EP1490324A2 - Derives de propargylaminoindane et derives de propargylaminotetraline utilises comme inhibiteurs de la mao cerebro-selectifs - Google Patents

Derives de propargylaminoindane et derives de propargylaminotetraline utilises comme inhibiteurs de la mao cerebro-selectifs

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Publication number
EP1490324A2
EP1490324A2 EP03716197A EP03716197A EP1490324A2 EP 1490324 A2 EP1490324 A2 EP 1490324A2 EP 03716197 A EP03716197 A EP 03716197A EP 03716197 A EP03716197 A EP 03716197A EP 1490324 A2 EP1490324 A2 EP 1490324A2
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European Patent Office
Prior art keywords
compound
alkyl
reacting
aralkyl
aryl
Prior art date
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EP03716197A
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German (de)
English (en)
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EP1490324A4 (fr
Inventor
Eran Blaugrund
Yaacov Herzig
Jeffrey Sterling
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Teva Pharmaceutical Industries Ltd
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Teva Pharmaceutical Industries Ltd
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Publication of EP1490324A2 publication Critical patent/EP1490324A2/fr
Publication of EP1490324A4 publication Critical patent/EP1490324A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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 rings other than six-membered aromatic rings being part of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the subject of this invention provides for derivatives of propargylaminoindans and propargylaminotetralins that are irreversible inhibitors of the enzyme monoamine oxidase A and/or B and also for prodrugs for the administration of these compounds .
  • Such compounds may be useful in the treatment of Parkinson's disease, Alzheimer's disease, depression and other neurological disorders.
  • the enzyme monoamine oxidase plays an essential role in the metabolic degradation of important amine neurotransmitters including dopamine, serotonin and noradrenaline .
  • agents that inhibit MAO are of potential therapeutic benefit for a variety of neurological disease indications, including Parkinson's disease, Alzheimer's disease, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , etc. (Szelnyi, I.; Bentue-Ferrer et al . ; Loscher et al . ; White et al . ; U.S. Patent No. 5,744,500) .
  • Other diseases and conditions which have been associated with toxic levels of monoamine oxidase-B are memory disorders (The interaction of L-deprenyl and scopolamine on spatial learning/memory in rats) , panic, post-traumatic stress disorder (PTSD) , sexual dysfunction, attention deficit and hyperactivity syndrome (ADHD) (Potential applications for monoamine oxidase B inhibitors) , attention deficit disorder (Kleywegt) , and Tourette' ⁇ syndrome (Treatment of Tourette's: Overview) .
  • MAO inhibitors can also be classified as reversible inhibitors which inhibit the enzyme by a competitive mechanism or as irreversible inhibitors which are generally mechanism based (suicide inhibitors) (Dostert) .
  • moclobemide is a reversible MAO-A- specific inhibitor (Fitton et al . ) developed as an anti-depre ⁇ sant .
  • rasagiline U.S. Patent No. 5,744,500
  • selegiline Chorisp et al .
  • MAO-B-selective irreversible inhibitors are MAO-B-selective irreversible inhibitors.
  • Irreversible inhibitors have the advantage of lower, less frequent dosing since their MAO inhibition is not based directly on the drugs' pharmacokinetic behavior, but rather on the de novo regeneration of the MAO enzyme.
  • MAO also plays an essential role in the oxidative deamination of biogenic and food-derived amines, both in the central nervous system and in peripheral tissues.
  • MAO is found in two functional isoenzyme forms, MAO-A and MAO-B, each of which shows preferential affinity for substrates and specificity toward inhibitors.
  • MAO-A preferentially oxidizes serotonin, noradrenaline and adrenaline
  • MAO-B preferentially metabolizes phenylethylamine .
  • Dopamine is a substrate for both forms of the enzyme (Szelenyi , I.).
  • N-Propargyl- (IR) -aminoindan is known to be a potent B-selective inhibitor of MAO (U.S. Patent No. 5,457,133).
  • Various derivatives of this compound have been prepared and shown to have varying degrees of potency and selectivity for the inhibition of MAO-A and/or -B.
  • SAR structure on the activity
  • U.S. Patent No. 6,303,650 discloses derivatives of 1-aminoindan as selective MAO B inhibitors that additionally inhibit acetylcholinesterase.
  • the reference teaches that its compounds can be used to treat depression, Attention Deficit Disorder (ADC) , Attention Deficit and Hyperactivity Disorder (ADHD) , Tourette's Syndrome, Alzheimer's Disease and other dementias such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
  • ADC Attention Deficit Disorder
  • ADHD Attention Deficit and Hyperactivity Disorder
  • Tourette's Syndrome Alzheimer's Disease and other dementias such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
  • PCT International Application No. PCT/IL96/00115 relates to pharmaceutical compositions comprising racemic, (S) , and (R)-N- propargyl-1-aminoindan.
  • (R) -N-propargyl-1-aminoindan selectively inhibits MAO-B in the treatment of Parkinson's disease and other neurological disorders (PCT/IL96/00115) .
  • PCT International Application No. PCT/US97 /24155 concerns aminoindan derivatives, including propargyl aminoindan, as inhibitors of MAO-A and MAO-B for the treatment of Parkinson's disease and other neurological conditions.
  • the publication reveals that the disclosed compounds exhibit a greater selectivity for MAO-A and MAO-B in the brain than in the liver or intestine.
