TEVA'S CEP 1347, KT 7515 a MAP3K11 (MLK3) inhibitor potentially for the treatment of Parkinson's disease.

CEP-1347; KT-7515

CAS. 156177-65-0

Cephalon Inc, Kyowa Hakko Kogyo Kk

WO2000013015

(9S,10R,12R)-5-16-Bis[(ethylthio)methyl]-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester
9,12-Epoxy-1H-diindolo(1,2,3-fg:3',2',1'-kl)pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid, 5,16-bis((ethylthio)methyl)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-, methyl ester, (9S-(9alpha,10beta,12alpha))-
METHYL (15S,16S,18S)-10,23-BIS[(ETHYLSULFANYL)METHYL]-15-METHYL-3-OXO-28-OXA-4,14,19-TRIAZAOCTACYCLO[12.11.2.1(1)?,(1)?.0(2),?.0?,(2)?.0?,(1)(3).0(1)?,(2)?.0(2)?,(2)?]OCTACOSA-1(26),2(6),7(27),8(13),9,11,20(25),21,23-NONAENE-16-CARBOPEROXOATE

3,9-Bis(etsm)-K-252a; CEP1347; 3,9-Bis((ethylthio)methyl)-K-252a; AC1L31ZX

Phase III

A MAP3K11 (MLK3) inhibitor potentially for the treatment of Parkinson's disease.

MW 615.76, MF C₃₃H₃₃N₃O₅S₂

Inhibitor of c-jun N-terminal kinase (JNK) signaling. Rescues motor neurons undergoing apoptosis (EC₅₀ = 20 nM). Blocks Aβ-induced cortical neuron apoptosis (EC₅₀ ~51 nM). Does not inhibit ERK1 activity. Neuroprotective.

Scheme 1 ^a

^a (a) Ac₂O, DMAP, THF, room temperature, 93%; (b) Cl₂CHOCH₃, TiCl₄, CH₂Cl₂, 66%; (c) NaBH₄ CH₃OH, CHCl₃, 65%; (d) NaOCH₃, CH₃OH, ClCH₂CH₂Cl, room temperature, 90%; (e) ROH, CSA, CH₂Cl₂; (f) RSH, CSA, CH₂Cl₂.

Inhibitor of c-jun N-terminal kinase (JNK) signaling. Rescues motor neurons undergoing apoptosis (EC₅₀ = 20 nM). Blocks Aβ-induced cortical neuron apoptosis (EC₅₀ ~51 nM). Does not inhibit ERK1 activity. Neuroprotective.

Apoptosis has been proposed as a mechanism of cell death in Alzheimer's, Huntington's and Parkinson's diseases and the occurrence of apoptosis in these disorders suggests a common mechanism.

Events such as oxidative stress, calcium toxicity, mitochondria defects, excitatory toxicity, and deficiency of survival factors are all postulated to play varying roles in the pathogenesis of the diseases.

However, the transcription factor c-jun may play a role in the pathology and cell death processes that occur in Alzheimer's disease.

Parkinson's disease (PD) is also a progressive disorder involving the specific degeneration and death of dopamine neurons in the nigrostriatal pathway. In Parkinson's disease, dopaminergic neurons in the substantia nigra are hypothesized to undergo cell death by apoptotic processes.

The commonality of biochemical events and pathways leading to cell death in these diseases continues to be an area under intense investigation.

The current therapy for PD and AD remains targeting replacement of lost transmitter, but the ultimate objective in neurodegenerative therapy is the functional restoration and/or cessation of progression of neuronal loss.

a novel approach for the treatment of neurodegenerative diseases through the development of kinase inhibitors that block the active cell death process at an early transcriptional independent step in the stress activated kinase cascade.

In particular, preclinical data will be presented on the c-Jun Amino Kinase pathway inhibitor, CEP-1347/KT-7515, with respect to it's properties that make it a desirable clinical candidate for treatment of various neurodegenerative diseases.

CEP-1347 is also known as KT-7515 and is being developed by Cephalon and Kyowa Hakko for treatment of Parkinson's disease and cognitive disorders.

It is believed to be a JNK-MAP kinase inhibitor. CEP-1347 has the chemical name 9alpha,12alpha-Epoxy-5,16-bis(ethylsulfanylmethyl)-10beta-hydroxy-9-methyl-1-oxo-2,3,9,10,11,12alpha-hexahydro-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4- i][1,6]benzodiazocine-10-carboxylic acid methyl ester and has the chemical structure as depicted in Formula 7.

 

PATENT

https://google.com/patents/WO2005082920A1?cl=en

The compound with the structure outlined below is presently in clinical trials for Parkinson's disease (Idrugs, 2003, 6(4), 377-383).

This compound is in the following referred to as Compound I. The chemical name of Compound I is [9S-(9α,10β,12α)]-5,16-Rw[(ethylthio)methyl]-2,3,9,10,l l,12-hexahydro- 10-hydroxy-9-methyl- 1 -oxo-9, 12-epoxy- 1 H-diindolo[l ,2,3 -fg:3 ',2', 1 '-kl]ρyrrolo[3,4- i][l,6]benzodiazocine-10-carboxylic acid methyl ester.

The following references relate to Compound I, in particular to methods for its preparation [J.Med. Chem. 1997, 40(12), 1863-1869; Curr. Med. Chem. - Central Nervous System Agents, 2002, 2(2), 143-155] and its potential medical uses, mainly in diseases in the central nervous system (CNS), in particular for treatment of neurodegenerative diseases, e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, peripheral neuropathy, AIDS dementia, and ear injuries such as noise-induced hearing loss [Progress in Medicinal Chemistry (2002), 40, 23-62; Bioorg. Med. Chem. Lett. 2002,12(2), 147-150; Neuroscience, Oxford, 1998, 86(2), 461-472; J. Neurochemistry (2001), 77(3), 849-863; J. Neuroscience (2000), 20(1), 43-50; J. Neurochemistry (2002), 82(6), 1424-1434; Hearing Research, 2002, 166(1-2), 33-43].

The following patent documents relate to Compound I, including its medical use and synthesis: WO 9402488, WO9749406, US 5621100, EP 0651754 and EP 112 932. By the known methods, Compound I is synthesized in a solid amorphous form. The inventors have now discovered 5 crystalline forms of Compound I (named alpha, beta, gamma, delta and epsilon) thereby providing an opportunity to improve the manufacturing process of Compound I and its pharmaceutical use. There exists a need for crystalline forms, which may exhibit desirable and beneficial chemical and physical properties. There also exists a need for reliable and reproducible methods for the manufacture, purification, and formulation of Compound I to permit its feasible commercialisation.

