WO1982000143A1 - Composes heterocycliques, procede de preparation de ces composes et compositions pharmaceutiques contenant de tels composes - Google Patents

Composes heterocycliques, procede de preparation de ces composes et compositions pharmaceutiques contenant de tels composes Download PDF

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Publication number
WO1982000143A1
WO1982000143A1 PCT/CH1981/000069 CH8100069W WO8200143A1 WO 1982000143 A1 WO1982000143 A1 WO 1982000143A1 CH 8100069 W CH8100069 W CH 8100069W WO 8200143 A1 WO8200143 A1 WO 8200143A1
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Prior art keywords
compounds
formula
indole
dibenz
ethyl
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PCT/CH1981/000069
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German (de)
English (en)
Inventor
Ag Sandoz
R Giger
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Ag Sandoz
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Publication of WO1982000143A1 publication Critical patent/WO1982000143A1/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
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • the invention relates to heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing these compounds.
  • Belgian Patent No. 877169 describes a class of 4,5,5a, 6-tetrahydro-dibenz [cd, f] indole derivatives which have a stimulating effect on the central dopaninergic receptors. All specifically listed compounds which have alkyl groups in positions 4 and 5 contain a methyl group as an alkyl group.
  • R 1 and R 2 independently of one another, are an ethyl or n-propyl group and the two R 3 substituents are identical and denote hydroxyl or acyloxy groups,
  • acyloxy groups are expediently groups of the formula R a - CO - O - in which R a is an alkyl group, a cycloalkyl group with 3-7 carbon atoms, a phenyl group or a 5-6 membered heterocyclic ring.
  • R a is an alkyl group, this conveniently has 1-17 carbon atoms, preferably 1-7 carbon atoms, and can be straight-chain or branched.
  • R a can be a substituted alkyl group which suitably contains 1-5 carbon atoms in the alkyl chain. It is expediently a monosubstituted alkyl group. Examples of the corresponding substituents are carboxy, hydroxy, amino, alkylamino with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, di- (C alkylamino, halogen, alkylthio with 1-4 carbon atoms, phenoxy, a phenyl group, 1-pyrrolidinyl, piperidino or morpholino, and expediently a phenyl group R a can also be, for example, an alkyl group which contains 1-4 carbon atoms in the alkyl chain and is substituted by a cycloalkyl group having 3-7 carbon atoms.
  • R a is a phenyl radical or an alkyl group which is represented by a
  • Phenyl radical is substituted, means that the phenyl ring can be unsubstituted or substituted by 1, 2 or 3 identical or different substituents which consist of halogen, trifluoromethyl, alkyl having 1-4 carbon atoms, alkoxy mi 1-4 carbon atoms, alkylthio with 1-4 carbon atoms and di- (C 1 -4 ) al kylamino or selected from a Kethylenendioxy devis.
  • the phenyl ring is preferably mono- or disubstituted.
  • R a is an alkyl group substituted by a phenyl radical
  • R a is preferably a benzyl radical.
  • the phenyl ring can carry substituents which can be selected, for example, from halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms and alkylthio with 1-4 carbon atoms.
  • R a stands for a heterocyclic ring, it is expediently a heterocyclic ring which contains oxygen
  • R a preferably represents an alkyl group having 1-7 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, an unsubstituted phenyl or a phenyl which is mono- or disubstituted by chlorine, fluorine, trifluoromethyl, alkyl having 1-4 carbon atoms or alkoxy 1-4 carbon atoms, an unsubstituted benzyl or a benzyl which is non- or disubstituted by chlorine, fluorine, an alkyl group with 1-4 carbon atoms or an alkoxy group with 1-4 carbon atoms.
