Patent Publication Number: US-3878206-A

Title: 9-(Substituted amino)imidazo{8 4,5-f{9 quinolines

Description:
United States Patent [191 Spencer et al.  
 [4 1 Apr. 15, 1975 9-( SUBSTITUTED AMINO)IMIDAZO[4,5-f]QUINOLINES [75] Inventors: Claude F. Spencer; Harry R.  
 Snyder, Jr., both of Norwich, NY.  
 [73] Assignee: Morton-Norwich Products, Inc., Norwich, NY.  
 [22] Filed: June 6, 1973 [21] Appl. No.2 367,498  
 [52] US. Cl. 260/247.5 EP; 260/288 R [51] Int. Cl C07d 33/52 [58] Field of Search 260/2475 EP, 288 R [56] References Cited OTHER PUBLICATIONS lshiwata et al., Chem. Pharm. Bull., 2455-2460 (1969).  
 Primary Examiner-Lorraine A. Weinberger Assistant ExaminerRichard D. Kelly Attorney, Agent, or Firm-Anthony J. Franze 571 I I ABSTRACT 22 Claims, N0 Drawings 1 9-(SUBSTITUTED AMINO)IMIDAZO[4,5-flQUINOLINES This invention is concerned with a series of 9- (substituted amino) imidazol4,5-f]quinolines of the formula:  
 wherein R is 4-ethylphenyl, 4-( 2-hydroxyethyl)phenyl, 4-n-dodecylpheny1, 9-anthryl, 4-chlorophenyl, 4- fluorophenyl, 3-chlorophenyl, 4-acetylaminophenyl, 4-(N-methylacetylamino)phenyl, 4- (methylamino)phenyl, 4-aminophenyl, 4- morpholinophenyl, 4-pyrrolidinophenyl, 4-[N-methyl- N-(2-hydroxyethyl)amino1phenyl,  
 morpholinophenyl, 4-hydroxyphenyl, 3- hydroxyphenyl, 3-chloro-4-hydroxyphenyl, &#39;4-carbethoxyphenyl, 4-benzoylphenyl, or 2-methoxy-5- acctylphenyl.  
  The compounds of this invention are prepared in accordance with methods described in the following examples. They are usually obtained in the form of hydrochloride salts.  
 EXAMPLE l 9-(p-Ethylanilin0 )-7-methyll H-imidazo[4,5- f]quinoline Hydrochloride A. Ethyl 3-(S-Benzimidazolylamino)crotonate An 82-g (0.5 mole) sampel of 5-nitrobenzimidazole in 900 ml of ethanol was reduced over 4 g of 5 percent Pd/C catalyst containing 50 percent H O. After filtration of the catalyst, 65 g (0.5 mole) of ethyl acetoacetate, g of anhydrous calcium sulfate, and 0.5 ml of HOAc was added. After filtration, the solution was concentrated in vacuo-till a solid remained. The product was filtered and washed with fresh ethanol and airdried. The yield was 84 g (69 percent), m.p. 160-l62C. B. 7-Methyl-9-imidazo[4,5-f]quinolinol 40 g of A. was added to 80 ml of boiling Dowtherm and the boiling was continued for 5 minutes. The product separated upon cooling. The product was filtered, washed with Dowtherm and then acetone and airdried. The yield was 29 g (91 percent), m.p. 345-347C. C. 9-Chloro-7-methylimidazo[4,5-f]quinoline Into a 22-1, 4-necked flask set in a tub and equipped with a stirrer, an air condenser (drying tube), thermometer, and dropping funnel was placed POCl (4590 ml). B (1062 g, 5.33 moles) was added wtih no heating effect noted. Dimethylformamide (4690 ml) was added dropwise over a 2 /2 hr period at a rate to control the temperature below 85. The resulting viscous solution was allowed to stand overnight at room temperature and then added cautiously to ice to a total volume of ca. 50 l. The resulting solution was then adjusted to a 3-chloro-4- pH of 7 to 8 by the addition of NaOHO pellets (9771 g). More ice was added as needed to keep the temperature below 45. The resulting precipitate was collected by filtration, washed well by stirring in water (3 X 20 l) and dried at 60 to yield 1107 g (95.5 percent). D. 9-(p-Ethylanilino)-7-methyl-1H-imidazo[4,5- f]quinoline Hydrochloride A 500 ml, 3-neck, r.b. flask fitted with stirrer, condenser and thermometer was charged with C. (21.7 g, 0.1 mole), p-ethylaniline (12.1 g, 0.1 mole) and ethanol (200 ml).-,The mixture was stirred and refluxed overnight. The reaction solution was concentrated to dryness by rotary evaporator. The residue was collected and dried at C to yield 34.8 g (103 percent) tan crystals, m.p. 328-335C. The crude material (29.3 g) was recrystallized from isopropanol (ca 1000 ml), treated with charcoal and filtered while hot. The filtrate was chilled and the crystals were collected by filtration and dried at 100C to yield 17.7 g light yellow crystals, m.p. 327-331C.  
