Crystalline morphinan derivatives and synthesis method thereof

FIELD: chemistry.

SUBSTANCE: present invention relates to 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride having sustained quality of production and high purity. Crystalline forms of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride are proposed, including A-forms, B-forms or C-forms, and method of producing said forms.

EFFECT: obtaining compounds which have analgesic, diuretic and antipruritic effect.

10 cl, 8 dwg, 2 tbl, 8 ex

 

The technical field

The present invention relates to the crystalline hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan, which has analgesic, diuretic and anti-itching effect and is useful as an active ingredient analgesic, diuretic and antipruritic agents, and to the method of obtaining these funds.

The level of technology

Hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan, represented by the following formula (I):

described in patent document 1. It is shown that this compound is useful as an active ingredient analgesic, diuretic and antipruritic agents.

Patent document 1 describes in detail the connection and its physicochemical properties.

[Patent document 1]: Japan Patent No. 2525552 (Example 68).

During an intensive study of the physical properties of compounds represented by the above formula (I), the inventors have found that while the compound (I)obtained in Example 68 in patent document 1, is amorphous, as shown in figure 4, the compound (I)obtained in a manner different from the above-mentioned method, has a crystalline polymorphism that is present in the form of ristalliceski A-, B - or C-forms, as described below.

In General, the connection, which is characterized by a crystalline polymorphism, sometimes has physical properties that are different for each crystal. Especially in the medical field, as you know, there are differences in terms of solubility, dissolution rate, stability, absorption, etc. Thus, it is possible that even using the same connection does not provide desirable activity or leads to activity than predicted due to differences in crystalline form, which cause unforeseen circumstances. For this reason, there is a need for the preparation of compounds of constant quality, which, as you might expect, will always be a constant activity.

Thus, when a compound having a crystalline polymorphism, used as a medicine, it is necessary to obtain a connection with a homogeneous crystalline form, to ensure consistent quality and constant activity.

The presence of a crystalline form of the compound represented by the above formula (I), previously was not known, and patent document 1 also describes and does not imply the presence of a crystalline form or crystalline polymorphism.

Accordingly, the inventors compared the or amorphous form of compound (I), obtained according to Example 68 in patent document 1, the crystalline compound (I)obtained by the method different from the above method. As a result, found that, while the amorphous compound is not constantly the quality upon receipt and has low purity, crystalline form has no such problems and is excellent as an active ingredient of medicines or as a preparation for the analysis of drugs.

Detailed description of the invention

The present invention includes the following objects:

(1) Crystalline hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

(2) Crystalline compound described in paragraph (1)with high-intensity diffraction peaks in 2θ values of approximately 12,0°, approximately 18,9° and approximately 19,2° on the x-ray powder diffraction pattern.

(3) Crystalline compound described in paragraph (1)with high-intensity diffraction peaks in 2θ values of approximately 7,6°, approximately 15,9° and approximately 18.5° in the x-ray powder diffraction pattern.

(4) Crystalline compound described in paragraph (1)with high-intensity diffraction peaks in 2θ values of approximately 7,2°, approximately 17.2° C and approximately 21.2° on the x-ray is Raskovoy the diffraction pattern.

(5) a method of obtaining a crystalline compounds described in paragraph (1) or (2), including interaction 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid in a strong solvent, followed by mixing the reaction solution with a weak solvent and stirring the mixture.

(6) the Method described in paragraph (5), in which a strong solvent is methanol, and the weak solvent is 2-propanol.

(7) a method of obtaining a crystalline compounds described in paragraph (1) or (3), including interaction 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid in water, followed by settling of the reaction solution.

(8) a method of obtaining a crystalline compounds described in paragraph (1) or (3), including interaction 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid in water followed by the addition of ethanol to the reaction solution and distillation of part of the solvent under reduced pressure before defending or stirring of the residue.

(9) a method of obtaining a crystalline compounds described in any of the PP(1)-(4), including the recrystallization of the hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-e is the hydroxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan in the solvent, selected from the group consisting of a mixture of methanol/2-propanol, a mixture of ethanol/water, water and ethanol.

