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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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BMS 986236
BMS-986236
CAS 2058035-15-5
MW C22 H25 N9 O
MF 431.49
1-(5-(4-(3-Hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
1H-Pyrazolo[3,4-b]pyridine-5-carbonitrile, 1-[5-[4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl]-4-[(1-methylethyl)amino]-2-pyridinyl]-
1-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(propan-2-ylamino)pyridin-2-yl]pyrazolo[3,4-b]pyridine-5-carbonitrile
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The present invention generally relates to heteroaryl substituted aminopyridine compounds useful as kinase inhibitors, including the modulation of IRAK-4. Provided herein are heteroaryl substituted aminopyridine compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to kinase modulation and methods of inhibiting the activity of kinases, including IRAK-4 in a mammal.
|
PATENT
US2018186799
https://patentscope.wipo.int/search/en/detail.jsf?docId=US222843237&tab=PCTDESCRIPTION&maxRec=1000
PATENT
Gardner, D. S.; Santella, J. B.; Paidi, V. R.; Wu, H.; Duncia, J. V.; Nair, S. K.; Hynes, J. (BMS, USA). Heteroaryl Substituted Aminopyridine Compounds. PCT Int. Appl. WO/2016/210034 A1, 2016.
https://patents.google.com/patent/WO2016210034A1/en
Clip
https://pubs.acs.org/doi/10.1021/acs.oprd.9b00023
Development of a Scalable Synthesis for the Potent Kinase Inhibitor BMS-986236; 1-(5-(4-(3-Hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
, Richard Rampulla‡, Muthalagu Vetrichelvan*† , Anuradha Gupta† , Arun Kumar Gupta†, and Arvind Mathur‡
A scalable route to 1-(5-(4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1, BMS-986236) was developed by incorporating an alternate azide intermediate following safety-driven processes. The newly developed process involved mitigating safety hazards and eliminating the column chromatography purification. The issue of trace metal contamination in the final API observed in the first-generation synthesis has been overcome.
1 (92.5 g, 73% yield, 99.5% purity by HPLC) as a cream-colored solid.
1H NMR (400 MHz, DMSO-d6) δ = 9.21–8.86 (m, 2H), 8.66 (s, 1H), 8.45–8.24 (m, 2H), 7.49 (s, 1H), 6.57 (d, J = 7.5 Hz, 1H), 4.33 (s, 1H), 3.83 (d, J = 7.0 Hz, 1H), 2.91–2.72 (m, 2H), 1.97–1.68 (m, 2H), 1.24 (d, J = 6.5 Hz, 12H).
13C NMR (100 MHz, DMSO) δ = 151.7, 150.8, 149.8, 147.9, 147.7, 143.7, 136.8, 136.3, 122.9, 118.9, 117.6, 116.0, 102.8, 99.4, 68.4, 43.6, 42.7, 29.2, 21.7, 20.2.
HRMS [M + H]+ calcd for C22H25N9O 432.2255, found 432.2259.
//////// BMS-986236, BMS 986236
CC(C)(O)CCc1cn(nn1)c2cnc(cc2NC(C)C)n4ncc3cc(cnc34)C#N
Acefylline
Acefylline
- Molecular FormulaC9H10N4O4
- Average mass238.200 Da
Acefylline (INN),[1] also known as acetyloxytheophylline, is a stimulant drug of the xanthine chemical class. It acts as an adenosine receptor antagonist. It is combined with diphenhydramine in the pharmaceutical preparation etanautine to help offset diphenhydramine induced drowsiness.[2]
Synthesis
DE 352980 (1922 to E. Merck); Frdl. 14, 1320; S. M. Ride et al., Pharmazie 32, 672 (1977).
Acefylline
- Use:cardiotonic, diuretic, antispasmodic, bronchodilator
- Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid
- Formula:C9H10N4O4
- MW:238.20 g/mol
- CAS-RN:652-37-9
- EINECS:211-490-2
- LD50:1180 mg/kg (M, i.p.); 2733 mg/kg (M, p.o.)
Acepifylline
- Use:
- Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid compd. with piperazine
- Formula:C9H10N4O4 • xC4H10N2
- MW:unspecified
- CAS-RN:18833-13-1
- EINECS:242-614-3
Acefylline heptaminol
- Use:
- Chemical name:1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7-acetic acid compd. with 6-amino-2-methyl-2-heptaminol (1:1)
- Formula:C9H10N4O3 • C8H19NO
- MW:367.45 g/mol
- CAS-RN:59989-20-7
- EINECS:262-012-4
References
- ^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 21” (PDF). World Health Organization. Retrieved 29 December 2016.
- ^ Zuidema, Jan. (1978). “Biofarmaceutische en farmacokinetische aspecten van theofylline en acefylline”. Thesis (doctoral)–Universiteit van Amsterdam. References
Baisse, J.: Bull. Soc. Chim. Fr. (BSCFAS) 1949, 769.
DE 352 980 (E. Merck; 1922).
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| Clinical data | |
|---|---|
| ATC code | |
| Identifiers | |
| CAS Number | |
| PubChemCID | |
| ChemSpider | |
| UNII | |
| ChEMBL | |
| ECHA InfoCard | 100.010.447  |
| Chemical and physical data | |
| Formula | C9H10N4O4 |
| Molar mass | 238.20 g/mol g·mol−1 |
| 3D model (JSmol) | |
////////Acefylline
DESLORATADINE, デスロラタジン
Desloratadine
- Molecular FormulaC19H19ClN2
- Average mass310.821 Da
Desloratadine (trade name Clarinex and Aerius) is a tricyclic H1-antihistamine that is used to treat allergies. It is an active metaboliteof loratadine.
It was patented in 1984 and came into medical use in 2001.[1]
Medical uses
Desloratadine is used to treat allergic rhinitis, nasal congestion and chronic idiopathic urticaria (hives).[2] It is the major metabolite of loratadine and the two drugs are similar in safety and effectiveness.[2] Desloratadine is available in many dosage forms and under many trade names worldwide.[3]
An emerging indication for desloratadine is in the treatment of acne, as an inexpensive adjuvant to isotretinoin and possibly as maintenance therapy or monotherapy.[4][5]
Side effects
The most common side-effects are fatigue, dry mouth, and headache.[2]
Interactions
A number of drugs and other substances that are prone to interactions, such as ketoconazole, erythromycin and grapefruit juice, have shown no influence on desloratadine concentrations in the body. Desloratadine is judged to have a low potential for interactions.[6]
Pharmacology
Pharmacodynamics
Desloratadine is a selective H1–antihistamine which functions as an inverse agonist at the histamine H1 receptor.[7]
At very high doses, is also an antagonist at various subtypes of the muscarinic acetylcholine receptors. This effect is not relevant for the drug’s action at therapeutic doses.[8]
Pharmacokinetics
Desloratadine is well absorbed from the gut and reaches highest blood plasma concentrations after about three hours. In the bloodstream, 83 to 87% of the substance are bound to plasma proteins.[6]
Desloratadine is metabolized to 3-hydroxydesloratadine in a three-step sequence in normal metabolizers. First, n-glucuronidation of desloratadine by UGT2B10; then, 3-hydroxylation of desloratadine N-glucuronide by CYP2C8; and finally, a non-enzymatic deconjugation of 3-hydroxydesloratadine N-glucuronide.[9] Both desloratadine and 3-hydroxydesloratadine are eliminated via urine and feces with a half-life of 27 hours in normal metabolizers.[6][10]
3-Hydroxydesloratadine, the main metabolite
It exhibits only peripheral activity since it does not readily cross the blood-brain barrier; hence, it does not normally cause drowsiness because it does not readily enter the central nervous system.[11]
Desloratadine does not have a strong effect on a number of tested enzymes in the cytochrome P450 system. It was found to weakly inhibit CYP2B6, CYP2D6, and CYP3A4/CYP3A5, and not to inhibit CYP1A2, CYP2C8, CYP2C9, or CYP2C19. Desloratadine was found to be a potent and relatively selective inhibitor of UGT2B10, a weak to moderate inhibitor of UGT2B17, UGT1A10, and UGT2B4, and not to inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15, UGT1A7, and UGT1A8.[9]
Pharmacogenomics
2% of Caucasian people and 18% of people from African descent are desloratadine poor metabolizers. In these people, the drug reaches threefold highest plasma concentrations six to seven hours after intake, and has a half-life of about 89 hours. However, the safety profile for these subjects is not worse than for extensive (normal) metabolizers.[6][10]
Clip
https://www.beilstein-journals.org/bjoc/articles/9/265
The value of substituted 3-picoline precursors is illustrated in the synthesis of clarinex (1.22, Desloratadine, Scheme 5), a dual antagonist of platelet activating factor (PAF) and of histamine used in the treatment of allergies. This compound consists of a highly functional tricyclic core with an unsaturated linkage to a pendant piperidine ring. The picoline derivative 1.23 is first treated with two equivalents of n-butyllithium (n-BuLi) followed by alkylation with benzyl chloride to give the chain elongated adduct [27]. The tert-butylamide 1.24 is then dehydrated with phosphorous oxychloride at elevated temperatures to yield the nitrile derivative 1.25. Introduction of the piperidine ring is achieved by utilisation of the appropriately substituted Grignard reagent 1.26. A Friedel–Crafts type acylation promoted by either triflic acid or polyphosphoric acid (PPA) furnishes the tricyclic structure 1.28 which upon N-demethylation affords clarinex (1.22).
CLIP
FTIR
SYN
Alcoholysis of 3-methylpyridine-2-carbonitrile (I) with hot tert-butanol and H2SO4 gives the N-tert-butylcarboxamide (II), which is alkylated with 3-chlorobenzyl chloride (III) and BuLi in THF, yielding N-tert-butyl-3-[2-(3-chlorophenyl)ethyl]pyridine-2-carboxamide (IV). The reaction of (IV) with refluxing POCl3 and then with NaOH affords the corresponding nitrile (V), which is condensed with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF to give the ketone (VII). Cyclization of (VII) by means of either BF3 in HF or trifluoromethanesulfonic acid yields 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII), which is reacted with cyanogen bromide in benzene to give the N-cyano compound (IX). Finally, this compound is treated with HCl in refluxing acetic acid/water. Alternatively, 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII) is treated with ethyl chloroformate in hot toluene, affording the carbamate (X) (2), which is finally decarboxylated with KOH or NaOH in refluxing ethanol/water.
SYN
Condensation of ethyl nicotinate (XI) with 3-chlorophenylacetonitrile (XII) by means of sodium ethoxide in ethanol gives 2-(3-chlorophenyl)-3-oxo-3-(3-pyridyl)propionitrile (XIII), which by refluxing with concentrated HBr yields 2-(3-chlorophenyl)-1-(3-pyridyl)ethanone (XIV). The reduction of (XIV) with hydrazine hydrate and NaOH in diethylene glycol at 235-40 C affords 3-(2-phenylethyl) pyridine (XV), which is oxidized with H2O2 in hot acetic acid to provide the corresponding N-oxide (XVI). Reaction of (XVI) with NaCN and dimethyl sulfate in water affords the previously described 3-(2-phenylethyl)pyridine-2-carbonitrile (V), which can be worked up as previously described or cyclized with polyphosphoric acid (PPA) at 180 C to give 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (XVII). The condensation of (XVII) with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF yields the corresponding carbinol (XVIII), which is dehydrated with PPA at 170 C to afford the previously reported 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII).
SYN
|
|
| Condensation of ethyl nicotinate (XI) with 3-chlorophenylacetonitrile (XII) by means of sodium ethoxide in ethanol gives 2-(3-chlorophenyl)-3-oxo-3-(3-pyridyl)propionitrile (XIII), which by refluxing with concentrated HBr yields 2-(3-chlorophenyl)-1-(3-pyridyl)ethanone (XIV). The reduction of (XIV) with hydrazine hydrate and NaOH in diethylene glycol at 235-40 C affords 3-(2-phenylethyl) pyridine (XV), which is oxidized with H2O2 in hot acetic acid to provide the corresponding N-oxide (XVI). Reaction of (XVI) with NaCN and dimethyl sulfate in water affords the previously described 3-(2-phenylethyl)pyridine-2-carbonitrile (V), which can be worked up as previously described or cyclized with polyphosphoric acid (PPA) at 180 C to give 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (XVII). The condensation of (XVII) with 1-methylpiperidin-4-ylmagnesium chloride (VI) in THF yields the corresponding carbinol (XVIII), which is dehydrated with PPA at 170 C to afford the previously reported 8-chloro-11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (VIII). |
Syn
2) By reaction of 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (III) with the Grignard reagent (IV) to give the tertiary carbinol (V), which is dehydrated with 85% H2SO4 affording 8-chloro-11-piperidinylidene derivative (VI). Finally, cornpound (VI) is treated with ethyl chloroformate (II) in toluene.
