]-3-[2-(2,6-dimethoxyphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 28, or by an obvious chemical equivalent.
78. 1-[Carbazolyl-(4)-oxy]-3-[2-(2-methoxyphenoxy)-propylamino]-propan-2-ol, whenever prepared by the process of claim 29, or by an obvious chemical equivalent.
79. 1-[Carbazolyl-(4)-oxy]-3-[2 -(2-methylthiophenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 30, or by an obvious chemical equivalent.
80. 1-[Carbazolyl-(4)-oxy]-3-[2-(2-benzyloxyphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 31, or by an obvious chemical equivalent
81. 1-[Carbazolyl-(4)-oxy]-3-[2-(2-methylphenoxy)-ethyl-amino]-propan-2-ol, whenever prepared by the process of claim 32, or by an obvious chemical equivalent.
82. 1-[Carbazolyl-(4)-oxy]-3-[2-(3-methylphenoxy)-ethyl-amino]-propan-2-ol, whenever prepared by the process of claim 33, or by an obvious chemical equivalent.
83. 1-[Carbazolyl-(4)-oxy]-3-[2 (2-chlorophenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 34, or by an obvious chemical equivalent.
84. 1-[Carbazolyl-(4)-oxy]-3-[2-(3-methoxyphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 35, or by an obvious chemical equivalent.
85. 1-[Carbazolyl-(4)-oxy]-3-[2-(4--methoxyphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 36, or by an obvious chemical equivalent.
86. 1-[Carbazolyl-(4)-oxy]-3-[2-(2-methoxyphenylthio)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 37, or by an obvious chemical equivalent
87. 1-[Carbazolyl-(4)-oxy]-3-[1-(2-methoxyphenoxy)-propyl-2-amino]-propan-2-ol, whenever prepared by the process of claim 38, or by an obvious chemical equivalent.
88. 1-[Carbazolyl-(4)-oxy]-3-[2-methylsulphinylphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 39 or 40, or by an obvious chemical equivalent.
89. 1-[Carbazolyl-(4)-oxy]-3-[N-benzyl-2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 41, or by an obvious chemical equivalent.
90. 1-[Carbazolyl-(4)-oxy]-3-[N-methyl-2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 42, or by an obvious chemical equivalent.
91. 1-[Carbazolyl-(4)-oxy]-3-[N-butyl-2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 43, or by an obvious chemical equivalent.
92. 1-[Carbazolyl-(4)-oxy]-3-[N-benzyl-2-(5-carbamoyl-2-pyridyloxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 44, or by an obvious chemical equivalent.
93. 1-[Carbazolyl-(4)-oxy]2-formyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propane whenever prepared by the process of claim 45, or by an obvious chemical equivalent.
94. 1-[Carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propane, whenever prepared by the process of claim 46, or by an obvious chemical equivalent.
95. 1-[Carbazolyl-(4)-oxy]-2-benzoyloxy-3-[N-benzyl-2-(2-methoxyphenoxy)-ethylamino]-propane, whenever prepared by the process of claim 47, or by an obvious chemical equivalent.
96. 1-[Carbazolyl-(4)-oxy]-2-formyloxy-3-[2-(2-methoxy-phenoxy)-ethylamino]-propane, whenever prepared by the process of claim 48, or by an obvious chemical equivalent.
97. 1-[Carbazolyl-(4)-oxy]-2-pivaloyloxy-3-[2-(2-methoxyphenoxy)-ethylamino]-propane hydrochloride, whenever prepared by the process of claim 49, or by an obvious chemical equivalent.
98. 1-[Carbazolyl-(4)-oxy]-2-benzoyloxy-3-[2-(2-methoxy-phenoxy)-ethylamino]-propane hydrochloride, whenever prepared by the process of claim 50, or by an obvious chemical equivalent.
99. 1-[Carbazolyl-(4)-oxy]-3-[2-(5-carbamoyl-2-pyridyloxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 51, or by an obvious chemical equivalent.
100. 1-[Carbazolyl-(4)-oxy]-3-[2-(2-hydroxyphenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 52, or by an obvious chemical equivalent.
101. 1-[Carbazolyl-(4)-oxy]-3-[2-(5-fluoro-2-methoxy-phenoxy)-ethylamino]-propan-2-ol, whenever prepared by the process of claim 53, or by an obvious chemical equivalent.
