Isomerisation of pharmaceutical intermediates

FIELD: chemistry.

SUBSTANCE: invention relates to a method of isomerising vitamin D analogues such as compounds used in synthesis of calcipotriol using a flow-type photoreactor or a photoreactor with continuous flow for preparing said vitamin D analogues. The invention also relates to use of intermediates produced using said method to produce calcipotriol or monohydrate of calcipotrol or its pharmaceutical medicinal forms.

EFFECT: improved properties of compounds.

21 cl, 4 ex, 1 tbl

 

The present invention relates to a method of isomerization of analogues of vitamin D, which is applicable for the synthesis of calcipotriol {(5Z,7E,22E,24S)-24-cyclopropyl-9,10-Scajola-5,7,10(19),22-tetraen-1α-3β-24-triol}, and to the use of streamline photoreactor or photoreactor with continuous flow for the preparation of such analogs of vitamin D. in Addition, the present invention relates to the use of intermediates produced by the described method, for the preparation of calcipotriol or calcipotriol monohydrate or its pharmaceutical dosage forms.

BACKGROUND of INVENTION

Calcipotriol, or calcipotriene (structure I) [CAS 112965-21-6], strongly inhibits undesirable proliferation of epidermal keratinocytes [F. A. C. M. Castelijins, M. J. Gerritsen, I. M. J. J. van Vlijmen-Willems, P. J. van Erp, P. C. M. van de Kerkhof; Acta Derm. Venereol. 79, 11, 1999]. In some clinical trials have shown the efficacy of calcipotriol or calcipotriol monohydrate (I-hydrate) in the treatment of psoriasis [D. M. Ashcroft et al.; Brit. Med. 3. 320, 963-67, 2000], and currently calcipotriol is used in several commercial dosage forms.

In the preparation of calcipotriol for the full manifestation of its biological activity required (Z)-configuration, the stereochemistry of the double bond at C-5. In the disclosed previously, the method of preparation kantipur is Ola I intermediate IIaaa protected hydroxyl and (E)-stereochemistry at C-5 will photoisomerize not described in the process in laboratory scale using anthracene as a photocatalyst for the corresponding (Z)-isomer IIIaaa with subsequent removal of the silyl protective groups, resulting in a gain of calcipotriol I [WO 87/00834, M. J. Calverley. Tetrahedron, 43 (20), 4609-19, 1987; E. Binderup. Drugs of the Future Vol. 15, No. 1, 1990, “Calcipotriol”, M. P. Folkmann, Ph.D. Thesis, The Danish Academy of Technical Sciences (ATV) EF 488, 1996].

The above sources do not report how to increase the scale isomerization IIaaa or related compounds to create a process that is applicable in large-scale production. So you want a standard method applicable to large-scale isomerization analogues of vitamin D for the synthesis of calcipotriol.

The problems associated with carrying out preparative synthetic photochemical reactions on a large scale, find it too difficult to resolve by conventional means used in industrial scale. As a rule, photochemical transformations, it is difficult (or even impossible) to implement on a larger scale. Along with other variables, which are also dependent on the scale of production, the effectiveness of a particular photochemical reaction often depends on the specific design of the reactor, and the light source.

The INVENTION

The present invention relates to a method applicable to large-scale photoisomerization analogues of vitamin D used in the synthesis of calcipotriol is. The authors of the present invention found that the use of streamline photoreactor, for example, of streamline photoreactor or photoreactor with continuous flow, can be obtained with a good yield of the desired 5-(Z)-isomers with the General structures IIIa, IIIb, IIIc and IIId in a convenient large-scale production process. Compared with the method of using a batch reactor, the fixed volume, the method of the present invention can reduce the time of exposure and to provide products photoisomerization higher purity.

In one aspect this invention relates to a method of isomerization of a solution of a derivative of vitamin D to the General structure IIa, IIb, IIc, IId or IIe, respectively;

to obtain a derivative of vitamin D to the General structure IIIa, IIIb, IIIc, IIId or IIIe, respectively,

in which X is hydrogen or-OR2;

R1,R2and R3may be the same or different and independently represent hydrogen or a protective group of hydroxyl group;

the method includes the irradiation of a solution of a derivative of vitamin D to the General structure IIa, IIb, IIc or IId, matched with the public,

a suitable light source in the presence of the photocatalyst in the flowing photoreactor or photoreactor continuous stream.

In another aspect this invention relates to a method for producing calcipotriol {(5Z,7E,22E,24S)-24-cyclopropyl-9,10-Scajola-5,7,10(19),22-tetraen-1α-3β-24-triol} or calcipotriol monohydrate comprising the stage

(i) isomerization derivative of vitamin D with the overall structure of IIaa

with the formation of a derivative of vitamin D with the overall structure of IIIaa

in which R1,R2and R3may be the same or different and independently represent hydrogen or a protective group of hydroxyl;

a suitable light source in the presence of photocatalyst;

characterized in that the solution moves in a continuous stream, passing once or repeatedly circulating relative to the light source in flow photoreactor or photoreactor with continuous flow;

(ii) removing the protection of hydroxyl groups of R1and/or R2and/or R3of compounds with the General structure IIIa with the formation of calcipotriol (in the case when R1and/or R2and/or R3are not hydrogen); and

(iv) optional crystallization of calcipotriol from a mixture of organic solvent and water treatment is the Finance of calcipotriol monohydrate.

In another aspect this invention relates to a method of preparation of calcipotriol or calcipotriol monohydrate, one or more stages which include the manner specified above.

In another aspect this invention relates to a method of isomerization of a solution of a derivative of vitamin D to the General structure IIaaa;

with the formation of a derivative of vitamin D to the General structure IIIaaa,

the method includes the irradiation of a solution of a derivative of vitamin D to the General structure IIaaa a suitable light source in the presence of photocatalyst;

wherein said solution is moving, passing repeatedly in a continuous flow relative to a light source in flow photoreactor or photoreactor with continuous flow, characterized by the fact that part of the overall solution and continuously re-circulated from the tank through a flow-through photoreactor or photoreactor with a continuous flow back to the tank.

In another aspect this invention relates to the use of streamline photoreactor or photoreactor with continuous flow in the production of calcipotriol or calcipotriol hydrate.

In another aspect this invention relates to a method for manufacture of pharmaceutical dosage forms or drug containing callpath the IOL or calcipotriol monohydrate, such as cream, ointment or gel, including the manner specified above.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows a longitudinal section of an example of a suitable of streamline photoreactor or photoreactor with a continuous flow of the present invention.

Figure 2 shows a cross-section of an example of a suitable of streamline photoreactor or photoreactor continuous flow depicted in Fig. 1.

