US3631057A - Novel 4 7 - dimethyl-6-(lower alkyl) isoxazolo(5 4-e)indoles and methods of preparing same - Google Patents

Novel 4 7 - dimethyl-6-(lower alkyl) isoxazolo(5 4-e)indoles and methods of preparing same Download PDF

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US3631057A
US3631057A US1038A US3631057DA US3631057A US 3631057 A US3631057 A US 3631057A US 1038 A US1038 A US 1038A US 3631057D A US3631057D A US 3631057DA US 3631057 A US3631057 A US 3631057A
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dimethyl
lower alkyl
isoxazolo
indoles
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William Alan Remers
Martin Joseph Weiss
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Wyeth Holdings LLC
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American Cyanamid Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

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  • This invention relates to new organic compounds and, more particularly, is concerned with novel 4,7-dimethyl-6- (lower alkyl)isoxazolo[5,4-e]indoles (I) and novel 4,5- dihydro 4,7 dimethyl-6-(lower alkyl)isoxazolo[5,4-e] indoles (II) and .with methods of preparing these compounds.
  • novel compounds of the present invention may be represented by the following general formulae:
  • Suitable lower alkyl groups contemplated by the present invention are those having from one to four carbon atoms such as, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, etc.
  • novel compounds of the present invention form non-toxic acid-addition salts with a variety of organic and inorganic salt-forming reagents.
  • acid-addition salts formed by admixture of the organic free base with an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and related acids.
  • the free bases are equivalent to their non-toxic acid-addition salts.
  • novel compounds of the present invention are white crystalline materials having characteristic melting points and absorption spectra and which may be purified by recrystallization from common organic solvents such as lower alkanols. They are appreciably soluble in many organic solvents such as glacial acetic acid, acetone, dimethylforamide, and the like but are sparingly soluble in water.
  • the acid-addition salts of the organic free bases of this invention 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.
  • novel 4,7-dimethyl-6-(lower alkyl) isoxazolo[5,4-e]- indoles (I) of the present invention are active analgesics when measured by the writhing syndrome test for analgesic activity as described by Siegmund et al., Proc. Soc. Exptl. Biol. Med., vol. 9, p. 729 (1957), with modifications. This method is based upon the reduction of the number of writhes following the intraperitoneal injection of one mg./kg. of body weight of phenyl-p-quinone in male Swiss Albino mice weighing 15-25 grams per mouse.
  • the syndrome is characterized by intermittent contractions of the abdomen, twisting and turning of the trunk, and extension of the hind legs beginning 3 to 5 minutes after injection of the phenyl-p-quinone.
  • the test compound is administered orally to groups of two mice each 30 minutes before injection of the phenyl-p-quinone.
  • the total number of writhes exhibited by each group of mice is recorded for a 3 minute period commencing 15 minutes after injection of the phenyl-p-quinone.
  • a compound is considered active if it reduces the total number of writhes in two test mice from a control value of approximately 30 per pair to a value of 18 or less.
  • 4,7-dimethyl-6- ethylisoxazolo[5,4-e]indole showed analgesic activity when tested by this procedure at an oral dose of 200 mg./kg. of body weight.
  • the median effective dose may be calculated from the results obtained by repeating this test in multiple groups of two mice each at each of several graded dose levels.
  • the antidepressant properties of the novel 4,5-dihydro- 4,7-dimethyl-6- (lower alkyl)isoxazolo [5,4-e1indoles (II) of the present invention are evident by measuring their ability to counteract a depression induced in animals by the administration of tetrabenazine hexamate.
  • Graded doses of the active compounds (II) of this invention are administered by intraperitoneal injection to groups of mice, and this is followed by administering intraperitoneally a dose of tetrabenazine which is known to markedly depress the exploratory behavior of normal mice.
  • the antidepressant treated groups show normal exploratory behavior, while the control groups, and groups treated with an ineffective antidepressant agent, do not show this normal exploratory behavior, but show the well known profound depression induced by tetrabenazine.
  • the results from several dose levels are used to establish effective dose ranges.
  • the antidepressant compounds (II) of this in vention show their desirable properties by this procedure at dose levels which produce little or no untoward reactions such as ataxia or reduced spontaneous motor activity.
  • 4,5-dihydro-4,7-dimethyl-6-ethylisoxazolo-[5,4-e] indole showed antidepressant activity when tested by this procedure at a dose of 25 mg./kg. of body weight.
  • novel compounds of the present invention may be readily prepared from 2-acetonyl-5-Inethyl-1,3-cyclohexanedione in accordance with the following reaction scheme wherein R is as hereinbefore defined.
  • the ring closure of 2-acetonyl-5-methyl-1,3-cyclohexanedione (V) with primary amines (RNH to afiord the corresponding 2,6-dimethyl-1-(lower alkyl)-4-oxo-4,5,6,7-tetrahydroindoles (IV) is readily carried out according to the general procedure of Stetter and Lauterbach, Ann. 655, 20 (1962).
  • Suitable primary amines which may be employed in this ring closure are, for example, methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, etc.
  • Conversion of the 2,6-dimethyl-1-(lower alkyl)-4-oxo- 4,5,6,7-tetrahydroindoles (IV) to the corresponding 2,6- dimethyl-l-(lower alkyl)-S-hydroxymethylene-4-oxo-4,5, 6,7-tetrahydroindoles (III) is accomplished by treatment with ethyl formate in the presence of a base such as sodium methoxide or sodium ethoxide.
  • This reaction is best carried out in an anhydrous solvent such as benzene or toluene at a temperature of from about 20 C. to the reflux temperature for a period of time of 15-20 hours.
  • Ring closure of the 2,6-dimethy1-l-(lower alkyl)-5-hydroxymethylene 4 oxo-4,5,6,7-tetrahydroindoles (III) with hydroxylamine hydrochloride to afford the corresponding 4,5-dihydro-4,7-dimethyl-6-(lower alkyl)isoxazolo[5,4-e]indoles (II) is readily carried out in warm aqueous ethanol for a period of a few minutes to an hour or more.
  • the desired product (II) crystallizes upon cooling the resulting solution.
  • Aromatization of the 4,5-dihydro-4,7-dimethyl-6-(lower alkyl)isoxazolo [5,4-e] indoles (II) to the corresponding 4,7-dimethyl-6-(lower alkyl) isoxazolo[5,4-e]indoles (I) is accomplished by treatment with the reagent 5,6-dichloro-2,3-dicyanobenzoquinone. This reaction is best carried out in dioxane as solvent at room temperature for a period of 2-3 days.
  • 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.
  • R is 1 wherein R is 1 wherein R is 6 wherein R is lower alkyl and the non-toxic pharmaceu- References Cited tically acceptable acid-addition salts thereof.
  • UNITED STATES PATENTS 7 A compound according to claim 6 wherein R is methyh 3,156,704 11/1964 Davis 260-396 d 6 et 1:, 1A compoun according to claim wherein R 1s 5 ALEX M AZEL, Primary Examiner 9.
  • R is R. V. RUSH, Assistant Examiner isopropyl.
  • R is US. Cl. X.R. n-butyl. 10 424-272 UNITED STATES PATEN'I OFFICE CERTIFICATE OF CORRECTION Dated Deoemher 98 "I971 Patent No. '5, 631. 057

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Abstract

4,7-DIMETHYL-6-(LOWER ALKYL) ISOXAZOLO (5,4-E) INDOES AND THE CORRESPONDING 4,5-DIHYDRO DERIVATAIVES THEREOF. THE COMPOUNDS ARE USEFUL AS ANALGESICS AND ANTIDEPRESSANTS, RESPECTIVELY.

Description

United States Patent 3,631,057 NOVEL 4,7 DlMETHYL-G-(LOWER ALKYL) ISOXAZOLO[5,4-e]INDOLES AND METHODS OF PREPARING SAME William Alan Remers, Suifern, N.Y., and Martin Joseph Weiss, Oradell, N.J., assignors to American Cyanamid Company, Stamford, Conn. N0 Drawing. Filed Jan. 6, 1970, Ser. No. 1,038
- Int. Cl. C07d 85/22 US. Cl. 260-307 10 Claims ABSTRACT OF THE DISCLOSURE 4,7-dimeth-yl-6-(lower alkyl) isoxazolo [5,4-e] indoles and the corresponding 4,5-dihydro derivatives thereof. The compounds are useful as analgesics and antidepressants, respectively.
BRIEF SUMMARY OF THE INVENTION This invention relates to new organic compounds and, more particularly, is concerned with novel 4,7-dimethyl-6- (lower alkyl)isoxazolo[5,4-e]indoles (I) and novel 4,5- dihydro 4,7 dimethyl-6-(lower alkyl)isoxazolo[5,4-e] indoles (II) and .with methods of preparing these compounds. The novel compounds of the present invention may be represented by the following general formulae:
I F (21% I 4H3 on l -on (I) R n n wherein R is lower alkyl. Suitable lower alkyl groups contemplated by the present invention are those having from one to four carbon atoms such as, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, etc.
DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention form non-toxic acid-addition salts with a variety of organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and related acids. For purposes of this invention, the free bases are equivalent to their non-toxic acid-addition salts.
The novel compounds of the present invention are white crystalline materials having characteristic melting points and absorption spectra and which may be purified by recrystallization from common organic solvents such as lower alkanols. They are appreciably soluble in many organic solvents such as glacial acetic acid, acetone, dimethylforamide, and the like but are sparingly soluble in water. The acid-addition salts of the organic free bases of this invention 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 4,7-dimethyl-6-(lower alkyl) isoxazolo[5,4-e]- indoles (I) of the present invention are active analgesics when measured by the writhing syndrome test for analgesic activity as described by Siegmund et al., Proc. Soc. Exptl. Biol. Med., vol. 9, p. 729 (1957), with modifications. This method is based upon the reduction of the number of writhes following the intraperitoneal injection of one mg./kg. of body weight of phenyl-p-quinone in male Swiss Albino mice weighing 15-25 grams per mouse. The syndrome is characterized by intermittent contractions of the abdomen, twisting and turning of the trunk, and extension of the hind legs beginning 3 to 5 minutes after injection of the phenyl-p-quinone. The test compound is administered orally to groups of two mice each 30 minutes before injection of the phenyl-p-quinone. The total number of writhes exhibited by each group of mice is recorded for a 3 minute period commencing 15 minutes after injection of the phenyl-p-quinone. A compound is considered active if it reduces the total number of writhes in two test mice from a control value of approximately 30 per pair to a value of 18 or less. In a representative operation, and merely by way of illustration, 4,7-dimethyl-6- ethylisoxazolo[5,4-e]indole showed analgesic activity when tested by this procedure at an oral dose of 200 mg./kg. of body weight. If desired, the median effective dose ('ED may be calculated from the results obtained by repeating this test in multiple groups of two mice each at each of several graded dose levels.
The antidepressant properties of the novel 4,5-dihydro- 4,7-dimethyl-6- (lower alkyl)isoxazolo [5,4-e1indoles (II) of the present invention are evident by measuring their ability to counteract a depression induced in animals by the administration of tetrabenazine hexamate. Graded doses of the active compounds (II) of this invention are administered by intraperitoneal injection to groups of mice, and this is followed by administering intraperitoneally a dose of tetrabenazine which is known to markedly depress the exploratory behavior of normal mice. The antidepressant treated groups show normal exploratory behavior, while the control groups, and groups treated with an ineffective antidepressant agent, do not show this normal exploratory behavior, but show the well known profound depression induced by tetrabenazine. The results from several dose levels are used to establish effective dose ranges. The antidepressant compounds (II) of this in vention show their desirable properties by this procedure at dose levels which produce little or no untoward reactions such as ataxia or reduced spontaneous motor activity. In a representative operation, and merely by way of illustration, 4,5-dihydro-4,7-dimethyl-6-ethylisoxazolo-[5,4-e] indole showed antidepressant activity when tested by this procedure at a dose of 25 mg./kg. of body weight.
The novel compounds of the present invention may be readily prepared from 2-acetonyl-5-Inethyl-1,3-cyclohexanedione in accordance with the following reaction scheme wherein R is as hereinbefore defined. The ring closure of 2-acetonyl-5-methyl-1,3-cyclohexanedione (V) with primary amines (RNH to afiord the corresponding 2,6-dimethyl-1-(lower alkyl)-4-oxo-4,5,6,7-tetrahydroindoles (IV) is readily carried out according to the general procedure of Stetter and Lauterbach, Ann. 655, 20 (1962). Suitable primary amines which may be employed in this ring closure are, for example, methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, etc. Conversion of the 2,6-dimethyl-1-(lower alkyl)-4-oxo- 4,5,6,7-tetrahydroindoles (IV) to the corresponding 2,6- dimethyl-l-(lower alkyl)-S-hydroxymethylene-4-oxo-4,5, 6,7-tetrahydroindoles (III) is accomplished by treatment with ethyl formate in the presence of a base such as sodium methoxide or sodium ethoxide. This reaction is best carried out in an anhydrous solvent such as benzene or toluene at a temperature of from about 20 C. to the reflux temperature for a period of time of 15-20 hours. Ring closure of the 2,6-dimethy1-l-(lower alkyl)-5-hydroxymethylene 4 oxo-4,5,6,7-tetrahydroindoles (III) with hydroxylamine hydrochloride to afford the corresponding 4,5-dihydro-4,7-dimethyl-6-(lower alkyl)isoxazolo[5,4-e]indoles (II) is readily carried out in warm aqueous ethanol for a period of a few minutes to an hour or more. The desired product (II) crystallizes upon cooling the resulting solution. Aromatization of the 4,5-dihydro-4,7-dimethyl-6-(lower alkyl)isoxazolo [5,4-e] indoles (II) to the corresponding 4,7-dimethyl-6-(lower alkyl) isoxazolo[5,4-e]indoles (I) is accomplished by treatment with the reagent 5,6-dichloro-2,3-dicyanobenzoquinone. This reaction is best carried out in dioxane as solvent at room temperature for a period of 2-3 days. Filtration of the reaction mixture, concentration of the filtrate, and recrystallization of the residue afiords the desired product 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.
4 EXAMPLE 1 Preparation of 2,6-dimethyl-1-ethyl- 4-oxo-4,5,6,7-tetrahydroindole This compound is prepared by the method described in Example of US. Pat. No. 3,226,399 to Allen et a1.
EXAMPLE 2 Preparation of 2,6-dimethyl-1-ethyl-5-hydr0xymethylene- 4-oxo-4,5,6,7-tetrahydroindole This compound is prepared by the method described in Example 48 of U8. Pat. No. 3,404,157 to McEvody et al.
EXAMPLE 3 Preparation of 4,5-dihydro-4,7-dimethyl- 6-ethylisoxazolo[5,4-e]indole To a solution of 16.92 g. of 2,6-dimethyl-1-ethyl-5- hydroxymethylene-4-oxo-4,5,6,7-tetrahydroindole in 100 ml. of warm ethanol is added a solution of 5.37 g. of hydroxylamine hydrochloride in 15 ml. of water. The desired product (14.8 g.) crystallizes upon cooling the resulting solution. Recrystallization from ethanol-water gives product having M.P. l38 C.
EXAMPLE 4 Preparation of 4,7-dimethyl-6-ethylisoxazolo[5,4-e]indole Solutions of 4.32 g. of 4,5-dihydro-4,7-dirnethyl-6- ethylisoxazolo[5,4-e]indole and 1.93 g. of 5,6-dichloro- 2,3-dicyanobenzoquinone, each in the minimum volume of dioxane, are combined. The resulting solution is stirred for 64 hours at room temperature and filtered. After partial decolorization with charcoal the filtrate is concentrated, whereupon the residue crystallizes. This product (1.69 g.) is recrystallized from ethanol whereby there is obtained the desired product having M.P. -15 8 C.
What is claimed is:
1. A compound selected from the group consisting of 4,5 -dihydro-4,7-dimethyl-6- (lower alkyl) isoxazolo 5,4-e] indoles represented by the formula:
1 wherein R is 1 wherein R is 1 wherein R is 6 wherein R is lower alkyl and the non-toxic pharmaceu- References Cited tically acceptable acid-addition salts thereof. UNITED STATES PATENTS 7. A compound according to claim 6 wherein R is methyh 3,156,704 11/1964 Davis 260-396 d 6 et 1:, 1A compoun according to claim wherein R 1s 5 ALEX M AZEL, Primary Examiner 9. A compound according to claim 6 wherein R is R. V. RUSH, Assistant Examiner isopropyl.
10. A compound according to claim 6 wherein R is US. Cl. X.R. n-butyl. 10 424-272 UNITED STATES PATEN'I OFFICE CERTIFICATE OF CORRECTION Dated Deoemher 98 "I971 Patent No. '5, 631. 057
Invent fl William an It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column 2, line 2, "dimethylforamide" should be -dimethylformamide Column 5, lines 5-8, the formula designated (IV) should be as follows and not as in the patent:
Column 3, lines 13-22, the formula designated (III) should be as follows and not as in the patent:
Q Hc-l CH3 L I CH3 R (III) Signed and sealed this 6th day of June 1972.
(SEAL) Attest:
EDWARD M.FLETCHER,JR. ROBERT GOTTSGHALK Commissioner of Patents Attesting Officer USCOMM'DC 6376P9 U. S. GOVIINIINT PRINTING OH'ICI "I, O-Jl-334 FORM PO-IOSO (10-69)
US1038A 1970-01-06 1970-01-06 Novel 4 7 - dimethyl-6-(lower alkyl) isoxazolo(5 4-e)indoles and methods of preparing same Expired - Lifetime US3631057A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010513490A (en) * 2006-12-22 2010-04-30 シェーリング コーポレイション 4,5-cyclic indole derivatives for the treatment or prevention of HCV and related viral diseases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010513490A (en) * 2006-12-22 2010-04-30 シェーリング コーポレイション 4,5-cyclic indole derivatives for the treatment or prevention of HCV and related viral diseases

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