102. 1-[Carbazolyl-(4)-oxy]-3-[1-(2-methoxyphenoxy)-propyl-2-amino]-propan-2-ol, whenever prepared by the process of claim 54 or 55, or by an obvious chemical equivalent.
103. 1-[Carbazolyl-(4)-oxy]-3-[3-(2-methoxyphenyl)-propylamino]-propan-2-ol, whenever prepared by the process of claim 56, or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2815926.4 | 1978-04-13 | ||
| DE19782815926 DE2815926A1 (en) | 1978-04-13 | 1978-04-13 | NEW CARBAZOLYL- (4) -OXY-PROPANOLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1129416A true CA1129416A (en) | 1982-08-10 |
Family
ID=6036838
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA324,667A Expired CA1129416A (en) | 1978-04-13 | 1979-04-02 | Carbazolyl-(4)-oxypropanolamine derivatives |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4503067A (en) |
| EP (1) | EP0004920B1 (en) |
| JP (2) | JPS54157558A (en) |
| AT (1) | AT375639B (en) |
| AU (1) | AU522975B2 (en) |
| BG (1) | BG61419B2 (en) |
| CA (1) | CA1129416A (en) |
| CS (2) | CS227007B2 (en) |
| DD (1) | DD143607A5 (en) |
| DE (2) | DE2815926A1 (en) |
| DK (1) | DK154555C (en) |
| ES (1) | ES479396A1 (en) |
| FI (1) | FI70406C (en) |
| HK (1) | HK2385A (en) |
| HU (1) | HU179433B (en) |
| IL (1) | IL57020A (en) |
| LT (1) | LT2628B (en) |
| LU (1) | LU88320I2 (en) |
| MX (1) | MX9203380A (en) |
| NL (1) | NL930110I2 (en) |
| SG (1) | SG52284G (en) |
| SU (1) | SU810079A3 (en) |
| ZA (1) | ZA791732B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007144785A2 (en) * | 2006-03-26 | 2007-12-21 | Uti Limited Partnership | Ryanodine receptor inhibitors and methods relating thereto |
Families Citing this family (114)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3131146A1 (en) * | 1981-08-06 | 1983-02-24 | Boehringer Mannheim Gmbh, 6800 Mannheim | NEW HETEROARYLOXYPROPANOLAMINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| DE3300933A1 (en) * | 1983-01-13 | 1984-07-19 | Boehringer Mannheim Gmbh, 6800 Mannheim | USE OF D, L- AND D-CARAZOLOL AS AN ANTI-GLAQUE AGENT AND MEDICINAL PRODUCTS CONTAINING THESE SUBSTANCES |
| DE3319027A1 (en) | 1983-05-26 | 1984-11-29 | Boehringer Mannheim Gmbh, 6800 Mannheim | METHOD FOR PRODUCING OPTICALLY ACTIVE CARBAZOL DERIVATIVES, NEW R- AND S-CARBAZOL DERIVATIVES, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| ZA938897B (en) * | 1992-12-01 | 1994-08-01 | Smithkline Beecham Corp | Antioxidant neuroprotective use of and method of treatment using hydroxycarbazole compounds |
| US5405863A (en) * | 1992-12-01 | 1995-04-11 | Smithkline Beecham Corporation | Antioxidant cardioprotective use of, and method of treatment using, hydroxycarbazole compounds |
| US5308862A (en) * | 1993-03-05 | 1994-05-03 | Boehringer Mannheim Pharmaceuticals Corporation - Smithkline Beecham Corp., Ltd. Partnership No. 1 | Use of, and method of treatment using, carbazolyl-(4)-oxypropanolamine compounds for inhibition of smooth muscle cell proliferation |
| WO1994020096A1 (en) * | 1993-03-05 | 1994-09-15 | Boehringer Mannheim Pharmaceuticals Corporation - Smithkline Beckman Corporation Limited | Method of employing carbazolyl-(4)-oxypropanolamine compounds for inhibition of smooth muscle cell proliferation |
| US5393772A (en) * | 1993-11-24 | 1995-02-28 | Boehringer Mannheim Pharmaceuticals Corporation | Use of, and method of treatment using, hydroxycarbazole compounds for inhibition of smooth muscle migration and proliferation |
