EP0407416A1 - Therapeutisch wertvolle tetralinabkömmlinge - Google Patents
Therapeutisch wertvolle tetralinabkömmlingeInfo
- Publication number
- EP0407416A1 EP0407416A1 EP89903628A EP89903628A EP0407416A1 EP 0407416 A1 EP0407416 A1 EP 0407416A1 EP 89903628 A EP89903628 A EP 89903628A EP 89903628 A EP89903628 A EP 89903628A EP 0407416 A1 EP0407416 A1 EP 0407416A1
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- EP
- European Patent Office
- Prior art keywords
- methoxy
- tetralin
- alkyl
- methyl
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
- A61K31/13—Amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- 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
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- 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
- A61P25/24—Antidepressants
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- 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
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/38—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
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- 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
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the present invention is related to new 1,2,3,4-tetrahydro-2- naphthylamines, to processes for preparing such compounds, pharmaceutical preparation of such compounds and the use of such compounds in manufacture of a pharmaceutical preparation.
- the mechanism of action for the drugs generally used today in the therapy of mental depression is generally believed to be indirect with the drugs acting by blocking the reuptake of the neurotransmitters, NA and/or 5-HT, released from nerve terminals in the CNS, which increases the concentration of these transmitters in the synaptic cleft and restores an adequate neurotransmission.
- the clinically documented antidepression drug zimelidine (dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl)propene) acts as such a reuptake inhibitor with high selectivity for 5-HT neurons.
- a fundamentally different way to improve the neurotransmission in the central 5-HT neurons would be to use a 5-HT receptor agonist acting directly upon the 5-HT receptors, and particularly the 5-HT 1A receptor. In order to minimize undesired side effects, a high selectivity for this kind of receptor would be necessary.
- 5-HT 1A agonists have also demonstrated anxiolytic properties.
- the drug, Buspirone is the only currently available marketed 5-HT 1A agonist having anxiolytic activity. This compound antagonizes dopamine receptors at the same dose it stimulates 5-HT 1A receptors.
- a similar drug, Gepirone also has dopamine antagonist properties. These dopamine antagonist properties reduce the clinical utility of these compounds however because long term treatment with dopamine antagonists can produce tardive dyskinesia.
- the search for new CNS active compounds is focused on finding compounds with selective 5-HT 1A receptor agonist effects without detrimentally influencing central dopamine receptors.
- Drugs acting on central dopamine transmission are clinically effective in treating a variety of central nervous system disorders such as parkinsonism, schizophrenia, and mano-depressive illness.
- parkinsonism for example, the nigro-neostriatal hypofunction can be restored by an increase in postsynaptic dopamine receptor stimulation.
- schizophrenia the condition can be normalized by achieving a decrease in postsynaptic dopamine receptor stimulation.
- Classical antipsychotic agents directly block the postsynaptic dopamine receptor. The same effect can be achieved by inhibition of intraneuronal presynaptic events essential for the maintenance of adequate neurotransmission, transport mechanism and transmitter synthesis.
- Direct dopamine receptor agonists like apomorphine, are able to activate the dopamine autoreceptors as well as the post synaptic dopamine receptors.
- the effects of autoreceptor stimulation appear to predominate when apomorphine is administered at low doses, whereas at higher doses the attenuation of dopamine transmission is outweighed by the enhancement of postsynaptic receptor stimulation.
- the antipsychotic and antidyskinetic effects in man of low doses of apomorphine are likely due to the autoreceptor-stimulator properties of this dopamine receptor agonist. This body of knowledge indicates dopamine receptor stimulants with a high selectivity for central nervous dopamine autoreceptors would be valuable in treating psychiatric disorders.
- Derwent 12191K (Belgium 893,917) discloses indanyl substituted imidazole derivatives and tetralyl imidazole derivatives wherein the aromatic ring of the indanyl and tetralyl groups may be substituted with various groups including halogen, alkyl (C 1 -C 6 , trihaloalkyl, alkoxy and alkylthio. The compounds are useful in treating atherosclerosis.
- British Patent 1,377,356 discloses 8-hydroxy and 8-methoxy substituted-1,1-dialkyl-2-aminotetralins wherein the amino group is unsubstituted or substituted with an alkyl C 1 -C 6 . These compounds are useful as analgesics.
- Derwent 40378A/23 (British 1,597,140) discloses, among other compounds, 2-aminotetralins substituted on the aromatic ring with halogen, di-chloro and additionally hydroxy or an alkanoyloxy group.
- Switzerland 637,363 (Derwent 729,386) and Switzerland 637,364 discloses, among other compounds, 2-aminotetralins substituted on the aromatic ring with halogen, di-chloro and additionally hydroxy, alkyl or other functional groups. These compounds are stimulants of ⁇ - and ⁇ -adrenergic and dopamine receptors rendering them useful in treating heart failure, cardiac infarct, hypertension and Parkinson's disease.
- Germany 2,333,847 discloses a very broad scope of compounds which can include amino tetralins and amino indanes substituted on the aromatic ring with alkoxy or halogen and additionally hydroxy, aralkyloxy or acyloxy. These compounds are water softening agents and corrosion inhibitors in lubricants as well as CNS-depressants and anti-arrhythmics.
- European 272,534-A discloses 2-aminotetralins substituted in the 8-position by halogen (fluorine, chlorine, bromine or iodine) among many other compounds within a broad disclosure. These compounds are useful serotonin antagonists or agonists with high affinity for cerebral 5-HT 1 receptors rendering them useful in the treatment of CNS disorders, cognitive deficiencies, Alzheimer's disease, cardiovascular disorders, pain and intestinal disorders.
