Process for synthesizing biaryl inhibitors of...

Details Process for synthesizing biaryl inhibitors of... Process for synthesizing biaryl inhibitors of...

1999-06-30

2001-05-29

Kight, John (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06239280

ABSTRACT:

BACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least three post-translational modifications are involved with Ras membrane localization, and all three modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a “CAAX” or “Cys-Aaa
1
-Aaa
2
-Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,
Nature
310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C
15
or C
20
isoprenoid, respectively. (S. Clarke.,
Ann. Rev. Biochem
. 61:355-386 (1992); W. R. Schafer and J. Rine,
Ann. Rev. Genetics
30:209-237 (1992)).
The peptide derived inhibitors of farnesyl-protein transferase (FPTase) that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al.,
J. Biol. Chem
., 265:14701-14704 (1990); Reiss et. al.,
Cell
, 62:81-88 (1990); Reiss et al.,
PNAS
, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl et al.,
Science
, 260:1934-1937 (1993); Graham, et al.,
J. Med. Chem
., 37, 725 (1994)). In general, while deletion of the thiol from a CAAX derivative has been shown to reduce the inhibitory potency of the compound, the thiol group can adversely affect the pharmacokinetics, pharmacodynamics and toxicity of FPTase inhibitors. Consequently, functional replacements for the thiol group have been achieved.
Thiol replacements that incorporate a 1,5 disubstituted imidazole with a biaryl component have been observed to be FPTase inhibitors. The synthesis of 1,5 disubstituted imidazoles from primary amines, dihydroxyacetone and potassium thiocyanate via thioimidazoles has been reported in the classical literature (Marckwald,
Chem Ber
. 1892, 25, 2354; Duncia, J. M. et al,
J. Med Chem
. 1990, 33, 1312-1330; Jones, R. G.,
J. Am. Chem. Soc
. 1949, 71, 383 and 644; Pyman,
J. Chem. Soc
. 1911, 99, 668). Literature protocols for the dethionation of 2-mercaptoimidazoles describe treatment with concentrated nitric acid, with or without a nitrite; such procedures give variable results and often result in the sudden violent release of nitrogen oxide gases.
Therefore, the need exists for a process for synthesizing 1,5 disubstituted imidazoles with biaryl components which has a predictably higher yield than known methods and which utilizes reaction conditions that are free from the drawbacks described above.
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of compounds with the formula (I), which are useful as FPTase inhibitors:
wherein:
R
1
, R
2
and R
3
are independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, substituted heterocycle, C
3
-C
10
cycloalkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, perfluoroalkyl, F, Cl, Br, R
11
O—, R
12
S(O)
m
—, R
11
C(O)NR
11
—, (R
11
)
2
NC(O)—, R
12
S(O)
2
NR
11
—, (R
11
)
2
NS(O)
2
—, R
11
2
N—C(NR
11
)—, CN, NO
2
, R
11
C(O)—, N
3
, —N(R
11
)
2
, or R
12
OC(O)NR
11
—, and
c) C
1
-C
6
alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C
3
-C
10
cycloalkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, perfluoroalkyl, F, Cl, Br, R
11
O—, R
12
S(O)
m—
, R
11
C(O)NR
11
—, (R
11
)
2
NC(O)—, R
12
S(O)
2
NR
11
—, (R
11
)
2
NS(O)
2
—, R
11
2
N—C(NR
11
)—, CN, R
11
C(O)—, N
3
, —N(R
11
)
2
, or R
11
OC(O)NH—;
R
5
, R
6
and R
7
are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C
3
-C
10
cycloalkyl, halogen, C
1
-C
6
perfluoroalkyl, R
13
O—, R
12
S(O)
