CA1099718A

CA1099718A - Process for the preparation of novel napthalene derivatives

Info

Publication number: CA1099718A
Application number: CA278,251A
Authority: CA
Inventors: Roger Canevari; Gilbert Regnier; Jean-Claude Poignant
Original assignee: Science Union et Cie
Current assignee: Science Union et Cie
Priority date: 1977-05-12
Filing date: 1977-05-12
Publication date: 1981-04-21

Abstract

De nouveaux dérivés du naphtalène de formule I: (I) dans laquelle R1 est hydrogène, halogène, alkyle ou alcoxy chacun de C1 à C5; R2 et R3, identiques ou différents, sont hydrogène, alkyle de C1 a C5, ou phényle ou R2 et R3 ensemble représentent un radical -CH=CH-CH-CH-, et leurs sels d'addition avec des acides compatibles, sont préparés: soit en condensant un dérivé halogéné de formule II: (II) avec une pipérazine N-monosubstituée de formule III: (III) soit en condensant un dérivé halogéné de formule IV: (IV) avec une pipérazine de formule V: (V) soit en soumettant un mélange d'un aldéhyde de formule VI: (VI) et d'une pipérazine N-monosubstituée de formule III, à une réduction alcoylante sous une pression d'hydrogène ? 5 atmosphères en présence de charbon palladié comme catalyseur, R1, R2 et R3 ayant dans les formules II à VI la même signification que dans la formule I et X représentant un atome de chlore ou de brome. Ces nouveaux dérivés sont utilisés comme médicaments notamment dans le traitement des troubles du système nerveux central, de la maladie de Parkinson et des troubles cardiovasculaires.New naphthalene derivatives of formula I: (I) in which R1 is hydrogen, halogen, alkyl or alkoxy each of C1 to C5; R2 and R3, identical or different, are hydrogen, C1 to C5 alkyl, or phenyl or R2 and R3 together represent a radical -CH = CH-CH-CH-, and their addition salts with compatible acids, are prepared : either by condensing a halogenated derivative of formula II: (II) with an N-monosubstituted piperazine of formula III: (III) or by condensing a halogenated derivative of formula IV: (IV) with a piperazine of formula V: (V) either by subjecting a mixture of an aldehyde of formula VI: (VI) and of an N-monosubstituted piperazine of formula III, to an alkylating reduction under a hydrogen pressure? 5 atmospheres in the presence of palladium carbon as catalyst, R1, R2 and R3 having in formulas II to VI the same meaning as in formula I and X representing a chlorine or bromine atom. These new derivatives are used as medicaments in particular in the treatment of disorders of the central nervous system, Parkinson's disease and cardiovascular disorders.

Description

l~g9q~8 La presente invention a pour objet le procede de preparation des derives du naphtalene de formule g~nerale I:

Rl ~ CH2 - N 3 ~ ~ R3 dans laquelle:
Rl represente un atome d'hydrogene, un atome d'halo-gene, tel que par exemple un atome de chlore, brome ou fluor, un radical alkyle ou alcoxy ayant chacun de 1 a 5 atomes de ~ :
carbone, et R2 et R3, qui peuvent être identiques ou differents, representent chacun un atome d'hydrogene, un radical alkyle contenant de 1 a 5 atomes de carbone, un radical phenyle, ou : ' R2 et R3 reunis ensemble representent un radical -CH-CH-CH=CH- de façon a former, avec le radical thiazolyle auquel ils sont lies, un radical benzothiazolyle.
Les derives de formule generale I sont nouveaux et ont ete prepares selon les methodes suivantes qui sont toutes incluses dans la présente invention.
La presente invention a donc pour objet le procede de preparation des derives de formule generale I, caracterise en ce que:
l'on condense un derive halogene de formule generale I I :

Rl~CH2 - X (II) dans laquelle Rl a la signification definie ci-dessus et X
represente un atome de chlore ou de brome, avec une piperazine N-mono-substituee de formule generale III:

