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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • 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
  • A61P35/00—Antineoplastic agents
• • 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
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• • 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
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
• • 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
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/32—Oxygen atoms
  • C07D209/34—Oxygen atoms in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems

Definitions

• the present invention relates to new derivatives of spiro [indolc-pyrrolidine] melatoninergic agonists, their preparation process and their use as medicaments.
• Melatonin N-acetyl-5-melhoxytryptamine
• Lcrner & al. J. am. Chem. Soc, 80, 1958, 2587
• testoslone for its activity at the level of the hypothalamus and in psychiatric disorders.
• melatonin and its analogs in particular for the treatment of depression and psychiatric disorders, in particular stress, anxiety, depression, insomnia, schizophrenia, psychoses, epilcpsic, but also for the treatment of travel-related sleep disorders ("jet lag"), neurodegenerative diseases of the central nervous system such as Par's disease. inson or Alzheimcr's disease, for the treatment of cancer, or as a contraceptive, or as an analgesic.
• the direct use of melatonin in vivo has not been shown to be very satisfactory, given a first hepatic passage which extracts more than 90% of the active principle.
• the present patent application proposes a new route for the development of melatonin analogs exhibiting improved activity.
• the present invention therefore relates to new spirofindol-pyrrolidine derivatives] of general formula I
• -X __ Y- represents a divalent radical selected from
• Z represents an alkylene of formula - (CH 2 ) n - with n equal to 1 or 2, preferably 1, RI, R2, R3 and R4 independently of one another represent a hydrogen atom, a hydroxyl radical , a lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, halo or nitro radical, R5 represents a hydrogen atom, a lower alkyl, aryl, lower aralkyl, lower alkoxy, (lower) alkylcarbonyl, or perhaloalkyl- radical (lower) -carbonyl, R6 and R7 independently of one another represent a hydrogen atom, a lower alkyl, aryl, lower aralkyl, lower alkoxy, alkyl- (lower) -carbonyl, pcrhaloalkyl- (inféricur) radical.
• R8 and R9 independently of one another represent a hydrogen atom, a lower alkyl, aryl or lower aralkyl radical,
• RIO represents a hydrogen atom, a lower alkyl, aryl, lower aralkyl radical, each optionally substituted by one or more halogens, a perhalogeno-lower alkyl radical, amino, alkyl- (lower) -amino or dialkyl- (lower) -amino radical, or lower alkoxy radical
• RI 1 represents an oxygen atom, a sulfur atom or an N- radical
• R15 represents a hydrogen atom or a lower alkyl radical
• R13 represents an oxygen atom, a sulfur atom, an N-R16 radical or a substituted or unsubstituted methylene radical
• R14 represents a hydrogen atom, a lower alkyl, lower alkoxy, lower alkylthio, aryl or lower aralkyl radical
• R15 and R16 independently of one another represent a hydrogen atom or a lower alkyl radical
• R1-R2, R2-R3, R3-R4 may be part of another ring, aromatic or not, with or without heteroatom, R9 and RIO may together form an al ylènc radical, preferably methylene, optionally substituted, their racemics, their pure enantiomers, or their mixtures in all proportions, and their therapeutically acceptable salts.
• alkyl alkoxy or perhaloalkyl
• alkoxy or perhaloalkyl we generally mean radicals in which the alkyl residue contains between 1 and 6 carbon atoms.
• C 4 -C 4 alkyl radicals are preferably linear or branched C 4 -C 4 alkyl radicals, more particularly chosen from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl groups.
• aryl is generally meant the aromatic and heteroaromatic groups, in particular the aryls chosen from phenylc, thienyl, furanyl, pyridyl or naphthyl groups.
• the aryl radicals can also be substituted by one or more substituents chosen in particular from the lower alkyl, lower alkoxy or halogeno radicals defined above.
• lower aralkyl is meant the combination of lower alkyl and aryl as defined above. It will preferably be the radical bcnzylc, optionally substituted.
• halo radicals are preferably chosen from fluorine, bromine chlorine or iodine atoms.
• the halogenated radicals are fluorinated radicals.
• R1-R2, R2-R3, R3-R4 are part of another, aromatic ring, with or without heteroatom, it is another benzenic ring, optionally substituted, of a pyridyl ring, possibly substituted.
