2-Amino[1,2,4]triazolo[1,5-c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure–Activity Relationships of Potent Adenosine Receptor Antagonists

Article abstract of DOI:10.1002/cmdc.201600255

2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A₃AR antagonists were discovered, including 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17, K_ihuman A₃AR 1.16 nm) and 5′-phenyl-1,2-dihydro-3′H-spiro[indole-3,2′-[1,2,4]triazolo[1,5-c]quinazolin]-2-one (20, K_ihuman A₃AR 6.94 nm). In addition, multitarget antagonists were obtained, such as the dual A₁/A₃antagonist 2,5-diphenyl[1,2,4]triazolo[1,5-c]quinazoline (13 b, K_ihuman A₁AR 51.6 nm, human A₃AR 11.1 nm), and the balanced pan-AR antagonists 5-(2-thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 c, K_ihuman A₁AR 131 nm, A_2AAR 32.7 nm, A_2BAR 150 nm, A₃AR 47.5 nm) and 9-bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 q, K_ihuman A₁AR 67.7 nm, A_2AAR 13.6 nm, A_2BAR 75.0 nm, A₃AR 703 nm). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species.

Full text of DOI:10.1002/cmdc.201600255

DOI: 10.1002/cmdc.201600255
Full Papers
2-Amino[1,2,4]triazolo[1,5-c]quinazolines and Derived
Novel Heterocycles: Syntheses and Structure–Activity
Relationships of Potent Adenosine Receptor Antagonists
Joachim C. Burbiel+,[a] Wadih Ghattas+,[a] Petra Kꢀppers,[a] Meryem Kçse,[a] Svenja Lacher,[a]
Anna-Maria Herzner,[a] Rajan Subramanian Kombu,[b] Raghuram Rao Akkinepally,[a, b]
Jçrg Hockemeyer,[a] and Christa E. Mꢀller*[a]
2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as
potent adenosine receptor (AR) antagonists. Synthetic strat-
egies were devised to gain access to a broad range of deriva-
tives including novel polyheterocyclic compounds. Potent and
selective A3AR antagonists were discovered, including 3,5-di-
phenyl[1,2,4]triazolo[4,3-c]quinazoline (17, Ki human A3AR
lo[1,5-c]quinazoline (13b, Ki human A1AR 51.6 nm, human A3AR
11.1 nm), and the balanced pan-AR antagonists 5-(2-thie-
nyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 c, Ki human A1AR
131 nm, A2AAR 32.7 nm, A2BAR 150 nm, A3AR 47.5 nm) and 9-
bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 q, Ki
human A1AR 67.7 nm, A2AAR 13.6 nm, A2BAR 75.0 nm, A3AR
703 nm). In many cases, significantly different affinities for
human and rat receptors were observed, which emphasizes
the need for caution in extrapolating conclusions between dif-
ferent species.
1.16 nm)
and
5’-phenyl-1,2-dihydro-3’H-spiro[indole-3,2’-
[1,2,4]triazolo[1,5-c]quinazolin]-2-one (20, Ki human A3AR
6.94 nm). In addition, multitarget antagonists were obtained,
such as the dual A1/A3 antagonist 2,5-diphenyl[1,2,4]triazo-
Introduction
The nucleoside adenosine acts as a neuromodulator via specif-
ic receptors in the cell membrane known as adenosine recep-
tors (ARs).[1] They belong to the superfamily of rhodopsin-like
G protein-coupled receptors (GPCRs) and comprise four differ-
ent subtypes, A1, A2A, A2B, and A3. Adenosine can be released
from cells through equilibrative nucleoside transporters, or it
can be formed extracellularly from adenine nucleotides by ec-
tonucleotidases.[1,2] The extracellular concentration of adeno-
sine may increase dramatically, from nanomolar to micromolar
concentrations, under hypoxic or inflammatory conditions, or
upon cell damage, thereby leading to enhanced activation of
ARs under these pathological conditions.[2] In recent years ARs
have therefore gained considerable interest as new drug tar-
gets.[3]
AR antagonists can be subdivided into three different classes
(Figure 1): 1) xanthine derivatives such as the alkaloids theo-
phylline (1) and caffeine (2), which are moderately potent non-
selective AR antagonists, and their more potent derivatives
Figure 1. Selection of adenosine receptor antagonists.
[a] Dr. J. C. Burbiel,+ Dr. W. Ghattas,+ Dr. P. Kꢀppers, Dr. M. Kçse, Dr. S. Lacher,
Dr. A.-M. Herzner, Prof. Dr. R. R. Akkinepally, Dr. J. Hockemeyer,
Prof. Dr. C. E. Mꢀller
such as the A2A-selective istradefylline (KW6002, 3), the A2B-se-
lective GS-6201 (CVT-6883, 4), and the A3-selective PSB-10 (5a)
and PSB-11 (5b); 2) amino-substituted heterocyclic compounds
related to adenine, such as the A2A antagonists CGS-15943 (6a)
and preladenant (SCH420814, 6b); and 3) novel structures
identified by screening approaches, such as the A3 antagonist
MRS1523 (7).[3] [1,2,4]Triazolo[1,5-c]quinazoline derivatives were
first discovered to be antagonists for ARs by Francis et al.[4]
Pharmazeutische Chemie I, Universitꢁt Bonn, Pharma-Zentrum Bonn,
Pharmazeutisches Institut, An der Immenburg 4, 53121 Bonn (Germany)
Fax: (+49)228-73-2567
E-mail: christa.mueller@uni-bonn.de
[b] Dr. R. S. Kombu, Prof. Dr. R. R. Akkinepally
University College of Pharmaceutical Sciences, Kakatiya University, 506009,
Warangal (India)
[+] These authors contributed equally to this work.
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The A2AAR antagonist istradefylline (3) has been approved in
Japan for the treatment of Parkinson’s disease, and several
other AR antagonists have been or are under clinical evalua-
tion.[5] For example, A1-selective AR antagonists have been of
interest for the treatment of heart failure with improvement of
renal function. However, a recent phase III clinical trial has
failed to show significant effects.[6] A2A-selective AR antagonists
are evaluated not only as therapeutics for Parkinson’s disease,
but may also be effective in Alzheimer’s disease, restless legs
syndrome, depression, addiction and cancer.[7] A2A and A2BAR
antagonists have recently been proposed as checkpoint inhibi-
tors for the immunotherapy of cancer, and clinical trials with
A2A antagonists have already started.[7f]
Results and Discussion
In the search for scaffolds suitable for the development of AR
antagonists, we identified substituted [1,2,4]triazolo[1,5-c]qui-
nazolines (Scheme 1) as a starting point by a screening ap-
proach. Initially, R1 was either H, phenyl or 2-thienyl and R2 was
modified. We observed that an exocyclic amino function as R2
was favorable to obtain high AR affinities. Thereafter R2 was
kept constant (R2 =NH2) while R1 was further investigated
using diverse substituents such as aliphatic, aromatic, and het-
eroaromatic groups as well as substituted amino and thio
functions. Moreover, the effect of halogen substituents on the
quinazoline ring was also studied.
GS-6201 (4) is the first A2B-selective AR antagonist that was
clinically evaluated for asthma therapy. To our knowledge,
there are no A3-selective AR antagonists in clinical develop-
ment so far. However, preclinical data indicate that they might
be useful for the treatment of glaucoma, asthma, stroke, in-
flammation and cancer,[8] highlighting the need for more such
antagonists. The non-selective A1/A2A/A2B/A3 antagonists theo-
phylline (1) and caffeine (2) have been applied as drugs for
a long time and are still being used for several indications. For
example, caffeine is used for central nervous system (CNS)
stimulation to restore alertness and to counteract fatigue as
well as for the treatment of apnea, especially in premature
babies. In combination with different analgesics, including
nonsteroidal anti-inflammatory drugs and paracetamol (acet-
aminophen), caffeine is used for the treatment of pain. Theo-
phylline (1) is mainly used for the treatment of bronchial
asthma and chronic obstructive pulmonary disease as
a second-line treatment, as well as a substitute for caffeine for
the prevention of sleep apnea in adults and premature babies.
More recently aminophylline (a mixture of theophylline/ethyle-
nediamine=2:1 with improved solubility) went into clinical
trials for faster recovery after sevoflurane anesthesia, as sevo-
flurane leads to indirect activation of ARs.[9]
Scheme 1. Method A: a) R1COCl, pyridine, CHCl3, 08C (for 9a: triethyl ortho-
formate, microwave irradiation, 20 min, 1408C); b) hydrazine hydrate, micro-
wave irradiation, 10 min, 1208C; c) BrCN, K2CO3, EtOH, 10 h, 1008C for 11 a–
m; triethyl orthoformate, microwave irradiation, 10 min, 1608C for 12a–c;
benzaldehyde, Et3N, 3 h, 658C for 13a; benzoyl chloride, microwave irradia-
tion, 10 min, 1608C for 13b; N-(dichloromethylene)-N-methylmethanamini-
um chloride (Viehe’s salt), K2CO3, CH2Cl2, 4 h, RT for 14b; 1,1’-carbonyldiimi-
dazole, toluene, 2 h, 1008C for 15b and 15c; 1,1’-thiocarbonyldiimidazole,
K2CO3, CH2Cl2/H2O, 4 h, 08C!RT for 16c and thiophosgene; DMF, 27 h, 608C
for 16b.
Effective drugs for CNS disorders, in particular for psychiatric
diseases, frequently do not only address a single target, but
may interact with two or even multiple targets.[10] Drugs with
a dual or multiple mechanism of action have been proposed
as advantageous for the treatment of neurodegenerative dis-
eases such as Alzheimer’s disease and Parkinson’s disease.[11]
Dual A1A2 AR antagonists were evaluated in rodent and pri-
mate models of Parkinson’s disease and found to be highly
active.[12,13] Furthermore, a dual A1/A2A antagonist was found to
additionally enhance cognitive function in rodent models via
A1 AR blockade, an effect not observed with the selective A2A
antagonist istradefylline that was investigated in the same
study.[13] The interest in drugs with dual and multiple mecha-
nisms of action has also been growing in other therapeutic
fields; for example, A2A/A2B dual antagonists were shown to be
useful in cancer immunotherapy[14] and A2B/A3 dual antagonists
appear to be useful for treating asthma and allergic diseas-
es.[15]
Synthetic methods
The synthesis of triazolo[1,5-c]quinazolines was essentially per-
formed following two methods, A and B, and resulted in vari-
ous products including unexpected poly-condensed heterocy-
clic structures, while methods C and D were only used to
obtain derivatives bearing substituted amino and thio func-
tions for R1. In Method A, 4-iminoquinazoline-3-amines 9 were
selected as versatile intermediates to prepare various [1,2,4]tri-
azolo[1,5-c]quinazolines. The synthesis of 9a–l was achieved
by condensation of 2-aminobenzonitrile (8) with appropriate
acyl halides in chloroform in the presence of pyridine as
a base. The resulting 2-cyanobenzamides were subsequently
reacted with hydrazine hydrate under microwave conditions.
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This constituted a new convenient route to produce diversity
at position 5 (R1, see Scheme 1). However, we observed that
with aliphatic acyl halides the un-cyclized intermediates 10i–m
were formed in addition to 9i–m. However, separation of the
mixtures obtained was not necessary because both isomers
led to the same [1,2,4]triazolo[1,5-c]quinazolines in the subse-
quent condensation step with all different reagents that were
used to provide diversity at position 2 (R2, see Scheme 1).
In some cases, Method A generated unexpected structures.
The reaction of 9a with a large excess of benzoyl chloride
under harsh conditions (1608C and microwave irradiation)
yielded 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17), a re-
gioisomer of 13b. Both structures could be distinguished by
Scheme 3. Method B: a) R1COCl/Ac2O; b) aminoguanidine bicarbonate, pyri-
dine, 24 h, 1008C; c) 10% P2O5/CH3SO3H, 1708C.
1
their different H NMR spectra. The reaction of 9a with 2,3-in-
dolindione led to a spontaneous cyclization yielding a polycyc-
lic derivative. Supposing that in a first step the exocyclic
amino-group of 9a attacks the 3-carbonyl function of the 2,3-
indolindione we suggest structure 18 for the deep-red-colored
new compound. In contrast, the reaction of 9b with 2,3-indo-
lindione under the same conditions stopped at the stage of in-
termediate 19, which was isolated and further converted into
the spiro-compound 20 by heating in a solution of 10% phos-
phorus pentoxide in methanesulfonic acid (see Scheme 2).[16]
to be successful only for 5-methyl derivatives (11 n, R1 =Me) in
our hands.[17]
The reaction of 23o with phosphorous pentoxide in DMF
under reflux conditions yielded the corresponding dimethylfor-
mamidine derivative 24o (Scheme 4). Starting from 2-aminoni-
cotinic acid (25) and benzoyl chloride pyridooxazinone 26 was
Scheme 4. Synthesis of 24o, 26, 27, and 15i. a) 10% P2O5/DMF, reflux;
b) benzoyl chloride, CH2Cl2, RT; c) 1. aminoguanidine, pyridine, 24 h at
1008C, 2. 10% P2O5/CH3SO3H, 1708C; d) semicarbazide, pyridine, microwave
irradiation, 30 min, 1608C.
Scheme 2. Unexpected polycyclic structures obtained using Method A:
a) benzoyl chloride, microwave irradiation, 10 min, 1608C; b) EtOH, 30 min
to 1 h, 1008C; c) 10% P2O5/CH3SO3H, 1708C.
formed, which was subsequently converted into 5-phenylpyri-
do[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-2-amine (27) as the only
final product with a nitrogen atom at the 7-position. Two
methods were used to obtain [1,2,4]triazolo[1,5-c]quinazolin-
4(3H)-ones 15. The reaction of 9b or 9c with 1,1’-carbonyldii-
midazole in toluene at 1008C led to the final compounds 15b
and 15c, respectively (see Scheme 1). Treatment of 2-isopro-
pyl-benzo[d][1,3]oxazin-4-one (22i) with semicarbazide in pyri-
dine for 30 min at 1608C under microwave irradiation afforded
5-isopropyl[2,3-e][1,2,4]triazolo[1,5-c]quinazolin-4(3H)-one (15i,
see Scheme 4).
