AU2011249843A1 - Process for the preparation of Bimosiamose - Google Patents

Abstract

A process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-α-D-mannopyranosyloxy)-phenyl] hexane (I) which comprises the steps of converting the compound (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) into the (2'-Methoxy-biphenyl-3-yl)-acetic acid ethyl ester, which is reacted with adipoyl chloride to 1,4-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxybenzoyl]-butane (B) which is catalytically reduced to 1,6-Bis-[3-(3-carboethoxy-methylphenyl)-4-methoxy- phenyl] -hexane (C), which is reacted with boron tribromide in a solvent to 1,6-Bis-[3-(3- carboethoxy-methylphenyl)-4-hydroxyphenyl]-hexane (D), which is reacted with a mannopyranosyl derivative to obtain 1,6-Bis-[3-(3-carboethoxy-methylphenyl)-4-(tetra-0- pivaloyl-α-D-mannopyranosyloxy)-phenyl]-hexane (E), which is reacted to form 1,6-Bis- [3-(3-carboxymethyl-phenyl)-4-(2-α-D-mannopyranosyloxy)-phenyl] hexane, which is re- crystallized, leads to the product (I) with high purity.

Description

WO 2011/138365 PCT/EP2011/057130 Process for the Preparation of Bimosiamose 5 The present invention relates to a novel process for the preparation of the pharmaceutical compound 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (also called Bimosiamose). By this process, Bimosiamose can be prepared in bigger quantities and in an improved manner with improved overall yield as compared to the methods of the prior art. This new method also allows for the technical production of Bimosiamose in a 10 selective crystal form (polymorph) and in an industrial scale. The structure of the drug compound 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D mannopyranosyloxy)-phenyl]-hexane (Bimosiamose or the compound of the formula (I)) is described in US 5 919 768 and US 5 712 387; by I. Scott et al., Carbohydrate Research 317 15 (1-4), 1999, 210-216; by T. Kogan et al., J. Medicinal Chemistry 41(7), 1998, 1099-1111 and in EP-A 0 840 606. The compound of formula (I) has many valuable pharmacological properties. Bimosiamose acts as a pan-selectin antagonist and inhibits the leukocyte extravasation. As leukocyte extravasation is a key step in the pathogenesis of many inflammatory disorders or conditions, the compound of formula (I) offers the opportunity 20 to be used in a variety of inflammatory and micro-inflammatory indications and conditions. The compound Bimosiamose of formula (I) has ten chiral centers and can be used for the prophylaxis, treatment and diagnosis of inflammatory disorders and for the treatment and 25 prophylaxis of cosmetic and dermatological conditions where micro-inflammatory conditions are involved. O O H O OH 0 0 HO,,. O HO,,. O OH OH WO 2011/138365 PCT/EP2011/057130 -2 The compound of formula (I) may also be administered to treat other diseases that are associated with cell-cell adhesion. As the compound of formula (I) modulates the binding of E-selectin or P-selectin or L-selectin, many disease that are related to this interaction may be treated by the modulation of this binding interaction. The compound of formula (I) 5 is also useful for the treatment, diagnosis, and prophylaxis of several forms of cancer, including lung and colon cancer, for instance. Furthermore, the compound of formula (I) can be used for the treatment, diagnosis, and prophylaxis of diseases or conditions, in which selectin mediated leukocyte retention is involved, e.g. in lung diseases [D. Bock et al., Curr. Respir. Med. Rev., 2006, 2, 339-354]. The compound of formula (I) and its 10 physiologically tolerable salts are suitable as active pharmaceutical ingredients (API) for the prevention, treatment, and diagnosis of various inflammatory or micro-inflammatory diseases or conditions. The compound of formula (I) and/or its physiologically tolerable salts are preferably employed for this in the form of pharmaceutical preparations which are tailored with respect to their composition and the dosage form to the medicinal effects desired in the specific 15 case. For example, Bimosiamose can be used in the form of (a) solid preparations such as tablets (e.g. compressed, layered, sugar, film or enteric coated, chewable, delayed or extended release, sublingual, buccal or effervescent) or capsules (e.g. hard filled or soft gelatine) or in the form 20 of (b) liquid preparations such as oral solutions, emulsions and suspensions, parenteral solutions e.g. for injections and infusions, including lyophilized powders and ready-to-use injections, or ophthalmic solutionsor in the form of (c) semi-solid formulations for topical administration such as ointments, creams, gels, or mircoemulsions. In addition, specialized formulations of Bimosiamose, like liposomes and related forms, micellar solutions, 25 microspheres, nanoparticles or therapeutic systems, e.g. transdermal therapeutic systems, implants or pumps, inhalative dosage forms, biodegradable or bioerodible polymer systems, surgical or edible foams, soft or hydro gels, microsponges, are also suitable dosage forms. Furthermore the compound of formula (I) may be used for treating ageing of the skin caused by extrinsic and intrinsic factors. The signs of skin ageing are defined by the 30 appearance of wrinkles and fine lines, by the yellowing of the skin which develops a wizened appearance along with the appearance of pigmentation blemishes, by a change in the thickness of the skin, generally resulting in a thickening of the stratum corneum and of the epidermis and a thinning of the dermis, by disorganization of the elastin and collagen fibers which causes a loss of elasticity, of suppleness and of firmness, and by the 35 appearance of telangiectasia.

