OA11275A - Crystalline n-acetyl neuraminic acid derivatives and processes for their preparation. - Google Patents
Crystalline n-acetyl neuraminic acid derivatives and processes for their preparation. Download PDFInfo
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- OA11275A OA11275A OA1200000004A OA1200000004A OA11275A OA 11275 A OA11275 A OA 11275A OA 1200000004 A OA1200000004 A OA 1200000004A OA 1200000004 A OA1200000004 A OA 1200000004A OA 11275 A OA11275 A OA 11275A
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- Prior art keywords
- guanidino
- crystalline form
- galacto
- glycero
- acetamido
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- 238000002360 preparation method Methods 0.000 title claims description 19
- 238000000034 method Methods 0.000 title claims description 18
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical class CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 title description 3
- 239000002253 acid Substances 0.000 claims abstract description 43
- 239000013078 crystal Substances 0.000 claims abstract description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 24
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 11
- 239000000725 suspension Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 3
- 230000032683 aging Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000007787 solid Substances 0.000 description 16
- 238000003828 vacuum filtration Methods 0.000 description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000007900 aqueous suspension Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 240000002234 Allium sativum Species 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 235000004611 garlic Nutrition 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000004619 light microscopy Methods 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DQSQEHIDUNVGNQ-MJNXMCJASA-N (2S,3R)-3,4,5-trihydroxy-2-[(1S,2R,3R)-1,2,3,4-tetrahydroxybutyl]-3,6-dihydro-2H-pyran-6-carboxylic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H]1OC(C(O)=O)C(O)=C(O)[C@@H]1O DQSQEHIDUNVGNQ-MJNXMCJASA-N 0.000 description 1
- 241000478345 Afer Species 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- -1 acetone Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
CRYSTALLINE N-ACETYL NEURAMINIC ACID DERIVATIVES
AND PROCESSES FOR THEIR PREPARATION
The présent invention relates to dérivatives of N-acetyl neuraminic acid and theiruse in medicine. More particularly the invention is concemed w'rth particularphysical forms of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-Ë-galacto-non-2-enopyranosonic acid (the 4-guanidino analogue of DANA; alsoknown as 5-(acetylamino)-2t6 anhydro-3,4,5-trideoxy-4-guanidino-n-glycereo-£)-galacto-non-2-enonic acid), pharmaceutical formulations thereof and their use intherapy. PCT/AU91/00161 (publication no.WO91/16320) describes a number of dérivativesof 5-acetamidino-2,3,5-trideoxy-n-glycero-n-galacto-non-2-enopyranosonic acid(2,3,-dideoxy-2,3-didehydro-N-acetyl-neuraminic acid; DANA) including the 4-guanidino analogue of DANA. The 4-guanidino analogue of DANA is prepared bythe reaction of the corresponding O-acyl protected 4-amino analogue of DANA byreaction with S-methylisourea followed by deprotection, purification bychromatography and freeze-drying.
The structure of the 4-guanidino analogue of DANA is shown below:
HO
HO
AcNH
(i)
NH
4-guanidino analogue of DANA
We hâve now found that the compound of formula (I) can be obtained in crystallineform. 0112 y ;
There is thus provided in a first aspect of the invention 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopvranosonic acid incrystalline form.
We hâve further found that the compound of formula (I) may be obtained bycrystallisation under certain conditions in the form of a crystalline hydrate(hereinafter Hydrate I). Hydrate I exists in the form of crystals having a low aspectratio, for example, tabular crystals, which are favoured for pharmaceuticalformulation because of their physical properties, e.g. good flow characteristics.The water content of Hydrate I is related to relative humidity (RH). Water uptake ofHydrate I varies from zéro at RH of 0% up to 10% at RH of 90 -100%.
The compound of formula (I) may also be crystallised in the form of a dihydrate(hereinafter Hydrate II). Hydrate II exists in the form of crystals having a highaspect ratio, for example, needle-shaped crystals. The water content of thesecrystals remains substantially constant over a broad relative humidity range (RHabout 10 - 90%). The stable water content of Hydrate II represents an advantageof this crystalline form for use in pharmacy.