(10) a method of obtaining a crystalline compounds described in any of the PP(1)-(4), including recrystallization from methanol/2-propanol hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan obtained by the interaction of the 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid.

(11) a method of obtaining a crystalline compounds described in paragraph (1) or (3), including recrystallization from a mixture of ethanol/water or water hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan obtained by the interaction of the 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid.

(12) a method of obtaining a crystalline compounds described in paragraph (1) or (4), including recrystallization from ethanol hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan, obtained by the reaction of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid.

Crystalline compound of the present invention optimally in the quality medicines which, as planned, will have a constant value of pH of the product upon receipt and will have a constant quality. Crystalline compound also has an extremely low content of the CIS isomer as the main impurities and high purity.

The best way of carrying out the invention

The present invention provides crystalline compound represented by the formula (1) above.

Crystalline compound of the present invention can be obtained by any of the methods described below.

The first way

17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan (hereinafter, in some cases, called "free derivative morphinane"), subject to interaction with hydrochloric acid in a strong solvent, followed by mixing the reaction solution with a weak solvent, and stirred the mixture.

The strong examples of the solvent include methanol, ethanol and n-propanol; preferably applied methanol. Examples of weak solvent include 2-propanol, 2-butanol and tert-butanol; preferably using 2-propanol.

The number of strong solvent used in the reaction with hydrochloric acid is typically 2-100 ml, preferably 8-12 ml, per 1 g of the free derived morphinane.

Hydrochloric acid usually is used at a concentration of 0.1-12 N., preferably 1-2 N. the Amount of hydrochloric acid is usually from 0.9 to 1.5 equivalent, preferably 1.0 to 1.1 equivalent.

The volume ratio of strong solvent to a poor solvent is usually 1-3:5, preferably 1.5 to 2.5:5.

After mixing with a weak solvent, and stirring the mixture preferably add the seed crystal. Examples of the seed crystal used here include A crystal form or crystal C-shape.

After adding the seed crystal (seed crystal) the mixture is typically stirred for 1-30 days, preferably 1-5 days. Mixing is performed at 0 to 30°C.

The processing performed using methanol as a strong solvent and 2-propanol as a weak solvent at the above conditions to obtain A crystalline form of the compound represented by formula (I), i.e. crystalline compounds having a high-intensity diffraction peaks in 2θ values at approximately 12,0°, approximately 18,9° and approximately 19,2° on the x-ray powder diffraction pattern.

The second way

Free derived morphinan subjected to interaction with the hydrochloric acid in water, followed by settling of the reaction solution.

The amount of water used as a solvent, is typically 2-100 ml, preferably 6-8 ml in races is n 1 g free derived morphinane.

Hydrochloric acid is usually used in a concentration of 0.1-12 N., preferably 1-2 N. the Amount of hydrochloric acid is usually from 0.9 to 1.5 equivalent, preferably from 0.95-1.05 equivalent.

After adding hydrochloric acid may be optionally added to the seed crystal (seed crystal). Examples of the seed crystal used here include the crystal B-form in Example 4.

After adding hydrochloric acid and optional seed mixture usually leave for 1-10 days, preferably 1-4 days.

The processing performed by the above-mentioned conditions obtaining crystalline B-forms of the compounds represented by the above formula (I), i.e. crystalline compounds having a high-intensity diffraction peaks in 2θ values of approximately 7,6°, approximately 15,9° and approximately 18.5° in the x-ray powder diffraction pattern.

The third way

Free derived morphinan subjected to interaction with the hydrochloric acid in water followed by the addition of ethanol to the reaction solution and distillation of part of the solvent under reduced pressure to defend or stirring of the residue.

The amount of water used as a solvent, is usually 1-100 ml, preferably 2-4 ml, per 1 g of the free derived morphinane.

Hydrochloric acid is usually used is the concentration of 0.1-12 N., preferably 1 to N. the Amount of hydrochloric acid is usually from 0.9 to 1.5 equivalent, preferably from 0.95-1.05 equivalent.

The volume ratio of water/ethanol typically 0.5-2:1, preferably 0.75 to 1.25 times:1.

