Claims
- 1. A method of treating coronary diseases, conditions resulting from sympathetic overstimulation, myocardial infarction, hypertension, migraine, glaucoma, thyrotoxicosis or heart rhythm disorders, which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of formula I, ##STR32## wherein R is phenyl or phenyl monosubstituted or independently disubstituted or independent trisubstituted 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,
- 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, 1-pyrrolyl, 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, or alkanoyl of 1 to 5 carbon atoms,
- R.sub.2 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 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, phenyl, phenylalkyl of 7 to 10 carbon atoms, or phenyl or phenylalkyl of 7 to 10 carbon atoms monosubstituted or independently disubstituted 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,
- A is alkylene of 2 to 5 carbon atoms,
- X is a bond, an oxygen or a sulfur atom,
- 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
- (a) when R.sub.2 is alkyl, then Z is an oxygen atom and the group --NH--A--X--R is other than a moiety of the formula ##STR33## (b) when R.sub.2 is alkyl and X is a bond or an oxygen atom, then Y is an oxygen atom, and
- (c) when R.sub.2 is cycloalkyl or cycloalkylalkyl and X is a bond, or
- when R.sub.2 is unsubstituted or monosubstituted phenyl,
- X is a bond and
- Z is an oxygen atom,
- then R.sub.1 is other than hydrogen, 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 acid addition salt form thereof.
- 2. 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 formula I, ##STR34## wherein R is phenyl or phenyl monosubstituted or independently disubstituted or independent trisubstituted 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,
- 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, 1-pyrrolyl, 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, or alkanoyl of 1 to 5 carbon atoms,
- R.sub.2 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 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, phenyl, phenylalkyl of 7 to 10 carbon atoms, or phenyl or phenylalkyl of 7 to 10 carbon atoms monosubstituted or independently disubstituted 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,
- A is alkylene of 2 to 5 carbon atoms,
- X is a bond, an oxygen or a sulfur atom,
- Y is an oxygen or a sulfur atom, and either
- Z is an oxygen atom and
- is 2 or 3 or
- Z is a bond and
- is 1, 2 or 3, with the provisos, that
- (a) when R.sub.2 is alkyl, then Z is an oxygen atom and th group --NH--A--X--R is other than a moiety of the formula ##STR35## (b) when R.sub.2 is alkyl and X is a bond or an oxygen atom, they Y is an oxygen atom, and
- (c) when R.sub.2 is cycloalkyl or cycloalkylalkyl and X is a bond, or
- when R.sub.2 is unsubstituted or monosubstituted phenyl,
- X is a bond and
- Z is an oxygen atom,
- then R.sub.1 is other than hydrogen, 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 acid addition salt form thereof.
- 3. A method of claim 1 or 2, wherein said compound of the formula I has the formula E, ##STR36## wherein R, R.sub.1, R.sub.2, A, X, Y, Z and n are as defined in claim 4 and
- R.sub.e is alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms, or phenyl or phenylalkyl of 7 to 12 carbon atoms monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, or mono- or independently disubstituted in the phenyl ring by halogen of atomic number of from 9 to 35, or mono- independently di- or independently trisubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms.
- 4. A method of claim 1 or 2, wherein said compound of formula I has formula Ia, ##STR37## wherein R, R.sub.1, n and Z are as defined in claim 4 or 5,
- R.sub.2.sup.a has the significance indicated in claim 4 or 5 for R.sub.2 with the exception that R.sub.2.sup.a is not alkyl of 1 to 4 carbon atoms,
- A.sup.a is alkylene of 2 to 5 carbon atoms and
- X.sup.a is an oxygen or a sulfur 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.
- 5. A method of claim 4, wherein R.sub.1 in formula Ia is other than hydrogen.
- 6. A method of claim 1 or 2 wherein said compound of formula I has formula Ib, ##STR38## wherein R and R.sub.1 are as defined in claim 4 or 5,
- R.sub.2.sup.b is alkyl of 1 to 4 carbon atoms,
- A.sup.b is ethylene or trimethylene,
- X.sup.b is a bond or an oxygen atom and
- nb is 2 or 3, or a physiologically acceptable hydrolyzable derivative thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form.
- 7. A method of claim 6, wherein R.sub.1 is other than hydrogen.
- 8. A method of claim 6, wherein X.sup.b is an oxygen atom.
