Celltrion files Remsima in the United States:
Celltrion announced that the company, on August 8, 2014, completed the filing procedure to obtain US FDA approval for its infliximab biosimilar. This marks the first 351(k) biosimilar mAb application to be filed in the U.S.A. and the second application for a biosimilar to be filed through the US BPCIA.
http://pubs.acs.org/doi/abs/10.1021/jm00105a018
……………………………………
Mylari, Banavara L.; Zembrowski, William J.; Beyer, Thomas A.; Aldinger, Charles E.; Siegel, Todd W.
Journal of Medicinal Chemistry, 1992 , vol. 35, 12 p. 2155 – 2162
………………………………..
Mylari; Beyer; Scott; Aldinger; Dee; Siegel; Zembrowski
Journal of Medicinal Chemistry, 1992 , vol. 35, 3 p. 457 – 465
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3-19-1992
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HETEROCYCLIC OXOPHTHALAZINYL ACETIC ACIDS
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3-6-1992
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3-(5-TRIFLUOROMETHYLBENZOTHIAZOL-2-YLMETHYL)-4-OXO-3H-PHYTHALAZIN-1-YLACETIC ACID MONOHYDRATE
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7-4-1990
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Heterocyclic oxophthalazinyl acetic acids
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3-24-2006
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Medical devices to treat or inhibit restenosis
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12-30-2004
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N-[(SUBSTITUTED FIVE-MEMBERED DI- OR TRIAZA DIUNSATURATED RING)CARBONYL]GUANIDINE DERIVATIVES FOR THE TREATMENT OF ISCHEMIA
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10-7-2004
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COMBINATION OF AN ALDOSE REDUCTASE INHIBITOR AND A GLYCOGEN PHOSPHORYLASE INHIBITOR COMBINATION OF AN ALDOSE REDUCTASE INHIBITOR AND A GLYCOGEN PHOSPHORYLASE INHIBITOR
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9-30-2004
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Aldose reductase inhibition in preventing or reversing diabetic cardiomyopathy
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5-27-2004
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SUBSTITUTED FUSED HETEROCYCLIC COMPOUNDS
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4-15-2004
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Compounds for treating and preventing diabetic complications
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3-32-2004
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IMPROVED MUTANTS OF (2,5-DKG) REDUCTASE A
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12-18-2003
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Pharmaceutical composition for use in treatment of diabetes
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11-14-2003
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Salts of zopolrestat
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4-18-2002
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Use of an aldose reductase inhibitor for reducing non-cardiac tissue damage
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Nanotechnology is the use of tiny structures – less than 1,000 nanometres across – that are designed to have specific properties. Nanotechnology is an emerging field in science that is used in a wide range of applications, from consumer goods to health products.
In medicine, nanotechnology has only partially been exploited. It is being investigated as a way to improve the properties of medicines, such as their solubility or stability, and to develop medicines that may provide new ways to:
The European Medicines Agency follows the latest developments in nanotechnology that are relevant to the development of medicines. Recommendations from the Agency’sCommittee for Medicinal Products for Human Use (CHMP) have already led to the approval of a number of medicines based on nanotechnology. These include medicines containing:
The development of medicines using newer, innovative nanotechnology techniques may raise new challenges for the Agency in the future. These include discussions on whether the current regulatory framework is appropriate for these medicines and whether existing guidelines and requirements on the way the medicines are assessed and monitored are adequate.
The Agency also needs to consider the acceptability of new testing methods and the availability of experts to guide the Agency’s opinion-making.
An overview of the initiatives taken by European Union (EU) regulators in relation to the development and evaluation of nanomedicines and nanosimilars was published in the scientific journal Nanomedicines. The article describes the regulatory challenges and perspectives in this field:
In 2009, the CHMP established an ad hoc expert group on nanomedicines.
This group includes selected experts from academia and the European regulatory network, who support the Agency’s activities by providing specialist input on new scientific knowledge and who help with the review of guidelines on nanomedicines. The group also helps the Agency’s discussions with international partners on issues concerning nanomedicines.
The group held the first ad hoc expert group meeting on nanomedicines on 29 April 2009.
In 2011, the CHMP began to develop in 2011 a series of four reflection papers on nanomedicines to provide guidance to sponsors developing nanomedicines.
These documents cover the development both of new nanomedicines and of nanosimilars (nanomedicines that are claimed to be similar to a reference nanomedicine), since the first generation of nanomedicines, including liposomal formulations, iron-based preparations and nanocrystal-based medicines, have started to come off patent:
The fourth document, a draft reflection paper on the data requirements for intravenous iron-based nanocolloidal products developed with reference to an innovator medicine, will be released for a six-month public consultation in 2013.
The Agency organises workshops on nanomedicines to explore the scientific aspects of nanomedicines and enable the sharing of experience at an international level, in order to assist future developments in the field:
REFLECTION PAPER ON NANOTECHNOLOGY-BASED MEDICINAL PRODUCTS FOR
HUMAN USE
Molecular formula of calcitonin is C145H241N43O49S2
• Molecular weight is 3434.8 g/mol
| Calcitonin-related polypeptide alpha | |||
|---|---|---|---|
 NMR solution structure of salmon calcitonin in SDS micelles.[1] |
Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear polypeptide hormone that is produced in humansprimarily by the parafollicular cells (also known as C-cells) of the thyroid, and in many other animals in the ultimobranchial body.[2] It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).[3]
Calcitonin has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis.[4] It belongs to the calcitonin-like protein family.
 |
||||
| Conditions : Concentration – 53 mg / 100 ml | ||||
| Solvent designation schedule |
Methanol |
Water |
0.1М HCl |
0.1M NaOH |
|---|---|---|---|---|
| The absorption maximum | 278 nm | – | 275 nm | – |
 |
4.9 | – | 4.4 | – |
| with | 1670 | – | 1500 | – |
| Wavelength (μm) |
|---|
 |
| Wavenumber (cm -1 ) |
| Calcitonin-related polypeptide alpha | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
NMR solution structure of salmon calcitonin in SDS micelles.[1] |
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|
|||||||||||
| Identifiers | |||||||||||
| Symbols | CALCA ; CALC1; CGRP; CGRP-I; CGRP1; CT; KC | ||||||||||
| External IDs | OMIM: 114130 MGI: 2151253HomoloGene: 88401 ChEMBL: 5293GeneCards: CALCA Gene | ||||||||||
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| RNA expression pattern | |||||||||||
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| More reference expression data | |||||||||||
| Orthologs | |||||||||||
| Species | Human | Mouse | |||||||||
| Entrez | 796 | 12310 | |||||||||
| Ensembl | ENSG00000110680 | ENSMUSG00000030669 | |||||||||
| UniProt | P01258 | P70160 | |||||||||
| RefSeq (mRNA) | NM_001033952 | NM_001033954 | |||||||||
| RefSeq (protein) | NP_001029124 | NP_001029126 | |||||||||
| Location (UCSC) | Chr 11: 14.99 – 14.99 Mb |
Chr 7: 114.63 – 114.64 Mb |
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| PubMedsearch | [1] | [2] | |||||||||
Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene (CALCA). The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.
Secretion of calcitonin is stimulated by:
The hormone participates in calcium (Ca2+) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH).
More specifically, calcitonin lowers blood Ca2+ levels in three ways:
However, effects of calcitonin that mirror those of PTH include the following:
In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation.
Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca2+. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS action involving the regulation of feeding and appetite.
The calcitonin receptor, found on osteoclasts,[12] and in kidney and regions of the brain, is a G protein-coupled receptor, which is coupled by Gs to adenylate cyclase and thereby to the generation of cAMP in target cells. It may also affect the ovaries in women and the testes in men.
Calcitonin was purified in 1962 by Copp and Cheney.[13] While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cellsof the thyroid gland.[14]
Salmon calcitonin is used for the treatment of:
It has been investigated as a possible non-operative treatment for spinal stenosis.[16]
The following information is from the UK Electronic Medicines Compendium[17]
Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.
Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).
Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.
There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea, vomiting, and secretory diarrhea.
Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic, and mutagenic potential.
An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.
In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.
Calcitonin was extracted from the ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. At present, it is produced either by recombinant DNA technology or by chemical peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.[17]
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.
Oral calcitonin may have a chondroprotective role in osteoarthritis (OA), according to data in rats presented in December, 2005, at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts. Although calcitonin is a known antiresorptive agent, its disease-modifying effects on chondrocytes and cartilage metabolisms have not been well established until now.