10997~8 N l ~ R2 HN ~NI~sJ--R3 (III) dans laquelle R2 et R3 ont les significations de~inies prece-demment, ou l'on condense un derive halogene de formule generale IV:

X ~ ~ R3 (IV) dans laquelle R2, R3 et X ont les significations enoncees prec~demment, avec une piperazine de formule generale V:

~1 ~ CH2 ~ N 3 H (V) dans laquelle Rl a la signification definie precedemment.
Dans les deux cas, il est avantageux d'effectuer la condensation des derives halogenes II ou IV avec une pip~razine N-monosubstituee III ou V en solution dans un solvant polaire tel que par exemple un alcool comme le butanol ou l'alcool isoàmylique ou une amide aliphatique comme, par exemple la dimethylformamide, ou dans un solvant non-polaire tel qu'un hydrocarbure aromatique comme, par exemple, le xylene. Il est avantageux d'operer a une temperature comprise entre 115 et 160C en presence d'un accepteur de l'hydracide forme au cours de la reaction. Comme accepteurs on peut mentionner par exemple les sels alcalins de l'acide carbonique tels que par exemple les carbonates de sodium ou de potassium, et les bases organiques telles que par exemple la triethylamine. Si on le desire, il est ~galement possible de remplacer de tels sels ou bases par un exces de la piperazine N-monosubstituee III ou V, cet exces agissant comme accepteur de l'hydracide forme.

~9g~8 La presente invention concerne aussi le procede de preparation des derives de formule generale I, caracterise en ce que l'on soumet un melange d'un aldehyde de formule generale VI:

Rl ~ CH0 (VI) dans laquelle Rl a la signification precedemment definie, et d'une piperazine N-monosubstituee de formule g~nerale III
precedemment definie, a une reduction alcoylante, sous une pression d'hydrogene ~ 5 atmospheres, de preference sous une pression comprise entre 2 et 5 atmosphères, en pr~sence d'une faible quantite de palladium sur charbon comme catalyseur, dans un solvant convenable, tel que par exemple un alcool ayant jusqu'a 5 atomes de carbone ou l'acetate d'ethyle.
La mise en oeuvre la plus adequate d'un tel procede consiste a soumettre a l'hydrogenation sous une pression d'hydrogene comprise entre 2 et 5 atmospheres, un melange sen-siblement equimoleculaire des derives III et VI, en solution dans l'acetate d'ethyle, en presence de charbon palladie comme catalyseur a une temperature comprise entre 60 et 80C.
Les matières premieres utilisees pour ces procedes sont des produits connus ou sont preparees selon des methodes decrites dans la litterature pour preparer des composes ana-logues.
Les derives de formule generale I sont des bases faibles qui peuvent être transformees avec des acides, en sels d'addition acides.
La presente invention inclut la preparation des sels d'addition acides des derives de formule gen~rale I et plus particulierement des sels qui sont physiologiquement tolerables.

