AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Cicaprost ZK-96480

 phase 2, Uncategorized  Comments Off on Cicaprost ZK-96480
Jan 132014
 

http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0094079808

Cicaprost

94079-80-8 , as in entry 4 ,  J. Org. Chem. 1988,53,1227-1231

ZK-96480

phase 2

Bayer Schering Pharma (Originator)

2-​[2-​[(2E,​3aS,​4S,​5R,​6aS)-​hexahydro-​5-​hydroxy-​4-​[(3S,​4S)-​3-​hydroxy-​4-​methyl-​1,​6-​nonadiyn-​1-​yl]-​2(1H)-​pentalenylidene]ethoxy]-​acetic acid

13,14-Didehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6-carbaprostaglandin I2;

5-(7-Hydroxy-6-(3-hydroxy-4-methylnona-1,6-diynyl)-bicyclo(3.3.0)octan-3-yliden)-3-oxapentanoic acid;

2-[(2E,3aβ,6aβ)-4β-[(3S,4S)-3-Hydroxy-4-methyl-1,6-nonadiynyl]-5α-hydroxyoctahydropentalene-2-ylidene]ethoxyacetic acid;

[2-[(2E,3aβ,4S,6aβ)-4β-[(3S,4S)-3-Hydroxy-4-methyl-1,6-nonadiynyl]-5α-hydroxyoctahydropentalene-2-ylidene]ethoxy]acetic acid;

[2-[[(2E,3aS,3aβ,6aβ)-5α-Hydroxy-4β-[(3S,4S)-3-hydroxy-4-methyl-1,6-nonanediynyl]octahydropentalen]-2-ylidene]ethoxy]acetic acid;

Acetic acid, ((2E)-2-((3as,4S,5R,6as)-hexahydro-5-hydroxy-4-((3S,4S)-3-hydroxy-4-methyl-1,6-nonadiynyl)-2(1H)-pentalenylidene)ethoxy)-;

2-[2-[(2E,3aS,4S,5R,6aS)-Hexahydro-5-hydroxy-4-[(3S,4S)-3-hydroxy-4-Methyl-1,6-nonadiyn-1-yl]-2(1H)-pentalenylidene]ethoxy]acetic Acid;

Acetic acid, (2-(hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1,6-nonadiynyl)-2(1H)-pentalenylidene)ethoxy)-, (3as-(2E,3aalpha,4alpha(3R*,4R*),5beta,6aalpha))-

Molecular Formula C22H30O5
Formula Weight 374.5

Prostaglandin I2 (PGI2, prostacyclin) is the most potent endogenous vasodilator that affects both the systemic and pulmonary circulation.Cicaprost is a PGI2 analog that is orally active with prolonged availabilityin vivo, having a terminal half life in plasma of one hour. In addition to their effects on smooth muscle, PGI2 analogs, including cicaprost, have been shown to inhibit the pro-inflammatory actions of certain leukocytes, suppress cardiac fibrosis, and block mitogenesis of certain cell types.Importantly, cicaprost has been shown to strongly reduce lung and lymph node metastasis in rats, suggesting that it might be useful in cancer therapy.

cicaprost

references

1. Drugs Fut 1986, 11(11): 913

2. Synthesis of a new chemically and metabolically stable prostacyclin analogue with high and long-lasting oral activity
J Med Chem 1986, 29(3): 313

 

3. Journal of Organic Chemistry, 1988 ,  vol. 53,  6  p. 1227 – 1231 entry4

http://pubs.acs.org/doi/pdf/10.1021/jo00241a020

 

4. Journal of the American Chemical Society, 2003 ,  vol. 125,  32  p. 9653 – 9667, nmr

5. WO 2009068190

6. US 5013758

7. WO 2005009446

8. WO 1992014438

9. US2007/196510 A1

10. US2007/293552 A1

11. US2009/221549 A1

12. US2009/54473 A1

 

EP0041661A2 * May 29, 1981 Dec 16, 1981 Schering Aktiengesellschaft Preparation of intermediates of carbaprostacyclines
EP0057660A2 * Feb 1, 1982 Aug 11, 1982 Schering Aktiengesellschaft Prostacycline derivatives, their preparation and applications as medicines
EP0086404A1 * Feb 3, 1983 Aug 24, 1983 Schering Aktiengesellschaft Carbacyclines, process for their preparation and their use as medicines
EP0086612A1 * Feb 7, 1983 Aug 24, 1983 The Upjohn Company 9-Substituted carbacyclin analogues
EP0087237A1 * Feb 7, 1983 Aug 31, 1983 The Upjohn Company Carbacyclin analogues
EP0098793A1 * Jul 1, 1983 Jan 18, 1984 Schering Aktiengesellschaft Carbacycline amides, process for their preparation and their use as medicines
EP0155901A1 * Mar 6, 1985 Sep 25, 1985 Schering Aktiengesellschaft Carbacyclines, process for their preparation and their use as medicines
EP0195379A2 * Mar 14, 1986 Sep 24, 1986 G.D. Searle & Co. Allenic prostacyclins
EP0195668A2 * Mar 19, 1986 Sep 24, 1986 Sankyo Company Limited Carbacyclin derivatives
EP0721783A1 * Jun 6, 1995 Jul 17, 1996 Toray Industries, Inc. Preventive and remedy for diseases caused by fibrinoid or thrombus formation in the lung and model animal for said diseases
EP2065054A1 Nov 29, 2007 Jun 3, 2009 Bayer Schering Pharma Aktiengesellschaft Combinations comprising a prostaglandin and uses thereof
DE3427797A1 * Jul 25, 1984 Feb 6, 1986 Schering Ag Zytoprotektive wirkung von prostacyclin-derivaten an leber, bauchspeicheldruese und niere
DE3448256C2 * Jul 25, 1984 Aug 18, 1988 Schering Ag, 1000 Berlin Und 4709 Bergkamen, De Cytoprotective action of prostacyclin derivatives on the pancreas
DE3448257C2 * Jul 25, 1984 Aug 18, 1988 Schering Ag, 1000 Berlin Und 4709 Bergkamen, De Cytoprotective action of prostacyclin derivatives on the kidney
DE4135193C1 * Oct 22, 1991 Mar 11, 1993 Schering Ag Berlin Und Bergkamen, 1000 Berlin, De Title not available
US5405870 * Nov 4, 1993 Apr 11, 1995 Sankyo Company, Limited Carbacyclin compounds; pharmaceutical compositions and method of use
US5489613 * Jan 21, 1992 Feb 6, 1996 Sankyo Company, Limited Carbacyclin derivatives, process for their preparation and compositions containing them
US5716989 * Nov 27, 1991 Feb 10, 1998 Schering Aktiengesellschaft Bicyclo 3.3.0!octane derivatives, process for their production and their pharmaceutical use
US5891910 * Jun 6, 1995 Apr 6, 1999 Schering Aktiengesellschaft 9-halogen-(Z) prostaglandin derivatives, process for their production and their use as pharmaceutical agents
US6040336 * Aug 6, 1996 Mar 21, 2000 Schering Aktiengesellschaft Prostane derivatives and the combination thereof with antibiotics in the treatment of bacterial infections
US6225347 Sep 27, 1994 May 1, 2001 Schering Aktiengesellschaft 9-halogen-(Z)-prostaglandin derivatives, process for their production and their use as pharmaceutical agents
WO1986000808A1 * Jul 18, 1985 Feb 13, 1986 Schering Ag Prostacycline derivatives with a cytoprotective action on the liver, the pancreas and the kidney
WO1987005294A1 * Mar 9, 1987 Sep 11, 1987 Schering Ag Cyclodextrinclathrates of carbacycline derivatives and their use as medicinal drugs
WO1988001867A1 * Sep 1, 1987 Mar 24, 1988 Schering Ag Topical agent containing prostacycline derivatives
WO1991014675A1 * Mar 27, 1991 Sep 29, 1991 Schering Ag Bicyclo[3.3.)]octane derivatives, process for producing them and their pharmaceutical use
WO1992014438A2 * Feb 11, 1992 Aug 13, 1992 Schering Ag Prostacycline and carbacycline derivatives as agents for treating feverish complaints
WO1994003175A1 * Aug 9, 1993 Feb 17, 1994 Schering Ag Use of prostane derivatives of formulae i and ii for the production of a medicament for the treatment of chronic polyarthritis
WO1997006806A1 * Aug 6, 1996 Feb 27, 1997 Schering Ag Use of prostane derivatives and the combination thereof with antibiotics in the treatment of bacterial infections

 

cicaprost

 

…………………………

Journal of Organic Chemistry, 1988 ,  vol. 53,  6  p. 1227 – 1231 entry4

http://pubs.acs.org/doi/pdf/10.1021/jo00241a020

ZK 96 480 (4). A solution of 19 (68 mg, 0.13 mmol) in eth-
er-toluene (3 mL, 2:l) was added to tetrabutylammonium hydrogen sulfate containing HzO (2 drops). After adding 50% aqueous NaOH (0.8 mL), the whole reaction mixture was stirred at 55 “C for 48 h. The reaction was quenched with HzO, acidified with 5% aqueous HC1, extracted with ethyl acetate, washed withH20 and brine, and concentrated to give ZK 96 480 (4) (42 mg, 86%) as a colorless viscous oil:

[alZzD +138.25O (c 1.025, CHCI,). see pdf file for correct cut paste

Other spectral data were identical with those of an authentic
sample.’

(1) Skuballa, W.; Schillinger, E.; Stiinebecher, C.-St.; Vorbriiggen, H.
J. Med. Chem. 1986,29, 313.

……………………………….

Skuballa, W.; Schillinger, E.; Stiinebecher, C.-St.; Vorbriiggen, H.
J. Med. Chem. 1986,29, 313.

http://pubs.acs.org/doi/pdf/10.1021/jm00153a001

see original pdf file for structures

we replaced the methylene group in the
3-position of 1, iloprost by an oxygen atom to prevent the 6-oxi-
dation of the upper side chain. The resulting decrease in
intrinsic activity was compensated for by modification of
the lower side chain. We converted the 13,14-double bond
into a triple bond, introduced a further methyl group at
(2-20, and synthesized selectively the pure 16(S)-methyl
diastereomer. These modifications resulted in the struc-
ture of 2 cicaprost (ZK 96 480), a carbacyclin analogue with a bio-
logical activity at least as high as that of prostacyclin and
iloprost.
The synthesis of 2 started with the preparation of the
lower side chain by resolving racemic 2-methyl-4-heptynoic
acid (3).7 By application of the method of Helmchen et
al.,” 3 was converted with phosphorus trichloride into the
acid chloride 4, which gave with D-(-)-a-phenylglycinol a
pair of diastereomeric amides. After chromatographic
separation on SOz, the more polar amide 5 (mp 124 ‘C)
was hydrolyzed with 3 N H2S04 in dioxane to furnish the
optically pure 2s-configurated acid 6 ([a]D -1.2’ (c 1,
EtOH), bp 128 ‘C (12 mm)). The 2s configuration of 6
was determined by hydrogenation of 6 to 2(S)-methyl-
heptanoic acid ([“ID +17.7′ (c 1, EtOH)), which was com-
pared with 2-methyl-alkanoic acids of known absolute
config~ration.~ Esterification of 6 with diazomethane
followed by reaction of the methyl ester 7 ([a]D +12.2’ (c
1, EtOH), bp 70 ‘C (12 mm)) with the lithium salt of ethyl
methylphosphonate afforded the optically pure phospho-
nate 8 ([‘Y]D +35.3’ (c 1, EtOH), bp 123 “C (0.3 mm)).

Condensation of the phosphonate 8 with the readily
available optically pure bicyclic aldehyde 93,4 (NaH, DME,

-20 “C) in the presence of N-bromosuccinimide furnished
the a,P-unsaturated bromo ketone 10 in 60% yield: oil;
(3 H, d, J = 7 Hz, CHCH,), 3.91 (4 H, m, OCH2CH20), 5.21
(1 H, m, H-llp), 7.09 (1 H, d, J = 10 Hz, H-13), 7.42-7.92
(5 H, m, COPh); IR (neat) 1720 (COPh), 1690 (COC=C)
cm-‘. Reduction of 10 (NaBH,, CH,OH, -40 “C) gave a
ca. 1:l mixture of the allylic alcohols lla and llb, which
was separated chromatographically.’O Dehydrobromina-
tion (50% aqueous NaOH, toluene, catalytic NBu4/HS04,
25 “C) of the less polar alcohol lla with concomitant sa-
ponification of the benzoate group followed by acidic
(HOAc, H20) cleavage of the ketal moiety afforded the
ketone 12 (73% from lla): oil; ‘H NMR (CD2C12) 6 1.06
(3 H, d, J = 6.8 Hz, CHCH,), 1.10 (3 H, t, J = 7.5 Hz,
CH,CH,), 4.22 (1 H, m, H-llb), 4.38 (1 H, m, H-158); IR
(neat) 1730 (C=O) cm-‘. After silylation of the hydroxyl
groups in 12 (C1SiMe2-t-Bu, DMF, imidazole), the ketone
13 was subjected to a Horner-Wittig reaction with triethyl
phosphonoacetate (KO-t-Bu, THF, 0 “C). Reduction of
the 1:l mixture of the isomeric a,p-unsaturated esters 14
with diisobutylaluminum hydride (toluene, 0 “C) gave after
chromatographic separation the E isomer 15a (32% from
12) and the less polar 2 isomer 15b.11

Etherification of 15a under phase-transfer conditions
with tert-butyl bromoacetate (50% aqueous NaOH, tolu-
ene, catalytic Bu4NHS04, 25 “C) was accompanied by
simultaneous cleavage of the tert-butyl ester to give 16
(87%). Finally, removal of the silyl ether groups (tetra-
n-butylammonium fluoride, THF, 25 “C) afforded 2 cicaprost,  in
86% yield: oil;

‘H NMR (CD,Cl,) 6= delta    1.07 (3 H, d, J = 6.8
Hz), 16@-CH3), 1.11 (3 H, t, J = 7.5 Hz, CH2CH3), 3.97 (1
H, m, H-llP), 4.06 (2 H, m, OCH,CO), 4.12 (2 H, m, =
H, m, H-5); IR (neat) 1730 (COOH) cm-‘.

 

………………

J. Am. Chem. Soc., 2003, 125 (32), pp 9653–9667
DOI: 10.1021/ja030200l

Abstract Image

 

An asymmetric synthesis of the anti-metastatic prostacyclin analogue cicaprost and a formal one of its isomer isocicaprost by a new route are described. A key step of these syntheses is the coupling of a chiral bicyclic C6−C14 ethynyl building block with a chiral C15−C21 ω-side chain amide building block with formation of the C14−C15 bond of the target molecules.

A highly stereoselective reduction of the thereby obtained C6−C21 intermediate carrying a carbonyl group at C15 of the side chain was accomplished by the chiral oxazaborolidine method. The chiral phosphono acetate method was used for the highly stereoselective attachment of the α-side chain to the bicyclic C6−C21 intermediate carrying a carbonyl group at C6.

Asymmetric syntheses of the bicyclic C6−C14 ethynyl building blocks were carried out starting from achiral bicyclic C6−C12 ketones by using the chiral lithium amide method. In the course of these syntheses, a new method for the introduction of an ethynyl group at the α-position of the carbonyl group of a ketone with formation of the corresponding homopropargylic alcohol was devised.

Its key steps are an aldol reaction of the corresponding silyl enol ether with chloral and the elimination of a trichlorocarbinol derivative with formation of the ethynyl group. In addition, a new aldehyde to terminal alkyne transformation has been realized. Its key steps are the conversion of an aldehyde to the corresponding 1-alkenyl dimethylaminosulfoxonium salt and the elimination of the latter with a strong base.

Two basically different routes have been followed for the synthesis of the enantiomerically pure C15−C21 ω-side chain amide building block. The first is based on the chiral oxazolidinone method and features a highly stereoselective alkylation of (4R)-N-acetyl-4-benzyloxazolidin-2-one, and the second encompasses a malonate synthesis of the racemic amide and its efficient preparative scale resolution by HPLC on a chiral stationary phase containing column

 

…….

https://www.google.co.in/patents/EP0119949A1

(5E) -13,14,18,13,19,19-Hecadehydro-3-oxa-6a-carba-prostaglandin I 2derivatives of the general formula I

Figure imgb0016

(5E) – (16S) -13,14-didehydro-16 ,20-dimezhyl-3-oxa-18 ,18,19,19-tetradehydro-6a-carbaprostaglandin 1 2

      Example 1(5E) – (16S) -13,14-didehydro-16 ,20-dimezhyl-3-oxa-18 ,18,19,19-tetradehydro-6a-carbaprostaglandin 1

2

    • [0028]
      To a solution of 0.4 g in 12 ml of tetrahydrofuran was added to 80 mg of 55% sodium hydride (in mineral oil) and cook for 1 hour reflux. Is added to a solution of 127 mg of bromoacetic in 4 ml of tetrahydrofuran, boiled under reflux for 18 hours, diluted with ether and extracted four times with 30 ml of 5% sodium hydroxide. This extract is adjusted with 10% sulfuric acid at 0 ° C to pH 3 and extracted with methylene chloride. The organic extract is shaken with brine, dried over magnesium sulfate and evaporated under vacuum. Obtained 220 mg hydropyranyläther), which are for the elimination of the protective groups is stirred for 18 hours with 15 ml of acetic acid / water / tetrahydrofuran (65/35/10) at 25 ° C. It is evaporated to the addition of toluene, and the residue is chromatographed on silica gel with ethyl acetate / 0.1 – 1% acetic acid. This gives 145 mg of the title compound as a colorless Ö1.
    • [0029]
      IR (CHC1 3): 3600, 3400 (broad), 2 93 0 222 3, 1730, 1600, 1425, 1380/cm.
    • [0030]
      The starting material for the above title compound is prepared as follows:

1 a)

    • [0031]
      To a suspension of 3.57 g of sodium hydride (55% in mineral oil) in 360 ml of dimethoxyethane was added dropwise at O ​​° C, a solution of 21.9 g of 3-methyl-2-oxo-oct-5-in-phosphonsäuredimethyl esters in 140 ml of dimethoxyethane was stirred for 1 hour at 0 ° C and then add 14.56 g of finely powdered N-bromosuccinimide. It is stirred for 1 hour at O ° C, treated with a solution of 22.5 g of (lR, 5S, 6R, 7R) -3,3 – ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo [3.3.0] octane in 180 ml of dimethoxyethane and 4 hours the mixture is stirred at 0 ° C. The reaction mixture is diluted with 3 1 ether, washed neutral with brine, dried with sodium sulfate and evaporated in vacuo. The residue is chromatographed with hexane / ether as eluent on silica gel. Following three chromatography of the respective diastereomeric mixed fractions obtained as polar compound 8.1 g and a polar compound 7.4 g of the title compound as colorless oils.
    • [0032]
      IR: 2935, 2878, 17 15, 1690, 1601, 1595, 1450, 1270, 948/cm.

1 b)

    • [0033]
      To a solution of 7.4. G of produced according to Example 1 a) ketone in 140 ml of methanol is added at -20 ° C. 3 g of sodium borohydride in portions and stirred for 30 minutes at -20 ° C. Then diluted with ether, washed neutral with water, dried over magnesium sulfate and evaporated under vacuum.
    • [0034]
      The crude product (15-epimer) is dissolved in 300 ml of methanol, added to 2.95 g of potassium carbonate and stirred for 21 hours at 23 ° C under argon. Then concentrated in vacuo, diluted with ether and washed neutral with brine. It is dried over magnesium sulfate and evaporated under vacuum. By column chromatography on silica gel with ether / methylene chloride (7 +3) first obtained 2.6 g of the 15SS-configured alcohol as well as 2.1 g of the more polar component 15a-configured alcohol (PG nomenclature) as colorless oils.
    • [0035]
      A solution of 2.1 g of the above prepared alcohol 15a, 20 mg of p-toluenesulfonic acid and 1.4 g of dihydropyran in 50 ml of methylene chloride is stirred for 30 minutes at 0 ° C. Then it is poured into dilute sodium bicarbonate solution, extracted with ether, washed neutral with water, dried over magnesium sulfate and evaporated under vacuum. Chromatography of the residue on silica gel, using hexane / ether (6 +4), 2.6 g of the title compound as a colorless oil.
    • [0036]
      IR: 2939, 2877, 1450, 969, 948 / cm.

1 c) bicyclo [3.3.0] octane-3-one

    • [0037]
      A solution of 290 mg of the of Example 1 b) the compound prepared in 2.5 ml of dimethyl sulfoxide and 1 ml of tetrahydrofuran is mixed with 112 mg of potassium tert-butoxide and stirred for 2 hours at 23 ° C. It is diluted with 10 ml of water and extracted three times with 10 ml of ether / hexane (7 +3), wash the extract with water until neutral, dried over brine and evaporated under vacuum.
    • [0038]
      It is stirred for 22 hours with the residue 15 ml of acetic acid / water / tetrahydrofuran (65/35/10) evaporated in a vacuum with the addition of toluene, and the residue is purified by chromatography on silica gel. With ether eluted 150 mg oily substance, which is reacted in 5 ml of dichloromethane with 140 mg of dihydropyran and 1 mg of p-toluenesulfonic acid at 0 ° C.. After 30 minutes, diluted with ether, extracted with 5% sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under vacuum. Chromatography of the residue on silica gel with hexane / ether (1 +1), 185 mg of the title compound as a colorless oil.
    • [0039]
      IR: 2940, 2876, 2216, 1738, 1020, 970 / cm.

1 d)

  • [0040]
    To a solution of 529 mg Phosphonoessigsäuretri acid ethyl ester in 10 ml of tetrahydrofuran is added at 0 C 225 mg of potassium tert-butoxide, stirred for 10 minutes, treated with a solution of 0.6 g of the product of Example 1 c) ketone in 6 ml of toluene and stirred for 22 hours at 23 ° C. It is diluted with 150 mL of ether, shake once with water, once with 20% sodium hydroxide, washed neutral with water, dried over magnesium sulfate and evaporated under vacuum. The residue is filtered using hexane / ether (6 +4) over silica gel. Thereby obtain 0.58 g of the unsaturated ester as a colorless oil.
  • [0041]
    IR: 2940, 2870, 2212, 1704, 1655, 970 / cm.
  • [0042]
    It adds 150 mg of lithium aluminum hydride in portions at 0 ° C to a stirred solution of 570 mg of the ester prepared in 25 ml of ether and stirred for 30 minutes at 0 ° C. Destroying the excess reagent by dropwise addition of ethyl acetate, added to 1 ml of water, stirred for 3 hours at 20 ° C, filtered and evaporated under vacuum. The residue is chromatographed with ether / hexane (3 +2) on silica gel. Thereby obtained as a non-polar compound 140 mg of 2 – {(Z) – (1S, 5S, 6S, 7R) -7 – (tetrahydropyran-2-yloxy) -6 – / R3S, 4S)-4-methyl-3-( tetrahydropyran-2-yloxy)-nona-1 ,6-diinyl]-bicyclo [3.3.0] octane-3-ylidene} – ethane-1-ol and 180 mg of the title compound as a colorless oil.
  • [0043]
    IR: 3620, 3450 (broad), 2940, 2860, 2212, 970/cm.

