PICLAMILAST

An antiasthmatic agent and phosphodiesterase 4 inhibitor.
144035-83-6

SANOFI

• CCRIS 8304
• Cpodpmb
• Piclamilast
• RP 73-401
• RP 73401
• RP-73-401
• RPR 73401
• UNII-WM58D7C3ZT

Piclamilast (RP 73401), is a selective PDE4 inhibitor.^[1] It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary disease, bronchopulmonary dysplasia andasthma. It is a second generation compound that exhibits structural functionalities of the PDE4 inhibitors cilomilast and roflumilast. The structure for piclamilast was first elucidated in a 1995 European patent application.^[2] The earliest mention of the name “piclamilast” was used in a 1997 publication.^[3]

Piclamilast functions through the selective inhibition of the four PDE4 isoforms (PDE4A-D). It shows no inhibition of the other PDEs. The PDE4 isoforms are especially important to inflammatory and immunomodulatory cells. They are the most common PDE in inflammatory cells such as mast cells, neutrophils, basophils, eosinophils, T lymphocytes, macrophages, and structural cells such as sensory nerves and epithelial cells. PDE4hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP thereby increasing levels of cAMP within cells. cAMP suppresses the activity of immune and inflammatory cells. PDE4 inhibition in an induced chronic lung disease murine model was shown to have anti-inflammatory properties, attenuate pulmonary fibrin deposition and vascular alveolar leakage, and prolong survival in hyperoxia-induced neonatal lung injury. A study of PDE4 inhibition in a murine model of allergic asthma showed that piclamilast significantly improves the pulmonary function, airway inflammation and goblet cell hyperplasia.^[4][5]

Emesis is the most commonly cited side effect of piclamilast. It has proven difficult to separate the emetic side effects from the therapeutic benefits of several PDE4 inhibitors, including piclamilast.^[6]

Chemical synthesis

The preparation steps for synthesis of piclamilast are as follows (both discovery^[7] and production^[8] routes have been documented)

1. Addition of cyclopentyl to isovanillin via Williamson ether synthesis.
2. Oxidation of aldehyde group to carboxylic acid.
3. Formation of acid chloride by treatment with thionyl chloride.
4. Formation of amide by reaction with deprotonated 4-amino-3,5-dichloropyridine.

SEE

J Med Chem 1994, 37(11): 1696

http://pubs.acs.org/doi/abs/10.1021/jm00037a021

AND

Org Process Res Dev 1998, 2(3): 157

http://pubs.acs.org/doi/full/10.1021/op9700385

3-(cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (1) (26.4 g, 69%) as an off-white solid, mp 155−157 °C (lit.1 mp 155−157 °C). 1H NMR:  δ 1.55−2.05 (m, 8H), 3.93 (s, 3H), 4.87 (m, 1H), 6.95 (d, 1H, J = 8 Hz), 6.98−7.53 (m, 2H), 7.65 (s, 1H), 8.56 (s, 2H). Anal. Calcd for C18H18Cl2N2O3:  C, 56.7; H, 4.76; Cl, 18.6; N, 7.35. Found:  C, 56.3; H, 4.7; Cl, 18.4; N, 7.2.

References

MILTEFOSINE

2-(hexadecoxy-oxido-phosphoryl)oxyethyl-trimethyl-azanium

58066-85-6

March 19, 2014 — The U.S. Food and Drug Administration today approved Impavido (miltefosine) to treat a tropical disease called leishmaniasis.

Leishmaniasis is a disease caused by Leishmania, a parasite which is transmitted to humans through sand fly bites. The disease occurs primarily in people who live in the tropics and subtropics. Most U.S. patients acquire leishmaniasis overseas.

Impavido is an oral medicine approved to treat the three main types of leishmaniasis: visceral leishmaniasis (affects internal organs), cutaneous leishmaniasis (affects the skin) and mucosal leishmaniasis (affects the nose and throat). It is intended for patients 12 years of age and older. Impavido is the first FDA-approved drug to treat cutaneous or mucosal leishmaniasis.

“Today’s approval demonstrates the FDA’s commitment to making available therapeutic options to treat tropical diseases,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

The FDA granted Impavido fast track designation, priority review, and orphan product designation. These designations were granted because the drug demonstrated the potential to fill an unmet medical need in a serious disease or condition, the potential to be a significant improvement in safety or effectiveness in the treatment of a serious disease or condition, and is intended to treat a rare disease, respectively. With this approval, Impavido’s manufacturer, Paladin Therapeutics, is awarded a Tropical Disease Priority Review Voucher under a provision included in the Food and Drug Administration Amendments Act of 2007 that aims to encourage development of new drugs and biological products for the prevention and treatment of certain tropical diseases.

Impavido’s safety and efficacy were evaluated in four clinical trials. A total of 547 patients received Impavido and 183 patients received either a comparator drug or a placebo. Results from these trials demonstrated that Impavido is safe and effective in treating visceral, cutaneous and mucosal leishmaniasis.

The labeling for Impavido includes a boxed warning to alert patients and health care professionals that the drug can cause fetal harm and therefore should not be given to pregnant women. Health care professionals should advise women to use effective contraception during and for five months after Impavido therapy.

The most common side effects identified in clinical trials were nausea, vomiting, diarrhea, headache, decreased appetite, dizziness, abdominal pain, itching, drowsiness and elevated levels of liver enzymes (transaminases) and creatinine.

Paladin Therapeutics is based in Montreal, Canada

Miltefosine (INN, trade names Impavido and Miltex) is a phospholipid drug. Chemically it is a derivative of alkylphosphocholinecompounds discovered in the early 1980s. It was developed in the late 1980s as an anticancer drug by German scientists Hansjörg Eibl and Clemens Unger.^[2] Simultaneously but independently it was found that the drug could kill Leishmania parasites, and since the mid-1990s successful clinical trials were conducted. The drug became the first (and still the only prescribed) oral drug in the treatment ofleishmaniasis. It is now known to be a broad-spectrum antimicrobial drug, active against pathogenic bacteria and fungi,^[1][3] as well as human trematode Schistosoma mansoni and its vector host, the snail Biomphalaria alexandrina.^[4] It can be administered orally and topically.

In the target cell, it acts as an Akt inhibitor. Therefore, it is also under investigation as a potential therapy against HIV infection.^[5][6]

Phospholipid group alkylphosphocholine were known since the early 1980s, particularly in terms of their binding affinity with cobra venom.^[7]In 1987 the phosholids were found to potent toxins on leukemic cell culture.^[8] Initial in vivo investigation on the antineoplastic activity showed positive result, but then only at high dosage and at high toxicity.^[9] At the same time in Germany, Hansjörg Eibl, at the Max Planck Institute for Biophysical Chemistry, and Clemens Unger, at the University of Göttingen, demonstrated that the antineoplastic activity of the phospholipid analogue miltefosine (at the time known as hexadecylphosphocholine) was indeed tumour-specific. It was highly effective against methylnitrosourea-induced mammary carcinoma, but less so on transplantable mammary carcinomas and autochthonous benzo(a)pyrene-induced sarcomas, and relatively inactive on Walker 256 carcinosarcoma and autochthonous acetoxymethylmethylnitrosamine-induced colonic tumors of rats.^[10][11] It was subsequently found that miltefosine was strucrally unique among lipds having anticancer property in that it lacks the glycerol group, is highly selective on cell types and acts through different mechanism.^[12][13]

In the same year as the discovery of the acticancer property, miltefosine was reported by S. L. Croft and his team at the London School of Hygiene and Tropical Medicine as having antileishmanial effect as well. The compound was effective against Leishmania donovani amastigotes in cultured mouse peritoneal macrophages at a dose of 12.8 mg/kg/day in a five-day course.^[14] However priority was given to the development of the compound for cutaneous metastases of breast cancer. In 1992 a new research was reported in which the compound was highly effective in mouse against different life cycle stages of different Leishmania species, and in fect more potent than the conventional sodium stibogluconate therapy by a factor of more than 600.^[15] Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety.^[16] This promising development promulgated a unique public–private partnership collaboration between ASTA Medica (later Zentaris GmbH), the WHO Special Programme for Research and Training in Tropical Diseases, and the Government of India. Eventually, several successful Phase II and III trials led to the approval of miltefosine in 2002 as the first and only oral drug for leishmaniasis.^[1]

Miltefosine is registered and used by Zentaris GmbH in India, Colombia and Germany for the treatment of visceral and cutaneous leishmaniasis, and is undergoing clinical trials for this use in several other countries, such as Brazil^[17] and Guatemala.^[18]

Miltefosine is a phosphocholine analogue that was originally launched in 1993 by Baxter Oncology for the treatment of cancer. In 2003, Zentaris (formerly part of Asta Medica) launched the drug for the oral treatment of visceral leishmaniasis. Zentaris has also brought the product to market for the treatment of cutaneous leishmaniasis. Jado Technologies is conducting phase II clinical trials for the treatment of antihistamine resistant urticaria. Clinical trials had been ongoing for several indications, including the treatment of cutaneous mastocytosis or cutaneous involvement of systemic mastocytosis. Jado is investigating topical and oral versions of the compound in phase II trials in several allergy indications.

Miltefosine is effective against promastigotes and intracellular amastigotes, which survive and multiply in phagolysosomal compartments of macrophages and make up the two stages of the leishmania lifecycle. Although the exact mechanism of action of the drug has not been determined, it may exert its therapeutic effect through inhibition of phospholipid metabolism. Another theory suggests that miltefosine may interfere with leishmaniacal membrane signal transduction, lipid metabolism and glycosylphosphatidylinositol anchor biosynthesis. The drug is well absorbed in the gastrointestinal tract after a single oral administration and is widely distributed throughout the body.

Miltefosine was originally developed under a collaboration between the Indian government, the German biopharmaceutical company Zentaris, and the Tropical Disease Research (TDR) programme, co-sponsored by the World Health Organization and the United Nations Development Programme (UNDP). Subsequent to the product’s approval, Zentaris partnered with various organizations for its distribution. In February 2004, Roche and Zentaris entered into a marketing agreement, pursuant to which Roche agreed to support Zentaris in the registration process and to market miltefosine in Brazil.

Several medical agents have some efficacy against visceral or cutaneous leishmaniasis, however a 2005 survey concluded that Miltefosine is the only effective oral treatment for both forms of leishmaniasis.^[19]

Miltefosine is being investigated by researchers interested in finding treatments for infections which have become resistant to existing drugs. Animal and in vitro studies suggest it may have broad anti-protozoal and anti-fungal properties:

• Animal studies suggest miltefosine may also be effective against Trypanosoma cruzi, the parasite responsible for Chagas’ disease.^[20]

• Several studies have found the drug to be effective against Cryptococcus neoformans, Candida, Aspergillus and Fusarium.^[21]

• An in vitro study found that miltefosine is effective against metronidazole-resistant variants of Trichomonas vaginalis, a sexually transmitted protozoal disease.^[22]

• Hexadecyltrimethylammonium bromide, a compound structurally similar to miltefosine, was recently found to exhibit potent in vitro activity against Plasmodium falciparum.^[23]

• Miltefosine is being made available in the United States through the CDC for emergency use under an expanded access IND protocol for treatment of free-living amoeba (FLA) infections:Primary amoebic meningoencephalitis caused by Naegleria fowleri and Granulomatous Amebic Encephalitis caused by Balamuthia mandrillaris, and Acanthamoeba species.^[24][25]

Investigatory usage against HIV infection

Miltefosine targets HIV infected macrophages, which play a role in vivo as long-lived HIV-1 reservoirs. The HIV protein Tat activates pro-survival PI3K/Akt pathway in primary human macrophages. Miltefosine acts by inhibiting the PI3K/Akt pathway, thus removing the infected macrophages from circulation, without affecting healthy cells.^[5] It significantly reduces replication of HIV-1 in cocultures of human dendritic cells (DCs) and CD4(+) T cells, which is due to a rapid secretion of soluble factors and is associated with induction of type-I interferon (IFN) in the human cells.^[26]

In leishmanisis the recommended dose as oral monotherapy is 2.5 mg/kg/day for a total of 28 days. However, due to frequent commercial shortage of the 10 mg capsule, dosages are often altered. For example, the Indian government recommends 100 mg/day miltefosine for patients with a body weight ≥25 kg (corresponding to ∼1.7–4 mg/kg/day) and 50 mg/day for body weights <25 kg (corresponding to ∼2–5.5 mg/kg/day).^[1] Even up to 150 mg/day for 28 days was found to be quite safe.^[27]

The main side effects reported with miltefosine treatment are nausea and vomiting, which occur in 60% of patients. Adverse effect is more severe in women and young children. The overall effects are quite mild and easily reverse.^[28] It is embryotoxic and fetotoxic in rats and rabbits, and teratogenic in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, andcontraception is required beyond the end of treatment in women of child-bearing age.^[29]

miltefosine (1-hexadecylphosphoryl-choline, HePC); Calbiochem 475841

Compounds of the general formula I belonging to the class of phospholipids (X is O and R² is a group of formula II), e.g. alkyloxy phospholipids (Y is O) and the corresponding alkylthio derivatives (Y is S), can be prepared as described in the literature (Bittman, R.; J. Med. Chem. 1997, 40, 1391-1395; Reddy, K. C.; Tetrahedron Lett. 1994, 35, 2679-2682; Guivisdalsky, P. N.; J. Med. Chem. 1990, 33, 2614-2621 and references cited therein) or by standard variations of the procedures described therein. Synthesis of the corresponding ester and thioester analogues (Y is OCO and SCO, respectively) can be accomplished by standard acylation of the hydroxy or thio precursor materials.

