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ATICAPRANT
1174130-61-0
BENZAMIDE, 4-(4-(((2S)-2-(3,5-DIMETHYLPHENYL)-1-PYRROLIDINYL)METHYL)PHENOXY)-3-FLUORO-
C26H27FN2O2, 418.512
Aticaprant, also known by its developmental codes JNJ-67953964, CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which is under development for the treatment of major depressive disorder.[2][3][4] A regulatory application for approval of the medication is expected to be submitted by 2025.[2] Aticaprant is taken by mouth.[1]
Side effects of aticaprant include itching, among others.[4][5] Aticaprant acts as a selective antagonist of the KOR, the biological target of the endogenous opioid peptide dynorphin.[3] The medication has decent selectivity for the KOR over the μ-opioid receptor (MOR) and other targets, a relatively long half-life of 30 to 40 hours, and readily crosses the blood–brain barrier to produce central effects.[4][6]
Aticaprant was originally developed by Eli Lilly, was under development by Cerecor for a time, and is now under development by Janssen Pharmaceuticals.[2] As of July 2022, it is in phase 3 clinical trials for major depressive disorder.[2] Like other kappa opioid antagonists currently under clinical investigation for the treatment of major depression, its efficacy may be compromised by the countervailing activation of pro-inflammatory cytokines in microglia within the CNS.[7]
Aticaprant was also under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal, but development for these indications was discontinued.[2]
Aticaprant is a potent, selective, short-acting (i.e., non-“inactivating”) antagonist of the KOR (Ki = 0.81 nM vs. 24.0 nM and 155 nM for the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), respectively; approximately 30-fold selectivity for the KOR).[8][9][10] The drug has been found to dose-dependently block fentanyl-induced miosis at 25 mg and 60 mg in humans (with minimal to no blockade at doses of 4 to 10 mg), suggesting that the drug significantly occupies and antagonizes the MOR at a dose of at least 25 mg but not of 10 mg or less.[10] However, a more recent study assessing neuroendocrine effects of the drug in normal volunteers and subjects with a history of cocaine dependence reported observations consistent with modest MOR antagonism at the 10 mg dose.[11] In animal models of depression, aticaprant has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[12]
Positron emission tomography imaging revealed that brain KORs were almost completely saturated by the drug 2.5 hours following a single dose of 10 mg, which supported the 4 mg to 25 mg dosages that aticaprant is being explored at in clinical trials.[13][14] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[15][14] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[15][14] No serious side effects were observed, and all side effects seen were mild to moderate and were not thought to be due to aticaprant.[14]
The oral bioavailability of aticaprant is 25%.[1] The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration.[1] It has an elimination half-life of 30 to 40 hours in healthy subjects.[1] The circulating levels of aticaprant increase proportionally with increasing doses.[1] Steady-state concentrations are reached after 6 to 8 days of once-daily dosing.[1] Aticaprant has been shown to reproducibly penetrate the blood–brain barrier.[13][14]
Aticaprant was originally developed by Eli Lilly under the code name LY-2456302.[2] It first appeared in the scientific literature in 2010 or 2011.[16][17] The compound was first patented in 2009.[18]
In February 2015, Cerecor Inc. announced that they had acquired the rights from Eli Lilly to develop and commercialize LY-2456302 (under the new developmental code CERC-501).[19]
As of 2016, aticaprant has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[20][12] A phase II study of aticaprant in heavy smokers was commenced in early 2016 and results of the study were expected before the end of 2016.[14] Aticaprant failed to meet its main endpoint for nicotine withdrawal in the study.[21]
In August 2017, it was announced that Cerecor had sold its rights to aticaprant to Janssen Pharmaceuticals.[22][21] Janssen was also experimenting with esketamine for the treatment of depression as of 2017.[21]
In addition to major depressive disorder, aticaprant was under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal.[2] However, development for these indications was discontinued.[2]
κ-Opioid receptor § Antagonists
SCHEME
SYNTHESIS
WO/2024/178082COMPOSITION OF OPIOID RECEPTOR MODULATOR AND MDMA FOR USE THEREOF
WO/2024/173843QUINOLINE DERIVATIVES WHICH ACT AS KAPPA-OPIOID RECEPTOR ANTAGONISTS
20240238245COMPOSITIONS AND METHODS FOR THE TREATMENT OF DEPRESSION
20240189274Compositions And Methods For The Treatment Of Depression
WO/2024/102802ZELATRIAZIN FOR THE TREATMENT OF DEPRESSION
WO/2024/100285TREATMENT OF A COGNITIVE DISORDER WITH AN AGENT THAT INCREASES THE..
117615757Compositions and methods for treating depression
117142999Racemization method of drug intermediate
20230348377PURE FORMS OF CRYSTALLINE ATICAPRANT
WO/2023/170550POLYMORPH FORMS OF ATICAPRANT FOR USE IN TREATING MAJOR DEPRESSIVE DISORDER
WO/2023/170547PURE FORMS OF CRYSTALLINE ATICAPRANT
20230277499Forms of aticaprant
20230277500COMPOSITIONS COMPRISING ATICAPRANT
WO/2023/164385NEUROACTIVE STEROIDS FOR TREATMENT OF GASTROINTESTINAL DISEASES OR CONDITIONS
20090186873Kappa selective opioid receptor antagonist
WO/2009/094260KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST
20100197669Kappa selective opioid receptor antagonist
2252581KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST
201500053151-substituted 4-arylpiperazine as kappa opioid receptor antagonists
WO/2013/0864961-SUBSTITUTED 4-ARYLPIPERAZINE AS KAPPA OPIOID RECEPTOR ANTAGONISTS
101925576Kappa selective opioid receptor antagonist
PAPERS
ACS Omega (2020), 5(41), 26938-26945 https://pubs.acs.org/doi/full/10.1021/acsomega.0c04329
REF https://pubs.acs.org/doi/suppl/10.1021/acsomega.0c04329/suppl_file/ao0c04329_si_001.pdf
N-Methoxy-N-methyl-4-chlorobutyramide (S1). To a mixture of N,O-dimethylhydroxylamine hydrochloride (95.0 mmol, 9.27 g) in CH2Cl2 (150 mL) was
added 2 M NaOH (300 mmol, 150 mL) and 4-chlorobutyryl chloride (100 mmol,
11.2 mL) at 0 ˚C. The mixture was stirred for 42 h at room temperature. The
organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phase was washed with 2 M NaOH (100 mL), dried over Na2SO4, filtered, and concentrated
to afford the title comlund in 75% yield as a colorless liquid.
1H NMR (400 MHz, CDCl3) : 2.08-2.15
(m, 2H), 2.63 (t, J = 7.0 Hz, 2H), 3.19 (s, 3H), 3.64 (t, J = 6.3 Hz, 2H), 3.71 (s, 3H).
13C{
1H} NMR (100
MHz, CDCl3) : 27.1, 28.6, 32.1, 44.6, 61.1. IR (max/cm-1
): 2965, 2940, 2821, 1656, 14421, 1417, 1387,
1178, 1107, 997. HRMS (ESI+): calculated for [M+Na]+
: 188.0449, found: 188.0450.
4-Chloro-1-(3,5-dimethylphenyl)butan-1-one (S2). To a mixture of N-methoxy-N-methyl-4-chlorobutyramide (S1, 65.0 mmol, 10.8 g) in anhydrous Et2O
(100 mL) was added dropwise 3,5-dimethylphenylmagnesium bromide (ca. 1 M
in Et2O, ca. 130 mmol, prepared from 1-bromo-3,5-dimethylbenzene (130 mmol,
17.7 mL) and Mg turnings (169 mmol, 4.11 g) in anhydrous Et2O (130 mL)) over 1 h at -40 ˚C under Ar.
The reaction mixture was stirred at room temperature for 20 h. After cooling to 0 ˚C, saturated NH4Cl
solution (200 mL) was added. The organic phase was separated, washed with water (100 mL) and brine
(100 mL), dried over Na2SO4, and filtered. After concentration, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent) to afford the title compound in 91% yield as a greenish
yellow liquid.
1H NMR (400 MHz, CDCl3) : 2.18-2.25 (m, 2H), 2.38 (s, 6H), 3.15 (t, J = 7.0 Hz, 2H),
3.67 (t, J = 6.3 Hz, 2H), 7.21 (s, 1H), 7.58 (s, 2H). 13C{
1H} NMR (100 MHz, CDCl3) : 21.2, 26.8, 35.4,
44.7, 125.8, 134.8, 136.8, 138.3, 199.4. IR (max/cm-1
): 3047, 3006, 2961, 2920, 2868, 1443, 1411, 1322,
1303, 1181, 1159, 844, 785, 687. HRMS (APCI+): calculated for [M+H]+
: 211.0884, found: 211.0884.
(RS)-N-(4-Chloro-1-(3,5-dimethylphenyl)butylidene)-tertbutanesulfinamide (S3). Ti(OEt)4 (100 mol, 21.0 mL) was added to a mixture
of (RS)-tert-butanesulfinamide (1.0 M in THF, 50 mmol, 50 mL) and 4-chloro1-(3,5-dimethylphenyl)butan-1-one (S2, 50.0 mmol, 10.5 g) under N2. The mixture was refluxed for 48 h. After cooling to room temperature, brine (100 mL)
was added, and the resulting mixture was filtered over Celite using EtOAc (ca.
