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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Prabotulinumtoxin A, プラボツリナムトキシンA

>Botulinum Toxin Type A Sequence

Prabotulinumtoxin A



Mol weight

AGN 191622 / ANT-1207 / ANT-1401 / ANT-1403 / NT 201

        • APPROVED , FDA 2019, Jeuveau, 2019/2/1

Image result for Prabotulinumtoxina

  • Purified botulinum toxin from Clostridium botulinum, purified from culture via dialysis and acid precipitation.
  • Originator Daewoong Pharmaceutical
  • Developer Daewoong Pharmaceutical; Evolus
  • Class Analgesics; Antidepressants; Antimigraines; Antispasmodics; Bacterial proteins; Bacterial toxins; Botulinum toxins; Eye disorder therapies; Muscle relaxants; Skin disorder therapies; Urologics
  • Mechanism of Action Acetylcholine inhibitors; Glutamate antagonists; Membrane transport protein modulators; Neuromuscular blocking agents
  • Marketed Glabellar lines
  • Phase III Muscle spasticity
  • Phase II/III Blepharospasm; Facial wrinkles
  • 27 Feb 2019 Evolus plans to launch prabotulinumtoxin A for Glabellar lines in USA (IM)
  • 01 Feb 2019 Registered for Glabellar lines in USA (IM)
  • 26 Nov 2018 Daewoong Pharmaceutical expects to launch prabotulinumtoxin A for Glabellar lines in eight Middle Eastern countries, including UAE and Kuwait in 2018 (Parenteral)
  • AbobotulinumtoxinA
  • Botulinum A neurotoxin
  • Botulinum toxin A
  • Botulinum toxin type A
  • BTX-A
  • Evabotulinumtoxina
  • IncobotulinumtoxinA
  • OnabotulinumtoxinA
  • Prabotulinumtoxin A
  • Toxina botulínica A
  • Toxine botulinique A

For the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia. Also for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents and for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above. Also used cosmetically to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) as well as for the treatment of excessive underarm sweating.

Botulinum toxin (BTX) is a neurotoxic protein produced by the bacterium Clostridium botulinum and related species.[1] It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction and thus causes flaccid paralysis.[2]Infection with the bacterium causes the disease botulism. The toxin is also used commercially in medicine, cosmetics and research.

Botulinum is the most acutely lethal toxin known, with an estimated human median lethal dose (LD50) of 1.3–2.1 ng/kg intravenously or intramuscularly and 10–13 ng/kg when inhaled.[3][clarification needed]

There are eight types of botulinum toxin, named type A–H. Types A and B are capable of causing disease in humans, and are also used commercially and medically.[4] Types C–G are less common; types E and F can cause disease in humans, while the other types cause disease in other animals.[5] Type H is considered the deadliest substance in the world – an injection of only 2 ng can cause death to an adult.[6] Botulinum toxin types A and B are used in medicine to treat various muscle spasms and diseases characterized by overactive muscle. Commercial forms are marketed under the brand names Botox and Dysport, among others.[7][8]

Medical uses

Botulinum toxin is used to treat a number of problems.

Muscle spasticity

Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including post-stroke spasticity, post-spinal cord injury spasticity, spasms of the head and neck,[9] eyelid,[10] vagina,[11] limbs, jaw, and vocal cords.[12] Similarly, botulinum toxin is used to relax clenching of muscles, including those of the oesophagus,[13] jaw,[14]lower urinary tract and bladder,[15] or clenching of the anus which can exacerbate anal fissure.[16] It may also be used for improper eye alignment.[17] Botulinum toxin appears to be effective for refractory overactive bladder.[18]

Other muscle disorders

Strabismus is caused by imbalances in the actions of muscles that rotate the eyes, and can sometimes be relieved by weakening a muscle that pulls too strongly, or pulls against one that has been weakened by disease or trauma. Muscles weakened by toxin injection recover from paralysis after several months, so it might seem that injection would then need to be repeated. However, muscles adapt to the lengths at which they are chronically held,[19] so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect. If there is good binocular vision, the brain mechanism of motor fusion, which aligns the eyes on a target visible to both, can stabilize the corrected alignment.

In January 2014, botulinum toxin was approved by UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for treatment of restricted ankle motion due to lower limb spasticity associated with stroke in adults.[20]

On July 29, 2016, Food and Drug Administration (FDA), of the United States of America approved abobotulinumtoxinA for injection for the treatment of lower limb spasticity in pediatric patients two years of age and older.[21] AbobotulinumtoxinA is the first and only FDA-approved botulinum toxin for the treatment of pediatric lower limb spasticity. In the United States of America, the FDA approves the text of the labels of prescription medicines. The FDA approves which medical conditions the drug manufacturer may sell the drug for. However, those approved by the FDA to prescribe these drugs may freely prescribe them for any condition they wish, called off-label use. Botulinum toxins have been used off-label for several pediatric conditions, including infantile esotropia.[22]

Excessive Sweating

Khalaf Bushara and David Park were the first to demonstrate a nonmuscular use of BTX-A while treating patients with hemifacial spasm in England in 1993, showing that botulinum toxin injections inhibit sweating, and so are useful in treating hyperhidrosis (excessive sweating).[23] BTX-A has since been approved for the treatment of severe primary axillary hyperhidrosis (excessive underarm sweating of unknown cause), which cannot be managed by topical agents.[12][24]


In 2010, the FDA approved intramuscular botulinum toxin injections for prophylactic treatment of chronic migraine headache.[25]


Botulinum toxin injected in human face

In cosmetic applications, botulinum toxin is considered safe and effective for reduction of facial wrinkles, especially in the uppermost third of the face.[26] Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin.[26] Smoothing of wrinkles is usually visible three days after treatment and is maximally visible two weeks following injection.[26] The treated muscles gradually regain function, and generally return to their former appearance three to four months after treatment.[26] Muscles can be treated repeatedly to maintain the smoothed appearance.[26]


Botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating,[24] neuropathic pain,[27] and some allergysymptoms.[12] In addition to these uses, botulinum toxin is being evaluated for use in treating chronic pain.[28]

Side effects

While botulinum toxin is generally considered safe in a clinical setting, there can be serious side effects from its use. Most commonly, botulinum toxin can be injected into the wrong muscle group or spread from the injection site, causing paralysis of unintended muscles.

Side effects from cosmetic use generally result from unintended paralysis of facial muscles. These include partial facial paralysis, muscle weakness, and trouble swallowing. Side effects are not limited to direct paralysis however, and can also include headaches, flu-like symptoms, and allergic reactions.[29] Just as cosmetic treatments only last a number of months, paralysis side-effects can have the same durations.[citation needed] At least in some cases, these effects are reported to dissipate in the weeks after treatment.[citation needed] Bruising at the site of injection is not a side effect of the toxin but rather of the mode of administration, and is reported as preventable if the clinician applies pressure to the injection site; when it occurs, it is reported in specific cases to last 7–11 days.[citation needed] When injecting the masseter muscle of the jaw, loss of muscle function can result in a loss or reduction of power to chew solid foods.[29]

Side effects from therapeutic use can be much more varied depending on the location of injection and the dose of toxin injected. In general, side effects from therapeutic use can be more serious than those that arise during cosmetic use. These can arise from paralysis of critical muscle groups and can include arrhythmiaheart attack, and in some cases seizures, respiratory arrest, and death.[29] Additionally, side effects which are common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes.[29]

In response to the occurrence of these side effects, in 2008 the U.S. Food and Drug Administration notified the public of the potential dangers of the botulinum toxin as a therapeutic. Namely, they warned that the toxin can spread to areas distant from the site of injection and paralyze unintended muscle groups, especially when used for treating muscle spasticity in children treated for cerebral palsy.[30] In 2009, the FDA announced that boxed warnings would be added to available botulinum toxin products, warning of their ability to spread from the injection site.[31] Additionally, the FDA announced name changes to several botulinum toxin products, meant to emphasize that the products are not interchangeable and require different doses for proper use. Botox and Botox Cosmetic were renamed onabotulinumtoxinA, Myobloc was renamed rimabotulinumtoxinB, and Dysport name renamed abobotulinumtoxinA.[31] In conjunction with this, the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each.[32] A similar warning was issued by Health Canada in 2009, warning that botulinum toxin products can spread to other parts of the body.[33]

Role in disease

Botulinum toxin produced by Clostridium botulinum is the cause of botulism.[10] Humans most commonly ingest the toxin from eating improperly-canned foods in which C. botulinumhas grown. However, the toxin can also be introduced through an infected wound. In infants, the bacteria can sometimes grow in the intestines and produce botulinum toxin within the intestine and can cause a condition known as floppy baby syndrome.[34] In all cases, the toxin can then spread, blocking nerves and muscle function. In severe cases, the toxin can block nerves controlling the respiratory system or heart, resulting in death.[1] Botulism can be difficult to diagnose, as it may appear similar to diseases such as Guillain–Barré syndromemyasthenia gravis, and stroke. Other tests, such as brain scan and spinal fluid examination, may help to rule out other causes. If the symptoms of botulism are diagnosed early, various treatments can be administered. In an effort to remove contaminated food which remains in the gut, enemas or induced vomiting may be used.[35] For wound infections, infected material may be removed surgically.[35] Botulinum antitoxin is available and may be used to prevent the worsening of symptoms, though it will not reverse existing nerve damage. In severe cases, mechanical respiration may be used to support patients suffering from respiratory failure.[35] The nerve damage heals over time, generally over weeks to months.[5] With proper treatment, the case fatality rate for botulinum poisoning can be greatly reduced.[35]

Two preparations of botulinum antitoxins are available for treatment of botulism. Trivalent (A,B,E) botulinum antitoxin is derived from equine sources using whole antibodies. The second antitoxin is Heptavalent (A,B,C,D,E,F,G) botulinum antitoxin, which is derived from equine antibodies which have been altered to make them less immunogenic. This antitoxin is effective against all known strains of botulism.

Mechanism of action

Target molecules of botulinum neurotoxin (abbreviated BoNT) and tetanus neurotoxin (TeNT), toxins acting inside the axon terminal.[36]

Botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. First, the toxin binds specifically to nerves which use the neurotransmitter acetylcholine. Once bound to the nerve terminal, the neuron takes up the toxin into a vesicle by receptor-mediated endocytosis.[37] As the vesicle moves farther into the cell, it acidifies, activating a portion of the toxin which triggers it to push across the vesicle membrane and into the cell cytoplasm.[1] Once inside the cytoplasm, the toxin cleaves SNARE proteins, meaning that the acetylcholine vesicles can’t bind to the intracellular cell membrane,[37] preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signaling, leading to paralysis.[1]

The toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases.[12] The active form consists of a two-chain protein composed of a 100-kDa heavy chain polypeptide joined via disulfide bond to a 50-kDa light chain polypeptide.[38] The heavy chain contains domains with several functions: it has the domain responsible for binding specifically to presynaptic nerve terminals, as well as the domain responsible for mediating translocation of the light chain into the cell cytoplasm as the vacuole acidifies.[1][38] The light chain is a zinc metalloprotease and is the active part of the toxin. It is translocated into the host cell cytoplasm where it cleaves the host protein SNAP-25, a member of the SNARE protein family which is responsible for fusion. The cleaved SNAP-25 is unable to mediate fusion of vesicles with the host cell membrane, thus preventing the release of the neurotransmitteracetylcholine from axon endings.[1] This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell.[1]

The seven toxin types (A-G) have different tertiary structures and sequence differences.[38][39] While the different toxin types all target members of the SNARE family, different toxin types target different SNARE family members.[36] The A, B, and E serotypes cause human botulism, with the activities of types A and B enduring longest in vivo (from several weeks to months).[38]


In 1820, Justinus Kerner, a small-town German medical officer and romantic poet, gave the first complete description of clinical botulism based on extensive clinical observations of so-called “sausage poisoning”.[40] Following experiments on animals and on himself, he concluded that the toxin acts by interrupting signal transmission in the somatic and autonomic motor systems, without affecting sensory signals or mental functions. He observed that the toxin develops under anaerobic conditions, and can be lethal in minute doses.[41] His prescience in suggesting that the toxin might be used therapeutically earned him recognition as the pioneer of modern botulinum toxin therapy.[42]

In 1895 (seventy-five years later), Émile van Ermengem, professor of bacteriology and a student of Robert Koch, correctly described Clostridium botulinum as the bacterial source of the toxin. Thirty-four attendees at a funeral were poisoned by eating partially salted ham, an extract of which was found to cause botulism-like paralysis in laboratory animals. Van Ermengem isolated and grew the bacterium, and described its toxin,[43] which was later purified by P Tessmer Snipe and Hermann Sommer.[44]

Food canning

Over the next three decades, 1895-1925, as food canning was approaching a billion-dollar-a-year industry, botulism was becoming a public health hazard. Karl Friedrich Meyer, a prodigiously productive Swiss-American veterinary scientist created a center at the Hooper Foundation in San Francisco, where he developed techniques for growing the organism and extracting the toxin, and conversely, for preventing organism growth and toxin production, and inactivating the toxin by heating. The California canning industry was thereby preserved.

World War II

With the outbreak of World War II, weaponization of botulinum toxin was investigated at Fort Detrick in Maryland. Carl Lamanna and James Duff[45] developed the concentration and crystallization techniques that Edward J. Schantz used to create the first clinical product. When the Army’s Chemical Corps was disbanded, Schantz moved to the Food Research Institute in Wisconsin, where he manufactured toxin for experimental use and generously provided it to the academic community.

The mechanism of botulinum toxin action – blocking the release from nerve endings of the neurotransmitter acetylcholine – was elucidated in the mid-1900s,[46] and remains an important research topic. Nearly all toxin treatments are based on this effect in various body tissues.


Ophthalmologists specializing in eye muscle disorders (strabismus) had developed the method of EMG-guided injection (using the electromyogram, the electrical signal from an activated muscle, to guide injection) of local anesthetics as a diagnostic technique for evaluating an individual muscle’s contribution to an eye movement.[47] Because strabismus surgery frequently needed repeating, a search was undertaken for non-surgical, injection treatments using various anesthetics, alcohols, enzymes, enzyme blockers, and snake neurotoxins. Finally, inspired by Daniel Drachman’s work with chicks at Johns Hopkins,[48] Alan B. Scott and colleagues injected botulinum toxin into monkey extraocular muscles.[49]The result was remarkable: a few picograms induced paralysis that was confined to the target muscle, long in duration, and without side-effects.

After working out techniques for freeze-drying, buffering with albumin, and assuring sterility, potency, and safety, Scott applied to the FDA for investigational drug use, and began manufacturing botulinum type A neurotoxin in his San Francisco lab. He injected the first strabismus patients in 1977, reported its clinical utility in 1980,[50] and had soon trained hundreds of ophthalmologists in EMG-guided injection of the drug he named Oculinum (“eye aligner”).

In 1986, Oculinum Inc, Scott’s micromanufacturer and distributor of botulinum toxin, was unable to obtain product liability insurance, and could no longer supply the drug. As supplies became exhausted, patients who had come to rely on periodic injections became desperate. For 4 months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections.[51]

Based on data from thousands of patients collected by 240 investigators, Allergan received FDA approval in 1989 to market Oculinum for clinical use in the United States to treat adult strabismus and blepharospasm, using the trademark Botox.[52] This was under the 1983 US Orphan Drug Act.[53]


Richard Clark, a plastic surgeon from Sacramento (CA), was the first to document a cosmetic use for botulinum toxin.[54] He treated forehead asymmetry caused by left sided forehead nerve paralysis that occurred during a cosmetic facelift. Since the injured nerve could possibly regenerate by 24 months, a two-year waiting period was necessary before definitive surgical treatment could be done. Clark realized that botulinum toxin, which had been previously used only for cross eyed babies and facial tics, could also be injected to smooth the wrinkles of the right forehead to match her paralyzed left. He received FDA approval for this cosmetic application of the toxin and successfully treated the person and published the case study in 1989.[54]

Marrying ophthalmology to dermatology, Jean and Alistair Carruthers observed that blepharospasm patients who received injections around the eyes and upper face also enjoyed diminished facial glabellar lines (“frown lines” between the eyebrows), thereby initiating the highly-popular cosmetic use of the toxin.[55] Brin, and a group at Columbia University under Monte Keen made similar reports.[56] In 2002, following clinical trials, the FDA approved Botox Cosmetic, botulinum A toxin to temporarily improve the appearance of moderate-to-severe glabellar lines.[57] The FDA approved a fully in vitro assay for use in the stability and potency testing of Botox in response to increasing public concern that LD50testing was required for each batch sold in the market.[58][59]

Chronic pain

William J. Binder reported in 2000 that patients who had cosmetic injections around the face reported relief from chronic headache.[60] This was initially thought to be an indirect effect of reduced muscle tension, but it is now known that the toxin inhibits release of peripheral nociceptive neurotransmitters, suppressing the central pain processing systems responsible for migraine headache.[61][62]

Society and culture


As of 2013, botulinum toxin injections are the most common cosmetic operation, with 6.3 million procedures in the United States, according to the American Society of Plastic Surgeons. Qualifications for Botox injectors vary by county, state and country. Botox cosmetic providers include dermatologists, plastic surgeons, aesthetic spa physicians, dentists, nurse practitioners, nurses and physician assistants.

