2-BROMO-1-TETRALONE DERIVATIVES

Abstract: 2-Bromo-1-tetralone derivatives of the formula wherein R₁ R₂ and R₃ form any one of the following combina­ tions (A), (B) and (C): (A) R₁ = R₂ = Cl and R₃ = H; (B) R₁ = R₃ = Cl and R₂ = H; and (C) R₁ = F and R₂ = R₃ = H. Results of experiments indicate that these derivatives have high antitumor activity and antifungal activity with low toxicity.

Description: 2-BROMO-1-TETRALONE DERIVATIVES BACKGROUND OF THE INVENTION The present invention relates to novel 2-bromol-tetralone derivatives. Generally, the physiological activities of chemicals depend greatly on their chemical structures. There has been a constant demand, therefore, for chemical substances having structures which differ from those of known compounds. SUMMARY OF THE INVENTION This invention presents one contribution toward meeting the above mentioned demand. More particularly, this invention provides 2bromo-l-tetralone derivatives of the formula (I): EMI1.1 -wherein R1, R2 and R3 form any one of the following combinations (A), (B) and (C): (A) R1 = R2 = C1. and R3 = H; (B) R1 = R3 = C1 and R2 = H; and (C) R1 = F and R2 = R3 = H. BRIEF DESCRIPTION OF THE DRAWINGS In the drawings: FIG. 1 is a diagram showing the infrared absorption spectrum of 2-bromo-6,7-dichloro-l-tetralone (in chloroform); FIG. 2 is a diagram showing the infrared absorption spectrum of 2-bromo-5,7-dichloro-I-tetralone (in chloroform); FIG. 3 is a diagram showing the infrared absorption spectrum of 2-bromo-7-fluoro-l-tetralone (in chloroform); FIG. 4 is a diagram showing the visible/ultraviolet absorption spectrum of 2-bromo-6,7-dichlorol-tetralone (in methanol); FIG. 5 is a diagram showing the visible/ultraviolet absorption spectrum of 2-bromo-5,7-dichloro l-tetralone (in methanol); and FIG. 6 is a diagram showing the visible/ultraviolet absorption spectrum of 2-bromo-7-fluoro-1- tetralone (in methanol). DETAILED DESCRIPTION OF THE INVENTION 2-Bromo-l-tetralone derivatives The 2-bromo-l-tetralone derivatives according to the present invention have a chemical structure as shown by the above formula (I) wherein the substituents R1, R2 and R3 form any one of the three combinations (A), (B) and (C), forming respectively 2-bromo-6,7-dichloro-1-tetralone, 2-bromo-5,7dichloro-l-tetralone and 2-bromo-7-fluoro-1-tetralone. The term 12-bromo-l-tetralone derivatives) n used herein refers to any one of these compounds or a mixture of two or more thereof. The physicochemical properties of these 2-bromo1-tetralone derivatives are summarized in Table 1. Table 1 Physicochemical properties of 2-Bromo-1-Tetralone Derivatives EMI3.1 <SEP> 2-bromo-6,7-dichloro- <SEP> 2-bromo-5,7-dichloro- <SEP> 2-bromo-7-fluoro-1 <SEP> 1-tetralone <SEP> 1-tetralone <SEP> tetralone <tb> <SEP> (Found) <SEP> (Found) <SEP> (Found) <tb> Elementary <SEP> analysis <SEP> C <SEP> = <SEP> 40.91, <SEP> H <SEP> = <SEP> 2.14 <SEP> C <SEP> = <SEP> 40.89, <SEP> H <SEP> = <SEP> 2.25 <SEP> C <SEP> = <SEP> 49.44, <SEP> H <SEP> = <SEP> 3.18 <tb> <SEP> (%) <SEP> (Calcd.) <SEP> (Calcd.) <SEP> (Calcd.) <tb> <SEP> C <SEP> = <SEP> 40.86, <SEP> H <SEP> = <SEP> 2.40 <SEP> C <SEP> = <SEP> 40.86, <SEP> H <SEP> = <SEP> 2.40 <SEP> C <SEP> = <SEP> 49.41, <SEP> H <SEP> = <SEP> 3.32 <tb> Mass <SEP> spectrum <SEP> 294 <SEP> (M+) <SEP> 