WO 2011/138365 PCT/EP2011/057130 -3 Various ways of synthesis for Bimosiamose are known, see e. g. 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 the known processes is rather low (2 to 3%). Furthermore, it turned out that the known methods are difficult to realize in an industrial production scale without further 5 losses in the overall yield and quality. Protecting the two carboxylic acid functions of Bimosiamose precursor substances as the corresponding methyl esters is known in prior art. However, surprisingly it turned out that the method of present invention works particularly 10 well when ethyl esters are applied as protecting groups. They have a clear advantage compared e. g. to the corresponding methyl esters. They are much more stable with respect to the conditions of an industrial scale and there is no need for the groups to be cleaved and re-installed during the synthesis process of Bimosiamose. Therefore, the number of reaction steps can be reduced as compared to the methods of the prior art [see T. Kogan et 15 al., J. Medicinal Chemistry 41(7), 1998, 1099-1111; US 5 919 768; US 5 712 387]. One task of the present invention is to provide a process that allows for the chemical synthesis of Bimosiamose also in an industrial production scale and in a high quality and purity. The quality of the product should be so high that it can be applied for the 20 manufacturing of drug products, diagnostics and/or cosmetics containing Bimosiamose. Additionally, the process or method of present invention shall make use of cost-effective starting materials, intermediates and reagents. The process of preparation shall be characterized by generating the product Bimosiamose in few process steps, in a high overall yield and with a high degree of purity. 25 The technical problem is solved by a process of preparation of 1,6-Bis-[3-(3 carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane, compound of formula (I) or Bimosiamose, O O H O OH O O HO,,. HO,, HO" ''OH HO" O 30 OH Bimosiamose OH (I) WO 2011/138365 PCT/EP2011/057130 -4 which comprises the steps of converting the compound (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) into the (2'-Methoxy-biphenyl-3-yl)-acetic acid ethyl ester, which is reacted with adipoyl chloride to obtain 1,4-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxybenzoyl] butane (B) which then is catalytically reduced to form 1,6-Bis-[3-(3-carboethoxy 5 methylphenyl)-4-methoxyphenyl]-hexane (C), which is reacted with boron tribromide in a solvent to obtain 1,6-Bis-[3-(3-carboethoxy-methylphenyl)-4-hydroxyphenyl]-hexane (D), which is reacted with a mannopyranosyl derivative (in particular a tetra-O-protected mannopyranosyl derivative) to obtain the 1,6-Bis-[3-(3-carbo-ethoxy-methylphenyl)-4 (tetra-O-protected-a-D-mannopyranosyloxy)-phenyl]-hexane-derivative, such as 1,6-Bis 10 [3-(3-carboethoxy-methylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyrano-syloxy)-phenyl] hexane (E), which then is reacted under basic reaction conditions to form 1,6-Bis-[3-(3 carboxymethyl-phenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane, which optionally is recrystallized from one, two or several organic solvents and/or water to obtain the product Bimosiamose of formula (I). 15 In a particular embodiment, the invention relates to a process for the preparation of 1,6-Bis [3-(3-carboxymethylphenyl)-4-(2-a-D-manno-pyranosyloxy)-phenyl] hexane (I), compri sing the following process steps: 20 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 which then is reacted with adipoyl chloride in a solvent to obtain 1,4-Bis-[3-(3-carboethoxymethylphenyl)-4 methoxybenzoyl] -butane (B), without the isolation of the intermediate (2'-Methoxy biphenyl-3-yl)-acetic acid ethyl ester, 25 b) 1,4-Bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane (B) is reduced by using hydrogen and a metal catalyst to form 1,6-Bis-[3-(3-carboethoxy methylphenyl)-4-methoxyphenyl]-hexane (C), 30 c) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) is reacted with boron tribromide in a solvent to obtain 1,6-Bis-[3-(3-carboethoxymethyl phenyl)-4-hydroxyphenyl]-hexane (D), d) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) is reacted 35 with a mannopyranosyl-derivative (such as a tetra-O-protected mannopyranosyl derivative), in particular a tetra-O-pivaloyl-D-manno-pyranosyl-halide or a tetra-O- WO 2011/138365 PCT/EP2011/057130 -5 acetyl-D-mannopyranosyl-halide, to obtain 1,6-Bis-[3-(3-carboethoxy methylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyranosyl-oxy)-phenyl]-hexane (E), or the corresponding 1,6-Bis-[3-(3-carboethoxy-methylphenyl)-4-(tetra-O-acetyl-a D-mannopyranosyl-oxy)-phenyl]-hexane, 5 e) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyranosyl oxy)-phenyl]-hexane (E) or the corresponding 1,6-Bis-[3-(3-carboethoxy-methyl phenyl)-4-(tetra-O-acetyl-a-D-mannopyranosyl-oxy)-phenyl]-hexane (or the corresponding tetra-O-protected mannopyranosyl-derivative) is reacted under basic 10 reaction conditions to form 1,6-Bis-[3-(3-carboxymethyl-phenyl)-4-(2-a-D mannopyranosyloxy)-phenyl] hexane (I), f) optionally the 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy) phenyl]-hexane is recrystallized from one or several organic solvents and/or water 15 or mixtures thereof to obtain the product of formula (I), Bimosiamose. In a further embodiment, the invention relates to a process for the preparation of 1,6-Bis-[3 (3-carboxymethylphenyl)-4-(2-a-D-manno-pyranosyloxy)-phenyl] hexane (I), comprising the following process steps: 20 a) (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is converted under acid conditions to form (2'-Methoxy-biphenyl-3-yl)-acetic acid ethyl ester which then is reacted with adipoyl chloride and a Lewis acid in a solvent to obtain 1,4-Bis-[3-(3-carboethoxy methylphenyl)-4-methoxybenzoyl]-butane (B) in a purity of more than 95% and a 25 yield of at least 70%, without isolation of the intermediate (2'-Methoxy-biphenyl-3 yl)-acetic acid ethyl ester, b) 1,4-Bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane (B) is reduced using hydrogen and a metal catalyst to form 1,6-Bis-[3-(3-carboethoxy 30 methylphenyl)-4-methoxyphenyl]-hexane (C), c) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) is reacted with boron tribromide in a solvent at a temperature range between -20'C to +20'C to obtain 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D), 35 d) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) is reacted with a tetra-O-pivaloyl-D-mannopyranosyl-halide in the presence of a catalytic WO 2011/138365 PCT/EP2011/057130 -6 amount of a Lewis acid and at a temperature range between -10 0 C to +15'C to obtain 1,6-Bis-[3-(3-carboethoxy-methylphenyl)-4-(tetra-O-pivaloyl-a-D-manno pyranosyloxy)-phenyl]-hexane (E), 5 e) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyranosyl oxy)-phenyl]-hexane (E) is reacted with sodium methylate and subsequently with aqueous sodium hydroxide to form 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D mannopyranosyloxy)-phenyl] hexane (I), 10 f) 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane is recrystallized from an organic solvent or from a mixture of an organic solvent and water to obtain the product of formula (I), Bimosiamose, in a purity of more than 98%. 15 In another embodiment, the invention relates to a process for the preparation of 1,6-Bis-[3 (3-carboxymethylphenyl)-4-(2-a-D-manno-pyranosyloxy)-phenyl] hexane (I), comprising the following process steps: a) (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is prepared from 2-Methoxyphenyl 20 boronic acid and a molar excess of 10% or more of 3-Bromophenylacetic acid at a temperature range between +60'C to +99'C, and then the (2'-Methoxy-biphenyl-3 yl)-acetic acid (A) is converted under acid conditions to form (2'-Methoxy biphenyl-3-yl)-acetic acid ethyl ester which then is reacted with adipoyl chloride and aluminum chloride in a solvent to obtain 1,4-Bis-[3-(3-carboethoxy 25 methylphenyl)-4-methoxybenzoyl] -butane (B), without isolation of the intermediate (2'-Methoxy-biphenyl-3-yl)-acetic acid ethyl ester, b) 1,4-Bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane (B) is reduced using hydrogen, a Pd-catalyst and a mixture of ethanol, ethylacetate and 30 trifluoroacetic acid to form 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4 methoxyphenyl]-hexane (C), c) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) is reacted with boron tribromide in dichloromethane at a temperature range from -5 0 C to 35 +5 0 C to obtain 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D), followed by hydrolysis of the reaction mixture with an excess of ethanol, and subsequent treatment of the hydrolyzed mixture in boiling ethanol in order to re- WO 2011/138365 PCT/EP2011/057130 -7 convert dimers and condensation products into the reaction product 1,6-Bis-[3-(3 carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D), d) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) is reacted 5 with tetra-O-pivaloyl-D-mannopyranosyl fluoride in the presence of a catalytic amount of boron trifluoride diethyletherate at a temperature range from -5'C to +10 0 C to obtain 1,6-Bis-[3-(3-carboethoxy-methylphenyl)-4-(tetra-O-pivaloyl-a-D mannopyranosyloxy)-phenyl]-hexane (E), 10 e) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyranosyl oxy)-phenyl]-hexane (E) is reacted with sodium methylate in a mixture of tetrahydrofuran and methanol at a temperature range between +15'C to +25'C and subsequently with aqueous sodium hydroxide at a temperature range between 0 0 C to +10 0 C to form 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyl 15 oxy)-phenyl] hexane (I), f) 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (I) is recrystallized from tetrahydrofuran or from a mixture of tetrahydro furan and water to obtain the product of formula (I), Bimosiamose, in a purity of 20 more than 98.5% and in the crystal form of its polymorph FORM 2. The invention also relates to a process for the preparation of 1,6-Bis-[3-(3 carboxymethylphenyl)-4-(2-a-D-manno-pyranosyloxy)-phenyl] hexane (I), in which as step a) the compound (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is converted to (2'-Methoxy 25 biphenyl-3-yl)-acetic acid ethyl ester by first reacting compound (A) with thionyl chloride and then reacting with ethanol. In a further embodiment, the invention relates to a process for the preparation of 1,6-Bis-[3 (3-carboxymethylphenyl)-4-(2-a-D-manno-pyranosyloxy)-phenyl] hexane (I), in which as 30 a step f) the compound 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy) phenyl]-hexane (I) is recrystallized from an ethanol/water mixture in order to obtain Bimosiamose in the crystal form of its polymorph FORM 2. In a particular embodiment, the invention relates to a process for the preparation of 1,6-Bis 35 [3-(3-carboxymethylphenyl)-4-(2-a-D-manno-pyranosyloxy)-phenyl] hexane (I), in which as step f) the compound 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyrano syloxy)-phenyl]-hexane (I) is recrystallized from an isopropanol/water mixture to obtain WO 2011/138365 PCT/EP2011/057130 Bimosiamose with a purity of at least 99.0% and in the crystal form of its polymorph FORM 2. In another embodiment, the invention relates to a process for the preparation of 1,6-Bis-[3 5 (3-carboxymethylphenyl)-4-(2-a-D-manno-pyranosyloxy)-phenyl] hexane (I), in which as step b) the intermediate 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) and in step c) the intermediate 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4 hydroxyphenyl]-hexane (D) are not isolated as solid products, but optionally as the respective solution. 