CA1093095A - Amines - Google Patents
AminesInfo
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- CA1093095A CA1093095A CA238,763A CA238763A CA1093095A CA 1093095 A CA1093095 A CA 1093095A CA 238763 A CA238763 A CA 238763A CA 1093095 A CA1093095 A CA 1093095A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D277/34—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- 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
- A61P9/06—Antiarrhythmics
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- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to amines of the general formula R1 in 2 or 3 position is selected from the group consisting of -CH2CH=CH2, -OCH2CH=CH2, -OCH2C=CH, alkoxyalkyl, HOCH2CH2NHCOCH2O-, CH3OCH2CH2NHCOCH2O-and -CH=NOR, wherein R is selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms, R2 is selected from the group consisting of hydrogen, halogen, alkyl and alkoxy, R5 is selected from the group con-sisting of hydrogen and alkyl, R9 is selected from the group consisting of hydrogen and carbamyl, Y is a divalent member selected from the group c???
sisting of -0-, and -CH2, n is an integer from 0 to 5, inclusive, m is an integer from 0 to 2, inclusive, and Ar is a phenyl nucleus, whereby R1 is bound in 2 or 3 position to the phenyl, whereby Y is CH2, n is a 1 - 5, or a therapeutically acceptable acid addition salt thereof. These compounds are prepared according to known methods. They are useful in treating cardio-vascular diseases by virtue of their ?-receptor activity.
This invention relates to amines of the general formula R1 in 2 or 3 position is selected from the group consisting of -CH2CH=CH2, -OCH2CH=CH2, -OCH2C=CH, alkoxyalkyl, HOCH2CH2NHCOCH2O-, CH3OCH2CH2NHCOCH2O-and -CH=NOR, wherein R is selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms, R2 is selected from the group consisting of hydrogen, halogen, alkyl and alkoxy, R5 is selected from the group con-sisting of hydrogen and alkyl, R9 is selected from the group consisting of hydrogen and carbamyl, Y is a divalent member selected from the group c???
sisting of -0-, and -CH2, n is an integer from 0 to 5, inclusive, m is an integer from 0 to 2, inclusive, and Ar is a phenyl nucleus, whereby R1 is bound in 2 or 3 position to the phenyl, whereby Y is CH2, n is a 1 - 5, or a therapeutically acceptable acid addition salt thereof. These compounds are prepared according to known methods. They are useful in treating cardio-vascular diseases by virtue of their ?-receptor activity.
Description
10~309S
The present invention relates to new amines havingJ~-receptor blocking activity and being useful in treating cardiovascular diseases and of the general formula I
Rl OH R5
The present invention relates to new amines havingJ~-receptor blocking activity and being useful in treating cardiovascular diseases and of the general formula I
Rl OH R5
2 > ArocH2cH~H2NH-c~l(cH2)n-y ~
R ~ 9 (CH2) mR
wherein Rl is in 2 or 3 position and is selected from the group consisting of -CH2CH=CH2, -OCH2CH-CH2, -OCH2C--CH, alkoxyalkyl, having up to 7 carbon atoms in each alkyl moiety, HOCH2CH2NHCOCH20-, CH30CH2CH2NH-COCH20-, and -CH=NOR, wherein R is selected from the group consisting of hydrogen and alkyl having 1 to 6 carbon atoms, R is se]ected from the group consisting of hydrogen, halogen, alkyl, having 1 - 4 carbon atoms, and alkoxy, having 1 - 4 carbon atoms, R5 is selected from the group consisting of hydrogen and alkyl, having 1 - 4 carbon atoms, R9 is selected from the group consisting of hydrogen and -CONH2, Y is selected from the group consisting of -O-, and -CH2, n is an integer from O to 5, m is an integer from O to 2 and Ar is phenylnucleus.
Alkoxyalkyl Rl has up to 7 carbon atoms in each alkyl chain, preferably up to 4 carbon atoms in each and each of them may be straight and/or branched. Alkoxyalkyl Rl is thus e.g., methoxymethyl, methoxyethyl, ethoxyethyl, isopropoxyethyl, n-propoxymethyl, and t-butyloxymethyl.
R1 bein~ -CH=NOR, wherein R is hydrogen, and alkyl with 1 to 6 carbon atoms is e.g., isonitrosomethyl, methylisonitrosomethyl, ethyl-isonitrosomethyl, n-propylisonitrosomethyl, isopropylisonitrosomethyl.
Halogen R is e.g., chloro, fluoro or bromo.
Alkyl R has up to 4 carbon atoms, and is straigh* or branched and is e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl.
Alkoxy R has up to 4 carbon atoms and is straight or branched and is e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
,~
Alkyl R has the same meaning as alkyl R and is e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and t-butyl.
The new compounds have valuable pharmacological properties.
Thus they block cardial js-receptors, which is shown at the determination of the antagonism of tachycardia after an intravenous injection of 0.5,ug/kg of d/l-isoproterenol sulphate on an anaesthetized cat at an intravenous dose of 0.002 to 2 mg/kg. Thus they block the vascular ~6-receptors which is shown at the determination of the antagonism of vasodilation after an intravenous injection of 0.5 ~g/kg of d/l-isoproterenol sulphate on an anaesthetized cat at an intravenous dose of 3 mg/kg or more. They are thus heart selective.
The new compounds can be used as cardioselective antagonists of adrenergic ~-receptor-stimulators, e.g., at the treatment of exogenously or endogenously caused arrythmias and angina pectoris. One may also use them as intermediates at the preparation of other valuable pharmaceutical compounds.
Outstanding amines are also those of formula Ia OHR3aR5a (Rla) (R2a)Ar-OCH2CHCHNCH~cH2)n-Y - ~ (Ia) R a (CH2)mR
wherein R is -CH2CH=CH2, R is selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy, R3a is hydrogen, R~a is hydrogen, R5a is the group consisting of hydrogen and alkyl, R9a is selected from the group consisting of hydrogen and -CONH2, Y is a divalent member sel-ected from the group consisting of -0-, and -CH2-, n is an integer from 0 to 5, m is an integer from 0 to 2, and Ar is phenyl, or a therapeutically acceptable salt thereof.
Of the compounds of the formula Ia, such compounds are especially advantageous, wherein R is o-CH2CH=CH2 or m-CH2CH=CH2, R is hydrogen, chloro, bromo, methyl, ethyl, methoxy and ethoxy, R is hydrogen, R is hydrogen, R a is hydrogen, methyl or ethyl, 1~93~95 R9a is hydro~en~ carbamyl, yla is -0- and -C~12-, n is an integer from 0 to 5 m is an integer from 0 to 2~ Ar is phenyl whereby when ya is CH2, n is 1-5, or a therapeutically acceptable salt thereof.
Preferably those compounds will be mentioned of formula Ia, wherein Rla is o-CH2CH=CH2, R a is hydrogen, chloro, methylJ and methoxy, R a is hydrogen, R a is hydrogen, R a is hydrogen or methyl, R a is hydrogen or carbamyl, ya is -0-, n is l or 2~ m is 0, 1 or 2J Ar is phenyl, or a thera-peutically acceptable salt thereof.
Outstanding amines are also those of the formula Ib (Rlb~ (R )ArOCH2CHCHI-CH(CH2)n ~ (Ib) (CH2) mR
wherein Rlb is selected from the group consisting of -OCH2CH=CH2 and -OCH2C--CHJ R2b is selected from the group consisting of hydrogenJ halogenJ
alkyl and alkoxyJ R b is hydrogenJ R b is hydrogenJ R5b is selected from the group consisting of hydrogenJ and alkylJ R b is selected from the group consisting of hydrogen and -CONH2J Y is a divalent member selected from the group consisting of -O-J and -CH2-J n is an integer from 0 to 5J m is an integer from 0 to 2J and Ar is phenylJ whereby yb is -CH2-J n is 1-5J and whereby Rl is bound in 2 or 3 position to the phenyl, or a therapeutically acceptable salt thereof.
Of the compounds of the formula Ib such compounds are especially advantageousJ wherein R is -OCH2CH=CH2 or -OCH2C--CHJ R b is hydrogenJ
chloroJ bromoJ methyl, ethyl, methoxy and ethoxy, R3b is hydrogen, R4b is hydrogen, R5b is hydrogen, methyl or ethyl, R9b is hydrogen, carbamyl, yb is -0-, and CH2, n is an integer from 0 to 5, m is an integer from 0 to 2 Ar is phenylJ whereby when Y is CH2 n is 1-5, and whereby R b is bound in 2 or 3 position to the phenyl, or a therapeutically acceptable salt thereof.
Preferably those compounds will be mentioned of formula Ib, wherein Rlb is o-OCH2CH=CH2 or o-OCH2C-CH, R b is hydrogen, chloro, methyl and
R ~ 9 (CH2) mR
wherein Rl is in 2 or 3 position and is selected from the group consisting of -CH2CH=CH2, -OCH2CH-CH2, -OCH2C--CH, alkoxyalkyl, having up to 7 carbon atoms in each alkyl moiety, HOCH2CH2NHCOCH20-, CH30CH2CH2NH-COCH20-, and -CH=NOR, wherein R is selected from the group consisting of hydrogen and alkyl having 1 to 6 carbon atoms, R is se]ected from the group consisting of hydrogen, halogen, alkyl, having 1 - 4 carbon atoms, and alkoxy, having 1 - 4 carbon atoms, R5 is selected from the group consisting of hydrogen and alkyl, having 1 - 4 carbon atoms, R9 is selected from the group consisting of hydrogen and -CONH2, Y is selected from the group consisting of -O-, and -CH2, n is an integer from O to 5, m is an integer from O to 2 and Ar is phenylnucleus.
