Products of interaction of fervenulin-3-one-4-oxide with o-phenylenediamines

Full text of DOI:10.1023/A:1005250510684

Pharmaceutical Chemistry Journal
Vol. 34, No. 9, 2000
PRODUCTS OF INTERACTION OF FERVENULIN-3-ONE-4-OXIDE
WITH o-PHENYLENEDIAMINES
Yu. A. Azev and G. G. Aleksandrov2
1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 34, No. 9, pp. 39 – 41, September, 2000.
Original article submitted September 9, 1999.
NH2
Pyrimidotriazine antibiotics were reported to exhibit a
broad spectrum of pharmacological activity [1 – 3]. For ex-
ample, reumycin – a representative of this series of com-
pounds – is used as an antitumor drug [4].
R
NH
2
As is known, fervenul-3-one smoothly reacts with vari-
ous C-nucleophilic compounds with the formation of addi-
tion products with respect to the C4a node atom of the
pyrimidotriazine nucleus [5]. At the same time, the synthesis
of new analogs of these compounds is hindered because of
low availability of fervenul-3-one. Recently, one of the au-
thors described fervenul-3-one-4-N-oxide and proposed a
simple method for the synthesis of this compound from more
available fervenulin-4-oxide [6].
O
H
O
O
N
H C
N
O
H
3
H C
O
H
3
N
N
IIà, IIb
N
N
O
N
N
O
N
N
I
CH3
CH3
IIIà, IIIb
R = H (a);
R = CH (b)
IIc – IIe
3
Below we will demonstrate that fervenul-3-one-4-oxide
I) interacts with o-phenylenediamines (IIa, IIb) with the for-
mation of known diaminophenyl derivatives IIIa and IIIb [5].
It is interesting to note that 4-chloro-, 4,5-dimethyl-, and
,6-dimethoxyphenylenediamines (IIc – IIe) do not attach to
OC H5
2
O
N
(
O
H
H C
N
N
O
H C
N
O
H
3
3
N
N
D
N
N
C H OH
3
2
5
O
H
O
N
N
the pyrimidotriazine nucleus and the reaction terminates by
the formation of a colorless adduct with ethanol (IV).
Heating compound IV may lead to detachment of the ethanol
fragment with the formation of fervenulone V. Recrystalliza-
tion of compound V from ethanol again leads to the forma-
tion of adduct IV.
CH3
V
CH3
IV
NH2
4
R
NH2
3
R
1
R
1
13
2
R
The H and C NMR spectra of compounds IIIa and IIIb
IIa – IIe
1
were described in [5]. The H NMR spectra indicate that pro-
1
2
3
4
tons of the 2-NH and 4-NH groups exhibit a spin – spin cou-
pling characterized by J2,4 = 1.9 Hz. The chemical shift and
the character of splitting of the signals corresponding to these
protons were affected neither by increasing temperature of
IIa: R = R = R = R = H;
1
2
3
4
IIb: R = CH , R = R = R = H;
3
1
3
4
2
IIc: R = R = R = H, R = Cl;
1
4
2
3
IId: R = R = H, R = R = CH ;
3
3
1
4
2
3
the solution nor by adding deuterated solvents. An impor-
IIe: R = R = OCH , R = R = H.
3
tant diagnostic feature of the 4a-substituted fervenulone de-
rivatives is the presence of a tetrahedral node occupied by a
carbon atom, the signal of which is observed at ~ 60 ppm in
Taking into account the unusual structural features of the
molecules of 4a-diaminophenyl derivatives, we have studied
the crystal structure of compound IIIa by x-ray diffraction. It
was found that IIIa crystallizes in the monoclinic system with
1
3
the C NMR spectrum.
a = 12.424(6) Å,
b = 12.583(6) Å,
c = 18.242(6) Å,
1
3
Ural Research Institute of Medicinal Preparation Technology,
Yekaterinburg, Russia.
State Scientific Center for Antibiotics, Moscow, Russia.
