# US 5,347,050 A · 3-aminopropoxyphenyl derivatives, their preparation and pharmaceutical compositions containing them

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- Number: US 5,347,050 A
- Document ID: US5347050A
- Status: Granted
- Kind: A
- Application number: 08/046,937
- Filed: 1993-04-13
- Granted: 1994-09-13
- Earliest claimed: 1980-11-06
- Inventors: Richard Berthold; William J. Louis
- Web page: https://patentgrep.com/patent/US5347050A

## CPC

- C07D 207/325: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07C 43/2055: {containing more than one ether bond}
- C07C 43/225: containing halogen
- C07C 255/00: Carboxylic acid nitriles (cyanogen or compounds thereof C01C3/00)
- C07C 275/26: having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C 275/28: having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C 275/30: being further substituted by halogen atoms, or by nitro or nitroso groups
- C07C 275/34: having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C 275/42: being further substituted by carboxyl groups
- C07D 303/24: with polyhydroxy compounds
- C07C 2601/02: with a three-membered ring
- C07C 2601/14: The ring being saturated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The compounds of formula I, ##STR1## wherein the substituents have various significances, and physiologically acceptable hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form, are useful as cardioselective .beta.-adrenoceptor blocking agents.

## Claims

### Claim 1

A compound of formula I ##STR49## wherein R is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or optionally substituted aryl, aralkyl or aralkenyl,
R.sub.1 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen of atomic number of from 9 to 53, trifluoromethyl, pyrrol-1-yl, cyano, carbamoyl, alkenyl of 2 to 5 carbon atom, alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom, alkanoyl of 2 to 5 carbon atoms, nitro, amino, alkanoylamino of 1 to 5 carbon atoms or alkoxycarbonylamino of 1 to 4 carbon atoms in the alkoxy moiety thereof,
R.sub.2 is hydrogen or has the significance indicated above for R,
A is alkylene,
X is a bond
Y is an oxygen or a sulfur atom and either Z is an oxygen atom and n is 2 or 3 or Z is a bond and n is 1, 2 or 3,
with the provisos that
when R.sub.2 is cycloalkylalkyl and R is alkyl then R.sub.1 is other than hydrogen,
and when R.sub.2 is hydrogen, then Z is an oxygen atom,
or physiologically acceptable hydrolyzable derivative thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form,
or a pharmaceutically acceptable salt form thereof.

### Claim 2 (depends on 1)

A compound of claim 1 of formula Ia, ##STR50## wherein X, Y, Z and n are as defined above and R.sup.a is alkyl of 1 to 4 carbon atoms, alkenyl of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to X, cycloalkyl of 5 to 7 carbon atoms, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety, and of 1 to 4 carbon atoms in the alkyl moiety thereof, or phenyl, phenylalkyl of 7 to 10 carbon atoms or phenylalkenyl of 8 to 11 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to X, the last three substituents optionally being:
i) monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35, hydroxy, cyano, trifluoromethyl, hydroxymethyl, carbamoyl, alkoxyalkoxy of 1 to 4 carbon atoms in each of the alkoxy moieties thereof, amino or alkanoylamino of 1 to 5 carbon atoms, or
ii) independently disubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, hydroxymethyl, carbamoyl, cyano, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35 or hydroxy, or
iii) independently trisubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms,
R.sub.1.sup.a is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen of atomic number of from 9 to trifluoromethyl, pyrrol-1-yl, cyano, carbamoyl, alkenyl of 2 to 5 carbon atoms, alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom, alkanoyl of 2 to 5 carbon atoms, nitro, amino, alkanoylamino of 1 to 5 carbon atoms or alkoxycarbonylamino of 1 to 4 carbon atoms in the alkoxy moiety thereof,
R.sub.2.sup.a is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to Y, cycloalkyl of 5 to 7 carbon atoms, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety thereof, or phenyl, phenylalkyl of 7 to 10 carbon atoms or phenylalkenyl of 8 to 11 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to Y, the last three substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35 and
A.sup.a is alkylene of 2 to 5 carbon atoms,
with the provisos that
when R.sub.2.sup.a is cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety thereof,
R.sup.a is alkyl of 1 to 4 carbon atoms and
X is a bond,
then R.sub.1.sup.a is other than halogen,
and when R.sub.2.sup.a is hydrogen, Z is an oxygen atom,
or a physiologically acceptable hydrolyzable derivative thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form, or a pharmaceutically acceptable salt form thereof.

### Claim 3 (depends on 1)

A process for the production of a compound of claim 1, which includes the step of appropriately 3-amino-2-oxypropylating a corresponding compound of formula IV, ##STR51## wherein R.sub.1, R.sub.2, Z, Y and n are as defined in claim 1, or a precursor form thereof.

### Claim 4 (depends on 1, 3)

A process according to claim 3 for the production of a compound of claim 1, which comprises reacting a corresponding compound of formula II, ##STR52## wherein R.sub.1, R.sub.2, Z, Y and n are as defined in claim 1 and R.sub.x is a group capable of reacting with a primary amine to give a 2-amino-1-hydroxyethyl group, with a corresponding compound of formula III,
H.sub.2 N--A--NHCO--X--R III
wherein A, X and R are as defined in claim 1 and, where required, appropriately esterifying the 2 position of the 3-aminopropoxy side chain in the resultant compound of formula I, and recovering the resultant compound in free form or in salt form.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 in association with a pharmaceutical carrier or diluent.

### Claim 6 (depends on 1)

A method of treating coronary diseases, conditions associated with sympathetic overstimulation, myocardial infarction, hypertension, migraine, glaucoma, thyreotoxicosis or heart rhythm disorders, which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of claim 1.

### Claim 7 (depends on 1)

A method of effecting .beta.-adrenoceptor blockade, which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of claim 1.