Crystalline hemihydrate 4-(5,6,7,8-tetrahydroimidazo [1, 5-a]pyridine-5-yl)-benzonitrile-hydrochloride

 

(57) Abstract:

Usage: in medicine, in the treatment of certain cancers. The inventive product: crystalline hemihydrate 4-(5, 6, 7, 8-tetrahydroimidazo [1,5-a]pyridin-5-yl) benzonitrile-hydrochloride, f-crystals 1. CF. C14H13N3HCl1/2 H2O. Reagent 1: 4-(5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile. Reagent 2: hydrogen chloride. Reaction conditions at 0-70oC. connection Structure of f-crystals 1:

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3 table.

The present invention relates to the class of bicyclic nitrogen-containing heterocyclic compounds. More specifically, it relates to new crystalline hemihydrate 4-(5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyridin-5-yl)-benzonitrile-hydrochloride of formula (1)

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which, having valuable biological active properties, can find application in medicine, in particular in the treatment of certain cancers.

The anhydrous form of this connection is called "5-(n-cianfrani)-5, 6, 7, 8 tetrahydroimidazo[1,5-a]pyridine hydrochloride (method thereof are described in European patent application N 165904, showing his ability to exert inhibitory effect on the enzyme aromatase is go, the crystals of the anhydrous form of anhydrate can exist in at least two different crystalline modifications. One of them, hereafter referred to as "agitator", characterized by the following interplanar lattice distances (d values) and the relative intensities of the lines x-rays:

The value of d in angstroms Intensity

9,5 very high

6,5 very weak

6,6 very high

of 5.89 average

5,10 high

4,87 average

4,75 weak

br4.61 high

4,30 very weak

4,19 very high

4,01 average

3,79 average

3,61 average

to 3.58 average

3,47 very high

3,37 very weak

3,30 very high

3,23 very weak

3,03 very weak

About the measurement technique we can say the following (the same is true equally for all below is a powder x-ray): to determine the interplanar spacings of the lattice (d values) recorded on film diffraction picture; survey carried out in transmitted light using a camera Genie (Enraf-Nonius FR 552), the emission of copper K1 (wavelength 154060 angstroms); for calibration use taken on the same film chart quartz; otenet, hereinafter b-ageratum, characterized by the following x-ray:

The value of d in angstroms Intensity

12,1 very high

7,3 weak

6,6 very high

6,0 very high

5,93 very weak

of 5.83 high

br4.61 high

4,53 average

4,46 high

or 4.31 average

4,13 high

4,03 average

3,99 weak

3,94 average

3,66 weak

3,51 very high

3,48 high

3,40 high

3,34 high

3,28 average

3,21 high

3,11 average

3,01 weak

2,97 average

Crystals as a-and b-anhydrate have a serious disadvantage they are hygroscopic, i.e. depending on the ambient humidity absorb different amounts of moisture. Even in relatively dry air, for example, with a relative humidity of 33 or 44% they adsorb water (see table. 1 and 2).

The hygroscopic crystals anhydrate 4-(5,6,7,8-tetrahydroimidazo-[1,5-a] pyridin-5-yl)-benzonitrile-hydrochlo - reed negatively affects its stability during storage, which complicates the manufacture of pharmaceutical preparations, in particular forms intended for oral administration, for example tablets. Besides, this is about pharmaceutical drugs, in particular solid form as constantly having to reckon with the possibility of transition to partial or complete one modification to another or to take measures to prevent such a transition. Various crystalline modifications can have different properties, e.g. ability to grinding, the ability to be subjected to pelletizing or solubility.

The aim of the invention was the creation of a new crystalline form of 4-(5,6,7,8-tetrahydroimidazo[1,5-a] pyridin-5-yl)-benzonitrile-hydrochloride, which would not have these shortcomings and would remain stable in storage for many years.

This goal was achieved new crystalline form of 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)-benzonitrile-hydrochloride in the form of a hemihydrate of formula I.

It was found that neither the fluctuation of relative humidity in the range from about 10 to about 75% or under heating for 8 Nam at 35 or 50oC does not occur in any noticeable changes radiographs or water content in the crystals of the hemihydrate of the formula I (see tab. 3).

From table. 3 shows that the crystals of the hemihydrate of formula I in accordance with the invention is stable under can not changing, stored for many years. In particular, they do not absorb water, i.e., the content of active substance in them during storage remains constant, and not constantly decreasing, as is the case known from the prior art of anhydrate (when comparing two samples have the same weight). This, in particular, is essential, given the extraordinarily high activity of the compounds and consequently low dosage when used for treatment of humans, which is located within only one or a few milligrams (see below).

