Tricyclic amide compounds

The invention relates to new tricyclic amide compounds, to processes for their preparation and to the pharmaceutical compositions which contain them.
Many studies in the last ten years have demonstrated the fundamental role of melatonin (5-methoxy-N-acetyltryptamine) in controlling the circadian rhythm and endocrine functions, and the melatonin receptors have been characterized and localized.
In addition to their beneficial effect on disorders of the circadian rhythm (J. Neurosurg., 1985, 63, pp 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp 222-226), ligands for the melatoninergic system have advantageous pharmacological properties as regards the central nervous system, in particular anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp 222-223), and for the treatment of Parkinson's disease (J. Neurosurg., 1985, 63, pp 321-341) and Alzheimer's disease (Brain Research, 1990, 528, pp 170-174). These compounds have likewise shown activity against certain cancers (Melatonin--Clinical Perspectives, Oxford University Press, 1988, page 164-165), on ovulation (Science 1987, 227, pp 714-720) and against diabetes (Clinical Endocrinology, 1986, 24, pp 359-364).
Compounds which make it possible to act on the melatoninergic system are therefore excellent medicaments which can be used by the clinician in the treatment of the abovementioned pathologies.
The Applicant Company has discovered new tricyclic amide compounds, of novel structure, which show a very high affinity for melatoninergic receptors and which exhibit, in vitro and in vivo, considerable pharmacological and therapeutic advantage.
The invention relates more particularly to the compounds of formula (I): ##STR2## in which: R.sup.1 represents a (C.sub.1 -C.sub.4)alkylene chain which is unsubstituted or substituted by a radical chosen from alkyl, hydroxyl, alkoxycarbonyl and carboxyl;
R.sup.2 represents a hydrogen atom or an alkyl;
R.sup.3 represents:
either a group of formula R.sup.31 ##STR3## in which n represents zero or an integer from 1 to 3 and R.sup.5 represents a hydrogen atom, an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted alkynyl, an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted dicycloalkylalkyl; and X' represents an oxygen or sulfur atom;
or a group of formula R.sup.32 : ##STR4## in which X represents an oxygen or sulfur atom, m represents zero or an integer from 1 to 3 and R.sup.6 represents a radical chosen from the same values as R.sup.5 ;
A represents a chain of formula --O--A.sup.1 -- in which A.sup.1 is a chain chosen from (C.sub.2 -C.sub.5)alkylene, (C.sub.2 -C.sub.5)alkenylene and (C.sub.2 -C.sub.5)alkynylene; A.sup.1 being unsubstituted or substituted by one or a number of groups chosen from alkyl, alkoxy, hydroxyl and oxo,
Y forming, with the benzene ring to which it is bonded, a y.sup.1 group chosen from naphthalene, partially hydrogenated naphthalene, benzofuran, partially hydrogenated benzofuran, benzothiophene, partially hydrogenated benzothiophene and indole;
it being understood that:
the expression "substituted" relating to the terms "alkyl", "alkenyl" and "alkynyl" means that these groups are substituted by one or a number of radicals chosen from halogen, alkyl and alkoxy,
the expression "substituted" relating to the term "cycloalkyl" or "dicycloalkylalkyl" means that these groups are substituted by one or a number of radicals chosen from: alkyl, alkoxy, hydroxyl and the oxo group,
the terms "alkyl" and "alkoxy" denote radicals containing from 1 to 6 carbon atoms,
the terms "alkenyl" and "alkynyl" denote unsaturated radicals containing 2 to 6 carbon atoms,
the term "cycloalkyl" denotes a saturated or unsaturated group containing 3 to 8 carbon atoms,
to their enantiomers and diastereoisomers, and to their addition salts with a pharmaceutically acceptable base.
The invention particularly relates to:
the compounds of formula (I) in which R.sup.1 represents an ethylene chain,
the compounds of formula (I) in which R.sup.2 represents a hydrogen atom,
the compounds of formula (I) in which R.sup.3 represents a group of formula R.sup.31,
the compounds of formula (I) in which R.sup.5 represents an alkyl,
the compounds of formula (I) in which R.sup.5 represents a cycloalkyl group,
the compounds of formula (I) in which R.sup.3 represents an R.sup.32 group,
the compounds of formula (I) in which R.sup.6 represents an alkyl,
the compounds of formula (I) in which R.sup.6 represents a cycloalkyl,
the compounds of formula (I) in which X' is an oxygen atom,
the compounds of formula (I) in which X' is a sulfur atom,
the compounds of formula (I) in which X is an oxygen atom,
the compounds of formula (I) in which X is a sulfur atom,
the compounds of formula (I) in which A.sup.1 is an ethylene chain,
the compounds of formula (I) in which A.sup.1 is a trimethylene chain,
the compounds of formula (I) in which A.sup.1 is a tetramethylene chain,
the compounds of formula (I) in which A.sup.1 is a vinylene chain,
the compounds of formula (I) in which A.sup.1 is a propenylene chain,
the compounds of formula (I) in which Y forms, with the benzene ring to which it is bonded, a naphthalene group,
the compounds of formula (I) in which Y forms, with the benzene ring to which it is bonded, a tetrahydronaphthalene group,
the compounds of formula (I) in which Y forms, with the benzene ring to which it is bonded, an indole group.
The invention more particularly relates to:
the compounds of formula (I.sub.1) ##STR5## in which A, R.sup.1, R.sup.2 and R.sup.3 are as defined in the formula (I) and the compounds of formula (I.sub.2) ##STR6## in which A, R.sup.1, R.sup.2 and R.sup.3 are as defined in the formula (I).
For example, the invention relates to the compounds of formula (I.sub.3): ##STR7## in which A, R.sup.2 and R.sup.3 are as defined in the formula (I) and to the compounds of formula (I.sub.4) ##STR8## in which A, R.sup.2 and R.sup.3 are as defined in the formula (I).
Mention may be made, as examples and in a nonlimiting way, among the pharmaceutically acceptable bases which can be used to form an addition salt with the compounds of the invention, of sodium, potassium, calcium or aluminium hydroxides, alkali metal or alkaline-earth metal carbonates and organic bases, such as triethylamine, benzylamine, diethanolamine, tert-butylamine, dicyclohexylamine and arginine.
The alkyl radicals present in the formula (I) can be chosen particularly from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.
The alkoxy radicals present in the formula (I) can be chosen from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
The halogens present in the formula (I) can be chosen from bromine, chlorine, fluorine and iodine.
The cycloalkyls present in the formula (I) can be chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The alkylene groups present in the formula (I) can be chosen from ethylene, trimethylene, tetramethylene and pentamethylene.
The invention also relates to the process for the preparation of the compounds of formula (I), wherein a compound of formula (II): ##STR9## in which R.sup.1, R.sup.2, R.sup.3, A.sup.1 and Y have the same definition as in the formula (I) and Z.sup.1 represents a reactive functional group, is cyclized in order to obtain the corresponding compound of formula (I), ##STR10## in which R.sup.1, R.sup.2, R.sup.3 and Y are as defined above and A is as defined in the formula (I), which compounds of formula (I) can be, if desired,
purified according to one or a number of purification methods chosen from crystallization, silica gel chromatography, extraction, filtration and passing through charcoal or resin,
separated, if appropriate, in the pure form or in the form of a mixture, into their possible enantiomers or diastereoisomers,
or salified by a pharmaceutically acceptable base.
The invention also relates to a process for the preparation of the compounds of formula (I), wherein a compound of formula (III): ##STR11## in which A, R.sup.1, R.sup.2 and Y are as defined in the formula (I), is reacted
a) with an acyl chloride of formula (IV): ##STR12## in which n and R.sup.5 are as defined in the formula (I), or with the corresponding acid anhydride (bis- or mixed-) or with formic acid,
b) or else with an isocyanate of formula (V):
X.dbd.C.dbd.N--(CH.sub.2)m--R.sup.6 (V)
with X, m and R.sup.6 as defined in the formula (I)
in order to obtain, respectively:
a) the compound of formula (I/b1): ##STR13## in which A, Y, R.sup.1, R.sup.2, R.sup.5 and n are as defined above, or b) the compound of formula (I/b2): ##STR14## in which A, Y, R.sup.1, R.sup.2, R.sup.6, X and m are as defined above, it being possible for the compounds of formula (I/b1) and (I/b2) to be, if desired,
purified according to one or a number of purification methods chosen from crystallization, silica gel chromatography, extraction, filtration and passing through charcoal or resin,
separated, if appropriate, in the pure form or in the form of a mixture, into their possible enantiomers or diastereoisomers,
or salified by a pharmaceutically acceptable base.