 

 

 

 

…………….

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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Iloprost (ciloprost) used to treat a serious heart and lung disorder called pulmonary arterial hypertension

 orphan status  Comments Off on Iloprost (ciloprost) used to treat a serious heart and lung disorder called pulmonary arterial hypertension
Jan 132014
 

http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0078919138

Iloprost (ciloprost)

MF C22H32O4
Formula Wgt 360.5

6,9ALPHA-METHYLENE-11ALPHA,15S-DIHYDROXY-16-METHYL-PROSTA-5E,13E-DIEN-18-YN-1-OIC ACID

6,​9α-​methylene-​11α,​15S-​dihydroxy-​16-​methyl-​prosta-​5E,​13E-​dien-​18-​yn-​1-​oic acid

 

Iloprost Molecule

ILOPROST (Ventavis®) is used to treat a serious heart and lung disorder called pulmonary arterial hypertension. While iloprost inhalation solution will not cure this disorder, it is designed to improve symptoms and the quality of life. Generic iloprost inhalation solution is not yet available.

Iloprost is a second generation structural analog of prostacyclin (PGI) with about ten-fold greater potency than the first generation stable analogs, typified by carbaprostacyclin.1 Iloprost binds with equal affinity to the human recombinant IP and EP1 receptors with a Ki of 11 nM.2Iloprost constricts the isolated guinea pig ilium and fundus circular smooth muscle (an EP1 receptor preparation) as strongly as prostaglandin E2 (PGE2) itself.3 Iloprost inhibits the ADP, thrombin, and collagen-induced aggregation of human platelets with an ED50 of about 13 nM.1 In whole animals, iloprost acts as a vasodilator, hypotensive, antidiuretic, and prolongs bleeding time.4 It has been evaluated in several human clinical studies as a treatment for idiopathic pulmonary hypertension.5,6 In these studies, an aerosolized dose of 30 µg/day was effective, and doses as high as 150 µg/day for up to a year were well tolerated.

73873-87-7 CAS NO

78919-13-8 PHENACYL ESTER

Launched – 1992 bayer

Ilomedin®, Ventavis™

Iloprost.pngiloprost

An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of EPOPROSTENOL, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation.

BAY-q-6256 E-1030 SH-401 ZK-36374

  • BAY Q6256
  • Ciloprost
  • Iloprost
  • Iloprostum
  • Iloprostum [Latin]
  • UNII-AHG2128QW6
  • UNII-JED5K35YGL
  • Ventavis
  • ZK 00036374
  • ZK 36374

Endoprost Ilomedin Ilomédine Ventavis Iloprost is a synthetic prostacyclin analog discovered and developed by Schering AG and Berlex which has been available for more than ten years as therapy for peripheral arterial occlusive disease (PAOD), including Raynaud’s phenomenon and Buerger’s disease.

Iloprost improves blood flow, relieves the pain associated with circulatory disturbances and improves the healing of ulcers, which can develop as a result of poor arterial blood flow. Iloprost also produces vasodilatation of the pulmonary arterial bed, with subsequent significant improvement in pulmonary artery pressure, pulmonary vascular resistance and cardiac output, as well as mixed venous oxygen saturation. In 2003, Schering AG received approval in the E.U. for an inhaled formulation of iloprost (Ventavis[R]) for the treatment of primary pulmonary hypertension and the following year, the product was launched in Germany and the U.K.

Introduction on the U.S. market took place in March 2005 by CoTherix for the same indication in patients with NYHA Class III or IV symptoms. Iloprost is also available for the treatment of pulmonary hypertension and peripheral vascular disease. CoTherix had been developing a dry powder for potential use in the treatment of pulmonary hypertension; however, no recent development has been reported for this research. In Japan, phase III clinical trials are ongoing for the treatment of pulmonary arterial hypertension. In 2003, CoTherix licensed exclusive rights from Schering AG to market iloprost in the U.S. for primary pulmonary hypertension while Schering AG retained rights to the product outside the U.S. In April 2005, CoTherix established a collaborative research and development agreement with Quadrant to develop an extended-release formulation of iloprost inhalation solution. Iloprost was designated as an orphan medicinal product for the treatment of pulmonary hypertension in December 2000 by the EMEA and will fall under orphan drug protection until 2013.

The FDA has assigned to iloprost several orphan drug designations. In 1989, iloprost solution for infusion was granted orphan drug designation for the treatment of Raynaud’s phenomenon secondary to systemic sclerosis followed by another orphan drug designation in 1990 for iloprost solution for injection for the treatment of heparin-associated thrombocytopenia. In 2004, an additional orphan drug designation for iloprost inhalation solution for the treatment of pulmonary arterial hypertension was assigned.

The status has also been assigned in the E.U. for this indication. In 2012, orphan drug designation was assigned in the U.S. for the treatment of purpura fulminans in combination with eptifibatide and for the treatment of pulmonary arterial hypertension. In 2007, Cotherix was acquired by Actelion.

ILOPROST

 

 

iloprost phenacyl ester

Ventavis (TN), Iloprost phenacyl ester, Iloprost-PE, Iloprost (INN), CHEMBL138694, CHEMBL236025, AC1O6009, DAP000273, CID5311181

Molecular Formula: C30H38O5   Molecular Weight: 478.61972

2-oxo-2-phenylethyl 5-[(2Z)-5-hydroxy-4-[(1E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-octahydropentalen-2-ylidene]pentanoate

IMPORTANT PUBLICATIONS

Ciloprost Drugs Fut 1981, 6(11): 676

A carbohydrate approach for the formal total synthesis of the prostacyclin analogue (16S)-iloprost Tetrahedron Asymmetry 2012, 23(5): 388

Angewandte Chemie, 1981 ,  vol. 93,   12  pg. 1080 – 1081

Tetrahedron Letters, 1992 ,  vol. 33,   52  pg. 8055 – 8056

Helvetica Chimica Acta, 1986 ,  vol. 69,  7  pg. 1718 – 1727

Journal of Medicinal Chemistry, 1986 ,  vol. 29,  3  pg. 313 – 315

US5286494 A1

US 4474802

 US 2013253049

uS 2013184295

WO 1992014438

WO 1993007876

WO 1993015739

WO 1994008584

WO 2013040068

WO 2012174407

WO 2011047048

EP0011591A1 * Oct 18, 1979 May 28, 1980 Schering Aktiengesellschaft Prostane derivatives, their production and pharmaceutical compositions containing them
EP0084856A1 * Jan 19, 1983 Aug 3, 1983 Toray Industries, Inc. 5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives
EP0099538A1 * Jul 11, 1983 Feb 1, 1984 Schering Aktiengesellschaft Carbacyclines, process for their preparation and their use as medicines

……………………………………

  •  5,6,7-trinor-4,8-inter-m-phenylene prostaglandin 12derivatives.
  • Prostaglandin I2, hereinafter referred to as PGI2, of

    Figure imgb0001

    was first found by J.R. Vane et.al. in 1976 and is biosynthe- sized from arachidonic acid via endoperoxide(PGH2 or PGG2) in the vascular wall. PGI2 is well known to show potent activity to inhibit platelet aggregation and to dilate peripheral blood vessels(C & EN, Dec. 20, 1976, page 17 and S. Moncade et al., Nature, 263,633(1976)).

  • [0003]
    Because of the unstable exo-enolether structure thereof, PGI2 is extremely unstable even in a neutral aqueous solution and is readily converted to 6-oxo-PGF1α which is almost physiologically inactive. Such instability of PGI2 is a big obstacle to its use as a drug. Furthermore, PGI2 is unstable in vivo as well and shows only short duration of action.
  • The compounds of the present invention are novel PGI2 derivatives in which the exo-enolether moiety characteristic of PGI2 is transformed into “inter-m-phenylene” moiety. In this sense the compounds may be regarded as analogs of PGI2.
  • The compounds of the present invention feature much improved stability in vitro as well as in vivo in comparison with PGI2. The compounds are highly stable even in an aqueous solution and show long duration of action in vivo. Further, the compounds have advantages over PGI2 for pharmaceutical application because they exhibit more selective physiological actions than PGI2, which has multifarious, inseperable biological activities.
  • Some prostaglandin I2 derivatives which have 5,6,7-tri- nor-4,8-inter-m-phenylene structure have already been described in publication by some of the present authors. (Kiyotaka Ohno, Hisao Nishiyama and Shintaro Nishio, U.S.P. 4,301,164 (1981)). But, the compounds of the present invention, which feature the presence of alkynyl side chain, have more potent physiological activities as well as decreased side effects than the already disclosed compounds analogous to those of the present invention.
  • It is an object of this invention to provide novel prostaglandin I2derivatives which are stable and possess platelet aggregation-inhibiting, hypotensive, anti-ulcer and other activities.

 

  • Figure imgb0004

    is named as 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2.

  • Alternatively, the compound of the formula (II) may be named as a derivative of butyric acid by the more formal nomenclature. In such a case, the condensed ring moiety is named after the basical structure of 1H-cyclopenta[b]benzofuran of the following formula:

    Figure imgb0005

    The term “synthetic prostacyclins” as used herein can refer to any prostacyclin that can be prepared via synthetic organic chemistry, including those prostacyclins that are also naturally occurring, such as Prostacyclin (PGI2):

     

    Figure imgf000025_0001

    which is also known as Epopreostenol.

    Thus, examples of synthetic prostacyclins include, but are not limited to: Prosta

     

    Figure imgf000025_0002

    lloprost, which has the structure:

     

    Figure imgf000025_0003

    Trepro inil (also known as Rumodolin), which has the structure:

     

    Figure imgf000025_0004

    Beraprost, which has the structure:

     

    Figure imgf000026_0001

    as well as the esters, stereoisomers, and salts thereof, or other analogues or derivatives of the recited synthetic prostacyclins, such as compounds comprising other aliphatic linker groups linking the carboxylic acid group to the cyclic components of the synthetic prostacyclins, compounds containing additional alkene and/or alkyne bonds, and/or compounds containing additional substituents on the cyclic components of the synthetic prostacyclins.

    Figure imgf000031_0001

     iloprost, in contrast to PGI.sub.2 a stable prostacyclin derivative, has been known since 1980 by European patent application EP 11591, no other prostacyclin derivative has previously been tested in this indication. It is therefore reasonable to assume that a spontaneous healing is involved in the published case.

    It has now been found, surprisingly, that iloprost is effective in the case of cerebral malaria.

    For salt formation of iloprost, inorganic and organic bases are suitable, as they are known to one skilled in the art for the formation of physiologically compatible salts. For example, there can be mentioned: alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.

    The β-cyclodextrin clathrate formation takes place according to EP 259468.

    The production of iloprost is described in detail in EP 11591.

    • Nileprost iloprost, and a process for preparing these compositions.
    • From EP 11 591 already carbacyclin derivatives of the cytoprotective effect on the gastric and intestinal mucosa, and the myocardial cytoprotection using carbacyclin derivatives is known.
    • It has now been found that iloprost (I) and Nileprost (II)

      Figure imgb0001

      and their salts with physiologically acceptable bases and cytoprotective effect in the kidney.

    • Forming salts of iloprost and Nileprost inorganic and organic bases are suitable, as are known to those skilled in the formation of physiologically compatible salts known. Examples which may be mentioned are: alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.
    • The production of iloprost and is described in detail in EP Nileprost 2234 and EP 11591.
    ………………..
    J. Med. Chem., 1986, 29 (3), pp 313–315
    DOI: 10.1021/jm00153a001

see paper

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The formal total synthesis of the synthetic and stable analogue of prostacyclin, (16S)– iloprost is described via a convergent synthesis starting from readily available d-glucose. Julia olefination and the aldol reaction are the key steps involved in the synthesis.
Full-size image (18 K)
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  • Used as the starting material for the method described above ketone of general formula II can be prepared by reacting an alcohol of the formula IV

    Figure imgb0006

    (EJCorey et al., J. Amer. Chem. 93, 1490 (1971)) transformed with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid in the tetrahydropyranyl ether V.

    Figure imgb0007
  • [0026]
    Lactone V with Diisobatylauminiumnydrid reduced at -70 ° C to the lactol VI, which is converted by Wittiereaktion Triphenylphosphoniummethylen with the olefin VII. After conversion to the tosylate with p-toluenesulfonyl chloride in the presence of pyridine is obtained by reaction with potassium nitrite in the dimethylsulfoxide 9SS-configured alcohol IX, which is converted with p-toluenesulfonyl chloride in the presence of pyridine in the tosylate X. Reaction with Malonsäurediäthylester in presence of potassium tert-butoxide gives the diester XI, which is converted by decarbalkoxylation with sodium cyanide in dimethyl sulfoxide in the ester XII.

    Figure imgb0008
  • [0027]
    Oxidative cleavage of the double bond in the compound XII with Hatrium p j o dat it out in the presence of catalytic amounts of osmium tetroxide to give the aldehyde XIII, which is oxidized with Jones reagent to the acid XIV which is then esterified with diazomethane to the compound XV. By Dieckmann condensation of XV with potassium tert-butoxide in tetrahydrofuran is obtained a mixture of isomers of the ketocarboxylic acid ester XVI and XVII, which by means of a decarbalkoxylation with 1,4-diazabicyclo [2,2,2] octane in xylene converted into ketone XVIII as the only reaction product is.

    Figure imgb0009
  • [0028]
    The removal of the Tetrahydropyranylätherschutzgruppe delivers the alcohol XIX, which is esterified with benzoyl chloride in the presence of pyridine to give the ester XX.

    Figure imgb0010
  • [0029]
    Benzyläthers hydrogenolytic cleavage of a catalytic amount of acid gives the alcohol XXI, which is according to ketalization compound XXII oxidized with Collins reagent to aldehyde XXIII.
  • [0030]
    This aldehyde XXIV with a phosphonate of the general formula

    Figure imgb0011

    wherein D, E and R 2 have the meanings given above is reacted in a Olefinicrungsreaktion to a ketone of the formula XXV.

    Figure imgb0012
  • [0031]
    After reduction of the 15-keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesium bromide or alkyllithium and. Epimerentrennung obtain the 15α-alcohols XXVI (PG numbering).

    Figure imgb0013
  • [0032]
    After hydrolysis of the ester group, for example with potassium carbonate in methanol and ketal cleavage with aqueous acetic acid yields the ketone of the formula XXVII,

    Figure imgb0014
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ANTHONY MELVIN CRASTO

THANKS AND REGARD’S

DR ANTHONY MELVIN CRASTO Ph.D GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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CILUPREVIR

 phase 2, Uncategorized  1 Response »
Jan 122014
 

CILUPREVIR

(1S,4R,6S,7Z,14S,18R)-14- {[(cyclopentyloxy)carbonyl]amino}-18-[(7-methoxy-2- {2-[(propan-2-yl)amino]-1,3-thiazol-4-yl}quinolin-4- yl)oxy]-2,15-dioxo-3,16- diazatricyclo[14.3.0.0{4,6}]nonadec-7-ene-4- carboxylic acid

Ciluprevir, BILN-2061, BILN 2061, CHEBI:161337, BILN2061, BILN 2061ZW, BILN-2061-ZW,

CAS , 300832-84-2

Molecular Formula: C40H50N6O8S   Molecular Weight: 774.9254
Abstract Image

Ciluprevir is used in the treatment of hepatitis C. It is manufactured by Boehringer Ingelheim Pharma GmbH & Co. KG under the research code of BILN-2061. It is targeted against NS2-3 protease.[1]

Ciluprevir is an HCV NS3 protease inhibitor which had been in phase II clinical trials at Boehringer Ingelheim for the treatment of hepatitis C, however, no recent developments from the company have been reported.

  1.  Abbenante, G; Fairlie, DP (2005). “Protease inhibitors in the clinic”. Medicinal chemistry 1 (1): 71–104. PMID 16789888.

 

1. Challenge and Opportunity in Scaling-Up Metathesis Reaction: Synthesis of Ciluprevir (BILN 2061)Peter J. Dunn, et al

http://onlinelibrary.wiley.com/doi/10.1002/9781118354520.ch10/summary
DOI: 10.1002/9781118354520.ch10

 

2. Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven antiviral effect in humans
Org Lett 2004, 6(17): 2901

http://pubs.acs.org/doi/full/10.1021/ol0489907

 

3. Efficient synthesis of (S)-2-(cyclopentyloxycarbonyl)-amino-8-nonenoic acid: Key buiding block for BILN 2061, an HCV NS3 protease inhibitor
Org Process Res Dev 2007, 11(1): 60

 

4. Chinese Journal of Chemistry, 2011 ,  vol. 29,  7  pg. 1489 – 1502

DOI: 10.1002/cjoc.201180270

 http://onlinelibrary.wiley.com/doi/10.1002/cjoc.201180270/abstract;jsessionid=F5F4331F5A95D00728394A254C2B1AE7.f01t04

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US 8222369

WO 2006071619

WO 2000059929

WO 2004092203

WO 2004039833

WO 2004037855

WO 2006036614

WO 2006033878

WO 2005042570

WO 2004093915

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https://www.google.co.in/patents/US8222369

 

 

Figure US08222369-20120717-C00019

 

Figure US08222369-20120717-C00021

 

 

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http://www.google.com/patents/WO2000059929A1

COMPD 822 IS CILUPREVIR IN TABLE 8

EXAMPLE 8 Synthesis of 4-hydroxy-7-methoxy-2[4(2-isopropylaminothiazolyl)] quinoline (8f ) Note: [ A variety of 2-alkylaminothiazolyl substituents were made using the same synthetic scheme where compound 8b was replaced by other alkyl thioureas.]

 

Figure imgf000045_0001

 

Figure imgf000045_0002

8b 8c 8d

Figure imgf000046_0001

A. The protocol used for the conversion of -anisidine to 8a was identical to that described in the literature: F.J. Brown et al. J. Med. Chem. 1989, 32 , 807-826. However, the purification procedure was modified to avoid purification by chromatography. The EtOAc phase containing the desired product was treated with a mixture of MgSO4, charcoal and 5% w/w (based on expected mass) silica gel. After filtration on celite, the product was triturated with ether. Compound 8a was obtained as a pale brown solid in >99% purity (as confirmed by HPLC).

B. A suspension of isopropyl thiourea (8b, 3.55 g, 30 mmol) and 3- bromopyruvic acid (8c, 5 g, 1 eq.) in dioxane (300 mL , 0.1 M) was heated to 80 °C.

Upon reaching 80 C the solution became clear and soon after the product precipitated as a white solid. After 2 hours of heating, the solution was cooled to RT and the white precipitate was filtered to obtain compound 8d in high purity (>98% purity as confirmed by NMR) and 94% yield (7.51 g). C. A mixture of the carboxylic acid 8d (4.85 g, 18.2 mmol) and the aniline derivative 8a (3 g, leq.) in pyridine (150 mL, 0.12 M) was cooled to -30 °C (upon cooling, the clear solution became partially a suspension). Phosphorus oxychloride (3.56 ml, 2.1 eq.) was then added slowly over a 5 min period. The reaction was stirred at -30 C for 1 h, the bath was removed and the reaction mixture was allowed to warm-up to RT. After 1.5 h the reaction mixture was poured into ice, the pH was adjusted to 11 with aqueous 3N NaOH, extracted with CH2C12, dried over anhydrous MgSO4, filtered and concentrated under vacuum. The beige solid was then purified by flash chromatography (45% EtOAc in hexane) to give compound 8e as a pale yellow solid in 73% yield (6.07 g). D. A solution of tBuOK (2.42 g, 21.6 mmol) in anhydrous tBuOH (40ml, 0.14 M, distilled from Mg metal) was heated to reflux. Compound 8e (1.8g, 5.4 mmol) was added portion-wise over 5 min and the dark red solution formed was stirred at reflux for an additional 20 min (completion of the reaction was monitored by HPLC). The mixture was cooled to RT and HCl was added (4 N in dioxane, 1.5 eq.). The mixture was then concentrated under vacuum, in order to assure that all of the

HCl and dioxane were removed, the product was re-dissolved twice in CH2C12 and dried under vacuum to finally obtain the HCl salt of compound 8f as a beige solid (1.62 g, 93% pure by HPLC). The product was then poured into a phosphate buffer

(IN NaH2PO4, pH=~4.5) and sonicated. The beige solid was filtered and dried under vacuum to give compound 8f (1.38 g, 81% yield) as a beige solid (91% pure by HPLC).

*H NMR (400 MHz, DMSO) δ 8.27 (s, IH), 8.12 (d, IH, J = 9.2 Hz), 7.97 (br.s, IH), 7.94 (s, IH), 7.43 (s, IH), 7.24 (dd, IH, J = 9.2, 2.2 Hz), 3.97 (m, IH), 3.94 (s, 3H), 1.24 (d, 2H, J = 6.4 Hz)

…………

METHYL ESTER

EXAMPLE 34c

Using the same procedure as described in example 34 but reacting bromoketone 34f with commercially available N-iso-propylthiourea gave # 822

 

Figure imgf000095_0002

Η NMR (400 MHz, DMSO-d6) δ 8.63 (s, IH), 8.33-8.23 (bs, IH), 8.21 (d, J = 9.2 Hz, IH), 8.04 (d, J = 8.3 Hz, IH), 7.86 (bs, IH), 7.77 (s, IH), 7.35-7.23 (m, 2H), 5.81 (bs, IH), 5.52 (dd, J = 8.5 Hz, IH), 5.27 (dd, J = 9.2 Hz, IH), 4.65 (d, J = 11.8 Hz, IH), 4.51 (dd, J = 7.6 Hz, IH), 4.37 (bs, IH), 4.15 (bs, IH), 4.07-3.98 (m, 2H), 3.97 (s, 3H), 3.88 (d, J = 8.9 Hz, IH), 2.60-2.53 (m, 2H), 2.47-2.37 (m, 2H), 2.19-2.10 (dd, J = 9.2 Hz, IH), 1.80-1.64 (m, 2H), 1.63-1.29 (m, 13H), 1.27 and 1.25 (2 x d, J – 6.5 Hz, 6H), 1.23-1.09 (m, 2H). MS; es+: 775.0 (M + H)+, es : 772.9 (M – H)\

CILUPREVIR IS FREE ACID OF ABOVE AND HAS ENTRY 822 TABLE 8

………

FREE AMINO COMPD

(Table 8)

 

Figure imgf000090_0001

 

Figure imgf000090_0002

 

Figure imgf000091_0001

 

Figure imgf000091_0002

A. To a solution of the macrocyclic intermediate 23b (13.05 g, 27.2 mmol, 1.0 eq.), Ph3P (14.28 g, 54.4 mmol, 2.0 eq) and 2-carboxymethoxy-4-hydroxy-7- methoxyquinoline (WO 00/09543 & WO 00/09558) (6.67 g, 28.6 mmol, 1.05 eq) in

THF (450 mL) at 0°C, DIAD (10.75 mL, 54.6 mmol, 2.0 eq) was added dropwise over a period of 15 min. The ice bath was then removed and the reaction mixture was stirred at RT for 3 h. After the complete conversion of starting material to products, the solvent was evaporated under vacuum, the remaining mixture diluted with

EtOAc, washed with saturated NaHCO3 (2x) and brine (lx), the organic layer was dried over anhydrous MgSO4, filtered and evaporated to dryness. Pure compound 34a was obtained after flash column chromatography; the column was eluted first with hexane/EtOAc (50:50), followed by CHCl3/EtOAc (95:5) to remove Ph3PO and

DIAD byproducts and elution of the impurities was monitored by TLC. Finally, the desired product 34a was eluted from the column with CHC13/ EtOAc (70:30).

