Benzodioxanyl-hydroxyethylene-piperazinyl acetanilides which effect calcium entry and .beta.-blockade

• US 4,558,129 A
• Filed: 05/18/1983
• Issued: 12/10/1985
• Est. Priority Date: 05/18/1983
• Status: Expired due to Fees

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntec Incorporated (Atos SE)
• Inventors: Kluge, Arthur F., Clark, Robin D., Strosberg, Arthur M.
• Primary Examiner(s): Hollrah, Glennon H.
• Assistant Examiner(s): Turnipseed, James H.
• Application Number:
  US06/495,870
• Time in Patent Office: 937 Days
• Field of Search: 544/377, 424/250
• US Class Current: 544/377
• CPC Class Codes: C07D 319/20 with substituents attached to the hetero ring
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond

Abstract

Novel compounds of the general formula: ##STR1## and the pharmaceutically acceptable esters and acid addition salts thereof, wherein:

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl; or

R² and R³ together form --OCH₂ O--; and

R¹⁰ and R¹¹ are each independently hydrogen or lower alkyl.

These compounds combine β-blockade and calcium entry blockade properties in the same compound and therefore are useful in therapy in the treatment of cardiovascular diseases, including hypertension, arrhythmias and variant and exercise induced angina.

Claims

1. A compound of the formula:

##STR13## and the pharmaceutically acceptable esters and acid addition salts thereof, wherein;

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl or lower alkyl sulfonyl;

or

R² and R³ together form --OCH₂ O--; and

R¹⁰ and R¹¹ are each independently hydrogen or lower alkyl.

2. The compound of claim 1 wherein R⁶, R⁷, R⁸ and R⁹ are each hydrogen.

3. The compound of claim 2 wherein R¹⁰ is hydrogen.

4. The compound of claim 3 wherein R¹¹ is hydrogen.

5. The compound of claim 4 wherein R¹ to R⁵ are each hydrogen, i.e., 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-(phenylaminocarbonylmethyl)piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.

6. The compound of claim 4 wherein R¹ and R⁵ are methyl and R², R³ and R⁴ are each hydrogen, i.e., 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.

7. The compound of claim 4 wherein R³ is chloro and R¹, R², R⁴ and R⁵ are each hydrogen, i.e. 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(4-chlorophenyl)aminocarbonylmethyl]piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.

8. The compound of claim 4 wherein R³ is methyl and R¹, R², R⁴ and R⁵ are each hydrogen, i.e., 1-[(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(4-methylphenyl)aminocarbonylmethyl]piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.

9. The compound of claim 4 wherein R³ is methoxy and R¹, R², R⁴ and R⁵ are each hydrogen, i.e., 1-[(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(4-methoxyphenyl)aminocarbonylmethyl]piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.

10. The compound of claim 4 wherein R¹ and R⁵ are each chloro and R², R³ and R⁴ are each hydrogen, i.e., 1-[(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dichlorophenyl)aminocarbonylmethyl]piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.

11. The compound of claim 4 wherein R³ is trifluoromethyl and R¹, R², R⁴ and R⁵ are each hydrogen, i.e. 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(4-trifluoromethylphenyl)aminocarbonylmethyl]piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.

12. The compound of claim 4 wherein R¹, R⁴ and R⁵ to R⁹ are hydrogen and R² and R³ together form --OCH₂ O--, i.e., 1-[2-(1,4-benzodioxan-2-yl)-2 hydroxyethyl]-4-[(3,4-methylenedioxyphenyl)aminocarboxylmethyl]piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.

13. The compound of claim 1 wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰ and R¹¹ are hydrogen;

and R⁸ is methylsulfinyl;

i.e., 1-[2-(6-methylsulfinyl-1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(phenyl)aminocarbonylmethyl]piperazine, and the pharmaceutically acceptable esters and acid addition salts thereof.