Synthesis and antiallergic activity of pyridothienopyrimidines

BIOORGANIC &

MEDICINAL

CHEMISTRY

Bioorganic & Medicinal Chemistry 6 (1998) 1911±1925

Synthesis and Antiallergic Activity of Pyridothienopyrimidines

Jose M. Quintela,^aCarlos Peinador,^aCarmen Veiga,^aLiliane Gonzalez,^a

Luis M. Botana,^bAmparo Alfonso^band Ricardo Riguera^c,*

a

Â

Departamento de Quõmica Fundamental e Industrial, Facultad de Ciencias, Universidad de La CorunÄa, La CorunÄa 15071, Spain

^bDepartamento de Farmacologia, Facultad de Veterinaria, Universidad de Santiago, Lugo, Spain

Â

Departamento de Quõmica Organica, Facultad de Quõmica, Universidad de Santiago, Santiago de Compostela 15706, Spain

c

Â

Received 20 November 1997; accepted 19 June 1998

AbstractÐThe synthesis of a series of pyridothienopyrimidines and their evaluation as inhibitors or inducers of the

release of histamine from rat mast cells is reported. The activity was measured after immunological stimulation with

ovoalbumin and chemical stimulation with polymer 48/80 and the drugs adryamicin and vinorelbine. The experiments

were carried out with and without preincubation of the stimulus with the cells before addition of the drug. Several

pyridothienopyrimidines show inhibitory IC₅₀values in the range 2±25 mM, indicating they are up to 100 times more

potent than cromoglycate (DSCG) and 10 times greater than Ketotifen. Compound 9l is a potent inhibitor in all the

conditions tested and shows IC₅₀=9±25 mM. Pyridothienopyrimidines 4l and 9e are very strong inducers of histamine

release in the immunological (4l, 170±230%) and chemical (9e, 100±150%) assays, respectively. Compounds 4l and 9i

are cytotoxic in vitro (IC₅₀=0.1±0.2 mg/mL) against P-388, A-549, HT-29, and MEL-28 tumor cell lines. # 1998

Introduction

wide range of biological activity, particularly in cancer

and virus research.⁶Among these heterocycles, the thie-

nopyrimidine class is also of interest because some deri-

vatives, such as Tiprinast⁷(Chart 1), have been shown

to be clinically eective antiallergics. In addition, anti-

anaphilactic,⁸anti-in¯ammatory⁹analgesic and anti-

pyretic,¹⁰and antineoplastic¹¹activities have been

described for these compounds.

Asthma is an in¯ammatory disease that aects a sig-

ni®cant portion of the population, with recent data

suggesting that the numbers of asthma suerers is

increasing.¹One of the most useful drugs for asthma

treatment is disodium cromoglycate^2a,b(DSCG, Chart

1). This compound inhibits IgE-mediated secretion of

vasoactive mediators from mast cells both in vivo and in

vitro, but unfortunately is not eective by oral admin-

istration and must be used as an insuated powder.

Several orally active drugs have been described and

many of them are nitrogen or sulfur-containing hetero-

cycles including tetrazoles,³naphthyridines,⁴pyrido-

thienotriazines⁵such as RHC 2963, and thiophenes as

Ketotifen^2c(Chart 1).

Our previous work^12aon the search for novel hetero-

cyclic compounds of pharmacological interest has

shown that certain guanadinocyanopyridines and pyr-

idopyrimidines are good inhibitors, and other strong

stimulants, of the release of histamine from mast rat

cells. These ®ndings, along with our interest in the

development of structurally novel compounds acting as

histamine release inhibitors, and the known eectiveness

of pyridothienotriazine RHC2963⁵and thienopyr-

imidine Tiprinast⁷as immunological inhibitors of the

release of histamine, prompted us to report here our

results on the preparation and study of the inhibition of

the release of histamine from rat mast cells and the

antitumor activity of a series of new pyridothienopyr-

imidines shown in Table 1.

Compounds containing a fused pyrimidine ring have

attracted attention in the past few years owing to their

Key words: Pyridothienopyrimidine; synthesis; histamine; rat

mast cells ; antiallergic; cytotoxicity.

*Corresponding author. Fax: 34 81 591091.

PII: S0968-0896(98)00150-3

1912

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

depending on the method employed for the cyclization.

Finally, R₄is introduced in the last step by means of an

aromatic nucleophilic substitution of a chloro-sub-

stituent. Several nucleophiles of nitrogen, oxygen, and

sulfur have been shown to be eective in this reaction.

The structure of the required starting compounds is

mainly determined by the nature of the substituents on

the pyrimidine ring and, as a rule, systems with an

amino group adjacent to another functional group are

the most widely used.

In this paper we have chosen bicyclic thienopyridines

with either an ortho amino nitrile (1a±b) or an ortho

amino carboxamide (5a±b) functionality as the starting

materials for the preparation of the tricyclic pyr-

idothienopyrimidines shown in Table 1. In accordance

with these two functionalities, two dierent types of

cyclization reaction were needed.

In the case of pyridothienopyrimidines,⁹cyclization was

carried out by the introduction of the required carbon

atom with orthoformate, while in the case of pyr-

idothienopyrimidines 4 and 21, carrying a dimethyl-

amino group at position 2, phosgene iminium salts were

employed.

Chart 1.

Chemistry

These salts are very useful synthetic reagents that can

function as Vilsmeier or Mannich acceptors and lead to

the insertion of a one-carbon unit bearing a dialkyl-

amino group.¹³This makes them especially useful in

one-step heterocyclization reactions such as those con-

sidered here.

For the preparation of the heterocycles we devised sui-

table procedures for the introduction of a variety of

substituents with a minimum change in the nature of the

chemistry used. Thus, substituents R, R₁, and R₂are

present in the pyridine or thienopyridine used as the

starting material. R can be either an aryl ring or hydro-

gen, R₁any alkoxy or amino group, and R₂a cyano

group or hydrogen. Substituent R₃is introduced during

the formation of the pyrimidine ring. Most of the com-

pounds described in this paper have R₃=H or NMe₂,

Thus, treatment of 3-aminothieno[2,3-b]pyridine-2-carbo-

nitriles 1a¹⁴and 1b¹⁵(Scheme 1) with phosgene iminium

chloride in re¯uxing 1,2-dichloroethane gave the amide

halide intermediates 2a±b, which were reacted with dry

Scheme 1.

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

1913

hydrogen chloride to undergo cyclization to chloropyr-

idothienopyrimidines 3a±b. These compounds were

easily converted into a variety of pyridothienopyr-

imidines 4a±l by aromatic substitution with nucleophiles

(Table 1).

Compounds 9a±l were prepared in two ways by the

reactions shown in Scheme 2. Re¯uxing heterocyclic

carboxamides 5a¹⁶and 5b¹⁵with ethyl orthoformate

gave the triheterocyclic compounds 7a±b, which were

converted to the corresponding chloro derivatives 8a±b

by treatment with phosphorous oxychloride. Aromatic

nucleophilic substitution with a variety of nucleophiles

aorded the new substituted pyridothienopyrimidine

derivatives 9a±l.

The structures of 2 and 3 were consistent with their ele-

mental analyses and spectral data. The mass spectra

showed the expected molecular ion peaks and the IR

spectrum of

2 exhibited an absorption band at

n=1640 cm due to the imino group. The ¹³C NMR

spectrum of 2a showed two signals at d=113.8 and

113.9 due to the cyano group, while compound 3a

showed only one signal for cyano groups at d=114.4.

An alternative method for the preparation of 7a con-

sisted of the reaction of 5a with dimethylformamide

dimethylacetal to give 6, which could readily be con-

verted into 7a by re¯uxing with sodium ethoxide.