There is thus provided in a further aspect of the invention 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-£)-galacto-non-2-enopyranosonic acid in theform of crystals having a low aspect ratio, such as tabular crystals.
In a further aspect there is provided 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-û-glycero-û-galacto-non-2-enopyranosonic acid in the form of crystals having ahigh aspect ratio, such as needle-shaped crystals.
Whilst tabular crystals are regarded as typical of Hydrate I and needle-shapedcrystals are regarded as typical of Hydrate II, it will be appreciated that thepossibility of either Hydrate I or Hydrate II existing in alternative crystal habitsunder certain circumstances cannot be excluded. It is to be understood that ailsuch alternative crystal habits are within the scope of the présent invention.
There is also provided 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-ÎD- galacto-non-2-enopyranosonic acid in the form of crystals which hâve stable water content over a broad humidity range, for example RH 10 - 90%. 3 01 1 2 71
Hydrate I loses substantially ail of its water of crystallisation at about 80-90°C. Décomposition occurs at 299°C.
Hydrate II loses one mole of water of crystallisation at about 84-90°C and a furthermole of water of crystallisation by about 135-143°C.
In a yet further aspect the invention provides 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-J2-galacto-non-2-enopyranosonic acid in the form of acrystalline hydrate which loses substantially ail its water of crystallisation at 80-90°C.
In a yet further aspect the invention provides 5-acetamido-2,3,4,5-tetradeoxy-4-guanidinO-n-glycero-JD-galacto-non-2-enopyranosonic acid in the form of acrystalline hydrate which loses one mole of water of crystallisation at 84-90°C anda further mole of water of crystallisation at 135-143°C.
In a preferred aspect the invention provides 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-n-galacto-non-2-enopyranosorïic acid in the form of Hydrate Ias herein defined substantially free of Hydrate II as herein defined.
In a further preferred aspect the invention provides 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£>-glycero-£-galacto-non-2-enopyranosonic acid in theform of Hydrate II as herein defined substantially free of Hydrate I as hereindefined.
By "substantially free" is meant containing less than 5% of the alternative hydrate,such as less than 2%, for example less than 1% of the alternative hydrate. 5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-Ê-glycero-n-galacto-non-2-ënopyranoscnic acid may be prepared in crystalline form by crystallisation of thecompound from aqueous solution.
Each of Hydrate I and Hydrate II may be prepared substantially free from the alternative Hydrate by controlling the solution concentration and température at which crystallisation occurs. 4 01 1 2 7
In general, 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-2-glycero-n-galacto-non- 2-enopyranosonic acid in the form of Hydrate I may be obtained by crystallisation of the compound from aqueous solution at a température greater than about 50°C, preferably 50-55°C.
In general, 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-n-glycero-n-galacto-non-2-enopyranosonic acid in the form of Hydrate II may be obtained by crystallisationof the compound from aqueous solution at a température below about 40°C,preferably about 20-30°C.
Crystallisation of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-n-galacto-non-2-enopyranosonic acid from aqueous solution at a température in the rangeof about 40-50°C typically results in a mixture of tabular and needle-shapedcrystals. Such mixtures are disfavoured for the préparation of pharmaceuticalformulations because of the differing physical properties of Hydrate I and HydrateII, in particular theirflow properties.
Seeding of an aqueous solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-n-glycero-n-galacto-non-2-enopyranosonic acid with crystals of Hydrate I or HydrateIl may lead to crystallisation of the seeded Hydrate. Préparation of Hydrate I orHydrate II should therefore be conducted in the absence of seeds of the undesiredHydrate. Conversely, Hydrate I may be prepared by seeding an aqueous solutionof 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-n-glycero-n-galacto-non-2-enopyranosonic acid with crystals of Hydrate I, and Hydrate II may be prepared byseeding an aqueous solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-£)-galacto-non-2-enopyranosonic acid with crystals of Hydrate II.