| US5760069A (en) | 1995-02-08 | 1998-06-02 | Boehringer Mannheim Pharmaceuticals Corporation-Smithkline Beecham Corporation Limited Partnership #1 | Method of treatment for decreasing mortality resulting from congestive heart failure |
| US6075040A (en) * | 1996-09-05 | 2000-06-13 | Eli Lilly And Company | Selective β3 adrenergic agonists |
| ZA967892B (en) * | 1995-09-21 | 1998-03-18 | Lilly Co Eli | Selective β3 adrenergic agonists. |
| US6177430B1 (en) | 1997-03-27 | 2001-01-23 | Pfizer Inc | Use of α1-adrenoreceptor antagonists in the prevention and treatment of benign prostatic hyperplasia |
| DE19628335A1 (en) * | 1996-07-13 | 1998-01-15 | Boehringer Mannheim Gmbh | Use of topical (carbazolyl-oxy)-propanolamine derivatives |
| CZ59199A3 (en) * | 1996-08-23 | 1999-08-11 | Boehringer Mannheim Pharmaceuticals Corporation-Smithkline Beecham Corporation Limited Partnership No. 1 | INHIBITION METHOD OF FaS EXPRESSION |
| ES2171839T3 (en) | 1996-09-05 | 2002-09-16 | Lilly Co Eli | CARBAZOL ANALOGS AS BETA3 SELECTIVE ADRENERGIC AGONISTS. |
| PL332638A1 (en) * | 1996-10-09 | 1999-09-27 | Boehringer Mannheim Pharm Corp | Method of inhibiting stress-activated proteinous kinases |
| US6730326B2 (en) | 1997-07-22 | 2004-05-04 | Roche Diagnostics Gmbh | Thermodynamically stable modification of 1-(4-carbazolyl-oxy-3[2-(2-methoxyphenoxy)-ethylamino]-2-propanol process for its preparation and pharmaceutical compositions containing it |
| EP0893440A1 (en) * | 1997-07-22 | 1999-01-27 | Roche Diagnostics GmbH | Thermodynamically stable modification of 1-(4-carbazolyloxy)-3-[2-(2-methoxyphenoxy)ethylamino]-2-propanole, process for its preparation and pharmaceutical compositions containing it |
| ZA989365B (en) * | 1997-10-15 | 1999-04-15 | Boehringer Mannheim Pharm Corp | Preparation for treating alzheimer's disease |
| IL136028A0 (en) * | 1997-11-12 | 2001-05-20 | Boehringer Mannheim Pharm Corp | Novel oral dosage form for carvedilol |
| HU227441B1 (en) * | 1997-11-24 | 2011-06-28 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Process for producing carvedilol, enantiomers and salts thereof |
| CO5011072A1 (en) * | 1997-12-05 | 2001-02-28 | Lilly Co Eli | ETANOLAMINAS PIRAZINIL SUBSTITUTED AS AGFONISTS OF THE RECEPTORS |
| EP0968714A1 (en) * | 1998-07-02 | 2000-01-05 | Roche Diagnostics GmbH | Process to prepare fast dissolving pharmaceutical compositions containing hardly soluble agents |
| KR100520589B1 (en) * | 1998-04-09 | 2005-10-10 | 로쉐 디아그노스틱스 게엠베하 | Carvedilol-galenics |
| DE19833119A1 (en) * | 1998-07-23 | 2000-01-27 | Roche Diagnostics Gmbh | Storage-stable injectable solution of vasodilator and beta blocker Carvedilol contains buffer, organic solvent, antioxidant and complexing agent |
| US6664284B2 (en) | 1998-07-23 | 2003-12-16 | Roche Diagnostics Gmbh | Stabilized carvedilol injection solution |
| AU5251999A (en) | 1998-08-04 | 2000-02-28 | Wisconsin Alumni Research Foundation | Method of reducing retinal ganglion cell degeneration |
| PE20001302A1 (en) | 1998-11-27 | 2000-11-30 | Hoffmann La Roche | PREPARATIONS OF A PHARMACEUTICAL COMBINATION CONTAINING CARVEDILOL AND HYDROCHLOROTHIAZIDE |
| MY125942A (en) | 1999-09-07 | 2006-09-29 | Upjohn Co | Aminoalkoxy carbazoles for the treatment of cns diseases |
