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US3821387A - The treatment of parkinsonism with 3-(omega-substituted alkyl)-indoles - Google Patents

The treatment of parkinsonism with 3-(omega-substituted alkyl)-indoles Download PDF

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US3821387A
US3821387A US00504087A US50408765A US3821387A US 3821387 A US3821387 A US 3821387A US 00504087 A US00504087 A US 00504087A US 50408765 A US50408765 A US 50408765A US 3821387 A US3821387 A US 3821387A
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parkinsonism
indole
ethyl
substituted
indoles
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US00504087A
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W Welstead
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AH Robins Co Inc
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AH Robins Co Inc
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Priority to US00504087A priority Critical patent/US3821387A/en
Priority to US556879A priority patent/US3642803A/en
Priority to GB44649/66A priority patent/GB1167562A/en
Priority to GB25960/69A priority patent/GB1167563A/en
Priority to BR18366866A priority patent/BR6683668D0/en
Priority to SE14453/66A priority patent/SE312556B/xx
Priority to FR1602626D priority patent/FR1602626A/fr
Priority to NL6615028A priority patent/NL6615028A/xx
Priority to DE19661620224 priority patent/DE1620224A1/en
Priority to AT993066A priority patent/AT269870B/en
Priority to CH1537666A priority patent/CH505824A/en
Priority to FR92054A priority patent/FR6253M/fr
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Priority to US05/586,699 priority patent/USRE28973E/en
Assigned to A.H. ROBINS COMPANY, INCORPORATED, A DE CORP. reassignment A.H. ROBINS COMPANY, INCORPORATED, A DE CORP. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). 12-14-89 DELAWARE Assignors: A.H. ROBINS COMPANY, INCORPORATED, A CORP. OF VA (INTO)
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

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  • the present invention relates to certain heterocyclic organic compounds which may be referred to as 3- (omega-substituted alkyl) indoles, acid addition and quaternary ammonium salts thereof, therapeutic compositions containing the same as active ingredients, and methods of making and administering them.
  • novel compounds of the present invention have utility as physiologically active agents and are particularly effective in diminishing the tremors and muscular rigidity of Parkinsonism.
  • the compounds are also useful as tranquilizers.
  • Prior art literature contains examples of 3-(omega substituted alkyl) indoles. Those which have been examined in animal bodies have shown limited therapeutic value and are not disclosed to have anti'Parkinson activity. More recently a series of l-,2-, and 3-[2-(4- substituted piperazinyl)ethyl]indoles has been the subject of US. Pat. No. 3,188,313 with the disclosure of their therapeutic application as CNS depressants. However, these are likewise not disclosed to have anti- Parkinsonism acitivity.
  • Medicaments that have been used to ameliorate the symptoms of Parkinsonism have been derived from the belladonna group of alkaloids, particularly atropine and scopolamine; in addition synthetic medicinals such as Pa'rsidol (TM), Artane (TM), Kemadrin (TM) and Disipal (TM) among others and certain antihistamine compounds have been used with varying degrees of success. Although all of the aforementioned drugs have been of therapeutic value in treating the tremors and muscular rigidity of Parkinsonism, prior to this invention no single preparation has been found to be universally tolerated.
  • An additional object is the provision of compounds useful as anti-Parkinson agents and which produce minimal side effects.
  • a further ob ject is to provide a method of using said drugs in the treatment of living animal and especially mammalian bodies.
  • a still further object is to provide pharmaceutical compositions which embody the said agents.
  • a still further object is to provide a method for preparing said novel 3-(omega substituted alkyl) indoles. Additional objects will be apparent to one skilled in the art and still further objects will become apparent hereinafter.
  • novel compounds of the present invention can be represented by the following formula:
  • R is selected from the group consisting of hydrogen. lower-alkyl, lower-alkanoyl, aroyl, monocarbocyclic aryl, phenyl-lower-alkyl and cycloalkyl;
  • R is selected from the group consisting of hydrogen, lower-alkyl and monocarbocyclic aryl;
  • R" is selected from the group consisting of halogen having an atomic weight less than 80, trifluoromethyl, hydroxyl, lower-alkyl, loweralkoxy and aralkoxy;
  • R' is selected from the group consisting of monocarbocyclic aryl and hydrogen;
  • A is selected from the group consisting of hydrogen, loweralkyl, lower-alkynyl, lower alkanoyl, monocarbocyclic aryl, monocarbocyclic aroyl and monocarbocyclic aryl carbamoyl;
  • n is an integer from 0-3 inclusive and m is either zero or one.
  • lower-alkyl as used herein includes straight and branched chain radicals of up to five carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, amyl and the like.
  • Lower-alkoxy has the formula --o--lower-alkyl.
  • cycloalkyl as used herein includes primarily cyclic alkyl radicals containing three up to nine carbon atoms inclusive and encompasses such groups as cyclopropyl, cyclobutyl, cyclopentyl, methylcyclohexyl, ethylcyclopentyl and propylcyclohexyl. Included in the term phenyllower alkyl" are groups such as benzyl, phenethyl, methylbenzyl, phenpropyl and the like. Lower-allkanoyl has the formula Ill lower-alkyl. Aroyl has the formula monocarbocyclic aryl, and aralkoxyl has the formula: o-lower-alkyl-monocarbocyclic aryl.
  • monocarbocyclic aryl is meant a phenyl radical or a phenyl radical substituted by one or more substitutents selected from the group consisting of halogen having an atomic weight less than 80, lower-alkyl, hydroxy, carboxy, lower-alkoxy and trifluoromethyl.
  • the lower-alkyl and lower-alkoxy radicals can contain up to about three carbon atoms and each monocarbocyclic aryl radical, together with said substituents, can contain from six to about nine carbon atoms.
  • the monocarbocyclic aryl radical is substituted by more than one of the above substituents, the substituent can be the same or different and can occupyany of the available positions on the phenyl ring.
  • R represents a monocarbocyclic aryl radical it can represent an organic radical such as phenyl or a phenyl radical substituted by one or more substituentssuch as fluoro, chloro, bromo,
  • This invention also includes acid addition salts of the above defined bases formed with nontoxic organic and inorganic acids.
  • Such salts are easily prepared by methods known in the art.
  • the toxicity or nontoxicity of the salt is immaterial when the compounds are to be used as pharmaceuticals, they are most conveniently used in the form of nontoxic acidaddition or quaternary ammonium salts. Both toxic and nontoxic salts are therefore within the purview of the invention.
  • the acids which can be used to prepare the preferred nontoxic acid-addition salts are those which produce, when combined with the free bases, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side-effects ascribable to the anions.
  • the base is reacted with the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as ethanol or isopropanol, with isolation of the salt by concentration and cooling, or the base is reacted with an excess of the acid in aqueous immiscible solvent, such as ethyl ether or isopropyl ether, with the desired salt separating directly.
