[2-(4-Oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitriles and benzoic acids

Abstract

The present invention relates to [2-(4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile and benzoic acids having the following structural formula: ##STR1## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are hydrogen, lower alkyl, halogen or lower alkoxy, and A is COOH or CN. The compounds of this invention exhibit anti-allergy properties and are indicated in the management of allergic manifestations such as bronchial asthma.

Description

The present invention relates to [2-(4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitriles and benzoic acids having the following structural formula: ##STR2## wherein R.sub.1 to R.sub.8 are hydrogen, lower alkyl, halogen or lower alkoxy, and A is COOH or CN.

In the above definitions for R.sub.1 to R.sub.8, lower alkyl and the lower alkyl portions of lower alkoxy are meant to embrace straight-or branched-chain alkyl radicals of 1-6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, n-amyl, n-hexyl, ethylbutyl, 2,3-dimethylbutyl, and so on. Halogen means chlorine, bromine, iodine and fluorine.

The above compounds exhibit anti-allergy properties in mammals. Thus, in tests conducted according to procedures described in I. Mota, Life Sciences, 7: 465 (1963) and Z. Ovary, O. Bier, Proc. Soc. Exptl. Biol. Med., 81: 584 (1952), they were found to prevent allergic and asthmatic reactions in rats at dosage levels of about 25 mg/kg intraperitoneally. These compounds are, therefore, indicated in the management of bronchial asthma, hay fever and other similar allergic conditions.

The compounds of the present invention can be administered orally and by such compositions as tablets, pills, dispersible powders, capsules, and the like. The active ingredient is mixed with at least one inert pharmaceutical diluent such as lactose, forming granules, using agents such as water or alcohol, and the resulting granules compressed into tablets utilizing standard tabletting procedures.

Liquid pharmaceutically administerable compositions are prepared by dissolving or suspending the active ingredient in a pharmaceutically acceptable carrier such as water or syrup. In addition, the compounds of this invention can be administered by inhalation therapy in which the compound is formulated by standard aerosol technique.

To treat allergic manifestations, the compounds of this invention are typically administered in dosages varying between 10-25 mg per kg of body weight 2 to 3 times daily. The precise dosage regimen can be varied depending on the mode of administration, the condition being treated and the host to whom the administration is being made, by methods well-known to the healing arts.

According to the present invention the above compound I is prepared by treating a compound of the formula: ##STR3## in which R.sub.1 - R.sub.4 have the same meaning as defined above.

Acidic hydrolysis of compounds of Structure I in which A is CN yields those compounds of this invention in which A is carboxy.

As will be obvious to those skilled in the art, the compounds of this invention in which A is carboxy can be readily converted to other derivatives, for example, to the corresponding esters by reacting with an alcohol, e.g., methanol, ethanol, etc., or to salts, by reacting with a base, e.g., sodium, potassium or calcium hydroxide.

Starting compounds of Formula II are prepared in accordance with the description set out in Patent 3,801,664 and starting compounds of Formula III are prepared by the disclosure in H. Fecht, Chem. Ber. 40, 3898 (1907).

To further illustrate the practice of this invention, the following examples are included:

EXAMPLE 1 ##STR4##

4-[2-(6-Methoxy-4H-1-benzopyran-2-yl)ethenyl]benzonitrile

This was prepared by reacting 11.4g of 2'-hydroxy-5'-methoxy-2-(methylsulfinyl)acetophenone with 7.85 g of p-cyanocinnamaldehyde in analogous fashion to 4-[2-(8-methoxy-4-oxo-4H-1-benzopyran-2-yl) ethenyl]benzonitrile. The material was recrystallized from toluene. mp 224.degree.-26.degree.; yield 6.5g (43%); .lambda. max m.mu. (.epsilon.) 224 (20,600), 294 (21,900), 332 (43,500); .nu. max 820 (m), 980 (ms), 1080 (m), 1290 (m), 1580 (m), 1620 (s), 1645 (s), 2240 (m) cm.sup.-.sup.1.

Anal. Calcd. for C.sub.19 H.sub.13 NO.sub.3 : C, 75.24; H, 4.32; N, 4.62. Found: C, 75.17; H, 4.44; N, 4.56.

EXAMPLE 2 ##STR5##

4-[2-(6-Methyl-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile

This was prepared by reacting 6.36 g of 2'-hydroxy-5'-methyl-2-(methylsulfinyl)acetophenone with 6.36 g of p-cyanocinnamaldehyde in analogous fashion to 4-[2-(8-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile. The material was recrystallized from toluene, mp 249.degree.-51.degree.; yield 3.5g (41%) .lambda. max m.mu. (.epsilon.) 219 (19,300); 278 (13,500), 339 (41,000); .nu. max 825 (m), 980 (m), 1235 (m), 1580 (m), 1630 (m), 1670 (s), 2240 (m) cm.sup.-.sup.1.

