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Iptacopan

December 17, 2023 2:40 am / Leave a comment

Iptacopan

1644670-37-0

422.525, C₂₅H₃₀N₂O₄

4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl) benzoic acid
BENZOIC ACID, 4-((2S,4S)-4-ETHOXY-1-((5-METHOXY-7-METHYL-1H-INDOL-4-YL)METHYL)-2-PIPERIDINYL)-
Iptacopan

LNP 023
LNP-023
LNP023
NVP-LNP023
NVP-LNP023-NX

Fda approved, To treat paroxysmal nocturnal hemoglobinuria, 12/5/2023, Fabhalta ‘CHINA 2024

Iptacopan is a small-molecule factor B inhibitor previously investigated as a potential treatment for the rare blood disease paroxysmal nocturnal hemoglobinuria (PNH) by inhibiting the complement factor B.¹ Factor B is a positive regulator of the alternative complement pathway, where it activates C3 convertase and subsequently C5 convertase.² This is of particular importance to PNH, where one of the disease hallmarks is the mutation of the PIGA gene. Due to this mutation, all progeny erythrocytes will lack the glycosyl phosphatidylinositol–anchored proteins that normally anchor 2 membrane proteins, CD55 and CD59, that protect blood cells against the alternative complement pathway.³ Additionally, iptacopan has the benefit of targeting factor B, which only affect the alternative complement pathway, leaving the classic and lectin pathway untouched for the body to still mount adequate immune responses against pathogens.²

On December 6th, 2023, Iptacopan under the brand name Fabhalta was approved by the FDA for the treatment of adults with PNH. This approval was based on favorable results obtained from the phase III APPL-PNH and APPOINT-PNH studies, where 82.3% and 77.5% of patients experienced a sustained hemoglobin improvement without transfusions respectively.⁵

Iptacopan , sold under the brand name Fabhalta, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria.^[1] It is a complement factor B inhibitor that was developed by Novartis.^[1] It is taken by mouth.^[1]

Iptacopan was approved by the US Food and Drug Administration (FDA) for the treatment of adults with paroxysmal nocturnal hemoglobinuria in December 2023.^[2]^[3]

Medical uses

Iptacopan is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria.^[1]^[4]

Side effects

The FDA label for iptacopan contains a black box warning for the risk of serious and life-threatening infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B.^[1]

Research

In a clinical study with twelve participants, iptacopan as a single drug led to the normalization of hemolytic markers in most patients, and no serious adverse events occurred during the 12-week study.^[5]^[6]

Iptacopan is also investigated as a drug in other complement-mediated diseases, like age-related macular degeneration and some types of glomerulopathies.^[7]

PATENT

US9682968

https://patents.google.com/patent/US9682968B2/en

Example-26Example-26a4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid ((+) as TFA Salt)

A mixture of methyl 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoate, Intermediate 6-2b peak-1 (tr=1.9 min), (84 mg, 0.192 mmol) and LiOH in H₂O (1 mL, 1 mmol) in THF (1 mL)/MeOH (2 mL) was stirred at room temperature for 16 h, and then concentrated. The resulting residue was purified by RP-HPLC (HC-A) to afford the title compound. Absolute stereochemistry was determined by comparison with enantiopure synthesis in Example-26c. ¹H NMR (TFA salt, 400 MHz, D₂O) δ 8.12 (d, J=8.19 Hz, 2H), 7.66 (br. d, J=8.20 Hz, 2H), 7.35 (d, J=3.06 Hz, 1H), 6.67 (s, 1H), 6.25 (d, J=3.06 Hz, 1H), 4.65 (dd, J=4.28, 11.49 Hz, 1H), 4.04 (d, J=13.00 Hz, 1H), 3.87-3.98 (m, 2H), 3.53-3.69 (m, 5H), 3.38-3.50 (m, 1H), 3.20-3.35 (m, 1H), 2.40 (s, 3H), 2.17-2.33 (m, 2H), 2.08 (br. d, J=15.70 Hz, 1H), 1.82-1.99 (m, 1H), 1.28 (t, J=7.03 Hz, 3H); HRMS calcd. for C₂₆H₃₁N₂O₃(M+H)⁺423.2284, found 423.2263.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US411167175&_cid=P12-LQ9ETC-78389-1

Example 1

Intermediate 1:

To a 3 L three-necked flask were successively added tetrahydrofuran (150 mL) and 4-bromoxynil (50 g). Isopropylmagnesium chloride lithium chloride coordination complex (1.3 M, 210 mL) was slowly added to the reaction system under nitrogen atmosphere. After the reaction was carried out at room temperature for 2 h, the reaction system was diluted with anhydrous tetrahydrofuran (500 mL) for dilution. The reaction system was cooled to −5° C., and 4-methoxypyridine (25 mL) was added, followed by slowly dropwise addition of benzyl chloroformate (35 mL) (the system temperature was maintained below 0° C.). After the dropwise addition was completed, the reaction system was successively reacted at 0° C. for 2 h, and then warmed to room temperature and reacted at that temperature for 16 h. After the reaction was completed, hydrochloric acid solution (6 M, 150 mL) was added. The mixture was stirred at room temperature for half an hour, added with water (1000 mL) for dilution, and extracted twice with ethyl acetate (500 mL). The extract phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting crude product was separated and purified by a silica gel column (petroleum ether:ethyl acetate=3:1 to 1:1) to give intermediate 1 (23 g, yield: 23%). MS m/z (ESI): 333.0 [M+H].

Intermediate 2:

To a 500 mL single-neck flask were successively added intermediate 1 (28 g), zinc powder (55 g) and acetic acid (200 mL). The reaction mixture was heated to 100° C. and reacted at that temperature for 16 h. After the reaction was completed, the reaction mixture was filtered. The filtrate was added with water (500 mL) for dilution and extracted with ethyl acetate (500 mL). The extract phase was washed twice with saturated aqueous sodium bicarbonate solution (500 mL), washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 2 (26 g, yield: 73%). MS m/z (ESI): 334.8 [M+H].

