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Tuberculosis: The drug development pipeline at a glanceReview Article |
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► This review presents anti-tuberculosis compounds currently in clinical trials. ► Promising strategies in preclinical development are described. ► The chemical synthesis, target and mechanism of action are highlighted. ► Activities observed in preclinical and clinical studies are reported.
Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60’s of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis.
Eur J Med Chem. 2012 May;51:1-16. doi: 10.1016/j.ejmech.2012.02.033. Epub 2012 Feb 25.
Villemagne, B.; Crauste, C.; Flipo, M.; Baulard, A.R.; Déprez, B.; Willand, N. Tuberculosis: Villemagne, B.; Crauste, C.; Flipo, M.; Baulard, A.R.; Déprez, B.; Willand, N. Tuberculosis: The drug development pipeline at a glance. . Eur. J. Med. Chem. 2012, 51, 1–16, doi:10.1016/j.ejmech.2012.02.033.
MRX I
MRX-I
IN phase 1 FOR GRAM POSITIVE BACTERIA
MicuRx Pharmaceuticals (USA)
MicuRx Pharmaceuticals is developing two oxazolidinone compounds MRX-I and MRX-II. MRX-I is an oral oxazolidinone antibiotic that targets infections due to resistant Gram-positive bacteria, including MRSA and vancomycin-resistant enterococci (VRE). The company announced the completion of a double-blinded, placebo-controlled Phase 1 clinical study, and that the compound has been shown to be safe and well-tolerated at all doses tested with no evidence of myelosuppression.
In October 2012, the company announced the establishment of Shanghai MengKe Pharmaceuticals, a joint venture with Shanghai Zhangjiang Biomedical Industry Venture Capital formed to fund the development and commercialization of MRX-I for the Chinese market. MRX-II is currently under pre-clinical development [1,2].
MRX-I: A Potent and Safe Oxazolidinone Antibiotic
MRX-I is a next-generation oral oxazolidinone antibiotic for treating Gram-positivebacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). In April 2012, MicuRx announced positive Phase I clinical results demonstrating that MRX-I is safe and well tolerated in human subjects, with no signs of myelosuppression, a major toxicity concern for most oxazolidinone agents, including linezolid.In preclinical studies, MRX-I cures in vivoinfections due to Gram-positive bacteria including MRSA and VRE effectively. In addition, MRX-I exhibits 2-fold improved activity against MRSA strains as compared to linezolid.
WO 2009020616 OR
http://www.google.fm/patents/US20090048305?cl=ja
Example 1 Compound of Structure
Scheme for the Compound of Example 1
Intermediate 17. 2,3,4,5-Tetrafluoronitrobenzene (1.17 g, 6.0 mmol) in N-methylpiperidone (NMP; 25 mL) was added dropwise with stirring to 4-piperidone hydrochloride (0.84 g, 6.2 mmol) and N,N-diisopropyl-N-ethylamine (DIEA; 2.45 mL, 14.0 mmol) in NMP (20 mL) at ca.-10 to −5° C. under nitrogen. The mixture was allowed to warm up to r.t. and stirred o.n. The mixture was taken into EtOAc (ca. 100 mL), washed with 2% aq. citric acid (2×50 mL), water (10×50 mL), brine, and dried (Na2SO4). Solvent was removed under vacuum, and the crude product was washed with hexanes (4×20 mL) and dried. Yellow crystals.1H NMR (400 MHz): 7.74 (m, 1H); 3.73 (t, J=6.0 Hz, 4H); 2.66 (t, J=6.0 Hz, 4H). MS (m/z): 275 [M+H].
Intermediate 18. Triethylamine (TEA; 5.6 mL, 43.87 mmol) was added to the Intermediate 17 (8.1 g, 29.56 mmol) in THF (120 mL) at 0° C., followed by triisopropylsilyl triflate (TIPSOTf; 10.7 g, 34.97 mmol). The mixture was allowed to warm up to r.t. over ca. 40 min, and stirred for another 2 h. Solvent was removed on a rotary evaporator. EtOAc (180 mL) was added, and the solution washed with 10% aq. NaHCO3 (40 mL), brine (60 mL) and dried (Na2SO4). Solvent was removed under vacuum and to afford the product as a red-brownish oil. This was directly used at the next step without purification.
Intermediate 19. Ceric ammonium nitrate (CAN, 19.0 g, 34.65 mmol) was added portionwise with stirring to a solution of the Intermediate 18 (12.4 g, 28.80 mmol) in dry DMF (100 mL) at 0° C. The reaction mixture was allowed to warm up to r.t. and stirred for another 4 h. Most of solvent was removed under vacuum. Water (ca. 75 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and dried (Na2SO4). Solvent was removed and the residue purified by column chromatography (gradient 20% to 30% EtOAc in petroleum ether). The product was obtained as a yellow solid. 1H NMR (400 MHz): 7.84 (m, 1H); 7.14 (m, 1H); 5.43 (d, J=8.2 Hz, 1H); 4.06 (t, J=7.2 Hz, 2H); 2.74 (t, J=7.2 Hz, 2H). MS (m/z): 273 [M+H].
Intermediate 20. NH4Cl (0.33 g, 6.2 mmol) in water (5 mL) was added to a hot solution of the Intermediate 19 (0.170 g, 0.62 mmol) in EtOH (10 mL). Iron powder (0.173 g, 3.1 mmol) was added portionwise with stirring, and the mixture at ca. 100-105° C. for 50 min. The solution was filtered, and the precipitate washed with EtOH (5×10 mL). EtOH was removed under vacuum, and residue distributed between EtOAc (ca. 50 mL) and water (10 mL). Aq. layer was washed with EtOAc (3×20 mL), and combined organic layers were washed with water (3×7 mL), brine, and dried (MgSO4). Solvent was removed under vacuum to afford the product as yellow crystals. 1H NMR (400 MHz): 7.03 (m, 1H); 6.36 (m, 1H); 5.19 (d, J=8.0 Hz, 1H); 4.12 (d, J=7.2 Hz, 2H); 3.80 (t, J=7.2 Hz, 2H); 2.66 (t, J=7.2 Hz, 2H). MS (m/z): 243 [M+H].
