KR20130056238A - Process for the preparation of bimosiamose - Google Patents

Abstract

Compound (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted to (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester which is reacted with adipoyl chloride 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is obtained, which is catalytically reduced to 1,6-bis- [3- (3- Carboethoxy-methylphenyl) -4-methoxy-phenyl] -hexane (C) is obtained, which is reacted with boron tribromide in a solvent to give 1,6-bis- [3- (3-carboethoxy- Methylphenyl) -4-hydroxyphenyl] -hexane (D) is obtained, which is reacted with a mannopyranosyl derivative to give 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra -O-pivaloyl-α-D-mannopyranosyloxy) -phenyl] -hexane (E) is obtained, which is reacted to give 1,6-bis- [3- (3-carboxymethyl-phenyl) -4 -(2-α-D-mannopyranosyloxy) -phenyl] hexane, which recrystallizes to induce high purity product (I) A process for producing 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I) comprising a system.

Description

Production method of non-mosia moss {PROCESS FOR THE PREPARATION OF BIMOSIAMOSE}

The present invention is novel for the pharmaceutical compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (also referred to as bimosymos) It relates to a manufacturing method. By this method it is possible to produce bimosciamos in a larger quantity and in an improved manner with improved overall yield compared to the methods of the prior art. The novel process also enables the technical production of non-mosiamos on selective crystalline forms (polymorphs) and on an industrial scale.

Of the drug compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (bimosiamos or compound of formula (I)) Structures are US 5 919 768 and US 5 712 387; by I. Scott et al., Carbohydrate Research 317 (1-4), 1999, 210-216; by T. Kogan et al., J. Medicinal Chemistry 41 (7), 1998, 1099-1111 and EP-A 0 840 606. Compounds of formula (I) have a number of important pharmacological properties. Bimosciamos acts as a pan-selectin antagonist and inhibits leukocyte extravasation. Since leukocyte extravasation is an important step in the development of numerous inflammatory disorders or conditions, the compounds of formula (I) provide opportunities for use in various inflammation and micro-inflammatory signs and conditions.

Compounds of formula (I) bimosciamos have ten chiral centers and can be used for the prevention, treatment and diagnosis of inflammatory disorders and for the treatment and prevention of cosmetic and dermatological conditions involving micro-inflammatory conditions.

The compounds of formula (I) can also be administered for the treatment of other diseases associated with cell-cell adhesion. Since the compound of formula (I) modulates the binding of E-selectin or P-selectin or L-selectin, many diseases associated with the interaction can be treated by the adjustment of the binding interaction. The compounds of formula (I) are also useful for the treatment, diagnosis and prevention of various forms of cancer, including, for example, lung and colon cancers. Furthermore, the compounds of formula (I) can be used for the treatment, diagnosis and prevention of diseases or conditions wherein selectin mediated leukocyte retention is implicated, for example, in lung diseases [D. Bock et al., Curr. Respir. Med. Rev., 2006, 2, 339-354. The compounds of formula (I) and their physiologically acceptable salts are suitable as active pharmaceutical ingredients (APIs) for the prevention, treatment and diagnosis of various inflammatory or micro-inflammatory diseases or conditions. The compounds of formula (I) and / or their physiologically tolerated salts are preferably utilized above in the form of pharmaceutical formulations adapted for these compositions and in certain cases in dosage forms for the desired medical effect.

For example, bimoximos may be (a) a solid formulation, such as a tablet (eg, compressed, stratified, sugar, film or long coat, chewable, delayed or prolonged release, sublingual, buccal or foam) or capsule (B) parenteral solutions for injection and infusion in the form of (eg, hard filled or soft gelatin) or (b) liquid preparations, such as oral solutions, emulsions and suspensions, for example lyophilized powders, and It may be used in the form of ready-to-use injections or ophthalmic solutions, or (c) in the form of semisolid formulations for topical administration such as ointments, creams, gels or microemulsions. In addition, special formulations of bimosiamos, such as liposomes and related forms, micelle solutions, microspheres, nanoparticles or therapeutic systems such as transdermal therapeutic systems, implants or pumps, inhaled dosage forms, biodegradable or Bioerodible polymer systems, surgical or edible foams, soft or hydrated gels, microsponges are also suitable dosage forms.

Furthermore, the compounds of formula (I) can be used for the treatment of skin aging caused by exogenous and endogenous factors. Signs of skin aging include changes in skin thickness, elasticity, flexibility, and the appearance of wrinkles and fine lines, yellowing of the skin that leads to a wrinkled appearance with apparent pigment defects, generally thickening of the stratum corneum and epidermis, and thinning of the skin. Breakdown of elastin and collagen fibers leading to loss of firmness, and apparent capillary dilatation.

Various methods of synthesis are known for nonmosiamos, for example [T. Kogan et al., J. Medicinal Chemistry 41 (7), 1998, 1099-1111 or US 5 919 768 or US 5 712 387. However, the overall yield of known methods is rather low (2-3%). Furthermore, known methods have proven difficult to realize industrial manufacturing scales without further loss of overall yield and quality. The protection of the two carboxylic acid functional groups of the bimosiamos precursor material as the corresponding methyl ester is known in the prior art.

Surprisingly, however, the process of the present invention has proved to work particularly well when ethyl esters are applied as protecting groups. These have obvious advantages over, for example, the corresponding methyl esters. They are much more stable under conditions of industrial scale and do not need to cut and reinstall these groups in the course of the synthesis of non-mosia moss. Thus, the number of reaction steps can be reduced compared to the methods of the prior art [T. Kogan et al., J. Medicinal Chemistry 41 (7), 1998, 1099-1111; US 5 919 768; See US 5 712 387].

One task of the present invention is also to provide a method that enables the chemical synthesis of non-mosiamos of high quality and purity on an industrial manufacturing scale. The quality of the product should be very high so that it can be applied to the manufacture of drug products, diagnostics and / or cosmetics comprising bimosciamos. In addition, the process or method of the present invention should use cost-effective starting materials, intermediates and reagents. The production process should be characterized by producing high overall yields and high purity product bimosyamos in a few process steps.

Technical problem is the preparation of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane, which is a compound of formula (I) As a method:

Compound (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted to (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester which is reacted with adipoyl chloride 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) was obtained, followed by catalytic reduction to 1,6-bis- [3- (3 -Carboethoxy-methylphenyl) -4-methoxyphenyl] -hexane (C), which is reacted with boron tribromide in a solvent to yield 1,6-bis- [3- (3-carboethoxy- Methylphenyl) -4-hydroxyphenyl] -hexane (D) is obtained, which is reacted with mannopyranosyl derivatives (particularly tetra-O-protected mannopyranosyl derivatives) to give 1,6-bis- [3- ( 3-carbo-ethoxy-methylphenyl) -4- (tetra-O-protected-α-D-mannopyranosyloxy) -phenyl] -hexane-derived, such as 1,6-bis- [3- (3 -Carboethoxy-methylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyrano-siloxy) -phenyl] -hexane (E) was obtained Which is reacted under basic reaction conditions to form 1,6-bis- [3- (3-carboxymethyl-phenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane, which optionally Is solved by a production process comprising the step of recrystallization from one, two or several organic solvents and / or water to obtain the product bimosiamos of the formula (I).