- German 2803582 discloses 2-aminotetralins wherein the amino group is substituted with inter alia alkyl, or cycloalkyl and wherein the aromatic ring is substituted with inter alia alkyl, halogen, di-chloro and additionally with hydroxy or an alkanoyloxy group. These compounds have a stimulant effect on ⁇ - and j9-adrenoreceptors and on dopamine receptors and are useful in the treatment of heart failure, cardiac infarct, elevated blood pressure and Parkinson's disease.
- Wikstrom, H., et al., J. Med. Chem. 30, 1115 (1987) discloses 4-hydroxy- and 4-methoxy-2-aminoindanes wherein the amino moiety is unsubstituted or is substituted with dimethyl or di-n-propyl; 5- hydroxy-2-dimethylaminoindane; and 7-hydroxy-2-aminotetralin wherein the amino moiety is substituted with dimethyl or di-n-propyl.
- This paper focuses on the conformational analysis of the compounds in relation to their central dopaminergic effects.
- J.G. Canon, et al., J. Med. Chem. 25, 1442-1446 (1982) and J. Med. Chem. 28, 515-518 (1985) disclose inter alia, 4-hydroxy- and 5-hydroxy-2-di-n-propylindane in a study dealing with the conformational analysis of a series of 2-aminoindans. Seeman, et al., Molecular Pharmacology 28, 291-299 (1985) includes a number of known hydroxy substituted and methoxy substituted aminotetralins and aminoindans in a U£ receptor binding affinity study.
- J.D. McDermed, et al., J. Med. Chem. 18, 362-367 (1975) discloses a large series of 2-aminotetralins wherein the aromatic ring is mono- or di-substituted with hydroxy, methyl or lower alkoxy and the amine moiety is unsubstituted or substituted with lower alkyl, benzyl, alkoxyalkyl or forms part of a monocyclic heterocyclic group. These compounds were evaluated for their dopaminergic activity.
- This invention encompasses compounds of Formula I and pharmaceutically acceptable acid addition salts thereof, wherein -YR 1 is one substituent on the 5, 6, 7 or 8 position of the aromatic ring and is -S( 1 -C 3 )alkyl or -OR 1 wherein R 1 is selected from the group consisting of (C 1 -C 8 ) alkyl, (C ⁇ -Cg) alkenyl, -CH 2 -(C 3 -C 8 ) cycloalkyl or benzyl; wherein R 2 is hydrogen or (C 1 -C 3 ) alkyl; wherein R 3 is-CH 2 -(C 3 -C 8 ) cycloalkyl; wherein R4 is hydrogen, (C ⁇ -Cg) alkyl, -CH 2 -(C 3 -C 4 ) cycloalkyl, -(CH 2 ) m -R 5 or -CH 2 CH 2 -X- (CH 2 ) n CH 3 ; wherein n is
- the compounds of this invention possess selective pharmacological properties and are useful in treating central nervous system disorders including antidepression symptoms, anxiolytic symptoms, panic attacks, obsessive-compulsive disturbances, senile dementia, emotional disturbances related to dementia disorders, and stimulation of sexual activity.
- the compounds of this invention are also useful to alleviate aggressive behavior, confusional delirious states and impotence.
- Certain compounds of this invention additionally possess blood pressure lowering affects . Processes for preparation of these compounds , their pharmaceutical use and pharmaceutical preparations employing such compounds constitute further aspects of the invention.
- the invention is related to compounds of Formula I wherein R 3 is -CH 2 -(C 3 -C 8 ) cycloalkyl, R 4 is (C 1 -C 8 ) alkyl or -CH 2 -(C 3 -C 4 ) cycloalkyl and R 1 is a methyl group.
- R 3 is cyclopropylmethyl
- R 4 is (C 1 -C 4 ) alkyl or cyclopropylmethyl and R 1 is a methyl group.
- An object of the invention is to provide compounds for therapeutic use, especially compounds having a therapeutic activity in the central nervous system. Another object is to provide compounds having an effect on the 5-HT 1A receptor in mammals including man. A further object of this invention is to provide compounds having an effect on the subclass of dopamine receptors known as the D2 receptor.
- Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl.
- Alkoxy as represented by -OR 1 when R 1 is (C 1 -C 8 ) alkyl refers to an alkyl radical which is attached to the remainder of the molecule by oxygen and includes branched or unbranched forms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, neo-pentoxy, n-hexoxy, isohexoxy, n-heptoxy, isoheptoxy, and n-octoxy.
- Alkenyl refers to a radical of an aliphatic unsaturated hydro-carbons having a double bond and includes both branched and unbranched forms such as ethenyl, 1-methyl-1-ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 1-methyl-4-hexenyl, 3-methyl-1-hexenyl, 3-methyl-2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-methyl-4-hexenyl, 3-methyl-1-hexenyl,
- Cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
- compounds of this invention may contain chiral centers.
- the scope of this invention includes all enantiomeric or diastereomeric forms of Formula I compounds either in pure form or as mixtures of enantiomers or diastereomers.
- the compounds of Formula I contain two asymmetric carbon atoms in the aliphatic ring moiety, including the ring carbon atoms adjacent to the nitrogen atom.
- the therapeutic properties of the compounds may to a greater or lesser degree depend on the stereo-chemistry of a particular compound. Pure enantiomers as well as enantiomeric or diastereomeric mixtures are within the scope of the invention.
- 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 are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmoic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid.
- These salts are readily prepared by methods known in the art.