Method B was developed mainly to obtain 2-amino[1,2,4]-
triazolo[1,5-c]quinazolines 11 with diversity at position 5 (R1)
and the benzene ring of the quinazoline core (see Scheme 3).
The required 4H-1,3-benzoxazin-4-ones 22 were either pur-
chased or prepared following literature procedures by reaction
of 2-aminobenzoic acids 21 with appropriate acyl halides.
Compounds 22b and 22n–q were reacted with aminoguani-
dine under microwave irradiation to produce guanidine inter-
mediates 23 that were subsequently, either in situ or after iso-
lation, treated with 10% phosphorus pentoxide in methanesul-
fonic acid to promote cyclization. Unfortunately, a microwave-
assisted one-step procedure described in the literature proved
2-Amino[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-thione (28), first
described by Leistner and Wagner,[18] was identified as a suita-
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for human A3ARs.[23] Because [3H]PSB-11 is not suitable for the
labeling of rat A3ARs the agonist radioligand N-ethylcarboxami-
doadenosine ([3H]NECA) was used instead.[24] Initially com-
pounds were screened at 10 mm unless otherwise noted. For
potent compounds (Ki <10000 nm at rat ARs or <1000 nm at
human ARs) full concentration–inhibition curves were record-
ed, and affinity constants (Ki values) were determined by non-
linear regression analysis (see the Experimental Section for fur-
ther details). For less potent compounds only the percent in-
hibition at 1 or 10 mm was measured, unless otherwise stated.
NaCl shift assays were performed for selected A2A antagonists
to confirm their antagonistic properties.
Scheme 5. Method C: corresponding amine, EtOH, 708C or corresponding
amine, H2O2, 1008C. Method D: a) CH3I, NaOH(aq), MeOH, 30 min, RT; c) corre-
sponding amine, 90 min, 120–1408C.
Structure–activity relationships
The affinities of the final compounds for the human (h) and rat
(r) ARs are listed in Tables 1 and 2. [1,2,4]Triazolo[1,5-c]quinazo-
lines 12a–c with R2 =H displayed low affinity for the hAR sub-
types regardless of the substitution pattern on R1. Similar re-
sults were obtained with the rat AR subtypes, with the excep-
tion of a moderate affinity observed at the rA1AR subtype with
12c having R1 =2-thienyl. [1,2,4]Triazolo[1,5-c]quinazolines 13a
and 13b bearing phenyl at R2 displayed moderate to high af-
finity for the hA1 and hA3 AR subtypes and moderate to low af-
finity for the rat AR subtypes regardless of the substitution pat-
tern on R1. Interestingly, differences in affinity were observed
between 13b (R1 =R2 =phenyl) and its [1,3,4]triazolo isomer
17. While the former was dually potent on hA1 (Ki =51.6 nm)
and hA3 (Ki =11.1 nm), the latter was dually potent on hA2A
(Ki =104 nm) and hA3ARs (Ki =1.16 nm).
Five [1,2,4]Triazolo[1,5-c]quinazolines bearing either O or S
(R2) were tested and revealed at best moderate affinity for
some AR subtypes. Compound 15b (R1 =phenyl, R2 =O)
showed weak affinity for rat A1 and A2AARs. Compound 16b
(R1 =phenyl, R2 =S) displayed moderate affinity and selectivity
for the hA3AR, while 15i (R1 =isopropyl, R2 =O) showed mod-
erate affinity and selectivity for the rA2AAR. Compound 16c
(R1 =2-thienyl, R2 =O) displayed weak affinity for the hA1AR
and moderate affinity for the hA3AR, while 15c (R1 =2-thienyl,
R2 =S) had moderate affinity for the human (and rat) A1 and
A2AARs and the hA3AR.
ble precursor for preparing 2-amino[1,2,4]triazolo[1,5-c]quina-
zolines 11 with amino or thio substituents attached to posi-
tion 5 (R1) following Methods C and D (Scheme 5). Method C:
heating of 28 with the appropriate amine either in the absence
or in the presence of H2O2 yielded the target compounds 11 t–
x. Methylsulfanyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 s)
was prepared by reaction of 28 with methyl iodide. This inter-
mediate was used in Method D: heating of 11 s with the ap-
propriate amine led to derivatives 11 y–ab.
Compound 28 was also reacted with hydrazine leading to 5-
hydrazino[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 ac), which
was finally cyclized with triethylorthoformate to form the tetra-
cyclic compound 29 (Scheme 6). Similar polyheterocyclic com-
pounds were first described by Pfeiffer et al.[19]
Scheme 6. Preparation of [1,2-4]triazolo[1,5-c]quinazolines 11 ac and the tet-
racyclic system 29: a) hydrazine hydrate, EtOH, 1 h, reflux; b) (EtO)3CH, mi-
crowave irradiation, 20 min, 1608C.
The heteropolycyclic derivatives 18 and 20 were found to
be only potent at the hA3AR with high selectivity versus all
other AR subtypes. Most notably compound 20 showed a Ki
value of 6.94 nm at the hA3AR subtype.
Biological evaluation
Radioligand binding at all four recombinant human AR sub-
types expressed in Chinese hamster ovary (CHO) cells, and at
native rat brain A1 (cortex) and A2A ARs (striatum) were per-
formed. Selected compounds were additionally tested at rat
Compared with the other substitution patterns, the amino
group at position 2 seemed to be responsible for the increase
in affinity at the A1, A2A, and A2BAR subtypes. Compound 11 b
with R1 =phenyl and R2 =NH2 displayed moderate to high af-
finities for the A1, A2A and A2BAR subtypes (Ki rA1 =280 nm, Ki
rA2A =38.0 nm, Ki hA1 =223 nm, Ki hA2A =79.2, Ki hA2B =178 nm)
and was inactive at the A3AR (Ki hA3 >1000 nm), while 14b
with R1 =phenyl, and a dimethylamino group at R2 showed de-
creased affinity for the A1, A2A and A2BAR subtypes (Ki rA1 >
A2B and A3 ARs expressed in CHO cells. Cell membrane prepara-
tions were used for binding studies using the following radioli-
gands: [3H]2-chloro-N6-cyclopentyladenosine ([3H]CCPA) for
A1ARs,[20]
[3H]3-(3-hydroxypropyl)-7-methyl-1-propargyl-8-(m-
methoxystryryl)xanthine ([3H]MSX-2) for A2AARs,[21] [3H]8-(4-(4-
(4-chlorophenyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine
([3H]PSB-603 for A2BARs,[22] and [3H]2-phenyl-8-ethyl-4-methyl-
(8R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one ([3H]PSB-11)
10000 nm, Ki rA2A >10000 nm, Ki hA1 =443 nm, Ki hA2A
=
421 nm, Ki hA2B >1000 nm) but good affinity for A3AR (Ki hA3 =
161 nm). An aromatic group at position 5 was found to be re-
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Table 1. Binding affinities of triazolo[1,5-c]quinazolines and related polyheterocyclic compounds at rat and human adenosine receptor subtypes.
Compd
R1
R2
Ki [nm][a]
rA1 vs. [3H]CCPA
rA2A vs. [3H]MSX-2 hA1 vs. [3H]CCPA hA2A vs. [3H]MSX-2
hA2B or rA2B
vs. [3H]PSB-603
hA3 vs. [3H]PSB-11 or
rA3 vs. [3H]NECA
2
3
6a
caffeine
istradefylline
preladenant
41000[25]
230[28]
12200ꢀ1210
44900[26]
841[28]
295ꢀ10
5640ꢀ539
33800
>10000[28]
>1000
13300[27]
4470[28]
>1000
4.46[29]
91.2[28]
68.7ꢀ8.68
0.661ꢀ0.126
0.884ꢀ0.232
12a
12b
12c
13a
13b
17
15b
16b
15c
16c
15i
24o
14b
29
H
H
H
H
>10000 (0%)
1230ꢀ110
377ꢀ35
>10000 (4%)
>10000 (0%)
7300ꢀ1500
2660ꢀ290
>1000 (15%)
>1000 (32%)
>1000 (32%)
187ꢀ20
>1000 (26%)
>1000 (6%)
>1000 (26%)
>1000 (31%)
>1000 (20%)
>1000 (9%)
>1000 (11%)
>1000 (27%)
>1000 (5%)
>1000 (12%)
>1000 (23%)[b]
>1000 (13%)
>1000 (36%)
>1000 (10%)
>1000 (0%)
>1000 (36%)
>1000 (17%)
>1000 (8%)
>1000 (6%)
>1000 (22%)
>1000 (20%)
>1000 (32%)
50.7ꢀ7.2
phenyl
2-thienyl
H
phenyl
(see above)
phenyl
phenyl
2-thienyl
2-thienyl
isopropyl
phenyl
phenyl
630ꢀ177
1940ꢀ153
>10000 (27%)
1350ꢀ36
>10000 (16%)
>10000 (10%)
1650ꢀ257
51.6ꢀ5.6 >1000 (28%)
11.1ꢀ1.7
>1000 (5%)
104ꢀ5
1.16ꢀ0.39
>1000 (34%)
107ꢀ9
O
S
O
S
>1000 (37%)
>1000 (36%)
388ꢀ38
>1000 (44%)
>1000 (36%)
442ꢀ39
>10000 (9%)
130ꢀ30
>10000 (2%)
437ꢀ64
477ꢀ134
>10000 (13%)
>10000 (22%)
>10000 (12%)
>10000 (8%)
8100ꢀ1550
>10000 (32%)
>10000 (47%)
>10000 (18%)
950ꢀ231
>1000 (28%)
>1000 (47%)
248ꢀ77
357ꢀ28
O
>1000 (27%)
655ꢀ8
>1000 (15%)
>1000 (34%)
161ꢀ24
3-pyridyl N=CHN(CH3)2 >10000 (37%)
phenyl
(see above)
(see above)
N(CH3)2
>10000 (33%)
>10000 (12%)
>10000 (39%)
443ꢀ57
421ꢀ143
>1000 (15%)
>1000 (39%)
>1000 (3%)
>1000 (44%)
>1000 (11%)
(r)>1000 (0%)
118 ꢀ9
18
20
(see above)
>10000 (19%)
>10000 (31%)
>1000 (25%)
>1000 (24%)
>1000 (0%)
(r)>1000 (11%)
6.94ꢀ1.13
[a] Values are the meanꢀSEM of n=3 assays, each carried out in duplicate or triplicate; h=human, r=rat. [b] Percent inhibition at 0.3 mm.
quired for high affinity at the A1 and A2A as well as the A2BAR
subtypes. A notable exception were nitrogen-containing aro-
matics, such as in 11 o and 11 p (R1 =3- and 4-pyridyl, respec-
tively), which were not tolerated leading to dramatically de-
creased affinity at all subtypes. The most potent compound
was 11 c with R1 =2-thienyl (Ki rA1 =22.0 nm, Ki rA2A =21.5 nm,
Ki hA1 =67.7 nm, Ki hA2A =13.6 nm, Ki hA2B =75.0 nm and Ki
hA3 =703 nm). Highly potent derivatives were also obtained
when R1 was either phenyl, 3-thienyl or 2-furyl. Compound
11 h (R1 =2-furyl) was found to be a balanced pan-AR antago-
nist, which also showed high affinity for the hA3AR (Ki hA1 =
328 nm, Ki hA2A =28.2 nm, Ki hA2B =130 nm and Ki hA3 =
101 nm). At rat ARs however, it only had high affinity for the A1
and A2AAR subtypes (Ki rA1 =87.0 nm, Ki rA2A =69.0 nm), but
not for the rA3AR. Halogen-containing aromatic residues at R1
in 11 d, 11 e and 11 f decreased the affinity on the A2BAR sub-
type relative to the parent 11 b leading to A1/A2A dual antago-
nists. The bromo-substituted derivative 11 d was well tolerated
by the A3AR.
as to 27 containing a nitrogen atom in the quinazoline ring.
The fluoro substituent only moderately influenced the affinities
at the ARs. In rat, the bromo substituent increased the affinity
for the rA1 and decreased it for rA2AAR. In human, on the other
hand, it slightly affected the affinities for hA1, hA2A and hA2B,
and significantly increased the affinity for the hA3AR (Ki =
47.5 nm), leading to another balanced pan-AR antagonist. The
nitrogen atom in 27 was also responsible for a moderate in-
crease in the affinity for the A3AR, but showed only minor in-
fluence on the affinities for the other receptor subtype.
Finally, [1,2,4]triazolo[1,5-c]quinazoline-2-amines bearing sub-
stituents connected by amino or thio groups at position 5 (R1)
(28 and 11 s–ac) displayed lower affinities at the hA2BAR than
derivatives with aromatic residues (11 b and 11 e–p). Nonethe-
less, two exceptions were observed: 11 o bearing a 3-pyridyl
ring had no affinity for the hA2BAR subtype, whereas 11 z bear-
ing an N-2-phenethylamino residue had moderate affinity for
this subtype. Similarly, R1 =H or methyl decreased the affinity
at all AR subtypes. The longer alkyl chain R1 =isopropyl was
only tolerated by the rA1 and hA2AARs resulting in the selective
potent antagonist 11 i. Benzyl and phenylethyl residues for R1
were well tolerated by the hA3AR and also to some extent by
The effects of modifications on the quinazoline ring were
studied by comparing the AR affinities of 11 b to those of the
fluoro- or bromo-substituted derivatives 11 q and 11 r as well
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Table 2. Binding affinities of 2-amino[1,2,3]triazolo[1,5-c]quinazolines 11 and related compounds for rat and human adenosine receptor subtypes.