1~99718 Comme acides pouvant être utilises pour la formation de ces sels on peut citer par exemple, dans la serie minerale les acideschlorhydrique, bromhydrique, sulfurique et phospho-rique et dans la serie organique les acides acetique, propio-nique, maleïque, fumarique, tartrique, citrique, oxalique, benzoique, methane sulfonique et isethionique.
Les derives de formule generale I peuvent être puri-fies par des methodes physiques telles que distillation, cris-tallisation ou chromatographie ou par des methodes chimiques connues, par exemple, la formation de sels d'addition, cristal-lisation de ces derniers et decomposition par les agents alcalins.
Les derives de formule generale I et leurs sels phy-siologiquement tolerables possedent des proprietes pharmacolo-giques et therapeutiques interessantes, notamment des propri-etes stimulante du systeme nerveux central, anti-parkinsonienne et cardiovasculaire. Ils peuvent en consequence être utilises comme medicament notamment dans le traitement de la maladie de Parkinson et des troubles cardiovasculaires.
Leur toxicite est faible et leur DL50 determinee chez la souris par voie intraperitoneale est superieure a 200 mg/kg.
Les proprietes neuroleptiques ont ete mises en evi-dence par les modifications observees chez le rat et la souris sur la stereotypie, la motricite, l'excitation.
Chez la souris, la dose efficace moyenne est d'envi-ron 50 mg/kg par voie intraperitoneale. A cette dose, on observe une diminution de la motricite et du tonus.
La determination des scores d'excitation ou des stereotypies a ete effectuee d'apres la methode de Quinton et Halliwell (Nature 200, n 4902, p. 178 (1963).
On a observe qu'a la dose de 80 mg/kg, par voie i'718 intraperitoneale, on obtient des scores allant jusqu'a 266 en 3 heures.
La presente invention comprend egalement la prepara-tion des compositions pharmaceutiques contenant un derive de formule generale I ou un de ses sels physiologiquement compa-tibles, melange ou associe a un excipient pharmaceutique appro-prie, comme par exemple l'eau distillee, le glucose, lactose, amidon, talc, ethylcellulose, stearate de magnesium ou beurre de cacao.
Les compositions pharmaceutiques ainsi obtenues se presentent, par exemple, sous forme de comprimes, dragees, gelules, suppositoires ou solutions et peuvent être adminis-trees par voie orale, rectale ou parenterale â la dose de 15 a 150 mg l a 5 fois par jour.
Les exemples suivants illustrent l'invention, les points de fusion etant determines dans un tube capillaire.

(naphtyl-2 methyl)-l (thiazolyl-2)-4 piperazine ~ CH2 - N 3 lère methode:
A une solution de 22.1 9 (0.1 mole) de bromomethyl-2 naphtalene dans 150 ml de dimethylformamide, on ajoute succes-sivement 10.7 9 (0.101 mole) de carbonate de potassium sec et 17.2 9 (0.101 mole) de (thiazolyl-2)-1 piperazine. On chauffe alors la suspension pendant 10 heures a 150C. On filtre ensuite le sel forme et evapore la d;methylformamide sous pression reduite. On obtient un residu brun cristallis~ qu'on lave à l'eau, puis filtre et essore. Les 29 9 de cristaux ainsi recueillis sont recristallises dans 150 ml d'ethanol.

A

971~3 On obtient finalement 20 9 de cristaux blanc creme de (naphtyl- l ~ g9q ~ 8 The subject of the present invention is the method of preparation of naphthalene derivatives of general formula I:

Rl ~ CH2 - N 3 ~ ~ R3 in which:
Rl represents a hydrogen atom, a halo atom gene, such as for example a chlorine, bromine or fluorine atom, an alkyl or alkoxy radical each having from 1 to 5 atoms of ~:
carbon, and R2 and R3, which may be the same or different, each represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a phenyl radical, or: ' R2 and R3 combined together represent a radical -CH-CH-CH = CH- so as to form, with the thiazolyl radical to which they are linked, a benzothiazolyl radical.
The derivatives of general formula I are new and were prepared according to the following methods which are all included in the present invention.
The present invention therefore relates to the method of preparation of derivatives of general formula I, characterized in what:
we condense a halogen derivative of general formula II:

Rl ~ CH2 - X (II) in which Rl has the meaning defined above and X
represents a chlorine or bromine atom, with an N-mono-substituted piperazine of general formula III:

10997 ~ 8 N l ~ R2 HN ~ NI ~ sJ - R3 (III) in which R2 and R3 have the meanings of ~ inies prece-demment, or we condense a halogen derivative of general formula IV:

X ~ ~ R3 (IV) in which R2, R3 and X have the meanings stated previously with a piperazine of general formula V:

~ 1 ~ CH2 ~ N 3 H (V) in which Rl has the meaning defined above.
In both cases, it is advantageous to carry out the condensation of halogen derivatives II or IV with a pip ~ razine N-monosubstituted III or V in solution in a polar solvent such as for example an alcohol such as butanol or alcohol isoamyl or an aliphatic amide such as, for example, dimethylformamide, or in a non-polar solvent such as aromatic hydrocarbon such as, for example, xylene. It is advantageous to operate at a temperature between 115 and 160C in the presence of a hydracid acceptor formed during of the reaction. As acceptors we can mention by example the alkaline salts of carbonic acid such as by example sodium or potassium carbonates, and bases organic such as for example triethylamine. If we desire, it is ~ also possible to replace such salts or bases by an excess of piperazine N-monosubstituted III or V, this excess acting as an acceptor of the hydracid forms.

