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Elobixibat hydrate, エロビキシバット水和物
Elobixibat
- Molecular FormulaC36H45N3O7S2
- Average mass695.888 Da
AJG-533
AZD-7806
Elobixibat hydrate
Approved 2018/1/19 Japan pmda
TRADE NAME Goofice to EA Pharma
| エロビキシバット水和物 |
C36H45N3O7S2▪H2O : 713.9
[1633824-78-8] CAS OF HYDRATE
Gooffice ® tablet 5 mg (hereinafter referred to as Gooffice ® ) is an oral chronic constipation remedy drug containing as active ingredient Erobi vat having bile acid transporter inhibitory action. It is the world’s first bile acid transporter inhibitor.
Elobixibat is an inhibitor of the ileal bile acid transporter (IBAT),[1] undergoing development in clinical trials for the treatment of chronic constipation and irritable bowel syndrome with constipation (IBS-C).
Mechanism of action
IBAT is the bile acid:sodium symporter responsible for the reuptake of bile acids in the ileum which is the initial step in the enterohepatic circulation. By inhibiting the uptake of bile acids, elobixibat increases the bile acid concentration in the gut, and this accelerates intestinal passage and softens the stool. Following several phase II studies, it is now undergoing phase III trials.[2]
Drug development
The drug was developed by Albireo AB, who licensed it to Ferring Pharmaceuticals for further development and marketing.[3] Albireo has partnered with Ajinomoto Pharmaceuticals, giving the Japan-based company the rights to further develop the drug and market it throughout Asia.[4]
- OriginatorAstraZeneca
- DeveloperAlbireo Pharma; EA Pharma
- Class2 ring heterocyclic compounds; Amides; Carboxylic acids; Laxatives; Small molecules; Sulfides; Sulfones; Thiazepines
- Mechanism of ActionSodium-bile acid cotransporter-inhibitors
- Orphan Drug StatusNo
- New Molecular EntityYes
Highest Development Phases
- RegisteredConstipation
- DiscontinuedDyslipidaemias; Irritable bowel syndrome
Most Recent Events
Approved 2018/1/19 japan pmda
- 24 Jan 2018Elobixibat is still in phase II trials for Constipation in Indonesia, South Korea, Taiwan, Thailand and Vietnam (Albireo pipeline, January 2018)
- 24 Jan 2018Discontinued – Phase-II for Irritable bowel syndrome in USA and Europe (PO) (Alberio pipeline, January 2018)
- 19 Jan 2018Registered for Constipation in Japan (PO) – First global approval
- In 2012, the compound was licensed to Ajinomoto (now EA Pharma) by Albireo for exclusive development and commercialization rights in several Asian countries. At the same year, the product was licensed to Ferring by Albireo worldwide, except Japan and a small number of Asian markets, for development and marketing. However, in 2015, this license between Ferring and Albireo was terminated and Albireo is seeking partner for in the U.S. and Europe. In 2016, Ajinomoto and Mochida signed an agreement on codevelopment and comarketing of the product in Japan.
Elobixibat
Elobixibat is an IBAT inhibitor approved in Japan for the treatment of chronic constipation, the first IBAT inhibitor to be approved anywhere in the world. EA Pharma Co., Ltd., a company formed via a 2016 combination of Eisai’s GI business with Ajinomoto Pharmaceuticals and focused on the gastrointestinal disease space, is the exclusive licensee of elobixibat for the treatment of gastrointestinal disorders in Japan and other select countries in Asia (not including China) and is expected to co-market elobixibat in Japan with Mochida Pharmaceutical Co., Ltd., and to co-promote elobixibat in Japan with Eisai, under the trade name GOOFICE®.
We also believe that elobixibat has potential benefit in the treatment of NASH based on findings on relevant parameters in clinical trials of elobixibat that we previously conducted in patients with chronic constipation and in patients with elevated cholesterol and findings on other parameters relevant to NASH from nonclinical studies that we previously conducted with elobixibat or a different IBAT inhibitor. In particular, in a clinical trial in dyslipidemia patients, elobixibat given for four weeks reduced low-density lipoprotein (LDL) cholesterol, with the occurrence of diarrhea being substantially the same as the placebo group. Also, in other clinical trials in constipated patients, elobixibat given at various doses and for various durations reduced LDL-cholesterol and, in one trial, increased levels of glucagon-like peptide 1 (GLP-1). Moreover, A4250 (an IBAT inhibitor) showed significant improvement (p < 0.05) on the nonalcoholic fatty liver disease activity score in an established model of NASH in mice known as the STAM™ model and improvement in liver inflammation and fibrosis in another preclinical mouse model. We are considering conducting a Phase 2 clinical trial of elobixibat in NASH
These benzothiazepines possess ileal bile acid transport (IBAT) inhibitory activity and accordingly have value in the treatment of disease states associated with hyperlipidaemic conditions and they are useful in methods of treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said benzothiazepine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit IBAT in a warm-blooded animal, such as man.
It is well-known that hyperlipidaemic conditions associated with elevated
concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for cardiovascular atherosclerotic disease (for instance “Coronary Heart Disease: Reducing the Risk; a Worldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999, 100, 1930-1938 and “Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association” Grundy S, Benjamin I., Burke G., et al; Circulation, 1999, 100, 1134-46). Interfering with the circulation of bile acids within the lumen of the intestinal tracts is found to reduce the level of cholesterol. Previous established therapies to reduce the concentration of cholesterol involve, for instance, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders, such as resins. Frequently used bile acid binders are for instance cholestyramine and cholestipol. One recently proposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) involved the treatment with substances with an IBAT inhibitory effect.
Re-absorption of bile acid from the gastro-intestinal tract is a normal physiological process which mainly takes place in the ileum by the IBAT mechanism. Inhibitors of EBAT can be used in the treatment of hypercholesterolaemia (see for instance “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties”, Biochemica et Biophysica Acta, 1210 (1994) 255- 287). Thus, suitable compounds having such inhibitory IBAT activity are also useful in the treatment of hyperlipidaemic conditions.
Compounds possessing such IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/50051 and EP 0 864 582.
A further aspect of this invention relates to the use of the compounds of the invention in the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In addition, these compounds are expected to be useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocytes, monocytes and/or macrophage infiltration, intimal thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks.
PATENTS
WO 2002050051
| STARKE, Ingemar; (SE). DAHLSTROM, Mikael; (SE). BLOMBERG, David; (SE) |
ASTRAZENECA
SYNTHESIS
WO 2002050051, WO 1996016051
PATENT
WO 2003051821
WO 2003020710
TW I291951
WO 2013063512
WO 2013063526
US 20140323412
EP 3012252
PATENT
https://patents.google.com/patent/WO2003020710A1/und
PATENT
WO 02/50051 discloses the compound 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘- [/V-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (elobixibat; lUPAC name: /V-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenyl-ethanolyl}glycine). This compound is an ileal bile acid transporter (I BAT) inhibitor, which can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases. According to the experimental section of WO 02/50051 , the last synthetic step in the preparation of elobixibat consists of the hydrolysis of a ie f-butoxyl ester under acidic conditions. The crude compound was obtained by evaporation of the reaction mixture under reduced pressure and purification of the residue by preparative HPLC using acetonitrile/ammonium acetate buffer (50:50) as eluent (Example 43). After freeze drying the product, no crystalline material was identified.
Example 1
Preparation of crystal modification I
Toluene (1 1 .78 L) was charged to a 20 L round-bottom flask with stirring and 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘-[/\/’-(i-butoxycarbonylmethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (2.94 kg) was added. Formic acid (4.42 L) was added to the reaction mass at 25-30 °C. The temperature was raised to 1 15-120 °C and stirred for 6 hours. The reaction was monitored by HPLC to assure that not more than 1 % of the starting material remained in the reaction mass. The reaction mass was cooled to 40-43 °C. Purified water (1 1 .78 L) was added while stirring. The reaction mass was further cooled to 25-30 °C and stirred for 15 min.
The layers were separated and the organic layer was filtered through a celite bed (0.5 kg in 3 L of toluene) and the filtrate was collected. The celite bed was washed with toluene (5.9 L), the filtrates were combined and concentrated at 38-40 °C under vacuum. The reaction mass was then cooled to 25-30 °C to obtain a solid.
Ethanol (3.7 L) was charged to a clean round-bottom flask with stirring, and the solid obtained in the previous step was added. The reaction mass was heated to 40-43 °C and stirred at this temperature for 30 min. The reaction mass was then cooled to 25-30 °C over a period of 30 min., and then further cooled to 3-5 °C over a period of 2 h, followed by stirring at this temperature for 14 h. Ethanol (3.7 L) was charged to the reaction mass with stirring, while maintaining the temperature at 0-5 °C, and the reaction mass was then stirred at this temperature for 1 h. The material was then filtered and washed with ethanol (1 .47 L), and vacuum dried for 30 min. The material was dried in a vacuum tray dryer at 37-40 °C for 24 h under nitrogen atmosphere. The material was put in clean double LDPE bags under nitrogen atmosphere and stored in a clean HDPE drum. Yield 1 .56 kg.
Crystal modification I has an XRPD pattern, obtained with CuKal -radiation, with
characteristic peaks at °2Θ positions: 3,1 ± 0.2, 4,4 ± 0.2, 4,9 ± 0.2, 5,2 ± 0.2, 6,0 ± 0.2, 7,4 ± 0.2, 7,6 ± 0.2, 7,8 ± 0.2, 8,2 ± 0.2, 10,0 ± 0.2, 10,5 ± 0.2, 1 1 ,3 ± 0.2, 12,4 ± 0.2, 13,3 ± 0.2, 13,5 ± 0.2, 14,6 ± 0.2, 14,9 ± 0.2, 16,0 ± 0.2, 16,6 ± 0.2, 16,9 ± 0.2, 17,2 ± 0.2, 17,7 ± 0.2, 18,0 ± 0.2, 18,3 ± 0.2, 18,8 ± 0.2, 19,2 ± 0.2, 19,4 ± 0.2, 20,1 ± 0.2, 20,4 ± 0.2, 20,7 ± 0.2, 20,9 ± 0.2, 21 ,1 ± 0.2, 21 ,4 ± 0.2, 21 ,8 ± 0.2, 22,0 ± 0.2, 22,3 ± 0.2, 22,9 ± 0.2, 23,4 ± 0.2, 24,0 ± 0.2, 24,5 ± 0.2, 24,8 ± 0.2, 26,4 ± 0.2,‘27,1 ± 0.2 and 27,8 ± 0.2. The X-ray powder diffractogram is shown in FIG. 4.
PATENT
WO 2014174066
| エロビキシバット水和物 Elobixibat Hydrate C36H45N3O7S2▪H2O : 713.9 [1633824-78-8] |
References
- Jump up^ “INN for A3309 is ELOBIXIBAT”. AlbireoPharma. Archived from the original on 18 January 2012. Retrieved 5 December 2012.
- Jump up^ Acosta A, Camilleri M (2014). “Elobixibat and its potential role in chronic idiopathic constipation”. Therap Adv Gastroenterol. 7 (4): 167–75. doi:10.1177/1756283X14528269. PMC 4107709
. PMID 25057297. - Jump up^ Grogan, Kevin. “Ferring acquires rights to Albireo’s bowel drug”. PharmaTimes. Retrieved 23 March 2017.
- Jump up^ “Ajinomoto Pharmaceuticals and Albireo Announce Japan and Asia License Agreement for Elobixibat”. Albireo. Retrieved 5 December2012.[permanent dead link]
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| Routes of administration |
Oral |
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| Formula | C36H45N3O7S2 |
| Molar mass | 695.89 g/mol |
| 3D model (JSmol) | |
//////////Elobixibat hydrate, japan 2018, A-3309, AJG-533, Goofice, A 3309, AJG 533, AZD 7806
CCCCC1(CN(C2=CC(=C(C=C2S(=O)(=O)C1)OCC(=O)NC(C3=CC=CC=C3)C(=O)NCC(=O)O)SC)C4=CC=CC=C4)CCCC
FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk) for patients who have limited treatment options
Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. Continue reading.
March 6, 2018
Release
Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications.
