Cardioactive pyrazole and imidazole aryloxypropanolamines

• US 4,608,383 A
• Filed: 10/03/1983
• Issued: 08/26/1986
• Est. Priority Date: 06/23/1980
• Status: Expired due to Fees

• Current Assignee: Ingrid Weidemann, Klaus Grunwald Wiedemann, Maja Schroeder, Marlies Makowski, Boehringer Mannheim GmbH (Roche Holding AG)
• Original Assignee: Boehringer Mannheim GmbH (Roche Holding AG)
• Inventors: Sponer, Gisbert, Kampe, Wolfgang, Wiedemann, deceased, Fritz, Dietmann, deceased, Karl
• Primary Examiner(s): Daus, Donald G.
• Assistant Examiner(s): Kapner, Stephen M.
• Application Number:
  US06/538,693
• Time in Patent Office: 1,058 Days
• Field of Search: 424/251, 544/312, 548/377, 548/337, 548/341, 548/378, 514/406, 514/407, 514/398
• US Class Current: 514/407
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 217/22 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 carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 219/12 Amino-alkylamino radicals attached in position 9
• CPC Class Codes: C07D 231/06 having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 231/20 One oxygen atom attached in position 3 or 5
• CPC Class Codes: C07D 231/32 Oxygen atoms
• CPC Class Codes: C07D 231/38 Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 231/52 Oxygen atom in position 3 and nitrogen atom in position 5, or vice versa
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/545 with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/557 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
• CPC Class Codes: C07D 239/56 One oxygen atom and one sulfur atom
• CPC Class Codes: C07D 239/84 Nitrogen atoms
• CPC Class Codes: C07D 239/95 with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: C07D 473/16 : two nitrogen atoms
• CPC Class Codes: C07D 473/34 : attached in position 6, e.g. adenine
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention provides aryloxypropanolamines of the general formula: ##STR1## wherein R₁, R₂, R₃ and R₄, which may be the same or different, are hydrogen or halogen atoms or lower alkyl, cyano, carboxamide, hydroxyl, lower acyloxy, lower alkoxy, lower alkenyloxy or aryl lower alkoxy radicals, R₅ and R₆, which may be the same or different, are hydrogen atoms or lower alkyl radicals, X is a straight or branched alkylene chain containing 2 to 6 carbon atoms, A is a mono-, bi- or tricyclic heteroaromatic or hydroheteroaromatic radical or, when at least one of the symbols R₁, R₂, R₃ and R₄ is other than a hydrogen atom, may also be a phenyl radical, with the proviso that when A is a uracil-6-yl radical, the 5-position of the uracil moiety does not contain a hydrogen atom, R₇, R₈, R₉, R₁₀ and R₁₁, which may be the same or different, are mono- or divalent substituents selected from hydrogen, halogen, notro, hydraxylamino, amino, lower acylamino, lower alkylamino, di-(lower alkyl)-amino, hydroxyethylamino, di-(hydroxyethyl)-amino, hydroxyl, lower alkoxy, allyloxy, methoxy lower alkoxy, cyano, carboxamido, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, halomethyl, aminomethyl, lower acylaminomethyl, halomethyl, aminomethyl, lower acylaminomethyl, di(lower alkyl)-aminomethyl, pyrrolidinomethyl, piperidinomethyl, di-(hydroxyethyl)-amino, hydroxyl, lower alkoxy, allyloxy, methoxy lower alkoxy, cyano, carboxamido, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, halomethyl, aminomethyl, lower acyaminomethyl, di-(lower alkyl)-aminomethyl, pyrrolidinomethyl, piperidinomethyl, di-(hydroxyethyl)-aminomethyl, morpholinomethyl, piperazinomethyl, 4-lower acylpiperazinomethyl, 4-lower alkylpiperazinomethyl, lower alkyl, lower alkenyl, 2-cyanoethyl, 2-hydroxyethyl, phenyl lower alkyl and phenyl, the phenyl radicals being optionally substituted with 1 or 2 hydroxyl or methoxy radicals, or from oxygen or sulphur; the optically-active forms and the racemic mixtures thereof, and the pharmacologically compatible salts thereof.

The present invention also provides processes for the preparation of these compounds and pharmaceutical compositions containing them. These compounds are useful for the prophylaxis and combatting of cardiac and circulatory diseases.

