JP2013525467A - Vimosia Morse Manufacturing Method - Google Patents

Abstract

化合物（２’−メトキシ−ビフェニル−３−イル）−酢酸（Ａ）を（２’−メトキシ−ビフェニル−３−イル）−酢酸エチルエステルに変換し、これを塩化アジポイルと反応させて１，４−ビス−［３−（３−カルボエトキシメチルフェニル）−４−メトキシベンゾイル］−ブタン（Ｂ）を得、次いで、接触還元して１，６−ビス−［３−（３−カルボエトキシ−メチルフェニル）−４−メトキシフェニル］−ヘキサン（Ｃ）を形成し、これを溶媒中三臭化ホウ素と反応させて１，６−ビス−［３−（３−カルボエトキシ−メチルフェニル）−４−ヒドロキシフェニル］−ヘキサン（Ｄ）を得、これをマンノピラノシル誘導体と反応させて１，６−ビス−［３−（３−カルボエトキシ−メチルフェニル）−４−（テトラ−Ｏ−ピバロイル−α−Ｄ−マンノピラノシルオキシ）−フェニル］−ヘキサン（Ｅ）を得、これを反応させて１，６−ビス−［３−（３−カルボキシメチル−フェニル）−４−（２−α−Ｄ−マンノピラノシルオキシ）−フェニル］ヘキサンを形成し、再結晶して生成物（Ｉ）を高純度で導く、方法。A process for producing 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I), comprising:
[Chemical 1]

The 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 to give 1,4 -Bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is obtained and then catalytically reduced to 1,6-bis- [3- (3-carboethoxy-methyl) Phenyl) -4-methoxyphenyl] -hexane (C) is formed and reacted with boron tribromide in a solvent to give 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- Hydroxyphenyl] -hexane (D) is obtained and reacted with a mannopyranosyl derivative to give 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra-O-pivaloyl-α-D -Mannopyranosyloxy) -phenyl] -hexane (E), which was reacted to give 1,6-bis- [3- (3-carboxymethyl-phenyl) -4- (2-α-D -Mannopyranosyloxy) -phenyl] hexane is formed and recrystallized to lead the product (I) in high purity.

Description

  The present invention also relates to the pharmaceutical compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (Bimosiamos). A new manufacturing method). By this method, Vimosia moos can be produced in an improved manner in a larger amount and improved overall yield compared to prior art methods. This novel process also allows the technical production of Vimosia moos on a selective crystalline form (polymorph) and on an industrial scale.

  The structure of the drug compound 1,6-bis [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyl-oxy) -phenyl] hexane (bimosamos or compound of formula (I)) is patented It is described in Document 1 and Patent Document 2; Non-Patent Document 1; Non-Patent Document 2 and Patent Document 3. The compounds of formula I have several useful pharmacological properties. It acts as a pan-selectin antagonist and inhibits leukocyte extravasation. Since leukocyte extravasation is an important step in the development of most inflammatory diseases or conditions, compounds of formula (I) have the opportunity to be developed in a variety of inflammatory and microinflammatory signs and symptoms.

The compounds Vimosia moose of formula (I) can be used for the prevention, treatment and diagnosis of inflammatory diseases, as well as the treatment and prevention of cosmetic and skin conditions involving micro-inflammatory symptoms.

  The compounds of formula (I) can also be administered to treat other diseases associated with cell-cell adhesion. Since the compounds of formula (I) modulate the binding of E-selectin or P-selectin or L-selectin, diseases associated with this interaction can potentially be treated by modulating the binding interaction. it can. The compounds of formula (I) are also useful in the treatment, diagnosis and prevention of various cancers including, for example, lung and colon cancer. Furthermore, the compounds of formula (I) can be used for the treatment, diagnosis and prevention of diseases or conditions involving the retention of selectin-mediated leukocytes such as lung diseases [Non-Patent Document 3]. The compounds of formula (I) and physiologically acceptable salts thereof are suitable as active pharmaceutical ingredients (APIs) for the prevention, treatment and diagnosis of various inflammatory or microinflammatory diseases or conditions. For this purpose, the compounds of the formula (I) and / or their physiologically acceptable salts are preferably used in the form of pharmaceutical preparations adapted to their compositions and in dosage forms adapted to the required efficacy in a particular case Is done.

  For example, biosia moss is (a) tablets (eg compressed tablets, multilayer tablets, dragees, film-coated tablets, enteric tablets, chewable tablets, delayed release tablets, sustained release tablets, sublingual tablets, buccal tablets or effervescent tablets) or capsules In the form of solid preparations such as agents (eg hard capsules or soft gelatin capsules), (b) oral solutions, emulsions and suspensions, parenteral solutions such as lyophilized powders and ready-to-use injections It can be used in the form of liquid preparations such as ointments and injections, or eye drops, or (c) in the form of semisolid preparations for topical administration such as ointments, creams, gels or microemulsions. In addition, liposomes and related forms, micelle solutions, microspheres, nanoparticles or therapeutic systems such as transdermal therapeutic systems, implants or pumps, inhaled dosage forms, biodegradable or biodegradable polymer systems, surgical or edible foams Special formulations of Vimosia moss such as soft gels or hydrogels, microsponges are also possible dosage forms.

  Furthermore, the compounds of formula (I) can be used to treat skin aging caused by exogenous and intrinsic factors. The signs of skin aging are the appearance of wrinkles and fine lines, the yellowing of the skin resulting in a crumpled appearance along with the appearance of stains due to pigmentation, generally the change in skin thickness resulting in thickening of the stratum corneum and epidermis and thinning of the dermis, Characterized by the collapse of elastin and collagen fibers causing loss of elasticity, flexibility and stiffness, and the appearance of telangiectasia.

  Various synthetic methods are known for vimosia moos. For example, see Non-Patent Document 4, Patent Document 4, or Patent Document 5. However, the overall yield with the known method is somewhat lower (2 to 3%). Furthermore, these known methods have proven difficult to achieve industrial production scales without further reducing overall yield and quality. It is known in the prior art to protect the two carboxylic acid functional groups of a Vimosia mors precursor as the corresponding methyl esters.

US Pat. No. 5,919,768 US Pat. No. 5,712,387 European Patent A08840606 US Pat. No. 5,919,768 US Pat. No. 5,712,387

I. Scott et al. , Carbohydrate Research 317 (1-4), 1999, 210-216. T.A. Kogan et al. , J .; Medicinal Chemistry 41 (7), 1998, 1099-1111. D. Bock et al. Curr. Respir. Med. Rev. 2006, 2, 339-354 T.A. Kogan et al. , J .; Medicinal Chemistry 41 (7), 1998, 1099-1111.

Surprisingly, however, it has been found that the process of the invention works particularly well when methyl esters are applied as protecting groups. For example, it has obvious advantages compared to the corresponding methyl ester. They are more stable with respect to industrial scale conditions and do not require groups that are cleaved and reintroduced during the synthesis of Vimosia moss. Thus, it is possible to reduce the number of reaction steps compared to prior art methods (eg T. Kogan et al., J. Medicinal Chemistry 41 (7), 1998, 1099-1111; US Pat. No. 5,919,768; US Pat. No. 5,712,387.
Issue).