~ 9g ~ 8 The present invention also relates to the method of preparation of derivatives of general formula I, characterized in what we submit a mixture of an aldehyde of general formula VI:

Rl ~ CH0 (VI) in which Rl has the previously defined meaning, and of an N-monosubstituted piperazine of general formula III
previously defined, to an alkylating reduction, under a hydrogen pressure ~ 5 atmospheres, preferably under a pressure between 2 and 5 atmospheres, in the presence of small amount of palladium on carbon as catalyst, in a suitable solvent, such as for example an alcohol having up to 5 carbon atoms or ethyl acetate.
The most adequate implementation of such a process involves submitting to hydrogenation under pressure of hydrogen between 2 and 5 atmospheres, a mixture approximately equimolecular of derivatives III and VI, in solution in ethyl acetate, in the presence of palladium carbon as catalyst at a temperature between 60 and 80C.
The raw materials used for these processes are known products or are prepared according to methods described in the literature for preparing ana-logues.
The derivatives of general formula I are bases weak which can be transformed with acids, into salts acid addition.
The present invention includes the preparation of salts of acid addition of the derivatives of general formula I and more particularly salts which are physiologically tolerable.

1 ~ 99718 As acids which can be used for training of these salts we can cite for example, in the mineral series hydrochloric, hydrobromic, sulfuric and phospho-risk and in the organic series the acetic acids, propio-nique, maleic, fumaric, tartaric, citric, oxalic, benzoic, methane sulfonic and isethionic.
The derivatives of general formula I can be purified made by physical methods such as distillation, tallization or chromatography or by chemical methods known, for example, the formation of addition salts, crystal-reading of these and breakdown by agents alkaline.
The derivatives of general formula I and their physical salts siologically tolerable have pharmacological properties interesting therapies and therapeutics, including properties stimulates the central nervous system, anti-parkinsonian and cardiovascular. They can therefore be used as a medicine especially in the treatment of Parkinson's and cardiovascular disorders.
Their toxicity is low and their LD50 determined in the intraperitoneal mouse is greater than 200 mg / kg.
The neuroleptic properties have been highlighted.
dence by the modifications observed in rats and mice on stereotypy, motor skills, excitement.
The average effective dose in mice is approximately ron 50 mg / kg intraperitoneally. At this dose, observes a decrease in motor skills and tone.
Determination of excitation scores or stereotypies was done according to the Quinton method and Halliwell (Nature 200, n 4902, p. 178 (1963).
It has been observed that at a dose of 80 mg / kg, by the i'718 intraperitoneally, scores of up to 266 are obtained in 3 hours.
The present invention also includes the prepara-tion of pharmaceutical compositions containing a derivative of general formula I or a physiologically comparable salt thereof tibles, mixed or combined with a suitable pharmaceutical excipient pray, such as distilled water, glucose, lactose, starch, talc, ethylcellulose, magnesium stearate or butter cocoa.
The pharmaceutical compositions thus obtained are present, for example, in the form of tablets, dragees, capsules, suppositories or solutions and can be administered trees by oral, rectal or parenteral route at a dose of 15 a 150 mg 5 times a day.
The following examples illustrate the invention, the melting points being determined in a capillary tube.

