US 4,130,663 AGrant
Styrylamidines
Issue Date:1978-12-19
•10 Claims
Abstract
Styrylamidines are prepared by treating styrylsulfonylamidines with base. The styrylamidines are effective in the prevention of aggregation of blood platelets and as analgesics. Compounds of the invention are also useful as anticonvulsants, diuretics, and antihypertensive agents. The styrylsulfonylamidines of the invention which serve as precursors to the styrylamidines also have analgesic properties. Illustrative of the styrylamidines of the present invention are 4-amino-N-(4-aminostyryl)benzamidine and N-(3,4-dichlorostyryl)acetamidine. An example of a styrylsulfonylamidine is N-(styrylsulfonyl)acetamidine.
Metadata
Assignee
- Mead Johnson & Company
Inventors
- William L. Matier
- William T. Comer
Application Information
Application Number:US 8948895
Filing Date:1978-04-10
Priority Date:1973-06-11
Art Unit:126
Classifications
IPC:
A61K 31155
Field of Search:
424260280;316;321;324;326562 R;556 AR;558;564 R
Patent Drawings
This patent does not have any drawings.
Description
EXAMPLE 1
N-(Styrylsulfonyl)benzamidine (4.3 g., 0.015 mole) is added portion-wise to a stirred mixture of 50% sodium hydroxide (1.2 g., 0.015 mole) in 25 ml. of dimethylsulfoxide. After stirring the mixture for 64 L hr., at 25.degree. C., the mixture is poured into 250 ml. of cold water and made strongly basic with 5% sodium hydroxide. The basified solution is extracted several times with ether, the ethereal extracts combined, washed with water, dried over potassium carbonate, and concentrated to provide the N-styrylbenzamidine free base as a yellow oily residue. The free base oil is taken up in ethanol, acidified with ethanolic hydrogen chloride and the hydrochloride salt isolated by dilution with ether. Trituration of the salt with acetone affords 0.25 g. (6.5% yield) of N-STYRYLBENZAMIDINE HYDROCHLORIDE, m.p. 226.5.degree.-228.0.degree. C. (corr.).
Analysis. Calcd. for C.sub.15 H.sub.14 N.sub.2.HCl (percent): C, 69.60; H, 5.84; N, 10.82. Found (percent): C, 69.34; H, 5.80; N, 10.79.
NMR (DMSO-d.sub.6, TMS): 6.95d (14.0 Hz), 7.10m, 8.25bd (14.0 Hz), 10.33bs, 12.03bs.
EXAMPLE 2
N-(Styrylsulfonyl)acetamidine is treated with sodium hydroxide according to the procedure of Example 1. Isolation of the styrylamidine product is carried out by quenching the reaction mixture in water, acidifying the aqueous mixture with 3N hydrochloric acid and filtering. The filtrate is made basic with sodium hydroxide and extracted with chloroform. Concentration of the chloroform extract provides the N-(styryl)acetamidine free base as a gum. The free base is converted to the hydrochloride in acetone with ethanolic hydrogen chloride. Acetone trituration of the crude hydrochloride and crystallization from isopropyl alcohol affords a 3% analytical yield of N-(STYRYL)ACETAMIDINE HYDROCHLORIDE having a capillary melting point of 167.0.degree.-183.0.degree. C. when inserted in bath at 95.degree. C.
Analysis. Calcd. for C.sub.10 H.sub.12 N.sub.2.HCl (percent): C, 61.05; H, 6.66; N, 14.24. Found (percent): C, 61.16; H, 6.76; N, 14.20.
NMR (DMSO-d.sub.6, TMS): 2.33s, 6.65d (14.0 Hz), 7.38m, 8.00bd (14.0 Hz), 9.87bs, 11.88bs.
EXAMPLE 3
N-(4-chlorostyryl)acetamidine treated with sodium hydroxide according to the procedure of Example 1 provides a 12% analytical yield of N-(4-CHLOROSTYRYL)ACETAMIDINE HYDROCHLORIDE, m.p. 228.degree.-234.5.degree. C. (corr.), from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.10 H.sub.11 ClN.sub.2.HCl (percent): C, 51.96; H, 5.24; N, 12.13. Found (percent): C, 51.79; H, 5.27; N, 11.94.
NMR (DMSO-d.sub.6, TMS): 2.38s, 6.66d (14.2 Hz), 7.57m, 8.10bd (14.2 Hz), 9.83bs, 11.88bs.
EXAMPLE 4
Treatment of N-(3,4-dichlorostyrylsulfonyl)acetamidine with sodium hydroxide according to the procedure of Example 1 affords N-(3,4-dichlorostyryl)acetamidine free base, m.p. 125.degree.-128.degree. C. Conversion of the free base to the hydrochloride salt with ethanolic hydrogen chloride in methanol provides N-(3,4-DICHLOROSTYRYL)ACETAMIDINE HYDROCHLORIDE, m.p. 215.degree.-224.degree. C. (dec.)(corr.), from methanol-acetone.
Analysis. Calcd. for C.sub.10 H.sub.10 Cl.sub.2 N.sub.2.HCl (percent): C, 45.22; H, 4.18; N, 10.55. Found (percent): C, 45.33; H, 4.39; N, 10.47.
NMR (DMSO-d.sub.6, TMS): 2.31s, 6.48d (14.0 Hz), 7.51m, 7.82m, 7.99bd (14.0 Hz), 9.83bs, 11.67bs.
EXAMPLE 5
Treatment of N-(3,4-dichlorostyrylsulfonyl)phenylacetamidine with sodium hydroxide according to the procedure of Example 1 affords a 41% yield of N-(3,4-dichlorostyryl)phenylacetamidine hydrochloride, m.p. 216.degree.-219.degree. C., from isopropanol. The hydrochloride is taken up in acetone, made basic with ammonium hydroxide and the free base extracted with ethyl acetate. After washing with water, the ethyl acetate extract is dried and made acid with isethionic acid to provide the isethionate salt. Analytically pure N-(3,4-DICHLOROSTYRYL)PHENYLACETAMIDINE ISETHIONATE is obtained by crystallization from acetonitrile, m.p. 132.5.degree.-134.5.degree. C.
Analysis. Calcd. for C.sub.16 H.sub.14 Cl.sub.2 N.sub.2.C.sub.2 H.sub.6 O.sub.4 S (percent): C, 50.12; H, 4.67; N, 6.50. Found (percent): C, 50.30; H, 4.78; N, 6.64.
NMR (DMSO-d.sub.6, TMS): 2.69t (6.6 Hz), 3.67t (6.6 Hz), 3.82m, 6.52d (13.9 Hz), 7.47m, 9.42bs, 9.78bs, 11.55bs.
EXAMPLE 6
N-(3,4-dichlorostyrylsulfonyl)benzamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(3,4-DICHLOROSTYRYL)BENZAMIDINE HYDROCHLORIDE, m.p. 243.0.degree.-248.5.degree. C. (dec.)(corr.), from ethanol-methanol-isopropyl ether.
Analysis. Calcd. for C.sub.15 H.sub.12 Cl.sub.2 N.sub.2.HCl (percent): C, 54.99; H, 4.00; N, 8.56. Found (percent): C, 55.09; H, 4.00; N, 8.55.
NMR (DMSO-d.sub.6, TMS): 6.89d (14.0 Hz), 7.83m, 8.38bd (14.0 Hz), 10.35bs, 12.10bs.
EXAMPLE 7
N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzamidine treated with sodium hydroxide according to the procedure of Example 1 provides a 64% yield of N-(3,4-DICHLOROSTYRYL)-3,4-DIMETHOXYBENZAMIDINE HYDROCHLORIDE, m.p. 239.0.degree.-240.0.degree. C., (corr.), from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.17 H.sub.16 Cl.sub.2 N.sub.2 O.sub.2.HCl (percent): C, 52.66; H, 4.42; N, 7.23. Found (percent): C, 52.56; H, 4.45; N, 7.22.
NMR (DMSO-d.sub.6, TMS): 3.92s, 6.93d (14.0 Hz), 7.65m, 8.21bd (14.0 Hz), 10.20bs, 11.93bs.
EXAMPLE 8
N-(4-nitrostyrylsulfonyl)acetamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(4-nitrostyryl)acetamidine free base, m.p. 142.degree.-143.degree. C. Conversion of the free base to the hydrochloride salt affords N-(4-NITROSTYRYL)ACETAMIDINE HYDROCHLORIDE, m.p. 247.0.degree.-247.5.degree. C. (dec.)(corr.), from methanol.
Analysis. Calcd. for C.sub.10 H.sub.11 N.sub.3 O.sub.2.HCl (percent): C, 49.69; H, 5.01; N, 17.39. Found (percent): C, 49.69; H, 4.95; N, 17.33.
NMR (DMSO-d.sub.6, TMS): 2.39s, 6.73d (14.1 Hz), 8.04d (14.1 Hz), 8.07m, 9.92bs, 11.95bs.
EXAMPLE 9
A suspension of 4-amino-N-(4-nitrostyrylsulfonyl)benzamidine (6.9 g., 0.02 mole) in 120 ml. of acetone is stirred with 50% sodium hydroxide (6.4 g., 0.08 mole) in 40 ml. of water for 1 hr. Concentration of the reaction mixture affords a residue which is stirred with 50 ml. of water, filtered, washed with water, and dried. Trituration of the dried filter cake with isopropyl alcohol yields 5.3 g. (95%) of N-(4-nitrostyryl)-4-aminobenzamidine free base, m.p. 195.degree.-197.degree. C. (dec.). The free base (5.0 g.) dissolved in 400 ml. of hot 1:1 methanol-acetone and acidified with ethanolic hydrogen chloride provides 3.5 g. of analytically pure 4-AMINO-N-(4-NITROSTYRYL)BENZAMIDINE HYDROCHLORIDE as a yellow solid, m.p. 247.degree.-248.degree. C. (dec.)(corr.). Concentration of the mother liquors and trituration of the residue provided an additional 2.6 g. of the hydrochloride salt.
Analysis. Calcd. for C.sub.15 H.sub.14 N.sub.4 O.sub.2.HCl (percent): C, 56.50; H, 4.74; N, 17.58. Found (percent): C, 56.89; H, 4.70; N, 17.74.
NMR (DMSO-d.sub.6, TMS): 3.83bs, 6.76m, 7.88m 9.68bs, 11.37bs.
EXAMPLE 10
N-(2-nitrostyrylsulfonyl)acetamidine treated with sodium hydroxide according to the procedure of Example 9 provides N-(2-NITROSTYRYL)ACETAMIDINE HYDROCHLORIDE, m.p. 227.degree.-229.degree. C. (dec.)(corr.), from ethanol-isopropyl ether.
Analysis. Calcd. for C.sub.10 H.sub.11 N.sub.3 O.sub.2.HCl (percent): C, 49.69; H, 5.01; N, 17.39. Found (percent): C, 49.39; H, 5.14; N, 17.10.