This new study, however, may help to explain how calcitonin affects osteoarthritis. “Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation,” says researcher Morten Karsdal, MSC, PhD, of the department of pharmacology at Nordic Bioscience in Herlev, Denmark. “Therefore, calcitonin may be a future efficacious drug for OA.”[18]
Subcutaneous injections of calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder.[19] However no further work on this potential application of calcitonin has been reported.
It may be used diagnostically as a tumor marker for medullary thyroid cancer, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g., lymph nodes that are swollen) to establish whether they are metastasis of the original cancer.
Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer:[20]
When over 3 years of age, adult cutoffs may be used
Increased levels of calcitonin have also been reported for various other conditions. They include: C-cell hyperplasia, Nonthyroidal oat cell carcinoma, Nonthyroidal small cell carcinoma and other nonthyroidal malignancies, acute and chronic renal failure, hypercalcemia, hypergastrinemia and other gastrointestinal disorders, and pulmonary disease.[21]
Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix.[1] Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type.[22]
The following are the amino acid sequences of salmon and human calcitonin:[23]
Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro
Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro
Compared to salmon calcitonin, human calcitonin differs at 16 residues.
Description: Cellular and molecular coordination of tissues which secrete chemical compounds to regulate growth, reproduction, metabolism, and ion homeostasis.
cas 57014-02-5
Haloperidol /hæloʊpɛridɒl/ (INN, BAN, USAN, AAN; most common brand names: Haldol, Serenace) is an antipsychotic medication used in the treatment of schizophrenia, acute psychosis, mania, delirium, tics in Tourette syndrome, choreas, nausea and vomiting inpalliative care, intractable hiccups, agitation and severe anxiety.[3][4][5] Haloperidol is a butyrophenone derivative and functions as aninverse agonist of dopamine. It is classified as a typical antipsychotic and has pharmacological effects similar to the phenothiazines.[4]
A long-acting decanoate ester of haloperidol is used as an injection given every four weeks to people with schizophrenia or related illnesses who have poor adherence to medication regimens (most commonly due to them forgetting to take their medication, or due to poor insight into their illness) and suffer frequent relapses of illness, or to overcome the drawbacks inherent to its orally administered counterpart.[6] Such long acting injections are controversial because it can be seen as denying people their right to stop taking their medication.
It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.[7]
Skeletal formula of haloperidol decanoate: The decanoate group is highlighted in blue.
| Salt | ATC | Formula | MM | CAS |
|---|---|---|---|---|
| – | N05AD01 | C 21 H 23 ClFNO 2 | 375.87 g / mol | 52-86-8 |
| Synthesis a) |
|---|
   |
| Country | Trade name | Manufacturer |
|---|---|---|
| Germany | Haldol-Janssen | Janssen-Cilag |
| various generic drugs | ||
| France | Haldol | Janssen-Cilag |
| United Kingdom | – “- | – “- |
| Serenak | Ivax | |
| Italy | Haldol | Janssen-Cilag |
| Serenas | Lusofarmaco | |
| Japan | Galomont | Janssen – Dainippon Sumitomo |
| Neoperidol | Janssen | |
| Serenak | Dainippon Sumitomo | |
| USA | various generic drugs | |
| Ukraine | Haloperidol | Ltd. “Gedeon Richter”, Hungary |
| various generic drugs | ||
1H NMR
13 C NMR
IR
MASS
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-40422012000200028
| Systematic (IUPAC) name | |
|---|---|
| 4-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one | |
| Clinical data | |
| Trade names | Haldol |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682180 |
| Pregnancy cat. | C (AU) C (US) |
| Legal status | Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US) |
| Routes | Oral, IM, IV, depot (asdecanoate ester) |
| Pharmacokinetic data | |
| Bioavailability | 60-70% (Oral)[1] |
| Protein binding | ~90%[1] |
| Metabolism | Liver-mediated[1] |
| Half-life | 14-26 hours (IV), 20.7 hours (IM), 14-37 hours (oral)[1] |
| Excretion | Biliary (hence in faeces) and in urine[1][2] |
| Identifiers | |
| CAS number | 52-86-8  |
| ATC code | N05AD01 |
| PubChem | CID 3559 |
| IUPHAR ligand | 86 |
| DrugBank | DB00502 |
| ChemSpider | 3438 |
| UNII | J6292F8L3D |
| KEGG | D00136 |
| ChEBI | CHEBI:5613 |
| ChEMBL | CHEMBL54 |
| Chemical data | |
| Formula | C21H23ClFNO2 |
| Mol. mass | 375.9 g/mol |
Haloperidol was discovered by Paul Janssen.[70] It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgiumlater that year.[71]
Haloperidol was approved by the U.S. Food and Drug Administration (FDA) on April 12, 1967; it was later marketed in the U.S. and other countries under the brand name Haldol byMcNeil Laboratories.[citation needed]
Coincident with civil unrest in the United States in the 1960s and 1970s, schizophrenia was racialized to match the behavior of angry/violent black men. Haldol was promoted as a way to pacify them, and was marketed to appeal to feelings of racial unease. (cf. Metzl 2010. The Protest Psychosis)
Soviet dissidents, including medical staff, have reported several times on the use of haloperidol in the Soviet Union for punitive purposes or simply to break the prisoners’ will.[72][73][74] Notable dissidents who were administered haloperidol as part of their court-ordered treatment were Sergei Kovalev and Leonid Plyushch.[75] The accounts Plyushch gave in the West, after he was allowed to leave the Soviet Union in 1976, were instrumental in triggering Western condemnation of Soviet practices at the World Psychiatric Association‘s 1977 meeting.[76] The use of haloperidol in the Soviet Union’s psychiatric system was prevalent because it was one of the few psychotropic drugs produced in quantity in the USSR.[77]
Haloperidol has been used for its sedating effects during the deportations of immigrants by the United States Immigration and Customs Enforcement (ICE). During 2002-2008, federal immigration personnel used haloperidol to sedate 356 deportees. By 2008, following court challenges over the practice, it was given to only three detainees. Following lawsuits, U.S. officials changed the procedure so the drug is administered only by the recommendation of medical personnel and under court order.[78][79]
Haloperidol is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halosten, Keselan, Linton, Peluces, Serenace and Sigaperidol.
Haloperidol is also used on many different kinds of animals. It appears to be particularly successful when given to birds, e.g., a parrot that will otherwise continuously pluck its feathers out.[80]
 |
|
| Systematic (IUPAC) name | |
|---|---|
| (RS)-6-(Difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzo[d]imidazole | |
| Clinical data | |
| Trade names | Protonix |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a601246 |
| Licence data | US FDA:link |
| Pregnancy cat. | B3 (AU) B (US) |
| Legal status | ℞ Prescription only |
| Routes | Oral and intravenous |
| Pharmacokinetic data | |
| Bioavailability | 77% |
| Metabolism | Hepatic (CYP3A4) |
| Half-life | 1 hour |
| Excretion | Renal |
| Identifiers | |
| CAS number | 102625-70-7 |
| ATC code | A02BC02 |
| PubChem | CID 4679 |
| DrugBank | DB00213 |
| ChemSpider | 4517 |
| UNII | D8TST4O562 |
| KEGG | D05353 |
| ChEBI | CHEBI:7915 |
| ChEMBL | CHEMBL1502 |
| Chemical data | |
| Formula | C16H15F2N3O4S |
| Mol. mass | 383.371 g/mol |
Pantoprazole is a proton pump inhibitor drug that inhibits gastric acid secretion.
Pantoprazole is a proton pump inhibitor drug used for short-term treatment of erosion and ulceration of the esophagus caused by gastroesophageal reflux disease.
Pantoprazole is used for short-term treatment of erosion and ulceration of the oesophagus caused by gastroesophageal reflux disease. Initial treatment is generally of eight weeks’ duration, after which another eight week course of treatment may be considered if necessary. It can be used as a maintenance therapy for long term use after initial response is obtained.
Antacid preparations such as pantoprazole work by suppressing the acid-mediated breakdown of proteins. This leads to an elevated risk of developing food and drug allergies due to undigested proteins passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with short-term or only long-term use.[1]
Wyeth pantoprazole 20mg.
