Journal of Medicinal Chemistry, 1975,Vol. 18,No.7 741
3-Hydrazinopyridazine Derivatives pared by the catalytic hydrogenation of a solution of 400 mg (1.53 mmol) of 19 in 50 ml of EtOH and 150 mg of 10% PdlC at room temperature. After the absorption of hydrogen ceased the reaction mixture yielded 320 mg (90%) of the product, mp 175-178', which was identical with an authentic sample of o-aminoglutethimide. 2-(p-Hydroxyphenyl)-2-ethylglutarimide (18). A solution of 700 mg (3.3 mmol) of 16 in 20 ml of 2 N HzS04 was cooled to 5' and diazotized with 480 mg (7 mmol) of NaNOz dissolved in 2 ml of H20 a t 5 O . The solution of diazonium salt was then added dropwise to 10 ml of boiling HzO and the solution was held a t reflux for 1hr and then allowed to cool. The reaction mixture was saturated with NaCl and extracted with CHZC12 (3 X 50 ml). The organic layer was dried (MgS04) and filtered and the solvent evaporated under reduced pressure. The oily residue was recrystallized from Et20 to yield 470 mg (61%) of a white crystalline solid: mp 143144O; ir (KBr) 3240 (OH, NH), 1710, 1680 cm-I (C=O imide); NMR (DMSO-&) d 0.86 (t, 3, CH3CH2), 1.68-2.33 (m, 6, CH3CHz and 2-methylene glutarimide ring), 6.73 (d, 2, H3 and H5 arom protons, J = 8.8 Hz, typical AzBz system of para-substituted benzene), 7.13 (d, 2, Hz and H6 arom protons, J = 8.8 Hz), 9.33 (s, 1, OH exchangeable with DzO), 8.3 (s, 1, NH, exchangeable with DzO); mass spectrum, M+ 233. Anal. (C13H15N03) C, H, N.
Acknowledgments. A preliminary account of this work was presented to the Medicinal Chemistry Section, APHA 121st National Meeting, Chicago, Ill., August 1974. This investigation was supported by U S . Public Health Service Grant GM 12675. We thank Dr. David E. Nichols for his suggestions and discussions during the preparation of this manuscript. The authors acknowledge Mr. Dennis Charkowski and Mr. Archie Jones for their technical assistance. An authentic sample of p-aminoglutethimide and o-aminoglutethimide was obtained from Dr. J. J. Clark, Ciba-Geigy Corp., Ardsley, N.Y. 10502. References and Notes (1) H. Keberle, K. Hoffmann, and K. Bernhard, Experientia, 18,
105 (1962). (2) E. Butikofer, P. Cottier, P. Imhof, H. Keberle, W. Reiss, and K. Schmid, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol., 244,97 (1962). (3) D. Post and H. Schutz, Beitr. Gerichtl. Med., 26,227 (1969). (4) W. G. Stillwell, M. Stafford, and M. G. Horning, Res. Commun. Chem. Pathol. Pharrnacol., 6,579 (1973).
J. Keberle, K. Schmid, K. Hoffmann, J. Vuilleumier, and K. Bernhard, Helu. Chim. Acta, 42,417 (1959). J. J. Ambre and L. J. Fischer, Res. Commun. Chem. Pathol. Pharrnacol., 4,307 (1972). J. J. Ambre and L. J. Fischer, Drug Metab. Dispos., 2, 151 (1974). (a) A. R. Hansen and L. J. Fischer, Clin. Chem., 20, 236 (1974); (b) A. R. Hansen, K. A. Kennedy, J. 3. Ambre, and L. J. Fischer, N. Engl. J. Med., 292,250 (1975). R. Brachini, C. Caradonna, G. Casini, and M. L. Stein, Farmaco, Ed. Sci., 16,387 (1961); Chem. Abstr., 56,5828~(1962). G. Casini, M. Ferappi, S. Gulinelli, and P. Mazzeo, Ann. Chim. (Rome), 52,1254 (1952); Chem. Abstr., 5 9 , 6 2 0 ~(1963). G. Casini, 0. Cicchetti, and M. Ferappi, Ric. Sci., Suppl., 30, 2535 (1960); Chem. Abstr., 60,7985 (1964). E. Tarcmann, E. Sury, and K. Hoffmann, Helv. Chim. Acta. 35,1541 (1952). F. Gross, K. Hoffmann, J. Keberle, and J. Tripod, Verh. Naturforsch. Ges. Basel. 67,479 (1956). Chim. Fr., 640 F..Salmon-Legagneur and Y. Oliver, Bull. SOC. (1965). A. Ercoli and P. DeRuggieri, J. Am. Chem. Soc., 75, 650 (1953). B. E. Betts and W. Davey, J. Chem. SOC.,4193 (1958). K. Hoffmann, B. Tagmann, and E. Tagmann, US. Patent 2,673,205 (March 23,1954). E. Urech, E. Tagmann, E. Sury, and K. Hoffmann, Helv. Chim. Acta, 36,1809 (1953). H. Y. Aboul-Enein, Or$. Prep. Proced. Int., in press. A. S. Tomcufcik and L. N. Starker, "Pyridine and Its Derivatives", Part 111, E. Klingsberg, Ed., Interscience, New York, N.Y., 1962, p 81. K. Hoffmann and E. Urech, U S . Patent 2,848,455 (1958); Chem. Abstr., 53,7103h (1959). E. G. C. Clarke, "Isolation and Identification of Drugs", The Pharmaceutical Press, London, 1969, p 187. (a) F. W. Kahnt and Neher, Helv. Chim. Acta, 49,725 (1966); (b) A. E. Daniels-Severs and J. Vernikos-Danellis, Pharmacology, 10,111 (1973), and references cited therein. S. Irwin, Psychopharmacologia, 13,222 (1968). R. D. Sofia, J. Pharm. Sci., 58,900 (1969). L. S. Goodman, M. Singh Grewal, W. C. Brown, and E. A. Swinyard, J . Pharrnacol. Exp. Ther., 108,168 (1953). W. J. Dixon and A. M. Mood, J. Am. Stat. Assoc., 43, 109 (1948). R. Paul, R. P. Williams, and E. Cohen, J . Med. Chem., 17, 539 (1974).