The global market for botulinum toxin products, driven by their cosmetic applications, is forecast to reach $2.9 billion by 2018. The facial aesthetics market, of which they are a component, is forecast to reach $4.7 billion ($2 billion in the U.S.) in the same timeframe.[63]


Botulinum toxin has been recognized as a potential agent for use in bioterrorism.[64] It can be absorbed through the eyes, mucous membranes, respiratory tract, or non-intact skin.[65]

The effects of botulinum toxin are different from those of nerve agents involved insofar in that botulism symptoms develop relatively slowly (over several days), while nerve agent effects are generally much more rapid and can be instantaneous.[citation needed] Evidence suggests that nerve exposure (simulated by injection of atropine and pralidoxime) will increase mortality by enhancing botulinum toxin’s mechanism of toxicity.[citation needed]

With regard to detection, current protocols using NBC detection equipment (such as M-8 paper or the ICAM) will not indicate a “positive” when samples containing botulinum toxin are tested.[citation needed] To confirm a diagnosis of botulinum toxin poisoning, therapeutically or to provide evidence in death investigations, botulinum toxin may be quantitated by immunoassay of human biological fluids; serum levels of 12–24 mouse LD50 units per milliliter have been detected in poisoned patients.[66]

The Japanese doomsday cult Aum Shinrikyo produced botulinum toxin and spread it as an aerosol in downtown Tokyo during the 1990s, but the attacks caused no fatalities.[67]

During the early 1980s, the German and French newspapers reported that the police had raided a Baader-Meinhof gang safe house in Paris and had found a makeshift laboratory that contained flasks full of Clostridium botulinum, which makes botulinum toxin. Their reports were later found to be incorrect; no such lab was ever found.[68]

Brand names

Botulinum toxin A is marketed under the brand names Botox and Xeomin. Botulinum toxin B is marketed under the brand name Myobloc.

In the United States, botulinum toxin products are manufactured by a variety of companies, for both therapeutic and cosmetic use. A U.S. supplier reported in its company materials in 2011 that it could “supply the world’s requirements for 25 indications approved by Government agencies around the world” with less than one gram of raw botulinum toxin.[69]Myobloc or Neurobloc, a botulinum toxin type B product, is produced by Solstice Neurosciences, a subsidiary of US WorldMeds. AbobotulinumtoxinA), a therapeutic formulation of the type A toxin manufactured by Galderma in the United Kingdom, is licensed for the treatment of focal dystonias and certain cosmetic uses in the U.S. and other countries.[32]

Besides the three primary U.S. manufacturers, there are numerous other botulinum toxin producers. Xeomin, manufactured in Germany by Merz, is also available for both therapeutic and cosmetic use in the U.S.[70] Lanzhou Institute of Biological Products in China manufactures a BTX-A product; as of 2014 it was the only BTX-A approved in China.[70] BTX-A is also sold as Lantox and Prosigne on the global market.[71] Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea in 2009;[72]

Toxin production

Botulism toxins are produced by bacteria of the genus Clostridium, namely Clostridium botulinumC. butyricum, C. baratii and C. argentinense,[73] which are widely distributed, including in soil and dust. As well, the bacteria can be found inside homes on floors, carpet, and countertops even after cleaning.[citation needed] Some food products such as honey can contain amounts of the bacteria.[citation needed]

Food-borne botulism results, indirectly, from ingestion of food contaminated with Clostridium spores, where exposure to an anaerobic environment allows the spores to germinate, after which the bacteria can multiply and produce toxin.[citation needed] Critically, it is ingestion of toxin rather than spores or vegetative bacteria that causes botulism.[citation needed]Botulism is nevertheless known to be transmitted through canned foods not cooked correctly before canning or after can opening, and so is preventable.[citation needed] Infant botulism cases arise chiefly as a result of environmental exposure and are therefore more difficult to prevent.[citation needed] Infant botulism arising from consumption of honey can be prevented by eliminating honey from diets of children less than 12 months old.[74]

Organism and toxin susceptibilities

Proper refrigeration at temperatures below 3 °C (38 °F) retards the growth of Clostridium botulinum. The organism is also susceptible to high salt, high oxygen, and low pH levels.[5]The toxin itself is rapidly destroyed by heat, such as in thorough cooking.[75] The spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.[76]

The botulinum toxin is denatured and thus deactivated at temperatures greater than 80 °C (176 °F).[77] As a zinc metalloprotease (see below), the toxin’s activity is also susceptible, post-exposure, to inhibition by protease inhibitors, e.g., zinc-coordinating hydroxamates.[38][78]


Blepharospasm and strabismus

University-based ophthalmologists in the USA and Canada further refined the use of botulinum toxin as a therapeutic agent. By 1985, a scientific protocol of injection sites and dosage had been empirically determined for treatment of blepharospasm and strabismus.[79] Side effects in treatment of this condition were deemed to be rare, mild and treatable.[80]The beneficial effects of the injection lasted only 4–6 months. Thus, blepharospasm patients required re-injection two or three times a year.

In 1986, Scott’s micromanufacturer and distributor of Botox was no longer able to supply the drug because of an inability to obtain product liability insurance. Patients became desperate, as supplies of Botox were gradually consumed, forcing him to abandon patients who would have been due for their next injection. For a period of four months, American blepharospasm patients had to arrange to have their injections performed by participating doctors at Canadian eye centers until the liability issues could be resolved.[51]

In December 1989, Botox was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old.[52]

Botox has not been approved for any pediatric use.[32] It has, however, been used off-label by physicians for several conditions. including spastic conditions in pediatric patients with cerebral palsy, a therapeutic course that has resulted in patient deaths.[32] In the case of treatment of infantile esotropia in patients younger than 12 years of age, several studies have yielded differing results.[22][better source needed]


The cosmetic effect of BTX-A on wrinkles was originally documented by a plastic surgeon from Sacramento, California, Richard Clark, and published in the journal Plastic and Reconstructive Surgery in 1989.[54] Canadian husband and wife ophthalmologist and dermatologist physicians, JD and JA Carruthers, were the first to publish a study on BTX-A for the treatment of glabellar frown lines in 1992.[55] Similar effects had reportedly been observed by a number of independent groups (Brin, and the Columbia University group under Monte Keen.[56]) After formal trials, on April 12, 2002, the FDA announced regulatory approval of botulinum toxin type A (Botox Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines).[57] Subsequently, cosmetic use of botulinum toxin type A has become widespread.[81] The results of Botox Cosmetic can last up to four months and may vary with each patient.[82] The US Food and Drug Administration approved an alternative product-safety testing method in response to increasing public concern that LD50 testing was required for each batch sold in the market.[58][59]

BTX-A has also been used in the treatment of gummy smiles,[83][84] the material is injected into the hyperactive muscles of upper lip, which causes a reduction in the upward movement of lip thus resulting in a smile with a less exposure of gingiva.[85] Botox is usually injected in the three lip elevator muscles that converge on the lateral side of the ala of the nose; the levator labii superioris (LLS), the levator labii superioris alaeque nasi muscle (LLSAN), and the zygomaticus minor (ZMi).[86][87]

Upper motor neuron syndrome

BTX-A is now a common treatment for muscles affected by the upper motor neuron syndrome (UMNS), such as cerebral palsy, for muscles with an impaired ability to effectively lengthen. Muscles affected by UMNS frequently are limited by weakness, loss of reciprocal inhibition, decreased movement control and hypertonicity (including spasticity). In January 2014, Botulinum toxin was approved by UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of ankle disability due to lower limb spasticity associated with stroke in adults.[20] Joint motion may be restricted by severe muscle imbalance related to the syndrome, when some muscles are markedly hypertonic, and lack effective active lengthening. Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, so improved ability to move and exercise.


Khalaf Bushara and David Park were the first to demonstrate a nonmuscular use of BTX-A while treating patients with hemifacial spasm in England in 1993, showing that botulinum toxin injections inhibit sweating, and so are useful in treating hyperhidrosis (excessive sweating).[23] BTX-A has since been approved for the treatment of severe primary axillary hyperhidrosis (excessive underarm sweating of unknown cause), which cannot be managed by topical agents.[12][24]

Cervical dystonia

BTX-A is commonly used to treat cervical dystonia, but it can become ineffective after a time. Botulinum toxin type B (BTX-B) received FDA approval for treatment of cervical dystonia on December 21, 2000. Trade names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.[70]

Chronic migraine

Onabotulinumtoxin A (trade name Botox) received FDA approval for treatment of chronic migraines on October 15, 2010. The toxin is injected into the head and neck to treat these chronic headaches. Approval followed evidence presented to the agency from two studies funded by Allergan showing a very slight improvement in incidence of chronic migraines for migraine sufferers undergoing the Botox treatment.[88][89]

Since then, several randomized control trials have shown botulinum toxin type A to improve headache symptoms and quality of life when used prophylactically for patients with chronic migraine[90] who exhibit headache characteristics consistent with: pressure perceived from outside source, shorter total duration of chronic migraines (<30 years), “detoxification” of patients with coexisting chronic daily headache due to medication overuse, and no current history of other preventive headache medications.[91]


A few small trials have found benefits in people with depression.[92][93]

Premature ejaculation

The drug is under development for the treatment of premature ejaculation.[93]


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  93. Jump up to:a b

External links

Botulinum toxin A
Cartoon representation of Botulinum toxin. PDB entry 3BTA
Clinical data
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IM (approved), SC, intradermal, into glands
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Legal status
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ECHA InfoCard 100.088.372 Edit this at Wikidata
Chemical and physical data
Formula C6760H10447N1743O2010S32
Molar mass 149 kg/mol (149,321g/mol) g·mol−1
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////////////Prabotulinumtoxin A, プラボツリナムトキシンA ,APPROVED , FDA 2019, Jeuveau, AGN 191622,  ANT-1207ANT-1401ANT-1403NT 201

Cetilistat, セチリスタット


ChemSpider 2D Image | Cetilistat | C25H39NO3

Cetilistat, セチリスタット

  • Molecular FormulaC25H39NO3
  • Average mass401.582 Da
CAS 282526-98-1
282526-98-1 [RN]
4H-3,1-Benzoxazin-4-one, 2-(hexadecyloxy)-6-methyl
ATL-962; ATL962;ATL 962
Trade Name:Oblean®
MOA:Pancreatic lipase inhibitor
Status:Approved, 2013-09-20 JAPAN,  Japan PMDA.
Company:Norgine (Originator) , Takeda
Image result for Cetilistat
UPDATE 09.07.2021 INDIA CDSCO For the treatment of Obseity (limited to
patients with both type 2 diabetes mellitus
and dyslipidaemia, and with a BMI ≥ 25
kg/m2 inspite of dietary treatment and /or
excersise therapy)…………Cetilistat bulk and Cetilistat 120 mg tablets 

Cetilistat was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on September 20, 2013. It was developed by Norgine and Takeda, then marketed as Oblean® by Takeda in Japan.

Cetilistat is a pancreatic lipase inhibitor, and it acts in the same way as the older drug orlistat (Xenical) by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested. It is usually used for the treatment of obesity (limited to patients with both type 2 diabetes mellitus and dyslipidemia, and with a BMI≥25 kg/m2 in spite of dietary treatment and/or exercise therapy).

Oblean® is available as tablet for oral use, containing 120 mg of free Cetilistat. The recommended dose is 120 mg three times a day immediately after each meal.

Cetilistat is a drug designed to treat obesity. It acts in the same way as the older drug orlistat (Xenical) by inhibitingpancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.[1]

In human trials, cetilistat was shown to produce similar weight loss to orlistat, but also produced similar side effects such as oily, loose stools, fecal incontinence, frequent bowel movements, and flatulence.[2][3] It is likely that the same precautions would apply in that absorption of fat-soluble vitamins and other fat-soluble nutrients may be inhibited, requiring vitamin supplements to be used to avoid deficiencies.

Central obesity have an important impact on the development of risk factors for coronary heart disease, including dislipidemia, glucose intolerance, insulin resistance and hypertension. These factors contribute to building cardiovascular (CV) disease as a major cause of death. The approach to obesity therapy should be designed to reduce CV risk and mortality. Diet and lifestyle changes remain the cornerstones of therapy for obesity, but the resultant weight loss is often small and long-term success is uncommon and disappointing. Drug therapy is considered for individuals with a body mass index greater than 30 kg/m2 or ranging from 25 to 30 kg/m2 if they have comorbid conditions. Antiobesity agents can be helpful to some patients in achieving and maintaining meaningful weight loss, but yet our pharmaceutical tools are of limited effectiveness considering the magnitude of the problem. At the present, only two drugs, orlistat and sibutramine, are approved for long-term treatment of obesity and promote no more than 5 to 10% of weight loss.

Rimonabant, a cannabinoid-1 receptor antagonist, was withdrawn from the market because of concerns about its safety, including risk of suicidal and seizures, although very effective in promoting clinically meaningful weight loss, reduction in waist circumference, and improvements in several metabolic risk factors, rimonabant, a cannabinoid-1 receptor antagonist was withdrawn from the market because it concerns about its safety, including risk of suicidal and seizures. Fortunately, recent fundamental insights into the neuroendocrine mechanisms regulating body weight provide an expanding list of molecular targets for novel, rationally designed antiobesity drugs. In this review, the therapeutic potential of some antiobesity molecules in the development will be analyzed based on an understanding of energy homeostasis.

Image result for CetilistatImage result for Cetilistat

Cetilistat has completed Phase 1 and 2 trials in the West and is currently in Phase 3 trials in Japan where it is partnered with Takeda.[4] Norgina BV has now acquired the full global rights to cetilistat from Alizyme after the latter went into administration.[5]

A published phase 2 trial found cetilistat significantly reduced weight with and was better tolerated than orlistat.[6

Image result for Cetilistat

Image result for Cetilistat


Cetilistat (Oblean®)
Cetilistat is a selective pancreatic lipase inhibitor which was approved in Japan in September 2013
for the treatment of obesity. The drug was discovered by Alizyme PLC and later co-developed with
Takeda. Cetilistat demonstrated a lower incidence of adverse gastrointestinal events during a 12 week clinical trial, and the degree of weight loss associated with cetilistat is comparable to that of other approved antiobesity therapies.30 The most likely process-scale preparation of cetilistat is described below in Scheme. 4.31
Commercially available hexadecanol (21) was treated with phosgene in THF/toluene to give the
corresponding chloroformate (22), which was immediately subjected to commercial 2-amino-5-
methylbenzoic acid (23) in pyridine. Subsequent slow addition of methyl chloroformate at room
temperature resulted in the formation of cetilistat (IV), which was produced in 31% overall yield from


30  Kopelman, P.; Groot, G. d. H.; Rissanen, A.; Rossner, S.; Toubro, S.; Palmer, R.; Hallam, R.;
Bryson, A.; Hickling, R. I. Obesity 2010, 18, 108.
31. Hodson, H. F.; Downham, R.; Mitchell, T. J.; Carr, B. J.; Dunk, C. R.; Palmer, R. M. J. US
Patent 20030027821A1, 2003.


Route 1



WO0040569A1 / US6656934B2.2. WO0040247A1 / US6624161B2.

Route 2

Carbamic ester derivatives of the general formula (1) and especially (2-carboxy-4-methylphenyl)carbamic esters of the general formula (1′)

Figure US07396952-20080708-C00004

are suitable intermediates for active pharmaceutical ingredients.

Thus, for example, hexadecyl (2-carboxy-4-methylphenyl)carbamate as compound of the formula (1′) with R═C16H33 is disclosed as an intermediate in the preparation of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one of the formula (3)

Figure US07396952-20080708-C00005

from the originally published version of WO-A 00/40569.

2-Hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one of the formula (3) is described therein as potential active ingredient for the treatment of obesity and type II diabetes.

In this originally published version of WO-A 00/40569, two synthetic routes 1 and 2 are described for preparing 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one (3), each of which starts from the 5-methyl-substituted anthranilic acid (4).