  • aqueous miscible solvent such as ethanol or isopropanol
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, citraconic, itaconic, hexamic, p-aminobenzoic, glutamic, stearic and the like.
  • inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • this invention includes pharmaceutically acceptable, nontoxic quaternary ammonium salts of the above defined bases.
  • the quaternary ammonium salts are readily formed by treatment of the corresponding free base with the appropriate salt-forming substance, including, for example, methyl chloride, methyl bromide, methyl iodide, methyl sulfate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-propyl iodide, isobutyl iodide, sec-butyl bromide, n-amyl chloride, n-amyl bromide, n-amyl iodide, isoamyl chloride, n-hexyl chloride, nhexyl bromide, n-hexyl iodide or similar quaternary salt-forming substances, according to general procedures which are
  • novel compounds of this invention are prepared starting from readily available selected indoles or from indoles prepared by the Fischer indole synthesis.
  • the indoles are reacted with oxalyl chloride at to 25C. according to the procedure of Speet'er and Anthony, J. Am. Chem. Soc. 76,6208-l0( 1954) in an organic solvent inert under the conditions of the reaction, such as ether, dioxane, and the like to give indole-3-glyoxyloyl chloride.
  • the preferred solvent is ether.
  • the indole-3-glyoxyloyl chloride is then reacted with an appropriate 4-substituted piperidine or 3-substituted pyrrolidine in a suitable solvent such as benzene, chloroform, dioxane, toluene, acetonitrile and the like, which will not enter into the reaction but which will provide a rection medium.
  • a suitable solvent such as benzene, chloroform, dioxane, toluene, acetonitrile and the like, which will not enter into the reaction but which will provide a rection medium.
  • An acid acceptor which may be an excess amount of the reacting pyrrolidine compound, a tertiary amine or an alkali metal salt of a weak acid may be used, the alkali metal salt of a weak acid, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, and the like being the preferred acid acceptor.
  • indole-3-glyoxyloyl chloride is not readily hydrolyzed by water at or about room temperature and in an alternative procedure the reaction between an indole-3-glyoxyloyl chloride and the selected substituted piperidine or pyrrolidine can be conveniently carried out in a chloroform-water mixture.
  • the alternate method is particularly convenient when the acid acceptor employed is an alkali metal salt of a weak acid.
  • The-purpose of the acid acceptor is to take up the hydrogen halide which is split out during the course of the reaction.
  • the reaction is conveniently carried out at or about room temperature for a period of about 3 to 5 hours.
  • Isolation of the product a l- (indol-3-ylglyoxyloyl)-3-substituted pyrrolidine or 4- substituted piperidine, is achieved by dilution of the reaction mixture with water, separation of the organic and aqueous layers, and drying and concentration of the organic layer.
  • the crude products are best purified by crystallization from a suitable solvent, chromatography or formation of a readily crystallizable organic or inorganic salt.
  • the preparation of the novel compounds of the present invention is not limited by the preceding described method and they can be prepared by alternative procedures.
  • appropriately substituted indole-3-acetic acids are prepared from appropriately substituted hydrazones by the Fischer indole synthesis.
  • the substituted indole-3-acetic acids thus prepared are reduced by metal hydrides to the corresponding substituted 3-(2-hydroxyethyl) indoles.
  • Reaction of the latter with a thionyl halide furnishes a substituted 3-(2-haloethyl) indole, the gaseous by-products sulfur dioxide and hydrogen halide being removed from the reaction system by application of a slight vacuum or by sweeping the by-product gases out of the reaction system by the use of an inert gas as, for example, nitrogen.
  • Preparation 3 b 3-Pyrrolidinol (0.95 g.; 0.01 mole) was added to a stirred mixture of 2.9 g. (0.01 mole) of 5,6? di'methoxy-ind0le-3-glyoxyloyl chloride, 4.0 g. of so dium carbonate and ml. of benzene. After stirring overnight at room temperature, 50 ml. of water was added. The mixture was stirred 30 minutes, filtered and the cake washed with water and then with benzene. The dried material weighed 1.45 g. (45 percent) and melted at 222 to 225.
  • trimethoxybenzoyloxy)-pyrrolidine trimethoxy-benzoyloxy)-pyrrolidine 1-[(2-Phenylindol-3-yl)glyoxyloyll]-3- ethoxypyrrolidine 1-[(5-Hydroxyindol-3-yl)glyoxylo yl]-3-(4- methoxyphenyl-carbamoyloxy)-pyrrolidine 1-(1ndol-3-y1glyoxyloyl)-3-(2-propynyloxy)- pyrrolidine 1-[(5,7-Dichloroindol-3-yl)glyoxyloyl]-3-(omethoxyphenoxy)-pyrrolidine 1-[( l -Ethylindol-3-yl)glyoxy1oyl]-3- hydroxypyrrolidine l-[(2,7-Dimethyl-4-chloroindol-3-yl)glyoxyloyl]
  • Example 1 3-[2-( 3-Hydroxypyrrolidinyl)ethyl]indole
  • a suspension of 11 g. (0.043- mole) of 1-(indol-3- ylglyoxyloyl)-3-pyrrolidinol in 50 ml. of tetrahydrofuran was added dropwise, under nitrogen, to a stirred suspension of 9.8 g. (0.026 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran.
  • the mixture was refluxed for 2 hours, cooled, and treated with enough water to destroy the excess lithium aluminum hydride.
  • the resulting aluminum hydroxide was filtered off and washed thoroughly with tetrahydrofuran. The filtrate was evaporated on a rotating evaporator to an oil which solidified on standing. Crystallization from acetonitrile gave a melting point of 144-146; yield, 7.7 g. (78 percent).
  • Example 2 2-Methyl-3- ⁇ 2-[ 3-( 3 ,4,S-trimethoxybenzoyloxy )pyrrolidinyl- ]ethyl ⁇ indole
  • the mixture was stirred under anhydrous conditions for 24 hours, then treated with 25ml. of water and stirred an additional hour.
  • the chloroform layer was separated, dried over magnesium sulfate and evaporated on a rotating evaporator to a viscous oil.
  • Example 3 with tetrahydrofuran. Evaporation of the combined filtrates gave an oil which would not crystallize. The oil was dissolved in acetone and treated with dry HCl gas. On cooling 18.5 g. of impure product precipitated. Recrystallization from isopropanol-acetonitrile (90:10)
  • Example 4 ⁇ 2-[3-(3,4,S-Trimethoxybenzoyloxy)pyrrolidinyl ]ethyl ⁇ indole Y
  • 3 g. (0.013 mole) of 3-[2-(3- hydroxypyrrolidinyl)ethyl]indole, 3 g. (0.013 mole) of 3,4,5-trimethoxybenzoyl chloride and 5 g. (0.05 mole) of sodium carbonate in 40 ml. of chloroform was.