Alkoxyalkyl Rl has up to 7 carbon atoms in each alkyl chain, preferably up to 4 carbon atoms in each and each of them may be straight and/or branched. Alkoxyalkyl Rl is thus e.g., methoxymethyl, methoxyethyl, ethoxyethyl, isopropoxyethyl, n-propoxymethyl, and t-butyloxymethyl.
R1 bein~ -CH=NOR, wherein R is hydrogen, and alkyl with 1 to 6 carbon atoms is e.g., isonitrosomethyl, methylisonitrosomethyl, ethyl-isonitrosomethyl, n-propylisonitrosomethyl, isopropylisonitrosomethyl.
Halogen R is e.g., chloro, fluoro or bromo.
Alkyl R has up to 4 carbon atoms, and is straigh* or branched and is e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl.
Alkoxy R has up to 4 carbon atoms and is straight or branched and is e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
,~
Alkyl R has the same meaning as alkyl R and is e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and t-butyl.
The new compounds have valuable pharmacological properties.
Thus they block cardial js-receptors, which is shown at the determination of the antagonism of tachycardia after an intravenous injection of 0.5,ug/kg of d/l-isoproterenol sulphate on an anaesthetized cat at an intravenous dose of 0.002 to 2 mg/kg. Thus they block the vascular ~6-receptors which is shown at the determination of the antagonism of vasodilation after an intravenous injection of 0.5 ~g/kg of d/l-isoproterenol sulphate on an anaesthetized cat at an intravenous dose of 3 mg/kg or more. They are thus heart selective.
The new compounds can be used as cardioselective antagonists of adrenergic ~-receptor-stimulators, e.g., at the treatment of exogenously or endogenously caused arrythmias and angina pectoris. One may also use them as intermediates at the preparation of other valuable pharmaceutical compounds.
Outstanding amines are also those of formula Ia OHR3aR5a (Rla) (R2a)Ar-OCH2CHCHNCH~cH2)n-Y - ~ (Ia) R a (CH2)mR
wherein R is -CH2CH=CH2, R is selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy, R3a is hydrogen, R~a is hydrogen, R5a is the group consisting of hydrogen and alkyl, R9a is selected from the group consisting of hydrogen and -CONH2, Y is a divalent member sel-ected from the group consisting of -0-, and -CH2-, n is an integer from 0 to 5, m is an integer from 0 to 2, and Ar is phenyl, or a therapeutically acceptable salt thereof.
Of the compounds of the formula Ia, such compounds are especially advantageous, wherein R is o-CH2CH=CH2 or m-CH2CH=CH2, R is hydrogen, chloro, bromo, methyl, ethyl, methoxy and ethoxy, R is hydrogen, R is hydrogen, R a is hydrogen, methyl or ethyl, 1~93~95 R9a is hydro~en~ carbamyl, yla is -0- and -C~12-, n is an integer from 0 to 5 m is an integer from 0 to 2~ Ar is phenyl whereby when ya is CH2, n is 1-5, or a therapeutically acceptable salt thereof.
Preferably those compounds will be mentioned of formula Ia, wherein Rla is o-CH2CH=CH2, R a is hydrogen, chloro, methylJ and methoxy, R a is hydrogen, R a is hydrogen, R a is hydrogen or methyl, R a is hydrogen or carbamyl, ya is -0-, n is l or 2~ m is 0, 1 or 2J Ar is phenyl, or a thera-peutically acceptable salt thereof.
Outstanding amines are also those of the formula Ib (Rlb~ (R )ArOCH2CHCHI-CH(CH2)n ~ (Ib) (CH2) mR
wherein Rlb is selected from the group consisting of -OCH2CH=CH2 and -OCH2C--CHJ R2b is selected from the group consisting of hydrogenJ halogenJ
alkyl and alkoxyJ R b is hydrogenJ R b is hydrogenJ R5b is selected from the group consisting of hydrogenJ and alkylJ R b is selected from the group consisting of hydrogen and -CONH2J Y is a divalent member selected from the group consisting of -O-J and -CH2-J n is an integer from 0 to 5J m is an integer from 0 to 2J and Ar is phenylJ whereby yb is -CH2-J n is 1-5J and whereby Rl is bound in 2 or 3 position to the phenyl, or a therapeutically acceptable salt thereof.
Of the compounds of the formula Ib such compounds are especially advantageousJ wherein R is -OCH2CH=CH2 or -OCH2C--CHJ R b is hydrogenJ
chloroJ bromoJ methyl, ethyl, methoxy and ethoxy, R3b is hydrogen, R4b is hydrogen, R5b is hydrogen, methyl or ethyl, R9b is hydrogen, carbamyl, yb is -0-, and CH2, n is an integer from 0 to 5, m is an integer from 0 to 2 Ar is phenylJ whereby when Y is CH2 n is 1-5, and whereby R b is bound in 2 or 3 position to the phenyl, or a therapeutically acceptable salt thereof.
Preferably those compounds will be mentioned of formula Ib, wherein Rlb is o-OCH2CH=CH2 or o-OCH2C-CH, R b is hydrogen, chloro, methyl and
-3-30~5 methoxy, R is hydrogen, R is hydrogen, R5b is hydrogen or methyl, R is hydrogen or carbamyl, yb is -O-, n is 1 or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts thereof.
Outstanding amines are also those of formula Ic oHR3c R5C
(R ) (R )~rOCH2CHCHN-lH(CH2) _yC ~ (Ic) R4C ( 2)m wherein RlC is alkoxyalkyl, R2C is selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy, R3c is hydrogen, R4c is hydrogen, R5c is selected from the group consisting of hydrogen and alkyl, R9c is selected from the group consisting of hydrogen and -CONH2, yC is a divalent member selected from the group consisting of -O-, and -CH2, n is an integer from O to 5, m is an integer from 0-2 and Ar is phenyl, whereby when Y is -CH2- n is 1-5, and whereby RlC is bound in 2 or 3 position to the phenyl.
Of the compounds of the formula Ic such compounds are especially advantageous, wherein RlC is alkoxyalkyl, R2C is hydrogen, chloro, bromo, methyl, ethyl, methoxy and ethoxy, R3c is hydrogen, R4c is hydrogen, R5c is hydrogen, methyl or ethyl, R9c is hydrogen or carbamyl, yC is -O-, and -CH2, n is an integer from O to 5, m is an integer from O to 2, Ar is phenyl whereby when yC is CH2 n is 1-5, and whereby RlC is bound in 2 or 3 posltion to the phenyl.
Preferably those compounds will be mentioned of formula Ic, wherein RlC is methoxymethyl, methoxyethyl, or ethoxyethyl, R2C is hydrogen, chloro, methyl and methoxy, R3c is hydrogen, R4c is hydrogen, R5c is hydrogen or methyl, R9c is hydrogen or carbamyl, yC is -O-, n is l or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts thereof.
Outstanding amines are also those of formula Ic oHR3c R5C
(R ) (R )~rOCH2CHCHN-lH(CH2) _yC ~ (Ic) R4C ( 2)m wherein RlC is alkoxyalkyl, R2C is selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy, R3c is hydrogen, R4c is hydrogen, R5c is selected from the group consisting of hydrogen and alkyl, R9c is selected from the group consisting of hydrogen and -CONH2, yC is a divalent member selected from the group consisting of -O-, and -CH2, n is an integer from O to 5, m is an integer from 0-2 and Ar is phenyl, whereby when Y is -CH2- n is 1-5, and whereby RlC is bound in 2 or 3 position to the phenyl.
Of the compounds of the formula Ic such compounds are especially advantageous, wherein RlC is alkoxyalkyl, R2C is hydrogen, chloro, bromo, methyl, ethyl, methoxy and ethoxy, R3c is hydrogen, R4c is hydrogen, R5c is hydrogen, methyl or ethyl, R9c is hydrogen or carbamyl, yC is -O-, and -CH2, n is an integer from O to 5, m is an integer from O to 2, Ar is phenyl whereby when yC is CH2 n is 1-5, and whereby RlC is bound in 2 or 3 posltion to the phenyl.
Preferably those compounds will be mentioned of formula Ic, wherein RlC is methoxymethyl, methoxyethyl, or ethoxyethyl, R2C is hydrogen, chloro, methyl and methoxy, R3c is hydrogen, R4c is hydrogen, R5c is hydrogen or methyl, R9c is hydrogen or carbamyl, yC is -O-, n is l or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts thereof.
-4-~ *,~, ., 10~3~9S
Outstanding amines are also those according to formula Ig OH~3g R5g (R g)(R g)ArOCH2CHCH~ CH(CH2) -Yg ~ (Ig) ( CH2 ) mR
wherein R g is selected from the group consisting of HOCH2CH2NHCOCH2O- and CH3OCH2NHCOCH20-, R g is selected from the group consisting of hydrogen, halogen, alkyl and alkoxy, R3g is hydrogen, R4g is hydrogen, R5g is selected from the group consisting of hydrogen, and alkyl, R g is selected from the group consisting of hydrogen and -CONH2, Yg is a divalent member selected from the group consisting of -0-, and -CH2-, n is an integer from 0 to 5, m is an integer from 0 to 2, and Ar is phenyl, whereby Rlg is bound in 2 or 3 position to the phenyl, whereby when Yg is -CH2- n is 1-5.
Of the compound of the formula Ig such compounds are especially advantageous, wherein R g is HocH2cH2~ocH2o- or CH30CH2CH2NHCOCH20, R2g is hydrogen, chloro, bromo, methyl, ethyl, methoxy and ethoxy, R3g is hydrogen, R4g is hydrogen, R5g is hydrogen, methyl or ethyl, R9g is hydrogen or carbamyl, Yg is -0-, and -CH2-, n is an integer from 0 to t,~m is an integer from 0 to 2, Ar is phenyl, whereby when Yg is CH2 n is 1-2, and whereby R g is bound in 2 or 3 position to the phenyl or a therapeutically acceptable salt thereof.