294 <SEP> (M+) <SEP> 242 <SEP> (M+) <tb> <SEP> (M/e) <tb> <SEP> (abundant <SEP> peak <SEP> only) <SEP> 214 <SEP> (M+ <SEP> - <SEP> 80) <SEP> 214 <SEP> (M+ <SEP> - <SEP> 80) <SEP> 162(M+ <SEP> - <SEP> 80) <tb> Infrared <SEP> absorption <tb> spectrum <SEP> (in <SEP> chloro- <SEP> FIG. <SEP> 1 <SEP> FIG. <SEP> 2 <SEP> FIG. <SEP> 3 <tb> form) <SEP> (1690 <SEP> cm-1) <SEP> (1695 <SEP> cm-1) <SEP> (1690 <SEP> cm-1) <tb> <SEP> # <tb> Visible/ultraviolet <SEP> FIG. <SEP> 4 <SEP> FIG. <SEP> 5 <SEP> FIg. <SEP> 6 <tb> absorption <SEP> spectrum <SEP> 261 <SEP> [13,800] <SEP> 296 <SEP> [8,070] <SEP> 251 <SEP> [10,300] <tb> <SEP> #max <SEP> (nm) <SEP> (#max) <SEP> 306 <SEP> [2, <SEP> 530] <SEP> 311 <SEP> [1,800] <SEP> 304 <SEP> [2,720] <tb> Appearance <SEP> Pale <SEP> yellowish <SEP> orange <SEP> Colorless <SEP> Yellow <tb> <SEP> Plate <SEP> crystal <SEP> Needle <SEP> crystal <SEP> Oily <tb> Melting <SEP> point <SEP> ( C) <SEP> 88.0 <SEP> - <SEP> 89.5 <SEP> 106 <SEP> - <SEP> 109 <tb> Table 1 (continued) EMI4.1 <SEP> 2-bromo-6,7-dichloro- <SEP> 2-bromo-5,7-dichloro- <SEP> 2-bromo-7-fluoro-1 <SEP> 1-tetralone <SEP> 1-tetralone <SEP> tetralone <tb> NMR <SEP> spectrum <SEP> (100 <SEP> MHz, <tb> in <SEP> deuterochloroform) <tb> <SEP> (6 <SEP> ppm) <tb> <SEP> C2 <SEP> - <SEP> H <SEP> 4.70(t., <SEP> 1H, <SEP> J <SEP> = <SEP> 4.0) <SEP> 4.70(t., <SEP> 1H, <SEP> J <SEP> = <SEP> 4.0) <SEP> 4.67(t., <SEP> 1H, <SEP> J <SEP> = <SEP> 4.1) <tb> <SEP> C8 <SEP> - <SEP> H <SEP> 8.15(s., <SEP> 1H) <SEP> 7.98(d., <SEP> 1H, <SEP> J <SEP> = <SEP> 2.2) <SEP> 7.81(d., <SEP> 1H, <SEP> J <SEP> = <SEP> 1.0) <tb> Thin <SEP> layer <SEP> chromatography <tb> Rf* <SEP> (Chloroform: <tb> <SEP> Hexane <SEP> = <SEP> 3:1) <SEP> 0.55 <SEP> 0.60 <SEP> 0.56 <tb> <SEP> Easily <SEP> soluble <SEP> in <SEP> methanol, <SEP> ethanol, <SEP> acetone, <SEP> chloroform <SEP> and <SEP> ether; <tb> Solubility <SEP> in <SEP> solvent <SEP> sparingly <SEP> soluble <SEP> in <SEP> n-hexane; <SEP> and <SEP> insoluble <SEP> in <SEP> water <SEP> (all <SEP> of <SEP> the <tb> <SEP> derivatives) <tb> Structural <SEP> formula <SEP> # <SEP> # <SEP> # <tb> * Silica gel plate (ART 5721 supplied by Merck & Co., Inc.) was used. Production of 2-bromo-l-tetralone derivatives 2-Bromo-l-tetralone derivatives can be produced by any process suitable for the desired purpose with respect to the introduction of substituents or the formulation of chemical structures. A specific example of such processes is illustrated below. EMI6.1 Note : R1, R2 and R3 are the same as defined in the formula (I) shown hereinbefore. First, Compound A and succinic anhydride are subjected to Friedel-Crafts reaction to obtain Compound B. The Compound B thus obtained is caused to undergo Clemmensen reduction to obtain Compound C, which is reacted - with thionyl chloride to produce Compound D. The Compound D is then cyclized by Friedel-Crafts reaction to produce Compound E. This Compound E is reacted with equimolar bromine in the presence of ethyl ether or carbon disulfide to obtain 2-bromo-l-tetralone derivatives. Utility of 2-bromo-1-tetralone derivatives The 2-bromo-l-tetralone derivatives in accordance with the present invention have antitumor activity coupled with antifungal activity, and are therefore useful as a medicine. Physiological