Spirocycles

• US 5,382,587 A
• Filed: 06/30/1993
• Issued: 01/17/1995
• Est. Priority Date: 06/30/1993
• Status: Expired due to Term

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Elliott, Jason M., Claremon, David A., Baldwin, John J.
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US08/085,573
• Time in Patent Office: 566 Days
• Field of Search: 546/17, 514/278
• US Class Current: 514/278
• CPC Class Codes: C07D 221/20 Spiro-condensed ring systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 495/10 Spiro-condensed systems

Abstract

Spirocycles of the general structural formulae: ##STR1## wherein: X is O, CH₂ or SO_m ;

R¹ is AlkylSO₂ NH--, AlkylO--, AlkylSO₂ --, AlkylCONH--, or NO₂ --;

R² is --H, --OAlkyl, or --Alkyl;

R³ is --NHCOCH₂ SO_m Phenyl, --NHCOCH₂ SO_m Alkyl,

--NHCOC(CH₃)₂ OH, or NHSO₂ Alkyl;

R⁴ and R⁵ are --H, or --Alkyl;

R⁶ is ##STR2## R⁷ is --H, --CN, --NHSO₂ Alkyl, --Br, --OAlkyl, --NH₂, --NO₂, --NHCOAlkyl, or NHCONHAlkyl;

R₈ is --H, --OH, --CN, --OAlkyl, --CONHAlkyl, --NHSO₂ Alkyl, --NHCOAlkyl, --SO_m Alkyl, or --CO₂ Alkyl;

and m is 0-2; or a pharmaceutically acceptable salt, hydrate or crystal form thereof; which are Class III antiarrhythmic agents.

Claims

1. A compound of the structural formulae:

##STR21## wherein;

X is O, CH₂ or SO_m ;

R¹ is AlkylSO₂ NH--, AlkylO--, AlkylSO₂ --, AlkylCONH--, or NO₂ --;

R² is --H, --OAlkyl, or --Alkyl;

R³ is --NHCOCH₂ SO_m Phenyl, --NHCOCH₂ SO_m Alkyl, or NHSO₂ Alkyl;

R⁴ and R⁵ are --H, or --Alkyl;

R⁶ is ##STR22## R⁷ is --H, --CN, --NHSO₂ Alkyl, --Br, --OAlkyl, --NH₂, --NO₂, --NHCOAlkyl, or NHCONHAlkyl;

R⁸ is --H, --OH, --CN, --OAlkyl, --CONHAlkyl, --NHSO₂ Alkyl, --NHCOAlkyl, --SO_m Alkyl, or --CO₂ Alkyl;

and m is 0-2;

or a pharmaceutically acceptable salt, hydrate or crystal form thereof.

2. The compounds of the formulae of claim 1, wherein:

X is O;

R¹ is AlkylSO₂ NH--, AlkylO--, AlkylSO₂ --, AlkylCONH--, or NO₂ --;

R² is --H, --OAlkyl, or --Alkyl;

R³ is --NHCOCH₂ SO_m Phenyl, --NHCOCH₂ SO_m Alkyl, or NHSO₂ Alkyl;

R₄ and R₅ are --H or --Alkyl;

R⁶ is ##STR23## R⁷ is --H, --CN, --NHSO₂ Alkyl, --Br, --OAlkyl, --NH₂, --NO₂, --NHCOAlkyl, or NHCONHAlkyl;

R⁸ is --H, --OH, --CN, --OAlkyl, --CONHAlkyl, --NHSO₂ Alkyl, --NHCOAlkyl, --SO_m Alkyl, or --CO₂ Alkyl;

and m is 0-2;

or a pharmaceutically acceptable salt, hydrate or crystal form thereof.

3. The compounds of the formulae of claim 1, wherein:

X is CH₂ ;

R₁ is AlkylSO₂ NH--, AlkylO--, AlkylSO₂ --, AlkylCONH--, or NO₂ --;

R² is --H, --OAlkyl, or --Alkyl;

R³ is --NHCOCH₂ SO_m Phenyl, --NHCOCH₂ SO_m Alkyl, or NHSO₂ Alkyl;

R⁴ and R⁵ are --H or --Alkyl;

R⁶ is ##STR24## R⁷ is --H, --CN, --NHSO₂ Alkyl, --Br, --OAlkyl, --NH₂, --NO₂, --NHCOAlkyl, or NHCONHAlkyl;

R₈ is --H, --OH, --CN, --OAlkyl, --CONHAlkyl, --NHSO₂ Alkyl, --NHCOAlkyl, --SO_m Alkyl, or --CO₂ Alkyl;

and m is 0-2;

or a pharmaceutically acceptable salt, hydrate or crystal form thereof.

