151
Acylaminofurazans
Potential Histamine H2-ReceptorAntagonists: Synthesis and Pharmacological Activity of Derivatives Containing Acylamino-furazan Moieties G. Sorba”),R. Frutteroa),A. Di Stiloa),A. Gasco”.’), and M. Orsettib) a)
b,
Diparthento die Scienza e Tecnologia del Farmaco - Universita di Torino, Via Piem Giuria 9,I-10125Torino, Italy Istituto di Farmacologiae Farmacognosia UnivenitAdi Torino. Carso Raffaello 31.1-10125Torino, Italy
-
Received January 14,1991
Synthese und phermaAnalogues of 3-amino-4-[2-[(5-dimthyla~nomethyl-2-fu~l)~thylthio]Potentlelle HlaIamln-H~-Reeeptorentagonlsten: kologische Aktlvitiit von Substanzen mit Acylamlnofurazan-Partialethylamino]furazan (1) containing carbonyl groups joined to the amino functions linked to the furazan system have been synthetized and investigated for struktur their H2-antagonist propenies on the isolated guinea pig right atrium. The Es wurden Cabonsaureamid-Analoga des Histamin-HyAntagonisten3-Amipresence of the carbonyl group lowers the activity in respect to the comeno-4-[2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino]furazan sponding leads. The decrease in activity is only by 1-2 orders of magnitude in the 3-acylaminofurazan series versus inactivity in the Cacylamino (1) synthetisiert und am isolierten spontan schlagenden rechten Meerschweinchen-Atrium auf H2-Antagonismus gepriift. Alle Saureamide sind isomers and in the diacylated series. schwkher wirksam als die entsprechenden kitstrukturen. Wahrend die Acylierung der 3-Aminogmppe von 1zu einer Abnahme der Aktivitat in der Grtifienordnung von 1 bis 2 Zehnerpotenzen fuhrt, besitzen die StNktUnWmeren CAcylaminofurazaneund die 3,Cdiacylierten Analoga praktisch keine Hq-antagonistische Wirkung (pA2 < 4).
In earlier investigation’) we showed that the introduction of alkyl substituents into the lateral itmino group of the ranitidine analogue 1 afforded Hz-antagonists with high activity. This prompted us to hypothesize on the existence of a H2-receptorof an additional binding area near the site fitted by the diaminofurazan moiety. Similar studies were done by other author~”~’ and more recently by Lampe and coif4’and Ardn and coil.”’. On this bases we designed a few open models related to classical Hz-antagonists with potent activity6).
This paper presents the results of our investigations on the relationship between H2-antihistaminic properties and the
,
presence in the model 1 of carbonyl groups joined to the amino functions linked to the furazan system (Figure 1).
Chemistry and Spectroscopy The intermediates used for the synthesis of the derivatives studied were synthetized according to Scheme 1. The intermediate 15 reacted with an equimolar amount of the appropriate acyl chloride to give derivatives 16. In similar way derivatives 18 were obtained from 17.Reduction of
H3C \
N-CH2
wNHBR
jC
1 % R
2 3
R
- -
A
CH2
B
H
9
%
C=O
H
12
‘gH5
‘gH5
A
C=O
C=O
B
CH2
C=O
Fig. 1:
Arch. Pharm. (Weinheim)325. I5I- I55 (1992)
OVCH VerlagsgesellschaftmbH. D-6940Weinheim. 1992
036S-6233/92/0303-0IS I $3.50 + 2510
152
Gasco, Orsetti er al.
a,R=CHJ
wNH-i-R H2NwNH2 R-6-C'
N''0'
'N
H2N
0
NJ' 9
-.
Li A l H&
'N
c
n
CI-CH,-
:-HN
c,R=(CH2+H~
NH - C H 2 - R H2NH N\o"
THF
17
LG
15 %
/
NH-R \n/
U
20
*
a, R=CH3-CH2 b, RzCbHs-CHz
c, R = H
Scheme 1
compounds 18 with LiAlK in THF gave 19 which were transformed into 20 by chloroacetyl chloride. Yields, melting points and recrystallization solvents of these products are reported in Table 1.
Synthesis and characterization of the intermediates 22 have been reported'). The final derivatives (see in Figure 1 compounds 2, 4-6, 8-10, 12, 14) were obtained according to Scheme 2.