activities (1) Antitumor activity 2-Bromo-l-tetralone derivatives exhibit antitumor activity against leukemia of subject animals. For example, into CDF1 mice were intraperitoneally transplanted P388 leukemia 1x106 cells/mouse as a suspension, and 2-bromo-6,7-dichloro-l-tetralone which is typical of the compounds of the present invention was administered to the mice 1 day and 5 days respectively after -the transplantation. The effect of the test compound was evaluated in terms of the increase of life span (E) as calculated by determining the survival days of the control group consisting of mice administered with physiological saline solution as 100. The results obtained were as shown in Table 2 below. Table 2 Antitumor Activity of 2-Bromo-6,7-Dichloro-l-Tetralone EMI8.1 <tb> <SEP> Dose <SEP> Increase <SEP> of <tb> (mg/kg/day) <SEP> life <SEP> span <SEP> (%) <tb> <SEP> 10.0 <SEP> 129 <tb> <SEP> 50.0 <SEP> 140 <tb> (2) Antifungal activity The 2-bromo-l-tetralone derivatives according to this invention exhibit antimicrobial activity against various fungi, and the minimum inhibitory concentration (MIC) of these compounds obtained by the Yamano et al. method (Yamano and Henmi, Shinkin Shi (Journal of Fungi), 10, 68(1969)) was as shown in Table 3, in which data on griseofulvin as a control are also set forth. Table 3 Minimum Inhibitory Concentration of S-Bromo-l-Tetralone Derivatives EMI8.2 <tb> <SEP> Micro- <SEP> Minimum <SEP> Inhibitory <SEP> Concentration <SEP> (MIC) <tb> <SEP> rganism <SEP> fi' <SEP> /ml) <tb> <SEP> Trichophyton <SEP> Trichophyton <SEP> Candida <tb> <SEP> mentagrophy- <SEP> asteroides <SEP> albicans <tb> Compound <SEP> tes <tb> 2-bromo-6, <tb> 7-dichloro- <SEP> 0.78 <SEP> 0.78-1.56 <SEP> 1.56 <tb> l-tetralone <tb> 2-bromo-5, <tb> 7-dichloro- <SEP> 1.56 <SEP> 1.56 <SEP> 1.56 <tb> l-tetralone <tb> 2-bromo-7 <tb> fluoro-l- <SEP> 3.13 <SEP> 3.13 <SEP> 6. <SEP> 2D <tb> tetralone <tb> griseofulvin <SEP> 6.25 <SEP> 6.25 <SEP> > 200 <tb> The minimum inhibitory concentration was determined as follows. Method of Determination of MIC (a) Culture medium Sabouraud's agar medium was used as a culture medium. (A liquid culture medium was prepared from the same ingredients except for agar.) Glucose 40 g Peptone 10 g Agar 15 g Distilled water 1 liter This culture medium was prepared by dissolving the above ingredients under heat, and the medium thus prepared was sterilized under the conditions of 1.05 "bar (15 lbs.lln2) for 15 minutes. (b) Preparation of suspension containing microorga nism to be tested The microorganisms to be tested were fungi of the species Trichophyton mentagrophytes (A), Trichophyton asteroides (B) and Candida albicans (C). Each of these microorganisms was cultivated on the corresponding slant medium at 270C for 7 days. A loopful of each of the microorganisms (A), (B) and (C) was triturated in a mortar, charged into a test tube containing 10 ml of physiological-sal-ine-selution, and suspended therein with a thermomixer. Each of the suspensions thus prepared was used in the test. (c) MIC on agar medium 9 ml of the culture medium and 1 ml of a dilute sample were thoroughly admixed with each other in a Petri dish to prepare an agar plate, which was then streaked with the suspension containing each of the microorganisms