- 9. A method of claim 1 or 2, wherein said compound of formula I has formula Ipa, ##STR39## wherein R.sup.p is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms,
- R.sub.1.sup.pa is hydrogen or halogen of atomic number of from 9 to 35,
- R.sub.2.sup.pa is alkyl of 1 to 4 carbon atoms,
- A.sup.pa is alkylene of 2 to 5 carbon atoms, and
- np is 2 or 3, with the proviso that --NH--A.sup.pa --O--R.sup.p is other than the moiety of the formula ##STR40##
- 10. A method of claim 1 or 2, wherein said compound of formula I has formula Ipb, ##STR41## wherein R.sup.p is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms,
- R.sub.2.sup.pb is alkyl of 1 to 4 carbon atoms,
- A.sup.pb is alkylene of 2 to 5 carbon atoms, and
- nb is 2 or 3 with the proviso that --NH--A.sup.pb --R.sup.p is other than the moiety of the formula ##STR42##
- 11. A method of claim 1 or 2, wherein said compound of formula I has formula Ipc, ##STR43## wherein R.sup.p is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms,
- Y.sup.pc is an oxygen or a sulfur atom,
- R.sub.1.sup.pc is 1-pyrrolyl, cyano or carbamoyl,
- R.sub.2.sup.pc is alkyl of 1 to 4 carbon atoms or cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety,
- A.sup.pc is alkylene of 2 to 5 carbon atoms,
- X.sup.p is an oxygen or sulfur atom, and
- np is 2 to 3 with the proviso that,
- (a) when R.sub.2.sup.pc is alkyl, then --NH--A.sup.pc --X.sup.p --R.sup.p is other than the moiety of the formula ##STR44## (b) when R.sub.2.sup.pc is alkyl and X.sup.p is an oxygen atom, then Y.sup.pc is an oxygen atom.
- 12. A method of claim 1 or 2, wherein said compound of formula I has formula Ipd, ##STR45## wherein R.sup.p is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms,
- Y.sup.pd is an oxygen or a sulfur atom,
- R.sub.1.sup.pd is 1-pyrrolyl, cyano or carbamoyl,
- R.sub.2.sup.pd is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety,
- A.sup.pd is alkylene of 2 to 5 carbon atoms, and
- np is 2 or 3 with the proviso that,
- (a) when R.sub.2.sup.pd is alkyl, then --NH--A.sup.pd --R.sup.p is other than the moiety of the formula ##STR46## and (b) when R.sub.2.sup.pd is alkyl, then Y.sup.pd is an oxygen atom.
- 13. A method of claim 1 or 2, wherein said compound of formula I has formula Ipe, ##STR47## wherein R.sup.p is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms,
- R.sub.1.sup.pe is hydrogen, halogen or atomic number of from 9 to 35 or cyano,
- R.sub.2.sup.pe is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms,
- A.sup.pe is alkylene of 2 to 5 carbon atoms, and
- np is 2 or 3.
- 14. A method of claim 9, wherein R.sup.p is substituted phenyl.
- 15. A method of claim 10, wherein R.sup.p is substituted phenyl.
- 16. A method of claim 11, wherein R.sup.p is substituted phenyl.
- 17. A method of claim 12, wherein R.sup.p is substituted phenyl.
- 18. A method of claim 13, wherein R.sup.p is substituted phenyl.
- 19. A method of claim 1 or 2, wherein said compound of formula I has formula Is, ##STR48## R.sup.s is phenyl or phenyl monosubstituted or independently disubstituted by alkoxy of 1 to 4 carbon atoms,
- R.sub.1.sup.s is hydrogen, halogen of atomic number of from 9 to 35, cyano, carbamoyl, alkenyl of 2 to 5 carbon atoms or cycloalkyl of 5 or 6 carbon atoms,
- R.sub.2.sup.s is alkyl of 1 to 4 carbon atoms, cyclopropylmethyl, phenylalkyl of 7 or 8 carbon atoms or phenylalkyl of 7 or 8 carbon atoms monosubstituted or independently disubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms,
- A.sup.s is ethylene or trimethylene,
- X.sup.s and Z.sup.s independently are a bond or an oxygen atom and
- ns is 2 or 3, with the proviso that,
- (a) when R.sub.2.sup.s is alkyl, then Z.sup.s is an oxygen atom and
- (b) when R.sub.2.sup.s is cyclopropylmethyl and X.sup.s is a bond, then R.sub.1.sup.s is other than hydrogen,
- or a physiologically acceptable hydrolyzable derivative thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form.
- 20. A method of claim 19, wherein R.sub.1.sup.s is other than hydrogen.