In certain embodiments, the present invention provides 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] hexane, comprising the following process steps: It relates to a process for preparing (I):

a) (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted under acidic conditions to form (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester Reaction with adipoyl chloride in a solvent affords 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B), wherein an intermediate (2'-methoxy Not biphenyl-3-yl) -acetic acid ethyl ester,

b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is reduced with hydrogen and a metal catalyst to reduce 1,6-bis- [3- Forming (3-carboethoxy-methylphenyl) -4-methoxyphenyl] -hexane (C),

c) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) is reacted with boron tribromide in a solvent to give 1,6-bis- [3- Obtaining (3-carboethoxymethyl-phenyl) -4-hydroxyphenyl] -hexane (D),

d) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) to mannopyranosyl-derivatives (eg, tetra-O-protected mannopyranosyl -Derivatives), in particular with tetra-O-pivaloyl-D-manno-pyranosyl-halide or tetra-O-acetyl-D-mannopyranosyl-halide to react with 1,6-bis- [3- (3- Carboethoxy-methylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) or the corresponding 1,6-bis- [3- ( Obtaining 3-carboethoxy-methylphenyl) -4- (tetra-O-acetyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane,

e) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) Or corresponding 1,6-bis- [3- (3-carboethoxy-methyl-phenyl) -4- (tetra-O-acetyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane ( Or the corresponding tetra-O-protected mannopyranosyl-derivatives) under basic reaction conditions to give 1,6-bis- [3- (3-carboxymethyl-phenyl) -4- (2-α-D-manno Forming pyranosyloxy) -phenyl] hexane (I),

f) optionally 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane with one or several organic solvents and / or water or Recrystallization from the mixture to obtain the product of formula (I), bimosciamos.

In a further embodiment, the invention provides 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] comprising the following process steps Relates to a process for the preparation of hexane (I):

a) (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted under acidic conditions to form (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester 1,4-bis- [3- (3-carboethoxy-methylphenyl) -4-methoxybenzoyl] -butane (B) reacting with adipoyl chloride and Lewis acid in a solvent to yield greater than 95% purity and a yield of at least 70% Yielding no intermediate (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester,

b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is reduced with hydrogen and a metal catalyst to reduce 1,6-bis- [3- Forming (3-carboethoxy-methylphenyl) -4-methoxyphenyl] -hexane (C),

c) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) with boron tribromide in a solvent at a temperature range of -20 ° C to + 20 ° C. Reacting to give 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D),

d) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in the presence of a catalytic amount of Lewis acid and a temperature of -10 ° C to + 15 ° C. 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra-O-pivaloyl by reacting with tetra-O-pivaloyl-D-mannopyranosyl-halide in the range obtaining -α-D-manno-pyranosyloxy) -phenyl] -hexane (E),

e) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) Is reacted with sodium methylate followed by aqueous sodium hydroxide to give 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I) Forming a step,

f) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane is recrystallized from an organic solvent or a mixture of organic solvent and water Obtaining a product of formula (I), bimosyamos, of greater than 98% purity.

In another embodiment, the invention provides 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] comprising the following process steps Relates to a process for the preparation of hexane (I):

a) (2'-methoxy-biphenyl-3-yl) -acetic acid (A) in the temperature range of + 60 ° C to + 99 ° C with 2-methoxyphenyl-boronic acid and at least 10% molar excess of 3- After preparation from bromophenylacetic acid, (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted under acidic conditions to (2'-methoxy-biphenyl-3-yl) -acetic acid After forming ethyl ester, 1,4-bis- [3- (3-carboethoxy-methylphenyl) -4-methoxybenzoyl] -butane (B) was reacted with adipoyl chloride and aluminum chloride in a solvent. Which does not isolate the intermediate (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester,

b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) with hydrogen, Pd-catalyst and ethanol, ethyl acetate and trifluoroacetic acid Reducing with a mixture to form 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C),

c) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) is boron tribromide in dichloromethane in the temperature range of -5 ° C to + 5 ° C. Reaction with to give 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D), followed by hydrolysis of the reaction mixture with excess ethanol, The hydrolyzed mixture was treated in boiling ethanol to dimer and condensate product to the reaction product 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D). Converting step,

d) catalytic amount of boron trifluoride of 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in the temperature range of -5 deg. 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra) by reaction with tetra-O-pivaloyl-D-mannopyranosyl fluoride in the presence of diethyletherate Obtaining -O-pivaloyl-α-D-mannopyranosyloxy) -phenyl] -hexane (E),

e) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) Is reacted with sodium methylate in a mixture of tetrahydrofuran and methanol at a temperature ranging from + 15 ° C. to + 25 ° C. and subsequently with aqueous sodium hydroxide at a temperature ranging from 0 ° C. to + 10 ° C. to 1,6-bis- [ 3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyl-oxy) -phenyl] hexane (I);

f) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (I) of tetrahydrofuran or tetrahydrofuran with water Recrystallization from the mixture to obtain the product of formula (I), bimosyamos, in purity form 98.5% and in the crystal form of polymorph FORM 2 thereof.

The invention also relates to a process for the preparation of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] hexane (I), which comprises first step a Compound (2'-methoxy-biphenyl-3-yl) -acetic acid (A) as thion) with thionyl chloride, followed by reaction with ethanol to give compound (A) (2'-methoxy-biphenyl- To 3-yl) -acetic acid ethyl ester.

In a further embodiment, the invention provides a process for the preparation of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] hexane (I) Compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (I) as ethanol / water mixture Recrystallization from the present invention relates to obtaining bimosiamos of the crystalline form of the polymorph FORM 2.

In certain embodiments, the invention provides a process for the preparation of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] hexane (I) , Compound f, 6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyrano-siloxy) -phenyl] -hexane (I) as step f) isopropanol / water Recrystallization from the mixture relates to obtaining bimociamos in purity of at least 99.0% and the crystalline form of the polymorph FORM 2.

In another embodiment, the invention provides a process for the preparation of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] hexane (I) Intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) as step b) and intermediate 1,6-bis- in step c) It is related to isolating [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) as a solid product and optionally as each solution.

The invention also provides a process for the preparation of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I), as step d). Intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) to α / β of tetra-O-pivaloyl-D-mannopyranosyl halide It deals with reacting with mixtures of stereoisomers.

Certain embodiments of the present invention are products prepared by the method as described above and having a purity of at least 99%, in particular at least 99.5%, 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D -Mannopyranosyloxy) -phenyl] hexane (I). In particular, compound (I) comprises less than 0.1% of stereoisomers of bimosiamos.