  • U.S. Patent No. 6,316,504 discloses that the R(+) enantiomer of N-propargyl-1-aminoindan is a selective irreversible inhibitor of MAO-B.
  • the patent indicates that (R) - N-propargyl-1-aminoindan is useful for the treatment of Parkinson's disease, a memory disorder, dementia, depression, hyperactive syndrome, an affective illness, a neurodegenerative disease, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, neurotrauma, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.
  • European Patent No. 436492 discloses the R enantiomer of N- propargyl-1-aminoindan as a selective irreversible inhibitor of MAO-B in the treatment of Parkinson's disease and other neurological conditions. Numerous U.S. patents also relate to the MAO B inhibition of (R) -N-propargyl-1-aminoindan and its use for treating patients suffering from Parkinson's Disease and other neurological disorders (U.S. Patents No.
  • PCT International Application No . PCT/IL.97/00205 disclpses S- (-) -N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder of neurotrauma or for improving memory.
  • the compounds were found to be neuroprotective, but not inhibitory of MAO-A or MAO-B (PCT/IL97/00205) .
  • U.S. Patent No. 5,486,541 provides N-propargyl-1-amonoindan onofluorinated in the phenyl ring as selective inhibitors. of MAO-B. These compounds are presented as useful in the treatment of Parkinson's disease, memory disorders, dementia of the Alzheimer's type, depression and the hyperactive syndrome in children.
  • N-propargylamino indanol also appears in E.P. 267024 as a hydrofluorene derivative, i.e., 3-amino-4-indanol (7-OH fluorene) .
  • the hydrofluorene derivatives and salts in E.P. 267024 are employed as cerebral activators in the treatment of anoxe ia and hypoxemia. In addition, such derivatives help prevent arrhythmia and heart failure caused by lack of oxygen (E.P. 267024).
  • the derivatives also act as antioxidants and cholinergic nerve system activating agents (E.P. 267024). Sm ⁇ mary of the Invention
  • the subject invention provides a compound having the structure:
  • R 3 is OC(0)R 9 and R 2 is H, wherein R 9 is branched or unbranched C 1 to C 6 alkyl, aryl, or aralkyl, or R is OC(0)R 4 and R 2 is OC(0)R 4 , wherein R 4 is branched or unbranched C 1 to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C B alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C 1 to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.
  • the subject invention also provides a compound having the structure:
  • R x is OH; wherein R 2 is H or OC(0)R 4 when R 2 is attached to the "a" carbon or the “d” carbon, or
  • R 2 is OC(0)R 4 when R x is attached to the "b" carbon or the "c” carbon; wherein R 4 is C a to C 6 branched or unbranched alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C B alkyl, C 6 to C 12 aryl, C 6 to C i2 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein n is 0 or 1, and m is 1 or 2 ; and wherein R 3 is H or Me when n is 1 and m is 1, or R 3 is H or C x to C 6 alkyl when n is 0 or m is 2, or a pharmaceutically acceptable salt thereof.
  • the compound is an optically pure enantiomer; wherein R ⁇ is OH; wherein R 2 is H; wherein R 3 is H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.
  • the subject invention further provides a compound having the structure: wherein R-, is H, C 2 to C 6 alkyl, aryl, aralkyl or C(0)R 4 , wherein R 4 is branched or unbranched C x to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C 2 to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C x to C 6 alkyl; wherein R 8 is H or t-butoxycarbonyl (Boc) .
  • the subject invention also provides a method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure:
  • R ⁇ is- OH or OC(0)R 9 , and wherein R 9 is branched or unbranched C ⁇ to C 6 alkyl, aryl, or aralkyl;
  • R 2 is H or OC(0)R 4 , or both R a and R 2 are OC(0)R 4 , wherein R 4 is branched or unbranched C a to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C x to C 8 ' alkyl, C 5 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C x to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological di ⁇ ease in the subject.
  • the subject invention provides a method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure:
  • Rj is OH or OC(0)R,; wherein R 2 is H or OC(0)R 4 ,
  • R 4 is branched or unbranched C x to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C x to' C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C 2 to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological disease in the subject.
  • Th e subj ect invention additionally provides a process for preparing a compound having the structure : wherein n is 0 or 1, and ra is 1 or 2 ; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; and wherein R s is branched or unbranched C y to C 6 alkyl, .aryl, or aralkyl; comprising the step of reacting or
  • the subject invention also provides a process for preparing a compound having the structure:
  • R 4 is branched or unbranched C ⁇ to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; which process comprises:
  • step (c) reacting the product formed in step (b) with MeNH 2 ⁇ Cl, NaCNBH 3 in tetrahydrofuran (THF) /MeOH to produce a compound having the structure:
  • step (d) reacting the product formed in step (c) with H 2 , Pd/C and MeOH to produce a compound having the structure: (e) reacting the product formed in step (d) with Boc 2 0, dioxane/H 2 0 and NaHC0 3 to produce a compound having the structure:
  • step (f) reacting the product formed in step (e) with R 4 C0C1, Et 3 N in CH 2 C1 2 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure: boc
  • step (g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the structure:
  • step (h) reacting the product formed in step (g) with propargyl bromide, K 2 C0 3 in CH 3 CN and then with HCl/ether and MeOH to produce a compound having the structure:
  • the subject invention also provides the use of a compound or a prodrug of a compound which become ⁇ the compound having the structure:
  • R ⁇ is OH or OC(0)R 4 ; 'wherein R 2 i ⁇ H, OH or OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C 1 to C 6 alkyl, aryl, aralkyl . or NR 5 R 6 , wherein R 5 and R 6 are each independently H, Ci to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C ⁇ to C 6 alkyl; wherein n i ⁇ 0 or 1 ; and wherein m i ⁇ 1. or 2, or a pharmaceutically acceptable ⁇ alt thereof, for the manufacture of a medicament for treating a subject afflicted with a neurological disea ⁇ e, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.