DETAILED description of the INVENTION

Previously described methods of photoisomerization IIaaa have several disadvantages, especially in the case of industrial scale, such as the need for large loads of photocatalyst and carrying out the reaction in a fairly dilute solutions, which requires large amounts of solvent.

Because rates of solvent and the volume of production equipment in industrial chemistry usually prefer high concentrations of substrates. However, the use of highly concentrated reaction solution in photochemistry difficult. Synthetic organic photochemical reaction is usually carried out in submerged reactors. This is usually the reactors periodic operation with a fixed volume of irradiated inside one lamp with a discharge in mercury vapor. These types of devices periodic action limitedly applicable in large-scale photochemical synthesis, because the number is in the solution, which can be effectively irradiated by this light source is dependent on the scale of production, since most of the photochemical reaction occurs only at a small distance from the lamp. High concentrations of substances that absorb light, can further reduce the thickness of the zone of expression (photocatalytic reaction proceeds only on the surface of the irradiated photocatalyst) and reduce the uniformity of exposure to the photons emitted by the light source. Concentrated solutions in the processes of periodic action can promote side reactions, as a consequence, many of the expression must be carried out in dilute solutions.

Moreover, traditional periodic ways isomerization (e.g., connection IIaaa) typically produce a mixture containing unreacted starting material (for example IIaaa), and often contain significant amounts of undesirable decomposition products (e.g., compounds with the General structure (IV), which requires the subsequent time-consuming chromatographic purification).

In General, the relationship between the applicable reactor design and the requirements of the specific photochemical reactions are still poorly understood. Therefore, the choice of a specific photochemical installation and suitable reaction conditions, such as the concentration of the emission substrate and the photocatalyst, the duration of exposure and the design of the reactor, remains unpredictable and is a serious problem, especially on an industrial scale.

DEFINITION

When you use here the expression "protective group of hydroxyl group"means any group that forms a derivative that is stable in the planned response, and indicated the protective group can be selectively removed with reagents not applicable to regenerated hydroxyl group. Specified derivative can be obtained by the selective reaction of the protective agent is a hydroxyl group with a hydroxyl group. Examples of protective agents hydroxyl groups are simillarity, such as tert-butyldimethylsilyl (TBSCl), trimethylsilane, triethylsilane, diphenylmethylsilane, triisopropylsilyl and tert-butyldiphenylsilyl. Examples of reagents that can remove the silyl groups are hydrogen fluoride, for example, aqueous HF in acetonitrile, or Tetra-n-butylammonium. Other protective groups for hydroxyl groups include ethers, such as tetrahydropyranyloxy simple ether (THP), including alkoxyalkyl ethers (acetals), such as methoxymethyl simple ether (MOM) or benzyl simple ether, or esters, such as chloroacetyl ester, imediatelly, acetate or benzoate esters. Non-limiting examples of protective groups of hydroxyl groups and the methods of protection and removal, all included in the scope of this application, can be found, for example, in the monographs Protective Groups in Organic Synthesis, 3rded., T. W. Greene &P. G. M. Wuts, eds., John Wiley 1999 and Protecting Groups, 1sted., P. J. Kocienski, G. Thieme 2000, which is fully included in here as references.

In this context, the term "alkyl" means a radical derived when one hydrogen atom is removed from a hydrocarbon. The specified alkyl contains 1-20, preferably 1-12 (for example, 1 to 7 or 1 to 4) carbon atoms. This term includes the subclasses of normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and tert-butyldimethylsilyl group.

In the present context the term "substantially soluble" means that the derivatives of vitamin D in the form of E - or Z-form or in the form of their mixtures can either completely dissolved or partially dissolved in the suspension emulsion. The term "solution" includes substantially dissolved substrates.

Embodiments of the

Suitable photochemical reactor for the present invention may be any reactor commonly used in photochemistry, which can be used or adapted for flow-through mode is working, for example, for continuous flow. Such reactors are well known to experts in the field of photochemistry; they can be found, for example, in Ullmann''s Encyclopedia of Industrial Chemistry, Photochemistry, A19, pp. 576-582 and in Vol B4 page 116-120 or International Chemical Engineering, Vol 12, No. 1, 1972, pp. 131-143. Examples of photoreaction include, but are not limited to, tubular reactor, the reactor in the form of a bubble column, enclosed reactor with stirring, the reactor with a falling liquid film or a reactor with a belt feed, which can be adapted to continuous operation mode or operation mode with continuous flow. The reactor can be used sequentially or in parallel, including various combinations of the different reactors. More generally applicable flow-through photoreactor or photoreactor with a continuous flow may include the reactor vessel, surrounding the longitudinal channel, usually having a circular cross-section, which, for example, takes the fluid passing between the inner wall of the reactor vessel and the outer wall of the tube, which transmits photons, which, for example, is placed in the inner part of the reactor is substantially coaxially aligned (i.e. longitudinally centered and concentric with the inner wall of the reactor. Another example applicable photoreactor reactor is built in a production line having a generally cylindrical inner wall is ku and the tube of the light source, placed coaxially in the center. Photoreactor may include mechanically static, fluid-dynamic elements for passively inducing turbulent flow inside the liquid passing through the channel, as described in WO 96/35508 and specified references, which are incorporated here as reference.

In one or more embodiments of the present invention flow-through photoreactor or photoreactor with a continuous flow is substantially axisymmetric tubular flow reactor, in which the solution moves parallel to the Central longitudinal axis. In one or more embodiments of the present invention substantially axisymmetric tubular flow reactor has at least one concentric cylindrical space located coaxially aligned, such as longitudinal cylinders, or tubes, placed one inside the other, such that in the inner cylindrical space in which is placed a transparent casing of the light source, and in which the external cylindrical space is the reaction chamber. In yet another embodiment, the present invention substantially axisymmetric tubular flow reactor has at least three concentric cylindrical space, for example, three concentric cylinders or three concentri the mini-tube, placed one inside the other, with the inner tube, the first cylindrical space, contains the light source, the second cylindrical space is the reaction chamber, and the third cylindrical space adapted for use as a cooling jacket. The irradiated volume, aligned along the Central axis, may, for example, have a length of from about 5 to about 100 cm, for example, 50-70 cm or 60 cm