EXAMPLES

In the following the starting material " Compound I" may, e.g., be prepared as described by Kaneko M. et al in J. Med. Chem. 1997, 40, 1863-1869.

Example 1. Preparation of crystalline alpha form of Compound I

Method I):

6.0 g amorphous Compound I was dissolved in 30 ml acetone. 0,6 g potassium carbonate was added and the suspension was stirred at room temperature for 1 hour before it was filtered to remove potential minor insoluble impurities and inorganic salts. The filter cake was washed with acetone. The filtrate was then evaporated on a rotary evaporator under reduced pressure at 60°C to a final volume of 10 ml to which 100 ml methanol was added slowly. The product separated as an oil, which almost dissolved on heating to reflux. Subsequently the residual insoluble impurities were removed by filtration. The filtrate was left with stirring at room temperature. A crystalline solid separated and was isolated by filtration. The filter cake was washed with methanol and dried in vacuo at 60°C overnight. Yield 2,83 g (47%), mp=182.4°C (DSC onset value), Weight loss by heating: 0.5%, Elemental analysis: 6.71%N, 63.93%C, 5.48%H, theoretical values corrected for 0.5% H₂O: 6.79%N, 64.05%C, 5.43%H. XRPD analysis conforms with the alpha form. Method II):

5 g amorphous Compound I was dissolved in 25 ml acetone by gentle heating. 10 ml Methanol was added very slowly until the solution got turbid. The solution was allowed to cool to room temperature by natural cooling. The suspension was filtered and the filter-cake discarded. During filtration more material precipitated in the filtrate. The filtrate was heated until all material redissolves. Cold methanol was then added to the solution until precipitation was observed. The slightly turbid solution was then heated until all material was in solution. The solution was allowed to cool to room temperature, and the precipitate was removed by filtration. The second filter-cake was discarded. During the filtration some material separated in the filtrate. Heating redissolved the beginning crystallisation in the filtrate. Cold methanol was then added to the solution until precipitation was observed. The suspension was heated until a clear solution was obtained. The solution was allowed to reach room temperature by natural cooling. After a short period of time (15 min) precipitation begun. The precipitated pale yellow product was isolated by filtration and dried in vacuo at 50°C overnight. mp=188.9°C (DSC onset value), Weight loss by heating: 0.3%>, Elemental analysis: 6.53%N, 64.33%C, 5.43%H, theoretical values: 6.82%N, 64.37%C, 5.37%H. XRPD analysis conforms with the alpha form. Method III:

0.5g Compound I in a mixture of isopropyl acetate (10 mL) and water (0.6 mL) was heated to reflux with stirring. The compound was not completely dissolved so isopropyl acetate (10 mL) and water (0.6 mL) were added and heated to reflux. Stirring was stopped and the experiment was allowed to cool to room temperature. The crystalline product obtained were isolated by filtration and dried in vacuo at 40° C. Yield = 0.25g, mp = 183.7°C (DSC onset value). XRPD analysis conforms with the alpha form. Method IV: 0.5g Compound I in a mixture of ethyl acetate (10 mL) and water (0.4 mL) was heated to 70° C with stirring. The experiment was allowed to cool to room temperature. The crystalline product obtained were isolated by filtration and dried in vacuo at 40° C. XRPD analysis conforms with the alpha form.

PATENT

https://www.google.com/patents/US20050261762

PATENT

http://www.google.co.ug/patents/EP2004158A2?cl=en

CEP-1347 (KT7515) (Maroney et al. 1998; Roux et al. 2002).

 

 

  PAPER

Neurotrophic 3,9-bis[(alkylthio)methyl]- and -bis(alkoxymethyl)-K-252a derivatives
J Med Chem 1997, 40(12): 1863

http://pubs.acs.org/doi/full/10.1021/jm970031d

The synthesis of the title compound used as the starting material was the indolocarbazole alkaloid K-252A (I). Compound (I) was protected as the diacetyl derivative (II) by treatment with Ac2O and DMAP. Formylation of (II) with dichloromethyl methyl ether in the presence of TiCl4 afforded dialdehyde (III), which was further reduced to diol (IV) using NaBH4 in MeOH-CHCl3. Condensation of diol (IV) with ethanethiol in the presence of camphorsulfonic acid furnished the bis-sulfanyl compound (V). The acetyl protecting groups of (V) were finally removed by treatment with sodium methoxide. Alternatively, diol (IV) was first deacetylated by treatment with NaOMe, and the deprotected bis(hydroxymethyl) compound (VI) was then condensed with ethanethiol to produce the title bis-sulfayl compound 8.

3,9-Bis[(ethylthio)methyl]-K-252a (8):

mp 163−165 °C;

IR (KBr) 1725, 1680 cm^-1; FAB-MSm/z 615(M⁺);

¹H-NMR (400 MHz, DMSO-d₆) δ 1.23 (t, 6H, J = 7.3 Hz), 1.99 (dd, 1H, J = 4.8, 14.1 Hz), 2.132 (s, 3H), 2.489 (q, 2H, J = 7.3 Hz), 2.505 (q, 2H, J = 7.3 Hz), 3.37 (dd, 1H, J = 7.6, 14.1 Hz), 3.92 (s, 3H), 3.94 (s, 2H), 3.98 (s, 2H), 4.95 (d, 1H, J = 17.6 Hz), 5.02 (d, 1H, J = 17.6 Hz), 6.32 (s, 1H), 7.10 (dd, 1H, J = 4.8, 7.6 Hz), 7.450 (m, 2H), 7.84 (d, 1H, J = 8.5 Hz), 7.88 (d, 1H, J = 8.8 Hz), 7.95 (d, 1H, J = 1.0 Hz), 8.60 (s, 1H), 9.13 (d, 1H, J = 0.7 Hz);

HRFAB-MS calcd for C₃₃H₃₃N₃O₅S₂ 615.1862, found 615.1869. Anal. (C₃₃H₃₃N₃O₅S₂·0.5H₂O) C, H, N.

References

Maroney et al (1998) Motoneuron apoptosis is blocked by CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling pathway. J.Neurosci. 18 104. PMID: 9412490.

Saporito et al (1998) Preservation of cholinergic activity and prevention of neuron death by CEP-1347/KT-7515 following excitotoxic injury of the nucleus basalis magnocellularis. Neuroscience 86 461. PMID: 9881861.