1

Table 1. Physicochemical data for pyridothienopyrimidines 3a, 4a±l, 9a±l, 13, and 21a±b

Compd

R

R₁

R₂

R₃

R₄

mp (^ꢀC) yield (%)

formula^a

3a

4a

4b

4c

4d

4e

4f

Ph

H

EtO

Ph

CN

H

NMe₂

H

Cl

OEt

220±222

192±194

204±206

184 dec

225 dec

170 dec

217±219

212±214

249±251

138±140

200±202

214±216

>300

86^f

72^b

71^b

64^f

C₂₀H₁₆N₅OClS

C₂₂H₂₁N₅O2S

C₂₅H₂₆N₆O₂S

C₂₆H₂₈N₆OS

C₂₄H₂₅N₇O₂S

C₂₅H₂₇N₇OS

C₂₇H₂₉N₇O₃S

C₃₂H₃₁N₇O₂S

C₃₁H₂₈N₇OF₃S

C₂₉H₂₉N₅S

piperidino

4-methylpiperidino

piperazino

77

4-methylpiperazino

4-ethoxycarbonylpiperazino

4-(4-acetylphenyl) piperazino

4-(tri¯uoro-m-tolyl)-piperazino

4-methylpiperidino

4-methylpiperazino

4-(4-acetylphenyl) piperazino

piperazino

65^d

77^b

65^b

72^b

59^e

64^b

58^b

72^d

75^b

74^c

80^b

74^d

65^d

81^d

85^d

83^d

68^c

65^e

84^b

62^d

71^d

77^b

75^b

4g

4h

4i

4j

Ph

H

C₂₈H₂₈N₆S

C₃₅H₃₂N₆OS

C₂₇H₂₆N₆S

4k

4l

H

Ph

H

9a

9b

9c

9d

9e

9f

EtO

Ph

CN

H

piperidino

189±191

210±212

220±222

212±214

229±231

226±228

213±215

191±193

145±148

190±192

230±232

209±211

235±237

218±220

C₂₃H₂₁N₅OS

C₂₄H₂₃N₅OS

C₂₂H₁₉N₅O₂S

C₂₂H₂₀N₆OS

C₂₃H₂₂N₆OS

C₂₉H₂₆N₆OS

C₃₀H₂₆N₆O₂S

C₂₉H₂₃N₆OF₃S

C₂₅H₂₁N₅S

H

4-methylpiperidino

morpholino

piperazino

H

4-methylpiperazino

4-benzylpiperazino

4-(4-acetylphenyl) piperazino

4-(tri¯uoro-m-tolyl)-piperazino

piperazino

H

9g

9h

9i

H

9j

Ph

H

4-methylpiperidino

4-methylpiperazino

4-(4-acetylphenyl) piperazino

4-benzylpiperazino

morpholino

C₂₇H₂₄N₄S

C₂₆H₂₃N₅S

9k

9l

H

Ph

EtO

H H

CN 2NO₂C₆H₄

C₃₃H₂₇N₅OS

C₃₅H₂₉N₇O₃S

C₂₀H₂₃N₇O₂S

C₂₀H₂₃N₇OS₂

13

21a

21b

morpholino CN

NMe₂

H

thiomorpholino

^aAll compounds analyzed for C, H, N; analytical results are within 0.4% of theoretical values.

^bRecrystallized from ethanol/acetone.

^cRecrystallized from ethanol.

^dRecrystallized from ethanol/dichloromethane.

^ePuri®ed by ¯ash chromatography with dichloromethane/hexane (3/1, v/v) as eluent.

^fPuri®ed by ¯ash chromatography with dichloromethane/hexane (1/2, v/v) as eluent.

1914

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

Table 2. Selected spectroscopic data for pyridothienopyrimidines

Compd ¹H NMR (CDCl₃) d^a,b

¹³C NMR (CDCl₃) d^a,b

MS (FAB)^cm/z (%)

3a

2.82 (br s, 6H, NMe₂)

36.9 (NMe₂)

411 (M⁺+2, 9),

410 (40), 409 (M⁺, 26),

408 (100), 380 (54),

352 (33)

4a

4b

1.52 (t, 3H, J=7.1 Hz, CH₃), 2.80 (s, 6H, NMe₂),

4.52 (q, 2H, J=7.1 Hz, OCH₂)

14.4 (CH₃), 36.7 (NMe₂),

62.3 (CH₂O)

419 (M⁺, 6), 391 (100),

376 (23), 362 (30)

458 (M⁺, 100), 443 (33),

429 (26), 415 (29),

403 (12)

1.69 (br s, 6H, CH₂CH₂CH₂), 2.74 (s, 6H, NMe₂),

3.78 (br s, 4H, N(CH₂)₂)

24.8, 25.8 (CH₂), 36.4 (NMe₂),

47.5 (NCH₂)

4c

0.96 (d, 2H, J=6.0 Hz, CHCH₃),

21.8 (CHCH₃), 31.4 (CH₃CH),

36.5 (NMe₂), 46.8 (NCH₂)

473 [(MH)⁺, 100],

1.23±1.34 (m, 2H, CHCH₂),

445 (23), 429 (8)

1.59±1.76 (m, 3H, CHCH₂, CHCH₂), 2.74 (s, 6H, NMe₂),

3.00 (t, 2H, J=12.7 Hz, NCH₂), 4.56±4.66 (m, 2H, NCH₂)

2.66 (s, 6H, NMe₂), 2.90 (br s, 4H, NCH₂),

3.75 (br s, 4H, NCH₂)

4d

4e

460 [(MH)⁺, 100],

432 (19), 403 (16)

474 [(MH)⁺, 100],

472 (12), 446 (10),

403 (12)

2.33 (s, 3H, NCH₃), 2.51 (t, 4H, J=4.9 Hz, NCH₂),

2.74 (s, 6H, NMe₂), 3.84 (t, 4H, J=4.9 Hz, NCH₂)

36.5 (NMe₂), 46.1,

54.7 (NCH₂)

4f

1.28 (t, 3H, J=7.1 Hz, CH₃), 2.74 (s, 6H, NMe₂),

3.58±3.83 (m, 8H, NCH₂), 4.17 (c, 2H, J=7.1 Hz, OCH₂)

14.6 (CH₃), 36.5 (NMe₂), 43.4, 46.0 (NCH₂), 61.6 (CH₂O),

155.4 (CO) 531 (M⁺, 58), 403 (100), 375 (16)

2.52 (s, 3H, CH₃CO), 2.75 (s, 6H, NMe₂),

4g

26.1 (CH₃CO), 36.5 (NMe₂),

578 [(MH)⁺, 39],

3.49 (t, 4H, J=5.1 Hz, NCH₂),

45.5, 46.8 (NCH₂), 113.2, 128.1, 403 (12), 217 (100)

130.3, 153.6 (C₆H₄), 194.6 (CO)

4.00 (t, 4H, J=5.1 Hz, NCH₂),

6.87, 7.89 (AB system, 4H, J=9.0 Hz, C₆H₄)

2.75 (s, 6H, NMe₂), 3.34 (t, 4H, J=5.0 Hz, NCH₂),

3.98 (t, 4H, J=4.9 Hz, NCH₂), 7.05±7.12 (m, 4H, C₆H₄CF₃)

4h

4i

36.5 (NMe₂), 45.8, 48.4 (NCH₂), 604 [(MH)⁺, 10],

112.1, 112.2, 129.6, 131.7 (C₆H₄) 403 (4), 217 (100)

1.00 (d, 2H, J=6.1 Hz, CHCH₃), 1.33±1.40 (m, 2H, CHCH₂), 21.9 (CHCH₃), 31.4 (CH₃CH),

480 [(MH)⁺, 100],

1.61±1.81 (m, 3H, CHCH₂, CHCH₂), 2.88 (s, 6H, NMe₂),

3.06 (dt, 2H, J=1.3 Hz, J=12.7 Hz, NCH₂),

4.71 (br s, 2H, NCH₂)

34.1 (CH₂CH), 36.6 (NMe₂),

46.9 (NCH₂)

437 (13), 410 (4)

4j

2.37 (s, 3H, NCH₃), 2.57 (t, 4H, J=4.8 Hz, NCH₂),

2.86 (s, 6H, NMe₂), 3.94 (t, 4H, J=4.8 Hz, NCH₂)

36.7 (NMe₂), 46.1 (NCH3),

46.2 (NCH₂), 54.9 (NCH2)

481 [(MH)⁺, 100],

467 (3), 424 (16),

410 (21)

4k

2.53 (s, 3H, COCH₃), 2.86 (s, 6H, NMe₂),

3.54 (t, 3H, J=5.1 Hz, NCH₂),

26.1 (CH₃CO), 36.7 (NMe₂),

45.7, 47.0 (NCH₂), 113.3,

127.5, 130.4, 153.8 (C₆H₄),

196.5 (CO)

585 [(MH)⁺, 40],

451 (69), 410 (46)

4.07 (t, 3H, J=5.2 Hz, NCH₂),

6.90, 7.91 (AB system, 4H, J=9.0 Hz, C₆H₄)

2.85 (s, 6H, NMe₂), 3.00 (t, 3H, J=5.0 Hz, NCH₂),

3.87 (t, 3H, J=5.0 Hz, NCH₂)

4l

36.6 (NMe₂), 45.9, 47.5 (NCH₂) 467 (M⁺, 25), 410 (100),

397 (60), 382 (28),

368 (29)

9a

9b

1.74 (br s, 6H, CH₂-CH₂-CH₂), 3.89 (br s, 4H, NCH₂),

8.35 (s, 1H, H-2)

24.6 (CH₂), 26.0 (CH₂),

47.6 (NCH₂)