In yet another embodiment, the present invention relates to the use of streamline photoreactor or photoreactor with continuous flow, in which the solution of the analogue of vitamin D moves in a continuous stream, passing once or repeatedly circulating relative to the light source. This allows the photoisomerization in a convenient large-scale production process that has a number of advantages. This operating mode may also allow control of the irradiation light by adjusting the light contact (exposure) using flow control. In addition, the flow can be interrupted and resumed at any time, e.g. for lamp replacement or repair. Unlike the process with a fixed frequency, the efficiency of this process may depend on the scale of production. The reactor is continuous in the eye can process any desired number of the source material, functioning for longer periods of time without adjustment for large quantities of product. Therefore, can be subjected to isomerization large volumes, using a relatively small flow-through photoreactor or photoreactor with a continuous flow, compared with a fixed periodic reactor. In one or more embodiments of implementation of the present invention the solution of the analogue of vitamin D can be collected and sent for recycling via a flow photochemical reactor, for example, part of the General solution can be continuously and re-circulate from the tank through a flow-through photochemical reactor back to the tank. The circulation of the solution through the flow-through photoreactor or photoreactor with continuous flow, e.g. in combination with one or more reservoirs, allows you to achieve great operational flexibility of the production installation. For example, one of the photoreactor can be used in the production, performed in one or more reactors periodic action (reservoirs) of different size, for example, a combination of serial or parallel photoreactor with one or more tanks that are not necessarily possible to connect tubes or hoses in series or parallel. For example, specific photoreactor can be provided from the remote khimicheskogo the reactor or tank by means of the respective tubes and hoses. Moreover, the exposure time (residence time), which for the most part is determined by the velocity of the flow can be monitored easily or quickly be adjusted between the parties with control in the reaction. Therefore, by adjusting the flow rate or the rate of recirculation, it is possible to adjust the contact time of the solution with a source of light (photon dose). Thus it is possible to compensate or adjust the differences between the parties or weakening of the intensity of the lamp and reduce the risk of decomposition upon exposure. In one or more embodiments of the present invention, the flow rate is such that the flow of the reaction mixture in photoreaction chamber is turbulent. Suitable flow rate, which along with other factors depend on the design and size of the process equipment may be, for example, in the range from 2 l/min to 200 l/min, for example, from 3.6 l/min to 100 l/min, from 4.8 l/min to 70 l/min, 10 l/min 65 l/min 40 l/min, 41 l/min 42 l/min 43 l/min 44 l/min 45 l/min, 46 l/min 47 l/min, 47,1 l/min, to 47.2 l/min, 47,3 l/min, with 47.4 l/min, and 47.5 l/min, 47,6 l/min, 47,7 l/min, to 47.8 l/min, 47,9 l/min, 48 l/min, 48 l/min, 48,1 l/min, 48,2 l/min, for 48.3 l/min, 48,4 l/min, 48,5 l/min, 48,6 l/min, 48,7 l/min, and 48.8 l/min, 48,9 l/min, 49 l/min, 50 l/min, 5 l/min 52 l/min, 53 l/min 54 l/min 55 l/min 56 l/min 57 l/min, 58 l/min, 59 l/min and 60 l/min

In one the or more embodiments of the present invention the solution is repeatedly collected and sent for recycling via a flow photoreactor or photoreactor with a continuous flow.

In one or more embodiments of the present invention part of the overall solution and continuously re-circulated from one or more tanks through flow-through photoreactor or photoreactor with a continuous flow back to the tank. The percentage of the total solution, which is present in photoreactor and actually irradiated, can be 0.5-99% of the total solution, for example, 1-35%, 2-30%, 3-25%, 4-20%, 5-10%, 6-7%. In one or more embodiments of the present invention, the irradiated volume of photoreactor is about 10 liters, and the volume of the tank is approximately 170 HP

In the present invention can use any light source or lamp, including a large number of lamps, providing spectral range and intensity appropriate for the photocatalyst and the substrate, optionally in combination with a suitable cut-off filter. Accordingly, the term "light source" includes the lamp in combination with a suitable cut-off filter. The light sources may have different geometry; preferably they are adapted to the geometry of the hull and/or reaction chamber, for example, the elongated light sources. Suitable light sources can be found, for example, in Ullmann''s Encyclopaedia of Industrial Chemistry, Photochemistry, A19, pp. 576-582. In one or more embodiments, the light source gives polychromatic the cue light, including UV light, such as in the range of 230-400 mesh nm, for example, 270-350, 300-340, 290-320 nm, 300-315 nm or 310-312 nm. Acceptable light sources are commercially available from different suppliers, such as Heraeus, Hanau or Gunther H. Peschl (Bodenheim, Germany). In one or more embodiments of the present invention the light source is a mercury lamp, for example, the lamp high pressure or lamp low pressure and, in particular, mercury lamp, medium pressure. Mercury lamp, medium pressure or high pressure may contain other metals, such as arsenic, bismuth, indium, thallium, or iron. Mercury medium pressure lamp may, for example, to work with the consumed electric power of about 2-60 kW, for example, 3-20 kW or 3,4-10 kW, for example, 3-7 kW, 6 kW. More specifically, the lamp may, for example, be a lamp TQ 718 Hanau, lamp Gunther H. Peschl Z0, Z2 or Z4 or lamp with similar parameters of photon emission. The typical length of the lamp may be in the range of from about 5 to about 100 cm, for example, from about 50 to about 70 cm, from about 55 to about 65 cm, for example, 60 cm

The light source can be used inside a reaction chamber or from its internal part, when it is inside two concentric tubes surrounding the lamp and defining the irradiated volume, or when it is immersed in the reaction solution. The reaction mixture m which should be irradiated from the outside of the reaction chamber, for example, using a focusing reflector or using lots of lamps, for example, in apparatus of the type Rayonet. The present invention includes all embodiments of, where, for example, use a variety of lamps, the same or different, including all variants of implementation, where the light sources are placed in different positions relative to the reaction chamber. In one or more embodiments of the present invention photochemical reactor comprises a housing for a light source. One of the advantages of having a specified enclosure for the light source is that it facilitates the access to this source of light and its replacement. In one or more embodiments of the present invention that the lamp cover has a hole at one end along its length for reversible installation of the lamp in its housing with the continued flow in the reactor. This allows you to insert the lamp without impacting the rest of photoreactor - dignity, especially valuable for the production scale, when the lamp can be replaced without interrupting the circulating flow. Moreover, the casing, if it is equipped with appropriate means of cooling, allows to cool the light source. For example, the light source can be cooled in a cooling fluid, such as water or gas flowing through the casing or around it. For example, water can flow between the inner and outer walls, surrounding the lamp. Or the lamp can be provided with a cooling system. The geometry of the light source can match the geometry of the casing. So that the light generated by this light source, had the opportunity to achieve the irradiated volume, the casing can have a transparent wall surrounding the light source, such as a wall, made of quartz or borosilicate glass. In one or more embodiments of the present invention the lamp inside the casing to cool the stream of inert gas, such as nitrogen, and the casing is advanced from the outer part cools the coolant, such as water.

