EP0000825B1 - Geminally disubstituted indene derivatives, processes for their preparation and pharmaceutical compositions containing them - Google Patents

Geminally disubstituted indene derivatives, processes for their preparation and pharmaceutical compositions containing them Download PDF

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EP0000825B1
EP0000825B1 EP78300226A EP78300226A EP0000825B1 EP 0000825 B1 EP0000825 B1 EP 0000825B1 EP 78300226 A EP78300226 A EP 78300226A EP 78300226 A EP78300226 A EP 78300226A EP 0000825 B1 EP0000825 B1 EP 0000825B1
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compound
formula
indene
group
cyclopentane
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EP0000825A1 (en
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Aake Nils Joensson
Tomas Goeran Kempe
Lembit Mikiver
Bengt Aake Sparf
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Phadia AB
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Kabi AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/38—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/453—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/93—Spiro compounds
    • C07C2603/94—Spiro compounds containing "free" spiro atoms

Definitions

  • This invention relates to new geminally disubstituted indenes, to methods for their preparation and to pharmaceutical compositions containing them.
  • the present invention provides geminally disubstituted indenes characterised in that they are of the general formula (I) wherein each of R 1 and R 2 is hydrogen or R 1 and R 2 together form a direct bond or an alkylene group -(CH 2 ) n -, in which n is an integer from 1 to 4, R 3 is hydrogen, C 1-3 -alkoxy or halogen, and each of R 4 and R 5 is hydrogen or C 1-4 -lower alkyl, or R 4 and R 5 together form an alkylene group -(CH 2 ) m -, in which m is an integer from 3 to 6; and the corresponding amine oxides, quaternary ammonium compounds and salts with physiologically acceptable acids.
  • R 1 and R 2 is hydrogen or R 1 and R 2 together form a direct bond or an alkylene group -(CH 2 ) n -, in which n is an integer from 1 to 4
  • R 3 is hydrogen, C 1-3 -alkoxy or halogen
  • the compounds of formula (I) contain an asymmetric carbon atom, and the invention includes racemic and other mixtures of the optical isomers as well as the optically active isomers themselves.
  • the more active isomer can be separated in conventional manner e.g. by fractional crystallization of diastereoisomeric salts.
  • preferred compounds are those in which R 1 and R 2 are each H or those where R 1 and R 2 together represent -(CH 2 ) 3 - or -CH 2 -CH 2 -, those where R 3 is H and those where R 4 is H and R 5 is H or CH 3 .
  • R 3 is alkoxy or halogen
  • the substituent may be for example, methoxy or ethoxy or chloro or bromo, particularly at the 5-position on the indene ring.
  • the compounds of the invention may be presented in free base form or as amino oxides, quaternary ammonium compounds or salts with pharmaceutically acceptable acids.
  • the acid may be inorganic e.g. hydrochloric, sulphuric or phosphoric acid or organic e.g. acetic, oxalic, fumaric or tartaric acids.
  • Quaternary ammonium compounds of interest include those which are triorgano ammonium halides or sulphates e.g. triethylammonium chlorides. Unless the context requires otherwise, references in this specification to the compounds of the invention includes a reference to their amine oxides, quaternary ammonium salts and salts with pharmaceutically acceptable acids.
  • the new compounds according to the invention exhibit interesting pharmacodynamical properties, indicating their utility as drugs.
  • the compounds present a pronounced sympatomimetic effect, illustrated by the effect on rat vas deferens, a screening test for noradrenaline like activity.
  • Tests on isolated urethra strips of cat have shown that a representative example of the compounds of the invention is considerably more active on this organ than noradrenaline, while at the same time exhibiting a clearly reduced hypertensive effect on anaesthetized cat compared to noradrenaline.