(naphthyl-2 methyl) -l (thiazolyl-2) -4 piperazine ~ CH2 - N 3 1st method:
To a solution of 22.1 9 (0.1 mole) of bromomethyl-2 naphthalene in 150 ml of dimethylformamide, add succes-10.7 9 (0.101 mole) of dry potassium carbonate and 17.2 9 (0.101 mole) of (2-thiazolyl) -1 piperazine. We heat then the suspension for 10 hours at 150C. We filter then the salt forms and evaporates d; methylformamide under reduced pressure. We obtain a brown crystallized residue ~ which wash with water, then filter and spin. The 29 9 of crystals thus collected are recrystallized from 150 ml of ethanol.

AT

971 ~ 3 Finally, 20 9 of creamy white crystals of (naphthyl-

2 methyl)-l (thiazolyl-2)-4 piperazine fondant a 83-84C.
2ieme methode: -En operant comme dans la methode ci-dessus, a partir de 45.2 9 (0.2 mole) de (naphtyl-2 methyl)-l piperazine et l2 9 (O.l mole) de chloro-2 thiazole dans l50 ml de dimethylforma-mide a l50C, on obtient l7 9 de (naphtyl-2 methyl)-l (thia-zolyl-2)-4 piperazine, sous forme de cristaux beige fondant a 83-84C.
3ieme methode:
Une solution de l5.6 9 (0.1 mole) de ~-naphtaldehyde ; et l6.9 9 (O.l mole) de (thiazolyl-2)-l piperazine dans l50 ml d'acetate d'ethyle est soumise a 1 ~ hydrogenation, sous 5 atmos-pheres d'hydrogene, en presence de 2 a 5 9 de charbon palladie contenant lO% de palladium, a une temperature de 50C. Lorsque la quantite theorique d'hydrogene a ete absorbee, on filtre le catalyseur et evapore le solvant sous pression reduite.
Le residu cristallin obtenu pesant 28 9 est recris-tallise dans l50 ml d'ethanol. On obtient finalement l8 9 de (naphtyl-2 methyl)-l (thiazolyl-2)-4 piperazine, scus forme de cristaux beige fondant a 83-84C.
EXEMPLES 2 a ll Les derives suivants ont ete prepares selon les methodes decrites dans l'exemple l.
2) (naphtyl-2 methyl)-l (methyl-4 thiazolyl-2)-4 piperazine, P.F.: 75-76C (ethanol anhydre), a partir de:
- bromomethyl-2 naphtalene et (methyl-4 thiazolyl-2)-l pipera-zine, ou ; - (naphtyl-2 methyl)-l piperazine et methyl-4 chloro-2 thiazole, ou - ~-naphtaldehyde et (m~thyl-4 thiazolyl-2)-l piperazine.

. ~ .

1~973~ 2 methyl) -l (2-thiazolyl) -4 piperazine melting at 83-84C.
2nd method: -By operating as in the above method, from 45.2 9 (0.2 mole) of (naphthyl-2 methyl) -l piperazine and l2 9 (Ol mole) of 2-chloro thiazole in 150 ml of dimethylforma-mide at l50C, we obtain l7 9 of (naphthyl-2 methyl) -l (thia-zolyl-2) -4 piperazine, in the form of beige crystals melting a 83-84C.
3rd method:
A solution of l5.6 9 (0.1 mole) of ~ -naphthaldehyde ; and 16.9 9 (Ol mole) of (2-thiazolyl) -1 piperazine in 150 ml of ethyl acetate is subjected to 1 ~ hydrogenation, under 5 atmos-hydrogen perheres, in the presence of 2 to 5 9 of palladium carbon containing 10% palladium, at a temperature of 50C. When the theoretical amount of hydrogen has been absorbed, we filter the catalyst and evaporate the solvent under reduced pressure.
The crystalline residue obtained weighing 28 9 is recreated mix in 150 ml of ethanol. We finally get l8 9 of (naphthyl-2 methyl) -l (thiazolyl-2) -4 piperazine, scus form of beige crystals melting at 83-84C.
EXAMPLES 2 to ll The following derivatives have been prepared according to the methods described in example l.
2) (2-naphthyl methyl) -1 (methyl-4 thiazolyl-2) -4 piperazine, PF: 75-76C (anhydrous ethanol), from:
- bromomethyl-2 naphthalene and (methyl-4 thiazolyl-2) -l pipera-zine, or ; - (naphthyl-2 methyl) -l piperazine and methyl-4 chloro-2 thiazole, or - ~ -naphthaldehyde and (m ~ thyl-4 thiazolyl-2) -l piperazine.