Usually, the chromatography step had to be repeated 2-3 times before compound 34a could be isolated in high purity as a white solid with an overall yield of 68% (12.8 g, 99.5% pure by HPLC).

B. To a solution of the Boc-protected intermediate 34a (1.567g) in CH2C12 (15 mL), 4N HCl in dioxane (12 mL) was added and the reaction mixture was stirred at RT for 1 h. [In the event that a thick gel would form half way through the reaction period, an additional 10 mL CH2C12 was added.] Upon completion of the deprotection the solvents were evaporate to dryness to obtain a yellow solid and a paste like material. The mixture was redissolved in approximately 5% MeOH in

CH2C12 and re-evaporated to dryness under vacuum to obtain compound 34b as a yellow solid, which was used in the next step without any purification. C. To a solution of cyclopentanol (614 μL, 6.76 mmoL) in THF (15 mL), a solution of phosgene in toluene (1.93 M, 5.96 mL, 11.502 mmol) was added dropwise and the mixture was stirred at R.T. for 2 h to form the cyclopentyl chloroformate reagent (z). After that period, approximately half of the solvent was removed by evaporation under vacuum, the remaining light yellow solution was diluted by the addition of CH2C12 (5 mL) and concentrated to half of its original volume, in order to assure the removal of all excess phosgene. The above solution of the cyclopentyl chloroformate reagent was further diluted with THF (15 mL) and added to the amine-2HCl salt 34b. The mixture was cooled to 0 C in an ice bath, the pH was adjusted to -8.5-9 with the addition of Et3N (added dropwise) and the reaction mixture was stirred at 0 C for 1 h. After that period, the mixture was diluted with

EtOAc, washed with water (lx), saturated NaHCO3 (2x), H2O (2x) and brine (lx).

The organic layer was dried over anhydrous MgSO4, filtered and evaporated under vacuum to obtain a yellow-amber foam. Compound 34c was obtained as a white foam after purification by flash column chromatography (using a solvent gradient from 30% hexane to 20% hexane in EtOAc as the eluent) in 80% yield (1.27 g) and >93% purity. D. The dimethyl ester 34c (1.17g) was dissolved in a mixture of

THF/MeOH/H2O (20 mL, 2:1:1 ratio), and an aqueous solution of NaOH (1.8 mL,

IN, 1 eq.) was added. The reaction mixture was stirred at RT for 1 h before it was evaporated to dryness to obtain the sodium salt 34d as a white solid (-1.66 mmol). Compound 34d was used in the next step without purification.

E. The crude sodium salt 34d (1.66 mmoL) was dissolved in THF (17 mL), Et3N was added and the mixture was cooled to 0 C in an ice bath. Isobutylchloroformate

(322 μl, 2.5 mmol) was added dropwise and the mixture was stirred at 0 C for 75 min. After that period, diazomethane (15 mL) was added and stirring was continued at 0 C for 30 min and then at RT for an additional 1 h. Most of the solvent was evaporated to dryness under vacuum, the remaining mixture was diluted with EtOAc, washed with saturated NaHCO3 (2x), H2O (2x) and brine (lx), dried over anhydrous MgSO4, filtered and evaporated to dryness to obtain compound 34e as a light yellow foam (1.2g, -1.66 mmol). The diazoketone intermediate 34e was used in the next step without purification.

F. The diazoketone 34e (1.2g, 1.66 mmoL) dissolved in THF (17 mL) was cooled to 0 C in an ice bath. A solution of aqueous HBr (48%, 1.24 mL) was added dropwise and the reaction mixture was stirred at 0 C for 1 h. The mixture was then diluted with EtOAc, wash with saturated NaHCO3 (2x), H2O (2x) and brine (lx), the organic layer was dried over anhydrous MgSO4, filtered and evaporated to dryness to obtain the β-bromoketone intermediate 34f as a light yellow foam (-1.657 mmol).

G. To a solution of the bromoketone 34f (600 mg,0.779 mmol) in isopropanol (5 mL), thiourea (118 mg, 1.55 mmol) was added and the reaction mixture was placed in a pre-heated oil bath at 75 C where it was allowed to stir for 1 hr. The isopropanol was then removed under vacuum and the product dissolved in EtOAc

(100 mL). The solution was washed with saturated NaHCO3 and brine, the organic layer was dried over anhydrous Na2SO4, filtered and evaporated to afford the crude product 34g (522 mg) as a red-brown solid. This material was used in the final step without any further purification.

H. The crude methyl ester 34g (122 mg, 0.163 mmol) was dissolved in a solution of THF/MeOH/H2O (2:1:1 ratio, 4 mL) and saponified using LiOH»H2O (89 mg, 2.14 mmol). The hydrolysis reaction was carried out over a 12-15 h period at RT. The solvents were then removed under vacuum and the crude product purified by C18 reversed phase HPLC, using a solvent gradient from 10% CH3CN in H2O to 100%

CH3CN, to afford the HCV protease inhibitor #812 as a yellow solid (24 mg, 20% overall yield for the conversion of intermediate 34f to inhibitor #812).

*H NMR (400 MHz, DMSO-d6) δ 8.63 (s, IH), 8.26-8.15 (m, 2H), 7.79 (bs, IH), 7.72

(bs, IH), 7.50 (bs, 2H), 7.33-7.25 (m, 2H), 5.77 (bs, IH), 5.52 (dd, J = 8.3 Hz, IH), 5.27 (dd, J = 9.2 Hz, IH), 4.64 (d, J = 10.8 Hz, IH), 4.50 (dd, J = 8.3 Hz, IH), 4.39-4.31 (m, IH), 4.08-3.99 (m, 2H), 3.94 (s, 3H), 3.87 (d, J = 9.5 Hz, 2H), 2.65-2.53 (m, 2H), 2.46- 2.36 (m, 2H), 2.20-2.12 (dd, J = 8.6 Hz, IH), 1.80-1.64 (m, 2H), 1.63-1.06 (m, 14H). MS; es+: 733.2 (M + H)+, es“: 731.2 (M – H)\

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http://www.google.com/patents/WO2006036614A2

(Z)-( 1S,4R, 14S, 18R)- 14-Cyclopentyloxycarbonylamino- 18-[2-(2- isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-2,15-dioxo-3,16-diaza- tricyclo[14.3.0.0 ‘ ]nonadec-7-ene-4-carboxylic acid , whose chemical structure is as follows:

Figure imgf000015_0001

, provided for in Tsantrizos et al., U.S. Patent No. 6,608,027 Bl,

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https://www.google.co.in/patents/WO2005090383A2

ENTRY 218

Figure imgf000034_0001

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http://www.google.com/patents/WO2004039833A1

Figure imgf000015_0003

 

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Org. Process Res. Dev., 2007, 11 (1), pp 60–63
DOI: 10.1021/op0601924

A new procedure for the practical synthesis of (S)-2-(cyclopentyloxycarbonyl)amino-8-nonenoic acid, a key building block for BILN 2061, an HCV NS3 protease inhibitor, has been developed. The key step features a kinetic resolution of racemic 2-acetylamino-8-nonenoic acid with acylase I. In addition, the undesired (R)-2-acetylamino-8-nonenoic acid was recycled after racemization. The procedure was implemented for the production of (S)-2-(cyclopentyloxycarbonyl)amino-8-nonenoic acid on pilot-plant scale.

Figure

 

Figure

……………

nmr

Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven antiviral effect in humans
Org Lett 2004, 6(17): 2901

http://pubs.acs.org/doi/full/10.1021/ol0489907

http://pubs.acs.org/doi/suppl/10.1021/ol0489907/suppl_file/ol0489907si20040715_032207.pdf  procedure

http://pubs.acs.org/doi/suppl/10.1021/ol0489907/suppl_file/ol0489907si20040715_032254.pdf nmr spectra

BILN 2061:

Methyl ester 18 (2.69 g, 3.41 mmol) was dissolved in a mixture of THF
(40 mL), MeOH (20 mL) and water (20 mL) and added LiOH.H2O (1.14 g, 27.3 mmol).The resulting mixture was left to stir at RT for 15 h. The solvents were then removedunder reduced pressure and the crude product was redissolved with EtOAc and dilutedwith brine. The pH of the aqueous layer was adjusted to 6 with aqueous HCl (1N) and theaqueous phase was extracted with EtOAc (3x). The combined organic phase werewashed with water, brine, dried over MgSO4 and concentrated under reduced pressure toafford BILN 2061 as a yellow solid (2.63 g, 99% yield). HPLC(A) 99%, MS m/z (ES+)773 (M+H)+, (ES-) 775 (M-H)-;

1H NMR (DMSO-d6) δ 8.63 (s, 1H), 8.26-8.15 (m, 2H),
7.79 (bs, 1H), 7.72 (bs, 1H), 7.50 (bs, 2H), 7.33-7.25 (m, 2H), 5.77 (bs, 1H), 5.52 (dd, J=8.3 Hz, 1H), 5.27 (dd, J= 9.2 Hz, 1H), 4.64 (d, J= 10.8 Hz, 1H), 4.50 (dd, J= 8.3 Hz, 1H),4.39-4.31 (m, 1H), 4.08-3.99 (m, 2H), 3.94 (s, 3H), 3.87 (d, J= 9.5 Hz, 2H), 2.65-2.53(m, 2H), 2.46-2.36 (m, 2H), 2.20-2.12 (dd, J= 8.6 Hz, 1H), 1.80-1.64 (m, 2H), 1.63-1.06(m, 14H); HRMS calcd for C40H51N6O8S: 775.3489; found: 775.3476

 

…………………………

WO2007019674A1 Aug 3, 2006 Feb 22, 2007 Boehringer Ingelheim Int Viral polymerase inhibitors
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ANTHONY MELVIN CRASTO

THANKS AND REGARD’S

DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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FAVIPIRAVIR ………… Phase 3 clinical trials for investigational flu treatment drug started

 Uncategorized  1 Response »
Jan 092014
 

 

FAVIPIRAVIR

Toyama (Originator)

RNA-Directed RNA Polymerase (NS5B) Inhibitors

Chemical Formula: C5H4FN3O2
CAS #: 259793-96-9
Molecular Weight: 157.1

Anti-influenza compound
clinical trials  http://clinicaltrials.gov/search/intervention=Favipiravir
Chemical Name: 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
Synonyms: T-705, T705, Favipiravir

T-705 is an RNA-directed RNA polymerase (NS5B) inhibitor which has been filed for approval in Japan for the oral treatment of influenza A (including avian and H1N1 infections) and for the treatment of influenza B infection.

The compound is a unique viral RNA polymerase inhibitor, acting on viral genetic copying to prevent its reproduction, discovered by Toyama Chemical. In 2005, Utah State University carried out various studies under its contract with the National Institute of Allergy and Infectious Diseases (NIAID) and demonstrated that T-705 has exceptionally potent activity in mouse infection models of H5N1 avian influenza.

T-705 (Favipiravir) is an antiviral pyrazinecarboxamide-based, inhibitor of of the influenza virus with an EC90 of 1.3 to 7.7 uM (influenza A, H5N1). EC90 ranges for other influenza A subtypes are 0.19-1.3 uM, 0.063-1.9 uM, and 0.5-3.1 uM for H1N1, H2N2, and H3N2, respectively. T-705 also exhibits activity against type B and C viruses, with EC90s of 0.25-0.57 uM and 0.19-0.36 uM, respectively. (1) Additionally, T-705 has broad activity against arenavirus, bunyavirus, foot-and-mouth disease virus, and West Nile virus with EC50s ranging from 5 to 300 uM.

Studies show that T-705 ribofuranosyl triphosphate is the active form of T-705 and acts like purines or purine nucleosides in cells and does not inhibit DNA synthesis

In 2012, MediVector was awarded a contract from the U.S. Department of Defense’s (DOD) Joint Project Manager Transformational Medical Technologies (JPM-TMT) to further develop T-705 (favipiravir), a broad-spectrum therapeutic against multiple influenza viruses.

Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P < 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families.

favipiravir

Favipiravir also known as T-705 is an experimental anti-viral drug with activity against many RNA viruses. It, like some other experimental antiviraldrugs—T-1105 and T-1106, is apyrazinecarboxamide derivative. Favipiravir is active against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyavirusesand alphaviruses.[1]

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase. Favipiravir does not inhibit RNA of DNA synthesis in mammalian cells and is not toxic to them.[1]

  1.  Furuta, Y.; Takahashi, K.; Shiraki, K.; Sakamoto, K.; Smee, D. F.; Barnard, D. L.; Gowen, B. B.; Julander, J. G.; Morrey, J. D. (2009). “T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections”. Antiviral Research 82 (3): 95–102. doi:10.1016/j.antiviral.2009.02.198. PMID 19428599. edit
  3. WO 2000010569
  4. WO 2008099874
  5. WO 201009504
  6. WO 2010104170
  7. WO 2012063931

 

Process route

OH

OH

hydrolysis

……………………………………………………………………………………

Influenza virus is a central virus of the cold syndrome, which has attacked human being periodically to cause many deaths amounting to tens millions. Although the number of deaths shows a tendency of decrease in the recent years owing to the improvement in hygienic and nutritive conditions, the prevalence of influenza is repeated every year, and it is apprehended that a new virus may appear to cause a wider prevalence.

For prevention of influenza virus, vaccine is used widely, in addition to which low molecular weight substances such as Amantadine and Ribavirin are also used

 

……………………………….

Synthesis of Favipiravir

ZHANG Tao1, KONG Lingjin1, LI Zongtao1,YUAN Hongyu1, XU Wenfang2*

(1. Shandong Qidu PharmaceuticalCo., Ltd., Linzi 255400; 2. School of Pharmacy, Shandong University, Jinan250012)

ABSTRACT: Favipiravir was synthesized from3-amino-2-pyrazinecarboxylic acid by esterification, bromination with NBS,diazotization and amination to give 6-bromo-3-hydroxypyrazine-2-carboxamide,which was subjected to chlorination with POCl3, fluorination with KF, andhydrolysis with an overall yield of about 22％.

………………………………..

US6787544

 

 

Figure US06787544-20040907-C00005

 

subs            G1 G2 G3 G4 R2
    compd 32 N CH C—CF3 N H

…………………

EP2192117

Figure US20100286394A1-20101111-C00001

Example 1-1

 

Figure US20100286394A1-20101111-C00002

 

To a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile, a 3.8 ml water solution of 7.83 g of potassium acetate was added dropwise at 25 to 35° C., and the solution was stirred at the same temperature for 2 hours. 0.38 ml of ammonia water was added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of this solution was adjusted to 9.4 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added. Then 7.71 g of dicyclohexylamine was added dropwise and the solution was stirred at 20 to 30° C. for 45 minutes. Then 15 ml of water was added dropwise, the solution was cooled to 10° C., and the precipitate was filtered and collected to give 9.44 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyradinecarbonitrile as a lightly yellowish white solid product.

1H-NMR (DMSO-d6) δ values: 1.00-1.36 (10H, m), 1.56-1.67 (2H, m), 1.67-1.81 (4H, m), 1.91-2.07 (4H, m), 3.01-3.18 (2H, m), 8.03-8.06 (1H, m), 8.18-8.89 (1H, broad)

Example 1-2

4.11 ml of acetic acid was added at 5 to 15° C. to a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then 7.27 g of triethylamine was added dropwise and the solution was stirred for 2 hours. 3.8 ml of water and 0.38 ml of ammonia water were added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of the joined solution was adjusted to 9.2 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added to the solution, followed by dropwise addition of 7.71 g of dicyclohexylamine. Then 15 ml of water was added dropwise, the solution was cooled to 5° C., and the precipitate was filtered and collected to give 9.68 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile as a slightly yellowish white solid product.

Examples 2 to 5

The compounds shown in Table 1 were obtained in the same way as in Example 1-1.

 

TABLE 1
Figure US20100286394A1-20101111-C00003
Example No. Organic amine Example No. Organic amine
2 Dipropylamine 4 Dibenzylamine
3 Dibutylamine 5 N-benzylmethylamine

 

Dipropylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile

1H-NMR (DMSO-d6) 6 values: 0.39 (6H, t, J=7.5 Hz), 1.10 (4H, sex, J=7.5 Hz), 2.30-2.38 (4H, m), 7.54 (1H, d, J=8.3 Hz)

Dibutylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile

1H-NMR (DMSO-d6) 6 values: 0.36 (6H, t, J=7.3 Hz), 0.81 (4H, sex, J=7.3 Hz), 0.99-1.10 (4H, m), 2.32-2.41 (4H, m), 7.53 (1H, d, J=8.3 Hz)

Dibenzylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile

1H-NMR (DMSO-d6) δ values: 4.17 (4H, s), 7.34-7.56 (10H, m), 8.07 (1H, d, J=8.3 Hz)

N-benzylmethylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile

1H-NMR (DMSO-d6) δ values: 2.57 (3H, s), 4.14 (2H, s), 7.37-7.53 (5H, m), 8.02-8.08 (1H, m)

Preparation Example 1

 

Figure US20100286394A1-20101111-C00004

 

300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25° C. and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30° C. and one-hour stirring at 20 to 30° C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50° C., and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10° C. the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid.

1H-NMR (DMSO-d6) δ values: 8.50 (1H, s), 8.51 (1H, d, J=7.8 Hz), 8.75 (1H, s), 13.41 (1H, s)

 

………………….

jan 2014

Investigational flu treatment drug has broad-spectrum potential to fight multiple viruses
First patient enrolled in the North American Phase 3 clinical trials for investigational flu treatment drug

BioDefense Therapeutics (BD Tx)—a Joint Product Management office within the U.S. Department of Defense (DoD)—announced the first patient enrolled in the North American Phase 3 clinical trials for favipiravir (T-705a). The drug is an investigational flu treatment candidate with broad-spectrum potential being developed by BD Tx through a contract with Boston-based MediVector, Inc.

Favipiravir is a novel, antiviral compound that works differently than anti-flu drugs currently on the market. The novelty lies in the drug’s selective disruption of the viralRNA replication and transcription process within the infected cell to stop the infection cycle.

“Favipiravir has proven safe and well tolerated in previous studies,” said LTC Eric G. Midboe, Joint Product Manager for BD Tx. “This first patient signifies the start of an important phase in favipiravir’s path to U.S. Food and Drug Administration (FDA) approval for flu and lays the groundwork for future testing against other viruses of interest to the DoD.”

In providing therapeutic solutions to counter traditional, emerging, and engineered biological threats, BD Tx chose favipiravir not only because of its potential effectiveness against flu viruses, but also because of its demonstrated broad-spectrum potential against multiple viruses.  In addition to testing favipiravir in the ongoing influenzaprogram, BD Tx is testing the drug’s efficacy against the Ebola virus and other viruses considered threats to service members. In laboratory testing, favipiravir was found to be effective against a wide variety of RNA viruses in infected cells and animals.

“FDA-approved, broad-spectrum therapeutics offer the fastest way to respond to dangerous and potentially lethal viruses,” said Dr. Tyler Bennett, Assistant Product Manager for BD Tx.

MediVector is overseeing the clinical trials required by the  FDA  to obtain drug licensure. The process requires safety data from at least 1,500 patients treated for flu at the dose and duration proposed for marketing of the drug. Currently, 150 trial sites are planned throughout the U.S.

SOURCE BioDefense Therapeutics

 

Efficient synthesis of 3H,3’H-spiro[benzofuran-2,1′-isobenzofuran]-3,3′-dione as novel skeletons specifically for influenza virus type B inhibition.

Malpani Y, Achary R, Kim SY, Jeong HC, Kim P, Han SB, Kim M, Lee CK, Kim JN, Jung YS.

Eur J Med Chem. 2013 Apr;62:534-44. doi: 10.1016/j.ejmech.2013.01.015. Epub 2013 Jan 29.

 

 

US3631036 * Nov 4, 1969 Dec 28, 1971 American Home Prod 5-amino-2 6-substituted-7h-pyrrolo(2 3-d) pyrimidines and related compounds
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US4404203 * May 14, 1981 Sep 13, 1983 Warner-Lambert Company Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents
US4545810 * Mar 25, 1983 Oct 8, 1985 Sds Biotech Corporation Herbicidal and plant growth regulant diphenylpyridazinones
US4565814 * Jan 18, 1984 Jan 21, 1986 Sanofi Pyridazine derivatives having a psychotropic action and compositions
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US5420130 May 16, 1994 May 30, 1995 Synthelabo 2-aminopyrazine-5-carboxamide derivatives, their preparation and their application in therapeutics
US5459142 * Aug 23, 1993 Oct 17, 1995 Otsuka Pharmaceutical Co., Ltd. Pyrazinyl and piperazinyl substituted pyrazine compounds
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US6159980 * Sep 15, 1997 Dec 12, 2000 Dupont Pharmaceuticals Company Pyrazinones and triazinones and their derivatives thereof
EP0023358A1 * Jul 28, 1980 Feb 4, 1981 Rohm And Haas Company Process for the preparation of pyridazine derivatives
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ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

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SURAMIN HEXASODIUM

 Uncategorized  Comments Off on SURAMIN HEXASODIUM
Jan 082014
 

 

suramin

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties.

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. Suramin is manufactured by Bayer in Germany as Germanin®.

Also known as: Naphuride, Germanin, Naganol, Belganyl, Fourneau, Farma, Antrypol, Suramine, Naganin

8,8′-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid) …FREE FORM

8,8′-[Ureylenebis[m-phenylenecarbonylimino(4-methyl-m-phenylene)carbonylimino]]di(1,3,5-naphthalenetrisulfonic acid) hexasodium salt

CAS  145-63-1 FREE FORM

129-46-4 of hexa sodium

LAUNCHED 1940 BAYER

Formula C51H40N6O23S6 
Mol. mass 1297.29

The molecular formula of suramin is C51H34N6O23S6. It is a symmetric molecule in the center of which lies urea, NH-CO-NH. Suramin contains eightbenzene rings, four of which are fused in pairs (naphthalene), four amide groups in addition to the one of urea and six sulfonate groups. When given as drug it usually contains six sodium ions that form a salt with the six sulfonate groups.