The compound of formula (I) in which R.sup.31 represents a --CS--(CH.sub.2).sub.n --R.sup.5 group can also be obtained from the corresponding compound of formula (I), in which R.sup.31 represents a --CO--(CH.sub.2).sub.n --R.sub.5 group, which is subjected to a thionation reagent, for example Lawesson's reagent.
The invention also relates to the preparation of compounds of formula (I/c1): ##STR15## in which R.sup.1, R.sup.2, R.sup.3 and Y are as defined in the formula (I) and A.sup.3 represents a (C.sub.2 -C.sub.5)alkylene chain substituted by a hydroxyl radical or a (C.sub.2 -C.sub.5)alkenylene chain, wherein the controlled reduction is carried out of a compound of formula (I/c0): ##STR16## in which R.sup.1, R.sup.2, R.sup.3 and Y are as defined above and A.sup.2 represents a (C.sub.2 -C.sub.5)alkylene chain substituted by an oxo group,
it being possible for the compounds of formula (I/c1) to be, if desired,
purified according to one or a number of purification methods chosen from crystallization, silica gel chromatography, extraction, filtration and passing through charcoal or resin,
separated, if appropriate, in the pure form or in the form of a mixture, into their possible enantiomers or diastereoisomers,
or salified by a pharmaceutically acceptable base.
The invention also relates to a process for the preparation of the compounds of formula (I/d), a specific case of the compounds of formula (I): ##STR17## in which Y, R.sup.1, R.sup.2 and R.sup.3 are as defined in the formula (I) and A.sup.5 represents a (C.sub.2 -C.sub.5)alkylene chain which is unsubstituted or substituted by a (C.sub.1 -C.sub.6)alkyl radical, wherein a compound of formula (VI): ##STR18## in which Y, R.sup.1, R.sup.2 and R.sup.3 are as defined above and A.sup.6 represents a (C.sub.2 -C.sub.5)alkenyl radical which is unsubstituted or substituted by a (C.sub.1 -C.sub.6)alkyl radical, is subjected to a cyclization reaction,
it being possible for the compounds of formula (I/d) to be, if desired,
purified according to one or a number of purification methods chosen from crystallization, silica gel chromatography, extraction, filtration and passing through charcoal or resin,
separated, if appropriate, in the pure form or in the form of a mixture, into their possible enantiomers or diastereoisomers,
or salified by a pharmaceutically acceptable base.
The invention also relates to the compounds of formula (VI): ##STR19## in which R.sup.1, R.sup.2, R.sup.3 and Y are as defined in the formula (I) and A.sup.6 represents a (C.sub.2 -C.sub.5)alkenyl radical which is unsubstituted or substituted by a (C.sub.1 -C.sub.6)alkyl radical, which are useful as synthetic intermediates.
The compounds of formula (II) as described above are accessible to a person skilled in the art by reaction of a compound of formula (II/a): ##STR20## in which R.sup.1, R.sup.2, R.sup.3 and Y are as defined in the formula (I), with a compound of formula (II/b):
Z.sup.2 --A.sup.1 --Z.sup.3 (II/b)
in which A.sup.1 has the same definition as in the formula (I), Z.sup.2 represents an optionally protected reactive functional group and Z.sup.3 represents a leaving group, for example a halogen atom or a tosyl group.
For example, Z.sup.2 represents a hydroxyl or carboxyl functional group, a double bond or a triple bond.
The invention also applies to the compounds of formula (II): ##STR21## in which R.sup.1, R.sup.2, R.sup.3 and A.sup.1 are as defined in the formula (I) and Z.sup.1 represents a reactive functional group, which are useful as synthetic intermediates.
The starting materials used in the processes described above are either commercially available or known in the state of the art or are easily accessible to a person skilled in the art according to processes which are well known in the literature. More specific reference will be made, for the compounds of general formula (II), to the descriptions of Patent EP 447,285 and of Patent Application EP 530,087.
The compounds of formula (I) have pharmacological properties which are of great interest the clinician.
The compounds of the invention and the pharmaceutical compositions containing them are proving to be useful in the treatment of disorders of the melatoninergic system.
The pharmacological study of the compounds of the invention has in fact shown that they were not toxic, that they had a very high selective affinity for melatonin receptors and that they had significant activities with respect to the central nervous system and, in particular, therapeutic properties with respect to sleep disorders, anxiolytic, antipsychotic and analgesic properties and properties with respect to the microcirculation were noted, which make it possible to establish that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depressions, cardiovascular pathologies, insomnia and tiredness due to jet lag, schizophrenia, panic attacks, melancholia, eating disorders, obesity, insomnia, psychotic disorders, epilepsy, Parkinson's disease, senile dementia, various disorders related to normal or pathological ageing, migrane, memory losses, Alzheimer's disease and disorders of cerebral circulation. In another field of activity, it appears that the products of the invention have ovulation-inhibiting and immunomodulating properties and that they are capable of being used in anticancer treatment.
The compounds will preferably be used in the treatment of seasonal depressions, sleep disorders, cardiovascular pathologies, insomnia and tiredness due to jet lag, eating disorders and obesity.
For example, the compounds will be used in the treatment of seasonal depressions and sleep disorders.
Another subject of the present invention is the pharmaceutical compositions containing the products of formula (I) or, if appropriate, one of their addition salts with a pharmaceutically acceptable base in combination with one or a number of pharmaceutically acceptable excipients.
Mention can more particularly be made, among the pharmaceutical compositions according to the invention, of those which are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration, may especially be mentioned, and in particular simple or sugar-coated tablets, sublingual tablets, chartulas, packets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and imbibable or injectable phials.
The dosage varies according to the age and weight of the patient, the administration route, the nature of the therapeutic indication or possible associated treatments and ranges between 0.1 mg and 1 g per 24 hours in 1 or 2 administrations and more particularly 1 to 100 mg, for example 1 to 10 mg.

The following examples illustrate the invention but do not limit it in any way.
PREPARATION 1
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}ACETAMIDE
Stage A: N-{2-�7-(Ethoxycarbonylmethyloxy)naphth-1-yl!ethyl}acetamide ##STR22## Reactants
______________________________________N-�2-(7-Hydroxynaphth-1-yl)ethyl!acetamide 7 mmol (1.60 g)Anhydrous acetone 30 cm.sup.3Potassium carbonate 14 mmol (1.93 g)Ethyl bromoacetate 10 mmol (1.67 g)______________________________________
Procedure
The N-�2-(7-hydroxynaphth-1-yl)ethyl!acetamide is dissolved in the anhydrous acetone, the potassium carbonate is added and the mixture is left stirring at reflux for a half-hour. The ethyl bromoacetate is added dropwise using a dropping funnel and the mixture is left stirring at reflux for three hours. The mixture is left to cool, the precipitate is filtered off, the filtrate is evaporated to dryness and the residue is recrystallized.
Characteristics
______________________________________Yield 80%Recrystallization solvent toluene/hexane (1/2)Melting point 95-97.degree. C.Molecular mass 315.355 g.mol.sup.-1 for C.sub.12 H.sub.21 NO.sub.4______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 68.55 6.71 4.49Found 68.26 6.57 4.71______________________________________
Infrared
______________________________________3300 cm.sup.-1 .nu. N--H2960-2860 cm.sup.-1 .nu. C--H alkyls1735 cm.sup.-1 .nu. C.dbd.O ester1620 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO) 300 MHz
______________________________________1.25 ppm triplet 3H H.sub.f, J.sub.f-e = 7.10 Hz1.85 ppm singlet 3H H.sub.c3.15 ppm triplet 2H H.sub.a, J.sub.a-b = 6.80 Hz3.35 ppm multiplet 2H H.sub.b4.20 ppm quartet 2H H.sub.e5.00 ppm singlet 2H H.sub.d7.20-7.35 ppm unresolved peak 3H H.sub.2, H.sub.3, H.sub.67.55 ppm doublet 1H H.sub.8, J.sub.8-6 = 2.15 Hz7.75 ppm double doublet 1H H.sub.4, J.sub.4-3 = 7.40 Hz, J.sub.4-2 = 2.60 Hz7.85 ppm doublet 1H H.sub.5, J.sub.5-6 = 9.00 Hz8.05 ppm triplet 1H N--H amide______________________________________
Stage B: N-{2-�7-(Carboxymethyloxy)naphth-1-yl!ethyl}acetamide ##STR23## Reactants N-{2-�7-(Ethoxycarbonylmethyloxy)naphth-1-yl!ethyl}acetamide: 5 mmol (1.57 g)
10% Aqueous sodium hydroxide solution: 10 mmol (40 cm.sup.3)
Procedure
The N-{2-�7-(ethoxycarbonylmethyloxy)naphth-1-yl!ethyl}acetamide and a 10% aqueous sodium hydroxide solution are introduced into a flask and left to stir at room temperature until dissolution is complete. The reaction mixture is cooled in an ice bath and acidified with a concentrated hydrochloric acid solution. The precipitate is filtered off, washed with water, dried and recrystallized.
