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WO2000076990A1 - Nouveaux composes - Google Patents

Nouveaux composes Download PDF

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Publication number
WO2000076990A1
WO2000076990A1 PCT/SE2000/001250 SE0001250W WO0076990A1 WO 2000076990 A1 WO2000076990 A1 WO 2000076990A1 SE 0001250 W SE0001250 W SE 0001250W WO 0076990 A1 WO0076990 A1 WO 0076990A1
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Prior art keywords
alkyl
benzofuran
dihydro
methyl
ethyl
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PCT/SE2000/001250
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English (en)
Inventor
Yevgeni Besidski
Britt-Marie Swahn
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Astrazeneca Ab
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Priority to AU60321/00A priority Critical patent/AU6032100A/en
Publication of WO2000076990A1 publication Critical patent/WO2000076990A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4

Definitions

  • the present invention relates to novel heterocyclic compounds, and pharmaceutically acceptable salts thereof, with an analgesic effect.
  • the compounds of the invention can thus be used in the prevention and treatment of pain.
  • the compounds of the invention are I 2 receptor ligands and/or sodium channel blockers and these compounds are useful in the treatment of disorders known to be responsive to the I 2 receptor and to blockade of sodium channels, especially in the treatment of disorders such as chronic pain.
  • the invention relates to compounds for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a pharmaceutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.
  • the invention also relates to new intermediates for use in the preparation of the novel compounds.
  • Certain 2-(aminoalkyl)coumarans are known as antidepressants from U.S. Patent No. 3,513,239 and some 2-(aminomethyl)coumarans are known as analgesic agents from Hirose et al. in Chem. Pharm. Bull. 1976, 24, 2661-2667 and 2912-2917.
  • Chronic pain can be caused by injury to nerves or by a variety of lesions.
  • analgesics such as opioids
  • These pain states are often referred to as neuropathic pain.
  • clinicians often prescribe drugs which are not considered true analgesics but which by trial and error have been found partly useful.
  • Such agents include tricyclic antidepressants, for example amitriptylin, anticonvulsants like carbamazepine and gabapentin, and some local anesthetics and an ti arrhythmic s, especially mexiletine.
  • tricyclic antidepressants for example amitriptylin, anticonvulsants like carbamazepine and gabapentin, and some local anesthetics and an ti arrhythmic s, especially mexiletine.
  • the invention thus relates to compounds of the general Formula I
  • R - R is independently selected from a group consisting of a) H, b) C]-C 6 alkyl, c) aiyl Ci-C f s alkyl, d) Cj -Cg alkenyl, and
  • R - R is independently selected from a group consisting of a) H b) C]-C 6 alkyl,
  • (R , R ), (R , R ) and (R , R ) may, together with the carbon or nitrogen atoms to which they are bonded, form a saturated or unsaturated 4, 5, 6, 7, or 8 membered ring, optionally containing one or more heteroatoms.
  • (R , R ), (R , R ) and (R , R ) may, together with the carbon atoms to which they are attached, form a further saturated or unsaturated 5, 6, 7 or 8-membered ring, optionally containing one or more further heteroatoms, and/or substituted with one or more substituents selected from halogen, C j -Cg alkyl, Cj-Cg alkoxy, CF 3 , OH, amino, C j -Cg alkyl-NH- or (C,-C 6 alkyl) 2 -N-;
  • n is zero or 1 ,
  • N inside the aryl moiety means that one of the carbon atoms in the aryl group optionally may be replaced with a nitrogen atom, provided that when the aryl group is benzene then at least one of the substituents R - R has to be other than hydrogen, and
  • Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents, such as alkali or by ion exchange.
  • the free base obtained may also form salts with organic or inorganic acids.
  • acids which form pharmaceutically acceptable salts.
  • acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic carboxylic or sulfonic acids, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid.
  • Preferred compounds of the invention are those of Formula I wherein R - R is independently selected from a group consisting of
  • R is independently selected from a group consisting of
  • (R , R ), (R , R ) and (R , R ) may, together with the carbon or nitrogen atoms to which they are bonded form a saturated or unsaturated 4, 5, 6, 7, or 8 membered ring, optionally containing one or more heteroatoms.