415 (M⁺, 100), 386 (43),

359 (17), 332 (22)

430 (M⁺, 95), 417 (87),

232 (16)

0.99 (d, 3H, J=6.2 Hz, CHCH₃), 1.20±1.38 (m, 2H, CHCH₂), 21.7 (CHCH₃), 31.2 (CH₃CH),

1.69±1.84 (m, 3H, CHCH₂+CHCH₂),

3.10 (t, 2H, J=12.3 Hz, NCH₂),

34.2 (CH₂CH), 46.9 (NCH₂)

4.63±4.70 (m, 2H, NCH₂), 8.35 (s, 1H, H-2)

3.83±3.94 (m, 8H, CH₂-CH₂), 8.39 (s, 1H, H-2)

9c

9d

46.6 (NCH₂), 66.7 (OCH₂)

47.4 (NCH₂), 52.9 (NCH₂)

417 (M⁺, 100), 388 (18),

386 (23), 360 (49)

417 [(MH)⁺, 100],

389 (9)

3.03 (t, 4H, J=4.9 Hz, NCH₂),

3.91 (t, 4H, J=4.9 Hz, NCH₂), 8.38 (s, 1H, H-2)

(continued)

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

1915

Table 2Ðcontd

9e

2.36 (s, 3H, NCH₃), 2.56 (t, 4H, J=4.9 Hz, NCH₂),

3.95 (t, 4H, J=4.9 Hz, NCH₂), 8.37 (s, 1H, H-2)

46.0 (NCH₃), 46.2 (NCH₂),

54.8 (NCH₂)

431 [(MH)⁺, 100],

429 (10), 374 (13),

346 (20)

9f

2.59 (t, 4H, J=4.8 Hz, NCH₂), 3.56 (s, 2H, CH₂Ph),

3.93 (t, 4H, J=4.9 Hz, NCH₂), 7.24±7.35 (m, 5H, C₆H₅),

8.35 (s, 1H, H-2)

46.3 (CH₂), 52.9 (NCH₂),

62.9 (NCH₂)

506 [(MH)⁺, 20],

217 (100)

9g

2.54 (s, 3H, CH₃CO), 3.55 (t, 4H, J=5.2 Hz, NCH₂),

4.12 (t, 4H, J=5.2 Hz, NCH₂), 6.90,

7.91 (AB system, 4H, J=9.0 Hz, C₆H₄),

8.40 (s, 1H, H-2)

26.0 (CH₃CO), 45.5,

535 [(MH)⁺, 12],

360 (2)

47.0 (NCH₂), 112.3, 113.4,

128.3, 130.4 (C₆H₄), 196.5 (CO)

9h

3.40 (t, 4H, J=5.1 Hz, NCH₂),

45.6, 48.6 (NCH₂), 112.4 (C-6⁰), 561 [(MH)⁺, 20],

4.11 (t, 4H, J=5.1 Hz, NCH₂),

116.5, 116.6 (C-2⁰, C-4⁰),

122.1 (CF₃), 131.4 (C-1⁰),

131.9 (C-3⁰), 151.0 (C-5⁰)

217 (100)

7.09±7.43 (m, 4H, C₆H₄CF₃), 8.42 (s, 1H, H-2)

9i

9j

3.11 (t, 4H, J=4.2 Hz, NCH₂),

424 [(MH)⁺, 100],

381 (25), 367 (14),

355 (11)

4.01 (t, 4H, J=4.5 Hz, NCH₂),

8.50 (s, 1H, H-2)

0.89 (d, 2H, J=6.2 Hz, CHCH₃),

1.16±1.31 (m, 2H, CHCH₂),

21.7 (CHCH₃),

31.3 (CH₃CH),

34.2 (CH₂CH),

46.9 (NCH₂),

437 [(MH)⁺, 100),

435 (10), 367 (9)

1.57±1.75 (m, 3H, CHCH₂+CHCH₂),

3.01 (dt, 2H, J=2.3 Hz, J=12.4 Hz, NCH₂),

4.63 (br s, 2H, NCH₂), 8.37 (s, 1H, H-2)

2.37 (s, 3H, NCH₃), 2.60 (t, 4H, J=4.8 Hz, NCH₂),

4.01 (t, 4H, J=4.8 Hz, NCH₂), 8.51 (s, 1H, H-2)

153.9 (C-2)

9k

9l

46.0 (NCH₃),

438 [(MH)⁺, 100],

481 (59), 367 (23)

46.2 (NCH₂),

54.9 (NCH₂),

153.8 (C-2)

2.53 (s, 3H, COCH₃), 3.55 (t, 3H, J=4.8 Hz, NCH₂),

4.13 (t, 3H, J=5.3 Hz, NCH₂), 6.89,

26.1 (COCH₃),

45.6, 47.0 (NCH₂),

153.9 (C-2), 113.3,

114.2, 129.9, 130.4 (C₆H₄),

196.4 (CO)

542 [(MH)⁺, 40],

486 (19), 367 (19)

7.90 (AB system, 4H, J=8.9 Hz, C₆H₄), 8.50 (s, 1H, H-2)

13

2.61 (s, 4H, NCH₂), 3.58 (s, 2H, CH₂Ph),

3.90 (s, 4H, NCH₂)

46.2 (NCH₂), 52.9 (NCH₂),

62.8 (C₆H₅CH₂)

609 (18), 518 (4),

481 (9), 146 (11),

91 (100)

21a

21b

3.81±3.88 (m, 16H, CH₂)

46.4 (NCH₂), 66.7 (CH₂O)

26.8 (SCH₂), 49.1 (NCH₂)

425 (M⁺, 41),

381 (4), 368 (24),

281 (15)

441 (M⁺, 57),

368 (100), 372 (30),

339 (7)

2.74 (t, 4H, J=5.0 Hz, SCH₂), 3.78±3.90 (m, 8H, CH),

4.77 (t, 4H, J=5.0 Hz, NCH)

^aThe NMR spectra of 4d and 9c were obtained in DMSO-d₆.

^bThe ¹H NMR spectra of compounds 3a, 4a±h, 9a±h, and 13 exhibited additional signals typical for C₆H₅[7.40, 7.50±7.46, 7.58 (m,

5H)], and OCH₂CH₃groups [1.41±1.54 (t, 3H, J=7.1 Hz), and 4.57±4.66 (q, 2H, J=7.1 Hz)]. Compounds 4i±l and 9i±l present also

resonances for C₆H₅[7.42, 7.49±7.59, 7.69 (m, 8H), and 8.02, 8.17±8.08, 8.22 (m, 2H)] and for H-8 [7.65±7.78 (s, 1H)]. Compounds

21a±b exhibit signals for NMe₂[3.22 (s, 6H)] and for H-9 [8.56±8.60 (s, 1H)].

^cThe ¹³C NMR spectra of 3a, 4a±h, 9a±h, and 13 (compounds 4d and 9i are not suciently soluble in DMSO-d₆or CDCl₃to produce

good ¹³C NMR data, showed signals at 14.2±14.4 (CH₃), 64.0±64.6 (CH₂O), 95.1±96.7 (C-8), 100.5±112.3 (C-4a), 114.5±115.0 (CN),

118.5±119.4 (C-9a), 127.7, 128.0±133.4, 134.4 (four peaks for C₆H₅), 154.9±155.7 (C-5a), 155.5±157.4 (C-9b), 157.3±158.6 (C-4), and

163.2±164.6 (two renonances for C-7 and C-9). Compounds 3a, 4a±c, 4e±h show a resonance for C-2 at 160.2 ppm. In the 9a±h series

C-2 resonates in the range 154.1±154.5 ppm. Compounds 4i±l and 9i±l showed signals at 102.7 (C-4a) (4i±l) and at 114.0 (C-4a) (9j±l),

118.9±119.2 (C-8), 122.8±123.4 (C-9a), 127.3±138.6 (seven absorptions for two C₆H₅groups), 149.0±149.7 (C-5a), 155.8±157.6 (C-9b),

157.4±158.2 (C-4), 158.1±158.8, and 162.7±163.4 (C-7 and C-9). Compounds 4i±l showed one resonance at 160.1±160.4 for C-2.

Compounds 21a±b present resonances at 37.1 (NMe), 48.8 (NCH₂), 66.6 (CH₂O), 92.8 (C-8), 100.4 (C-4a), 118.2 (CN), 120.4 (C-9a),

139.5 (C-9), 156.6 (C-5a), 157.6±158.4 (C-9b), 160.4 (C-2), 160.8 (C-7), 165.0 (C-4).