Compounds of the general formula I belonging to the class of phosphonolipids (X is a direct bond and R² is a group of formula II), e.g alkyloxy phosphonolipids (Y is O and R² is a group of formula II) and the corresponding alkylthio derivatives (Y is S) can be prepared as published by Bittman et al. (Bittman, R.; J. Med. Chem. 1993, 36, 297-299; Bittman, R.; J. Med. Chem.1994, 37, 425-430 and references cited therein) or by synthetic variations of the procedures described therein. Synthesis of the corresponding ester and thioester analogues (Y is OCO or SCO) can be accomplished by standard acylation of the hydroxy or thio precursor materials.

SEE

Antitumor ether lipids: An improved synthesis of ilmofosine and an enantioselective synthesis of an ilmofosine analog
Tetrahedron Lett 1994, 35(17): 2679

AND

Hexadecylphosphocholine, a new antineoplastic agent: Cytotoxic properties in leukaemic cells
J Cancer Res Clin Oncol 1986, 111: 24

References

• Max Planck Innovation
• FDA Panel Endorses Miltefosine for Leishmaniasis
• Med India
• Drugs.com

an animation to soothe ones eye

Cabazitaxel

For treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate

(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(Acetyloxy)-15-{[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoyl]oxy}-1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0^3,10.0^4,7]heptadec-13-ene-2-yl benzoate

183133-96-2

EMA:Link, US FDA:link

Cabazitaxel is prepared by semi-synthesis from 10-deacetylbaccatin III (10-DAB) which is extracted from yew tree needles. The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxy-tax-11-en-2-yl benzoate and is marketed as a 1:1 acetone solvate (propan-2-one),

Cabazitaxel is an anti-neoplastic used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has progressed despite treatment with docetaxel. Cabazitaxel is prepared by semi-synthesis with a precursor extracted from yew needles (10-deacetylbaccatin III). It was approved by the U.S. Food and Drug Administration (FDA) on June 17, 2010.

Cabazitaxel (previously XRP-6258, trade name Jevtana) is a semi-synthetic derivative of a natural taxoid.^[1] It was developed by Sanofi-Aventis and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer on June 17, 2010. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.^[2]

Nagesh Palepu, “CABAZITAXEL FORMULATIONS AND METHODS OF PREPARING THEREOF.” U.S. Patent US20120065255, issued March 15, 2012.

US20120065255 

Cabazitaxel in combination with prednisone is a treatment option for hormone-refractory prostate cancer following docetaxel-based treatment.

Clinical trials

In a phase III trial with 755 men for the treatment of castration-resistant prostate cancer, median survival was 15.1 months for patients receiving cabazitaxel versus 12.7 months for patients receiving mitoxantrone. Cabazitaxel was associated with more grade 3–4 neutropenia (81.7%) than mitoxantrone (58%).^[3]

JEVTANA (cabazitaxel) is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles.

The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one(1:1).

Cabazitaxel has the following structural formula:

Cabazitaxel is a white to almost-white powder with a molecular formula of C₄₅H₅₇NO₁₄^•C₃H₆O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol.

JEVTANA (cabazitaxel) Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80. Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80.

DILUENT for JEVTANA is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL.

JEVTANA requires two dilutions prior to intravenous infusion. JEVTANA injection should be diluted only with the supplied DILUENT for JEVTANA, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution.

The taxane family of terpenes has received much attention in the scientific and medical community, because members of this family have demonstrated broad spectrum of anti-leukemic and tumor-inhibitory activity. A well-known member of this family is paclitaxel (Taxol®).

Paclitaxel (Taxol) Paclitaxel was first isolated from the bark of the pacific yew tree (Taxus brevifolia) in 1971 , and has proved to be a potent natural anti-cancer agent. To date, paclitaxel has been found to have activity against different forms of leukemia and against solid tumors in the breast, ovary, brain, and lung in humans.

As will be appreciated, this beneficial activity has stimulated an intense research effort over recent years with a view to identifying other taxanes having similar or improved properties, and with a view to developing synthetic pathways for making these taxanes, such as paclitaxel.

This research effort led to the discovery of a synthetic analogue of paclitaxel, namely, docetaxel (also known as Taxotere®). As disclosed in U.S. Patent No. 4,814,470, docetaxel has been found to have a very good anti-tumour activity and better bioavailability than paclitaxel. Docetaxel is similar in structure to paclitaxel, having t- butoxycarbonyl instead of benzoyl on the amino group at the 3′ position, and a hydroxy group instead of the acetoxy group at the C-10 position.

As will be appreciated, taxanes are structurally complicated molecules, and the development of commercially viable synthetic methods to make taxanes has been a challenge. A number of semi-synthetic pathways have been developed over the years, which typically begin with the isolation and purification of a naturally occurring starting material, which can be converted to a specific taxane derivative of interest. Cabazitaxel (I) is an anti-tumor drug which belongs to the taxol family. It differs from docetaxel in that it has methoxy groups at positions 7 and 10 of the molecule, as opposed to the hydroxyl groups at equivalent positions in docetaxel. Cabazitaxel is obtained by semi-synthesis from an extract of Chinese yew (Taxus mairei). It is understood that cabazitaxel can be obtained via semi-synthesis from other taxus species including T.candensis, T.baccatta, T.chinensis, T. mairei etc.

Cabazitaxel is a semi-synthetic derivative of the natural taxoid 0-deacetylbaccatin III (10-DAB) with potentially unique antineoplastic activity for a variety of tumors.

Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. This drug is a microtubule depolymerization inhibitor, which can penetrate blood brain barrier (BBB).

Cabazitaxel was recently approved by the US Federal Drug Administration (FDA) for the treatment of docetaxel resistant hormone refractory prostate cancer. It has been developed by Sanofi-Aventis under the trade name of Jevtana. The CAS number for the compound is 183133-96-2. A synonym is dimethoxydocetaxel. The compound is also known as RPR-1 16258A; XRP6258; TXD 258; and axoid XRP6258.

The free base form of cabazitaxel has the chemical name

(2aR,4S,4aS,6R,9S, 1 1 S,12S,12aR, 12bS)-12b-acetoxy-9-(((2R,3S)-3-((tert- butoxycarbonyl)amino)-2-hydroxy-3-phenylpropanoyl)oxy)-11-hydroxy-4,6-dimethoxy- 4a,8, 13, 13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9, 10, 11 , 12, 12a, 12b-dodecahydro-1 H- 7, 1 1-methanocyclodeca[3,4]benzo[1 ,2-b]oxet-12-yl benzoate. In a first part of this description, taxel drugs including paclitaxel (taxol), docetaxel (taxotere) and cabazitaxel may be prepared starting from 10-deacetylbaccatin (known as 10-DAB) derived from Taxus plants, via semi-synthesis. Furthermore, the same inventive methodologies can be used to semi-synthesize cabazitaxel starting from 9- dihydro-13-acetylbaccatin III (9-DHB).

Patent numbers CN1213042C, CN152870, CN1179716 and CN1179775 disclose methods to prepare cabazitaxel from 10-DAB (herein compound II).

10-DAB (II)

A typical prior art synthesis route is as follows:

OCOCH₃

OCOC₆H₅

The method above which synthesizes cabazitaxel has many synthetic steps, a very low overall yield and high price.

There is therefore a need in the art to develop new methods to synthesize cabazitaxel and its intermediates to improve the yield of cabazitaxel, simplify the methodology and optimize the synthetic technology.

Cabazitaxel, chemically known as 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate, is represented by formula (I).

It is a microtubule inhibitor, indicated in combination with prednisone for treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, under the trade name Jevtana®.

Cabazitaxel is known from U.S. Pat. No. 5,847,170. Process for preparation of Cabazitaxel as described in U.S. Pat. No. 5,847,170 involves column chromatography, which is cumbersome tedious and not commercially viable.

The acetone solvate of 4-acetoxy-2α-benzoyloxy-5β-20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxotan-11-en-13α-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (Form A) is formed by crystallization by using acetone and is characterized by XRD in U.S. Pat. No. 7,241,907.

U.S. 20110144362 describes anhydrous crystalline Forms B to Form F, ethanolates Form B, D, E and F and mono and dihydrate Forms of Cabazitaxel. All the anhydrous crystalline forms are prepared either by acetone solvate or ethanol solvate. Mono and dihydrate forms are formed at ambient temperature in an atmosphere containing 10 and 60% relative humidity, respectively.

Cabazitaxel (also called dimethoxy docetaxel) is a dimethyl derivative of docetaxel, which itself is semi-synthetic, and was originally developed by Rhone-Poulenc Rorer and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer on Jun. 17, 2010. Cabazitaxel is a microtubule inhibitor. The acetone solvate crystalline form of cabazitaxel and a process for its preparation is disclosed in the U.S. Pat. No. 7,241,907.

U.S. Pat. No. 5,847,170 describes cabazitaxel and its preparation methods. One of the methods described in U.S. Pat. No. 5,847,170 includes a step-wise methylation of 10-DAB (the step-wise methylation method is shown in FIG. 1) to provide the key intermediate (2αR,4S,4αS,6R,9S,11S,12S,12αR,12βS)-12β-acetoxy-9,11-dihydroxy-4,6-dimethoxy-4α,8,13,13-tetramethyl-5-oxo-2α,3,4,4α,5,6,9,10,11,12,12α,12β-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl benzoate, herein referred to as 7,10-di-O-methyl-10-DAB (XVa). The intermediate XVa is coupled with the 3-phenylisoserine side chain derivative VI to provide XVa′, which is followed by removal of the oxazolidine protecting group from the side chain of XVa′ to give cabazitaxel.

Another method described in U.S. Pat. No. 5,847,170 utilizes methylthiomethyl (MTM) ethers as shown in FIG. 2. MTM ethers can be prepared from alcohols using two common methods. One method comprises deprotonation of an alcohol with a strong base to form an alkoxide followed by alkylation of the alkoxide with a methylthiomethyl halide. This approach is only useful when the alcohol is stable to treatment with a strong base. 10-DAB and some of its derivatives in which C7-OH is not protected displays so instability in the presence of strong bases and epimerization of the C7-OH can occur upon contact of 10-DAB and some of its derivatives in which C7-OH is not protected with strong bases. Another method for the synthesis of MTM ethers from alcohols utilizes Ac2O and DMSO. One disadvantage of this method is that it can also lead to the oxidation of alcohols to aldehydes or ketones. For example when the synthesis of the 10-di-O-MTM derivative of 10-DAB without protecting groups at the C13 hydroxyl group is attempted undesired oxidation of the C13-OH to its corresponding ketone occurs.

U.S. Pat. No. 5,962,705 discloses a method for dialkylation of 10-DAB and its derivatives to furnish 7,10-di-O-alkyl derivatives, as shown in FIG. 3. This has been demonstrated as a one-step, one-pot reaction, however, provides the best isolated yield when potassium hydride is used at −30° C. From an industrial point of view, the use of low reaction temperature is less favorable than using ambient temperature. Furthermore the use of a strong base can cause some epimerization of the C7-OH chiral center with an associated loss of yield. Potassium hydride is a very reactive base and must be treated with great caution.

Accordingly, there is a need for an alternative processes for the preparation of cabazitaxel and its key intermediate, 7,10-di-O-methyl-10-DAB (XVa) that is short in number of synthetic steps and avoids the use of low temperatures and strong bases such as metal hydrides in the C7-O methyl ether formation step. Such a process would also be useful for the preparation of analogues of cabazitaxel wherein the C7-O and C10-O functional groups were substituted with other alkyl groups.

FIG. 1 shows the chemistry employed in the examples of U.S. Pat. No. 5,847,170.

FIG. 2 shows the chemistry employed in the examples of U.S. Pat. No. 5,847,170.

FIG. 3 shows the chemistry employed in the examples of U.S. Pat. No. 5,962,705.

FIG. 4 shows key steps of the general synthetic scheme as per Method A/A′ of the present invention for the synthesis of cabazitaxel and cabazitaxel analogues.

FIG. 5 shows key steps of the general synthetic scheme as per Method B/B′ of the present invention for the synthesis of cabazitaxel and cabazitaxel analogues.

FIG. 6 shows the general scheme for the hydrodesulfurization reaction.

FIG. 7 shows the complete synthetic route of Method A that can be used for conversion of 10-DAB to cabazitaxel.

FIG. 8 shows the complete synthetic route of Method B that can be used for conversion of 10-DAB to cabazitaxel.

FIG. 9 shows the complete synthetic route of Method A′ that can be used for conversion of 10-DAB, via XIV′, to cabazitaxel.

FIG. 10 shows the complete synthetic route of Method B′ that can be used for conversion of 10-DAB, via XVI′, to cabazitaxel.

FIG. 11 shows the synthetic relationship between two methods (A and B) used to convert 7,10-di-O-alkyl-10-DAB (XV) to cabazitaxel.

FIG. 12 shows the synthetic scheme for the preparation of XIVa.

FIG. 13 shows the synthetic scheme for the preparation of XIVb from 10-DAB.

FIG. 14 shows the synthetic scheme for the preparation of XIVb from XIVb′.

FIG. 15 shows the synthetic scheme for the preparation of XIVc.

FIG. 16 shows the synthetic scheme for the preparation of XIVa′ from XIVa.

FIG. 17 shows the synthetic scheme for the preparation of XIVa′ from XX.

FIG. 18 shows the synthetic scheme for the preparation of XIVb′.

FIG. 19 shows the synthetic scheme for the preparation of XIVc′.

FIG. 20 shows the synthetic scheme for the preparation of XVa from XIVa.

FIG. 21 shows the synthetic scheme for the preparation of XVa from XIVb.

FIG. 22 shows the synthetic scheme for the preparation of XVa from XIVc.

FIG. 23 shows the synthetic scheme for the preparation of XVa′ from XIVa.