SYN
1) By carboxylation of 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyctohepta[1,2-b]pyridine (I) with ethyl chloroformate (II) in refluxing benzene.
SYN
The condensation of S-methylisothiourea (I) with trans-4-(aminomethyl)cyclohexanecarboxylic acid (II) by means of NaOH in water gives trans-4-(guanidinomethyl)cyclohexanecarboxylic acid (III) (I), which is esterified with benzyl salicylate (IV) by means of dicyclohexylcarbodiimide (DCC) or SOCl2 yielding 2-benzyloxycarbonylphenyl trans-4-(guanidinomethyl)cyclohexanecarboxylate (V). Finally, this compound is treated with cyclodextrin in aqueous solution to afford the corresponding complex.
SPECTROSCOPY
[0052] Table 1, desloratadine sample IH-NMR data of the DMS0_d6
[0055] The desloratadine 1H spectra of the samples were assigned:
[0056] (I) 1H spectra show that there are 10 groups of hydrogen from low field to high field integral hydrogen ratio was 1: 1: 1: 1: 1: 1: 2: 4:
2: 4, and desloratadine structure match.
[0057] (2) δ 8.334 处 hydrogen as a set of double doublet, number of protons is I, attributed to two hydrogen;
[0058] (3) δ 7.560 处 hydrogen as a set of double doublet, number of protons is I, attributed to four hydrogen;
[0059] (4) δ 7.282 处 doublet hydrogen as a group, the number of protons is I, 12 attributed to hydrogen.
[0060] (5) δ 7.198 处 hydrogen as a set of double doublet, number of protons is I, 14 attributed to hydrogen;
[0061] (6) δ 7.174 处 hydrogen as a set of double doublet, number of protons is I, attributed to three hydrogen;
[0062] (7) δ 7.064 处 doublet hydrogen as a group, the number of protons is I, 15 attributed to hydrogen;
[0063] (8) δ 3.314 处 hydrogen as a group multiplet, 2 protons attributable to 10 hydrogen;
[0064] (9) δ 2.831,2.554 hydrogen groups at multiplet, protons of 4, 18, 20, the home position is hydrogen;
[0065] (10) δ 2.819 处 hydrogen as a group multiplet, 2 protons attributable to 11 hydrogen;
[0066] (11) δ 2.108 处 hydrogen as a single peak, the number of protons is I, home to 19 active hydrogen;
[0067] (12) δ 2.205, 2.002 处 two hydrogen multiplet, protons of 4, 17, 21 bits attributed to hydrogen; [0068] From the foregoing, 1H-NMR spectrum data and the resulting product in this embodiment is of he will be loratadine same structure as the target product.
http://www.google.com/patents/CN103755682A?cl=en
References
- ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 549. ISBN 9783527607495.
- ^ Jump up to:a b c See S (2003). “Desloratadine for allergic rhinitis”. Am Fam Physician. 68 (10): 2015–6. PMID 14655812.
- ^ Drugs.com Desloratadine entry at drugs.com international Page accessed May 4, 2015
- ^ Lee HE, Chang IK, Lee Y, Kim CD, Seo YJ, Lee JH, Im M (2014). “Effect of antihistamine as an adjuvant treatment of isotretinoin in acne: a randomized, controlled comparative study”. J Eur Acad Dermatol Venereol. 28 (12): 1654–60. doi:10.1111/jdv.12403. PMID 25081735.
- ^ Layton AM (2016). “Top Ten List of Clinical Pearls in the Treatment of Acne Vulgaris”. Dermatol Clin. 34 (2): 147–57. doi:10.1016/j.det.2015.11.008. PMID 27015774.
- ^ Jump up to:a b c d “Aerius: EPAR – Product Information” (PDF). European Medicines Agency. 2017-06-07.
- ^ Canonica GW, Blaiss M (2011). “Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence”. World Allergy Organ J. 4 (2): 47–53. doi:10.1097/WOX.0b013e3182093e19. PMC 3500039. PMID 23268457.
 |
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| Clinical data | |
|---|---|
| Trade names | Clarinex (US), Aerius, Dasselta, Deslordis (EU), others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a602002 |
| License data |
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| Pregnancy category |
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| Routes of administration |
Oral (tablets, solution) |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | Rapidly absorbed |
| Protein binding | 83 to 87% |
| Metabolism | UGT2B10, CYP2C8 |
| Metabolites | 3-Hydroxydesloratadine |
| Onset of action | within 1 hour |
| Elimination half-life | 27 hours |
| Duration of action | up to 24 hours |
| Excretion | 40% as conjugated metabolites into urine Similar amount into the feces |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| ECHA InfoCard | 100.166.554 |
| Chemical and physical data | |
| Formula | C19H19ClN2 |
| Molar mass | 310.82 g/mol g·mol−1 |
| 3D model (JSmol) | |
//////////Desloratadine, Descarboethoxyloratadine, Sch-34117, DCL, Denosin, Clarinex RediTabs, Allex, Desalex, Opulis, Clarinex, Neoclarityn, Aerius, MK-4117
E 2212
C25 H23 F3 N6 O, 480.48
CAS 1123197-68-1
(+) -2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
- (+)-5,6,7,8-Tetrahydro-2-[(1E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)-3-pyridinyl]ethenyl]-8-[2-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyridine
- (+)-2-[(E)-2-[5-Methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]ethenyl]-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
E2212
CAS 1123197-82-9
- C25 H23 F3 N6 O . 3/2 C4 H6 O6
- [1,2,4]Triazolo[1,5-a]pyridine, 5,6,7,8-tetrahydro-2-[(1E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]ethenyl]-8-[2-(trifluoromethyl)phenyl]-, (8S)-, (2S,3S)-2,3-dihydroxybutanedioate (2:3)
PATENT
https://patents.google.com/patent/US9453000B2/en
Examples 394 and 395 Synthesis of (+) and (−)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
230 mg of the racemic title compound was obtained from 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (343 mg) and (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid (500 mg) by the same method as in Examples 194 and 195. The racemic title compound (220 mg) was separated by CHIRALPAK™ IC manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: methanol) to obtain the title optically active compound with positive optical rotation and a retention time of 16 minutes (92 mg) and the title optically active compound with negative optical rotation and a retention time of 19 minutes (79 mg).
The property value of the title optically active compound with a retention time of 16 minutes is as follows.
ESI-MS; m/z 481 [M++H].
The property values of the title optically active compound with a retention time of 19 minutes are as follows.
ESI-MS; m/z 481 [M++H]. 1H-NMR (CDCl3) δ (ppm): 1.90-2.01 (m, 1H), 2.10-2.35 (m, 2H), 2.29 (s, 3H), 2.43-2.52 (m, 1H), 3.95 (s, 3H), 4.27-4.41 (m, 2H), 4.69 (dd, J=6.0, 8.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.08 (d, J=16.4 Hz, 1H), 7.40 (dd, J=7.6, 7.6 Hz, 1H), 7.44-7.53 (m, 4H), 7.73 (d, J=8.0 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.34 (s, 1H).
PATENT
WO2009028588
https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=D6AD22B6CC7302560AE1ADCED305CDCE.wapp2nC?docId=WO2009028588&tab=FULLTEXT&queryString=%28PA%2Feisai%29%2520&recNum=93&maxRec=725
（＋）および（－）－２－｛（Ｅ）－２－［５－メトキシ－６－（４－メチル－１Ｈ－イミダゾール－１－イル）ピリジン－３－イル］ビニル｝－８－（２－トリフルオロメチルフェニル）－５，６，７，８－テトラヒドロ－［１，２，４］トリアゾロ［１，５－ａ］ピリジンの合成
[化221]
実施例１９４および実施例１９５と同様の方法により、１－アミノ－３－（２－トリフルオロメチルフェニル）ピペリジン－２－オン（３４３ｍｇ）および（Ｅ）－３－［５－メトキシ－６－（４－メチル－１Ｈ－イミダゾール－１－イル）ピリジン－３－イル］アクリル酸（５００ｍｇ）から、ラセミ体の表題化合物を２３０ｍｇ得た。ラセミ体の表題化合物（２２０ｍｇ）をダイセル製ＣＨＩＲＡＬＰＡＫ ＴＭ ＩＣ（２ｃｍ×２５ｃｍ：移動相；メタノール）にて分取し、（＋）の旋光性を有する保持時間１６分の表題光学活性化合物（９２ｍｇ）および（－）の旋光性を有する保持時間１９分の表題光学活性化合物（７９ｍｇ）を得た。
保持時間１６分の表題光学活性体の物性値は以下の通りである。
ＥＳＩ－ＭＳ；ｍ／ｚ ４８１［Ｍ ＋＋Ｈ］．
保持時間１９分の表題光学活性体の物性値は以下の通りである。
ＥＳＩ－ＭＳ；ｍ／ｚ ４８１［Ｍ ＋＋Ｈ］． １Ｈ－ＮＭＲ（ＣＤＣｌ ３）δ（ｐｐｍ）：１．９０－２．０１（ｍ，１Ｈ），２．１０－２．３５（ｍ，２Ｈ），２．２９（ｓ，３Ｈ），２．４３－２．５２（ｍ，１Ｈ），３．９５（ｓ，３Ｈ），４．２７－４．４１（ｍ，２Ｈ），４．６９（ｄｄ，Ｊ＝６．０，８．４Ｈｚ，１Ｈ），７．０２（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．０８（ｄ，Ｊ＝１６．４Ｈｚ，１Ｈ），７．４０（ｄｄ，Ｊ＝７．６，７．６Ｈｚ，１Ｈ），７．４４－７．５３（ｍ，４Ｈ），７．７３（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），８．１３（ｄ，Ｊ＝１．６Ｈｚ，１Ｈ），８．３４（ｓ，１Ｈ）．
Example 394 and Example 395
(+) and (−)-2-{(E) -2- [5-methoxy-6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl] Synthesis of vinyl} -8- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridine [Formula
221]
Example 194 and By a method similar to Example 195, 1-amino-3- (2-trifluoromethylphenyl) piperidin-2-one (343 mg) and (E) -3- [5-methoxy-6- (4-methyl-) 1 H-Imidazol-1-yl) pyridin-3-yl] acrylic acid (500 mg) gave 230 mg of the racemic title compound. Racemic title compound (220 mg) a Daicel CHIRALPAK TM IC (2 cm × 25 cm: mobile phase; methanol) was collected by min (+) title optically active compound of the retention time of 16 minutes with a optical rotation of (92 mg) The title optically active compound (79 mg) having a polarizability of (−) and a retention time of 19 minutes was obtained.
The physical property values of the title optically active substance with a retention time of 16 minutes are as follows.
ESI-MS; m / z 481 [M + + H].
The physical property values of the title optically active substance with a retention time of 19 minutes are as follows.
ESI-MS; m / z 481 [M + + H]. 1 H-NMR (CDCl 3)) Δ (ppm): 1.90 to 2.01 (m, 1 H), 2.10 to 2.35 (m, 2 H), 2.29 (s, 3 H), 2.43 to 2.52 (m) , 1 H), 3.95 (s, 3 H), 4.27-4. 41 (m, 2 H), 4.69 (dd, J = 6.0, 8.4 Hz, 1 H), 7.02 (d , J = 8.0 Hz, 1 H), 7.08 (d, J = 16.4 Hz, 1 H), 7.40 (dd, J = 7.6, 7.6 Hz, 1 H), 7.44-7. 53 (m, 4H), 7.73 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 1.6 Hz, 1 H), 8.34 (s, 1 H).
PATENT
https://patents.google.com/patent/WO2010098490A1/it
As a novel compound that has an effect of reducing the production of Aβ40 and
42 and is expected as a therapeutic or prophylactic agent for Alzheimer’s disease or the like, the present inventors have found a compound represented by the following formula (1) (compound
(D): [Formula 1]
and filed a patent application for the invention (PCT/JP08/065365).