Bozyczko-Coyne et al (2001) CEP-1347/KT-7515, an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Abeta-induced cortical neuron apoptosis. J.Neurochem. 77 849. PMID: 11331414.

WO1994002488A1 *	Jul 26, 1993	Feb 3, 1994	Cephalon Inc	BIS-STAUROSPORINE AND K-252a DERIVATIVES
Reference
1	*	KANEKO M ET AL: "Neurotrophic 3,9-Bis[(alkylthio)methyl]- and -Bis(alkoxymethyl)-K-252a Derivatives" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 40, no. 12, 1997, pages 1863-1869, XP002128804 ISSN: 0022-2623 cited in the application

SEE.....http://newdrugapprovals.org/2015/12/13/tevas-cep-1347-kt-7515-amap3k11-mlk3-inhibitor-potentially-for-the-treatment-of-parkinsons-disease/

//////////CEP 1347, KT 7515 ,

CCSCC1=CC2=C(C=C1)N3C4CC(C(O4)(N5C6=C(C=C(C=C6)CSCC)C7=C8CNC(=O)C8=C2C3=C75)C)C(=O)OOC

PF-04191834 for Patients With Osteoarthritis Of The Knee

PF 4191834

CAS 1029317-21-2

UNII-YX55DXP4T1; PF-4191834;  DVNQWYLVSNPCJZ-UHFFFAOYSA-N;

4-(3-{[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl) tetrahydro-2H-pyran-4-carboxamide;

4-[3-[4-(2-methylpyrazol-3-yl)phenyl]sulfanylphenyl]oxane-4-carboxamide

Molecular Formula:	C22H23N3O2S
Molecular Weight:	393.50192 g/mol

https://www.clinicaltrials.gov/ct2/show/NCT01147458

PF-04191834 works in animal models by inhibiting one of the enzymes, 5-lipoxygenasein which is involved in the pathway that causes inflammation and pain. The purpose of this study is to test how effective, safe and tolerated PF-04191834 is in patients with osteoarthritis of the knee by itself or with naproxen, particularly to test if patients have less pain.

http://www.ncats.nih.gov/files/PF-04191834.pdf

Mechanism:

5-Lipoxygenase (5-LO) inhibitor

Original Development Indication:

AsthmaChronic osteoarthritis pain

 

PATENT

US 20080125474

http://www.google.co.in/patents/US20080125474

formula (Ib):

A compound of formula (Ib) may be prepared according to the following process:

Example 1
• 

4-(3-{[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4 carboxamideStep 1: Preparation of 4-(3-bromophenyl)-tetrahydro-2H-pyran-4-carboxamide

• 4-(3-bromophenyl)tetrahydro-2H-pyran-4-carbonitrile made by the procedures described in EP 108114 (1.05 kg, 3.95 mole) was stirred in 98% H₂SO₄ (3.00 L) at room temperature for about 40 h. The mixture was then poured onto ice and the very fine suspension was filtered and washed with H₂O thoroughly until pH of wash is neutral. The white solid was washed with hexanes and was then dried in vacuo at 35-40° C. to give 1119 g (99.8% yield) of product in 99.9% purity. LC/MS: 5%-100% CH3CN:H20-0.01% TFA gradient over 10 minutes: 4.68 min. (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.50-7.49 (m, 1H), 7.43-7.40 (m, 1H), 7.36-7.30 (m, 1H), 7.27 (d, J=7.92 Hz, 1H) 7.06 (s, 1H), 5.00 (brs, 1H) 3.71 (dt, J=11.7, 3.7 Hz, 2H), 3.42 (t, J=10.7 Hz, 2H), 2.38 (d, J=13.6 Hz, 2H), 1.75 (td, J=12.2, 4.3 Hz, 2H).

Step 2: Preparation of 4-(3-(triisopropylsilylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide

• Alternative 1
• 4-(3-Bromophenyl)-tetrahydro-2H-pyran-4-carboxamide prepared in step 1 (300 g (1.06 mole), sodium tert-butoxide (122 g, 1.27 mole), Pd(OAc)₂ (4.74 g 0.0211 mole) and DIPPF (1,1-bis(diisopropylphosphino)ferrocene) (10.6 g 0.0253 mole) were placed in a flask which was evacuated and filled with N₂ 3 times. Anhydrous dioxane (2.3 L) was added and the mixture was stirred at room temperature for 1 h. To the mixture was added triisopropylsilane thiol (221 g 1.16 mole) and the resulting mixture was heated to reflux. Reflux was stopped after 1 h and the mixture was allowed to cool to room temperature. The mixture was then poured into ethyl acetate (7 L) which was then washed with H₂O (2×4 L) and brine (2 L). The combined aqueous washes were back extracted with ethyl acetate (3 L) which was then washed with H₂O (2×2 L) and brine (1 L). The combined organic layers were dried over MgSO₄, filtered and concentrated to dryness. Ethyl acetate (0.5 L) was added to the solid and the mixture was stirred on the rotary evaporator to give a fine suspension. Hexanes (1.5 L) was then added and the suspension was allowed to stand for 1 hour. The solid was filtered, washed with 1:1 ethyl acetate-hexanes (1 L) and then hexanes. The resulting brown solid was dried in vacuo to give 334 g (80% yield) of the product in 99% purity. A second crop was obtained from the filtrate which was washed as before and dried to give an additional 15 g product for a total yield of 84%. LC/MS: 5%-100% CH3CN:H20-0.01% TFA gradient over 10 minutes: 9.35 min. 394.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.52-7.51 (m, 1H) 7.42-7.39 (m, 1H), 7.22-7.21 (m, 2H), 5.35 (brs, 1H), 5.13 (brs, 1H) 3.78-3.75 (m, 4H) 2.36-2.32 (m, 2H), 2.06-2.00 (m, 2H), 1.27-1.16 (m, 3H), 1.05 (d, J=7.25 Hz, 18H).