NMR (DMSO-d.sub.6, TMS): 2.36s, 7.02d (13.9 Hz), 7.93m, 10.18bs, 11.97bs.
EXAMPLE 11
N-(2-nitrostyrylsulfonyl)benzamidine treated with sodium hydroxide according to the procedure of Example 9 provides a 78% analytical yield of N-(2-NITROSTYRYL)BENZAMIDINE HYDROCHLORIDE, m.p. 219.5.degree.-221.5.degree. C. (dec.)(corr.), from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.15 H.sub.13 N.sub.3 O.sub.2.HCl (percent): C, 59.32; H, 4.65; N, 13.84. Found (percent): C, 59.04; H, 4.83; N, 13.72.
NMR (DMSO-d.sub.6, TMS): 7.25d (13.9 Hz), 7.87m, 10.50bs, 11.83bs.
EXAMPLE 12
N-(4-nitrostyrylsulfonyl)benzamidine treated with sodium hydroxide according to the procedure of Example 9 provides N-(4-nitrostyryl)benzamidine free base, m.p. 163.degree.-165.degree. C. N-(4-Nitrostyryl)benzamidine hydrochloride obtained from the free base in the usual manner has a melting point of 255.degree.-257.degree. C. The free base treated with a slight excess of isethionic acid in methanol affords N-(4-NITROSTYRYL)BENZAMIDINE ISETHIONATE, m.p. 204.degree.-206.5.degree. C. (dec.)(corr.), from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.15 H.sub.13 N.sub.3 O.sub.2.C.sub.2 H.sub.6 O.sub.4 S (percent): C, 51.90; H, 4.86; N, 10.69. Found (percent): C, 51.56; H, 4.94; N, 10.54.
NMR (DMSO-d.sub.6, TMS): 2.68t (6.7 Hz), 3.52t (6.7 Hz), 4.43s, 6.89d (14.0 Hz), 3.05m, 10.17bs, 11.83bs.
EXAMPLE 13
A solution of 4-nitro-N-(4-nitrostyrylsulfonyl)benzamidine (15.0 g., 0.04 mole) and 100 ml. of 2N sodium hydroxide in 200 ml. of acetone is stirred at 25.degree. C. for a period of 1 hr. Acetone is removed under reduced pressure, the mixture filtered and the filter cake washed with water and dried affording 8.4 g. (68% yield) of 4-nitro-N-(4-nitrostyryl)(benzamidine free base, m.p. 214.degree.-216.degree. C. 4-Nitro-N-(4-nitrostyryl)benzamidine hydrochloride obtained in the usual manner has a melting point of 243.degree.-244.degree. C. (dec.). The free base taken up in methanol and acidified with isethionic acid provides 4-NITRO-N-(4-NITROSTYRYL)BENZAMIDINE ISETHIONATE, m.p. 206.5.degree.-208.degree. C., (corr.).
Analysis. Calcd. for C.sub.15 H.sub.12 N.sub.4 O.sub.4.C.sub.2 H.sub.6 O.sub.4 S (percent): C, 46.57; H, 4.14; N, 12.77. Found (percent): C, 46.17; H, 4.27; N, 12.71.
NMR (DMSO-d.sub.6, TMS): 2.63t (6.7 Hz), 3.62t (6.7 Hz), 3.88s, 6.78d (14.0 Hz), 7.93m, 8.37bd (14.0 Hz), 10.33bs.
EXAMPLE 14
3,5-Diamino-N-(4-nitrostyrylsulfonyl)benzamidine treated with sodium hydroxide according to the procedure of Example 9 affords 3,5-diamino-N-(4-nitrostyryl)benzamidine free base, m.p. 121.degree.-126.degree. C. (dec.) in a yield of 75%. Conversion of the free base with ethanolic hydrogen chloride in acetone affords 3,5-DIAMINO-N-(4-NITROSTYRYL)BENZAMIDINE TRIHYDROCHLORIDE, m.p. 210.5.degree.-214.5.degree. C. (dec.)(corr.), from 90% ethanol.
Analysis. Calcd. for C.sub.15 H.sub.15 N.sub.5 O.sub.2.3HCl (percent): C, 44.29; H, 4.46; N, 17.22. Found (percent): C, 44.35; H, 4.86; N, 17.06.
NMR (DMSO-d.sub.6, TMS): 5.82bs, 6.73m, 7.97m, 10.08bs, 10.45bs.
EXAMPLE 15
3-Nitro-N-(4-nitrostyrylsulfonyl)benzamidine treated with sodium hydroxide according to the procedure of Example 9 provides 3-nitro-N-(4-nitrostyryl)benzamidine free base, m.p. 152.degree.-155.degree. C. The free base in acetone acidified with isethionic acid provides 3-NITRO-N-(4-NITROSTYRYL)BENZAMIDINE ISETHIONATE MONOHYDRATE, m.p. 195.0.degree.-198.0.degree. C. (corr.), from ethanol.
Analysis. Calcd. for C.sub.15 H.sub.12 N.sub.4 O.sub.4.HOC.sub.2 H.sub.4 SO.sub.3 H.H.sub.2 O (percent): C, 44.73; H, 4.42; N, 12.27. Found (percent): C, 44.90; H, 4.20; N, 12.05.
NMR (DMSO-d.sub.6, TMS): 2.62t (6.7 Hz), 3.62t (6.7 Hz), 3.79s, 6.80d (14.0 Hz), 8.07m, 10.25bs.
EXAMPLE 16
3-Amino-N-(4-nitrostyrylsulfonyl)benzamidine treated with sodium hydroxide according to the procedure of Example 9 provides 3-amino-N-(4-nitrostyryl)benzamidine free base, m.p. 146.degree.-148.degree. C. in 79% yield, from isopropyl alcohol-ether. Conversion of the free base to the hydrochloride salt with ethanolic hydrogen chloride affords 3-AMINO-N-(4-NITROSTYRYL)BENZAMIDINE DIHYDROCHLORIDE MONOHYDRATE, m.p. 183.0.degree.-192.5.degree. C. (dec.)(corr.).
Analysis. Calcd. for C.sub.15 H.sub.14 N.sub.4 O.sub.2.2HCl.H.sub.2 O (percent): C, 48.27; H, 4.86; N, 15.02. Found (percent): C, 47.99; H, 4.55; N, 14.96.
NMR (DMSO-d.sub.6, TMS): 6.80d (14.0 Hz), 7.77m, 3.90bs, 10.25bs.
EXAMPLE 17
4-(Dimethylamino)-N-(4-nitrostyrylsulfonyl)benzamidine treated with sodium hydroxide according to the procedure of Example 9 provides 4-(dimethylamino)-N-(4-nitrostyryl)benzamidine free base, m.p. 191.degree.-193.degree. C. Acidification of the free base in methanol with isethionic acid affords 4-(DIMETHYLAMINO)-N-(4-NITROSTYRYL)BENZAMIDINE ISETHIONATE, m.p. 260.5.degree.-262.5.degree. C. (dec.)(corr.), from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.17 H.sub.18 N.sub.4 O.sub.2.HOC.sub.2 H.sub.4 SO.sub.3 H (percent): C, 52.28, H, 5.54; N, 12.83. Found (percent): C, 52.44; H, 5.54; N, 12.82.
NMR (DMSO-d.sub.6, TMS): 2.63t (6.7 Hz), 3.64t (6.7 Hz), 4.38s, 3.04s, 6.73m, 7.92m, 11.17bs.
EXAMPLE 18
N-(4-Nitrostyrylsulfonyl)cinnamamidine treated with sodium hydroxide according to the procedure of Example 9 provides N-(4-nitrostyryl)cinnamamidine free base, m.p. 120.degree.-125.degree. C. (dec.). Acidification of the free base in acetone with isethionic acid affords N-(4-NITROSTYRYL)CINNAMAMIDINE ISETHIONATE, m.p. 224.5.degree.-228.0.degree. C. (corr.), from methanol.
Analysis. Calcd. for C.sub.17 H.sub.15 N.sub.3 O.sub.2.HOC.sub.2 H.sub.4 SO.sub.3 H (percent): C, 54.41; H, 5.05; N, 10.02. Found (percent): C, 54.29; H, 5.09; N, 9.84.
NMR (DMSO-d.sub.6, TMS): 2.73t (6.7 Hz), 3.69t (6.7 Hz), 4.18bs, 6.69d (13.9 Hz), 6.85d (16.2 Hz), 7.83m, 9.68bs.
EXAMPLE 19
A nitrogen atmosphere is employed throughout the reaction. A solution of sodium borohydride (3.8 g., 0.1 mole) in 10 ml. of water is added to a suspension of about 200 mg. of 10% palladium on carbon in 10 ml. of water. After 5 min., 200 ml. of methanol is added followed by portion-wise addition of finely powdered N-(4-nitrostyryl)benzamidine (8.0 g., 0.03 mole) over a period of 5 min. During the addition, the mixture refluxes and continues to boil for about 5-10 min. thereafter. The reaction mixture is stirred without external heating for 0.5 hr., filtered through celite, concentrated under reduced pressure and the residue stirred with 25 ml. of water and filtered. The filter cake washed with cold water, dried, and triturated with isopropyl alcohol provides 6.8 g. (86% yield) of N-(4-aminostyryl)benzamidine free base, m.p. 166.degree.-168.degree. C. Treating the free base in methanol with ethanolic hydrogen chloride and evaporating the solvent under reduced pressure provides the crude hydrochloride. Analytically pure N-(4-AMINOSTYRYL)BENZAMIDINE DIHYDROCHLORIDE, m.p. 217.5.degree.-219.5.degree. C. (dec.)(corr.), (60% yield) is obtained by first triturating the crude hydrochloride with acetone and then recrystallizing from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.15 H.sub.15 N.sub.3.2HCl (percent): C, 58.06; H, 5.53; N, 13.55. Found (percent): C, 58.43; H, 5.60; n, 13.36.
NMR (DMSO-d.sub.6, TMS): 6.97d (14.0 Hz), 7.70m, 9.53bs, 10.18bs, 10.57bs, 12.00bs.
EXAMPLE 20
Reduction of N-(2-nitrostyrylsulfonyl)benzamidine with sodium borohydride according to the procedure of Example 19 provides N-(2-AMINOSTYRYL)BENZAMIDINE DIHYDROCHLOIDE, m.p. 226.5.degree.-227.5.degree. C. (dec.)(corr.), from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.15 H.sub.15 N.sub.3.2HCl (percent): C, 58.06; H, 5.53; N, 13.55. Found (percent): C, 58.30; H, 5.44; N, 13.71.
NMR (DMSO-d.sub.6, TMS): 6.84d (14.0 Hz), 7.58m, 9.92bm, 11.75bs.
