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Syntheses of Potentially Active 1-Substituted Imidazo-[12-c]pyrimidine Derivatives.

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102
Dhgosz and Machoh
~
Arch. Pharm.
~~
Arch. Pharm. (Weinheim) 319, 102-108 (1986)
Syntheses of Potentially Active 1-Substituted Imidazo[1,2-c]pyrimidine Derivatives
Anna Dlugosz* and ZdzisIaw Machoh
Department of Organic Chemistry, School of Medicine 50-137 WrocIaw, ul. Grodzka 9, Poland
Eingegangen am 29. November 1984
A series of 1-substituted 7-methyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5-oneshas been obtained by
treatment of 2-hydroxy-4-mercapto-6-methyl-5-pyrimidinecarboxylic
acid (1)with aminoalcohols
followed by chlorination, cyclization and alkylation. Some of the obtained imidazo[1,l-c]pyrimidine
derivatives were CNS active and showed antiinflammatory activity.
Synthese von potentieli biologisch aküven 1-substituiertenI m i d a z o [ l , 2 - ~ ] p ~ d i n d e ~ v a t e n
Eine Reihe von 1-substituierten 7-Methyl-2,3-dihydroimidazo[l,2-c]pyrimidin-5-onen
wurde durch
(1)mit Aminoalkoholen
Umsetzung der 2-Hydroxy-4-mercapto-6-methyl-5-pyrimidincarbonsäure
und nachfolgende Chlorierung, Cyclisierung und Alkylierung dargestellt. Einige der erhaltenen
Verbindungen erwiesen sich als CNS aktiv und zeigten entzündungshemmende Wirkung.
In the previous papers',') the reaction of ethyl 2-hydroxy-4-mercapto-6-methyl-5-pyrimidinecarboxylate with aromatic amines was described to give 4-amino derivatives. Some of the obtained
compounds showed antiinflammatoryand CNS activity. As a continuation of our investigation of the
new biologically active compounds we now descnbe the reactions of 2-hydroxy-4-mercapto6-methyl-5-pyrimidinecarboxylic
acid (1)with aminoalcohols.
When acid 1 was heated with ethanolamine in pyridine, 2-hydroxy-4-mercapto6-methylpyrimidine (2) was isolated. It means that no condensation but decarboxylation
occurred. The structure of 2 was confirmed by the elemental analysis and 'H-NMR. In the
'H-NMR spectrum of 2 appears a proton signal characteristic for an unsubstituted 5
position of pyrimidine ring (6 = 6,16ppm), and there is no signal of methylene groups in
the spectrum.
The heating of acid 1 with ethanolamine without any solvent gave 2-hydroxy4-~-hydroxyethylamino-6-methyl-pyrimidine
(3) on the base of the spectra1 date
(IH-NMR, MS). This result leads to the conclusion that compound 1 undergoes
simultaneously condensation and decarboxylation reactions. The IH-NMR spectrum of 3
showed methylene protons (6 4,13; 3,8ppm) and the proton of free 5 pyrimidine position
(6 6,15 ppm). The mass spectrum of 3 is in good agreement with the structure proposed for
the compound (Míe - 169).
Similarly during heating of 2 and diethanolamine without any solvent 2-hydroxy4-diethanoioamino-6-methylpyrimidine (4) is formed (scheme 1). Compound 3 with
SOC1, is converted into the 2-chloroethylamino-derivative5, which under mild conditions
0365-óZ33/%íû20'2-ûlûi $ M.50/0
0 VCH Verlagsgesellschaft mbH,D-6940Weinheim, 1986
319/86
103
Imidazo[l,2-~]pyrimidines
m =2
5: R = C1, n = 1,
m = l
R = OH
b: R = C 1
ïa:
\
C1o
0
TYH-C
H 2-C H 2-SR
ga-c: R - s e e table 3
(e.g. crystallisationin methanol) cyclized to 1H-7-methyl-2,3-dihydroimidazo[l
,2-c]pyrimidine-5-onhydrochloride (6). The structure of 6 was confirmed by 'H-NMR, MS and the
fact that the chlorine atom covalent in 5 changesinto an ionic one in 6. We have found that
the 1-$-hydroxyethyl-derivativeof 6 7a is better to synthesize from 4 using hydrochloric
acid instead of thionyl chloride. It is possible to use the crude mixture obtained after
melting 1with diethanolaminefor the reaction of 4 with hydrochloricacid. Chlorinationof
the crude mixture of 4 with thionyl chloride gives poor results. Purification of 4 from
excess of diethanolamine gives a low yield decreasing the yield of the final imidazo[ i ,2-c]pyrimidine derivative 7a.
