US3772325A - Novel hexahydro cyclohept(b)indoles - Google Patents

Abstract

THIS DISCLOSURE DESCRIBES 5,6,7,8,9,10 - HEXAHYDRO -2METHOXY-5-METHYLCYCLOHEPT(B)INDOLE; 5,6,7,8,9,10 - HEXAHYDRO-2-METHOXYCYCLOHEPT(B)INDOL - L - OL; AND 4,5,6,-11TETRAHYDRO-8-METHOXY-2H - PYRAZOLO(4'',3'':6,7)CYCLOHEPT(1,2-B)IDOLE; ALL THREE USEFUL AS ANTIFUNGAL AGENTS.

Description

3,772,325 NOVEL HEXAHYDRO CYCLOHEPT[b]INDOLES Joseph William Epstein, Monroe, and Leon Goldman,

Nanuet, N.Y.', assignors to American Cyanamid Company, Stamford, Conn. i

No Drawing. Filed Mar. 24, 1972, Ser. No. 237,977 Int. Cl. C07d 49/18 US. Cl. 260311 1 Claim ABSTRACT OF THE DISCLOSURE This disclosure describes 5,6,7,8,9,10 hexahydro -2- methoxy-5-methylcyclohept[b]indole; 5,6,7,8,9,l0 hexahydro-Z-methoxycyclohept[b]indol 6 01; and 4,5,6-11- tetrahydro-S-methoxy-ZH pyrazolo[4',3':6,7]cyclohept- [1,2-b]indole; all three useful as antifungal agents.

BRIEF SUMMARY OF THE INVENTION cum-W3 ego-@133 on: H OH (I) (n) CH30--/\ NNH (III) DETAILED DESCRIPTION OF THE INVENTION The novel compound of Formula III forms useful pharmaceutically acceptable acid-addition salts with a variety of non-toxic organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with an acid in a suitable solvent, are formed with such acids as citric, hydrochloric, hydrobromic, sulfuri, phosphoric, tartaric, and the like. For purposes of this invention, the organic free base equivalent to its non-toxic acid-addition salts. I

The novel compounds of the present invention are generally obtainable as colorless to yellow crystalline materials having characteristic melting points and absorption spectra and which may be purified by recrystallization from common organic solvents. They are appreciably soluble in many organic solvents such as methanol, ethanol, acetone, chloroform, benzene, dioxane, dimethyl sulfoxide and N,N-dimethylforrnamide, but are relatively insoluble in water. The acid addition salts of the compound of Formula III are, in general, crystalline solids relatively soluble in water, methanol, and ethanol but relatively insoluble in non-polar organic solvents such as diethyl ether, benzene, toluene, and the like.

The novel compounds of the present invention are useful as antifungal agents, and possess activity in vitro against fungal cultures capable of causing disease in man) or animals. This activity, against a variety of standard laboratory microorganisms, is determined by the agardilution technique. In this assay, the compound to be tested is dissolved in dimethyl sulfoxide so that 10.0 mg.

United States Patent 0" 3,772,325 Patented Nov. 13, 1973 of test compound is contained per milliliter of solution. Observing sterile techniques, ten-fold series dilutions are made of the test solution. Two-tenths ml., 0.1 ml. and 0.05 ml. amounts of the original solution and of each of decimal dilutions are then added to and mixed with 20 ml. of warm sterile asparagine-meat extract agar capable of supporing growth ofthe test cultures. The standard sterile nutrient agar solutions containing the different dilutions of the test compound, along with suitable and comparable control dilutions containing no test compound, are then allowed to cool in Petri dishes thereby forming solid agar plates. The yeast-like test fungi are prepared for use by growing in Trypticase Soy broth overnight. These broth cultures are diluted tenfold in physiological saline at the time of use. The filamentous fungi are grown to maturity on slants of potato dextrose agar. Spores and mycelia are harvested by washing the growth from the slants with sterile physiological saline solution. Using the Steers Replicator a standarized amount of each of the resulting live suspensions is then, still employing sterile techniques, imprinted upon the s rfaces of each of the agar plates and the resulting inoculated plates are then incubated. After an appropriate period of time, each of the inoculated areas on each of the plates is inspected visually and the extent, if any, of growth is noted. The minimal inhibitory concentration (meg/ml.) is defined as the concentration of test compound causing essentially complete inhibition of any particular organism. In a representative operation, the minimal inhibitory concentration of the compounds of this invention against standard laboratory microorganisms, as determined in the abovedescribed assays, are set forth in Table I, below.