After adding the ethanol portion of the solvent is distilled off under reduced pressure; the degree of concentration is usually 2 to 10 times, preferably 3-5 times.

The residue is usually left for 1-30 days, preferably 1-10 days.

The processing performed by the above-mentioned conditions obtaining crystalline B-forms of the compounds represented by the above formula (I), i.e. crystalline compounds having a high-intensity diffraction peaks in 2θ values of approximately 7,6°, approximately 15,9° and approximately 18.5° in the x-ray powder diffraction pattern.

The fourth way

Hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan recrystallized from a solvent selected from the group consisting of a mixture of methanol/2-propanol, ethanol/water, water and ethanol.

The method of obtaining hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan used in the fourth method is not specifically limited; examples include a method which involves interaction derived free morphinane with Sol is Noah acid.

The volume ratio of methanol to 2-propanol in the mixture of methanol/2-propanol used as the solvent recrystallization is usually 1-3:5, preferably 1.5 to 2.5:5. The volume ratio of ethanol to water in the mixture of ethanol/water is used as solvent recrystallization is usually 0.5-2:1, preferably 0.75 to 1.25 times:1.

The amount of solvent recrystallization is usually 10-100 ml, preferably 30-40 ml, per 1 g of the hydrochloride.

The use of methanol/2-propanol as solvent recrystallization gives the above-mentioned crystalline A-form; the use of a mixture ethanol/water or water gives crystalline B-form.

The use of ethanol as solvent recrystallization also leads to the crystalline C-form of the compounds represented by the above formula (I), that is, crystalline compound with a high-intensity diffraction peaks in 2θ values of approximately 7,2°, approximately 17.2° C and approximately 21.2° on the x-ray powder diffraction pattern.

The resulting crystals can be isolated by washing and drying in the usual way.

Crystalline A-form, B-form and C-form of the present invention have essentially the same powder x-ray diffraction pattern as those shown in figures 1, 2 and 3 respectively the state, and essentially the same IR spectra as those shown in figure 5, 6 and 7, respectively.

These spectral data should not strictly be interpreted as subject to change due to their origin. For example, due to the origin of the spectrum data of powder x-ray diffraction the diffraction angle 2θ and the complete diffraction pattern is important in defining the identity of the crystals; the relative intensity can vary somewhat depending on the direction of crystal growth, size of the crystalline particles and the measurement conditions. In addition, the full range of important in defining the identity of the crystals according to infrared absorption spectrum; the spectrum can vary somewhat depending on the measurement conditions. Thus, the crystalline compound of the present invention includes such a crystalline compound, which has a spectrum that is fully similar to the spectrum data of powder x-ray diffraction or infrared absorption spectrum of the crystalline compounds of the present invention.

Brief description of drawings

Figure 1 shows the x-ray powder diffraction pattern of crystalline A-form of the hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

Figure 2 presents the powder p is nenovsky the diffraction pattern of the crystal In the form of hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

3 shows the x-ray powder diffraction pattern of crystalline S-form of the hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

4 shows x-ray powder diffraction pattern of amorphous powder hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan disclosed in patent document 1.

Figure 5 presents infrared absorption spectrum of crystalline A-form of the hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

Figure 6 presents the spectrum of infrared absorption In crystalline form of the hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

Figure 7 presents infrared absorption spectrum of crystalline A-form of the hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

On Fig presents infrared absorption spectrum of amorphous powder hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

This description includes part or all of the contents disclosed in the description and/or drawings of Japanese patent application No. 2005-110096, which is the priority document for the present application.

Examples

The present invention is more specifically described below based on Examples. However, the invention should not be limited by these Examples.

Comparative example 1

Amorphous powder of the compound (I)

2,02 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 20 ml of ethanol, then added to 4.2 ml of 1 N. hydrochloric acid, the mixture was concentrated and dried to obtain 2,34 g of an amorphous powder of the connection.

Range of infrared absorption of this compound is shown in Fig. X-ray powder diffraction pattern of this powder is shown in figure 4.