In one or more embodiments of the present invention, the shortest distance traveled in the irradiated volume of the light emitted in the vertical or perpendicular direction from the surface light source or a surface of a casing of the light source, or the average diameter of the reaction chamber, or the distance between the cylindrical walls, respectively, is less than about 30 cm, for example, less than about 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9,7, 9, 8, 7, 6, 5, 4 or 3 cm, for example, 2,5, 2,0, 1,5, 1,0, 0,9, 0,85, 0,8, 0,75, 0,6, 0,5, 0,4, 0,3, 0,2 cm or 0.15, see one or more embodiments of the present invention, the reaction chamber is defined by the distance between the inner edge of the pipe and the outer edge of pipe is, the value of which is in the range from about 2 mm to about 15 cm, such as, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9,7, 9, 8, 7, 6, 5, 4 or 3 cm, for example, 2,5, 2,0, 1,5, 1,0, 0,9, 0,85, 0,8, 0,75, 0,6, 0,5, 0,4, 0,3, 0,2 cm or 0.15, see

In one or more embodiments of the present invention photoisomerization is carried out at substantially oxygen-free conditions. The presence of oxygen in the reaction mixture can lead to the formation of singlet oxygen, which can decompose derivatives of vitamin D. a Substantially oxygen-free conditions can be achieved by carrying out the isomerization in an inert atmosphere such as an atmosphere of argon, helium or SF6, preferably in a nitrogen atmosphere. All reagents and solvents can degassing and/or to evacuate the reaction chamber and purging it with an inert gas prior exposure to lower concentrations of oxygen.

Non-limiting examples of photoreaction and light sources and their combinations can be found, for example, in U.S. patent No. 5012106, U.S. patent No. 3554887, U.S. patent No. 4456512, DE 3625006, DE 10236717, EP 0000773, U.S. patent No. 4087342, U.S. patent No. 4454835, J. Org. Chem. 2005, 70, 7558-7564, U.S. patent No. 5126111, U.S. patent No. 4296066, Adv. in Photochemistry Vol. 18, 235-313, 1993), which are all included here as a reference.

It is assumed that the drawings shown in Fig. 1 and Fig. 2, will make the invention more understandable; these drawings show Neagra icehouse example photoreactor, applicable for the implementation of the present invention.

Photoreactor101consists of the reaction vessel125,the outer casing of the light source109internal casing of the light source110, light source or lamp102the upper cover106and the connection element124.

The reaction vessel125,, the external casing of the light source109the inner casing of the light source110top cover106the light source is102and the connection element124adapted to the connecting means123that allows them to connect concentrically. Suitable connecting means include, but are not limited to, the connector or fastening means, such as screw and nut, coupling, clamp, clamp, bolt, or combinations thereof.

The outer casing of the light source109suited for installation in the reaction vessel125using the connection tool123, connecting the124adapted for installation on the reaction vessel125using the connection tool123the inner casing of the light source110suited for installation in the connection element124using the connection tool123,and the upper lid106adapted for mounting on the connecting element124using the connection tool123.

The outer casing East is cnica light 109top cover106and the connection element124limit the amount of internal camera111a light source adapted for mounting a light source102. Internal camera111light source is provided with means for supplying gas, such as gazovykh outlet104and the flue pipe105placed on the top cover106for gas diffusion through the specified camera111. In addition, the internal camera111a light source provided with a means of power supply103to the source of light102. The inner casing of the light source110,the connecting element124,the outer casing of the light source109and the reaction vessel125form(limit) the amount of external camera112a light source adapted to supply cooling means for attenuating heat produced by the light source102such as inlet107cooling fluid or gas and the discharge port108the cooling liquid or gas, is placed in the connecting element124for diffusion of the coolant (e.g. water) or gas through the said camera112.

Preferably the means to supply gas and the coolant are the inlet pipes122or126for cooling liquid or gas, respectively, and finishing the Tr which side are at the bottom of camera light source 111and112, respectively, and outlet connections for gas and coolant105and108are in the upper chambers of the light source111and112respectively.

The reaction vessel125includes the outer wall of the cooling jacket121and the inner wall of the reaction chamber119that form (determine) volume dvuhstrochnym cooling jacket120. The reaction vessel125equipped with cooling means, for example, the outer wall of the cooling jacket121equipped with inlet or the outlet of the coolant114and the outlet or the inlet manifold coolant115that is preferably placed in spatially separated parts of the cooling jacket, for example, an outlet of the coolant115placed in the lower part of the reaction vessel125and inlet coolant114placed in the upper part of the reaction vessel125for water circulation, cooling solution designed to photoisomerization in the reaction chamber113by removing the heat generated by the light source102. In addition, the reaction vessel125equipped with the filing of the substrate, such as inlet substrate116and the outlet substrate117. Preferably the inlet nozzle substrate116/b> placed in the lower part of the reaction vessel125and the outlet substrate117placed in the upper part of the reaction vessel125. All inlet and outlet connections may need to have the valves and/or fittings.

The outer casing of the light source109and the reaction vessel125form a centrally symmetric concentric reaction chamber113mainly defined by the parallel position of the inner wall of the reaction chamber119and the external surface of the external casing of the light source109and capable of withstanding the reagents of this photochemical reaction. The outer casing of the light source109the reaction vessel125the inner casing of the light source110and the source of light102can be mutually adapted when installed to the intensity of light inside the reaction chamber113could almost evenly distributed at equal distances at issue in the vertical direction from the outer surface of the outer casing127.

The light source is102optional can be equipped with a barrier (opaque screen) for the light128at the lower end of the specified light source, preventing the propagation of light generated by the specified light source, in a direction vertically downwards.

The inner surface of the inner wall p is a promotional camera 119may have a covering118absorbing light, such as black Teflon capable of reducing the reflection of light.

Reaction chamber113, cooling jacket120,external camera light source112and internal camera light source111can look like a series of concentric cylinders or tubes placed one inside the other.

Preferably the casing of the light source and the reaction chamber is made mainly of quartz or glass, which transmits light. Usually prefer non-metallic materials, such as poly-(methyl methacrylate), standard window glass, Pyrex (Corning 774), Vycor 791, Suprasil I (Heraeus), Suprasil-W (Heraeus), borosilicate glass, such as borosilicate glass 3.3 (ISO 3585:1998). In one or more embodiments of the present invention the casing of the light source consists mainly of quartz, and of the wall of the reaction chamber, closest to the light source109that is mainly composed of borosilicate glass. Quartz due to its transparency and thermal properties is the preferred material for the inner casing of the light source110. In one or more embodiments of the present invention the material for the outer casing of the light source109is of 3.3 borosilicate glass (ISO 3585:1998 and EN 1595). A suitable material for the reaction SOS is Yes 125, connecting124and the top cover106is stainless steel.