Compd
R1
Ki [nm][a]
rA1
rA2A
vs. [3H]MSX-2
hA1
vs. [3H]CCPA
hA2A
hA2B or rA2B
vs. [3H]PSB-603
hA3 vs. [3H]PSB-11 or
rA3 vs. [3H]NECA
vs. [3H]CCPA
vs. [3H]MSX-2
11 a
11 n
11 i
11 j
11 m
11 l
11 k
11 b
11 e
11 f
11 d
11 c
11 g
11 h
H
4690ꢀ379
>10000 (31%)
168ꢀ15
2170ꢀ135
4450ꢀ529
1920ꢀ147
1870ꢀ67.0
870ꢀ212
>1000 (29%)
>1000 (3%)
>1000 (38%)
>1000 (38%)
332ꢀ113
>1000 (59%)
>1000 (18%)
89.5ꢀ26.9
>1000 (42%)
358ꢀ89
>1000 (10%)
>1000 (11%)
>1000 (25%)
>1000 (14%)
>1000 (11%)
>1000 (32%)
>1000 (3%)
178ꢀ57
>1000 (32%)
>1000 (13%)
>1000 (7%)
183ꢀ35
methyl
isopropyl
benzyl
(R,S)-1-methylbenzyl
2-phenethyl
2-(3,4,5-trimethoxyphenyl)ethyl >10000 (18%)
phenyl
3-fluorophenyl
4-fluorophenyl
4-bromophenyl
2-thienyl
>10000 (53%)
1240ꢀ215
162ꢀ26
4100ꢀ1180
5060ꢀ1510 >1000 (37%)
964ꢀ83
178ꢀ25
>10000 (28%)
38.0ꢀ5.2
>1000 (25%)
223ꢀ28
640ꢀ107
79.2ꢀ19.9
95.3ꢀ24.3
134ꢀ42
>1000 (21%)
>1000 (30%)
>1000 (19%)
>1000 (44%)
60.4ꢀ4.4
280ꢀ15
324ꢀ109
3090ꢀ714
90.3ꢀ2.2
22.0ꢀ15.0
87.0ꢀ12.0
87.0ꢀ6.0
117 ꢀ27
271ꢀ78
>1000 (42%)
>1000 (28%)
>1000 (15%)
75.0ꢀ28.2
1710ꢀ291
985ꢀ105
21.5ꢀ1.2
408ꢀ106
130ꢀ14
231ꢀ33
67.7ꢀ16.6
353ꢀ47
13.6ꢀ2.0
51.2ꢀ5.1
703ꢀ110
3-thienyl
2-furyl
55.5ꢀ11.4
69.0ꢀ15.0
198ꢀ13
>1000 (36%)
(r)>1000 (1%)
101ꢀ25
328ꢀ33
28.2ꢀ5.7 (r)>1000 (37%)
130ꢀ7
11 o
11 p
11 q
3-pyridyl
4-pyridyl
(see above)
1120ꢀ130
1090ꢀ67
87.0ꢀ28.0
1360ꢀ500
420ꢀ65
150ꢀ12
>1000 (35%)
>1000 (0%)
131ꢀ48
>1000 (19%)
>1000 (0%)
>1000 (15%)
(r) 111 ꢀ38
150ꢀ11
41.7ꢀ7.8
464ꢀ570
32.7ꢀ2.5
>1000 (21%)
(r)>1000 (0%)
47.5ꢀ16.8
>1000 (33%)
468ꢀ54
11 r
27
28
11 s
11 t
11 u
11 v
11 w
11 x
11 y
11 z
11 aa
11 ab
11 ac
(see above)
(see above)
S
S-methyl
N-pyrrolidinyl
N-piperidinyl
N-morpholinyl
N-butylamino
N-benzylamino
N-hydroxyethylamino
N-2-phenethylamino
N-2-tetrahydrofurfurylamino
N-3-pyridine-3-ylmethylamino
NHꢁNH2
220ꢀ38
73.0ꢀ10.0
54.8ꢀ10.0
97.6ꢀ16.5
>10000 (43%)
303ꢀ78
342ꢀ167
184ꢀ24
145ꢀ21
346ꢀ139
>1000 (20%)
247ꢀ47
345ꢀ62
283ꢀ42
>10000 (17%)
962ꢀ207
>1000 (32%)
785ꢀ181
>1000 (2%)
>1000 (41%)
>1000 (21%)
>1000 (20%)
>1000 (12%)
>1000 (27%)
>1000 (29%)
>1000 (9%)
394ꢀ28
>1000 (0%)
>1000 (46%)
>1000 (18%)
>1000 (33%)
>1000 (8%)
438ꢀ53
864ꢀ197
274ꢀ44
708ꢀ197
338ꢀ38
2650ꢀ164
845ꢀ44
>1000 (32%)
>1000 (2%)
892ꢀ351
535ꢀ21
>10000 (34%)
555ꢀ74
5450ꢀ930
208ꢀ41
>1000 (30%)
300ꢀ90
>10000 (49%)
1730ꢀ420
2540ꢀ661
2080ꢀ40
244ꢀ38
149ꢀ17
239ꢀ29
>1000 (24%)
>1000 (1%)
>1000 (40%)
>1000 (17%)
>1000 (27%)
>1000 (34%)
72.0ꢀ7.8
502ꢀ17
>1000 (25%)
241ꢀ56
>10000 (41%)
2280ꢀ284
7230ꢀ147
1340ꢀ135
>10000 (0%)
>10000 (48%)
>1000 (22%)
>1000 (33%)
>1000 (14%)
>1000 (9%)
>1000 (33%)
>1000 (18%)
>10000 (0%)
>10000 (27%)
527ꢀ38
>1000 (38%)
[a] Values are the meanꢀSEM of n=3 assays, each carried out in duplicate or triplicate; h=human, r=rat.
the hA2AAR, while the bulkier derivative 11 k (trimethoxy-
phenylethyl-substituted) was only moderately tolerated by the
hA2AAR.
in extrapolating results between species and emphasize the
importance of determining the affinity constants on the spe-
cies of interest, for example, on receptors of rodents that are
used in preclinical studies.
Species differences
Functional properties
Differences in affinities between species were noted for several
compounds. The most potent compounds on either rA1 or
rA2AARs also showed high affinity for either hA1 or hA2AARs.
However, several compounds displayed significant affinity for
the hAR subtypes, but not for the rat subtypes (e.g., 11 x, 11 z,
14b, and 24o). Species differences are particularly high for the
A3 receptor, as typically observed for A3 antagonists.[1,28] This
was demonstrated for the potent A3-selective antagonist 18.
Such differences between species highlight the possible errors
The antagonistic character of 2-amino[1,2,4]triazolo[1,5-c]qui-
nazolines and analogues was confirmed by sodium chloride
shift experiments at the A2AARs using the following procedure.
Concentration-dependent inhibition of [3H]MSX-2 binding to
rat brain striatal membranes was measured in the presence
and absence of 100 mm sodium chloride. The agonist 5’-N-eth-
ylcarboxamidoadenosine (NECA), which was used as a reference
compound, displays a 16-fold shift. In contrast, for the selected
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tion of DMSO was 2.5%. The radioligand concentrations were:
[3H]CCPA, 0.5 nm (rat and human A1); [3H]MSX-2 1.0 nm (rat and
human A2A); [3H]PSB-603, 0.3 nm (rat and human A2B); [3H]PSB-11,
0.5 nm (human A3); [3H]NECA, 10 nm (rat A3). Binding assays were
performed as described previously.[20,21,23,32,33] About 30–70 mgmLꢁ1
of protein were used in the assays. At least three separate experi-
ments were performed, each in duplicate or triplicate. Data were
analyzed with GraphPad Prism ver. 4 (San Diego, CA, USA). For cal-
culation of Ki values by nonlinear regression analysis, the Cheng–
Prusoff equation and KD values of 0.5 nm (rat A1); 0.61 nm (human
A1) for [3H]CCPA, 8 nm for [3H]MSX-2 (human and rat A2A); 0.41 nm
for [3H]PSB-603 (human A2B); 0.2 nm (rat A2B); 4.9 nm for [3H]PSB-11
(human A3); and 48 nm for [3H] NECA (rat A3) were used. Sodium
shift assays were performed as previously described.[34]
Table 3. Sodium shift assays of selected triazolo[1,5-c]quinazolines.
Compd
IC50 [nm][a,c]
IC50 [nm][b,c]
Shift
NECA
11b
11c
11g
11r
27
109ꢀ29
1740ꢀ21
91.5ꢀ25.5
48.7ꢀ9.1
94.7ꢀ18.7
144ꢀ23
16-fold
2.4-fold
2.2-fold
1.7-fold
2.6-fold
1.2-fold
38.0ꢀ5.2
21.5ꢀ1.2
55.5ꢀ11.4
54.8ꢀ10.0
97.6ꢀ16.5
119 ꢀ10
Chemistry
[a] In the absence of NaCl. [b] In the presence of 100 mm NaCl. [c] Mea-
sured at the A2AAR of rat brain striatal membrane preparations; values
are the meanꢀSEM (n=3, except for NECA: n=4), with each assay car-
ried out in duplicate or triplicate.
Microwave-assisted reactions were carried out in 10 mL sealed
glass tubes in a focused mono-mode microwave oven (“Discover”,
CEM Corporation, Matthews, NC, USA). Mass spectra were recorded
on an API 2000 mass spectrometer (electrospray ion source, Ap-
plied Biosystems, Darmstadt, Germany) coupled with an Agilent
1100 HPLC system using a Macherey–Nagel Nucleodur C18 Gravity
3 mm column (50ꢂ2.00 mm, particle size: 3 mm) that was used to
measure purity of the compounds. 1H and 13C NMR spectra were
recorded on a Bruker Avance 500 MHz spectrometer. Chemical
shifts are referenced to residual solvent signals, and coupling con-
stants are reported in Hz. 13C NMR spectra were recorded for se-
lected compounds from each subfamily only, or if necessary for
structural assignment. Starting materials 22b,[35] 22i,[36] 22o,[35]
22p,[37] 22q,[38] 26,[39] 28,[18] and 30[40] were prepared according to
published procedures. Syntheses of products 11 b,[41] 11 n,[41b,c]
12b,[42] 13a,[43] 13b,[42,43b,44] 15b,[45] and 16b[45,46] were previously
reported. (R,S)-2-Phenylpropionyl chloride and 3-(3,4,5-trimethoxy-
phenyl)propionyl chloride were prepared from the corresponding
acids. Purification by column chromatography was performed with
silica gel 60. All commercially available reagents and solvents were
used without further purification. The petroleum ether (PE) used
had a boiling point of 40–608C.
2-amino[1,2,4]triazolo[1,5-c]quinazoline derivatives (11 b,c,g,r)
and the aza-analogue 27, the presence of sodium chloride did
not have a significant influence on the binding affinity (shift
<3-fold, Table 3). These results confirm that the compounds
act as antagonists.
Conclusions
In this study we identified 2-aminotriazolo[1,5-c]quinazolines
as a potent class of AR antagonists. Novel pathways for the
synthesis of such derivatives were developed, and we prepared
a series of 48 final products. SARs were explored on all four AR
subtypes. Besides compounds that bind to several AR subtypes
with high potency, A3-selective derivatives with low nanomolar
Ki values were discovered.
General procedure 1: in a first step, 2-aminobenzonitrile (8, 2.36 g,
20 mmol) and pyridine (2.0 g, 25 mmol) were dissolved in anhy-
drous CHCl3 (20 mL) and cooled to 08C. To this mixture, a solution
of the corresponding acyl chloride (24 mmol) in anhydrous CHCl3
(20 mL) was slowly added. After stirring for 5 h at RT, all volatile
components were removed under reduced pressure. Water (40 mL)
and solid sodium carbonate were added to the residue until pH 9
was reached. After vigorous stirring, the precipitate was collected
and washed with cold water (20 mL). The 2-cyanobenzamides thus
obtained were dried at 1108C and used without further purifica-
tion. In a second step, the 2-cyanobenzamide (5.0 mmol) and hy-
drazine hydrate (2 g, 40 mmol) were heated under microwave con-
ditions (1208C, 40 W) for 10 min. After the addition of EtOH (2 mL)
the mixture was heated at 70–808C and then left at 48C for several
hours. The precipitate (9 or a mixture of 9 and 10, respectively)
was collected, washed with EtOH (2ꢂ2 mL) and dried at 808C.
Experimental Section
Biology
Radioligands were obtained from the following sources: [3H]CCPA
from Amersham (58 Cimmolꢁ1), [3H]MSX-2 from Amersham
(84 Cimmolꢁ1), [3H]PSB-603 from Amersham (73 Cimmolꢁ1),
[3H]PSB-11 (53 Cimmolꢁ1) from Quotient Biosciences, and [3H]NECA
(15.5 Cimmolꢁ1) from PerkinElmer. Some of the precursors were
synthesized in our laboratory. Membranes from Chinese hamster
ovary (CHO) cells stably transfected with either human A1, human
A2A, human A2B, rat A2B, or human A3 AR were prepared as de-
scribed previously[22,23,30] and used in radioligand binding assays.
Commercially available membrane preparations containing rat
A3AR expressed in human embryonic kidney (HEK) cells were ob-
tained from Biotrend (Cologne, Germany). Frozen rat brains ob-
tained from Pel Freez, Rogers, AR (USA) were dissected as previous-
ly described to obtain either cortical membrane prepara-
tions[20,21,24,31] for A1AR assays, or striatal membrane preparations
for A2AAR assays.
General procedure 2: the starting 4-iminoquinazoline-3-amine 9
and either triethyl orthoformate for R2 =H or the corresponding
benzoyl halide for R2 =benzyl were stirred at 1608C under micro-
wave irradiation (60 W) for 10 min. EtOH (5 mL) was added, and
the mixture was heated at 808C, then left at 48C overnight. A pre-
cipitate was formed, which was collected, washed with EtOH (2ꢂ
1 mL) and dried at 808C.
Radioligand binding assays: Stock solutions of the compounds
were prepared in dimethyl sulfoxide (DMSO); the final concentra-
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General procedure 3: the appropriate 4-iminoquinazoline-3-amine
9 (0.5 mmol), potassium carbonate (0.14 g, 1.0 mmol), cyanogen
bromide (64 mg, 0.6 mmol) and EtOH (5 mL) were heated at 1008C
in a sealed glass tube for 10 h. Several times during the reaction,
the mixture was cooled to 508C in order to safely release the
formed gas. Thereafter, the mixture was allowed to cool to RT,
water (10 mL) was added and the solution was left at 48C over-
night. The formed precipitate was collected, washed with water
(10 mL) and EtOH (2 mL) then dried at 1008C.
1.3 Hz, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.36 (t, J=7.6 Hz,
1H), 5.60 ppm (s, 2H, NH2); MS (EI, 70 eV) m/z (%): 161 (100) [M+
H]+, purity: 94.1%.