Suramin is a drug developed by Oskar Dressel and Richard Kothe of Bayer, Germany in 1916, and is still sold by Bayer under the brand nameGermanin.

Suramin sodium is a heparanase inhibitor that was first launched in 1940 by Bayer under the brand name Antrypol for the treatment of helminthic infection. It was later launched by Bayer for the treatment of trypanosomiasis (African sleeping sickness).

More recently, the product has entered early clinical development at Ohio State University for the treatment of platinum-pretreated patients with stage IIIB/IV non-small cell lung cancer, in combination with docetaxel or gemcitabine.

The National Cancer Institute (NCI) is conducting phase II clinical studies for the treatment of glioblastoma multiforme and for the treatment of adrenocortical carcinoma.

According to the National Cancer Institute there are no active clinical trials (as of April 1, 2008). Completed and closed clinical trials are listed here:[1]

In addition to Germanin, the National Cancer Institute also lists the following “Foreign brand names”: 309 F or 309 Fourneau,[1] Bayer 205, Moranyl, Naganin, Naganine.

It is used for treatment of human sleeping sickness caused by trypanosomes.[2]

It has been used in the treatment of onchocerciasis.[3]

It has been investigated as treatment for prostate cancer.[4]

Also, suramin as treatment for autism is being evaluated. [5]

Suramin is administered by a single weekly intravenous injection for six weeks. The dose per injection is 1 g.

The most frequent adverse reactions are nausea and vomiting. About 90% of patients will get an urticarial rash that disappears in a few days without needing to stop treatment. There is a greater than 50% chance of adrenal cortical damage, but only a smaller proportion will require lifelongcorticosteroid replacement. It is common for patients to get a tingling or crawling sensation of the skin with suramin. Suramin will cause clouding of the urine which is harmless: patients should be warned of this to avoid them becoming alarmed.

Kidney damage and exfoliative dermatitis occur less commonly.

Suramin has been applied clinically to HIV/AIDS patients resulting in a significant number of fatal occurrences and as a result the application of this molecule was abandoned for this condition. http://www.ncbi.nlm.nih.gov/pubmed/3548350

Suramin is also used in research as a broad-spectrum antagonist of P2 receptors[6][7] and agonist of Ryanodine receptors.[8]

ChemSpider 2D Image | 8,8'-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid) | C51H40N6O23S6suramin

Its effect on telomerase has been investigated.[9]

It may have some activity against RNA viruses.[10]

In addition to antagonism of P2 receptors, Suramin inhibits the acitivation of heterotrimeric G proteins in a variety of other GPCRs with varying potency. It prevents the association of heteromeric G proteins and therefore the receptors Guanine exchange functionality (GEF). With this blockade the GDP will not release from the Gα subunit so it can not be replaced by a GTP and become activated. This has the effect of blocking downstream G protein mediated signaling of various GPCR proteins including Rhodopsin, the A1 Adenosine receptor, and the D2 dopamine receptor.[11]

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. Suramin is manufactured by Bayer in Germany as Germanin®.

8-1-2012
InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential anticancer agents.
Bioorganic & medicinal chemistry letters
9-1-2012
Identification of a sirtuin 3 inhibitor that displays selectivity over sirtuin 1 and 2.
European journal of medicinal chemistry
1-1-2013
Inhibition of the human deacylase Sirtuin 5 by the indole GW5074.
Bioorganic & medicinal chemistry letters
5-9-2013
Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.
Journal of medicinal chemistry
  1.  The formula of suramin was kept secret by Bayer for commercial reasons. But it was elucidated and published in 1924 by Fourneau and his team of the Pasteur Institute, and it is only on this date that its exact chemical composition was known. (E. Fourneau, J. and Th. Tréfouël and J. Vallée (1924). “Sur une nouvelle série de médicaments trypanocides”, C. R. Séances Acad. Sci. 178: 675.)
  2. Darsaud A, Chevrier C, Bourdon L, Dumas M, Buguet A, Bouteille B (January 2004). “Megazol combined with suramin improves a new diagnosis index of the early meningo-encephalitic phase of experimental African trypanosomiasis”. Trop. Med. Int. Health 9 (1): 83–91.doi:10.1046/j.1365-3156.2003.01154.x. PMID 14728611.
  3.  Anderson J, Fuglsang H (July 1978). “Further studies on the treatment of ocular onchocerciasis with diethylcarbamazine and suramin”. Br J Ophthalmol 62 (7): 450–7.doi:10.1136/bjo.62.7.450. PMC 1043255. PMID 678497.
  4.  Ahles TA, Herndon JE, Small EJ, et al. (November 2004). “Quality of life impact of three different doses of suramin in patients with metastatic hormone-refractory prostate carcinoma: results of Intergroup O159/Cancer and Leukemia Group B 9480”. Cancer 101 (10): 2202–8.doi:10.1002/cncr.20655. PMID 15484217.
  5.  http://medicalxpress.com/news/2013-03-drug-treatment-autism-symptoms-mouse.html
  6.  Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA. (september 2006). “International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy”. Pharmacol Rev. 58 (3): 281–341.doi:10.1124/pr.58.3.3. PMID 16968944.
  7.  Khakh BS, Burnstock G, Kennedy C, King BF, North RA, Séguéla P, Voigt M, Humphrey PP. (march 2001). “International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits”. Pharmacol Rev. 53 (1): 107–118.PMID 11171941.
  8.  Wolner I, Kassack MU, Ullmann H, Karel A, Hohenegger M (October 2005). “Use-dependent inhibition of the skeletal muscle ryanodine receptor by the suramin analogue NF676”. Br. J. Pharmacol. 146 (4): 525–33. doi:10.1038/sj.bjp.0706359. PMC 1751178.PMID 16056233.
  9.  Erguven M, Akev N, Ozdemir A, Karabulut E, Bilir A (August 2008). “The inhibitory effect of suramin on telomerase activity and spheroid growth of C6 glioma cells”. Med. Sci. Monit. 14(8): BR165–73. PMID 18667993.
  10.  Mastrangelo E, Pezzullo M, Tarantino D, Petazzi R, Germani F, Kramer D, Robel I, Rohayem J, Bolognesi M, Milani M (2012) Structure-based inhibition of norovirus RNA-dependent RNA-polymerases. J Mol Biol
  11.  Beindl W, Mitterauer T, Hohenegger M, Ijzerman AP, Nanoff C, Freissmuth M. (August 1996).“Inhibition of receptor/G protein coupling by suramin analogues”. ol. Pharmacology. 50 (2): 415–23. PMID 8700151.
  12. Drugs Fut 1986, 11(10): 860
  13. WO 2012159107
  14. WO 2012087336
  15. US 2011257109
  16. WO 2009022897
  17. WO 2009020613
  18. WO 2008094027
  19.   EP 0486809
  20. US 5158940
  21. US 5173509
  22. WO 1993007864
  23. WO 1994008574

 

SURAMIN

Enterovirus-71 (EV71) is one of the major causative reagents for hand-foot-and-mouth disease. In particular, EV71 causes severe central nervous system infections and leads to numerous dead cases. Although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. In the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit EV71 proliferation with an IC50 value of 40μM. We further revealed that suramin could block the attachment of EV71 to host cells to regulate the early stage of EV71 infection, as well as affected other steps of EV71 life cycle. Our results are helpful to understand the mechanism for EV71 life cycle and provide a potential for the usage of an approved drug, suramin, as the antiviral against EV71 infection.

 

  • Suramin Hexasodium
  • 129-46-4

Synonyms

  • 309 F
  • Antrypol
  • BAY 205
  • Bayer 205
  • CI-1003
  • EINECS 204-949-3
  • Fourneau 309
  • Germanin
  • Moranyl
  • Naganin
  • Naganine
  • Naganinum
  • Naganol
  • Naphuride sodium
  • NF060
  • NSC 34936
  • SK 24728
  • Sodium suramin
  • Suramin Hexasodium
  • Suramin sodium
  • Suramina sodica
  • Suramina sodica [INN-Spanish]
  • Suramine sodique
  • Suramine sodique [INN-French]
  • Suramine sodium
  • Suraminum natricum
  • Suraminum natricum [INN-Latin]
  • UNII-89521262IH

 

Suramin Sodium, is an anticancer agent with a wide variety of activities.

Recently suramin was shown to inhibit FSH binding to its receptor (Daugherty, R. L.; Cockett, A. T. K.; Schoen, S. R. and Sluss, P. M. “Suramin inhibits gonadotropon action in rat testis: implications for treatment of advanced prostate cancer” J. Urol. 1992, 147, 727-732).

This activity causes, at least in part, the decrease in testosterone production seen in rats and humans that were administered suramin(Danesi, R.; La Rocca, R. V.; Cooper, M. R.; Ricciardi, M. P.; Pellegrini, A.; Soldani, P.; Kragel, P. J.; Paparelli, A.; Del Tacca, M.; Myers, C. E, “Clinical and experimental evidence of inhibition of testosterone production by suramin.” J. Clin. Endocrinol. Metab. 1996, 81, 2238-2246).

Suramin is the only non-peptidic small molecule that has been reported to be an FSH receptor binding antagonist.

Figure US06200963-20010313-C00003

Suramin is 8,8′ – (carbonylbis(imino-3,1-phenylenecarbonylimino (4-methyl-3,1-phenylene) carbonylimino)) bis-1,3 ,5-naphthalenetrisulfonic acid (GB Patent No. 224849). This polyanionic compound has been used for many decades as a prophylactic and therapeutic agent for try- panosomiasis. It was subsequently shown that suramin is able to block the activity of a variety of proteins like cellular and viral enzymes and growth factors (Mitsuya, M. et al. Science 226 : 172 (1984), Hosang, M. J. Cell. Biochem. 29 : 265 (1985), De Clercq, E. Cancer Lett. 8 : 9 (1979)).

 

5-32-1977
Complement inhibitors
5-25-1977
Aromatic amidines as antiviral agents in animals
5-4-1977
Complement inhibitors
5-4-1977
Complement inhibitors
4-27-1977
Cyclodextrin sulfate salts as complement inhibitors
4-20-1977
Ureylenebis methyl-phenylene-carbonyl-bis-dihydro-2-oxo-naphthoxazine disultonic acids
3-30-1977
Water treatment for controlling the growth of algae employing biguanides
3-2-1977
Isoxazole substituted nitroimidazoles
2-16-1977
Amidophenyl-azo-naphthalenesulfonic complement inhibitors and method of use thereof
2-9-1977
Complement inhibitors
2-10-2011
MODULATION OF HUMAN MAST CELL ACTIVATION MODULATION OF HUMAN MAST CELL ACTIVATION
11-18-2010
Admixtures for inorganic binders based on a hydrogenated disaccharide, inorganic binders containing these admixtures and process for their preparation Admixtures for inorganic binders based on a hydrogenated disaccharide, inorganic binders containing these admixtures and process for their preparation
10-28-2010
THERAPEUTIC INHIBITORS OF VASCULAR SMOOTH MUSCLE CELLS
9-9-2010
APPARATUS FOR USING ELECTROPORATION MEDIATED DELIVERY OF DRUGS AND GENES
4-8-2010
PREPARATION AND USE OF SULFATED OLIGOSACCHARIDES
10-29-2009
THERAPEUTIC INHIBITOR OF VASCULAR SMOOTH MUSCLE CELLS THERAPEUTIC INHIBITOR OF VASCULAR SMOOTH MUSCLE CELLS
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METHOD OF MAKING MINERAL FIBRES METHOD OF MAKING MINERAL FIBRES
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OXYGEN-FUEL BOOST REFORMER PROCESS AND APPARATUS
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METHODS OF TREATING VASCULAR DISEASE WITH TNF ANTAGONISTS METHODS OF TREATING VASCULAR DISEASE WITH TNF ANTAGONISTS
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COPOLYMER COMPOSITIONS FOR ORAL DELIVERY
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1,3,5- Or 1,3,6-naphthalenetriyltris(sulfonylimino)aryl acids and salts
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Nitroimidazoles
2-15-1978
Treatment of rheumatoid arthritis and related diseases
1-4-1978
AROMATIC AMIDINES AS ANTIVIRAL AGENTS IN ANIMALS
1-4-1978
Malto-dextrin poly(H-)sulfates
12-14-1977
Disazo compounds useful as complement inhibitors
12-7-1977
Bis-substituted naphthalene-azo phenyleneazo-stilbene-disulfonic and naphthalene-sulfonic acid
9-28-1977
UREIDOPHENYLENEBIS(CARBONYLIMINO)DINAPHTHALENETRISULFONIC ACID COMPOUNDS
9-21-1977
Substituted bisnaphthylazo diphenyl ureido complement inhibitors
9-7-1977
Substituted-hydroxy-naphthalenedisulfonic acid compounds

 

1-12-1977
Complement inhibitors
12-22-1976
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10-13-1976
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EP0183352A2 * Sep 27, 1985 Jun 4, 1986 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Use of suramin for clinical treatment of infection with any of the members of the family of human-t-cell leukemia (htvl) viruses including lymphadenopathy virus (lav)
EP0205077A2 * Jun 3, 1986 Dec 17, 1986 Bayer Ag Suramin sodium for use as an immunostimulant

 

EP0515523A1 * Feb 13, 1991 Dec 2, 1992 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Use of suramin to treat rheumatologic diseases
EP0755254A1 * Mar 24, 1995 Jan 29, 1997 The Trustees Of The University Of Pennsylvania Prevention and treatment of ischemia-reperfusion and endotoxin-related injury using adenosine and purino receptor antagonists
EP1460087A1 * Feb 17, 1997 Sep 22, 2004 The Kennedy Institute Of Rheumatology Methods of treating vascular disease with TNF antagonists
EP1940376A2 * Oct 3, 2006 Jul 9, 2008 Rottapharm S.P.A. Use of neboglamine in the treatment of toxicodependency
EP1945204A2 * Oct 27, 2006 Jul 23, 2008 Brane Discovery S.R.L. V-atpase inhibitors for use in the treatment of septic shock
US5453444 * Oct 6, 1994 Sep 26, 1995 Otsuka Pharmaceutical Co., Ltd. Method to mitigate or eliminate weight loss
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US7476693 Mar 26, 2003 Jan 13, 2009 Eastern Virginia Medical School Suramin and derivatives thereof as topical microbicide and contraceptive
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WO1994010990A1 * Nov 12, 1993 May 26, 1994 British Bio Technology Inhibition of tnf production
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WO2004113920A1 * Jun 18, 2004 Dec 29, 2004 Babon Jeff James Screening method for substances binding to merozoite surface protein-1/42
WO2008138943A2 * May 14, 2008 Nov 20, 2008 Mara Galli Prophylactic and therapeutic use of sirtuin inhibitors in tnf-alpha mediated pathologies
WO2009137471A2 * May 5, 2009 Nov 12, 2009 University Of Miami Azo dye related small molecule modulators of protein-protein interactions
WO2010016628A1 * Jul 10, 2009 Feb 11, 2010 Sammy Opiyo Conjugated suramin amino compounds for medical conditions
WO2012159107A1 * May 21, 2012 Nov 22, 2012 Rhode Island Hospital Inhibition of renal fibrosis

 

 

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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need help, email or call me

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I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

 

 

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CASOPITANT

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Jan 072014
 

CASOPITANT

Tachykinin NK1 Antagonists

(2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide

4-(S)-(4-Acetyl-piperazin-1-yl)-2- (R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-methylamide

414910-30-8  MESYLATE
414910-27-3 (free base)

679769
GW-679769
GW-679769B

MF C30H35F7N4O2.CH4O3S MESYLATE
 Molecular Weight 712.719

 

Casopitant (trade names Rezonic (US), Zunrisa (EU)) is an neurokinin 1 (NK1) receptor antagonist undergoing research for the treatment of chemotherapy-induced nausea and vomiting (CINV).[1] It is currently under development by GlaxoSmithKline (GSK).

In July 2008, the company filed a marketing authorisation application with the European Medicines Agency. The application was withdrawn in September 2009 because GSK decided that further safety assessment was necessary.[2]    Casopitant mesylate, a tachykinin NK1 receptor antagonist, had been filed for approval in the U.S. and the E.U. by GlaxoSmithKline for the prophylaxis of chemotherapy-induced nausea/vomiting.

In 2009 the company discontinued the development of the drug candidate for this indication. An MAA had also been filed for the treatment of postoperative nausea and vomiting, and in 2009 the application was withdrawn by the company.

Additional phase II clinical trials were ongoing at GlaxoSmithKline for the treatment of depression, anxiety, sleep disorders, fibromyalgia and overactive bladder, however, no recent developments have been reported for these indications.

  1.  Lohr L (2008). “Chemotherapy-induced nausea and vomiting”. Cancer J 14 (2): 85–93.doi:10.1097/PPO.0b013e31816a0f07. PMID 18391612.
  2.  “GlaxoSmithKline withdraws its marketing authorisation application for Zunrisa”. London: EMEA. 13 October 2009. Retrieved 21 December 2009
  3. Casopitant mesilate
    Drugs Fut 2008, 33(9): 737
  4. WO 2002032867
  5. WO 2008046882
  6. Development of a control strategy for a defluorinated analogue in the manufacturing process of casopitant mesylate
    Org Process Res Dev 2010, 14(4): 832 NMR FREE BASE, MESYLATE
  7. WO 2006061233
  8. WO 2004091616
  9. US20040014770 ENTRY 1B MP MESYLATE 243
  10. Tetrahedron, 2010 ,  vol. 66,  26  p. 4769 – 4774 NMR FREE BASE
  11. Journal of Medicinal Chemistry, 2011 ,  vol. 54,   4  p. 1071 – 1079 NMR MESYLATE
WO2006061233A1 * Dec 7, 2005 Jun 15, 2006 Glaxo Group Ltd The use of medicament 4-(s)-(4-acetyl-piperazin-1-yl)-2-(r)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(r)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide

 

WO2001044200A2 * Dec 14, 2000 Jun 21, 2001 David J Blythin Selective neurokinin antagonists
WO2002010141A1 * Jul 25, 2001 Feb 7, 2002 Michael Kirk Ahlijanian Imidazole derivatives
WO2002032867A1 * Oct 12, 2001 Apr 25, 2002 Giuseppe Alvaro Chemical compounds
US20020123491 * Dec 14, 2000 Sep 5, 2002 Neng-Yang Shih Selective neurokinin antagonists
US20030064980 * Jun 6, 2002 Apr 3, 2003 Neng-Yang Shih Selective neurokinin antagonists
US20030144270 * Nov 12, 2002 Jul 31, 2003 Schering Corporation NK1 antagonists

 

Casopitant (Rezonic, Zunrisa, casopitant mesylate, GW-679769, 679769, CAS #414910-27-3), 4-(4-Acetyl-piperazin-1-yl)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide, is a NK-1 receptor antagonist.

Casopitant is under investigation for the treatment of emesis, nausea, drug-induced nausea, chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, sleep disorders, anxiety disorders, depressive disorders, overactive bladder, and myalgia (Drug Report for Casopitant, Thomson Investigational Drug Database (Sep. 15, 2008); Reddy et al., Supportive Cancer Therapy 2006, 3(3), 140-142; and WO 2006/061233).

Casopitant has also shown promise in treating disorders of the central nervous system, tinitis, and sexual dysfunction (WO 2006/061233).

compound may be of value in the treatment of Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder and Sexual Aversion Disorder sexual arousal disorders such as Female Sexual Arousal Disorder and Male Erectile Disorder orgasmic disorders such as Female Orgasmic Disorder, Male Orgasmic Disorder and Premature Ejaculation sexual pain disorder such as Dyspareunia and Vaginismus, Sexual Dysfunction Not Otherwise Specified; paraphilias such as Exhibitionism, Fetishism, Frotteurism, Pedophilia, Sexual Masochism, Sexual Sadism Transvestic Fetishism, Voyeurism and Paraphilia Not Otherwise Specified gender identity disorders such as Gender Identity Disorder in Children and Gender Identity Disorder in Adolescents or Adults and Sexual Disorder Not Otherwise Specified.

 

Figure US20100137332A1-20100603-C00002

 

Casopitant is subject to CYP3A4-mediated oxidative metabolism at the 3-carbon of the piperazine ring to form a hydroxylated metabolite which may be further oxidized to the corresponding 3-oxo metabolite (Minthorn et al, Drug Metab. Disp., 2008, 36(9), 1846-1852). Adverse effects associated with casopitantadministration include: neutropenia, nausea, hiccups, headache, constipation, dizziness, pruritis, alopecia, and fatigue.

Overactive bladder is a term for a syndrome that encompasses urinary frequency, with or without urge incontinence, generally but not necessarily combined with pollacisuria and nocturia. Overactive bladder is also characterised by involuntary detrusor contractions which are either triggered by provocation or occur spontaneously. If the detrusor hyperactivity observed is based on neurological causes (e. g. Parkinson’s disease, apoplexy, some forms of multiple sclerosis, spinal cord injury or the cross section of the bone marrow) it is known as neurogenic detrusor hyperactivity. If no clear cause can be detected this is known as idiopathic detrusor hyperactivity. In addition, detrusor hyperactivity may be associated with anatomical changes in the lower urinary tract, for example, in patients with bladder outlet obstruction (an enlargement of the prostate gland in males)

International patent application WO 02/32867 describes novel piperidine derivatives. A 0 particular preferred compound described therein is 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)- (4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid

 

…………………………………………………………………

CASOPITANT MESYLATE

http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0414910308

US20040014770

EXAMPLE 4

[0330] 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-Carboxylic Acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide Methanesulphonate

[0331] A solution of intermediate 4a (7.7 g) in acetonitrile (177 mL) was added to a solution of 1-acetyl-piperazine (3.9 g) in acetonitrile (17.7 mL) followed by sodium triacetoxyborohydride (6.4 g) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and then quenched with a saturated sodium hydrogen carbonate (23.1 mL) and water (61.6 mL). The resulting solution was concentrated in vacuo, then AcOEt (208 mL) was added; the layers were separated and the aqueous layer was back-extracted with further AcOEt (2×77 mL). The collected organic phases were washed with brine (2×118 mL), dried and concentrated in vacuo to give the crude mixture of syn and anti diastereomers (nearly 1:1) as a white foam (9.5 g).

[0332] A solution of this intermediate in THF (85.4 mL) was added to a solution of methansulfonic acid (0.890 mL) in THF (6.1 mL) at r.t. After seeding, the desired syn diastereomer started to precipitate. The resulting suspension was stirred for 3 hours at 0° C. and then filtered under a nitrogen atmosphere. The resulting cake was washed with cold THF (15.4 mL) and dried in vacuo at +20° C. for 48 hours to give the title compound as a white solid (4.44 g).