In one specific embodiment of the present invention the outer diameter of the inner casing of the light source110approximately 61 mm, inner diameter of the outer casing of the light source109approximately 72 mm, and its outer diameter is equal to about 79 mm, which corresponds to the wall thickness of the external casing of the light source is equal to about 3.5 mm In another specific embodiment of the present invention the length of the outer casing of the light source109approximately 100 cm In one specific embodiment of the present invention, the internal diameter of the cylindrical space bounded by the inner wall of the119reaction chamber, equal to about 95 mm, resulting in the thickness of the irradiated layer, equal to about 8 mm In yet another specific embodiment, the present invention lamp102has a length of about 60 cm, and the lower end of the specified light source is located 10 cm above the bottom of the inner casing of the light source110and specified the casing of the light source110, for example, has a length of about 130 cm

Suitable photocatalysts are, for example, the triplet sensitizers with a triplet energy in the range of 150-270 kJ/mol, for example, men who e 185 kJ/mol, for example, 170-180 kJ/mol, for example, 176-178 kJ/mol. The ratio of E/Z isomerization equilibrium can be adjusted by choosing the triplet sensitizer with the appropriate energy. Photocatalysts include, but are not limited to, anthracene, 9-acetylanthracene, anthracene-9-carboxylic acid, intracisternally, fenesin, anthracene-9-sulphonic acid, 4,4-bis-(dimethoxy)-thiobenzophenone, 4,4-bis-(dimethylamino)-benzophenone, 4,4-bis-(dimethylamino)-thiobenzophenone, 4,4-bis-(dimethoxy)-benzophenone or 9,10-diphenylanthracene. Photocatalysts can be used as mixtures, but preferably they are used as individual compounds. In one or more embodiments of the present invention, the photocatalyst is present in a molar ratio approximately equal to 0.08 to 0.35 mol of photocatalyst per mole derivative of vitamin D, for example, approximately 0.1 to 0.2 mol of photocatalyst per mole derivative of vitamin D, for example, 0.15 to 0.18 mole of photocatalyst per mole derivative of vitamin D, for example, reports 0.175 mol of photocatalyst per mole derivative of vitamin D.

Applicable solvents include any solvent or mixture of solvents, which may at least partially dissolve the derivatives of vitamin D and the photosensitizer are not significantly interfere with the reaction and do not absorb much light generated by the source is MD of light, in the spectral range required for the expression. Applicable solvents include halogenated hydrocarbons such as dichloromethane, ethers such as tert-butylmethylamine simple ether (MTBE), tetrahydrofuran, dioxane, dimethoxyethane, hydrocarbons such as hexane, heptane, toluene and triethylamine or mixtures thereof. It may be useful to add trace amounts of bases such as triethylamine, since the derivatives of vitamin D are usually sensitive to acids. Preferred solvents are dichloromethane, or MTBE. Particularly beneficial use of MTBE, optionally containing triethylamine, in the case when the photocatalyst use 9-acetylanthracene. The present invention includes mixtures of these solvents in all songs. Electrification can be avoided by adding a proton to the solvent (e.g. tert-butanol), who do not participate in the expression.

In one or more embodiments of the present invention derivatives of vitamin D to the General structure II is dissolved in a solvent at a concentration (or above it) in the approximate range of 0.003-0,0134 g/ml solvent, for example, of 0.025-0.1 g/ml solvent, for example, 0.04 to 0.06 g/ml solvent, for example, 0.05 g/ml of solvent.

Photoisomerization can be in the approximate temperature range is 20-50 is With, for example, 10-40°C, for example, 0-30°C, for example, 5-25°C, for example, at temperatures of about 10-15°C, for example, about 10, 11, 12, 13, 14, or 15°C.

To optimize the yield of the desired product photoisomerization irradiation can be performed until at least 80% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97,5%, 98%, 98,5%, 99%, 99,5%, 99,6%, 99,7%, 99,8%, 99,9%) derivative of vitamin D to the General structure IIa, IIb, IIc or IId not isomerized to IIIa, IIIb, IIIc or IIId, respectively. The light irradiation can usually hold for about 1-25 hours, for example, 6-20 hours 7-10 hours, or 5-8 hours; depending on the specific conditions used for the reaction, radiation can be long or short.

Any numeric interval described in this proposal should include any specific number or a narrower interval lying within the interval, as a more specific variant of implementation of the present invention. The term "about" in addition to its accepted value is intended to indicate the inclusion of a numeric interval, which is 10% below or above the value or number to which it refers.

How photoisomerization described herein may be useful in the synthesis of other derivatives of vitamin D, for example, isomerization of intermediates useful for the synthesis of calcitriol or alpha calcitriol, for example, for the isomerization of 5-o-predestin the ka calcitriol in 5-Z-calcitriol, in which one or more hydroxyl groups may be protected, for example, tert-butyldimethylsilyl, or unsecured; or for the isomerization of 5-S-predecessor alpha calcidol with two protected hydroxyl up to 5-Z-alpha-calcidol with two protected hydroxyl; for example, isomerization, (1a,3b,5E,7E)-9,10-Scajola-5,7,10(19)-triene-1,3-bis(((1,1-dimethylethyl)-dimethylstyryl)-hydroxy-isomer to the corresponding 5Z-isomer, followed by removal of protective groups and education (5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1a,3b-diol.

The SYNTHESIS METHODS

Connection with the General framework IIa, IIb, IIc, IId or IIe can, for example, be synthesized by the methods disclosed, for example, in the work of M. J. Calverley. Tetrahedron, Vol. 43, No. 20, pp. 4609-4619, 1987, in WO 87/00834, WO 2005/095336, WO 2005/087719, U.S. patent No. 5763426, WO 03/106412, or in Drugs of the Future Vol 15, No. 1, 1990, page 15, or in Bioorg. Chem. Lett. Vol 3 No. 9 1841-184, 1993. These links open and methods transformation of compounds of the General structure IIIb, IIIc, IIId or IIIe in calcipotriol or intermediates suitable for the synthesis of calcipotriol.

General methods of synthesis of derivatives of vitamin D, such as compounds of General structure IIa, IIb, IIc, IId or IIe, can also be found in the monograph Vitamin D, D. Feldman, Ed., Academic Press, San Diego, USA, 1997, and in the work of G.-D. Zhu et al., Chem. Rev. 1995, 95, 1877-1952 and in the references mentioned there. Pharmaceutical form of calcipotriol or calcipotriol hydrate, such as creams, ointments, shall estuary, lotions, etc. can be found in U.S. patent No. 6753013, U.S. patent No. 5763426, U.S. patent No. 6787529 and U.S. patent No. 4866048 or can be prepared by any method known in this field, such as described by Lawrence H. Block, Medicated Applications, II Remington: The Science and Practice of Pharmacy 1577, 1585-91 (19th ed., Alfonso R. Gennaro, ed., 1995).