EXAMPLE 21
Reduction of 4-nitro-N-(4-nitrostyryl)benzamidine with sodium borohydride according to the procedure of Example 19 affords 4-AMINO-N-(4-AMINOSTYRYL)BENZAMIDINE TRIHYDROCHLORIDE, m.p. 259.0.degree. C. (dec.)(corr.), from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.15 H.sub.16 N.sub.4.3HCl (percent): C, 49.80; H, 5.30; N, 15.49. Found (percent): C, 49.60; H, 5.34; N, 15.66.
NMR (DMSO-d.sub.6, TMS): 6.80m, 7.62m, 9.53bs, 9.75bs, 11.33bs.
EXAMPLE 22
Reduction of 3,5-diamino-N-(4-nitrostyryl)benzamidine with sodium borohydride according to the procedure of Example 19 provides 3,5-DIAMINO-N-(4-AMINOSTYRYL)BENZAMIDINE TRIHYDROCHLORIDE, m.p. 286.5.degree.-288.0.degree. C. (dec.)(corr.), from aqueous ethanol.
Analysis. Calcd. for C.sub.15 H.sub.17 N.sub.5.3HCl (percent): C, 47.82; H, 5.35; N, 18.60. Found (percent): C, 47.60; H, 5.44; N, 18.54.
NMR (D.sub.2 O, DSS): 4.67s, 6.70d (14.0 Hz), 7.47m,
EXAMPLE 23
Reduction of 3-nitro-N-(4-aminostyryl)benazmidine with sodium borohydride according to the procedure of Example 19 provides 3-AMINO-N-(4-AMINOSTYRYL)BENZAMIDINE TRIHYDROCHLORIDE MONOHYDRATE, m.p. 224.5.degree.-226.5.degree. C. (dec.)(corr.), from methanol-isopropyl acetate.
Analysis. Calcd. for C.sub.15 H.sub.16 N.sub.4.3HCl.H.sub.2 O (percent): C, 47.44; H, 5.58; N, 14.76; H.sub.2 O, 4.74. Found (percent): C, 47.40; H, 5.65; N, 14.56; H.sub.2 O, 4.68.
NMR (D.sub.2 O, DSS): 4.67s, 6.68d (14.0 Hz), 7.43m.
EXAMPLE 24
Reduction of N-(4-nitrostyryl)-2-naphthamidine according to the procedure of Example 19 with sodium borohydride provides N-(4-aminostyryl)-2-naphthamidine free base, m.p. 151.degree.-153.degree. C. Acidification of the free base in acetone with 5N hydrochloric acid affords N-(4-AMINOSTYRYL)-2-NAPHTHAMIDINE DIHYDROCHLORIDE, m.p. 235.degree.-237.degree. C. (dec.)(corr.), from methanol-isopropyl ether.
Analysis. Calcd. for C.sub.19 H.sub.17 N.sub.3.2HCl (percent): C, 63.33; H, 5.32; N, 11.66. Found (percent): C, 63.41; H, 5.25; N, 11.65.
NMR (DMSO-d.sub.6, TMS): 6.86d (14.0 Hz), 7.71m, 8.50d (2.0 Hz), 9.13bs, 10.08bs, 10.42bs, 11.85bs.
EXAMPLE 25
A solution of N-(4-aminostyryl)benzamidine (2.4 g., 0.01 mole) in 25 ml. of acetic acid and 5 ml. of acetic anhydride is heated at 100.degree. C. for a period of 15 min., cooled and quenched in 50 ml. of iced-water. The yellow solution thus obtained is acidified with 3N hydrochloric acid providing a yellow precipitate which is collected, triturated with acetone and crystallized from methanol-ethanol to yield 2.0 g., (63%) of analytically pure N-(4-ACETAMIDOSTYRYL)BENZAMIDINE HYDROCHLORIDE, m.p. 249.degree.-251.degree. C. (dec.)(corr.).
Analysis. Calcd. for C.sub.17 H.sub.17 N.sub.3 O.HCl (percent): C, 64.66; H, 5.74; N, 13.30. Found (percent): C, 64.72; H, 6.05; N, 13.11.
NMR (DMSO-d.sub.6, TMS): 2.05s, 6.74d (13.5 Hz), 7.64m, 9.83bm, 10.05s, 11.55bm.
EXAMPLE 26
The following styrylamidine products of Formula I are obtained by treating the enumerated styrylsulfonylamidine precursor with sodium hydroxide in dimethylsulfoxide according to the procedure of Example 1:
(a) N-(4-CARBAMOYLSTYRYL)ACETAMIDINE from N-(4-carbamoylstyrylsulfonyl)acetamidine;
(b) N-(4-SULFAMOYLSTYRYL)ACETAMIDINE from N-(4-sulfamoylstyrylsulfonyl)acetamidine;
(c) N-(3-METHYLSULFONYLSTYRYL)ACETAMIDINE from N-(3-methylsulfonylstyrylsulfonyl)acetamidine;
(d) N-(4-CYCLOHEXYLSTYRYL)ACETAMIDINE from N-(4-cyclohexylstyrylsulfonyl)acetamidine;
(e) N-(3-Bromo-4-cyclohexylstyrylsulfonyl)acetamidine provides N-(3-BROMO-4-CYCLOHEXYLSTYRYL)ACETAMIDINE HYDROCHLORIDE, m.p. 212.degree.-215.degree. C. (dec.)(corr.).
Analysis. Found (percent): C, 53.46; H, 6.22; N, 7.72. NMR (DMSO-d.sub.6, TMS): 1.60m, 2.29s, 2.82m, 6.46d (14.0 Hz), 7.5bm, 10.25bs.
(f) N-(STYRYL)-4-CHLOROBENZAMIDINE from N-(styrylsulfonyl)-4-chlorobenzamidine;
(g) N-(STYRYL)-3-ACETAMIDOBENZAMIDINE from N-(styrylsulfonyl)-3-acetamidobenzamidine;
(h) N-(STYRYL)-3,4-DICHLOROBENZAMIDINE from N-(styrylsulfonyl)-3,4-dichlorobenzamidine;
(i) N-(4-NITROSTYRYL)-4-STYRYLBENZAMIDINE from N-(4-nitrosturylsulfonyl)-4-styrylbenzamidine;
(j) N-(4-NITROSTYRYL)-4-(PHENYLBUTADIENYL)BENZAMIDINE from N-(4L -nitrostyrylsulfonyl)-4-(phenylbutadienyl)benzamidine;
(k) N-(2-FLUOROSTYRYL)BENZAMIDINE from N-(2-fluorostyrylsulfonyl)benzamidine;
(l) N-(2,5-DICHLOROSTYRYL)BENZAMIDINE from N-(2,4-dichlorostyrylsulfonyl)benzamidine;
(m) N-(STYRYL)-4-(di-n-BUTYLAMINO)BENZAMIDINE from N-(styrylsulfonyl)-4-(di-n-butylamino)benzamidine;
(n) N-[3-(2-METHYLPROPIONAMIDO)STRYL]ACETAMIDINE from N-[3-(2-methylpropionamido)styrylsulfonyl]acetamidine;
(o) N-(STYRYL)-2-sec.-BUTYRAMIDINE from N-(styrylsulfonyl)-sec.-butyramidine;
(p) N-[2,6-DICHLOROSTYRYL)SULFONYL]ACETAMIDINE provides N-(2,6-dichlorostyryl)acetamidine hydrochloride, m.p. 154.5.degree.-158.5.degree. C. (corr.). Analysis. Found (percent): C, 45.20; H, 4.13; N, 10.66. NMR (DMSO-d.sub.6, TMS): 2.35s, 6.65d (13.8 Hz), 7.40m, 9.5bs, 9.8bs, 12.0.
EXAMPLE 27
Reaction of the aminostyrylamidines enumerated below with acetic anhydride according to the procedure of Example 25 provides the following acetamidostyrylamidine products of Formula I:
(a) N-(4-ACETAMIDOSTYRYL)-4-STYRYLBENZAMIDINE from N-(4-aminostyryl)-4-styrylbenzamidine;
(b) N-(4-ACETAMIDOSTYRYL)-4-(PHENYLBUTADIENYL)BENZAMIDINE from N-(4-aminostyryl)-4-(phenylbutadienyl)benzamidine.
EXAMPLE 28
Reduction of the nitrostyrylamidines enumerated below with sodium borohydride according to the procedure of Example 19 provides the following aminostyrylamidines of Formula I:
(a) N-(4-AMINOSTYRYL)-4-STYRYLBENZAMIDINE from N-(4-nitrostyryl)-4-styrylbenzamidine;
(b) N-(4-AMINOSTYRYL)-4-(PHENYLBUTADIENYL)BENZAMIDINE from N-(4-nitrostyryl)-4-(phenylbutadienyl)benzamidine.
EXAMPLE 29
PREPARATION OF STYRYLSULFONYLAMIDINES.
(a) 4-Nitrobenzamidine hydrochloride obtained according to method of L. Weintraub, et al., J. Org. Chem., 33, 1679 (1968) is hydrogenated in methanol solution in a Parr Apparatus employing a 10% palladium on carbon catalyst to provide 4-aminobenzamidine hydrochloride.
Addition of 50% sodium hydroxide (4.0 g., 0.05 mole) to a solution of 4-aminobenzamidine hydrochloride (0.5 mole) in 10 ml. of water affords 4-aminobenzamidine free base. Acetone (50 ml.) is added to the liberated free base and the mixture cooled to 5.degree. C. 4-Nitrostyrylsulfonyl chloride is added to the mixture in a period of 5 min. while maintaining a temperature below 15.degree. C. The mixture is stirred for 10 min., the reaction mixture concentrated under reduced pressure provides a residue which diluted with 100 ml. of water and neutralized with 3N hydrochloric acid affords a pale yellow solid precipitate. The precipitate is collected, washed thoroughly with water and then triturated first with isopropanol and then with ether to yield 7.3 g. (84%) of N-(4-NITROSTYRYLSULFONYL)-4-AMINOBENZAMIDINE, m.p. 188.degree.-189.degree. C.
(b) A mixture of acetamidine hydrochloride (28.8 g., 0.15 mole) and 50% sodium hydroxide (12.0 g., 0.15 mole) in 150 ml. of acetone is stirred for a period of 10 min. to liberate the free base. A solution of styrylsulfonyl chloride (10.1 g., 0.05 mole) in 50 ml. of acetone is added dropwise to the mixture at a temperature of 20.degree.-25.degree. C. with stirring. After further stirring for 10 min., the mixture is concentrated under reduced pressure to remove acetone, the concentrate diluted with 200 ml. of water and acidified with 3N hydrochloric acid to provide a precipitate. The precipitate is collected, dissolved in chloroform and the chloroform extract dried. Evaporation of the chloroform solvent under reduced pressure provides a white solid, m.p. 130.degree.-134.degree. C. which is crystallized from isopropyl acetate affording 8.5 g. (76% yield) of N-(STYRYLSULFONYL)ACETAMIDINE, m.p. 134.5.degree.-137.0.degree. C. (corr.).