^dElectron impact MS data (EIMS) is shown for compounds 3a, 4a, 4b, 4f, 4l, 9a±c, 13, 21a, and 21b. The IR spectra 21a±b shows an

absorption for the nitrile group at 2900 and 2220 cm ¹(CN), while compounds 3a, 4a±h, 9a±h, and 13 showed the CN band at 2210±

1

2220 cm

.

1916

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

Compound 13 was obtained from 5a by the sequence

shown in Scheme 3. 5a was reacted with o-nitro-

benzaldehyde in re¯uxing toluene containing a catalytic

amount of p-toluensulfonic acid, with azeotropic

removal of water, to give 10 in 81% yield. Re¯uxing

compound 10 with DDQ in THF for a few hours aor-

ded pyridothienopyrimidone 11, [EIMS m/z=427

(M⁺OCN) and 292 (M⁺OCNRHC)]. Reaction of

10 with POCl₃yielded the expected 4-chloropyrido-

thienopyrimidine derivative 12, which gave 13 on

reaction with 4-benzylpiperazine. The ¹H NMR spec-

trum of pyridothienopyrimidine 10 showed signals at

d=6.25 for H-2, and two other signals at d=5.13 and

d=8.26, which could be exchanged with deuterium

oxide, assigned to the N-bonded protons at positions 1

and 3, respectively. The ¹³C NMR spectrum of 10

showed one signal at d=63.2 corresponding to the car-

bon at position 2 of the newly formed pyrimidine ring.

The EIMS of pyridothienopyrimidone 11 showed

the expected molecular ion and other fragments at

m/z=427 (M⁺OCN) and 292 (M⁺OCNRHC).

For the preparation of pyridothienopyrimidines 21a±b

we started from the aminocyanopyridine 14.¹⁷This

compound was ®rst converted into the thienopyridine

19 and then cyclized to give the pyridothienopyrimidines

using the phosgene iminium chloride method discussed

above. The whole synthetic process is represented in

Scheme 4. All compounds gave elemental analyses and

spectra consistent with the assigned structures.

Scheme 2.

Scheme 3.

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

1917

Biological Results

Immunological stimulus

added to the cells 10 min before than the stimulus,

Fig. 1), the inhibitory action of 4k, 9i, 9k, 9l, and 21a is

of around 40%, compound 21a being the most active

showing a 60% inhibitory activity.

Initial information about the ability of the pyr-

idothienopyrimidines to inhibit the release of histamine

from rat mast cells was obtained by screening the activ-

ity using a single dose (100 mg/mL) of compound. In the

experiments performed with preincubation (compound

When the experiments were carried out with simulta-

neous addition of the compound and the stimulus (i.e.

without preincubation, Figure 2), the inhibitory pattern

Scheme 4.

Figure 1. Histamine release in mast cells stimulated with 3.5 mg/mL of antigen (ovoalbumin) in the presence of pyridothieno-

pyrimidines. The compounds were added to the cells 10 min before the addition of the stimulus (10 min preincubation). The activity

data are normalized to the response of the control experiments (29.631.59% in the presence of 5 mg/mL of antigen).

1918

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

is very similar to that in the previous ®gure, with a

consistent inhibition of around 40% for several

compounds. Nevertheless, 4h, 4i, 9a, and 21a show a

higher inhibitory activity (60%) and values of 90%

inhibition are obtained with 9b and 9l. From those

experiments, pyridothienopyrimidines 9l and 21a

emerge as especially interesting since they show con-

sistent inhibition of the immunological stimulus and a

low desensitization.

active one in the experiments with preincubation is 9e

(100%). In the assays performed with simultaneous

addition of the stimulus (Fig. 4) there is only one good

inducer in the whole series and this is again 9e (170%),

which therefore is a good releaser both with and without

preincubation.

The activity of the pyridothienopyrimidines was also

tested using the antineoplastic drugs adryamicin and

vinorelbine, recently reported to induce histamine

release,¹⁹as chemical inducers. The results (not shown)

obtained with a selection of pyridothienopyrimidines

(4b, 9a, 9c, 9g, 9h, and 13) indicated that the amount of

histamine released after simultaneous addition of

adryamicin was practically the same as in the absence of

the chemical. Experiments carried out with preincuba-

tion of the cells with the pyridothienopyrimidines before

addition of the antineoplastic drug, showed a small

increase in the inhibition values that reached up to 30%

in some cases. Similar tests with vinorelbine as hist-

amine releaser did not show any clear inhibitory action

either with or without preincubation. In summary, no

clear correlation was observed between the results of the

experiments using adryamicin, vinorelbine and com-

pound 48/80 as chemical releasers of histamine.

In contrast to the inhibitory activity found in those het-

erocycles, two compounds, 9d (40±60%) and 4l (170±

220%) have been shown to be activators of the exocy-

tosis in rat mast cells.

Non-immunological stimulus

The pyridothienopyrimidines were also tested when the

release of histamine was induced by the chemical indu-

cer compound 48/80.¹⁸

The results of single dose experiments (at 100 mg/mL)

are presented in Figures 3 and 4 and show that com-

pounds 4c, 4i, 4k, and 9l produce a 50±60% inhibition

when preincubated with the stimulus while in the

experiments carried out with simultaneous addition only

four compounds (4c, 4e, 4k, and 9l) show some inhibi-

tory action (20±30%). Overall, 4c, 4k, and 9l are active

in both conditions 9l being the most eective inhibitor

with inhibition values of 30% (simultaneous addition)

and 60% (preincubated), respectively. Figure 3 indicates

the presence of several histamine releasers too. The most

In order to get a better picture of the ability of these

heterocycles to inhibit the release of histamine, and to

allow a direct comparison of their potency with that of

known antiallergics as cromoglycate (DSCG) and keto-

tifen,²⁰experiments using ®ve concentrations of inhi-

bitor were carried out. Table 3 shows the results

Figure 2. Histamine release in mast rat cells stimulated with 3.5 mg/mL of antigen (ovoalbumin) in the presence of pyridothieno-

pyrimidines. The compounds were added to the cells simultaneously with the stimulus (no preincubation). The activity data are normal-

ized to the response of the control experiments (21.472.4% in the presence of 5 mg/mL of antigen).

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

1919

expressed as IC₅₀values, for a selection of pyrido-

Antitumor activity

thienopyrimidines. The ®gures are in the range 2±25 mM

well below those of cromoglycate (DSCG) and similar

to ketotifen in the immunologically stimulated assays.

In the chemical stimulated experiments, the selected

pyridothienopyrimidines are clearly much more active

than both references. These results prove that these

heterocycles are up to 10±100 times more active than the

standards and con®rm their potential interest.

The pyridothienopyrimidines shown in Table 1 have

been tested in vitro for their antitumor activity against

four standard tumor cell lines. The IC₅₀®gures pre-

sented in Table 4 show that four pyridothienopyr-

imidines can be considered to be active in these assays.

These are 4d and 9d (IC₅₀: 2.5±0.5 mg/mL) and 9i and 4l,

which show IC₅₀values of 0.12±0.25 mg/mL. Structurally,

Figure 3. Histamine release in mast rat cells stimulated with 2 mg/mL of compound 48/80 in the presence of pyridothienopyrimidines.

The compounds were added to the cells simultaneously with the stimulus (no preincubation). The activity data are normalized to the

response of the control experiments (32.04.7% in the presence of 2 mg/mL of compound 48/80.

Figure 4. Histamine release in mast rat cells stimulated with 2 mg/mL of compound 48/80 in the presence of pyridothienopyrimidines.

The compounds were added to the cells 10 min before the addition of the stimulus (10 min preincubation). The activity data are nor-

malized to the response of the control experiments (35.03.5% in the presence of 2 mg/mL of compound 48/80).

1920

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

Table 3. Histamine release inhibition (IC₅₀mM) of selected pyridothienopyrimidines

Immunological stimulation

(5 mg/mL)

Chemical stimulation

(2 mg/mL)

Immunological stimulation

(5 mg/mL)

Chemical stimulation

(2 mg/mL)

Compd

(Preinc.)

IC₅₀(mM)

Compd

(Preinc.)

IC₅₀(mM)

Compd

(No preinc.)

IC₅₀(mM)

Compd

(No preinc.)

IC₅₀(mM)

DSCG^a

400

10

DSCG^a

200

100

4h

4i

40.73

61.2

4c

4e

4k

9l

61.1

20.4

51.0

151.7

Ketotifen^a

4k

9i

101.2

4c

4i

101.0

200.9

141.3

251.7

9a

9b

9l

200.8

252.4

91.3

252.5

141.3

201.7

253.5

9k

9l

4k

9l

21a

203.2

21a

^aSee ref. 20.

the last two compounds have signi®cantly dierent

combinations of R₁, R₂, and R₃but have in common

the piperazine substituent (R), suggesting that this unit

plays an important role in their action. It is interesting

to note that 4l and 9d are the stronger stimulants for the

liberation of histamine found in the series of pyr-

idothienopyrimidines studied.