  • Halogen can be chlorine, bromine or fluorine, preferably chlorine or fluorine.
  • R 1 represents an n-propyl group and R 2 represents an ethyl group.
  • R 1 and R 2 are identical and represent an ethyl or n-propyl group.
  • the R 3 substituents are preferably a hydroxyl group.
  • the preferred compounds are the optical (4S, 5aR) isomers.
  • the invention also relates to a process for the preparation of compounds of the formula I, which is characterized in that either a) to compounds of the formula Ia
  • R 1 and R 2 have the above meaning, and the radicals R ' 3 denote identical acyloxy groups, by using compounds of Forrel Ia, in. racemic form with the relative configuration 4R *, 5aS * or in the form of an optically active Isomers with the absolute configuration 4S, 5aR, acylated.
  • the ether cleavage described in process a) can be carried out in a manner known per se.
  • the reaction can be carried out by treating the starting material with a strong Mineral acid, for example a hydrochloric acid or hydroiodic acid, at temperatures of at least 100 ° C., preferably from 100 ° C. to the boiling point of the reaction mixture, in particular at about 130 ° C.
  • the ether group Z is preferably a methoxy group.
  • the acylation described in process b) can be based on. known manner using the methods known for the selective acylation of phenol groups in the presence of amino groups.
  • a functional derivative of an acid for example an acid chloride, can be used as the acylating agent.
  • Acid bromide or an acid anhydride can be used.
  • the reaction is expediently carried out with the aid of acid chlorides in the presence of trifluoroacetic acid at temperatures from 20 ° C. to the boiling point of the reaction mixture or in the presence of pyridine at temperatures from 0 ° C. to room temperature.
  • the compounds of formula I obtained can be isolated and purified in a known manner from the reaction mixture.
  • the free bases of the compounds of formula I can be converted in a known manner into acid addition salts and vice versa.
  • Acids suitable for salt formation are, for example, hydrochloric acid, tartaric acid, di-0.0-p-toluoyl-D- or L-wainic acid and hydrobromic acid.
  • the racemates of the formula I can be obtained from racemic starting compounds.
  • the optically active isomers of the formula I can be obtained from the corresponding optically active starting compounds having the configuration (4S, 5aR) or from the racemates.
  • the 4S, 5aR enantiomer can be obtained from the racemate in a known manner, for example by fractional crystallization of the ciastereoisomeric salts, for example of their salts with (+) - di-0,0-p-toluoyl-D-tartaric acid or (-) - di-0,0-p-toluoyl-L-tartaric acid.
  • the racemates are preferably separated into the optically active isomers in an earlier stage of the synthesis, for example before the ether groups are split up.
  • the starting compounds of formula II can be prepared by using compounds of formula III
  • R 1 , R 2 and Z have the above meaning, reduced.
  • the reduction is conveniently carried out under acid. conditions suitable for the reduction of enamines or inines, for example with the aid of zinc in aqueous mineral acid, preferably hydrochloric acid, advantageously in the presence of a mercury (II) salt, for example mercury (II) chloride.
  • the reduction is conveniently carried out e.g. in Aethsnol and at temperatures from 50 ° C to the boiling point of the reaction mixture.
  • R 1 , R 2 and Z have the above meaning and R ' 2 represents a methyl or ethyl group.
  • the reactions can be carried out in a conventional manner, and the products obtained can be isolated and purified in a known manner.
  • the ether groups Z are preferably methoxy groups.
