Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-10-05
2001-09-11
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S198000, C544S208000, C544S209000, C544S210000, C514S245000
Reexamination Certificate
active
06288228
ABSTRACT:
TECHNICAL FIELD
The present invention relates to substituted triazines which are useful for treating pathological states which arise from or are exacerbated by angiogenesis, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting angiogenesis in a mammal.
BACKGROUND OF THE INVENTION
Angiogenesis, the process by which new blood vessels are formed, is essential for normal body activities including reproduction, development and wound repair. Although the process is not completely understood, it is believed to involve a complex interplay of molecules which regulate the growth of endothelial cells (the primary cells of capillary blood vessels). Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or, in some cases, decades. When necessary (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a 5 day period (Folkman, J. and Shing, Y.,
The Journal of Biological Chemistry
, 267(16), 10931-10934, (1992) and Folkman, J. and Klagsbrun, M.,
Science
, 235, 442-447 (1987).
Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as angiogenic diseases) are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition. For example, ocular neovascularization has been implicated as the most common cause of blindness and dominates approximately twenty eye diseases. In certain existing conditions, such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also dependent on angiogenesis (Folkman, J.,
Cancer Research
, 46, 467-473 (1986), Folkman, J.,
Journal of the National Cancer Institute
, 82, 4-6 (1989). It has been shown, for example, that tumors which enlarge to greater than 2 mm must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as liver, lung or bone (Weidner, N., et al.,
The New England Journal of Medicine
, 324(1), 1-8 (1991).
Several angiogenesis inhibitors are currently under development for use in treating angiogenic diseases (Gasparini, G. and Harris, A. L.,
J. Clin. Oncol
., 13(3): 765-782, 1995), but there are disadvantages associated with these compounds. Suramin, for example, is a potent angiogenesis inhibitor but causes severe systemic toxicity in humans at doses required for antitumor activity. Compounds such as retinoids, interferons and antiestrogens are relatively safe for human use but have weak antiangiogenic effects. Irsogladine, an anti-tumor drug with low toxicity, has only weak anti-angiogenic effects. Thus there is still a need for compounds useful in treating angiogenic diseases in mammals.
SUMMARY OF THE INVENTION
In one embodiment of the present invention are disclosed compounds having Formula I:
or pharmaceutically acceptable salts or prodrugs thereof, wherein
R
1
, R
2
, R
3
, and R
4
are independently selected from the group consisting of hydrogen, C
1
-C
20
alkyl, and C
1
-C
20
alkanoyl; or
R
1
and R
2
together with the nitrogen atom to which they are attached form a ring independently selected from the group consisting of morpholine, piperidine, piperazine, and pyrrolidine; or
R
3
and R
4
together with the nitrogen atom to which they are attached form a ring independently selected from the group consisting of morpholine, piperidine, piperazine, and pyrrolidine;
A is selected from the group consisting of heterocycle, (heterocycle)-C
1
-C
20
-alkyl, C
3
-C
10
cycloalkyl, C
6
-C
15
spiroalkyl, and —B—L—Y;
B and Y are independently aryl, C
3
-C
10
cycloalkyl, C
4
-C
10
cycloalkenyl, heterocycle, or C
6
-C
15
spiroalkyl;
L is a covalent bond, —C(═W)—, C
1
-C
20
alkylene, —NR
5
—, —NR
6
C(X)NR
7
—, C
2
-C
20
alkynylene, C
2
-C
20
alkenylene, —O—, —S(O)
t
—, —NR
6
C(X)—, —C(X)NR
6
—, —NR
6
SO
2
NR
7
—, —NR
6
SO
2
—, —SO
2
NR
6
—, or —O(CR
1
R
2
)—;
R
5
is hydrogen, C
1
-C
20
alkyl, C
1
-C
20
alkanoyl, and C
1
-C
20
arylalkyl;
R
6
and R
7
are independently hydrogen, C
1
-C
20
alkyl, and aryl-C
1
-C
20
-alkyl;
R
1
and R
2
are previously defined;
W is O, S, or (═N—O—R
6
);
X is O or S;
t is 0-2;
each L is shown with its left end attached to B and its right end attached to Y; and
at each occurence, aryl, cycloalkyl, cycloalkenyl, heterocycle, spiroalkyl, alkylene, and (heterocycle)alkyl may be optionally substituted with 1-3 substituents independently selected from C
1
-C
20
alkoxy, C
1
-C
20
alkyl, amino, aryl, azido, cyano, halo, C
1
-C
20
haloalkyl, heterocycle, nitro, or R
10
and R
11
wherein R
10
and R
11
together are
wherein A and D are independently oxygen or S(O)
t
and n is 2-3, with the proviso that when B and Y are unsubstituted phenyl and L is a covalent bond, then at least one of R
1
, R
2
, R
3
, and R
4
is other than hydrogen, and with the proviso that when L is a covalent bond and one of B or Y is unsubstituted imidazole and the other is unsubstituted phenyl, then at least one of R
1
, R
2
, R
3
, and R
4
is other than hydrogen.