  The object of the present invention is to enable chemical synthesis of Vimosia moss on an industrial production scale and with high quality and purity. The quality of this product must be high enough to be applicable to the manufacture of drug products, diagnostics and / or cosmetics containing bimothermoss. Furthermore, the method of the present invention should utilize cost-effective starting materials, intermediates and reagents. The production process should be characterized by producing the product Vimosia moos with high overall yield and high purity with few production steps.

この方法は、化合物（２’−メトキシ−ビフェニル−３−イル）−酢酸（Ａ）を（２’−メトキシ−ビフェニル−３−イル）−酢酸エチルエステルに変換し、これを塩化アジポイルと反応させて１，４−ビス−［３−（３−カルボエトキシメチルフェニル）−４−メトキシベンゾイル］−ブタン（Ｂ）を得、次いで、接触還元して１，６−ビス−［３−（３−カルボエトキシ−メチルフェニル）−４−メトキシフェニル］−ヘキサン（Ｃ）を形成し、これを溶媒中三臭化ホウ素と反応させて１，６−ビス−［３−（３−カルボエトキシ−メチルフェニル）−４−ヒドロキシフェニル］−ヘキサン（Ｄ）を得、これを保護マンノピラノシル誘導体と反応させて１，６−ビス−［３−（３−カルボ−エトキシ−メチルフェニル）−４−（テトラ−Ｏ−保護（ｐｒｏｔｅｃｔｅｄ）−α−Ｄ−マンノピラノシルオキシ）−フェニル］−ヘキサン−誘導体を得、次いでこれを塩基性反応条件下で反応させて１，６−ビス−［３−（３−カルボキシメチル−フェニル）−４−（２−α−Ｄ−マンノピラノシルオキシ）−フェニル］−ヘキサンを得、これを場合により１、２または数種の有機溶媒および／または水から再結晶することにより式（Ｉ）の生成物ビモシアモースを得る工程を包含する。 The technical problem is that the compound of formula (I) or bimothermoss, 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy)- Solved by a method of producing phenyl] hexane,

This method converts the compound (2′-methoxy-biphenyl-3-yl) -acetic acid (A) 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) and then catalytically reduced to 1,6-bis- [3- (3- Carboethoxy-methylphenyl) -4-methoxyphenyl] -hexane (C) is formed and reacted with boron tribromide in a solvent to give 1,6-bis- [3- (3-carboethoxy-methylphenyl). ) -4-hydroxyphenyl] -hexane (D), which is reacted with a protected mannopyranosyl derivative to give 1,6-bis- [3- (3-carbo-ethoxy-methylphenyl) -4- (tetra-O Protected-α-D-mannopyranosyloxy) -phenyl] -hexane-derivative is obtained, which is then reacted under basic reaction conditions to give 1,6-bis- [3- (3- Carboxymethyl-phenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane, which is optionally recrystallized from 1, 2 or several organic solvents and / or water Thereby obtaining the product Bimosia moose of formula (I).

In certain embodiments, the present invention provides 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I). A manufacturing method comprising:
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 is then 1,4-bis- [3- (3-carboethoxymethylphenyl) -4 without reaction of the intermediate (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester by reaction with adipoyl chloride. -Methoxybenzoyl] -butane (B);
b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is reduced by using hydrogen and a metal catalyst and 1,6-bis- [ Forming 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 give 1,6-bis- [3- Obtaining (3-carboethoxymethyl-phenyl) -4-hydroxyphenyl] -hexane (D);
d) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) with a mannopyranosyl-derivative (especially tetra-O-pivaloyl-D-mannopyranosyl-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- (3-carboethoxy-methylphenyl) -4- (tetra-O-acetyl-α-D-mannopyranosyl-oxy)- Obtaining 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 is reacted under basic conditions to give 1, Forming 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 Obtaining a product of formula (I), vimosia moss, by recrystallization from an organic solvent and / or water or mixtures thereof;
Including a method.

In a further embodiment, the present invention provides the preparation of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I). The method is as follows:
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 is then Reacting with adipoyl chloride and Lewis acid in a solvent, without isolation of the intermediate (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester, 1,4-bis- [3- (3-carboethoxy- Obtaining (methylphenyl) -4-methoxybenzoyl] -butane (B) with a purity of greater than 95% and a yield of at least 70%;
b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is reduced with hydrogen and a metal catalyst to give 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 in a solvent in the temperature range of −20 ° C. to + 20 ° C. to give 1,6- Obtaining 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 in the temperature range of −10 ° C. to + 15 ° C. Reaction with tetra-O-pivaloyl-D-mannopyranosyl-halide to react with 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyr Nosyloxy) -phenyl] -hexane (E),
e) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) was converted to sodium methoxide And then reacted with an aqueous sodium hydroxide solution to produce 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane ( Forming I);
f) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl]-from an organic solvent or a mixture of an organic solvent and water Recrystallizing hexane to obtain the product of formula (I), vimosia moss, with a purity higher than 98%;
Including a method.

In another embodiment, the present invention provides 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I) The manufacturing method of the following:
a) (2′-Methoxy-biphenyl-3-yl) -acetic acid (A) is converted from 2-methoxyphenyl-boronic acid and a molar excess of 3-bromophenylacetic acid to a temperature of + 60 ° C. to + 99 ° C. Followed by conversion of (2′-methoxy-biphenyl-3-yl) -acetic acid (A) under acidic conditions to form (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester. It is then reacted with adipoyl chloride and aluminum chloride in a solvent to give 1,4-bis- [3- (3 without isolation of the intermediate (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester. -Carboethoxy-methylphenyl) -4-methoxybenzoyl] -butane (B);
b) Reduction of 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) with hydrogen, Pd catalyst and a mixture of ethanol, ethyl acetate and trifluoroacetic acid Forming 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C);
c) reacting 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) with boron tribromide in dichloromethane at a temperature range of −5 ° C. to + 5 ° C. 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D), then the reaction mixture is hydrolyzed with excess ethanol, followed by dimer and condensation products The product hydrolyzed to reconvert the product to the reaction product 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in boiling ethanol. Treating with:
d) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in the presence of a catalytic amount of boron trifluoride diethyl etherate; Reaction with tetra-O-pivaloyl-D-mannopyranosyl fluoride in the temperature range of + 10 ° C. yields 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra- 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) with tetrahydrofuran and methanol In the mixture at a temperature range of + 15 ° C. to + 25 ° C., followed by a reaction with an aqueous sodium hydroxide solution at a temperature range of 0 ° C. to + 10 ° C. to give 1,6-bis- [3- (3- Forming 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) with isrecrystallized from tetrahydrofuran or tetrahydrofuran Recrystallizing from a mixture of water to obtain the product Vimosia moose of formula (I) in a crystalline form of its polymorph Form 2 with a purity higher than 98.5%;
Including a method.

