EP2566580A1 - Verfahren zur herstellung von bimosiamose - Google Patents

Verfahren zur herstellung von bimosiamose

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Publication number
EP2566580A1
EP2566580A1 EP11720069A EP11720069A EP2566580A1 EP 2566580 A1 EP2566580 A1 EP 2566580A1 EP 11720069 A EP11720069 A EP 11720069A EP 11720069 A EP11720069 A EP 11720069A EP 2566580 A1 EP2566580 A1 EP 2566580A1
Authority
EP
European Patent Office
Prior art keywords
bis
hexane
phenyl
carboethoxymethylphenyl
bimosiamose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11720069A
Other languages
English (en)
French (fr)
Inventor
Remo Kranich
Daniel Bock
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Revotar Biopharmaceuticals AG
Original Assignee
Revotar Biopharmaceuticals AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Revotar Biopharmaceuticals AG filed Critical Revotar Biopharmaceuticals AG
Priority to EP11720069A priority Critical patent/EP2566580A1/de
Publication of EP2566580A1 publication Critical patent/EP2566580A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel process for the preparation of the pharmaceutical compound l,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl]- hexane (also called Bimosiamose).
  • 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 selective crystal form (polymorph) and in an industrial scale.
  • Bimosiamose acts as a pan-selectin antagonist and inhibits the leukocyte extravasation.
  • leukocyte extravasation is a key step in the pathogenesis of many inflammatory disorders or conditions, the compound of formula (I) offers the opportunity 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 prophylaxis of cosmetic and dermatological conditions where micro -inflammatory conditions are involved.
  • the compound of formula (I) may also be administered to treat other diseases that are associated with cell-cell adhesion.
  • 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) is also useful for the treatment, diagnosis, and prophylaxis of several forms of cancer, including lung and colon cancer, for instance.
  • 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.
  • the compound of formula (I) and its 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.
  • API active pharmaceutical ingredients
  • 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 case.
  • 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 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.
  • 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)
  • liquid preparations such as oral solutions, emul
  • Bimosiamose like liposomes and related forms, micellar solutions, 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.
  • 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 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 appearance of telangiectasia.
  • Various ways of synthesis for Bimosiamose are known, see e. g. T. Kogan et al, J.
  • the method of present invention works particularly 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 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 manufacturing of drug products, diagnostics and/or cosmetics containing Bimosiamose.
  • 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.
  • 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 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 l,4-Bis-[3-(3-carboethoxymethylphenyl)-4- methoxybenzoyl] -butane (B), without the isolation of the intermediate (2'-Methoxy- biphenyl-3-yl)-acetic acid ethyl ester, b) l,4-Bis-[3-(3-carboxymethylpheny
  • 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 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 l,4-Bis-[3-(3-carboethoxy- methylphenyl)-4-methoxybenzoyl] -butane (B) in a purity of more than 95% and a yield of at least 70%, without isolation of the intermediate (2'-Methoxy-biphenyl-3- yl)-acetic acid
  • the invention relates to a process for the preparation of l,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- 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 l,4-Bis-[3-(3-
  • the invention also relates to a process for the preparation of l,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- biphenyl-3-yl)-acetic acid ethyl ester by first reacting compound (A) with thionyl chloride and then reacting with ethanol.
  • step a) the compound (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is converted to (2'-Methoxy- biphenyl-3-yl)-acetic acid ethyl ester by first reacting compound (A) with thionyl chloride and then reacting with ethanol.
  • 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 a step f) the compound l,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.
  • 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 step f) the compound l,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyrano- syloxy)-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.
  • the invention relates to a process for the preparation of l,6-Bis-[3- (3-carboxymethylphenyl)-4-(2-a-D-manno-pyranosyloxy)-phenyl] hexane (I), in which as step b) the intermediate l,6-Bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) and in step c) the intermediate l,6-Bis-[3-(3-carboethoxymethylphenyl)-4- hydroxyphenyl] -hexane (D) are not isolated as solid products, but optionally as the respective solution.
  • the invention also deals with a process for the preparation of l,6-Bis-[3-(3- carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl] hexane (I), in which as step d) the intermediate l,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) is reacted with a mixture of the ⁇ / ⁇ -stereoisomers of tetra-O-pivaloyl-D-mannopyranosyl halide.
  • a particular aspect of the invention is the product, l,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 %.
  • the compound (I) contains less than 0.1 % of stereoisomers of Bimosiamose.
  • 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).
  • 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).
  • 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.