Characteristics
______________________________________Yield 70%Recrystallization solvent alcohol/water (2/1)Melting point 181-184.degree. C.Molecular mass 296.311 g.mol.sup.-1 for C.sub.16 H.sub.17 NO.sub.4 + 0.5H.sub.2 O______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 64.85 6.12 4.72Found 64.84 5.77 4.87______________________________________
Infrared
______________________________________3320 cm.sup.-1 .nu. N--H amide2920-2860 cm.sup.-1 .nu. C--H alkyls2500 cm.sup.-1 .nu. CO.sub.2 H1700 cm.sup.-1 .nu. C.dbd.O acide1610 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO) 300 MHz
______________________________________1.80 ppm singlet 3H H.sub.c3.10 ppm triplet 2H H.sub.a, J.sub.a-b = 7.15 Hz3.35 ppm quartet 2H H.sub.b4.90 ppm singlet 2H H.sub.d7.30 ppm unresolved peak 3H H.sub.2, H.sub.3, H.sub.67.55 ppm singlet 1H H.sub.87.80 ppm doublet 1H H.sub.4, J.sub.4-3 = 7.15 Hz7.90 ppm doublet 1H H.sub.5, J.sub.5-6 = 8.60 Hz8.10 ppm signal 1H N--H13.00 ppm signal 1H O--H, acidic, disappears with D.sub.2______________________________________ O
PREPARATION 2
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}ACETAMIDE ##STR24## Reactants
______________________________________N-�2-(7-hydroxynaphth-1-yl)ethyl!acetamide 5 mmol (1.15 g)Sodium hydride 18.75 mmol (0.45 g)Tosylate of propargyl alcohol! 20 mmolDimethylformamide 30 cm.sup.3______________________________________
Procedure
The N-�2-(7-hydroxynaphth-1-yl)ethyl!acetamide and the dimethylformamide are introduced into a three-necked, round-bottomed flask, the sodium hydride is added in small portions and the reaction mixture is left stirring for two hours under nitrogen at room temperature. The tosylate of propargyl alcohol is added dropwise using a dropping funnel and the reaction mixture is left stirring for a half-hour under nitrogen. The reaction mixture is poured into water with stirring and extracted with ethyl acetate, the extract is washed with water, dried over calcium chloride, filtered and evaporated to dryness and the residue is recrystallized.
Characteristics
______________________________________Yield 59%Recrystallization solvent hexane/toluene (2/1)Melting point 87-89.degree. C.Molecular mass 267.313 g.mol.sup.-1 for C.sub.17 H.sub.17 NO.sub.2______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 76.37 6.41 5.24Found 76.12 6.30 5.33______________________________________
Infrared
______________________________________3270 cm.sup.-1 .nu. N--H3200 cm.sup.-1 .nu. C.tbd.C--H2100 cm.sup.-1 .nu. C.tbd.C1620 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO) 300 MHz
______________________________________1.85 ppm singlet 3H H.sub.c3.15 ppm triplet 2H H.sub.a, J.sub.a-b = 6.70 Hz3.30 ppm multiplet 2H H.sub.b3.60 ppm singlet 1H H.sub.e5.00 ppm singlet 2H H.sub.d7.20-7.35 ppm unresolved peak 3H H.sub.2, H.sub.3, H.sub.67.65 ppm singlet 1H H.sub.87.75 ppm doublet 1H H.sub.4, J.sub.4-3 = 7.40 Hz7.85 ppm doublet 1H H.sub.5, J.sub.5-6 = 9.00 Hz8.05 ppm signal 1H NH amide______________________________________
By proceeding in an analogous way, the following preparations are obtained:
PREPARATION 3
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}PROPIONAMIDE
PREPARATION 4
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}BUTYRAMIDE
PREPARATION 5
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}ISOBUTYRAMIDE
PREPARATION 6
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}TRIFLUOROACETAMIDE
PREPARATION 7
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}FORMAMIDE
PREPARATION 8
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}PENTANAMIDE
PREPARATION 9
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}IODOACETAMIDE
PREPARATION 10
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}CYCLOPROPANECARBOXAMIDE
PREPARATION 11
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}CYCLOBUTANECARBOXAMIDE
PREPARATION 12
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}CYCLOPENTANECARBOXAMIDE
PREPARATION 13
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}CYCLOHEXANECARBOXAMIDE
PREPARATION 14
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}PROPENE-1-CARBOXAMIDE
PREPARATION 15
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}-N'-METHYLUREA
PREPARATION 16
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}-N'-ETHYLUREA
PREPARATION 17
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}-N'-n-PROPYLUREA
PREPARATION 18
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}-N'-CYCLOPROPYLUREA
PREPARATION 19
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}-N'-n-PROPYLTHIOUREA
PREPARATION 20
N-{2-�7-(CARBOXYMETHYLOXY)NAPHTH-1-YL!ETHYL}-N'-CYCLOPROPYLTHIOUREA
PREPARATION 21
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}PROPIONAMIDE
PREPARATION 22
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}BUTYRAMIDE
PREPARATION 23
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}ISOBUTYRAMIDE
PREPARATION 24
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}TRIFLUOROACETAMIDE
PREPARATION 25
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}FORMAMIDE
PREPARATION 26
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}PENTANAMIDE
PREPARATION 27
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}IODOACETAMIDE
PREPARATION 28
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}CYCLOPROPANECARBOXAMIDE
PREPARATION 29
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}CYCLOBUTANECARBOXAMIDE
PREPARATION 30
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}CYCLOPENTANECARBOXAMIDE
PREPARATION 31
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}CYCLOHEXANECARBOXAMIDE
PREPARATION 32
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}PROPENE-1-CARBOXAMIDE
PREPARATION 33
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}-N'-METHYLUREA
PREPARATION 34
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}-N'-ETHYLUREA
PREPARATION 35
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}-N'-PROPYLUREA
PREPARATION 36
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}-N'-CYCLOPROPYLUREA
PREPARATION 37
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}-N'-METHYLTHIOUREA
PREPARATION 38
N-{2-�7-(PROPARGYLOXY)NAPHTH-1-YL!ETHYL}-N'-CYCLOPROPYLTHIOUREA
PREPARATION 39
2-�7H-8,9-DIHYDROPYRANO�3,2-e!INDOLYL!ETHYLAMINE
This compound is described in J. Med. Chem., 1992, 35, p. 3625-3632.
PREPARATION 40
N-�2-(8-ALLYL-7-HYDROXYNAPHTH-1-YL)ETHYL!ACETAMIDE
Stage A: 2-(7-HYDROXYNAPHTH-1-YL)ETHYLAMINE HYDROBROMIDE ##STR25## Reactants
______________________________________2-(7-Methoxynaphth-1-yl)ethylamine hydrochloride 58 mmol (13.8 g)47% Aqueous HBr solution 390 mmol (46 cm.sup.3)______________________________________
Procedure
The ethylamine hydrochloride and the 47% HBr solution are introduced into a 250 cm.sup.3 round-bottomed flask. The mixture is brought to reflux for 5 hours. After cooling, the reaction mixture is filtered.
Characteristics
______________________________________Molecular mass: 268.16 g for C.sub.12 H.sub.14 BrNOAppearance: white solidMelting point: 174-175.degree. C.R.sub.f: 0.72eluent: methanol/28% aqueous ammonia (4/1)yield: 80%Recrystallization solvent: ethyl acetate/hexane (1/3)______________________________________
Infrared
______________________________________3240-3460 cm.sup.-1 .nu. OH3040-3100 cm.sup.-1 .nu. C.dbd.C twisting2950-3060 cm.sup.-1 .nu. CH2720-2480 cm.sup.-1 .nu. NH.sub.3.sup.+______________________________________
NMR (d.sub.6 -DMSO, .delta.)80 MHz
______________________________________3.0-3.4 ppm unresolved peak 4H H.sub.2, H.sub.37.0-7.9 ppm unresolved peak 6H H, aromatic protons8.1 ppm singlet 3H H.sub.49.8 ppm singlet 1H H.sub.1______________________________________
Microanalysis:
______________________________________ % C % H % N______________________________________Calculated 53.75 5.26 5.22Found 53.84 5.30 5.32______________________________________
Stage B: N-�2-(7-HYDROXYNAPHTH-1-YL)ETHYL!ACETAMIDE ##STR26## Reactants
______________________________________2-(7-Hydroxynaphth-1-yl)ethylamine hydrobromide 3.8 mmol (1.02 g)Sodium carbonate 8.5 mmol (0.90 g)Acetyl chloride 3.8 mmol (0.30 g)______________________________________
Procedure
The sodium carbonate is dissolved in 5 cm.sup.3 of water in a 50 cm.sup.3 flask and the hydrobromide is added with stirring. 20 cm.sup.3 of ethyl acetate are added to the suspension obtained and then the acetyl chloride is run in dropwise. Stirring is maintained for 30 minutes (the solution is clear). The organic phase is extracted with water, then with a 1N aqueous HCl solution and then with water until the wash liquors are neutral. The organic phase is dried over magnesium sulfate, filtered and dried under reduced pressure.