  • dibenz [cd, f] indole (compound of the formula III) 25 g (58.14 mM) 9- (N-ethyl-N-butyrylamino) -8-bromo-3,4-dimethoxy-phenanthrene are dissolved in 450 ml of anhydrous tetrahydrofuran with stirring and the solution obtained is brought to -25 ° with Cooled using a bath of methylene chloride and dry ice. 73 ml (116.28 mM) of a 1.7 molar solution of tert. Butyllithium in pentane are then added dropwise within 4 minutes.
  • reaction mixture is poured onto 500 ml of a mixture of water and ice, extracted three times, each time with 500 ml of methylene chloride, and the organic phases are washed with water, dried and she evaporates. After drying the product under high vacuum, the (4RS) -5-ethyl-4, 5-dihydro-4-hydroxy-9,10-dimethoxy-4-nrpropyl-dibenz [cd, f] -indole is obtained in the form of a yellow-green foam.
  • the zinc powder-mercury chloride mixture can also be added to the dibenzindole.
  • the reaction mixture is heated to reflux, 360 ml of 182.
  • Hydrochloric acid are added dropwise within 15 to 20 minutes and the mixture is heated to reflux with stirring overnight.
  • the reaction mixture is cooled to room temperature, filtered and the zinc amalgam is washed with 500 ml of methylene chloride.
  • the filtrate is made alkaline with 1 liter of concentrated ammonium hydroxide and the alkaline phase is extracted, once with 1 liter of ethylene chloride and twice, each time with 500 ml of methylene chloride.
  • the combined organic phases are washed with water, dried and evaporated.
  • the (4RS) -5-ethyl-4,5-di-hydro-4-hydroxy-9,10-dimethoxy-4-n-propy1-dibenz [cd, f] indole obtained in Example 1b) can also be prepared as follows are: a) 9-amino-3,4-dimethoxy-phenanthrene (compound of the formula X) A mixture of 430 ml (3.08 M) trifluoroacetic anhydride and 430 ml (5.62 M) trifluoroacetic acid is added at room temperature under a nitrogen atmosphere 53.6 g (0.19 M) of 3,4-dimethoxyphenanthrene-9-carboxylic acid were added and the mixture was stirred for 10 minutes.
  • the product obtained is recrystallized in the same manner using 1.7 liters of acetone and 35 ml of methanol to obtain colorless crystals.
  • the crystals obtained are recrystallized in the same manner using 1.2 liters of acetone and 60 ml of methanol.
  • Example 4b) Using the appropriate starting materials, the following compounds can be prepared as described in Example 4b): a) (-) - (4S, 5aR) -4,5-diaethyl-4,5,5a, 6-tetrahydro-9,10-dihydroxy - dibenz [cd, f] indole hydrochloride, mp.
  • (+) - (4S, 5aR) -5-ethyl-9,10-dibenzoyloxy-4,5,5a, 6-tetrahydro-4-n-propyl-di-benz [cd, f] indole- L (+) - tartrate; it melts at 161-162 ° after recrystallization from a mixture of ethyl acetate and ether; [ ⁇ ] D 20 - + 23.5 ° (c 0.28 from methanol).
  • the compounds of formula I have pharmacological properties. In particular, they exert a stimulating effect on the central dopaminergic receptors, as can be seen from the following standard experiments.
  • the dopaminergic effect of the compounds of the formal I was studied in the rat, according to that of U. Ungerstedt in Acta Physiol. Scand. Suppl. 367, 69-93 (1971). After one week, the unilateral injection of 6-hydroxydop ⁇ min into the substantia nigra causes unilateral degeneration of the nigrostriatal pathways. After intraperitoneal administration of a dose between about 0.03 and about 1 mg / kg of the compounds of the formula I, a long-lasting activation was found in the rats, which manifested itself in the fact that the rats rotated in the direction of the undenervated side.
  • Rats weighing between 180 and 222 g were placed in Perspex cylinders with a diameter of 30 cm on one latticed floor laid. After allowing the rats 30 minutes to get used to the cage, the compound to be tested was injected. The behavior of the rats was observed for 2 minutes, at intervals of 30 minutes, for 2 hours and then at intervals of 60 minutes for a total of up to 6 hours. The degree of stereotypical behavior observed was determined from that of Costall, Kaylor and Olley [Euro. J. Pharmac. 18, 83-94 (1972) 3 described evaluation system. The following evaluation criteria were applied:
