Pharmaceuticals

Antivirals

A virus is a submicroscopic infectious agent that replicates only inside the living cells of organisms. When infected, a host cell is often forced to rapidly produce thousands of copies of the attacking virus. Viruses have different mechanisms by which they cause disease in human organism. Mechanism at the cellular level primarily include cell lysis, the breaking open and subsequent death of the cell. Because viruses use vital metabolic pathways within host cells to replicate, they are difficult to eliminate without using drugs. The most effective medical approaches to viral diseases are vaccinations to provide immunity to infection and antiviral drugs (antivirals) that selectively interfere with viral replication.

Hepatitis C

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, abdominal pain, and yellow tinged skin occurs. The virus persists in the liver in about 75% to 85% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer or dilated blood vessels in the esophagus and stomach. HCV is spread primarily by blood-to-blood contact associated with injection drug use, poorly sterilized medical equipment, needlestick injuries in healthcare and transfusions.

Sofosbuvir

Sofosbuvir ((2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro -3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]-amino]propanoate) is a drug used to treat hepatitis C infection. In combination with other therapies, Sofosbuvir can effectively cure hepatitis in 90 percent of patients. It inhibits the RNA polymerase that the hepatitis C virus uses to replicate its RNA. Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate. The triphosphate serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase and thus acts as an inhibitor of viral RNA synthesis.

Synhydrid® is used during Sofosbuvir synthesis in reduction step where lactone (fluorolactone dibenzoate) is reduced partially to corresponding lactol. For such kind of reduction Synhydrid® is too strong reducing agent. Therefore, before this reduction step Synhydrid® has to be modified by 1 equivalent of 2,2,2-trifluoroethanol to become milder. It means that during this modification sodium bis(2-methoxyethoxy)(2,2,2-trifluoroethoxy)aluminiumhydride is formed and this in-situ prepared reducing agent is then used for reduction of lactone to desired lactol. With Synhydrid® alone the reduction would continue to diol as product of total reduction and for reaching lactol stage the extremely low cryogenic reaction temperatures would have to be applied.

Synhydrid® can be also used in syntheses of other APIs effective against Hepatitis C, namely Boceprevir, Telaprevir and Valopicitabine.

Hepatitis B

Hepatitis B is an infectious disease caused by the Hepatitis B virus (HBV) that affects the liver. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. For others, symptoms may appear 30 to 180 days after becoming infected and can include a rapid onset of sickness with nausea, vomiting, yellowish skin, fatigue, dark urine and abdominal pain. Symptoms during acute infection typically last for a few weeks, though some people may feel sick for up to six months. Deaths resulting from acute stage HBV infections are rare. An HBV infection lasting longer than six months is usually considered chronic. Most of those with chronic disease have no symptoms; however, cirrhosis and liver cancer eventually develop in about 25% of those with chronic HBV. The HBV is transmitted by exposure to infectious blood or body fluids.

Synhydrid® can be used in several reducing steps during syntheses of Hepatitis B antivirals Lamivudine, Tenofovir and Entecavir.

HIV

The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. In most cases, HIV is a sexually transmitted infection.

Reducing potential of Synhydrid® could be used in syntheses of HIV antivirals Lamivudine, Tenofovir, Atazanavir, Emtricitabine, Lodenosine and Ritonavir. As you can see relatively many of HIV antivirals are also effective against HBV infections.

Covid-19

Coronavirus disease 2019 (Covid-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The symptoms of Covid 19 are variable but often include fever, cough, headache, fatigue, breathing difficulties, loss of smell and loss of taste. Symptoms may begin one to fourteen days after exposure to the virus. At least a third of people who are infected do not develop noticeable symptoms. Of those who develop symptoms noticeable enough to be classified as patients, most (81%) develop mild to moderate symptoms (up to mild pneumonia), while 14% develop severe symptoms (dyspnea, hypoxia or more than 50% lung involvement) and 5% develop critical symptoms (respiratory failure, shock or multiorgan dysfunction). Older people are at a higher risk of developing severe symptoms. Covid 19 dominantly transmits when people breathe air contaminated by droplets and small airborne particles containing the virus.

Nirmatrelvir/Ritonavir

Nirmatrelvir/ritonavir antivirals combination is sold under the brand name Paxlovid by company Pfizer as a co-packaged oral medication used as a treatment for Covid-19. This co-packaged medication is indicated for the treatment of mild to moderate Covid-19 in people aged twelve years of age and older weighing at least 40 kilograms with positive results of direct SARS-CoV-2 testing and who are at high risk for progression to severe Covid-19, including hospitalization or death. If administered within five days of symptom onset, the efficacy of the co-packaged medication against hospitalization or death in unvaccinated adults is about 88 %.

There exists several routes of Ritonavir synthesis with reducing steps in which Synhydrid® can provide very interesting results with high yield of desired reduction product.

Influenza

Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin from one to four days after exposure to the virus (typically two days) and last for about 2–8 days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection. Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.

Peramivir

Peramivir ((1S,2S,3R,4R)-3-[(1S)-1-(Acetylamino)-2-ethylbutyl]-4-(carbam-imidoylamino)-2-hydroxycyclopentanecarboxylic acid)) is an antiviral API for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells.

In one of the Peramivir synthetic route Synhydrid® can be used for reductive opening of heterocyclic ring containing bond between nitrogen and oxygen atoms resulting in forming of amine.

Alzheimer's disease treatment

Alzheimer's disease is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.