When mixed with suitable excipients or diluents, the compounds of this invention can be prepared as pills, capsules, tablets, powders, solutions, suspensions, and the like for unit dosage and to simplify administration.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Preparation of 5,6,7,8,9,1o-hexahydro-2-methoxy-5- methylcyclohept [b] indole To a stirred suspension of 3.0 g. of 54% sodium hydride-mineral oil dispersion in 15 m1. of-N,N-din1ethylformamide is added 10.70 g. of 5,6,7,8,9,l0-hexahydro-2- methoxycyclohept[b]indole in 20 ml. of N,N-dimethylformamide at such a rate as not to cause excessive effervescence. The mixture is stirred for 1 hour and then 8.0 g. of methyl iodide in 10 ml. of N,N-dimethylformamide is added over a /2 hour period, and then stirring is continued for an additional 1 hour. The reaction mixture is poured into 250 ml. of water and a brown crystalline mass forms. The crystals are removed by filtration and dissolved in dichloromethane and the solution is washed with water. The solution is then evaporated under reduced pressure to yield an oil which is dissolved in hexane and this solution is dried over sodium sulfate. The yellow solution is filtered through magnesium silicate, the adsorbant is washed with hexane, then ether, and finally with dichloromethane. Evaporation of the combined filtrates gives 9.85 g. of pale yellow crystals, M.P. 59 C.-62 C. A sample of the product, on sublimation at 105 C. (0.014 mm.), gives 5,6,7,8,9,10-hexahydro-2- methoxy-S-methylcyclohept[b]indole as colorless crystals, M.P. 6l.5 C.62.5 C.

EXAMPLE 2 Preparation of l,2-cycloheptanedione (p-methoxyphenyl)hydrazone To a mixture of 47.6 g. of p-anisidine in 180 ml. of water containing 36 ml. of concentrated sulfuric acid and 350 g. of ice is added 26 g. of sodium nitrite in 100 ml. of water followed by a concentrated aqueous solution of 100 g. of sodium acetate. To the vigorously stirred mixture is added 40.0 g. of 2-hydroxymethylenecycloheptanone over a minute period and stirring is continued for an additional /2 hour. A dark oil separates which then crystallizes. The orange-brown solid is removed by filtration, washed with water and then air-dried. The yield of crude product is 59.0 g., M.P. 59. C.61 C. Recrystallization from ethanol gives 50.9 g. of 1,2-cycloheptanedione (p-methoxyphenyl)hydrazone as orange prisms, M.P. 62 C.-64 C.

EXAMPLE 3 Preparation of 7,8,9,10-tetrahydro-2-methoxycyclohept[b]indol-6-(5H)-one A solution of 100 g. of 1,2-cycloheptanedione (pmethoxyphenyl)hydrazone in 375 ml. of acetic acid containing 40 ml. of concentrated hydrochloric acid is heated on a steam bath for 1 hour. The black solution is cooled and then is filtered to yield 38.0 g. of black crystals. The filtrate is then diluted with water to yield an additional 20.4 g. of tarry black solid. The crude product is dissolved in 250 ml. of tetrahydrofuran and filtration of the solution through magnesium silicate, followed by evaporation of the filtrate under reduced pressure, gives 43.0 g. of olive green crystals, M.P. 179 C.181 C. Recrystallization from ethanol/chloroform gives 35.4 g. of 7,8, 9,10 tetrahydro-2-methoxycyclohept[b]indol 6(5H)-one as pale yellow needles, M.P. 182 C.-184 C.