| JP2003514019A (en) | 1999-11-15 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | Carvedilol methanesulfonate |
| JP2003528914A (en) * | 2000-04-03 | 2003-09-30 | エフ．ホフマン−ラ ロシュ アーゲー | Concentrated solution of carvedilol |
| US20010036959A1 (en) * | 2000-04-03 | 2001-11-01 | Gabel Rolf Dieter | Carvedilol-hydrophilic solutions |
| DK174645B1 (en) * | 2000-05-18 | 2003-08-04 | Gea Farmaceutisk Fabrik As | Process and intermediates for the preparation of 1- (9H-carbazol-4-yloxy) -3- [2- (2-methoxy-phenoxy) -ethylamino] -propan-2-ol, carvedilol and acid addition salts thereof |
| MXPA02012795A (en) | 2000-06-28 | 2004-07-30 | Teva Pharma | Carvedilol. |
| EP1655285A1 (en) * | 2000-06-28 | 2006-05-10 | Teva Pharmaceutical Industries Ltd. | Method for preparation of a crystalline form of carvedilol (form II) |
| WO2003079972A2 (en) | 2002-02-22 | 2003-10-02 | New River Parmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
| GB0106953D0 (en) * | 2001-03-20 | 2001-05-09 | Univ Aberdeen | Neufofibrillary labels |
| US20050009897A1 (en) * | 2001-04-02 | 2005-01-13 | Karen Anderson | Method of treatment |
| IN191028B (en) * | 2001-05-17 | 2003-09-13 | Sun Pharmaceutical Ind Ltd | |
| ATE328595T1 (en) * | 2001-07-13 | 2006-06-15 | Smithkline Beecham Corp | CARVEDILOL POLYMORPHOUS |
| AU2002323135A1 (en) * | 2001-08-14 | 2003-03-03 | Variant Holdings, Llc. | System for marketing goods and services utilizing computerized central and remote facilities |
| US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
| US20040234602A1 (en) * | 2001-09-21 | 2004-11-25 | Gina Fischer | Polymer release system |
| ES2291503T3 (en) * | 2001-09-28 | 2008-03-01 | F. Hoffmann-La Roche Ag | PSEUDOPOLIMORFICAS FORMS OF CARVEDILOL. |
| WO2003028718A1 (en) * | 2001-10-01 | 2003-04-10 | Smithkline Beecham Corporation | Novel formulations of carvedilol |
| US8101209B2 (en) * | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
| PL371409A1 (en) | 2002-01-15 | 2005-06-13 | Teva Pharmaceutical Industries Ltd. | Crystalline solids of carvedilol and processes for their preparation |
| AU2003231283A1 (en) * | 2002-04-30 | 2003-11-17 | Sb Pharmco Puerto Rico Inc. | Carvedilol monocitrate monohydrate |
| CA2484621A1 (en) * | 2002-05-03 | 2003-11-13 | Smithkline Beecham Pharmco Puerto Rico, Inc. | Carvedilol formulations |
| EP1501502A2 (en) * | 2002-05-03 | 2005-02-02 | SmithKline Beecham Pharmco Puerto Rico, Inc. | Carvedilol pharmasolve solvate |
| US20050261355A1 (en) * | 2002-06-27 | 2005-11-24 | Sb Pharmco Puerto Rico Inc., | Carvedilol hydobromide |
| EA008384B1 (en) | 2002-06-27 | 2007-04-27 | Эс Би ФАРМКО ПУЭРТО РИКО ИНК. | Carvedilol phosphate salts and/or solvates thereof, compositions and methods to treat hypertension, congestive heart failur and angina |
| US20040152756A1 (en) * | 2002-07-15 | 2004-08-05 | Wei Chen | Carvedilol polymorph |
| US20060013877A1 (en) * | 2002-07-22 | 2006-01-19 | Nanohybrid Co., Ltd. | Hybrid of itraconazole, cyclosporine or carvedilol with a layered silicate and a process for preparing the same |
| GEP20074134B (en) | 2002-08-19 | 2007-06-25 | Pfizer Prod Inc | Combination therapy for hyperproliferative diseases |
| US6632832B1 (en) | 2002-09-10 | 2003-10-14 | Dabur Research Foundation | Anti-cancer activity of carvedilol and its isomers |