Overall, the data shown in Table 3 demonstrates that

pyridothienopyrimidines are worth considering for their

potential antiallergic activity. Compound 9l is particu-

larly interesting because it is the only one that conserves

its strong inhibitory activity (IC₅₀=9±25 mM) in all the

conditions tested (chemical and immunological stimu-

lus, with/without preincubation).

From the structure±activity point of view, our results

indicate that the modi®cation of the substituents on the

pyridothienopyrimidine skeleton is not as eective in

improving the inhibitory action as similar changes in the

cyanopyridines and pyridopyrimidine series,^12aand this

may explain why so many pyridothienopyrimidines

show some inhibition. Nevertheless, some trends can be

distinguished and for example, comparison of the inhi-

bitors 9b and 9l with the inactive 9g and 9j may illus-

trate the in¯uence of R₁and R₂. Similarly, the good

inhibitory action of 9a is lost in its N-dimethyl deriva-

tive 4b.

Conclusions

In conclusion, we have presented ecient synthetic

procedures for the preparation of pyridothienopyr-

imidines of interest as antiallergics. Their activity has

been evaluated with rat mast cells and the assays have

been carried out under dierent conditions and with

dierent types of stimulus. Under immunological sti-

mulus with ovoalbumin (Figs 1 and 2, Table 3), several

pyridothienopyrimidines are stronger inhibitors of the

release of histamine than DSCG (up to 100 times more

potent) and of the same order of potency as Ketotifen,²⁰

although only two compounds, 9l and 21a are active

with and without preincubation. In the assays using

compound 48/80 as chemical inducer (Figs 3 and 4,

Table 3), there are also several inhibitors, 10±100 times

more potent than DSCG and Ketotifen.²⁰Three of

them, 4c, 4k, and 9l, are active with and without

preincubation.

The fact that some inhibitory action is observed in vir-

tually all cases examined (Figs 1±4), the absence of any

apparent link between the chemical and the immuno-

logically stimulated experiments, prevents the formula-

tion of any further conclusion. Similarly, comparison of

the results obtained with compound 48/80¹⁸and the

drugs adryamicin and vinorelbine indicate that no

apparent correspondence exists between those three

chemical releasers.

Table 4. Antitumoral activity of selected pyridothienopirim-

idines expressed in IC₅₀

A completely dierent picture is seen if our attention is

focussed on the heterocycles acting as inducers of the

release of histamine. This action is found to be very

selective among the compounds studied. Indeed, only

one pyridothienopyrimidine (4l) acts as a releaser of

histamine under immunological conditions (170±220%),

and another one (9e, 100±170%) in the chemically dri-

ven experiments. This eect is observed in both pre-

Compd

IC₅₀(mg/mL)

A-549 HT-29

P-388

MEL

4d

4l

2.5

0.25

1

2.5

0.25

2

2.5

0.50

1

0.25

0.5

9d

9i

0.12

0.25

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

1921

incubated and non-preincubated experiments, because,

as expected, is independent of the stimulus itself. Both

structures share the same R substituent (R=piperidine)

but comparison with other members of the series, and

particularly with the inactive compounds 4d and 9i,

suggests that the combination of substituents repre-

sented by 4l is necessary to obtain the maximum activity.

analyzed using the Student's t-test for umpaired data.

A probability level of 0.05 or less was used for statistical

signi®cance and the results are expressed as mean

SEM. Five concentrations of inhibitor (0.1, 1, 10, 100,

and 500 mg/mL) were used in order to obtain the IC₅₀

values.

The antineoplasic activity was measured^12das IC₅₀

against P-388 (ATCC CCL 46; suspension culture of a

lymphoid neoplasm from a DBA/2 mouse), A-549

(ATCC CCL 185; monolayer culture of a human lung

carcinoma), HT-29 (ATCC HTB-38; monolayer culture

of a human colon carcinoma), and MEL-28 (ATCC

HTB-72; monolayer culture of a human melanoma).

The discovery of strong histamine releasers among the

compounds investigated is interesting because, although

inducers have no clinical interest so far, knowledge of

their structures may provide an aid to the prediction²¹

of unwanted side eects.

Some pyridothienopyrimidines¹¹and pyridopyr-

imidines²²have been reported to be antineoplastic. In

our tests, only four compounds were found to be active,

so cytotoxicity would not pose a problem in the even-

tual use of these compounds as antiallergics. However,

it is worth noting that two of the stronger stimulants, 4l

and 9d, are among the more cytotoxic pyridothienopyr-

imidines.

3-Chlorodimethylaminomethylenamino-2-cyanothieno[2,3-

b]-pyridine: General procedure (2a,b). A solution of 1a

or 1b (1.3 mmol) and phosgene iminium salt (0.26 g,

1.6 mmol) in 1,2-dichloroethane (20 mL) was re¯uxed

for 45 min. The solvent was removed under reduced

pressure and the resulting solid was puri®ed by ¯ash

chromatography using CH₂Cl₂/hexane (2/1) as eluent.

3-Chlorodimethylaminomethylenamino-2,5-dicyano-6-ethoxy-

4-phenylthieno[2,3-b]pyridine (2a). Yield 78%; mp 220±

222 ^ꢀC; C₂₀H₁₆N₅OClS calcd C, 58.61; H, 3.93; N,

17.09. found: C, 58.67; H, 4.07; N, 17.17; ¹H NMR

(CDCl₃) d 1.50 (t, 3H, J=7.1 Hz, CH₃), 2.70 (s, 6H,

NMe₂), 4.61 (q, 2H, J=7.1 Hz, CH₂), 7.27±7.55 (m, 5H,

C₆H₅); ¹³C NMR (CDCl₃) d 14.4 (CH₃), 39.6 (NMe₂),

64.4 (CH₂), 90.9 (C-2), 96.6 (C-5), 113.8 (CN), 113.9

(CN), 119.2 (C-3a), 127.5, 128.4, 128.9, 133.6 (C₆H₅),

139.8, 151.1, 154.2, 162.1, 162.6; MS (EI, m/z, %): 411

(M⁺+2, 33), 409 (M⁺, 85), 374 (100), 346 (40), 289

(31); IR (KBr, cm ¹): 2220 (CN), 2200 (CN), 1640,

1550, 1430.

Experimental

Chemistry

All reagents used were commercial grade chemicals

from freshly opened containers. The histamine releaser

compound 48/80, is a condensation product of N-

methyl-p-methoxy-phenethylamine, was obtained from

Sigma Chemical Co. Melting points were determined

using a Buchi 510 apparatus and are uncorrected. IR

spectra were recorded as potassium bromide disks using

a Perkin-Elmer 783 spectrophotometer. ¹H and ¹³C

NMR spectra were obtained using a Bruker AC 200F

instrument at room temperature. Mass spectra were

obtained using a VG QUATTRO spectrometer. The

silica gel 60 HF254+366 used for analytical thin-layer

chromatography and the silica gel 60 (230±400 mesh)

employed for ¯ash chromatography were purchased

from Merck. Microanalyses for C, H, and N, were per-

formed by the Servicio General de Analisis Elemental at

the University of La Coruna.

3-Chlorodimethylaminomethylenamino-2-cyano-4,6-phenyl-

thieno[2,3-b]pyridine (2b). Yield 95%; mp 153±155 ^ꢀC;

C₂₃H₁₇N₄ClS calcd C, 66.26; H, 4.11; N, 13.44. found:

C, 66.07; H, 4.01; N, 13.58; ¹H NMR (CDCl₃) d 2.76 (s,

6H, NMe₂), 7.34±7.55 (m, 8H, C₆H₅), 7.65 (s, 1H, H-5),

8.09±8.15 (m, 2H, C₆H₅); ¹³C NMR (CDCl₃) d 39.7

(NMe₂), 93.3 (C-2), 114.5 (CN), 119.2 (C-5), 123.0 (C-

3a), 127.3, 127.4, 127.9, 128.9, 129.1, 129.8, 137.8, 138.0

(C₆H₅), 140.0 (C±Cl), 148.3 (C-3), 150.9, 157.3, 161.6

(C-4, C-6, C-7a); MS (EI, m/z, %): 418 (M⁺+2, 37),

416 (M⁺, 94), 381 (100), 365 (20), 336 (28), 324 (46); IR

(KBr, cm ¹): 2200 (CN), 1640, 1560, 1320.