- a compound of the formula, C-1 may be converted into a compound of Formula I, when R 1 and R 4 are the same, by alkylation of the nitrogen and oxygen atoms with an appropriate alkylating agent.
- the compound of the formula, C-1 may be treated with an alkyl-halide or tosylate of the formula R a X, when R a is alkyl or cycloalkyl, and when X is Cl, Br, I or TsO, in an organic solvent such as acetonitrile or acetone and in the presence of a base such as potassium carbonate or sodium hydroxide.
- the compounds of this invention may be obtained from a compound of the formula, C-2, by alkylation of the hydroxy moiety with an appropriate alkylating agent.
- the starting compound, C-2 may be treated with an alkyl halide or tosylate R b -X, when R b is alkyl, alkenyl, cycloalkyl, or benzyl, when X is Cl, Br, I or TsO, in an organic solvent such as acetonitrile or acetone and in the presence of a base such as potassium carbonate or sodium hydroxide.
- a compound of the formula, C-3 may be converted into a compound of Formula I, by alkylation of the nitrogen, atom with an appropriate alkylating agent.
- the starting compound may be treated with an alkyl halide or tosylate R c X, when R c is alkyl, cycloalkyl, heterocyclic alkyl, ethylalkoxy or ethylthiaalkyl, when X is Cl, Br, I or TsO, in an organic solvent such as acetonitrile or acetone and in the presence of a base such as potassium carbonate or sodium hydroxide, or the starting compound, C-3, may be treated with a carboxylic acid sodium borobydride complex, when the carboxylic acid is HOOC- (C 1 -C 7 )alkyl, HOOC- (C 3 -C 8 )cycloalkyl, HOOC- (CH 2 ) p -R 5 , or HOOC-CH 2
- the starting compound, C-3 may be dissolved in methanol and treated with an aldehyde and sodium cyanoborohydride, when the aldehyde is HOC- (C 1 -C 7 )alkyl, HOC- (C 3 -C 8 )cycloalkyl, HOC-(CH 2 ) p -R 5 , or HOC-CH 2 -X-(CH 2 ) n -CH 3 , when p is one or 2, n is zero to 3 and X is oxygen or sulfur.
- aldehyde is HOC- (C 1 -C 7 )alkyl
- HOC- (C 3 -C 8 )cycloalkyl HOC-(CH 2 ) p -R 5
- HOC-CH 2 -X-(CH 2 ) n -CH 3 when p is one or 2, n is zero to 3 and X is oxygen or sulfur.
- an amide of the formula, C-4 when R d is (C 1 -C 7 ) alkyl, (C 3 -C 8 )cycloalkyl, (CH 2 ) p -R 5 , or -CH 2 -X- (CH 2 ) n -CH 3 , when p is one or 2, n is zero to 3 and X is oxygen or sulfur, may be reduce by a hydride reducing agent such as lithium aluminum hydride in ether or tetrahydrofuran, diborane in tetrahydrofuran or QBH 4 (where Q represents tetrabutylammonium ion) in a mixture of dichloromethane and dichloroethane, to give a compound of Formula I.
- a hydride reducing agent such as lithium aluminum hydride in ether or tetrahydrofuran, diborane in tetrahydrofuran or QBH 4 (where Q represents tetrabutylammonium
- R 1 Y is -S(C 1 -C 3 )alkyl
- R 1 Y is -S(C 1 -C 3 )alkyl
- OR 1 is replaced by a hydroxy group by converting the hydroxy group to an amine which is subsequently converted to bromine via a Sandmeyer reaction.
- the bromine substituted intermediate is lithiated using n-butyllithium in THF or ether and quenched with (C 1 -C 3 )alkyl-SS-alkyl(C 1 -C 3 ) to the alkylthio substituted compounds.
- a compound of the formula, C-6 is acylated with a carboxylic acid chloride in the presence of triethylamine and subsequently reduced by a hydride reducing agent such as lithium aluminum hydride in ether or tetrahydrofuran, diborane in tetrahydrofuran or QBH 4 (where Q represents tetrabutylammonium ion) in a mixture of dichloromethane and dichloroethane.
- a hydride reducing agent such as lithium aluminum hydride in ether or tetrahydrofuran, diborane in tetrahydrofuran or QBH 4 (where Q represents tetrabutylammonium ion) in a mixture of dichloromethane and dichloroethane.
- the ketone, C-5 can be converted directly to the secondary amine, C-6, by reacting the ketone with a primary amine of the formula R e -NH 2 , when R e is alkyl, cycloalkyl, heterocyclic alkyl, ethylalkoxy or ethy1thiaalkyl, with sodium cyanoborohydride in methanol acidified to about pH 5 with the addition of a few drops of concentrated acetic acid.
- R e is alkyl, cycloalkyl, heterocyclic alkyl, ethylalkoxy or ethy1thiaalkyl
- the preparation of the compounds of this invention with an alkyl group at the one position of the aliphatic ring are obtained by alkylating a compound of formula, C-7, either via the enamine or by direct alkylation of the ketone, C-7, under basic conditions, to give a compound of formula, C-5, converting compound, C-5, into the secondary amine using methods already described, separation of the cis- and trans- isomers formed, and finally converting the secondary amine into the tertiary amine using methods already described.
- a pure enantiomer of compound, C-3 may be prepared by converting the cis-secondary amine, C-3, Into the (-)-O-methylmandelic acid amide, C-8, followed by chromatographic separation of the two diastereomers and cleavage by subsequent reaction with potassium tert-butoxide in tetrahydrofuran with traces of water and methyl lithium.