Table 1: 3-Acylamino-4-(2-chloroethylamino)furazans16 3-Acylamino-4-aminofurazans 18 3-Alkylamino-4-aminofurazans19 3-Alkylamino-4-(2-chloroacetamido~furazans 20
R
!IELD
M.P. ('C)
RECRYSTALLIZATION
FORMULA
SOLVENT
80
97-98
a
79
124-125
a
a7
113-114
a
89
128-129
b
72
191-192
C
a0
147-148
b
65
86-87
d
63
103-104
d
85
117-118
a
78
107-108
a
a: ethyl acetate / petroleum ether 40-60'C b: ethanol / water c: water d: methylene chloride / petroleum ether 40-6WC
Arch. Pharni. (U'i~inlieini)325. 151-155 (1992)
153
Acylaminofurazans
Pharmacology N-CH,
a)
H 3C‘
2, 4-6, 8-10, 12, 14 oxalates were tested as antagonists of the positive chronotropic effect of histamine on isolated spontaneously beating guinea pig atria according to Black et al?). The activity, expressed as pA2, is reported in Table 2. None of the compounds produced a modification of the spontaneous contraction frequency of the atria when tested alone with the exception of derivatives 9 and 10 which showed a negative chronotropic effect. Specificity for H2-receptors was evaluated on the basis of the ability of these compounds to antagonize the positive chronotropic response to isoprenaline in the guinea pig atria (P-adrenergic receptors) and the contractile response to histamine and carbamoylcholine in the guinea pig ileum (HI and muscarinic receptors, respectively). None of them modified the effect of isoprenaline. On the contrary derivatives 12 and 14 antagonized reversibly and noncompetitively the response to histamine and carbamoylcholine. This noncompetitive antagonism arose at a concentration about ten fold higher than derivative 12 or similar to derivative 14 that producing competitive H2-receptor block.
31
b)
C )
Scheme 2
Table 2: Reaction yields, melting points and H2-antagonist activity of 1-14 ’IELD 4
M.P.
(OC)‘)
-
-
pA2 i 95% CL
7.43 i 0.33
SLOPE OF SCHILD PLOT f 95% CL
1.05 f 0.18
No.
OF
EXPERIMENTS
19
-
-
< 4
-
7.34 i 0.32
0.89 i 0.23
16
60
143-144
6.14 i 0.12
1.02 f 0 . 1
20
80
15 3 15 4
-
< 4
-
6
80
70
-
63
m - u a
-
< 4 7.65 f 0 . 2 1
1.12 f 0.18
21
150-151
6.98 f 0 . 4 1
0.91 f 0.25
18
138-139
-
C
-
8.82 f 0.18
1.05 f 0.16
20
162-163
6.96 f 0.16
1.05 f 0.24
15
8.69 f 0.23
1.04 f 0.19
21
6.46 f 0 . 1 1
1.04 f 0.26
12
110-111
C
78
152-153
61
-
60
-
a
-
78
-
6
-
136-137
-
-
a) All derivatives were recrystallized from a mixture of methanol/isopropanol b) pA2 values are taken from ref.’) c) Negative chronotropic effect
The reaction of the intermediates 16, 20, 22 with [5-di-
m e t h ~ 1 a m i n o ~ ~ t h ~ 1 ) - 2 - f u ~ 1 ~ m e t21 h ~ ~was ~ t hcarried io1 out under N2 in ethanol solution containing NaOH. For reaction yields, melting points and recrystallization solvents of the final products see Table 2, for I3C-NMR characterizationTable 3.
Arch, Pharm. (Weinheim) 325. 151-155 (1992)
ResultsandDiscussion The data reported in Table 2 show that the presence of carbonyl groups linked to amino functions of the ”urea equivalent“ moiety deeply influences the H2-antagonist activity. Substitution of the alkyl groups joined to the lateral amino function in the leads 3, 7, 11, and 13 with the corresponding acyl groups to give
151.1/150.0
I
m.1/110.2
151.4/150.3
I
151.8
30.4
For the carbons c/f, d/e, Urn two alternative assignments are reported
23.0
14.1
I Jo.1/151 .l
31.1
R
169.0
35.2
170.2
31.2
151.0/151,1
14.3
35.5
28.2
1%.3/151.4
J-7
49.9A51.4
n
m
I
1
h
0
151.4/150.0
1w.2/109.7
10.2/toal
d
148.6/151.4
109.7/1 m.2
51.4/148.6
f
151.1/151 .O
4
%
151.4/149.9
u.l
*7
I I
I
23.6
35.7
28.5
149.9/151.4
, 127.' 127.