Comparative example 2

Amorphous powder of the compound (I)

3.00 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 30 ml of ethanol, then added to 6.25 ml of 1 N. hydrochloric acid, the mixture was concentrated and dried to obtain of 3.45 g of an amorphous powder compounds. The infrared absorption spectrum of this compound was consistent with the spectrum of the compound obtained in Comparative example 1.

Comparative example 3

Amorphous powder of the compound (I)

2,01 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 20 ml of ethanol, then added to 4.2 ml of 1 N. hydrochloric acid, with whom ect was concentrated and dried to obtain 2,31 g of an amorphous powder compounds. The infrared absorption spectrum of this compound was consistent with the spectrum of the compound obtained in Comparative example 1.

Example 1

Crystalline A-form of compound (I)

2,00 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 20 ml of methanol was then added to 4.4 ml of 1 N. hydrochloric acid and filtered. The filtrate was added to 50 ml of 2-propanol with stirring. As a seed crystal was added to the crystals of C-shape in Example 7 or A-form for Example 2 or 3, was stirred for 5 days, then was filtered and dried crystals at room temperature. This has resulted in 1,82 g of crystalline A-form specified in the title compound.

Range of infrared absorption of this compound is shown in figure 5. Powder diffractogram of this compound are shown in figure 1.

Example 2

Crystalline A-form of compound (I)

20,65 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 200 ml of methanol was then added and 22.6 ml of 2 N. hydrochloric acid and filtered. The filtrate was added to 500 ml of 2-propanol with stirring. As a seed crystal was added to the crystals of C-shape in Example 7 or A-shape as in Example 1 or 3, was stirred overnight, then was filtered and dried crystals when it is matney temperature. This has resulted in 16,66 g of crystalline A-form specified in the title compounds. This compound had a powder x-ray diffraction pattern and infrared spectrum of absorption, consistent with the data of this compound, obtained in Example 1.

Example 3

Crystalline A-form of compound (I)

2,00 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 20 ml of methanol was then added to 4.4 ml of 1 N. hydrochloric acid and filtered. The filtrate was added to 50 ml of 2-propanol with stirring. As a seed crystal was added to the crystals of C-shape in Example 7 or A-shape according to Example 1 or 2 was stirred overnight, then was filtered and dried crystals at room temperature. This has resulted in to 1.21 g of crystalline A-form specified in the title compound.

Range of infrared absorption of this compound is consistent with the spectrum obtained for compound Example 1.

Example 4

Crystal B-form of compound (I)

of 10.01 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 79 ml of water was then added to 20.8 ml of 1 N. hydrochloric acid. The mixture was left in the dark for 4 days; the resulting crystal was filtered and dried under reduced pressure at room is based temperature and 40°C. This has resulted in 6,87 g of crystalline B-form of the connection.

Range of infrared absorption of this compound is shown in Fig.6. X-ray powder diffractogram of this compound are shown in figure 2.

Example 5

Crystal B-form of compound (I)

2,01 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 14 ml of water was then added to 4.2 ml of 1 N. hydrochloric acid. As a seed crystal was added to the crystals In the form of case 4 or 6 and the mixture was left in the dark for 3 days; the resulting crystal was filtered and dried under reduced pressure at room temperature and 40°C. were obtained and 0.61 g of crystalline B-form specified in the title compounds. This compound had an infrared absorption spectrum that is consistent with the spectrum of the compound obtained in Example 4.

Example 6

Crystal B-form of compound (I)

2,01 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 5.8 ml of water was then added to 4.2 ml of 1 N. hydrochloric acid. To the resulting solution was added 10 ml of ethanol and concentrated under reduced pressure until the weight of the solution was not to 6.3, the Concentrate was left in the refrigerator for 8 days; the resulting crystal is then filtered and dried under reduced pressure at room temperature. This has resulted in a rate of 1.67 g of crystalline B-form specified in the title compounds. This compound had a powder x-ray diffraction pattern and infrared absorption spectrum consistent with those of the compound obtained in Example 4.

