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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Novobiocin, ノボビオシン;

August 14, 2019 9:19 am / 1 Comment on Novobiocin, ノボビオシン;

ChemSpider 2D Image | novobiocin | C31H36N2O11

Novobiocin

ノボビオシン;

Molecular FormulaC₃₁H₃₆N₂O₁₁
Average mass612.624 Da

(3R,4S,5R,6R)-5-hydroxy-6-(4-hydroxy-3-(4-hydroxy-3-(3-methylbut-2-enyl)benzamido)-8-methyl-2-oxo-2H-chromen-7-yloxy)-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate

(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methyl-2-buten-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name) [ACD/IUPAC Name]

(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name)

1476-53-5 [RN]

17EC19951N

216-023-6 [EINECS]

224-321-2 [EINECS]

575

Albamycin[Trade name]

Biotexin

UNII17EC19951N

CAS number303-81-1

WeightAverage: 612.6243
Monoisotopic: 612.231910004

Chemical FormulaC₃₁H₃₆N₂O₁₁

For the treatment of infections due to staphylococci and other susceptible organisms

Novobiocin

CAS Registry Number: 303-81-1

CAS Name: N-[7-[[3-O-(Aminocarbonyl)-6-deoxy-5-C-methyl-4-O-methyl-b-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl]-4-hydroxy-3-(3-methyl-2-butenyl)benzamide

Additional Names: crystallinic acid; streptonivicin

Manufacturers’ Codes: PA-93; U-6591

Molecular Formula: C31H36N2O11

Molecular Weight: 612.62

Percent Composition: C 60.78%, H 5.92%, N 4.57%, O 28.73%

Literature References: Antibiotic substance produced by Streptomyces spheroides: Kaczka et al., J. Am. Chem. Soc. 77, 6404 (1955); Wolf, US 3000873 (1961 to Merck & Co.); Stammer, Miller; Miller; Wallick, US 3049475; US 3049476; US 3049534 (all 1962 to Merck & Co.). By Streptomyces niveus: Hoeksema et al., J. Am. Chem. Soc. 77, 6710 (1955); Antibiot. Chemother. 6, 143 (1956); French, US 3068221 (1962 to Upjohn). Structure: Shunk et al., J. Am. Chem. Soc. 78, 1770 (1956); Hoeksema et al., ibid.2019; Walton et al., ibid. 82, 1489 (1960). Conformation: Golding, Richards, Chem. Ind. (London) 1963, 1081. Revised configuration: O. Achmatowicz et al., Tetrahedron 32, 1051 (1976). Synthesis: Stammer, US 2925411 (1960); Walton, Spencer, US2966484 (1960 to Merck & Co.); Vaterlaus et al., Helv. Chim. Acta 47, 390 (1964). Conversion of isonovobiocin to novobiocin: Caron et al., US 2983723 (1961 to Upjohn). Antiviral activity: Chang, Weinstein, Antimicrob. Agents Chemother. 1970, 165. Efficacy in canine respiratory infections: B. W. Maxey, Vet. Med. Small Anim. Clin. 75, 89 (1980). Mechanism of action studies: Smith, Davis, J. Bacteriol. 93, 71 (1967); H. T. Wright et al., Science 213, 455 (1981); I. W. Althaus et al., J. Antibiot. 41, 373 (1988). Review: Brock in Antibiotics vol. 1, R. Gottlieb, P. Shaw, Eds. (Springer-Verlag, New York, 1967) pp 651-665; M. J. Ryan, ibid. vol. 5(pt. 1), F. E. Hahn, Ed. (1979) pp 214-234.

Properties: Pale yellow orthorhombic crystals from ethanol. Sensitive to light. d 1.3448. Dec at 152-156° (a rarer modification dec 174-178°). Acid reaction: pKa1 4.3; pKa2 9.1. [a]D24 -63.0° (c = 1 in ethanol). uv max (0.1N NaOH; 0.1N methanolic HCl; pH 7 phosphate buffer): 307; 324; 390 nm (E1%1cm 600, 390, 350 resp.). Sol in aq soln above pH 7.5. Practically insol in more acidic solns. Sol in acetone, ethyl acetate, amyl acetate, lower alcohols, pyridine. Additional soly data: Weiss et al., Antibiot. Chemother.7, 374 (1957).

pKa: pKa1 4.3; pKa2 9.1

Optical Rotation: [a]D24 -63.0° (c = 1 in ethanol)

Absorption maximum: uv max (0.1N NaOH; 0.1N methanolic HCl; pH 7 phosphate buffer): 307; 324; 390 nm (E1%1cm 600, 390, 350 resp.)

Density: d 1.3448

Derivative Type: Monosodium salt

CAS Registry Number: 1476-53-5

Trademarks: Albamycin (Pharmacia & Upjohn)

Molecular Formula: C31H35N2NaO11

Molecular Weight: 634.61

Percent Composition: C 58.67%, H 5.56%, N 4.41%, Na 3.62%, O 27.73%

Properties: Minute crystals, dec 220°. [a]D24 -38° (c = 2.5 in 95% ethanol); [a]D24 -33° (c = 2.5 in water). Freely sol in water. A 100 mg/ml soln has a pH of 7.5 and a half-life of ~30 days at 25° and several months at 4°. Soly data: Weiss et al., loc. cit. Properties: Birlova, Traktenberg, Antibiotiki 13, 997 (1968).

Optical Rotation: [a]D24 -38° (c = 2.5 in 95% ethanol); [a]D24 -33° (c = 2.5 in water)

Therap-Cat: Antibacterial.

Therap-Cat-Vet: Antimicrobial.

INGREDIENT	UNII	CAS	INCHI KEY
Novobiocin sodium	Q9S9NQ5YIY	1476-53-5	WWPRGAYLRGSOSU-RNROJPEYSA-M

Reata Pharmaceuticals Inc

Abgentis is investigating a novobiocin analog, GYR-12 (discovery), as a re-engineered, previously-marketed-but-uncompetitive (undisclosed) antibacterial compound inhibiting ATPase activity of DNA supercoiling GyrB/ParE, for the potential broad-spectrum treatment of bacterial infections, including multi-drug resistant Gram-negative infections. In April 2017, development was underway [1924695].

Novobiocin, also known as albamycin or cathomycin, is an aminocoumarin antibiotic that is produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym for S. spheroides^[1] a member of the order Actinobacteria. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.^[2] Novobiocin was first reported in the mid-1950s (then called streptonivicin).^[3]^[4]

It is active against Staphylococcus epidermidis and may be used to differentiate it from the other coagulase-negative Staphylococcus saprophyticus, which is resistant to novobiocin, in culture.

Novobiocin was licensed for clinical use under the tradename Albamycin (Pharmacia And Upjohn) in the 1960s. Its efficacy has been demonstrated in preclinical and clinical trials.^[5]^[6] The oral form of the drug has since been withdrawn from the market due to lack of efficacy.^[7] Novobiocin is an effective antistaphylococcal agent used in the treatment of MRSA.^[8]

Mechanism of action

The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined.^[2]^[9]^[10]^[11]^[12] Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy transduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.

Novobiocin has been shown to weakly inhibit the C-terminus of the eukaryotic Hsp90 protein (high micromolar IC50). Modification of the novobiocin scaffold has led to more selective Hsp90 inhibitors.^[13] Novobiocin has also been shown to bind and activate the Gram-negative lipopolysaccharide transporter LptBFGC.^[14]^[15]

Structure

Novobiocin is an aminocoumarin. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose.^[9] X-ray crystallographic studies have found that the drug-receptor complex of Novobiocin and DNA Gyrase shows that ATP and Novobiocin have overlapping binding sites on the gyrase molecule.^[16] The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity.^[17]

Structure–activity relationship

In structure activity relationship experiments it was found that removal of the carbamoyl group located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin.^[17]

Biosynthesis

This aminocoumarin antibiotic consists of three major substituents. The 3-dimethylallyl-4-hydroxybenzoic acid moiety, known as ring A, is derived from prephenate and dimethylallyl pyrophosphate. The aminocoumarin moiety, known as ring B, is derived from L-tyrosine. The final component of novobiocin is the sugar derivative L-noviose, known as ring C, which is derived from glucose-1-phosphate. The biosynthetic gene cluster for novobiocin was identified by Heide and coworkers in 1999 (published 2000) from Streptomyces spheroidesNCIB 11891.^[18] They identified 23 putative open reading frames (ORFs) and more than 11 other ORFs that may play a role in novobiocin biosynthesis.

The biosynthesis of ring A (see Fig. 1) begins with prephenate which is a derived from the shikimic acid biosynthetic pathway. The enzyme NovF catalyzes the decarboxylation of prephenate while simultaneously reducing nicotinamide adenine dinucleotide phosphate (NADP⁺) to produce NADPH. Following this NovQ catalyzes the electrophilic substitution of the phenyl ring with dimethylallyl pyrophosphate (DMAPP) otherwise known as prenylation.^[19] DMAPP can come from either the mevalonic acid pathway or the deoxyxylulose biosynthetic pathway. Next the 3-dimethylallyl-4-hydroxybenzoate molecule is subjected to two oxidative decarboxylations by NovR and molecular oxygen.^[20] NovR is a non-heme iron oxygenase with a unique bifunctional catalysis. In the first stage both oxygens are incorporated from the molecular oxygen while in the second step only one is incorporated as determined by isotope labeling studies. This completes the formation of ring A.

Figure 1. Biosynthetic scheme of benzamide portion of novobiocin (4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acid)

The biosynthesis of ring B (see Fig. 2) begins with the natural amino acid L-tyrosine. This is then adenylated and thioesterified onto the peptidyl carrier protein (PCP) of NovH by ATPand NovH itself.^[21] NovI then further modifies this PCP bound molecule by oxidizing the β-position using NADPH and molecular oxygen. NovJ and NovK form a heterodimer of J2K2 which is the active form of this benzylic oxygenase.^[22] This process uses NADP⁺ as a hydride acceptor in the oxidation of the β-alcohol. This ketone will prefer to exist in its enol tautomer in solution. Next a still unidentified protein catalyzes the selective oxidation of the benzene (as shown in Fig. 2). Upon oxidation this intermediate will spontaneously lactonize to form the aromatic ring B and lose NovH in the process.

Figure 2. Biosynthesis of 3-amino-4,7-dihydroxy-2H-chromen-2-one component of novobiocin (ring B)

The biosynthesis of L-noviose (ring C) is shown in Fig. 3. This process starts from glucose-1-phosphate where NovV takes dTTP and replaces the phosphate group with a dTDP group. NovT then oxidizes the 4-hydroxy group using NAD⁺. NovT also accomplishes a dehydroxylation of the 6 position of the sugar. NovW then epimerizes the 3 position of the sugar.^[23] The methylation of the 5 position is accomplished by NovU and S-adenosyl methionine (SAM). Finally NovS reduces the 4 position again to achieve epimerization of that position from the starting glucose-1-phosphate using NADH.

Figure 3. Biosynthesis of L-noviose component of novobiocin (ring C)

Rings A, B, and C are coupled together and modified to give the finished novobiocin molecule. Rings A and B are coupled together by the enzyme NovL using ATP to diphosphorylate the carboxylate group of ring A so that the carbonyl can be attacked by the amine group on ring B. The resulting compound is methylated by NovO and SAM prior to glycosylation.^[24] NovM adds ring C (L-noviose) to the hydroxyl group derived from tyrosine with the loss of dTDP. Another methylation is accomplished by NovP and SAM at the 4 position of the L-noviose sugar.^[25] This methylation allows NovN to carbamylate the 3 position of the sugar as shown in Fig. 4 completing the biosynthesis of novobiocin.

Figure 4. Completed biosynthesis of novobiocin from ring systems A, B, and C.

CLIP

PATENT

US-20190241599

Novel co-crystal forms of novobiocin and its analogs and proline, processes for their preparation and compositions comprising them are claimed. Also claims are methods for inhibiting heat shock protein 90 and treating or preventing neurodegenerative disorders, such as diabetic peripheral neuropathy.

References

^ Lanoot B, Vancanneyt M, Cleenwerck I, Wang L, Li W, Liu Z, Swings J (May 2002). “The search for synonyms among streptomycetes by using SDS-PAGE of whole-cell proteins. Emendation of the species Streptomyces aurantiacus, Streptomyces cacaoi subsp. cacaoi, Streptomyces caeruleus and Streptomyces violaceus”. International Journal of Systematic and Evolutionary Microbiology. 52 (Pt 3): 823–9. doi:10.1099/ijs.0.02008-0. PMID 12054245.
^ Jump up to:^a ^b Alessandra da Silva Eustáquio (2004) Biosynthesis of aminocoumarin antibiotics in Streptomyces: Generation of structural analogues by genetic engineering and insights into the regulation of antibiotic production. DISSERTATION
^ Hoeksema H.; Johnson J. L.; Hinman J. W. (1955). “Structural studies on streptonivicin, a new antibiotic”. J Am Chem Soc. 77 (24): 6710–6711. doi:10.1021/ja01629a129.
^ Smith C. G.; Dietz A.; Sokolski W. T.; Savage G. M. (1956). “Streptonivicin, a new antibiotic. I. Discovery and biologic studies”. Antibiotics & Chemotherapy. 6: 135–142.
^ Raad I, Darouiche R, Hachem R, Sacilowski M, Bodey GP (November 1995). “Antibiotics and prevention of microbial colonization of catheters”. Antimicrobial Agents and Chemotherapy. 39 (11): 2397–400. doi:10.1128/aac.39.11.2397. PMC 162954. PMID 8585715.
^ Raad II, Hachem RY, Abi-Said D, Rolston KV, Whimbey E, Buzaid AC, Legha S (January 1998). “A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2”. Cancer. 82 (2): 403–11. doi:10.1002/(SICI)1097-0142(19980115)82:2<412::AID-CNCR22>3.0.CO;2-0. PMID 9445199.
^ “Determination That ALBAMYCIN (Novobiocin Sodium) Capsule, 250 Milligrams, Was Withdrawn From Sale for Reasons of Safety or Effectiveness”. The Federal Register. 19 January 2011.
^ Walsh TJ, Standiford HC, Reboli AC, John JF, Mulligan ME, Ribner BS, Montgomerie JZ, Goetz MB, Mayhall CG, Rimland D (June 1993). “Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome”. Antimicrobial Agents and Chemotherapy. 37 (6): 1334–42. doi:10.1128/aac.37.6.1334. PMC 187962. PMID 8328783.
^ Jump up to:^a ^b Maxwell A (August 1993). “The interaction between coumarin drugs and DNA gyrase”. Molecular Microbiology. 9 (4): 681–6. doi:10.1111/j.1365-2958.1993.tb01728.x. PMID 8231802.
^ Maxwell A (February 1999). “DNA gyrase as a drug target”. Biochemical Society Transactions. 27 (2): 48–53. doi:10.1042/bst0270048. PMID 10093705.
^ Lewis RJ, Tsai FT, Wigley DB (August 1996). “Molecular mechanisms of drug inhibition of DNA gyrase”. BioEssays. 18 (8): 661–71. doi:10.1002/bies.950180810. PMID 8760340.
^ Maxwell A, Lawson DM (2003). “The ATP-binding site of type II topoisomerases as a target for antibacterial drugs”. Current Topics in Medicinal Chemistry. 3 (3): 283–303. doi:10.2174/1568026033452500. PMID 12570764.
^ Yu XM, Shen G, Neckers L, Blake H, Holzbeierlein J, Cronk B, Blagg BS (September 2005). “Hsp90 inhibitors identified from a library of novobiocin analogues”. Journal of the American Chemical Society. 127 (37): 12778–9. doi:10.1021/ja0535864. PMID 16159253.
^ Mandler MD, Baidin V, Lee J, Pahil KS, Owens TW, Kahne D (June 2018). “Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport”. Journal of the American Chemical Society. 140 (22): 6749–6753. doi:10.1021/jacs.8b02283. PMC 5990483. PMID 29746111.
^ May JM, Owens TW, Mandler MD, Simpson BW, Lazarus MB, Sherman DJ, Davis RM, Okuda S, Massefski W, Ruiz N, Kahne D (December 2017). “The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport”. Journal of the American Chemical Society. 139 (48): 17221–17224. doi:10.1021/jacs.7b07736. PMC 5735422. PMID 29135241.
^ Tsai FT, Singh OM, Skarzynski T, Wonacott AJ, Weston S, Tucker A, Pauptit RA, Breeze AL, Poyser JP, O’Brien R, Ladbury JE, Wigley DB (May 1997). “The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin”. Proteins. 28 (1): 41–52. doi:10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>3.3.co;2-b. PMID 9144789.
^ Jump up to:^a ^b Flatman RH, Eustaquio A, Li SM, Heide L, Maxwell A (April 2006). “Structure-activity relationships of aminocoumarin-type gyrase and topoisomerase IV inhibitors obtained by combinatorial biosynthesis”. Antimicrobial Agents and Chemotherapy. 50 (4): 1136–42. doi:10.1128/AAC.50.4.1136-1142.2006. PMC 1426943. PMID 16569821.
^ Steffensky M, Mühlenweg A, Wang ZX, Li SM, Heide L (May 2000). “Identification of the novobiocin biosynthetic gene cluster of Streptomyces spheroides NCIB 11891”. Antimicrobial Agents and Chemotherapy. 44 (5): 1214–22. doi:10.1128/AAC.44.5.1214-1222.2000. PMC 89847. PMID 10770754.
^ Pojer F, Wemakor E, Kammerer B, Chen H, Walsh CT, Li SM, Heide L (March 2003). “CloQ, a prenyltransferase involved in clorobiocin biosynthesis”. Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2316–21. Bibcode:2003PNAS..100.2316P. doi:10.1073/pnas.0337708100. PMC 151338. PMID 12618544.
^ Pojer F, Kahlich R, Kammerer B, Li SM, Heide L (August 2003). “CloR, a bifunctional non-heme iron oxygenase involved in clorobiocin biosynthesis”. The Journal of Biological Chemistry. 278 (33): 30661–8. doi:10.1074/jbc.M303190200. PMID 12777382.
^ Chen H, Walsh CT (April 2001). “Coumarin formation in novobiocin biosynthesis: beta-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI”. Chemistry & Biology. 8 (4): 301–12. doi:10.1016/S1074-5521(01)00009-6. PMID 11325587.
^ Pacholec M, Hillson NJ, Walsh CT (September 2005). “NovJ/NovK catalyze benzylic oxidation of a beta-hydroxyl tyrosyl-S-pantetheinyl enzyme during aminocoumarin ring formation in novobiocin biosynthesis”. Biochemistry. 44 (38): 12819–26. CiteSeerX 10.1.1.569.1481. doi:10.1021/bi051297m. PMID 16171397.
^ Thuy TT, Lee HC, Kim CG, Heide L, Sohng JK (April 2005). “Functional characterizations of novWUS involved in novobiocin biosynthesis from Streptomyces spheroides”. Archives of Biochemistry and Biophysics. 436 (1): 161–7. doi:10.1016/j.abb.2005.01.012. PMID 15752721.
^ Pacholec M, Tao J, Walsh CT (November 2005). “CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis”. Biochemistry. 44 (45): 14969–76. doi:10.1021/bi051599o. PMID 16274243.
^ Freel Meyers CL, Oberthür M, Xu H, Heide L, Kahne D, Walsh CT (January 2004). “Characterization of NovP and NovN: completion of novobiocin biosynthesis by sequential tailoring of the noviosyl ring”. Angewandte Chemie. 43 (1): 67–70. doi:10.1002/anie.200352626. PMID 14694473.

