Efficient synthesis and biological evaluation of 1,2,9-trisubstituted 1,9-dihydro-6H-purin-6-ones

Article abstract of DOI:10.1016/j.bmcl.2008.12.007

The carbodiimides 4, obtained from aza-Wittig reactions of iminophosphorane 3 with aromatic isocyanates, reacted with amines in the presence of a catalytic amount of RO^-Na⁺ to give the 1,2,9-trisubstituted 1,9-dihydro-6H-purin-6-ones

Full text of DOI:10.1016/j.bmcl.2008.12.007

Bioorganic & Medicinal Chemistry Letters 19 (2009) 831–833
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Efficient synthesis and biological evaluation of 1,2,9-trisubstituted
1,9-dihydro-6H-purin-6-ones
b,
a
Nian-Yu Huang a, Yong-Ju Liang b, Ming-Wu Ding a, , Li-Wu Fu , Hong-Wu He
*
*
a Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan, Hubei 430079, PR China
b Cancer Institute Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The carbodiimides 4, obtained from aza-Wittig reactions of iminophosphorane 3 with aromatic isocya-
nates, reacted with amines in the presence of a catalytic amount of ROÀNa+ to give the 1,2,9-trisubsti-
Received 23 October 2008
Revised 27 November 2008
Accepted 3 December 2008
Available online 7 December 2008
tuted 1,9-dihydro-6H-purin-6-ones
various cancer cells. For example, compounds 6b showed the best inhibition activities against KB, HepG2
and OVCAR3 with IC50 9.5, 20.4 and 10.0 M.
6 in good yields. Compound 6 exhibited cytotoxicity against
l
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
1,9-Dihydro-purin-6-one
Iminophosphorane
Carbodiimide
Aza-Wittig reaction
Antitumor activity
1,9-Dihydro-6H-purin-6-ones, which are also named as gua-
nines, are of great importances because of their fundamental role
in nucleic acid chemistry and cellular biochemistry. Some deriva-
tives of them have shown remarkable biological properties such
as antitumor and antiviral activities,1–5 whereas others were eval-
uated as corticotropin releasing factor-1 (CRF1) receptor antago-
nists or as DPP-IV inhibitors.6,7 The methods described for the
preparation of this ring system either involves reaction of properly
substituted diaminopyrimidines with aldehyde or acid anhydride,
or reaction of aminoimidazolecarbohydrazides with orthoesters,
or cyclization of 4-acetamido-5-ethoxycarbonylimidazoles with
amine in the presence of phosphorus pentoxide.8–13 However,
these methods often require relatively harsh acid, dehydrating
conditions or heating at high temperature, and there is no report
of a generally useful synthesis of 2-amino substituted 1,9-dihy-
dro-6H-purin-6-ones starting from easily accessible 5-amino-4-
ethoxycarbonylimidazoles.
The 5-aminoimidazole 2, obtained by reaction of ethyl 2-amino-
2-cyanoacetate 1 with triethyl orthoformate and phenylamine,20
was converted easily to iminophosphorane 3 via reaction with tri-
phenylphosphine, hexachloroethane and triethylamine in good
yield.21
COOEt
COOEt
CN
N
i) HC(OEt)3
ii) PhNH2
H2N
NH2
N
Ph
1
2
COOEt
N
Ph3P, C2Cl6
NEt3
N
PPh3
N
Recently, we have been interested in the synthesis of quinazoli-
nones, thienopyrimidinones and imidazolinones via aza-Wittig
reaction, with the aim of evaluating their biological activities.14–
Ph
3
19
Here, we wish to reported a new efficient synthesis and antitu-
mor activities of 1,2,9-trisubstituted-1,9-dihydro-6H-purin-6-ones
6 from easily accessible iminophosphorane 3.
Iminophosphorane 3 reacted with aromatic isocyanates to give car-
bodiimides 4, which were allowed to react with secondary amines
to provide guanidine intermediates 5. In the presence of catalytic
amount of sodium ethoxide, 5 were converted easily to 2-dialkyla-
mino-1,9-dihydro-6H-purin-6-ones 6 in satisfactory yields at room
temperature.22 It is noteworthy that the isolated yield of 6 was good
* Corresponding authors. Tel.: +86 27 67867958; fax: +86 27 67862041.
