CA1231972A - Substituted 1-arylamino-3-amino-2-propanols: preparation and therapeutic applications - Google Patents
Substituted 1-arylamino-3-amino-2-propanols: preparation and therapeutic applicationsInfo
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Abstract
ABSTRACT OF THE DISCLOSURE
Preparation and therapeutic activity of 1-arylamino-3-amino-2-propanols, of general formula (I) (I) where R represents an isopropyl group in ring position 2 or a methyl group in ring position 4, or an isopropyl group in ring position 2 simultaneously with a methyl group in ring position 5, and where NR1R2 represents an NHC(CH3)3 group, an NHCH(CH3)2 group, or an N(CH3)2 group, and pharmaceutically suitable salts thereof, such as the hydrochlorides.
The general preparation of these products is in two steps: the arylamine (II) (II) is reacted with epichlorohydrin in a solvent such as ethanol at the boiling point of the solvent, yielding the hydrochloride of (III) (III) This hydrochloride, in a solvent such as ethanol and at a temperature equal to or greater than the boiling point of the solvent, yields, with the amine NR1R2, the product of formula (I).
The inventive products are employed therapeutically, notably in the treatment of arrhythmias.
114/map
Preparation and therapeutic activity of 1-arylamino-3-amino-2-propanols, of general formula (I) (I) where R represents an isopropyl group in ring position 2 or a methyl group in ring position 4, or an isopropyl group in ring position 2 simultaneously with a methyl group in ring position 5, and where NR1R2 represents an NHC(CH3)3 group, an NHCH(CH3)2 group, or an N(CH3)2 group, and pharmaceutically suitable salts thereof, such as the hydrochlorides.
The general preparation of these products is in two steps: the arylamine (II) (II) is reacted with epichlorohydrin in a solvent such as ethanol at the boiling point of the solvent, yielding the hydrochloride of (III) (III) This hydrochloride, in a solvent such as ethanol and at a temperature equal to or greater than the boiling point of the solvent, yields, with the amine NR1R2, the product of formula (I).
The inventive products are employed therapeutically, notably in the treatment of arrhythmias.
114/map
Description
~3~
TITLE OF THE INVENTIO~
SUBSTIT~T~D l-ARYLAMINO-3-AMINO-2-PROPANOLS:
PR~PARATION AND THERAPEUTIC APPLICATIONS
BACKGROUND O~ THE IN~ENTION
Field of the Invention The present invention relates to various novel substituted l-arylamino-3-amino-2-propanols, the method of preparing these, and their therapeutic applications, particularly in treatment of arrhythmias.
The general formula of the products comprising the object of the present invention is:
4 ~ ~ C~l2 ~ Cl~ ~ CH2~R1~2 (I~
where R represents an isopropyl group in position 2 or a methyl group in position 4/ or an isopropyl group in position 2 simultaneously with a methyl group in position 6, and where NRlR2 represents a t-butylamino qroup, an isopropylamino groupl or a dimethylamino group. The products may be in the form of the free . base or of salts which are pharmaceutically suitable such as the hydrochlorideq.
~?~3i~
Description of_the Prior Art various substituted l-arylamino-3-amino-2-propanols are already known. Thus, Ferrari, G., Ferrini, R., and C. Casagrande, 1968, Boll. Chim.
Farm., 107:234-247, describe 1-arylamino-3-amino-2-propanols and reveal their beta-blocking and local anesthetic properties. The beta-blocking propJerties of these derivatives are either very weak or very inferior to the beta-blocking properties of their l-aryloxy homologs. Accordingly, these authors did not study the properties of the compounds in more detail.
Sinha, J.N., Rastogi, V.K., and S.S. Parmar described the specific beta-2 blocking activity of 1-(2,4-dimethylphenylamino)-3-(1-methylethyl)amino-2-propanol (1972, Eur. J. Pharmacol., 19:285-287).
SUMMARY OF THE INVENTION
We have discovered that the novel l-arylamino-3-amino-2-propanols comprising the object of the present invention have antiarrhythmic properties ~hich enables their use in treatment of arrhythmias. They also have local anesthetic activity, antiaggregation activity with regard to platelets, activity against calcium deposition or calcification, hypolipemic activity, diuretic activity, and Hl and H2 antihistaminic activity, thus enabling said products to be employed therapeutically for various conditions.
The general preparation of the inventive product begins with the arylamine (II) ~ NH2 (II) which is reacted with epichlorohydrin (III) Cl - CH2 - CH\-f H2 (III) in a solvent such as ethanol at the boiling point of the solvent, leading to the hydrochloride of (IV) R ~ ~ C~2 ~ C~\ ~C~2 ~IV) This hydrochloride, in the presence of the amine NHRlR2 in a solvent such as ethanol at or above the boiling point of the solvent yields a product of formula (I) NH - CH2 CH ~ CH2NRlR2 (I) OH
where R, Rl, and R2 are as defined supra.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The examples hereinafter serve to describe the invention in more detail without in any way limiting its scope.