Example 7

Crystalline C-form of compound (I)

2,02 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 100 ml of ethanol, then added to 4.2 ml of 1 N. hydrochloric acid. The resulting solution was concentrated under reduced pressure and dried to a solid state. Was added 200 ml of ethanol and the solid was dissolved by heating to 40-50°C and then concentrated solution under reduced pressure up until the weight was not 17,31 g after concentration. The concentrate was left in the dark for 12 days; the resulting crystals were filtered and dried at room temperature. This has resulted in 1.92 g of crystalline C-shape specified in the title compound.

Range of infrared absorption of this compound is shown in Fig.7. X-ray powder diffraction pattern of this compound is shown in figure 3.

Example 8

Crystalline C-form of compound (I)

2,00 g 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan suspended in 100 ml of ethanol, then added to 4.2 ml of 1 N. hydrochloric acid. The resulting solution was concentrated under reduced pressure and dried to a solid state. Was added 200 ml of ethanol and the solid was dissolved by heating to 40-50°C and then concentrated solution under reduced pressure up until the weight was not 17,31 g after concentration. As a seed crystal was added to the crystals To form in Example 7, and the concentrate was left in the dark for 4 days; the resulting crystals were filtered and dried at room temperature. This has resulted in 1,77 g of crystalline C-shape specified in the title compounds. This compound had an infrared absorption spectrum consistent with those for compound obtained in Example 7.

Test Example 1

The amorphous powder obtained in Comparative Example 3, and the crystals obtained in Examples 2, 5 and 8, were tested for purity using high-performance liquid chromatography (HPLC). Column: YMC-Pack ODS-AM-303.

The mobile phase: solution A: 50 mmol/l aqueous solution of nutregisterdevice, solution B: 50 mmol/l aqueous solution of nutregisterdevice / acetonitrile = 60/40 (by volume).

The composition of the solution B, mobile phase: from 0 to 30 min: 0 → 50%, from 30 to 75 min: 50 → 100%, from 75 to 90 min: 100%, from 90 to 120 min: 0%.

Volumetric flow rate: 1 ml/min column Temperature: 40°C. UV: 210 n is.

As shown in Table 1, the crystalline hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan of the present invention has high purity due to the extremely low content of the CIS isomer 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-CIS-3-(3-furyl)acrylamide]morphinan as the main impurities contained in the connection.

Table 1
The content of the CIS isomer of the connection.
ConnectionThe content of the CIS isomer
Free form0,12%
Hydrochloride (amorphous powder obtained in Comparative example 3)0,13%
Hydrochloride (crystalline A-form obtained in Example 2)0,05%
Hydrochloride (crystalline form obtained in Example 5)0,03%
Hydrochloride (crystal form obtained in Example 8)0,09%

Test Example 2

Take 100 mg of each of the amorphous powders obtained in Comparative The Examples 1-3 and crystals A-form, obtained in Examples 1-3, add 10 ml decarbonising water for dissolution and measure the pH. The results are shown in Table 2.

Table 2
ConnectionpH
Amorphous
powder
Comparative example 13,7
Comparative example 2the 4.7
Comparative example 33,5
Crystal
A-form
Example 15,8
Example 2of 5.4
Example 35,6

While amorphous powder hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan had no reproducibility in the pH value after receipt, A crystalline form of the present invention had a constant value of pH, which is very useful for achieving a stable quality.

All publications, patents and patent applications, about aerovane in this application, intended for inclusion in the review here by reference in their entirety.

Industrial application

The present invention is used in medicine.

1. The crystalline hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan.

2. Crystalline compound according to claim 1, having a high intensity diffraction peaks in 2θ values of approximately 12,0°, approximately 18,9° and approximately 19,2° on the x-ray powder diffraction pattern.

3. Crystalline compound according to claim 1, having a high intensity diffraction peaks in 2θ values of approximately 7,6°, approximately 15,9° and approximately 18.5° in the x-ray powder diffraction pattern.

4. Crystalline compound according to claim 1, having a high intensity diffraction peaks in 2θ values of approximately 7,2°, approximately 17.2° C and approximately 21.2° on the x-ray powder diffraction pattern.

5. The method of obtaining crystalline compounds according to claim 2, including interaction 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid in a strong solvent and then mixing the reaction solution with a weak solvent and stirring the mixture.