  • the subject invention provides the use of a compound or a prodrug of a compound which becomes the compound having the structure:
  • R ⁇ is OH or 0C(0)R 9 , and wherein R 9 is branched or unbranched C ⁇ to C 6 alkyl, aryl, or aralkyl;
  • R 2 is H or OC(0)R 4 , or both R 2 and R 2 are OC(0)R 4 , wherein R 4 is C a to C 5 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, Ci to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to • C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable ⁇ alt thereof, for the manufacture of a medicament for treating neurological disease in a subject, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.
  • Figure 1 presents routes for the manufacture of compounds with the following structures:
  • Figure 2 displays routes for the manufacture of a compound with the following structure:
  • the letter ⁇ a) - i) are used to designate the following: a) A1C1 3 , toluene; b) BnCl, K 2 C0 3 , DMF; c) R 3 -NH 2 , HCl, NaCNBH 3 , THF/MeOH; d) H 2( Pd/C, MeOH; e) Boc 2 0, dioxane/H 2 0, NaHC0 3 ; f) R 4 -COCl, Et 3 N, DMAP, CH 2 Cl 2 ; g) HCl/dioxane; h) propargyl bromide, K 2 C0 3 , CH 3 CN; and i) HCl/ether, MeOH.
  • Figure 3 depicts routes for the manufacture of compounds with the structures:
  • the letters g) - 1) are u ⁇ ed to designate the following: g) NaCNBH 3 , NH 4 0Ac; h) propargyl bromide, ACN, K 2 C0 3 ; i) NaCNBH 3 , paraformaldehyde; j) N-methylpropargylamine, NaCNBH 3 ; k) BBr 3 ; and 1) R 4 COCl, TFA or DMAP.
  • the subject invention provides a compound having the structure: wherein R x is 0C(0)R 9 and R 2 is H, wherein R 9 is branched or unbranched Cj to C 6 alkyl, aryl, or aralkyl, or R-i is OC(0)R 4 and R 2 is 0C(0)R 4 , wherein R 4 i ⁇ branched or unbranched C x to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R E and R 6 are each independently H, C : to C B alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C 1 to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2 , or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is the acetate salt, mesylate ⁇ alt, esylate, tartarate salt, hydrogen tartarate salt, benzoate ⁇ alt, phenylbutyrate salt, phosphate ⁇ alt, citrate salt, ascorbate ⁇ alt, mandelate ⁇ alt, adipate ⁇ alt, octanoate salt, the myristate ⁇ alt, the succinate salt, or fumarate ⁇ alt.
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • n i ⁇ 1 the compound has the structure:
  • n 0.
  • the compound has the structure:
  • the compound has the structure: In one embodiment, R 9 is Me and R 3 is H.
  • R 9 is tBu and R 3 i ⁇ H.
  • R g is nBu and R 3 i ⁇ H.
  • R 9 is CHPh and R 3 is H.
  • R 9 is Ph and R 3 is H. In still another embodiment, wherein R 9 is Me and R 3 is Me. .
  • R 9 i ⁇ nBu and R 3 is Me.
  • R 9 is Ph and R 3 is Me.
  • R 9 is tBu and R 3 is Me.
  • R 9 l ⁇ Ph(OMe) 2 and R 3 is Me.
  • R 0 i ⁇ Ph(OMe) 2 and R 3 is H.
  • the compound has the structure:
  • R 3 is Me and R 9 is Me.
  • R 3 i ⁇ Me and R 9 i ⁇ Ph In another embodiment, R 3 is Me and R 9 i ⁇ Ph(OMe) 2 .
  • R 3 is Me and R 9 is Me.
  • R 3 is H and R 9 is Ph.
  • r R 3 i ⁇ H and R 9 is Ph(OMe) 2 . 5871
  • the compound has the structure:
  • R 4 is Ph and R 3 is Me.
  • R 3 is Me.
  • the compound has the structure:
  • the subject invention also provides a compound having the structure: wherein R a i ⁇ OH; wherein R 2 i ⁇ H or OC(0)R 4 when R x i ⁇ attached to the "a" carbon or the "d" carbon, or
  • the pharmaceutically acceptable salt is the acetate salt, mesylate salt, esylate, tartarate ⁇ alt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate salt, ascorbate salt, mandelate salt, adipate salt, octanoate salt, the myristate salt, the ⁇ uccinate salt, or fumarate salt.
  • the compound has the structure:
  • R 3 is H.
  • R 3 is Me
  • R 3 is H.
  • n i ⁇ 0 the subject invention provides a compound having the structure: wherein the compound is an optically pure enantiomer; wherein R 2 is OH; wherein R 2 is H; wherein R 3 i ⁇ H or C 3 to C 6 alkyl; wherein n is 0 or 1 ; and wherein m i ⁇ 1 or 2 , or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is the acetate salt, mesylate ⁇ alt, esylate, tartarate salt, hydrogen tartarate ⁇ alt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate ⁇ alt, a ⁇ corbate salt, mandelate ⁇ alt, adipate salt, octanoate salt, the myristate salt, the succinate salt, or fumarate salt.
