Water-soluble complex of inclusion compounds of benzothiophene with a water-soluble cyclodextrin, method thereof and pharmaceutical composition

 

(57) Abstract:

Describes a new water-soluble complex inclusion containing the compound of formula (I), where R1and R3each independently is hydrogen, C1-C4alkyl, -CO-(C1-C6alkyl) or-CO-AG, where AG is optionally substituted phenyl; R2selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino, or its salt and a water-soluble cyclodextrin in a concentration of 10-50% (weight/volume). Also describes pharmaceutical compositions such inclusion complexes and methods of use of these complexes for inhibition of bone shrinkage and reduction of serum cholesterol in mammals. 3 S. and 6 C.p. f-crystals.

The invention relates to the field of pharmaceutical and organic chemistry and relates to new inclusion complexes and pharmaceutical compositions based on them, which are used for treatment of certain medical conditions in mammals.

Benzothiophene formula I

< / BR>
where R1and R3each independently hydrogen, C1-C4alkyl, -CO-(C1-C6alkyl) or-CO-Ar in which Ar is optionally substituted phenyl; and

R2selected from the group consisting of p is N 4133814). These compounds are known as effective in various medical conditions in mammals, particularly humans, including, for example, postmenopausal osteoporosis, and high serum cholesterol (see, e.g., Draper et al., Effects of Rloxifene (LY 13948 HCl) on Biochemical Markers of Bone and Liped Metabolism in Healthy Postmenopausal Women, and Bryant, et al., Protection from Bone Loss and Lowering of Serum Cholesterol in the Absence of Uterine Stimulation in overiectomized Rats, Am. Soc. Bone and Min. Res., Tampa, 9/18 - 22/93).

The compounds of formula I, and, in particular, forms salts of acids of these compounds, including, for example, hydrochloride, sulfate, hydrobromide, citrate and the like, are usually poorly soluble in water at room temperature. Due to the poor solubility in water it is necessary to assign these compounds in suspension in water with the use of a suspending agent such as carboxymethyl cellulose (CMC), polyethylene glycol and the like. However, these pharmaceutical compositions may be used in many ways.

In particular, the compositions used for intravenous (IV) fluids must be in the form of solutions. BB introduction of the suspension is extremely dangerous, because the material particles in suspension may be stuck in the microcapillaries (microvasculature) lecapitaine for intranasal and aerosol injection of pharmaceutical agents because of such agents is required solubility in water for the passage of the upper and lower membranes of the respiratory tract. Low solubility in water forms these agents usually leads to low absorption of the medication and/or irritation of the respiratory tract.

In addition, it is desirable, though less sharply, to have water-soluble formulations acceptable for other routes of administration. For example, liquid compositions for oral administration are desirable because they are more homogeneous than other forms of pharmaceutical agents and, therefore, provide a greater dispersion and absorption in LC (GI) tract. Water soluble pharmaceutical agent also provides greater security and convenience for the patient and the treating physician.

Although previous attempts to solubilize the compounds of formula I for use in the pharmaceutical compositions were usually unsuccessful, the present invention relates to new water-soluble inclusion complexes, pharmaceutical compositions and methods of use of these complexes.

The present invention relates to water-soluble complex containing the compound of formula I, above, and water-soluble cyclodiathermy complex inclusions as described above, in combination with a pharmaceutically acceptable carrier, diluent or additive.

The present invention relates to a further method of inhibiting the shrinkage of the bone, and a method of lowering cholesterol levels in the blood, which consists in the introduction of an effective amount of the above inclusion complex to a mammal in need of such treatment.

One aspect of the present invention relates to water-soluble complex inclusion containing the compounds of formula I

< / BR>
where

R1and R3each independently hydrogen, C1-C4alkyl, -CO-(C1-C6alkyl) or-CO-Ar in which Ar is optionally substituted phenyl; and

R2selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; or its salt and a water-soluble cyclodextrin.