to be tested by using a sterile platinum wire loop. The microorganisms (A), (B) and (C) thus inoculated on the agar plates were cultivated at 270C for 7 days, and thereafter the MIC thereof was determined. The 2-bromo-l-tetralone derivatives according to the present invention exhibit antifungal activity superior to that of known antifungal agents such as griseofulvin. Examples of fungi whose growth can be inhibited by the 2-bromo-l-tetralone derivatives of this invention are Trichophyton microorganisms such as Trichophyton mentagrophytes and Trichophyton asteroides, and yeast such as Candida albicans. Among these, the compounds of the present invention are most effective against Trichophyton microorganisms. (3) Toxicity The toxicity of the compounds of the present invention as evaluated in terms of LD50 of 2-bromo 6,7-dichloro-l-tetralone to mice is tabulated below. EMI10.1 <tb> <SEP> Route <SEP> of <tb> Administration <SEP> LD50 <SEP> (mg/kg) <tb> <SEP> Oral <SEP> > 1,500 <tb> <SEP> Intra <tb> <SEP> peritoneal <SEP> <SEP> 820 <SEP> <tb> <SEP> Subcutaneous <SEP> > 1.500 <tb> ppii'cability of 2-bromo-l-tetralone derivatives as anti tumor agents The 2-bromo-l-tetralone derivatives in accordance with the present invention can be used as antitumor agents'or Barmaceutical compositions for treatment of tumors. 2-Bromo-l-tetralone derivatives as antitumor agents can be administered via any route suited for the desired purpose in a dosage form determined by the particular route of administration selected. Ordinarily, the compounds diluted with pharmaceutically acceptable carriers or diluents are administered as drugs. A typical method of administering 2-bromo-ltetralone derivatives as antitumor agents is by injection of the solution thereof in distilled water for injection use or in physiological saline solution. Examples of injection are intraperitoneal injection, subcutaneous injection, intravenous or intraarterial injection, and topical administration in the case of animals; and intravenous or intraarterial injection, and topical administration in the case of humans. The doses of 2-bromo-l-tetralone derivatives are determined in accordance with the results of animal experiments and varying circumstances in such a manner that the total of the doses given continuously or intermittently in each case will not exceed a specific limit. Needless to say, particular doses required vary depending on the mode of administration; situations of patients or animals to be treated, such as age, body weight, sex and susceptibility; food; times of administration; concomitant drugs; and conditions of patients or animals or severity of their diseases. The optimum doses and the frequency of administration under certain conditions must be determined by experts' optimum dose determination tests on the basis of the above-mentioned factors. Experimental Example Production of 2-Bromo-6 , 7-Dichloro-l-Tetralone (a) Preparation of 6-(34-dichloro)benzoylpropionic acid To 19.4 g of o-dichlorobenzene were added 10 g of succinic anhydride and then 29.3 g of powdery anhydrous aluminum chloride. The mixture was refluxed with stirring for approximately 1 hour, and thereafter water was added to decompose an aluminum complex salt. The resultant mixture was extracted with ethyl