External links

Novobiocin bound to proteins in the PDB

Novobiocin
Clinical data


AHFS/Drugs.com	International Drug Names
Routes of administration	intravenous
ATCvet code	QJ01XX95 (WHO)
Pharmacokinetic data
Bioavailability	negligible oral bioavailability
Metabolism	excreted unchanged
Elimination half-life	6 hours
Excretion	renal
Identifiers
IUPAC name [show]
CAS Number	303-81-1
PubChem CID	9346
DrugBank	DB01051
ChemSpider	10226117
UNII	17EC19951N
KEGG	C05080
ChEMBL	ChEMBL36506
CompTox Dashboard(EPA)	DTXSID3041083
ECHA InfoCard	100.005.589
Chemical and physical data
Formula	C₃₁H₃₆N₂O₁₁
Molar mass	612.624 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CC(C)=CCc1c(O)ccc(c1)C(=O)NC=2C(=O)Oc3c(C2O)ccc(c3C)O[C@@H]4OC(C)(C)[C@H](OC)[C@H]([C@H]4O)OC(=O)N
InChI [hide] InChI=1S/C31H36N2O11/c1-14(2)7-8-16-13-17(9-11-19(16)34)27(37)33-21-22(35)18-10-12-20(15(3)24(18)42-28(21)38)41-29-23(36)25(43-30(32)39)26(40-6)31(4,5)44-29/h7,9-13,23,25-26,29,34-36H,8H2,1-6H3,(H2,32,39)(H,33,37)/t23-,25+,26-,29-/m1/s1 Key:YJQPYGGHQPGBLI-KGSXXDOSSA-N

Novobiocin calcium.png

4309-70-0 CAS

calcium;7-[(2R,3R,4S,5R)-4-carbamoyloxy-3-hydroxy-5-methoxy-6,6-dimethyloxan-2-yl]oxy-3-[[4-hydroxy-3-(3-methylbut-2-enyl)benzoyl]amino]-8-methyl-2-oxochromen-4-olate

///////// Novobiocin, ノボビオシン , Antibacterial, Antimicrobial, crystallinic acid, streptonivicin,

Manufacturers’ Codes: PA-93; U-6591

History

Novobiocin is a coumarin antibiotic obtained from Streptomyces niveus and other Streptomyces species. Novobiocin is useful primarily in infections involving staphylococci, and other gram-positive organisms. It acts by inhibiting the initiation of DNA replication in bacterial and mammanlian cells. Evidences indicated that Novobiocin blocks prokaryotic DNA gyrase and eukaryotic II topoisomerase, enzymes that relax super-coiled DNA and are crucial for DNA replication.¹

Novobiocin

UIPAC Name	4-Hydroxy-3-4-hydroxy-3-(3-methylbut-2-enyl)benzamido-8-methylcoumarin-7-yl 3-O-carbamoyl-5,5-di-C-methyl-α-l-lyxofuranoside
CAS Number	303-81-1
Molecular Mass	612.624 g / mol
Chemical Formular	C₃₁H₃₆N₂O₁₁

Biosynthesis

The substituted coumarin (ring B, red) and the 4-OH benzoyl moiety (ring A, aqua) in novobiocin were derived from -Tyr based on earlier labeling studies. β-OH-Tyr is proposed to be a common intermediate in these two biosynthetic pathways.²

NovH is a -Tyr specific didomain NRPS that generates the -tyrosyl-S-NovH intermediate. NovH, isolated from E. coli is primed by a PPTase with CoA. The A domain activates -Tyr as -tyrosyl-AMP and then transfers the -tyrosyl group to the HS-pant-PCP domain of NovH through thioester formation.³

-tyrosyl-S-NovH is then function as a cytochrome P450 monooxygenase that hydroxylates the β-carbon of the tethered -tyrosyl group on NovH. While the substrate -tyrosyl-S-NovH provides two electrons for a single round of the hydroxylation reaction, the other two electrons needed to reduce the oxygen atom are provided by NADPH via two-electron transfer effected by electron transfer proteins ferrodoxin (Fd) and ferrodoxin reductase (Fd Red).³ The electron transfer route is from NADPH→FAD in Fd Red→Fe–S center in Fd→Heme in NovI→oxygen.

Both NovJ and NovK are similar to 3-keto-ACP reductase and they may form a heterodimer and operate in the reverse direction to oxidize 3-OH to 3-keto. NovO is similar to some quinone C-methyltransferases ³ but the timing of methylation is not clear. NovC resembles flavin-dependent monooxygenases (35 and 32% similarity to dimethylaniline and cyclohexanone monooxygenases, respectively) ³ and is proposed to hydroxylate the ortho position of the phenyl ring. The nucleophilic attack of the ortho hydroxyl group on the thioester carbonyl center would release the coumarin ring and regenerate NovH. Ring B is then synthesized.

Synthesis

Mechanism of action

E.Coli DNA gyrase utilizes ATP to catalyze the negative supercoiling, or under-twisting, of duplex DNA. The energy coupling components of the supercoiling reaction includes 1) the DNA-dependent hydrolysis that converts ATP to ADP and Pi, and 2) the gyrase cleavage reaction that targets the specified DNA site. The two activities are induced by treating the stable gyrase-DNA complex trapped by the inihibitor oxolinic acid with sodium dodecyl sulfate (SDS or Sulphate). ⁴ Novobiocin competes with ATP in the ATPase and supercoiling assays, hence Novobiocin prevents the ATP from shifting the primary cleavage site on ColE1 DNA by places the site of action of the antibiotics at a reaction step prior to ATP hydrolysis and blocks the binding of ATP. ⁴ Such a simple mechanism of action represents for all effects of the drugs on DNA gyrase.

Clinical Use

Due to factors as low solubility, poor pharmacokinetics, and limited activity agasinst Gram-negative bacteria, the clinical usage of Novobiocin is not achieved. ⁵ Therefore, it is of interest to study the novobiocin biosynthetic pathway in order to generate analogs with enhanced solubility and pharmacokinetic properties while maintaining the gyrase inhibitory properties.

References

^{1 J.C. D’Halluin, M. Milleville, and P. Boulanger. “Effect of Novobiocin on adenovirus DNA synthesis and encapsidation”. Nucleic Acids Research 1980; 8: 1625-1641}

^{2 M. Steffensky, S.M. Li and L. Heide, “Cloning, overexpression, and purification of novobiocic acid synthetase from Streptomyces spheroides ” NCIB 11891. J. Biol. Chem. 275 (2000), pp. 21754–21760.}

^{3 Huawei Chen and Christopher T. Walsh, “Coumarin formation in novobiocin biosynthesis: β-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI” Chemistry and Biology; 2001; 8: 301-312}

^{4 K. Scheirer and N. P. Higgins. “The DAN Cleavage Reaction of DNA Gyrase ” The Journal of Biological Chemistry; 1997; 272 (43): 27202-27209}

^{5 N Pi, C. L. F. Meyers, M. Pacholec, C. T. Walsh, and J. A. Leary. “Mass spectrometric characterization of a three-enzyme tandem reacton for assembly and modification of the novobiocin skeleton” PNAS 2004;101;10036-10041}

Imipenem, イミペネム水和物

August 8, 2019 10:49 am / Leave a comment

ChemSpider 2D Image | Imipenem hydrate | C12H19N3O5S

Imipenem

イミペネム水和物

Cas 74431-23-5

Molecular FormulaC₁₂H₁₉N₃O₅S
Average mass317.361 Da

(5R,6S)-3-((2-(Formimidoylamino)ethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid monohydrate

1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-[(1R)-1-hydroxyethyl]-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-, (5R,6S)-, monohydrate

264-734-5 [EINECS]

74431-23-5 [RN]

N-Formimidoylthienamycin Monohydrate

Primaxin monohydrate

Tienam monohydrate

(5R,6S)-3-((2-Formimidamidoethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid hydrate

(5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid and hydrate

8174596 [Beilstein]

imipemide monohydrate

Antibacterial, Cell wall biosynthesis inhibitor

Imipenem

CAS Registry Number: 74431-23-5; 64221-86-9 (anhydrous)

CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate

Additional Names: N-formimidoylthienamycin monohydrate; imipemide

Manufacturers’ Codes: MK-787

Molecular Formula: C12H17N3O4S.H2O

Molecular Weight: 317.36

Percent Composition: C 45.41%, H 6.03%, N 13.24%, O 25.21%, S 10.10%

Literature References: Extremely broad-spectrum semi-synthetic antibiotic; first stable derivative of thienamycin, q.v. Prepn: W. J. Leanza et al., J. Med. Chem. 22, 1435 (1979); T. W. Miller, EP 6639 (1980 to Merck & Co.), C.A. 93, 155845y (1980); B. G. Christensen et al., US 4194047 (1980 to Merck & Co.). Totally synthetic prepn without formation of thienamycin: I. Shinkai et al.,Tetrahedron Lett. 23, 4903 (1982). HPLC determn in serum: C. M. Myers, J. L. Blumer, Antimicrob. Agents Chemother. 26, 78 (1984). Series of articles on in vitro activity, pharmacokinetics, clinical efficacy of combination with cilastatin sodium, q.v., a renal dehydropeptidase I inhibitor: J. Antimicrob. Chemother. 12, Suppl. D, 1-155 (1983); Rev. Infect. Dis. 7, Suppl. 3, S389-S536 (1985); Am. J. Med. 78, Suppl. 6A, 1-167 (1985); Infection 14, Suppl. 2, S111-S180 (1986). Comprehensive description: E. R. Oberholtzer, Anal. Profiles Drug Subs. 17, 73-114 (1988).

Properties: Crystals from water-ethanol. [a]D25 +86.8° (c = 0.05 in 0.1M phosphate, pH 7). pKa1 ~3.2, pKa2 ~9.9. uv max (water): 299 nm (e 9670, 98% NH2OH ext). Soly (mg/ml): water 10, methanol 5, ethanol 0.2, acetone <0.1, dimethylformamide <0.1, dimethylsulfoxide 0.3.

pKa: pKa1 ~3.2, pKa2 ~9.9

Optical Rotation: [a]D25 +86.8° (c = 0.05 in 0.1M phosphate, pH 7)

Absorption maximum: uv max (water): 299 nm (e 9670, 98% NH2OH ext)

Derivative Type: Combination with cilastatin sodium

CAS Registry Number: 85960-17-4

Trademarks: Imipem (Neopharmed); Primaxin (Merck & Co.); Tenacid (Sigma-Tau); Tienam (Merck & Co.); Zienam (Merck & Co.)

Therap-Cat: Antibacterial.

Keywords: Antibacterial (Antibiotics); ?Lactams; Carbapenems.

Imipenem (Primaxin among others) is an intravenous β-lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s.^[1] Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria,^[2] thus play a key role in the treatment of infections not readily treated with other antibiotics.^[3]

Imipenem was patented in 1975 and approved for medical use in 1985.^[4] It was discovered via a lengthy trial-and-error search for a more stable version of the natural product thienamycin, which is produced by the bacterium Streptomyces cattleya. Thienamycin has antibacterial activity, but is unstable in aqueous solution, so impractical to administer to patients.^[5] Imipenem has a broad spectrum of activity against aerobic and anaerobic, Gram-positive and Gram-negative bacteria.^[6] It is particularly important for its activity against Pseudomonas aeruginosa and the Enterococcus species. It is not active against MRSA, however.

Medical uses

Spectrum of bacterial susceptibility and resistance

Acinetobacter anitratus, Acinetobacter calcoaceticus, Actinomyces odontolyticus, Aeromonas hydrophila, Bacteroides distasonis, Bacteroides uniformis, and Clostridium perfringens are generally susceptible to imipenem, while Acinetobacter baumannii, some Acinetobacter spp., Bacteroides fragilis, and Enterococcus faecalis have developed resistance to imipenem to varying degrees. Not many species are resistant to imipenem except Pseudomonas aeruginosa (Oman) and Stenotrophomonas maltophilia.^[7]

Coadministration with cilastatin

Imipenem is rapidly degraded by the renal enzyme dehydropeptidase 1 when administered alone, and is almost always coadministered with cilastatin to prevent this inactivation^[8]

Adverse effects

Common adverse drug reactions are nausea and vomiting. People who are allergic to penicillin and other β-lactam antibiotics should take caution if taking imipenem, as cross-reactivity rates are high. At high doses, imipenem is seizurogenic.^[9]

Mechanism of action

Imipenem acts as an antimicrobial through inhibiting cell wall synthesis of various Gram-positive and Gram-negative bacteria. It remains very stable in the presence of β-lactamase (both penicillinase and cephalosporinase) produced by some bacteria, and is a strong inhibitor of β-lactamases from some Gram-negative bacteria that are resistant to most β-lactam antibiotics.

SYM

By reaction of thienamycin (I) with methyl formimidate (II) by means of NaOH in water.

DE 2652679; FR 2332012; GB 1570990; NL 7612939

SYN 2

WO 0294828

The reaction of (3R,5R,6S)-6-(1(R)-hydroxyethyl)-2-oxo-1-carbapenem-3-carboxylic acid p-nitrobenzyl ester (I) with diphenyl chlorophosphate by (II) means of DMAP and DIEA in DMA/dichloromethane gives the enol phosphate (III), which is condensed with 2-aminoethanethiol (IV) in DMA to yield the 2-aminoethylsulfanyl derivative (V). The reaction of (V) with benzyl formimidate (VI) by means of DIEA in DMA affords the intermediate p-nitrobenzyl ester (VII), which is finally hydrogenated with H2 over Pd/C in water/isopropanol/N-methylmorpholine to provide the target Imipemide.

SYN 3

Tetrahedron Lett 1982,23(47),4903

The condensation of 7-oxo-6-(1-hydroxyethyl)-3-(diphenoxyphosphate)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrophenyl ester (I) with the bis(trimethylsilyl) derivative of 2-(iminomethylamino)ethanethiol (II) in the presence of base gives p-nitrophenyl ester of MK-0787, protected with a trimethylsilyl group (III), which is finally deprotected by hydrogenolysis.

CLIP

Image result for imipenem synthesis

Synthesis Path

References

^ U.S. Patent 4,194,047
^ Clissold, SP; Todd, PA; Campoli-Richards, DM (Mar 1987). “Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy”. Drugs. 33 (3): 183–241. doi:10.2165/00003495-198733030-00001. PMID 3552595.
^ Vardakas, KZ; Tansarli, GS; Rafailidis, PI; Falagas, ME (Dec 2012). “Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis”. The Journal of Antimicrobial Chemotherapy. 67 (12): 2793–803. doi:10.1093/jac/dks301. PMID 22915465.
^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 497. ISBN 9783527607495.
^ Kahan, FM; Kropp, H; Sundelof, JG; Birnbaum, J (Dec 1983). “Thienamycin: development of imipenen-cilastatin”. The Journal of Antimicrobial Chemotherapy. 12 Suppl D: 1–35. doi:10.1093/jac/12.suppl_d.1. PMID 6365872.
^ Kesado, Tadataka; Hashizume, Terutaka; Asahi, Yoshinari (1980). “Antibacterial activities of a new stabilized thienamycin, N-formimidoyl thienamycin, in comparison with other antibiotics”. Antimicrobial Agents and Chemotherapy. 17 (6): 912–7. doi:10.1128/aac.17.6.912. PMC 283902. PMID 6931548.
^ “Imipenem spectrum of bacterial susceptibility and Resistance” (PDF). Retrieved 4 May 2012.
^ “IMIPENEM/CILASTATIN”. livertox.nih.gov. Retrieved 2019-03-08.
^ Cannon, Joan P.; Lee, Todd A.; Clark, Nina M.; Setlak, Paul; Grim, Shellee A. (2014-08-01). “The risk of seizures among the carbapenems: a meta-analysis”. Journal of Antimicrobial Chemotherapy. 69 (8): 2043–2055. doi:10.1093/jac/dku111. ISSN 0305-7453.

External links

Imipenem bound to proteins in the PDB

Imipenem
Clinical data


Trade names	Primaxin
AHFS/Drugs.com	International Drug Names
MedlinePlus	a686013
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	IM, IV
ATC code	J01DH51 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	20%
Metabolism	Renal
Elimination half-life	38 minutes (children), 60 minutes (adults)
Excretion	Urine (70%)
Identifiers
IUPAC name [show]
CAS Number	64221-86-9
PubChem CID	5282372
DrugBank	DB01598
ChemSpider	4445535
UNII	Q20IM7HE75
KEGG	D00206
ChEBI	CHEBI:51799
ChEMBL	ChEMBL43708
CompTox Dashboard (EPA)	DTXSID2023143
ECHA InfoCard	100.058.831
Chemical and physical data
Formula	C₁₂H₁₇N₃O₄S
Molar mass	299.347 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O=C(O)/C1=C(\SCC/N=C/N)C[C@H]2N1C(=O)[C@@H]2[C@H](O)C.O
InChI [hide] InChI=1S/C12H17N3O4S.H2O/c1-6(16)9-7-4-8(20-3-2-14-5-13)10(12(18)19)15(7)11(9)17;/h5-7,9,16H,2-4H2,1H3,(H2,13,14)(H,18,19);1H2/t6-,7-,9-;/m1./s1 Key:GSOSVVULSKVSLQ-JJVRHELESA-N

- Synonyms:Imipemide
- ATC:J01DH51

Use:carbapenem antibiotic
Chemical name:[5R-[5α,6α(R*)]]-6-(1-hydroxyethyl)-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Formula:C₁₂H₁₇N₃O₄S

MW:299.35 g/mol
CAS-RN:64221-86-9
InChI Key:ZSKVGTPCRGIANV-ZXFLCMHBSA-N
InChI:InChI=1S/C12H17N3O4S/c1-6(16)9-7-4-8(20-3-2-14-5-13)10(12(18)19)15(7)11(9)17/h5-7,9,16H,2-4H2,1H3,(H2,13,14)(H,18,19)/t6-,7-,9-/m1/s1
EINECS:264-734-5
LD₅₀:1660 mg/kg (M, i.v.); >5 g/kg (M, p.o.);
1972 mg/kg (R, i.v.); >5 g/kg (R, p.o.)

Derivatives, monohydrate

Formula:C₁₂H₁₇N₃O₄S • H₂O
MW:317.37 g/mol
CAS-RN:74431-23-5

References

- Leanza, W.J. et al.: J. Med. Chem. (JMCMAR) 22, 1435 (1979).
- a Salzmann, T.L. et al.: J. Am. Chem. Soc. (JACSAT) 102, 6161-6163 (1980).
- Reider, P.J.; Grabowski, E.J.J.: Tetrahedron Lett. (TELEAY) 23, 2293-2296 (1982).
- Grabowski, E.J.J.: Chirality (CHRLEP) 17, 249-259 (2005).
- US 4 194 047 (Merck & Co.; 18.3.1980; prior. 21.11.1975).
- DOS 2 652 679 (Merck & Co.; appl. 19.11.1976; USA-prior. 21.11.1975).
- b US 5 998 612 (Merck & Co.; 7.12.1999; appl. 12.6.1992; prior. 23.10.1981).
- c US 4 981 992 (Takasago; 27.1.1998; appl. 13.5.1996; J-prior. 11.5.1995).
- US 5 204 460 (Takasago; 20.4.1993; appl. 8.11.1991; J-prior. 8.11.1990).
- US 5 204 462 (Takasago; 20.4.1993; appl. 8.11.1991; J-prior. 8.11.1990).
- US 5 712 388 (Takasago; 27.1.1998; appl. 13.5.1996; J-prior. 11.5.1995).
- US 5 081 239 (Takasago; 14.1.1992; appl. 29.11.1989; J-prior. 29.11.1988).

Acetoxylation of 2-azetidinones in 4-position:
- Noyori, R. et al.: J. Am. Chem. Soc. (JACSAT) 111, 9134-9135 (1989).
- Noyori, R. et al.: Angew. Chem. (ANCEAD) 114, 2108-2123 (2002).
- US 5 288 862 (Takasago; 22.2.1994; appl. 16.4.1992; J-prior. 18.4.1991).
- US 5 606 052 (Takasago; 25.2.1997; appl. 16.4.1992; J-prior. 18.4.1991).

Noyori-catalyst:
- US 4 739 084 (Takasago; 19.4.1988; appl. 15.4.1987; J-prior. 13.5.1986).

d process of Nippon Soda (Nisso):
- US 5 026 844 (Suntory & Nippon Soda; 25.6.1991; appl. 13.10.1989; J-prior. 19.10.1988).
- US 5 792 861 (Tanabe Seiyaku & Nippon Soda; 11.8.1998; appl. 29.6.1994, 4.11.1996; J-prior. 30.6.1993).
- US 5 808 055 (Suntory & Nippon Soda; 15.9.1998; appl. 30.3.1993, 5.7.1995; J-prior. 30.3.1993).
- e US 4 791 198 (Kanegafuchi; 13.12.1988; appl. 1.7.1985, 6.1.1987; J-prior. 5.7.1984, 14.1.1986).
- US 4 861 877 (Kanegafuchi; 29.8.1989; appl. 1.7.1985, 6.1.1987; J-prior. 5.7.1984, 14.1.1985, 14.1.1986).
- US 5 061 817 (Kanegafuchi; 29.10.1991; appl. 1.7.1985, 6.1.1987, 31.5.1988; J-prior. 5.7.1984, 14.1.1986).
- US 4 914 200 (Kanegafuchi; 3.4.1990; appl. 28.4.1987, 14.2.1989; J-prior. 30.4.1986, 13.11.1986, 9.2.1987).

Enzymatic reduction of alkyl-2-(N-benzoylamino)methyl-3-oxobutyrates with bakers yeast:
- US 5 463 047 (Ciba-Geigy; 31.10.1995; appl. 15.9.1994; CH-prior. 4.5.1987).

Further synthesis processes of Merck & Co. for thienamycin:
- Johnston, D.B.R. et al.: J. Am. Chem. Soc. (JACSAT) 100, 313-315 (1978).
- Mellilo, D.G. et al.: Tetrahedron Lett. (TELEAY) 21, 2783 (1980).
- Melillo, D.G. et al.: J. Org. Chem. (JOCEAH) 51, 1498-1504 (1986).
- Karady, S. et al.: J. Am. Chem. Soc. (JACSAT) 103, 6765-6767 (1981).
- US 4 269 772 (Merck & Co.; 26.5.1981; appl. 14.1.1980).
- US 4 282 148 (Merck & Co.; 4.8.1981; appl. 14.1.1980).
- US 4 287 123 (Merck & Co.; 1.9.1981; appl. 14.1.1980).
- US 4 290 947 (Merck & Co.; 22.9.1981; appl. 29.5.1980).
- US 4 360 684 (Merck & Co.; 23.11.1982; appl. 8.4.1981).
- US 4 206 219 (Merck & Co.; 3.6.1980; appl. 24.10.1978).
- US 4 348 320 (Merck & Co.; 7.9.1982; appl. 20.8.1980; USA-prior. 19.11.1976).
- US 4 460 507 (Merck & Co.; 17.7.1984; appl. 29.4.1982; USA-prior. 10.10.1980).
- US 5 055 573 (Merck & Co.; 8.10.1991, appl. 24.8.1990; USA-prior. 19.11.1976).
- US 5 037 974 (Merck & Co.; 6.8.1991; appl. 14.8.1990; prior. 23.5.1988, 10.4.1990).