138.2
128.5
.
48.8
154.9
149.9
43.4
31.2
216
149.7/150.2
10&4/110.9
110.9/1 M A
150.2/149.7
55.0
--t -t
51.4/149.9
3
%
+ + -+-
-I-
I
C
b
a
(b P P ~ )
l3C
Tab. 3: 13Cchemical shifts (ppm from TMS)
167.1
151.3
44.7
151.9
143.8
169.1
44.7
1 p i
145.3/144.7
I51.7/149.6
150.7/154.4
151.5/14#.7
+ +
, 25.2 25.3
29.15
176.1
lU.2
128.4 38.2
141.5
128.45. 126. 37.6 30.9
,
140.1
, 125.7 , 30.6
, 128.
172.3
143.95
151.6
43.6
30.5
28.2
149.9/1 51a
108.4/110.6
110.6/10&4
, 128.4
43.33
150.3/1502
1503/150.3
4435
u.9
151.7
31.3
28.1
149.7/151.8
1Ok3/110.7
151.8/149.9 I l l .8/149.7
~
54.9
44.1 1
R3
14
55.3
U.32
30.3
283
149.3/151.7
lOk2/110.9
110.9/10&2
54.4
43.6
12
Acy laminofurazans derivatives 4.8.12, and 14 is accompanied by a decrease in the H2-antagonist activity and in 12 and 14 by a loss of selectivity. The decrease in activity is about two orders of magnitude in 12 and 14 and one order of magnitude in 4 and in 8. The influence of the introduction of the carbonyl-group on the inner amino group of the diaminofurazan substructure is more dramatic (derivatives 2,s. 9).In fact this manipulation is accompanied by the disappearence of the activity (2, 5; pA2 c 4) and in compound 9 by a negative chronotropic action on the atria. The above discussed trends are confinned by the complete inactivity of derivative 6 bearing a carbonyl group on both the amino functions. In 10 this last manipulation is responsible for the negative chronotropiceffect of the compound. At this state of our research we have not found definitive explanations for these structure activity relationships. Probably the change of the electronic and lipophilic properties is one of the factors determining the decrease in the activity in moving from alkyl to acyl substituted derivatives. But the dramatic effect following the introduction of the carbonyl-group on the amino group present in the chain connecting the furan ring with the furazan system shows that other factors must play important roles. Certainly the conformational domain in the carbonyl derivatives i s deeply different from that of alkyl analogues and this should be the principal reason for the difference in activity between these compounds. Studies are in progress to confirm this point. This work has been supported by a grant from “Studi e Ricerche Finanziate 40%” MURST (Rome, Italy)
Experimental Part Melting points: BIichi 530 capillary melting point apparatus, uncorrected.- IR (Perkin-Elmer 781).- Mass Spectroscopy (Varian CH7 MAT).The spectra agree with the proposed structures.- l3C-NMR AC-200 MHz Bruker, 5 mm tubes, solvent CDCl3: chemical shifts relative to TMS are reported in Table 3. Compounds 3, 7, 11, 13, 22”; 1, 15, 20c8’; 179’. 21”’ were synthetized according to the lit. methods. Silica gel Merck Kieselgel60,230-400 mesh ASTM, was employed for chromatographicpurification. Microanalyses for C, H, N are within 0.4% of theoretical values. Anhydrous MgS04 was used for drying.
3-Acylamino-4-(2-chloroerhylaminolfurazans( 16a-d) 10 mmoles of the appropriate acylchloride were added under stirring to a solution of 1S O g (9.2 mmol) of 3-amino-4-(2-chloroethylamino)furazan 15 in dry THF (40 ml). The solution was kept for 2 h at room temp. and treated with 0.84 g (10.0 mmol) of solid NaHCOp The solvent was removed under reduced pressure, the residue was treated with water and extracted with ethyl acetate. The org. layers were filtered and evaporated under reduced pressure. 16a and 16b were obtained as solids. 16c and 16d, obtained as oily products, were purified by silica gel column chromatography eluting with petroleum ether 40-60°C ethyl acetate (0-20%) before crystallization. Reaction yields, recrystallization solvents and melting points: Table 1.