Claims

1. An aryloxypropanolamine of the formula ##STR17## wherein R₁, R₂, R₃ and R₄, which may be the same or different, are hydrogen or halogen atoms or lower alkyl, cyano, carboxamide, hydroxyl, lower acyloxy, lower alkoxy, lower alkenyloxy or aryl lower alkoxy radicals,

R₅ and R₆, which may be the same or different, are hydrogen atoms or lower alkyl radicals,

X is a straight or branched alkylene chain having 2 to 6 carbon atoms,

A is a pyrazole or imidazole group attached to the --X--NR₆ -- chain through a ring carbon atom or a partially hydrogenated pyrazole or imidazole group attached to the --X--NR₆ -- chain through a ring carbon atom but not a fully hydrogenated monocyclic and

R₇, R₈, R₉ and R₁₀, which may be the same or different are mono or divalent substituents selected from hydrogen, halogen, nitro, hydroxylamino, amino, lower acylamino, lower alkylamino, di-(lower alkyl)-amino, hydroxyethylamino, di-(hydroxyethyl)amino, hydroxyl, lower alkoxy, allyloxy, methoxy lower alkoxy, cyano, carboxamido, carboxy, methoxy lower alkoxycarbonyl, hydroxymethyl, lower alkoxymehtyl, halomethyl, aminomethyl, lower acylaminomethyl, di-(lower alkyl-aminomethyl, pyrrolidinomethyl, piperidinomethyl, di-(hydroxyethyl)-aminomethyl, morpholinomethyl, piperazinomethyl, 4-lower acylpiperazinomethyl, 4-lower alkylpiperazinomethyl, lower alkyl, lower alkenyl, 2-cyanoethyl, 2-(lower alkoxycarbonyl)-ethyl, 2-carboxyethyl, 2-hydroxyethyl, phenyl lower alkyl and phenyl, the phenyl radicals being optionally substituted with 1 or 2 -hydroxyl or methoxy radicals, oxygen or sulphur, with the exception of mixed alkoxy and hydroxy substituents on the pyrazole, imidazole or phenyl groups or a pharmacologically compatible salt thereof.

2. A compound or salt according to claim 1, wherein

R₁, R₂, R₃ and R₄ each independently is hydrogen, chlorine, bromine, fluorine;

C_1-4 -alkyl, cyano, carboxamido, hydroxyl, C_2-5 -alkenyloxy or phenyl-C_1-4 -alkoxy,

R₅ and R₆ each independently is hydrogen or C_1-4 -alkyl, X is an ethylene or propylene radical,

R₇, R₈, R₉, R₁₀ and R₁₁ each independently is hydrogen, amino, C_1-4 -alkyl or C_2-5 -alkenyl.

3. A compound according to claim 1, wherein such compound is 1-phenoxy-3-[2-(1,3,5-trimethylpyrazol-4-ylamino)-ethylamino]-propan-2-ol or a pharmacologically acceptable salt thereof.

4. A compound or salt according to claim 1, wherein such compound is 1-(4-hydroxyphenoxy)-3-[2-(1,3,5-trimethylpyrazol-4-ylamino)-ethylamino]-propan-2-ol.

5. A compound or salt according to claim 1, wherein such compound is 1-phenoxy-3-[2-(3,5-dimethyl-1-n-propylpyrazol-4-ylamino)-ethylamino]-propan-2-ol.

6. A compound or salt according to claim 1, wherein such compound is 1-phenoxy-3-[2-(3,5-dimethyl-1-allylpyrazol-4-ylamino)-ethylamino]-propan-2-ol.

7. A compound or salt according to claim 1, wherein such compound is 1-phenoxy-3-[2-(1,4-dimethyl-pyrazol-5-ylamino)-ethylamino]-propan-2-ol.

8. A composition for combating cardiac and circulatory diseases comprising an amount effective therefor of a compound or salt according to claim 1 in admixture with a pharmacologically acceptable diluent.

9. A method of combating cardiac and circulatory diseases comprising administering to a patient suffering therefrom an amount effective therefor of a compound or salt according to claim 1.

10. The method according to claim 9, wherein the material administered is

1-phenoxy-3-[2-(1,3,5-trimethylpyrazol-4-ylamino)-ethylamino]-propan-2-ol,

1-(4-hydroxyphenoxy)-3-[2-(1,3,5-trimethylpyrazol-4-ylamino)-ethylamino]-propan-2-ol,

1-phenoxy-3-[2-(3,5-dimethyl-1-n-propyl-pyrazol-4-ylamino)-ethylamino]-propan-2-ol,

1-phenoxy-3-[2-(3,5-dimethyl-1-allyl-pyrazol-4-ylamino)-ethylamino]-propan-2-ol or

1-phenoxy-3-[2-(1,4-dimethyl-pyrazol-5-ylamino)-ethylamino]-propan-2-ol,

or a pharmacologically compatible salt thereof.