WO2004071515A1 - Preparation de derives de monosaccharide - Google Patents

Preparation de derives de monosaccharide Download PDF

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Publication number
WO2004071515A1
WO2004071515A1 PCT/IB2003/000471 IB0300471W WO2004071515A1 WO 2004071515 A1 WO2004071515 A1 WO 2004071515A1 IB 0300471 W IB0300471 W IB 0300471W WO 2004071515 A1 WO2004071515 A1 WO 2004071515A1
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WIPO (PCT)
Prior art keywords
formula
compound
group
carried out
disorder
Prior art date
Application number
PCT/IB2003/000471
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English (en)
Inventor
Mohammad Salman
Gyan Chand Yadav
Viswajanani Jitendra Sattigeri
Original Assignee
Ranbaxy Laboratories Limited
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.)
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Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to PCT/IB2003/000471 priority Critical patent/WO2004071515A1/fr
Priority to AU2003202767A priority patent/AU2003202767A1/en
Publication of WO2004071515A1 publication Critical patent/WO2004071515A1/fr

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
    • 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

Definitions

  • the present invention relates to an improved and industrially advantageous process for the preparation of derivatives of monosaccharides. More particularly, derivatives corresponding to compounds of Formula I.
  • CAM's cell adhesion molecules
  • CAM's cell adhesion molecules
  • CAM's cell adhesion molecules
  • CAM's have been demonstrated to participate in various cell-cell, cell-extracellular matrix, and platelet- platelet interactions.
  • CAM's influence the leukocytes, adhesion to the vascular endothelium, their transendothelial migration, retention at extravascular sites, and activation of T cells and eosinophils. These processes are central to the pathogenesis of inflammatory and autoimmune diseases. Therefore, CAM's are considered potential targets in treating such disorders.
  • CAM's can be classified into three groups: integrins, selectins and the immunoglobulins superfamily. Of these, integrins are key mediators in the adhesive interactions between hemopoietic cells, and other components in their microenvironments. Integrins can be classified on the basis of beta subunits they contain.
  • the alpha - 4 beta — 1 integrin also known as NLA (very late activation antigen 4), is a member of the beta - 1 integrin family and comprises alpha - 4 and beta - 1 subunits.
  • NLA interacts with two specific ligands: the vascular cell adhesion molecule (NC AM- 1 ) and the CS 1 region of fibronectin.
  • Adhesion mediated by NLA is central to the process of transendothelial migration of leukocytes. Ligation of NLA 4 is followed by gross rearrangement of the cytoskeleton, leading to flattening of cells along the blood vessel wall, followed by expression of specific molecules that digest the endothelial cell wall diapedesis.
  • NLA 4 . With extracellular fibronectin play a crucial role in the migration of leukocytes to the site of inflammation, T cell proliferation and expression of cytokines and inflammatory mediators. Additionally, NLA 4 . ligation provides co-stimulatory signals to the leukocytes, resulting in enhanced immunoreactivity. Thus, appropriate N A antogonists would, in theory, ameliorate the immune response through a two fold action inhibition of T cell recruitment at the site of inflammation and inhibition of co-stimulatory activation of immune cells.
  • compounds of Formula I are useful for, inter alia, the inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies, including inflammatory and autoimmune diseases, such as bronchial asthma, rheumatoid arthritis, type-I diabetes, multiple sclerosis, allograft rejection and psoriasis.
  • United States Patent No. 6,329,344 also discloses the synthesis of compounds of Formula I
  • R is C1 to C15 alkyl, alkene, straight chain alkyne or branched alkyne, aryl, substituted aryl or alkylaryl;
  • R is SO2C6H5, SO2C6H .CH3-P., or SO2C6H4CI-P, phenyl or substituted phenyl, represented as C 6 H 4 -R"'-p wherein R'" is CI, NO 2 , OCH3, CH3, CH 2 COOH,
  • R" is H or CH 3; which comprises reacting 2,3-O-isopropylidine-6-deoxy-l-O-alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkylaryl mai ofuranoside of Formula II
  • the present invention is directed to solving the problems associated with processes for the preparation of compounds of Formula I described in the prior art and to providing an efficient process for the preparation of compounds of Formula I. Benefits with respect to economics, safety, and convenience in commercial scale operations are offered.
  • the present invention relates to processes for the syntheses of compounds of Formula I
  • R is C to C15 alkyl, alkene, straight chain alkyne or branched alkyne, aryl, substituted aryl or alkylaryl;
  • R * is SO2C6H5, SO2C6H4CH3-p i or SO2C6H4CI-P, phenyl or substituted phenyl, represented as C6H 4 -R"'-p wherein R'" is CI, NO 2 , OCH3, CH3, CH 2 COOH, CH 2 COOCH 3 , CH 2 COLDNP, CH 2 CODNP, CH 2 CONP wherein LDNP, DNP and NP represent tetrapeptide (Leucyl-aspartyl-valyl-prolyl), tripeptide (aspartyl-valyl-prolyl) and dipeptide (valyl-prolyl), respectively (alternate terra-, hi- and dipeptides containing amino acids which are equivalent to those described can also be used);
  • R" is H or CH 3 , which comprises, reacting a compound of Formula II
  • R and R" are the same as defined above, with a leaving group, for example, methanesulphonyl chloride, in an organic solvent such as nonpolar, aprotic solvents, including dichloromethane, dichloroethane, chloroform, tetrahydrofuran or acetone, in presence of an organic base, such as triethylamine, triethylamine, ⁇ -methyl morpholine or isopropylamine, and the reaction mixture is allowed to stir for about 30 minutes to yield the organic compound of Formula IN
  • this compound of Formula-N is further treated with palladium-carbon in presence of an acid such as formic acid or acetic acid in an alcohol such as methanol or ethanol to yield the compound of Formula III
  • L represents a leaving group such as alkoxy, aryloxy or arylalkoxy
  • R is the same as defined above in an organic solvent such as dichloromethane, dichloroethane, chloroform, tetrahydrofuran and acetone in presence of an organic base such as triethylamine, ⁇ -methyl morpholine and isopropylamine to yield the compound of Formula I
  • Particular compounds synthesized according to the invention and capable of being produced by the above mentioned process include: l-O-dodecyl-2,3-O-isopropylidene-5,6-dideoxy-5- ⁇ -[4-(2-methoxy-2- oxoethyl)phenylamino carbonyl]amino- ⁇ ,L-gulofuranoside.
  • the compounds of Formula I prepared by the processes disclosed herein can be used to make up pharmaceutical compositions. Such compositions can be formulated into solid dosage forms for oral administration, such as, for example, tablets, granules, capsules, pills, and the like.
  • the medicaments can be prepared by conventional methods, including a therapeutically effective amount of a compound of Formula I, and pharmaceutically acceptable excipients.
  • the administration of pharmaceutical compositions can be by injection or by gradual infusion over time.
  • the compositions can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
  • Preferred methods for delivery of the compositions include orally, by encapsulation in microspheres or proteinoids, by aerosol delivery to the lungs, or transdermally by iontophoresis or transdermal electroporation. Other methods of administration will be known to those skilled in the art.
  • the compositions may also be administered by controlled release means and/or delivery devices, with modifications known to those of ordinary skill in the art.
  • compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • terapéuticaally effective amount is meant the quantity of a compound or composition according to the invention necessary to prevent, cure or at least partially arrest the symptoms of the disorder and its complications.
  • cell adhesion inhibiting amounts or cell adhesion preventing amounts are the amounts of compound or composition necessary to inhibit or prevent cell adhesion. Amounts effective to achieve this goal will, of course, depend on the severity of the disease and the weight and general state of the patient. Methods of Treatment
  • compositions provided herein can be utilized for various treatment methods, such as those for treating inflammatory and autoimmune diseases, such as bronchial asthma, rheumatoid arthritis, type-I diabetes, multiple sclerosis, allograft rejection, and psoriasis.
  • inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type-I diabetes, multiple sclerosis, allograft rejection, and psoriasis.
  • the methods include administering to a mammal a therapeutically effective amount of a pharmaceutical composition as described herein.
  • a pharmaceutical composition as described herein.
  • the administration of pharmaceutical compositions can be by oral or buccal administration,. Other methods of administration will be known to those skilled in the art.
  • Example 1 Preparation of l-O-dodecyl-2,3-O-isopropyridene— 5, 6-dideoxy-5-N-
  • Benzylamine (2.16 kg, 20.18 moles, 8.27 equivalents) was added in one lot to 1- O-dodecyl-2, 3-0 -isopropylidene-6-deoxy-5-O-methanesulphonyl- ⁇ , D- mamiofuranoside (1.1 kg, 2.44 moles) and the mixture was stirred at 120° C for 5 - 6 hours. The progress of the reaction was monitored by TLC (30% ethyl acetate in hexane). After completion of the reaction, benzylamine was removed by distillation under vacuum and the reaction mixture was cooled to 50 - 60°C. Hexane (2.75 L) was added and cooled to room temperature.
  • Step 3 Preparation of l-O-dodecyI-2, 3-O-isopropylidene-5, 6-dideoxy-5-amino- ⁇ , L-gulofuranoside
  • Step 4 Preparation of l-O-dodecyl-2,3-O-isopropylidene-5, 6-dideoxy-5-N-[4-(2- methoxy -2-oxoethyl)phenyIaminocarbonyl]amino- ⁇ , L-gulofuranoside