Review of thienamycin syntheses:
- Nicolaou, K.C.; Sorensen, E.J.: Classics in Total Synthesis, VCH 1996, Weinheim & New York, chapter 16, p. 249-263.
- Berks, A.H.: Tetrahedron (TETRAB) 52, 331-375 (1996).

Alternative 2-azetidinone ring closure with chlorosulfonyl isocyanate:
- US 4 350 631 (Merck & Co.; 21.9.1982; appl. 18.3.1981; prior. 18.12.1980).

Thienamycin (by fermentation of S. cattleya):
- US 3 950 357 (Merck & Co.; 13.4.1976; appl. 25.11.1974).
- DOS 2 552 638 (Merck & Co.; appl. 24.11.1975; USA-prior. 25.11.1974).

Combination with cilastatin:
- EP 48 301 (Merck & Co.; appl. 24.9.1980).

/////////////Imipenem, イミペネム水和物 , MK-787,

Quinacillin

July 22, 2019 1:24 pm / Leave a comment

Quinacillin

Image result for Quinacillin drug future

Quinacillin

UNII-83NB50X92M

Cas 1596-63-0

83NB50X92M

Quinacilina

MW 416.4 g/mol, MF C₁₈H₁₆N₄O₆S

(2S,5R,6R)-6-[(3-carboxyquinoxaline-2-carbonyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-(3-carboxy-2-quinoxalinecarboxamido)-3,3-dimethyl-7-oxo- (7CI,8CI)
4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[[(3-carboxy-2-quinoxalinyl)carbonyl]amino]-3,3-dimethyl-7-oxo-, [2S-(2α,5α,6β)]-
(2S,5R,6R)-6-[[(3-Carboxy-2-quinoxalinyl)carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
3-Carboxy-2-quinoxalinylpenicillanic acid
3-Carboxy-2-quinoxalinylpenicillin

6-(3-Carboxy-2-quinoxalinecarboxamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Penicillin, (3-carboxy-2-quinoxalinyl)-

CAS Registry Number: 1596-63-0

CAS Name: (2S,5R,6R)-6-[[(3-Carboxy-2-quinoxalinyl)carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

Additional Names: 3-carboxy-2-quinoxalinylpenicillin

Molecular Formula: C18H16N4O6S

Molecular Weight: 416.41

Percent Composition: C 51.92%, H 3.87%, N 13.45%, O 23.05%, S 7.70%

Literature References: Semi-synthetic antibiotic related to penicillin. Prepd by condensation of quinoxaline-2,3-dicarboxylic anhydride with 6-aminopenicillanic acid: Richards et al., Nature 199, 354 (1963).

Derivative Type: Disodium salt

CAS Registry Number: 985-32-0

Molecular Formula: C18H14N4Na2O6S

Molecular Weight: 460.37

Percent Composition: C 46.96%, H 3.07%, N 12.17%, Na 9.99%, O 20.85%, S 6.97%

Properties: Crystals, dec 261-262°. [a]D23 +183.5° (water). Very hygroscopic. uv max (containing 9.2% water): 242, 326 nm (e32,100; 7280). Acquires a bright yellow color on exposure to strong sunlight but is stable at 100° for at least 3 months. Freely sol in water; a 25% aq soln is stable for 2 months at 0°. Antimicrobial activity is highest against Staphylococcus aureus.

Optical Rotation: [a]D23 +183.5° (water)

Absorption maximum: uv max (containing 9.2% water): 242, 326 nm (e 32,100; 7280)

cas 13549-27-4

Derivative Type: Bistriethylammonium salt monohydrate

Molecular Formula: C30H46N6O6S.H2O

Molecular Weight: 636.80

Percent Composition: C 56.58%, H 7.60%, N 13.20%, O 17.59%, S 5.04%

Properties: Crystals from acetone, dec 135-137°. [a]D20 +142° (c = 0.376 in water).

Optical Rotation: [a]D20 +142° (c = 0.376 in water)

Therap-Cat: Antibacterial.

Keywords: Antibacterial (Antibiotics); ?Lactams; Penicillins.

Quinacillin is a semisynthetic penicillase-resistant penicillin with antibacterial activity. Quinacillin binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall. Inactivation of PBPs interferes with the cross-linkage of peptidoglycan chains necessary for bacterial cell wall strength and rigidity. This interrupts bacterial cell wall synthesis and results in the weakening of the bacterial cell wall, eventually causing cell lysis.

PATENTS

GB 867890

GB 967890

JP 47026513

DE 2161659

WO 2014111957

IN 2013MU00181

US 20150328323

PAPER

https://www.nature.com/articles/199354a0

DOI: 10.1038/199354a0

//////Quinacillin

CC1(C(N2C(S1)C(C2=O)NC(=O)C3=NC4=CC=CC=C4N=C3C(=O)O)C(=O)O)C

Nicotinamide riboside chloride

July 4, 2019 9:20 am / Leave a comment

ChemSpider 2D Image | Nicotinamide riboside | C11H15N2O5

Image result for nicotinamide riboside chloride

1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methylol-tetrahydrofuran-2-yl]pyridin-1-ium-3-carboxamide

CAS 1341-23-7 [RN]

3-(aminocarbonyl)-1-β-D-ribofuranosyl-Pyridinium

Nicotinamide riboside chloride

CAS 23111-00-4 CHLORIDE

CAS : 1341-23-7 (cation) 23111-00-4 (chloride) 445489-49-6 (Triflate)

3-Carbamoyl-1-((2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium chloride

Nicotinamide ribose chloride

UNII-8XM2XT8VWI

MW 290.7 g/mol

1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyridin-1-ium-3-carboxamide;chloride

C1=CC(=C[N+](=C1)C2C(C(C(O2)CO)O)O)C(=O)N.[Cl-]

Nicotinamide riboside; SRT647; SRT-647; SRT 647; Nicotinamide Riboside Triflate, α/β mixture

EH-301, nicotinamide riboside chloride,AND pterostilbene,, BY Elysium Health Inc

Nicotinamide riboside, also known as NR and SRT647, is a pyridine-nucleoside form of vitamin B3 that functions as a precursor to nicotinamide adenine dinucleotide or NAD+. NR blocks degeneration of surgically severed dorsal root ganglion neurons ex vivo and protects against noise-induced hearing loss in living mice. Nicotinamide riboside prevents muscle, neural and melanocyte stem cell senescence. Increased muscular regeneration in mice has been observed after treatment with nicotinamide riboside, leading to speculation that it might improve regeneration of organs such as the liver, kidney, and heart. Nicotinamide riboside also lowers blood glucose and fatty liver in prediabetic and type 2 diabetic models while preventing the development of diabetic peripheral neuropathy. Note: Nicotinamide Riboside chloride is a α/β mixture

Nicotinamide riboside (NR) is a pyridine–nucleoside form of vitamin B₃ that functions as a precursor to nicotinamide adenine dinucleotide or NAD+.^[1]^[2]

Chemistry

While the molecular weight of nicotinamide riboside is 255.25 g/mol,^[3] that of its chloride salt is 290.70 g/mol.^[4]^[5] As such, 100 mg of nicotinamide riboside chloride provides 88 mg of nicotinamide riboside.

History

Nicotinamide riboside (NR) was first described in 1944 as a growth factor, termed Factor V, for Haemophilus influenza, a bacterium that lives in and depends on blood. Factor V, purified from blood, was shown to exist in three forms: NAD+, NMN and NR. NR was the compound that led to the most rapid growth of this bacterium.^[6] Notably, H. influenza cannot grow on nicotinic acid, nicotinamide, tryptophan or aspartic acid, which were the previously known precursors of NAD+.^[7]

In 2000, yeast Sir2 was shown to be an NAD+-dependent protein lysine deacetylase,^[8] which led several research groups to probe yeast NAD+ metabolism for genes and enzymes that might regulate lifespan. Biosynthesis of NAD+ in yeast was thought to flow exclusively through NAMN (nicotinic acid mononucleotide).^[9]^[10]^[11]^[12]^[13]

When NAD+ synthase (glutamine-hydrolysing) was deleted from yeast cells, NR permitted yeast cells to grow. Thus, these Dartmouth College investigators proceeded to clone yeast and human nicotinamide riboside kinases and demonstrate the conversion of NR to NMN by nicotinamide riboside kinases in vitro and in vivo. They also demonstrated that NR is a natural product found in cow’s milk.^[14]^[15]

Properties

Although it is a form of vitamin B3, NR exhibits unique properties that distinguish it from the other B3 vitamins—niacin and nicotinamide. In a head-to-head experiment conducted on mice, each of these vitamins exhibited unique effects on the hepatic NAD+ metabolome with unique kinetics, and with NR as the form of B3 that produced the greatest increase in NAD+ at a single timepoint.^[16]

Different biosynthetic pathways are responsible for converting the different B3 vitamins into NAD+. The enzyme nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of the two-step pathway converting nicotinamide to NAD+. Two nicotinamide riboside kinases (NRK1 and NRK2) convert NR to NAD+ via a pathway that does not require Nampt.^[14]

Animal studies have demonstrated that these enzymes respond differently to age and stress. In a mouse model of dilated cardiomyopathy, NRK2 mRNA expression increased, while Nampt mRNA expression decreased.^[17] A similar increase in NRK1 and NRK2 expression has been observed in injured central and peripheral neurons.^[18]^[19]^[20]^[21]^[22]

Niacin is known for its tendency to cause an uncomfortable flushing of the skin. This flushing is triggered by the activation of the GPR109A G-protein coupled receptor. NR does not activate this receptor,^[23] and has not been shown to cause flushing in humans—even at doses as high as 2,000 mg/day.^[16]^[24]^[25]^[26]

Despite being an NAD+ precursor, nicotinamide acts as an inhibitor of the NAD+-consuming sirtuin enzymes.^[10] When sirtuins consume NAD+, they create nicotinamide and O-acetyl-ADP-ribose as products of the deacetylation reaction. Consistent with high-dose nicotinamide as a sirtuin inhibitor, NR and niacin, but not nicotinamide, have been shown to increase hepatic levels of O-acetyl-ADP-ribose.^[16]

Commercialization

In 2004, Dartmouth Medical School researcher Dr. Charles Brenner discovered that NR could be converted to NAD+ via the eukaryotic nicotinamide riboside kinase biosynthetic pathway^[14] Dartmouth was subsequently issued patents for nutritional and therapeutic uses of NR, in 2006.^[27] ChromaDex licensed these patents in July 2012, and began to develop a commercially viable, full-scale process to bring NR to market.^[28]

Human Clinical Testing

There have been five published clinical trials on groups of both men and women testing for safety. One of these trials studied NR in combination with pterostilbene,^[29] while the other four examined the effects of NR alone.^[16]^[24]^[25]^[26]

The first published clinical trial established the safety and characterized the pharmacokinetics of single doses of NR.^[16] Since then, doses as high as 2,000 mg/day have been administered over periods as long as 12 weeks.^[25] These studies show that NR can significantly increase levels of NAD+ and some of its associated metabolites in both whole blood and peripheral blood mononuclear cells.^[16]^[24]^[26]

In a 12 week clinical trial of obese insulin-resistant men using 2000 mg/day, NR appeared safe, but did not improve insulin sensitivity or whole-body glucose metabolism.^[26] In a trial of NR 250 mg plus 50 mg of pterostilbene, as well as with double this dose, the combined supplement raised NAD+ levels in a trial of older adults.^[29]

PATENT

WO-2019126482

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E20C1C824C8C705AFA323203013A909F.wapp1nB?docId=WO2019126482&tab=PCTDESCRIPTION

Crystalline form of nicotinamide riboside chloride, useful for treating motor neuron disease or ALS, infertility, kidney damage, and liver damage or fatty liver. Elysium Health in collaboration with Mayo Clinic , is developing EH-301 (clinical, in July 2019), a combination of nicotinamide riboside chloride and pterostilbene for the treatment of amyotrophic lateral sclerosis. See WO2019108878 , claiming use of composition comprising nicotinamide riboside and pterostilbene, for treating obesity.

Nicotinamide riboside is a pyridine-nucleoside form of niacin ( i.e ., vitamin B₃) that serves as a precursor to nicotinamide adenine dinucleotide (NAD⁺). NAD⁺promotes cellular metabolism, mitochondrial function, and energy production. Currently, nicotinamide riboside is made through synthetic methods or fermentation processes. Because of its significant potential to confer health benefits when used as a dietary supplement, there exists a need to develop highly efficient and scalable processes for the manufacture and purification of nicotinamide riboside.

SUMMARY OF THE INVENTION

In certain aspects, the present invention provides a crystalline form of a compound having the structure of formula (I)

Example 1. Scale-Up Synthesis and Crystallization of Nicotinamide Riboside Chloride

900 kg of nicotinamide riboside triacetate and 2133 kg of methanol were charged to a reactor and mixed, then cooled to 0 °C. 747 kg of 7M mmmonia in methanol (i.e.,“methanolic NH₃”) was slowly charged to the reactor at 0 °C. The reaction mixture was passed through a polish filter, then the reaction mixture was stirred for 14 hours. A sample from the reaction mixture was taken to assess reaction progress. Upon completion of the reaction, the reaction mixture was

placed under vacuum, then warmed to 20 °C to 25 °C for 4 hours. Vacuum was applied until solids formed. Once solids were formed, the resultant slurry was filtered on a Nutsche filter dryer. Solids were washed with 1422 kg of ethanol, then 1422 kg of acetone, then 1322 kg of methyl tert butyl ether (MTBE). The resultant solids were then dried at 40 °C. Product was formed with 60% yield. The process flow diagram for this reaction is shown in FIG. 6.

Example 2. Optional Secondary Isolation

The crystalline form may optionally undergo a second isolation process according to the following steps: The solids obtained in Example 1 were dissolved in purified water at 30 °C to 40 °C. Ethanol was slowly added to the solution and mixed for 10 hours, over which time the solids began to precipitate. MTBE was then added and mixed for 2 hours. The mixture was then filtered on a Buchner funnel, and the solids were washed with ethanol, then acetone, then MTBE. Solids were dried at 40 °C.

Example 3. Spectroscopic Data.

The crystalline form made by the process described in Examples 1 and 2 has an XRD spectrum substantially as shown in FIG. 1. The instrument utilized in collecting the XRD data is a Rigaku Smart Lab X-Ray diffraction system.

Specifically, in order to collect the XRD data, The Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg-Brentano geometry using a line source X-ray beam. The X-ray source is a Cu Long Fine Focus tube that was operated at 40 kV and 44 mA. That source provides an incident beam profile at the sample that changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line. The Bragg-Brentano geometry is a para-focusing geometry controlled by passive divergence and receiving slits with the sample itself acting as the focusing component for the optics. The inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1 °2Q or less. The axial divergence of the X-ray beam is controlled by 5.0-degree Sober slits in both the incident and diffracted beam paths.

The samples were prepared in a low background Si holder using light manual pressure to keep the sample surface flat and level with the reference surface of the sample holder. The single crystal Si low background holder has a small circular recess (10 mm diameter and about 0.2 mm depth) that held between 20 and 25 mg of the sample. The samples were analyzed from 2 to 40

°2Q using a continuous scan of 6 °20 per minute with an effective step size of 0.02 °20. The data collection procedure used to analyze these samples was not validated. The peak lists were generated using PDXL2 v.2.3.1.0. The figures were created using PlotMon VI.00.

PATENT

WO2019108878 , claiming use of composition comprising nicotinamide riboside and pterostilbene, for treating obesity.

CLIP

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186459

CLIP

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

February 2019
Beilstein Journal of Organic Chemistry 15(1):401-430

DOI: 10.3762/bjoc.15.36

License, CC BY

Image result for Nicotinamide riboside chloride SYNTHESIS

References

^ Bogan, K.L., Brenner, C. (2008). “Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition”. Annu. Rev. Nutr. 28: 115–130. doi:10.1146/annurev.nutr.28.061807.155443. PMID 18429699.
^ Chi Y, Sauve AA (November 2013). “Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection”. Curr Opin Clin Nutr Metab Care. 16 (6): 657–61. doi:10.1097/MCO.0b013e32836510c0. PMID 24071780.
^ “Nicotinamide riboside”. pubchem.ncbi.nlm.nih.gov.
^ “GRAS Notices, GRN No. 635”. http://www.accessdata.fda.gov. Retrieved 18 February 2019.
^ “Spherix/ChromaDex GRAS submission” (PDF). FDA.gov. Retrieved 18 February2019.
^ Gingrich, W; Schlenk, F (June 1944). “Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae”. Journal of Bacteriology. 47 (6): 535–50. PMC 373952. PMID 16560803.
^ Belenky, P.; et al. (2007). “NAD+ Metabolism in Health and Disease”. Trends in Biochemical Sciences. 32 (1): 12–19. doi:10.1016/j.tibs.2006.11.006. PMID 17161604.
^ Imai, S.; et al. (2000). “Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase”. Nature. 403 (6771): 795–800. doi:10.1038/35001622. PMID 10693811.
^ Anderson; et al. (2003). “Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae”. Nature. 423 (6936): 181–185. doi:10.1038/nature01578. PMC 4802858. PMID 12736687.
^ Jump up to:^a ^b Bitterman; et al. (2002). “Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1”. J. Biol. Chem. 277 (47): 45099–45107. doi:10.1074/jbc.m205670200. PMID 12297502.
^ Gallo; et al. (2004). “Nicotinamide clearance by pnc1 directly regulates sir2-mediated silencing and longevity”. Mol. Cell. Biol. 24 (3): 1301–1312. doi:10.1128/mcb.24.3.1301-1312.2004.
^ Panozzo, C.; et al. (2002). “Aerobic and anaerobic NAD+ metabolism in Saccharomyces cerevisiae”. FEBS Lett. 517 (1–3): 97–102. doi:10.1016/s0014-5793(02)02585-1. PMID 12062417.
^ Sandmeier, JJ; Celic, I; Boeke, JD; Smith, JS (March 2002). “Telomeric and rDNA silencing in Saccharomyces cerevisiae are dependent on a nuclear NAD(+) salvage pathway”. Genetics. 160 (3): 877–89. PMC 1462005. PMID 11901108.
^ Jump up to:^a ^b ^c Bieganowki, P. & Brenner, C. (2004). “Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans”. Cell. 117 (4): 495–502. doi:10.1016/s0092-8674(04)00416-7. PMID 15137942.
^ Hautkooper, R.H.; et al. (2012). “Sirtuins as regulators of metabolism and healthspan”. Nat. Rev. Mol. Cell Biol. 13 (4): 225–238. doi:10.1038/nrm3293. PMC 4872805. PMID 22395773.
^ Jump up to:^a ^b ^c ^d ^e ^f Trammell, Samuel A. J.; Schmidt, Mark S.; Weidemann, Benjamin J.; Redpath, Philip; Jaksch, Frank; Dellinger, Ryan W.; Li, Zhonggang; Abel, E. Dale; Migaud, Marie E.; Brenner, Charles (10 October 2016). “Nicotinamide riboside is uniquely and orally bioavailable in mice and humans”. Nature Communications. 7 (1): 12948. doi:10.1038/ncomms12948. PMC 5062546. PMID 27721479.
^ Diguet, Nicolas; Trammell, Samuel A.J.; Tannous, Cynthia; Deloux, Robin; Piquereau, Jérôme; Mougenot, Nathalie; Gouge, Anne; Gressette, Mélanie; Manoury, Boris; Blanc, Jocelyne; Breton, Marie; Decaux, Jean-François; Lavery, Gareth G.; Baczkó, István; Zoll, Joffrey; Garnier, Anne; Li, Zhenlin; Brenner, Charles; Mericskay, Mathias (22 May 2018). “Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy”. Circulation. 137 (21): 2256–2273. doi:10.1161/CIRCULATIONAHA.116.026099. PMID 29217642.
^ Vaur, Pauline; Brugg, Bernard; Mericskay, Mathias; Li, Zhenlin; Schmidt, Mark S.; Vivien, Denis; Orset, Cyrille; Jacotot, Etienne; Brenner, Charles; Duplus, Eric (December 2017). “Nicotinamide riboside, a form of vitamin B , protects against excitotoxicity-induced axonal degeneration”. The FASEB Journal. 31 (12): 5440–5452. doi:10.1096/fj.201700221RR. PMID 28842432.
^ Sasaki, Y.; Araki, T.; Milbrandt, J. (16 August 2006). “Stimulation of Nicotinamide Adenine Dinucleotide Biosynthetic Pathways Delays Axonal Degeneration after Axotomy”. Journal of Neuroscience. 26 (33): 8484–8491. doi:10.1523/JNEUROSCI.2320-06.2006. PMID 16914673.
^ Frederick, David W.; Loro, Emanuele; Liu, Ling; Davila, Antonio; Chellappa, Karthikeyani; Silverman, Ian M.; Quinn, William J.; Gosai, Sager J.; Tichy, Elisia D.; Davis, James G.; Mourkioti, Foteini; Gregory, Brian D.; Dellinger, Ryan W.; Redpath, Philip; Migaud, Marie E.; Nakamaru-Ogiso, Eiko; Rabinowitz, Joshua D.; Khurana, Tejvir S.; Baur, Joseph A. (August 2016). “Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle”. Cell Metabolism. 24 (2): 269–282. doi:10.1016/j.cmet.2016.07.005. PMC 4985182. PMID 27508874.
^ Cantó, Carles; Jiang, Lake Q.; Deshmukh, Atul S.; Mataki, Chikage; Coste, Agnes; Lagouge, Marie; Zierath, Juleen R.; Auwerx, Johan (March 2010). “Interdependence of AMPK and SIRT1 for Metabolic Adaptation to Fasting and Exercise in Skeletal Muscle”. Cell Metabolism. 11 (3): 213–219. doi:10.1016/j.cmet.2010.02.006. PMC 3616265. PMID 20197054.
^ Rappou, Elisabeth; Jukarainen, Sakari; Rinnankoski-Tuikka, Rita; Kaye, Sanna; Heinonen, Sini; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Saunavaara, Virva; Rissanen, Aila; Virtanen, Kirsi A.; Pirinen, Eija; Pietiläinen, Kirsi H. (March 2016). “Weight Loss Is Associated With Increased NAD /SIRT1 Expression But Reduced PARP Activity in White Adipose Tissue”. The Journal of Clinical Endocrinology & Metabolism. 101 (3): 1263–1273. doi:10.1210/jc.2015-3054. PMID 26760174.
^ Cantó, Carles; Houtkooper, Riekelt H.; Pirinen, Eija; Youn, Dou Y.; Oosterveer, Maaike H.; Cen, Yana; Fernandez-Marcos, Pablo J.; Yamamoto, Hiroyasu; Andreux, Pénélope A.; Cettour-Rose, Philippe; Gademann, Karl; Rinsch, Chris; Schoonjans, Kristina; Sauve, Anthony A.; Auwerx, Johan (June 2012). “The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity”. Cell Metabolism. 15 (6): 838–847. doi:10.1016/j.cmet.2012.04.022. PMC 3616313. PMID 22682224.
^ Jump up to:^a ^b ^c Airhart, Sophia E.; Shireman, Laura M.; Risler, Linda J.; Anderson, Gail D.; Nagana Gowda, G. A.; Raftery, Daniel; Tian, Rong; Shen, Danny D.; O’Brien, Kevin D.; Sinclair, David A. (6 December 2017). “An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers”. PLOS ONE. 12 (12): e0186459. doi:10.1371/journal.pone.0186459. PMC 5718430. PMID 29211728.
^ Jump up to:^a ^b ^c Dollerup, Ole L; Christensen, Britt; Svart, Mads; Schmidt, Mark S; Sulek, Karolina; Ringgaard, Steffen; Stødkilde-Jørgensen, Hans; Møller, Niels; Brenner, Charles; Treebak, Jonas T; Jessen, Niels (August 2018). “A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects”. The American Journal of Clinical Nutrition. 108 (2): 343–353. doi:10.1093/ajcn/nqy132. PMID 29992272.
^ Jump up to:^a ^b ^c ^d Martens, Christopher R.; Denman, Blair A.; Mazzo, Melissa R.; Armstrong, Michael L.; Reisdorph, Nichole; McQueen, Matthew B.; Chonchol, Michel; Seals, Douglas R. (29 March 2018). “Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults”. Nature Communications. 9 (1): 1286. doi:10.1038/s41467-018-03421-7. PMC 5876407. PMID 29599478.
^ Brenner, Charles (20 April 2006). “Nicotinamide riboside kinase compositions and methods for using the same”. Google Patents. Dartmouth College. Retrieved 19 February2019.
^ “ChromaDex Licenses Exclusive Patent Rights for Nicotinamide Riboside (NR) Vitamin Technologies”. 2012-07-16. Retrieved 15 February 2019.
^ Jump up to:^a ^b Dellinger, Ryan W.; Santos, Santiago Roel; Morris, Mark; Evans, Mal; Alminana, Dan; Guarente, Leonard; Marcotulli, Eric (24 November 2017). “Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study”. NPJ Aging and Mechanisms of Disease. 3 (1): 17. doi:10.1038/s41514-017-0016-9. PMC 5701244. PMID 29184669.