“While most patients living with HIV can be successfully treated using a combination of two or more antiretroviral drugs, a small percentage of patients who have taken many HIV drugs in the past have multidrug resistant HIV, limiting their treatment options and putting them at a high risk of HIV-related complications and progression to death,” said Jeff Murray, M.D., deputy director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Trogarzo is the first drug in a new class of antiretroviral medications that can provide significant benefit to patients who have run out of HIV treatment options. New treatment options may be able to improve their outcomes.”
The safety and efficacy of Trogarzo were evaluated in a clinical trial of 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Many of the participants had previously been treated with 10 or more antiretroviral drugs. The majority of participants experienced a significant decrease in their HIV-RNA levels one week after Trogarzo was added to their failing antiretroviral regimens. After 24 weeks of Trogarzo plus other antiretroviral drugs, 43 percent of the trial’s participants achieved HIV RNA suppression.
The clinical trial focused on the small patient population with limited treatment options and demonstrated the benefit of Trogarzo in achieving reduction of HIV RNA. The seriousness of the disease, the need to individualize other drugs in the treatment regimen, and safety data from other trials were considered in evaluating the Trogarzo development program.
A total of 292 patients with HIV-1 infection have been exposed to Trogarzo IV infusion. The most common adverse reactions to Trogarzo were diarrhea, dizziness, nausea and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome).
The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. Trogarzo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted approval of Trogarzo to TaiMed Biologics USA Corp.
Theratechnologies Announces FDA Approval of Breakthrough Therapy, Trogarzo™ (ibalizumab-uiyk) Injection, the First HIV-1 Inhibitor and Long-Acting Monoclonal Antibody for Multidrug Resistant HIV-1
- First HIV treatment approved with a new mechanism of action in more than 10 years
- Infused every two weeks, only antiretroviral treatment (ART) that does not require daily dosing
- Trogarzo™ has no drug-drug interactions and no cross-resistance with other ARTs
MONTREAL, March 6, 2018 /PRNewswire/ – Theratechnologies Inc. (Theratechnologies) (TSX: TH) and its partner TaiMed Biologics, Inc. (TaiMed) today announced that the U.S. Food and Drug Administration (FDA) has granted approval of Trogarzo™ (ibalizumab-uiyk) Injection. In combination with other ARTs, Trogarzo™ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.1
Trogarzo™ represents a critical new treatment advance as the first HIV therapy with a new mechanism of action approved in 10 years and proven effectiveness in difficult-to-treat patients with limited options. Unlike all other classes of ARTs, Trogarzo™ is a CD4-directed post-attachment HIV-1 inhibitor that binds to CD4+ receptors on host cells and blocks the HIV virus from infecting the cells.1
“Today’s approval of Trogarzo™ by the FDA is great news for people infected with difficult-to-treat multidrug resistant HIV. We look forward to bringing this much-needed therapy to patients in the U.S within six weeks,” said Luc Tanguay, President and Chief Executive Officer, Theratechnologies Inc. “We are grateful to the patients, investigators, as well as the FDA who supported the clinical development of Trogarzo™, and are helping address this critical unmet medical need.”
Trogarzo™ previously received Breakthrough Therapy and Orphan Drug designations as well as Priority Review status from the FDA, underscoring the significance of the treatment for this patient population.
“I witnessed some of the earliest cases of HIV and AIDS, at a time when the diagnosis was terrifying to patients because in many cases it was a death sentence,” said David Ho, M.D., chief scientific advisor of TaiMed and scientific director and CEO of the Aaron Diamond AIDS Research Center. “Since then, treatment advances and the discovery that combinations of ARTs was the best way to bring viral load below the level of detection have allowed most people to manage HIV like a chronic condition and live long, healthy lives. However, this is not the reality for people whose HIV is resistant to multiple drugs and whose viral load is not controlled, which is why TaiMed dedicated the past decade to advancing ibalizumab in the clinic. For these patients, it represents the next breakthrough.”
Up to 25,000 Americans with HIV are currently multidrug resistant, of which 12,000 are in urgent need of a new treatment option because their current treatment regimen is failing them and their viral load has risen to detectable levels, jeopardizing their health and making HIV transmittable.2-13 The best way to prevent the transmission of multidrug resistant HIV is to control the virus in those living with it. According to new guidance from the Centers for Disease Control and Prevention (CDC), the HIV virus cannot be transmitted if it is being fully suppressed.13
“I’ve struggled with multidrug resistant HIV for almost 30 years and it was completely debilitating to feel like I had run out of options – I made no long-term plans,” said Nelson Vergel, founder of the Program for Wellness Restoration (PoWeR) and Trogarzo™ patient. “Since starting treatment with Trogarzo™ six years ago and getting my viral load to an undetectable level, I have been my happiest, most productive self. Trogarzo™ is a new source of hope and peace of mind for people whose treatments have failed them, and I feel incredibly lucky to have been able to participate in the clinical trial program.”
TaiMed and Theratechnologies partnered on the development of Trogarzo™ so patients who can benefit from the treatment have access to it. For patients who need assistance accessing Trogarzo™ or who face challenges affording medicines, Theratechnologies has a team of patient care coordinators available to help. Patients can get assistance and expert support by contacting THERA patient support™ at 1-833-23-THERA (84372).
“In Phase 3 ibalizumab trials, we saw marked improvements in patients’ health who not only were heavily treatment-experienced and had limited remaining treatment options, but in cases they also had extremely high viral loads and significantly impaired immune systems,” said Edwin DeJesus, M.D., Medical Director for the Orlando Immunology Center. “As an investigator for ibalizumab clinical trials over nearly 10 years, it was remarkable and inspiring to see the dramatic effect ibalizumab had on such vulnerable patients. As a clinician, I am excited that we will now have another option with a different mechanism of action for our heavily pretreated patients who are struggling to keep their viral load below detection because their HIV is resistant to multiple drugs.”
Clinical Trial Findings
Clinical studies show that Trogarzo™, in combination with other ARTs, significantly reduces viral load and increases CD4+ (T-cell) count among patients with multidrug resistant HIV-1.
The Phase 3 trial showed:1
- Trogarzo™ significantly reduced viral load within seven days after the first dose of functional monotherapy and maintained the treatment response when combined with an optimized background regimen that included at least one other active ART for up to 24 weeks of treatment, while being safe and well tolerated.
- More than 80% of patients achieved the study’s primary endpoint – at least a 0.5 log10 (or 70%) viral load reduction from baseline seven days after receiving a 2,000 mg loading dose of Trogarzo™ and no adjustment to the failing background regimen.
- The average viral load reduction after 24 weeks was 1.6 log10 with 43% of patients achieving undetectable viral loads.
Patients experienced a clinically-significant mean increase in CD4+ T-cells of 44 cells/mm3, and increases varied based on T-cell count at baseline. Rebuilding the immune system by increasing T-cell count is particularly important as people with multidrug resistant HIV-1 often have the most advanced form of HIV.1
The most common drug-related adverse reactions (incidence ≥ 5%) were diarrhea (8%), dizziness (8%), nausea (5%) and rash (5%). No drug-drug interactions were reported with other ARTs or medications, and no cross-resistance with other ARTs were observed.1
About Trogarzo™ (ibalizumab-uiyk) Injection
Trogarzo™ is a humanized monoclonal antibody for the treatment of multidrug resistant HIV-1 infection. Trogarzo™ binds primarily to the second extracellular domain of the CD4+ T receptor, away from major histocompatibility complex II molecule binding sites. It prevents HIV from infecting CD4+ immune cells while preserving normal immunological function.
IMPORTANT SAFETY INFORMATION
Trogarzo™ is a prescription HIV medicine that is used with other antiretroviral medicines to treat human immunodeficiency virus-1 (HIV-1) infections in adults.
Trogarzo™ blocks HIV from infecting certain cells of the immune system. This prevents HIV from multiplying and can reduce the amount of HIV in the body.
Before you receive Trogarzo™, tell your healthcare provider if you:
- are pregnant or plan to become pregnant. It is not known if Trogarzo™ may harm your unborn baby.
- are breastfeeding or plan to breastfeed. It is not known if Trogarzo™ passes into breast milk.
Tell your healthcare provider about all the medicines you take, including all prescription and over-the-counter medicines, vitamins, and herbal supplements.
Trogarzo™ can cause serious side effects, including:
Changes in your immune system (Immune Reconstitution Inflammatory Syndrome) can happen when you start taking HIV-1 medicines. Your immune system might get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your health care provider right away if you start having new symptoms after starting your HIV-1 medicine.
The most common side effects of Trogarzo™ include:
- Diarrhea
- Dizziness
- Nausea
- Rash
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Trogarzo™. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to at 1-833-23THERA (1-833-238-4372).
About Theratechnologies
Theratechnologies (TSX: TH) is a specialty pharmaceutical company addressing unmet medical needs to promote healthy living and an improved quality of life among HIV patients. Further information about Theratechnologies is available on the Company’s website at www.theratech.com and on SEDAR at www.sedar.com.
/////Trogarzo, ibalizumab-uiyk, fda 2018, Fast Track, Priority Review, Breakthrough Therapy designations, Orphan Drug designation
Forodesine Hydrochloride
Forodesine
- Molecular FormulaC11H14N4O4
- Average mass266.253 Da
CAS No. : 284490-13-7
Molecular Formula: C11H15ClN4O4
Average Mass: 302.72 g/mol
Forodesine (INN; also known as Immucillin H; trade names Mundesine and Fodosine) is a transition-state analog inhibitor of purine nucleoside phosphorylase[1] studied for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and for treatment of B-cell acute lymphocytic leukemia (B-ALL).
Forodesine was originally discovered by Vern Schramm‘s laboratory at the Albert Einstein College of Medicine in New York and Industrial Research Limited in New Zealand.
Forodesine is being developed by BioCryst Pharmaceuticals. As of 2008, it is currently in phase II clinical trials.[2].
In 2006, BioCryst entered into a licensing agreement with Mundipharma International Holdings Limited to develop and commercialize forodesine in markets across Europe, Asia, and Australasia for use in oncology.[3]
In April 2017, forodesine was approved in Japan for the treatment of relapsed/refractory peripheral T-cell lymphoma.[4]
ema
On 20 September 2010, orphan designation (EU/3/10/780) was granted by the European Commission to Mundipharma Research Limited, United Kingdom, for forodesine for the treatment of chronic lymphocytic leukaemia
| Active substance | Forodesine hydrochloride |
|---|---|
| Decision number | P/69/2010 |
| PIP number | EMEA-000785-PIP01-09 |
| Pharmaceutical form(s) | Hard capsule |
| Condition(s)/indication(s) | Cutaneous T-cell lymphoma (CTCL) |
| Route(s) of administration | Oral use |
| PIP applicant | Applicant: Mundipharma Research Ltd E-mail: paediatric@mundipharma-rd.eu Country: United Kingdom Phone: +44 1223424900 Fax: +44 1223426054 |
| Decision type | W: decision granting a waiver in all age groups for the listed condition(s) |
On 20 September 2010, orphan designation (EU/3/10/780) was granted by the European Commission to Mundipharma Research Limited, United Kingdom, for forodesine for the treatment of chronic lymphocytic leukaemia.
What is chronic lymphocytic leukaemia?
Chronic lymphocytic leukaemia (CLL) is cancer of a type of white blood cell called B lymphocytes. In this disease, the lymphocytes multiply too quickly and live for too long, so that there are too many of them circulating in the blood. The cancerous lymphocytes look normal, but they are not fully developed and do not work properly. Over a period of time, the abnormal cells replace the normal white blood cells, red blood cells and platelets (components that help the blood to clot) in the bone marrow (the spongy tissue inside the large bones in the body). CLL is the most common type of leukaemia and mainly affects older people. It is rare in people under the age of 40 years. CLL is a long-term debilitating and life-threatening disease because some patients develop severe infections. What is the estimated number of patients affected by the condition? At the time of designation, CLL affected approximately 3 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 152,000 people, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).
What treatments are available? Treatment for CLL is complex and depends on a number of factors, including the extent of the disease, whether it has been treated before, and the patient’s age, symptoms and general state of health. Patients whose CLL is not causing any symptoms or is only getting worse very slowly may not need
Forodesine Hydrochloride was originally developed by BioCryst Pharmaceuticals and then licensed to Mundipharma and in particular is marketed in Japan under the trade name Mundesine®. Forodesine Hydrochloride is a transitional analogue inhibitor of purine nucleoside phosphorylase (PNP). Mundesine® is approved for the treatment of peripheral T-cell lymphoma (PTCL).