300 mL). The organic was separated, dried over Na2SO4, and filtered. After concentration under reduced
pressure, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent) to
afford the title compound in 57% yield as a brown viscous liquid.
1H NMR (400 MHz, CDCl3) : 1.33
(s, 9H), 2.10-2.22 (m, 2H), 2.36 (s, 6H), 3.27 (s, 1H), 3.43 (s, 1H), 3.64 (t, J = 6.5 Hz, 2H), 7.13 (s, 1H),
7.47 (s, 2H).
13C{
1H} NMR (100 MHz, CDCl3) : 21.3, 22.7, 30.2, 31.6, 44.7, 57.7, 125.2, 133.4, 137.6,
138.2, 178.6. IR (max/cm-1
): 3046, 2958, 2922, 2866, 1599, 1577, 1455, 1361, 1320, 1308, 1069, 856.
HRMS (ESI+): calculated for [M+H]
+
: 314.1340, found: 314.1344. []D
20 +11.0 (c = 1.01, CH2Cl2).
(RS,S)-1-tert-Butylsulfinyl-2-(3,5-dimethylphenyl)pyrrolidine (S4). To a solution of (RS)-N-(4-chloro-1-(3,5-dimethylphenyl)butylidene)-tert-butanesulfinamide
(S3, 25.6 mmol, 8.06 g) in anhydrous THF (100 mL) at -78 °C was added LiBEt3H
(28 mmol, 0.5 M in THF, 28.2 mL) under Ar. The reaction was stirred at -78 °C for
1 h, subsequently allowed to warm up to room temperature and stirred for additional
20 h. Saturated NaHCO3 solution (80 mL) was slowly added. The mixture was filtered and extracted
with EtOAc (3 × 100 mL). The combined organic phase was dried over Na2SO4 and filtered. After
concentration, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent)
to afford the title compound in 72% yield as pale yellow solid. mp.: 56 ˚C. 1H NMR (400 MHz, CDCl3)
: 1.12 (s, 9H), 1.74-1.90 (m, 3H), 1.93-2.02 (m, 1H), 2.18-2.27 (m, 1H), 2.30 (s, 6H), 2.94-3.02 (m, 1H),
3.85-3.91 (m, 1H), 4.55-4.59 (m, 1H), 6.88 (s, 1H), 6.90 (s, 2H).
13C{
1H} NMR (100 MHz, CDCl3) :
21.3, 23.8, 26.3, 36.0, 42.1, 57.2, 69.2, 125.0, 128.7, 137.7, 143.2. IR (max/cm-1
): 3023, 2957, 2920,
2866, 1607, 1471, 1360, 1061, 957, 847. HRMS (ESI+): calculated for [M+Na]+
: 302.1549, found:
302.1548. []D
20
-137 (c = 0.49, CH2Cl2)
(S)-2-(3,5-Dimethylphenyl)pyrrolidine hydrochloride (1j•HCl). To a solution
of (RS,S)-1-tert-butylsulfinyl-2-(3,5-dimethylphenyl)pyrrolidine (S4, 14.7 mmol,
4.12 g) in dioxane (250 mL) was added dropwise HCl (ca. 150 mmol, 4 M in dioxane, 38 mL). The mixture was stirred for 1 h at room temperature under N2, and
then the mixture was concentrated under reduced pressure. Then, Et2O (200 mL) was added to the residue
and the mixture was cooled to 0 ˚C. The precipitate was collected by filtration, washed with Et2O (40
mL), and dried under reduced pressure to afford the title compound in 94% yield as white solid. mp.: 198
˚C. 1H NMR (400 MHz, D2O) : 2.00-2.15 (m, 3H), 2.18 (s, 6H), 2.27-2.35 (m, 1H), 3.27-3.36 (m, 2H),
4.45 (t, J = 8.0 Hz, 1H), 6.97 (s, 2H), 7.01 (s, 1H). 13C{
1H} NMR (100 MHz, D2O) : 20.9, 24.19, 30.9,
46.0, 63.8, 119.79, 125.6, 131.4, 135.3, 140.1. IR (max/cm-1
): 3033, 3012, 2970, 2855, 2743, 2571, 2480,
1608, 1590, 1414, 850. HRMS (ESI+): calculated for [M-Cl]
+
: 176.1434, found: 176.1435. []D
20 +7.1
(c = 1.01, MeOH).
(S)-2-(3,5-Dimethylphenyl)pyrrolidine (1j). To a suspension of (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride (1j•HCl, 13.5 mmol, 2.86 g) in anhydrous Et2O
(200 mL) was added a saturated solution of NaHCO3 (200 mL). The resulting mixture
was stirred for 20 min at room temperature. The organic was separated and the aqueous
phase was extracted with Et2O (2 × 100 mL). The combined organic phase was dried over MgSO4 and
filtered. The solvent was removed under reduced pressure to afford the title compound as a pale yellow
liquid in 99% yield.
1H NMR (400 MHz, CDCl3) : 1.60-1.71 (m, 1H), 1.78-1.96 (m, 2H), 1.98 (s, 1H),
2.11-2.19 (m, 1H), 2.30 (s, 6H), 2.95-3.02 (m, 1H), 3.17-3.23 (m, 1H), 4.03 (t, J = 7.7 Hz, 1H), 6.87 (s,
1H), 6.97 (s, 2H). 13C{
1H} NMR (100 MHz, CDCl3) : 21.3, 25.5, 34.2, 46.9, 62.6, 124.2, 128.4, 137.8,
144.7. IR (max/cm-1
): 3332, 3010, 2960, 2915, 2869, 1605, 1458, 1101, 845. HRMS (ESI+): calculated
for [M+H]+
: 176.1434, found: 176.1436. []D
20
-30.5 (c = 1.01, MeOH). Chiral HPLC (ChiralPak ODH, 4.6 mm × L 250 mm, hexane:2-propanol = 90:10, 0.5 mL/min, = 254 nm): tR/min = 18.7 (1%),
19.8 (99%).
3-Fluoro-4-(4-formylphenoxy)benzonitrile2
(S5). A mixture of 3,4-
difluorobenzonitrile (35.0 mmol, 4.87 g), 4-hydroxybenzaldehyde (35.0
mmol, 4.27 g), and K2CO3 (70.0 mmol, 9.67 g) in N,N-dimethylacetamide
(90 mL) was stirred at 100 ˚C for 2 h under N2. After cooling, the reaction
mixture was poured into ice water. White precipitate was collected by filtration, washed with water, and dried under reduced pressure to afford the title compound as pale yellow
solid in 82% yield. mp.: 101 ˚C. 1H NMR (400 MHz, CDCl3) : 7.11-7.15 (m, 2H), 7.20 (t, J = 8.2 Hz,
1H), 7.49-7.51 (m, 1H), 7.54 (dd, J = 9.7, 1.9 Hz, 1H), 7.91-7.94 (m, 2H), 9.98 (s, 1H).
13C{
1H} NMR
(100 MHz, CDCl3) : 109.1 (d, 3
JC-F = 8.2 Hz), 117.1 (d, 4
JC-F = 2.5 Hz), 117.9, 121.3 (d, 2
JC-F = 21.3 Hz),
122.5 (d, 4
JC-F = 1.6 Hz), 129.6 (d, 3
JC-F = 4.1 Hz), 132.1, 132.7, 147.0 (d, 2
JC-F = 11.5 Hz), 153.6 (d, 1
JCF = 254.8 Hz), 160.7, 190.4. IR (max/cm-1
): 3100, 3060, 2846, 2812, 2761, 2232, 1697, 1687, 1585, 1497,
1277, 1216, 1166, 1114, 836. HRMS (APCI+): calculated for [M+H]+
: 242.0612, found: 242.0616.
3-Fluoro-4-(4-formylphenoxy)benzamide2
(2f). To a mixture of 3-
fluoro-4-(4-formylphenoxy)benzonitrile (S5, 26.0 mmol, 6.27 g) and
K2CO3 (13.0 mmol, 1.80 g) in DMSO (24 mL) was added dropwise 35%
H2O2 (ca. 29 mmol, 3.1 mL) at 10 ˚C over 5 min. The reaction mixture
was stirred at room temperature for 2 h. The reaction mixture was
poured into ice water. White precipitate was collected by filtration, washed with water, and dried under
reduced pressure to afford the title compound as white solid in 92% yield. mp. 129 ˚C. 1H NMR (400
MHz, (D3C)2SO) : 9.96 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.93 (dd, J = 1.9, 10.0 Hz, 1H),
7.85-7.82 (m, 1H), 7.58 (s, 1H), 7.42 (t, J = 8.2 Hz, 1 H), 7.20 (d, J = 8.2 Hz, 2H).