. ~.

1 ~ 973 ~

3) (naphtyl-2 methyl)-l (phenyl-4 thiazolyl-2)-4 piperazine, a partir de:
- bromomethyl-2 naphtalene et (phenyl-4 thiazolyl-2)-1 pip~ra-zine, ou - (naphtyl-2 methyl)-l piperazine et phenyl-4 chloro-2 thiazole, ou - ~-naphtaldehyde et (phenyl-4 thiazolyl-2)-1 piperazine. 3) (2-naphthyl methyl) -l (4-phenyl-2-thiazolyl) -4 piperazine, from:
- 2-bromomethyl naphthalene and (4-phenyl-2-thiazolyl) -1 pip ~ ra-zine, or - (naphthyl-2 methyl) -l piperazine and phenyl-4 chloro-2 thiazole, or - ~ -naphthaldehyde and (4-phenyl-2-thiazolyl) -1 piperazine.

4) (naphtyl-2 methyl)-l (dimethyl-4,5 thiazolyl-2)-4 pipera-zine, à partir de:
- bromom~thyl-2 naphtalene et (dimethyl-4,5 thiazolyl-2)-1 -~
piperazine, ou - (naphtyl-2 methyl)-l piperazine et dimethyl-4,5 chloro-2 thiazole, ou - ~-naphtaldehyde et (dimethyl-4,5 thiazolyl-2)-1 piperazine. 4) (2-naphthyl methyl) -l (4,5-dimethyl-2-thiazolyl) -4 pipera-zine, from:
- bromom ~ 2-thyl naphthalene and (4,5-dimethyl-2-thiazolyl) -1 - ~
piperazine, or - (naphthyl-2 methyl) -l piperazine and dimethyl-4,5 chloro-2 thiazole, or - ~ -naphthaldehyde and (4,5-dimethyl-2-thiazolyl) -1 piperazine.

5) (naphtyl-2 methyl)-l (benzothiazolyl-2)-4 piperazine a partir de:
-bromomethyl-2 naphtalene et (benzothiazolyl-2)-1 piperazine, ou - (naphtyl-2 methyl)-l piperazine et chloro-2 benzothiazole, ou - ~-naphtaldehyde et (benzothiazolyl-2)-1 piperazine. 5) (2-naphthyl methyl) -1 (benzothiazolyl-2) -4 piperazine a from:
-bromomethyl-2 naphthalene and (benzothiazolyl-2) -1 piperazine, or - (naphthyl-2 methyl) -l piperazine and 2-chloro benzothiazole, or - ~ -naphthaldehyde and (2-benzothiazolyl) -1 piperazine.

6) (chloro-6 naphtyl-2 methyl)-l (thiazolyl-2)-4 piperazine, P.F.: 134-135C (ethanol) a partir de:
- chloro-6 chloromethyl-2 naphtalene et (thiazolyl-2)-1 pipera-zine, ou - (chloro-6 naphtyl-2 methyl)-1 pip~razine et chloro-2 thiazole, ou - chloro-6 ~-naphtaldehyde et (thiazolyl-2)-1 piperazine. 6) (6-chloro-2-naphthyl-methyl) -l (2-thiazolyl) -4 piperazine, PF: 134-135C (ethanol) from:
- chloro-6 chloromethyl-2 naphthalene and (thiazolyl-2) -1 pipera-zine, or - (chloro-6 naphthyl-2 methyl) -1 pip ~ razine and chloro-2 thiazole, or - chloro-6 ~ -naphthaldehyde and (2-thiazolyl) -1 piperazine.