The production methods of calcipotriol and its monohydrate described here can be modified in relation to the order of the reaction stages, excluding the one or more reaction stages or introducing additional cleaning or additional reaction stage at any stage of the reaction sequence. The present invention includes all such modifications. The production method of calcipotriol described herein, and includes all the cases in which the protective group of the hydroxyl R1and/or R2and/or R3in the compounds or intermediates (where R1and/or R2and/or R3are not hydrogen) is removed or replaced with one or more other protective groups at any stage of the reaction sequence. Compounds or intermediates, in which R1and/or R2and/or R3are hydrogen, can be protected by protective agents at any stage of the reaction sequence, including such protective agents, which form the other protective groups that are distinct from previously deleted in the reaction sequence is. The present invention includes all isomeric forms as in pure form, or their mixtures. A reference to a specific conformation or configuration in formulas or names of the compounds or intermediates of the present invention should specify that this particular conformation or configuration is the preferred embodiment of the invention. Indicating the specific conformation or configuration in formulas or in the names of compounds or intermediates of the present invention should include any other isomer other than specifically indicated, both in pure form and in mixtures, as another variant implementation of the present invention. Pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained by using procedures that are known in this field, such as chromatography or crystallization, or by stereoselective synthesis.

Methods of crystallization, for example, derivatives of vitamin D, and in particular, of calcipotriol can be found, for example, in the work of M. J. Calverley. Tetrahedron, Vol. 43, No. 20, pp. 4609-4619, 1987, WO 94/15912; WO 2004/046097; they include crystallization from mixtures of ethyl acetate and hexane or heptane appropriate polarity. The calcipotriol hydrate can be obtained by crystallization of calcipotriol from mixtures of organic solvents and water, for example, by the way, is written in WO 94/15912. Accordingly, the present invention relates to the use of streamline photoreactor or photoreactor with continuous flow in the production of alpha-calcidol or calcitriol.

EXAMPLES

General information:

All chemicals, unless otherwise stated, were from commercial sources. Analytical HPLC was carried out on the equipment Merck-Hitachi pump L-6200 or L-6000A, the detector L-4000, integrator D-2500, the noise level 6, sensitivity 10. Chromatography was performed on silica gel, using optional flash technique. The preferred silica gel was LiChroprep® Si60 (15-25 µm) from Merck KGaA, Germany. Unless otherwise specified, as the eluents used ethyl acetate, dichloromethane, or an appropriate mixture of ethyl acetate, dichloromethane, methanol and petroleum ether (40-60) or heptane. Spectra1H-NMR (300 MHz) were recorded on the device Bruker DRX. The magnitude of chemical shift (δ) (h/m) is shown, unless otherwise indicated, for solutions in deuterium chloroform on tetramethylsilane (δ=0,00) or chloroform (δ=7,26) as internal standards.

Example 1:

Continuous photoisomerization using flow-through photochemical reactor

7.5 kg 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-(3'-cyclopropyl-3(S)'-hydroxyprop-1'(E)-enyl)-9,10-scoprega-5(E),7(E),10(19)-triens (IIa: X = OR2, R1, R23= hydrogen), prepared as previously described in M. J. Calverley. Tetrahedron, Vol. 43, No. 20, pp. 4609-4619, 1987 or in WO 87/00834, and 45 g of 9-acetylanthracene dissolved in 150 l practically free from oxygen tert-butyl simple ether (MTBE) under stirring in nitrogen atmosphere. The mixture was continuously pumped from the tank periodic reactor with stirrer volume of 180 l through photoreactor with a constant stream having the dimensions described earlier in the specification, including mercury lamp, medium pressure with the addition of iron (power 8 kW, UVH5822F-1, the power supply/ballast: 10 kW Heraeus), and back into the batch reactor, the (approximate flow rate of 48 l/min). The temperature of the reaction mixture was maintained around 10°C, periodic cooling the reactor with stirring and the photoreactor. Circulation and light irradiation was stopped when HPLC (with a mixture of n-heptane and ethyl acetate (100:2) as eluent, at a flow rate of 3.0 ml/min, column LiChrosorb Si60 5 microns and with a UV detector at 270 nm) showed that there are not more than 1.5% of the source material. The remaining contents of photoreactor moved to stir periodic reactor photoreactor once washed 10 liters of MTBE and the wash liquid is also moved in the mixed periodic reactor. The solvent was removed under vacuum and after chromatography got 1(S),3(R-bis-(tert-butyldimethylsilyloxy)-20(R)-(3'-cyclopropyl-3(S)'-hydroxyprop-1'(E)-enyl)-9,10-scoprega-5(Z),7(E),10(19)-triene (IIa: X = OR 2, R1, R2= tert-butyldimethylsilyl, R3= hydrogen) in full accordance with data described by M. J. Calverley in Tetrahedron, Vol. 43, No. 20, p. 4618, 1987 for connection 28.

Example 2:

Calcipotriol

1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-(3'-cyclopropyl-3(S)'-hydroxyprop-1'(E)-enyl)-9,10-scoprega-5(Z),7(E),10(19)-triens (IIa: X = OR2, R1, R2= tert-butyldimethylsilyl, R3= hydrogen)obtained from example 1, removed protection, using tetrabutylammonium in tetrahydrofuran at 60°C followed by chromatography as previously described M. J. Calverley. Tetrahedron, Vol. 43, No. 20, pp. 4609-4619, 1987 or in WO 87/00834. Crystallization from a mixture of ethyl acetate with hexane containing a few drops of triethylamine, gives calcipotriol in full accordance with data described by M. J. Calverley in Tetrahedron, Vol. 43, No. 20, p. 4618, 1987 to connect 4.

Example 3:

The calcipotriol monohydrate

Calcipotriol, obtained as described in example 2, crystallizes from a mixture of ethyl acetate with water, as described in WO 94/15912, with the formation of calcipotriol monohydrate in full accordance with data described in the patent.