| SK285547B6 (en) * | 2002-11-08 | 2007-03-01 | Zentiva, A. S. | Preparation process of Carvedilol |
| US20040151772A1 (en) * | 2002-11-08 | 2004-08-05 | Egalet A/S | Controlled release carvedilol compositions |
| WO2004094378A1 (en) * | 2003-04-21 | 2004-11-04 | Matrix Laboratories Ltd | Process for the preparation of carvedilol form-ii |
| EP2319843B1 (en) * | 2003-05-30 | 2013-04-03 | Ranbaxy Laboratories Limited | Substituted pyrrole derivatives and their use as HMG-CO inhibitors |
| WO2004113296A1 (en) * | 2003-06-20 | 2004-12-29 | Sun Pharmaceutical Industries Limited | A process for preparation of 1-[9h-carbazol-4-yloxy]- 3-[{2-(2-(-(methoxy)phenoxy)-ethyl}-amino]-propan-2-ol |
| US20050037063A1 (en) * | 2003-07-21 | 2005-02-17 | Bolton Anthony E. | Combined therapies |
| JP5072364B2 (en) | 2003-11-25 | 2012-11-14 | スミスクライン ビーチャム （コーク） リミテッド | Carvedilol free base, carvedilol salt, anhydrous form or solvate thereof, corresponding pharmaceutical composition, controlled release formulation and treatment or delivery method |
| US7750036B2 (en) * | 2003-11-25 | 2010-07-06 | Sb Pharmco Puerto Rico Inc. | Carvedilol salts, corresponding compositions, methods of delivery and/or treatment |
| JP2007512350A (en) * | 2003-11-25 | 2007-05-17 | エスビー・ファルムコ・プエルト・リコ・インコーポレイテッド | Carvedilol composition treatment and delivery methods |
| US20070191456A1 (en) * | 2004-04-22 | 2007-08-16 | Tarur Venkatasubramanian R | Novel process for the preparation of 1-(9h-carbazol-4-yloxy)-3-[[2-(-methoxyphenoxy)-ethyl] amino]-propan-2-ol |
| GB0411273D0 (en) * | 2004-05-20 | 2004-06-23 | Cipla Ltd | Process and product |
| CA2588947A1 (en) * | 2004-11-30 | 2006-06-08 | Artesian Therapeutics, Inc. | Cardiotonic compounds with inhibitory activity against beta-adrenergic receptors and phosphodiesterase |
| JP2008523025A (en) * | 2004-12-09 | 2008-07-03 | ザック システム エス．ピー．エー． | Process for the preparation of carvedilol and its enantiomers |
| US20070027202A1 (en) * | 2005-06-07 | 2007-02-01 | Ashok Kumar | Process for the preparation of carvedilol and its salts |
| WO2006135757A1 (en) * | 2005-06-09 | 2006-12-21 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of carvedilol and processes for their preparation |
| GT200600381A (en) | 2005-08-25 | 2007-03-28 | ORGANIC COMPOUNDS | |
| JP2009511562A (en) * | 2005-10-13 | 2009-03-19 | オーキッド リサーチ ラボラトリーズ リミティド | Novel heterocyclic compounds as pSTAT3 / IL-6 inhibitors |
| US7741317B2 (en) | 2005-10-21 | 2010-06-22 | Bristol-Myers Squibb Company | LXR modulators |
| SG166829A1 (en) * | 2005-11-08 | 2010-12-29 | Ranbaxy Lab Ltd | Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt |
| US7888376B2 (en) | 2005-11-23 | 2011-02-15 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
| US8367112B2 (en) * | 2006-02-28 | 2013-02-05 | Alkermes Pharma Ireland Limited | Nanoparticulate carverdilol formulations |
| AR059838A1 (en) * | 2006-03-14 | 2008-04-30 | Ranbaxy Lab Ltd | FORMULATIONS FOR STABILIZING DOSES OF STATIN |
| WO2008002683A2 (en) * | 2006-06-28 | 2008-01-03 | Teva Pharmaceutical Industries Ltd. | Polymorphous forms of carvedilol phosphate |
| BRPI0714361A2 (en) * | 2006-07-14 | 2013-03-26 | Ranbaxy Lab Ltd | crystalline polymorph, pharmaceutical composition containing the same, method of preparation and method of treatment |