- 21. A method of claim 19, wherein R.sub.2.sup.s is other than alkyl.
Priority Claims (6)
| Number |
Date |
Country |
Kind |
| 8022412 |
Jul 1980 |
GBX |
|
| 5999/80 |
Aug 1980 |
CHX |
|
| 8247/80 |
Nov 1980 |
CHX |
|
| 8245/80 |
Nov 1980 |
CHX |
|
| 8041155 |
Dec 1980 |
GBX |
|
| 8104585 |
Feb 1981 |
GBX |
|
Parent Case Info
This is a division of application Ser. No. 07/022,502 filed Mar. 9, 1987, now U.S. Pat. No. 4,816,604 which is a continuation of application Ser. No. 06/790,576 filed Oct. 23, 1985, abandoned, which is a continuation of Ser. No. 06/691,497 filed Jan. 14, 1985, abandoned, which is a continuation of Ser. No. 06/481,775 filed Apr. 4, 1983, abandoned, which is a continuation of Ser. No. 06/281,459 filed on July 8, 1981 abandoned.
The present invention relates to 3-aminopropoxyphenyl derivatives, their preparation and pharmaceutical compositions containing them.
In accordance with the invention there are provided compounds of formula I, ##STR2## wherein R is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted 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,
R.sub.2 is alkyl of 1 to 4 carbon atoms, 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, phenyl, phenylalkyl of 7 to 10 carbon atoms, or phenyl or phenylalkyl of 7 to 10 carbon atoms monosubstituted or independently disubstituted 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,
A is alkylene of 2 to 5 carbon atoms,
X is a bond, an oxygen or a sulfur atom,
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
Physiologically hydrolyzable derivatives are those derivatives which under physiological conditions are split to the corresponding compounds having a hydroxy group in the 2 position of the 3-aminopropoxy side chain.
A group of derivatives in esterified form of the compounds of formula I is e.g. the compounds of formula E, ##STR4## wherein
R, R.sub.1, R.sub.2, A, X, Y, Z and n are as defined above and R.sub.e is alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms, or phenyl or phenylalkyl of 7 to 12 carbon atoms monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, or mono- or independently disubstituted in the phenyl ring by halogen of atomic number of from 9 to 35, or mono- or independently di- or independently trisubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms.
Any trisubstituted phenyl ring preferably is substituted by alkoxy; preferably the substituents are identical.
Preferred are the compounds wherein the hydroxy group in the 2 position of the 3-aminopropoxy side chain is in unesterified form.
"Alkylene" only comprises radicals having a carbon chain of at least 2 carbon atoms separating X from the nitrogen atom of the 3-aminopropoxy side chain.
Alkyl and/or alkoxy and/or alkylthio preferably are of 1 or 2 carbon atoms, especially of 1 carbon atom. Halogen preferably is chlorine or bromine, especially bromine Cycloalkyl preferably is of 3, 5 or 6 carbon atoms, especially 5 or 6 carbon atoms, when it is R.sub.1, and preferably of 5 or 6 carbon atoms, when it is R.sub.2. Alkenyl preferably is of 2 or 3 carbon atoms, it especially is allyl. Alkenyloxy preferably is of 3 or 4 carbon atoms, it especially is allyloxy. Cycloalkylalkyl is especially of 3, 5 or 6 carbon atoms in the cycloalkyl moiety and especially of 1 or 2 carbon atoms in the alkyl moiety, it preferably is cyclopropylmethyl. Phenylalkyl preferably is of 7 or 8 carbon atoms, it especially is benzyl.
A preferably is ethylene When A is of more than 2 carbon atoms, then it preferably is trimethylene or a moiety branched in the a position, such as --CH(CH.sub.3)CH.sub.2 --, --C(CH.sub.3).sub.2 CH.sub.2 --or --C(CH.sub.3).sub.2 (CH.sub.2).sub.2 --. Conveniently, when R.sub.2 is alkyl, A preferably is unbranched
X preferably is a bond or an oxygen atom, especially an oxygen atom. R preferably is substituted phenyl, preferably mono- or disubstituted, especially monosubstituted. It preferably is substituted by alkoxy. When it is monosubstituted, it preferably is substituted in the para position. When it is disubstituted, it preferably is substituted in the meta and para positions. When it is trisubstituted, it preferably is substituted in the meta ,meta and para positions. When R.sub.1 is alkanoyl it is preferably acetyl. R.sub.1 preferably is hydrogen, cycloalkyl, alkenyl, halogen or cyano, especially hydrogen or cyano. R.sub.2 preferably is alkyl, cycloalkylalkyl or phenylalkyl, especially cycloalkylalkyl or phenylalkyl. When R.sub.2 is phenyl or phenylalkyl, it preferably is substituted, preferably mono- or disubstituted, especially monosubstituted. It preferably is substituted by alkoxy. When it is monosubstituted phenyl or phenylalkyl, it preferably is substituted in the para position. When it is disubstituted phenyl or phenylalkyl, it preferably is substituted in the meta and para positions. When it is trisubstituted phenyl or phenylalkyl, it preferably is substituted in the meta, meta and para positions. Y preferably is an oxygen atom. n preferably is 2. Z preferably is an oxygen atom.