Example 4:

Comparison of photoisomerization stir in a batch reactor, actions and photoisomerization in a continuous stream

Photoisomerization of free oxygen from the solution of 1(S),3(R)-bis-(tert-is utilimetrics)-20(R)-(3'-cyclopropyl-3(S)'-hydroxyprop-1'(E)-enyl)-9,10-scoprega-5(E),7(E),10(19)-triens (IIaaa) in MTBE (1 g/20 ml), containing 450 mg of 9-acetylanthracene, conducted in two different settings for direct comparison of the periodic process and process with continuous flow. Photoreaction plants have been designed to allow operation as in periodic mode and in a continuous flow through photoreactor, parallel to the longitudinal axis of the reactor. In both settings lamp that gives UV light (mercury lamp with the addition of iron, medium pressure, from Heraeus: TQ718 Z4, 800 watts; power supply cat. No. 56002316), enclosed in a quartz tube casing with the inner and outer sleeves of the water cooling was placed in the center of the standard submersible photoreactor fit (adding close the inlet and outlet openings) to work in periodic mode with stirring and in a continuous flow mode. The inlet opening of photoreactor was done in the bottom of photoreactor, and the outlet is at the top of photoreactor, just below the surface when the reactor is filled during operation, to allow the stream to flow into the reactor along the longitudinal axis of the submerged lamps when pumping solution. The temperature of the lamp is regulated, cooling tube housing cooling water (10°C). The thickness of the irradiated layer photoreactor accounted for 9.7 mm, the Reaction mixture constant is about were in a nitrogen atmosphere.

a) the continuous flow Mode:

In this setting, the inlet and outlet of photoreactor were hoses connected to the pump and reservoir. When the pump portion of the solution from the reservoir was continuously pumped and re-circulated from the tank through a flow-through photochemical reactor back into the tank. Inside photoreactor was moving approximately 450 ml of the reaction mixture, and approximately 1050 ml of the reaction mixture remained mainly in the tank (remaining small amount circulated in the connecting hoses). The flow rate was set in the range from 3600 ml/min up to 4800 ml/min. and the Temperature of the reaction mixture was constantly maintained at 10°C, the cooling tank.

b) Mode of the reactor of periodic action with stirring:

In this setting, the photoreactor was the same as above, except that the inlet and outlet were closed and the pump was not working. The temperature of the reaction mixture was constantly maintained at 10°C, cooling photoreactor from the inside. In addition, the reaction mixture of 450 ml was mixed with the lower magnet and a magnetic stirrer, providing intensive mixing and circulation around the lamp inside total photoreactor. Visual observation found that mixing was effective to the to the vertical, and in horizontal directions.

The reaction was monitored by taking samples at appropriate intervals and analyzing them using HPLC (eluent: n-heptane:EtOAc (100:2), flow: 3.0 ml/min, column: LiChrosorb Si60 5 µm, UV detector at 270 nm). The same method was used to determine purity. The content of pollutants to the General structure IV was determined using the1H-NMR, comparing the integration Teenboy system hydrogen 22/23 when the 5.45 h/m with the integration of hydrogen-24 in the side chain at 3,42 h/m the results of the experiments shown in the following table:

Modea) a continuous streamb) with periodic mixing
The exposure time for full conversion*54 min
(75 g substrate)
37 min
(22,5 g of substrate)
The exposure time/number of substrateto 0.72 min/gof 1.64 min/g
Purity IIIa#(HPLC)80%65%
A pollutant to the General structure IV#(NMR) 5 molar %15 molar %
*a): 98.9 per cent; (b): 99,2%
#(R1= tert-butyldimethylsilyl, X = tert-butyldimethylsilyloxy, R3= hydrogen)

These results unexpectedly show that the E-Z photoisomerization IIaaa gives the product IIIa#with improved purity in a more efficient process with improved space-time yield.

1. The way isomerization of a solution of a derivative of vitamin D to the General structure IIa, IIb, IIc, IId or IIe, respectively



with the formation of a derivative of vitamin D to the General structure IIIa, IIIb, IIIc, IIId or IIIe, respectively



in which X represents hydrogen or-OR2;
R1, R2and R3may be the same or different and independently represent hydrogen or a protective group of hydroxyl group; the method comprising the irradiation of a solution of a derivative of vitamin D to the General structure IIa, IIb, IIc, IId or IIe, respectively;
a suitable light source in the presence of the photocatalyst in the flowing photoreactor and the and photoreactor with continuous flow, wherein said solution is moving in a continuous stream, passing once or repeatedly circulating relative to the light source in flow photoreactor or photoreactor continuous stream.

2. The method of producing calcipotriol {(5Z,7E,22E,243)-24-cyclopropyl-9,10-Scajola-5,7,10(19),22-tetraen-1α-3β-24-triol} or calcipotriol monohydrate comprising the stage
(i) isomerization derivative of vitamin D with the overall structure of IIaa

with the formation of a derivative of vitamin D with the overall structure of IIIaa

in which R1, R2and R3may be the same or different and independently represent hydrogen or a protective group of hydroxyl group;
a suitable light source in the presence of photocatalyst,
characterized in that the solution moves in a continuous stream, passing once or repeatedly circulating relative to the light source in flow photoreactor or photoreactor with continuous flow;
(ii) removing the hydroxyl protecting groups R1and/or R2and/or R3compounds with the General structure IIIa with the formation of calcipotriol (in the case when R1and/or R2and/or R3are not hydrogen); and
(iv) optionally, a crystallization of calcipotriol from a mixture of organic dissolve the La and water with the formation of calcipotriol monohydrate.

3. The method according to claim 1, in which R3represents hydrogen, X represents-OR2.

4. The method according to any one of claims 1 and 2, in which R1and R2are alkylsilane or hydrogen.

5. The method according to any one of claims 1 and 2, in which R1and R2represent tert-butyldimethylsilyl, a R3represents hydrogen.

6. The method according to any one of claims 1 and 2, in which the flow-through photoreactor or photoreactor with a continuous flow is essentially axisymmetric tubular flow reactor, in which the solution moves parallel to the Central longitudinal axis.

7. The method according to any one of claims 1 and 2, in which the solution is repeatedly collected and recycled through flow-through photoreactor or photoreactor with a continuous flow.

8. The method according to any one of claims 1 and 2, in which a part of the solution and continuously re-circulated from a reservoir (tank) via a flow photoreactor or photoreactor with a continuous flow back to the tank (tanks), and this solution is optional, mix and regulate its temperature in the specified tank (tanks).

9. The method according to any one of claims 1 and 2, in which the light source is a mercury lamp, medium pressure with the addition of iron.

10. The method according to any one of claims 1 and 2, in which the light source provides UV light, in particular, in the range of about is about 300 to about 340 nm.

11. The method according to any one of claims 1 and 2, in which the light source is a mercury lamp, medium pressure with the addition of iron, and in which a mercury medium pressure lamp operates with a power supply with a power consumption of about 3 to about 7 kW.

12. The method according to any one of claims 1 and 2, in which the photocatalyst is selected from the group consisting of anthracene, 9-acetylanthracene, anthracene-9-carboxylic acid, intracisternally, phenazine, anthracene-9-sulphonic acid, 4,4-bis-(dimethoxy)-thiobenzophenone, 4,4-bis-(dimethylamino)-benzophenone, 4,4-bis-(dimethylamino)-thiobenzophenone, 4,4-bis-(dimethoxy)-benzophenone and 9,10-diphenylanthracene or mixtures thereof.

13. The method according to claim 2, in which the solvent is selected from the group consisting of dichloromethane, tert-butylmethylether simple ether, tetrahydrofuran, dioxane, dimethoxyethane, hexane, heptane, toluene, triethylamine or mixtures thereof.

