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WO1996021640A1 - Derives d'aminoindane optiquement actifs et leur preparation - Google Patents

Derives d'aminoindane optiquement actifs et leur preparation Download PDF

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Publication number
WO1996021640A1
WO1996021640A1 PCT/US1996/000169 US9600169W WO9621640A1 WO 1996021640 A1 WO1996021640 A1 WO 1996021640A1 US 9600169 W US9600169 W US 9600169W WO 9621640 A1 WO9621640 A1 WO 9621640A1
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Prior art keywords
aminoindan
optically active
unsubstituted
substituted
enantiomer
Prior art date
Application number
PCT/US1996/000169
Other languages
English (en)
Inventor
Ramy Lidor
Eliezer Bahar
Original Assignee
Teva Pharmaceutical Industries, Ltd.
Lemmon Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Industries, Ltd., Lemmon Company filed Critical Teva Pharmaceutical Industries, Ltd.
Priority to AU48960/96A priority Critical patent/AU4896096A/en
Publication of WO1996021640A1 publication Critical patent/WO1996021640A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C—CHEMISTRY; METALLURGY
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    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/86—Separation
    • C07C209/88—Separation of optical isomers
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • 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
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • 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
    • C07C217/74—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 rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/06—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/23—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/74—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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    • 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
    • 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
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • Oshiro et al . disclose a wide range of 7-hydroxy-l-aminoindan derivatives that they subjected to screening for use as a cerebroprotective agent using an antihypoxic test and as a CNS stimulatory agent using a cerebral trauma test.
  • 7-hydroxy group is essential to obtain the desired activity. This is evident from their subsequent paper wherein a broader range of 7- hydroxy derivatives are screened (J.Med.Chem 1991 34 2014-2020) .
  • These 7-hydroxy-l-aminoindans are defined in US Patents 4,788,130, 4,792,628, 4,895,847, 5,055,474 and 5,242919 all assigned to Otsuka Pharmaceutical Co. Japan.
  • a range of substituted and unsubstituted l-aminoindans have activity in suppressing the symptoms emanating from the dopaminergic hypofunction that is associated with Parkinson's Disease; in improving cognition in dementias such as senile dementia, Parkinson-type dementia and dementia of the Alzheimer's type; in providing protection against epilepsy, convulsions, seizures; and in improving post-head trauma motor function, and reducing trauma- induced cerebral oedema.
  • the present invention also relates to a process for the synthesis of optically active aminoindan derivatives that have been described as possessing utility in the treatment of Parkinson's Disease, dementia, epilepsy, convulsions or seizures.
  • Optically active compounds containing an amine group attached to a chiral carbon atom may be prepared by the resolution of a racemic mixture of the R and S enantiomers. Such a resolution can be accomplished by resolution methods well known to a person skilled in the art, such as the formation of diastereomeric salts with chiral acids, or those described in U.S. Patent No. 4, 833, 273, issued May 23, 1989 (Goel) and those listed in J. Jacques, A.
  • This invention provides a method for treating Parkinson's disease, dementia, epilepsy, convulsions, or seizures in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula:
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted C ⁇ C ⁇ alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 - C_ ⁇ 2 aralkyl, -C(0)-R 6 , -Y-C(0)-R 7 , or Y- (SO 2 )NR 9 R 10 ; wherein R 6 is hydrogen, hydroxy, substituted or unsubstituted C, .
  • A is substituted or unsubstituted alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, and R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C ⁇ -C 12 aralkyl, or indanyl; Y is substituted or unsubstituted C ⁇ C !
  • R 7 is hydrogen, hydroxy, - 6 - substituted or unsubstituted C x -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 - C 12 aralkyl or NR 9 R 10 , wherein R s and R : - are each independently hydrogen, substituted or unsubstituted C..-C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C ⁇ - C l2 aralkyl, or indanyl.