  • carriers e. g. for parenteral injection
  • 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 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 emulsions and sterile powders for reconstitution into sterile injectable solution or dispersion.
  • sterile aqueous or nonaqueous solutions 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 emulsions and sterile powders for reconstitution into sterile injectable solution or dispersion.
  • preservatives e.g. ascorbic acid, sodium sulfite, sodium hydrogene sulfite,
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing agents and or antibacterial and antifungal agents. If desired, and for more 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 acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • Compositions for rectal administrations are preferably suppositories.
  • Dosage forms for topical administration of a compound of this invention include ointments, cremes, gels, powder, sprays and inhalants.
  • the pure compound of formula (I) 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, 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 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 and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
  • the compound (I) is prepared 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%).
  • (2'-Methoxy-biphenyl-3-yl)-acetic acid (A) is converted to (2 - Methoxy-biphenyl-3-yl)-acetic acid ethyl ester and then subsequently reacted with adipoyl chloride and a Lewis acid (Aluminum chloride) to l,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%).
  • (B) is chemically reduced under an atmosphere of hydrogen to l,6-bis-[3-(3- carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C), applying a metal catalyst, in particular a catalyst comprising Pd.
  • a metal catalyst in particular a catalyst comprising Pd.
  • l,6-bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl]-hexane (D) 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°C to +15°C to obtain l,6-bis-[3-(3-carboethoxymethylphenyl)-4-(tetra-0-pivaloyl-a-D-mannopyranosyl- oxy)-phenyl]-hexane (E) or the corresponding O-protected derivative, In one embodiment l,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
  • l,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyl-oxy)- phenyl] -hexane is recrystallized from an organic solvent (such as ethanol, methanol or tetrahydrofuran) and optionally water to obtain Bimosiamose in high quality and purity of more than 98% (in particular more than 98.5%).
  • an organic solvent such as ethanol, methanol or tetrahydrofuran
  • Bimosiamose The introduction of the mannose units into the molecule Bimosiamose is known in prior art 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 ⁇ / ⁇ -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 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%.
  • recrystallization of crude Bimosiamose from tetrahydrofuran water mixtures gives the polymorph FORM 2 in a yield of 85%.
  • 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 Kai : at approximately 5.3° (strong peak),
  • the polymorph FORM 2 is further characterized in that is has a melting range of 158°C to 161°C.
  • recrystallization of the crude product Bimosiamose from ethanol/water mixtures or isopropanol/water mixtures is a suitable method which leads to purified 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%).
  • the method for the preparation of l,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl]-hexane 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 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%.
  • the invention also relates to a pharmaceutical composition comprising Bimosiamose for new medical uses.
  • pharmaceutical formulations containing 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 WO2008028950] or Interleukin-8 mediated disorders related to viral infections [see WO2008098985].
  • 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.
  • MMP matrix metalloproteinases
  • the invention also relates to a method for 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 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 the use of Bimosiamose and/or a salt of Bimosiamose and/or a 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
  • a 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.
  • the invention also relates to a pharmaceutical composition
  • a 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.
  • the invention also relates to a pharmaceutical composition
  • a 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, 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 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.
  • Erye 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.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising Bimosiamose 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.
  • Inflammations include (or means) eye inflammation, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucitis, pneumonia, abdominal inflammation, and cystitis.
  • Erye 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.
  • 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% 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 pharmaceutically active ingredient.
  • 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 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 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.
  • the present invention further relates to the Bimosiamose for the use (e. g. as a pharmaceutical composition) for the treatment, diagnosis, or prophylaxis of hypersensitivity pneumonitis and pulmonary sarcoidosis.
  • One embodiment of the invention relates to a pharmaceutical composition
  • 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, 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.
  • 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.
  • 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 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 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 (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 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.
  • pulmonary emphysema or particular inflammations such as eye inflammation, anaphylaxis, periodontal disease, otitis, ulcer, ulcerative colitis, mucitis, pneumonia, abdominal inflammation
  • 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, 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 gland disease. and optionally in combination with at least one further pharmaceutically inactive ingredient.
  • pulmonary emphysema or particular inflammations such as eye inflammation, anaphylaxis,
  • 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 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.
  • a mixture of 3-bromophenyl-acetic acid, 2-methoxyphenylboronic acid, potassium carbonate and catalytic amounts of (PPh3) 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 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 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 3°C. Obtained 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.
  • Step 1 of the process is 87 %, but can be improved to 91%, when 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 V max /V m i n ratio decreases and the two washing steps with diluted sulfuric acid are omitted.
