US 4,970,238 AGrant
3-Aminopropoxyphenyl Derivatives, Their Preparation and Pharmaceutical Compositions Containing Them
Issue Date:1990-11-13
•21 Claims
Abstract
The compounds of formula I, ##STR1## where 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.
Metadata
Assignee
- Louis; John William
Inventors
- W. John Louis
- Richard Berthold
- Andre Stoll
Application Information
Application Number:US 3218155
Filing Date:1989-03-10
Priority Date:1980-07-09
Art Unit:126
Classifications
IPC:
A61K 31135
Field of Search:
5605645485585141;55;65;73;106;107;122;123;124349;165;162563414;416;422427;524;529;530;531;534;618;620;652
Patent Drawings
This patent does not have any drawings.
Description
EXAMPLE 1:
2-{2-hydroxy-3-[2-(4-methoxyphenoxy)ethylamino]-propoxy}-5-(2-methoxyethoxy )benzonitrile
2.4 g of 2-(2,3-epoxypropoxy)-5-(2-methoxyethoxy)-benzonitrile and 8.35 g of 2-(4-methoxyphenoxy) ethylamine are dissolved in 30 ml of ethanol, the solvent is then evaporated and the resulting mixture stirred for 1 hour at 70.degree.. The reaction melt is then dissolved in ether and allowed to crystallize under cooling. Purification is effected by recrystallization in benzene. The title compound is obtained (M.P. 95.degree.-97.degree.).
The starting material is obtained as follows:
Bromine dissolved in chloroform is added at 0.degree. to a solution of 4-(2-methoxyethoxy)phenol (M.P. 98.degree.-99.degree.) [prepared by reacting 4-benzyloxyphenol with 2-chloroethyl methyl ether and debenzylating the resultant 1-benzyloxy-4-(2-methoxyethoxy) benzene (M.P. 41.degree.-43.degree.) by hydrogenation with palladium on charcoal] in methanol and the mixture stirred for 2 hours. After chromatography over silicagel, the resultant 2-bromo-4-(2-methoxyethoxy)phenol (oil) is reacted for 60 hours with a mixture of potassium carbonate, acetone and benzyl bromide. After chromatography over silicagel, the resultant 1-benzyloxy-2-bromo-4-(2-methoxyethoxy)benzene (oil) is reacted in dimethylformamide for 5 hours with cuprous cyanide. After purification by partition between aqueous hydrochloric acid solution and ethyl acetate, the resultant 2-benzyloxy-5-(2-methoxyethoxy)benzonitrile (M.P. 50.degree.-51.degree.) is debenzylated over 10% palladium on charcoal in methanol. The resultant 2-hydroxy-5-(2-methoxyethoxy)benzonitrile (oil) is reacted at 100.degree. with epichlorhydrin and a catalytic amount of piperidine,and 2-(2,3-epoxypropoxy)-5-(2-methoxyethoxy)benzonitrile (oil) is obtained.
From the appropriate compounds of formula II, wherein R.sub.x is ##STR27## and the appropriate compounds of formula III the following compounds of formula I may be obtained in analogous manner to Example 1:
The following compounds of formula I may also be obtained in a manner analogous to Example 1.
The following derivatives, esters of the compounds of formula I (which are compounds of formula E) may be obtained by appropriately esterifying the 2 position of the 3-aminopropoxy side chain in the corresponding compounds of formula I (the other substituents are as for the corresponding compound of formula I):
In a first group of compounds X is a bond.
In a 2nd group of compounds X is an oxygen atom.
In a 3rd group of compounds X is a sulfur atom.
In a 4th group of compounds R is mono- or disubstituted phenyl.
In a 5th group of compounds A is alkylene.
In a 6th group of compounds A is straight-chain alkylene.
In a 7th group of compounds R.sub.1 is hydrogen.
In a 8th group of compounds R.sub.1 is other than hydrogen.
In a 9th group of compounds R.sub.1 is 1-pyrrolyl.
In a 10th group of compounds R.sub.1 is cyano.
In a 11th group of compounds Z is an oxygen atom.
In a 12th group of compounds Z is a bond.
In a 13th group of compounds Y is an oxygen atom
In a 14th group of compounds Y is a sulfur atom.
In a 15th group of compounds R.sub.2 is alkyl.
In a 16th group of compounds R.sub.2 is cycloalkyl or cycloalkylalkyl.
In a 17th group of compounds R.sub.2 is cycloalkylalkyl.
In a 18th group of compounds R.sub.2 is unsubstituted or substituted phenyl or phenylalkyl.
In a 19th group of compounds R.sub.2 is unsubstituted or substituted phenylalkyl.
In a 20th group of compounds R.sub.1 is alkanoyl.
The compounds of the invention exhibit interesting pharmacological activity.