Preferably those compounds will be mentioned according to form-ula Ig, wherein R g is HOCH2CH2NHCOCH2O- or CH3OCH2CH2NHCOCH2O-, R2g is hydrogen, chloro, methyl and methoxy, R3g is hydrogen, R4g is hydrogen, R5g is hydrogen or ~ethyl, R9g is hydrogen or carbamyl, Yg is -0-, n is 1 or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts thereof.
~'~ -5-~ ~j5 ~)93(~95 Outstanding amines are also those according to formula Ik oHR3k R5k (Rlk~ (R2k)ArOCH2CHCHN-CH~CH2)n-Y ~ (Ik) R4k (CH2)mR
wherein R is -CH=NOR, wherein R is selected from the group consisting of hydrogen and alkyl having l to 6 carbon atoms, R k is selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy, R is hydrogen, R is hydrogen, R k is selected from the group consisting of hydrogen, and alkyl, R is selected from the group consisting of hydrogen and -CONH2, yk is a divalent member selected from the group consisting of -0-, and -CH2, n is an integer from 0 to 5, m is an integer from 0 to 2, and Ar is phenyl, whereby Rlk is bound in 2 or 3 position to the phenyl, whereby when yk is -CH2 n is 1-5.
Of the compound of the formula Ik such compounds are especially advantageous, wherein Rlk is -CH=NOR, wherein Rk is hydrogen or alkyl having 1 to 6 carbon atoms, R2k is hydrogen, chloro, bromo, methyl, ethyl, methoxy, and ethoxy, R3k is hydrogen, R4k is hydrogen, R5k is hydrogen, methyl or ethyl, R9k is hydrogen or carbamyl, yk is -0-, and -CH2-, n is an integer from O to 5, m is an integer from O to 2, Ar is phenyl, whereby when Y is CH2 n is 1-5 and whereby R k is bound in 2 or 3 position to the phenyl or a therapeutically acceptable salt thereof, Preferably those compounds will be mentioned according to form-ula Ik, wherein Rlk is isonitroso methyl, methylisonitrosomethyl, ethyl-isonitrosomethyl, propylisonitrosomethyl, or t-butylisonitrosomethyl, R is hydrogen, chloro, methyl and methoxy, R is hydrogen, R is hydrogen, R5k is hydrogen or methyl, R9k is hydrogen or carbamyl, yk is -O-, n is 1 or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts thereof.
, ~ -6-The following compounds are especially mentioned:
1) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(2-allylphenoxy)propanol-2.
2) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(2-methoxyethylphenoxy)propanol-2.
3) 1-[1-methyl-2-(4-carbamylphenoxy)ethylamino]-3-(2-allylphenoxy)propanol-2.
4) 1-[1-methyl-2-(4-carbamylphenoxy)ethylamino]-3-(2-methylisonitrosomethyl-phenoxy)propanol-2.
Outstanding amines are also those according to formula Ig OH~3g R5g (R g)(R g)ArOCH2CHCH~ CH(CH2) -Yg ~ (Ig) ( CH2 ) mR
wherein R g is selected from the group consisting of HOCH2CH2NHCOCH2O- and CH3OCH2NHCOCH20-, R g is selected from the group consisting of hydrogen, halogen, alkyl and alkoxy, R3g is hydrogen, R4g is hydrogen, R5g is selected from the group consisting of hydrogen, and alkyl, R g is selected from the group consisting of hydrogen and -CONH2, Yg is a divalent member selected from the group consisting of -0-, and -CH2-, n is an integer from 0 to 5, m is an integer from 0 to 2, and Ar is phenyl, whereby Rlg is bound in 2 or 3 position to the phenyl, whereby when Yg is -CH2- n is 1-5.
Of the compound of the formula Ig such compounds are especially advantageous, wherein R g is HocH2cH2~ocH2o- or CH30CH2CH2NHCOCH20, R2g is hydrogen, chloro, bromo, methyl, ethyl, methoxy and ethoxy, R3g is hydrogen, R4g is hydrogen, R5g is hydrogen, methyl or ethyl, R9g is hydrogen or carbamyl, Yg is -0-, and -CH2-, n is an integer from 0 to t,~m is an integer from 0 to 2, Ar is phenyl, whereby when Yg is CH2 n is 1-2, and whereby R g is bound in 2 or 3 position to the phenyl or a therapeutically acceptable salt thereof.
Preferably those compounds will be mentioned according to form-ula Ig, wherein R g is HOCH2CH2NHCOCH2O- or CH3OCH2CH2NHCOCH2O-, R2g is hydrogen, chloro, methyl and methoxy, R3g is hydrogen, R4g is hydrogen, R5g is hydrogen or ~ethyl, R9g is hydrogen or carbamyl, Yg is -0-, n is 1 or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts thereof.
~'~ -5-~ ~j5 ~)93(~95 Outstanding amines are also those according to formula Ik oHR3k R5k (Rlk~ (R2k)ArOCH2CHCHN-CH~CH2)n-Y ~ (Ik) R4k (CH2)mR
wherein R is -CH=NOR, wherein R is selected from the group consisting of hydrogen and alkyl having l to 6 carbon atoms, R k is selected from the group consisting of hydrogen, halogen, alkyl, and alkoxy, R is hydrogen, R is hydrogen, R k is selected from the group consisting of hydrogen, and alkyl, R is selected from the group consisting of hydrogen and -CONH2, yk is a divalent member selected from the group consisting of -0-, and -CH2, n is an integer from 0 to 5, m is an integer from 0 to 2, and Ar is phenyl, whereby Rlk is bound in 2 or 3 position to the phenyl, whereby when yk is -CH2 n is 1-5.
Of the compound of the formula Ik such compounds are especially advantageous, wherein Rlk is -CH=NOR, wherein Rk is hydrogen or alkyl having 1 to 6 carbon atoms, R2k is hydrogen, chloro, bromo, methyl, ethyl, methoxy, and ethoxy, R3k is hydrogen, R4k is hydrogen, R5k is hydrogen, methyl or ethyl, R9k is hydrogen or carbamyl, yk is -0-, and -CH2-, n is an integer from O to 5, m is an integer from O to 2, Ar is phenyl, whereby when Y is CH2 n is 1-5 and whereby R k is bound in 2 or 3 position to the phenyl or a therapeutically acceptable salt thereof, Preferably those compounds will be mentioned according to form-ula Ik, wherein Rlk is isonitroso methyl, methylisonitrosomethyl, ethyl-isonitrosomethyl, propylisonitrosomethyl, or t-butylisonitrosomethyl, R is hydrogen, chloro, methyl and methoxy, R is hydrogen, R is hydrogen, R5k is hydrogen or methyl, R9k is hydrogen or carbamyl, yk is -O-, n is 1 or 2, m is 0, 1 or 2, Ar is phenyl or therapeutically acceptable salts thereof.
, ~ -6-The following compounds are especially mentioned:
1) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(2-allylphenoxy)propanol-2.
2) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(2-methoxyethylphenoxy)propanol-2.
3) 1-[1-methyl-2-(4-carbamylphenoxy)ethylamino]-3-(2-allylphenoxy)propanol-2.
4) 1-[1-methyl-2-(4-carbamylphenoxy)ethylamino]-3-(2-methylisonitrosomethyl-phenoxy)propanol-2.
5) 1-[2-(4-carbamylphenoxy)ethylamino]-3-(3-allylphenoxy~propanol-2.
The new compounds are obtained in accordance to methods known ~ se. Thus (a) a compound of formula II
Xl 3 (R )(R )ArOCH21H HZ II
wherein Ar, Rl, R and R3 have the meanings given above, Xl is a hydroxy group and Z is a reactive, esterified hydroxy group, or Xl and Z together form an epoxy group, is reacted with an amine of the formula (III) HN - CH(CH2) ~ III
~ 2)m wherein R4, R5, R9, Y, m and n have the same meanings as given above.
A reactive, esterified hydroxy group is particularly a hydroxy group esteritied with a strong, ~norganic or organic acid, preferably a hydrohalogen acid, as hydrochloric acid, hydrobromic acid, or hydroiodic acid, further sulphuric acid or a strong organic sulphonic acid as a strong aromatiC sulphonic acid, e.g., benzenesulphonic acid, 4-bromoben~ene-sulphonio acid or 4-toluenesulphonic acid. Thus, Z is preferably chloro, bromo or iodo.
This reaction is carried out in a common way. At the use of a reactive ester as a starting material the preparation takes place preferably in the presence of a basic condensating agent and/or with an excess of an , ~ -7 ~0~33V95 amine. Suitable basic condensating agents are e.g., alkalimetal hydroxides as sodium or potassium hydroxide, alkalimetal carbonates as potassium carbonate and alkalimetal alcoholates as sodium methylate, potassium ethyl-ate and potassium tert.butylate.
~urther, (b) a compound of formula IV
(R )(R )ArOCH2CHOHCHN(R )H (IV) wherein Ar, Rl, R , R3 and R have the same meanings as given above, is reacted with a compound of the formula V
Z - CH (CH2)m - Y ~ (V) (C 2)n wherein R J R9, Y, m, n and Z have the same meanings as given above.
This reaction is carried out in a common way, preferably in the presence of a basic condensating agent and/or an excess of an amine. Suit-able basic condensating agents are e.g., alkaline alcoholates, preferably sodium or po~assium alcoholate, or also alkaline carbonates as sodium or potassium carbonate.
ThusJ for example, basic, neutral or mixed salts may be obtained as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds may in a manner known ~ se be transformed into free compounds using e.g., basic agents as alkali or ion exchanger. On the other hand, the free bases obtained may form salts with organic or inorganic acids.