3-Aceramido-4-aminofurazan(Ua) and 3-amino-4-benzamidofurazan (18b) These compounds were synthetized following the method used for the synthesis of 16, starting from 17 and acetyl chloride or benzoyl chloride diluted with few ml of anhydrous THE The reaction for 18a was complete in 3 hat room temp. For the preparation of 18b the solution of benzoyl chloride was added to the boiling solution of a slight excess of 17 and the mixture was refluxed for 1 h. The reactions were worked up as reported for 16.
Arch. Pharm. (Weinheinl) 325,151-155(1992)
155 Reaction yields, recrystallization solvents and melting points: Table I ,
3-Alkylamino-4-aminofurazuns (19a.b) 7.3 mmoles of the appropriate 18 were added portionwise to a chilled (ice-salt) mixture of LiAIH, (0.84 g, 2.2 mmol) in 40 ml dry THF. The reaction mixture was kept 1 h under cooling then 2 h at room temp. Excess of ethyl acetate was added and the mixture was cautiously treated with 10% H2S04 until all the solid material was dissolved. The org. phase was collected and the aqueous one was extracted with ethyl acetate. The combined org. phases were vigorously stirred for 30 rnin with powdered anhydrous NaZC03 and then filtered. The solvent was evaporated under reduced pressure: yellow oil. The oil was purified by silica gel column chromatography using petroleum ether 40-60°C-dichIoromethane-ethylacetate 2:l:l. Reaction yields, recrystallization solvents and melting points: Table 1. 3-Alkylamino-4-(2-chloroaceramido)furazans(20a.b)
These compounds were synthetized with the method used for 16. starting from 19 and chloroacetyl chloride. The reaction was complete in 1 h at room temp. Reaction yields, recrystallization solvents and melting points: Table 1. 3-Amino-4-[2-[(5-dime1h~luminome1hyl-2-~~ljme1hyl1hio]aceiam~dofurazan (2)
3-Acylamino-4-[2-[(5-dimethylaminomethyl-2-furyl)merhyl1hio] erhylamino]furazans (4). (8). (12), (14) 3-Acylumino-4-[2-~(5-dimethylaminomethyl-2-fu~i)merhylthio] acetamido]furazans (6), (10) 3-Alkylamino-4-[2 -[(S-dimethylaminomethyl-2-furyl)methylthio] aceramidolfurazans(5). (9) These compounds were synthetized according to the method reported’’ starting from 21 and the appropriate intermediates 16,20,22. The reaction time for compounds 2, 5, 6, 9, 10 was 1 h at room temp. while for compounds 4,8. 12. 14 was 2 h at reflux. The oils obtained after working up were purified by silica gel column chromatography using dichloromethane/methanol 98:2 (955 for 6) as mobil phase. The oils obtained after solvent removal were immediately transformed into the correspondingoxalates. Reaction yields, recrystallization solvents and melting points: Table 2.
References G. Sorba, A. Gasco, and M. Orsetti, Eur. J. Med. Chem. 24, 475 (1989). J.C. Emmett, G.J. Durant, C.R. Ganellin, A.M. Roe, and J.L. Turner, J. Med. Chem. 25,1168 (1982). J.P. Spengler, K. Wegner, and W. Schunack, Agents Actions 14. 566 (1984). J.W. Lampe, R.G. Hanna, T.A. Piscitelli, Y.L. Chon. P.W. Erhardt. W.L. Lumma, S.S. Greenberg, W.R. Ingebretsen, D.C. Marshall, and J. Wiggins, J. Med. Chem.33, 1688(1990). V.J. Alan. E. Dhnila, M. Frances, P. Gosa, J. Gras, A. Martinez, N. Mylonakis, and 1. Pardo, Arzneim.-Forsch.40, 1003 (1990). G. Sorba, R. Fruttero, A. Gasco, and M. Orsetti, Arzneim.-Forsch. 39, 1092 ( 1989). J.W. Black, W.A.M. Duncan. C.S. Durant. C.R. Ganellin, and E.H. Parsons, Nature 236,385 (1972). G. Sorba, R. Calvino, A. Defilippi, A. Gasco, and M. Orsetti, Eur. J. Med. Chem. 20,571 (1985). M.D. Coburn, J. Heterocycl. Chem. 5.83 (1968). 10 G. Sorba, R. Fruttero, R. Calvino, A. Gasco, and M. Orsetti, Arch. Pharm. (Weinheim)317,469 (1984). [Ph906]
Acylaminofurazans
