WO2023218251A1 - Nouveaux analogues du néfazodone enrichis en deutérium et leur procédé de préparation - Google Patents

Nouveaux analogues du néfazodone enrichis en deutérium et leur procédé de préparation Download PDF

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Publication number
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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formula
deuterium
compound
nefazodone
enriched
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Inventor
Mr. VIJAY AMBATI
Mr. MANISH KOTHARI
Dr. Praful GUPTA
Dr. SAKHTIVEL KANDASAMY
Dr. Mallikarjuna Katukuri REDDY
Dr. Nagashivrao JONNALAGADDA
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Clearsynth Labs Limied
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    • 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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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux analogues du néfazodone. Plus précisément, l'invention concerne de nouveaux analogues du néfazodone enrichis en deutérium et un procédé de préparation desdits analogues. Les analogues du néfazodone deutérés présentent des activités biologiques améliorées, de préférence une activité antidépressive. Les analogues du néfazodone enrichis en deutérium de formule (II) sont choisis parmi le composé de formule (IIA), formule (IIB) et formule (IIC).
PCT/IB2023/051786 2022-05-10 2023-02-27 Nouveaux analogues du néfazodone enrichis en deutérium et leur procédé de préparation Ceased WO2023218251A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
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 (fr) * 2008-02-20 2009-08-27 Auspex Pharmaceuticals, Inc. Triazolopyridines substituées
US20200405726A1 (en) * 2015-03-20 2020-12-31 Gaba Therapeutics Inc. Deuterated analogs of etifoxine, their derivatives and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
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 (fr) * 2008-02-20 2009-08-27 Auspex Pharmaceuticals, Inc. Triazolopyridines substituées
US20200405726A1 (en) * 2015-03-20 2020-12-31 Gaba Therapeutics Inc. Deuterated analogs of etifoxine, their derivatives and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
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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