_4_ ~3~2 Example 1 1-(2-isopropylanilino)-3-(t-butylamino)-2-propanol dihydrochloride, or COR37 05C, the dihydrochloride of a product of formula (I) with R = 2-(1-methylethyl), and NRlR2 = NHC(CH3)3, was prepared as follows~
One mole 2-isopropylaniline and 1.1 mole epichlorohydrin are refluxed 24 hours in absolute ethanol, yielding the hydrochloride of (V) H ~ CH
NH - CH2 - C \ / H2 (V) This is dissolved in absolute ethanol and refluxed 24 hours in the presence of a large excess of t-butylamine. After evaporation of the solvents, the product obtained is purified in an alumina or silica column, ~nd recrystallized. The resulting base is obtained in 70% yield~ Th~ ba~e is then converted to the dihyclrochloride (COR 37 0~C~.
Physicochemical characteristics: Melting point =
140C. Melting point of the corresponding base =
82~C. NMR spectrum of the base/TMS: ~ = 1.05 ppm (1 s, 9 H, t-Bu), S = 1.25 ppm ~1 d, 6 H, J = 7 Hz; CMe2), ~ = 2.70 ppm ~1 m, 2 H; CH2N(t-Bu)); ~ = 3.2 ppm ~1 ~, 5~ 3~2 3 H, ArNCH2 ~ ArCHMe2) ~ = 3.8 ppm (1 m, 1 H: CHO) = 6.7 ppm (1 m, 2 H, 2 aromatic protons), ~ = 7.1 ppm (1 m, 2 H; 2 aromatic protons).
Example 2 1-(2-isopropyl-6-methylanilino)-3-(t-butylamino)-
TITLE OF THE INVENTIO~
SUBSTIT~T~D l-ARYLAMINO-3-AMINO-2-PROPANOLS:
PR~PARATION AND THERAPEUTIC APPLICATIONS
BACKGROUND O~ THE IN~ENTION
Field of the Invention The present invention relates to various novel substituted l-arylamino-3-amino-2-propanols, the method of preparing these, and their therapeutic applications, particularly in treatment of arrhythmias.
The general formula of the products comprising the object of the present invention is:
4 ~ ~ C~l2 ~ Cl~ ~ CH2~R1~2 (I~
where R represents an isopropyl group in position 2 or a methyl group in position 4/ or an isopropyl group in position 2 simultaneously with a methyl group in position 6, and where NRlR2 represents a t-butylamino qroup, an isopropylamino groupl or a dimethylamino group. The products may be in the form of the free . base or of salts which are pharmaceutically suitable such as the hydrochlorideq.
~?~3i~
Description of_the Prior Art various substituted l-arylamino-3-amino-2-propanols are already known. Thus, Ferrari, G., Ferrini, R., and C. Casagrande, 1968, Boll. Chim.
Farm., 107:234-247, describe 1-arylamino-3-amino-2-propanols and reveal their beta-blocking and local anesthetic properties. The beta-blocking propJerties of these derivatives are either very weak or very inferior to the beta-blocking properties of their l-aryloxy homologs. Accordingly, these authors did not study the properties of the compounds in more detail.
Sinha, J.N., Rastogi, V.K., and S.S. Parmar described the specific beta-2 blocking activity of 1-(2,4-dimethylphenylamino)-3-(1-methylethyl)amino-2-propanol (1972, Eur. J. Pharmacol., 19:285-287).
SUMMARY OF THE INVENTION
We have discovered that the novel l-arylamino-3-amino-2-propanols comprising the object of the present invention have antiarrhythmic properties ~hich enables their use in treatment of arrhythmias. They also have local anesthetic activity, antiaggregation activity with regard to platelets, activity against calcium deposition or calcification, hypolipemic activity, diuretic activity, and Hl and H2 antihistaminic activity, thus enabling said products to be employed therapeutically for various conditions.
The general preparation of the inventive product begins with the arylamine (II) ~ NH2 (II) which is reacted with epichlorohydrin (III) Cl - CH2 - CH\-f H2 (III) in a solvent such as ethanol at the boiling point of the solvent, leading to the hydrochloride of (IV) R ~ ~ C~2 ~ C~\ ~C~2 ~IV) This hydrochloride, in the presence of the amine NHRlR2 in a solvent such as ethanol at or above the boiling point of the solvent yields a product of formula (I) NH - CH2 CH ~ CH2NRlR2 (I) OH
where R, Rl, and R2 are as defined supra.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The examples hereinafter serve to describe the invention in more detail without in any way limiting its scope.
_4_ ~3~2 Example 1 1-(2-isopropylanilino)-3-(t-butylamino)-2-propanol dihydrochloride, or COR37 05C, the dihydrochloride of a product of formula (I) with R = 2-(1-methylethyl), and NRlR2 = NHC(CH3)3, was prepared as follows~
One mole 2-isopropylaniline and 1.1 mole epichlorohydrin are refluxed 24 hours in absolute ethanol, yielding the hydrochloride of (V) H ~ CH
NH - CH2 - C \ / H2 (V) This is dissolved in absolute ethanol and refluxed 24 hours in the presence of a large excess of t-butylamine. After evaporation of the solvents, the product obtained is purified in an alumina or silica column, ~nd recrystallized. The resulting base is obtained in 70% yield~ Th~ ba~e is then converted to the dihyclrochloride (COR 37 0~C~.
