(Gem-heterocyclodimethanamine-n,n′)platinum complexes

Details (Gem-heterocyclodimethanamine-n,n′)platinum complexes (Gem-heterocyclodimethanamine-n,n′)platinum complexes

1989-05-26

2001-08-28

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S245000, C546S246000, C548S566000, C549S074000, C549S426000, C549S492000

Reexamination Certificate

active

06281365

ABSTRACT:

SUMMARY OF THE INVENTION
This invention is concerned with new organic compounds of the formulae:
where n and n′ are integers 0-3; A is selected from the group consisting of O,
N-alkyl(C
1
-C
5
) and NCO-alkyl-(C
1
-C
5
); L and L′ are selected from the group consisting of halide, nitrate, sulfate, and a monobasic carboxylate such as acetate, hydroxy acetate and propionate; or L and L′ taken together may be a dibasic carboxylate selected from the group consisting of:
or L and L′ taken together may be a tribasic carboxylate selected from the group consisting of
taken together is ascorbic acid and X is selected from the group consisting of halogen and hydroxy.
The compounds of this invention may be prepared according to the following reaction schemes:
According to Flowchart A tribromopentaerythritol (1) is reacted with potassium hydroxide in methanol at reflux temperature, giving 3,3-bis(bromomethyl) oxetane (2) which is reacted with ammonia in methanol in a sealed condition, then with sodium methoxide and finally hydrochloric acid, giving 3,3-oxetanedimethanamine, dihydrochloride (3). Reaction of (3) with sodium acetate and potassium tetrachloroplatinate in water gives the product (4).
Product (4) may then be reacted with silver nitrate in water, giving the nitrate derivative (5) which is then reacted with a dibasic organic acid HL—L′H in the presence of two equivalents of sodium hydroxide giving the products (6).
According to Flowchart B dichloroethyl ether (7) and malononitrile (8) are reacted with potassium carbonate in acetonitrile at reflux, giving tetrahydro-4H-pyran-4,4-dicarbonitrile (9) which is then reacted with 1N borane in tetrahydrofuran followed by treatment with hydrochloric acid, giving tetrahydro-4H-pyran-4,4-dimethanamine dihydrochloride (10) which is then reacted with sodium acetate and potassium tetrachloroplatinate in water, giving the product (11).
In Flowchart C, compound 13 is derived by treating 12 with chlorine gas in dilute hydrochloric acid.
In Flowchart D, compound 15 is derived by treating 14 with hydrogen peroxide.
The novel completed compounds of this invention possess the property of inhibiting the growth of tumors in mammals as established by the following tests.
Lymphocytic Leukemia P388 Test
The animals used were BDF/1 mice, all of one sex, weighing a minimum of 18 g and all within a 3 g weight range. There were 5 or 6 animals per test group. The tumor transplant was by intraperitoneal injection of 0.5 ml of dilute ascitic fluid containing 10
6
cells of lymphocytic leukemia P388. The test compounds were administered intraperitoneally on days 1, 5 and 9 relative to tumor inocultion, at various doses. The animals were weighed and the survivors recorded on a regular basis for 30 days. The median survival time and the ratio of survival time for treated (T)/control (C) animals were calculated. The positive control compound was Cisplatin. The results of this test with representative compounds of this invention appear in Table I.
TABLE I
Lymphocytic Leukemia P388 Test
Median
Dose
Survival
T/C × 100
Compound
(mg/kg)
(Days)
(%)
dichloro(3,3-oxetanedimethan-
12.5
21
193
amine-
N
,
N
′)platinum
6.2
18
165
3.1
15
138
Control
—
10.9
—
Cisplatin
1
20.5
188
0.25
15
138
0.06
11.5
106
(3,3-oxetanedimethanamine-
50
25
253
N
,
N
′)[propanedioato(2−)-0
1
,0
3
]-
25
21
212
platinum
12.5
19
192
6.2
12.5
126
3.1
13.5
136
1.5
11.5
116
Control
—
9.9
—
Cisplatin
1
20
202
0.25
12.5
126
0.06
11
111
bis(acetato-O)(3,3-oxetane-
12.5
21.5
217
dimethanamine-
N
,
N
′)platinum
6.2
17
172
3.1
11.5
116
1.5
11
111
Control
—
9.9
—
Cisplatin
1
20
202
0.25
12.5
126
0.06
11
111
[1,1,2-ethanetricarboxylato(2−)-
50
18.5
162
0
1
,0
1
](3,3-oxetanedimethanamine-