  • the selective effect on urethra has also been illustrated by similar tests on aortic strips of rabbit.
  • the compounds of the invention useful as drugs against stress incontinence in women, and the compounds are also of interest as mucous membrane decongestants, as blood pressure reducing agents, and as vasoconstrictors (together with local anaesthetics). Some of the compounds also have anti-reserpine effect.
  • formula I compounds can be prepared by one of the syntheses described below in which the symbol "Ring” denotes the ring system; where R 1 , R 2 and R 3 are as defined above.
  • This reduction can also be carried out when the amino group is blocked by an amino protecting group, which is removed after the reduction.
  • Preferred reducing agents are complex metal hydrides such as sodium borohydride and lithium aluminium hydride, and the reaction is preferably carried out in an inert solvent.
  • Suitable groups Z which can be reduced to the aminomethyl group -CH 2 NR 4 , R 5 under the reduction conditions, are carbamic ester derivatives such as -CH 2 NR 4 , COOAlkyl (which are reduced to imines -CH 2 NR 4 , CH 3 ), dicarboxylic acid-amidomethyl derivatives wherein 1 is an integer from 2 to 4 (which are reduced to tert.amines -CH 2 -N(CH 2 ) 1+2 , amide groups such as -CO-NR 4 R 5 (in which the -CO-group is reduced to -CH 2 -), azidomethyl groups such as -CH 2 -N 3 (which are reduced to -CH 2 -NH 2 ), diazomethyl groups such as -CHN 2 (which are reduced to -CH 2 NH 2 ), and nitromethyl groups -CH 2 NO 2 (which are reduced to -CH 2 NH 2 ).
  • carbamic ester derivatives such as -CH 2 NR 4
  • This reaction can also be carried out by reducing a compound of formula (V), in which the hydroxyl group is protected e.g. by esterification or silylation.
  • the hydroxy protecting group is removed either during the reduction or afterwards, e.g. by hydrolysis.
  • the reductions according to syntheses b) and c) can be carried out by using a great variety of reducing agents and reaction conditions, it being well within the competence of chemists experienced in organic synthesis to choose suitable reducing agents and conditions depending on the nature of the groups to be reduced.
  • the reduction can, for example, be carried out by using a complex metal hydride such as sodium borohydride or lithium aluminium-hydride in an inert solvent.
  • catalytically activated hydrogen can be used, the reaction being carried out in an inert solvent and in the presence of a catalyst such as a platinum, a palladium or a nickel catalyst.
  • This reaction can also be carried out using a compound corresponding to formula (VI), in which the amino group is protected, acyl groups being suitable amino protecting groups. In this case the amino protecting group is removed after the reaction.
  • Preferred oxidizing agents are peroxy acids such as peracetic acid, perbenzoic acid or chloroperbenzoic acid, permanganates or osmium tetroxide.
  • amino protecting group are available to chemists experienced in organic synthesis. These groups can, for example, be split off by hydrolysis (acid or alkaline), by hydrogenation or by hydrazinolysis depending on the nature of the group.
  • Primary and secondary amines of formula (I) can be converted into the corresponding secondary or tertiary amines by alkylation, e.g. by treatment with an alkylating agent such as an alkyl halide.
  • Tertiary amines can similarly be converted into the corresponding quaternary ammonium compounds, especially lower alkyl ammonium compounds.
  • the alkylation can also be carried out by acylation of the primary or secondary amine, whereupon the acyl group is reduced to the corresponding alkyl group in analogy with method b) above.
  • the amines of formula (I) can, if desired, be converted into the corresponding salts with physiologically acceptable acids, and tertiary amines of formula (I) can be converted into the corresponding amine oxides by treatment with a suitable oxidation agent, for example a peroxide such as hydrogen peroxide.