Crystals of the hemihydrate of formula I are characterized by the following interplanar lattice distances (d values) and the relative intensities of the lines x-rays:

The value of d in angstroms Intensity

13,4 very high

9,5 average

8,2 weak

7,5 high

6,7 very weak

6,5 very high

5,65 very high

5,42 high

5,34 very high

5,15 average

4,99 average

4,84 high

4,60 high

4,51 high

4,20 high

4.09 to average

4,00 high

3,83 high

3,81 average

3,76 weak

3,74 average

3,66 average

3,62 in the high

3,21 weak

3,19 weak

3,15 average

3,13 very weak

3.04 from high

3,01 weak

Crystals of the hemihydrate of the formula I, in addition, are characterized by elemental analysis data are in accordance with those calculated for the gross formula C14H13N3HCl1/2H2O (MB: 268,75) values, namely: C 62,57% H 5,63% N 15,64% Cl 13,19%

Preferably the invention relates to crystals of the hemihydrate of formula I in substantially pure form.

Crystals of the hemihydrate of formula I get in a known manner by, for example, h

(a) interaction of 4-(5,6,7,8-tetrahydroimidazo[1,5-a] pyridin-5-yl)-benzonitrile with hydrogen chloride in the presence of water, or

(b) processing one of the forms of 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)-benzonitrile-hydrochloride containing less water than the resulting hemihydrate of formula I, water, or

(c) removing water from the form of 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)-benzonitrile-hydrochloride containing more water than the resulting hemihydrate of formula I, or

(d) a translation other than the hydrochloride salt of 4-(5,6,7,8-tetrahydroimidazo[15-a] pyridine-5-yl)-benzonitrile in the presence of water in the hydrochloride hemihydrate of formula I.

Preferably the free base was transferred to the hydrochloride hemihydrate of formula I by reacting it with an aqueous solution of hydrogen chloride. The concentration of the aqueous hydrogen chloride is not significant. However, in order to reduce losses to a minimum, it is desirable to use concentrated hydrochloric acid, in particular, 37% hydrochloric acid.

The reaction is carried out at a temperature of, for example 0-70oC, preferably at 20-55oC, most preferably at room temperature.

Method (b)

Processing preferably solid forms of 4-(5,6,7,8-tetrahydroimidazo[1,5-a] pyridin-5-yl)-benzonitrile-hydrochlo - reed, containing less water than the hemihydrate of formula I in accordance with the invention, which can be used, for example, the above-anhydrate formula Ia, carry water in the usual way, using at least necessary for the formation of hemihydrate quantity. It is desirable that the water was in a liquid or gaseous state.

When processing water in the liquid state containing less dissolved in water or in aqueous solvent mixtures and then allocate the crystals formed hemihydrate of formula I in the usual way. In that case, if the processing is subjected to solution, you need the usual manner to effect crystallization of the hemihydrate of the formula I, for example, by evaporation of the solution, i.e., partial evaporation of the solution; adding a miscible with water solvent, in which the hemihydrate of formula I is dissolved worse than in water, or by lowering the temperature. In a preferred variant implementation of the crystallization of the hemihydrate of formula I cause or accelerate by introducing into the solution embryonic crystal.

In the case of processing water in gaseous source material is exposed to atmosphere containing water vapor, for example, moist air. Necessary to carry out the transformation of the duration of exposure decreases with increasing relative humidity. At room temperature the relative humidity should preferably be approximately 50-70%

The allocation of the resulting product is carried out in the usual manner, for example by centrifugation, filtration or filtration under pressure ("suction"). The dried product is preferably carried out at 20-30oC. Most preferably dried in vacuum at 20oC.

Method (c)

As ichogo form, which are solid or liquid, such as wet crystals, aqueous suspensions, aqueous solutions, suspensions in aqueous mixtures of solvents or solutions in aqueous mixtures of solvents.

Removal of excess water is carried out by, for example, drying, preferably at 20-30oC, most preferably in vacuum at 30oC.

In the case of use as source material solutions or suspensions, the crystals of the hemihydrate of the formula I before drying preferably is separated, for example, as indicated in the description of the method (b), by crystallization and/or centrifugation, filtration or pressure filtration. It is possible, however, a solution, a suspension, and was evaporated in vacuum, for example, at 20-30oC.