Potential Histamine H2-ReceptorAntagonists: Synthesis and Pharmacological Activity of Derivatives Containing Acylamino-furazan Moieties G. Sorba”),R. Frutteroa),A. Di Stiloa),A. Gasco”.’), and M. Orsettib) a)
b,
Diparthento die Scienza e Tecnologia del Farmaco - Universita di Torino, Via Piem Giuria 9,I-10125Torino, Italy Istituto di Farmacologiae Farmacognosia UnivenitAdi Torino. Carso Raffaello 31.1-10125Torino, Italy
-
Received January 14,1991
Synthese und phermaAnalogues of 3-amino-4-[2-[(5-dimthyla~nomethyl-2-fu~l)~thylthio]Potentlelle HlaIamln-H~-Reeeptorentagonlsten: kologische Aktlvitiit von Substanzen mit Acylamlnofurazan-Partialethylamino]furazan (1) containing carbonyl groups joined to the amino functions linked to the furazan system have been synthetized and investigated for struktur their H2-antagonist propenies on the isolated guinea pig right atrium. The Es wurden Cabonsaureamid-Analoga des Histamin-HyAntagonisten3-Amipresence of the carbonyl group lowers the activity in respect to the comeno-4-[2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino]furazan sponding leads. The decrease in activity is only by 1-2 orders of magnitude in the 3-acylaminofurazan series versus inactivity in the Cacylamino (1) synthetisiert und am isolierten spontan schlagenden rechten Meerschweinchen-Atrium auf H2-Antagonismus gepriift. Alle Saureamide sind isomers and in the diacylated series. schwkher wirksam als die entsprechenden kitstrukturen. Wahrend die Acylierung der 3-Aminogmppe von 1zu einer Abnahme der Aktivitat in der Grtifienordnung von 1 bis 2 Zehnerpotenzen fuhrt, besitzen die StNktUnWmeren CAcylaminofurazaneund die 3,Cdiacylierten Analoga praktisch keine Hq-antagonistische Wirkung (pA2 < 4).
In earlier investigation’) we showed that the introduction of alkyl substituents into the lateral itmino group of the ranitidine analogue 1 afforded Hz-antagonists with high activity. This prompted us to hypothesize on the existence of a H2-receptorof an additional binding area near the site fitted by the diaminofurazan moiety. Similar studies were done by other author~”~’ and more recently by Lampe and coif4’and Ardn and coil.”’. On this bases we designed a few open models related to classical Hz-antagonists with potent activity6).
This paper presents the results of our investigations on the relationship between H2-antihistaminic properties and the
,
presence in the model 1 of carbonyl groups joined to the amino functions linked to the furazan system (Figure 1).
Chemistry and Spectroscopy The intermediates used for the synthesis of the derivatives studied were synthetized according to Scheme 1. The intermediate 15 reacted with an equimolar amount of the appropriate acyl chloride to give derivatives 16. In similar way derivatives 18 were obtained from 17.Reduction of
H3C \
N-CH2
wNHBR
jC
1 % R
2 3
R
- -
A
CH2
B
H
9
%
C=O
H
12
‘gH5
‘gH5
A
C=O
C=O
B
CH2
C=O
Fig. 1:
Arch. Pharm. (Weinheim)325. I5I- I55 (1992)
OVCH VerlagsgesellschaftmbH. D-6940Weinheim. 1992
036S-6233/92/0303-0IS I $3.50 + 2510
152
Gasco, Orsetti er al.
a,R=CHJ
wNH-i-R H2NwNH2 R-6-C'
N''0'
'N
H2N
0
NJ' 9
-.
Li A l H&
'N
c
n
CI-CH,-
:-HN
c,R=(CH2+H~
NH - C H 2 - R H2NH N\o"
THF
17
LG
15 %
/
NH-R \n/
U
20
*
a, R=CH3-CH2 b, RzCbHs-CHz
c, R = H
Scheme 1
compounds 18 with LiAlK in THF gave 19 which were transformed into 20 by chloroacetyl chloride. Yields, melting points and recrystallization solvents of these products are reported in Table 1.
Synthesis and characterization of the intermediates 22 have been reported'). The final derivatives (see in Figure 1 compounds 2, 4-6, 8-10, 12, 14) were obtained according to Scheme 2.
