Classifications

• • 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
  • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
  • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/10—Separation; Purification; Stabilisation; Use of additives

Definitions

• the present invention is related to new 1,2,3,4-tetra-hydro-2- -naphtyl amines, to processes for preparing such compounds, pharmaceutical preparation of such compounds and the use of such compounds in therapy.
• An object of the invention is to provide compounds for therapeutic use, especially compounds having a therapeutic activity in the central nervous system.
• R III is COOH, COOCH 3 , COCH 3 , COC 6 H 5 , CH 2 OH and CH 2 OCOC 6 H 5 .
• the compounds have been tested for analgesic activity.
• German Patent 2,752,659 describes i.a. compounds of the formula
• Y I is 5-OH, 6-OH and 7-OH
• R I is H, CH 3 , n-C 3 H 7 , i-C 3 H 7 or benzyl and R I I is H, CH 3 or C 3 H 7 .
• the compounds are stated to have stimulating effects on ⁇ - and ⁇ -adrenoreceptors as well as on dopamine receptors.
• Y is OH, R 4 COO, (R 5 ) 2 NCOO or R 6 O, whereby R 4 is an alkyl group having 1-5 carbon atoms or a possibly substituted phenyl group, R 5 is an alkyl group having 1-5 carbon atoms and R 6 is an allyl or benzyl group, R is an alkyl group having 1-3 carbon atoms, R 2 is an alkyl group having 1-6 carbon atoms, and R 3 is an alkyl group having 1 -3 carbon atoms, as bases and pharmaceutically acceptable acid addition salts thereof, possess unexpected pharmacological properties rendering them useful in therapy and full- filling the objects stated above. Processes for preparation of such compounds, their pharmaceutical and medical use and pharmaceutical preparations and methods of treatment employing such compounds constitute further aspects of the invention.
• the alkyl groups may be straight alkyl groups or branched alkyl groups .
• a possibly substituted phenyl group R 4 may be a phenyl, 2,6-d ⁇ methyl- phenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxypnenyl group with the formula
• R 7 is an alkyl group having 1-6 carbon atoms.
• Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention.
• Illustrative acids a re sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic and benzoic acid.
• These salts are readily prepared by methods known in the art.
• the invention is related to compounds of the formula I above wherein Y is OH, R 4 COO, (R 5 ) 2 NCOO and R 6 O, wherebv R 4 is a possibly substituted phenyl group, R 5 is CH 3 and R 6 is an allyl group, and R 1 , R 2 and R 3 are as specified above.
• the invention is related to compounds of the formula I above wherein Y is OH, R 4 COO and R 6 O, whereby R 4 is a possibly substituted phenyl group and R 6 is an allyl group, and R 1 , R 2 and R 3 are as specified above.
• the invent ion is related to compounds of the formula I above wherein Y is OH, R 4 COO, (R 5 ) 2 NCOO and R 6 O wherein R 4 is methyl, phenyl, or 4-alkanoyloxyphenyl wherein the alkyl group has 1-4 carbon atoms, R 5 is methyl, R 6 is ally], R 1 is alkyl having 1-3 carbon atoms, R 2 is alkyl having 3-6 carbon atoms, and R 3 is methyl or ethyl.
• Preferred among the compounds of the formula 1 wherein y represents R 4 COO are those wherein R 4 is a 4-alkainoyloxyphenyl group wherein the alkyl group (R 7 ) has 4-6 carbon atoms.
• the invention is related to compounds of the formula 1 wherein R 1 is n-C 3 H 7 .
• Preferred compounds are those wherein R 1 is n-C 3 H 7 , R 2 is an alkyl group containing 3 ⁇ 6 carbon atoms and R 3 is CH 3 or C 2 H 5 . Further preferred are compounds wherein R 1 is n-C 3 H 7 , R 2 is an alkyl group with 3-5 carbon atoms and R 3 is CH 3 .
• the compounds of the invention contain an asymm atric carbon atom in the heterocyclic ring moiety.
• the therapeutic properties of the compounds may to a greater or lesser degree be ascribed to either or both of the two enantiomers occurring.
• the pure enantiomers as well as mixtures thereof are within the scope of the invention.
• Preferred among the two pure enantiomeric forms is that form which has the same absolute configuration (at the nitrogen - carrying 2-carbon atom) as the levorotameric (-)-5-hydroxy-2-methyl-2-(di-n-propylamino) tetralin.
• the invention takes into consideration that compounds which structurally deviates from the formula I, after administration to a living organism may be transformed to a compound of the formula I and in this structural form exert their effects. This consideration is a further aspect of the invention. Likewise, certain compounds of formula I may be metabolized into other compounds of formula I before exerting their effect. Compouuds of the invention wherein Y is R 4 COO, ( R 5 ) 2 NCOO or R 6 O are thus believed to exert their main activity after metabolism to compounds wherein Y is OH.
