Pyrrole derivatives useful for farnesyl transferase...

Details Pyrrole derivatives useful for farnesyl transferase... Pyrrole derivatives useful for farnesyl transferase...

2001-10-11

2003-01-28

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254050, C544S139000, C544S141000, C544S370000, C544S372000, C548S314700

Reexamination Certificate

active

06511978

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel compound represented by the following formula (1) which has a pyrrole structure and shows an inhibitory activity against farnesyl transferase:
in which
A represents hydrogen, lower alkyl, or a structure selected from the following group:
wherein
m
1
, m
2
, m and n independently of one another denote an integer of 0 to 5,
Y represents O, S, S═O or SO
2
,
R
1
represents hydrogen, or represents optionally saturated 3- to 6-membered heterocycle or bicyclo 9- to 10-membered aromatic heterocycle, each of which has one or more hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen, or represents a structure selected from the following group:
wherein,
X represents hydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy or phenoxy,
R
2
represents optionally saturated 3- to 9-membered heterocycle or bicyclo 9- to 10-membered aromatic heterocycle, each of which has one or more hetero atoms selected from a group consisting of nitrogen, sulfur and oxygen, or represents a structure selected from the following group:
wherein,
p denotes an integer of 1 to 3, Y is defined as previously described, R
11
and R
12
independently of one another represent lower alkyl optionally substituted by phenyl or naphthyl, or represent C
3
-C
7
-cycloalkyl, phenyl or naphthyl,
R
3
represents lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl or lower alkylsulfonyl, each of which is optionally substituted by phenyl or naphthyl, or represents sulfonyl substituted by phenyl or naphthyl,
R
4
and R
8
independently of one another represent hydrogen, lower alkyl, lower alkoxy or halogen,
R
5
and R
7
independently of one another represent hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy,
R
6
represents hydrogen, lower alkyl, lower alkoxy, hydroxy, di(lower alkyl)amine, C
3
-C
6
-cycloalkyl, C
3
-C
6
-cycloalkyl-lower alkyl, halogen, phenyl or phenoxy,
R
9
represents hydrogen or lower alkyl,
R
10
represents aralkyl optionally substituted by lower alkyl or halogen,
B represents hydrogen, lower alkyl, lower alkylthio or amino,
D represents hydrogen, lower alkyl, halogen, lower alkylthio, nitro or amino,
E represents phenyl, or naphthyl optionally substituted by halogen,
G represents nitro or amino, or represents a structure of
wherein
L represents a structure selected from the following group:
wherein
R
13
and R
14
independently of one another represent hydrogen, hydroxy, lower alkyl or lower alkoxy,
Y is defined as previously described,
J represents hydrogen, lower alkyl, lower alkylthio or phenyl,
provided that A does not represent hydrogen, lower alkyl or any one structure selected from the following group:
wherein m and R
3
to R
9
are defined as previously described, m′ denotes an integer of 1 to 5, when B, J and D represent hydrogen at the same time and G does not represent nitro or amino, or pharmaceutically acceptable salts or isomers thereof.
The present invention also includes processes for the preparation of said compound of formula (1), and compositions useful for treating or preventing cancer, restenosis (Erick E. Brooks, et. al.
The Journal of Biological Chemistry,
272 (14), 29207-29211, 1997), atherosclerosis (Russell Ross,
Nature,
362, 801-809, 1993; Joseph L. Goldstein, et. al.,
Nature,
343, 425-430, 1990) or infections from viruses (James C. Otto, et. al.,
The Journal of Biological Chemistry,
272(9), 4569-4572, 1996), which comprise as an active ingredient the compound of formula (1) together with the pharmaceutically acceptable carrier. Therefore, those processes and compositions are subject matters of the present invention.
BACKGROUND ART
