Biologically active ethanamine of benzothiazolone

 

(57) Abstract:

The invention relates to a new derived benzothiazolone formulas I and II, where X denotes naphthyl and its pharmaceutically acceptable salts. The method of obtaining the compounds of formula I includes a selective reduction of the compounds of formula II. The compounds of formula I can be used for getting medicines for the treatment of respiratory diseases such as asthma and chronic bronchitis. The technical result - getting a new derived benzothiazolone. 3 s and 5 C.p. f-crystals, 1 PL.

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The invention relates to new ethanaminium of benzothiazolone, methods for their preparation and the pharmaceutical compositions and methods of treatment using them. New connections are shown for use as agonists dopamine-DA2-and receptor agonists2-adrenergic receptors.

Derivatives benzothiazolone known in the art. For example, in applications for international patent publications numbers W0 92/08708 and W0 93/23385 reveal biologically active amines and among them biologically active aminoacyl derivatives benzothiazolone, which are agonists2-adrenergic receptors and the diseases of the respiratory tract.

Publication number W0 93/24473 discloses 7-(2-amino-ethyl)-benzothiazolinone the compounds of formula:

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where X and Y represent independently from each other, - S(O)nor-O-; n takes on the values 0, 1 or 2; p, q and r are independently of each value of 2 or 3; Z is a phenyl, optionally substituted with halogen, OR1, NO2or NR2R3; or Z represents a five - or six-membered heterocycle containing N, O or S; and R1, R2and R3represent independently from each other hydrogen or C1-6alkyl. The compounds are agonists2-adrenergic receptors and agonists dopamine-DA2-receptor and can be used to treat reversible obstructive diseases of the respiratory tract.

Found a new group of ethanamine of benzothiazolone may be used as agonists2-adrenergic receptors and agonists dopamine-DA2-receptor.

The present invention is the creation of new compounds of formula I,

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where X denotes a naphthyl, optionally substituted by alkyl or halogen;

p, q and r independently of one another represent 2 or 3; and their physiologically acceptable salts.

Sceptor and K2-adrenergic receptors. However, they do not show or show a small agonism to1-adrenergic receptors. These compounds have a high duration of action and coefficient DA2/2.

In the above formula I preferably p is 3; q is preferably equal to 2; g is preferably equal to 2.

X preferably represents an unsubstituted naphthyl.

When X represents an alkyl-substituted naphthyl, a Deputy may be selected from C1-6the alkyl linear or branched chain, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentila straight or branched chain or hexyl straight or branched chain. Preferred halogen substituents are F, Cl and Br. When the alkyl substituent is chiral, can be formed optical isomers, and all of them are also included in the scope of the present invention. In the scope of the invention also includes compounds of formula I in tautomeric form.

Pharmaceutically acceptable salts of compounds of formula I include additive salts of inorganic and organic acids, such as hydrochloride, hydrobromide, sulfates, phosphates, maleate, t is ursuleti, naphthalenesulfonate, methanesulfonate, sulfamate, ascorbates, salicylates, acetates, diphenylacetate, trimeniaceae, adipate, fumarate, succinate, lactates, glutarate, gluconate, hydroxyethylmethacrylate, for example 1-hydroxy or 3-hydroxy-2-naphthaleneacetic or oleates. Compounds can also form salts with suitable bases. The compounds of formula I can be obtained in the form of salts, which represents a pharmaceutically acceptable salt. When this is desirable, such salts can be converted into the free base using conventional methods. Pharmaceutically acceptable salts can be obtained by the reaction of compounds of formula I with an appropriate acid or base in the presence of a suitable solvent.

The present invention also relates to a method for producing compounds of formula I, comprising a selective reduction of the compounds of formula II,

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in which p, q, g and X are defined above.

