HRP980171A2 - Therapeutic naphthalene derivatives - Google Patents

Description

This invention relates to a new class of chemical compounds and their use in medicine. More specifically, this invention relates to new naphthalene derivatives, to processes for their preparation, to pharmaceutical preparations containing them and to their use as selective agonists at atypical 1-adrenoreceptors (which are also known as 1-3-adrenoreceptors). Such receptors are described, for example, by J. R. S. Arch, et al.: "Nature", 309, 163-165, (1984); C. Wilson, et al.: "Eur. J. Pharmacol.", 100, 309-319, (1984); L.J. Emorine: "Science", 245, 1118-1121, (1989); and A. Bianchetti, et al.: No. "J. Pharmacol.", 100, 831-839, (1990). Phenethanolamine derivatives having atypical �-adrenoreceptor activity are described in, for example, European Patent Applications EP-A-0455006 and EP-A-0543662.

Atypical �-adrenoreceptors belong to the family of adrenoreceptors that determine the physiological effects of the hormones adrenaline and noradrenaline. Subtypes of adrenoreceptors, �1-, �2-, �1- , �2- and �3-(atypical) can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents that stimulate or block these receptors (but not �3) have been widely used in clinical medicine. More recently, attention has been focused on specific receptor selectivity in order to reduce side effects caused by interactions with other receptors.

Atypical �-adrenoreceptors are known to occur in adipose tissue and in the gastrointestinal tract.

Agonists of atypical �-adrenoreceptors have been found to be particularly applicable as thermogenic agents against obesity and as antidiabetic agents. Compounds possessing agonistic activity of atypical �-adrenoreceptor are also applicable in the treatment of hyperglycemia, as promoters of animal growth, as inhibitors of blood platelet aggregation, as positive inotropic agents and as antiatherosclerotic agents, and are applicable in the treatment of glaucoma.

The invention therefore describes, in a first aspect, the compounds of formula I:

[image]

where

groups N(R3) and R4 are separated by at least 4 ring carbon atoms;

R1 represents a phenyl, naphthyl, phenoxy methyl, thiazolyl, pyridyl or pyrimidyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-6 alkoxy, C1-6 alkyl, nitro, cyano, hydroxy methyl , trifluoro methyl, NR6R7 and NHSO2R6;

R 2 represents hydrogen or C 1-6 alkyl;

R 3 represents hydrogen or C 1-4 alkyl;

R4 represents CO2R6 or SO3H;

R 5 represents one or more groups each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, trifluoro methyl and C 1-6 alkoxy;

n represents an integer from 1 to 6;

R 6 and R 7 each independently represent hydrogen or C 1-4 alkyl;

or their pharmaceutically acceptable derivatives.

A preferred subclass of compounds of formula I is represented by compounds of formula Ia:

[image]

where

groups N(R3) and R4 are separated by at least 4 ring carbon atoms;

R1 represents a phenyl, naphthyl, pyridyl or pyrimidyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-6 alkoxy, C1-6 alkyl, nitro, cyano, hydroxy methyl, trifluoro methyl, NR6R7 and NHSO 2 R 6 ;

R 2 represents hydrogen or C 1-6 alkyl;

R 3 represents hydrogen or C 1-4 alkyl;

R4 represents CO2R6 or SO3H;

R 5 represents one or more groups each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, trifluoro methyl and C 1-6 alkoxy;

n represents an integer from 1 to 6;

R 6 and R 7 each independently represent hydrogen or C 1-4 alkyl;

or their pharmaceutically acceptable derivatives.

With reference to general formula I, the term "alkyl" as used herein contains the appropriately indicated number of carbon atoms and appropriately includes normal chain alkyl groups, for example, methyl and ethyl groups and normal and branched chain propyl and butyl groups. Similarly, the term "alkoxy" includes both normal and branched chain groups.

Referring to the general formula (I), halogen includes, fluorine, chlorine, bromine and iodine.

Suitably R 1 represents phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, nitro, cyano, hydroxy methyl and trifluoro methyl. Preferably, R1 represents phenyl substituted with a chlorine, fluorine, bromine atom or with a methyl or trifluoromethyl group, where this atom or group is preferably located in the meta position. Even more preferably, R 1 represents phenyl substituted with a chlorine atom located in the meta position.

R 2 is suitably hydrogen or methyl;

R 3 is suitably hydrogen or methyl. R 3 is preferably hydrogen.

R 4 is suitably CO 2 H or SO 3 H. Preferably R4 is CO2H.

R 5 is suitably hydrogen.

A further preferred subclass of compounds of formula I is represented by the compound of formula Ib:

[image]

where

the naphthyl amino group and the R4 group are separated by at least 4 ring carbon atoms;

R 2 represents hydrogen or C 1-6 alkyl;

R4 represents CO2H or SO3H;

or their pharmaceutically acceptable derivatives.

It is understood here that further references to compounds of formula I apply equally to compounds of formulas Ia and Ib.

It is quite understandable that the above compounds of formula I may contain optically active centers. Individual, isolated isomers and their mixtures, including racemates, are within the scope of protection of the described invention. Mixtures of diastereomers of the compounds of formula I can usually be obtained which are enriched with or contain more than 80% by weight of one diastereomer. Particularly preferred compounds of formula I are those in which the asymmetric carbon atoms in the groups CH(OH)- and -CH(R2)- are both in the (R)-configuration.

Preferred compounds of formula I of the described invention include the following compounds:

6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid

5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid

6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-1-sulfonic acid

7-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid

5-{2-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-ethyl amino}-naphthalene-2-sulfonic acid

5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid

6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid

6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-1-carboxylic acid

5-{2S-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid

Methyl 5-{2S-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]}-naphthoate

Methyl 5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]}-naphthoate;

and their pharmaceutically acceptable derivatives.

Preferred compounds of the invention also include the following compounds:

5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid;

and its pharmaceutically acceptable derivatives.

The term "pharmaceutically acceptable derivative" means a pharmaceutically acceptable salt, ester or salt of such an ester of a compound of formula I or some other compound, which after application to the recipient can provide (directly or indirectly) a compound of formula I or its metabolite or residue.

A person skilled in the art will understand that the compounds of formula I can be modified on some of their functional groups, in order to obtain their pharmaceutically acceptable derivatives. Of special interest in this case are compounds that are modified on the carboxyl function, on the hydroxyl functions or on the amino groups.

It will be clear to a person skilled in the art that pharmaceutically acceptable derivatives of the compounds of formula I can be derivatized at several (not only one) positions.

Preferred pharmaceutically acceptable derivatives of the compounds of formula I are their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of the compounds of formula I include those salts which are derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene- 2-sulfonic and benzenesulfonic acid. Other such acids such as oxalic, which themselves are not pharmaceutically acceptable, can be used in the preparation of salts which are applicable as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable addition salts with acids.

Salts derived from appropriate bases include alkali metal salts (for example sodium salts), alkaline earth metal salts (for example magnesium salts), ammonium salts and NR4+ (where R is C1-4 alkyl).