Pantoprazole is metabolized in the liver by the cytochrome P450 system.[3] Metabolism mainly consists of demethylation by CYP2C19followed by sulfation. Another metabolic pathway is oxidation by CYP3A4. Pantoprazole metabolites are not thought to have any pharmacological significance. Pantoprazole is relatively free of drug interactions;[4] however, it may alter the absorption of other medications that depend on the amount of acid in the stomach, such as ketoconazole or digoxin. Generally inactive at acidic pH of stomach, thus it is usually given with a pro kinetic drug. Pantoprazole binds irreversibly to H+K+ATPase (proton pumps) and suppresses the secretion of acid. As it binds irreversibly to the pumps, new pumps have to be made before acid production can be resumed. The drug’s plasma half-life is about 2 hours.[5]
Absorption
Distribution
Metabolism
Excretion
Elimination Half Life
Pantoprazole was developed by Altana (owned by Nycomed) and was licensed in the USA to Wyeth (which was taken over by Pfizer). It was initially marketed under the brand name Protonix by Wyeth-Ayerst Laboratories and now is available as a generic. It is available by prescription in delayed-release tablets. It is also available for intravenous use.
On 24 December 2007, Teva Pharmaceutical released an AB-rated generic alternative to Protonix.[6] This was followed by generic equivalents from Sun Pharma and Kudco Pharma. Wyeth sued all three for patent infringement and launched its own generic version of Protonix with Nycomed.[7][8]
On October 18, 2010 the U.S. Food and Drug Administration (FDA) accepted the filing of an ANDA for a delayed release generic version of Protonix by Canadian companyIntelliPharmaCeutics.[9]
Pantoprazole is available from a range of international suppliers under brand names including Pantazone, Pantop-D, Pantasan, Pantrol, Prazolin, Pantochem, Pansev, Pantec, Somac, API, Tecta, Protium, Pantodac, Perizole, Pansped, Percazole, Astropan, Fenix, Pantecta, Pantoloc, Controloc, Somac, Tecta, Protium, Inipomp, Eupantol, Pantozol, Pantodac, Perizole, Pansped, Zurcazol, Protonex, Pantup,Pantomed, TopZole, Nolpaza, Controloc, UXL-D, Pantid, Pantogen, Pantpas and Prazolin.
| Salt | ATC | Formula | MM | CAS |
|---|---|---|---|---|
| – | A02BC02 A02BD04 |
C 16 H 14 F 2 N 3 NaO 4 S | 405.36 g / mol | 138786-67-1 |
| hydrate | A02BC02 A02BD04 |
C 16 H 14 F 2 N 3 NaO 4 S · 3 / 2H 2 O | 864.76 g / mol | 164579-32-2 |
| (+) – Isomer | A02BC02 A02BD04 |
C 16 H 14 F 2 N 3 NaO 4 S | 405.36 g / mol | 160098-11-3 |
| (-) – Isomer | A02BC02 A02BD04 |
C 16 H 14 F 2 N 3 NaO 4 S | 405.36 g / mol | 160488-53-9 |
| racemate | A02BC02 A02BD04 |
C 16 H 14 F 2 N 3 NaO 4 S | 405.36 g / mol | 142678-34-0 |
| Country | Patent Number | Approved | Expires (estimated) |
|---|---|---|---|
| Canada | 2428870 | 2006-05-23 | 2021-11-17 |
| Canada | 2092694 | 2005-04-05 | 2011-09-06 |
| Canada | 2341031 | 2006-04-04 | 2019-08-12 |
| United States | 7544370 | 2006-12-07 | 2026-12-07 |
| United States | 4758579 | 1993-07-19 | 2010-07-19 |
| Synthesis a) |
|---|
      |
http://www.google.com/patents/EP1335913A1?cl=en
Pantoprazole is the international non-proprietary name of the chemical product 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfmyl]-lH-benzimidazole of formula
Pantoprazole This product is an active ingredient used in the treatment of gastric ulcers, usually in the form of its sodium salt.
The product was described for the first time in European patent application EP-A-0166287 that also describes several processes for the preparation of products assignable to a general formula among which pantoprazole is to be found. The reaction sequences of these processes, applied precisely to the preparation of pantoprazole, are given in Scheme 1.
Scheme 1
In Scheme 1, the variables Y, Z, Z’ and Z” are leaving groups, for example atoms of halogen, and the variables M and M’ are atoms of alkali metals.
Austrian patent AT-B-394368 discloses another process based on a different route of synthetis, the reaction sequence of which is given in Scheme 2.
Pantoprazole Scheme 2
Nevertheless, this process has obvious drawbacks, since the methylation can take place not only in OH in the 4-position of the pyridine ring, but also in the nitrogen linked to a hydrogen of the benzimidazole ring, which can give place to mixtures of the desired product with the two possible methylated isomers of the benzimidazole compounds obtained, 3- methyl or 1 -methyl, which means that additional chromatographic purification steps are needed and the yields obtained are low.
PCT application WO97/29103 discloses another process for the preparation of pantoprazole, the reaction sequence of which is given in Scheme 3.
Scheme 3 As may be seen, different synthesis strategies have been proposed for the preparation of pantoprazole, some of them recently, which is an indication that the preparation of the product is still not considered to be sufficiently well developed, whereby there is still a need for developing alternative processes that allow pantoprazole to be prepared by means of simpler techniques and more accessible intermediate compounds and with good chemical yields.
EXAMPLES
Example 1. – Preparation of compound (IX)
47.5 ml (0.502 mol) of acetic anhydride were mixed with 1.65 g (0.0135 mol) of 4-dimethylaminopyridine, giving a transparent yellow solution which was heated to 65° – 70°C. This temperature was held by cooling since the reaction is exothermic. 25 g (0.1441 mol) of 2-methyl-3- methoxy-4-chloropyridine N-oxide (X) were added over a period of about 70 minutes. Once the addition was completed, the reaction was held at 65° – 70°C for a further 2h 20 minutes and after this time it was allowed to cool down to below 65°C and 90 ml of methanol were added gradually, while holding the temperature below 65°C. The resulting reaction mass was distilled at reduced pressure in a rotavap to remove the volatile components and the residue containing compound (IX) was used as such for the following reaction. Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: 1), showed a single spot at Rf – 0.82, indicating that the reaction has been completed.
Example 2. – Preparation of compound fVIII
(IX) (VIII)
11.5 ml methanol and 11.5 ml of water were added over the crude residue from Example 1 containing compound (IX), and thereafter, while holding the temperature to between 25° and 30°C with a water bath, the residual acetic acid contained in the crude residue was neutralized by the addition of 33% aqueous NaOH. Once the residual acid had been neutralized, 19 ml (0.2136 mol) of the 33% aqueous NaOH were added over 20 minutes, while holding the temperature to between 25° and 30°C, and, on completion of the addition, the hydrolysis reaction at pH 11.7 – 11.8 was held for 2h 30 minutes, to between 25° and 30°C. On completion of the reaction, the pH was adjusted to 7.0 – 7.5 by the addition of HC1 35%, while holding the temperature to 25°C. Thereafter, 50 ml of methylene chloride were added and, after stirring and allowing to rest, the phases were decanted. A further five extractions were carried out with 30 ml methylene chloride each and the pooled organic phases were dried with anhydrous sodium sulfate, were filtered and washed, and were evaporated at reduced pressure in a rotavap, providing a solid residue having a melting point around 73°C and containing compound (VIII). Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: 1), gave a main spot at Rf = 0.55, showing that the reaction was complete. The thus obtained crude residue was used as such in the following reaction.