Imidazopyrimidine 6 was alkylated by ethylene bromohydrin and the product was
identical with 7 obtained by HCl cyclization of 4. The alkylation of 6 with diethylaminoethyl chloride to l-N-diethylaminoethyl-7-methyl-2,3-dihydroimidazo[l,2-c]pyrimidine-5-one (8) takes place similarly. The low yield of alkylation can be explained by the
tautomeric structure of 6 (scheme 1). Such examples among imidazopyrimidines are
described in the literature3).
1-N-substituted aminoethyl-derivativesof imidazo[1,2-c]pyrirnidine7,8 were obtained
by condensation of different amines with the chlorocompound 7b. 7b was formed in the
reaction of 7a with SOCl,. When amines were replaced by thioureas and their derivatives,
the corresponding isothiuronium salts 9a-e could be isolated.
Pharmacology
The 1-substituted derivatives of imidazo[l,2-c]pyrimidine (tables 1,3) were tested for
their effect on CNS as wel1 as antiinflammatoryand antiulcer activities. The investigations
were carried out on Albino Swiss male mice and Wistar rats. Among the tested
compounds 8a and 8c indicated antiserotonin activity and 8c in dose 29mg/kg totally
104
Arch. Pharm.
DIugosz and Machoh
Tab. 1:Derivatives of 7-methyl-2,3-dihydroimidazo
[1,2-c] pyrimidine-5-one8à-j
~~
~
Comp.
No
R
M.p.'C
solvent
Yield Formula
% M.wt.
Caicd. :
C
8d P - C ~ H ~ O C ~.H
HC1
S 239
47
ethanol
8e p-CbH4Cl. HC1
8f
3,4-C6H3C12 . HCl
31
263-265
57
methanol
8g m-C&CF3.
HC1
236-237
42
8h P - C ~ H ~ C H SHCl
.
292
53
8i CsHdN(2). HCl
270
28
ethanol/acetone
8j -C(=NH)(NHCN). HCl90-92
acetonitrile
44
58,s
6,81 16,O 10,s
341,2
52,6 5,42
16,l
C15H17C13N40
48,O 4,56
47,8 4 3 5
14,9 28,3
14,7 27,8
20,2
C16H18ClF3N40 51,3 4,73 15,O
338,3
methanol
l
C I ~ H ~ ~ C ~ Z52,8
N~O
5,31 16,4 20,8
375,6
methanol/acetone
C
C17H~ClN402 58,2 6,56 16,O 10,l
350,8
295-297
80 % methanol
Found:
H N
51,3 4 5 9 15,O
C ~ ~ H Z ~ C ~59,9
N ~ O6,59 17,s 11,l
320,8
59,9 6,45 17,4 10,8
C14H18ClN50
307,8
54,6 5,89 22,8
54,2 5,95 23,l
C1,H19C1Nlo08a
526,7
38,8 3,63 26,6
38,9 3 3 4 26,3
6,7
6,s
a - forrnula and analyses for the picrate (M.P.: 165-167°C)
inhibits the action of the standard dose of 5-HTP according to Tedeschi method4).
Compound 7a in dose 16,6 mgíkg raises the action of DOPA like imipramine. Compounds
8i,j,9b tested for antiulcer activity on histamine H,-receptors were inactive.