When a phenyl ring is polysubstituted, the substituents preferably are identical.
A group of compounds of the invention is the compounds of formula Ia, ##STR5## wherein
R, R.sub.1, n and Z are as defined above,
R.sub.2.sup.a with the exception of alkyl of 1 to 4 carbon atoms has the significance indicated above for R.sub.2,
A.sup.a is alkylene of 2 to 5 carbon atoms and
X.sup.a is an oxygen or a sulfur atom, and physiologically acceptable hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form.
In a sub-group R.sub.1 in formula Ia is other than hydrogen.
Another group of compounds of the invention is the compounds of formula Ib, ##STR6## wherein
R and R.sub.1 are as defined above,
R.sub.2.sup.b is alkyl of 1 to 4 carbon atoms,
A.sup.b is ethylene or trimethylene,
X.sup.b is a bond or an oxygen atom and
nb is 2 or 3 and physiologically acceptable hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form.
In a subgroup R.sub.1 in formula Ib is other than hydrogen. In another subgroup X.sup.b is an oxygen atom.
Another group of compounds of the invention is the compounds of formula Ipa, ##STR7## wherein
R.sup.p is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms,
R.sub.1.sup.pa is hydrogen or halogen of atomic number of from 9 to 35,
R.sub.2.sup.pa is alkyl of 1 to 4 carbon atoms,
A.sup.pa is alkylene of 2 to 5 carbon atoms and
np is 2 or 3, with the proviso that --NH--A.sup.pa --O--R.sup.p is other than the moiety of formula ##STR8##
Another group of compounds of the invention is the compounds of formula Ipb, ##STR9## wherein
R.sup.p and np are as defined above,
R.sub.2.sup.pb is alkyl of 1 to 4 carbon atoms and
A.sup.pb is alkylene of 2 to 5 carbon atoms, with the proviso that --NH--A.sup.pb --R.sup.p is other than the moiety of formula ##STR10##
Another group of compounds of the invention is the compounds of formula Ipc, ##STR11## wherein
R.sup.p and np are as defined above,
Y.sup.pc is an oxygen or a sulfur atom,
R.sub.1.sup.pc is 1-pyrrolyl, cyano or carbamoyl,
R.sub.2.sup.pc is alkyl of 1 to 4 carbon atoms or cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety,
A.sup.pc is alkylene of 2 to 5 carbon atoms and
X.sup.p is an oxygen or sulfur atom, with the provisos that,
(a) when R.sub.2.sup.pc is alkyl, then --NH--A.sup.pc --X.sup.p --R.sup.p is other than the moiety of formula ##STR12## and
(b) when R.sub.2.sup.pc is alkyl and X.sup.p is an oxygen atom, then Y.sup.pc is an oxygen atom.
Another group of compounds of the invention is the compounds of formula Ipd, ##STR13## wherein
R.sup.p and np are as defined above,
Y.sup.pd is an oxygen or a sulfur atom,
R.sub.1.sup.pd and R.sub.2.sup.pd have the significance indicated above for R.sub.1.sup.pc and R.sub.2.sup.pc, respectively, and
A.sup.pd is alkylene of 2 to 5 carbon atoms, with the provisos that,
(a) when R.sub.2.sup.pd is alkyl, then --NH--A.sup.pd --R.sup.p is other than the moiety of formula ##STR14## and
(b) when R.sub.2.sup.pd is alkyl, then Y.sup.pd is an oxygen atom.
Another group of compounds of the invention is the compounds of formula Ipe, ##STR15## wherein
R.sup.p and np are as defined above,
R.sub.1.sup.pe is hydrogen, halogen of atomic number of from 9 to 35 or cyano;
R.sub.2.sup.pe is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms and
A.sup.pe is alkylene of 2 to 5 carbon atoms.