Physicochemical characteristics: Melting point =
140C. Melting point of the corresponding base =
82~C. NMR spectrum of the base/TMS: ~ = 1.05 ppm (1 s, 9 H, t-Bu), S = 1.25 ppm ~1 d, 6 H, J = 7 Hz; CMe2), ~ = 2.70 ppm ~1 m, 2 H; CH2N(t-Bu)); ~ = 3.2 ppm ~1 ~, 5~ 3~2 3 H, ArNCH2 ~ ArCHMe2) ~ = 3.8 ppm (1 m, 1 H: CHO) = 6.7 ppm (1 m, 2 H, 2 aromatic protons), ~ = 7.1 ppm (1 m, 2 H; 2 aromatic protons).
Example 2 1-(2-isopropyl-6-methylanilino)-3-(t-butylamino)-
2-propanol dihydrochloride, or COR37 06C, the dihydrochloride of formula (I) with R = 2-(1-methylethyl)-6-methyl, and NRlR2 = NHC(Me)3, was prepared as follows:
One mole 2-isopropyl-6-methylaniline and 1.1 mole epichlorohydrin are refluxed 24 hours in absolute ethanol, yieldiny the hydrochloride of (VI) NH ~ CB2 ~ CH ~ CH2 (VI) C~(CH3)~
This is dissolved in absolute ethanol and refluxed 24 hours in the presence of a large excess of t-butylamine. After evaporation of the solvents, the product obtained i~ purified in an alumina or silica column, and recrystallized. The resulting base is obtained in 70% yield. The base is then converted to the dihydrochloride (COR37 06C)~
Physicochemical characteristics: Melting point =
158DCo NMR spectrum of the base~TMS: ~ = 1.1 ppm (1 s, 9 H, t-Bu), ~ = 1.25 ppm (1 d, 6 H, J = 7 H~, CMe2);
~ = 2.3 ppm (1 s, 3 ~ ArCH3), ~ = 2.7 ppm (1 m, 2 H;
CH2NH(t-Bu)) ~ = 3.0 ppm (1 m, ~ H, ArNCH2); ~ - 3.2 ppm (1 sp, 1 H ArCHMe2), ~ = 3.8 ppm (1 m, 1 H, CHO) = 6.9 ppm (1 m, 3 H; 3 aromatic protons).
Example 3 1-(4-methylanilino)-3-(t-butylamino)-2-propanol dihydrochloride, or COR37 O9C, the dihydrochloride of formula ~I) with R = 4-Me, and NRlR2 = NH(t-Bu), was prepared as follows:
One mole 4-methylaniline and 1.1 mole epichlorohydrin are refluxed 24 hours in absolute ethanol, yielding the hydrochloride of (VII) H3C { ~ NH CH2 C \ /CH2 (VII) This is dissolved in absolute ethanol and refluxed 24 hours in the presence of a large excess of t-butylamine. After evaporation of the solvents, the product obtained is purified in an a~umina or silica column, and recrystallized. The resulting base is obtained ia 60~ yield. The base is th~n converted to the dihydrochloride (C0~37 O9C).
~7- ~3~2 Physicochemical characteristics: Melting point of the corresponding base = 82~C. NMR spectrum of the base/TMS: ~ = 1.1 ppm (1 s, 9 H, t-Bu); ~ = 2.2 ppm (1 s, 3 H; ArCH3) ~ = 2.6 ppm (1 m, 2 H. CH2NH(t-Bu)):~
= 3.1 ppm (1 m, 2 H, ArNCH2); ~ = 3.7 ppm (1 m, 1 H;
CHO); and ~ = 6.5 and 6.95 ppm ~AB, 4 H, J = 8 Hz; 4 aromatic protons~.
Example 4 1-(2-isopropylanilino)-3-dimethylamino-2-propanol, or COR37 49C, the dihydrochloride of formula (I) with R
= 2-isopropyl, and NRlR2 = NMe2, was prepared as follows:
The hydrochloride of ~V), prepared according to Example 1, is dissolved in absolute ethanol and maintained 24 hours in an autoclave at 100C in the presence of a large excess of dimethylamine. After evaporation of the solvents, the product obtained is purified in an alumina or silica column, and recrystallized. The resulting base is obtained in 47%
yield. 'rhe ba~e is then converted to the dihydrochloride (COR37 49C).
Physicochemical properties: MMR spectrum of the . ba~e/TMS: ~ = 1.15 ppm (l d, 6 H, J = 6 Hz, CMe2). ~ =
1.95 ppm (1 ~, 6 H, NMe2), ~ = 2.5 to 3.3 ppm (1 m, 5 H~ CMe2 ~ 2 CH2N), ~ = 3.8 pp~ (1 m, 1 H; C~10) ~ = 6.
-8- ~D~3 ppm (1 m, 2 H, 2 aromatic protons~' ~ = 6.95 ppm (1 m 2 H, 2 aromatic protons) Example 5 1-(2-isopropyl~6-methylanilino)-3-dimethylamino-2-propanol, or COR37 50C, the dihydrochloride of formula (I) with R = 2-(1-methylethyl)-6-methyl, and NRlR2 =
NMe2, was prepared as follows The hydrochloride of (VI), prepared according to Example 2, is dissolved in absolute ethanol and maintained 24 hours in an autoclave at 110C in the presence of a large excess of dimethylamine. After evaporation of the solvents, the product obtained is purified in an aluminum or silica column, and recrystallized. The resulting base is obtained in 42%
yield. The base is then conver~ed to the dihydrochloride (COR37 50C).