Histamine release and neoplastic assays^12b-d

Rat mast cells and human and mouse tumoral cells were

prepared and incubated as previously described.^12bHist-

amine release was measured spectro¯uorometrically^12c

both in the pellet and in the supernatants with and

without preincubation (10 min) of each drug (100 mg/mL

in the single dose experiments) with the cells before

addition of the stimulus. All the experiments were repe-

ated at least three times in duplicate and the data was

4-Chloro-2-dimethylaminopyrido[3⁰,2⁰:4,5]thieno[3,2-d]-

pyrimidine: General procedure (3a,b). A stream of dry

hydrogen chloride was passed through a solution of 2a

or 2b (0.43 mmol) in 1,2-dichloroethane (10 mL) for 3 h.

After that time, the reaction mixture was allowed to

stand overnight at room temperature, the solvent was

1922

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

removed under reduced pressure and the resulting solid

was puri®ed by ¯ash chromatography eluting with

CH₂Cl₂/Hexane (2/1) to yield 3a (Tables 1 and 2) or 3b.

solid was ®ltered o to yield 7a (0.42 g, 82%). Method

B: A solution of 5a or 5b (3.00 mmol) and a catalytic

amount of PTSA in HC(OEt)₃(15 mL) was re¯uxed

until the starting material had disappeared (TLC). The

solid was ®ltered o and the crude product was used in

the next step without further puri®cation.

4-Chloro-7,9-diphenylpyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyr-

imidine (3b). Yield 83%; mp 237±239 ^ꢀC; C₂₃H₁₇N₄ClS

calcd C, 66.26; H, 4.11; N, 13.44. found: C, 66.34; H,

4.19; N, 13.51; ¹H NMR (CDCl₃) d 2.94 (s, 6H, NMe₂),

7.48±7.65 (m, 8H, C₆H₅), 7.75 (s, 1H, H-8), 8.16±8.21

(m, 2H, C₆H₅); ¹³C NMR (CDCl₃) d 37.1 (NMe₂), 119.2

(C-8), 122.9 (C-9a), 127.5, 127.7, 128.4, 128.9, 129.6,

130.0, 137.4, 138.1 (C₆H₅), 150.2, 154.3, 158.3, 158.7,

160.3, 165.2; MS (EI, m/z, %): 418 (M⁺+2, 40), 416

(M⁺, 100), 401 (37), 387 (86), 372 (32); IR (KBr, cm ¹):

1590, 1530, 1480, 1410.

8-Cyano-7-ethoxy-9-phenylpyrido[3⁰,2⁰:4,5]thieno[3,2-d]-

pyrimidin-4(3H)-one (7a). Yield 98%; mp >300 ^ꢀC;

C₁₈H₁₂N₄O₂S calcd C, 62.06; H, 3.47; N, 16.08; found:

C, 62.20; H, 3.55; N, 16.25; ¹H NMR (DMSO-d₆) d 1.43

(t, 3H, J=7.1 Hz, CH₃), 4.61 (q, 2H, J=7.1 Hz, CH₂),

7.49±7.67 (m, 5H, C₆H₅), 8.03 (s, 1H, H-2), 12.89 (br s,

1H, exchangeable with D₂O, NH). MS (EI, m/z, %): 348

(M⁺, 73), 319 (100), 306 (19), 292 (23), 264 (20), 236

(32), 165 (31); IR (KBr, cm ¹): 3240 (NH), 2220 (CN),

1680 (CO), 1330, 1230.

8-Cyano-4,7-diethoxy-2-dimethylaminopyrido[3⁰,2⁰:4,5]-

thieno[3,2-d]pyrimidine (4a). A solution of 3a (0.15 g,

0.37 mmol) in ethanol (20 mL) containing NaOEt (0.08 g

of Na, 3.7 mmol) was re¯uxed for 1 h. The solid was ®l-

tered o and recrystallized from ethanol/acetone to

yield 4a (Tables 1 and 2).

7,9-Diphenylpyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidin-4(3H)-

one (7b). Yield 93%; mp >300 ^ꢀC; C₂₁H₁₃N₃OS calcd

C, 70.97; H, 3.69; N, 11.82; found: C, 71.07; H, 3.57; N,

11.75; ¹H NMR (DMSO-d₆) d 7.47±7.70 (m, 8H, C₆H₅),

7.98 (s, 1H, H-8), 8.11 (s, 1H, H-2), 8.26±8.30 (m, 2H,

C₆H₅), 12.85 (br s, 1H, exchangeable with D₂O, NH);

¹³C NMR (DMSO-d₆) d 119.6 (C-8), 122.7 (C-9a), 123.5

(C-4a), 127.4, 127.6, 128.7, 129.0, 130.0, 130.1, 136.7,

137.2 (C₆H₅), 146.5 (C-2), 149.4, 157.4, 162.8 (C-5a, C-

7, C-9), 151.4 (C-9b), 156.7 (CO); MS (EI, m/z, %): 355

(M⁺, 100), 299 (23), 255 (16), 227 (16); IR (KBr, cm ¹):

1660 (CO), 1540, 1400.

2-Dimethylaminopyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidine-

4-substituted (4b±l): General procedure. A solution of 3a

or 3b (0.37 mmol) and the appropriate amine

(0.44 mmol) in ethanol (10 mL) was re¯uxed until the

starting material had disappeared (TLC). The solid was

®ltered o and recrystallized or was puri®ed by ¯ash

chromatography (Tables 1 and 2).

5-Cyano-6-ethoxy-3-dimethylaminomethylenamino-4-phenyl-

thieno[2,3-b]pyridine-2-carboxamide (6). A solution con-

taining 5a (1.0 g, 3.0 mmol) and DMFDMA (0.54 g,

4.5 mmol) in DMF (5 mL) was stirred at 80 ^ꢀC for

15 min. Ethanol (20 mL) was added and the solid was

®ltered o and recrystallized from ethanol/acetone to

yield 6 (1.03 g, 89%): mp 242 ^ꢀC; C₂₀H₁₉N₅O₂S calcd C,

61.05; H, 4.87; N, 17.80. found: C, 60.89; H, 4.99; N,

17.74; ¹H NMR (CDCl₃) d 1.47 (t, 3H, J=7.1 Hz, CH₃),

3.12 (s, 3H, NMe₂), 3.12 (s, 3H, NMe₂), 4.59 (q, 2H,

J=7.1 Hz, CH₂), 7.45±7.59 (m, 5H, C₆H₅), 8.53 (s, 1H,

CH N); ¹³C NMR (CDCl₃) d 14.3 (CH₃), 35.3

(NMe₂), 41.3 (NMe₂), 63.9 (CH₂), 94.4 (C-5), 105.6 (C-

2), 114.7 (CN), 117.6 (C-3a), 128.1, 129.1, 130.1, 133.2

(C₆H₅), 146.1, 153.1, 158.9, 162.2, 163.7, 174.5 (CO);

MS (EI, m/z, %): 393 (M⁺, 28), 349 (100), 321 (59), 294

(9); IR (KBr, cm ¹): 3460 (NH), 3300 (NH), 2220 (CN),

1630 (CO), 1570, 1330.

4-Chloropyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidine (8a,b). A

stirred solution of 7a or 7b (2.37 mmol) and phosphor-

ous pentachloride (3.55 mmol) in phosphorous oxy-

chloride (6 mL) was re¯uxed until starting material had

disappeared (TLC). The solvent was removed under

reduced pressure and the resulting solid was puri®ed by

¯ash chromatography using CH₂Cl₂/hexanes as eluent

(3:2 for 8a and 2:1 for 8b).

4-Chloro-8-cyano-7-ethoxy-9-phenylpyrido[3⁰,2⁰:4,5]thieno-

[3,2-d]pyrimidine (8a). Yield 85%; mp 202±204 ^ꢀC;

C₁₈H₁₁N₄OClS calcd C, 58.94; H, 3.02; N, 15.27; found:

C, 59.14; H, 3.20; N, 15.09; ¹H NMR (CDCl₃) d 1.56 (t,

3H, J=7.1 Hz, CH₃), 4.72 (q, 2H, J=7.1 Hz, CH₂),

7.48±7.61 (m, 5H, C₆H₅), 8.77 (s, 1H, H-2); ¹³C NMR

(CDCl₃) d 14.2 (CH₃), 65.1 (CH₂), 97.4 (C-8), 113.9

(CN), 118.7 (C-9a), 128.3, 129.1, 130.3, 132.6 (C₆H₅),

154.3 (C-5a), 154.7 (C-2), 156.6, 156.8, 164.8, 166.0.

MS (EI, m/z, %): 368 (M⁺+2, 38), 366 (M⁺, 100), 337

(99), 324 (35); IR (KBr, cm ¹): 2220 (CN), 1540, 1320,

1030.

Pyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones (7a,b):

General procedure. Method A: A solution of 6 (0.58 g,

1.48 mmol) and an excess of NaOEt in ethanol (25 mL)

was re¯uxed for 30 min. The solvent was removed under

reduced pressure and water (40 mL) was added. The

solution was neutralized with 2 N HCl and the resulting

4-Chloro-7,9-diphenylpyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidine

(8b). Yield 68%; mp 199±201 ^ꢀC; C₂₁H₁₂N₃ClS calcd C,

67.47; H, 3.24; N, 11.24; found: C, 67.22; H, 3.41; N,

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

1923

11.06; ¹H NMR (CDCl₃) d 7.45±7.66 (m, 8H, C₆H₅),

7.80 (s, 1H, H-8), 8.11±8.16 (m, 2H, C₆H₅), 8.81 (s, 1H,

H-2); ¹³C NMR (CDCl₃) d 120.0 (C-8), 122.4 (C-9a),

127.5, 128.0, 128.9, 129.1, 129.5, 130.3, 136.5, 137.4

(C₆H₅), 150.6, 153.9 (C-2), 154.4, 157.0, 159.4, 164.3;

MS (EI, m/z, %): 375 (M⁺+2, 16), 373 (M⁺, 44), 372

(100), 337 (8), 309 (8); IR (KBr, cm ¹): 1560, 1540,

1490, 1420.

4-Chloro-8-cyano-7-ethoxy-9-phenyl-2-(2-nitrophenyl)-

pyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidine (12).

stirred

A

solution of 11 (0.14 g, 0.29 mmol) and phosphorous

pentachloride (0.06 g, 0.29 mmol) in phosphorous oxy-

chloride (5 mL) was re¯uxed for 15 h. The more volatile

components of the reaction mixture were evaporated

under reduced pressure, and ice (10 g) was added. The

resulting solid was ®ltered o and recrystallized from

ethanol/acetone to yield 12 (0.13 g, 90%): mp 241±

243 ^ꢀC; C₂₄H₁₃N₅O₃ClS calcd C, 59.08; H, 2.89; N,

14.35; found: C, 59.09; H, 2.75; N, 14.50; ¹H NMR

(DMSO-d₆) d 1.46 (t, 3H, J=7.1 Hz, CH₃), 4.63 (q, 2H,

J=7.1 Hz, CH₂), 7.52±7.93 (m, 9H, C₆H₅and C₆H₄);

¹³C NMR (CDCl₃) d 14.3 (CH₃), 65.2 (CH₂), 97.3 (C-8),

114.0 (CN), 118.7 (C-9a), 127.5 (C-4a), 124.0, 128.3,

128.8, 129.9, 130.6, 131.2, 131.7, 131.8, 132.5, 149.5

(C₆H₄NO2 and C₆H₅), 154.1, 156.5, 156.8, 159.2, 164.8,

166.2 MS (EI, m/z, %): 489 (M⁺+2, 5), 487 (M⁺, 13),

470 (100), 440 (59), 411 (36), 221 (8); IR (KBr, cm ¹):

2220 (CN), 1540, 1340, 1310.

Pyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidine-4-substituted (9a±l):

General procedure. A solution of 8a or 8b (0.27 mmol)

and the appropriate amine (0.32 mmol) in ethanol

(10 mL) was re¯uxed until the starting material had dis-

appeared (TLC). The solvent was removed under

reduced pressure and the resulting solid was puri®ed by

¯ash chromatography or, alternatively, ®ltered o and

recrystallized to yield (9a±l) (Tables 1 and 2).

8-Cyano-7-ethoxy-9-phenyl-2-(2-nitrophenyl)-4-oxo-1,2,3,4

tetrahydropyrido[3⁰,2⁰:4,5]thieno[3,2-d] pyrimidine (10).

A catalytic amount of PTSA was added to a solution

of 5a (0.3 g, 0.87 mmol) and 2-nitrobenzaldehyde

(0.14 g, 0.95 mmol) in toluene (30 mL). The reaction

mixture was re¯uxed for 2 h and the water formed was

continuously removed by means of a Dean±Stark trap.

The desired product was ®ltered o and recrystallized

from ethanol/acetone to yield 10 (0.33 g, 81%): mp 291±

293 ^ꢀC; C₂₄H₁₇N₅O₄S calcd C, 61.14; H, 3.63; N, 14.85;

4-(4-Benzylpiperazino)-8-cyano-7-ethoxy-9-phenyl-2-(2-

nitrophenyl)-pyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidine (13).

A solution of 12 (0.10 g, 0.22 mmol) and 4-benzylpiper-

azine (0.08 g, 0.44 mmol) in ethanol (7 mL) was re¯uxed

for 3 h. The solid was ®ltered o and recrystallized from

ethanol/dichloromethane (Tables 1 and 2).

1

found: C, 61.31; H, 3.75; N, 14.64; H NMR (DMSO-

2-Amino-3,5-dicyano-6-morpholinopyridine (15). A solu-

tion of 14¹⁷(0.18 g, 1.12 mmol) and morpholine (0.12 g,

1.34 mmol) in ethanol/THF (1/3, 15 mL) was re¯uxed

until the starting material had disappeared (TLC). The

solid was ®ltered o and recrystallized from ethanol to

yield 15 (0.14 g, 54%): mp 198±200 ^ꢀC; C₁₁H₁₁N₅O

calcd C, 57.63; H, 4.84; N, 30.55; found: C, 57.72; H,

4.68; N, 30.47; ¹H NMR (CDCl₃) d 3.78 (m, 4H,

NCH₂), 3.88 (m, 4H, CH₂O), 5.36 (br s, 2H, exchange-

able with D₂O, NH₂), 7.77 (s, 1H, H-4); ¹³C NMR

(CDCl₃) d 47.3 (NCH₂), 66.5 (CH₂O), 81.4, 82.6 (C-3,

C-5), 115.8 (CN), 117.8 (CN), 149.5 (C-4), 159.1, 159.4

(C-2, C-6); MS (EI, m/z, %): 229 (M⁺, 32), 172 (38),

144 (100), 117 (51), 89 (47); IR (KBr, cm ¹): 3400, 3315,

3210 (NH), 2210 (CN), 1650, 1600, 1540, 1480.

d₆) d 1.37 (t, 3H, J=7.1 Hz, CH₃), 4.52 (q, 2H,

J=7.1 Hz, CH₂), 5.13 (d, 1H, exchangeable with D₂O,

J=3.5 Hz, NH), 6.25 (t, 1H, J=3.4 Hz, H-2), 7.28±7.79

(m, 9H, C₆H₅and C₆H₄), 8.26 (d, 1H, exchangeable

with D₂O, J=3.5 Hz, NH); ¹³C NMR (DMSO-d₆) d

14.1 (CH₃), 63.2 (C-2), 64.1 (CH₂O), 95.1, 103.3, 114.2

(CN), 116.8, 125.4, 127.9, 128.2, 128.4, 128.8, 129.1,

130.0, 130.3, 132.2, 134.0, 135.2, 143.1, 146.9, 153.5,

161.1, 162.0, 163.4; MS (EI, m/z, %): 471 (M⁺, 80), 349

(100), 322 (69), 294 (49); IR (KBr, cm ¹): 3410 (NH),

3170 (NH), 2220 (CN), 1650 (CO).

8-Cyano-7-ethoxy-9-phenyl-2-(2-nitrophenyl)-4-oxo-3,4-

dihydropyrido[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidine (11).

A

solution of 10 (0.20 g, 0.45 mmol) and 2,3-dichloro-5,6-

dicyano-1,4-benzoquinone (DDQ) (0.15 g, 0.67 mmol) in

tetrahydrofuran (10 mL) was re¯uxed for 3 h. After

cooling, the precipitate obtained was ®ltered o and the

crude solid 11 was used in the next step without further

puri®cation. Compound 11, (0.15 g, 70%): mp >300 ^ꢀC;

C₂₄H₁₃N₅O₄S calcd C, 61.40; H, 3.22; N, 14.92; found:

C, 61.56; H, 3.14; N, 14.99; ¹H NMR (DMSO-d₆) d 1.43

(t, 3H, J=7.1 Hz, CH₃), 4.60 (q, 2H, J=7.1 Hz, CH₂),

7.34±8.14 (m, 9H, C₆H₅and C₆H₄), 13.21 (br s, 1H,

exchangeable with D₂O, NH). MS (EI, m/z, %): 469

(M⁺, 61), 292 (69), 264 (42); IR (KBr, cm ¹): 2220

(CN), 1640 (CO).