The compounds of formula I act as agonists at atypical �-adrenoreceptors and as such are applicable in the treatment of clinical conditions that are subject to improvement with the administration of atypical �-adrenoreceptor agonists. Such conditions include the following conditions: hyperglycemia, obesity, hyperlipemia, bladder irritation syndrome and related pain, mobility dysfunction, excess abdominal secretion, nonspecific diarrhea, neurogenic inflammation, intraocular pressure regulation, triglyceridemia, diabetes, for example, non-insulin-dependent diabetes mellitus ( NIDDM or Type II), such as obesity NIDDM or non-obesity NIDDM, complications of diabetes such as retinopathy, nephropathy, neuropathy, cataracts, coronary heart disease and arteriosclerosis, osteoporosis and gastrointestinal disorders, especially inflammatory gastrointestinal disorders. These compounds are also applicable for increasing the concentration of high-density lipoprotein (HDL) cholesterol and reducing the concentration of triglycerides in blood serum, especially in human blood serum, and are therefore potentially applicable in the treatment and/or prophylaxis of atherosclerosis. These compounds may also be applicable in the treatment of hyperinsulinemia, depression, muscle wasting, and urinary incontinence.

Therefore, the described invention provides, as a further aspect, a method for treating a mammal, including a human, suffering from a condition ameliorated by the administration of an atypical �-adrenoreceptor agonist, comprising administering to such a subject an effective amount of a compound of general formula I or a pharmaceutically acceptable derivative thereof .

References in this specification to treatment include prophylactic treatment as well as relief of symptoms.

In a further aspect, the invention provides the use of a compound of the general formula I or a pharmaceutically acceptable salt or solvate thereof, for the production of a medicament for the treatment of a condition that is amenable to the use of an atypical �-adrenoreceptor agonist.

Although it is possible that, for use in therapy, the compound of the invention is administered in the form of a raw chemical, it is preferred that it is administered in the form of an active ingredient in a pharmaceutical formulation.

Thus, the invention further provides a pharmaceutical formulation comprising a compound of formula I or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers and, optionally, together with other therapeutic and/or prophylactic ingredients. The carrier(s) or excipient(s) must be "applicable" in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient.

Thus, the compounds for administration according to the described invention may be formulated for oral, buccal, parenteral, rectal or transdermal administration, or in a form for administration by inhalation or insufflation (either through the mouth or nose).

For oral administration, the pharmaceutical preparations may be in the form of, for example, tablets or capsules obtained in a conventional manner with pharmaceutically acceptable excipients such as binding agents (for example pregelatinized corn starch, polyvinyl pyrrolidone or hydroxy propyl methyl cellulose); fillers (for example lactose, microcrystalline cellulose or calcium bisphosphate); lubricants (eg magnesium stearate, talc or silicon dioxide); disintegrants (for example potato starch or sodium starch glycolate); or wetting agents (for example sodium lauryl sulfate). The tablets may be coated using methods well known in the art. Liquid preparations for oral administration may be, for example, in the form of solutions, syrups or suspensions, or may be present as a dry product for reconstitution with water or other suitable vehicle prior to administration. Such liquid preparations can be obtained in the usual way with pharmaceutically acceptable additives, such as suspending agents (for example sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example lecithin or acacia); non-aqueous carriers (for example almond oil, oil esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example methyl or propyl-p-hydroxybenzoates or sorbic acid). These preparations may also contain suitable buffer salts, aromatic and sweetening agents, and coloring agents.

Preparations for oral administration may be suitably formulated to ensure controlled release of the active compound.

For buccal administration, preparations can be in the form of tablets or lozenges that are formulated in the usual way.

The compounds of the present invention may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be present in unit dosage form, for example in an ampoule or in multidose containers, with an additional preservative. The preparations may be present in such a form as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain formulation agents, such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for mixing with a suitable carrier, i.e. pyrogen-free water, prior to administration.

The compounds according to the described invention can also be formulated into rectal preparations, such as suppositories or retention enemas, that is, those containing the usual suppository bases, such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long-acting formulations can also be administered by implantation (for example, subcatanous, transcatanous or intramuscular) or by intramuscular injection. Thus, for example, the compounds according to the described invention can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion or an acceptable oil) or ion-exchange resins or as sparingly soluble derivatives, for example as a sparingly soluble salt.

Suitable therapeutic ingredients that can be formulated with the compounds of the invention, together with one or more pharmaceutical carriers or excipients, include ingredients that can be used in the same clinical conditions as those listed herein for atypical β-adrenoreceptor agonists. Such ingredients may include, for example (-PRAR agonists.

The suggested dose of the compounds according to the described invention for use in humans (body weight of about 70 kg) is 0.1 mg to 1 g, preferably from 1 mg to 100 mg of the active ingredient per unit dose, expressed as the mass of the free base. A unit dose can be administered, for example, 1 to 4 times a day. The dose will depend on the method of administration. It is clear that it is necessary to make routine variations of the dose, depending on the age and weight of the patient, as well as on the severity of the condition being treated.

The precise dose and method of administration will be solely at the discretion of the doctor or veterinarian.

The compounds of the described invention can be obtained by methods known in the art for obtaining similar compounds. For example, according to the first process (A), where R 1 , R 2 , R 3 , R 5 and n are as defined for formula I, compounds of formula I may be obtained from compounds of formula II:

[image]

where P1 and P2 are suitable protecting groups for oxygen and nitrogen groups respectively, R4 is CO2R6 or SO3H and R6 is C1-6 alkyl, by deprotection of P1 and P2 under suitable conditions, such as treatment with an acid, for example, with with an aqueous solution of hydrochloric acid in a suitable solvent, such as dioxane.

According to the following process (B), compounds of formula I can be obtained from other compounds of formula I. For example, a compound of formula I where R 6 is H can be obtained from a compound of formula I where R 6 is C 1-6 alkyl, by hydrolysis, for example base hydrolysis with a reagent such as lithium hydroxide in a solvent such as tetrahydrofuran.

Compounds of formula II can be obtained by reacting a compound of formula III with a compound of formula IV:

[image]

where P 1 and P 2 are suitable protecting groups for oxygen and nitrogen groups respectively, R 4 is CO 2 R 6 or SO 3 H and R 6 is C 1-6 alkyl in the presence of a reducing agent.

According to the following procedure (C), obtaining the compounds of formula II, as defined above, followed by step (A), can be carried out without purification of the intermediate products.

Compounds of formula III are described in WO95/33724, and as described herein.

Compounds of formula IV are known compounds, or can be obtained by standard procedures.

For example, when the compound of formula IV is a 5-amino-2-naphthoate ester, this can be obtained from the compound of formula V:

[image]

wherein R 5 and n are as defined above and R 6 is C 1-4 alkyl, by reaction with benzylamine and cesium carbonate in the presence of a suitable catalyst (or catalysts), for example (R)-(+)-2,2'-bis (diphenylphosphino)-1,1'-binaphthyl and tris(dibenzylidene acetone)dipalladium(0), which is further followed by a suitable reduction, for example, with hydrogenation of the benzyl group.

Compounds of formula V are known compounds or can be prepared by standard procedures, for example see "Aust. J. Chem.", 18, 1351-64, (1965).