13C{
1H} NMR (100
MHz, (D3C)2SO) : 116.6 (d, 2
JC-F = 19.7 Hz), 116.9, 122.6, 125.1 (d, 4
JC-F = 3.3 Hz), 131.9 (d, 2
JC-F =
21.3 Hz), 132.1, 132.7 (d, 3
JC-F = 5.7 Hz), 143.7 (d, 3
JC-F = 12.3 Hz), 153.1 (d, 1
JC-F = 248.2 Hz), 161.3,
165.8, 191.5. IR (max/cm-1
): 3356, 3185, 2844, 1668, 1598, 1504, 1433, 1382, 1269, 1218, 1156, 1128,
NEXT
Reaction Chemistry & Engineering (2022), 7(8), 1779-1785
Journal of Medicinal Chemistry (2011), 54(23), 8000-8012
| Clinical data | |
|---|---|
| Other names | JNJ-67953964; CERC-501; LY-2456302 |
| Routes of administration | By mouth[1] |
| Pharmacokinetic data | |
| Bioavailability | 25%[1] |
| Elimination half-life | 30–40 hours[1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1174130-61-0 |
| PubChem CID | 44129648 |
| IUPHAR/BPS | 9194 |
| DrugBank | DB12341 |
| ChemSpider | 28424203 |
| UNII | DE4G8X55F5 |
| KEGG | D11831 |
| ChEMBL | ChEMBL1921847 |
| CompTox Dashboard (EPA) | DTXSID90151777 |
| Chemical and physical data | |
| Formula | C26H27FN2O2 |
| Molar mass | 418.512 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
^ Jump up to:a b c d e f g h i Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, et al. (2016). “Major Depressive Disorder and Kappa Opioid Receptor Antagonists”. Translational Perioperative and Pain Medicine. 1 (2): 4–16. PMC 4871611. PMID 27213169.
Aticaprant – Eli Lilly and Company/Janssen Pharmaceuticals – AdisInsight
//////ATICAPRANT, CERC-501, JSPA 0658, JSPA-0658, JSPA0658, LY 2456302, LY-2456302, LY2456302, Phase 3, ELI LILLY, Major depressive disorder, JNJ-67953964, WHO 10582
EDIVOXETINE, LY 2216684
(1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol
Edivoxetine (INN; LY-2216684) is a drug which acts as a selective norepinephrine reuptake inhibitor and is currently under development by Eli Lilly for attention-deficit hyperactivity disorder (ADHD) and as an antidepressant treatment.[1][2] It was in phase IIIclinical trials, in 2012, for major depressive disorder, but failed to get approval.[1][3]
In a study published in 2010, edivoxetine failed to prove superiority over placebo, as measured by Hamilton Depression Rating Scale. However, effectiveness could be observed using the Self-Rated Quick Inventory of Depressive Symptomatology.[4]
In a study published in 2011, using the Montgomery-Åsberg Depression Rating Scale and the Sheehan Disability Scale, edivoxetine showed superiority over placebo, with higher response and remission rates.[5]
In December 2013, Eli Lilly announced that the clinical development of edivoxetine will be stopped due to lack of efficacy compared to SSRI alone in three separate clinical trials.[6]
Side effects significantly associated with edivoxetine are headache, nausea, constipation, dry mouth and insomnia.[4]
The above mention studies report increases of the cardiac rhythm, and one also increases of diastolic and systolic blood pressures.[4][5]
There is a growing trend in Ireland toward greater collaboration between academia and the pharmaceutical industry. This is an activity encouraged at a national policy level as a means of providing researchers from academic institutions the opportunity to gain important first-hand experience in a commercial research environment, while also providing industry access to expertise and resources to develop new and improved processes for timely medicines. The participating company benefits in terms of its growth, the evolution of its strategic research and development, and the creation of new knowledge that it can use to generate commercial advantage. The research institute benefits in terms of developing skill sets, intellectual property, and publications, in addition to access to identified current industry challenges. A case study is provided describing the collaborative partnership between a synthetic chemistry research team at University College Cork (UCC) and Eli Lilly and Company.
| Systematic (IUPAC) name | |
|---|---|
| (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(tetrahydro-2H-pyran-4-yl)ethanol | |
| Clinical data | |
| Legal status |
?
|
| Identifiers | |
| CAS number | 1194508-25-2 1194374-05-4 (hydrochloride) |
| ATC code | None |
| PubChem | CID 11186829 |
| ChemSpider | 9361913 |
| Chemical data | |
| Formula | C18H26FNO4 |
| Molecular mass | 339.402 g/mol |
![(1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol NMR spectra analysis, Chemical CAS NO. 1194508-25-2 NMR spectral analysis, (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol H-NMR spectrum](https://i0.wp.com/pic11.molbase.net/nmr/nmr_image/2014-09-06/001/570/465/1194508-25-2-1h.png) CAS NO. 1194508-25-2, (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol H-NMR spectral analysis |
![(1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol NMR spectra analysis, Chemical CAS NO. 1194508-25-2 NMR spectral analysis, (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol C-NMR spectrum](https://i0.wp.com/pic11.molbase.net/nmr/nmr_image/2014-09-06/001/570/465/1194508-25-2-13c.png) CAS NO. 1194508-25-2, (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol C-NMR spectral analysis |
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MAHABALIPURAM, INDIA
Mahabalipuram, also known as Mamallapuram is a town in Kancheepuram district in the Indian state of Tamil Nadu. It is around 60 km south from the city of …Shore Temple – Seven Pagodas – Pancha Rathas –
.
.
Krishna’s Butter Ball in Mahabalipuram, India. The surface below the rock is …
http://www.weather-forecast.com/locations/Mamallapuram
Come to Mahabalipuram (also known as Mammallapuram), an enchanting beach that is located on the east coast of India.
Moonraikers Restaurant, Mamallapuram
Hotel Mamalla Bhavan – Mahabalipuram Chennai – Food, drink and entertainment
.
A carving at the Varaha Temple, Mahabalipuram
/////////////
CARIPRAZINE
CAS 839712-12-8 (free base)
CAS 1083076-69-0…HYDROCLORIDE SALT
trans-N-[4-[2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N’,N’-dimethylurea
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea
trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine
trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,
3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea
IN PHASE 3 FOR MAJOR DEPRESSION
Cariprazine (RGH-188) is an antipsychotic drug under development by Gedeon Richter. It acts as a D2 and D3 receptor partial agonist, with high selectivity towards the D3 receptor.[1] Positive Phase III study results were published for schizophrenia and maniaearly 2012, while Phase II studies in bipolar disorder I, and for bipolar depression are in progress.[2] Action on the dopaminergic systems makes it also potentially useful as an add-on therapy in major depressive disorder [3]
Forest Laboratories obtained a license on development (from the Richter – Hungary) and exclusive commercial rights in the US in 2004.
NEWS………….DUBLIN and BUDAPEST, Hungary, Jan. 6, 2015 /PRNewswire/ — Actavis plcand Gedeon Richter Plc. today announced that the U.S. Food and Drug Administration (FDA) has acknowledged receipt of Actavis’ New Drug Application (NDA) resubmission for its atypical antipsychotic cariprazine, a potent dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors. The Prescription Drug User Fee Act (PDUFA) date is expected to be in the second quarter of 2015…….
Production building of the company in Budapest
Cariprazine is currently in clinical trials for schizophrenia and bipolar disorder. It has also been investigated as a potential adjunct in treatment-resistant major depressive disorder.[4]
Illustrated Pill Packaging
The most prevalent side effects for cariprazine include akathisia, insomnia, and weight gain. Cariprazine does not appear to impact metabolic variables or prolactin levles, and unlike many other antipsychotics, does not increase the electrocardiogram (ECG) QT interval. In short term clinical trials extrapyramidal effects, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation were observed. One review characterized the frequency of these events as “not greatly different from that seen in patient treated with placebo”[5] but a second called the incidence of movement-related disorders “rather high”[6][7] .
Cariprazine acts as an antipsychotic that is effective against the positive and negative symptoms of schizophrenia.[8] Unlike many antipsychotics that are D2 and 5-HT2A receptor antagonists, cariprazine is a D2 and D3 partial agonist. It also has a higher affinity for D3 receptors. The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia.[9] Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazine’s high selectivity towards D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D3receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors.[8] Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies).[8][10] In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted.[8] This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.
Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity.[11] In monkey studies, the administration of increasing does of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D2/D3 receptors were 94 % occupied, while at the lowest dose (1 μg/kg), receptors were 5 % occupied.[10]
| Receptor | Ki (nM)[4] | Pharmacodynamic action[4] |
|---|---|---|
| 5-HT1A | 3 | Partial agonism |
| 5-HT2A | 19 | Inverse agonism/antagonism |
| 5-HT2B | 0.58 | Inverse agonism/Antagonism |
| 5-HT2C | 134 | Inverse agonism/Antagonism |
| 5-HT7 | 111 | Antagonism |
| D2S | 0.69 | Partial agonism |
| D2L | 0.49 | Partial agonism |
| D3 | 0.085 | Partial agonism |
| H1 | 23 | Inverse agonism/antagonism |
Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic.[2] In rats, the oral bioavailability was 52 % (with a dose of 1 mg/kg).[7]
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PATENT
http://www.google.com/patents/EP1663996A1?cl=en
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 )
Example 1 1-(2,3-dichlorophenyl)-[1,4]diazepine (starting material)
2.25 g (10 mmol) 1-bromo-2,3-dichloro-benzene was dissolved in dry toluene (50 ml), 2.3 (11 mmol) of [1 ,4]diazepine-1 -carboxylic acid tert-butylester was added followed by 0.2 g BINAP (2,2-bis(diphenylρhosphino)-1 ,1′-binaphtyl), 85 mg tris(dibenzylideneacetone)dipalladium(0) and 1.2 g (12mmol) sodium-tert-butoxyde. The reaction mixture was refluxed for eight hours and filtered. The organic layer was washed with water, dried and evaporated in vacuo. The residue was purified by chromatography and deprotected at 10 °C using 20 ml ethylacetate saturated with gaseous hydrochloric acid, the precipitate was filtered giving 2.1 g (yield: 75 %) hydrochloride salt of the title compound, melting at 182-3 °C. Example 2 Trans-N-{4-[2-[4-(2,3-dichloro-phenyl)-hexahydro-[1 ,4]diazepin-1-yl]-ethyl]- cyclohexyl}-carbamic acid tert-butylester (intermediate) 0.7 g (2.5 mmol) of 1 -(2,3-dichlorophenyl)-[1 ,4]diazepine hydrochloride and
0.6 g (2.5 mmol) of frat?s-2-{1 -[4-(N-tert-butyloxycarbonyl)amino]cyclohexyl}- acetaldehyde were dissolved in dichloroethane (35 ml), 0.35 ml (2.5 mmol) triethylamine was added, then 0.79 g (3.7 mmol) sodium triacetoxyborohydride was added portionswise and the reaction mixture was stirred for 20 hours at ambient temperature, then 20 % potassium carbonate solution in water (20 ml) was added. The organic layer was separated, dried and evaporated to dryness in vacuo. The precipitate was recrystallized from acetonitrile to give the title compound 1 .0 g (yield: 85.8 %), m.p.: 95-8 °C. Example 3
Trans-4-[2-[4-(2,3-dichloro-phenyl)-hexahydro-[1 ,4]diazepin-1-yl]-ethyl]- cyclohexylamine (intermediate)
0.93 g (2.1 mmol) frarjs-N-{4-[2-[4-(2,3-dichloro-phenyl)-hexahydro- [1 ,4]diazepin-1 -yl]-ethyl]-cyclohexyl}-carbamic acid tert-butylester was deprotected at
10 °C using 15 ml ethylacetate saturated with gaseous hydrochloric acid, after 4 hours the precipitate was filtered giving 0.91 g (yield: 98 %) dihydrochloride salt of the title compound, melting at 260-6 °C. Method A
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yi]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 ) 1 .39g (3 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-ρiperazin-1 -yl]-ethyl}- cyclohexyl-amine trihydrochloride was suspended in dichloromethane (100 ml), triethylamine (2.1 ml, 15 mmol) was added followed by 0.30 ml (3.3 mmol) N,N- dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature, filtered. The filtrate was washed with water (2 x 20 ml), dried and evaporated in vacuo. Recrystallizing from methanol gave the title compound (0.83 g, 65 %), melting at 212-4 °C.
Method B
7rans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-ethyl- urea (compound 2) 0.56g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}- cyclohexyl-amine was dissolved in dry dichloromethane (20 ml), ethylisocyanate (0.1 ml, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was stirred with water, the precipitate was filtered, giving the title compound (0.33 g, 65 %). Melting point:
235-8 °C.
Method C rrans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea (compound 1 )
0.56g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}- cyclohexyl-amine trihydrochloride was suspended in dry dichloromethane (50 ml), triethylamine 0.77 ml, 6 mmol) was added and 0.13g (0.44 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature dimetilamine hydrochloride (0.49 g, 6 mmol) followed by triethylamine (0.84 ml, 6 mmol) was added and the stirring was continued for 20 hours. The mixture was filtered, the filtrate washed with water, dried and evaporated in vacuo. Recrystallizing the product from methanol gave the title compound (0.27 g, 52 %). Melting point: 212-4 °C.
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PATENT
http://www.google.com/patents/US20090023750
U.S. Patent Publication No. 2006/0229297 discloses (thio)-carbamoyl-cyclohexane derivatives that are D3 and D2 dopamine receptor subtype preferring ligands, having the formula (I):
(I)
wherein R1, R2, X, and n are as defined therein. One particular compound disclosed therein is trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, which is also known as trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine, the structural formula for which is shown below:
Compounds of formula (I) act as a dopamine receptor antagonists, particularly D3/D2 receptor antagonists, and are useful in the treatment and prevention of pathological conditions which require modulation of dopamine receptors.
In some cases, an appropriate salt of an active may improve certain properties suitable for pharmaceutical compounds (i.e., stability, handling properties, ease of large scale synthesis, etc.). However, selection of a suitable salt for a particular active agent is not always straightforward, since the properties of salts of different compounds formed with the same salt forming agent may differ greatly. Moreover, formation of particular salts of a compound possessing more than one basic centre may be difficult to achieve in high yield due to formation of multiple products.
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see
WO 2011073705
http://www.google.com/patents/WO2011073705A1?cl=en
We have surprisingly found that by reacting trans 4-{2-[4-(2,3-dichlorophenyl)- piperazine-l-yl]-ethyl}-cyclohexylamine of formula (III)
with a carbonic acid derivative of general formula (VI)R-O-CO-Z (VI)
then reacting the compound of general formula (IV) obtained
with an amine derivative of general formula (V)
get the compounds of general formula (I)
EXAMPLES
The invention is illustrated by the following non-limiting examples.
Example 1
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid methylester 6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The so obtained suspension was added to a solution of 2.3 ml (0.03 mol) methyl chloroformate in 25 ml of dichloromethane at a temperature between 5-10°C. The reaction mixture obtained was stirred at a temperature between 20-25°C for 3 hours then extracted with 3×150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue was recrystallized from methanol. In this manner 4.5 g of the title product was obtained.
Yield: 72 %.
Melting point: 143-147 °C
Example 2
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid isopropylester
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C-on for one hour. The suspension was added to a solution of 3.7 g (0.03 mol) of isopropyl chloroformate in 30 ml of toluene at a temperature between 5-10°C. The reaction mixture was stirred at a temperature between 20-25°C for 3 hours and then extracted with 3×150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue obtained was recrystallized from isopropanole.
In this manner 4,4 g of title compound was obtained. Yield: 67 %.
Melting point: 128-131°C
Example 3
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 130 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.6 g of title compound was obtained.
Yield: 95 %
Melting point: 208-211 °C Example 4
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyI}-N,N-dimethylcarbamoyl- cyclohexylamine 4.4 g (0.011 mol) of trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}- cyclohexyl)-carbamic acid methylester was dissolved in 120 ml of dichloromethane. The solution obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (100 ml, 0.3 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 100 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 120 ml under vacuum. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 4.3 g of title compound was obtained.
Yield: 95 %
Melting point: 208-211 °C
Example 5
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine hydrochloride 6.45 g (0.015 mol) dihydrochloride of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes 100 ml of distilled water was added to the reaction mixture under stirring. Then the pH of the aqueous phase is adjusted to 2-3 by adding concentrated hydrochloric acid and the reaction mixture was concentrated to 130 ml, additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml. The suspension was stirred at 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained.
Yield: 96 %
Melting point: 221-224 °C
Example 6
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoil- cyclohexylamine hydrochloride 6.72 g (0.015 mol) dihydrochloride monohydrate of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25 °C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IP A) (40 ml, 0,12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added and the pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 130 ml under vacuum then additional 70 ml of water was added and the mixture was concentrated to 170 ml. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained.
Yield: 96 %.
Melting point: 221-224 °C
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SEE
http://www.google.com/patents/WO2014031162A1?cl=en
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PAPER
Cariprazine, a potential atypical antipsychotic agent has been identified during the optimization of novel series of 4-aryl-piperazine derivatives. The recently available top line results from pivotal clinical trials demonstrated the safety and efficacy of cariprazine in bipolar mania and schizophrenia indications.
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Journal of Medicinal Chemistry, 2013 , vol. 56, 22 pg. 9199 – 9221
http://pubs.acs.org/doi/abs/10.1021/jm401318w
Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.
3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (2).(ref…………Ágai-Csongor, É.; Domány, G.; Nógrádi, K.; Galambos, J.; Vágó, I.; Keserű, G. M.; Greiner, I.; Laszlovszky, I.; Gere, A.; Schmidt, É.; Kiss, B.; Vastag, M.; Tihanyi, K.; Sághy,K.; Laszy, J.; Gyertyán, I.; Zájer-Balázs, M.; Gémesi, L.; Kapás, M.; Szombathelyi,Z.Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D3/D2receptors Bioorg. Med. Chem. Lett. 2012, 22, 3437– 3440)
the metabolite of the present invention is selected from:
0.8 g (1.6 mmol) trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea was dissolved in dichloromethane (60 ml). A solution of 0.54 g (2.4 mmol) 3-chloro-perbenzoic acid in dichloromethane (10 ml) was dropped in and the reaction mixture stirred for 24 hours at room temperature. The reaction was monitored by TLC. The solution was washed twice with saturated NaHCO3 solution, the organic layer dried and evaporated in vacuo. Flash chromatography gave 0.45 g (63.3%) of the title compound melting at 175-8° C.