In another embodiment of the invention are disclosed methods of treating diseases comprising administering an effective amount of a compound having Formula I.
In yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds of Formula I.
Compounds of this invention include, but are not limited to, a compound selected from the group consisting of:
6-[1-(diphenylmethyl)-3-azetidinyl]-1,3,5-triazine-2,4-diamine,
6-(1-phenyl-4-piperidinyl)-1,3,5-triazine-2,4-diamine,
trans-6-(4-phenylcyclohexyl)-1,3,5-triazine-2,4-diamine,
6-[3-(1H-pyrrol-1-yl)phenyl]-1,3,5-triazine-2,4-diamine,
cis/trans-6-(3-phenylcyclobutyl)-1,3,5-triazine-2,4-diamine,
6-[1,1′-biphenyl]-2-yl-1,3,5-triazine-2,4-diamine,
6-(4′-nitro[1,1′-biphenyl]-4-yl)-1,3,5-triazine-2,4-diamine,
6-[4-(4-pentylcyclohexyl)phenyl]-1,3,5-triazine-2,4-diamine,
6-(4-phenoxyphenyl)-1,3,5-triazine-2,4-diamine,
N-cyclohexyl-N′-[4-(4,6-diamino-1,3,5-triazin-2-yl)phenyl]urea,
(4,6-diamino-1,3,5-triazine-2-yl)phenylmethenone,
N-[4-(4,6-diamino-1,3,5-triazin-2-yl)phenyl]-N′-phenyl urea,
6-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-1,3,5-triazine-2,4-diamine,
6-(4′-pentyl[1,1′-biphenyl]-4-yl)-1,3,5-triazine-2,4-diamine,
6-[4′-(pentyloxy)[1,1′-biphenyl]-4-yl]-1,3,5-triazine-2,4-diamine,
6-(6-methoxy-2-benzothiazolyl)-1,3,5-triazine-2,4-diamine,
6-(4′-amino[1,1′-biphenyl]-4-yl)-1,3,5-triazine-2,4-diamine,
6-[4-(5-oxazolyl)phenyl]-1,3,5-triazine-2,4-diamine,
6-[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]-1,3,5-triazine-2,4-diamine,
4′-(4,6-diamino-1,3,5-triazine-2-yl)[1,1′-biphenyl]-4-carbonitrile,
6-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,3,5-triazine-2,4-diamine,
6-(4′-fluoro[1,1′-biphenyl]-4-yl)-1,3,5-triazine-2,4-diamine
N-[4-(4,6-diamino-1,3,5-triazin-2-yl)phenyl]benzenesulfonamide,
6-[1-([1,1′-biphenyl]-4-yl)-4-piperidinyl]-1,3,5-triazine-2,4-diamine,
N-[4-(4,6-diamino-1,3,5-triazin-2-yl)phenyl]-2naphthalenesulfonamide,
2,5-dichloro-N-[4-(4,6-diamino-1,3,5-triazin-2-yl)phenyl]benzenesulfonamide,
6-(1-phenylcyclohexyl)-1,3,5-triazine-2,4-diamine,
6-[1-(4-methoxyphenyl)-4-piperidinyl]-1,3,5-triazine-2,4-diamine,
6-[2-[4-(trifluoromethyl)phenyl]-4-thiazolyl]-1,3,5-triazi
Davidson Donald J.
Henkin Jack
McCroskey Richard W.
Sheppard George S.
Woods Keith W.
Abbott Laboratories
Balasubramanian Venkataraman
Donner B. Gregory
Shah Mukund J.
Steele Gregory W.
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