WO2023218251A1 - Novel deuterium-enriched nefazodone analogues and method for preparing thereof - Google Patents
Novel deuterium-enriched nefazodone analogues and method for preparing thereof Download PDFInfo
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- WO2023218251A1 WO2023218251A1 PCT/IB2023/051786 IB2023051786W WO2023218251A1 WO 2023218251 A1 WO2023218251 A1 WO 2023218251A1 IB 2023051786 W IB2023051786 W IB 2023051786W WO 2023218251 A1 WO2023218251 A1 WO 2023218251A1
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- WIPO (PCT)
- Prior art keywords
- formula
- deuterium
- compound
- nefazodone
- enriched
- Prior art date
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- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 title claims abstract description 68
- 229910052805 deuterium Inorganic materials 0.000 title claims abstract description 68
- VRBKIVRKKCLPHA-UHFFFAOYSA-N nefazodone Chemical class O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 VRBKIVRKKCLPHA-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 129
- 230000015572 biosynthetic process Effects 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000000460 chlorine Substances 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 11
- 239000011630 iodine Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 150000001350 alkyl halides Chemical class 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 6
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
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- 150000002576 ketones Chemical class 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical group [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 229960003750 ethyl chloride Drugs 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
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- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical group [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 claims description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
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- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
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- 150000004292 cyclic ethers Chemical class 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- LKKWNBWRPDKMIB-UHFFFAOYSA-N 3-chloro-1-phenylpiperazine Chemical class C1CNC(Cl)CN1C1=CC=CC=C1 LKKWNBWRPDKMIB-UHFFFAOYSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
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- 230000002440 hepatic effect Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 150000008530 meta-chlorophenylpiperazines Chemical class 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013643 reference control Substances 0.000 description 1
- 239000002484 serotonin 2C antagonist Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
Definitions
- the present invention relates to novel nefazodone analogues. More specifically, it relates to deuterated nefazodone analogues and method for preparing the said analogues.
- the deuterated nefazodone analogues show improved biological activities, preferably anti-depressant activity.
- Nefazodone (SERZONE®), 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]-propyl-]5- ethyl-2,4-dihydro-4-(2-phenoxy-ethyl)-3H-1 ,2,4-triazol-3-one hydrochloride is a novel antidepressant chemically unrelated to tricyclic or tetracyclic antidepressants and the selective serotonin uptake inhibitors in current use. Nefazodone bears following structural formula:
- Nefazodone is an atypical anti-depressant which was first marketed by Bristol- Myers Squibb in 1994. Nefazodone is a phenylpiperazine compound and is related to trazodone. It has been described as a serotonin antagonist and reuptake inhibitor (SARI) due to its combined actions as a potent serotonin 5- HT2A receptor and 5-HT2C receptor antagonist and weak serotonin- norepinephrine-dopamine reuptake inhibitor (SNDRI). It was discontinued in 2003 in some countries, due to the small possibility of hepatic (liver) injury. Drug- induced hepatic injuries were associated with a risk of elevated need for a liver transplant, or even death. On May 20, 2004, Bristol-Myers Squibb discontinued the sale of SERZONE in the United States.
- Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor. It also has high affinity for the a1-adrenergic receptor and serotonin 5-HT1A receptor, and relatively lower affinity for the a2-adrenergic receptor and dopamine D2 receptor. Nefazodone has low but significant affinity for the serotonin, norepinephrine, and dopamine transporters as well, and therefore acts as a weak serotonin- norepinephrine-dopamine reuptake inhibitor (SNDRI).
- SNDRI serotonin- norepinephrine-dopamine reuptake inhibitor
- Nefazodone has negligible activity at muscarinic acetylcholine receptors, and accordingly, has no anti-cholinergic effects.
- nefazodone The bioavailability of nefazodone is low and variable, about 20%. Its plasma protein binding is approximately 99%, but it is bound loosely. Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Half-life of the parent compound is 2 to 4hr.
- US4338317 discloses a process for the manufacture of Nefazodone free base and Nefazodone hydrochloride.
- the process involving the reaction of 2- piperazinylalkyltriazolone with suitable phenoxyalkylhalide to form Nefazodone free base.
- the Nefazodone free base is then converted to Nefazodone hydrochloride by using hydrogen chloride.
- CA1233826 discloses a purported improved process in which the Nefazodone free base is produced by reacting a phenoxyalkylcarbamate with an N-substituted hydrazide of a carboxylic acid.
- US5900485 describes another process for preparing nefazodone from semicarbazide dihydrochloride and triethyl orthopropionate in the presence of hydrochloride.
- CA1198436, US4338317 describes a process for the preparation of nefazodone hydrochloride involve the preparation of nefazodone free base first and then the conversion of it to nefazodone hydrochloride.
- ADME absorption, distribution, metabolism and/or excretion
- Deuterium ( 2 H or D) is a stable, non-radioactive isotope of hydrogen. 2 H forms stronger bonds with carbon compared to hydrogen. In some cases, the increased bond strength imparted by 2 H can positively impact the ADME properties of a pharmaceutical compound, creating the potential for improved efficacy, safety, and/or tolerability of the pharmaceutical compound. At the same time, because the size and shape of 2 H are essentially identical to those of hydrogen, replacement of hydrogen by 2 H would not be expected to affect the biochemical potency and selectivity of the pharmaceutical compound as compared to the original chemical entity that contains only hydrogen (Graham et al., “Deuterated drugs: where are we now?”, Expert Opinion on Therapeutic Patents, 2014, 24(10): 1067-1075.)
- the present invention utilise the deuteration strategy at different position of nefazodone moiety that help in metabolism of the parent compound and improve its half-life and reduce daily dose requirement.
- One of the objects of the present invention is to provide a novel deuterium- enriched nefazodone or a pharmaceutically accepted salt thereof.