10 The invention also deals with a process for the preparation of 1,6-Bis-[3-(3 carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (I), in which as step d) the intermediate 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) is reacted with a mixture of the a/-stereoisomers of tetra-O-pivaloyl-D-mannopyranosyl 15 halide. A particular aspect of the invention is the product, 1,6-Bis-[3-(3-carboxymethylphenyl)-4 (2-a-D-mannopyranosyloxy)-phenyl] hexane (I) prepared by a process as described above and having a purity of at least 99 %, in particular 99.5 %. In particular, the compound (I) contains 20 less than 0.1 % of stereoisomers of Bimosiamose. Another embodiment of the invention is directed to a pharmaceutical composition comprising 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (I) prepared by a process as described above and having a purity of at least 99 %, in 25 particular 99.5 %, and at least one further pharmaceutically acceptable carrier. Pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier and a compound of formula (I), whereby a pharmaceutically acceptable carrier can also be a classical excipient for pharmaceutical compositions, but also can be e.g. an appropriate nano-particle, dendrimer, liposome, microbubble or polyethylene glycol (PEG). The 30 pharmaceutical compositions of the present invention may include compound (I) formulated together with one or more, physiologically acceptable carriers, adjuvants or vehicles, which are collectively referred to herein as carriers, e. g. for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration. 35 The compositions can be administered to humans and animals e. g. orally, rectally, parenterally (intravenously, intramuscularly, intradermaly or subcutaneously), intracisternally, intravaginally, interperitoneally, locally (powders, ointments or drops), as WO 2011/138365 PCT/EP2011/057130 -9 a buccal formulation or by inhalation (nebulized, or as nasal sprays). Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, stabilizers, antioxidants, preservatives (e.g. ascorbic acid, sodium sulfite, sodium hydrogene sulfite, benzyl alcohol, EDTA), dispersions, suspensions or 5 emulsions and sterile powders for reconstitution into sterile injectable solution or dispersion. These compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing agents and or antibacterial and antifungal agents. If desired, and for more 10 effective distribution, the compounds can be incorporated into slow or timed release or 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 employed as fillers in soft and hard-filled gelatine capsules. Liquid dosage forms for oral administration include pharmaceutically 15 acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers, adjuvants, such as wetting agents, emulsifying and suspending agents, sweeting, flavouring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents. 20 Compositions for rectal administrations are preferably suppositories. Dosage forms for topical administration of a compound of this invention include ointments, crimes, gels, powder, sprays and inhalants. For the process of preparation of the composition, the pure compound of formula (I) 25 normally is admixed under sterile conditions with a physiologically acceptable carrier and any needed preservatives, buffers or propellants as may be required. Actual dosage levels of the compound (I) in the composition of the invention may be varied so as to obtain an amount of active ingredient that is effective to obtain the desired therapeutic response for a particular composition and method of administration. The selected dosage level, therefore, 30 depends on the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors. The total daily dosage of the compound (I) of this invention administered to a host in single or divided doses may be in the range up to 50 mg per kilogram of body weight. Dosage unit compositions may contain such submultiples thereof as may be used to make up the daily dosage. It will be understood, however, that 35 the specific dose level for any particular patient, whether human or other animal, will depend upon a variety of factors including the body weight, general health, sex, diet, time WO 2011/138365 PCT/EP2011/057130 - 10 and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated. In one particular embodiment of the method of preparation, the compound (I) is prepared 5 starting from 2-Methoxyphenylboronic acid (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) which is generated by means of a Pd catalyst and in a high purity of more than 98% (in particular more than 99%) and a yield of more than 90% (in particular more than 93%). In one embodiment, (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is converted to (2' 10 Methoxy-biphenyl-3-yl)-acetic acid ethyl ester and then subsequently reacted with adipoyl chloride and a Lewis acid (Aluminum chloride) to 1,4-bis-[3-(3 carboethoxymethylphenyl)-4-methoxybenzoyl]-butane (B) in a high purity of more than 95% (in particular more than 96 %) and yield of at least 70 % (in particular at least 75%). 15 In one embodiment, 1,4-bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane (B) is chemically reduced under an atmosphere of hydrogen to 1,6-bis-[3-(3 carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C), applying a metal catalyst, in particular a catalyst comprising Pd. 20 In one embodiment, 1,6-bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) is reacted with boron tribromide in dichloromethane in a temperature range between -20'C to +20'C to 1,6-bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D). In one embodiment 1,6-bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) 25 is reacted with an appropriately protected mannopyranosyl halide in the presence of a catalytic amount of a Lewis acid and in a temperature range between -10 0 C to +15'C to obtain 1,6-bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-0-pivaloyl-a-D-mannopyranosyl oxy)-phenyl]-hexane (E) or the corresponding O-protected derivative, 30 In one embodiment 1,6-bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-0-pivaloyl-a-D mannopyranosyl-oxy)-phenyl]-hexane (E) or the corresponding O-protected derivative is reacted with sodium methylate and subsequently with aqueous sodium hydroxide to 1,6 bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl]-hexane, the crude product (I), 35 In one embodiment 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyl-oxy) phenyl]-hexane is recrystallized from an organic solvent (such as ethanol, methanol or WO 2011/138365 PCT/EP2011/057130 - 11 tetrahydrofuran) and optionally water to obtain Bimosiamose in high quality and purity of more than 98% (in particular more than 98.5%). The introduction of the mannose units into the molecule Bimosiamose is known in prior art 5 to work well, when the aglycon of Bimosiamose is reacted with tetra-O-pivaloyl-a-D mannopyranosyl fluoride, see US 5 712 387. It surprisingly turned out, that tetra-O pivaloyl-D-mannopyranosyl fluoride as a mixture of the a/ -forms - which is much easier accessible and more cost-effective than the pure a-anomer - gives Bimosiamose in the same optical (stereochemical) purity. The recrystallization of the crude product 10 Bimosiamose from ethanol/water mixtures or isopropanol/water mixtures can lead to the so-called polymorph FORM 2, as described in WO 2008/028966, whereby the yield is 70%. Surprisingly, recrystallization of crude Bimosiamose from tetrahydrofuran/water mixtures gives the polymorph FORM 2 in a yield of 85%. 15 The polymorph FORM 2, see WO 2008/028966, is characterized in that it provides an X ray powder diffraction pattern for this crystalline form which shows the following diffraction angles (2Theta) based on cupric K1: at approximately 5.3' (strong peak), 20 at approximately 5.60 (strong peak), at approximately 17.40 (strong peak), at approximately 9.9' (medium peak), at approximately 10.30 (medium peak), at approximately 13.80 (medium peak), 25 at approximately 15.00 (medium peak), at approximately 16.30 (medium peak), at approximately 16.60 (medium peak), at approximately 18.70 (medium peak), at approximately 19.10 (medium peak), 30 at approximately 19.20 (medium peak), at approximately 19.80 (medium peak), at approximately 20.10 (medium peak), at approximately 20.40 (medium peak), at approximately 20.70 (medium peak), 35 at approximately 21.50 (medium peak), at approximately 24.30 (medium peak), WO 2011/138365 PCT/EP2011/057130 - 12 at approximately 24.80 (medium peak), at approximately 25.50 (medium peak), and at approximately 26.5' (medium peak). 5 The polymorph "FORM 2" of compound (I), see WO 2008/028966, provides an X-ray powder diffraction pattern substantially in accordance with Figure 1. The polymorph FORM 2 is further characterized in that is has a melting range of 158'C to 161'C. Alternatively, recrystallization of the crude product Bimosiamose from ethanol/water mixtures or isopropanol/water mixtures is a suitable method which leads to purified 10 Bimosiamose in the polymorph FORM 2 as well. A further advantage of the method of present invention is that the product Bimosiamose is obtained in an overall yield of at least 30 % (in particular 34 %) which is much higher than the yield obtained with a method of the prior art (about 2 to 3%). 15 In a further preferred embodiment of the present invention, the method for the preparation of 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl]-hexane (Bimosiamose) applies in the second step (step b) ) a conversion of (2'-Methoxy-biphenyl-3 yl)-acetic acid to (2'-Methoxy-biphenyl-3-yl)-acetic acid ethyl ester, in particular by 20 reaction with thionyl chloride, first in order to generate the corresponding acid chloride and then ethanol having the advantage of a quantitative yield and a purity of (2'-Methoxy biphenyl-3-yl)-acetic acid ethyl ester of more than 99.0%. One aspect of the present invention can be illustrated by the following scheme: WO 2011/138365 PCT/EP2011/057130 - 13 CO H COH CO2Et EtO2C OMe (H2C0-2H-2 00 -- 2 Br 1) EtOH, H 2