Method (d)

As a non-hydrochloride salt, it is preferable to use a pharmaceutically acceptable salt.

Method (d) is known. According to this method, other than the hydrochloride salt is dissolved in an aqueous solvent or solvent mixture and mix the resulting solution with an excess of chloride ions or preferably with hydrogen chloride. Preferably the solvent should be chosen in such a way, lorida original salt get for example, by reacting the free base of 4-(5,6,7,8-tetrahydroimidazo[1,5-a] pyridin-5-yl)-benzonitrile with the appropriate acid.

The following specific examples illustrate the invention but do not limit its scope. Temperatures are given in degrees Celsius.

Example 1

Hemihydrate 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)-benzonitrile-hydrochloride.

To 200 l of stirred acetone added at 20-25oC 33 kg of 4-(5,6,7,8-tetrahydroimidazo[1,5-a] pyridin-5-yl)benzonitrile. After complete dissolution of the free base to the solution is added to 1.56 liters of water and a suspension of 1.8 kg of activated carbon in 6 l of acetone. After stirring for 45 min at 20-25oC the whole mass is filtered and the residue on the filter is washed 136 l of acetone. To the United filters added gradually under stirring at 20-25oC 12.5 l of 37% hydrochloric acid to achieve a pH of 2.5 to 1.0. The resulting suspension was stirred at 20-25oC for a further 3 hours, centrifuged and the residue is washed several times with acetone at the General expense of its 80 HP After vacuum drying at 20oC obtain the target compound in the form of white crystalline powder.

Radiograph: interplanar is supplemented flax), 2225 (strong) cm-1< / BR>
Elemental analysis calculated for the formula C14H13N3HCl1/2 H2O (MB 268,75)

Calculated: C 62,57% H 5,63% N 15,64% Cl 13,19%

Found: C 62,53% H 5,57% N 15,66% Cl 13,21%

The water content (analysis Fisher)

Calculated: 3,35%1)< / BR>
Found: 3.43% of

1)Calculated water content (based on the molecular weight of the hemihydrate of formula (1) is not contrary are given in table. 3 value, which refers to the dry weight equal to the molecular weight, anhydrate.

Used as source material receive free base is described in European patent A-165904 way, namely by cyclization of 5-(3-chlorpropyl)-1-(p-cianfanelli-1H-imidazole when interacting with tert.-the piperonyl potassium in the environment of tetrahydrofuran (see example 1 in the patent).

Example 2

Hemihydrate 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)-benzonitrile-hydrochloride

To a stirred mixture of 1.5 l of water and 4.4 l of acetone add 5,3 kg of 4-(5,6,7,8-tetrahydroimidazo[1,5-a] pyridin-5-yl)-benzonitrile-hydrochloride (or anhydrite). The mixture is heated at 50-55oC and stirred to obtain a clear solution. Then the solution is cooled to 30oC is after the beginning of crystallization, the mixture is cooled for 45 min to 0oC, add to it at 0-5oC for 1 h 35 l of acetone and the suspension is stirred at 0-5oC for another 2 h, centrifuged and the crystalline residue was washed with 8 liters of acetone. After drying in a vacuum get the target connection.

Radiograph: the interplanar distances of the lattice and intensity are the same as above, values.

IR (nujol): 3430 (strong), 3375 (strong), 2225 (strong) cm-1< / BR>
Elemental analysis calculated for the formula C14H13N3HCl1/2 H2O (MB 268,75).

Calculated: C 62,57% X 5,63% N 15,64% Cl 13,19%

Found: C 62,63% H 5,58% N 15,64% Cl 13,19%

The water content (analysis Fisher):

Calculated: 3,35%

Found: of 3.46%

Used as the starting material a-anhydrate get described in European patent A-1659014 way, namely, by dissolving the free base in a small amount of acetone and neutralize the solution with ethereal solution of hydrogen chloride (see example 1 in the patent).

On the basis of obtained according to the above examples hemihydrate I prepare pharmaceutical products that are affordable and of high activity for use in medical practice.

Such preparations contain the active substance alone or preferably in combination with one or more pharmaceutically acceptable carriers. The dosage of the active substance depends on the type of disease, but also subject to the treatment of the subject, its age, weight and individual condition and, in addition, the method of use of the drug.

