HK1126200B - Isoquinoline et benzo[h]isoquinoline derivatives, preparation and therapeutic use thereof as antagonists of histamine h3 receptor - Google Patents

Description

Isoquinoline and benzo [ H ] isoquinoline derivatives, their preparation and their therapeutic use as histamine H3 receptor antagonists

The invention relates to ethers derived from tetrahydroisoquinoline and tetrahydrobenzo [ h ] isoquinoline, to a method for the production thereof and to the therapeutic use thereof.

WO 02/076925 describes the histamine receptor H₃An antagonist of (1). Some of these isoquinoline or benzisoquinoline ether derivatives are ethers to which a linear or cyclic alkylamine is attached.

The inventors propose the objective of obtaining certain modulators of the histamine receptor H₃Active novel compounds.

Accordingly, a first object of the present invention is novel compounds corresponding to formula I below:

in the formula:

represents an unsaturated carbocyclic group having a double bond, such as phenyl or naphthyl; the carbocyclic group being optionally substituted by one or two substituents independently chosen from halogen atoms, hydroxyl groups, nitro groups, cyano groups, C_1-2Perhaloalkyl, C_1-3An alkyl or phenyl group;

i can take a value of 0-4;

m may take a value of 0-3;

n may take a value of 0-6;

- (C) l-, - (C) m-and- (C) n-independently of one another represent-C_x-zAlkylene groups, optionally substituted with 1 to 4 substituents chosen from halogen atoms, hydroxyl, nitro, cyano, amino, C_1-2Perhaloalkyl, C_1-3An alkyl or phenyl group; and, in addition, when I, m and/or n take the value 0, - (C)₀Represents a key;

r1 represents a hydrogen atom, C_1-3Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl groups, these C_1-3Alkyl radical, C_1-6Alkylcarbonyl and C_1-6The alkoxycarbonyl group may be substituted with: halogen atom, hydroxy group, C_1-3Alkoxy, nitro, cyano, amino or aryl groups, such as benzyloxycarbonyl; c_1-3Alkyl-aryl, such as benzyl or phenethyl, monocyclic heteroaryl, such as thienyl, furyl or pyrrolyl or aryl, such as phenyl or naphthyl; these aryl and heteroaryl groups are optionally substituted with 1 to 4 substituents selected from the group consisting of halogen atoms, hydroxy, nitro, cyano, amino, C_1-3Monoalkylamino group, C_2-6Dialkylamino radical, C_1-3Alkyl radical, C_1-2Perhaloalkyl, C_1-3Haloalkyl, C_1-3Alkoxy radicals or C_1-3An alkylenedioxy group;

r2 represents a hydrogen atom or C_1-6Alkyl or C_3-6Cycloalkyl groups, optionally substituted with 1 to 4 substituents selected from halogen atoms, hydroxy, nitro, cyano, amino, C_1-3Monoalkylamino group, C_2-6Dialkylamino radical, C_1-2Perhaloalkyl, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_3-6Cycloalkyl, monocyclic heteroaryl, such as thienyl, furyl or pyrrolyl, bicyclic heteroaryl, such as benzotriazolyl, or aryl groups, such as phenyl or naphthyl;the aryl group is optionally substituted with 1 to 4 substituents selected from the group consisting of halogen atom, hydroxy group, nitro group, cyano group, amino group, C_1-3Monoalkylamino group, C_2-6Dialkylamino radical, C_1-3Alkyl radical, C_1-2Perhaloalkyl, C_1-3Haloalkyl, C_1-3Alkoxy radicals or C_1-3An alkylenedioxy group.

Within the scope of the invention, it should be understood that:

-C_x-zwherein x and z can take values of 0-6, the carbon chain can have x-z carbon atoms, however, when x takes a value of 0, C_oRepresents a key; e.g. C_1-6Represents a carbon chain which may have 1 to 6 carbon atoms; c_0-6Represents a bond or a carbon chain which may have 1 to 6 carbon atoms;

-an alkyl, linear or branched saturated aliphatic group; e.g. C_1-6The alkyl group represents a straight or branched saturated carbon chain of 1 to 6 carbon atoms, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.;

the term C_x-yAlkylene represents a divalent straight or branched chain C_x-yAn alkyl group; term C_2-8Alkenylene (alkenylidene) represents a divalent unsaturated straight or branched chain C_x-yAn alkyl group;

-C_x-yalkoxy, a saturated straight or branched chain aliphatic alkanoyloxy group containing x to y carbon atoms;

-a halogen atom, fluorine, chlorine, bromine or iodine;

-C_1-3monoalkylamino radicals, with C_1-3An alkyl group monosubstituted amino;

-C_2-6dialkylamino, with two identical or different C_1-3An amino group disubstituted with an alkyl group;

-C_1-2perhaloalkyl, C having all hydrogen atoms substituted by halogen atoms_1-2An alkyl group;

-C_1-3haloalkyl, C having at least one hydrogen atom substituted by a halogen atom_1-3An alkyl group.