Physicochemical characteristics: NMR spectrurn of the base/TMS: ~ = 1.25 ppm (1 d, 6 Hl J = 6 Hz, CMe2), ~ = 2.25 ppm (1 ~, 9 H. Ar ~ + NMe2), ~ = 2.5 to 3.5 ppm (1 m, 5 H, CHMe2 + 2 NCH2): ~ = 3.85 ppm (1 m, 1 H, CHO), ~ = 7.0 ppm (1 mJ 3 H, 3 aromatic protons).
The toxicological and pharmacological properties of the inventive products will now be described:
The acute lethal toxicity W25 determined o~
mice. By oral administration, in solution in Tween, COR37 05C caused 0% mortality at 500 mg/kg, 40~ at 750, ~L~a~
and 40~ at 1000 mg/kg. ~iortality with COR37 06C was 03 at 100 mg/kg, 10~ at 200, 10~ at 250, 90% at 375, and 100% at 500 ppm (L~50 = 294 mg/kg (261 to 332)).
t~ortality with C0~37 ~9C, COR37 49C, and COR37 50C was 0~ at 300 my/kg. Intraperitoneally, in solution in 'l'ween, COR37 05C caused 0% moetality at 200 mg/kg.
Mortality with CoR37 06C was 0% at 100 mg/kg and 100%
at 200 mg/kg. Mortality with COR37 09C was 0~ at 50 mg/kg and 100% at 100 mg/kg. I~ortalities with COR37 49C and CoR37 50C were 0% at 200 mg/kg. Intravenously, the LD50 of COR37 05C was 56 mg/kg (53.8 to 59.5).
The antiarrhythmic activity was determined on various models. COR37 05C and COR37 06C administered intraperitoneally to mice undee profound chloroEorm anesthesia had antiarrllythmic activity beginning at a dose of 25 mg/kg, and COR37 50C at 100 mg/kg. Under the sama conditions, propranolol is active at a dose of 40 mg/kg, and quinidirle at a dose of 100 mg/kg.
In vitro, on an isolated ateium of a guinea pig, stimulated electrically, COR37 05C and COR37 06C were active with Ci30 of 6.22 (4.37 to 8.86) x 10-6 moles/liter and 7.26 (~.68 to 11.2) x 10 6 mole~liter, re~pectively, compared to 10 5 moles/liter for procaine, 4 ~ 10 6 moles/liter for quinidine, and 4.5 x 10-6 moles/liter for propeanolol.
*Trademark ~ ~..
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Tl-ese products were tested on the model of aconitine induced arrl~ythmia in rats. The results are expressed as the percellt increase in the amount of aconitine to produce extrasystoles (E), fibrilloflutter (F), tachycardia (T), and death (D). When administered by i.v. prior to infusion of aconitine, 10 mg/kg CoR37 05C showed the following activity: E 78%, T 87~, and D
83~. Activity of 5 mg/ky COR37 06C was E 45%, T 39%, and D 79%. When administered orally 45 minutes prior to perfusion of aconitine, the activity of 100 mg/kg COR37 05C was F, ~3~, T 99%, F 43~, and D 107~, and that of 100 mg/kg COR37 06C was E 25%, T 32%, F 29~, and D
105~. Further, after oral administration of COR37 05C
and COR37 06C, tlle percent of animals showing no fibrillofluttering was 70~ and 60%t respectively.
The local anesthetic activity was determined in tests on guinea pig corneas subjected to tactile stimulation. COR37 06C employed in a concentration of 0.5~ was active for 30 minutes.
The antiaggregation activity on platelets wa~
determined in vitro. On the model of platelet-rich plasma (PRP) of rabbits, aggregation induced by 0.05 ml of a atandardized preparation of bovine collagen was inhibited 100~ by CoR37 06C at 1 microgram/ml, as compared ta 10 ~Ig/ml Aspirin or 0.5 ~g/ml indometllacin. On the same model, aggregation of ~Trademark 3V~
platelets induced by ADP, 100 ~g/ml COR37 09C had inhibiting activity of 79%, C0~37 50C 80%, and adenosine 64~.
The products according to the present invention do not have beta-blocking activity. This was determined in vitro on guinea pig atriums stimulated electrically, with activity measured in terms of blocking of the inotropic action of isoproterenol; and in vivo on tachycardia induced by isoproterenol in mice, and on the inhibiting activity on the effects of isoproterenol on arterial pressure and cardiac frequency in anesthetized normal rats. COR37 05C is not active with respect to beta-2 adrenergic receptors' and COR37 06C, COR37 09C, COR37 49C, and COR37 50C do not have beta-blocking properties.
The activity against calcium deposition and calcification was detertnined in vitro on the left atrium of a guinea pig stimulated electrically at 150 beats/min, with the test compound in a Tyrode's solution low in calcium (0.6 mM~. COR37 49C and COR37 50C at 100 ~g/l inhibited the increase of the contractile force induced by the addition of 0~6 mM of calcium.