Generally, properties of salts of compounds and those crystals that are useful as pharmaceuticals are highly important for the development of pharmaceuticals, because the properties greatly affect bioavailability of drugs, purity of drug substances, formulation of preparations, and the like. Therefore, it is necessary to research which salts and crystal forms of the compound of the formula (1) are most excellent as pharmaceuticals. Specifically, since their properties depend on the character of the individual compounds, it is generally difficult to estimate salts and crystal forms for drug substances having excellent properties and it is demanded to actually make various studies for each compound.
EXAMPLES [0023] The present invention will be described in detail below with reference to reference examples and examples; however, the present invention is not limited to these reference examples and examples. [0024]
The following abbreviations are used in the following reference examples and examples.
DMF: N,N’-dimethylformamide
THF: Tetrahydrofuran
EDC: lrEmyl-S-β-dimemylammopropytycarbodiimide hydrochloride HOBT: 1-Hydroxybenzotriazole IPEA: Diisopropylethylamine [0025]
In powder X-ray diffractometry of the crystals produced in the following examples, the resulting crystals were placed on a sample stage of a powder X-ray diffractometer and analyzed under the following conditions. [0026] Measurement conditions
Sample holder: Aluminum Target: Copper
Detector: Scintillation counter Tube voltage: 50 kV Tube current: 300 mA
Slit: DS 0.5 mm (Height limiting slit 2 mm), SS Open, RS Open Scanning rate : 5 °/min
Sampling interval: 0.02° Scan range: 5 to 35° Goniometer: Horizontal goniometer [0027] Reference Example 1
Svnmesis ofr8SV2-(fE)-246-memoxy-5-(4-memyl-lH-imidazol-l-vnpyridin-2-yllvmvU-8-(2-trifluoromethylphenyl‘)-5,6J,8-tetrahvdro-[1.2,41triazolo[l.,5-a]pyridine
[Formula 2]
Synthesis of l-amino-3-(2-trifluoromemylphenyl)piperidin-2-one Thionyl chloride (2.72 mL) was added to a solution of 2-trifluoromethylphenylacetic acid (1.9 g) in methanol (38 mL), followed by stirring at room temperature for three hours. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with DMF. Sodium hydride (containing 40% mineral oil, 410 mg) was added under ice-cooling, followed by stirring for 10 minutes. The reaction solution was further stirred for 30 minutes and then ice-cooled again. l-Chloro-3-iodopropane (1.02 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was diluted with ethanol (26.6 mL). Hydrazine monohydrate (7.6 mL) was added, and the reaction solution was stirred at room temperature for two hours and then at 60°C for further three hours. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 1.68 g of the title compound. The property values of the compound are as follows.
ESI-MS; m/z 259 [M+H-H]. 1H-NMR (CDCl3) δ (ppm): 1.82-2.10 (m, 3H), 2.18-2.26 (m, IH), 3.58-3.76 (m, 2H), 4.07 (dd, J = 10.0, 5.6 Hz, IH), 4.60 (s, 2H), 7.24 (d, J = 7.6 Hz, IH), 7.35 (t, J = 7.6 Hz, IH), 7.51 (t, J = 7.6 Hz, IH)5 7.66 (d, J = 7.6 Hz, IH). [0028] Synthesis of (EV3-[6-methoxy-5-(4-methyl- 1 H-imidazol- 1 -yl)pyridin-2-yl]-N-f2-oxo-3 -(2-trifluoromethylphenyl)piperidin- 1 -yl]acrylamide
EDC (834 mg), HOBT (588 mg) and IPEA (2.03 mL) were added to a suspension of (E)-3-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridm-2-yl]acrylic acid trifluoroacetate (1.42 g) and l-amήio-3-(2-trifluoromethylphenyl)piperidin-2-one (750 mg) in DMF (30 mL). After stirring at room temperature for 14 hours, a saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 1.23 g of the title compound. The property values of the compound are as follows. ESI-MS; m/z 500 [M1H-HJ. [0029]
Synthesis of r8S>-2-(fEV2-r6-methoxy-5-r4-methyl-lH-imidazol-l-vnpyridm’2-vnvinvU-8-(2-trifluoromethvlphenvD-5.6.7.8-tetrahvdro-ri.2.41triazoloπ.5-a1pvridine Phosphorus oxychloride (24.2 mL) was added to (E)-3~[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]-N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-l-yl]acrylamide (1.2 g). The reaction solution was stirred at 1000C for one hour and then concentrated under reduced pressure. Subsequently, the residue was diluted with acetic acid (24.2 mL) and then ammonium acetate (1.9 g) was added, followed by stirring at 1500C for two hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution and ethyl acetate were added to the resulting residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain a racemate of the title compound (750 mg). The resulting racemate (410 mg) was separated by CHIRALP AK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm x 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 10 mL/min) to obtain the title compound with a retention time of 33 minutes and negative optical rotation (170 mg) as crystals. The property values of the title compound are as follows.
1H-NMR (CDCl3) δ (ppm): 1.90-2.01 (m, IH), 2.10-2.35 (m, 2H), 2.29 (d, J = 1.2 Hz, 3H), 2.42-2.51 (m, IH), 4.03 (s, 3H), 4.28-4.41 (m, 2H), 4.70 (dd, J = 8.4, 6.0 Hz, IH), 6.92 (d, J = 8.0 Hz, IH), 6.95 (t, J = 1.2 Hz, IH), 7.01 (d, J = 7.6 Hz, IH), 7.39 (t, J = 7.6 Hz5 IH), 7.44 (d, J = 16.0 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.49 (t, J = 7.6 Hz, IH), 7.63 (d, J = 16.0 Hz5 IH), 7.72 (d, J = 7.6 Hz, IH), 7.76 (d, J = 1.2 Hz, IH). [0030]
(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-lH-imidazol-l-yl)ρyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine synthesized according to the above reference example was used for the following synthesis of salts. [0031] Example 1
Synthesis of r8SV2-{rEV2-[6-methoxy-5-(4-methyl-lH-imidazol-l-vπpyridin-2-vnvinvU-8-f2-trifluoromethylphenyl)-5.6.7.8-tetrahvdro-fl,2,4]triazolo[l.,5-a]pyridine 1.5 D-tartrate
(8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine (33.70 mg) was dissolved in 285 μL of a D-tartaric acid-ethanol solution (110.92 mg/3 mL) with stirring at room temperature. The oil was precipitated when 1 mL of heptane was added. Accordingly, the oily substance was dissolved by adding 1 mL of ethanol. Further, 0.5 mL of heptane was added, and the mixture was transferred to a low temperature laboratory at about 50C (under shading) and continuously stirred for 24 hours. Thus, partial gelation occurred. Thereafter, the mixture was brought back to room temperature and continuously stirred, resulting in precipitation of a solid. The solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 21.25 mg of the title compound as white solid crystals. 1H-NMR (600 MHz, DMSOd6) δ (ppm): 1.96 (m, IH), 2.14 (s, 3H), 2.16 (m, 2H), 2.29 (m, IH), 3.98 (s, 3H), 4.28 (m, 2H), 4.29 (s, 3H), 4.51 (dd, J = 9, 6 Hz, IH), 7.22 (s, IH), 7.25 (brd, J = 8 Hz, IH), 7.27 (d, J = 8 Hz, IH), 7.32 (d, J = 16 Hz, IH)5 7.46 (d, J = 16 Hz, IH), 7.49 (brdd, J = 8 Hz, IH), 7.61 (brdd, J = 8 Hz5 IH), 7.77 (brd, J = 8 Hz, IH), 7.78 (d, J = 8 Hz, IH), 7.91 (s, IH). [0032] Example 2
Synthesis of (‘8SV2-l(Ε)-2-f6-methoxy-5-(4-methyl-lH-imidazol-l-vnpyridm-2-yllvinyl>-8-f2-trifluoromethylphenylV5,6J,8-tetrahvdro-[l ,2,4]triazolo[l ,5-a]pyridine di-D-tartrate
(8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,657,8-tetrahydro-[l ,2,4]triazolo[l ,5-a]ρyridine (810.18 mg) was dissolved in 8 mL of a D-tartaric acid-ethanol solution (751.13 mg/10 mL) with stirring at room temperature. The oil was precipitated when 2 mL of heptane was added. Accordingly, the oily substance was dissolved by ultrasonic treatment to prepare a clear solution. Several mg of crystals of the 1.5 D-tartrate prepared according to Example 1 were added, followed by stirring at room temperature. Stirring for about one hour resulted in gelation and subsequent precipitation of a solid. Further, stirring was continued while gradually adding 14 mL of heptane. A part of the suspension (2 mL) was separated and the solid was collected by filtration through a glass filter. The solid was dried under reduced pressure at room temperature to obtain 71.14 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSOd6) δ (ppm): 1.97 (m, IH), 2.15 (s, 3H), 2.16 (m, 2H), 2.30 (m, IH), 3.98 (s, 3H), 4.28 (m, 2H), 4.29 (s, 4H), 4.51 (dd, J = 9, 6 Hz, IH), 7.22 (brs, IH), 7.25 (brd, J = 8 Hz, IH), 7.27 (d, J = 8 Hz, IH), 7.32 (d, J = 16 Hz, IH), 7.46 (d, J = 16 Hz, IH), 7.49 (brdd, J – 8 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.77 (brd, J = 8 Hz, IH), 7.78 (d, J = 8 Hz, IH), 7.91 (brs, IH). [0033] Example 3
Synthesis of r8SV2-(rE)-2-r6-methoxy-5-r4-methyl-lH-imidazol-l-vnpyridin-2-yl1vinvU-8-α-trifluoromethylphenyl)-5,6J,8-tetrahydro-[1.2,4]triazolo[l,5-a]pyridine disulfate
Concentrated sulfuric acid (11.5 μL) was added to a solution of (8S)-2-{(E)-2-[6- methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-txifluoromethylphenyl)-5,6,7,8-tetrahydro-[l52,4]triazolo[l55-a]pyridine (98.09 mg) in ethanol (1 mL), and 1 mL of ethyl acetate was added with stirring at room temperature. Since the oily portion was confirmed on the bottom of the recovery flask, the oily substance was dissolved by ultrasonic treatment. Stirring at room temperature under shading for about 30 minutes resulted in precipitation of a solid. The solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 127.94 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSOd6) δ (ppm): 1.97 (m, IH), 2.17 (m, 2H), 2.30 (m, IH), 2.34 (brd, J = 1 Hz, 3H), 4.01 (s, 3H), 4.29 (m, 2H), 4.52 (dd, J = 9, 6 Hz, IH)5 7.25 (brd, J = 8 Hz, IH), 7.37 (d, J = 16 Hz, IH), 7.40 (d, J = 8 Hz, IH), 7.50 (brdd, J = 8 Hz, IH), 7.55 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.77 (m, IH), 7.78 (m, IH), 8.00 (d, J = 8 Hz, IH), 9.36 (d, J = 2 Hz, IH). [0034] Example 4 Synthesis of (8SV2-((E)-2-[“6-methoxy-5-(4-methyl-lH-imidazol-l-ylN)ρyridin-2-yllvinvU-8-(‘2-trifluoromethylphenyl)-5,6,7,8-tetrahvdiO-[1.2,41triazolo[l,5-a]pyridine dihydrobromide
Concentrated hydrobromic acid (24.8 μL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,84etrahydro-[l,254]triazolo[l55-a]pyridine (51.42 mg) m ethanol (1 mL), and 1 mL of heptane was added with stirring at room temperature. After several minutes, 1 mL of heptane was further added to the solution and stirring was continued. The solution was stirred at room temperature for one hour and then further stirred at about 50C for 20 minutes. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 49.24 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.99 (m, IH), 2.17 (m, 2H), 2.30 (m, IH), 2.34 (brd, J = 1 Hz5 3H), 4.01 (s, 3H), 4.30 (m, 2H), 4.52 (dd, J = 9, 6 Hz5 IH), 7.25 (brd, J = 8 Hz5 IH), 7.37 (d, J = 16 Hz, IH), 7.40 (d, J = 7 Hz, IH)57.50 (brdd, J = 8 Hz, IH), 7.55 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz5 IH), 7.77 (m, IH)5 7.78 (m, IH), 8.00 (d, J = 7 Hz, IH), 9.37 (d, J = 2 Hz, IH). [0035] Example 5
Synthesis of r8SV2-((Ε)-2-r6-methoxy-5-r4-methyl-lH-imidazol-l-yl)ρyridin-2-vnvinyl}-8-r2-trifluoromethylphenyl)-5,6J,8-tetrahvdro-[1.2,41triazolo[1.5-alpyridine hydrochloride
Concentrated hydrochloric acid (3.6 μL) was added to a solution of (8S)-2-{(E)- 2-[6-methoxy-5-(4-metiiyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylplienyl)-5,6,7,8-te1xahydro-[l,2,4]triazolo[l,5-a]pyridme (19.80 mg) in 2-propanol (1 mL), and a total of 4 mL of heptane was added in 1 mL portions with stirring at room temperature. The solution was stirred at room temperature under shading for five days. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 7.45 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSOd6) δ (ppm): 1.97 (m, IH), 2.17 (m, 2H)5 2.30 (m, IH), 2.30 (s, 3H), 4.00 (s, 3H), 4.30 (m, 2H)5 4.52 (dd, J = 9, 6 Hz5 IH), 7.25 (brd, J – 8 Hz5 IH), 7.36 (d, J = 16 Hz5 IH), 7.37 (d5 J = 8 Hz, IH), 7.50 (brt, J = 8 Hz5 IH)5 7.53 (d, J = 16 Hz5 IH)5 7.61 (brt, J = 8 Hz5 IH)5 7.66 (brs, IH), 7.77 (brd, J = 8 Hz, IH)5 7.96 (d, J = 8 Hz5 IH), 9.06 (brs, IH). [0036] Example 6
Synthesis of (8S)-2-((ΕV2-r6-methoxy-5-(‘4-methyl-lH-imidazol-l-yl)pyridin-2-yl1vinvU-8-(2-trifluoromethylphenyl)-5.6,7,8-tetrahvdro-[l,2,4]triazolo[L5-a1pyridine hydrochloride Concentrated hydrochloric acid (14.3 μL) and heptane (7 mL) were added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,657,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine (79.77 mg) in 2-propanol (3 mL). A small amount of the crystals obtained in Example 5 were added as seed crystals with stirring at room temperature. The mixture was transferred to a low temperature laboratory at about 50C and stirred for one hour. Thereafter, 1 mL of heptane was further added, followed by stirring for several minutes. When the precipitated solid was collected by filtration through a glass filter, the solid was precipitated in the filtrate. The precipitated solid was collected by filtration through a glass filter and dried under reduced pressure at room temperature to obtain 38.02 mg of the title compound as white solid crystals. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.97 (m, IH), 2.17 (m5 2H), 2.29 (m, IH), 2.32 (brd, J = 1 Hz, 3H), 4.00 (s, 3H), 4.30 (m, 2H), 4.52 (dd, J = 9, 6 Hz, IH), 7.25 (brd, J = 8 Hz, IH), 7.37 (d, J = 16 Hz5 IH), 7.38 (d, J = 8 Hz, IH), 7.50 (brdd, J = 8 Hz, IH)5 7.54 (d, J = 16 Hz, IH), 7.61 (brdd, J = 8 Hz, IH), 7.72 (brs, IH), 7.77 (brd, J = 8 Hz, IH), 7.98 (d, J = 8 Hz5 IH)5 9.24 (brs, IH). [0037] Example 7
SvnJhesis off8SV2-f(E>2-r6-memoxy-5-(4-mefovπ trifluoromethylt>henylV5,6,7,8-tetrahvdro-[l,2,4]triazolo[l,5-a]pyridine mesylate
Mesylic acid (0.8 μL) was added to a mixed solution of (8S)-2-{(E)-2-[6- methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphen^ tetrahydro-[l52,4]triazolo[l,5-a]pyridine (50 mg) in t-butyl methyl ether (0.8 mL)-ethaαol (0.1 mL). The mixture was solidified as a result of stirring at room temperature for two hours. The solid was collected by filtration through a glass filter. The solid was washed with t-butyl methyl ether-ethanol (8:1) and then dried under reduced pressure at room temperature to obtain 51.9 mg of the title compound as pale yellow solid crystals.
