KRN5500

Antitumor agent

151276-95-8  cas

IUPAC/Chemical name: 

(2E,4E)-N-(2-(((2R,3R,4R,5R,6S)-6-((7H-purin-6-yl)amino)-2-((S)-1,2-dihydroxyethyl)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)amino)-2-oxoethyl)tetradeca-2,4-dienamide

C28H43N7O7

Exact Mass: 589.32240

L-glycero-beta-L-manno-Heptopyranosylamine, 4-deoxy-4-((((1-oxo-2,4-tetradecadienyl)amino)acetyl)amino)-N-1H-purin-6-yl-, (E,E)-

L-glycero-beta-L-manno-Heptopyranosylamine, 4-deoxy-4-(((((2E,4E)-1-oxo-2,4-tetradecadienyl)amino)acetyl)amino)-N-1H-purin-6-yl-

Kirin Brewery (Originator), National Cancer Institute (Codevelopment)

DARA BioSciences receives FDA orphan drug designation for KRN5500
DARA BioSciences has received orphan drug designation from the US Food and Drug Administration’s (FDA) Office of Orphan Products Development for KRN5500, for treating multiple myeloma

http://www.pharmaceutical-technology.com/news/newsdara-biosciences-receives-fda-orphan-drug-designation-for-krn5500-4295251?WT.mc_id=DN_News

Multiple myeloma is a hematologic cancer or cancer of the blood.

KRN5500 is a non-opioid, non-narcotic compound that is currently being tested in Phase I clinical trial.

Earlier this year, KRN5500 received orphan status to be developed for the parenteral treatment of painful, chronic, chemotherapy-induced peripheral neuropathy (CCIPN) that is refractory to conventional analgesics in patients with cancer.

“We believe this myeloma-specific orphan designation enhances both the viability and the future market opportunity for this valuable pipeline product.”

DARA BioSciences MD, CEO and chief medical officer David J Drutz said: “It is noteworthy in this regard that up to 20% of myeloma patients have intrinsic peripheral neuropathy, an incidence that increases to the range of 75% in patients treated with neurotoxic drugs such as thalidomide or bortezomib.

KRN5500 is a semisynthetic derivative of the nucleoside-like antineoplastic antibiotic spicamycin, originally isolated from the bacterium Streptomyces alanosinicus. KRN 5500 inhibits protein synthesis by interfering with endoplasmic reticulum and Golgi apparatus functions. This agent also induces cell differentiation and caspase-dependent apoptosis.

KRN5500 is available as a solution for intravenous (IV) administration.  KRN5500 was discovered in an effort to identify new agents that induced differentiation of myeloid leukemia cells.

Safety and efficacy data from Phase I trials have been leveraged to support DARA Therapeutics’ active IND and ongoing Phase 2a clinical trial.  The objective of this Phase 2a feasibility study is to determine the potential of KRN5500 (a spicamycin analogue) to be a breakthrough medicine for the treatment of neuropathic pain in cancer patients.

Four clinical trials have been conducted in cancer patients, including one in Japan and 3 in the United States.  Three of these studies are complete; the fourth was closed to patient accrual and treatment in December 2004.

A total of 91 patients with solid tumors have been treated with single IV KRN5500 doses of up to 21 mg/m2 and weekly doses of up to 42 mg/m2.  While KRN5500 has not shown anti-cancer efficacy in any trial, its use in pain elimination is encouraging. (source: http://www.darabiosciences.com/krn5500.htm).

Chemical structures of KRN5500 and its known metabolites.

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http://www.google.com/patents/EP0525479A1?cl=en

spk 241

• 6-[4′-N-(N’-trans,trans-2,4-tridecadienylglycyl)spicamynyl-amino]purine,
• (20) SPK241:
  