The antiinflammatory activity was checked in carrageenine and in cotton tests according
to the Winter and Lence methods'~~).Compounds 8e-h showed weaker effect than
acetylsalicylic acid and decreased the oedema in the paw of the rat after 4 h in 52-57 %
compared to 64-69 % of acetylsalicylic acid. More details concerning pharmacological
investigations of the described cornpounds 7a,8a-j, 9ab wil1 be given in a separate
pubìication.
We acknowledge financial support from the Polish Academy of Sciencies (Project MR I
12.2.3).
319186
105
lmidazo[l,2-c]pyrimidines
Tab. 2: 'H-NMR spectra of S&j, 9a,c (8 = ppm.TMS)
Compound (No)
Solvent
-CH3
8-H
-CH2 -
H-aromat.
8d
(DzO)
2,49 (s, 3H)
1,6 (t, 3H,=-CH2)
5,85 (s, 1H)
4,27 (m,6H)
3,82 (m, 4H)
7,O (q,4H, C6H4)
8f
(D2O)
2,4 (s, 3H)
6,O (s, 1H)
3,9 (m,4H)
4,l (m, 4H)
7,4 (m, 3H, C6H3)
8g
2,08 (s, 3H)
5 3 6 (s, 1H)
3,56 (m, 4H)
3,92 (m, 4H)
6,84 (m, 3H)
7,24 (m,1H)
8h
(D2O)
2,49 (s, 6H)
5,89 (s, 1H)
3,98 (m,4H)
4,25 (m, 4H)
6,89 (d, 2H)
7,32 (d, 2H)
8i
(D2O)
2,s (s, 3H)
5,6 (s, 1H)
3,85 (m, 4H)
4 3 (m, 4H)
6,O (d, lH, 3-CHpyr.)
7,2 (m,2H, 43-H,
pyr.), 8,l (d, lH,
WHPYr. 1
8j picrate
(DMSO)
2 3 (s, 3H)
6,52 (s, 1H)
4,07 (m, 4H)
4,31 (m, 4H)
8,78 (s, 2H, C6H2)
9a
(&O)
2,62 (s, 3H)
6,s (s, 1H)
4,35 (m, 4H)
4 3 (m, 4H)
7,72 (m, SH, C6H5)
-~
~
Tab. 3.: Derivatives of isothiuroniumsalts 9a-c
Comp.
No
R
M.p.'C
(solvent)
Yield
%
Formula
M.wt.
C
9a
-C(-NHC6H~) = NHZ CIQ . HCI 235-237
(waterlacetone)
9b
-C(-NHz) = NHT C1
9c
-C N(CzHS)z = NHZ CIQ. 2HC1 170-172
35
(methanol/acetone)
. HCl
a: S: Calcd.: 8,O Found 7,9.
60-61
(absol. ethanol)
Calcd.:
Found:
H
N
C
I
29
C16HziClzNsOS 47,8
402,3
47,s
5.26 17,4 17,6a
5,23 17,4 17,4
51
CIOHl7ClzNSOS 36,8 5,23 21,4 21,7
326,2
36,3 5 5 8 22,O 20,3
C14H26C13NSOS40,l 6,20
418,7
40,8 6,87
16,7
16,s
106
Dtugosz and Machoh
Arch. Pharm.
Experimental Part
IR: Unicam SP-1OOO sepctrophotometer; 'H-NMR:Tesla-80 spectrometer (TMS); MS: MS-9 AEI
(70 eV) spectrometer; M.p.:uncorr.
2-Hydroxy-4-mercapto-6-methylpyrimidine(2)
2g (0,011mol) 17)was heated with 2,7g (0,044mol) of ethanolamine and 25 ml of pyridine 6 h under
reflux. The mixture was filtered and evaporated i.vac. to 113vol., from dioxan yellow crystals. M.p.:
320°C (decomp.) Yield: 52 % 0,9g 2. CsH6N,0S (142,2) Calcd. C 42,3 H 4,22 N 19,7Found C 42,7 H
4,35 N 19,6. 'H-NMR (DMSO): S (ppm) = 12,2 (s; NH), 113 (s; NH), 6,16 (s; 5-H), 3 3 3 (s,SH),
2,06 (s, 6-CH3).