In the two-stage synthetic route 1, the 5-methyl-substituted anthranilic acid (4) is reacted with hexadecyl chloroformate (5) and subsequently with methyl chloroformate to give 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one (3), although the overall yield obtained is only 31%.

The one-stage synthetic route 2 with an excess of pyridine affords 2-hexadecyl-oxy-6-methyl-4H-3,1-benzoxazin-4-one (3) in an even lower yield of 15%.

Figure US07396952-20080708-C00006

The starting compound which is required for both the synthetic routes 1 and 2, the 5-methyl-substituted anthranilic acid (4), is not easily obtainable, however.

It is prepared by the method described in J. Org. Chem. 1952, 17, 141. This starts from p-toluidine, which is reacted with chloral hydrate and hydroxylamine hydrochloride. The resulting oxime is cyclized with acid catalysis, and subsequently the ring is cleaved again by oxidation under basic conditions.

Figure US07396952-20080708-C00007

The disadvantages of this synthesis are the low yields and the fact that only very low concentrations can be used. For this reason, this synthetic route is unattractive for an industrial reaction.

Further alternative routes known in principle for obtaining anthranilic acids are as follows:

J. Org. Chem. 1978, 43, 220 and Chem. Ber. 1909, 42, 430 disclose initial nitration of 3-cyanotoluene, then reduction of the nitro group and subsequent hydrolysis of the nitrile to the carboxylic acid.

Figure US07396952-20080708-C00008
A disadvantage of this synthesis is that the nitration of 3-cyanotoluene does not proceed selectively and therefore a further purification step is necessary. This requires additional effort and reduces the yield.
The synthesis which is described in J. Chem. Soc. Perkin I, 1973, 2940 and which starts from 3-toluic acid with subsequent nitration and reduction of the nitro group also has the same disadvantage.
The synthesis which is disclosed in Monatsh. Chem. 1920, 41, 155 and starts from 2,4-dimethyl-1-nitrobenzene is likewise unsuitable because oxidation of the methyl group next to the nitro group does not proceed selectively and therefore an elaborate separation of isomers is necessary.
Figure US07396952-20080708-C00009
EP-A 0 034 292 discloses a process for preparing optionally substituted anthranilic acids which includes a transition metal-catalysed carbonylation reaction with carbon monoxide to give an anthranilic acid derivative. This carbonylation reaction takes place in an aqueous reaction medium containing a trialkylamine and a catalyst formed from palladium and a tertiary phosphine. The anthranilic acid derivatives can be obtained by eliminating the protective group. The precursors employed for the carbonylation are obtained starting from optionally substituted anilines as shown in principle in the reaction scheme below:
Figure US07396952-20080708-C00010
EP-A 0 034 292 describes this reaction sequence of acetylation (a), halogenation (b), carbonylation (c) and subsequent elimination of the acetyl group (d) as affording the optionally substituted anthranilic acids in good yields (>80%). However, the introduction of the acetyl group is a disadvantage. This is necessary because the free anilines give only poor yields in transition metal-catalysed carbonylation reactions because of pronounced complexation [J. Org. Chem. 1981, 46, 4614-4617].
WO-A 97/28118 discloses a comparable process.

Because of the diverse difficulties, described above, associated with the known processes for preparing optionally substituted anthranilic acids and the yields, which are only unsatisfactory and thus limiting for the overall process, of the subsequent synthetic routes 1 and 2, the object of the present invention was to provide an improved process for preparing carbamic ester derivatives of the general formula (1).


EXAMPLES Example 1 Synthesis of hexadecyl 4-methylphenylcarbamate

Figure US07396952-20080708-C00027

91 g (375 mmol) of 1-hexadecanol were added to a solution of 50 g (375 mmol) of p-tolyl isocyanate in 50 ml of toluene, and the resulting solution was heated under reflux for 8 h. After cooling to room temperature and stirring at this temperature for 12 h, the precipitated solid was filtered off. The colourless solid was washed twice with 10 ml of toluene each time and then dried in vacuo. 80 g (213 mmol, 57%) of the desired carbamate were obtained in the form of a colourless solid with a melting point of 75° C. The melting point agreed with literature data (75-76° C., Microchem J. 1962, 6, 179).

1H-NMR (CDCl3, 400 MHz): δ=0.88 ppm (t, J=7.3 Hz, 3H), 1.25-1.40 (m, 26 H), 1.66 (sext, J=6.9 Hz, 2H), 2.30 (s, 3H), 4.14 (t, J=6.9 Hz, 2H), 6.53 (br, 1 H), 7.10 (d, J=7.8 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H). Elemental Analysis Showed: Calculated: C 76.8%, H 11.0%, N 3.7% Found: C 76.9%, H 11.2%, N 3.7%.

Example 2 Synthesis of hexadecyl (2-bromo-4-methylphenyl)carbamate

Figure US07396952-20080708-C00028

19 g (119 mmol) of bromine were added dropwise to a solution of 45 g (119 mmol) of the carbamate in 225 ml (235 g) of glacial acetic acid at room temperature over the course of 1 h, and then the resulting solution was stirred at room temperature for 1 h. After addition of a further 25 ml (26 g, 437 mmol) of glacial acetic acid, the reaction mixture was stirred at 40° C. for 5 h and then cooled to room temperature. The precipitated solid was filtered off and washed with 20 ml of glacial acetic acid. Drying in vacuo resulted in 40 g (88 mmol, 74%) of the desired bromo compound in the form of a colourless solid with a melting point of 57° C.

1H-NMR (CDCl3, 400 MHz): δ=0.93 ppm (t, J=6.6 Hz, 3H), 1.25-1.43 (m, 26 H), 1.73 (sext, J=6.8 Hz, 2H), 2.33 (s, 3H), 4.21 (t, J=6.7 Hz, 2H), 7.04 (br, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 8.02 (d, J=8.3 Hz, 1H). 13C-NMR (CDCl3, 100 MHz): δ=14.2 ppm, 20.4, 22.7. 25.9, 29.0, 29.3, 29.4, 29.6 (2C), 29.7 (2C), 29.8 (4C), 32.0, 65.7, 112.5, 120.3, 129.0, 132.5, 133.5, 134.1, 153.5. Elemental Analysis Showed: Calculated: C 63.4%, H 8.9%, N 3.1% Found: C 63.6%, H 8.9%, N 3.1%.

Example 3 Synthesis of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid

Figure US07396952-20080708-C00029

217.5 g (478.5 mmol) of hexadecyl (2-bromo-4-methylphenyl)carbamate, 0.5 g (0.7 mmol) of bis(triphenylphosphine)palladium dichloride and 2.5 g (9.3 mmol) of triphenylphosphine were introduced into an autoclave. The autoclave was closed, flushed with nitrogen and an oxygen-free solution of 78.1 g (565.3 mmol) of potassium carbonate in 400 ml of water is added. The autoclave is evacuated and then 2 bar of carbon monoxide are injected and heated to 115° C. The pressure is subsequently adjusted to 8 bar. After CO uptake ceases, the mixture is cooled to RT and 200 ml of toluene are added. The pH is adjusted to 2 with 2M aqueous HCl solution, and the organic phase is separated off. The aqueous phase is extracted anew with 100 ml of toluene, the organic phase is separated off, and the two toluene extracts are combined. Removal of the solvent in vacuo results in 154.9 g (369.2 mmol, 77%) of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid in the form of a pale yellow-coloured solid.

1H-NMR (CDCl3, 400 MHz): δ=0.88 ppm (t, J=6.7 Hz, 3H), 1.24-1.40 (m, 26 H), 1.70 (sext, J=6.8 Hz, 2H), 2.33 (s, 3H), 4.17 (t, J=6.8 Hz, 2H), 7.38 (d, J=8.7 Hz, 1H), 7.90 (s, 1H), 8.35 (d, J=8.6 Hz, 1H). Signal of the NH proton not identifiable.13C-NMR (CDCl3, 100 MHz): δ=14.1 ppm, 20.5, 22.7. 25.9, 29.0, 29.3, 29.4, 29.6 (2 C), 29.7 (6 C), 32.0, 65.5, 113.6, 119.0, 131.1, 131.8, 136.3, 140.1, 153.9, 172.5.

Example 4 Synthesis of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one

Figure US07396952-20080708-C00030

4.0 g (10.0 mmol) of 2-hexadecyloxycarbonylamino-5-methylbenzoic acid are introduced into 20 ml of pyridine at 0° C. under a nitrogen atmosphere, and 4.93 g (45.4 mmol) of ethyl chloroformate are added dropwise to the resulting solution at 0° C. over the course of 20 min. After the reaction mixture has been stirred at 0° C. for 1 h and at room temperature for 2 h it is added to 30 ml of ice-water. The solid is filtered off and dried in vacuo. 3.3 g (8.2 mmol, 82%) of 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one are obtained in the form of a pale yellow coloured solid with a melting point of 67° C. (literature: 72-73° C., WO 00/40569).

1H-NMR (CDCl3, 400 MHz): δ=0.86 ppm (t, J=6.6 Hz, 3H), 1.24-1.42 (m, 26 H), 1.75-1.82 (m, 2H), 2.40 (s, 3H), 4.41 (t, J=6.8 Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.51 (dd, J=8.2, 1.9 Hz, 1H), 7.90 (d, J=0.9 Hz, 1H).

The 1H-NMR data agree with the literature data from WO-A 00/40569.


cetirizine orlistat (2-methyl-6-firing sixteen -4H-3, 1- benzo ah winded -4- Korea, cetilistat) is a long-acting Alizyme developed and potent specific gastrointestinal lipase inhibitor, with the active serine site of the gastric and intestinal lumen gastric lipase and lipase membrane forms a covalent bond to inactivate the enzyme, and to reduce calorie intake, weight control therapeutic effect. The biggest advantage of the drug is not acting on the nervous system, does not affect other activity in the gastrointestinal tract, it is more secure than existing similar drugs orlistat. Its structural formula is as follows:

Figure CN104341370AD00061

West Division for the benefit of his synthesis and intermediates have been described in U.S. Patent US2007232825 and US2003027821, domestic literature orlistat no cetirizine synthesis of relevant reports.

U.S. Patent US2007232825 2-amino-5-methyl-benzoic acid starting material, direct and vilify chloroformate cetyl alcohol vinegar into the ring, get cetirizine orlistat. The reaction byproducts and more difficult W purification needs over baby gel column, resulting in a low yield, suitable for mass industrialization. Directions are as follows:

Figure CN104341370AD00062

Patent US2003027821 W toluene different acid vinegar as raw material to produce amino acid vinegar intermediate chloroformate, cetyl alcohol and vinegar reaction, after the desert generation essays glycosylation chloroformate caprolactone ring closure to give cetirizine orlistat. This method requires a great deal of glacial acetic acid, the presence of H waste discharge more harsh reaction conditions, equipment requirements, is not conducive to industrial production and other defects.

Figure CN104341370AD00063

The present invention is a W under the technical program realization:

Figure CN104341370AD00064
Figure CN104341370AD00065
Figure CN104341370AD00066
Figure CN104341370AD00071

Figure CN104341370AD00072

Figure CN104341370AD00091

Figure CN104341370AD00116

The following combination of embodiments of the present invention will be further described below.

(Sixteen essays firing oxygen-amino) -5- Preparation of 2-methyl benzoate desert vinegar; [0041] Example 1

Figure CN104341370AD00101

4. 9g H phosgene will be added to 50 blood dichloromethane firing, the temperature was lowered to OC, a solution of 2-amino-5 Desert benzoic acid methyl ester (5g) and H hexylamine (13.8 blood) dichloro A firing (20 blood) solution, the addition was complete OC to maintain 15min, warmed to room temperature the reaction mix of football.

Figure CN104341370AD00102

[0042] The 5. 26g cetyl alcohol was added to the reaction solution at room temperature the reaction of. After completion of the reaction, filtered and the filtrate was concentrated in vacuo spin dry, dry methanol residue fight starched coating, filtration, the filter cake is dried to constant weight. To give a white solid powder 9. Ig, namely 2- (sixteen essays firing oxygen-ylamino) -5-benzoic acid methyl ester desert; Yield; 85%.

2- (grilled oxygen sixteen essays) -5-methyl-benzoic acid methyl ester prepared; [0043] Example 2

Figure CN104341370AD00111

Under nitrogen blanket IOg 2- (sixteen grilled oxygen essays) -5- desert benzoic acid methyl ester was dissolved in 1,4-dioxane (50mL) and water Qiao blood), and Ilg anhydrous carbonate Bell, 1.44g methacrylic acid test, 0. 731g Pd (dppf) 2Cl2, the mixture at 105C for 3 hours. Completion of the reaction, cool down, filtered and the filtrate spin dry, the residue of anhydrous methanol wash coating, the filter cake dried to give a gray solid 6. 5g, is 2- (xvi grilled oxygen essays) -5-methyl benzoic acid methyl ester in 75% yield.

2- (grilled oxygen sixteen essays) -5-methyl-benzoic acid; [0044] Example 3

Figure CN104341370AD00112

The 7g 2- (sixteen grilled oxygen essays) -5-methyl-benzoic acid methyl ester was added to 35mL tetraammine clever furans and 7mL water mixture, adding ammonia oxidation in 20. Ig, 6 (TC reaction of the reaction is completed, the reaction mixture was concentrated, the residue was added 70mL of ice water, 6M hydrochloric suppression of 7, the filter cake was dried to constant weight to give a gray solid 6. 2g, namely 2- (sixteen firing oxygen-ylamino essays ) -5-methyl-benzoic acid, yield 92%.

Preparation of 2-methyl-6-firing sixteen -4H-3, 1- benzo Lai ah winded -4- (cetirizine Division him); 4 [0045] Example

Figure CN104341370AD00113

The 66g 2- (XVI essays firing oxo-ylamino) -5-methylbenzoic acid in 330mL of information coincidence floating in an ice bath, was slowly added dropwise 45mL chloroformate caprolactone, after the addition was complete, naturally rise to room temperature The reaction of. After completion of the reaction, the reaction solution was poured into 700mL ice water, filtered, and the filter cake was dried to constant weight to give a gray solid 56g, that is, sixteen firing-6-methyl-2- -4H-3, 1- benzo Lai ah winded -4- (cetirizine orlistat), a yield of 85%. Mass spectrum shown in Figure 2, ESI-MS〇b / z): 402 [M + Tin +; X- ray diffraction as shown in (3 consistent with the data reported in FIG patent US2012101090), analyzed as shown in Table 1, Figure 1 FIG. 2 W and W Table 1 confirm that the product was obtained as cetirizine orlistat.

[0046] Table 1

Figure CN104341370AD00114
Figure CN104341370AD00115
Figure CN104341370AD00116
Figure CN104341370AD00117
Figure CN104341370AD00118
Figure CN104341370AD00121
CJPH  2015, Vol. 46 Issue (09): 946-947    DOI: 10.16522/j.cnki.cjph.2015.09.003
Synthesis of Cetilistat
1. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050; 2. Beijing Union Pharmaceutical Factory, Beijing 102600
Cetilistat was synthesized from 2-amino-5-methylbenzoic acid and cetyl chloroformate via acylation to give 2-[[(hexadecyloxy)carbonyl]amino]-5-methylbenzoic acid, which was subjected to intramolecular dehydrationcyclization in the presence of POCl3 with an overall yield of 90% and purity over 99%. This one-pot method was simple and suitable for large-scale application.



Cetilistat, a new lipase inhibitor for the treatment of obesity – AMOGS

by R Padwal – ‎Cited by 26 – ‎Related articles

clinical trials, and the above-mentioned lipase inhibitor cetilistat, which is the focus of this review.Synthesis and SAR. Cetilistat (2-hexadecyloxy-6-methyl-4H-3 …




Taken from Ayurajan


Cetilistat | Inhibitor of Gastrointestinal Lipases | Inhibitor of Pancreatic Lipases | Anti-Obesity Drug

Cetilistat [2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one] is a novel highly lipophilic benzoxazinone that inhibits gastrointestinal (GI) and pancreatic lipases, and is chemically distinct from Orlistat [1].

Cetilistat: 2D and 3D Structure

Pancreatic lipase is the enzyme that breaks down triglycerides in the intestine. Inhibition of this enzyme ensures that triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.

In Phase I clinical trials in healthy volunteers, Cetilistat increased faecal fat excretion and was well tolerated. Cetilistat produced a clinically and statistically significant weight loss in obese patients in this short-term 12-week study. This was accompanied by significant improvements in other obesity-related parameters. Cetilistat treatment was well tolerated. The risk-benefit demonstrated in this study in terms of weight loss vs intolerable GI adverse effects shows that Cetilistat merits further evaluation for the pharmacotherapy of obesity and related disorders.