Intermediate 21.60% NaH in mineral oil (1.4 g, 36.0 mmol) was added portionwise with stirring to the Intermediate 20 (2.9 g, 11.94 mmol) in THF (20 mL) at 0° C. under Ar, and the mixture was stirred at this temperature for 30 min. Benzyl chloroformate (4.1 g, 24.03 mmol) was added dropwise with stirring. The reaction mixture was allowed to warm up to r.t. and stirred o.n. The reaction was carefully quenched with water (10 mL), and THF was removed under vacuum. The residue was taken in DCM (80 mL). Organic layer was washed with brine (50 mL) and dried (Na2SO4). Solvent was removed under vacuum, and the residue dissolved with MeOH (40 mL). Aq. NH3 (25 mL) was added with stirring, and the mixture was stirred at r.t. for 2 h. Solvent was removed under vacuum, and EtOAc (100 mL) was added. The organic layer was washed with brine and dried (Na2SO4). Solvent was removed under vacuum, and the residue purified by column chromatography (gradient 25% to 100% DCM/petroleum ether). White solid. 1H NMR (400 MHz): 7.95 (m, 1H); 7.41 (m, 6H); 7.07 (m, 2H); 5.28 (s, 2H); 3.88 (t, J=7.6 Hz, 2H); 2.69 (t, J=7.6 Hz, 2H). MS (m/z): 377 [M+H].
Compound of Example 1. 1.06M Lithium hexamethyldisilylamide (LHMDS; 3.0 mL, 3.18 mmol) in THF was added dropwise with stirring to a solution of the Intermediate 21 (1.0 g, 2.66 mmol) in THF (8.0 mL) at −78° C., and the mixture was stirred at this temperature for 30 min. (R)-Glycidyl butyrate (0.8 mL, 5.55 mmol) was added dropwise, and the mixture was allowed to warm up to r.t. and stirred o.n. The reaction was quenched with 10% aq. NH4Cl (15 mL), and THF was removed under vacuum. The residue was extracted with EtOAc (2×30 mL). Combined organic layers were washed with brine and dried (Na2SO4). Solvent was removed under vacuum. MeOH (5 mL) and 20% aqueous Cs2CO3 (5 mL) were added, and the mixture was stirred at r.t. for 20 min. The mixture was taken into EtOAc (50 mL), washed with water (2×15 mL), brine, and dried (Na2SO4). Solvent was removed under vacuum and the crude product was purified by column chromatography (2% methanol/DCM). Off-white solid. 1H NMR (400 MHz): 7.44 (m, 1H); 7.10 (d, J=7.6 Hz, 1H); 5.33 (d, J=8.0 Hz, 1H); 4.84 (m, 1H); 4.19 (m, 1H); 4.08 (m, 2H); 3.92 (t, J=7.4 Hz, 2H); 3.81 (dd, J=12.4, 3.2 Hz, 1H); 2.71 (t, J=7.4 Hz, 2H); 2.14 (br, 1H). MS (m/z): 343 [M+H].
………………………………..
WO2010091272A1
http://www.google.com/patents/WO2010091272A1?cl=en
Scheme 4 below.
Scheme 4. Example for synthesis of (isoxazole-3-yl)amino compounds of formula I.
a) Piperidin-4-one hydrochloride, DIEA, NMP, -5 0C to r.t; b) TMSOTf,
TEA, THF, 0 0C to r.t.; c) O-allyl-0′ -methyl carbonate, Pd(OAc)2, DMSO, 2,3,4,5-tetrafluoronitrobenzene, 60 0C; d) Fe, NH4Cl, EtOH, 95 0C; e) isobutyl chloroformate, Py, DCM, 0 0C to r.t.; f) two steps: 1) (Λ)-glycidyl butyrate or chlorohydrine, Bu1OLi, THF, MeCN, 0-30 0C; 2) 10% aq. K2CO3; g) MsCl, TEA, THF, 0 0C; h) 3-[N-(/er/-butoxycarbonyl)amino]isoxazole, Bu1OK, DMF, 20-40 0C; i) aq. HCl, EtOH, EtOAc, 0 0C to r.t.
Select innovative steps pertaining to the particular utility of Scheme 4 for an efficient synthesis and production of the compounds of formula I (illustrated by structure 26 in the Scheme 4) are summarized in paragraphs (i-iv) below:
i) The novel efficient method for an installation of the dihydropyridone ring into an ortho-F compound of formula I provided herein involve the use of an alkoxide (e.g, methoxide) capture reagent (e.g., 2,3,4,5-tetrafluoronitrobenzene). The dihydropyri done-forming step for a transformation of the compounds 19 to compounds 20 performed in absence of the methoxide-capture reagent(s) is accompanied by formation of the hard-to-remove ort/zo-methoxy impurity (e.g., l-(2,6-difluoro-3-methoxy-4-nitrophenyl)-2,3-dihydropyridone) resulted from undesired substitution of ortho-F atom with MeOH, AIkOH, or anion thereof. This is a serious problem specific for the synthesis of ortho-F dihydropyridone compounds, arising from the unique reactivity of ortho-F substrates 19 and may not be encountered in synthesis of des-ortho-F compounds lacking the key ortho-F substitution. The methods disclosed herein involve the use of a methoxide-capture nitrobenzene additive to eliminate or minimize above methoxy-aryl by-product to allow for a high-yielding preparation and manufacture of precursors 19 and compounds of formula I, with a purity suitable for pharmaceutical applications (generally, better than 90-95%). Additional MeO-capture additives may include acylating, alkylating, or arylating agents (e.g., carboxylic acid anhydride or an active ester capable of methoxide acylation). Optionally, one or more alkoxide-capture reagent(s), or a combination thereof can be used.
ii) New practical method for the key oxazolidinone-forming step (from
22 to 23) provided herin involves the use of an alkali metal alkoxide (e.g., LiOBu- 1) instead of the conventionally used BuLi (as more generally described, e.g., in J. Med. Chem., 1988, vol. 41, pp. 3727-3735). The procedure provided herein thus eliminates the use of a highly flammable and unstable organometallic chemical. Moreover, the new processes provided herein also eliminates the need for costly cryogenic (-78 0C) conditions impractical for the industrial manufacture of the reagents 23 and of the compounds of formula I. [00111] iii) Novel process for the preparation of 5-[(isoxazole-3-yl)amino]methyl derivatives 25 that employs an alkali metal alkoxide ( e.g., KOBu-t) in place of previously used NaH (as more generally described, e.g., in International Patent Publication No. WO 00/21960, incorporated herein by reference in its entirety). This eliminates the use of an extremely flammable base and allows for an efficient preparation and manufacture of the precursors 25 and the compounds of formula I.