4-Imino-2-phenylquinazolin-3-amine (9b): following general pro-
cedure 1, starting from benzoyl chloride and 2-aminobenzonitrile,
1
9b was obtained as a yellow solid (0.71 g, 60%). H NMR (500 MHz,
[D6]DMSO): d=9.63 (s, 1H, NH), 8.56 (m, 2H), 8.19 (d, J=8.2 Hz,
1H), 7.74 (m, 2H), 7.49 (m, 3H), 7.44 (ddd, J=2.7 Hz, J=5.4 Hz, J=
8.2 Hz, 1H), 4.89 ppm (s, 2H, NH2); MS (EI, 70 eV) m/z (%): 237 (100)
[M+H]+, purity: 96.3%.
General procedure 4: the appropriate (4H)-3,1-benzoxazin-4-one
22 (1.0 mmol), aminoguanidine bicarbonate (0.20 g, 1.5 mmol), and
pyridine (2 mL) were stirred at 1008C for 24 h. After cooling to RT,
the suspension was acidified to pH~1 using HCl (2n) and subse-
quently filtered. The filtrate was neutralized with solid sodium car-
bonate and left at 48C overnight. The formed precipitate was col-
lected, washed with water (2ꢂ5 mL) and dried at 1008C.
4-Imino-2-(2-thienyl)quinazolin-3-amine (9c): following general
procedure 1, starting from 2-thiophenecarbonyl chloride and 2-
aminobenzonitrile, 9c was obtained as a yellow solid (0.42 g, 35%).
1H NMR (500 MHz, [D6]DMSO): d=9.68 (s, 1H, NH), 8.15 (d, J=
8.2 Hz, 1H), 8.03 (dd, J=1.3 Hz, J=3.6 Hz, 1H), 7.71 (t, J=7.3 Hz,
1H), 7.66 (m, 2H), 7.40 (t, J=7.1 Hz, 1H), 7.17 (dd, J=3.6 Hz, J=
5.1 Hz, 1H), 4.87 ppm (s, 2H, NH2); MS (EI, 70 eV) m/z (%): 243 (100)
[M+H]+, purity: 94.7.
General procedure 5: starting from the appropriate guanidine de-
rivative 23 (0.5 mmol) 10% phosphorus pentoxide in methanesul-
fonic acid (1 mL) were added. The suspension was heated at 1708C
until white fumes emerged (~1 min). After cooling to RT, water
(2 mL) was added and solid sodium carbonate was used to bring
the solution to neutral pH, at which a precipitate formed. It was
collected, washed with water (2 mL) and dried at 1008C.
2-(4-Bromophenyl)-4-iminoquinazolin-3-amine (9d): following
general procedure 1, starting from 4-bromobenzoyl chloride and 2-
aminobenzonitrile 9d was obtained as an off-white solid (0.85 g,
1
54%). H NMR (500 MHz, [D6]DMSO): d=9.68 (s, 1H, NH), 8.51 (d,
J=8.5 Hz, 2H), 8.19 (d, J=8.2 Hz, 1H), 7.74 (d, J=3.8 Hz, 2H), 7.68
(dt, J=1.9 Hz, J=8.5 Hz, 2H), 7.45 (dt, J=4.1 Hz, J=8.2 Hz, 1H),
4.90 ppm (s, 2H, NH2); MS (EI, 70 eV) m/z (%): 317 (97), 315 (100)
[M+H]+, purity: 94.6%.
General procedure 6: the appropriate (4H)-3,1-benzoxazin-4-one
22 (1.0 mmol), aminoguanidine bicarbonate (0.20 g, 1.5 mmol), and
pyridine (2 mL) were stirred at 1008C for 24 h. After cooling to RT,
the suspension was acidified to pH~1 using HCl (2n) and filtered.
The filtrate was neutralized with solid sodium carbonate and left at
48C overnight. The formed precipitate was collected, washed with
water (2ꢂ5 mL), dried, and then suspended in a 10% phosphorus
pentoxide in methanesulfonic acid (2 mL). The suspension was
heated at 1708C until white fumes emerged (~1 min). After cooling
to RT, water (5 mL) was added, and solid sodium carbonate was
used to bring the solution to neutral pH, at which a precipitate
formed. It was collected, washed with water (5 mL), and dried at
1008C.
2-(3-Fluorophenyl)-4-iminoquinazolin-3-amine (9e): following
general procedure 1, starting from 3-fuorobenzoyl chloride and 2-
aminobenzonitrile, 9e was obtained as off-white crystals (0.60 g,
1
47%). H NMR (500 MHz, [D6]DMSO): d=9.69 (s, 1H, NH), 8.40 ppm
(d, J=7.6 Hz, 1H), 8.31 (dquart, J=1.3 Hz, J=10.7 Hz, 1H), 8.20 (d,
J=8.2 Hz, 1H), 7.45 (ddd, J=3.2 Hz, J=4.7 Hz, J=8.2 Hz, 1H), 7.76
(m, 2H), 7.53 (dt, J=6.0 Hz, J=7.9 Hz, 1H), 7.31 (dt, J=2.5 Hz, J=
8.0 Hz, 1H), 4.91 ppm (s, 2H, NH2); MS (EI, 70 eV) m/z (%): 255 (100)
[M+H]+, purity: 98.3%.
General procedure 7: a mixture of 28 (0.11 g, 0.5 mmol) and the
appropriate amine (2 mL) was stirred at 608C. A 30% solution of
aqueous hydrogen peroxide was added slowly until no remaining
compound 28 could be detected by TLC. After cooling to RT, water
(10 mL) was added. The formed precipitate was collected, washed
with water (10 mL) and dried at 1008C.
2-(4-Fluorophenyl)-4-iminoquinazolin-3-amine (9 f): following
general procedure 1 starting from 4-fluorobenzoyl chloride and 2-
aminobenzonitrile, a mixture was obtained as orange crystals. Ana-
lytically pure 9 f was obtained after column chromatography (SiO2,
1
CHCl3/MeOH 98:2, 0.71 g, 56%). H NMR (500 MHz, [D6]DMSO): d=
9.66 (s, 1H, NH), 8.61 (dd, J=5.7 Hz, J=8.8 Hz, 2H), 8.18 (d, J=
8.2 Hz, 1H), 7.74 (d, J=3.8 Hz, 2H), 7.43 (quint, J=4.1 Hz, 1H), 7.31
(dt, J=2.4 Hz, J=8.8 Hz, 2H), 4.89 ppm (s, 2H, NH2); MS (EI, 70 eV)
m/z (%): 255 (100) [M+H]+, purity: 99.5%.
General procedure 8: a mixture of 11 s (0.12 g, 0.5 mmol) and the
appropriate amine (2 mL) was heated at 1208C for an appropriate
time. The resulting solution was allowed to cool to RT, then water
(5 mL) was added, and the mixture was kept at 48C overnight. The
formed precipitate was collected, washed with water (10 mL), and
dried at 1008C.
4-Imino-2-(3-thienyl)quinazolin-3-amine (9g): following general
procedure 1, starting from 3-thiophenecarbonyl chloride and 2-
aminobenzonitrile, 9g was obtained as a yellow solid (0.50 g,
1
51%). H NMR (500 MHz, [D6]DMSO): d=9.59 (s, 1H, NH), 8.45 (dd,
J=1.3 Hz, J=3.2 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.92 (d, J=4.7 Hz,
1H), 7.69 (m, 2H), 7.58 (dd, J=3.2 Hz, J=4.7 Hz, 1H), 7.40 (t, J=
6.5 Hz, 1H), 4.89 ppm (s, 2H, NH2); MS (EI, 70 eV) m/z (%): 243 (100)
[M+H]+, purity: 89.7%.
Synthesis of triazoloquinazolines using Method A
4-Iminoquinazolin-3-amine (9a): 2-aminobenzonitrile (2.36 g,
20 mmol) and triethyl orthoformate (3.7 g, 25 mmol) were placed
in a microwave tube and stirred at 1408C under microwave irradia-
tion (60 W) for 20 min. After removal of all volatiles at 808C under
reduced pressure, the remaining residue was stirred at RT for 16 h
in EtOH (2 mL) in the presence of hydrazine hydrate (1.5 g,
30 mmol). The resulting precipitate was collected, washed with
EtOH (2ꢂ4 mL) and dried at 808C to yield 9a as a yellow solid
4-Imino-2-(2-furyl)quinazolin-3-amine (9h): following general pro-
cedure 1, starting from 2-furoyl chloride and 2-aminobenzonitrile,
1
9h was obtained as a yellow solid (0.19 g, 33%). H NMR (500 MHz,
[D6]DMSO): d=9.64 (s, 1H, NH), 8.14 (d, J=8.2 Hz, 1H), 7.84 (s,
1H), 7.70 (m, 2H), 7.40 (m, 1H), 7.35 (dd, J=0.9 Hz, J=3.5 Hz, 1H),
6.65 (dd, J=1.7 Hz, J=3.3 Hz, 1H), 4.84 ppm (s, 2H, NH2); MS (EI,
70 eV) m/z (%): 227 (100) [M+H]+, purity: 91.1%.
1
(1.93 g, 60%). H NMR (500 MHz, [D6]DMSO): d=8.54 (brs, 1H, NH),
8.20 (dd, J=1.3 Hz, J=7.9 Hz, 1H), 7.95 (brs, 1H), 7.58 (dt, J=
&
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Full Papers
4-Imino-2-isopropylquinazolin-3-amine (9i) and N-(2-cyanophen-
yl)-isopropylcarboximidic acid hydrazide (10i): according to gen-
eral procedure 1, starting from isobutyryl chloride and 2-aminoben-
zonitrile, a clear green solution evolved after the addition of EtOH,
from which green oil separated upon the addition of water
(10 mL). The supernatant was decanted and the residual oil taken
up in diethyl ether. After solvent evaporation PE was added, lead-
ing to a yellow solid which was collected washed with PE and
dried at 608C, to yield a yellow solid mixture (0.39 g, 38%).
general procedure 1, starting from 3-phenylpropanoyl chloride and
2-aminobenzonitrile, a clear yellow solution evolved after the addi-
tion of EtOH. Water (20 mL) was mixed with the ethanolic solution
and the products were extracted in CHCl3 (2ꢂ20 mL). The organic
phases were combined and washed with brine (2ꢂ10 mL), dried
over MgSO4, filtered, and solvents were evaporated under reduced
pressure to yield a green oily mixture (0.51 g, 96%).
1
2-Phenethyl-4-iminoquinazolin-3-amine (9l) (38% of the H NMR
1
signals): H NMR (500 MHz, [D6]DMSO): d=10.48 (s, 1H, NH), 8.09
1
4-Imino-2-isopropylquinazolin-3-amine (9i) (70% of the H NMR
(dd, J=1.3 Hz, J=7.9 Hz, 1H), 7.54 (dt, J=1.6 Hz, J=7.6 Hz, 1H),
7.13–7.30 (m), 7.37 (d, J=7.3 Hz, 1H), 4.12 (s, 2H, NH2), 3.00 (m,
2H), 2.94 ppm (m, 2H); MS (EI, 70 eV) m/z (%): 265 (100) [M+H]+,
purity: 36.2%.
1
signals): H NMR (500 MHz, [D6]DMSO): d=9.45 (s, 1H, NH), 8.10 (d,
J=8.5 Hz, 1H), 7.67 (t, J=7.4 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.37
(t, J=7.4 Hz, 1H), 4.71 (s, 2H, NH2), 2.96 (hept, J=6.8 Hz, 1H),
1.35 ppm (d, J=6.9 Hz, 6H); MS (EI, 70 eV) m/z (%): 203 (100) [M+
H]+, purity: 68.4%.
N-(2-Cyanophenyl)-3-phenylpropanimidic acid hydrazide (10l)
(62% of the 1H NMR signals): 1H NMR (500 MHz, [D6]DMSO): d=
8.92 (s, 1H, NH), 7.35 (dd, J=1.6 Hz, J=7.9 Hz, 1H), 7.13–7.30 (m),
6.78 (d, J=8.5 Hz, 1H), 6.57 (dt, J=1.3 Hz, J=7.6 Hz, 1H), 5.97 (s,
2H, NH2), 2.80 (t, J=7.7 Hz, 2H), 2.31 ppm (t, J=7.8 Hz, 2H); MS
(EI, 70 eV) m/z (%): 265 (100) [M+H]+, purity: 59.7%.
N-(2-Cyanophenyl)isopropylcarboximido acid hydrazide (10i)
(30% of the 1H NMR signals): 1H NMR (500 MHz, [D6]DMSO): d=
10.31 (s, 1H, NH), 7.60 (d, J=8.2 Hz, 1H), 7.22 (t, J=7.4 Hz, 1H),
7.02 (t, J=7.1 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 5.79 (s, 2H, NH2),
2.59 (hept, J=6.9 Hz, 1H), 1.20 ppm (d, J=6.7 Hz, 6H); MS (EI,
70 eV) m/z (%): 203 (100) [M+H]+, purity: 28.0%.
[1,2,4]Triazolo[1,5-c]quinazoline (12a): following general proce-
dure 2, starting from 9a (80 mg, 0.5 mmol) and triethyl orthofor-
mate (1 mL), the product obtained was collected recrystallized
from EtOH (2 mL) then dried at 808C to yield golden platelets
2-Benzyl-4-iminoquinazolin-3-amine (9j) and N-(2-cyanophenyl)-
2-phenylacetimidic acid hydrazide (10j): according to general
procedure 1, starting from phenylacetic acid (2-cyanophenyl)amide
(30) (5.0 mmol) and hydrazine hydrate (40 mmol), yielded a green
solid mixture (0.19 g, 37%).
1
(36 mg, 42%), purity: 99.9%. H NMR (500 MHz, CDCl3): d=9.24 (s,
1H), 8.55 (ddd, J=0.8 Hz, J=1.6 Hz, J=7.9 Hz, 1H), 8.42 (s, 1H),
8.08 (d, J=8.2 Hz, 1H), 7.86 (ddd, J=1.3 Hz, J=6.9 Hz, J=8.5 Hz,
1H), 7.76 ppm (ddd, J=1.2 Hz, J=7.3 Hz, J=8.2 Hz, 1H); MS (EI,
70 eV) m/z (%): 171 (100) [M+H]+, purity: 99.9%.