Intermediate 3:

To a 1 L single-neck flask were successively added tetrahydrofuran (100 mL), ethanol (100 mL) and intermediate 2 (26 g), and sodium borohydride (2 g) was added in batches. The mixture was reacted at room temperature for 2 h. After the reaction was completed, the system was cooled to 0° C., and saturated aqueous ammonium chloride solution (100 mL) was added until the temperature did not increase any more. Water (300 mL) was added for dilution, followed by extraction with ethyl acetate (200 mL×2). The extract phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 3 (25 g, yield: 76%). MS m/z (ESI): 336.9 [M+H].

Intermediate 4:

Dichloromethane (200 mL) was added to a 500 mL single-neck flask, and then intermediate 3 (25 g), imidazole (6.6 g) and tert-butyldiphenylchlorosilane (25 g) were successively added. The mixture was reacted at room temperature for 2 h. After the reaction was completed, water (500 mL) was added for dilution, followed by the extraction with dichloromethane (200 mL). The extract phase was washed with water (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by a silica gel column (petroleum ether:ethyl acetate=10:1) to give intermediate 4 (5.7 g, yield: 13%, R _f=0.55; isomer R _f=0.50). MS m/z (ESI): 597.0 [M+23].

Intermediate 5:

To a 250 mL single-neck flask were successively added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 30 mL) and intermediate 4 (5 g). The mixture was reacted at room temperature for 2 h. After the reaction was completed, water (100 mL) was added for dilution, followed by the extraction with ethyl acetate (50 mL×3). The extract phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by a silica gel column (petroleum ether:ethyl acetate=3:1 to 0:1) to give a racemic intermediate. The intermediate was subjected to SFC chiral resolution (apparatus: SFC Thar prep 80; column: CHIRALPAK AD-H, 250 mm×20 mm, 5 m; modifier: 35% methanol (0.2% aqueous ammonia); column temperature: 40° C.; column pressure: 60 bar; wavelength: 214/254 nm; flow rate: 40 g/min; Rt=4.78 min) to give intermediate 5 (1.2 g, yield: 41%). MS m/z (ESI): 358.8 [M+23].

Intermediate 6:

To a 100 mL single-neck flask were successively added N,N-dimethylformamide (15 mL) as a solvent, intermediate 5 (1.2 g) and iodoethane (1.1 g). After the reaction system was cooled to 0° C., sodium hydrogen (60%, 243 mg) was added. Then the system was warmed to room temperature and reacted at that temperature for 2 h. After the reaction was completed, water (30 mL) was added for dilution, followed by the extraction with ethyl acetate (50 mL). The extract phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 6 (1.2 g, yield: 83%). MS m/z (ESI): 386.9 [M+23].

Intermediate 7:

To a 100 mL single-neck flask were successively added methanol (10 mL), water (10 mL), concentrated sulfuric acid (10 mL) and intermediate 6 (1.2 g). The mixture was heated to 80° C. and reacted at that temperature for 48 h. After the reaction was completed, the reaction mixture was concentrated to remove methanol. The residue was made neutral with saturated aqueous sodium hydroxide solution and extracted three times with ethyl acetate (10 mL). The extract phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate 7 (850 mg, yield: 81%). MS m/z (ESI): 264.1 [M+H]. ¹H NMR (400 MHz, CDCl ₃) δ 8.01 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 4.13 (dd, J=11.7, 2.4 Hz, 1H), 3.92 (s, 3H), 3.82-3.70 (m, 1H), 3.62-3.47 (m, 2H), 3.27-3.10 (m, 1H), 3.02-2.88 (m, 1H), 2.07-1.97 (m, 1H), 1.95-1.85 (m, 1H), 1.82-1.62 (m, 2H), 1.27 (t, J=7.0 Hz, 3H).

Intermediate 8:

To a 250 mL single-neck flask were successively added dichloromethane (50 mL), 5-methoxy-7-methyl-1H-indole (3 g), BOC anhydride (5.68 g), 4-dimethylaminopyridine (227 mg) and triethylamine (2.26 g). The mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction mixture was quenched by adding saturated ammonium chloride solution (5 mL) and extracted three times with dichloromethane (20 mL). The combined organic phases were washed with water (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1) to give intermediate 8 (4.6 g, yield: 94%). MS m/z (ESI): 262.0 [M+H].

Intermediate 9:

To a 250 mL single-neck flask were successively added dichloromethane (80 mL), N-methylformanilide (3.8 g) and oxalyl chloride (3.6 g). The mixture was stirred at room temperature for 3 h. Then the reaction temperature was lowered to −14° C., and intermediate 8 (2.5 g) was added. The reaction system was naturally warmed to room temperature and stirred for 1 h. After the reaction was completed, the reaction liquid was poured into ice water and extracted three times with dichloromethane (100 mL). The combined extract phases were washed twice with water (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was separated and purified by a silica gel column (petroleum ether:ethyl acetate=20:1) to give intermediate 9 (1.3 g, yield: 47%). MS m/z (ESI): 290.0 [M+H]. ¹H NMR (400 MHz, CDCl ₃) δ 10.65 (s, 1H), 7.65 (d, J=3.4 Hz, 1H), 7.49 (d, J=3.4 Hz, 1H), 6.76 (s, 1H), 3.98 (s, 3H), 2.70 (s, 3H), 1.65 (s, 9H).

Intermediate 10:

To a 50 mL three-necked flask were successively added 1,2-dichloroethane (5 mL), intermediate 7 (127 mg) and intermediate 9 (130 mg). The mixture was reacted at room temperature for 18 h. Then sodium triacetoxyborohydride (438.72 mg) was added, and the system was successively reacted at room temperature for 18 h. After the reaction was completed, dichloromethane (10 mL) was added for dilution, followed by a wash with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was separated and purified by a silica gel column (methanol:dichloromethane=1:10) to give intermediate 10 (50 mg, yield: 14.58%). MS m/z (ESI): 437.3 [M+H], RT=1.142 min.

Intermediate 11:

To a 50 mL three-necked flask were successively added tetrahydrofuran (0.5 mL), methanol (0.5 mL), water (0.5 mL), sodium hydroxide (44 mg) and intermediate 10 (50 mg). The mixture was reacted at room temperature for 18 h. After the reaction was completed, the reaction liquid was directly concentrated under reduced pressure and lyophilized to give intermediate 11 (50 mg, yield: 92%). MS m/z (ESI): 423.1 [M+H].