E-mail addresses: ding5229@yahoo.com.cn (M.-W. Ding), fulw@mail.sysu.edu.cn
(L.-W. Fu).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.007

832
N.-Y. Huang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 831–833
even when NR1R2 is bulky di-iso-propylamino group. The results are
listed in Table 1.
Table 2
In vitro cytotoxicity (IC50
a
, lM) of 1,9-dihydro-6H-purin-6-ones 6
Compound
KB
HepG2
OVCAR3
6a
6b
6c
6d
6e
6f
6g
6h
6i
83.8
9.5
>100
20.4
>100
10.0
COOEt
COOEt
PPh3
HNR1R2
N
N
ArNCO
53.5
10.6
72.8
>100
>100
>100
37.7
34.3
>100
>100
>100
>100
>100
>100
77.6
>100
>100
>100
>100
>100
>100
94.8
N
C
NAr
O
N
N
N
Ph
Ph
3
4
Ar
COOEt
6j
62.1
46.7
N
N
Base
a
NHAr
NR1R2
N
IC50 is the concentration of compound required to inhibit the cell growth by 50%
compared to an untreated control.
NR1R2
N
N
N
N
Ph
Ph
tion of functionalized carbodiimides with various amines. The pre-
liminary investigation on the biological activities of 6 shows that
some of them exhibited cytotoxicity against various cancer cells.
6
5
The reaction of carbodiimides 4 with primary amine R1R2NH
(R1 = H) in the presence of EtONa provided only 2-alkylamino-1,9-
dihydro-6H-purin-6-ones 6, one of the possible regioisomers.22
We obtained only 6 from the reaction mixture after recrystalliza-
tion; the other isomer was not found by 1H NMR analysis of the
reaction mixture. Whenever the primary amine used is small or
bulky, the cyclization was achieved all in good yields with similar
selectivity. The results are also listed in Table 1. The solitary forma-
tion of 6 can be rationalized in terms of a base catalytic cyclization
of the guanidine intermediate 5 to give 6 across the arylamino
group rather than the alkylamino one. This may probably be due
to the preferential generation of –NÀAr from more acidic –NHAr.
The same selectivity is also observed in similar cases.17,23
The structure of 1,9-dihydro-6H-purin-6-ones 6 was confirmed
by their spectral data. For example, the IR spectra of 6g revealed N–
H and C@O absorption bands at 3445 and 1703 cmÀ1, respectively.
The 1H NMR spectrum of 6g shows the signals of NH at 4.14 ppm as
a broad absorption and NCH2 at 3.40–3.33 ppm as multiple absorp-
tion, which strongly suggest the existence of NHCH2CH3 group in
6g. The signals attributable to the imidazole-H and other Ar–Hs
are found at 7.82 and 7.74–7.26 ppm as singlet and multiplet.
The MS spectrum of 6g shows strong molecular ion peak at m/z
331 with 100% abundance.
Acknowledgments
We gratefully acknowledge financial support of this work by
the National Natural Science Foundation of China (Nos.
20772041, 20772042), Key Project of Chinese Ministry of Educa-
tion (No. 107082) and 863 Project (No. 2006AA09Z419).
References and notes
1. Kode, N.; Chen, L.; Murthy, D.; Adewumi, D.; Phadtare, S. Eur. J. Med. Chem.
2007, 42, 327.
2. Muehlhausen, U.; Schirrmacher, R.; Piel, M.; Lecher, B.; Briegert, M.; Piee-Staffa,
A.; Kaina, B.; Roesch, F. J. Med. Chem. 2006, 49, 263.
3. Ohtawa, M.; Ichikawa, S.; Teishikata, Y.; Fujimuro, M.; Yokosawa, H.; Matsuda,
A. J. Med. Chem. 2007, 50, 2007.
4. David-Cordonnier, M.-H.; Laine, W.; Lansiaux, A.; Kouach, M.; Briand, G.; Pierre,
A.; Hickman, J. A.; Bailly, C. Biochemistry 2002, 41, 9911.