- the secondary amine can be converted into the tertiary amine using methods already described.
- 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, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable non-toxic, acid addition salt such as the hydrochloride, lactate, acetate, sulfamate salt
- the suitable daily doses of the compounds of the invention are 1-2000 mg for oral application, preferentially 50-500 mg, and 0.1-100 mg for parenteral application, preferentially 0.5-50 mg.
- the compounds of this invention where -OR 1 is in the 8 position in the aromatic ring are very selective 5-HT 1A receptor agonists having little or no dopaminergic activity.
- the IC50 ratio of dop- amine D2 to 5HT 1A in vitro binding data shown in Table 1 for one compound of this invention, 8-methoxy-2-(N,N-dicyclopropylmethyl)- tetralin demonstrates the selectivity for the 5-HT 1A receptor.
- These compounds are particularly effective anxiolytic and anti- depressant agents.
- Other uses for these compounds include panic attacks, obsessive-compulsive disturbances, and senile dementia particularly the emotional disturbances seen in dementia disorders.
- central 5-HT receptor activation are believed to be Involved in mediating sexual behavior. These compounds would be useful to stimulate sexual activity and to alleviate impotence.
- the compounds of this invention where -0R ⁇ is in the 5-, 6-, or 7-position show selective affinity for D2 receptors. These compounds are particularly effective in treating psychoses, mano-depressive illness and parkinsonism.
- the compounds of this invention also have been shown to have high oral potency and a long duration of action. Both these features are beneficial to effective clinical treatment.
- the utility of the compounds of this invention to treat central nervous system disorders is shown in behavioral and biochemical activity in reserpine-pretreated rats.
- Stimulation of the dopamine receptors gives rise to both locomotion and stereotyped behavior such as sniffing, gnawing and jumping.
- stimulation of the 5-HT receptors, with 5-hydroxytryptophane (5-HTP) combined with MAO- inhibitors for example gives rise to a very different behavior.
- the animals lie flat on the cage floor exhibiting forward movements with extended forepaws padding, "piano-playing," and abducted hindlegs, occasionally with some tremor in the forebody and with Straub tail, stiff tail erection.
- Dopamine and 5-HTP formation are taken as indirect measures of dopamine and 5-HT-synthesis rates, respectively. Analogous conditions probably exist also for central NA-neurons. Effects on the dopamine formation in the NA-predominated hemispheral parts (mainly cortex) may thus be considered to reflect NA-receptor-mediated changes.
- Rats 150-300 g pretreated with reserpine (5 mg/kg, 18 hours before) were given the test compounds. Gross behavioral observations (changes in motility, hindleg abduction, etc.) were made. Subsequen administration of NSD 1015, decapitation, brain dissection (corpor striata, the limbic forebrain and the remaining hemispheral portions (mainly cortex) or rat brain), homogenization, centrifugation, ion-exchange chromatography. and spectrofluorimetric measurements (all as described in detail by Wikstrom, et al., J. Med.
- Certain compounds of the present invention also demonstrate blood pressure lowering effects, e.g., the compounds of Examples 12, 13, and 17 when measured in spontaneously hypertensive rats as described by Grodin, et al., J. Pharm. Pharmacol. 37, 263-265 (1984). Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. Examples
- 8-Methoxy-2-(N-cyclopropylmethylamino) tetralin 8-Methoxy-2-aminotetralin hydrochloride (0.5 g, 2.35 mmol) is dissolved in dichloromethane (50 ml), and triethylamine (3 ml) and cyclopropanecarboxylic acid chloride (0.95 ml) are added. The reaction is stopped after 2 hours by the addition of 10% sodium carbonate (50 ml). The organic layer is separated, washed with water (50 ml), dried over sodium carbonate, filtered and the solvent is evaporated yielding the amide as an oil (0.85 g).
- the amide is dissolved in dichloromethane (25 ml) and reduced with the addition of dichloroethane (25 ml) and QBH 4 (2.5 g) (where Q denotes the tetrabutylammonium ion) under reflux for 6 hours.
- the reaction is stopped by the addition of 10% sodium carbonate (100 ml) and dichloromethane (2 ⁇ 100 ml).
- the organic layer is separated, washed with water (50 ml) dried (sodium carbonate), filtered and the solvent evaporated yield- ing the amine (95% purity according to GC analysis) as an oil (0.47 g).
- the reaction is stopped after one night's reflux by the addition of 10% sodium carbonate (100 ml) and dichloromethane (2 ⁇ 100 ml).
- the organic layer is separated, washed with water (50 ml), dried (sodium carbonate), filtered and the solvent is evaporated yielding the amine as an oil (0.40 g).
- the amine is chromatographed (silica gel, 40 g) eluting first with petroleum ether:ether (3:1) and then with ether. The fractions containing pure product are pooled and the solvent is evaporated.
- the residual amine is converted into the hydrochloride by the addition of hydrochloric acid-saturated ethanol and evaporation.
- Example 3 cis-5-Methoxy-1-methyl-2-(N-cyclopropylmethylamino)- tetralin To a solution of 5-methoxy-1-methyl-2-tetralone (2.0 g) in absolute ethanol (50 ml) are added acetic acid (1.9 g), cyclopropyl- methylamine (2.0 g) and 4 A molecular sieves.
- the mixture is heated in a closed flask at 80oC for one hour.
- the molecular sieves are filtered off and the solution is hydrogenated (PtO 2 ) at atmospheric pressure.
- the catalyst is filtered off (Celite) and the volatiles are evaporated.