Synthesis and Antihypertensive Properties of New 3-Hydrazinopyridazine Derivatives Giorgio Pifferi,* Francesco Parravicini, Carlo Carpi, and Lucian0 Dorigotti ISF, Italseber Research Laboratories, Trezzano SIN, Milan, Italy 20090. Received September 25,1974 3-Hydrazinopyridazines substituted in position 6 with a primary amine, secondary amine, or an alkoxy group were synthesized and screened for antihypertensive activity. In general, the 6-dialkylamino derivatives are the most active; the (2-hydroxypropyl)methylaminochain provides the best combination of high antihypertensive activity and low toxicity.
The potent and long-lasting antihypertensive activity of hydrazinophthalazines,l exemplified by hydralazine and dihydralazine, encouraged the investigation of modified heterocyclic analogs2 and particularly of six-membered rings containing the essential moiety A.3 In the case of pyI - -
'
--CNHNH,
II
RX-@""'
A\,,N
A
B (X = NR', NH, 0)
ridazine series B, various 6-substituted derivatives with alkyl: aryl: methoxy," phenoxy," carbamyl: and hydrazino8 groups have been synthesized, but only few of them retained interesting hypotensive properties. Compounds of type B in which X is NR', NH, or 0 had received little attention until a remarkable improvement in activity and decrease in toxicity was recently obtained by replacing RX with a secondary amino re~idue.~JO These results prompted us to undertake a more detailed study designed to define structure-activity relationships and to optimize activity in this class of 6-substituted 3-hydrazinopyridazines.
Pifferi, Parrauicini, Carpi, Dorigotti
742 Journal of Medicinal Chemistry, 1975, Vol. 18, No. 7
Scheme I
Y Chemistry. Scheme I depicts the synthetic routes employed for the preparation of 6-dialkylamino-, 6-aralkylamino-, and 6-cycloalkylamino-substituted 3-hydrazinopyridazines V. A conventional approach1' involved displacement of one chlorine from 3,6-dichloropyridazine (I) with an appropriate secondary amine. The experimental conditions (see methods A-C) varied depending on the physicochemical properties and reactivity of organic bases. The resulting 6-amino-3-chloropyridazines I1 (Table I) were then heated with hydrazine; this reaction proved to be much more difficult than that of 6-unsubstituted derivatives due to the deactivating effect of the 6-amino group.12 The hydrazines V could be directly isolated as hydrochlorides from the reaction mixture (method H), but this was satisfactory only in a few cases and on small-scale preparations, owing to high water solubility of the salts and the ensuing
difficulties in the separation from hydrazine hydrochloride. A more efficient process involved formation of the hydrazones IV (Table 111) with benzaldehyde (method F) followed by hydrolysis with hydrochloric acid to give the corresponding hydrochlorides (Table IV). 6-Alkoxy-3-hydrazinopyridazines(VI, Table V) were prepared by heating I in xylene with the appropriate sodium alkoxide (method D) to give I11 ( X = 0),with the exception of 20 which was obtained by heating I with N - ( 2 hydroxyethy1)aniline in anhydrous DMF in the presence of KzC03 (method E). These intermediates 17-20 (Table 11) were then allowed to react with hydrazine to afford the products (method I). The 6-monoalkylamino-substituted compounds 21-24 (Table 11) were prepared by heating I with the appropriate primary amine (methods B and C). Since the chlorine atom
Table I. 3-Chloro-6-dialkyl(cycloalkyl,aralkyl)aminopyridazines
11
-N/
R
'R:
KV.
