Cyanoguanidine compounds

Details Cyanoguanidine compounds Cyanoguanidine compounds

2000-04-07

2001-07-03

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S163000, C546S306000, C514S353000

Reexamination Certificate

active

06255323

ABSTRACT:

BACKGROUND
Cancer remains a formidable disease with a high mortality rate in today's society. Indeed, cancer is second only to cardiovascular disease as a cause of death, killing one out of four people in developed countries.
Cancerous tumors commonly originate from normal cells which transform into malignant cells or tumors. The initial tumor growth may be slow and thus may be difficult to detect. The growth often becomes more aggressive and invasive with time, eventually spreading throughout the whole body and resulting in death.
Cancer treatment usually includes immunotherapy, surgery, radiation, hormones, and chemotherapy. In the past forty years, cancer chemotherapy has truly revolutionized the treatment of malignant tumors. Curative treatment has been discovered for many of the cancers that affect children and young adults, including acute lymphocytic leukemia, Hodgkin's disease, testicular carcinoma, and many others. However, despite being a powerful method of treating cancer, chemotherapy does suffer from a few problems. The most prominent problem is the low specificity of the anticancer agents. That is, most anticancer agents do not adequately distinguish normal cells from cancer cells. As a result, they often carry undesirable serious side effects. Such limitations of conventional chemotherapies underscore the urgent need for new anticancer agents with high antitumor activities and specificity to the cancerous cells.
SUMMARY
An aspect of this invention relates to compounds of formula (I):
R
1
is 3-pyridyl, 4-pyridyl, or quinolinyl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, or alkylsulfonyl. Each of R
2
and R
3
, independently, is hydrogen, alkyl, alkoxy, hydroxylalkyl, thioalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, or aminocarbonyl. L
1
is —X
1
—Y
1
—X
2
—. Each of X
1
and X
2
, independently, is a bond, or a C
1-6
alkylene chain optionally containing a double bond or a triple bond and further optionally substituted with alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl. Y
1
is —O—, —S—, —SO—, —SO
2
—, —N(R
a
)—, —CO—, —N(R
a
)—CO—, —CO—N(R
a
)—, —N(R
a
)—CO—CO—, —N(R
a
)—SO
2
—, —SO
2
—N(R
a
)—, —N(R
a
)—CO—O—, —O—CO—N(R
a
)—, —N(R
a
)—CO—N(R
b
)—, —N(R
a
)—CS—N(R
b
)—CO—, —CO—, —CO —N(R
a
)—CS—N(R
b
)—, —O—CO—, —CO—O—, —O—SO
2
—, —SO
2
—O—, —O—S—CO—N(R
a
)—, —N(R
a
)—CO—S—O—, —O—CO—O—, —CO—N(R
a
)—S—CO—N(R
b
)—, —N(R
a
)—CO—S—N(R
b
)—CO—, or a bond. Each of R
a
and R
b
, independently, is hydrogen, alkyl, alkoxy, hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. R
4
is aryl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, oxo, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, or alkylsulfonyl. L
2
is —X
3
—Y
2
—X
4
— in which each of X
3
and X
4
, independently, is a bond, or a C
1-6
alkylene chain optionally containing a double bond or a triple bond and further optionally substituted with alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl. Y
2
is —O—, —S—, —SO—, —SO
2
—, —N(R
c
)—, —CO—, —N(R
c
)—CO—, —CO—N(R
c
)—, —N(R
c
)—CO—CO—, —N(R
c
)—SO
2
—, —SO
2
—N(R
c
)—, —N(R
c
)—CO—O—, —O—CO—N(R
c
)—, —N(R
c
)—CO—N(R
d
)—, —N(R
c
)—CS—N(R
d
)—CO—, —CO—N(R
c
)—CS—N(R
d
)—, —O——CO—, —CO—O—, —O—SO
2
—, —SO
2
—O—, —O—S—CO—N(R
c
)—, —N(R
c
)—CO—S—O—, —O—CO—O—, —CO—N(R
c
)—S—CO—N(R
d
)—, —N(R
c
)—CO—S—N(R
d
)—CO— or a bond. Each of R
c
and R
d
, independently, is hydrogen, alkyl, alkoxy, hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. R
5
is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxyalkyl aryloxycarbonylalkyl, alkylcarbonyl, formyl, oxo, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, aminocarbonyloxy, or alkyloxycarbonylamino. Note that each of Y
1
and Y
2
is not a bond simultaneously, and that when neither Y
1
nor Y
2
is a bond, at least one of X
2
, R
4
, and X
3
is not a bond.
Another aspect of this invention relates to cyanoguanidine compounds having the formula (I) as depicted above. R
1
is 3-pyridyl, 4-pyridyl, or quinolinyl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, or alkylsulfonyl. Each of R
2
and R
3
, independently, is hydrogen, alkyl, alkoxy, hydroxylalkyl, thioalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, or aminocarbonyl. L
1
is —X
1
—Y
1
—X
2
—. Each of X
1
and X
2
, independently, is a bond, or a C
1-6
alkylene chain optionally containing a double bond or a triple bond and further optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl. Y
1
is —O—, —S—, —SO—, —SO
2
—, —N(R
a
)—, —CO—, —N(R
a
)—CO—, —CO—N(R
a
)—, —N(R
a
)—CO—CO—, —N(R
a
)—SO
2
—, —SO
2
—N(R
a
)—, —N(R
a
)—CO—O—, —O—CO—N(R
a
)—, —N(R
a
)—CO—N(R
b
)—, —N(R
a
)—CS—N(R
b
)—CO—, —CO—N(R
a
)—CS—N(R
b
)—, —O—CO—, —CO—O—, —O—SO
2
—, —SO
2
—O—, —O—S—CO—N(R
a
)—, —N(R
a
)—CO—S—O—,—O—CO—O—, —CO—N(R
a
)—S—CO—N(R
b
)—, N(R
a
)—CO—S—N(R
b
)—CO—, or a bond. Each of R
a
and R
b
, independently, is hydrogen, alkyl, alkoxy, hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. R
4
is a bond, or cycloalkyl, cycloalkenyl, or aryl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, oxo, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, or alkylsulfonyl. L
2
is —X
3
—Y
2
—X
4
—. Each of X
3
and X
4
, independently, is a bond, or a C
1-6
alkylene chain optionally containing a double bond or a triple bond and further optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl; and Y
2
is —O—, —S—, —SO—, —SO
2
—, —N(R
c
)—, —CO—, —N

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