SO

4

(CH

2 I PdCl 2 (PPh3) 2 2) Adipoyl chloride 23 MeO AlCl 3 / CH 2 Cl 2 MeO OMe (B) (A) CO2Et EtO2C CO2Et EtO2C

H

2 , Pd/C EtOH, EtOAc BBr 3 / CH 2

CI

2 TFA

(CH

2 )I

(CH

2 ) MeO (C) OMe HO (D) OH F CO 2 Et EtO 2 C CO 2 H HOC OPiv &'aOPiv 1 1) NaOMe I O~ivOPiv (CH 2

)

6 / THF / MeOH (CH 2

)

6

BF

3 Et 2 2) Recrystallization O

CH

2 Cl 2 p v OPiv OH OH r = p rY" aopiv r OH r _OH OPivOPiv (E) OPivOPiv OH OH (I) OH OH Bimosiamose The invention also relates to a pharmaceutical composition comprising Bimosiamose for new medical uses. It is known in the prior art that pharmaceutical formulations containing 5 Bimosiamose are useful for a method for the treatment of pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD) or acute lung injury, dermatological diseases such as psoriasis and atopic dermatitis, skin aging caused by micro-inflammatory conditions [see W02008028950] or Interleukin-8 mediated disorders related to viral infections [see W02008098985]. 10 The invention also relates to a method for diminishing the concentration of matrix metalloproteinases (MMP) in the sputum (e.g. of a human) by application of a pharmaceutical composition comprising Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof The invention also relates to a method for 15 diminishing the concentration of matrix metalloproteinase 9 (MMP-9) in the sputum (e.g. of a human) by application of a pharmaceutical composition comprising Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof. The invention also relates to a method for decreasing the number of lymphocytes in the 20 sputum (e.g. of a human) by application of a pharmaceutical composition comprising WO 2011/138365 PCT/EP2011/057130 - 14 Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof. The invention also relates to the use of Bimosiamose and/or a salt of Bimosiamose and/or a 5 stereoisomeric or polymorphic form thereof for the preparation of a pharmaceutical composition for the treatment, prophylaxis (or diagnosis) of hypersensitivity pneumonitis and pulmonary sarcoidosis. The invention also relates to a pharmaceutical composition comprising Bimosiamose 10 and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof and at least one further pharmaceutically inactive ingredient for the treatment, prophylaxis (or diagnosis of hypersensitivity pneumonitis and/or pulmonary sarcoidosis. The invention also relates to a pharmaceutical composition comprising Bimosiamose 15 and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof and at least one further pharmaceutically active ingredient for the treatment, prophylaxis (or diagnosis) of hypersensitivity pneumonitis and pulmonary sarcoidosis. The invention also relates to a pharmaceutical composition comprising Bimosiamose 20 and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof and at least one further pharmaceutically inactive ingredient for the treatment, diagnosis, or prophylaxis of hypersensitivity pneumonitis and pulmonary sarcoidosis. The invention also relates to the use of Bimosiamose and/or a salt of Bimosiamose and/or a 25 stereoisomeric or polymorphic form thereof for the (preparation of a pharmaceutical composition for the) treatment, prophylaxis (or diagnosis) of particular inflammations, pulmonary emphysema and eye diseases. "Inflammations" include (or means) eye inflammation, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucitis, pneumonia, abdominal inflammation, and cystitis. "Eye diseases" include (or means) 30 corneal injury, corneal ulcer, infectious diseases in the ophthalmologic field, dry eye sensation, eye diseases, retinal macular degeneration, pterygium, uveitis and lacrimal gland disease. The invention also relates to a pharmaceutical composition comprising Bimosiamose 35 and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof and at least one further pharmaceutically acceptable component for the treatment, prophylaxis (and diagnosis) of particular inflammations, pulmonary emphysema and eye diseases.

WO 2011/138365 PCT/EP2011/057130 - 15 "Inflammations" include (or means) eye inflammation, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucitis, pneumonia, abdominal inflammation, and cystitis. "Eye diseases" include (or means) corneal injury, corneal ulcer, infectious diseases in the ophthalmologic field, dry eye sensation, eye diseases, retinal macular degeneration, 5 pterygium, uveitis and lacrimal gland disease. The invention also relates to a process for the preparation of a pharmaceutical composition encompassing the step of mixing Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof The composition often comprises from 0.01% 10 to 20% by weight of Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof. The invention also relates to a process as above, where the composition comprises from 0.01% to 10% by weight of Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof The invention also relates to a process as above, where the composition comprises at least one further 15 pharmaceutically active ingredient. In addition, it now has been surprisingly found during a study in human volunteers that Bimosiamose significantly diminished the sputum concentration of matrix metalloproteinases (MMP), in particular matrix metalloproteinase-9 (MMP-9). Even more 20 surprisingly, the number of sputum lymphocytes was significantly decreased under treatment with Bimosiamose. These findings are illustrated in the graphic of Figure 2. In Fig. 2 the effect of Bimosiamose treatment in human volunteers on the enzyme MMP-9 (reduction of concentration of enzyme per volume of sputum) and the effect of 25 Bimosiamose on Lymphocytes (reduction of number of lymphocytes per volume of sputum) are shown. The surprising result of reducing MMP-9 levels and lymphocyte numbers in sputum by the administration of Bimosiamose and the impact of both, MMP-9 levels and lymphocyte count, on a variety of diseases provides new opportunities and uses of compositions for the treatment, diagnosis and prophylaxis of medical indications and 30 diseases, in particular treatments with a pharmaceutical composition comprising Bimosiamose (or alternatively a pharmaceutical composition comprising Bimosiamose and at least one further pharmaceutically active ingredient) and/or at least one further pharmaceutically inactive ingredient. Thus, the present invention further relates to the Bimosiamose for the use (e. g. as a pharmaceutical composition) for the treatment, 35 diagnosis, or prophylaxis of hypersensitivity pneumonitis and pulmonary sarcoidosis.