[0333] NMR (d6-DMSO): δ (ppm) 9.52 (bs, 1H); 7.99 (bs, 1H); 7.68 (bs, 2H); 7.23 (m, 1H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.31 (q, 1H); 4.45 (bd, 1H); 4.20 (dd, 1H); 3.99 (bd, 1H); 3.65-3.25 (bm, 5H); 3.17 (m, 1H); 2.96 (m, 1H); 2.88-2.79 (m+m, 2H); 2.73 (s, 3H); 2.36 (s, 3H); 2.30 (s, 3H); 2.13-2.09 (bd+bd, 2H); 2.01 (s, 3H); 1.89-1.73 (m+m, 2H); 1.46 (d, 3H).

[0334] m.p 243.0° C.

[0335] The compound is isolated in a crystalline form.

 

intermediate 4a is needed  for above syn, ignore 4b

[0168] Intermediate 4

[0169] 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-Carboxylic Acid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)ethyl]-Methylamide (4a) and 2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-Carboxylic Acid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-Methylamide (4b) Method A

[0170] A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was added drop-wise to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM (15 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 2 hours, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (503 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) were added and the mixture was heated to 70° C. for 16 hours. Further [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (170 mg) and DIPEA (100 μL) were added and the mixture was stirred at 70° C. for further 4 hours. Next, the mixture was allowed to cool to r.t., taken up with AcOEt (30 mL), washed with a 1N hydrochloric acid cold solution (3×15 mL) and brine (2×10 mL). The organic layer was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH/AcOEt 8:2) to give:

[0171] 1. intermediate 4a (230 mg) as a white foam,

[0172] 2. intermediate 4b (231 mg) as a white foam. …………….ignore

[0173] Intermediate 4a

[0174] NMR (d6-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

[0175] Intermediate 4b

[0176] NMR (d6-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48 (m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H). …….. ignore

[0177] Intermediate 4a

[0178] Method B

[0179] A saturated sodium hydrogen carbonate solution (324 mL) was added to a solution of intermediate 9 (21.6 g) in AcOEt (324 mL) and the resulting mixture was vigorously stirred for 15 minutes. The aqueous layer was back-extracted with further AcOEt (216 mL) and the combined organic extracts were dried and concentrated in vacuo to give intermediate 8 as a yellow oil, which was treated with TEA (19 mL) and AcOEt (114 mL). The solution obtained was added drop-wise over 40 minutes to a solution of triphosgene (8 g) in AcOEt (64 mL) previously cooled to 0° C. under a nitrogen atmosphere, maintaining the temperature between 0° C. and 8° C.

[0180] After stirring for 1 hours at 0° C. and for 3 hours at 20° C., [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (29.7 g), AcOEt (190 mL) and TEA (38 mL) were added to the reaction mixture which was then heated to reflux for 16 hours.

[0181] The solution was washed with 10% sodium hydroxide solution (180 mL), 1% hydrochloric acid solution (4×150 mL), water (3×180 mL) and brine (180 mL). The organic layer was dried and concentrated in vacuo to a residue, which was purified through a silica pad (CH/AcOEt 9:1) to give the title compound (21.5 g) as a brown thick oil.

[0182] NMR (d6-DMSO): 6 (ppm) 7.97-7.77 (bs+bs, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

intermediate 2

[0152] Intermediate 2

[0153] 2-(4-Fluoro-2-methyl-phenyl)-piperidine-4-one

[0154] Method A

[0155] 2-Methyl-4-fluoro-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluensulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.

[0156] Method B

[0157] L-selectride (1M solution in dry THF, 210 mL) was added drop-wise, over 80 minutes, to a solution of intermediate 1 (50 g) in dry THF (1065 mL) previously cooled to −72° C. under a nitrogen atmosphere. After 45 minutes, 2% sodium hydrogen carbonate solution (994 mL) was added drop-wise and the solution was extracted with AcOEt (3×994 mL). The combined organic phases were washed with water (284 mL) and brine (568 mL). The organic phase was dried and concentrated in vacuo to get 1-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a pale yellow thick oil (94 g) which was used as a crude.

[0158] This material (94 g) was dissolved in AcOEt (710 mL), then 10% Pd/C (30.5 g) was added under a nitrogen atmosphere. The slurry was hydrogenated at 1 atmosphere for 30 minutes. The mixture was filtered through Celite and the organic phase was concentrated in vacuo to give the crude 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a yellow oil. This material was dissolved in AcOEt (518 mL) at r.t. and racemic camphorsulphonic acid (48.3 g) was added. The mixture was stirred at r.t for 18 hours, then the solid was filtered off, washed with AcOEt (2×50 mL) and dried in vacuo for 18 hours to give 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one, 10-camphorsulfonic acid salt as a pale yellow solid (68.5 g). (M.p.: 167-169° C.-NMR (d6-DMSO): 6 (ppm) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 (m, 2H); 4.97 (bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 2.37 (s+d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03 (s, 3H); 0.73 (s, 3H).

[0159] This material (68.5 g) was suspended in AcOEt (480 mL) and stirred with a saturated sodium hydrogen carbonate (274 mL). The organic layer was separated and washed with further water (274 mL). The organic phase was dried and concentrated in vacuo to give the title compound (31 g) as a yellow-orange oil.

[0160] NMR (d6-DMSO): 6 (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).

[0161] MS (ES/+): m/z=208 [MH]+.

 

intermediate 9

[0220] Intermediate 9

[0221] 2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one Mandelic Acid.

[0222] A solution of L-(+)-mandelic acid (22.6 g) in AcOEt (308 mL) was added to a solution of intermediate 2 (31 g) in AcOEt (308 mL). Then isopropanol (616 mL) was added and the solution was concentrated in vacuo to 274 mL. The solution was then cooled to 0° C. and further cold isopropanol (96 mL) was added. The thick precipitate was stirred under nitrogen for 5 hours at 0° C., then filtered and washed with cold Et2O (250 mL) to give the title compound as a pale yellow solid (20.3 g).

[0223] M.p.: 82-85° C.

[0224] NMR (d6-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26 (m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88 (m, 1H); 2.49-2.2 (m, 4H); 2.29 (s, 3H).

[0225] Chiral HPLC: HP 1100 HPLC system; column Chiralcel OD-H, 25 cm×4.6 mm; mobile phase: n-hexane/isopropanol 95:5+1% diethylamine; flow: 1.3 ml/min; detection: 240/215 nm; retention time 12.07 minutes.

 

 

………………….

NMR

mesylate

Org. Process Res. Dev., 2010, 14 (6), pp 1337–1346
DOI: 10.1021/op100150b

http://pubs.acs.org/doi/abs/10.1021/op100150b

Abstract Image

1H NMR (600 MHz, DMSO-d6): 9.57 (br s, 1H), 7.99 (br s, 1H), 7.68 (br s, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H), MS: m/z 617 [MH]+, as free base.

 

 

……………

http://pubs.acs.org/doi/full/10.1021/op100209c

Org. Process Res. Dev., 2010, 14 (6), pp 1407–1419
DOI: 10.1021/op100209c
(2R,4S)-4-(4-Acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide Methanesulfonate Salt (Casopitant Mesylate 1)

A solution of casopitant 2 (0.86 wt) was diluted with EtOAc (overall solution of 2 in EtOAc was 4 L) and acetone (4.5 L) and was heated to the required temperature (from 39 °C). Thereafter, neat methanesulfonic acid (0.12 L, 1.64 mol) was charged, followed by a slurry of 2 (0.005 kg) in EtOAc (0.05 L) as seed. The obtained suspension was stirred for 1 h followed by the addition of 3 L of isooctane in the required time (1 h). The slurry was cooled to 20 °C in 2 h and aged 3 h. The suspension was filtered and the solid washed with EtOAc (3 × 4 L). The white solid was dried overnight under vacuum at 40 °C to give the desired casopitant mesylate 1 (0.94 kg).
1H NMR (600 MHz, DMSO-d6) δ 9.57 (br s, 1H), 7.99 (br s, 1H), 7.68 (br s, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H). MS: m/z 617 [MH]+, as free base.
………….
Org. Process Res. Dev., 2010, 14 (4), pp 805–814
DOI: 10.1021/op1000622
http://pubs.acs.org/doi/abs/10.1021/op1000622
NMR CASOPITANT FREE BASE
(2R,4S)-4-(4-Acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide (Casopitant 2)

HCOOH (0.49 L, 13 mol) was added to a cooled suspension of NaBH(OAc)3 (0.82 kg, 3.87 mol) in CH3CN (4 L), keeping the internal temperature between 10−15 °C; then the lines were washed with more CH3CN (1 L), and the mixture was stirred for 40 min.
1-Acetylpiperazine (0.7 kg, 5.46 mol) was added neat over the solution of piperidone-urea 3, and the mixture was diluted with CH3CN (3 L). The resulting mixture was added over the previous suspension; fresh CH3CN (4 L) was used to wash the line. The reaction mixture was stirred at 15 °C for 12 h. The solvent was evaporated under reduced pressure to 4 L.
The resulting suspension was diluted with fresh EtOAc (4 L), and then washed with ammonia [21% w/w solution (4 L, 11.25 M in NH3)], Na2CO3 [15% w/w solution (4 L)]. More EtOAc (4 L) was added, and the organic layer was washed with water (4 L). The organic phase was then concentrated to 2.5 L; again fresh EtOAc (4 L) was added, and the solution was concentrated to 2.5 L to give a solution of casopitant 2.
1H NMR (600 MHz, DMSO-d6): δ 7.99 (s, 1H), 7.68 (s, 2H), 7.18 (dd, 1H), 6.90 (dd, 1H), 6.76 (td, 1H), 5.33 (q, 1H), 4.14 (dd, 1H), 3.38 (m, 5H), 2.71 (s, 3H), 2.72 (m, 1H), 2.54 (m, 1H), 2.47 (m, 2H), 2.41 (m, 2H), 2.34 (s, 3H), 1.95 (s, 3H), 1.85 (m, 1H), 1.77 (m, 1H), 1.62 (dq, 1H), 1.47 (d, 3H), 1.40 (q, 1H).
Abstract Image

picture animation

 

……………………………….

J. Med. Chem., 2011, 54 (4), pp 1071–1079
DOI: 10.1021/jm1013264

http://pubs.acs.org/doi/full/10.1021/jm1013264?prevSearch=casopitant&searchHistoryKey=

(2R,4S)-1′-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4′-bipiperidine-1-carboxamide methanesulfonate salt 16a (casopitant)

nmr mesylate

1H NMR (600 MHz, DMSO-d6): 9.57 (bs, 1H), 7.99 (bs, 1H), 7.68 (bs, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H). MS: m/z 617 [MH]+, as free base.

syn of intermediates

Figure

a(a) (i) 2-Bromo-5-fluorotoluene, Mg, THF, 60−70 °C; (ii) 4-methoxypyridine, benzyl chloroformate, THF, −20 °C, then Grignard’s reagent, −20 °C, 1 h; (b) (i) tris(triphenylphosphine)rhodium(I) chloride, 2-propanol, H2 (p = 5 atm), 60 °C, 5 h; (ii) Pd/C 5%, H2 (p = 4 atm), 20 °C, 5 h; (iii) (R,S)-10-camphorsulfonic acid, toluene; (c) CH2Cl2, H2O, 8% NaHCO3 (aq); l-(+)-mandelic acid, 2-propanol, heptanes; (d) MeNH2, EtOH, NaBH4, 25 °C, 1.5 h; (e) (i) ethyl acetate, NaHCO3 (aq. sat. soln), 5; (ii) triphosgene, triethylamine, ethyl acetate, then 5, 20 °C, 2 h; (f) R′RNH, CH3CN, NaBH(OAc)3, room temp, 24 h.

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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SOVAPREVIR in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1

 phase 2, Uncategorized  Comments Off on SOVAPREVIR in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1
Jan 062014
 

SOVAPREVIR

(2S, 4R) -1 – [(2S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl) butanoyl]-N-{(1R, 2S) -1 – [(cyclopropanesulfonyl) carbamoyl]-2-ethenylcyclopropyl} -4 – [(7-methoxy-2-phenylquinolin-4-yl) oxy] pyrrolidine-2-carboxamide

http://www.ama-assn.org/resources/doc/usan/sovaprevir.pdf

PATENT

US 2009048297 ENTRY 60

WO 2008008502

CN 103420991

 

THERAPEUTIC CLAIM ….Treatment of hepatitis C

CHEMICAL NAMES

1. 2-Pyrrolidinecarboxamide, N-[(1R,2S)-1-[[(cyclopropylsulfonyl)amino]carbonyl]-2-
ethenylcyclopropyl]-1-[(2S)-3,3-dimethyl-1-oxo-2-[2-oxo-2-(1-piperidinyl)ethyl]butyl]-4-
[(7-methoxy-2-phenyl-4-quinolinyl)oxy]-, (2S,4R)-

2. (2S,4R)-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-1-{(2S)-
3,3-dimethyl-2-[2-oxo-2-(piperidin-1-yl)ethyl]butanoyl}-4-[(7-methoxy-2-phenylquinolin-
4-yl)oxy]pyrrolidine-2-carboxamide

MOLECULAR FORMULA C43H53N5O8S

MOLECULAR WEIGHT 800.0

SPONSOR Achillion Pharmaceuticals, Inc.

CODE DESIGNATION ACH-0141625

CAS REGISTRY NUMBER 1001667-23-7

  • ACH-0141625
  • Sovaprevir
  • UNII-2ND9V3MN6O

Sovaprevir (formerly ACH-0141625), an HCV NS3 protease inhibitor, is in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1.

In 2012, fast track designation was assigned by the FDA for the treatment of hepatitis C (HCV). In 2013, a clinical hold was placed for the treatment of hepatitis C (HCV) in combination with atazanavir after elevations in liver enzymes associated with the combination of both compounds.

Sovaprevir, previously referred to as ACH-1625, is an investigational, next-generation NS3/4A protease inhibitor discovered by Achillion that is currently on clinical hold. In 2012, Fast Track status was granted by the U.S. Food and Drug Administration (FDA) to sovaprevir for the treatment of chronic hepatitis C viral infection (HCV).

Achillion has initiated a Phase 2 clinical trial (007 Study) to evaluate the all-oral, interferon-free combination of sovaprevir and its second-generation NS5A inhibitor, ACH-3102, with ribavirin (RBV), for a 12 week treatment duration, in treatment naïve, genotype 1 (GT1) HCV patients. In July 2013, sovaprevir was placed on clinical hold after elevated liver enzymes were observed in a Phase 1 healthy subject drug-drug interaction study evaluating the effects of concomitant administration of sovaprevir with ritonavir-boosted atazanavir.

In accordance with the clinical hold, the FDA provided that no new clinical trials that included dosing with sovaprevir could be initiated, however, the FDA allowed continued enrollment and treatment of patients in the Phase 2 -007 clinical trial evaluating 12-weeks of sovaprevir in combination with ACH-3102 and RBV for patients with treatment-naive genotype 1 HCV. In September 2013, after reviewing Achillion’s response, the FDA stated that although all issues identified in the June 2013 letter had been addressed, it had concluded that the removal of the clinical hold was not warranted at this time.

The FDA requested, among other things, additional analysis to more fully characterize sovaprevir pharmacokinetics and the intrinsic and extrinsic factors that may lead to higher than anticipated exposures of sovaprevir or other potential toxicities in addition to the observed liver enzyme elevations.

The FDA also requested Achillion’s proposed plan for future clinical trials in combination with other directly-acting antivirals. At the request of the FDA, Achillion plans to submit a proposed plan for analyzing the additional clinical, non-clinical and pharmacokinetic data requested before the end of 2013, and if that analysis plan is approved by the FDA, submit a complete response during the first half of 2014. Achillion retains worldwide commercial rights to sovaprevir.

 

Sovaprevir has demonstrated activity against all HCV genotypes (GT), including equipotent activity against both GT 1a and 1b (IC50 ~ 1nM) in vitro.

 

With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios, sovaprevir has been clinically demonstrated to allow for once-daily, non-boosted dosing.

The current safety database for sovaprevir includes more than 560 subjects dosed to date and demonstrates that sovaprevir is well tolerated in these subjects.

Sovaprevir has demonstrated high rates of clinical cures in combination with pegylated-interferon and RBV in a challenging, real world, patient population of genotype 1 treatment-naive patients.

100% of GT1b subjects achieved a rapid virologic response (RVR) in the 007 Study evaluating the interferon-free combination of sovaprevir + ACH-3102 + RBV for 12 weeks. The Phase 2 study is ongoing.

 

Sovaprevir in vitro retains activity against mutations that confer resistance to 1st-generation protease inhibitors.

In clinical studies to date, sovaprevir has demonstrated a high pharmacologic barrier to resistance with no on-treatment viral breakthrough reported to date in GT1b patients.

 

Sovaprevir is believed to be synergistic when combined with other classes of DAAs, including the second-generation NS5A inhibitor, ACH-3102.

For more information about the next-generation NS3/4A protease inhibitor, sovaprevir, please see the Related Links on this page or visit Resources.

Sovaprevir is an investigational compound. Its safety and efficacy have not been established. (Updated December 2013)

SOVAPREVIR

 

An estimated 3% of the world’s population is infected with the hepatitis C virus. Of those exposed to HCV, 80% become chronically infected, at least 30% develop cirrhosis of the liver and 1-4% develop hepatocellular carcinoma. Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the U.S., Australia, and most of Europe. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will clear HCV.

HCV is an enveloped, single-stranded RNA virus that contains a positive-stranded genome of about 9.6 kb. HCV is classified as a member of the Hepacivirus genus of the family Flaviviridae. At least 4 strains of HCV, GT-1-GT-4, have been characterized.

The HCV lifecycle includes entry into host cells; translation of the HCV genome, polyprotein processing, and replicase complex assembly; RNA replication, and virion assembly and release. Translation of the HCV RNA genome yields a more than 3000 amino acid long polyprotein that is processed by at least two cellular and two viral proteases. The HCV polyprotein is:

NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.

The cellular signal peptidase and signal peptide peptidase have been reported to be responsible for cleavage of the N-terminal third of the polyprotein (C-E1-E2-p7) from the nonstructural proteins (NS2-NS3-NS4A-NS4B-NS5A-NS5B). The NS2-NS3 protease mediates a first cis cleavage at the NS2-NS3 site. The NS3-NS4A protease then mediates a second cis-cleavage at the NS3-NS4A junction. The NS3-NS4A complex then cleaves at three downstream sites to separate the remaining nonstructural proteins. Accurate processing of the polyprotein is asserted to be essential for forming an active HCV replicase complex.

Once the polyprotein has been cleaved, the replicase complex comprising at least the NS3-NS5B nonstructural proteins assembles. The replicase complex is cytoplasmic and membrane-associated. Major enzymatic activities in the replicase complex include serine protease activity and NTPase helicase activity in NS3, and RNA-dependent RNA polymerase activity of NS5B. In the RNA replication process, a complementary negative strand copy of the genomic RNA is produced. The negative strand copy is used as a template to synthesize additional positive strand genomic RNAs that may participate in translation, replication, packaging, or any combination thereof to produce progeny virus. Assembly of a functional replicase complex has been described as a component of the HCV replication mechanism. Provisional application 60/669,872 “Pharmaceutical Compositions and Methods of Inhibiting HCV Replication” filed Apr. 11, 2005, is hereby incorporated by reference in its entirety for its disclosure related to assembly of the replicase complex.

Current treatment of hepatitis C infection typically includes administration of an interferon, such as pegylated interferon (IFN), in combination with ribavirin. The success of current therapies as measured by sustained virologic response (SVR) depends on the strain of HCV with which the patient is infected and the patient’s adherence to the treatment regimen. Only 50% of patients infected with HCV strain GT-1 exhibit a sustained virological response. Direct acting antiviral agents such as ACH-806, VX-950 and NM 283 (prodrug of NM 107) are in clinical development for treatment of chronic HCV. Due to lack of effective therapies for treatment for certain HCV strains and the high mutation rate of HCV, new therapies are needed.

 

…………………………………………

https://www.google.co.in/patents/US20090048297

(2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

 

Figure US20090048297A1-20090219-C00105

 

SOVAPREVIR IS DESCRIBED AS 60 IN CLAIM

 

SYNTHESIS OF INTERMEDIATE 13 BELOW AND ALSO  COMPD 8 IE SOVAPREVIR IN STEP 4

 

Example 1

SYNTHESIS OF 1-((2S,4R)-1-((S)-2-TERT-BUTYL-4-OXO-4-(PIPERIDIN-1-YL)BUTANOYL)-4-(7-METHOXY-2-PHENYLQUINOLIN-4-YLOXY)PYRROLIDINE-2-CARBOXAMIDO)-2-VINYLCYCLOPROPANECARBOXYLIC ACID

Step 1. Preparation of N-(cyclopropylsulfonyl)-1-(BOC-amino)-2-vinylcyclopropanecarboxamide

 

Figure US20090048297A1-20090219-C00047

 

CDI (2.98 g, 18.4 mm, 1.1 eq) is dissolved in ethyl acetate. N-Boc-cyclopropylvinyl acid (3.8 g, 16.7 mm, 1.0 eq), prepared via the procedure given by Beaulieu, P. L. et al. (J. Org. Chem. 70: 5869-79 (2005)) is added to the CDI/ethyl acetate mixture and stirred at RT until the starting material is consumed. Cyclopropyl sulfonamine (2.2 g, 18.4 mm, 1.1 eq) is added to this mixture followed by DBU (2.1 ml, 20.5 mm, 1.23 eq) and the mixture is stirred at RT for 2 h. Workup and purification by silica gel chromatography provides 2g of compound 2.

Step 2. Preparation of (2S,4R)-tert-butyl 2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carboxylate and (2S,4R)—N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

Figure US20090048297A1-20090219-C00048

 

Compound 1 (4.3 g, 9.3 mmol, 1.1 eq), prepared according to the method given ins WO 02/060926, in DMF is stirred with O-(Benzotriazol-lyl)-N,N,N′,N′-Tetramethyluronium hexafluorophosphate (4.1 g, 10.5 mmol, 1.3 eq) for 30 minutes, followed by addition of cyclopropylamine 2 (1.92 g, 8.3 mmol, 1.0 eq) and N-methylmorpholine (2.52 g, 25.0 mmol, 3.0 eq). The mixture is stirred over night and the solvent removed under reduced pressure. The resulting residue is diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic solvent is dried over MgSO4 and concentrated under reduced pressure to afford crude 3, which is used for next step without further purification.

Compound 3 in 10 ml dry CH2Cl2 is treated with 5 mL TFA and stirred over night. The solvent is removed and the residue recrystallized from ethyl acetate to afford 4.12 g Compound 4 (61% yield two steps).