  • This invention provides a method for treating epilepsy, convulsions, or seizures in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula:
  • R- and R 2 are each independently hydrogen, hydroxy, substituted or unsubstituted C-.-C, alkyl, substituted or unsubstituted C-.-C, alkoxy, halogen, nitro, NH-R 3 , C(0)-R 3 , or C(O)-NR 9 R 10 ;
  • R 3 is hydrogen, substituted or unsubstituted C--C 4 alkyl, hydroxy, substituted or unsubstituted C 1-4 alkoxy, or substituted or unsubstituted c e-i 2 a -*-"yl/' an d
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 - C 12 aralkyl, alkynyl
  • C 6 -C 12 aryl substituted or unsubstituted C 7 -C 12 aralkyl, or indanyl
  • Y is substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C e -C 12 aryl or substituted or unsubstituted C 7 -C 12 aralkyl
  • R 7 is hydrogen, hydroxy, substituted or unsubstituted C z -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C-- C 12 aralkyl or NR 9 R 10 , wherein R 9 and R 10 are each independentlyhydrogen, substituted or unsubstituted C ⁇ -C, 2 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, or indanyl
  • This invention provides a compound selected from the group consisting of 7-methyl-l-aminoindan, 5-methyl-l- aminoindan, (R) -6-hydroxy-l-aminoindan, 3,5,7-trimethyl- l-aminoindan, 4,5-di ethoxy-l-aminoindan, (R)-4,5- dimethoxy-1-aminoindan, (S) -4,5-dimethoxy-l-aminoindan, 4-hydroxy-5-methoxy-1-aminoindan, 6-hydroxy-5-methoxy-1- aminoindan, N- (4-aminobutanoyl) -l-aminoindan, (R) -N- formyl-l-aminoindan, (S) -N-formyl-l-aminoindan, (R) -N- acetyl-l-aminoindan, N-acetyl-7-methyl-l-aminoindan, N- ace
  • the compounds of general formula 1 possess neuroprotective activity. Accordingly, this invention provides a method for treating acute neurological traumatic disorder or neurotrauma in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula:
  • R ⁇ and R 2 are each independently hydrogen, hydroxy, substituted or unsubstituted C,_-C 4 alkyl, substituted or unsubstituted C»_-C 4 alkoxy, halogen, nitro, NH-R 3 , C(0)-R 3 , or C(O) -NR 9 R 10 ;
  • R 3 is hydrogen, substituted or unsubstituted C j _-C 4 alkyl, hydroxy, substituted or unsubstituted C 1-4 alkoxy, or substituted or unsubstituted C ⁇ - 12 aryl,* and R perpetrat and R 5 are each independently hydrogen, substituted or unsubstituted C x -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 - C 12 aralkyl, -C(0)-R 6
  • This invention provides a method for preparing an optically active enantiomer of a compound of the formula:
  • This invention provides a method for preparing racemic N- benzyl-l-aminoindan comprising reacting 1-chloroindane with benzylamine in an inert solvent.
  • Figure 1 Experiment 1A: a-MpT-induced hypokinesia in hypoxic rat. Effect of the hypoxic episode as compared to control animals.
  • X-axis hours after ⁇ -MpT injection.
  • Y-axis percent of respective control recorded as total movements.
  • Figure 2 Experiment 1A: a-MpT-induced hypokinesia in hypoxic rat. Effect of the drug treated group as compared to the untreated hypoxic group.
  • X-axis hours after ⁇ -MpT injection.
  • Y-axis percent of respective control recorded as total movements.
  • Figure 3 Experiment 1A: ⁇ -MpT-induced hypokinesia in hypoxic rat. Effect of the hypoxic episode as compared to control animals.
  • X-axis hours after ⁇ -MpT injection.
  • Y-axis percent of respective control recorded as big movements.
  • Figure 4 Experiment 1A: ⁇ -MpT-induced hypokinesia in hypoxic rat. Effect of the drug treated group as compared to the untreated hypoxic group.