Step 2: Preparation of 4-(3-(triisopropylsilylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide

• Alternative 2
• Purge a 3-neck flask (overhead stirrer, nitrogen inlet, serum cap) with nitrogen. Add 4-(3-Bromophenyl)-tetrahydro-2H-pyran-4-carboxamide prepared in step 1 (10 g, 0.03519 mole). Add sodium t-butoxide (4.1 g, 0.04223 moles). Add anhydrous toluene. Toluene should be as dry as possible, <0.01% water by KF is sufficient. Initiate stirring. Purge the reaction mixture with 4 vacuum/nitrogen purge cycles, maintaining 60 torr vacuum for 30 seconds with each cycle. Add the thiol (9.1 g, 0.04223 moles) assuring that oxygen is not introduced into the vessel. Heat to 75° C. Add PdCl2(diphenyl-phosphino ferrocene) (0.258 g, 0.00035 moles). Continue heating to reflux (reaction temperature about 107° C.) for a minimum of 1 hour. The mixture should reach reflux within 30 minutes.
• Cool the reaction mixture to 25° C. Add ethyl acetate (300 mL, 30 mL/g) and stir the resulting suspension for 30 min. Filter the suspension through celite (30 g). Rinse the celite with ethyl acetate for rinse (100 mL, of product to be rinsed), combining filtrates. Concentrate the filtrate via vacuum distillation at 70 torr at 30° C. until 80% of the filtrate volume has been removed. Add hexane (200 mL, 20 mL/g of product to be crystallized) for crystallization to the slurry over 5 minutes. Stir and cool the mixture to 5° C. Maintain the mixture at 5° C. for a minimum of 1 hour. Isolate product by filtration. Rinse the cake with hexane (100 mL, of product to be rinsed). Dry the cake on the filter to LOD of no more than 5%. Dry the solid at 45-50° C. under vacuum to an LOD of no more than 1.5%. Yield 12 grams (85% yield).
• Any mL/g amount indicated above is referred to grams of bromo carboxamide.

Step 3: Preparation of 5-(4-bromophenyl)-1-methyl-1H-pyrazole

• Alternative 1
• A N,N′-dimethylformamide (15 mL) solution of 4-bromoacetophenone (10.60 g, 53.25 mmols) and N,N′-dimethylformamide dimethyl acetal (2.5 equivalents) was heated at 125 degrees Celcius for 3 hours. The dark red solution was cooled to room temperature. The volatiles were removed by rotary evaporation providing a red viscous oil. To this substance was added anhydrous N,N′-dimethylformamide (15 mL) and methyl hydrazine (7.6 g, 160 mmols, 3 equivalents). The mixture was stirred at room temperature for 1 hour and then heated at 75 degrees Celcius for 4 hours. The volatiles were removed by rotary evaporation and the crude residue was taken up in a small volume of methylene chloride. This red solution was applied to a cartridge of silica gel. The cartridge was eluted with a 20:80 mixture of ethyl acetate and hexanes, respectively. The appropriate fractions were combined and concentrated to produce 12.5 g of a white solid.
• ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.87-3.95 (m, J=2.22 Hz, 3H) 6.29-6.36 (m, 1H) 7.31 (dd, J=8.36 Hz, 2H) 7.52-7.56 (m, 1H) 7.62 (dd, J=2.05 Hz, 2H).

Step 3: Preparation of 5-(4-bromophenyl)-1-methyl-1H-pyrazole

• Alternative 2
• 4-bromoacetophenone (20.0 g; 0.10 mole) and N,N-dimethylformamide dimethylacetal (28.5 mL; 0.20 mole) were mixed together in DMF (12 mL) and heated to 110° C. for 4 hours. The methanol and water that were generated during the reaction were distilled (6.2 mL). The mixture was cooled to 25° C. Methyl t-butyl ether (100 mL) and methylhydrazine (21.2 mL; 0.40 moles) were added and the mixture was stirred over night. The reaction mixture was washed with 1 M aqueous ammonium chloride (3×40 mL) and water (40 mL). The organic phase was dried by azeotropic distillation using a Dean-Stark apparatus. As an alternative to distillation, the solution was dried through an anhydrous magnesium sulfate cartridge. The solution was filtered through a silica gel cartridge (60 g). The product was flushed from the cartridge with methyl t-butyl ether. The fraction(s) containing product were combined and concentrated to about 70 mL by distillation. Heptane (120 mL) was added and distillation was continued until the pot temperature reached 98.4° C. About 100 mL of distillate was collected. The mixture was cooled to 40° C. The mixture was seeded and the temperature was maintained at 40° C. for 30 minutes while crystallization was initiated. The mixture was slowly chilled to 0° C. over 90 minutes. The mixture was held at 0° C. for 30 minutes. The mixture was filtered and the solid was washed (3×) with chilled (0° C.) heptane. The solid was dried on the filter. A cream-colored, crystalline solid (16.3 g; 68% yield) was obtained. The NMR data of the title compound are as per alternative 1.

Step 4: Preparation of 4-(3-{[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl) tetrahydro-2H-pyran-4-carboxamide

• A mixture of 5-(4-bromophenyl)-1-methyl-1H-pyrazole (0.50 g, 2.10 mmols,), 4-{3-[(tri-isopropylsilyl)thio]phenyl}tetrahydro-2H-pyran-4-carboxamide (0.83 g, 2.10 mmols), Tetrakis(triphenylphosphine)palladium(0) (243 mg, 0.10 equivalents), bis[(2-diphenyl-phosphino)]phenyl ether (113 mg, 0.10 equivalents), and 1.0 M potassium tert-butoxide in THF (6.3 mmols, 3 equivalents) in iPrOH (15 mL) that contained 5% water was heated for 4 hours at 90 degrees Celcius in an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and 7 mL of 1N HCl was added. The product was precipitated by the addition of water (30 mL). The precipitate was collected by suction filtration and washed with water (2×20 mL) and cold ethyl ether (4×20 mL). The tan brown solid was dissolved in a small volume of methylene chloride containing 1% methanol and applied to a 140 g cartridge of silica gel. The cartridge was eluted with an acetone:hexane gradient. The appropriate fractions were concentrated and triturated with methanol to produce a white solid (710 mg) as product. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.75-1.84 (m, 3H) 2.40 (d, J=13.54 Hz, 3H) 3.43-3.51 (m, 1H) 3.72 (d, J=11.34 Hz, 3H) 3.84 (s, 3H) 6.40 (d, J=1.46 Hz, 1H) 7.02 (s, 1H) 7.22-7.30 (m, 2H) 7.34 (d, J=8.05 Hz, 1H) 7.38-7.43 (m, 2H) 7.45-7.52 (m, 3H). HRMS calc M+H, 394.1589, found 394.1630.