- Another object of the present invention is to provide deuterated version of nefazodone with limit the formation of toxic metabolite and that may increase the half-life of nefazodone compound in the systemic circulation.
- Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of at least one of the deuterium-enriched compounds of the present invention or a pharmaceutically accepted salt thereof.
- Yet another object of the present invention is to provide use of a novel deuterium- enriched nefazodone or its pharmaceutically accepted salt for medical treatment.
- One of the aspects of the present invention is to provide a deuterium-enriched compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
- R! to 27 is independently selected from hydrogen (H), deuterium (D), 0 ⁇ 04 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, and aryl; at least one of R! to R 27 is deuterium (D);
- X is halogen selected from a group consisting of fluorine, chlorine, bromine, iodine;
- Z is O or S.
- Another aspect of the present invention is to provide a method for preparing the deuterium-enriched compound of formula (II), wherein the method comprises the steps of: i. reacting a compound of formula (1) with a haloalkyl amine hydrochloride salt in a ratio of 1 :1 in a solvent at a temperature in the range of 125 to 175°C for a time period in the range of 10 to 14 hrs under stirring in an inert atmosphere to obtain a compound of formula (2);
- Figure 1 shows relative amounts of hydroxyl and dealkylated metabolites formed from Nefazodone and Nefazodone-D4
- Figure 2 shows chromatographically extracted Nefazodone-D4 and its metabolites (A-C) and the respective m/z (D-F)
- pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
- terapéuticaally effective amount refers to an amount of a compound of the present invention that is effective when administered alone or in combination to treat the desired condition or disorder.
- the combination of compounds is preferably a synergistic combination.
- hydrate used herein means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces.
- solvate used herein means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non- covalent intermolecular forces.
- halo-alkanes refers to a group of chemical compounds comprised of an alkane with one or more hydrogens replaced by a halogen atom (fluorine, chlorine, bromine, or iodine).
- Halo-alkane can be monohaloalkane, dihaloalkane, trihaloalkane.
- solvent refers to a substance that can dissolve another substance, or in which another substance is dissolved, forming a solution.
- the solvent used in the present invention can be polar or nonpolar solvent.
- the solvent includes such as but not limit to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
- deuterium enriched refers to compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%, should be considered unnatural and, as a result, novel over their nonenriched counterparts.
- D and d both refer to deuterium. D and “d” can be used interchangeably in the specification.
- the present invention provides Deuteration at para position of nefazodone that help to reduce the formation of toxic metabolite and further it reduces the possibility if hepatotoxicity. Further, reduction in metabolism of the Nefazodone compound improves its half-life and reduce daily dose requirement.
- One of the embodiment of the present invention provides a deuterium-enriched compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
- R! to R 27 is independently selected from hydrogen (H), deuterium (D), 0 ⁇ 4 alkyl, C2-C4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, and aryl; at least one of R! to R 27 is deuterium (D);
- X is halogen selected from a group consisting of fluorine, chlorine, bromine, iodine;
- Z is O or S.
- Another embodiment of the present invention provides a deuterium-enriched compound of formula (I), wherein R! to R 27 is independently selected from hydrogen (H) and deuterium (D).
- Yet another embodiment of the present invention provides a deuterium-enriched compound of formula (I), wherein X is chlorine.
- Yet another embodiment of the present invention provides a deuterium-enriched compound of formula (I), wherein Z is O.
- Another embodiment of the present invention provides a deuterium-enriched compound of formula (I), wherein the deuterium-enriched compound of formula (I) is selected from the compounds including such as but not limited to
- R! to R 4 in the compound of formula (II) is independently selected from hydrogen (H), deuterium (D); preferably deuterium (D); R 3 in the compound of formula (III) is hydrogen (H) or deuterium (D);
- X in the compound of formula (II) and formula (III) is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine; and Z in the compound of formula (II) and formula (III) is O.
- a deuterium-enriched compound represented by formula (II) is selected from
- a deuterium- enriched compound of formula (I) wherein intermediates or starting materials may be selected from the compounds including such as but not limited to the following compounds,
- R R 2 , R 3 and R 4 may be independently selected from hydrogen (H), deuterium (D), C r C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, and aryl; preferably hydrogen (H) and deuterium (D); at least one deuterium (D);
- X is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine.
- Yet another embodiment of the present invention provides an intermediate compound represented by formula (1), wherein R ⁇ R 2 , and R 4 is hydrogen (H) and R 3 is halogen selected from the group consisting of fluorine, chlorine, bromine and iodine; preferably R 3 is bromine.
- Another embodiment of the present invention provides an intermediate compound of formula (2),
- R R 2 , R 3 and R 4 may be independently selected from hydrogen (H), deuterium (D), C r C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, and aryl; preferably hydrogen (H) and deuterium (D); at least one of R! to R 4 is deuterium (D);
- X is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine.
- Yet another embodiment of the present invention provides an intermediate compound of formula (2), wherein R ⁇ R 2 , and R 4 is hydrogen (H) and R 3 is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably R 3 is bromine.
- Another embodiment of the present invention provides an intermediate compound of formula (3),
- R ⁇ R 2 , R 3 , and R 4 may be independently selected from hydrogen (H), deuterium (D), C r C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, and aryl; preferably hydrogen (H) and deuterium (D); at least one of R! to R 4 is deuterium (D);
- X is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine.
- X is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine.
- Ri, R 2 , and R 4 is hydrogen (H) and R 3 is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably R 3 is bromine.
- Another embodiment of the present invention provides an intermediate compound of formula (4),
- the intermediate compound can be in deuterated form in which one or more hydrogen replaced by deuterium (d).