Another embodiment of the invention is 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D prepared by the method as described above and having a purity of at least 99%, in particular at least 99.5%. -Mannopranosyloxy) -phenyl] hexane (I) and one or more additional pharmaceutically acceptable carriers. The pharmaceutical composition of the invention comprises a pharmaceutically acceptable carrier and a compound of formula (I), wherein the pharmaceutically acceptable carrier may also be a conventional excipient for the pharmaceutical composition, as well as eg suitable nano -Particles, dendrimers, liposomes, microbubbles or polyethylene glycols (PEG). The pharmaceutical compositions of the present invention may comprise, for example, one or more physiologically acceptable carriers, adjuvants or vehicles, collectively referred to herein as carriers for parenteral injection, oral administration in solid or liquid form, rectal or topical administration. Compound (I) formulated together.

The composition may be, for example, orally, rectally, parenterally (intravenously, intramuscularly, intradermally or subcutaneously), intracavitally, intravaginally, intraperitoneally, locally (powder, ointment or drop), as an oral formulation. Or by inhalation (as a spray or nasal spray) to humans and animals. Compositions suitable for parenteral injection include physiologically acceptable sterile aqueous or nonaqueous solutions, stabilizers, antioxidants, preservatives (e.g. ascorbic acid, sodium sulfite, sodium hydrogen sulfite, benzyl alcohol, EDTA), dispersions, suspensions Water or emulsions, and sterile powders that are reconstituted into sterile injectable solutions or dispersions.

These compositions may also include preservatives, wetting agents, emulsifiers, dispersants and / or adjuvants such as antibacterial and antifungal agents. If desired, for more effective dispensing, the compounds may be incorporated into slow or sustained release, or into targeted delivery systems such as polymer matrices, liposomes and microspheres. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Solid compositions of a similar type may also be utilized as fillers in soft and hard-filled gelatin capsules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms can include inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and fragrances. have. In addition to the active compound, the suspension may comprise suspending agents. Compositions for rectal administration are preferably suppositories. Dosage forms for topical administration of a compound of this invention include ointments, creams, gels, powders, sprays and inhalants.

For the preparation of the composition, the pure compound of formula (I) is usually admixed under sterile conditions with a physiologically acceptable carrier and any necessary preservatives, buffers or propellants as required. The actual dosage level of compound (I) in the compositions of the present invention can be varied to obtain an amount of active ingredient effective to obtain the desired therapeutic response for the particular composition and method of administration. Thus, the dosage level chosen depends on the desired therapeutic effect, route of administration, desired duration of treatment and other factors. The total daily dose of Compound (I) of the invention administered to the host in single or divided doses may range up to 50 mg / kg body weight. Dosage unit compositions may include such submultiples thereof as may be used to make up the daily dosage. However, specific dosage levels for any particular patient, whether human or other animal, include body weight, general health, sex, diet, time and route of administration, rate of absorption and excretion, combination with other drugs, and the severity of the particular disease being treated. It will be considered according to various factors.

In one specific embodiment of the preparation process, starting from 2-methoxyphenylboronic acid (2'-methoxy-biphenyl-3-yl) -acetic acid (A) and greater than 98% (especially 99) by Pd catalyst Compound (I) is prepared in a high purity of greater than%) and in a yield of greater than 90% (in particular greater than 93%).

In one embodiment, (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted to (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester followed by 1,4-bis- [3- (3- with a high purity of greater than 95% (particularly greater than 96%) and a yield of at least 70% (particularly at least 75%) by reaction with foil chloride and Lewis acid (aluminum chloride) Carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is obtained.

In one embodiment, 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is applied by applying a metal catalyst, in particular a catalyst comprising Pd It is chemically reduced under hydrogen atmosphere with, 6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C).

In one embodiment, 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) is dichloromethane in a temperature range of -20 ° C to + 20 ° C. In the reaction with boron tribromide to give 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D).

In one embodiment, 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) is reacted in the presence of a catalytic amount of Lewis acid and from -10 ° C to + 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D- by reacting with a properly protected mannopyranosyl halide in the temperature range of 15 ° C. Mannopyranosyl-oxy) -phenyl] -hexane (E) or the corresponding O-protected derivative is obtained.

In one embodiment, 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl]- Hexane (E) or the corresponding O-protected derivative is reacted with sodium methylate followed by aqueous sodium hydroxide to give crude product (I) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane is obtained.

In one embodiment, 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyl-oxy) -phenyl] -hexane is added to an organic solvent (eg, ethanol, Methanolyte or tetrahydrofuran) and optionally recrystallization from water to give a high quality and greater than 98% (especially greater than 98.5%) of bimosyamos.

It is known in the prior art that the introduction of mannose units into the molecular nonmosiamos works well when the aglycone of bimosiamos is reacted with tetra-O-pivaloyl-α-D-mannopyranosyl fluoride. (See US 5 712 387). Surprisingly, tetra-O-pivaloyl-D-mannopyranosyl fluoride as a mixture of α / β-forms, which is much more readily available and more cost-effective than pure α-anomers, has the same optical ( Stereochemistry) and has been shown to provide purity of non-mosiamos. Recrystallization of the crude product bimosyamos from an ethanol / water mixture or isopropanol / water mixture can lead to the so-called polymorph FORM 2 as described in WO 2008/028966, where the yield is 70%. Surprisingly, the recrystallization of the crude bimosiamos from the tetrahydrofuran / water mixture gives a polymorph FORM 2 with a yield of 85%.

Polymorph FORM 2 (see WO 2008/028966) is characterized by providing an X-ray powder diffraction pattern for this crystalline form exhibiting the following diffraction angles based on copper K _α1 .

About 5.3 ° (strong peak),

About 5.6 ° (strong peak),

About 17.4 ° (strong peak),

About 9.9 ° (medium peak),

About 10.3 ° (medium peak),

About 13.8 ° (medium peak),

About 15.0 ° (medium peak),

About 16.3 ° (medium peak),

About 16.6 ° (medium peak),

About 18.7 ° (medium peak),

About 19.1 ° (medium peak),

About 19.2 ° (medium peak),

About 19.8 ° (medium peak),

About 20.1 ° (medium peak),

About 20.4 ° (medium peak),

About 20.7 ° (medium peak),

About 21.5 ° (medium peak),

About 24.3 ° (medium peak),

About 24.8 ° (medium peak),

About 25.5 ° (medium peak), and

About 26.5 ° (medium peak).

The polymorph “FORM 2” of compound (I) (see WO 2008/028966) substantially gives the X-ray powder diffraction pattern according to FIG. 1. Furthermore, polymorph FORM 2 is characterized by having a melting range of 158 ° C to 161 ° C. Alternatively, recrystallization of the crude product bimosyamos from an ethanol / water mixture or isopropanol / water mixture is also a suitable method of inducing purified bimosiamos of the polymorph FORM 2.

A further advantage of the process of the present invention is that the product bimosciamos is obtained in an overall yield of at least 30% (particularly 34%), which is much higher than the yields obtained by the methods of the prior art (about 2-3%).