The NDA submission is based on the results of three Phase 3 clinical trials in obese patients with type 2 diabetes and dyslipidemia: a 52-week placebo-controlled, double-blind study to evaluate the efficacy and safety, and two open-label studies to evaluate safety, 24-week and 52-week respectively. The results of the 52-week placebo-controlled, double-blind study demonstrate that Cetilistat 120mg three times daily is superior to placebo in the primary endpoint, with a mean reduction in body weight from baseline of -2.776% with Cetilistat versus -1.103% with placebo (p=0.0020). Greater reduction in HbA1c and low-density lipoprotein cholesterol were also observed in patients treated with Cetilistat, compared to placebo. In all these three studies, Cetilistat showed a good safety profile and was well tolerated.

Cetilistat was approved in Japan in September 2013 for the treatment of obesity. Cetilistat (Tradename: Oblean) is approved for a dosage of 120 mg three times a day for the treatment of obesity with complications.

The drug was discovered by UK based Alizyme PLC and in 2003 Takeda acquired the rights for development and commercialisation for Japan. Norgine acquired all rights to the product from Alizyme in October 2009 [3].

Cetilistat Synthesis

US20030027821A1: It appears to be the industrial process. The yields are in the range of 30-35%.


1H NMR (Estimated) for Cetilistat

Experimental: 1H-NMR δH (400 MHz, CDCl3) 0.87 (3H, t, J 6.8, CH2CH3), 1.24-1.45 (26H, m, 13×CH2), 1.75-1.83 (2H, m, OCH2CH2), 2.41 (3H, s, ArCH3), 4.41 (2H, t, J 6.7, OCH2), 7.3 (1H, d, J 8.3, ArH), 7.51 (1H, dd, J 8.5, 2.0, ArH), 7.90 (1H, d, J 1.1, ArH); m/z (ES+) 402 (MH+); M Pt. 72-73° C.

Sideeffects: The most frequently experienced adverse events were those involving the gastrointestinal (GI) tract. The proportion of patients and the total number of GI adverse events reported in each of the active treatment groups were higher compared to the placebo group. However, GI adverse events were predominantly mild to moderate in intensity, with no evidence of a dose relationship.

The most frequently reported GI-related adverse events included increased defecation, soft stools, abdominal pain, flatulence and fatty/oily stool, which were all reported more frequently in the treatment arms compared to the placebo arm.

Faecal incontinence, flatus with discharge, oily evacuation and oily spotting occurred in only 1.8-2.8% of subjects in the active treatment arms and was not dose-related. Adverse events generally occurred on only one occasion and resolved rapidly.

Serum vitamin D, vitamin E and β-carotene levels were decreased significantly in the Cetilistat treatment arms. Generally, these reductions in vitamin levels did not take the levels outside the normal range and none required the use of vitamin supplements.


  1. Kopelman, P.; et. al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes (Lond) 2007, 31(3), 494-499.
  2. Hodson, H.; et. al. 2-Oxy-benzoxazinone derivatives for the treatment of obesity.US20030027821A1
  3. Cetilistat Approval (here).

Image result for Cetilistat

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CN1785967A * Dec 12, 2005 Jun 14, 2006 兰爱克谢斯德国有限责任公司 Process for the preparation of carbamic acid derivatives
CN103936687A * Mar 24, 2014 Jul 23, 2014 重庆东得医药科技有限公司 Method for preparing cetilistat
WO2013166037A1 * Apr 30, 2013 Nov 7, 2013 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of eye disorders
Cited Patent Filing date Publication date Applicant Title
US20030013707 6 Jul 2001 16 Jan 2003 Hodson Harold Francis 2-amino-benzoxazinone derivatives for the treatment of obesity
EP0034292A2 31 Jan 1981 26 Aug 1981 F. HOFFMANN-LA ROCHE &amp; CO. Aktiengesellschaft Process for the preparation of anthranilic acid derivatives
WO1997028118A1 30 Jan 1997 7 Aug 1997 Hoechst Celanese Corporation Process for preparing anthranilic acids
1 Chem. Ber. 1909, 42, 430.
2 J. Chem. Soc. Perkin I, 1973, 2940; Peter H. Gore et al. Friedel-Crafts Reactions, Part XXV.<SUP>1 </SUP>Acetylation and Benzoylation of Iodobenzene and of o-, m-, and p- Iodotoluenes.
3 J. Org. Chem. 1952, 17, 141 B. R. Baker et al.; “An Antimalarial Alkaloid From Hydrangea, XIV, Synthesis of 5- ,6-,7-, and 8-Monosubstituted Derivatives“.
4 J. Org. Chem. 1978, vol. 43, No. 2, 220 T.H. Fisher et al.; “Kinetic Study of the N-Bromosuccin-imide Bromination of Some 4-Substituted 3-Cyanotoluenes“.
5 J. Org. Chem. 1981, 46, 4614-4617 Donald Valentine, Jr. et al; “Practical, Catalytic Synthesis of Anthranilic Acids“.
6 Monatsch. Chem. 1920, 41, 155.
7 Thomas G. Back et al.: “Conjugate Additions of o-Iodoanilines and Methyl Anthranilates to Acetylenic Sulfones. A New Route to Quinolones Including First Syntheses of Two Alkaloids from the Medical Herb Ruta chalepensis” Journal of Organic Chemistry., Bd. 68, 2003, Seiten 2223-2233, XP002371555 USAmerican Chemical Society, Easton. Seite 2227, Spalte 1, Reaktionsschema 4 und Spalte 2, Zeile 8-Zeile 9; Seite 2231, Spalte 2, Zeile 43-Zeile 54.
8 * Yadav et al., New Journal of Chemistry (2000), 24(8), 571-573.
Citing Patent Filing date Publication date Applicant Title
US8883780 22 Apr 2010 11 Nov 2014 Norgine B.V. Crystal of a benzoxazinone compound


  1.  Yamada Y, Kato T, Ogino H, Ashina S, Kato K (2008). “Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats”. Hormone and Metabolic Research. 40 (8): 539–43. doi:10.1055/s-2008-1076699. PMID 18500680.
  2.  Kopelman, P; Bryson, A; Hickling, R; Rissanen, A; Rossner, S; Toubro, S; Valensi, P (2007). “Cetilistat (ATL-962), a novel lipase inhibitor: A 12-week randomized, placebo-controlled study of weight reduction in obese patients”. International journal of obesity (2005). 31 (3): 494–9. doi:10.1038/sj.ijo.0803446. PMID 16953261.
  3.  Padwal, R (2008). “Cetilistat, a new lipase inhibitor for the treatment of obesity”. Current opinion in investigational drugs (London, England : 2000). 9 (4): 414–21. PMID 18393108.
  4. Archived January 7, 2009, at the Wayback Machine.
  5.  Norgine acquires cetilistat
  6.  “Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical).”. Obesity. 18: 108–15. Jan 2010. doi:10.1038/oby.2009.155. PMID 19461584.
  7. Japan PMDA.


C25H39NO3 : 401.58

Systematic (IUPAC) name
CAS Number 282526-98-1 Yes
ATC code none
PubChem CID 9952916
ChemSpider 8128526 
KEGG D09208 Yes
Chemical data
Formula C25H39NO3
Molar mass 401.582 g/mol

///////////////Cetilistat, ATL-962, ATL962, ATL 962, 2013-09-20, JAPAN, APPROVED,  Japan PMDA, 282526-98-1, セチリスタット

str1 SEE

Annual Reports in Medicinal Chemistry

2014 – ‎Science

… versus vehicle-treated mice.34Noteworthy in the multistep synthesis of canagliflozin is …CETILISTAT (ANTIOBESITY)43–52 Class: Pancreatic lipase inhibitor …

Olanexidine, オラネキシジングルコン酸塩


Olanexidine Gluconate

OPB-2045G, Gluconate olanexidin,  Olanedine,  OPB-2045,  OPB 2045G, 

(Olanedine®)Approved in Japan PMDA 2015-07-03, Olanedine® by Otsuka

Image result for JAPAN ANIMATED FLAG

A disinfectant uesd to prevent of postoperative bacterial infections.


CAS .146510-36-3(Olanexidine free form), 

Imidodicarbonimidic diamide, N-((3,4-dichlorophenyl)methyl)-N’-octyl

Formula Weight: 372.341


CAS 799787-53-4(Olanexidine Gluconate)

Formula C17H27Cl2N5 ● C6H12O7

1-(3,4-Dichlorobenzyl)-5-octylbiguanide mono-D-gluconate

Olanexidine Gluconate

C17H27Cl2N5▪C6H12O7 : 568.49

Indication:Bacterial infection

Otsuka (Originator)

Image result for otsuka logo

  • Marketed Bacterial infections

Image result for Olanedine®

Most Recent Events

  • 16 Sep 2015 Launched for Bacterial infections (Prevention) in Japan (Topical)
  • 03 Jul 2015 Registered for Bacterial infections (Prevention) in Japan (Topical) – First global approval
  • 30 Sep 2014 Preregistration for Bacterial infections (Prevention) in Japan (Topical)
  • Image result for JAPAN ANIMATED FLAG


Image result for Olanexidine

Olanexidine hydrochloride [USAN]

146509-94-6 HCL
RN: 218282-71-4 HCL HYDRATE
UNII: R296398ALN

Molecular Formula, C17-H27-Cl2-N5.Cl-H.1/2H2-O

Molecular Weight, 835.6192

Imidodicarbonimidic diamide, N-((3,4-dichlorophenyl)methyl)-N’-octyl-, monohydrochloride, hydrate (2:1)


Olanexidine gluconate was approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jul 03, 2015. It was developed and marketed as Olanedine® by Otsuka in Japan.

Olanexidine gluconate is an antiseptic/disinfectant compound with potent bactericidal activity against Gram-negative and Gram-positive bacteria, for use in preparing patients for surgery and preventing of postoperative bacterial infections.

Olanedine® is available as topical solution (1.5%), containing 3 g/200 mL, 0.15 g/10 mL and 0.375 g/25 mL, and the recommendation is applying appropriate amount of the drug.


WO 2004105745

Kazuyoshi Miyata, Yasuhide Inoue, Akifumi Hagi, Motoya Kikuchi, Hitoshi Ohno, Kinji Hashimoto, Kinue Ohguro, Tetsuya Sato,Hidetsugu Tsubouchi, Hiroshi Ishikawa,Takashi Okamura, Koushi Iwata,

Otsuka Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Factory, Inc.






Example 1: l-cyano-3-n-octylguanidine

A 7.00-kg quantity of Compound (4) (54.16 mol) was dissolved in 105 liters of ethyl acetate, and the resulting mixture was cooled to 5°C or below. A 2.66-kg quantity of concentrated sulfuric acid (27.12 mol) was added thereto dropwise at a temperature of 4O0C or below while stirring. To the thus- obtained suspension of 1/2 sulfate of Compound (4) was added 5.06 kg of sodium dicyanamide (56.83 mol), and the resulting suspension was heated under reflux for 7 hours. The reaction solution was cooled to 400C or below, and 70 liters of water was added thereto. Subsequently, the resulting solution was heated to 80 to 900C (internal temperature) to distill the ethyl acetate off. The remaining liquid was cooled to 400C or below, and 70 liters of toluene was then added thereto, followed by the extraction of 1-cyano — 3-n-octyl guanidine at about 500C. The extracted toluene layer was washed with 35 liters of water at about 500C and cooled to 100C or below, followed by stirring for about 30 minutes. The resulting precipitated crystals were separated and washed with 7 liters of toluene. The resulting crystals were dried at 400C for 7.5 hours, yielding l-cyano-3-n- octylguanidine. 2007/067107


Yield: 9.11 kg (The yield was 85.7% based on the Compound(4).) White crystals having a melting point of 69 to 740C (no clear melting point was observed)

IR(KBr) spectrum: 3439, 3296, 2916, 2164, 1659, 1556, 1160, 718, and 572 cm“1

Thermogravimetric measurement/differential thermal analysis: 73.5°C (weak), an endothermic peak at 77.50C

1H-NMR(CDCl3) spectrum: 0.88 ppm (t, J = 6.6 Hz, 3H), 1.20-1.38 ppm (m, 10H), 1.43-1.62 ppm (m, 2H), 3.17 ppm (dd, J = 6.9 Hz, J = 6.0 Hz, 2H), 5.60-5.70 ppm (bs, 2H), 5.80-5.95 ppm (bs, IH)

Reference Example 2: Acidolysis of 1- (3,4-dichlorobenzyl) -5- octylbiguanide dihydrochloride

A 1-g quantity of 1- (3, 4-dichlorobenzyl) -5-octyl biguanide dihydrochloride was dissolved in 15 ml of 10% ethanol, followed by refluxing for 5 hours. HPLC analysis was conducted under the conditions described below.

The yield of 1-[N- (3,4-dichlorobenzyl) carbamoyl-3- octyl]guanidine (holding time: 9.84 minutes) was 0.91%, and the yield of 1- (N-octyl-carbamoyl) -3- (3, 4-dichlorobenzyl) guanidine

(holding time: 10.54 minutes) was 0.22%.

HPLC analysis conditions:

Column: YMC AM302 4.6 mm I. D. x 150 mm

Eluate: MeCN/0.05 M aqueous solution of sodium 1- octanesulfonate/acetic acid = 700/300/1

Detector: UV 254 nm

The physical property values of the resulting 1-[N- (3,4- dichlorobenzyl) carbamoyl-3-octyl] guanidine were as follows: NMR (DMSO-de) δ: 0.86 (3H, t, J = 6.0 Hz), 1.07-1.35 (1OH, m) , 1.35-1.49 (2H, m) , 2.95-3.15 (2H, m) , 4.12 (2H, d, J = 6.3 Hz), 6.78-7.40 (4H, m) , 7.23 (IH, dd, J = 2.1 Hz, J = 8.4 Hz), 7.46 (IH, d, J = 2.1 Hz), 7.54 (IH, d, J = 8.4 Hz)

The physical property values of the resulting 1- (N-octyl- carbamoyl) -3- (3, 4-dichlorobenzyl) guanidine were as follows: NMR (DMSO-d6) δ: 0.85 (3H, t, J = 6.6 Hz), 1.02-1.40 (12H, m) , 2.89-2.95 (2H, m) , 4.33 (2H, bs) , 5.76-7.00 (4H, m) , 7.28 (IH, dd, J = 2.1 Hz, J = 8.1 Hz), 7.52 (IH, d, J = 2.1 Hz), 7.58 (IH, d, J = 8.1 Hz)

Example 1: 1- (3, 4-dichlorobenzyl) -5-octylbiguanide monohydrochloride 1/2 hydrate

A 9.82-g quantity of Compound (2) (0.05 mol) and 10.63 g of 3, 4-dichlorobenzylamine (0.05 mol) were added to 49 ml of butyl acetate, followed by refluxing for 6 hours. The reaction solution was concentrated under reduced pressure, and a mixture of 12 ml of water and 47 ml of isopropyl alcohol was added and dissolved into the remainder. To the thus-obtained solution was added, dropwise, 10.13 g of concentrated hydrochloric acid. The resulting mixture was stirred at 28 to 300C for 30 minutes, and the precipitated crystals were then filtered out. The thus- obtained crystals were washed with a small amount of isopropyl alcohol, yielding 23.42 g of (non-dried) 1- (3, 4-dichlorobenzyl) – 5-octylbiguanide dihydrochloride. The resulting crystals were suspended in 167 ml of water without drying, the suspension was then stirred at 25 to 27°C for 2 hours, followed by separation of the crystals by filtration. The thus-obtained crystals were washed with a small amount of water and dried at 400C for 20 hours, yielding 17.05 g of 1- (3, 4-dichlorobenzyl) -5-octyl biguanide monohydrochloride 1/2 hydrate having a purity of 99.9% at a yield of 81.6%.

Example 2 : 1- (3, 4-dichlorobenzyl) -5-octylbiguanide dihydrochloride

A 100-g quantity of Compound (4) (0.774 mol) was dissolved in 1 liter of n-butyl acetate, and 37.6 g of concentrated sulfuric acid (0.383 mol) was added thereto while stirring. To the thus-obtained suspension of 1/2 sulfate of Compound (4) was added 68.9 g of sodium dicyanamide (0.774 mol), 7107

-18- and the resulting suspension was heated under reflux for 3 hours. The reaction solution was cooled to about 200C, and the organic layer thereof was sequentially washed with about 500 ml each of (i) 5% hydrochloric acid, (ii) 5% aqueous caustic soda solution, (iii) 5% aqueous sodium bicarbonate solution, and (iv) water.