iv) New practical method for the synthesis of the compounds of formula I
(Ri = (isoxazole-3-yl)amino; structure 26 in Scheme 4) employing aq. HCl – organic solvent(s) system for deprotection of acid-cleavable protective groups (PG; e.g., PG = tert-butoxycarbonyl or Boc group). The method provided herein eliminates the use of highly toxic and expensive reagents conventionally employed for des-ortho-F 1-phenyldihydropyridone compounds (the method as described, for example, in International Patent Publication No. WO 2004/033449, advocating the use of trifluoroacetic acid and 1 ,2-dichloroethane Boc-deprotection system). The efficiency of the new deprotection method invented herein is particularly surprising in view of the fact that enamino ketones (such as dihydropyridones) are generally degradable by a strong aqueous acids, such as aq. HCl (as more generally described, e.g., by Katritzky et al. in J. Chem. Research, Miniprint, 1980, pp. 3337-3360).
……………………………….
US8178683
https://www.google.com/patents/US8178683
Example 5 Compound of Structure
Scheme for Compound of Example 5
Intermediate 25.
Method A. A solution of tert-butyl isoxazol-3-ylcarbamate (187 mg, 1.00 mmol) in DMF (1 mL) was added dropwise with stirring to a suspension of NaH (60% in mineral oil, 48 mg, 1.20 mmol) in DMF (2 mL). The mixture was stirred under N2 for 15 min. at 35° C. The Intermediate 22 (357 mg, 0.85 mmol) in DMF (1 mL) was added, and the mixture was stirred at 50° C. for 1.5 h. The reaction mixture was taken into EtOAc (30 mL), washed with 10% aq. NH4Cl (2×15 mL), brine, and dried (Na2SO4). Solvent was removed under vacuum and the crude material was purified by column chromatography (2% MeOH/DCM) to afford the product as a light yellow solid.
Method B. A solution of tert-butyl isoxazol-3-ylcarbamate (694 mg, 3.8 mmol) in DMF (3 mL) was added dropwise with stirring to ButOK (439 mg, 3.8 mmol) in DMF (3 mL) at 0° C. The mixture was warmed up to r.t. and stirred for 30 min. The Intermediate 22 (1.34 g, 3.2 mmol) in DMF (6 mL) mL) was added, and the mixture was stirred at 35° C. for 2 h. The reaction was quenched with saturated aq. NH4Cl solution (10 mL), and isolation performed just as described above for Method A to afford the product as a light yellow solid. 1H NMR (400 MHz): 8.28 (s, 1H), 7.44 (m, 1H), 7.09 (d, J=7.6 Hz, 1H), 7.00 (s, 1H, 5.32 (d, J=7.6 Hz, 1H), 5.15 (m, 1H), 4.44 (m, 1H), 4.20 (m, 2H, 3.94 (m, 3H), 2.70 (t, J=7.4 Hz, 2H), 1.45 (s, 9H). MS (m/z): 509 [M+H].
Compound of Example 5
Method A. TFA (2.0 mL) was added dropwise to the solution of the Intermediate 25 (310 mg, 0.61 mmol) in 1,2-dichloroethane (DCE; 2 mL) at 0° C., and the solution was stirred at 0° C. for 30 min. Volatiles were removed under vacuum, and the residue taken into EtOAc (30 mL). The solution was washed with saturated NaHCO3 solution (2×15 mL), brine, and dried (Na2SO4). Solvent was removed under vacuum and the crude product was purified by column chromatography (3% MeOH/DCM). Light-yellow solid.
Method B. 4M HCl in THF (56 mL) was added dropwise to the Intermediate 25 (3.0 g, 5.9 mmol) at 0° C. Water (0.59 mL) was added, and the solution was stirred at r.t. for 2 h. Most of volatiles were removed under vacuum, the residue taken into water (30 mL) and sat. aq. NaHCO3 (15 mL), and pH adjusted to ca. 8. After stirring for 15 min, the mixture was extracted with EtOAc (3×60 mL). Combined organic layers were washed with brine (2×30 mL), and dried (Na2SO4). Solvent was removed under vacuum. The residue was re-dissolved in 2% MeOH in DCM (3 mL), and passed through a short pad of silica, eluting the product with 2% MeOH in DCM. Light-yellow solid. 1H NMR (400 MHz, DMSO-d6): 8.41 (d, J=1.6 Hz, 1H); 7.57 (m, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.58 (t, J=5.8 Hz, 1H), 6.02 (d, J=1.6 Hz, 1H), 5.08 (d, J=8.0 Hz, 1H), 4.90 (m, 1H), 4.17 (t, J=8.6 Hz, 1H), 3.86 (m, 3H), 3.48 (t, J=5.6 Hz, 2H), 2.49 (m, overlapped with DMSO-d6, 2H). MS (m/z): 409 [M+H].
pick up int 22
from below
Example 3 Compound of Structure
Scheme for Compound of Example 3
Intermediate 22. Methylsulfonyl chloride (MsCl; 79 uL, 1.00 mmol) was added dropwise with stirring to the compound of Example 1 (290 mg, 0.85 mmol) and TEA (177 uL, 1.27 mmol, 1.50 equiv.) in DCM (5 mL) at ca. 0° C. The mixture was stirred for 20 min and allowed to warm up to r.t. The reaction mixture distributed between water and the DCM. Aq. layer was extracted with DCM (2×10 mL), and the combined organic layers washed with brine and dried (Na2SO4). Solvent was removed under vacuum to afford the product that was used for the next step without purification.
Intermediate 23. A mixture of the Intermediate 22 (567 mg, 1.35 mmol) and NaN3 (438 mg, 6.75 mmol) in DMF (5 mL) was stirred at 55° C. o.n. After cooling to r.t., water (15 mL) was added, and the reaction mixture was extracted with DCM (3×30 mL). Combined organic layers were washed with brine (30 ml) and dried (Na2SO4). Solvent was removed under vacuum to afford the product as a light yellow solid. This was used directly for the next step without further purification.