For the préparation of Hydrate II it is préférable to employ a relatively diluteaqueous solution, for example a solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-Ë-glycero-n-galacto-non-2-enopyranosonic acid in 15-30 volumes ofwater, for example 20 volumes of water. Hydrate I may conveniently becrystallised from a relatively concentrated aqueous solution, for example a solutionof 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-Ë)-glycero-£)-galacto-non-2- enopyranosonic acid in 12-20 volumes of water, such as 12 - 15 volumes of water. 0112 7:.
We hâve found that Hydrate II may be converted into Hydrate I in aqueoussuspension or saturated solution. Such interconversion may be effected byprolonged ageing of an aqueous suspension or saturated solution of Hydrate II, forexample ageing for a period of days, for example more than 10 days, such asabout 15 days. Altematively, interconversion may be effected in the presence of abase, for example an organic base such as imidazole.
Recovery of either Hydrate I or Hydrate II from aqueous solution may be enhancedby the addition to the solution of a suitable counter-solvent. Suitable counter-solvents are water-miscible solvents in which the compound of formula (I) has poorsolubility. Conveniently the counter-solvent will be a ketone, such as acetone, oran alkanol such as propan-2-ol. A preferred counter-solvent is acetone.
We hâve also found that addition * an aqueous solution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-i>-galacto-non-2-enopyranosonic acid to asimilar volume of a counter-solvent as previously defined results in précipitation ofHydrate II. For example, addition of a solution of 5-acetamido-2,3,4,5-tetradeoxy- 4- guanidino-£>-glycero-£-galacto-non-2-enopyranosonic acid in 12 -15 volumes ofwater to 12 - 20 volumes of acetone gives crystals of Hydrate II.
The methods for the préparation of crystalline material, and in particular methodsfor the préparation of Hydrate I and Hydrate II, described herein constitute furtheraspects of the présent invention. 5- Acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-JD-galacto-non-2-enopyranosonic acid in crystalline form may be used as an antiviral agent asdescribed in WO 91/16320, which is incorporated herein by référencé. 5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-2-glycero-Ë-galacto-non-2-enopyranosonic acid in crystalline form may be formulated as a pharmaceuticalcomposition for use as an antiviral agent as described in WO 91/16320.
Preferred pharmaceutical formulations of 5-acetamido-2,3,4,5-tetradeoxy-4- guanidino-£)-glycero-E-galacto-non-2-enopyranosonic acid include powder formulations and aqueous solutions or suspensions. Préparation of powder 01 1 2 7 formulations requires micronisation of the drug substance. The good flow properties of Hydrate I render it particularly suitable for micronisation. Hydrate il has adéquate flow properties and also a particularîy rapid dissolution rate in water.
These properties render Hydrate II particular advantageous for the préparation of 5 aqueous solutions/suspensions.
Hydrates I and II hâve been subjected to X-ray powder diffraction studies.Diffraction traces were obtained using a Seimens D-500 diffractometer and CuK^radiation. X-Ray intensities were measured at 0.02° incréments for 5 second 10 intervals using a scintillation counter, between values of 5 and 55° 2Θ. The d-spacings and line intensities obtained for Hydrate I and Hydrate II are shown inTables I and II, respectively.