Analysis. Calcd. for C.sub.10 H.sub.12 N.sub.2 O.sub.2 S (percent): C, 53.55; H, 5.39; N, 12.49. Found (percent): C, 53.37; H, 5.30; N, 12.54.
NMR (CDCl.sub.3, TMS): 2.16s, 6.73bs, 6.92d (15.5 Hz), 7.45m, 7.64d (15.5 Hz), 7.84bs.
(c) Reaction of benzamidine and styrylsulfonyl chloride according to the above procedure provides N-(STYRYLSULFONYL)BENZAMIDINE, m.p. 192.5.degree.-194.5.degree. C. (corr.), crystallized from acetone.
Analysis. Calcd. for C.sub.15 H.sub.14 N.sub.2 O.sub.2 S (percent): C, 62.91; H, 4.93; N, 9.79. Found (percent): C, 63.13; H, 5.06; N, 9.64.
NMR (DMSO-d.sub.6, TMS): 7.4-8.1m, 8.20bs, 9.20bs.
(d) Reaction of acetamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure provides N-(4-NITROSTYRYLSULFONYL)ACETAMIDINE, m.p. 203.0.degree.-203.5.degree. C. (dec.)(corr.), crystallized from acetonitrile.
Analysis. Calcd. for C.sub.10 H.sub.11 N.sub.3 O.sub.4 S (percent): C, 44.59; H, 4.12; N, 15.61. Found (percent): C, 44.85; H, 4.21; N, 15.74.
NMR (DMSO-d.sub.6, TMS): 2.16s, 7.56s, 8.15m, 8.62bs.
(e) Reaction of acetamidine with 3,4-dichlorostyrylsulfonyl chloride according to the above procedure affords N-[(3,4-DICHLOROSTYRYL)SULFONYL]ACETAMIDINE, m.p. 197.5.degree.-198.5.degree. C. (corr.), crystallized from acetone-isopropanol.
Analysis. Calcd. for C.sub.10 H.sub.10 Cl.sub.2 N.sub.2 O.sub.2 S (percent): C, 40.96; H, 3.44; N, 9.56. Found (percent): C, 41.15; H, 3.64; N, 9.49.
NMR (DMSO-d.sub.6, TMS): 2.14s, 7.43s, 7.73m, 7.96bs, 8.08m, 8.57bs.
(f) Reaction of acetamidine with 4-chlorostyrylsulfonyl chloride according to the above procedure affords N-[(4-CHLOROSTYRYL)SULFONYL]ACETAMIDINE, m.p. 161.degree.-163.degree. C., crystallized from ethyl acetate.
(g) Reaction of phenylacetamidine benzenesulfonate, obtained according to the method of P. Oxley and W. F. Short, J. Chem. Soc., 147 (1946), with 3,4-dichlorostyrylsulfonyl chloride according to the above procedure affords N-[(3,4-DICHLOROSTYRYL)SULFONYL]PHENYLACETAMIDINE, m.p. 151.degree.-155.degree. C.
(h) Reaction of benzamidine with 3,4-dichlorostyrylsulfonyl chloride according to the above procedure affords N-[(3,4-DICHLOROSTYRYL)SULFONYL]BENZAMIDINE, m.p. 144.degree.-146.degree. C.
(i) Reaction of acetamidine with 2-nitrostyrylsulfonyl chloride according to the above procedure affords N-(2-NITROSTYRYLSULFONYL)ACETAMIDINE, m.p. 175.degree.-178.degree. C.
(j) Reaction of benzamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)BENZAMIDINE, m.p. 173.degree.-175.degree. C., by triturating with methanol.
(k) 4-Nitrostyrylsulfonyl chloride (2.5 g., 0.01 mole) is added portion-wise to a solution of 4-nitrobenzamidine (1.65 g., 0.01 mole), prepared according to the procedure of L. Weintraub, et al., J. Org. Chem., 33, 1679 (1968), and triethylamine (1.01 g., 0.01 mole) in 50 ml. of acetone at 10.degree. C. After stirring for a period of 1 hr. at 25.degree. C., the mixture is concentrated under reduced pressure and the residual material stirred with water and collected. Triturating the filter cake with acetone provides N-(4-NITROSTYRYLSULFONYL)-4-NITROBENZAMIDINE, m.p. 173.degree.-177.degree. C.
(1) Reaction of 3-nitrobenzamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure provides N-(4-NITROSTYRYLSULFONYL)-3-NITROBENZAMIDINE, m.p. 230.degree.-232.degree. C.
(m) Reaction of 3-aminobenzamidine, obtained by catalytic reduction of 3-nitrobenzamidine in methanol in a Parr Apparatus employing 10% palladium on carbon catalyst, with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)-3-AMINOBENZAMIDINE, m.p. 162.degree.-170.degree. C., by triturating with isopropanol.
(n) Reaction of 4-(N,N-dimethylamino)benzamidine, obtained according to the procedure of "Organic Synthesis", Coll. Vol. 1, 2nd Ed., page 5, (Wiley, 1932), with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)-4-Dimethylaminobenzamidine, m.p. 192.degree.-196.degree. C., by triturating with acetone.
(o) Reaction of cinnamamidine, obtained according to the procedure of "Organic Synthesis", Coll. Vol. 1, 2nd, Ed. page 5, (Wiley, 1932), with 4-nitrostyrylsulfonyl chloride by the above procedure affords N-(4-NITROSTYRYLSULFONYL)CINNAMAMIDINE, m.p. 188.degree.-192.degree. C., by triturating with ethyl acetate.
(p) Reaction of .beta.-naphthamidine with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)-.beta.-NAPHTHAMIDINE, m.p. 180.degree.-182.5.degree. C., by triturating with isopropanol.
(q) Reaction of 3,5-diaminobenzamidine obtained by catalytic reduction of 3,5-dinitrobenzamidine benzenesulfonate, with 4-nitrostyrylsulfonyl chloride according to the above procedure affords N-(4-NITROSTYRYLSULFONYL)-3,5-DIAMINOBENZAMIDINE.
(r) Hydrogen chloride is bubbled through a mixture of 4L -cyanostilbene (13.5 g., 0.065 mole), obtained according to the method of Belgian Patent 641,415 (Chem. Abs. 63: 3092g (1965)), in 35 ml. of dry benzene and 17.5 ml. of absolute ethanol at 0.degree. to 5.degree. C. for a period of 3 hr. The reaction is maintained at 0.degree. to 5.degree. C. for 48 hr. and the solvent and excess hydrogen chloride removed under reduced pressure. The residue stirred with 50 ml. of dry benzene and collected provides 13.0 g. of ethyl-4-styrylbenzimidate hydrochloride. A methanol solution of the benzimidate salt is cooled to 5.degree. to 10.degree. C., saturated with ammonia and heated at a temperature of 100.degree. C. for a period of 3 hr. in an enclosed container. Concentration of the reaction mixture provides 4-styrylbenzamidine hydrochloride.
Reaction of 4-styrylbenzamidine with 4-nitrostyrylsulfonyl chloride according to the procedure of Example 29 (a) provides N-(4-NITROSTYRYLSULFONYL)-4-STYRYLBENZAMIDINE.
(s) By substituting 4-(4-phenylbuta-1,3-dienyl)benzonitrile for 4-cyanostilbene according to Example 29 (r) there is obtained ethyl-4-(4-phenylbuta-1,3-dienyl)benzimidate hydrochloride, m.p. 245.degree.-260.degree. C. (dec.) by triturating with acetone. The ethylbenzimidate salt is converted to 4-(4-phenylbuta-1,3-dienyl)benzamidine hydrochloride by dissolving in methanol saturated with ammonia.
Reaction of 4-(4-phenylbuta-1,3-dienyl)benzamidine with 4-nitrostyrylsulfonyl chloride according to the procedure of Example 29 (a) provides N-(4-NITROSTYRYLSULFONYL)-4-PHENYLBUTADIENYLBENZAMIDINE.
(t) Ammonia is bubbled through a solution of 3,4-dichlorostyrylsulfonyl chloride (27.2 g., 0.1 mole) in 250 ml. of ether for a period of 30 min. at about 20.degree. C. The solvent is evaporated and the residue stirred with water, collected and dried at 100.degree. C. under vacuum affords 24.6 g. (97% yield) of 3,4-dichlorostyrylsulfonamide, m.p. 127.degree.-130.degree. C.
A mixture of 3,4-dichlorostyrylsulfonamide (12.6 g., 0.05 mole) and 3,4-dimethoxybenzoyl chloride (11.0 g., 0.055 mole) in 15 ml. of phosphorus oxychloride is heated at steam bath temperature for a period of 30 min. Excess phosphorus oxychloride is removed under reduced pressure and dry benzene added. The benzene is evaporated and the treatment repeated two times. Benzene (50 ml.) is added to the residue thus obtained and the insoluble solid collected providing 14.6 g. (70% yield) of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzamide, m.p. 145.degree.-147.degree. C.
A suspension of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzamide (8.3 g., 0.02 mole) in 100 ml. of dry benzene is stirred and refluxed with phosphorus pentachloride (4.6 g., 0.022 mole) for a period of 1.5 hr. providing a clear solution which is concentrated under reduced pressure. Benzene is added to the residue and evaporated. The benzene treatment is repeated several times and the residue thus obtained triturated with isopropyl ether provides a quantitative yield of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzimidoyl chloride, m.p. 120.degree.-125.degree. C.
Ammonium gas is bubbled through a solution of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzimidoyl chloride (8.7 g., 0.02 mole) in 100 ml. of dry benzene for a period of 1 hr. The solvent evaporated under reduced pressure and the solid residue stirred with 50 ml. of water and filtered affords 8.0 g. (96% yield) of N-(3,4-DICHLOROSTYRYLSULFONYL)-3,4-DIMETHOXYBENZAMIDINE, m.p. 205.degree.-210.degree. C. A sample crystallized from acetonitrile has a melting point of 208.degree.-211.degree. C.
(u) Reaction of acetamidine with 2,6-dichlorostyrylsulfonyl chloride according to the procedure of Example 29(b) affords N'-[(2,6-dichlorostyryl)sulfonyl]acetamidine, m.p. 154.5.degree.-158.5.degree. C. (corr.), from absolute ethanol.
Analysis. Calcd. for C.sub.10 H.sub.10 Cl.sub.2 N.sub.2 O.sub.2 S (percent): C, 40.96; H, 3.44; N, 9.56. Found (percent): C, 40.60; H, 3.36; N, 9.37.