These compounds of formula I may contain one or more asymmetric carbon atoms. Thus, they may exist as enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures thereof, are part of the present invention.

These compounds of formula I, which may be in the form of the free bases or of addition salts with acids, are also part of the present invention. The salts of the present invention include salts with pharmaceutically acceptable acids, but also salts with inorganic or organic acids which allow suitable isolation or crystallization of the compounds of formula I. These salts can be prepared according to methods known to those skilled in the art, for example by reacting a compound of formula I in base form in a suitable solvent (e.g. an alcoholic or organic solvent) with an acid and then evaporating off this solvent or separating the medium containing it by filtration.

These compounds of formula I may also exist in the form of hydrates or solvates, i.e. in association or combination with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the present invention.

Another object of the invention is a compound selected from the following subgroups, taken individually or in combination, wherein:

represents an unsaturated carbocyclic group such as phenyl or naphthyl; the carbocyclyl being optionally substituted by 1 or 2 substituents independently chosen from halogen atoms, hydroxy, nitro, cyano, C_1-2Perhaloalkyl or C_1-3An alkyl group;

i may take a value of 1, 2 or 3;

m may take the value 0, 1 or 2;

n may take the value 0, 1, 2 or 3;

- (C) l-and- (C) m-together with the-NR 1-group form an amino ring bound to the-O- (C) n-group via a carbon atom, e.g. azetidine, pyrrolidine, piperidine or azepine and/or

- (C) n-represents-C optionally substituted by 1-4 substituents_0-3An alkylene group, the substituents being selected from halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, C_1-2A perhaloalkyl group; when n takes the value 0, - (C)_o-represents a bond;

r1 represents a hydrogen atom, C_1-3Alkyl radical, C_1-4Alkylcarbonyl group, C_1-6Alkoxycarbonyl group, C_1-3Alkylaryl groups such as benzyl, heteroaryl groups such as thienyl or furyl, aryl groups such as phenyl or naphthyl; these aryl and heteroaryl groups are optionally substituted with 1 to 4 substituents selected from the group consisting of halogen atoms, hydroxy, cyano, amino, C_1-3Monoalkylamino group, C_1-3Alkyl radical, C_1-2Perhaloalkyl, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3An alkylenedioxy group.

More particularly, when the amino ring of which- (C) l-, - (C) m-and-NR 1-form part and which is bonded to the-O- (C) n-group via a carbon is selected from the following groups:

r2 represents a hydrogen atom, C_1-4Alkyl or C_5·6Cycloalkyl radicals, optionally substituted by 1 to 4 substituents selected from phenyl, monocyclic heteroaryl, e.g. thienyl, bicyclic heteroaryl, e.g. benzotriazolyl, C_3-6Cycloalkyl radical, C_1-2Perhaloalkyl, C_1-3Haloalkyl or C_1-3An alkoxy group; the phenyl and heteroaryl groups are optionally substituted with 1 to 4 substituents selected from halogen atoms, hydroxy, nitro, cyano, amino, C_1-3Monoalkylamino group, C_2-6Dialkylamino radical, C_1-3Alkyl radical, C_1-2Perhaloalkyl, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3An alkylenedioxy group.

Another object of the invention relates to the following compounds and their pharmaceutically acceptable salts:

compound 1: 7- {2- [ 1-methylpiperidin-2-yl ] ethoxy } -2-propyl-1, 2, 3, 4-tetrahydroisoquinoline;

compound 2: 2-isobutyl-7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 3: 2- (3-methylbutyl) -7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 4: 7- [ (1-methyl azepan-4-yl) oxy ] -2- (3-methyl butyl) -1, 2, 3, 4-four hydrogen isoquinoline

