Therapeutic heterocycles

Details Therapeutic heterocycles Therapeutic heterocycles

2000-09-22

2002-06-04

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S287000, C544S238000, C544S119000, C514S260100, C514S252020

Reexamination Certificate

active

06399603

ABSTRACT:

BACKGROUND
Apoptosis, or programmed cell death, is a well-defined sequence of events that result in the death of mammalian cells. The process of apoptosis is a normal part of physiology, and a key mechanism in the removal of unwanted cells during various phases of life, for example, fetal development. Upon induction of apoptosis, cells undergo a number of characteristic morphological changes, including cell shrinkage, membrane blebbing, membrane ruffling, loss of cell-cell contact and condensation of nuclear chromatin.
One of the most characteristic events which helps to define apoptosis is the condensation and destruction of nuclear DNA. Following a signal for induction of apoptosis, a variety of nuclear enzymes are activated which cleave DNA at specific points, resulting in production of DNA fragments that are approximately 180-200 base pairs in length. Hence, examination of the DNA of a cell undergoing apoptosis by electrophoresis results in a pattern of “DNA laddering”, which is characteristic of these cells.
As apoptosis is a normal physiological process, dysregulation of the amount of apoptosis occurring in a cell population can be considered as an indicator of existence of a disease state. In certain cancer states, it has been suggested that insufficient apoptosis occurs within the cancerous tumor as a consequence of deletion or mutation of the tumor suppressor gene p53. In contrast, excessive apoptosis is believed to occur in individuals afflicted with Alzheimer's disease, as evidenced by increased loss of certain neuronal cell types. Increased apoptotic cell death has also been observed in certain T-cell populations in HIV-infected individuals, and in neurons of individuals who have suffered an ischemic event such as a stroke.
Caspase-3 (also known as CPP32, Apopain or Yama) is a 29 kDa cysteine protease. It is a member of a larger family of caspase enzymes, which share sequence homology with one another, including a highly conserved region centered around a cysteine residue believed to be involved in the hydrolysis of the target substrate(s). Included in this larger family is the interleukin-1&bgr; converting enzyme (ICE) and several other mammalian-derived caspases. Much of the understanding of the involvement of caspase-3 in apoptosis has arisen as the result of study of related cysteine proteases expressed by the nematode
Caenorhabditis elegans
. During normal development of this nematode, 131 of the 1090 cells generated die by apoptosis. Apoptosis of cells during development of
C. elegans
is vitally dependent upon two enzymes, CED-3 and CED-4, which are cysteine proteases, with CED-3 being highly homologous to both caspase-3 and ICE, including identity of amino acids in the enzyme active site.
Caspase-3 is believed to play a key role in apoptosis. In cells, caspase-3 has been shown to cleave many proteins, including the nuclear enzyme PARP (poly-ADP ribose polymerase), a DNA repair enzyme; U1-70, an enzyme that splices RNA; and DNA-PK
CS
, an enzyme that repairs double-strand breaks in DNA. As a consequence of the cleavage of these and other proteins by caspase-3, DNA repair is compromised and cells undergo apoptosis. The cleavage of proteins by caspase-3 has been shown to occur at well-defined amino acid sequences in the substrate proteins, in particular at the C-terminal side of a DXXD sequence. Peptide-based inhibitors of caspase-3 capable of blocking the cleavage of protein substrates in assays designed to measure caspase-3 mediated cleavage have been designed. Even though examples of these peptide-based inhibitors—such as the peptide aldehyde Ac-DEVD-CHO—may inhibit the isolated enzyme, their relative instability to chemical degradation precludes their use as effective inhibitors of caspase-3 in intact cells or in vivo.