Step 3. Preparation of (3S)-3-((2S,4R)-2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

 

Figure US20090048297A1-20090219-C00049

 

The Acid 5 (58 mg, 0.25 mmol, 1.2 eq), prepared via the procedure given by Evans, D. A., et al. (J. Org. Chem. 64: 6411-6417 (1999)) in 1.2 mL DMF is stirred with 4 (138 mg, 0.21 mmol), HATU (160 mg, 0.42 mmol, 2.0 eq), and DIEA (0.63 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 121 mg 6 (77% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent was removed to provide Compound 7 in 100% yield.

Step 4. Preparation of (2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide

 

Figure US20090048297A1-20090219-C00050

PLEASE  NOTE 8 IS SOVAPREVIR

The Acid 7 (0.15 mmol) in 1.0 mL DMF is stirred with pepridine (excess, 0.6 mmol, 4 eq), HATU (115 mg, 0.3 mmol, 2.0 eq), and DIEA (0.45 mmol, 3.0 eq) for 4 hrs. The mixture is subjected to HPLC purification to afford 77.1 mg 8.

Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

 

Figure US20090048297A1-20090219-C00051

 

Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid

The Acid 5 (105 mg, 0.46 mmol, 1.2 eq) in 1.2 mL DMF is stirred with 9 (202 mg, 0.38 mmol), HATU (290 mg, 0.76 mmol, 2.0 eq), and DIEA (1.2 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 204.3 mg 10 (75% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent is removed to provide 11 in 100% yield.

 

Figure US20090048297A1-20090219-C00052

 

Step 6. Preparation of Final Product

The Acid 11 (30 mg, 0.045 mmol) in 1.0 mL DMF is stirred with pepridine (0.27 mmol, 6 eq), HATU (34 mg, 0.09 mmol, 2.0 eq), and DIEA (0.14 mmol, 3.0 eq) for 2 hrs. The mixture is subjected to HPLC purification to afford 21.2 mg 12 (65% yield), which is hydrolyzed in methanol with 2N NaOH for 6 hrs. The mixture is acidified with 6N HCl and subjected to HPLC purification to afford 7.6 mg 13.

………………………………

 

picture animation

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

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VESTIPITANT (Phase II GSK)

 Uncategorized  Comments Off on VESTIPITANT (Phase II GSK)
Jan 062014
 

 

VESTIPITANT

(2S)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperazine-1-carboxamide

 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-l- carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide 

2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant)

Vestipitant [INN], UNII-S052TOI9BI,  DCL001035,

CAS NO 334476-46-9

Molecular Formula: C23H24F7N3O   Molecular Weight: 491.444982

Elemental Analysis: C, 56.21; H, 4.92; F, 27.06; N, 8.55; O, 3.26

Vestipitant, also known as GW597599,  is one of the most potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. Its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression.

Vestipitant is a drug developed by GlaxoSmithKline which acts as a selective antagonist for the NK1 receptor. It is under development as a potential antiemetic and anxiolytic drug, and as a treatment for tinnitus.

Vestipitant mesylate is a tachykinin NK1 receptor antagonist in phase II clinical trials at GlaxoSmithKline for the treatment of postoperative nausea and vomiting. The drug candidate had been in clinical development at the company for several indications, including the treatment of tinnitus as monotherapy or in combination with paroxetine, the treatment of primary insomnia, the treatment of depression and anxiety and the treatment of chemotherapy-induced nausea and vomiting; however, no recent development has been reported for this research.

Vestipitant has anxiolytic properties and a good safety profile. Vestipitant was investigated for potential effect against chronic tinnitus as a stand-alone treatment and in conjunction with a selective serotonin reuptake inhibitor, paroxetine. No statistically significant treatment benefit effect was detected for tinnitus (intensity, pitch, and distress) VAS scores, arousal-anxiety VAS scores, Tinnitus Handicap Inventory, or tinnitus aggravation scores assessed on Days 1 and 14. However, a statistically significant worsening of tinnitus intensity and distress scores was observed after vestipitant compared with placebo for the mean data collected over the treatment period. No relevant differences in vestipitant plasma concentrations were observed between the subjects given the combination with paroxetine and those receiving vestipitant alone. No specific relationships were observed between tinnitus intensity and vestipitant plasma concentrations.
CONCLUSION: Although well-tolerated vestipitant, alone or in combination with paroxetine, was not effective in ameliorating tinnitus in this patient group.

Vestipitant is a drug developed by GlaxoSmithKline which acts as a selective antagonist for the NK1 receptor. It is under development as a potentialantiemetic and anxiolytic drug,[1][2] and as a treatment for tinnitus.[3]

  1.  Reddy, GK; Gralla, RJ; Hesketh, PJ (2006). “Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis”. Supportive cancer therapy 3 (3): 140–2.doi:10.3816/SCT.2006.n.011. PMID 18632487.
  2.  Brocco, M; Dekeyne, A; Mannoury La Cour, C; Touzard, M; Girardon, S; Veiga, S; De Nanteuil, G; Dejong, TR et al. (2008). “Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents”. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 18 (10): 729–50.doi:10.1016/j.euroneuro.2008.06.002. PMID 18657401.
  3.  ClinicalTrials.gov NCT00394056 Vestipitant Or Vestipitant/Paroxetine Combination In Subjects With Tinnitus And Hearing Loss

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vestipitant

 

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VESTIPITANT MESYLATE

 

CAS:  334476-64-1 of MESYLATE

  • GW597588B
  • UNII-OWR424W90Q

D06293, 334476-64-1

Journal of Thermal Analysis and Calorimetry, 2010 ,  vol. 102,   1  pg. 297 – 303

 

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INTRODUCTION

 

Figure US20090264388A1-20091022-C00012

International patent application number WO2001/25219 describes piperazine derivatives. One such compound described therein is 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-l- carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide (otherwise known as vestipitant) and it has the following chemical structure (I).

Figure imgf000002_0001

WO2001/25219 also describes the methanesulphonate salt of the compound (I).

The compound (I) and its pharmaceutically acceptable salts may be prepared by the processes described in International patent applications WO2001/25219 and WO2007/048642, which are incorporated herein by reference. Specifically, Examples 37 and 36 of WO2001/25219 describe the synthesis of the compound (I) as free base and as methanesulphonate salt respectively. Hydrochloride and acetate salts of the compound(I) are described in the Examples

38 and 18 respectively. Example 1 of WO2007/048642 discloses a process for preparing an intermediate in the synthesis of the compound(I).

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Synthetic Process of Vestipitant

The following synthetic route was reported by Giuseppe Guercio et al from GlaxoSmithKline:

Org. Process Res. Dev., 2009, 13 (6), pp 1100–1110

DOI: 10.1021/op9002032

The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste. Through a targeted process of research and development, application of novel techniques and extensive route scouting, a new synthetic route for GW597599 was developed. This paper reports the optimisation work of the third and last stage in the chemical synthesis of GW597599 and the development of a pilot-plant-suitable process for the manufacturing of optically pure arylpiperazine derivative 1. In particular, the process eliminated the use of triphosgene in the synthesis of an intermediate carbamoyl chloride, substantially enhancing safety, overall yield, and throughput.

 

 

Figure

 

1H NMR (600 MHz, DMSO-d6) δ 1.48 (d, J = 6.9 Hz, 3H); 2.31 (s, 3H); 2.39 (s, 3H); 2.74 (s, 3H); 2.95 (t, J = 12.2 Hz, 1H); 3.00−3.06 (m, 1H); 3.27 (dd, J = 12.5, 2.3 Hz, 1H); 3.28−3.35 (m, 1H); 3.38−3.43 (m, 1H); 3.47 (dt, J = 13.3, 3.1 Hz, 1H); 4.49 (dd, J = 11.8, 3.3 Hz, 1H); 5.35 (q, J = 6.5 Hz, 1H); 6.84 (td, J = 8.4, 2.6 Hz, 1H); 7.01 (dd, J = 10.2, 2.7 Hz, 1H); 7.29 (dd, J = 8.5, 6.0 Hz, 1H); 7.71 (bs, 2H); 8.02 (bs, 1H); 8.71 (bs, 1H); 9.02 (bs, 1H).

ES+: m/z 492 [MH − CH3SO3H]+, 341, 221; ES−: m/z 586 [M − H]−; 95 [CH3SO3]−.
13C NMR (150 MHz, DMSO-d6) δ 16.37, 18.81, 30.54, 39.79, 42.41, 45.70, 46.58, 52.41, 53.42, 112.48, 116.55, 121.02, 123.19 (d), 127.19, 127.44 (d), 130.34 (d), 134.00, 138.56, 144.79, 160.89, 163.2.
IR (Nujol mull, cm−1): 1653 (str. C═O), 1600 (str. C═C aromatic) (cm−1).
HPLC column type Betabasic C18; mobile phase A: buffer ammonium hydrogen carbonate 5 mM pH = 10/methanol 40/60% v/v and B buffer ammonium hydrogen carbonate 5 mM pH = 10/methanol 10/90% v/v; gradient: 0 min 100% A to 20 min 100% B. flow 1 mL/min; column temperature 40 °C; detector UV DAD @210 nm. Retention times 1: 13 min, purity >98%.
HPLC column type Chiralpack AD; mobile phase n-hexane/ethanol 86/14% v/v + 0.2% v/v purified water; flow 1 mL/min; column temperature 25 °C; detector UV DAD @210 nm. Retention time1: 4.56 min and opposite enantiomer 4.15 min, other diastereomers 5.20 and 14.2 min, respectively.

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SYNTHESIS

 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-l- carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide

http://www.google.com/patents/WO2012175434A1

Preparation 1

(S)-2-(4-fluoro-2-methylphenyl)piperazine dihydrochloride

A suspension of (S)-3-(4-fluoro-2-methylphenyl)piperazin-2-one (S)-2-hydroxy-2- phenylacetate (14.0Kg; contains 16%w/w EtOAc hence 11.8 kg corrected for solvent) and tetrabutylammoniunn bromide (TBAB, 236g) in THF (94L) was warmed to 40°C to obtain a clear solution that was cooled to 30°C and then added to a slurry of sodium borohydride (powder grade, 5.5kg) in THF (41L) at 20°C, followed by THF (5.6L). The mixture was warmed to 35°C and then boron trifluoride-THF complex (36.6kg) was added over 90min, followed by THF (1L). The mixture was stirred for 6h and then IMS (47L) added over 3 hours. The mixture was distilled to ca. 94L, diluted with IMS (47L) and further distilled to 94L. The slurry was cooled to 25°C, filtered and the solids washed with IMS (2x35L). The combined filtrates were heated to 70°C and hydrogen chloride (5-6N in isopropanol, 15kg) added over 72min. The resulting slurry was heated at reflux for 3h, cooled to 20°C over 2h and then held at this temperature for 2h. The suspension was filtered, washed with IMS (3x24L) and the solids dried under vacuum at 45-50°C to give the title compound (6.87kg) as a white powder.

*H NMR NMR (D20) δ (ppm) 7.44 (dd, 1H), 7.03-7.00 (m, 2H), 4.89 (dd, 1H), 3.82-3.51 (m, 6H), 3.35 (s, 3H).

Preparation 2

(S)-tert-butyl3-(4-fluoro-2-methylphenyl)piperazine-l-carboxylate

hydrochloride

Triethylamine (5.5kg) was added to a slurry of (S)-2-(4-fluoro-2-methylphenyl)piperazine dihydrochloride (6.60kg, 94.6% assay) in EtOAc (38L) and was rinsed in with EtOAc (1L). The slurry was stirred at 40°C for 120 minutes and was then cooled to 20°C. 79.2%w/w Di-fe/ -butyl dicarbonate in EtOAc solution (6.29kg) was added over 60 minutes and was rinsed in with EtOAc (1L). The slurry was stirred for 15 minutes. Further 79.2%w/w di-fe/ -butyl dicarbonate in EtOAc solution (0.19kg) and EtOAc (1L) was added and the slurry was stirred for 43 minutes. EtOAc (5L), 79.2%w/w di-fe/ -butyl dicarbonate in EtOAc solution (0.25kg) and EtOAc (1L) were added and the slurry was then stirred for 15 minutes to complete the reaction. Water (18.7L) was added to dissolve all solids present and the lower aqueous layer was separated. The organic layer was washed with water (18.7L). The solution was distilled under reduced pressure to a total volume of 25L. Fresh EtOAc (37L) was added and the solution was distilled under reduced pressure to a total volume of 25L. EtOAc (49L) was added and the temperature was adjusted to 15°C. A slurry of the title compound (31.2g) in EtOAc (310ml) was added followed by 5.5M hydrogen chloride in isopropanol solution (0.412kg) rinsed in with EtOAc (1L). The mixture was stirred for 60 minutes to give a slurry. 5.5M Hydrogen chloride in isopropanol solution (3.6kg) was added portionwise over 55 minutes and was rinsed in with EtOAc (1L). The resultant slurry was stirred for 30 minutes at 15°C. The slurry was filtered and the solid was washed with EtOAc (2 x 16.8kg). The solid was dried under vacuum at 40°C to give the title compound (6.84kg) as a white solid.

*H NMR (500 MHz, DMSO-o^) δ ppm 9.89 (brs, 2 H), 7.88 (dd, 1 H), 7.13 – 7.20 (m, 2 H), 4.43 (d, 1 H), 4.07 (d, 1 H), 3.96 (d, 1 H), 3.30 – 3.38 (m, 2 H), 3.21 (m, 2 H), 2.39 (s, 3 H), 1.42 (s, 9 H). Preparation 3

(R)-l-(3,5-bis(trifluoromethyl)phenyl)-N-methylethanamine

To a suspension of (R)-l-(3,5-bis(trifluoromethyl)phenyl)-N-nnethylethanannine (S)-2- hydroxysuccinate (9Kg) in EtOAc (27L), 13% w/w aqueous sodium carbonate solution (27L) was added. The mixture was stirred for 30 minutes at 25°C to ensure complete dissolution. The layers were separated and the organic phase was washed with water (27L). EtOAc (36L) was added and the solution concentrated in vacuo to 18L. Further EtOAc (49Kg) was added and the solution concentrated in vacuo to 18L to give a colourless 33.4% w/w solution of the title compound in EtOAc (17.9Kg).

*H NMR for title compound (500 MHz, DMSO-i¼) δ ppm 8.01 (s, 2 H), 7.90 (s, 1 H), 3.79 (q, 7=6.56 Hz, 1 H), 2.35 (br s, 1 H), 2.10 (s, 3 H), 1.25 (d, 7=6.56 Hz, 3 H)

H NMR for EtOAc peaks (500 MHz, DMSO-i¼) δ ppm 4.02 (q, 7=7.17 Hz, 2 H), 1.98 (s, 3 H), 1.17 (t, 7=7.10 Hz, 3 H)

NMR shows a ratio of 1:6.1 the title compound: EtOAc.

Preparation 4

(S)-N-((R)-l-(3,5-bis(trifluoromethyl)phenyl)ethyl)-2-(4-fluoro-2- methylphenyl)-N-methylpiperazine-l-carboxamide methanesulfonate (Crystalline Form 1)

To a 33.4% w/w solution of (R)-l-(3,5-bis(trifluoromethyl)phenyl)-N-methylethanamine in EtOAc (14.70Kg) was added EtOAc (22L). The solution was vacuum purged three times with carbon dioxide gas and stirred under a flow of C02 at 20°C for 1 hour. Triethylamine (2.40Kg) was added followed by EtOAc (1.35Kg) and the solution stirred for 50 minutes under a flow of C02. Chlorotrimethylsilane (2.50Kg) was added over 30 minutes keeping the internal temperature below 25°C followed by EtOAc (1.35Kg) and the suspension stirred under a flow of C02 at 20°C for 30 minutes. Pyridine (2.85Kg) was added followed by EtOAc (2.70Kg). Thionyl chloride (3.25Kg) was added over 20 minutes followed by EtOAc (2.70Kg) and the suspension heated to 25°C for 6 hours. The reaction was cooled to 10°C and quenched with 28% w/w aqueous malic acid solution (14.30Kg). The layers were separated at 20°C and the organic phase washed with 14% w/w aqueous malic acid solution (13.50Kg), water (12.70Kg) and 20% w/w aqueous potassium phosphate dibasic solution (22.40Kg). EtOAc (4.50Kg) was added and the solution concentrated in vacuo to 15L. Further EtOAc (15L) was added and the solution concentrated in vacuo to 15L.

To the concentrated solution, EtOAc (5L) was added followed by (S)-tert-butyl 3-(4-fluoro-2- methylphenyl)piperazine-l-carboxylate hydrochloride (5.00Kg) and EtOAc (2.50Kg). Tributylamine (7.00Kg) was added and the suspension heated to reflux for 1 hour. The reaction was cooled to 30°C and EtOAc (27.20Kg) followed by water (15.00Kg) were added. The layers were separated, diethylamine (l.lOKg) was added to the organic phase and the solution heated to 40°C for 1 hour. The reaction was cooled to 30°C and washed with 0.5M sulfuric acid (25.90Kg), 0.5M sulfuric acid (15.45Kg) and water (15.00Kg).

To the organic phase, methanesulfonic acid (5.85Kg) was added and the solution heated to 40°C for 1 hour. The reaction was cooled to 10°C then 13%w/w aqueous ammonia solution (23.75Kg) was added over 30 minutes keeping the internal temperature below 35°C. The layers were separated at 30°C and the organic phase was washed with 1% w/w aqueous ammonia solution (15.15Kg) and water (15.00Kg). EtOAc (4.50Kg) was added to the organic phase and the solution was concentrated in vacuo to 15L. EtOAc (40L) was added and the solution concentrated in vacuo to 15L

Further EtOAc (10L) was added followed by methanesulfonic acid (1.20Kg) and (S)-N-((R)- l-(3,5-bis(trifluoromethyl)phenyl)ethyl)-2-(4-fluoro-2-methylphenyl)-N-methylpiperazine-l- carboxamide methansulfonate (25g) in isooctane (0.25Kg) and the suspension was stirred at 20°C for 70 minutes. Isooctane (50L) was added over 90 minutes and the reaction stirred for 1 hour. The suspension was filtered and washed with 2: 1 isooctane/EtOAc (12.5L) three times. The solid was co- milled to give the title compound (6.31Kg) as a white solid.

*H NMR (400 MHz, DMSO-i¾) δ ppm 8.96 (br. s., 2 H), 8.00 (s, 1 H), 7.71 (s, 2 H), 7.29 (dd,

7=8.56, 6.11 Hz, 1 H), 6.99 (dd, 7=10.27, 2.69 Hz, 1 H), 6.83 (td, 7=8.56, 2.45 Hz, 1 H), 5.35 (q, 7=6.60 Hz, 1 H), 4.52 (dd, 7=11.74, 3.18 Hz, 1 H), 3.52-3.22 (m, 4 H), 3.12-2.92 (m, 2 H), 2.74 (s, 3 H), 2.39 (s, 3 H), 2.37 (s, 3 H), 1.49 (d, 7=7.09 Hz, 3 H)

ES+: m/z 492 [MH – CH3S03H]+

Melt onset is 171°C obtained by Differential Scanning Calorimetry (DSC).

 

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SYNTHESIS

https://www.google.co.in/patents/WO2001025219A2

 

Example 36 2-(SM4-Fluoro-2-methyl-phenyl)-piperazine-1 -carboxylic acid M -(R)-

(3.5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide methansulphonate

To a suspension of intermediate 81 (4.9Kg) in AcOEt (137.2L), triethylamine (5.63L) was added. The mixture was cooled to 0°C then a solution of diterbuthyl dicarbonate (3.134Kg) in AcOEt (24.5L) was added in 35 min, maintaining the temperature between 0 and 5°C. The suspension was stirred at 0°C for 15 min, at 20/25°C for 1 hr, then washed with water (3 x 39.2L), concentrated to 24.5L and then added to a solution of triphosgene (1.97Kg) in AcOEt (24.5L) cooled to 0°C. Triethylamine (3.28L) was then added in 40 min, maintaining the temperature between 0 and 8°C. The suspension was stirred for 1 h and 45 min at 20/25°C and 30 min at 70Cand then the solution of intermediate 82 diluted with AcOEt (49L) and triethylamine (2.6L) was added in 30 min. The mixture was refluxed for 15 hrs.

The reaction mixture, cooled at 20/25°C was treated with aqueous solution of NaOH 10%v/v (36.75L). Organic phase was washed with HCI 4%v/v (46.55L) and NaCI 11 ,5%p/p (4 x 24.5L) then concentrated to 14.7L. and diluted with Ciclohexane (39.2L). The mixture was filtered through a silica pad (4.9Kg) that was washed twice with a mixture of CH/AcOEt 85/15 (2 x 49L). To the Eluted phases (14.7L) cooled at 20/25°C, methyl tertbutyl ether (49L) and methansulphonic acid (4.067L) were added. The mixture was washed with NaOH 10%v/v (31.85L) then with water (4 x 31.85L). Organic phase was concentrated to 9.8L, methyl tertbutyl ether (49L) was added and the solution filtered through a δmicron filter then concentrated to 9.8L. At 20/25°C MTBE (29.4L) and metansulphonic acid (1.098L) were added. The suspension was refluxed for 10 min, stirred at 20/25°C for 10hrs and 2 hrs at O°C.Then the precipitate was filtered, washed with methyl tertbutyl ether (4.9L) dried under vacuum at 20/25°C for 24 hrs to obtain the title compound (5.519Kg.) as white solid.

1H-NMR (DMSO) δ (ppm) 8.99 (bm, 1 H); 8.66 (bm, 1 H); 8.00 (bs, 1 H) 7.69 (bs, 2H); 7.27 (dd, 1 H); 7.00 (dd, 1 H); 6.83 (m, 1 H); 5.32 (q, 1 H) 4.47 (dd, 1 H); 3.50-3.20 (m, 4H); 2.96 (m, 2H); 2.72 (s, 3H); 2.37 (s, 3H) 2.28 (s, 3H); 1.46 (d, 3H). ES+: m/z 492 [MH – CH3SO3H]+ ES“: m/z 586 [M – H]“; 95 [CH3SO3]“

Example 37

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1 -carboxylic acid Ii -(R)- (3.5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide

To a solution of intermediate 40a (15.6g) in anhydrous THF (94ml), at 0°C, under N2, BH3THF 1 M/THF (154ml) was added. The solution was heated at reflux for 3 hr. HCI 37% (54ml) was slowly added maintaining the reaction mixture in an ice-bath and the reaction mixture was stirred at rt for 1 hr. Water was then added (125 ml) and solid NaHCO3 (62.4g) was added portionwise until a pH of 6.5.The aqueous phase was extracted with Et O (4×160 ml) and the combined organic extracts were dried over

Na2SO , the solids were filtered and evaporated to leave a colourless oil which was purified by flash chromatography (silica gel, EtOAc/Methanol 7/3). The obtained product was suspended in Et2O (220ml) and washed with NaHCO3 sat. (2x36ml). The combined organic phases were dried (Na2SO ) and evaporated to give the title compound as white foam (8.7g,). 1H-NMR (CDCI3) δ (ppm) 7.78 (s, 1 H); 7.60 (s, 2H); 7.28 (m, 1 H); 6.85 (dd, 1 H); 6.79 (td, 1 H); 5.53 (q, 1 H); 4.43 (dd, 1 H); 2.9-3.5 (m, 5H); 2.78 (m, 1 H), 2.71 (s, 3H); 2.43 (s, 3H); 1.47 (d, 3H).

