# US 5,703,090 A · Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases

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- Number: US 5,703,090 A
- Document ID: US5703090A
- Status: Granted
- Kind: A
- Application number: 08/714,023
- Filed: 1996-09-11
- Granted: 1997-12-30
- Earliest claimed: 1995-03-24
- Assignees: Schering Corporation
- Inventors: Adriano Afonso; Joseph M. Kelly; Ronald L. Wolin
- Web page: https://patentgrep.com/patent/US5703090A

## CPC

- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A method of inhibiting Ras function and therefore inhibiting cellular growth is disclosed. The method comprises the administration of a novel compound of the formula (Ia), (Ib) or (Ic) ##STR1## wherein: R and R.sup.1 are H, alkyl, halogeno, OH, alkoxy, NH.sub.2, alkylamino, dialkylamino, CF.sub.3, SO.sub.3 H, CO.sub.2 R.sup.3, NO.sub.2, SO.sub.2 NH.sub.2, or CONHR.sup.4 ; n is 0 or 1; R.sup.2 is a group of the formula R.sup.5 C(O)--, R.sup.5 CH.sub.2 C(O)--, R.sup.5 C(R.sup.6).sub.2 C(O)--, R.sup.5 SO.sub.2 --, R.sup.5 CH.sub.2 SO.sub.2 --, R.sup.5 SCH.sub.2 C(O)--, R.sup.5 OC(O)--, R.sup.5 NHC(O)--, R.sup.5 C(O)C(O)-- or R.sup.5 SC(O)--; R.sup.5 is alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl or heterocycloalkyl; and R.sup.6 is alkyl or C(R.sup.6).sub.2 is a carbocyclic ring; or pharmaceutically aceptable salts thereof.

## Claims

### Claim 1

A method for inhibiting farnesyl protein transferase in humans in need of such treatment comprising administering an effective amount of a compound of formula (Ib) ##STR101## wherein: R and R.sup.1 are independently selected from H, (C.sub.1 -C.sub.6)alkyl, halogeno, OH, (C.sub.1 -C.sub.6)alkoxy, NH.sub.2, (C.sub.1 -C.sub.6)alkylamino, di((C.sub.1 -C.sub.6)alkyl)amino, CF.sub.3, SO.sub.3 H, CO.sub.2 R.sup.3, NO.sub.2, SO.sub.2 NH.sub.2, and CONHR.sup.4 ;
R.sup.2 is R.sup.5 SO.sub.2 -- wherein R.sup.5 is a heterolaryl group selected from: thienyl or furanyl, and wherein said thienyl or furanyl optionally substituted by 1 to 3 substituents selected from: halogeno, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, amino, alkylamino, dialkylamino, C.sub.6 H.sub.5 C(O)NHCH.sub.2 -- or --COOR.sup.8 wherein R.sup.8 is H or (C.sub.1 -C.sub.6)alkyl;
R.sup.3 is (C.sub.1 -C.sub.6)alkyl or aryl;
R.sup.4 is (C.sub.1 -C.sub.6)alkyl;
n is 0 or 1; and
the dotted line represents an optional double bond;
and pharmaceutically acceptable salts thereof.

### Claim 2

A compound selected from a compound of formula (Ib) ##STR102## wherein: R and R.sup.1 are independently selected from H, (C.sub.1 -C.sub.6)alkyl, halogeno, OH, (C.sub.1 -C.sub.6)alkoxy, NH.sub.2, (C.sub.1 -C.sub.6)alkylamino, di((C.sub.1 -C.sub.6)alkyl)amino, CF.sub.3, SO.sub.3 H, CO.sub.2 R.sup.3, NO.sub.2, SO.sub.2 NH.sub.2, and CONHR.sup.4 ;
R.sup.2 is R.sup.5 SO.sub.2 -- wherein R.sup.5 is a heteroaryl group selected from: thienyl or furanyl, and wherein said thienyl or furanyl is optionally substituted by 1 to 3 substituents selected from: halogeno, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, amino, alkylamino, dialkylamino, C.sub.6 H.sub.5 C(O)NHCH.sub.2 -- or COOR.sup.8 wherein R.sup.8 is H or (C.sub.1 -C.sub.6)alkyl;
R.sup.3 is (C.sub.1 -C.sub.6)alkyl or aryl;
R.sup.4 is (C.sub.1 -C.sub.6)alkyl;
n is 0 or 1; and
the dotted line represents an optional double bond;
and pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 2)

A compound of claim 2 wherein R and R.sup.1 are independently selected from H or halogeno.

### Claim 4 (depends on 3)

A compound of claim 3 wherein R.sup.5 is 2-thienyl, 5-chloro-2-thienyl, 5-(benzoylaminomethyl)-2-thienyl, 2-methoxycarbonyl-3-thienyl, 2-furanyl,
or the sodium salt of 2-carboxy-3-thienyl.

### Claim 5 (depends on 2)

A compound of claim 2 having the structural formula ##STR103##

### Claim 6 (depends on 2)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 2.

### Claim 7

A method for treating human epidermal carcinoma or human colon adenocarcinoma in humans in need of such treatment comprising administering an effective amount of a compound of formula (Ib) ##STR104## wherein: R and R.sup.1 are independently selected from H, (C.sub.1 -C.sub.6)alkyl, halogeno, OH, (C.sub.1 -C.sub.6)alkoxy, NH.sub.2, (C.sub.1 -C.sub.6)alkylamino, di((C.sub.1 -C.sub.6)alkyl)amino, CF.sub.3, SO.sub.3 H, CO.sub.2 R.sup.3, NO.sub.2, SO.sub.2 NH.sub.2, and CONHR.sup.4 ;
R.sup.2 is R.sup.5 SO.sub.2 -- wherein R.sup.5 is a heteroaryl group selected from: thienyl or furanyl, and wherein said thienyl or furanyl is optionally substituted by 1 to 3 substituents selected from: halogeno, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, amino, alkylamino, dialkylamino, C.sub.6 H.sub.5 C(O)NHCH.sub.2 -- or --COOR.sup.8 wherein R.sup.8 is H or (C.sub.1 -C.sub.6)alkyl;
R.sup.3 is (C.sub.1 -C.sub.6)alkyl or aryl;
R.sup.4 is (C.sub.1 -C.sub.6)alkyl;
n is 0 or 1; and
the dotted line represents an optional double bond;
and pharmaceutically acceptable salts thereof.

### Claim 8 (depends on 2)

A compound of claim 2 wherein R.sup.5 is 2-thienyl, 5-chloro-2-thienyl, 5-(benzoylaminomethyl)-2-thienyl, 2-methoxycarbonyl-3-thienyl, or the sodium salt of 2-carboxy-3-thienyl.