  • a suitable oxidation agent for example a peroxide such as hydrogen peroxide.
  • Tertiary amines of formula (I) can be dealkylated to the corresponding secondary amines, for example as described in the following Examples.
  • the compounds of the invention can be formulated into pharmaceutical compositions together with pharmaceutically acceptable carriers, and the invention includes such compositions, which may be in the form of e.g. tablets or solutions, preferably in unit dose form.
  • the invention also comprises the use of the compounds of the invention in treating stress incontinence, as mucous membrane decongestants, as blood pressure reducing agents, as vasoconstrictors and as anti-reserpine agents and methods of treating the above mentioned conditions by administering a therapeutically effective amount of a compound of formula (I) to a host in need of such treatment.
  • the required dosage varies depending on the needs and requirements in the specific situation and on the specific substance used. For adults, a daily dosage of 0.1 mg to 100 mg is usually sufficient.
  • the 1,1-dialkylindene (1 mole) in dichloromethane (100 ml) is treated dropwise with stirring at 5°C with a solution of bromine (1 mole) in dichloromethane (500 ml). After stirring for an additional 30 minutes, the solvent is evaporated under reduced pressure and the crude 2,3-dibromo-1,1-dialkylindene is dissolved in tetrahydrofuran (1100 ml) and treated at -20°C with potassium tert.-butoxide (112 g). After completed addition, the mixture is allowed to come to about 20°C, diluted with water (3 litres) and extracted with diethyl ether (3 x 400 ml).
  • 3'-Bromospiro(cyciopentane-1,1'-indene) (23 g) is dissolved in tetrahydrofuran (200 ml) and cooled to -70°C. While stirring under nitrogen, n-butyllithium (75 ml of a 2M solution in hexane) is added followed after 30 minutes by acetaldehyde (14 g) in one portion. Stirring and cooling is maintained for 30 minutes whereupon the mixture is allowed to come to about 20°C and is kept there for 2 hours. Water (600 ml) is then added and the solution is extracted three times with diethyl ether. The ether extracts are washed, dried over sodium sulphate and the ether is distilled off. Distillation of the residual oil gives the title alcohol, b.p. 139°C/0.4 torr.
  • step a) The alcohol from step a) (14.3 g) is stirred for 2 days at about 20°C with manganese dioxide (150 g) in light petroleum ether (b.p. 40-60°C; 450 ml). Solid material is filtered off and the filtrate concentrated. Distillation of the residual oil gives the title ketone, b.p. 148-150°C/0.5 torr.
  • Pyrrolidone hydrotribromide [(pyrrolidone) 3 HBr 3] is added at about 20°C to the ketone from step b) (12 g) in tetrahydrofuran (1500 ml) containing 10 drops of concentrated sulphuric acid. The mixture is stirred for 24 hours. Precipitated salts are removed by filtration and the filtrate is concentrated to a small volume. Water (200 ml) is added and the mixture is extracted three times with diethyl ether. After drying the solvent is evaporated, yielding semi-crystalline residue. Crystallization from methanol gives the pure bromoacetyl title compound, m.p. 75-77°C.
  • the bromoacetyl compound from step c) (7.0 g) is added to a solution of dimethylamine (19 g) in methanol (100 ml) and kept for 2 hours. After concentration of the solution, the residual oily material is treated with water and diethyl ether. The ether extract is washed and dried. Evaporation of the solvent gives the title ketoamine as a colourless oil. A sample in diethyl ether is treated with oxalic acid, giving the crystalline hydrogen oxalate, m.p. 215°C.
  • the reaction mixture is stirred under reflux for 4 hours, concentrated hydrochloric acid (2 ml) is added, and the mixture is heated for 15 minutes.
  • the solution is cooled, filtered from the solid precipitate and concentrated to a small volume.
  • the concentrate is made alkaline with 2N sodium hydroxide solution and repeatedly extracted with diethyl ether. Evaporation of the ether and crystallization of the residual product from cyclohexane gives 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, m.p. 76-78°C.