WO 2011/138365 PCT/EP2011/057130 - 16 One embodiment of the invention relates to a pharmaceutical composition comprising Bimosiamose for the treatment, diagnosis and prophylaxis of particular inflammations, pulmonary emphysema and eye diseases. "Inflammations" include (or means) eye inflammation, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucitis, 5 pneumonia, abdominal inflammation, and cystitis. "Eye diseases" include (or means) corneal injury, corneal ulcer, infectious diseases in the ophthalmologic field, dry eye sensation, eye diseases, retinal macular degeneration, pterygium, uveitis and lacrimal gland disease. 10 The invention relates to the use of a compound of formula (I), a salt of this compound or a stereoisomeric or polymorphic form thereof for the preparation of a pharmaceutical composition for the treatment, diagnosis or prophylaxis of MMP-9 mediated disorders. 15 The pharmaceutical composition can be used for the treatment, diagnosis or prophylaxis of hypersensitivity pneumonitis. The pharmaceutical composition can be used for the treatment, diagnosis or prophylaxis of pulmonary sarcoidosis. The invention relates to pharmaceutical compositions comprising the compound of formula (I) and/or a salt of compound of formula (I) and/or a stereoisomeric or polymorphic form thereof optionally in combination with at least one 20 further pharmaceutically inactive ingredient for the treatment, diagnosis, or prophylaxis of hypersensitivity pneumonitis or pulmonary sarcoidosis. The invention relates to the pharmaceutical compositions comprising the compound of formula (I) and/or a salt of compound of formula (I) and/or a stereoisomeric or polymorphic form thereof 25 in combination with at least one further pharmaceutically active ingredient and optionally in combination with at least one further pharmaceutically inactive ingredient for the treatment, diagnosis, or prophylaxis of hypersensitivity pneumonitis or pulmonary sarcoidosis. The invention relates to the pharmaceutical compositions comprising the compound of formula 30 (I) and/or a salt of compound of formula (I) and/or a stereoisomeric or polymorphic form thereof optionally in combination with at least one further pharmaceutically inactive ingredient for the treatment, diagnosis, or prophylaxis of pulmonary emphysema or particular inflammations such as eye inflammation, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucitis, pneumonia, abdominal inflammation, pulmonary emphysema and cystitis, or eye 35 diseases such as corneal injury, corneal ulcer, infectious diseases in the ophthalmologic field, dry eye sensation, eye diseases, retinal macular degeneration, pterygium, uveitis and lacrimal gland disease.

WO 2011/138365 PCT/EP2011/057130 - 17 The invention relates to pharmaceutical compositions comprising the compound of formula (I) and/or a salt of compound of formula (I) and/or a stereoisomeric or polymorphic form thereof in combination with at least one further pharmaceutically active ingredient and optionally in combination with at least one further pharmaceutically inactive ingredient for the treatment, 5 diagnosis, or prophylaxis of pulmonary emphysema or particular inflammations such as eye inflammation, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucitis, pneumonia, abdominal inflammation, pulmonary emphysema and cystitis, or eye diseases such as corneal injury, corneal ulcer, infectious diseases in the ophthalmologic field, dry eye sensation, eye diseases, retinal macular degeneration, pterygium, uveitis and lacrimal 10 gland disease.and optionally in combination with at least one further pharmaceutically inactive ingredient. The invention relates to a process for the preparation of these pharmaceutical compositions. The process for the preparation of a pharmaceutical composition encompasses the step of 15 mixing a compound of formula (I) and/or a salt of compound of formula (I) and/or a stereoisomeric or polymorphic form thereof . The composition often comprises from 0.01% to 20% by weight of compound of formula (I) and/or a salt of compound of formula (I) and/or a stereoisomeric or polymorphic form thereof, and from 0.01% to 10% by weight of at least one further pharmaceutically active ingredient based on the total weight of the composition. 20 The present invention is described in more detail by the following examples: Example 1 (Process for Preparation) 25 Step 1: (2'-Methoxy-biphenyl-3-yl)-acetic acid A mixture of 3-bromophenyl-acetic acid, 2-methoxyphenylboronic acid, potassium carbonate and catalytic amounts of (PPh 3

)