1H-NMR (DMSO-d6) δ (ppm): 1.90-2.05 (m, IH)3 2.10-2.22 (m, 2H), 2.28-2.40 (m, IH), 2.31 (s, 3H), 2.35 (s, 3H)5 4.02 (s, 3H)5 4.25-4.39 (m, 2H), 4.50-4.55 (m, IH), 7.27 (d5 J = 8.0 Hz5 IH)5 7.38 (d, J = 16.0 Hz5 IH)5 7.41 (d, J = 8.0 Hz, IH)5 7.51 (t5 J = 8.0 Hz5 IH)5 7.55 (d, J = 16.0 Hz5 IH), 7.63 (t, J = 8.0 Hz5 IH)5 7.78 (d, J = 8.0 Hz5 IH)5 7.79 (s, IH), 8.01 (d, J = 8.0 Hz5 IH), 9.37 (s, IH). [0038] Example 8 Synthesis of (8S)-2-((ΕV2-r6-methoxy-5-(4-methyl-lH-imidazol-l-vnpyridin-2-vnvinvn-8-r2-trifluoromethylphenyl)-5.6,7,8-tetrahydro-[l.,2,4‘|triazolo[l,5-a]pyridine diphosphate
A solution of phosphoric acid (52.8 mg) in acetonitrile (0.2 mL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-mτidazol-l-yl)ρyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5565758-tetrahydro-[l5254]triazolo[l,5-a]pyridine (100 mg) in acetonitrile (0.8 mL) at room temperature. The precipitated oil was solidified as a result of stirring with spatula. The solid was collected by filtration through a glass filter. The solid was washed with ice-cold acetonitrile, air-dried at room temperature for 10 minutes and then dried under reduced pressure at room temperature to obtain 120 mg of the title compound as white solid crystals. 1H-NMR (DMSO-d6) δ (ppm): 1.90-2.05 (m, IH), 2.11-2.20 (m, 2H), 2.15 (s, 3H), 2.25-2.35 (m, IH), 3.99 (s, 3H)5 4.24-4.39 (m, 2H), 4.50-4.55 (m, IH)5 7.23 (s, IH), 7.26 (d, J = 7.0 Hz, IH), 7.28 (d, J = 8.0 Hz, IH), 7.33 (d, J = 16.0 Hz5 IH), 7.47 (d, J = 16.0 Hz5 IH), 7.51 (t, J = 7.0 Hz, IH), 7.63 (t, J = 7.0 Hz, IH), 7.78 (d, J = 7.0 Hz, IH), 7.79 (d, J = 8.0 Hz, IH), 7.90 (s, IH). [0039] Example 9 Svnmesis of(8SV2-{(E)-2-[6-memoxy-5-(4-methyl-lH-irnidazol-l-yl)pyridin-2-yl1vinvU-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahvdro-[l .2.41triazolo[l .5-a]pyridine diphosphate
A solution of phosphoric acid (13.2 mg) in ethanol (0.05 mL) was added to a mixed solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-lH-imidazol-l-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[l,2!,4]triazolo[l,5-a]pyridme (50 mg) in heptane (0.6 mL)-ethanol (0.15 mL) at room temperature. The reaction solution was stirred at room temperature, and the precipitated solid was collected by filtration through a glass filter. The solid was washed with heptane-ethanol (3:1) and then dried under reduced pressure at room temperature to obtain 37.6 mg of the title compound as white solid crystals. 1H-NMR (DMSOd6) δ (ppm): 1.90-2.05 (m, IH), 2.11-2.20 (m, 2H), 2.15 (s, 3H), 2.25-2.35 (m, IH), 3.99 (s, 3H), 4.24-4.39 (m, 2H), 4.50-4.55 (m, IH), 7.23 (s, IH), 7.26 (d, J = 7.0 Hz, IH), 7.28 (d, J = 8.0 Hz, IH), 7.33 (d, J = 16.0 Hz, IH), 7.47 (d, J = 16.0 Hz, IH), 7.51 (t, J = 7.0 Hz, IH), 7.63 (t, J = 7.0 Hz, IH), 7.78 (d, J = 7.0 Hz, IH), 7.79 (d, J = 8.0 Hz, IH), 7.90 (s, IH).
CLIP
Development of an Efficient Manufacturing Process for E2212 toward Rapid Clinical Introduction
, Taiju Nakamura‡, Atsushi Kamada†, Takeo Sasaki§, Toshiyuki Uemura§, Yorihisa Hoshino†, Masaaki Matsuda†, Yongbo Hu∥, Daiju Hasegawa§, Kazato Inanaga‡, Nobuaki Sato§, Kazuhiro Yoshizawa‡, George A. Moniz∥, Gordon D. Wilkie∥, Francis G. Fang∥, Yoshihiro Nishikawa‡, and Katsuya Tagami*‡
Process studies of E2212 (1) toward rapid clinical introduction are described. Through comprehensive route-finding studies and optimization of key condensation and cyclization steps, a racemate-based manufacturing route was established and successfully scaled-up to the hundred kilogram scale. For the rapid delivery of a drug substance containing the Z isomer for preclinical safety studies, the successful scale-up of the photoisomerization of an olefin in a flow system is also presented.
https://pubs.acs.org/doi/10.1021/acs.oprd.8b00444
E2212 (1) (18.0 kg, 92.5% yield) as a white solid. Mother liquor 3 were recycled according to the procedure described below. FTIR (cm–1, KBr) 3461, 3173, 2956, 1734, 1584, 1536, 1476, 1309, 1130, 835, 765, 752; 1H NMR (600 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.77 (br d, J = 8.4 Hz, 1H), 7.61 (br dd, J = 7.8, 7.8 Hz, 1H), 7.49 (br dd, J = 7.8, 7.8 Hz, 1H), 7.46 (d, J= 15.6 Hz, 1H), 7.32 (d, J = 15.6 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.25 (br d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 4.51 (dd, J = 9.0, 6.0 Hz, 1H), 4.29 (s, 3H), 4.28 (m, 2H), 3.98 (s, 3H), 2.29 (m, 1H), 2.14 (s, 3H), 2.16 (m, 2H), 1.96 (m, 1H); 13C NMR (150 MHz, DMSO-d6) δ 173.3, 159.3, 155.4, 155.0, 150.1, 141.1, 137.1, 136.9, 133.6, 132.9, 131.0, 130.5, 127.6, 127.1 (q, JC–F = 30 Hz), 125.8 (q, JC–F = 5.6 Hz), 124.7 (q, JC–F = 270 Hz), 122.2, 120.7, 117.2, 116.5, 72.3, 53.7, 47.0, 37.6, 30.7, 21.3, 13.6; HRMS (ESI+) calcd for C25H23F3N6O ([M + H]+) 481.1958, found 481.1953.
///////////E2212, E 2212
Certolizumab pegol, セルトリズマブペゴル (遺伝子組換え)
>Amino acid sequence of the light chain DIQMTQSPSSLSASVGDRVTITCKASQNVGTNVAWYQQKPGKAPKALIYSASFLYSGVPY RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPLTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Amino acid sequence of the heavy chain EVQLVESGGGLVQPGGSLRLSCAASGYVFTDYGMNWVRQAPGKGLEWMGWINTYIGEPIY ADSVKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCARGYRSYAMDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCAA
Certolizumab pegol
CAS: 428863-50-7
セルトリズマブペゴル (遺伝子組換え)
CDP 870 / CDP-870 / CDP870 / PHA-738144
| Formula |
C2115H3252N556O673S16
|
|---|---|
| Cas |
428863-50-7
|
| Mol weight |
47748.8128
|
Reducing signs and symptoms of Crohn’s disease and treatment of moderately to severely active rheumatoid arthritis (RA).