Compound of Example 3. A mixture of the Intermediate 23 (785 mg, 2.14 mmol) and bicyclo[2.2.1]hepta-2,5-diene (2.2 mL, 21.4 mmol) in 1,4-dioxane (22 mL) under N2 was heated at 100° C. for 3 h. Most of volatiles were removed under vacuum, and the residue was purified by column chromatography (1% MeOH/DCM). Thus isolated product was recrystallized from MeOH. White solid. 1H NMR (400 MHz): 7.83 (s, 2H), 7.05 (m, 2H), 5.30 (d, J=8 Hz, 1H), 5.16 (m, 1H), 4.83 (d, J=3.6 Hz, 2H), 4.33 (m, 1H), 4.06 (m, 1H), 3.91 (t, J=14.8 Hz, 2H), 2.69 (t, J=14.8 Hz, 2H). MS (m/z): 394 [M+H].
| US5668286 * | Pharmacia & Upjohn Company | Oxazolidinone derivatives and pharmaceutical compositions containing them | ||
| US6919329 * | Feb 24, 2003 | Jul 19, 2005 | Pharmacia & Upjohn Company | N-Aryl-2-oxazolidinone-5-carboxamides and their derivatives |
| US7105547 * | Oct 3, 2003 | Sep 12, 2006 | Pharmacia And Upjohn Company | Antimicrobial 1-aryl dihydropyridone compounds |
| US7141588 * | Aug 22, 2003 | Nov 28, 2006 | Pfizer, Inc. | N-aryl-2-oxazolidinone-5-carboxamides and their derivatives |
| WO2003006440A2 | Jul 12, 2002 | Jan 23, 2003 | Jackson B Hester Jr | Amide-containing compound having improved solubility and method of improving the solubility of an amide-containing compound |
| WO2003072553A1 * | Feb 24, 2003 | Sep 4, 2003 | Upjohn Co | N-aryl-2-oxazolidinone-5-carboxamides and their derivates and their use as antibacterials |
| WO2004033449A1 * | Oct 3, 2003 | Apr 22, 2004 | Mikhail Fedor Gordeev | Antimicrobial 1-aryl dihydropyridone compounds |
| WO2004059120A1 | Dec 16, 2003 | Jul 15, 2004 | Baker Hughes Inc | Anchor device to relieve tension from the rope socket prior to perforating a well |
| WO2004087697A1 | Mar 22, 2004 | Oct 14, 2004 | Christina Renee Harris | N-aryl-2-oxazolidinone-5-carboxamides derivatives with antibacterial activity |
| WO2005019213A1 | Aug 9, 2004 | Mar 3, 2005 | Robert Charles Gadwood | N-aryl-2-cyanooxazolidinones and their derivatives |
| WO2005113520A1 | May 9, 2005 | Dec 1, 2005 | Michael Robert Barbachyn | Substituted 2,3,5-trifluorphenyl oxazolidinones for use as antibacterial agents |
| WO2006038100A1 | Oct 6, 2005 | Apr 13, 2006 | Ranbaxy Lab Ltd | Oxazolidinone derivatives as antimicrobials |
| WO2007000644A1 | Jun 20, 2006 | Jan 4, 2007 | Pharmacia & Upjohn Co Llc | Homomorpholine oxazolidinones as antibacterial agents |
| WO2007004049A1 | Jun 26, 2006 | Jan 11, 2007 | Pharmacia & Upjohn Co Llc | Oxazolidinones containing azetidine as antibacterial agents |
Moringa Oleifera Kills 97% of Pancreatic Cancer Cells in Vitro:
A hot-water extract of moringa leaves was shown to kill up to 97% of human pancreatic cancer cells (Panc-1) after 72 hours in this study. Moringa, also called the “miracle tree,” has a long history of use in traditional and Ayurvedic medicine due to its many beneficial properties as an anti-fungal, anti-bacterial, antidepressant, anti-diabetes, pain and fever reducer and even relief from asthma. But it also contains numerous powerful anti-cancer compounds such as kaempferol, rhamnetin, isoquercetin and others.
Latest research is now proving out moringa’s anti-cancer potential with positive results so far against ovarian cancer, liver cancer, lung cancer, and melanoma. Moringa is now extensively cultivated throughout Southeast Asia, Oceania, the Caribbean and Central America, but the largest crop in the world is produced by India – where it grows natively.
That may be one reason why the death rate from pancreatic cancer in India is a stunning 84% lower than in the United States.
http://www.ncbi.nlm.nih.gov/pubmed/23957955
POSIZOLID
252260-02-9 CAS NO
(5R)-3-[4-[1-[(2S)-2,3-Dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluorophenyl]-5-(1,2-oxazol-3-yloxymethyl)-1,3-oxazolidin-2-one
AstraZeneca (Originator)
AZD-2563, AZD-5847
Posizolid is an oxazolidinone antibiotic under investigation by AstraZeneca for the treatment of bacterial infections. At a concentration of 2 mg/L it inhibited 98% of all Gram-positive bacteria tested in vitro.[1]
Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtu), which in 1990 was declared a global epidemic by the World Health Organisation (WHO). It affects more than one third of the world’s population resulting in 8 million new patients and 2 million deaths every year. Also there exists a scenario called “Latent TB”, which occurs when germs remain in the body in a quiescent state but without any apparent effect on the health of the individual. In many cases this stage may last for many years or decades. In case of normal human being the chance of activation is 2-23% in a lifetime. However in case of immuno-compromised patients (like HIV) the chances of activation rise to 10% every year.
The current treatment of drug sensitive tuberculosis is at least six months long and requires a combination of isoniazid, rifampicin, pyrazinamide and ethambutol in the first two months followed by isoniazid and rifampicin for a period of four months. In recent years, drug resistance to these drugs has increased and the last of drugs for tuberculosis was introduced into clinical practice in the late 1960’s. The evolution of resistance could result in strains against which currently available antitubercular agents will be ineffective and treatment in such cases may last two years with no guarantee of cure. So there is an urgent need to introduce new drugs particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups and new treatment regimens to overcome not only rising drug resistance but also improve the overall treatment duration.