PAPER

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01870

The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.

a Reagents and conditions: (a) i PrMgCl·LiCl, Cbz-Cl, THF; (b) Zn, AcOH; (c) LiBH4, THF; (d) TBDPS-Cl, imidazole, DMF; (e) separation of diastereomers by flash chromatography; (f) TBAF, THF; (g) NaH, EtI, DMF; (h) Ba(OH)2, i PrOH, H2O; (i) K2CO3, MeI, DMF; (j) H2, Pd/C, MeOH; (k) (±)-50, DIPEA, DMA; (l) K2CO3, MeOH; then TMS-diazomethane, toluene, MeOH; (m) chiral SFC; (n) LiOH, H2O, MeOH, THF; (o) (2S,4S)-50, NaBH(OAc)3, DCE.

4-((2S,4S)-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl))benzoic Acid (41, LNP023). Step 1: tert-Butyl 4-(((2S,4S)-4-Ethoxy-2-(4-(methoxycarbonyl)phenyl)- piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (58). To a solution of tert-butyl 4-formyl-5-methoxy-7-methyl1H-indole-1-carboxylate (57) (1.5 g, 5.18 mmol) and methyl 4- ((2S,4S)-4-ethoxypiperidin-2-yl)benzoate ((2S,4S)-50) (1.185 g, 4.50 mmol) in DCE (20 mL) was added NaBH(OAc)3 (3 g, 14.1 mmol), and this was stirred at rt for 21.5h. Additional tert-butyl 4-formyl-5- methoxy-7-methyl-1H-indole-1-carboxylate (57) (500 mg, 1.90 mmol) was added, and this was stirred for 20 h. The reaction was diluted with EtOAc, washed successively with 5% aqueous NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated to provide the title compound (2.415 g, quant) which was used without further purification. MS (ESI+) m/z 537.4 (M + H). The absolutestereochemistry was ultimately determined via cocrystallization of 41 with the catalytic domain of FB. Step 2: 4-((2S,4S)-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl))benzoic Acid (41, LNP023). To a solution of tert-butyl 4-(((2S,4S)-4-ethoxy-2-(4-(methoxycarbonyl)phenyl)- piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (58) (2.415 g, 4.50 mmol) in THF (10 mL) and MeOH (20 mL) was added 1 M LiOH in H2O (15 mL, 15 mmol), and this was stirred at 70 °C for 8 h. The reaction was cooled to rt, diluted with H2O, half saturated aqueous KHSO4 and citric acid, saturated with sodium chloride, then extracted with 9:1 DCM/TFE, dried with Na2SO4, filtered, and concentrated. RP-HPLC-B purification provided the title compound (730 mg, 38% for 2 steps). 1 H NMR (400 MHz, D2O) δ 7.96 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 3.2 Hz, 1H), 6.66 (s, 1H), 6.20 (s, 1H), 4.62−4.47 (m, 1H), 4.06 (d, J = 13.2 Hz, 1H), 3.97−3.76 (m, 2H), 3.66−3.48 (m, 5H), 3.43−3.29 (m, 1H), 3.26−3.15 (m, 1H), 2.35 (s, 3H), 2.31−2.11 (m, 2H), 2.00 (d, J = 15.4 Hz, 1H), 1.93−1.74 (m, 1H), 1.25−1.07 (m, 3H). HRMS calcd for C25H31N2O4 (M + H)+ 423.2284, found 423.2263. 4-((2S,4S)-(4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4- yl)methyl)piperidin-2-yl))benzoic Acid Hydrochloride (41· HCl). To a solution of 41 (620 mg, 1.47 mmol) in H2O (10 mL) and acetonitrile (3 mL) was added 5 M aqueous HCl (0.5 mL, 2.5 mmol). The mixture was then lyophilized, and the resulting solid was suspended in i PrOH and heated to 70 °C. The mixture turned into a solution after 1.5 h and was then cooled to rt with stirring. After about 5 h, the mixture turned into a suspension and the solid was collected by filtration and dried under high vacuum at 50 °C to provide the title compound as the hydrochloride salt (450 mg, 65%). 1 H NMR (400 MHz, methanol-d4) δ 10.73 (s, 1H), 8.23 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.36−7.31 (m, 1H), 6.77 (s, 1H), 6.42−6.31 (m, 1H), 4.40−4.19 (m, 2H), 3.87−3.80 (m, 1H), 3.76 (s, 3H), 3.68− 3.50 (m, 4H), 3.45−3.38 (m, 1H), 2.51 (s, 3H), 2.30−2.18 (m, 2H), 2.13−1.89 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H). MS (ESI+) m/z 423.3 (M + H).

SYN
European Journal of Medicinal Chemistry 291 (2025) 117643

Iptacopan (Fabhalta®), a first-in-class oral therapeutic agent discovered by Novartis, specifically targets the complement Factor B protein within the alternative complement system. NMPA granted
marketing authorization in 2024, indicated for complement inhibitor-naïve adult patients diagnosed with paroxysmal nocturnal hemoglobinuria (PNH) [75]. By competitively binding to the catalytic domain of
Factor B, the drug effectively blocks C3 convertase assembly, thereby suppressing downstream cleavage of C3 into its active fragments. This dual inhibitory action addresses both intravascular erythrocyte
destruction and extravascular hemolytic processes characteristic of PNHpathogenesis [76]. Clinical validation emerged from the multinational APPOINT-PNH study (ClinicalTrials.gov identifier NCT04820530), where treatment-naïve participants exhibited sustained hemoglobin
stabilization (≥12 g/dL) in 79.6 % of cases, achieving transfusion in dependence over 24 weeks. Secondary endpoints revealed significant improvements in fatigue scores and health-related quality metrics [77]. Safety monitoring identified encapsulated bacterial infection as critical risks, necessitating mandatory vaccination ≥2 weeks pre-treatment. Common treatment-emergent adverse events comprised transient gastrointestinal disturbances (nausea 18.3 %, diarrhea 14.7 %) and mild
cephalgia (22.1 %), with resolution typically occurring within 4 weeks [78].
The synthetic pathway of Iptacopan, delineated in Scheme 18, initiates with nucleophilic substitution between Ipta-001 and Ipta-002, followed by Grignard coupling yielding Ipta-003 [79]. This intermedi
ate undergoes NaBH4-mediated reduction and TMSCl-induced silanization to afford Ipta-004. Acid-catalyzed TMS deprotection (HCl/MeOH) delivers Ipta-005, which progresses through sequential alkylation (methyl iodide/K2CO3 catalytic hydrogenation (H)/Pd–C), transesterification (EtONa), and to construct Ipta-006. Condensation with Ipta-007 and subsequent reduction forms Ipta-008. Strategic TFA-mediated Boc cleavage in DCM followed by HCl-induced salt formation in dioxane ultimately furnishes Iptacopan hydrochloride.