2-Benzyl-4-iminoquinazolin-3-amine (9j) (67% of the 1H NMR
1
signal): H NMR (500 MHz, [D6]DMSO): d=9.55 (s, 1H, NH), 8.09 (m,
1H), 7.67 (m, 1H), 7.61 (m, 1H), 7.15–7.43 (m), 4.72 (s, 2H, NH2),
4.02 ppm (s, 2H); MS (EI, 70 eV) m/z (%): 251 (100) [M+H]+, purity:
66.5%
5-Phenyl[1,2,4]triazolo[1,5-c]quinazoline (12b): following general
procedure 2, starting from 9b (0.12 g, 0.5 mmol) and triethyl ortho-
formate (1 mL) the product was obtained as light-yellow needles
(0.10 g, 83%). 1H NMR (500 MHz, CDCl3): d=8.95 (s, 1H), 8.67 (d,
J=7.9 Hz, 1H), 8.03 (dd, J=0.8 Hz, J=8.2 Hz, 1H), 7.93 (m, 2H),
7.81 (dt, J=1.6 Hz, J=7.7 Hz, 1H), 7.72 (dt, J=1.3 Hz, J=7.6 Hz,
1H), 7.65 ppm (m, 3H); 13C NMR (125 MHz, CDCl3): d=144.5, 141.5,
136.0, 132.3, 132.2, 132.0, 129.5 (2C), 129.4, 148.5, 128.7, 128.5 (2C),
123.7, 115.7 ppm; MS (EI, 70 eV) m/z (%): 147 (100) [M+H]+,
purity: 99.9%.
N-(2-Cyanophenyl)-2-phenylacetimidic acid hydrazide (10j)
(33% of the 1H NMR signal): 1H NMR (500 MHz, [D6]DMSO): d=
10.66 (s, 1H, NH), 7.61 (m, 1H), 7.15–7.43 (m, 8H), 7.04 (m, 1H),
6.93 (m, 1H), 5.76 (s, 2H, NH2), 3.65 ppm (s, 2H); MS (EI, 70 eV) m/z
(%): 251 (100) [M+H]+, purity: 31.1%.
2-(3,4,5-Trimethoxyphenethyl)-4-iminoquinazolin-3-amine (9k)
and
N-(2-cyanophenyl)-2-(3,4,5-trimethoxyphenyl)propionic
imido acid hydrazide (10k): according to procedure 1, starting
from 3-(3,4,5-trimethoxyphenyl)propionyl chloride and 2-amino-
benzonitrile, a clear yellow solution evolved after the addition of
EtOH. The green solid precipitate formed upon addition of water
(20 mL) was filtered off, washed with water (2ꢂ4 mL), and dried in
a desiccator, to yield a green solid mixture (0.12 g, 33%).
5-(2-Thienyl)[1,2,4]triazolo[1,5-c]quinazoline (12c): following gen-
eral procedure 2, starting from 9c (0.12 g, 0.5 mmol) and triethyl
orthoformate (1 mL), the product was obtained as a colorless solid
1
(0.07 g, 55%). H NMR (500 MHz, [D6]DMSO): d=9.85 (s, 1H), 8.49
(ddd, J=0.5 Hz, J=1.6 Hz, J=8.5 Hz, 1H), 8.30 (dd, J=0.9 Hz, J=
3.8 Hz, 1H), 8.03 (dd, J=0.9 Hz, J=5.0 Hz, 1H), 7.85 (ddd, J=
1.6 Hz, J=7.3 Hz, J=8.2 Hz, 1H), 7.95 (m, 1H), 7.75 (ddd, J=1.2 Hz,
J=7.3 Hz, J=7.9 Hz, 1H), 7.36 ppm (dd, J=3.8 Hz, J=5.0 Hz, 1H);
13C NMR (125 MHz, [D6]DMSO): d=147.8, 140.8, 139.6, 137.1, 135.3,
132.8, 132.1, 131.3, 129.0, 128.9, 127.9, 122.9, 115.5 ppm; MS (EI,
70 eV) m/z (%): 253 (100) [M+H]+, purity: 98.8%.
2-(3,4,5-Trimethoxyphenethyl)-4-iminoquinazolin-3-amine (9k)
(70% of the 1H NMR signal): 1H NMR (500 MHz, [D6]DMSO): d=
9.51 (s, 1H, NH), 7.67 (t, J=7.6 Hz, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.60
(d, J=8.2 Hz, 1H),7.38 (t, J=7.1 Hz, 1H), 6.57 (s, 2H), 4.73 (s, 2H,
NH2), 3.71 (s, 6H), 3.60 (s, 3H), 3.04 ppm (m, 4H); MS (EI, 70 eV) m/
z (%): 355 (100) [M+H]+, purity: 67.5%.
2-Phenyl[1,2,4]triazolo[1,5-c]quinazoline (13a): 4-imino-quinazo-
lin-3-amine (9a) (0.16 g, 1.0 mmol), benzaldehyde (0.2 g, 2.0 mmol),
EtOH (5 mL) and a drop of triethylamine were stirred at 658C for
3 h. The mixture was cooled to RT and kept at 48C overnight. The
precipitate formed was collected, washed with EtOH (2ꢂ1 mL) and
dried at 808C to yield a colorless, cotton-like solid (0.11 g, 43%).
1H NMR (500 MHz, CDCl3): d=9.23 (s, 1H); 8.61 (dd, J=1.0 Hz, J=
7.6 Hz, 1H), 8.34 (m, 2H), 8.06 (d, J=8.5 Hz, 1H), 7.85 (ddd, J=
1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.75 (dt, J=1.3 Hz, J=7.6 Hz, 1H),
7.50 ppm (m, 3H); 13C NMR (125 MHz, CDCl3): d=165.1, 151.4,
142.9, 137.7, 132.0, 130.6, 130.0 (2C), 129.0, 128.9, 128.8, 127.6 (2C),
N-(2-Cyanophenyl)-2-(3,4,5-trimethoxyphenyl)propionic
imido
acid hydrazide (10k) (30% of the 1H NMR signal): 1H NMR
(500 MHz, [D6]DMSO): d=10.47 (s, 1H, NH), 7.60 (d, J=8.2 Hz, 1H),
7.22 (t, J=7.1 Hz, 1H), 7.03 (t, J=7.3 Hz, 1H), 6.90 (d, J=7.9 Hz,
1H), 6.59 (s, 2H), 5.82 (s, 2H, NH2), 3.72 (s, 6H), 3.61 (s, 3H), 2.95 (t,
J=8.0 Hz, 2H), 2.66 ppm (t, J=7.9 Hz, 2H); MS (EI, 70 eV) m/z (%):
355 (100) [M+H]+, purity: 28.6%.
2-Phenethyl-4-iminoquinazolin-3-amine (9l) and N-(2-cyano-
phenyl)-2-phenylacetimidic acid hydrazide (10l): according to
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Full Papers
123.8, 118.2 ppm; MS (EI, 70 eV) m/z (%): 247 (100) [M+H]+,
purity: 99.9%.
(dd, J=6.0 Hz, J=8.8 Hz, 2H), 8.26 (d, J=7.9 Hz, 1H), 7.85 (t, J=
7.4 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.44 (t, J=8.8 Hz, 2H), 6.51 ppm
(s, 2H, NH2); MS (EI, 70 eV) m/z (%): 280 (100) [M+H]+, purity:
97.3%.
2,5-Diphenyl[1,2,4]triazolo[1,5-c]quinazoline (13b): following
general procedure 2, starting from 9b (0.12 g, 0.5 mmol) and ben-
zoyl chloride (1 mL), the product was obtained as colorless solid
5-(3-Thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11g): start-
ing from 9g and following general procedure 3, a yellow solid was
1
(0.08 g, 51%). H NMR (500 MHz, CDCl3): d=8.64 (m, 3H), 8.40 (dd,
1
J=1.3 Hz, J=7.9 Hz, 2H), 8.11 (d, J=8.2 Hz, 1H), 7.84 (t, J=7.7 Hz,
1H), 7.71 (t, J=7.4 Hz, 1H), 7.61 (m, 3H), 7.51 ppm (m, 3H);
13C NMR (125 MHz, CDCl3): d=163.9, 152.9, 146.5, 143.0, 132.1,
131.8, 131.6, 130.5 (2C), 130.2, 128.8 (2C), 128.4 (br, 3C), 128.3 (2C),
127.7 (2C), 123.9, 117.3 ppm; MS (EI, 70 eV) m/z (%): 323 (100) [M+
H]+, purity: 98.9%.
isolated (109 mg, 82%). H NMR (500 MHz, [D6]DMSO): d=9.16 (dd,
J=1.3 Hz, J=3.2 Hz, 1H), 8.25 (dd, J=1.0 Hz, J=7.9 Hz, 1H), 8.17
(dd, J=1.3 Hz, J=5.0 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.84 (ddd,
J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.75 (dd, J=2.8 Hz, J=5.0 Hz,
1H), 7.66 (ddd, J=1.0 Hz, J=7.2 Hz, J=8.0 Hz, 1H), 6.52 ppm (s,
2H, NH2); 13C NMR (125 MHz, [D6]DMSO): d=166.0, 151.5, 142.6,
140.6, 133.5, 132.4, 131.9, 128.8, 128.1, 127.6, 126.5, 123.1,
115.4 ppm; MS (EI, 70 eV) m/z (%): 268 (100) [M+H]+, purity:
98.3%.
[1,2,4]Triazolo[1,5-c]quinazolin-2-amine (11a): starting from 9a
and following general procedure 3, a light-orange solid was ob-
tained (53 mg, 39%). 1H NMR (500 MHz, [D6]DMSO): d=9.21 (s,
1H), 8.23 (dd, J=1.3 Hz, J=8.2 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H),
7.83 (ddd, J=1.6 Hz, J=7.0 Hz, J=8.5 Hz, 1H), 7.71 (dt, J=1.3 Hz,
J=7.6 Hz, 1H), 6.42 ppm (s, 2H, NH2); 13C NMR (125 MHz,
[D6]DMSO): d=166.5, 149.9, 142.7, 137.9, 131.6, 128.3, 128.2, 123.0,
116.4 ppm; MS (EI, 70 eV) m/z (%): 186 (100) [M+H]+, purity:
98.0%.
5-(2-Furyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11h): starting
from 9h and following general procedure 3, a yellow solid was iso-
lated (106 mg, 84%). 1H NMR (500 MHz, [D6]DMSO): d=8.25 ppm
(dd, J=0.9 Hz, J=7.9 Hz, 1H), 8.14 (d, J=3.3 Hz, 1H), 8.12 (m, 1H),
7.97 (d, J=8.2 Hz, 1H), 7.84 (ddd, J=1.4 Hz, J=6.9 Hz, J=7.9 Hz,
1H), 7.67 (ddd, J=0.9 Hz, J=7.0 Hz, J=8.0 Hz, 1H), 6.86 (dd, J=
1.9 Hz, J=3.6 Hz, 1H), 6.56 ppm (s, 2H, NH2); 13C NMR (125 MHz,
[D6]DMSO): d=166.1, 151.2, 147.1, 144.6, 142.5, 136.3, 132.0, 128.1,
127.7, 123.1, 119.7, 115.3, 112.7 ppm; MS (EI, 70 eV) m/z (%): 252
(100) [M+H]+, purity: 97.6%.
5-Phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11b): starting
from 9b and following general procedure 3, a colorless solid was
isolated (102 mg, 78%). The synthesis of this compound is also de-
1
scribed following Method B. H NMR (500 MHz, [D6]DMSO): d=8.45
(m, 2H), 8.27 (ddd, J=0.6 Hz, J=1.6 Hz, J=7.9 Hz, 1H), 7.99 (dt,
J=0.8 Hz, J=7.9 Hz, 1H), 7.85 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz,
1H), 7.71 (ddd, J=1.1 Hz, J=6.9 Hz, J=9.1 Hz, 1H), 7.59 (m, 3H),
6.49 ppm (s, 2H, NH); 13C NMR (125 MHz, [D6]DMSO): d=166.0,
151.6, 145.1, 142.6, 132.2, 131.9, 131.2, 130.1 (2C), 128.3, 128.2 (2C),
127.9, 123.1, 115.7 ppm; MS (EI, 70 eV) m/z (%): 262 (100) [M+H]+,
purity: 99.3%.
5-Isopropyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11i): starting
from the mixture of 9i and 10i and following general procedure 3,
a yellow solid was isolated (81 mg, 71%). 1H NMR (500 MHz,
[D6]DMSO): d=8.20 (dd, J=1.0 Hz, J=8.2 Hz, 1H), 7.88 (d, J=
8.2 Hz, 1H), 7.79 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.64
(ddd, J=1.1 Hz, J=7.3 Hz, J=8.2 Hz, 1H), 6.41 (s, 2H, NH2), 3.72
(hept, J=6.8 Hz, 1H), 1.39 ppm (d, J=6.9 Hz, 6H); 13C NMR
(125 MHz, [D6]DMSO): d=165.8, 153.3, 150.3, 142.5, 131.5, 127.9,
127.3, 123.0, 115.6, 30.6, 19.6 ppm (2C); MS (EI, 70 eV) m/z (%): 228
(100) [M+H]+, purity: 98.7%.
5-(2-Thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11c): start-
ing from 9c and following general procedure 3, a yellow solid was
1
isolated (93 mg, 70%). H NMR (500 MHz, [D6]DMSO): d=8.79 (dd,
J=1.2 Hz, J=3.9 Hz, 1H), 8.24 (dd, J=1.3 Hz, J=8.0 Hz, 1H), 7.99
(dd, J=1.3 Hz, J=5.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.83 (ddd,
J=1.4 Hz, J=7.1 Hz, J=8.4 Hz, 1H), 7.66 (ddd, J=1.1 Hz, J=7.2 Hz,
J=8.2 Hz, 1H), 7.34 (dd, J=3.8 Hz, J=5.0 Hz, 1H), 6.59 ppm (s, 2H,
NH2); MS (EI, 70 eV) m/z (%): 268 (100) [M+H]+, purity: 98.1%.