Certolizumab pegol is a recombinant Fab’ antibody fragment against tumor necrosis factor alpha which is conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). Polyethylene glycol helps to delay the metabolism and elimination of the drugs. Chemically, the light chain is made up of 214 amino acid residues while the heavy chain is composed of 229 amino acid residues. The molecular mass of the Fab’ antibody fragment itself is 47.8 kDa. It is used for the treatment of rheumatoid arthritis and Crohn’s disease. FDA approved on April 22, 2008
Certolizumab pegol (CDP870, tradename Cimzia) is a biologic medication for the treatment of Crohn’s disease,[1][2] rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. It is a fragment of a monoclonal antibody specific to tumor necrosis factor alpha(TNF-α) and is manufactured by UCB.[3][4][5]
Medical uses
- Crohn’s Disease
- On April 22, 2008, the U.S. FDA approved Cimzia for the treatment of Crohn’s disease in people who did not respond sufficiently or adequately to standard therapy.[4][6][7]
- Rheumatoid arthritis
- On June 26, 2009, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending that the European Commission grant a marketing authorisation for Cimzia for the treatment of rheumatoid arthritis only – the CHMP refused approval for the treatment of Crohn’s disease. The marketing authorisation was granted to UCB Pharma SA on October 1, 2009.[8]
- Psoriatic arthritis
- On September 27, 2013, the U.S. FDA approved Cimzia for the treatment of adult patients with active psoriatic arthritis.[9]
Method of action
Certolizumab pegol is a monoclonal antibody directed against tumor necrosis factor alpha. More precisely, it is a PEGylated Fabfragment of a humanized TNF inhibitor monoclonal antibody.[10]
Clinical trials
- Crohn’s disease
- Positive results have been demonstrated in two phase III trials (PRECiSE 1 and 2) of certolizumab pegol versus placebo in moderate to severe active Crohn’s disease.[1][10][11][12]
- Axial spondyloarthritis
- In 2013, a phase 3 double blind randomized placebo-controlled study found significantly positive results in patient self-reported questionnaires, with rapid improvement of function and pain reduction, in patients with axial spondyloarthritis.[13]
- Rheumatoid arthritis
- Certolizumab appears beneficial in those with rheumatoid arthritis.[14]
Side effects
Significant side effects occur in 2% of people who take the medication.[14]
References
- ^ Jump up to:a b Sandborn WJ, Feagan BG, Stoinov S, et al. (July 2007). “Certolizumab pegol for the treatment of Crohn’s disease”. N. Engl. J. Med. 357 (3): 228–38. doi:10.1056/NEJMoa067594. PMC 3187683. PMID 17634458.
- ^ Goel, Niti; Sue Stephens (2010). “Certolizumab pegol”. mAbs. 2 (2): 137–147. doi:10.4161/mabs.2.2.11271. PMC 2840232. PMID 20190560.
- ^ Kaushik VV, Moots RJ (April 2005). “CDP-870 (certolizumab) in rheumatoid arthritis”. Expert Opinion on Biological Therapy. 5 (4): 601–6. doi:10.1517/14712598.5.4.601. PMID 15934837.
- ^ Jump up to:a b index.cfm?fuseaction=Search.Label_ApprovalHistory “Cimzia Label and Approval History” Check
|url=value (help). Drugs@FDA. U.S. Food and Drug Administration(FDA). Retrieved 2009-11-15. - ^ “Cimzia Prescribing Information” (PDF). US Food and Drug Administration (FDA). April 2016. Retrieved 2016-08-21.
- ^ UCB press release – Cimzia Approved in the US for the Treatment of Moderate to Severe Crohn’s Disease. Retrieved April 22, 2008.
- ^ Waknine, Yael (May 1, 2008). “FDA Approvals: Patanase, Actonel, Cimzia”. Medscape. Retrieved 2008-05-01.
- ^ “Cimzia European Public Assessment Report”. European Medicines Agency. Retrieved November 15, 2009.
- ^ “Cimzia (certolizumab pegol) approved by the U.S. FDA for treatment of adult patients with active psoriatic arthritis”. Archived from the original on October 1, 2013. Retrieved October 1, 2013.
- ^ Jump up to:a b Schreiber S. et al., Certolizumab pegol, a humanised anti-TNF pegylated FAb’ fragment, is safe and effective in the maintenance of response and remission following induction in active Crohn’s disease: a phase 3 study (precise), Gut, 2005, 54, suppl7, A82
- ^ Sandborn et al., Certolizumab pegol administered subcutaneously is effective and well tolerated in patients with active Crohn’s disease: results from a 26-week, placebo-controlled Phase 3 study (PRECiSE 1), Gastroenterology, 2006, 130, A107
- ^ “New Analysis Shows Cimzia (Certolizumab Pegol) Maintained Remission and Response in Recent Onset Crohn’s Disease” (Press release). UCB. October 23, 2006. Retrieved 2009-11-15.
- ^ Sieper J, Tubergen A, Coteur G, Woltering F, Landewe R (May 2013). “PMS50 – Rapid Improvements In Patient-Reported Outcomes With Certolizumab Pegol In Patients With Axial Spondyloarthritis, Including Ankylosing Spondylitis And Non-Radiographic Axial Spondyloarthritis: 24-Week Results Of A Phase 3 Double Blind Randomized Placebo-Controlled Study”. Value in Health. 16 (3): A227. doi:10.1016/j.jval.2013.03.1150.
- ^ Jump up to:a b Ruiz Garcia, V; Jobanputra, P; Burls, A; Vela Casasempere, P; Bort-Marti, S; Bernal, JA (Sep 8, 2017). “Certolizumab pegol (CDP870) for rheumatoid arthritis in adults”(PDF). The Cochrane Database of Systematic Reviews. 9: CD007649. doi:10.1002/14651858.CD007649.pub4. PMID 28884785.
External links
- certolizumab+pegol at the US National Library of Medicine Medical Subject Headings (MeSH)
- Cimzia Website
FDA approves treatment Cimzia (certolizumab pegol) for patients with a type of inflammatory arthritis
March 28, 2019
Release
The U.S. Food and Drug Administration today approved Cimzia (certolizumab pegol) injection for treatment of adults with a certain type of inflammatory arthritis called non-radiographic axial spondyloarthritis (nr-axSpA), with objective signs of inflammation. This is the first time that the FDA has approved a treatment for nr-axSpA.
“Today’s approval of Cimzia fulfills an unmet need for patients suffering from non-radiographic axial spondyloarthritis as there has been no FDA-approved treatments until now,” said Nikolay Nikolov, M.D., associate director for rheumatology of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.
Nr-axSpA is a type of inflammatory arthritis that causes inflammation in the spine and other symptoms. There is no visible damage seen on x-rays, so it is referred to as non-radiographic.
The efficacy of Cimzia for the treatment of nr-axSpA was studied in a randomized clinical trial in 317 adult patients with nr-axSpA with objective signs of inflammation, indicated by elevated C-reactive protein (CRP) levels and/or sacroiliitis (inflammation of the sacroiliac joints) on MRI. The trial measured the improvement response on the Ankylosing Spondylitis Disease Activity Score, a composite scoring system that assesses disease activity including patient-reported outcomes and CRP levels. Responses were greater for patients treated with Cimzia compared to patients treated with placebo. The overall safety profile observed in the Cimzia treatment group was consistent with the known safety profile of Cimzia.
The prescribing information for Cimzia includes a Boxed Warning to advise health care professionals and patients about the increased risk of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis (infection in the blood steam), invasive fungal infections (such as histoplasmosis, an infection that affects the lungs), and other infections. Cimzia should be discontinued if a patient develops a serious infection or sepsis. Health care providers are advised to perform testing for latent TB and, if positive, to start treatment for TB prior to starting Cimzia. All patients should be monitored for active TB during treatment, even if the initial latent TB test is negative. The Boxed Warning also advises that lymphoma (cancer in blood cells) and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, of which Cimzia is a member. Cimzia is not indicated for use in pediatric patients. Cimzia must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
Cimzia was originally approved in 2008 and is also indicated for adult patients with Crohn’s disease, moderate-to-severe rheumatoid arthritis, active ankylosing spondylitis (AS) and moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
The FDA granted the approval of Cimzia to UCB.
Syringe with 200mg Certolizumab pegol
|
|
| Monoclonal antibody | |
|---|---|
| Type | Fab’ fragment |
| Source | Humanized (from mouse) |
| Target | TNF alpha |
| Clinical data | |
| Trade names | Cimzia |
| AHFS/Drugs.com | Consumer Drug Information |
| MedlinePlus | a608041 |
| License data | |
| Pregnancy category |
|
| Routes of administration |
Subcutaneous |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Elimination half-life | about 11 days |
| Excretion | Renal (PEG only) |
| Identifiers | |
| CAS Number | |
| ChemSpider |
|
| UNII | |
| KEGG | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C2115H3252N556O673S16 |
| Molar mass | 47,750 g/mol g·mol−1 |
///////////////FDA 2019, Cimzia, certolizumab pegol, inflammatory arthritis, UCB
Cevimeline, セビメリン
Cevimeline
セビメリン
- Molecular FormulaC10H17NOS
- Average mass199.313 Da
Cevimeline hydrochloride
-
- Synonyms:AF-102B, SNI-2011, SNK-508, Evoxac
- ATC:N07
- Use:cognition disorder, treatment of Sjogren’s syndrome, muscarinic M3-receptor agonist
- Chemical name:(2′R,3R)-rel-2′-methylspiro[1-azabicyclo[2.2.2]octane-3,5′-[1,3]oxathiolane] hydrochloride hydrate (2:2:1)
- Formula:C10H17NOS • HCl • 1/2H2O
- MW:489.57 g/mol
- CAS-RN:153504-70-2
- InChI Key:SURWTGAXEIEOGY-GHXDPTCOSA-N
- InChI:InChI=1S/C10H17NOS.ClH/c1-8-12-10(7-13-8)6-11-4-2-9(10)3-5-11;/h8-9H,2-7H2,1H3;1H/t8-,10-;/m1./s1
Derivatives
base
- Formula:C10H17NOS
- MW:199.32 g/mol
- CAS-RN:107233-08-9
anhydrous hydrochloride
- Formula:C10H17NOS • HCl
- MW:235.78 g/mol
- CAS-RN:107220-28-0
Cevimeline is cis-2′-methylspiro {1-azabicyclo [2.2.2] octane-3, 5′ -[1,3] oxathiolane} hydro-chloride, hydrate (2:1). Its empirical formula is C10H17NOS•HCl•½ H2O, and its structural formula is:
Cevimeline has a molecular weight of 244.79. It is a white to off white crystalline powder with a melting point range of 201 to 203°C. It is freely soluble in alcohol and chloroform, very soluble in water, and virtually insoluble in ether. The pH of a 1% solution ranges from 4.6 to 5.6. Inactive ingredients include lactose monohydrate, hydroxypropyl cellulose, and magnesium stearate.
Cevimeline hydrochloride [USAN]
RN: 153504-70-2
(+-)-cis-2-Methylspiro(1,3-oxathiolane-5,3′-quinuclidine) hydrochloride, hemihydrate
Cevimeline (trade name Evoxac) is a parasympathomimetic and muscarinic agonist,[1] with particular effect on M1 and M3 receptors. It is used in the treatment of dry mouth and especially associated with Sjögren’s syndrome.
Mechanism of action
By activating the M3 receptors of the parasympathetic nervous system, cevimeline stimulates secretion by the salivary glands, thereby alleviating dry mouth.
Side effects
Known side effects include nausea, vomiting, diarrhea, excessive sweating, rash, headache, runny nose, cough, drowsiness, hot flashes, blurred vision, and difficulty sleeping.[2]
Contraindications include asthma and angle closure glaucoma.
Clip
https://www.sciencedirect.com/science/article/abs/pii/S0731708515302260
CLIP
https://www.sciencedirect.com/science/article/pii/S0040403913005042
CLIP
CLIP
- Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid affords a mixture of two diastereomeric spiroracemates, the (?-trans (V) and (?-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid. The (?-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3. Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane.
- Synthesis of Cevimeline Hydrochloride (EN:134916): Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III) (1,2). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate (1) or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid (2) affords a mixture of two diastereomeric spiro-racemates, the (?-trans (V) and (?-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid (1,2). The (?-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3 (2,3). Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane (4).(Scheme 13491601a) Description M.p. 203 C (4). Sources Discovered by Israel Institute for Biological Research, Ness-Ziona (IL) and licensed to Snow Brand Milk Products Co. Ltd. (JP). In the U.S., comarketed by Snow Brand Milk Products and Daiichi Pharmaceutical Co., Ltd. In Japan, codeveloped with Nippon Kayaku Co. Ltd. Ishihara Sangyo Co., Ltd. (JP) is the bulk supplier. References 1. Fisher, A., Heldman, E., Grunfeld, Y., Karton, I., Levy, A. (Israel Institute for Biological Research); Derivs. of quinuclidine; EP 0205247, JP 1986280497, US 4855290. 2. Hayashi, K., Tokumoto, S., Yoshizawa, H., Isogai, T. (Ishihara Sangyo Kaisha, Ltd.); Method for producing 2-methylspiro(1,3-oxathiolan-5,3′)quinuclidine; EP 0683168, US 5571918. 3. Haga, T., Koyanagi, T., Hara, K., Maeda, M., Shigehara, I. (Ishihara Sangyo Kaisha, Ltd.); Method for isomerization of trans-form 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine or acid addition salts thereof; EP 0298491, US 4861886. 4. Saito, K., Ono, T., Honda, N. (Snow Brand Milk Products Co., Ltd.); Preparation method of cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine hydrochloride.1/2 hydrate capable of disgregating easily; JP 1992108792.