  • X-axis hours after ⁇ -MpT injection.
  • Y-axis percent of respective control recorded as big movements.
  • Figure 5 Experiment IB: ⁇ -MpT-induced hypokinesia in hypoxic rat . Effect of the drug treated group as compared to the untreated hypoxic group.
  • X-axis hours after ⁇ -MpT injection.
  • Y-axis percent of respective control recorded as total movements.
  • Figure 6 Experiment IB: ⁇ -MpT-induced hypokinesia in hypoxic rat. Effect of the drug treated group as compared to the untreated hypoxic group.
  • X-axis hours after ⁇ -MpT injection.
  • Y-axis percent of respective control recorded as big movements.
  • Figure 7 Experiment 3B: Water Maze Working Memory Test.
  • X-axis water maze - working memory performance.
  • Y-axis ratio of averages of latencies of run2/runl in four sessions. Bars are, from left to right: control; hypoxia,* hypoxia + Al; hypoxia + deprenyl
  • Figure 8 Experiment 1C: -MpT-induced hypokinesia in hypoxic rat. Effect of the drug treated group as compared to the untreated hypoxic group. Y-axis: total movements over 10 hours. The drugs tested are identified in the figure legend using codes, identified as follows:
  • This invention provides a method for treating Parkinson's disease, dementia, epilepsy, convulsions, or seizures in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula:
  • R x and R 2 are each independently hydrogen, hydroxy, substituted or unsubstituted C-.-C 4 alkyl, substituted or unsubstituted C-.-C 4 alkoxy, halogen, nitro, NH-R 3 , C(0)-R 3 , or C(0) -NR 9 R 10 ;
  • R 3 is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, hydroxy, substituted or unsubstituted C 1-4 alkoxy, or substituted or unsubstituted C 6 -i 2 ar yl; and
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted C -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 - C 12 aralkyl, -C(0)-R 6 , -Y-C
  • R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, or indanyl;
  • Y is substituted or unsubstituted C x -C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl or substituted or unsubstituted C ⁇ - C 12 aralkyl, and
  • R 7 is hydrogen, hydroxy, substituted or unsubstituted C»,-C 12 alkyl, substituted or unsubstituted C 6 - C 12 aryl, substituted or unsubstituted C 7 - C 12 aralkyl or
  • substituted or unsubstituted alkyl refers to both straight-chain and branched-chain alkyl groups.
  • Halogen is used herein to refer to fluoro, chloro, bromo, and iodo groups.
  • the subject is any animal, preferably a mammal. In an embodiment, the subject is a human subject. In another embodiment, the subject is a mouse or a rat.
  • the administering can be performed according to techniques well known to those of skill in the art.
  • the administering comprises administering orally, rectally, transdermally, or parenterally.
  • the therapeutically effective amount is from about 1 mg to about 1000 mg, preferably from about 10 mg to about 100 mg.
  • compositions and their preparation are well known to those of skill in the art.
  • examples of pharmaceutically acceptable salts are a hydrochloride salt, a mesylate salt, an ethylsulphonate salt, or a sulfate salt.
  • n is 1. In another embodiment n is 2.
  • R-. and R 2 are each independently hydrogen, fluoro, hydroxy, methyl or methoxy .
  • R 3 is hydrogen or methyl.
  • R 4 and R 5 are each independently hydrogen, or substituted or unsubstituted C 1 -C 12 alkyl.
  • R 4 is C 1 -C 12 alkyl substituted with a lipophilic group, C 6 -C 12 aryl substituted with a lipophilic group, or C 7 -C 12 aralkyl substituted with a lipophilic group.
  • the lipophilic group is selected from the group consisting of piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, adamantyl, quinuclidinyl, and substituted derivatives thereof.
  • R 5 is C 1 -C 12 alkyl substituted with a lipophilic group, C 6 -C 12 aryl substituted with a lipophilic group, or C 7 -C 12 aralkyl substituted with a lipophilic group.