Compound 5: (2-cyclohexylmethyl) -7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 6: (2-cyclohexylmethyl) -7- {2- [ (2R) -1-methylpyrrolidin-2-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline;

compound 7: (2-cyclohexylmethyl) -7- {2- [ (2S) -1-methylpyrrolidin-2-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline;

compound 8: (2-cyclohexylmethyl) -7- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 9: (2-cyclohexylmethyl) -7- [2- (1-methylpiperidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 10: 2-benzyl) -7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 11: 2-benzyl-7- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 12: 7- [ (1-methylazepan-4-yl) oxy ] -2- (2-thienylmethyl) -1, 2, 3, 4-tetrahydroisoquinoline;

compound 13: (2-cyclohexylmethyl) -8- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline;

compound 14: (2-cyclohexylmethyl) -8- {2- [ (2R) -1-methylpyrrolidin-2-yl ] ethoxy } -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline;

compound 15: (2-cyclohexylmethyl) -8- {2- [ (2S) -1-methylpyrrolidin-2-yl ] ethoxy } -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline;

compound 16: 2- (cyclohexylmethyl) -8- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline;

compound 17: (2-cyclohexylmethyl) -8- [2- (1-methylpiperidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline;

compound 20: 2-butyl-7- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 21: 2-butyl-7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

compound 22: 7- [ (1-methylazepan-4-yl) oxy ] -2-propyl) -1, 2, 3, 4-tetrahydroisoquinoline;

compound 23: 7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -2-propyl-1, 2, 3, 4-tetrahydroisoquinoline.

On the other hand, in the context of the present invention, a protecting group Pg is to be understood as a group which, on the one hand, is capable of protecting a reactive function (for example a hydroxyl group or an amine) during synthesis and, on the other hand, is capable of regenerating the complete reactive function after synthesis. Examples of protecting groups and methods of protection and deprotection are given in protecting groups in Organic Synthesis (protective groups in Organic Synthesis), 3 rd edition, Greene and Wuts (John Wiley & Sons, Inc., New York, 1999).

A second object of the invention is a process for the preparation of the compounds of formula I according to the invention.

Thus, these compounds of formula I can be prepared according to the methods shown in scheme 1.

The flow chart is as follows:

these compounds of formula I, wherein R1, R2, I, m, n and ring A are as defined in formula I, can be prepared by nucleophilic substitution when a phenol of formula II, wherein R2 and ring A are as defined in formula I, is reacted with an amine of formula III, wherein R1, I, m and n are as defined in formula I and Y represents a halogen atom (such as, for example, chlorine, iodine or bromine), or represents a "pseudo-halogen" (such as, for example, mesylate, triflate, p-toluenesulfonate, p-bromophenylsulfonate or nosylate). This reaction can be carried out under the following conditions to give compounds of formula I: in protic or aprotic solvents, such as water, methanol, acetone, butanone, ethyl acetate, toluene, N-dimethylformamide, acetonitrile or mixtures of these solvents, at temperatures of from 0 to 110 ℃ in the presence of bases, such as, for example, sodium or potassium hydroxide, sodium or potassium carbonate, triethylamine or diisopropylethylamine. In the case of non-miscible solvent mixtures, phase transfer catalysts, for example ammonium or phosphonium salts, preferably tetrabutylammonium bromide or tetraethylammonium chloride, can be used in mixtures of toluene and water at temperatures of from 20 to 110 ℃. These compounds of the formulae II and III may, if desired, be protected beforehand before the reaction according to methods known to the person skilled in the art. The compound of formula I is then optionally deprotected according to conditions known to those skilled in the art.

Alternatively, these compounds of formula I may be prepared by a Mitsunobu-type reaction. According to this option, a phenol of formula II, wherein R2 and ring A are as defined for formula I, is reacted with an amine of formula III, wherein R1, I, m and n are as defined for formula I and Y represents a hydroxyl group, the amine being obtained according to methods known to those skilled in the art. This reaction is carried out in the classical manner in the presence of Mitsunobu reagents, for example azo derivatives, such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1 ' - (azodicarbonyl) dipiperidine or N, N, N ', N ' -tetramethyl azodicarbonamide, and phosphines, for example triphenylphosphine or tributylphosphine. The reaction may be carried out in an aprotic solvent, such as tetrahydrofuran or dioxane or mixtures of these solvents, at temperatures of 0 to 100 ℃ to give compounds of formula I. If these reagents are protected beforehand before the reaction, the compounds of the formula I should be deprotected according to conditions known to the person skilled in the art.

The initially protected compound (formula VI) or unprotected compound (formula II) can be prepared according to scheme 2 or can be synthesized using classical methods known to those skilled in the art, for example as described in Journal of Medicinal Chemistry, 40, 3997-containing 4005(1997) or tetrahedron asymmetry, 12, 2427-containing 2434 (2001).

