WO1992021654A2 - Derives de carboxamido-(3,2n)-2-aminotetralinecarbocyclique - Google Patents

Derives de carboxamido-(3,2n)-2-aminotetralinecarbocyclique Download PDF

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Publication number
WO1992021654A2
WO1992021654A2 PCT/US1992/001652 US9201652W WO9221654A2 WO 1992021654 A2 WO1992021654 A2 WO 1992021654A2 US 9201652 W US9201652 W US 9201652W WO 9221654 A2 WO9221654 A2 WO 9221654A2
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WO
WIPO (PCT)
Prior art keywords
compounds
dopamine
carboxamido
propyl
hexahydro
Prior art date
Application number
PCT/US1992/001652
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English (en)
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WO1992021654A3 (fr
Inventor
Chiu-Hong Lin
Montford E. Piercey
Susanne R. Haadsma-Svensson
Original Assignee
The Upjohn Company
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Priority to JP5500378A priority Critical patent/JPH06507906A/ja
Publication of WO1992021654A2 publication Critical patent/WO1992021654A2/fr
Publication of WO1992021654A3 publication Critical patent/WO1992021654A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention is related to new carboxamido-(3 ,2N)-carbocyclic-2-amino- 1,2,3,4-tetrahydronaphthylene derivatives, to processes for preparing such compounds, pharmaceutical preparation of such compounds and the use of such compounds in manufacture of a pharmaceutical preparation.
  • Psychiatric diseases are thought to be due to dysfunctions in monoaminergic neuronal systems, particularly those involving serotonin (5-HT) and dopamine (DA).
  • Schizophrenia is thought to be due to hyperactivity in DA systems.
  • DA antagonists Dopamine autoreceptors depress DA neuron firing rates, DA synthesis and release.
  • DA autoreceptor agonists can also be expected to be anti-psychotics.
  • DA agonists are also useful for treating Parldnsonism, a disease caused by degeneration of DA neurons, and hyperprolactinemia, since DA agonists depress prolactin release.
  • Dopamine autoreceptor antagonists are a new class of drug that increase release of DA by releasing the DA neuron from autoreceptor control. Thus, these drugs can be expected to be useful in conditions treatable with amphetamine and other similar stimulants which directly release DA. However, because DA autoreceptor agonists will be much milder stimulants because, rather than directly releasing DA, they simply increase the release associated with the normal DA activity by releasing the cell from autoreceptor control. Thus, DA autoreceptor antagonists can be expected to be useful in treating overeating, attention deficit disorders, psychiatric, cognitive and motor retardation in demented and elderly patients, and in treating nausea and dizziness with space travel.
  • the compounds of the present invention have a variety of effects at the DA receptors, and offer a variety of utilities associated with those activities.
  • Drugs acting on central dopamine transmission are clinically effective in treating a variety of central nervous system disorders such as parldnsonism, schizophrenia, and manic-depressive illness.
  • parldnsonism 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 anti-psychotic 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 neuro- transmission, transport mechanism and transmitter synthesis.
  • Direct dopamine receptor agonists like apomoiphine, are able to activate the dopamine autoreceptors as well as the post synaptic dopamine receptors.
  • the effects of autoreceptor stimulation appear to predominate when apomoiphine is administered at low doses, whereas at higher doses the attenuation of dopamine transmission is outweighed by the enhancement of postsynaptic receptor stimulation.
  • the anti-psychotic and anti- dyskinetic effects in man of low doses of apomoiphine are likely due to the autoreceptorstimulator 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.
  • 5-HT receptor agonist devoid of dopamine receptor stimulating activity.