  • the mixture is refluxed overnight and the excess of hydride is decomposed with a slight excess of saturated sodium sulphate solution.
  • the inorganic salts are filtered off and washed with ether and the filtrate is dried.
  • the solution is concentrated to about 200 ml and added to oxalic acid (2.0 g) in diethyl ether.
  • the hydrogen oxalate precipitates and is recrystallized from a mixture of isopropyl alcohol/diisopropyl ether; m.p. 167°C.
  • 5'-Methoxyspiro(cyclopentane-1,1'-indene)-3'-carbaldehyde (4.4g) is added to anhydrous aluminium chloride (0.1 g) in dichloromethane (25 ml). Trimethylsilyl cyanide (2.1 g) is added dropwise to the stirred mixture at about 20°C and the mixture is stirred for 2 hours. The solvent is then removed under reduced pressure at about 25°C bath temperature. The remaining oil is dissolved in anhydrous diethyl ether (50 ml) and slowly added to lithium aluminium hydride (3.5 g) in diethyl ether (200 ml).
  • the mixture is stirred overnight and decomposed by careful addition of saturated, aqueous sodium sulphate solution (30 ml).
  • the solid precipitate is removed by filtration and washed with diethyl ether.
  • the combined filtrate and washings are concentrated to dryness and the solid is crystallized from diisopropyl ether; m.p. 118°C.
  • the hydrogen fumarate is obtained from the base and an excess of fumaric acid in ethanol; m.p. 182°C.
  • N-Methyl-[spiro(cyclopentane-1,1'-indan)-3'-yliden]acetamide (9.6 g; Swedish Patent No. 7203905-0) is dissolved in dichloromethane (200 ml) and added to sodium bicarbonate solution (30 ml; 0.5M). The solution is treated with m-chloroperbenzoic acid (13.76 g of a 50% product) in small portions with stirring at about 20°C. After stirring for an additional 2 hours, the solution is washed with saturated sodium carbonate solution and water and dried with sodium sulphate. The solvent is evaporated and the remaining oil is dissolved in tetrahydrofuran (100 ml).
  • N-Methyl-2-[spiro(cyclopentane-1,1'-indene)-3'-yliden]ethylamine (8.1 g; Swedish Patent No. 7203905-0) in diethyl ether (100 ml) is treated with trifluoroacetic anhydride (8 ml) while being stirred with powdered anhydrous sodium carbonate (6 g). The solid is filtered off and the solvent is evaporated from the filtrate.
  • the crude N-trifluoroacetyl-N-methylspiro(cyclopentane-1,1'-indan)-3'-ylideneethylamine is dissolved in dichloromethane (100 ml), added to sodium bicarbonate solution (40 ml; 0.5M) and treated in portions with m-chloroperbenzoic acid (50%; 3.4 g) with stirring at about 20°C. After stirring for 2 hours, the solution is washed with saturated sodium carbonate solution and water, and dried with sodium sulphate. After filtration, the solvent is evaporated.
  • the crude epoxy compound is dissolved in tetrahydrofuran (100 ml), and treated with perchloric acid (10 drops) at room temperature for 2 hours.
  • Butyllithium in hexane (13 ml of a 2M solution) is added to 3'-bromospiro(cyclopentane-1,1'- indene) (5.0 g) in tetrahydrofuran at -70°C. After 10 minutes a solution of tetramethyloxyamide (5.8 g) in tetrahydrofuran (50 ml) is rapidly added. The mixture is stirred and allowed to come to about 20°C. After 2 hours, it is poured into a mixture of 50 ml 1 M hydrochloric acid and diethyl ether (100 ml) and the ether layer is separated.
  • This oil is dissolved in acetonitrile (100 ml) and added to a hot solution of oxalic acid (2.10 g) in 500 ml of acetonitrile. On' cooling the solution forms colourless crystals of the hydrogen oxalate of the title compound. The crystals are collected and recrystallized from acetonitrile; m.p. 180°C.
  • Ethyl chloroformate (2.06 g) is added dropwise at about 7°C to a stirred mixture of 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (3.35 g) in chloroform (50 ml) and sodium hydroxide (0.9 g) in water (20 ml). After 2 hours, the chloroform phase is separated and the aqueous phase is extracted twice with chloroform. The combined chloroform solutions are dried and concentrated under reduced pressure.