Example 3. – Preparation of compound (VI)
24.5 g of the residue obtained in Example 2, containing approximately 0.142 mol of the compound 2-hydroxymethyl-3-methoxy-4-chloropyridine (VIII), were mixed with 0.5 ml of DMF and 300 ml of anhydrous methylene chloride, to give a brown solution which was cooled to 0° – 5°C in an ice water bath. Thereafter, a solution of 11.5 ml (0.1585 mol) of thionyl chloride in 50 ml of anhydrous methylene chloride was added over 20 minutes, while holding the above-mentioned temperature,. Once the addition was complete, the reaction was held at 0° – 5°C for a further 90 minutes and then 120 ml of water and NaOH 33% were added to pH 5 – 6, requiring approximately 29 ml of NaOH. The phases were then decanted and separated. The organic phase was extracted with a further 120 ml of water and the pooled aqueous phases were extracted with a further 4×25 ml of methylene chloride, in order to recover the greatest possible amount of product. The pooled organic phases were dried over anhydrous sodium sulfate, filtered and washed, and evaporated at reduced pressure in a rotavap, to give a residue containing the compound 2-chloromethyl-3- methoxy-4-chloropyridine (VI). Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15:1), showed a main spot at Rf = 0.83, indicating that the reaction was complete. The thus obtained crude residue was used as such in the following reaction. Example 4. – Preparation of compound (III)
26.11 g of the residue obtained in the Example 3 containing approximately 0.136 mol of the compound 2-chloromethyl-3-methoxy-4- chloropyridine (VI) were mixed with 370 ml of methylene chloride, to give a brown solution over which were added, at 20° – 25°C, 29.3 g (0.136 mol) of 5-difluoromethoxy-2-mercaptobenzimidazole (VII) and 17.10 ml (0.136 mol) of tetramethylguanidine (TMGH). The mixture was stirred at this temperature for 2 hours, after which 450 ml of water were added, with the pH being held to between 9.5 and 10. Thereafter the phases were decanted and the organic phase was washed 5×50 ml of a IN NaOH aqueous solution and, thereafter, with 2×50 ml of water. The organic phase was treated with 50 ml of water and an amount of HC1 30% sufficient to adjust the pH to between 5 and 6. Thereafter, the phases were decanted, and the organic phase was dried over anhydrous sodium sulfate, was filtered and washed, and evaporated at reduced pressure in a rotavap, to give a solid residue of melting point 64° – 73 °C that contains the compound (III). Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: 1), presented a main spot at Rf = 0.52. Yield 82%. The thus obtained compound 5-(difluoromethoxy)-2-[[(3-methoxy-4-chlorine-2 pyridinyl)methyl]mercapto]- lH-benzimidazole (III) was used as such in the following reaction Example 5. – Preparation of compound (IV)
25.8 g (0.0694 mol) of the compound (III) obtained in the Example 4 were mixed with 88 ml of methanol, to give a brown solution to which 3.7 ml of water, 0.99 g of ammonium molybdate and 0.78 g of sodium carbonate were added. The system was cooled to 0°C – 5°C, 3.4 ml (0.0756 mol) of 60% hydrogen peroxide were added, and the reaction mixture was held at 0°C – 5°C for 1 – 2 days, the end point of the reaction being checked by thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: l).
During the reaction the presence of hydrogen peroxide in the reaction medium was controlled by testing with potassium iodide, water and starch. When effected on a sample containing hydrogen peroxide, it provides a brown-black colour. If the assay is negative before the chromatographic control indicates completion of the reaction, more hydrogen peroxide is added.
On completion of the reaction, 260 ml of water were added, the system was cooled to 0°C – 5°C again and the mixture was stirred for 2 hours at this temperature. The solid precipitate was filtered, washed with abundant water, and dried at a temperature below 60°C, to give 5-(difluoromethoxy)-2-[[(3- methoxy-4-chlorine-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole (IV), melting point 130° – 136°C, with an 83.5% yield. Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: 1), gave a main spot at Rf = 0.5.
Compound (IV) can be purified, if desired, by the following crystallization method:
5 g of crude product was suspended in 16 ml of acetone and was heated to boiling until a dark brown solution was obtained. Thereafter the thus obtained solution was allowed to cool down to room temperature and then was then chilled again to -20°C, at which temperature the mixture was held for 23 hours without stirring. Thereafter the solid was filtered and washed with 6×4 ml of acetone chilled to -20°C. Once dry, the resulting white solid weighed 2.73 g, had a point of melting of 142°C and gave a single spot in thin layer chromatography. The IR spectrum of the compound on KBr is given in Figure 1.
The acetonic solution comprising the mother liquors of filtration and the washes was concentrated to a volume of 20 ml and a further 5 g of crude compound were added. The above described crystallization process was repeated to obtain a further 4.11 g of purified product of characteristics similar to the previous one.
The acetonic solution from the previous crystallization was concentrated to a volume of 17 ml and a further 4 g of crude compound were added. The above described crystallization process was repeated to obtain a further 2.91 g of purified product of similar characteristics to the previous ones.
The acetonic solution from the previous crystallization was concentrated to a volume of 15 ml and a further 4 g of crude compound were added. The above described crystallization process was repeated to obtain a further 3.3 g of purified product of similar characteristics to the previous ones.
The acetonic solution from the previous crystallization was concentrated to a volume of 16 ml and a further 4.36 g of crude compound were added. The above described crystallization process was repeated to obtain a further 3.62 g of purified product of similar characteristics to the previous ones.
Finally, the acetonic solution from the previous crystallization was concentrated to a volume of 10 – 12 ml and held at -20°C for two days without stirring. Thereafter, the solid was filtered and washed with 5×3 ml of acetone chilled to -20°C. Once dry, the solid weighed 1.26 g and had similar characteristics to the previous ones.
The total yield of all the crystallizations was 80%.
Example 6. – Preparation of pantoprazole
12.95 g (0.0334 mol) of compound (IV) purified by crystallization of Example 5 were mixed with 38 ml of N,N-dimethylacetamide and thereafter 7.03 g (0.1003 mol) of potassium methoxide were added, while holding the temperature to between 20°C and 30°C, whereby a dark brown mixture was obtained. The system was held at approximately 25°C for about 23 hours, after which, once the reaction was complete, the pH was adjusted to 7 with the addition of 3.82 ml of acetic acid. The N,N-dimethylacetamide was removed at reduced pressure at an internal temperature of not more than 75°C. 65 ml of water and 50 ml of methylene chloride were added over the thus obtained residue, followed by decantation of the phases. Once the phases were decanted, the aqueous phase was extracted a with further 3×25 ml of methylene chloride, the organic phases were pooled and the resulting solution dried over anhydrous sodium sulfate, was filtered and washed, and evaporated at reduced pressure in a rotavap, to give a crude residue over which 55 ml of water were added, to give a suspension (if the product does not solidify at this point the water is decanted and a further 55 ml of water are added to remove remains of N,N-dimethylacetamide that hinder the solidification of the product). The solid was filtered and, after drying, 11.61 g of crude pantoprazole of reddish brown colour were obtained (Yield 90%). The thus obtained crude product was decoloured by dissolving the crude product in 150 ml of methanol, whereby a dark brown solution was obtained. 7.5 g of active carbon were added, while maintaining stirring for 45 minutes at 25°C – 30°C, after which the carbon was filtered out and the filter was washed. The methanol was then removed in the rotavap at reduced pressure, a temperature below 40°C. 10.33 g of a solid residue were obtained and were mixed with 14.9 ml of methylethylketone, and the suspension was heated to 45°C for about 10 minutes, after which it was cooled, first to room temperature and then to -20°C. This temperature was held over night and thereafter the solid was filtered, washed with 6×5 ml of methylethylketone chilled to -20°C. Once dry, 7.75 g of a white solid, melting point 140°C – 141 °C, were obtained. Thin layer chromatography on silica gel F254, eluting with CHCl3/MeOH (15: 1), gave a single spot at Rf =
0.41 and a IR spectrum corresponding identically with that of pantoprazole.
The ketonic solution comprising the mother liquors of filtration and the washes, was concentrated to 9.7 ml, was heated to 40°C, was held at this temperature for about five minutes and was then cooled, first to room temperature and then to -20°C, this temperature being held for 4 hours. At the end of this time, the solid was filtered and was washed with 4×2 ml of methylethylketone chilled to -20°C. Once dry, 0.42 g of a white solid of similar characteristics to the previous one was obtained.
The ketone solution from the previous treatment was concentrated to 3.1 ml, was heated to 40°C, was held to this temperature for about five minutes and then was cooled, first to room temperature and then to -20°C, this temperature being held for 4 hours. At the end of this time, the solid was filtered and was washed with 5×3 ml of methylethylketone chilled to – 20°C. Once dry, 0.41 g of a white-beige solid of similar characteristics to the previous one was obtained. The total yield, including purifications, was 67%.