- Dilute hydrochloric acid 50 ml is added to the solid residue.
- the resulting acidic solution is washed with ether, made basic 5% sodium hydroxide and extracted twice with ether.
- the ether extracts are combined, dried (sodium sulfate) and evaporated.
- the resulting crude base is eluted through an alumina column with ether-light petroleum (1:4).
- Example 4 cis-5-Methoxy-1-methyl-2-(N,N-dicyclopropylmethyl- amino) tetralin hydrochloride Cyclopropanecarboxylic acid chloride (0.49 g) in dry ether (10 ml) is added to a solution of cis-5-methoxy-l-methyl-2-(N-cyclopropylmethylamino) tetralin (400 mg) and triethylamine (0.49 g) in dry ether (80 ml). After 30 minutes at room temperature the reaction mixture is filtered and the ether is evaporated. The resulting crude amide is passed through an alumina column eluted with ether.
- Example 6 (+)-cis-7-methoxy-1-methyl-2-(N-cyclopropylmethyl- amino) tetralin
- acetic acid (1.85 g, 31.5 mmol)
- cyclopropylmethylamine (1.85 g)
- 4 A molecular sieves The mixture is refluxed for 3.5 hours.
- the molecular sieves are filtered off and the solution is hydrogenated with 0.3 g PtO 2 in a Parr apparatus.
- the catalyst is filtered off (Celite) and the volatiles are evaporated.
- the resulting crude base is eluted through an silica gel column with methanol, affording an oil of 80% isomeric purity (GC).
- GC isomeric purity
- Example 7 (+)-cis-7-methoxy-1-methyl-2-(N,N-dicyclopropylmethylamino)tetralin Sodium borohydride (0.41 g, 10.1 mmol) is added portionwise to a stirred solution of cyclopropanecarboxylic acid chloride (2.4 g) in dry benzene (20 ml) under N2, keeping the temperature below 20°C. After 2 hours, (+)-cis-7-methoxy-l-methyl-2-(cyclopropylmethylamino)-tetralin (0.5 g) is added and the mixture is refluxed for 4 hours and then treated with 10% sodium bicarbonate solution. The benzene layer is dried (sodium sulfate) and the solvent is evaporated. The hydrochloride salt is prepared and recrystallized from methanol-ether.
- Example 8 Preparation of soft gelatine capsules
- Active substance (1 g), sodium chloride (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 mg of active substance per ml, is used in filling ampoules, which are sterilized by heating at 120°C for 20 minutes.
- 8-methoxy-2-(benzylamino)tetralin are debenzylated, yielding the corresponding enantiomers of 8-methoxy-2-aminotetralin, i.e., R-(+)- and S-(-)-8-methoxy-2-aminotetralin.
- the primary amine (+)-R-8-methoxy-2-aminotetralin (3.29 g) is acylated with cyclopropanecarboxylic acid chloride (1.8 ml) and th amide produced (3.63 g) is reduced with QBH 4 as described in above, yielding the secondary amine, which is acylated again in the same way with cyclopropanecarboxylic acid chloride (3.2 ml).
- the amide produced (3.57 g) is dissolved in dry THF (25 ml) and reduced with
- Example 13 (-)-R-8-Methoxy-2-(di-cyclopropylmethylamino) tetralin
- the primary amine (-)-R-8-methoxy-2-aminotetralin (5.0 g) is converted into the secondary amine (-)-R-8-methoxy-2-(cyclopropylmethylamino) tetralin, which is further converted into the tertiary amine (-)-R-8-methoxy-2-(di-cyclopropylmethylamino) tetralin (2.42 g) as described for the corresponding (+)-enantiomer in Example 3 above.
- Example 14 8-Methoxy-2-(N-cyclopropylmethyl-N-ethylamino)tetralin 8-Methoxy-2-(cyclopropylmethylamino)tetralin (200 mg) is dissolved in CH 2 CI 2 (25 ml) and the solution is basified by the addition of Et 3 N (3 ml). Acetylchloride (150 ⁇ l) is added and the reaction mixture is left stirring for 3 hours. 10% Na 2 CO 3 is added and the raw amide product is extracted to the organic layer, which is dried and filtered. The organic solvent is removed by evaporation yielding 210 mg of the amide as an oil, which is dissolved in dry ether (10 ml).
- the amide is dissolved in dry ether and reduced with LiAlH 4 (0.9 g).
- the reaction is quenched after 2 hours in the usual way (0.9 ml H 2 O, 0.9 ml 15% NaOH and 2.7 ml H 2 O) and workup yields an oil, which is chromatographed on SiO 2 (70 g), eluting with petroleumether: ether (1:1).
- the fractions containing pureproduct are pooled and the solvent is evaporated yielding an oil (210 mg) which is converted to the hydrochloride with HCl-saturated EtOH and evaporation of the solvent.
- Crystals (170 mg) are obtained from aceton: ether, and they melt at 143-145oC.
- the reaction mixture is refluxed for 36 hours and is then chilled to room temperature and extracted with water several times.
- the solvents of the organic phase are evaporated and to the residue is added ether.
- the ether phase is washed with water several times, separated, dried (Na 2 SO 4 ), filtered and the solvent is evaporated to give 453 mg of an oil, which is chromatographed (200 g SiO 2 ; eluting with petroleumether: ether (9:1), yielding the product as an oil.
- This oil is converted to the hydrochloride with HCl-saturated EtOH and evaporation to yield an oil (436 mg) .