Alternatively, a compound of formula IV which is a 5-amino-naphthoate ester can be obtained from a compound of formula VI:

[image]

wherein R5 and n are as defined above and P3 represents a suitable primary nitrogen protecting group, for example isoindole, by reaction with carbon monoxide, under pressure and at an elevated temperature, for example 100°C, in the presence of a suitable catalyst or catalysts, such as palladium (II) acetate and 1,1'-bis(diphenylphosphino)-ferrocene and lithium chloride, in a suitable solvent, such as triethylamine and methanol, followed by deprotection of the amino protecting group under suitable conditions , for example hydrazine in methanol at elevated temperature.

A compound of formula VI may be prepared from the corresponding 5-amino-2-naphthol by sequential reaction with a suitable reagent such as phthalic anhydride in a suitable solvent such as N,N-dimethylacetamide followed by reaction with trifluoromethanesulfonic anhydride and triethylamine in a suitable solvent, such as dichloromethane.

Suitable reducing agents for use in the reactions include hydrogen in the presence of a catalyst, such as a catalytic noble metal, for example palladium, platinum or platinum oxide, Raney-nickel, or hydride reducing agents, such as borohydrides, for example sodium borohydride, sodium triacetoxy borohydride or sodium cyano borohydride. Suitable reaction conditions will be well known to one skilled in the art and are further illustrated in the attached examples.

The protecting groups used in the preparation of the compounds of formula I can be used in the usual way. See for example J. F. W. McOmie: "Protective Groups in Organic Chemistry", Plenum Press, (1973); or Teodora W Greene and P. M. G. Wuts: "Protective Groups in Organic Synthesis", published by John Wiley and Sons, (1991).

Common amino protecting groups may include, for example, such groups as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as benzyloxycarbonyl and t-butoxycarbonyl.

Common oxygen protecting groups may include, for example, alkyl silyl groups, such as trimethylsilyl and tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters, such as acetate.

Removal of any protecting group present can be accomplished using conventional procedures.

Atypical �-adrenoreceptor agonists are compounds that exhibit a pharmacological response developed at atypical �-adrenoreceptors. This activity was measured as the ability to stimulate lipolysis by rat adipocytes at submicromolar concentrations, a response that is resistant to blockade by standard β-adrenoreceptor blocking drugs, such as propranolol.

Another applicable way to identify an atypical ?-adrenoreceptor agonist involves measuring agonist activity at atypical ?-adrenoreceptors in isolated rat esophagus. Typically in this test, the compound of general formula I for use according to the described invention has an equipotential molar ratio (EPMR) to isoprenaline of less than 30. The rat esophagus test is based on the method described by Ford, et al.: "No. J. Pharmacol.", 105 (supplement). p. 235, (1992).

A particularly applicable method for determining agonist activity at human atypical ?-adrenoreceptors involves the use of Chinese hamster ovary (CHO) cells that have been infected with human ?-3-adrenoreceptor according to procedure 1. Cell lines can also be infected with human ? -2 adrenoreceptor in a similar way, in order to provide a procedure for determining the selectivity of the compounds of the invention on all three receptors.

Procedure 1

General instructions for cell culture were followed (Fershney R. A.: "Culture of animal cells; A manual of basic technique", published by Wiley-Liss, Inc., N.Y., (1987)). A standard cell culture incubator was used (37°C, 5% CO2 in air, 95% relative humidity). H �3 CHO cells were grown in DMEM/F12 medium (containing pyroxidine HCl, 15 mM HEPES, L-glutamine), which was supplemented with 10% heat-inactivated FBS, 500 µg/ml G418, 2 mM L-glutamine , 100 units of penicillin G and 100 g of streptomycin sulfate. One pouring bottle of cells was trypsinized and resuspended in the upper medium at a concentration of 30-40,000 cells/100 ul, and a 96-well plate was placed on the bottom. The cells are then used for testing during 18-24 hours.

Experimental procedure

The medium is aspirated from each well and replaced with 180:l DMEM/F12 medium containing 500 mM IBMX. At this stage, antagonists are added, if required. The plate is then returned to the incubator for 30 minutes. Drugs (20 µl, 100 × required final concentration) are then added to the wells over 60 minutes. Responses are determined by measuring the cAMP level of a 20 µl sample of the extracellular medium using a scintillation environment based on a radio-immunoassay (NEN Flashplates).

CHO-6CRE-luciferase cell lines that stably express the h�3 receptor were seeded at a concentration of 30,000 cells/well for 24 hours in DMEM/F12 containing 10% FBS. The medium was separated from the cells and replaced with DMEM/F12 buffer (180 µl) containing 300 mM IBMX and 1 mM ascorbic acid for 30 min before compound addition. Vehicle or agonist (20 µl) is added and incubated at 37 °C for 60 minutes. At the end of the incubation period, samples of the extracellular medium are taken for direct testing in cAMP Flashplates (NEN).

The relative potency of each tested agonist (EPMR) is compared to that of isoprenaline as follows:

[image] .

Using isoprenaline as a non-selective 1-adrenoreceptor agonist as a reference agonist, compounds selective for atypical 1-adrenoreceptors should preferably be at least 10-30 times less potent than isoprenaline at 1- or 2-adrenoreceptors, and more preferably 300-1000 times less potent of isoprenaline on �1 or �2-adrenoreceptors. In addition to their activity on the atypical �-adrenoreceptor, the compounds of the described invention have been shown to be highly selective for the �-adrenoreceptor in contrast to their selectivity for �1- or �2-adrenoreceptors.

The invention is further illustrated by the following intermediates and examples. All temperatures are given in degrees Celsius (°C).

HPLC characterization was performed using a Dynamax-60A C18 83-201-C, 25cm × 4.6mm column, eluted with a 5-40% mixture of CH3CN in water with 0.1% TFA buffer, with time programming at 30.0 minutes and with a flow rate of 1.5 ml/min). Retention times are expressed as tr in minutes.

Optical rotation values are expressed as [�]D values.

Mass spectra were obtained using electrospray analysis (positive or negative ion).

Intermediary 1

Methyl ester of (R)-(3-chloro-phenyl)-hydroxy-acetic acid

A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid (19.98 g) in methanol (250 ml) containing concentrated sulfuric acid (1 ml) was heated under reflux for 6.5 hours. The solution is cooled, neutralized with an aqueous solution of sodium carbonate and concentrated. The solution was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried and evaporated to give the title compound (21.13 g) as a slightly yellow oil.

[�]D= -104 ° (c 1.00 MeOH).

Intermediary 2

(R)-(3-chloro-phenyl)-(tert-butyl-dimethyl-silanoxy)-acetic acid methyl ester

A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (21.0 g) in imidazole (14.25 g) and tert-butyldimethylsilyl chloride (25.0 g) in N,N-dimethylformamide (250 ml) is stirred at room temperature for 18 hours. The mixture is poured into water and extracted with ethyl acetate. The combined extracts are washed with water and saturated saline, dried and concentrated. The residue is purified by chromatography eluting with a mixture of cyclohexane:ethyl acetate (9:1) to obtain the title compound (32.63 g) in the form of a colorless oil.

[�]D= -55.4 ° (c 1.21 MeOH).

