WO2004071515A1

WO2004071515A1 - Preparation of monosaccharide derivatives

Info

Publication number: WO2004071515A1
Application number: PCT/IB2003/000471
Authority: WO
Inventors: Mohammad Salman; Gyan Chand Yadav; Viswajanani Jitendra Sattigeri
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2003-02-12
Filing date: 2003-02-12
Publication date: 2004-08-26
Anticipated expiration: 2005-08-12
Also published as: AU2003202767A1

Abstract

Process for the preparation of monosaccharide derivatives, providing industrial advantages, including convenience, safety, and economic advantages. The monosaccharide derivatives can be used for the inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies.

Description

PREPARATION OF MONOSACCHARIDE DERIVATIVES

FIELD OF INVENTION

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.

Formula I

BACKGROUND OF INVENTION

Cell adhesion is a process by which cells associate with each other, migrate towards a specific target localized within the extracellular matrix. Specialized molecules, called cell adhesion molecules (CAM's), mediate these interactions. 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 NLA₄ 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. Once in the extraluminal region, the interactions of NLA₄. 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, NLA₄. 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 known from United States Patent No. 6,329,344, and were screened for inhibitory activity in NLA mediated cell adhesion assay and the classical murine hypersensitivity assay in mice. Several compounds exhibited significant inhibitory activity in both tests. The salts of these compounds could be easily solubilized in water and used in the treatment of chronic, cell adhesion mediated, allergic, autoimmune and inflammatory disorders, such as bronchial asthma and rheumatoid arthritis.

Thus, 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

Formula I

wherein

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 C₆H₄-R"'-p wherein R'" is CI, NO₂, OCH3, CH3, CH₂COOH,

CH₂COOCH₃, CH₂COLDVP, CH₂CODNP, CH₂CONP wherein LDNP, DNP and NP represent tetrapeptide (Leucyl-aspartyl-valyl-prolyl), tripeptide (aspartyl-valyl-prolyl) and dipeptide (valyl-prolyl), respectively (amino acids generally regarded as equivalent to these can also be substituted);

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

Formula II

with p-toluenesulphonyl chloride, followed by reaction with sodium azide, and then reduction with lithium aluminum hydride to yield the corresponding 5-deoxy-5-amino epimannofuranoside derivatives of Formula III,

FORMULA III which on further treatment with the suitable sulphonyl isocyanates afforded the desired ureido compounds of Formula I.

The method described in United States Patent No. 6,329,344 for the preparation of compounds of Formula I has the following general characteristics: Overall yield of about 17%; reagents which are highly toxic (that is, irritating to the respiratory tract, e.g., sodium azide, pyridine, tetrahydrofuran, lithium aluminum hydride), explosive, flammable, moisture sensitive, corrosive and difficult to handle at a commercial scale are required; reaction conditions include potential for explosion and fire and hence are inconvenient to carry out at a commercial scale, for example, sodium azide releases hydrazoic acid, which is formed in situ and which might explode on heating, also the use of tetrahydrofuran involves the risk of explosive peroxide formation; byproducts of p- toluenesulphonyl chloride are difficult to remove; removal of the high boiling point solvent, dimethylformamide, is difficult; preparation of isocyanate generally involves the use of highly toxic phosgene gas; tetrahydrofuran is an expensive solvent and adds a significant cost factor in the overall cost of preparation of the final product; and purification involves use of column chromatography which can be cumbersome and disadvantageous at a commercial scale.

SUMMARY

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 overall yield of compounds of Formula I by the process described herein is increased to about 40% against about 17% as reported in United States Patent No. 6,329,344.

The present invention relates to processes for the syntheses of compounds of Formula I

Formula I

wherein

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 C6H₄-R"'-p wherein R'" is CI, NO₂, OCH3, CH3, CH₂COOH, CH₂COOCH₃, CH₂COLDNP, CH₂CODNP, CH₂CONP 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 CH₃, which comprises, reacting a compound of Formula II

Formula II

wherein, 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, Ν-methyl morpholine or isopropylamine, and the reaction mixture is allowed to stir for about 30 minutes to yield the organic compound of Formula IN

FORMULA IN wherein R and R are the same as defined earlier. The compound of Formula IN is further reacted with benzylamine to yield organic compound of Formula N,

FORMULA - V wherein R and R" are the same as defined earlier, 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

FORMULA III which is reacted with the carbamate of Formula VI

L — C— H— FT FORMULA VI

wherein L represents a leaving group such as alkoxy, aryloxy or arylalkoxy; and 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, Ν-methyl morpholine and isopropylamine to yield the compound of Formula I

Formula I wherein R, R and R are the same as defined earlier.