75-79

[75] Iptacopan, Drugs and Lactation Database (Lactmed®), National Institute of Child
Health and Human Development, Bethesda (MD), 2006.
[76] J.H. Jang, L. Wong, B.S. Ko, S.S. Yoon, K. Li, I. Baltcheva, P.K. Nidamarthy,
R. Chawla, G. Junge, E.S. Yap, Iptacopan monotherapy in patients with paroxysmal
nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study, Blood
Adv 6 (2022) 4450–4460.
[77] A.M. Risitano, C. de Castro, B. Han, A.G. Kulasekararaj, J.P. Maciejewski,
P. Scheinberg, Y. Ueda, S. Vallow, G. Bermann, M. Dahlke, R. Kumar, R. Peffault de
Latour, Patient-reported improvements in patients with PNH treated with
iptacopan from two phase 3 studies, Blood Adv 9 (2025) 1816–1826.
[78] C.M. de Castro, B.J. Patel, Iptacopan for the treatment of paroxysmal nocturnal
hemoglobinuria, Expert Opin Pharmacother 25 (2024) 2331–2339.
[79] N. Mainolfi, T. Ehara, R.G. Karki, K. Anderson, A. Mac Sweeney, S.M. Liao, U.
A. Argikar, K. Jendza, C. Zhang, J. Powers, D.W. Klosowski, M. Crowley,
T. Kawanami, J. Ding, M. April, C. Forster, M. Serrano-Wu, M. Capparelli,
R. Ramqaj, C. Solovay, F. Cumin, T.M. Smith, L. Ferrara, W. Lee, D. Long,
M. Prentiss, A. De Erkenez, L. Yang, F. Liu, H. Sellner, F. Sirockin, E. Valeur,
P. Erbel, D. Ostermeier, P. Ramage, B. Gerhartz, A. Schubart, S. Flohr, N. Gradoux,
R. Feifel, B. Vogg, C. Wiesmann, J. Maibaum, J. Eder, R. Sedrani, R.A. Harrison,
M. Mogi, B.D. Jaffee, C.M. Adams, Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-
methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (LNP023), a
factor B inhibitor specifically designed to be applicable to treating a diverse array
of complement mediated diseases, J. Med. Chem. 63 (2020) 5697–5722.

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Clinical data


Trade names	Fabhalta
Other names	LNP023
AHFS/Drugs.com	Fabhalta
License data	US DailyMed: Iptacopan
Routes of administration	By mouth
Drug class	Complement factor B inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1644670-37-0
PubChem CID	90467622
DrugBank	DB16200
ChemSpider	75533872
UNII	8E05T07Z6W
KEGG	D12251 D12252
ChEMBL	ChEMBL4594448
PDB ligand	JGQ (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₂₅H₃₀N₂O₄
Molar mass	422.525 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Fabhalta- iptacopan capsule”. DailyMed. 5 December 2023. Archived from the original on 10 December 2023. Retrieved 10 December 2023.
^ “Novartis receives FDA approval for Fabhalta (iptacopan), offering superior hemoglobin improvement in the absence of transfusions as the first oral monotherapy for adults with PNH”. Novartis (Press release). Archived from the original on 12 December 2023. Retrieved 6 December 2023.
^ “Novel Drug Approvals for 2023”. U.S. Food and Drug Administration (FDA). 6 December 2023. Archived from the original on 21 January 2023. Retrieved 10 December 2023.
^ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/218276Orig1s000ltr.pdf Archived 10 December 2023 at the Wayback Machine This article incorporates text from this source, which is in the public domain.
^ Jang JH, Wong L, Ko BS, Yoon SS, Li K, Baltcheva I, et al. (August 2022). “Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study”. Blood Advances. 6 (15): 4450–4460. doi:10.1182/bloodadvances.2022006960. PMC 9636331. PMID 35561315.
^ “Novartis Phase III APPOINT-PNH trial shows investigational oral monotherapy iptacopan improves hemoglobin to near-normal levels, leading to transfusion independence in all treatment-naïve PNH patients”. Novartis (Press release). Archived from the original on 12 December 2023. Retrieved 6 September 2023.
^ Schubart A, Anderson K, Mainolfi N, Sellner H, Ehara T, Adams CM, et al. (April 2019). “Small-molecule factor B inhibitor for the treatment of complement-mediated diseases”. Proceedings of the National Academy of Sciences of the United States of America. 116 (16): 7926–7931. Bibcode:2019PNAS..116.7926S. doi:10.1073/pnas.1820892116. PMC 6475383. PMID 30926668.

External links

Clinical trial number NCT04558918 for “Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment (APPLY-PNH)” at ClinicalTrials.gov
Clinical trial number NCT04820530 for “Study of Efficacy and Safety of Twice Daily Oral Iptacopan (LNP023) in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy (APPOINT-PNH)” at ClinicalTrials.gov

///////Iptacopan, fda 2023, approvals, 2023, paroxysmal nocturnal hemoglobinuria, 12/5/2023, Fabhalta , LNP 023, LNP-023, LNP023, NVP-LNP023, NVP-LNP023-NX

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Terlipressin acetate

September 22, 2022 2:47 am / Leave a comment

Terlipressin acetate

テルリプレシン酢酸塩

C52H74N16O15S2. (C2H4O2)x

CAS: 914453-96-6 ACETATEFREE FORM 14636-12-5

Terlipressin acetate (JAN);
Heamopressin (TN);
Terlivaz (TN)

Cardiovascular agent

Antidiuretic, Vasoconstrictor, Arginine vasopressin receptor agonist

USFDA APPROVED 2022/9/14

An inactive peptide prodrug that is slowly converted in the body to lypressin. It is used to control bleeding of ESOPHAGEAL VARICES and for the treatment of HEPATORENAL SYNDROME.