  • (R , R ), (R , R ) and (R , R ) may, together with the carbon atoms to which they are attached, form a further saturated or unsaturated 5, 6, 7 or 8-membered ring, optionally containing one or more further heteroatoms, and/or substituted with one or more o substituents selected from halogen, Cj-Cg alkyl, C ] -Cg alkoxy, CF 3 , OH, amino, C ] -C 6 alkyl-NH-, or (C j -C 6 alkyl) 2 -N-;
  • n is zero or 1 , 5
  • N inside the benzene moiety means that one of the carbon atoms in the aryl group optionally may be replaced with a nitrogen atom, provided that when the aryl group is benzene then at least one of the substituents R - R has to be other than hydrogen, and excluding the racemic compounds l-(2,3-dihydro-l-benzofuran-2-yl)ethylamine, N-[ l-(2,3- dihydro- 1 -benzofuran-2-yl)ethyl]-N-methylamine, N-f 1 -(2,3-dihydro- 1 -benzofuran-2- yl)ethyl]-N,N-dimethylamine, 1 -(7-methyl-2,3-dihydro- 1 -benzofuran-2-yl)ethylamine, N- methyl-N-[ l-(7-methyl-2,3-dihydro-l-benzofuran-2-yl)
  • More preferred compounds of the invention are those of Formula I wherein R - R is independently selected from a group consisting of
  • R is independently selected from a group consisting of a) H b) C ⁇ -C " 6 alkyl,
  • R - R is independently selected from a group consisting of a) H, b) C ⁇ -C 6 alkyl, c) Ci-Cg alkoxy, d) ⁇ O 2 , e) NH 2 , and f) halogen m is zero or 1 n is zero or 1
  • N inside the benzene moiety means that one of the carbon atoms in the aryl group optionally may be replaced with a nitrogen atom, provided that when the aryl group is benzene then at least one of the substituents R - R has to be other than hydrogen, and
  • C j -Cg alkyl denotes a straight or branched, substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms.
  • alkyl include, but is not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • C ⁇ -C 6 alkoxy denotes a group O-alkyl, wherein alkyl is as defined above.
  • halogen includes fluoro, chloro, bromo and iodo groups.
  • aryl denotes a substituted or unsubstituted C..-C14 aromatic hydrocarbon and includes, but is not limited to, benzene, naphtalene, indene, antracene, fenantrene, and fluorene
  • substituted denotes an Cj-C 6 alkyl, C
  • heteroatoms denotes a nitrogen, oxygen, sulfur, phosphorous atom.
  • Another aspect of the present invention is therefore the enantiomers of the compounds of the general Formula I.
  • the compounds of the present invention can be prepared by methods known in the art using commercially available or readily prepared starting materials.
  • the heterocyclic part of the compounds of the invention can be synthesized using several different synthetic routes. Some general procedures for the synthesis of the heterocyclic nucleus are described below.
  • the furan derivative (II) can be synthesized by a condensation reaction between a suitably substituted aromatic rtb -hydroxyaldehyde or ortb ⁇ -hydroxyarylalkylketone and chloroacetone, chloroacetaldehyde or ethyl chloroacetate as described by Elliot E. D. in J. Am. Chem. Soc. 1951, 73, 754.
  • the furan derivative (HI) can be synthesized using a palladium catalyzed reaction between a suitably substituted rtbo-iodophenol or ⁇ rtbo-iodopyridinol and an alkyne as described by Arcardi A. et al. in Synthesis 1986, 749.
  • the coumarin derivatives can be prepared by standard procedures as described by Gilchrist T.L, in Heterocyclic Chemistry, Pitman, 1985. Subsequent hydrogenation of the double bond and reduction of the lactone with diisobutyl aluminium hydride afforded the desired chroman-2-ol derivatives (IN).