To the thus-obtained n-butyl acetate solution of Compound (2) were added 118.5 g of Compound (3) (0.673 mol) and then 58.4 ml of concentrated hydrochloric acid while stirring. The reaction solution was heated, and about 800 ml of n-butyl acetate was distilled off under atmospheric pressure (ordinary pressure) , followed by heating the reaction solution under reflux for 3.5 hours . Subsequently, the reaction solution was cooled to about 400C, and 900 ml of isopropanol, 100 ml of water, and 134 ml of concentrated hydrochloric acid were added thereto. The mixture was stirred at 60 to 70°C for 1 hour and cooled to 100C or below and the precipitated crystals were then separated. The resulting crystals were washed with 200 ml of isopropanol and dried at 6O0C, yielding 1- (3, 4-dichlorobenzyl) -5-octylbiguanide dihydrochloride. Yield: 243.8 g (The yield was 81.3% based on the Compound (3).) Melting point: 228.90C IR(KBr) spectrum: 2920, 1682, 1634, 1337, 1035, 820, and 640 cm“1







Olanexidine is a compound with high bactericidal activity having the chemical name 1-(3,4-dichlorobenzyl)-5-octylbiguanide. Research has been carried out into bactericides containing, olanexidine hydrochloride as an active ingredient (see Japanese Patent No. 2662343, etc.).

Olanexidine has very poor solubility in water, and hitherto known salts of olanexidine are also poorly soluble in water. For example, the solubility at 0° C. of olanexidine hydrochloride in water has been measured to be less than 0.05% (W/V), and the solubility of free olanexidine is a further order of magnitude less than this. Consequently, sufficient bactericidal activity cannot be expected of an aqueous solution merely having olanexidine dissolved therein, and moreover, depending on the conditions the olanexidine may precipitate out.

In the case of making an aqueous preparation of olanexidine in particular, to make the concentration of the olanexidine sufficient for exhibiting effective bactericidal activity, and to reduce the possibility of the olanexidine precipitating out, it has thus been considered necessary to use a dissolution aid such as a surfactant.

EXAMPLE 1 Preparation of an Aqueous Solution Aqueous Solution 1

20.9 g (50 mmol) of olanexidine hydrochloride hemihydrate was added to 250 mL of a 1 N aqueous sodium hydroxide solution, and the suspension was stirred for 1.5 hours at room temperature (25° C.). The solid was filtered off, and washed with water. The solid obtained was further suspended in 250 mL of purified water, the suspension was stirred for 5 minutes at room temperature, and the solid was filtered off, and washed with water. This operation was carried out once more to remove sodium chloride formed. The solid obtained (free olanexidine) was put into purified water in which 8.9 g (50 mmol) of gluconolactone had been dissolved, and the mixture was stirred at room temperature until the solid dissolved, and then purified water was further added to give a total volume of 300 mL. The concentration of olanexidine in the aqueous solution obtained was measured by using high performance liquid chromatography to be 6% in terms of free olanexidine.

This aqueous solution was still transparent and colorless even after being left for several months at room temperature.


Image result for Olanexidine

Image result for Olanexidine


Patent ID Date Patent Title
US8979785 2015-03-17 Fluid application device and method
US8911771 2014-12-16 Fluid application device and method
US8858484 2014-10-14 Fluid application device and method
US7829518 2010-11-09 Aqueous solution of olanexidine, method of preparing the aqueous solution, and disinfectant
US7825080 2010-11-02 Aqueous solution of olanexidine, method of preparing the aqueous solution, and disinfectant
Patent ID Date Patent Title
US7622469 2009-11-24 2, 4-diamino-1, 3, 5-triazine derivatives
US2007053942 2007-03-08 Disinfectant and/or bactericidal aqueous compositions
EP0507317A2 * Apr 3, 1992 Oct 7, 1992 Otsuka Pharmaceutical Co., Ltd. Biguanide derivatives, manufacturing method thereof, and disinfectants containing the derivatives
EP1634589A1 * May 25, 2004 Mar 15, 2006 Otsuka Pharmaceutical Co., Ltd. Aqueous olanexidine solution, method of preparing the same, and disinfectant
1 * TSUBOUCHI H ET AL: “Synthesis and Structure-Activity Relationships of Novel Antiseptics” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 7, no. 13, 8 July 1997 (1997-07-08), pages 1721-1724, XP004136287 ISSN: 0960-894X

//////////Olanexidine Gluconate, OPB-2045G, (Olanedine®, Approved, japan 2015-07-03, Olanedine,  Otsuka, PMDA, Olanexidine, オラネキシジングルコン酸塩 , Gluconate olanexidin,  Olanedine,  OPB-2045,  OPB 2045G, JAPAN 2015





Istradefylline, KW-6002

(Nouriast®) Approved

A selective adenosine A2A receptor antagonist used to treat Parkinson’s disease.


CAS No. 155270-99-8

Istradefylline; 155270-99-8; KW-6002; KW 6002; 8-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6 -dione; (E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione;

Molecular Formula: C20H24N4O4
Molecular Weight: 384.42896 g/mol

Istradefylline (KW-6002) is a selective antagonist at the A2A receptor. It has been found to be useful in the treatment of Parkinson’s disease.[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.


Kyowa Hakko Kirin is developing istradefylline, a selective adenosine A2A receptor antagonist, for the once-daily oral treatment of Parkinson’s disease (PD). Adenosine A2A receptors are considered to be present particularly in the basal ganglia of the brain; the degeneration or abnormality observed in PD is believed to occur in the basal ganglia, which is recognized to play a significant role in motor control.

Commercially available dopamine replacement therapies effectively treat the early motor symptoms of PD; however, these agents are associated with development of motor complications, limiting usefulness in late stages of the disease. Istradefylline is proposed to possess a clearly distinct action site from existing agents which act on dopamine metabolism or dopamine receptors. Kyowa Hakko Kirin has received approval for istradefylline in the adjunctive treatment of PD in Japan. A New Drug Application was filed in the USA, but the FDA issued a non-approvable letter in February 2008.




Synthesis of KW 6002 (2). Reagents and conditions: (i) acetic anhydride, 80°C, ...

Scheme 1.

Synthesis of KW 6002 (2). Reagents and conditions: (i) acetic anhydride, 80 °C, 2 h, 83%; (ii) sodium nitrite, 50% acetic acid, 60 °C, 15 min, 86%; (iii) sodium dithionite, NH4OH solution (12.5% (w/v)), 60 °C, 30 min, 98%; (iv) SOCl2, toluene, 75 °C, 2 h, 97%; (v) pyridine, DCM, rt, 16 h, 66%; (vi) HMDS, cat. (NH4)2SO4, CH3CN, 160 °C, microwave, 5 h, 100% followed by (vii) MeI, K2CO3, DMF, rt, 2 h, 75%.

Chemical structures of some important adenosine receptor antagonists and their ...


(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione (2)3

  1. J. Hockemeyer; J. C. Burbiel; C. E. Müller, J. Org. Chem. 2004, 69, 3308.

(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-1H-purine-2,6(3H,7H)-dione (1.11 g, 3.00 mmol) was taken up in dimethylformamide (15 mL) and potassium carbonate (828 mg, 6.00 mmol). To the milky white mixture was added iodomethane (468 µL, 7.50 mmol) and it was allowed to stir at room temperature for 2 h. The mixture was then filtered and washed with water (100 mL), leaving the title compound 2 as a pale yellow solid which was dried in the oven at 110 °C (863 mg, 75%), mp: 192 °C (lit.3 191 °C). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 15.7 Hz, 1H), 7.18 (dd, J = 8.4, 1.9 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 15.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.12 – 4.04 (m, 5H), 3.95 (s, 3H), 3.93 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 155.0 (C), 150.8 (C), 150.4 (C), 150.3 (C), 149.2 (C), 148.2 (C), 138.1 (CH), 128.6 (C), 121.2 (CH), 111.2 (CH), 109.5 (CH), 109.3 (CH), 108.0 (C), 55.98 (CH3), 55.97 (CH3), 38.4 (CH2), 36.3 (CH2), 31.5 (CH3), 13.43 (CH3), 13.39 (CH3). LCMS: m/z (ESI 20 V) 385.2 (MH+, 100).


Specific synthetic route is as follows:

Figure CN103254194AD00071

the above reaction is a synthetic Parkinson’s disease clinical drug KW-6002 against a yield of 83%.

Example 26 (a new synthetic method for anti-Parkinson’s disease in clinical drug KW-6002):

In addition to use in place of 3,4-dimethoxy-styryl boronic acid (0.4mmol, i.e., in formula IV, R5 is 3,4_-dimethoxy-styryl) benzene boronic acid in Example 23 and 1,3 – two-ethyl-8-phenylthio-9-methyl-xanthine (0.4mmol, i.e., Formula I, R1 is methyl, R2 and R3 are ethyl, R4 is a phenyl group) in place of Example 23 in 1 , 3,9-trimethyl xanthine -8- phenylthio, the remaining steps in Example 23 to give a white solid, yield 83%, mp = 101~103 ° C I1H NMR (⑶CI3, 600MHz): δ 7.71 (d, J = 15.6Hz, 1H), 7.17 (dd, J = 8.2,1.9Hz, 1H), 7.07 (d, J = L 9Hz, 1H), 6

• 88 (d, J = 8.2Hz, 1H), 6.74 (d, J = 15.8Hz, 1H), 4.19 (q, J = 7Hz, 2H), 4.07 (q, J = 7Hz, 2H), 4.03 (s , 3H), 3.93 (s, 3H), 3.90 (s, 3H), 1.36 (t, J = 7Hz, 3H), 1.23 (t, J = 7Hz, 3H); 13C NMR (150MHz, CDCl3): 155.1, 150.8,150.4,150.2,149.2,148.2,138.2,128.6,121.2, 111.2,109.5,109.3,108.0,56.0,55.9,38.4,36.3,31.5,13.4,13.4; HRMS: calcd for C20H25N4O4 (M + H) +385.187

6, Found385.1879. It indicates that the white solid was 8- (3,4-dimethoxy-styryl) structural formula shown KW-6002 (E) -1,3_ diethyl-7-methylxanthine.

Figure CN103254194AD00162

 In contrast, KW-6002 is a new drug to treat Parkinson’s disease developed by Kyowa Hakko in Japan, Japan and the United States is currently the second phase of clinical trials. Literature (. J.Hockemeyer, JCBurbiel andC.E.Muller, J.0rg.Chem, 2004,69,3308) through the following synthetic route:

Figure CN103254194AD00171

The synthetic route requires five steps, with a total yield of 33%, and there is the use of environmentally unfriendly halogenated solvent methylene chloride, the reaction requires high pressure high temperature (170~180 ° C) and other shortcomings. By comparison, the present invention starting from 8- phenylthio xanthine coupling reaction catalyzed by palladium simple, a yield of 83% was synthesized KW6002, it is currently the most efficient synthesis route KW-6002’s. In particular, the multi-step synthesis route to avoid the complex operation of the reactor, but under relatively mild conditions (60 ° C) conduct, simple operation, suitable for scale synthesis.


itraconazole theophylline (Istradefylline, KW6002), the chemical name 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl -7 – methyl-purine-2,6-dione, CAS number: 155270-99-8, structural formula shown below.

Figure CN104744464AD00031

 itraconazole Theophylline is a selective adenosine A2a receptor antagonist, by changing the activity of neurons in Parkinson’s disease patients to improve motor function, for the treatment of Parkinson’s disease and Parkinson’s disease improve early dyskinesia.

The invention and JPH0940652A European Patent 0,590,919 discloses a method for preparing itraconazole and theophylline. WO 2004/099207 published good solubility stability of a particle size of less than 50 micrometers 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3- diethyl-7-methyl-purine-2,6-dione crystallites.

Example 1 Preparation of theophylline itraconazole  Example

Figure CN104744464AD00051

ships equipped with a mechanical stirrer, a thermometer, a 2L 4-neck flask was added 30g8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl- -7- hydrogen – purine-2,6-dione (Intermediate A), 400mL N, N- dimethylformamide and 15g of potassium carbonate, and 25g of methyl iodide and heated to 80 ° C after the reaction was stirred 8h, added 200mL water, cooled to room temperature, and stirring was continued crystallization 2h. The resulting suspension was suction filtered, washed with water after the cake was 800mL sash, 50 ° C under blast drying 24h, 32g give a pale yellow solid, for each polymorph of itraconazole theophylline preparation example the following examples.


  1.  Peter A. LeWitt, MD, M. Guttman, James W. Tetrud, MD, Paul J. Tuite, MD, Akihisa Mori, PhD, Philip Chaikin, PharmD, MD, Neil M. Sussman, MD (2008). “Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson’s disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)”. Annals of Neurology 63 (3): 295–302. doi:10.1002/ana.21315. PMID 18306243.

Reference:1. EP0590919A1.

2. US5484920A.

3. US5543415A.

4. J. Org. Chem. 2004, 69, 3308-3318.

5. Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352.

6. Bioorgan. Med. Chem. 2003, 11, 1299-1310.

7. Bioorg. Med. Chem. Lett. 2013, 23, 3427-3433.

8. Chinese Journal of Pharmaceuticals 2010, 41, 241-243.

9. JP0940652A.

10. Org. Biomo. Chem. 2010, 8, 4155-4157.

1. Chem. Commun. 2012, 48, 2864-2866.

2. CN103254194A.

CN104744464A * Nov 15, 2013 Jul 1, 2015 南京华威医药科技开发有限公司 Istradefylline crystal forms
  1. Istradefylline
    Systematic (IUPAC) name
    CAS Number 155270-99-8 Yes
    ATC code none
    PubChem CID 5311037
    IUPHAR/BPS 5608
    ChemSpider 4470574 Yes
    UNII 2GZ0LIK7T4 Yes
    KEGG D04641 Yes
    ChEMBL CHEMBL431770 Yes
    Chemical data
    Formula C20H24N4O4
    Molar mass 384.429 g/mol

//////Istradefylline, KW-6002, Nouriast®, Approved, A selective adenosine A2A receptor antagonist, Parkinson’s disease,


Polmacoxib, CG-100649


Polmacoxib, CG-100649


A COX-2 inhibitor used to treat osteoarthritis.

  • OriginatorCrystalGenomics
  • ClassAntirheumatics; Benzene derivatives; Fluorobenzenes; Furans; Nonsteroidal anti-inflammatories; Small molecules; Sulfonamides
  • Mechanism of ActionCarbonic anhydrase inhibitors; Cyclo-oxygenase 2 inhibitors
  • 12 Jan 2016Polmacoxib licensed to TR-Pharm for commercialisation in Turkey and Middle East and North Africa region
  • 01 Sep 2015Launched for Osteoarthritis in South Korea (PO)
  • 12 Aug 2015Polmacoxib licensed to Dong-A ST for commercialisation in South Korea
Molecular Formula: C18H16FNO4S
Molecular Weight: 361.387343 g/mol

CAS No.301692-76-2




Polmacoxib (Acelex) is a nonsteroidal anti-inflammatory drug (NSAID) used to treat osteoarthritis. It was developed as CG100649 and approved for use in South Korea in February 2015.[1] It inhibits the enzymes carbonic anhydrase and COX-2. A study in healthy volunteers showed drug effects on urinary prostaglandin metabolites for both CG100649 and celecoxib that suggest a similar cardiovascular risk profile.[2] Further work by this group developed dose-exposure relationsships of CG100649 to guide clinical development strategies. [3]

Dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase inhibitor
Molecular Target Cyclooxygenase-2 (COX-2) ; Carbonic anhydrase l (CAI)
Mechanism of Action Cyclooxygenase-2 (COX-2) inhibitor; NSAID


01 FEB


CrystalGenomics, announced today that it has received approval for Acelex® (polmacoxib) from the Korean Ministry of Food and Drug Safety (MFDS) for the treatment of osteoarthritis.

The company said that “Pre-commercialization will commence immediately and a commercial launch partner for the Korean market will be announced very shortly.”

Acelex® (polmacoxib) is the first, tissue-specific once-a-day osteoarthritis drug with a novel mode of action that specifically targets affected joints to relieve pain and restore mobility, while simultaneously preserving the integrity and safety of the gastrointestinal and cardiovascular systems. The results from the Phase 3 study suggest that Acelex 2mg once-a-day provides more rapid onset of relief from the signs and symptoms of osteoarthritis in comparison to celecoxib 200mg once-a-day, without added safety risk.