In a further preferred embodiment of the invention, 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (bimociamos) The process for the preparation of the second step (step b) is carried out in which the corresponding acid chlorides are firstly quantitative in yield and the purity of (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester is above 99.0%. In order to produce ethanol with the advantage, in particular, reaction with thionyl chloride to give (2'-methoxy-biphenyl-3-yl) -acetic acid to (2'-methoxy-biphenyl-3-yl) -ethyl acetate Conversion to ester is added.

One aspect of the invention can be illustrated by the following scheme:

The present invention also relates to pharmaceutical compositions comprising bimosiamos for novel medical uses. Pharmaceutical formulations, including non-mosciamos, may be used for skin aging caused by lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) or acute lung injury, skin diseases such as psoriasis and atopic dermatitis, micro-inflammatory conditions [WO2008028950 Or known in the prior art as useful for methods of treatment of interleukin-8 mediated disorders associated with viral infection [see WO2008098985].

The present invention also applies to pharmaceutical compositions comprising bimosciamos and / or salts of bimosciamos and / or stereoisomeric or polymorphic forms thereof, for example matrix metalloproteinases in sputum (eg, in humans) A method of reducing the concentration of (MMP). The present invention also applies to pharmaceutical compositions comprising bimosciamos and / or salts of bimosciamos and / or stereoisomeric or polymorphic forms thereof, for example matrix metalloproteinases in sputum (eg, in humans) 9 (MMP-9).

The present invention also applies to pharmaceutical compositions comprising salts of bimosciamos and / or bimosciamos and / or stereoisomeric or polymorphic forms thereof to reduce the number of lymphocytes in (e.g., human) sputum. It is about a method.

The present invention also relates to the use of salts of and / or stereoisomers or polymorphic forms thereof for the preparation of pharmaceutical compositions for the treatment, prevention (or diagnosis) of irritable pneumonia and pulmonary sarcoidosis. will be.

The invention also relates to salts of and / or stereoisomer or polymorphic forms thereof and / or one or more additional pharmaceutical agents for the treatment, prevention (or diagnosis) of irritable pneumonia and / or pulmonary sarcoidosis. It relates to a pharmaceutical composition comprising an inert component.

The invention also provides salts of and / or stereoisomer or polymorphic forms thereof and one or more additional pharmaceutically active ingredients for the treatment, prevention (or diagnosis) of irritable pneumonia and pulmonary sarcoidosis. It relates to a pharmaceutical composition comprising a.

The invention also includes salts of and / or stereoisomer or polymorphic forms thereof and one or more additional pharmaceutically inactive ingredients for the treatment, diagnosis or prevention of irritable pneumonia and pulmonary sarcoidosis. It relates to a pharmaceutical composition.

The present invention also relates to salts of and / or stereoisomeric or polymorphic forms of bimosiamos and / or bimosiamos (for the preparation of pharmaceutical compositions) for the treatment, prevention (or diagnosis) of certain inflammations, pulmonary emphysema and ocular diseases. It relates to the use of. "Inflammation" includes (or means) ocular inflammation, hypersensitivity, periodontal disease, otitis, ulcer, ulcerative colitis, mucositis, pneumonia, celiac inflammation and cystitis. "Ocular disease" includes (or means) corneal damage, corneal ulcer, infectious diseases in the field of ophthalmology, dry eye, ocular disease, corneal macular degeneration, pterygium, uveitis and lacrimal disease.

The invention also relates to salts of and / or stereoisomers or polymorphic forms thereof and one or more additional pharmaceutical agents for the treatment, prevention (and diagnosis) of certain inflammations, pulmonary emphysema and ocular diseases. It relates to a pharmaceutical composition comprising a generally acceptable component.

"Inflammation" includes (or means) ocular inflammation, hypersensitivity, periodontal disease, otitis, ulcer, ulcerative colitis, mucositis, pneumonia, celiac inflammation and cystitis. "Ocular disease" includes (or means) corneal damage, corneal ulcer, infectious diseases in the field of ophthalmology, dry eye, ocular disease, corneal macular degeneration, pterygium, uveitis and lacrimal disease.

The invention also relates to a process for the preparation of a pharmaceutical composition comprising the step of admixing a salt of bimosciamos and / or a salt of bimosciamos and / or stereoisomeric or polymorphic forms thereof. The composition sometimes comprises from 0.01% to 20% by weight of the bimoscias and / or salts of bimoscias and / or stereoisomeric or polymorphic forms thereof. The invention also relates to such a method, wherein the composition comprises from 0.01% to 10% by weight of non-mosia moss and / or salts of non-mosia moss and / or stereoisomeric or polymorphic forms thereof. The invention also relates to such a method, wherein the composition comprises one or more additional pharmaceutically active ingredients.

In addition, at present, surprisingly, studies of human volunteers have shown that bimosiamos significantly reduces the sputum concentration of matrix metalloproteinases (MMP), in particular matrix metalloproteinase-9 (MMP-9). lost. Even more surprisingly, the number of sputum lymphocytes was significantly reduced under treatment with non-mosiamos. These findings are illustrated in the graph of FIG. 2.

In FIG. 2, the effect of treatment of bimosiamos on the enzyme MMP-9 (reduction of enzyme concentration per sputum volume) and the effect of nonmosamos on lymphocytes (reduction of lymphocytes per sputum volume) in human volunteers are shown. . Surprising results in the reduction of MMP-9 levels and lymphocyte count in sputum with the administration of non-mosciamos, and influencing both MMP-9 levels and lymphocyte counts in various diseases are new opportunities, and the treatment of medical signs and diseases , The use of the composition for diagnosis and prophylaxis, in particular a pharmaceutical composition (or alternatively bimosiamos and one or more additional pharmaceutically active ingredients) comprising bimosiamos and / or one or more additional pharmaceutically inactive ingredients To a pharmaceutical composition). Accordingly, the present invention further relates to bimoximos, which is used (eg, as a pharmaceutical composition) for the treatment, diagnosis or prevention of irritable pneumonia and pulmonary sarcoidosis.

One embodiment of the invention relates to a pharmaceutical composition comprising bimosiamos for the treatment, diagnosis and prevention of certain inflammations, lung emphysema and eye diseases. "Inflammation" includes (or means) ocular inflammation, hypersensitivity, periodontal disease, otitis, ulcer, ulcerative colitis, mucositis, pneumonia, celiac inflammation and cystitis.

"Ocular disease" includes (or means) corneal damage, corneal ulcer, infectious diseases in the field of ophthalmology, dry eye, ocular disease, corneal macular degeneration, pterygium, uveitis and lacrimal disease.

The present invention relates to the use of a compound of formula (I), a salt of the compound or a stereoisomer or polymorphic form thereof, for the manufacture of a pharmaceutical composition for the treatment, diagnosis or prophylaxis of MMP-9 mediated disorders.

The pharmaceutical composition can be used for the treatment, diagnosis or prevention of irritable pneumonia. The pharmaceutical composition can be used for the treatment, diagnosis or prevention of pulmonary sarcoidosis. The present invention optionally comprises one or more additional compounds of formula (I) and / or salts of compounds of formula (I) and / or stereoisomeric or polymorphic forms thereof for the treatment, diagnosis or prevention of irritable pneumonia or pulmonary sarcoidosis. It relates to a pharmaceutical composition comprising in combination with a pharmaceutical inert ingredient.