TABLE I 15 iMfiÛ 10.06 6.776.636.356.055.385.054.614.424.314.173.983.90 3.773.693.483.413.373.163.02
MB 30.2569.81 89.6112.6954.5625.11 98.58 12.58100.00 8.28 11.67 75.00 52.6120.33 36.1726.53 53.25 17.6118.3931.08 2.98 9.25 2.92 6.28 2.87 13.58 2.82 10.78 2.78 6.78 2.74 18.03 2.69 15.33 2.65 6.25 2.63 6.44 2.59 11.44 2.49 14.31 2.45 18.81 2.41 8.64 2.35 11.36 2.19 5.42 2.13 12.25 2.11 6.56 2.02 8.33 1.98 5.47
TABLE II diA) 16.88 66.34 10.38 50.60 9.50 16.08 8.47 40.46 7.12 100.00 5.84 11.78 5.33 18.83 5.21 33.99 4.78 12.94 4.57 75.81 4.32 16.37 4.25 18.49 01 1
r. »7Z / Z 8 4.14 43.26 3.96 10.33 3.76 22.11 3.64 25.16 3.57 37.04 3.52 15.69 3.40 16.85 3.34 21.20 3.17 13.52 3.13 17.04 3.06 7.48 2.94 10.19 2.92 8.45 2.86 9.17 2.76 9.56 2.72 9.22 2.67 6.81 2.64 8.06 2.60 5.46 2.58 6.52 2.51 5.31 2.49 6.66 2.45 5.55 2.43 5.89 2.39 15.93 2.38 10.38 2.31 8.40 2.22 5.94 2.16 5.36 2.11 6.28 2.03 7.24 1.91 6.57
The following examples illustrate the invention but are not intended as a limitationthereof. Ail températures are in °C. 01 1 27
Example 1
Préparation of Hydrate I A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-n-glycero-n-galacto-non-2-enopyranosonic acid (5.0g) and water (60ml) was heated at 100° to give a clearsolution. The solution was cooled during 30 min to 55° and maintained at between55° and 50° during 4h, to give a crystalline suspension. Acetone (80ml) wasadded during 90 min, the température being maintained between 48 and 55°.The résultant slurry was stirred 1 h, the température being allowed to fall to ca.20°, and the suspension was allowed to stand 17h at ambient température. Theproduct was collected by vacuum filtration and the filter bed was washed with 4:1acetone/water (2 x 10ml) then with acetone (10ml). The product was air dried atambient température and humidity to give Hydrate I (tabular crystals) (4.5g). PMR (D2O) 2.04 (3H,s), 3.67 (2H,m), 4.23 (1H,m), 4.42 (2H,m), 5.63 (1H, d, J, 2.5Hz)
IR (Nujol) 3248, 3338, 3253; NH, OH
1692, 1666,1646, 1619, 1575; CO (CH3CONH, CO2), CN
Water content 8.4% w/w; calculated for C12H20N4O7.1.7H2O
Exemple 2
Prep3rati.Qn.ef Hydrate l A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-£>-gaiacto-non-2-enopyranosonic acid (15.0g) and water (180ml) was heated at 100° to give aclear solution. The solution was darified by vacuum filtration through a filter paperthen cooled to ca. 55° and maintained at between 55° and 50° during 4h, allowingcrystallisation to become established. Acetone (210ml) was added with stirring,during 2h, the température being maintained at 48-55°. The résultant suspensionwas stirred and cooled to 30°and was then allowed to stand at ambienttempérature 17h. The solid was fiitered and the product was washed with 4:1acetone/water (2x30ml) and then acetone (30ml). The solid was air dried atambient température and humidity to give Hydrate I (tabular crystals) (12.0g).
Characterisation as above. 10 01127c
Example 3
Préparation of Hydrate H A mixture of 5-acetamido-2,314,5-tetradeoxy-4-guanidino-£)-glycero-E)-galacto-non-2-enopyranosonic acid (10.0g) and water (100ml) was heâted to 95°. Therésultant solution was clarifîed by vacuum filtration. The solution was then cooledto 30° and acetone (250ml) was added during 5 min stirring. The résultant thickwhite suspension was allowed to stand at ambient température 20 h. The solidwas collected by vacuum filtration and was washed with 4:1 acetone/water(2x20ml) then with acetone (20ml). The solid was dried in a vacuum oven at 35°for 24h and then equilibrated with atmospheric moisture at ambient températureand humidity to give Hydrate ll.(needle-shaped crystals) (8.16g).