- the amide is reduced with QBH 4 (1 g) in a reflxixing (8 hours) mixture of CH 2 CI 2 (50 ml) and 1,2-dichloroethane (50 ml).
- the reaction mixture is chilled to room temperature and the organic layer is washed several times with water.
- the organic layer is separated and the solvents are evaporated, yielding an oil, which is treated with EtOAc and water.
- This mixture is acidified with HCl (10%) and stirred for 30 minutes and then the mixture is basified.
- the organic layer is separated, dried (Na 2 SO 4 ) and filtered.
- the solvent is evaporated to give the amine as an oil (900 mg).
- This oil (400 mg) is dissolved in CH 2 CI 2 (25 ml) and Et 3 N (1 ml) and cyclopropanecarboxylic acid chloride (1.0 ml) is added and the reaction mixture is left stirring for one hour. 10% Na 2 CO 3 is added and the raw amide product is extracted to the organic layer, which is dried and filtered. The organic solvent is removed by evaporation yielding 600 mg of the amide as an oil, which is chromatographed (SiO 2 and eluting with petroleumether : ether (2:1)), yielding 270 mg of the pure amide. This amide (270 mg) is dissolved in 1,2-dichloroethane (20 ml).
- (+)-cis-1S,2R-5-Methoxy-1-methyl-2-(N-cyclopropylmethyl-N-n-propylamino)tetralin (+)-cis-1S,2R-5-Methoxy-1-methyl-2-(n-propylamino)tetralin (500 mg) is dissolved in CH 2 CI 2 (20 ml) and Et 3 N (3 ml) is added together with cyclopropanecarboxylic acid chloride (300 ⁇ l) . The reaction mixture is left stirring for one hour. 10% Na 2 CO 3 is added and the raw amide product is extracted to the organic layer, which is dried and filtered. The organic solvent is removed by evaporation yielding 550 mg of the amide as an oil.
- This raw amide (550 mg) is dissolved in dry ether (15 ml) and this solution is added dropwise to a suspension of LiAIH 4 (0.60 g) in dry ether (10 ml). The reaction mixture is stirred at room temperature overnight and usual workup gives 483 mg of the desired product as an oil, which is chromatographed (100 g SiO 2 and eluting with hexane: ether (3:1)), yielding the desired product as an oil (280 mg) . This oil is converted to the hydrochloride salt, but no crystals are achieved.
- (+)-cis-1S,2R-5-Methoxy-1-methyl-2-(cyclopropylmethylamino) tetralin (+)-cis-1S,2R-5-Methoxy-1-methyl-2-aminotetralin (970 mg) is dissolved in CH 2 CI 2 (20 ml) and Et 3 N (3 ml) is added together with cyclopropanecarboxylic acid chloride (500 ⁇ l). The reaction mixture is left stirring for one hour. 10% Na 2 CO 3 is added and the raw amide product is extracted to the organic layer, which is dried and filtered. The organic solvent is removed by evaporation yielding 1.0 g of the amide as an oil.
- This raw amide (1.0 g) is dissolved in 1,2-dichloroethane (60 ml). To this solution is added QBH 4 (where Q means tetrabutylammonium) (1.4 g) dissolved in CH 2 CI 2 (60 ml). The reaction mixture is refluxed for 48 hours and is then chilled to room temperature and extracted with water several times . The solvents of the organic phase are evaporated and to the residue is added trichloroethylene.
- QBH 4 where Q means tetrabutylammonium
- the raw amide product was extracted to the organic layer, which was dried and filtered. The organic solvent was removed by evaporation yielding 60 mg of the amide as an oil.
- This raw amide (60 mg) was dissolved in 1,2-dichloroethane (10 ml). To this solution was added QBH 4 (where Q means tetraethylammonium) (200 mg) dissolved in CH 2 CI 2 (30 ml).
- reaction mixture was refluxed overnight and was then chilled to room temperature and extracted with water several times, separated, dried (Na 2 SO 4 ), filtered and the solvent was evaporated to give 60 mg of the desired product as an oil, which was chromatographed (15 g SiO 2 and eluting with hexane:ether (3:1)), yielding the desired product as an oil (20 mg). This oil was converted to the hydrochloride salt, but no crystals were achieved.
- (+)-R-8-Methoxy-2-(N-cyclopropylmethyl-N-(3-methoxy- phenylethyl)amino)- tetralin (+)-R-8-Methoxy-1-methyl-2-(-yclopro ⁇ ylmethylamino)tetralin (250 mg) was dissolved in CH 2 CI 2 (25 ml) and 10% NaOH (25 ml) was added together with a 3-methoxyphenylacetic acid chloride (0.4 g). The reaction mixture was left stirring for 2 days. The raw amide product was extracted to the organic layer, which was dried and filtered. The organic solvent was removed by evaporation yielding 400 mg of the amide as an oil.
- Example 25 7-Methylthio-2-(N-cyclopropylmethyl(-N-n-propylamino)- tetralin 7-Bromo-2-(di-n-propylamin)tetralin HCl (600 mg) was converted to the base with 10% Na 2 C03 and extraction with CH 2 CI 2 . The organic layer was dried and filtered and the solvent was evaporated under reduced pressure. The residual oil was dissolved in dry THF (40 ml) and poured into a flask equipped with N 2 ( g ) inlet, a drug funnel, a thermometer and septum for syringe injections of reagents and sample collection.
- This flask was chilled to -78oC and n-BuLi in hexane (1.4M, 3 ml) was injected through the septum.
- the reaction mixture was stirred for 0.5 hour for the halogen-lithium exchange to take place. This was checked with a small sample quenched in water and GC analysis.