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de dérivés de monosaccharide présentant des avantages dans le secteur industriel, à savoir des avantages pratiques, sûrs et économiques. Les dérivés de monosaccharide peuvent être utilisés pour l'inhibition et la prévention d'adhésion cellulaire et de pathologies induites par l'adhésion cellulaire.
PCT/IB2003/000471 2003-02-12 2003-02-12 Preparation de derives de monosaccharide WO2004071515A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IB2003/000471 WO2004071515A1 (fr) 2003-02-12 2003-02-12 Preparation de derives de monosaccharide
AU2003202767A AU2003202767A1 (en) 2003-02-12 2003-02-12 Preparation of monosaccharide derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2003/000471 WO2004071515A1 (fr) 2003-02-12 2003-02-12 Preparation de derives de monosaccharide

Publications (1)

Publication Number Publication Date
WO2004071515A1 true WO2004071515A1 (fr) 2004-08-26

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WO (1) WO2004071515A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092907A2 (fr) * 2004-03-26 2005-10-06 Ranbaxy Laboratories Limited Derives de monosaccharide
WO2005100373A2 (fr) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Derives du monosaccharide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329344B1 (en) * 1998-10-22 2001-12-11 Ranbaxy Laboratories Limited Derivatives of monosaccharides as cell adhesion inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329344B1 (en) * 1998-10-22 2001-12-11 Ranbaxy Laboratories Limited Derivatives of monosaccharides as cell adhesion inhibitors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092907A2 (fr) * 2004-03-26 2005-10-06 Ranbaxy Laboratories Limited Derives de monosaccharide
WO2005092907A3 (fr) * 2004-03-26 2006-04-27 Ranbaxy Lab Ltd Derives de monosaccharide
WO2005100373A2 (fr) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Derives du monosaccharide
WO2005100373A3 (fr) * 2004-04-13 2006-04-06 Ranbaxy Lab Ltd Derives du monosaccharide

Also Published As

Publication number Publication date
AU2003202767A1 (en) 2004-09-06

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