  The present invention is also a process for producing 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I). As step a), the compound (2′-methoxy-biphenyl-3-yl) -acetic acid (A) is first reacted with compound (A) and thionyl chloride and then with ethanol ( 2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester.

  In a further embodiment, the present invention provides the preparation of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I). Method 1, wherein as step f) said compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane It relates to a process in which (I) is recrystallised from an ethanol / water mixture to obtain vimosia moss in its polymorphic Form 2 crystalline form.

  In certain embodiments, the present invention provides 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I). In the production method, as the step f), the compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -It relates to a process in which hexane (I) is recrystallized from an isopropanol / water mixture to obtain vimosia moss with a purity of at least 99.0% and in its polymorph Form 2 crystalline form.

  In another embodiment, the present invention provides 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I) In the step c), the intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) is used as the step b) in the step c). The intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) is not isolated as a solid product.

  The present invention is also a process for producing 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I). As step d), the intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) is converted to tetra-O-pivaloyl-D-manno. It relates to a method of reacting with a mixture of α / β stereoisomers of pyranosyl halide.

  A particular aspect of the invention is the product 1,6-bis- [3- (3-carboxymethylphenyl) -4-, produced by the above method and having a purity of at least 99%, in particular 99.5%. (2-α-D-mannopyranosyloxy) -phenyl] hexane (I). In particular, compound (I) contains less than 0.1% of the biisomeric stereoisomer.

  Another embodiment of the present invention is a 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2) produced by the above method and having a purity of at least 99%, in particular 99.5%. -Α-D-Mannopyranosyloxy) -phenyl] hexane (I) and at least one further pharmaceutically acceptable carrier.

  The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound of formula (I), whereby the pharmaceutically acceptable carrier is a traditional excipient for pharmaceutical compositions. There may be, for example, suitable nanoparticles, dendrimers, liposomes, microbubbles or polyethylene glycol (PEG). The pharmaceutical composition of the present invention may comprise one or more physiologically acceptable carriers, adjuvants or vehicles, for example for parenteral injection, oral administration in an antibody or liquid formulation, rectal administration or topical administration. It may comprise compound (I) formulated together (these are collectively referred to herein as carriers).

  This composition is for example oral or rectal, parenteral (intravenous, intramuscular or subcutaneous), intracapsular, intravaginal, intraperitoneal, topical (powder, ointment) in humans and animals Or an instillation), or orally or by inhalation (with a nebulizer or as a nasal spray). Compositions suitable for parenteral injection are physiologically acceptable sterile water or non-aqueous solutions, stabilizers, antioxidants, preservatives (eg, ascorbic acid) for reconstitution into sterile injectable solutions or suspensions. , Sodium sulfite, sodium bisulfite, benzyl alcohol, EDTA), dispersants, suspensions or emulsions and sterile powders.

  These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, antibacterial and antifungal agents. If desired, the compounds can be incorporated into sustained or sustained release or targeted delivery systems such as polymer matrices, liposomes, and microspheres for more effective distribution. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. The same type of solid composition can also be utilized as a filler for soft and hard gelatin capsules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to these active compounds, station embodiments and forms include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, adjuvants (eg, wetting agents, emulsifiers, and Suspending agents), intercalants, fragrances and perfumes. Suspending agents can contain a suspending agent in addition to the active compound. The composition for rectal administration is preferably a suppository. Dosage forms for topical administration of the compounds of the present invention include ointments, creams, gels, powders, sprays and inhalants.

  For the preparation of the compositions of the invention, the pure compound of formula (I) is usually prepared under sterile conditions by a pharmaceutically acceptable carrier and other required preservatives, buffers or, if required Mixed with propellant. The actual dosage of compound (I) in the compositions of the present invention can be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic effect in the particular composition and method of administration. . Thus, the dosage selected will depend on the desired therapeutic effect, the route of administration, the duration of treatment required and other factors. The total daily dose of compound (I) of the present invention administered to a patient in single or divided doses ranges up to 50 mg / kg body weight. Dosage unit compositions can contain divisors of the total dosage that can be used to formulate the daily dose. However, specific doses for specific patients, whether humans or other animals, are: body weight, general health, sex, diet, time and route of administration, absorption rate, excretion rate, combination with other drugs, and Depends on a variety of factors, including the severity of the particular disease being treated.

  In one particular embodiment of the preparation process, compound (I) starts from 2-methoxyphenylboronic acid (2′-methoxy-biphenyl-3-yl) -acetic acid (A) made by means of a Pd catalyst. And with a purity higher than 98% (especially higher than 99%) and a yield higher than 90% (especially higher 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 adipoyl chloride and Lewis (2′-methoxy-biphenyl-3-yl) reacted with an acid (aluminum chloride) in a purity higher than 95% (especially higher than 96%) and a yield of at least 70% (especially at least 75%) -Acetic acid ethyl ester.

  In one embodiment, 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is chemically reduced under an atmosphere of hydrogen to produce a metal catalyst (particularly (Catalyst containing Pd) is applied to obtain 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C).

  In one embodiment, 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) is odorated in dichloromethane at a temperature range of −20 ° C. to + 20 ° C. It reacts with boron fluoride 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 -10 ° C to + 15 ° C in the presence of a catalytic amount of a Lewis acid. Reaction with appropriately protected mannopyranosyl halide in the temperature range of 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D -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 corresponding The O-protected derivative is reacted with sodium methoxide followed by aqueous sodium hydroxide solution to give crude product (I) 1,6-bis- [3- (3-carboxymethylphenyl)- 4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane.

  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, methanol). Or tetrahydrofuran) and optionally recrystallized from water to obtain high quality and purity greater than 09% (especially greater than 98.5%).

  The introduction of mannose units into Vimosia moos is known in the prior art and works well when Vimosia mors aglycone is reacted with tetra-O-pivaloyl-α-D-mannopyranosyl fluoride. See U.S. Pat. No. 5,712,387. Surprisingly, tetra-O-pivaloyl-D-mannopyranosyl fluoride as a mixture of α / β forms (which is more easily reachable and more cost effective than the pure α anomer) (High) was found to provide bimosia moos with the same optical (stereochemical) purity. Recrystallization of the crude product Vimosia moss from an ethanol / water mixture or an isopropanol / water mixture can lead to the so-called polymorphic form 2, as described in WO2008 / 028966, where the yield is 70%. . Surprisingly, recrystallization of the crude Vimosia moss from the tetrahydrofuran / water mixture gives polymorph Form 2 in 85% yield.

Polymorph Form 2 (see WO2008 / 28966) is characterized in that it gives an X-ray powder diffraction pattern showing the following diffraction angle (2θ) based on cupric K _α1 in this crystalline form:
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).