Mundesine® is a capsule that contains 100mg of free Forodesine per capsule. The recommended dose is 300mg orally, twice daily.
In 2004, the compound was eligible for orphan drug treatment for non-Hodgkin’s lymphoma (NHL), chronic myelogenous leukemia (CLL) and hairy cell leukemia, respectively. In 2007, the compound was eligible for the EU orphan drug for the treatment of acute lymphoblastic leukemia (ALL) and cutaneous T-cell lymphoma (CTCL). In 2010, the compound was eligible for EU orphan drug for treatment of CLL. In 2006, the compound obtained Japanese orphan drug eligibility for CTCL treatment.
Forodesine, or 7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-pyrrolidinyl]-l,5-dihydropyrrolo[2,3-e]pyrimidin-4-one, is an inhibitor of purine nucleoside phosphorylase. It is currently in development as a treatment for peripheral T-Cell Lymphoma .
W099/19338 describes a compound genus as a new class of inhibitors of nucleoside metabolism, including Forodesine. The compounds effect as inhibitors of purine nucleoside phosphorylase is taught as efficacious to suppress T-cell function and to treat infections caused by protozoan parasites.
WO00/61783 describes a number of processes for preparing molecules described in W099/19338. Reaction scheme 3 on page 23 of the published application describes a synthesis of Forodesine, characterised by the removal of two acid labile protecting groups in the final step to yield the hydrochloride salt.
Forodesine is a particularly difficult molecule to make on a commercial scale. The current process for manufacture requires a coupling reaction under cryogenic temperature conditions of -55C. Subsequent steps involve the use of a high pressure hydrogenation reaction. Such extreme reaction conditions provide for safety concerns, particularly when conducted on a bulk scale. Further the products of the reaction were extremely challenging to purify. The effect of all this is to require more sophisticated and expensive equipment at the manufacturing plant; all of which add up to an increased cost of goods for patients. Accordingly a new manufacturing process was sought.
Surprisingly a new route has been invented which is shorter, cheaper, less dangerous and provides an increased overall yield whilst still conforming to the required purity profile.
The current manufacturing process is described in Fig 1.
5C
, MeOH, reflux xchange
tallisation
Fig l
Within the diagram, the following acronyms are used, wherein NCS is N-Chlorosuccinimide, OTBDMS is t-butyldimethylsiloxy protecting group, MtBE is methyl t-butyl ether, (BOC)20 is di-t-butyldicarbonate and BOC is t-butyloxycarbonyl protecting group,
Particularly problematic in this process is the requirement to conduct the coupling of process step (iii) at exceptionally low temperature. Further challenges are provided by process step (v) the hydrogenation reaction to remove the benxylyoxymethyl (BOM) protecting group, before removing the other acid labile protecting groups.
Conducting hydrogenation reactions with their need for a high pressure environment requires specialist equipment. Such apparatus is expensive, adding to the cost of the materials produced. Despite the use of specialist equipment, safety concerns can never be eradicated. Whilst BOM can, in certain circumstances, be acid labile, treatment of analogues of the molecules described in Fig 1 with acid has always resulted in incomplete removal of the protecting group, leading to a large number of partially deprotected impurities. This makes purification exceptionally difficult as well as reducing the overall yield for the step.
A new improved process has been developed as described in Fig 2:
Toluene
Fig 2
The new route has a number of clear advantages. The coupling reaction (ix) is conducted at a warmer -15°C, rather than the challenging cryogenic conditions of -55°C required previously. It eradicates the hydrogenation step, avoiding the need for dangerous high pressure conditions. It also makes the overall process much quicker and cheaper; not only are the conditions challenging, but the reagents used in large quantities such as palladium are expensive and environmentally challenging.
The classical method to remove a BOM protecting group is by catalytic hydrogenation. It is however known to be unstable in acid conditions. For this reasons there have been previous attempts to remove BOM at the same time as the three acid labile protecting groups. This has always been unsuccessful as treatment with acid typically resulted in incomplete deprotection, leading to a mixture of products. This made for a tricky purification and a reduced yield. Surprisingly under the particular conditions described herein it has been possible to effect the transformation in greater yield and without a difficult purification. The final product is obtained in equal or greater purity than material obtained from the previous route.
PATENT
Scheme 13
HO OH 1 . HCI/Acetone, MeOH OCH,
2. PPh3, imidazole I
HO (EtO)2POCH2CN
OH O O
Ribose Λ 13a
References for preparation of compound 13a:
1. Mishra, Girija Prasad; Rao, Batchu Venkateswara; Tetrahedron: Asymmetry (2011), 22(7), 812-817.
2. Brock, E. Anne; Davies, Stephen G.; Lee, James A.; Roberts, Paul M.; Thomson,
James E; Organic Letters (2011), 13(7), 1594-1597.
3. WO 2010/085377 A2 (incorporated by reference).
4. Yadav, J. S.; Reddy, P. Narayana; Reddy, B. V. Subba; Synlett (2010), (3), 457- 461.
5. Song, Kai; Zheng, Guo-jun; Huaxue Shiji (2010), 32(2), 171-172.
6. Prabhakar, Peddikotla; Rajaram, Singanaboina; Reddy, Dorigondla Kumar;
Shekar, Vanam; Venkateswarlu, Yenamandra; Tetrahedron: Asymmetry (2010), 21(2), 216-221.
7. CN 101182342 A.
8. Baird, Lynton J.; Timmer, Mattie S. M.; Teesdale-Spittle, Paul H.; Harvey, Joanne
E; Journal of Organic Chemistry (2009), 74(6), 2271-2277.
9. Wang, Xiang-cheng; Wang, Gang; Qu, Gang-lian; Huaxue Shijie (2008), 49(4), 226-228.
10. Ivanova, N. A.; Valiullina, Z. R.; Shitikova, O. V.; Miftakhov, M. S; Russian
Journal of Organic Chemistry (2007), 43(5), 742-746.
11. Braga, Fernanda Gambogi; Coimbra, Elaine Soares; Matos, Magnum de Oliveira;
Lino Carmo, Arturene Maria; Cancio, Marisa Damato; da Silva, Adilson David; European Journal of Medicinal Chemistry (2007), 42(4), 530-537.
12. Wender, Paul A.; Bi, F. Christopher; Buschmann, Nicole; Gosselin, Francis; Kan, Cindy; Kee, Jung-Min; Ohmura, Hirofumi; Organic Letters (2006), 8(23), 5373- 5376.
13. Fei, Xiangshu; Wang, Ji-Quan; Miller, Kathy D.; Sledge, George W.; Hutchins, Gary D.; Zheng, Qi-Huang; Nuclear Medicine and Biology (2004), 31(8), 1033- 1041.
14. Abdel-Rahman, Adel A.-H.; Abdel-Megied, Ahmed E.-S.; Goda, Adel E.-S.; Zeid,
Ibrahim F.; El Ashry, El Sayed H; Nucleosides, Nucleotides & Nucleic Acids (2003), 22(11), 2027-2038.
15. Palmer, Andreas M.; Jager, Volker; European Journal of Organic Chemistry
(2001), (7), 1293-1308.
16. Paquette, Leo A.; Bailey, Simon; Journal of Organic Chemistry (1995), 60(24),
7849-56.
17. Classon, Bjoern; Liu, Zhengchun; Samuelsson, Bertil; Journal of Organic
Chemistry (1988), 53(26), 6126-30.
18. Kissman, Henry M.; Baker, B. R; Journal of the American Chemical Society
(1957), 79 5534-40.
References for cyclizations related to preparation of compounds of type 13d:
1. Davies, Stephen G.; Durbin, Matthew J.; Goddard, Euan C; Kelly, Peter M.;
Kurosawa, Wataru; Lee, James A.; Nicholson, Rebecca L.; Price, Paul D.;
Roberts, Paul M.; Russell, Angela J.; Scott, Philip M.; Smith, Andrew D; Organic & Biomolecular Chemistry (2009), 7(4), 761-776.
2. Davies, Stephen G.; Nicholson, Rebecca L.; Price, Paul D.; Roberts, Paul M.;
Russell, Angela J.; Savory, Edward D.; Smith, Andrew D.; Thomson, James E; Tetrahedron: Asymmetry (2009), 20(6-8), 758-772.
3. Davies, Stephen G.; Nicholson, Rebecca L.; Price, Paul D.; Roberts, Paul. M.;
Smith, Andrew D; Synlett (2004), (5), 901-903.
4. Brock, E. Anne; Davies, Stephen G.; Lee, James A.; Roberts, Paul M.; Thomson, James E; Organic Letters (2011), 13(7), 1594-1597.
5. Gary B. Evans, Richard H. Furneaux, Andrzej Lewandowicz, Vern L. Schramm, and Peter C. Tyler, Journal of Medicinal Chemistry (2003), 46, 3412-3423.
PATENT
WO 2016110527
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016110527
The invention also provides for the synthesis of a compound of formula (II)
By reacting a compound of Formula (VII)
With di-t-butyldicarbonate.
Preferably the reaction is conducted at -10 to -20°C, in methyl t-butyl ether & heptane
The invention also provides for the synthesis of a compound of formula (VII)
By reacting a compound of Formula (IV)
With a suitable base to form
Before reacting with a compound of Formula (III)
Example 1
Stage 1 Manufacture of (III)
Compound of formula (III) (approx. 130g) in toluene solution is added to a suspension of N-Chlorosuccinimide in toluene at 20°C over a period of 90min. The reaction mixture is stirred at 20°C for 1 hour then chilled to 0°C and stirred for a further hour. The precipitated succinimide by-product is removed by filtration and the filtered solution charged directly to a 45% potassium hydroxide solution (aq) containing
tetrabutylammonium bromide. The reaction mixture is stirred at 0°C and completion of reaction is confirmed by GC analysis. Water is then added to the two-phase mixture to dissolve inorganic precipitates and the toluene product solution is washed with a 28% ammonium hydroxide/acetic acid buffer mixture with sodium chloride added. After phase separation the organic phase solution is stabilised with triethylamine. Magnesium sulfate is added to dry the solution. After filtration, the yield of (III) is determined by R.O.E. and GC purity.
Stage 2 Manufacture of (II)
Stage 2a Lithiation
A suspension of compound of formula (IV) (approx. 200g) in MtBE is chilled to -15°C and treated with /7-Hexyl lithium (2.5M in hexanes) added over 2h, maintaining the reaction mixture at -15°C. The mixture is then stirred for 3h at -15°C.
Stage 2b Coupling with (IV)
After lithiation is complete, a compound formula (III) in toluene solution is added to the reaction mixture maintaining the contents at -15°C. The reaction mixture is then stirred at this temperature for 1.5h.
Stage 2c Boc anhydride quench
A solution of di-t-butyldicarbonate in MtBE is added to the above reaction mixture at -15°C. The solution is stirred for a further 30min.
Workup and Purification
The reaction mixture is quenched by addition of RO water, then filtered. The aqueous layer is separated and run to waste. The organic layer is again washed with water. The organic layer is concentrated to a low volume and solvent replaced by heptane. The mix is stirred for 16h and filtered again.
The solution is passed through a silica gel column and eluted with heptane. The resulting solution is treated with charcoal – stirred for 3h, then filtered. The product (II) is progressed as a solution in heptane to the next stage.
Stage 3 Manufacture of Crude Forodesine (la)
Stage 3 Deprotection with cone. HCI
Concentrated hydrochloric acid is added to (II) in heptane and the mixture stirred. The acid phase is separated off and stirred for 16h at ambient temperature. The solution is then heated to 40°C for 6h. The water is then distilled off under reduced pressure to a minimum volume.
Ethanol is then added to precipitate the crude Forodesine (la) which is isolated by filtration after cooling 0-5°C. It is washed with ethanol and dried in a vacuum oven at 75°C to a constant weight.
