WO2008081477A1 - Propanamines à 3-substitution 3-aryloxy - Google Patents

Propanamines à 3-substitution 3-aryloxy Download PDF

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WO2008081477A1
WO2008081477A1 PCT/IN2008/000001 IN2008000001W WO2008081477A1 WO 2008081477 A1 WO2008081477 A1 WO 2008081477A1 IN 2008000001 W IN2008000001 W IN 2008000001W WO 2008081477 A1 WO2008081477 A1 WO 2008081477A1
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compound
substituted
alkyl
formula
phenyl
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PCT/IN2008/000001
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English (en)
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Muddasani Pulla Reddy
Junnarkar Ajit Yashwant
Reddy Peddi Rajasekhara
Bhujanga Rao Adibatla Kali Satya
Umamaheshwar Rao Naidu Madireddi
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain

Definitions

  • Present invention relates to novel 3-aryloxy 3-substituted propanamines, method of preparing the same and to their use in inhibiting serotonin and norepinephrine reuptake.
  • Numerous 3-aryloxy-3-phenyl substituted and 3 -heteroaryloxy-3 -phenyl substituted propanamines have been reported in the literature, more particularly, US 4314081, US 5023269, WO02/094262 claim 3-aryloxy-3-phenyl and 3-heteroaryloxy-3-phenyl- substituted propanamines possessing antidepressant activity.
  • serotonin reuptake inhibitors are extremely effective in the treatment of depression. They increase the availability of serotonin in the synapse by reducing the uptake of serotonin by serotonin uptake carrier. Dysfunction of the serotonin neurons resulting from excessive uptake results in depression. Serotonin reuptake inhibitors are spectacularly effective in treating the depression. They are effective in treating numerous other conditions.
  • the serotonin reuptake inhibitors are citalopram, fluoxetine, paroxetine, sertraline, venlafaxine. Primary activity of these drugs is the inhibition of the reuptake of serotonin.
  • the compounds of the invention are 3-aryloxy 3-substituted propanamines having the general formula I
  • A is a phenyl which is optionally substituted with up to five substituents selected from cyano, halogeno, C
  • R is cyano, halogeno, halogenoalkyl, C
  • a preferred point of attachment of 5-membered heteroaryl group to the propyl chain is attachment at the carbon atom.
  • the compounds of the present invention are useful in selectively inhibiting the reuptake of serotonin and norepinephrine in mammals.
  • Medicaments comprising the compounds of formula I can be administered to a patient in need thereof for treating disorders associated with serotonin and norepinephrine dysfunction in mammals.
  • the disorder is selected from depression, anxiety, memory loss, urinary incontinence, conduct disorders, ADHD, obesity, alcoholism, erectile dysfunction, smoking cessation, and pain.
  • A is a phenyl which is substituted with cyano, halogeno, Ci. 6 -alkyl, Ci -6 -alkoxy, trifluoromethyl, aralkyloxy, ethynyl, carboalkoxy, formyl, sulfonamido, carboxamido, triazolyl or tetrazolyl;
  • R is cyano, halogeno, C ⁇ - 6 -alkyl, Ci -6 -alkoxy, trifluoromethyl, aralkyloxy, ethynyl, aryloxy, carboalkoxy, formyl, sulfonamido, carboxamido, triazolyl or tetrazolyl and one of Ri and R 2 is hydrogen.
  • A is a phenyl which is mono-, di- or tri-substitued with cyano, halogeno, C ⁇ - 6 -alkyl, trifluoromethyl, aralkyloxy, ethynyl, carboalkoxy, formyl, sulfonamido, carboxamido, triazolyl or tetrazolyl.
  • A is a five member heteroaryl radical having the structural formula given below:
  • radicals represented by Ri and R 2 as defined for the compound of formula I are particularly radicals selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n-pentyl, benzyl, 2-phenylethyl, 3-phenylpropyl, phenyl, cyclopropyl, cyclopentyl, cyclo- hexyl, cycloheptyl, cyclooctyl, cyclododecyl, 2-methyl-cyclohexyl, 3-methylcyclohexyl, cis- or trans-4-methylcyclohexyl, cis- or trans-4-tert-butylcyclohexyl, 2,6- dimethylcyclohexyl, 1-adamantyl, 2-adamantyl, cyclohexylmethyl.