FIG. 24 shows the synthetic scheme for the preparation of XVa′ from XIVa′.

FIG. 25 shows the synthetic scheme for the preparation of XVa′ from XIVb′.

FIG. 26 shows the synthetic scheme for the preparation of XVa′ from XIVc′.

FIG. 27 shows the synthetic scheme for the preparation of XVa′ from XVa.

FIG. 28 shows the synthesis of cabazitaxel.

FIG. 29 shows the synthesis of XVIIa.

FIG. 30 shows the synthesis of XVIIIa.

FIG. 31 shows the synthesis of XIXa.

FIG. 32 shows the synthesis of XVIa.

FIG. 33 shows the synthesis of XVa from XVIa.

see this at  http://www.google.com/patents/US20130116444

………..

WO2013057260A1

Detailed description

The invention provides a new method for the preparation of cabazitaxel, one embodiment of which can be summarized as follows, showing the preparation of a protected taxane intermediate and its deprotection to taxane compounds:

OH OCOCH₃

OCOC₆H₅

This reaction is also depicted in Figure 1. The reaction of the invention reduces the number of steps and increases yield of cabazitaxel.

The deprotection methods of the invention can also be used for the preparation of paclitaxel (taxol):

The deprotection methods of the invention can also be applied to the preparation of docetaxel:

10-DAB synthetic routes

Example 12

Dissolve 100 g of 2′-THP-cabazitaxel in 1730 ml of HOAc/H₂0/THF (3:1 :1 ). under N₂ atmosphere, increase temperature to 50 degrees C and stir 4 hrs. Then cool to room temperature. Add 2L of ethyl acetate, 2 L of H₂0, stir, separate layers, wash organic layer with saturated NaHC0₃ (3 L x 2), saturated NaCI (3 L), dry with Na₂S0₄.

Concentrate to obtain white 77.8 g of cabazitaxel (yield 83%).

MS(m/z) :859(M+Na)„ _jHNMR (500MHz) δ 1.21(611, d) , 1.36(911, s) , 1.59(lH, s) , 1.64(lH,s) , 1.79(lH,m) , 1.87 (3H, s) ,2.27 (2H, m) , 2.35(3H,m) ,2.69(lH,m) ,3.30 (3H, s) ,

3.45 (3H, s) , 3.85 (2H, m) , 4.16 (1H, d) , 4.29 (1H, d) , 4.62 (1H, bs) , 4.79 (1H, s) , 5.29 (1H, m),5.42(lH, d),5.62(lH, d),6.21 (1H, t),7.2 ~ 7.4(6H, m) , 7.48 (2H, t),7.59(lH, t) , 8.11 (2H, d) ,

References

• Cabazitaxel - Official web site of manufacturer.
• Cabazitaxel Prescribing Information - Official prescribing information.
• U.S. National Library of Medicine: Drug Information Portal – Cabazitaxel

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FLORBETABEN F18

Diagnostic radiopharmaceutical

1. Benzenamine, 4-[(1E)-2-[4-[2-[2-[2-(fluoro-18F)ethoxy]ethoxy]ethoxy]phenyl]
ethenyl]-N-methyl-

2. 4-{(1E)-2-(4-{2-[2-(2-[18F]fluoroethoxy)ethoxy]ethoxy}phenyl)eth- 1-en-1-yl}-N-methylaniline

C21H26[18F]NO3
358.5
Bayer Healthcare

UNII-TLA7312TOI
CAS REGISTRY NUMBER  902143-01-5
https://www.ama-assn.org/resources/doc/usan/florbetaben-f18.pdf

Berlin/Boston, March 20, 2014‒ Piramal Imaging today announced that the U.S. Food and Drug Administration (FDA) has approved Neuraceq. This approval comes only four weeks after receiving marketing authorization for Neuraceq from the European Commission.

Neuraceq is indicated for Positron Emission Tomography (PET) imaging of the brain to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and other causes of cognitive decline.

read at

http://www.drugs.com/newdrugs/fda-approves-neuraceq-florbetaben-f18-pet-imaging-beta-amyloid-plaques-4021.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+March+20%2C+2014

4-[(E)-2-(4-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline has been labeled with [F-18]fluoride and is claimed by patent application WO2006066104 and members of the corresponding patent family.

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

The usefulness of this radiotracer for the detection of Αβ plaques have been reported in the literature (W. Zhang et al., Nuclear Medicine and Biology 32 (2005) 799-809; C. Rowe et al., Lancet Neurology 7 (2008) 1 -7).

The synthesis of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)- vinyl]-N-methylaniline has been described before:

a) W. Zhang et al., Nuclear Medicine and Biology 32 (2005) 799-809.

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

4 mg precursor 2a (2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate) in 0.2 mL

DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCI and neutralized with

NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi-preparative HPLC. 20% (decay corrected), 1 1 % (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N- methylaniline were obtained in 90 min.

WO2006066104

4 mg precursor 2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate in 0.2 mL DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediates was deprotected with HCI and neutralized with NaOH. The mixture was extracted with ethyl acetate. The solvent was dried and evaporated, the residue was dissolved in acetonitrile and purified by semi- preparative HPLC. 30% (decay corrected), 17% (not corrected for decay) 4- [(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N- methylaniline were obtained in 90 min. to yield N-Boc protected 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline. The unreacted perfluorinated precursor was removed using a fluorous phase cartridge.

Deprotection, final purification and formulation to obtain a product, suitable for injection into human is not disclosed. Furthermore, the usefulness (e.g. regarding unwanted F-19/F-18 exchange) of this approach at a higher radioactivity level is not demonstrated. Finally, this method would demand a two-pot setup (first reaction vessel: fluorination, followed by solid-phase- extraction, and deprotection in the second reaction vessel).

However, the focus of the present invention are compounds and methods for an improved “one-pot process” for the manufacturing of 4-[(E)-2-(4-{2-[2-(2- [F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline.

Very recently, further methods have been described:

d) US201001 13763

The mesylate precursor 2a was reacted with [F-18]fluoride species in a solvent mixture consisting of 100 μΙ_ acetonitrile and 500 μΙ_ tertiary alcohol. After fluorination for 10 min at 100-150 °C, the solvent was evaporated. After deprotection (1 N HCI, 5 min, 100-120 °C), the crude product was purified by HPLC (C18 silica, acetonitrile / 0.1 M ammonium formate).

e) H. Wang et al., Nuclear Medicine and Biology 38 (201 1 ) 121 -127

5 mg precursor 2a (2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]- phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl methanesulfonate) in 0.5 ml_

DMSO were reacted with [F-18]fluoride/kryptofix/potassium carbonate complex. The intermediate was deprotected with HCI and neutralized with NaOH. The crude product was diluted with acetonitrile / 0.1 M ammonium dformate (6/4) and purified by semi-preparative HPLC. The product fraction was collected, diluted with water, passed through a C18 cartridge and eluted with ethanol, yielding 17% (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline within 50 min. In the paper, the conversion of an unprotected mesylate precursor (is described:

5 mg unprotected mesylate precursor (2-{2-[2-(4-{(E)-2-[4- (methylamino)phenyl]vinyl}phenoxy)ethoxy]-ethoxy}ethyl 4- methanesulfonate) in 0.5 ml_ DMSO were reacted with [F- 18]fluoride/kryptofix/potassium carbonate complex. The crude product was diluted with acetonitrile / 0.1 M ammonium formate (6/4) and purified by semi- preparative HPLC. The product fraction was collected, diluted with water, passed through a C18 cartridge and eluted with ethanol, yielding 23% (not corrected for decay) 4-[(E)-2-(4-{2-[2-(2-[F-

18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline within 30 min. Beside the purification by HPLC, a process based on solid-phase-extraction was investigated, but the purity was inferior to that with HPLC purification. So far, one-pot radiolabelings have been performed using a mesylate precursor. It is know, that for F-18 labeling of stilbenes, mesylates have advantages over corresponding tosylates by providing more clean reactions with less amount of by-products (W. Zhang et al. Journal of Medicinal Chemistry 48 (2005) 5980- 5988), whereas the purification starting from the tosylate precursor was tedious and time consuming resulting in a low yield.

In contrast to this teaching of the prior art, we found advantages of tosylate and further arylsulfonate precursors for 4-[(E)-2-(4-{2-[2-(2-[F- 18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline compared to the corresponding mesylate. Less non-radioactive by-products that eluted close to the retention time of 4-[(E)-2-(4-{2-[2-(2-[F-

18]fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-N-methylaniline were found in the crude products if arylsulfonate precursors were used (Example 2 – Example 6) compared to the crude mixture that was obtained after conversion of the mesylate precursor (Example 1 ).

The favorable by-product profile after radiolabeling of tosylate precursor 2b (Figure 10) compared to the radiolabeling of mesylate precursor 2a (Figure 7) supported an improved cartridge based purification (Example 8, Example 9).

…………………

WO2011151281A1

The term “F-18″ means fluorine isotope ¹⁸F. The term”F-19″ means fluorine isotope ¹⁹F. EXAMPLES

Example 1 Radiolabeling of mesylate precursor 2a

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2a (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 1 ). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 21 % (corrected for decay).

Example 2 Synthesis and radiolabeling of tosylate precursor 2b

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

4-Dimethylaminopyridine (26.7 mg) and triethylamine (225 μΙ_) were added to a solution of 1 .0 g terf-butyl {4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate (4) in dichloromethane (12 mL) at 0 °C. A solution of p- toluenesulfonyl chloride (417 mg) in dichloromethane (13.5 mL) was added at 0 °C. The resulting mixture was stirred at room temperature over night. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (silica, 0- 80% ethyl acetate in hexane). 850 mg 2b were obtained as colorless solid.

1 H NMR (300 MHz, CDCI3) δ ppm 1 .46 (s, 9 H), 2.43 (s, 3 H), 3.27 (s, 3 H), 3.59-3.73 (m, 6 H), 3.80- 3.86 (m, 2 H), 4.05-4.19 (m, 2 H), 6.88-7.05 (m, 4 H), 7.21 (d, J = 8.3 Hz, 2 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.39-7-47 (m, 4 H), 7.80 (d, J = 8.3 Hz, 2 H). MS (ESIpos): m/z = 612 (M+H)⁺

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FX_N). Precursor 2b (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 2). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 25% (corrected for decay).

Example 3 Synthesis and radiolabeling of 2c (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-bromobenzenesulfonate)

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline To a stirred solution of 100 mg (0,219 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104) in 2 mL THF was added a solution of 140 mg (0.548 mmol) 4-brombenzene sulfonylchlorid in 3 mL THF drop by drop. The reaction mixture was cooled to 0°C. 156.8 mg (1 .1 mmol) potassium trimethylsilanolat was added. The milky suspension was stirred at 0°C for 2 hours and at 80°C for another 2 hours. The reaction mixture was poured onto ice-cooled water. The aqueous solution was extracted with dichloromethane several times. The combined organic phases were dried with sodium sulphate and concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2c was obtained with 77 mg (0.1 14 mmol, 52.0 % yield).

¹ H NMR (300 MHz, CDCI₃) δ ppm 1 .39 (s, 10 H) 3.20 (s, 3 H) 3.50 – 3.57 (m, 2 H) 3.57 – 3.61 (m, 2 H) 3.61 – 3.66 (m, 2 H) 3.72 – 3.80 (m, 2 H) 4.02 – 4.10 (m, 2 H) 4.10 – 4.17 (m, 2 H) 6.79 – 6.85 (m, 2 H) 6.91 (d, J=8.10 Hz, 2 H) 7.10 – 7.17 (m, 2 H) 7.32 – 7.41 (m, 5 H) 7.57 – 7.65 (m, 2 H) 7.67 – 7.74 (m, 2 H)

MS (ESIpos): m/z = 676/678 (M+H)⁺

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2c (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 3). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 43% (corrected for decay). Example 4 Synthesis and radiolabeling of 2d (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-(adamantan-1 -yl)benzenesulfonate)

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

To a stirred solution of 151 mg (0,330 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 4.03 mg (0,033 mmol) DMAP und 36.7 mg (363 mmol) triethylamine in 4 mL dichlormethane was added a solution of 97,4 mg (0,313 mmol) 4-(adamantan-1 -yl)benzene sulfonylchloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred at 0°C for 1 hour and over night at room temperature. 7.3 mg (0,072 mmol) triethylamin und 19.5 mg (0.062 mmol) 4- (adamantan-l -yl)benzenesulfonyl chloride were added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. It was concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2d was obtained with 104 mg (0.142 mmol, 43.4% yield).

¹ H NMR (300 MHz, CDCI₃) δ ppm 1 .51 (s, 9 H), 1 .62 (s, 1 H), 1 .74 – 1 .91 (m, 6 H), 1 .94 (d, J=3.20 Hz, 6 H), 2.16 (br. s., 3 H), 3.31 (s, 3 H), 3.63 – 3.69 (m, 2 H), 3.69 – 3.73 (m, 2 H), 3.76 (dd, J=5.27, 4.52 Hz, 2 H), 3.89 (d, J=4.90 Hz, 2 H), 4.13 – 4.26 (m, 4 H), 6.95 (d, J=8.85 Hz, 2 H), 7.02 (d, J=8.29 Hz, 2 H), 7.25 (d, J=8.48 Hz, 2 H), 7.40 – 7.52 (m, 4 H), 7.55 (m, J=8.67 Hz, 2 H), 7.89 (m, J=8.67 Hz, 2 H)

MS (ESIpos): m/z = 732 (M+H)⁺

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FX_N). Precursor 2d (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 4). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 27% (corrected for decay).