Stage 4a Decolourization of crude Forodesine (la) using Ion-Exchange Column
Crude Forodesine (la) is dissolved in water and loaded onto a freshly prepared ion-exchange column containing Dowex 50WX4 resin in the Na+ form activated with 30% sodium hydroxide solution. The ion-exchange column is eluted with 4 x lOOmL water followed by 4 x lOOmL 2M HCI. The HCI fractions are collected separately as they contain the desired product. The 2M HCI fractions are combined and concentrated under vacuum with minimum RO water added to dissolve the residue. 1,4-Dioxane is added to the aqueous solution to precipitate the product. The mixture is stirred at 20°C for 1.5h. The product is filtered, washed with 1,4-dioxane and dried in a vacuum oven at 35°C to a constant weight to give decolourised BCX1777.
Stage 4b Recrystallization of Forodesine
Decolourised Forodesine is added to in 0.6M dilute hydrochloric acid and heated to 45°C to dissolve. The resulting solution is hot filtered and washed through with some RO Water. The solution is cooled to 20°C and ethanol added over at least lh. The mixture is then seeded with Forodesine HCI. The resulting slurry is stirred for 8h at 20°C, then cooled to 2°C for a further 1.5h. The product is isolated by filtration, washed twice with cold ethanol then dried in a vacuum oven at 75°C to a constant weight to give a white crystalline Forodesine HCI (approx. 50g).
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one of skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. Moreover, all embodiments described herein are considered to be broadly applicable and combinable with any and all other consistent embodiments, as appropriate.
PAPER
Journal of Medicinal Chemistry (2009), 52(4), 1126-1143.
Third-Generation Immucillins: Syntheses and Bioactivities of Acyclic Immucillin Inhibitors of Human Purine Nucleoside Phosphorylase
* To whom correspondence should be addressed. Phone: +64-4-9313040. Fax: +64-4-9313055. E-mail: g.evans@irl.cri.nz., †
Carbohydrate Chemistry Team, Industrial Research Limited.
, ‡
Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University.
References
- Jump up^ Kicska GA, Long L, Hörig H, et al. (April 2001). “Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes”. Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4593–8. Bibcode:2001PNAS…98.4593K. doi:10.1073/pnas.071050798. PMC 31879 . PMID 11287638.
- Jump up^ “Complete list of clinical trials for forodesine (BCX-1777) (ClinicalTrials.gov)”. Retrieved 2008-07-22.
- Jump up^ “Biocryst Initiates Pivotal Fodosine Phase IIb Clinical Trial In Patients With Relapsed/Refractory T-Lymphoblastic Leukemia/Lymphoma”(Press release). January 16, 2007.
- Jump up^ “BioCryst Announces Mundipharma Receives Approval for Mundesine® in Japan” (Press release). April 3, 2017.
External links
- “From cell biology to therapy: forodesine”. Hematology Meeting Reports. 2 (5): 106–111. 2008.
- Gore, L; Stelljes, M; Quinones, R (2007). “Forodesine treatment and post-transplant graft-versus-host disease in two patients with acute leukemia: Facilitation of graft-versus-leukemia effect?”. Seminars in Oncology. 34 (6 Suppl 5): S35–9. doi:10.1053/j.seminoncol.2007.11.005. PMID 18086346.
- 18 December 2006 Fodosine orphan designation by the European Commission for acute lymphoblastic leukaemia.
- BioCryst Pharmaceuticals, Inc. have entered into an exclusive license agreement with Mundipharma for develop and commercialize BioCryst’s lead compound, Forodesine.
- Birmingham, Alabama – February 2, 2006 Mundipharma will obtain rights in markets across Europe, Asia and Australasia to Forodesine™ in the field of oncology in exchange for a $10 million up-front payment. Furthermore, Mundipharma will commit up to an additional $15 million to assist in the evaluation of Forodesine’s™ therapeutic safety and efficacy profile. BioCryst may also receive future event payments totalling $155 million in addition to royalties on product sales of Forodesine™ by Mundipharma.
- News BioCryst provides Fodosine update March 27, 2007. “Voluntarily Placed on Hold by BioCryst (…) we don’t think the final response rate will be as high as 18%”.
- The European Commission granted a marketing authorisation valid throughout the European Union for Atriance on 22 August 2007 for acute lymphoblastic leukaemia. What benefit has Atriance shown during the studies? Atriance was shown to be effective in a proportion of the patients in both studies. In the first study, among the 39 children and young adults who se cancer had not responded to two or more previous treatments, five (13%) had a complete response to treatment after a month, with no evidence of disease and normal blood counts. In the second study, among the 28 adults and adolescents with cancer that had not responded to two or more previous tre atments, five (18%) had a complete response to treatment. In both studies, more patients had a partial response to Atriance treatment, with blood counts returning towards normal levels.
- Lino Berton collects all the information on Forodesine in www.linoberton.com site, putting them in a row. In 2014 he published the book Qualcosa che non muore where he tells his incredible experience in the closed trial early in 2007.
- Il Giornale.it (in Italian). “Come si boicotta un farmaco che funziona”. Dated 08-01-2016.
 |
|
| Clinical data | |
|---|---|
| Trade names | Mundesine and Fodosine |
| Routes of administration |
oral |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C11H14N4O4 |
| Molar mass | 266.26 g·mol−1 |
| 3D model (JSmol) | |
/////////Forodesine Hydrochloride, Forodesine, BCX 1777, Immucillin-H, FOSODINE, JAPAN 2017
DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent
DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent
CRYSTAL FORM OF ANDROGEN RECEPTOR ANTAGONIST MEDICATION, PREPARATION METHOD THEREFOR, AND USE
一种式(I)所示ODM-201的晶型B，其特征在于，其X射线粉末衍射在衍射角2θ为16.2°±0.2°、9.0°±0.2°、22.5°±0.2°处有特征峰。
Novel crystalline forms of an androgen receptor antagonist medication, particularly ODM-201 (also known as darolutamide; designated as Forms B and C), processes for their preparation and compositions comprising them are claimed. Represents a first filing from Crystal Pharmaceutical Co Ltd and the inventors on this API.
Orion and licensee Bayer are codeveloping darolutamide, an androgen receptor antagonist, for treating castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer.
专利CN102596910B公开了ODM-201的制备方法，但并未公开任何的晶型信息。专利WO2016120530A1公开了式(I)(CAS号：1297538-32-9)所示的晶型I，式(Ia)(CAS号：1976022-48-6)所示的晶型I’和式(Ib)(CAS号：1976022-49-7)所示的晶型I”。文献Expert Rev.Anticancer Ther.15(9),(2015)已报道：ODM-201是由1:1比例的(Ia)和(Ib)两种非对应异构体组成，即为式(I)所示结构。因此，现有关于ODM-201的晶型只有晶型I报道。
Prostate cancer has become an important disease threatening the health of men. Its incidence is higher in western countries and shows a year-by-year upward trend. In the past, Asian countries with a lower incidence of the disease have also seen an increase in the number of patients in recent years. Clinical treatment of prostate cancer commonly used methods are surgical resection, radiation therapy and blocking androgen endocrine therapy. Androgen is closely related to the growth of prostate and the occurrence of prostate cancer. Therefore, endocrine therapy has become an effective way to treat prostate cancer. The method includes orchidectomy, estrogen therapy, gonadotropin-releasing hormone analog therapy, gonadotropin-releasing hormone antagonist therapy, androgen antagonistic therapy, etc., wherein androgen antagonist therapy can be both early treatment of prostate cancer can also be combined Surgery for adjuvant therapy is currently one of the main clinical treatment of prostate cancer. Androgen receptor as a biological target of androgen play an important role in the field of biomedical research.
Clinical trials have shown that exogenous androgen administration to patients with prostate cancer can lead to an exacerbation of the patient’s condition; conversely, if the testicles are removed and the level of androgens in the patient is reduced, the condition is relieved, indicating that androgens contribute to the development of prostate cancer Significant influence. According to receptor theory, androgen must bind with androgen receptor (AR) to cause subsequent physiological and pathological effects, which is the basis for the application of androgen receptor (AR) antagonist in the treatment of prostate cancer. In vitro experiments have shown that AR antagonists can inhibit prostate cell proliferation and promote apoptosis. Depending on the chemical structure of AR antagonists, they can be divided into steroidal AR antagonists and non-steroidal AR antagonists. Non-steroidal anti-androgen activity is better, there is no steroid-like hormone-like side effects, it is more suitable for the treatment of prostate cancer.
ODM-201 (BAY-1841788) is a non-steroidal oral androgen receptor (AR) antagonist used clinically to treat prostate cancer. The binding affinity of ODM-201 to AR was high, with Ki = 11nM and IC50 = 26nM. Ki was the dissociation constant between ODM-201 and AR complex. The smaller the value, the stronger the affinity. half maximal inhibitory concentration “refers to the half-inhibitory concentration measured, indicating that a certain drug or substance (inhibitor) inhibits half the amount of certain biological processes. The lower the value, the stronger the drug’s inhibitory ability. In addition, ODM-201 does not cross the blood-brain barrier and can reduce neurological related side effects such as epilepsy. Bayer Corporation has demonstrated in clinical trials the effectiveness and safety of ODM-201, demonstrating its potential for treating prostate cancer.
The chemical name of ODM-201 is: N – ((S) -l- (3- (3- chloro-4-cyanophenyl) -lH-pyrazol-l-yl) -propan- The chemical name contains the tautomer N – ((S) -1- (3- (3- 4-cyanophenyl) -1H-pyrazol- 1 -yl) -propan-2-yl) -5- (1 -hydroxyethyl) 1297538-32-9, the structural formula is shown in formula (I) :
The different crystalline forms of solid chemical drugs can lead to differences in their solubility, stability, fluidity and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compounds (see K. Knapman, Modern Drug Discovery, 3, 53 -54,57,2000.), Resulting in differences in clinical efficacy. It has been found that new crystalline forms (including anhydrates, hydrates, solvates, etc.) of the active ingredients of the medicinal product may give rise to more processing advantages or provide substances with better physical and chemical properties such as better bioavailability, storage stability, ease Processed, purified or used as an intermediate to promote conversion to other crystalline forms. The new crystalline form of the pharmaceutical compound can help improve the performance of the drug and broaden the choice of starting material for the formulation.
Patent CN102596910B discloses the preparation of ODM-201, but does not disclose any crystal form information. Patent WO2016120530A1 discloses a crystalline form I represented by the formula (I) (CAS number: 1297538-32-9), a crystalline form I ‘represented by the formula (Ia) (CAS number: 1976022-48-6) and a compound represented by the formula (CAS No. 1976022-49-7). Document Expert Rev. Anticancer Ther. 15 (9), (2015) It has been reported that ODM-201 is composed of a 1: 1 ratio of (Ia) And (Ib), which is the structure shown in Formula (I), so the only existing crystal form I for ODM-201 is reported.
However, the lower solubility of Form I and the high hygroscopicity, and the preparation of Form I requires the use of highly toxic acetonitrile solvents, which are carcinogenic in animals and are the second class of solvents that should be controlled during the process development stage. Form I preparation method is more complex, long preparation cycle, the process needs heating, increasing the cost of industrial preparation, is not conducive to industrial production. In order to overcome the above drawbacks, there is still a need in the art for a systematic and comprehensive development of other polymorphs of ODM-201 of formula (I), simplifying the preparation thereof, enabling its pharmacological development and releasing its potential, Preparation of a better formulation of the drug ingredients.
The inventors found through experiments that Form B and Form C of the present invention, and found that Form B and Form C of the present invention have more excellent properties than the prior art. Dissolution is a prerequisite for drug absorption, and increased solubility will help to increase the bioavailability of the drug and thereby improve the drug’s druggability. Compared with the prior art, the crystalline forms B and C of the invention have higher solubility and provide favorable conditions for drug development. Compared with the prior art, the crystalline forms B and C of the invention also have lower hygroscopicity. Hydroscopic drug crystal form due to adsorption of more water lead to weight changes, so that the raw material crystal component content is not easy to determine. In addition, the crystalline form of the drug substance absorbs water and lumps due to high hygroscopicity, which affects the particle size distribution of the sample in the formulation process and the homogeneity of the drug substance in the preparation, thereby affecting the dissolution and bioavailability of the sample. The crystal form B and the crystal form C have the same moisture content under different humidity conditions, and overcome the disadvantages caused by high hygroscopicity, which is more conducive to the long-term storage of the medicine, reduces the material storage and the quality control cost.