• R1-R2, R2-R3, R3-R4 are part of another non-aromatic ring, they preferably together form a divalent radical of formula -O- (CH 2 ) m -, m being equal to 2 or 3 , optionally substituted, or a divalent radical of formula -0- (CH 2 ) p-0-, p being equal to 1 or 2, optionally substituted.
• the derivatives according to the invention comprise at least one asymmetric carbon of R or S configuration, the carbon in 3 of the spiro nucleus being in all cases linked to 4 distinct substituents.
• the present invention therefore relates to the racemates of the derivatives of general formula I, as well as its pure enantiomers, or their mixtures in all proportions.
• the therapeutically acceptable salts of the derivatives according to the invention are the usual salts of the technique, organic or inorganic, in particular hydrochlorides, tosylates, mesilates, citrates as well as solvates such as hydrates or hemihydrates of the compounds of general formula I.
• the present invention relates more particularly to the derivatives of general formula I for which n is equal to 1.
• Rl 1 represents an oxygen atom and R8 cl R9 represent a hydrogen atom.
• At least one of the substituents R2 or R3 is different from a hydrogen atom and preferably represents a hydroxyl or lower alkoxy radical, in particular a methoxy radical.
• RI, R4 and R6 represent a hydrogen atom.
• R12 represents a hydrogen atom and RIO is advantageously a lower alkyl radical, preferably a methyl, an ethyl, an n-propyl or a pcrfluoromethyl, pcrfluoroethyl or perfluoropropyl radical, preferably pcrfluoroethyl.
• the present invention also relates to the process for the preparation of the derivatives of general formula I, as defined above.
• the derivatives of general formula I, for which -X; _. Y- represents a divalent radical of formula la are obtained by reduction of the derivative of formula corresponding according to the usual techniques, as for example with a metal hydride, to give the derivative of formula la for which R5 represents a hydrogen atom then , where appropriate transformed so as to introduce the substituent R5 different from a hydrogen atom, according to the usual methods of condensation on an amine.
• R1 represents an oxygen atom
• RIO represents a perhalogeno-lower alkyl radical (-R20)
• R5 an a pcrhalo-lower alkyl carbonyl radical (-CO-R20)
• R6 represents a hydrogen atom
• R7 is a lower perhalogeno-alkyl carbonyloxy radical (-O-CO-R20)
• the derivatives of formula la can be obtained directly by reacting the compound of general formula Ha
• R17 represents a hydrogen atom, with an excess of anhydride of formula III
• R20 represents a lower perhalo-al yl residue.
• RIO represents a perhalo-lower alkyl radical.
• the "deprotection" of the spiroindolic amine is then carried out by reacting the derivative of general formula I'b obtained previously with a base, preferably potassium carbonate, in a suitable solvent, for example methanol, or a methanol / water mixture.
• a base preferably potassium carbonate
• a suitable solvent for example methanol, or a methanol / water mixture.
• the R10-CO- radical is condensed, for which RIO is different from a phalhalo-lower alkyl radical, on the free amine according to the usual techniques for the preparation of aids, in particular the techniques for activating the acids with optionally a coupling agent, as used in peptide synthesis, or also by reaction with the anhydride of formula R10- CO-O-CO-R10 corresponding.
• R1, R2, R3, R4, R8, R9, R12 and Z are defined above, and R14 is different from a hydrogen atom, with an excess of anhydride of formula III defined above.
• RIO represents a perhalo-lower alkyl radical.
• the "deprotection" of the spiroindolic amine is then carried out by reacting the derivative of general formula I'c obtained previously with a base, preferably potassium carbonate, in a suitable solvent, for example methanol, or a methanol / water mixture.
• the radical R10-CO- is condensed, for which RIO is different from a perhalogeno-lower alkyl radical, on the free amine according to the usual techniques for preparing the amides, in particular the techniques for activating the acids with optionally a coupling agent, as used in peptide synthesis, or also by reaction with the anhydride of formula R10-CO -O-CO-R10 corresponding.
• the starting materials of formula II are commercially available, such as melatonin, or are in particular described in EP-A-0 527 687 and WO-A- 89/01472, or can be prepared from these derivatives.
• the present invention also relates to the derivatives of formulas Ha and Ilb, as defined above, with R17 representing a hydrogen atom or a bromine atom and R14 is different from a hydrogen atom, as products necessary for the preparation of the derivatives of general formula I according to the invention.