| WO2008038301A1 (en) * | 2006-09-26 | 2008-04-03 | Morepen Laboratories Limited | A process for the preparation of carvedilol |
| US20090028935A1 (en) * | 2006-12-01 | 2009-01-29 | Kristin Arnold | Carvedilol forms, compositions, and methods of preparation thereof |
| WO2008070072A2 (en) * | 2006-12-01 | 2008-06-12 | Mutual Pharmaceutical Company, Inc. | Carvedilol forms, compositions, and methods of preparation thereof |
| ATE547394T1 (en) | 2006-12-01 | 2012-03-15 | Bristol Myers Squibb Co | N-((3-BENZYL)-2,2-(BIS-PHENYL)-PROPANE-1- AMINE DERIVATIVES AS CETP INHIBITORS FOR THE TREATMENT OF ATHEROSCLERosis AND CARDIOVASCULAR DISEASES |
| WO2008084494A1 (en) * | 2007-01-08 | 2008-07-17 | Matrix Laboratories Limited | Novel polymorphic forms of carvedilol dihydrogen phosphate and process for preparing the same |
| NZ577560A (en) * | 2007-01-16 | 2012-01-12 | Egalet Ltd | Use of i) a polyglycol and ii) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse |
| CZ302357B6 (en) * | 2007-01-26 | 2011-03-30 | Zentiva, A. S. | Purification process of Carvedilol |
| WO2008105794A1 (en) * | 2007-02-26 | 2008-09-04 | Teva Pharmaceutical Industries Ltd. | Process for the purification of carvedilol or its salts thereof |
| US20080249317A1 (en) * | 2007-04-04 | 2008-10-09 | Apotex Inc. | Novel amorphous form of carvedilol phosphate and processes for the preparation thereof |
| WO2008142703A1 (en) * | 2007-05-17 | 2008-11-27 | Wanbury Limited | A novel cost effective process for production of carvedilol phosphate |
| AU2008258596B2 (en) | 2007-06-04 | 2013-02-14 | Egalet Ltd | Controlled release pharmaceutical compositions for prolonged effect |
| WO2009024997A1 (en) * | 2007-08-21 | 2009-02-26 | Lupin Limited | Stable amorphous form of carvedilol dihydrogen phosphate with stabilizer |
| WO2009035535A2 (en) * | 2007-09-07 | 2009-03-19 | Scinopharm Taiwan Ltd. | Method of crystallizing carvedilol phosphate and the product thereof |
| US20090076116A1 (en) * | 2007-09-13 | 2009-03-19 | Protia, Llc | Deuterium-enriched carvediolo |
| US20090111998A1 (en) * | 2007-10-25 | 2009-04-30 | Srinivas Reddy Gade | Process for the preparation of carvedilol dihydrogen phosphate hemihydrate and pharmaceutical compositions thereof |
| US8889728B2 (en) * | 2008-03-04 | 2014-11-18 | Lupin Limited | Stable pharmaceutical compositions of carvedilol |
| WO2009115902A1 (en) * | 2008-03-19 | 2009-09-24 | Cadila Pharmaceuticals Ltd. | Process for the preparation of carvedilol via silyl protection of substituted amine |
| WO2009115906A2 (en) * | 2008-03-19 | 2009-09-24 | Cadila Pharmaceuticals Ltd. | An improved process for preparation of carvedilol involving halohydrin derivative |
| WO2009122425A1 (en) * | 2008-04-04 | 2009-10-08 | Shodhana Laboratories Limited | Novel crystalline form of carvedilol dihydrogen phosphate and related processes |
| US7763645B2 (en) * | 2008-05-23 | 2010-07-27 | Wanbury Limited | Carvedilol dihydrogen phosphate monohydrate |
| WO2010092589A2 (en) * | 2008-05-26 | 2010-08-19 | Alkem Laboratories Ltd. | Process for preparation of amorphous carvedilol phosphate |
| NZ594207A (en) | 2009-02-06 | 2013-03-28 | Egalet Ltd | Immediate release composition resistant to abuse by intake of alcohol |
| EP2445487A2 (en) | 2009-06-24 | 2012-05-02 | Egalet Ltd. | Controlled release formulations |