No treatments stop or reverse its progression, though some may temporarily improve symptoms. Affected people increasingly rely on others for assistance, often placing a burden on the caregiver. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioral problems or psychosis due to dementia are often treated with antipsychotics.

Donepezil

Donepezil ((RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one) is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of Alzheimer's disease. Common side effects include gastrointestinal upset. It has an oral bioavailability of 100% and easily crosses the blood–brain barrier. Because it has a biological half-life of about 70 hours, it can be taken once a day.

In Donepezil synthesis Synhydrid® can be used for reduction of ethyl-1-benzylpiperidin-4-carboxylate to (1-benzylpiperidin-4-yl)methanol, i.e. for reduction of carboxylic acid ester to corresponding alcohol.

Galantamine

Galantamine ((4aS,6R,8aS)- 5,6,9,10,11,12- hexahydro- 3-methoxy- 11-methyl- 4aH- [1]benzofuro[3a,3,2-ef] [2] benzazepin- 6-ol) is used for the treatment of mild to moderate Alzheimer's disease and various other memory impairments, in particular those of vascular origin.

Synhydrid® may be used during Galantamine synthesis for reduction of amide group to amine.

The other APIs for Alzheimer's disease treatment, for which syntheses Synhydrid® could be potentially used, are Rivastigmine, Idebenone, Debromoflustramine B and Physostigmine.

Chemotherapy medication

Chemotherapy is a type of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen. Anti-cancer drugs inhibits cell division (cytostatics or cytostatic agents) which prevent tumor growth.

Gemcitabine

Gemcitabine (4-amino-1-(2-deoxy-2,2-difluoro-β-D-erythro-pentofuranosyl)pyrimidin-2(1H)-on) is a nucleoside analog in which the hydrogen atoms on the 2' carbon of deoxycytidine are replaced by fluorine atoms. Gemcitabine is used in chemotherapy against various carcinomas: non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. It is being investigated for use in esophageal cancer and is used experimentally in lymphomas and various other tumor types. Gemcitabine represents an advance in pancreatic cancer care.

In one Gemcitabine synthesis pathway Synhydrid® is used for reduction of 3,5-bis(tertiary-butyl diphenyl sililoxy)-2-deoxy 2,2-difluoro-1-oxoribose to 3,5-bis(tertiary-butyl diphenyl sililoxy)-2-deoxy 2,2-difluororibose, i.e. for partial reduction of lactone to lactol.

The other anti-cancer APIs, in which syntheses Synhydrid® is usable, are e.g. Capecitabine, Camptothecin, Fostriecin, Paclitaxel, Romidepsin and Trabectedin.

Treatment of gastrointestinal disorders

Gastrointestinal disorders are a group of conditions that occur when the digestive system does not function as it should. These disorders can be split into two categories - organic and functional. Organic gastrointestinal disorders occur when there are structural abnormalities in the digestive system, which prevents it from working properly. In functional gastrointestinal disorders, the gastrointestinal tract appears to be structurally normal but still does not function well. Common gastrointestinal disorders are irritable bowel syndrome, small intestinal bacterial overgrowth, gastroesophageal reflux disease, gallstones, celiac disease, Crohn´s disease and ulcerative colitis.

Trimebutine

Trimebutine (2-(Dimethylamino)-2-phenylbutyl 3,4,5-trimethoxybenzoate) is an API with anti-muscarinic and weak mu opioid agonist effects. It is used for the treatment of irritable bowel syndrome and other gastrointestinal disorders. The major product from drug metabolism of trimebutine in human beings is nortrimebutine, which comes from removal of one of the methyl groups attached to the nitrogen atom.

During synthesis of Trimebutine Synhydrid® is used for reduction of methyl ester of 2-(dimethylamino)-2-phenyl butyric acid to 2-(dimethylamino)-2-phenylbutanol, i.e. for reduction of carboxylic acid ester to corresponding alcohol.

Synhydrid® can be used also in synthetic route for preparation of Mosapride, which is intended for the treatment of gastritis, gastro-oesophageal reflux disease, functional dyspepsia and irritable bowel syndrome.

Antihistamines

Antihistamines are drugs which treat allergies. Antihistamines suppress the histamine-induced wheal response (swelling) and flare response (vasodilation) by blocking the binding of histamine to its receptors or reducing histamine receptor activity on nerves, vascular smooth muscle, glandular cells, endothelium and mast cells. Antihistamines are subclassified according to the histamine receptor that they act upon. The two largest classes of antihistamines are H₁-antihistamines and H₂-antihistamines.

Fexofenadine

Fexofenadine ((±)-4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α, α-dimethyl benzeneacetic acid) is an antihistamine pharmaceutical drug used in the treatment of allergy symptoms, such as hay fever and urticaria. Therapeutically, fexofenadine is a selective peripheral H1 blocker. It is classified as a second-generation antihistamine because it is less able to pass the blood–brain barrier and cause sedation, compared to first-generation antihistamines. Fexofenadine is used for relief from physical symptoms associated with seasonal allergic rhinitis and for treatment of chronic urticaria. It does not cure, but rather prevents the aggravation of allergic rhinitis and chronic idiopathic urticaria, and reduces the severity of the symptoms associated with those conditions, providing relief from repeated sneezing, runny nose, itchy eyes or skin and general body fatigue.

During synthesis of Fexofenadine Synhydrid® can be used in early stage for reduction of methyl 2-methyl-2-phenylpropanoate to 2-methyl-2-phenylpropan-1-ol, i.e. for reduction of carboxylic acid ester to corresponding alcohol. This reduction runs very smoothly with very high yield of desired alcohol more than 99 %.