  • the product was chromatographed on a Florisil column (60-100 mesh) and eluted with benzene, then benzene with increasing amounts of acetone. At 10 percent acetone-benzene pure product began to elute from the column (TLC shows single spot); yield 4.3 g. (78 percent).
  • the glassy solid could be crystallized from benzene orbenzene-ligroin giving a solid which melted between 79 and 86 with gas evolution. Analysis as well as the infrared spectrum indicated thatthe solid was a benzene solvate.
  • Example 7 6-Dimethoxy-3-[2-( 3-hydroxypyrrolidinyl )ethyl]indole hydrochloride monohydrate
  • a mixture of 5.5 g. (0.017 mole of l-[(5,6- dimethoxy-indol-3-yl)glyoxyloyll-3-pyrrolidinol in 50 ml. of dry tetrahydrofuran was added dropwise to a stirred suspension of 2.85 g. (0.075 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran under nitrogen. After addition the mixture was refluxed for 4 hours, cooled in ice and treated with a saturated sodium sulfate solution.
  • compositions comprising, as active ingredient, at least one of the compounds according to the invention in association with a pharmaceutical carrier or excipient.
  • the compounds may be presented in a form suitable for oral or parenteral administration.
  • compositions for oral administration can be solid or liquid and can take the form of capsules, tablets, coated tablets, suspensions, etc., such compositions comprising carriers or excipients conveniently used in the pharmaceutical art.
  • suitable tableting excipients inelude lactose, potato and maize starches, talc, gelatin, and stearic and 'silicic acids, magnesium stearate, and polyvinyl pyrrolidone.
  • the carrier or excipient may be -a sterile, parenterally acceptable liquid, e.g., water or a parenterally acceptable oil, e.g., araehis oil, contained in ampoules.
  • compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient.
  • Tablets, coated tablets, capsules, and ampoules are examples of preferred dosage unit forms according to the invention.
  • Each dosage unit adapted for oral administration can conve-' niently contain 25 to 500 mg., and preferably 100 to 250 mg. of the active ingredient; whereas each dosage unit adapted for intramuscular administration can conveniently contain to 150 mg, and preferably 50 to 150 mg. of the active ingredient.
  • compositions within the preferred ranges given are as follows:
  • Tablets Ingredients MgJTab.
  • step No. l Add sufficient water portionwise 'to the blend from step No. l with careful stirring after each addition. Such additions of water and stirring continue until the mass is of a consistency to permit its conversion to wet granules.
  • the wet mass is converted to granules by passing it through the oscillating granulator, using 8-mesh screen.
  • the wet granules are then dried in an oven at 5.
  • the dried granules are then passed through an oscillating granulator, using a IO-mesh screen.
  • the lubricated granules are compressed on a suitable tablet press.
  • Intramuscular Injection Ingredients Per ml.
  • Active Ingredient 50.0 mg.
  • Isotonic Buffer Solution 4.0 q.s. to 2.0 ml.
  • Procedure I Dissolve the active ingredient in the buffer solution.
  • the ampoules are sealed under aseptic conditions.
  • a therapeutic composition for anti-Parkinsonism comprising (1) an effective amount of at least about I wherein:
  • R is selected from the group consisting of hydrogen
  • lower-alkyl lower-alkanoyl, benzoyl, phenyl, phenyllower-alkyl and cycloalkyl having three to nine carbon atoms; 7 i
  • R is selected from the group consisting of hydrogen
  • A is selected from the group consisting of hydrogen, lower-alkyl, lower-alkynyl, lower-alkanoyl, phenyl, benzoyl and N-phenyl carbamoyl;
  • n is zero or one and n is zero to three inclusive
  • a method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of a compound of claim 2.
  • a method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body 7.
  • a method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of 3-[2-(4- h ydroxy-4-phenylpiperidinyl )ethyl lzindole.

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Abstract

3-(Omega-substituted alkyl) indoles and their use in the treatment of Parkinsonism.

Description

United States Patent [191 Welstead, Jr. 1 June 28, 1974 THE TREATMENT OF PARKINSONISM 424/274, 267
WITH S-(OMEGA-SUBSTITUTED ALKYDJNDOLES [56] References Cited [75] Inventor: William J. Welstead, Jl'., Richmond, UNITED STATES PATENTS 3,075,986 1/1963 Jacob 260/294 [73] Assignee: A. H. Robins Company, Inc., 3,183,235 5/1965 Zenitz 260/294 Richmond, Va 3,217,011 11/1965 Zenitz 260/294 3,238,215 3/1966 Zenitz 260/294 [22] Filed: Oct. 23, 1965 [21] Appl. No.: 504,087 Primary Examiner-Stanley J. Friedman [52] U.S. C1 424/267, 260/294, 260/294.3, [57] ABSTRACT 260/294'7 26052615 424/274 3-(Omega-substituted alkyl) indoles and their use in [51] h lt. the treatment of Parkinsonism. [58] Field of Search 167/65 M, 65, 65 AC; 1
260/294.7 G, 294 A, 294.3 A, 326.15;
7 Claims, N0 Drawings THE TREATMENT OF PARKINSONISM WITH 3-(OMEGA-SUBSTIIUTET) ALKYl -IlflDOLES The present invention relates to certain heterocyclic organic compounds which may be referred to as 3- (omega-substituted alkyl) indoles, acid addition and quaternary ammonium salts thereof, therapeutic compositions containing the same as active ingredients, and methods of making and administering them.
The novel compounds of the present invention have utility as physiologically active agents and are particularly effective in diminishing the tremors and muscular rigidity of Parkinsonism. The compounds are also useful as tranquilizers.
Prior art literature contains examples of 3-(omega substituted alkyl) indoles. Those which have been examined in animal bodies have shown limited therapeutic value and are not disclosed to have anti'Parkinson activity. More recently a series of l-,2-, and 3-[2-(4- substituted piperazinyl)ethyl]indoles has been the subject of US. Pat. No. 3,188,313 with the disclosure of their therapeutic application as CNS depressants. However, these are likewise not disclosed to have anti- Parkinsonism acitivity.