2-Hydroxy-4-(2-hydroxyethylamino)-6-methylpyrimidine
(3)
20g (0,ll mol) of 1was mixed with 3 3 3 g (O,% mol) of ethanolamine and heated slowly to 130°Cand
after hydrogensulfide had stopped bubbling vigorously, the temp. was encreased to 16&170 "C and
kept for 4 h. The cooled mixture was washed with 50ml absol. ethanol, from 80 % pyridine white
crystals: 3 (16,5g) M.p.: 273-274"C, yield 83 %. ÇHllN30, (169,l) Calcd. C 49,7 H 6,55 N 24,8
Found49,3H6,23N24,5. 'H-NMR (CF3COOH): S(ppm) = 8,s (s, NH), 6,15 (s, 5-H), 9,13,3,8(m,
m-CH,-CH2-) 2,4 (s, 6-CH3). MS (70 eV): d e = 169 (10 % M').
2-Hydroxy-4[NN-bk
(2-hydroxyethyl)amino/-6-methyl-pyrimidine
hydrochloride (4)
The mixture obtained after melting 0,011 mol 2 with 0,044mol diethanolamine in a similar way as for
preparing3 was dissolved in methanol, acidified with HCUmethanol and evaporated i.vac. to dryness.
The residue was recrystallized from absol. ethanol, m.p.: 277-279°C. Yield: 13,4% 0,5g 4
hydrochloride. C9HlSN3O3X HCI (249,s) Calcd. C 48,l H 6,Ol N 16,8C114,2 Found C48,O H 5,86 N
17,4 C1 14,6. IR (KBr) = 3350 (NH) 2900-3100 (CH), 1760 (C=O), 1650 (-C=N-), 1320 (OH),
1070cm-' ((2-0).
2-Hydroxy-4-(2-chloroethylamino)-6-methylpyrimidine
(5)
To the mixture of 15,9g (0,94 mol) of 3 and 159ml CHC13 119 ml SOCl, was added dropwise, and the
solution was stirred 6 h at 60 "C. The precipitate was dissolved in 70 ml water and filtered. The filtrate
was made alkaline (pH-8) with sodium hydrogencarbonate and 5 was isolated. M.p.: 360'C. Yield:
91 %. C7HloCIN30(187,6) Calcd. CI 18,9 Found C1 19,4. Similarly 7a with SOCl, gives 7b mp.
95-97°C. C9Hl,Cl N30X HCl (250,O) Calcd. C128,4 Found C128,9.
I -H-7-methyl-2,3-dihydroimidazo[l,2-c~pyrimidine-5-one
(6)
20g (0,ll mol) of 5 was dissolved in 250 ml of ethanol and the solution was reflwed 0,5 h, purified
with charcoal. After cooling 10,9g hydrochlonde of 6 was dissolved in 50 ml water and basified with
sodium hydrogencarbonate. The solution was concentrated i.vac. at 50°C and from the residue after
recrystallisation from absol. ethanol 6 was separated. M.p.: 232°C Yield 46%. ÇH 9N 30 (151,l).