Nicotinamide riboside


Names
Other names 1-(β-D-Ribofuranosyl)nicotinamide; N-Ribosylnicotinamide
Identifiers
CAS Number	1341-23-7
3D model (JSmol)	Interactive image
ChEBI	CHEBI:15927
ChemSpider	388956
KEGG	C03150
PubChem CID	439924
InChI [show]
SMILES [show]
Properties
Chemical formula	C₁₁H₁₅N₂O₅⁺
Molar mass	255.25 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Quinupramine, キヌプラミン

July 3, 2019 10:39 am / Leave a comment

Quinupramine

キヌプラミン

5-(1-azabicyclo[2.2.2]oct-3-yl)-10,11-dihydro-5H-dibenz[b,f]azepine
Formula:C₂₁H₂₄N₂

MW:304.44 g/mol
CAS:31721-17-2

Quinupramine

CAS Registry Number: 31721-17-2

CAS Name: 5-(1-Azabicyclo[2.2.2]oct-3-yl)-10,11-dihydro-5H-dibenz[b,f]azepine

Additional Names: 10,11-dihydro-5-(3-quinuclidinyl)-5H-dibenz[b,f]azepine

Manufacturers’ Codes: LM-208

Trademarks: Kinupril (Bellon); Kevopril (Rhone-Poulenc)

Molecular Formula: C21H24N2

Molecular Weight: 304.43

Percent Composition: C 82.85%, H 7.95%, N 9.20%

Literature References: Analog of imipramine, q.v. Prepn: C. Gueremy, P. C. Wirth, DE 2030492 (1971 to Sogeras), C.A. 74,141581e (1971). Animal studies: W. Van Dorsser, A. Dresse, Arch. Int. Pharmacodyn. Ther. 208, 373 (1974); eidem, ibid. 220, 164 (1976). Clinical study: R. Volmat et al., Clin. Neurol. Psychiat. 239, 445 (1978).

Properties: Crystals, mp 150°.

Melting point: mp 150°

Therap-Cat: Antidepressant.

Keywords: Antidepressant; Tricyclics.

Quinupramine (brand names Kevopril, Kinupril, Adeprim, Quinuprine) is a tricyclic antidepressant (TCA) used in Europe for the treatment of depression.^[1]^[2]

Pharmacologically, quinupramine acts in vitro as a strong muscarinic acetylcholine receptor antagonist (anticholinergic) and H₁ receptor antagonist (antihistamine), moderate 5-HT₂ receptor antagonist, and weak serotonin and norepinephrine reuptake inhibitor.^[3] It has negligible affinity for the α₁-adrenergic, α₂-adrenergic, β-adrenergic, or D₂ receptor.^[3]

Clinically, quinupramine is reported to be stimulating similarly to imipramine, desipramine, and demexiptiline.^[4] It can be inferred that its in vivo metabolites may have stronger effects on the reuptake of norepinephrine and/or serotonin than quinupramine itself

SYN

References

^ Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug Directory (Book with CD-ROM). Boca Raton: Medpharm Scientific Publishers. p. 908. ISBN 3-88763-075-0.
^ José Miguel Vela; Helmut Buschmann; Jörg Holenz; Antonio Párraga; Antoni Torrens (2007). Antidepressants, Antipsychotics, Anxiolytics: From Chemistry and Pharmacology to Clinical Application. Weinheim: Wiley-VCH. p. 248. ISBN 978-3-527-31058-6.
^ Jump up to:^a ^b Sakamoto H, Yokoyama N, Kohno S, Ohata K (December 1984). “Receptor binding profile of quinupramine, a new tricyclic antidepressant”. Japanese Journal of Pharmacology. 36 (4): 455–60. doi:10.1254/jjp.36.455. PMID 6098759.
^ Kent, Angela; M. Billiard (2003). Sleep: physiology, investigations, and medicine. New York: Kluwer Academic/Plenum. p. 233. ISBN 0-306-47406-9.

- DOS 2 030 492 (Sogeras; appl. 20.6.1970; GB-prior. 20.6.1969).
- GB 1 252 320 (Sogeras; valid from 29.5.1970; prior. 20.6.1969).

Quinupramine
Clinical data

Routes of administration	Oral
ATC code	N06AA23 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life	33 hours
Identifiers
IUPAC name [show]
CAS Number	31721-17-2
PubChem CID	93154
ChemSpider	84098
UNII	29O61HFF4L
KEGG	D07336
ECHA InfoCard	100.046.149
Chemical and physical data
Formula	C₂₁H₂₄N₂
Molar mass	304.43 g/mol g·mol⁻¹

//////////////Quinupramine, キヌプラミン

TENAPANOR

June 28, 2019 9:45 am / Leave a comment

ChemSpider 2D Image | Tenapanor | C50H66Cl4N8O10S2

Image result for tenapanor

2D chemical structure of 1234423-95-0

Tenapanor

Molecular FormulaC₅₀H₆₆Cl₄N₈O₁₀S₂

Average mass1145.049 Da

1234423-95-0 [RN]

1234423-95-0 (free base) 1234365-97-9 (2HCl)

9652

3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl)benzenesulfonamide

Benzenesulfonamide, N,N’-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]-

12,15-Dioxa-2,7,9-triazaheptadecanamide, 17-[[[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulfonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulfonyl]amino]ethoxy]ethoxy]ethyl]-8-oxo-

1-[2-[2-[2-[[3-[(4S)-6,8-dichloro-2-methyl-3,4-dihydro-1H-isoquinolin-4-yl]phenyl]sulfonylamino]ethoxy]ethoxy]ethyl]-3-[4-[2-[2-[2-[[3-[(4S)-6,8-dichloro-2-methyl-3,4-dihydro-1H-isoquinolin-4-yl]phenyl]sulfonylamino]ethoxy]ethoxy]ethylcarbamoylamino]butyl]urea

17-[[[3-[(4S)-6,8-Dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulfonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulfonyl]amino]ethoxy]ethoxy]ethyl]-8-oxo-12,15-dioxa-2,7,9-triazaheptadecanamide

WYD79216A6

AZD1722

N,N’-(10,17-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-4-isoquinolinyl]benzenesulfonamide}

N,N’-(10,17,-Dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(((4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide)

RDX-5791

UNII:WYD79216A6

Inhibits intestinal sodium-hydrogen exchanger 3.

Tenapanor, also known as AZD-1722 and RDX 5791, is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. Tenapanor possesses an excellent preclinical safety profile and, as of now, there are no serious concerns about its side effects.

Tenapanor is a drug developed by Ardelyx, which acts as an inhibitor of the sodium-proton exchanger NHE3. This antiporterprotein is found in the kidney and intestines, and normally acts to regulate the levels of sodium absorbed and secreted by the body. When administered orally, tenapanor selectively inhibits sodium uptake in the intestines, limiting the amount absorbed from food, and thereby reduces levels of sodium in the body.^[1] This may make it useful in the treatment of chronic kidney disease and hypertension, both of which are exacerbated by excess sodium in the diet.^[2]

Ardelyx and licensees Kyowa Hakko Kirin and Fosun Pharma are developing tenapanor, an NHE3 (Na+/H+ exchange-3) inhibitor that increases fluid content in the GI tract and which also reduces GI tract pain via an unknown TRPV-1-dependent pathway, for treating constipation-predominant irritable bowel syndrome (IBS-C) and hyperphosphatemia in patients with end stage renal disease (ESRD).

Syn

PATENT

WO2010078449

PATENT

WO-2019091503

A novel crystalline form of tenapanor free base, process for its preparation, composition comprising it and its use for the preparation of tenapanor with chemical purity >98.8% is claimed. Also claimed are salt forms of tenapanor, preferably tenapanor phosphate and their use for treating irritable bowel syndrome, constipation, hyperphosphatemia, final stage renal failure, chronic kidney disease and preventing excess sodium in patients with kidney and heart conditions. Further claimed are processes for the preparation of tenapanor comprising the steps of reaction of a diamine compound with 1,4-diisocyanatobutane, followed by deprotection and condensation to obtain tenapanor. Novel intermediates of tenapanor and their use for the preparation of tenapanor are claimed. Tenapanor is known to be a sodium hydrogen exchanger 3 inhibitor and analgesic.

enapanor, having the chemical name 17-[[[3-[(4S)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulphonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl -4-isoquinolinyl] phenyl] sulphonyl] amino] ethoxy] ethoxy ] ethyl] – 8 -oxo- 12,15 -dioxa-2 ,7,9-triazaheptadecaneamide, is a selective inhibitor of the sodium protonic NHE3 antiporter. Orally administered tenapanor selectively inhibits the absorption of sodium in the intestine. This leads to an increase of water content in the digestive tract, improved bowel flow and normalization of the frequency of bowel movement and stool consistency. At the same time it exhibits antinociceptive activity and ability to lower serum phosphate levels. Because of these properties, it is clinically tested for the treatment of irritable bowel syndrome, especially when accompanied by constipation, treatment of hyperphosphatemia, especially in patients with dialysis with final stage renal failure, treatment of chronic kidney disease, and prevention of excess sodium in patients with kidney and heart conditions. The tenapanor molecule, which was first described in the international patent application WO 2010/078449, has the following structural formula:

In this document, tenapanor was prepared as bishydrochloride salt. The bishydrochloride salt was prepared only in the form of an amorphous foam, which, after solidification, required grinding for further processing. However, the thus obtained particles are of varying sizes, while a narrow particle size distribution is required for pharmaceutical use in order to ensure uniform behavior. The amorphous foam obtained in the said document is essentially a thickened reaction mixture or a slightly purified reaction mixture containing, in addition to tenapanor, various impurities. The possibilities to purify the reaction mixtures are limited. Moreover, amorphous foams tend to adsorb solvents, and it is usually difficult to remove (or dry out) the residual solvents from the amorphous foam. This is undesirable for pharmaceutical use. A typical feature of amorphous foams is a large specific surface, resulting in a greater interaction of the substance with the surrounding environment. This significantly increases the risk of decomposition of the substance, for example through air oxygen, moisture or light. The present invention aims at overcoming these problems.

It would be advantageous to provide tenapanor solid forms (tenapanor free base or tenapanor salts) which are precipitated in solid forms, thus allowing to filter off the liquid reaction mixture containing the impurities. This results in a significantly improved purity.

The process used in WO 2010/078449 for the preparation of bishydrochloride salt of tenapanor was based on the preparation of 3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzene-l-sulfonyl chloride of formula III from 4-(3-bromophenyl)-6,8-dichloro-2-methyl-l, 2,3,4-te

Scheme 1

The said document also discloses resolution of the starting tetrahydroisoquinoline of formula II by L-or D-dibenzoylt

(II) (S-II) (R-II)

Scheme 2

WO 2010/078449 discloses further steps of preparation of tenapanor, as shown in Scheme 3.

(V) (I)

Scheme 3

Individual synthetic steps described in Scheme 3 result in low yields: 42% for the reaction of the chloride of formula III with 2-(2-(2-aminoethoxy)ethoxy)ethylamine of formula IV, and 59% for the subsequent reaction with 1,4-diisocyanatobutane of formula V. The products of both synthetic steps are isolated by preparative chromatography which is technologically an unsuitable isolation and purification technique. The low yields and the need to use preparative chromatography for the isolation are caused by an abundance of side products and impurities and by the inability of the intermediates as well as of the product to provide a crystalline form.

Thus present invention thus further aims at providing a method of preparation of tenapanor which would be economically effective, in particular in relation to the expensive starting compound 4-(3-bromophenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline, and which would also enable industrial scale production, in particular by removing steps which cannot be scaled up effectively or which cannot be scaled up at all. Furthermore, the method of preparation of tenapanor should provide tenapanor in a form which is useful for use in pharmaceutical forms and does not have the disadvantages of an amorphous foam.

Tenapanor free base in the form of an amorphous solid foam was prepared by the procedure disclosed in patent application WO 2010/078449, Example 202. The chemical purity of the tenapanor prepared by this procedure was 96.5% (HPLC). The structure of tenapanor was verified by MS and H and ¹³C NMR spectra.

Step A

Preparation of (5)- -(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline

Potassium carbonate (9.30 g) and anhydrous xylene (500 ml) were added to the reaction vessel. Benzyl mercaptane (25 g) was added dropwise to the stirred mixture under ice -cooling. The resulting mixture was stirred at 25 °C for lh.

(S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline 50 g in anhydrous xylene (500 ml), Pd₂(dba)₃ (3 g) and Xantphos (3 g). The resulting solution was stirred at 25 °C for 30 minutes and then added to a solution of benzyl mercaptane. The resulting reaction mixture was maintained at 140 °C for 16 h. The mixture was then concentrated and the residue was subjected to preparative chromatography on silica gel with the mobile phase ethyl acetate / petroleum ether (1: 100-1 :50). 20 g of product are obtained as a yellow oil (36% yield).

Ste B

Preparation of (5) -3 -(6 , 8 -dichloro-2 -methyl- 1,2,3 ,4-tetr ahydroisoquinolin-4-yl)benzenesulf onyl chloride hydrochloride

(S)-4-(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline (16 g) was dissolved in the reaction vessel in acetic acid/water (160 mL: 16 mL) mixture. The mixture was cooled in an ice bath and then gaseous Cl₂ was introduced into the well stirred mixture. After disappearance of the starting material, the reaction mixture was purged with nitrogen and concentrated in vacuo. A product (10 g, 66.6%) was obtained as a colorless substance.

Step C

Preparation of (S)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l, 2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide

2-(2-(2-Aminoethoxy)ethoxy)ethylamine HC1 (30 g; 0.2 mol) and triethylamine (5.2 g; 52 mmol) were dissolved in dichloromethane (500 ml) and the mixture was chilled in an ice bath. (S)-3-(6,8-Dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonyl chloride hydrochloride (10 g; 26 mmol) was added in parts during 40 minutes to the chilled reaction mixture. The ice bath was removed and the reaction mixture was stirred at laboratory temperature for additional 30 minutes.

The dichloromethane solution was extracted three times by brine (2x 250 ml), dried over sodium sulphate, and concentrated in vacuo. The residue was purified using preparative chromatography on silica gel with dichloromethane-methanol mobile phase.

Yield 7.2 g. HRMS 502.1247 [M+H]⁺, C₂₂H₂₉CI₂N₃O₄S.

Step D

Preparation of 17-[[[3-[(4S)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulphonyl]amino]-N-[2-[2-[2-[[[3-[(4S)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl -4-isoquinolinyl] phenyl] sulphonyl] amino] ethoxy] ethoxy ] ethyl] – 8 -oxo- 12,15 -dioxa-2 ,7,9-triazah

(S)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (5g; 10 mmol) prepared in step A was dissolved in dichloromethane (50 ml). Triethylamine (1.5 g; 14.9 mmol) and 1 ,4-diisocyanatobutane (0.48 g; 3.4 mmol) were added to the solution. The reaction mixture was cooled using ice and stirred overnight. The resulting fine suspension was filtered off, the filtrate was concentrated and the obtained product was purified by preparative chromatography on on silica gel with dichloromethane-methanol mixture as a mobile phase

Yield: 2 g of tenapanor in the form of amorphous solid foam. HPLC purity 96.5 %.

HRMS 1143.3186 [M+H]⁺, C₅oH₆₆Cl₄N₈0₁₀S2. *H NMR (500MHz, DMSO, ppm):7.69-7.66 (m, 6H), 7.54-7.50 (m, 6H), 6.89 (bs, 2H), 5.9 (t, 2H), 5.79 (t, 2H), 4.4 (dd, 2H), 3.7 (dd, 4H), 3.44-3.44 (m, 8H), 3.35 (dd, 8H), 3.12 (dd, 4H), 2.96-2.64 (m, 12H), 2.37 (s, 6H), 1.31 (bs, 4H).

Ste E

Preparation of bishydrochloride salt of tenapanor

Tenapanor free base (1 g; 0.85 mmol) prepared in step B was dissolved in a mixture of methanol (10 ml) and 4M aqueous HCl (0.5 ml; 2 mmol) under mild reflux. The solution was concentrated on rotary vacuum evaporator, and the title product was obtained in the yield of 1 g of amorphous solid foam.

Example 1

Preparation of tenapanor, crystalline form I

Tenapanor free base (200 mg, 0.17 mmol), prepared as in step D of the comparative example, was dissolved in 0.4 ml acetonitrile under mild reflux. The clear solution was cooled at the rate of 1 °C/min with stirring to laboratory temperature (i.e., range from 22 °C to 26 °C) and then stirred for additional 2 hours at this temperature. The resulting crystals were isolated by filtration on sintered glass filter and dried for 6 hours in a vacuum oven at 40 °C. Crystallization yield was 170 mg of crystalline form I of tenapanor. HPLC showed a purity of 99.5%.

Examples 4 to 9 illustrate the inventive method of preparation of crystalline tenapanor.

Example 4

Preparation of (5)- -(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-l ,2,3,4-tetrahydroisoquinoline

DIPEA (9.6 mL) and anhydrous dioxane (100 mL) were added to a reaction vessel. Benzyl mercaptan (8.1 ml) was added dropwise to the stirred mixture under ice -cooling. The resulting mixture was stirred at 25 °C for lh.

In a second reaction vessel, (S)-4-(3-bromophenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline (21.2 g) in anhydrous dioxane (140 mL), Pd₂(dba)₃ (835 mg)and Xantphos (835 mg) were mixed. The resulting solution was stirred at 25 °C for 30 minutes and then added to the solution of benzyl mercaptan. The resulting reaction mixture was maintained at gentle reflux for 3 hours.

After cooling, the suspension obtained was filtered through a thin layer of celite. HC1 was added to the filtrate. The precipitated hydrochloride was isolated by filtration, washed well and dried. 21 g of pinkish product were obtained (81.6% yield).