• the enantiomers of the derivatives of formula I and their mixtures in all proportions can be obtained by the usual methods for resolving racemates, in particular by selective crystallization in the presence of a chiral acid.
• Ci 4 H ⁇ 8 N 2 O 2 M 246.30g.mol- ⁇ NMR: i H (CD 3 COCD 3 ): 1.88 (s, 3H, CH 3 acelyl), 2.92 (t, 2H , CH 2 ), 3.45
• Example 6 The procedure of Example 6 is repeated, with compound 14 as the starting product, and compound J ⁇ 5 is obtained with similar yields.
• Example 3 The procedure of Example 3 is repeated, with 2-ethyl melatonin as the starting product, and the compound _19 is obtained with similar yields.
• Example 6 The procedure of Example 6 is repeated, with compound 20 as starting material, and compound 2J_ is obtained with similar yields.
• Example 5 The procedures of Example 5 (first or second method) are repeated, with compound 22 as the starting product, and compound 23 is obtained with similar yields.
• Ci 2 H ⁇ 2 N 2 OM 200.24 g.mol-i NMR: iH (CDC1 3 ): 1.78 (s, 3H, CH 3 ), 2.33 (m, H, H-4 ' a or b), 2.66
• Example 3 The procedure of Example 3 is repeated, with 2-ethyl N ⁇ -acetyltryptamine as starting material, and the compound 25 is obtained with similar yields.
• Example 24 The procedure of Example 24 is repeated, with compound 26 as the starting product, and compound 27 is obtained, with similar yields.
• the hypnotic and sedative effects of the derivatives, according to the invention, prepared above, were compared with those of three reference products, diazepam, pcnlobarbital. sodium and melatonin, in chickens of JA657 label, 10 to 18 days old.
• the animals are subjected to alternating breeding programs comprising 12 hrs of darkness (8 p.m. to 8 a.m.) and 12 hrs of breeding (8 a.m. to 8 p.m.).
• the ambient temperature is 25 ° C during the first week of chick rearing and 22 ° C from the second week.
• the lighting is provided by a 20 W x 60 cm neon lamp, placed 30 cm above the floor of the vivarium.
• the bodyweight of the chicks varied between 85 and 120 g.
• the tests are carried out between 10 a.m. and 2 p.m.
• the chicks are allotted in groups of 3 in identical vivariums of 30 cm x 50 cm x 30 cm.
• the products tested are administered intramuscularly (IM) into the pectoral major muscle, in hydro-ethanolic solution (ethanol / distilled water mixture, 50/50, V / V), in an amount of 0.2 ml of ethanolic solution per 100 g bodyweight.
• IM intramuscularly
• the doses administered for the products tested are equimolar (1 M / 100 g of live weight, or 2 g / 100 g for some compounds).
• the placebo corresponds to 0.2 ml of the ethanol / distilled water mixture (aa). Since ethanol is used as solvent, its effect was compared beforehand with that of physiological solution (0.9% NaCl solution) or distilled water.
• the hydro-ethanolic solutions of the test products were prepared extemporaneously by successive dilution of a mother solution, obtained from 10 ⁇ M of exactly weighed product, added with 1 ml of pure ethanol, stirred with ultrasound, then made up to 2 ml. with 1 ml of distilled water for injection.
• Table I are presented the results obtained after IM administrations of 1 Mole of the products tested, in solution in 0.2 ml of the ethanol / distilled water mixture, per 100 g of live weight. For each chick, the volume injected is adjusted, depending on the actual bodyweight, to 0.2 ml per 100 g of bodyweight. For some compounds the doses administered were 2 M / I 00 g of live weight.
• the parameters observed are the locomotor activity and the waking state of the chicks for 2 h, the equivalent of 6 theoretical sleep-wake cycles of the chick of this age. They are recorded by video camera for 90 minutes, the first 30 minutes being the time to adapt to the device. Five stages of vigilance have been defined: - stage 1: active watch; - stage 2: lying animal, maintenance of the head with tone, open eye;
• stage 3 light sleep, drowsy animal: closed eye with intermittent opening, immobile posture not modified by stimulation;
• stage 4 deep sleep lying down: relaxation of the neck, characteristic posture of the head under the wing or behind;
• stage 5 standing sleep: closed eye, motionless, drooping head (catatonic).
• stage 4 “slow wave sleep” (SWS)
• Stage 3 could correspond to phases of REM sleep, with shaking of the head, for example.