  • the amine can be a mono or di substituted with simple alkyl groups, benzyl groups alkylalkoxy groups or the amine can be a 5 or 6 membered hydrocarbon or heterocyclic amine. These compounds are indicated to have dopaminergic properties although certain compounds are reported to be inactive.
  • Rusterholz, et al., J. Med. Chem., 19, 99 (1976) describes 5,8 disubstituted-2-aminotetralins with the amine being substituted with hydrogen, methyl, or cyanopropyl groups. Some of these compounds are potent prolactin inhibitors and believed to be dopamine agonists.
  • German Patent DE-A1-2 803 582 describes 2-aminotetralins where the aromatic ring is substituted on the 5,6,7 or 8 position a group R 1 , where R 1 is hydrogen, alkanoyl having 1 to 20 carbon atoms or a group -CO-(CH 2 ) n -R7, n is a number 0 to 5, R 7 is a phenyl group with substituents as defined further, R 2 is hydrogen, hydroxy, halogen or alkylsulfonylamino, R 3 is hydrogen, R 4 is hydrogen, CH 2 OH, CH 2 O-CO-R 8 or CH 2 -O-CO-(CH 2 ) n -R 7 with further definition and R 5 and R 6 are hydrogen, alkyl or aryl or aralkyl groups further defined or R 5 and R 6 are together an alkylene with 4 to 6 carbon atoms.
  • R 1 is hydrogen, alkanoyl having 1 to 20 carbon atoms or a group -CO-(CH 2
  • the compounds are disclosed as having pharmacodynamic activity in particular a stimulating effect on alpha-and beta-adrenoceptors and dopamine receptors.
  • the compounds described are compounds having the group R 10 in the 8 position and having R 2 or R 4 other than hydrogen.
  • 29348D/17 and 06733V/05 refer to 8-carboxyamino tetralins. Additional 07833V/05 refers to 8-amido and 8-alkylamido tetralin.
  • EPO patent application EPO 270947 (1988) discloses 8-hydroxy and 8-methoxy- tetralins.
  • 86-298374/45 discloses tetra-hydro-benzo-isindoline derivatives which interact specifically with various androgenic receptors and are useful for treating hypertension. 86-298374/45 also discloses that the compounds also have sedative activity.
  • U.S. Patent 4,622,405 discloses 1,2,3,3 ⁇ ,8,8 ⁇ -hexahydro indero(1,2-C)pyrroles(s).
  • Derwent 67323W/41 discloses benzoisoindolines as anti-aggressive and analgesic agents.
  • This invention encompasses compounds of Formula I, wherein R is C 1 -C 8 alkyl and n is 1 or 2.
  • the compounds of this invention possess selective pharmacological properties and are useful in treating central nervous system disorders including schizophrenia, Parkinson's disease, anxiety and depression.
  • Preferred compounds for treating schizophrenia and Parkinson's disease are those wherein the carboxamide group is in the 5, 6 or 7 position.
  • Particularly preferred compounds are those wherein the carboxamide group is in the 5 position.
  • the compounds of this invention are also useful in treating hypertension, congestive heart failure and cardiac arrythmias. Processes for preparation of these compounds, their pharmaceutical use and pharmaceutical preparations employing such compounds constitute further aspects of the invention.
  • An object of the invention is to provide compounds for therapeutic use, especially compounds having a therapeutic activity in the central nervous system.
  • a further object of this invention is to provide compounds having an effect on the subclass of dopamine receptors known as the D 2 receptor.
  • the compounds of this invention have been found to have unexpectedly superior resistance to liver metabolism and have excellent oral plasma bioavailability.
  • the compounds of this invention are identified in two ways: by the descriptive name and reference to labelled structures contained in appropriate charts. In appropriate situations, the proper stereochemistry is also represented in the charts.
  • 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.
  • LDA is lithium diisopropyl amide.
  • 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 stereochemistry of a particular compound. Pure enantiomers as well as enantiomeric or diastereomeric mixtures are within the scope of the invention.
  • the compounds of this invention may be obtained by one of the following methods described below and outlined in the appropriate charts.
