US3689657A - Indole derivatives in the treatment of skeletal muscle fatigability - Google Patents

Indole derivatives in the treatment of skeletal muscle fatigability Download PDF

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Publication number
US3689657A
US3689657A US92299A US3689657DA US3689657A US 3689657 A US3689657 A US 3689657A US 92299 A US92299 A US 92299A US 3689657D A US3689657D A US 3689657DA US 3689657 A US3689657 A US 3689657A
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lower alkyl
indole
halo
structural formula
skeletal muscle
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US92299A
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Nathan Norman Share
Cyril Stephen Mcfarlane
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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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • 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
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom

Definitions

  • ABSTRACT Skeletal muscle fatigability is treated by administration of a composition containing a skeletal muscle stimulant which is a derivative of indole-3-acetic acid or of indole-3-ylmethyltetrazole.
  • phenyl either unsubstituted or substituted with nitro, halo such as chloro, bromo or fluoro, or lower alkyl of one to about three carbon atoms,
  • phenoxy either unsubstituted or substituted with nitro, halo such as fluoro, chloro or bromo, or lower alkyl of from one to about three carbon atoms,
  • R represents 1. hydrogen
  • alkenyl of from three to about five carbon atoms, such as allyl, butenyl and the like;
  • R represents 1. lower alkyl of one to about eight carbon atoms
  • R represents 1. hydrogen
  • halo such as chloro, bromo or fluoro.
  • the active agents of the method of this invention have been found in standard laboratory animals to produce myotonic symptoms consisting of temporary rigid extension of the legs when the animal is disturbed.
  • the overt appearance is readily distinguishable from convulsions caused by central stimulation.
  • This stimulation of striated muscle is useful in the treatment of disease entities characterized by progressive fatigability of the muscles such as myasthenia gravis.
  • acetylcholinesterase inhibitors and/or skeletal muscle facilitators. These substances often exhibit side effects such as extreme salivation, involuntary defecation and urination, sweating, lacrimation, bradycardia and hypotension. They have a relatively low therapeutic index and are not always effective.
  • the compounds of the novel method of this invention on the other hand operate through a mechanism of .action different from that of the acetylcholinesterase inhibitors and fail to produce any of the adverse side-effects described above in experimental animals, and have a much higher therapeutic index. They have further been shown to facilitate the activity of acetylcholinesterase inhibitors and therefore may also be used in combination with them to reduce their toxicity.
  • Treatment with the active agents of this invention can be orally in the form of powders, granules, wafers, tablets, capsules or pills, or by injection intravenously, or intraperitoneally in suspension or in solution.
  • Z is hydroxyl they can be administered as a pharmaceutically acceptable salt, such as an alkali metal salt, preferably the potassium or sodium salt.
  • the dose is from 1 to about 50 mgs./kg./day either singly or on a multidose regimen depending on the severity of the disorder and the discretion of the physician.
  • the indole skeleton of the active compounds of this invention is prepared by standard chemical synthetic procedures well known in the art and are represented by the following reaction sequences:
  • R, and R are as previously defined, and R is other than chloro-, bromo-, dichloroor trichlorolower alkyl.
  • ester derivatives of Compound VIII are performed by standard chemical syntheses well known in the art, and a detailed procedure'is included in the examples below.
  • Step B Preparation of 2-Butyl-5-methylindole
  • 20.5 g. (0.1 mole) of N-(2,4- dimethylphenyl)pentanamide in 250 ml. diethylaniline under nitrogen is added in portions, 20 g. (0.526 mole) of sodamide.