  • An identical product is obtained by reduction of crude 2-acetamido-1-[spiro-(cyclopentane-1,1'-indene)-3'-yl]ethanol acetate obtained by the treatment of 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yljethanol with acetylchloride in diethyl ether containing an excess of triethylamine, removal of the precipitated triethylamine hydrochloride by filtration and evaporation of the filtrate.
  • Phosgene (1 g) is added to dimethylamino-l-[spiro(cyclopentane-1,1'-indene)-3'-yllethanol (2.9 g) in benzene (25 ml). The mixture is stirred at room temperature for 30 minutes and then under reflux for 2 hours. Evaporation of the solvent under reduced pressure gives an oil which crystallizes. Recrystallization from diisopropyl ether gives a pure product, m.p. 75-77°C.
  • the crude title compound is dissolved in acetonitrile and treated with a slight excess of oxalic acid dissolved in acetonitrile.
  • the slowly depositing hydrogen oxalate is collected by filtration and recrystallization from acetonitrile; m.p. 133-134°C.
  • Methyl iodide (8 g) is added to 2-dimethylamino-l-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (1.3 g) in diethyl ether (100 ml). The mixture is kept for 24 hours and the precipitated methiodide is collected by filtration; m.p. 115-120°C (decomposition).
  • (+)-2-Methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (12 g) is dissolved in ethanol (75 ml) and added to a solution of D(-)-tartaric acid (15 g) in water (300 ml) at about 20°C. The mixture is concentrated at reduced pressure to 200 ml and kept overnight at 4°C. The crystalline precipitate is collected and recrystallised from water until constant specific rotation is obtained, which requires 3 to 5 recrystallizations.
  • the technique for making cululative dose-response curves in accordance with van Rossum (1963) was employed.
  • the stimulating drug, noradrenaline (NA) was added to the bath in a manner to achieve geometrically increasing concentrations in the organ bath without washings in between. After each injection of NA the organ was allowed to contract until a state of equilibrium had been reached, and then the next dose of NA was added. This procedure was repeated until no further increase in contraction was obtained.
  • the dosage of NA was adapted to give a concentration step in the bath of 1/2 log 10.
  • the tested concentration interval was 10 -8 -10 -4 M, 3 x 10 -4 M plus maximum effect at 3 x 10- 5 and 10- 4 M.
  • Compounds of formula I, identified as 2-11, and comparison compounds 12-14, were tested by the same technique. The compounds conform to the formula below except where indicated for other values of R 1 , R 2 and R 3 . The test results are given in Table 1 below.
  • the effect is highly structure-specific.
  • the corresponding ketone is inactive; see comparison compound No. 12.
  • the effect disappears when the indene double bond is hydrogenated (see comparison compound No. 13) or when the hydroxyl group is removed (see comparison compound No. 14).
  • the preparation was maintained at pH 7.5 by bubbling a mixture of 93.5 volume-% 0 and 6.5 volume-% C ⁇ 7 through the solution.
  • This experimental set up thus allowed the recording of circular muscle activity as isometric tension changes.
  • the initial tension was set at approximately 0.5 g.
  • the preparation was allowed 1 hour for acclimatization before starting the experiment. All recordings were made from the base line.
  • the drugs were added directly to the organ- baths and cumulative dose-response curves were recorded.
  • Noradrenaline has consistently been used as a reference drug for agonistic action.
  • the substances tested as agonists were noradrenaline bitartrate (NA) and the above compound No. 3.
  • NA noradrenaline bitartrate
  • the test results are reported in Table 2 below, which also indicates the results of corresponding tests on aortic strips of rabbit in order to illustrate the selective effect on urethra of the compound according to the invention.