2 PdCl 2 in water is heated at 77'C for 2 h until practically no 3-bromophenyl-acetic acid is left. The mixture is extracted with toluene at ambient temperature to get rid of impurities. Toluene and further water are added to the 30 aqueous layer. Concentrated sulfuric acid is added under cooling until pH ~1 is reached. The bi-layered mixture is filtered and the layers are separated at ambient temperature. The aqueous layer is extracted with toluene. The combined organic layers are washed with diluted sulfuric acid in two portions, followed by washing with water. Some toluene is 35 distilled off and the mixture is cooled to 35'C. Heptane is added to the solution in not less than 1 h while the product precipitates. The suspension is cooled down to 3C. Obtained WO 2011/138365 PCT/EP2011/057130 - 18 crystals of (2'-methoxy-biphenyl-3-yl)-acetic acid (A) are isolated by solid-liquid separation, washed with heptane and used in the next step without drying. The yield of this step 1 of the process is 87 %, but can be improved to 91%, when 5 modifying the workup procedure as follows: A 32% hydrochloric acid is applied for the acidification instead of concentrated sulfuric acid and more water, having the positive effect that no potassium (bi-)sulfate precipitation occurs, the Vmax/Vmin ratio decreases and the two washing steps with diluted sulfuric acid are omitted. 10 Step 2: 1,4-Bis- [3-(3-carboethoxymethylphenyl)-4-methoxybenzoyl] -butane (B) A solution of (2'-methoxy-biphenyl-3-yl)-acetic acid (A) in ethanol is refluxed in the presence of catalytic amounts of concentrated sulfuric acid for 2 h until practically no (2' methoxy-biphenyl-3-yl)-acetic acid is left. The mixture is treated with a concentrated aqueous solution of potassium carbonate at ambient temperature until pH 7 is reached. 15 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 get rid of residual water. The mixture is filtered and the filtrate is evaporated to remove residual water and ethanol. The distillation residue ((2'-Methoxy 20 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 maximum 0 0 C in a rate that allows for keeping the 25 temperature of the resulting mixture at 0 0 C. A solution of adipoyl chloride in dichloromethane is slowly added at maximum 0' C (in not less than 1 hour). The mixture is stirred at 5'C until practically no (2'-Methoxy-biphenyl-3-yl)-acetic acid ethyl ester is left. The solution is added to an ice-water-mixture at maximum 5'C for hydrolysis. The layers are separated at ambient temperature. The aqueous layer is extracted with 30 dichloromethane. The combined organic layers are washed with water in two portions. 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 35 treated with a small amount of water and seeded. After cooling to ambient temperature the mixture is stirred for at least 2 h. After further cooling to 3C and stirring for at least 1 h WO 2011/138365 PCT/EP2011/057130 - 19 the obtained crystals are isolated by solid-liquid-separation, washed with cold isopropyl acetate and dried under vacuum at ~45'C. The obtained crude 1,4-bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane 5 (B) is diluted in isopropyl acetate and treated with charcoal at 75'C for 1-2 h. Then charcoal is 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 h. After further cooling to 3C and stirring for at least 1 h the obtained white crystals are isolated by solid-liquid-separation, washed with cold isopropyl acetate 10 and dried under vacuum at ~45'C to obtain 1,4-bis-[3-(3-carboethoxymethylphenyl)-4 methoxybenzoyl] -butane (B). The yield of this step 2 of the process is 70 %, but can be improved to 74%, when modifying the procedure as follows: (1) Amount of EtOH for the esterification step is 15 halved and catalytic amount of sulfuric acid is limited to not more than 5% w/w having the positive effect that neutralization of reaction mixture with potassium carbonate is omitted and EtOH is simply distilled off after the esterification reaction. (2) Further, remaining water is removed from the crude esterification product by azeotrop distillation with toluene thus omitting the drying procedure with sodium sulfate. (3) Aluminum chloride suspended 20 in dichloromethane and adipoyl chloride are pre-mixed in a reactor at 0 0 C and the ester is then added slowly to this mixture. Step 3: 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) A solution of 1,4-bis-[3-(3-carboethoxymethylphenyl)-4-methoxybenzoyl]-butane (B) in a 25 mixture of ethanol and ethyl acetate is hydrogenated in the presence of catalytic amounts of a Palladium catalyst (Pd/C catalyst of type "E101 O/W 5 % wnass" of Evonik Degussa GmbH, Germany) and trifluoroacetic acid at 52'C under a pressure of 8 bar for 6 hours until practically no 1,4-bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane and partially hydrogenated intermediates are left. The reaction mixture is cooled to 30 ambient temperature and the catalyst is filtered off and washed with ethyl acetate. Solvents are distilled off under vacuum at max. 40' C. The distillation residue is diluted with toluene and the distillation is repeated under the same conditions. The distillation residue is dissolved in toluene to obtain a toluene solution of 1,6-bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) which can be 35 isolated but which also can be used directly (without isolation) in the following reaction step. The yield of this step 3 of the process is nearly 100 %.

WO 2011/138365 PCT/EP2011/057130 - 20 Step 4: 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) The toluene solution of 1,6-bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl] hexane (C) from Step 3 above is diluted with further toluene and evaporated under vacuum at max. 500 C. The distillation residue is dissolved in dichloromethane and the absence of 5 water is checked. Boron tribromide is added in not less than 2 h at max. 00 C. The reaction mixture is stirred at 3C for 2 h until practically no 1,6-bis-[3-(3-carboethoxymethyl phenyl)-4-methoxyphenyl]-hexane and partially de-methylated intermediate is left. An amount of ethanol sufficient for the hydrolysis of the reaction mixture is added at a rate that allows for keeping the temperature of the resulting mixture at 3C. After warming to 10 15'C a larger amount of ethanol is added in not less than 1.5 h. Solvents are cautiously distilled off without vacuum. Ethanol is added and the mixture is refluxed for 2 h until practically no condensation side product is left. Solvents are distilled off without vacuum and the distillation residue is 15 dissolved in dichloromethane. The solution is added to an ice-water-mixture at max. 50 C. The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layers are washed with water in two portions. Dichloromethane is distilled off without vacuum and the distillation residue is diluted with toluene. 20 As one option, toluene is distilled off under vacuum at max. 700 C. The distillation residue is dissolved in toluene again to obtain a toluene solution of 1,6-bis-[3-(3-carbo ethoxymethyl-phenyl)-4-hydroxyphenyl]-hexane (D) which can be isolated but also can be used directly in the following reaction step. 25 Alternatively, the following workup procedure may be applied in order to isolate 1,6-bis [3-(3-carboethoxymethyl-phenyl)-4-hydroxyphenyl]-hexane (D) in solid form: Toluene is distilled off under vacuum at max. 800 C. The distillation residue is dissolved in diisopropylether and some diisopropylether is distilled off to remove residual toluene. The mixture is cooled to 30 0 C and seeded. After cooling to ambient temperature the suspension 30 is stirred for at least 8 h. After further cooling to 50 C and stirring for at least 3 h crystals are isolated by solid liquid-separation, washed with diisopropylether and dried under vacuum at 35 0 C to obtain 1,6-bis-[3-(3-carboethoxymethyl-phenyl)-4-hydroxy-phenyl]-hexane (D) as a white solid. The yield of this step 4 of the process is nearly 100 %. 35 Step 5: 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-manno pyranosyloxy)-phenyl]-hexane (E) WO 2011/138365 PCT/EP2011/057130 - 21 The toluene solution of 1,6-bis-[3-(3-carboethoxymethyl-phenyl)-4-hydroxy-phenyl] hexane (D) from Step 4 above is diluted with further toluene and evaporated under vacuum at max. 800 C. The distillation residue is dissolved in dichloromethane and an a/ -mixture of tetra-O-pivaloyl-D-mannopyranosyl fluoride is added. Alternatively, the a- or 5 -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 diethyletherate is added in not less than 2 h at max. 30 C. The reaction mixture is stirred at 0 0 C for 6 h until practically no 1,6-bis-[3-(3-carboethoxymethyl-phenyl)-4-hydroxy phenyl]-hexane and intermediates are left. The solution is added to an ice-water-mixture at 10 max. 100 C. The layers are separated and the aqueous layer is extracted with dichloromethane. The combined organic layers are washed with aqueous sodium carbonate solution in two portions and water. Dichloromethane is distilled off without vacuum and the distillation residue is diluted with toluene. Toluene is distilled off under vacuum at 65 0 C. The distillation residue is dissolved in methanol. Some methanol is distilled off and 15 the mixture is cooled to 45'C. The solution is seeded and stirred for at least 90 min at 45 0 C. After cooling to 22 0 C and stirring for at least 2 h the obtained crystals are isolated by solid liquid-separation, washed with methanol and dried under vacuum at ~40 0 C to obtain 1,6 20 bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-manno-pyranosyl-oxy) phenyl]-hexane (E). The yield of this step 5 of the process is 86 %. Step 6: 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane, crude Bimosiamose (I) 25 1,6-bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-manno-pyranosyloxy) phenyl]-hexane (E) is diluted with toluene and evaporated under vacuum at max. 700 C. The distillation residue is dissolved in a mixture of tetrahydrofuran and methanol. The absence of water is checked. Cell floc (as physical auxiliary based on cellulose) and methanolic sodium methylate 30 solution (30 %) are added at 23 0 C. The reaction mixture is stirred at 23 0 C 0 C for 8 h until practically no 1,6-bis-[3-(3-carbo-ethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-manno pyranosyloxy)-phenyl]-hexane and intermediates are left. The mixture is filtered and washed with a mixture of tetrahydrofuran and methanol, followed by washing with methanol. The filter cake (mixture of 1,6-bis-[3-(3-carbomethoxymethylphenyl)-4-(tetra 35 O-pivaloyl-a-D-manno-pyranosyloxy)-phenyl]-hexane and cell floc) is suspended in water and aqueous NaOH solution (30 %) is added at 5 0 C. The reaction mixture is stirred at 5 0