Step 4: Preparation of 4-(3-{[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl) tetrahydro-2H-pyran-4-carboxamideScale-Up Alternative

• 4-{3-[(tri-isopropylsilyl)thio]phenyl}tetrahydro-2H-pyran-4-carboxamide (200 g, 0.51 moles), 5-(4-bromophenyl)-1-methyl-1H-pyrazole (126 g, 0.53 moles), and 2-methyltetrahydrofuran (2,000 mL, 10 mL/g of tips carboxamide) were put into the reactor and sparged with nitrogen while heating to 60° C. The sodium methoxide (244.0 mL, 1.07 moles, added as sodium methoxide in methanol solution 25% w/w) was added to the reactor and sparging was continued for another 30 minutes. PdCl₂DPPF (3.7 g, 0.005 moles) was added to the reactor and the mixture was heated to 70° C. Once the amount of tips carboxamide was less than 1% of starting amount, the mixture was cooled to 0° C. The mixture was held at 0° C. for one hour. The mixture was filtered and the solid was washed with 2-methyltetrahydrofuran (3×2.5 mL/g). The solid was dried on the filter. The solid was returned to a clean reactor and triturated with water (2,000 mL, 10 mL/g) for two hours at 20° C. The mixture was filtered and the solid was washed with water (2,000 mL, 2×5 mL/g). The solid was dried on the filter. The solid was returned to a clean reactor with the Si-thiol (90.0 g, 0.5 g/g) and THF (about 12.8 L, 70 mL/g). The mixture was heated to 60-65° C. and held for two hours. The mixture was cooled to 25° C. and filtered. The Si-thiol was washed with THF (about 0.9 L, 5 mL/g). The solution was distilled to a concentration of 10 mL/g. The mixture was cooled to 25° C. and hexanes (422.5 mL, 5 mL/g) was added. The mixture was filtered and the solid was washed with hexanes (422.5 mL, 5 mL/g). The solid was dried in a vacuum oven at 70° C.
• For 2-methyltetrahydrofuran and water, mL/g are referred to grams of tips carboxamide. For Si-thiol, tetrahydrofuran and hexanes, mL/g are referred to grams of title compound.

Step 5: Purification of 4-(3-{[4-(1-methyl-1H-pyrazol-5-yl)phenyl]thio]phenyl) tetrahydro-2H-pyran-4-carboxamide Crude title compound (181.0 g, 1.0 eq.) obtained from step 4, scale-up version, was returned to a clean reactor with Si-thiol (0.5 g/g of title compound) and THF (75 mL/g of title compound). The mixture was heated to 60-65° C. and held overnight. The mixture was cooled to 25° C. and filtered. The Si-thiol was washed with THF (5 mL/g of title compound). The solution was distilled to a concentration of 10 mL/g. Product may cake on reactor wall during the distillation. The mixture was cooled to 25° C. Hexanes (5 mL/g of title compound) was added and the mixture was held for 30 minutes. The mixture was filtered and the solid was dried on the filter. The reactor was rinsed with methanol to remove residual THF. The solid was returned to the reactor with methanol (20 mL/g of title compound). The mixture was heated to reflux and held over night. The mixture was cooled to 20° C. and held for 2 hours. The mixture was filtered. The solid was dried in a vacuum oven at 70° C. 162 g of purified title compound was obtained (85% yield). The NMR data of the title compound are as per Step 4. Any mL/g amount indicated above is referred to grams of crude title compound.

PAPER

Transition Metal-Catalyzed Couplings in Process Chemistry (2013), 253-266

http://onlinelibrary.wiley.com/doi/10.1002/9783527658909.ch18/summary;jsessionid=D7E55F3129F650B7655507743ACBA8DA.f02t02

Book Title

Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry

18. Development of Migita Couplings for the Manufacture of a 5-Lipoxygenase Inhibitor

Published Online: 19 JUL 2013

DOI: 10.1002/9783527658909.ch18

• 5-lipoxygenase inhibitor;
• isooctyl 3-mercaptopropionate;
• Migita couplings;
• one-pot process;
• triisopropylsilanethiol (TIPS-SH)

Summary

The biggest shortcoming of the medicinal chemistry route is the introduction of the sulfur source for the first of two Migita couplings. The authors felt that the initial Migita coupling was a better candidate for a kinetic study on the formation of impurity, as it was harder to maintain a constant concentration of active Pd for the second coupling with two sources of Pd/ligand in this step. As depicted in the mechanism of the Migita coupling, the catalytic cycle is composed of three steps: oxidative addition, transmetalation, and reductive elimination. This chapter develops a three-step, one-pot process for the synthesis of 5-lipoxygenase inhibitor via a sequence of two Migita couplings. This strategy employed cheap, odorless, and readily available isooctyl 3-mercaptopropionate as the sulfur source for the initial Migita coupling as a general alternative to the popular triisopropylsilanethiol (TIPS-SH) for the formation of diaryl thioethers.



  PAPER

Development of the Commercial Route for the Manufacture of a 5-Lipoxygenase Inhibitor PF-04191834

Brian Chekal, David Damon, Danny LaFrance, Kyle Leeman, Carlos Mojica, Andrew Palm, Michael St. Pierre, Janice Sieser, Karen Sutherland, Rajappa Vaidyanathan, John Van Alsten, Brian Vanderplas, Carrie Wager, Gerald Weisenburger, Gregory Withbroe, and Shu Yu

Publication Date (Web): July 17, 2015 (Article)

DOI: 10.1021/op500412a

http://pubs.acs.org/doi/abs/10.1021/op500412a

 A de novo three-step-one-pot process for the formation of PF-04191834 was developed. This methodology employed inexpensive, odorless, and readily available commodity chemical iso-octyl-3-mercaptopropionate as a sulfur source, which could be a general alternative to the popular TIPS-SH in the formation of diarylthioethers via Migita coupling. A kinetic study revealed that, at high temperature, reductive elimination could be the rate-limiting step in the catalytic cycle, which opens pathways for the generation of undesired impurities. By proper control of the reaction conditions, the desired API was synthesized in >70% crude yield and in 55% isolated yield after vigorous purifications. This process was successfully demonstrated on a 20 kg scale.

Pure API after drying under vacuum. Mp 173 °C.

¹H NMR (400 MHz, DMSO-d6) 7.52 (2H, m), 7.48 (2H, m), 7.42 (2H, m), 7.35 (2H, m), 7.29 (2H, m), 7.07 (1H, br. s), 6.42 (1H, d, J = 1.8 Hz), 3.85 (3H, s), 3.74 (2H, dt, J = 11.7, 3.7 Hz), 3.47 (2H, br. t, J = 11.7 Hz), 2.41 (2H, br. d, J = 13.3 Hz), 1.80 (2H, m).