Intermediary 3

(R)-(3-chloro-phenyl)-(tert-butyl-dimethyl-silanoxy)-acetaldehyde

In a solution of (R)-(3-chloro-phenyl)-(tert-butyl-dimethyl-silanoxy)-acetic acid methyl ester (4.0 g) in anhydrous ether (10 ml) maintained at a temperature below -60 °C, a 1.5 M solution of diisobutylaluminum hydride in toluene (10 ml) is added dropwise. When the addition is complete, the solution is stirred at -65 °C for the next 1 hour, and then treated with ethanol (100 ml) to stop the reaction. The mixture was allowed to reach room temperature, absorbed on silica and purified by chromatography eluting with cyclohexane:ethyl acetate (9:1) to give the title compound (3.09 g) as a colorless liquid.

[�]D= -45.3 ° (c 1.50 MeOH).

Intermediary 4

5-amino-2-naphthalene carboxylic acid methyl ester (i)

A solution of methyl-2-naphthoate (10.00 g) in acetic acid (54 ml) was stirred at 0 °C and nitronium tetrafluoroborate (7.13 g) was added. The solution was stirred at 0 °C for 1 hour and then at room temperature for 3 hours. The mixture is diluted with water and then extracted with chloroform. The organic layer is washed with saturated aqueous sodium bicarbonate solution, dried with MgSO4, filtered and evaporated. The residue is chromatographed on silica gel, eluted with a mixture of ethyl acetate:hexane (1:9) to obtain a mixture of nitro-naphthalene-2-carboxylic acid methyl ester. The mixture was suspended in methanol (365 ml) and stirred with the addition of 10% palladium on carbon (1.05 g). The resulting mixture is stirred under a hydrogen atmosphere for 18 hours and then filtered through a Celite insert and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of cyclohexane:ethyl acetate (1:4), and then recrystallized from methanol to give the title compound (1.005 g).

Found by testing: C 71.72; H 5.58; N 6.97.

C12H11NO2 required: C 71.63; H 5.51; N 6.96%.

Intermediary 5

2-(6-hydroxy-1-naphthyl)-1H-isoindole-1,3(2H)-dione

A solution of 5-amino-2-naphthol (25.24 g) and phthalic anhydride (24.66 g) in N,N-dimethyl acetamide (200 ml) was stirred at 172 °C under vacuum for 3.5 hours. The reaction mixture is then concentrated at 50 °C and 0.3 torr, and methanol (600 ml) is added to the resulting dark red residue. The mixture is sonicated and heated, which leads to the formation of a crystalline solid. The mixture was then cooled to 0 °C and the crystalline solid was isolated by filtration, and washed with methanol (50 ml). It was then dried under vacuum to give the title compound as a colorless solid (18.96 g). The filtrate was concentrated and then triturated with methanol (200 ml) to give a second yield after filtration and vacuum drying (18.56 g).

Found by testing: C 74.44; H 3.94; N 4.96.

C18H11NO3 required: C 74.73; H 3.83; N 4.84%.

Similarly, the following are obtained:

Intermediary 6

2-(6-Bromo-2-naphthyl)-1H-isoindole-1,3(2H)-dione as a colorless crystalline solid (10.81 g).

Found by testing: C 61.30; H 3.09; N 3.93,

C18H10NO2Br requirement: C 61.39; H 2.86; N 3.98%,

from 6-bromo-2-naphthalene amine (9.50 g) ("Journal of Organic Chemistry", 25, 214, (1960)).

Intermediary 7

2-(5-hydroxy-2-naphthyl)-1H-isoindole-1,3(2H)-dione as a red solid contaminated with N,N-dimethyl acetamide (1.10 g).

Electrospray ms (positive ion) (M+H) 290,

from 6-amino-1-naphthol (4.20 g).

Intermediary 8

5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-naphthyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (10.09 ml) was added dropwise under breath to a suspension of 2-(6-hydroxy-1-naphthyl)-1H-isoindole-1,3(2H)-dione (14.46 g) in dichloromethane (200 ml ) containing triethylamine (13.9 ml) at -78 °C. After 2 hours, 1N hydrochloric acid (100 ml) is added. The mixture is allowed to warm to room temperature and the two phases are separated. The yellow aqueous phase is extracted with dichloromethane and the extracts are combined with the organic layer. The combined organic phase was then washed with 1N hydrochloric acid (50 ml), then washed with saturated aqueous sodium chloride (50 ml). The solution is dried (magnesium sulfate), decolorized with activated carbon and filtered through a silica pad eluting with a mixture of hexane/ethyl acetate (4:1). The filtrate was then concentrated to give the title compound as a slightly pink crystalline solid (19.71 g). The analytical sample is obtained by recrystallization from a mixture of hexane/ethyl acetate (4:1).

Found by testing: C 54.07; H 2.37; N 3.28; With 7.58.

C19H10NO5SF required: C 54.16; H 2.39; N 3.32; With 7.61 %.

Similarly, the following are obtained:

Intermediary 9

6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-naphthyl as a colorless crystalline solid (481 mg).

1H n.m.r. (CDCl3): � values include 7.54(s); 7.54-7.60(m); 7.78 (dd); 7.81-7.87(m); 7.94(dd), 8.00-8.04(m); 8.08(d); 8.21(d),

from 2-(5-hydroxy-2-naphthyl)-1H-isoindole-1,3(2H)-dione (950 mg).

Intermediary 10

Methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-naphthoate in the form of a colorless crystalline solid (240 mg).

Found by testing: C 72.34; H 3.95; N 4.17,

C20H13NO4 requirements: C 72.50; H 3.95; N 4.23%,

from 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-naphthyl trifluoromethanesulfonate (313 mg).

Intermediary 11

Methyl 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-naphthoate

A solution of 2-(6-bromo-2-naphthyl)-1H-isoindole-1,3(2H)-dione (3.52 g), palladium (II) acetate (111 mg), 1,1'bis(diphenylphosphino) - ferrocene (554 mg), lithium chloride (1.271 g), triethylamine (6.97 ml) and methanol (8.10 ml) in N,N-dimethylformamide (50 ml), mixed in a Parr bomb at 100 ° C under 2.0685 bar (30 psi) of carbon monoxide for 3 hours. After cooling to room temperature, the bomb is vented and the contents are distributed between ethyl acetate (800 ml) and 1N hydrochloric acid solution (400 ml). The aqueous layer and undissolved solid are then extracted with ethyl acetate. These extracts are combined with the organic layer, washed with 1N hydrochloric acid solution and saturated aqueous sodium chloride solution and dried (magnesium sulfate). Filtration through a pad of Celite and concentration under vacuum gave a black solid which was chromatographed on silica gel and eluted with hexane/ethyl acetate (4:1 to 1:2). The product was then recrystallized from ethyl acetate to give the title compound (1.82 g) as colorless crystals.

Found by testing: C 72.39; H 4.02; N 4,18.

C20H13NO4 requirements: C 72.50; H 3.95; N 4.23%.

Similarly, we get:

Intermediary 12

Methyl 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-naphthoate as a colorless crystalline solid (73 mg).

Electrospray MS (positive ion) (M+H) 332,

from 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-naphthyl trifluoromethanesulfonate (290 mg).