  • the present invention also provides the following processes A, B and C for the preparation of compounds of the general Formula I.
  • Process A for the preparation of compounds of the general Formula I comprises the following steps:
  • Process B for the preparation of compounds of the general Formula I comprises the following steps:
  • Process C for the preparation of compounds of the general Formula I comprises the following steps:
  • the present invention relates to compounds of the formula I, or a pharmaceutically acceptable salt thereof for use in therapy, in particular for use in the treatment and/or prophylactics of pain, anxiety, mania, depression, panic disorders and/or aggression.
  • the invention also provides the use of a compound of the formula I in the manufacture of a medicament for the treatment of pain, anxiety, mania, depression, panic disorders and/or aggression.
  • the compounds of the invention are useful in therapy, especially for the treatment of pain of widely different origins and causes and include acute as well as chronic pain states. Examples are pain caused by chemical, mechanical, radiation, thermal, infectious or inflammatory tissue trauma or cancer, postoperative pain, headache and migraine, various arthritic and inflammatory conditions such as osteo- and rheumatoid arthritis, myofascial and low back pain.
  • neuropathic conditions of central or peripheral origin can be treated with the compounds of the invention.
  • these pain conditions are trigeminal neuralgia, postherpetic neuralgia (PHN), diabetic mono/poly neuropathy, nerve trauma, spinal cord injury, central post stroke, multiple sclerosis and Parkinson's disease.
  • the compounds of the invention are useful in disease states with inappropriate neuronal activity or in neuroprotection for example as anticonvulsants in epilepsy, in the treatment of itch, tinnitus, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer, stroke, traumatic bram injury, Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including arcadian rhythm disorders, insomnia & narcolepsy), tics (e g Tourette's syndrome), and muscular rigidity (spasticity)
  • the compounds of the invention are also useful for treatment of effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines
  • the invention relates to pharmaceutical compositions containing at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, as active ingredient
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other mode of administration
  • the pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule
  • the amount of active compounds is between 0 1-95% by weight of the preparation
  • the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain granules of the active compound.
  • Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing the active ingredient and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent before use.
  • the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 0.1 to 1000 mg, per day, of active substance.
  • the compounds according to the present invention can also be used in formulations, together or in combination for simultaneous, separate or sequential use, with other active ingredients, e.g. opioids, like morphine and fentanyl; NMDA antagonists, like ketamine and remacemide; lighter analgesic, like acetylsalicylic acid and paracetamol; and ⁇ - blockers, like propranolol.
  • active ingredients e.g. opioids, like morphine and fentanyl
  • NMDA antagonists like ketamine and remacemide
  • lighter analgesic like acetylsalicylic acid and paracetamol
  • ⁇ - blockers like propranolol.
  • a further aspect of the invention is new intermediate compounds which are useful in the preparation of compounds according to the invention.
  • the invention includes compounds of the general formula XI
  • R - -R , m, and n are as defined for Formula I and Y is N3 or NO 2 , and compounds of the general formula XIa
  • R - -R , m, and n are as defined for Formula I and Y is N3, NH 2 or NO 2 .
  • Example 1 l-(2,3-Dihvdro-l-benzofuran-2-yl)-ethylamine.
  • l-(2,3-Dihydro-benzofuran-2-yl)-ethylamine was separated into the corresponding diastereoisomers by passing the substance (5 g, 30.6 mmol) through a column packed with silica gel (200 g) using 30 to 50% acetone in heptane as an eluent.
  • Racemate (R,S and S,R) [l-(2,3-dihydro-benzofuran-2-yl)- ethyl] -isopropylidene-amine was treated with 10% HCl at 40°C for 0.5 h; the solution was neutralised with sodium carbonate and extracted with chloroform (3x50 ml). The extract was dried over sodium sulfate and concentrated in vacuum to leave a racemic (R,S and S,R) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine (1.87 g, 88%).