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-Ν-[4-(2-methoxy-2- oxoethyl)phenylamino carbonyl]amino-β,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. In these cases, 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. In addition to the common dosage forms set out, 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.

The 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.

By "therapeutically 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. In particular, 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

The pharmaceutical 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.

The methods include administering to a mammal a therapeutically effective amount of 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.

Using the process parameters of the present invention, a convenient, reproducible stable pharmaceutical composition of the compounds of Formula I maybe obtained. The present invention is further illustrative by, but is by no-means limited to, the following examples.

In the following section particular embodiments are described in a way to illustrate the process of invention. However, this is not intended in any way to limit the scope of the present invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example 1: Preparation of l-O-dodecyl-2,3-O-isopropyridene— 5, 6-dideoxy-5-N-|^"4- (2-methoxy-2-oxoethyl phenylaminocarbonyl1amino -β, I-- ulofuranoside Step 1: Preparation of l-O-dodecyl-2,3-O-isopropylidene-5,6-dieoxy-5-O-methane sulphonyl-α , D-mannofuranoside

To a solution of l-O-dodecyl-2,3-O-isopropylidene-6-deoxy-α, D- mannofuranoside (0.91 kg, 2.45 moles) in dichloromethane (4.55 L) cooled at -5° C was added triethylamine (0.297 kg, 2.94 moles) was added followed by slow addition of methanesulphonyl chloride (0.336 kg. 2.94 moles) over a period of 30 minutes with stirring. After 30 minutes of stirring at 0 to 5° C, water was added. The layers were separated and aqueous layer was re-extracted with dichloromethane (2.28 L), combined organic layer was washed first with 2.5% (w/v) aqueous sodium bicarbonate solution (3.64 L) and then with water (3.64 L), and then dried over anliydrous sodium sulphate. The solvent was removed under vacuum to obtain the desired compound in 100% yield.

The spectral information obtained from this compound was as follows: ¹HNMR (300 MHz, CDC1₃) δ : 0.86 - 0. 90 (3H, t), 1.17 - 1.19 (3H,d), 1.25 (18H, bs), 1.30 (3H,s) 1.42 (3H, s), 1.47 - 1.54 (2H,m), 1.94 (lH,m) 3.13 - 3.18 (lH,m), 3.32 - 3.35 (lH,m) 3.60 - 3.63 (lH-m), 3.73 - 3.93 (3H,m) 4.56 - 4.58 (lH,d) 4.68 - 4.71 (1H, m), 4.98 (1H, s) 7.24 - 7.36 (5H,m); IR cm^"1 (DCM): 3456.2, 2996.4, 1591.1, 1475.6; Mass: 462.2 [M + Step 2: Preparation of l-O-dodecyl-2,3-O-isopropylidene-5-6-dideoxy-5-(N- benzyι)amino-β, L-gulofuranoside

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-α, 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. Water (2.75 L) was added and stirred for 30 - 40 minutes. Organic layer was separated and aqueous layer was reextracted with hexane(0.55 L), combined hexane layer was washed with water (3 x 3.3 L). The hexane layer was concentrated under reduced pressure at 40 — 45° C. The residue was purified by column chromatography using silica gel (100 - 200 mesh), hexane: ethyl acetate as eluent to obtain the desired product (0.702 kg) in 62.34% yield.

The spectral information of this product was as follows: IR cm^"1 (DCM): 3423.9, 2926.3, 2854.9, 1459.7, 1361.1; ¹HNMR (300 MHz, CDC1₃) δ : 0.86 - 0.90 (3H,t), 1.26 - 1.30 (21H, bs ), 1.46 (3H, s), 1.51 - 1.53 (2H,m), 1.57 - 1.59 (3H,d), 3.07 (3H,bs), 3.38 - 3.42 (lH,m), 3.58 - 3.61 (lH,m), 3.87 - 3.91 (lH,m), 4.59 - 4.61 (lH,d), 4.72 - 4.75 (lH,m), 4.88 - 4.93 (lH,m), 4.98 (1H, s).