Intermediary 13

5-Benzylamino-naphthalene-2-carboxylic acid methyl ester

Cesium carbonate (15.48 g) was added to a solution of 5-bromo-naphthalene-2-carboxylic acid methyl ester (9.0 g) ("Aust. J. Chem.", 18, 1351-64, (1965) ) and benzylamine 94.46 ml) in toluene (100 ml) and the mixture is concentrated. Add (R)-(+)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (315.2 mg) and tris(dibenzylacetone)dipalladium(0) (154.4 mg) and reaction the mixture is heated to 81 °C for 16 hours. 5-Benzylamino-naphthalene-carboxylic acid methyl ester was obtained by collecting the resulting yellow solid (4.86 g) and washing with tetrahydrofuran. Additional product (2.40 g) is obtained by washing the filtrate with water, concentrating and dusting the residue with diethyl ether.

1H n.m.r. (DMSO-d6): � values include 3.88(d); 6.45-6.49(m); 7.11(t); 7.16-7.24(m); 7.28(t); 7.37(d); 7.86(dd); 8.34(d); 8.42(s).

Intermediary 14

Methyl ester of 5-amino-2-naphthalene carboxylic acid (ii)

A suspension of methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-naphthoate 93.24 g) in methanol (100 ml) is heated at reflux. Hydrazine (313:1) is then added and the reaction mixture is stirred. The mixture is cooled after 3 hours and the volatile components are removed under vacuum. The remaining yellow solid was suspended in water (100 ml) containing 1M hydrochloric acid solution (12.25 ml) and heated to 55 °C for 15 minutes. The mixture is then cooled to room temperature and filtered to remove the precipitated solid. The filter layer is extracted with a mixture of ethyl acetate/methanol (10:1). These extracts are combined and washed with a saturated aqueous solution of sodium bicarbonate. The precipitated solid substance is cast off with the aqueous layer. The pH of the filtrate is then adjusted to a value of about 8 with 1M aqueous sodium hydroxide solution and the obtained cloudy mixture is extracted with ethyl acetate. The extracts were combined with that of the filter bed, dried (magnesium sulfate) and concentrated to give the title compound (1.62 g).

Similarly, the following are obtained:

Intermediary 15

Methyl 6-amino-2-naphthoate in the form of a slightly pink solid (335 mg).

Found by testing: C 71.63; H 5.51; N 6.96,

C12H11NO2 required: C 71.44; H 5.58; N 6.90%,

from 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-naphthoate (994 mg).

Intermediary 16

Methyl 6-amino-1-naphthoate in the form of a colorless oil (83 mg),

from 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-naphthoate (168 mg).

Electrospray MS (positive ion) (M+H) 202.

Intermediary 17

Methyl ester of 5-amino-2-naphthalene carboxylic acid (iii)

10% palladium on carbon (2.5 g) was added to a solution of 5-benzylamino-naphthalene-carboxylic acid methyl ester (8.2 g) in tetrahydrofuran (115 ml). The reaction vessel is evacuated and purged with air and then with hydrogen. The mixture is then stirred under hydrogen (1 bar) for 4 hours. The reaction mixture was filtered through a Celite insert and concentrated to give the title compound (5.47 g) as a yellow solid.

Intermediary 18

Methyl (2S)-2-[(2R)-2-[tert-butyl (dimethyl)silyl]-oxy-2-(3-chlorophenyl)ethyl]amino propanoate

A solution of (2R)-2-[tert-butyl (dimethyl)silyl]oxy-2-(3-chlorophenyl)ethanol (5.0 g) in dichloromethane was stirred in the presence of a 4A molecular sieve (about 50 beads) for 5 minutes. L-alanine methyl ester (2.45 g) was added and the mixture was stirred for an additional 5 minutes. Sodium triacetoxy borohydride (5.6 g) was added and the cloudy mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate (200 ml) and extracted with dichloromethane (3 x 150 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (150 ml), dried (magnesium sulfate) and concentrated under vacuum to give a yellow oil (5.0 g) which was chromatographed on silica gel. Elution with hexane/ethyl acetate (9:1) gave the title compound as a slightly yellow oil (4.0 g).

Electrospray ms (positive ion) (M+H) 372.

Intermediary 19

Methyl (2S)-2-(tert-butoxycarbonyl)[(2R)-2-[tert-butyl (dimethyl)silyl]-oxy-2-(3-chlorophenyl)ethyl]amino propanoate

Di-tert-butyl dicarbonate (2.05 g) was added to methyl (2S)-2-[(2R)-2-[tert-butyl (dimethyl)silyl]oxy-2-(3-chlorophenyl)ethyl] -amino propanoate (3.50 g) and the mixture was heated to 95 °C under fume hood for 10 minutes. The solution is cooled to room temperature and chromatographed on silica gel eluting with a mixture of hexane/ethyl acetate (95:5). The title compound (4.15 g) is obtained as a colorless oil.

Electrospray ms (positive ion) (M+Na) 494/496.

Intermediary 20

{2S-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chloro phenyl)-ethyl]-amino}propion aldehyde

Diisobutyl ammonium hydride (4 ml, 1.5M in toluene) was added dropwise under breath to a solution of methyl (2S)-2-(tert-butoxycarbonyl)[(2R)-2-[tert-butyl (dimethyl)silyl]oxy -2-(3-chloro phenyl)ethyl]-amino propanoate (1.28 g) in toluene (20 ml) at -78 °C. The resulting colorless solution was stirred at this temperature for 90 minutes before a saturated aqueous Rochelle salt solution (20 ml) was added dropwise. The obtained mixture is allowed to warm to room temperature and then it is filtered through a Celite insert, washed with water (50 ml) and with ethyl acetate. The filtrate was separated into its two layers and the aqueous layer was extracted with ethyl acetate. The extracts were combined with the organic layer of the filtrate, washed with saturated aqueous sodium chloride solution (20 ml), dried (magnesium sulfate) and concentrated to give the title compound as a colorless oil (1.08 g).

1H n.m.r. (CDCl3): � values include 0.00; 0.03 and 0.07(3s); 0.22 and 0.24(2s); 1.06(s), 1.46 and 1.51(2d); 1.62 and 1.65(2s); 5.11 and 5.27 (2m); 7.36-7.60(m); 9.76 and 9.83 (2s).

Intermediary 21

Methyl 6-[((2R)-2-(tert-butoxy carbonyl)[(2R)-2-[tert-butyl (dimethyl)silyl]oxy)-2-(3-chloro phenyl)ethyl]amino propyl)amino ]- 2-naphthoate

Methyl 6-amino-2-naphthoate (201 mg) was dissolved in a 0.14 M solution of {2R-(tert-butoxy carbonyl)-[2R-(tert-butyl dimethyl silanoxy)-2-(3-chloro phenyl)- ethyl]-amino}propionaldehyde in 1,2-dichloroethane (12.0 mL) under vacuum. Acetic acid (87:1) and 4A molecular sieve (4 beads) are added and the mixture is stirred for 25 minutes. Sodium triacetoxy borohydride (636 mg) was then added and the mixture was stirred at room temperature for 17 h, before being diluted with ethyl acetate (30 ml) and saturated aqueous Rochelle salt (15 ml). The mixture is filtered through a Celite insert, washed with ethyl acetate (30 ml) and the two layers are separated. The aqueous phase is extracted with ethyl acetate. The extracts are then combined with the organic phase, dried (magnesium sulfate) and concentrated to a yellow oil. Silica gel chromatography eluting with hexane/ethyl acetate (10:1) gave the crude title compound (804 mg) which was used in the next step without further purification.