If a whiter solid is desired, one or several washes can be carried with isopropyl acetate as follows: 6.6 g of pantoprazole from the methylethylketone treatment were suspended in 50 ml of isopropyl acetate. The system (white suspension) was stirred for about 30 minutes at 25°C, was then cooled to 0°C – 5°C, was stirred for about 15 minutes at this temperature and the solid was then filtered, was washed with 3×15 ml of isopropyl acetate. Once dry, 6.26 g of a pure white solid were obtained.
| Country | Trade name | Manufacturer |
|---|---|---|
| Germany | Pantozol | Nycomed |
| Rifun | – “- | |
| France | Eupantol | Altana |
| Inipomp | Sanofi-Aventis | |
| United Kingdom | Protium | ALTANA |
| Italy | Pantekta | Abbott |
| Pantopan | Pharmacia | |
| Pantork | Altana | |
| USA | Protonix | Wyeth |
| Ukraine | Kontrolok | Nycomed Oranienburg GmbH, Germany |
| Nolpaza | Krka | |
| Pultset | Nobel Ilach Sanayi ve Ticaret AS, Turkey | |
| Proksium | JSC “Lubnyfarm”, Ukraine | |
| various generic drugs | ||
UV – spectrum
 |
||||
| Conditions : Concentration – 1 mg / 100 ml | ||||
| Solvent designation schedule |
Methanol |
Water |
0.1 M HCl |
0.1M NaOH |
|---|---|---|---|---|
| The absorption maximum | 289 nm | 291nm | Observed decay |
295 nm |
 |
391 | 346 | – | 418 |
| ε | 16600 | 14700 | – | 17700 |
| Wavelength (μm) |
|---|
 |
| Wavenumber (cm -1 ) |
will be added
| Biological Role(s): | antifungal agent
An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce. Antifungal agents differ from industrial fungicides in that they defend against fungi present in human or animal tissues.
|
| Application(s): | antifungal agent
An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce. Antifungal agents differ from industrial fungicides in that they defend against fungi present in human or animal tissues.
|
GÖTEBORG, Sweden.–(BUSINESS WIRE)–Cortendo AB (OSE:CORT) today announced that the first patient has been enrolled into the Phase 3 SONICS trial, i.e., “Study Of NormoCort In Cushing’s Syndrome.”
“The enrollment of the first patient into the SONICS trial represents a significant milestone for Cortendo”
The patient was enrolled by one of the trial’s lead principal investigators at a Pituitary Center from a prestigious institution in Baltimore, Maryland. “The enrollment of the first patient into the SONICS trial represents a significant milestone for Cortendo”, said Dr. Theodore R Koziol. ”The SONICS clinical trial team is acutely focused on the implementation of the trial following a successful EU Investigator’s meeting in Barcelona in July, which we believe further solidified the foundation for the trial.”
Cortendo successfully completed its European Investigator meeting supporting SONICS held in Barcelona, Spain on July 17-18. More than 35 investigators/study coordinators, including many of the world’s leading Cushing’s experts from 24 study sites, were in attendance and received training for the trial. Based on the positive feedback from the meeting, Cortendo has gained further confidence that NormoCort (COR-003) has the potential to be an important future treatment option for patients afflicted with Cushing’s Syndrome. A second US Investigator meeting is also being planned for later this year.
”It was gratifying to participate in the NormoCort SONICS trial investigator meeting in my home town of Barcelona with so many esteemed colleagues dedicated to treating patients with Cushing’s Syndrome”, said Susan Webb M.D. Ph.D. Professor of Medicine Universitat Autonoma de Barcelona. ”There remains a significant unmet medical need for patients, and I am delighted to be part of the development of this new therapy”.
Cortendo has also further strengthened its internal as well as external teams to support the study and to position the trial for an increased recruitment rate. In July, Cortendo added both an experienced physician and internal Clinical Operations Director to the NormoCort development team. Cortendo, working in concert with its CROs supporting the SONICS trial, now has a team of approximately 20 personnel on the NormoCort development program.
Cortendo has previously communicated its plan to meet the recruitment goal by increasing the number of study sites from 38 to 45 worldwide. The company is at various levels of activation with more than 30 study sites to date. Therein, Cortendo expects a large proportion of the sites to be activated by the end of the third quarter this year and remains confident that essentially all sites will be open by the end of 2014.
Risk and uncertainty
The development of pharmaceuticals carries significant risk. Failure may occur at any stage during development and commercialization due to safety or clinical efficacy issues. Delays may occur due to requirements from regulatory authorities not anticipated by the company.
About Cortendo
Cortendo AB is a biopharmaceutical company headquartered in Göteborg, Sweden. Its stock is publicly traded on the NOTC-A-list (OTC) in Norway. Cortendo is a pioneer in the field of cortisol inhibition and has completed early clinical trials in patients with Type 2 diabetes. The lead drug candidate NormoCort, the 2S, 4R-enantiomer of ketoconazole, has been re-focused to Cushing’s Syndrome, and has entered Phase 3 development. The company’s strategy is to primarily focus its resources within orphan drugs and metabolic diseases and to seek opportunities where the path to commercialization or partnership is clear and relatively near-term. Cortendo’s business model is to commercialize orphan and specialist product opportunities in key markets, and to partner non-specialist product opportunities such as diabetes at relevant development stages.
Cortendo AB (publ)
Sweden: Box 47 SE-433 21 Partille Tel. / Fax: +46 (0)31-263010
USA: 555 East Lancaster Ave Suite 510 Radnor, PA 19087 Tel: +1 610-254-9200 Fax: +1 610-254-9245
This information was brought to you by Cision http://news.cision.com
Alexander Lindström
Chief Financial Officer Office
+1 610 254 9200
Mobile : +1 917 349 7210
E-mail : alindstrom@cortendo.com
…………………………
http://www.google.com/patents/EP1853266B1?cl=en
| Component | Percentage |
| 2S,4R ketoconazole; DIO-902 |
50% |
| Silicified Microcrystalline Cellulose, NF (Prosolv HD 90) |
16.5 |
| Lactose Monohydrate, NF (316 Fast-Flo) | 22.4 |
| Corn Starch, NF (STA-Rx) | 10 |
| Colloidal Silicon Dioxide, NF (Cab-O-Sil M5P) | 0.5 |
| Magnesium Stearate, NF | 0.6 |
The drug product may be stored at room temperature and is anticipated to be stable for at least 2 years at 25° C and 50% RH. The drug is packaged in blister packs.
ketoconazole 2S,4R enantiomer
ketoconazole 2S,4S enantiomer
ketoconazole 2R,4S enantiomer
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Journal of Medicinal Chemistry (Impact Factor: 5.61). 08/1992; 35(15):2818-25. DOI: 10.1021/jm00093a015
http://pubs.acs.org/doi/abs/10.1021/jm00093a015
…………………….
http://www.sciencedirect.com/science/article/pii/S1383586611001638
A new process has been developed to separate ketoconazole (KTZ) enantiomers by membrane extraction, with the oppositely preferential recognition of hydrophobic and hydrophilic chiral selectors in organic and aqueous phases, respectively. This system is established by adding hydrophobic l-isopentyl tartrate (l-IPT) in organic strip phase (shell side) and hydrophilic sulfobutylether-β-cyclodextrin (SBE-β-CD) in aqueous feed phase (lumen side), which preferentially recognizes (+)-2R,4S-ketoconazole and (−)-2S,4R-ketoconazole, respectively. The studies performed involve two enantioselective extractions in a biphasic system, where KTZ enantiomers form four complexes with SBE-β-CD in aqueous phase and l-IPT in organic phase, respectively. The membrane is permeable to the KTZ enantiomers but non-permeable to the chiral selector molecules. Fractional chiral extraction theory, mass transfer performance of hollow fiber membrane, enantioselectivity and some experimental conditions are investigated to optimize the separation system. Mathematical model of I/II = 0.893e0.039NTU for racemic KTZ separation by hollow fiber extraction, is established. The optical purity for KTZ enantiomers is up to 90% when 9 hollow fiber membrane modules of 30 cm in length in series are used.
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Stereoselective synthesis of both enantiomers of ketoconazole from (R)- and (S)-
Original Research Article
Bromobenzoates (2R,4R)- and (2S,4S)-18, prepared stereoselectively from (R)- and (S)-epichlorohydrin, were transformed into (2R,4S)-(+)- and (2S,4R)-(−)-Ketoconazole, respectively, following the known synthetic protocols for the racemic mixture.
Tetrahedron Asymmetry 1995, 6(6): 1283
Stereoselective syntheses of both enantiomers of ketoconazole (1) from commercially available (R)- or (S)-epichlorohydrin has been developed. The key-step of these syntheses involves the selective substitution of the methylene chlorine atom by benzoate on a mixture of 
and 
or of their enantiomers, followed by crystallization of the corresponding cis-benzoates, (2S,4R)-18 or(2S,4S)-18, from which (+)- or (−)-1 were obtained as described for (±)-1. The ee’s of (+)- and (−)-ketoconazole were determined by HPLC on the CSP Chiralcel OD-H.
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WO 1996029325
http://www.google.com/patents/WO1996029325A1?cl=en
The incidence of fungal infections has considerably increased over the last decades. Notwithstanding the utility of the antifungal compounds commercialized in the last 15 years, the investigation in this field is however very extensive. During this time, compounds belonging to the azole class have beer, commercialized for both the topical and oral administrations, such a class including imidazoles as well as 1,2,4-triazoles. Some of these compounds car. show m some degree a low gastrointestinal tolerance as well as hepatotoxycity.