In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts. Such acids are e.g., hydrohalogen acids, sulphuric acid, phosph~ric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulphonic acids, as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, phenyl-r~
l~g3095 acetic, benzoic, p-aminobenzoic, antranilic, p-hydroxyhenzoic, salicyclic or p-aminosalicyclic acid, embonic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylenesulphonic acids, halogenbenzenesulphonic, toluenesulphonic, naphthylsulphonic acids or sulphanilic acid: methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds as e.g., picrates may serve as purifying agents of the free bases obtained as the free bases are transformed into salts, these are separated and the bases are then set free from the salts again. According to the close relationship between the new compounds in free form and in the form of their salts it will be understood from the above and the below that, if possible, the corresponding salts are included in the free compound.
Further, one may in a manner known per se react a phenol of form-ula V
~Rl)(R2~ A OH (V) ; with an acetidinol of the formula XXXIX
CH2-N-CH-(CH2)n ~ (XXXIX) HO-CH-CH2 ( 2)m 2 wherein R5, Y, m and n have the meanings to the formation of a compound of formula I.
This reaction is carried out in a common way. Thus the reaction is carried out under alkaline conditions in a suitable solvent, as benzyl-alcohol by boiling the reaction mixture for some hours. Thereby the phenol is primarily converted to its metalphenolate as alkalimetalphenolate before it ïs added to the acetidinol of formula XXX.
The new compounds may, depending on the choice of starting mat-erial and process, be present as optical antipodes or racemate, or, if they contain at least one asymmetric carbon atom, be present as an isomer mixture (racemate mixture~.
_9_
The new compounds are obtained in accordance to methods known ~ se. Thus (a) a compound of formula II
Xl 3 (R )(R )ArOCH21H HZ II
wherein Ar, Rl, R and R3 have the meanings given above, Xl is a hydroxy group and Z is a reactive, esterified hydroxy group, or Xl and Z together form an epoxy group, is reacted with an amine of the formula (III) HN - CH(CH2) ~ III
~ 2)m wherein R4, R5, R9, Y, m and n have the same meanings as given above.
A reactive, esterified hydroxy group is particularly a hydroxy group esteritied with a strong, ~norganic or organic acid, preferably a hydrohalogen acid, as hydrochloric acid, hydrobromic acid, or hydroiodic acid, further sulphuric acid or a strong organic sulphonic acid as a strong aromatiC sulphonic acid, e.g., benzenesulphonic acid, 4-bromoben~ene-sulphonio acid or 4-toluenesulphonic acid. Thus, Z is preferably chloro, bromo or iodo.
This reaction is carried out in a common way. At the use of a reactive ester as a starting material the preparation takes place preferably in the presence of a basic condensating agent and/or with an excess of an , ~ -7 ~0~33V95 amine. Suitable basic condensating agents are e.g., alkalimetal hydroxides as sodium or potassium hydroxide, alkalimetal carbonates as potassium carbonate and alkalimetal alcoholates as sodium methylate, potassium ethyl-ate and potassium tert.butylate.
~urther, (b) a compound of formula IV
(R )(R )ArOCH2CHOHCHN(R )H (IV) wherein Ar, Rl, R , R3 and R have the same meanings as given above, is reacted with a compound of the formula V
Z - CH (CH2)m - Y ~ (V) (C 2)n wherein R J R9, Y, m, n and Z have the same meanings as given above.
This reaction is carried out in a common way, preferably in the presence of a basic condensating agent and/or an excess of an amine. Suit-able basic condensating agents are e.g., alkaline alcoholates, preferably sodium or po~assium alcoholate, or also alkaline carbonates as sodium or potassium carbonate.
ThusJ for example, basic, neutral or mixed salts may be obtained as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds may in a manner known ~ se be transformed into free compounds using e.g., basic agents as alkali or ion exchanger. On the other hand, the free bases obtained may form salts with organic or inorganic acids.
In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts. Such acids are e.g., hydrohalogen acids, sulphuric acid, phosph~ric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulphonic acids, as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, phenyl-r~
l~g3095 acetic, benzoic, p-aminobenzoic, antranilic, p-hydroxyhenzoic, salicyclic or p-aminosalicyclic acid, embonic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylenesulphonic acids, halogenbenzenesulphonic, toluenesulphonic, naphthylsulphonic acids or sulphanilic acid: methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds as e.g., picrates may serve as purifying agents of the free bases obtained as the free bases are transformed into salts, these are separated and the bases are then set free from the salts again. According to the close relationship between the new compounds in free form and in the form of their salts it will be understood from the above and the below that, if possible, the corresponding salts are included in the free compound.
Further, one may in a manner known per se react a phenol of form-ula V
~Rl)(R2~ A OH (V) ; with an acetidinol of the formula XXXIX
CH2-N-CH-(CH2)n ~ (XXXIX) HO-CH-CH2 ( 2)m 2 wherein R5, Y, m and n have the meanings to the formation of a compound of formula I.
This reaction is carried out in a common way. Thus the reaction is carried out under alkaline conditions in a suitable solvent, as benzyl-alcohol by boiling the reaction mixture for some hours. Thereby the phenol is primarily converted to its metalphenolate as alkalimetalphenolate before it ïs added to the acetidinol of formula XXX.
The new compounds may, depending on the choice of starting mat-erial and process, be present as optical antipodes or racemate, or, if they contain at least one asymmetric carbon atom, be present as an isomer mixture (racemate mixture~.
_9_
6~ ~
The isomer mixtures (racemate mixtures) obtained may, depending on physical-chemical differences of the components, be separated into the both stereoisomeric ~diastereomeric) forms e.g., by means of chromatography and/or fractionated crystallisation.
The racemates obtained can be separated according to known methods, e.g., by means of recrystallisation from an optically active solvent, by means of microorganisms, or by a reaction with optically active acids form-ing salts of the compound and separating the salts thus obtained, e.g., by means of their different solubility in the diastereomers-. from which the antipodes by the influence of a suitable agent may be set free. Suitably useable optically active acid are e.g., the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphersulphonic acid or china acid. Preferably the more active part of two antipodes is isolated.
Suitably such starting materials are used for carrying out the reactions of the invention, which material leads to groups of end products primarily especially desired and especially to the specifically described and preferred end products.
The starting materials ~re known or may, if they should be new, be obtained according to processes known ~ se.
In clinical use the compounds of the invention are administered normally orally, rectally or by injection in the form of a pharmaceutical preparation, which contains an active component either as free base or as pharmaceutically acceptable non-toxic acid additions salts, as e.g., the hydrochloride lactate, acetate, sulphamate or the like in combination with a pharmaceutically acceptable carrier. Thereby the mentioning of the new compounds of the invention is here related to either the free amine base or the acid addition salts of the free base, even if the compounds are gen-erally or specifically described, provided that the context in which such expressions are used, e.g., in the examples, with this broad meaning should not correspond. The carrier may be a solid, semisolid or liquid diluent 109309, j or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compound is between 0.1 to 95% by weight of the preparation, suitably between 0.5 to 20% by weight in prep-arations for injection and between 2 to 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical preparations containing a compound of the present invention in the form of dosage units for oral ad-ministration the compound selected may be mixed with a solid, pulverulent carrier, as e.g., with lactose, saccharose, sorbitol, mannitol, starch, as potato starch, corn starch amylopectin, cellulose derivatives or gel-atine, as well as with an antifriction agent as magnesium stearate, calcium stearate, polyethyleneglycol waxes or the like, and be pressed into tablets.
If coated tablets are wanted, the above prepared core may be coated with con-centrated solution of sugar, which solution may contain e.g., gum arabicum, gelatine, talc, titandioxide or the like. Furthermore, the tablets may be coated with a lacquer dissolved in an easily volatile organic solvent or mixture of solvents. To this coating a dye may be added in order to easily distinguish between tablets with different active compounds or with differ-ent amounts of the active compound present.
In the preparation of soft gelatine capsules (pearl-shaped, closed capsules), wh;ch consist of gelatine and e.g., glycerine or in the preparat-ion of similar closed capsules the active compound is mi~ed with a vegetable oil. Hard gelatine capsules may contain granules of the active compound in combination with a solid, pulverulent carrier as lactose, saccharose, sorbitol, mannitol, starch, (as e.g., potato starch, corn starch or amylo-pectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active substance in a mixture with a neutral fat base, or they may be prepared in the form of gelatine-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil.
,;.~,' 10~?3095 Liquid preparations for oral administration may be present in the form of syrups or suspensions, e.g., solutions containing from about 0.2% by weight to about 20% by weight of the active substance described, whereby the residue consists of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thick-ening agent.
Solutions for parenteral administration by injection may be pre-pared as an aqueous solution of a watersoluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from about 0.5%
by weight to about 0.10% by weight. These solutions may also contain stab-ilizing agents and/or buffering agents and may suitably be available in different dosage unit ampoules.
The preparation of pharmaceutical tablets for peroral use is carried out in accordance with the following method:
The solid substances included are ground or sieved to a certain particle size. The binding agent is homogenized and suspended in a certain amount of solvent. The therapeutic compound and necessary auxiliary agents are mixed during a continuous and constantly mixing with the binding agent solution and are moistened so that the solution is uniformly divided in the mass without overmoistening any parts. The amount of solvent is usually so adapted that the mass obtains a consistency reminding of wet snow. The moistening of the pulverulent mixture with the binding agent solution causes the particles to gather together slightly to aggregates and the real gran-ulating process is carried out in such a way that the mass is pressed through a sieve in the form of a net of stainless steel having a mesh size of about 1 mm. The mass is then placed in thin layers on a tray to be dried in a drying cabinet. This drying takes place during lO hours and has to be stand-ardized carefully as the damp degree of the granulate is of utmost importance for the following process and for the feature of the tablets. Drying in a r ~
. ~, ~ .
1~9309S
fluid bed may possibly be used. In this case the mass is not put on a tray but is poured into a container having a net bottom.
After the drying step the granules are sieved so that the particle size wanted is obtained. Under certain circumstances powder has to be re-moved.