  • Racemate (R,R and S,S) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine was dissolved in dichloromethane (40 ml); to that solution R-methoxymandelic acid (1.73 g, 10.5 mmol) was added followed by dicyclohexylcarbodiimide (2.9 g, 14 mmol). The mixture was stirred for 4 h at room temperature before it was quenched with methanol. The volatiles were removed in vacuo.
  • Example 2 l-(2,3-Dihydro-l-benzofuran-2-yl)-N-ethyl-l-ethanamine was synthesized as described for l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine by using ethylamine in the reductive amination.
  • Example 3 l-ri-(2,3-Dihvdro-l-benzofuran-2-yl)ethyl]pyrrolidine was synthesized as described for l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine by using pyrrolidine in the reductive amination.
  • reaction mixture was filtered, concentrated on a rotary evaporator thereafter diluted with 10% NaOH solution and extracted twice with dichloromethane. The combined organic layers were dried (MgSO 4 ), filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with ethyl acetate as eluent to yield 0.090 g of l-(2,3-dihydro-5-nitro-l-benzofuran-2-yl)ethylamine as a 1 : 1 mixture of diastereomers.
  • Example 8 l-(2,3-Dihydro-5-methoxy-l-benzofuran-2-yl)ethylamine was synthesized from l-(5-methoxy-l-benzofuran-2-yl)-l-ethanone according to the
  • N-r2-(Diethylamino)ethvIl-N-[l-(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)ethvnamine was synthesized from l-(7-methoxy-l-benzofuran-2-yl)-l-ethanone by using 2- diethylaminoethylamine in the reductive amination according to the procedure described for the synthesis of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine.
  • N-ri-(2,3-Dihydro-l-benzofuran-2-yl)ethyll-N-(3-phenylpropyl)amine was synthesized from l-(l-benzofuran-2-yl)-l-ethanone by using 3-phenyl-l-propylamine in the reductive amination according to the procedure described for the synthesis of l-(2,3- dihydro-l-benzofuran-2-yl)-ethylamine.
  • N-ri-(2,3-Dihvdro-l-benzofuran-2-yl)ethyll-N-[3-(l-pyrrolidinyl)propyl]amine was synthesized from l-(l-benzofuran-2-yl)- 1-ethanone by using ⁇ -(3- aminopropyl)pyrrolidine in the reductive amination according to the procedure described for the synthesis of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine.
  • Example 13 N-ri-(2,3-Dihydro-l-benzofuran-2-yl)ethyl1-N-[4-(dimethylamino)butyl]amine was synthesized from l-(l-benzofuran-2-yl)- 1-ethanone by using 4- dimethylaminobuthylamine in the reductive amination according to the procedure described for the synthesis of l-(2,3-dihydro-l-benzofuran-2-yl)-ethylamine.
  • Methyl lithium (1.6 M in THF, 6.25 ml) was added to a solution of l-(l-benzofuran-2-yl)- 1-ethanone (1.0 g, 6.24 mmol) in THF (20 ml) at -70 °C. After stirring for 0.5 h at -70 °C water was added and the mixture was allowed to reach room temperature. The solvent was evaporated in vavuo and the residue was dissolved in ethyl acetate and extracted. The organic layer was dried (MgSO 4 ), filtered, and then concentrated in vacuo to yield a slightly yellow oil of 2-(l-benzofuran-2-yl)-2-propanol.
  • Trifluoroacetic acid (3.71 ml, 48.2 mmol) was slowly added to a stirred and cooled (0 °C) mixture of sodium azide (1.25 g, 19.2 mmol) in chloroform (15 ml). The mixture was stirred for 1 h and then 2-(l-benzofuran-2-yl)-2-propanol (1.7 g, 9.6 mmol) dissolved in chloroform (10 ml) was added slowly. The mixture was stirred for 0.5 h and then ammonium hydroxide was added. The mixture was extracted with chloroform and the organic layer was dried (MgSO 4 ), filtered, and then concentrated in vacuo.