EXAMPLE 30
Reaction of the styrylsulfonyl chlorides and amidines enumerated below according to the procedures set forth in Example 29 provides the following styrylsulfonylamidine precursors of the products of Formula I:
(a) N-(4-CARBAMOYLSTYRYLSULFONYL)ACETAMIDINE from 4-carbamoyl-styrylsulfonyl chloride and acetamidine;
(b) N-(4-SULFAMOYLSTYRYLSULFONYL)ACETAMIDINE from 4-sulfamoylstyrylsulfonyl chloride and acetamidine;
(c) N-(3-METHYLSULFONYLSTYRYLSULFONYL)ACETAMIDINE from 3-methylsulfonylstyrylsulfonyl chloride and acetamidine;
(d) N-(4-CYCLOHEXYLSTYRYLSULFONYL)ACETAMIDINE from 4-cyclohexylstyrylsulfonyl chloride and acetamidine;
(e) N-(3-BROMO-4-CYCLOHEXYLSTYRYLSULFONYL)ACETAMIDINE, m.p. 148.degree.-156.degree. C., from 3-bromo-4-cyclohexylstyrylsulfonyl chloride and acetamidine;
(f) N-(STYRYLSULFONYL)-4-CHLOROBENZAMIDINE from styrylsulfonyl chloride and 4-chlorobenzamidine;
(g) N-(STYRYLSULFONYL)-3-ACETAMIDOBENZAMIDINE from styrylsulfonyl chloride and 3-acetamidobenzamidine;
(h) N-(STYRYLSULFONYL)-3,4-DICHLOROBENZAMIDINE from styrylsulfonyl chloride and 3,4-dichlorobenzamidine;
(i) N-(4-NITROSTYRYLSULFONYL)-4-STYRYLBENZAMIDINE from 4-nitrostyrylsulfonyl chloride and 4-styrylbenzamidine;
(j) N-(4-NITROSTYRYLSULFONYL)-4-PHENYLBUTADIENYLBENZAMIDINE from 4-nitrostyrylsulfonyl chloride and 4-phenylbutadienylbenzamidine;
(k) N-(2-FLUOROSTYRYLSULFONYL)BENZAMIDINE from b 2-fluorostyrylsulfonyl chloride and benzamidine;
(l) N-(2,5-DICHLOROSTYRYLSULFONYL)BENZAMIDINE from 2,5-dichlorostyrylsulfonyl chloride and benzamidine;
(m) N-(STYRYLSULFONYL)-4-(di-n-BUTYLAMINO)BENZAMIDINE from styrylsulfonyl chloride and 4-(di-n-butylamino)benzamidine;
(n) N-[3-(2-methylpropionamido)styrylsulfonyl ACETAMIDINE from 3-(2-methylpropionamido)styrylsulfonyl chloride and acetamidine;
(o) N-(STYRYLSULFONYL)-sec.-BUTYRAMIDINE from styrylsulfonyl chloride and sec.-butyramidine.
EXAMPLE 31
PREPARATION OF STYRYLSULFONYL CHLORIDES
(a) 3,4-DICHLOROSTYRYLSULFONYL CHLORIDE.- Sulfur trioxide (20.0 g., 0.25 mole) is distilled from 20% fuming sulfuric acid into a flask containing 200 ml. of dry dichloroethane. Dioxane (21.0 g., 0.25 mole) is added dropwise to the solution of sulfur trioxide while maintaining a temperature of from -10.degree. to 0.degree. C. After the addition of dioxane, a solution of 3,4-dichlorostyrene (43.8 g., 0.25 mole) in 50 ml. of dichloroethane is added over a 10 min. period at 0.degree. C. The solution is stirred for 3 hr. at 25.degree. C., refluxed for 0.5 hr. and then poured into 400 ml. of cold water. The reaction mixture is extracted with ether, basified with 50% sodium hydroxide, and the aqueous fraction concentrated under reduced pressure to a small volume yielding 35.4 g. (51%) of the sodium salt of 3,4-dichlorostyrylsulfonic acid.
A mixture of the sodium sulfonate salt (35 g., 0.126 mole) and phosphorus pentachloride (30 g., 0.144 mole) is heated at a temperature of 100.degree. C. for a period of 5 hr. After removal of the phosphorus oxychloride by-product under vacuum the reaction mixture is added to ice water, the resulting mass broken up and the mixture filtered. The filter cake is dissolved in ether, the ethereal solution, washed with water and dried over magnesium sulfate. Evaporation of the ether solvent provides 3,4-dichlorostyrylsulfonyl chloride, m.p. 91.degree.-96.degree. C. in 92% yield. A sample crystallized from chloroform melts at 95.degree.-98.degree. C.
(b) Substituting 4-chlorostyrene for 3,4-dichlorostyrene in the above procedure provides 4-CHLOROSTYRYLSULFONYL CHLORIDE, m.p. 133.degree.-135.degree. C. in 88% yield.
(c) Substituting styrene in the above procedure for 3,4-dichlorostyrene provides STYRENESULFONYL CHLORIDE, m.p. 86.degree.-89.degree. C. in 95% yield.
(d) Nitration of styrenesulfonyl chloride according to the procedure of F. G. Bordwell, et al., J. Amer. Chem. Soc., 68, 1778 (1946) provides 2-NITROSTYRYLSULFONYL CHLORIDE, m.p. 102.degree.-105.degree. C., and 4-NITROSTYRYLSULFONYL CHLORIDE, m.p. 171.degree.-174.degree. C.
(e) Substituting 4-carbamoylstyrene for 3,4-dichlorostyrene in the above procedure provides 4-CARBAMOYLSTYRLSULFONYL CHLORIDE.
(f) Substituting 4-sulfamoylstyrene for 3,4-dichlorostyrene in the above procedure provides 4-SULFAMOYLSTYRYLSULFONYL CHLORIDE.
(g) Substituting 3-methylsulfonylstyrene for 3,4-dichlorostyrene in the above procedure provides 3-METHYLSULFONYLSTYRYLSULFONYL CHLORIDE.
(h) Substituting 4-cyclohexylstyrene for 3,4-dichlorostyrene in the above procedure provides 4-CYCLOHEXYLSTYRYLSULFONYL CHLORIDE.
(i) Substituting 3-bromo-4-cyclohexylstyrene for 3,4-dichlorostyrene in the above procedure provides 3-BROMO-4-CYCLOHEXYLSTYRYLSULFONYL CHLORIDE, m.p. 93.degree.-97.degree. C.
(j) Substituting 2-fluorostyrene for 3,4-dichlorostyrene in the above procedure provides 2-FLUOROSTYRYLSULFONYL CHLORIDE.
(k) Substituting 2,5-dichlorostyrene for 3,4-dichlorostyrene in the above procedure provides 2,5-DICHLOROSTYRYLSULFONYL CHLORIDE.
(l) Substituting 3-(2-methylpropionamido)styrene for 3,4-dichlorostyrene in the above procedure provides 3-(2-METHYLPROPIONAMIDO)STYRYLSULFONYL CHLORIDE.
(m) Substituting 2,6-dichlorostyrene for 3,4-dichlorostyrene in the above procedure provides 2,6-DICHLOROSTYRYLSULFONYL CHLORIDE, m.p. 88.degree.-90.degree. C.
EXAMPLE 32
Preparation of N-Methyl-N-(4-nitrostyryl)benzamidine Hydrochloride
(a) N-(4-Nitrostyrylsulfonyl)benzimidoyl chloride. A mixture of 4-nitrostyrylsulfonamide (18.2 g., 0.08 mole), benzoyl chloride (12.6 g., 0.09 mole) and phosphorus oxychloride (13.8 g., 0.09 mole) is heated at steam bath temperature for 1.5 hr. The reaction mixture diluted with 20 ml. of ethyl acetate, cooled and filtered affords 19.0 g. (76% yield) of N-(4-nitrostyrylsulfonyl)benzamide, m.p. 192.degree.-195.degree. C., from ethyl acetate-hexane.
A suspension of N-(4-nitrostyrylsulfonyl)benzamide (14.9 g., 0.045 mole) in 500 ml. of dry benzene is refluxed and stirred with phosphorus pentachloride (10.4 g., 0.05 mole) for 8 hr. The reaction mixture after standing overnight at 25.degree. C. provides 8.2 g. of solid, m.p. 158.degree.-166.degree. C. Concentration of the mother liquor to about 100 ml. provides an additional 2.5 g. of solid, m.p. 158.degree.-161.degree. C. The combined crude solid crystallized from ethyl acetate affords analytically pure N-(4-nitrostyrylsulfonyl)benzimidoyl chloride, m.p. 168.degree.-175.degree. C.
Anal. Found: C, 51.46; H, 3.09; N, 7.79.
(b) N-Methyl-N'-(4-nitrostyrylsulfonyl)benzamidine. Methylamine is passed slowly into a solution of N-(4-nitrostyrylsulfonyl)benzimidoyl chloride (6.3 g., 0.018 mole) in 50 ml. of dry acetone for 5 min. at 25.degree. C. After stirring the mixture for 25 min. at 25.degree. C., the mixture is concentrated and 50 ml. water and 150 ml. of chloroform added. The resulting mixture is shaken vigorously and filtered. Insoluble material is triturated with 200 ml. of hot chloroform, cooled and filtered providing 0.6 g. of N-methyl-N'-(4-nitrostyrylsulfonyl)benzamidine. The chloroform fractions are combined, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Trituration of the residue thus obtained with methanol affords an additional 3.5 g. of the benzamidine. Analytically pure N-methyl-N'-(4-nitrostyrylsulfonyl)benzamidine has a melting point of 155.5.degree.-157.degree. C. (dec.) from acetonitrile.
Anal. Calcd. for C.sub.16 H.sub.15 N.sub.3 O.sub.4 S: C, 55.65; H, 4.38; N, 12.17. Found: C, 55.29; H, 4.24; N, 12.16.
NMR (DMSO-d.sub.6, TMS): 2.92d (4.0 Hz), 7.12d (15.0 Hz), 7.70-7.25m, 7.85d (9.0 Hz), 8.21d (9.0 Hz), 9.00bs.
(c) N-Methyl-N-(4-nitrostyryl)benzamidine. A mixture of N-methyl-N'-(4-nitrostyrylsulfonyl)benzamidine (3.45 g., 0.01 mole) in 100 ml. of acetone and 25 ml. of 10% aqueous sodium hydroxide is stirred at 25.degree. C. for 30 min. The solvent is removed under reduced pressure and the residue diluted with water and extracted with chloroform. The chloroform extract is washed with water, dried over potassium carbonate and concentrated affording the benzamidine free base. The free base is taken up in ethanol, acidified with ethanolic hydrogen chloride and the hydrochloride salt isolated by dilution with ether. Trituration of the crude salt with acetone and crystallization from methanol-isopropyl ether provides 2.4 g. (75%) of analytically pure N-methyl-N-(4-nitrostyryl)benzamidine hydrochloride, m.p. 247.5.degree.-249.5.degree. C. (dec.)(corr.).
Anal. Calcd. for C.sub.16 H.sub.15 N.sub.3 O.sub.2.HCl: C, 60.47; H, 5.08; N, 13.22. Found: C, 60.66; H, 5.03; N, 13.35.