¹³C NMR (100.6 MHz, DMSO-d6) 174.6, 146.0, 141.9, 137.9, 136.0, 133.2, 130.1, 129.7, 129.4, 129.3, 128.6, 125.6, 105.9, 64.6, 47.8, 37.6, 33.9.

LCMS: found m/z 394.17 [M + H]⁺. Anal. Calcd for C₂₂H₂₃N₃O₂S: C, 67.15; H, 5.89; N, 10.68; S, 8.15. Found: C, 67.09; H, 5.93; N, 10.69; S, 8.16.

After pd removal

Mp 173 °C.

¹H NMR (400 MHz, DMSO-d₆) 7.52 (2H, m), 7.48 (2H, m), 7.42 (2H, m), 7.35 (2H, m), 7.29 (2H, m), 7.07 (1H, br. s), 6.42 (1H, d, J = 1.8 Hz), 3.85 (3H, s), 3.74 (2H, dt, J = 11.7, 3.7 Hz), 3.47 (2H, br. t, J = 11.7 Hz), 2.41 (2H, br. d, J = 13.3 Hz), 1.80 (2H, m).

¹³C NMR (100.6 MHz, DMSO-d6) 174.6, 146.0, 141.9, 137.9, 136.0, 133.2, 130.1, 129.7, 129.4, 129.3, 128.6, 125.6, 105.9, 64.6, 47.8, 37.6, 33.9.

LCMS: found m/z 394.17 [M + H]⁺. Anal. Calcd for C₂₂H₂₃N₃O₂S: C, 67.15; H, 5.89; N, 10.68; S, 8.15. Found: C, 67.09; H, 5.93; N, 10.69; S, 8.16.

Patent	Submitted	Granted
Pyrazole Analogs [US7772269]	2008-05-29	2010-08-10
Pyrazole Derivatives as 5-LO-Inhibitors [US8097733]	2009-09-10	2012-01-17
NOVEL TREATMENT FOR AGE RELATED MACULAR DEGENERATION AND OCULAR ISCHEMIC DISEASE ASSOCIATED WITH COMPLEMENT ACTIVATION BY TARGETING 5-LIPOXYGENASE [US2011269807]	2011-11-03
TREATMENT AND PREVENTION OF DISEASES MEDIATED BY MICROORGANISMS VIA DRUG-MEDIATED MANIPULATION OF THE EICOSANOID BALANCE [US2014171445]	2012-08-02	2014-06-19

SEE........http://newdrugapprovals.org/2015/12/14/pf-04191834-for-patients-with-osteoarthritis-of-the-knee/





////////

c1c(cc(cc1)C2(C(=O)N)CCOCC2)Sc3ccc(cc3)c4ccnn4C      or

CN1C(=CC=N1)C2=CC=C(C=C2)SC3=CC=CC(=C3)C4(CCOCC4)C(=O)N

Ataciguat

 Ataciguat

HMR-1766 Hoechst Marion Roussel De Gmbh 

5-Chloro-2-[[(5-chloro-2-thienyl)sulfonyl]amino]-N-[4-(4-morpholinylsulfonyl)phenyl]benzamide C₂₁H₁₉Cl₂N₃O₆S_{3 UNII-QP166M390Q; 576.49306 g/mol}


A guanylate cyclase activator potentially for the treatment of aortic valve stenosis.

CAS No. 254877-67-3

• Originator sanofi-aventis
• Developer Mayo Clinic; National Center for Advancing Translational Sciences; Sanofi; sanofi-aventis
• Class Anthranilic acids; Benzamides; Cardiovascular therapies; Chlorobenzenes; Morpholines; Small molecules; Sulfonamides; Thiophenes
• Mechanism of Action Guanylate cyclase stimulants

• 30 Jun 2015 Mayo Clinic plans a phase II trial for Aortic valve stenosis in USA (NCT02481258)
• 29 Jan 2014 Phase-I clinical trials in Aortic valve stenosis in USA (PO)
• 01 Jan 2010 Discontinued - Phase-II for Peripheral arterial occlusive disorders in Austria, Canada, France, Germany, Italy, Poland, Portugal, Russia, South Africa and USA (PO) prior to 2010

SYNTHESIS

     The Intermediates shown above is used in next step shown below


 


 Paper


 Organic Letters (2013), 15(7), 1638-1641


  http://pubs.acs.org/doi/abs/10.1021/ol400411v http://pubs.acs.org/doi/suppl/10.1021/ol400411v/suppl_file/ol400411v_si_001.pdf  

The Ru(II)-catalyzed intermolecular o-C–H amidation of arenes in N-benzoylated sulfoximine with sulfonyl azides is demonstrated. The reaction proceeds with broad substrate scope and tolerates various functional groups. Base hydrolysis of the amidation product provides the anthranilic acid derivatives and methylphenyl sulfoximine (MPS) directing group. This method is successfully employed for the synthesis of HMR 1766.

 PATENT

 WO 2009043495 http://www.google.com/patents/WO2009043495A1?cl=en



 Patent http://www.google.com/patents/WO2008124505A2?cl=en


 HMR-1766 (ataciguat sodium, see patent publication WO2000002851)

 PATENT http://www.google.com/patents/WO2000002851A1?cl=en

Patent	Submitted	Granted
TRA COMBINATION THERAPIES [US2007238674]	2007-10-11
sGC STIMULATORS OR sGC ACTIVATORS ALONE AND IN COMBINATION WITH PDE5 INHBITORS FOR THE TREATMENT OF CYSTIC FIBROSIS [US2013035340]	2011-02-03	2013-02-07
SOLUBLE GUANYLATE CYCLASE (SGC) MODULATORS FOR TREATMENT OF LIPID RELATED DISORDERS [US2013123354]	2013-01-08	2013-05-16
Novel combination [US2005059660]	2004-07-29	2005-03-17
SGC STIMULATORS OF SGC ACTIVATORS IN COMBINATION WITH PDE5 INHBITORS FOR THE TREATMENT OF ERECTILE DYSFUNCTION [US2014288079]	2014-03-18	2014-09-25