The positions and temperature parameters of H atoms revealed by differ-
ence Fourier syntheses were not refined.
b = 93.15(3)°, V = 2847(2) Å , Z = 8, space group C2/c. The
structure was solved by direct method and refined by the
least squares method in the full-matrix anisotropic approxi-
mation to final R = 0.071. The data for 1630 reflections were
2
*
494
0
091-150X/00/3409-0494$25.00 © 2001 Plenum Publishing Corporation

Products of Interaction of Fervenulin-3-one-4-oxide with o-PhenylenediamineS
495
N(7)
N(6)
1
.410(7)
11
1
0
1
2 121.3(5)
20.5(5)
1
9
1
3
8
119.1(4)
1
.393(7)
O(2)
O(1)
N(1)
3
1
4
106.0(4)
N(2)
N(4)
125.1(4)
6
118.6(4)
2
N(3)
120.6(5)
5
N(5)
O(3)
7
Fig. 1. Bond lengths (Å) and angles (deg) in IIIa molecule.
TABLE 1. Coordinates of Nonhydrogen Atoms ( ´ 104)
Atom
x/a
y/b
z/c
Atom
x/a
y/b
z/c
O(1)
2024(3)
5431(3)
7573(3)
3766(3)
3263(3)
4157(3)
6521(3)
5858(3)
5060(3)
6484(4)
2967(4)
1923(3)
2181(3)
–133(4)
1768(4)
1061(4)
381(4)
779(2)
–462(2)
857(2)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
4918(4)
4876(4)
5612(4)
6695(4)
7387(4)
5973(5)
5272(4)
4980(4)
5380(4)
6083(4)
6362(4)
5981(4)
669(4)
1667(4)
1632(5)
285(5)
1161(3)
723(2)
O(2)
O(3)
N(1)
N(2)
N(3)
N(4)
N(5)
N(6)
N(7)
C(1)
75(3)
428(2)
748(3)
1520(2)
1569(2)
186(2)
1153(5)
–850(5)
2624(4)
3648(4)
4530(4)
4374(5)
3357(5)
2486(5)
–344(3)
1691(3)
1197(3)
974(3)
1020(4)
47(4)
1167(2)
1178(2)
2381(2)
899(2)
5577(4)
5274(4)
1629(4)
1364(3)
1988(3)
2200(3)
1808(3)

4
96
Yu. A. Azev and G. G. Aleksandrov
TABLE 2. Coefficients of the Mean-Square Plane Equations (Ax + By + Cz = D ) and Deviations of Atoms (Å) for Some Planar Fragments
of IIIa Molecule
No.
1
Plane
A
B
C
D
C(8)
C(9)
0.00
C(10)
0.00
C(11)
– 0.01 – 0.01
C(12)
C(13)
0.01
C(2)*
– 0.41
C(4)*
1.56
N(6)* N(7)* N(1)* 0.1238 0.4757 –11.3524 4.1097
–
0.01
– 0.06
0.00
– 0.70
2
3
4
N(1)
N(2)
0.12
N(3)
– 0.13 – 0.04
C(1)
C(2)
0.62
C(3)
4.1343 9.7584 9.4386 3.7046
4.5189 8.6641 11.0626 4.0468
3.9533 9.2663 10.5557 3.7056
–
0.02
N(4)
N(5) C(2) 0.04 C(4) C(5) 0.05C(3) 0.40
–
0.01 – 0.07
– 0.01
N(1)
0.12
N(2)
0.17
N(3)
– 0.05
N(4)
0.01
N(5)
C(1)
C(2)
C(4)
0.10
C(5)
– 0.01
–
– 0.11 – 0.07 – 0.08
*
Atoms not included in calculations for a given plane.
obtained with Syntex-PI diffractometer using Ni-filtered
fervenulin-3-one-4-oxide (I), 0.1 ml concentrated HCl, and
lCuK radiation (q/2q scan technique, 3 £ 2q £ 120°). The
0.087 g (0.8 mmole) o-phenylenediamine IIa was boiled in
a
coordinates of nonhydrogen atoms in IIIa are listed in Ta-
ble 1; the bond lengths and angles are indicated in Fig. 1.
