Ibipinabant Revisited – Drug Approvals International (2024)

Ibipinabant

cas 464213-10-3; UNII-O5CSC6WH1T; BMS-646256; SLV-319;

(4S)-5-(4-chlorophenyl)-N-(4-chlorophenyl)sulfonyl-N’-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide

1H-Pyrazole-1-carboximidamide, 3-(4-chlorophenyl)-N’-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N-methyl-4-phenyl-, (4S)-

(4S)-3-(4-Chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N’-methyl-4-phenyl-1H-pyrazole-1-carboximidamide

1H-Pyrazole-1-carboximidamide, 3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N‘-methyl-4-phenyl-, (4S)-

(-)-(4S)-N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine

4S)-(−)-3-(4-Chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine

It was originally developed by Solvay,whichwas acquiredby Abbott in 2010.

SLV 319,UNII:O5CSC6WH1T,(S)-SLV 319,BMS 646256,JD 5001

• OriginatorSolvay
• ClassAntipsychotics; Imides; Obesity therapies; Pyrazoles; Small molecules; Sulfonamides
• Mechanism of ActionCannabinoid receptor CB1 antagonists

Ibipinabant, also known as BMS-646256, JD-5001 and SLV-319, is a potent and highly selective CB1 antagonist. It has potent anorectic effects in animals, and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists

Ibipinabant (SLV319, BMS-646,256) is a drug used in scientific research which acts as a potent and highly selective CB₁antagonist.^[1] It has potent anorectic effects in animals,^[2] and was researched for the treatment of obesity, although CB₁ antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB₁ antagonists.^[3][4][5]

PATENT

WO2002076949

https://www.google.com/patents/WO2002076949A1?cl=en

Example IV

(-)-(4S)-N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine

(-)-(4S)-N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (7.16 gram, 0.0147 mol)) ([α²⁵ _D] = -150°, c = 0.01 , MeOH) (melting point: 169-170 °C) was obtained via chiral chromatographic separation of racemic N-methyl-N’-((4-chlorophenyl)sulfonyl)-3- (4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (18 gram, 0.037 mol) using a Chiralpak AD, 20 μm chiral stationary phase. The mobile phase consisted of a mixture of hexane/ethanol (80/20 (v/v)) and 0.1 % ammonium hydroxide (25 % aqueous solution).

Example III N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine

Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 ml) in 1 ,4-dioxane (20 ml) is added 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100 °C After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1 N HCI and water, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to a volume of 20 ml. Methyl-tert-butyl ether (60 ml) is added and the resulting solution is concentrated to a volume of 20 ml. The formed crystals are collected by filtration and recrystallised from methyl-te/τ-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1-carboxamide (4J5 gram, 76 % yield) Melting point: 211-214 °C

Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole-1 -carboxamide (3.67 gram, 7J5 mmol) and phosphorus pentachloride (1.69 gram, 8.14 mmol) in chlorobenzene (40 ml) is heated at reflux for 1 hour. After thorough concentration in vacuo, the formed N-((4- chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1- carboximidoyl chloride is suspended in dichloromethane and reacted with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo. The residue is crystallised from diethyl ether to give N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1 H-pyrazole-1 -carboxamidine (2.29 gram, 61 % yield). Melting point: 96-98 °C(dec).

PATENT

WO2008074816

https://google.com/patents/WO2008074816A1?cl=en

PAPER

An expedient atom-efficient synthesis of the cannabinoid CB₁receptor inverse agonist ibipinabant

• Jos H.M. Lange,
• Hans J. Sanders,
• Jeroen van Rheenen

• Abbott Healthcare Products B.V., Chemical Design & Synthesis Unit, C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands

http://www.sciencedirect.com/science/article/pii/S0040403911000955

http://dx.doi.org/10.1016/j.tetlet.2011.01.068

A novel synthetic route to the highly selective and orally active cannabinoid CB₁ receptor inverse agonist ibipinabant is described which combines the use of inexpensive, commercially available reagents and mild reaction conditions with a high degree of atom-efficiency. The method is expected to enable the rapid synthesis of a variety of sulfonylguanidines.