- \
1
-,
10
N(CHJ)~ N(CH, )(CH,CH,OH) Thiomorpholinyl Piperazinyl N(C2H?)2 N( C,H,)( CH2CH,0H) N(CH1)(CH,CHOHCH,) N(C2Hj)(CHZCHOHCHI) N(CH,CH,OH)(CH,CHOHCH,) N(CH,CH=CH,),
11
\"/Y
8 9
Mp o r bp (mm). 'C
Rxn temp, Method 'C
103-104" 6647 139-141 101-1 03 51-53" 136-1 3 8 82-43
A B A A
B B
80 105 80 80 150 110 105
145-14 7
B
69 -71
Crystn solvent
-Pr20 Toluene EtOH
i
Yield, (
I
Formula
Analyses
88 Cl. N C1, N, S C1. N
30
EtOAc
80 40 60 55 95
110
E tOH-Mes CO
85
B
140
EtOAc
68
C1, N
138-140(0.5)b
B
110
96
C1, N
147-149
B
135
i -PrOH
35
C1. N
144-1 4 6
B
110
EtOH
50
C,,H,,ClN,O
Cl, N
EtOAc r-PrOH EtOH
38 30 25
C,,H,,ClN,O2 C1ZHIzClN,.HCl C12H,,ClN,O*HCl
C1, N C1, N C1, N
DMF
30
C12H1ZCLZN6
C1, N
c
EtOAc i -Pr20 2
-PrOH
Cl, N C1, N CqH 1 ,ClN,O*€IC1
Cl, N
('tl 011
12
13 14 15
16
\
L(Il(H0tl
U
N(CH,CHOHCH,), N(CZH;)(CGH~) N(CH,CH,OH)(C,H,) I*(\
3-Hydrazinopyridazine Derivatives pared by the catalytic hydrogenation of a solution of 400 mg (1.53 mmol) of 19 in 50 ml of EtOH and 150 mg of 10% PdlC at room temperature. After the absorption of hydrogen ceased the reaction mixture yielded 320 mg (90%) of the product, mp 175-178', which was identical with an authentic sample of o-aminoglutethimide. 2-(p-Hydroxyphenyl)-2-ethylglutarimide (18). A solution of 700 mg (3.3 mmol) of 16 in 20 ml of 2 N HzS04 was cooled to 5' and diazotized with 480 mg (7 mmol) of NaNOz dissolved in 2 ml of H20 a t 5 O . The solution of diazonium salt was then added dropwise to 10 ml of boiling HzO and the solution was held a t reflux for 1hr and then allowed to cool. The reaction mixture was saturated with NaCl and extracted with CHZC12 (3 X 50 ml). The organic layer was dried (MgS04) and filtered and the solvent evaporated under reduced pressure. The oily residue was recrystallized from Et20 to yield 470 mg (61%) of a white crystalline solid: mp 143144O; ir (KBr) 3240 (OH, NH), 1710, 1680 cm-I (C=O imide); NMR (DMSO-&) d 0.86 (t, 3, CH3CH2), 1.68-2.33 (m, 6, CH3CHz and 2-methylene glutarimide ring), 6.73 (d, 2, H3 and H5 arom protons, J = 8.8 Hz, typical AzBz system of para-substituted benzene), 7.13 (d, 2, Hz and H6 arom protons, J = 8.8 Hz), 9.33 (s, 1, OH exchangeable with DzO), 8.3 (s, 1, NH, exchangeable with DzO); mass spectrum, M+ 233. Anal. (C13H15N03) C, H, N.
