Farnesyl protein transferase inhibitors for treating...

Details Farnesyl protein transferase inhibitors for treating... Farnesyl protein transferase inhibitors for treating...

2001-01-03

2002-09-17

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S311000, C514S314000

Reexamination Certificate

active

06451812

ABSTRACT:

The present invention is concerned with the finding that farnesyl protein transferase inhibitors are useful for preparing a pharmaceutical composition for treating arthropathies such as, for example, rheumatoid arthritis, osteoarthritis, juvenile arthritis, and gout.
In Arthritis and Rheumatism, 40 (9), 1997, 1636-1643, Roivanen et al. describe H-ras oncogene point mutations in arthritic (and in healthy) synovium. Mutations in codon 13 and unexpectedly also in codon 14 could be detected in arthritic synovia from patients with rheumatoid arthritis, osteoarthritis and other arthropathies, but also in the synovia of controls without any joint disease. Whether the mutations have any importance in the pathogenesis of joint diseases therefore remains unanswered.
WO-97/21701 describes the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II) and (III), as well as intermediates of formula (II) and (HI) that are metabolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (III) are represented by
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
the dotted line represents an optional bond;
X is oxygen or sulfur;
R
1
is hydrogen, C
1-12
alkyl, Ar
1
, Ar
2
C
1-6
alkyl, quinolinylC
1-6
alkyl, pyridylC
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, aminoC
1-6
alkyl, or a radical of formula -Alk
1
-C(═O)—R
9
, -Alk
1
-S(O)—R
9
or -Alk
1
-S(O)
2
—R
9
,
 wherein
Alk
1
is C
1-6
alkanediyl,
R
9
is hydroxy, C
1-6
alkyl, C
1-6
alkyloxy, amino, C
1-8
alkylamino or C
1-8
alkylamino substituted with C
1-6
alkyloxycarbonyl;
R
2
, R
3
and R
16
each independently are hydrogen, hydroxy, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxy, hydroxyC
1-6
alkyloxy, C
1-6
alkyloxyC
1-6
alkyloxy, aminoC
1-6
alkyl-oxy, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyloxy, Ar
1
, Ar
2
C
1-6
alkyl, Ar
2
oxy, Ar
2
C
1-6
alkyloxy, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C
2-6
alkenyl, 4,4-dimethyloxazolyl; or when on adjacent positions R
2
and R
3
taken together may form a bivalent radical of formula
—O—CH
2
—O—  (a-1),
—O—CH
2
—CH
2
—O—  (a-2),
—O—CH═CH—  (a-3),
—O—CH
2
—CH
2
—  (a-4),
—O—CH
2
—CH
2
—CH
2
—  (a-5),
or
—CH═CH—CH═CH—  (a-6);
R
4
and R
5
each independently are hydrogen, halo, Ar
1
, C
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylthio, amino, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylS(O)C
1-6
alkyl or C
1-6
alkylS(O)
2
C
1-6
alkyl;
R
6
and R
7
each independently are hydrogen, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxy, Ar
2
oxy, trihalomethyl, C
1-6
alkylthio, di(C
1-6
alkyl)amino, or when on adjacent positions R
6
and R
7
taken together may form a bivalent radical of formula
—O—CH
2
—O—  (c-i),
or
—CH═CH—CH═CH—  (c-2);
R
8
is hydrogen, C
1-6
alkyl, cyano, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylcarbonylC
1-6
alkyl, cyanoC
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
alkyl, carboxyC
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, mono- or di(C
1-6
alkyl)-aminoC
1-6
alkyl, imidazolyl, haloC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, aminocarbonylC
1-6
alkyl, or a radical of formula
—O—R
10
  (b-1),
—S—R
10
  (b-2),
—N—R
11
R
12
  (b-3),
 wherein
R
10
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, Ar
1
, Ar
2
C
1-6
alkyl, C
1-6
alkyloxycarbonyiC
1-6
alkyl, or a radical or formula -Alk
2
-OR
13
or -Alk
2
-NR
14
R
15
;
R
11
is hydrogen, C
1-12
alkyl, Ar
1
or Ar
2
C
1-6
alkyl;
R
12
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylaminocarbonyl, Ar