  • the compound has the structure: In another embodiment, the compound ha ⁇ the structure:
  • R 3 is H.
  • R 3 is Me.
  • R 3 is Me
  • the ⁇ ubject invention further provides a compound having the structure: wherein R 7 is H, C ⁇ to C 6 alkyl, aryl, aralkyl or C(0)R 4 , wherein R 4 i ⁇ branched or unbranched C to C 6 alkyl, aryl, aralkyl or NR £ R 6 , wherein R 5 and R f are each independently H, C : to C e alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally sub ⁇ tituted; wherein R 3 is H or C 1 to C 6 alkyl; wherein R 8 i ⁇ H or t-butoxycarbonyl (Boc) .
  • the compound has the structure:
  • the compound ha ⁇ the ⁇ tructure: In still another embodiment, the compound has the structure;
  • the compound has the structure:
  • the subject invention additionally provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having the structure:
  • R x is OC(0)R 9 and R 2 i ⁇ H, wherein R 9 is branched or unbranched Ci to C 6 alkyl, aryl, or aralkyl, or R : i ⁇ OC(0)R 4 and R 2 i ⁇ OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C r to C 5 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C 2 to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2 , or a pharmaceutically acceptable ⁇ alt thereof.
  • the ⁇ ubject invention further provides a pharmaceutical compo ⁇ ition compri ⁇ ing a compound having the ⁇ tructure:
  • R 2 is 0C(0)R 4 when R x i ⁇ attached to the "b" carbon or the "c" carbon; wherein R 4 is C 1 to C 6 branched or unbranched alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C 8 alkyl, C e to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein n i ⁇ 0 or 1, and i ⁇ 1 or 2; and wherein Rj is H or Me when n i ⁇ 1 and m is 1, or R 3 is H or C 1 to C 6 alkyl when n is 0 or m i ⁇ 2, or a pharmaceutically • acceptable ⁇ alt thereof.
  • the subject invention al ⁇ o provides a pharmaceutical composition comprising a compound having the ⁇ tructure:
  • the compound is an optically pure enantiomer; wherein R ⁇ is OH; wherein R 2 i ⁇ H; wherein R 3 i ⁇ H or C to C 6 alkyl; wherein n i ⁇ 0 or 1; and wherein m i ⁇ 1 or 2, or a pharmaceutically acceptable ⁇ alt thereof.
  • the ⁇ ubject invention al ⁇ o provides a method of treating a subject afflicted with a neurological disease comprising administering to the ⁇ ubject a compound having the structure: wherein R ⁇ is OH or OC(0)R 4 ; wherein R 2 is H, OH or 0C(0)R 4 , wherein R 4 is branched or unbranched C ⁇ to C 6 .
  • R 5 and R 6 are each independently H, C x to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n i ⁇ 0 or 1; and wherein m i ⁇ 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which become ⁇ the compound in the ⁇ ubject, ⁇ o as to thereby treat the neurological di ⁇ ea ⁇ e in the subject.
  • the subject invention provides a method of treating a subject afflicted with a neurological disease comprising administering to the ⁇ ubject a compound having the structure : wherein R ⁇ is OH or OC(0)R 9 , and R 2 i ⁇ H or 0C(0)R 4 , or both R- L and R 2 are 0C(0)R 4 , wherein R 9 is branched or unbranched C 2 to C 6 alkyl, aryl, or aralkyl; wherein R 4 i ⁇ branched or unbranched C ⁇ to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C x to C 8 alkyl, C 6 to C l2 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n is 0 or 1;
  • the compound has the ⁇ tructure: wherein 2 i ⁇ 0C(0)R 9 and R 2 i ⁇ H, wherein R s i ⁇ branched or unbranched Cx to C 6 alkyl, ' aryl, or aralkyl, or R x is OC(0)R 4 and R 2 i ⁇ OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C ⁇ to C 6 alkyl, aryl, aralkyl or NR 5 R 6 ,
  • R 5 and R 6 are each independently H, Cj to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally sub ⁇ tituted; wherein R 3 is H or Cj to C 6 alkyl; wherein n is 0 or 1; and wherein m i ⁇ 1 or 2.
  • the compound ha ⁇ the structure : wherein R ⁇ is OH; wherein R 2 is H or OC(0)R 4 when R ⁇ is attached to the "a" carbon or the “d” carbon, or
  • R 2 is 0C(0)R 4 when R i ⁇ attached to the "b" carbon or the "c” carbon; wherein R 4 is C a to C 6 branched or unbranched alkyl, ⁇ aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C- . to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally ⁇ ub ⁇ tituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m i ⁇ 1 or 2.
  • the compound has the structure:
  • the compound i ⁇ an optically pure enantiomer; wherein x i ⁇ OH; wherein R 2 i ⁇ H; wherein R 3 is H or C 1 to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
  • the ⁇ ubject i human.
  • the admini ⁇ tration comprises oral, parenteral, intravenous, tran ⁇ dermal, or rectal admini ⁇ tration.
  • the effective amount i ⁇ from about 0.01 mg per day to about 100.0 mg per day.
  • the effective amount i ⁇ from about 0.01 mg per day to about 50.0 mg per day.