In particular, the compounds possess .beta.-adrenoceptor blocking activity, as indicated by standard tests. For example, in the spontaneously beating guinea pig atrium (A. Bertholet et al, Postgrad. Med. 57, Suppl.1 [1981]9-18) they inhibit the positive chonotropic isoprenaline effect at bath concentrations of from about 10.sup.-8 M to about 10.sup.-6 M.
Some of the compounds, e.g. the compounds of Examples 12, 14 and 15 also exhibit .alpha.-blocking activity as indiqated in standard tests. For example the activity is observed in the everted rat aorta (according to the principles of K.K.F.Ng, S. Duffy, W.J. Louis and A.E. Doyle (1975); Proceedings of the Australian Physiological and Pharmacological Society, 6, 158P). The activity is also confirmed in binding studies, e.g. basically as described by R.J. Summers, B. Jarrott and W.J. Louis Neuroscience letters 20(1980) 347-350.
The compounds are therefore useful as .beta.- and also .alpha.-adrenoceptor blocking agents, e.g. for the prophylaxis and therapy of coronary diseases, such as angina pectoris, conditions which are associated with sympathetic over-stimulation, e.g. nervous heart complaints, myocardial infarction, hypertension, for the intermediate treatment of migraine and for the treatment of glaucoma and thyrotoxicosis. In view of their antiarrhythmic effect, they are useful as antiarrhythmics for the treatment of disturbances in the heart rhythm, such as supraventricular tachycardia.
For these uses, the dosage to be used varies of course according to the substance used, the mode of administration and the desired treatment. In general, however, satisfactory results are obtained with a daily dosage of approximately 0.1 to 10 mg per kg body weight; administration may be effected in 2 to 4 divided doses, or in sustained release form. For the larger mammal, the daily dosage is from about 10 to about 500 mg; suitable forms for oral administration generally contain from about 2.5 to about 250 mg of the compounds together with solid or liquid carriers and/or diluents.
The compounds have more marked and wider spread beneficial pharmacological properties than could be expected for compounds having this type of structure. In particular their activity is more cardioselective than could be expected from similar known compounds. This cardioselectivity can be demonstrated in vitro by the use of isolated tissues of the guinea-pig, in accordance with standard procedures. Thus, left ventricular and lung membranes of a guinea-pig can be prepared according to standard pharmacological procedures (G. Engel et al., Triangle 19 [1980]69-76) and made to react with an exogenously added radioactive .beta.-ligand such as I125 2-cyano-pindolol (I-CYP) to determine affinity of the test compound to .beta..sub.1 and .beta..sub.2 adrenoceptors.
For the compound of Example 1, the cardioselectivity amounts to about 80 times, for the compound of Example 2, to about 410 times, for the compound of Example 3, to about 170 times and for the compound of Example 7, to about 640 times.
Guinea pig lung and left ventricular membranes may e.g. be prepared as follows:
Adult guinea pigs (350-500g) are killed by decapitation. The heart and lung are perfused with Tris saline buffer (Tris-HCl 10 mM, pH=7.5, NaCl 0.154 M, 37.degree. C.), removed and freed from connective tissues and trachea. The lung membranes are prepared as described by Kleinstein, J. and Glossmann H., Naunyn-Schmiedeberg's Arch. Pharmacol. 305, [1978], 191-200 with the modification that medium A contains only 20 mM NaHCO.sub.3. The final pellet is suspended in 10 ml 20 mM NaHCO.sub.3 and stored in liquid nitrogen. The preparation of the left ventricle membranes follows the procedure published by McNamara, D.B. et al., J. Biochem. 75, [1974], 795-803 until the step where the 'membrane fraction' is received. These membranes are stored in liquid nitrogen and immediately before use further diluted to the appropriate concentrations as indicated in the text.
The compounds of Examples 1 to 18 exhibit effective .beta.-adrenoceptor blocking activity in the above in vitro tests at concentrations of 10.sup.-9 M to 10.sup.-5 M.
The high selectivity of blockade for these compounds is of major importance in the treatment of hypertension where exacerbation of an existing asthmatic condition may be precipitated by currently commercially available compounds.
The compounds also possess a degree of intrinsic sympathomimetic activity, a property which is useful in preventing undue bradycardia and helps reduce the incidence of heart failure in subjects with heart muscle disease.
Of the compounds in optically active form, those in which the carbon atom in the 2-position of the 3-aminopropoxy side chain has the (S)-configuration are pharmacologically more active than the corresponding (R)-enantiomers.
The preferred uses of the compounds are the use against coronary diseases and hypertension.
Preferred are the compounds of Examples 1,2, 3 and 11, especially of Examples 1 and 3.
The compounds in free form or in the form of their pharmaceutically acceptable acid addition salts may be administered alone or in suitable dosage forms. The present invention also provides a pharmaceutical composition comprising a compound of the invention in free base form or in acid addition salt form in association with a pharmaceutical carrier or diluent. Such forms, e.g. a solution or a tablet, may be produced according to known methods.
Claims
We claim:
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.