The hypolipemic activity was demonstrated in mice rendered hypercholesterolemic by a regimen rich in cholesterol and cholic acid administered for 7 days.
Administration of COR37 49C at 400 mg/kg on days 6 and 7 resulted in a 22% reduction of serum cholesterol.
The diuretic activity was determined on the rat.
COR37 49C administered in an oral dose of 20 mg/kg to a rat which had been administered excess water, increased the urinary excretion of sodium by a factor of 2.2.
The anti-H2 antihistaminic activity was demonstrated in vitro. On the model comprised of the right atrium of a guinea pig without stimulation, 25 ~g/ml COR37 49C produced 50% inhibition of the chronotropic effect induced by 5 ~g/ml histamine.
The anti-Rl antihistaminic activity was demonstrated in vitro on guinea pig ileum. 25 ~g/ml COR37 49C produced 80% inhibition of the contractions induced by histamine.
Taking into account their pharmacological activities as well as their moderate toxicity, the inventive products may be employed in human and veterinary therapy. Formulated with customary excipients, they may be used, for example, in treating cardiac arrhythmias. They may also be employed in local anesthesia by infiltration or conduction, in contact anesthesia, in treatment of hyperaggregability states of platelets, treatment of hyperlipemia, hyperlipoproteinemia and edematous states, ulcerous disorder~, allergic or pruritic conditions, and transport disorders.
~;~3 ~3~
They may be administered orally in the form, e.g., of coated pills, compressed tablets, syrups, or capsules; rectally in the form of suppositories;
intramuscularly or intravenously, or topically in the form of an ointment or gel. Dosages will vary according to the indication and the patient, from 1 to 100 mg/day in one to six oral administrations or one or two administrations rectally, or from 0.5 to 50 mg per day parenterally by injection.
One mole 2-isopropyl-6-methylaniline and 1.1 mole epichlorohydrin are refluxed 24 hours in absolute ethanol, yieldiny the hydrochloride of (VI) NH ~ CB2 ~ CH ~ CH2 (VI) C~(CH3)~
This is dissolved in absolute ethanol and refluxed 24 hours in the presence of a large excess of t-butylamine. After evaporation of the solvents, the product obtained i~ purified in an alumina or silica column, and recrystallized. The resulting base is obtained in 70% yield. The base is then converted to the dihydrochloride (COR37 06C)~
Physicochemical characteristics: Melting point =
158DCo NMR spectrum of the base~TMS: ~ = 1.1 ppm (1 s, 9 H, t-Bu), ~ = 1.25 ppm (1 d, 6 H, J = 7 H~, CMe2);
~ = 2.3 ppm (1 s, 3 ~ ArCH3), ~ = 2.7 ppm (1 m, 2 H;
CH2NH(t-Bu)) ~ = 3.0 ppm (1 m, ~ H, ArNCH2); ~ - 3.2 ppm (1 sp, 1 H ArCHMe2), ~ = 3.8 ppm (1 m, 1 H, CHO) = 6.9 ppm (1 m, 3 H; 3 aromatic protons).
Example 3 1-(4-methylanilino)-3-(t-butylamino)-2-propanol dihydrochloride, or COR37 O9C, the dihydrochloride of formula ~I) with R = 4-Me, and NRlR2 = NH(t-Bu), was prepared as follows:
One mole 4-methylaniline and 1.1 mole epichlorohydrin are refluxed 24 hours in absolute ethanol, yielding the hydrochloride of (VII) H3C { ~ NH CH2 C \ /CH2 (VII) This is dissolved in absolute ethanol and refluxed 24 hours in the presence of a large excess of t-butylamine. After evaporation of the solvents, the product obtained is purified in an a~umina or silica column, and recrystallized. The resulting base is obtained ia 60~ yield. The base is th~n converted to the dihydrochloride (C0~37 O9C).
~7- ~3~2 Physicochemical characteristics: Melting point of the corresponding base = 82~C. NMR spectrum of the base/TMS: ~ = 1.1 ppm (1 s, 9 H, t-Bu); ~ = 2.2 ppm (1 s, 3 H; ArCH3) ~ = 2.6 ppm (1 m, 2 H. CH2NH(t-Bu)):~
= 3.1 ppm (1 m, 2 H, ArNCH2); ~ = 3.7 ppm (1 m, 1 H;
CHO); and ~ = 6.5 and 6.95 ppm ~AB, 4 H, J = 8 Hz; 4 aromatic protons~.
Example 4 1-(2-isopropylanilino)-3-dimethylamino-2-propanol, or COR37 49C, the dihydrochloride of formula (I) with R
= 2-isopropyl, and NRlR2 = NMe2, was prepared as follows:
The hydrochloride of ~V), prepared according to Example 1, is dissolved in absolute ethanol and maintained 24 hours in an autoclave at 100C in the presence of a large excess of dimethylamine. After evaporation of the solvents, the product obtained is purified in an alumina or silica column, and recrystallized. The resulting base is obtained in 47%
yield. 'rhe ba~e is then converted to the dihydrochloride (COR37 49C).
Physicochemical properties: MMR spectrum of the . ba~e/TMS: ~ = 1.15 ppm (l d, 6 H, J = 6 Hz, CMe2). ~ =
1.95 ppm (1 ~, 6 H, NMe2), ~ = 2.5 to 3.3 ppm (1 m, 5 H~ CMe2 ~ 2 CH2N), ~ = 3.8 pp~ (1 m, 1 H; C~10) ~ = 6.