Suitable reducing agents include electrophilic reducing agents such as DIBORANE and Alan (aluminum hydride), or nucleophilic reducing agents, for example a complex metal hydride, such as sodium bis(2-methoxyethoxy) aluminerie. Preferred aprotic solvents such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. The reaction may be conducted at a temperature of from about 0oC to about 100oC, preferably at the boiling point under reflux.

The compounds of formula II can be obtained through the interaction of the amine of formula III:

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with the appropriate acid of the formula IV

HOOC-(CH2)p-1-SO2-(CH2)d-O-(CH2)r-X IV

or with the appropriate acid chloride using traditional methods. For example, the interaction may be carried out in the presence of dicyclohexylcarbodiimide using the method of Sheehan and Hess (Sheehan and Hess, J. Am.Chem.Soc., 1955, 77, 1067), or in the presence of 1,1'-carbonyldiimidazole as described Stabm (Staab, Angew. Chem. Int. Ed. Engl., 1962, 1, 351), or in the presence of hexaflurophosphate postreproductive in solvent type DMF. Acid necessary for the above-mentioned process may be obtained from the corresponding esters by hydrolysis in aqueous methanol in the presence of lithium hydroxide. The acid chlorides can be obtained from acids, for example, through reaction with oxalylamino or thionyl chloride in toluene at a temperature is obtained by the known methods for example, using a method described in literature (J. Med.Chem., 1987, 30, 1116).

The compounds of formula IV can be obtained, as described in the above examples, and methods used for this easily reproducible by any technician with a medium level of knowledge in this area and can be adapted for a list of compounds of the formula IV.

In the above methods may be necessary to protect certain functional groups, for example hydroxy - or amino-groups present in the original compounds. Suitable protecting groups and methods for their removal are described, for example, in the following activities ("Protective Groups in Organic Synthesis" by T. W. Green and P. G. M. Wuts, John Wiley and Sons Inc., 1991).

Hydroxy-group can be, for example, protected with allotropic groups, such as phenylmethyl, diphenylmethyl or triphenylmethyl or such as derivatives tetrahydropyranyl. Suitable protective groups for amino groups include arylmethyl groups such as benzyl, (R,S)--phenylethyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or TRIFLUOROACETYL. For removal of the protective groups can be used traditional methods. For example, arylmethylidene palladium on charcoal. Tetrahydropyranyl groups can be cleaved by hydrolysis under acidic conditions. Acyl groups can be removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, or grouping, such as trichloroacetyl, you can delete the recovery, for example, zinc and acetic acid.

Intermediate compounds of formula II are new compounds and are also included in the scope of the present invention.

The compounds of formula I and their salts are agonists dopamine-DA2-receptor. Linking the ability of the tested compounds against the binding site of the receptor DA2on the membranes of bovine pituitary gland can be determined by studying the substitution of [3H]-N-n-propylnorapomorphine and [3H] -spiperone, respectively in the absence and in the presence of neytralinogo analogue of GTP (D. R. Sibley, A. DeLean and I. Creese, Anterior Pituitary Dopamine Receptors, Demonstration of Interconvertible High and Low Affinity States of the D-2 Dopamine Receptor, J. Biol.Chem., 1982, 257(11), 6351-6361). The activity of DA2the receptor can also be demonstrated in functional screening test on an isolated ear artery of the rabbit, as described by brown and O'connor (Brown and O'connor, Br. J. Pharmacol., 1981, 73, 189P). Join vlauterbach Guinea pigs, as described by Dougallm, Harper, Jackson and Leff (I. G. Dougall, D. Harper, D. M. Jackson and P. Leff, Br.J.Pharmacol., 1991, 104, 1057).

Activity1the receptor can be analyzed using isolated ear artery of the rabbit under the test described in the examples.

The duration can be investigated using the method of Coleman and co-authors (Coleman et al., in "Novel and versatile superfusion system: its use in the evaluation of some spasmogenic and spasmolytic agents using guinea-pig isolated tracheal smooth muscle". Journal of Pharmacological Methods 21, 71-86 (1989)).

