Tricyclic carbamate compounds useful for inhibition of G-protein function and for treatment of proliferative diseases

• US 6,075,025 A
• Filed: 03/11/1998
• Issued: 06/13/2000
• Est. Priority Date: 10/15/1993
• Status: Expired due to Fees

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Njoroge, F. George, Doll, Ronald J., Wolin, Ronald L., Taveras, Arthur G., Piwinski, John J., Mallams, Alan K., Remiszewski, Stacy W., Bishop, W. Robert, Petrin, Joanne M.
• Primary Examiner(s): Rotman, Alan L.
• Application Number:
  US09/038,416
• Time in Patent Office: 825 Days
• Field of Search: 514/254, 544/361
• US Class Current: 514/253.03
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

A method of inhibiting Ras function and therefore inhibiting cellular growth is disclosed. The method comprises the administration of a compound of Formula 1.0 ##STR1## Also disclosed are novel compounds of the formulas: ##STR2## Also disclosed are processes for making 3-substituted compounds of the Formulas 1.1, 1.2 and 1.3.

Further disclosed are novel compounds which are intermediates in the processes for making the 3-substituted compounds of Formulas 1.1, 1.2, and 1.3.

Claims

1. A compound of the formula:

##STR154## or a pharmaceutically acceptable salt or solvate thereof, wherein;

one of a, b, c and d represents N or NR⁹ wherein R⁹ is O--, --CH₃ or --(CH₂)_n CO₂ H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR²² or CR²⁴ ;

R²² and R²⁴ are the same or different and each independently represents H, halo, --CF₃, --OR¹⁰, --COR¹⁰, --SR¹⁰, --N(R¹⁰)₂, --NO₂, --OC(O)R¹⁰, --CO₂ R¹⁰, --OCO₂ R¹¹, benzotriazol-1-yloxy, CN, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, --OR¹⁰ or --CO₂ R¹⁰ ;

R²⁶ and R²⁸ are the same or different and each independently represents any of the substituents of R²² and R²⁴ ;

R⁵, R⁶, R⁷ and R⁸ each independently represents H;

R¹⁰ represents H, alkyl, aryl, or aralkyl;

R¹¹ represents alkyl or aryl;

X represents N;

the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent --R¹⁰, halo --OR¹¹, --OCO₂ R¹¹ or --OC(O)R¹⁰, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H₂, --(OR¹¹)₂ ;

H and halo, dihalo, alkyl and H, (alkyl)₂, --H and --OC(O)R¹⁰, H and --OR¹⁰, ═

O, aryl and H, ═

NOR¹⁰ or --O--(CH₂)_p --O-- wherein p is 2, 3 or 4;

V represents --OR³⁰ ;

R³⁰ represents aralkyl, aryl, or alkyl.

2. The compound of claim 1 wherein a represents N and the remaining b, c, and d groups represent carbon;

each R²² and R²⁴ is independently selected from H, --CF₃, halo, benzotriazol-1yloxy or C₁ to C₄ alkyl;

each R²⁶ and R²⁸ is the same or different and each independently represents H or halo;

when the dotted line between carbon atoms 5 and 6 represents a double bond, then A and B independently represent H, and when no double bond is present between carbon atoms 5 and 6, then A and B each independently represent H₂.

3. The compound of claim 2 wherein R²² and R²⁴ are independently selected from H, halo, benzotriazol-1yloxy or C₁ to C₄ alkyl;

R²⁶ is Cl at the C-8 position;

R²⁸ is H; and

R³⁰ represents phenyl, or substituted phenyl.

4. The compound of claim 3 wherein R²² and R²⁴ are independently selected from H, Br, Cl or methyl.

5. The compound of claim 1 selected from:

##STR155##

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1.

7. A method of inhibiting pancreatic tumor cells, lung cancer tumor cells, epidermal carcinoma tumor cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic cells, bladder carcinoma tumor cells or colon tumor cells comprising administering an effective amount of a compound of claim 1.

8. A method of inhibiting farnesyl protein transferase comprising administering an effective amount of a compound of claim 1.