Patent	Submitted	Granted
novel use of activators and stimulators of soluble guanylate cyclase for the prevention or treatment of renal disorders [US2010016305]	2010-01-21
HETEROARYL-SUBSTITUTED PIPERIDINES [US8119663]	2009-12-10	2012-02-21
Use of soluble guanylate cyclase activators for the treatment of Raynaud's Phenomenon [US2009215769]	2009-08-27
Use of Activators of Soluble Guanylate Cyclase for Promoting Wound Healing [US2009221573]	2009-09-03
Use of Suluble Guanylate Cyclase Acitvators for Treating Acute and Chronic Lung Diseases [US2009286781]	2009-11-19
Use of Activators of Soluble Guanylate Cyclase for Treating Reperfusion Damage [US2009298822]	2009-12-03
HETEROCYCLIC DERIVATIVE AND USE THEREOF [US2011028493]	2011-02-03
SUBSTITUTED PIPERIDINES [US8202862]	2010-12-02	2012-06-19
METHODS AND COMPOSITIONS FOR TREATING CARDIAC DYSFUNCTIONS [US2009022729]	2009-01-22
sGC STIMULATORS [US2014323448]	2014-04-29	2014-10-30

  

SEE.....http://newdrugapprovals.org/2015/12/11/ataciguat/



///////// C1COCCN1S(=O)(=O)C2=CC=C(C=C2)NC(=O)C3=C(C=CC(=C3)Cl)NS(=O)(=O)C4=CC=C(S4)Cl

Lixivaptan

Lixivaptan

CRTX-080; VPA-985; WAY-VPA-985

N-[3-chloro-4-(6,11-dihydropyrrolo[2,1-c][1,4]benzodiazepine-5-carbonyl)phenyl]-5-fluoro-2-methylbenzamide

• 5-fluoro-2-methyl-N-(4-(5H-pyrrolo(2,1-c)-(1,4)benzodiazepin-10-(11H)-ylcarbonyl)-3-chlorophenyl)benzamide
• N-4-(3-chloro-4-(5H-pyrrolo(2,1-C)(1,4)benzodiazepin-10(11H)-ylcarbonyl)phenyl)-5-fluoro-2-methylbenzamide
• N-[3-chloro-4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylBenzamide
• N-(3-CHLORO-4-{3,9-DIAZATRICYCLO[8.4.0.0(3),?]TETRADECA-1(10),4,6,11,13-PENTAENE

CAS 168079-32-1

MW 473.9,

	MF C27H21ClFN3O2

NDA Filing

A vasopressin (AVP) V2 antagonist potentially for treatment of heart failure and hyponatremia.

Lixivaptan (VPA-985) is a phase III pharmaceutical being developed by Cardiokine, Inc., a specialty pharmaceutical company based in Philadelphia, PA, focused on the development of pharmaceuticals for the treatment and prevention of cardiovascular diseases. Lixivaptan is, as of May 2010, in Phase III clinical trials involving patients with hyponatremia, including those with concomitant heart failure.^[1] Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. Lixivaptan may help some patients eliminate excess fluids while retaining electrolytes.



ChemistryLixivaptan is synthesized as follows:^[2]

 

 

 

 

 

Mechanism of action

Lixivaptan is a potent, non-peptide, selective vasopressin 2 receptor antagonist. The oral capsule works by reducing the action of the hormone vasopressin that blocks fluid excretion. Lixivaptan acts by blocking vasopressin, an anti-diuretic hormone that causes the kidneys to retain water. When the body needs to remain hydrated under certain conditions, vasopressin can have protective effects. But an excess of vasopressin is counterproductive in a body retaining too much fluid. The drug shows promise in treating heart failure in patients with hyponatremia.

THE BALANCE study

In February 2008, Cardiokine and its worldwide partner, Biogen Idec, initiated THE BALANCE (Treatment of HyponatrEmia BAsed on LixivAptan in N Yha class III/IV Cardiac patient Evaluation) study. THE BALANCE study is a 650-patient Phase III, global, multi-center, randomized, placebo-controlled, double-blind, study of lixivaptan for hyponatremia in patients with heart failure. The primary objective is to evaluate the safety and effectiveness of lixivaptan, when compared to the placebo, in increasing serum sodium from baseline in heart failure patients with hyponatremia.^[3][4]

Previous studies

In previous studies, lixivaptan improved blood sodium levels, lowered body weight and increased urine volume. Those studies suggest that lixivaptan may play an important role in treating hyponatremia and the signs and symptoms of water retention associated with heart failure, Syndrome of Inappropriate Anti-Diuretic Hormone(SIADH), and Liver Cirrhosis with Ascites (LCWA). In clinical trials involving patients with water volume overload, lixivaptan resulted in correction of hyponatremia together with marked aquaresis.

Vaptans

The vasopressin receptor antagonists, dubbed vaptans, target the vasopressin hormonal feedback system. Vasopressin, also called the anti-diuretic hormone or ADH, is an important part of regulation in the circulatory system and is integral to the balance of water in the body. As a fundamental part of hormonal control in the body, it is implicated in many different conditions. Vaptans can be administered orally or intravenously. They work by competing for the active sites on cells meant for vasopressin binding—in this way, the vasopressin is blocked from acting, which earns the title of vasopressing antagonists.

SYNTHESIS COMING....................

JMC 1998, 41, 2442

US 5516774

http://www.google.co.in/patents/US5516774

CN103694240

Lixiputan (Lixivaptan, I) is pressurized by a Wyeth (wyeth) research and development of non-peptide hormone arginine oral selective V2 receptor antagonist, chemical name N- [3- chloro-4- (10, 11- dihydro -5H- pyrrolo [2,1-c] [1,4] benzodiazepine-10-yl carbonyl) phenyl] -5-fluoro-2- methylbenzamide. Clinical studies have shown that, compared with traditional diuretic, Lixiputan for the treatment of congestive heart failure (CHF), cirrhosis of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion disorders (SIADH) patients, its in increase free water clearance without affecting renal sodium discharge, it will not activate the neuroendocrine system, and has a high safety and tolerability. Lixiputan V2 receptor selectivity higher than in May 2009 the FDA approved tolvaptan, Phase III clinical studies for the treatment of hyponatremia have been completed in the United States, in the pre-registration stage.
Document (Journalof medicinal chemistry, 1998,41 (14):. 2442-2444) reported Lixiputan there are two synthetic routes, one route to 10,11-dihydro -5H- pyrrolo [2, ι-c] [1,4] benzodiazepine (2) as raw materials, in turn with 2-chloro-4-nitrobenzoyl and 5-fluoro-2-methylbenzoyl docking, to obtain I; the second is the first line of 2-chloro-4-amino benzoic acid methyl ester (5) and 5-fluoro-2-methylbenzoyl chloride (7) butt, by hydrolysis, acylation reaction of 2-chloro-like -4 - [(5-fluoro-2-methylbenzoyl) amino] benzoyl chloride (10), and then with 2 reaction of I. 2 As the raw material is expensive, Route One to two as the starting material, the multi-step reaction, its low efficiency, high cost of production. Therefore, this study reference line two, 2-chloro-4-nitro-benzoic acid (3) as the starting material, by esterification, hydrogenation, acylation, hydrolysis, chloride, and so the reaction of 10; 10 and then with 2 After acylation reaction of N- I. I synthetic route follows.

