Tricyclic antitumor farnesyl protein transferase inhibitors

Details Tricyclic antitumor farnesyl protein transferase inhibitors Tricyclic antitumor farnesyl protein transferase inhibitors

1999-07-13

2001-08-21

Aulakh, Charanjit S. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S361000, C544S121000, C544S081000, C544S058200, C514S228200, C514S231500, C514S232800

Reexamination Certificate

active

06277854

ABSTRACT:

SUMMARY OF THE INVENTION
This invention relates to compounds of the formula (1.0):
wherein:
X is N, CH, or C when the double bond is present at the C-11 position;
one of a, b, c and d represents N or NR
9
wherein R
9
is O−, —CH
3
or —(CH
2
)
n
CO
2
H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR
1
or CR
2
; or
each of a, b, c, and d are independently selected from CR
1
or CR
2
;
each R
1
and each R
2
is independently selected from H, halo, —CF
3
, —OR
10
(e.g., —OCH
3
), —COR
10
, —SR
10
(e.g., -SCH
3
and —SCH
2
C
6
H
5
), —S(O)
t
R
11
(wherein t is 0, 1 or 2, e.g., —SOCH
3
and —SO
2
CH
3
), —SCN, —N(R
10
)
2
, —NR
10
R
11
, —NO
2
, —OC(O)R
10
, —CO
2
R
10
, —OCO
2
R
11
, —CN, —NHC(O)R
10
, —NHSO
2
R
11
, —CONHR
10
, —CONHCH
2
CH
2
OH, —NR
10
COOR
11
,
 —SR
11
C(O)OR
11
(e.g., —SCH
2
CO
2
CH
3
), —SR
11
N(R
12
)
2
wherein each R
12
is independently selected from H and —C(O)OR
11
(e.g., —S(CH
2
)
2
NHC(O)O-t-butyl and —S(CH
2
)
2
NH
2
), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol-5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, —OR
10
or —CO
2
R
10
;
R
3
and R
4
are the same or different and each independently represents H, any of the substituents of R
1
and R
2
, or R
3
and R
4
taken together represent a saturated or unsaturated C
5
-C
7
fused ring to the benzene ring (Ring III);
R
5
, R
6
, R
7
and R
8
each independently represents H, —CF
3
, —COR
10
, alkyl or aryl, said alkyl or aryl optionally being substituted with —OR
10
, —SR
10
, —S(O)
t
R
11
, —NR
10
COOR
11
, —N(R
10
)
2
, —NO
2
, —COR
10
, —OCOR
10
, —OCO
2
R
11
, —CO
2
R
10
, OPO
3
R
10
, or R
5
is combined with R
6
to represent ═O or ═S and/or R
7
is combined with R
8
to represent ═O or ═S;
R
10
represents H, alkyl, aryl, or aralkyl (e.g., benzyl);
R
11
represents alkyl or aryl;
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 —R
10
, halo, —OR
11
, —OCO
2
R
11
or —OC(O)R
10
, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H
2
, —(OR
11
)
2
; H and halo, dihalo, alkyl and H, (alkyl)
2
, —H and —OC(O)R
10
, H and —OR
10
, ═O, aryl and H, ═NOR
10
or —O—(CH
2
)
p
—O— wherein p is 2, 3 or 4;
v is 0 to 5;
w is 0 or 1;
 —O-C
1
-C
6
-alkyl or —OM+, wherein M+ is an alkali metal cation;
R
21
and R
22
are each independently H, C
1
-C
6
alkyl, —CH
2
CONH
2
, phenyl, benzyl, —SO
2
-(C
1
-C
6
-alkyl), —NH-phenyl, acyl, C
3
-C
6
cycloalkyl, pyridyl, chloro-phenyl,
or R
21
and R
22
taken together with the nitrogen to which they are attached form
a dashed line means an optional chemical bond;
wherein Q is benzene, or a heterocyclic ring such as pyridine, pyrazine, or thiophene;
or a pharmaceutically acceptable salt thereof.
Preferred among compounds of the invention are compounds of the formula (1.0)
wherein R
1
, R
2
, X, A, B, a, b, c, d, are as described above, v is 0 to 4;
w is 0; and Y is
wherein R
21
and R
22
are as described above.
Also preferred are compounds of formula (1.0) wherein a is N; R
5
, R
6
, R
7
and R
8
are all H; and R
1
, R
2
, and R
3
are each independently selected from the group consisting of H or halo.
Also preferred are compounds of formula (1.0) wherein R
1
is H; and R
2
is Br; and R
3
and R
4
are each independently selected from the group consisting of Br and Cl.
Also preferred are compounds of formula (1.0) wherein X is CH.
Also preferred are compounds of any one of formula (1.0) wherein R
3
is Cl; and R
4
is Br.