25
16
140
N
,
N
′]platinum
12.5
16.5
145
6.2
13
114
3.1
12.5
110
1.5
12
105
Control
—
11.4
—
Cisplatin
1
16
140
0.25
11
97
bis(butanoato-O)(3,3-oxetane-
25
24
218
dimethanamine-
N
,
N
′)platinum
12.5
19
173
6.2
18
164
3.1
15
136
Control
—
11
—
Cisplatin
1
14.5
132
0.25
13.5
123
[3,4-dihydroxy-3-cyclobutene-
25
12.5
114
1,2-diaonato(2−)-0
3
,0
4
](3,3-oxe-
12.5
21.5
195
tanedimethanamine-
N
,
N
′)platinum
6.2
15.5
141
3.1
13
118
Control
—
11
—
Cisplatin
1
14.5
132
0.25
13.5
123
[1,1-cyclobutanedicarboxylato-
50
24
218
(2−)-0
1
,0
1
](3,3-oxetanedi-
25
20
182
methanamine-
N
,
N
′)platinum
12.5
16.5
150
6.2
11.5
105
3.1
12
109
Control
—
11
—
Cisplatin
1
14.5
132
0.25
13.5
123
(3,3-oxetanedimethanamine-
N
,
N
′)-
12.5
20.5
186
[[2,2′-oxybis[acetato]](2−)-
6.2
12.5
114
0
1
,0
1
]platinum
3.1
13
118
Control
—
11
—
Cisplatin
1
14.5
132
0.25
13.5
123
(3,3-oxetanedimethanamine-
100
17
155
N
,
N
′,)[propanedioato(2−)-0
1
,0
3
]-
50
21.5
195
platinum
25
14.5
132
12.5
14
127
6.2
12
109
3.1
12
109
Control
—
11
—
Cisplatin
1
14.5
132
0.25
13.5
123
(3,3-oxetanedimethanamine-
100
10.5
105
N
,
N
′,)[pentanedioato(2−)-0
1
,0
5
]-
50
18.5
185
platinum
25
16
160
12.5
14
140
6.2
13
130
3.1
12
120
Control
—
10
—
Cisplatin
1.25
25.5
255
0.62
20.5
205
Melanotic Melanoma B16
The animals used were C57BC/6 mice, all of the same sex, weighing a minimum of 17 g and all within a 3 g weight range. There were 10 animals per test group. A 1 g portion of melanotic melanoma B
16
tumor was homogenized in 10 ml of cold balanced salt solution and a 0.5 ml aliquot of the homogenate was implanted intraperitoneally into each of the test mice. The test compounds were administered intraperitoneally on days 1 through 9, relative to tumor inoculation, at various doses. The animals were weighed and survivors recorded on a regular basis for 60 days. The median survival time for treated (T)/control (C) animals were calculated. The positive control compound was Cisplatin. The results of this test appear in Table II.
TABLE II
Melanotic Melanoma B16 Test
Median
Dose
Survival
T/C × 100
Compound
(mg/kg)
(Days)
(%)
(3,3-oxetanedimethanamine-
25
30
176
N
,
N
′)[propanedioato(2−)-0
1
,0
3
]-
12
30
176
platinum
6
27.5
162
Control
—
17
—
Cisplatin
0.5
22.5
132
0.25
25
147
bis(acetato-0)(3,3-oxetane-
3
23
135
dimethanamine-
N
,
N
′)platinum
1.5
19
112
0.8
24.5
144
Control
—
17
—
Cisplatin
0.5
22.5
132
0.25
25
147
bis(butanoato-0)(3,3-oxetane-
3
26
153
dimethanamine-
N
,
N
′) platinum
Control
—
17
—
Cisplatin
0.5
22.5
132
0.25
25
147
[1,1-cyclobutanedicarboxylato-
12
20.5
121
(2−)-0
1
,0
1
](3,3-oxetanedimethan-
6
26
153
amine-
N
,
N
′)platinum
3
20
118
1.5
20.5
121
Control
—
17
—
Cisplatin
0.5
22.5
132
0.25
25
147
dichloro(3,3-oxetanedimethan-
1.5
26
137
amine-
N
,
N
′)platinum
0.8
21.5
113
Control
—
19
—
Cisplatin
0.4
29.5
155
0.2
25.5
134
0.1
20.5
108
Colon 26 Adenocarcinoma Test
The animals used were Balb/C mice all of one sex, weighing a minimum of 17 g and all within a 3 g weight range. There were 5 or 6 mice per test group with three groups of 5 or 6 animals used as untreated controls for each test. The tumor implant was by intraperitoneal (or subcutaneous) injection of 0.5 ml of a 2% Colon 26 tumor brei in Eagle's MEM medium containing antibiotics. The test compounds were administered intraperitoneally on days 1, 5 and 9 (relative to tumor implant doses). The mice were weighed and deaths recorded on a regular basis for 30 days. The median survival times and the ratio of survival time for treated (T)/control (C) animals were calculated. The positive control compound was Cisplatin. The results of this test on representative compounds of this invention appear in Table III.
TABLE III
Colon 26 Adenocarcinoma Test
Median
Dose
Survival
T/C × 100
Compound
(mg/kg)
(Days)
(%)
(3,3-oxetanedimethanamine-
N
,
N
′)-
50
27.5
172
[propanedioato(2−)0
1
,0
3
]platinum
25
30
188
12
26
163
6
21
131
Control
—
16
—
Cisplatin
1
25
156
0.5
18
113
0.25
18
113
bis(acetato-0)(3,3-oxetanedim-
12
19.5
118
ethanamine-
N
,
N
′)platinum
6
22.5
136
3
19
115
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