Example 5 Synthesis and radiolabeling of 2e (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

4-cyanobenzenesulfonate)

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- ethoxy}phenyl)vinyl]-N-methylaniline

To a stirred solution of 151 mg (0.330 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 4.03 mg (0.033 mmol) DMAP und 36.7 mg (0.363 mmol) triethylamine in 4 mL dichlormethane was added a solution of 63.2 mg (0.313 mmol) 4-cyanobenzenesulfonyl chloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred over night and concentrated in vacuum. The crude product was purified using silica gel with ethyl acetate/hexane-gradient as mobile phase. The desired product 2e was obtained with 118 mg (0.190 mmol, 57.6 % yield).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .47 (s, 9 H) 3.28 (s, 3 H) 3.58 – 3.63 (m, 2 H) 3.63 – 3.68 (m, 2 H) 3.70 – 3.75 (m, 2 H) 3.81 – 3.87 (m, 2 H) 4.1 1 – 4.18 (m, 2 H) 4.24 – 4.30 (m, 2 H) 6.91 (d, J=8.59 Hz, 2 H) 6.99 (dt, 2 H) 7.22 (d, J=8.34 Hz, 2 H) 7.39 – 7.50 (m, 4 H) 7.83 (m, J=8.59 Hz, 2 H) 7.98 – 8.1 1 (m, 2 H)

MS (ESIpos): m/z = 623 (M+H)⁺

Radiolabeling was performed on a remote controlled synthesis module (Tracerlab FXN). Precursor 2e (2 mg) in 0.5 mL DMSO + 0.5 mL acetonitrile was treated with dried potassium carbonate/kryptofix/[F-18]fluoride complex for 6 min at 100 °C. 1 M HCI (1 mL) + 10 mg ascorbic acid was added and the mixture was heated for 4 min at 100 °C. 2M NaOH (0.5 mL), water (6 mL) and ethanol (1 mL) were added and the crude mixture was trapped on a C18 cartridge. The crude product mixture was eluted with acetonitrile and diluted with 0.1 M ammonium formiat buffer (1 mL) + 5 mg ascorbic acid. A sample of the crude product was taken and analyzed by analytical HPLC (Figure 5). After purification by semi- preparative HPLC, the product was diluted with water + 5 mg ascorbic acid, trapped on a C18 cartridge and eluted with 1 mL ethanol.

Yield of 4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]ethoxy}phenyl)-vinyl]-N- methylaniline: 31 % (corrected for decay).

Example 6 Synthesis and radiolabeling of 2f (2-[2-(2-{4-[(E)-2-{4-[(tert- butoxycarbonyl)(methyl)amino]phenyl}vinyl]phenoxy}ethoxy)ethoxy]ethyl

2-nitrobenzenesulfonate)

4-[(E)-2-(4-{2-[2-(2-[F-18]fluoroethoxy)ethoxy]- eth oxy} phe nyl )vi ny I] -N -methyla n i I i ne

To a stirred solution of 200 mg (0.437 mmol) tert-butyl-{4-[(E)-2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)vinyl]phenyl}methylcarbamate

(WO2006/066104), 5.34 mg (0.044 mmol) DMAP und 47.5 mg (0.470 mmol) triethylamine in 4 mL dichlormethane was added a solution of 92 mg (0,415 mmol) 2-nitrobenzenesulfonyl chloride in 1 mL dichlormethane at 0°C. The reaction mixture was stirred over night and concentrated in vacuum. The crude product was purified with ethyl acetate/hexane-gradient as mobile phase using silica gel. The desired product 2f was obtained with 77 mg (0.1 19 mmol, 59.5 % yield). ¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .39 (s, 9 H) 3.20 (s, 3 H) 3.55 – 3.63 (m, 4 H) 3.59 (m, 4 H) 3.69 – 3.74 (m, 2 H) 3.75 – 3.80 (m, 2 H) 4.06 (dd, J=5.68, 3.92 Hz,

2 H) 4.32 – 4.37 (m, 2 H) 6.80 – 6.84 (m, 2 H) 6.84 – 6.98 (dt, 2 H) 7.14 (d, J=8.59 Hz, 2 H) 7.35 (d, J=3.03 Hz, 2 H) 7.37 (d, J=2.78 Hz, 2 H) 7.62 – 7.74 (m,

3 H) 8.06 – 8.1 1 (m, 1 H)

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If you have been diagnosed with kidney stones, you know how painful it is to live with these stones- big or small- in your kidneys. The acute pain in your left or right flanks going towards the lower abdomen and groin area and even towards your back is something that makes you shudder even if thought about. The feeling of nausea and vomiting along with the burning sensation while you pass urine and also the urgency and frequency of urinating, all these has led you to wish that you get rid of kidney stones as soon as possible.
While most kidney stones are small, it doesn’t mean they are harmless bunnies. One little stone in the urinary tract can make you suffer more than you can imagine.http://www.rapidhomeremedies.com/remedies-to-cure-kidney-stones.html

More than 100 countries have now approved Boehringer Ingelheim’s Pradaxa® for the prevention of stroke and systemic embolism for adult patients with the most common sustained heart rhythm condition (non-valvular atrial fibrillation, nvAF).

The 100th approvalwas announced by the Jordan Food and Drug Administration. Further regulatory approvals for Pradaxa® are expected to be received in the near future. The continuous flow of regulatory approvals from health authorities all over the world reaffirms the overarching benefits delivered to patients by the treatment and supports previous announcements by the U.S. Food and Drugs Administation (FDA) and the European Medicines Agency (EMA).Pradaxa®, in addition, offers the most robust clinical data set and the longest real-world experience for stroke prevention in atrial fibrillation (SPAF) compared to any of the novel oral anticoagulants, providing ongoing support for physician use of the novel treatment

http://www.worldpharmanews.com/boehringer-ingelheim/2720-pradaxar-dabigatran-etexilate-now-approved-in-more-than-100-countries-for-stroke-prevention-in-atrial-fibrillation

4-(acetyloxy)- 6,7-didehydro- 15-((2R,6R,8S)-4-ethyl- 1,3,6,7,8,9-hexahydro- 8-(methoxycarbonyl)- 2,6-methano- 2H-azecino(4,3-b)indol-8-yl)- 3-hydroxy- 16-methoxy- 1-methyl- methyl ester,

71486-22-1  ^cas

(2R,3R)-2,3-Dihydroxysuccinic acid – methyl (2ξ,3β,4β,5α,12β,19α)-4-acetoxy-15-[(12S,14R)-16-ethyl-12-(methoxycarbonyl)-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6, 8,15-pentaen-12-yl]-3-hydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidine-3-carboxylate (2:1)

Vinorelbine Tartrate 

125317-39-7 

Vinorelbine (trade name Navelbine) is an anti-mitotic chemotherapy drug that is given as a treatment for some types of cancer, including breast cancer and non-small cell lung cancer.

Clinicians sometimes use the abbreviation “NVB” for vinorelbine, although (like many medical abbreviations) it is not a unique identifier.

The antitumor activity is due to inhibition of mitosis through interaction with tubulin.^[2] Vinorelbine is the first 5´NOR semi-synthetic vinca alkaloid. It is obtained by semi-synthesis from alkaloids extracted from the rosy periwinkle, Catharanthus roseus. It is marketed in India by Abbott Healthcare under the brand name Navelbine.

History

Vinorelbine was invented by the pharmacist Pierre Potier and his team from the CNRS in France in the 1980s and was licensed to the oncology department of the Pierre Fabre Group. The drug was approved in France in 1989 under the brand name Navelbine for the treatment of non-small celllung cancer. It gained approval to treat metastatic breast cancer in 1991. Vinorelbine received approval by the United States Food and Drug Administration (FDA) in December 1994 sponsored by Burroughs Wellcome Company. Pierre Fabre Group now markets Navelbine in the U.S., where the drug went generic in February 2003.

In most European countries, vinorelbine is approved to treat non-small cell lung cancer and breast cancer. In the United States it is approved only for non-small cell lung cancer.

NAVELBINE (vinorelbine tartrate) Injection is for intravenous administration. Each vial contains vinorelbine tartrate equivalent to 10 mg (1-mL vial) or 50 mg (5-mL vial) vinorelbine in Water for Injection. No preservatives or other additives are present. The aqueous solution is sterile and nonpyrogenic. Vinorelbine tartrate is a semi-synthetic vinca alkaloid with antitumor activity. The chemical name is 3′,4′-didehydro-4′-deoxy-C’-norvincaleukoblastine [R-(R*,R*)-2, 3-dihydroxybutanedioate (1:2)(salt)]. Vinorelbine tartrate has the following structure:

http://images.rxlist.com/images/rxlist/navelbine1.gif” width=”450″ height=”230″ />

vinorelbine tartrate is a white to yellow or light brown amorphous powder with the molecular formula C₄₅H₅₄N₄O₈•2C₄H₆O₆ and molecular weight of 1079.12. The aqueous solubility is > 1,000 mg/mL in distilled water. The pH of NAVELBINE (vinorelbine tartrate) Injection is approximately 3.5.

Uses

As stated above, Vinorelbine is approved for the treatment of non small cell lung cancer and metastatic breast cancer. It is also active inrhabdomyosarcoma.^[3]

Oral formulation

An oral formulation has been marketed and registered in most European countries for the same settings. It has similar efficacy as the intravenous formulation, avoids venous toxicities of an infusion and is easier to take.

Side effects

Vinorelbine has a number of side-effects that can limit its use:

Chemotherapy-induced peripheral neuropathy (a progressive, enduring and often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs^[4]), lowered resistance to infection, bruising or bleeding, anaemia,constipation, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which it was injected (phlebitis). Seldom severe hyponatremia is seen.

Less common effects are hair loss and allergic reaction.

http://www.google.com/patents/EP2135872A1?cl=en

References

Sulfoaildenafil

An analog of Sildenafil which has been used as an illegal adulterant in some dietary supplements.

856190-47-1  ^{cas no}

5-(5-(((3R,5S)-3,5-Dimethylpiperazin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7(4H)-thione

• 7H-Pyrazolo(4,3-d)pyrimidine-7-thione, 5-(5-(((3R,5S)-3,5-dimethyl-1-piperazinyl)sulfonyl)-2-ethoxyphenyl)-1,6-dihydro-1-methyl-3-propyl-, rel-

• Sildenafil thione
• Thioaildenafil
• UNII-33DX49E09G
• • C23-H32-N6-O3-S2
  • 504.6768

Sulfoaildenafil (thioaildenafil) is a synthetic chemical compound that is a structural analog of sildenafil (Viagra).^[1] It was first reported in 2005,^[2] and it is not approved by any health regulation agency. Like sildenafil, sulfoaildenafil is a phosphodiesterase type 5 inhibitor.

Sulfoaildenafil has been found as an adulterant in a variety of supplements which are sold as “natural” or “herbal” sexual enhancement products.^[3][4][5][6] A range of designer analogues of USA FDA-approved inhibitors of type-5 cGMP-specific phosphodiesterase (PDE₅), such as sildenafil and vardenafil, have been detected in recent years as adulturants in over-the-counter herbal aphrodisiac products and dietary supplements,^[7][8][9] in an apparent attempt to circumvent both the legal restrictions on sale of erectile dysfunction drugs, which are prescription-onlymedicines in most Western countries, and the patent protection which prevents sale of these drugs by competitors except under license to their inventors.

Figure 1. Biological pathway of penile erection

These compounds have been demonstrated to display PDE₅ inhibitory activity in vitro and presumably have similar effects when consumed, but have undergone no formal testing in either humans or animals, and as such represent a significant health risk to consumers of these products due to their unknown safety profile.^[10] Some attempts have been made to ban these drugs as unlicensed medicines, but progress has been slow so far, as even in those jurisdictions which have laws targeting designer drugs, the laws are drafted to ban analogues of illegal drugs of abuse, rather than analogues of prescription medicines. However at least one court case has resulted in a product being taken off the market.^[11]

Figure 2. PDE5 domains

In December 2010, the United States Food and Drug Administration (FDA) issued a warning to consumers about such products stating, “The FDA has found many products marketed as dietary supplements for sexual enhancement during the past several years that can be harmful because they contain active ingredients in FDA-approved drugs or variations of these ingredients.”^[12]

Figure 3. PDE5 Domains

References

BERAPROST

https://www.ama-assn.org/resources/doc/usan/beraprost.pdf

2,3,3a,8b-tetrahydro-2-hydroxy-1-(3-hydroxy-4-methyl-1-octen-6-ynyl)-1H-cyclopenta(b)benzofuran-5-butanoic acid

(±)-(IR*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octene-6-inyl]-1H-cyclopenta[b]benzofuran-5-butyric acid

rac-4-{(1R,2R,3aS,8bS)-2-hydroxy-1-[(1E,3S,4RS)-3-hydroxy-4-methyloct-1-en-6-ynyl]-2,3,3a,8b-tetrahydro-1H-cyclopenta[b][1]benzofuran-5-yl}butanoic acid

88430-50-6 88475-69-8

• Beraprost
• Beraprostum
• Beraprostum [INN-Latin]
• MDL 201229
• MDL-201229
• ML 1229
• ML-1229
• UNII-35E3NJJ4O6

Beraprost is a synthetic analogue of prostacyclin, under clinical trials for the treatment of pulmonary hypertension. It is also being studied for use in avoiding reperfusion injury.

As an analogue of prostacyclin PGI₂, beraprost effects vasodilation, which in turn lowers the blood pressure. Beraprost also inhibits plateletaggregation, though the role this phenomenon may play in relation to pulmonary hypertension has yet to be determined.