5-Benzyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11j): starting
from the mixture of 9j and 10j and following general procedure 3,
an off-white solid was isolated (218 mg, 93%). 1H NMR (500 MHz,
[D6]DMSO): d=8.20 ppm (dd, J=1.3 Hz, J=8.2 Hz, 1H), 7.87 (d, J=
7.9 Hz, 1H), 7.79 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.66
(ddd, J=1.3 Hz, J=7.3 Hz, J=8.2 Hz, 1H), 7.39 (m, 2H), 7.30 (tt, J=
1.8 Hz, J=7.6 Hz, 2H), 7.23 (tt, J=1.8 Hz, J=7.3 Hz, 1H), 6.45 (s,
2H, NH2), 4.51 ppm (s, 2H); 13C NMR (125 MHz, [D6]DMSO) d=
165.9, 150.4, 147.9, 142.5, 135.9, 131.7, 129.1, 128.6, 127.9, 127.6,
126.9, 123.1, 115.6, 38.4 ppm; MS (EI, 70 eV) m/z (%): 276 (100)
[M+H]+, purity: 99.3%.
5-(4-Bromophenyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11d):
starting from 9d and following general procedure 3, a yellow solid
1
was isolated (152 mg, 90%). H NMR (500 MHz, [D6]DMSO): d=8.46
(m, 2H), 8.26 (dd, J=1.0 Hz, J=7.9 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H),
7.85 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.80 (m, 2H), 7.71
(ddd, J=1.0 Hz, J=7.0 Hz, J=7.9 Hz, 1H), 6.52 ppm (s, 2H, NH2);
13C NMR (125 MHz, [D6]DMSO): d=166.0, 151.6, 144.0, 142.5, 132.1
(2C), 131.9, 131.4, 131.3 (2C), 128.3, 128.1, 125.1, 123.2, 115.7 ppm;
MS (EI, 70 eV) m/z (%):342 (97), 340 (100) [M+H]+, purity: 98.2%.
5-(3’,4’,5’-Trimethoxy-2-phenethyl)[1,2,4]triazolo[1,5-c]quinazo-
lin-2-amine (11k): starting from 9k and following general proce-
1
dure 3, a yellow solid (112 mg, 60%). H NMR (500 MHz, [D6]DMSO):
d=8.20 (dd, J=1.0 Hz, J=8.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.80
(ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.66 (ddd, J=1.3 Hz, J=
7.3 Hz, J=8.2 Hz, 1H), 6.60 (s, 2H), 6.43 (s, 2H, NH2), 3.71 (s, 6H),
3.60 (s, 3H), 3.46 (t, J=7.7 Hz, 2H), 3.18 ppm (t, J=7.9 Hz, 2H); MS
(EI, 70 eV) m/z (%): 380 (100) [M+H]+, purity 98.4%.
5-(3-Fluorophenyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11e):
starting from 9e and following general procedure 3, a yellow solid
was isolated (190 mg, 85%). H NMR (500 MHz, [D6]DMSO): d=8.35
(m, 2H), 8.28 (dd, J=1.0 Hz, J=7.6 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H),
7.87 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.73 (ddd, J=
1.0 Hz, J=6.9 Hz, J=8.2 Hz, 1H), 7.65 (dt, J=6.0 Hz, J=8.2 Hz, 1H),
7.48 (ddd, J=1.0 Hz, J=2.5 Hz, J=8.5 Hz, 1H), 6.54 ppm (s, 2H,
NH2); MS (EI, 70 eV) m/z (%): 280 (100) [M+H]+, purity: 98.5%.
1
5-(2-Phenethyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine
(11l):
starting from the mixture of 9l and 10l and following general pro-
cedure 3, a brown residue was isolated and purified by column
chromatography (SiO2, CHCl3/EtOH 98:2) to yield colorless solid
(80 mg, 28%). 1H NMR (500 MHz, [D6]DMSO): d=8.20 (ddd, J=
0.6 Hz, J=1.6 Hz, J=7.9 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.80 (ddd,
5-(4-Fluorophenyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 f):
starting from 9 f and following general procedure 3, a tan solid
1
was isolated (190 mg, 85%). H NMR (500 MHz, [D6]DMSO): d=8.57
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J=1.6 Hz, J=7.0 Hz, J=8.5 Hz, 1H), 7.65 (ddd, J=1.3 Hz, J=7.3 Hz,
J=8.2 Hz, 1H), 7.29 (m, 3H), 7.18 (tt, J=1.7 Hz, J=6.9 Hz, 1H), 6.43
(s, 2H, NH2), 3.45 (t, J=7.9 Hz, 2H), 3.23 ppm (t, J=7.9 Hz, 2H); MS
(EI, 70 eV) m/z (%): 290 (100) [M+H]+, purity: 99.9%.
Cooling at 48C for 1 h resulted in a white precipitate, which was
collected by filtration, washed with water (2ꢂ5 mL) and dried by
1
desiccator to yield a colorless solid (38 mg, 28). H NMR (500 MHz,
[D6]DMSO): d=12.61 (s, 1H, NH), 8.29 (dd, J=1.2 Hz, J=3.9 Hz,
1H), 8.06 (m, 1H), 7.85 (dd, J=1.1 Hz, J=5.0 Hz, 1H), 7.69 (m, 2H),
7.55 (ddd, J=2.2 Hz, J=6.3 Hz, J=7.9 Hz, 1H), 7.20 ppm (dd, J=
3.9 Hz, J=5.0 Hz, 1H); 13C NMR (125 MHz, [D6]DMSO): d=149.8,
142.3, 141.2, 141.1, 134.8, 134.4, 132.1, 131.7, 128.4, 127.7, 127.5,
121.7, 116.2 ppm; MS (EI, 70 eV) m/z (%): 269 (100) [M+H]+,
purity: 98.4%.
5-((R,S)-1-Phenethyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine
(11m): (R,S)-2-phenylpropionyl chloride (1.6 g, 1 mmol) and hydra-
zine hydrate (2 g, 40 mmol) were stirred at 1208C under microwave
irradiation (40 W) for 10 min. The mixture was allowed to cool to
RT, and EtOH (2 mL) was added. Then the solution was heated at
70–808C and subsequently left at 48C for 16 h. The resulting
turbid solution was filtered, and water (10 mL) was added to the
filtrate. After extraction with CHCl3 (3ꢂ10 mL) the combined or-
ganic phases were dried over MgSO4, filtered and evaporated
under reduced pressure to yield a viscous pale-green oil (528 mg).
Starting from this oil and following general procedure 3, a brown
residue was obtained. It was purified by column chromatography
(SiO2, CHCl3/EtOH 98:2) to yield an off-white solid (448 mg, 15%).
1H NMR (500 MHz, DMSO): d=8.20 (dd, J=1.0 Hz, J=7.9 Hz, 1H),
7.96 (d, J=8.2 Hz, 1H), 7.82 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz,
1H), 7.67 (ddd, J=1.3 Hz, J=7.3 Hz, J=8.2 Hz, 1H), 7.37 (m, 2H),
7.28 (t, J=7.6 Hz, 2H), 7.19 (tt, J=1.3 Hz, J=7.3 Hz, 1H), 6.38 (s,
2H, NH2), 4.99 (quart, J=7.2 Hz, 1H), 1.73 ppm (d, J=7.3 Hz, 3H);
MS (EI, 70 eV) m/z (%): 290 (100) [M+H]+, purity: 98.8%.
5-Phenyl[1,2,4]triazolo[1,5-c]quinazolin-2(3H)-thione (16b): thio-
phosgene (70 mg, 0.5 mmol) was slowly added to a mixture of po-
tassium carbonate (70 mg, 0.5 mmol), water (1 mL) and CHCl3
(20 mL) at 08C. A solution of 9b (0.12 g, 0.5 mmol) in CHCl3
(10 mL) at 08C was added drop-wise to the mixture. The resulting
solution was stirred at RT for 4 h. Then 27% aqueous ammonia so-
lution (1 mL) was added and the mixture was stirred at RT for 2 h.
Volatiles were removed at reduced pressure and water (10 mL) was
added to the residual solution. Then the solution adjusted to
pH 11–12 by the addition of aqueous sodium hydroxide solution
(2n). The resulting turbid solution was filtered and the filtrate was
subsequently acidified to pH 3–4 by the addition of HCl (2n) solu-
tion. Cooling at 48C for 1 h resulted in the formation of a yellow
precipitate, which was collected by filtration, washed with water
(2ꢂ5 mL) and dried in a desiccator. The product was recrystallized
2-Dimethylamino-5-phenyl[1,2,4]triazolo[1,5-c]quinazoline (14b):
a mixture of 9b (0.12 g, 0.5 mmol), N-(dichloromethylene)-N,N-di-
methylammonium chloride (125 mg, 0.75 mmol), anhydrous potas-
sium carbonate (0.17 g, 1.2 mmol), and CHCl3 (10 mL) was stirred
at RT for 4 h. After addition of water (15 mL), the mixture was ex-
tracted with CHCl3 (2ꢂ15 mL). The combined organic phases were
washed with brine, dried over magnesium sulfate, filtered, and
1
from EtOH (2 mL) to yield a colorless solid (76 mg, 55%). H NMR
(500 MHz, [D6]DMSO): d=14.44 (s, 1H, NH), 8.26 (d, J=7.9 Hz, 1H),
7.83 (m, 2H), 7.70 (t, J=6.8 Hz, 1H), 7.61 (d, J=7.3 Hz, 2H), 7.49 (t,
J=7.4 Hz, 1H), 7.42 ppm (t, J=7.6 Hz, 2H); 13C NMR (125 MHz,
[D6]DMSO): d=162.9, 147.8, 145.7, 141.1, 132.7, 132.6, 130.0 (2C),
129.8, 129.2, 128.2, 126.8 (2C), 122.4, 116.3 ppm; MS (EI, 70 eV) m/z
(%): 279 (100) [M+H]+, purity: 99.8%.
evaporated under reduced pressure to yield
a yellow solid
(134 mg, 93%). 1H NMR (500 MHz, [D6]DMSO): d=8.41 (ddd, J=
0.4 Hz, J=1.5 Hz, J=7.9 Hz, 1H), 7.91 (ddd, J=0.4 Hz, J=1.2 Hz,
J=8.2 Hz, 1H), 7.79 (m, 3H), 7.70 (dt, J=1.3 Hz, J=7.9 Hz, 1H),
7.60 (dt, J=1.9 Hz, J=7.6 Hz, 1H), 7.51 (m, 2H), 2.39 ppm (s, 6H);
MS (EI, 70 eV) m/z (%): 290 (100) [M+H]+, purity: 97.5%.
5-(2-Thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2(3H)-thione (16c):
a mixture of 9c (0.12 g, 0.5 mmol), thiocarbonyldiimidazole (0.18 g,
1.0 mmol) and DMF (1 mL) was stirred at 608C for 27 h. The mix-
ture was poured into water (5 mL) and the solution was adjusted
to pH 13 by the addition of aqueous sodium hydroxide (2n) solu-
tion. The resulting turbid solution was filtered and the filtrate sub-
sequently acidified to pH 3 using an aqueous HCl solution (2n).
Cooling overnight at 48C resulted a yellow precipitate, which was
collected, washed with water (10 mL) and dried at 808C to yield
a yellow solid (116 mg, 82%). 1H NMR (500 MHz, [D6]DMSO): d=
14.51 (s, 1H, NH), 8.24 (d, J=7.8 Hz, 1H), 7.83 (m, 2H), 7.79 (dd, J=
1.3 Hz, J=5.0 Hz, 1H), 7.70 (ddd, J=2.1 Hz, J=6.5 Hz, J=8.0 Hz,
1H), 7.60 (dd, J=1.2 Hz, J=3.7 Hz, 1H), 7.14 ppm (dd, J=3.7 Hz,
J=5.0 Hz, 1H); MS (EI, 70 eV) m/z (%): 285 (100) [M+H]+, purity:
98.1%.
5-Phenyl[1,2,4]triazolo[1,5-c]quinazolin-2(3H)-one (15b): a mix-
ture of 9b (0.12 g, 0.5 mmol), carbonyldiimidazole (0.12 g,
0.75 mmol) and toluene (20 mL) was stirred at 1008C for 2 h. After
cooling to RT the mixture was filtered and the residue was washed
with PE (2ꢂ5 mL), then dried at 808C to yield a yellow solid
(168 mg) that was suspended in cold water (30 mL). The solution
was adjusted to pH 10–11 by the addition of aqueous ammonia so-
lution. The resulting turbid solution was filtered and the filtrate
was subsequently acidified to pH 3 using aqueous HCl solution
(1n). Cooling at 48C for 1 h resulted in a white precipitate, which
was collected by filtration, washed with water (2ꢂ5 mL) and dried
in a desiccator to yield a colorless solid (76 mg, 58%). 1H NMR
(500 MHz, [D6]DMSO): d=7.46 (t, J=7.4 Hz, 2H), 7.53 (t, J=7.4 Hz,
1H), 7.61 (dt, J=1.7 Hz, J=8.2 Hz, 1H), 7.73 (m, 4H), 8.12 (d, J=
7.9 Hz, 1H), 12.49 ppm (s, 1H, NH); MS (EI, 70 eV) m/z (%): 263
(100) [M+H]+, purity: 98.6%.
3,5-Diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17): following gen-
eral procedure 2, starting from 9a (80 mg, 0.5 mmol) and benzoyl
chloride (1 mL), the product was obtained as a colorless solid
(67 mg, 54%). 1H NMR (500 MHz, CDCl3): d=8.89 ppm (d, J=
8.1 Hz, 1H), 8.62 (dd, J=1.9 Hz, J=7.9 Hz, 2H), 8.46 (dd, J=2.5 Hz,
J=7.9 Hz, 2H), 8.15 (d, J=8.2 Hz, 1H), 7.89 (ddd, J=1.3 Hz, J=
7.4 Hz, J=8.2 Hz, 1H), 7.77 (dt, J=1.2 Hz, J=7.7 Hz, 1H), 7.62 (m,
3H), 7.53 ppm (m, 3H); 13C NMR (125 MHz, CDCl3): d=162.5, 152.0,
146.3, 143.2, 133.0, 131.9, 131.3, 131.1, 130.3, 130.6 (2C), 128.9,
128.8, 128.7, 128.5 (2C), 128.0 (2C), 124.7, 116.2 ppm; MS (EI, 70 eV)
m/z (%): 323(100) [M+H]+, purity: 98.3%.