EXAMPLE 4 Preparation of 5,6,7,8,9,10-hexahydro-2-methoxycyclohept [b]indol-6-ol To a stirred solution of 17.00 g. of 7,8,9,10-tetrahydro- 2-methoxycyclohept[b]indol-6(5H)-one in 300 ml. of methanol/tetrahydrofuran (1:1) at room temperature is added 0.80 g. of sodium borohydride. After stirring the mixture for 1 /2 hours an additional 0.80 g. of sodium borohydride is added and stirring is continued for 1 hour, at which time 0.30 g. of sodium borohydride is added, followe by /2 hour of stirring. The solvents are removed under reduced pressure at 40 C., the oily residue is dissolved in dichloromethane and the solution is filtered through magnesium silicate. Evaporation of this solution under reduced pressure at 40 C. gives an oil which is then triturated with hexane and filtered to yield 13.84 g.

4 0f 5,6,7,8,9,10-hexahydro-2-rnethoxycyclohept[b]indol-6- 01 as off-white crystals, M.P. 865 C.-87.5 C.

EXAMPLE 5 Preparation of 7,8,9,l0-tetrahydro-7-(hydroxymethylene)-2-methoxycyclohept [b] indol-6 (5H)-one To a stirred suspension of 2.0 g. of sodium methoxide in 50 ml. of dioxane at room temperature is added 2.29 g. of powdered 7,8,9,lO-tetrahydro-2-methoxycyclohept [b]indol-6(5H)-one. When all solids have dissolved, 2.8 ml. of ethyl formate is added to the yellow solution in one portion and stirring is continued for 1 /2 hours, at which time the reaction mixture is poured into 500 ml. of water. Upon acidification with acetic acid a yellow precipitate forms which is collected by filtration, washed with water and air-dried to yield 2.45 g. of bright yellow microcrystals, M.P. 157 C.159 C. Recrystallization from methanol/chloroform gives 1.95 g. of 7,8,9,l0-tetrahydro 7 (hydroxymethylene)-2-methoxycyclohept[b] indol-6(5H)-one as yellow crystals, M.P. 159 C.-l6l C.

EXAMPLE 6 Preparation of 4,5,6,11-tetrahydro-8-methoxy-2H- pyrazolo[43 6,7]cyclohept[ 1,2-b] indole To a solution of 4.00 g. of 7,8,9,10-tetrahydro-7-(hydroxymethylene) 2 methoxycyclohept[b]indol-6(5H)- one in ml. of dioxane is added 2.0 ml. of hydrazine hydrate in one portion and this solution is heated under reflux for 1 /2 hours. The solvent is removed under reduced pressure to yield 4.10 g. of yellow crystals, M.P. 209 C.-217 C. (insert at 205 C.). Recrystallization from ethyl acetate gives 2.09 g. of 4,5,6,ll-tetrahydro-8 methoxy-2H-pyrazolo [4,3' 6,7]cyclohept[ 1,2 b] indole as yellow needles, M.P. 218 C.-222 C. (insert at 205 C.).

What is claimed is:

1. A compound selected from the group consisting of 4,5,6,11-tetrahydro-8-methoxy 2H pyrazolo[4,3':6,7] cyclohept[l,2-b]indole and the non-toxic pharmaceutically acceptable acid-addition salts thereof.

References Cited UNITED STATES PATENTS 3,321,486 5/1967 Remers et a1 260310 R 3,364,227 1/1968 Robinson 2603l0 R 3,404,157 10/1968 McEvoy et al. 260310 R 3,637,738 l/1972 Gschwend et al. 260-310R OTHER REFERENCES Teuber et al.: Chem. Abst., vol. 73, No. 130928b (1970).

Chemical Abstracts, seventh collective index, vols. 56- 65, 1962-1966, subjects CHQ-DIB, p. 6858s (1969).

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.