Characterisation as above.
Water content 10.6% w/w; calculated for C12H2oN407.2H20 9.8% w/w.
Example 4
Préparation of-Hydrale II A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-]D-glycero-D-galacto-non-2-enopyranosonic acid (10.0g) and water (400ml) was heated to 20° for 2h.The résultant solution was clarifîed by vacuum filtration. Acetone (110ml) wasadded and solid began to crystallise. The résultant suspension was stirred for2.5h at 20°. The solid was collected by vacuum filtration and was washed with 4:1v/v acetone/water (2x20ml) then with acetone (20ml). The solid was dried in avacuum oven at 30° and then equilibrated with atmospheric moisture at ambienttempérature and humidity to give Hydrate II (needle-shaped crystals) (7.7g)
Characterisation as above.
Water content 11.1% w/w calculated for Ci2H2oN407.2H20 9.8 w/w.
Example .5
Préparation of.HydrateJl A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-n-galacto-non-2-eno-pyranosonic acid (50g) and water (1150ml) was heated to 75°. Therésultant solution was clarifîed by vacuum filtration, washing through with water 11 01 1 27;: (1OOml). The solution was then cooled to 7° over 1h and acetone (500ml) wasadded. The résultant solution was stirred slowly for 0.5h, during which time solidbegan to crystallise. Acetone (750ml) was then added to the suspension over 2h,maintaining the température at 5 - 10°. The solid was collected by vacuum 5 filtration and washed with 4 : 1 v/v acetone/water (2 x 100ml) then with acetone(100ml). The solid was air-dried at ambient température and humidity to giveHydrate II (needle-shaped crystals) (46.0g).
Water content 9.8% w/w; calculated for C12H20N4O7.2H2O 9.8% w/w. 10 XRD; consistent with Hydrate II (>99%).
Example 6
Précipitation of Hydrate II 15 A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£)-glycero-D-galacto-non-2-eno-pyranosonic acid (50g) and water (600ml) was heated to 100°. Therésultant clear hot solution was added over 8 minutes to acetone (700ml) stirredrapidly at ambient température, causing the température of the mixture to rise from20° to 56° and précipitation of solid. The résultant suspension was allowed to cool 20 to 20° with stirring, then the solid was collected by vacuum filtration and washedwith 4 : 1 acetone/water (2 x 100ml) then with acetone (100ml). The solid was air-dried at ambient température and humidity to give Hydrate II (needle-shapedcrystals) (47.9g). .5 Water content 10.0 w/w; calculated for C12H20N4O7.2H2O 9.8% w/w. XRD; consistent with Hydrate II (>99%).
Example 7 30 Crystallisation of Hydrate I from_W.afer A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-n-glycero-S-galacto-non-2-eno-pyranosonic acid (35.7g) and water (350ml) was heated at 95° to give aclear solution. This was adjusted to pH7.0 (from pH6.4) with aqueous acetic acid 35 (100μΙ, 10%v/v), The resulting solution was allowed to cool to ambienttempérature with stirring, to give a crystalline suspension. The product was 12 01 1 27 collected by vacuum filtration, then vacuum-dried at ambient température to give
Hydrate I (tabular crystals) (28.9g).