ether under acidic conditions, and a fraction soluble in an aqueous alkali solution was extracted from the ethyl ether extract. The aqueous solution thus obtained was acidified to form a precipitate. This precipitate was recrystallized from hot water, filtered off and dried to obtain 14.23 g of B-(3,4-dichloro)benzoylpropionic acid. The yield was 57.6%. (b) Preparation of y- (3 ,4-dichloro) phenylbutyric acid To 7 g of the ss-(3,4-dichloro)benzoylpropionic acid obtained in the step (a) were added 16.8 g of zinc amalgam, 11 ml of water, 30 ml of concentrated hydrochloric acid and 14 ml of toluene. The mixture was then refluxed. To the mixture was further added 7 ml of concentrated hydrochloric acid every 6 hours during the reflux until the reaction would not proceed further. After cooling, the reaction solution was extracted with ethyl ether, concentrated to dryness under reduced pressure and purified by silica gel column chromatography to obtain 4.82 g of y (3,4-dichloro)phenylbutyric acid. The yield was 73.08. (c) Preparation of 6,7-dichloro-l-tetralone To 1.9 g of the y-(3,4-dichloro)phenylbutyric acid obtained in the step (b) was added 6 ml of thionyl chloride, and the mixture was caused to react in solution state. Thereafter, the thionyl chloride was removed from the reaction solution to which 10 ml of carbon disulfide and 1.8 g of powdery anhydrous aluminum chloride were added. The resultant solution was refluxed with stirring for 10 minutes; an aluminum complex salt was decomposed with water; and the solution was then extracted with ethyl ether. The ethyl ether extract obtained was concentrated to dryness under reduced pressure and purified by silica gel column chromatography to produce 1.5 g of 6,7-dichloro-ltetralone. The yield was 85.4%. (d) Production of 2-bromo-6,7-dichloro-l-tetralone 1 g of the 6,7-dichloro-l-tetralone obtained in the step (c) was dissolved in 10 ml of ethyl ether or carbon disulfide, and 0.25 ml of bromine was added dropwise to the resulting solution at room temperature with stirring. After 30 minutes' reaction, water was added and the reaction solution was extracted with ethyl ether. The ethyl ether extract obtained was neutralized with an aqueous solution of sodium hydrogencarbonate, and then concentrated to dryness under reduced pressure to obtain 1.43 g of a crude product of 2-bromo-6,7dichloro-l-tetralone. The yield was 99.6%. This crude product was purified by silica gel column chromatography and subsequently recrystallized from n-hexane to produce 1.10 g of 2-bromo-6,7-dichlorol-tetralone in the form of a pale yellowish orange plate crystal. The yield was 76.5%. Elementary analysis Calcd. C; 40.86% H: 2.40% (for C10H7BrCl2O) Found C: 40.918 H: 2.14%

Claims: WHAT IS CLAIMED IS: 2-Bromo-l-tetralone derivatives of the formula EMI14.1 wherein R1, R2 and R3 form any one of the following combinations (A), (B) and (C): (A) R1 = R2 = Cl and R3 = H; (B) R1 = R3 = Cl and R2 = H; and (C) R1 = F and R2 = R3 = B.

Inventors: INOUE, HIDEO KIRIN BEER K.K., MIZOBUCHI, SHIGEYUKI KIRIN BEER K.K., SATO, YUKO KIRIN BEER K.K., TANABE, KOZO KIRIN BEER K.K.
Applicants: KIRIN BEER KABUSHIKI KAISHA
Application year: 1984
Main classification: C07C49
IPC codes: A61K31, C07C59, A61P31, C07C67, C07C49, A61P35, C07C57, C07C45