- Another embodiment of the present invention provides a method for preparing the deuterium-enriched compound of formula (II) or formula (III), wherein the method comprises the steps of: i. reacting a compound of formula (1) with a haloalkyl amine hydrochloride salt in a ratio of 1 : 1 in a solvent at a temperature in the range of 125 to 175°C for a time period in the range of 10 to 14 hrs under stirring in an inert atmosphere to obtain a compound of formula (2); ii. dissolving the compound of formula (2) in a solvent and adding a base and followed by adding a haloalkane slowly at room temperature under stirring to obtain a compound of formula (3); iii.
- step (ii) reacting a compound of formula (4) with the compound of formula (3) obtained from step (ii) in presence of a base in a solvent and heating at reflux temperature for the time period in the range of 10 to 14 hrs under constant stirring to obtain the deuterium-enriched compound of formula (II) or formula iv.
- step (ii) reacting a compound of formula (8) with a base followed by D2O in a solvent to obtain the deuterium-enriched compound of formula (II) comprising a compound of formula (IIB).
- Another embodiment of the present invention provides a method for preparing the deuterium-enriched compound of formula (I) or formula (II), wherein the solvent including such as but not limit to hydrocarbon solvents, alcohols, water, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
- the solvent including such as but not limit to hydrocarbon solvents, alcohols, water, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
- pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid.
- Another embodiment of the present invention provides a method for preparing the deuterium-enriched compound of formula (II) or formula (III), wherein the halo-alkylamine hydrochloride salt is bis(2-chloroethyl)amine hydrochloride.
- Another embodiment of the present invention provides a method for preparing the deuterium-enriched compound of formula (II) or formula (III), wherein the halo-alkane is selected from such as but not limited to mono haloalkane (e.g. CH3-CH2-X); di-haloalkane (e.g. X-CH 2 -CH 2 -X); tri-haloalkane (e.g. X-CH 2 -CHX- CH 2 -X) wherein X can be Cl, F, Br or I).
- mono haloalkane e.g. CH3-CH2-X
- di-haloalkane e.g. X-CH 2 -CH 2 -X
- tri-haloalkane e.g. X-CH 2 -CHX- CH 2 -X
- haloalkane is selected from methyl chloride, ethyl bromide, isopropyl chloride, ethyl chloride, propyl chloride, 1-bromo-2- chloroethane.
- Another embodiment of the present invention provides a method for preparing deuterium-enriched compounds and/or its intermediate compounds, wherein the base that can be used includes, but is not limited to organic bases such as ammonia, diethyl amine, triethylamine, di-isopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole; and inorganic bases including such as but not limited potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, calcium hydroxide, potassium hydroxide, sodium alkoxide (for example sodium ethoxide, sodium-methoxide), magnesium hydroxide, n-butyllithium and combinations thereof.
- organic bases such as ammonia, diethyl amine, triethylamine, di-isopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole
- Another embodiment of the present invention provides a method for preparing deuterium-enriched compound of formula (II) or formula (III), wherein purification of deuterium-enriched compounds and/or intermediate compounds may be carried out by any conventional methods known in the prior art. For example, column chromatography, activated charcoal treatment, precipitation, recrystallization etc. alone or in combinations thereof.
- Another embodiment of the present invention also provides pharmaceutical formulations which include a compound of formula (I), formula (II) (wherein formula II is IIA, IIB, and IIC), pharmaceutically acceptable salts, solvates, and pro-drugs thereof; and one or more pharmaceutically acceptable excipients, carriers or diluents.
- Such formulations contain a therapeutically effective amount of a compound of formula (I) or formula (II), pharmaceutically acceptable salts, solvates, and prodrugs thereof, and one or more pharmaceutically acceptable excipients, carriers or diluents.
- the present invention provides nefazodone D1 , nefazodone D3, nefazodone D4 or it’s pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, intermediates and pharmaceutical compositions thereof.
- Nefazodone-D3 (Compound of formula (IIC) was also synthesised using similar procedure used in A for the synthesis of nefazodone-D4. Only change in the procedure was usage on 3-chloro aniline-D3 (compound of formula (1A))
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Abstract
The present invention provides novel nefazodon analogues. More specifically, it provides novel deuterium-enriched nefazodone analogues and method for preparing the said analogues. The deuterated nefazodone analogues show improved biological activities, preferably anti-depressant activity. The deuterium-enriched nefazodone analogues of formula (II) are selected from the compound of formula (IIA), formula (IIB) and formula (IIC).
Description
NOVEL DEUTERIUM-ENRICHED NEFAZODONE ANALOGUES AND
METHOD FOR PREPARING THEREOF
PRIORITY:
This application claims the benefit of Indian complete application number 202121051634 dated 10th May 2022 entitled, ‘NOVEL DEUTERIUM-ENRICHED NEFAZODONE ANALOGUES AND METHOD FOR PREPARING THEREOF’, the contents of which are incorporated herein by reference.
FIELD OF INVENTION
The present invention relates to novel nefazodone analogues. More specifically, it relates to deuterated nefazodone analogues and method for preparing the said analogues. The deuterated nefazodone analogues show improved biological activities, preferably anti-depressant activity.
BACKGROUND OF INVENTION
Nefazodone (SERZONE®), 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]-propyl-]5- ethyl-2,4-dihydro-4-(2-phenoxy-ethyl)-3H-1 ,2,4-triazol-3-one hydrochloride is a novel antidepressant chemically unrelated to tricyclic or tetracyclic antidepressants and the selective serotonin uptake inhibitors in current use. Nefazodone bears following structural formula:
Nefazodone is an atypical anti-depressant which was first marketed by Bristol- Myers Squibb in 1994. Nefazodone is a phenylpiperazine compound and is related to trazodone. It has been described as a serotonin antagonist and reuptake inhibitor (SARI) due to its combined actions as a potent serotonin 5- HT2A receptor and 5-HT2C receptor antagonist and weak serotonin- norepinephrine-dopamine reuptake inhibitor (SNDRI). It was discontinued in 2003 in some countries, due to the small possibility of hepatic (liver) injury. Drug-
induced hepatic injuries were associated with a risk of elevated need for a liver transplant, or even death. On May 20, 2004, Bristol-Myers Squibb discontinued the sale of SERZONE in the United States.
Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor. It also has high affinity for the a1-adrenergic receptor and serotonin 5-HT1A receptor, and relatively lower affinity for the a2-adrenergic receptor and dopamine D2 receptor. Nefazodone has low but significant affinity for the serotonin, norepinephrine, and dopamine transporters as well, and therefore acts as a weak serotonin- norepinephrine-dopamine reuptake inhibitor (SNDRI). It has low but potentially significant affinity for the histamine H1 receptor, where it is an antagonist, and hence may have some antihistamine activity. Nefazodone has negligible activity at muscarinic acetylcholine receptors, and accordingly, has no anti-cholinergic effects.
The bioavailability of nefazodone is low and variable, about 20%. Its plasma protein binding is approximately 99%, but it is bound loosely. Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Half-life of the parent compound is 2 to 4hr.
US4338317 discloses a process for the manufacture of Nefazodone free base and Nefazodone hydrochloride. The process involving the reaction of 2- piperazinylalkyltriazolone with suitable phenoxyalkylhalide to form Nefazodone free base. The Nefazodone free base is then converted to Nefazodone hydrochloride by using hydrogen chloride.
CA1233826 discloses a purported improved process in which the Nefazodone free base is produced by reacting a phenoxyalkylcarbamate with an N-substituted hydrazide of a carboxylic acid.
US5900485 describes another process for preparing nefazodone from semicarbazide dihydrochloride and triethyl orthopropionate in the presence of hydrochloride.
CA1198436, US4338317 describes a process for the preparation of nefazodone hydrochloride involve the preparation of nefazodone free base first and then the conversion of it to nefazodone hydrochloride.
Many current pharmaceutical compounds have poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use. These poor ADME properties are a major reason for the failure of pharmaceutical compounds in clinical trials. It is possible to improve some ADME properties by using formulation technologies and pro-drug strategies. However, these approaches often fail to address the underlying ADME problems that exist for many pharmaceutical compounds. One such problem is rapid metabolism that causes a number of pharmaceutical compounds, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid clearance is high or frequent dosing to attain a sufficiently high plasma level of the pharmaceutical compound. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. One potential strategy for improving a pharmaceutical compound’s metabolic properties is deuterium modification (Roger et al., “The Development of Deuterium-Containing Drugs”, Innovations in Pharmaceutical Technology, 2010, issue 32).
Deuterium (2H or D) is a stable, non-radioactive isotope of hydrogen. 2H forms stronger bonds with carbon compared to hydrogen. In some cases, the increased bond strength imparted by 2H can positively impact the ADME properties of a pharmaceutical compound, creating the potential for improved efficacy, safety, and/or tolerability of the pharmaceutical compound. At the same time, because the size and shape of 2H are essentially identical to those of hydrogen, replacement of hydrogen by 2H would not be expected to affect the biochemical potency and selectivity of the pharmaceutical compound as compared to the
original chemical entity that contains only hydrogen (Graham et al., “Deuterated drugs: where are we now?”, Expert Opinion on Therapeutic Patents, 2014, 24(10): 1067-1075.)
Thus, there is a continuing need to develop new deuterated nefazodone analogues that may help in reducing the formation of toxic metabolite and further reduce the possibility if hepatotoxicity. The toxicity is thought to be predominantly mediated by an active hydroxychloro-derivative (chlorophenyl piperazine) that forms covalent adducts with cellular and membrane protein. It is thought that heavy isotope labelling (deuteration) of Nefazodone could possibly improve its safety profile through reduce formation of the reactive metabolite. Hence, reduction in metabolism of the parent pharmaceutical compound may improve its half-life and reduce daily dose requirement.
Thus, to solve the problems highlighted in the above said prior art, the present invention utilise the deuteration strategy at different position of nefazodone moiety that help in metabolism of the parent compound and improve its half-life and reduce daily dose requirement.
OBJECTS OF THE INVENTION
One of the objects of the present invention is to provide a novel deuterium- enriched nefazodone or a pharmaceutically accepted salt thereof.
Another object of the present invention is to provide deuterated version of nefazodone with limit the formation of toxic metabolite and that may increase the half-life of nefazodone compound in the systemic circulation.
Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of at least one of the deuterium-enriched compounds of the present invention or a pharmaceutically accepted salt thereof.
It is still further object of the present invention to provide a method for preparing the novel deuterium-enriched nefazodone or its pharmaceutically accepted salt.
Yet another object of the present invention is to evaluate the biological activity of the deuterium-enriched nefazodone or its pharmaceutically accepted salt.
Yet another object of the present invention is to provide use of a novel deuterium- enriched nefazodone or its pharmaceutically accepted salt for medical treatment.
SUMMARY OF THE INVENTION
One of the aspects of the present invention is to provide a deuterium-enriched compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Wherein
R! to 27 is independently selected from hydrogen (H), deuterium (D), 0^04 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and aryl; at least one of R! to R27 is deuterium (D);
X is halogen selected from a group consisting of fluorine, chlorine, bromine, iodine; and
Z is O or S.
Another aspect of the present invention is to provide a method for preparing the deuterium-enriched compound of formula (II), wherein the method comprises the steps of: i. reacting a compound of formula (1) with a haloalkyl amine hydrochloride salt in a ratio of 1 :1 in a solvent at a temperature in the range of 125 to 175°C for a time period in the range of 10 to 14 hrs under stirring in an inert atmosphere to obtain a compound of formula (2);
Hi. reacting a compound of formula (4) with the compound of formula (3) obtained from step (ii) in presence of a base in a solvent and heating at reflux temperature for time period in the range of 10 to 14 hrs under constant stirring to obtain the deuterium-enriched compound of formula (II);
iv. Optionally, reacting a compound of formula (8) with a base followed by D2O in a solvent to obtain the deuterium-enriched compound of formula (II) comprising a compound of formula (I IB).