Calcd. C 55,6 H 5,96 N 27,8 Found C 55,8 H 5,43 N 28,O. 'H-NHR (CF3COOH): S (ppm) = 8,38
(s,NH), 6,37 (s,8-H), 4,25 (m, -CH2-CH2-)2,38 (s, 7-CH,). MS (70 eV): d e = 151 (65 %), 150
(100%).
i (2-Hydroxyethyl)-7-methyl-2,3-dihydroimidazo
[1,2-c]pyrimidine-5-ohydrochloride
ne
(7a)
Method A: 12g (0,065 mol) of 1was melted with 23,8 g (0,2 mol) of diethanolamine as is descnbed for
3. To the crude mixture 72 ml of conc. HCl was added and al1 was heated on the steam bath for 18h at
319/86
Imidazo[l,2-c]pyrimidines
107
100°C. Then the reaction mixture was concentrated i.vac. and the residue purified with water and
concentrated to remove the excess of hydrochloric acid. The residue was recrystallized from
methanol to give white crystalline 7a. M.p.: 232°C (methanol) Yield: 61 %.
Method B. To a mixture of 1,Sg (0,Olmol) of 6 in 90ml of dry DMSO, 0,7ml (0,033mol) of
2-bromoethanol and 1,s g (0,011 mol) of anhydr. kalium carbonate were added in portions. After 1h
stirring at room temp. the reaction mixture was stirred at 70°C for 12hand then DMSO was removed
by distillation i.vac. The residue was dissolved in water and the water layer after extraction with
chloroform was concentrated i.vac. The oil residue was dissolved in methanol. The filtrate was
acidified with HCVmethanol and 7a was precipitated with acetone. M.p.: 230-232 "C (methanol)
Yield: 25 %. C$1~N302 x HCI (231,s) Calcd. C 46,7 H 6.04 N 18,l C115,3 Found. C 46,5 H 6,00 N
18,4 C1 15,2.
1-N-Diethylaminoethyl-7-methyl-2,3-dihydroimidazo[l.2-c]pyrimidine-5-one
hydrochloride (8a)
Method A: The mixture of 2g (0,013mol) of 6, 2,75g (0,016mol) of the hydrochloride of
diethylaminoethylchloride and 2,l g (0,025 mol) of anhydrous sodium acetate in 25 mi absol. ethanol
was refluxed 3 h, then ethanol was removed i.vac. and the residue was dissolved in 20ml of water. The
water layer after extraction with chloroform was concentrated i.vac. and the residue was dissolved in
acetone. The solution was acidified with HCVmethanoland 8a was obtained. M.p. 120"C, yield 32 %
(methanoVacetone).
Method B: 1.7g (7mmol) of 7b was refluxed with 20ml (0,27mol) of diethylamine 5 h and
concentrated i.vac. The residue was dissolved in methanol, filtered, acidified with HCVmethanol and
8s hydrochloride was isolated, m.p.: 120-125 "C (methanoiíacetone). Yield: 43 %.
C,,H,N,O
x HCI (286,7) Calcd. C 5 4 3 H 8,02 N 19,s Found C 54,2 H 8,21 N 19,8. 'H-NMR
337 (m, 8H-CH2), 2,7 (s, 7-CH3), 1,47 (t, 6H,
(CF3COOD): 6 (ppm) = 4,O (9,4H-=-CH3),
m-CHZ-).
7-Methyl-1-piperidinethyl-2,3-dihydroimidazo[l,2-c]pyrimidine-S-one
hydrochloride (8b)
1,4 g (5,6 mmol) of 7b was refluxed 6 h with 5 ml of piperidine. Piperidine hydrochloride was removed
by filtration and the filtrate was concentrated i.vac. The oil residue was dissolved in 1Oml of dried
acetone. 8b: m.p.: 296°C (methanol). Yield: 53 %. C14H12N402x 2HC1 (335,16) Calcd. C 50,2 H
7,37 N 16,7 Ci 21,2 Found C 49,8 H 7,16 N 16,5 C1 21,4.