PATENT
https://patents.google.com/patent/US8080663B2/en
The present invention refers to a novel, industrially advantageous process for the preparation of an intermediate useful for the preparation of Cevimeline hydrochloride (1, cis-2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine, Scheme 1). This pharmaceutical is useful for the treatment of diseases of the central nervous system due to disturbances of central cholinergic function and autoimmune system (Sjörgen’s syndrome) and is marketed as Evoxac®.
U.S. Pat. No. 4,855,290 describes a process for preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1). The process comprises the preparation of the epoxide of 3-methylenequiniclidine, which is subsequently reacted with hydrogen sulfide to produce 3-hydroxy-3-mercaptomethylquiniclidine and condensed with acetaldehyde in the presence of a Lewis acid (boron trifluoride etherate) to provide 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine. This process is depicted in Scheme I.
This process suffers from major disadvantages when transiting to industrial scale. These include the use of the highly hazardous and difficult to handle hydrogen sulfide gas. Also, boron trifluoride etherate is employed during the condensation step with acetaldehyde. The boron trifluoride etherate reagent is an air and moisture sensitive Lewis acid which has to be used under anhydrous conditions, thus creating a serious disadvantage in industrial settings. Another drawback of this process is the use of sodium hydride. U.S. Pat. Nos. 5,571,918 and 4,861,886 relate to the isomerization of the trans- to cis-form of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine but do not describe methods for its preparation. Thus, an industrially acceptable and cost-effective method for the preparation of Cevimeline hydrochloride which overcomes the deficiencies of the prior art is required.
Further and other objects of the invention will be realized by those skilled in the art from the following Summary of the Invention and Detailed Description of Preferred Embodiments of the Invention thereof.
According to one aspect of the invention, a novel process is provided for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1). The process is industrially practical, efficient, safe and economical, as well as being environmentally friendly. The general method is shown in the Scheme II.
wherein R is selected from C1 to C6 alkyl and aryl groups, most preferably a methyl, ethyl or propyl group; R1 is hydrogen or a C2 to C7 alkyl or aryl carbonyl group; R2 is a C1 to C6 alkyl group, preferably methyl, ethyl, propyl, or butyl group.
EXAMPLE I Preparation of the Epoxide of 3-methylenequiniclidine (3)
A mixture of the hydrochloric salt of 3-quiniclidinone (2, 120 g, 795.7 mmol) and trimethylsulfoxonium iodide (219 g, 993.3 mmol) in dimethylsulfoxide (91.0 g, 0.63 mol) was cooled to 0-5° C. in an ice/water bath under nitrogen atmosphere. A solution of potassium tert-butoxide (201 g, 1789.1 mmol) in dimethylsulfoxide (500 mL) was added dropwise over 45 minutes. The mixture was warmed gradually to room temperature and stirred for an additional 16 hours at room temperature. After cooling to 0-5° C. (ice/water bath) the mixture was poured into an ice/water mixture (500 g) and then sodium chloride (300 g) was added. The mixture was stirred for 30 minutes and extracted with toluene (3×400 mL). The toluene phase was dried over sodium sulfate, filtered and evaporated to furnish the epoxide of 3-methylenequiniclidine (60 g, 431.7 mmol, 54% yield) as a yellow oil. The product could be used in the next step neat or as toluene solution after the extraction without further purification.
1H NMR (400 MHz, CDCl3): δ=3.10 (d, 1H, J=14.6 Hz); 2.98-2.77 (m, 5H); 2.74 (d, 1H, J=4.8 Hz); 2.70 (d, 1H, J=4.8 Hz); 1.96-1.89 (m, 1H); 1.79-1.62 (m, 2H); 1.60-1.54 (m, 1H); 1.38-1.36 (m,1H).
LRMS (ES+): 140.0 (100, M+H+).
EXAMPLE II Preparation of the Thiolacetic Acid Salt of 3-hydroxy-3-acetoxymercaptomethylquiniclidine (4)
A solution of the epoxide of 3-methylenequiniclidine (3, 54 g, 388.5 mmol) in toluene (200 mL) was cooled to 0-5° C. (ice/water bath). Thiolacetic acid was added dropwise over 10-15 minutes. The mixture was stirred at 0-5° C. for 30 minutes and then allowed to come to room temperature. After stirring at room temperature for 2 hours the formed precipitate was filtered and washed with toluene (2×100 mL) to give the 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R1 is H and R is methyl, 77 g, 264.6 mmol, 68%) as a light yellow solid. The product was used in the next step without any further purification.
1H NMR (400 MHz CD3OD): δ=3.47 (d, 1H, J=14.1 Hz); 3.37-3.18 (m, 7H); 2.40 (s, 3H); 2.38 (s, 3H); 2.36-2.27 (m, 1H), 2.14-2.05 (m, 2H); 2.03-1.93 (m, 1H); 1.81-1.78 (m, 1H).
LRMS (ES+): 216.1 (100, M−[SCOCH3]−+H+).
EXAMPLE III Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine using p-toluenesulfonic acid (1)
To a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R1 is H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL) was added p-toluenesulfonic acid monohydrate (5.9 g, 30.9 mmol) and the mixture was heated to reflux for 3.5 hours. The mixture was cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was heated to reflux and stirred for an additional 3 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (50 mL). The mixture was cooled to 0-5° C. and a 25% aqueous solution of sodium hydroxide (80 mL) was added. The mixture was stirred for 10-15 minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (3×50 mL). The organic phases were combined and extracted with 5% aqueous solution of sulfuric acid (3×50 mL). The acidic aqueous phases were combined and the pH was adjusted to 12 with a 25% aqueous solution of sodium hydroxide. The aqueous phase was extracted with heptane (3×50 mL) and the organic phases were combined, dried over sodium sulfate and the solvent was evaporated to give 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.8 g, 9.2 mmol, 89% yield) as a 3:1 cis/trans ratio mixture of diastereomers (determined by 1H NMR).
LRMS (ES+): 200.1 (100, M+H+).
EXAMPLE IV Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using racemic camphorsulfonic acid
In a similar experiment as Example III, racemic camphorsulfonic acid (7.2 g, 30.9 mmol) was added to a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R1 is H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL). The mixture was refluxed for 5 h, cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was refluxed for an additional an 8 hours and processed according to Example III to give 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.32 g, 6.63 mmol, 64% yield) in a 3.5:1 cis/trans ratio mixture of diastereomers (determined by 1H NMR).
EXAMPLE V Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using phenyl sulfonic acid
In a similar experiment as Example III, to a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R1 is H and R is methyl, 3 g, 10.3 mmol) in iso-propanol (50 mL) was added phenyl sulfonic acid (4.9 g, 30.9 mmol) and the mixture was refluxed 5 h, cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was refluxed for an additional 8 hours and worked up in a manner similar to Example III to furnish 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.6 g, 8.2 mmol, 80% yield) as a 2.5:1 cis/trans ratio mixture of diastereomers (determined by 1H NMR).
EXAMPLE VI Preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1) using p-toluenesulfonic acid in butanol
To a solution of 3-hydroxy-3-acetoxymercaptomethylquiniclidine thiolacetic acid salt (4 wherein R1 is H and R is methyl, 3 g, 10.3 mmol) in butanol (100 mL) was added of p-toluenesulfonic acid monohydrate (5.9 g, 30.9 mmol) and the mixture was refluxed for 3 hours with a Dean-Stark apparatus attached to the flask. The reaction mixture was cooled to room temperature and acetaldehyde diethyl acetal (6.1 g, 51.5 mmol) was added. The mixture was heated to 80° C. for an additional 8 h and worked up according to Example III to afford 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine (1.8 g, 9.2 mmol, 89% yield) as a 3:1 cis/trans ratio mixture of diastereomers (determined by 1H NMR).
References
- ^ Ono M, Takamura E, Shinozaki K, et al. (July 2004). “Therapeutic effect of cevimeline on dry eye in patients with Sjögren’s syndrome: a randomized, double-blind clinical study”. Am. J. Ophthalmol. 138 (1): 6–17. doi:10.1016/j.ajo.2004.02.010. PMID 15234277.
- ^ [1] MedicineNet: Cevimeline. Accessed 10/12/2007
-
- US 4 855 290 (Israel Institute for Biological Research; 8.8.1989; IL-prior. 10.5.1985).
- US 4 876 260 (Israel Institute for Biological Research; 24.10.1989; USA-prior. 28.10.1987).
- EP 683 168 (Ishihara Sangyo Kaisha; appl. 19.5.1995; J-prior. 19.5.1994).
-
Method for isomerization of trans-isomer:
- US 4 861 886 (Ishihara Sangyo Kaisha; 29.8.1989; J-prior. 10.7.1987).
-
Method of separation:
- IL 81 652 (Israel Institute for Biological Research; 12.5.1991; appl. 23.2.1987).
- JP 01 290 680 (Ishihara Sangyo Kaisha; 22.11.1989; J-prior. 18.5.1988).
-
Synthesis of enantiomerically pure (S)-3-hydroxy-3-mercaptomethylquinuclidine (S)-II:
- Bos, M.; Canesso, R.: Heterocycles (HTCYAM) 38 (8), 1889 (1994).
-
Synthesis of 3-quinuclidone:
- Sternbach, L.H.; Kaiser, S.: J. Am. Chem. Soc. (JACSAT) 74, 2215 (1952).
-
External links
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| Clinical data | |
|---|---|
| Trade names | Evoxac |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608025 |
| Pregnancy category |
|
| Routes of administration |
By mouth (capsules) |
| ATC code | |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Protein binding | <20% |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C10H17NOS |
| Molar mass | 199.31308 g/mol g·mol−1 |
| 3D model (JSmol) | |
/////////// Cevimeline, AF-102B, SNI-2011, SNK-508, Evoxac, セビメリン
Batimastat, バチマスタット
| Formula |
C23H31N3O4S2
|
|---|---|
| cas |
130370-60-4
|
| Mol weight |
477.6399
|
Batimastat (INN/USAN, codenamed BB-94) is an anticancer drug that belongs to the family of drugs called angiogenesis inhibitors. It acts as a matrix metalloproteinase inhibitor (MMPI) by mimicking natural MMPI peptides.
Batimastat was the first MMPI that went into clinical trials. First results of a Phase I trial appeared in 1994. The drug reached Phase III but was never marketed; mainly because it couldn’t be administered orally (as opposed to the newer and chemically similar MMPI marimastat), and injection into the peritoneum caused peritonitis.[1]
SYN
U.S. Patent 5,453,438
U.S. Patent 5,240,958
U.S. Patent 5,530,161
SYN
US 5240958; US 5310763; WO 9005719
The treatment of D-leucine (I) with NaNO2, H2SO4 and NaBr gives 2(R)-bromo-5-methylpentanoic acid (II), which is esterified with isobutene and H2SO4 to the corresponding tert-butyl ester (III). The condensation of (III) with dibenzyl malonate (IV) by means of potassium tert-butoxide in DMF yields the malonyl derivative (V), which is treated with trifluoroacetic acid to hydrolyze the tert-butyl ester, and without isolation is condensed with L-phenylalanine methyl amide (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC), affording 4-benzyloxy-3-(benzyloxycarbonyl)-2(R)-isobutylsuccinyl-L-phenylalanine methylamide (VII). The elimination of the benzyl groups of (VII) by hydrogenolysis over Pd/C in ethanol gives the dicarboxylic acid (VIII), which by partial decarboxylation and reaction with aqueous formaldehyde and piperidine yields 4-hydroxy-2(R)-isobutyl-3-methylenesuccinyl-L-phenylalanine methylamide (IX). The addition of thiophene-2-thiol (X) to the double bond of (IX) affords 4-hydroxy-2(R)-isobutyl-3(S)-(2-thienylsulfanylmethyl)succinyl-L-phenylalanine methylamide (XI), which is finally treated with hydroxylamine and hydroxybenzotriazole in dichloromethane/DMF.
SPEC
HPLC
References
- ^ Rothenberg, M. L.; Nelson, A. R.; Hande, K. R. (1999). “New Drugs on the Horizon: Matrix Metalloproteinase Inhibitors”. Stem Cells. 17 (4): 237–240. doi:10.1002/stem.170237. PMID 10437989.