  • N-l " 1 -(2,3-Dihydro- 1 -benzofuran-2-yl)- 1 -methylethyl 1-NN-diethylamine was synthesized from N-[l-(2,3-dihydro-l-benzofuran-2-yl)-l-methylethyl]-N-ethylamine and acetyl chloride according to the procedure described for the synthesis of N-[l-(2,3- dihydro-l-benzofuran-2-yl)-l-methylethyl]-N-ethylamine.
  • Example 17 N-Methyl-N-r(3-methyl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine
  • 3-methylbenzofuran-2-carboxylic acid 1.0 g, 5.67 mmol
  • thionyl chloride 1.3 ml, 17 mmol
  • DMF 2 drops
  • the reaction mixture was heated to 70 °C for 1 h.
  • the mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (10 ml).
  • Example 19 N,N-Diethyl-N-r(3-methyl-2,3-dihvdro-l-benzofuran-2-yl)methyl1amine was synthesized according to the procedure described for N-Methyl-N-[(3-methyl-2,3- dihydro-l-benzofuran-2-yl)methyl]amine by using diethylamine instead of methylamine as starting material.
  • Example 23 l-(2,3-Dihydro-l-benzofuran-2-yl)-2-propanamine Sodium hydride (0.36 g, 15.1 mmol) was added to a solution of benzofuran-2-carbaldehyde (2 g, 13.7 mmol) and nitroethane (1.47 ml, 20.5 mmol) in dimethylformamide (40 ml) at 0°C. The mixture was stirred at room temperature for 0.5 h before it was quenched with water (100 ml). The pH of the solution was adjusted to 5-6 with acetic acid and then extracted with chloroform (3x60 ml). The extract was washed with water and concentrated in vacuum to leave a crude l-benzofuran-2-yl-2-nitropropanol-l-ol (3.0 g).
  • the 2-(2-nitropropyl)-benzofuran (1.5 g, 7.53 mmol) was subjected to hydrogenation under 60 psi H 2 in methanol, first over Raney nickel for 3 h then over Pd/C (10%) for 72 h.
  • the catalysts were removed by filtration and the solvent was evaporated in vacuo.
  • the residue was chromatographed on a column packed with silica gel using 50-100% ethyl acetate in methanol to elute 2-benzofuran-2-yl- 1 -methylethylamine (0.42 g, 2.4 mmol, 32%) and then - 0-10% water in methanol to elute the title compound (0.47g, 2.6 mmol, 35%).
  • Example 25 l-(5-Methyl-2,3-dihvdro-furor3,2-b]pyridin-2-yl)-ethylamine was synthesized from 2-iodo-6-methyl-pyridin-3-ol instead of 2-iodo-pyridin-3-ol according to the procedure described for the synthesis of l-(2,3-dihydro-furo[3,2-b]pyridin- 2-yl)-ethylamine.
  • Example 26 ri-(2,3-Dihvdro-furor3,2-blpyridin-2-yl)-ethyll-ethylamine l-Furo[3,2-b]pyridin-2-yl-ethanol (0.5 g, 3.1 mmol), synthesized according to to the procedure described above, was treated with methanesulfonyl chloride (0.48 ml, 6.1 mmol) and triethylamine (0.85 ml, 6.1 mmol) in dichloromethane at -20°C for 2 h. The mixture was washed with water, dried over sodium sulfate and concentrated in vacuum.
  • the synthesized 2-diethoxymethyl- 5-methyl-furo[3,2-b]pyridine was hydrolyzed with 5% HCl (30 ml) at room temperature overnight. The solvents were removed in vacuo. The residue was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate (3x50 ml). The extract was dried with sodium sulfate and concentrated in vacuo to leave 5- methyl-furo[3,2-b]pyridine-2-carbaldehyde (1.34 g, 8.3 mmol, 92%).
  • 6-Methyl-2-chromanol (1 g, 6.1 mmol) was stirred with an excess of nitroethane and potassium carbonate at 90°C for 3 h. The potassium carbonate was filtered off and the nitroethane was evaporated in vacuum. The residue was purified on a column packed with silica gel using 10-20% ethyl acetate in heptane as an eluent to yield 6-methyl-2-(l- nitroethyl)-chromane (0.9 g, 4.1 mmol, 67%) which was hydrogenated in methanol over Raney nickel under 50 psi ⁇ 2 overnight. The catalyst was filtered off and the methanol was evaporated.