  Polymorph Form 2 of Compound (I) (see WO2008 / 028966) gives an X-ray diffraction pattern substantially according to FIG. This polymorph foam 2 is further characterized by having a melting range of 158 ° C to 161 ° C. Alternatively, recrystallization of the crude product Vimosia moss from an ethanol / water mixture or an isopropanol / water mixture is a suitable method resulting in purified Vimosia moos to polymorph Form 2.

  A further advantage of the process according to the invention is that the product Vimosia moos is obtained in an overall yield of at least 30% (especially 34%), which is the yield obtained with the prior art process (about 2-3%). Much higher than the rate.

  In a further preferred embodiment of the invention, 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane (Bimcia moose) The production method is applied to the conversion of the second step (step b) (2′-methoxy-biphenyl-3-yl) -acetic acid to (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester, In particular by reaction with thionyl chloride, the corresponding acid chloride is first produced, then ethanol, with a quantitative yield of (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester higher than 99.0% and Has the advantage of purity.

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

  The present invention also relates to a pharmaceutical composition containing Vimosia moos for novel pharmaceutical uses. Pharmaceutical formulations containing Vimosia moss include asthma, chronic obstructive pulmonary disease (COPD) or acute lung injury, skin diseases (eg psoriasis, atopic dermatitis, skin aging caused by minor inflammatory conditions, etc.) (see WO2008028950) ) Or interleukin-8 mediated diseases associated with viral infection (see WO2008099855).

  The present invention also reduces the concentration of matrix methanoprotease (MMP) in sputum (eg human) by application of vimosia moss and / or salts of bimosia moss and / or pharmaceutical compositions comprising these stereoisomeric or polymorphic forms. It relates to the method of making it. The present invention also relates to the use of matrix methanoprotease 9 (MMP-9) in vaginal (eg human) by application of pharmaceutical compositions comprising bimothermoss and / or salts of bimothermoss and / or their stereoisomeric or polymorphic forms. It relates to a method for reducing the concentration.

  The invention also relates to a method of reducing the number of lymphocytes in (eg human) sputum by application of vimosia moss and / or salts of bimosia moss and / or pharmaceutical compositions comprising these stereoisomeric or polymorphic forms.

  The present invention also provides bimotherose and / or salts of bimotherose and / or stereoisomeric or polymorphic forms thereof for the manufacture of a pharmaceutical composition for the treatment, prevention (or diagnosis) of hypersensitivity pneumonia and pulmonary sarcoidosis. About the use of.

  The present invention also provides bimothermoses and / or salts of bimothermoss and / or their stereoisomeric or polymorphic forms and at least one further pharmaceutical for the treatment, prevention (or diagnosis) of hypersensitivity pneumonia and / or pulmonary sarcoidosis It relates to a pharmaceutical composition comprising a chemically inert ingredient.

  The present invention also provides bimothermoses and / or salts of bimothermoss and / or their stereoisomeric or polymorphic forms and at least one further pharmaceutical for the treatment, prevention (or diagnosis) of hypersensitivity pneumonia and / or pulmonary sarcoidosis Relates to a pharmaceutical composition comprising an active ingredient.

  The present invention also provides bimotherose and / or salts of bimotherose and / or their stereoisomeric or polymorphic forms and at least one further pharmaceutically for the treatment, diagnosis or prevention of hypersensitivity pneumonia and / or pulmonary sarcoidosis. It relates to a pharmaceutical composition comprising an inactive ingredient.

  The present invention also provides bimothermoses and / or salts of bimothermoses and / or their stereoisomeric forms for the treatment, prevention (or diagnosis) (manufacture of pharmaceutical compositions) for specific inflammation, emphysema and eye diseases Or the use of polymorphic forms. “Inflammation” includes (means) the following: ophthalmitis, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucositis, pneumonia, abdominal inflammation, and cystitis; The following includes (means) corneal damage, corneal ulcer, infection in the ophthalmic field, dry eye, eye disease, macular retinal degeneration, pterygium, uveitis and tear line disease.

  The present invention also provides bimothermoses and / or salts of bimothermoss and / or their stereoisomeric or polymorphic forms and at least one additional pharmacological agent for the treatment, prevention (and diagnosis) of certain inflammations, emphysema and eye diseases. Relates to a pharmaceutical composition comprising a chemically acceptable ingredient. “Inflammation” includes (means) the following: ophthalmitis, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucositis, pneumonia, abdominal inflammation, and cystitis; The following includes (means) corneal damage, corneal ulcer, infection in the ophthalmic field, dry eye, eye disease, macular retinal degeneration, pterygium, uveitis and tear line disease.

  The present invention also relates to a process for the manufacture of a pharmaceutical composition, including crafts of mixing bimothermoss and / or salts of bimothermoss and / or their stereoisomeric or polymorphic forms. This composition often comprises 0.01% to 20% by weight of bimothermoses and / or salts of bimothermoss and / or their stereoisomeric or polymorphic forms. The invention also relates to a method as described above, wherein the composition comprises 0.01% to 10% by weight of bimotherose and / or salts of bimotherose and / or their stereoisomeric or polymorphic forms. The invention also relates to the above method, wherein the composition comprises at least one additional pharmaceutically active ingredient.

  Even more surprisingly, during studies in human volunteers, it was revealed that Vimosia mors significantly reduces sputum concentrations of matrix metalloproteases (MMP), particularly matrix metalloprotease-9 (MMP-9). Even more surprisingly, the number of sputum lymphocytes was clearly reduced under the treatment with Vimosia moos. These findings are shown in the graph of FIG.

  FIG. 2 shows the effect of Vimosiamoos treatment in human volunteers on the enzyme MMP-9 (decreasing the concentration of enzyme per sputum amount) and the effect of Vimosiamooth on lymphocytes (decreasing the number of lymphocytes per sputum amount). ing. The surprising consequences of reducing MMP-9 levels and lymphocyte counts in sputum by the administration of Vimosia moss and the effects of both MMP-9 levels and lymphocyte counts on various diseases are related to medical applications and disease treatment, diagnosis and prevention, New for treatment with Vimosia Morse (or alternatively a pharmaceutical composition comprising Vimosia Morse and at least one further pharmaceutically active ingredient) and / or compositions comprising at least one further pharmaceutically inactive ingredient Opportunities and application of the composition are provided. Accordingly, the present invention further relates to Vimosiamors for use (eg, as a pharmaceutical composition) for the treatment, diagnosis or prevention of hypersensitivity pneumonia and pulmonary sarcoidosis.

  One embodiment of the present invention relates to a pharmaceutical composition comprising Vimosia Morse for the treatment, diagnosis and prevention of certain inflammations, emphysema and eye diseases. “Inflammation” includes (means): ophthalmitis, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucositis, pneumonia, abdominal inflammation, and cystitis.

  Eye diseases include (meaning) the following: corneal injury, corneal ulcer, infection in the ophthalmic field, dry eye, eye disease, macular retinal degeneration, pterygium, uveitis and tear line disease.