Table 1: 3-Acylamino-4-(2-chloroethylamino)furazans16 3-Acylamino-4-aminofurazans 18 3-Alkylamino-4-aminofurazans19 3-Alkylamino-4-(2-chloroacetamido~furazans 20
R
!IELD
M.P. ('C)
RECRYSTALLIZATION
FORMULA
SOLVENT
80
97-98
a
79
124-125
a
a7
113-114
a
89
128-129
b
72
191-192
C
a0
147-148
b
65
86-87
d
63
103-104
d
85
117-118
a
78
107-108
a
a: ethyl acetate / petroleum ether 40-60'C b: ethanol / water c: water d: methylene chloride / petroleum ether 40-6WC
Arch. Pharni. (U'i~inlieini)325. 151-155 (1992)
153
Acylaminofurazans
Pharmacology N-CH,
a)
H 3C‘
2, 4-6, 8-10, 12, 14 oxalates were tested as antagonists of the positive chronotropic effect of histamine on isolated spontaneously beating guinea pig atria according to Black et al?). The activity, expressed as pA2, is reported in Table 2. None of the compounds produced a modification of the spontaneous contraction frequency of the atria when tested alone with the exception of derivatives 9 and 10 which showed a negative chronotropic effect. Specificity for H2-receptors was evaluated on the basis of the ability of these compounds to antagonize the positive chronotropic response to isoprenaline in the guinea pig atria (P-adrenergic receptors) and the contractile response to histamine and carbamoylcholine in the guinea pig ileum (HI and muscarinic receptors, respectively). None of them modified the effect of isoprenaline. On the contrary derivatives 12 and 14 antagonized reversibly and noncompetitively the response to histamine and carbamoylcholine. This noncompetitive antagonism arose at a concentration about ten fold higher than derivative 12 or similar to derivative 14 that producing competitive H2-receptor block.
31
b)
C )
Scheme 2
Table 2: Reaction yields, melting points and H2-antagonist activity of 1-14 ’IELD 4
M.P.
(OC)‘)
-
-
pA2 i 95% CL
7.43 i 0.33
SLOPE OF SCHILD PLOT f 95% CL
1.05 f 0.18
No.
OF
EXPERIMENTS
19
-
-
< 4
-
7.34 i 0.32
0.89 i 0.23
16
60
143-144
6.14 i 0.12
1.02 f 0 . 1
20
80
15 3 15 4
-
< 4
-
6
80
70
-
63
m - u a
-
< 4 7.65 f 0 . 2 1
1.12 f 0.18
21
150-151
6.98 f 0 . 4 1
0.91 f 0.25
18
138-139
-
C
-
8.82 f 0.18
1.05 f 0.16
20
162-163
6.96 f 0.16
1.05 f 0.24
15
8.69 f 0.23
1.04 f 0.19
21
6.46 f 0 . 1 1
1.04 f 0.26
12
110-111
C
78
152-153
61
-
60
-
a
-
78
-
6
-
136-137
-
-
a) All derivatives were recrystallized from a mixture of methanol/isopropanol b) pA2 values are taken from ref.’) c) Negative chronotropic effect
The reaction of the intermediates 16, 20, 22 with [5-di-
m e t h ~ 1 a m i n o ~ ~ t h ~ 1 ) - 2 - f u ~ 1 ~ m e t21 h ~ ~was ~ t hcarried io1 out under N2 in ethanol solution containing NaOH. For reaction yields, melting points and recrystallization solvents of the final products see Table 2, for I3C-NMR characterizationTable 3.
Arch, Pharm. (Weinheim) 325. 151-155 (1992)
ResultsandDiscussion The data reported in Table 2 show that the presence of carbonyl groups linked to amino functions of the ”urea equivalent“ moiety deeply influences the H2-antagonist activity. Substitution of the alkyl groups joined to the lateral amino function in the leads 3, 7, 11, and 13 with the corresponding acyl groups to give
151.1/150.0
I
m.1/110.2
151.4/150.3
I
151.8
30.4
For the carbons c/f, d/e, Urn two alternative assignments are reported
23.0
14.1
I Jo.1/151 .l
31.1
R
169.0
35.2
170.2
31.2
151.0/151,1
14.3
35.5
28.2
1%.3/151.4
J-7
49.9A51.4
n
m
I
1
h
0
151.4/150.0
1w.2/109.7
10.2/toal
d
148.6/151.4
109.7/1 m.2
51.4/148.6
f
151.1/151 .O
4
%
151.4/149.9
u.l
*7
I I
I
23.6
35.7
28.5
149.9/151.4
, 127.' 127.