Electrospray ms (positive ion) (M+H) 627/629.

They are obtained similarly

Intermediary 22

Methyl 6-[((2R)-2-(tert-butoxy carbonyl)[(2R)-2-[tert-butyl (dimethyl)silyl]oxy)-2-(3-chloro phenyl)ethyl]amino propyl)amino ]- 1-naphthoate in the form of a yellow oil (260 mg).

MS low resolution (ES+) 627/629,

from methyl 6-amino-1-naphthoate (85 mg) and {2R-(tert-butoxy carbonyl)-[2R-(tert-butyl dimethyl silanoxy)-2-(3-chloro phenyl)-ethyl]-amino} propion aldehyde in 1,2-dichloroethane (6.0 ml, 0.83 mmol aldehyde).

Intermediary 23

Methyl 5-[((2S)-2-(tert-butoxycarbonyl)[(2R)-2-[tert-butyl (dimethyl)silyl]oxy)-2-(3-chloro phenyl)ethyl]amino propyl)amino ]-2-naphthoate in the form of a slightly yellow oil (720 mg).

MS low resolution (ES+) 627/629,

from methyl 5-amino-2-naphthoate (328 mg) and {2S-(tert-butoxy carbonyl)-[2R-(tert-butyl dimethyl silanoxy)-2-(3-chloro phenyl)-ethyl]-amino} propion aldehyde (1.08 g).

Example 1

6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid

A suspension of 6-amino-2-naphthalene sulfonic acid (0.505 g) and {2R-(tert-butoxycarbonyl)-[2R-(tert-butyl-dimethyl-silanoxy)-2-(3-chloro-phenyl)-ethyl] -amino}-propionaldehyde (0.500 g) in N,N-dimethylformamide (8 ml) was stirred for 10 minutes, before sodium triacetoxy borohydride (0.479 g) was added. The mixture is stirred for 18 hours. A 15% aqueous solution of Rochelle's salt is added and the mixture is stirred for 1 hour. The mixture is extracted with toluene. The organic layer was dried with magnesium sulfate, concentrated and evaporated to a dark oil which was purified by chromatography on silica gel with a mixture of chloroform/methanol/water (60:30:4) to give the blocked compound as an oil (0.38 g). . This oil was dissolved in terahydrofuran (4 ml) and 6N hydrochloric acid solution was added. The mixture is stirred at room temperature for 2 days. The solution is neutralized with ammonium hydroxide and evaporated. The residue is purified by column chromatography on silica gel with a mixture of chloroform/methanol/water/ammonium hydroxide (60:30:2:2) to obtain the title compound as an oil. The sample is solidified with an ethanol/water mixture to give the title compound as a dark yellow oil (87.1 mg).

1H NMR (DMSO-d6): � values include 1.29(d); 3.09 (no m); 3.24 (no m); 3.50 (no m); 4.97(d); 6.23 (number m); 6.30(d); 6.82(s); 6.98 (m); 7.37 (m); 7.48 (m); 8.62 (no. s).

HPLC: tr=16.2 min (t0=1.6 min).

Example 2

5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid

A suspension of 5-amino-2-naphthalene sulfonic acid (0.118 g) and {2R-(tert-butoxycarbonyl)-[2R-(tert-butyl-dimethyl-silanoxy)-2-(3-chloro-phenyl)-ethyl] -amino}-propionaldehyde (0.115 g) in N,N-dimethylformamide (1.9 ml) was stirred for 10 minutes, before sodium triacetoxy borohydride (0.113 g) was added. The mixture is stirred for 18 hours. A 15% aqueous solution of Rochelle's salt is added and the mixture is stirred for 1 hour. The mixture is extracted with toluene. The organic layer is dried with magnesium sulfate, concentrated and evaporated to a dark oil. The residue was dissolved in dichloromethane (10 ml), trifluoroacetic acid (1 ml) was added and the resulting solution was stirred at room temperature for 4 hours before being concentrated. The residue was dissolved in 1,4-dioxane (3.3 ml) and 6N hydrochloric acid solution was added. The mixture was stirred at room temperature for 18 hours, when it was concentrated to give a purple solid, which was purified by chromatography on silica gel with a mixture of chloroform/methanol/water/ammonium hydroxide (60:30:2:2). The concentrated extracts were suspended with ethanol to give the title compound as a pale yellow powder (21.5 mg).

1H NMR (DMSO-d6): � values include 1.36(d); 3.15 (no m); 3.26(m, 1); 3.43 (br m); 3.62 (br m); 4.97(d); 6.35 (no m); 6.66(d); 7.28-7.16(m); 7.40-7.30 (m); 7.42 (m); 7.54(s); 7.66(d); 8.02(s); 8.13(d); 8.61 (no. s).

HPLC: tr=19.4 min (t0=1.6 min).

Example 3

6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-1-sulfonic acid

A suspension of 6-amino-1-naphthalene sulfonic acid (0.118 g) and {2R-(tert-butoxycarbonyl)-[2R-(tert-butyl-dimethyl-silanoxy)-2-(3-chloro-phenyl)-ethyl] -amino}-propionaldehyde (0.115 g) in N,N-dimethylformamide (1.9 ml) was stirred for 10 minutes, before sodium triacetoxy borohydride (0.113 g) was added. The mixture is stirred for 18 hours. A 15% aqueous solution of Rochelle salt is added and the mixture is stirred for 30 minutes. The mixture was extracted with toluene and the organic layer was dried with magnesium sulfate, concentrated and evaporated to a dark oil, which was purified by chromatography on silica gel with a mixture of chloroform/methanol/water (60:30:4) to give the blocked compound in the form of oil (0.105 g). The oil was dissolved in 1,4-dioxane (4 ml) and 4N hydrochloric acid solution was added. The resulting mixture is stirred at room temperature for 18 hours. The solution is then neutralized with ammonium hydroxide and evaporated. The residue was purified by column chromatography on silica gel with a mixture of chloroform/methanol/water/ammonium hydroxide (60:30:2:2) to give the title compound as a dark yellow powder (26 mg).

1H NMR (DMSO-d6): � values include 1.35(d); 3.13(br m); 3.36(br m, overlapping H2O); 3.54 (no m); 4.98(d); 6.13 (number m); 6.36(d); 6.87(s); 7.02(dd); 6.27 (m); 7.42 (m); 7.62-7.50(m); 8.62(d).

C21H23ClN2O4S: MH+ 435.1148 (error about 0.3 ppm).