| TWI415604B (en) | 2009-09-29 | 2013-11-21 | Tsh Biopharm Corp Ltd | Controlled release carvediolol formulation |
| US20110229564A1 (en) * | 2010-03-22 | 2011-09-22 | Amneal Pharmaceuticals, L.L.C. | Pharmaceutical Compositions Of Carvedilol Salts And Process For Preparation Thereof |
| BR112014014480A2 (en) | 2011-12-16 | 2017-06-13 | 3M Innovative Properties Co | bisirhydrohexitol derivatives containing oxirane and uses thereof |
| EP2877161A1 (en) | 2012-07-06 | 2015-06-03 | Egalet Ltd. | Abuse deterrent pharmaceutical compositions for controlled release |
| US8492426B1 (en) * | 2012-07-12 | 2013-07-23 | Anis Ahmad | Use of carvedilol for treatment of diabetes mellitus |
| CN105143203A (en) | 2013-04-17 | 2015-12-09 | 辉瑞大药厂 | N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases |
| WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
| US10357476B1 (en) | 2018-10-30 | 2019-07-23 | Anis Ahmad | Method for treating coronary artery disease |
| JOP20210193A1 (en) | 2019-01-18 | 2023-01-30 | Astrazeneca Ab | Pcsk9 inhibitors and methods of use thereof |
| CN111170997A (en) * | 2019-12-31 | 2020-05-19 | 广州医科大学 | Carbazole compound and preparation method and application thereof |
| CN113372260A (en) * | 2021-07-05 | 2021-09-10 | 大连蒙迪科技有限公司 | Synthesis method of carvedilol impurity |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1834015A (en) * | 1929-06-29 | 1931-12-01 | Gen Aniline Works Inc | Manufacture of hydroxy carbazoles |
| DE1152107B (en) * | 1956-06-27 | 1963-08-01 | Chem Fab Promonta G M B H | Process for the preparation of basic substituted carbazole derivatives and their salts |
| US3932424A (en) * | 1970-06-15 | 1976-01-13 | Richardson-Merrell Inc. | Bis-basic ethers of carbazole |
| BE789072A (en) * | 1971-09-23 | 1973-03-21 | Astra Laekemedel Ab | COMPOUNDS REDUCING THE LIPID LEVEL OF THE SERUM AND THEIR OBTAINING |
| AT336176B (en) * | 1971-12-10 | 1977-04-25 | Sandoz Ag | METHOD FOR MANUFACTURING A PHARMACEUTICAL PREPARATION |
| US3975398A (en) * | 1973-08-01 | 1976-08-17 | Boehringer Mannheim G.M.B.H. | 9-Substituted 3-aminocarbazole compounds |
| DE2339396C2 (en) * | 1973-08-03 | 1984-06-28 | Boehringer Mannheim Gmbh, 6800 Mannheim | N-substituted 1-amino-3-phenoxypropan-2-ols, their salts, processes for their preparation and pharmaceuticals which contain these compounds |
| DE2424523A1 (en) * | 1974-05-21 | 1975-12-11 | Boehringer Mannheim Gmbh | NEW 1,2,3,4-TETRAHYDROCARBAZOLE DERIVATIVES AND PROCESS FOR THE PREPARATION |
| US4076829A (en) * | 1974-11-16 | 1978-02-28 | Boehringer Mannheim Gmbh | Aminopropanol compounds and compositions for the treatment of cardiac and circulatory diseases |
| DE2454406A1 (en) * | 1974-11-16 | 1976-05-20 | Boehringer Mannheim Gmbh | Adrenergic beta-receptor inhibitory amino propanol derivs - prepd by reacting substd propoxyindoles with amines |
| US4152446A (en) * | 1974-11-16 | 1979-05-01 | Boehringer Mannheim Gmbh | Aminopropanol compounds and compositions for the treatment of cardiac and circulatory diseases |
| US4115409A (en) * | 1975-12-05 | 1978-09-19 | Imperial Chemical Industries Limited | Alkanolamine derivatives |
| GB1508208A (en) * | 1975-12-05 | 1978-04-19 | Ici Ltd | Amide derivatives |
-
1978
- 1978-04-13 DE DE19782815926 patent/DE2815926A1/en not_active Withdrawn
-
1979