Example 2Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea (compound C)
0.92 g (2 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dichloromethane (60 ml), triethylamine (1.26 ml, 9 mmol) was added followed by 0.21 ml (2.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature. The solution was washed with water (2×10 ml), dried and evaporated in vacuo. Purification with flash chromatography gave 0.66 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, melting at 196-8° C. This product was dissolved in dichloromethane (60 ml), then 6.4 ml (6.4 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added, followed by 25 ml saturated NaHCO3 solution. After separation the organic layer was dried and evaporated in vacuo. Purification with flash chromatography gave 0.4 g of the title compound, melting at 278-80° C.
Example 3Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-urea (compound B)
1.38 g (3 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (100 ml), triethylamine (1.72 ml, 12.4 mmol) was added and 0.34 g (1.14 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature methylamine (33% solution in ethanol) was added and the stirring was continued for 20 hours. The mixture was evaporated. 20 ml water was added, the precipitate filtered, washed with water, dried. Recrystallizing the product from methanol gave trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3-methyl-urea (0.86 g, 65%) melting above 250° C. This product was dissolved in dichloromethane (60 ml), then 10 ml (10 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added and the mixture evaporated. 35 ml saturated NaHCO3 solution was added. The precipitate was filtered, washed with water and dried, recrystallized from methanol giving 0.34 g of title compound, melting at 237-41° C.
Example 4Trans-1-{4-[2-[4-(2,3-dichloro-4-hydroxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-urea (compound A)
1.38 g (3 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (100 ml), triethylamine 1.72 ml, 12.4 mmol) was added and 0.34 g (1.14 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature ammonia (20% solution in methanol) was added and the stirring was continued for 20 hours. The mixture was evaporated. 20 ml water was added, the precipitate filtered, washed with water, dried. Recrystallizing the product from methanol gave 0.86 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-urea melting above 250° C. This product was dissolved in dichloromethane (60 ml), then 10 ml (10 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added and the mixture evaporated. 35 ml saturated NaHCO3 solution was added. The precipitate was filtered, washed with water and dried, recrystallized from methanol giving 0.37 g of title compound, melting at 195-8° C.
| WO2005012266A1 * | May 21, 2004 | Feb 10, 2005 | Richter Gedeon Vegyeszet | (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists |
| WO2008142461A1 * | May 15, 2008 | Nov 27, 2008 | Richter Gedeon Nyrt | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
| WO2010070370A1 * | Dec 18, 2009 | Jun 24, 2010 | Richter Gedeon Nyrt. | Process for the preparation of piperazine compounds and hydrochloride salts thereof |
| WO2010070371A1 * | Dec 18, 2009 | Jun 24, 2010 | Richter Gedeon Nyrt. | Process for the preparation of piperazine derivatives |
| HU0302451A2 | Title not available |
| WO1996007331A1 * | Sep 8, 1995 | Mar 14, 1996 | Helena Halttunen | Composition comprising co-crystals, method for its manufacture, and its use |
| US20090023750 * | May 9, 2008 | Jan 22, 2009 | Richter Gedeon Nyrt. | Novel salts of piperazine compounds as d3/d2 antagonists |
| US20090030007 * | May 9, 2008 | Jan 29, 2009 | Forest Laboratories Holdings Limited | crystalline form of trans-1 {4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea hydrochloride (Form III) Cariprazine {RGH-188); Dysfunction of the dopaminergic neurotransmitter system is involved in the pathology of several neuropsychiatric and neurodegenerative disorders |
| US20090054455 * | Feb 2, 2007 | Feb 26, 2009 | Dr. Reddy’s Laboratories Ltd. | Aripiprazole co-crystals |
| US20100137335 * | May 15, 2008 | Jun 3, 2010 | Eva Againe Csongor | Metabolites of (thio) carbamoyl-cyclohexane derivatives |
Richter Gedeon Gyógyszergyár
Vortioxetine
ボルチオキセチン 臭化水素酸塩
1-[2-(2,4-dimethylphenyl)sulfanylphenyl]piperazine
| VORTIOXETINE; CAS 508233-74-7;
1-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazine; Lu AA21004; UNII-3O2K1S3WQV; C18H22N2S; |
|
| Molecular Formula: | C18H22N2S |
|---|---|
| Molecular Weight: | 298.44568 g/mol |
Vortioxetine Hydrobromide
C18H22N2S.HBr : 379.36
[960203-27-4] HYDROBROMIDE
Vortioxetine is an atypical antipsychotic and antidepressant indicated for the treatment of major depressive disorder (MDD). It is classified as a serotonin modulator and simulator (SMS) as it has a multimodal mechanism of action towards the serotonin neurotransmitter system whereby it simultaneously modulates one or more serotonin receptors and inhibits the reuptake of serotonin. More specifically, vortioxetine acts via the following biological mechanisms: as a serotonin reuptake inhibitor (SRI) through inhibition of the serotonintransporter, as a partial agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and an antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors. SMSs were developed because there are many different subtypes of serotonin receptors, however, not all of these receptors appear to be involved in the antidepressant effects of SRIs. Some serotonin receptors seem to play a relatively neutral or insignificant role in the regulation of mood, but others, such as 5-HT1A autoreceptors and 5-HT7 receptors, appear to play an oppositional role in the efficacy of SRIs in treating depression.
Sept. 30, 2013 — The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.
Major depressive disorder (MDD),
Commonly referred to as depression, is a mental disorder characterized by mood changes and other symptoms that interfere with a person’s ability to work, sleep, study, eat and enjoy once-pleasurable activities. Episodes of depression often recur throughout a person’s lifetime, although some may experience a single occurrence.
READ ALL AT
http://www.drugs.com/newdrugs/fda-approves-brintellix-major-depressive-disorder-3918.html
Vortioxetine (vor-tye-OX-e-teen, code name Lu AA21004) is an experimental drug currently under development by Lundbeck and Takeda for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).Commercial names chosen are Brintellix and Rexulti.
Regulatory approval for the treatment of MDD for the European market has been filed in September 2012, for the United States in October 2012, and filing for Canada should follow. Filing for the Japanese market is expected in 2013.
In May 22 2011, Lundbeck presented the results of four phase III trials on vortioxetine at the 2011 Annual Meeting of the American Psychiatric Association. A statistically significant effect was shown in two of the studies (one for active treatment using the Hamilton Depression Rating Scale (HAM-D), the second as a maintenance treatment), vortioxetine failed to prove superiority over placebo in a third (again using the HAM-D) and the fourth was nullified by an exceptionally high placebo response (according to the Montgomery-Åsberg Depression Rating Scale (MADRS)).
In July 2011, Lundbeck published the results of a double-blind, randomized, placebo-controlled clinical trial with venlafaxine as an active reference. It was found to be superior to placebo in treating MDD while having fewer side effects than venlafaxine. Similarly, in May 2012, Lundbeck published the results of a double-blind, randomized, placebo-controlled clinical trial with duloxetine evaluating vortioxetine in elderly depressed patients, and it was found superior to placebo, with fewer side effects than duloxetine.
In May 2012, Lundbeck disclosed the results of three phase III clinical trials, showing vortioxetine’s superiority over placebo according to the MADRS.
In August 2012, a randomized, double-blind trial confirms the superiority of vortioxetine over placebo according to all measures, excepted the Sheehan Disability scale.
In September 2012, a randomised, double-blind trial reveals that a dose of 5mg shows superiority over placebo only in patients that suffer from comorbid anxiety.This is consistent with results from another trial published in December 2012, demonstrating that 2.5 mg and 5 mg doses are ineffective.
August 2012, contradictory results of two randomized, double-blind trial were published. While the first demonstrated vortioxetine’s superiority over the placebo, the second showed that the drug had no efficacy, leading the authors to question the designs of the different trials.
United States Patent Number: 7,144,884 , 8,476,279
related to Chinese patent: CN1319958 C , CN1561336 A; CN1319958C, CN1561336A
patent validity: January 9, 2023 (U.S. Patent Number: 7,144,884), October 2, 2022 (U.S. Patent No.: 8,476,279)
peak annual sales (estimated): $ 2 billion
drug companies: Lundbeck (Lundbeck), Takeda (Takeda)
Method II:
815g of the NaOBut (8,48 mo1), 844 g of piperazine Qin (9,8 mol), 6,6 g of Pd (dba) 2 (11,48 mmol) and 13,6 g of rac-BINAP (21, 84 mmol) was stirred for 50 minutes with 4L ofbenzene. Then, 840 g 2 – bromo – iodobenzene (2,97 mol) and 1.5L of Yue added to the mixture with benzene, and the stirring was continued for 30 minutes. Finally, 390.8g of 2,4 -thiophenol (2,83 mol) was added together with 1.5L toluene. The resulting suspension was heated to reflux and reflux was continued for 5 hours. The reaction mixture was cooled overnight. 2L of water was added and stirred for l hour and then filtered through a filter aid, the resulting mixture. Then, the filtrate was washed with brine 3xlL. Subsequently, the combined aqueous phase extracted with 600ml of benzene. Then, Yue The combined benzene phase was heated to 70 ° C, then adding 329.2ml 48-wt. / HBr (aq.) and 164.6ml water o’s. The mixture was cooled to room temperature overnight. Final product was collected by filtration (l-[2 – (2,4 – di曱group – phenylsulfanyl) – phenyl] – piperazine hydrobromide Qin), and dried under vacuum (60 0 C), to give 895g of product (84% yield).