5-(2-Thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2(3H)-one
(15c):
a mixture of 9c (0.12 g, 0.5 mmol), carbonyldiimidazole (0.12 g,
0.75 mmol) and toluene (20 mL) was stirred at 1008C for 2 h. After
cooling to RT the mixture was filtered and the residue was washed
with PE (2ꢂ5 mL) and dried at 808C to yield a bright-orange solid
(210 mg) that was suspended in cold water (30 mL). Then the solu-
tion was adjusted to pH 10–11 by the addition of 27% aqueous
ammonia solution. The resulting turbid solution was filtered and
subsequently acidified to pH 3 using aqueous HCl solution (1n).
5,6a,7a,12,13-Pentaazaindeno[1,2-b]phenanthrene
or
5,6a,7,8,13-pentaazaindeno[2,1-b]phenanthrene (18): a mixture
of 9a (0.16 g, 1.0 mmol), isatin (0.16 g, 1.1 mmol), and EtOH (5 mL)
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was stirred in a glass pressure tube at 1008C for 30 min. The pre-
cipitate formed upon cooling to RT was collected by filtration,
washed with EtOH (2ꢂ1 mL) and dried at 808C to yield dark-red
crystals (0.21 g, 79%). 1H NMR (500 MHz, [D6]DMSO): d=9.40 (s,
1H), 8.89 (dd, J=0.8 Hz, J=8.2 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H),
8.04 (m, 2H), 7.89 (ddd, J=1.6 Hz, J=7.0 Hz, J=8.2 Hz, 1H), 7.82
(dt, J=1.3 Hz, J=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.44 ppm (dt,
J=1.3 Hz, J=7.3 Hz, 1H); 13C NMR (125 MHz, [D6]DMSO): d=160.6,
150.9, 147.4, 146.0, 145.4, 143.1, 134.7, 134.3, 129.3, 128.0, 125.2,
123.5, 122.8, 121.5, 120.0, 119.9 ppm; MS (EI, 70 eV) m/z (%): 272
(100) [M+H]+, purity: 99.0%
NH), 12.52 (s, 1H, NH), 8.85 (m, 2H), 8.72 (d, J=8.2 Hz, 2H), 8.10 (d,
J=7.5 Hz, 1H), 7.97 (dd, J=1.6 Hz, J=4.4 Hz, 2H), 7.40 (t, J=
7.7 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 6.46 (s, 2H, NH2); MS (EI, 70 eV)
m/z (%): 281 (100) [M+H]+, purity 98.2%.
5-Phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11b): following
general procedure 5, starting from 23b a colorless solid (96 mg,
74%) was obtained, purity: 99.1%. Analytical data and preparation
via Method A are described above.
5-Methyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11n): following
general procedure 6, starting from 22n the product was isolated
and further purified by column chromatography (SiO2, in CHCl3/
EtOH 95:5) instead of the addition of water, neutralization and fil-
3-(4-Imino-2-phenyl-4H-quinazolin-3-ylimino)-1,3-dihydroindol-
2-one (19): A mixture of 9b (0.12 g, 0.5 mmol), isatin (0.9 g,
0.6 mmol), and EtOH (5 mL) was stirred in a glass pressure tube at
1008C for 1 h. The precipitate formed upon cooling to RT was col-
lected by filtration, washed with EtOH (2ꢂ1 mL) and dried at 808C
to yield bright-orange needles (0.19 g, 98%). 1H NMR (500 MHz,
[D6]DMSO): d=11.36 (brs, 1H, NH), 10.66 (s, 1H, NH), 8.44 (d, J=
6.3 Hz, 2H), 8.08 (d, J=5.7 Hz, 2H), 7.83 (brs, 1H), 7.65 (m, 5H),
7.33 (t, J=7.4 Hz, 1H), 7.08 (t, J=7.3 Hz, 1H), 6.88 ppm (d, J=
7.6 Hz, 1H); 13C NMR (125 MHz, [D6]DMSO): d=165.6, 146.0, 143.8,
132.9, 131.9, 129.0, 128.2, 127.4, 125.0, 122.1, 117.8, 110.3 ppm; MS
(EI, 70 eV) m/z (%): 366 (100) [M+H]+, purity: 99.5%.
1
tration, to yield a colorless solid (67 mg, 34%). H NMR (500 MHz,
[D6]DMSO): d=8.19 (ddd, J=0.6 Hz, J=1.6 Hz, J=7.9 Hz, 1H), 7.86
(d, J=7.9 Hz, 1H), 7.79 (ddd, J=1.6 Hz, J=7.0 Hz, J=8.5 Hz, 1H),
7.64 (ddd, J=1.3 Hz, J=7.3 Hz, J=8.2 Hz, 1H), 6.40 (s, 2H, NH2),
2.78 ppm (s, 3H); MS (EI, 70 eV) m/z (%): 200 (100) [M+H]+, purity
99.7%.
5-(3-Pyridyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11o): follow-
ing general procedure 5, starting from 22o golden platelets
(65 mg, 50%) were obtained. 1H NMR (500 MHz, [D6]DMSO): d=
9.58 (s, 1H, 2’-H), 8.79 (m, 2H), 8.28 (d, J=7.9 Hz, 1H), 8.02 (d, J=
8.2 Hz, 1H), 7.87 (t, J=7.3 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.64 (dd,
J=5.0 Hz, J=7.0 Hz, 1H), 6.54 ppm (s, 2H, NH2); MS (EI, 70 eV) m/z
(%): 263 (100) [M+H]+, purity: 99.9%.
5’-Phenyl-1,2-dihydro-3’H-spiro[indole-3,2’-[1,2,4]triazolo[1,5-
c]quinazolin]-2-one (20): 3-(4-imino-2-phenyl-4H-quinazolin-3-yli-
mino)-1,3-dihydroindol-2-one (19) (10 mg, 0.03 mmol) and a 10%
solution of phosphorous pentoxide in methanesulfonic acid (1 mL)
were heated at 1708C until the black solution turned orange (~
1 min) and then cooled to RT. The precipitate formed upon addi-
tion of water (5 mL) and neutralization with solid sodium carbon-
ate, was collected by filtration, washed with water (2ꢂ5 mL), and
dried at 808C to yield a yellow solid (10 mg, 95%). 1H NMR
(500 MHz, [D6]DMSO): d=13.90 (s, 1H), 11.37 (s, 1H), 8.56 (m, 3H),
7.99 (m, 2H), 7.76 (d, J=6.9 Hz, 1H), 7.56 (m, 3H), 7.74 (ddd, J=
1.6 Hz, J=6.3 Hz, J=8.2 Hz, 1H), 7.40 (dt, J=1.0 Hz, J=7.6 Hz, 1H),
7.16 (dt, J=1.0 Hz, J=7.6 Hz, 1H), 6.99 ppm (d, J=7.9 Hz, 1H);
13C NMR (125 MHz, [D6]DMSO): d=163.5, 159.2, 156.4, 151.9, 142.0,
137.6, 135.5, 134.2, 131.3, 130.8, 128.7 (2C), 128.2 (3C), 127.4, 123.5,
122.7, 120.7, 120.3, 112.9, 111.3 ppm; MS (EI, 70 eV) m/z (%): 366
(100) [M+H]+, purity: 97.7%.
5-(4-Pyridyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11p): follow-
ing general procedure 5, starting from 22p a solid was obtained,
which was further purified by column chromatography (SiO2,
1
CHCl3/EtOH 80:20) to yield a colorless solid (67 mg, 51%). H NMR
(500 MHz, [D6]DMSO): d=8.84 (d, J=6.0 Hz, 2H), 8.39 (dd, J=
1.6 Hz, J=4.4 Hz, 2H), 8.04 (d, J=8.0 Hz, 1H), 8.29 (dd, J=1.0 Hz,
J=8.1 Hz, 1H), 7.89 (ddd, J=1.5 Hz, J=7.1 Hz, J=8.2 Hz, 1H), 7.76
(ddd, J=1.3 Hz, J=7.3 Hz, J=8.2 Hz, 1H), 6.57 ppm (s, 2H, NH2);
MS (EI, 70 eV) m/z (%): 263 (100) [M+H]+, purity 99.8%.
9-Bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11q):
following general procedure 6, starting from 22q a dark solid was
obtained that was further purified by column chromatography
(SiO2, CHCl3/EtOH 98:2) to obtain an analytically pure colorless
solid (884 mg, 66%). 1H NMR (500 MHz, CDCl3): d=8.54 (d, J=
2.2 Hz, 1H), 8.43 (m, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.86 (dd, J=
2.2 Hz, J=8.8 Hz, 1H), 7.48 (m, 3H), 4.75 ppm (s, 2H, NH2); MS (EI,
70 eV) m/z (%): 340 (100) 342 (97) [M+H]+, purity: 99.6%.
Synthesis of triazoloquinazolines using Method B
3-Guanidino-2-phenylquinazolin-4(3H)-one (23b): following gen-
eral procedure 4, starting from 22b a colorless solid (178 mg, 64%)
9-Fluoro-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11r):
benzoyl chloride (2.2 equiv, 168 mg, 1.2 mmol) was added drop-
wise to a stirred solution of 2-amino-5-fluorobenzoic acid (77 mg,
0.5 mmol) in pyridine (1.5 mL). After 30 min, water (15 mL) was
added and the formed precipitate was collected by filtration,
washed with water, and subsequently used as a starting material
for the subsequent reaction following general procedure 6. The ob-
tained product was further purified by column chromatography
(SiO2, CHCl3/EtOH 98:2) to provide a colorless solid (57 mg, 41%).
1H NMR (500 MHz, [D6]DMSO): d=8.44 (m, 2H), 8.07 (dd, J=5.0 Hz,
J=9.1 Hz, 1H), 7.92 (dd, J=2.8 Hz, J=8.4 Hz, 1H), 7.73 (dt, J=
2.8 Hz, J=8.8 Hz, 1H), 7.60 (m, 3H), 6.53 ppm (s, 2H, NH2); MS (EI,
70 eV) m/z (%): 280 (100) [M+H]+, purity: 99.9%.
1
was obtained. H NMR (500 MHz, [D6]DMSO): d=12.55 (s, 1H, NH),
12.51 (s, 1H, NH), 8.75 (d, J=8.5 Hz, 1H), 8.10 (m, 3H), 7.61 (m,
3H), 7.38 (t, J=7.4 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 6.39 (s, 2H,
NH2); MS (EI, 70 eV) m/z (%): 280 (100) [M+H]+, purity 99.5%.
3-Guanidino-2-(3-pyridyl)quinazolin-4(3H)-one (23o): following
general procedure 4, starting from 22o a colorless solid (199 mg,
1
71%) was obtained. H NMR (500 MHz, [D6]DMSO): d=12.62 (s, 1H,
NH), 12.55 (s, 1H, NH), 9.21 (d, J=1.9 Hz, 1H), 8.80 (dd, J=1.6 Hz,
J=5.0 Hz, 1H), 8.72 (d, J=8.2 Hz, 1H), 8.42 (d, J=7.9 Hz, 1H), 8.10
(d, J=7.6 Hz, 1H), 7.64 (dd, J=4.7 Hz, J=7.6 Hz, 1H), 7.40 (t, J=
7.6 Hz, 1H), 7.18 (t, J=7.4 Hz, 1H), 6.40 (s, 2H, NH2); 13C NMR
(125 MHz, [D6]DMSO): d=163.3, 158.0, 156.7, 152.5, 148.7, 148.4,
136.7, 135.0, 130.4, 129.2, 127.6, 124.2, 123.6, 119.9, 119.1; MS (EI,
70 eV) m/z (%): 281 (100) [M+H]+, purity 99.0%.
N,N-Dimethyl-N’-(5-(3-pyridyl)[1,2,4]triazolo[1,5-c]quinazolin-2-
yl)formamidine (11o): following procedure 5 starting from 23o,
performing the cyclization step with phosphorus pentoxide
(120 mg) in DMF (3 mL) at 1558C instead of methanesulfonic acid,
3-Guanidino-2-(4-pyridyl)quinazolin-4(3H)-one (23p): following
general procedure 4, starting from 22p a colorless solid (246 mg,
1
88%) was obtained. H NMR (500 MHz, [D6]DMSO): d=12.82 (s, 1H,
yielded
a
colorless solid (33 mg, 21%). 1H NMR (500 MHz,
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[D6]DMSO): d=9.58 (s, 1H, 2’-H), 8.85 (dt, J=1.9 Hz, J=8.0 Hz, 1H),
8.80 (dd, J=1.6 Hz, J=4.8 Hz, 1H), 8.66 (s, 1H), 8.37 (dd, J=0.9 Hz,
J=7.9 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.90 (dt, J=1.4 Hz, J=
7.3 Hz, 1H), 7.77 (dt, J=0.9 Hz, J=7.3 Hz, 1H), 7.67 (dd, J=4.9 Hz,
J=7.9 Hz, 1H), 3.17 (s, 3H), 3.05 ppm (s, 3H); MS (EI, 70 eV) m/z
(%): 318 (100) [M+H]+, purity: 99.5%.
5-Piperidino[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11u): the
product was obtained by two different methods. In the first
method, 28 (0.11 g, 0.5 mmol) and piperidine (1 mL) were stirred at
1008C for 9 h. EtOH (~5 mL) was added until a clear boiling solu-
tion evolved. After cooling to RT, the solution was left at 48C over-
night. The precipitate formed was collected, washed with EtOH
(5 mL) and dried at 1208C to yield 11 u as a colorless solid (72 mg,
53%). In the second method, the reaction was performed accord-
ing to general procedure 7 but at 808C starting from piperidine, af-
fording 11 u as a colorless solid (69 mg, 51%). 1H NMR (500 MHz,
[D6]DMSO): d=8.05 (dd, J=1.0 Hz, J=8.2 Hz, 1H), 7.63 (ddd, J=
1.6 Hz, J=6.9 Hz, J=8.5 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.36 (ddd,
J=1.3 Hz, J=7.3 Hz, J=8.2 Hz, 1H), 6.28 (s, 2H, NH2), 3.88 (m, 4H),
1.66 ppm (brs, 6H); MS (EI, 70 eV) m/z (%): 269 (100) [M+H]+,
99.7%.