138.2
128.5
.
48.8
154.9
149.9
43.4
31.2
216
149.7/150.2
10&4/110.9
110.9/1 M A
150.2/149.7
55.0
--t -t
51.4/149.9
3
%
+ + -+-
-I-
I
C
b
a
(b P P ~ )
l3C
Tab. 3: 13Cchemical shifts (ppm from TMS)
167.1
151.3
44.7
151.9
143.8
169.1
44.7
1 p i
145.3/144.7
I51.7/149.6
150.7/154.4
151.5/14#.7
+ +
, 25.2 25.3
29.15
176.1
lU.2
128.4 38.2
141.5
128.45. 126. 37.6 30.9
,
140.1
, 125.7 , 30.6
, 128.
172.3
143.95
151.6
43.6
30.5
28.2
149.9/1 51a
108.4/110.6
110.6/10&4
, 128.4
43.33
150.3/1502
1503/150.3
4435
u.9
151.7
31.3
28.1
149.7/151.8
1Ok3/110.7
151.8/149.9 I l l .8/149.7
~
54.9
44.1 1
R3
14
55.3
U.32
30.3
283
149.3/151.7
lOk2/110.9
110.9/10&2
54.4
43.6
12
Acy laminofurazans derivatives 4.8.12, and 14 is accompanied by a decrease in the H2-antagonist activity and in 12 and 14 by a loss of selectivity. The decrease in activity is about two orders of magnitude in 12 and 14 and one order of magnitude in 4 and in 8. The influence of the introduction of the carbonyl-group on the inner amino group of the diaminofurazan substructure is more dramatic (derivatives 2,s. 9).In fact this manipulation is accompanied by the disappearence of the activity (2, 5; pA2 c 4) and in compound 9 by a negative chronotropic action on the atria. The above discussed trends are confinned by the complete inactivity of derivative 6 bearing a carbonyl group on both the amino functions. In 10 this last manipulation is responsible for the negative chronotropiceffect of the compound. At this state of our research we have not found definitive explanations for these structure activity relationships. Probably the change of the electronic and lipophilic properties is one of the factors determining the decrease in the activity in moving from alkyl to acyl substituted derivatives. But the dramatic effect following the introduction of the carbonyl-group on the amino group present in the chain connecting the furan ring with the furazan system shows that other factors must play important roles. Certainly the conformational domain in the carbonyl derivatives i s deeply different from that of alkyl analogues and this should be the principal reason for the difference in activity between these compounds. Studies are in progress to confirm this point. This work has been supported by a grant from “Studi e Ricerche Finanziate 40%” MURST (Rome, Italy)
Experimental Part Melting points: BIichi 530 capillary melting point apparatus, uncorrected.- IR (Perkin-Elmer 781).- Mass Spectroscopy (Varian CH7 MAT).The spectra agree with the proposed structures.- l3C-NMR AC-200 MHz Bruker, 5 mm tubes, solvent CDCl3: chemical shifts relative to TMS are reported in Table 3. Compounds 3, 7, 11, 13, 22”; 1, 15, 20c8’; 179’. 21”’ were synthetized according to the lit. methods. Silica gel Merck Kieselgel60,230-400 mesh ASTM, was employed for chromatographicpurification. Microanalyses for C, H, N are within 0.4% of theoretical values. Anhydrous MgS04 was used for drying.
3-Acylamino-4-(2-chloroerhylaminolfurazans( 16a-d) 10 mmoles of the appropriate acylchloride were added under stirring to a solution of 1S O g (9.2 mmol) of 3-amino-4-(2-chloroethylamino)furazan 15 in dry THF (40 ml). The solution was kept for 2 h at room temp. and treated with 0.84 g (10.0 mmol) of solid NaHCOp The solvent was removed under reduced pressure, the residue was treated with water and extracted with ethyl acetate. The org. layers were filtered and evaporated under reduced pressure. 16a and 16b were obtained as solids. 16c and 16d, obtained as oily products, were purified by silica gel column chromatography eluting with petroleum ether 40-60°C ethyl acetate (0-20%) before crystallization. Reaction yields, recrystallization solvents and melting points: Table 1.