Step 3: Preparation of l-O-dodecyI-2, 3-O-isopropylidene-5, 6-dideoxy-5-amino- β, L-gulofuranoside

To a solution of l-O-dodecyl-2, 3-O-isopropylidene-5, 6-dideoxy-5-(N- benzyl)amino-β, l-gulofuranoside (0.7 kg, 1.518 moles) in methanol (3.5 L), 10% palladium - carbon (50% at 0.35 kg) was added under nitrogen atmosphere at room temperature. Formic acid (0.7L) was added slowly over the period of 30 - 60 min., the reaction mixture was stirred for 2 - 3 hours at 40 - 55°C the progress of the reaction mixture was monitored by TLC (30% ethylacetate in hexane). After completion of reaction the catalyst was filtered through celite pad. The celite cake was washed with methanol (1.75 L). The combined methanol layer was concentrated under reduced pressure at 40 - 45°C. To the residve dichloromethane (3.5L) was added and neutralized to pH 7 - 8 using aqueous sodium bicarbonate solution. Organic layer was separated and concentrated under reduced pressure at 35 - 45°C. The residue was purified by column chromatography using silica gel (100-200 mesh, 3Kg), dichloromethane and 2% triethylamine in ethyl acetate as eluent.

¹ The spectral information was as follows: ¹HNMR (300 MHz, CDC1₃) δ : 0.86 -

0.90 (3H,t), 1.13 - 1.16 (3H,d), 1.26 - 1.30 (21H,m), 1.45(3H,s)1.52 - 1.57 (2H,m), 3.24 -

3.38 (2H,m), 3.55 - 3.64 (2H,m), 4.56 - 4.58 (lH,d), 4.65 - 4.67 (lH,m), 4.97 (lH,s);

IR cm^"1 (DCM): 3381.1, 2925.9, 2855.1, 1598.7, 1460.6; Mass: 372.1 [M⁺+l].

Step 4: Preparation of l-O-dodecyl-2,3-O-isopropylidene-5, 6-dideoxy-5-N-[4-(2- methoxy -2-oxoethyl)phenyIaminocarbonyl]amino-β, L-gulofuranoside

[Methyl-4-(phenoxycarbonyl)amino phenylacetate (0.30kg, 1.06 moles, 0.9 equivalent] was added slowly to a mixture of l-O-dodecyl-2,3-O-isopropylidene-5, 6- dideoxy-5-amino~β,L- gulofuranoside (0.440 kg, 1.19 moles, 1 equivalent), dichloromethane (3.08 L) and triethylamine (0.12 Kg, 1.19 mmols, 1 equivalent) at room temperature. The reaction mixture was heated under reflux for 30 - 60 minutes and the progress of the reaction was monitored by TLC (30% ethylacetate in hexane). After completion, the reaction mixture was cooled to 20 - 25° C and water (3.08 L) was added. Dichloromethane layer was separated and aqueous layer was extracted with dichloromethane (1.76 L). The combined organic layer was washed with water (2x3.08 L) and concentrated under reduced pressure at 35 - 40°C. The residue was crystallized with ethyl acetate - hexane to afford the title compound as white solid (0.528 kg) in 80% yield, with an HPLC Purity of >98%.

The spectral information for this compound was as follows: ¹H MR (300MHz, CDC1₃) δ : 0.86 - 0.90 (3H,t) 1.25 - 1.33 (24H,m), 1.45 (3H,s), 1.49 - 1.52 (2H,m), 3.34 - 3.39 (lH,m), 3.57 - 3.63 (3H,m), 3.68 (3H,s), 3.80 - 3.84 (lH,m), 4.04 - 4.09 (lH,m),4.58 - 4.60 (lH,d), 4.67 - 4.70 (lH,d), 4.88 - 4.9, (lH,m), 5.03 (lH,s), 7.17 - 7.20 (2H,d), 7.26 - 7.29 (2H,d); IR cm^"1 (KBr) = 3441.3, 3344.6, 2921.2, 853.5, 1725.6, 1668.1, 1598.9, 1528; SOR [ α]_D ²⁵ = (+) 19.63; Mass: 563.3 = [M⁺+l].