Characteristics
______________________________________Molecular mass: 229.27 g for C.sub.14 H.sub.15 BrNO.sub.2Appearance: white solidMelting point: 125-126.degree. C.R.sub.f : 0.32eluent: acetone/toluene/cyclohexane (4/4/2)Yield: 60%Recrystallization solvent: water______________________________________
Infrared
______________________________________3340 cm.sup.-1 .nu. OH2980 cm.sup.-1 .nu. CH1460 cm.sup.-1 .nu. CH.sub.31640 cm.sup.-1 .nu. CO amide______________________________________
NMR (CDCl.sub.3, .delta.)80 MHz
______________________________________2.0 ppm singlet 3H H.sub.53.2 ppm triplet 2H H.sub.2, J.sub.2-3 = 7.1 Hz3.6 ppm quintet 2H H.sub.3, J.sub.3-2 = 7.1 Hz, J.sub.3-4 = 7.1 Hz5.8 ppm signal 1H H.sub.47.0-7.9 ppm unresolved peak 6H H, aromatic protons9.8 ppm singlet 1H H1______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 73.34 6.59 6.11Found 72.99 6.57 6.29______________________________________
Stage C: N-�2-(7-ALLYLOXYNAPHTH-1-YL)ETHYL!ACETAMIDE ##STR27## Reactants
______________________________________N-�2-(7-Hydroxynaphth-1-yl)ethyl!acetamide 20 mmol (5 g)Sodium carbonate 50 mmol (6.63 g)Allyl bromide 30 mmol (3.63 g)______________________________________
Procedure
The compound obtained in the preceding stage is dissolved in 100 cm.sup.3 of anhydrous acetone. The sodium carbonate is added and the reaction mixture is left stirring at reflux for 30 minutes. The allyl bromide is added dropwise. The reaction mixture is left at reflux and with stirring for 3 hours. After cooling, the reaction mixture is filtered and the filtrate is dried under reduced pressure. The oil obtained is purified by column chromatography.
Characteristics
______________________________________Molecular mass: 269.33 g for C.sub.17 H.sub.19 NO.sub.2Appearance: oilR.sub.f : 0.19eluent: acetone/toluene/cyclohexane (2/3/5)Yield: 87%______________________________________
Infrared
______________________________________3260 cm.sup.-1 .nu. NH amide2920-2840 cm.sup.-1 .nu. CH1635 cm.sup.-1 .nu. CO amide1590 cm.sup.-1 .nu. C.dbd.C______________________________________
NMR (CDCl.sub.3, .delta.)300 MHz
______________________________________1.90 ppm singlet 3H H.sub.g3.20 ppm triplet 2H H.sub.e J.sub.e-d = 7,00 Hz3.60 ppm quintet 2H H.sub.d4.70 ppm doublet 2H H.sub.c J.sub.c-b = 5.28 Hz5.30 ppm doublet 1H H.sub.a cis, J.sub.a-b = 10.46 Hz5.50 ppm doublet 1H H.sub.a trans, J.sub.a-b = 17.30 Hz5.60 ppm signal 1H H.sub.f6.15 ppm multiplet 1H H.sub.b7.15 ppm double doublet 1H H.sub.6 J.sub.ortho = 8,90 J.sub.meta = 2,307.25 ppm multiplet 2H H.sub.2,37.40 ppm doublet 1H H.sub.87.65 ppm multiplet 1H H.sub.37.75 ppm doublet 1H H.sub.5 J.sub.ortho = 8,30______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 75,80 7,11 5,20Found 75,75 7,15 5,20______________________________________
Stage D: N-�2-(8-ALLYL-7-HYDROXYNAPHTH-1-YL)ETHYL!ACETAMIDE ##STR28## Reactants
______________________________________N-�2-(7-Alloxynaphth-1-yl)ethyl!acetamide 7.4 mmol (2 g)N,N-Dimethylaniline 7.4 mmol (10 cm.sup.3)______________________________________
Procedure
The N-�2-(7-allyloxynaphth-1-yl)ethyl!acetamide is dissolved in the N,N-dimethyl-aniline and the reaction mixture is brought to reflux (200.degree. C.) for 2 hours. After cooling, 20 cm.sup.3 of ether are added and the organic phase is extracted with a 10% aqueous sodium hydroxide solution and then with water. The aqueous phase is then acidified with a 6N aqueous HCl solution and left stirring for a few minutes. The precipitate obtained is filtered.
Characteristics
______________________________________Molecular mass: 269.33 g .multidot. mol.sup.-1 for C.sub.17 H.sub.19 NO.sub.2Appearance: pale yellow solidR.sub.f : 0.38eluent: acetone/toluene/cyclohexane (4/4/2)Melting point: 157-159.degree. C.Yield: 84%Recrystallization solvent: cyclohexane______________________________________
Infrared
______________________________________3280 cm.sup.-1 .nu. NH amide2860-3000 cm.sup.-1 .nu. CH1600 cm.sup.-1 .nu. CO amide______________________________________
NMR (d.sub.6 -DMSO, .delta.)300 MHz
______________________________________1.83 ppm singlet 3H H.sub.h3.20 ppm signal 2H H.sub.e3.25 ppm signal 2H H.sub.f3.90 ppm signal 2H H.sub.d4.65 ppm doublet 1H H.sub.b trans, J.sub.b-c = 17.2 Hz4.95 ppm doublet 1H H.sub.b cis, J.sub.b-c = 8.8 Hz6.05 ppm multiplet 1H H.sub.c7.17 ppm signal 1H H.sub.67.18 ppm signal 1H H.sub.3, J.sub.3-2 = 7.4 Hz, J.sub.3-4 = 4.33 Hz7.21 ppm signal 1H H.sub.2, J.sub.2-3 = 7.5 Hz7.65 ppm signal 1H H.sub.4, J.sub.4-3 = 7.4 Hz7.67 ppm signal 1H H.sub.5, J.sub.5-6 = 8.6 Hz8.08 ppm signal 1H H.sub.g9.60 ppm signal 1H H.sub.a, exchangeable in D.sub.2 O______________________________________
PREPARATION 41
N-�2-(8-ALLYL-7-HYDROXYNAPHTH-1-YL)ETHYL!-N'-METHYLUREA
EXAMPLE 1
2,3-DIHYDRO-3-OXO-4-(2-ACETAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN ##STR29## Reactants
______________________________________N-{2-�7-(Carboxymethyloxy)naphth-1-yl!ethyl} 10 mmol (2.9 g)acetamide (Preparation 1)Polyphosphoric acid 30 g______________________________________
Procedure
The N-{2-�7-(carboxymethyloxy)naphth-1-yl!ethyl}acetamide and the polyphosphoric acid are introduced into a 100 cm.sup.3 round-bottomed flask with a ground-glass neck and the reaction mixture is stirred using a mechanical stirrer at 85.degree. C. for two hours and a half. The reaction mixture is left stirring for one hour and is poured into ice-cold water. Extraction is carried out with ethyl acetate and the organic phase is washed twice with a 10% aqueous sodium carbonate solution, then washed with water, dried over calcium chloride, filtered and evaporated to dryness. The product is purified on a column with 60 .ANG. silica gel, using the acetone/toluene (1/1) eluent.