The present invention provides a compound of formula (I) and / or a salt of a compound of formula (I) and / or a stereoisomeric or polymorphic form thereof for the treatment, diagnosis or prevention of irritable pneumonia or pulmonary sarcoidosis. It relates to a pharmaceutical composition comprising in combination with the active ingredient and optionally in combination with one or more further pharmaceutical inert ingredients.

The present invention relates to pulmonary emphysema or certain inflammations such as ocular inflammation, hypersensitivity, periodontal disease, otitis, ulcers, ulcerative colitis, mucositis, pneumonia, celiac inflammation, pulmonary emphysema and cystitis, or ocular diseases such as corneal damage, corneal ulcers, ophthalmology Compounds of formula (I) and / or salts of compounds of formula (I) for the treatment, diagnosis or prevention of infectious diseases, dry eye, ocular disease, corneal macular degeneration, pterygium, uveitis and lacrimal disease in the field A pharmaceutical composition comprising a stereoisomeric or polymorphic form, optionally in combination with one or more additional pharmaceutically inactive ingredients.

The present invention relates to pulmonary emphysema or certain inflammations such as ocular inflammation, hypersensitivity, periodontal disease, otitis, ulcers, ulcerative colitis, mucositis, pneumonia, celiac inflammation, pulmonary emphysema and cystitis, or ocular diseases such as corneal damage, corneal ulcers, ophthalmology Compounds of formula (I) and / or salts of compounds of formula (I) for the treatment, diagnosis or prevention of infectious diseases, dry eye, ocular disease, corneal macular degeneration, pterygium, uveitis and lacrimal disease in the field A pharmaceutical composition comprising a stereoisomeric or polymorphic form in combination with one or more additional pharmaceutically active ingredients and optionally in combination with one or more additional pharmaceutically inactive ingredients.

The present invention relates to a process for the preparation of these pharmaceutical compositions.

The process for the preparation of the pharmaceutical composition comprises mixing a compound of formula (I) and / or a salt of a compound of formula (I) and / or a stereoisomer or polymorphic form thereof. The composition may sometimes comprise from 0.01% to 20% by weight of the compound of formula (I) and / or salts of the compound of formula (I) and / or stereoisomeric or polymorphic forms thereof, and 0.01% by weight, based on the total weight of the composition To 10% by weight of one or more additional pharmaceutically active ingredients.

The invention is described in more detail by the following examples:

Example  1 (manufacturing method)

Step 1: (2'- Methoxy - Biphenyl Yl) -acetic acid

A mixture of 3-bromophenyl-acetic acid, 2-methoxyphenylboronic acid, potassium carbonate and a catalytic amount of (PPh ₃ ) ₂ PdCl ₂ in water for 2 hours until 3-bromophenyl-acetic acid is virtually free Heat at 77 ° C. The mixture is extracted with toluene at ambient temperature to remove impurities. Toluene and additional water are added to the aqueous layer. Concentrated sulfuric acid is added under cooling until pH ˜1 is reached.

The two-layer mixture is filtered and the layer is separated at ambient temperature. The aqueous layer is extracted with toluene. The combined organic layers were washed twice with dilute sulfuric acid, and then washed with water. Some toluene is distilled off and the mixture is cooled to 35 ° C. Heptane is added to the solution within 1 hour or more, while the product precipitates. The suspension is cooled to 3 ° C. The crystals of (2'-methoxy-biphenyl-3-yl) -acetic acid (A) obtained are isolated by solid-liquid separation, washed with heptane and used in the next step without drying.

The yield of step 1 of the process is 87%, but can be improved to 91% by changing the workup procedure as follows: 32% hydrochloric acid is applied to acidification instead of concentrated sulfuric acid and additional water. This has the positive effect that no precipitation of potassium (bi-) sulfate occurs, the V _max / V _min ratio is reduced, and two washing steps with dilute sulfuric acid are omitted.

Step 2: 1,4- Vis -[3- (3- Carboethoxymethylphenyl )-4- Methoxybenzoyl ] -Bhutan (B)

A solution of (2'-methoxy-biphenyl-3-yl) -acetic acid (A) in ethanol was added for 2 hours until (2'-methoxy-biphenyl-3-yl) -acetic acid was virtually free. Reflux in the presence of a catalytic amount of concentrated sulfuric acid. The mixture is treated with concentrated aqueous solution of potassium carbonate at ambient temperature until pH 7 is reached. Ethanol is distilled off under vacuum and the distillation residue is diluted with dichloromethane. The solution is washed with water and the aqueous layer is extracted with dichloromethane. The combined organic layers are treated with sodium sulfate at ambient temperature to remove residual water. The mixture is filtered and the filtrate is evaporated to remove residual water and ethanol. Distillation residue ((2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester) is diluted with dichloromethane and the absence of water and ethanol is checked.

The solution is added to a suspension of aluminum chloride (as Lewis acid) in a polar solvent, preferably dichloromethane, at a maximum of 0 ° C. at a rate that makes it possible to maintain the temperature of the obtained mixture at 0 ° C. A solution of adipoyl chloride in dichloromethane is added slowly at up to 0 ° C. (within 1 hour or more). The mixture is stirred at 5 ° C. until no (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester remains. The solution is added to the ice water mixture at up to 5 ° C for hydrolysis. The layers are separated at ambient temperature. The aqueous layer is extracted with dichloromethane.

The combined organic layers were washed twice with water. Dichloromethane is distilled off without vacuum and the distillation residue is diluted with isopropyl acetate. Isopropyl acetate is partially distilled off and the mixture is cooled to 53 ° C. The solution is treated with a small amount of water and seeded. After cooling to ambient temperature, the mixture is stirred for at least 2 hours. After further cooling to 3 ° C. and stirring for at least 1 hour, the obtained crystals are isolated by solid-liquid-separation, washed with cold isopropyl acetate and dried at ˜45 ° C. under vacuum.

The crude 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) obtained was diluted in isopropyl acetate and kept at 75 ° C. for 1-2 hours. Treat with charcoal. The charcoal is then filtered off and the filtrate is cooled to 53 ° C. The solution is treated with a small amount of water and seeded. After cooling to ambient temperature, the mixture is stirred for at least 2 hours. After further cooling to 3 ° C. and stirring for at least 1 hour, the white crystals obtained are isolated by solid-liquid-separation, washed with cold isopropyl acetate and dried under vacuum at ˜45 ° C. to give 1,4- Bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is obtained.

The yield of step 2 of the process is 70%, but can be improved to 74% by changing the procedure as follows: (1) bisect the amount of EtOH for the esterification step and add 5% of the catalytic amount of sulfuric acid; Limited to w / w or less (which has the positive effect of eliminating neutralization of the reaction mixture to potassium carbonate) and simply distilling EtOH after the esterification reaction. (2) Further, the drying procedure to sodium sulfate is omitted by removing residual water from the crude esterified product by azeotropic distillation to toluene. (3) The aluminum chloride suspended in dichloromethane and adipoyl chloride is premixed in a reactor at 0 ° C., and then ester is slowly added to the mixture.