  • the (3,2N) compounds can be made in accordance with the process illustrated in Chart A.
  • the methoxy derivative A-1 is resolved as described in prep 1.
  • the resolved A-1 is demethylated using diphenylphosphine and n-butyl lithium in THF to yield the hydroxy derivative A-2.
  • a process for the preparation of 2,3,3a,4,9,91-hexahydro-5-methoxy-1-n-propyl-1H-benz[f]indole is described in Example 4 and Chart E of application PCT/US90/03551 filed June 27, 1990 and published January 24, 1991.
  • step 2 the hydroxy derivative A-2 is reacted with trifluoromethanesulfonic anhydride in the presence of pyridine and methylene chloride to provide the triflate A-3.
  • step 3 the triflate A-3 is then reacted with palladium acetate and 1,3- bis(diphenylphosphino)propane in methanol/ dimethylformamide in the presence of gaseous carbon monoxide to yield the methyl ester A-4.
  • step 4 A-4 is first hydrolyzed to the carboxylic acid which is coupled with gaseous ammonia in the presence of diethylcyanophosphonate and triethylamine in dimethylformamide to give the carboxamido derivative A-5.
  • 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 in association with a pharmaceutically acceptable carrier.
  • 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.
  • the suitable daily doses of the compounds of the invention are 0.1-2000 mg/kg for oral application, preferably 0.5-500 mg/kg, and 0.1-100 mg/kg for parenteral application, preferably 0.5-50 mg/kg.
  • the compounds of this invention wherein the carboxamide group is in the 5, 6 and 7 position in the aromatic ring have dopaminergic activity with little 5-HT 1A agonist activity. It has been found that the compounds of the present invention and pharmacologically acceptable salts thereof have unexpectedly superior resistance to liver metabolism and excellent oral plasma bioavailability. Generally aminotetralins agonist activity are rapidly metabolized by the liver and have poor oral plasma bioavailability. The excellent oral bioavailability of compounds contained in this invention results in good potency and long duration of action following oral administration of the compounds. Both these features are beneficial to effective clinical treatment.
  • the agent In order to be a dopaminergic agonist, the agent must bind to the dopamine receptor.
  • tissue high in dopamine receptors trans-(+)-2,3,3a,4,9,9a-Hexahydro—5-carboxamido-1-n-propyl-1H-benz[f]- indole [(-)A-5] dopamine receptors with an extremely high affinity (56 nM Table 1);
  • Dopaminergic agonists such as apomoiphine depress nerve impulses generated by dopaminergic neurons. Indeed, all full dopamine agonists can completely suppress impulse generation so that the dopamine cells stop firing completely. In contrast, dopamine antagonists either do not affect nerve impulse activity of dopamine neurons or increase them.
  • Trans-(+)-2,3,3a,4,9,9a-Hexahydro-5-carboxamido-1-n-propyl-1H-benz[f]indole [(-)A-5] was a very potent dopamine agonist, depressing dopamine nerve discharges by 50% with a dose of only 4 ug/kg i.v.
  • the HCl-salt of this material is recrystallized from ethyl acetate/methanol to give a white solid as a (-) enantiomer of A-1: mp. 263-265 °C, [ ⁇ ] D -140o (c 0.70, MeOH).
  • the mother liquor is free-based as described above and recrystallized from methanol using an appropriate amount (1.05 equivalents) of di-p-toluoyl-D-tartaric acid to give 11.6 g (42 %) of apure diastereomeric salt as a white solid after two recrystallizations.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des tetralines aux propriétés thérapeutiques et des sels d'addition acides pharmaceutiquement acceptables de ces tétralines de formule (I) où R est alkyle C1-C8 et n est 1 ou 2.
PCT/US1992/001652 1991-05-20 1992-03-11 Derives de carboxamido-(3,2n)-2-aminotetralinecarbocyclique WO1992021654A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP5500378A JPH06507906A (ja) 1991-05-20 1992-03-11 カルボキサミド−（３，２ｎ）−カルボサイクリック−２−アミノテトラリン誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70281391A 1991-05-20 1991-05-20
US702,813 1991-05-20