The flow chart is as follows:

according to the process of scheme 2, the secondary amines of formula IV, wherein R2 represents H, are reacted with aldehydes or ketones of formula V, wherein R3 and R4 after reaction generate all R2 which are not hydrogen as defined in formula I, to prepare these compounds of formula II, wherein R2 is as defined in formula I, but not a hydrogen atom, by amino-reduction. These compounds of formula IV, wherein R2 represents a hydrogen atom, can be obtained according to classical methods known to those skilled in the art, such as those described in Journal of Medicinal Chemistry, 40, 3997-4005 (1997). These compounds of formula II can then be obtained using compounds of formula VI, which can be deprotected according to conditions known to those skilled in the art. For example, where Pg is a methyl group, these compounds of formula VI may be deprotected in the presence of an acid such as hydrobromic acid, in a protic solvent such as water or acetic acid or mixtures of these solvents, at a temperature of from 0 to 100 ℃ in the presence or absence of a phase transfer catalyst such as an ammonium or phosphonium salt to give phenols of formula II. These examples illustrate this approach.

Alternatively, these compounds of formula II, wherein R2 is as defined for formula I but is not a hydrogen atom, may be prepared by reacting a protected compound of formula VI, wherein R2 represents a benzotriazolylmethyl group, with an alkylating agent, such as a suitable Grignard reagent, according to the process of scheme 3, for example as described in Tetrahedron assistance, 12, 2427-2434 (2001).

The flow chart is as follows:

according to this option, a compound of formula VIa, in which R2 represents a benzotriazolylmethyl group, is reacted with a Grignard reagent of formula VII, in which W represents a halogen atom, such as for example chlorine, iodine or bromine, R5 represents C_1-5Alkyl radical, C_1-2Perhaloalkyl, C_1-3Haloalkyl, C_3-6(II) preparation of these compounds of formula II wherein R2 is as defined for formula I by nucleophilic substitution of a cycloalkyl group, a monocyclic heteroaryl group such as thienyl or furyl, or an aryl group such as phenyl or naphthyl; after reaction, a compound of formula II is formed wherein R2 is as defined for formula I but is not hydrogen. This reaction can be carried out in an aprotic solvent, such as diethyl ether, tetrahydrofuran or dioxane, or a mixture of these solvents, at a temperature of-70-100 ℃ to give the compound of formula VI. These compounds of formula II can then be obtained from some of the compounds of formula VI which have been prepared in accordance with the present techniqueDeprotection is carried out under conditions known to those skilled in the art. For example, when Pg is a methyl group, these compounds of formula VI may be deprotected in the presence of an acid such as hydrobromic acid, in a protic solvent such as water or acetic acid or mixtures of these solvents, at a temperature of from 0 to 100 ℃ in the presence or absence of a phase transfer catalyst such as an ammonium or phosphonium salt to give phenols of formula II. The examples illustrate this approach.

These starting compounds II and the amines of the formula III are either directly available on the market or can be synthesized as described above, by classical methods known to the person skilled in the art or are known from the literature.

According to another of its aspects, the invention relates to a medicament containing a compound of formula I or an addition salt of this compound with a pharmaceutically acceptable acid or a hydrate or solvate of the compound of formula I.

The compounds of the invention are useful in therapy, in particular by modulating the histamine receptor H₃To improve the treatment of the disorder, and in H₃Histamine receptor antagonists have utility in the treatment of pathologies where they provide therapeutic benefits. In particular, such pathologies are obesity and diabetes.

These compounds having these properties act as histamine receptor H in the treatment of central nervous system disorders₃Antagonists and inverse agonists of (a).

These compounds may also be useful in the treatment of central nervous system disorders such as waking states and sleep disorders, narcolepsy, Alzheimer's disease and other dementias, Parkinson's disease, hyperkinetic childhood attention disorders, memory and learning disorders, epilepsy, schizophrenia, reduced cognitive disorders, depression and anxiety. Depressive and anxiety symptom states include, for example, pre-precedent anxiety (pre-surgery, pre-dental treatment, etc.), anxiety caused by alcohol addiction or alcohol withdrawal, drug induced anxiety, mania, seasonal affective disorder, migraine and nausea. They can also be used for the treatment of sexual dysfunction, dizziness and travel disorders.

The use of the compounds of the invention for the preparation of a medicament for the treatment of the above pathologies is also an integral part of the present invention as a whole.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of said compound, and at least one or more pharmaceutically acceptable excipients. The excipients are selected according to the pharmaceutical dosage form and the desired mode of administration, and are selected from the usual excipients known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, external, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula I above, or a salt, optionally a solvate or hydrate thereof, may be administered in unit dosage form in admixture with usual pharmaceutical excipients for animal and human administration for the prevention or treatment of the above-mentioned disorders or diseases.