Step 3: 1,6- Vis -[3- (3- Carboethoxymethylphenyl )-4- Methoxyphenyl ] - Hexane  (C)

A solution of 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) in a mixture of ethanol and ethyl acetate was dissolved in 1,4-bis- [3- ( 3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane and a catalytic amount of palladium catalyst (Evonik Degussa GmbH, Germany) at 52 ° C. under a pressure of 8 bar for 6 hours until virtually no intermediate remains. Pd / C catalyst of type "E101 0 / W 5% mass") and hydrogen in the presence of trifluoroacetic acid. The reaction mixture is cooled to ambient temperature, the catalyst is filtered off and washed with ethyl acetate. The solvent is distilled off at 40 ° C. under vacuum.

Distillation residue is diluted with toluene and distillation is repeated under the same conditions. 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] that can be isolated by dissolving the distillation residue in toluene but can also be used directly (without isolation) in the following reaction step Toluene solution of -hexane (C) is obtained. The yield of step 3 of the process is almost 100%.

Step 4: 1,6- Vis -[3- (3- Carboethoxymethylphenyl )-4- Hydroxyphenyl ] - Hexane  (D)

Toluene solution of 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) from step 3 above was diluted with additional toluene and at a maximum of 50 ° C. Evaporate under vacuum. The distillation residue is dissolved in dichloromethane and the absence of water is checked. Boron tribromide is added at up to 0 ° C. in no less than 2 hours. The reaction mixture was stirred at 3 ° C. for 2 hours until 1,6-bis- [3- (3-carboethoxymethyl-phenyl) -4-methoxyphenyl] -hexane and partially demethylated intermediates were virtually free. Stir. A sufficient amount of ethanol for the hydrolysis of the reaction mixture is added at a rate that makes it possible to maintain the temperature of the mixture at 3 ° C. After warming to 15 ° C., a large amount of ethanol is added within 1.5 hours or more. The solvent is carefully distilled off without vacuum.

Ethanol is added and the mixture is refluxed for 2 hours until virtually no condensation byproduct remains. The solvent is distilled off without vacuum and the distillation residue is dissolved in dichloromethane. The solution is added to the ice water mixture at up to 5 ° C. The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layers were washed twice with water. Dichloromethane is distilled off without vacuum and the distillation residue is diluted with toluene.

As one option, toluene is distilled off under vacuum at up to 70 ° C. The distillation residue is again dissolved in toluene to give a toluene solution of 1,6-bis- [3- (3-carbo-ethoxymethyl-phenyl) -4-hydroxyphenyl] -hexane (D), which is It can be isolated but can also be used directly in the following reaction step.

Alternatively, the following work up procedure can be applied to isolate 1,6-bis- [3- (3-carboethoxymethyl-phenyl) -4-hydroxyphenyl] -hexane (D) in solid form. The toluene can be distilled off under vacuum at up to 80 ° C. The distillation residue is dissolved in diisopropyl ether and some diisopropyl ether is distilled off to remove residual toluene. The mixture is cooled to 30 ° C. and seeded. After cooling to ambient temperature, the suspension is stirred for at least 8 hours.

After further cooling to 5 ° C. and stirring for at least 3 hours, the crystals are isolated by solid-liquid-separation, washed with diisopropylether and dried under vacuum at 35 ° C. to yield 1,6-bis as a white solid. -[3- (3-Carboethoxymethyl-phenyl) -4-hydroxy-phenyl] -hexane (D) is obtained. The yield of step 4 of the process is almost 100%.

Step 5: 1,6- Vis -[3- (3- Carboethoxymethylphenyl )-4-( Tetra -O- Pivaloyl -α-D-manno- Pyranosyloxy ) - Phenyl ] - Hexane  (E)

Toluene solution of 1,6-bis- [3- (3-carboethoxymethyl-phenyl) -4-hydroxy-phenyl] -hexane (D) from step 4 above was diluted with additional toluene and Evaporate under vacuum at 80 ° C. The distillation residue is dissolved in dichloromethane and the α / β-mixture of tetra-O-pivaloyl-D-mannopyranosyl fluoride is added. Alternatively, α- or β-stereoisomers of tetra-O-pivaloyl-D-mannopyranosyl fluoride can be used. Some dichloromethane is distilled off and the absence of water is checked. Boron trifluoride diethyl etherate is added at up to 3 ° C. in at least 2 hours. The reaction mixture is stirred at 0 ° C. for 6 hours until 1,6-bis- [3- (3-carboethoxymethyl-phenyl) -4-hydroxy-phenyl] -hexane and intermediates are virtually free. . The solution is added to the ice water mixture at up to 10 ° C. The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layers are divided twice with aqueous sodium carbonate solution and washed with water. Dichloromethane is distilled off without vacuum and the distillation residue is diluted with toluene. Toluene is distilled off under vacuum at 65 ° C. The distillation residue is dissolved in methanol. Some methanol is distilled off and the mixture is cooled to 45 ° C. The solution is seeded and stirred at 45 ° C. for at least 90 minutes.

After cooling to 22 ° C. and stirring for at least 2 hours, the obtained crystals are isolated by solid-liquid-separation, washed with methanol and dried under vacuum at ˜40 ° C. to give 1,6-bis- [3- ( 3-Carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-manno-pyranosyl-oxy) -phenyl] -hexane (E) is obtained. The yield in step 5 of the process is 86%.

Step 6: 1,6- Vis -[3- (3- Carboxymethylphenyl ) -4- (2-α-D- Mannopyranosyloxy ) - Pe Nyl] - Hexane , Unrefined Bimoshia Moss  (I)

1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-manno-pyranosyloxy) -phenyl] -hexane (E) to toluene Dilute and evaporate under vacuum at up to 70 ° C. The distillation residue is dissolved in a mixture of tetrahydrofuran and methanol. Check for the absence of water.

Cell bunch and methanolic sodium methylate solution (30%) are added (as a cellulose-based physical aid) at 23 ° C. The reaction mixture was prepared 1,6-bis- [3- (3-carbo-ethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-manno-pyranosyloxy) -phenyl] -hexane and Stir at 23 ° C. for 8 hours until no intermediate remains virtually. The mixture is filtered, washed with a mixture of tetrahydrofuran and methanol and then with methanol. Filter cake (1,6-bis- [3- (3-carbomethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-manno-pyranosyloxy) -phenyl] -hexane and cell bunch ) Is suspended in water and aqueous NaOH solution (30%) is added at 5 ° C. The reaction mixture was substantially left with 1,6-bis- [3- (3-carbomethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-manno-pyranosyloxy) -phenyl] -hexane Stir at 5 ° C. for 5 hours until not present.

