Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-30
2002-04-02
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S154000, C514S04400A
Reexamination Certificate
active
06365600
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with a method of use of compounds of formula (I) for the inhibition of smooth muscle cell proliferation.
BACKGROUND OF THE INVENTION
Proliferation of smooth muscle cells of the arterial wall in response to local injury is an important aetiologic factor of vascular proliferative disorders such as atheorsclerosis and restenosis after angioplasty. The incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA) has been reported to be as high as 45% within three to six months after PTCA treatment (Indolfi et al.,
Nature medicine,
1, 541-545 (1995)). Hence, compounds that inhibit smooth muscle cell proliferation can be very useful to prevent or treat vascular proliferative disorders such as atherosclerosis and restenosis.
Heparin is a well known compound to inhibit proliferation of smooth muscle cells after coronary angioplasty (Buchwald et al.,
J. Cardiovasc. Pharmacol.,
28,481-487 (1996)).
In out co-pending application PCT/EP96/04515, published on Jun. 19, 1997 as W)-97/21701, the compounds of formula (I), their preparation and compositions containing them are disclosed as farnesyl transferase inhibitors useful for the treatment of ras dependent tumors
DETAILED DESCRIPTION OF THE INVENTION
Unexpectedly, it has been found that the compounds of formula (I) can be used to inhibit smooth muscle cell proliferation. Consequently, the present invention relates to a method of use of compounds of formula (I) for treating vascular proliferative disorders in a warm-blooded animal.
The present invention relates to a method of use of compounds of formula (I)
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, cyanao, C
1-6
alkyl, C
1-6
alkyloxy, hydroxyC
1-6
alkyloxy, C
1-6
alkyloxyC
1-6
alkyloxy, aminoC
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, trihaalomethyl, 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-1), or
—C=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, imidazoly, haloC
1-6
alkyl, C
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
alkyloxycarbonylC
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
alkylcarbonyl, C
1-6
alkylaminocarbonyl, Ar
1
, Ar
2
C
1-6
alkyl, C
1-6
alkylcarbonylC
1-6
alkyl, a natural amino acid, Ar
1
carbonyl, Ar
2
C
1-6
alkylcarbonyl, aminocarbonylcarbonyl, 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, hydroxyC
1-6
alkyl, Ar
1
or AR
2
C
1-6
alkyl;
R
14
is hydrogen, C
1-6
alkyl, Ar
1
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; for the inhibition of smooth muscle cell proliferation.
R
4
or R
5
may also be bound to one of the nitrogen atoms in the imidazole ring. In that case the hydrogen on the nitrogen is replaced by R
4
and R
5
and the meaning of R
4
and R
5
when bound to the nitrogen is limited to hydrogen, Ar
1
, C
1-6
alkyl, hydroxy-C
1-6
alkyl, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkyloxycarbonyl, C
1-6
alkylS(O)C
1-6
alkyl, C
1-6
alkylS(O)
2
C
1-6
alkyl.
As used in the foregoing definitions and hereinafter halo defines fluro, chloro, bromo and iodo; C
1-6
alkyl defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; C
1-8
alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C
1-6
alkyl as well as the higher homologues thereof containing 7 or 8 carbon atoms such as, for example heptyl or octyl; C
1-12
alkyl again encompasses C
1-8
alkyl and the higher homologues thereof containing 9 to 12 carbon atoms, such as, for example, nonyl, decyl, undecyl, dodecyl; C
1-16
alkyl again encompasses C
1-12
alkyl and the higher homologues thereof containing 13 to 16 carbon atoms, such as, for example tridecyl, tetradecyl, pentedecyl and hexadecyl; C
2-6
alkenyl defines straight and branded chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethylyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like; C
1-6
alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof. The term “C(=O)” refers to a carbonyl group, “S(O)” refers to a sulfoxide and “S(O)
2
” to a sulfon. The term “natural amino acid” refers to a natural amino acid that is bound via a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of the amino acid and the amino group of the remainder of the molecule. Examples of natural amino acids are glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylanaline, tryptophan, serine, threonine, cycsteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine.
The pharmaceutically acceptable acid or base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and non-toxic base addition salt forms which the compounds of formula (I) are able to form. The compounds
End David William
Zelesko Michael J.
Fay Zohreh
Janssen Pharmaceutica N.V.
Kwon Brian-Yong
McCormack Myra
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