Polmacoxib is a first-in-class NSAID drug candidate that is a dual inhibitor of COX-2 and carbonic anhydrase (CA). Polmacoxib’s interaction with CA in red blood cells provides it with a novel ’tissue-specific’ transport mechanism that is designed to deliver sustained levels of drug to inflamed tissues, while maintaining low systemic exposure. Its unique dual COX-2 and CA binding properties are designed to provide potentially superior safety to cardiovascular, renal, and gastrointestinal tissues compared to traditional NSAIDs or COX-2 inhibitor drugs.

Acelex® is expected to rapidly capture at least 10% of the arthritis market in Korea that is estimated to be worth more than KRW 500 billion per year as of 2013. Osteoarthritis is quite common in Korea, as it affects about 50% of the population aged 65 years or older. Moreover, the overall number of patients is growing rapidly due to an aging population coupled with an increasing prevalence of obesity.

Nonsteroidal antiinflammatory drugs (NSAIDs) have been widely used over 100 years to alleviate symptoms of arthritis, arthritis-associated disorders, fever, post-operative pain, migraine, and so on. Despite their widespread use and desirable therapeutic efficacy for the treatment of inflammation and inflammation-associated disorders, NSAIDs are generally regarded to have life-threatening toxicity in the gastrointestinal (GI) tract. Severity of the GI toxicity is well illustrated by a report that 16 500 patients on NSAIDs therapy died due to the GI toxicity in the year of 1994 alone in the US. Frequently, the gastric toxicity of perforation, ulceration, and bleeding (PUB) is not noticed by patients before hospitalization, leading to such a high mortality rate upon chronic use of NSAIDs.
Despite the huge amount of efforts directed to reduce the GI toxicity of NSAIDs, it was only about a decade ago that the origin of the GI toxicity began to be understood through the discovery of an inducible isoform of cyclooxygenases. There are at least two kinds of cyclooxygenases, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is constitutively expressed in various tissues including the GI tract, the kidneys, and the platelets. COX-1 is known to be responsible for bodily homeostasis such as the gastrointestinal integrity, vascular dilatation, renal functions, and so on. Overt inhibition of COX-1 can, therefore, elicit undesirable side effects such as gastric PUB and blood thinning. In the meantime, COX-2 is induced upon inflammatory stimuli and is known to be responsible for progression of inflammation. Traditional NSAIDs, such as aspirin, naproxen, piroxicam, ibuprofen, diclofenac, etc., inhibit both COX-1 and COX-2, which accounts for NSAIDs’ antiinflammatory effects as well as their notorious side effects of GI toxicity and blood thinning. Thus, selective inhibition of COX-2 over COX-1 should be useful for treatment of inflammation without incurring the side effects associated with inhibition of COX-1.
A study with COX-2 knockout mice suggests that complete inhibition of COX-2 could lead to peritonitis secondary to intestinal toxicity. Animal safety data for COX-2 inhibitors indicated that the intestinal toxicity was the dose-limiting toxicity in the dog and the rat. However, primates seem to possess robust intestinal tolerance to selective inhibition of COX-2. Indeed, COX-2 inhibitors are regarded to have better gastrointestinal safety profiles than traditional NSAIDs.
Long term use of traditional NSAIDs has been known to elicit cardiorenal toxicity such as edema and worsening blood pressure. There have been some attempts to assess cardiorenal safety of COX-2 inhibitors; however, more clinical data are needed to estimate the cardiorenal safety of COX-2 inhibitors. Considering that COX-2 inhibitors are supposed to be chronically taken mostlyby elderly arthritis patients, the importance of the long-term cardiorenal safety can never be overemphasized. COX-2 is constitutively expressed in the glomerular region and the small blood vessels of the kidneys in primates including the human, suggesting that the smaller inhibition of renal COX-2 could lead to smaller renal and consequently cardiovascular adverse effects. Given that only protein-unbound drug molecules are subject to glomerular filtration, a drug with higher plasma protein binding is expected to exert a smaller renal effect for a given lipophilicity or hydrophilicity of drug.
There are already several COX-2 inhibitors being prescribed for chronic indications, and they mostly maintain a tricyclic structure as in rofecoxib, celecoxib, valdecoxib, and etoricoxib.

Prostaglandins are known to play an important role in the inflammation.

Since prostaglandins are produced from arachidonic acid by cyclooxygenases, inhibition of prostagalndin synthesis by cyclooxygenases, especially synthesis of PGE2, PGG2, and PGH2, leads to the treatment of inflammation.

There are at least two kinds of cyclooxygenases, cyclooxygenase-1

(abbreviated as COX-1) and cyclooxygenase-2 (abbreviated as COX-2). COX-1 is constitutively present in the gastrointestinal tract and the kidney, and is implicated to be responsible for the maintenance of the physiological homeostasis, such as gastrointestinal integrity and renal function. Interruption of COX-1 activity can lead to life-threatening toxicities to the gastrointestinal tract, such as ulceration and bleeding. In the meantime, COX-2 is induced upon inflammatory stimuli and known to be responsible for progression of inflammation. Thus, selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation-associated disorders without incurring gastrointestinal toxicities.

Conventional non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, ketoprofen, ibuprofen, piroxicam, diclofenac etc, inhibit both COX-1 and COX-2, which would demonstrate their gastrointestinal toxicities as well as anti-inflammatory potency. However, they possess serious life-threatening gastrointestinal toxicities of bleeding and ulceration arising from their inhibition of COX-1, which limit their clinical use. Thus, a selective inhibitor of COX-2 can be useful as an anti-inflammatory therapeutic agent without the gastrointestinal toxicities, frequently occurring upon chronic use of conventional NSAIDs.

COX-2 inhibitors are implicated to possess a broad therapeutic spectrum besides anti-inflammatory, analgesic, and antipyretic activity. For example inhibition of COX-2 can prevent growth of certain types of cancer, especially colon cancer [J. Clin. Invest. 100. 1 (1997)]. Another application of a COX-2 inhibitor can be found in the treatment of degenerative chronic neurological disorders, such as Alzheimer’s disease [Neurology 4£, 626 (1997)]. COX-2 inhibition would be useful in reducing the infarct volume accompanying the stroke [J. Neuroscience 17, 2746 (1997)].

Recently two of COX-2 selective antiinflammatory drugs, celecoxib and rofecoxib, were introduced into the clinic for arthritic indications. Celecoxib and rofecoxib show anti-inflammatory potency comparable to conventional NSAIDs without COX-2 selectivity. In the meantime, these drugs show appreciably lower gastrointestinal toxicities than conventional NSAIDs without COX-2 selectivity over COX-1. Thus, COX-2 selective inhibition itself can be enough for anti-arthritic potency and the inhibition of COX-1 is largely responsible for the gastro-intestinal toxicities associated with conventional NSAIDs without COX-2 selectivity.

.s-l,2-Diaryl-alkenes or its structural-equivalents are known to be a pharmacophore for achieving selective COX-2 inhibition over COX-1 [Ann. Rep. Med. Chem. 22, 211 (1997)]. In case of celecoxib and rofecoxib, pyrazole and 2(JH)-furanone correspond to the scaffold, respectively.

Celecoxib Rofecoxib By adopting an appropriate scaffold for the c/s-alkene pharmacophore, it would be possible to modulate both in vitro and in vivo characteristics of such inhibitors, such as dosing regimen, daily dose, clinical indications arising from tissue distribution characteristics, safety profile, and so on.

In this invention, 3(2H)-furanone is adopted as a scaffold for COX-2 inhibitors.

3(2H)-furanone derivatives were prepared for use in the treatment of glaucoma [EP 0

737 476 A2]. However, there is no precedent case that 3(2H)-furanone derivatives have been ever used as COX-2 inhibitors. There is no reported case of 4,5-diaryl-3(2H)-furanone derivatives, either.

The 4,5-diaryl-3(2H)-furanone derivatives disclosed herein selectively inhibit COX-2 over COX-1 and relieve the effects of inflammation. 4,5-Diaryl-3(2H)-furanone derivatives of this invention do not show substantial inhibition of COX-1 and consequently show reduced gastrointestinal side effects. Thus, 4,5-diaryl-3(2H)-furanone derivatives of this invention are found useful as anti -inflammatory agents with significantly reduced gastrointestinal side effects, when compared with conventional NSAIDs.


Shin, Song Seok; Journal of Medicinal Chemistry 2004, V47(4), P792-804

In Vitro Structure−Activity Relationship and in Vivo Studies for a Novel Class of Cyclooxygenase-2 Inhibitors:  5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone Derivatives

Drug Discovery, AmorePacific R&D Center, 314-1 Bora-ri, Kiheung-eup, Yongin-si, Kyounggi-do 449-729, South Korea
J. Med. Chem., 2004, 47 (4), pp 792–804
DOI: 10.1021/jm020545z
Abstract Image

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC50 comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED50 of 0.1 mg kg-1 day-1 was observed against adjuvant-induced arthritis by a preventive model, positioning20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED50 of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague−Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.



WO 2015080435 

non-steroidal anti-inflammatory drugs (nonsteroidal ant i- inf lammatory drug, NSAID) has a problem that causes serious side effects such as renal toxicity or distress Gastrointestinal. NSAID is to inhibit the activity of the enzyme cyclo-oxy-related prostaglandin G / H synthesis to tyrosinase (cyclooxygenase, COX) inhibits the biosynthesis of prostaglandins in the stomach and kidney, as well as inflammation. C0X is present in the two types of C0X C0X-1 and-2.

C0X-1 is induced by the other hand to adjust the height of the above features and is expressed in normal cells, it is C0X-2 mitogen or inflammation occurred in inflammation and other immune banung cytokines. To avoid the toxicity of the NSAID due to the inhibitory action of coexisting C0X-1 which, has been the selective inhibitors of the study C0X-2.

To 4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) benzenesulfonamide represented by the general formula (1), such as 4, 5- diaryl-3- (0-furanones and derivatives thereof are compounds, wherein the by-1 do not inhibit the C0X standing substantially inhibit only C0X-2 selectively – represents a reduced gastrointestinal side effects while showing the inflammatory effect.

In addition, the compound of Formula 1 has C0X-2, as well as CA carbonic anhydrase) in inhibitory effect shown, in the CA-rich than C0X-2 tissues such as the gastrointestinal tract is to neutralize the inhibitory activity of C0X-2 gastrointestinal bleeding, such as side effects and more while the reduction, the less the distribution of the CA, such as joint tissue has a characteristic showing the effect to inhibit only C0X eu 2. Thus, 4, 5-diaryl-3- (0-furanones derivatives compared to conventional NSAIDs significantly reduced gastrointestinal side effects having an anti-inflammatory substance is useful as a.

Compounds and their derivatives of the formula (1) are of various inflammatory diseases; Pain accompanying diseases; viral infection; It is useful in the relief of inflammation, pain and fever, and the like accompanying surgery; diseases such as diabetes. Sikimyeo compounds and their derivatives of the formula (1) and they also inhibit the growth of cancer, including colorectal cancer C0X- parameter, reducing the infarction area of reperfusion injuries to (reperfusion injury) caused by the stroke, treatment of neurodegenerative diseases, including Alzheimer’s disease it is useful. Diabetes accompanying retinopathy (retinopathy) in the treatment of useful and eu C0X-mediated vascularization (angiogenesis) to engage it (Mart in SG et al., Oral surgery oral medicine oral pathology, 92 (4), 2001, 399; James RH et al., oral surgery oral medicine oral pathology, 97 (2), 2004, 139; RE Harris et al., Inflammopharmacology, 12,2009, 55;

K. Oshima et al. , J. Invest. Surg. , 22 (4), 2009, 239; The Journal of

Pharmacology and Experimenral Therapeutics, 318 (3), 2006, 1248; JM. SL et al. , Int. J. Geriatr. Psychiatry, 2011; Jennifer L. et al. , Invest.

Ophthalmol. Vis. Sci. March, 44 (3), 2003, 974; K. M. Leahy et al. , Current Medicinal Chemistry, 7, 2000, 1163).

Method for producing a compound of formula I is disclosed in the International Patent Publication W0 00/615 sign, are incorporated herein by reference in their entirety.However, using the -78-butyllithium, which discloses in the above production method ° banung in C is not a m- chloroperoxybenzoic acid not suitable for commercial use it is difficult to practically carried out, as well as the yield for each step to be low, there are also overall yield is very low, so that problems 2.22%. ”

Therefore, the way to mass production of a compound of formula 1 without problems, such as the high yield and a low cost has been desired still.

o provide the production method ol compound represented by Formula 1:

[Formula 4]

[Formula 5]

[Formula 8]

[Formula 9]

4- (3- (3-fluorophenyl) -5,5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) -benzenesulfonamide The total yield by the method represented by Reaction Scheme 1 It is very easy to about 46% of the high yield and can be economically mass-produced:

Or less, on the basis of the example embodiments The invention will be described in more detail. The following examples are not be the only, and the scope of the invention to illustrate the present invention be limited to these.

Example 1: 2- (3-fluorophenyl) Preparation of the acetyl chloride

2- (3-fluorophenyl) acetic acid (305.5 g, 1.98 mol), thionyl chloride (500 mL, 6.85 mol) to dissolve by stirring the solution in a catalytic amount of dimethylformamide (2.1 mL, 25.83让ol) to the It was. This solution banung 110 ° and heated to sikimyeo C was stirred under reflux for 3 hours. After nyaenggak banung the solution to room temperature, the excess thionyl chloride under reduced pressure using a concentrator was removed by distillation. The stage was distilled off under reduced pressure to about 5mm¾ burgundy red oily objective compound (323 g, 94.4%) was obtained.

Example 2: 2- (3-fluorophenyl) -1- [4- (methylthio) phenyl] ethanone discussed prepared

Aluminum chloride (225 g, 1.91 mol) in dichloromethane (2500 mL), and then the suspension to 5 ° C a solution banung 2- (3-fluorophenyl) acetyl chloride (305 g in cooling,

It was added 1.77 mol). The reaction was stirred for about 5 minutes after the common compounds, the liquid Ndo of banung

5 ° while keeping the C was added dropwise the thio Enigma sol (237 g, 1.91 mol). After stirring for 3 hours banung common compounds at room temperature, it was slowly poured into cold aqueous hydrochloric acid solution. After separation the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration chest and diluted to a concentration under reduced pressure to concentrate the nucleic acid (1,000 mL). The diluted solution was 10 ° after the nyaenggak C to crystallize, it was stirred for 1 hour and then filtered and washed with a nucleic acid (1,000 mL). The filtered solid 50 ° and vacuum-dried for 2 hours in the target compound C (406 g, 88.3%) was obtained.

mp: 94.5 – 95.5 ° C

¾-NMR (CDCls, 300 MHz): δ 2.52 (s, 3H), 4.23 (s, 2H), 6.95-7.05 On, 3H), 7.25-7.30 (m, 3H), 7.92 (d, J = 8.7 Hz , 2H)

Example 3: 2,2-dimethyl-eu 4- (3-phenyl pool Luo) -5- [4- (methylthio) phenyl] -3 () – furanyl discussed prepared

Eu 2 (3-fluorophenyl) – 1- [4- (methylthio) phenyl] was cooled 30 minutes with stirring at ice-water was dissolved ethanone (512 g, 1.97 mol) in tetrahydrofuran (3,900 mL) . Sodium hydride in the reaction solution (60%, 180 g, 7.5 mol) was added to the subdivision for at least 15 minutes, the common banung compounds was stirred for 30 minutes at room temperature. The reaction common compounds 5 ° after nyaenggak in C, the 2-bromo butyryl cattle feeders cyanide (403 g, 2.29 mol) was added dropwise while maintaining the temperature. After the addition the solution was slowly stirred for 5 hours banung to room temperature. Banung ^ the compounds 5 ° and cooled to C, and then slowly added to de-ionized water and neutralized with acetic acid (122 g). After concentration under reduced pressure the banung solution was extracted with dichloromethane (2, 500 mL) and deionized water (2, 000 mL). The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and filtered.