Acknowledgments. A preliminary account of this work was presented to the Medicinal Chemistry Section, APHA 121st National Meeting, Chicago, Ill., August 1974. This investigation was supported by U S . Public Health Service Grant GM 12675. We thank Dr. David E. Nichols for his suggestions and discussions during the preparation of this manuscript. The authors acknowledge Mr. Dennis Charkowski and Mr. Archie Jones for their technical assistance. An authentic sample of p-aminoglutethimide and o-aminoglutethimide was obtained from Dr. J. J. Clark, Ciba-Geigy Corp., Ardsley, N.Y. 10502. References and Notes (1) H. Keberle, K. Hoffmann, and K. Bernhard, Experientia, 18,
105 (1962). (2) E. Butikofer, P. Cottier, P. Imhof, H. Keberle, W. Reiss, and K. Schmid, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol., 244,97 (1962). (3) D. Post and H. Schutz, Beitr. Gerichtl. Med., 26,227 (1969). (4) W. G. Stillwell, M. Stafford, and M. G. Horning, Res. Commun. Chem. Pathol. Pharrnacol., 6,579 (1973).
J. Keberle, K. Schmid, K. Hoffmann, J. Vuilleumier, and K. Bernhard, Helu. Chim. Acta, 42,417 (1959). J. J. Ambre and L. J. Fischer, Res. Commun. Chem. Pathol. Pharrnacol., 4,307 (1972). J. J. Ambre and L. J. Fischer, Drug Metab. Dispos., 2, 151 (1974). (a) A. R. Hansen and L. J. Fischer, Clin. Chem., 20, 236 (1974); (b) A. R. Hansen, K. A. Kennedy, J. 3. Ambre, and L. J. Fischer, N. Engl. J. Med., 292,250 (1975). R. Brachini, C. Caradonna, G. Casini, and M. L. Stein, Farmaco, Ed. Sci., 16,387 (1961); Chem. Abstr., 56,5828~(1962). G. Casini, M. Ferappi, S. Gulinelli, and P. Mazzeo, Ann. Chim. (Rome), 52,1254 (1952); Chem. Abstr., 5 9 , 6 2 0 ~(1963). G. Casini, 0. Cicchetti, and M. Ferappi, Ric. Sci., Suppl., 30, 2535 (1960); Chem. Abstr., 60,7985 (1964). E. Tarcmann, E. Sury, and K. Hoffmann, Helv. Chim. Acta. 35,1541 (1952). F. Gross, K. Hoffmann, J. Keberle, and J. Tripod, Verh. Naturforsch. Ges. Basel. 67,479 (1956). Chim. Fr., 640 F..Salmon-Legagneur and Y. Oliver, Bull. SOC. (1965). A. Ercoli and P. DeRuggieri, J. Am. Chem. Soc., 75, 650 (1953). B. E. Betts and W. Davey, J. Chem. SOC.,4193 (1958). K. Hoffmann, B. Tagmann, and E. Tagmann, US. Patent 2,673,205 (March 23,1954). E. Urech, E. Tagmann, E. Sury, and K. Hoffmann, Helv. Chim. Acta, 36,1809 (1953). H. Y. Aboul-Enein, Or$. Prep. Proced. Int., in press. A. S. Tomcufcik and L. N. Starker, "Pyridine and Its Derivatives", Part 111, E. Klingsberg, Ed., Interscience, New York, N.Y., 1962, p 81. K. Hoffmann and E. Urech, U S . Patent 2,848,455 (1958); Chem. Abstr., 53,7103h (1959). E. G. C. Clarke, "Isolation and Identification of Drugs", The Pharmaceutical Press, London, 1969, p 187. (a) F. W. Kahnt and Neher, Helv. Chim. Acta, 49,725 (1966); (b) A. E. Daniels-Severs and J. Vernikos-Danellis, Pharmacology, 10,111 (1973), and references cited therein. S. Irwin, Psychopharmacologia, 13,222 (1968). R. D. Sofia, J. Pharm. Sci., 58,900 (1969). L. S. Goodman, M. Singh Grewal, W. C. Brown, and E. A. Swinyard, J . Pharrnacol. Exp. Ther., 108,168 (1953). W. J. Dixon and A. M. Mood, J. Am. Stat. Assoc., 43, 109 (1948). R. Paul, R. P. Williams, and E. Cohen, J . Med. Chem., 17, 539 (1974).
Synthesis and Antihypertensive Properties of New 3-Hydrazinopyridazine Derivatives Giorgio Pifferi,* Francesco Parravicini, Carlo Carpi, and Lucian0 Dorigotti ISF, Italseber Research Laboratories, Trezzano SIN, Milan, Italy 20090. Received September 25,1974 3-Hydrazinopyridazines substituted in position 6 with a primary amine, secondary amine, or an alkoxy group were synthesized and screened for antihypertensive activity. In general, the 6-dialkylamino derivatives are the most active; the (2-hydroxypropyl)methylaminochain provides the best combination of high antihypertensive activity and low toxicity.