5. Guan, H.-P.; Qiu, Y.-L.; Ksebati, M. B.; Kern, E. R.; Zemlicka, J. Tetrahedron 2002,
58, 6047.
6. Hartz, R. A.; Nanda, K. K.; Ingalls, C. L.; Ahuja, V. T.; Molski, T. F.; Zhang, G.;
Wong, H.; Peng, Y.; Kelley, M.; Lodge, N. J.; Zaczek, R.; Gilligan, P. J.; Trainor, G.
L. J. Med. Chem. 2004, 47, 4741.
7. Nakahira, H.; Hochigai, H. PCT Int. Appl. WO 2004096806, 2004; Chem. Abstr.
2004, 141, 410949.
8. Ridley, H. F.; Spickett, R. G. W.; Timmis, G. R. J. Heterocycl. Chem. 1965, 2, 453.
9. Bredereck, H.; Hennig, I.; Pfleiderer, W.; Weber, G. Chem. Ber. 1953, 86, 333.
10. Bridson, P. K.; Davis, R. A.; Renner, L. S. J. Heterocycl. Chem. 1985, 22, 753.
11. Nielsen, F. E.; Pedersen, E. B. Tetrahedron 1982, 38, 1435.
12. Alhede, B.; Clausen, F. P.; Juhl-Christensen, J.; McCluskey, K. K.; Preikschat, H. F.
J. Org. Chem. 1991, 56, 2139.
The biological activities of 6 were investigated, and the results
showed that some of them exhibited cytotoxicity against various
cancer cells.24 As indicated in Table 2, most of the compounds
showed good to moderate cytotoxicity against KB. Compounds
6b showed the best inhibition activities against KB, HepG2 and OV-
CAR3 with IC50 9.5, 20.4 and 10.0 lM (Table 2).
In conclusion, we have developed a new efficient synthesis of 2-
substituted 1,9-dihydro-6H-purin-6-ones via base-catalyzed reac-
13. Bridson, P. K.; Wang, X. Synthesis 1995, 855.
14. Ding, M. W.; Xu, S. Z.; Zhao, J. F. J. Org. Chem. 2004, 69, 8366.
15. Zhao, J. F.; Xie, C.; Xu, S. Z.; Ding, M. W.; Xiao, W. J. Org. Biomol. Chem. 2006, 4,
130.
16. Yuan, J. Z.; Fu, B. Q.; Ding, M. W.; Yang, G. F. Eur. J. Org. Chem. 2006, 4170.
17. Liu, M. G.; Hu, Y. G.; Ding, M. W. Tetrahedron 2008, 64, 9052.
18. Ding, M. W.; Fu, B. Q.; Cheng, L. Synthesis 2004, 1067.
19. Li, H. X.; Xie, C.; Ding, M. W.; Liu, Z. M.; Yang, G. F. Synlett 2007, 2280.
20. (a) Brown, T.; Shaw, G.; Durant, G. J. J. Chem. Soc., Perkin Trans. I 1980, 2310; (b)
Robinson, D. H.; Shaw, G. J. Chem. Soc., Perkin Trans. I 1972, 1715.
21. Preparation of iminophosphorane (3): To
a mixture of aminoimidazole (2)
Table 1
(1.85 g, 8 mmol), PPh3 (3.14 g, 12 mmol) and C2Cl6 (2.84 g, 12 mmol) in dry
CH2Cl2 (40 mL), was added dropwise NEt3 (2.42 g, 24 mmol) at room
temperature. The color of the reaction mixture quickly turned yellow. After
stirred for 4–6 h, the solvent was removed under reduced pressure and the
residue was recrystallized from ethanol–petroleum ether (1:3) to give
Preparation of 2-substituted 1,9-dihydro-6H-purin-6-ones 6
Compound
Ar
NR1R2
Conditions
Yielda (%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
Ph
Ph
4-Cl-C6H5
4-Cl-C6H5
Ph
–NMe2
rt/4 h
rt/6 h
rt/10 h
rt/6 h
rt/4 h
rt/4 h
rt/5 h
rt/6 h
rt/6 h
rt/6 h
81
72
71
70
85
85
84
89
82
88
–N(n-Bu)2
–N(i-Pr)2
–N(n-C5H11
Piperidin-1-yl
MeNH
EtNH
MeNH
n-BuNH
PhCH2NH
iminophosphorane
3 as pale yellow crystals (3.4 g, yield 85%), mp 123–
125 °C. IR (KBr): 1689 (C@O), 1542, 1502, 1438, 1417, 1137. 1H NMR (CDCl3,
400 MHz): d = 7.69–7.34 (m, 21H, Ar–H), 3.86 (q, J = 7.0 Hz, 2H, OCH2), 1.05 (t,
J = 6.9 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz): d = 163.0 (C@O), 145.4, 145.3,
136.0, 132.4, 132.0, 131.9, 131.7, 131.6, 131.5, 130.9, 130.8, 128.4, 128.1, 128.0,
127.7, 127.6, 127.0, 126.1, 114.6, 58.2, 14.2. MS m/z (%): 491 (M+, 100), 446
(12), 418 (16), 262 (66), 185 (11), 103 (21), 77 (29). Anal. Calcd for
C30H26N3O2P: C, 73.31; H, 5.33; N, 8.55. Found: C, 73.42; H, 5.19; N, 8.61.