Suitable unit dosage forms for administration include oral dosage forms, such as tablets, soft or hard capsules, powders, granules and oral liquids or suspensions, sublingual, buccal, intratracheal, intranasal dosage forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal and implant dosage forms. For topical application, the compounds of the invention may be used in creams, gels, ointments or lotions.

The dose of the active ingredient may be 0.1. mu.g to 50mg per kg body weight per day in order to achieve the desired prophylactic or therapeutic effect. Each unit dose may contain 0.1-1000mg, preferably 1-500mg, of the active ingredient in combination with a pharmaceutical excipient. This unit dose may be administered 1 to 5 times per day, so that the daily dose is 0.5 to 5000mg, preferably 1 to 2500 mg.

There may be particular instances where higher or lower dosages are appropriate. Such dosages are also within the scope of the present invention. The appropriate dosage for each patient is conventionally determined by a physician based on the mode of administration, the weight and response of the patient in question.

By way of example, administration unit dosage forms of the compounds of the invention:

compound of the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl-methylcellulose 2.25mg

Magnesium stearate 3.0mg

One aspect of the present invention also relates to a method for the treatment of the above pathologies, which comprises the administration to a patient of an effective dose of a compound according to the invention or of one of its pharmaceutically acceptable salts or hydrates or solvates.

The following examples illustrate methods and techniques suitable for the preparation of the present invention without limiting its scope.

EXAMPLE 1 (2-cyclohexylmethyl) -7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline oxalate (2: 1)

1.1-2- (cyclohexylmethyl ] -7-methoxy-1, 2, 3, 4-tetrahydroisoquinoline

To a solution of 10.41g (0.035mol) of 2- (1H-1, 2, 3-benzotriazol-1-ylmethyl) -7-methoxy-1, 2, 3, 4-tetrahydroisoquinoline in 150ml of tetrahydrofuran which was cooled to-40 ℃ was added 35ml (0.070mol) of a solution of 2N cyclohexylmagnesium chloride in tetrahydrofuran. Stirring was maintained at 40 ℃ for two hours, and then the mixture was allowed to stand at room temperature overnight. 2N aqueous sodium hydroxide (50ml) was added. The aqueous phase is extracted 3 times with 20ml of diethyl ether, and the organic phases are dried and evaporated to dryness in vacuo. 8.20g of an oil were obtained which was used without further purification.

Rdt (yield): 90 percent of

PF ═ oil

1.2-2- (cyclohexylmethyl ] -1, 2, 3, 4-tetrahydroisoquinolin-7-ol hydrobromide

8.20g (0.032mol)2- (cyclohexyl methyl) -7-methoxy-1, 2, 3, 4-four hydrogen isoquinoline in 80ml water hydrogen bromide (48%) solution at 120 degrees C heating six hours, the mixture is cooled, concentrated to dryness, the residue with 60ml ethanol/ether mixture for treatment, solid for filtration, ether washing and drying, 9.70g desired product, pure white solid.

Rdt：94％

PF＝210-214℃

3- (2-Cyclohexylmethyl) -7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline oxalate (2: 1)

To a mixture of 5.00g (0.020mol) of the compound obtained in 1.2 above, 11.2g (0.0061mol)2- (2-chloroethyl) -1-methylpyrrolidine and 0.41g (0.002mol) triethylammonium chloride in 125ml toluene was added a mixture of 9.7g (0.244mol) sodium hydroxide in 125ml water. The reaction was heated to reflux for eight hours. The phases were separated and the aqueous phase was extracted 2 times with 20ml of toluene. The organic phases are dried and then evaporated to dryness. 7g (97%) of a crude oil are obtained which is purified by column chromatography on silica gel using a dichloromethane/methanol mixture (98: 2) as eluent. The desired product was obtained as an oil (0.70 g; 10%) with a maximum Rf.

¹H-NMR(CDCl3)δ(ppm)：7.1(1H，d)、6.7(1H，d)、6.5(1H，s)、4.0(2H，m)、3.5(2H，s)、3.0(1H，m)、2.7(2H，m)、2.6(2H，m)、2.4(3H，s)、2.2(2H，d)，2.1(2H，m)2.0(1H.m)、1.7(11H，m)、1.1(3H，m)、0.9(2H，m)。

The above oil (0.65 g; 0.002mol) was dissolved in 10ml of ethanol, and then 0.36g (0.004mol) of oxalic acid dissolved in 10ml of ethanol was added. The precipitate was filtered and washed with cold ethanol. 0.46g of the expected product is obtained as a white solid.

