Tetrahydroisoquinoline analogs as modulators of chemokine...

Details Tetrahydroisoquinoline analogs as modulators of chemokine... Tetrahydroisoquinoline analogs as modulators of chemokine...

2002-11-07

2003-11-18

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S307000, C514S412000, C540S594000, C546S139000, C548S492000

Reexamination Certificate

active

06649606

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to tetrahydroisoquinoline analogs which are chemokine receptor modulators, and to methods for treating inflammatory diseases such as asthma, constrictive obstructive pulmonary disease (COPD), inflammatory bowel syndrome, allergic diseases, psoriasis, and arthritis.
BACKGROUND OF THE INVENTION
Chemokines are chemotactic cytokines that are released by a variety of cell types to attract and activate other cell types such as macrophages, T and B lymphocytes, basophils, neutrophils, mast cells, and eosinophils. They are broadly classified as C, CC, CXC, or CX
3
C chemokines dependent upon their amino acid sequence. For example, in CC chemokines the first two cysteines in the sequence are adjacent, while in CXC chemokines these cysteines are separated by one or more amino acid residues.
Chemokines bind to specific cell-surface receptors that belong to the family of G protein coupled seven transmembrane domain proteins. Upon ligand binding, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in calcium flux, changes in cell morphology, upregulated expression of cellular adhesion molecules, degranulation, and promotion of cell migration.
Chemokine receptors are implicated as key mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma, COPD, and allergic diseases; rheumatoid arthritis, atherosclerosis, and psoriasis; solid organ transplant rejection, osteoarthritis, and inflammatory bowel syndrome. To illustrate, the CCR3 receptor appears to be a key mediator in attracting eosinophils and Th2 polarized CD4+ T cells to sites of inflammation in the lung, and also plays an important role in activating these cells. The ligands that bind CCR3 can induce a rapid increase in the intracellular calcium ion concentration (calcium flux), degranulation, increased expression of cell adhesion molecules, and cell migration. Agents that could modulate activity of the CCR3 receptor would have utility in the treatment of disorders and diseases in which eosinophils or Th2 CD4+ T cells appear to play a prominent role. A similar utility has been demonstrated using antibodies specific for the murine CCR3 chemokine receptor. Such antibodies can be used to deplete eosinophils in in vivo inflammatory models in mice.
Several mammalian viruses such as, but not limited to, cytomegaloviruses, herpesviruses, and poxviruses have been shown to express proteins with the binding properties of chemokine receptors in infected cells. In addition, several chemokine receptors have been demonstrated to act as cellular receptors for a variety of viruses, as well as some bacteria, and parasites. Thus, agents which modulate chemokine receptor activity may also have utility in infectious diseases. Examples would include, but not be limited to, blocking of HIV infection of CCR3, CCR5, or CXCR4 expressing cells; or in the prevention of manipulation of the immune response by viruses such as cytomegaloviruses that use a chemokine receptor for cellular infection.
SUMMARY OF THE INVENTION
In accordance with the present invention tetrahydroisoquinoline analogs are provided which are chemokine receptor modulators (especially modulators of CCR3) and have the structure
wherein R
1
is alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, arylcycloalkyl cycloalkylalkyl, cycloalkyl-alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylalkoxyalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, or heteroarylalkyl, and where these groups may be optionally substituted with 1 to 3 J1 groups which may be the same or different and the R
1
aryls may be further optionally substituted with 1 to 5 halogens, aryl, —CF
3
, —OCF
3