Anal. Calcd. for C.sub.19 H.sub.13 NO.sub.2 : C, 79.43; H, 4.56; N, 4.88. Found: C, 79.27; H, 4.59; N, 4.94.

EXAMPLE 3 ##STR6##

4-[2-(6-Methyl-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzoic acid

A mixture of 2 g of 4-[2-(6-methyl-4-oxo-4HL- benzopyran-2yl)ethenyl] benzonitrile and 50ml of 50% H.sub.2 SO.sub.4 was refluxed for 1 hr. The mixture was chilled, and the solid filtered, washed with cold H.sub.2 O, and recrystallized from glacial acetic acid, mp 308.degree.-12.degree.; yield 1.5 g (70%); .lambda. max m.mu. (.epsilon.) 271 (10,800), 334 (37,300); .nu. max 770 (ms), 825 (m), 980 (m), 1170 (m), 1225 (s), 1580 (m), 1610 (s), 1710 (ms) cm.sup.-.sup.1.

Anal. Calcd. for C.sub.19 H.sub.14 O.sub.4 : C, 74.45; H, 4.60. Found: C, 74.04; H, 4.66.

EXAMPLE 4 ##STR7##

4-[2-(8-Methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]-benzoic acid

A mixture of 4 g of 4-[(8-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl] benzonitrile and 100ml of 50% sulfuric acid was refluxed for 1 hr. The mixture was chilled, and the solid filtered, washed with cold H.sub.2 O and recrystallized from DMF, mp 298.degree.-300.degree.; yield 3 g (70%); .lambda. max m.mu. (.epsilon.) 211 (18,700), 333 (41,000); .nu. max 740 (m), 800 (m), 1060 (m), 1185 (m), 1650 (s), 1700 (ms) cm.sup.-.sup.1.

Anal. Calcd. for C.sub.19 H.sub.14 O.sub.3 : C, 70.80; H, 4.38. Found: C, 70.73; H, 4.50.

EXAMPLE 5 ##STR8##

4-[2-(8-Methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile

A mixture of 7.85 g of 4-cyanocinnamaldehyde (U.S. Pat. No. 2,993,834), 11.4 g of 2'-hydroxy-3'-methoxy-2-(methylsulfinyl)acetophenone, 250 ml of toluene, and 0.5 ml of piperidine was refluxed for 3 hrs. The mixture was chilled, and the crystalline ppt. filtered, and recrystallized from toluene, mp. 274.degree.-75.degree.; yield 7 g (46%); .lambda. max m.mu. (.epsilon.) 222 (20,600), 328 (42,500); .nu. max 745 (m), 845 (m), 1060 (m), 1275 (m), 1570 (m), 1595 (m), 1655 (ms), 2230 (m) cm.sup.-.sup.1.

Anal. Calcd. for C.sub.19 H.sub.13 NO.sub.3 : C, 75.24; H, 4.32; N, 4.62. Found: C, 75.16; H, 4.50; N, 4.57.

EXAMPLE 6 ##STR9##

4-[2-(6-Methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzoic acid A mixture of 4 g of 4-[2-(6-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl] benzonitrile and 100 ml of 50% sulfuric acid was refluxed for 1 hr. with stirring. The mixture was chilled, and the precipitate washed with cold H.sub.2 O and recrystallized from DMF, mp 293.degree.-97.degree. ; yield 1.5 g (36%); .lambda. max m.mu. (.epsilon.) 224 (18,800), 293 (17,200), 340 (42,200); .nu. max 770 (m), 975 (m), 1290 (ms), 1670 (ms), 1650 (ms), 1685 (s) cm.sup.-.sup.1.

Anal. Calcd. for C.sub.19 H.sub.14 O.sub.5 : C, 70.80; H, 4.38. Found: C, 71.08; H, 4.34.

EXAMPLE 7 ##STR10##

4-[2-(6-Bromo-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzoic acid

A mixture of 0.5 g of 4-[2-(6-bromo-4-oxo-4H-1-benzopyran-2-yl)ethenyl] benzonitrile and 10 ml of 50% H.sub.2 SO.sub.4 was refluxed for 1 hr. The mixture was chilled, and the precipitate filtered, washed with cold H.sub.2 O, and recrystallized from DMF, mp 359.degree. -62.degree. ; yield 0.2 g (18%); .lambda. max m.mu. (.epsilon.) 270 (11,400), 334 (41,000); .nu. max 760 (m), 820 (m), 960 (m), 1280 (ms), 1610 (m), 1660 (s), 1690 (ms) cm.sup.-1.