- 1979-04-02 CA CA324,667A patent/CA1129416A/en not_active Expired
- 1979-04-06 SU SU792745301A patent/SU810079A3/en active
- 1979-04-06 AU AU45820/79A patent/AU522975B2/en not_active Expired
- 1979-04-06 ES ES479396A patent/ES479396A1/en not_active Expired
- 1979-04-06 FI FI791142A patent/FI70406C/en not_active IP Right Cessation
- 1979-04-06 DK DK141979A patent/DK154555C/en not_active IP Right Cessation
- 1979-04-07 DE DE7979101063T patent/DE2960553D1/en not_active Expired
- 1979-04-07 EP EP79101063A patent/EP0004920B1/en not_active Expired
- 1979-04-08 IL IL57020A patent/IL57020A/en unknown
- 1979-04-09 DD DD79212096A patent/DD143607A5/en not_active IP Right Cessation
- 1979-04-10 CS CS792434A patent/CS227007B2/en unknown
- 1979-04-11 ZA ZA791732A patent/ZA791732B/en unknown
- 1979-04-11 JP JP4311979A patent/JPS54157558A/en active Granted
- 1979-04-12 AT AT0276279A patent/AT375639B/en not_active IP Right Cessation
- 1979-04-12 HU HU79BO1774A patent/HU179433B/en unknown
-
1983
- 1983-04-04 US US06/479,921 patent/US4503067A/en not_active Expired - Lifetime
-
1984
- 1984-07-20 SG SG52284A patent/SG52284G/en unknown
-
1985
- 1985-01-10 HK HK23/85A patent/HK2385A/en not_active IP Right Cessation
-
1987
- 1987-03-31 JP JP62076548A patent/JPS63258416A/en active Pending
-
1991
- 1991-12-31 CS CS914200A patent/CS420091A3/en unknown
-
1992
- 1992-06-25 MX MX9203380A patent/MX9203380A/en unknown
-
1993
- 1993-06-22 LU LU88320C patent/LU88320I2/en unknown
- 1993-06-29 NL NL930110C patent/NL930110I2/en unknown
- 1993-09-27 LT LTRP1124A patent/LT2628B/en unknown
-
1994
- 1994-02-28 BG BG98612A patent/BG61419B2/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007144785A2 (en) * | 2006-03-26 | 2007-12-21 | Uti Limited Partnership | Ryanodine receptor inhibitors and methods relating thereto |
| WO2007144785A3 (en) * | 2006-03-26 | 2008-04-17 | Uti Limited Partnership | Ryanodine receptor inhibitors and methods relating thereto |
| US8703804B2 (en) | 2006-03-26 | 2014-04-22 | Uti Limited Partnership | Ryanodine receptor inhibitors and methods relating thereto |
Also Published As
| Publication number | Publication date |
|---|---|
| NL930110I1 (en) | 1993-10-18 |
| SU810079A3 (en) | 1981-02-28 |
| JPS63258416A (en) | 1988-10-25 |
| BG61419B2 (en) | 1997-07-31 |
| HK2385A (en) | 1985-01-18 |
| IL57020A0 (en) | 1979-07-25 |
| ATA276279A (en) | 1984-01-15 |
| LT2628B (en) | 1994-04-25 |
| SG52284G (en) | 1985-03-29 |
| DK154555C (en) | 1989-06-19 |
| DE2960553D1 (en) | 1981-11-05 |
| EP0004920B1 (en) | 1981-08-05 |
| DK154555B (en) | 1988-11-28 |
| DE2815926A1 (en) | 1979-10-18 |
| ZA791732B (en) | 1980-05-28 |
| DD143607A5 (en) | 1980-09-03 |
| EP0004920A1 (en) | 1979-10-31 |
| MX9203380A (en) | 1992-09-01 |
| IL57020A (en) | 1982-07-30 |
| LU88320I2 (en) | 1994-05-04 |
| JPH0123462B2 (en) | 1989-05-02 |
| US4503067A (en) | 1985-03-05 |
| ES479396A1 (en) | 1980-04-16 |
| FI70406C (en) | 1986-09-19 |
| AT375639B (en) | 1984-08-27 |
| JPS54157558A (en) | 1979-12-12 |
| HU179433B (en) | 1982-10-28 |
| CS420091A3 (en) | 1992-04-15 |
| AU4582079A (en) | 1979-10-18 |
| NL930110I2 (en) | 1994-12-01 |
| AU522975B2 (en) | 1982-07-08 |
| FI70406B (en) | 1986-03-27 |
| FI791142A (en) | 1979-10-14 |
| DK141979A (en) | 1979-10-14 |
| CS227007B2 (en) | 1984-04-16 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |