US3631174A - 4 5-heterocyclic substituted-6 7-dihydrobenzothiophenes - Google Patents

4 5-heterocyclic substituted-6 7-dihydrobenzothiophenes Download PDF

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US3631174A
US3631174A US1039A US3631174DA US3631174A US 3631174 A US3631174 A US 3631174A US 1039 A US1039 A US 1039A US 3631174D A US3631174D A US 3631174DA US 3631174 A US3631174 A US 3631174A
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dihydrobenzothiophenes
heterocyclic substituted
mice
dose
compound
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US1039A
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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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This invention relates to new organic compounds and, more particularly, is concerned with 4,5-dihydrothieno- [2,3-g] 1,2-benzisoxazole and 4,5-dihydro-2H-thieno[2,3- g]indazole and with methods of preparing these compounds.
  • 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 nontoxic 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 ethanol or n-hexane. They are appreciably soluble in many organic solvents such as glacial acetic acid, acetone, dimethylformamide, 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 compound 4,5-dihydrothieno[2,3-g]-l,2-benzisoxazole is an active analgesic 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.
  • the compound 4,5-dihydrothieno[2,3- g]-l,2-benzisoxazole showed analgesic activity when tested by this procedure at an oral dose of 200 mg./kg. of body weight.
  • the median effective dose (ED Patented Dec. 28, 1971 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.
  • 4,5 dihydro 2H thieno[2,3-g]indazole is a central nervous system depressant of low toxicity and was shown to possess CNS depressant activity as determined by animal experiments as follows.
  • the compound was administered intraperitoneally in a 2% starch vehicle to groups of six mice at three or more graded dose levels.
  • each animal was placed on the midpoint of a horizontal steel rod (1.55 cm. in diameter and about 6 dm. in length), positioned 45.7 cm. above the surface of the table, and forced to walk toward a platform at either end of the rod.
  • the criterion of inability to perform this act was consistent slipping to the slide or falling off the rod.
  • the effective dose for reduced rod-walking ability was calculated or approximated from the data, and the time of peak efiect was estimated from the data.
  • One-half of the RWD dose was given intraperitoneally to each mouse in groups of five.
  • each group of mice was put into the actophotometer for a period of five minutes and the motor activity counts were recorded and compared to controls.
  • the compound was administered to additionally groups of five mice at graded doses and tested similarly.
  • the dose (MDDeo) that caused a 50% reduction in motor activity was estimated.
  • 4,5-dihydro-2H-thieno[2,3-g]indazole was shown to induce ataxia (RWD at a dose of 70 mg./kg. of body weight and to reduce locomotor activity (MDD at a dose of 17 rug/kg. of body weight.
  • 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.
  • Example 1 Preparation of 4,5-dihydrothieno- [2,3-g]-l,2-benzisoxazo1e
  • a solution of 5.09 g. of 5-hydroxymethylene-4-oxo- 4,5, 6,7 tetrahydrobenzothiophene [C. R. Acad. Sci., Paris, 266, Ser. C, 1545 (1968)] in 200 ml. of acetic acid is treated with 2.9 g. of hydroxylamine hydrochloride. The mixture is stirred at steam-bath temperature for 6 hours, decolorized with charcoal, cooled, and poured into 350 ml. of ice water. The product (2.15 g.) crystallizes in white needles when this mixture is cooled overnight at 10 C. Recrystallization from hexane at low temperature gives product with M.P. 4041.5 C.

Abstract

THIS DISCLOSURE DESCRIBES COMPOUNDS OF THE CLASS OF 4,5 - HETEROCYCLIC SUBSTITUTED-6,7-DIHYDROBENZOTHIOPHENES USEFUL AS AN ANALGESIC AGENT OR CENTRAL NERVOUS SYSTEM DEPRESSANT.