  • the mixture is heated slowly to 220 C. and maintained at this temperature for 5 hours.
  • the reaction mixture is cooled to about 50 C., and the excess sodamide carefully decomposed by the addition of 300 ml. of water.
  • the organic phase is extracted into 300 ml. ether and washed with portions of cold 4N l-lCl and water.
  • the ether solution is dried and concentrated to 20.2 g. of residual solid. Recrystallization from petroleum ether gives 2-butyl-5-methylindole, m.p. 73.5-75.5 C.
  • reaction mixture is allowed to warm to room temperature over a period of 18 hours. It is diluted with 300 ml. water and filtered to remove a small amount of gummy by-product. The filtrate is chilled in an ice-bath and made basic (pl-1 10- 11) with ION KOH. The precipitated product is filtered, washed with water and dried. Recrystallization from n-hexane gives 5.0 g. (63.3 percent) of 3- (dimethylaminomethyl)-2-butyl-5-methylindole, m.p.
  • Step B Preparation of 2-Butyl-3-(cyanomethyl)-5- methylindole A solution of 3.42 g. (0.014 mole) of 3- dimethylaminomethyl)-5-methyl-2-butylindole dissolved in 60 ml. dry ether is added dropwise with stirring to an ice-cooled solution of 19.5 ml. of iodomethane and stirred for 6 hours at 0 C. The precipitate is filtered, washed with ether and dried to yield 4.7 g. (87 percent) of the methiodide salt of 3- (dimethylaminomethyl)-5-methyl-2-butylindole.
  • Step B Preparation of 2-(2-chloroethyl)indole-3- acetonitrile 2-(2-Hydroxyethyl)indole-3-acetonitrile (200 mg.), phosphorus trichloride (250 mg.) and ml. of toluene are heated at reflux under nitrogen for 18 hours. The mixture is evaporated and the residue mixed with ice water and sodium carbonate.
  • Step C Preparation of methyl 2-( 2-chloroethyl)indo1e- 3-acetate An ice cold solution of 2-(2-chloroethyl)indo1e-3- acetonitrile (220 mg.) in 5 ml. of methanol containing 0.05 ml. Water is saturated with hydrogen chloride gas. After stirring at room temperature for 48 hours the solution is evaporated to dryness, and the residue treated with sodium bicarbonate solution and then extracted with methylene chloride.
  • Step D Preparation of 2-(2-chloroethy1)indo1e-3- acetic acid Methyl 2-(2-chloroethy1')indole-3-acetate 100 mg.) is hydrolyzed by refluxing in a mixture of 20 ml. benzene-10 ml. 10 percent hydrochloric acid for 3 hours. After cooling, the benzene layer is evaporated to dryness to yield 2-(2-chloroethy1)indo1e-3-acetic acid.
  • EXAMPLE 38 2-(2-Bromoethyl)indole-3-acetic acid Employing the process of Example 37 but substituting for the phosphorus trichloride used therein an equivalent'amount of phosphorus tribromide, there is produced 2-(2-bromoethy1)indole-3-acetic acid.
  • Example 40 Employing the procedure of Example 40 but substituting for the octanol and the 5-methyl-2-propylindole-3-acetic acid utilized therein equivalent amounts of an alcohol of formula 21-] and a l-R-2-R -5(or 6)- R -indole-3-acetic acid described in Table 111, there are produced the Z 1-R-2-R -5(or 6)-R"-indo1e-3- acetates, also described in Table 111.
  • EXAMPLE 5 7 2-Propionylindole-3-acetic acid lndole-3-acetic acid l 1.0 g.) and propionyl chloride (100 ml.) in diethyl ether (100 ml.) is added to finely powdered zinc chloride (7.0 g.) and the mixture refluxed with stirring for 1 hour. The reaction mixture is decomposed by the careful addition of water and the crude product which precipitates is filtered. Recrystallization from acetone-petroleum ether yields 4.5 g. (32 percent) of 2-propionylindole-3-acetic acid, m.p. 226-228 C.
  • EXAMPLE 5 8 5-(5-Methyl-2-propylindole-3-ylmethyl)tetrazole To a solution of 1.8 g. (0.0085 mole) of 3- cyanomethyl-S-methyl-2-propylindole in 20 ml. methyl cellosolve is added 1.1 g. (0.017 mole) powdered sodium azide and 0.72 g. (0.017 mole) powdered lithium chloride and the suspension refluxed and stirred for 114 hours. The solvent is removed by distillation in vacuo and the residue taken up in ether and water and treated with 12N HCl to decompose azide salts. A stream of nitrogen is bubbled through the reaction mixture to remove hydrazoic acid.
  • the crude product which precipitates is filtered and washed with water and ether.