The chemical structure:

formula = C27H21ClFN3O2
 Molecular Weight: 473.93
The method for producing foreign products have been reported, such as the literature Journal of medicinalchemistry, 1998,41 (14):. 2442-2444 and US, 5516774 [P], 1996-5-14. Currently, Lixiputan (Iixivaptan) abroad in Phase III clinical studies, there are good prospects for development, given the value of the pharmaceutical compounds, high purity, with a very determined and reproducible crystalline compounds are important .
The present inventors have repeated the document US, 5,516,774 Lixiputan method of purity, obtained was 97.5%, mpl91-195 ° C, by the study of a plurality of batches, the melting point of the same, by a powder X- ray diffraction pattern See

preparation of Lixiputan solvate Lixiputan, by two synthetic methods. As literature Journalof medicinal chemistry, 1998, 41 (14):. 2442-2444 and US, 5516774 [P],
The method reported in [0026] 1996-5-14. Preclude the use of the route of the present invention is represented by the following reaction:

  synthetic Lixiputan by proton nuclear magnetic resonance spectroscopy (1H-NMRX mass spectrometry (MS), infrared spectroscopy (IR) and other confirmed its chemical structure (see Figure 3 MS). Test equipment for nuclear magnetic resonance Bruker AV400 meter, gas generation agent for CambridgeIsotope Laboratories Company DMS0_d6.
  ES1-HRMS (m / z): 474.17 [M + H] + NMR (400MHz, DMS0_d6) δ: 10.49 (s, 1H), 7.84 (s, 1H), 7.40 (d, J = 6.8Hz, 2H), 7.33 (d, J = 8.4Hz, 3H), 7.23 (t, J = 8.4Hz, 1H), 7.13 (t, J = 5.6Hz, 2H), 7.05 (d, J = 6.8Hz, 1H) , 6.82 (s, 1H), 5.94 (d, J = 32Hz, 2H), 5.23 (br, 4H), 2.30 (s, 3H).
The product obtained, with a purity of 97.5%, mp 191-195 ° C.

Lixiputan solvates H NMR spectrum, δ: 1.147-1.182 "3" methyl hydrogens; δ: 1.971-1.977 for the "I" position methyl hydrogen; δ: 3.994-4.047 "2" position methylene hydrogen.

CN104059070

CN104140429

IN 2012 MUM 03309

References

 

Patent	Submitted	Granted
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5854237]	1998-12-29
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5889001]	1999-03-30
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5843944]	1998-12-01
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5624923]	1997-04-29
Compositions for delivery of insoluble agents [US8877746]	2010-08-24	2014-11-04

Patent	Submitted	Granted
AURIS FORMULATIONS FOR TREATING OTIC DISEASES AND CONDITIONS [US2009306225]	2009-12-10
Vasopressin antagonist and diuretic combination [US6656931]	2003-04-10	2003-12-02
Pharmaceutical carrier formulation [US6437006]		2002-08-20
Vasopressin antagonist formulation and process [US6352718]		2002-03-05
Nonpeptide agonists and antagonists of vasopressin receptors [US2002128208]	2002-09-12
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5968930]	1999-10-19
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5968937]	1999-10-19
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5516774]	1996-05-14
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5733905]	1998-03-31
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists [US5736540]	1998-04-07

Lixivaptan

Systematic (IUPAC) name
N-[3-chloro-4-(6,11-dihydropyrrolo[2,1-c][1,4]benzodiazepine-5-carbonyl)phenyl]-5-fluoro-2-methylbenzamide
Identifiers
CAS Number	168079-32-1
ATC code	None
PubChem	CID: 172997
IUPHAR/BPS	2238
ChemSpider	151067
UNII	8F5X4B082E
ChEMBL	CHEMBL49429
Chemical data
Formula	C27H21ClFN3O2
Molecular mass	473.926 g/mol

CN102020609A *	Sep 17, 2009	Apr 20, 2011	北京本草天源药物研究院	Tolvapta crystal or amorphous substance and preparation method thereof
CN102918038A *	Mar 31, 2011	Feb 6, 2013	万梯雅有限公司	New polymorph
US5516774 *	Jun 13, 1994	May 14, 1996	American Cyanamid Company	Tricyclic diazepine vasopressin antagonists and oxytocin antagonists

1	*	吕扬 等: "《晶型药物》", 31 October 2009, article ""第七章 晶型药物的研究方法"", pages: 136-139

 

 

• 1 Lixivaptan: a novel vasopressin receptor antagonist
• 2 Albright, J. D.; Reich, M. F.; Delos Santos, E. G.; Dusza, J. P.; Sum, F. W.; Venkatesan, A. M.; Coupet, J.; Chan, P. S.; Ru, X.; Mazandarani, H.; Bailey, T. (1998). "5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]- [1,4]benzodiazepin-10(11H)-ylcarbonyl)-3- chlorophenyl]benzamide (VPA-985): An Orally Active Arginine Vasopressin Antagonist with Selectivity for V2Receptors". Journal of Medicinal Chemistry 41 (14): 2442–2444. doi:10.1021/jm980179c. PMID 9651149.
• 3 http://www.clinicaltrials.gov/ct2/show/NCT00578695?term=Lixivaptan+Heart+Failure&rank=3
• 4 http://onlinelibrary.wiley.com/doi/10.1111/j.1752-8062.2010.00217.x/pdf
•  

SEE.....http://newdrugapprovals.org/2015/12/13/lixivaptan/

//////////Lixivaptan, CRTX-080,  VPA-985,  WAY-VPA-985

CC1=C(C=C(C=C1)F)C(=O)NC2=CC(=C(C=C2)C(=O)N3CC4=CC=CN4CC5=CC=CC=C53)Cl

CC1=C(C=C(C=C1)F)C(=O)NC2=CC(=C(C=C2)C(=O)N3CC4=CC=CN4CC5=CC=CC=C53)Cl