NMR (DMSO-d.sub.6, TMS): 3.44s, 6.90d, 7.6-8.0m, 8.22d (9.0 Hz), 10.70bs.
EXAMPLE 33
Preparation of 5,6-dihydro-4-methyl-5-(4-nitrophenyl)-3-phenyl-4H-1,2,4-thiadiazine 1,1-dioxide.
Methylamine is bubbled into a solution of N-(4-nitrostyrylsulfonyl)benzimidoyl chloride (5.25 g., 0.015 mole) in 100 ml. of acetone for a period of 2.5 hr. The reaction mixture is concentrated under reduced pressure, diluted with 50 ml. of water and acidified with 3N hydrochloric acid. After stirring for several minutes the acidified mixture is filtered and insolubles air dried. Trituration of this crude product with 30 ml. of isopropanol and then isopropyl ether affords 3.2 g. (61%) of 5,6-dihydro-4-methyl-5-(4-nitrophenyl)-3-phenyl-4H-1,2,4-thiadiazine 1,1-dioxide, m.p. 179.5.degree.-181.degree. C., (dec.)(corr.), from acetonitrile.
Anal. Calcd. for C.sub.16 H.sub.15 N.sub.3 O.sub.4 S: C, 55.64; H, 4.38; N, 12.17. Found: C, 55.77; H, 4.32; N, 12.23.
NMR (DMSO-d.sub.6, TMS): 3.02s, 3.40m, 5.03dd (8.5 Hz, 6.0 Hz), 7.50s, 7.66d (8.5 Hz), 8.15d (8.5 Hz).
Oral or intraperitoneal administration of 5,6-dihydro-4-methyl-5-(4-nitrophenyl)-3-phenyl-4H- 1,2,4-thiadiazine 1,1-dioxide to the mouse produced non-specific CNS depression. 5,6-Dihydro-4-methyl-5-(4-nitrophenyl)-3-phenyl-4H-1,2,4-thiadiazine 1,1-dioxide was not effective in preventing the phenylquinone writhing syndrome in mice at an oral dose of 100 mg./kg. body weight or subcutaneous dose of 6 mg./kg. body weight.
EXAMPLE 34
Treating N-isopropyl-N'-(3,4-dichlorostyrylsulfonyl)acetamidine with aqueous sodium hydroxide in acetone or dimethylsulfoxide according to the procedure of Example 32 (c) provides N-isopropyl-N-(3,4-dichlorostyryl)acetamidine.
EXAMPLE 35
Treating N-methyl-N'-(3,4-dichlorostyrylsulfonyl)acetamidine with aqueous sodium hydroxide in acetone according to the procedure of Example 32 (c) provides N-methyl-N-(3,4-dichlorostyryl)acetamidine.
EXAMPLE 36
N-(3,4-Dichlorostyrylsulfonyl)propionamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(3,4-DICHLOROSTYRYL)PROPIONAMIDINE HYDROCHLORIDE, m.p. 205.0.degree.-209.0.degree. C., (corr.), in 29% analytical yield by crystallization from isopropyl alcohol-isopropyl ether.
Analysis. Calcd. for C.sub.11 H.sub.12 Cl.sub.2 N.sub.2.HCl (percent): C, 47.25; H, 4.69; N, 10.02. Found (percent): C, 46.98; H, 4.77; N, 9.95.
NMR (DMSO-d.sub.6, TMS): 1.25t (7.5 Hz), 2.60quartet (7.5 Hz), 6.56d (13.9 Hz), 7.51m, 7.92m, 9.9bs, 11.9bs.
EXAMPLE 37
N-(3,4-Dichlorostyrylsulfonyl)butyramidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(3,4-DICHLOROSTYRYL)BUTYRAMIDINE HYDROCHLORIDE, m.p. 222.5.degree.-224.5.degree. C., in 41% analytical yield by crystallization from isopropyl alcohol-isopropyl ether.
Analysis. Calcd. for C.sub.12 H.sub.14 Cl.sub.2 N.sub.2.HCl (percent): C, 49.09; H, 5.15; N, 9.54. Found (percent): C, 48.94; H, 5.08; N, 9.74.
NMR (DMSO-d.sub.6, TMS): 0.93t (7.0 Hz), 1.67m, 2.58m, 6.56d (14.0 Hz), 7.53m, 7.90m, 9.9bs, 11.9bs.
EXAMPLE 38
N-(3,4-Dichlorostyrylsulfonyl)pentanamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(3,4-DICHLOROSTYRYL)PENTANAMIDINE HYDROCHLORIDE, m.p. 218.0.degree.-220.0.degree. C., (corr.), in 52% analytical yield from ethyl acetate.
Analysis. Calcd. for C.sub.13 H.sub.16 Cl.sub.2 N.sub.2.HCl (percent): C, 50.75; H. 5.57; N, 9.10. Found (percent): C, 50.72; H, 5.74; N, 8.96.
NMR (DMSO-d.sub.6, TMS): 0.90t (6.0 Hz), 1.50m, 2.59m, 6.57d (14.0 Hz), 7.53m, 7.95m, 9.9bs, 10.0bs, 12.0bd (10.0 Hz).
EXAMPLE 39
N-(3,4-Dichlorostyrylsulfonyl)-2-methylpropionamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(3,4-DICHLOROSTYRYL)-2-METHYLPROPIONAMIDINE HYDROCHLORIDE, m.p. 219.5.degree.-222.degree. C. (corr.), in 44% analytical yield by crystallization from acetone.
Analysis. Calcd. for C.sub.12 H.sub.12 Cl.sub.2 N.sub.2.HCl (percent): C, 49.09; H, 5.15; N, 9.54. Found (percent): C, 49.09; H, 5.14; N, 9.50.
NMR (DMSO-d.sub.6, TMS): 1.27d (7.0 Hz), 3.01septet (7.0 Hz), 6.61d (13.9 Hz), 7.61m, 7.90m, 9.7bs, 10.0bs, 11.8bs.
EXAMPLE 40
N-(3,4-Dichlorostyrylsulfonyl)-3-methylbutyramidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(3,4-DICHLOROSTYRYL)-3-METHYLBUTYRAMIDINE HYDROCHLORIDE, m.p. 218.0.degree.-220.0.degree. C. (corr.), in 55% analytical yield from ethyl acetate-methanol.
Analysis. Calcd. for C.sub.13 H.sub.16 Cl.sub.2 N.sub.2.HCl (percent): C, 50.75; H, 5.57; N, 9.10. Found (percent): C, 50.50; H, 5.54; N, 9.17.
NMR (DMSO-d.sub.6, TMS): 0.95d (6.2 Hz), 2.10m, 2.48m, 6.58d (14.0 Hz), 7.55m, 7.97m, 10.3bs, 12.2bs.
EXAMPLE 41
N-(3,4-Dichlorostyrylsulfonyl)-2,2-dimethylpropionamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(3,4-DICHLOROSTYRYL)-2,2-DIMETHYLPROPIONAMIDINE HYDROCHLORIDE, m.p. 246.5.degree.-248.5.degree. C. (dec.)(corr.) in 35% analytical yield, by crystallization from ethyl acetate-methanol.
Analysis. Calcd. for C.sub.13 H.sub.16 Cl.sub.2 N.sub.2.HCl (percent): C, 50.75; H, 5.57; N, 9.10. Found (percent): C, 50.65; H, 5.37; N, 9.07.
NMR (DMSO-d.sub.6, TMS): 1.37s, 6.90d (13.6 Hz), 7.53m, 7.93m, 9.8bs.
EXAMPLE 42
N-(3,4-Dichlorostyrylsulfonyl)cyclopropanecarboxamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(3,4-DICHLOROSTYRYL)CYCLOPROPANECARBOXAMIDINE HYDROCHLORIDE, m.p. 214.0.degree.-216.0.degree. C. (corr.), in 65% analytical yield by crystallization from ethyl acetate.
Analysis. Calcd. for C.sub.12 H.sub.12 Cl.sub.2 N.sub.2.HCl (percent): C, 49.43; H, 4.49; N, 9.61. Found (percent): C, 49.20; H, 4.43; N, 9.34.
NMR (DMSO-d.sub.6, TMS): 1.25m, 2.09m, 6.58d (14.0 Hz), 7.52 m, 7.90m, 9.2bs, 9.7bs, 11.9bd (10.0 Hz).
EXAMPLE 43
N-(2,6-Dichlorostyrylsulfonyl)propionamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(2,6-DICHLOROSTYRYL)PROPIONAMIDINE HYDROCHLORIDE, m.p. 222.degree.-227.degree. C., (corr.) in 29% analytical yield by crystallization from isopropyl alcohol-isopropyl ether.
Analysis. Calcd. for C.sub.11 H.sub.12 Cl.sub.2 N.sub.2.HCl (percent): C, 47.25; H, 4.69; N, 10.02. Found (percent): C, 47.18; H, 4.74; N, 10.06.
NMR (DMSO-d.sub.6, TMS): 1.28t (7.4 Hz), 2.64quartet (7.4 Hz), 6.71d (14.0 Hz), 7.44m, 9.9bs, 12.2bs.
EXAMPLE 44
N-(2,6-Dichlorostyrylsulfonyl)butyramidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(2,6-DICHLOROSTYRYL)BUTYRAMIDINE HYDROCHLORIDE, m.p. 195.5.degree.-198.5.degree. C., (corr.) in 43% analytical yield by crystallization from isopropyl alcohol-isopropyl ether.
Analysis. Calcd. for C.sub.12 H.sub.14 Cl.sub.2 N.sub.2.HCl (percent): C, 49.09; H, 5.15; N, 9.54. Found (percent): C, 48.78; H, 5.34; N, 9.62.
NMR (DMSO-d.sub.6, TMS): 0.94t (6.8 Hz), 1.71m, 2.59m, 6.69d (14.0 Hz), 7.41m, 7.47d (14.0 Hz), 9.8bs.
EXAMPLE 45
Treatment of N-(2,6-dichlorostyrylsulfonyl)-2-methylpropionamidine with sodium hydroxide according to the procedure of Example 1 provides N-(2,6-DICHLOROSTYRYL)-2-METHYLPROPIONAMIDINE HYDROCHLORIDE, m.p. 210.5.degree.-213.5.degree. C. (corr.), in 38% analytical yield by crystallization from ethyl acetate-methanol.
Analysis. Calcd. for C.sub.12 H.sub.14 Cl.sub.2 N.sub.2.HCl (percent): C, 49.09; H, 5.15; L N, 9.54. Found (percent): C, 48.84; H, 5.19; N, 9.29.
NMR (DMSO-d.sub.6, TMS): 1.30d (6.7 Hz), 3.06septet (6.7 Hz), 6.78d (14.1 Hz), 7.42m, 9.7bs, 11.9bs.