  • the product is purified by dissolving in dilute sodium hydroxide and'precipitating with dilute hydrochloric acid to yield 0.5 g. of 5-(5-m'ethyl-2- propylindole-3-yl-methyl)tetrazole, m.p. l83-l84 C.
  • Example 58 Employing the method of Example 58 but substituting for the 3-cyanomethyl-5-methyl-2-propylindole used therein, equivalent amounts of the 3- cyanomethyl-5-R -2-R -l-R-indoles described in Table IV, there are produced the 5-(5-R -2-R -l-R-- indol-3-ylmethyl)tetrazoles also described in Table IV.
  • the compounds were initially tested for skeletal muscle stimulant properties at doses of 32 mg/kg. intraperitoneally (i.p.). Effective doses (ED were then determined for active compounds by that route, and subsequently by intravenous (i.v.) and oral (p.o.) administration.
  • mice Male albino mice (Swiss strain, Canadian Breeding Laboratories), weighing 18-22 grams were employed. Compounds were suspended in 1 percent Methocel (methyl cellulose, 400 cps, 65 Hg.) with the aid of an homogenizer and administered, i.v., i.p. or p.o. in a volume of 0.2 ml/20 g. of body weight.
  • Methocel methyl cellulose, 400 cps, 65 Hg.
  • results obtained following the above procedure upon the administration of the skeletal muscle stimulant agents of this invention indicate that the ED by intravenous, intraperitoneal, and oral administration are in the ranges 04-71, 07-30, 0.5-1 4 mg/kg; respectively.
  • muscle stimulant agent to be employed in the method of this invention will depend upon the age, condition, weight and other factors relevant to the animal to be treated and necessarily needs .to be individualized by the physician or veterinarian for each patient.
  • a suitable unit dosage form for oral administration is described in the following example:
  • EXAMPLE 65 Capsule containing 25 mgs. of active ingredient mgs./capsule Ingredient S-Methyl -2-propylindole-3-acetic acid 25 corn starch U.S.P. l0 lactose U.S.P. I30
  • EXAMPLE 66 Injectable preparation containing 10 mg. of active ingredient The sodium salt of 5-methyl-2-propylindole-3-acetic acid is dissolved in pyrogen free water at a concentration of 10 mg./ml. and the resulting solution is dispensed into 1 cc. pharmaceutical vials.
  • the soluble salts can be formed from any phar- Q maceutically acceptable materials such as sodium,
  • the active ingredients can also be administered in aqueous suspension as the procaine salt.
  • the active ingredients can be administered in aqueous suspension as the free acids or as the esters described herein.
  • a method of treatment of skeletal-muscle fatigability which comprises the administration to an afflicted animal of an effective amount of a skeletal muscle stimulant having the structural formula wherein R is a member selected from the group consisting of l. a carbonyl group of formula COZ wherein Z is a member selected from the group consisting of a. hydroxyl, b. lower alkoxy, c. di(lower alkyl)aminomethyl-lower alkoxy, d. hydroxy-lower alkoxy, e. phenyl-lower alkoxy, f. nitrophenyl-lower alkoxy, g. halophenyl-lower alkoxy, h.
  • R is a member selected from the group consisting of 1. hydrogen, 2. lower alkyl, and 3. lower alkenyl; R is a member selected from the group consisting of l lower alkyl, 2. lower alkoxy-lower alkyl, 3. lower alkylthio-lower alkyl, 4. halo-lower alkyl, and 5. lower alkylcarbonyl; R is a member selected from the group consisting of 1. hydrogen, Y 2. lower alkyl, 3. halo-lower alkyl, 4. lower alkoxy-lower alkyl, 5. nitro, and
  • the muscle stimulant has the formula amount of a skeletal muscle stimulant having the structural formula wherein R is a member selected from the group consisting of l. a carbonyl group of formula COZ wherein Z is a member selected from the group consisting of a. hydroxyl,
  • R is a member selected from the group consisting of 1 hydrogen, 2. lower alkyl, and 3. lower alkenyl;
  • R is a member selected from the group consisting of l. lowenalkyl
  • R is a member selected from the group consisting of 1. hydrogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US92299A 1970-02-03 1970-11-23 Indole derivatives in the treatment of skeletal muscle fatigability Expired - Lifetime US3689657A (en)