m
—, R
11
C(O)NR
11
—, (R
11
)
2
NC(O)—, R
12
C(O)O—, R
11
2
N—C(NR
11
)—, R
11
C(O)—, —N(R
11
)
2
, or R
12
OC(O)NR
11
—,
c) unsubstituted C
1
-C
6
alkyl,
d) substituted C
1
-C
6
alkyl wherein the substituent on the substituted C
1
-C
6
alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C
3
-C
10
cycloalkyl, R
13
O—, R
12
S(O)
m
—, R
11
C(O)NR
11
—, (R
11
)
2
NC(O)—, R
11
2
N—C(NR
11
)—, R
11
C(O)—, —N(R
11
)
2
, and R
12
OC(O)—NR
11
—;
R
8
, R
9
and R
10
are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C
3
-C
10
cycloalkyl, halogen, C
1
-C
6
perfluoroalkyl, R
13
O—, R
12
S(O)
m
—, R
11
C(O)NR
11
—, (R
11
)
2
NC(O)—, R
12
S(O)
2
NR
11
—, (R
11
)
2
NS(O)
2
—, R
12
C(O)O—, R
11
2
N—C(NR
11
)—, R
11
C(O)—, —N(R
11
)
2
, or R
12
OC(O)NR
11
—,
c) unsubstituted C
1
-C
6
alkyl,
d) substituted C
1
-C
6
alkyl wherein the substituent on the substituted C
1
-C
6
alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C
3
-C
10
cycloalkyl, R
13
O—, R
12
S(O)
m
—, R
11
C(O)NR
11
—, (R
11
)
2
NC(O)—, R
12
S(O)
2
NR
11
—, (R
11
)
2
NS(O)
2
—, R
11
2
N—C(NR
11
)—, R
11
C(O)—, —N(R
11
)
2
, and R
12
OC(O)—NR
11
—; or
any two of R
8
, R
9
and R
10
on adjacent carbon atoms are combined to form a diradical selected from —CH═CH—CH═CH—, —CH═CH—CH
2
—, —(CH
2
)
4
— and —(CH
2
)
3
—;
A is:
a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are replaced by a heteroatom selected from N, S and O, and wherein A is attached to B through a carbon atom;
B is:
a 4, 5, 6 or 7 membered heterocyclic ring which comprises a nitrogen atom through which B is attached to A and 0-2 additional heteroatoms selected from N, S and O, and which also comprises a carbonyl, thiocarbonyl, —C(═NR
14
)— or sulfonyl moiety adjacent to the nitrogen atom attached to A;
R
11
is independently selected from hydrogen, C
1
-C
6
alkyl, amino-C
1
-C
6
alkyl, N-(unsubstituted or substituted benzoyl)-amino-C
1
-C
6
alkyl, (C
1
-C
6
alkyl)
2
-amino-C
1
-C
6
alkyl, acetylamino-C
1
-C
6
alkyl, phenyl-C
1
-C
6
alkyl, 2,2,2-trifluoroethyl, aryl and substituted aryl;
R
12
is independently selected from C
1
-C
6
alkyl and aryl;
R
13
is independently selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
aralkyl, C
1
-C
6
substituted aralkyl, C
1
-C
6
heteroaralkyl, C
1
-C
6
substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C
1
-C
6
perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
R
14
is selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkylsulfonyl and C
1
-C
6
acyl;
m is 0, 1 or 2.
Compounds of the formula (I) are synthesized by dethionating a thioimidazole of the formula (II):
The thioimidazole of formula (II) is prepared by coupling a hydroxyketone of formula (III):
with a benzylic amine of formula (IV):
The instant invention also involves the synthesis of the novel hydroxyketone of formula (III) and the novel benzylic amine of formula (IV).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a novel process for the separation of compounds of the formula (I):
(wherein R
1
, R
2
, R
3
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, A and B are defined as set forth above)
which comprises dethionating a thioimidazole of formula (II):
(wherein R
1
, R
2
, R
3
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, A and B are defined as set forth above)
with an oxidizing agent in the presence of a first acid. The thioimidazole of formula (II) is prepared by condensing a hydroxyketone of the formula (III):
wherein R
1
, R
2
and R
3

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