1
, Ar
2
C
1-6
alkyl, C
1-6
alkylcarbonyl-C
1-6
alkyl, a natural amino acid, Ar
1
carbonyl, Ar
2
C
1-6
alkylcarbonyl, aminocarbonyicarbonyl, C
1-6
alkyloxyC
1-6
alkylcarbonyl, hydroxy, C
1-6
alkyloxy, aminocarbonyl, di(C
1-6
alkyl)aminoC
1-6
alkylcarbonyl, amino, C
1-6
alkylamino, C
1-6
alkylcarbonylamino, or a radical or formula -Alk
2
-OR
13
or -Alk
2
-NR
14
R
15
;
 wherein
Alk
2
is C
1-6
alkanediyl;
R
13
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, hydroxy-C
1-6
alkyl, Ar
1
or Ar
2
C
1-6
alkyl;
R
14
is hydrogen, C
1-6
alkyl, Ar
1
or Ar
2
C
1-6
alkyl;
R
15
is hydrogen, C
1-6
alkyl, C
1-6
alkylcarbonyl, Ar
1
or Ar
2
C
1-6
alkyl;
R
17
is hydrogen, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxycarbonyl, Ar
1
;
R
18
is hydrogen, C
1-6
alkyl, C
1-6
alkyloxy or halo;
R
19
is hydrogen or C
1-6
alkyl;
Ar
1
is phenyl or phenyl substituted with C
1-6
alkyl, hydroxy, amino, C
1-6
alkyloxy or halo; and
Ar
2
is phenyl or phenyl substituted with C
1-6
alkyl, hydroxy, amino, C
1-6
alkyloxy or halo.
WO-97/16443 concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by
the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein the dotted line represents an optional bond;
X is oxygen or sulfur;
R
1
is hydrogen, C
1-12
alkyl, Ar
1
, Ar
2
C
1-6
alkyl, quinolinylC
1-6
alkyl, pyridylC
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl, aminoC
1-6
alkyl, or a radical of formula -Alk
1
-C(═O)—R
9
, -Alk
1
-S(O)—R
9
or -Alk
1
-S(O)
2
—R
9
,
 wherein
Alk
1
is C
1-6
alkanediyl,
R
9
is hydroxy, C
1-6
alkyl, C
1-6
alkyloxy, amino, C
1-8
alkylamino or C
1-8
galkylamino substituted with C
1-6
alkyloxycarbonyl;
R
2
and R
3
each independently are hydrogen, hydroxy, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxy, hydroxyC
1-6
alkyloxy, C
1-6
alkyloxyC
1-6
alkyloxy, amino-C
1-6
alkyloxy, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyloxy, Ar
1
, Ar
2
C
1-6
alkyl, Ar
2
oxy, Ar
2
C
1-6
alkyloxy, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C
2-6
alkenyl; or
when on adjacent positions R
2
and R
3
taken together may form a bivalent radical of formula
—O—CH
2
—O—  (a-1),
—O—CH
2
—CH
2
—O—  (a-2),
—O—CH═CH—  (a-3),
 —O—CH
2
—CH
2
—  (a-4),
—O—CH
2
—CH
2
—CH
2
—  (a-5),
or
—CH═CH—CH═CH—  (a-6);
R
4
and R
5
each independently are hydrogen, Ar
1
, C
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylthio, amino, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylS(O)C
1-6
alkyl or C
1-6
alkylS(O)
2
C
1-6
alkyl;
R
6
and R
7
each independently are hydrogen, halo, cyano, C
1-6
alkyl, C
1-6
alkyloxy or Ar
2
oxy;
R
8
is hydrogen, C
1-6
alkyl, cyano, hydroxycarbonyl, C
1-6
alkyloxycarbonyl, C
1-6
alkyl-carbonylC
1-6
alkyl, cyanoC
1-6
alkyl, C
1-6
alkyloxycarbonylC
1-6
alkyl, hydroxy-carbonylC
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, mono- or di(C
1-6
alkyl)-aminoC
1-6
alkyl, haloC
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, aminocarbonylC
1-6
alkyl, Ar
1
, Ar
2
C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkylthioC
1-6
alkyl;
R
10
is hydrogen, C
1-6
alkyl, C
1-6
alkyloxy or halo;
R
11
is hydrogen or C
1-6
alkyl;
Ar
1
is phenyl or phenyl substituted with C
1-6
alkyl,hydroxy,amino,C
1-6
alkyloxy or halo;
Ar
2
is phenyl or phenyl substituted with C
1-6
alkyl,hydroxy, amino, C
1-6
alkyloxy or halo.
PCT/EP98/01296, filed Mar. 3, 1998, concerns the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII)
the pharmaceutically acceptable acid addition salts and the stereochernically isomeric forms thereof, wherein the dotted line represents an optional bond;
X is oxygen or sulfur;
—A— is a bivalent radical of formula
—CH═CH—
(a-1),
—CH
2
—S—
(a-6),
—CH
2
—CH
2
—
(a-2),
—CH
2
—CH
2
—S—
(a-7),
—CH
2
—CH
2
—CH
2
—
(a-3),
—CH&bo

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