  • the effective amount is from about 0.1 mg per day to about 100.0 mg per day.
  • the effective amount is from about 0.1 mg per day to about 10.0 mg per day.
  • the effective amount is from about 0.01 mg to about 100.0 mg .
  • the effective amount is from about 0.01 mg to about 50.0 mg .
  • the effective amount is from about 0.1 mg to about 100.0 mg.
  • the effective amount is from about 0.1 mg to about 10.0 mg .
  • the neurological disease is Parkinson's disease, Alzheimer's disease, depre ⁇ sion, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , memory disorder ⁇ , panic, po ⁇ t-traumatic ⁇ tre ⁇ s disorder (PTSD), ⁇ exual dy ⁇ function, attention deficit and hyperactivity syndrome (ADHD), attention deficit di ⁇ order, or Tourette's syndrome.
  • the di ⁇ ease may also be neuropathy, hyperactive syndrome, neurotrauma, stroke, Parkinson' ⁇ di ⁇ ease, Huntington' ⁇ di ⁇ ease, and other dementia such as senile dementia, dementia .of the vascular dementia or Lewy body dementia.
  • the neurological disease i ⁇ depression.
  • the compound has the structure:
  • the subject invention further provides a proce ⁇ s for preparing a compound having the ⁇ tructure: wherein n i ⁇ 0 or 1, and m is 1 or 2 ; wherein R 3 is H or C ⁇ to C ⁇ alkyl; and wherein R 9 is branched or unbranched C x to C 6 alkyl, aryl , or aralkyl ; comprising the step of reacting or with in the presence of an acid or 4-dimethylaminopyridine (DMAP) to form the compound.
  • DMAP 4-dimethylaminopyridine
  • R 9 is branched or unbranched Cj , to C 6 alkyl, aryl, or aralkyl ; which process comprises:
  • the leaving group in step (a) is selected from the group consi ⁇ ting of a halogen and benzene sulfonate and the aprotic solvent in step (b) is CHC1 3 .
  • the subject invention further provides a process for preparing a compound having the structure:
  • step (d) deprotecting the compound formed in step (c) with HCl to produce a compound having the ⁇ tructure:
  • the leaving group in step (a) is selected from the group consisting of a halogen and benzene sulfonate and the aprotic solvent in step (b) is CHC1 3 .
  • the subject invention additionally provides a process for preparing a compound having the structure:
  • R 9 i ⁇ branched or unbranched ⁇ to C 6 alkyl, aryl, or aralkyl; which process comprises:
  • step ( c ) reacting the compound formed in step (b) with a compound having the structure:
  • the leaving group in ⁇ tep (a) is ⁇ elected from the group consisting of a halogen and benzene sulfonate and the aprotic ⁇ olvent in step (c) is CHC1 3 .
  • the subject invention provides another process for preparing a compound having the structure:
  • step (b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the structure :
  • step (c) reacting the compound formed in step (b) with a compound having the ⁇ tructure:
  • the aprotic solvent in step (c) is CHC1 3
  • the subject invention provides yet another process for preparing a compound having the structure:
  • R 9 is branched or unbranched C ⁇ - to C 6 alkyl, aryl, or aralkyl ; which process comprises:
  • step (b) reacting the compound formed in step (b) with a compound having the structure:
  • the aprotic solvent in step (d) is CHC1 3
  • the subject invention provides a process for preparing a compound having the structure:
  • step (b) reacting the compound formed in step (a) with NaCNBH 3 and paraformaldehyde to produce a compound having the structure :
  • step (b) reacting the compound formed in step (b) with a compound having the structure:
  • the leaving group in step (a) is selected from the group consisting of a halogen and benzene sulfonate and the aprotic ⁇ olvent in step (c) is CHC1 3 .
  • the ⁇ ubject invention provides another process for preparing a compound having the structure: which comprises:
  • step (b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the structure: (c) reacting the compound formed in ⁇ tep (b) with a compound having the structure:
  • the aprotic solvent in step (c) i ⁇ CHCl i ⁇ CHCl
  • the subject invention provide ⁇ yet another process for preparing a compound having the structure: which comprises:
  • step (b) reacting the compound formed in step (a) with a compound having the structure:
  • the aprotic ⁇ olvent in step (d) i ⁇ CHC1 3 .
  • the ⁇ ubject invention further provides a process for preparing a compound having the structure:
  • step (d) reacting the product formed in step (c) with H 2 , Pd/C and MeOH to produce a compound having the structure: (e) reacting the product formed in ⁇ tep (d) with Boc 2 0, dioxane/H 2 0 and NaHC0 3 to produce a compound having the ⁇ tructure :
  • step (f) reacting the product formed in step (e) with R 4 COCl, Et 3 N in CH 2 C1 2 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:
  • the ⁇ ubject invention provides a process for preparing a compound having the ⁇ tructure:
  • step (b) reacting the product formed in step (a) with benzyl chloride and K 2 C0 3 in the presence of dimethyl formamide (DMF) to produce a compound having the structure: .