IR consistent with Hydrate I
Exampl£-S
Préparation of-Hydrate II bv Seeding A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-eno-pyranosonic acid (30.0g) and water (540ml) was heated at 75° to give asolution. The résultant solution was clarified by vacuum filtration, washing throughwith water (54ml). The solution was heated to 100°, cooled to 40°, then seededwith Hydrate II (0.3g). Crystallisation occurred as the température was furtherreduced to ambient température. The résultant slurry was stirred for 1h at ambienttempérature, cooled to 5°, then acetone (600ml) was added over 1.5h. The solidwas collected by vacuum filtration and washed with 4:1v/v acetone/water (2x60ml)then with acetone (60ml). The solid was air-dried at ambient température andhumidity to give Hydrate II (needle-shaped crystals) (26.5g). XRD 90-95% Hydrate II (5-10% Hydrate I)
Exampfe-9
Interconversion of Hydrate II to Hydrate.I bv Aoeino A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-eno-pyranosonic acid (10.0g) and water (200ml) was heated at 100° to give asolution. The résultant solution was rapidly cooled to 30°, seeded with Hydrate II(0.05g) then left unstirred ovemight. Light-microscopy showed exclusively thecharacteristic needles of Hydrate II. The suspension was aged unstirred atambient température for 11 days (when light-microscopy showed the presence ofsome crystals of Hydrate I), then stirred for 3 days. Acetone (200ml) was added,and the slurry was stirred for 1h. The solid was collected by vacuum filtration andwashed with 4:1v/v acetone/water (2 x 20ml) then with acetone (20ml). The solidwas air-dried at ambient température and humidity to give Hydrate I (tabularcrystals) (9.0g). XRD: Consistent with Hydrate I >99%) 13 01 12/
Example.1Q interconversion of Hydrate II to Hydrate I usina Base A suspension of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-2-glycero-Ei-galacto- non-2-enopyranosonic acid (5.0g, Hydrate 11) in water (30ml), containing imidazole 5 (2.96g) was stirred and heated at 30° for 40h. The remaining solid was collected by vacuum filtration and washed w'ith water (2 x 1ml, 2 x 5ml) then air-dried atambient température and humidity to give Hydrate I (tabular crystals) (3.98g).
IR consistent with Hydrate I 10
Example 11
Préparation of Hydrate I bySeeding A mixture of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-£-glycero-D-galacto-non-2-eno-pyranosonic acid (5.0g) and water (60ml) was heated at 100° to give a 15 solution. The résultant solution was clarified by vacuum filtration. The résultantsolution was cooled to about 50°, seeded with Hydrate I, left unstirred at 50-55° for1h, then stirred for 1h at 50-55°. Acetone (70ml) was added whilst a températureof 48 - 55° was maintained. The slurry was stirred for 1h at 50 - 55°, then agedunstirred ovemight at ambient température. The solid was collected by vacuum 20 filtration and washed with 4:1v/v acetone/water (2 x 10ml) then with acetone (2 x10ml). The solid was vacuum-dried, then allowed to re-equilibrate at ambienttempérature and humidity to give Hydrate I (tabular crystals) (3.8g). XRD: Consistant with Hydrate I (>99%) 25
Claims (22)
14 01 1 CLA1MS. 1. 5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-giycero-I^galacto-non-2-enopyranosonic acid in crystalline form. 2. 5J\cetamido-2,3,4,54etradeo)o/-4-guanidino-:Q-glycero-Q-galacto--non-2-enopyranosonic acid in the form of crystals having a low aspect ratio.
3. The crystalline form as claimed in Claim 2 wherein the crystals aretabular.
4. The crystalline form as claimed in any one of Claims 1 to 3 whereinsubstantially ail water of crystallisation is lost at about 80 to 90°C.
5. The crystalline form as claimed in any one of Claims 1 to 4 for which theX-ray data are as shown in Table I. 6. 5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-Û-glycero-D-galacto-non-2-enopyranosonic acid in the form of crystals having a high aspect ratio.
7. The crystalline form as claimed in Claim 6 wherein the crystals areneedle-shaped.
8. The crystalline form as claimed in any one of Claims 1, 6 or 7 whereinwater content is stable over a broad range of relative humidity.
9. The crystalline form as claimed in any one of Claims 1, 6 to 8 whereinone mole of water of crystallisation is lost at about 84-90°C and a furthermole of water of crystallisation is lost by about 135-143°C.