7) (methyl-6 naphtyl-2 methyl)-l (thiazolyl-2)-4 piperazine, P.F.: 104-106C (ethanol a 80%) a partir de:
- methyl-6 bromomethyl-2 naphtalene et (thiazolyl-2)-1 pipera-zine, ou 1~99718 - (methyl-6 naphtyl-2 methyl)-l piperazine et chloro-2 thiazole, ou - methyl-6 ~-naphtaldehyde et (thiazolyl-2)-1 piperazine. 7) (methyl-6 naphthyl-2 methyl) -l (thiazolyl-2) -4 piperazine, PF: 104-106C (80% ethanol) from:
- methyl-6 bromomethyl-2 naphthalene and (thiazolyl-2) -1 pipera-zine, or 1 ~ 99718 - (methyl-6 naphthyl-2 methyl) -l piperazine and chloro-2 thiazole, or - methyl-6 ~ -naphthaldehyde and (2-thiazolyl) -1 piperazine.

8) (methoxy-6 naphtyl-2 methyl)-l (thiazolyl-2)-4 piperazine, P.F. 146-148C (ethanol anhydre), a partir de:
- methoxy-6 bromom~thyl-2 naphtalene et (thiazolyl-2)-1 pipera-zine, ou - -(methoxy-6 naphtyl-2 methyl)-l piperazine et chloro-2 thiazole, ou - methoxy-6 ~-naphtaldehyde et (thiazolyl-2)-1 piperazine. 8) (6-methoxy-2-naphthyl) -l (2-thiazolyl) -4 piperazine, PF 146-148C (anhydrous ethanol), from:
- 6-methoxy bromom ~ 2-thyl naphthalene and (2-thiazolyl) -1 pipera-zine, or - - (methoxy-6 naphthyl-2 methyl) -l piperazine and chloro-2 thiazole, or - methoxy-6 ~ -naphthaldehyde and (thiazolyl-2) -1 piperazine.

9) (chloro-7 naphtyl-l methyl)-l (thiazolyl-2)-4 piperazine, P.F. 139-140C (ethanol), a partir de:
- chloro-7 chloromethyl-l naphtalene et (thiazolyl-2)-1 pipera-zine, ou - (chloro-7 naphtyl-l methyl)-l piperazine et chloro-2 thiazole, ou - chloro-7 -naphtald~hyde et (thiazolyl-2)-1 piperazine. 9) (7-chloro-naphthyl-l methyl) -l (2-thiazolyl) -4 piperazine, PF 139-140C (ethanol), from:
- chloro-7 chloromethyl-l naphthalene and (thiazolyl-2) -1 pipera-zine, or - (chloro-7 naphthyl-l methyl) -l piperazine and chloro-2 thiazole, or - chloro-7 -naphthald ~ hyde and (thiazolyl-2) -1 piperazine.

10) (methyl-7 naphtyl-l methyl)-l (thiazolyl-2)-4 piperazine, P.F. 101-103C (ethanol a 80%) a partir de:
- methyl-7 chloromethyl-l naphtalene et (thiazolyl-2)-1 pipera-zine, ou - (methyl-7 naphtyl-l methyl)-l piperazine et chloro-2 thiazole, ou - methyl-7 -naphtaldehyde et (thiazolyl-2)-1 piperazine. 10) (methyl-7 naphthyl-l methyl) -l (thiazolyl-2) -4 piperazine, PF 101-103C (80% ethanol) from:
- methyl-7 chloromethyl-l naphthalene and (thiazolyl-2) -1 pipera-zine, or - (methyl-7 naphthyl-l methyl) -l piperazine and chloro-2 thiazole, or - methyl-7 -naphthaldehyde and (2-thiazolyl) -1 piperazine.