BRIEF DESCRIPTION OF FIGURE
Figure 1 shows relative amounts of hydroxyl and dealkylated metabolites formed from Nefazodone and Nefazodone-D4
Figure 2 shows chromatographically extracted Nefazodone-D4 and its metabolites (A-C) and the respective m/z (D-F)
DETAILED DESCRIPTION OF THE INVENTION
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art.
The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
It must also be noted that as used herein, the singular forms "a", "an," and "the" include plural references unless the context clearly dictates otherwise. Although any systems and methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred, systems are now described.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. Throughout this specification, unless the context requires otherwise the word “comprise”, and variations, such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. The terms “Including” and “including but not limited to” are used interchangeably.
The term “at least one” is used to mean one or more and thus includes individual components as well as mixtures/combinations.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described.
Detailed embodiments of the present invention are disclosed herein, however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific functional and structural details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure.
The term “compound” used herein, is also intended to include any salts, solvates, or hydrates thereof. Thus, it is to be understood that when any compound is referred to herein by name and structure, salts, solvates, and hydrates thereof are included.
The term “pharmaceutically acceptable salt” used herein means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
The term “therapeutically effective amount” used herein refers to an amount of a compound of the present invention that is effective when administered alone or in combination to treat the desired condition or disorder. The combination of compounds is preferably a synergistic combination.
The term “hydrate” used herein means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces.
The term “solvate” used herein means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non- covalent intermolecular forces.
The term “halo-alkanes” used herein refers to a group of chemical compounds comprised of an alkane with one or more hydrogens replaced by a halogen atom (fluorine, chlorine, bromine, or iodine). Halo-alkane can be monohaloalkane, dihaloalkane, trihaloalkane.
The term “solvent” used herein refers to a substance that can dissolve another substance, or in which another substance is dissolved, forming a solution. The solvent used in the present invention can be polar or nonpolar solvent. The solvent includes such as but not limit to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
The term “deuterium enriched” used herein refers to compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%, should be considered unnatural and, as a result, novel over their nonenriched counterparts.
“D” and “d” both refer to deuterium. D” and “d” can be used interchangeably in the specification.
The present invention provides Deuteration at para position of nefazodone that help to reduce the formation of toxic metabolite and further it reduces the possibility if hepatotoxicity. Further, reduction in metabolism of the Nefazodone compound improves its half-life and reduce daily dose requirement.
One of the embodiment of the present invention provides a deuterium-enriched compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Wherein
R! to R27 is independently selected from hydrogen (H), deuterium (D), 0^4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and aryl; at least one of R! to R27 is deuterium (D);
X is halogen selected from a group consisting of fluorine, chlorine, bromine, iodine; and
Z is O or S.
Another embodiment of the present invention provides a deuterium-enriched compound of formula (I), wherein R! to R27 is independently selected from hydrogen (H) and deuterium (D).
In most preferred embodiment of the present invention provides a deuterium- enriched compound of formula (I), wherein R^ R2, R3, R4 is independently selected from hydrogen (H) and deuterium (D).
Yet another embodiment of the present invention provides a deuterium-enriched compound of formula (I), wherein X is chlorine.
Yet another embodiment of the present invention provides a deuterium-enriched compound of formula (I), wherein Z is O.
Another embodiment of the present invention provides a deuterium-enriched compound of formula (I), wherein the deuterium-enriched compound of formula (I) is selected from the compounds including such as but not limited to
Wherein
R! to R4 in the compound of formula (II) is independently selected from hydrogen (H), deuterium (D); preferably deuterium (D); R3 in the compound of formula (III) is hydrogen (H) or deuterium (D);
X in the compound of formula (II) and formula (III) is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine; and Z in the compound of formula (II) and formula (III) is O.
In an embodiment, a deuterium-enriched compound represented by formula (II) is selected from
In another embodiment of the present invention there is provided a deuterium- enriched compound of formula (I), wherein intermediates or starting materials may be selected from the compounds including such as but not limited to the following compounds,
Another embodiment of the present invention provides an intermediate compound represented by formula (1),
s Wherein R R2, R3 and R4 may be independently selected from hydrogen (H), deuterium (D), CrC4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and aryl; preferably hydrogen (H) and deuterium (D); at least one deuterium (D);
X is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine.
Yet another embodiment of the present invention provides an intermediate compound represented by formula (1), wherein R^ R2, and R4 is hydrogen (H) and R3 is halogen selected from the group consisting of fluorine, chlorine, bromine and iodine; preferably R3 is bromine.
Another embodiment of the present invention provides an intermediate compound of formula (2),
Wherein R R2, R3 and R4 may be independently selected from hydrogen (H), deuterium (D), CrC4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and aryl; preferably hydrogen (H) and deuterium (D); at least one of R! to R4 is deuterium (D);
X is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine.
Yet another embodiment of the present invention provides an intermediate compound of formula (2), wherein R^ R2, and R4 is hydrogen (H) and R3 is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably R3 is bromine.
Another embodiment of the present invention provides an intermediate compound of formula (3),
Wherein R^ R2, R3, and R4 may be independently selected from hydrogen (H), deuterium (D), CrC4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and aryl; preferably hydrogen (H) and deuterium (D); at least one of R! to R4 is deuterium (D);
X is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably chlorine.
Yet another embodiment of the present invention provides an intermediate compound of formula (3), wherein Ri, R2, and R4 is hydrogen (H) and R3 is halogen selected from the group consisting of fluorine, chlorine, bromine, iodine; preferably R3 is bromine.