EXAMPLE 46
N-(2,6-Dichlorostyrylsulfonyl)-2,2-dimethylpropionamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(2,6-DICHLOROSTYRYL)-2,2-DIMETHYLPROPIONAMIDINE HYDROCHLORIDE, m.p. 207.degree.-210.degree. C. (corr.) in 48% analytical yield by crystallization from ethyl acetate-methanol.
Analysis. Calcd. for C.sub.13 H.sub.16 Cl.sub.2 N.sub.2.HCl (percent): C,50,75; H, 5.57; N, 9.10. Found (percent): C, 50.86; H, 5.77; N, 9.01.
NMR (DMSO-d.sub.6, TMS): 1.39s, 7.06d (13.8 Hz), 7.42m, 7.49d (13.8 Hz), 9.5bs.
EXAMPLE 47
N-(2,6-Dichlorostyrylsulfonyl)cyclopropanecarboxamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(2,6-DICHLOROSTYRYL)CYCLOPROPANECARBOXAMIDINE HYDROCHLORIDE, m.p. 199.5.degree.-201.5.degree. C. (corr.) in 49% analytical yield by crystallization from ethyl acetate-methanol.
Analysis. Calcd. for C.sub.12 H.sub.12 Cl.sub.2 N.sub.2.HCl (percent): C, 49.43; H, 4.49; N, 9.61. Found (percent): C, 49.41; H, 4.57; N, 9.54.
NMR (DMSO-d.sub.6, TMS): 1.27m, 2.18m, 6.70d (14.0 Hz), 7.41m, 9.2bs, 12.0bs.
EXAMPLE 48
N-(2,6-Dichlorostyrylsulfonyl)benzamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(2,6-DICHLOROSTYRYL)BENZAMIDINE HYDROCHLORIDE, m.p. 201.degree.-205.5.degree. C. (corr.), in 49% analytical yield by crystallization from ethyl acetate-methanol.
Analysis. Calcd. for C.sub.15 H.sub.12 Cl.sub.2 N.sub.2.HCl (percent): C, 54.99; H, 4.00; N, 8.55. Found (percent): C, 54.93; H, 4.01; N, 8.40.
NMR (DMSO-d.sub.6, TMS): 6.98D (13.8 Hz), 7.64m, 10.0bs.
EXAMPLE 49
N-(2,6-Dichlorostyrylsulfonyl)phenylacetamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(2,6-DICHLOROSTYRYL)PHENYLACETAMIDINE HYDROCHLORIDE, m.p. 207.5.degree.-210.5.degree. C. in 44% analytical yield by crystallization from ethyl acetate-methanol.
Analysis. Calcd. for C.sub.16 H.sub.14 Cl.sub.2 N.sub.2.HCl (percent): C, 56.25; H, 4.43; N, 8.20. Found (percent): C, 55.97; H, 4.46; N, 8.15.
NMR (DMSO-d.sub.6, TMS): 3.99septet, 6.77d (14.2 Hz), 7.45m, 10.0bs.
EXAMPLE 50
N-(2,4-Dichlorostyrylsulfonyl)acetamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(2,4-DICHLOROSTYRYL)ACETAMIDINE HYDROCHLORIDE, m.p. 228.0.degree.-232.0.degree. C. (corr.) in 50% analytical yield.
Analysis. Calcd. for C.sub.10 H.sub.10 Cl.sub.2 N.sub.2. HCl (percent): C, 45.23; H, 4.18; N, 10.55. Found (percent): C, 45.20; H, 4.17; N, 10.44.
NMR (DMSO-d.sub.6, TMS): 2.32s, 6.81d (14.0 Hz), 7.41m, 7.91d (8.1 Hz), 8.03d (14.0 Hz), 10.0bs.
EXAMPLE 51
N-(2-Chlorostyrylsulfonyl)acetamidine treated with sodium hydroxide according to the procedure of Example 1 provides N-(2-CHLOROSTYRYL)ACETAMIDINE HYDROCHLORIDE HYDRATE, m.p. 193.degree. C. (corr.).
Analysis. Calcd. for C.sub.10 H.sub.11 ClN.sub.2.HCl.H.sub.2 O: C,49.64; H, 5.50; N, 11.57; H.sub.2 O, 4.46. Found: C, 49.58; H, 5.49; N, 11.51; H.sub.2 O, 4.42.
EXAMPLE 52
The following 3,4-dichlorostyrylamidine products of Formula I are obtained by treating the enumerated styrylsulfonylamidine precursors with sodium hydroxide in dimethylsulfoxide according to the procedure of Example 1:
(a) N-(3,4-DICHLOROSTYRYL)-3-METHYLBUTYRAMIDINE from N-(3,4-dichlorostyrylsulfonyl)-3-methylbutyramidine,
(b) N-(3,4-DICHLOROSTYRYL)-2,2-DIMETHYLPROPIONAMIDINE from N-(3,4-dichlorostyrylsulfonyl)-2,2-dimethylpropionamidine,
(c) N-(3,4-DICHLOROSTYRYL)HEXANAMIDINE from N-(3,4-dichlorostyrylsulfonyl)hexanamidine,
(d) N-(3,4-DICHLOROSTYRYL)HEPTANAMIDINE from N-(3,4-dichlorostyrylsulfonyl)heptanamidine,
(e) N-(3,4-DICHLOROSTYRYL)-2-METHYLHEXANAMIDINE from N-(3,4-dichlorostyrylsulfonyl)-2-methylhexanamidine,
(f) N-(3,4-DICHLOROSTYRYL)-2,2-DIMETHYLBUTYRAMIDINE from N-(3,4-dichlorostyrylsulfonyl)-2,2-dimethylbutyramidine,
(g) N-(3,4-DICHLOROSTYRYL)CYCLOBUTANECARBOXAMIDINE from N-(3,4-dichlorostyrylsulfonyl)cyclobutanecarboxamidine,
(h) N-(3,4-DICHLOROSTYRYL)CYCLOPENTANECARBOXAMIDINE from N-(3,4-dichlorostyrylsulfonyl)cyclopentanecarboxamidine,
(i) N-(3,4-DICHLOROSTYRYL)CYCLOHEXANECARBOXAMIDINE from N-(3,4-dichlorostyrylsulfonyl)cyclohexanecarboxamidine,
(j) N-METHYL-N-(3,4-DICHLOROSTYRYL)ACETAMIDINE from N-methyl-N'-(3,4-dichlorostyrylsulfonyl)acetamidine.
An alternate method for the preparation of N-methyl-N-(3,4-dichlorostyryl)acetamidine involves the N-methylation of N-(3,4-dichlorostyryl)acetamidine (9.2 g., 0.04 mole) with methyl fluorosulfonate (5.7 g., 0.05 mole) in 50 ml. of dichloromethane. The reaction mixture is basified with 10% sodium hydroxide and the organic layer separated, dried, and concentrated to provide the free base which is taken up in acetone and acidified with ethanolic hydrogen chloride. The product thus obtained is crystallized from ethanol-isopropyl ether to afford analytically pure N-METHYL-N-(3,4-DICHLOROSTYRYL)ACETAMIDINE HYDROCHLORIDE, m.p. 238.degree.-239.degree. C., (dec.)(corr.).
Analysis. Found (percent): C, 47.24; H, 4.77; N, 10.03. NMR (DMSO-d.sub.6, TMS): 2.58s, 3.39s, 6.70d (14.0 Hz), 7.80m, 10.2bs.
EXAMPLE 53
The following styrylamidine products of Formula I are obtained by treating the enumerated styrylsulfonylamidine precursor with sodium hydroxide in dimethylsulfoxide according to the procedure of Example 1:
(a) N-(2-CHLORO-6-METHYLSTYRYL)ACETAMIDINE from N-(2-Chloro-6-methylstyrylsulfonyl)acetamidine,
(b) N-(4-METHYLSULFONYLSTYRYL)ACETAMIDINE from N-(4-methylsulfonylstyrylsulfonyl)acetamidine,
(c) N-(2,6-DITRIFLUOROMETHYLSTYRYL)ACETAMIDINE from N-(2,6-ditrifluoromethylstyrylsulfonyl)acetamidine,
(d) N-(2-TRIFLUOROMETHYLSTYRYL)ACETAMIDINE from N-(2-trifluoromethylstyrylsulfonyl)acetamidine,
(e) N-(2,3,6-TRICHLOROSTYRYL)ACETAMIDINE from N-(2,3,6-trichlorostyrylsulfonyl)acetamidine,
(f) N-CYCLOPROPYL-N-(2,6-DICHLOROSTYRYL)ACETAMIDINE from N-cyclopropyl-N'-(2,6-dichlorostyrylsulfonyl)-acetamidine.
(g) N-CYCLOPROPYL-N-(3,4-DICHLOROSTYRYL)ACETAMIDINE from N-cyclopropyl-N'-(3,4-dichlorostyrylsulfonyl)-acetamidine.
(h) N-METHYL-N-(2,6-DICHLOROSTYRYL)ACETAMIDINE from N-methyl-N'-(2,6-dichlorostyrylsulfonyl)acetamidine.
Methylation of N-(2,6-dichlorostyryl)acetamidine with methyl fluorosulfonate according to the method of Example 52(j) provides an alternate method for preparing N-methyl-N-(2,6-dichlorostyryl)acetamidine. N-Methyl-N-(2,6-dichlorostyryl)acetamidine hydrochloride is obtained analytically pure by crystallization from absolute ethanol-isopropyl ether and has a melting point of 215.degree.-217.degree. C. (dec.)(corr.).
Analysis. Found (percent): C, 47.15; H, 4.67; N, 9.91. NMR (DMSO-d.sub.6, TMS): 2.55s, 3.47s, 6.55d (14.1 Hz), 7.60m, 10.5bs.
EXAMPLE 54
Reaction of the styrylsulfonyl chlorides and amidines enumerated below according to the procedures set forth in Example 29 provides the following styrylsulfonylamidine precursors of styrylamidine products of the instant invention.
(a) N-(2,6-DICHLOROSTYRYLSULFONYL)BENZAMIDINE, m.p. 154.degree.-157.degree. C. (corr.), from 2,6-dichlorostyrylsulfonyl chloride and benzamidine.
Analysis. Calcd. for C.sub.15 H.sub.12 Cl.sub.2 N.sub.2 O.sub.2 S (percent): C, 50.72; H, 3.41; N, 7.88. Found (percent): C, 50.68; H, 3.58; N, 7.72.
(b) N-(2,6-DICHLOROSTYRYLSULFONLY)PHENYLACETAMIDINE, m.p. 183.degree.-185.degree. C. (corr.), from 2,6-dichlorosulfonyl chloride and phenylacetamidine.
Analysis. Calcd. for C.sub.16 H.sub.14 Cl.sub.2 N.sub.2 O.sub.2 S (percent): C, 52.64; H, 3.82; N, 7.59. Found (percent): C, 51.91; H, 3.91; N, 7.45.