- Dimethylsulfide (0.5 ml) was added dropwise from the funnel during 30 minutes at -78°C. The CO 2 (s)-bath was. removed and the temperature was allowed to reach room temperature before the reaction was quenched with water.
- Extractive workup yielded an oil (700 mg) , which contained 2-(di-n-propylamino) tetralin and the desired product in an approximative ration of 45:55.
- This raw oil was chromatographed and the fractions containing pure product were pooled and the solvent was evaporated yielding 110 mg of the product as an oil, which was used in the next step without further purifica tion.
- the oil (95 mg) was dissolved in CH 2 CI 2 (10 ml) and excess Br 2 (35 ⁇ l) was added.
- the organic phase was extracted with 10% Na 2 CO 3 and separated. Excess Br2 was removed with the addition of anisole (1 ml).
- the product in the organic phase was then extracted to 10% HCl and the acidic organic phase (containing the brominated anisoles) was discarded.
- the acidic water was basified (10% Na 2 CO 3 ) and extracted with ether, dried (Na 2 CO 3 ) , filtered and the solvent was evaporated, yielding 40 mg of an oil.
- the secondary amine produced (40 mg, 0.17 mmol) was dissolved in CH 2 CI 2 (5 ml) N-acylated with cyclopropanecarboxylic acid chloride (23 ⁇ l) in the presence of Et 3 N (50 ⁇ l). After 30 minutes the reaction mixture was washed with 10% Na 2 CO 3 and the organic phase was separated, dried (Na 2 CO 3 ), filtered and the solvent was evaporated, yielding 55 mg of an oil.
- (+)-R-8-Methoxy-2-(cyclopropylmethylamino) tetralin 500 mg was dissolved in CH 2 Cl 2 (25 ml) and 10% Na 2 CO 3 (25 ml) was added together with acetyl chloride (0.4 g) .
- the reaction mixture was left stirring for 2 hours.
- the raw amide product was extracted to the organic layer, which was dried and filtered.
- the organic solvent was removed by evaporation yielding the amide as an oil.
- This raw amide was chromatographed SiO 2 and eluting with petroleumether: ether (3.1)). The fractions containing pure product were pooled and the solvent was evaporated yielding an oil (324 mg).
- P denotes partial agonist, i.e., a submaximal decrease in DOPA or 5-HTP formation was noted at the highest dose (shown in brackets in ⁇ mol/kg) tested.
- cMotor activity as measured in photocell-equipped motility boxes.
- +” and “-” denote activation and no change, respectively, as compared to controls (essentially no locomotion was registered in these controls (reserpinized rats)).
- dT The gross behavior of the animals was observed during the course of the experiments.
- the 5-HT behavioral syndrome consisted of flat body posture, abducted hind- and forelegs, forepaw treading (piano- playing) and Stra ⁇ b tail. TABLE 1 (continued)
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US17313088A | 1988-03-25 | 1988-03-25 | |
US173130 | 1988-03-25 |
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EP89302533A Expired - Lifetime EP0334538B1 (de) | 1988-03-25 | 1989-03-15 | Tetralin-Derivate, verwendbar in der Therapie |
EP89903628A Pending EP0407416A1 (de) | 1988-03-25 | 1989-03-15 | Therapeutisch wertvolle tetralinabkömmlinge |
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EP (2) | EP0334538B1 (de) |
JP (1) | JP2750187B2 (de) |
KR (1) | KR970005323B1 (de) |
AT (1) | ATE82954T1 (de) |
AU (1) | AU616253B2 (de) |
CA (1) | CA1331191C (de) |
DE (1) | DE68903659T2 (de) |
DK (1) | DK223490D0 (de) |
ES (1) | ES2053979T3 (de) |
FI (1) | FI102893B1 (de) |
GR (1) | GR3006983T3 (de) |
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EP0584558A2 (de) * | 1992-07-28 | 1994-03-02 | Snow Brand Milk Products Co., Ltd. | Zusammensetzung zum Unterdrücken von Infektion und Wachstum des menschlichen Immunschwäche-Virus unter Verwendung eines eisenbindenden Proteins |
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ZA899033B (en) * | 1988-12-01 | 1990-09-26 | Merrell Dow Pharma | Phenoxy and phenylthio,amino substituted benzocycloalkane derivatives in the treatment and prevention of drug-resistant protozoal infections |
ZA901277B (en) * | 1989-02-27 | 1991-10-30 | Lilly Co Eli | Ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes and 3-aminochromanes |
EP0476016B1 (de) * | 1989-05-31 | 1998-10-28 | PHARMACIA & UPJOHN COMPANY | ZNS-wirksame 8-Heterocyclyl-2-aminotetralin Derivate |
US5071875A (en) * | 1989-09-25 | 1991-12-10 | Northwestern University | Substituted 2-amidotetralins as melatonin agonists and antagonists |
SE8904127D0 (sv) * | 1989-12-07 | 1989-12-07 | Astra Ab | New biocyclic amino-substituted compounds |