  • Organic and inorganic acids examples include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid, pyruvic acid, citric acid, salicylic acid, methanesulfonic acid, 2-hydroxynaphthoic . acid, acetic acid, mandelic acid, camphorsulfonic acid, p- toluenesulfonic acid, benzenesulfonic acid,
  • alkyl is intended to mean straight or branched alkyl radicals bearing from one to six carbon atoms.
  • the condensation process may be carried out in the presence of a base such as sodium or potassium hydroxide, carbonate, bicarbonate, sodium hydride, lithium diisopropylamide, trialkylamine, such as triethylamine, or the amine of formula III.
  • a base such as sodium or potassium hydroxide, carbonate, bicarbonate, sodium hydride, lithium diisopropylamide, trialkylamine, such as triethylamine, or the amine of formula III.
  • the reaction may be carried out in a solvent medium such as toluene, cyclohexane, heptane, tetrahydrofuran, dioxane, N,N-diernthylformamide, dimethyl sulfoxide, and conveniently at a temperature of-10 to 100 0 C.
  • Compounds of formula II can be prepared by reacting the hydroxy compound of formula IV,
  • compounds of formula I can be prepared by reacting an alcoholic compound of formula VI,
  • reaction may be carried out in the presence of base such as sodium or potassium hydroxide, carbonate, bicarbonate, sodium hydride, lithium diisopropylamide.
  • base such as sodium or potassium hydroxide, carbonate, bicarbonate, sodium hydride, lithium diisopropylamide.
  • the reaction may be carried out in a solvent medium such as toluene, cyclohexane, heptane, tetrahydrofuran, dioxane, N,N-diemthylformamide, dimethyl sulfoxide, and conveniently at a temperature of -10 to 100°C.
  • N-methyl compounds can be reacted with cyanogen bromide or alkyl chloroformates and hydrolyzed to get the N-demethylated compounds.
  • N-benzyl compounds can be hydrogenated to get the required secondary amines of formula I wherein Ri is hydrogen.
  • mice Compounds of formula I are tested on healthy, adult, Albino mice to establish the antidepressant activity.
  • Some of the pharmacological studies carried out on mice include determination of maximum tolerated dose (MTD), gross behavioral studies including body temperature, forced locomotor activity, immobility test, antagonism of apomorphine-induced hypothermia, antagonism of reserpine-induced hypothermia and ptosis, reversal of anti-reserpine activity of desipramine, antagonism of oxotremorine, antagonism of tetrabenazine induced ptosis, and in-vitro receptor binding study. All these studies were carried out in comparison with some of the market available compounds for same activity. Studied compounds are found to be better than or equal to the activity of market compounds.
  • Toluene layer was washed with water, treated with carbon and dried with sodium sulphate. Toluene was distilled of and the residue dissolved in 1:1 mixture of hexane:diisopropyl ether. The solution was cooled to 5-10 0 C and filtered the solid. After drying 18.5g of title compound was obtained as white solid. Melting point is 78.5°C.
  • p-Chlorobenzotrifluoride (3.Ig) was added to the reaction mass at RT.
  • the reaction mass was heated to 65-7O 0 C and maintained for 4h.
  • the reaction mass was cooled to RT and quenched with 3ml of methanol.
  • the reaction mass was poured into 150ml of water.
  • the reaction mass was extracted with 2x 100ml of toluene. Combined toluene layer was washed with water, decolorized with carbon, dried with sodium sulfate and distilled of solvent under vaccum to get 4g of crude compound.
  • Hydrochloride salt (I-A) melted at 1 13.2-1 15 0 C 0 C after recrystallization from ethyl acetate-diisopropyl ether.
  • step (ii) Preparation of phenyl 3-(4-chIorophenyl)-3-hydroxypropyl(methyl)carbamate
  • step (ii) compound (15g), 90ml of chloroform, and 15g of potassium carbonate.
  • Phenyl chloroformate was slowly added to the reaction mass and kept under stirring for overnight.