Medicaments that have been used to ameliorate the symptoms of Parkinsonism have been derived from the belladonna group of alkaloids, particularly atropine and scopolamine; in addition synthetic medicinals such as Pa'rsidol (TM), Artane (TM), Kemadrin (TM) and Disipal (TM) among others and certain antihistamine compounds have been used with varying degrees of success. Although all of the aforementioned drugs have been of therapeutic value in treating the tremors and muscular rigidity of Parkinsonism, prior to this invention no single preparation has been found to be universally tolerated. Moreover, all previously known drugs which have been demonstrated to be useful in treating Parkinsonism have produced undesirable side effects, and in some instances the effective therapeutic dose produces the toxic symptoms common to all the drugs, including, for example, dryness of mouth, nausea, giddiness, blurred vision, nervousness, tinnitus, sore mouth, mental confustion, marked agitation, epigastric burning, heavy feeling in the limbs of sensations of tingling in them, disorientation, anorexia and transient psychotic episodes. The ability to suppress the distressing and sometimes incapacitating symptoms of Parkinsonism without concurrent undesirable side effects is highly desirable in an anti-Parkinson agent. Agents possessing this ability have been diligently sought.
It is an object of the present invention to provide novel compounds that are useful in the palliative treatment of Parkinsonism. An additional object is the provision of compounds useful as anti-Parkinson agents and which produce minimal side effects. A further ob ject is to provide a method of using said drugs in the treatment of living animal and especially mammalian bodies. A still further object is to provide pharmaceutical compositions which embody the said agents. A still further object is to provide a method for preparing said novel 3-(omega substituted alkyl) indoles. Additional objects will be apparent to one skilled in the art and still further objects will become apparent hereinafter.
The novel compounds of the present invention can be represented by the following formula:
wherein:
R is selected from the group consisting of hydrogen. lower-alkyl, lower-alkanoyl, aroyl, monocarbocyclic aryl, phenyl-lower-alkyl and cycloalkyl; R is selected from the group consisting of hydrogen, lower-alkyl and monocarbocyclic aryl; R" is selected from the group consisting of halogen having an atomic weight less than 80, trifluoromethyl, hydroxyl, lower-alkyl, loweralkoxy and aralkoxy; R' is selected from the group consisting of monocarbocyclic aryl and hydrogen; A is selected from the group consisting of hydrogen, loweralkyl, lower-alkynyl, lower alkanoyl, monocarbocyclic aryl, monocarbocyclic aroyl and monocarbocyclic aryl carbamoyl; n is an integer from 0-3 inclusive and m is either zero or one.
In the definition of symbols in the foregoing Formula (l) and where they appear elsewhere throughout this specification, the terms have the following significance.
The term lower-alkyl as used herein includes straight and branched chain radicals of up to five carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, amyl and the like. Lower-alkoxy" has the formula --o--lower-alkyl. The term cycloalkyl as used herein includes primarily cyclic alkyl radicals containing three up to nine carbon atoms inclusive and encompasses such groups as cyclopropyl, cyclobutyl, cyclopentyl, methylcyclohexyl, ethylcyclopentyl and propylcyclohexyl. Included in the term phenyllower alkyl" are groups such as benzyl, phenethyl, methylbenzyl, phenpropyl and the like. Lower-allkanoyl has the formula Ill lower-alkyl. Aroyl has the formula monocarbocyclic aryl, and aralkoxyl has the formula: o-lower-alkyl-monocarbocyclic aryl.
By monocarbocyclic aryl is meant a phenyl radical or a phenyl radical substituted by one or more substitutents selected from the group consisting of halogen having an atomic weight less than 80, lower-alkyl, hydroxy, carboxy, lower-alkoxy and trifluoromethyl. The lower-alkyl and lower-alkoxy radicals can contain up to about three carbon atoms and each monocarbocyclic aryl radical, together with said substituents, can contain from six to about nine carbon atoms. When the monocarbocyclic aryl radical is substituted by more than one of the above substituents, the substituent can be the same or different and can occupyany of the available positions on the phenyl ring. When the substituent is lower alkyl, said constituent can be straight or branched and can contain from about one to about three carbon atoms. Thus when R represents a monocarbocyclic aryl radical it can represent an organic radical such as phenyl or a phenyl radical substituted by one or more substituentssuch as fluoro, chloro, bromo,
methyl, isopropyl, hydroxy, carboxy, methoxy, propoxy or trifluoromethyl.
This invention also includes acid addition salts of the above defined bases formed with nontoxic organic and inorganic acids. Such salts are easily prepared by methods known in the art. When the compounds are to be used as intermediates for preparing other compounds or for any other non-pharmaceutical use, the toxicity or nontoxicity of the salt is immaterial when the compounds are to be used as pharmaceuticals, they are most conveniently used in the form of nontoxic acidaddition or quaternary ammonium salts. Both toxic and nontoxic salts are therefore within the purview of the invention. The acids which can be used to prepare the preferred nontoxic acid-addition salts are those which produce, when combined with the free bases, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side-effects ascribable to the anions.
The base is reacted with the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as ethanol or isopropanol, with isolation of the salt by concentration and cooling, or the base is reacted with an excess of the acid in aqueous immiscible solvent, such as ethyl ether or isopropyl ether, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, citraconic, itaconic, hexamic, p-aminobenzoic, glutamic, stearic and the like. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
In addition, this invention includes pharmaceutically acceptable, nontoxic quaternary ammonium salts of the above defined bases. The quaternary ammonium salts are readily formed by treatment of the corresponding free base with the appropriate salt-forming substance, including, for example, methyl chloride, methyl bromide, methyl iodide, methyl sulfate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-propyl iodide, isobutyl iodide, sec-butyl bromide, n-amyl chloride, n-amyl bromide, n-amyl iodide, isoamyl chloride, n-hexyl chloride, nhexyl bromide, n-hexyl iodide or similar quaternary salt-forming substances, according to general procedures which are well known in the art.
It will be readily apparent to one skilled in the art that certain compounds of this invention may be present as optical isomers. The connotation of the general formulas presented herein is to include all isomers, the separated d or 1 isomers as well as the dl mixtures of these isomers.
In general, the novel compounds of this invention are prepared starting from readily available selected indoles or from indoles prepared by the Fischer indole synthesis. The indoles are reacted with oxalyl chloride at to 25C. according to the procedure of Speet'er and Anthony, J. Am. Chem. Soc. 76,6208-l0( 1954) in an organic solvent inert under the conditions of the reaction, such as ether, dioxane, and the like to give indole-3-glyoxyloyl chloride. The preferred solvent is ether.