In addition, the present invention provides Form B and Form C of ODM-201 represented by formula (I), which have good stability, excellent flowability, suitable particle size and uniform distribution. The solvent used in the preparation method of crystal form B and crystal form C of the invention has lower toxicity, is conducive to the green industrial production, avoids the pharmaceutical risk brought by the residue of the toxic solvent, and is more conducive to the preparation of the pharmaceutical preparation. The novel crystal type provided by the invention has the advantages of simple operation, no need of heating, short preparation period and cost control in industrialized production. Form B and Form C of the present invention provide new and better choices for the preparation of pharmaceutical formulations containing ODM-201, which are of great significance for drug development.
The problem to be solved by the invention
The main object of the present invention is to provide a crystal form of ODM-201 and a preparation method and use thereof.
//////////DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent, CRYSTAL
ANTHONY MELVIN CRASTO gets Outstanding contribution in Pharma at World Health and wellness Congress award, 14th Feb, 2018, at Taj Lands ends, Bandra, Mumbai, India
All my hard work gets International recognition and makes me feel to work more
Bestowed on me an International award for Outstanding contribution in Pharma at World Health and wellness Congress award, 14th Feb, 2018, at Taj Lands ends, Bandra, Mumbai, India
My family Shobha Crasto Lionel crastoAishal Crasto too get all credit for sacrifices done to help me achieve this honour.
They help me in my activities and have to sacrifice tremendously in time patience finances vacations and several other factors.
I now feel like an open superstar with 9 million google hits, 60lakh blog views, dozen plus bogs and 5lakh viewers in USA alone and 60 lakh Views in 216 countries and 7 continents
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Drug Patents International
All about Patents and Intellectual property by DR ANTHONY MELVIN CRASTO, worlddrugtracker, Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry, Serving chemists around the world. THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India
FDA alerts health care professionals and patients not to use compounded drugs from Cantrell Drug Company; agency seeks action to stop production and distribution
The U.S. Food and Drug Administration is alerting health care professionals and patients not to use drug products produced by Cantrell Drug Company of Little Rock, Arkansas, including opioid products and other drugs intended for sterile injection, that were produced by the company and distributed nationwide. The agency is concerned about serious deficiencies in Cantrell’s compounding operations, including its processes to ensure quality and sterility assurance that put patient safety at risk. Administration of contaminated or otherwise poor quality drug products can result in serious and life-threatening injury or death. Continue reading.
FDA warns of fraudulent and unapproved flu products
FDA warns of fraudulent and unapproved flu products
As part of the U.S. Food and Drug Administration’s ongoing efforts to protect consumers from health fraud, the agency is reminding consumers to be wary of unapproved products claiming to prevent, treat or cure influenza, or flu. This year’s severe flu season raises new concerns about the potential for consumers to be lured into buying unproven flu treatments, and even worse, buying counterfeit antivirals online from websites that appear to be legitimate online pharmacies. Continue Reading
ALOFISEL, darvadstrocel Cx-601
ALOFISEL
darvadstrocel
Cx-601
On 14 December 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Alofisel, intended for the treatment of complex perianal fistulas in patients with Crohn’s disease. As Alofisel is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. Alofisel was designated as an orphan medicinal product on 8 October 2009. The applicant for this medicinal product is Tigenix, S.A.U.
Alofisel will be available as a suspension for injection (5 million cells/ml). The active substance of Alofisel is darvadstrocel. Darvadstrocel contains expanded adipose stem cells which, once activated, impair proliferation of lymphocytes and reduce the release of pro-inflammatory cytokines at inflammation sites. This immunoregulatory activity reduces inflammation and may allow the tissues around the fistula tract to heal.
The benefits with Alofisel are its ability to improve the healing process of complex perianal fistulas in patients with Crohn’s disease. The most commonly reported side effects include anal abscess and fistula, as well as procedural pain and proctalgia.
The full indication is: “Alofisel is indicated for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response to at least one conventional or biologic therapy. Alofisel should be used after conditioning of fistula, see section 4.2.”
It is proposed that Alofisel be administered by specialist physicians experienced in the diagnosis and treatment of conditions for which Alofisel is indicated.
Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
| Name | Alofisel |
|---|---|
| INN or common name | darvadstrocel |
| Therapeutic area | Rectal Fistula |
| Active substance | darvadstrocel |
| Date opinion adopted | 14/12/2017 |
| Company name | Tigenix, S.A.U. |
| Status | Positive |
| Application type | Initial authorisation |
New medicine to treat perianal fistulas in patients with Crohn’s disease
CHMP summary of positive opinion for Alofisel
Cx601
Cx601 is a local administration of expanded adipose-derived stem cells (eASCs) for the treatment of complex perianal fistulas in Crohn’s disease patients. The treatment is administered as a single dose and has been proven to have long-term efficacy in the healing of complex perianal fistulas in Crohn’s disease patients (ADMIRE-CD study completed in 2015 with positive 2 year follow-up data). The 24-week results of this trial were published in The Lancet in July 2016.
Cx601 has been designated as an orphan drug by the EMA and SwissMedic, in Switzerland.
On 4th July 2016, Takeda Pharmaceuticals acquired an exclusive right to develop and commercialize Cx601 for complex perianal fistulas in Crohn’s disease patients outside of the U.S. Takeda is a leading pharmaceutical company in the gastroenterology space. TiGenix retains full rights to the product in the US as well as to the development of Cx601 in other indications.
- OriginatorCellerix
- DeveloperLa Fundacion para la Investigacion Biomedica del Hospital Universitario La Paz; Takeda; TiGenix
- ClassStem cell therapies
- Mechanism of ActionCell replacements
- Orphan Drug StatusYes – Rectal fistula
- New Molecular EntityNo
Highest Development Phases
- PreregistrationRectal fistula
- No development reportedRectovaginal fistula
Most Recent Events
- 15 Dec 2017Committee for Medicinal Products for Human Use (CHMP) and Committee for Advanced Therapies (CAT) recommend approval for darvadstrocel for Rectal fistula in European Union
- 14 Dec 2017TiGenix in-licenses patents related to adipose-derived mesenchymal stem cells from Mesoblast
- 16 Nov 2017Cx 601 is now called darvadstrocel
15/12/2017
New medicine to treat perianal fistulas in patients with Crohn’s disease
Alofisel is the tenth advanced therapy recommended for marketing authorisation
The European Medicines Agency (EMA) has recommended granting a marketing authorisation in the European Union (EU) for a new advanced therapy medicinal product (ATMP) for the treatment of complex perianal fistulas in patients with Crohn’s disease. Alofisel is the tenth ATMP that has received a positive opinion from the Agency’s Committee for Medicinal Products for Human Use (CHMP).
Crohn’s disease is a long-term condition that causes inflammation of the digestive system or gut. Apart from affecting the lining of the bowel, inflammation may also go deeper into the bowel wall. Perianal fistulas are common complications of Crohn’s disease and occur when an abnormal passageway develops between the rectum and the outside of the body. These can lead to incontinence (a lack of control over the opening of the bowels) and sepsis (blood infection). Complex fistulas are known to be more treatment resistant than simple fistulas. There is currently no cure for Crohn’s disease, so the aim of treatment is to stop the inflammatory process, relieve symptoms and avoid surgery wherever possible. Crohn’s disease can affect people of all ages, with a higher incidence in the younger population.
The active substance of Alofisel is darvadstrocel. Darvadstrocel contains expanded adipose stem cells which, once activated, impair proliferation of lymphocytes and reduce the release of pro-inflammatory cytokines at inflammation sites. This immunoregulatory activity reduces inflammation and may allow the tissues around the fistula tract to heal.
The benefits of Alofisel were studied in a main phase III clinical trial involving 212 patients. After 24 weeks of treatment, half of the patients treated with Alofisel (49.5%) were in remission, compared to a third of the patients under placebo. An extended ongoing follow-up study, which will cover a period of up to 104 weeks of treatment, has supported this result to date.
Although there is a moderate difference between the treatment groups, the effect is considered to be clinically meaningful when other treatment options for fistulas have failed. The most common side effects observed include anal abscess and fistula, as well as procedural pain and proctalgia.
Alofisel was assessed by the Committee for Advanced Therapies (CAT), EMA’s specialised scientific committee for ATMPs, such as gene or cell therapies. At its December 2017 meeting, the CAT recommended a positive opinion for Alofisel to the CHMP. The CHMP agreed with the CAT’s recommendation and adopted a positive opinion for the authorisation of Alofisel across the EU at its 11-14 December 2017 meeting.
Because complex perianal fistulas are rare, Alofisel was granted an orphan designation. As always at time of approval, this orphan designation will now be reviewed by EMA’s Committee for Orphan Medicinal Products (COMP) to determine whether the information available to date allows maintaining Alofisel’s orphan status and granting this medicine ten years of market exclusivity.
The opinion adopted by the CHMP is an intermediary step on Alofisel’s path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of this medicine in the context of the national health system of that country.
Takeda and TiGenix announce that Cx601 (darvadstrocel) has received a positive CHMP opinion to treat complex perianal fistulas in Crohn’s disease
- First allogeneic stem cell therapy to receive positive CHMP opinion in Europe
- Cx601 offers potential new treatment option for patients who do not respond to current available therapies and are subject to numerous invasive surgeries1
Takeda Pharmaceutical Company Limited (TSE: 4502) (“Takeda”) and TiGenix NV (Euronext Brussels and NASDAQ: TIG) (“TiGenix”) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), in conjunction with the Committee for Advanced Therapies (CAT), has adopted a positive opinion recommending a marketing authorization (MA) for investigational compound Cx601 (darvadstrocel). Cx601 is expected to be indicated for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response to at least one conventional or biologic therapy.2 This recommendation marks the first allogeneic stem cell therapy to receive a positive CHMP opinion in Europe.
“Following today’s news, physicians and surgeons in Europe can look forward to offering these Crohn’s disease patients a novel and minimally invasive alternative treatment option in the future, which in clinical trials achieved higher combined remission and lower relapse rates* than the current standard of care,” said Professor Julian Panés, Head of the Gastroenterology Department at the Hospital Clinic of Barcelona (Spain) and President of the European Crohn’s and Colitis Organisation (ECCO). “Perianal fistulas are estimated to affect up to 28% of patients in the first two decades after Crohn’s disease diagnosis and Cx601 offers new hope for those suffering from this severe and debilitating condition.”
Cx601 was assessed by the CAT, the EMA’s specialized scientific committee for Advanced Therapy Medicinal Products (ATMP), such as gene or cell therapies. The positive CHMP opinion was based on results from TiGenix’s Phase III ADMIRE-CD pivotal trial. The ADMIRE-CD trial is a randomized, double-blind, controlled, Phase III trial designed to investigate the efficacy and safety of investigational compound Cx601.3 24-week results were published in The Lancet and showed that Cx601 achieved statistically significant superiority versus the control group in the primary efficacy endpoint of combined remission.**,1 In addition, the rates and types of treatment related adverse events (non-serious and serious) and number of discontinuations due to adverse events were comparable between Cx601 and control arms, the most common of which were anal abscess and proctalgia.1Further follow-up data indicated that Cx601 maintained long-term remission of treatment refractory complex perianal fistulas in patients with Crohn’s disease over 52 weeks.4
Dr. María Pascual, VP Regulatory Affairs and Corporate Quality at TiGenix, said, “We believe that this first approval recommendation for an allogeneic stem cell therapy in Europe reflects the maturity of our technology and its potential to offer new approaches for difficult to treat conditions. We have worked closely with the EMA and provided a robust data package from a well-designed clinical trial with challenging endpoints. In parallel, we will continue working hard to obtain regulatory approval in the U.S. and to develop Cx601 for additional indications, to fulfil our aim of allowing patients to benefit from the full potential of Cx601 across multiple geographies and diseases.”
The opinion will now be referred to the European Commission with a decision anticipated in the coming months. An MA will allow Cx601 to be marketed in all 28 member states of the EU, plus Norway, Iceland and Lichtenstein.