-8- ~D~3 ppm (1 m, 2 H, 2 aromatic protons~' ~ = 6.95 ppm (1 m 2 H, 2 aromatic protons) Example 5 1-(2-isopropyl~6-methylanilino)-3-dimethylamino-2-propanol, or COR37 50C, the dihydrochloride of formula (I) with R = 2-(1-methylethyl)-6-methyl, and NRlR2 =
NMe2, was prepared as follows The hydrochloride of (VI), prepared according to Example 2, is dissolved in absolute ethanol and maintained 24 hours in an autoclave at 110C in the presence of a large excess of dimethylamine. After evaporation of the solvents, the product obtained is purified in an aluminum or silica column, and recrystallized. The resulting base is obtained in 42%
yield. The base is then conver~ed to the dihydrochloride (COR37 50C).
Physicochemical characteristics: NMR spectrurn of the base/TMS: ~ = 1.25 ppm (1 d, 6 Hl J = 6 Hz, CMe2), ~ = 2.25 ppm (1 ~, 9 H. Ar ~ + NMe2), ~ = 2.5 to 3.5 ppm (1 m, 5 H, CHMe2 + 2 NCH2): ~ = 3.85 ppm (1 m, 1 H, CHO), ~ = 7.0 ppm (1 mJ 3 H, 3 aromatic protons).
The toxicological and pharmacological properties of the inventive products will now be described:
The acute lethal toxicity W25 determined o~
mice. By oral administration, in solution in Tween, COR37 05C caused 0% mortality at 500 mg/kg, 40~ at 750, ~L~a~
and 40~ at 1000 mg/kg. ~iortality with COR37 06C was 03 at 100 mg/kg, 10~ at 200, 10~ at 250, 90% at 375, and 100% at 500 ppm (L~50 = 294 mg/kg (261 to 332)).
t~ortality with C0~37 ~9C, COR37 49C, and COR37 50C was 0~ at 300 my/kg. Intraperitoneally, in solution in 'l'ween, COR37 05C caused 0% moetality at 200 mg/kg.
Mortality with CoR37 06C was 0% at 100 mg/kg and 100%
at 200 mg/kg. Mortality with COR37 09C was 0~ at 50 mg/kg and 100% at 100 mg/kg. I~ortalities with COR37 49C and CoR37 50C were 0% at 200 mg/kg. Intravenously, the LD50 of COR37 05C was 56 mg/kg (53.8 to 59.5).
The antiarrhythmic activity was determined on various models. COR37 05C and COR37 06C administered intraperitoneally to mice undee profound chloroEorm anesthesia had antiarrllythmic activity beginning at a dose of 25 mg/kg, and COR37 50C at 100 mg/kg. Under the sama conditions, propranolol is active at a dose of 40 mg/kg, and quinidirle at a dose of 100 mg/kg.
In vitro, on an isolated ateium of a guinea pig, stimulated electrically, COR37 05C and COR37 06C were active with Ci30 of 6.22 (4.37 to 8.86) x 10-6 moles/liter and 7.26 (~.68 to 11.2) x 10 6 mole~liter, re~pectively, compared to 10 5 moles/liter for procaine, 4 ~ 10 6 moles/liter for quinidine, and 4.5 x 10-6 moles/liter for propeanolol.
*Trademark ~ ~..
; r ~3~
Tl-ese products were tested on the model of aconitine induced arrl~ythmia in rats. The results are expressed as the percellt increase in the amount of aconitine to produce extrasystoles (E), fibrilloflutter (F), tachycardia (T), and death (D). When administered by i.v. prior to infusion of aconitine, 10 mg/kg CoR37 05C showed the following activity: E 78%, T 87~, and D
83~. Activity of 5 mg/ky COR37 06C was E 45%, T 39%, and D 79%. When administered orally 45 minutes prior to perfusion of aconitine, the activity of 100 mg/kg COR37 05C was F, ~3~, T 99%, F 43~, and D 107~, and that of 100 mg/kg COR37 06C was E 25%, T 32%, F 29~, and D
105~. Further, after oral administration of COR37 05C
and COR37 06C, tlle percent of animals showing no fibrillofluttering was 70~ and 60%t respectively.
The local anesthetic activity was determined in tests on guinea pig corneas subjected to tactile stimulation. COR37 06C employed in a concentration of 0.5~ was active for 30 minutes.
The antiaggregation activity on platelets wa~
determined in vitro. On the model of platelet-rich plasma (PRP) of rabbits, aggregation induced by 0.05 ml of a atandardized preparation of bovine collagen was inhibited 100~ by CoR37 06C at 1 microgram/ml, as compared ta 10 ~Ig/ml Aspirin or 0.5 ~g/ml indometllacin. On the same model, aggregation of ~Trademark 3V~
platelets induced by ADP, 100 ~g/ml COR37 09C had inhibiting activity of 79%, C0~37 50C 80%, and adenosine 64~.