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WO1992021654A2 true WO1992021654A2 (fr) 1992-12-10
WO1992021654A3 WO1992021654A3 (fr) 1993-01-07

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EP (1) EP0586553A1 (fr)
JP (1) JPH06507906A (fr)
AU (1) AU2153592A (fr)
MX (1) MX9202291A (fr)
TW (1) TW200460B (fr)
WO (1) WO1992021654A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047602A1 (fr) * 1996-06-11 1997-12-18 Smithkline Beecham Plc Derives d'amine tricycliques
WO2000007986A1 (fr) * 1998-07-31 2000-02-17 Boehringer Ingelheim Pharma Kg Nouveaux 2,3,3,a,4,9,9a-hexahydro-8-hydroxy-1h-benz[f] indoles, leurs procedes de preparation et leur utilisation comme medicament

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3402601A1 (de) * 1983-02-01 1984-08-02 Sandoz-Patent-GmbH, 7850 Lörrach Neue pharmazeutisch aktive 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)chinolinderivate, deren herstellung und verwendung
EP0272534A2 (fr) * 1986-12-22 1988-06-29 Bayer Ag Tétralines 2-amino 8-substituées
WO1991000856A2 (fr) * 1989-07-13 1991-01-24 The Upjohn Company DERIVES DE (1,2N) et (3,2N)-CARBOCYCLIQUE-2-AMINO TETRALINES

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3402601A1 (de) * 1983-02-01 1984-08-02 Sandoz-Patent-GmbH, 7850 Lörrach Neue pharmazeutisch aktive 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)chinolinderivate, deren herstellung und verwendung
EP0272534A2 (fr) * 1986-12-22 1988-06-29 Bayer Ag Tétralines 2-amino 8-substituées
WO1991000856A2 (fr) * 1989-07-13 1991-01-24 The Upjohn Company DERIVES DE (1,2N) et (3,2N)-CARBOCYCLIQUE-2-AMINO TETRALINES

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 106, no. 3, 19 January 1987, Columbus, Ohio, US; abstract no. 18332B, 'p-dimethoxy-substituted trans-octahydrobenzo(f)- and -(g)quinolines: synthesis and assessment of dopaminergic agonist effects' page 584 ; *
MOLECULAR PHARMACOLOGY vol. 35, no. 5, 1989, pages 643 - 651; 'characterization of dopamine receptor subtypes by comparative structure-activity relationships' *
PHARMAC. BIOCHEM. BEHAV. vol. 17, no. SUP1, 1982, pages 11 - 19; 'presynaptic Dopamine Receptor Agonists' *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047602A1 (fr) * 1996-06-11 1997-12-18 Smithkline Beecham Plc Derives d'amine tricycliques
US6080752A (en) * 1996-06-11 2000-06-27 Smithkline Beecham Plc Tricyclic amine derivatives
WO2000007986A1 (fr) * 1998-07-31 2000-02-17 Boehringer Ingelheim Pharma Kg Nouveaux 2,3,3,a,4,9,9a-hexahydro-8-hydroxy-1h-benz[f] indoles, leurs procedes de preparation et leur utilisation comme medicament
EA003370B1 (ru) * 1998-07-31 2003-04-24 Бёрингер Ингельхайм Фарма Кг Новые 2,3,3a,4,9,9a-гексагидро-8-гидрокси-1h-бенз[f]индолы, способ их получения и их применение в качестве лекарственных средств

Also Published As

Publication number Publication date
JPH06507906A (ja) 1994-09-08
TW200460B (fr) 1993-02-21
WO1992021654A3 (fr) 1993-01-07
EP0586553A1 (fr) 1994-03-16
AU2153592A (en) 1993-01-08
MX9202291A (es) 1992-11-01

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