Rdt：47％

PF＝78-98℃

Example 2 (2-cyclohexylmethyl) -7- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydroisoquinoline oxalate (2: 1)

According to the method described previously at 1.3, an oil with a minimum Rf is obtained (1.30 g; 0.002mol), which corresponds to the structure of (2-cyclohexylmethyl) -7- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydroisoquinoline.

¹H-NMR(CDCl3)δ(ppm)：7.1(1H，d)、6.7(1H，d)、6.5(1H，s)、4.5(1H，m)、3.5(2H，s)、2.7(2H，m)、2.6-2.4(5H，m)、2.3(3H，s)、2.2(2H，d)、2.0(2H，m)、1.7(11H，m)、1.1(3H，m)、0.9(2H，m)。

This oil was dissolved in 12ml of ethanol, and then 0.24g (0.003mol) of oxalic acid dissolved in 12ml of ethanol was added. The precipitate was filtered and washed with cold ethanol. 0.46g of the expected product is obtained as a white solid.

Rdt：86％

PF＝110-112℃

EXAMPLE 32-Cyclohexylmethyl) -8- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline oxalate (2: 1)

3.1-2- (cyclohexylmethyl ] -8-methoxy-1, 2, 3, 4-tetrahydroisobenzo [ h ] quinoline

To a solution of 3g (0.014mol) 8-methoxy-1, 2, 3, 4-tetrahydroisobenzo [ h ] quinoline and 1.6g (0.014mol) cyclohexane-aldehyde in 70ml methanol was added 0.32g (0.0003mol) 10% palladium on charcoal. The solution was hydrogenated in a Paar hydrogenator at a pressure of 45Psi for 24 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness. 4g of the expected product oil are obtained.

Rdt：93％

PF: oil

3.22- (Cyclohexylmethyl ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinolin-7-ol hydrobromide

A solution of 2g (0.006mol)2- (cyclohexylmethyl ] -8-methoxy-1, 2, 3, 4-tetrahydroisobenzo [ h ] quinoline in 30ml aqueous hydrogen bromide (48%) is heated at 120 ℃ for six hours the mixture is cooled, concentrated to dryness and the residue is treated with 20ml ethanol/diethyl ether mixture the solid formed is filtered, washed with diethyl ether and dried to give 2.3g of the desired product as a pure white solid.

Rdt：96％

PF＝270-276℃

3.32-Cyclohexylmethyl) -8- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline oxalate (2: 1)

To a mixture of 2.00g (0.005mol) of the compound obtained in the above 3.2, 2.4g (0.014mol) of 2- (2-chloroethyl) -1-methylpyrrolidine and 0.11g (0.0006mol) of triethylammonium chloride in 75ml of toluene was added a mixture of 2.5g (0.064mol) of sodium hydroxide in 75ml of water. The reaction was heated to reflux for eight hours. The phases were separated and the aqueous phase was extracted 2 times with 20ml of toluene. The organic phases are dried and then evaporated to dryness. 3g (> 100%) of a crude oil are obtained which is purified by column chromatography on silica gel using a dichloromethane/methanol mixture (98: 2) as eluent. The desired product was obtained as an oil (0.70 g; 10%) with a maximum Rf.

¹H-NMR(CDCl3)δ(ppm)：)，7.7(1H，d)、7.5(1H，d)、7.1-7.0(3H，m)、4.2(2H，m)、4.0(2H，s)、3.0(1H，m)、2.9(2H，m)、2.7(2H，m)、2.4(2H，d)、2.3(3H，s)、2.2-2.0(3H，m)、1.7(11H，m)、1.1(31-1，m)、0.9(2H，m).

The above oil (0.5 g; 0.001mol) was dissolved in 10ml of ethanol, and then 0.24g (0.003mol) of oxalic acid dissolved in 10ml of ethanol was added. The precipitate was filtered and washed with cold ether to give 0.50g of the desired product as a white solid.

Rdt：70％

PF＝127-135℃

Example 42- (cyclohexylmethyl) -8- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline oxalate (2: 1)

According to the procedure described in the preceding 3.3, an oil with a minimum Rf is obtained (0.67 g; 0.002mol), which corresponds to the structure of (2-cyclohexylmethyl) -7- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydroisoquinoline.

¹H-NMR(CDCl3)δ(ppm)：)，7.8(1H，d)、7.6(1H，d)、7.2-7.0(3H，m)、4.7(1H，m)、4.0(2H，s)、3.0(2H，m)、2.9(2H，m)、2.7(2H，m)、2.4(2H，d)、2.3(3H，s)、2.3-1.7(14H，m)、1.1(3H，m)、0.9(2H，m)。

The oil was dissolved in 10ml of ethanol and then 0.37g (0.004mol) of oxalic acid dissolved in 10ml of ethanol was added. The precipitate was filtered and washed with cold ether to give 0.25g of the desired product as a white solid.