The indole-3-glyoxyloyl chloride is then reacted with an appropriate 4-substituted piperidine or 3-substituted pyrrolidine in a suitable solvent such as benzene, chloroform, dioxane, toluene, acetonitrile and the like, which will not enter into the reaction but which will provide a rection medium. An acid acceptor which may be an excess amount of the reacting pyrrolidine compound, a tertiary amine or an alkali metal salt of a weak acid may be used, the alkali metal salt of a weak acid, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, and the like being the preferred acid acceptor. It was observed that indole-3-glyoxyloyl chloride is not readily hydrolyzed by water at or about room temperature and in an alternative procedure the reaction between an indole-3-glyoxyloyl chloride and the selected substituted piperidine or pyrrolidine can be conveniently carried out in a chloroform-water mixture. The alternate method is particularly convenient when the acid acceptor employed is an alkali metal salt of a weak acid. The-purpose of the acid acceptor is to take up the hydrogen halide which is split out during the course of the reaction. The reaction is conveniently carried out at or about room temperature for a period of about 3 to 5 hours. Isolation of the product, a l- (indol-3-ylglyoxyloyl)-3-substituted pyrrolidine or 4- substituted piperidine, is achieved by dilution of the reaction mixture with water, separation of the organic and aqueous layers, and drying and concentration of the organic layer. The crude products are best purified by crystallization from a suitable solvent, chromatography or formation of a readily crystallizable organic or inorganic salt.
The reduction of the l-(indol-3-ylglyoxyloyl)-3- substituted pyrrolidines and 4-substituted piperidines to the novel 3-[2-(3-substituted pyrrolidinyl)ethyl]indoles and 3-[2-(4-substituted piperidinyl)ethyl]indoles of the present invention is achieved by metal hydride reduction in anhydrous tetrahydrofuran. The com pound to be reduced is dissolved or suspended in tetrahydrofuran and added dropwise, under nitrogen, to a stirred suspension of lithium aluminum hydride in the aforementioned organic solvent. After refluxing the stirred reaction mixture for about 2 to 5 hours, the reaction mixture is worked up by procedures well known in the art. The indoles may be purified by vacuum distillation or by crystallization of their well-defined organic or inorganic salts.
The preparation of the novel compounds of the present invention isnot limited by the preceding described method and they can be prepared by alternative procedures. In one alternative method appropriately substituted indole-3-acetic acids are prepared from appropriately substituted hydrazones by the Fischer indole synthesis. The substituted indole-3-acetic acids thus prepared are reduced by metal hydrides to the corresponding substituted 3-(2-hydroxyethyl) indoles. Reaction of the latter with a thionyl halide furnishes a substituted 3-(2-haloethyl) indole, the gaseous by-products sulfur dioxide and hydrogen halide being removed from the reaction system by application of a slight vacuum or by sweeping the by-product gases out of the reaction system by the use of an inert gas as, for example, nitrogen. By treating the resulting substituted 3-( 2-haloethyl) indoles with a selected 3-substituted pyrrolidine or 4- substituted piperidine in the presence of a suitable acid acceptor which may be an excess of the pyrrolidine compound, a tertiary amine or an alkali metal salt of a weak acid, the desired 3-[2'(3-substituted pyrrolidinyl) PREPARATION OF INTERMEDIATES Preparation 1 1( lndol-3-ylgloxyloyl )-3-( o-methoxyphenoxy) pyrrolidine To a stirred mixture of 11.5 g. (0.06 mole) of 3-(0- methoxyphenoxy) pyrrolidine and g. of sodium carbonare in 100 ml. of chloroform and 35 ml. of water was added slowly over a 10 minute period 11.5 g. (0.056 mole) of indole-3-glyoxyloyl chloride. After stirring one hour ml. of water was added and stirring continued an additional 2 hours; The organic layer was separated and washed successively with water, 3N hydrochloric acid, water and 3N sodium hydroxide. The chloroform solution was dried over magnesium sulfate and concentrated leaving a viscous oil which solidified on standing. The solid was suspended in hot benzene and treated with absolute ethanol until solution of the solid occurred. After concentrating the solution to twothirds of the original volume, isooctane was added to the hot solution. After cooling 17.0 g. (83 percent) of product separated, m.p. 173 to 176C. Recrystallization from the same solvent system raised the melting point to 175 to 177C.
Analysis: Calculated for C, H N,O,: Found:
Preparation 2 l-[(2-Methylindol-3-yl )glyoxyloyl]-3- hydroxypyrrolidine 3-Pyrrolidinol 12.5 g.; 0.144 mole) was added dropwise over a 30 minute period to a vigorously stirred mixture of 32 g. (0.144 mole) of 2-methylindole-3- glyoxyloyl chloride, 40 g. of sodium carbonate and 400 ml. of dry benzene. After stirring 24 hours at room temperature, 200 ml. of water was added, the original solid suspension changing to a red gum. After standing several days in benzene the red gum solidified to a red solid melting at 180 to 190. The melting point could not be improved but thin layer chromatography indicated the material to be quite pure. The uield was 25.0 g. (64 percent).
Preparation 3 b. 3-Pyrrolidinol (0.95 g.; 0.01 mole) was added to a stirred mixture of 2.9 g. (0.01 mole) of 5,6? di'methoxy-ind0le-3-glyoxyloyl chloride, 4.0 g. of so dium carbonate and ml. of benzene. After stirring overnight at room temperature, 50 ml. of water was added. The mixture was stirred 30 minutes, filtered and the cake washed with water and then with benzene. The dried material weighed 1.45 g. (45 percent) and melted at 222 to 225.
Preparation 4 Analysis: Calculated for C H N O C.65.l0;H,5.46;N.10.85 Found: C.65.19: 11.5.48; N,lO.97
By following the manipulative procedures of Preparations 1-4 and substituting for the reactants used therein an appropriated indole-3-glyoxyloyl chloride and an appropriate 3 -substituted oxypyrrolidine or 4- substituted oxypiperidine the following intermediates are prepared.
l (Indol-3-ylglyoxyloyl)-3-(3,4,5 trimethoxyphenylcarbamoyloxy)-pyrrolidine l-(Indol-3-ylglyoxyloyl)-3-(4- methoxyphenylcarbamoyloxy)-pyrrolidine l-(Indol-3-ylglyoxyloyl)-3-(3,4,5-
' trimethoxybenzoyloxy)-pyrrolidine trimethoxy-benzoyloxy)-pyrrolidine 1-[(2-Phenylindol-3-yl)glyoxyloyll]-3- ethoxypyrrolidine 1-[(5-Hydroxyindol-3-yl)glyoxylo yl]-3-(4- methoxyphenyl-carbamoyloxy)-pyrrolidine 1-(1ndol-3-y1glyoxyloyl)-3-(2-propynyloxy)- pyrrolidine 1-[(5,7-Dichloroindol-3-yl)glyoxyloyl]-3-(omethoxyphenoxy)-pyrrolidine 1-[( l -Ethylindol-3-yl)glyoxy1oyl]-3- hydroxypyrrolidine l-[(2,7-Dimethyl-4-chloroindol-3-yl)glyoxyloyl]-3- phenoxy-pyrrolidine Theexamples below illustrate in detail some of the compounds which comprise this invention and methods for their production. However, this invention is not to be construed as limited thereby in spirit or in scope. It will be apparent to one skilled in the art that numerous modifications in materials and methods'can be adopted without departing from the invention.