R. Sood et al (Infectious Disorders—Drug Targets 2006, 343-354) report that “Oxazolidinones are a new class of totally synthetic antibacterial agents with wide spectrum of activity against a variety of clinically significant susceptible and resistant bacteria. These compounds have been shown to inhibit translation at the initiation phase of protein synthesis. DuP-721, the first oxazolidinone showed good activity against M. tuberculosis when given orally or parenterally to experimental animals but was not developed further due to lethal toxicity in animal models. Later two oxazolidinones, PNU-100480 and Linezolid, demonstrated promising antimycobacterial activities in the murine model. While Linezolid has been approved for clinical use for broad spectrum area, PNU-100840 was not developed further. DA-7867 showed good in vitro and better in vivo efficacy than Linezolid but was poorly tolerated in rat toxicology studies. The antimycobacterial activity of AZD2563 has not been explored. RBx 7644 had modest antimycobacterial activity whilst RBx 8700 has potent antibacterial and concentration dependent activity against all slow growing mycobacteria. It demonstrated better activity than RBx 7644 against MDR strains of M. tuberculosis along with intracellular activity”.
In published patent application WO-99/64417 we disclose the compound
ie. (5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one also known as AZD2563. As reported by R. Sood et al (op cit) the antimycobacterial activity of AZD2563 has not been explored.
In a first aspect of the invention we now provide (5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, for use in the treatment of Mycobacterium tuberculosis.
The compound can form stable acid or basic salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following.
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, α-glycerophosphate. fumarate, hydrochloride, citrate, maleate, tartrate and hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such as lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. In one aspect of the invention the pharmaceutically-acceptable salt is the sodium salt.
Synthesis of 5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one (AZD 2563) is disclosed in our published patent application WO-99/64417.
……………….
http://www.google.com/patents/WO1999064417A2?cl=en
Example 22: 5(R)-IsoxazoI-3-yloxymethyl-3-(4-(l-(2(S)-hvdroxy-3-phosphoryl- propanovD-l^^S^-tetrahvdropyrid^-vπ^^-difluorophenvDoxazolidin^-one
To a stiπed solution of the starting material Reference Example 15 (lOOmg, 0.15mmol) in dioxan (1ml) was added 4M HCl / dioxan (3ml). The solution was stiπed at ambient temperature for 30 mins. and then evaporated. The residue was triturated well with ether giving the title compound as a white powder (80mg, 96%).
NMR (300Mz. DMS0-d6): 2.43 (m, partially obscured), 3.6 – 4.35 (m, 8H), 4.35 – 4.60 (m, 3H), 5.09 (m, IH), 5.85 (s, IH), 6.30 (s, IH), 7.31 (d, 2H), 8.60 (s, IH). MS: ESP+ (M+H) = 546.
…………………….
EP 1082323; JP 2002517498; WO 9964417
The condensation of the protected 3,5-difluoroaniline (I) with 1-benzyl-4-piperidone (II) by means of BuLi in THF gives 4-(1-benzyl-4-hydroxypiperidin-4-yl)-3,5-difluoroaniline (III), which is dehydrated with refluxing conc. HCl to yield the tetrahydropyridine (IV). The reaction of (IV) with benzyl chloroformate in acetone/water affords the carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) by means of BuLi in THF to provide the oxazolidinone (VII). The condensation of (VII) with isoxazol-3-ol (VIII) by means of PPh3 and DIAD in THF gives the expected ether adduct (IX), which is debenzylated by reaction with 1-chloroethyl chloroformate in dichloromethane, yielding the free tetrahydropyridine derivative (X). The condensation of (X) with (S)-2,3-O-isopropylideneglyceric acid (XI) by means of DEC or DCC and TEA in dichloromethane affords the corresponding acyl tetrahydropyridine (XII), which is finally deprotected with HCl in THF to provide the target dihydroxy compound.
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WO 0140236
The condensation of the protected 3,5-difluoroaniline (I) with 1-benzyl-4-piperidone (II) by means of BuLi in THF gives 4-(1-benzyl-4-hydroxypiperidin-4-yl)-3,5-difluoroaniline (III), which is dehydrated with refluxing conc. HCl to yield the tetrahydropyridine (IV). The reaction of (IV) with benzyl chloroformate in acetone/water affords the carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) by means of BuLi in THF to provide the oxazolidinone (VII). The condensation of (VII) with isoxazol-3-ol (VIII) by means of PPh3 and DIAD in THF gives the expected ether adduct (IX), which is debenzylated by reaction with 1-chloroethyl chloroformate in dichloromethane, yielding the free tetrahydropyridine derivative (X). The condensation of (X) with (S)-2,3-O-isopropylideneglyceric acid (XI) by means of DEC or DCC and TEA in dichloromethane affords the corresponding acyl tetrahydropyridine (XII), which is finally deprotected with HCl in THF to provide the target dihydroxy compound.
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2-10-2012
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Compound for the Treatment of Tuberculosis
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| WO1993022298A1 * | Apr 28, 1993 | Nov 11, 1993 | Hiroyuki Kawamura | Oxazolidine derivative and pharmaceutically acceptable salt thereof |
| WO1993023384A1 * | Apr 21, 1993 | Nov 25, 1993 | Michael Robert Barbachyn | Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials |
| WO1994022857A1 * | Apr 7, 1994 | Oct 13, 1994 | Masakazu Fukushima | Thiazolidine derivative and pharmaceutical composition containing the same |
| WO1997006791A1 * | Aug 13, 1996 | Feb 27, 1997 | Scripps Research Inst | METHODS AND COMPOSITIONS USEFUL FOR INHIBITION OF αvβ5 MEDIATED ANGIOGENESIS |
| WO1997009328A1 * | Aug 13, 1996 | Mar 13, 1997 | David J Anderson | Phenyloxazolidinones having a c-c bond to 4-8 membered heterocyclic rings |
| EP0645376A1 * | Sep 15, 1994 | Mar 29, 1995 | MERCK PATENT GmbH | Substituted 1-phenyl-oxazolidin-2-one derivatives, their preparation and their use as adhesion-receptor antagonists |
| EP0710657A1 * | Oct 19, 1995 | May 8, 1996 | MERCK PATENT GmbH | Antagonists of adhesion receptors |
BC-3781
Topical pleuromutilin antibiotic agent
Gram-positive, including MRSA, PHASE 2 COMPLETED
Nabriva (Austria)
SEE UPDATED POST AT https://newdrugapprovals.org/2014/10/10/nabrivas-lefamulin-bc-3781-receives-fda-fast-track-status-to-treat-cabp-and-absssi/ ………….C0NTAINS SYNTHESIS
BC-3781
The pleuromutilin BC-3781 belongs to the first generation of pleuromutilins to combine excellent oral
bioavailability with substantial activity against Gram-positive pathogens and atypicals as well as some
Gram-negative pathogens. In particular, BC-3781 is highly active against multi-drug resistant (MDR)
pathogens including methicillin resistant Staphylococcus aureus (MRSA), MDR Streptococcus pneumonia
(i.e. macrolide and quinolone resistance), and vancomycin resistant Enterococcus faecium. It is
characterized by excellent in vivo activities (e.g. pneumonia model), outstanding PK/PD parameters,
allowing once a day dosing, and a novel mode of action. BC-3781 is being developed for both oral and IV
administration and is intended for the treatment of serious multi-drug resistant skin & skin structure
infections (CSSI) and moderate to severe pneumonia (CAP, HAP etc).