• Observation of the chicks is carried out by a trained observer with continuous video control for at least 1 hour after the animals wake up.
• Awakening is defined by the appearance of conscious conscious behavior of seeking and consuming food or drink.
• the Sleep Time is defined by the sum of the durations of the phases of light sleep (stage 3), deep sleep (stage 4) and standing sleep (stage 5).
• the Sedation Time after awakening, corresponds to stage 2.
• the Sleeping Time (TA) is equal (to within 1 minute) to the time necessary for the transition from active standby state (stage 1) to a non-alert state (stages 3, 4 and 5).
• sleep time equal to the time necessary to pass from the active standby state to a non-vigilant state
• - TS sleep time, equal to the length of the sleep period from falling asleep to waking up; .
• NA not applicable, awake animals or absence of sedation * duration of inactivity corresponding to the sum of sleep time and sedation time. Marked sedation, after awakening, was observed for compounds 1, 2, 3, 4, 9, 10, 13, 16 and 19 which are fluorinated derivatives.
• the hypno-sedative activity of melatonin is low (administration at 10 h), or even zero (administration at 14 h); the results observed depend on the time of administration of melatonin. On the other hand, for all the other products tested, the results are independent of the time of administration during the lighting phase (between 10 h and 14 h).
• melatonin has no direct hypnotic activity, specific to its structure. Its hypnotic activity depends on the activity of the enzyme N Acetyl Trans erase (NAT) in the pineal gland of the chick at the time of administration of melatonin.
• NAT enzyme is an acetylation enzyme.
• IM administration of melatonin induces a hypnotic effect of high intensity (sleep time between 250 and 300 minutes for a dose equal to 1 ⁇ M of melatonin / 100 g of bodyweight) - Melatonin is therefore the precursor of acetylated metabolites with direct hypnotic activity, among which is compound 6.
• the derivatives of the invention described above appear as acylation derivatives of melatonin or derivatives of neighboring chemical structures.
• all the derivatives of the invention described above have direct hypnotic or sedative activities, which are independent of the time of administration, IM, to the chick.
• the results obtained show, for the derivatives according to the invention, a hypnotic effect greater than that of the reference products (pentobarbital, melatonin) cl equivalent to that of diazepam.
• the derivatives according to the invention are therefore particularly advantageous for the treatment of diseases linked to disorders of the activity of melatonin.
• the present invention therefore relates to the derivatives of general formula I, as defined above for their use in therapy, in particular for the treatment of depression and psychiatric disorders, in particular stress, anxiety, depression, insomnia, schizophrenia, psychoses, epilcpsic, but also for the treatment of sleep disorders linked to travel ("jet lag"), neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease, for cancer treatment, or as a contraceptive, or as an analgesic.
• the melatoninergic analogs according to the invention are also useful for the treatment of benign prostatic hyperplasia, skin cancers, skin conditions such as psoriasis, acne, mycoses, glaucoma, as well as for increase immune resistance. They are also useful for preventing the symptoms of menopause, pre-menstrual syndromes, the effects of aging and sudden death of the newborn.
• the present invention therefore also relates to pharmaceutical compositions suitable for the administration of the derivatives of general formula I, in particular by oral, parental, rectal route, in the form of capsules, tablets, capsules, oral solutions, injectable solutions, including the forms retard and prolonged-release dressings for transdermal administration of the active ingredient, nasal sprays, or topical formulations (cream, emulsion, etc.), comprising a derivative of general formula I according to the invention and at least one acceptable excipient pharmaceutically.
• compositions according to the invention are advantageously dosed to deliver the active principle in a single "take".
• the effective unit doses are between 0.1 ⁇ g and 500 mg.
• the effective unit doses are between 0.1 ⁇ g and 100 mg.
• the melatoninergic analogs according to the invention are also useful in cosmetics, in particular for protecting the skin against aging, but also against hair loss.
• the present invention therefore also relates to a cosmetic composition comprising a derivative of general formula I according to the invention.
• compositions according to the invention are formulated in an appropriate manner, for their topical application, in particular in the form of ointments, creams, emulsions, ointments, lotions, etc.

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• 1995
  • 1995-04-06 JP JP7526122A patent/JPH09511514A/ja active Pending
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  • 1995-04-06 WO PCT/FR1995/000443 patent/WO1995027712A1/fr not_active Application Discontinuation
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