Another embodiment of the present invention provides an intermediate compound of formula (4),
Wherein the compound of formula (4) is synthesised by [Synthesized from phenol following reported procedure. Journal of Heterocyclic Chemistry, 1985, 22(4), 1121-1126]:
In an embodiment, the intermediate compound can be in deuterated form in which one or more hydrogen replaced by deuterium (d).
Another embodiment of the present invention provides a method for preparing the deuterium-enriched compound of formula (II) or formula (III), wherein the method comprises the steps of: i. reacting a compound of formula (1) with a haloalkyl amine hydrochloride salt in a ratio of 1 : 1 in a solvent at a temperature in the range of 125 to 175°C for a time period in the range of 10 to 14 hrs under stirring in an inert atmosphere to obtain a compound of formula (2);
ii. dissolving the compound of formula (2) in a solvent and adding a base and followed by adding a haloalkane slowly at room temperature under stirring to obtain a compound of formula (3);
iii. reacting a compound of formula (4) with the compound of formula (3) obtained from step (ii) in presence of a base in a solvent and heating at reflux temperature for the time period in the range of 10 to 14 hrs under constant stirring to obtain the deuterium-enriched compound of formula (II) or formula
iv. Optionally, reacting a compound of formula (8) with a base followed by D2O in a solvent to obtain the deuterium-enriched compound of formula (II) comprising a compound of formula (IIB).
Wherein the deuterium-enriched compound of formula (I) or formula (II) prepared is biological active.
Another embodiment of the present invention provides a method for preparing the deuterium-enriched compound of formula (I) or formula (II), wherein the solvent including such as but not limit to hydrocarbon solvents, alcohols, water,
ethers, ketones, acids, esters, acetonitrile (ACN) halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid.
Another embodiment of the present invention provides a method for preparing the deuterium-enriched compound of formula (II) or formula (III), wherein the halo-alkylamine hydrochloride salt is bis(2-chloroethyl)amine hydrochloride.
Another embodiment of the present invention provides a method for preparing the deuterium-enriched compound of formula (II) or formula (III), wherein the halo-alkane is selected from such as but not limited to mono haloalkane (e.g. CH3-CH2-X); di-haloalkane (e.g. X-CH2-CH2-X); tri-haloalkane (e.g. X-CH2-CHX- CH2-X) wherein X can be Cl, F, Br or I).
In an embodiment of the present invention, wherein haloalkane is selected from methyl chloride, ethyl bromide, isopropyl chloride, ethyl chloride, propyl chloride, 1-bromo-2- chloroethane.
Another embodiment of the present invention provides a method for preparing deuterium-enriched compounds and/or its intermediate compounds, wherein the base that can be used includes, but is not limited to organic bases such as ammonia, diethyl amine, triethylamine, di-isopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole; and inorganic bases including such as but not limited potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, calcium hydroxide, potassium hydroxide, sodium alkoxide (for example sodium ethoxide, sodium-methoxide), magnesium hydroxide, n-butyllithium and combinations thereof.
Another embodiment of the present invention provides a method for preparing deuterium-enriched compound of formula (II) or formula (III), wherein purification of deuterium-enriched compounds and/or intermediate compounds may be carried out by any conventional methods known in the prior art. For example, column chromatography, activated charcoal treatment, precipitation, recrystallization etc. alone or in combinations thereof.
Another embodiment of the present invention also provides pharmaceutical formulations which include a compound of formula (I), formula (II) (wherein formula II is IIA, IIB, and IIC), pharmaceutically acceptable salts, solvates, and pro-drugs thereof; and one or more pharmaceutically acceptable excipients, carriers or diluents. Such formulations contain a therapeutically effective amount of a compound of formula (I) or formula (II), pharmaceutically acceptable salts, solvates, and prodrugs thereof, and one or more pharmaceutically acceptable excipients, carriers or diluents.
In an embodiment the present invention provides nefazodone D1 , nefazodone D3, nefazodone D4 or it’s pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, intermediates and pharmaceutical compositions thereof.
The details of the present invention are provided in the examples given below to illustrate the invention only and therefore they should not be construed to limit the scope of invention.
Example:
A. Preparation of Nefazodone-D4(compound of formula (II)):
Synthesis of Nefazodone-D4 is carried out in following steps: a. Synthesis of compound of formula (2)
In an atmosphere of dry N2, a mixture 3-chloro aniline-D4 (compound of formula (1)) (3.4 g 3.0 mmol), bis(2-chloroethyl) amine hydrochloride (5.4 g, 3.0 mmol), and diethylene glycol monomethyl ether (1 ml) was heated at 150°C for 12 h. After being cooled to room temperature, the mixture was dissolved in MeOH (4 mL) followed by addition of Et2O (150 mL). The precipitate was filtered off and
washed with Et2O to provide HCI salt. The HCI salt was further converted to free amine by treatment with Na2CO3 solution and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to provide the pure free amine product (2). Yield: (5.1g). b. Synthesis of compound of formula (3)
Compound of formula (2) (400mg, 2.0 mmol) was dissolved in acetone (20ml), potassium carbonate (K2CO3, 552 mg, 4.0 mmol) was added and followed by drop-wise addition of 1-bromo-3- chloroethane (0.34 ml, 4.01 mmol) The reaction mixture was stirred at room temperature (r.t.) The reaction mixture was filtered after the completion of reaction and was concentrated. The obtained product was purified by column chromatography with n-hexane: ethyl acetate = 6:1 to obtain 3 (330 mg, 60%) as clear liquid. Retention factor Rf = 0.66 (n-hexane: EtOAc is 2:1). c. Synthesis of compound of formula (4)
To a solution of 88.4 g (1 .58 mole) of potassium hydroxide in 10.0 litres of water
heated to 95°C was added with stirring 396.1g (1.58 mole) of compound of formula (3a). The mixture was stirred at 95-96° for 40 minutes and filtered while hot. The filtrate was then cooled in an ice-bath (the potassium salt of the title compounds started to precipitate) as 146 ml (1.75 mole) of 37 to hydro-chloric acid was added. The mixture was stirred at 10°C for 1 hour. The solid was collected, rinsed with water and air dried to obtain compound (4). Yield: (233.5 g, 64 to of theory), m. p. 136-139°C.