To the so called final mixture, disintegrating, antifriction agents and antiadhesive agents are added. After this mixture the mass shall have its right composition for the tabletting step.
The cleaned tablet punching machine is provided with a certain set of punches and dies, whereupon the suitable adjustment for the weight of the tablets and the degree of compression is tested out. The weight of the tablets is decisive for the size of the dose in each tablet and is calculated starting from the amount of therapeutic agent in the granules. The degree of compression affects the size of the tablet, its strength and its ability to disintegrate in water. Especially as regards the two latter properties the choice of compression pressure (0.5 to 5 ton~ means something of a bal-ancestes. When the right adjustment is set, the preparation of tablets is started, which is carried out with a rate of 20,000 to 200,000 tablets per hour. The pressing of the tablets requires different times and depends on the size of the batch.
The tablets are freed from adhering powder in a specific apparatus and are thon stored in closed packages until they are delivered.
Many tablets, especially those which are rough or bitter, are coated with a coating. This means that these are coated with a layer of sugar or some other suitable coating.
The tablets are usually packed by machines having an electronic counting device. The different types of packages consist of glass or plastic gallipots, but also boxes, tubes and specific dosage adapted pack-ages.
i U~ ' ~.0930'35 The daily dose of the active substance varies and is dependent on the type of administration, but as a general rule it is 100 to 400 mg/day of active substance at peroral administration and 5 to 20 mg/day at intra-venous administration.
The following illustrates the principle and the adaptation of invention, however, without being limited thereto. Temperature is given in degree Celsius.
Example 1 1.9 g of 1,2-epoxy-3-(2-allylphenoxy)-propane and 1.8 g of 4-(2-aminoethoxy)-benzamide were refluxed in 25 ml of isopropanol for 1.5 hours. The reaction mixture was evaporated in vacuo, whereupon the residue was dissolved in acetone and the hydrochloride of 1[2-(4-carbamoylphenoxy)-ethylamino]-3-(2-allylphenoxy)propanol-2 was precipitated by introducing ether containing HCl. Mp. 211C. The structure was verified with NMR.
Example 2 2.1 g of 1,2-epoxy-3-[2-(2~ethoxyethyl)phenoxy]-propane and 1.8 g of 4-(2-aminoethoxy)benzamide were reacted with each other in accordance with Example 1. The melting point of 1-[2-(4-carbamoylphenoxy)ethylamino]-3-[2-~2-methoxyethyl)phenoxy]propanol-2 hydrochloride was 105C. The structure was verified with NMR.
Example 3 1.9 g of 1,2-epoxy-3-~2-allylphenoxy)propane and 2,5 g of 4-~2-aminopropoxy)benzamide were reacted in accordance with Example 1. The hydrochloride of l-[l-methyl-2-~4-carbamoylphenoxy)-ethylamino]-3-(2-allyl-phenoxy)propanol-2 melted at 94C. The structure was verified using NMR.
Example 4 1.8 g of 1-amino-3-~2-methylisonitrosomethylphenoxy)-propanol-2 and 1.55 g of 4-methylcarbonylmethoxybenzamide were dissolved in 25 ml of methanol and cooled to 0C. 1.8 g of NaBH4 were then added during 1/2 hour.
50 ml of water were added and the product was extracted with ethylacetate.
10'33095 The ethylacetate phase is evaporated in vacuo and the substance, l-[l-methyl-2-(4-carbamoylphenoxy~ethylamino]-3-(2-methylisonitrosomethylphenoxy)-propanol-2, is washed with ether and ethylacetate. Mp. 106C. (HCl) Example 5 1-[2-(4-carbamoylphenoxy)ethylamino]-3-(3-allylphenoxy)propanol-2 was prepared in accordance with Example 1 starting from 1,2-epoxy-3-(3-allyl-phenoxy)propane and 4-aminoethoxybenzamide. Mp. 228C. as hydrochloride.
Example 6 A syrup containing 2% (weight per volume) of active substance was 0 prepared from the following ingredients:
1-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-allyl-phenoxy)propanol-2 HCl 2.0 g Saccharine 0.6 g Sugar 1 30.0 g Glycerine 5.0 g Plavouring agent 0.1 g Ethanol 96% 10.0 ml Distilled water ad 100.0 ml Sugar, saccharine and the hydrochloride salt were dissolved in 60 g of warm water. After cooling,glycerine and a solution of flavouring agents dissolved in ethanol were added. To the mixture water was then added to 100 ml.
The above given active substance may be replaced with other pharma-ceutically acceptable acid addition salts.
Example 7 1-[2-~4-carbamoylphenoxy)ethylamino]-3-~2-chloro-5-methylphenoxy) propanol-2-hydrochloride (250g) was mixed with lactose ~175.8g), potato starch ~169,7 g~ and colloidal silicic acid ~32 g). The mixture was moist-ened with a 10% solution of gelatine and was granulated through a 12-mesh sieve. After drying potato starch (160 g), talc (50 g) and magnesium stear-io930gs ate (5 g) were admixed and the mixture thus obtained was pressed into tablets (lO,000) which contain 25 mg of substance. The tablets are sold on the market provided with a breaking score to give another dose than 25 mg or to give ~mlltiples thereof when broken.
Example 8 Granules were prepared from 1-[2-~4-carbamoylphenoxy)ethylamino]-3-(2-(2-methoxyethyl)phenoxy-propanol-2-hydrochloride ~250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After drying step the granules were mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) and was pressed into 10,000 tablets being biconvex. These tablets are primarily coated with a 10% alcoholic solution of shellac and thereupon with an aqueous solution containing saccharose (45%), gum arabicum (5%), gelatine (4%) and dyestuff (0.2%). Talc and powder sugar were used for powdering after the first five coatings. The coating was then coated with a 66% sugar syrup and polished with a 10%
carnauba wax solution in carbon tetrachloride.
Example 9 1-~2-(4-carbamoylphenoxy)ethylamino]-3-(4-chloro-3-thiazoloxy) propanol-2-hydrochloride (1 g), sodiumchloride (0.8 g) and ascorbic acid (0.1 g) were dissolved in sufficient amount of distilled water to give 100 ml of solution. This solution, which contains lO mg of active sub-stance on each ml, was used in filling ampoules, which were sterilized by heating at 120C. for 20 minutes.
.: .
10~33095 The following compounds have also been prepared:
~Arocl1zcH~ 2~c}l~cH2)n ~3~CH2~mR9 -Example Ar Rl R R n m R Mp.
C
10 Phenyl 2-CH2=CH-CH2- H H 1 04-NH2C0136-7 (HCl) 11 " 2-CH-C-CH20- H H 1 04-NH2CO-215 (HCl) 12 2-HCH2CH2NHCCH2- H H 1 0~-NH CO-66 (p-OH-2 benzoate 13 " 2-CH2=CH-CH20- H H 2 04-NH2CO-200 (HCl) 14 " 2-CH2=CH-CH20 H H 4 04-NH2CO-oil (HCl) Biological effects The~-receptor blocking agents of the present invention were tested as regards their biological properties. All compounds uere thereby tested inana~sthetized cats (males and females weighing 2.5-3.5 kg) pre-treated with reserpine (5 mg/kg bodyweight administered intra musculary) about 16 hours before the experiments. The animals were pretreated with reserpine in order to eliminate the endogenous sympathetic control of heart rate and vascular smooth muscle tone. The cats wereanaesthetized wlth pentobarbital (30 mg/kg bodyweight administered i.p.) and artificially ventilated with room air. A bilateral vagotomy was performed in the neck.
Blood pressure was obtained from a cannulated carotid artery and heart rate was registered from a cardiotachometer, triggered by the electrocardiogram.
(ECG) Intrinsic beta-mimetic activity on the heart was seen as increased heart rate after drug administration. The test compounds were given intra-venously in logarithmically increasing doses. The values obtained were plotted on dose-response curves~ from which affinity values (ED50) were estimated. At the end of each experiment high doses of isoprenaline were . -17-3{)9S
given in order to obtain the maximal heart rate response.
The compounds were also tested on conscious dogs. Beagle dogs were trained to be lying quietly and to be lifted to an erect position by placing their forelegs on a table for 2 minutes. Arterial blood pressure was registered via a blood pressure transducer attached to the dog at the heart level. Heart rate was triggered from the ECG. All dogs were pre-treated with methylscopolamine to avoid vagal influences. Recordings were taken before and 15 and 75 minutes after administration of the test compound, first in supine position for 2 minutes and then in the erect position for 2 minutes. The test compounds were given in increasing doses with 2 hour int-ervals.
Table 1 below shows affinity values and intrinsic ~-mimetic activity in reserpinized cats and effects on blood pressure in conscious dogs of compounds of the present invention. Corresponding values for propanolol, (l-isopropylamino-3-(1-naphthoxy)-propanol-2), practolol, (4-(2-hydroxy-3-isopropylaminopropoxy)acetanilide), metoprolol, (l-iso-propylamino-3-[4-(2-methoxyethyl)phenoxy]-propanol-2), tolamolol, (4-[2-(2-hydroxy-3-o-tolyloxypropylamino)ethoxy]-benzamide) and AH 5158 (5-[1-hydroxy-2-l(l-methyl-3-phenylpropyl)-amino[ethyl]salicylamide), are shown for comparison.
~- __ __ , v ~ o t~ N 1` u~ ~ `D
t~O h I ~ `O ~ ~ q L ~ n O C O
a~ r1 n n ~ oo co L $~ ~ + I N L~ N e~ N
~ a n o a- ~ o o n oo h ~rl ~ ,_1 N ~1 ~ ' ~ ~ ~d + + + + + + +
~ ~d _ I
~ ; ~ _I ~ n ~ n N Ln ~ n E~ b h O n ~ ~ O ~ oO O --~ O ~0 CC L~
~ ~.