Claims

We claim:

1. A process for the preparation of compound of Formula I

Formula I

wherein R is Ci to C₁₅ alkyl, alkene, straight chain alkyne or branched alkyne, aryl, substituted aryl or alkylaryl;

R' is SO₂C₆H₅, SO₂C₆H CH₃-j->, or SO₂C₆H₄Cl-p, phenyl or substituted phenyl, represented as C₆H₄-R'"-^ wherein R is CI, NO₂, OCH₃, CH₃, CH₂COOH, CH₂COOCH₃, CH₂COLDNP, CH₂CODNP, CH₂CONP wherein LDNP, DNP and NP represent tetrapeptide (leucyl-aspartyl-valyl-prolyl), tripeptide (aspartyl-valyl-prolyl) and dipeptide (valyl-prolyl), respectively;

R" is H or CH₃ comprising reacting compound of Formula II

Formula II

with methanesulphonyl chloride in an organic solvent and in presence of an organic base to yield a compound of Formula IN

FORMULA IV

further reacting the compound of Formula IN with benzylamine to yield a compound of

Formula N,

FORMULA V debenzylating the compound of Formula N in presence of an acid in alcohol to give a compound of Formula III,

FORMULA III reacting the compound of Formula III with a carbamate of Formula NI,

O L — C— ΝH— R^{^}

Formula VI wherein L is a leaving group and R is the same as defined above, to yield a compound of Formula I.

2. The process of claim 1, wherein the compound of Formula I is l-O-dodecyl-2,3-O- isopropylidene-5,6-dideoxy-5-N-[4-(2-methoxy-2-oxoethyl)phenylaminocarbonyl] amino-β, L-gulofuranoside.

3. The process of claim 1 , wherein the reaction of compound of Formula II with methane sulphonyl chloride is carried out in an organic solvent, wherein the organic solvent is selected from the group comprising of dichloromethane, dichloroethane, chloroform, tetrahydrofuran and acetone.

4. The process of claim 1 wherein the reaction of compound of Formula II with methanesulphonyl chloride is carried out in presence of an organic base, which is selected from the group comprising of triethylamine, trimethylamine, N-methyl morpholine and isopropylamine.

5. The process of claim 1 wherein the debenzylation of compound of Formula V is carried out preferably with palladium carbon.

6. The process of claim 1 wherein the debenzylation of compound of Formula V is carried out in presence of an acid selected from the group comprising of formic acid and acetic acid.

7. The process of claim 1 wherein the debenzylation of compound of Formula V is carried out in alcohol selected from the group comprising of methanol and ethanol.

8. The process of claim 1 wherein the reaction of compound of Formula III with compound of Formula VI is carried out in an organic solvent, wherein the organic solvent is selected from the group comprising of dichloromethane, dichloroethane, chloroform, tetrahydrofuran and acetone.

9. The process of claim 1 wherein the reaction of compound of Formula III with compound of Formula N is carried out in presence of an organic base, which is selected from the group comprising of triethylamine, trimethylamine, Ν-methyl morpholine and isopropylamine.

10. The process of claim 1 wherein the leaving group L is selected from the group comprising of alkoxy, aryloxy and alkyloxy.

11. A method of inhibiting or preventing cell adhesion in mammals comprising administering a cell adhesion inhibiting or preventing amount of a compound of Formula I prepared according to the process of claim 1.

2. A method of treating cell adhesion-mediated disorders comprising administering a cell adhesion inhibiting or preventing amount of a compound of Formula I prepared according to the process of claim 1. 3 The method of claim 12, wherein the disorder is bronchial asthma. 4 The method of claim 12, wherein the disorder is rheumatoid arthritis. 5 The method of claim 12, wherein the disorder is type-I diabetes. 6 The method of claim 12, wherein the disorder is multiple sclerosis. 7 The method of claim 12, wherein the disorder is allograft rejection. 8 The method of claim 12, wherein the disorder is psoriasis.