Filtered and concentrated under reduced pressure then gave a precipitate is dissolved with stirring in methanol (700 mL). After filtering the precipitate is washed with acid and methane. The filtered solid 50 ° and vacuum-dried for 2 hours at C, to give the desired compound (534.7 g, 82.8%). mp: 106 ° C

NMR-¾ (CDCI 3 , 300 MHz): δ 1.55 (s, 6H), 2.50 (s, 3H), 6.97-7.11 (m, 3H), 7.18 (d, J = 9.0 Hz, 2H), 7.26-7.36 (m, 1H), 7.55 ( d, J = 9.0 Hz, 2H)

Example 4: [4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) phenylsulfonyl] Preparation of methyl acetate

2,2-dimethyl-eu eu eu 4 (3_ fluorophenyl) _5- [4- (methylthio) phenyl] -3 (0 furanones (5.5 Kg) and acetonitrile (27.2 Kg) and dichloromethane (45.43 Kg) after heunhap dissolved in a solvent, the compounds banung common -5 ° was cooled to C. to binary dissolved in acetic acid solution to the other reaction by injecting a peracetic acid (18%) and injection of dichloromethane and 23.4 Kg 13.9 Kg acetonitrile a common hapaek was prepared. hapaek prepared common to -5 ° keeping the C and slowly 0-5 was added to the reaction common compounds for 2 h ° and stirred for 30 to 90 minutes in the C. and the reaction common compounds with purified water 109.2 L separating the washed organic layer was then washed with aqueous sodium thiosulfate and aqueous sodium bicarbonate solution. the organic layer is concentrated 4- (3-fluorophenyl eu) eu 2,2-dimethyl-5- (4-eu

(Methyl sulfinyl) phenyl) furan -3 (2H) – one to give the as an oil form.

NiP: 143-144 ° C

¾-NMR (CDCls, 300 腿 ζ): δ 1.58 (s, 6Η), 2.76 (s, 3H), 7.26-7.08 (m, 3H), 7.30-7.38 (111, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H)

After the thus obtained compound was dissolved in acetic anhydride (42.3 Kg) was added anhydrous sodium acetate (5.1 Kg). A liquid banung 130 ° under reflux for 12 hours at C and then cooled to room temperature after stirring. By filtration, washed with acetic anhydride solution banung the filtrate was 55 ° and concentrated in C. 63.5 Kg of purified water to the acid concentrate and 20.7

Injecting L and 10 ° after a nyaenggak C, it was added oxone 32.3 Kg followed by stirring for 3 hours. A liquid banung 50 ° and then concentrated in C until the residual liquid was added ½ and purified water (89.5 L) was stirred for 3 hours. The precipitated compound was filtered and then, washed with purified water and heptane and 50 °followed by drying for 12 hours at C, to give the desired compound (6.4 Kg, 91.3%).

¾ -赚(DMS0-d 6 (300 MHz): δ 8.01 (d, 2H), 7.83 (d, 2H), 7.43 (q, 1H), 7.20 (t, 1H), 7.07 (q, 1H), 5.47 (s, 2H), 2.06 ( s, 3H), 1.52 (s, 6H)

Example 5: Preparation of sodium 4- (3- (3-fluorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydro-2-yl) Preparation of benzene sulfinate

[4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-eu 4, 5-dihydro-furan-2-yl) phenylsulfonyl] methyl acetate (6.4 Kg) in tetrahydrofuran was dissolved in (34.3 Kg) and ethanol (15.3 Kg), the liquid temperature banung 0 ° was cooled to C. It was dissolved in sodium hydroxide (0.7 Kg) in purified water (16.1 L) to the other reaction section was prepared the solution cooled to C. It was added slowly for 5 hours, the prepared aqueous sodium hydroxide solution to the reaction solution, further stirring the reaction solution after about 1 hour and concentrated at 45 ° C. After concentration is completed, when added to absolute ethanol (10.0 Kg) and the toluene (11.0 Kg) was dissolved in concentrated 5C C. When concentration is complete, and then the absolute ethanol (10.0 Kg) was dissolved was added to toluene (10.1 Kg) and concentrated in 5C C. When the concentration is completed with absolute ethanol (7.7 Kg) was dissolved in 50 was added to toluene (8.4 Kg) ° was repeated in the course of concentration C twice. After re-concentrated solution of absolute ethanol (4.6 Kg) and the dissolution was added to toluene (5.1 Kg) to 50 ° and concentrated in C. Rouen (20.7 When the concentrate is completed,

Kg) was added and the resultant mixture was stirred for 2 hours, filtered and the washed with toluene (12.5 Kg). Was added to 20.7 Kg of toluene to the obtained solid was filtered after stirring for one to two hours. The filtered solid to a toluene (11.9 Kg) and washed with heptane (11.9 Kg) and then 45 ° was obtained in a quantitative and dried for 12 hours in C.

¾- 赚 (DMSO-de, 300 MHz): δ 7.52 (s, 4H), 7.40 (m, 1H), 7. 19-7.02

(M, 3H), 1.49 (s, 6H) .

Example 6: 4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) Preparation of benzenesulfonamide

Sodium 4- (3 eu (3_-fluorophenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl eudi) after the benzene sulfinate (6.0 Kg) was dissolved in dichloromethane – 5 ° and cooled to C. After stirring for another part banung ^ the combined dichloromethane (6.0 Kg) and sulfonic sulfuryl chloride (2. 1 Kg), 0 to the reaction solution obtained in the above ° was added slowly for 1 hour under C. A common banung hapaek eu 5 ° and after stirring for 4 hours at C and the organic layer was separated and washed with brine. After filtering the organic layer was dried over sodium sulfate (4.2 Kg), the filtrate was 40 ° and concentrated in C or less to give the intermediates of sulfonyl chloride compounds.

Tetrahydrofuran (36.3 Kg) and aqueous ammonia (16.9K the other part banung g were combined for common) was nyaenggak to 0 ° C. By dissolving the obtained sulfonic ponal chloride compound in 8.9 Kg of tetrahydrofuran 5 ° , while maintaining the below C was added slowly to the prepared aqueous ammonia solution for 1 hour.This solution banung -5 ° was concentrated after stirring for 30 to 120 minutes in the C. Once completed, the concentrated, purified water 40.2 L

It was added and stirred for 1 to 2 hours. Filtered and the resulting solid was then washed with purified water (16.9 L) and heptane (11.4 Kg). The filtered solid 45 °followed by drying for 12 hours at C, to give the desired compound (4.3 Kg, 73%).

mp: 204-205 ° C

¾-NMR (CDCls, 300 MHz): δ 1.57 (s, 6H), 4.96 (br s, 2H), 6.78 (m,

1H), 6.82 (m, 2H), 7.78 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H) IR (cm- 1 ): 3267, 1686, 1218, 1160

Example 7: Preparation of 2-bromo butyryl cattle feeders cyanide

Was added trimethylsilyl cyanide (283.4 g, 2.86 mol) in 2-bromo cattle feeders butyryl bromide (557 g, 2.24 mol). This solution banung 90 ° After stirring at C for 3 hours to nyaenggak to room temperature. Banung completed under reduced pressure (79画¾), 66 to 75 ° to fractional distillation under a C, to give the desired compound (384 g, 90.04%).

-醒(CDC1 3) 300 MHz): δ 1.97 (s, 6H)


WO 2000061571


Patent ID Date Patent Title
US2008306146 2008-12-11 Dosing Regimens for Cox-2 Inhibitor
US2005222251 2005-10-06 Dual inhibition of cyclooxygenase-2 and carbonic anhydrase
US6492416 2002-12-10 4,5-diaryl-3(2H)-furanone derivatives as cyclooxygenase-2 inhibitors


  1.  “CrystalGenomics Receives MFDS Approval for Acelex® (Polmacoxib)”. PR Newswire.
  2.  Skarke, C.; Alamuddin, N.; Lawson, J. A.; Cen, L.; Propert, K. J.; Fitzgerald, G. A. (2012). “Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649”. Clinical Pharmacology & Therapeutics 91 (6): 986–93. doi:10.1038/clpt.2012.3.PMC: 3740579. PMID 22278334.
  3.  Hirankarn, S.; Barrett, J.S.; Alamuddin, N.; Fitzgerald, G. A.; Skarke, C. (2013). “GCG100649, A Novel Cyclooxygenase-2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase-I/II: Preliminary Dose–Exposure Relationships to Define Clinical Development Strategies”. Clinical Pharmacology in Drug Development 2 (4): 379–386. doi:10.1002/cpdd.47.
Systematic (IUPAC) name
Clinical data
Trade names Acelex
CAS Number 301692-76-2
PubChem CID 9841854
ChemSpider 8017569
Synonyms CG100649
Chemical data
Formula C12H16FNO4S
Molar mass 361.3914 g/mol

///////Polmacoxib, CG-100649, 301692-76-2


MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan

MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved MARIZEV® (omarigliptin) 25 mg and 12.5 mg tablets, an oral, once-weekly DPP-4 inhibitor indicated for the treatment of adults with type 2 diabetes. Japan is the first country to have approved omarigliptin……….


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/////////////MARIZEV,  (Omarigliptin), Merck’s,  Once-Weekly,  DPP-4 Inhibitor,   Type 2 Diabetes, Approved, Japan



Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties. The chemical name of defibrotide sodium is polydeoxyribonucleotide, sodium salt. Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between defibrotide sodium, plasmin and a plasmin substrate. The primary structure of defibrotide sodium is shown below.


DEFITELIO (defibrotide sodium) injection is a clear, light yellow to brown, sterile, preservative-free solution in a single-patient-use vial for intravenous use. Each milliliter of the injection contains 80 mg of defibrotide sodium and 10 mg of Sodium Citrate, USP, in Water for Injection, USP. Hydrochloric Acid, NF, and/or Sodium Hydroxide, NF, may have been used to adjust pH to 6.8-7.8.

Defibrotide is the sodium salt of a mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has been shown to have antithrombotic, anti-inflammatory and anti-ischemic properties (but without associated significant systemic anticoagulant effects). It is marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries, but is currently not approved in the USA. The manufacturer is Gentium.

Defibrotide is used to treat or prevent a failure of normal blood flow (occlusive venous disease, OVD) in the liver of patients who have had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others.

In 2012, an IND was filed in Japan seeking approval of the compound for the treatment of veno-occlusive disease.

Approved 3/30/3016 US FDA, defibrotide sodium, (NDA) 208114


To treat adults and children who develop hepatic veno-occlusive disease with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation

Polydeoxyribonucleotides from bovine lung or other mamalian organs with molecular weight between 15,000 and 30,000 Da

CAS 83712-60-1

Defibrotide is a polydisperse mixture of oligonucleotides produced by random, chemical cleavage (depolymerisation) of porcine DNA. It is predominantly single stranded, of varying base sequence, lengths and conformations; unfolded, folded or combined. The mean oligonucleotide length is 50 bases with a mean molecular weight of 17 ± 4 kDa. No individually defined component is at more than femtomolar concentration. The only meaningful scientific information that can be obtained about the biochemical nature of defibrotide (aside from determination of percentage of each nucleobase) is a measurement of its average length and its average percentage double stranded character. Therefore, it can be established that this active substance is of highly heterogenic nature.



Defibrotide (Defitelio, Gentium)[1] is a deoxyribonucleic acid derivative (single-stranded) derived from cow lung or porcine mucosa. It is an anticoagulant with a multiple mode of action (see below).

It has been used with antithrombin III.[2]

Jazz Pharmaceuticals plc announced that the FDA has accepted for filing with Priority Review its recently submitted New Drug Application (NDA) for defibrotide. AS ON OCT 2015

Defibrotide is an investigational agent proposed for the treatment of patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with evidence of multi-organ dysfunction (MOD) following hematopoietic stem-cell transplantation (HSCT).

Priority Review status is designated for drugs that may offer major advances in treatment or provide a treatment where no adequate therapy exists. Based on timelines established by the Prescription Drug User Fee Act (PDUFA), FDA review of the NDA is expected to be completed by March 31, 2016.

“The FDA’s acceptance for filing and Priority Review status of the NDA for defibrotide is an important milestone for Jazz and reflects our commitment to bringing meaningful medicines to patients who have significant unmet needs,” said Karen Smith, M.D., Ph.D., Global Head of Research and Development and Chief Medical Officer of Jazz Pharmaceuticals. “We look forward to continuing to work closely with the FDA to obtain approval for defibrotide for patients with hepatic VOD with evidence of MOD in the U.S. as quickly as possible, as there are no other approved therapies for treating this rare, often fatal complication of HSCT.”

The NDA includes safety and efficacy data from three clinical studies of defibrotide for the treatment of hepatic VOD with MOD following HSCT, as well as a retrospective review of registry data from the Center for International Blood and Marrow Transplant Research. The safety database includes over 900 patients exposed to defibrotide in the clinical development program for the treatment of hepatic VOD.

The compound was originally developed under a collaboration between Sanofi and Gentium. In December 2001, Gentium entered into a license and supply agreement with Sigma-Tau Pharmaceuticals, pursuant to which the latter gained exclusive rights to distribute, market and sell the product for the treatment of VOD in the U.S. This agreement was expanded in 2005 to include all of North America, Central America and South America.

Defibrotide was granted orphan drug designations from the FDA in July 1985, May 2003 and January 2007 for the treatment of thrombotic thrombocytopenic purpura (TTP), for the treatment of VOD and for the prevention of VOD, respectively. Orphan drug was also received in the E.U. for the prevention and treatment of hepatic veno-occlusive disease (VOD) in 2004 and for the prevention of graft versus host disease (GvHD) in 2013.


Defibrotide is available as an oral, intravenous, and intramuscular formulation. Its oral bioavailability is in the range of 58-70% of theparenteral forms. T1/2 alpha is in the range of minutes while T1/2 beta is in the range of hours in studies with oral radiolabelleddefibrotide. These data suggest that defibrotide, in spite of its macromolecular nature, is absorbed well after oral administration. Due to the drug’s short half-life, it is necessary to give the daily dose divided in 2 to 4 doses (see below).

In 2014, Jazz Pharmaceuticals (parent of Gentium) acquired the rights of the product in U.S. and in the Americas

Mode of action

The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing tissue plasminogen activator (tPA-)function, and decreasing activity of tissue plasminogen activator inhibitor. Prostaglandin I2 relaxes the smooth muscle of blood vessels and prevents platelets from adhering to each other. Prostaglandin E2 at certain concentrations also inhibits platelet aggregation. Moreover, the drug provides additional beneficial anti-inflammatory and antiischemic activities as recent studies have shown. It is yet unclear, if the latter effects can be utilized clinically (e.g., treatment of ischemic stroke).

Unlike heparin and warfarin, defibrotide appears to have a relatively mild anticoagulant activity, which may be beneficial in the treatment of patients at high risk of bleeding complications. Nevertheless, patients with known bleeding disorders (e.g., hemophilia A) or recent abnormal bleedings should be treated cautiously and under close medical supervision.

The drug was marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. It is currently not approved in the USA. The manufacturer is Gentium.

Defibrotide also received fast track designation from the FDA for the treatment of severe VOD in recipients of stem cell transplants. In 2011, the compound was licensed to Medison Pharma by Gentium in Israel and Palestine. The license covers the management of named-patient sales program and local registration, authorization, marketing, reimbursement and medical affairs for the treatment of peripheral vascular disease.

Usual indications

Defibrotide is used to treat or prevent a failure of normal blood flow (Veno-occlusive disease, VOD) in the liver of patients having had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others. Without intensive treatment, VOD is often a fatal condition, leading to multiorgan failure. It has repeatedly been reported that defibrotide was able to resolve the condition completely and was well tolerated.

Other indications are: peripheral obliterative arterial disease, thrombophlebitis, and Raynaud’s phenomenon. In very high doses, defibrotide is useful as treatment of acute myocardial infarction. The drug may also be used for the pre- and postoperative prophylaxis of deep venous thrombosis and can replace the heparin use during hemodialytic treatments.

It has been investigated for use in treatment of chronic venous insufficiency.[3]

Potential indications in the future

Other recent preclinical studies have demonstrated that defibrotide used in conjunction with Granulocyte Colony-Stimulating Factor (rhG-CSF) significantly increases the number of Peripheral Blood Progenitor Cells (Stem cells). The benefit of this increase in stem cells may be crucial for a variety of clinical indications, including graft engineering procedures and gene therapy programs. This would expand the clinical usefulness of defibrotide to a complete distinct area.

Very recently (since early 2006) combination therapy trials (phase I/II) with defibrotide plus melphalan, prednisone, and thalidomide in patients with multiple myeloma have been conducted. The addition of defibrotide is expected to decrease the myelosuppressive toxicity of melphalan. However, is too early for any definitive results at that stage.