A large number of pharmaceutically active compounds are commercialized as stereoisomeric mixtures. On the other hand, the case in which only one of said stereoisomers is pharmaceutically active is frequent.
The undesired enantiomer has a lower activity and it sometimes may cause undesired side-effects.
Ketoconazole (1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine), terconazole (1-[4-[[2(2,4-dichlorophenyl)-2-[(1H-1 , 2 ,4-triazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine) and other related azole antifungal drugs contain in their structure a substituted 1,3-dioxolane ring, in which carbon atoms C2 and C4 are stereogenic centres, therefore four possible stereoisomers are possible. These compounds are commercialized in the form or cis racemates which show a higher antifungal activity than the corresponding trans racemates.
The cis homochiral compounds of the present invention, which are intermediates for the preparation of enantiomerically pure antifungal drugs, have been prepared previously in the racemic form and transformed into the different azole antifungal drugs in the racemic form [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979). J . Med . Chem . , 26, 611 (1983), J . Med . Chem . , 27 , 894 (1984) and US 4,144,346, 4,223,036, 4,358,449 and 4,335,125].
Scheme 1 shows the synthesis described for racemic ketoconazole [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979)]. Scheme 1
)
The synthesis of racemic terconazole [J. Heeres et al., J. Med . Chem . , 26 , 611 11983)] is similar. differing in the introduction of a 1 H- 1 , 2,4-triazol-1-yl substituent in place of 1H-imidazol-1-yl and in the nature of the phenol used in the last step of the synthetic sequence, which phenol is 1-methylethyl-4-(4- hydroxyphenyl)piperazme instead of 1-acetyl-4-(4-nydroxyphenyl)piperazine.
The preparation of racemic itraconazole [J. Heeres et al., J. Med . Chem. , 27 , 894 (1984)] is similar to that of terconazole, differing only in the nature of the phenol used in the last step of the synthetic sequence.
In the class of azoles containing a 1,3-dioxolane ring and a piperazine ring and moreover they are pure enantiomers, only the preparation of (+)- and (-)-ketoconazole has been described [D. M. Rotstein et al., J. Med . Chem . , 35, 2818 (1992)] (Scheme 2) starting from the tosylate of (+)- and (-) 2,2-dimethyl-1,3-dioxolane-4-methanol.
Scheme 2
This synthesis suffers from a series of drawbacks, namely: a) the use of expensive, high molecular weight starting products which are available only on a laboratory scale, and b) the need for several chromatographies during the process in order to obtain products of suitable purity, which maKes said synthesis economically unattractive and difficult to apply industrially.
Recently (N. M. Gray, WO 94/14447 and WO 94/14446) the use of (-)-ketoconazole and (+)-ketoconazole as antifungal drugs causing less side-effects than (±)-ketoconazole has been claimed.
The industrial preparation of enantiomerically pure antifungal drugs with a high antifungal activity and less side-effects is however a problem in therapy. The present invention provides novel homochiral compounds which are intermediates for the industrial preparation of already known, enantiomerically pure antifungal drugs such as ketoconazole enantiomers, or of others which have not yet been reported in literature, which are described first in the present invention, such as (+)-terconazole and (-)-terconazoie, which show the cited antifungal action, allowing to attain the same therapeutical effectiveness using lower dosages than those required for racemic terconazole
Example 14 : (2S,4R)-(-)-1-acetyl-4-[4-[ [2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine, (2S,4R) -(- )-ketoconazole.
This compound is prepared following the process described above for (2R,4S)-(+)-ketoconazole. Starting from HNa (60-65% dispersion in paraffin, 32 mg, 0.80 mmol), 1-acetyl-4-(4-hydroxyphenyl)piperazine (153 mg, 0.69 mol) and (2S,4S)-(-)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH3) (250 mg, 0.61 mmol), upon crystallization from an acetone:ethyl acetate mixture, (2S,4R) -(-)-ketoconazole is obtained [(2S,4R)-V Ar = 2,4-dichlorophenyl, Y = CH, Z = COCH3] (196 mg, 61% yield) as a solid, m.p. 153-155ºC (lit. 155-157ºC); [α]D 20 = -10.50 (c = 0.4, CHCl3) (lit. [α]D 25 = -10.58. c = 0.4, CHCl3) with e.e. > 99% (determined by HPLC using the chiral stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1 % diethylamine as the eluent).
+ KETOCONAZOLE…. UNDESIRED
Example 7: (2 R ,4S)-(+)-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine (22, 4 S)-(+)-ketoconazole.
To a suspension of NaH (dispersed in 60-65% paraffin, 19.2 mg, 0.48 mmol) in anhydrous DMSO (3 ml),
1-acetyl-4-(hydroxyphenyl)piperazine (102 mg, 0.46 mmol) is added and the mixture is stirred for 1 hour at room temperature. Then, a solution of (2R,4R) – (+)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH3) (160 mg, 0.39 mmol) in anhydrous DMSO (5 ml) is added, and the mixture is heated at 80ºC for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with water
(20 ml) and extracted with CH2Cl2 (3 × 25 ml). The combined organic phases are washed with water (3 × 25), dried with Na2SO4 and the solvent is evaporated off under vacuum. The oily residue thus obtained is crystallized from an acetone:ethyl acetate mixture to give (2R,4S)-(+)-ketoconazole ( (2R, 4 S) -V , Ar 2,4-dichlorophenyl, Y = CH , Z = COCH3 ) ( 110 mg , 5 3 % yie ld ) as a white solid, m.p. 155-156°C (lit. 154-156ºC), [α]D 20 = + 8.99 (c = 0.4, CHCl3) (lit. [α]D 25 = + 8.22, c = 0.4, CHCl3), with e.e. > 99% (determined by HPLC using the chirai stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1% of diethylamine, as the eluent; (+)-Ketoconazole retention time 73,28 min. (-)-Ketoconazole, retention time 79.06 min).
IR (KBr), ʋ : 2875, 1645, 1584, 1511, 1462, 1425, 1250, 103S, 313 cm-1.
1H NMR (500 MHz, CDCl3), δ : 2.12 (s, 3H, COCH3),
3.02 (m, 2H, 3-H2), 3.05 (m, 2H, 5-H2), 3.27 (dd, J= 9.5
Hz, J’=7.0 Hz, 1H) and 3.70 (dd, J=9.5 Hz, J’=5.0 Hz, 1 H) (4″-CH2), 3.60 (m, 2H, 6-H2), 3.76 (m, 2H, 2-H2), 3.73 (dd, J=8.0 Hz, J’=5.0 Hz, 1H) and 3.86 (dd, J=8.0 Hz, J’=6.5 Hz, 1H) (5″-H2), 4.34 (m, 1H, 4″-H), 4.40 (d, J=15.0 Hz, 1H) and 5.00 (d, J=15.0 Hz, 1H) (CH2-N), 4.34
(m, 1H, 4″-H), 6.76 [d, J = 9.0 Hz, 2H, 2′(C6′ )-H], 6.88
[d, J=9.0 Hz, 2H, C3′(C5)-H], 6.96 (s, 1H, imidazole 5- H), 6.99 (s, 1H, imidazole 4-H), 7.25 (dd, J=8.5 Hz, J’=2.0 Hz, 1H, 5″‘-H), 7.46 (d, J=2.0 Hz, 1H, 3″‘-H),
7.53 (s, 1H, imidazole 2-H), 7.57 (d, J=8.5 Hz, 1H,
6″‘-H).
13C NMR (75.4 MHz, CDCI3), δ : 21.3 (CH3, COCH3), 41.4 (CH2, C2), 46.3 (CH2, C6), 50.6 (CH2, C3), 51.0 (CH2, C5), 51.2 (CH2, CH2-N), 67.6 [CH2, C5″ and 4″-CH2), 74.7 (CH, C4″), 108.0 (C, C2″), 115.2 [CH, C2′(6′)], 118.8 [CH, C3′(5′)], 121.2 (CH, imidazole C5), 127.2 (CH, C5″‘), 128.5 (CH, imidazole C4), 129.5 (CH, C6′”), 131.3 (CH, C3″‘), 133.0 (C, C2″‘), 134.6 (C, C1′”), 135.8 (C, C4″‘), 138.8 (CH, imidazole C2), 145.6 (C, C1′), 152.8 (C, C4’), 168.9 (C, CO).