Characteristics
______________________________________Yield 32%Recrystallization solvent hexane/toluene (2/1)Melting point 157-158.degree. C.Molecular mass 269.287 g .multidot. mol.sup.-1 for C.sub.16 H.sub.15 NO.sub.3______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 71.35 5.61 5.20Found 71.33 5.46 5.17______________________________________
Infrared
______________________________________3270 cm.sup.-1 .nu. N--H amide2920-2860 cm.sup.-1 .nu. C--H alkyl1685 cm.sup.-1 .nu. C.dbd.O ketone1610 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO)300 MHz
______________________________________1.75 ppm singlet 3H H.sub.c3.25 ppm quartet 2H H.sub.b3.60 ppm triplet 2H H.sub.a, J.sub.a-b = 6.60 Hz7.45 ppm unresolved peak 3H H.sub.5, H.sub.6, H.sub.97.75 ppm signal 1H N--H7.85 ppm doublet 1H H.sub.7, J.sub.7-6 = 7.40 Hz8.30 ppm doublet 1H H.sub.8, J.sub.8-9 = 9.00______________________________________ Hz
EXAMPLE 2
2,3-DIHYDRO-3-HYDROXY-4-(2-ACETAMIDOETHYL)-1-NAPHTHO-�2,1 -b!FURAN ##STR30## Reactants
______________________________________2,3-Dihydro-3-oxo-4-(2-acetamidoethyl)-1-naphtho 5 mmol (1.35 g)�2,1-b!furan (Example 1)Methanol 30 cm.sup.3Sodium borohydride 10 mmol (0.32 g)______________________________________
Procedure
The 2,3-dihydro-3-oxo-4-(2-acetamidoethyl)-1-naphtho�2,1-b!furan and the methanol are introduced into a 100 cm.sup.3 flask with a ground-glass neck, the sodium borohydride (5 mmol) is added in small portions and the reaction mixture is left stirring. After two hours, sodium borohydride (5 mmol) is added in small portions and the reaction mixture is left to stir overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is taken up in water and acidified with a 6N hydrochloric acid solution. The precipitate is filtered off, washed with water until the wash liquors are neutral, dried and recrystallized from toluene.
Characteristics
______________________________________Yield 51%Melting point 153-156.degree. C.Molecular mass 271.303 g .multidot. mol.sup.-1 for C.sub.16 H.sub.17 NO.sub.3______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 70.82 6.31 5.16Found 70.61 6.28 5.04______________________________________
Infrared
______________________________________3250 cm.sup.-1 .nu. O--H and N--H1620 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO)300 MHz
______________________________________1.80 ppm singlet 3H H.sub.c3.00-3.65 ppm unresolved peak 4H H.sub.a, H.sub.b4.50 ppm multiplet 2H H.sub.25.60 ppm doublet 1H OH, disappears with D.sub.2 O, J = 7.005.70 ppm multiplet 1H H.sub.37.20-7.35 ppm unresolved peak 3H H.sub.5, H.sub.6, H.sub.97.75 ppm doublet 1H H.sub.7, J.sub.7-6 = 7,85 Hz7.90 ppm doublet 1H H.sub.8, J.sub.8-9 = 8,80 Hz8.05 ppm signal 1H N--H amide______________________________________
EXAMPLE 3
4-(2-ACETAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN ##STR31## Reactants
______________________________________2,3-Dihydro-3-oxo-4-(2-acetamidoethyl)-1-naphtho 5 mmol (1.38 g)�2,1-b!furan (Example 1)Methanol 30 cm.sup.3Sodium borohydride 20 mmol (0.76 g)______________________________________
Procedure
The 2,3-dihydro-3-oxo-4-(2-acetamidoethyl)-1-naphtho�2,1-b!furan and the methanol are introduced into a 100 cm.sup.3 round-bottomed flask and 10 mmol of sodium borohydride are added in small portions with stirring.
After two hours, sodium borohydride (10 mmol) is added in small portions with stirring. The reaction mixture is left stirring at room temperature and acidified with a 6N hydrochloric acid solution, the methanol is evaporated, the residue is taken up in water and the precipitate is filtered off, washed with water until the wash liquors are neutral, dried and recrystallized from toluene/hexane.
______________________________________Yield 85%Melting point 142-144.degree. C.Molecular mass 253.287 g .multidot. mol.sup.-1 for C.sub.16 H.sub.15 NO.sub.2______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 75.80 5.96 5.53Found 75.57 5.97 5.47______________________________________
Infrared
______________________________________3240 cm.sup.-1 .nu. N--H amide1625 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO)300 MHz
______________________________________1.85 ppm singlet 3H H.sub.c3.40 ppm multiplet 4H H.sub.a, H.sub.b7.50 ppm multiplet 2H H.sub.3, H.sub.97.80-7.95 ppm unresolved peak 4H H.sub.5, H.sub.6, H.sub.7, H.sub.88.20 ppm multiplet 2H H.sub.2, NH______________________________________
EXAMPLE 4
5-(2-ACETAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN ##STR32## Reactants
______________________________________N-{2-�7-(Propargyloxy)naphth-1-yl!ethyl}acetamide 10 mmol (2.67 g)(Preparation 2)Triethylene glycol 40 cm.sup.3______________________________________
Procedure
The N-{2-�7-(propargyloxy)naphth-1-yl!ethyl}acetamide and the triethylene glycol are introduced into a two-necked, round-bottomed flask. The reaction mixture is heated at 160.degree.-170.degree. C. under nitrogen and with stirring for five hours. The reaction mixture is poured into ice-cold water and extracted with ethyl acetate and the extract is washed with water, dried over calcium chloride, filtered and evaporated to dryness.
The product is purified on a 60 .ANG. silica column with an acetone/toluene (1/1) eluent.
Characteristics
______________________________________Yield 23%Recrystallization solvent toluene/hexaneMelting point decomposes at 113.degree. C.Molecular mass 267.313 g .multidot. mol.sup.-1 for C.sub.17 H.sub.17 NO.sub.2______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 76.37 6.41 5.24Found 76.16 6.40 5.52______________________________________
Infrared
______________________________________3250 cm.sup.-1 .nu. N--H2960-2840 cm.sup.-1 .nu. C--H alkyls1630 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO)300 MHz
______________________________________1.80 ppm singlet 3H H.sub.c3.20 ppm triplet 2H H.sub.a, J.sub.a-b = 6.80 Hz3.40 ppm multiplet 2H H.sub.b4.65 ppm doublet 2H H.sub.2, J.sub.2-3 = 4.30 Hz5.90 ppm multiplet 1H H.sub.37.10 ppm doublet 1H H.sub.4, J.sub.4-3 = 8.80 Hz7.30 ppm unresolved peak 3H H.sub.6, H.sub.7, H.sub.107.70 ppm doublet 1H H.sub.8, J.sub.8-7 = 7.50 Hz7.80 ppm doublet 1H H.sub.9, J.sub.9 -10 = 9.80 Hz8.10 ppm signal 1H N--H amide______________________________________
EXAMPLE 5
3,4,5,6,7,8-HEXAHYDRO-5-(2-ACETAMIDOETHYL)-2H-1-NAPHTHO-�2,1-b!PYRAN ##STR33## Reactants
______________________________________5-(2-Acetamidoethyl)-2H-1-naphtho�2,1-b!pyran 2 mmol (5.34 mg)(Example 4)Methanol 25 cm.sup.3Raney nickel a few mg______________________________________
Procedure
The 5-(2-acetamidoethyl)-2H-1-naphtho�2,1-b!pyran is dissolved in the methanol, the Raney nickel is added and the reaction mixture is stirred under a hydrogen atmosphere at ordinary pressure at room temperature for six hours. The reaction mixture is filtered. The filtrate is evaporated to dryness and the residue is recrystallized.
Characteristics
______________________________________Yield 55%Recrystallization solvent tolueneMelting point 117-118.degree. C.Molecular mass 273.361 g .multidot. mol.sup.-1 for C.sub.17 H.sub.23 NO.sub.2______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 74.68 8.48 5.12Found 74.46 8.39 5.16______________________________________
Infrared
______________________________________3240 cm.sup.-1 .nu. N--H amide2980-2800 cm.sup.-1 .nu. C--H alkyls1610 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO)80 MHz
______________________________________1.30-2.15 ppm unresolved peak 11H H.sub.a, H.sub.c, H.sub.3, H.sub.6, H.sub.72.35-2.80 ppm unresolved peak 5H H.sub.4, H.sub.5, H.sub.83.20 ppm multiplet 2H H.sub.b4.00 ppm multiplet 2H H.sub.26.50 ppm doublet 1H H.sub.10, J.sub.10-9 = 9.20 Hz6.75 ppm doublet 1H H.sub.9, H.sub.9-10 = 9.20 Hz7.90 ppm signal 1H N--H amide______________________________________
EXAMPLE 6
3,4-DIHYDRO-5-(2-ACETAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN ##STR34## Reactants
______________________________________5-(2-Acetamidoethyl)-2H-1-naphtho�2,1-b!pyran 2 mmol (5.34 mg)(Example 4)Methanol 80 cm.sup.3Magnesium 80 mmol (1.35 g)______________________________________
Procedure
The 5-(2-acetamidoethyl)-2H-1-naphtho�2,1-b!pyran is dissolved in the methanol and the reaction mixture is cooled using an ice/salt bath. The magnesium is added in small portions and the reaction mixture is left stirring at room temperature for 16 hours. 30 cm.sup.3 of a 6N hydrochloric acid solution are added little by little, with stirring. The reaction mixture is left to cool, is extracted with ether and the organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated to dryness.