11) (naphtyl-l methyl)-l (thiazolyl-2)-4 piperazine, P.F.: 128-130C, ~ partir de:
- bromomethyl-l naphtalene et (thiazolyl-2)-1 piperazine, ou - (naphtyl-l methyl)-l piperazine et chloro-2 thiazole, ou - ~-naphtaldehyde et (thiazolyl-2)-1 piperazine.

~ - 8 -11) (naphthyl-l methyl) -l (thiazolyl-2) -4 piperazine, PF: 128-130C, ~ from:
- bromomethyl-l naphthalene and (2-thiazolyl) -1 piperazine, or - (naphthyl-l methyl) -l piperazine and 2-chloro thiazole, or - ~ -naphthaldehyde and (2-thiazolyl) -1 piperazine.

~ - 8 -

Claims

The embodiments of the invention about which an exclusive right of property or privilege is claimed, are defined as follows:

1. Process for the preparation of naphthalene derivatives of general formula I:
in which:
R1 represents a hydrogen atom, a halo atom gene, an alkyl or alkoxy radical each having from 1 to 5 atoms carbon, and R2 and R3, which are identical or different, represent each feel a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, and their addition salts with mineral acids or organic compatible, characterized in that:
either we condense a halogenated derivative of formula general II:
(II) in which R1 has the meaning given above and X
represents a chlorine or bromine atom, with an N-monosubstituted piperazine of the general formula Lane III:

(III) in which R2 and R3 have the above meanings, either we condense a halogenated derivative of formula general IV:

(IV) in which R2 and R3 have the previously mentioned significatians demment and X represents a chlorine or bromine atom, with a piperazine of general formula V:
(V) in which R1 has the meaning defined above, either subject a mixture of an aldehyde of formula general VI:
(VI) in which R1 has the meaning given above and of an N-monosubstituted piperazine of general formula III such as defined above, to an alkyl reduction under a hydrogen pressure? 5 atmospheres, in the presence of coal palliated as a catalyst, and the derivatives thus obtained are treated with compatible acids to give acid addition salts correspondents.

2. Method according to claim 1 for preparing the (naphthyl-2 methyl) -1 (thiazolyl-2) -4 piperazine, from 2-bromomethyl naphthalene and (2-thiazolyl) -1 piperazine, or (2-naphthyl methyl) -1 piperazine and 2-chloro thiazole, or .beta.-naphthaldehyde and (2-thiazolyl) -1 piperazine.

3. Method according to claim 1 for preparing the (1-naphthyl-methyl) -1 (2-thiazolyl) -4 piperazine, from bromomethyl-1 naphthalene and (2-thiazolyl) -1 piperazine, or (1 naphthyl-methyl) -1 piperazine and 2-chloro thiazole, or alpha.-naphthaldehyde and (2-thiazolyl) -1 piperazine.

4. Method according to claim 1 for preparing the (7-methyl-1-naphthyl) -1 (2-thiazolyl) -4 piperazine, to from 7 methyl-1 chloromethyl naphthalene and (thiazolyl-2) -1 piperazine, or (7 methyl-naphthyl-1 methyl) -1 piperazine and 2-chloro thiazole, or 7-methyl .alpha.-naphthaldehyde and (2-thiazolyl) -1 piperazine.

5. The naphthalene derivatives of general formula I:
(I) in which:
R1 represents a hydrogen atom, a halo atom gene, an alkyl or alkoxy radical each having from 1 to 5 atoms carbon, and R2 and R3, which are identical or different, represent each feel a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, and their addition salts with mineral acids or compatible organic, when prepared according to a process of claim 1 or by an equivalent chemical process.

6. La (naphthyl-2 methyl) -1 (thiazolyl-2) -4 pipéra-zine, when prepared according to a process of claim 2 or by an equivalent chemical process.

7. La (naphthyl-1 methyl) -1 (thiazolyl-2) -4 pipéra-zine, when prepared according to a process of claim 3 or by an equivalent chemical process.

8. La (7-methyl-1-naphthyl) -1 (2-thiazolyl) -4 piperazine, when prepared according to a process of the claim tion 4 or by an equivalent chemical process.