Conveniently R.sup.p in formulae Ipa to Ipe is substituted phenyl.
Another group of compounds of the invention is the compounds of formula Is, ##STR16## wherein
R.sup.s is phenyl or phenyl monosubstituted or independently disubstituted by alkoxy of 1 to 4 carbon atoms,
R.sub.1.sup.s is hydrogen, halogen of atomic number of from 9 to 35, cyano, carbamoyl, alkenyl of 2 to 5 carbon atoms or cycloalkyl of 5 or 6 carbon atoms
R.sub.2.sup.s is alkyl of 1 to 4 carbon atoms, cyclopropylmethyl, phenylalkyl of 7 or 8 carbon atoms or phenylalkyl of 7 or 8 carbon atoms monosubstituted or independently disubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms,
A.sup.s is ethylene or trimethylene,
X.sup.s and Z.sup.s independently are a bond or an oxygen atom and
ns is 2 or 3,
(a) when R.sub.2.sup.s is alkyl, then Z.sup.s is an oxygen atom and
(b) when R.sub.2.sup.s is cyclopropylmethyl and X.sup.s is a bond,
then R.sub.1.sup.s is other than hydrogen, and physiologically acceptable hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form.
In a subgroup R.sub.1.sup.s in formula Is is other than hydrogen. In another subgroup R.sub.2.sup.s is other than alkyl.
In accordance with the invention, a compound of the invention may be obtained by a process comprising reacting a corresponding compound of formula II, ##STR17## wherein R.sub.1, R.sub.2, Y, Z and n are as defined above and R.sub.x is a group capable of reacting with a primary amine to give a 2-amino-1-hydroxyethyl group, with an appropriate compound of formula III,
The amination process may be effected in conventional manner for the production of analogous 3-amino-2-hydroxypropoxyaryl compounds. For example, R.sub.x may be a group of formula ##STR18## or a derivative of this group, e.g. a group of formula --CH(OH)--CH.sub.2 L, wherein L is chlorine, bromine or a group R.sub.y --SO.sub.2 --O--, wherein R.sub.y is phenyl, tolyl or lower alkyl. L is especially chlorine. The reaction is preferably effected in ethanol or in an appropriate ether such as dioxane. Optionally an excess of the amine may be used as solvent. Alternatively, the reaction may be effected in a fusion melt. Suitable reaction temperatures may be from about 20.degree. to about 200.degree. C., conveniently the reflux temperature of the reaction mixture when a solvent is present.
The optional esterification of the 2 hydroxy group in the side chain may be effected in manner known for the production cf analogous esters of 3-amino-2-hydroxypropoxyaryl compounds, if necessary using selective reactions when other reactive groups are present.
Free base forms of the compounds of the invention may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for acid addition salt formation include hydrochloric, malonic and fumaric acids.
In the compounds of the invention, the carbon atom in e.g. the 2 position of the 3-aminopropoxy side chain is asymmetrically substituted. The compounds may thus exist in the racemic form or in individual optical isomer form. The preferred optical isomer has the S configuration at this asymmetrically substituted carbon atom of the 3-aminopropoxy side chain. Individual optical isomer forms may be obtained in conventional manner, for example by using optically active starting materials or by fractional crystallisation of racemate salts using optically active acids.
A compound used as a starting material may be obtained in conventional manner.
In particular, a compound of formula II may be obtained by introducing by b 0-alkylation a group --OCH.sub.2 --R.sub.x into a compound of formula IV, ##STR19## wherein R.sub.1, R.sub.2, Y, Z and n are as defined above. A compound of formula IV preferably is reacted in anionic form.
A compound of formula IVa ##STR20## wherein
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 53,1-pyrrolyl, 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, or alkanoyl of 1 to 5 carbon atoms,
n' is 2 or 3 and
Y and R.sub.2 are as defined above,
under appropriate conditions, e.g. with palladium on charcoal or by acidic hydrolysis.
A compound of formula IVb, ##STR22## wherein
R.sub.2, Y and n' are as defined above and
R.sub.1 " is alkylthio of 1 to 4 carbon atoms or trifluoromethyl,
A compound of formula Va, ##STR23## wherein Bz, Y, R.sub.2 and n' are as defined above, may e.g. be obtained by appropriately etherifying 4-benzyloxyphenol, e.g. with an appropriate bromine derivative, conveniently in more than 1 step, e.g. by first forming the moiety --O(CH.sub.2).sub.n' --Y--H and then alkylating to introduce the moiety R.sub.2.