Therefore, it would be very desirable to discover other molecules that exhibit similar or better ability to inhibit the cleavage of protein substrates by caspase-3, and possess significantly better physicochemical properties; for example chemical and hydrolytic stability. If discovered, such agents would be expected to be effective at reducing excessive apoptosis, and hence would provide a treatment for diseases characterized by this inappropriate cell death.
SUMMARY OF THE INVENTION
One aspect of this invention relates to quinazolines having the general structure I
wherein R
2
, R
4
, R
5
, R
6
, R
7
, R
8
, R
3′
, R
4′
and R
5′
are defined herein.
Another aspect of this invention relates to the use of the above compounds to retard apoptosis in cells and as therapies that are beneficial in the treatment of immune, proliferative and degenerative diseases including, but not limited to, immune deficiency syndromes (such as AIDS), autoimmune diseases, pathogenic infections, cardiovascular and neurological injury, alopecia, aging, cancer, Parkinson's disease, Alzheimer's disease, Huntington's disease, acute and chronic neurodegenerative disorders (e.g. stroke, vascular dementia, head trauma, ALS, neuromuscular disease), myocardial ischemia, cardiomyopathy, macular degeneration, osteoarthritis, diabetes, acute liver failure and spinal cord injury.
A third aspect of this invention relates to pharmaceutical composition containing the above compounds with a pharmaceutically-acceptable carrier or diluent.
DETAILED DESCRIPTION
The compounds of this invention are quinazolines having the general structure I.
For structure I, R
2
and R
4
are, independently, H, acetyl or (C
1
-C
5
)alkyl. In another embodiment, R
2
and R
4
are H.
R
5
, R
6
and R
7
are independently selected from H, halogen, (C
1
-C
2
)alkyl, halo(C
1
-C
2
)alkyl, nitro and cyano. In another embodiment, R
6
is selected from halogen, (C
1
-C
2
)alkyl, halo(C
1
-C
2
)alkyl, nitro and cyano; and R
5
and R
7
are as above. In another embodiment, R
6
is selected from nitro, halogen, —CH
3
, —CF
3
and cyano; and R
5
and R
7
are independently selected from H, halogen, (C
1
-C
2
)alkyl, —CF
3
, nitro and cyano. In a more specific embodiment, R
6
is selected from nitro and halogen.
R
8
is selected from H, phenyl, (C
1
-C
6
)alkyl, R
i
, heterocycle, substituted heterocycle, —(CH
2
)
m
C(═O)N—((CH
2
)
p
R
g
)R
b
,—(CH
2
)
m
N((CH
2
)
p
R
g
)R
b
, —CH═CH—R
c
, halogen, —(CH
2
)
m
C(═O)(CH
2
)
m
R
o
, —C(═O)R
p
, —(CH
2
)
m
C(═O)O((CH
2
)
p
R
g
), —(CH
2
)
m
N((CH
2
)
p
R
g
)C(═O)R
b
, —(CH
2
)
m
OC(═O)((CH
2
)
p
R
g
), —CHOR
d
OR
e
, —CH
2
XR
f
, —S(═O)
2
N((CH
2
)
p
R
g
)R
b
, —N((CH
2
)
p
R
g
)S(═O)
2
R
b
, —S(═O)
2
N((CH
2
)
p
R
g
)R
b
, —C(═O)H, allyl and 4-hydroxybut-1-en-4-yl. In another embodiment, R
8
is selected from H, phenyl, (C
1
-C
6
)alkyl, R
i
, heterocycle, substituted heterocycle, —(CH
2
)
m
C(═O)N((CH
2
)
p
R
g
)R
b
, —(CH
2
)
m
N((CH
2
)
p
R
g
)R
b
, —CH═CH—R
c
, halogen, —C(═O)(CH
2
)
m
R
o
, —(CH
2
)
m
C(═O)O((CH
2
)
p
R
g
), —(CH
2
)
m
N((CH
2
)
p
R
g
)C(═O)R
b
, —(CH
2
)
m
OC(═O)((CH
2
)
p
R
g
), —CHOR
d
OR
e
, —CH
2
XR
f
, —S(═O)
2
N((CH
2
)
p
R
g
)R
b
, —N((CH
2
)
p
R
g
)S(═O)
2
R
b
, —C(═O)H, allyl and 4-hydroxybut-1-en-4-yl. In a more specific embodiment, R
8
is —(CH
2
)
m
C(═O)N((CH
2
)
p
R
g
)R
b
. In another more specific embodiment, R
8
is —CH═CH—R
c
.
R
3′
, R
4′
and R
5′
are independently selected from H, halogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy and halo(C
1
-C
4
)alkyl. In another embodiment, R
3′
, R
4′
and R
5′
are independently selected from H, halogen and —CF
3
.
It is important that at least one of R
5
, R
6
, R
7
, R
8
, R
3′
and R
5′
is not H; and also that R
4′
is not equal to R
7
.
R
b
is independently at each instance H, (C
1
-C
4
)alkyl or substituted (C
1
-C
4
)alkyl. In another embodiment, R
b
is H, —CH
3
or —CH
2
CH
3
.
R
c
is independently at each instance selected from H, phenyl, R
i
, heterocycle, substituted heterocycle, —CO
2
R
b
, —C(═O)NR
b
R
b
, —S(═O)
n
—R
f
, 2-hydroxyisopropyl and cyano. In anoth

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