The compounds of formula I and their salts can be used in the treatment of a wide range of respiratory diseases, including conditions such as asthma, including bronchial asthma, allergic asthma, endogenous asthma (e.g. late asthma and hypersensitivity of the respiratory tract), as well as bronchitis and others (see, for example, UK Patent N 2022078 and Br. J. Pharmacol., 1987, 24, 4983).

The compounds of formula I and their salts are also used in the treatment of glaucoma and various other conditions, such as inflammatory and allergic skin diseases, and cancer, such as small-cell lung cancer, and congestive heart failure.

In the context of the present invention the term "treatment" clucosamine is the creation of compounds of the formula I, their pharmaceutically acceptable salts, used in therapy.

In addition, the invention relates to the use of compounds of the formula I or their pharmaceutically acceptable salts for obtaining medicines used in the treatment of respiratory diseases, in particular, in the treatment of asthma or chronic bronchitis.

Another objective of the present invention is a method of treatment of respiratory diseases, this method includes the introduction of a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt to a patient suffering from such condition or are sensitive to it.

Another objective of the present invention is to provide a method for treatment or prevention of glaucoma, this method includes the introduction of a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt to a patient suffering from such condition or tend to him.

To solve the aforementioned problems of injected dose will, of course, vary depending on the method of administration and the treatment. However, in General, satisfactory results can be obtained with the introduction of the connection tradeline this dose is 1-4 servings per day, or in the form of slow release. For a person's total daily dose ranges from about 70 mg to 1400 mg, and standard forms suitable for injection include from 20 mg to 1400 mg of the compound in a mixture with a solid or liquid pharmaceutical diluent or carrier.

The compound of the formula I can be used by itself or in the form of appropriate pharmaceutical compositions for local, enteral or parenteral administration.

For example, ingaliruyet device with a measured dose can be used for introducing connections, dispersible in a suitable propellant in the presence or in the absence of fillers, such as ethanol, surfactants, lubricating and stabilizing agents.

Suitable propellants include hydrocarbons, harperperennial and hydrofluroalkane propellants or mixtures of any of such propellants. Especially preferred propellants are P134a and P227, each of which can be used by itself or in combination with other propellants and/or surfactants and/or other fillers, for example, in combination with each other.

Can also be sprayed aqueous suspension or, p is the only dosage forms.

Dry powder inhalers can be used for introducing connections, single or in combination with pharmaceutically acceptable carrier, while in the latter case is either finely ground powder, or an ordered mixture. A dry powder inhaler may be a single dose or mnogochasovym and may use dry powder or capsules containing the powder.

Inhaler with measured dose dispenser and ingaliruyet device for spraying a dry powder is well known in the art, and many such devices is available.

Tablets and gelatin capsules, which may be optionally coated, containing the active substance may include one or more ingredients selected from diluents, carriers, binders, lubricants, stabilizers and other commonly used ingredients.

Injectable solutions of the active ingredient may also contain, for example, one or more ingredients selected from preservatives, stabilizers, means regulating the viscosity, emulsifying agents, buffers and other commonly used ingredients.

The present invention relates also to pharmaceutical is rmula I or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable diluent or carrier.

The present invention is illustrated without in any way limiting its scope to the following examples in which all temperatures are in degrees Celsius.

Example 1

4-hydroxy-7-[2-[3-[2-[2-(1- naphthalenyl)ethoxy]ethylsulfanyl]propylamino]ethyl]-1,3-benzothiazol-2(3H)-she hydrochloride

a) 1-[2-(adenylate)ethyl]naphthalene

A mixture of freshly etilenovogo ether (60 ml), 2-(1-naphthalenyl)ethanol (8,61 g) and acetate mercury (0.4 g) is heated at boiling temperature under reflux for 20 hours. Volatile material is removed under vacuum (water pump) and the residue is distilled in Kugeler (Kugelrohr) to give the compound indicated in the title, in the form of oil (8,15 g), which was contaminated with a small amount of 2-(1-naphthalenyl)ethanol.