Example 1 3-[2-( 3-Hydroxypyrrolidinyl)ethyl]indole A suspension of 11 g. (0.043- mole) of 1-(indol-3- ylglyoxyloyl)-3-pyrrolidinol in 50 ml. of tetrahydrofuran was added dropwise, under nitrogen, to a stirred suspension of 9.8 g. (0.026 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran. After addition, the mixture was refluxed for 2 hours, cooled, and treated with enough water to destroy the excess lithium aluminum hydride. The resulting aluminum hydroxide was filtered off and washed thoroughly with tetrahydrofuran. The filtrate was evaporated on a rotating evaporator to an oil which solidified on standing. Crystallization from acetonitrile gave a melting point of 144-146; yield, 7.7 g. (78 percent).
Analysis:
Calculated for CHHHNZO: c.7301; H.788; N.l2.16
Found: c.7230; H,7.94;N.12.20
. Example 2 2-Methyl-3- {2-[ 3-( 3 ,4,S-trimethoxybenzoyloxy )pyrrolidinyl- ]ethyl}indole To a suspension of 5 g. (0.02 mole of 2-methyl-3-[2- (3-hydroxypyrrolidinyl)ethyl]indole and 8 g. (0.075 mole) of sodium carbonate in 40 ml. of chloroform was added 4.2 g. (0.018 mole) of 3,4,5-trimethoxybenzoyl chloride in 30 ml. of chloroform. The mixture was stirred under anhydrous conditions for 24 hours, then treated with 25ml. of water and stirred an additional hour. The chloroform layer was separated, dried over magnesium sulfate and evaporated on a rotating evaporator to a viscous oil.
The oil was chromatographed on a Florisil column (60-100 mesh) and eluted with benzene, then benzene with increasing amounts of acetone. Pure product began eluting with 10 percent acetone-benzene; yield 6.2 g. (79 percent). The pure oil slowly crystallized from ethanol giving 4.8 g. of crystalline solid melting at 119 to 121.
Analysis: Calculated for C H MO C,68.47; H.690, N639 Found: C, 8.41; H.7.l0; N.6.22
Example 3 with tetrahydrofuran. Evaporation of the combined filtrates gave an oil which would not crystallize. The oil was dissolved in acetone and treated with dry HCl gas. On cooling 18.5 g. of impure product precipitated. Recrystallization from isopropanol-acetonitrile (90:10)
gave 13 g. (52 percent) of pure product melting at 208 to 209.
Analysis:
Calculated for C H ClN oz (164.16 H754; N.9.98
Found: (.6437 H.798; N.9.72
Example 4 {2-[3-(3,4,S-Trimethoxybenzoyloxy)pyrrolidinyl ]ethyl}indole Y A mixture of 3 g. (0.013 mole) of 3-[2-(3- hydroxypyrrolidinyl)ethyl]indole, 3 g. (0.013 mole) of 3,4,5-trimethoxybenzoyl chloride and 5 g. (0.05 mole) of sodium carbonate in 40 ml. of chloroform was.
stirred under anhydrous conditions for 24 hours. Then 0.3 g. of additional acid chloride was added and the mixture stirred another 24 hours. The mixture was treated with 50 ml. of water, stirred for 1 hour and the chloroform layer separated and dried over magnesium sulfate. Evaporation of the chloroform on a rotating evaporator gave an oil which would not crystallize.
The product was chromatographed on a Florisil column (60-100 mesh) and eluted with benzene, then benzene with increasing amounts of acetone. At 10 percent acetone-benzene pure product began to elute from the column (TLC shows single spot); yield 4.3 g. (78 percent). The glassy solid could be crystallized from benzene orbenzene-ligroin giving a solid which melted between 79 and 86 with gas evolution. Analysis as well as the infrared spectrum indicated thatthe solid was a benzene solvate.
Analysis: Calculated for JUHJNQOgi C,7l.69', H.682. N.5.57 Found: 1 C,71.46; H.677; N.5.94
Benzene mlvule Example 5 1 mesh Florisil, eluting first with benzene and then benzene with increasing amounts of acetone. At 25 percent acetone-benzene pure product was obtained as a glassy solid; yield 4.2 g. (74 percent).
Analysis: Calculated for C,.H N, O,: C.65.58; H.665; N.9.56 Found: C,65.34; 11.6.86; N.9.57
Example 6 '3- 2-[3-(4- Methoxyphenylcarbamoyloxy)-pyrro1id-.
A stirred suspension of 3.5 g. (0.015 mole) of 3-[2- (3-hydroxypyrrolidinyl)ethyl]indole in 50 ml. of dry benzene was treated dropwise with 2.3 g. (0.015 mole) of p-methoxyphenylisocyanate in 15 ml. of dry benzene. After addition (0.5 hours) the mixture was refluxed for 12 hours after which time only a small amount of solid remained suspended. The residue was filtered off and the filtrate was evaporated under vacuum to an orange gum. The product was dissolved in benzene and chromatographed on 200 g. of 60-100 mesh Florisil, eluting first with benzene then benzene with increasing amounts of acetone. At 20 percent acetone-benzene pure product wasobtained from the column; yield 3.5 g. (60 percent). The glassy solid would not crystallize.
Analysis:
Calculated for C H N O .C,69.63; 11,6.64; N,l 1.07
Found: C,69.35: H,6.76; N,l l.l2
Example 7 ,6-Dimethoxy-3-[2-( 3-hydroxypyrrolidinyl )ethyl]indole hydrochloride monohydrate A mixture of 5.5 g. (0.017 mole of l-[(5,6- dimethoxy-indol-3-yl)glyoxyloyll-3-pyrrolidinol in 50 ml. of dry tetrahydrofuran was added dropwise to a stirred suspension of 2.85 g. (0.075 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran under nitrogen. After addition the mixture was refluxed for 4 hours, cooled in ice and treated with a saturated sodium sulfate solution. The inorganic salts were removed by filtration and washed thoroughly with tetra hydrofuran. The filtrates were evaporated under reduced pressure yielding 4 g. of crude product. Although separation of the pure material from its impurities could be effected using partition chromatography on thin-layer plates, several attempts using larger amounts on a column failed.
The remaining crude product (2 g.) was dissolved in isopropanol and treated with ethereal hydrogen chloride. After standing several days in the cold the drak gray amorphous solid was filtered off, washed with ether and air dried. The product decomposed slowly above 95 and was shown to be a monohydrate by analysis', yield 0.7 g.