 Anal. Calcd. for C,,,H,,,N ,.HC|: C, 67.3  
 Found: C, 66.92,  
 EXAMPLE ll 9-[p-(2-l-l-ydroxyethyl)ani1ino]-7-methyl-1H- imidazo[4,5-f]-quinoline Hydrochloride Calcd. for C,,,H,,,N O.HCl: C. 6 5.40: 9 .36; .64  
  4.31. H. Found: C. 63.76; H, 5  
 EXAMPLE lll 9-(p-Dodecylanilino )-7-methyll H-imidazo 4,5- f]quinoline Hydrochloride Tetartohydrate A 500 ml, 3-neck, r.b. flask fitted with condenser, stirrer and thermometer was charged with the compound of Example I,- C. (21.7 g, 0.1 mole), pdodecylaniline (26.1 g, 0.1 mole) and ethanol (300 ml) and the mixture was stirred overnight while heating at reflux. The reaction solution was treated with charcoal and filtered while hot. The filtrate was concentrated to dryness by rotary evaporator and the residue was collected and dried to yield 38.6 g (80.6 percent) brown crystals, m.p. 188l95C. A small sample (2.0 g) was dissolved in DMF (50 ml), treated .with charcoal and filtered while hot and then cooled. The crystals were collected by filtration and dried at 100C to yield 0.9 g, m.p. 2132l6C. Another recrystallization gave m.p. 2l6-220C.  
 Anal. Calcd. for C H N HCI V4H O: C, 72.0  
 Found: C, 72.05;  
 EXAMPLE [V 9-[(9-Anthryl)amino]-7-methyll H-imidazo[4,5- f]quinoline Preparation of 9-aminoanthracene:  
  A mixture of 9-nitroanthracene (22.3 g, 0.1 mole) and dimethylformamide (200 ml) was shaken with hydrogen over /2 teaspoon Raney active nickel catalyst in water. A hydrogen uptake of 26 psi. was recorded (calcd. 25.9 pail). The catalyst was removed by filtration and the fluorescent filtrate was used in part B.  
 B. Preparation of 9-(aminoanthraceno)-7-methyl-1H- imidazo[4,5-f]quinoline A mixture of the compound of Example I, C. (16 g,  
 EXAMPLE VI 9-( p-Fluoroanilino )-7-methyll H-imidazo[4,5- f]quinoline hydrochloride Anal. Calcd. for C H,;,FN ,.HCl: C.  