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

  This pharmaceutical composition can be used for the treatment, diagnosis or prevention of hypersensitivity pneumonia. This pharmaceutical composition can be used for the treatment, diagnosis or prevention of pulmonary sarcoidosis. The present invention relates to compounds of formula (I) and / or formula (I), optionally in combination with at least one pharmaceutically inert ingredient, for the treatment, diagnosis or prevention of hypersensitivity pneumonia or pulmonary sarcoidosis. And / or pharmaceutical compositions containing these stereoisomeric or polymorphic forms.

  The present invention is combined 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 prevention of hypersensitivity pneumonia and pulmonary sarcoidosis To a pharmaceutical composition comprising a compound of formula (I) and / or a salt of a compound of formula (I) and / or a stereoisomeric or polymorphic form thereof.

  The invention relates to emphysema or certain inflammations (e.g. ophthalmitis, anaphylaxis, periodontal disease, otitis, ulcers, ulcerative colitis, mucositis, pneumonia, abdominal inflammation, emphysema and cystitis) or eye diseases (e.g. Optionally at least one for the treatment, diagnosis or prevention of corneal damage, corneal ulcer, infection in the ophthalmic field, dry eye, eye disease, macular degeneration of the retina, pterygium, uveitis and tear line disease) It relates to a pharmaceutical composition comprising a compound of formula (I) and / or a salt of a compound of formula (I) and / or a stereoisomeric or polymorphic form thereof in combination with a pharmaceutically inert ingredient.

  The invention relates to emphysema or certain inflammations (e.g. ophthalmitis, anaphylaxis, periodontal disease, otitis, ulcers, ulcerative colitis, mucositis, pneumonia, abdominal inflammation, emphysema and cystitis) or eye diseases (e.g. At least one further pharmacology for the treatment, diagnosis or prevention of corneal damage, corneal ulcers, infections in the field of ophthalmology, dry eye, eye diseases, macular degeneration of the retina, pterygium, uveitis and tear line diseases) A compound of formula (I) and / or a salt of a compound of formula (I) and / or their stereoisomeric forms, in combination with an pharmaceutically active ingredient and optionally in combination with at least one further pharmaceutically inert ingredient Or relates to a pharmaceutical composition comprising a polymorphic form.

  The present invention relates to a method for producing these pharmaceutical compositions.

  The process for producing the pharmaceutical composition comprises the step of mixing the compound of formula (I) and / or the salt of the compound of formula (I) and / or their stereoisomeric or polymorphic forms. This composition is often 0.01% to 20% by weight of the compound of formula (I) and / or the salt of the compound of formula (I) and / or their stereoisomeric forms, based on the total weight of the composition Or polymorphic form, as well as from 0.01% to 10% by weight of at least one further pharmaceutically active ingredient.

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

Example 1 (manufacturing method)
Step 1: (2′-Methoxy-biphenyl-3-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 aqueous solution Heated to 0 ° C. for 2 hours until practically no residual 3-bromophenyl-acetic acid. The mixture was extracted with toluene at ambient temperature to remove impurities. Toluene and additional water were added to the aqueous layer. Concentrated sulfuric acid was added with cooling until pH = 1 was reached.

  The bilayer mixture was filtered and separated at their ambient temperature. The aqueous layer was extracted with toluene. The combined organic phases were washed in two portions with dilute sulfuric acid and then with water. Some toluene was distilled and the mixture was cooled to 35 ° C. More than 1 hour after the product precipitated, heptane was added to the solution. The suspension was cooled to 3 ° C. The obtained crystals of (2'-methoxy-biphenyl-3-yl) -acetic acid (A) were washed with solid, separated by solid-liquid separation, washed with heptane, and used in the next step without drying.

The yield of step 1 of this method was 87%, but can be improved to 91% by returning the work procedure as follows: 32% hydrochloric acid can be acidified instead of concentrated sulfuric acid and water. When applied, there is an obvious effect that (2) no precipitation of potassium sulfate occurs, the V _max / V _min ratio is reduced, and two washing steps with dilute sulfuric acid are omitted.

Step 2: 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B)
An ethanol solution of (2′-methoxy-biphenyl-3-yl) -acetic acid (A) is practically (2′-methoxy-biphenyl-3-yl)-in the presence of a catalytic amount of concentrated sulfuric acid for 2 hours. The mixture was refluxed until no acetic acid remained. This mixture was treated with concentrated aqueous potassium carbonate solution until pH 7 was reached at ambient temperature. Ethanol was distilled under reduced pressure and the distillation residue was diluted with dichloromethane. This solution was washed with water and the aqueous layer was extracted with dichloromethane. The combined organic layers were treated with sodium sulfate at ambient temperature to remove the remaining water. The mixture was filtered and the filtrate was evaporated to remove residual water and ethanol. The distillation residue ((2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester) was diluted with dichloromethane and confirmed to be free of water and ethanol.

  This solution was added to a suspension of aluminum chloride (as Lewis acid) in a polar solvent (preferably dichloromethane) at a maximum so that the temperature of the resulting mixture could be maintained at 0 ° C. A solution of adipoyl chloride in dichloromethane was added slowly at a maximum temperature of 0 ° C. (over 1 hour). The mixture was stirred at 5 ° C until practically no (2'-methoxy-biphenyl-3-yl) -acetic acid ethyl ester remained. This solution was added to the ice-water mixture at a maximum of 5 ° C. to hydrolyze. These layers were separated at ambient temperature. The aqueous layer was extracted with dichloromethane.

  The combined organic layers were washed in two portions with water. Dichloromethane was distilled without decompression and the distillation residue was diluted with isopropyl acetate. Isopropyl acetate was partially distilled and the mixture was cooled to 53 ° C. This solution was treated with a small amount of water to be seeded. After cooling to ambient temperature, the mixture was stirred for at least 2 hours. After further cooling to 3 ° C., it was cooled for at least 1 hour, and the resulting crystals were isolated by solid-liquid separation, washed with cold isopropyl acetate, and dried at about 45 ° C. under reduced pressure.

  The resulting crude 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is diluted with isopropyl acetate and treated with charcoal for 1-2 hours at 75 ° C. did. The charcoal was then removed by filtration and the filtrate was cooled to 53 ° C. This solution was treated with a small amount of water and seeded. After cooling to ambient temperature, the mixture was stirred for at least 2 hours. After further cooling to 3 ° C., stirring for at least 1 hour, the resulting white crystals were isolated by solid-liquid separation, washed with cold isopropyl acetate, dried at about 45 ° C. under reduced pressure, and 1,4- Bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) was obtained.