Beraprost …sodium salt

ML 1129; Procyclin; TRK 100 (CAS 88475-69-8)

Beraprost sodium is a prostacyclin analog and an NOS3 expression enhancer that was first launched in 1992 in Japan pursuant to a collaboration between Astellas Pharma and Toray for the oral treatment of peripheral vascular disease (PVD), including Raynaud’s syndrome and Buerger’s disease. In 2000, the drug was commercialized for the treatment of pulmonary hypertension. Development for the oral treatment of intermittent claudication associated with arteriosclerosis obliterans (ASO) was discontinued at Kaken and United Therapeutics after the product failed to demonstrate statistically significant results in a phase III efficacy trial.

In terms of clinical development, beraprost sodium is currently in phase II clinical trials at Kaken for the treatment of lumbar spinal canal stenosis and at Astellas Pharma for the oral treatment of primary chronic renal failure. The company is also conducting phase III trials for the treatment of nephrosclerosis. The drug has also been studied through phase II clinical trials at Kaken for the oral treatment of diabetic neuropathy, but recent progress reports for this indication have not been made available.

Beraprost is an oral form of prostacyclin, a member of the family of lipid molecules known as eicosanoids. Prostacyclin is produced in the endothelial cells from prostaglandin H2 by the action of the enzyme prostacyclin synthase. It has been shown to keep blood vessels dilated and free of platelet aggregation.

Beraprost sodium was originally developed at Toray in Japan, and rights to the drug were subsequently acquired by Astellas Pharma. A 1972 alliance between Toray and Kaken Pharmaceutical to develop and commercialize prostaglandin led to a later collaboration agreement for the development of beraprost. In 1990, Toray granted the right to market the drug to Sanofi (formerly known as sanofi-aventis), a licensing agreement that was later expanded to include Canada, the U.S., South America, Africa, Southeast Asia, South Asia, Korea and China. In September 1996, Bristol-Myers Squibb entered into separate agreements with Sanofi and Toray to acquire all development and marketing rights to beraprost in the U.S. and Canada. In January 1999, United Therapeutics and Toray agreed to cooperatively test the drug in North America, and in July 2000, a new agreement was signed pursuant to which United Therapeutics gained exclusive North American rights to develop and commercialize sustained-release formulations of beraprost for all vascular and cardiovascular diseases. In 1999, orphan drug designation was received in the U.S. for the treatment of pulmonary arterial hypertension associated with any New York Heart Association classification (Class I, II, III, or IV). In 2011, orphan drug designation was assigned in the U.S. for the treatment of pulmonary arterial hypertension.

• The compound name of beraprost which is used as an antimetastasis agent of malignant tumors according to the present invention is (±)-(IR*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octene-6-inyl]-1H-cyclopenta[b]benzofuran-5-butyric acid. This compound has the following structure.

  Beraprost is described in Japanese Laid-open Patent Application (Kokai) Nos. 58-32277, 57-144276 and 58-124778 and the like as a PGI₂ derivative having a structure in which the exoenol moiety characteristic to beraprost is converted to inter-m-phenylene structure. However, it is not known that beraprost has an activity to inhibit metastasis of malignant tumors.

• The beraprost which is an effective ingredient of the agent of the present invention includes not only racemic body, but also d-body and l-body. Beraprost can be produced by, for example, the method described in the above-mentioned Japanese Laid-open Patent Application (Kokai) No. 58-124778. The salts of beraprost include any pharmaceutically acceptable salts including alkaline metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; primary, secondary and tertiary amine salts; and basic amino acid salts.

EP0623346A1

…………………..

US7005527

EXAMPLE 6 Beraprost of the Formula (I)

0.246 g (0.6 mmol) of compound of the general formula (II) obtained in Example 5 is dissolved in 1 ml of methanol and 1 ml of 1 M aqueous sodium hydroxide solution is added dropwise slowly thereto. After stirring for an hour the methanol is distilled off from the reaction mixture in vacuum. The aqueous residue is diluted with 10 ml of water extracted with methyl-tert.butyl-ether and the combined organic phase is washed with saturated NaCl solution, dried on Na₂SO₄ and evaporated. The residue of evaporation is crystallized from ethylacetate-hexane mixture and the pure above mentioned title compound is obtained as colourless crystals.

Yield: 0.21 g (87%)

TLC-R_f (toluene-dioxan-acetic acid 20:10:1)=0.41

Melting point: 98–112° C.

¹H NMR (400 MHz, CDCl₃), δH (ppm): 1.00d, 1.03d [3H; J=6.8 Hz; 21-H₃]; 1.79m [1H; 16-H]; 1.80t, 1.81t [3H, J=2.5,2.4 Hz; 20-H₃]; 2.3–1.9m [5H, 3-H₂, 10H_b, 17-H₂]; 2.34t [1H; J=7.4 Hz; 2-H₂]; 2.43m [1H; 12-H]; 2.64m [3H; 10-H_a, 4-H₂]; 3.43t, 3.44t [1H, J=8.7,8.5 Hz; 8-H]; 3.92m [1H; 11-H]; 4.07t, 4.17t [1H, J=7.3,5.6 Hz; 15-H]; 4.3b [2H; OH]; 5.09m [1H, 9-H]; 5.58dd, 5.61dd [1H; J=15.3,6.5 Hz; 14-H]; 5.67dd, 5.68dd [1H; J=15.3,8.0 Hz; 13-H]; 6.77m [1H; 2′-H]; 6.95m [2H; 1′-H,3′-H]¹³C NMR (100 MHz, CDCl₃), δC (ppm): 3.5, 3.6 [C-20]; 14.7, 15.8 [C-21]; 22.3, 22.6 [C-17]; 24.6 [C-2]; 29.1 [C-4]; 33.1 [C-3]; 38.2, 38.3 [C-16]; 41.2 [C-10]; 50.4 [C-8]; 58.8 [C-12]; 75.8, 76.3, 76.4 [C-11, C-15]; 77.2, 77.4 [C-18, C-19]; 84.5, 84.6 [C-9]; 120.6 [C-2′]; 121.9 [C-3′]; 123.2 [C-5]; 129.0 [C-1′]; 129.7 [C-7]; 132.3, 133.0, 133.8, 134.0 [C-13, C-14]; 157.2 [C-6]; 178.3 [C-1].

EXAMPLE 7 Beraprost Sodium Salt (The Sodium Salt of the Compound of Formula (I)

0.199 g of beraprost is dissolved in 2 ml of methanol, 0.5 ml of 1 M aqueous solution of sodium hydroxide is added thereto and after their mixing the solvent is evaporated in vacuum and thus the above title salt is obtained as colourless crystals.

Yield: 0.21 g (100%)

Melting point: >205° C.

¹H NMR (400 MHz, DMSO-d₆), δH (ppm): 0.90d, 0.92d [3H; J=6.7 Hz; 21-H₃]; 1.75–1.55m [7H; 10H_b, 16-H, 3-H₂, 20-H₃]; 1.89t [2H, J=7.6 Hz; 2-H₂]; 1.94m [1H; 17-H_b]; 2.16q [1H, J=8.5 Hz; 12-H]; 2.25m [1H; 17-H_a]; 2.44t [2H; J=7.5 Hz; 4-H₂]; 2.50o [1H; 10-H_a]; 3.39t [1H, J=8.5 Hz; 8-H]; 3.72td [1H; J=8.5,6.1 Hz; 11-H]; 3.84t 3.96t [1H, J=6.5,6.0 Hz; 15-H]; 4.85b [2H, OH]; 5.01dt [1H, J=8.5,6.6 Hz; 9-H]; 5.46dd, 5.47dd [1H; J=15.4,6.5 Hz, J=15.4,6.0 Hz; 14-H]; 5.65dd, 5.66dd [1H; J=15.4,8.5 Hz; 13-H]; 6.71m [1H; 2′-H]; 6.92m [2H; 1′-H, 3′-H] During the above thin layer chromatography (TLC) procedures we used plates MERCK Kieselgel 60 F₂₅₄, thickness of layer is 0.2 mm, length of plates is 5 cm.

…………….

•  Reaction Scheme A.
• The starting material of bromocarboxylic acid, Compound 1, and the process for the preparation thereof are disclosed in Japanese Patent Application No. 29637/81.

• Scheme B.

REACTION SCHEME B

• REACTION SCHEME C
  • https://www.google.com/patents/EP0084856A1

    Org Lett 2012, 14(1): 299

    http://pubs.acs.org/doi/abs/10.1021/ol203060v

    http://pubs.acs.org/doi/suppl/10.1021/ol203060v/suppl_file/ol203060v_si_001.pdf

    EP0024943A1	Sep 2, 1980	Mar 11, 1981	Toray Industries, Inc.	5,6,7-Trinor-4,8-inter-m-phenylene PGI2 derivatives and pharmaceutical compositions containing them
    EP0084856A1	Jan 19, 1983	Aug 3, 1983	Toray Industries, Inc.	5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives
    JP3069909B				Title not available

APREMILAST

PDE4 inhibitor

N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide

(+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methanesulfonylethyl]-4-acetylaminoisoindolin-l,3-dione,

(S)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
(S)-N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
Molecular Formula: C₂₂H₂₄N₂O₇S   Molecular Weight: 460.50016

608141-41-9 CAS NO

Celgene (Originator)

MARCH 22, 2014

Just as the American Academy of Dermatology meeting opens its doors in Denver, Celgene Corp has been boosted by a green light from US regulators for Otezla as a treatment for psoriatic arthritis.

The US Food and Drug Administration has approved Otezla (apremilast), making it the first oral treatment for adults with active PsA. The thumbs-up for the phosphodieasterase-4 (PDE-4) inhibitor is primarily based on three trials involving 1,493 patients where Otezla showed improvement in signs and symptoms of the disease, including tender and swollen joints and physical function, compared to placebo.

Read more at:

http://www.pharmatimes.com/Article/14-03-22/FDA_approves_Celgene_s_Otezla_for_psioratic_arthritis.aspx

COPY PASTE LINK

CC-10004, , Apremilast (USAN), SureCN302992, Apremilast (CC-10004), QCR-202,

• Apremilast
• CC 10004
• CC-10004
• CC10004
• UNII-UP7QBP99PN
• CLINICAL TRIALS….http://clinicaltrials.gov/search/intervention=Apremilast+OR+CC-10004

Apremilast is an orally available small molecule inhibitor of PDE4 being developed byCelgene for ankylosing spondylitis, psoriasis, and psoriatic arthritis.^[1][2] The drug is currently in phase III trials for the three indications. Apremilast, an anti-inflammatory drug, specifically inhibits phosphodiesterase 4. In general the drug works on an intra-cellular basis to moderate proinflammatory and anti-inflammatory mediator production.

APREMILAST

Apremilast is being tested for its efficacy in treating “psoriasis, psoriatic arthritis and other chronic inflammatory diseases such as ankylosing spondylitis, Behcet’s disease, and rheutmatoid arthritis.

“Apremilast is Celgene’s lead oral phosphodiesterase IV inhibitor and anti-TNF alpha agent in phase III clinical studies at Celgene for the oral treatment of moderate to severe plaque-type psoriasis and for the oral treatment of psoriatic arthritis.

Early clinical development is also ongoing for the treatment of acne, Behcet’s disease, cutaneous sarcoidosis, prurigo nodularis, ankylosing spondylitis, atopic or contact dermatitis and rheumatoid arthritis. No recent development has been reported for research for the treatment of skin inflammation associated with cutaneous lupus erythematosus.

In 2011, Celgene discontinued development of the compound for the management of vision-threatening uveitis refractory to other modes of systemic immunosuppression due to lack of efficacy.

Celgene had been evaluating the potential of the drug for the treatment of asthma; however, no recent development has been reported for this research. The drug candidate is also in phase II clinical development at the William Beaumont Hospital Research Institute for the treatment of chronic prostatitis or chronic pelvic pain syndrome and for the treatment of vulvodynia (vulvar pain).

In 2013, orphan drug designations were assigned to the product in the U.S. and the E.U. for the treatment of Behcet’s disease.

Celgene Corp has been boosted by more impressive late-stage data on apremilast, an oral drug for psoriatic arthritis, this time in previously-untreated patients.

The company is presenting data from the 52-week PALACE 4 Phase III study of apremilast tested in PsA patients who have not taken systemic or biologic disease modifying antirheumatic drugs (DMARDs) at the American College of Rheumatology meeting in San Diego. The results from the 527-patient trial show that at week 16, patients on 20mg of the  first-in-class oral inhibitor of phosphodiesterase 4 (PDE4) achieved an ACR20 (ie a 20% improvement in the condition) response of 29.2% and 32.3% for 30mg aapremilast, compared with 16.9% for those on placebo.

After 52 weeks, 53.4% on the lower dose and 58.7% on 30mg achieved an ACR20 response. ACR50 and 70 was reached by 31.9% and 18.1% of patients, respectively, for apremilast 30mg. The compound was generally well-tolerated and discontinuation rates for diarrhoea and nausea were less than 2% over 52 weeks.

Commenting on the data, Alvin Wells, of the Rheumatology and Immunotherapy Center in Franklin, Wisconsin, noted that apremilast demonstrated long-term safety and tolerability and significant clinical benefit in treatment-naive patients. He added that “these encouraging results suggest that apremilast may have the potential to be used alone and as a first-line therapy”. Celgene is also presenting various pooled data from the first three trials in the PALACE programme which, among other things, shows that apremilast significantly improves swollen and tender joints.

Treatment for PSA, which affects about 30% of the 125 million people worldwide who have psoriasis, currently involves injectable tumour necrosis factor (TNF) inhibitors, notably AbbVie’s Humira (adalimumab) and Pfizer/Amgen’s Enbrel (etanercept), once patients have not responded to DMARDs (at least in the UK). While the biologics are effective, the side effect profile can be a concern, due to the risk of infection and tuberculosis and many observers believe that apremilast will prove popular with patients and doctors due to the fact that it is oral, not injectable.