The compounds of formula Vb, ##STR24## wherein R.sub.2, Y, n' and Bz are as defined above, and R.sub.1 '" with the exception of hydrogen has the significance indicated above for R.sub.1 ', may e.g. be obtained by mono-chlorinating, -brominating or -iodinating a compound of formula IVa, wherein R.sub.1 is hydrogen, in the position ortho to the hydroxy moiety, subsequently, if desired, appropriately protecting the hydroxy group in a resultant compound of formula IVa, wherein P.sub.1 ' is bromine, to obtain a compound of formula Vc, ##STR25## wherein R.sub.2, Y, n' and Bz are as defined above and subsequently, if desired, converting a compound of formula Vc, in a Grignard-type reaction, e.g. with lithium, to a corresponding compound of formula Vb, wherein R.sub.1 '" is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms or alkenyl of 2 to 5 carbon atoms. Alternatively, a compound of formula Vc may be converted to a corresponding cyano compound, e.g. with cuprous cyanide in dimethyl formamide and subsequently, if desired, the cyano group hydrolyzed to a corresponding compound of formula Vb, wherein R.sub.1 '" is carbamoyl. Subsequently, if desired, this carbamoyl compound may be converted in a Hofman type degradation into a corresponding amino derivative and this amino derivative converted e.g. with 2,5-dimethoxyfurane to a corresponding compound of formula Vb, wherein R.sub.1 '" is 1-pyrrolyl. Alternatively, if desired, the amino derivative may be converted into a corresponding diazonium salt, e.g with nitrous acid, and this diazonium salt further reacted with e.g. potassium fluoride in water to a corresponding compound of formula Vb, wherein R.sub.1 '" is fluorine. Alternatively, the diazonium salt may be converted by reaction with aqueous acid to a corresponding hydroxy compound and this hydroxy compound converted by etherification into a corresponding compound of formula Vb, wherein R.sub.1 '" is alkoxy of 1 to 4 carbon atoms or alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom.
The R.sub.1 '"=alkanoyl derivative may be made by Friedel-Crafts acylation. If desired, the diazonium group may be converted into many other moieties, e.g. alkylthio by reaction with an alkali metal mercaptide. If required, the trifluoromethyl group may be obtained by fluorinating a corresponding carboxylic group which is in turn obtained from hydrolysing a cyano group.
Instead of Protected compounds of formula Vb it may be alternatively possible to use directly the corresponding unprotected compounds. For example, the group R.sub.1 =.beta..gamma.-alkenyl may be introduced into the ortho position by subjecting the corresponding .beta..gamma.-alkenyl ether to a Claisen rearrangement. If desired, the cyclopentyl group may be introduced by subjecting the corresponding cyclopent-2-enyl ether to a Claisen rearrangement to form the ortho cyclopent-2-enyl phenol which is then hydrogenated.
A compound of formula IVc, ##STR26## wherein
R.sub.1 and Y are as defined above,
R.sub.2 ' has the significance indicated above for
R.sub.2 and n" is 1, 2 or 3, may e.g. be obtained essentially in analogous manner to that described above for the production of compounds of formula IVa from the corresponding protected compounds. If desired the protecting group may be methyl instead of benzyl or tetrahydropyranyl. The deprotecting reaction may be carried out in the presence of an alkali metal alkyl mercaptide.
The protected compounds wherein R.sub.1 is other than hydrogen, alkylthio or trifluoromethyl may be produced in analogous manner to that described above for the production of compounds of formula Vb.
It may alternatively be possible to convert one substituent R.sub.1 into another substituent when the compound is in unprotected form, e.g. orthobromo derivatives may be formed simply from the corresponding phenol.
The protected compounds wherein R.sub.1 is hydrogen may be produced by building up the ether moiety --(CH.sub.2)n"--Y--R.sub.2 ' in conventional manner, e.g. by a Williamson synthesis.
Insofar as the preparation of any particular starting material is not particularly described, this may be effected in conventional manner.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
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| Number |
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Divisions (1)
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| Parent |
22502 |
Mar 1987 |
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Continuations (4)
|
Number |
Date |
Country |
| Parent |
790576 |
Oct 1985 |
|
| Parent |
691497 |
Jan 1985 |
|
| Parent |
481775 |
Apr 1983 |
|
| Parent |
281459 |
Jul 1981 |
|
Patent Grant
4970238