Cx601 has been licensed to Takeda for the exclusive development and commercialization outside of the U.S. Receipt of the MA will trigger a milestone payment from Takeda to TiGenix of €15 million. The companies have been working closely together to advance preparations for commercialization, with a potential start of the commercial launch by Takeda anticipated after MA is transferred from TiGenix to Takeda.
“Today’s positive CHMP opinion is a crucial step to bringing a new treatment option to patients with complex perianal fistulas in Crohn’s disease,” said Dr. Asit Parikh, Head of Takeda’s Gastroenterology Therapeutic Area Unit. “We would like to thank the scientific community and patients involved in the ADMIRE-CD trial for their support in helping us reach this important milestone. We remain committed to delivering innovative, therapeutic options for patients suffering from gastrointestinal disorders.”
Complex perianal fistulas are considered one of the most disabling complications of Crohn’s disease5 and can cause intense pain6 and swelling, infection and incontinence.1 Despite available therapies and surgical advancements, they currently remain challenging for clinicians to treat7 and have a significant negative impact on patient quality of life.6
* Relapse defined as reopening of any of the treated external openings with active drainage as clinically assessed, or development of perianal collection ≥2cm of the treated perianal fistula confirmed by centrally blinded pelvic MRI assessment in patients with clinical remission at any previous visit
** Combined remission defined as clinical assessment of closure of all treated external openings draining at baseline, despite gentle finger compression, and absence of collections >2cm confirmed by pelvic MRI
About TiGenix
TiGenix NV (Euronext Brussels and NASDAQ: TIG) is an advanced biopharmaceutical company developing novel therapies for serious medical conditions by exploiting the anti-inflammatory properties of allogeneic, or donor-derived, stem cells.
TiGenix´ lead product, Cx601, has successfully completed a European Phase III clinical trial for the treatment of complex perianal fistulas – a severe, debilitating complication of Crohn’s disease. Cx601 has been filed for regulatory approval in Europe and a global Phase III trial intended to support a future U.S. Biologic License Application (BLA) started in 2017. TiGenix has entered into a licensing agreement with Takeda, a global pharmaceutical company active in gastroenterology, under which Takeda acquired the exclusive right to develop and commercialize Cx601 for complex perianal fistulas outside the U.S. TiGenix’ second adipose-derived product, Cx611, is undergoing a Phase I/II trial in severe sepsis – a major cause of mortality in the developed world. Finally, AlloCSC-01, targeting acute ischemic heart disease, has demonstrated positive results in a Phase I/II trial in acute myocardial infarction (AMI). TiGenix is headquartered in Leuven (Belgium) and has operations in Madrid (Spain) and Cambridge, MA (USA). For more information, please visit http://www.tigenix.com.
About Cx601
Cx601 is a local administration of allogeneic (or donor derived) expanded adipose-derived stem cells (eASCs) for the treatment of complex perianal fistulas in adult Crohn’s disease patients that have previously shown an inadequate response to at least one conventional therapy or biologic therapy. Crohn’s disease is a chronic inflammatory disease of the intestine and complex perianal fistulas are a severe and debilitating complication for which there is currently no effective treatment. Cx601 was granted orphan drug designation by the European Commission in 2009 and by the U.S Food and Drug Administration (FDA) in 2017. TiGenix completed a European Phase III clinical trial (ADMIRE-CD) in August 2015 in which both the primary endpoint and the safety and efficacy profile were met, with patients receiving Cx601 showing a 44% greater probability of achieving combined remission compared to control (placebo).1 A follow-up analysis was completed at 52 weeks4 and 104 weeks post-treatment, confirming the sustained efficacy and safety profile of the product. The 24-week results of the Phase III ADMIRE-CD trial were published in The Lancet in July 2016.1 Based on the positive 24 weeks Phase III study results, TiGenix submitted a Marketing Authorization Application to the European Medicines Agency (EMA). A global Phase III clinical trial (ADMIRE-CD II) intended to support a future U.S. Biologic License Application (BLA) started in 2017, based on a trial protocol that has been agreed with the FDA through a special protocol assessment procedure (SPA) (clinicaltrials.gov; NCT03279081). ADMIRE-CD II is a randomized, double-blind, placebo-controlled study designed to confirm the efficacy and safety of a single administration of Cx601 for the treatment of complex perianal fistulas in Crohn’s disease patients. In July 2016, TiGenix entered into a licensing agreement with Takeda, a global pharmaceutical company active in gastroenterology, under which Takeda acquired exclusive rights to develop and commercialize Cx601 for complex perianal fistulas in Crohn’s patients outside of the U.S.
Forward-looking information
This press release may contain forward-looking statements and estimates with respect to the anticipated future performance of TiGenix and the market in which it operates. Certain of these statements, forecasts and estimates can be recognised by the use of words such as, without limitation, “believes”, “anticipates”, “expects”, “intends”, “plans”, “seeks”, “estimates”, “may”, “will” and “continue” and similar expressions. They include all matters that are not historical facts. Such statements, forecasts and estimates are based on various assumptions and assessments of known and unknown risks, uncertainties and other factors, which were deemed reasonable when made but may or may not prove to be correct. Actual events are difficult to predict and may depend upon factors that are beyond the Company’s control. Therefore, actual results, the financial condition, performance or achievements of TiGenix, or industry results, may turn out to be materially different from any future results, performance or achievements expressed or implied by such statements, forecasts and estimates. Given these uncertainties, no representations are made as to the accuracy or fairness of such forward-looking statements, forecasts and estimates. Furthermore, forward-looking statements, forecasts and estimates only speak as of the date of the publication of this press release. TiGenix disclaims any obligation to update any such forward-looking statement, forecast or estimates to reflect any change in the Company’s expectations with regard thereto, or any change in events, conditions or circumstances on which any such statement, forecast or estimate is based, except to the extent required by Belgian law.
References
1 Panés J, García-Olmo D, Van Assche G, et al., Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomized, double-blind controlled trial. The Lancet. 2016; 388(10051): 1281-1290.
2 European Medicines Agency. Available at: http://www.ema.europa.eu/ema/. Accessed December 15, 2017.
3 Clinicaltrials.gov. Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn’s Disease (ADMIRE-CD). Available at: https://clinicaltrials.gov/ct2/show/NCT01541579?term=cx601 &rank=2. Published February 2012. Accessed December 15, 2017.
4 Panés J, García-Olmo D, Van Assche G, et al., Long-term efficacy and safety of Cx601, allogeneic expanded adipose-derived mesenchymal stem cells, for complex perianal fistulas in Crohn’s Disease: 52-week results of a phase III randomized controlled trial. ECCO 2017; Barcelona: Abstract OP009.
5 Marzo M, Felice C, Pugliese D, et al., Management of perianal fistulas in Crohn’s disease: An up-to-date review. World J Gastroenterol. 2015; 21(5): 1394-1395.
6 Mahadev S, Young JM, Selby W, et al., Quality of life in perianal Crohn’s disease: what do patients consider important? Dis Colon Rectum. 2011; 54(5): 579-585.
7 Geltzeiler C, Wieghard N and Tsikitis V. Recent developments in the surgical management of perianal fistula for Crohn’s disease. Ann Gastroenterol. 2014; 27(4): 320-330.
Notes
- The applicant for Alofisel is Tigenix, S.A.U.
- AGA technical review on perianal Crohn’s disease 2003; 125(5):1508-1530
- TiGenix company presentation, June 2017 (http://tigenix.com/wp-content/themes/tigenix/images/TiGenix_Corporate_Presentation.pdf , accessed on June 22nd, 2017).
- Panes J et al. Long-term efficacy and safety of Cx601, allogeneic expanded adipose-derived mesenchymal stem cells, for complex perianal fistulas in Crohn’s disease: 52-week results of a Phase III randomized controlled trial. The 12th Congress of ECCO, February 15-18, 2017, Barcelona, Spain
- Cohen RD et al, 2008. Effects of fistula on healthcare costs and utilization for patients with Crohn’s disease treated in a managed care environment.
- nice.org.uk
- Gene therapy: understanding the science, assessing the evidence, and paying for the value: a report from the 2016 ICER membership policy summit. March 2017.
- Chaparro M. et al., 2013 Health care costs of complex perianal fistula in Crohn’s disease.
- Takeda’s press release, January 5, 2018.
- http://tigenix.com/wp-content/themes/tigenix/images/TiGenix_Corporate_Presentation.pdf
/////////////////ALOFISEL, darvadstrocel, Cx-601, eu 2017, ema 2017
PADELIPORFIN
PADELIPORFIN
759457-82-4; 457P824,
RN: 759457-82-4
UNII: EEO29FZT86
3-[(2S,3S,12R,13R)-8-acetyl-13-ethyl-20-(2-methoxy-2-oxoethyl)-3,7,12,17-tetramethyl-18-(2-sulfoethylcarbamoyl)-2,3,12,13-tetrahydroporphyrin-22,24-diid-2-yl]propanoic acid;palladium(2+)
(SP-4-2)-[(7S,8S,17R,18R)-13-acetyl-18-ethyl-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato (4-)-kN21,kN22,kN23,kN24] palladate(2-)
Other Names
- (SP-4-2)-[(7S,8S,17R,18R)-13-Acetyl-18-ethyl-7,8-dihydro-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato(4-)-κN21,κN22,κN23,κN24]palladate(2-)
| Molecular Formula: | C37H43N5O9PdS |
|---|---|
| Molecular Weight: | 840.257 g/mol |
Chemical Formula: C37H41K2N5O9PdS
Molecular Weight: 916.43
cas 698393-30-5
WST11; WST-11; WST 11; Stakel; padeliporfin; palladiumbacteriopheophorbide monolysine taurine.
Palladate(2-), [(7S,8S,17R,18R)-13-acetyl-18-ethyl-7,8-dihydro-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato(4-)-κN21,κN22,κN23,κN24]-, potassium (1:2), (SP-4-2)-
Tookad : EPAR -Product Information
| Tookad : EPAR – Summary for the public | (English only) | 29/11/2017 |
Product details
Pharmacotherapeutic group
Antineoplastic agents
Therapeutic indication
Tookad is indicated as monotherapy for adult patients with previously untreated, unilateral, low risk, adenocarcinoma of the prostate with a life expectancy ≥ 10 years and:
- Clinical stage T1c or T2a;
- Gleason Score ≤ 6, based on high-resolution biopsy strategies;
- PSA ≤ 10 ng/mL;
- 3 positive cancer cores with a maximum cancer core length of 5 mm in any one core or 1-2 positive cancer cores with ≥ 50 % cancer involvement in any one core or a PSA density ≥ 0.15 ng/mL/cm³.
| Name | Tookad |
|---|---|
| Agency product number | EMEA/H/C/004182 |
| Active substance | padeliporfin di-potassium |
| International non-proprietary name(INN) or common name | padeliporfin |
| Therapeutic area | Prostatic Neoplasms |
| Anatomical therapeutic chemical (ATC) code | L01XD07 |
| Additional monitoring | This medicine is under additional monitoring. This means that it is being monitored even more intensively than other medicines. For more information, see medicines under additional monitoring. |
| Marketing-authorisation holder | STEBA Biotech S.A |
|---|---|
| Revision | 0 |
| Date of issue of marketing authorisation valid throughout the European Union | 10/11/2017 |
Contact address:
STEBA Biotech S.A
7 place du theatre
L-2613 Luxembourg
Luxembourg
Padeliporfin is a vascular-acting photosensitizer consisting of a water-soluble, palladium-substituted bacteriochlorophyll derivative with potential antineoplastic activity. Upon administration, paldeliporfin is activated locally when the tumor bed is exposed to low-power laser light; reactive oxygen species (ROS) are formed upon activation and ROS-mediated necrosis may occur at the site of interaction between the photosensitizer, light and oxygen. Vascular-targeted photodynamic therapy (VTP) with padeliporfin may allow tumor-site specific cytotoxicity while sparing adjacent normal tissues.
WST-11 (Stakel) is a water-soluble bacteriochlorophyll (chemical structure shown below) derivative coordinated with palldium, which has maximum absorption wavelength in the near infrared (753 nm) and rapid clearance from the body ( t 1/2 = 0.37 hour for a 10-mg/kg drug dose in the rat and t 1/2 = 0.51 hour, 1 hour, and 2.65 hours for 1.25-, 2.5-, and 5-mg/kg drug doses, respectively. It binds to serum albumin and has potent antivascular activity through the generation of hydroxyl radicals when stimulated by the proper light wavelength.