Apremilast was filed for PsA with the US Food and Drug Administration in the first quarter and will be submitted on both sides of the Atlantic for psoriasis before year-end. The European filing will also be for PsA.

Apremilast impresses for Behcet’s disease

Celgene has also presented promising Phase II data on apremilast as a treatment for the rare inflammatory disorder Behcet’s disease. 71% of patients achieved complete response at week 12 in clearing oral ulcers

APREMILAST

1.  “Apremilast Palace Program Demonstrates Robust and Consistent Statistically Significant Clinical Benefit Across Three Pivotal Phase III Studies (PALACE-1, 2 & 3) in Psoriatic Arthritis” (Press release). Celgene Corporation. 6 September 2012. Retrieved 2012-09-10.
2.  “US HOT STOCKS: OCZ, VeriFone, Men’s Wearhouse, AK Steel, Celgene”. The Wall Street Journal. 6 September 2012. Retrieved 2012-09-06.
3. Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor.

   Man HW, Schafer P, Wong LM, Patterson RT, Corral LG, Raymon H, Blease K, Leisten J, Shirley MA, Tang Y, Babusis DM, Chen R, Stirling D, Muller GW.

   J Med Chem. 2009 Mar 26;52(6):1522-4. doi: 10.1021/jm900210d.

4. Therapeutics: Silencing psoriasis.Crow JM.Nature. 2012 Dec 20;492(7429):S58-9. doi: 10.1038/492S58a. No abstract available.
5. NMR…http://file.selleckchem.com/downloads/nmr/S803401-Apremilast-HNMR-Selleck.pdf
6. WO 2003080049
7. WO 2013126495
8. WO 2013126360
9. WO 2003080049
10. WO 2006065814
11. US2003/187052 A1 …..MP 144 DEG CENT
12. US2007/155791
13. J. Med. Chem., 2008, 51 (18), pp 5471–5489
    DOI: 10.1021/jm800582j
14. J. Med. Chem., 2011, 54 (9), pp 3331–3347
    DOI: 10.1021/jm200070e

…………………………………………

INTRODUCTION

2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione is a PDE4 inhibitor that is currently under investigation as an anti-inflammatory for the treatment of a variety of conditions, including asthma, chronic obstructive pulmonary disease, psoriasis and other allergic, autoimmune and rheumatologic conditions. S-enantiomer form of 2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione can be prepared by reacting (5)-aminosulfone 1 with intermediate 2.

Existing methods for synthesizing (S)-aminosulfone 1 involve resolution of the corresponding racemic aminosulfone by techniques known in the art. Examples include the formation and crystallization of chiral salts, and the use of chiral high performance liquid chromatography. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). In one example, as depicted in Scheme 1 below, (5)-aminosulfone 1 is prepared by resolution of racemic aminosulfone 3 with N-Ac-L-Leu. Racemic aminosulfone 3 is prepared by converting 3-ethoxy-4-methoxybenzonitrile 4 to enamine intermediate 5 followed by enamine reduction and borate hydrolysis. This process has been reported in U.S. Patent

Application Publication No. 2010/0168475.

CH₂CI₂, NaOH

Scheme 1

The procedure for preparing an enantiomerically enriched or enantiomerically pure aminosulfone, such as compound 1, may be inefficient because it involves the resolution of racemic aminosulfone 3. Thus, a need exists as to asymmetric synthetic processes for the preparation of an enantiomerically enriched or enantiomerically pure aminosulfone, particularly for manufacturing scale production. Direct catalytic asymmetric hydrogenation of a suitable enamine or ketone intermediate is of particular interest because it eliminates the need for either classic resolution or the use of stoichiometric amount of chiral auxiliary, and thus, may be synthetically efficient and economical.

……………………………………….

SYNTHESIS OF KEY INTERMEDIATE

WO2013126495A2

Example 1

Synthesis of 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine

[00232] A slurry of dimethylsulfone (85 g, 903 mmol) in THF (480 ml) was treated with a

1.6M solution of n-butyllithium in hexane (505 ml, 808 mmol) at 0 – 5 °C. The resulting mixture was agitated for 1 hour then a solution of 3-ethoxy-4-methoxybenzonitrile (80 g, 451 mmol) in THF (240 ml) was added at 0 – 5 °C. The mixture was agitated at 0 – 5 °C for 0.5 hour, warmed to 25 – 30 °C over 0.5 hour and then agitated for 1 hour. Water (1.4 L) was added at 25 – 30 °C and the reaction mass was agitated overnight at room temperature (20 – 30 °C). The solid was filtered and subsequently washed with a 2: 1 mixture of water :THF (200 ml), water (200 ml) and heptane (2 x 200 ml). The solid was dried under reduced pressure at 40 – 45 °C to provide the product as a white solid (102 g, 83% yield); 1H NMR (DMSO-d₆) δ 1.34 (t, J=7.0 Hz, 3H), 2.99 (s, 3H), 3.80 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.03 (s, 1H), 6.82 (s, 2H), 7.01 (d, J=8.5 Hz, 1H), 7.09 – 7.22 (m, 2H).

Example 2

Synthesis of (R)- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine

[00233] A solution of bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (36 mg, 0.074 mmol) and (i?)-l-[(5)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (40 mg, 0.074 mmol) in 25 mL of 2,2,2-trifluoroethanol was prepared under nitrogen. To this solution was then charged l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50 °C and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. The mixture was evaporated and the residue was purified by chromatography on a CI 8 reverse phase column using a water-acetonitrile gradient. The appropriate fractions were pooled and evaporated to -150 mL. To this solution was added brine (20 mL), and the resulting solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgS0₄) and evaporated to provide the product as a white crystalline solid (1.4 g, 70% yield); achiral HPLC (Hypersil BDS C₈, 5.0 μπι, 250 x 4.6 mm, 1.5 mL/min, 278nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 9.11 (99.6%); chiral HPLC (Chiralpak AD-H 5.0 μιη Daicel, 250 x 4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-z-PrOH-diethylamine): 7.32 (97.5%), 8.26 (2.47%); 1H NMR (DMSO-de) δ 1.32 (t, J= 7.0 Hz, 3H), 2.08 (s, 2H), 2.96 (s, 3H), 3.23 (dd, J= 3.6, 14.4 Hz, 1H), 3.41 (dd, J= 9.4, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J= 7.0 Hz, 2H), 4.26 (dd, J= 3.7, 9.3 Hz, 1H), 6.89 (s, 2H), 7.02 (s, 1H); ¹³C NMR (DMSO-d₆) δ 14.77, 41.98, 50.89, 55.54, 62.03, 63.68, 111.48, 111.77, 118.36, 137.30, 147.93, 148.09. Example 3

Synthesis of (6 -l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-Ac-L-Leu salt

[00234] A solution of bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (17 mg, 0.037 mmol) and (5)-l-[(i?)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (20 mg, 0.037 mmol) in 10 mL of 2,2,2-trifluoroethanol was prepared under nitrogen. To this solution was then charged l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol). The resulting mixture was heated to 50 °C and hydrogenated under 90 psig hydrogen pressure. After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator. Ecosorb C-941 (200 mg) was added and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered through Celite, and the filter was washed with additional trifluoroethanol (2 mL). Then, the mixture was heated to 55 °C, and a solution of N- acetyl-L-leucine (1.3 g, 7.5 mmol) was added dropwise over the course of 1 h. Stirring proceeded at the same temperature for 1 h following completion of the addition, and then the mixture was cooled to 22 °C over 2 h and stirred at this temperature for 16 h. The crystalline product was filtered, rinsed with methanol (2 x 5 mL), and dried under vacuum at 45 °C to provide the product as a white solid (2.6 g, 80% yield); achiral HPLC (Hypersil BDS Cg, 5.0 μιη, 250 x 4.6 mm, 1.5 mL/min, 278nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 8.57 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 μιη Daicel, 250 x 4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-z-PrOH-diethylamine): 8.35 (99.6%); 1H NMR (DMSO-<¾) δ 0.84 (d, 3H), 0.89 (d, J= 6.6 Hz, 3H), 1.33 (t, J= 7.0 Hz, 3H), 1.41 – 1.52 (m, 2H), 1.62 (dt, J= 6.7, 13.5 Hz, 1H), 1.83 (s, 3H), 2.94 (s, 3H), 3.28 (dd, J= 4.0, 14.4 Hz, 1H), 3.44 (dd, J= 9.1, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J= 6.9 Hz, 2H), 4.18 (q, J= 7.7 Hz, 1H), 4.29 (dd, J= 4.0, 9.1 Hz, 1H), 5.46 (br, 3H), 6.90 (s, 2H), 7.04 (s, 1H), 8.04 (d, J= 7.9 Hz, 1H); Anal. (C₂₀H₃₄N₂O₇S) C, H, N. Calcd C, 53.79; H, 7.67; N 6.27. Found C, 53.78; H, 7.57; N 6.18.

SUBSEQUENT CONVERSION

S-enantiomer form of 2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- acetylaminoisoindoline-l ,3-dione can be prepared by reacting (5)-aminosulfone 1 with intermediate 2.

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APREMILAST

GENERAL SYNTHESIS AND SYNTHESIS OF APREMILAST

WO2012083153A1

(apremilast)

[0145] Preparation of 3-Ethoxy-4-methoxybenzonitrile (Compound 2). 3-Ethoxy-

4-methoxybenzaldehyde (Compound 1, 10.0 gm, 54.9 mmol, Aldrich) and hydroxylamine hydrochloride (4.67 gm, 65.9 mmol, Aldrich) were charged to a 250 mL three-necked flask at room temperature, followed by the addition of anhydrous acetonitrile (50 mL). The reaction mixture was stirred at room temperature for thirty minutes and then heated to reflux (oil bath at 85 °C). After two hours of reflux, the reaction mixture was cooled to room temperature, and added 50 mL of deionized water. The mixture was concentrated under reduced pressure to remove acetonitrile and then transferred to a separatory funnel with an additional 80 mL of deionized water and 80 mL dichloromethane. The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed successively with water (80 mL) and saturated sodium chloride (80 mL). The organic layer was dried over anhydrous sodium sulfate (approximately 20 gm). The organic layer was filtered and concentrated under reduced pressure to give a yellow oil. Purification by silica gel chromatography (0 to 1 % MeOH/DCM ) afforded 3-Ethoxy-4-methoxybenzonitrile

(Compound 2) as a white solid (7.69 gm, 79 % yield). MS (ESI positive ion) m/z 178.1 (M + 1). HPLC indicated >99% purity by peak area. 1H-NMR (500 MHz, DMSO-c¾: δ ppm 1.32 (t, 3H), 3.83 (s, 3H), 4.05 (q, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 2.0 Hz, 1H).

[0146] Preparation of l-(3-Ethoxy-4-methoxyphenyi)-2-

(niethylsulfonyl)ethanamine (Compound 3). Dimethyl sulfone (2.60 gm, 27.1 mmol, Aldrich) and tetrahydrofuran (10 mL, Aldrich) were charged to a 250 mL three-necked flask at room temperature. The mixture was cooled to 0 – 5 °C, and the solution gradually turned white. n-Butyllithium (10.8 mL, 27.1 mmol, 2.5 M solution in hexanes, Aldrich) was added to the flask at a rate such that the reaction mixture was maintained at 5 – 10 °C. The mixture was stirred at 0 – 5 °C for one hour, turning light-yellow. 3-Ethoxy-4-methoxybenzonitrile (Compound 2, 4.01 gm, 22.5 mmol) in tetrahydrofuran (8 mL) was then charged to the flask at a rate such that the reaction mixture was maintained at 0 – 5 °C. The mixture was stirred at 0 – 5 °C for another 15 minutes. After warming to room temperature, the reaction mixture was stirred for another 1.5 hours and then transferred to a second 250 mL three-necked flask containing a suspension of sodium borohydride (1.13 gm, 29.3 mmol, Aldrich) in

tetrahydrofuran (1 1 mL), maintained at – 5 – 0 °C for 30 minutes. Trifluoroacetic acid (“TFA,” 5.26 mL, 68.3 mmol, Aldrich) was charged to the flask at a rate such that the reaction mixture was maintained at 0 – 5 °C. The mixture was stirred at 0 – 5 °C for 40 minutes and an additional 17 hours at room temperature. The reaction mixture was then charged with 2.7 mL of deionized water over five minutes at room temperature. The mxiture was stirred at room temperature for 15 hours. Aqueous NaOH (10 N, 4.9 mL) was charged to the flask over 15 minutes at 45 °C. The mixture was stirred at 45 °C for two hours, at 60 °C for 1.5 hours, and at room temperature overnight. After approximately 17 hours at room temperature the mixture was cooled to 0 °C for thirty minutes and then concentrated under reduced pressure. The residual material was charged with deionized water (3 mL) and absolute ethanol (3 mL) and stirred at 0 – 5 °C for 2 hours. The mixture was filtered under vacuum, and the filtered solid was washed with cold absolute ethanol (3 x 5 mL), followed by deionized water until the pH of the wash was about 8. The solid was air dried overnight, and then in a vacuum oven at 60 °C for 17 hours to afford Compound 3 as a white solid (4.75 gm, 77 %). MS (ESI positive ion) m/z 274.1 (M + 1). Ή-NMR (500 MHz, DMSO-c¾): δ ppm 1.32 (t, J = 7.0 Hz, 3H), 2.08 (bs, 2H), 2.95 (s, 3H), 3.23 (dd, J = 4.0 Hz, 1H), 3.40 (dd, J = 9.5 Hz, 1H), 3.72 (s, 3H), 4.01 (q, J = 7.0 Hz, 2H), 4.25 (dd, J = 3.5 Hz, 1H), 6.88 (s, 2H), 7.02 (s, 1H).