The compounds of formula I are well known in the art and can be obtained according to a known method, such as described in U.S. patent 4133814, 4418068 and 4380635, each of which is presented here for reference. Basically, the method proceeds from benzo[b]thiophene, 6-hydroxyl group and 2-(4-hydroxyphenyl). The original connection is protected, alkylated or allegiani presented in U.S. patents above.

The term "substituted phenyl" includes phenyl, substituted by one or two C1-C6the alkyl, C1-C4alkoxy, hydroxy, nitro, chlorine, fluorine or three(chlorine or fluorine)stands.

The term "alkyl" by itself or as part of another substituent means remotemachine or branched alkyl radical having the specified number of carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl and the like, and higher homologs and isomers.

The term "alkoxy" means an alkyl group having the specified number of carbon atoms linked by an oxygen atom such as, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like, and also includes branched chain structure, such as, for example, isopropoxy, isobutoxy.

The compounds used in the methods of the present invention form pharmaceutically acceptable salt accession of acids and bases with a wide range of different organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this izobreteny is native, iododecane, nitric, sulfuric, phosphoric, hypophosphorous and the like. Can also be used salts, derivatives of organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate acid and hydroxyalkanoate acids, aromatic acids, aliphatic and aromatic sulfonic acids. Thus, such pharmaceutically acceptable salts include the acetate, phenyl acetate, triptorelin, arylacetic, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, -hydroxybutyrate, butene-1,4-diet, hexyne-1,4-diet, capret, kaprilat, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymet, malonate, mandelate, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydratefast, dihydrophosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacina, succinate, suberinite, sulfate, bisulfate, persulfate, sulfite, bisulfite, sulfonate, bansilalpet, p-bromophenylacetate, chlorobenzenesulfonate, aconsultant, 2-hydroxyethane the expenses and the like. The preferred salt is the hydrochloric salt.

Pharmaceutically acceptable salt accession acid is usually formed by the interaction of the compounds of formula I with an equimolar or excess amount of acid. The reagents usually interact in a solvent such as diethyl ether or benzene. Salt is usually planted from the solution for about one hour to 10 days and can be separated by filtration or solvent can be separated by known methods.

The base is usually used for the formation of phenolic salts include ammonium hydroxide and a hydroxide of alkali or alkaline earth metal carbonates and aliphatic primary, secondary and tertiary amines and aliphatic diamines. Grounds, especially those used to obtain the addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, Ethylenediamine and cyclohexylamine.

According to the present invention, a preferred compound of formula I is one in which each of R1and R3denotes hydrogen and R2- piperidino. Usually it is preferable to form hydrochloric salt of this compound, which is known for the th product of the present invention, which in the presence of another source of product, water-soluble cyclodextrin to form water-soluble inclusion complexes of the present invention.

Cyclodextrins are cyclic molecules containing six or more D-glucopyranose units attached at the 1,4 - positions in public relations, as in the amylase. Due to the cyclic structure of the molecule is characterized as not having any hi end group or non terminal group. Therefore, I believe that there is free rotation around glikozidnykh relations and cyclodextrins exist in the form of a cone-shaped molecules with primary hydroxyl, located at the small end of the cone, and a secondary hydroxyl, located at the big exit cone. The Central cavity formed by the conformation of the cyclic - D-glucopyranose units, surrounded by hydrogen atoms and oxygen atoms of obtaining relatively lipophilic cavity, but the outer surface is hydrophilic. Cyclodextrins, therefore, have the ability to form complexes with some organic and inorganic molecules.

A large number of cyclodextrins and their floor is haunted cyclodextrins. Other derivatives include cyclodextrins with cationic properties [Parmeter (II) U.S. patent N 3453257], insoluble Poperechnaya cyclodextrins (Solms, U.S. patent N 3420788) and cyclodextrins with anionic properties [Parmeter (III) U.S. patent N 3426011]. In addition to the cyclodextrin derivatives with anionic properties related to the cyclodextrins should be added carboxylic acid, phosphorous acid, phosphinic acid, phosphonic acid, phosphoric acid, tiofosfornoy acid thiosulfinate acid and sulfonic acid [see Parmeter (III), supra]. Moreover, derivatives sulfoalkyl ether cyclodextrin described Stella, et al. (U.S. patent N 5134127).