~ ~o n ~ ~
O u~ _I t~ N--I N ~ I O --I O O
~a Ll O 0 ~0 0 0 0 '-i O O O O
. . _ _ .... _ .. _._._.. _ ~ _l O ,t O ~
.~ ~ ~ ~ 3 ~ ~ N t~ O ~ N
~ h ~ O ~ X X X X X X
. .
.,.~"~,, 93~95 The experiments demonstrate that the compounds tested are potent ~receptor antagonists with or without intrinsic ~6-mimetic activity. The compounds also decrease blood pressure in conscious dogs significantly more than propranolol, practolol and metoprolol and the same extent as tolamolol.
The orthostatic effects of the new compounds are not as pronounced as that of AH 5158, i.e., the blood pressure does not decrease markedly from supine to erect position.
~ ;.
,,~ , .
The isomer mixtures (racemate mixtures) obtained may, depending on physical-chemical differences of the components, be separated into the both stereoisomeric ~diastereomeric) forms e.g., by means of chromatography and/or fractionated crystallisation.
The racemates obtained can be separated according to known methods, e.g., by means of recrystallisation from an optically active solvent, by means of microorganisms, or by a reaction with optically active acids form-ing salts of the compound and separating the salts thus obtained, e.g., by means of their different solubility in the diastereomers-. from which the antipodes by the influence of a suitable agent may be set free. Suitably useable optically active acid are e.g., the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphersulphonic acid or china acid. Preferably the more active part of two antipodes is isolated.
Suitably such starting materials are used for carrying out the reactions of the invention, which material leads to groups of end products primarily especially desired and especially to the specifically described and preferred end products.
The starting materials ~re known or may, if they should be new, be obtained according to processes known ~ se.
In clinical use the compounds of the invention are administered normally orally, rectally or by injection in the form of a pharmaceutical preparation, which contains an active component either as free base or as pharmaceutically acceptable non-toxic acid additions salts, as e.g., the hydrochloride lactate, acetate, sulphamate or the like in combination with a pharmaceutically acceptable carrier. Thereby the mentioning of the new compounds of the invention is here related to either the free amine base or the acid addition salts of the free base, even if the compounds are gen-erally or specifically described, provided that the context in which such expressions are used, e.g., in the examples, with this broad meaning should not correspond. The carrier may be a solid, semisolid or liquid diluent 109309, j or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compound is between 0.1 to 95% by weight of the preparation, suitably between 0.5 to 20% by weight in prep-arations for injection and between 2 to 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical preparations containing a compound of the present invention in the form of dosage units for oral ad-ministration the compound selected may be mixed with a solid, pulverulent carrier, as e.g., with lactose, saccharose, sorbitol, mannitol, starch, as potato starch, corn starch amylopectin, cellulose derivatives or gel-atine, as well as with an antifriction agent as magnesium stearate, calcium stearate, polyethyleneglycol waxes or the like, and be pressed into tablets.
If coated tablets are wanted, the above prepared core may be coated with con-centrated solution of sugar, which solution may contain e.g., gum arabicum, gelatine, talc, titandioxide or the like. Furthermore, the tablets may be coated with a lacquer dissolved in an easily volatile organic solvent or mixture of solvents. To this coating a dye may be added in order to easily distinguish between tablets with different active compounds or with differ-ent amounts of the active compound present.
In the preparation of soft gelatine capsules (pearl-shaped, closed capsules), wh;ch consist of gelatine and e.g., glycerine or in the preparat-ion of similar closed capsules the active compound is mi~ed with a vegetable oil. Hard gelatine capsules may contain granules of the active compound in combination with a solid, pulverulent carrier as lactose, saccharose, sorbitol, mannitol, starch, (as e.g., potato starch, corn starch or amylo-pectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active substance in a mixture with a neutral fat base, or they may be prepared in the form of gelatine-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil.
,;.~,' 10~?3095 Liquid preparations for oral administration may be present in the form of syrups or suspensions, e.g., solutions containing from about 0.2% by weight to about 20% by weight of the active substance described, whereby the residue consists of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thick-ening agent.
Solutions for parenteral administration by injection may be pre-pared as an aqueous solution of a watersoluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from about 0.5%
by weight to about 0.10% by weight. These solutions may also contain stab-ilizing agents and/or buffering agents and may suitably be available in different dosage unit ampoules.
The preparation of pharmaceutical tablets for peroral use is carried out in accordance with the following method:
The solid substances included are ground or sieved to a certain particle size. The binding agent is homogenized and suspended in a certain amount of solvent. The therapeutic compound and necessary auxiliary agents are mixed during a continuous and constantly mixing with the binding agent solution and are moistened so that the solution is uniformly divided in the mass without overmoistening any parts. The amount of solvent is usually so adapted that the mass obtains a consistency reminding of wet snow. The moistening of the pulverulent mixture with the binding agent solution causes the particles to gather together slightly to aggregates and the real gran-ulating process is carried out in such a way that the mass is pressed through a sieve in the form of a net of stainless steel having a mesh size of about 1 mm. The mass is then placed in thin layers on a tray to be dried in a drying cabinet. This drying takes place during lO hours and has to be stand-ardized carefully as the damp degree of the granulate is of utmost importance for the following process and for the feature of the tablets. Drying in a r ~
. ~, ~ .
1~9309S
fluid bed may possibly be used. In this case the mass is not put on a tray but is poured into a container having a net bottom.
After the drying step the granules are sieved so that the particle size wanted is obtained. Under certain circumstances powder has to be re-moved.
To the so called final mixture, disintegrating, antifriction agents and antiadhesive agents are added. After this mixture the mass shall have its right composition for the tabletting step.
The cleaned tablet punching machine is provided with a certain set of punches and dies, whereupon the suitable adjustment for the weight of the tablets and the degree of compression is tested out. The weight of the tablets is decisive for the size of the dose in each tablet and is calculated starting from the amount of therapeutic agent in the granules. The degree of compression affects the size of the tablet, its strength and its ability to disintegrate in water. Especially as regards the two latter properties the choice of compression pressure (0.5 to 5 ton~ means something of a bal-ancestes. When the right adjustment is set, the preparation of tablets is started, which is carried out with a rate of 20,000 to 200,000 tablets per hour. The pressing of the tablets requires different times and depends on the size of the batch.
The tablets are freed from adhering powder in a specific apparatus and are thon stored in closed packages until they are delivered.
Many tablets, especially those which are rough or bitter, are coated with a coating. This means that these are coated with a layer of sugar or some other suitable coating.
The tablets are usually packed by machines having an electronic counting device. The different types of packages consist of glass or plastic gallipots, but also boxes, tubes and specific dosage adapted pack-ages.
i U~ ' ~.0930'35 The daily dose of the active substance varies and is dependent on the type of administration, but as a general rule it is 100 to 400 mg/day of active substance at peroral administration and 5 to 20 mg/day at intra-venous administration.
The following illustrates the principle and the adaptation of invention, however, without being limited thereto. Temperature is given in degree Celsius.
Example 1 1.9 g of 1,2-epoxy-3-(2-allylphenoxy)-propane and 1.8 g of 4-(2-aminoethoxy)-benzamide were refluxed in 25 ml of isopropanol for 1.5 hours. The reaction mixture was evaporated in vacuo, whereupon the residue was dissolved in acetone and the hydrochloride of 1[2-(4-carbamoylphenoxy)-ethylamino]-3-(2-allylphenoxy)propanol-2 was precipitated by introducing ether containing HCl. Mp. 211C. The structure was verified with NMR.
Example 2 2.1 g of 1,2-epoxy-3-[2-(2~ethoxyethyl)phenoxy]-propane and 1.8 g of 4-(2-aminoethoxy)benzamide were reacted with each other in accordance with Example 1. The melting point of 1-[2-(4-carbamoylphenoxy)ethylamino]-3-[2-~2-methoxyethyl)phenoxy]propanol-2 hydrochloride was 105C. The structure was verified with NMR.
Example 3 1.9 g of 1,2-epoxy-3-~2-allylphenoxy)propane and 2,5 g of 4-~2-aminopropoxy)benzamide were reacted in accordance with Example 1. The hydrochloride of l-[l-methyl-2-~4-carbamoylphenoxy)-ethylamino]-3-(2-allyl-phenoxy)propanol-2 melted at 94C. The structure was verified using NMR.
Example 4 1.8 g of 1-amino-3-~2-methylisonitrosomethylphenoxy)-propanol-2 and 1.55 g of 4-methylcarbonylmethoxybenzamide were dissolved in 25 ml of methanol and cooled to 0C. 1.8 g of NaBH4 were then added during 1/2 hour.
50 ml of water were added and the product was extracted with ethylacetate.
10'33095 The ethylacetate phase is evaporated in vacuo and the substance, l-[l-methyl-2-(4-carbamoylphenoxy~ethylamino]-3-(2-methylisonitrosomethylphenoxy)-propanol-2, is washed with ether and ethylacetate. Mp. 106C. (HCl) Example 5 1-[2-(4-carbamoylphenoxy)ethylamino]-3-(3-allylphenoxy)propanol-2 was prepared in accordance with Example 1 starting from 1,2-epoxy-3-(3-allyl-phenoxy)propane and 4-aminoethoxybenzamide. Mp. 228C. as hydrochloride.
Example 6 A syrup containing 2% (weight per volume) of active substance was 0 prepared from the following ingredients:
1-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-allyl-phenoxy)propanol-2 HCl 2.0 g Saccharine 0.6 g Sugar 1 30.0 g Glycerine 5.0 g Plavouring agent 0.1 g Ethanol 96% 10.0 ml Distilled water ad 100.0 ml Sugar, saccharine and the hydrochloride salt were dissolved in 60 g of warm water. After cooling,glycerine and a solution of flavouring agents dissolved in ethanol were added. To the mixture water was then added to 100 ml.
The above given active substance may be replaced with other pharma-ceutically acceptable acid addition salts.