, 1-3 hydroxyls, 2 of which substituents where possible, may be joined by a methylene bridge;
R
2
is H, alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkylalkoxy, heteroaryl, or heteroarylalkyl, and where these groups may be optionally substituted with a J1a group and the aryls may be further optionally substituted with 1 to 5 halogens, —CF
3
, —OCF
3
, or 1-3 hydroxyls;
X is a bond, —O—, or —NR
4
—;
R
3
and R
3a
are the same or different and are independently selected from H, alkoxy, halogen, —CF
3
, alkyl, or aryl;
R
4
, R
4a
, R
4b
, R
4c
, R
4d
, R
4e
, R
4f
, R
4g
, R
4h
, R
4i
, R
4j
, R
4k
, and R
4l
are the same or different and are independently selected from H, C
1
-C
6
alkyl, or aryl;
m, n and p are the same or different and are independently 0 or 1;
Y is a bond,
where x and y are the same or different and are independently 0 to 3 and z is 1 to 3;
R
5
and R
5a
are the same or different and are independently H, alkyl, alkoxy, hydroxyl, halogen, —CF
3
, aryl, alkaryl, and cycloalkyl; or R
5
and R
5a
can be independently joined to one or both of R
6
and R
7
groups (see X
2
) to form an alkylene bridge of 1 to 5 carbon atoms; or R
5
and R
5a
can be joined together to form a ring of from 4-7 carbon atoms;
X
2
is aryl optionally substituted with 1 to 3 J1 groups which may be the same or different, cycloheteroalkyl optionally substituted with 1 to 3 J1 groups which may be the same or different, pyridinyl optionally substituted with 1 to 3 J1 groups which may be the same or different,
R
6
and R
7
are the same or different and are independently H or alkyl where the alkyl may be optionally substituted with halogen, 1 to 3 hydroxys, 1 to 3 C
1
-C
10
alkanoyloxy, 1 to 3 C
1
-C
6
alkoxy, phenyl, phenoxy, or C
1
-
6
alkoxycarbonyl; or R
6
and R
7
can together form —(CH
2
)
t
X
5
(CH
2
)
u
— where X
5
is —C(R
4c
)(R
4d
)—, —C(R
4c
)(NT
1
T
1a
)—, —O— or —N(R
4e
)—, t and u are the same or different and are independently 0 to 4;
R
8
is H, C
1
-C
6
alkyl, —CF
3
, alkaryl, or aryl, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxys, 1 to 3 C
1
-C
10
alkanoyloxy, 1 to 3 C
1
-C
6
alkoxy, phenyl, phenoxy or C
1
-C
6
alkoxycarbonyl;
R
9
and R
10
are the same or different and are independently H, C
1
-C
6
alkyl, —CF
3
, alkaryl, aryl, or halogen, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxys, 1 to 3 C
1
-C
10
alkanoyloxy, 1 to 3 C
1-
6
alkoxy, phenyl, phenoxy or C
1
-C
6
alkoxycarbonyl;
X
3
is a bond, —C(O)—, —C(O)O—, —C(O)N(R
4f
)—, —S(O)
2
—, or —S(O)
2
N(R
4f
)—;
X
4
is a bond, —O—, —OC(O)—, —N(R
4g
)—, —N(R
4g
)C(O)—, —N(R
4g
)C(O)N(R
4h
)—, —N(R
4g
)S(O)
2
—, —N(R
4g
)S(O)
2
N(R
4h
), —OC(O)N(R
4g
)—, —C(O)—, —C(O)N(R
4g
)—, —S—, —S(O)
2
—, or —S(O)
2
N(R
4g
)—;
J1 and J1a are the same or different and are independently nitro, halogen, hydroxyl, —OCF
1
, —CF
3
, alkyl, aryl, —(CH
2
)
v
CN, —(CH
2
)
v
N(T
1a
)C(O)T
1
, —(CH
2
)
v
N(T
1a
)C(O)OT
1
, —(CH
2
)
v
N(T
1a
)C(O)N(T
1a
)T
1
, —(CH
2
)
v
NT
1
(T
1a
) —(CH
2
)
v
N(T
1a
)SO
2
T
1
, —(CH
2
)
v
C(O)N(T
1a
)T
1
, —(CH
2
)
v
C(O)OT
1
, —(CH
2
)
v
OC(O)OT
1
, —(CH
2
)
v
OC(O)T
1
, —(CH
2
)
v
OC(O)OT
1
, —(CH
2
)
v
OC(O)T
1
, —(CH
2
)
v
OC(O)N(T
1a
)T
1
, —(CH
2
)
v
N(T
1a
)SO
2
N(T
1b
)T
1
, —(CH
2
)
v
OT
1
, —(CH
2
)
v
SO
2
T
1
, —(CH
2
)
v
SO
2
N(T
1a
)T
1
, —(CH
2
)
v
C(O)T
1
, —(CH
2
)
v
CH(OH)T
1
, or heteroaryl as defined below, with v being 0-3;
T
1
, T
1a
and T
1b
are the same or different and are independently H, alkyl, alkenyl, alkynyl, lower alkythioalkyl, alkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, or cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, —C(O)NR
4i
R
4j
, —NR
4i
C(O)R
4j
, —CN, —N(R
4i
)SO
2
R
11
, —OC(O)R
4i
, —SO
2
NR
4i
R
4j
, —SOR
11
, —SO
2
R
11
, alkoxy, —COOH, cycloheteroalkyl, or —C(O)OR
11
; with the proviso that T
1
cannot be hydrogen when it is connected to sulfur, as in SO
2
T
1
; or T
1
and T
1a
or T
1
and T
1b
can together form —(CH
2
)
r
X
5a
(CH
2
)
s
— where X
5a
is —C(R
4k
)(R
4l
)—, —C(R
4k
)(NT
1
T
1a
)—, —O— or —N(R
4k
)—, r and s are the same or different an

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