PAPER

JD-5006 and JD-5037: Peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities

• Robert J. Chorvat^, ,
• Jennifer Berbaum,
• Kristine Seriacki,
• John F. McElroy

• Jenrin Discovery, 2515 Lori Lane North, Wilmington, DE 19810, USA

http://dx.doi.org/10.1016/j.bmcl.2012.08.004

http://www.sciencedirect.com/science/article/pii/S0960894X12009936

Scheme 1.

Reagents and conditions: (a) ArylSO₂NHCO₂CH₃, toluene, reflux, 3–6h, 30–95%; (b) PCl₅, chlorobenzene, reflux, 2–4h, 50–90%; (c) NH₂Me.HCl, Et₃N, CH₂Cl₂, ice-bath to rt, 16–20h, 30–70%; (d) X=CO₂Et/X′=CO₂H: LiOH, H₂O/THF(1:3), 50%; X′=CO₂H/X′=CONH₂, (1) IBCF, NMM, CH₂Cl₂, (2) NH₃/THF, 60%; X′=CO₂H/X′=CONHOH, (1) IBCF, NMM, CH₂Cl₂, (2) NH₂OH·HCl, NMM, CH₂Cl₂, 40%; X=OCH₂CO₂Et/OCH₂CO₂H: LiOH, H₂O/THF(1:3), rt, 50%; X′=OCH₂CO₂H/X′=OCH₂CONH₂: (1) IBCF, NMM, CH₂Cl₂, (2) NH₃/THF, 30%; X=NO₂:/X′=NHCOCH₃: (1) Fe/HCl, EtOH, H₂O, reflux 1–2h, 90%; (2) Ac₂O, pyr, CH₂Cl₂, rt, 8h, 90%; X=NO₂:/X′=NHCO₂Et: (1) Fe/HCl, EtOH, H₂O, reflux 1–2h, 90%; (2) ClCO₂Et, pyr, CH₂Cl₂, 0°C to rt, 8h, 90%

Clip

http://molpharm.aspetjournals.org/content/87/2/197.full.pdf

Paper

Lange et al (2005) Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity. Bioorg.Med.Chem.Lett. 15 4794. PMID: 16140010.

http://www.sciencedirect.com/science/article/pii/S0960894X05010139

http://dx.doi.org/10.1016/j.bmcl.2005.07.054

Paper

Lange et al (2004) Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB₁ cannabinoid receptor antagonists. J.Med.Chem. 47 627. PMID:14736243.

A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB₁ and hCB₂) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitroCB₁ antagonistic activities and in general exhibited high CB₁ vs CB₂ receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C₄ position as 4S. Bioanalytical studies revealed a high CNS−plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB₁ receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH₂ moiety with a -NHCH₃ group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80

4S)-(−)-3-(4-Chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (80) and (4R)-(+)-3-(4-chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (81). Chiral preparative HPLC separation of racemic 67 (18 g, 0.037 mol) using a Chiralpak AD, 20 μm chiral stationary phase yielded 80 (7.16 g, 0.0147 mol) and 81 (7.46 g, 0.0153 mol), respectively. The mobile phase consisted of a mixture of n-hexane/ethanol (80/20 (v/v)) and 0.1% NH₄OH (25% aqueous solution).

DESIRED

80: [ ] = −150°, c = 0.01, MeOH; mp 171−172 °C;

¹H NMR (400 MHz, DMSO-d₆) δ 2.94 (d, J = 4 Hz, 3H), 3.96 (dd, J = 11 and 4 Hz, 1H), 4.46 (t, J = 11 Hz, 1H), 5.05 (dd, J = 11 and 4 Hz, 1H), 7.20−7.35 (m, 5H), 7.45 (dt, J = 8 and 2 Hz, 2H), 7.53 (dt, J = 8 and 2 Hz, 2H), 7.77 (dt, J = 8 and 2 Hz, 2H), 7.82 (dt, J = 8 and 2 Hz, 2H), 8.19 (br d, J = 4 Hz, 1H);

HRMS (C₂₃H₂₁Cl₂N₄O₂S) [M+H]⁺:  found m/z 487.0768, calcd 487.0762. Anal. (C₂₃H₂₀Cl₂N₄O₂S) C, H, N.