Example 7 1-[2-~4-carbamoylphenoxy)ethylamino]-3-~2-chloro-5-methylphenoxy) propanol-2-hydrochloride (250g) was mixed with lactose ~175.8g), potato starch ~169,7 g~ and colloidal silicic acid ~32 g). The mixture was moist-ened with a 10% solution of gelatine and was granulated through a 12-mesh sieve. After drying potato starch (160 g), talc (50 g) and magnesium stear-io930gs ate (5 g) were admixed and the mixture thus obtained was pressed into tablets (lO,000) which contain 25 mg of substance. The tablets are sold on the market provided with a breaking score to give another dose than 25 mg or to give ~mlltiples thereof when broken.
Example 8 Granules were prepared from 1-[2-~4-carbamoylphenoxy)ethylamino]-3-(2-(2-methoxyethyl)phenoxy-propanol-2-hydrochloride ~250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After drying step the granules were mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) and was pressed into 10,000 tablets being biconvex. These tablets are primarily coated with a 10% alcoholic solution of shellac and thereupon with an aqueous solution containing saccharose (45%), gum arabicum (5%), gelatine (4%) and dyestuff (0.2%). Talc and powder sugar were used for powdering after the first five coatings. The coating was then coated with a 66% sugar syrup and polished with a 10%
carnauba wax solution in carbon tetrachloride.
Example 9 1-~2-(4-carbamoylphenoxy)ethylamino]-3-(4-chloro-3-thiazoloxy) propanol-2-hydrochloride (1 g), sodiumchloride (0.8 g) and ascorbic acid (0.1 g) were dissolved in sufficient amount of distilled water to give 100 ml of solution. This solution, which contains lO mg of active sub-stance on each ml, was used in filling ampoules, which were sterilized by heating at 120C. for 20 minutes.
.: .
10~33095 The following compounds have also been prepared:
~Arocl1zcH~ 2~c}l~cH2)n ~3~CH2~mR9 -Example Ar Rl R R n m R Mp.
C
10 Phenyl 2-CH2=CH-CH2- H H 1 04-NH2C0136-7 (HCl) 11 " 2-CH-C-CH20- H H 1 04-NH2CO-215 (HCl) 12 2-HCH2CH2NHCCH2- H H 1 0~-NH CO-66 (p-OH-2 benzoate 13 " 2-CH2=CH-CH20- H H 2 04-NH2CO-200 (HCl) 14 " 2-CH2=CH-CH20 H H 4 04-NH2CO-oil (HCl) Biological effects The~-receptor blocking agents of the present invention were tested as regards their biological properties. All compounds uere thereby tested inana~sthetized cats (males and females weighing 2.5-3.5 kg) pre-treated with reserpine (5 mg/kg bodyweight administered intra musculary) about 16 hours before the experiments. The animals were pretreated with reserpine in order to eliminate the endogenous sympathetic control of heart rate and vascular smooth muscle tone. The cats wereanaesthetized wlth pentobarbital (30 mg/kg bodyweight administered i.p.) and artificially ventilated with room air. A bilateral vagotomy was performed in the neck.
Blood pressure was obtained from a cannulated carotid artery and heart rate was registered from a cardiotachometer, triggered by the electrocardiogram.
(ECG) Intrinsic beta-mimetic activity on the heart was seen as increased heart rate after drug administration. The test compounds were given intra-venously in logarithmically increasing doses. The values obtained were plotted on dose-response curves~ from which affinity values (ED50) were estimated. At the end of each experiment high doses of isoprenaline were . -17-3{)9S
given in order to obtain the maximal heart rate response.
The compounds were also tested on conscious dogs. Beagle dogs were trained to be lying quietly and to be lifted to an erect position by placing their forelegs on a table for 2 minutes. Arterial blood pressure was registered via a blood pressure transducer attached to the dog at the heart level. Heart rate was triggered from the ECG. All dogs were pre-treated with methylscopolamine to avoid vagal influences. Recordings were taken before and 15 and 75 minutes after administration of the test compound, first in supine position for 2 minutes and then in the erect position for 2 minutes. The test compounds were given in increasing doses with 2 hour int-ervals.
Table 1 below shows affinity values and intrinsic ~-mimetic activity in reserpinized cats and effects on blood pressure in conscious dogs of compounds of the present invention. Corresponding values for propanolol, (l-isopropylamino-3-(1-naphthoxy)-propanol-2), practolol, (4-(2-hydroxy-3-isopropylaminopropoxy)acetanilide), metoprolol, (l-iso-propylamino-3-[4-(2-methoxyethyl)phenoxy]-propanol-2), tolamolol, (4-[2-(2-hydroxy-3-o-tolyloxypropylamino)ethoxy]-benzamide) and AH 5158 (5-[1-hydroxy-2-l(l-methyl-3-phenylpropyl)-amino[ethyl]salicylamide), are shown for comparison.
~- __ __ , v ~ o t~ N 1` u~ ~ `D
t~O h I ~ `O ~ ~ q L ~ n O C O
a~ r1 n n ~ oo co L $~ ~ + I N L~ N e~ N
~ a n o a- ~ o o n oo h ~rl ~ ,_1 N ~1 ~ ' ~ ~ ~d + + + + + + +
~ ~d _ I
~ ; ~ _I ~ n ~ n N Ln ~ n E~ b h O n ~ ~ O ~ oO O --~ O ~0 CC L~
~ ~.
~ ~o n ~ ~
O u~ _I t~ N--I N ~ I O --I O O
~a Ll O 0 ~0 0 0 0 '-i O O O O
. . _ _ .... _ .. _._._.. _ ~ _l O ,t O ~
.~ ~ ~ ~ 3 ~ ~ N t~ O ~ N
~ h ~ O ~ X X X X X X
. .
.,.~"~,, 93~95 The experiments demonstrate that the compounds tested are potent ~receptor antagonists with or without intrinsic ~6-mimetic activity. The compounds also decrease blood pressure in conscious dogs significantly more than propranolol, practolol and metoprolol and the same extent as tolamolol.
The orthostatic effects of the new compounds are not as pronounced as that of AH 5158, i.e., the blood pressure does not decrease markedly from supine to erect position.
~ ;.
,,~ , .
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of amines of the general formula I
(I) wherein R1 is in the 2- or 3-position and is selected from the group con-sisting of -CH2CH=CH2, -OCH2CH=CH2, -OCH2C?CH, alkoxyalkyl having up to 7 carbon atoms in each alkyl moiety HOCH2CH2NHCOCH2O-, CH3OCH2CH2NHCOCH2O-and -CH=NOR, wherein R is selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms, R2 is selected from the group consist-ing of hydrogen, halogen, alkyl having 1-4 carbon atoms and alkoxy having 1-4 carbon atoms, R5 is selected from the group consisting of hydrogen and alkyl having 1-4 carbon atoms, R9 is selected from the group consisting of hydrogen and -CONH2, Y is a divalent member selected from the group con-sisting of -O-, and -CH2-, n is an integer from 0 to 5, inclusive, m is an integer from 0 to 2, inclusive, and Ar is a phenyl nucleus, or a therapeut-ically acceptable acid addition salt thereof, characterized by a) reacting a compound of the formula II
(II) wherein Ar, R1 and R2 have the same meanings as given above, and X1 is a hydroxy group and Z is a reactive, esterified hydroxy group or X1 and Z
together form an epoxy group with an amine of the formula III
(III) wherein R4, R5, R9, Y, n, and m have the same meanings as given above; or b) reacting a compound of the formula IV
(IV) wherein Ar, R1, and R2 have the same meanings as given above, with a compound of the formula V
(V) wherein Z, R , R , Y, n, and m have the same meanings as given above; or c) reacting a compound of the formula V
(R1)(R2)ArOM (V) wherein Ar, R1 and R2 have the same meanings as given above and M is hydro-gen, with a compound of formula XXXVIII
(XXXVIII) wherein n and m have the same meanings as given above; and where required free bases of formula I so obtained are transformed into their therapeut-ically acceptable salts and/or salts obtained are transformed into their free bases.
(I) wherein R1 is in the 2- or 3-position and is selected from the group con-sisting of -CH2CH=CH2, -OCH2CH=CH2, -OCH2C?CH, alkoxyalkyl having up to 7 carbon atoms in each alkyl moiety HOCH2CH2NHCOCH2O-, CH3OCH2CH2NHCOCH2O-and -CH=NOR, wherein R is selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms, R2 is selected from the group consist-ing of hydrogen, halogen, alkyl having 1-4 carbon atoms and alkoxy having 1-4 carbon atoms, R5 is selected from the group consisting of hydrogen and alkyl having 1-4 carbon atoms, R9 is selected from the group consisting of hydrogen and -CONH2, Y is a divalent member selected from the group con-sisting of -O-, and -CH2-, n is an integer from 0 to 5, inclusive, m is an integer from 0 to 2, inclusive, and Ar is a phenyl nucleus, or a therapeut-ically acceptable acid addition salt thereof, characterized by a) reacting a compound of the formula II
(II) wherein Ar, R1 and R2 have the same meanings as given above, and X1 is a hydroxy group and Z is a reactive, esterified hydroxy group or X1 and Z
together form an epoxy group with an amine of the formula III
(III) wherein R4, R5, R9, Y, n, and m have the same meanings as given above; or b) reacting a compound of the formula IV
(IV) wherein Ar, R1, and R2 have the same meanings as given above, with a compound of the formula V
(V) wherein Z, R , R , Y, n, and m have the same meanings as given above; or c) reacting a compound of the formula V
(R1)(R2)ArOM (V) wherein Ar, R1 and R2 have the same meanings as given above and M is hydro-gen, with a compound of formula XXXVIII
(XXXVIII) wherein n and m have the same meanings as given above; and where required free bases of formula I so obtained are transformed into their therapeut-ically acceptable salts and/or salts obtained are transformed into their free bases.