  • DMF dimethyl formamide
  • step (d) reacting the product formed in ⁇ tep (c) with H 2 , Pd/C and MeOH to produce a compound having the ⁇ tructure: (e) reacting the product formed in step (d) with Boc 2 0, dioxane/H 2 0 and NaHC0 3 to produce a compound having the structure:
  • step (f) reacting the product formed in step (e) with PhCOCl, Et 3 N in CH 2 C1 2 in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure: boc
  • step (g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the structure:
  • step (h) 'reacting the product formed in step (g) with propargyl bromide, K 2 C0 3 in CH 3 CN and then with HCl/ether and MeOH to produce a compound having the ⁇ tructure:
  • the ⁇ ubject invention further provides the use of a compound or a prodrug of a compound which become ⁇ the compound having the structure: wherein R a is OH or OC(0)R 4 ; wherein R 2 is H, OH or OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C 1 to C € alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C x to C 8 alkyl, C 6 to C 12 aryl, C 6 to C ⁇ 2 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C ⁇ to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a ⁇ ubject afflicted with a neurological disease, wherein the compound is to be periodically administered to the subject
  • the subject invention al ⁇ o provides the use of a compound or a prodrug of a compound which become ⁇ the compound having the structure: wherein R i ⁇ OH or OC(0)R 9 , and wherein R 9 i ⁇ branched or unbranched C x to C 6 alkyl, aryl, or aralkyl; R 2 i ⁇ H or 0C(0)R 4 , or both R and R 2 are OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched CT , to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C 1 to C 8 alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 i ⁇ H or C a to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a
  • R x is OC(0)R 9 and R 2 is H, wherein R 9 is branched or unbranched C : to C £ alkyl, aryl, or aralkyl, or Ri is OC(0)R 4 and R 2 is OC(0)R 4 , wherein R 4 i ⁇ branched or unbranched C : to C 6 alkyl, aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, C ⁇ to C s alkyl, C 6 to C 12 aryl, C 5 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally ⁇ ubstituted; wherein R, is H or Cj to C 6 alkyl; wherein n is 0 or 1; and wherein i ⁇ 1 or 2.
  • Rj is OH; wherein R 2 is H or OC(0)R 4 when R is attached to the "a" carbon or the “d” carbon, or
  • R 2 is OC(0)R 4 when R : is attached to the "b" carbon or the "c” carbon; wherein R 4 is Cj , to C 6 branched or unbranched alkyl, • aryl, aralkyl or NR 5 R 6 , wherein R 5 and R 6 are each independently H, Ci to C ⁇ alkyl, C 6 to C 12 aryl, C 6 to C 12 aralkyl or C 6 to C 12 cycloalkyl, each optionally substituted; wherein R 3 is H or C 1 to C 5 alkyl; wherein n is 0 or 1; and wherein m i ⁇ 1 or 2
  • the compound has the structure:
  • the compound i ⁇ an optically pure enantiomer; wherein R 1 i ⁇ OH; wherein R 2 is H; wherein R 3 is H or Cj to C 6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.
  • the sub ect is human.
  • the medicament is formulated for oral, parenteral, intravenous, transdermal, or rectal administration.
  • the therapeutically effective amount is from about 0.01 mg per day to about 50.0 mg per day.
  • the therapeutically effective amount is from about 0.1 mg per day to about 100.0 mg per day.
  • the therapeutically effective amount is from about 0.1 mg per day to about 10.0 mg per day .
  • the neurological disease is Parkinson's disease, Alzheimer's di ⁇ ea ⁇ e, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , . memory disorders, panic, po ⁇ t-traumatic ⁇ tre ⁇ di ⁇ order (PTSD), ⁇ exual dysfunction, attention deficit and hyperactivity ⁇ yndrome (ADHD), attention deficit disorder, or Tourette's ⁇ yndrome.
  • the neurological disease i ⁇ depres ⁇ ion.
  • the ⁇ ubject invention thu ⁇ disclo ⁇ e ⁇ various derivatives and isomers of hydroxylated propargylamino indan and tetralin which have surpri ⁇ ingly varied potency and ⁇ electivity for MAO inhibition.
  • the ⁇ ubject invention also provide ⁇ modification ⁇ of the hydroxy compound ⁇ which have surprisingly varied MAO inhibitory propertie ⁇ depending upon the substitution pattern, however, the hydroxy compound i ⁇ alway ⁇ a more potent inhibitor than the modified ver ⁇ ion. Thu ⁇ , the modified version may be considered a prodrug of the more active hydroxy compound into which it will be metabolized in vivo .
  • the prodrug compound i ⁇ a carboxylic acid e ⁇ ter of the hydroxy compound.
  • the parent is a carbamate derivative of the hydroxy compound.
  • the compound ⁇ are dihydroxy derivative ⁇ of propargylamino indan or tetralin. These derivative ⁇ are expected to be antioxidants, as well a ⁇ MAO inhibitor ⁇ .
  • the subject invention provide ⁇ ester prodrug ⁇ .
  • the ⁇ ubject invention provide ⁇ esters or carbamates of propargylamino indanols, propargylamino indandiol ⁇ , propargylamino tetralinol ⁇ or propargylamino tetralindiol ⁇ , and may be prepared by method ⁇ of esterification or carbamoylation of hydroxy compounds.
  • Ester derivatives when R 2 equals hydrogen were prepared by reacting the propargylamino indanol ⁇ with acyl chloride ⁇ in the presence of a ⁇ trong organic acid such a ⁇ trifluoroacetic acid or an acylation cataly ⁇ t ⁇ uch a ⁇ 4-dimethylaminopyridine (DMAP) , with or without an inert organic ⁇ olvent ⁇ uch a ⁇ chloroform.