  N I Found: C. N. 17.15; Cl. 10.84  
 0.0736 mole) and the filtrate from part A plus an additional 100 ml dimethylformamide was stirred overnight while heating at reflux. The solution was concentrated to about 130 ml by rotary evaporator. The solution was heated, treated with charcoal and filtered while hot. Ether (ca 400 ml) was slowly added to the filtrate and the soluton was chilled. After standing in the ice bath, the crystals which formed which were collected by filtration and dried at 60C to yield 22.2 g (73.5 percent). The 22.2 g was dissolved in methanol (800 ml), treated with charcoal and filtered while hot. The filtrate was concentrated to 350 ml by rotary evaporator and chilled. The crystals were collected by filtration and dired at 60C to yield 6.3 g tan crystals, m.p. 194-204C.  
 Anal. Calcd. for C H Na C. 80. 9; H. 4.  
 Found: C. 78. 3; H, 4  
 EXAMPLE V 9-(4-Chloroanilino)-7-methyl-1H-imidazol[4,5- flquinoline Hydrochloride Hydrate A solution of the compound of Example I, C. (44 g.,  
 Calcd. for C H N CLHCLH O: C, Found: C.  
 Anal. Calcd. for C H N ,O.HCl: C, 62.04; H,  
 EXAMPLE Vll 9-(3-Chloroanilino)-7-methyl-1H-imidazo[4,5- f]quinoline Hydrochloride A 500 ml, 3-neck, r.b. flask fitted with stirrer, con- I denser and thermometer was charged with a mixture of the compound of Example I, C. (21.7 g, 0.1 mole) and p-chloroaniline (12.7 g, 0.1 mole) in dimethylformamide (200 ml). The mixture was stirred while heating at steam bath temperature overnight. The mixture was concentrated to dryness by rotary evaporator. The residue was collected and dried at C to yield 30.4 g (88 percent) yellow-brown crystals, m.p. 339345C. A 10 g sample was recrystallized from anhydrous methanaol (275 ml), treated with charcoal and filtered while hot. The filtrate was chilled and the crystals were collected by filtration and dried at 100C to yield 5.5 g yellow crystals, m.p. 347355C. Another recrystallization gave m.p. 35 l-353C.  
 EXAMPLE VIII 9-( p-Acetamidoanilino )-&#39;7-rnethyll H-imidazo 4,5- f]quinoline hydrochloride A mixture of 40 g (0.184 m) of the compound of Example I, C., 27.7 g (0.184 m) of p-aminoacetanilide and 500 ml of ethanol was stirred and refluxed overnight. The solution was concentrated in vacuo to give 51 g of crude product. It was then recrystallized from 3,000 ml of MeOH, with charcoal to give 42 g, m.p. 384-387C, with decomposition. A second recrystallization from MeOH, with charcoal, gave m.p. 38 l-384C, with decomposition.  
  4.93; N, 19.04; Cl, 9.64 Found: C. 6 4.69; N, 19.06; Cl, 9.51  
  6 EXAMPLE IX room temperature. The product was filtered, washed 9-lp-(N-Methylacetamido)anilinol-7-methyl-lH- with ethanol and air-dried to give 12 g of material. Reimidazol4,5-f]quinoline Hydrochloride Sesquihydrate crystallization from 500 ml of water gave 7.5 g of pale A N Methy[Amitroacetanilide yellow needles which darken slowly above ca 350.  