Method III:
The benzene is placed 500ml three-necked 1L round bottom flask equipped with a mechanical stirrer and add 809mg Pd2dba3 (0.88mmol; 0.5 mol%) and 952 mg DPEPhos (1.77 mmol; 0.5mol-%). The deep red solution was purged with nitrogen for 5 minutes, then add 100g2-bromo-iodobenzene (353 mmol) and 48.9 g 2,4 – bis thiophenol (353 mmol). Add 43.6g KOBut (389 mmol) caused an exothermic reaction, so that the temperature rise of 20 ° C 42 ° C, while forming a non-uniform mixture, and the color changed from deep red to orange / brown. The force of the suspension under nitrogen was heated to port 100 ° C. After only 20 minutes, HPLC showed complete conversion to have l-(2 – bromo – phenylsulfanyl) -2,4 – Yue group – benzene. The mixture was cooled to 40 ° C, was added to 600ml 15-wt% NaCl, and stirred for 5 minutes. The organic phase was separated, and the aqueous phase was washed 2xl00mwith benzene. The combined organic phase was washed with HCl (aq) NaCl and washed with 100ml 2M 100ml 15-wt%, and then Na 2 S04 dried by activated charcoal (10 g) at reflux for 15 minutes, filtered twice and evaporated to 107.3 g of orange-red oil (103%), the oil was found by HPLC purity of 98%.
To 90 g of the orange-red oil (307 mmol) in 500ml of anhydrous toluene was added 57 g boc-piperazine Qin (307 mmol), degassed with nitrogen for 5 minutes, was added 1.4g Pd2dba3 (1.53 mmol- %; 0.5 mol%) and 2.9g mc-BINAP (4.6 mmol; 1.5 mol-%), degassed and then another 2 minutes, then add 35.4 g of NaOtBu (368 mmol), and heated to 80 ° C for 18 hours. HPLC showed complete conversion to have the reaction mixture was cooled to RT, filtered, and the filter cake was washed with 2 x 100ml of曱benzene. % NaCl, washed twice in Na2S04 dried, added charcoal, refluxed for 30 minutes, filtered twice and evaporated to 140.7 g of a brown oil (4 – – The combined filtrates with 2 x 150ml 15 [2 – (2, 4 – di曱group – phenylsulfanyl) -. phenyl]-BOC-piperazine Qin). The resulting crude oil was dissolved in 300ml MeOH and 200ml 6MHCl (aq.) and refluxed for l hour, after which HPLC showed complete deprotection. After cooling to RT, the vacuum on a rotary evaporator to remove曱alcohol was added 20ml of concentrated NaOH (pH was measured to 13-14), after which the mixture with 1000ml EtOAc – 15 minutes from stirring. The organic phase was collected and dried 300ml 15wtQ /. Saline extraction in Na2S04 dried, and added 46.3 g of fumaric acid in 300mlMeOH (399 mmol) was added. The mixture was heated to reflux, cooled to room temperature and then placed in the tank (-18. C) overnight. The precipitate was collected, washed with 100ml and 100ml of acetone with EtOAc, and dried in vacuo (50 ° C), to give 103.2g of l-[2 – (2,4 – di group – phenylsulfanyl) – phenyl] – piperazine. Qin fumarate (249mmo1), as a white powder, overall yield 81%, determined by LC-MS and the purity was 99% fumarate. Use EtOAc/H20 / concentrated NaOH to the fumarate salt into the free base (l-[2 – (2,4 – dimethyl – phenylsulfanyl) – phenyl] – piperazine Qin), The organic phase was washed with brine, dried over Na 2 S04 sulfate, filtered and to the filtrate was added 34ml48-wto / o of HBr (aq.), to form a white solid precipitated. The solid was collected, and the solid was washed with 1000ml H20 boiling process, the resultant was cooled to room temperature and purified by forming a slurry. The final product was collected by filtration (l-[2 – (2,4 – digroup – phenylsulfanyl) – phenyl] – piperazine hydrobromide Qin Kr), and dried in vacuo (50 ° C), to produce 83g of white powder (total yield 71%).
1) Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB “Discovery of 1 -. [2 – (2,4 – dimethylphenylsulfanyl) phenyl] PIPERAZINE (Lu AA21004): a novel multimodal Major Compound for the treatment of depressive disorder. ” Journal of Medicinal Chemistry 54 (9): 3206-21.
2) Thomas Ruhland, Garrick Paul Smith, Benny Bang-Andersen, Ask Puschl, Ejner Knud Moltzen, Kim Andersen,; Phenyl-piperazine derivatives as serotonin reuptake inhibitors; US patent number 7144884 ; also published as CA2462110A1, CA2462110C , CN1319958C, CN1561336A, DE60225162D1, DE60225162T2, DE60233608D1, EP1436271A1, EP1436271B1, EP1749818A2, EP1749818A3, EP1749818B1, US7138407, US7148238, US7683053, US8110567, US8476279, US20050014740, US20060084662, US20060089368, US20070060574, US20110009423, US20120302553, WO2003029232A1; H. Lundbeck A / S;
T · Rouland, G · P · Smith, B · Bang – Anderson, A · Pi Shier, E · K · Moore Cen, K · Anderson; as serotonin reuptake inhibitors phenyl piperazine derivatives matter; CN 1319958 C
T · Rouland, G · P · Smith, B · Bang – Anderson, A · Pi Shier, E · K · Moore Cen, K · Anderson; as serotonin reuptake inhibitors phenyl piperazine derivatives; CN 1561336 A
3) Benny Bang-Andersen; Phenyl-piperazine derivatives as serotonin reuptake inhibitors; US patent number 8476279 B2 ; Also published as CA2462110A1, CA2462110C, CN1319958C, CN1561336A, DE60225162D1, DE60225162T2, DE60233608D1, EP1436271A1, EP1436271B1, EP1749818A2, EP1749818A3, EP1749818B1, US7138407, US7144884, US7148238, US7683053, US8110567, US20050014740, US20060084662, US20060089368, US20070060574, US20110009423, US20120302553, WO2003029232A1; H. Lundbeck A / S;
4) Kim Lasse Christensen; Process for the manufacture of 1 – [2 – (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine; PCT application, WO2013102573 A1
5) Benny Bang-Andersen, Joergen Brodersen, Andre Faldt, Rene Holm, Morten Joergensen, De Diego Heidi Lopez, Michael J Mealy, Arne Moerk, Nicholas Moore, Lone Munch Ringgaard, Michael Harold Rock, Tine Bryan Stensboel; 1 – [2 – (2, 4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment; WO2007144005 A1
Updated oct 2015…………….
Vortioxetine (vor-tye-oks-e-teen, trade name Trintellix) is an atypical antidepressant (a serotonin modulator and stimulator) made by Lundbeck and Takeda.[1]
Vortioxetine [1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine] is an orally administered small molecule developed as once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). As a drug, Vortioxetine is a bis-aryl-sulphanyl amine compound that combines serotonin (5-HT) reuptake inhibition with other characteristics, including receptor activity modulation.
Animal and in vitro studies indicate that several neurotransmitter systems may be impacted by vortioxetine, with the drug enhancing levels of 5-HT, noradrenaline, dopamine, acetylcholine and histamine in certain areas of the brain, as well as modulating γ-aminobutyric acid and glutamate neurotransmission. Results from additional animal models suggest vortioxetine may also improve measures of cognitive function, such as memory. In healthy volunteers, single or repeated administration of vortioxetine (10 mg) did not impair cognitive function, psychomotor performance or driving ability in a placebo-controlled study.