  The yield of step 2 of this method is 70%, but can be improved to 74% by changing the procedure as follows: (1) The amount of EtOH in the esterification step is halved and the amount of catalyst By limiting the sulfuric acid to 5% w / w or less, neutralization of the reaction mixture with potassium carbonate is omitted, and EtOH is easily distilled after the esterification reaction. (2) Furthermore, when the remaining water is removed from the crude esterification product by azeotropic distillation using toluene, the drying procedure with sodium sulfate can be omitted. (3) Aluminum chloride suspended in dichloromethane and adipoyl chloride are premixed in a reactor at 0 ° C., and the ester is then slowly added to the 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 mixture of ethanol and ethyl acetate was added to a catalytic amount of palladium catalyst (Evonik Degussa GmbH, Germany's “E101 O / W 5% wnass” type Pd / C catalyst) and trifluoroacetic acid in the presence of trifluoroacetic acid and practically 1,4-bis- [3- ( Hydrogenated for 6 hours until 3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane disappeared and a partially hydrogenated intermediate remained. The reaction mixture was cooled to ambient temperature and the catalyst was filtered off and washed with ethyl acetate. The solvent was distilled at reduced pressure up to 40 ° C. The distillation residue was diluted with toluene and the distillation was repeated under the same conditions. The distillation residue can be dissolved in toluene and isolated, but can also be used directly in the next reaction step (without isolation) 1,6-bis- [3- (3-carboethoxymethyl A toluene solution of (phenyl) -4-methoxyphenyl] -hexane (C) was obtained. The yield of Step 3 was almost 100%.

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) obtained in step 3 above is diluted with additional toluene and reduced to a maximum of 50 under reduced pressure. Evaporated at ° C. The distillation residue was dissolved in dichloromethane and confirmed to be free of water. Boron tribromide was added at maximum 0 ° C. after more than 2 hours. The reaction mixture is practically free of 1,6-bis- [3- (3-carboethoxymethyl-phenyl) -4-methoxyphenyl] -hexane at 3 ° C. and partially demethylated intermediate remains. The mixture was stirred for 2 hours. An amount of ethanol sufficient to hydrogenate the reaction mixture was added at a rate that allowed the temperature of the remaining mixture to be maintained at 3 ° C. After warming to 15 ° C., a large amount of ethanol was added after 1.5 hours or more. The solvent was distilled to elongation without reduced pressure.

  Ethanol was added and the mixture was refluxed for 2 hours until practically a concentrated byproduct remained. The solvent was distilled without reducing the pressure, and the distillation residue was dissolved in dichloromethane. This solution was added to the ice-water mixture at a maximum of 5 ° C. These layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed in two portions with water. Dichloromethane was distilled without reduced pressure and the distillation residue was diluted with toluene.

  As part, toluene was distilled at a maximum of 70 ° C. under reduced pressure. The distillation residue can be dissolved again in toluene and isolated, but can also be used directly in the next reaction step, 1,6-bis- [3- (3-carbo-ethoxymethyl-phenyl) A toluene solution of -4-hydroxyphenyl] -hexane (D) was obtained.

  Alternatively, the following work procedure can be applied to isolate 1,6-bis- [3- (3-carboethoxymethyl-phenyl) -4-hydroxyphenyl] -hexane (D) in solid form. Toluene was distilled at a maximum of 80 ° C. under reduced pressure. The distillation residue was dissolved in diisopropyl ether and some diisopropyl ether was distilled to remove residual toluene. The mixture was cooled to 30 ° C. and seeded. After cooling to ambient temperature, the suspension was stirred for at least 8 hours. After further cooling to 5 ° C. and stirring for at least 3 hours, the crystals were isolated by solid-liquid separation, washed with diisopropyl ether, dried at 35 ° C. under reduced pressure, and 1,6-bis- [3 as a white solid. -(3-Carboethoxymethyl-phenyl) -4-hydroxy-phenyl] -hexane (D) was obtained. The yield of step 4 of this method was almost 100%.

Step 5: 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyloxy) -phenyl] -hexane (E)
The toluene solution of 1,6-bis- [3- (3-carboethoxymethyl-phenyl) -4-hydroxy-phenyl] -hexane (D) obtained in Step 4 above is diluted with further toluene and reduced in vacuo. Evaporated at a maximum of 80 ° C. The distillation residue was dissolved in dichloromethane and an α / β mixture of tetra-O-pivaloyl-D-mannopyranosyl fluoride was added. Alternatively, the α- or β-stereoisomer of this tetra-O-pivaloyl-D-mannopyranosyl fluoride could be used. Some dichloromethane was distilled to confirm the absence of water. Boron trifluoride diethyl etherate was added at up to 3 ° C. after more than 2 hours. The reaction mixture is allowed to react at 0 ° C. for 6 hours until practically no 1,6-bis- [3- (3-carboethoxymethyl-phenyl) -4-hydroxy-phenyl] -hexane and intermediate remains. Stir. The solution was added to the ice-water mixture at a maximum of 10 ° C. These layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with two portions of aqueous sodium carbonate and water. Dichloromethane was distilled without reduced pressure and the distillation residue was diluted with toluene. Toluene was distilled at 65 ° C. under reduced pressure. This distillation residue was dissolved in methanol. Some methanol was distilled and the mixture was cooled to 45 ° C. This solution was seeded and stirred at 45 ° C. for at least 90 minutes.
After cooling to 22 ° C. and stirring for at least 2 hours, the resulting crystals are isolated by solid-liquid separation, washed with methanol, dried at about 40 ° C. under reduced pressure, and 1,6-bis- [3- ( 3-Carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane (E) was obtained. The yield of step 5 of this method was 86%.

Step 6: 1,6-Bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane, crude bimothermoss (I)
1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyloxy) -phenyl] -hexane (E) with toluene Diluted and evaporated at reduced pressure up to 70 ° C. This distillation residue was dissolved in a mixture of tetrahydrofuran and methanol. It was confirmed that no water was present. Cell aggregation factor (as a cellulose-based physical aid) and methanolic sodium methoxide solution (30%) were added at 23 ° C. This reaction mixture is practically converted to 6-bis- [3- (3-carbo-ethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyloxy) -phenyl]- The mixture was stirred at 23 ° C. for 8 hours until no hexane and intermediate remained. The mixture was filtered and washed with a mixture of tetrahydrofuran and methanol followed by methanol. Filter cake (1,6-bis- [3- (3-carbomethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyloxy) -phenyl] -hexane and cell aggregation factor ) Was suspended in water and aqueous NaOH (30%) was added at 5 ° C. The reaction mixture is practically 1,6-bis- [3- (3-carbomethoxymethylphenyl) -4- (tetra-O-pivaloyl-α-D-mannopyranosyloxy)-at 5 ° C. The mixture was stirred for 5 hours until no phenyl] -hexane remained.

  Cell aggregation factor was filtered and washed with water. Dilute hydrochloric acid was added to the filtrate at 2 ° C. until pH 2.5-3.0 was reached. After stirring at 2 ° C. for at least 3.5 hours, the resulting crystals were isolated by solid-liquid separation. The wet cake was suspended in water and warmed to 45 ° C. Ethanol was added and the mixture was cooled to 5 ° C. After stirring for at least 3 hours at 5 ° C., the crystals obtained are isolated by solid-liquid separation, washed with a mixture of water and ethanol, dried at 45 ° C. under reduced pressure and 1,6-bis- [3- (3 -Carboxy-methylphenyl) -4- (2- [alpha] -D-mannopyranosyloxy) -phenyl] -hexane (crude bimotherose) was obtained. The yield of step 6 of this method was 69%.