 To 500 ml of acetic anhydride was addedportionwise, 100 g (0.658) of N-methyl-p-nitroaniline. Following the addition, the solution was heated on a-steam Anal. Calcd. for C ;H N HCl. /2H- OI C. 60 bath for 2 hrs, then stirred overnight at room tempera- Found: 91  
 zure. The white precipitate was collected by filtration, washed with ether and air-dried to give 53 g, m.p. 153-156C. The filtrate was concentrated in vacuo to EXAMPLE X give another 61 g, m.p. 150-154C. B. Q-[p-(N-methylacetamido)anilinol-7-methyl-l-H- imidazo[4,5-flquinoline Hydrochloride Sesquihydrate A mixture of 114 g (0.587 m) of N-methyl-4- l. 4-M0rpholinonitrobenzene (34 g, 0.163 mole) and nitroacetanilide (part A) and 800 ml of ethanol was ethanol (200 ml) were placed in a 500 ml reduction shaken with hydrogen over one teaspoon of Raney acbottle. The compound was reduced with hydrogen over tive nickel catalyst in water. A pressure drop of 127 psi one-half teaspoon of Raney active nickel catalyst in wawas d d lm, 1 18 i) Th t l t was 20 ter. A hydrogen uptake of 40 psi was recorded (calcd. moved by filtration and the ethanol filtrate refluxed 4 P The aly t a m d by filtration. overnight with 127 g (0.587 m) of the compound of Ex- 2. A 500 ml, 3-neck, r.b. flask fitted with stirrer, conample l, C. The mixture was chilled, filtered, washed denser nd th rm m t r was Charged with the comwith ether and air-dried to give 115 g, m,p pound Of Example I, C. (35.4 g, 0163 mole). The 315 318C, Th Crude d t was t lli d above filtrate (l) was added and the mixture stirred from 4,000 ml of MeOH, with charcoal to yield 75.5 g, and refluxed overnight. The reaction mixture was con- 9-(4-Morpholinoanilino)-7-methyl-1H-imidazo[4,5- f]quinoline Hydrochloride 315 3 17C centrated to dryness by rotary evaporator and the resi- Anal. Calcd. for C ,,H ,N,,O.HC1.l&#39;/2H O: c, 58.75; H, 5.69; N. 17.13; C1. 8.67 Found: C. 58.97; H 5 32&#39; N 17.33; Cl, 9.27  
 EXAMPLE X due was collected and dried to yield 63.9 g (99.5%)  
 7-Meth l-9-( th l mino ili 1H-i id z [4,5- dark green crystals, m.p. 364-374C. A small sample f]quinoline Dihydrochloride Monohydrate g) Was dissolved in anhydrous methanol 35 treated with charcoal and filtered while hot. Ether (ca 1,000 ml) was added until the filtrate became turbid and the mixture was chilled. The crystals were collected by filtration and dried at 100C to yield 7.6 g green crystals, m.p. 346352C. A second recrystallization gave m.p. 351353C.  
  A solution of 30 g of the compound of Example IX, in 450 ml of conc. HCl was heated under reflux for 4 hr and allowed to cool. The bright yellow crystals which separated were filtered, washed with HCl, airdried briefly and then suspended in 300 ml of methanol and heated on the steam bath for a few minutes, during which time the yellow color disappeared. The product was filtered, washed with methanol and air dried to give 26 g as white needles which gradually decomposed in a melting point capillary to a dark, semi-liquid mass at Calcd&#39; for g g i g: 23%;; :1: 2:28; E: H12; 335.  
 Anal. Calcd. for C,,.H N,,.2HCLH O: C, 54.83; H, 5.37; N, 17.76;Cl, 17.98 Found: C, 55.37; H. 5 25; N. 17.71; Cl, 18.31  
 EXAMPLE XI EXAMPLE XIII 9-(p-Aminoanilino)-7-methyl-1H-imidazo[4,5- 9-(4-Pyrro1idinoanilino)-7-methyl-1H-imidazo[4,5-  
 f]quinoline Hydrochloride f]quinoline Hydrochloride A solution of 20 g of the compound of Example VIII 5S 1. Pyrrolidino-4-nitrobenzene (27.4 g, 0.143 mole) in 300 ml Of conc. HCl was heated under reflux for 30 and ethanol (200 ml) were placed in a 500 ml reducmin. A clear yellow solution formed after about 15 min; tion bottle. The compound was reduced with hydrogen in another 5 min crystals began to separate. After coolover one teaspoon of Raney active nickel catalyst in ing the product was filtered, washed with HCl, then water. A hydrogen uptake Of &#39;33 psi was recorded with methanol and air-dried to give 20 g of yellow crys- (calcd. 42.3 psi). The catalyst was removed by filtratals containing a variable amount of HCl after drying in {i n vacuo. It was therefore converted to the monohydro-- 2. A 500 ml, 3-neck, r.b. flask fitted with stirrer, conchloride by the following procedure. a solution of the denser and thermometer was charged with the commaterial in 200 ml of water was made alkaline with pound of Example I, C. (31.1 g, 0.143 mole). The 4 The yellow precipiate was filtered, Washed above filtrate (l) was added and the mixture was with water and suspended in 300 ml of&#39;wate&#39;r. One stirred and refluxed overnight. The reaction mixture equivalent (4.2 m1) of HCl was added and the mixture was concentrated to dryness by rotary evaporator and was heated on the steam bath, then kept overnight at the residue was collected and dried at C to yield 50.6 g (93.5 percent) tan crystals. m.p. 378382C. A portion g) of the crude material was dissolved in anhydrous methanol (1300 ml) treated with charcoal and filtered while hot. The filtrate was concentrated by rotary evaporator to about volume and then warmed. Ether was added to the warm solution until it became turbid and the mixture was then chilled. The crystals were collected by filtration and dried to yield 7.7 g yellow-brown crystals. m.p. 361373C.  