We offer pharmaceutical preparations contain from about 0.1 to about 40% of the active substance and form of an individual dose preferably contains from about 0.1 to about 20, and forms, is not composed of individual doses of from about 0.1 to about 10% of the active substance. Form of unit doses, such as pills, tablets or capsules containing from about 0.1 to about 20, preferably from about 1 to about 4 mg of active substance.

Pharmaceutical preparations in accordance with the invention receives a known manner, for example, by conventional mixing, granulating, drazhirovanija, dissolution or lyophilization. So, for example, pharmaceutical compositions for oral administration can be obtained by mixing the active substance with one or more solid carriers, granulating when atelinae supplements in tablets or pills.

Suitable carriers are in particular fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose materials and/or calcium phosphate, for example tricalcium phosphate or calcium phosphate, and binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, oksipropilmetiltselljuloza, carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, fillers such as the above-mentioned starches, and also carboxymethylate starches, crosslinked polyvinylpyrrolidone, alginic acid or its salts, for example sodium alginate.

As auxiliary additives are used primarily means regulating the fluidity and lubricants, for example silicic acid, talc, stearic acid or its salts, such as magnesium stearate or potassium, and/or polyethylene glycol or its derivatives.

The basis of pills may be coated with suitable, in particular, stand in relation to gastric juice, shell, for the manufacture of which can, for example, to use concentrated sugar solutions which may contain gum Arabic, talc, polyvinyle esah solvents, or (for shells, which are resistant to gastric juice) solutions of suitable cellulose preparations, such as cellulose acetate phthalate or phthalate of oksipropilmetiltselljulozy. Shell pills or tablets may also be provided by the addition of dye or pigment, for example, to identify or indicate different doses of active substance.

As pharmaceutical compositions for oral administration can also be used a compound gelatine capsules and soft one-piece capsules made of gelatine and a softener, such as glycerol or sorbitol. Composite capsules can contain the active substance in the form of a granulate, for example, in a mixture with fillers, such as corn starch, binders and/or substances, which impart lubricity, such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules the active substance is preferably in the form of solution or suspension in a suitable liquid auxiliary materials, such as fatty oils, paraffin oil or liquid polyethylene glycols, and they can also contain additives stabilizers.

Pharmaceutical preparations for rectal application can be, for example, Sisowath, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

Needlejuice examples are given to illustrate the obtained some compositions and tablets from them.

Example 1

Get 10,000 tablets each weighing 100 mg each with a content of active substance in the tablet 2 mg

The composition of

Hemihydrate 4-(5,6,7,8-tetrahydroimidazo-[1,5-a]pyridin-5-yl)-benzonitrile-hydrochl - oride - 20,70 g

Colloidal silicon dioxide 2,00 g

Microcrystalline cellulose 100,00 g

Lactose, dried in the spray dryer 817,30 g

Magnesium stearate 10,00 g

Sodium carboxymethylcellulose 50,00 g

Just 1000,00 g

All main components of the tablet is stirred to obtain a homogeneous mixture, which is then pressed into tablets.

Example II

Get 10,000 tablets each weighing 100 mg each with a content of active substance in the tablet 1 mg

The composition of

Hemihydrate 4-(5,6,7,8-tetrahydroimidazo-[1,5-a]pyridin-5-yl)-benzonitrile-hydrochl - orig - 10,35 g

Crystalline lactose 739,65 g

Microcrystalline cellulose 230,00 g

Colloidal silicon dioxide 10,00 g

Magnesium stearate 10,00 g

Just Wat tablets.

Crystalline hemihydrate 4-(5,6,7,8-tetrahydroimidazo [1,5-a] pyridin-5-yl)-benzonitrile-hydrochloride of the formula I

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characterized by the following interplanar lattice distances (d values) and the relative intensities of the lines x-ray powder obtained in the camera hinge, when the radiation of copper K1):

The interplanar distances (d) in angstroms, Relative intensity

13,4 very high

9,5 average

8,2 weak

7,5 high

6,7 very weak

6,5 very high

5,65 very high

5,42 high

5,34 very high

5,15 average

4,99 average

4,84 high

4,60 high

4,51 high

4,20 high

4.09 to average

4,00 high

3,83 high

3,81 average

3,76 weak

3,74 average

3,66 average

3,62 high

3,56 average

3,51 average

3,40 very weak

3,35 average

3,29 very weak

3,25 high

3,21 weak

3,19 weak

3,15 average

3,13 very weak

3.04 from high

3,01 Kabal

 

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3 ex

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