Cautions and contraindications

  • The efficacy of the drug has been reported to be poorer in patients with diabetes mellitus.
  • Pregnancy: The drug should not be used during pregnancy, because adequate and well controlled human studies do not exist.
  • Lactation: No human data is available. In order to avoid damage to the newborn, the nursing mother should discontinue either the drug or breastfeeding, taking into account the importance of treatment to the mother.
  • Known Bleeding Disorders or Bleeding Tendencies having occurred recently: Defibrotide should be used cautiously. Before initiation of treatment, the usual coagulation values should be obtained as baseline and regularly controlled under treatment. The patient should be observed regularly regarding local or systemic bleeding events.


Increased bleeding and bruising tendency, irritation at the injection site, nausea, vomiting, heartburn, low blood pressure. Serious allergic reactions have not been observed so far.

Drug interactions

Use of heparin with defibrotide may increase the aPTT, reflecting reduced ability of the body to form a clot. Nothing is known about the concomitant application of other anticoagulants than heparin and dextran containing plasma-expanders, but it can be anticipated that the risk of serious bleeding will be increased considerably.



WO 2001078761

G-CSF (CAS registry number 143011-2-7/Merck Index, 1996, page 4558) is a haematopoietic growth factor which is indispensable in the proliferation and differentiation of the progenitor cells of granulocytes; it is a 18-22 kDa glycoprotein normally produced in response to specific stimulation by a variety of cells, including monocytes, fibroblasts and endothelial cells. The term defibrotide (CAS registry number 83712-60-1) normally identifies a polydeoxyribonucleotide obtained by extraction (US 3,770,720 and US 3,899,481) from animal and/or vegetable tissue; this polydeoxyribonucleotide is normally used in the form of a salt of an alkali metal, generally sodium. Defibrotide is used principally for its anti- thrombotic activity (US 3,829,567) although it may be used in different applications, such as, for example, the treatment of acute renal insufficiency (US 4,694,134) and the treatment of acute myocardial ischaemia (US 4,693,995). United States patents US 4,985,552 and US 5,223,609, finally, describe a process for the production of defibrotide which enables a product to be obtained which has constant and well defined physico-chemical characteristics and is also free from any undesired side-effects




  1.  “Jazz Pharma Acquiring Gentium for $1B”. Gen. Eng. Biotechnol. News (paper) 34 (2). January 15, 2014. p. 10.
  2.  Haussmann U, Fischer J, Eber S, Scherer F, Seger R, Gungor T (June 2006). “Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy”. Haematologica 91 (6): 795–800. PMID 16769582.
  3.  Coccheri S, Andreozzi GM, D’Addato M, Gensini GF (June 2004). “Effects of defibrotide in patients with chronic deep insufficiency. The PROVEDIS study”. Int Angiol 23 (2): 100–7.PMID 15507885.

External links

WO2003101468A1 * Jun 2, 2003 Dec 11, 2003 Guenther Eissner Method for the protection of endothelial and epithelial cells during chemotherapy
US4985552 Jul 5, 1989 Jan 15, 1991 Crinos Industria Farmacobiologica S.P.A. Process for obtaining chemically defined and reproducible polydeoxyribonucleotides
US5223609 May 26, 1992 Jun 29, 1993 Crinos Industria Farmacobiologica S.P.A. Process for obtaining chemically defined and reproducible polydeoxyribonucleotides
Cited Patent Filing date Publication date Applicant Title
WO1999026639A1 * 24 Nov 1998 3 Jun 1999 Allegheny University Of The He Methods for mobilizing hematopoietic facilitating cells and hematopoietic stem cells into the peripheral blood
EP0317766A1 * 20 Oct 1988 31 May 1989 Crinos Industria Farmacobiologica S.p.A. A method for preventing blood coaguli from being formed in the extra-body circuit of dialysis apparatus and composition useful thereof
EP0416678A1 * 10 Aug 1990 13 Mar 1991 Crinos Industria Farmacobiologica S.p.A. Topical compositions containing Defibrotide
US5199942 * 26 Sep 1991 6 Apr 1993 Immunex Corporation Method for improving autologous transplantation
US5977083 * 5 Jun 1995 2 Nov 1999 Burcoglu; Arsinur Method for using polynucleotides, oligonucleotides and derivatives thereof to treat various disease states
1 * CARLO-STELLA, C. (1) ET AL: “Defibrotide significantly enhances peripheral blood progenitor cell mobilization induced by recombinant human granulocyte colony – stimulating factor ( rhG – CSF.” BLOOD, ( NOVEMBER 16, 2000 ) VOL. 96, NO. 11 PART 1, PP. 553A. PRINT. MEETING INFO.: 42ND ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY SAN FRANCISCO, CALIFORNIA, USA DECEMBER 01-05, 2000 AMERICAN SOCIETY OF HEMATOLOGY. , XP002176349
Citing Patent Filing date Publication date Applicant Title
WO2005017160A2 * 12 Aug 2004 24 Feb 2005 Childrens Hosp Medical Center Mobilization of hematopoietic cells
WO2009115465A1 * 13 Mar 2009 24 Sep 2009 Gentium Spa Synthetic phosphodiester oligonucleotides and therapeutical uses thereof
EP2103689A1 * 19 Mar 2008 23 Sep 2009 Gentium S.p.A. Synthetic phosphodiester oligonucleotides and therapeutical uses thereof
US7417026 12 Aug 2004 26 Aug 2008 Children’s Hospital Medical Center Mobilization of hematopoietic cells
US7915384 5 Jan 2009 29 Mar 2011 Children’s Hospital Medical Center Chimeric peptides for the regulation of GTPases
US8242246 28 Feb 2011 14 Aug 2012 Children’s Hospital Medical Center Chimeric peptides for the regulation of GTPases
US8674075 13 Aug 2012 18 Mar 2014 Children’s Medical Center Corporation Chimeric peptides for the regulation of GTPases
US8980862 12 Nov 2010 17 Mar 2015 Gentium S.P.A. Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD)
Clinical data
AHFS/ International Drug Names
  • X
Legal status
  • Rx only (where available)
Routes of
oral, i.m., i.v.
Pharmacokinetic data
Bioavailability 58 – 70% orally (i.v. and i.m. = 100%)
Biological half-life t1/2-alpha = minutes; t1/2-beta = a few hours
CAS Registry Number 83712-60-1 Yes
ATC code B01AX01
DrugBank DB04932 Yes
KEGG D07423 Yes

///////////Approved,  3/30/3016,  US FDA, defibrotide sodium, NDA 208114, FDA 2016


FDA approves first treatment for rare disease in patients who receive stem cell transplant from blood or bone marrow

For Immediate Release

March 30, 2016


The U.S. Food and Drug Administration today approved Defitelio (defibrotide sodium) to treat adults and children who develop hepatic veno-occlusive disease (VOD) with additional kidney or lung abnormalities after they receive a stem cell transplant from blood or bone marrow called hematopoietic stem cell transplantation (HSCT). This is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition.

HSCT is a procedure performed in some patients to treat certain blood or bone marrow cancers. Immediately before an HSCT procedure, a patient receives chemotherapy. Hepatic VOD can occur in patients who receive chemotherapy and HSCT. Hepatic VOD is a condition in which some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage. In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs. Fewer than 2 percent of patients develop severe hepatic VOD after HSCT, but as many as 80 percent of patients who develop severe hepatic VOD do not survive.

“The approval of Defitelio fills a significant need in the transplantation community to treat this rare but frequently fatal complication in patients who receive chemotherapy and HSCT,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

The efficacy of Defitelio was investigated in 528 patients treated in three studies: two prospective clinical trials and an expanded access study. The patients enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after HSCT. The studies measured the percentage of patients who were still alive 100 days after HSCT (overall survival). In the three studies, 38 to 45 percent of patients treated with Defitelio were alive 100 days after HSCT. Based on published reports and analyses of patient-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for patients with severe hepatic VOD who received only supportive care or interventions other than Defitelio.

The most common side effects of Defitelio include abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis). Serious potential side effects of Defitelio that were identified include bleeding (hemorrhage) and allergic reactions. Defitelio should not be used in patients who are having bleeding complications or who are taking blood thinners or other medicines that reduce the body’s ability to form clots.

The FDA granted the Defitelio application priority review status, which facilitates and expedites the development and review of certain drugs in light of their potential to benefit patients with serious or life-threatening conditions. Defitelio also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Defitelio is marketed by Jazz Pharmaceuticals based in Palo Alto, California

FDA approves Praluent for the treatment of high LDL cholesterol

26 August 2015

Sanofi and Regeneron have announced that the US Food and Drug Administration (FDA) has approved Praluent® (alirocumab) Injection.


Praluent is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low-density lipoprotein (LDL) cholesterol. The effect of Praluent on cardiovascular morbidity and mortality has not been determined.

////////Sanofi, Regeneron,  US Food and Drug Administration, FDA, approved,  Praluent®  , alirocumab

FDA approves Keytruda for advanced melanoma, First PD-1 blocking drug to receive agency approval

September 4, 2014

FDA Release

The U.S. Food and Drug Administration today granted accelerated approval to Keytruda (pembrolizumab) for treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs.

Melanoma, which accounts for approximately 5 percent of all new cancers in the United States, occurs when cancer cells form in skin cells that make the pigment responsible for color in the skin. According to the National Cancer Institute, an estimated 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease this year.

Keytruda is the first approved drug that blocks a cellular pathway known as PD-1, which restricts the body’s immune system from attacking melanoma cells. Keytruda is intended for use following treatment with ipilimumab, a type of immunotherapy. For melanoma patients whose tumors express a gene mutation called BRAF V600, Keytruda is intended for use after treatment with ipilimumab and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations.

“Keytruda is the sixth new melanoma treatment approved since 2011, a result of promising advances in melanoma research,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Many of these treatments have different mechanisms of action and bring new options to patients with melanoma.”

The five prior FDA approvals for melanoma include: ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

The FDA granted Keytruda breakthrough therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. It also received priority review and orphan product designation. Priority review is granted to drugs that have the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan product designation is given to drugs intended to treat rare diseases.

The FDA action was taken under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. An improvement in survival or disease-related symptoms has not yet been established.

Keytruda’s efficacy was established in 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with Keytruda, either at the recommended dose of 2 milligrams per kilogram (mg/kg) or at a higher dose of 10 mg/kg. In the half of the participants who received Keytruda at the recommended dose of 2 mg/kg, approximately 24 percent had their tumors shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients. A similar percentage of patients had their tumor shrink at the 10 mg/kg dose.

Keytruda’s safety was established in the trial population of 411 participants with advanced melanoma. The most common side effects of Keytruda were fatigue, cough, nausea, itchy skin (pruritus), rash, decreased appetite, constipation, joint pain (arthralgia) and diarrhea. Keytruda also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands and liver, occurred uncommonly.

Keytruda is marketed by Merck & Co., based in Whitehouse Station, New Jersey.




Pembrolizumab, LambrolizumabMK-3475

Heavy chain
Light chain
Disulfide bridges
22-96 22”-96” 23′-92′ 23”’-92”’ 134-218′ 134”-218”’ 138′-198′ 138”’-198”’
147-203 147”-203” 226-226” 229-229” 261-321 261”-321” 367-425 367”-425”
Glycosylation sites (N)
Asn-297 Asn-297”
lambrolizumab, or MK-3475


  C6504H10004N1716O2036S46 (peptide)
MOL. MASS 146.3 kDa (peptide)

Pembrolizumab, Lambrolizumab (also known as MK-3475) is a drug in development by Merck that targets the PD-1 receptor. The drug is intended for use in treating metastatic melanoma.  structureof lambrolizumab, or MK-3475  

Statement on a Nonproprietary Name Adopted by the USAN Council. November 27, 2013.

see above link for change in name

may 2, 2013,

An experimental drug from Merck that unleashes the body’s immune system significantly shrank tumors in 38 percent of patients with advanced melanoma, putting the company squarely in the race to bring to market one of what many experts view as the most promising class of drugs in years.

The drugs are attracting attention here at the annual meeting of the American Society of Clinical Oncology, even though they are still in the early stage of testing. Data from drugs developed by Bristol-Myers Squibb and by Roche had already been released.

The drugs work by disabling a brake that prevents the immune system from attacking cancer cells. The brake is a protein on immune system cells called programmed death 1 receptor, or PD-1.

Merck’s study, which was presented here Sunday and also published in the New England Journal of Medicine, involved 135 patients. While tumors shrank in 38 percent of the patients over all, the rate was 52 percent for patients who got the highest dose of the drug, which is called lambrolizumab, or MK-3475.

But that is what is disclosed tonight, as to pembrolizumab, or MK-3475. Wow. With over $44 billion in 2013 worldwide revenue, that disclosure implies (to seasoned SEC lawyers) that spending on this one drug (or, biologic, to be more technical about it — but remember 40 years ago, Merck had no protein chain biologics research & development programs in its pipe — only chemical drug compounds). . . is material, to that number. Normally that would, in turn, mean that the spending is approaching 5 per cent of revenue. So — Merck may be spending $2.2 billion over the next 12 rolling months, on MK-3475. That’s one BIGhairy science bet, given that Whitehouse Station likely already had over $2 billion invested in the program, at year end 2013.

About Pembrolizumab
Pembrolizumab (MK-3475) is an investigational selective, humanized monoclonal anti-PD-1 antibody designed to block the interaction of PD-1 on T-cells with its ligands, PD-L1 and PD-L2, to reactivate anti-tumor immunity. Pembrolizumab exerts dual ligand blockade of PD-1 pathway.
Today, pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials across 30 different tumor types, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide, including new Phase 3 studies in head and neck and other cancers. For information about Merck’s oncology clinical studies, please click here.
The Biologics License Application (BLA) for pembrolizumab is under priority review with the U.S. Food and Drug Administration (FDA) for the proposed indication for the treatment of patients with advanced melanoma previously-treated with ipilimumab; the PDUFA date is October 28, 2014. Pembrolizumab has been granted FDA’s Breakthrough Therapy designation for advanced melanoma. If approved by the FDA, pembrolizumab has the potential to be the first PD-1 immune checkpoint modulator approved in this class. The company plans to file a Marketing Authorization Application in Europe for pembrolizumab for advanced melanoma in 2014.
About Head and Neck Cancer
Head and neck cancers are a related group of cancers that involve the oral cavity, pharynx and larynx. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer (epithelium) of the head and neck (called the). The leading risk factors for head and neck cancer include tobacco and alcohol use. Infection with certain types of HPV, also called human papillomaviruses, is a risk factor for some types of head and neck cancer, specifically cancer of the oropharynx, which is the middle part of the throat including the soft palate, the base of the tongue, and the tonsils. Each year there are approximately 400,000 cases of cancer of the oral cavity and pharynx, with 160,000 cancers of the larynx, resulting in approximately 300,000 deaths.

About Merck Oncology: A Focus on Immuno-Oncology
At Merck Oncology, our goal is to translate breakthrough science into biomedical innovations to help people with cancer worldwide. Harnessing immune mechanisms to fight cancer is the priority focus of our oncology research and development program. The Company is advancing a pipeline of immunotherapy candidates and combination regimens. Cancer is one of the world’s most urgent unmet medical needs. Helping to empower people to fight cancer is our passion. For information about Merck’s commitment to Oncology visit the Oncology Information Center at

About Merck
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit and connect with us on Twitter, Facebook and YouTube.


Hamid, O; Robert, C; Daud, A; Hodi, F. S.; Hwu, W. J.; Kefford, R; Wolchok, J. D.; Hersey, P; Joseph, R. W.; Weber, J. S.; Dronca, R; Gangadhar, T. C.; Patnaik, A; Zarour, H; Joshua, A. M.; Gergich, K; Elassaiss-Schaap, J; Algazi, A; Mateus, C; Boasberg, P; Tumeh, P. C.; Chmielowski, B; Ebbinghaus, S. W.; Li, X. N.; Kang, S. P.; Ribas, A (2013). “Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma”. New England Journal of Medicine 369 (2): 134–44. doi:10.1056/NEJMoa1305133PMID 23724846

key words
FDA,  approved,  Keytruda,  advanced melanoma, PD-1 blocking drug, pembrolizumab, LambrolizumabMK-3475, Monoclonal antibody




World’s first biosimilar antibody is approved in Korea

celltrion Worlds first biosimilar antibody* is approved in Korea

celltrion Worlds first biosimilar antibody* is approved in Korea

South Korean biosimilar manufacturer Celltrion, today declared that, Korean Food and Drug Administration approved its first biosimilar monoclonal antibody, Remsima.


Remsima is a biosimilar version of Remicade, the blockbuster in Rheumatoid Arthitis (RA). Korean FDA approved the product in several indications including RA, ankylosing spondylitis, ulcerative colitis, psoriasis and Crohn’s disease.

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