 

Intermediate 40

2-(S)-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1 -carboxylic acid ri-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide ( 40a ) 2-(S)-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1 -carboxylic acid ri-(S)-(3.5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide.(-40b) To a solution of intermediate 39 (12.1g) in anhydrous DCM (270 mL), TEA (16.4 mL) was added. The solution was cooled down to 0°C and a solution of triphosgene (7.3 g) in anh. DCM (60 mL) was added drop-wise over 40 min. The reaction mixture was stirred at 0°C for 4 hr and was brought back to r.t. DIPEA (20.2 mL) was then added, followed by a solution of [1-(3,5- bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (23.6 g) in acetonitrile (300 mL) and an additional amount of acetonitrile (300 mL). The reaction mixture was warmed up to 95°C (oil bath T°C) without a water condenser to evaporate the DCM. When the internal temperature had reached 70°C, the flask was equipped with a water condenser, and the reaction mixture was heated at 70°C for an additional 2 hr (4 hr total). It was then brought back to r.t. and the solvent was evaporated. The residue was partitioned between DCM / 2% HCI and the phases were separated. The aqueous layer was extracted with DCM (1x) and the combined organic extracts were dried. The solids were filtered and the solvent evaporated to give a crude mixture of title compounds which were purified by flash chromatography (AcOEt/CH 8:2) to obtain the title compounds 40a (8.8 g) and 40 b (9.0 g) as white foams.

NMR (1H, DMSO-de): δ 8.16 (s, 1 H), 7.98 (s, 2H), 7.19 (dd, 1 H), 6.97 (dd, 1 H), 6.87 (td, 1 H), 5.34 (s, 1 H), 5.14 (q, 1 H), 3.45-3.2 (m, 4H), 2.53 (s, 3H), 2.27 (s, 3H), 1.56 (d, 3H).

Intermediate 40b: NMR (1H, DMSO-d6): δ 8.16 (s, 1 H), 7.95 (s, 2H), 7.19 (dd, 1 H), 6.98 (dd, 1 H), 6.90 (td, 1 H), 5.29 (q, 1 H), 5.28 (s, 1 H), 3.45-3.15 (m, 4H), 2.66 (s, 3H), 2.27 (s, 3H), 1.52 (d, 3H).

 

Intermediate 81 (S)-3-(4-Fluoro-2-methyl-phenyl)-piperazine dihydrochloride

To a solution of intermediate 39 (60.35g) in dry THF (180ml), at 0-3°C, under N2, BH3 THF 1 M/THF (1220mL) was added dropwise. The solution was refluxed for 4 hours then cooled to 0-3°C and methanol (240mL) was added. The reaction mixture was heated to room temperature then it was concentrated to dryness. The residue was redissolved in methanol (603.5mL), excess HCI 1 N in Et2O (1207mL) was added and the mixture was refluxed for 2 hours then cooled at 3°C for 4 hours. The suspension was filtered to obtain a white solid that was washed with Et2O (60.35mL) and dried to yield the title compound (72.02q)

1H-NMR (DMSO) δ (ppm) 11.0-9.5 (b, 4H); 7.99-7.19 (dd-m, 3H); 4.96 (dd, 1 H); 3.65-3.15 (m, 6H); 2.42 (s, 3H).

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HYDROCHLORIDE SALT

WO2001025219A2

Example 38

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1 -carboxylic acid |i -(R)-

(3,5-bis-trifluoromethyl-phenyl)-ethvπ-methyl-amide hydrochloride Example 37 (0.1 g) was dissolved in Ethyl Ether (0.8ml) at room temperature, then 1 M HCI solution in Ethyl Ether (0.6ml) was added. The suspension was stirred at 3°C for 3 hour, then filtered and washed with Ethyl Ether (1 ml) to afford the title compound ( 0.015g ) as a white solid. 1H-NMR (DMSO) δ (ppm) 9.31 (bm, 1 H); 9.11 (bm, 1 H); 8.02 (bs, 1 H); 7.72 (bs, 2H); 7.28 (dd, 1 H); 7.00 (dd, 1 H); 6.84 (m, 1 H); 5.34 (q, 1 H); 4.54 (dd, 1 H); 3.50-3.20 (m, 4H); 3.08 (m, 1 H); 2.93 (m, 1 H); 2.73 (s, 3H); 2.38 (s, 3H); 1.48 (d, 3H).

 

ACETATE SALT

Example 18

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1 -carboxylic acid M -(R)-

(3.5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide acetate salt

To a solution of intermediate 40a (8.8 g) in dry THF (33 mL) under N2 BH3.THF (1 M solution in THF – 87 mL) was added and the reaction mixture was stirred at reflux for 3 hr, then cooled to r.t. and HCI (37%, 30 mL) was added drop-wise maintaining the reaction mixture in an ice-bath. The reaction mixture was stirred at r.t. for 1 hr. Water was then added (70 mL) and solid NaHCO3 (35.2 g) was added portion-wise until a pH of 6.5. The THF was evaporated and the aqueous phase was extracted with Et2θ (3 x 88 mL). The combined organic phases were dried, and evaporated to leave a colourless oil (7.37 g).

This crude oil was purified by flash chromatography (AcOEt/MeOH 7:3). The product obtained was suspended in Et2θ (125 mL) and washed with NaHCO3 sat. (2 x 20 mL). The clear combined organic phases were dried and evaporated to obtain the 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine- 1 -carboxylic acid [1 -(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl- amide as white foam (5.27 g). This material (5.27 g) was dissolved in Et2θ (79 mL) and acetic acid (613 μL) was added drop-wise. The mixture was stirred at r.t. for 1 h and then at 0°C for 1h. The suspension was filtered to give the title compound (4.366 g) as a white solid. NMR (1H, DMSO-de): δ (ppm) 7.98 (s, 1 H), 7.70 (s, 2H), 7.87 (m, 1 H), 6.91 (m, 1 H), 6.77 (m, 1 H), 5.29 (q, 1 H), 4.23 (dd, 1 H), 3.2-2.6 (m, 6H), 2.68 (s, 3H), 2.3 (s, 3H), 1.89 (s, 3H), 1.48 (d, 3H). MS (m/z): 492 [M-CH3COO]+.

[ ]D = – 120.4°C Solvent (CHCI3); Source: Na; Cell volume [mL]: 1 ; Cell pathlength [dm]: 1 ; Cell temperature [°C]: 20; Wavelength [nm]: 589

 

””””””””””””””””””””””””””””””””””’

http://www.google.com/patents/US8188290

 

EXAMPLE 1 N-[1-(R) 3,5-bis-trifluoromethyl phenyl)-ethyl]-N-methyl carbamoyl chloride

[1-(R) 3,5-bis-trifluoromethyl phenyl)-ethyl]methyl amine L(−)maleate (13.5 g; 33.33 mmol) was suspended in ethyl acetate (39.9 ml) and ethanol (0.1 ml); aqueous sodium carbonate 13% (40 ml) was added and the mixture was stirred at a temperature 20-25° C. until a clear solution was formed. The water phase was discarded and the organic phase was washed with water (40 ml). Fresh ethyl acetate (49.87 ml) and ethanol (0.13 ml) were added, the solution was concentrated to 40 ml, a second amount of fresh ethyl acetate (49.87 ml) and ethanol (0.13 ml) was added and the solution was concentrated to 40 ml. Fresh ethyl acetate (109.7 ml) and ethanol (0.3 ml) were added under CO2 flow. A cycle of vacuum and CO2 in the vessel was applied, then CO2 was maintained for 10 minutes. Then, a neat Et3N (6.1 ml; 46.34 mmol) was added and the reaction mixture was stirred at a temperature 20-25° c. for 30 minutes. Trimethylmethylsilylchloride (6.4 ml; 40.42 mmol) was added in 30 minutes (exothermic step) and the reaction mixture was stirred for further 30 minutes at room temperature. Pyridine (5.4 ml; 66.66 mmol) was added, then SOCl2 (3.6 ml; 40.42 mmol) was added in 10 minutes. The reaction mixture was stirred at room temperature for 10 hours under CO2 atmosphere. 13% w/w aqueous racemic malic acid (60 ml) was added and the mixture was stirred for 15 minutes; the water phase was discarded then the organic phase was washed with water (60 ml); the water phase was discarded then the organic phase was washed with sodium carbonate 13% w/w (60 ml). Finally, the water phase was discarded and ethyl acetate (49.87 ml) and ethanol (0.13 ml) were added and the solution was concentrated to 50 ml; further ethyl acetate (49.87 ml) and ethanol (0.13 ml) were added and the solution was concentrated to dryness to give the title compound as a pale yellow (10.41 gr; 31.33 mmol 94% yield)

NMR-(d6-DMSO) δ (ppm)

8.04 δ (br s, 1H), 7.97 δ (br s, 2H), 5.52 δ (q, 1H), 2.97 δ (s, 3H), 1.66 δ (d, 3H)

EXAMPLE 2 (2R)-2-(4-fluoro-2-methylphenyl)-4-oxo-1-piperidinyl carbonyl; chloride

(2R)-2-(4-fluoro-2-methylphenyl)-4-oxo-1-piperidine L(−) mandelate (2 g; 5.57 mmol) was suspended in ethyl acetate (8 ml); aqueous sodium carbonate 13% w/w (10 ml) was added and the mixture was stirred at a temperature 20-25° C. until a clear solution was formed.

The water phase was discarded and the organic phase was washed with aqueous sodium chloride 10% w/w (4 ml). Fresh ethyl acetate (8 ml) were added, the solution was concentrated to 6 ml, a second amount of fresh ethyl acetate (8 ml) was added and the solution was concentrated to 6 ml.

Fresh ethyl acetate (2 ml) and neat Et3N (1.94 ml; 13.92 mmol) were added under CO2 flow at 0° C. The mixture was stirred for 10 minutes, then Trimethylmethylsilylchloride (1.42 ml; 11.14 mmol) was added in 5 minutes (exothermic step) and the reaction mixture was stirred for further 30 minutes at 0° C. Pyridine (0.58 ml; 7.24 mmol) was added, then SOCl2 (0.53 ml; 7.24 mmol) was added in 5 minutes. The reaction mixture was stirred at 0° C. for 1 h, then at a temperature 20-25° C. for 5 hours under CO2 atmosphere. Water (20 ml) was added was added; the water phase was discarded then the organic phase was washed with sodium carbonate 13% w/w (20 ml); the water phase was discarded then the organic phase was dried on sodium sulphate. The organic phase was filtered and concentrated to dryness to give the title compound as a pale yellow (1.5 gr; 5.57 mmol 100% yield)

HPLC Rt: 2.33 min; MS: [H+] 270

………………….

J. Med. Chem., 2009, 52 (10), pp 3238–3247

DOI: 10.1021/jm900023b

Figure

 

a(a) (i) Mg, I2, THF, T = 70 °C, 2 h; (ii) LiBr, Cu2Br2, THF, room temp 1 h; (iii) CH3OCOCOCl, room temp, 2 h; (b) ethylenediamine, toluene, reflux, 6 h; (c) H2 (1 atm), 10% Pd/C, MeOH, 16 h; (d) (i) S-(+)-mandelic acid orR-(−)-mandelic acid, AcOEt, T = 3−5 °C, 2 h; (ii) filtration of the salt, then crystallization in AcOEt; (iii) 0.73 M NaOH; (e) (i) triphosgene, Et3N, CH2Cl2, T = 0 °C, 4 h; (ii) 1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-N-methylamine, N(i-Pr)2Et, CH3CN, T = 70 °C, 2 h; (f) (i) 1 M BH3·THF, THF, reflux, 3 h; (ii) Et2O, AcOH.

……………..

patents

WO 2012175434

WO 2008046882

WO 2004091624

WO 2004067093

WO 2001025219…

……………….

WO1993005791A1 Sep 18, 1992 Apr 1, 1993 Univ Pennsylvania Prevention of hemolysis
WO2001025219A2 Oct 5, 2000 Apr 12, 2001 Giuseppe Alvaro Piperazine compounds
WO2004091624A1 * Apr 16, 2004 Oct 28, 2004 Renzo Carletti Combinations comprising paroxetine and 2- (s) – (4-fluoro-2-methyl-phenyl) -piperazine-1-carboxylic acid [1- (r)- (3,5-bis-trifluoro-2-methyl-phenyl) -ethyl]-methyl amide for treatment of depression and/or anxiety
WO2005082419A1 Jan 6, 2005 Sep 9, 2005 Wayne Alan Boettner Pharmaceutical compositions of neurokinin receptor antagonists and cyclodextrin and methods for improved injection site toleration
WO2007048642A1 Oct 26, 2006 May 3, 2007 Ilaria Bientinesi Process for preparing n, n-substituted carbamoyl halides
EP1897542A1 Sep 7, 2006 Mar 12, 2008 Sanofi-Aventis Aqueous formulation comprising an antitumor agent

…………………………………

1. Organic Process Research and Development, 2009 ,  vol. 13,   6  pg. 1100 – 1110

2. Magnetic Resonance in Chemistry, 2010 ,  vol. 48,   7  pg. 523 – 530

3. Org. Process Res. Dev., 2009, 13 (3), pp 489–493.

4. Synthesis of the NK1 receptor antagonist GW597599. Part 1: Development of a scalable route to a key chirally pure arylpiperazine
Org Process Res Dev 2008, 12(6): 1188………….

5.Journal of Thermal Analysis and Calorimetry, 2010 ,  vol. 102,   1  pg. 297 – 303

 

Di Fabio R, Alvaro G, Griffante C, Pizzi DA, Donati D, Mattioli M, Cimarosti Z, Guercio G, Marchioro C, Provera S, Zonzini L, Montanari D, Melotto S, Gerrard PA, Trist DG, Ratti E, Corsi M.

J Med Chem. 2011 Feb 24;54(4):1071-9. doi: 10.1021/jm1013264. Epub 2011 Jan 13.

 

Provera S, Guercio G, Turco L, Curcuruto O, Alvaro G, Rossi T, Marchioro C.

Magn Reson Chem. 2010 Jul;48(7):523-30. doi: 10.1002/mrc.2611.

 

Provera S, Martini L, Guercio G, Turco L, Costa L, Marchioro C.

J Pharm Biomed Anal. 2010 Nov 2;53(3):389-95. doi: 10.1016/j.jpba.2010.04.027. Epub 2010 Apr 29.

 

Sabbatini FM, Di Fabio R, Griffante C, Pentassuglia G, Zonzini L, Melotto S, Alvaro G, Capelli AM, Pippo L, Perdona’ E, St Denis Y, Costa S, Corsi M.

Bioorg Med Chem Lett. 2010 Jan 15;20(2):623-7. doi: 10.1016/j.bmcl.2009.11.078. Epub 2009 Nov 20.

 

Di Fabio R, Griffante C, Alvaro G, Pentassuglia G, Pizzi DA, Donati D, Rossi T, Guercio G, Mattioli M, Cimarosti Z, Marchioro C, Provera S, Zonzini L, Montanari D, Melotto S, Gerrard PA, Trist DG, Ratti E, Corsi M.

J Med Chem. 2009 May 28;52(10):3238-47. doi: 10.1021/jm900023b.

 

 

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ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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GALDANSETRON

 Uncategorized  1 Response »
Jan 022014
 

cas no 116684-92-5

(3R)-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)methyl]-2,3-dihydro-1H-carbazol-4-one

Molecular Formula: C18H19N3O   Molecular Weight: 293.36296

GR-81225X
GR-82115C (hydrochloride)

GSK

PRECLINICAL

Nausea and Vomiting, Treatment of

 CA 2081709     EP 0542364     US 4859662

 

 

GALDANSETRON HYDROCHLORIDE

CAS NO 156712-35-5 (HCl)

Molecular Formula: C18H20ClN3O   Molecular Weight: 329.8239

  • Galdansetron HCl
  • Galdansetron hydrochloride
  • GR 81225C
  • GR 81225X [as the base]
  • UNII-E3M2R8Q947

 

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GALDANSETRON RACEMIC

GR 67330
CAS NO 116684-93-6

2D image of a chemical structure

………………………………………………………………

Patents

  • US 20050209293 A
  • US 20060024365
  •  US 4859662 A
  • DE 3740352 A1
  • WO 2001095902 A1
  •  WO 2009146537 A1
  •  US 20100226943 A1

picture animation

DE3740352A1

Example 1

(E) -1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methylene]-4H-carbazol-4-one maleate

A solution of 1,2,3,9-tetrahydro-3-[hydroxy [5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl] methyl]-9-methyl-4H-carbazol-4-one (2.70 g) in glacial acetic acid (100 ml) was treated with p-toluenesulfonic acid monohydrate (10.80 g) and the stirred solution was heated to reflux for 4 hours. The cool dark liquid was evaporated, treated with aqueous saturated sodium bicarbonate solution (250 ml) and extracted into ethyl acetate (4 × 250 ml). The combined, dried organic extracts were evaporated and purified by SPCC. The eluting with System A (978: 20: 2 → 945: 50: 5) afforded the free base of the title compound as a light yellow-brown solid (488 mg). A hot solution of the free base (87 mg) in ethanol, about 16 ml) was treated with a hot solution of maleic acid (38 mg) in ethanol (1 ml). After cooling, the precipitate was collected to give the title compound (81 mg), mp 205-209 ° was obtained.

Analysis found: C: 65.1, H 5.2, N 10.2; C ₁ ₈ H ₁ ₇ N ₃ O · C ₄ H ₄ O ₄
theoretical values: C: 64.9, H 5.2, N 10.3%.

 

Example 7 1,2,3,9-tetrahydro-9-methyl-3-[(1H-imidazol-4-yl) methylene] – 4H-carbazol-4-one

A solution of diisopropylamine (1.54 ml) in dry THF (20 ml) of -78 ° was treated dropwise with n-butyllithium (1.32 M in hexane, 8.3 ml). The mixture was allowed to warm to 0 ° and cooled to -78 ° again. It was then in the course of 3 minutes to a stirred suspension of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (2.0 g) in dry THF (80 ml) of -78 optionally °. The resulting suspension was stirred at -78 ° on this for 2 hours and then treated with 1 – treated (triphenylmethyl)-1H-imida zol-4-carboxaldehyde (3.72 g). The mixture was stirred for a further 2 hours, during which time it was allowed to warm slowly to room temperature. Then it was cooled to -78 ° and quenched with acetic acid (2 ml). The resulting solution was allowed to warm to room temperature and 8% aqueous sodium bicarbonate solution (600 ml) was poured.

The mixture was extracted with dichloromethane (3 x 150 ml) and the combined, dried organic extracts were evaporated to give a foam. A solution of this foam and p-toluenesulfonic acid monohydrate (18 g) in a mixture of glacial acetic acid (25 ml) and dry THF (150 ml) was heated for 5 hours under reflux. The cooled mixture was carefully added to an 8% aqueous sodium bicarbonate solution (650 ml) and extracted with dichloromethane (3 x 150 ml). The combined, dried organic extracts were evaporated to give a solid which was obtained by FCC eluting with System A (100: 1: 10) was purified. In this way the title compound (1.42 g), mp 225-232 ° was obtained.

Analysis found: C: 73.3, H 5.6, N 14.7; C ₁ ₇ H ₁ ₅ N ₃ O
theoretical values: C: 73.6, H 5.5, N 15.1%

 

 

Example 8

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one maleate

A solution of 1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methylene]-4H-carbazol-4-one (3.50 g) in DMF (85 ml) and ethanol (50 ml) was added to a prereduced suspension of 10% palladium on carbon added (3.4 g) in ethanol (50 ml) and hydrogenated at room temperature and atmospheric pressure until hydrogen uptake ceased (270 ml). The catalyst was filtered off and the filtrate was evaporated. The residue was adsorbed from methanol (170 ml) of SPCC-FCC silica and applied to a column. A gradient elution system A (967: 30: 3 → 912: 80: 8) afforded the free base of the title compound as a solid (2.32 g). A portion of this solid (500 mg) in hot ethanol (15 ml) was treated with a hot solution of maleic acid (224 mg) in ethanol (2 ml). Upon cooling, a precipitate was collected, the title compound (415 mg), mp 130.5-137 ° revealed. tlc (system A 200: 10: 1) 0.30.

Analysis found: C: 63.2, H 5.5, N 9.7; C ₁ ₈ H ₁ ₉ N ₃ O · C ₄ H ₄ O ₄ · 0.33 H ₂ O
theoretical values: C: 63.6, H 5.7, N 10.1%. Water sample found: 1.55% wt. / Wt. 0.33 mol H ₂ O ≡

¹ H-NMR (d ⁶-DMSO) δ 1.8-1.98 (1H, m), 2.1-2.25 (1H, m), 2.25 (3H, s), 2.68 to 2, 84 (2H, m), 2.85 to 3.3 (3H, m), 3.75 (3H, s), 6.0 (2H, s-maleate), 7.18-7.32 (2H, m), 7.57 (1H, brd), 8.03 (1H, brd), 8.88 (1H, s).

 

+FORM

Example 31

(+) -1,2,3,9-Tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one

A solution of (±) -1,2,3,9-tetrahydro-9-methyl-3-[(5-me thyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one (500 mg) in warm methanol (30 ml) was treated with a solution of (+) -2,3-bis [[(4-methylphenyl) carbonyl] oxy] butanedioic acid (690 mg) in methanol (10 ml), and The solution was allowed to stand for 3 days at 0 °. It was then filtered to give a solid remained which was recrystallized from methanol to give the desired salt (195 mg), mp 146-148 ° was obtained. A part of this salt (186 mg) was suspended (10 ml) in water and treated with potassium carbonate (79.2 mg) and the mixture was extracted with dichloromethane (2 x 40 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (79.2 mg) as a solid, mp 230-232 ° stayed behind. [Α] = 49.7 ° (c = 0.41%, CHCl ₃).