2. Compounds of formula (I) defined in claim 1 and their therapeut-ically acceptable acid addition salts, when prepared by the process of claim I or by an obvious chemical equivalent thereof.
3. A process according to claim 1 wherein R2 is hydrogen, R5 is hydrogen or methyl, R9 is carbamoyl, Y is oxygen, m is zero and n is an integer from 1 to 4.
4. A process according to claim 1 or 3 wherein in the starting materials R is in the 2-position and is selected from -CH2CH=CH2,-OCH2CH=CH2, -OCH2C-CH, 2-methoxyethyl, HOCH2CH2NHCOCH2O-, CH3OCH2CH2NHCOCH2O and -CH=NOCH3.
5. A process according to claim 3 wherein n is the integer 1.
6. A process according to claim 1, 3 or 5 wherein in the starting materials R1 is -CH2CH=CH2.
7. A process according to claim 1, 3 or 5 wherein in the starting materials R1 is -OCH2CH=CH2.
8. A process according to claim 1, 3 or 5 wherein in the starting materials R1 is -OCH2C-CH.
9. A process according to claim 1, 3 or 5 wherein in the starting materials R1 is 2-methoxyethyl.
10. A process according to claim 1, 3 or 5 wherein in the starting materials R1 is HOCH2CH2NHCOCH2O-.
11. A process according to claim 1, 3 or 5 wherein in the starting materials R1 is CH3OCH2CH2NHCOCH2O-.
12. A process according to claim 1, 3 or 5 wherein in the starting materials R1 is -CH=NOCH3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7413789A SE422052B (en) | 1974-11-01 | 1974-11-01 | PROCEDURE FOR PREPARING CERTAIN STATED 1-PHENOXY-2-HYDROXY-3-AMINOPHENYL PROPYL DERIVATIVES |
| SE7413789-4 | 1974-11-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1093095A true CA1093095A (en) | 1981-01-06 |
Family
ID=20322597
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA238,763A Expired CA1093095A (en) | 1974-11-01 | 1975-10-31 | Amines |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS51131839A (en) |
| AT (1) | AT344142B (en) |
| AU (1) | AU498770B2 (en) |
| BE (2) | BE835090A (en) |
| CA (1) | CA1093095A (en) |
| CH (3) | CH618417A5 (en) |
| CS (1) | CS189726B2 (en) |
| DD (1) | DD119207A5 (en) |
| DE (1) | DE2531312A1 (en) |
| DK (1) | DK444475A (en) |
| FI (1) | FI752201A (en) |
| FR (1) | FR2289172A1 (en) |
| GB (1) | GB1524036A (en) |
| HK (1) | HK36081A (en) |
| HU (1) | HU172652B (en) |
| IE (1) | IE41652B1 (en) |
| LU (1) | LU73703A1 (en) |
| MY (1) | MY8200085A (en) |
| NL (1) | NL7509548A (en) |
| NO (1) | NO144773C (en) |
| NZ (1) | NZ178313A (en) |
| SE (1) | SE422052B (en) |
| SU (3) | SU906368A3 (en) |
| ZA (2) | ZA754241B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4119718A (en) * | 1977-05-02 | 1978-10-10 | Merck & Co., Inc. | 3-Amino-2-oxy-propoxy-substituted isothiazoles |
| SE7807408L (en) * | 1978-06-30 | 1979-12-31 | Haessle Ab | HEART ACTIVE ASSOCIATIONS |
| DD150456A5 (en) * | 1979-03-01 | 1981-09-02 | Ciba Geigy Ag | PROCESS FOR THE PREPARATION OF DERIVATIVES OF 3-AMINO-1,2-PROPANDIOL |
| DE3125870C2 (en) * | 1980-07-09 | 1994-09-15 | William John Louis | 3-aminopropoxyphenyl derivatives, their preparation and medicaments containing them |
| US4410548A (en) * | 1980-07-09 | 1983-10-18 | Reckitt & Colman Products Limited | Propanolamine derivatives |
| FR2508032A1 (en) * | 1981-06-17 | 1982-12-24 | Delalande Sa | 3-Amino-2-aryloxy-methyl-1-propanol derivs. - are used to treat cardiovascular troubles, esp. angina esp 3-tri:methoxy-cinnamoyl-piperazino- 2-1,4-benzodioxan-5-yl-oxy-methyl cpds. |
| DE3151201A1 (en) * | 1981-12-23 | 1983-07-28 | Beiersdorf Ag, 2000 Hamburg | SUBSTITUTED PHENOXYALKANOLAMINE AND PHENOXYALKANOL-CYCLOALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AND INTERMEDIATE PRODUCTS |
| SE457505B (en) * | 1984-01-10 | 1989-01-09 | Lejus Medical Ab | LAMINATED ORAL PHARMACEUTICAL COMPOSITION AND PROCEDURES FOR ITS PREPARATION |
| DE3433616A1 (en) * | 1984-08-08 | 1986-02-20 | BBC Aktiengesellschaft Brown, Boveri & Cie., Baden, Aargau | PROTECTIVE DEVICE FOR AN ELECTRICAL NET |
| JPS6341451A (en) * | 1986-08-06 | 1988-02-22 | Nippon Kayaku Co Ltd | Ether derivative and miticidal and insecticidal composition containing said derivative as active component |
| US5321036A (en) * | 1993-02-10 | 1994-06-14 | Bristol-Myers Squibb Company | Thiazole and oxazole-based β3 adrenergic receptor agonists |
-
1974
- 1974-07-02 ZA ZA00754241A patent/ZA754241B/en unknown
- 1974-11-01 SE SE7413789A patent/SE422052B/en unknown
-
1975
- 1975-07-02 ZA ZA00754240A patent/ZA754240B/en unknown
- 1975-07-12 DE DE19752531312 patent/DE2531312A1/en not_active Ceased
- 1975-07-31 AT AT592975A patent/AT344142B/en not_active IP Right Cessation
- 1975-07-31 FI FI752201A patent/FI752201A/fi not_active Application Discontinuation
- 1975-08-04 AU AU83637/75A patent/AU498770B2/en not_active Expired
- 1975-08-06 NZ NZ178313A patent/NZ178313A/en unknown
- 1975-08-06 NO NO752765A patent/NO144773C/en unknown
- 1975-08-08 DD DD187775A patent/DD119207A5/xx unknown
- 1975-08-08 SU SU752163123A patent/SU906368A3/en active
- 1975-08-11 NL NL7509548A patent/NL7509548A/en not_active Application Discontinuation
- 1975-08-14 IE IE1809/75A patent/IE41652B1/en unknown
- 1975-09-09 GB GB37073/75A patent/GB1524036A/en not_active Expired
- 1975-09-16 CH CH1196775A patent/CH618417A5/en not_active IP Right Cessation
- 1975-10-02 DK DK444475A patent/DK444475A/en unknown
- 1975-10-21 FR FR7532204A patent/FR2289172A1/en active Granted
- 1975-10-30 CS CS757328A patent/CS189726B2/en unknown
- 1975-10-30 HU HU75HE694A patent/HU172652B/en unknown
- 1975-10-31 CA CA238,763A patent/CA1093095A/en not_active Expired
- 1975-10-31 BE BE161438A patent/BE835090A/en unknown
- 1975-10-31 BE BE161439A patent/BE835091A/en unknown
- 1975-10-31 JP JP50131345A patent/JPS51131839A/en active Pending
- 1975-10-31 LU LU73703A patent/LU73703A1/xx unknown
-
1976
- 1976-09-03 SU SU762393515A patent/SU637078A3/en active
- 1976-09-03 SU SU762393516A patent/SU625599A3/en active
-
1979
- 1979-08-28 CH CH780979A patent/CH622490A5/en not_active IP Right Cessation
- 1979-08-28 CH CH781079A patent/CH622491A5/en not_active IP Right Cessation
-
1981
- 1981-07-31 HK HK360/81A patent/HK36081A/en unknown
-
1982
- 1982-12-30 MY MY85/82A patent/MY8200085A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH618417A5 (en) | 1980-07-31 |
| DK444475A (en) | 1976-05-02 |
| SU637078A3 (en) | 1978-12-05 |
| NL7509548A (en) | 1976-05-04 |
| NZ178313A (en) | 1978-06-02 |
| CH622491A5 (en) | 1981-04-15 |
| SU625599A3 (en) | 1978-09-25 |
| NO144773C (en) | 1981-11-04 |
| GB1524036A (en) | 1978-09-06 |
| AU498770B2 (en) | 1979-03-22 |
| MY8200085A (en) | 1982-12-31 |
| ATA592975A (en) | 1977-11-15 |
| JPS51131839A (en) | 1976-11-16 |
| BE835091A (en) | 1976-04-30 |
| DE2531312A1 (en) | 1976-05-06 |
| IE41652L (en) | 1976-05-01 |
| SU906368A3 (en) | 1982-02-15 |
| FR2289172A1 (en) | 1976-05-28 |
| DD119207A5 (en) | 1976-04-12 |
| NO144773B (en) | 1981-07-27 |
| AT344142B (en) | 1978-07-10 |
| AU8363775A (en) | 1977-02-10 |
| CS189726B2 (en) | 1979-04-30 |
| FR2289172B1 (en) | 1980-11-21 |
| NO752765L (en) | 1976-05-04 |
| SE7413789L (en) | 1976-05-03 |
| FI752201A (en) | 1976-05-02 |
| HU172652B (en) | 1977-11-28 |
| HK36081A (en) | 1981-07-31 |
| SE422052B (en) | 1982-02-15 |
| LU73703A1 (en) | 1976-08-13 |
| IE41652B1 (en) | 1980-02-27 |
| ZA754240B (en) | 1976-06-30 |
| CH622490A5 (en) | 1981-04-15 |
| BE835090A (en) | 1976-04-30 |
| ZA754241B (en) | 1976-06-30 |
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