)
2
Ph
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
22. Preparation of 1,9-dihydro-6H-purin-6-ones (6): To
a
solution of
6j
iminophosphorane (3) (1.5 g, 3 mmol) in dry methylene dichloride (15 mL)
was added phenyl isocyanate (3 mmol) under nitrogen at room temperature.
a
Isolated yields based on iminophosphorane 3.

N.-Y. Huang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 831–833
4.97; N, 17.25. Found: C, 65.01; H, 4.88; N, 17.28.
833
After the reaction mixture was left unstirred for 8–12 h at 0–5 °C, the solvent
was removed off under reduced pressure and Et2O/petroleum ether (1:2,
12 mL) was added to precipitate triphenylphosphine oxide. Removal of the
solvent gave carbodiimides 4, which were used directly without further
purification. To the solution of carbodiimide (4) prepared above in methylene
dichloride (15 mL) was added amines (3 mmol). After the reaction mixture was
stirred for 6 h, the solvent was removed and anhydrous ethanol (10 mL)
containing several drops of EtONa in EtOH was added. The reaction mixture
was stirred for 6–12 h at room temperature. The solution was condensed and
the residual was recrystallized from ethanol to give 1,9-dihydro-6H-purin-6-
ones 6.
1,9-Diphenyl-2-methylamino-1,9-dihydro-6H-purin-6-one (6f): White crystals.
Mp >300 °C. IR (KBr): 3445 (N–H), 1703 (C@O), 1571, 1545, 1515, 1443, 1382,
1077 cmÀ1 1H NMR (DMSO-d6, 400 MHz): d = 8.20 (s, 1H, Ar–H), 7.91–7.30 (m,
.
10H, Ar–H), 5.92 (d, J = 4.0 Hz, 1H, NH), 2.72 (d, J = 4.0 Hz, 3H, NCH3). MS m/z
(%): 317 (M+, 100), 287 (15), 183 (12), 125 (19), 104 (17), 77 (65). Anal. Calcd
for C18H15N5O: C, 68.13; H, 4.76; N, 22.07. Found: C, 68.24; H, 4.90; N, 21.98.
1,9-Diphenyl-2-ethylamino-1,9-dihydro-6H-purin-6-one (6g): White crystals.
Mp >300 °C. IR (KBr): 3445 (N–H), 1703 (C@O), 1556, 1535, 1505 cmÀ1 1H
.
NMR (CDCl3, 400 MHz): d = 7.82 (s, 1H, Ar–H), 7.74–7.26 (m, 10H, Ar–H), 4.14
(br, 1H, NH), 3.40–3.33 (m, 2H, NCH2), 1.10 (t, J = 7.2 Hz, 3H, CH3). MS m/z (%):
331 (M+, 100), 302 (21), 287 (27), 227 (18), 184 (11), 103 (30). Anal. Calcd for
C19H17N5O: C, 68.87; H, 5.17; N, 21.13. Found: C, 68.91; H, 5.31; N, 21.02.