  • Water was added to the reaction mass and the product extracted into chloroform, dried and distilled to get the crude title compound as syrup.
  • Reaction mass was extracted with toluene and the toluene layer washed with water, dried and distilled of solvent to get 9.Og of crude compound.
  • the crude compound was converted to its oxalate salt and recrystallized from methanol-diisopropyl ether to get 4.Og of the title compound as white solid. Melting point is 199.1 0 C.
  • Corresponding hydrochloride salted melted at 160.1 0 C after recrystallizing from methanol/ethyl acetate.
  • (+) ⁇ 3-(4-Fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenoxy)- propan-1-amine oxalate (+)-l-(4-Fluorophenyl)-3-(methylamino)propan-l-ol (25g), prepared according to the process disclosed in WO05/063707 is converted to (+)-3-(4-fluorophenyl)-N-methyl-3- (4-(trifluoromethyl)phenoxy)propan-l -amine oxalate as per the process given in Example 1 above. Melting point is 210-212 0 C (methanol).
  • mice showed marked afrodesic activity in a group treated with fluoxetine, compounds of formula I (I-A, I-B, and I-C) at lower dose 5.0 mg/Kg and 50 mg/Kg (po) till 120 min.
  • compounds of formula I (I-A, I-B, and I-C) at lower dose 5.0 mg/Kg and 50 mg/Kg (po) till 120 min.
  • toxic doses animals showed chronic convulsion followed by death.
  • Table 1 The results of maximum tolerated doses are tabulated in Table 1.
  • mice weighing 20-22gm The various parameters mentioned in below Table 2 were recorded after administration of fluoxetine (25.0 mg/kg), I-A (6.25 mg/kg), I-B (25.0 mg/kg), and I-C (6.25 mg/kg).
  • the behavioral parameters were scored as per the method outlined by Irwin (Irwin S. Gorden, Res. On Medicinal Chem. Cited in Turner RA ed.: Screening Methods in Pharmacology Vol. I New York, London, Academic Press 1965, 133) and modified by Singh et al (Singh PP, Junnarkar AY, Reddi GS, Singh KV, Fitoterpia, 1987, 58, 235 -238). The results of various gross observations are tabulated in Table-2.
  • I-B (12.5, 25.0 and 50.0 mg/kg) orally were administered.
  • the animals were tested for immobility from 30 min to 360 min.
  • the compounds fluoxetine, I-A, I-B, and I-C exhibited decreased immobility with dose-dependent manner. However, at a higher-dose all compounds increased the immobility period. The results are tabulated in Table 3.
  • mice Female Swiss albino weighing 25-30 gm. Each group consisted of 6 mice (Vogel 2002). The mice were given pretreatment of desipramine (20.0 mg/kg), fluoxetine & I-B (25.0 mg/kg), I-A & I-C (6.25 mg/kg po). After 60 min of compound administration each group was injected with apomorphine 16 mg/kg (sc). The rectal temperature of each animal was recorded by using Digital Tele thermometer and thermocouple probe from 30 min to 240 min. The percentage antagonism was calculated by comparing group with control. Desipramine (20.0 mg/kg) po antagonized apomorphine induced hypothermia to tune of 86%.
  • mice The rectal temperature of each mice was recorded from 30 min till 360 min of compound administration.
  • the percentage antagonism was carried out by comparing activity with control. Desipramine (20.0 mg/kg) po antagonized reserpine induced hypothermia by 78% while fluoxetine, I-A, I-B, and I-C failed to antagonize reserpine induced hypothermia.
  • Table-5 The results are tabulated in Table-5.
  • mice were administered reserpine (2.0 mg/kg) subcutaneously (sc). After 18 h desipramine (20.0 mg/kg po) followed by fluoxetine & I-B (25.0 mg/kg po), I-A & I-C (6.25 mg/kg po) were administered concurrently. The rectal temperature of each mice was recorded by digital thermometer and thermocouple probes from 30 min till 360 min after drug administration.
  • Table 6 antagonism of antireserpine activity of desipramine by concurrent administration of fluoxetine, I-A, I-B, and I-C (mice)
  • Compounds of present invention have better antidepressant activity than the market compounds like fluoxetine.
  • Compounds of present invention are less toxic and safer than the market compounds.