C

WO 2011/138365 PCT/EP2011/057130 - 22 for 5 h until practically no 1,6-bis-[3-(3-carbomethoxymethylphenyl)-4-(tetra-O-pivaloyl a-D-manno-pyranosyloxy)-phenyl]-hexane is left. Cell floc is filtered off and washed with water. Diluted HCl is added to the filtrate at 2 0 C 5 until pH 2.5-3.0 is reached. After stirring at 2 0 C for at least 3.5 h the obtained crystals are isolated by solid-liquid-separation. The wet cake is suspended in water and warmed to 45 0 C. Ethanol is added and the mixture is cooled to 5 0 C. After stirring at 5 0 C for at least 3 h the obtained crystals are isolated by solid-liquid-separation, washed with a mixture of water and ethanol and dried under vacuum at ~45 0 C to obtain 1,6-bis-[3-(3-carboxy 10 methylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl]-hexane (crude Bimosiamose). The yield of this step 6 of the process is 69 %. Step 7: Pure Bimosiamose Crude Bimosiamose (I) is dissolved in aqueous tetrahydrofuran at or slightly below reflux 15 temperature. The solution is filtered through a micro filter cloth and cooled to about 52 0 C. The solution is seeded with about 0.5 w/w% Bimosiamose and subsequently cooled to 0 0 C with a temperature gradient of 18 K/h. Without interruption of the cooling ramp additional tetrahydrofuran is added starting at 18 0 C over a period of 1 h. The white suspension is agitated for not less than 2 hours at the final temperature of 0 0 C. The product is isolated by 20 centrifugation. The wet cake is first washed with aqueous tetrahydrofuran followed by isopropanol. The wet product is dried in an agitated vacuum dryer. The yield of this purification step 7 of the process of preparation is 85 %. The compound (I) isolated corresponds to Bimosiamose in the crystal form of its 25 polymorph FORM 2, which is characterized by the X-ray spectrum of Figure 1. In this Figure 1, the relative intensity [RI] of the signals of the X-ray spectrum is shown as a function of the 2 Theta-value (based on cupric K (alpha 1)). Example 2 (Bimosiamose treatment on volonteers) 30 A study was designed to show the effect of Bimosiamose on ozone induced sputum neutrophilia after repeated inhalative doses of Bimosiamose. Using a double-blind, placebo controlled, two-period randomized cross-over clinical study design, the efficacy of Bimosiamose was examined after administration to 18 human volunteers (subjects). The 35 subjects were randomly assigned to each treatment, Bimosiamose or corresponding WO 2011/138365 PCT/EP2011/057130 - 23 placebo; the treatments were separated by a wash-out period of at least 10 days (at least 14 days between ozone challenges). In each period, eight doses of Bimosiamose (10 mg each) or corresponding placebo, were 5 administered over a period of 4 days. In order to provoke an inflammatory response, the subjects were exposed to an ozone challenge, that means to an airflow containing 250 ppb of ozone for three hours starting approximately 30 minutes after the end of the last dosing on day 4 of each treatment period. Ozone challenge was performed according to the method described by J6rres et al. [Am J Respir Crit Care Med. 161 (6), 2000, 1855-1861] 10 and Holz et al. [Clin Exp Allergy. 32 (5), 2002, 681-689]. Three hours after completion of the ozone challenge sputum was induced and processed and investigated according to the method described by Pin et al. [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]. (The induction of sputum herein is a process where sputum is induced from the respiratory tract by an inhaled saline 15 stimulus). Sputum was analyzed for cellular composition (e.g. neutrophil count, lymphocyte count) and non-cellular mediators (e.g. interleukin-8 and MMP-9 levels). As compared to placebo treatment, treatment with Bimosiamose resulted in a remarkable reduction of sputum neutrophil counts and sputum interleukin-8 levels. However, Bimosiamose surprisingly also diminished significantly the sputum concentration of matrix 20 metalloproteinase-9 (MMP-9). Example 3 (Bimosiamose treatment for patients) Another study was designed to show the effect of Bimosiamose on Chronic Obstructive 25 Pulmonary Disease (COPD) after repeated inhalative doses of Bimosiamose. Using a double-blind, placebo controlled, two-period randomized cross-over clinical study design, safety and efficacy of Bimosiamose were examined in 77 patients with COPD (subjects). The subjects were randomly assigned to each treatment, Bimosiamose or corresponding placebo; the treatments were separated by a wash-out period of at least 14 days. 30 Bimosiamose (10 mg) or corresponding placebo, were administered twice daily for 28 days. Sputum was induced before and after each treatment period and processed and investigated according to the method described by 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 35 recipients with or without chronic rejection: correlation with lung function. Thorax. 2001; 56: 557-60]. (The induction of sputum herein is a process where sputum is induced from the respiratory tract by an inhaled saline stimulus).

WO 2011/138365 PCT/EP2011/057130 - 24 The Sputum was analyzed for cellular composition (e.g. neutrophil count, lymphocyte count) and non-cellular mediators (e.g. interleukin-8 and MMP-9 levels). As compared to placebo treatment, treatment with Bimosiamose resulted in a reduction of 5 sputum neutrophil counts and sputum interleukin-8 levels. Bimosiamose also diminished significantly the sputum concentration of matrix metalloproteinase-9 (MMP-9). The results are shown in the Figure 3. This Fig.3 shows the reduction (percentage of treatment differences) of non-cellular IL-8, 10 MPO (myeloperoxidase), MMP-9) and of different cellular (Non-squamous, Neutrophils, Macrophages, Lymphocytes and Eosinophils) parameters in the sputum of patients treated with Bimosiamose compared to patients treated with placebo on treatment day 28. 15 20 25 30 35

Claims (7)