Characteristics
______________________________________Yield 42%Recrystallization solvent ether/petroleum etherMelting point 137-139.degree. C.Molecular mass 291.849 g .multidot. mol.sup.-1 for C.sub.17 H.sub.19 NO.sub.2 + 1.25H.sub.2 O______________________________________
Microanalysis
______________________________________ % C % H % N______________________________________Calculated 69.95 6.99 4.79Found 70.00 6.63 4.75______________________________________
Infrared
______________________________________3240 cm.sup.-1 .nu. N--H amide2980-2800 cm.sup.-1 .nu. C--H alkyls1610 cm.sup.-1 .nu. C.dbd.O amide______________________________________
NMR (d.sub.6 -DMSO)300 MHz
______________________________________1.50-2.10 ppm unresolved peak 5H H.sub.3, H.sub.c3.10-3.85 ppm unresolved peak 6H H.sub.a, H.sub.b, H.sub.43.95 ppm multiplet 2H H.sub.27.15-7.30 ppm unresolved peak 3H H.sub.6, H.sub.7, H.sub.107.65 ppm doublet 1H H.sub.8, J.sub.8-7 = 7.45 Hz7.80 ppm doublet 1H H.sub.9, J.sub.9-10 = 9.90 Hz8.10 ppm signal 1H N--H______________________________________
EXAMPLES 7 TO 114
By proceeding as in Examples 1 to 6, but by using the appropriate preparations, the compounds of the following examples are obtained.
EXAMPLE 7
2,3-DIHYDRO-3-OXO-4-(2-PROPIONAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 8
2,3-DIHYDRO-3-OXO-4-(2-BUTYRAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 9
2,3-DIHYDRO-3-OXO-4-(2-ISOBUTYRAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 10
2,3-DIHYDRO-3-OXO-4-(2-TRIFLUOROACETAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 11
2,3-DIHYDRO-3-OXO-4-(2-FORMAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 12
2,3-DIHYDRO-3-OXO-4-(2-PENTANAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 13
2,3-DIHYDRO-3-OXO-4-�2-(IODOACETAMIDO)ETHYL!-1-NAPHTHO-�2,1-b!FURAN
EXAMPLE 14
2,3-DIHYDRO-3-OXO-4-�2-(CYCLOPROPANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURA
EXAMPLE 15
2,3-DIHYDRO-3-OXO-4-�2-(CYCLOBUTANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 16
2,3-DIHYDRO-3-OXO-4-�2-(CYCLOPENTANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 17
2,3-DIHYDRO-3-OXO-4-�2-(CYCLOHEXANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 18
2,3-DIHYDRO-3-OXO-4-�2-(PROPENE-1-CARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 19
2,3-DIHYDRO-3-HYDROXY-4-(2-PROPIONAMIDOETHYL)-1-NAPHTHO-�2,1-b!FURAN
EXAMPLE 20
2,3-DIHYDRO-3-HYDROXY-4-(2-BUTYRAMIDOETHYL)-1-NAPHTHO-�2,1-b!FURAN
EXAMPLE 21
2,3-DIHYDRO-3-HYDROXY-4-(2-ISOBUTYRAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 22
2,3-DIHYDRO-3-HYDROXY-4-(2-TRIFLUOROACETAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 23
2,3-DIHYDRO-3-HYDROXY-4-(2-FORMAMIDOETHYL)-1-NAPHTHO-�2,1-b!FURAN
EXAMPLE 24
2,3-DIHYDRO-3-HYDROXY-4-(2-PENTANAMIDOETHYL)-1-NAPHTHO-�2,1-b!FURAN
EXAMPLE 25
2,3-DIHYDRO-3-HYDROXY-4-�2-(IODOACETAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 26
2,3-DIHYDRO-3-HYDROXY-4-�2-(CYCLOPROPANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 27
2,3-DIHYDRO-3-HYDROXY-4-�2-(CYCLOBUTANECARBOXAMIDO)ETHYL!-1 -NAPHTHO�2,1-b!FURAN
EXAMPLE 28
2,3-DIHYDRO-3-HYDROXY-4-�2-(CYCLOPENTANECARBOXAMIDO)ETHYL!-1 -NAPHTHO�2,1-b!FURAN
EXAMPLE 29
2,3-DIHYDRO-3-HYDROXY-4-�2-(CYCLOHEXANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 30
2,3-DIHYDRO-3-HYDROXY-4-�2-(PROPENE-1-CARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 31
4-(2-PROPIONAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 32
4-(2-BUTYRAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 33
4-(2-ISOBUTYRAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 34
4-(2-TRIFLUOROACETAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 35
4-(2-FORMAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 36
4-(2-PENTANAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 37
4-�2-(IODOACETAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 38
4-�2-(CYCLOPROPANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 39
4-�2-(CYCLOBUTANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 40
4-�2-(CYCLOPENTANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 41
4-�2-(CYCLOHEXANECARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 42
4-�2-(PROPENE-1-CARBOXAMIDO)ETHYL!-1-NAPHTHO�2,1-b!FURAN
EXAMPLE 43
5-(2-PROPIONAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 44
5-(2-BUTYRAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 45
5-(2-ISOBUTYRAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 46
5-(2-TRIFLUOROACETAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 47
5-(2-FORMAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 48
5-(2-PENTANAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 49
5-�2-(IODOACETAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 50
5-�2-(CYCLOPROPANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO-�2,1-b!PYRAN
EXAMPLE 51
5-�2-(CYCLOBUTANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 52
5-�2-(CYCLOPENTANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 53
5-�2-(CYCLOHEXANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 54
5-�2-(PROPENE-1-CARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 55
3,4,5,6,7,8-HEXAHYDRO-5-(2-PROPIONAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 56
3,4,5,6,7,8-HEXAHYDRO-5-(2-BUTYRAMIDOETHYL)-2H-1-NAPHTHO-�2,1-b!PYRAN
EXAMPLE 57
3,4,5,6,7,8-HEXAHYDRO-5-(2- ISOBUTYRAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 58
3,4,5,6,7,8-HEXAHYDRO-5-(2-TRIFLUOROACETAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 59
3,4,5,6,7,8-HEXAHYDRO-5-(2-FORMAMIDOETHYL)-2H-1-NAPHTHO-�2,1-b!PYRAN
EXAMPLE 60
3,4,5,6,7,8-HEXAHYDRO-5-(2-PENTANAMIDOETHYL)-2H-1-NAPHTHO-�2,1-b!PYRAN
EXAMPLE 61
3,4,5,6,7,8-HEXAHYDRO-5-�2-(IODOACETAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 62
3,4,5,6,7,8-HEXAHYDRO-5-�2-(CYCLOPROPANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 63
3,4,5,6,7,8-HEXAHYDRO-5-�2-(CYCLOBUTANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 64
3,4,5,6,7,8-HEXAHYDRO-5-�2-(CYCLOPENTANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 65
3,4,5,6,7,8-HEXAHYDRO-5-�2-(CYCLOHEXANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 66
3,4,5,6,7,8-HEXAHYDRO-5-�2-(PROPENE-1-CARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 67
3,4-DIHYDRO-5-(2-PROPIONAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 68
3,4-DIHYDRO-5-(2-BUTYRAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 69
3,4-DIHYDRO-5-(2-ISOBUTYRAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 70
3,4-DIHYDRO-5-(2-TRIFLUOROACETAMIDOETHYL)-2H-1-NAPHTHO-�2,1-b!PYRAN
EXAMPLE 71
3,4-DIHYDRO-5-(2-FORMAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 72
3,4-DIHYDRO-5-(2-PENTANAMIDOETHYL)-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 73
3,4-DIHYDRO-5-�2-(IODOACETAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b !PYRAN
EXAMPLE 74
3,4-DIHYDRO-5-�2-(CYCLOPROPANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 75
3,4-DIHYDRO-5-�2-(CYCLOBUTANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 76
3,4-DIHYDRO-5-�2-(CYCLOPENTANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 77
3,4-DIHYDRO-5-�2-(CYCLOHEXANECARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 78
3,4-DIHYDRO-5-�2-(PROPENE-1-CARBOXAMIDO)ETHYL!-2H-1-NAPHTHO�2,1-b!PYRAN
EXAMPLE 79