6. The method according to claim 5, in which a strong solvent is methanol, and SLA is the first solvent is 2-propanol.

7. The method of obtaining crystalline compounds according to claim 3, including interaction 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid in water, followed by settling of the reaction solution.

8. The method of obtaining crystalline compounds according to claim 3, including interaction 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid in water followed by the addition of ethanol to the reaction solution and distillation of part of the solvent under reduced pressure before defending or stirring of the residue.

9. The method of obtaining crystalline compounds according to claim 4, comprising recrystallization of the hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan from ethanol.

10. The method of obtaining crystalline compounds according to claim 4, including recrystallization from ethanol hydrochloride 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan obtained by the interaction of the 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamide]morphinan with hydrochloric acid.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 6-amino-morphinane derivatives of formula I wherein meanings of R1-R4 and X are as defined in specification; composition based on the same having analgesic action, and uses thereof as high active analgesics.

EFFECT: new high active analgesics.

9 cl, 4 tbl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to compounds, namely, to derivative of 14-hydrxoynormorphinone of the formula (IV) , derivative of morphinone of the formula (III) , derivative of morphine of the formula (II) wherein R1 represents (C1-C7)-alkyl; R2 represents benzyl or benzyl substituted with one or some (C1-C6)-alkoxy-groups, or benzyl substituted with one or some halogen atom. Also, invention relates to a method for synthesis of derivative of 14-hydroxynormorphinone of the formula (IV) involving interaction of compound of the formula (III) with cobalt (II) as oxidant in the presence of a weak base and air or oxygen as co-oxidant. Also, invention relates to a method for synthesis of derivative of morphinone of the formula (III) involving interaction of derivative of morphine of the formula (II) with oxidizing agent that is effective in oxidation of allyl hydroxy-groups. Mainly, invention relates to a method for synthesis of noroxymorphone. The process involves oxidation of derivative of morphinone of the formula (III) to derivative of 14-hydroxynormorphinone of the formula (IV), removal of protection from 3-position and reduction of double bond at 7,8-position in derivative of 14-hydroxynormorphinone of the formula (IV) to yield derivative of 3,14-hydroxynormorphinone of the formula (V) and hydrolysis of derivative of 3,14-hydroxynormorphinone of the formula (V) to yield noroxymorphone of the formula (VI) wherein formulae (V) and (VI) are given in the invention description. Invention provides synthesis of noroxymorphone using novel intermediate compounds.

EFFECT: improved method of synthesis.

25 cl, 1 sch, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to compounds, namely, to derivative of 14-hydrxoynormorphinone of the formula (IV) , derivative of morphinone of the formula (III) , derivative of morphine of the formula (II) wherein R1 represents (C1-C7)-alkyl; R2 represents benzyl or benzyl substituted with one or some (C1-C6)-alkoxy-groups, or benzyl substituted with one or some halogen atom. Also, invention relates to a method for synthesis of derivative of 14-hydroxynormorphinone of the formula (IV) involving interaction of compound of the formula (III) with cobalt (II) as oxidant in the presence of a weak base and air or oxygen as co-oxidant. Also, invention relates to a method for synthesis of derivative of morphinone of the formula (III) involving interaction of derivative of morphine of the formula (II) with oxidizing agent that is effective in oxidation of allyl hydroxy-groups. Mainly, invention relates to a method for synthesis of noroxymorphone. The process involves oxidation of derivative of morphinone of the formula (III) to derivative of 14-hydroxynormorphinone of the formula (IV), removal of protection from 3-position and reduction of double bond at 7,8-position in derivative of 14-hydroxynormorphinone of the formula (IV) to yield derivative of 3,14-hydroxynormorphinone of the formula (V) and hydrolysis of derivative of 3,14-hydroxynormorphinone of the formula (V) to yield noroxymorphone of the formula (VI) wherein formulae (V) and (VI) are given in the invention description. Invention provides synthesis of noroxymorphone using novel intermediate compounds.

EFFECT: improved method of synthesis.

25 cl, 1 sch, 1 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 6-amino-morphinane derivatives of formula I wherein meanings of R1-R4 and X are as defined in specification; composition based on the same having analgesic action, and uses thereof as high active analgesics.

