Spirocycles

• US 5,403,846 A
• Filed: 11/22/1993
• Issued: 04/04/1995
• Est. Priority Date: 11/22/1993
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Selnick, Harold G., Claremon, David A., Baldwin, John J., Ponticello, Gerald S.
• Primary Examiner(s): TSANG, CECILIA J
• Application Number:
  US08/155,668
• Time in Patent Office: 498 Days
• Field of Search: 546/15, 549/331, 549/23, 549/336, 549/345, 549/15, 514/278, 514/456
• US Class Current: 514/278
• CPC Class Codes: C07D 311/96 spiro-condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds of the general formula: ##STR1## or a pharmaceutically acceptable salt, hydrate or crystal form enantiomer, diastereomer or mixtures thereof are Class III antiarrhythmic agents.

Claims

1. A compound of the (general) structural formula:

##STR29## or a pharmaceutically acceptable salt, hydrate or crystal form thereof, wherein;

X is O, S, or CH₂

Y is C or O with the proviso that;

If Y=O, than R5 and R6 are nothing

If Y=O, than X=CH₂

If X=O or S, than Y=C

R¹ is H₃ CSO₂ NH--, H₃ CO--, C_1-6 AlkylSO₂ --, C_1-6 AlkylCONH-- or NO₂ --;

R² is --H, --OCH₃ or C_1-6 Alkyl;

R³ and R⁴ taken together are=O, or R³ is H and R⁴ is one of the following --OH, --NHCOCH₃, --NHCOCH₃ SO₂ Phenyl, --NHCOCH₃ SO₂ C_1-6 Alkyl, NHCOCH₂ SPhenyl, NHCOCH₂ S C_1-6 Alkyl, --NHCOC(CH₃)₂ OH or NHSO₂ C_1-6 Alkyl;

or R3=R4=H

R⁵ and R⁶ are independently H, C1-C6 Alkyl(, or when taken together are --(CH₂)_n --, where n=2-5);

or =CH₂ ;

R⁷ is selected from ##STR30## And R8 is H, --CH3, --OH, --CN, --O--C1-C6-alkyl, --NHCO C_1-6 Alkyl, --NHSO2 C_1-6 Alkyl, --SO2 C_1-6 Alkyl are Class III antiarrhythmic agents.

4. A pharmaceutical formulation for use in the treatment of arrhythmia comprising a carrier and (a therapeutically effective amount of a) an amount of a compound of claim 1 such that a dosage form prepared from the formulation contains from 1 to 100 mg of the compound.

5. The pharmaceutical formulation of claim 4, comprising, in addition, a pharmaceutically effective amount of one or more of a Class I, Class II or Class IV antiarrhythmic agent.

6. The pharmaceutical formulation of claim 4, wherein the pharmaceutically effective amount of compound ranges from about 0.0001 to about 20 mg per kg of body weight per day.

7. The pharmaceutical formulation of claim 4, wherein the pharmaceutically effective amount of compound ranges from about 0.001 to about 10 mg per kg of body weight per day.

8. A method of treating arrhythmia and/or impaired cardiac pump function in a patient in need of such treatment which comprises administering to such patient a therapeutically effective amount of the comound of claim 1.

9. The method of claim 7, comprising, in addition, the admnistration of one or more of a Class I, Class II or Class IV antiarrhythmic agent.

10. The method of claim 7 wherein the therapeutically effective amount of compound is administered orally, intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously.

11. The method of claim 7 wherein the therapeutically effective amount of comound is administered orally or intravenously.

2. Compounds of the (general) structural formula:

##STR31## or a pharmaceutically acceptable salt, hydrate or crystal form thereof, wherein;

X is O, S, or CH₂

Y is C or O with the proviso that;

If Y=O, than R5 and R6 are nothing

If Y=O, than X=CH₂

If X=O or S, than Y=C

R¹ is H₃ CSO₂ NH--, H₃ CO--, C_1-6 AlkylSO₂ --, C_1-6 AlkylCONH-- or NO₂ --;

R² is --H, --OCH₃ or C_1-6 Alkyl;

R³ and R⁴ taken together are=O, or R³ is H and R⁴ is one of the following --OH, --NHCOCH₃, --NHCOCH₃ SO₂ Phenyl, --NHCOCH₃ SO₂ C_1-6 Alkyl, NHCOCH₂ SPhenyl, NHCOCH₂ S C_1-6 Alkyl, --NHCOC(CH₃)₂ OH or NHSO₂ C_1-6 Alkyl;

or R3=R4=H

R⁵ and R⁶ are independently H, C1-C6 Alkyl(, or when taken together are --(CH₂)_n --,where n=2-5);

or =CH₂ ;

R⁷ is selected from ##STR32## And R8 is H, --CH₃, --OH, --CN, --O--C1-C6-alkly, --NHCO C_1-6 Alkyl, --NHSO₂ C_1-6 Alkyl, --SO₂ C_1-6 Alkyl are class III antiarrhythmic agents.

3. A compound selected from the group consisting of N-[4'"'"'-(3,4-dihydro-2 (1H )-isoquinolinyl)-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1 '"'"'-cyclohexan]-6-yl]methanesulfonamide alpha and beta isomers ##STR33## or pharmaceutically acceptable salts, hydrates and crystal forms thereof.