Ras is a 21 kDa protein which plays an important role in the events associated with cell growth and differentiation. It combines with guanine nucleotide, whereby catalyzes the hydrolysis reaction from guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Further, this protein has been reported to act as a molecular switch regulating the specific GTPase cycle inside the cell (see: Bourne, H. R., Sanders, D. A., McCormick, F.
Nature
1991, 349, 117).
The mammalian Ras protein is coded by three (3) types of ras gene and classified into four (4) types; i.e., K-Ras-4B consisting of 188 amino acid residues and H-Ras, K-Ras-4A and N-Ras consisting of 189 residues, respectively. Amino acids 12, 13 and 61 of Ras, positioned in the neighborhood of phosphoryl group of GTP, regulate the activity of GTPase by having a large effect on spacial position of a water molecule which participates in the GTP hydrolysis. In human cancers, mutations are observed at the above amino acid positions. Since Ras mutations inhibit its ability to regulate GTPase activity, GTP-binding state of Ras is maintained, and thus, growth signal is transduced abnormally to cause cancer. In particular, ras oncogene is related to pancreatic cancer, urinary bladder carcinoma, lung cancer and skin cancer, etc. (see: Bos, J. L.,
Cancer Res.,
1989, 49, 4682).
To be in its biologically activated state, Ras must be attached to cell membrane and for this reason, modification or carboxyl terminus of the protein is required after the transportation of protein. The modification process comprises the steps of farnesylation of Ras by Ras farnesyl transferase, displacement of AAX peptide consisting of 3 amino acids at the C-terminus of Ras by peptide cleavage enzyme, methyl esterification of Ras by methyl transferase and palmitoylation of Ras by palmitoyl transferase. Among the above-described steps of modifying carboxyl terminus of Ras, the farnesylation step is proceeded by farnesyl transferase (FTase), and substrate for the transferase is CA
1
A
2
X peptide consisting of 4 amino acids at the C-terminus or Ras, where A
1
and A
2
are aliphatic amino acids having no charge and X is methionine, alanine or serine, etc. The farnesylation occurs at cysteine, and sulfur ether bond is formed. While, in H-Ras and N-Ras, palmitoylation occurs at another cysteine proximate to the C-terminus. The above-described farnesylation results in the enhancement of hydrophobicity of Ras, and hence its affinity for cell membrane increases. The farnesylated Ras is subjected to the cleavage of AAX peptide from the C-terminus thereof by the cleavage enzyme and methyl-esterified so that it can attach to the lipid layer of cell membrane or other receptors more easily. K-Ras-4B, differently from H-Ras or N-Ras, has a multiple lysine-arranged-region named polybasic domain, instead of having cysteine required for palmitoylation. It has been known that the polybasic domain facilitates Ras to bind to anionic lipid of cell membrane. All the above-described steps attribute to enhancing the attachment of Ras to cell membrane under the optimal condition, but only the farnesylation step is essentially required to express the biological activity of Ras. That is, if farnesylation step is inhibited, the resulting mutant Ras is prevented from being attached to cell membrane. Hence, inhibitors of farnesylation have been subjects of many studies (see: J. E. Buses et al.,
Chemistry
&
Biology,
1995, 2, 787).
As results of the studies, when farnesyl transferase is inhibited in a cell transformed by Ras, it is observed that the conditions of abnormal cells caused by mutant Ras are improved while growth of cells is inhibited.
Several inhibitors of farnesyl transferase are found to selectively inhibit intracellular prenyl group reaction of oncogenic Ras (see: Kohl, N. E. et al.,
Proc. Natl. Acad. Sci.
USA, 91, 9141(1994); Kohl, N. E. et al.,
Nature Medicine,
1, 792(1995)). The inhibitors of farnesyl transferase being studied recently include peptide variants having cysteine thiol group imitating CAAX and improved inhibitors (see: U.S. Pat. No. 5,141,851; Kohl, N. E. et al.,
Science,
260, 1934(1993); Graham et al., PCT/US95/12224), peptides modified by phenyl group (see: Sebti, S. M.,
J. Biol. Chem.,
270, 26802, 1995), variants using benzodiazepin, a frame structure of positive psycopharmaceuticals, as turn

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