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| Clinical data | |
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| Pregnancy category |
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| Routes of administration |
Injection into pleural space or abdomen |
| ATC code |
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| Legal status | |
| Legal status |
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| Identifiers | |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| ECHA InfoCard | 100.222.897 |
| Chemical and physical data | |
| Formula | C23H31N3O4S2 |
| Molar mass | 477.64 g/mol g·mol−1 |
| 3D model (JSmol) | |
//////////Batimastat, BB-94, バチマスタット ,
[H][C@@](CC1=CC=CC=C1)(NC(=O)[C@]([H])(CC(C)C)[C@]([H])(CSC1=CC=CS1)C(=O)NO)C(=O)NC
Abikoviromycin
- Molecular FormulaC10H11NO
- Average mass161.200 Da
Journal of Antibiotics (2003), 56, (9), 801-804.
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
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Cenobamate
Cenobamate
CAS: 913088-80-9
Chemical Formula: C10H10ClN5O2
Molecular Weight: 267.67
Related CAS #: 913088-80-9 913087-59-9
Synonym: YKP-3089; YKP3089; YKP3089; Cenobamate
IUPAC/Chemical Name: (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate
- 2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, carbamate (ester), (αR)- (9CI)
- (1R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate
- Carbamic acid (R)-(+)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl ester
- 2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, 2-carbamate, (αR)-
Cenobamate, also known as YKP-3089, is a novel new antiepileptic drug candidate. Cenobamate showed broad-spectrum anticonvulsant activity. Cenobamate entered into clinical trials and was discontinued in 2015.
PATENT
WO 2006112685
SK HOLDINGS CO., LTD. [KR/KR]; 99 Seorin-dong Jongro-ku Seoul 110-110, KR
| CHOI, Yong-Moon; US |
| KIM, Choon-Gil; KR |
| KANG, Young-Sun; KR |
| YI, Han-Ju; KR |
| LEE, Hyun-Seok; KR |
| KU, Bon-Chul; KR |
| LEE, Eun-Ho; KR |
| IM, Dae-Joong; KR |
| SHIN, Yu-Jin; KR |
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006112685
Patent
US 20100323410
PATENT
WO 2011046380
Clip
REFERENCES
1: Mula M. Emerging drugs for focal epilepsy. Expert Opin Emerg Drugs. 2013
Mar;18(1):87-95. doi: 10.1517/14728214.2013.750294. Epub 2012 Nov 26. Review.
PubMed PMID: 23176519.
2: Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress
report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT
IX). Epilepsy Res. 2009 Jan;83(1):1-43. doi: 10.1016/j.eplepsyres.2008.09.005.
Epub 2008 Nov 12. PubMed PMID: 19008076.
/////////////YKP-3089, YKP3089, YKP3089, Cenobamate
NC(O[C@H](C1=CC=CC=C1Cl)CN2N=CN=N2)=O
Viloxazine, ヴィロキサジン;
Viloxazine
- Molecular FormulaC13H19NO3
- Average mass237.295 Da
update FDA APPROVED 2021/4/2, Qelbree, Viloxazine hydrochloride
| Formula |
C13H19NO3. HCl
|
|---|---|
| CAS |
35604-67-2
|
| Mol weight |
273.7558
|
NEW DRUG APPROVALS
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Viloxazine (trade names Vivalan, Emovit, Vivarint and Vicilan) is a morpholine derivative and is a selective norepinephrine reuptake inhibitor (NRI). It was used as an antidepressant in some European countries, and produced a stimulant effect that is similar to the amphetamines, except without any signs of dependence. It was discovered and brought to market in 1976 by Imperial Chemical Industries and was withdrawn from the market in the early 2000s for business reasons.
Clip
https://www.sciencedirect.com/science/article/pii/S0040402015302659
Patent
US 20180265482
| Viloxazine ((R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine]) is a bicyclic morpholine derivative, assigned CAS No. 46817-91-8 (CAS No. 35604-67-2 for the HCl salt). It is characterized by the formula C 13H 19NO 3, with a molecular mass of 237.295 g/mol. Viloxazine has two stereoisomers, (S)-(−)- and (R)-(+)-isomer, which have the following chemical structures: |
| Viloxazine is known to have several desirable pharmacologic uses, including treatment of depression, nocturnal enuresis, narcolepsy, sleep disorders, and alcoholism, among others. In vivo, viloxazine acts as a selective norepinephrine reuptake inhibitor (“NRI”). |
| Between the two stereoisomers, the (S)-(−)-isomer is known to be five times as pharmacologically active as the (R)-(+)-isomer. See, e.g., “Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4 oxazine (viloxazine) and Related Compounds” (Journal of Medicinal Chemistry, Jan. 9, 1976, 19(8); 1074) in which it is disclosed that optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine were prepared and absolute configurations assigned. The synthesis of optical isomers of viloxazine analogs of known configuration was accomplished by resolution of the intermediate 4-benzyl-2-(p-toluenesulfonyloxymethyl)tetrahydro-1,4-oxazine isomers. |
| Some unsatisfactory methods of synthesizing viloxazine are known in the art. For example, as disclosed in U.S. Pat. No. 3,714,161, viloxazine is prepared by reacting ethoxyphenol with epichlorohydrin to afford the epoxide intermediate 1-(2-ethoxyphenoxy)-2,3-epoxypropane. This epoxide intermediate is then treated with benzylamine followed with chloroacetyl chloride. The resulting morpholinone is then reduced by lithium aluminum hydride and then by Pd/C-catalyzed hydrogenation to yield viloxazine free base. |
| Yet another unsatisfactory synthesis of viloxazine is disclosed in U.S. Pat. No. 3,712,890, which describes a process to prepare viloxazine HCl, wherein the epoxide intermediate, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, is reacted with 2-aminoethyl hydrogen sulfate in ethanol in the presence of sodium hydroxide to form viloxazine free base. The product is extracted with diethyl ether from the aqueous solution obtained by evaporating the solvent in the reaction mixture then adding water to the residue. The ethereal extract is dried over a drying agent and the solvent is removed. Viloxazine HCl salt is finally obtained by dissolving the previous residue in isopropanol, concentrated aqueous HCl, and ethyl acetate followed by filtration. |
| The foregoing methods of synthesizing viloxazine suffer from a number of deficiencies, such as low reaction yield and unacceptably large amount of impurities in the resulting product. Effective elimination or removal of impurities, especially those impurities possessing genotoxicity or other toxicities, is critical to render safe pharmaceutical products. For example, certain reagents traditionally utilized in viloxazine HCl preparation, such as epichlorohydrin and 2-aminoethyl hydrogen sulfate, present a special problem due to their toxicity. There is a need for effective methods to remove or limit harmful impurities down to a level that is appropriate and safe according to contemporary sound medical standards and judgment. Accordingly, a continuing and unmet need exists for new and improved methods of manufacturing viloxazine and its various salts to yield adequate quantities of pharmacologically desirable API with predictable and reliable control of impurities. |
| Polymorph control is also an important aspect of producing APIs and their associated salts that are used in pharmaceutical products. However, no polymorphs of viloxazine HCl have previously been disclosed. A need therefore exists for new polymorphic forms of viloxazine that have improved pharmacological properties. |
PATENT
WO 2011130194
For the sake of convenience and without putting any limitations thereof, the methods of manufacture of viloxazine have been separated into several steps, each step being disclosed herein in a multiplicity of non-limiting embodiments. These steps comprise Step 1, during which 2-ethoxyphenol and epichlorhydrin are reacted to produce l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1); Step 2, during which l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1) is converted into viloxazine base which is further converted into viloxazine salt, and Step 3, during which viloxazine salt is purified/recrystallized, and various polymorphic forms of viloxazine salt are prepared.
The above-mentioned steps will be considered below in more details.
[0031] The process of the Step 1 may be advantageously carried out in the presence of a phase-transfer catalyst to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane. Alternatively, the process may make use of a Finkelstein catalyst described in more details below. Additionally, the reaction may take place without the use of the catalyst.
FIG. 1, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with Step I of an exemplary synthesis of viloxazine:
STEP I:
Epoxide 1
In one embodiment of the Step 1, the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (epoxide 1) can be effected by the use of a phase transfer catalyst in the presence of a solid or liquid base with a solution of a corresponding phenol and epichlorohydrin in one or more solvents (Fig. 1). The phase transfer catalyst can be selected from ammonium salts, such as benzyltriethylammonium salts, benzyltrimethylammonium salts, and tetrabutylammonium salts, phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The solid or liquid base can be a carbonate such as alkali carbonate, NaOH, KOH, LiOH, LiOH/LiCl, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, or other appropriate base. The solvents used in the solution of a corresponding phenol and epichlorohydrin include but are not limited to ethers such as methyl t-butyl ether, ketones, non-substituted or substituted aromatic solvents (xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, DMF, dioxanes, non-substituted and substituted pyridines, acetonitrile, pyrrolidones, nitromethane , or other appropriate solvent. Additional catalyst, such as, for example, Finkelstein catalyst, can also be used in the process of this embodiment. This reaction preferably takes place at an elevated temperature. In one variation of the embodiment, the temperature is above 50°C. In another variation, epichlorohydrin, potassium carbonate, and a phase transfer catalyst are mixed with a solution of 2-ethoxyphenol in a solvent at an elevated temperature, such as 50 – 60°C. After the reaction is complete, the reaction mixture can be washed with water, followed by work-up procedures known in the art. Variations of this embodiment of the invention are further disclosed in Examples 1-8.
[0033] In one variation of the above embodiment of the Step 1 , Epoxide 1 is prepared by reacting 2-ethoxyphenol and epichlorohydrin in a solvent in the presence of two different catalysts, and a base in a solid state. The first catalyst is a phase transfer catalyst as described above; the second catalyst is a Finkelstein reaction catalyst. Without putting any limitation
hereon, metal iodide and metal bromide salts, such as potassium iodide, may be used as an example of a Finkelstein catalyst. The phase transfer catalyst and a solvent may be selected from any phase transfer catalysts and solvents known in the art. Potassium carbonate may be used as a non-limiting example of a solid base. Using the solid base in a powdered form may be highly beneficial due to the greatly enhanced interface and limiting the side reactions. This variation of the embodiment is further illustrated by Example 9. In another variation of the embodiment, liquid base such as triethylamine can be used to replace the solid base.
[0034] In a different embodiment of Step 1 , 2-ethoxyphenol and epichlorohydrin are reacted in a solvent-free system that comprises a solid or liquid base, a phase transfer catalyst as listed above and a Finkelstein catalyst.
[0035] FIG. 2, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with the Step I of another exemplary synthesis of viloxazine ( biphasic):
STEP I (alternative embodiment):
In this embodiment of Step 1, illustrated in Fig. 2, Epoxide 1 can be prepared by reacting epichlorohydrin with 2-ethoxyphenol in the presence of a catalytic amount of a phase transfer catalyst without the use of solvents at elevated temperatures in a two-stage process to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane with very few side products. This embodiment of the invention is further illustrated by a non-limiting Example 12. The phase transfer catalyst for this embodiment can be selected from ammonium salts such as benzyltriethylammonium salts, benzyltrimethylammonium salts, tetrabutylammonium salts, etc; phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The first stage of the process of this embodiment may take place without a solvent in a presence of a large excess of epichlorohydrin. This stage is followed by a de-chlorination stage, before or after
removal of excess epichlorohydrin, using a base and a solvent. The reaction produces l-(2-ethoxyphenoxy)-2,3-epoxypropane in high yield. Example of the bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di-or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine etc.), DMAP. In one variation of this embodiment of Step 1, the phase transfer catalyst may be used only at the de-chlorination stage of the process. The de-chlorination stage can be carried out in a biphasic system or in a single phase system. For a biphasic system, it can be an organic-aqueous liquid biphasic system, or a liquid-solid biphasic system. Solvents that are useful for the process include but are not limited to non-substituted and substituted aromatic solvents (e.g. toluene, benzene, chlorobenzene, dimethylbenzene, xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, dioxanes, DMF, DMSO, non-substituted and substituted pyridines, ketones, pyrrolidones, ethers, acetonitrile, nitromethane. As mentioned above, this process takes place at the elevated temperature. In one variation of the embodiment, the temperature is above 60°C. In another variation, 2-ethoxyphenol and epichlorohydrin are heated to 60 – 90°C for a period of time in the presence of phase transfer catalyst. Excess of epichlorohydrin is removed and the residue is dissolved in a solvent such as toluene or benzene treated with an aqueous base solution, such as NaOH, KOH, LiOH, LiOH/LiCl. In yet another variation of the embodiment, the residue after epichlorohydrin removal can be dissolved in one or more of the said solvent and treated with a base (solid or liquid but not an aqueous solution) and optionally a second phase transfer catalyst, optionally at elevated temperatures.