5-Phenylpyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-2-amine (27):
following general procedure 5, starting from 26 (0.22 g, 1.0 mmol)
yielded
a
colorless solid (86 mg, 33%). 1H NMR (500 MHz,
[D6]DMSO): d=9.06 (dd, J=1.9 Hz, J=4.4 Hz, 1H), 8.66 (dd, J=
1.9 Hz, J=7.9 Hz, 1H), 8.51 (m, 2H), 7.71 (dd, J=4.4 Hz, J=7.9 Hz,
1H), 7.62 (m, 3H), 6.60 ppm (s, 2H, NH2); MS (EI, 70 eV) m/z (%):
263 (100) [M+H]+, purity: 98.6%.
5-Isopropyl[1,2,4]triazolo[1,5-c]quinazolin-2(3H)-one (15i): 22i
(0.19 g, 1.0 mmol), semicarbazide hydrochloride (0.13 g, 1.2 mmol)
and pyridine (2 mL) were heated in a tube at 1608C under micro-
wave irradiation (60 W) for 30 min. After allowing the mixture to
cool to RT, water (5 mL) was added and the resulting solution was
stored at 48C overnight. The formed solid was filtered off, washed
with water (10 mL) and dried in a desiccator to yield a colorless
solid (23 mg, 10%). 1H NMR (500 MHz, CDCl3): d=11.17 (s, 1H),
8.28 (ddd, J=0.5 Hz, J=1.5 Hz, J=8.1 Hz, 1H), 7,75 (ddd, J=
1.6 Hz, J=6.9 Hz, J=8.2 Hz, 1H), 7.70 (ddd, J=0.5 Hz, J=1.1 Hz,
J=8.2 Hz, 1H), 7.44 (ddd, J=1.3 Hz, J=6.9 Hz, J=8.1 Hz, 1H), 3.02
(hept, J=7.0 Hz, 1H), 1.42 ppm (d, J=7.2 Hz, 6H); MS (EI, 70 eV)
m/z (%): 229 (100) [M+H]+, purity 98.5%.
5-Morpholino[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11v): ac-
cording to general procedure 7, starting from morpholine, a color-
less solid (91 mg, 67%) was obtained. 1H NMR (500 MHz,
[D6]DMSO): d=8.08 (dd, J=0.9 Hz, J=7.9 Hz, 1H), 7.66 (ddd, J=
1.6 Hz, J=6.9 Hz, J=8.2 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.40 (ddd,
J=1.0 Hz, J=7.9 Hz, 1H), 6.33 (s, 2H, NH2), 3.91 (m, 4H), 3.78 ppm
(m, 4H); MS (EI, 70 eV) m/z (%): 271 (100) [M+H]+, purity: 98.1%.
5-Butylamino[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11w): ac-
cording to general procedure 7, starting from butylamine, a color-
less solid was obtained (20 mg, 16%). 1H NMR (500 MHz,
[D6]DMSO): d=7.98 (dd, J=1.3 Hz, J=7.9 Hz, 1H), 7.59 (ddd, J=
1.6 Hz, J=6.9 Hz, J=8.5 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.30 (t, J=
5.8 Hz, 1H, NH), 7.27 (ddd, J=1.3 Hz, J=7.9 Hz, 1H), 6.17 (s, 2H,
NH2), 1.63 (quint, J=7.3 Hz, 2H), 1.63 (quart, J=6.7 Hz, 2H), 1.36
(sext, J=7.4 Hz, 2H), 0.92 ppm (t, J=7.4 Hz, 3H); MS (EI, 70 eV) m/
z (%): 257 (100) [M+H]+, purity: 98.7%.
N,N-Dimethyl-N’-(5-(3-pyridyl)[1,2,4]triazolo[1,5-c]quinazolin-2-
yl)formamidine (24o) was obtained as a colorless solid (13 mg,
21%) when general procedure 5 was applied to 23o (56 mg,
0.2 mmol) replacing the usual reagent by phosphorus pentoxide
(240 mg) in DMF (3 mL). TLC: Rf =0.1 (eluent: CHCl3/EtOAc=1:1).
1H NMR (500 MHz, DMSO): d=3.05 (s, 3H, CH3), 3.17 (s, 3H, CH3),
7.67 (dd, J=4.9 Hz, J=7.9 Hz, 1H), 7.77 (dt, J=0.9 Hz, J=7.3 Hz,
1H), 7.90 (dt, J=1.4 Hz, J=7.3 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.37
(dd, J=0.9 Hz, J=7.9 Hz, 1H), 8.66 (s, 1H, N=CH-N), 8.80 (dd, J=
1.6 Hz, J=4.8 Hz, 1H), 8.85 (dt, J=1.9 Hz, J=8.0 Hz, 1H), 9.58 ppm
(s, 1H, 2’-H).
5-Benzylamino[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11x): ac-
cording to general procedure 7 starting from benzylamine a color-
less solid (107 mg, 73%) was obtained which was purified by addi-
tional washing with EtOH. 1H NMR (500 MHz, [D6]DMSO): d=8,00
(m, 2H), 7.58 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.50 (d, J=
8.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.30 (m, 3H), 7.21 (dt, J=
1.3 Hz, J=7.3 Hz, 1H), 6.21 (s, 2H, NH2), 4.73 ppm (d, J=6.3 Hz,
2H); MS (EI, 70 eV) m/z (%): 291 (100) [M+H]+, purity: 97.8%.
Synthesis of triazoloquinazolines using Methods C and D
5-Methylsulfanyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine
methyl iodide (0.78 g, 5.5 mmol) was added to a mixture of 2-ami-
no[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-thione (28, 1.09 g,
(11s):
5-(2-Hydroxyethylamino)[1,2,4]triazolo[1,5-c]quinazolin-2-amine
(11y): according to general procedure 8, starting from ethanola-
mine and heating at 1208C for 90 min a colorless solid (103 mg,
1
5.0 mmol), MeOH (5 mL), and 2% aqueous sodium hydroxide solu-
tion (15 mL). After stirring for 30 min at RT, the precipitate was col-
lected, washed with water (20 mL), and dried in a desiccator to
84%) was obtained. H NMR (500 MHz, [D6]DMSO): d=8.00 (dd, J=
1.6 Hz, J=7.9 Hz, 1H), 7.60 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz,
1H), 7.52 (d, J=7.9 Hz, 1H), 7.30 (ddd, J=1.0 Hz, J=7.9 Hz, 1H),
7.14 (t, J=5.5 Hz, 1H, NH), 6.21 (s, 2H, NH2), 4.84 (t, J=5.4 Hz, 1H,
OH), 3.61 ppm (m, 4H); MS (EI, 70 eV) m/z (%): 245 (100) [M+H]+,
purity: 99.0%
1
yield a colorless solid (1.16 g, 97%). H NMR (500 MHz, [D6]DMSO):
d=8.17 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.80 (t, J=
7.3 Hz, 1H), 7.60 (t, J=7.3 Hz, 1H), 6.52 (s, 2H, NH2), 2.71 ppm
(SCH3); 13C NMR (151 MHz, [D6]DMSO): d=165.9, 149.6, 148.4,
143.1, 131.8, 127.0, 126.7, 123.2, 114.3, 12.9 ppm (SCH3); MS (EI,
70 eV) m/z (%): 232 (100) [M+H]+, purity: 99.3%.
5-(2-Phenethylamino)[1,2,4]triazolo[1,5-c]quinazolin-2-amine
(11z): according to general procedure 8 using 2-phenethylamine
(2 mL) and heating at 1208C for 15 h a colorless solid (33 mg,
22%) was obtained after washing the crude product with EtOH.
1H NMR (500 MHz, [D6]DMSO): d=8.00 (dd, J=1.3 Hz, J=8.2 Hz,
1H), 7.60 (ddd, J=1.3 Hz, J=6.6 Hz, J=8.2 Hz, 1H), 7.56 (d, J=
8.5 Hz, 1H), 7.37 (t, J=5.8 Hz, 1H, NH), 7.29 (m, 5H), 7.20 (m, 1H),
6.19 (s, 2H, NH2), 3.75 (m, 2H), 3.00 ppm (t, J=3.0 Hz, 2H); MS (EI,
70 eV) m/z (%): 305 (100) [M+H]+, purity: 98.0%.
5-Pyrrolidino[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11t): com-
pound 28 (95 mg, 0.44 mmol), pyrrolidine (1 g) and EtOH (10 mL)
were held at reflux for 18 h. The mixture was cooled to RT and left
standing for several days. The formed yellow crystals were collect-
ed by filtration and dried (45 mg, 38%). 1H NMR (500 MHz,
[D6]DMSO): d=7.98 (dd, J=1.0 Hz, J=7.9 Hz, 1H), 7.56 (ddd, J=
1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.25 (ddd,
J=1.3 Hz, J=7.4 Hz, J=7.9 Hz, 1H), 6.13 (s, 2H, NH2), 3.94 (m, 4H),
1.92 ppm (m, 4H); MS (EI, 70 eV) m/z (%): 255 (100) [M+H]+,
purity: 99.9%.
5-Tetrahydrofurfurylamino[1,2,4]triazolo[1,5-c]quinazolin-2-
amine (11aa): following general procedure 8, starting from tetra-
hydrofurfurylamine (2 mL) and heating the mixture at 1208C for
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
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Full Papers
a
colorless solid (96 mg, 68%) was obtained. 1H NMR
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17 h,
(500 MHz, [D6]DMSO): d=8.00 (dd, J=1.3 Hz, J=7.9 Hz, 1H), 7.60
(ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H),
7.30 (ddd, J=1.0 Hz, J=7.9 Hz, 1H),7.07 (t, J=5.8 Hz, 1H, NH), 6.24
(s, 2H, NH2), 4.05 (quint, J=6.3 Hz, 2H), 3.65 (quart, J=7.1 Hz, 1H),
3.65 (quart, J=7.3 Hz, 1H), 3.57 (t, J=5.8 Hz, 2H), 1.89 (m, 2H),
1.67 ppm (m, 1H); MS (EI, 70 eV) m/z (%): 285 (100) [M+H]+,
purity: 98.6%.
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5-(3-Picolylamino)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11ab):
following general procedure 8, starting from 3-picolylamine (2 mL)
the mixture was heated for 9 h at 1408C. The resulting solution
was allowed to cool to RT, isopropanol (5 mL) was added followed
by diethyl ether (30 mL). The supernatant was decanted and the
residue was recrystallized from isopropanol (10 mL) to yield an off-
1
white solid (22 mg, 8%). H NMR (500 MHz, [D6]DMSO): d=8.66 (s,
1H), 8.42 (d, J=3.2 Hz, 1H), 8.12 (t, J=6.3 Hz, 1H), 8.00 (d, J=
6.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.58 (t, J=6.9 Hz, 1H), 7.52 (d,
J=8.2 Hz, 1H), 7.31 (quart, J=7.4 Hz, 2H), 6.21 (s, 2H, NH2),
4.73 ppm (d, J=6.3 Hz, 2H); MS (EI, 70 eV) m/z (%): 292 (100) [M+
H]+, purity: 98.5%.
5-Hydrazino[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11ac): com-
pound 28 (0.22 mg, 1.0 mmol), hydrazine hydrate (2.0 g, 40 mmol)
and EtOH (10 mL) were refluxed for 1 h. The mixture was allowed
to cool to RT, then left at 48C overnight. The formed precipitate
was collected by filtration, washed with EtOH (10 mL), and dried at
1
1008C to yield colorless needles (214 mg, 99%). H NMR (500 MHz,
[D6]DMSO): d=8.44 (s, 1H, NH), 8.02 (dd, J=1.0 Hz, J=7.9 Hz, 1H),
7.63 (m, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.32 (dt, J=1.3 Hz, J=6.9 Hz,
1H), 6.21 (s, 2H, NH2), 4.56 ppm (s, 2H, NH2); 13C NMR (125 MHz,
[D6]DMSO): d=165.6, 150.7, 145.1, 144.5, 131.6, 125.3, 123.1, 123.0,
112.7 ppm; MS (EI, 70 eV) m/z (%): 216 (100) [M+H]+, purity:
99.9%.
Bis[1,2,4]triazolo[4,3-a:1’,5’-c]quinazolin-2-amine (29): compound
11 ac (53 mg, 0.25 mmol) and triethyl orthoformate (2 mL) were
placed in a microwave tube and heated at 1608C under microwave
irradiation of 120 W for 20 min. The solution was allowed to cool
to RT. The formed precipitate was collected by filtration, washed
with EtOH (5 mL), and dried at 1008C to yield a beige-colored solid
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1
(39 mg, 31%). H NMR (500 MHz, [D6]DMSO): d=8.36 (d, J=8.5 Hz,
1H), 8.23 (dd, J=0.9 Hz, J=7.9 Hz, 1H), 7.88 (dt, J=1.6 Hz, J=
7.9 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 6.36 ppm (s, 2H, NH2); MS (EI,
70 eV) m/z (%): 226 (100) [M+H]+, purity: 98.2%.
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Acknowledgements
R.R.R.A. was on leave from the University College of Pharmaceuti-
cal Sciences, Kakatiya University, Warangal (India), supported by
the Deutscher Akademischer Austauschdienst (DAAD) (PPP pro-
gramme). This study was supported by the Bundesministerium
fꢀr Bildung und Forschung (BMBF) within the BioPharma-Neuro-
allianz consortium.
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Keywords: A3
adenosine
receptor
·
antagonists
·
iminoquinazolinamines · microwave-assisted synthesis · species
differences
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Published online on && &&, 0000
ChemMedChem 2016, 11, 1 – 16
www.chemmedchem.org
15
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

FULL PAPERS
J. C. Burbiel, W. Ghattas, P. Kꢀppers,
M. Kçse, S. Lacher, A.-M. Herzner,
R. S. Kombu, R. R. Akkinepally,
J. Hockemeyer, C. E. Mꢀller*
&& – &&
2-Amino[1,2,4]triazolo[1,5-
c]quinazolines and Derived Novel
Heterocycles: Syntheses and
Structure–Activity Relationships of
Potent Adenosine Receptor
Antagonists
The A-team: 2-Amino[1,2,4]triazolo[1,5-
c]quinazolines and derivatives were
identified as novel adenosine receptor
(AR) antagonists. Efficient syntheses
were developed, allowing broad struc-
tural variations, and novel related het-
erocycles were prepared. Potent and se-
lective A3AR antagonists as well as an-
tagonists with dual affinity, and those
that potently block all AR subtypes,
were obtained.
&
ChemMedChem 2016, 11, 1 – 16
www.chemmedchem.org
16
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!