The products according to the present invention do not have beta-blocking activity. This was determined in vitro on guinea pig atriums stimulated electrically, with activity measured in terms of blocking of the inotropic action of isoproterenol; and in vivo on tachycardia induced by isoproterenol in mice, and on the inhibiting activity on the effects of isoproterenol on arterial pressure and cardiac frequency in anesthetized normal rats. COR37 05C is not active with respect to beta-2 adrenergic receptors' and COR37 06C, COR37 09C, COR37 49C, and COR37 50C do not have beta-blocking properties.
The activity against calcium deposition and calcification was detertnined in vitro on the left atrium of a guinea pig stimulated electrically at 150 beats/min, with the test compound in a Tyrode's solution low in calcium (0.6 mM~. COR37 49C and COR37 50C at 100 ~g/l inhibited the increase of the contractile force induced by the addition of 0~6 mM of calcium.
The hypolipemic activity was demonstrated in mice rendered hypercholesterolemic by a regimen rich in cholesterol and cholic acid administered for 7 days.
Administration of COR37 49C at 400 mg/kg on days 6 and 7 resulted in a 22% reduction of serum cholesterol.
The diuretic activity was determined on the rat.
COR37 49C administered in an oral dose of 20 mg/kg to a rat which had been administered excess water, increased the urinary excretion of sodium by a factor of 2.2.
The anti-H2 antihistaminic activity was demonstrated in vitro. On the model comprised of the right atrium of a guinea pig without stimulation, 25 ~g/ml COR37 49C produced 50% inhibition of the chronotropic effect induced by 5 ~g/ml histamine.
The anti-Rl antihistaminic activity was demonstrated in vitro on guinea pig ileum. 25 ~g/ml COR37 49C produced 80% inhibition of the contractions induced by histamine.
Taking into account their pharmacological activities as well as their moderate toxicity, the inventive products may be employed in human and veterinary therapy. Formulated with customary excipients, they may be used, for example, in treating cardiac arrhythmias. They may also be employed in local anesthesia by infiltration or conduction, in contact anesthesia, in treatment of hyperaggregability states of platelets, treatment of hyperlipemia, hyperlipoproteinemia and edematous states, ulcerous disorder~, allergic or pruritic conditions, and transport disorders.
~;~3 ~3~
They may be administered orally in the form, e.g., of coated pills, compressed tablets, syrups, or capsules; rectally in the form of suppositories;
intramuscularly or intravenously, or topically in the form of an ointment or gel. Dosages will vary according to the indication and the patient, from 1 to 100 mg/day in one to six oral administrations or one or two administrations rectally, or from 0.5 to 50 mg per day parenterally by injection.
Claims (12)
1. A method of preparation of products of general formula (I) (I) where R represents an isopropyl group in ring position 2 or a methyl group in ring position 4, or an isopropyl group in ring position 2 simulta-neously with a methyl group in ring position 6; and where NR1R2 represents a t-butylamino group, an isopropylamino group or a dimethylamino group; with the proviso that R may not represent a methyl group in ring position 4 when NR1R2 represents a dimethylamino group; and pharmaceuti-cally suitable salts thereof, characterized in that an arylamine of general formula (II) (II) where R represents an isopropyl group in ring position 2 or a methyl group in ring position 4, or an isopropyl group in ring position 2 simulta-neously with a methyl group in ring position 6, is reacted with epichlorohydrin (III) (III) in a solvent, at the boiling point of the solvent;
and in that the hydrochloride thus obtained is reacted with the amine NHR1R2 where NR1R2 represents an NHC(CH3)3 group, an NHCH(CH3)2 group, or an N(CH3)2 group, in a solvent such as ethanol, at temperatures greater than or equal to the boiling point of the solvent.
and in that the hydrochloride thus obtained is reacted with the amine NHR1R2 where NR1R2 represents an NHC(CH3)3 group, an NHCH(CH3)2 group, or an N(CH3)2 group, in a solvent such as ethanol, at temperatures greater than or equal to the boiling point of the solvent.
2. A method of preparation of pharmaceuti-cally suitable salt of products of general formula (I) (I) where R represents an isopropyl group in ring position 2 or a methyl group in ring position 4, or an isopropyl group in ring position 2 simulta-neously with a methyl group in ring position 6; and where NR1R2 represents a t-butylamino group, an isopropylamino group or a dimethylamino group; characterized in that an arylamine of general formula (II) (II) where R represents an isopropyl group in ring position 2 or a methyl group in ring position 4, or an isopropyl group in ring position 2 simulta-neously with a methyl group in ring position 6, is reacted with epichlorohydrin (III) (III) in a solvent, at the boiling point of the solvent;
and in that the hydrochloride thus obtained is reacted with the amine NHR1R2 where NR1R2 represents an NHC(CH3)3 group, an NHCH(CH3)2 group, or an N(CH3)2 group, in a solvent such as ethanol, at temperatures greater than or equal to the boiling point of the solvent, and converting the product obtained into pharmaceutically suitable salts thereof.
and in that the hydrochloride thus obtained is reacted with the amine NHR1R2 where NR1R2 represents an NHC(CH3)3 group, an NHCH(CH3)2 group, or an N(CH3)2 group, in a solvent such as ethanol, at temperatures greater than or equal to the boiling point of the solvent, and converting the product obtained into pharmaceutically suitable salts thereof.