  • the compounds of the formula I triggered a stereotypical sniffing, elicking and biting in the rats.
  • the compounds of the formula I are therefore known to be used to stimulate the central dopaminergic receptors, for example for the treatment of Parkinson's disease.
  • the suitable daily dose is between about 0.1 and about 20 mg and is expediently administered 2 to 4 times a day in the form of single doses which contain between about 0.025 and about 10 mg, or also in pvetard form.
  • the compounds of the formula I also have antidepressant properties, such as the inhibition of catalepsy caused by reserpine in the mouse, after subcutaneous administration of from about 0.001 mg to about 1 mg / kg of the compounds of the formula I and the inhibition of those in the rat catalepsy caused by tetrabenazine after intraperiteneal administration of about 0.2 to about 2 mg / kg of the compounds of formula I.
  • the compounds of formula I can therefore be used as anti depressants.
  • the suitable daily dose is between about 0.05 and 2 mg and is expediently administered 2 to 4 times a day in the form of single doses which contain about 0.01 mg to about 1 mg of the compounds of the formula I in addition to solid or liquid carriers or
  • the compounds of formula I can therefore be used as prolactin inhibitors, for example for the treatment of conditions which include hyperprolactinemia, such as menstrual disorders, for example amenorrhea and galactorrhea, or hypertension, breast cancer in connection with an increased level of prolactin in the serum, or for treatment hypogcnadism, for example sterility or impotence, or to regulate postnatal lactation.
  • hyperprolactinemia such as menstrual disorders, for example amenorrhea and galactorrhea
  • hypertension breast cancer in connection with an increased level of prolactin in the serum
  • hypogcnadism for example sterility or impotence, or to regulate postnatal lactation.
  • the suitable daily dose is between about 5 and about 50 mg and is expediently administered 2 to 4 times a day in the form of single doses which contain about 1.25 mg to about 25 mg of the compounds of the formula I in addition to solid or liquid
  • the compounds of formula I also have antipsychotic properties, which results from the inhibition of locomotion in the mouse, after subcutaneous administration of about 0.001 to about 0.1 mg / kg of the compounds of formula I, and from the do-paminagonistic effect on the presynaptic Receptors of Rat at doses between about 1 mg and about 10 mg / kg of the compounds of formula I, according to the following experiment;
  • the dopamine agonistic effect of the compounds of the formula I on the presynaptic receptors was determined in the rat according to the method described by J.R. Walters and co-workers in Naunyn Schmiede.erg's Arch. Pharmacol. 296, 5-14 (1976) described in vivo method.
  • the dopaminergic impulse flow was inhibited pharmacologically by means of ⁇ -butyrolactone.
  • the action of the aromatic amino acid decarboxylase was inhibited by means of hydroxybenzylhydrazine (NSD 1015) and the rats were sacrificed half an hour later.
  • the resulting DOPA accumulation in striatal tissue over 30 minutes was taken as a measure of the in vivo action of tyrosine hydroxylase.
  • the compounds of the formula I can therefore be used as antipsychotics, for example for the treatment of schizophrenia.
  • the suitable daily dose is between about 0.01 and about 1 mg and is expediently administered 2 to 4 times a day in the form of single doses which contain about 0.0025 mg to about 0.5 mg of the compounds of the formula I in addition to solid or liquid carriers or diluents.
  • the preferred indication is anti-parkin diction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Steroid Compounds (AREA)