 Anal. Calcd. for C H- N HCI: C. 66.39; H. 5.  
  84; Found: C. 65.98; H. 5.85;  
 EXAMPLE XIV A. N-(2-Hydroxyethy1)-N-methyl-4-nitroaniline A 500 ml, 3-neck, r.b. flask fitted with condenser, stirrer and thermometer was charged with pnitrochlorobenzene (39.3 g, 0.25 mole) and N- methylethanolamine (37.5 g, 0.5 mole) and the mixture was heated at 160170C for 3 hr. The reaction mixture was diluted with water (ca 200 ml) and stirred thoroughly. The solid was collected by filtration and recrystallized from ethanol (200 ml treated with charcoal and filtered while hot. The filtrate was chilled and the crystals were collected by filtration and dried to yield 27 g brown crystals, m.p. 94-97C. A small sample (2.0 g) was again recrystallized from ethanol ml), chilled, collected and dried to yield 1.1 g yellow crystals, m.p. 97-99C.  
 Anal. Calcd. for C H,. ,N C C 55.09; H,  
 Found: C. 55.07;  
 B. Preparation of title compound:  
  1. The compound of A. (23.2 g, 0.119 mole) and ethanol (200 ml) were placed in a 500 ml reduction bottle. The compound was reduced with hydrogen over one teaspoon of Raney active nickel catalyst in water and the catalyst was removed by filtration.  
  2. A 500 ml, 3-neck, r.b. flask fitted with stirrer, condenser and thermometer was charged with the compound of Example 1, C. (25.8 g, 0.119 mole). The above filtrate 1. was added and the mixture was stirred and refluxed overnight. The reaction mixture was concentrated to dryness by rotary evaporator and the residue was collected and dried at 100C to yield 49.1 g (107.2 percent) yellow green crystals, m.p. 299303C. A portion (10 g) of the material was dissolved in methanol (200 ml), treated with charcoal and filtered while hot. Ether was added until the filtrate became turbid and was then chilled. The crystals were collected by filtration and dried at 100C to yield 6.7 g dark green crystals, m.p. 300-304C.  
 Anal. Calcd. for C H N -,O.HCl b HCI: C, 61.13; Found: C, 61.48;  
 LII  
 Anal. Calcd. for C H N QHCIJ/ H O: C. 60.81  
 EXAMPLE xv 9-(4-Morpholino-3-chloroanilino)-7-methyl-1H- imidazo[4,5-f]quinoline Hydrochloride Trihydrate A. 3-Chloro-4-morpholinoaniline Z-Chloro-l-morpholino-4-nitrobenzene (19.5 g, 0.0806 mole) was placed in a 500 ml reduction bottle with ethanol (200 ml). The mixture was shaken with hydrogen over /2 teaspoon of Raney active nickel catalyst in water. A hydrogen uptake of 19 psi was recorded (calcd. 20.9 psi). The catalyst was removed by filtration and the filtrate was concentrated to ml by rotary evaporator and chilled. The crystals were collected by filtration and dried at 60C to yield 10.8 g off white crystals, m.p. 9397C. The filtrate was further concentrated to about 10 ml and chilled. The second crop was collected and dried at 60C to yield 3.2 g gray crystals, m.p. 9293C. Total yield 14 g (81.8 percent).  