Step 7: Pure Vimosia Morse Crude Vimosia moose (I) was dissolved in an aqueous tetrahydrofuran solution at the reflux temperature or a temperature slightly below the reflux temperature. The solution was filtered through a microfilter cloth and cooled to about 52 ° C.

  This solution was seeded with about 0.5 w / w% Bimosia moose and then cooled to 0 ° C. with a temperature gradient of 18 K / h. Without interrupting the cooling ramp, additional tetrahydrofuran was begun at 18 ° C. over 1 hour. The white suspension was stirred for over 2 hours and the final temperature was 0 ° C. The product was isolated by centrifugation. The wet cake was washed first with tetrahydrofuran followed by isopropanol. The wet product was dried in a stirred vacuum dryer. The yield of purification step 7 of this method was 85%.

  The isolated compound (I) corresponds to the polymorphic Form 2 crystal form of Vimosia moose, which is characterized by the X-ray spectrum of FIG. In FIG. 1, the relative intensity (RI) of the signal of the X-ray spectrum is shown as a function of 2θ values (based on Cu K (α1)).

Example 2 (Bimosia Mohs treatment for volunteers)
The study was designed to show the effect of Vimosia moos on ozone-induced sputum neutrophil increase after repeated inhalation doses of Vimosia moos. The effect of Vimosia moose was tested after administration to 18 human volunteers (subjects) using a double-blind, placebo-controlled, two-period randomized crossover clinical trial design. These subjects were randomly assigned to each treatment with Vimosia moose or corresponding placebo: these treatments were separated by a washout period of at least 10 days (at least 14 days between ozone challenges).

  In each period, 8 doses of Vimosia moose (10 mg each) or corresponding placebo were administered over a period of 4 days. To elicit an inflammatory response, subject is challenged with ozone (this means running an air stream containing 250 ppb of ozone for 3 hours starting approximately 30 minutes after the end of the last dose on day 4 of each treatment period) Exposed to. The ozone challenge is described by Joerres 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 challenge, sputum was induced and 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], which were treated and investigated (where sputum induction is a treatment induced from the respiratory tract by the stimulation of saline inhaled by sputum) . Spiders were analyzed for cellular composition (eg, neutrophil count, lymphocyte count) and non-cell transmitter (eg, interleukin-8 and MMP-9 levels). Compared to placebo treatment, treatment with Vimosiamoos resulted in a clear reduction in sputum neutrophil count and sputum interleukin-8 levels. However, Vimosia moos surprisingly also significantly reduced the level of matrix metalloprotease-9 (MMP-9) sputum.

Example 3 (Bimosia Mohs treatment for patients)
Another study was designed to show the effect of Vimosiamoos on chronic obstructive pulmonary disease (COPD) after repeated inhalation administration of Vimosiamoos. Using a double-blind, placebo-controlled, two-period randomized crossover clinical trial design, the safety and efficacy of Vimosia moos was investigated in 77 patients (subjects) with COPD. These subjects were randomly assigned to each treatment with Vimosia moose or the corresponding placebo: these treatments were separated by a washout period of at least 14 days.

  Vimosia moos (10 mg) or corresponding placebo was administered twice daily for 28 days. Induction of wrinkles before and after each treatment period, Holz et al. [Changes in sputum composition duty sputum instruction in health and asthmatic patents. Clin Exp Allergy 1998; 28: 284-292] and Beeh et al. [Induced sputum cell profiles in lug tranplant recipients with or without chronic rejection: correlation with long function. Thorax. 2001; 56: 557-60], where the sputum induction is a process in which sputum is induced from the respiratory tract by stimulation of inhaled saline.

  Spiders were analyzed for cellular composition (eg, neutrophil count, lymphocyte count) and non-cell transmitter (eg, interleukin-8 and MMP-9 levels).

  Compared to placebo treatment, treatment with Vimosiamoos resulted in a clear reduction in sputum neutrophil count and sputum interleukin-8 levels. Vimosia moss also significantly reduced the level of matrix metalloprotease-9 (MMP-9) sputum. These results are shown in FIG.

  This FIG. 3 shows non-cellular IL-8, MPO (myeloperoxidase), MMP-9) and different cells in the sputum of patients treated with Vimosia moss compared to patients treated with placebo on day 28 of therapy ( Shows a reduction (ratio of treatment difference) of non-squamous epithelium, neutrophils, macrophages, lymphocytes and eosinophils.

2 shows the X-ray spectrum of Vimosia Moz crystal polymorph Form 2 of compound (1), where the relative intensity (RI) of the signal of the X-ray spectrum is shown as a function of the 2θ value (based on CuKα1). After administration of Vimosia moos or corresponding placebo, subjects were exposed to an ozone challenge to induce sputum, and the sputum was analyzed for cellular composition (lymphocyte count) and non-cell mediator (MMP9 levels) It is a graph which shows an effect. After the administration of vimosiamous or a corresponding placebo to a subject suffering from COPD, the effects of vimosiamooth when inducing sputum were shown to be non-cellular (IL-8, MPO, MMP9) in sputum and different cells (non-squamous epithelium) , Neutrophils, macrophages, lymphocytes, and eosinophils) parameters are graphs showing the effect of Vimosia moos obtained by analysis.

Claims (15)

A process for the preparation of a compound of formula (I) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane,