4. The compounds of the formulae of claim 1, wherein:

X is SO_m ;

R₁ is AlkylSO₂ NH--, AlkylO--, AlkylSO₂ --, AlkylCONH--, or NO₂ --;

R₂ is --H, --OAlkyl, or --Alkyl;

R³ is --NHCOCH₂ SO_m Phenyl, --NHCOCH₂ SO_m Alkyl, or NHSO₂ Alkyl;

R₄ and R₅ are --H or --Alkyl;

R⁶ is ##STR25## R⁷ is --H, --CN, --NHSO₂ Alkyl, --Br, --OAlkyl, --NH₂, --NO₂, --NHCOAlkyl, or NHCONHAlkyl;

R⁸ is --H, --OH, --CN, --OAlkyl, --CONHAlkyl, --NHSO₂ Alkyl, --NHCOAlkyl, --SO_m Alkyl, or --CO₂ Alkyl;

and m is 0-2;

or a pharmaceutically acceptable salt, hydrate or crystal form thereof.

5. The compounds of the formulae of claim 1, wherein

X is O;

R¹ is H₃ CSO₂ NH--;

R² is --H;

R³ is --NHCOCH₂ SO_m Phenyl, --NHCOCH₂ SO_m Alkyl, or NHSO₂ Alkyl;

R⁴ and R⁵ are --H;

and R⁶ is ##STR26## or a pharmaceutically acceptable salt, hydrate or crystal form thereof.

6. The compounds of the formula of claim 1, wherein:

X is O;

R¹ is H³ CSO₂ NH--;

R² is --H;

R³ is --NHCOCH₂ SO_m Phenyl, --NHCOCH₂ SO_m Alkyl, or NHSO₂ Alkyl;

R⁴ and R⁵ are --H;

and R⁶ is ##STR27## or a pharmaceutically acceptable salt, hydrate or crystal form thereof.

9. A pharmaceutical formulation comprising a carrier and a therapeutically effective amount of a compound of claim 1.

10. The pharmaceutical formulation of claim 9, wherein the pharmaceutically effective amount of compound ranges from about 0.0001 to about 20 mg per kg of body weight per day.

11. A method of treating arrhythmia in a patient in need of such treatment which comprises administering to such patient a therapeutically effective amount of the compound of claim 1.

12. The method of claim 11, wherein the therapeutically effective amount of compound is administered orally, intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously.

13. The method of claim 11, wherein the therapeutically effective amount of compound is administered orally or intravenously.

7. A compound selected from the group consisting of:

##STR28## '"'"' -[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-6-methanesulfonamido-4-[2-(phenylsulfonyl)acetamido]spiro(2H- 1-benzopyran-2,4'"'"'-piperidine);

##STR29##'"'"' -[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-6-methanesulfonamido-4-[2-(methanesulfonyl)acetamido]spiro(2H-1-benzopyran-2,4'"'"'-piperidine);

##STR30## '"'"' -[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-6-methanesulfonamido-4-[2-(phenylthio)acetamido]spiro(2H- 1-benzopyran-2,4'"'"'-piperidine);

##STR31## '"'"' -[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-6-methanesulfonamido-4-[2-(methylthio)acetamido]spiro(2H- 1-benzopyran-2,4'"'"'-piperidine);

##STR32## '"'"' -[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-4,6-bis(methanesulfonamido)spiro(2H-1-benzopyran-2,4'"'"'-piperidine);

as diastereomers and enantiomers, or mixtures thereof, or pharmaceutically acceptable salts, hydrates or crystal forms thereof.

8. A compound selected from the group consisting of:

##STR33## (4S, 2"R)-1'"'"'-[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-6-methanesulfonamido-4-[2-(phenylsulfonyl)acetamido]spiro(2H-1-benzopyran-2,4'"'"'-piperidine);

##STR34## (4S, 2"R)- 1'"'"'-[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-6-methanesulfonamido-4-[2-(methanesulfonyl)acetamido]spiro(2H-1-benzopyran-2,4'"'"'-piperidine);

##STR35## (4S, 2"R)-1'"'"'-[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-6-methanesulfonamido-4-[2-(phenylthio)acetamido]spiro(2H-1-benzopyran-2,4'"'"'-piperidine);

##STR36## (4S, 2"R )-1'"'"'-[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-6-methanesulfonamido-4-[2-(methylthio)acetamido]spiro(2H-1-benzopyran-2,4'"'"'-piperidine);

##STR37## (4S, 2"R)-1'"'"'-[(6-Cyano-1,2,3,4-tetrahydronaphthalene)-2-yl]-3,4-dihydro-4,6-bis(methanesulfonamido )spiro(2H- 1-benzopyran-2,4'"'"'-piperidine);

or pharmaceutically acceptable salts, hydrates or crystal forms thereof.