SVG Image
IUPAC Condensed	H-Gly-Gly-Gly-Cys(1)-Tyr-Phe-Gln-Asn-Cys(1)-Pro-Lys-Gly-NH2.CH3CO2H
Sequence	GGGCYFQNCPKG
IUPAC	glycyl-glycyl-glycyl-L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparagyl-L-cysteinyl-L-prolyl-L-lysyl-glycinamide (4->9)-disulfide acetic acid

EINECS 238-680-8
Terlipressin
Terlipressina
Terlipressina [INN-Spanish]
Terlipressine
Terlipressine [INN-French]
Terlipressinum
Terlipressinum [INN-Latin]
UNII-7Z5X49W53P

acetic acid;(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-benzyl-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(2S)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]pyrrolidine-2-carboxamide

FREE FORM

Formula:	C₅₂H₇₄N₁₆O₁₅S₂
Molecular Weight:	1227.39

14636-12-5

(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-13-benzyl-10-(2-carbamoylethyl)-7-(carbamoylmethyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(1S)-5-amino-1-(carbamoylmethylcarbamoyl)pentyl]pyrrolidine-2-carboxamide;N-(N-(N-Glycylglycyl)glycyl)-8-L-lysinevasopressin;Glypressin;Terlipressin Acetate;Remestyp;Thymosin α1 Acetate;Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2 (disulfide bridge 4:9);Glycylpressin;

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Terlipressin, sold under the brand name Terlivaz among others, is an analogue of vasopressin used as a vasoactive drug in the management of low blood pressure. It has been found to be effective when norepinephrine does not help. Terlipressin is a vasopressin receptor agonist.^[1]

Medical uses

Terlipressin is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.^[1]

Indications for use include norepinephrine-resistant septic shock^[2] and hepatorenal syndrome.^[3] In addition, it is used to treat bleeding esophageal varices.^[4]

Contraindications

Terlipressin is contraindicated in people experiencing hypoxia or worsening respiratory symptoms and in people with ongoing coronary, peripheral or mesenteric ischemia.^[1] Terlipressin may cause fetal harm when used during pregnancy.^[1]

Society and culture

Terlipressin is available in New Zealand,^[5] Australia, the European Union,^[6] India, Pakistan & UAE. It is sold under various brand names including Glypressin.

Clinical data

Trade names	Terlivaz
AHFS/Drugs.com	International Drug Names
Routes of administration	Intravenous
ATC code	H01BA04 (WHO)
Legal status
Legal status	US: ℞-only ^[1]
Pharmacokinetic data
Protein binding	~30%
Identifiers
show IUPAC name
CAS Number	14636-12-5
PubChem CID	72081
DrugBank	DB02638
ChemSpider	65067
UNII	7Z5X49W53P
KEGG	D06672
CompTox Dashboard (EPA)	DTXSID7048952
ECHA InfoCard	100.035.149
Chemical and physical data
Formula	C₅₂H₇₄N₁₆O₁₅S₂
Molar mass	1227.38 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
(verify)

References

^ Jump up to:^a ^b ^c ^d ^e “Archived copy” (PDF). Archived (PDF) from the original on 2022-09-19. Retrieved 2022-09-19.
^ O’Brien A, Clapp L, Singer M (2002). “Terlipressin for norepinephrine-resistant septic shock”. Lancet. 359 (9313): 1209–10. doi:10.1016/S0140-6736(02)08225-9. PMID 11955542. S2CID 38463837.
^ Uriz J, Ginès P, Cárdenas A, Sort P, Jiménez W, Salmerón J, Bataller R, Mas A, Navasa M, Arroyo V, Rodés J (2000). “Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome”. J Hepatol. 33 (1): 43–8. doi:10.1016/S0168-8278(00)80158-0. PMID 10905585.
^ Ioannou G, Doust J, Rockey D (2003). Ioannou GN (ed.). “Terlipressin for acute esophageal variceal hemorrhage”. Cochrane Database Syst Rev (1): CD002147. doi:10.1002/14651858.CD002147. PMC 7017851. PMID 12535432.
^ http://www.medsafe.govt.nz/profs/datasheet/g/Glypressin01mgmlFerringinj.pdf Archived 2021-12-20 at the Wayback Machine^{[bare URL PDF]}
^ “Terlipressin”. Archived from the original on 2019-06-26. Retrieved 2018-01-23.

External links

“Terlipressin”. Drug Information Portal. U.S. National Library of Medicine.

////Terlipressin acetate, テルリプレシン酢酸塩 , FDA 2022, APPROVALS

2022, CC(=O)O.C1CC(N(C1)C(=O)C2CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N2)CC(=O)N)CCC(=O)N)CC3=CC=CC=C3)CC4=CC=C(C=C4)O)NC(=O)CNC(=O)CNC(=O)CN)C(=O)NC(CCCCN)C(=O)NCC(=O)N

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RPL 554, Ensifentrine

August 25, 2016 1:59 am / Leave a comment

RPL-554, Ensifentrine

Molecular FormulaC₂₆H₃₁N₅O₄
Average mass477.555

FDA 6/26/2024, Ohtuvayre, To treat chronic obstructive pulmonary disease
Drug Trials Snapshot

RPL 554

Urea, N-[2-[(2E)-6,7-dihydro-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl]ethyl]-

(2-[(2E)-9,10-DIMETHOXY-4-OXO-2-[(2,4,6-TRIMETHYLPHENYL)IMINO]-2H,3H,4H,6H,7H-PYRIMIDO[4,3-A]ISOQUINOLIN-3-YL]ETHYL)UREA

2-[9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-3-yl]ethylurea

{2-[(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-2H,3H,4H,6H,7H-pyrimido[4,3-a]isoquinolin-3-yl]ethyl}urea

2-[4-keto-9,10-dimethoxy-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[4,3-a]isoquinolin-3-yl]ethylurea

2-[9,10-dimethoxy-4-oxo-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[4,3-a]isoquinolin-3-yl]ethylurea

298680-25-8 CAS

UNII:3E3D8T1GIX

CFTR stimulator; PDE 3 inhibitor; PDE 4 inhibitor

RPL-554 is a mixed phosphodiesterase (PDE) III/IV inhibitor in phase II clinical development at Verona Pharma for the treatment of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD) and inflammation.