Abstract

Composes (4, 5, 5a), 6-tetrahydrodibenz (cd, f) indole de formule I (FORMULE) dans laquelle R1 et R2, independamment l'un de l'autre, signifient un groupe ethyle ou n-propyle; et dans laquelle les substituants R3 sont identiques et signifient des groupes hydroxy- ou acyloxy-; ces composes, soit en leur forme racemique de configuration relative (4R*, 5aS*), soit en leur forme d'isomere optiquement actif de configuration absolue (4S, 5aR), se pretent particulierement a la stimulation de recepteurs centraux dopaminergues.
PCT/CH1981/000069 1980-06-27 1981-06-24 Composes heterocycliques, procede de preparation de ces composes et compositions pharmaceutiques contenant de tels composes WO1982000143A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH4972/80800627 1980-06-27
CH497280 1980-06-27
GB8037586 1980-11-24
GB8037586 1980-11-24

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WO1982000143A1 true WO1982000143A1 (fr) 1982-01-21

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AT (1) AT380875B (fr)
AU (1) AU546599B2 (fr)
CA (1) CA1155447A (fr)
CY (1) CY1399A (fr)
DE (1) DE3124086A1 (fr)
DK (1) DK285481A (fr)
ES (3) ES503432A0 (fr)
FI (1) FI75153C (fr)
FR (2) FR2485530A1 (fr)
GB (1) GB2136418B (fr)
IE (1) IE51341B1 (fr)
IL (1) IL63174A (fr)
IT (1) IT8148776A0 (fr)
KE (1) KE3749A (fr)
NL (1) NL8103041A (fr)
NZ (1) NZ197529A (fr)
PH (1) PH22773A (fr)
PT (1) PT73258B (fr)
SE (1) SE449222B (fr)
SG (1) SG62087G (fr)
WO (1) WO1982000143A1 (fr)
YU (1) YU159481A (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2524882A1 (fr) * 1982-04-13 1983-10-14 Sandoz Sa Nouveaux derives du dibenz(cd,f)indole, leur preparation et leur utilisation en therapeutique a titre de principes actifs de medicaments
EP0216072A2 (fr) * 1985-07-27 1987-04-01 Sandoz Ag Utilisation de dérivés de la dibenz[cd,f]indole pour la prévention de l'abus d'alcool
US5220536A (en) * 1989-09-01 1993-06-15 Quantronix, Inc. Measuring method and apparatus
US5422861A (en) * 1989-09-01 1995-06-06 Quantronix, Inc. Measuring method and apparatus

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT381090B (de) * 1983-04-12 1986-08-25 Sandoz Ag Herstellung von neuen (4r*,5as*)2,4,5-trialkylch8204132231/8

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE877169A (fr) * 1978-06-23 1979-12-21 Sandoz Sa Nouveaux derives du phenantrene, leur preparation et leur application comme medicaments

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI70407C (fi) * 1978-06-23 1986-09-19 Sandoz Ag Foerfarande foer framstaellning av nya terapeutiskt anvaendbara 4,5,5a,6-tetra-hydro-dibens/cd f/indol derivat

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE877169A (fr) * 1978-06-23 1979-12-21 Sandoz Sa Nouveaux derives du phenantrene, leur preparation et leur application comme medicaments

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2524882A1 (fr) * 1982-04-13 1983-10-14 Sandoz Sa Nouveaux derives du dibenz(cd,f)indole, leur preparation et leur utilisation en therapeutique a titre de principes actifs de medicaments
EP0216072A2 (fr) * 1985-07-27 1987-04-01 Sandoz Ag Utilisation de dérivés de la dibenz[cd,f]indole pour la prévention de l'abus d'alcool
EP0216072A3 (en) * 1985-07-27 1989-11-23 Sandoz Ag Use of dibenzûcd,f¨indole derivatives in the prevention of alcohol abuse
US5220536A (en) * 1989-09-01 1993-06-15 Quantronix, Inc. Measuring method and apparatus
US5422861A (en) * 1989-09-01 1995-06-06 Quantronix, Inc. Measuring method and apparatus

Also Published As

Publication number Publication date
AT380875B (de) 1986-07-25
DE3124086A1 (de) 1982-03-04
AU546599B2 (en) 1985-09-12
ES8400089A1 (es) 1983-10-16
IE811421L (en) 1981-12-27
IE51341B1 (en) 1986-12-10
PT73258B (en) 1982-11-16
DK285481A (da) 1981-12-28
FI811922L (fi) 1981-12-28
IL63174A0 (en) 1981-09-13
SG62087G (en) 1987-10-23
FI75153C (fi) 1988-05-09
GB2136418B (en) 1985-05-09
PT73258A (en) 1981-07-01
NZ197529A (en) 1984-07-06
YU159481A (en) 1984-02-29
SE449222B (sv) 1987-04-13
FR2485530A1 (fr) 1981-12-31
ES8300701A1 (es) 1982-11-01
KE3749A (en) 1987-10-02
NL8103041A (nl) 1982-01-18
GB2136418A (en) 1984-09-19
FR2485530B1 (fr) 1983-11-10
PH22773A (en) 1988-12-12
IL63174A (en) 1985-04-30
ATA284481A (de) 1985-12-15
ES515567A0 (es) 1983-10-16
ES515568A0 (es) 1983-10-16
FR2510996A1 (fr) 1983-02-11
ES8400088A1 (es) 1983-10-16
ES503432A0 (es) 1982-11-01
AU7202881A (en) 1982-01-07
CA1155447A (fr) 1983-10-18
CY1399A (en) 1987-12-18
FI75153B (fi) 1988-01-29
IT8148776A0 (it) 1981-06-26
GB8325760D0 (en) 1983-10-26
SE8103983L (sv) 1981-12-28

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