Example 5

Preparation of (5) -3 -(6 , 8 -dichloro-2 -methyl- 1,2,3 ,4-tetr ahydroisoquinolin-4-yl)benzenesulf onyl chloride hydrochlorid

(S)-4-(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride (11.1 g) was stirred in DCM/2M HC1 (70 mL:6 mL) mixture in a reaction vessel. The mixture was cooled in an ice bath and then gaseous Cl₂ was introduced into the vigorously stirred mixture. After disappearance of the starting material, the resulting suspension was bubbled through by nitrogen and the product was filtered off and washed with DCM. 9.2 g of white product was obtained (82.7% yield).

Example 6

In the reaction vessel, t-butyl 2-(2-(2-amionoethoxy)ethoxy)ethylcarbamate (21.8 g) was stirred in DCM. The mixture was cooled in an ice bath under an inert atmosphere. To the cooled solution was

added 1 ,4-diisocyanatobutane (6.14 g) and TEA (0.1 mL). The cooling bath was removed and the reaction mixture was further stirred for 2 h.

35% HCl was added to the reaction mixture and the mixture was stirred under gentle reflux overnight.

After cooling, the precipitated product was filtered off and washed with DCM.

The product was recrystallized from propan-2-ol. 22.3 g of white product was obtained (80% yield).

Example 7

Preparation of (5)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l , 2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide

(S)-3-(6,8-dichloro-2-methyl-l ,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonyl chloride hydrochloride (11.7 g) prepared in Example 2 was stirred in dichloromethane (100 ml) and the suspension was cooled in an ice bath. To the cooled suspension was added a solution of t-butyl 2-(2-(2-amionoethoxy)ethoxy)ethylcarbamate (6.8 g) and DIPEA (14 ml) in DCM (50 ml). The resulting solution was stirred for 2 hours in an ice bath. The reaction mixture was extracted twice with water. Concentrated HCl (15 mL) was added to the dichloromethane solution and the mixture heated at gentle reflux for 2 h.

The precipitated product, after cooling, was extracted into water. The aqueous phase was separated and basified with Na₂C0₃. The product as the free base was extracted into DCM and the dichloromethane solution was dried over sodium sulfate and concentrated in vacuo. 12.9 g of product were obtained.

Yield 93.4%. HRMS 502.1247 [M+H]⁺, C₂₂H₂₉CI₂N₃O₄S.

Example 8

Preparation of 17-[[[3-[(45)-6,8-dichloro-l ,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl] sulfonyl]amino]-N-[2-[2-[2-[[[3-[(45)-6,8-dichloro-l ,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl] phenyl] sulf onyl] amino] ethoxy ] ethoxy ] ethyl] – 8 -oxo- 12,15 -dioxa-2 ,7 ,9-triazaheptadecanamide (tenapanor free base)

(S)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-l,2,3,4- tetrahydroisoquinolin- 4-yl)benzenesulfonamide (12.9 g) prepared in Example 4 was dissolved in dichloromethane (150 ml). To the solution was added triethylamine (0.3 ml) and 1,4-diisocyanatobutane (1.7 g). The reaction mixture was stirred at 25 °C for 2 h. The resulting reaction mixture was extracted with water and aqueous Na₂C0₃. The dichloromethane solution of the product was dried over sodium sulfate and concentrated to a solid foam. Yield 13.9 g. The crude product was taken up in acetone (100 ml) and then recrystallized from methanol (80 ml). 7.3 g of white crystalline product was obtained. Yield 49.8%.

HRMS 1143.3186 [M+H]⁺, C₅oH₆₆Cl₄N₈0₁₀S₂. ^!H NMR (500MHz, DMSO, ppm):7.69-7.66 (m, 6H), 7.54-7.50 (m, 6H), 6.89 (bs, 2H), 5.9 (t, 2H), 5.79 (t, 2H), 4.4 (dd, 2H), 3.7 (dd, 4H), 3.44-3.44 (m, 8H), 3.35 (dd, 8H), 3.12 (dd, 4H), 2.96-2.64 (m, 12H), 2.37 (s, 6H), 1.31 (bs, 4H)

Example 9

Preparation of 17-[[[3-[(45)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl] sulfonyl]amino]-N-[2-[2-[2-[[[3-[(45)-6,8-dichloro-l,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl] phenyl] sulf onyl] amino] ethoxy ] ethoxy ] ethyl] – 8 -oxo- 12,15 -dioxa-2 ,7 ,9-

(S)-3-(6,8-dichloro-2-methyl-l,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonyl chloride hydrochloride (0.81 g) prepared in Example 2 and l,l’-(butane-l,4-diyl)bis(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)urea) dihydrochloride prepared according to Example 3 (0.48 g) were stirred in anhydrous ΝΜΡ (10 ml). To the suspension was added DIPEA (2 mL) and the resulting solution was stirred at 60 °C for 1.5 h. Water (10 mL) was added dropwise to the reaction mixture and the mixture was cooled to 5 °C. The precipitated product was isolated and stirred in acetone at 5 °C overnight. The beige product was filtered off (0.67 g) and recrystallized from methanol (12 ml).

0.53 g of a colorless crystalline product was obtained.

Yield 78.7 %. HRMS 502.1247 [M+H]⁺, C₂₂H₂₉CI₂N₃O₄S. DSC analysis showed the melting temperature of 130.5 °C.

Example 10

Tenapanor (1.48 g, 1.3 mmol) is dissolved in 10 ml of tetrahydrofurane (THF). From the thus prepared solution, 1 ml is taken and phosphoric acid (0.4 mmol) is added. The mixture is stirred at room temperature for 24 hours. Salt of tenapanor with phosphoric acid precipitated from the solution in solid stable form, the salt was filtered off, washed with THF and dried by stream of inert gas. XRPD confirmed amorphousness of the product.

Example 11

Tenapanor (1.48 g, 1.3 mmol) is dissolved in 10 ml of tetrahydrofurane (THF). From the thus prepared solution, 1 ml is taken and hydrobromic acid (0.4 mmol) is added. The mixture is stirred at room temperature for 24 hours. Salt of tenapanor with hydrobromic acid precipitated from the solution in solid stable form, the salt was filtered off, washed with THF and dried by stream of inert gas. XRPD confirmed amorphousness of the product.

Example 12

Tenapanor (1.48 g, 1.3 mmol) is dissolved in 10 ml of acetone. From the thus prepared solution, 1 ml is taken and phosphoric acid (0.4 mmol) is added. The mixture is stirred at room temperature for 24 hours. Salt of tenapanor with phosphoric acid precipitated from the solution in solid stable form, the salt was filtered off, washed with acetone and dried by stream of inert gas. XRPD confirmed amorphousness of the product.

Example 13

Tenapanor (1.48 g, 1.3 mmol) is dissolved in 10 ml of acetone. From the thus prepared solution, 1 ml is taken and citric acid (0.4 mmol) is added. The mixture is stirred at room temperature for 24 hours. Salt of tenapanor with citric acid precipitated from the solution in solid stable form, the salt was filtered off, washed with acetone and dried by stream of inert gas. XRPD confirmed amorphousness of the product.

Other pharmaceutically acceptable acids were tested by the procedures shown in Examples 10-13, but did not yield salts which would precipitate in amorphous stable solid form from the solution. The tested acids were: methanesulfonic acid, benzenesulfonic acid, oxalic acid, maleinic acid, tartaric acid, fumaric acid, trichloroacetic acid.

Example 14

Tenapanor (500 mg, 0.44 mmol) is dissolved in 20 ml of THF at 45 °C. To this clear solution, a solution of phosphoric acid in THF (50 μ1/5 ml) is added dropwise during 10 minutes. The resulting suspension is stirred at room temperature for 30 minutes. The precipitated salt of tenapanor with phosph (79 %) oric is filtered off, washed with 3 ml of THF and dried by stream of inert gas. Yield: 430 mg of colourless salt of tenapanor with phosphoric acid. XRPD showed amorphousness of the product.

Example 15

Tenapanor (500 mg, 0.44 mmol) is dissolved in 20 ml of THF at 45 °C. To this clear solution, hydrobromic acid (48%; 100 μΐ) is added dropwise during 10 minutes. A fine precipitate forms already during the dropwise addition of HBr, and the suspension is stirred at room temperature for 30 minutes. The precipitated salt of tenapanor with HBr is filtered off, washed with 3 ml of THF and dried by stream of inert gas. Yield: 397 mg (69 %) of colourless salt of tenapanor with HBr (1 :2). XRPD showed amorphousness of the product.

References

^ Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D (2014). “Intestinal inhibition of the na+/h+ exchanger 3 prevents cardiorenal damage in rats and inhibits na+ uptake in humans”. Sci Transl Med. 6 (227): 227ra36. doi:10.1126/scitranslmed.3007790. PMID 24622516.
^ Salt-buster drug cuts sodium absorbed from food. New Scientist, 14 March 2014

REFERENCES

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Tenapanor
Clinical data

Routes of administration	Oral
Identifiers
IUPAC name [show]
CAS Number	1234423-95-0
PubChem CID	71587953
ChemSpider	32056950
CompTox Dashboard (EPA)	DTXSID40154016
ECHA InfoCard	100.243.471
Chemical and physical data
Formula	C₅₀H₆₆Cl₄N₈O₁₀S₂
Molar mass	1145.046 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CN1C[C@H](C2=C(C1)C(=CC(=C2)Cl)Cl)C3=CC(=CC=C3)S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)C4=CC=CC(=C4)[C@@H]5CN(CC6=C5C=C(C=C6Cl)Cl)C
InChI [hide] InChI=1S/C50H66Cl4N8O10S2/c1-61-31-43(41-27-37(51)29-47(53)45(41)33-61)35-7-5-9-39(25-35)73(65,66)59-15-19-71-23-21-69-17-13-57-49(63)55-11-3-4-12-56-50(64)58-14-18-70-22-24-72-20-16-60-74(67,68)40-10-6-8-36(26-40)44-32-62(2)34-46-42(44)28-38(52)30-48(46)54/h5-10,25-30,43-44,59-60H,3-4,11-24,31-34H2,1-2H3,(H2,55,57,63)(H2,56,58,64)/t43-,44-/m0/s1 Key:DNHPDWGIXIMXSA-CXNSMIOJSA-N

//////////////Tenapanor, AZD 1722, RDX 5791, chronic kidney disease, hypertension

CN1CC(C2=CC(=CC(=C2C1)Cl)Cl)C3=CC(=CC=C3)S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)C4=CC=CC(=C4)C5CN(CC6=C(C=C(C=C56)Cl)Cl)C

Etosalamide, этосаламид , إيتوسالاميد , 依托柳胺 ,

May 15, 2019 9:36 am / Leave a comment

Image result for Etosalamide

Etosalamide

ethosalamide

Cas 15302-15-5
Chemical Formula: C11H15NO3
Molecular Weight: 209.245

o-(2-Ethoxyethoxy)benzamide

1585

1PU994YJUH

этосаламид [Russian] [INN]

إيتوسالاميد [Arabic] [INN]

依托柳胺 [Chinese] [INN]

2-(2-ethoxyethoxy)benzamide

Etosalamide, also known as Ethosalamide, is an antipyretic and analgesics agent

SYN

CAS:592-55-2, 2-Bromoethyl ethyl ether

Cas, 611-20-1, 2-Hydroxybenzonitrile

PATENT

DE 1013643

PATENT

GB 774635

PATENT

US2822391

78 – 79 MP

PAPER

Journal of Chemical and Engineering Data (1962), 7, 265-6

70 – 71.5 MP

PATENT

WO 2004003198

US 20100226943

/////////Etosalamide, этосаламид , إيتوسالاميد , 依托柳胺 , ethosalamide

O=C(N)C1=CC=CC=C1OCCOCC

KETOROLAC

May 4, 2019 1:50 pm / Leave a comment

Ketorolac

Molecular FormulaC₁₅H₁₃NO₃
Average mass255.269 Da

1H-Pyrrolizine-1-carboxylic acid, 5-benzoyl-2,3-dihydro-

413572 [Beilstein]

5-(Phenylcarbonyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid

5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid

5-Benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid

74103-06-3 [RN]

Ketorolac

CAS Registry Number: 74103-06-3

CAS Name: 5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid

Additional Names: 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid

Manufacturers’ Codes: RS-37619

Molecular Formula: C15H13NO3

Molecular Weight: 255.27

Percent Composition: C 70.58%, H 5.13%, N 5.49%, O 18.80%

Literature References: Prostaglandin biosynthesis inhibitor. Prepn and separation of isomers: BE 856681; J. M. Muchowski, A. F. Kluge, US 4089969 (both 1978 to Syntex). Alternate processes: J. M. Muchowski, R. Greenhouse, US 4347186 (1982 to Syntex); F. Franco et al., J. Org. Chem. 47, 1682 (1982); J. B. Doherty, US 4496741 (1985 to Merck & Co.). Absolute configuration: A. Guzman et al., J. Med. Chem. 29, 589 (1986). Structure-activity relationships: J. M. Muchowski et al., ibid. 28, 1037 (1985). Pharmacology and analgesic, anti-inflammatory profile of ketorolac and its tromethamine salt: W. H. Rooks et al., Agents Actions12, 684 (1982); eidem, Drugs Exp. Clin. Res. 11, 479 (1985). Clinical comparison with acetaminophen in post-operative pain: H. J. McQuay et al., Clin. Pharmacol. Ther. 39, 89 (1986).

Properties: Crystals from ethyl acetate + ether, mp 160-161°. uv max in methanol: 245, 312 nm (e 7080, 17400). pKa 3.49 ±0.02. LD50 orally in mice: ~200 mg/kg (Rooks).

Melting point: mp 160-161°

pKa: pKa 3.49 ±0.02

Absorption maximum: uv max in methanol: 245, 312 nm (e 7080, 17400)

Toxicity data: LD50 orally in mice: ~200 mg/kg (Rooks)

Derivative Type: (±)-Form tromethamine salt

CAS Registry Number: 74103-07-4

Trademarks: Acular (Allergan); Dolac (Syntex); Lixidol (Farmitalia); Tarasyn (Syntex); Toradol (Syntex); Toratex (Syntex)

Molecular Formula: C19H24N2O6

Molecular Weight: 376.40

Percent Composition: C 60.63%, H 6.43%, N 7.44%, O 25.50%

Derivative Type: (+)-Form

Properties: Crystals from hexane + ethyl acetate, mp 174° (Guzman); also reported as mp 154-156° (Muchowski, Kluge). [a]D+173° (c = 1 in methanol).

Melting point: mp 174° (Guzman); mp 154-156° (Muchowski, Kluge)

Optical Rotation: [a]D +173° (c = 1 in methanol)

Derivative Type: (-)-Form

Properties: Crystals from hexane + ethyl acetate, mp 169-170° (Guzman); also reported as mp 153-155° (Muchowski, Kluge). [a]D-176° (c = 1 in methanol).

Melting point: mp 169-170° (Guzman); mp 153-155° (Muchowski, Kluge)

Optical Rotation: [a]D -176° (c = 1 in methanol)

Therap-Cat: Analgesic; anti-inflammatory.

Keywords: Analgesic (Non-Narcotic); Anti-inflammatory (Nonsteroidal); Arylcarboxylic Acids.

Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain.^[1]Specifically it is recommended for moderate to severe pain.^[2] Recommended duration of treatment is less than six days.^[1] It is used by mouth, by injection into a vein or muscle, and as eye drops.^[1]^[2] Effects begin within an hour and last for up to eight hours.^[1]

Common side effects include sleepiness, dizziness, abdominal pain, swelling, and nausea.^[1] Serious side effects may include stomach bleeding, kidney failure, heart attacks, bronchospasm, heart failure, and anaphylaxis.^[1] Use is not recommended during the last part of pregnancy or during breastfeeding.^[1] Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2) thereby decreasing prostaglandins.^[1]^[3]

Ketorolac was patented in 1976 and approved for medical use in 1989.^[4]^[1] It is avaliable as a generic medication.^[2] In the United Kingdom it costs the NHS less than a £ per injectable dose as of 2019.^[2] In the United States the wholesale cost of this amount is about 1.50 USD.^[5] In 2016 it was the 296th most prescribed medication in the United States with more than a million prescriptions.^[6]

Medical uses

Ketorolac is used for short-term management of moderate to severe pain.^[7]It is usually not prescribed for longer than five days.^[8]^[9]^[10]^[11] Ketorolac is effective when administered with paracetamol to control pain in neonates because it does not depress respiration as do opioids.^[12] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea.^[11] Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation.^[13]

Ketorolac is used for short-term pain control not lasting longer than five days, and can be administered orally, by intramuscular injection, intravenously, and by nasal spray.^[8] Ketorolac is initially administered by intramuscular injection or intravenously.^[7] Oral therapy is only used as a continuation from the intramuscular or intravenous starting point.^[8]^[12]

Ketorolac is used during eye surgery help with pain.^[14] Ketorolac is effective in treating ocular itching.^[15] The ketorolac ophthalmic formulation is associated with a decreased development of macular edema after cataract surgery and is more effective alone rather than as an opioid/ketorolac combination treatment.^[16]^[17] Ketorolac has also been used to manage pain from corneal abrasions.^[18]

During treatment with ketorolac, clinicians monitor for the manifestation of adverse effects and side effects. Lab tests, such as liver function tests, bleeding time, BUN, serum creatinine and electrolyte levels are often used and help to identify potential complications.^[8]^[9]

Contraindications

Ketorolac is contraindicated in those with hypersensitivity, allergies to the medication, cross-sensitivity to other NSAIDs, prior to surgery, history of peptic ulcer disease, gastrointestinal bleeding, alcohol intolerance, renal impairment, cerebrovascular bleeding, nasal polyps, angioedema, and asthma.^[8]^[9] Recommendations exist for cautious use of ketorolac in those who have experienced cardiovascular disease, myocardial infarction, stroke, heart failure, coagulation disorders, renal impairment, and hepatic impairment.^[8]^[9]

Adverse effects

Though uncommon, potentially fatal adverse effects are stroke, myocardial infarction, GI bleeding, Stevens-Johnson Syndrome, toxic epidermal necrolysis and anaphylaxis. A less serious and more common (>10%) side effect is drowsiness. Infrequent (<1%) side effects are paresthesia, prolonged bleeding time, injection site pain, purpura, sweating, abnormal thinking, increased production of tears, edema, pallor, dry mouth, abnormal taste, urinary frequency, increased liver enzymes, itching and others. Ketorolac can cause premature constriction of the ductus arteriosis in an infant during the third trimester of pregnancy.^[8]^[9] Platelet function is decreased related to the use of ketorolac.^[19]

The practice of restricting treatment with ketorolac is due to its potential to cause kidney damage.^[20]

Interactions

Ketorolac can interact with other medications. Probenecid can increase the probability of having an adverse reaction or experiencing a side effect when taken with ketorolac. Pentoxifylline can increase the risk of bleeding. When aspirin is taken at the same time as ketorolac, the effectiveness is decreased. Problematic GI effects are additive and become more likely if potassium supplements, aspirin, other NSAIDS, corticosteroids, or alcohol is taken at the same time. The effectiveness of antihypertensives and diuretics can be lowered. The use of ketorolac can increase serum lithium levels to the point of toxicity. Toxicity to methotrexate is more likely if ketorolac is taken at the same time. The risk of bleeding increases with the concurrent medications clopidogrel, cefoperazone, valproic acid, cefotetan, eptifibatide, tirofiban, and copidine. Anticoagulants and thrombolytic medications also increase the likelihood of bleeding. Medications used to treat cancer can interact with ketorolac along with radiation therapy. The risk of toxicity to the kidneys increases when ketorolac is taken with cyclosporine.^[8]^[9]

Interactions with ketorolac exist with some herbal supplements. The use of Panax ginseng, clove, ginger, arnica, feverfew, dong quai, chamomile, and Ginkgo biloba increases the risk of bleeding.^[8]^[9]

Mechanism of action

The primary mechanism of action responsible for ketorolac’s anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor.^[21] Ketorolac has been assessed to be a relatively higher risk NSAID when compared to aceclofenac, celecoxib, and ibuprofen.^[13] It is considered a first-generation NSAID.^[19]

History

In the US, ketorolac was the only widely available intravenous NSAID for many years; an IV form of paracetemol, which is not an NSAID, became available in Europe in 2009 and then in the US.^[12]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular around 2006.^{[citation needed]}

In 2007, there were concerns about the high incidence of reported side effects. This led to restriction in its dosage and maximum duration of use. In the UK, treatment was initiated only in a hospital, although this was not designed to exclude its use in prehospital care and mountain rescue settings.^[7] Dosing guidelines were published at that time.^[22]

Concerns over the high incidence of reported side effects with ketorolac trometamol led to its withdrawal (apart from the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide.^[23]

The eye-drop formulation was approved by the FDA in 1992.^[24] An intranasal formulation was approved by the FDA in 2010^[25] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.

Synthesis

DOI: 10.1021/jo00348a014

Image result for Ketorolac SYNTHESIS

1H-Pyrrolizine-1-carboxylic acid, 2,3-dihydro-5-benzoyl-, (+-)-, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Ketorolac

2-Methylthiopyrrole (I) is benzoylated with N,N-dimethylbenzamide (II) to produce 5-benzoyl-2-methylthiopyrrole (III) in the presence of POCl₃ in refluxing CH₂Cl₂, and the yielding product is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) in the presence of NaH in DMF giving compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH₂Cl₂affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol.Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.