The cell cluster is filtered off and washed with water. Dilute HCl is added to the filtrate at 2 ° C. until pH 2.5-3.0 is reached. After stirring at 2 ° C. for at least 3.5 hours, the obtained crystals are isolated by solid-liquid-separation. The wet cake is suspended in water and warmed to 45 ° C. Ethanol is added and the mixture is cooled to 5 ° C. After stirring at 5 ° C. for at least 3 hours, the obtained crystals are isolated by solid-liquid-separation, washed with a mixture of water and ethanol and dried under vacuum at ˜45 ° C. to yield 1,6-bis- [3- (3-carboxy-methylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (crude bimosyamos) is obtained. The yield in step 6 of the process is 69%.

Step 7: Pure Bimoshia Moss

Crude bimosciamos (I) is dissolved in aqueous tetrahydrofuran or slightly below reflux temperature. The solution is filtered through a micro filtration cloth and cooled to about 52 ° C. The solution is seeded with about 0.5 w / w% bimocymoss and then cooled to 0 ° C. with a temperature gradient of 18 K / h. Additional tetrahydrofuran is added over a period of 1 hour starting at 18 ° C. without interruption of the cooling ramp. The white suspension is shaken for at least 2 hours at a final temperature of 0 ° C. The product is isolated by centrifugation. First, the wet cake is washed with isopropanol after aqueous tetrahydrofuran. The wet product is dried in a shake vacuum dryer. The yield in purification step 7 of the preparation method is 85%.

Isolated compound (I) corresponds to the bimoximos of the crystalline form of the polymorph FORM 2, which is characterized by the X-ray spectrum of FIG. In FIG. 1 above, the relative intensity [RI] of the signal in the X-ray spectrum is shown as a function of 2 Theta-values (based on copper K (alpha 1)).

Example  2 (for applicants Bimoshia moss  process)

The study was designed to show the effect of non-mosia moss on ozone-induced sputum neutropenia after repeated inhalation administration of non-mosia moss. Using the double-blind, placebo controlled, two-period randomized cross-clinical study design, the efficacy of non-mosiamos was tested after administration to 18 human volunteers (subjects). Subjects were randomly assigned to each treatment, non-mosiamos or corresponding placebo; The treatments were separated with a cleaning period of 10 days or more (14 days or more between ozone faces).

In each period, bimosiamos (10 mg each) or the corresponding placebo was administered over a period of 4 days at 8 doses. In order to elicit an inflammatory response, subjects were ozone faced, meaning an airflow containing 250 ppb of ozone for three hours beginning about 30 minutes after completion of the last dose in each treatment period of four days. Ozone facing Jorres et al. Am J Respir Crit Care Med. 161 (6), 2000, 1855-1861 and Holz et al. Clin Exp Allergy. 32 (5), 2002, 681-689]. Three hours after completion of the ozone facing, Pin sputum [Thorax. 47, 1992, 25-29 and Holz et al. Am J Respir Crit Care Med. 159 (3), 1999, 776-784; Thorax. 53 (2), 1998, 83-86, induction, treatment and investigation (induction of sputum herein is a process in which sputum is induced from the airways by inhalation saline stimulation). Sputum was analyzed for cell composition (eg neutrophil count, lymphocyte count) and non-cell mediators (eg interleukin-8 and MMP-9 levels). Compared with the placebo treatment, treatment with non-mosiamoss induced a significant decrease in sputum neutrophil count and sputum interleukin-8 levels. However, bimoximos surprisingly also significantly reduced the sputum concentration of matrix metalloproteinase-9 (MMP-9).

Example  3 (for patients Bimoshia Moss  process)

Another study was devised to demonstrate the effect of non-mosia moss on chronic obstructive pulmonary disease (COPD) after repeated inhalation administration of non-mosia moss. Using a double-blind, placebo controlled, two-period randomized cross-clinical study design, the stability and efficacy of non-mosiamos were tested in 77 patients (subjects) with COPD. Subjects were randomly assigned to each treatment, non-mosiamos or corresponding placebo; The treatments were separated with a cleaning period of 14 days or more.

Bimosciamos (10 mg) or the corresponding placebo was administered twice daily for 28 days. Sputum was induced before and after each treatment period, Holz et al. Changes in sputum composition during sputum induction in healthy and asthmatic patients. Clin Exp Allergy 1998; 28: 284-292] and Beeh et al. [Induced sputum cell profiles in lung transplant recipients with or without chronic rejection: correlation with lung function. Thorax. 2001; 56: 557-60 and treated according to the method described herein (induction of sputum herein is a process in which sputum is induced from the airways by inhalation saline stimulation).

Sputum was analyzed for cell composition (eg neutrophil count, lymphocyte count) and non-cell mediators (eg interleukin-8 and MMP-9 levels).

Compared with the placebo treatment, treatment with bimosiamos induced a decrease in sputum neutrophil count and sputum interleukin-8 levels. Bimosiamos also significantly reduced the sputum concentration of matrix metalloproteinase-9 (MMP-9). The results are shown in FIG.

FIG. 3 shows non-cell IL-8, MPO (myeloperoxidase), MMP-9, and different cells (non-s) in sputum of patients treated with non-mosamos as compared to patients treated with placebo on day 28 of treatment. Epithelial, neutrophil, macrophage, lymphocyte and coral leukocyte) parameters (percentage of treatment differences).

Claims (15)

As a method for producing 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane which is a compound of formula (I):