Pleuromutilins have been known since 1951, but only entered the market
in 2007 with the approval of retapamulin for topical use. Until today, there are no pleuromutilins for systemic use approved in human clinical practice.
Nabriva is currently working on the development of new compounds is this class. The lead compound, BC-3781, if approved, will be the first pleuromutilin for systemic use in humans.
The compound shows potent in vitro activity against a large collection of staphylococci, streptococci, andE. faecium. When compared to linezolid and vancomycin, the compound shows greater overall potency againstS. aureus [121]. BC-3781 shows improved activity against most bacteria commonly associated with community-acquired respiratory tract infections, the compound is especially potent against S. pneumoniaincluding penicillin resistant strains. It also shows improved activity against H. influenza, M. catarrhalis, M. pneumoniae and C. pneumoniae.
BC-3781 is undergoing Phase I clinical trials for CAP and in March of 2011 has completed a Phase II clinical study comparing it to vancomycin for treatment of aBSSSI [119,120,121,122,123]. Nabriva Therapeutics AG announced that the cooperation with Forest Laboratories to develop the compound had elapsed, and that Nabriva retained all rights in BC-3781. The company informed that the product was Phase III ready and that it was seeking partners to continue further development [203].
Nabriva is also developing BC-7013 for topical use against Gram-positive infections and working on the discovery of new pleuromutilins [119,124].
Dr William Prince, CMO Nabriva Therapeutics commented:
“This is the first patient study with a systemic pleuromutilin. It will be an important proof of concept
for an exciting new class of antibiotics. The phase II study builds on our extensive preclinical and
phase I data which have demonstrated that BC-3781 can achieve therapeutically relevant blood and
tissue levels in man with excellent tolerability when administered by either oral or intravenous
routes.”
Dr. David Chiswell, CEO Nabriva Therapeutics commented:
“With a worldwide problem due to antibiotic resistant bacteria, there is a very significant need for
new classes of antibiotics with unique modes of action such as the pleuromutilins. The commercial
prospects for BC-3781 as the leading compound of an exciting new class are excellent, especially as it
has an ideal anti-bacterial spectrum for both skin and respiratory infections and is being developed
with both oral and intravenous formulations”
BC-3781 is highly active against key pathogens, including MRSA, associated with skin infections and
community and hospital acquired pneumonia and is more potent than Linezolid and vancomycin. The
compound’s novel mode of action ensures that it overcomes resistance mechanisms affecting all
approved classes of antibiotics. BC-378
About Nabriva Therapeutics
Nabriva Therapeutics is a biotechnology company focused on developing a new class of antibiotics for
the treatment of serious infections caused by resistant pathogens. Nabriva’s lead systemic product,
BC-3781, is being developed for the treatment of serious skin infections and bacterial pneumonia
caused by S. aureus, , S. pneumoniae, H. influenza, Mycoplasma, Legionella and other bacteria,
including drug resistant strains such as MRSA and vancomycin resistant E. faecium. In addition,
Nabriva Therapeutics’ topical pleuromutilin product candidate, BC-7013, is in clinical phase I. Nabriva
Therapeutics has a proven track record in world-class medicinal chemistry, clinical expertise, a
seasoned management team and solid IP. Nabriva Therapeutics is located in Vienna, Austria.
For more information on Nabriva please visit http://www.nabriva.com.
REF
http://www.phase4-partners.com/wp-content/uploads/2013/09/100412.pdf
http://www.glsv-vc.com/downloads/2010-06-02_First%20Patient_PressRelease.pdf
119
Nabriva. Pleuromutilins. Available online: http://www.nabriva.com/programs/pleuromutilins/ (accessed on 7 December 2012).
120
Forest Laboratories. Our pipeline: Solid, and set for further growth. Available online: http://www.frx.com/research/pipeline.aspx (accessed on 13 April 2013).
121
Sader, H.S.; Biedenbach, D.J.; Paukner, S.; Ivezic-Schoenfeld, Z.; Jones, R.N. Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. Antimicrob. Agents Chemother. 2012,56, 1619–1623, doi:10.1128/AAC.05789-11.
122
Sader, H.S.; Paukner, S.; Ivezic-Schoenfeld, Z.; Biedenbach, D.J.; Schmitz, F.J.; Jones, R.N. Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community-acquired respiratory tract infections (CARTIs). J. Antimicrob. Chemother. 2012, 67, 1170–1175, doi:10.1093/jac/dks001.
123
Nabriva Therapeutics AG. Study comparing the safety and efficacy of two doses of BC-3781 vs. vancomycin in patients with acute bacterial skin and skin structure infection (ABSSSI). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01119105 (accessed on 13 April 2013).
124
Novak, R. Are pleuromutilin antibiotics finally fit for human use? Ann. NY Acad. Sci. 2011, 1241, 71–81, doi:10.1111/j.1749-6632.2011.06219.x.
valnemulin
retapamulin
Human pluripotent stem cells (hPSCs) show great potential and versatility in regenerative medicine and new therapeutic approaches to fight disease. Patient-specific, individualized treatments using stem cells have even been generated for a number of diseases. Although further research into hPSCs is needed in order to harness their full potential, preserving the stem cells and storing them in the large numbers required for research has proved difficult.
Teruo Akuta and colleagues at the RIKEN Center for Developmental Biology, together with scientists from the Foundation for Biomedical Research and Innovation, have now developed a cost-effective, efficient and reliable slow-freezing method for preserving hPSCs in large numbers with a high survival rate.