Photodynamic therapy (PDT) is a non-surgical treatment of tumors in which non-toxic drugs and non-hazardous photosensitizing irradiation are combined to generate cytotoxic reactive oxygen species in situ. This technique is more selective than the commonly used tumor chemotherapy and radiotherapy. To date, porphyrins have been employed as the primary photosensitizing agents in clinics. However, current sensitizers suffer from several deficiencies that limit their application, including mainly: (1) relatively weak absorption in the visible spectral range which limits the treatment to shallow tumors; (2) accumulation and long retention of the sensitizer in the patient skin, leading to prolonged (days to months) skin phototoxicity; and (3) small or even no differentiation between the PDT effect on illuminated tumor and non-tumor tissues. The drawbacks of current drugs inspired an extensive search for long wavelength absorbing second-generation sensitizers that exhibit better differentiation between their retention in tumor cells and skin or other normal tissues.
In order to optimize the performance of the porphyrin drugs in therapeutics and diagnostics, several porphyrin derivatives have been proposed in which, for example, there is a central metal atom (other than Mg) complexed to the four pyrrole rings, and/or the peripheral substituents of the pyrrole rings are modified and/or the macrocycle is dihydrogenated to chlorophyll derivatives (chlorins) or tetrahydrogenated to bacteriochlorophyll derivatives (bacteriochlorins).
Due to their intense absorption in favorable spectral regions (650-850 nm) and their ready degradation after treatment, chlorophyll and bacteriochlorophyll derivatives have been identified as excellent sensitizers for PDT of tumors and to have superior properties in comparison to porphyrins, but they are less readily available and more difficult to handle.
Bacteriochlorophylls are of potential advantage compared to the chlorophylls because they show intense near-infrared bands, i.e. at considerably longer wavelengths than chlorophyll derivatives.
The spectra, photophysics, and photochemistry of native bacteriochlorophylls (Bchls) have made them optimal light-harvesting molecules with clear advantages over other sensitizers presently used in PDT. In particular, these molecules have a very high extinction coefficient at long wavelengths (λmax=760-780 nm, ε=(4-10)xl04 M-1cm-1), where light penetrates deeply into tissues. They also generate reactive oxygen species (ROS) at a high quantum yield (depending on the central metal).
Under normal delivery conditions, i.e. in the presence of oxygen at room temperature and under normal light conditions, the BChl moieties are labile and have somewhat lower quantum yields for triplet state formation, when compared with, e.g., hematoporphyrin derivative (HPD). However, their possible initiation of biological redox reactions, favorable spectral characteristics and their ready degradation in vivo result in the potential superiority of bacteriochlorophylls over other compounds, e.g. porphyrins and chlorophylls, for PDT therapy and diagnostics and for killing of cells, viruses and bacteria in samples and in living tissue. Chemical modification of bacteriochlorophylls is expected to further improve their properties, but this has been very limited due to lack of suitable methods for the preparation of such modified bacteriochlorophylls .
The biological uptake and PDT efficacy of metal-free derivatives of Bchl have been studied with the objective to manipulate the affinity of the sensitizers to the tumor cellular compartment. Cardinal to this approach is the use of highly lipophilic drugs that may increase the accumulation of the drug in the tumor cells, but also renders its delivery difficult. In addition, the reported biodistribution shows significant phototoxic drug levels in non-tumor tissues over prolonged periods (at least days) after administering the drug.
In applicant’s previous Israel Patent No. 102645 and corresponding EP 0584552, US 5,726,169, US 5,726,169, US 5,955,585 and US 6,147,195, a different approach was taken by the inventors. Highly efficient anti- vascular sensitizers that do not extravasate from the circulation after administration and have short lifetime in the blood were studied. It was expected that the inherent difference between vessels of normal and abnormal tissues such as tumors or other tissues that rely on neovessels, would enable relatively selective destruction of the abnormal tissue. Hence, it was aimed to synthesize Bchl derivatives that are more polar and, hence, have better chance to stay in the vascular compartment, where they convey the primary photodynamic effect. To this end, the geranylgeranyl residue at the C-17 position of Bchl a (Compound 1, depicted in Scheme 1 herein) has been replaced by various residues such as amino acids, peptides, or proteins, which enhance the sensitizer hydrophilicity. One particular derivative, Bchl-Ser (Scheme 1, Compound 1, wherein R is seryl), was found to be water-soluble and highly phototoxic in cell cultures. Following infraperitoneal injection, the Bchl-Ser cleared from the mouse blood and tissues bi-exponentially in a relatively short time (t1/2~2 and 16 h, respectively). Clearance from the circulation was even faster following intravenous injection. Under the selected treatment protocol (light application within minutes after drug injection), phototoxicity was predominantly conferred to the tumor vasculature (Rosenbach-
Belkin et al., 1996; Zilberstein et al., 2001 and 1997). However, unfortunately, like native Bchl, the Bchl-Ser derivative undergoes rapid photo-oxidation, forming the corresponding 2-desvinyl-2-acetyl-chlorophyllide ester and other products.
To increase the stability of the Bchl derivatives, the central Mg atom was replaced by Pd in the later applicant’s PCT Publication WO 00/33833 and US 6,569,846. This heavy atom was previously shown to markedly increase the oxidation potential of the Bchl macrocycle and, at the same time, to greatly enhance the intersystem-crossing (ISC) rate of the molecule to its triplet state. The metal replacement was performed by direct incorporation of Pd2+ ion into a Bpheid molecule, as described in WO 00/33833. Based on the pigment biodistribution and pharmacokinetics, it was assumed that the derivative Pd-Bpheid remained in the circulation for a very short time with practically no extravasation to other tissues, and is therefore a good candidate for vascular-targeting PDT that avoids skin phototoxicity. The treatment effect on the blood vessels was demonstrated by intravital microscopy of treated blood vessels and staining with Evans-Blue. Using a treatment protocol with a minimal drug-to-light interval, Pd-Bpheid (also designated Tookad) was found to be effective in the eradication of different tumors in mice, rats and other animal models and is presently entering Phase I/II clinical trials in patients with prostate cancer that failed radiation therapy (Chen et al, 2002; Schreiber et al., 2002; Koudinova et al., 2003).
Because of its low solubility in aqueous solutions, the clinical use of Pd-Bpheid requires the use of solubilizing agents such as Cremophor that may cause side effects at high doses. It would be highly desirable to render the Pd-Bpheid water-soluble while retaining its physico-chemical properties. Alternatively, it would be desirable to prepare Bchl derivatives that are cytophototoxic and, at the same time, more water-soluble than Pd-Bpheid itself. Such water solubility is expected to further enhance the drug retention in the circulation and, thereby, the aforementioned selectivity. In addition, having no need to use carriers such as detergents or lyposomes, may prevent side effects.
SYNTHESIS
START FROM CAS 17499-98-8, Phorbine, magnesium deriv., Bacteriochlorophyll aP
PADELIPORFIN
Paper
Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: Synthesis, solubility, phototoxicity and the effect of serum proteins
Photochemistry and Photobiology (2005), 81, (July/Aug.), 983-993
PAPER
Journal of Medicinal Chemistry (2014), 57(1), 223-237
With the knowledge that the dominant photodynamic therapy (PDT) mechanism of 1a (WST09) switched from type 2 to type 1 for 1b (WST11) upon taurine-driven E-ring opening, we hypothesized that taurine-driven E-ring opening of bacteriochlorophyll derivatives and net-charge variations would modulate reactive oxygen species (ROS) photogeneration. Eight bacteriochlorophyll a derivatives were synthesized with varying charges that either contained the E ring (2a–5a) or were synthesized by taurine-driven E-ring opening (2b–5b). Time-dependent density functional theory (TDDFT) modeling showed that all derivatives would be type 2 PDT-active, and ROS-activated fluorescent probes were used to investigate the photogeneration of a combination of type 1 and type 2 PDT ROS in organic- and aqueous-based solutions. These investigations validated our predictive modeling calculations and showed that taurine-driven E-ring opening and increasing negative charge generally enhanced ROS photogeneration in aqueous solutions. We propose that these structure–activity relationships may provide simple strategies for designing bacteriochlorins that efficiently generate ROS upon photoirradiation.
Modulation of Reactive Oxygen Species Photogeneration of Bacteriopheophorbide a Derivatives by Exocyclic E-Ring Opening and Charge Modifications
CHEMICAL EXAMPLES
Example 1. Palladium 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt ( Compound 4)
Nine hundred and thirty five (935) mg of Pd-Bpheid (3) were dissolved in a 1 L round bottom flask with 120 ml of DMSO while stirring under Argon (bubbled in the solution). Taurine (1288 mg) was dissolved in 40 ml of 1M K2HPO4 buffer, and the pH of the solution was adjusted to 8.2 (with HCl ). This aqueous solution was added into the DMSO solution while stirring, and the Argon was bubbled in the solution for another 20 minutes. Then the reaction mixture was evaporated at 30°C for 3.5 hours under ~2 mbar and then for another 2 hours at 37°C to a complete dryness. The dry solids were dissolved in 300 ml of MeOH and the colored solution was filtered through cotton wool to get rid of buffer salts and taurine excess.
The progress of the reaction was determined by TLC (Rf of unreacted Pd- Bpheid is 0.8-0.85 and of the reaction (aminolysis) product is 0.08-0.1) and by following the optical absorption spectrum of the reaction mixture after liophylization and resolubihzation in MeOH. The absorption spectrum was characterized by a Qytransition shift from 756 nm (for Pd-Bpheid) to 747 nm (for the product 4) and by Qx shift from 534 nm of Pd-Bpheid to 519 nm (of the product 4). The MeOH was evaporated and the product 4 was purified by HPLC with ODS-A 250X20 S10P μm column (YMC, Japan). Solvent A: 95% 0.005 M phosphate buffer, pH 8.0 and 5% MeOH. Solvent B: 100% MeOH. The dry solid was dissolved in 42 ml of distilled water and injected in portions of 1.5 ml each .
The elution profile is described in Table 1. The product 4_(Scheme 1, see below) was eluted and collected at ~ 9-11 minutes. The main impurities, collected after at 4-7 min (ca 5-10%), corresponded to byproduct(s) with the proposed structure 7. Peaks at 22-25 min (ca 2-5%) possibly corresponded to the iso-form of the main product 4 and untreated Pd-Bpheid residues.
The solvent (aqueous methanol) was evaporated under reduced pressure. Then, the purified product 4 ]was re-dissolved in ~150 ml MeOH and filtered through cotton wool. The solvent was evaporated again and the solid pigment 4 was stored under Ar in the dark at -20°C. The reaction yield: ~90% (by weight, relative to 3).
The structure of product 4 was confirmed by electrospray mass spectroscopy. (ESI-MS, negative mode, Fig.2), (peaks at 875 (M–K-H), 859 (M–2K-H+Na), 837 (M–2K), 805 (M2K-H-OMe), 719) and 1H-NMR spectrum (Fig. 4 in MeOH-d4). Table 4 provides the shifts (in ppm units) of the major NMR peaks.
Optical absorption (UN-VIS) spectrum (MeOH): λ, 747 (1.00), 516 (0.13), 384 (0.41), 330 (0.50); ε747 (MeOH) is 1.2 x 105 mol-1 cm _1.
ΝMR (MeOH-d4): 9.38 (5-H, s), 8.78 (10-H, s), 8.59 (20-H, s), 5.31 and 4.95 (151-CH2, dd), 4.2-4.4 (7,8,17,18-H, m), 3.88 (153-Me, s), 3.52 (21-Me, s), 3.19 (121 -Me, s), 3.09 (32-Me, s), 1.92-2.41, 1.60-1.75 (171, 172-CH2, m), 2.19 (81-CH2, m), 1.93 (71-Me, d), 1.61 (181-Me, d), 1.09 (82-Me, t), 3.62, 3.05 (CH2‘s of taurine).
Octanol/water partition ratio is 40:60.