SYN

DE 2731678; ES 460706; ES 470214; FR 2358406; FR 2375234; GB 1554075

The condensation of dimethylacetone-1,3-dicarboxylate (X) with ethanolamine (XI) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (XII), which is cyclized with bromoacetaldehyde diethylacetal (XIII) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (XIV). Acylation of (XIV) with methanesulfonyl chloride (XV) and triethylamine in CH2Cl2 yields the corresponding mesylate (XVI), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (XVII). The cyclization of (XVII) with NaH in DMF yields dimethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (XVIII), which is hydrolyzed with KOH in refluxing methanol – water to the corresponding diacid (XIX). Partial esterification of (XIX) with isopropanol and HCl gives isopropyl 1,2-dihydro-3H-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (XX), which is decarboxylated by heating at 270 C affording isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXI). Benzoylation of (XXI) with N,N-dimethylbenzamide (XXII) and POCl3 in refluxing CH2Cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXIII), which is finally hydrolyzed with K2CO3 or NaOH in methanol – water.

SYN2

The benzoylation of 2-methylthiopyrrole (I) with N,N-dimethylbenzamide (II) by means of POCl3 in refluxing CH2Cl2 gives 5-benzoyl-2-methylthiopyrrole (III), which is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) by means of NaH in DMF yielding compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2 affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol. Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Ketorolac Tromethamine Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
^ Jump up to:^a ^b ^c ^d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1144, 1302–1303. ISBN 9780857113382.
^ “DailyMed – ketorolac tromethamine tablet, film coated”. dailymed.nlm.nih.gov. Retrieved 14 April 2019.
^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 521. ISBN 9783527607495.
^ “NADAC as of 2019-02-27”. Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
^ “The Top 300 of 2019”. clincalc.com. Retrieved 22 December 2018.
^ Jump up to:^a ^b ^c Mallinson, Tom (2017). “A review of ketorolac as a prehospital analgesic”. Journal of Paramedic Practice. 9 (12): 522–526. doi:10.12968/jpar.2017.9.12.522. Retrieved 2 June 2018.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ Vallerand, April H. (2017). Davis’s Drug Guide for Nurses. Philadelphia: F.A. Davis Company. p. 730. ISBN 9780803657052.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g Physician’s Desk Reference 2017. Montvale, New Jersey: PDR, LLC. 2017. pp. S–474–5. ISBN 9781563638381.
^ “Ketorolac-tromethamine”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
^ Jump up to:^a ^b Henry, p. 291.
^ Jump up to:^a ^b ^c Martin, Lizabeth D; Jimenez, Nathalia; Lynn, Anne M (2017). “A review of perioperative anesthesia and analgesia for infants: updates and trends to watch”. F1000Research. 6: 120. doi:10.12688/f1000research.10272.1. ISSN 2046-1402. PMC 5302152. PMID 28232869.
^ Jump up to:^a ^b Schwier, Nicholas; Tran, Nicole (2016). “Non-Steroidal Anti-Inflammatory Drugs and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic Pericarditis”. Pharmaceuticals. 9 (2): 17. doi:10.3390/ph9020017. ISSN 1424-8247. PMC 4932535. PMID 27023565.
^ Saenz-de-Viteri, Manuel; Gonzalez-Salinas, Roberto; Guarnieri, Adriano; Guiaro-Navarro, María Concepción (2016). “Patient considerations in cataract surgery – the role of combined therapy using phenylephrine and ketorolac”. Patient Preference and Adherence. 10: 1795–1801. doi:10.2147/PPA.S90468. ISSN 1177-889X. PMC 5029911. PMID 27695298.
^ Karch, Amy (2017). Focus on nursing pharmacology. Philadelphia: Wolters Kluwer. p. 272. ISBN 9781496318213.
^ Lim, Blanche X; Lim, Chris HL; Lim, Dawn K; Evans, Jennifer R; Bunce, Catey; Wormald, Richard; Wormald, Richard (2016). “Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery”. Cochrane Database Syst Rev. 11: CD006683. doi:10.1002/14651858.CD006683.pub3. PMID 27801522.
^ Sivaprasad, Sobha; Bunce, Catey; Crosby-Nwaobi, Roxanne; Sivaprasad, Sobha (2012). “Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery”. Cochrane Database Syst Rev (2): CD004239. doi:10.1002/14651858.CD004239.pub3. PMID 22336801.
^ Wakai A, Lawrenson JG, Lawrenson AL, Wang Y, Brown MD, Quirke M, Ghandour O, McCormick R, Walsh CD, Amayem A, Lang E, Harrison N (2017). “Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions”. Cochrane Database Syst Rev. 5: CD009781. doi:10.1002/14651858.CD009781.pub2. PMID 28516471.
^ Jump up to:^a ^b Henry, p. 279.
^ Henry, p. 280.
^ Lee, I. O.; Seo, Y. (2008). “The Effects of Intrathecal Cyclooxygenase-1, Cyclooxygenase-2, or Nonselective Inhibitors on Pain Behavior and Spinal Fos-Like Immunoreactivity”. Anesthesia & Analgesia. 106 (3): 972–977, table 977 contents. doi:10.1213/ane.0b013e318163f602. PMID 18292448.
^ MHRA Drug Safety Update October 2007, Volume 1, Issue 3, pp 3-4.
^ Committee on the Safety of Medicines, Medicines Control Agency: Ketorolac: new restrictions on dose and duration of treatment. Current Problems in Pharmacovigilance:June 1993; Volume 19 (pages 5-8).
^ “Ketorolac ophthalmic medical facts from”. Drugs.com. Retrieved 2013-10-06.
^ “Sprix Information from”. Drugs.com. Retrieved 2013-10-06.

Bibliography

AHFS drug information. Bethesda, MD: American Society of Health-System Pharmacists. 2011. ISBN 9781585282609.
Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 9. ISBN 9781284057560.
Handley, Dean A.; Cervoni, Peter; McCray, John E.; McCullough, John R. (1998). “Preclinical enantioselective pharmacology of (R)- and (S)- ketorolac”. J Clin Pharmacol. 38 (2 Suppl): 25S–35S. doi:10.1002/j.1552-4604.1998.tb04414.x. ISSN 0091-2700. PMID 9549656.
Henry, Norma (2016). RN pharmacology for nursing : review module. Overland Park, KS: Assessment Technologies Institute. ISBN 9781565335738.
Kizior, Robert (2017). Saunders nursing drug handbook 2017. St. Louis, MO: Elsevier. ISBN 9780323442916.

External links

DailyMed

Ketorolac
Clinical data


Trade names	Toradol, Acular, Sprix, others
Synonyms	Ketorolac tromethamine
AHFS/Drugs.com	Monograph
MedlinePlus	a693001
License data	EU EMA: by INN US DailyMed: 9090 US FDA: Toradol
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	By mouth, IM, IV, eye drops
ATC code	M01AB15 (WHO) S01BC05 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	100% (All routes)
Metabolism	Liver
Elimination half-life	3.5 h to 9.2 h, young adults; 4.7 h to 8.6 h, elderly (mean age 72)
Excretion	Kidney: 91.4% (mean) Biliary: 6.1% (mean)
Identifiers
IUPAC name [show]
CAS Number	74103-06-3
PubChem CID	3826
DrugBank	DB00465
ChemSpider	3694
UNII	YZI5105V0L
KEGG	D08104
ChEBI	CHEBI:6129
ChEMBL	ChEMBL469
PDB ligand	KTR (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID8023189
ECHA InfoCard	100.110.314
Chemical and physical data
Formula	C₁₅H₁₃NO₃
Molar mass	255.27 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES [hide] O=C(c1ccc2n1CCC2C(=O)O)c3ccccc3
InChI [hide] InChI=1S/C15H13NO3/c17-14(10-4-2-1-3-5-10)13-7-6-12-11(15(18)19)8-9-16(12)13/h1-7,11H,8-9H2,(H,18,19) Key:OZWKMVRBQXNZKK-UHFFFAOYSA-N

//////////Ketorolac,

Cefamandole, セファマンドール ,цефамандол , سيفاماندول , 头孢孟多 ,

April 17, 2019 9:21 am / Leave a comment

Cefamandole

ChemSpider 2D Image | Cefamandole | C18H18N6O5S2

Image result for Cefamandole

Cefamandole

セファマンドール

цефамандол [Russian] [INN]

سيفاماندول [Arabic] [INN]

头孢孟多 [Chinese] [INN]

CAS Registry Number: 34444-01-4

CAS Name: (6R,7R)-7-[[(2R)-Hydroxyphenylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Additional Names: 7-mandelamido-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-D-mandelamido-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-3-cephem-4-carboxylic acid; 7-D-mandelamido-3-(1-methyl-1,2,3,4-tetrazole-5-thiomethyl)-D3-cephem-4-carboxylic acid; CMT

Manufacturers’ Codes: compd 83405

Molecular Formula: C18H18N6O5S2

Molecular Weight: 462.50

Percent Composition: C 46.74%, H 3.92%, N 18.17%, O 17.30%, S 13.87%

Literature References: Broad-spectrum semi-synthetic cephalosporin antibiotic. Prepn: C. W. Ryan, DE 2018600; idem, US3641021 (1970, 1972 to Lilly); J. M. Greene, DE 2312997; idem, US 3840531 (1973, 1974 to Lilly). Biological properties: W. E. Wick, D. A. Preston, Antimicrob. Agents Chemother. 1, 221 (1972). Antibacterial activity: S. Eykyn et al., ibid. 3, 657 (1973); H. C. Neu, ibid. 6, 177 (1974); A. D. Russell, J. Antimicrob. Chemother. 1, 97 (1975). Pharmacologic studies: B. R. Meyers et al.,Antimicrob. Agents Chemother. 9, 140 (1976); R. S. Griffith et al., ibid. 10, 814 (1976). Comprehensive description: R. H. Bishara, E. C. Rickard, Anal. Profiles Drug Subs. 9, 125-154 (1980).

Derivative Type: Nafate

CAS Registry Number: 42540-40-9

Trademarks: Bergacef (Bergamon); Cedol (Tiber); Cefam (Magis); Cefiran (Poli); Cemado (Francia); Cemandil (SIT); Fado (Errekappa); Kefadol (Lilly); Kefandol (Lilly); Lampomandol (AGIPS); Mandokef (Lilly); Mandol (Lilly); Mandolsan (San Carlo); Neocefal (Metapharma); Pavecef (IBP)

Molecular Formula: C19H17N6NaO6S2

Molecular Weight: 512.49

Percent Composition: C 44.53%, H 3.34%, N 16.40%, Na 4.49%, O 18.73%, S 12.51%

Properties: White, odorless needles, mp 190° (dec). uv max (H2O): 269 nm (e 10800). pKa 2.6-3.0. Sol in water, methanol. Practically insol in ether, chloroform, benzene, cyclohexane.

Melting point: mp 190° (dec)

pKa: pKa 2.6-3.0

Absorption maximum: uv max (H2O): 269 nm (e 10800)

Therap-Cat: Antibacterial.

Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.

Use:antibiotic
Chemical name:[6R-[6α,7β(R*)]]-7-[(hydroxyphenylacetyl)amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Formula:C₁₈H₁₈N₆O₅S₂

MW:462.51 g/mol
CAS-RN:34444-01-4
InChI Key:OLVCFLKTBJRLHI-AXAPSJFSSA-N
InChI:InChI=1S/C18H18N6O5S2/c1-23-18(20-21-22-23)31-8-10-7-30-16-11(15(27)24(16)12(10)17(28)29)19-14(26)13(25)9-5-3-2-4-6-9/h2-6,11,13,16,25H,7-8H2,1H3,(H,19,26)(H,28,29)/t11-,13-,16-/m1/s1
EINECS:252-030-0

Derivatives

Formate monosodium salt (nafate)

Formula:C₁₉H₁₇N₆NaO₆S₂
MW:512.50 g/mol
CAS-RN:42540-40-9
EINECS:255-877-4
LD₅₀:3915 mg/kg (M, i.v.);
2562 mg/kg (R, i.v.)

Cefamandole (INN, also known as cephamandole) is a second-generation broad-spectrum cephalosporin antibiotic. The clinically used form of cefamandole is the formate estercefamandole nafate, a prodrug which is administered parenterally. Cefamandole is no longer available in the United States.

The chemical structure of cefamandole, like that of several other cephalosporins, contains an N-methylthiotetrazole (NMTT or 1-MTT) side chain. As the antibiotic is broken down in the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of the enzyme vitamin K epoxide reductase)(vitamin K supplement is recommended during therapy) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase.

Cefamandole has a broad spectrum of activity and can be used to treat bacterial infections of the skin, bones and joints, urinary tract, and lower respiratory tract. The following represents cefamandole MIC susceptibility data for a few medically significant microorganisms.

Escherichia coli: 0.12 – 400 μg/ml
Haemophilus influenzae: 0.06 – >16 μg/ml
Staphylococcus aureus: 0.1 – 12.5 μg/ml

^[1]

CO₂ is generated during the normal constitution of cefamandole and ceftazidime, potentially resulting in an explosive-like reaction in syringes.^[2]

SYNTHESIS

US 3641021

US 3840531 US 3974153 US 3903278 US 2018600 US 2065621 DE 2018600 DE 2065621 DE 2730579

DE 2312997

SYN

The formylation of 7-aminocephalosporanic acid (I) by the usual techniques produces 7-formamidocephalosporanic acid (II), which is then treated with the sodium salt of 1-methyl-1H-tetrazole-5-thiol (III) to yield 7-formamido-3-(1-methyl-1H-tetrazol-5-ylthio)methyl-3-cephem-4-carboxylic acid (IV). The resulting product (IV) is deformylated affording 7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)methyl-3-cephem-4-carboxylic acid (V), which is finally acylated with anhydro-O-carboxymandelic acid (VI) using the usual techniques.

References

^ http://www.toku-e.com/Assets/MIC/Cefamandole%20sodium%20salt.pdf
^ Stork CM (2006). “Antibiotics, antifungals, and antivirals”. In Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA. Goldfrank’s toxicologic emergencies. New York: McGraw-Hill. p. 847. ISBN 0-07-143763-0. Retrieved 2009-07-03.

- US 3 641 021 (Lilly; 8.2.1972; appl. 18.4.1969).
- DE 2 018 600 (Lilly; appl. 17.4.1970; USA-prior. 18.4.1969).
- DAS 2 065 621 (Lilly; appl. 17.4.1970; USA-prior. 18.4.1969).
- US 3 840 531 (Lilly; 8.10.1974; appl. 21.3.1972).
- US 3 903 278 (Smith Kline Corp.; 2.9.1975; prior. 4.11.1971).
- DOS 2 730 579 (Pierrel S.p.A.; appl. 6.7.1977; GB-prior. 10.7.1976).

preparation and/or purification via the trimethylsilyl-derivatives:
- DOS 2 711 095 (Lilly; appl. 14.3.1977; USA-prior. 17.3.1976).

purification:
- US 4 115 644 (Lilly; 19.9.1978; appl. 19.9.1978).
- DOS 2 839 670 (Lilly; appl. 12.9.1978; USA-prior. 19.9.1977).

crystalline sodium salt:
- US 4 054 738 (Lilly; 18.10.1977; appl. 22.12.1975).
- US 4 168 376 (Lilly; 18.9.1979; appl. 5.6.1978).

lithium salt:
- GB 1 546 757 (Lilly; appl. 10.4.1975; valid from 7.4.1976).

O-formyl-derivative:
- US 3 928 592 (Lilly; 23.12.1975; appl. 21.2.1974).
- GB 1 493 676 (Lilly; appl. 20.2.1975; USA-prior. 22.2.1974).
- GB 1 546 898 (Lilly; appl. 7.4.1976; USA-prior. 11.4.1975).
- DOS 2 506 622 (Lilly; appl. 17.2.1975; USA-prior. 22.2.1974).

crystalline sodium salt of O-formylcefamandole:
- US 4 006 138 (Lilly; 1.2.1977; appl. 11.4.1975).

complex of cefamandole sodium with 1,4-dioxane and water:
- US 3 947 414 (Lilly; 30.3.1976; appl. 23.12.1974).

complex of cefamandole sodium with ethyl l-(–)-lactate:
- US 3 947 415 (Lilly; 30.3.1976; appl. 23.12.1974).

Cefamandole
Clinical data

Trade names	former Mandol
AHFS/Drugs.com	Micromedex Detailed Consumer Information
MedlinePlus	a601206
Pregnancy category	AU: B1
Routes of administration	Intramuscular, intravenous
ATC code	J01DC03 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: Discontinued
Pharmacokinetic data
Protein binding	75%
Elimination half-life	48 minutes
Excretion	Mostly renal, as unchanged drug
Identifiers
IUPAC name [show]
CAS Number	34444-01-4 42540-40-9
PubChem CID	456255
DrugBank	DB01326
ChemSpider	401748
UNII	5CKP8C2LLI
KEGG	D02344
ChEBI	CHEBI:3480
ChEMBL	ChEMBL1146
ECHA InfoCard	100.047.285
Chemical and physical data
Formula	C₁₈H₁₈N₆O₅S₂
Molar mass	462.505 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O=C2N1/C(=C(\CS[C@@H]1[C@@H]2NC(=O)[C@H](O)c3ccccc3)CSc4nnnn4C)C(=O)O
InChI [hide] InChI=1S/C18H18N6O5S2/c1-23-18(20-21-22-23)31-8-10-7-30-16-11(15(27)24(16)12(10)17(28)29)19-14(26)13(25)9-5-3-2-4-6-9/h2-6,11,13,16,25H,7-8H2,1H3,(H,19,26)(H,28,29)/t11-,13-,16-/m1/s1 Key:OLVCFLKTBJRLHI-AXAPSJFSSA-N

/////////////Cefamandole, セファマンドール ,цефамандол , سيفاماندول , 头孢孟多 ,

Tegaserod, テガセロド

April 16, 2019 10:34 am / Leave a comment

ChemSpider 2D Image | Tegaserod | C16H23N5O

Tegaserod

Molecular FormulaC₁₆H₂₃N₅O
Average mass301.387 Da
テガセロド

145158-71-0 cas

HTF 919 / HTF-919 / SDZ HTF 919 / SDZ-HTF-919

N’-[(E)-[(5-methoxy-1H-indol-3-yl)methylidene]amino]-N-pentylguanidine

(2E)-2-[(5-Methoxy-1H-indol-3-yl)methylene]-N-pentylhydrazinecarboximidamide [ACD/IUPAC Name]

(2E)-2-[(5-methoxy-1H-indol-3-yl)methylidene]-N’-pentylhydrazinecarboximidamide

(2E)-2-[(5-methoxy-1H-indol-3-yl)methylidene]-N-pentylhydrazinecarboximidamide

145158-71-0 [RN]

7606

Hydrazinecarboximidamide, 2-[(5-methoxy-1H-indol-3-yl)methylene]-N-pentyl-, (2E)

Sundaram Venkataraman, Srinivasulu Gudipati, Brahmeshwararao Mandava Venkata Naga, Goverdhan Banda, Radhakrishna Singamsetty, “Process for preparing form I of tegaserod maleate.” U.S. Patent US20050272802, issued December 08, 2005.US20050272802

2D chemical structure of 189188-57-6

Tegaserod maleate [USAN]
189188-57-6

Tegaserod

CAS Registry Number: 145158-71-0

CAS Name: 2-[(5-Methoxy-1H-indol-3-yl)methylene]-N-pentylhydrazinecarboximidamide

Molecular Formula: C16H23N5O

Molecular Weight: 301.39

Percent Composition: C 63.76%, H 7.69%, N 23.24%, O 5.31%

Literature References: Selective serotonin 5HT4-receptor partial agonist. Prepn: R. K. A. Giger, H. Mattes, EP 505322; eidem, US5510353 (1992, 1996 both to Sandoz); K.-H. Buchheit et al., J. Med. Chem. 38, 2331 (1995). Clinical pharmacology: S. Appel et al., Clin. Pharmacol. Ther. 62, 546 (1997); and pharmacokinetics: idem et al., J. Clin. Pharmacol. 37, 229 (1997). Clinical trial in irritable bowel syndrome: S. A. Müller-Lissner et al., Aliment. Pharmacol. Ther. 15, 1655 (2001); in female patients: J. Novick et al.,ibid. 16, 1877 (2002). Review of clinical efficacy: B. W. Jones et al., J. Clin. Pharm. Ther. 27, 343-352 (2002); of mechanism of action, efficacy and safety: M. Corsetti, J. Tack, Expert Opin. Pharmacother. 3, 1211-1218 (2002).

Properties: mp 155°.

Melting point: mp 155°

Derivative Type: Maleate

CAS Registry Number: 189188-57-6

Manufacturers’ Codes: SDZ-HTF-919

Trademarks: Zelmac (Novartis); Zelnorm (Novartis)

Molecular Formula: C16H23N5O.C4H4O4

Molecular Weight: 417.46

Percent Composition: C 57.54%, H 6.52%, N 16.78%, O 19.16%

Therap-Cat: Gastroprokinetic; in treatment of irritable bowel syndrome.

Keywords: Gastroprokinetic; Serotonin Receptor Agonist.

Tegaserod is a 5-HT₄ agonist manufactured by Novartis and sold under the names Zelnorm and Zelmac for the management of irritable bowel syndrome and constipation.^[1] Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects. Before then, it was the only drug approved by the United States Food and Drug Administration to help relieve the abdominal discomfort, bloating, and constipation associated with irritable bowel syndrome. Its use was also approved to treat chronic idiopathic constipation.^[2]

In 2000, originator Novartis established an alliance with Bristol-Myers Squibb for the codevelopment and copromotion of tegaserod maleate, which is now available in more than 55 countries worldwide for the treatment of IBS with constipation. In 2015, Zelnorm was acquired by Sloan Pharma from Novartis.