EFFECT: new high active analgesics.

9 cl, 4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride having sustained quality of production and high purity. Crystalline forms of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride are proposed, including A-forms, B-forms or C-forms, and method of producing said forms.

EFFECT: obtaining compounds which have analgesic, diuretic and antipruritic effect.

10 cl, 8 dwg, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying plant extracts which mainly consist of noroxymorphone compounds and contain α,β-unsaturated noroxymorphone compounds as impurities, through (a) conversion of a plant extract or product of the next step in synthesis of the selected noroxymorphone compound as a result of conversion of hydroxyl groups present in the mixture to groups of formula -OR2 which can be split, in which R2 is an introduced radical of the said group which can be split, (b) said groups, if necessary, can be removed once more, after which (c) the obtained mixture is subjected to selective hydrogenation so that a saturated bond forms in the α,β-position of unsaturated noroxymorphone compounds and all the remaining groups which can be split are converted to a hydroxyl group, after which (d) a pure noroxymorphone compound is extracted; processing the purified noroxymorphone to naltrexone or naloxone or a salt of these compounds or a quaternary derivative of these compounds, which are known pharmaceutically active compounds particularly used for reducing psychological dependency and during drug abuse.

EFFECT: improved purification of compounds.

21 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compound of general formula (I): , where R1 and R2, each independently, represent hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, etc., R3 represents hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkinyl, optionally substituted lower alkoxy, etc, R4 represents hydrogen or lower alkyl, R5 represents hydrogen, lower alkyl, cycloalkyl-lower alkyl or lower alkenyl, or its pharmaceutically acceptable salt or solvate.

EFFECT: obtaining pharmaceutical composition for treatment and/or prevention of nausea, vomiting and/or constipation.

13 cl, 68 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a product of oxymorphone hydrochloride exhibiting an analgesic activity and containing less than 10 parts/million of alpha, beta unsaturated ketones by HPLC, also the invention refers to a pharmaceutical formulation containing said product of oxymorphone hydrochloride and to a method of oxymorphone hydrochloride purification involving reduction of a basic substance of oxymorphone hydrochloride in highly acid aqueous and alcohol reaction medium with hydrogen gas at temperature within 60 to 70°C.

EFFECT: there is produced and described improved analgesic oxymorphone hydrochloride containing less than 10 parts/million of alpha, beta unsaturated ketones.

22 cl, 3 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly a method for making the oxymorphone derivative naltrexone being an opiate antagonist by naltrexone processing by diazomethane in the presence of palladium acetate.

EFFECT: method eliminates using hardly accessible and expensive parent compounds, and it is characterised by ease of implementation.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of 6-aminomorphinane of formula (the substitute values are presented in the patent claim) to be used as high-active analgesics.

EFFECT: invention relates to pharmaceutically acceptable salts and easily accessible derivatives (eg ester or amino acid amide derivatives), and the use thereof for preparing pharmaceutical preparations.

11 cl, 57 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds, namely nalmefene prodrugs of formula (I) wherein R1 means C16-20alkyloxycarbonylC2-4alkyl, as well as to pharmaceutical compositions containing the above compounds, as well as to a method for preparing the above compounds.

EFFECT: compounds possess action of an opioid receptor antagonist and may be used for treating substance abuse disorders, wherein the above disorder represents abuse of alcohol and alcohol dependence.

8 cl, 1 tbl, 2 ex

Nalmefene prodrugs // 2495042

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to ester prodrug forms of nalmefene of formula (I) wherein R1 means C6-16alkyl or C8-12alkylamino; or a pharmaceutically acceptable acid additive salt thereof. Also the invention claims the pharmaceutical compositions possessing action of an opioid receptor agonist containing a pharmaceutically acceptable salt and a therapeutically acceptable amount of the compound of formula (I).

EFFECT: invention describes the chemical methods for preparing the above compounds and using them in treating substance abuse disorders, such as abuse of alcohol and alcohol dependence, and pulse control disorders, such as compulsive gambling and shopping addiction.

14 cl, 5 ex, 1 tbl, 1 dwg

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