 

– FORM

Example 32

(-) -1,2,3,9-Tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one

A solution of (±) -1,2,3,9-tetrahydro-9-methyl-3-[(5-me thyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one (500 mg) in warm methanol (30 ml) was added a solution of (- treated) -2,3-bis [[(4-methylphenyl) carbonyl] oxy] butanedioic acid (690 mg) in methanol (10 ml), and The solution was allowed to stand at 0 ° for 3 days. It was filtered, producing a solid remained which was recrystallized from methanol to give the desired salt (162 mg), mp 147-148 ° was obtained. This was suspended in water (15 ml) and treated with a solution of potassium carbonate (1 g in 10 ml water). The mixture was extracted with dichloromethane (2 x 30 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (72.5 mg) as a solid, mp 230-232 ° stayed behind. [Α] = 48.4 ° (c = 0.44%, CHCl ₃).

Example 33

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) – methyl]-4H-carbazol-4-one

A solution of Intermediate 7 (190 mg) in dry DMF (1 ml) was added dropwise to a stirred suspension of sodium hydride, under nitrogen (52% dispersion in oil, 20 mg) in dry DMF (0.4 ml). After 15 minutes, iodomethane (0.027 ml) was added and the mixture was stirred for 1.5 hours. Water (20 ml) was added and the suspension was extracted with dichloromethane (3 x 10 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 300 mg) in a mixture of THF (4 ml), acetic acid (4 ml) and water (4 ml) was dissolved. The mixture was heated at reflux for 1.5 hours. It was poured (20 ml) in saturated potassium carbonate solution and extracted with dichloromethane (3 x 10 ml). The combined, dried organic extracts were evaporated to give a semi-solid (ca 255 mg) was obtained by SPCC eluting with System A (200: 1: 10) was purified. In this way the title compound (7 mg) was obtained. The ¹ H NMR and tlc of this material were values ​​with the corresponding values ​​of the product of Example 8 in line.

Example 34

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) – methyl]-4H-carbazol-4-one

n-Butyllithium (1.45M in hexane; 2.07 ml) was added dropwise to a cold (-70 (20 ml) under nitrogen. The solution was allowed to reach 0 30 min, cooled to -70 solution of) 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (500 mg) in dry THF (10 ml under nitrogen. Hexamethylphosphoramide (0.44 ml) was added and the mixture was allowed to reach 0 cooled to -70 4-(chloromethyl)-5-methyl-1-(triphenylmethyl) -1H-imidazole (936 mg) in dry THF (15 ml) was added and the mixture was allowed to reach ca. 20 sodium bicarbonate solution (100 ml) and extracted with dichloromethane (3 give a semi-solid which was treated with a mixture of acetic acid (10 ml), water (10 ml) and THF (10 ml) and heated at reflux for 1.5 h. The solution was poured into saturated potassium carbonate solution (100 mml) and extracted with dichloromethane (3 organic extracts were evaporated to give a solid (ca. 1.8 g) which was purified by SPCC eluting with System A (200:10:1) to give the title compound (17 mg). The .sup.1 H-n.m.r. and t.l.c. of this material were consistent with those obtained from the product of Example 8.

 

BREAKING OF MALEATE SALT

Example 35

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) – methyl]-4H-carbazol-maleate (37 mg) was partitioned between 2 N sodium bicarbonate solution (10 ml) and chloroform (3 x 15 ml) separated. The combined, dried organic layers were evaporated to give the free base (26 mg) was obtained, which was dissolved at -10 ° under nitrogen in 10% aqueous THF (4 ml). To this stirred solution, a solution of 2,3-dichloro-5 ,6-dicyano-1 ,4-benzoquinone (49 mg) was added in dry THF (1.6 ml) was added dropwise, and the reaction mixture was added over 3 hours allowed to warm to 0 °. The solution was evaporated in vacuo and purified by FCC eluting with System A (94.5: 5: 0.5) to give the title compound (10 mg) was obtained as a solid.The ¹ H NMR and tlc values ​​of this material were consistent with the corresponding values ​​of the product of Example 8

INTERMEDIATE 7

Intermediate 7

1,2,3,9-Tetrahydro-3-[(5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one

A solution of triphenylchloromethane (4.2 g) in dry DMF (40 ml) was added dropwise to a solution of 1,2,3,9 – tetrahydro-3-[(5-methyl-1H-imidazol-4-yl) methyl ]-4H-carbazol-4-one (3.5 g) and triethylamine (1.75 ml) in dry DMF (35 ml) under nitrogen.After stirring for 4 hours the mixture was poured (300 ml) in water and extracted with dichloromethane (3 x 100 ml). The combined extracts were washed with water (200 ml), dried and evaporated to give an oil (about 9 g) was obtained. This was purified by FCC eluting with System A (200: 1: 10) to give the title compound (4.57 g) as a foam, tlc (system A 200: 10: 1), Rf 0.32 was obtained.

 

Intermediate 8

4 – (chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole

A solution of thionyl chloride (1.3 ml) in dry dichloromethane (10 ml) was added over 5 minutes to a stirred suspension of 5-methyl-1-(triphenylmethyl) – 1H-imidazol-4-methanol (5.0 g ) in a mixture of dichloromethane (100 ml) and dry DMF (2 ml) at 0 °. The mixture was stirred at 0 ° for 30 minutes and washed successively with 8% sodium bicarbonate (2 x 50 ml), water (50 ml), dried and evaporated in vacuo below 40 ° to give an oil (5 g) was obtained. This was dissolved in ether (100 ml), and the resulting solution was filtered through a silica pad which was eluted with ether (2 x 100 ml) further. The combined filtrates were evaporated below 40 °, whereby a foam was obtained which was triturated with cold hexane and filtered. There was thus obtained the title compound (4.2 g) as a solid, mp 133-135 °, was obtained

 

Intermediate 14

1,2,3,9-tetrahydro-9-methyl-3 [[5-methyl-1-(triphenylmethyl) – 1H-imidazol-4-yl] methyl]-4H-carbazol-4-one

A solution of triphenylchloromethane (286 mg) in dry DMF (10 ml) was added dropwise to a stirred solution of 1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4 – optionally yl) methyl]-4H-carbazol-4-one (292 mg) and triethylamine (101 mg) in dry DMF (20 ml). The resulting solution was stirred for 3.5 hours at room temperature under nitrogen. The reaction mixture was then poured into water (100 ml) and the resulting suspension was extracted with dichloromethane (3 x 50 ml). The combined, dried organic extracts were adsorbed onto FCC silica, which was then applied to a column. FCC eluting with System A (150: 8: 1) afforded a solid which, by crystallization from dichloromethane: hexane (2: 1) was further purified to give the title compound (304 mg), mp 193 to 195 °, was obtained.

 

INTERMEDIATES

CAS 27387-31-1

C13 H13 N O
4H-​Carbazol-​4-​one, 1,​2,​3,​9-​tetrahydro-​9-​methyl-
Carbazol-​4(1H)​-​one, 2,​3-​dihydro-​9-​methyl-
INTERMEDIATE 2 
CAS  113140-81-1
C24 H20 N2 O
1H-​Imidazole-​4-​carboxaldehyde, 5-​methyl-​1-​(triphenylmethyl)​
INTERMEDIATE 3
CAS : 116684-96-9
C37 H33 N3 O2
4H-​Carbazol-​4-​one, 1,​2,​3,​9-​tetrahydro-​3-​[hydroxy[5-​methyl-​1-​(triphenymethyl)​-​1H-​imidazol-​4-​yl]​methyl]​-​9-​methyl-
4H-Carbazol-4-one, 1,2,3,9-tetrahydro-3-[hydroxy[5-methyl-1-(triphenylmethyl)-1H-imidazol- 4-yl]methyl]-9-methyl-
INTEMEDIATE 4
triphenylchloromethane
ChemSpider 2D Image | Triphenylchloromethane | C19H15Cl
CAS 76-83-5
INTERMEDIATE 5
4-(chloromethyl)-5-methyl-1-(triphenylmethyl) -1H-imidazole
……………………………………………………………………………………….
art animation
ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

MOBILE-+91 9323115463
web link

I was  paralysed in dec2007

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ALOSETRON HYDROCHLORIDE

 Uncategorized  1 Response »
Jan 012014
 

ALOSETRON

5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one

132414-02-9, Hydrochloride
122852-42-0 (free base)

122852-69-1 CHECK…..

GR-68755C

  • Alosetron HCl
  • Alosetron hydrochloride
  • GR 68755c
  • HSDB 7055
  • Lotronex
  • UNII-2F5R1A46YW

GSK

LAUNCHED 2002

United States  PATENT  US5360800 APPROVED1993-01-13  EXPIRY 2013-01-13

Alosetron is a 5-HT3 antagonist used only for the management of severe diarrhoea-predominant irritable bowel syndrome (IBS) in women. Alosetron has an antagonist action on the 5-HT3 receptors and thus may modulate serotonin-sensitive gastrointestinal (GI) processes. Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or ruptured bowel, and death. In June 2002, the FDA approved a supplemental new drug application allowing the remarketing of the drug under restricted conditions of use.

Alosetron hydrochloride (initial brand name: Lotronex; originator: GSK) is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only. It is currently marketed by Prometheus Laboratories Inc. (San Diego), also under the trade name Lotronex. Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability and use restricted.

Alosetron hydrochloride is a potent and selective 5-HT3 antagonist marketed by GlaxoSmithKline for the oral treatment of irritable bowel syndrome (IBS) in female patients whose predominant bowel symptom is diarrhea. It is currently marketed in a tablet formulation. In 2000, the drug was withdrawn from several markets based on adverse reactions, however, was reintroduced on the U.S. market in 2002 following a recommendation of a joint FDA advisory panel comprising members of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Pharmaceutical Science Committee which stipulated reintroduction of the drug in conjunction with a risk management plan.

Alosetron was originally approved by the U.S. Food and Drug Administration (FDA) on February 9, 2000,[1] after a seven month review.[2] At the time of the initial approval U.S. Food and Drug Administration (FDA) reviewers found that alosetron improved symptoms in 10% to 20% of patients.[3]

Shipment to pharmacies started in March, 2000. On July 17, a health professional filed a report with the FDA on the death of a 50-year-old woman who suffered mesenteric ischemia. The report identified alosetron as the “primary suspect” in the death.[4]

Alosetron was withdrawn from the market voluntarily by GlaxoWellcome on November 28, 2000 owing to the occurrence of serious life-threateninggastrointestinal adverse effects, including 5 deaths and additional bowel surgeries.[2] The FDA said it had reports of 49 cases of ischemic colitis and 21 cases of “severe constipation” and that ten of the 70 patients underwent surgeries and 34 others were examined at hospitals and released without surgery. Through November 17, 2000, pharmacists had filled 474,115 prescriptions for Alosetron.[2] Severe adverse events continued to be reported, with a final total of 84 instances of ischaemic colitis, 113 of severe constipation, 143 admissions to hospital, and 7 deaths.[5]

Patient advocacy groups, most notably the Lotronex Action Group and the International Foundation for Functional Gastrointestinal Disorders (IFFGD) lobbied for the drug’s return. Public Citizen Health Research Group, another patient advocacy group, opposed the reintroduction.[6][7]

On June 7, 2002, the FDA announced the approval of a supplemental New Drug Application (sNDA) that allows restricted marketing of Lotronex (alosetron hydrochloride), to treat only women with severe diarrhea-predominant irritable bowel syndrome (IBS).[8] It was the first drug ever returned to the U.S. market after withdrawal for safety concerns.[9][10]

It is not known whether alosetron has been filed for registration in the EU.

GSK sold Lotronex to the Californian corporation Prometheus in late 2007.[11]

Alosetron hydrochloride works through antagonism of the serotonin 5-HT3 receptor, distributed extensively on visceral neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of 5-HT3 channels results in neuronal depolarization and affects the regulation of visceral pain, colonic transit and gastrointestinal secretions. Alosetron inhibits activation of non-selective cation channels and modulates the enteric nervous system. In previous clinical trials, the drug increased colonic transit time without affecting orocecal transit time, increased basal jejunal water and sodium absorption and significantly increased colonic compliance. In 2007, the compound was licensed to Prometheus Laboratories by GlaxoSmithKline in the U.S. for the treatment of IBS in patients whose predominant bowel symptom is diarrhea.

 

Criticism of the FDA

In 2001, the editor of the renowned medical journal The Lancet, Richard Horton, criticized the FDA’s handling of alosetron in an unusually sharp language.[12] Horton argued that the treatment of a non-fatal condition did not justify the use of a drug with potentially lethal side effects, and that the FDA should have revoked the approval for alosetron sooner when postmarketing surveillance revealed that many patients had suffered constipation necessitating surgical intervention and ischaemic colitis. He asserted that FDA officials were improperly motivated to maintain and reinstate the approval for alosetron because of the extent to which the FDA’s Center for Drug Evaluation and Research is funded by user fees paid by pharmaceutical manufacturers, and that the reinstatement of alosetron was negotiated in confidential meetings with representatives ofGlaxoSmithKline.

An article published in the British Medical Journal (BMJ) noted: “By allowing the marketing of alosetron, a drug that poses a serious and significant public health concern according to its own terms, the FDA failed in its mission.”[13] Others have argued that the approval process of Lotronex was an example of regulatory capture.[7]

Alosetron has an antagonist action on the 5-HT3 receptors of the enteric nervous system of the gastrointestinal tract. While being a 5-HT3 antagonist like ondansetron, it is not classified or approved as an antiemetic. Since stimulation of 5-HT3 receptors is positively correlated with gastrointestinal motility, alosetron’s 5-HT3 antagonism slows the movement of fecal matter through the large intestine, increasing the extent to which water is absorbed, and decreasing the moisture and volume of the remaining waste products.[14]

  1. U.S. Food and Drug Administration. “Drug Details”. Retrieved 11 December 2012.
  2.  Willman, David (29 November 2000). “Drug Lotronex Pulled Over Safety Fears”. The Los Angeles Times. Retrieved 11 December 2012.
  3.  Willman, David (20 December 2000). “Officer Foresaw Deadly Effects”. The Los Angeles Times. Retrieved 11 December 2012.
  4.  Willman, David (2 November 2000). “FDA Minimized Issue of Lotronex’s Safety”. The Los Angeles Times. Retrieved 11 December 2012.
  5. CENTER FOR DRUG EVALUATION AND RESEARCH (23 April 2002). “GASTROINTESTINAL DRUGS ADVISORY COMMITTEE AND DRUG SAFETY AND RISK MANAGEMENT SUBCOMMITTEE OF THE ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE”. U.S. Food and Drug Administration. Retrieved 11 December 2012.
  6.  Grady, Denise (23 April 2002). “Appeals Prompt U.S. Agency to Consider Allowing Sales of Diarrhea Drug Linked to Deaths”. The New York Times. Retrieved 11 December 2012.
  7.  Moynihan, Ray (14 September 2002). “Alosetron: a case study in regulatory capture, or a victory for patients’ rights?”. The British Medical Journal 325 (7364): 592–595.PMC 1124108. PMID 12228140. Retrieved 11 December 2012.
  8.  U.S. Food and Drug Administration. “Lotronex (alosetron hydrochloride) Information”. U.S. Food and Drug Administration. Retrieved 11 December 2012.
  9.  Pollack, A (2006-03-09). “F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk”. The New York Times. Retrieved 2008-03-13.
  10.  Grady, Denise (8 June 2002). “U.S. Lets Drug Tied to Deaths Back on Market”. The New York Times. Retrieved 11 December 2012.
  11.  Prometheus Laboratories Inc. Press Release of 7 November 2007. Retrieved on 27 August 2008.
  12.  Horton, R. (2001). “Lotronex and the FDA: a fatal erosion of integrity”. The Lancet 357 (9268): 1544–1545. doi:10.1016/S0140-6736(00)04776-0. edit
  13.  Lièvre, Michel (14 September 2002). “Alosetron for irritable bowel syndrome”. The British Medical Journal 325 (7364): 555–556. PMC 1124090. PMID 12228116. Retrieved 11 December 2012.
  14.  “HIGHLIGHTS OF PRESCRIBING INFORMATION”. Prometheus Laboratories Inc. April 2008. Retrieved 11 December 2012.
  15.  Camilleri, M.; Northcutt A.R., Kong S., Dukes G.E., McSorley D., Mangel A.W. (25 March 2000). “Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.”. The Lancet 355 (1035): 1035–40. doi:10.1016/S0140-6736(00)02033-X. PMID 10744088.
  16.  Barbehenn, Elizabeth; Peter Lurie, Sidney M. Wolfe (9 December 2000). “Alosetron for irritable bowel syndrome”. The Lancet 356 (9246): 2009. doi:10.1016/S0140-6736(05)72978-0. Retrieved 11 December 2012.

IMPORTANT REF

Drugs Fut 1992, 17(8): 660

US 2012178937

JP 2012140415

WO 2010121038

US 200815392

WO 2006119329

JP 2005225844

WO 1999017755

WO 2001087305

WO 2001045685

US 5229407

US 5008272

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8-7-2002
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RECEPTOR AGONISTS AND ANTAGONISTS COMPOUND FOR USE AS A MEDICAMENT FOR TREATMENT OF DISORDERS INVOLVING BRONCHOCONTRACTION COMPOUND FOR USE AS A MEDICAMENT FOR TREATMENT OF DISORDERS INVOLVING BRONCHOCONTRACTION
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The Alosetron hydrochloride is a potent and selective antagonist of the serotonin 5-HT3 receptor type. Chemically, Alosetron is designated as 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, monohydrochloride. This is marketed in United States under trade name of LOTRONEX®

U.S. Pat. No. 5,360,800 discloses a preparation of Alosetron by condensing 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one with 4-chloromethyl-5-methylimidazole in presence of strong base such as sodium hydride. The sodium hydride was corrosive and highly flammable. This type of reaction required extra care, special type of equipments and it is commercially not feasible. This process also provides low yield.

U.S. Pat. No. 6,175,014 patent describes a process for the process Alosetron by reacting of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one of formula (II) with 4-hydroxymethyl-5-methylimidazole of formula (IIIa) or its salt in presence of mineral acid like hydrochloric acid or sulfonic acids such as p-toluene sulfonic acid or methane sulfonic acid. The process requires purification to get pure Alosetron.

 

Figure US20120178937A1-20120712-C00003

 

Hence there is a need for a simple and commercially viable process for the preparation of Alosetron which avoids hazardous base such as sodium hydride.

The present inventors identified a new process for the preparation of Alosetron by reaction of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one of formula (II) with 4-hydroxymethyl-5-methylimidazole of formula (III) or its protected derivative. This process is simple to carryout for large scale preparation and industrially viable

medical use for compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors.

5-HT3 receptor antagonists may be identified by methods well known in the art, for example by their ability to inhibit 3-(5-methyl-1H-imidazole-4-yl)-1-[1-[3H]- methyl-1 H-indol-3-yl]-1-propanone binding in rat entorhinal cortex homogenates (following the general procedure described by G Kilpatrick et al, Nature, 1987, 330, 746-748), and/or by their effect on the 5-HT-induced Bezold-Jarisch (B-J) reflex in the cat (following the general method described by A Butler et al, Br. J. Pharmacol., 94, 397-412 (1988)).

A number of different 5-HT3 receptor antagonists have been disclosed, for example those of group A: indisetron, Ro-93777, YM-114, granisetron, talipexole, azasetron, tropisetron, mirtazapine, ramosetron, ondansetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620, lintopride, KAE- 393, itasetron, mosapride and dolasetron.

In UK Patent No. 2209335, incorporated herein by reference, there is disclosed, inter alia, the compound 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4- yl)methyl]-1H-pyrido[4,3-b]indol-1-one, now known as alosetron, which may be represented by the formula (I):

 

Figure imgf000003_0001

and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof, in particular its hydrochloride salt.

…………………………………………………………………………………………………………

US20120178937

Figure US20120178937A1-20120712-C00004

EXAMPLE 1 Process for the Preparation of Alosetron

To a mixture of acetic acid and dimethylformamide, 3N-BOC-(-hydroxymethyl-5-methyl imidazole (95.4 g), 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (50 g), trifluoroacetic acid were added and heated to 100-115° C. After completion of the reaction, the reaction mass was cooled to room temperature. To the reaction mass, carbon was added, stirred and filtered though hyflo bed. The bed was washed with dimethylformamide. The filtrate was distilled under vacuum. To the residue, water was added and washed the reaction mass with toluene followed by isopropyl ether. The pH of the reaction mass was adjusted to 6.8-7 using potassium carbonate solution, stirred, cooled and the obtained solid was dried.

EXAMPLE 2 Process for the Preparation of Alosetron

To trifluoroacetic acid, 3N-BOC-4-hydroxymethyl-5-methylimidazole (95.4 g), dimethylformamide (480 mL) and 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (58 g) were added and heated to 100-115° C. After completion of the reaction, the reaction mass was cooled to room temperature. To the reaction mass, carbon was added and filtered though hyflo bed. The bed was washed with dimethylformamide and the filtrate was distilled under vacuum. To the residue, water was added and washed the aqueous layer with toluene followed by isopropyl ether. The pH of the reaction mass was adjusted to 6.8-7 using potassium carbonate solution, cooled and the obtained solid was dried.

 

TABLE 1
Solvent System Reaction time Yield
TFA & DMF 6-7 hours 65%
acetic acid alone  20 hours 17%
acetic acid & DMF No reaction

The above table clearly indicates that the use trifluoroacetic acid (TFA) enhances the reaction progress and also increases the yield of the product.

 

EXAMPLE 3 Purification of Alosetron

To acetic acid, crude Alosetron containing >0.2% of compound of formula (IV) was added and heated to 60-65° C., the reaction mass maintained at same temperature and cooled to 40-45° C. To the reaction mass acetone was added and refluxed. The reaction mass was cooled to 0-5° C., the solid obtained was filtered, washed with acetone (slurry) and dried to yield pure Alosetron having less than 0.02% of Impurity of formula (IV) by HPLC. Yield: 53-50 g

Reference Example 1 Preparation of Alosetron Hydrochloride

To a methanol (50 mL), Alosetron (10 g) and of IPA.HCl (8.5 mL) were added and heated to 40-45° C. The reaction mass was cooled, stirred and filtered and washed with methanol. The reaction mass was dissolved in methanol, treated with carbon, filtered and washed with methanol. The reaction mass was distilled and isopropyl ether was added to the residue and stirred at room temperature. The reaction mass was cooled, stirred. The solid obtained was filtered and washed with chilled methanol and dried.

Yield: 7.8 g Reference Example-2 Process for the preparation of 3N-BOC-(4-hydroxymethyl)-5-methylimidazole

4-Hydroxymethyl-5-methylimidazole (100 g) was dissolved in water, to the solution was added sodium carbonate (107 g) and stirred. To the reaction mass acetonitrile (400 mL) was added and cooled to 10-15° C. followed by addition of solution of DIBOC (di-tert-butyl dicarbonate) in acetonitrile. After completion of the reaction, water was added to the reaction mass and filtered. The filtrate was washed with 1:1 acetonitrile and water and than washed with hexane. The mass was extracted with toluene and the organic layer was washed with water followed by brine. The organic layer was distilled under vacuum to get oily mass of the title compound.

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