[0147] Preparation of 4-Nitroisobenzofuran-l,3-dione (Compound 5). Into a 250 mL round bottom flask, fitted with a reflux condenser, was placed 3-nitrophthalic acid (21.0 gm, 99 mmol, Aldrich) and acetic anhydride (18.8 mL, 199 mmol, Aldrich). The solid mixture was heated to 85 °C, under nitrogen, with gradual melting of the solids. The yellow mixture was heated at 85 °C for 15 minutes, and there was noticeable thickening of the mixture. After 15 minutes at 85 °C, the hot mixture was poured into a weighing dish, and allowed to cool. The yellow solid was grinded to a powder and then placed on a cintered funnel, under vacuum. The solid was washed with diethyl ether (3 x 15 mL), under vacuum and allowed to air dry overnight, to afford 4-nitroisobenzofuran-l ,3-dione, Compound 5, as a light-yellow solid (15.8 gm, 82 %). MS (ESI positive ion) m/z 194.0 (M + 1). TLC: Rf = 0.37 (10% MeOH/DCM with 2 drops Acetic acid) Ή-NMR (500 MHz, DMSO-i¾: δ ppm 8.21 (dd, J = 7.5 Hz, 1H), 8.39 (dd, J = 7.5 Hz, 1H), 8.50 (dd, J = 7.5 Hz, 1 H).

[0148] Preparation of 2-(l-(3-Ethoxy-4-methoxyphenyI)-2-

(methylsulfonyl)ethyl)-4-nitroisoindoline-l,3-dione (Compound 6). Into a 2 – 5 mL microwave vial was added 4-nitroisobenzofuran-l ,3-dione (Compound 5, 0.35 gm, 1.82 mmol), the amino-sulfone intermediate (Compound 3, 0.50 gm, 1.82 mmol) and 4.0 mL of glacial acetic acid. The mixture was placed in a microwave at 125 °C for 30 minutes. After 30 minutes the acetic acid was removed under reduced pressure. The yellow oil was taken up in ethyl acetate and applied to a 10 gm snap Biotage samplet. Purification by silica gel chromatography (0 to 20 % Ethyl Acetate/Hexanes) afforded Compound 6 as a light-yellow solid (0.67 gm, 82 %). MS (ESI positive ion) m/z 449.0 (M + 1). TLC: Rf = 0.19

(EtOAc:Hexanes, 1 : 1). HPLC indicated 99% purity by peak area. Ή-NMR (500 MHz, DMSO-c¾: δ ppm 1.32 (t, 3H), 2.99 (s, 3H), 3.73 (s, 3H), 4.02 (m, 2H), 4.21 (dd, J = 5.0 Hz, 1H), 4.29 (dd, J = 10.0 Hz, 1H), 5.81 (dd, J = 5.0 Hz, 1H), 6.93 (d, J – 8.5 Hz, 1H), 7.00 (dd, J = 2.0 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 8.07 (t, J = 15.5 Hz, 1H), 8.19 (dd, J = 8.5 Hz, 1H), 8.30 (dd, J = 9.0 Hz, 1H).

[0149] Preparation of 4-Amino-2-(l-(3-ethoxy-4-methoxyphenyl)-2-

(methylsulfonyl)ethyl)isoindoline-l,3-dione (Compound 7). Compound 6 (0.54 gm, 1.20 mmol) was taken up in ethyl acetate / acetone (1 : 1 , 24 mL) and flowed through the H-cube™ hydrogen reactor using a 10 % Pd/C CatCart™ catalyst cartridge system (ThalesNano, Budapest Hungary). After eluting, the yellow solvent was concentrated under reduced pressure to give Compound 7 as a yellow foam solid (0.48 gm, 95 %). MS (ESI positive ion) m/z 419.1 (M + 1). 1H-NMR (500 MHz, DMSO-<¾): δ ppm 1.31 (t, J = 7.0 Hz, 3H), 2.99 (s, 3H), 3.72 (s, 3H), 4.04 (q, J = 7.0 Hz, 2H), 4.09 (m, 1H), 4.34 (m, 1H), 5.71 (dd, J = 5.5 Hz, 1H), 6.52 (bs, 2H), 6.92-6.98 (m, 3H), 7.06 (bs, 1 H), 7.42 (dd, J = 7.0 Hz, 1H).

[0150] Preparation of N-(2-(l-(3-ethoxy-4-methoxyphenyl)-2-

(methylsuIfonyl)ethyl)-l,3-dioxoisoindolin-4-yl)acetamide (Apremilast, Compound 8).

Into a 2-5 mL microwave vial was placed Compound 7 (0.18 gm, 0.43 mmol), acetic anhydride (0.052 mL, 0.53 mmol) and acetic acid (4 mL). The microwave vial was placed into a Biotage microwave and heated to 125 ^°C for 30 minutes. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (0 to 5% MeOH/DCM) to afford apremilast (Compound 8) as a yellow oil (0.14 gm, 71%). HPLC indicated 94.6% purity by peak area.

1H-NMR (500 MHz, DMSO-c ₆): δ ppm 1.31 (t, 3H), 2.18 (s, 3H), 3.01 (s, 3H), 3.73 (s, 3H), 4.01 (t, J = 7.0 Hz, 2H), 4,14 (dd, J = 4.0 Hz, 1H), 4.33 (m, 1H), 5.76 (dd, J = 3.0 Hz, 1H), 6.95 (m, 2H), 7.06 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 9.72 (bs, 1H).

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SYNTHESIS

EP2501382A1

5. EXAMPLES

Certain embodiments provided herein are illustrated by the following non-limiting examples.

5.1 PREPARATION OF (+)-2-[l-(3-ETHOXY-4-METHOXYPHENYL)-2- METHANESULFONYLETHYLJ-4- ACETYL AMINOISOINDOLIN-1,3- DIONE (APREMILAST)

5.1.1 Preparation of 3-aminopthalic acid

10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) were charged to a 2.5 L Parr hydrogenator under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 55 psi. The mixture was shaken for 13 hours, maintaining hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was reslurried in ether and isolated by vacuum filtration. The solid was dried in vacua to a constant weight, affording 54 g (84%> yield) of 3-aminopthalic acid as a yellow product. 1H-NMR (DMSO-d₆) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (brs, 2H). ¹³C-NMR(DMSO-d₆) δ: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.

5.1.2 Preparation of 3-acetamidopthalic anhydride

A I L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5. degree. C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacua at ambient temperature to a constant weight, giving 75 g (61% yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCI₃) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).

5.1.3 Resolution of 2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulphonyl)- ethyl-2-amine

A 3 L 3 -necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-l-(methylsulphonyl)-eth-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 mL). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30°C. to a constant weight, yielding 49.6 g (90%> recovery) of (S)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl)-eth-2-ylamine-N-acety 1-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH₂P0₄ @pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm.times.4.6 mm, 0.5 mL/min., @240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%)

5.1.4 Preparation of (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methanesulfonylethyl] -4-acetylaminoisoindolin- 1 ,3-dione

A 500 mL 3 -necked round bottom flask was equipped with a mechanical stirrer,

thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g, 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50°C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL x

2), saturated aqeous NaHC0₃ (250 mL.times.2), brine (250 mL.times.2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL.times.2). The product was dried in vacuo at 60°C. to a constant weight, affording 19.4 g (75% yield) of Compound 3 APREMILAST with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH₂P0₄ @pH 3.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%).

1H-NMR (CDC1₃) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H).

¹³C-NMR(DMSO-d₆) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.

…………………………………..

NMR

US20100129363

¹H-NMR (CDCl₃) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). ¹³C-NMR (DMSO-d₆) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.

…………….

APREMILAST

J. Med. Chem., 2009, 52 (6), pp 1522–1524

DOI: 10.1021/jm900210d

^aReagents and conditions: (a) LiN(SiMe₃)₂, then Me₂SO₂/n-BuLi/BF₃Et₂O, −78 °C; (b) N-Ac-l-leucine, MeOH; (c) HOAc, reflux.

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SARCOIDOSIS

Sarcoidosis is a disease of unknown cause. Sarcoidosis is characterized by the presence of granulomas in one or more organ systems. The most common sites of involvement are the lungs and the lymph nodes in the mediastinum and hilar regions. However, sarcoidosis is a systemic disease and a variety of organ systems or tissues may be the source of primary or concomitant clinical manifestations and morbidity. The clinical course of sarcoidosis is extremely variable, and ranges from a mild or even asymptomatic disease with spontaneous resolution to a chronic progressive disease leading to organ system failure and, in 1-5% of cases, death. See Cecil

Textbook of Medicine, 21st ed. (Goldman, L., Bennett, J. C. eds), W. B. Saunders Company, Philadelphia, 2000, p. 433-436.

While the cause of sarcoidosis is unknown, a substantial body of information suggests that immune mechanisms are important in disease pathogenesis. For example, sarcoidosis is

characterized by enhanced lymphocyte and macrophage activity. See Thomas, P.D. and

Hunninghake, G.W., Am. Rev. Respir. Dis., 1987, 135: 747-760. As sarcoidosis progresses, skin rashes, erythema nodosum and granulomas may form. Granulomas or fibrosis caused by sarcoidosis can occur throughout the body, and may affect the function of vital organs such as the lungs, heart, nervous system, liver or kidneys. In these cases, the sarcoidosis can be fatal. See

http://www.nlm.nih.gov/medlineplus/sarcoidosis.html (accessed November 12, 2009).

Moreover, a variety of exogenous agents, both infectious and non-infectious, have been hypothesized as a possible cause of sarcoidosis. See Vokurka et ah, Am. J. Respir. Crit. Care Med., 1997, 156: 1000-1003; Popper et al, Hum. Pathol, 1997, 28: 796-800; Almenoff et al, Thorax, 1996, 51 : 530-533; Baughman et al., Lancet, 2003, 361 : 1111-1118. These agents include mycobaceria, fungi, spirochetes, and the agent associated with Whipple’s disease. Id.

Sarcoidosis may be acute or chronic. Specific types of sarcoidosis include, but are not limited to, cardiac sarcoidosis, cutaneous sarcoidosis, hepatic sarcoidosis, oral sarcoidosis, pulmonary sarcoidosis, neurosarcoidosis, sinonasal sarcoidosis, Lofgren’s syndrome, lupus pernio, uveitis or chronic cutaneous sarcoidosis.

As the lung is constantly confronted with airborne substances, including pathogens, many researchers have directed their attention to identification of potential causative transmissible agents and their contribution to the mechanism of pulmonary granuloma formation associated with sarcoidosis. See Conron, M. and Du Bois, R.M., Clin. Exp. Allergy, 2001, 31 : 543-554; Agostini et al, Curr. Opin. Pulm. Med. , 2002, 8: 435-440.

Corticosteroid drugs are the primary treatment for the inflammation and granuloma formation associated with sarcoidosis. Rizatto et al. , Respiratory Medicine, 1997, 91 : 449-460. Prednisone is most often prescribed drug for the treatment of sarcoidosis. Additional drugs used to treat sarcoidosis include methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, minocycline, doxycycline and chloroquin. TNF-a blockers such as thalidomide and infliximab have been reported to be effective in treating patients with sarcoidosis. Baughman et al, Chest, 2002, 122: 227-232; Doty et al, Chest, 2005, 127: 1064-1071. Antibiotics have also been studied for the treatment of sarcoidosis, such as penicillin antibiotics, cephalosporin antibiotics, macrolide antibiotics, lincomycin antibiotics, and tetracycline antibiotics. Specific examples include minocycline hydrochloride, clindamycin, ampicillin, or clarithromycin. See, e.g., U.S. Patent Publication No. 2007/0111956.

There currently lacks a Food and Drug Administration-approved therapeutic agent for the treatment of sarcoidosis, and many patients are unable to tolerate the side effects of the standard corticosteroid therapy. See Doty et al, Chest, 2005, 127: 1064-1071. Furthermore, many cases of sarcoidosis are refractory to standard therapy. Id. Therefore, a demand exists for new methods and compositions that can be used to treat patients with sarcoidosis.

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PATENTS

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Asymmetric hydrogentation of unfunctionalised olefins/enamines/imines

The reaction survey found that the predominant strategy for the introduction of chirality was through classical chemical resolutions as opposed to introductions through biotransformation or transition metal or organometallic catalytic means.

Asymmetric hydrogenation provides an elegant methodology for the introduction of chirality, meeting many of the goals of green chemistry and is finding increasing application in API synthesis.⁴⁷

The efficiency of this approach is elegantly exemplified by the Merck second generation synthesis of sitagliptin 5 (Scheme ), where an unprecedented final stage asymmetric hydrogenation of the unprotected enamide 6 resulted in an increase in overall yield of almost 50% and produced 100 kg less waste per kg sitagliptin⁴⁸ when compared with the first generation approach.⁴⁹

	Scheme  The synthesis of sitagliptin.

There are challenging areas remaining within the field, for example, the hydrogenation of enamides and related substrates in the synthesis of amino acids has numerous examples⁵⁰ but few examples exist for unsubstitued enamines⁴¹ and imines. Some classes of alkene offer additional challenges.⁵¹ For the pharmaceutical industry, the limited time for synthetic route identification is an issue and access to catalyst and ligand diversity is required to ensure the application of this approach.⁵²

Some pharmaceutical companies have synthesised their own ligands and have found very effective catalysts.⁵³ The majority of academic asymmetric hydrogenation approaches are based on homogeneous catalysis to overcome issues of activation and mass transfer. For pharmaceutical use, efficient catalyst and ligand recovery, and eliminating heavy metal contamination of the API are significant requirements for the industry.