Example 2. Preparation of 31-oxo-15-methoxycarbonylmethyl- Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt (Compound 5) One hundred and sixty (160) mg of taurine were dissolved in 5 ml of 1M
K2HPO4 buffer, and the pH of the solution was adjusted to 8.2. This solution was added to 120 mg of compound 2 dissolved in 15 ml of DMSO, and the reaction and following purification were analogous to those described in previous Example.
Absorption spectrum (MeOH): λ, 750 (1.00), 519 (0.30), 354 (1.18) nm.
ESI-MS (-): 734 (M–2K).
ΝMR (MeOH-d4): 9.31 (5-H, s), 8.88 (10-H, s), 8.69 (20-H, s), 5.45 and 5.25 (151-CH2, dd), 4.35 (7,18-H, m), 4.06 (8,17-H, m), 4.20 and 3.61 (2-CH2, m of taurine), 3.83 (153-Me, s), 3.63 (21-Me, s), 3.52 (3-CH2, m oftaurine), 3.33 (121-Me, s), 3.23 (32-Me, s), 2.47 and 2.16 (171-CH2, m), 2.32 and 2.16 (81-CH2, m), 2.12 and 1.65 (172-CH2, m), 1.91 (71-Me, d), 1.66 (181– Me, d), 1.07 (82-Me, t).
Octanol/water partition ratio is 60:40.
Example 3. Preparation of copper(II) 31-oxo-15-methoxycarbonylmethyl- Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt (Compound 10)
Fifty (50) mg of compound 5 of Example 2 and 35 mg of copper (II) acetate were dissolved in 40 ml of methanol, and argon was bubbled into solution for 10 minutes. Then 500 mg of palmitoyl ascorbate was added, and the solution was stirred for 30 min. The absorption spectrum was characterized by a Qy transition shift from 750 nm (for 5) to 768 nm (for the product 10) and by Qx shift from 519 nm of 5 to 537 nm (of the product 10). Then the reaction mixture was evaporated, re-dissolved in acetone and filtered through cotton wool to get rid of acetate salt excess. The acetone was evaporated and the product was additionally purified by HPLC at the conditions mentioned above with the elution profile, described in Table 2.
The solvent (aqueous methanol) was evaporated under reduced pressure. Then, the purified pigment 10 was re-dissolved in methanol and filtered through cotton wool. The solvent was evaporated again and the solid pigment 10 was stored under Ar in the dark at -20°C. Reaction yield: -90%.
Absorption spectrum (MeOH): λ, 768 (1.00), 537 (0.22), 387 (0.71) and 342 (0.79) nm.
ESI-MS (-): 795 (M–2K).
Octanol/water partition ratio is 40:60.
Example 4. Preparation of zinc 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt (Compound 11)
Zn insertion into compound 5 was carried out with Zn acetate in acetic acid as previously described (US Patent No. 5,726,169). Final purification was carried out by HPLC in the same conditions as for compound 5 in Example 2 above.
Absorption spectrum (MeOH): λ, 762 (1.00), 558 (0.26), 390 (0.62) and 355 (0.84) nm.
Octanol/water partition ratio is 50:50.
Example 5. Preparation of manganese(III) 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt (Compound 12)
Mn insertion into compound 5 was carried out with Zn acetate in acetic acid as previously described (WO 97/19081; US 6,333,319) with some modifications. Thus, fifty (50) mg of compound 5 in 10 ml of DMF were stirred with 220 mg of cadmium acetate and heated under argon atmosphere at 110°C about 15 min (Cd-complex formation is monitored by shifting Qx transition absorption band from 519 to 585 nm in acetone). Then the reaction mixture was cooled and evaporated. The dry residue was re-dissolved in 15 ml of acetone and stirred with manganese (II) chloride to form the Mn(III)-product 12. The product formation is monitored by shifting Qx transition band from 585 to 600 nm and Qy transition band from 768 to 828 nm in acetone. The acetone was evaporated and the product 12 was additionally purified by HPLC in the conditions mentioned in Example 2 above with the elution profile described in Table 3 below where the] solvent system consists of: A – 5% aqueous methanol, B -methanol.
The solvent (aqueous methanol) was evaporated under reduced pressure and the solid pigment 12 was stored under Ar in the dark at -20°C.
Absorption spectrum (MeOH): λ, 828 (1.00), 588 (0.32) and 372 (0.80) nm. Octanol/water partition ratio is 5:95.
Example 6. Preparation of palladium bacteriopheophorbide a 17 -(3-sulfo-1-oxy- succinimide)ester sodium salt (Compound 6)
Fifty (50) mg of Pd-Bpheid (compound 2), 80 mg of N-hydroxy- sulfosuccinimide (sulfoNHS) and 65 mg of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) were mixed in 7 ml of dry DMSO for overnight at room temperature. Then the solvent was evacuated under reduced pressure. The dry residue was re-dissolved in chloroform (ca. 50 ml), filtered from insoluble material, and evaporated. The conversion was ab. 95%) (TLC). The product 6 was used later on without further chromatographic purification. ESI-MS (-): 890 (M–Na).
NMR (CDCl3): 9.19 (5-H, s), 8.49 (10-H, s), 8.46 (20-H, s), 5.82 (132-H, s), 4.04- 4.38 (7,8,17,18-H, m), 3.85 (134-Me, s), 3.47 (21-Me, s), 3.37 (^-Me, s), 3.09 (32– Me, s), 1.77 (71-Me, d), 1.70 (lδ’-Me, d), 1.10 (82-Me, t), 4.05 (CH2 of sNHS), 3.45 (CH ofs NHS).
Example 7. Preparation of palladium bacteriopheophorbide a 173-(3-sulfopropyl) amide potassium salt (Compound 7)
Ten (10) mg of compound 6 in 1 ml of DMSO was mixed with 20 mg of homotaurine (3-amino-1-propane-sulfonic acid) in 1 ml of 0.1 M K-phosphate buffer, pH 8.0 for overnight. Then the reaction mixture was partitioned in chloroform/water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The dry residue was re-dissolved in chloroform-methanol (19:1) and applied to a chromatographic column with silica. The product 7 was obtained with chloroform-methanol (4:1) elution. The yield was about 80-90%.
ESI-MS (-): 834 (M-K) m/z.
NMR (MeOH-d4): 9.16 (5-H, s), 8.71 (10-H, s), 8.60 (20-H, s), 6.05 (132-H, s), 4.51, 4.39, 4.11, 3.98 (7,8,17,18-H, all m), 3.92 (134-Me, s), 3.48 (21-Me, s), 3.36 (121-Me, s), 3.09 (32-Me, s), 2.02-2.42 (171 arid 172-CH2, m), 2.15 ( 81-CH2, q), 1.81 (71-Me, d), 1.72 (181-Me, d), 1.05 (82-Me, t), 3.04, 2.68, and 2.32 (CH2‘s of homotaurine, m).
Example 8. Preparation of palladium 31-oxo-15-methoxycarbonylmethyl-Rhodo-bacteriochlorin 13 ,17 -di(3-sulfopropyl)amide dipotassium salt (Compound 8)
Ten (10) mg of compound 6 or 7 were dissolved in 3 ml of DMSO, mixed with 100 mg of homotaurine in 1 ml of 0.5 M K-phosphate buffer, pH 8.2, and incubated overnight at room temperature. The solvent was then evacuated under reduced pressure as described above, and the product 8 was purified on HPLC. Yield: 83%.
Absorption spectrum (MeOH): 747 (1.00), 516 (0.13), 384 (0.41), 330 (0.50), ε747 =1.3×105 modern-1.
ESI-MS(-):1011 (M–K), 994 (M–2K+Na),972 (M–2K), 775 (M–2K-CO2Me-homotaurineNHCH2CH2CH2SO3), 486 ([M-2K]/2)
NMR (MeOH-d4): 9.35 (5-H, s), 8.75 (10-H, s), 8.60 (20-H, s), 5.28 and 4.98 (15-1-CH2, dd), 4.38, 4.32, 4.22, 4.15 (7,8,17,18-H, all m), 3.85 (15~3-Me, s), 3.51 (21-Me, s), 3.18 (121-Me, s), 3.10 (32-Me, s 2.12-2.41 (171-CH2, m), 2.15-2.34 (81-CR2, m), 1.76-2.02 (172-CH2, m), 1.89 (71-Me, d), 1.61 (lδ^Me, d), 1.07 (82-Me, t). 3.82, 3.70,
3.20, 3.10, 2.78, 2.32, 1.90 (CH2‘s of homotaurine at C-131 and C-173)
Example 9. Palladium 31-(3-sulfopropylimino)-15-methoxycarbonylmethyl-Rhodo-bacteriochlorin 131,173-di(3-sulfopropyl)amide tripotassium salt (Compound 9)
Compound 9 was obtained from HPLC as a minor product during synthesis of 8.
Absorption spectrum (MeOH): 729 (1.00), 502 (0.10), 380 (0.69), 328 (0.57).
ESI-MS (30.4.2000): 1171 (M-K+H), 1153 (M–2K-H+Na), 1131 (M-2K), 566 ([M-K]/2), 364 ([M-3K]/3).
NMR (MeOH-d4): 8.71 (1H), 8.63 (1.5H), 8.23 (0.5H) (5-, 10- and 20-H, all-m), 5.30 and 4.88 (151-CH2, dd), 4.43 and 4.25 (7,8,17,18-H, m), 3.85 (15~3-Me, s), 3.31 (21-Me, s), 3.22 (121-Me, s), 3.17 (32-Me, m), 1.89-2.44 (171 and 172-CH2, m), 2.25 (81-CH2, m), 1.91 (71-Me, s), 1.64 (181– Me, s), 1.08 (82-Me, t), 4.12, 3.56, 3.22, 3.16, 2.80 and 2.68 (CH2‘s of homotaurine).
Example 10. Palladium 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-sulfoethyl)amide, 173-(N-immunoglobulin G)amide potassium salt (Compound 13)
Ten (10) mg of compound 4 were reacted with 20 mg of sulfo-NHS and 15 mg of EDC in 1 ml of dry DMSO for 1 hour at room temperature, then rabbit IgG (0.6 mg) in PBS (2.5 ml) was added, and the mixture was further incubated overnight at room temperature. The mixture was evaporated to dryness, then re-dissolved in 1 ml of PBS and loaded on Sephadex G-25 column equilibrated with PBS. A colored band was eluted with 4-5 ml of PBS. The pigment/protein ratio in the obtained conjugate 13 was determined by optical density at 753 and 280 mn, respectively, and varied between 0.5/1 to 1/1 of pigment 13/protein.
Example 11. Preparation of palladium 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(2-carboxyethyl)amide dipotassium salt (Compound
M)
The preparation and purification of the title compound 14 were carried out as described in Example 2, by reaction of compound 2 with 3-aminopropionic acid (β-alanine) (150 mg) instead of taurine. Yield: 85%.
Example 12. Preparation of palladium 31-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131-(3-phosphopropyl)amide tripotassium salt (Compound
15)
The preparation and purification of the title compound 15 were carried out as described in Example 2, by reaction of compound 2 with 3 -amino- 1-propanephosphonic acid (180 mg) instead of taurine. Yield: 68%.
Example 13. Palladium 31-(3-sulfopropylamino)-15-methoxycarbonylmethyl-Rhodobacteriochlorin 131,173-di(3-sulfopropyl)amide tripotassium salt (Compound 16)
For reduction of the imine group in 31-(3-sulfopropylimino) to the correspondent 31-(3-sulfopropylamino) group, compound 9 (8 mg) was reacted by stirring with sodium cyanoborohydride (15 mg) in 5 ml of methanol overnight at room temperature. Then the reaction mixture was treated with 0.05 M HCl (5 ml), neutralized with 0.01 M KOH, and evaporated. The title product 16 was purified using HPLC conditions as described in Example 2. Yield: 80-90%).
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////////PADELIPORFIN, WST11, WST-11, WST 11, Stakel, padeliporfin, palladiumbacteriopheophorbide monolysine taurine, EU 2017, EMA 2017
CCC1C(C2=NC1=CC3=C(C(=C([N-]3)C(=C4C(C(C(=N4)C=C5C(=C(C(=C2)[N-]5)C(=O)C)C)C)CCC(=O)O)CC(=O)OC)C(=O)NCCS(=O)(=O)O)C)C.[Pd+2]
DR ANTHONY MELVIN CRASTO
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