UNDESIRED

81:  [ ] = + 150°, c = 0.01, MeOH; mp 171−172 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.94 (d, J = 4 Hz, 3H), 3.96 (dd, J = 11 and 4 Hz, 1H), 4.46 (t, J = 11 Hz, 1H), 5.05 (dd, J = 11 and 4 Hz, 1H), 7.20−7.35 (m, 5H), 7.45 (dt, J = 8 and 2 Hz, 2H), 7.53 (dt, J = 8 and 2 Hz, 2H), 7.77 (dt,J = 8 and 2 Hz, 2H), 7.82 (dt, J = 8 and 2 Hz, 2H), 8.19 (br d, J = 4 Hz, 1H); HRMS (C₂₃H₂₁Cl₂N₄O₂S) [M+H]⁺:  found m/z 487.0749, calcd 487.0762. Anal. (C₂₃H₂₀Cl₂N₄O₂S) C, H, N.

Paper

Org. Process Res. Dev., 2012, 16 (4), pp 567–576

Modeling-Based Approach Towards Quality by Design for the Ibipinabant API Step

This work presents a process modeling-based methodology towards quality by design that was applied throughout the development lifecycle of the ibipinabant API step. By combining mechanistic kinetic modeling with fundamental thermodynamics, the degradation of the API enantiomeric purity was described across a large multivariate process knowledge space. This knowledge space was then narrowed down to the process design space through risk assessment, target quality specifications, practical operating conditions for scale-up, and plant control capabilities. Subsequent analysis of process throughput and yield defined the target operating conditions and normal operating ranges for a specific pilot-plant implementation. Model predictions were verified via results obtained in the laboratory and at pilot-plant scale. Future efforts were focused on increasing fundamental process knowledge, improving model confidence, and using a risk-based approach to reevaluate the design space and selected operating conditions for the next scale-up campaign.

API process at the time of the first pilot-plant campaign

changed to

Process for the second pilot-plant implementation

Process parameter ranges and typical results from approximately 20 lab experiments conducted on the process shown in Scheme

Figure 3. Ishikawa diagram for the API step, highlighting factors that potentially affect the enantiomeric purity of the product. Factors shown in blue were accounted for in the sulfonylation reaction and distillative crystallization models. Factors shown in red were not included in the models

REFERENCES

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2: Chorvat RJ, Berbaum J, Seriacki K, McElroy JF. JD-5006 and JD-5037: peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities. Bioorg Med Chem Lett. 2012 Oct 1;22(19):6173-80. doi: 10.1016/j.bmcl.2012.08.004. Epub 2012 Aug 20. PubMed PMID: 22959249.

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6: Rohrbach K, Thomas MA, Glick S, Fung EN, Wang V, Watson L, Gregory P, Antel J, Pelleymounter MA. Ibipinabant attenuates β-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight. Diabetes Obes Metab. 2012 Jun;14(6):555-64. doi: 10.1111/j.1463-1326.2012.01563.x. Epub 2012 Feb 24. PubMed PMID: 22268426.

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8: Gamble JF, Leane M, Olusanmi D, Tobyn M, Supuk E, Khoo J, Naderi M. Surface energy analysis as a tool to probe the surface energy characteristics of micronized materials–a comparison with inverse gas chromatography. Int J Pharm. 2012 Jan 17;422(1-2):238-44. doi: 10.1016/j.ijpharm.2011.11.002. Epub 2011 Nov 10. PubMed PMID: 22100516.

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References

Ibipinabant

Systematic (IUPAC) name
4S-(−)-3-(4-chlorophenyl)-N-methyl-N’-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine
Identifiers
CAS Number	464213-10-3
ATC code	none
PubChem	CID 9826744
ChemSpider	24765166
UNII	O5CSC6WH1T
KEGG	D09349
ChEMBL	CHEMBL158784
Chemical data
Formula	C24H22Cl2N4O2S
Molar mass	501.427

/////////464213-10-3, UNII-O5CSC6WH1T, BMS-646256, SLV-319,Ibipinabant,JD 5001, solvay, abbott

c2cc(Cl)ccc2C1=NN(C(NC)=NCS(=O)(=O)c3ccc(Cl)cc3)CC1c4ccccc4