RPL-554 is expected to have long duration of action and will be administered nasally thereby preventing gastrointestinal problems often resulting from orally administered PDE4 antiinflammatory drugs.

The company is now seeking licensing agreements or partnerships for the further development and commercialization of the drug.

RPL-554 (LS-193,855) is a drug candidate for respiratory diseases. It is an analog of trequinsin, and like trequinsin, is a dual inhibitor of the phosphodiesterase enzymes PDE-3 and PDE-4.^[1] As of October 2015, inhaled RPL-554 delivered via a nebulizer was in development for COPD and had been studied in asthma.^[2]

PDE3 inhibitors act as bronchodilators, while PDE4 inhibitors have an anti-inflammatory effect.^[1]^[3]

RPL554 was part of a family of compounds invented by Sir David Jack, former head of R&D for GlaxoSmithKline, and Alexander Oxford, a medicinal chemist; the patents on their work were assigned to Vernalis plc.^[4]^[5]^:19-20

In 2005, Rhinopharma Ltd, acquired the rights to the intellectual property from Vernalis.^[5]^:19-20 Rhinopharma was a startup founded in Vancouver, Canada in 2004 by Michael Walker, Clive Page, and David Saint, to discover and develop drugs for chronic respiratory diseases,^[5]^:16 and intended to develop RPL-554, delivered with an inhaler, first for allergic rhinitis, then asthma, then forCOPD.^[5]^:16-17 RPL554 was synthesized at Tocris, a contract research organization, under the supervision of Oxford, and was studied in collaboration with Page’s lab at King’s College, London.^[1] In 2006 Rhinopharma recapitalized and was renamed Verona Pharma plc.^[5]

This was first seen in April 2015 when it was published as a France national. Verona Pharma (formerly Rhinopharma), under license from Kings College via Vernalis, is developing the long-acting bronchodilator, RPL-554 the lead in a series dual inhibitor of multidrug resistant protein-4 and PDE 3 and 4 inhibiting trequinsin analogs which included RPL-565, for treating inflammatory respiratory diseases, such as allergic rhinitis, asthma, and COPD.

RPL554

Verona Pharma’s lead drug, RPL554, is a “first-in-class” inhaled drug under development for chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis. The drug is an inhibitor of the phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) enzymes, two enzymes known to be of importance in the development and progression of immunological respiratory diseases. The drug has the potential to act as both a bronchodilator and an anti-inflammatory which would significantly differentiate it from existing drugs.

RPL554 was selected from a class of compounds co-invented by Sir David Jack, the former Director of Research at Glaxo who led the team that discovered many of the commercially successful drugs in the respiratory market.

Verona Pharma has successfully completed two double-blind placebo controlled randomised Phase 2b studies of RPL554: one in mild to moderate asthma and another in mild to moderate COPD. The drug was found to be well tolerated, free from drug-related adverse effects (especially cardiovascular and gastro-intestinal effects) and generated significant bronchodilation. Additionally, double-blind placebo controlled exploratory studies in healthy volunteers challenged with an inhaled irritant also generated consistent, clinically meaningful anti-inflammatory effects.

Verona Pharma is also carrying out exploratory studies to investigate the potential of RPL554 as a novel treatement for cystic fibrosis. In November 2014, the Company received a Venture and Innovation Award from the UK Cystic Fibrosis Trust to further such studies.

For further information on the potential of RPL554 for the treatment of respiratory diseases, refer to the peer-reviewed paper available on-line in the highly-respected medication journal, The Lancet Respiratory Medicine, entitled “Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials”.

The competitive advantages of RPL554 include the following:

combining bronchodilator (PDE 3) and anti-inflammatory actions (PDE 4) in a single drug, something that is currently only achieved with a combination LABA and glucocorticosteroid inhaler,
unique in not using steroids or beta agonists, which have known side effects,
planned to be administered by nasal inhalation, thereby reducing the unwanted gastrointestinal side effects of many orally administered drugs.

History of Clinical Trials

Following completion in May 2008 of toxicological studies of RPL554, the Company commenced in February 2009 a Phase I/IIa clinical trial of the drug at the Centre for Human Drug Research (CHDR) at Leiden in the Netherlands. In September 2009, the Company announced that it had successfully completed the trial, demonstrating that RPL554 has a good safety profile and has beneficial effects in terms of bronchodilation and bronchoprotection in asthmatics and a reduction in the numbers of inflammatory cells in the nasal passages of allergic rhinitis patients.
In November 2010, the Company successfully completed a further trial that examined the safety and bronchodilator effectiveness of the drug administered at higher doses.
In August 2011, the Company demonstrated that bronchodilation is maintained over a period of 6 days with daily dosing of RPL554 in asthmatics.
In November 2011, the Company successfully demonstrated safety and bronchodilation of RPL554 in patients with mild to moderate forms of COPD.
In March 2013, the Company demonstrated positive airway anti-inflammatory activity with respect to COPD at a clinical trial carried out at the Medicines Evaluation Unit (MEU) in Manchester, UK.

Synthesis

WO 2000058308

Cyclization of 1-(3,4-dimethoxyphenethyl)barbituric acid in refluxing POCl3 produces the pyrimidoisoquinolinone , which is further condensed with 2,4,6-trimethylaniline in boiling isopropanol to afford the trimethylphenylimino derivative . Subsequent alkylation of with N-(2-bromoethyl)phthalimide in the presence of K2CO3 and KI, followed by hydrazinolysis of the resulting phthalimidoethyl compound yields the primary amine . This is finally converted into the title urea RPL 554 by reaction with sodium cyanate in aqueous HCl.

Example 1 : 9 Λ 0-Dimethoxy-2-(2.4-6-trimethy-phen yliminoY-3-(N-carbamoyl-2- aminoethylV3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one

Sodium cyanate (6.0g, 0.092 mol) in water (100 ml) was added dropwise to a stirred solution of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7- tetrahydro-2H-pyrimido[6,l-a]isoquinolin-4-one, prepared according to Preparation 4 above (20.0g, 0.046 mol) in water (600 ml) and IN ΗC1 (92 ml) at 80°C. After stirring for 2h at 80°C the mixture was cooled in an ice-bath and basified with 2N NaOH. The mixture was extracted with dichloromethane (3 x 200 ml) and the combined extract was dried (MgSO- ) and evaporated in vacuo. The resulting yellow foam was purified by column chromatography on silica gel eluting with CH2CI2 / MeOH (97:3) and triturated with ether to obtain the title compound as a yellow solid, 11.9g, 54%.