Compound (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted to (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester which is reacted with adipoyl chloride 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) was obtained, followed by catalytic reduction to 1,6-bis- [3- (3 -Carboethoxy-methylphenyl) -4-methoxyphenyl] -hexane (C), which is reacted with boron tribromide in a solvent to yield 1,6-bis- [3- (3-carboethoxy- Methylphenyl) -4-hydroxyphenyl] -hexane (D) is obtained, which is reacted with a protected mannopyranosyl derivative to yield 1,6-bis- [3- (3-carbo-ethoxy-methylphenyl) -4 -(Tetra-O-protected-α-D-mannopyranosyloxy) -phenyl] -hexane-derivative was obtained, followed by reaction under basic reaction conditions to give 1,6-bis- [3- (3-carboxy Methyl-phenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane, optionally 1, 2 Or recrystallising from various organic solvents and / or water to obtain the product bimosiamos of formula (I). The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] hexane (I) according to claim 1, comprising the following process steps: Of)
a) (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted under acidic conditions to form (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester Reaction with adipoyl chloride in a solvent affords 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B), wherein an intermediate (2'-methoxy Not biphenyl-3-yl) -acetic acid ethyl ester,
b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is reduced with hydrogen and a metal catalyst to reduce 1,6-bis- [3- Forming (3-carboethoxy-methylphenyl) -4-methoxyphenyl] -hexane (C),
c) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) is reacted with boron tribromide in a solvent to give 1,6-bis- [3- Obtaining (3-carboethoxymethyl-phenyl) -4-hydroxyphenyl] -hexane (D),
d) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) is mannopyranosyl-derivative, in particular tetra-O-pivaloyl-D- Reacted with manno-pyranosyl-halide or tetra-O-acetyl-D-mannopyranosyl-halide to give 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra-O- Pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) or the corresponding 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra- Obtaining O-acetyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane,
e) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) Or the corresponding 1,6-bis- [3- (3-carboethoxy-methyl-phenyl) -4- (tetra-O-acetyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane Reacting under basic reaction conditions to form 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I),
f) optionally 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane with one or several organic solvents and / or water or Recrystallization from the mixture to obtain the product of formula (I), bimosciamos. The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl according to claim 1 or 2, comprising the following process steps. Method for preparing hexane (I):
a) (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted under acidic conditions to form (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester 1,4-bis- [3- (3-carboethoxy-methylphenyl) -4-methoxybenzoyl] -butane (B) reacting with adipoyl chloride and Lewis acid in a solvent to yield greater than 95% purity and a yield of at least 70% Yielding no intermediate (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester,
b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is reduced with hydrogen and a metal catalyst to reduce 1,6-bis- [3- Forming (3-carboethoxy-methylphenyl) -4-methoxyphenyl] -hexane (C),
c) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) with boron tribromide in a solvent at a temperature range of -20 ° C to + 20 ° C. Reacting to give 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D),
d) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in the presence of a catalytic amount of Lewis acid and a temperature of -10 ° C to + 15 ° C. 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra-O-pivaloyl by reacting with tetra-O-pivaloyl-D-mannopyranosyl-halide in the range obtaining -α-D-manno-pyranosyloxy) -phenyl] -hexane (E),
e) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) Is reacted with sodium methylate followed by aqueous sodium hydroxide to give 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I) Forming a step,
f) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane is recrystallized from an organic solvent or a mixture of organic solvent and water Obtaining a product of formula (I), bimosyamos, of greater than 98% purity. The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyl according to any one of claims 1 to 3 comprising the following process steps. Oxy) -phenyl] Hexane (I)
a) (2'-methoxy-biphenyl-3-yl) -acetic acid (A) in the temperature range of + 60 ° C to + 99 ° C with 2-methoxyphenyl-boronic acid and at least 10% molar excess of 3- After preparation from bromophenylacetic acid, (2'-methoxy-biphenyl-3-yl) -acetic acid (A) is converted under acidic conditions to (2'-methoxy-biphenyl-3-yl) -acetic acid After forming ethyl ester, 1,4-bis- [3- (3-carboethoxy-methylphenyl) -4-methoxybenzoyl] -butane (B) was reacted with adipoyl chloride and aluminum chloride in a solvent. Which does not isolate the intermediate (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester,
b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) with hydrogen, Pd-catalyst and ethanol, ethyl acetate and trifluoroacetic acid Reducing with a mixture to form 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C),
c) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) is boron tribromide in dichloromethane in the temperature range of -5 ° C to + 5 ° C. Reaction with to give 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D), followed by hydrolysis of the reaction mixture with excess ethanol, The hydrolyzed mixture was treated in boiling ethanol to dimer and condensate product to the reaction product 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D). Converting step,
d) catalytic amount of boron trifluoride of 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in the temperature range of -5 deg. 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra) by reaction with tetra-O-pivaloyl-D-mannopyranosyl fluoride in the presence of diethyletherate Obtaining -O-pivaloyl-α-D-mannopyranosyloxy) -phenyl] -hexane (E),
e) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) Is reacted with sodium methylate in a mixture of tetrahydrofuran and methanol at a temperature ranging from + 15 ° C. to + 25 ° C. and subsequently with aqueous sodium hydroxide at a temperature ranging from 0 ° C. to + 10 ° C. to 1,6-bis- [ 3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyl-oxy) -phenyl] hexane (I);
f) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (I) of tetrahydrofuran or tetrahydrofuran with water Recrystallization from the mixture to obtain the product of formula (I), bimosyamos, in a crystal form of polymorph FORM 2 with a purity of more than 98.5%. The process according to any one of claims 1 to 4, wherein first the compound (2'-methoxy-biphenyl-3-yl) -acetic acid (A) as step a) is reacted with thionyl chloride, 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2, wherein the reaction (A) converts compound (A) to (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester -α-D-manno-pyranosyloxy) -phenyl] hexane (I). The compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy)-according to any one of claims 1 to 5. 1,6-bis- [3- (3-carboxymethylphenyl) -4, wherein the phenyl] -hexane (I) is recrystallized from an ethanol / water mixture to give the bimocymoses in crystalline form of the polymorph FORM 2. -(2-α-D-manno-pyranosyloxy) -phenyl] hexane (I). The compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy)-according to any one of claims 1 to 5. Phenyl] -hexane (I) is recrystallized from an isopropanol / water mixture to give bisocyanmos of at least 99.0% purity and in crystalline form of the polymorph FORM 2 thereof. Carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] hexane (I). 8. Intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) as claimed in any one of claims 1 to 7, and 1,6-bis, wherein intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in step c) is not isolated as a solid product -[3- (3-carboxymethylphenyl) -4- (2-α-D-manno-pyranosyloxy) -phenyl] process for the preparation of hexane (I). The process according to any one of claims 1 to 8, wherein intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) as step d) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α, which is reacted with a mixture of α / β-stereoisomers of tetra-O-pivaloyl-D-mannopyranosyl halide -D-mannopyranosyloxy) -phenyl] hexane (I). 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α- with a purity of at least 99%, in particular at least 99.5%, prepared by the process according to claim 1. D-mannopyranosyloxy) -phenyl] hexane (I). 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α- with a purity of at least 99%, in particular at least 99.5%, prepared by the process according to claim 1. D-mannopyranosyloxy) -phenyl] hexane (I) and one or more additional pharmaceutically acceptable carriers. Salts and / or stereoisomeric or polymorphic forms of bimosiamos and / or bimosiamos for the treatment, prevention or diagnosis of irritable pneumonia and pulmonary sarcoidosis. A salt of and / or a stereoisomer or polymorphic form thereof, and one or more additional pharmaceutically inactive ingredients, for the treatment, prevention or diagnosis of irritable pneumonia and / or pulmonary sarcoidosis. Pharmaceutical composition. A pharmaceutical composition comprising a salt of non-mosamic and / or non-mosamic and / or stereoisomer or polymorphic form thereof and one or more additional pharmaceutically active ingredients for the treatment, prevention or diagnosis of irritable pneumonia and pulmonary sarcoidosis. . As salts and / or stereoisomers or polymorphic forms of bimosiamos and / or nonmosamos for the treatment, prevention or diagnosis of certain inflammations, pulmonary emphysema and ocular diseases, the specific inflammation is ocular inflammation, hypersensitivity, periodontal disease , Otitis, ulcer, ulcerative colitis, mucositis, pneumonia, intraperitoneal inflammation and cystitis; Salts and / or salts of non-moscias and / or non-mosamoss wherein the ocular disease means corneal injury, corneal ulcer, infectious disease in the field of ophthalmology, dry eye, ocular disease, corneal macular degeneration, pterygium, uveitis and lacrimal disease Their stereoisomeric or polymorphic forms.

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