N-�2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-METHYLUREA
EXAMPLE 80
N-�2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-ETHYLUREA
EXAMPLE 81
N-�2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-n-PROPYLUREA
EXAMPLE 82
N-�2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-CYCLOPROPYLUREA
EXAMPLE 83
N-�2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-n-PROPYLTHIOUREA
EXAMPLE 84
N-�2-(2,3-DIHYDRO-3-OXO-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-CYCLOPROPYLTHIOUREA
EXAMPLE 85
N-�2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-METHYLUREA
EXAMPLE 86
N-�2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-ETHYLUREA
EXAMPLE 87
N-�2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-PROPYLUREA
EXAMPLE 88
N-�2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-CYCLOPROPYLUREA
EXAMPLE 89
N-�2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-PROPYLTHIOUREA
EXAMPLE 90
N-�2-(2,3-DIHYDRO-3-HYDROXY-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-CYCLOPROPYLTHIOUREA
EXAMPLE 91
N-�2-(1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-METHYLUREA
EXAMPLE 92
N-�2-(1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-ETHYLUREA
EXAMPLE 93
N-�2-(1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-PROPYLUREA
EXAMPLE 94
N-�2-(1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-CYCLOPROPYLUREA
EXAMPLE 95
N-�2-(1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-PROPYLTHIOUREA
EXAMPLE 96
N-�2-(1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-CYCLOPROPYLTHIOUREA
EXAMPLE 97
N-�2-(2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-METHYLUREA
EXAMPLE 98
N-�2-(2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-ETHYLUREA
EXAMPLE 99
N-�2-(2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-n-PROPYLUREA
EXAMPLE 100
N-�2-(2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-CYCLOPROPYLUREA
EXAMPLE 101
N-�2-(2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-PROPYLTHIOUREA
EXAMPLE 102
N-�2-(2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-CYCLOPROPYLTHIOUREA
EXAMPLE 103
N-�2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-METHYLUREA
EXAMPLE 104
N-�2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-ETHYLUREA
EXAMPLE 105
N-�2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-PROPYLUREA
EXAMPLE 106
N-�2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-CYCLOPROPYLUREA
EXAMPLE 107
N-�2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-PROPYLTHIOUREA
EXAMPLE 108
N-�2-(3,4,5,6,7,8-HEXAHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-CYCLOPROPYLTHIOUREA
EXAMPLE 109
N-�2-(3,4-DIHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-METHYLUREA
EXAMPLE 110
N-�2-(3,4-DIHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-ETHYLUREA
EXAMPLE 111
N-�2-(3,4-DIHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-PROPYLUREA
EXAMPLE 112
N-�2-(3,4-DIHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-CYCLOPROPYLUREA
EXAMPLE 113
N-�2-(3,4-DIHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-PROPYLTHIOUREA
EXAMPLE 114
N-�2-(3,4-DIHYDRO-2H-1-NAPHTHO�2,1-b!PYRAN-5-YL)ETHYL!-N'-CYCLOPROPYLTHIOUREA
EXAMPLE 115
N-�2-(7H-8,9-DIHYDROPYRANO�3,2-e!INDOLYL)ETHYL!ACETAMIDE ##STR35## By proceeding on the compound of Preparation 39 with acetyl chloride, the title compound is obtained.
EXAMPLES 116 TO 118
By proceeding as in Example 115, but using the appropriate acyl chloride, the compounds of the following examples are obtained:
EXAMPLE 116
N-�2-(7H-8,9-DIHYDROPYRANO�3,2-e!INDOLYL)ETHYL!PROPIONAMIDE
EXAMPLE 117
N-�2-(7H-8,9-DIHYDROPYRANO�3,2-e!INDOLYL)ETHYL!CYCLOPROPANECARBOXAMIDE
EXAMPLE 118
N-�2-(7H-8,9-DIHYDROPYRANO�3,2-e!INDOLYL)ETHYL!CYCLOBUTANECARBOXAMIDE
EXAMPLE 119
2,3-DIHYDRO-2-METHYL-4-(2-ACETAMIDOETHYL)-1-NAPHTHO�2,1-b!FURAN ##STR36## Reactants
______________________________________N-�2-(8-Allyl-7-hydroxynaphth-1-yl)ethyl!acetamide 3.7 mmol (1 g)(Preparation 40)Trifluoroacetic acid (99%, d = 1.48) 32 mmol (2.33 cm.sup.3)______________________________________
Procedure
The compound from Preparation 40 is dissolved in the trifluoroacetic acid in a 50 cm.sup.3 flask and the mixture is brought to reflux for 8 h. It is left to cool. The medium is evaporated to dryness and the residue is taken up in water and extracted with ethyl acetate (3.times.10 cm.sup.3). The organic phase is washed with 2.times.2 cm.sup.3 of a 10% aqueous sodium hydroxide solution and then with water. The organic phase is dried over MgSO.sub.4 and brought to dryness. The product is purified on a silica column using acetone/toluene/cyclohexane as eluent.
Characteristics
______________________________________Molecular mass: 269.34 g for C.sub.17 H.sub.19 NO.sub.2Appearance: whitish solidMelting point: 136.degree. C.R.sub.f : 0.32eluent: acetone/toluene/cyclohexane (4/4/2)Yield: 73%Recrystallization solvent: toluene/cyclohexane (1/3)______________________________________
Infrared
______________________________________3240 and 3050 cm.sup.-1 .nu. NH amide2960-2840 cm.sup.-1 .nu. CH alkyls1630 cm.sup.-1 .nu. CO amide1000-1580 cm.sup.-1 .nu. C.dbd.C aromatics______________________________________
NMR (CDCl.sub.3, .delta.)300 MHz
______________________________________1.54 ppm doublet 3H H.sub.a, J.sub.a-b = 6.30 Hz1.96 ppm singlet 3H H.sub.g3.29 ppm multiplet 2H H.sub.d3.40 ppm double doublet 1H H.sub.c "cis" J = 7.6 Hz; J.sub.c'-b = 7,7 Hz; J.sub.c'-c = 15,2 Hz3.56 ppm multiplet 2H H.sub.e3.94 ppm double doublet 1H H.sub.c "trans" J = 9.2 Hz; J.sub.c'-c = 15,2 Hz5.05-5.07 ppm unresolved peak 1H H.sub.b5.53 ppm signal 1H H.sub.f7.08-7.23 ppm unresolved peak 3H H, aromatic protons, H.sub.5, H.sub.6, H.sub.97.67-7.70 ppm unresolved peak 2H H, aromatic protons, H.sub.8,______________________________________ H.sub.7
EXAMPLE 120
N-�2-(2,3-DIHYDRO-2-METHYL-1-NAPHTHO�2,1-b!FURAN-4-YL)ETHYL!-N'-METHYLUREA
By proceeding as in Example 119, but using the compound from Preparation 41 at the start, the title product is obtained.
Melting point: 165.degree.-169.degree. C.
EXAMPLES 121 TO 130
EXAMPLE 121
N-�2-(7H-8,9-DIHYDROTHIENO�3,2-f!BENZOTHIOPYRAN-1-YL)ETHYL!ACETAMIDE ##STR37##
EXAMPLE 122
N-�2-(7H-8,9-DIHYDRO-THIENO�3,2-f!BENZOPYRAN-1-YL)ETHYL!PROPIONAMIDE
EXAMPLE 123
N-�2-(7H-8,9-DIHYDRO-THIENO�3,2-f!BENZOPYRAN-1-YL)ETHYL!CYCLOPROPANECARBOXAMIDE
EXAMPLE 124
N-�2-(7H-8,9-DIHYDRO-THIENO�3,2-f!BENZOPYRAN-1-YL)ETHYL!CYCLOBUTANECARBOXAMIDE
EXAMPLE 125
N-�2-(7H-8,9-DIHYDRO-THIENO�3,2-f!BENZOPYRAN-1-YL)ETHYL!TRIFLUOROACETAMIDE
EXAMPLE 126
N-�2-(7H-8,9-DIHYDRO-FURO�3,2-f!BENZOPYRAN-1-YL)ETHYL!ACETAMIDE ##STR38##
EXAMPLE 127
N-�2-(7H-8,9-DIHYDROFURO�3,2-f!BENZOPYRAN-1-YL)ETHYL!PROPIONAMIDE
EXAMPLE 128
N-�2-(7H-8,9-DIHYDROFURO�3,2-f!BENZOPYRAN-1-YL)ETHYL!CYCLOPROPANECARBOXAMID
EXAMPLE 129
N-�2-(7H-8,9-DIHYDROFURO�3,2-f!BENZOPYRAN-1-YL)ETHYL!CYCLOBUTANECARBOXAMIDE
EXAMPLE 130
N-�2-(7H-8,9-DIHYDROFURO�3,2-f!BENZOPYRAN-1-YL)ETHYL!TRIFLUOROACETAMIDE
PHARMACOLOGICAL STUDY
EXAMPLE A
STUDY OF THE ACUTE TOXICITY
The acute toxicity was assessed after oral administration to batches of 8 mice (26.+-.2 grams). The animals were observed at regular intervals during the first day and daily during the two weeks following the treatment. The LD.sub.50, resulting in the death of 50% of the animals, was evaluated.