1-[N-(2-hydroxyethyl)-N'-ethylpiperazineJ-7-methyl-2,3-dihydroimida~o[l,2-c]pyrimidine-S-one
hydrochloride (Sc)
3 g (0,012mol) of 7b and 3,4g (0,0264 mol) N-2-hydroxyethylpiperazinein 50 ml absol. ethanol were
refluxed for 6 h. The mixture was fiitered and concentrated i.vac. The oil residue was dissolved in
methanol and acidified with methanolíHC1. The white precipitate (5 g) was refluxed with ethanol and
2,s g of 8c was obtained. M.p.: 278 "C (methanol). Yield 52 %. C1,-H2,NSO2x 3HC1(380,2) Calcd. C
43,2 H 6,72 N 16,8 C125,6. Found C 4 3 3 H 6,91 N 16,4 C125,3. IR (KBr) = 3300 (OH), 3150 (CH)
1750 (C=O). Similarly comp. 8&8j were obtained. For comp. 8e and 8h ethanol was replaced by
xyiene. Comp. Sj was synthesized in chloroform. Analyses for 8d-8j see in table 1, 'H-NHR in
table 2.
Hydrochloride of N-phenyl-S-[I
-(7-methyl-5-oxo-2,3-dihydroimidazo[l,2-c]pyrimidinyl-l)ethyl2]isothiuronium chloride (9a)
To the solution of 5 g (0,02mol) of 7b in 50 ml of absol. ethanol6,7 g (0,044mol) of N-phenylthiourea
was added and the mixture was refluxed 10h. After cooling the filtrate was concentrated i.vac. The oil
108
Görlitzer und Michels
Arch. Pharm.
residue was treated with 25ml of water and unreacted N-phenylthiourea filtered. The filtrate was
evaporated i.vac. The residue after recrystallization from methanol gives 3,3g of 9a (table 3,2).
Similarly comp. 9b,c were obtained.
References
Z. Machoh and A. Dtugosz, Pol. J. Pharmacol. Pham. 28, 511 (1976).
Z. Machoh and A. Dlugosz, Acta Pol. Pharm. XL,1 (1983).
T. Ueda and J.J. Fox, J. Am. Chem. Soc. 85,4024 (1963).
R.T. Tedeschi, H.G. Tedeschi, A. Mucha, L.Cook and P.A. Mattis, J. Pharmacol. Exp. Ther.
125, 29 (1959).
5 C.A. Winter, E.A. Risley and G.W. Wuss, Proc. Soc. Biol. Med. 111, 544 (1962).
6 P. Lence, Arch. Int. Pharmacodyn. Ther. 136, 237 (1962).
7 Z. Machoh and A. Dlugosz, Pol. J. Pharmacol. Pharm. 25,579 (1973).
1
2
3
4
[Ph 231
Arch. Pharm. (Weinheim) 319, 108-112 (1986)
Untersuchungen an 1,3-Dicarbonylverbindungen,25. Mitt.’)
Pyrano[3,2-b]indol-4( 5H)-on und 9-Chlor-l-oxo-l H-pyrrolo [1,2a]indol-2-carbaldehyd**
Kìaus Görlitzer+ und Klaus Michels’)
Institut für Pharmazie der Freien Universität Berlin, 1OOO Berlin 33, Königin-Luise-Str.2+4
Eingegangen am 3. Dezember 1984
Ausgehend von der 1,3-Dicarbonylverbindung1 gelingt durch Umsetzung des BF,-Chelats 2 mit
POCIflMF die Darstellung der Titelsubstanzen 5 und 9 . 5 wird durch das Thion 6 und das Oxonol7,
9 durch die 1 ,CDihydropyndine 10 charakterísiert.
l,3-Dicarbonyl Compounds, X X V Pyrano[3,2-b]indole-4(5H)-oneand 9-chloro-~-oxo-1~pyrroloIl,2-s]indole-2-carbaidehyde
On treatment with POC13/DMF the BF2 chelate 2, obtained from the 1,3-dicarbonyl compound 1,
yields the title substances 5 and 9. Compound 5 is characterized by way of the thione 6 and the oxonol
7, compound 9 by way of the l,4-dihydropyndines 10.
**Herrn Prof. Dr. F. Eiden mit den besten Wiinschen zum 60.Geburtstag gewidmet.
0365-6233/&/@?024108 $02.50/0
0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1%
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