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Experimental and theoretical analysis of the interaction of (+/-)-cis-ketoconazole with beta-cyclodextrin in the presence of (+)-L-tartaric acid
J Pharm Sci 1999, 88(6): 599
Enrico Redenti, Paolo Ventura, Giovanni Fronza, Antonio Selva, Silvia Rivara, Pier Vincenzo Plazzi and Marco Mor
Article first published online: 12 JUN 2000 | DOI: 10.1021/js980468o
http://onlinelibrary.wiley.com/doi/10.1021/js980468o/pdf
1H NMR spectroscopy was used for determining the optical purity of cis-ketoconazole enantiomers obtained by fractional crystallization. The chiral analysis was carried out using β-cyclodextrin in the presence of (+)-l-tartaric acid. The mechanism of the chiral discrimination process, the stability of the complexes formed, and their structure in aqueous solution were also investigated by 1H and 13C chemical shift analysis, two-dimensional NOE experiments, relaxation time measurements, and mass spectrometry experiments. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analysis on the relevant fragments on ketoconazole and docking studies on the components of the complex. The model derived from a folded conformation of ketoconazole turned out to be fully consistent with the molecular assembly found in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiomers is also provided on the basis of the interaction energies.
| WO1993019061A1 * | Mar 10, 1993 | Sep 30, 1993 | Janssen Pharmaceutica Nv | Itraconazole and saperconazole stereoisomers |
| WO1994025452A1 * | Apr 28, 1994 | Nov 10, 1994 | Ashit K Ganguly | Process for preparing intermediates for the synthesis of antifungal agents |
| EP0050298A2 * | Oct 13, 1981 | Apr 28, 1982 | Hoechst Aktiengesellschaft | 1-(1,3-Dioxolan-2-ylmethyl) azoles, process for their preparation and their use |
| EP0052905A1 * | Nov 19, 1981 | Jun 2, 1982 | Janssen Pharmaceutica N.V. | Novel (2-aryl-4-phenylthioalkyl-1,3-dioxolan-2-yl-methyl)azole derivatives |
| US5208331 * | Jun 18, 1992 | May 4, 1993 | Syntex (U.S.A.) Inc. | Process for preparing 1,3-dioxolane derivatives |
August 11, 2014
The U.S. Food and Drug Administration today approved Cologuard, the first stool-based colorectal screening test that detects the presence of red blood cells and DNA mutations that may indicate the presence of certain kinds of abnormal growths that may be cancers such as colon cancer or precursors to cancer.
Colorectal cancer primarily affects people age 50 and older, and among cancers that affect both men and women, it is the third most common cancer and the second leading cause of cancer-related death in the United States, according to the Centers for Disease Control and Prevention (CDC). Colorectal cancer screening is effective at reducing illness and death related to colon cancer. The CDC estimates that if everyone age 50 or older had regular screening tests as recommended, at least 60 percent of colorectal cancer deaths could be avoided.
Colorectal cancer occurs in the colon (large intestine) or rectum (the passageway that connects the colon to the anus). Most colorectal cancers start as abnormal raised or flat tissue growths on the wall of the large intestine or rectum (polyps). Some very large polyps are called advanced adenomas and are more likely than smaller polyps to progress to cancer.
Using a stool sample, Cologuard detects hemoglobin, a protein molecule that is a component of blood. Cologuard also detects certain mutations associated with colorectal cancer in the DNA of cells shed by advanced adenomas as stool moves through the large intestine and rectum. Patients with positive test results are advised to undergo a diagnostic colonoscopy.
“This approval offers patients and physicians another option to screen for colorectal cancer,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health. “Fecal blood testing is a well-established screening tool and the clinical data showed that the test detected more cancers than a commonly used fecal occult test.”
Today’s approval of the Cologuard does not change current practice guidelines for colorectal cancer screening. Stool DNA testing (also called “fecal DNA testing”) is not currently recommended as a method to screen for colorectal cancer by the United States Preventive Services Task Force (USPSTF). Among other guidelines, the USPSTF recommends adults age 50 to 75, at average risk for colon cancer, be screened using fecal occult blood testing, sigmoidoscopy, or colonoscopy.
The safety and effectiveness of Cologuard was established in a clinical trial that screened 10,023 subjects. The trial compared the performance of Cologuard to the fecal immunochemical test (FIT), a commonly used non-invasive screening test that detects blood in the stool. Cologuard accurately detected cancers and advanced adenomas more often than the FIT test. Cologuard detected 92 percent of colorectal cancers and 42 percent of advanced adenomas in the study population, while the FIT screening test detected 74 percent of cancers and 24 percent of advanced adenomas. Cologuard was less accurate than FIT at correctly identifying subjects negative for colorectal cancer or advanced adenomas. Cologuard correctly gave a negative screening result for 87 percent of the study subjects, while FIT provided accurate negative screening results for 95 percent of the study population.
Today the Centers for Medicare & Medicaid Services (CMS) issued a proposed national coverage determination for Cologuard. Cologuard is the first product reviewed through a joint FDA-CMS pilot program known as parallel review where the agencies concurrently review medical devices to help reduce the time between the FDA’s approval of a device and Medicare coverage. This voluntary pilot program is open to certain premarket approval applications for devices with new technologies and to medical devices that fall within the scope of a Part A or Part B Medicare benefit category and have not been subject to a national coverage determination.
“Parallel review allows the last part of the FDA process to run at the same time as the CMS process, cutting as many as six months from the time from study initiation to coverage,” said Nancy Stade, CDRH’s deputy director for policy. “The pilot program is ongoing, but we will apply what we have learned to improve the efficiency of the medical device approval pathway for devices that address an important public health need.”
“This is the first time in history that FDA has approved a technology and CMS has proposed national coverage on the same day,” said Patrick Conway, chief medical officer and deputy administrator for innovation and quality for CMS. “This parallel review represents unprecedented collaboration between the two agencies and industry and most importantly will provide timely access for Medicare beneficiaries to an innovative screening test to help in the early detection of colorectal cancer.”
CMS proposes to cover the Cologuard test once every three years for Medicare beneficiaries who meet all of the following criteria:
Cologuard is manufactured by Exact Sciences in Madison, Wisconsin.
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read at
http://pharma-marketing-india.blogspot.in/2014/08/why-india-is-becoming-preferable-place.html
Cefuroxime Axetil
Cefuroxime Axetil (1-(acetyloxy) ethyl ester of cefuroxime, is (RS)-1-hydroxyethyl (6R,7R)-7-[2-(2-furyl)glyoxyl-amido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylate, 7 2 -(Z)-(O-methyl-oxime), 1-acetate 3-carbamate.
Its molecular formula is C 20 H 22 N 4 O 10S, and it has a molecular weight of 510.48.
Cefuroxime Axetil is used orally for the treatment of patients with mild-to-moderate infections, caused by susceptible strains of the designated microorganisms.
Cefuroxime axetil is a second generation oral cephalosporin antibiotic. It was discovered by Glaxo now GlaxoSmithKline and introduced in 1987 as Zinnat.[1] It was approved by FDA on Dec 28, 1987.[2] It is available by GSK as Ceftin in US[3] and Ceftum in India.[4]
It is an acetoxyethyl ester prodrug of cefuroxime which is effective orally.[5] The activity depends on in vivo hydrolysis and release of cefuroxime.
Cefuroxime is chemically (6R, 7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-iminoacetamido] ceph-3-em-4-carboxylic acid and has the structural Formula II:
Cefuroxime axetil having the structural Formula I:
is the 1-acetoxyethyl ester of cefuroxime, a cephalosporin antibiotic with a broad spectrum of activity against gram-positive and gram negative micro-organisms.
This compound as well as many other esters of cefuroxime, are disclosed and claimed in U.S. Pat. No. 4,267,320. According to this patent, the presence of an appropriate esterifying group, such as the 1-acetoxyethyl group of cefuroxime axetil, enhances absorption of cefuroxime from the gastrointestinal tract, whereupon the esterifying group is hydrolyzed by enzymes present in the human body.
Because of the presence of an asymmetric carbon atom at the 1-position of the 1-acetoxyethyl group, cefuroxime axetil can be produced as R and S diastereoisomers or as a racemic mixture of the R and S diastereoisomers. U.S. Pat. No. 4,267,320 discloses conventional methods for preparing a mixture of the R and S isomers in the crystalline form, as well as for separating the individual R and S diastereoisomers.