So Kip. 160-170oC at 0.04 mm Hg;

Mass spectrum: gc/ms 198 (M), 155 (100).

b) Methyl 3-[2-[2-(1-naphthalenyl)ethoxy]ethylthio]propanoate

The product obtained in stage a), (8,15 g), methyl 3-mercaptopropanol (a 4.86 g) and 2,2'-azobis(2-methylpropionitrile) (0.2 g) is heated at a temperature of 50oC for 1 hour, after this time TLC indicates that some amount of starting material still remains in the mixture. In the mixture contribute more to the Crude reaction mixture was purified using flash chromatography (petrol:diethyl ether 5:1 as eluent) to give the compounds specified in the header, in the form of oil (11,07 g).

Mass spectrum: gc/ms 318 (M), 154 (100);

1H NMR (360 MHz, CDCl3) : 2,61 (2H, T.), of 2.72 (2H, T.), of 2.81 (2H, etc), to 3.38 (2H, etc), to 3.64 (2H, etc), 3,70 (3H, s), 3,80 (2H, etc), 7,40 (2H, m), and 7.5 (2H, m), 7,73 (1H, d), a 7.85 (1H, d), of 8.06 (1H, d).

C) Methyl 3-[2-[2-(1-naphthalenyl)ethoxy]ethylsulfanyl]propanoate

A solution of OXONETM(18,4 g) in water (70 ml) is added dropwise at 10oC to a solution of the product obtained at stage b) (3,18 g) in methanol (70 ml). The suspension is stirred at room temperature for 5 hours. The reaction mixture was diluted with water (200 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic extracts washed with water and a solution of sodium sulfite, and then dried to obtain the connection specified in the header (3,39 g), which is used in the next stage without further purification.

Mass spectrum: gc/ms 350 (M), 154 (100);

1H NMR (360 MHz, CDCl3) 2,70 (2H, etc), 3,06 (2H, etc), 3,17 (2H, etc), 3,26 (2H, etc ), 3,71 (3H, s), 3,85 (4H, m), 7,40 (2H, m), and 7.5 (2H, m), 7,73 (1H, d), a 7.85 (1H, d), of 8.06 (1H, d).

g) 3-[2-[2-(1-naphthalenyl)ethoxy]ethylsulfanyl]propanoic acid

The solution of the monohydrate of lithium hydroxide (2,02 g) in water (30 ml) are added to a suspension of the product obtained at stage b) (3,35 g) in methanol (40 ml). The mixture of the PE the IDF spent. A large part of the methanol is removed under vacuum and the residue diluted with water (100 ml). The basic solution was washed with ether. The aqueous layer is acidified with hydrochloric acid and extracted with ether. The ether is washed with water, brine, then dried (MgSO4) and remove the solvent under vacuum to obtain the compound indicated in the title (is 3.08 g). It then purified using flash chromatography (chloroform:acetic acid 9:1 as eluent) to obtain the compound indicated in the heading, after trituration with hexane as a white solid (0,687 g).

So pl. 105-108oC;

Mass spectrum: gc/ms 336 (M),141 (100);

1H NMR (360 MHz, CDCl3) : 2,73(2H, etc), 3,15-up 3.22 (4H, m), 3.33 and-3,37 (2H, etc ), 3,79-3,86 (4H, m), 7,33-rate of 7.54 (4H, m), 7,72 (1H, d), to 7.84 (1H, d), of 8.00 (1H, d).

Data analysis: found: C - 60,90; H - 6,34; S - 9,48%

Calculated data: 60,70; H - 5,99; S - AT 9.53%

d) N-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl] -3-[2-[2-(1-naphthalenyl)ethoxy]ethylsulfanyl]propanamide

The product obtained in stage g) (0.625 g), dissolved in dimethylformamide (10 ml) under nitrogen atmosphere. To this stirred solution was added 1,1'-carbonyldiimidazole (0,301 g) and the mixture is stirred for 2 hours at room temperature. Nam (0,259 ml). The mixture is stirred overnight, after which the volatile products are removed under vacuum. The residue is transferred into ethyl acetate and washed with diluted hydrochloric acid and then brine. The organic layer is dried (MgSO4) and remove the solvent under vacuum to obtain the connection specified in the header (1,30 g), in the form of oil, which is then used without further purification.