Though it is a large variety of cyclodextrins is described in the above patents and it is known that cyclodextrins can be used in the manufacture of pharmaceutical agents for some drug delivering systems, specialists also well known that cyclodextrins will not help in the preparation of such systems with all pharmaceutical agents.

Thus, the use of cyclodextrins of the present invention is limited to water-soluble cyclodextrins, which form aqueous solutions by the addition of water. Vestnik ways. Of the water-soluble cyclodextrin is preferable to use hydroxyalkyl -- cyclodextrins (see for example, U.S. patent 4727064) and, in particular, hydroxypropyl -- cyclodextrin, for the preparation of inclusion complexes of the present invention.

Typically the water-soluble inclusion complexes of the present invention is prepared by adding water to the desired aqueous solution, synthesized or commercially available (see, for example, Jansen Chimica, Geel, Belgium; Sigma Chemical Company, St.Louis, MO; Aldrich Chemical Company, Inc., Milwaukee, WI: Pharmtec, Alachuo, FL; And Lancaster Syntheses, Inc., Windham, NH) cyclodextrin. Sufficient amount of water, preferably deionized water, is added so that the final concentration of cyclodextrin ranged from about 10 to about 50% (m/V), preferably from about 15 to 25% (weight/volume). The concentration of cyclodextrin of about 5% (weight/volume) or less undesirable. A mixture of water and cyclodextrin is stirred until the solution becomes transparent, and thus prepare a water cyclodextrines solution.

Then to the above described transparent aqueous solution of the water and cyclodextrin add the compound of the formula I and is usually treated with ultrasound for a short PE is Uchenie in the present invention. The concentration of the desired compounds of formula I in the final inclusion complex is about 0.1 to about 20 mg/ml, preferably from about 5 to about 15 mg/ml

Obtaining water-soluble complex incorporating the present invention is usually carried out at room temperature.

the pH of these inclusion complexes is slightly acidic to neutral (from about 5.0 to around 7.0). Usually the pH is not required to install before obtaining pharmaceutical compositions.

In addition, the present invention also relates to pharmaceutical compositions containing the water-soluble inclusion complex in combination with a pharmaceutically acceptable carrier, diluent or additive. Such pharmaceutical compositions produced by the method well known in the art, and are either individually, or in combination with other therapeutic agents, preferably parenterally. Especially preferred route is intravenous. Other preferred routes of administration include oral, intranasal and inhalation.

In the manufacture of compositions according to the present invention the active ingredients, which include at least one water-soluble complexvalued as a diluent, it should be liquid material, which acts as a solvent, carrier or medium for the active ingredient.

Some examples of suitable additives include water or syrup, and the formulations can additionally include wetting agents, protecting agents, such as methyl - and propyl-hydroxy-benzoate, incremental, sweetening agents and flavouring agents.

The compositions are preferably in unit dosage forms, each dosage typically contains from about 1 to about 100 ml, more usually from about 20 to about 60 ml of the active ingredient in aqueous solution. The term "unit dosage form" refers to physically discrete units, acceptable as single doses to humans and other mammals, each unit containing a certain quantity of active material calculated in order to achieve the desired therapeutic effect in combination with a pharmaceutical acceptable additive.

The specific dose of water-soluble complex incorporating the present invention, required for curing the above medical conditions, will depend on the extent of the disease or condition, the way it widenet about 0.1 to about 1000 mg, more usually, from about 50 to about 600 mg, These doses will be administered to a mammal in need of such treatment one to three times a day.

The following examples of compounds are only illustrative and are not given with the intention to limit the scope of the present invention in any way.

Composition 1.

Intravenous composition can be prepared in the following way:

100 ml of 20% cyclodextrine solution containing

100 mg/ml of the compounds of formula I;

and q.s. to 1000 ml isotonic.

Part 2.