10. The crystalline form as claimed in any one of Claims 1, 6 to 9 for whichthe X-ray data are as shown in Table II.
11. The crystalline form claimed in any one of Claims 2 to 5 substantially freeof the crystalline form claimed in any one of Claims 6 to 10. 15
12. The crystalline form claimed in any one of Claims 6 to 10 substantiallyfree of the crystalline form claimed in any one of Claims 2 to 5. T* 5 13. * A method for the préparation of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-G-glycero-D-galacto-non-2-enopyranosonic acid in crystallineform, which method comprises crystallisation of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-n-glycero-D-galacto-non-2-enopyranosonic acidfrom aqueous solution. 10 ( 14. A method as claimed in Claim 13 for the préparation of the crystallineform as claimed in any one of Claims 2 to 5. 15. 15 A method as claimed in Claim 14 wherein the température of theaqueous solution is greater than about 50°C. 16. A method as claimed in Claim 15 wherein the température of theaqueous solution is in the range 50 to 55°C. 20 17. A method as claimed in any one of Claims 14 to 16 wherein the aqueoussolution is seeded with crystals of the crystalline form as claimed in anyone of Claims 2 to 5. 18. 25 A method as claimed in Claim 13 for the préparation of the crystallineform as claimed in any one of Claims 6 to 10. 19. A method as claimed in Claim 18 wherein the température of theaqueous solution is less than about 40°C. 30 20 A method as claimed in Claim 19 wherein the température of theaqueous solution is in the range 20 to 30°C. 21. A method as claimed in any one of Claims 18 to 20 wherein the aqueoussolution is seeded with crystals of the crystalline form as claimed in any 35 one of Claims 6 to 10. 01 1 2 16
22. A method as claimed in any one of Claims 13 to 21 comprising additionof a counter solvent to the aqueous solution.
23. A method as claimed in Claim 22 wherein the counter solvent is a ketoneor an alkanol.
24. A method as claimed in Claim 23 wherein the counter solvent is acetone.
25. A method for the préparation of the crystalline form as claimed in any oneof Claims 2 to 5, which method comprises interconversion of thecrystalline form as claimed in any one of Claims 6 to 10.
26. The method as claimed in Claim 25 wherein interconversion is effectedby ageing of the aqueous solution.
27. The method as claimed in Claim 25 wherein the interconversion iseffected by addition of a base to the aqueous solution.
28. A method for the préparation of the crystalline form as claimed in any oneof Claims 6 to 10, which process comprises addition of an aqueoussolution of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid to a similar volume of a countersolvent.
29. The method as claimed in Claim 28 wherein the counter solvent isacetone.
30. A pharmaceutica! formulation comprising 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-Q-galacto-non-2-enopyranosonic acid incrystalline form and a pharmaceutically acceptable carrier therefor.
31. A pharmaceutical formulation as claimed in Claim 30 in the form of apowder. 17 01127.
32. A pharmaceutical formulation as claimed in Claim 30 in the form of anaqueous solution or suspension. 33. 5-acetamido-2,3,4,5-tetradeoxy-4-guanidmo-D“gIycero-P-galacto-non-2enopyranosonic acid as ciaimed in any one of daims 1-5, in micronised firm.