Mass spectrum FAB 529 (M+H).

e) 4-hydroxy-7-[2-[3-[2-[2-(1-naphthalenyl)ethoxy] ethylsulfanyl] propylamino]ethyl]-1,3-benzothiazol-2(3H)-she hydrochloride

Borane-tertrahydrofuran ring solution (1.0 M in THF to 8.6 ml) is added dropwise to a stirred solution of the product obtained in stage d) (1,30 g) in dry tetrahydrofuran (100 ml). The reaction mixture is heated at the boiling point under reflux in an inert atmosphere for 1 hour. HPLC treatment phase using acetonitrile and 0.1% triperoxonane acid as eluent shows the presence of a large amount of starting material, and therefore contribute an additional amount of borane (8.6 ml) and then heated the mixture at the boiling point under reflux for 1 hour. The reaction mixture is cooled and carefully add metabasic concentrated hydrochloric acid (beats. the density of 1.18; 0.75 ml). This solution is heated at the boiling point under reflux for 20 minutes and then remove the solvent under vacuum. The residue was subjected to purification by using preparative HPLC with a treatment phase using acetonitrile and 0.1% triperoxonane acid as eluent. Eventually, after receiving cleaners containing hydrochloride salt and recrystallization from ethanol obtain the target product as a white powder (0,38 g).

So pl. 174-176oC;

Mass spectrum: FAB 515(M+H);

1H NMR (360 MHz, D6-DMSO) : 2,00-of 2.08 (2H, m), 2,86 - only 2.91 (2H, m), 2,96 (2H, m),3,06 (2H, m) and 3.15 (2H, etc), to 3.33 (2H, etc), 3,38 is 3.40 (2H, m ), 3,76-3,82 (4H, m ), to 6.80 (1H, d), 6.89 in (1H, d), 7,42-7,58 (4H, m), 7,80 (1H, d), a 7.92 (1H, d), of 8.09 (1H, D), which 9.22 (2H, sh.C.), and 10.20 (1H, s ), 11,82 (1H, s).

Data analysis:

found: 56,16; H is 5.98; N - 5,40; S - 11,77; Cl - 6,00; H2ON - 1,20%

designed for 0,28 mol of water:

With - 56,16; H - of 5.89; N - 5,04; S - To 11.52; Cl - 6,39; H2O - 0,91%

The activity of DA2-receptor has been demonstrated in functional screening test on an isolated ear artery of the rabbit, as described by brown and O'connor (Brown and O'connor, Br.J.Pharmacol., 1981, 73, 189R) (see table 1).

Activity2-adrenergic receptors was demonstrated on isolated trachea of the Guinea pig, CT>Activity1the receptor was analyzed by means of a screening test using an isolated ear artery of the rabbit, as described below (see table 1).

Isolated ear artery of the rabbit

Rabbits male NZW (2.5 to 3.0 kg) killed by intravenous injection pentobarbitone sodium (60 mg/kg). Remove the ears, cut out the proximal part of the artery in the middle ear and kanyoro it using polypropylene cannula (outer diameter 0.75 mm). After removal of artery cleaned of residues of connective tissue and cook 6 rings width of 5 mm, containing part of the vascular smooth muscle. Tissue is placed on a thin hooks made of tungsten wire (0.25 mm in diameter) in the bath for bodies with a volume of 20 ml containing Krebs solution of the following composition (mm): NaCl - 117,56; NaHCO3- 25,00; KCl And 5.36; NaH2PO4- 0,89; MgSO4- 1,18; glucose - 11,10 and CaCl2is 2.55. In the Krebs solution is injected cocaine (30 μm) and propranolol (1 μm) to block the absorption of neurons and receptors, respectively. Add ascorbate (100 μm) to prevent oxidation of the catecholamine. This solution support at a temperature of 37oC and continuously bubbled through him, a mixture of 95% O2and 5% CO2. Top Provolone stationary substrate in the bath. Changes in isometric load recorded on flat recorder Advance Bryans AB500.