Aerosol solution can be prepared containing the following components:

10 ml of 20% cyclodextrine solution containing

100 mg of the compounds of formula I;

25% ethanol;

70% of propellant 22 (Chlorodifluoromethane).

Part 3.

The composition for oral administration can be prepared containing the following components:

20 ml of 20% cyclodextrine solution containing

200 mg of the compounds of formula I.

Due to the fact that previous attempts to solubilisate sufficiently the compounds of formula I have been mostly unsuccessful, we unexpectedly found that the compounds of formula I could obrazovyvat the next question we found that oral administration to monkeys soluble complex incorporating the present invention leads to a more than 15-fold increase in overall levels of blood plasma of the compounds of formula I, especially Raloxifene (Raloxifene), compared with the introduction of equal doses prepared in the form of a granular composition.

Water-soluble inclusion complexes of the present invention is effective in the treatment of postmenopausal osteoporosis. Thus, the present invention further relates to a method of inhibiting the shrinkage of the bone, which is to assign to a mammal, in particular women in the postmenopausal state, if necessary, of such treatment, an effective amount of water-soluble complex incorporating the present invention.

Water-soluble inclusion complexes of the present invention is also effective in the treatment of high cholesterol in serum. The present invention also relates to a method of lowering cholesterol levels in the serum, which is to assign to a mammal, particularly a human, in need of treatment, an effective amount of water-soluble complex inclusion on this image is with the intention to limit the scope of the present invention any of the following example.

Example 1. Receiving raloxifene-hydroxypropyl -- cyclodextrine complex inclusions.

20% (weight/volume) solution of hydroxypropyl -- cyclodextrin, prepared by adding 500 ml of deionized water to 100 g of hydroxypropyl -- cyclodextrin. The mixture is stirred until the formation of a transparent solution. To a 50 ml aliquot of the above solution was added 500 mg of raloxifene and the resulting solution was placed in sonicator for 3 minutes. The resulting inclusion complex is transparent, yellow aqueous solution.

1. Water-soluble complex inclusion containing compound of the formula I

< / BR>
where R1and R3each independently is hydrogen, C1- C4alkyl, -CO-(C1- C6alkyl) or-CO-Ar in which Ar is optionally substituted phenyl;

R2selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino,

or its salt and a water-soluble cyclodextrin at a concentration of 10 - 50% (weight/volume).

2. Complex inclusion under item 1, wherein R2the compounds of the formula I denotes piperidino, R1and R3each is hydrogen, and its specified cleaners containing hydrochloride salt is salt.

3. Complex inclusion under item 2, from the ptx2">

4. Complex inclusion under item 3, characterized in that the concentration of the compounds of formula I is from about 0.1 to about 20 mg/ml, and the concentration of the specified hydroxypropyl--cyclodextrin is from about 10 to about 30% (weight/volume).

5. Complex inclusion under item 4, characterized in that the concentration of the compounds of formula I is from about 5 to about 10 mg/ml, and the concentration of the specified hydroxypropyl--cyclodextrin is from about 15 to 25% (weight/volume).

6. The inclusion complex according to any one of paragraphs.1 to 5 for use as an agent that inhibits the drying of the bones.

7. The inclusion complex according to any one of paragraphs.1 to 5 for use as an agent for lowering the cholesterol level in the serum.

8. Pharmaceutical composition, characterized in that it contains as active ingredient the inclusion complex according to any one of paragraphs.1 to 5 in combination with one or more pharmaceutically acceptable carrier, additive or diluent, provided that the total amount of the compounds of formula I in the composition is 0.1 - 1000,0 mg.

9. The way to obtain the inclusion complex according to any one of paragraphs.1 to 5, characterized in that added to water appropriate amount of water-soluble O its transparency and add to the mixture a suitable amount of compounds of formula I

< / BR>
where R1and R3each independently represents hydrogen, C1- C4- alkyl, -CO-(C1- C6alkyl) or-CO-Ar in which Ar is optionally substituted phenyl;

R2selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino,

provided that the final concentration of the compounds of formula I is 0.1 - 20.0 mg/ml or its salts.

 

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< / BR>
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