Novartis’ brand name Zelnorm (tegaserod) had originally received approval from the US FDA in 2002 for the treatment of irritable bowel syndrome with constipation (IBS-C) ^[5, 8]. It was, however, voluntarily withdrawn from widespread use in the US market in 2007 after concerns arose over the possibility that tegaserod could potentially cause dangerous cardiovascular events in patients ^[5,8]. Since then, closer evaluations of the original data suggesting such cardiovascular risk have resulted in the limited reintroduction or ‘re-approval’ of tegaserod for treatment of IBS-C specifically in female patients less than 65 years of age and whom are considered to be at a lower risk of a cardiovascular event than the broader population . Zelnorm (tegaserod) by Sloan Pharma subsequently gained re-approval in April of 2019 ^[5]. Nevertheless, tegaserod remains un-approved in certain regions ^[7].

Despite the relative complications involved in its history of regulatory approval, ever since its first introduction in 2002 tegaserod remains the only therapy for IBS-C that possesses the unique mechanism of action of acting on serotonin-4 (5-HT(4)) receptors in smooth muscle cells and in the gastrointestinal wall to facilitate actions like esophageal relaxation, peristaltic gut movement, and natural secretions in the gut, among others

Mechanism of action

The drug functions as a motility stimulant, achieving its desired therapeutic effects through activation of the 5-HT₄ receptors of the enteric nervous system in the gastrointestinal tract. It also stimulates gastrointestinal motility and the peristaltic reflex, and allegedly reduces abdominal pain.^[3] Additionally, tegaserod is a 5-HT_2B receptor antagonist.^[4]

Withdrawal from market

On 30 March 2007, the United States Food and Drug Administration requested that Novartis withdraw Zelnorm from shelves.^[5] The FDA alleges a relationship between prescriptions of the drug and increased risks of heart attack or stroke. An analysis of data collected on over 18,000 patients demonstrated adverse cardiovascular events in 13 of 11,614 patients treated with Zelnorm (a rate of 0.11%) as compared with 1 of 7,031 patients treated with placebo (a rate of 0.01%). Novartis alleges all of the affected patients had preexisting cardiovascular disease or risk factors for such, and further alleges that no causal relationship between tegaserod use and cardiovascular events has been demonstrated.^[6] On the same day as the FDA announcement, Novartis Pharmaceuticals Canada announced that it was suspending marketing and sales of the drug in Canada in response to a request from Health Canada.^[7] In a large cohort study based on a US health insurance database, no increase in the risk of cardiovascular events were found under tegaserod treatment.^[8] Currently, tegaserod may only be used in emergency situations only with prior authorization from the FDA.^[9]

Paper

The serotonin 5-HT4 receptor. 2. Structure-activity studies of the indole carbazimidamide class of agonists
J Med Chem 1995, 38(13): 2331

https://pubs.acs.org/doi/abs/10.1021/jm00013a010

PATENT

US 5510353

WO 2005105740

WO 2007119109

WO 2007126889

CN 103467358

WO 2006116953

Syn

PATENT

https://patents.google.com/patent/US20090306170A1/en

Image result for tegaserod synthesis

In a preferred embodiment of the first aspect of the present invention, the process of preparing tegaserod or a salt thereof comprises the steps of:
- (a) coupling S-methyl-isothiosemicarbazide or a salt thereof and 5-methoxy-indole-3-carboxaldehyde to form 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide:
and
- (b) reacting the 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide with n-pentyl amine to form tegaserod:
[0013]
The skilled person will appreciate that:
- - S-methyl-isothiosemicarbazide and salts thereof exist in two tautomeric forms:
- - 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide exists in four tautomeric forms:
- - tegaserod exists in four tautomeric forms:
[0017]
It is to be understood that where tautomeric forms occur, the present invention embraces all tautomeric forms and their mixtures, i.e. although S-methyl-isothio-semicarbazide and 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemi-carbazide are mostly defined for convenience by reference to one isothiosemicarbazide form only, and although tegaserod is mostly defined for convenience by reference to one guanidino form only, the invention is not to be understood as being in any way limited by the particular nomenclature or graphical representation employed.
[0018]
When an S-methyl-isothiosemicarbazide salt is used in the process of the present invention, this may be an acid addition salt with acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid), or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene-2-sulfonic or camphorsulfonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). Preferably the S-methyl-isothiosemicarbazide salt is a hydrohalide (such as the hydrofluoride, hydrochloride, hydrobromide, or hydroiodide) or a sulfonate (such as the methanesulfonate, benzenesulfonate, or p-toluenesulfonate). Preferably the S-methyl-isothiosemicarbazide salt is S-methyl-isothiosemicarbazide hydroiodide.

- The following synthetic scheme demonstrates a preferred process of the present invention.
- [0032]
  The invention is now demonstrated by the following non-limiting illustrative example.

EXAMPLE Step 1: Schiff’s Base Formation of 5-methoxy-indole-3-carboxaldehyde and S-methyl-isothiosemi-carbazide hydroiodide

- [0033]
  5-Methoxy-indole-3-carboxaldehyde (1.5 g, 1 eq) and S-methyl-isothiosemicarbazide hydroiodide (3.99 g, 2 eq) in methanol (15 ml, 10 vol) were stirred in the presence of triethylamine (3 ml, 2 vol) at 25-30° C. for 2 hours. After completion of the reaction, the methanol was removed by distillation under reduced pressure at 45-50° C. and ethyl acetate (10.5 ml, 7 vol) was added to the residue to precipitate out the product. The product, 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemi-carbazide, was separated by filtration, washed with ethyl acetate (3 ml, 2 vol) and dried under vacuum at 45-50° C. The yield was almost quantitative (˜100%).

Step 2: Conversion of 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide to 1-((5-methoxy-1H-indol-3-yl)methyleneamino)-3-pentyl-guanidine (Tegaserod)

- [0034]
  A solution of 1-((5-methoxy-1H-indol-3-yl)methylene)-S-methyl-isothiosemicarbazide (8.0 g, 1 eq) and n-pentyl amine (2.65 g, 1 eq) was refluxed in methanol (8 ml, 1 vol) at 66° C. for 4 hours. After completion of the reaction, the methanol was removed by distillation under reduced pressure at 45-50° C. to obtain tegaserod free base as a yellowish brown solid. Yield=97%. HPLC purity=95%.

Step 3: Conversion of 1-((5-methoxy-1H-indol-3-yl)methyleneamino)-3-pentyl-guanidine (Tegaserod) to Tegaserod Maleate

[0035]
1-((5-Methoxy-1H-indol-3-yl)methyleneamino)-3-pentyl-guanidine (55 g, 1 eq) was taken in methanol (357.5 ml, 6.5 vol) and stirred. To this reaction mixture was added at room temperature a solution of maleic acid (74.15 g, 3.5 eq) in water (137.5 ml, 2.5 vol) and the reaction mixture stirred for one hour at room temperature. The solid obtained was then filtered through a Buchner funnel and dried at 700 mmHg and 500° C. Yield=36.8 g, 48.42%. HPLC purity=99.45%.

Polymorphs

WO 2007084697

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007084697

EXAMPLES

PXRD:

EV 320 251 655 US Powder X-ray diffraction (“PXRD”) analysis using a SCINTAG powder X-ray diffϊactometer model X’TRA equipped with a solid-state detector. Copper radiation of λ=1.5418 A was used. The sample was introduced using a round standard aluminum sample holder with round zero background quartz plate in the bottom.
Thermal Gravimetric Analysis TTGA):
TGA/SDTA 85 r, Mettler Toledo , Sample weight 7-15 mg.
Heating rate: 10⁰C/ min., in N₂ stream: flow rate: 50 ml/min

Example 1 : Preparation of Tegaserod maleate Form B
To a mixture of 90 g MICHO and 63 g NaOH [47 %] was added a solution of 212 g AGPΗI dissolved in 566 mL of water at room temperature. The resultant reaction mixture was heated to 40⁰C. After 3 hours, 522 mL of ethyl acetate was added and the reaction mixture was stirred for an additional hour. The organic phase was washed with water (3 x 450 mL), and vacuum filtered. After addition of 211 mL ethyl acetate and 870 mL of n-propanol, the mixture was heated to 60⁰C and a solution of maleic acid (86.5 g in 180 mL water), at the same temperature, was added to the reaction mixture and stirred at the same temperature. After 2 hours the reaction mixture was cooled to about 10⁰C and stirred for an additional hour. The resulting solid was filtered off, washed with n-propanol, and dried in a vacuum oven over night to give 195.8 g of tegaserod maleate Form B.

6
EV 320251 655 US

PATENT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=0DB6F8E3A17F95B3E74D6454382AF545.wapp1nC?docId=WO2007084761&tab=PCTDESCRIPTION&maxRec=1000

Tegaserod maleate is an aminoguanidine indole 5HT4 agonist for the treatment of irritable bowel syndrome (IBS). Tegaserod maleate has the following structure:

According to the prescribing information (Physician’s Desk Reference, 57^th Ed., at Page 2339), tegaserod as the maleate salt is a white to off-white crystalline powder and is slightly soluble in ethanol and very slightly soluble in water. Tegaserod maleate is available commercially as ZELNORM^®, in which it is present as crystalline form.
Tegaserod maleate is disclosed in US patent No. 5,510,353 and in its equivalent EP 0 505 322 (example 13), and is reported to have a melting point of 190⁰C (table 1 example 13).
The literature (Buchheit K.H, et al., J.Med.Chem., 1995, 38, 2331) describes a general method for the condensation of amino guanidines with indole-3-carbadehydes in methanol in the presence of HCl (pH 3-4). The product obtained after solvent evaporation maybe converted to its hydrochloride salt by treatment of the methanolic solution with diethylether/HCl followed by recrystallization from
methanol/diethylether. Tegaserod base prepared according to this general method is characterized solely by a melting point of 155 ⁰C (table 3 compound 5b). Additional Tegaserod maleate characterization was done by ¹H and ¹³C-NMR according to the literature (Jing J. et. al., Guangdong Weiliang Yuansu Kexue, 2002, 9/2, 51).
WO 04/085393 discloses four crystalline forms of tegaserod maleate. The search report for WO 04/085393 further identifies WO 00/10526, and Drugs Fut. 1999, 24(1) which provides an overview for tegaserod maleate. Additional crystalline forms of tegaserod maleate are provided in WO 2005/058819, one of which is characterized by an X-ray Diffraction pattern having peaks at 15.7, 16.9, 17.2, 24.1, 24.6 and 25.2±0.2 two theta (designated as Form B in that PCT publication).
The solid state physical properties of tegaserod salt may be influenced by controlling the conditions under which tegaserod salt is obtained in solid Form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient’s stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally- administered active ingredient may reach the patient’s bloodstream. The rate of dissolution is also a consideration in
formulating syrups, elixirs and other liquid medicaments. The solid state Form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic Form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic Form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some polymorphic forms from others. A particular polymorphic Form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state C NMR spectrometry and infrared spectrometry.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
The polymorphic forms may further help in purification of tegaserod, particularly if they possess high crystallinity. In the event of metastability, a metastable polymorphic form may be used to prepare a more stable polymorph.
Hence, discovery of new polymorphic forms and new processes help in advancing a formulation scientist in preparation of tegaserod as an active pharmaceutical ingredient in a formulation.
The present invention provides an additional polymorphic form of a maleate salt of tegaserod.

Example 1 : Preparation of sesqui-tefiaserod maleate Foπn H2 through tegaserod base

To a mixture of AGPΗI (112.7 g) in 283 mL of water was added 5-MICHO (45 g) followed by NaOH (52.8 g, 47%) and stirred at room temperature. After three hours, 522 mL of ethyl acetate were added and the mixture stirred for an additional four hours. After phase separation at 40⁰C the organic phase was washed with water (3 x 218 ml), and filtrated under vacuum. The resulting solution was heated to 60 ⁰C and a solution of maleic acid (14.4 g) in 45 mL water was dropped during half hour, and the reaction mixture stirred at the same temperature for an additional two hours. The mixture was cooled to 10⁰C during one hour, kept under stirring at the same temperature for 12 hrs and then filtered under vacuum. The wet product was washed twice with 65 ml of ethyl acetate and dried in a vacuum oven at 45°C for 16 hours to give 85% of the product.

Example 2: Preparation of sesqui-tegaserod maleate Form H2
45 gr MICHO were added to a 1 L reactor at RT. A solution of 112.7 gr of AGP HI and 283 ml water was added to the reactor. 52.8 gr of NaOH 47% were added to the mixture while stirring. The mixture was heated to 40⁰C and stirred for 12 hrs. 522 ml of Ethyl Acetate were added and the mixture was stirred for 4 hrs.
After phase separation at 40⁰C the organic phase was washed with water (3 x 218 ml), and filtrated under vacuum.
The mixture was heated to 60⁰C and a mixture o 14.4 gr of Maleic Acid in 45 ml water was dropped during 5 min.
The mixture was stirred at 60⁰C for 2 hrs.
The mixture was cooled to 10⁰C during 1 hour, stirred at 10⁰C for 13 hrs and then filtered under vacuum. The wet product was washed twice with 65 ml of n-Propanol. The wet product was dried in a vacuum oven at 45°C.
Yield: 71.2%

Example 3: Preparation of Tegaserod maleate Form B from Sesqui-tegaserod maleate Form H2
6.9 g of maleic acid were added to a slurry of Sesqui-Tegaserod maleate Form H2 (41.5 g) in 208 ml n-propanol at room temperature. The mixture was stirred for 5 hours at the same temperature, filtered and washed with n-propanol. After drying on vacuum oven at 45⁰C for 15 hours the product was analyzed by XRD and found to be Form B (89% yield).

PATENT

https://patents.google.com/patent/WO2005058819A2/en

PATENT

https://patents.google.com/patent/WO2005105740A2/en

The formation of hydrazones is catalyzed by both general acids and general bases. General base catalysis of dehydration of the tetrahedral intermediate involves nitrogen deprotonation concerted with elimination of hydroxide ion as shown in the Scheme (Sayer J.M., et al. J. Am. Chem. Soc. 1973, 95, 4277). R fast O I H h° NH₂R’ R- -NHR’ R R

In many cases, the equilibrium constant for their formation in aqueous solution is high. The additional stability may be attributed to the participation of the atom adjacent to the nitrogen in delocalized bonding. – + RRC = N – NH₂ ~*→- RRC – N = NH₂

In order to obtain only the maleic salt, the product when using an acid halide (HA) or other acids has to first be converted into the free base, before the addition of maleic acid (Path a), which results in an additional step to the synthesis. On the other hand, the reaction of the present invention in the presence of organic or inorganic base results in the formation of tegaserod free base which gives only the maleate salt after the addition of maleic acid (Path b).

TGS

TGS-MA

EXAMPLES

HPLC method for detecting the level of the impurities:

Column: Atlantis dcl8(150*4.6),

Mobile phase: A.80% KH₂PO₄(0.02M) pH=5, 20% acetonitrile(ACN), B.100% ACN. Gradient: time 0= A: 100 B: 0, time 25 min= A:50%, B:50%, time 30 min= A:50%, B:50%, + 10 minutes of equilibration time. Wavelength= 225 nm

Sample concentration: 0.5 mg/mL

Temperature = 25°C

Example 1- Preparation of Tegaserod maleate in water with HCl.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by HCl (37%) until pH 4. The mixture was heated to reflux for 1 hour and then cooled to room temperature. To the resulting slurry was added a solution of NaHCO₃ (10%) until pH 9, and heated to 65°C for 20 minutes. After cooling, 100 mL of EtOAc were added, and the organic phase washed with water. A solution of maleic acid (3.48 g, 0.03 mol) in 100 mL EtOAc was added, and the resulting solid was filtered off and washed with EtOAc to give 6.27 g of crude tegaserod maleate with a purity of 99.70% (by HPLC).

Example 2- Preparation of Tegaserod maleate in water with HCl in two steps. a. Preparation of Tegaserod free base.

To a mixture of AGP-HI (163.3 g, 0.6 mol) in 375 mL water was added 5-MICHO (52.5 g, 0.3 mol) followed by HCl (37%) until pH 4. The mixture was heated to reflux for 1 hour and then cooled to room temperature. To the resulting slurry was added a liter of a solution of NaHCO (10%) until pH 9, and heated to 65 °C for one hour. After cooling, 1500 mL of EtOAc were added, and the organic phase washed with water. The remaining organic phase was evaporated to dryness to give tegaserod free base with a purity of 87.42 % (by HPLC). b. Preparation of Tegaserod maleate. To a solution of 2 g of tegaserod free base in MeOH was added a solution of maleic acid (1.28 g, 0.011 mol) in 10 mL MeOH. The resulting solid was filtered off and washed with MeOH to give 1.09 g of crude tegaserod maleate with a purity of 96.81 % (by HPLC).

Example 3- Preparation of Tegaserod maleate in water with TEA.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 100 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by TEA (11.0 mL, 0.08 mol) and stirred at room temperature. After one hour, 25 mL of EtOAc was added, and the organic phase washed with water. A solution of maleic acid (3.48 g, 0.03 mol) in 100 mL EtOAc was added, and the resulting solid was filtered off and washed with EtOAc to give 7.92 g of crude tegaserod maleate with a purity of 94 % (by HPLC).

Example 4- Preparation of Tegaserod maleate in water with NaHCO₃. To a mixture of AGP-HI (10.88 g, 0.04 mol) in 100 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by NaHCO₃ (6.72 g, 0.08 mol) and heated to reflux for 1 hour. After cooling, 50 mL of EtOAc was added, and the organic phase washed with water. A solution of maleic acid (3.48 g, 0.03mol) in 100 mL EtOAc was added, and the resulting solid was filtered off and washed with EtOAc to give 6.71 g of crude tegaserod maleate with a purity of 98 % (by HPLC) .

Example 5- Preparation of Tegaserod maleate in water with NaHCO₃ in two steps. a. Preparation of Tegaserod free base. To a mixture of AGP-HI (32.66 g, 0.12 mol) in 300 mL water was added 5-MICHO (10.51 g, 0.06 mol) followed by NaHCO₃(20.16 g, 0.24 mol) and heated to reflux for 1 hour. After cooling, 150 mL of EtOAc was added, and the organic phase washed with water and evaporated to dryness to give 20.4 g of tegaserod free base (91.55%) purity by HPLC). b. Preparation of Tegaserod maleate.

To a solution of 2g of the resulting tegaserod free base in 8 mL MeOH was added a solution of maleic acid (1.28 g, 0.011 mol) in 5 mL MeOH. The resulting solid was filtered off and washed with MeOH to give 2.1 g of crude tegaserod maleate with a purity of 99.63 % (by HPLC).

Example 6- Preparation of Tegaserod maleate in water with Na₂CO₃. To a mixture of AGP-HI (10.88 g, 0.04 mol) in 100 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by Na₂CO₃ (4.24 g, 0.04 mol) and heated to reflux for 1 hour. After cooling, 50 mL of EtOAc was added, and the organic phase washed with water. A solution of maleic acid (3.48 g, 0.03 mol) in 100 mL EtOAc was added, and the resulting solid was filtered off and washed with EtOAc to give 6.48 g of crude tegaserod maleate with a purity of 98.2 % (by HPLC).

Example 7- Preparation of Tegaserod maleate in MeOH with TEA in two steps. a. Preparation of tegaserod free base

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL MeOH was added 5-MICHO (3.50 g, 0.02 mol) followed by triethylamine (11.0 mL, 0.08 mol). After 1 h at room temperature the mixture was evaporated to dryness, and washed with water, giving 5.79 g of tegaserod free base (86.90 % purity by HPLC). b. Preparation of tegaserod maleate

To a solution of 2 g of the resulting tegaserod free base in 10 mL MeOH was added a solution of maleic acid (1.16 g, 0.01 mol) in water. The resulting solid was filtrated and washed with water to give 1.45 g of crude tegaserod maleate as a white solid (94.60 % purity by HPLC). Crystallization in MeOH improved the purity to 98.94% by HPLC.

Example 8- Preparation of Tegaserod maleate in IPA with K₂CO₃.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL IPA was added 5-MICHO (3.50 g, 0.02 mol) followed by K₂CO₃ (5.53g, 0.04 mol). After 22 h at room temperature the mixture was washed with brine. The organic phase was treated with a solution of maleic acid (3.48 g, 0.03 mol) in IPA. The resulting solid was filtrated and washed with IPA to give 3.26 g of a white solid (98.97% purity by HPLC).

Example 9- Preparation of Tegaserod maleate in TEA.

To a mixture of AGP-HI (10.88 g, 0.04 mol) and 5-MICHO (3.50 g, 0.02 mol) was added 11 mL of TEA (0.08 mol). After 2 h at room temperature 25 mL of EtOAc were added and the mixture was stirred for 1 h. The resulting solid was filtrated and washed with 25 mL EtOAc, to give 5.7 g of crude.

2 g of the residue was dissolved in 13 mL MeOH and treated with 7 mL of a solution of maleic acid (2.7 g, 0.023 mol) in water. The resulting solid was filtered and washed with water to give 1.5 g of tegaserod maleate (99.26 % purity by HPLC). Crystallization of the solid in MeOH improved the purity to 99.89%) by HPLC.