Example 4

7-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid

A suspension of the sodium salt of 7-amino-1-naphthalene sulfonic acid (0.554 g) and {2R-(tert-butoxycarbonyl)-[2R-tert-butyl-dimethyl-silanoxy)-2-(3-chloro-phenyl)-ethyl ]-amino}-propionaldehyde (0.500 g) in N,N-dimethylformamide (8.1 ml) was stirred for 10 minutes before sodium triacetoxy borohydride (0.479 g) was added. The mixture is stirred for 18 hours. A 15% aqueous solution of Rochelle's salt is added and the mixture is stirred for 1 hour. The mixture is then extracted with toluene. The organic layer is dried with magnesium sulfate, filtered and evaporated to obtain a dark oil which is purified by chromatography on silica gel with a mixture of chloroform/methanol/water (60:30:4) to obtain the blocked compound in the form of an oil (0.46 g). . The oil was dissolved in tetrahydrofuran (4 ml) and 6N hydrochloric acid solution was added. The resulting mixture is stirred at room temperature for 2 days. The solution is then neutralized with ammonium hydroxide and evaporated. The residue is purified by column chromatography on silica gel with a mixture of chloroform/methanol/water/ammonium hydroxide (60:30:2:2) to obtain the title compound as an oil. The sample is solidified with an ethanol/water mixture to obtain a dark yellow powder (63.9 mg).

HPLC: tr=17.54 min (t0=1.6 min).

C21H23ClN2O4S: MH+ 435.1163 (error about 1.8 ppm).

Example 5

5-{2-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-ethyl amino}-naphthalene-2-sulfonic acid

A solution of {2-(tert-butoxycarbonyl)-[2R-(tert-butyl-dimethyl-silanoxy)-2-(3-chloro-phenyl)-ethyl]-amino}-acetaldehyde (0.32 g) and 5- of amino-2-naphthalene sulfonic acid (0.335 g) in N,N-dimethylformamide (5.4 ml) was stirred for 10 minutes, before sodium triacetoxy borohydride (0.318 g) was added. The resulting mixture is stirred for 18 hours. A 15% aqueous solution of Rochelle's salt is added and the mixture is stirred for another 1 hour. The mixture is then extracted with toluene. The organic layer is dried with magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel with a mixture of chloroform/methanol/water (60:30:4) to obtain the blocked product (0.56 g), which was dissolved in tetrahydrofuran (5 ml). After the addition of 6N hydrochloric acid solution, the mixture was stirred at room temperature for 18 hours, before being evaporated. The residue was purified by column chromatography on silica gel with a mixture of chloroform/methanol/water/ammonium hydroxide (60:30:2:2) to give the title compound as a dark yellow powder (73.7 mg).

HPLC: tr=17.8 min (t0=1.8 min).

C20H21ClN2O4S: MH+ 421.0999 (error about 1.1 ppm).

Example 6

Methyl 5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethylamino}-naphthoate dihydrochloride

Methyl 5-[((2S)-2-(tert-butoxycarbonyl)-[(2R)-2-[tert-butyl (dimethyl)-silyl] oxy-2-(3-chloro-phenyl)-ethyl]- (aminopropyl)amino]-2-naphthoate (1.21 g) was introduced into a 4N solution of hydrochloric acid (9 ml). The mixture was stirred for 2 hours and diethyl ether (30 ml) was added. The resulting precipitate was collected by suction filtration and dried under vacuum to give the title compound (807 mg) as a light green powder.

1H NMR (DMSO-d6): � values include 1.51(d); 3.99(s); 5.02(dd); 6.88(d); 8.01(d); 8.20(d); 8.53(s).

Electrospray ms (positive ion) (M+H) 413.2.

Similarly, the following are obtained:

Example 7

Methyl 5-{2S-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino}-naphthoate dihydrochloride

Electrospray ms (negative ion) 413/415,

from methyl 5-[((2S)-2-(tert-butoxycarbonyl)-[(2R)-2-[tert-butyl (dimethyl)-silyl] oxy-2-(3-chloro-phenyl)-ethyl] -aminopropyl)amino]-2-naphthoate (580 mg).

Example 8

5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid

A solution of 5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino}-naphthalene-2-carboxylic acid methyl ester dihydrochloride (1.55 g) and lithium hydroxide monohydrate (852 mg) in 3 :1 methanol/water mixture (20 ml), stirred for 16 hours. The mixture is concentrated to obtain a residue which is purified using silica gel chromatography eluting with a mixture of chloroform/methanol/ammonium hydroxide to obtain, after concentration of the appropriate fractions, a yellow powder. Trituration with water and drying under vacuum afforded the title compound (946 mg) as a light yellow powder.

Found by testing: C 65.53; H 5.89; N 6.91.

C22H23N2O3ClŽ0.25H2O requirements: C 65.50; H 5.87; N 6.94%.

Electrospray ms (positive ion) (M+H) 399.3.

Similarly, we get:

Example 9

5-{2S-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid (114 mg)

Found by testing: C 66.48; H 5.96; N 6.79; Cl 8,72.

C22H23N2O3Cl required: C 66.24; H 5.81; N 7.02; Cl 8.89%.

Electrospray ms (negative ion) (M-H) 399/401,

from methyl 5-{2S-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino}-2-naphthoate dihydrochloride

Example 10

6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl] amino propyl) amino]-naphthalene-2-carboxylic acid

Solution methyl 6-[((2R)-2-(tert-butoxy carbonyl)[(2S)-2-[tert-butyl (dimethyl) silyl] oxy-2-(3-chloro phenyl) ethyl] amino propyl) amino ]-2-naphthoate (804 mg) in a 4N solution of hydrochloric acid in dioxane (7ml), was stirred for 5.5 hours under vacuum. The volatile components are then removed under vacuum leaving behind a gummy purple solid which is redissolved in dioxane/water (10 ml, 5:1). Lithium hydroxide monohydrate (378 mg) was then added and the pink solution was stirred for 16 hours. Volatile components are then removed under vacuum. Portions of methanol are distilled off under vacuum to remove water, and the orange gum that remains is chromatographed on silica gel eluting with a mixture of chloroform/methanol/ammonium hydroxide (80:15:2). Portions of ethanol are distilled under vacuum to obtain a colorless solid. The resulting material was triturated in water (5 ml) and dried under vacuum to give the title compound (141 mg) as a white powder.

Found by examination: C 65.18; H 5.99; N 6.85; Cl 8,67.

C22H23N2O3Cl•0.04 H2O•0.2 C2H6O required: C 65.81; H 5.99; N 6.85; Cl 8.67%.

mp: 206-207 °C (decomposes).

Similarly, we get:

Example 11

6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl]aminopropyl)amino]-naphthalene-1-carboxylic acid (98 mg)

Found by testing: C 64.41; H 6.00; N 6.58; Cl 8,66.

C22H23N2O3Cl•0.06 H2O•0.6 C2H6O requirements: C 64.41; H 6.00; N 6.79; Cl 8.60%.

m.p.: 224-226 °C (decomposes),

from methyl 6-[((2R)-2-(tert-butoxy carbonyl)[(2R)-2-[tert-butyl (dimethyl)silyl] oxy-2-(3-chloro phenyl) ethyl] amino propyl) amino ]-2-naphthoate (260 mg).

TABLETS FOR ORAL ADMINISTRATION

Tablets can be obtained using conventional processes, such as direct compression or wet granulation.

The tablets may be film coated with a suitable film forming material such as hydroxy propyl methyl cellulose using standard techniques. Alternatively, the tablets can be coated with sugar.