(c) N-(2,6-DICHLOROSTYRYLSULFONYL)-2-METHYLPROPIONAMIDINE, m.p. 146.degree.-148.degree. C., from 2,6-dichlorostyrylsulfonyl chloride and 2-methylpropionamidine.
Analysis. Calcd. for C.sub.12 H.sub.14 Cl.sub.2 N.sub.2 O.sub.2 S (percent): C, 44.87; H, 4.39; N, 8.72. Found (percent): C, 44.88; H, 4.38; N, 8.77.
(d) N-(2,6-DICHLOROSTYRYLSULFONYL)BUTYRAMIDINE, m.p. 155.degree.-157.degree. C., from 2,6-dichlorostyrylsulfonyl chloride and butyramidine.
Analysis. Calcd. for C.sub.12 H.sub.14 Cl.sub.2 N.sub.2 O.sub.2 S (percent): C, 44.87; H, 4.39; N, 8.72. Found (percent): C, 44.77; H, 4.37; N, 8.78.
(e) N-(2,6-DICHLOROSTYRYLSULFONYL)-2,2-DIMETHYLPROPIONAMIDINE, m.p. 160.degree.-162.degree. C., from 2,6-dichlorostyrylsulfonyl chloride and 2,2-dimethylpropionamidine.
Analysis. Calcd. for C.sub.13 H.sub.16 Cl.sub.2 N.sub.2 O.sub.2 S (percent): C, 46.57; H, 4.81; N, 8.35. Found (percent): C, 46.37; H, 4.79; N, 8.23.
(f) N-(2,6-DICHLOROSTYRYLSULFONYL)CYCLOPROPANECARBOXAMIDINE, m.p. 176.degree.-179.degree. C., from 2,6-dichlorostyrylsulfonyl chloride and cyclopropanecarboxamidine.
(g) N-(2,6-DICHLOROSTYRYLSULFONYL)PROPIONAMIDINE from 2,6-dichlorostyrylsulfonyl chloride and propionamidine.
(h) N-(3,4-DICHLOROSTYRYLSULFONYL)-2-METHYLPROPIONAMIDINE, m.p. 177.degree.-180.degree. C., from 3,4-dichlorostyrylsulfonyl chloride and 2-methylpropionamidine.
(i) N-(3,4-DICHLOROSTYRYLSULFONYL)BUTYRAMIDINE, m.p. 140.degree.-145.degree. C., from 3,4-dichlorostyrylsulfonyl chloride and butyramidine.
(j) N-(3,4-DICHLOROSTYRYLSULFONYL)-2,2-DIMETHYLPROPIONAMIDINE, m.p. 135.degree.-137.degree. C., from 3,4-dichlorostyrylsulfonyl chloride and 2,2-dimethylpropionamidine.
(k) N-(3,4-DICHLOROSTYRYLSULFONYL)CYCLOPROPANECARBOXAMIDINE, m.p. 208.degree.-213.degree. C., from 3,4-dichlorostyrylsulfonyl chloride and cyclopropanecarboxamidine.
(l) N-(3,4-DICHLOROSTYRYLSULFONYL)PROPIONAMIDINE, m.p. 194.degree.-197.degree. C., from 3,4-dichlorostyrylsulfonyl chloride and propionamidine.
(m) N-(3,4-DICHLOROSTYRYLSULFONYL)PENTANEAMIDINE, m.p. 135.degree.-140.degree. C., from 3,4-dichlorostyrylsulfonyl chloride and pentanamidine.
(n) N-(3,4-DICHLOROSTYRYLSULFONYL)-3-METHYLBUTYRAMIDINE, m.p. 184.degree.-186.degree. C., from 3,4-dichlorostyrylsulfonyl chloride and 3-methylbutyramidine.
(o) N-(2,4-DICHLOROSTYRYLSULFONYL)ACETAMIDINE, m.p. 216.degree.-219.degree. C., from 2,4-dichlorostyrylsulfonyl chloride and acetamidine.
(p) N-(2-CHLOROSTYRYLSULFONYL)ACETAMIDINE, m.p. 161.degree.-165.degree. C. from 2-chlorostyrylsulfonyl chloride and acetamidine.
(q) N-(2-CHLORO-6-METHYLSTYRYLSULFONYL)ACETAMIDINE from 2-chloro-6-methylstylrylsulfonyl chloride and acetamidine.
(r) N-(2,3,6-TRICHLOROSTYRYLSULFONYL)ACETAMIDINE from 2,3,6-trichlorostyrylsulfonyl chloride and acetamidine.
EXAMPLE 55
Reaction of Cyclopropylamine with N-(2,6-dichlorostyrylsulfonyl)chloroacetimidate according to the procedure of Example 32(b) affords N-cyclopropyl-N'-(2,6-dichlorostyrylsulfonyl) acetamidine, m.p. 121.degree.-124.degree. C. when crystallized from benzene.
The corresponding N-cyclopropyl-N'-(3,4-dichlorostyrylsulfonyl)acetamidine is obtained in a similar fashion by reaction of cyclopropylamine with N-(3,4-dichlorostyrylsulfonyl)chloroacetimidate.
EXAMPLE 56
Oral Administration of Representative Styryl-Amidines
The styrylamidine is orally administered to each rabbit in a group of 2-6 rabbits at a single dose of 25 mg./kg. body weight. A 8 ml. portion of blood is drawn just prior to dosing in order to obtain a control value and at various time periods thereafter. Platelet rich plasma is prepared from each blood sample by centrifugation at 200 times gravity for 10 min. at room temperature. Samples (0.5 ml.) of platelet rich plasma are tested for their ability to aggregate with either collagen or adenosine-5'-diphosphate added as specified in the modification of Born and O'Brien method which has been fully described hereinbefore. The results shown below indicate the inhibition of blood platelet aggregation induced by the lowest amount of collagen giving maximal aggregation or 0.25-1.0 microgram adenosine-5'-diphosphate for representative amidines.
Claims
What is claimed is:
1. A method for preventing aggregation of blood platelets in a mammal having a thromboembolic condition which comprises administering to said mammal an antithrombogenic effective dose of a styrylamidine or a salt thereof of a pharmaceutically acceptable acid to provide a blood level of from 0.5 to 90 mcg. of said styrylamidine per 0.5 ml. blood, said styrylamidine being selected from the group consisting of the compounds having the formula ##STR9## wherein R.sub.1 is selected from lower alkyl of 1 to 4 carbon atoms inclusive, hydrogen, nitro, amino, halogen, cyclohexyl, carbamoyl, lower alkylsulfonyl from 1 to 4 carbon atoms inclusive, sulfamoyl or lower alkanoylamido of from 2 to 4 carbon atoms inclusive; R.sub.2 is selected from hydrogen or halogen with the proviso that when R.sub.1 is halogen, R.sub.2 can represent up to two additional halogen; R.sub.3 is hydrogen, cyclopropyl or lower alkyl of 1 to 4 carbon atoms inclusive; A is selected from lower alkyl of from 1 to 8 carbon atoms inclusive, di(lower)alkylaminophenyl, phenyl, benzyl, .beta.-naphthyl, styryl, phenylbutadienyl, cycloalkyl of 3 to 6 carbon atoms inclusive, or a substituted phenyl radical represented by the symbol ##STR10## wherein X is selected from (lower) alkoxy from 1 to 4 carbon atoms inclusive, halogen, nitro, amino, lower alkanoylamido of from 2 to 4 carbon atoms inclusive, and n represents the integer 1 or 2.
2. The method as claimed in claim 1 employing N-(3,4-dichlorostyryl)acetamidine or a salt thereof of a pharmaceutically acceptable acid.
3. The method as claimed in claim 1 employing N-(3,4-dichlorostyryl)cyclopropanecarboxamidine or a salt thereof of a pharmaceutically acceptable acid.
4. A method of producing an antihypertensive effect comprising systemic administration to a mammal in need thereof an effective dose of a styrylamidine of from about 0.01 to 100 mg./kg. body weight of said mammal to provide an antihypertensive effect, said styrylamidine selected from the group consisting of N-(2,6-dichlorostyryl)acetamidine, N-2,6-dichlorostyryl)propionamidine, N-(2,6-dichlorostyryl)cyclopropanecarboxamidine and N-methyl-N-(2,6-dichlorostyryl)acetamidine.
5. An antithrombogenic or an antihypertensive composition in dosage unit form comprising a pharmaceutical carrier and a compound selected from the group consisting of styrylamidines having the formula ##STR11## and a salt thereof of a pharmaceutically acceptable acid wherein R.sub.1 is selected from lower alkyl of 1 to 4 carbon atoms inclusive, hydrogen, nitro, amino, halogen, cyclohexyl, carbamoyl, lower alkylsulfonyl from 1 to 4 carbon atoms inclusive, sulfamoyl or lower alkanoylamido of from 2 to 4 carbon atoms inclusive; R.sub.2 is hydrogen or halogen with the proviso that when R.sub.1 is halogen, R.sub.2 can represent up to two additional halogen; R.sub.3 is hydrogen, cyclopropyl or lower alkyl of 1 to 4 carbon atoms inclusive; A is selected from lower alkyl of from 1 to 8 carbon atoms inclusive, di(lower)alkylaminophenyl, phenyl, benzyl, .beta.-naphthyl, styryl, phenylbutadienyl, cycloalkyl of 3 to 5 carbon atoms inclusive, or a substituted phenyl radical represented by the symbol ##STR12## wherein X is selected from (lower)alkoxy from 1 to b 4 carbon atoms inclusive, halogen, nitro, amino, lower alkanoylamido of from 2 to 4 carbon atoms inclusive, and n represents the integer 1 or 2.
6. The composition of claim 5 in which the active ingredient is N-(3,4-dichlorostyryl)cyclopropanecarboxamidine or a pharmaceutically acceptable acid addition salt thereof.
7. The composition of claim 5 in which the active ingredient is N-(3,4-dichlorostyryl)acetamidine or a pharmaceutically acceptable acid addition salt thereof.
8. The composition of claim 5 in which the active ingredient is N-(2,6-dichlorostyryl)acetamidine or a pharmaceutically acceptable acid addition salt thereof.
9. The composition of claim 5 in which the active ingredient is N-(2,3,6-trichlorostyryl)acetamidine or a pharmaceutically acceptable acid addition salt thereof.
10. The composition of claim 5 in which the active ingredient is N-(2-chloro-6-methylstyryl)acetamidine or a pharmaceutically acceptable acid addition salt thereof.
Patent Citations (1)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3413345 | 1968-11-01 | Mull |
Non-Patent Literature (2)
- Matier et al., "Formation of 5-aryl-1,2,4-thiadiazine-1,1-dioxides and Strylamidines from Strylsulfonylamidines," 4th Int'n Congress of Heterocyclic Chemistry, Salt Lake City, Utah (Jul. 1973).
- Madison & Boyd, "Organic Chemistry," pp. 111-112, 526-534 (1962).