Vortioxetine is used as first-line treatment for major depressive disorder.[1][2][3][4][5]
Vortioxetine reaches peak plasma concentration (Cmax) within 7 to 11 hours post-administration (Tmax), and its mean terminal half-life (t½) is ≈ 66 hours. Steady-state plasma concentrations are typically reached within two weeks.[1] It has no active metabolites (i.e. it is not a prodrug).[1]
Vortioxetine has been studied in several clinical trials as a potential treatment for general anxiety disorder but results were inconsistent.[9][10]
Vortioxetine was discovered by scientists at Lundbeck who reported the rationale and synthesis for the drug (then called Lu AA21004) in a 2011 paper.[7][11]
In 2007, the compound was in Phase II clinical trials, and Lundbeck and Takeda entered into a partnership in which Takeda paid Lundbeck $40 million upfront, with promises of up to $345 million in milestone payments, and Takeda agreed to pay most of the remaining cost of developing the drug. The companies agreed to co-promote the drug in the US and Japan, and that Lundbeck would receive a royalty on all such sales. The deal included another drug candidate, tedatioxetine (Lu AA24530), and could be expanded to include two other Lundbeck compounds.[12]
Vortioxetine was approved by the U.S. FDA for the treatment of major depressive disorder (MDD) in adults in September, 2013,[13] and it was approved in Europe later that year.[14]
Vortioxetine was previously trademarked as Brintellix in the United States, but on May 2, 2016, the US FDA approved a name change to Trintellix in order to avoid confusion with the blood-thinning medication ticagrelor (Brilinta).[15]
WO2015155153, SYNTHESIS OF VORTIOXETINE VIA (2,4-DIMETHYLPHENYL)(2-IODOPHENYL)SULFANE INTERMEDIATE
| LEK PHARMACEUTICALS D.D. [SI/SI]; Verovskova 57 1526 Ljubljana (SI) | |
| Inventors:ZUPANCIC, Borut; (SI) |
Vortioxetine is disclosed as Example 1 e in WO 2003/029232 A1 and is described as being prepared analogously to Example 1 . The process used to prepare Example 1 involves the preparation of 1 -(2-((2-(trifluoromethyl)phenyl)thio)phenyl)piperazine on a solid polystyrene support, followed by decomplexation using visible light irradiation, and purification by preparative LC-MS and ion-exchange chromatography. The overall yield for the preparation of vortioxetine is described as 17%.
Several alternative palladium catalyzed processes for the preparation of vortioxetine are described in Examples 17 to 25 of WO 2007/144005 A1 . These processes describe the preparation of vortioxetine from 2,4-dimethylthiophenol and 2-bromoiodobenzene (or 1 ,2-dibromobenzene) starting materials via a 1 -(2-bromo-phenylsulfanyl)-2,4-dimethyl-benzene intermediate. Each of these processes involves the use of a palladium catalyst and a phosphine ligand.
The preparation of vortioxetine is also described by Bang-Andersen et al. in J. Med. Chem. (201 1 ), Vol. 54, 3206-3221 . Here, in a first step, te/t-butyl 4-(2-bromophenyl)piperazine-1 -carboxylate intermediate is prepared from Boc-piperazine and 2-bromoiodobenzene in a palladium catalyzed coupling reaction. te/t-Butyl 4-(2-bromophenyl)piperazine-1 -carboxylate is then reacted with 2,4-dimethylthiophenol, again in the presence of palladium catalyst and a phosphine ligand, to provide Boc-protected vortioxetine. In the final step, vortioxetine is deprotected using hydrochloric acid to give vortioxetine hydrochloride.
WO 2013/102573 A1 describes a reaction between 1 -halogen-2,4-dimethyl-phenyl, 2-halogen-thiophenol and an optionally protected piperazine in the presence of a base and a palladium catalyst consisting of a palladium source and a phosphine ligand.
Each of the above processes has disadvantages. The process described in WO 2003/029232 is low yielding and unsuitable for the large scale production of vortioxetine, whereas the processes described in WO 2007/144005 A1 , WO 2013/102573 A1 and by Bang-Andersen et al. require the use of expensive starting materials, palladium catalyst and phosphine ligand. In addition, the toxicity of palladium is well known, Liu et al. Toxicity of Palladium, Toxicology Letters, 4 (1979) 469-473, and the European Medicines Agency’ s Guideline on the Specification for Residues of Metal Catalysts sets clear limits on the permitted daily exposure to palladium arising from palladium residue within drug substances, http://www.ema.europa.eu. Thus it would be desirable to avoid the use of a palladium catalyst in the synthesis of vortioxetine and the subsequent purification steps required to remove palladium residue from the final pharmaceutical product.
The invention is described below in further detail by embodiments, without being limited thereto.
A general concept of the process of the present invention may be represented in Scheme 1 .
Scheme 1 : General representation of the basic synthetic concept of the present invention.
Scheme 2.
X = NH2: lb
Scheme 2: Representation of a particular synthetic embodiment of the present invention.
Compound III can also be prepared from 2,4-dimethylbenzenethiol (II) and 1 -fluoro-2-nitrobenzene (l”‘a) or 1 -chloro-2-nitrobenzene (l'”b). In the first step (2,4-dimethylphenyl)(2- nitrophenyl)sulfane (III’) is formed and in the second reaction step nitro group is reduced to ami
Z = F: l”‘a
Z = CI: l”‘b
Scheme 3: Representation of a particular synthetic embodiment of the present invention.
Example 7: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine vortioxetine, VII)
Mixture of (2,4-dimethylphenyl)(2-iodophenyl)sulfane V (0.34 g, 1 .0 mmol), piperazine VI (0.13 g, 1 .5 mmol), K3P03 (0.42 g, 2.0 mmol), Cul (19 mg, 0.1 mmol), and 2-phenylphenol (68 mg, 0.4 mmol) in dry and degassed DMSO (2 mL) was heated under nitrogen atmosphere at 120°C for 20 h. Water (10 mL) is then added and product is extracted to EtOAc (3 x 10 mL). Combined organic layers were washed with water (3 x 10 mL) and brine (2 x 10 mL) and dried over Na2S04. After evaporation of the solvent crude product is purified by chromatography to afford title compound: H NMR (CDCI3, 500 MHz) δ 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H), 3.02-
3.09 (m, 8H), 6.52 (m, 1 H), 6.87 (m, 1 H), 7.04 (m, 1 H), 7.06-7.10 (m, 2H), 7.16 (m, 1 H), 7.39 (d, J= 7.8 Hz, 1 H); MS (ESI) m/z: 299 [MH]+.
Example 8: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine (vortioxetine, VII)
Mixture of (2,4-dimethylphenyl)(2-iodophenyl)sulfane V (0.34 g, 1 .0 mmol), piperazine VI (0.13 g, 1 .5 mmol), K3P03 (0.42 g, 2.0 mmol), Cul (19 mg, 0.1 mmol), and N,N-diethyl-2-hydroxybenzamide (39 mg, 0.2 mmol) in dry and degassed DMSO (2 mL) was heated under nitrogen atmosphere at 120 ^ for 20 h. Water (10 mL) is then added and product is extracted to EtOAc (3 x 10 mL). Combined organic layers were washed with water (3 x 10 mL) and brine (2 x 10 mL) and dried over Na2S04. After evaporation of the solvent crude product is purified by chromatography to afford title compound: H NMR (CDCI3, 500 MHz) δ 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H), 3.02-3.09 (m, 8H), 6.52 (m, 1 H), 6.87 (m, 1 H), 7.04 (m, 1 H), 7.06-7.10 (m, 2H), 7.16 (m, 1 H), 7.39 (d, J= 7.8 Hz, 1 H); MS (ESI) m/z: 299 [MH]+.
Example 9: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide
(vortioxetine HBr, VII.HBr)
To a solution of vortioxetine VII (1 .80 g, 6.03 mmol) in iPrOAc (20 mL) at room temperature 48% HBr (0.68 mL, 6.03 mmol) was slowly added. Obtained mixture was stirred at room temperature for 1 h, white precipitate was then filtered off, washed with acetone (2 x 20 mL), and dried to afford title compound VII.HBr as a white powder (2.15 g, 94% yield): H NMR (DMSO-d6, 500 MHz) δ 2.23 (s, 3H), 2.32 (s, 3H), 3.15-3.27 (m, 8H), 6.40 (m, 1 H), 6.96 (m, 1 H), 7.08-7.17 (m, 3H), 7.24 (m, 1 H), 7.32 (d, J= 7.8 Hz, 1 H), 8.85 (br, 2H).
Reference Example 1 : Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine
(vortioxetine, VII)
Mixture of piperazine (1 .0 g, 1 1 .6 mmol), NaOtBu (1 .37 g, 13.8 mmol), Pddba2 (40 mg, 0.07 mmol), and 1 ,3-bis(2,6-di-i-propylphenyl)imidazolium chloride (24 mg, 0,07 mmol) in dry and degassed toluene (10 mL) is stirred at room temperature for 1 h. (2,4-Dimethylphenyl)(2-iodophenyl)sulfane V (1 .32 g, 3.86 mmol) is then added, reaction mixture is heated to l OO’C and stirred for 24 h. After cooling to room temperature to the reaction mixture water (5 mL) and Celite (0.4 g) is added. After stirring for 20 min salts are filtered off, organic layer is separated, washed with brine (2 x 10 mL), dried over Na2S04 and solvent is evaporated to afford crude product, which is then purified by chromatography to afford title compound as yellowish crystals: H NMR (CDCI3, 500 MHz) δ 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H),
Reference Example 2: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine
(vortioxetine, VII)
Mixture of piperazine (1 .29 g, 15.0 mmol), NaOtBu (1 .77 g, 17.8 mmol), Pddba2 (52 mg, 0.09 mmol), and rac-BINAP (93 mg, 0,15 mmol) in dry and degassed toluene (10 mL) was stirred at room temperature for 1 h. (2,4-Dimethylphenyl)(2-iodophenyl)sulfane V (1 .70 g, 5.0 mmol) was then added, reaction mixture was heated to 100°C and stirred for 24 h. After cooled to room temperature to the reaction mixture water (5 mL) and Celite (0.4 g) were added. After stirring for 20 min salts were filtered off, organic layer was separated, washed with brine (2 x 10 mL), dried over Na2S04 and solvent was evaporated to afford product as an orange oil (1 .41 g, 95% yield): H NMR (CDCI3, 500 MHz) δ 1 .63 (br s, 1 H), 2.33 (s, 3H), 2.37 (s, 3H), 3.02-3.09 (m, 8H), 6.52 (m, 1 H), 6.87 (m, 1 H), 7.04 (m, 1 H), 7.06-7.10 (m, 2H), 7.16 (m, 1 H), 7.39 (d, J = 7.8 Hz, 1 H); MS (ESI) m/z: 299 [MH]+.