• the compounds of the invention may be obtained by one of the following methods constituting a further aspect of the invention.
• R represents a hydrocarbon or acyl residue, preferably an alkyl group having 1-5 carbon atoms or a benzyl group, or an alkylcarbonyl grouo having 2-6 carbon atoms, and R 1 , R 2 and R 3 are as defined above, may be cleaved to form a compoundof formula I wherein Y is a hydroxy group
• the cleavage may be carried out by treating the compound of formula II with an acidic nucleophilic reagent such as aqueous HBr, or HI, HBr/CH 3 OOH, BBr 3 , AlCl 3 , pyridine-HCl or (CH 3 ) 3 SiI, or with a basic nucleophil ⁇ c reayent such as CH 3 C 6 H 4 -S or C 2 H 5 -S .
• an acidic nucleophilic reagent such as aqueous HBr, or HI, HBr/CH 3 OOH, BBr 3 , AlCl 3 , pyridine-HCl or (CH 3 ) 3 SiI
• a basic nucleophil ⁇ c reayent such as CH 3 C 6 H 4 -S or C 2 H 5 -S .
• R is a benzyl group
• the cleavage may also be carried out by reduction, preferably with hydrogen using Pd or PtO 2 as catalyst.
• R is an acyl residue
• the cleavage may be carried out by hydrolysis in an aqueous acid or base or by reduction, preferably by LiAlH 4 .
• the compound of formula II is obtainable by the following synthetic route:
• a pure enantiomer of compound II may be prepared by first conversion of II E into the (-)-0-methylmandelic acid amide II F followed by chromatographic separation of the two diastereomers and cleavage by subsequent reaction with potassium tert-butoxide in tetrahydrofuran with traces of water and CH 3 Li, and then the desired of the two enantiomers (II E 'and E") is alkylated.
• R 1 , R 2 and R 3 a re as defined above may be converted into a compound of formula I wherein Y is R 4 COO, ( R 5 ) 2 NCOO or R 6 O by treating the. first mentioned compound with an appropriate carboxylic acid halide R 4 COX or anhydride ( R 4 CO) 2 O or with an appropriate carba ⁇ oyl halide (R KNCOX in the presence of a base such as tr iethylamine or pyridine or an acid such as H 2 SO 4 or CF 3 COOH or with an appropriate allyl or benzyl halide R 6 X in the presence of a base such as triethylam ⁇ ne, pyridine or potassium t-butoxide.
• X represents a halogen, preferably Cl or Br.
• R a is either R 1 or R 2 , and R 1 , R 2 , R 3 and Y are as defined above, may be converted into a compound of formula 1 by alkylation of the nitrogen atom with an appropriate alkylating agent.
• the starting compound wherein R a is R 1 may be treated with an alkyl halide or tosylate R 1 X 1 , wherein X represents C1 , Br, I or -OSO 2 - C 6 H 4 CH 3 in an organic solvent such as acetonitrile or acetone and in the presence of a base such as K 2 CO 3 or NaOH, or said starting compound may be treated with a carboxylic acid NaBH 4 complex R b COOH-NaBH 4 , wherein R b is defined by the relation R b -CH 2 equals R 2 .
• the alkylation reaction may be carried out by treatment of the comp ⁇ und of formula IV with a formaldehyde - Na(CN)8H 3 mixture, or with formaldehyde and formic acid.
• R C is an alkyl group defined by the relation R C -CH 2 - equals either R 1 or R 2 and R d is the other of R 1 and R 2 , may be reduced, e.g. by treatment with a hydride reducing agent such as LiAlH 4 in ether or tetrahydrofuran or BH 3 in tetrahydro furan, to the formation of a compound of formula I.
• a hydride reducing agent such as LiAlH 4 in ether or tetrahydrofuran or BH 3 in tetrahydro furan
• M 1 and M 2 are the same or different and each represents -CH 2 -, when M 1 and M 2 are -CH 2 - and in other cases M 3 is R 3 , Z 1 is a group sensitive to hydrogenolys is such as hydroxy in benzyl ic position (M 1 or M 2 ) or halogen, R is hydrogen, methyl or ethyl, Y is other than allyloxy and R 1 , R 2 and R 3 are as defined above may be converted to a compound of formula I by reduction.
• a keto function may be either directly converted to CHward by treatment with e.g. hydrazine under alkaline conditions or by a stepwise reduction by using e.g.
• catalytic hydrogenat ⁇ on which may involve an intermediary formation of an hydroxy group and,where possible, also an elimination to a double bond.
• Reduction of a group ⁇ CH-Z' may be carried out by using a nucleophilic hydride reducing agent such as LiAlH 4 , or catalytic hydro genat ion.
• Y is other than allyloxy and R 1 and R 2 are as defined above may be converted by reduction, preferably by catalytic hydrogenation, into a compound of the formula I wherein R 3 is CH 3 .