The molecule of compound IIIa contains two
six-membered heterocycles (pyrimidine and triazine) sharing
the C(2) – C(3) bond and a diaminophenyl fragment con-
nected to the C(3) atom. The pentaatomic fragments of the
six-membered nitrogen-containing heterocycles are almost
flat (except for the protruding C(3) atom), forming a dihedral
angle of 7.4° (Table 2) and making angles 90.6 and 92.3°
with the plane of the benzene ring. The phenyl group is ro-
tated about C(3) – C(8) bond so that the plane of the benzene
ring is almost perpendicular to the C(3) – C(4) bond: the tor-
sion angles C(4)C(3)C(8)C(13) and C(4)C(3)C(8)C(9) are
close to 90°. The tetrahedral coordination of C(3) atom re-
sults in a considerable shift of this atom [by 0.53 Å toward
C(8)] from the median plane passing through atoms
N(1) – N(5), C(1)C(2)C(5)C(4). The C(3) – C(8) bond
length is somewhat greater as compared to the standard value
Csp3 – Csp2 = 1.50 Å [7]. The other bond lengths in the
heterocycle system are rather close to the corresponding
standard values: the single bonds Csp2 – N vary from
7
1
ml
ethanol
for
3 h.
The
precipitate
of
,2,3,5,6,7,8,8a-octahydro-6,8-dimethyl-4a-(3,4-diaminophe
nyl)pyrimido[5,4-e][1,2,4]triazine-3,5-trione was separated
by filtration. The aqueous hydrochloride solution was treated
with sodium acetate to obtain a base of the target product IIIa
(yield, 65%).
The target product IIIb was obtained using a similar proce-
dure with o-phenylenediamine IIb (yield, 75%). Compounds IIa
and IIIb are identical to the samples described in [5].
Reaction of fervenulin-3-one-4-oxide with o-phenyl-
enediamines IIc – IIe. A mixture of 1.0 mmole) fervenu-
lin-3-one-4-oxide (I), 1.0 mmole diamine, and 0.2 ml con-
centrated HCl was boiled in 5 ml ethanol for 1 h. Upon cool-
ing, the precipitate of 2,3,4,4a,5,6,7,8-octahydro-4a-ethoxy-
6
,8-dimethylpyrimido[5, 4-e][1,2,4]triazine-3,5,7-trione IV
was separated by filtration (yield, 70 – 75%). On heating to
150 – 155°C, compound IV converts into V with a quantita-
tive yield. Compounds IV and V are identical to the samples
described in [5].
1
.358(6) to 1.405(6) Å and the length of the double bond
C(2) = N(3) is 1.287(6) Å. The molecule contains six active
protons [two protons at each nitrogen in the amino groups
and one proton at each of N(1) and N(2) atoms] capable of
forming hydrogen bonds. However, only three of these pro-
tons are actually involved in H-bonds: O(1)…N(1) (1/2 – x,
REFERENCES
1
. S. M. Navashin, Yu. O. Sazykin, I. P. Fomina, et al., Targeted
Search for New Anticancer and Antiviral Compounds [in Rus-
sian], Riga (1978), pp. 140 – 163.
1
/2 – y, z ), O(1)…N(6) (–1/2 + x, –1/2 + y, z ), and
2. D. J. Brown and R. K. Lynn, Chemistry and Biology of Pyri-
dines, New York (1975), pp. 575 – 601.
3. F. Yoneda, Kagaku Ryoki, 24(12), 1077 – 1088 (1970).
N(2)…N(7) (–1/2 + x, –1/2 + y, z ). The donor – acceptor
distances are 2.878, 3.090, and 2.952 Å (with the corre-
sponding O–H and N – H distances being 1.88, 2.01, and
4
. Register of Drugs in Russia [in Russian], Inpharmchem, Moscow
1993), p. 738.
(
1
.98 Å, respectively).
5. Yu. A. Azev, I. I. Mudretsov, E. O. Sidorov, et al., Khim.-Farm.
Zh., 21(7), 829 (1987).
EXPERIMENTAL CHEMICAL PART
6
7
. Yu. A. Azev, Khim.-Farm. Zh., 31(1), 47 (1997).
. L. E. Sutton, Tables of Interatomic Distances and Configuration
Reaction of fervenulin-3-one-4-oxide with o-phenyl-
enediamines IIa and IIb. A mixture of 0.09 g (0.4 mmole)
in Molecules and Ions. (Special publ.), Chemical Society, Lon
don (1965), No. 18, p. 105.
-