3. A method according to claim 1, wherein the hydrochloride is reacted with the amine NHR1R2 where NR1R2 represents NHC(CH3)3.
4. A method according to claim 1, wherein the hydrochloride is reacted with the amine NHR1R2 where NR1R2 represents N(CH3)2.
5. A method according to claim 1, which comprises reacting 2-isopropylaniline with epichlorohydrin to give the hydrochloride of which is reacted with t-butylamine to give 1-(2-isopropylanilino)-3-t-butylamino-2-propanol, and optionally converting the latter compound into pharmaceutically suitable salts thereof.
6. A method according to claim 1, which comprises reacting 2-isopropyl-6-methylaniline with epichlorohydrin to give the hydrochloride which is reacted with t-butylamine to give 1-(2-isopropyl-6-methylanilino)-3-(t-butylamino)-2-propanol, and optionally converting the latter compound into pharmaceutically suitable salts thereof.
7. A product of general formula (I) (I) where R represents an isopropyl group in ring position 2 or a methyl group in ring position 4, or an isopropyl group in ring position 2 simulta-neously with a methyl group in ring position 6; and where NR1R2 represents a t-butylamino group, an isopropylamino group, or a dimethylamino group; with the proviso that R may not represent a methyl group in ring position 4 when NR1R2 represents a dimethylamino group; and pharmaceuti-cally suitable salts thereof, whenever prepared by the process of claim 1 or its obvious chemical equivalents.
8. A pharmaceutically suitable salt of a product of general formula (I) (I) where R represents an isopropyl group in ring position 2 or a methyl group in ring position 4, or an isopropyl group in ring position 2 simulta-neously with a methyl group in ring position 6; and where NR1R2 represents a t-butylamino group, an isopropylamino group, or a dimethylamino group, whenever prepared by the process of claim 2 or its obvious chemical equivalents.
9. The product according to claim 7, characterized in that NR1R2 represents NHC(CH3)3, whenever prepared by the process of claim 3 or its obvious chemical equivalents.
10. The product according to claim 7, characterized in that NR1R2 represents N(CH3)2, whenever prepared by the process of claim 4 or its obvious chemical equivalents.
11. The product according to claim 7 which is 1-(2-isopropylanilino)-3-t-butylamino-2-propanol, ancl pharmaceutically suitable salts thereof, whenever prepared by the process of claim 5 or its obvious chemical equivalents.
12. The product according to claim 7 which is 1-(2-isopropyl-6-methylanilino)-3-t-butylamino-2-propanol, and pharmaceutically suitable salts thereof, whenever prepared by the process of claim 6 or its obvious chemical equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR83.20.747 | 1983-12-22 | ||
| FR8320747A FR2557102B1 (en) | 1983-12-22 | 1983-12-22 | NOVEL VARIOUSLY SUBSTITUTED ARYLAMINO-1 AMINO-3 PROPANOLS-2, THEIR PREPARATION METHOD AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1231972A true CA1231972A (en) | 1988-01-26 |
Family
ID=9295545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000470939A Expired CA1231972A (en) | 1983-12-22 | 1984-12-21 | Substituted 1-arylamino-3-amino-2-propanols: preparation and therapeutic applications |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0148096B1 (en) |
| JP (1) | JPS60139651A (en) |
| CA (1) | CA1231972A (en) |
| DE (1) | DE3465189D1 (en) |
| ES (1) | ES537796A0 (en) |
| FR (1) | FR2557102B1 (en) |
| MA (1) | MA20288A1 (en) |
| OA (1) | OA07909A (en) |
| PT (1) | PT79584B (en) |
| ZA (1) | ZA8410027B (en) |
-
1983
- 1983-12-22 FR FR8320747A patent/FR2557102B1/en not_active Expired
-
1984
- 1984-11-13 EP EP84450025A patent/EP0148096B1/en not_active Expired
- 1984-11-13 DE DE8484450025T patent/DE3465189D1/en not_active Expired
- 1984-11-19 JP JP59244316A patent/JPS60139651A/en active Pending
- 1984-11-20 ES ES537796A patent/ES537796A0/en active Granted
- 1984-11-30 PT PT79584A patent/PT79584B/en not_active IP Right Cessation
- 1984-12-03 MA MA20512A patent/MA20288A1/en unknown
- 1984-12-21 CA CA000470939A patent/CA1231972A/en not_active Expired
- 1984-12-21 ZA ZA8410027A patent/ZA8410027B/en unknown
- 1984-12-21 OA OA58486A patent/OA07909A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2557102A1 (en) | 1985-06-28 |
| ES8507465A1 (en) | 1985-09-16 |
| ES537796A0 (en) | 1985-09-16 |
| PT79584A (en) | 1984-12-01 |
| JPS60139651A (en) | 1985-07-24 |
| EP0148096B1 (en) | 1987-08-05 |
| OA07909A (en) | 1986-11-20 |
| FR2557102B1 (en) | 1987-08-14 |
| EP0148096A1 (en) | 1985-07-10 |
| DE3465189D1 (en) | 1987-09-10 |
| ZA8410027B (en) | 1985-08-28 |
| MA20288A1 (en) | 1985-07-01 |
| PT79584B (en) | 1986-09-11 |
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