Anal. Calcd. for C.sub.18 H.sub.11 BrO.sub.4 : C, 58.24; H, 2.99. Found: C, 58.08; H, 3.05.

EXAMPLE 8 ##STR11##

4-[(6-bromo-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile

A mixture of 3.9 g of 5'-bromo-2'-hydroxy-2-(methylsulfinyl)acetophenone, 2.2 g of p-cyanocinnamaldehyde, 50 ml of toluene and 0.1 ml of piperidine was refluxed for 4 hrs. The mixture was chilled, and the precipitate was filtered and recystallized from DMF, mp 275.degree.-76.degree. ; yield 1 g (20%); .lambda. max m.mu. (.epsilon.) 223 (22,700), 273 (12,900), 330 (41,000); .nu. max 840 (m), 980 (m), 1280 (m), 1640 (m), 1660 (ms), 2240 (m) cm.sup.-.sup.1.

Anal. Calcd. for C.sub.18 H.sub.10 BrNO.sub.2 : C, 61.39; H, 2.86; N, 3.98. Found: C, 61.18; H, 2.97; N, 3.99.

EXAMPLE 9 ##STR12##

4-[2-(6-Isopropyl-4-oxo-4H-1-benzopyran-2-benzopyran-2yl)ethenyl]benzoic acid

A mixture of 3 g of 4-[2-(6-isopropyl-4-oxo-4H-1-benzopyran-2-yl)ethenyl] benzonitrile and 125 ml of 50% H.sub.2 SO.sub.4 was refluxed for 2 hrs. The mixture was chilled, and the precipitate filtered, washed with cold H.sub.2 O and recrystallized from CH.sub.3 CN, mp 264.degree. -65.degree. ; yield 2 g (63%); .lambda. max m.mu. (.epsilon.) 272 (11,900), 331 (43,600); .nu. max 765 (m), 1280 (ms), 1620 (s), 1640 (s), 1690 (s) cm.sup.-.sup.1.

Anal. Calcd. for C.sub.21 H.sub.18 O.sub.4 : C, 75.43; H, 5.43. Found: C, 75.41; H, 5.45.

EXAMPLE 10 ##STR13##

4-[2-(6-Isopropyl-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile

A mixture of 12 g of 2'-hydroxy-5'-isopropyl-2-(methylsulfinyl)acetophenone, 7.8 g of p-cyanocinnamaldehyde, 125 ml of toluene, and 0.5 ml of piperidine was combined and refluxed for 3 hrs. The solution was chilled, and the crystalline precipitate that was formed was filtered and recrystallized from CH.sub.3 CN, mp 189.degree. -91.degree. ; yield 5 g (31%); .lambda. max m.mu. (.epsilon.) 220 (22,400), 276 (14,100), 328 (41,600); .nu. max 835 (m), 980 (m), 1580 (m), 1635 (ms), 2225 (m) cm.sup.-.sup.1.

Anal. Cacd. for C.sub.21 H.sub.17 NO.sub.2 : C, 79.98; H, 5.43; N, 4.44. Found: C, 79.86; H, 5.42; N, 4.20.

Claims

1. A compound of the formula: ##STR14## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 are hydrogen, lower alkyl, halogen or lower alkoxy and A is COOH or CN.

2. A compound according to claim 1 which is 4-[2-(6-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile.

3. A compound according to claim 1 which is 4-[2-(6-methyl-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile.

4. A compound according to claim 1 which is 4-[2-(6-methyl-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzoic acid.

5. A compound according to claim 1 which is 4-[2-(8-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]-benzoic acid.

6. A compound according to claim 1 which is 4-[2-(8-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile.

7. A compound according to claim 1 which is 4-[2-(6-methoxy-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzoic acid.

8. A compound according to claim 1 which is 4-[2-(6-bromo-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzoic acid.

9. A compound according to claim 1 which is 4-[(6-bromo-4-oxo-4H-1-benzopryan-2-yl)ethenyl]benzonitrile.

10. A compound according to claim 1 which is 4-[2-(6-isopropyl-4-oxo-4H-1-benzopyran-2-yl)ethenyl]benzoic acid.

11. A compound according to claim 1 which is 4-[2-(6-isopropyl-4oxo-4H-1-benzopyran-2-yl)ethenyl]benzonitrile.