Compounds useful in treating sickle cell anemia

#U.S. Pat. Nos. 3,478,085 and 3,255,241 and British Published application 998,835 disclose general structures which include the compounds claimed in the present invention. None of these references, however, specifically disclose the claimed compounds. E. J. Cragoe, Jr., Ed., Diuretics: Chemistry, Pharmacology and Medicine, John Wiley and Sons, New York 1983, discloses an analogue of the claimed compounds on page 213.

#This invention relates to compounds useful in treating sickle cell anemia and, more specifically, it relates to a method of resisting sickling of sickle hemoglobin in a sickle cell anemia patient.

#Sickle cell anemia is a hereditary blood disease which primarily afflicts people of African, Mediterranean and Mideastern origin or their descendants. The anemia results from the physical aggregation of a mutant hemoglobin protein constituent, hemoglobin S, in red blood cells. This aggregation results in a distortion in shape of deoxygenated red blood cells and causes impairment of flow of the blood through the capillaries (sickle cell "crises"). As the principal function of hemoglobin is to transport oxygen from the lungs to body tissues, efficient flow of oxygen throughout the body's tissues is impeded by the anemia due to a lower number of red blood cells. Sickle cell anemia also may have an indirect effect on the heart, lungs, kidneys, spleen, bones and brain. Sickle cell anemia crises can be extremely painful, can result in infections such as pneumonia, can result in skin ulceration, can contribute to strokes and seizures in the afflicted individuals and can also result in the development of chronic bone infections.

#The following examples are included to illustrate the synthesis of representative compounds of Formula II, the preparation of representative dosage forms and the preparation of sterile solutions for use in the extracorporeal treatment of the blood of patients with sickle cell anemia. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the claims of the invention.

#A mixture of 2,3-dichloro-4-butyrophenone (21 g, 0.090 mole) and potassium carbonate (37 g, 0.27 mole) in N,N-dimethylformamide (100 ml) were stirreed and heated to 60.degree. C. 4-Bromo-1-butene (26.7 g, 0.2 mole) was added and the mixture stirred and heated at 60.degree.-65.degree. C. for five hours. The reaction mixture was poured into ice water and the mixture extracted with ether. The ether layer was washed with water and then with brine and finally dried over MgSo.sub.4. The ether was removed by evaporation at reduced pressure to give 25 g of 2,3-dichloro-4-(3-butenyloxy)-butyrophenone as confirmed by elementary analysis.

#2,3-Dichloro-4-(3-butenyloxy)butyrophenone (31.5 g, 0.11 mole) and benzyltriethylammonium chloride (2.3 g) in methylene chloride (350 ml) was added dropwise to a solution of potassium permanganate (45.8 g) in water (900 ml) at 5.degree. C. The mixture was then stirred at 20.degree. C. for 1.5 hours after which tests showed that the oxidation was complete. Sodium bisulfite and dilute hydrochloric acid was added until the color due to KMnO.sub.4 disappeared. The mixture was filtered to remove a small amount of solid and the methylene chloride layer from the filtrate was separated. This layer was washed with water and then extracted with a dilute sodium hydroxide solution. The aqueous layer was poured into ice water containing dilute hydrochloric acid. The solid that separated was removed by filtration, washed with water, dried and recrystallized to give 9 g of 3-(2,3-dichloro-4-butyrylphenoxy)propionic acid, m.p. 138.degree.-139.degree..