  • 6,7-Dimethyl-chromen-2-one (2 g, 11.5 mmol) was hydrogenated over 10% Pd/C in ethyl acetate under 50 psi ⁇ 2 for 48 h.
  • the catalyst was filtered off and the solvent was evaporated.
  • the residue was dissolved in toluene and diisobutyl aluminium hydride (13.8 ml, 1M, 13.8 mmol) was added at -78°C.
  • the mixture was stirred at this temperature for 2 h before it was quenched with 10% solution of ammonium chloride.
  • the organic solvent was removed in vacuum, and the product was extracted with ethyl acetate (2x70 ml). The solution was dried over sodium sulfate and concentrated in vacuum.
  • Example 35 l-(6-Bromo-3,4-dihydro-2H-chromen-2-yl)-ethylamine
  • l-(2,3-Dihydro-benzofuran-2-yl)-ethylamine was separated into the corresponding diastereoisomers by passing the substance (5 g, 30.6 mmol) through a column packed with silica gel (200 g) using 30 to 50% acetone in heptane as an eluent.
  • Racemate (R,S and S,R) [l-(2,3-dihydro-benzofuran-2-yl)- ethyl] -isopropylidene-amine was treated with 10% HCl at 40°C for 0.5 h; the solution was neutralised with sodium carbonate and extracted with chloroform (3x50 ml). The extract was dried over sodium sulfate and concentrated in vacuum to leave a racemic (R,S and S,R) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine (1.87 g, 88%).
  • Racemate (R,R and S,S) l-(2,3-dihydro-benzofuran-2-yl)-ethylamine was dissolved in dichloromethane (40 ml); to that solution R-methoxymandelic acid (1.73 g, 10.5 mmol) was added followed by dicyclohexylcarbodiimide (2.9 g, 14 mmol). The mixture was stirred for 4 h at room temperature before it was quenched with methanol. The volatiles were removed in vacuo.
  • the absolute configuration was determined by X-ray crystallography.
  • the absolute configuration could also be determined by NMR experiments after derivatization with (S)-O-methylmandelic acid as described by Trost B. M. et al. in J. Org. Chem. 1994, 59, 4202.
  • the analgesic effects of the compounds of the invention were evaluated in the mouse formalin test as described by Tjoelsen A. et al. in Pain, 1992, 51, 5.
  • the mouse formalin test employs a tonic painful stimulus with both a first phase of direct chemical activation (acute pain) and a second phase involving central sensitization and peripheral inflammation.
  • the analgesic activities were estimated as ED 50 values and were for the compounds of the invention between 5 and 200 ⁇ mol/kg.
  • Some of the compounds of the invention were also found to be active in the rat Chung model which is indicative of activity in neuropathic pain (Kim and Chung. Pain 1992, 50, 355). Antiinflammatory activity was evaluated in the rat carrageenan model essentially as described by Tonussi, C. and Ferreira, S., Pain 1992, 48, 421 and Coderre, T.J. and Wall, P.D., Pain 1987, 28, 379.

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Abstract

La présente invention concerne certains composés hétérocycliques à substitution aminoalkyle, de formule (I), ainsi que leurs sels acceptables d'un point de vue pharmaceutique. Ces composés présentent de bonnes propriétés analgésiques et sont particulièrement efficaces dans le traitement de la douleur chronique.