The 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 to give 1,4 -Bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is obtained, which is then catalytically reduced to 1,6-bis- [3- (3-carboethoxy -Methylphenyl) -4-methoxyphenyl] -hexane (C), 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 protected mannopyranosyl derivative to give 1,6-bis- [3- (3-carbo-ethoxy-methylphenyl) -4- (tetra-O-protected α-D-mannopyranosyloxy) -phenyl] -hexane-derivative is obtained, which is then reacted under basic reaction conditions to give 1,6-bis- [3- (3-carboxymethyl-phenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] -hexane, which is optionally recrystallized from 1, 2 or several organic solvents and / or water to give the formula ( A process as described above, comprising the step of obtaining the product Vimosia moose of I). The method for producing 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I) according to claim 1. And the following:
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 is then 1,4-bis- [3- (3-carboethoxymethylphenyl) -4 without reaction of the intermediate (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester by reaction with adipoyl chloride. -Methoxybenzoyl] -butane (B);
b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is reduced by using hydrogen and a metal catalyst and 1,6-bis- [ Forming 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 give 1,6-bis- [3- Obtaining (3-carboethoxymethyl-phenyl) -4-hydroxyphenyl] -hexane (D);
d) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) with a mannopyranosyl-derivative (especially tetra-O-pivaloyl-D-mannopyranosyl-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- (3-carboethoxy-methylphenyl) -4- (tetra-O-acetyl-α-D-mannopyranosyl-oxy)- Obtaining phenyl] -hexane;
e) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4- (tetramadol-O-pivaloyl-α-D-man pyranosyl-oxy) -phenyl] -hexane (E) or Reaction of the corresponding 1,6-bis- [3- (3-carboethoxy-methyl-phenyl) -4- (tetra-O-acetyl-α-D-mannopyranosyl-oxy) -phenyl] -hexane under basic conditions Forming 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 Obtaining a product of formula (I), vimosia moss, by recrystallization from an organic solvent and / or water or mixtures thereof;
Including the above method. Production of 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane (I) according to claim 1 or 2. The method is as follows:
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 is then Reacting with adipoyl chloride and Lewis acid in a solvent, without isolation of the intermediate (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester, 1,4-bis- [3- (3-carboethoxy- Obtaining (methylphenyl) -4-methoxybenzoyl] -butane (B) with a purity of greater than 95% and a yield of at least 70%;
b) 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) is reduced with hydrogen and a metal catalyst to give 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 in a solvent in the temperature range of −20 ° C. to + 20 ° C. to give 1,6- Obtaining 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 in the temperature range of −10 ° C. to + 15 ° C. Reaction with tetra-O-pivaloyl-D-mannopyranosyl-halide to react with 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra-O-pivaloyl-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) was converted to sodium methoxide And then reacted with an aqueous sodium hydroxide solution to produce 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane ( Forming I);
f) 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl]-from an organic solvent or a mixture of an organic solvent and water Recrystallizing hexane to obtain the product of formula (I), vimosia moss, with a purity higher than 98%;
Including the above method. The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane according to any one of claims 1 to 3. A manufacturing method of (I), which is as follows:
a) (2′-Methoxy-biphenyl-3-yl) -acetic acid (A) is converted from 2-methoxyphenyl-boronic acid and a molar excess of 3-bromophenylacetic acid to a temperature of + 60 ° C. to + 99 ° C. Followed by conversion of (2′-methoxy-biphenyl-3-yl) -acetic acid (A) under acidic conditions to form (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester. It is then reacted with adipoyl chloride and aluminum chloride in a solvent to give 1,4-bis- [3- (3) without isolation of the intermediate (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester. Obtaining 3-carboethoxy-methylphenyl) -4-methoxybenzoyl] -butane (B);
b) Reduction of 1,4-bis- [3- (3-carboethoxymethylphenyl) -4-methoxybenzoyl] -butane (B) with hydrogen, Pd catalyst and a mixture of ethanol, ethyl acetate and trifluoroacetic acid Forming 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C);
c) reacting 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) with boron tribromide in dichloromethane at a temperature range of −5 ° C. to + 5 ° C. 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D), then the reaction mixture is hydrolyzed with excess ethanol, followed by dimer and condensation products The product hydrolyzed to reconvert the product to the reaction product 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in boiling ethanol. Treating with:
d) 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) in the presence of a catalytic amount of boron trifluoride diethyl etherate; Reaction with tetra-O-pivaloyl-D-mannopyranosyl fluoride in the temperature range of + 10 ° C. yields 1,6-bis- [3- (3-carboethoxy-methylphenyl) -4- (tetra- 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) with tetrahydrofuran and methanol In the mixture at a temperature range of + 15 ° C. to + 25 ° C., followed by a reaction with an aqueous sodium hydroxide solution at a temperature range of 0 ° C. to + 10 ° C. to give 1,6-bis- [3- (3- Forming 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) in tetrahydrofuran or tetrahydrofuran and water Recrystallizing from the mixture to obtain the product Bimosia moose of formula (I) in a crystalline form of its polymorphic Form 2 with a purity higher than 98.5%;
Including the above method.   The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane according to any one of claims 1 to 4. In step (a), the compound (2′-methoxy-biphenyl-3-yl) -acetic acid (A) is first reacted with the compound (A) and thionyl chloride, The process as described above, which is converted to (2′-methoxy-biphenyl-3-yl) -acetic acid ethyl ester by reaction with ethanol.   The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane according to any one of claims 1 to 5. It is a manufacturing method of (I), Comprising: As a process f), the compound 1, 6-bis- [3- (3-carboxymethylphenyl) -4- (2- (alpha) -D-mannopyranosyloxy)- The above process, wherein phenyl] -hexane (I) is recrystallized from an ethanol / water mixture to obtain bimosia moss in its polymorph Form 2.   The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane according to any one of claims 1 to 5. A method for producing (I), wherein as step f) compound 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -Phenyl] -Hexane (I) is recrystallized from an isopropanol / water mixture to obtain bimothermoss with a purity of at least 99.0% and in its polymorph Form 2 crystalline form.   The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane according to any one of claims 1 to 7. In the production method of (I), the intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-methoxyphenyl] -hexane (C) is used as the step b) in the step c. ) Wherein the intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) is not isolated as a solid product.   The 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2-α-D-mannopyranosyloxy) -phenyl] hexane according to any one of claims 1 to 8. A process for preparing (I), wherein as step d) the intermediate 1,6-bis- [3- (3-carboethoxymethylphenyl) -4-hydroxyphenyl] -hexane (D) is converted to tetra- Process as described above, wherein the reaction is carried out with an α / β stereoisomer mixture of O-pivaloyl-D-mannopyranosyl halide.   A 1,6-bis- [3- (3-carboxymethylphenyl) -4 produced by the process according to any one of claims 1 to 9 and having a purity of at least 99%, in particular 99.5%. -(2- [alpha] -D-mannopyranosyloxy) -phenyl] hexane (I).   A 1,6-bis- [3- (3-carboxymethylphenyl) -4- (2) produced by the process according to any one of claims 1 to 9 and having a purity of at least 99%, in particular 99.5%. A pharmaceutical composition comprising -α-D-mannopyranosyloxy) -phenyl] hexane (I) and at least one further pharmaceutically acceptable carrier.   Vimosiamors and / or salts of Vimosiamors and / or their stereoisomeric or polymorphic forms for the treatment, prevention or diagnosis of hypersensitivity pneumonia and pulmonary sarcoidosis.   Including bimothermoses and / or salts of bimothermoss and / or stereoisomeric or polymorphic forms thereof and at least one further pharmaceutically inactive ingredient for the treatment, prevention or diagnosis of hypersensitivity pneumonia and / or pulmonary sarcoidosis , Pharmaceutical composition.   A medicament comprising vimosiamors and / or salts of vimosiamors and / or their stereoisomeric or polymorphic forms and at least one further pharmaceutically active ingredient for the treatment, prevention or diagnosis of hypersensitivity pneumonia and pulmonary sarcoidosis Composition.   Bimosia moss and / or salts of bismuth moss and / or their stereoisomeric or polymorphic forms for the treatment, prevention or diagnosis of specific inflammation, emphysema and eye diseases, wherein the specific inflammation is: Means ophthalmitis, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucositis, pneumonia, abdominal inflammation, and cystitis; eye disease means the following: corneal damage, corneal ulcer, ophthalmology The above compounds meaning infectious diseases, dry eye, eye diseases, macular retinal degeneration, pterygium, uveitis and lacrimal gland diseases.

Images