2-Chloro-3,5-dicyano-6-morpholinopyridine (16). To a

stirred suspension of anhydrous CuCl₂(4.4 g,

32.8 mmol) in dry CH₃CN (100 mL), containing isoamyl

nitrite (3.8 g, 32.8 mmol), was added compound 15

(5.0 g, 21.8 mmol). The reaction mixture was heated at

65 ^ꢀC for 2.5 h. After cooling, the reaction mixture was

poured into 20% HCl (200 mL) and extracted with

CH₂Cl₂(3Â50 mL). The organic layers were combined

and evaporated under reduced pressure and the result-

ing solid was puri®ed by ¯ash chromatography using

CH₂Cl₂/AcOEt (35/1) as eluent to yield 16 (2.9 g, 53%):

mp 186±188 ^ꢀC; C₁₁H₉N₄ClO calcd C, 53.13; H, 3.65;

1924

J. M. Quintela et al./Bioorg. Med. Chem. 6 (1998) 1911±1925

1

N, 22.53; found: C, 53.35; H, 3.76; N, 22.57; H NMR

(CDCl₃) d 3.82 (m, 4H, NCH₂), 4.02 (m, 4H, CH₂O),

7.96 (s, 1H, H-4), ¹³C NMR (CDCl₃) d 47.5 (NCH₂),

66.4 (CH₂O), 89.9, 98.1 (C-3, C-5), 114.1 (CN), 115.9

(CN), 149.9 (C-4), 154.8, 157.2 (C-2, C-6); MS (EI, m/z,

%): 250 (M⁺+2, 13), 248 (M⁺, 39), 217 (35), 205 (65),

191 (66), 163 (100), 128 (44); IR (KBr, cm ¹): 2220

(CN), 1600, 1535, 1410, 1275.

228 (80), 200 (100), 173 (59); IR (KBr, cm ¹): 3400,

3340, 3220 (NH), 2210 (CN), 2190 (CN), 1655, 1595,

1565, 1555, 1510, 1435.

Method B (from compound 17). A mixture of 17 (2.3 g,

9.3 mmol), chloroacetonitrile (0.8 g, 11.2 mmol), potas-

sium carbonate (1.5 g, 11.2 mmol), and a catalytic

amount of KI in acetone (50 mL) was stirred at room

temperature for 4 h. The solvent was removed under

reduced pressure and the crude solid obtained was stir-

red at room temperature for 1 h with a solution of

potassium carbonate (1.5 g, 11.2 mmol) in ethanol

(50 mL). The solid was ®ltered o and recrystallized

from ethanol to yield 19 (2.6 g, 99%).

3,5-Dicyano-6-morpholinopyridine-2-(1H)-thione (17). A

mixture of 16 (2.4 g, 9.8 mmol) and NaHSÂH₂O (2.4 g)

in ethanol (100 mL) was stirred at room temperature for

1.5 h. The solvent was removed under reduced pressure.

After addition of water (50 mL) the solution was acid-

i®ed with 2 N HCl and 17 deposited as a solid that was

®ltered o and used in the next step without further

puri®cation. Compound 17 (2.3 g, 9.5 mmol): mp 228±

230 ^ꢀC; C₁₁H₁₀N₄OS calcd C, 53.65; H, 4.09; N, 22.75;

4-Chloro-8-cyano-2-dimethylamino-7-morpholinopyrido-

[3⁰,2⁰:4,5]thieno[3,2-d]pyrimidine (20). A solution of 19

(2.3 g, 8.1 mmol) and phosgene iminium salt (2.0 g,

12.2 mmol) in 1,2-dichloroethane (20 mL) was re¯uxed

for 6 h. After cooling, a stream of dry hydrogen chloride

was passed through the reaction mixture for 30 min, and

the stirring continued at room temperature for 48 h. The

resulting solid was ®ltered o and recrystallized from

ethanol/acetone to yield 20 (1.6 g, 53%): mp 225±

227 ^ꢀC; C₁₆H₁₅N₆OClS calcd C, 51.26; H,4.03; N, 22.42;

1

found: C, 53.47; H, 4.33; N, 22.59; H NMR (acetone-

d₆) d 3.66 (br s, 1H, exchangeable with D₂O), 3.88 (m,

8H, NCH₂CH₂O), 8.05 (s, 1H, H-4); MS (EI, m/z, %):

246 (M⁺, 49), 215 (34), 189 (82), 161 (100), 134 (46), 128

(17); IR (KBr, cm ¹): 2210 (CN), 1590, 1495, 1280.

3,5-Dicyano-2-cyanomethylthio-6-morpholinopyridine (18).

A mixture of 17 (0.1 g, 0.4 mmol), chloroacetonitrile

(40 mg, 0.5 mmol), potassium carbonate (70 mg,

0.5 mmol), and a catalytic amount of KI in acetone

(15 mL) was stirred at room temperature for 4 h. The

insoluble solid was removed by ®ltration and washed

with acetone. The ®ltrate and the washings were com-

bined and the solvent was evaporated. The resulting

solid was recrystallized from acetone to yield 18 (75 mg,

0.3 mmol): mp 176±178 ^ꢀC; C₁₃H₁₁N₅OS calcd C, 54.73;

H, 3.89; N, 24.55; found: C, 54.62; H, 3.78; N, 24.42; ¹H

NMR (CDCl₃) d 3.87 (m, 6H, NCH₂and SCH₂), 4.05

(m, 4H, CH₂O), 7.88 (s, 1H, H-4); ¹³C NMR (CDCl₃) d

16.1 (SCH₂), 47.7 (NCH₂), 66.5 (CH₂O), 88.5, 95.3 (C-3,

C-5), 113.9 (CN), 115.4 (CN), 116.4 (CN), 148.4 (C-4),

157.5, 162.3 (C-2, C-6). MS (EI, m/z, %): 285 (M⁺, 46),

245 (100), 226 (61), 173 (25), 160 (20); IR (KBr, cm ¹):

2240 (CN), 2215 (CN), 1580, 1535, 1400, 1340.

1

found: C, 51.37; H, 3.95; N, 22.49; H NMR (CDCl₃) d

3.25 (s, 6H, NMe₂), 3.89 (m, 8H, NCH₂CH₂O), 8.48 (s,

1H, H-9); ¹³C NMR (CDCl₃) d 37.4 (NMe₂), 48.5

(NCH₂), 66.6 (CH₂O), 92.2 (C-8), 114.4 (C-4a), 117.9

(CN), 119.2 (C-9a), 140.0 (C-9), 153.7 (C-4), 157.4 (C-

5a), 159.9 (C-9b), 160.8 (C-7), 167.0 (C-2); MS (EI, m/z,

%): 374 (M⁺, 92), 359 (15), 344 (6), 330 (11), 317 (62),

287 (29), 238 (24); IR (KBr, cm ¹): 2970, 2210 (CN),

1600, 1580, 1550, 1490.

8-Cyano-2-dimethylamino-7-morpholinopyrido[3⁰,2⁰:4,5]-

thieno[3,2-d]pyrimidine-4-substituted (21a,b). A solution

of 20 (0.15 g, 0.27 mmol) and the appropriate amine

(0.32 mmol) in ethanol/THF (1/3, 10 mL) was re¯uxed

until the starting material had disappeared (TLC). The

solid was ®ltered o and recrystallized from ethanol/

acetone to yield 21a,b (Tables 1 and 2).

5-Amino-3,6-dicyano-2-morpholinothieno[2,3-b]pyridine (19).

Method A. A mixture of 18 (2.0 g, 7.0 mmol) and potas-

sium carbonate (1.2 g, 8.4 mmol) was stirred at room

temperature for 1 h. The solid was ®ltered o and

recrystallized from ethanol to yield 19 (1.7 g, 88%): mp

294±296 ^ꢀC; C₁₃H₁₁N₅OS calcd C, 54.73; H, 3.89; N,

24.55; found: C, 54.65; H, 3.76; N, 24.45; ¹H NMR

(DMSO-d₆) d 3.69 (m, 8H, NCH₂CH₂O), 7.28 (br s, 2H,

exchangeable with D₂O, NH₂), 8.75 (s, 1H, H-4); ¹³C

NMR (DMSO-d₆) d 48.3 (NCH₂), 65.8 (CH₂O), 68.5

(C-6), 92.2 (C-3), 115.8 (CN), 116.5 (CN), 117.9 (C-4a),

140.1 (C-4), 150.1 (C-5), 158.8, 162.6 (C-2, C-7a); MS

(EI, m/z, %): 285 (M⁺, 95), 270 (15), 254 (33), 240 (34),

Acknowledgements

We acknowledge ®nancial support from Rhone-Pou-

lenc-Espana. We are also grateful to CICYT (Grants

MAR95-1933-CO2-O2 and PM95 0135) and to the

Xunta de Galicia (XUGA-20908B97).

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Synthesis and antiallergic activity of pyridothienopyrimidines

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