34. A pharmaceutical formulation comprising 5-acetamido-2,3,4,5-tecradeox] '-4-guanidmo-D-glycero-D-galacto-non-2-enopyranosonic acid as claimed in anyone of daims 1-5, in micronised form, and apharmaceuticaîly acceptablecarrier therefor.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB939325841A GB9325841D0 (en) | 1993-12-17 | 1993-12-17 | Chemical compounds |
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| OA60842A OA10325A (en) | 1993-12-17 | 1996-06-14 | Crystalline N-acetyl neuraminic acid derivatives and processes for their preparation |
| OA1200000004A OA11275A (en) | 1993-12-17 | 2000-01-06 | Crystalline n-acetyl neuraminic acid derivatives and processes for their preparation. |
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| OA60842A OA10325A (en) | 1993-12-17 | 1996-06-14 | Crystalline N-acetyl neuraminic acid derivatives and processes for their preparation |
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Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9325841D0 (en) * | 1993-12-17 | 1994-02-23 | Glaxo Group Ltd | Chemical compounds |
| US5866601A (en) * | 1995-02-27 | 1999-02-02 | Gilead Sciences, Inc. | Carbocyclic compounds |
| CN100409844C (zh) * | 1995-02-27 | 2008-08-13 | 吉里德科学公司 | 神经氨酸苷酶抑制剂 |
| US5763483A (en) * | 1995-12-29 | 1998-06-09 | Gilead Sciences, Inc. | Carbocyclic compounds |
| US6340702B1 (en) | 1996-07-22 | 2002-01-22 | Sankyo Company, Limited | Neuraminic acid derivatives, their preparation and their medical use |
| DE69709795T2 (de) * | 1996-07-22 | 2002-09-26 | Sankyo Co., Ltd. | Neuraminsäuredervate, ihre Herstellung und medizinische Verwendung |
| US6451766B1 (en) | 1996-07-22 | 2002-09-17 | Sankyo Company, Limited | Neuraminic acid derivatives, their preparation and their medical use |
| US6518438B2 (en) | 1996-08-23 | 2003-02-11 | Gilead Sciences, Inc. | Preparation of cyclohexene carboxylate derivatives |
| US5859284A (en) * | 1996-08-23 | 1999-01-12 | Gilead Sciences, Inc. | Preparation of carbocyclic compounds |
| US5994377A (en) | 1996-10-21 | 1999-11-30 | Gilead Sciences, Inc. | Piperidine compounds |
| US5886213A (en) * | 1997-08-22 | 1999-03-23 | Gilead Sciences, Inc. | Preparation of carbocyclic compounds |
| TW480247B (en) * | 1997-12-12 | 2002-03-21 | Gilead Sciences Inc | Novel compounds useful as neuraminidase inhibitors and pharmaceutical compositions containing same |
| TWI291462B (en) * | 2000-04-25 | 2007-12-21 | Daiichi Sankyo Co Ltd | Hydrate crystal of neuraminic acid compound |
| US20080063722A1 (en) * | 2006-09-08 | 2008-03-13 | Advanced Inhalation Research, Inc. | Composition of a Spray-Dried Powder for Pulmonary Delivery of a Long Acting Neuraminidase Inhibitor (LANI) |
| EP2960237A1 (fr) * | 2011-12-16 | 2015-12-30 | Daiichi Sankyo Company, Limited | Procede de production d'un derive de l'acide neuraminique |
| CN109232677B (zh) * | 2018-10-18 | 2021-12-28 | 中国科学院合肥物质科学研究院 | 一种使n-乙酰神经氨酸水合物转化为n-乙酰神经氨酸的方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SU469694A1 (ru) * | 1972-12-22 | 1975-05-05 | Московский Ордена Трудового Красного Знамени Институт Тонкой Химической Технологии Им.М.В.Ломоносова | Способ получени 2-алкокси-6-алкил (арил)- -дигидропиранов |
| SK282950B6 (sk) * | 1990-04-24 | 2003-01-09 | Biota Scientific Management Pty Ltd | Deriváty alfa-D-neuramínovej kyseliny, spôsob ich prípravy, ich použitie a farmaceutické prípravky na ich báze |
| CA2081068C (fr) * | 1991-10-23 | 2005-11-29 | Laurence Mark Von Itzstein | Derives antiviraux de 2-desoxy-2,3-deshydro a substituant en 4 de l'acide .alpha.-d-neuraminique |
| GB9126725D0 (en) * | 1991-12-17 | 1992-02-12 | Glaxo Group Ltd | Process |
| US5639786A (en) | 1992-12-04 | 1997-06-17 | Biota Scientific Management, Pty., Ltd. | Antiviral 4-substituted-2-deoxy-2,3-didehydro-derivatives of α-D-neuraninic acid |
| GB9325841D0 (en) * | 1993-12-17 | 1994-02-23 | Glaxo Group Ltd | Chemical compounds |
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