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Abstract

La présente invention concerne de nouvelles propanamines à 3-substitution 3-aryloxy représentées par la formule (I), des procédés d'élaboration correspondant et leur utilisation pour bloquer la recapture de la sérotonine et de la norépinéphrine. En l'occurrence, A est un phényle qui est éventuellement substitué par un maximum de 5 substituants; un 1- ou 2-naphtyle éventuellement substitué; un radical hétéroaryle à 5 noyaux qui contient, comme hétéroatomes, 2 à 4 atomes N ou 1 ou 2 atomes N ainsi que 1 atome O ou S, et qui est non substitué ou C-substitué par alkyle inférieur, phényle ou phényle substitué et/ou est N-substitué au niveau d'un atome N qui est capable de substitution par alkyle inférieur, alcoxy inférieur et/ou halogène; un 2-benzimidazolyle éventuellement non substitué ou substitué; et R1 et R2 sont chacun indépendamment hydrogène, C1-6-alkyle, C3-7-cycloalkyle, C3-6-cycloalkyle C1-3-alkyle; ou R1 et R2 peuvent former ensemble un noyau C5-7-carbocyclique contenant 0-2 hétéroatomes tels que N, O ou S et l'un de leurs sels avec un acide pharmaceutiquement admis. Les composés représentés par la formule (I) (I-A: R=4-CF3, R1=H, R2=CH3; A=4-fluorophényle), (I-B: R=4-CF3, R1=H, R2=CH3; A=4-méthylphényle), (I-C: R=4-CF3, R1=H, R2=CH3; A=4-méthoxyphényle) s'avèrent être meilleurs que les antidépresseurs à base de fluoxétine.
PCT/IN2008/000001 2007-01-04 2008-01-02 Propanamines à 3-substitution 3-aryloxy WO2008081477A1 (fr)

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Cited By (7)

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EP2385944A2 (fr) * 2009-01-09 2011-11-16 President and Fellows of Harvard College Composés fluorés et leurs procédés d'utilisation
US8686158B2 (en) 2008-06-05 2014-04-01 President And Fellows Of Harvard College High-valent palladium fluoride complexes and uses thereof
US9024093B2 (en) 2008-11-20 2015-05-05 President And Fellows Of Harvard College Fluorination of organic compounds
US9150516B2 (en) 2011-04-12 2015-10-06 President And Fellows Of Harvard College Fluorination of organic compounds
US9273083B2 (en) 2012-09-26 2016-03-01 President And Fellows Of Harvard College Nickel fluorinating complexes and uses thereof
WO2017025511A1 (fr) 2015-08-10 2017-02-16 Biogasol Aps Pastilles de biomasse de composition mixte
US10759764B2 (en) 2013-10-18 2020-09-01 President And Fellows Of Harvard College Fluorination of organic compounds

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BHANDARI ET AL: "Synthesis and appetite suppressant activity of 1-aryloxy-2-substituted aminomethyltetrahydronaphthalenes as conformationally rigid analogues of fluoxetine", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 14, no. 8, 15 April 2006 (2006-04-15), pages 2535 - 2544, XP005323443, ISSN: 0968-0896 *

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