9-(Arylalkyl or aroylalkyl)-1-oxa-4,9-diazaspiro(5.5)undecan-3-ones

• US 4,353,900 A
• Filed: 10/19/1981
• Issued: 10/12/1982
• Est. Priority Date: 10/19/1981
• Status: Expired due to Fees

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntec Incorporated (Atos SE)
• Inventors: Clark, Robin D.
• Primary Examiner(s): Milestone, Norma S.
• Application Number:
  US06/312,448
• Time in Patent Office: 358 Days
• Field of Search: 544/71, 424/248.57, 424/248.54
• US Class Current: 514/230.8
• CPC Class Codes: C07D 498/10 Spiro-condensed systems

Abstract

Compounds useful in the prevention and/or treatment of hypertension, congestive heart failure, arrhythmia, migraine, vasospastic disorders, and asthma are represented by the formula ##STR1## wherein: R¹ is ##STR2## wherein X is hydrogen, lower alkyl, lower alkoxy, halo, carboxamido or hydroxy; m is 1, 2 or 3; and n is 1, 2 or 3;

R², R³ and R⁴ are independently hydrogen or lower alkyl; and

the pharmaceutically acceptable acid addition salts thereof.

Claims

1. A compound of the formula ##STR12## wherein:

R¹ is ##STR13## wherein X is hydrogen, lower alkyl of one to four carbon atoms, lower alkoxy of one to four carbon atoms, halo, carboxamido or hydroxy;

m is 1, 2 or 3; and

n is 1, 2 or 3;

R², R³ and R⁴ are independently hydrogen or lower alkyl of one to four carbon atoms; and

the pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 of the formula ##STR14## wherein R², R³ and R⁴ are independently hydrogen or lower alkyl of one to four carbon atoms;

X is hydrogen, lower alkyl of one to four carbon atoms, lower alkoxy of one to four carbon atoms, halo, carboxamido or hydroxy;

m is 1, 2 or 3; and

n is 1, 2 or 3; and

the pharmaceutically acceptable acid addition salts thereof.

3. A compound of claim 2 wherein R⁴ is hydrogen and R² and R³ are hydrogen or lower alkyl of one to four carbon atoms.

4. A compound of claim 3 wherein R² and R³ are both hydrogen.

5. A compound of claim 4 wherein X is hydrogen, m is 1, and n is 2, which is 9-(2-phenylethyl)-1-oxa-4,9-diazaspiro[5.5]-undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

6. A compound of claim 4 wherein X is methoxy, m is 2 and n is 2, which is 9-[2-(3,4-dimethoxyphenyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

7. A compound of claim 4 wherein X is hydroxy, m is 1 and n is 2, which is 9-[2-(4-hydroxyphenyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

8. A compound of claim 4 wherein X is methoxy, m is 1 and n is 2, which is 9-[2-(4-methoxyphenyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]-undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

9. A compound of claim 4 wherein X is chloro, m is 1 and n is 2, which is 9-[2-(4-chlorophenyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

10. A compound of claim 4 wherein X is fluoro, m is 1 and n is 2, which is 9-[2-(4-fluorophenyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

11. A compound of claim 1 of the formula ##STR15## wherein R², R³ and R⁴ are independently hydrogen or lower alkyl of one to four carbon atoms;

X is hydrogen or halo;

m is 1, 2 or 3;

n is 1, 2 or 3; and

the pharmaceutically acceptable acid addition salts thereof.

12. A compound of claim 11 wherein R⁴ is hydrogen and R² and R³ are hydrogen or lower alkyl of one to four carbon atoms.

13. A compound of claim 12 wherein X is hydrogen, R² is ethyl, R³ is hydrogen, m is 1, and n is 3, which is 9-(3-benzoylpropyl)-5-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

14. A compound of claim 12 wherein X is fluoro, R² is hydrogen, R³ is methyl, m is 1 and n is 3, which is 9-[3-(4-fluorobenzoyl)propyl]-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

15. A compound of claim 12 wherein X is fluoro, R² is hydrogen, R³ is ethyl, m is 1 and n is 3, which is 9-[3-(4-fluorobenzoyl)propyl]-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

16. A compound of claim 12 wherein R² and R³ are both hydrogen.

17. A compound of claim 16 wherein X is fluoro, m is 1 and n is 3, which is 9-[3-(4-fluorobenzoyl)propyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

18. A compound of claim 16 wherein X is fluoro, m is 1 and n is 2, which is 9-[2-(4-fluorobenzoyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one and the pharmaceutically acceptable acid addition salts thereof.

19. A pharmaceutical composition comprising 5 to 95% by weight of a compound of the formula ##STR16## or a pharmaceutically acceptable acid addition salt thereof, wherein:

R¹ is ##STR17## wherein X is hydrogen, lower alkyl of one to four carbon atoms, lower alkoxy of one to four carbon atoms, halo, carboxamido or hydroxy;

m is 1, 2 or 3; and

n is 1, 2 or 3;

R², R³ and R⁴ are independently hydrogen or lower alkyl of one to four carbon atoms;

in admixture with 95 to 5% of a pharmaceutically acceptable, non-toxic carrier.

20. A method for treating and/or preventing hypertension, congestive heart failure, arrhythmia, migraine, vasospastic disorders and asthma in a mammalian subject comprising administering to said subject a therapeutically effective amount of a compound of the formula ##STR18## or a pharmaceutically acceptable acid addition salt thereof, wherein:

R¹ is ##STR19## wherein X is hydrogen, lower alkyl of one to four carbon atoms, lower alkoxy of one to four carbon atoms, halo, carboxamido or hydroxy;

m is 1, 2 or 3; and

n is 1, 2 or 3;

R², R³ and R⁴ are independently hydrogen or lower alkyl of one to four carbon atoms or a pharmaceutical composition containing such compound as an active ingredient.

21. A method of claim 20 for treating and/or preventing hypertension in a mammalian subject.