The potent and long-lasting antihypertensive activity of hydrazinophthalazines,l exemplified by hydralazine and dihydralazine, encouraged the investigation of modified heterocyclic analogs2 and particularly of six-membered rings containing the essential moiety A.3 In the case of pyI - -
'
--CNHNH,
II
RX-@""'
A\,,N
A
B (X = NR', NH, 0)
ridazine series B, various 6-substituted derivatives with alkyl: aryl: methoxy," phenoxy," carbamyl: and hydrazino8 groups have been synthesized, but only few of them retained interesting hypotensive properties. Compounds of type B in which X is NR', NH, or 0 had received little attention until a remarkable improvement in activity and decrease in toxicity was recently obtained by replacing RX with a secondary amino re~idue.~JO These results prompted us to undertake a more detailed study designed to define structure-activity relationships and to optimize activity in this class of 6-substituted 3-hydrazinopyridazines.
Pifferi, Parrauicini, Carpi, Dorigotti
742 Journal of Medicinal Chemistry, 1975, Vol. 18, No. 7
Scheme I
Y Chemistry. Scheme I depicts the synthetic routes employed for the preparation of 6-dialkylamino-, 6-aralkylamino-, and 6-cycloalkylamino-substituted 3-hydrazinopyridazines V. A conventional approach1' involved displacement of one chlorine from 3,6-dichloropyridazine (I) with an appropriate secondary amine. The experimental conditions (see methods A-C) varied depending on the physicochemical properties and reactivity of organic bases. The resulting 6-amino-3-chloropyridazines I1 (Table I) were then heated with hydrazine; this reaction proved to be much more difficult than that of 6-unsubstituted derivatives due to the deactivating effect of the 6-amino group.12 The hydrazines V could be directly isolated as hydrochlorides from the reaction mixture (method H), but this was satisfactory only in a few cases and on small-scale preparations, owing to high water solubility of the salts and the ensuing
difficulties in the separation from hydrazine hydrochloride. A more efficient process involved formation of the hydrazones IV (Table 111) with benzaldehyde (method F) followed by hydrolysis with hydrochloric acid to give the corresponding hydrochlorides (Table IV). 6-Alkoxy-3-hydrazinopyridazines(VI, Table V) were prepared by heating I in xylene with the appropriate sodium alkoxide (method D) to give I11 ( X = 0),with the exception of 20 which was obtained by heating I with N - ( 2 hydroxyethy1)aniline in anhydrous DMF in the presence of KzC03 (method E). These intermediates 17-20 (Table 11) were then allowed to react with hydrazine to afford the products (method I). The 6-monoalkylamino-substituted compounds 21-24 (Table 11) were prepared by heating I with the appropriate primary amine (methods B and C). Since the chlorine atom
Table I. 3-Chloro-6-dialkyl(cycloalkyl,aralkyl)aminopyridazines
11
-N/
R
'R:
KV.
- \
1
-,
10
N(CHJ)~ N(CH, )(CH,CH,OH) Thiomorpholinyl Piperazinyl N(C2H?)2 N( C,H,)( CH2CH,0H) N(CH1)(CH,CHOHCH,) N(C2Hj)(CHZCHOHCHI) N(CH,CH,OH)(CH,CHOHCH,) N(CH,CH=CH,),
11
\"/Y
8 9
Mp o r bp (mm). 'C
Rxn temp, Method 'C
103-104" 6647 139-141 101-1 03 51-53" 136-1 3 8 82-43
A B A A
B B
80 105 80 80 150 110 105
145-14 7
B
69 -71
Crystn solvent
-Pr20 Toluene EtOH
i
Yield, (
I
Formula
Analyses
88 Cl. N C1, N, S C1. N
30
EtOAc
80 40 60 55 95
110
E tOH-Mes CO
85
B
140
EtOAc
68
C1, N
138-140(0.5)b
B
110
96
C1, N
147-149
B
135
i -PrOH
35
C1. N
144-1 4 6
B
110
EtOH
50
C,,H,,ClN,O
Cl, N
EtOAc r-PrOH EtOH
38 30 25
C,,H,,ClN,O2 C1ZHIzClN,.HCl C12H,,ClN,O*HCl
C1, N C1, N C1, N
DMF
30
C12H1ZCLZN6
C1, N
c
EtOAc i -Pr20 2
-PrOH
Cl, N C1, N CqH 1 ,ClN,O*€IC1
Cl, N
('tl 011
12
13 14 15
16
\
L(Il(H0tl
U
N(CH,CHOHCH,), N(CZH;)(CGH~) N(CH,CH,OH)(C,H,) I*(\