Vitrification, which involves the use of cryoprotectants to chill cells to low temperatures without freezing, and conventional slow-freezing techniques are currently used for the cryopreservation of hPSCs. “Vitrification using liquid nitrogen is a highly skilled task,” notes Akuta, “and is not…
View original post 263 more words
Plazomicin
Plazomicin is a neoglycoside antibiotic with activity against a broad range of Gram-positive and Gram-negive pathogens. Plazomicin showed potent in vitro activity against multidrug-resistant Klebsiella pneumoniae and Escherichia coli.
| Synonyms: O-2-Amino-2,3,4,6-tetradeoxy-6-[(2-hydroxyethyl)amino]-α-D-glycero-hex-4-enopyranosyl-(1→4)-O-[3-deoxy-4-C-methyl-3-(methylamino)-β-L-arabinopyranosyl-(1→6)]-N1-[(2S)-4-amino-2-hydroxy-1-oxobutyl]-2-deoxy-D-streptamine; ACHN 490; |
| CAS Number: 1154757-24-0 |
| Achaogen (USA)Phase II completed |
| Mol. Formula: C25H48N6O10 |
| Aminoglycosides, Broad-spectrum, |
| Mol. Weight: 592.68 |
To continue the development of plazomicin, the company has received a contract option of US$ 60M from the Biomedical Advanced Research and Development Authority (BARDA) to support a global Phase III clinical study. The study will evaluate plazomicin in treating patients with serious Gram-negative bacterial infections due to carbapenem-resistant Enterobacteriaceae. The study is expected to start in the fourth quarter of 2013 [4].
Achaogen (a-KAY-o-jen) is developing plazomicin, its lead product candidate, for the treatment of serious bacterial infections due to MDR Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae, or CRE. In 2013, the Centers for Disease Control and Prevention identified CRE as a “nightmare bacteria” and an immediate public health threat that requires “urgent and aggressive action.” We expect to initiate a Phase 3 superiority trial of plazomicin in the first quarter of 2014.
CRE are one of many types of MDR gram-negative pathogens threatening patients. Bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, and extended-spectrum beta-lactamase producing Enterobacteriaceae each pose “serious” resistance threats, according to the CDC, and also drive a great need for new, safe, and effective antibiotics. We have assembled the chemistry and microbiology expertise and capabilities required to develop new agents for the treatment of gram-negative infections. Plazomicin was the first clinical candidate from our gram-negative antibiotic discovery engine. In addition, our research and development pipeline includes two antipseudomonal programs targeting P. aeruginosa—a program to discover and develop small molecule inhibitors of LpxC, which is an enzyme essential for the synthesis of the outer membrane of gram-negative bacteria, and a therapeutic antibody program. We are also pursuing small molecule research programs targeting other essential gram-negative enzymes.
Achaogen has built an exceptional research and development team with deep expertise in the discovery and development of new drugs from research through commercialization. Our executive team has over 60 years of combined industry experience, and a proven track record of leadership, global registration, and lifecycle management for over 20 products. Our facility is located on the shores of the San Francisco Bay, ten minutes from the San Francisco International Airport, and only fifteen minutes from downtown San Francisco.
http://www.google.com/patents/US20100099661
Common Intermediates Sisomicin
Amberlite IRA-400 (OH form) (200 g) was washed with MeOH (3×200 m1). To a stirring suspension of the washed resin in MeOH (150 mL) was added sisomicin sulfate (20.0 g, 0.029 mol) and the mixture was stirred overnight. The resin was then filtered and washed with MeOH (100 mL) and the combined organic layers were concentrated to dryness to yield the desired sisomicin (11.57 g, 0.026 mol, 89.6% yield): MS m/e [M+H]+ calcd 448.3, found 448.1.
Example 1 6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin
6′-(2-tert-Butyldimethylsililoxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin
2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (0.10 g, 0.105 mmol) was treated with tert-butyldimethylsilyloxy acetaldehyde following Procedure 1-Method A to yield the desired 6′-(2-tert-butyldimethylsilyloxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (MS m/e [M+H]+ calcd 1107.6, found 1107.4), which was carried through to the next step without further purification.
6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin
6′ -(2-tert-butyldimethylsililoxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (0.105 mmol) was submitted to Procedure 3-Method B for Boc removal to yield a crude, which was purified by RP HPLC Method 1-Column A to yield 6′-(2-hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin: MS m/e [M+H]+ calcd 593.3, found 593.2, [M+Na]+615.3 ; CLND 97.5% purity.
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4-23-2010
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ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
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| US8318685 | Nov 14, 2011 | Nov 27, 2012 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8367625 | Apr 7, 2011 | Feb 5, 2013 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8372813 | Apr 7, 2011 | Feb 12, 2013 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8377896 | Mar 9, 2011 | Feb 19, 2013 | Isis Pharmaceuticals, Inc | Antibacterial 4,6-substituted 6′, 6″ and 1 modified aminoglycoside analogs |
| US8399419 | Mar 9, 2011 | Mar 19, 2013 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8481502 | Apr 6, 2012 | Jul 9, 2013 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8492354 | Nov 14, 2011 | Jul 23, 2013 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8524675 | Nov 14, 2011 | Sep 3, 2013 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8524689 | Nov 14, 2011 | Sep 3, 2013 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8569264 | Jan 5, 2012 | Oct 29, 2013 | Isis Pharmaceuticals, Inc. | Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents |
| US8653041 | Oct 15, 2012 | Feb 18, 2014 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8653042 | Nov 14, 2011 | Feb 18, 2014 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
| US8658606 | Nov 14, 2011 | Feb 25, 2014 | Achaogen, Inc. | Antibacterial aminoglycoside analogs |
7-[(4S)-4-Amino-6-azaspiro[2.4]heptan-6-yl]-8-chloro-6-fluoro-1-[(2S)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid
(1R-(1a(S*),2a))-7-(7-Amino-5-azaspiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-(2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic Acid
SYNTHESIS……….http://www.drugfuture.com/synth/syndata.aspx?ID=176447
127254-10-8 [RN]
127254-10-8(ACETATE)
Sitafloxacin (INN; also called DU-6859a) is a fluoroquinolone antibiotic[1] that shows promise in the treatment of Buruli ulcer. The molecule was identified by Daiichi Sankyo Co., which brought ofloxacin and levofloxacin to the market. Sitafloxacin is currently marketed in Japan by Daiichi Sankyo under the tradename Gracevit.