PCT/SE2000/001250 1999-06-16 2000-06-15 Nouveaux composes WO2000076990A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6638972B2 (en) 2001-10-04 2003-10-28 Wyeth Chroman and benzofuran derivatives as 5-hydroxytryptamine-6 ligands
US6706757B2 (en) 2001-10-04 2004-03-16 Wyeth Chroman derivatives as 5-hydroxytryptamine-6 ligands
US6846817B2 (en) * 1999-06-02 2005-01-25 Regents Of The University Of Minnesota Nicotine receptor ligands
US6852731B2 (en) 2002-01-14 2005-02-08 Pfizer Antiviral compounds
US6861438B2 (en) 2002-01-14 2005-03-01 Pfizer Antiviral agents
US6878705B2 (en) 2002-01-14 2005-04-12 Pfizer 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide antiviral agents
US6924283B2 (en) 2001-08-30 2005-08-02 Pfizer 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamides as antiviral agents
WO2006116170A1 (fr) * 2005-04-22 2006-11-02 Wyeth Derives de dihydrobenzofurane et utilisations de ceux-ci
WO2006116171A1 (fr) * 2005-04-22 2006-11-02 Wyeth Traitement de douleur
WO2006116149A1 (fr) * 2005-04-22 2006-11-02 Wyeth Nouvelles associations therapeutiques pour le traitement ou la prevention de la depression
WO2006116148A3 (fr) * 2005-04-22 2008-09-12 Wyeth Corp Traitement de l'abus de substances toxiques
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7728155B2 (en) 2003-10-24 2010-06-01 Wyeth Llc Dihydrobenzofuranyl alkanamines and methods for using same as cns agents
JP2020079282A (ja) * 2015-02-11 2020-05-28 サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． Ｃｎｓ疾患を治療するための１−複素環イソクロマニル化合物およびアナログ
WO2020160202A1 (fr) 2019-02-01 2020-08-06 Fmc Corporation Pyridines et pyrimidines diamino-substituées à titre d'herbicides

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6846817B2 (en) * 1999-06-02 2005-01-25 Regents Of The University Of Minnesota Nicotine receptor ligands
US6924283B2 (en) 2001-08-30 2005-08-02 Pfizer 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamides as antiviral agents
US6638972B2 (en) 2001-10-04 2003-10-28 Wyeth Chroman and benzofuran derivatives as 5-hydroxytryptamine-6 ligands
US6706757B2 (en) 2001-10-04 2004-03-16 Wyeth Chroman derivatives as 5-hydroxytryptamine-6 ligands
US6852731B2 (en) 2002-01-14 2005-02-08 Pfizer Antiviral compounds
US6861438B2 (en) 2002-01-14 2005-03-01 Pfizer Antiviral agents
US6878705B2 (en) 2002-01-14 2005-04-12 Pfizer 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide antiviral agents
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7728155B2 (en) 2003-10-24 2010-06-01 Wyeth Llc Dihydrobenzofuranyl alkanamines and methods for using same as cns agents
WO2006116171A1 (fr) * 2005-04-22 2006-11-02 Wyeth Traitement de douleur
WO2006116149A1 (fr) * 2005-04-22 2006-11-02 Wyeth Nouvelles associations therapeutiques pour le traitement ou la prevention de la depression
US7396857B2 (en) 2005-04-22 2008-07-08 Wyeth Therapeutic combinations for the treatment or prevention of depression
WO2006116148A3 (fr) * 2005-04-22 2008-09-12 Wyeth Corp Traitement de l'abus de substances toxiques
WO2006116170A1 (fr) * 2005-04-22 2006-11-02 Wyeth Derives de dihydrobenzofurane et utilisations de ceux-ci
JP2020079282A (ja) * 2015-02-11 2020-05-28 サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． Ｃｎｓ疾患を治療するための１−複素環イソクロマニル化合物およびアナログ
JP7023994B2 (ja) 2015-02-11 2022-02-22 サノビオン ファーマシューティカルズ インク Ｃｎｓ疾患を治療するための１－複素環イソクロマニル化合物およびアナログ
JP2022065050A (ja) * 2015-02-11 2022-04-26 サノビオン ファーマシューティカルズ インク Ｃｎｓ疾患を治療するための１－複素環イソクロマニル化合物およびアナログ
WO2020160202A1 (fr) 2019-02-01 2020-08-06 Fmc Corporation Pyridines et pyrimidines diamino-substituées à titre d'herbicides

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