d. Synthesis of Nefazodone D4 (compound of formula (IIA)) from compound of formula (4)
A mixture of compound of formula (4) (259 mg, 1.1 mmol) and compound (3) (332.4 mg, 1.22 mmol), and 192 .5 mg of 50% aqueous sodium hydroxide (2.44 mmol) in 20 ml of isopropanol was stirred and heated at reflux for 12 hr. Mixture was filtered hot and filtrate was treated with activated charcoal, filtered and concentrated in vacuo to give viscous oil. Crystallization of viscous oil from isopropanol/heptane obtained nefazodone D4 (formula (II)) as free base (400
B. Preparation of Nefazodone-D1 (compound of formula (IIB)):
Following steps are involved in the synthesis of Nefazodone-D1 . a. Synthesis of compound of formula (2)
In an atmosphere of dry N2, a mixture 4-bromo-3-chloro-aniline (compound of formula (5)) (5.8 g 3.0 mmol), bis(2-chloroethyl)amine hydrochloride (5.4 g, 3.0 mmol), and diethylene glycol monomethyl ether (1 ml) was heated at 150°C for 12 h. After being cooled to room temperature, the mixture was dissolved in MeOH (4 ml) followed by addition of Et2O (150 mL). The precipitate was filtered off and washed with Et2O to provide HCI salt. The HCI salt was further converted to free amine by treatment with Na2CO3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated in vacuo to provide the pure free amine product (6). Yield: (5.5 g).
b. Synthesis of compound of formula (7)
The synthesised compound of formula (6) (550 mg, 2.0 mmol) was dissolved in acetone (20 ml), potassium carbonate (K2CO3, 552 mg, 4.0 mmol) was added and followed by drop wise addition of 1-bromo-3- chloropropane (0.34 ml, 4.01 mmol). The reaction mixture was stirred at room temperature (r.t.). The reaction mixture was filtered after the completion of reaction and was concentrated. The obtained product was purified by column chromatography with n-hexane: ethyl acetate = 6:1 to obtain the compound of formula (7) (440 mg, 60%) as clear liquid.
c. Synthesis of intermediate compound of formula (9)
A mixture of compound (4) (259 mg, 1.1 mmol) [Synthesized from phenol following reported procedure. Journal of Heterocyclic Chemistry, 1985,22(4), 1121-1126], compound (7) (430 mg, 1.22 mmol), and 192 .5 mg of 50% aquous sodium hydroxide (2.44 mmol) in 20 mL of isopropanol was stirred and heated at reflux for 12 hr. Mixture was filtered hot and filtrate was treated with activated charcoal, filtered and concentrated in vacuo to give viscous oil. Crystallization of this oil from isopropanol/heptane gave bromo-Nefazodone compound (8) as free base (400 mg).
Compound of formula (8) (200 mg, 0.5 mmol) in THF 10 mL was stirred at -70°C for 30 minutes and n-Bultylithium (2 M solution in THF, 2.6 mmol) 1.3 ml was added and reaction mixture was brought to -20°C and stirred for 1 hr. D2O was added slowly to the reaction mixture and saturated ammonium chloride was added. Mixture was extracted with ethyl acetate and concentrated to dryness. Crude product was further crystalized using isopropanol and heptane to get pure product Nefazodone-D1 (IIB) [125mg],
C. Preparation of Nefazodone-D3 (Compound of formula (IIC))
Nefazodone-D3 (Compound of formula (IIC) was also synthesised using similar procedure used in A for the synthesis of nefazodone-D4. Only change in the
procedure was usage on 3-chloro aniline-D3 (compound of formula (1A))
Instead of 3-chloroaniline D4.
D. comparison of formation of reactive metabolite:
Comparison of formation of Reactive Metabolite (m-Cholorophenylpiperazine) from Nefazodone and D4- Nefazodone generated in vitro with human liver microsomes
Main objective of this study was to compare metabolism of Nefazodone and D4- labeled Nefazodone, especially formation of the hydroxychloro-derivative m- chlorophenyl piperazine considered as a toxic intermediate. Well -know anti - anxiety drug buspirone was used as reference control to establish formation of metabolites using LC-MS/MS methods. Human liver microsome (HLM) was used as CYP450 source to generate metabolites in in vitro assays.
In preliminary studies, formation of major metabolites of Nefazodone was established based on m/z values. After incubation with HLM and cofactor NADPH, formation of OH - Nefazodone, D4-OH- Nefazodone, m-chlorophenyl piperazine and D4-M-chlophenyl piperazine was clearly seen. Further assays were conducted for a quantitative estimation of various metabolites (due to lack of specific standards) based on the analyte response (area counts) in LC-MS- MS. A comparative difference in the levels and rates of formation of these metabolites with time (till 30min), especially with regard to m-chlorophenyl piperazine (m-chorophenyl piperazine I D4-m-chlophenyl piprazine), between Nefazodone and D4-Nefazodone was observed. Overall reduction in formation of D4-m-chlophenyl piprazine was ~60% compared to that of m-chlorophenyl piperazine under similar assays conditions. It is concluded that metabolism of D4- Nefazodone generates lesser amount of m-chlorophenyl piperazine than unlabeled Nefazodone in in vitro conditions.
Conclusion:
• Formation of hydroxylated and dealkylated metabolites from Nefazodone and D4-Nefazodone after incubation with human liver microsome and NADPH was studied using LC-MS/MS method.