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EP78300226A 1977-08-05 1978-08-01 Geminally disubstituted indene derivatives, processes for their preparation and pharmaceutical compositions containing them Expired EP0000825B1 (en)

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GB3294777 1977-08-05
GB3294777 1977-08-05

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EP0000825A1 EP0000825A1 (en) 1979-02-21
EP0000825B1 true EP0000825B1 (en) 1982-04-14

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US (1) US4218472A (en:Method)
EP (1) EP0000825B1 (en:Method)
JP (1) JPS5444651A (en:Method)
AT (1) AT367018B (en:Method)
AU (1) AU527825B2 (en:Method)
CA (1) CA1109066A (en:Method)
DE (1) DE2861735D1 (en:Method)
DK (1) DK150538C (en:Method)
ES (1) ES472291A1 (en:Method)
FI (1) FI71724C (en:Method)
IE (1) IE47716B1 (en:Method)
IT (1) IT1099587B (en:Method)
NO (1) NO147420C (en:Method)
NZ (1) NZ188037A (en:Method)
PT (1) PT68383A (en:Method)
ZA (1) ZA784349B (en:Method)

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US4331549A (en) * 1980-04-21 1982-05-25 The Dow Chemical Company Hydraulic fluids containing cyano derivatives of ketones
KR100595963B1 (ko) * 2004-04-13 2006-07-05 한국화학연구원 인덴 유도체 및 이의 제조방법
KR101959636B1 (ko) * 2017-10-25 2019-07-04 경북대학교 산학협력단 인데엔 화합물을 유효성분으로 함유하는 골 재생 및 골 질환 예방 또는 치료용 조성물

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE371190B (en:Method) * 1972-03-24 1974-11-11 Kabi Ab
US2532292A (en) * 1947-12-12 1950-12-05 Searle & Co Diarylmethyl ethers of amino alkanols
DE955594C (de) * 1953-11-15 1957-01-03 Schering Ag Verfahren zur Herstellung von 3-Aminoindanen
US2914561A (en) * 1957-08-06 1959-11-24 Wm S Merrell Co Amine derivatives of triphenylethylene
US2987442A (en) * 1959-02-17 1961-06-06 Smith Kline French Lab Method of treating hypertension with [2-(2, 6-dimethylphenoxy)-propyl]-trimethyl ammonium salts
US2971001A (en) * 1959-10-21 1961-02-07 Wm S Merrell Co Quaternary salts of triphenylethanols, -ethylenes, and -ethanes
US3205136A (en) * 1962-12-24 1965-09-07 Smith Kline French Lab Antidepressant phenyloxyalkylamines
US3255249A (en) * 1963-04-26 1966-06-07 Ici Ltd 2-branched lower alkyl-amino-1-(indan-, hydrogenated indan- and hydrogenated naphth-2-yl) lower alkanols
GB1059968A (en) * 1964-01-20 1967-02-22 Ici Ltd Naphthalene derivatives
US3532752A (en) * 1965-12-30 1970-10-06 Merck & Co Inc 1-alkylidene-3-indenyl aliphatic amines
GB1187255A (en) * 1966-12-01 1970-04-08 Mead Johnson & Co 0-(2-Dimethylaminoethyl)-1-Phenylindene-N-Oxide, Acid Addition Salts thereof, and Process for Preparing the same
CH540221A (de) * 1968-03-20 1973-08-15 Hoffmann La Roche Verfahren zur Herstellung von tricyclischen Verbindungen
US4136116A (en) * 1968-05-03 1979-01-23 Hoffmann-La Roche Inc. Tricyclic compounds
US4127675A (en) * 1968-11-12 1978-11-28 Yamanouchi Pharmaceutical Co., Ltd. 4-(Alkylamino-2-hydroxypropoxy)-indenes and method of use
US3940443A (en) * 1973-06-07 1976-02-24 The United States Of America As Represented By The Secretary Of The Navy Amino ethanol-indane and tetrahydronaphthalene derivatives
FR2363327A1 (fr) * 1976-08-31 1978-03-31 Continental Pharma Nouveaux amino-alcools heterocycliques, leurs sels et leur procede de preparation

Also Published As

Publication number Publication date
JPS6344737B2 (en:Method) 1988-09-06
IT1099587B (it) 1985-09-18
NO147420C (no) 1983-04-06
NO782651L (no) 1979-02-06
CA1109066A (en) 1981-09-15
PT68383A (en) 1978-09-01
NO147420B (no) 1982-12-27
IE47716B1 (en) 1984-05-30
AU527825B2 (en) 1983-03-24
IE781561L (en) 1979-02-05
AU3857878A (en) 1980-02-07
AT367018B (de) 1982-05-25
ATA563378A (de) 1981-10-15
FI782382A7 (fi) 1979-02-06
DK344778A (da) 1979-02-06
DK150538B (da) 1987-03-23
ZA784349B (en) 1979-07-25
FI71724C (fi) 1987-02-09
IT7826404A0 (it) 1978-08-02
ES472291A1 (es) 1979-02-16
DE2861735D1 (en) 1982-05-27
JPS5444651A (en) 1979-04-09
FI71724B (fi) 1986-10-31
EP0000825A1 (en) 1979-02-21
NZ188037A (en) 1984-07-06
DK150538C (da) 1987-10-12
US4218472A (en) 1980-08-19

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