• X represents SO 3 H, Cl or NH 2
• a hydroxy group may be substituted for the group X to the formation of a compound of formula I wherein Y represents a hydroxy group.
• said reaction may be carried out by treatment with a strong alkali under heating, suitably with an alkali melt such as KOH when X is SO 3 H, and with a strong aqueous alkali such as NaOH or KOH when X is Cl.
• X is NH 2
• the reaction may be carried out by treatment with aqueous nitrous acid to the formation of an intermediate diazo ⁇ um compound which is then subjected to hydro lysis in water.
• enantiomeric separation may be done by methods known in the art. These methods include recrystallization of diastereomeric saltswith pure enantiomers of acids such as tartaric acid, 0,0- -dibenzoyltartaric acid, mandelic acid and camphor-10-sulphonic acid.
• Free bases formed may subsequently be converted into their acid addition salts, and acid addition salts formed may subsequently be converted into the corresponding bases or other acid addition salts.
• the compounds of the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, lactate, acetate, sulfamate, and the like, in association with a pharmaceutically acceptable carrier.
• a pharmaceutically acceptable non-toxic, acid addition salt e.g. the hydrochloride, lactate, acetate, sulfamate, and the like, in association with a pharmaceutically acceptable carrier.
• the carrier may be a solid, semlsolid or liquid diluent or capsule.
• These pharmaceutical preparations constitute a further aspect of this invention.
• the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparation intended for injection and between 0.2 and 95% by weight for preparations sui table for oral administration.
• compositions containing a compound of the invention in a solid form of dosage units for oral application may preferably contain between 2 and 95% by weight of the active substance, in such preparations the selected compound may be mixed with a solid fine grain carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopect in, cellulose derivatives, or gelatin and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets.
• a concentrated sugar solution which may contain, e.g.
• the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents.
• Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.
• soft gelatin capsules pearl-shaped closed capsules consisting of gelatin and, for example, glycerol, or similar closed capsules
• the active substance may be admixed with a vegetable oil.
• Hard gelatin capsules may contain granulates of the active substance in combination with solid, fine grain carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.
• Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2% to about 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
• Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.
• Solutions for parenteral applications by injection can be prepared in a aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about
• solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
• the suitable daily doses of the compounds of the invention are 100-5000 mg for oral application, preferentially 500-3000 mg, and 0.5-500 mg for parenteral application, preferentiaIly 25-250 mg.
• This compound was prepared from 5-methoxy-2-methyltetralIn-2-carboxylic acid (8.75 g, 38 mmol) according to the method used by Nichols et al. (J. Med. Chem. 21 , 395 (1978) for the preparation of 2,3-dimethoxy-9- amIno-9, 10-dihydrophenantrene from 2,3-dimethoxy-9, 10-dihydrophenantrene- -9-carboxylic acid.
• the amine was converted to the hydrochlor ide and recrystallized twice from EtOH-ether. Yield 5.8 g (76%), mp 249.5 - 251-5 ⁇ C (decomp.) ( ⁇ )-5-Methoxy-2-methyl -2- (n -propyla min o ) tetral i n
• R-(-)-0-Methylmandelic acid chloride (6,0 g, 0.033 mol), prepared from R-(-)-0-methylmandelic acid by treatment with thionyl chloride at 20 ⁇ C for 10 hours, dissolved in CH 2 Cl 2 (5 ml) was added at room temperature to a stirred mixture of (+)-5-methoxy-2-methyl-2-(n-pro ⁇ ylamino) tetralin (7.0 g, 0.026 mol), CH 2 C1 2 (50 ml), H 2 O (50 ml) and 5% aqueous NaOH (80 ml).
• the diastereomer which was secondly eluated (0.5 g) showed to be the same as the diastereomeric amide which first crystallized.
• the crystals (see above) and the diastereomer which was secondly eluated (0.9 + 0.5 g;totally: 1.4 g) were stereochemical ly pure according to HPLC.
• This diastereomeric amide (1.4 g, 0.0037 mol) was dissolved in THF (50 ml) and kept at -15 ⁇ C. Potassium tert-butoxide (4.0 g) was added and the mixture was kept at this temperature and under stirring for 5 hours. Ehter and H 2 O were added and the phases were separated.
• the ether phase was extracted with 10% HCl, dried (Na 2 SO 4 ) and evaporated giving an oil which was dissolved in day THF (20 ml) and stirred with 1.6 M solution of CH 3 Li in ether (5 ml) for 30 minutes at -15 ⁇ C and then extracted with 10% HCl.
• the aqueous phase was combined with the 10% HCl-extract of above, alkalized with Na 2 CO 3 , extracted with ether.