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US (1) US3689657A (enrdf_load_stackoverflow)
BE (1) BE759744A (enrdf_load_stackoverflow)
CA (1) CA957281A (enrdf_load_stackoverflow)
FR (1) FR2081480B1 (enrdf_load_stackoverflow)
GB (1) GB1290795A (enrdf_load_stackoverflow)
IL (1) IL35772A (enrdf_load_stackoverflow)
NL (1) NL7017489A (enrdf_load_stackoverflow)
ZA (1) ZA708144B (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6890948B1 (en) * 2000-06-30 2005-05-10 Cancer Research Technology Limited Use of indole-3-acetic acid derivatives in medicine
US20050203166A1 (en) * 2000-06-30 2005-09-15 Cancer Research Technology Limited Indole-3-acetic acid derivatives
US20080194553A1 (en) * 2003-10-03 2008-08-14 Gillessen Hubert Jean-Marie Francois Use Of Compounds That Are Able To Increase The Serum Igf-1 Level For The Preparation Of A Therapeutical Composition For Treatment Of Various Disease States Associated With A Reduced Igf-1 Serum Level In Humans And Animals

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3322786A (en) * 1965-10-07 1967-05-30 Merck & Co Inc 3-indolyl aliphatic acids
NL6702635A (enrdf_load_stackoverflow) * 1966-03-04 1967-09-05

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Walton et al. J. of Med. Chem., Vol. 8, pp. 204 208 (1965). *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6890948B1 (en) * 2000-06-30 2005-05-10 Cancer Research Technology Limited Use of indole-3-acetic acid derivatives in medicine
US20050203166A1 (en) * 2000-06-30 2005-09-15 Cancer Research Technology Limited Indole-3-acetic acid derivatives
US20080194553A1 (en) * 2003-10-03 2008-08-14 Gillessen Hubert Jean-Marie Francois Use Of Compounds That Are Able To Increase The Serum Igf-1 Level For The Preparation Of A Therapeutical Composition For Treatment Of Various Disease States Associated With A Reduced Igf-1 Serum Level In Humans And Animals
US9408405B2 (en) * 2003-10-03 2016-08-09 Veijlen N.V. Use of compounds that are able to increase the serum IGF-1 level for the preparation of a therapeutical composition for treatment of various disease states associated with a reduced IGF-1 serum level in humans and animals
US10716778B2 (en) 2003-10-03 2020-07-21 Veijlen Use of compounds that are able to increase the serum IGF-1 level for the preparation of a therapeutical composition for treatment of various disease states associated with a reduced IGF-1 serum level in humans and animals

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IL35772A0 (en) 1971-02-25
FR2081480A1 (enrdf_load_stackoverflow) 1971-12-03
IL35772A (en) 1974-06-30
CA957281A (en) 1974-11-05
ZA708144B (en) 1972-07-26
FR2081480B1 (enrdf_load_stackoverflow) 1974-08-30
NL7017489A (enrdf_load_stackoverflow) 1971-08-05
DE2061985A1 (de) 1971-08-12
BE759744A (fr) 1971-06-02
GB1290795A (enrdf_load_stackoverflow) 1972-09-27

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