FR2659853A1 (fr) * | 1990-03-22 | 1991-09-27 | Midy Spa | Utilisation de derives 2-aminotetraliniques pour la preparation de medicaments destines a combattre les troubles de la motricite intestinale. |
EP0450238A1 (de) * | 1990-03-30 | 1991-10-09 | Merrell Dow Pharmaceuticals Inc. | Verbindungen für die Behandlung von Migräne |
US5096908A (en) * | 1990-05-04 | 1992-03-17 | Eli Lilly And Company | Method of inhibiting gastric acid secretion |
US5258379A (en) * | 1990-05-04 | 1993-11-02 | Eli Lilly And Company | Method of inhibiting gastric acid secretion with n-arylpiperazines |
EP0471515B1 (de) * | 1990-08-15 | 1997-03-05 | Eli Lilly And Company | Ring-substituierte 2-Amino-1,2,3,4-tetra-hydronaphthaline, 3-Aminochromane und 3-Aminothiochromane |
IT1251877B (it) * | 1991-09-26 | 1995-05-26 | Zambon Spa | Processo per la preparazione di 2-ammino-5,6 dimetossi-tetralina |
WO1995004713A1 (en) * | 1993-08-06 | 1995-02-16 | The Upjohn Company | 2-aminoindans as selective dopamine d3 ligands |
ES2235521T3 (es) * | 1998-10-07 | 2005-07-01 | Ortho-Mcneil Pharmaceutical, Inc. | N-aralquilaminotetralina como ligando para el neuropeptido y el receptor y5. |
AU2001228681A1 (en) * | 2000-01-28 | 2001-08-07 | Melacure Therapeutics Ab | Novel aromatic amines and amides acting on the melanocortin receptors |
PL370799A1 (en) | 2001-12-03 | 2005-05-30 | F.Hoffmann-La Roche Ag | Aminotetralin derivatives as muscarinic receptor antagonists |
CN100352806C (zh) | 2001-12-03 | 2007-12-05 | 弗·哈夫曼-拉罗切有限公司 | 作为毒蕈碱受体拮抗剂的4-哌啶基烷基胺衍生物 |
DE10334187A1 (de) * | 2003-07-26 | 2005-03-03 | Schwarz Pharma Ag | Substituierte 2-Aminotetraline zur Behandlung von Depressionen |
DE10334188B4 (de) | 2003-07-26 | 2007-07-05 | Schwarz Pharma Ag | Verwendung von Rotigotin zur Behandlung von Depressionen |
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CA1017359A (en) | 1972-07-03 | 1977-09-13 | Frederic P. Hauck | Substituted cyclic polymethylene phenols |
JPS5124508B2 (de) | 1972-08-14 | 1976-07-24 | ||
DE2752659A1 (de) | 1976-12-07 | 1978-06-08 | Sandoz Ag | Neue tetralinderivate, ihre herstellung und verwendung |
CH637363A5 (en) | 1977-11-24 | 1983-07-29 | Sandoz Ag | Process for preparing novel 2-aminotetralins |
DE2803582A1 (de) | 1978-01-27 | 1979-08-02 | Sandoz Ag | Neue tetralinderivate, ihre herstellung und verwendung |
ZA825142B (en) | 1981-07-23 | 1983-04-27 | Erba Farmitalia | N-imidazolyl derivatives of 1,2,3,j-tetrahydro-naphthalene, indan and 2-substituted-1-chroman, and process for their preparation |
EP0168505B1 (de) * | 1984-05-22 | 1989-08-09 | Whitby Research Incorporated | Substituierte 2-Aminotetraline und Verfahren zur Herstellung |
IL79323A (en) * | 1985-07-10 | 1990-03-19 | Sanofi Sa | Phenylethanolaminotetralines,their preparation and pharmaceutical compositions containing them |
WO1987002035A1 (en) * | 1985-10-04 | 1987-04-09 | Maggioni-Winthrop S.P.A. | Fused cycloaliphatic aminoalcohols |
DE3718317A1 (de) * | 1986-12-10 | 1988-06-16 | Bayer Ag | Substituierte basische 2-aminotetraline |
DE3719924A1 (de) | 1986-12-22 | 1988-06-30 | Bayer Ag | 8-substituierte 2-aminotetraline |
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Cited By (2)
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EP0584558A2 (de) * | 1992-07-28 | 1994-03-02 | Snow Brand Milk Products Co., Ltd. | Zusammensetzung zum Unterdrücken von Infektion und Wachstum des menschlichen Immunschwäche-Virus unter Verwendung eines eisenbindenden Proteins |
EP0584558A3 (de) * | 1992-07-28 | 1994-12-21 | Snow Brand Milk Products Co Ltd | Zusammensetzung zum Unterdrücken von Infektion und Wachstum des menschlichen Immunschwäche-Virus unter Verwendung eines eisenbindenden Proteins. |
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KR970005323B1 (ko) | 1997-04-15 |
GR3006983T3 (de) | 1993-06-30 |
JPH03503411A (ja) | 1991-08-01 |
AU616253B2 (en) | 1991-10-24 |
AU3284689A (en) | 1989-10-16 |
FI102893B (fi) | 1999-03-15 |
EP0334538A1 (de) | 1989-09-27 |
NZ228392A (en) | 1991-11-26 |
DK223490A (da) | 1990-09-17 |
ZA891903B (en) | 1989-11-29 |
FI102893B1 (fi) | 1999-03-15 |
DK223490D0 (da) | 1990-09-17 |
JP2750187B2 (ja) | 1998-05-13 |
DE68903659D1 (de) | 1993-01-14 |
ES2053979T3 (es) | 1994-08-01 |
DE68903659T2 (de) | 1993-04-22 |
EP0334538B1 (de) | 1992-12-02 |
ATE82954T1 (de) | 1992-12-15 |
FI904696A0 (fi) | 1990-09-24 |
WO1989009050A1 (en) | 1989-10-05 |
CA1331191C (en) | 1994-08-02 |
KR900700088A (ko) | 1990-08-11 |
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