• (+)-5-Hydroxy-2-methyl-2-(di-n-propylamino) tetralin was dissolved in acetic anhydride (10 ml).Triethylamine (0.5 ml) was added and the solution was refluxed for 1.5 h.EtOH ("25 'ml) was added and the solvents were evaporated giving an oil. The oil was made alkaline with diluted NaOH to pH 10 during external cooling and then extracted with ether. The organ'ic phase was dried and evaporated giving the desired compound as an oil. Ethereal HCl gave the hydrochloride of the desired compound, mp ⁇ C ,
• 500 g of active substance are mixed with 500 g of corn oil, whereupon the mixture is filled in soft gelatine capsules, each capsule containing 100 mg of the mixture (i.e. 50 mg of active substance).
• 0.5 kg of active substance are mixed with 0.2 kg of silicic acid of the trade mark Aerosil. 0.45 kg of potato starch and 0.5 kg of lactose are mixed therewith and the mixture is moistened with a starch paste prepared from 50 g of potato starch and distilled water, whereupon the mixture is granulated through a sieves. The granulate is dried and sieved, whereupon 20 g of magnesium stearate are mixed into it. Finally the mixture is pressed into tablets each weighing 172 mg.
• Active substance hybrobromide (1 g), sodiumchloride (0.8 g) and ascorbic acid (0.1 g) are dissolved in sufficient amount of distilled water to give 100 ml of solution.
• This solution which contains 10 rng of active substance per ml, is used in filling ampoules, which are sterilized by heating at 120°C for 20 minutes.
• Drugs affecting neurohumoral transmission are of considerable interest in the treatment of a variety of disease states of central and peripheral origin.
• compounds having specific effects on the monoamin ergic systems are of great value in the therapy of e.g. parkinsoni sm, schizophrenia, mental depression, senile mental and motor disturbances, hypo- and hypertensive states etc.
• reserpine Depletion of the monoamine stores with reserpine brings about a "neuroleptic syndrome" characterized by akinesia, catalepsy, muscle rigidity, hunch-backed posture as well as a number of other central and peripheral signs of monoamine depletion.
• the reserpine-induced syndrome has been frequently used as an animal model mimicking Parkinson's disease as well as mental depression. The whole or parts of this syndrome can be reversed by the administration of drugs that stimulate DA or 5-HT receptors directly or indirectly.
• the compounds under evaluation were tested biochemically for central DA- and 5-HT-receptor (pre- and/or postsynaptic) stimulating activity.
• the concept of this biochemical screening method is that a DA- or 5-HT-receptor agonist will stimulate the receptor and through regulatory feedback systems effect a decline in tyrosine or tryptophan hydroxylating activity, respect ively, and a subsequent reduction in the synthesis rate for DA and 5-HT in the presynaptic neuron.
• Dopa and 5-HTP formation as determined after in-vivo inhibition of the aromatic L-amino acid decarboxylase with NSD 1015
• NSD 1015 Subsequent administration of NSD 1015, decapitation, brain dissection (corpora striata, the limbic forebrain, cortex, diencephalon, brain stem), homogenization, centrifugation, ion-exchange chromatography and spectrofluorimetric measurements (all as described in detail by Wikström et al., J. Med. Chem., 21, 864-867, 1978 and references cited therein) gave the actual dopa and 5-HTP levels.
• the test drug was given without any other treatment and the brain levels of the monoarnines , their precursors and metabol ites were determined by means of high performance liquid chromatography (HPLC) with electrochemical detection.
• HPLC high performance liquid chromatography
• the locomotor activity elicited by compound 2 was never accompanied by any signs of stereotypies typical of DA-receptor stimulation (licking, sniffing, gnawing etc.) and was totally resistant to pretreatment with haloperidol, given in a dose producing an efficient blockade of the DA receptors (Table 1).
• the pharmacological data demonstrate that compounds of the present invention have pronounced pharmacodynamic actions.
• the concomitant behavioural and biochemical alterations Induced by the compounds under consideration constitute a unique pharmacological profile, not previously described.
• Said compounds are of great clinical interest in the therapy of pathological states referred to in the Introduction, for example Parkinson's disease, mental depression and senile disturbances in the nervous system.

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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 1982
  • 1982-05-10 EP EP82901557A patent/EP0091437A1/de not_active Withdrawn
  • 1982-05-10 WO PCT/SE1982/000160 patent/WO1982004042A1/en not_active Application Discontinuation
  • 1982-05-10 JP JP57501585A patent/JPS58500714A/ja active Pending
  • 1982-05-10 AU AU84550/82A patent/AU8455082A/en not_active Abandoned
  • 1982-12-28 DK DK576182A patent/DK576182A/da not_active Application Discontinuation
• 1983
  • 1983-01-07 NO NO830040A patent/NO830040L/no unknown
  • 1983-06-10 FI FI832108A patent/FI832108A0/fi not_active Application Discontinuation

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