These controls are often easier to achieve with heterogeneous methodology where there are less examples.⁵⁰ The demonstration of organocatalytic hydride transfer offers the possibility of future access to metal free asymmetric hydrogenations.⁵⁴

1. 47………V. Farina, J. T. Reeves, C. H. Senanayake and J. J. Song, Chem. Rev., 2006, 106, 2734–2793. See also Asymmetric Catalysis on Industrial Scale Challenges, Approaches and Solutions, ed. H.-U. Blaser and E. Schmidt, Wiley-VCH, Weinheim, 2004 Search PubMed  .
2. 48………..http://www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa06.html .
3. 49……K. B. Hansen, J. Balsells, S. Dreher, Y. Hsiao, M. Kubryk, M. Palucki, N. Rivera, D. Steinhuebel, J. D. Armstrong III, D. Askin and E. J. J. Grabowski, Org. Process Res. Dev., 2005, 9, 634–639 Search PubMed  .
4. 50………..M. Studer, H.-U. Blaser and C. Exner, Adv. Synth. Catal., 2003, 345, 45–65 CrossRef  CAS  Search PubMed  .
5. 51……..X. Cui and K. Burgess, Chem. Rev., 2005, 105, 3272–3296 CrossRef  CAS  Search PubMed 
6.  52……….I. C. Lennon and C. J. Pilkington, Synthesis, 2003, 1639–1642 CrossRef  CAS  Search PubMed  .
7. 53………G. Hoge, H.-P. Wu, W. S. Kissel, D. A. Plum, D. J. Greene and J. Bao, J. Am. Chem. Soc., 2004, 126, 5966–5967 CrossRef  CAS  Search PubMed  .
8. 54……..H. Adolfsson, Angew. Chem., Int. Ed., 2005, 44, 3340–3342 CrossRef  CAS  Search PubMed  .

PRINOMASTAT

Molecular Formula: C₁₈H₂₁N₃O₅S₂   
Molecular Weight: 423.5064
CAS No: 192329-42-3
IUPAC Name: 2-[(Hydroxyamino)methyl]-5,6-dimethyl-4-(4-pyridin-4-yloxyphenyl)sulfonylmorpholine-3-thione

3-Thiomorpholinecarboxamide,N-hydroxy-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-, (S)-; AG 3340;KB-R 9896; Prinomastat

Prinomastat, AG-3362(maleate), AG-3354(HCl), AG-3340

Agouron (Originator)

Prinomastat (AG-3340) is a matrix metalloprotease (MMP) inhibitor with specific selectivity for MMPs 2, 3, 9, 13, and 14. Investigations have been carried out to determine whether the inhibition of these MMPs is able to block tumour metastasis by preventing MMP degradation of the extracellular matrix proteins and angiogenesis.

Prinomastat is a synthetic hydroxamic acid derivative with potential antineoplastic activity. Prinomastat inhibits matrix metalloproteinases (MMPs) (specifically, MMP-2, 9, 13, and 14), thereby inducing extracellular matrix degradation, and inhibiting angiogenesis, tumor growth and invasion, and metastasis. As a lipophilic agent, prinomastat crosses the blood-brain barrier.

Prinomastat underwent a Phase III trial to investigate its effectiveness against non-small cell lung cancer (nsclc), in combination with gemcitabine chemotherapy. However, it was discovered that Prinomastat did not improve the outcome of chemotherapy in advanced Non-Small-Cell Lung Cancer. ^[1] [2]

Matrix metalloproteinases (“MMPs”) are a family of enzymes, including, collagenases, gelatinases, matrilysin, and stromelysins, that are involved in the degradation and remodeling of connective tissues. These enzymes are contained in a number of cell types that are found in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells and metastatic tumor cells. They also share a number of properties, including zinc and calcium dependence, secretion as zymogens, and, 40-50% amino acid sequence homology.

Matrix metalloproteinases degrade the protein components of the extracellular matrix, i.e., the protein components found in the linings of joints, interstitial connective tissue, basement membranes, cartilage and the like. These proteins include collagen, proteoglycan, fibronectin and lamanin.

In a number of pathological disease conditions, however, deregulation of matrix metalloproteinase activity leads to the uncontrolled breakdown of extracellular matrix. These disease conditions include arthritis (e.g., rheumatoid arthritis and osteoarthritis), periodontal disease, aberrant angiogenesis, tumor metastasis and invasion, tissue ulceration (e.g., comeal ulceration, gastric ulceration or epidermal ulceration), bone disease, HIV-infection and complications from diabetes.

Administration of matrix metalloproteinase inhibitors has been found to reduce the rate of connective tissue degradation, thereby leading to a favorable therapeutic effect. For example, in Cancer Res., 53, 2087 (1993), a synthetic matrix metalloproteinase inhibitor was shown to have in vivo efficacy in a murine model for ovarian cancer with an apparent mode of action consistent with inhibition of matrix remodeling. The design and uses of MMP inhibitors are reviewed, for example, in J. Enzyme Inhibition, 2, 1-22 (1987); Progress in Medicinal Chemistry, 29, 271-334 (1992); Current Medicinal Chemistry, 2, 743-762 (1995); Exp. Opin. Ther. Patents, 5, 12871296 (1995); and Drug Discovery Today, 1, 16-26 (1996).

Matrix metalloproteinase inhibitors are also the subject of numerous patents and patent applications, including: U.S. Pat. Nos. 5,189,178; 5,183,900; 5,506,242; 5,552,419; and 5,455,258; European Patent Application Nos. EP 0 438 223 and EP 0 276 436; International Publication Nos. WO 92/21360; WO 92/06966; WO 92/09563; WO 96/00214; WO 95/35276; and WO 96/27583.

Further, U.S. patent application Ser. Nos. 6,153,757 and 5,753,653 relate to prinomistat and its synthesis, the disclosures of each are incorporated herein by reference in their entireties.

Prinomastat, shown below, is a potent inhibitor of certain metalloproteinases (MMP), particularly matrix metalloproteinases and tumor necrosis factor-α convertase. International Publication No. WO 97/208824 discloses the chemical structure of prinomastat, its pharmaceutical composition, as well as pharmaceutical uses, methods of its preparation and intermediates useful in its synthesis.

Until now, metabolites of prinomastat have not been identified, isolated, purified or synthesized. Further, it is shown that some of these metabolites are potent matrix metalloproteinase inhibitors

The sulfonation of 4-chlorodiphenyl ether (I) with chlorosulfonic acid in dichloromethane gives the 4-(4-chlorophenoxy)benzenesulfonic acid (II), which is treated with oxalyl chloride and DMF in the same solvent yielding the sulfonyl chloride (III).

The reduction of (III) with trimethyl phosphite and KOH in toluene affords the methylsulfanyl derivative (IV), which is chlorinated with SO2Cl2 in dichloromethane to give the chloromethylsulfanyl derivative (V). The condensation of (V) with the silylated enol ether (VI) by means of ZnCl2 and KOH in refluxing dichloromethane yields 4-[4-(4-chlorophenoxy)phenylsulfanylmethyl]tetrahydropyran-4-carboxylic acid (VII), which is treated with oxalyl chloride affording the corresponding acyl chloride (VIII).

The reaction of (VIII) with NH2OH in dichloromethane provides the carbohydroxamic acid (IX), which is finally oxidized with oxone (potassium peroxymonosulfate) in N-methyl-2-pyrrolidone/H2O to furnish the target sulfone.

The cyclization of D-penicillamine (I) with 1,2-dichloroethane by means of DBU and TMS-Cl in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid (XV), which is treated with isobutylene (XVI) and sulfuric acid in dioxane to yield the corresponding tert-butyl ester (XVII). The sulfonation of (XVII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid tert-butyl ester (XVIII), which is finally treated with HCl in refluxing dioxane to give the previously reported free acid intermediate (XIV).

The cyclization of D-penicillamine methyl ester (XIX) with 1,2-dibromoethane by means of DBU in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid methyl ester (XX), which is sulfonated with the sulfonyl chloride (VI) as before, affording 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid methyl ester (XXI). Finally, this compound is hydrolyzed with refluxing aqueous HCl to yield the previously reported intermediate (XIV).

The silylation of D-penicillamine (I) with dimethylhexylsilyl chloride (Dmhs-Cl) and DBU gives the ester (XI), which is cyclized with 1,2-dichloroethane and DBU in DMF, yielding 2,2-dimethylthiomorpholine-3(S)-carboxylic acid dimethylhexylsilyl ester (XII).

The sulfonation of (XII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid dimethylhexylsilyl ester (XIII), which is desilylated in refluxing methanol to give the free acid (XIV) Finally, this compound is treated with oxalyl chloride and hydroxylamine in dichloromethane.

References

zabofloxacin, 219680-11-2

Example 1. l-Cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4- oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid methanesulfonate

30 350mg of

7-[2-(t-buthoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3.4]oct-6-yl]-l- cyclopropyl-6-fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid was dissolved in 5ml of dichloromethane and thereto 0.6ml of trifluoroacetic acid was dropped. The mixture was stirred for 5 hours at room temperature and thereto 10ml (if ethylether was added. It was stirred additionally for 1 hour and thus precipitated solid was filtered, dissolved in 5ml of diluted NaOH and neutralized with diluted hydrochloric acid. The precipitate thus obtained was filtered and dried. The resulting solid was added to 5ml of lN-methanesulfonic acid in ethanol and stirred for 1 hour. Thus obtained precipitate was filtered and dried to give 185g of the titled compound(yield : 47.8%). m.p. : 228- 229 ^°C

1H-NMR(DMSO-dG+CF₃COOD, ppm): 0.97(s, 2H), 1.14(d, 2H), 2.48(s, 3H), 3.57(bs, IH), 3.88(s, 3H), 4.06-4.17(m, 411), 4.40(s, 2H), 4.49(s, 2H), 7.88(d, Hi, J=12.67Hz), 8.49(s, IH).

 

………………………………..

US20100184795

aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid comprises a step of reacting 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid with aspartic acid in a solvent. The method can be represented by Scheme 1.

 

Example 1 Preparation of the D-Aspartic Acid Salt of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid

1-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (5.0 g) was added to 50% ethanol (80 mL), and then the mixture was stirred at 50° C. for 10 minutes. D-Aspartic acid (2.0 g) was added and then the mixture was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature, and then the resulting solid was collected by filtration. Ethanol (100 mL) was added to the filtrate, and then the mixture was stirred for 30 minutes. The resulting solid was collected by filtration to obtain a total of 5.55 g of the target compound (yield: 83%). Melting point: 200-201° C. ¹H NMR (D₂O): δ 0.97 (bs, 2H), 1.27 (d, 2H), 2.00 (dd, 1H, J=8.8, 17.6 Hz), 2.77 (dd, 1H, J=3.3, 17.0 Hz), 3.53 (bs, 1H), 3.84 (dd, 1H, J=3.3, 8.78 Hz), 4.01 (s, 3H), 4.31-4.45 (m, 8H), 7.46 (d, 1H, J=12.2 Hz), 8.42 (s, 1H).

Example 2 Preparation of L-Aspartic Acid Salt of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid

1-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (500 mg) was added to 50% ethanol (20 mL), and then the mixture was stirred at 50° C. for 10 minutes. L-Aspartic acid (174 mg) was added and then the mixture was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature. Ethanol (20 mL) was added to the reaction mixture, and then the mixture was stirred for 30 minutes. The resulting solid was collected by filtration to obtain 550 mg of the target compound (yield: 82%). Melting point: 205-206° C. ¹H NMR (d₆-DMSO): δ 0.93 (d, 2H, J=3.5 Hz), 1.20 (d, 2H, J=6.8 Hz), 2.42 (dd, 1H, J=9.2, 17.3 Hz), 2.59 (dd, 1H, J=3.3, 17.2 Hz), 3.50 (m, 1H), 3.59 (1H, dd, J=3.1, 9.1 Hz), 3.91 (s, 3H), 4.24 (m, 6H), 4.41 (br, 2H), 7.59 (d, 1H, J=12.4 Hz), 8.41 (s, 1H).

Example 3 Preparation of Hydrochloric Acid Salt, Phosphate Salt, and Formate Salt of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid

3-1 Hydrochloric Acid Salt

Ethanol (3 mL) was cooled to 0° C. and acetyl chloride (1.13 mL) was added, and then the mixture was stirred for 30 minutes. 1-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (800 mg) was added to the reaction mixture, and then stirred at 0° C. for 30 minutes. Tetrahydrofuran (4 mL) was added, and then the mixture was stirred for 30 minutes. The resulting solid was collected by filtration and dried to obtain 776 mg of the target compound (yield: 89%). Melting point: 244-245° C. ¹H NMR (d₆-DMSO): δ 1.07 (d, 2H, J=4.7 Hz), 1.21 (d, 2H, J=6.8 Hz), 3.68 (m, 1H), 3.94 (s, 3H), 4.17 (m, 2H), 4.40 (s, 2H), 4.53 (s, 2H), 8.03 (d, 1H, J=12.5 Hz), 8.59 (s, 1H).

Total Payment received for the mpges-1 program from Forest Laboratories is USD 15 million

March 25, 2014: Glenmark Pharmaceuticals Ltd. has informed the Stock Exchange today that the company through its Swiss subsidiary has received

USD 4 million as research fee payment from Forest Laboratories Inc. on a collaboration for the development of novel mPGES-1 inhibitors to treatchronic inflammatory conditions, including pain.

Under the terms of the agreement signed in FY 2012-13, Forest made USD 6 million upfront payment and also provided an additional USD 3 million

to support the next phase of work. In September 2013, Glenmark received an additional amount of USD 2 million as research fee payment from Forest Laboratories Inc.

Hence, the total amount received by Glenmark from Forest Laboratories Inc towards its novel mPEGS-1 inhibitors program is USD15 million.

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