Sitafloxacin is a new-generation, broad-spectrum oral fluoroquinolone antibiotic.It is very active against many Gram-positive, Gram-negative and anaerobic clinical isolates, including strains resistant to other fluoroquinolones, was recently approved in Japan for the treatment of respiratory and urinary tract infections. Sitafloxacin is active against methicillin-resistant staphylococci, Streptococcus pneumoniae and other streptococci with reduced susceptibility to levofloxacin and other quinolones and enterococci
AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127
The condensation of 3-chloro-2,4,5-trifluorobenzoylacetic acid ethyl ester (I) with (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) and ethyl orthoformate (II) in hot acetic anhydride gives (1R,2S)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(2-fluorocyclopropylamino)acrylic acid ethyl ester (IV). The cyclization of (IV) by means of NaH yields the quinolone (V), which is hydrolyzed with HCl to the free acid (VI). The condensation of (VI) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) by means of triethylamine in refluxing acetonitrile affords the protected final product (VIII), which is finally deprotected with trifluoroacetic acid and anisole.
The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) is obtained as follows: 1) The cyclization of butadiene (IX) with dibromofluoromethane by means of BuONa, followed by oxidation with KMnO4, esterification with ethanol – sulfuric acid and reduction with tributyltin hydride gives 2-fluorocyclopropanecarboxylic acid ethyl ester as a cis/trans mixture (X), which is separated by crystallization. The cis-racemic-isomer (XI) is hydrolyzed with NaOH to the corresponding acid (XII), which is condensed with (R)-alpha-methylbenzylamine (XIII) by means of diphenyl chlorophosphate to give the mixture of diastereomers (XIV). This mixture is separated by crystallization, yielding pure (1S,2S)-2-fluoro-N-[alpha(R)-methylbenzyl]cyclopropanecarboxamide (XV), which is hydrolyzed with HCl to the corresponding free acid (XVI). Finally, this compound is converted into (III) by treatment with diphenylphosphoryl azide in refluxing tert-butanol.
b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 1) The cyclopropanation of ethyl acetoacetate (XXXI) with 1,2-dibromoethane (XXXII) by means of K2CO3 in DMF gives 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII), which is brominated with Br2 in ethanol yielding the bromoacetyl derivative (XXXIV). The cyclization of (XXXI) with (R)-alpha-methylbenzylamine (XIII) by means of triethylamine affords 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), which by reaction with hydroxylamine is converted into the monooxime (XXXVI). The reduction of (XXXVI) with H2 over RaNi in methanol affords 7-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one as a diastereomeric mixture (XXXVII) + (XXXVIII), which is separated by column chromatography. The reduction of the (7S)-isomer (XXXVIII) with LiAlH4 in THF gives 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXXIX), which is protected in the usual way to the tert-butoxycarbonyl derivative (XL). Finally, this compound is debenzylated to (VII) by hydrogenation with H2 over Pd/C in ethanol.
The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) is obtained as follows: 1) The cyclization of butadiene (IX) with dibromofluoromethane by means of BuONa, followed by oxidation with KMnO4, esterification with ethanol – sulfuric acid and reduction with tributyltin hydride gives 2-fluorocyclopropanecarboxylic acid ethyl ester as a cis/trans mixture (X), which is separated by crystallization. The cis-racemic-isomer (XI) is hydrolyzed with NaOH to the corresponding acid (XII), which is condensed with (R)-alpha-methylbenzylamine (XIII) by means of diphenyl chlorophosphate to give the mixture of diastereomers (XIV). This mixture is separated by crystallization, yielding pure (1S,2S)-2-fluoro-N-[alpha(R)-methylbenzyl]cyclopropanecarboxamide (XV), which is hydrolyzed with HCl to the corresponding free acid (XVI). Finally, this compound is converted into (III) by treatment with diphenylphosphoryl azide in refluxing tert-butanol.
b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 2) The reaction of 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII) with (R)-alpha-methylbenzylamine (XIII) by means of NaOH and ethyl chloroformate gives the corresponding amide (XLI), which by reaction with ethylene glycol and p-toluenesulfonic acid is converted into the ethylene ketal (XLII). The bromination of (XLII) with Br2 in dioxane affords the bromomethyl dioxolane (XLIII), which is finally cyclized to 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), already obtained as an intermediate in the preceding synthesis.
The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) can also be obtained as follows: 3) A study of the influence of different substituents in the cis/trans ratio of the cyclopropanation process has been performed. The general method is as follows: the reaction of benzylamine (XXIII) with acetaldehyde and trichloromethyl chloroformate gives the N-benzyl-N-vinylcarbamoyl chloride (XXIV), which by treatment with alcohol yields the N-vinylcarbamate (XXV). The cyclopropanation of (XXV) with fluorodiiodomethane and diethyl zinc as before preferentially affords the cis-N-(2-fluorocyclopropyl)carbamate (XXVI), which is purified by crystallization. The hydrogenolysis of (XXVI) with H2 over Pd/C in acetic acid gives cis-racemic-2-fluorocyclopropylamine (XXVII), which is submitted to optical resolution with L-menthyl chloroformate to afford pure (1R,2S)-isomer (XXII). Finally, this compound is converted into (III) with tert-butoxycarbonyl anhydride as before.
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3-7-2012
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Method for Production of Quinolone-Containing Lyophilized Preparation
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12-5-2007
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Stabilized liquid preparation
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8-24-2007
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PHARMACEUTICAL COMPOSITION
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6-29-2007
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PHARMACEUTICAL COMPOSITION
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7-15-2005
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Pharmaceutical composition
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3-2-2005
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Highly absorptive solid preparation
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7-9-2004
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Highly absorbable solid preparation
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2-6-2004
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Medicinal composition
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12-17-1999
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NOVEL THERAPEUTIC AGENTS THAT MODULATE ENZYMATIC PROCESSES
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Men suffering from sexual dysfunction can be successful at reversing their problem, by focusing on lifestyle factors and not just relying on medication, according to new research at the University of Adelaide.
In a new paper published in the Journal of Sexual Medicine, researchers highlight the incidence of erectile dysfunction and lack of sexual desire among Australian men aged 35-80 years.
Over a five-year period, 31% of the 810 men involved in the study developed some form of erectile dysfunction.
“Sexual relations are not only an important part of people’s wellbeing. From a clinical point of view, the inability of some men to perform sexually can also be linked to a range of other health problems, many of which can be debilitating or potentially fatal,” says Professor Gary Wittert, Head of the Discipline of Medicine at the University of Adelaide and Director of the University’s Freemasons Foundation Centre for…
View original post 255 more words
New Drug Approvals 