Description

United States Patent O US. Cl. 260-307 D 2 Claims ABSTRACT OF THE DISCLOSURE This disclosure describes compounds of the class of 4,5 heterocyclic substituted-6,7-dihydrobenzothiophenes useful as an analgesic agent or central nervous system depressant.
BRIEF SUMMARY OF THE INVENTION This invention relates to new organic compounds and, more particularly, is concerned with 4,5-dihydrothieno- [2,3-g] 1,2-benzisoxazole and 4,5-dihydro-2H-thieno[2,3- g]indazole and with methods of preparing these compounds.
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 nontoxic 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 ethanol or n-hexane. They are appreciably soluble in many organic solvents such as glacial acetic acid, acetone, dimethylformamide, 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 compound 4,5-dihydrothieno[2,3-g]-l,2-benzisoxazole is an active analgesic 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. The compound 4,5-dihydrothieno[2,3- g]-l,2-benzisoxazole 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 Patented Dec. 28, 1971 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.
4,5 dihydro 2H thieno[2,3-g]indazole is a central nervous system depressant of low toxicity and was shown to possess CNS depressant activity as determined by animal experiments as follows. The compound was administered intraperitoneally in a 2% starch vehicle to groups of six mice at three or more graded dose levels. At 15-minute and 30-minute intervals after treatment, each animal was placed on the midpoint of a horizontal steel rod (1.55 cm. in diameter and about 6 dm. in length), positioned 45.7 cm. above the surface of the table, and forced to walk toward a platform at either end of the rod. The criterion of inability to perform this act was consistent slipping to the slide or falling off the rod. The effective dose for reduced rod-walking ability (RWD wascalculated or approximated from the data, and the time of peak efiect was estimated from the data. One-half of the RWD dose was given intraperitoneally to each mouse in groups of five. At the time of peak effect, as determined above, each group of mice was put into the actophotometer for a period of five minutes and the motor activity counts were recorded and compared to controls. The compound was administered to additionally groups of five mice at graded doses and tested similarly. The dose (MDDeo) that caused a 50% reduction in motor activity was estimated. 4,5-dihydro-2H-thieno[2,3-g]indazole was shown to induce ataxia (RWD at a dose of 70 mg./kg. of body weight and to reduce locomotor activity (MDD at a dose of 17 rug/kg. of body weight.
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 4,5-dihydrothieno- [2,3-g]-l,2-benzisoxazo1e A solution of 5.09 g. of 5-hydroxymethylene-4-oxo- 4,5, 6,7 tetrahydrobenzothiophene [C. R. Acad. Sci., Paris, 266, Ser. C, 1545 (1968)] in 200 ml. of acetic acid is treated with 2.9 g. of hydroxylamine hydrochloride. The mixture is stirred at steam-bath temperature for 6 hours, decolorized with charcoal, cooled, and poured into 350 ml. of ice water. The product (2.15 g.) crystallizes in white needles when this mixture is cooled overnight at 10 C. Recrystallization from hexane at low temperature gives product with M.P. 4041.5 C.
Example 2.Preparation of 4,5-dihydro-2H- thieno [2,3-g] indazole A mixture of 3.60 g. of 5-hydroxymethylene-4-oxo- 4,5,6,7-tetrahydrobenzothiophene [C. R. Acad. Sci., Paris, 266, Ser. C, 1545 (1968)], 20 ml. of hydrazine hydrate and ml. of ethanol is heated at reflux temperature for 3 hours. The mixture is then cooled and diluted with 250 ml. of water, whereupon white crystals of product separate (2.87 g.). Recrystallization from ethanol affords white crystals, M.P. 166 168 C.
We claim:
1. A compound selected from the group consisting of 4,5 dihydrothieno[2,3-g]-l,2-benzisoxazole represented by the formula:
and the non-toxic pharmaceutically acceptable acid-addition salts thereof.
References Cited UNITED STATES PATENTS 9/1932 Herz et a1. 260-310 C 10/1968 McEvoy et a1 260-310 R 4 OTHER REFERENCES Chemical Abstracts, Decennial Index to Chemical Abstracts, volumes 2130, Subject Index E-O, p. 5061 (1927- 1936-).
Chemical Abstracts, volume 58, Subject Index, A-I p. 957s (JanuaryJune, 1963).
Chemical Abstracts, Seventh Collective Index, volumes 56-65, Subjects Flu-HW, p. 97, 585 (1962-1966).
Moskalenko et al.: Chem. Abst., v01. 68, No. 96,790]: 1968).
Moskalenko: 1969).
Royer et al.: Chem. Abst., vol. 69, No. 10316W (1968).
Chem. Abst., vol. 70, No. 87,815m
NATALIE TROUSOF, Primary Examiner US. Cl. X.R.
US1039A 1970-01-06 1970-01-06 4 5-heterocyclic substituted-6 7-dihydrobenzothiophenes Expired - Lifetime US3631174A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4560558A (en) * 1983-05-16 1985-12-24 Abbott Laboratories 3-Alkyl-8-chloro-5,6-dihydrofuro-[3,2-f]-1,2-benzisoxazole-6-carboxylic acids
WO1990003380A1 (en) * 1988-09-21 1990-04-05 Yoshitomi Pharmaceutical Industries, Ltd. Thienocycloheptapyridazine compounds and medicinal uses thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4560558A (en) * 1983-05-16 1985-12-24 Abbott Laboratories 3-Alkyl-8-chloro-5,6-dihydrofuro-[3,2-f]-1,2-benzisoxazole-6-carboxylic acids
WO1990003380A1 (en) * 1988-09-21 1990-04-05 Yoshitomi Pharmaceutical Industries, Ltd. Thienocycloheptapyridazine compounds and medicinal uses thereof

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