Example 52: Preparation of SPK241

• [0214]
  To trans-2-dodecenal (4.5 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenylphosphorane (8.3 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane- ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g). Potassium hydroxide (6.5 g) was dissolved in a mixed solvent of ethanol-water (1:1) (100 ml). The methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g) was added to the mixture, and the resulting mixture was stirred at 60 °C for 40 minutes. After the reaction mixture was cooled, it was adjusted to the weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tetradecadienoic acid (4.4 g). Hereafter, the title compound can be synthesized by the two methods described below.
• [0215]
  In the first method, trans,trans-2,4-tetradecadienoic acid (4.3 g) is first dissolved in N,N-dimethylformamide (DMF, 50 ml). Para-nitrophenol (2.67 g) and N,N’-dicyclohexylcarbodiimide (3.9 g) were added to trans,trans-2,4-tetradecadienoic acid solution, and the mixture was stirred for 12 hours. After precipitates produced were removed by filtration and the solvent (DMF) was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-tetradecadienoic acid (5.1 g). To the active ester (500 mg) dissolved in DMF (30 ml) were added 6-(4′-N-glycyl-spicamynyl-amino)purine hydrochloride (556 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK241 in the yield of 398 mg.
• [0216]
  In the second method, trans,trans-2,4-tetradecadienoic acid (99.6 g) was dissolved in thionyl chloride (87 ml), and the mixture was stirred at room temperature. The excessive thionyl chloride was removed by distillation to give trans,trans-2,4-tetradecadienoic acid chloride (102.0 g). To glycine (66.8 g) dissolved in an aqueous 2N sodium hydroxide solution (540 ml) were added at the same time trans,trans-2,4-tetradecadienoic acid chloride (102.0 g) and 2N sodium hydroxide (270 ml) with 1/10 portions at a 3 minute interval. After the addition was completed, the mixture was warmed to room temperature, stirred for 15 minutes and acidified with concentrated hydrochloric acid (140 ml) under ice-cooling. Precipitates thus produced were collected by filtration and desiccated to give trans,trans-2,4-tetradecadienoyl glycine (75.0 g). To the solution of trans,trans-2,4-tetradecadienoyl glycine (4.7 g) and 6-(4′-N-glycyl-spicamynyl-amino)-purine (5.1 g) in N,N-dimethylformamide (DMF, 60 ml) was added N-hydroxysuccinimide (2.1 g), and the mixture was ice-cooled. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.4 g) dissolved in DMF (100 ml) was added dropwise to the mixture. After the addition was completed, the mixture was heated to room temperature and stirred for 12 hours. Water (500 ml) was added to the reaction mixture, and precipitates produced were collected by filtration and desiccated. Sodium methoxide (3.1 g) was added to a suspension of the precipitates in methanol (100 ml), and the mixture was stirred at room temperature, then ice-cooled and acidified by adding dropwise thereto a 10% methanolic hydrochloric acid solution. Precipitates produced were filtered, dried and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK241 in the yield of 5.00 g.

Physicochemical properties of SPK241

• [0217]
  • (1) Melting point: 182-183 °C,
  • (2) Specific rotation [a]₀ ^2S = 0 (c = 0.1, in methanol),
  • (3) Elementary analysis:
    
  • (4) FD mass spectrum (m/z): 590 (M + H) , C₂₈ H_{4 3} N₇0₇
  • (5) Infrared spectrum (KBr disc): 3250 cm-¹, 1650 cm-¹, 1620 cm-¹,
  • (6) Proton nuclear magnetic resonance spectrum (500 MHz, in CD₃0D) δ_H: 0.89 (3H, t, J = 7.3 Hz), 1.20-1.50 (14H, m), 2.18 (2H, dt, J = 7.3, 7.3 Hz), 3.6-3.8 (5H, m), 3.95 (1 H, d, J = 16.3 Hz), 3.98 (1H, d, J = 16.3 Hz), 4.00 (1H, dd, J = <1, 2.9 Hz), 4.15 (1H, dd, J = 10.8, 10.8 Hz), 5.66 (1 H, brs), 5.98 (1 H, d, J = 15.7 Hz), 6.12 (1 H, dt, J = 7.3, 15.7 Hz), 6.22 (1 H, dd, J = 10.0, 15.7 Hz), 7.17 (1 H, dd, J = 10.0, 15.7 Hz), 8.15 (1 H, s), 8.30 (1 H, s).

The hydrolysis of the spicamycin mixture (I) with R = alkyl by means of HCl in alcohol or water gives 6-(spicaminylamino)purine (II). (The hydrolysis can also be performed with other inorganic acids such as H2SO4 or organic ones such as acetic acid or formic acid.) The condensation of (II) with N-(tert-butoxycarbonyl)glycine (III) by the active ester method yields the protected glycyl derivative (IV), which is deprotected with TFA (or methanolic HCl) to afford the glycyl derivative (V). Finally, this compound is condensed with tetradeca-2(E),4(E)-dienoic acid (VI) by the active ester method to provide the target carboxamide derivative.