Rdt：31％

PF＝77-101℃

Example 5 (2-cyclohexylmethyl) -7- {2- [ (2S) -1-methylpyrrolidin-2-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline hydrochloride (2: 1)

To a mixture of 7.3g (0.030mol) of 2- (cyclohexylmethyl) -1, 2, 3, 4-tetrahydroisoquinolin-7-ol obtained in the above 1.2, 3.5g (0.027mol) of (S) -2- (2-hydroxyethyl) 1-methylpyrrole and 9.2g (0.036 mol) of triphenylphosphine in 150ml of tetrahydrofuran (the mixture was cooled to-5 ℃ C.), 6.6g (0.032mol) of diisopropyl azodicarboxylate was added. Stirring was maintained overnight at room temperature. The solution was evaporated to dryness to give a crude oil which was purified by column chromatography on silica gel using a dichloromethane/methanol mixture (95: 5) as eluent. The expected product was obtained as an oil (1.4 g; 15%).

¹H-NMR(CDCl3)δ(ppm)：7.1(1H，d)、6.7(1H，d)、6.5(1H，s)、4.0(2H，m)、3.5(2H，s)、3.0(1H，m)、2.7(2H，m)、2.6(2H，m)、2.4(3H，s)、2.2(2H，d)，2.1(2H，m)2.0(1H，m)、1.7(11H，m)、1.1(3H，m)、0.9(2H，m)。

This oil was dissolved in 25ml of isopropanol, followed by HCl saturated isopropanol. The precipitate was filtered and washed with 1ml of cold isopropanol. 1g of the expected product is obtained as a white solid.

Rdt：59％

PF＝238-241℃

Example 62-Cyclohexylmethyl) -8- [ (2S) - (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinoline hydrochloride (2: 1)

To a mixture of 2.2g (0.007mol)2- (cyclohexylmethyl ] -1, 2, 3, 4-tetrahydrobenzo [ h ] isoquinolin-7-ol compound obtained in the previous 3.2, 0.95g (0.007mol) of (S) -2- (2-hydroxyethyl) 1-methylpyrroline and 2.14g (0.008mol) of triphenylphosphine in 150ml of tetrahydrofuran (cooled to-5 ℃) was added 1.88g (0.008mol) of diisopropyl azocarboxylate, stirring was maintained overnight at room temperature, the solution was evaporated to dryness to give a crude oil which was purified by column chromatography on silica gel, a dichloromethane/methanol mixture (95: 5) was used as eluent to give the desired product as an oil (1.1 g; 36%).

¹H-NMR(CDCl3)δ(ppm)：)7.7(1H，d)、7.5(1H，d)、7.1-7.0(3H，m)、4.2(2H，m)、4.0(2H，s)、3.0(1H，m)、2.9(2H，m)、2.7(2H，m)、2.4(2H，d)、2.3(3H，s)、2.2-2.0(3H，m)、1.7(11H，m)、1.1(3H，m)、0.9(2H，m)。

This oil was dissolved in 15ml of isopropanol and then HCl saturated isopropanol. The precipitate was filtered and washed with 1ml of cold isopropanol. 0.8g of the expected product is obtained as a white solid.

Rdt：62％

PF＝260℃

The following table illustrates the chemical structure and physical properties of certain compounds of the present invention. Elemental microanalysis and NMR, IR or mass spectrometry confirmed the structure of the resulting compound.

In the table, the "p.f." of the compounds of formula I corresponds to the melting point and "Config" denotes the stereochemical configuration, i.e. the (R), (S) or (R, S) racemic mixture of carbon atoms is denoted by an asterisk (#).

Watch (A)

The compounds of the formula I according to the invention form the subject of pharmacological tests which show their significance as therapeutically active substances.

More particularly, the compound of the invention is H₃Antagonists of the histamine receptor type. These H₃Type receptors are known to those skilled in the art and are described in the reference ("Histamine H₃Receptor antagonists "", "exp. opinion Ther. patents" (2000)10(7): 1045-1055) have been described for their therapeutic significance.

Thus, Korte, A. et al, "biochem. Biophys. Res. Commun," 168, 979-986(1990) neutralizing West, r.e.jr. et al in mol.pharmacol,38610-³H]Specific binding of N-alpha-methyl histamine to this receptor in adult mouse meninges, the compounds of formula I of the invention were subjected to in vitro H-pairing₃Affinity assay for type histamine natural receptor.