14. The method according to any one of claims 1 and 2, in which the isomerization is carried out at a temperature of from about 0 to about 35°C in an inert atmosphere.

15. The method according to any one of claims 1 and 2, which essentially axisymmetric tubular flow reactor comprises at least two concentric cylindrical space located coaxially, so that a longitudinally extended cylinders or tubes placed one inside the other, and within Annee cylindrical space forming permeable to the light housing for the light source, and the external cylindrical space forms a reaction chamber.

16. The method according to any one of claims 1 and 2, which essentially axisymmetric tubular flow reactor comprises at least two concentric cylindrical space located coaxially, so that a longitudinally extended cylinders or tubes placed one inside the other, with the inner cylindrical space forming permeable to light the casing for the light source, and an external cylindrical space forms a reaction chamber in which a reaction chamber is formed by a space between the inner edge of the pipe and the outer edge of the pipe with a width of about 2 mm to about 15 cm

17. The method according to any one of claims 1 and 2, in which the photocatalyst is present in a molar ratio of from about 0.08 to about 0,35 mol of photocatalyst per mole derivative of vitamin D, and in which the derivatives of vitamin D dissolved in the solvent at a concentration of from about 0.025 g to about 0.1 g per ml of solvent.

18. The way isomerization derivative of vitamin D to the General structure IIaaa

with the formation of a derivative of vitamin D to the General structure IIIaaa

the method includes the irradiation of a solution of a derivative of vitamin D to the General structure IIaaa suitable source St is in the presence of photocatalyst;
wherein said solution is moving in a continuous stream, repeatedly circulating relative to the light source in flow photoreactor or photoreactor with continuous flow; characterized in that part of the overall solution and continuously re-circulated from the tank through a flow-through photoreactor or photoreactor with a continuous flow back to the tank.

19. The use of streamline photoreactor or photoreactor continuous flow production of calcipotriol or calcipotriol hydrate.

20. The use of streamline photoreactor or photoreactor with continuous flow in the production of alpha-calcidol or calcitriol.

21. The application of claim 19, wherein the flow photoreactor or photoreactor with a continuous flow is essentially axisymmetric tubular flow reactor, in which an elongated tube casing is placed essentially in the center of the inner part of the reaction chamber, and in which the longitudinal orientation of the specified lamp casing coincides with the direction of flow.



 

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7 cl, 2 dwg, 21 ex, 6 tbl

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes compounds of the general formula (I): or their salts wherein dotted line means a double bond optionally; L means fragment of group comprising -CH2-CH2-CH2-, -CH2-CH=CH- and CH2-C≡C-; each R2 and R3 means independently alkyl or halogenalkyl; R1 and R4 mean independently hydrogen atom, acyl group or hydroxy-protecting group under condition that at least one radical among R1 and R4 mean acyl group. Also, invention relates to using compounds of the formula (I) or their salts as medicinal agents used in treatment of hyperthyroidism, renal osteodystrophy or osteoporosis.

EFFECT: valuable medicinal properties of compounds.

28 cl, 4 tbl, 13 ex

FIELD: organic chemistry, vitamins, medicine.

SUBSTANCE: invention relates to analogues of vitamin D of the general formula (I): wherein R1 and R2 mean halogen atom, (C1-C6)-hydrocarbon radical possibly substituted with 1, 2 -OH groups, 1, 2 fluorine (F) atoms, or R1 and R in common means (C3-C6)-carbocycle, or R1 and R2 in common mean a direct bond, or R1 and R2 in common mean hydrogen atom (H); R3 means H or (C1-C3)-hydrocarbon radical; X means (E)-ethylene, (Z)-ethylene, ethynylene or a bond; Y and Z mean H, -CH3; A means -OH, F or H; B means -CH2- or H2 under condition that compound of the formula (I) doesn't mean 3(S)-hydroxy-9,10-secocholesta-5(Z),7(E),10(19),22(E),24-pentaene. Compounds elicit strong suppression effect on secretion of parathyroid hormone and useful in treatment of secondary hyperparathyroiditis possibly associated with renal insufficiency.

EFFECT: valuable medicinal properties of vitamin D analogues.

19 cl, 2 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: method implies carbonylation of compound of formula , where each of R12, R13 and R14 stands for eliminated group, in solvent, in the presence of organoaluminium reagent (preferably, dimethylaluminium chloride) and palladium catalyst (preferably, tetrakis(triphenylphosphine)palladium) in carbon oxide atmosphere, to obtain compounds of formula , where R12 and R13 stand for above protective groups, and R15 stands for СН3, С2Н5, С3Н7 or С4Н9.

EFFECT: improved carbonylation method for preparation of intermediates in synthesis of new vitamin D derivatives.

2 cl, 6 ex, 2 tbl

FIELD: medicine; pharmaceutical.

SUBSTANCE: invention refers to pharmaceutical formulation and therapeutic method including introduction to related patient of composition 2-alkyliden derivative of 19-nor-vitamin D and bisphosphonate. In particular, this invention refers to pharmaceutical formulation and therapeutic methods including introduction to related patient of 2-methylene-19-nor-20(S)-1α,25- dihydroxyvitamin D3 and bisphosphonate selected from tyludronate, alendronate, zoledronate, ibanedronate, risedronate, ethydronate, clodronate or pamydronate. Stated invention allows increasing of therapeutic efficiency of such diseases as senile osteoporosis, postclimacteric osteoporosis, bone fracture, bone graft, osteopeny and male osteoporosis.

EFFECT: increased therapeutic efficiency.

18 cl, 2 ex, 2 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention describes application of derivatives of 10,10-dialkylprostanic acid as effective ophthalmic antihypertensive agents. Animal suffering from ocular hypertension or glaucoma is introduced with therapeutically effective amount of composition of general formula : where dotted line indicates presence or absence of bond, cross-hatch wedge designates α-configuration and solid triangle designates β-configuration; B is simple, double or triple covalent bond; n - 0-6; X - CH2, S or O; Y is any pharmaceutically acceptable salt of group CO2H, or group CO2R, CONR2, CONHCH2CH2OH, CON (CH2CH2OH)2, CH2OR, P(O)(OR)2, CONRSO2R, CONR2 or of formula Ia; R - H, C1-6alkyl or C2-6alkenyl; R2 and R3 represent C1-6normal alkyl which can be same or another, and can be connected with each other so that to form ring including carbon atom to which both of them are connected.

EFFECT: invention provides higher efficiency of composition and method of treatment.

52 cl, 1 ex, 2 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to novel methods for synthesis of intermediate compounds which are used in synthesis of calcipotriol.

EFFECT: present invention relates to use of intermediate compounds, obtained using said methods for synthesis of calcipotriol or monohydrate of calcipotriol.

15 cl, 10 ex

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