 Anal. Calcd. for C ,H,;,ClN O: C. 56.47; H. 6.16; Found: C.&#39;56.43: H. 6.05:  
 B. Preparation of title compound:  
  A 500 m1, 3-neck, r.b. flask fitted with condenser, stirrer and thermometer was charged with a mixture of 3-chloro-4-morpho1inoaniline (12.9 g, 0.061 mole), the compound of Example 1, C. (13.2 g, 0.061 mole) and dimethylformamaide (300 ml). The mixture was heated at C, with stirring, for about 2 hrs when a yellow solid formed. Heating was stopped and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to dryness by rotary evaporator. The residue was washed with ether, collected by filtration and dried at 100C to yield 26.9 g (100.2 percent) yellow crystals. The crude product was dissolved in methanol (800 ml), treated with charcoal and filtered while hot. Ether was added until the filtrate became turbid and was then chilled. The crystals were collected by filtration and dried at 100C to yield 12.4 g light yellow crystals, melting 320327C (dec).  
  2. Found: C. 52.  
 EXAMPLE XVI 9-(p-Hydroxyanilino)-7-methyl-1H-imidazo[4,5- flquinoline Hydrochloride Hemihydrate A mixture of 33 g (0.15 mole) of the compound of Example I, C. and 15.5 g (0.15 mole) of p-aminophenol in 1.800 ml of ethanol was refluxed for 6 hr. The solvent was removed by evaporation in vacuo to leave a solid residue. The residue was recrystallized from methyl alcohol. The product was collected as tan needles melting at 390 (.dec) in a yield of 24 g (48 percent).  
  ;H. 4.80; Found: C, 60. 5; H, 5.11  
 EXAMPLE XVlI 9-( m-Hydroxyanilino )-7-methyll H-imidazo[4,5- flquinoline hydrochloride A mixture of 29.9 g (0.138 m) of the compound of Example 1, C., g (0.138 m) of m-aminophenol and 200 ml of ethanol was stirred, and refluxed overnight. The solvent was removed by vacuum distillation to give 44 g m.p. 390 with decomposition. The crude product 5 was recrystallized from 5,000 ml of MeOH. The yield after oven-drying (100) was 33 g, m.p. 389391 with decomposition. Recrystallization from MeOH, with charcoal, gave m.p. 396398 with decomposition.  
  l0 EXAMPLE xx1 9-(5 Acetyl 2-methoxyanilino)-7-methyl-1H- imidazo[4,5-f]quinoline hydrochloride Hemihydrate A mixture of 236 g (0.11 m) of the compound of Example 1, C., 18 g (0.04 m) of 3-amino-4- methoxyacetophenone and 200 ml of ethanol was refluxed with stirring overnight. The reaction was chilled,  
 . filtered, washed with ether and air-dried to give 62 g,  
 m.p. 400C.  
 Anal. Calcd. for c,,H,,N,o.1-1c1= 0, Found: C.  
 468 N. 16.97; Cl, 1  
 Anal. Calcd. for  
 EXAMPLE XVIII 9-( 3-Chloro-4-hydroxyanilino )-7-methyll H- imidazo[4,5-f]quinoline Hydrochloride A stirred mixture of the compound of Example 1, C., (22 g, 0.1 mole) and 3-chloro-4-hydroxyaniline (14 g, 0.1 mole) in 200 ml of dimethylformamide was refluxed for 6 hours. The reaction solution was stripped in vacuo to give g (97 percentlof tan solid which when recrystallized from methanol/ether, melted at 387 dec.  