Also preferred are compounds of formula (1.0) wherein a is N or NO—, and R
5
, R
6
, R
7
and R
8
are all H; and R
1
, R
2
, R
3
and R
4
are each independently selected from the group consisting of H or halo.
Also preferred are compounds of formula (1.0) wherein A and B are each H
2
; b and d are preferably CH.
Another group of preferred compounds is that wherein w is 1; v is 0-5; R
1
is H; R
2
is Br; R
3
and R
4
are independently Cl and Br; R
5
-R
8
are each H; X is CH; and Y is —O-C
1
-C
6
alkyl, NH
2
or —OM+.
Exemplary of compounds of the invention are:
The compounds of formula (1.0) are useful as famesyl protein transferase inhibitors. Accordingly, the compounds of formula (1.0) are useful for inhibiting tumor growth. Examples of tumors which may be inhibited include, but are not limited to, breast cancer, prostatic cancer, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma and epidermal carcinoma.
The invention also relates to pharmaceutical compositions for treating tumors which comprise a compound of formula (1.0) and a pharmaceutically acceptable carrier material.
The invention also relates to a method for treating tumors which comprises administering an anti-tumor effective amount of a compound of formula (1.0).
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula (1.0) can exist in unsolvated as well as solvated forms, including hydrated forms, e.g. the hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention.
Certain compounds of the invention can exist in stereoisomeric form. All such isomeric forms and mixtures thereof are within the scope of the present invention. Unless otherwise indicated, the methods of preparation disclosed herein may result in product distributions which include all possible structural isomers, although it is understood that physiological response may vary according to stereochemical structure. The isomers may be separated by conventional means such as fractional crystallization or HPLC (high performance liquid chromatography).
The compounds of formula (1.0) form pharmaceutically acceptable salts. The preferred pharmaceutically acceptable salts are nontoxic acid addition salts formed by adding to a suitable compound of the invention about a stoichiometric amount of a mineral acid , such as HCl, HBr, H
2
SO
4
or H
3
PO
4
or of an organic acid such as acetic, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, para-toluenesulfonic, methane sulfonic, citric, maleic, fumaric, succinic and the like, respectively.
When utilized herein and in the appended claims, the following terms, unless otherwise specified have the following meanings:
alkyl (including the alkyl portions of alkoxy, alkylamino and dialkylamino) represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
acyl represents a moiety of the formula
 wherein R is C
1
-C
6
alkyl, phenyl, pyridyl, chlorophenyl, as described above;
alkanediyl represents a divalent, straight or branched hydrocarbon chain having from 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, the two available bonds being from the same or different carbon atoms thereof, e.g., methylene, ethylene, ethylidene, —CH
2
CH
2
CH
2
—, —CH
2
CHCH
3
, —CHCH
2
CH
3
, etc.
cycloalkyl represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;
chlorophenyl represents a phenyl moiety where one of the hydrogens is replaced by a chlorine;
alkenyl represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms;
alkynyl represents straight and branched carbon chains having at least one ca

Affiliated with

Also associated with

Rating

Tricyclic antitumor farnesyl protein transferase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Tricyclic antitumor farnesyl protein transferase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tricyclic antitumor farnesyl protein transferase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2452933