The difference in the activity of different polymorphic forms of a given drug has drawn the attention of many workers in recent years to undertake the study on polymorphism. Cefuroxime axetil is the classical example of amorphous form exhibiting higher bioavailability than the crystalline form.
U.S. Pat. No. 4,562,181 and the related U.S. Pat. Nos. 4,820,833; 4,994,567 and 5,013,833, disclose that cefuroxime axetil in amorphous form, essentially free from crystalline material and having a purity of at least 95% aside from residual solvents, has a higher bioavailability than the crystalline form while also having adequate chemical stability.
These patents disclose that highly pure cefuroxime axetil can be recovered in substantially amorphous form from a solution containing cefuroxime axetil by spray drying, roller drying, or solvent precipitation. In each case, crystalline cefuroxime axetil is dissolved in an organic solvent and the cefuroxime axetil is recovered from the solution in a highly pure, substantially amorphous form.
Another U.S. Pat. No. 5,063,224 discloses that crystalline R-cefuroxime axetil which is substantially free of S-isomer is readily absorbed from the stomach and gastrointestinal tract of animals and is therefore ideally suited to oral therapy of bacterial infections.
According to this patent, such selective administration of R-cefuroxime axetil results in surprisingly greater bioavailability ability of cefuroxime, and thus dramatically reduces the amount of unabsorbable cefuroxime remaining in the gut lumen, thereby diminishing adverse side effects attributable to cefuroxime.
British Patent Specification No. 2,145,409 discloses a process for obtaining pure crystalline cefuroxime axetil and is said to be an improvement over British Patent Specification No. 1,571,683. Sodium cefuroxime is used as the starting material in the disclosed specification, which in turn, is prepared from either 3-hydroxy cefuroxime or cefuroxime.
Said process involves an additional step of preparing sodium cefuroxime, and therefore is not economical from commercial point of view.
CEFTIN (cefuroxime axetil) Tablets and CEFTIN (cefuroxime axetil) for Oral Suspension contain cefuroxime as cefuroxime axetil. CEFTIN (cefuroxime axetil) is a semisynthetic, broad-spectrum cephalosporin antibiotic for oral administration.
Chemically, cefuroxime axetil, the 1-(acetyloxy) ethyl ester of cefuroxime, is (RS)-1-hydroxyethyl (6R,7R)-7-[2-(2-furyl)glyoxyl-amido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylate, 72-(Z)-(O-methyl-oxime), 1-acetate 3-carbamate. Its molecular formula is C20H22N4O10S, and it has a molecular weight of 510.48.
Cefuroxime axetil is in the amorphous form and has the following structural formula:
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CEFTIN (cefuroxime axetil) Tablets are film-coated and contain the equivalent of 250 or 500 mg of cefuroxime as cefuroxime axetil. CEFTIN (cefuroxime axetil) Tablets contain the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hydrogenated vegetable oil, hypromellose, methylparaben, microcrystalline cellulose, propylene glycol, propylparaben, sodium benzoate, sodium lauryl sulfate, and titanium dioxide.
CEFTIN (cefuroxime axetil) for Oral Suspension, when reconstituted with water, provides the equivalent of 125 mg or 250 mg of cefuroxime (as cefuroxime axetil) per 5 mL of suspension. CEFTIN (cefuroxime axetil) for Oral Suspension contains the inactive ingredients acesulfame potassium, aspartame, povidone K30, stearic acid, sucrose, tutti-frutti flavoring, and xanthan gum.
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|
| Systematic (IUPAC) name | |
|---|---|
| 1-Acetoxyethyl (6R,7R)-3-[(carbamoyloxy)methyl]-7-{[(2Z)-2-(2-furyl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | |
| Clinical data | |
| Identifiers | |
| PubChem | CID 6321416 |
| ChemSpider | 4882027 |
| ChEMBL | CHEMBL1095930 |
| Synonyms | Cefuroxime 1-acetoxyethyl ester |
| Chemical data | |
| Formula | C20H22N4O10S |
| Mol. mass | 510.475 g/mol |
dsc
http://www.google.com/patents/US5013833
http://www.google.com/patents/US6833452
EXAMPLE 1
Dicyclohexylamine (17.2 g) in N,N-dimethylacetamide (50 ml) was added to a solution of cefuroxime acid (42.4 g) in N,N-dimethylacetamide (300 ml) at about −10° C. (R,S)1-Acetoxethylbromide (33.4 g) in N,N-dimethylacetamide (50 ml) was added to the above solution and the reaction mixture was stirred for 45 minutes at about −3 to 0° C. Potassium carbonate (1.1 g) was added to the reaction mixture and it was further stirred at that temperature for about 4 hours. The reaction mixture was worked up by pouring into it ethyl acetate (1.0 It), water (1.2 It) and dilute hydrochloric acid (3.5% w/w, 200 ml). The organic layer was separated and the aqueous layer was again extracted with ethyl acetate. The combined organic extracts were washed with water, dilute sodium bicarbonate solution (1%), sodium chloride solution and evaporated in vacuo to give a residue. Methanol was added to the residue and the crude product was precipitated by adding water.
The resulting precipitate was filtered off and recrystallized from the mixture of ethylacetate, methanol and hexane. The precipitated product was filtered, washed and dried to give pure crystalline cefuroxime axetil (42.5 g).
Assay (by HPLC on anhydrous basis)-98.2% w/w; Diastereoisomer ratio-0.53; Total related substances-0.48% w/w.
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http://www.google.com/patents/EP1409492B1?cl=en
BACKGROUND OF THE INVENTION
Example – 1
Without use of GrouplI
II metal phosphate and C1-4 alcohol
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5-18-2005
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Intermediates in cephalosporin production
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12-22-2004
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Process for the preparation of highly pure crystalline (R,S)-cefuroxime axetil
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| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| US5847118 * | Jul 25, 1997 | Dec 8, 1998 | Apotex, Inc. | Methods for the manufacture of amorphous cefuroxime axetil |
| US6060599 * | Jun 17, 1998 | May 9, 2000 | Ranbaxy Laboratories Limited | Process for the preparation of cefuroxime axetil in an amorphous form |
| US6107290 * | Sep 16, 1999 | Aug 22, 2000 | Hammi Pharm Co., Ltd. | Non-crystalline cefuroxime axetil solid dispersant, process for preparing same and composition for oral administration thereof |
| US6323193 | Aug 21, 2000 | Nov 27, 2001 | Ranbaxy Laboratories Limited | Bioavailable oral dosage form of cefuroxime axetil |
| US6384213 | May 19, 2000 | May 7, 2002 | Ranbaxy Laboratories Limited | Process for preparing a pure, pharmacopoeial grade amorphous form of cefuroxime axetil |
| US6534494 | Jan 27, 1999 | Mar 18, 2003 | Ranbaxy Laboratories Limited | Process for the preparation of cefuroxime axetil in an amorphous form |
| US6833452 | Jul 16, 2001 | Dec 21, 2004 | Ranbaxy Laboratories Limited | Process for the preparation of highly pure crystalline (R,S)—cefuroxime axetil |
| US6911441 * | Dec 16, 2002 | Jun 28, 2005 | Akzo Nobel N.V. | Prolonged release pharmaceutical composition |
| US7507813 | Jul 22, 2005 | Mar 24, 2009 | Nanomaterials Technology Pte Ltd. | Amorphous cefuroxime axetil and preparation process therefore |
| CN1909889B | Jan 10, 2005 | Jun 2, 2010 | 韩美药品株式会社 | Cefuroxime axetil granule and process for the preparation thereof |
| EP1619198A1 * | Jul 14, 2005 | Jan 25, 2006 | Nanomaterials Technology Pte Ltd | Amorphous cefuroxime axetil and preparation process therefore |
| WO1999065919A1 * | Jan 27, 1999 | Dec 23, 1999 | Ranbaxy Lab Ltd | Process for the preparation of cefuroxime axetil in an amorphous form |
| WO2001010410A1 * | Jul 25, 2000 | Feb 15, 2001 | Hanmi Pharm Ind Co Ltd | Non-crystalline cefuroxime axetil solid dispersant, process for preparing same and composition for oral administration thereof |
| WO2003014126A1 * | Aug 1, 2002 | Feb 20, 2003 | Marco Alpegiani | Process for the preparation of highly pure cefuroxime axetil |
| WO2005065658A1 * | Jan 10, 2005 | Jul 21, 2005 | Hee Chul Chang | Cefuroxime axetil granule and process for the preparation thereof |