• In in vitro incubation, both Nefazodone and D4- Nefazodone were rapidly metabolized (Clint in vitro>150pl/min/mg protein).
• In metabolite identification assays, rapid formation of OH- Nefazodone and m- Chlorophenyl piperazine from Nefazodone was observed. In case of D4- Nefazodone, both hydroxylated and dealkylated (D4-m Chlorophenyl Piperazine) formation occurred. Metabolites formation was found to reach maximum levels by about 10 min under the experimental condition employed. The metabolites were further characterized by MRM methods to observe specific fragments.
• Comparison of formation of OH- and m- Chlorophenyl piperazine metabolites based on response in LC-MS/MS showed that D4-Nefazodone generates notably less levels of both metabolites (50-60% lower in D4-Nefazodone).
Claims
1. A deuterium-enriched compound represented by formula (II)
or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates thereof;
Wherein R! to R4 is independently selected from hydrogen (H), deuterium (D), C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and aryl; at least one of R! to R4 is deuterium (D);
X is halogen selected from a group consisting of fluorine, chlorine, bromine, iodine; and
Z is O or S.
2. The deuterium-enriched compound of formula (I) as claimed in claim 1 , wherein R! to R4 is independently selected from hydrogen (H) and deuterium (D).
3. The deuterium-enriched compound of formula (I) as claimed in claim 1 , wherein R^ R2, R3, R4 is independently selected from hydrogen (H) and deuterium (D).
4. The deuterium-enriched compound of formula (I) as claimed in claim 1 , wherein X is chlorine.
5. The deuterium-enriched compound of formula (I) as claimed in claim 1 , wherein Z is O.
A deuterium-enriched compound represented by formula (II) is selected from
A method for preparing the deuterium-enriched compound of formula (II) as claimed in claim 1 , wherein the method comprises the steps of: i. reacting a compound of formula (1) with a haloalkyl amine hydrochloride salt in a ratio of 1 : 1 in a solvent at a temperature in the range of 125 to 175°C for a time period in the range of 10 to 14 hrs under stirring in an inert atmosphere to obtain a compound of formula
ii. dissolving the compound of formula (2) in a solvent and adding a base and followed by adding a haloalkane slowly at room temperature under stirring to obtain a compound of formula (3);
iii. reacting a compound of formula (4) with the compound of formula (3) obtained from step (ii) in presence of a base in a solvent and heating at reflux temperature for the time period in the range of 10 to 14 hrs under constant stirring to obtain the deuterium-enriched compound of formula (II) with 50 to 60% lower formation of OH- and m-chlorphenyl piperazine metabolite compared to Nefazodone moiety.
iv. Optionally reacting a compound of formula (8) with a base followed by D2O in a solvent to obtain the deuterium-enriched compound of formula (II) comprising a compound of formula (IIB).
Wherein Ri, R2, R3, R4 is independently selected from hydrogen (H) and deuterium (D); wherein X is halogen selected from chlorine, bromine; wherein Z is O. . The method for preparing the deuterium-enriched compound of formula (I) as claimed in claim 7, wherein the halo-alkylamine hydrochloride salt is bis (2-chloroethyl)amine hydrochloride; and wherein the halo-alkane is selected from methyl chloride, ethyl bromide, isopropyl chloride, ethyl chloride, propyl chloride, . The method for preparing the deuterium-enriched compound of formula (I) as claimed in claim 7, wherein the solvent is selected from water,
alcohols, ethers, cyclic ethers, ketones, acids, esters, acetonitrile (ACN), halogenated solvent(s) or deuterated form of water, alcohols, ethers, cyclic ethers, ketones, acids, esters, acetonitrile (ACN), halogenated solvent(s) and combinations thereof. The method for preparing the deuterium-enriched compound of formula (I) as claimed in claim 7, wherein the base is selected from ammonia, diethyl amine, triethylamine, di-isopropylethylamine, pyridine, dimethylaminopyridine, imidazole; potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, calcium hydroxide, potassium hydroxide, sodium ethoxide, sodium-methoxide, magnesium hydroxide, n- butyllithium and combinations thereof.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4487773A (en) * | 1981-03-16 | 1984-12-11 | Mead Johnson & Company | 1,2,4-Triazol-3-one antidepressants |
| WO2009105604A1 (en) * | 2008-02-20 | 2009-08-27 | Auspex Pharmaceuticals, Inc. | Substituted triazolopyridines |
| US20200405726A1 (en) * | 2015-03-20 | 2020-12-31 | Gaba Therapeutics Inc. | Deuterated analogs of etifoxine, their derivatives and uses thereof |
-
2023
- 2023-02-27 WO PCT/IB2023/051786 patent/WO2023218251A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4487773A (en) * | 1981-03-16 | 1984-12-11 | Mead Johnson & Company | 1,2,4-Triazol-3-one antidepressants |
| WO2009105604A1 (en) * | 2008-02-20 | 2009-08-27 | Auspex Pharmaceuticals, Inc. | Substituted triazolopyridines |
| US20200405726A1 (en) * | 2015-03-20 | 2020-12-31 | Gaba Therapeutics Inc. | Deuterated analogs of etifoxine, their derivatives and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| D. M. BAILEY AND D. M. BAILEY: "ANNUAL REPORTS IN MEDICINAL CHEMISTRY", vol. 46, 1 January 2011, ACADEMIC PRESS , US , ISSN: 0065-7743, article SCOTT L. HARBESON, TUNG ROGER, MACOR JOHN E.: "Deuterium in Drug Discovery and Development", pages: 403 - 417, XP055422117, DOI: 10.1016/B978-0-12-386009-5.00003-5 * |
| LIU ET AL.: "A general and convenient synthesis of N-aryl piperazines", TETRAHEDRON LETTERS, vol. 46, 2005, pages 7921 - 7922, XP025385819, DOI: 10.1016/j.tetlet. 2005.09.09 2. * |
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