Directly pressed tablets

and)

[image]

* quality suitable for direct pressing. The active ingredient is sifted through a 60 mesh sieve, mixed with calcium biphosphate, croscarmellose sodium and magnesium stearate. The resulting mixture is pressed into tablets using a Manesty F3 tableting machine equipped with 5.5 mm punches with straight edges. ;ii) ;[image] ;The active ingredient is sifted through a 60-mesh sieve, mixed with lactose, pregelatinary starch and magnesium stearate. The resulting mixture is pressed into tablets using a Manesty F3 tabletting machine equipped with 7.5 mm normally concave punches. ;Syrup ;Sucrose may or may not be present in the syrup. ;AND. ;[image] ;The active ingredient, buffer, flavoring agent, coloring agent and preservative are dissolved in some water and glycerin is added. The remaining water is heated until the sucrose dissolves and then cooled. Both solutions are combined, adjusted to the desired volume and then mixed. The syrup is made clear by filtering. B. ;[image] ;Hydroxy propyl methyl cellulose is dispersed in warm water, cooled and then mixed with an aqueous solution containing the active ingredient and other components of the formulation. The resulting solution is adjusted to the desired volume and mixed. The syrup is made clear by filtering. ;Injection for intravenous use ;(i) ;[image] ;The active ingredient is dissolved in a suitable volume of injectable sodium chloride BP, the pH of the resulting solution is adjusted to pH = 3.5 with dilute hydrochloric acid BP, then the volume of the solution is adjusted with injectable sodium chloride BP and mix well. The solution is placed in transparent 5 ml Type I ampoules, which are sealed under air using glass fusion, and then sterilized by autoclaving at 120 °C for not less than 15 minutes. ;(ii) ;[image] ;Sodium chloride can be added to adjust the tonicity of the solution, and the pH can be adjusted using acid or alkali, to optimal stability and/or capacity of the active ingredient. Alternatively, suitable buffer salts can be used. The solution is prepared, clarified and introduced into ampoules of appropriate size, which are sealed with glass fusion. The injection is sterilized by heating in an autoclave using one of the acceptable cycles. Alternatively, the solution may be sterilized by filtration and introduced into sterilized ampoules under aseptic conditions. The solution may be packaged under an inert atmosphere of nitrogen or other suitable gas. ;Suppository for rectal use ;[image] ;* satisfactory quality Adeps Solidus Ph. Eur.

A suspension of the active ingredient in dissolved Witepsol is prepared and introduced using a suitable machine into 1 g suppository molds.

BIOLOGICAL RESULTS

Example compounds were tested for �-3-adrenoreceptor activity using the procedure described above with the following results:

[image]

Claims (16)

1. Compound of formula I: [image] indicated by what groups N(R3) and R4 are separated by at least 4 ring carbon atoms; R1 represents a phenyl, naphthyl, phenoxy methyl, thiazolyl, pyridyl or pyrimidyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-6 alkoxy, C1-6 alkyl, nitro, cyano, hydroxy methyl , trifluoro methyl, NR6R7 and NHSO2R6; R 2 represents hydrogen or C 1-6 alkyl; R 3 represents hydrogen or C 1-4 alkyl; R4 represents CO2R6 or SO3H; R 5 represents one or more groups each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, trifluoro methyl and C 1-6 alkoxy; n represents an integer from 1 to 6; R 6 and R 7 each independently represent hydrogen or C 1-4 alkyl; or its pharmaceutically acceptable derivatives. 2. Compound according to claim 1 of formula Ia: [image] indicated by what groups N(R3) and R4 are separated by at least 4 ring carbon atoms; R1 represents a phenyl, naphthyl, pyridyl or pyrimidyl group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-6 alkoxy, C1-6 alkyl, nitro, cyano, hydroxy methyl, trifluoro methyl, NR6R7 and NHSO 2 R 6 ; R 2 represents hydrogen or C 1-6 alkyl; R 3 represents hydrogen or C 1-4 alkyl; R4 represents CO2R6 or SO3H; R 5 represents one or more groups each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, trifluoro methyl and C 1-6 alkoxy; n represents an integer from 1 to 6; R 6 and R 7 each independently represent hydrogen or C 1-4 alkyl; or its pharmaceutically acceptable derivatives. 3. A compound according to claim 1 or 2, characterized in that R1 represents phenyl which is optionally substituted with 1 to 3 substituents selected from the group comprising halogen, hydroxy, C1-6 alkoxy, C1-6 alkyl, nitro, cyano, hydroxy methyl and trifluoro methyl. 4. A compound according to one of claims 1 to 3, characterized in that R1 represents a phenyl group substituted with a chlorine atom located in the meta position. 5. A compound according to one of claims 1 to 4, characterized in that R2 represents methyl or hydrogen. 6. A compound according to one of claims 1 to 5, characterized in that R3 represents hydrogen. 7. A compound according to one of claims 1 to 6, characterized in that R4 represents CO2H. 8. Compound according to claim 1 represented by formula Ib: [image] indicated by what R 2 represents hydrogen or methyl; R4 represents CO2H or SO3H; or its pharmaceutically acceptable derivatives. 9. A compound characterized by being selected from the group comprising the following compounds: 6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid; 5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid; 6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-1-sulfonic acid; 7-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-sulfonic acid; 5-{2-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-ethyl amino}-naphthalene-2-sulfonic acid; 5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid; 6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid; 6-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-1-carboxylic acid; 5-{2S-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino]-propyl amino}-naphthalene-2-carboxylic acid; Methyl 5-{2S-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino}-naphthoate; Methyl 5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethyl amino}-naphthoate; and their pharmaceutically acceptable derivatives. 10. The compound according to claim 1, characterized in that it refers to 5-{2R-[2-(3-chloro-phenyl)-2R-hydroxy-ethylamino]-propylamino}-naphthalene-2-carboxylic acid, and its pharmaceutical acceptable derivatives. 11. A compound according to one of claims 1 to 10, characterized in that it is used in therapy. 12. A method for treating mammals, including humans, suffering from a condition that is ameliorated by the use of an atypical adrenoceptor agonist, characterized in that it comprises the use of an effective amount of the compound according to any of claims 1 to 10 or a pharmaceutically acceptable derivative thereof. 13. A compound according to any one of claims 1 to 10 or its pharmaceutically acceptable derivative, characterized in that it is used for the production of a medication for the treatment of a condition that is amenable to the use of an atypical �-adrenoreceptor agonist. 14. Pharmaceutical preparation, characterized in that it comprises a compound according to one of claims 1 to 10 or its pharmaceutically acceptable derivative together with one or more pharmaceutically acceptable carriers. 15. A pharmaceutical preparation, characterized in that it comprises a compound according to one of claims 1 to 10 and a non-steroidal anti-inflammatory drug together with one or more pharmaceutically acceptable carriers. 16. A process for obtaining a compound according to claim 1 or its pharmaceutically acceptable derivative, characterized in that it comprises (A) reaction of the compound of formula II: [image] where P1 and P2 are suitable protecting groups for oxygen and nitrogen groups respectively, R4 is CO2R6 or SO3H and R6 is C1-6 alkyl, to remove protective P1 and P2 under suitable conditions; or (B) reaction of a compound of formula I to obtain another compound of formula (I); or (C) reaction of a compound of formula III with a compound of formula IV: [image] where P1 and P2 are suitable protecting groups for oxygen and nitrogen groups respectively, R4 is CO2R6 or SO3H and R6 is C1-6 alkyl followed by deprotection of the protecting groups, without purification of the intermediate product.