The LD.sub.50 of the products tested is greater than 1000 mg.multidot.kg.sup.-1 for the compounds studied, which indicates the low toxicity of the compounds of the invention.
EXAMPLE B
STUDY OF THE BINDING TO MELATONIN RECEPTORS
B1) STUDY ON SHEEP PARS TUBERALIS CELLS
Studies of the binding of the compounds of the invention to melatonin receptors were carried out according to conventional techniques on sheep pars tuberalis cells. The pars tuberalis of the adenohypophysis is in fact characterized, in mammals, by a high density of melatonin receptors (Journal of Neuroendocrinology, 1, pp 1-4, 1989).
PROTOCOL
1) Sheep pars tuberalis membranes are prepared and used as target tissue in saturation experiments in order to determine the binding capacities and affinities for 2-(.sup.125 I) iodomelatonin.
2) Sheep pars tuberalis membranes are used as target tissue, with the various compounds to be tested, in competitive binding experiments with respect to 2-iodo-melatonin.
Each experiment is carried out in triplicate and a range of different concentrations is tested for each compound.
The results make it possible to determine, after statistical treatment, the binding affinities of the compound tested.
RESULTS
It appears that the compounds of the invention have a very high affinity for melatonin receptors. In particular, the compound of Example 119 has an extremely powerful affinity for melatonin receptors, with an IC.sub.50 of 6.9.times.10.sup.-15 M.
B2) STUDY ON CHICKEN BRAIN CELL MEMBRANES (GALLUS DOMESTICUS)
The animals used are 12-day old chickens (Gallus domesticus). They are sacrificed between 1300 and 1700 hours on the day of their arrival. The brains are quickly removed and frozen at -200.degree. C. and then stored at -80.degree. C. The membranes are prepared according to the method described by Yuan and Pang (Journal of Endocrinology, 128, pages 475-482, 1991). 2-(.sup.125 I)Iodomelatonin is incubated in the presence of the membranes in a buffered solution at pH 7.4 for 60 min at 25.degree. C. At the end of this period, the membrane suspension is filtered (Whatman GF/C). The radioactivity retained on the filter is determined using a Beckman.RTM. LS 6000 liquid scintillation counter.
The products used are:
2-(.sup.125 I)iodomelatonin
melatonin
compounds of the invention
In primary screening, the molecules are tested at 2 concentrations (10.sup.-7 and 10.sup.-5 M). Each result is the mean of 3 independent measurements. The active molecules retained after the results of the primary screening were made the subject of a quantitative determination of their efficiency (IC.sub.50). They are used at 10 different concentrations.
Thus, the IC.sub.50 values found for the preferred compounds of the invention, which correspond to the values of the affinity, show that the binding of the compounds tested is very powerful.
EXAMPLE C
FOUR PLATES TEST
The products of the invention are administered via the esophagus to batches of ten mice. One batch receives acacia syrup. 30 minutes after administration of the test products, the animals are placed in compartments, the floor of which comprises four metal plates. Every time the animal passes from one plate to another, it receives a mild electric shock (0.35 mA). The number of transfers from one plate to another is recorded during one minute. After administration, the compounds of the invention significantly increase the number of transfers from one plate to another, demonstrating the anxiolytic activity of the compounds of the invention.
EXAMPLE D
COMPOUNDS OF THE INVENTION ON THE CIRCADIAN RHYTHMS OF RAT LOCOMOTORY ACTIVITY
The involvement of melatonin in controlling, by day/night alternation, the majority of the physiological, biochemical and behavioral circadian rhythms has made it possible to establish a pharmacological model for researching melatoninergic ligands.
The effects of the molecules are tested on many parameters and in particular on the circadian rhythms of locomotory activity which represent a reliable marker for the activity of the endogenous circadian clock.
In this study, the effects of these molecules on a specific experimental model, namely the rat placed in temporal isolation (permanent darkness), were evaluated.
PROTOCOL
Male Long Evans rats, aged one month, are subjected, from their arrival in the laboratory, to a light cycle of 12 h of light per 24 h (LD 12:12).
After adapting for 2 to 3 weeks, they are placed in cages equipped with a wheel connected to a recording system in order to detect the phases of locomotory activity and thus to monitor the nyctohemeral (LD) or circadian (DD) rhythms.
As soon as the rhythms recorded testify to stable control by the light cycle LD 12:12, the rats are placed in permanent darkness (DD).
Two to three weeks later, when the free mode (rhythm reflecting that of the endogenous clock) is clearly established, the rats receive a daily administration of the test molecule. The observations are carried out by making visible the rhythms of activity:
control of the rhythms of activity by the light rhythm,
disappearance of rhythm control in permanent darkness,
control by the daily administration of the molecule; transitory or lasting effect.
A computer program makes it possible:
to measure the duration and the intensity of the activity, and the period of the rhythm in animals in free mode and during the treatment,
optionally to demonstrate, by spectral analysis, the existence of circadian and noncircadian (ultradien, for example) components.
RESULTS
It clearly appears that the compounds of the invention make it possible to have a powerful effect on the circadian rhythm via the melatoninergic system.
EXAMPLE E
ANTIARRHYTHMIC ACTIVITY
PROTOCOL
(Ref: Lawson J. W. et al., J. Pharmacol. Expert. Therap., 160, 22-31, 1968)
The substance tested is administered intraperitoneally to a group of 3 mice 30 min before exposure to anesthesia by chloroform. The animals are then observed for 15 min. The absence of any recording of arrhythmias and of heart rates above 200 beats/min (control: 400-480 beats/min) in two animals at least indicates significant protection.
EXAMPLE F
PLATELET AGGREGATION-INHIBITORY ACTIVITY
PROTOCOL
(Ref.: Bertele V. et al., Science, 220, 517-519, 1983 ibid, Eur. J. Pharmacol., 85, 331-333, 1982)
The compounds of the invention (100 .mu.g/ml) are tested for their ability to inhibit the irreversible platelet aggregation induced by sodium arachidonate (50 .mu.g/ml) in platelet-enriched rabbit plasma.
Inhibition of the maximum aggregation by more than 50% indicates significant activity for the compounds of the invention.
This in vitro test shows that the compounds of the invention are good candidates for the treatment of cardiovascular diseases, in particular thromboses.
EXAMPLE G
EXTENSION OF THE BLEEDING TIME
PROTOCOL
(Ref.: Djana E. et al., Thrombosis Research, 15, 191-197, 1979) Butler K. D. et al., Thromb. Haemostasis, 47, 46-49, 1982)
The test compounds are administered orally (100 mg/kg) to a group of 5 mice 1 h before standardized sectioning of the end of each tail (0.5 mm).
The mice are immediately suspended vertically, their tails being immersed for a length of 2 cm in a test tube containing an isotonic saline solution at 37.degree. C.
The time required for the bleeding to stop for a period of 15 seconds is then determined.
An extension in the bleeding time of more then 50% relative to a group of control animals is regarded as significant for the compounds of the invention.
This in vivo test confirms the benefit of the compounds of the invention in the treatment of cardiovascular pathologies since the compounds of the invention extend the bleeding time.
EXAMPLE H
HYPOBARIC HYPOXIA TEST
PROTOCOL
(Ref.: Gotti B. and Depoortere H., Circ. Cerebrale, Congres de Circulation Cerebrale �Cerebral Circulation Congress!, Toulouse, 105-107, 1979)
The test compounds are administered intraperitoneally (100 mg/kg) to a group of 3 mice 30 minutes before being placed in a chamber at a hypobaric pressure of 20 cm Hg.
The extension in the survival time, with respect to a group of animals treated with the vehicle, of more than 100% and in the absence of a depressant effect on the central nervous system indicates a cerebral protective activity of the compounds of the invention.
Example I
PHARMACEUTICAL COMPOSITION:TABLETS
1000 tablets, containing a dose of 5 mg of 5-(2-acetamidoethyl)-2h-1-naphtho�2,1-b!pyran
5-(2-acetamidoethyl)-2H-1-naphtho�2,1-b!pyran 5 g
Wheat starch 20 g
Maize starch 20 g
Lactose 30 g
Magnesium stearate 2 g
Silica 1 g
Hydroxypropylcellulose 2 g

Number	Date	Country
286516	Oct 1988	EPX
286515	Oct 1988	EPX
447285	Sep 1991	EPX
530087	Mar 1993	EPX
562956	Sep 1993	EPX
9529173	Nov 1995	WOX

Tricyclic amide compounds

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Entry
Glennon et al. in Drug Development Research 22 25-36 (1991).
S. Conway et al. In Society for Neuroscience, 23, Item 420.14 (1997).