1. 2. Process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-manno 25 pyranosyloxy)-phenyl] hexane (I) according to claim 1, comprising the following process steps: 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 which then is reacted with 30 adipoyl chloride in a solvent to obtain 1,4-Bis-[3-(3-carboethoxymethylphenyl)-4- WO 2011/138365 PCT/EP2011/057130 - 26 methoxybenzoyl] -butane (B), without the isolation of the intermediate (2'-Methoxy biphenyl-3-yl)-acetic acid ethyl ester, b) 1,4-Bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane (B) is reduced 5 by using hydrogen and a metal catalyst to form 1,6-Bis-[3-(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 obtain 1,6-Bis-[3-(3-carboethoxymethyl 10 phenyl)-4-hydroxyphenyl]-hexane (D), d) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) is reacted with a mannopyranosyl-derivative, in particular a tetra-O-pivaloyl-D-manno pyranosyl-halide or a tetra-O-acetyl-D-mannopyranosyl-halide, to obtain 1,6-Bis 15 [3-(3-carboethoxy-methylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyranosyl-oxy) phenyl]-hexane (E), or the corresponding 1,6-Bis-[3-(3-carboethoxy-methylphenyl)
2. 4-(tetra-O-acetyl-a-D-mannopyranosyl-oxy)-phenyl]-hexane, e) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyranosyl 20 oxy)-phenyl]-hexane (E) or the corresponding 1,6-Bis-[3-(3-carboethoxy-methyl phenyl)-4-(tetra-O-acetyl-a-D-mannopyranosyl-oxy)-phenyl]-hexane is reacted under basic reaction conditions to form 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a D-mannopyranosyloxy)-phenyl] hexane (I), 25 f) optionally the 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy) phenyl]-hexane is recrystallized from one or several organic solvents and/or water or mixtures thereof to obtain the product of formula (I), Bimosiamose. 3. Process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-manno 30 pyranosyloxy)-phenyl] hexane (I) according to claim 1 or 2, comprising the following process steps: a) (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is converted under acid conditions to form (2'-Methoxy-biphenyl-3-yl)-acetic acid ethyl ester which then is reacted with 35 adipoyl chloride and a Lewis acid in a solvent to obtain 1,4-Bis-[3-(3-carboethoxy methylphenyl)-4-methoxybenzoyl]-butane (B) in a purity of more than 95% and a WO 2011/138365 PCT/EP2011/057130 - 27 yield of at least 70%, without isolation of the intermediate (2'-Methoxy-biphenyl-3 yl)-acetic acid ethyl ester, b) 1,4-Bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane (B) is reduced 5 using hydrogen and a metal catalyst to form 1,6-Bis-[3-(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 at a temperature range between -20'C to +20'C 10 to obtain 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D), d) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) is reacted with a tetra-O-pivaloyl-D-mannopyranosyl-halide in the presence of a catalytic amount of a Lewis acid and at a temperature range between -10 0 C to +15'C to 15 obtain 1,6-Bis-[3-(3-carboethoxy-methylphenyl)-4-(tetra-O-pivaloyl-a-D-manno pyranosyloxy)-phenyl]-hexane (E), e) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyranosyl oxy)-phenyl]-hexane (E) is reacted with sodium methylate and subsequently with 20 aqueous sodium hydroxide to form 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D mannopyranosyloxy)-phenyl] hexane (I), f) 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane is recrystallized from an organic solvent or from a mixture of an organic 25 solvent and water to obtain the product of formula (I), Bimosiamose, in a purity of more than 98%. 4. Process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-manno pyranosyloxy)-phenyl] hexane (I) according to one of the claims 1 to 3, comprising the 30 following process steps: a) (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is prepared from 2-Methoxyphenyl boronic acid and a molar excess of 10% or more of 3-Bromophenylacetic acid at a temperature range between +60'C to +99'C, and then the (2'-Methoxy-biphenyl-3 35 yl)-acetic acid (A) is converted under acid conditions to form (2'-Methoxy biphenyl-3-yl)-acetic acid ethyl ester which then is reacted with adipoyl chloride and aluminum chloride in a solvent to obtain 1,4-Bis-[3-(3-carboethoxy- WO 2011/138365 PCT/EP2011/057130 - 28 methylphenyl)-4-methoxybenzoyl] -butane (B), without isolation of the intermediate (2'-Methoxy-biphenyl-3-yl)-acetic acid ethyl ester, b) 1,4-Bis- [3 -(3 -carboethoxymethylphenyl)-4-methoxybenzoyl] -butane (B) is reduced 5 using hydrogen, a Pd-catalyst and a mixture of ethanol, ethylacetate and trifluoroacetic acid to form 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4 methoxyphenyl]-hexane (C), c) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) is reacted 10 with boron tribromide in dichloromethane at a temperature range from -5 0 C to +5 0 C to obtain 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D), followed by hydrolysis of the reaction mixture with an excess of ethanol, and subsequent treatment of the hydrolyzed mixture in boiling ethanol in order to re convert dimers and condensation products into the reaction product 1,6-Bis-[3-(3 15 carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D), d) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) is reacted with tetra-O-pivaloyl-D-mannopyranosyl fluoride in the presence of a catalytic amount of boron trifluoride diethyletherate at a temperature range from -5 0 C to 20 +10 0 C to obtain 1,6-Bis-[3-(3-carboethoxy-methylphenyl)-4-(tetra-O-pivaloyl-a-D mannopyranosyloxy)-phenyl]-hexane (E), e) 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-O-pivaloyl-a-D-mannopyranosyl oxy)-phenyl]-hexane (E) is reacted with sodium methylate in a mixture of 25 tetrahydrofuran and methanol at a temperature range between +15 0 C to +25 0 C and subsequently with aqueous sodium hydroxide at a temperature range between 0 0 C to +10 0 C to form 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyl oxy)-phenyl] hexane (I), 30 f) 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (I) is recrystallized from tetrahydrofuran or from a mixture of tetrahydrofuran and water to obtain the product of formula (I), Bimosiamose, in a purity of more than 98.5 % and in the crystal form of its polymorph FORM 2. 35 5. Process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-manno pyranosyloxy)-phenyl] hexane (I) according to one of the claims 1 to 4, in which as step a) the compound (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is converted to (2'-Methoxy- WO 2011/138365 PCT/EP2011/057130 - 29 biphenyl-3-yl)-acetic acid ethyl ester by first reacting compound (A) with thionyl chloride and then reacting with ethanol.
3. 6. Process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-manno 5 pyranosyloxy)-phenyl] hexane (I) according to one of the claims 1 to 5, in which as a step f) the compound 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (I) is recrystallized from an ethanol/water mixture in order to obtain Bimosiamose in the crystal form of its polymorph FORM 2. 10 7. Process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-manno pyranosyloxy)-phenyl] hexane (I) according to one of the claims 1 to 5, in which as step f) the compound 1,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (I) is recrystallized from an isopropanol/water mixture to obtain Bimosiamose with a purity of at least 99.0% and in the crystal form of its polymorph FORM 2. 15
4. 8. Process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-manno pyranosyloxy)-phenyl] hexane (I) according to one of the claims 1 to 7, in which as step b) the intermediate 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) and in step c) the intermediate 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl] 20 hexane (D) are not isolated as solid products.
5. 9. Process for the preparation of 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D mannopyranosyloxy)-phenyl] hexane (I) according to one of the claims 1 to 8, in which as step d) the intermediate 1,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane 25 (D) is reacted with a mixture of the a/p-stereoisomers of tetra-O-pivaloyl-D mannopyranosyl halide.
6. 10. 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (I) prepared by a process according to one of the claims 1 to 9 and having a purity of at 30 least 99 %, in particular 99.5 %.
7. 11. Pharmaceutical composition comprising 1,6-Bis-[3-(3-carboxymethylphenyl)-4-(2 a-D-mannopyranosyloxy)-phenyl] hexane (I) prepared by a process according to one of the claims 1 to 9 and having a purity of at least 99 %, in particular 99.5 %, and at least one further 35 pharmaceutically acceptable carrier. WO 2011/138365 PCT/EP2011/057130 - 30 12. Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof for the treatment, prophylaxis or diagnosis of hypersensitivity pneumonitis and pulmonary sarcoidosis. 5 13. Pharmaceutical composition comprising Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof and at least one further pharmaceutically inactive ingredient for the treatment, prophylaxis or diagnosis of hypersensitivity pneumonitis and/or pulmonary sarcoidosis. 10 14. Pharmaceutical composition comprising Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof and at least one further pharmaceutically active ingredient for the treatment, prophylaxis or diagnosis of hypersensitivity pneumonitis and pulmonary sarcoidosis. 15 15. Bimosiamose and/or a salt of Bimosiamose and/or a stereoisomeric or polymorphic form thereof for the treatment, prophylaxis or diagnosis of particular inflammations, pulmonary emphysema and eye diseases, where particular inflammations means: eye inflammation, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucitis, pneumonia, abdominal inflammation, and cystitis; and where eye diseases means: corneal 20 injury, corneal ulcer, infectious diseases in the ophthalmologic field, dry eye sensation, eye diseases, retinal macular degeneration, pterygium, uveitis and lacrimal gland disease. 25 30