3-Aceramido-4-aminofurazan(Ua) and 3-amino-4-benzamidofurazan (18b) These compounds were synthetized following the method used for the synthesis of 16, starting from 17 and acetyl chloride or benzoyl chloride diluted with few ml of anhydrous THE The reaction for 18a was complete in 3 hat room temp. For the preparation of 18b the solution of benzoyl chloride was added to the boiling solution of a slight excess of 17 and the mixture was refluxed for 1 h. The reactions were worked up as reported for 16.
Arch. Pharm. (Weinheinl) 325,151-155(1992)
155 Reaction yields, recrystallization solvents and melting points: Table I ,
3-Alkylamino-4-aminofurazuns (19a.b) 7.3 mmoles of the appropriate 18 were added portionwise to a chilled (ice-salt) mixture of LiAIH, (0.84 g, 2.2 mmol) in 40 ml dry THF. The reaction mixture was kept 1 h under cooling then 2 h at room temp. Excess of ethyl acetate was added and the mixture was cautiously treated with 10% H2S04 until all the solid material was dissolved. The org. phase was collected and the aqueous one was extracted with ethyl acetate. The combined org. phases were vigorously stirred for 30 rnin with powdered anhydrous NaZC03 and then filtered. The solvent was evaporated under reduced pressure: yellow oil. The oil was purified by silica gel column chromatography using petroleum ether 40-60°C-dichIoromethane-ethylacetate 2:l:l. Reaction yields, recrystallization solvents and melting points: Table 1. 3-Alkylamino-4-(2-chloroaceramido)furazans(20a.b)
These compounds were synthetized with the method used for 16. starting from 19 and chloroacetyl chloride. The reaction was complete in 1 h at room temp. Reaction yields, recrystallization solvents and melting points: Table 1. 3-Amino-4-[2-[(5-dime1h~luminome1hyl-2-~~ljme1hyl1hio]aceiam~dofurazan (2)
3-Acylamino-4-[2-[(5-dimethylaminomethyl-2-furyl)merhyl1hio] erhylamino]furazans (4). (8). (12), (14) 3-Acylumino-4-[2-~(5-dimethylaminomethyl-2-fu~i)merhylthio] acetamido]furazans (6), (10) 3-Alkylamino-4-[2 -[(S-dimethylaminomethyl-2-furyl)methylthio] aceramidolfurazans(5). (9) These compounds were synthetized according to the method reported’’ starting from 21 and the appropriate intermediates 16,20,22. The reaction time for compounds 2, 5, 6, 9, 10 was 1 h at room temp. while for compounds 4,8. 12. 14 was 2 h at reflux. The oils obtained after working up were purified by silica gel column chromatography using dichloromethane/methanol 98:2 (955 for 6) as mobil phase. The oils obtained after solvent removal were immediately transformed into the correspondingoxalates. Reaction yields, recrystallization solvents and melting points: Table 2.
References G. Sorba, A. Gasco, and M. Orsetti, Eur. J. Med. Chem. 24, 475 (1989). J.C. Emmett, G.J. Durant, C.R. Ganellin, A.M. Roe, and J.L. Turner, J. Med. Chem. 25,1168 (1982). J.P. Spengler, K. Wegner, and W. Schunack, Agents Actions 14. 566 (1984). J.W. Lampe, R.G. Hanna, T.A. Piscitelli, Y.L. Chon. P.W. Erhardt. W.L. Lumma, S.S. Greenberg, W.R. Ingebretsen, D.C. Marshall, and J. Wiggins, J. Med. Chem.33, 1688(1990). V.J. Alan. E. Dhnila, M. Frances, P. Gosa, J. Gras, A. Martinez, N. Mylonakis, and 1. Pardo, Arzneim.-Forsch.40, 1003 (1990). G. Sorba, R. Fruttero, A. Gasco, and M. Orsetti, Arzneim.-Forsch. 39, 1092 ( 1989). J.W. Black, W.A.M. Duncan. C.S. Durant. C.R. Ganellin, and E.H. Parsons, Nature 236,385 (1972). G. Sorba, R. Calvino, A. Defilippi, A. Gasco, and M. Orsetti, Eur. J. Med. Chem. 20,571 (1985). M.D. Coburn, J. Heterocycl. Chem. 5.83 (1968). 10 G. Sorba, R. Fruttero, R. Calvino, A. Gasco, and M. Orsetti, Arch. Pharm. (Weinheim)317,469 (1984). [Ph906]