M.p.: 234-236°C m/z: C26H31N5O4 requires M=477 found (M+l) = 478

HPLC: Area (%) 99.50 Column ODS (150 x 4.6 mm)

MP pH3 KH₂PO₄ / CH3CN (60/40)

FR (ml/min) 1.0 RT (min) 9.25 Detection 250 nm

^lK NMR (300 MHz, CDCI3): δ 1.92 (1H, br s, NH), 2.06 (6H, s, 2xCH₃), 2.29 (3H, s, CH₃), 2.92 (2H, t, CH₂), 3.53 (2H, m, CH₂), 3.77 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.05 (2H, t, CH₂), 4.40 (2H, t, CH₂), 5.35 (2H, br s, NH₂), 5.45 (1H, s, C=CH), 6.68 (1H, s, ArH), 6.70 (1H, s, ArH), 6.89 (2H, s, 2xArH).

Preparation 1 : Synthesis of 2-Chloro-6.7-d-hydro-9.10-Dimethoxy-4H-pyrimido- [6,l-a]isoquinoHn-4-one (shown as (1) in Figure 1

A mixture of l-(3,4-dimethoxyphenyl) barbituric acid (70g, 0.24mol), prepared according to the method described in B. Lai et al. J.Med.Chem. 27 1470-1480 (1984), and phosphorus oxychloride (300ml, 3.22mol) was refluxed for 2.5h. The excess phosphorous oxychloride was removed by distillation (20mmHg) on wa ming. After cooling the residue was slurried in dioxan (100ml) and cautiously added to a vigorously stirred ice/water solution (11). Chloroform (11) was added and the resulting mixture was basified with 30% sodium hydroxide solution. The organic layer was separated and the aqueous phase further extracted with chloroform (2x750ml). The combined organic extracts were washed with water (1.51), dried over magnesium sulphate and concentrated in vacuo to leave a gummy material (90g). This was stirred in methanol for a few minutes, filtered and washed with methanol (200ml), diethyl ether (2x200ml) and dried in vacuo at 40°C to yield the title compound as a yellow/orange solid. 47g, 62%

(300MHz, CDCI3) 2.96(2H, t, C(₇) H₂); 3.96(6H, s, 2xOCH₃; 4.20(2H, t, C(₆₎ H₂); 6.61(1H, s, C₍₁₎ H); 6.76(1H, s, Ar-H); 7.10(1H, s, Ar-H). Preparation 2: 9.10-Dimethoxy-2-(2.4.6-trimethylphenyliminoV3.4.6.7- tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one (shown as (2) in Figure 1

2-Chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-4-one, prepared according to Preparation 1, (38.5g, 0.13 mol) and 2,4,6-trimethylaniline (52.7g, 0.39 mol) in propan-2-ol (3 1) was stirred and heated at reflux, under nitrogen, for 24h. After cooling to room temperature, the solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel, eluting with CΗ2CI2 /

MeOH, initially 98:2, changing to 96:4 once the product began to elute from the column. The title compound was obtained with a slight impurity, (just above the product on tic). Yield 34.6g, 67%.

Preparation 3: 9.10-Dimethoxy-2-(2.4.6-trimethylphenyliminoV3-(2-N- phthalimidoethyπ-3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquinolin-4-one

(shown as (3 in Figure 1)

A mixture of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3,4,6,7-tetrahydro-2H- pyrimido[6,l-a]isoquinolin-4-one (which was prepared according to Preparation 2) (60.0g, 0.153 mol), potassium carbonate (191g, 1.38 mol), sodium iodide (137g, 0.92 mol) and N-(2-bromoethyl)phthalimide (234g, 0.92 mol) in 2-butanone (1500 ml) was stirred and heated at reflux, under nitrogen, for 4 days. After cooling to room temperature the mixture was filtered and the filtrate was evaporated in vacuo. The residue was treated with methanol (1000 ml) and the solid filtered off, washed with methanol and recrystallised from ethyl acetate to obtain the title compound as a pale yellow solid in yield 40. Og, 46%. Evaporation of the mother liquor and column chromatography of the residue on silica gel (CΗ2C-2 / MeOH 95:5) provided further product 11.7g, 13.5%. Preparation 4: 9.10-Dimethoxy-2-(2A6-trimethylphenylimino)-3-(2-arninoethyO- 3.4.6.7-tetrahydro-2H-pyrimido[6.1-a]isoquino-in-4-one (shown as (4) in Figure 1)

A mixture of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-N- phthalimidoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,l-a]isoquinolin-4-one (22. Og, 0.039 mol), prepared according to Preparation 3, and hydrazine hydrate (11.3g, 0.195 mol) in chloroform (300 ml) and ethanol (460 ml) was stined at room temperature, under nitrogen, for 18h. Further hydrazine hydrate (2.9g, 0.05 mol) was added and the mixture was stirred a further 4h. After cooling in ice / water, the solid was removed by filtration and the filtrate evaporated in vacuo. The residue was dissolved in dichloromethane and the insoluble material was removed by filtration. The fitrate was dried (MgSO-i) and evaporated in vacuo to afford the title compound as a yellow foam in yield 16.2g, 96%.

PATENT

WO-2016128742

Novel crystalline acid addition salts forms of RPL-554 are claimed, wherein the salts, such as ethane- 1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid. .

RPL554 (9, 10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(/V-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6, l-a]isoquinolin-4-one) is a dual PDE3/PDE4 inhibitor and is described in WO 00/58308. As a combined PDE3/PDE4 inhibitor, RPL554 has both antiinflammatory and bronchodilatory activity and is useful in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). The structure of RPL554 is shown below.