Experiment

General description of the experiment

At the beginning of each experiment, each tissue sample is subjected to the action of the load in 1.0, This load is restored two or three times during the stabilization period of about 60 minutes, until, until it becomes constant. At that time, as there is a stabilization load, bath wash. Curves the concentration of agonist-effect (E/[A]) construct the cumulative addition of agonist increments of 0.5 Log10. Reaction (reduction) is recorded as a percentage of the maximum response to the standard agonist.

Quantitative expression of agonism

As standard agonist phenylephrine was used. First build the curve E/[A] to phenylephrine. Then phenylephrine washed and build a curve E/[a] for the tested compounds. Answers to compounds that cause agonism, expressed as a percentage of the maximum response to phenylephrine. The value of the asymptote to the curve of the tested compounds, related to the corresponding value on the curve for phenylephrine, shows the specific activity of these compounds (Specifices the East. It represents the negative logarithm of the concentration of agonist that causes a response equal to half of the maximum response. For compounds with specific activity is significantly below 1, for example, of 0.8, it is possible to calculate the efficiency ( ) and the value of the affinity (pKAusing the comparative analysis method. This analysis assumes that phenylephrine acts in this system as a full agonist, and thus uses it to define the parameters of the operating model Emand n (ref. Leff et al., "Estimation of agonist affinity and efficacy by direct and operational model fitting", J. Pharmacol. Methods. , 1989, 23, 225-237). These parameters can then be used for comparative analysis of the tested compounds. Affinity is expressed as pKA(the negative logarithm of the concentration of the agonist, which involved half of the receptors).

Quantitative expression of antagonism

Compounds that do not exhibit agonism, were tested as antagonists by incubating tissue in such a high concentration of the compound, to the extent possible, with the subsequent construction of curves E/[A] to phenylephrine. Degree offset to the right of these curves to phenylephrine in CPA the evaluation of the affinity shown as the values of pA2(the negative logarithm of the concentration of antagonist that causes a 2-fold shift to the right from the reference curve E/[A]).

Confirmation1-mediated agonism

As a standard antagonist1was used prazosin. If the tested compound showed agonism when the level of the asymptotes on the curve E/[a] for the tested compounds were added prazosin (1 μm) in order to determine if the response is reversible. If1antagonist leads to a reversion of the response of the tested compounds, it confirms that agonism in this case is 1-mediated.

1. Derived benzothiazolone formula I

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where X denotes naphthyl,

and its pharmaceutically acceptable salts.

2. Derived under item 1, characterized in that it is a salt, such as hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2 - or 4-hydroxybenzoate, 4-chlorobenzoate, bansilalpet, p-toluensulfonate, naphthalenesulfonate, methanesulfonate, sulpham, ascorbate, salicylate, acetate, diphenylacetate, trimeniaceae, adipate, fumarate, succinate, lactate, glutarate, gluconate, 1-hydroxy-2-on is characterized in that it is a salt, such as hydrochloride.

4. Derivative of the formula I on p. 1, characterized in that it is suitable for the production of medicines for the treatment of respiratory diseases.

5. Derivative of the formula I on p. 4, wherein the respiratory disease is asthma.

6. Derivative of the formula I on p. 4, wherein the respiratory disease is chronic bronchitis.

7. The method of obtaining the derived benzothiazolone formula I, comprising a selective reduction of the compounds of formula II

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in which X is defined in paragraph 1.

8. Derived benzothiazolone formula II

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where X is defined in paragraph 1.

 

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