Example 10- Preparation of Tegaserod maleate in toluene/water with NaHCO₃. a. Preparation of tegaserod free base To a mixture of AGP-HI (10.88 g, 0.04 mol) in 200 mL of water/toluene 1:1 was added 5-MICHO (3.50 g, 0.02 mol) followed by NaHCO₃ (6.72 g, 0.08 mol) and heated to reflux for 1 hour. After cooling, the solid was filtrated out of the mixture and washed with water. After drying 6.25 g of tegaserod free base was obtained (93.8 % purity by HPLC). b. Preparation of tegaserod maleate To a solution of 3 g of the product in 10 mL MeOH was added a solution of maleic acid (2.31 g, 0.02 mol) in 10 mL water. The resulting solid was filtered off and washed with a solution of MeOH / water to give 2.50 g of crude tegaserod maleate with a purity of 96.6 % (by HPLC).

Example 11- Preparation of Tegaserod maleate in water with NaOH. a. Preparation of tegaserod free base

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL of water was added 5-MICHO (3.50 g, 0.02 mol) followed by NaOH (2 g, 0.05 mol) and stirred at room temperature. After 3 hours 50 mL of EtOAc was added, and the organic phase washed with water and evaporated to dryness to give 5.6 g of tegaserod free base (98.80% purity by HPLC). b. Preparation of Tegaserod maleate.

To a solution of 1.6 g of tegaserod free base in 15 mL ethyl acetate was added a solution of maleic acid (0.7 g, 0.006 mol) in 5 mL ethyl acetate. The resulting solid was filtered off and washed with ethyl acetate to give 1.65 g of crude tegaserod maleate, with a purity of 99.87 % (by HPLC)

Example 12- Preparation of Tegaserod maleate in water with maleic acid. To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL of water was added 5-MICHO (3.50 g, 0.02 mol) followed by maleic acid (9.3 g, 0.08 mol) and heated to reflux for 1 hour. After cooling, the solid was filtrated out of the mixture and washed with water. After drying 6.92 g of tegaserod maleate crude was obtained (92.4 % purity by HPLC).

Example 13- Preparation of Tegaserod maleate in methanol with maleic acid.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL of methanol was added 5- MICHO (3.50 g, 0.02 mol) followed by maleic acid (9.29 g, 0.08 mol) and heated to reflux for 2 hours. After cooling, the solid was filtrated out of the mixture and washed with water. After drying 6.51 g of tegaserod maleate crude was obtained (97.4 % purity by HPLC).

Example 14- Preparation of Tegaserod maleate in water with NaOH in one pot. To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL of water was added 5-MICHO (3.50 g, 0.02 mol) followed by NaOH (2 g, 0.05 mol) and stirred at room temperature. After 4 hours a solution of maleic acid (4.35 g, 0.0375 mol) in 25 mL water was added, and the reaction mixture was stirred overnight. The resulting solid was filtered off and washed with water to give 7.87 g of crude tegaserod maleate (99.16% purity by HPLC).

Example 15- Preparation of Tegaserod maleate in water with NaOH in one pot.

To a mixture of AGP-HI (174.2 g, 0.64 mol) in 362 mL of water was added 5-MICHO (56.2 g, 0.32 mol) followed by NaOH (68.1 g, 47%) and stirred at room temperature. After 4.5 hours, 640 mL of EtOAc was added, and the organic phase washed with water, treated with active carbon and filtrated through hyper flow bed. A solution of maleic acid (44.57 g, 0.38 mol) in 415 mL ethyl acetate / water 97:3 was added, and the reaction mixture was heating to 65 °C and stirrer overnight. The resulting solid was filtered off and washed with water and ethyl acetate to give 121.4 g of crude tegaserod maleate (up to 99.88 % purity by HPLC).

Example 16- Preparation of Tegaserod maleate (from Tegaserod acetate).

To a solution of 8.2 g of tegaserod acetate in 15 mL ethyl acetate heated to 65 °C was added a solution of 3.3 g maleic acid in 5 ml ethyl acetate/water 95:5, and the mixture was stirred at the same temperature for an additional 2 hours, followed by cooling to room temperature and stirring overnight. The resulting solid was filtered off and washed with ethyl acetate/water 95:5. After drying on vacuum oven at 45 °C for 15 hours, 9.18 g of tegaserod maleate were obtained. Tegaserod acetate is prepared according to Examples 19, 20 and 21 of U.S. Appl. No. 11/015,875 and PCT/US04/42822.

Example 19 of U.S. Appl. No. 11/015,875 reads as follows: A slurry of tegaserod base amorphous (6 g) in 50 mL ethyl acetate was stirred at 20- 30 °C for 24 hours. The solid was filtrated and washed with 15 mL of same solvent and dried in a vacuum oven at 40 °C for 16 hours.

Example 20 of U.S. Appl. No. 11/015,875 reads as follows:

A slurry of tegaserod base amorphous (6 g) in 50 mL ethyl acetate was stirred at reflux for 24 hours. The solid was filtrated and washed with 15 mL of same solvent and dried in a vacuum oven at 40 °C for 16 hours.

Example 21 of U.S. Appl. No. 11/015,875 reads as follows:

To a slurry of tegaserod maleate Form A (15 g) in EtOAc (210 mL) and water (210 mL) was added 38.4 g of NaOH 47%. The mixture was stirred overnight and the resulting white solid was isolated by filtration and washed with 100 mL of water. Drying in vacuum oven at 40 °C for 16 hours gives 12.38 g (90% yield). Tegaserod acetate was characterized by H and C-NMR.

Example 17: General method for the preparation of Tegaserod maleate Form A from crystallization.

Tegaserod maleate (1 g) was combined with the appropriate solvent (5 mL), and heated to reflux. Then, additional solvent was added until complete dissolution. After the compound was dissolved, the oil bath was removed and the solution was cooled to room temperature. The solid was filtrated and washed with 5 mL of the same solvent and dried in a vacuum oven at 40 C for 16 hours.

Example 18: Preparation of Tegaserod maleate in water with p-TSOH.

To a mixture of AGP-HI (10.88 g, 0.04 mol) in 25 mL water was added 5-MICHO (3.50 g, 0.02 mol) followed by para-toluenesulfonic acid monohydrate (0.45 g, 0.0024 mol). The mixture was heated to reflux for 4 hour and then cooled to room temperature. The resulting solid was filtered off and washed with water to give 8.32 g of a white solid (84.74 % purity by HPLC).

Example 19: Preparation of Tegaserod maleate from Tegaserod Hemi-maleate hemihydrate

To a solution of 1.72 g of Tegaserod Hemi-maleate hemihydrate in 20 mL ethyl acetate at room temperature was added a solution of 0.134 g maleic acid in 5 ml ethyl acetate/water 95:5, and the mixture was stirred at the same temperature for overnight. The resulting solid was filtered off and washed with ethyl acetate/water 95:5. After drying on vacuum oven at 45°C for 15 hours, 1.68 g of tegaserod maleate were obtained. Tegaserod Hemi-maleate hemihydrate was prepared according to Example 23 of U.S. Appl. No. 11/015,875 and PCT/US04/42822. Example 23 of U.S. Appl. No. 11/015,875 and PCT/US04/42822 reads as follows: A solution of maleic acid (2.32 g in 22 mL ethyl acetate/water 97:3) was added to a mixture of tegaserod base in ethyl acetate, and the reaction mixture was heated to 65 °C and stirrer overnight. The resulting solid was filtered off and washed with water and ethyl acetate. Drying in vacuum oven at 40 °C for 16 hours gives 12.19 g of Tegaserod hemi-maleate hemihydrate. Depending on the base polymorph used a solution or slurry is obtained. When using amorphous tegaserod base, a solution is obtained, while when using any other base polymorph of tegaserod, a slurry is obtained.

PATENT

https://patents.google.com/patent/WO2009063247A1/en

Tegaserod, chemically named 2-[(5-methoxy-liϊ-indol-3-yl)methylene]-IV-pentylhydrazine- carboximidamide, is a selective serotonin 4 (5-HT₄) receptor agonist, which can be used to treat gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudoobstruction, irritable bowel syndrome and gastro-oesophageal reflux. Tegaserod as the maleate salt is marketed for the short-term treatment of irritable bowel syndrome in women whose primary bowel symptom is constipation.

Tegaserod, represented by the formula (I), was first described in US 5 510 353 as well as processes for its preparation. The maleate salt of tegaserod is also disclosed, but interestingly a method of manufacturing tegaserod maleate is not disclosed. The only characterizing data is the melting point which is disclosed as 190⁰C for the maleate salt and 124°C for the tegaserod base.

WO 2006/116953 describes crystalline forms of the hydrobromide, dihydrogen phosphate and oxalate salts of tegaserod. Also claimed is a process for preparing the hydrochloride, hydrobromide, dihydrogen phosphate, tartrate, citrate, lactate, mesylate, oxalate, succinate, glutarate, adipate, salicylate, sulfate, mandelate, camphor sulfonate and hydrogen sulfate salts of tegaserod from a specific crystalline form of tegaserod base. Another process described is a method of preparing the dihydrogen phosphate, maleate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulfate and hydrogen sulfate from a hydrogen halide salt of tegaserod.

There are often major hurdles to overcome before an active pharmaceutical ingredient (API) can be formulated into a composition that can be marketed. For example, the rate of dissolution of an API that has poor aqueous solubility is often problematic. The aqueous solubility is a major influence on the bioavailability of the API such that a poorly soluble API can mean the API is not available to have a pharmaceutical effect on the body. The API can also cause problems during manufacture of a pharmaceutical composition. For example, flowability, compactability and stickiness are all factors affected by the solid state properties of an API.

It has thus always been an aim of the pharmaceutical industry to provide many forms of an API in order to mitigate the problems described above. Different salts, crystalline forms also known as polymorphs, solvates and amorphous forms are all forms of an API that can have different physiochemical and biological characteristics. Indeed, it has been discovered that the tegaserod maleate product on the market, Zelnorm , has been linked to an increase in heart problems in a proportion of individuals. One possible reason is that the maleate moiety reacts with the tegaserod, resulting over time in the production of a toxic impurity.

This impurity could be a contributor to the heart problems seen in some patients.

PATENT

https://patents.google.com/patent/WO2004085393A1/en

Figure 1 is a x-ray powder diffraction pattern of tegaserod maleate Form I. Figure 2 is a x-ray powder diffraction pattern of tegaserod maleate Form II. Figure 3 is a x-ray powder diffraction pattern of tegaserod maleate Form III. Figure 4 is a x-ray powder diffraction pattern of tegaserod maleate Form IV. x-Ray powder diffraction spectrum was measured on a Siemens D5000 x- ray powder diffractometer having a copper-Kα radiation.

The following examples further illustrate the invention.

Example 1 Tegaserod free base (10 gm) is dissolved in acetone (100 ml). Maleic acid (4 gm) is added to the solution and the contents are maintained for 1 hour at 25°C. The separated solid is filtered to give 12.5 gm of tegaserod maleate Form I.

Example 2 Tegaserod maleate Form II (5 gm) and acetone (70 ml) are mixed and refluxed for 1 hour and cooled to 25°C and filtered to give 4.8 gm of tegaserod maleate Form I.

Example 3 Tegaserod maleate Form I (10 gm) is dissolved in methanol (100 ml). Acetonitrile (150 ml) is added to the solution and the contents are heated to reflux. The contents are then cooled to 25°C and maintained for 30 minutes. The separated crystals are collected by filtration to give 9 gm of tegaserod maleate Form II.

Example 4 Tegaserod free base (10 gm) is dissolved in methanol (100 ml) and maleic acid (4 gm) is added to the solution. Then the contents are maintained for 30 minutes at 25°C. Then the separated solid is filtered to give 13 gm of tegaserod maleate Form III.

Example 5

Tegaserod maleate (5 gm) is dissolved in methanol (50 ml) and the solution is maintained at 25°C for 30 minutes. The separated crystals are collected by filtration to give 4.8 gm of tegaserod maleate Form III. Example 6 Tegaserod free base (10 gm) is dissolved in methanol (50 ml), maleic acid (4 gm) is added and the contents are refluxed for 30 minutes and then the resulting solution is cooled to 25°C. Methylene dichloride (200 ml) is added and the contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 13 gm of tegaserod maleate Form IV.

Example 7 Maleic acid (4 gm) is added to a solution of tegaserod free base (10 gm) in methanol (50 ml). The contents are maintained for 30 minutes at 25°C and isopropyl alcohol (150 ml) is mixed and contents are maintained for 30 minutes at 25°C. The separated solid is collected by filtration to give 12.5 gm of tegaserod maleate Form IV

CLIP

References

^ “New Data for Zelnorm”. Archived from the original on December 9, 2007. Retrieved March 30, 2007.
^ “FDA approves first treatment for women with irritable-bowel syndrome”. Archived from the original on February 5, 2007. Retrieved March 30, 2007.
^ Rossi, S. (2004). Australian Medicines Handbook. Adelaide: Health Communication Network. ISBN 0-9578521-4-2.
^ Beattie DT, Smith JA, Marquess D, et al. (November 2004). “The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo”. Br. J. Pharmacol. 143 (5): 549–60. doi:10.1038/sj.bjp.0705929. PMC 1575425. PMID 15466450.
^ “FDA Announces Discontinued Marketing of GI Drug, Zelnorm, for Safety Reasons”. FDA Press Release. 30 March 2007.
^ “Zelnorm” (PDF). Novartis. Archived from the original (PDF) on 2007-04-10. Retrieved 2007-03-30.
^ “Novartis suspends Canadian marketing and sales of Zelnorm in response to request from Health Canada”. Retrieved 2007-03-30.
^ Loughlin J, Quinn S, Rivero E, Wong J, Huang J, Kralstein J, Earnest DL, Seeger JD (2010). “Tegaserod and the Risk of Cardiovascular Ischemic Events: An Observational Cohort Study”. J Cardiovasc Pharmacol Ther. 15 (2): 151–7. doi:10.1177/1074248409360357. PMID 20200325.
^ http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103223.htm

Beattie DT, Smith JA, Marquess D, Vickery RG, Armstrong SR, Pulido-Rios T, McCullough JL, Sandlund C, Richardson C, Mai N, Humphrey PP: The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Br J Pharmacol. 2004 Nov;143(5):549-60. Epub 2004 Oct 4. [PubMed:15466450]
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Tegaserod
Clinical data


Trade names	Zelnorm, Zelmac
AHFS/Drugs.com	Monograph
Pregnancy category	AU: B3 US: B (No risk in non-human studies)
Routes of administration	Oral
ATC code	A06AX06 (WHO)
Legal status
Legal status	US: Usage requires authorization from the FDA
Pharmacokinetic data
Bioavailability	10%
Protein binding	98%
Metabolism	Gastric and hepatic
Elimination half-life	11 ± 5 hours
Excretion	Fecal and renal
Identifiers
IUPAC name [show]
CAS Number	189188-57-6
PubChem CID	5362436
IUPHAR/BPS	226
DrugBank	DB01079
ChemSpider	10609889
UNII	458VC51857
KEGG	D02730
ChEMBL	ChEMBL76370
Chemical and physical data
Formula	C₁₆H₂₃N₅O
Molar mass	301.39 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CCCCCNC(=N)NN=Cc1c[nH]c2ccc(OC)cc12
InChI [hide] InChI=1S/C16H23N5O/c1-3-4-5-8-18-16(17)21-20-11-12-10-19-15-7-6-13(22-2)9-14(12)15/h6-7,9-11,19H,3-5,8H2,1-2H3,(H3,17,18,21)/b20-11+ Key:IKBKZGMPCYNSLU-RGVLZGJSSA-N

PATENT NUMBER	PEDIATRIC EXTENSION	APPROVED	EXPIRES (ESTIMATED)
US5510353	No	1996-04-23	2013-04-26

References

- Buchheit, K.-H. et al.: J. Med. Chem. (JMCMAR) 38, 2331 (1995).
- US 5 510 353 (Novartis; 23.4.1996; GB-prior. 22.3.1991).
- EP 505 322 (Sandoz; GB-prior. 22.3.1991).

Preparation of 5-methoxyindole:
- Tsuji, Y. et al.: J. Org. Chem. (JOCEAH) 55 (2), 580 (1990).
- Jones, G.B. et al.: J. Org. Chem. (JOCEAH) 58 (20), 5558 (1993).
- Kondo, Y. et al.: J. Org. Chem. (JOCEAH) 62 (19), 6507 (1997).
- JP 3 024 055 (Kawaken Fine Chemicals; 1.2.1991; J-prior. 21.6.1989).

/////////Tegaserod, HTF 919, HTF-919, SDZ HTF 919, SDZ-HTF-919, テガセロド , Sloan Pharma, Novartis,
CCCCCNC(=N)N\N=C\C1=CNC2=C1C=C(OC)C=C2

	DR ANTHONY MELVIN CR… on AK 3280
	DR ANTHONY MELVIN CR… on Novobiocin, ノボビオシン;
	DR ANTHONY MELVIN CR… on CT 1812
	DR ANTHONY MELVIN CR… on ACLIMOSTAT
	DR ANTHONY MELVIN CR… on SRT 1720

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Mechanism of action

Structure

Structure–activity relationship

Biosynthesis

References

External links

History

Mechanism of action

References

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Medical uses

Spectrum of bacterial susceptibility and resistance

Coadministration with cilastatin

Adverse effects

Mechanism of action

Synthesis Path

References

Further reading

External links

Derivatives, monohydrate

References

Leanza, W.J. et al.: J. Med. Chem. (JMCMAR) 22, 1435 (1979).

a Salzmann, T.L. et al.: J. Am. Chem. Soc. (JACSAT) 102, 6161-6163 (1980).

Reider, P.J.; Grabowski, E.J.J.: Tetrahedron Lett. (TELEAY) 23, 2293-2296 (1982).

Grabowski, E.J.J.: Chirality (CHRLEP) 17, 249-259 (2005).

US 4 194 047 (Merck & Co.; 18.3.1980; prior. 21.11.1975).

DOS 2 652 679 (Merck & Co.; appl. 19.11.1976; USA-prior. 21.11.1975).

b US 5 998 612 (Merck & Co.; 7.12.1999; appl. 12.6.1992; prior. 23.10.1981).

c US 4 981 992 (Takasago; 27.1.1998; appl. 13.5.1996; J-prior. 11.5.1995).

US 5 204 460 (Takasago; 20.4.1993; appl. 8.11.1991; J-prior. 8.11.1990).

US 5 204 462 (Takasago; 20.4.1993; appl. 8.11.1991; J-prior. 8.11.1990).

US 5 712 388 (Takasago; 27.1.1998; appl. 13.5.1996; J-prior. 11.5.1995).

US 5 081 239 (Takasago; 14.1.1992; appl. 29.11.1989; J-prior. 29.11.1988).

Acetoxylation of 2-azetidinones in 4-position:

Noyori, R. et al.: J. Am. Chem. Soc. (JACSAT) 111, 9134-9135 (1989).

Noyori, R. et al.: Angew. Chem. (ANCEAD) 114, 2108-2123 (2002).

US 5 288 862 (Takasago; 22.2.1994; appl. 16.4.1992; J-prior. 18.4.1991).

US 5 606 052 (Takasago; 25.2.1997; appl. 16.4.1992; J-prior. 18.4.1991).

Noyori-catalyst:

US 4 739 084 (Takasago; 19.4.1988; appl. 15.4.1987; J-prior. 13.5.1986).

d process of Nippon Soda (Nisso):

US 5 026 844 (Suntory & Nippon Soda; 25.6.1991; appl. 13.10.1989; J-prior. 19.10.1988).

US 5 792 861 (Tanabe Seiyaku & Nippon Soda; 11.8.1998; appl. 29.6.1994, 4.11.1996; J-prior. 30.6.1993).

US 5 808 055 (Suntory & Nippon Soda; 15.9.1998; appl. 30.3.1993, 5.7.1995; J-prior. 30.3.1993).

e US 4 791 198 (Kanegafuchi; 13.12.1988; appl. 1.7.1985, 6.1.1987; J-prior. 5.7.1984, 14.1.1986).

US 4 861 877 (Kanegafuchi; 29.8.1989; appl. 1.7.1985, 6.1.1987; J-prior. 5.7.1984, 14.1.1985, 14.1.1986).

US 5 061 817 (Kanegafuchi; 29.10.1991; appl. 1.7.1985, 6.1.1987, 31.5.1988; J-prior. 5.7.1984, 14.1.1986).

US 4 914 200 (Kanegafuchi; 3.4.1990; appl. 28.4.1987, 14.2.1989; J-prior. 30.4.1986, 13.11.1986, 9.2.1987).

Enzymatic reduction of alkyl-2-(N-benzoylamino)methyl-3-oxobutyrates with bakers yeast:

US 5 463 047 (Ciba-Geigy; 31.10.1995; appl. 15.9.1994; CH-prior. 4.5.1987).

Further synthesis processes of Merck & Co. for thienamycin:

Johnston, D.B.R. et al.: J. Am. Chem. Soc. (JACSAT) 100, 313-315 (1978).

Mellilo, D.G. et al.: Tetrahedron Lett. (TELEAY) 21, 2783 (1980).

Melillo, D.G. et al.: J. Org. Chem. (JOCEAH) 51, 1498-1504 (1986).

Karady, S. et al.: J. Am. Chem. Soc. (JACSAT) 103, 6765-6767 (1981).

US 4 269 772 (Merck & Co.; 26.5.1981; appl. 14.1.1980).

US 4 282 148 (Merck & Co.; 4.8.1981; appl. 14.1.1980).

US 4 287 123 (Merck & Co.; 1.9.1981; appl. 14.1.1980).

US 4 290 947 (Merck & Co.; 22.9.1981; appl. 29.5.1980).

US 4 360 684 (Merck & Co.; 23.11.1982; appl. 8.4.1981).