1-(4-Chlorophenyl)-2-methylamino-9-phenyl-1,9-dihydro-6H-purin-6-one (6h):
White crystals. Mp >300 °C. IR (KBr): 3442 (N–H), 1703 (C@O), 1555, 1489,
2-Dimethylamino-1,9-diphenyl-1,9-dihydro-6H-purin-6-one (6a): White crystals.
Mp 243–245 °C. IR (KBr): 1693 (C@O), 1525, 1382, 1189 cmÀ1 1H NMR (CDCl3,
.
400 MHz): d = 7.90 (s, 1H, Ar–H), 7.74–7.34 (m, 10H, Ar–H), 2.64 (s, 6H, 2CH3).
MS m/z (%): 331 (M+, 100), 316 (18), 287 (49), 274 (25), 259 (32), 232 (18), 184
(15), 120 (21), 104 (36). Anal. Calcd for C19H17N5O: C, 68.87; H, 5.17; N, 21.13.
Found: C, 68.62; H, 5.25; N, 21.01.
1433, 1306 cmÀ1 1H NMR (CDCl3, 400 MHz): d = 7.82 (s, 1H, Ar–H), 7.74–7.25
.
(m, 9H, Ar–H), 4.23 (br, 1H, NH), 2.90 (d, J = 4.0 Hz, 3H, CH3). MS m/z (%): 351
(100, M+), 321 (11), 185 (9), 184 (9), 159 (7), 77 (8). Anal. Calcd for
C18H14ClN5O: C, 61.46; H, 4.01; N, 19.91. Found: C, 61.61; H, 4.20; N, 20.03.
2-(n-Butylamino)-1-(4-chlorophenyl)-9-phenyl-1,9-dihydro-6H-purin-6-one
(6i): White crystals. Mp 185–187 °C. IR (KBr): 3440 (N–H), 1708 (C@O),
2-Di(n-butyl)amino-1,9-diphenyl-1,9-dihydro-6H-purin-6-one
crystals. Mp 122–123 °C. IR (KBr): 1718 (C@O), 1606, 1535, 1494, 1464,
1372, 1118 cmÀ1 1H NMR (CDCl3, 400 MHz): d = 7.96 (s, 1H, Ar–H), 7.73–7.26
(6b):
White
.
(m, 10H, Ar–H), 2.97 (t, J = 7.4 Hz, 4H, 2NCH2), 1.21–1.08 (m, 8H, 4CH2), 0.82 (t,
J = 7.2 Hz, 6H, 2CH3). MS m/z (%): 415 (M+, 100), 372 (54), 358 (60), 316 (27),
287 (88), 240 (51), 128 (17), 104 (16). Anal. Calcd for C25H29N5O: C, 72.26; H,
7.03; N, 16.85. Found: C, 72.19; H, 6.95; N, 16.92.
.
1540, 1433 cmÀ1 1H NMR (CDCl3, 400 MHz): d = 7.83 (s, 1H, Ar–H),
7.73–7.24 (m, 9H, Ar–H), 4.17 (br, 1H, NH), 3.32 (m, 2H, NCH2), 1.51–
1.23 (m, 4H, 2CH2), 0.87 (t, J = 7.6 Hz, 3H, CH3). 13C NMR (CDCl3,
100 MHz): d = 157.2, 151.9, 149.1, 136.2, 135.8, 135.1, 133.2, 130.8,
130.5, 129.4, 127.5, 123.0, 117.8, 41.8, 31.0, 19.8, 13.6. MS m/z (%): 393
(M+, 100), 352 (11), 337 (26), 335 (79), 322 (11), 321 (34), 77 (20).
Anal. Calcd for C21H20ClN5O: C, 64.04; H, 5.12; N, 17.78. Found: C,
64.15; H, 5.25; N, 17.90.