Compound of the present invention to H₃The Ki of the receptor is between 0.1nM and 5.0. mu.M, more particularly, (2-cyclohexylmethyl) -7- [2- (1-methylpyrrolidin-2-yl) ethoxy]Ki of-1, 2, 3, 4-tetrahydroisoquinoline (Compound 5 of this Table) was 0.1 nM.

The following tests were also carried out on the compounds of the formula I according to Lovenberg, T.W. et al, J.Pharmacol.Exp.The., 293, 771-778 (2000): transfection of H in CHO cells by inhibition of agonism induced by specific binding of R-alpha-methyl histamine to this receptor₃Assay for cAMP production on type histamine human receptors.

Compound of the present invention to H₃CI of the receptor₅₀Is 0.1nM to 5.0. mu.M.

By way of example, this Table for CI for Compound 5₅₀< 10nM, therefore the transfection H in CHO cells by inhibition of agonism induced by specific binding of R-. alpha. -methyl histamine to this receptor was measured using the EIA kit (Amersham)₃cAMP produced on the histamine-type human receptor.

The compounds of the invention have H₃Selective activity of histamine receptor type. Effectively, according to liuy.q. et al in j.pharmacol.exp.the.268The method described in 959(1994), by³H]Specific ligation of pirilamine to this receptor for H in vitro in adult murine meninges₁Type histamine natural receptor affinity assays, these compounds have Ki's higher than 7.0. mu.M.

Claims (10)

1. A compound of the formula I:

in the formula:

represents an unsaturated carbocyclic group having a double bond, selected from phenyl orA naphthyl group;

l may take a value of 2 or 3;

m may take a value of 0 or 2;

n may take a value of 0 or 2;

and- (CH) when m and/or n takes the value 0₂)_o-represents a bond;

r1 represents C_1-3An alkyl group;

r2 represents cyclohexylmethyl;

the compounds are in the form of a base or of an addition salt with an acid.

2. The compound of claim 1, named as follows:

(2-cyclohexylmethyl) -7- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

(2-cyclohexylmethyl) -7- {2- [ (2R) -1-methylpyrrolidin-2-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline;

(2-cyclohexylmethyl) -7- {2- [ (2S) -1-methylpyrrolidin-2-yl ] ethoxy } -1, 2, 3, 4-tetrahydroisoquinoline;

(2-cyclohexylmethyl) -7- [ (1-methylazepan-4-yl) oxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

(2-cyclohexylmethyl) -7- [2- (1-methylpiperidin-2-yl) ethoxy ] -1, 2, 3, 4-tetrahydroisoquinoline;

and their pharmaceutically acceptable salts.

3. A pharmaceutical composition comprising a compound of formula I, or a salt thereof, according to any one of claims 1 or 2, and at least one pharmaceutical excipient.

4. Use of a compound of formula I or a salt thereof according to any one of claims 1 or 2 in the manufacture of a medicament for the treatment of obesity and/or diabetes.

5. Use of a compound of formula I according to any one of claims 1 or 2 or a salt thereof for the manufacture of a medicament for the treatment of a disease selected from: mania, seasonal affective disorder, migraine and nausea.

6. Use of a compound of formula I according to any one of claims 1 or 2 or a salt thereof for the manufacture of a medicament for the treatment of a disease selected from: central nervous system diseases.

7. Use of a compound of formula I according to claim 6 or a salt thereof for the preparation of a medicament for the treatment of a central nervous disease selected from: waking states and sleep disorders, narcolepsy, Alzheimer's disease and other dementias, Parkinson's disease, hyperkinetic attention disorders in children, memory and learning disorders, epilepsy, schizophrenia, reduced cognitive impairment, depression and anxiety disorders.

8. The use of a compound of formula I according to claim 7 or a salt thereof for the preparation of a medicament for the treatment of an anxiety disorder selected from the group consisting of pre-emptive anxiety disorder, anxiety disorder caused by alcohol addiction and alcohol withdrawal, drugs.

9. Use of a compound of formula II:

wherein Pg represents a hydrogen atom or a protecting group and R2 and A are as defined in claim 1.

10. A process for the preparation of a compound of formula I, wherein R1, R2, l, m, n and ring a are as defined according to claim 1, according to the following reaction:

wherein a nucleophilic substitution reaction is carried out by reacting a phenol of formula II, wherein R2 and ring A are as defined for formula I, with an amine of formula III, wherein R1, l, m and n are as defined for formula I, and Y represents a halogen atom or represents a "pseudo-halogen" or represents a hydroxyl group.