Comparative Example 1 : Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine
(vortioxetine, VII)
Mixture of (2,4-dimethylphenyl)(2-bromohenyl)sulfane V” (0.29 g, 1 .0 mmol), piperazine VI (0.13 g, 1 .5 mmol), K3P03 (0.42 g, 2.0 mmol), Cul (19 mg, 0.1 mmol), and 2-phenylphenol (68 mg, 0.4 mmol) in dry and degassed DMSO (2 mL) was heated under nitrogen atmosphere at 120°C for 20 h. Vortioxetine VII was not formed.
Comparative Example 2: Preparation of 1 -(2-((2,4-dimethylphenyl)thio)phenyl)piperazine
(vortioxetine, VII)
Mixture of (2,4-dimethylphenyl)(2-bromophenyl)sulfane V (0.29 g, 1 .0 mmol), piperazine VI (0.13 g, 1 .5 mmol), K3P03 (0.42 g, 2.0 mmol), Cul (19 mg, 0.1 mmol), and N,N-diethyl-2-hydroxybenzamide (39 mg, 0.2 mmol) in dry and degassed DMSO (2 mL) was heated under nitrogen atmosphere at 120 ^ for 20 h. Vortioxetine VII was not formed.
WO2007144005A1: Industrial process
The synthesis and structure−activity relationship of a novel series of compounds with combined effects on 5-HT3A and 5-HT1A receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT1A (Ki = 15 nM), 5-HT1B (Ki = 33 nM), 5-HT3A (Ki = 3.7 nM), 5-HT7 (Ki = 19 nM), and noradrenergic β1 (Ki = 46 nM) receptors, and SERT (Ki = 1.6 nM). Compound 5mdisplayed antagonistic properties at 5-HT3A and 5-HT7 receptors, partial agonist properties at 5-HT1B receptors, agonistic properties at 5-HT1A receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.
1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine Hydrochloride (5m)
ALERT HYDROCHLORIDE DATA
| Patent ID | Date | Patent Title |
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| US7683053 | 2010-03-23 | PHENYL-PIPERAZINE DERIVATIVES AS SEROTONIN REUPTAKE INHIBITORS |
| US7148238 | 2006-12-12 | Phenyl-piperazine derivatives as serotonin reuptake inhibitors |
| US7144884 | 2006-12-05 | Phenyl-piperazine derivatives as serotonin reuptake inhibitors |
| US7138407 | 2006-11-21 | Phenyl-piperazine derivatives as serotonin reuptake inhibitors |
| Patent ID | Date | Patent Title |
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| US2013184291 | 2013-07-18 | THERAPEUTIC USES OF 1-[2-(2,4-DIMETHYL-PHENYLSUFLANYL)PHENYL]PIPERAZINE |
| US8476279 | 2013-07-02 | Phenyl-piperazine derivatives as serotonin reuptake inhibitors |
| US2013115292 | 2013-05-09 | ENTERIC TABLET |
| US2012189697 | 2012-07-26 | COMPOSITIONS OF 1-[2-(2,4-DIMETHYL-PHENYLSULFANYL)-PHENYL]PIPERAZINE |
| US2012035188 | 2012-02-09 | LIQUID FORMULATIONS OF SALTS OF 1-[2-(2,4-DIMETHYLPHENYLSULFANYL)PHENYL]-PIPERAZINE |
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| US2012004409 | 2012-01-05 | Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine |
| US2011201617 | 2011-08-18 | Therapeutic Uses Of Compounds Having Combined SERT, 5-HT3 And 5-HT1A Activity |
| US2011009422 | 2011-01-13 | 1- [2-(2,4-DIMETHYLPHENYLSULFANYL)-PHENYL] PIPERAZINE AS A COMPOUND WITH COMBINED SEROTONIN REUPTAKE, 5-HT3 AND 5-HT1A ACTIVITY FOR THE TREATMENT OF PAIN OR RESIDUAL SYMPTOMS IN DEPRESSION RELATING TO SLEEP AND COGNITION |
| US2010297240 | 2010-11-25 | 1- [2- (2,4-DIMETHYLPHENYLSULFANYL)-PHENYL] PIPERAZINE AS A COMPOUND WITH COMBINED SEROTONIN REUPTAKE, 5-HT3 AND 5-HT1A ACTIVITY FOR THE TREATMENT OF COGNITIVE IMPAIRMENT |
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| US2015094316 | 2015-04-02 | LIQUID FORMULATIONS OF SALTS OF 1-[2-(2,4-DIMETHYLPHENYLSULFANYL)PHENYL]PIPERAZINE |
| US8969355 | 2015-03-03 | 1-[2-(2,4 dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1a activity for the treatment of cognitive impairment |
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| US2014343287 | 2014-11-20 | Process for the Manufacture of 1-[2-(2,4-Dimethyl-Phenylsulfanyl)-Phenyl]-Piperazine |
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| US2014256943 | 2014-09-11 | 1-[2-(2,4-Dimethylphenylsulfanyl)-Phenyl]Piperazine As A Compound With Combined Serotonin Reuptake, 5-HT3 And 5-HT1a Activity For The Treatment Of Cognitive Impairment |
| US2014248355 | 2014-09-04 | 1-[2-(2,4-Dimethylphenylsulfanyl)-Phenyl]Piperazine As A Compound With Combined Serotonin Reuptake, 5-HT3 And 5-HT1a Activity For The Treatment Of Cognitive Impairment |
| US2014248356 | 2014-09-04 | 1-[2-(2,4-Dimethylphenylsulfanyl)-Phenyl]Piperazine As A Compound With Combined Serotonin Reuptake, 5-HT3 And 5-HT1a Activity For The Treatment Of Cognitive Impairment |
| US2014163043 | 2014-06-12 | PHENYL-PIPERAZINE DERIVATIVES AS SEROTONIN REUPTAKE INHIBITORS |
| Patent ID | Date | Patent Title |
|---|---|---|
| US2016083359 | 2016-03-24 | 1-[2-(2,4-DIMETHYLPHENYLSULFANYL)-PHENYL]PIPERAZINE AS A COMPOUND With COMBINED SEROTONIN REUPTAKE, 5-HT3 AND 5-HT1A ACTIVITY FOR THE TREATMENT OF COGNITIVE IMPAIRMENT |
| US2016060215 | 2016-03-03 | New Process For The Synthesis Of 1-(2-((2,4-Dimethylphenyl)Thio)Phenyl)Piperazine |
| US2016015706 | 2016-01-21 | CRYSTALLINE FORMS OF AN ANTIDEPRESSANT COMPOUND |
| US2016009670 | 2016-01-14 | VORTIOXETINE MANUFACTURING PROCESS |
| US9211288 | 2015-12-15 | Compositions comprising vortioxetine and donepezil |
| US2015297585 | 2015-10-22 | COMPOSITIONS COMPRISING VORTIOXETINE AND DONEPEZIL |
| US2015266841 | 2015-09-24 | Novel Crystalline Form Of Vortioxetine Hydrobromide |
| US2015150867 | 2015-06-04 | COMPOSITIONS OF 1-[2-(2,4-DIMETHYL-PHENYLSULFANYL)-PHENYL]PIPERAZINE |
| US2015110873 | 2015-04-23 | ENTERIC TABLET |
| US2015094316 | 2015-04-02 | LIQUID FORMULATIONS OF SALTS OF 1-[2-(2,4-DIMETHYLPHENYLSULFANYL)PHENYL]PIPERAZINE |
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| Systematic (IUPAC) name | |
|---|---|
|
1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine
|
|
| Clinical data | |
| Trade names | Trintellix, Brintellix |
| License data |
|
| Pregnancy category |
|
| Routes of administration |
Oral |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | 75% (peak at 7–11 hours) |
| Protein binding | 98% |
| Metabolism | extensive hepatic, primarilyCYP2D6-mediated oxidation |
| Biological half-life | 66 hours |
| Excretion | 59% in urine, 26% in feces |
| Identifiers | |
| CAS Number | 508233-74-7  |
| ATC code | N06AX26 (WHO) |
| PubChem | CID 9966051 |
| IUPHAR/BPS | 7351 |
| ChemSpider | 8141643  |
| KEGG | D10184 |
| ChEBI | CHEBI:76016 |
| Synonyms | Lu AA21004 |
| Chemical data | |
| Formula | C18H22N2S |
| Molar mass | 298.45 g/mol (379.36 as hydrobromide) |
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New Drug Approvals 