 Anal. Calcd. for c,,H,.,C1N,o.1-1c|. C, 56.52; H, 3.91; N. 15.51 30 Found: C. 56.25; H. 3.91; N, 15.29  
 EXAMPLE XIX 9-(4-Carbethoxyanilino)-7-methyl-1H-imidazo[4,5- 3  
 f]quinoline hydrochloride The compounds of this invention possess antibacterial qualities. They are particularly noteworthy for their ability to inhibit Haemophilus vaginalis, a causative agent of bacterial vaginitis. The table herebelow depicts the ability of these compounds to suppress the growth of that organism as determined using the commonly employed serial dilution technique.  
 Minimum inhibitory concentration:  
 Compound of Example in meg/ml 111 IV V VI VII Vlll IX X Xl Xll Xlll XIV XV XVl XVll XVlll XlX XX XXl To provide a carrier for the compounds of this inven- Anal. Calcd. for C .,H ;N O .HCl: C, 62, H, 4.6 F N, 14.7  
  74; 5.00; 0; ound: C, 62.56; H, 4.88; 5;  
 CI. 9.2 CI. 9.4  
 EXAMPLE XX 9-(p-Benzoylanilino )-7-methyll H-imidazo[4,5-  
 f]quinoline hydrochloride A mixture of 6.51 g of the compound of Example 1, C., 5.92 g of 4-amino-benzophenone and 150 ml of ethanol was refluxed with stirring overnight. It was then concentrated in vacuo to give 1 1.9 g of yellow crystals. The crude product was recrystallized from 200 ml of 6 MeOH, with charcoal, followed by concentration of the filtrate to dryness to yield 11.2 g, m.p. 348-350C, after oven-drying (C).  
 tion various pharmaceutical forms such as sprays, douches, ointments, creams and suppositories can be employed.  
 What is claimed is:  
 l. A compound of the formula:  
 3.51; Cl, 8 3.58; CI, 8  
 Anal. Calcd. for C- H N OHCI: C, 6  
  N, l ound: N, l  
 wherein R is 4-ethylphenyl. 4-(2-hydroxyethyl)phenyl, 4-n-d0decylphenyl, 9-anthryl, 4-chlorophenyl, 4- fluorophenyl. 3-chlorophcnyl 4-acetylaminophenyl, 4-(N-methylacetylamino)phenyl, 4- methylaminophenyl, 4-aminophenyl. 4- morpholinophenyl, 4-pyrrolidinophenyl, 4-[N-methyl- N(-2-hydroxyethyl)amino]phenyl. 3-chloro-4- hydroxyphenyl. 4-carbethoxy phenyl, 3-chloro-4- morpholinophenyl, 4-hydroxyphenyl, 3- hydroxyphenyl, 4-benzoylphenyl, or 2-methoxy-5- acetylphenyl.  
  2. The compound of claim 1 wherein R is 4-- -ethylphenyl.  
  3. The compound of claim 1 wherein R is 4-( 2-hydroxyethyl )phenyl.  
  4. The compound of claim 1 wherein R is 4-ndodecylphenyl.  
  5. The compound of claim 1 wherein R is 9-anthryl. 6. The compound of claim 1 wherein R is 4- chlorophenyl.  
  7. The compound of claim 1 wherein R is 4- fluorophenyl.  
  8. The compound of claim 1 wherein R is 3- chlorophenyl.  
  9. The compound of claim acetylaminophenyl.  
 10. The compound of claim 1 wherein R is 4-N- 1 wherein R is 4- wherein R wherein R wherein R wherein R is 4- hydroxyphenyl.  
  20. The compound of claim 1 wherein R is 4-carbethoxyphenyl.  
  21. The compound of claim 1 wherein R is 4- benzoylphenyl.  
  22. The compound of claim 1 wherein R is 2-methoxy-S-acetylphenyl.