  • a ⁇ trong organic acid such as a ⁇ trifluoroacetic acid or an acylation cataly ⁇ t ⁇ uch a ⁇ 4-dimethylaminopyridine (DMAP)
  • Propargylamino indanols may ..be prepared by reacting amino indanols with propargyl bromide in a polar organic solvent such as N,N-dimethylacetamide or acetonitrile in the presence of a base such as potassium carbonate.
  • N-Methyl, N-propargylamino indanol ⁇ may be prepared by reductive alkylation of propargylamino indanol ⁇ by method ⁇ known to tho ⁇ e ⁇ killed in the art, e.g., with NaCNBH 3 and paraformaldehyde .
  • N- methyl, N-propargylamino indanol ⁇ were prepared by fir ⁇ t methylating amino indanols either by NaCNBH 3 /paraformaldehyde or by ethyl formate followed by LiAlH 4 reduction, and then reacting the N-methylamino indanols thus obtained with propargyl bromide a ⁇ described above.
  • N-propargyl derivatives of, inter alia , 3-amino-indan-4-ol, l-amino-indan-4-ol, 3-amino-indan-5-ol and 7-amino-5, 6, 7 , 8- tetrahydro-naphthalen-2-ol were prepared.
  • the diester tetralin derivative numbered 12 ( Figure 3) was prepared by esterification of the dihydroxy tetralin numbered 11 ( Figure 3) .
  • Table 1 Chemical Data P T/US03/05871
  • stereochemistry pos position mesylate salts wide range, hygroscopic
  • the' propargylation reaction was run in acetonitrile at elevated temperature, e.g., 60°C for 4 hours.
  • the reaction mixture was then filtered, and the cake washed with acetonitrile.
  • the combined layers were evaporated, to dryness, and the residue (brown oil) subjected to flash column chromatography (hexane : EtOAc, 2:1).
  • the product (white solid) wa ⁇ thu ⁇ obtained in 40 - 55 % yield.
  • Thu ⁇ were prepared: (R) -3-prop-2-ynylamino-5-indanol mesylate, (S) -3-prop-2-ynylamino-5-indanol mesylate, l-prop-2-ynylamino-4- indanol HCl, and 3-prop-2-ynylamino-4-indanol HCl.
  • Lithium aluminium hydride (4.5 g) was added portionwise to stirred and cooled dry THF (100 ml) at 0°C.
  • the reaction mixture wa ⁇ stirred at ambient temperature for 9 hr, cooled and treated with water (100 ml) .
  • the pH was adjusted to 8-9, water (200 ml) wa ⁇ added, and the mixture was extracted with ether (6 X 300 ml) .
  • the etheral extract wa ⁇ evaporated to dryness to give 3.2 g (94%) .
  • EXAMPLE 3 GENERAL PROCEDURE FOR ESTERIFICATION OF PROP-2-YNYL AMINO INDANOLS AND TERALINOLS , EXEMPLIFIED BY PENTANOIC ACID (R)-3-PROP-2-YNYLAMINO-INDAN-5-YL ESTER HCL (Cmpd # 107)
  • EXAMPLE 4 ALTERNATIVE PROCEDURE, EXEMPLIFIED BY BENZOIC ACID (R)-3-PROP-2-YNYLAMINO-INDAN-5-YL ESTER (Cmpd # 111)
  • the aqueous layer wa ⁇ washed wit methylene chloride (4x100 ml) , and the combined organic phases were dried evaporated to dryness in vacuo.
  • the crude product (3.78 g brown oil) wa ⁇ purified by flash column chromatography (hexane: EtOAc 4:1) to give 1.6 g (5.3 mmol, 71%) of a yellow oil.
  • the free base was converted to the HCl salt (etheral HCl, 2 hours, RT) , 1.39g (4.07 mmol, 77%, 55% from the hydroxy compound) .
  • the MAO enzyme source was a homogenate of rat brain in 0.3 M sucrose 1:20 w/v.
  • the homogenate was pre-incubated with serial dilutions of the test compounds (Table 5) for 60 minutes at 37°C.
  • 14 C-labeled substrates (2-phenylethylamine, hereinafter PEA; 5-hydroxytryptamine, hereinafter 5-HT) were then added, and the incubation continued for a further 20 minutes (PEA) , or 30- 45 minutes (5-HT) .
  • PEA 2-phenylethylamine
  • 5-HT 5-hydroxytryptamine
  • the enzyme concentration wa ⁇ chosen so that not more than 10% of the ⁇ ub ⁇ trate was metabolized during the course of the reaction.
  • the reaction was then 1 stopped by addition of citric acid.
  • the activity determined using PEA as substrate is referred to a ⁇ MAO-B, and that determined using 5-HT as MAO-A.
  • Rat ⁇ were treated with the te ⁇ t compounds (Table 5) at several dose levels by oral admini ⁇ tration, one dose daily for 7-21 days, and decapitated 2 hour ⁇ after the la ⁇ t dose.
  • the activities of MAO-A and MAO-B were determined in the brain, liver and intestine a ⁇ described in the previous example.
  • Inhibition of MAO activity wa ⁇ calculated by dividing MAO activity in the treated rats by MAO activity in the control rat ⁇ (saline treated, MAO activity in these rats was taken as 100%) .