1-(4-Chlorophenyl)-9-phenyl-2-phenylmethylamino-1,9-dihydro-6H-purin-6-one
(6j): White crystals. Mp 251–253 °C. 1H NMR (CDCl3, 400 MHz): d = 7.80
(s, 1H, Ar–H), 7.58–7.19 (m, 14H, Ar–H), 4.70 (br, 1H, NH), 4.50 (d,
J = 5.6 Hz, 2H, NCH2). 13C NMR (CDCl3, 100 MHz): d = 157.2, 151.7, 148.8,
138.1, 136.4, 136.0, 134.9, 133.1, 130.9, 130.5, 129.4, 128.5, 127.6, 127.4,
127.3, 123.2, 118.1, 46.0. MS m/z (%): 427 (M+, 100), 336 (6), 201 (2),
103 (17), 91 (65), 77 (27). Anal. Calcd for C24H18ClN5O: C, 67.37; H,
4.24; N, 16.37. Found: C, 67.46; H, 4.40; N, 16.19.
1,9-Diphenyl-2-di(i-propyl)amino-1,9-dihydro-6H-purin-6-one
(6c):
White
crystals. Mp 182–183 °C. 1H NMR (CDCl3, 400 MHz): d = 7.87 (s, 1H, Ar–H),
7.69–7.28 (m, 10H, Ar–H), 3.56–3.49 (m, 2H, 2NCH), 1.04 (d, J = 6.8 Hz, 12H,
4CH3). 13C NMR (CDCl3, 100 MHz): d = 158.9, 155.7, 147.6, 138.9, 137.1, 134.8,
129.4129.3, 128.7, 127.8, 127.7, 123.4, 119.9, 50.1, 21.3. MS m/z (%): 387 (M+,
31), 344 (100), 302 (13), 287 (67), 104 (19), 77 (33). Anal. Calcd for C23H25N5O:
C, 71.29; H, 6.50; N, 18.07. Found: C, 71.47; H, 6.32; N, 18.23.
1-(4-Chlorophenyl)-2-di(n-pentyl)amino-9-phenyl-1,9-dihydro-6H-purin-6-one
(6d): White crystals. Mp 177–178 °C. IR (KBr): 1698 (C@O), 1525, 1494, 1377,
1347, 1092 cmÀ1 1H NMR (CDCl3, 400 MHz): d = 7.94 (s, 1H, Ar–H), 7.70–7.25
.
(m, 9H, Ar–H), 2.96 (t, J = 7.8 Hz, 4H, 2NCH2), 1.26–1.05 (m, 12H, 6CH2), 0.84 (t,
J = 7.4 Hz, 6H, 2CH3). MS m/z (%): 477 (M+, 98), 406 (58), 350 (28), 321 (100),
296 (27), 240 (28), 183 (7). Anal. Calcd for C27H32ClN5O: C, 67.84; H, 6.75; N,
14.65. Found: C, 67.91; H, 6.82; N, 14.52.
23. (a) Ding, M. W.; Sun, Y.; Liu, X. P.; Liu, Z. J. Chin. J. Chem. 2003, 21, 577; (b) Ding,
M. W.; Xu, R. J.; Xu, J.; Chen, Y. F. Chin. Chem. Lett. 2005, 16, 189; (c) Blanco, G.;
Seguí, N.; Quintela, J. M.; Peinador, C.; Chas, M.; Toba, R. Tetrahedron 2006, 62,
11124.
24. Cytotoxic activities were evaluated by using standard MTT assay after
exposure of cells to the tested compounds for 72 h. Results are presented as
mean values of three independent experiments done in quadruplicates.
Coefficients of variation were <10%.
1-(4-Chlorophenyl)-2-(piperidin-1-yl)-9-phenyl-1,9-dihydro-6H-purin-6-one
(6e): White crystals. Mp 266–268 °C. IR (KBr): 1708 (C@O), 1550, 1515, 1245,
1092 cmÀ1 1H NMR (CDCl3, 400 MHz): d = 7.94 (s, 1H, Ar–H), 7.72–7.26 (m, 9H,
.
Ar–H), 3.05 (t, J = 5.4 Hz, 4H, 2NCH2), 1.45–1.28 (m, 6H, 3CH2). 13C NMR (CDCl3,
100 MHz): d = 157.8, 157.2, 147.4, 137.3, 136.2, 134.8, 133.7, 130.2, 129.5,
129.0, 127.8, 123.0, 120.2, 50.2, 24.7, 23.9. MS m/z (%): 405 (M+, 100), 376 (15),
321 (28), 266 (15), 183 (7), 103 (11). Anal. Calcd for C22H20ClN5O: C, 65.10; H,