[0036] In yet another embodiment of Step 1 , Epoxide 1 can also be prepared by using a catalyst for a so-called Finkelstein reaction in the presence of a Finkelstein catalyst but without the need to use a phase transfer catalyst. Finkelstein catalysts useful herein include metal iodide salts and metal bromide salts, among others. In one variation of this embodiment, 2-ethoxyphenol and epichlorohydrin are dissolved in a polar aprotic solvent such as DMF, and a catalytic amount of an iodide such as potassium iodide and a base, as solid or liquid, are used. Preferably, the base is used as a solid, such as potassium carbonate powder. This embodiment is further illustrated by the Example 11.
[0037] In the alternative embodiment of Step 1 , Epoxide 1 can also be prepared by a different method that comprises reacting epichlorohydrin and the corresponding phenol in the presence of a base at a temperature lower than the ambient temperature, especially when a base solution is used, and without the use of a phase transfer catalyst. This embodiment is illustrated by the Example 10.
[0038] A very high, almost quantitative, yield of 1 -(2-ethoxyphenoxy)-2,3-epoxypropane can be obtained through realizing the above-described embodiments of Step 1 , with less impurities generated in Epoxide 1.
[0039] Epoxide 1 , produced in Step 1 as described above, is used to prepare viloxazine base (viloxazine), which is further converted into viloxazine salt through the processes of Step 2.
[0040] FIG. 3, depicted below, schematically illustrates the preparation of viloxazine
(“Step Ila”) and the preparation of viloxazine hydrochloride (“Step lib”), as well as their purification (“Step III”) in accordance with another example embodiment hereof:
STEP Ila:
Hydrogen Sulfate
STEP lib:
Step III:
Conversion
Viloxazine free base ► Viloxazine salt
Wash/ raction
Recrystallization
Purified viloxazine salt
In the embodiment of Step 2, illustrated in Fig. 3, the preparation of viloxazine base is achieved by reacting the Epoxide 1 intermediate prepared in Step 1 and aminoethyl hydrogen sulfate in presence of a large excess of a base as illustrated by the Examples 5-7 and 14. The base may be present as a solid or in a solution. Preferably, the molar ratio of the base to Epoxide 1 is more than 10. More preferably the ratio is more than 12. Even more preferably, the ratio is between 15 and 40. It was unexpectedly discovered that the use of a higher ratio of a base results in a faster reaction, less impurities, and lower reaction temperature.
[0041] Further advantages may be offered by a specific variation of this embodiment, wherein the base is added to the reaction mixture in several separate steps. For example, a third of the base is added to the reaction mixture, and the mixture is stirred for a period of time. Then the rest of the base is added followed by additional stirring. Alternatively, half of the base is added initially followed by the second half after some period of time, or the base is added in three different parts separated by periods of time. The bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, and combinations thereof. . In one embodiment of the invention, the base is KOH. In another embodiment, the base is NaOH. In a further embodiment, the base is K2C03 powder. In yet further embodiment, the base is triethylamine. This embodiment is illustrated further by
Examples 13,15 and 16.
[0042] In another exemplary embodiment of Step 2, viloxazine is produced by cyclization of novel intermediate compound “Diol 1 ,” which is made from Epoxide 1 and N-benzyl-aminoethanol. This method allows one to drastically reduce the use of potentially toxic materials in the manufacturing process, completely eliminating some of them such as aminoethyl hydrogen sulfate. The first stage of the reaction results in the formation of an intermediate of Formula 3 (Diol 1), which is a new, previously unidentified compound.
[0043] Formula 3
Diol 1
FIG. 4, depicted below, schematically illustrates the preparation of viloxazine and its salts via “Diol 1” in accordance with another exemplary embodiment hereof (Bn = benzyl, Et = ethyl):
Viloxazine HCI
As illustrated in Fig. 4, Diol 1 is turned into N-benzyl viloxazine by cyclization. Removal of the benzyl protective group yields viloxazine base. Similarly, FIG. 5, depicted below, schematically illustrates the cyclization of Diol 1, as well as some side-reactions thereof.
Uses
Viloxazine hydrochloride was used in some European countries for the treatment of clinical depression.[4][5]
Side effects
Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy,[6]) and increased libido.[7]
Drug interactions
Viloxazine increased plasma levels of phenytoin by an average of 37%.[8] It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,[9] sometimes resulting in accidental overdose of theophylline.[10]
Mechanism of action
Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.[11] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.[11]
It was also found to up-regulate GABAB receptors in the frontal cortex of rats.[12]
Chemical properties
It is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.[13]
History
Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.[14]:610[15]:9 The drug was first marketed in 1976.[16] It was never approved by the FDA,[5] but the FDA granted it an orphan designation (but not approval) for cataplexy and narcolepsy in 1984.[17] It was withdrawn from markets worldwide in 2002 for business reasons.[14][18]
As of 2015, Supernus Pharmaceuticals was developing formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812.[19][20]
Research
Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.[21][22] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[23]
In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM[24] without really improving daytime somnolence.[25]
In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.[18]
Viloxazine has also been studied for the treatment of alcoholism, with some success.[26]
While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.[27]
It is also under investigation as a treatment for attention deficit hyperactivity disorder.[28]
REFERNCES
- ^ Bouchard JM, Strub N, Nil R (October 1997). “Citalopram and viloxazine in the treatment of depression by means of slow drop infusion. A double-blind comparative trial”. Journal of Affective Disorders. 46 (1): 51–8. doi:10.1016/S0165-0327(97)00078-5. PMID 9387086.
- ^ Case DE, Reeves PR (February 1975). “The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans”. Xenobiotica. 5 (2): 113–29. doi:10.3109/00498257509056097. PMID 1154799.
- ^ “SID 180462– PubChem Substance Summary”. Retrieved 5 November 2005.
- ^ Pinder, RM; Brogden, RN; Speight, ™; Avery, GS (June 1977). “Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness”. Drugs. 13 (6): 401–21. doi:10.2165/00003495-197713060-00001. PMID 324751.
- ^ Jump up to:a b Dahmen, MM, Lincoln, J, and Preskorn, S. NARI Antidepressants, pp 816-822 in Encyclopedia of Psychopharmacology, Ed. Ian P. Stolerman. Springer-Verlag Berlin Heidelberg, 2010. ISBN 9783540687061
- ^ Edwards JG, Glen-Bott M (September 1984). “Does viloxazine have epileptogenic properties?”. Journal of Neurology, Neurosurgery, and Psychiatry. 47 (9): 960–4. doi:10.1136/jnnp.47.9.960. PMC 1027998. PMID 6434699.
- ^ Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). “Antidepressants and sexual stimulation: the correlation” [Antidepressants and sexual stimulation: the correlation]. L’Encéphale (in French). 24 (3): 180–4. PMID 9696909.
- ^ Pisani F, Fazio A, Artesi C, et al. (February 1992). “Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction”. Journal of Neurology, Neurosurgery, and Psychiatry. 55 (2): 126–7. doi:10.1136/jnnp.55.2.126. PMC 488975. PMID 1538217.
- ^ Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B (September 1989). “A study of the interaction of viloxazine with theophylline”. Therapeutic Drug Monitoring. 11 (5): 520–2. doi:10.1097/00007691-198909000-00005. PMID 2815226.
- ^ Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P (1986). “Theophylline intoxication following viloxazine induced decrease in clearance”. European Journal of Clinical Pharmacology. 30 (3): 351–3. doi:10.1007/BF00541543. PMID 3732375.
- ^ Jump up to:a b Lippman W, Pugsley TA (August 1976). “Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities”. Canadian Journal of Physiology and Pharmacology. 54 (4): 494–509. doi:10.1139/y76-069. PMID 974878.
- ^ Lloyd KG, Thuret F, Pilc A (October 1985). “Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock”. The Journal of Pharmacology and Experimental Therapeutics. 235 (1): 191–9. PMID 2995646.
- ^ Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA (May 1984). “Behavioral and radioreceptor analysis of viloxazine stereoisomers” [Behavioral and radioreceptor analysis of viloxazine stereoisomers]. Biulleten’ Eksperimental’noĭ Biologii i Meditsiny (in Russian). 97 (5): 576–8. PMID 6326891.
- ^ Jump up to:a b Williams DA. Antidepressants. Chapter 18 in Foye’s Principles of Medicinal Chemistry, Eds. Lemke TL and Williams DA. Lippincott Williams & Wilkins, 2012. ISBN 9781609133450
- ^ Wermuth, CG. Analogs as a Means of Discovering New Drugs. Chapter 1 in Analogue-based Drug Discovery. Eds.IUPAC, Fischer, J., and Ganellin CR. John Wiley & Sons, 2006. ISBN 9783527607495
- ^ Olivier B, Soudijn W, van Wijngaarden I. Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors. Prog Drug Res. 2000;54:59-119. PMID 10857386
- ^ FDA. Orphan Drug Designations and Approvals: Viloxazine Page accessed August 1, 2-15
- ^ Jump up to:a b Vignatelli L, D’Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003724. Review. PMID 18254030
- ^ Bloomberg Supernus profile Page accessed August 1, 2015
- ^ Supernus. Psychiatry portfolio Page accessed August 1, 2015
- ^ Attenburrow AA, Stanley TV, Holland RP (January 1984). “Nocturnal enuresis: a study”. The Practitioner. 228 (1387): 99–102. PMID 6364124.
- ^ ^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). “Viloxazine versus imipramine in the treatment of enuresis”. The Turkish Journal of Pediatrics. 29 (4): 227–30. PMID 3332732.
- ^ Libert MH (1990). “The use of viloxazine in the treatment of primary enuresis” [The use of viloxazine in the treatment of primary enuresis]. Acta Urologica Belgica (in French). 58 (1): 117–22. PMID 2371930.
- ^ Guilleminault C, Mancuso J, Salva MA, et al. (1986). “Viloxazine hydrochloride in narcolepsy: a preliminary report”. Sleep. 9 (1 Pt 2): 275–9. PMID 3704453.
- ^ Mitler MM, Hajdukovic R, Erman M, Koziol JA (January 1990). “Narcolepsy”. Journal of Clinical Neurophysiology. 7 (1): 93–118. doi:10.1097/00004691-199001000-00008. PMC 2254143. PMID 1968069.
- ^ Altamura AC, Mauri MC, Girardi T, Panetta B (1990). “Alcoholism and depression: a placebo controlled study with viloxazine”. International Journal of Clinical Pharmacology Research. 10 (5): 293–8. PMID 2079386.
- ^ León CA, Vigoya J, Conde S, Campo G, Castrillón E, León A (March 1994). “Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia” [Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia]. Acta Psiquiátrica Y Psicológica de América Latina (in Spanish). 40 (1): 41–9. PMID 8053353.
- ^ Mattingly, GW; Anderson, RH (December 2016). “Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems”. CNS Spectrums. 21 (S1): 45–59. doi:10.1017/S1092852916000808. PMID 28044946.
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| Clinical data | |
|---|---|
| Routes of administration | By mouth, intravenous infusion[1] |
| ATC code | N06AX09 (WHO) |
| Legal status | |
| Legal status | In general: uncontrolled |
| Pharmacokinetic data | |
| Elimination half-life | 2–5 hours |
| Excretion | Renal[2] |
| Identifiers | |
| IUPAC name[show] | |
| CAS Number | 46817-91-8 35604-67-2 (HCl salt) |
| PubChem CID | 5666 |
| ChemSpider | 5464 |
| UNII | 5I5Y2789ZF |
| KEGG | D08673 |
| ChEMBL | ChEMBL306700 |
| ECHA InfoCard | 100.051.148 |
| Chemical and physical data | |
| Formula | C13H19NO3 |
| Molar mass | 237.295 g/mol g·mol−1 |
| 3D model (JSmol) | Interactive image |
| Chirality | Racemic mixture |
| SMILES[hide]O(c1ccccc1OCC)CC2OCCNC2 | |
| InChI[hide]InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3 Key:YWPHCCPCQOJSGZ-UHFFFAOYSA-N |
/////////////////Viloxazine, ヴィロキサジン , Emovit, Vivalan, Emovit, Vivarint, Vicilan
New Drug Approvals 