  • Tourette's An Overview, (http: //www. haverford. edu/psych/biopsych217b/tourettes/TSwebtreat . caf .html) . •

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Abstract

La présente invention concerne des dérivés de propargylaminoindane (PAI) et de propargylaminotétraline inhibant sélectivement la monoamine oxydase (MAO) dans le cerveau et présentant la structure (I), ou un sel pharmaceutiquement acceptable correspondant. Dans cette structure, R1 est OC(O)R9 et R2 est H, R9 étant alkyle C1-C6 ramifié ou non ramifié, aryle ou aralkyle, ou R1 est OC(O)R4 et R2 est OC(O)R4, R4 étant alkyle C1-C6 ramifié ou non ramifié, aryle, aralkyle ou NR5R6, R5 et R6 étant chacun indépendamment H, alkyle C1-C8, aryle C6-C12, aralkyle C6-C12 ou cycloalkyle C6-C12, chacun d'eux étant éventuellement substitué, R3 est H ou alkyle C1-C6, n vaut 0 ou 1 et m vaut 1 ou 2. En outre, la présente invention concerne des méthodes de traitement de troubles neurologiques au moyen de ces composés, des utilisations de ces composés dans la fabrication de médicaments destinés à traiter des troubles neurologiques, ainsi que des procédés de synthèse desdits composés.
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US7491847B2 (en) 2005-11-17 2009-02-17 Teva Pharmaceutical Industries, Ltd. Methods for isolating propargylated aminoindans
US7572834B1 (en) 2005-12-06 2009-08-11 Teva Pharmaceutical Industries, Ltd. Rasagiline formulations and processes for their preparation
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CN101442997B (zh) 2006-04-03 2012-11-14 泰华制药工业有限公司 雷沙吉兰用于治疗多动腿综合征

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011761A1 (fr) * 1991-12-18 1993-06-24 H. Lundbeck A/S Aryltriflates et composes associes
WO1996036596A1 (fr) * 1995-05-19 1996-11-21 Chiroscience Limited 3,4-phenylsulfamides disubstitues et leur utilisation therapeutique

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1187017A (en) * 1966-07-16 1970-04-08 Aspro Nicholas Ltd Substituted 1-Amino Indanes and Tetrahydronaphthalens
EP0697894A4 (fr) * 1993-03-31 1996-05-01 Univ Pennsylvania Ligands de recepteurs de la dopamine d-3 et de la serotonine (5-ht 1a?) et agents d'imagerie
CA2180841C (fr) * 1994-01-10 2007-03-27 Sasson Cohen Derives de 1-amino-indane et leurs compositions
WO1997030999A1 (fr) * 1996-02-21 1997-08-28 Darwin Discovery Limited Quinolones et leur utilisation therapeutique
IL130528A (en) * 1996-12-18 2004-12-15 Teva Pharma Aminoindan derivatives, pharmaceutical compositions comprising them and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011761A1 (fr) * 1991-12-18 1993-06-24 H. Lundbeck A/S Aryltriflates et composes associes
WO1996036596A1 (fr) * 1995-05-19 1996-11-21 Chiroscience Limited 3,4-phenylsulfamides disubstitues et leur utilisation therapeutique

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; CHUMPRADIT, SUMALEE ET AL: "Synthesis and optical resolution of (R)- and (S)-trans-7-hydroxy-2- [N-propyl-N-(3'-iodo-2'-propenyl)amino]tet ralin: a new D3 dopamine receptor ligand" XP002434898 retrieved from STN Database accession no. 1994:8313 & JOURNAL OF MEDICINAL CHEMISTRY , 36(26), 4308-12 CODEN: JMCMAR; ISSN: 0022-2623, 1993, *
HAZELHOFF, BERNARD ET AL: "N-Methyl,N-propargyl-2-aminotetralins: novel dopamine agonists with monoamine oxidase inhibiting properties" EUROPEAN JOURNAL OF PHARMACOLOGY , 109(2), 229-40 CODEN: EJPHAZ; ISSN: 0014-2999, 1985, XP002434896 *
R. SARGES, J.R. TRETTER, S.S. TENEN, A. WEISSMAN: "5,8-Disubstituted 1-Aminotetralines. A Class of Compounds with a Novel Profile of Central Nervous System Activity." JOURNAL OF MEDICINAL CHEMISTRY, vol. 16, 1973, pages 1003-1011, *
See also references of WO03072055A2 *
STERLING, JEFFREY ET AL: "Novel Dual Inhibitors of AChE and MAO Derived from Hydroxy Aminoindan and Phenethylamine as Potential Treatment for Alzheimer's Disease" JOURNAL OF MEDICINAL CHEMISTRY , 45(24), 5260-5279 CODEN: JMCMAR; ISSN: 0022-2623, 2002, XP002296523 *
Y.C. MARTIN, C.H. JARBOE, R.A. KRAUSE, K.R. LYNN, D. DUNNIGAN, J.B. HOLLAND: "Potential Anti-Parkinson Drugs Designed by Receptor Mapping" JOURNAL OF MEDICINAL CHEMISTRY, vol. 16, 1973, pages 147-150, *

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WO2003072055A3 (fr) 2003-12-31
CA2477218A1 (fr) 2003-09-04
AU2003219913A1 (en) 2003-09-09
WO2003072055A2 (fr) 2003-09-04
AU2003219913A8 (en) 2003-09-09
EP1490324A4 (fr) 2007-10-10
JP2005523289A (ja) 2005-08-04

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