Analysis: Calculated for Found:
Am; ysis: Calculated for C H ClN,O,(dried at 162;): Found: cIsoI Example 8 3- 2-[ 3-( o-Methoxyphenoxy)pyrrolidinyl]ethyl} indole hydrochloride A solution of 13.5 g. (0.037 mole) of I-(indol-3- ylglyoxyloyl)-3-(o-methoxyphenoxy)pyrrolidine in 50 ml. of anhydrous tetrahydrofuran was added dropwise to a stirred slurry of 7 g. (0.18 mole) of lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran. The reaction mixture was worked up in the usual manner and the oily basic material which was isolated was dissolved in ether and treated with ethereal hydrogen chloride. The isolated hydrochloride weighed 10.7 g.
(73 percent) and melted with decomposition (gas evolution) near 55 as a result of solvated ether. Thin layer chromatography of a sample of regenerated free base showed a single spot.
Analysis: Calculated for C H CIN Q: Found (after drying at Examples 919 Using the manipulative procedures described in the I above examples the following compounds are pre pared.
Z-Phen'yl-B- 2-( 3 -ethoxypyrrolidinyl )ethyl indole 5-Hydroxy-3- -{2-[3-(4-methoxyphenylcarbamoyloxy)pyrrolidinyl]ethyl}indole 6-Trifluoromethyl-3-[2-(B-benzoyloxypyrrolidinyl)ethyl]indole 3-{2-[3-(2-Propynyloxy)pyrrolidinyl]ethyl}indole 5,7-Dichloro-3-[2-(3-omethoxyphenoxypyrrolidinyl)ethyl]indole l-Ethyl-3-[2-( 3-hydroxypyrrolidinyl)ethyl]indole 2,7-Dimethyl-4-chloro-3-[2-( 3-phenoxypyrrolidinyl- )ethyl]indole 3-[2-(3-Propionyloxypyrrolidinyl)ethyl]indole 5,7-Dihydroxy-3 {2-[ 3-(4-methoxyphenylcarbamoyloxy)pyrrolidinyl]ethyl}indole 3-[2-(4-l-lydroxy-4-phenylpiperidinyl)ethylIindole 3-[ 2-( 4-Phenyl-4-propionoxypiperidinyl )ethyl1indole Pharmacology The compounds of the present invention were scrrened for anti-Parkinsonsim and were observed to be effective in eliminating the pronounced symptom complex of tremor, motor incoordination, lacrimation and catatonia. Injection of 4-methoxyphenethylamine into laboratory animals results in the syndrome of Parkinsonism. The efficacy of the novel compounds was determined by administering each of them to groups of five mice. One hour later 4-methoxypheneth'ylamine was given intraperitoneally. The mice were observed for the symptoms of Parkinsonism and a drugs effectiveness was determined by the complete prevention of tremor, motor incoordination, lacrimation and catatonia. The ED of each drug was determined by the injection of appropriate number of doses and subjecting the results to probit analysis according to the method of J. T. Litchfield and F. Wilcoxon, J. Pharm. and Exptl. Therap. 96, 99 (1949).
The high order of activity of the active agents of the present invention, as evidenced by tests in lower animals (representative of which are reported herein) is indicative of utility in human beings as well as in lower animals. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the Federal Food and Drug Administration, which are responsible for and authorized to pass judgment on such questions.
The invention further provides pharmaceutical compositions comprising, as active ingredient, at least one of the compounds according to the invention in association with a pharmaceutical carrier or excipient. The compounds may be presented in a form suitable for oral or parenteral administration. Thus, for example, compositions for oral administration can be solid or liquid and can take the form of capsules, tablets, coated tablets, suspensions, etc., such compositions comprising carriers or excipients conveniently used in the pharmaceutical art. Thus suitable tableting excipientsinelude lactose, potato and maize starches, talc, gelatin, and stearic and 'silicic acids, magnesium stearate, and polyvinyl pyrrolidone.
For parenteral administration, the carrier or excipient may be -a sterile, parenterally acceptable liquid, e.g., water or a parenterally acceptable oil, e.g., araehis oil, contained in ampoules.
Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, and ampoules are examples of preferred dosage unit forms according to the invention. Each dosage unit adapted for oral administration can conve-' niently contain 25 to 500 mg., and preferably 100 to 250 mg. of the active ingredient; whereas each dosage unit adapted for intramuscular administration can conveniently contain to 150 mg, and preferably 50 to 150 mg. of the active ingredient.
Examples of compositions within the preferred ranges given are as follows:
1. Dissolve 6 and 7 in hot water.
2. This solution, when cool, is mixed with No. 3 and the mixture is stirred until uniform.
3. Dissolve 1,2,4,5 and 8 in this solution and stir until uniform.
Capsules Ingredients Per Cap.
1. Active Ingredient 125.000 mg. 2. Lactose 146.000 mg. 3. Magnesium stcurutc 4.000 mg.
Procedure 1. Blend 1,2 and 3.
2. Mill this blend and blend again. 3. This milled blend is then filled into No. 1 hard gelatin capsules.
Tablets Ingredients MgJTab.
1. Active Ingredient 125.0 mg. 2. Corn Starch 20.0 mg. 3. Kelacid 20.0 mg. 4. Keltose 20.0 mg. 5. Magnesium Stearate 1.3 mg.
Procedure I. Blend 1,2,3 and 4.
2. Add sufficient water portionwise 'to the blend from step No. l with careful stirring after each addition. Such additions of water and stirring continue until the mass is of a consistency to permit its conversion to wet granules.
3. The wet mass is converted to granules by passing it through the oscillating granulator, using 8-mesh screen.
4. The wet granules are then dried in an oven at 5. The dried granules are then passed through an oscillating granulator, using a IO-mesh screen.
6. Lubricate the dry granules with 0.5 percent magnesium stearate.
7. The lubricated granules are compressed on a suitable tablet press.
Intramuscular Injection Ingredients Per ml.
1. Active Ingredient 50.0 mg. 2. Isotonic Buffer Solution 4.0 q.s. to 2.0 ml.
Procedure I. Dissolve the active ingredient in the buffer solution.
2. Aseptically filter the solution from step No. 1.
3. The sterile solution is now aseptically filled into sterile ampoules.
4. The ampoules are sealed under aseptic conditions.
What is claimed and desired to be secured by US.
Letters Patents is:
l. A therapeutic composition for anti-Parkinsonism comprising (1) an effective amount of at least about I wherein:
R is selected from the group consisting of hydrogen,
lower-alkyl, lower-alkanoyl, benzoyl, phenyl, phenyllower-alkyl and cycloalkyl having three to nine carbon atoms; 7 i
R is selected from the group consisting of hydrogen,
lower-alkyl and phenyl;
A is selected from the group consisting of hydrogen, lower-alkyl, lower-alkynyl, lower-alkanoyl, phenyl, benzoyl and N-phenyl carbamoyl; I
m is zero or one and n is zero to three inclusive, and
non-toxic pharmaceutically acceptable acidaddition salts thereof.
3. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of a compound of claim 2.
4. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body 7. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of 3-[2-(4- h ydroxy-4-phenylpiperidinyl )ethyl lzindole.

Claims (6)

  1. 2. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of a compound selected from the group having the structural formula:
  2. 3. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of a compound of claim 2.
  3. 4. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of 3-(2-(3-hydroxypyrrolidinyl)ethyl)indole.
  4. 5. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of a hydrohalide salt of 2-methyl-3-(2-(3-hydroxypyrrolidinyl)ethyl)indole.
  5. 6. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of 2-methyl-3-(2-(3-hydroxypyrrolidinyl)ethyl)indole hydrochloride.
  6. 7. A method of alleviating symptoms of Parkinsonism which comprises administering to a living animal body afflicted therewith an effective amount of 3-(2-(4-hydroxy-4-phenylpiperidinyl)ethyl)indole.
US00504087A 1965-10-23 1965-10-23 The treatment of parkinsonism with 3-(omega-substituted alkyl)-indoles Expired - Lifetime US3821387A (en)

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US00504087A US3821387A (en) 1965-10-23 1965-10-23 The treatment of parkinsonism with 3-(omega-substituted alkyl)-indoles
US556879A US3642803A (en) 1965-10-23 1966-06-13 3-(omega-substituted alkyl)-indoles
GB44649/66A GB1167562A (en) 1965-10-23 1966-10-06 Novel 3-(2-Substituted Ethyl)Indoles and Processes for Their Manufacture
GB25960/69A GB1167563A (en) 1965-10-23 1966-10-06 Novel 3-(2-Substituted Ethyl) Indoles and Processes for Their Manufacture
BR18366866A BR6683668D0 (en) 1965-10-23 1966-10-14 3-ALCOIL (OMEGA REPLACED) -INDOIS
SE14453/66A SE312556B (en) 1965-10-23 1966-10-21
FR1602626D FR1602626A (en) 1965-10-23 1966-10-22
NL6615028A NL6615028A (en) 1965-10-23 1966-10-24
DE19661620224 DE1620224A1 (en) 1965-10-23 1966-10-24 Process for the preparation of indole compounds
AT993066A AT269870B (en) 1965-10-23 1966-10-24 Process for the production of new indole derivatives and their salts
CH1537666A CH505824A (en) 1965-10-23 1966-10-24 Process for the preparation of indoles substituted in the 3-position
FR92054A FR6253M (en) 1965-10-23 1967-01-20
US05/586,699 USRE28973E (en) 1965-10-23 1975-06-13 3-(Omega-substituted alkyl)-indoles

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US4160862A (en) * 1972-06-12 1979-07-10 Sterling Drug Inc. 1-Acyl-3-(amino-lower-alkyl)indoles
US4031221A (en) * 1974-06-17 1977-06-21 American Hoechst Corporation Method of treating pain and hypertension
US4242347A (en) * 1979-06-18 1980-12-30 Ciba-Geigy Corporation Hypotensive indolylalkylpiperidyl guanidines and isoureas
US4861880A (en) * 1982-09-20 1989-08-29 Pfizer Inc. 1-phenyl-2(1H,3H)-indolone psycho-therapeutic agents
US4977178A (en) * 1982-09-20 1990-12-11 Pfizer Inc. Method of treating anxiety and depression with 1-phenyl-2(1H,3H)-indolone psycho-therapeutic agents
US4879391A (en) * 1982-09-20 1989-11-07 Pfizer Inc. 1-Phenyl-2(1H,3H)-indolone psychotherapeutic agents
DE3308668A1 (en) * 1983-03-11 1984-09-13 Merck Patent Gmbh, 6100 Darmstadt INDOLDER DERIVATIVES
DE3430284A1 (en) * 1984-08-17 1986-02-27 Troponwerke GmbH & Co KG, 5000 Köln NEW TRYPTAMINE DERIVATIVES, A METHOD FOR THEIR PRODUCTION AND THEIR USE
EP0187619A3 (en) * 1985-01-03 1987-08-26 Ciba-Geigy Ag 1,3-disubstituted tetrahydropyridines
EP0187122A3 (en) * 1985-01-03 1987-12-16 Ciba-Geigy Ag 1,3,4-trisubstituted azacycloalkanes or azacycloalkenes
DE3835291A1 (en) * 1988-04-19 1989-11-02 Bayer Ag 1,3-DISUBSTITUTED PYRROLIDINES
US5274097A (en) * 1988-04-19 1993-12-28 Bayer Aktiengesellschaft 1,3-disubstituted pyrrolidines
SE9603283D0 (en) * 1996-09-10 1996-09-10 Astra Ab New compounds
TW472045B (en) 1996-09-25 2002-01-11 Astra Ab Protein kinase C inhibitor compounds, method for their preparation, pharmaceutical composition thereof and intermediate used for their preparation
AR017200A1 (en) 1997-12-23 2001-08-22 Astrazeneca Ab INHIBITING COMPOUNDS OF PROTEIN CINASE C, PHARMACEUTICALLY ACCEPTABLE SALTS OF THE SAME, PHARMACEUTICAL FORMULATIONS THAT UNDERSTAND THEM, USE THE SAME AND PROCESS FOR THE SYNTHESIS OF SUCH COMPOUNDS
SE9800835D0 (en) 1998-03-13 1998-03-13 Astra Ab New Compounds
SI1076657T1 (en) 1998-04-28 2004-12-31 Elbion Ag New hydroxyindoles, their use as phosphodiesterase 4 inhibitors and method for producing same
US6492406B1 (en) 1999-05-21 2002-12-10 Astrazeneca Ab Pharmaceutically active compounds
US6346625B1 (en) 1999-06-23 2002-02-12 Astrazeneca Ab Protein kinase inhibitors

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EP0046179A1 (en) * 1980-07-07 1982-02-24 Hoechst-Roussel Pharmaceuticals Incorporated 3-(3-(4-(4-Fluorobenzoyl)piperidyl)propyl)-2-methyl indole and pharmaceutical composition containing it
US20160052924A1 (en) * 2013-03-27 2016-02-25 Bristol-Myers Squibb Company 2-keto amide derivatives as hiv attachment inhibitors
US9586957B2 (en) * 2013-03-27 2017-03-07 VIIV Healthcare UK (No.5) Limited 2-keto amide derivatives as HIV attachment inhibitors

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SE312556B (en) 1969-07-21
US3642803A (en) 1972-02-15
GB1167563A (en) 1969-10-15
FR1602626A (en) 1971-01-04
NL6615028A (en) 1967-04-24
FR6253M (en) 1968-08-19
DE1620224A1 (en) 1970-02-12
CH505824A (en) 1971-04-15
GB1167562A (en) 1969-10-15

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