  • Step 2 l,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.
  • 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- 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°C in a rate that allows for keeping the temperature of the resulting mixture at 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 dichloromethane.
  • 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 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 in dichloromethane and adipoyl chloride are pre-mixed in a reactor at 0°C and the ester is then added slowly to this mixture.
  • a solution of l,4-bis-[3-(3-carboethoxymethylphenyl)-4-methoxybenzoyl]-butane (B) in a 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 l,4-bis-[3-(3-carboethoxymethylphenyl)-4-methoxybenzoyl]-butane and partially hydrogenated intermediates are left.
  • the reaction mixture is cooled to 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 l,6-bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]-hexane (C) which can be 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 %.
  • Step 4 l,6-Bis-[3-(3-carboethoxymethylphenyl)-4-hydroxyphenyl] -hexane (D)
  • the toluene solution of l,6-bis-[3-(3-carboethoxymethylphenyl)-4-methoxyphenyl]- hexane (C) from Step 3 above is diluted with further toluene and evaporated under vacuum at max. 50° C.
  • the distillation residue is dissolved in dichloromethane and the absence of water is checked.
  • Boron tribromide is added in not less than 2 h at max. 0° C.
  • the reaction mixture is stirred at 3°C for 2 h until practically no l,6-bis-[3-(3-carboethoxymethyl- phenyl)-4-methoxyphenyl] -hexane and partially de-methylated intermediate is left.
  • the distillation residue is dissolved in diisopropylether and some diisopropylether is distilled off to remove residual toluene.
  • the mixture is cooled to 30°C and seeded. After cooling to ambient temperature the suspension is stirred for at least 8 h.
  • Step 5 1 ,6-Bis- [3-(3-carboethoxymethylphenyl)-4-(tetra-0-pivaloyl-a-D-manno- pyranosyloxy)-phenyl] -hexane
  • E The toluene solution of l,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. 80° C.
  • the distillation residue is dissolved in dichloromethane and an ⁇ / ⁇ -mixture of tetra-O-pivaloyl-D-mannopyranosyl fluoride is added.
  • dichloromethane is distilled off and the absence of water is checked.
  • Boron trifluoride diethyletherate is added in not less than 2 h at max. 3° C.
  • the reaction mixture is stirred at 0°C for 6 h until practically no l,6-bis-[3-(3-carboethoxymethyl-phenyl)-4-hydroxy- phenyl] -hexane and intermediates are left.
  • the solution is added to an ice-water-mixture at max. 10° 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°C.
  • the distillation residue is dissolved in methanol. Some methanol is distilled off and the mixture is cooled to 45°C.
  • the solution is seeded and stirred for at least 90 min at 45°C.
  • Step 6 l,6-bis-[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)-phenyl]- hexane, crude Bimosiamose (I)
  • the filter cake (mixture of l,6-bis-[3-(3-carbomethoxymethylphenyl)-4-(tetra- 0-pivaloyl-a-D-manno-pyranosyloxy)-phenyl]-hexane and cell floe) is suspended in water and aqueous NaOH solution (30 %) is added at 5°C. The reaction mixture is stirred at 5°C for 5 h until practically no l,6-bis-[3-(3-carbomethoxymethylphenyl)-4-(tetra-0-pivaloyl- a-D-manno-pyranosyloxy)-phenyl]-hexane is left.
  • the compound (I) isolated corresponds to Bimosiamose in the crystal form of its polymorph FORM 2, which is characterized by the X-ray spectrum of 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)).
  • cellular composition e.g. neutrophil count, lymphocyte count
  • non-cellular mediators e.g. interleukin-8 and M
  • This Fig.3 shows the reduction (percentage of treatment differences) of non-cellular IL-8, 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.

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US5444050A (en) * 1994-04-29 1995-08-22 Texas Biotechnology Corporation Binding of E-selectin or P-selectin to sialyl Lewisx or sialyl-Lewisa
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US5712387A (en) * 1996-05-20 1998-01-27 Texas Biotechnology Corporation High yield stereospecific mannosylation
US5919768A (en) 1996-06-26 1999-07-06 Texas Biotechnology Corporation Di- and trivalent small molecule selectin inhibitors
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EP1903049A1 (de) 2006-09-08 2008-03-26 Revotar Biopharmaceuticals AG Kristalline Formen von 1,6-Bis [3-(3-carboxymethylphenyl)-4-(2-alpha -D-mannopyranosyloxy)-phenyl] hexane
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