Owing to its applicability in the treatment of respiratory disorders, it is often preferable to administer RPL554 by inhalation. Franciosi et al. disclose a solution of RPL554 in a citrate-phosphate buffer at pH 3.2 (The Lancet: Respiratory Medicine 11/2013; l(9):714-27. DOI: 10.1016/S2213-2600(13)70187-5). The preparation of salts of RPL554 has not been described.

PATENT

http://www.google.ch/patents/WO2000058308A1?cl=en&hl=de

PATENT

http://www.google.ch/patents/WO2012020016A1?cl=en

U.S. Pat. No. 6,794,391, 7,378,424, and 7,105,663, which are each incorporated herein by reference, discloses compound RPL-554 (N-{2-[(2iT)-2-(mesityiimino)-9,10- dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,l-a]-isoquinolin-3 4H)-yl]ethyl}urea).

It would be beneficial to provide a composition of a stable polymorph of RPL-554, that has advanrtages over less stable polymorphs or amorphous forms, including

stability, compressibility, density, dissolution rates, increased potency or. lack toxicity.

WO2000058308A1 *	Mar 29, 2000	Oct 5, 2000	Vernalis Limited	DERIVATIVES OF PYRIMIDO[6,1-a]ISOQUINOLIN-4-ONE
US6794391	Sep 26, 2001	Sep 21, 2004	Vernalis Limited	Derivatives of pyrimido[6.1-a]isoquinolin-4-one
US7105663	Feb 24, 2004	Sep 12, 2006	Rhinopharma Limited	Derivatives of pyrimido[6,1-a]isoquinolin-4-one
US7378424	Feb 24, 2004	May 27, 2008	Verona Pharma Plc	Derivatives of pyrimido[6, 1-A]isoquinolin-4-one

Patent ID	Date	Patent Title
US7378424	2008-05-27	Derivatives of pyrimido[6, 1-A]isoquinolin-4-one
US7105663	2006-09-12	Derivatives of pyrimido[6, 1-a]isoquinolin-4-one
US6794391	2004-09-21	Derivatives of pyrimido[6.1-a]isoquinolin-4-one
US2004001895	2004-01-01	Combination treatment for depression and anxiety
US2003235631	2003-12-25	Combination treatment for depression and anxiety

Patent ID	Date	Patent Title
US2015210655	2015-07-30	CERTAIN (2S)-N-[(1S)-1-CYANO-2-PHENYLETHYL]-1, 4-OXAZEPANE-2-CARBOXAMIDES AS DIPEPTIDYL PEPTIDASE 1 INHIBITORS
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US2011201665	2011-08-18	Compositions, Methods, and Kits for Treating Influenza Viral Infections
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WO2012020016A1 *	9. Aug. 2011	16. Febr. 2012	Verona Pharma Plc	Crystalline form of pyrimidio[6,1-a]isoquinolin-4-one compound
WO2014140647A1	17. März 2014	18. Sept. 2014	Verona Pharma Plc	Drug combination
WO2014140648A1	17. März 2014	18. Sept. 2014	Verona Pharma Plc	Drug combination
WO2015173551A1 *	11. Mai 2015	19. Nov. 2015	Verona Pharma Plc	New treatment
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References

Boswell-Smith V et al. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J Pharmacol Exp Ther. 2006 Aug;318(2):840-8. PMID 16682455
Nick Paul Taylor for FierceBiotech. October 1, 2015 Verona sets sights on PhIIb after COPD drug comes through early trial
Turner MJ et al. The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia. Am J Physiol Lung Cell Mol Physiol. 2016 Jan 1;310(1):L59-70. PMID 26545902
Jump up^ see US20040171828, identified in the citations of PMID 16682455
ISIS Resources, PLC. August 23, 2006 Proposed Acquisition of Rhinopharma

REFERENCES

1: Calzetta L, Cazzola M, Page CP, Rogliani P, Facciolo F, Matera MG. Pharmacological characterization of the interaction between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on human isolated bronchi and small airways. Pulm Pharmacol Ther. 2015 Jun;32:15-23. doi: 10.1016/j.pupt.2015.03.007. Epub 2015 Apr 18. PubMed PMID: 25899618.

2: Franciosi LG, Diamant Z, Banner KH, Zuiker R, Morelli N, Kamerling IM, de Kam ML, Burggraaf J, Cohen AF, Cazzola M, Calzetta L, Singh D, Spina D, Walker MJ, Page CP. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med. 2013 Nov;1(9):714-27. doi: 10.1016/S2213-2600(13)70187-5. Epub 2013 Oct 25. PubMed PMID: 24429275.

3: Wedzicha JA. Dual PDE 3/4 inhibition: a novel approach to airway disease? Lancet Respir Med. 2013 Nov;1(9):669-70. doi: 10.1016/S2213-2600(13)70211-X. Epub 2013 Oct 25. PubMed PMID: 24429260.

4: Calzetta L, Page CP, Spina D, Cazzola M, Rogliani P, Facciolo F, Matera MG. Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther. 2013 Sep;346(3):414-23. doi: 10.1124/jpet.113.204644. Epub 2013 Jun 13. PubMed PMID: 23766543.

5: Gross N. The COPD pipeline XX. COPD. 2013 Feb;10(1):104-6. doi: 10.3109/15412555.2013.766103. PubMed PMID: 23413896.

6: Gross NJ. The COPD Pipeline XIV. COPD. 2012 Feb;9(1):81-3. doi: 10.3109/15412555.2012.646587. PubMed PMID: 22292600.

7: Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6, 7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquino lin-4-one]. J Pharmacol Exp Ther. 2006 Aug;318(2):840-8. Epub 2006 May 8. PubMed PMID: 16682455.

RPL-554
Systematic (IUPAC) name

N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea
Identifiers
PubChem	CID 9934746
ChemSpider	8110374
Synonyms	9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one
Chemical data
Formula	C₂₆H₃₁N₅O₄
Molar mass	477.554 g/mol

///////////RPL-554, LS-193,855, 298680-25-8, UNII:3E3D8T1GIX, RPL554, RPL 554, phase 2, Chronic Obstructive Pulmonary Diseases , COPD, Allergic Rhinitis, Asthma Therapy, Cystic Fibrosis, Inflammation, Bronchodilators

Cc3cc(C)cc(C)c3N=c2cc1-c(cc4OC)c(cc4OC)CCn1c(=O)n2CCNC(N)=O

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