  • the lipophilic group is selected from the group consisting of piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, adamantyl, quinuclindyl, and substituted derivatives thereof.
  • This invention provides the above method wherein A is substituted or unsubstituted C 1 -C 12 alkyl.
  • This invention provides the above method wherein Y is substituted or unsubstituted C 1 -C 12 alkyl.
  • This invention provides the above method wherein R 7 is substituted or unsubstituted C ⁇ C ⁇ alkyl.
  • R 4 is -C(0)-R 6 , wherein R 6 is alkyl or ANR 9 R 10 , wherein A is alkyl, and R Q and R 10 are each independently hydrogen, or substituted or unsubstituted C ⁇ -C 12 alkyl.
  • R 5 is -C(0)-R fi , wherein R 6 is alkyl or ANR 9 R 10 , wherein A is alkyl, and R 9 and R 10 are each independently hydrogen, or substituted or unsubstituted C-.-C 12 alkyl.
  • R 4 is -Y-C(0)-R 7 , wherein Y is substituted or unsubstituted C--C 12 alkyl and R 7 is ⁇ R 9 R 10 .
  • R 5 is -Y-C(0)-R 7 , wherein Y is substituted or unsubstituted C x -C 12 alkyl and R7 is NR 9 R 10 .
  • R 3 and NR 4 R 5 are in a cis spatial configuration. In another specific embodiment R 3 and NR 4 R 5 are in a trans spatial configuration.
  • the compound may also be a mixture of the cis and trans isomers.
  • the compound may be a racemate of the R and S enantiomers.
  • the compound is an R enantiomer.
  • the compound is selected from the group consisting of l-aminoindan, (R) - l -aminoindan, 1 -aminotetralin, 1 - aminobenzocyclobutane, 6-hydroxy-l-aminoindan, (R) -6- hydroxy-l-aminoindan, 7-hydroxy-1-aminoindan, 6-fluoro-l- aminoindan, (R) -6-fluoro-1-aminoindan, 5-methoxy-l- ammoindan, 7-methyl-1-aminoindan, 5-methyl-l-amino ⁇ ndan, 4 , 5-dimethoxy- l-aminoindan, (R.
  • This invention provides the above method for treating Parkinson's disease in a subject. For treating
  • Parkinson's disease in a subject the compound is preferably an R enantiomer.
  • the method of the present invention may involve the administration of any one of the compounds of formula 1 alone or in combination with conventional L-DOPA treatments. In combination treatments the compound of formula 1 may be administered before, after, or together with the conventional L-DOPA treatments.
  • This invention also provides the above method which further comprises administering to the subject a therapeutically effective amount of Levodopa.
  • the therapeutically effective amount of Levodopa is from about 50 mg to about 250 mg.
  • Another embodiment further comprises administering to the subject a therapeutically effective amount of decarboxylase inhibitor.
  • a decarboxylase inhibitor as well as the identity of specific decarboxylase inhibitors, is well known in the art to which this application pertains.
  • the decarboxylase inhibitor is L-Carbidopa.
  • the therapeutically effective amount of L-Carbidopa is from about 10 mg to about 25 mg.
  • the decarboxylase inhibitor is benserazide.
  • the therapeutically effective amount of benserazide is from about 12.5 mg to about 50 mg.
  • This invention provides the above method for treating dementia, epilepsy, convulsions, or seizures in a subject.
  • the compound is an R enantiomer.
  • the compound is an S enantiomer.
  • the compound is selected from 1640
  • This invention provides the above method for treating Parkinson's-type dementia. This invention also provides the above method for treating senile dementia in a subject. This invention also provides the above method for treating Alzheimer's-type dementia in a subject.
  • This invention provides a method for treating epilepsy, convulsions, or seizures in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula:
  • R x and R 2 are each independently hydrogen, hydroxy, substituted or unsubstituted C ⁇ C, alkyl, substituted or unsubstituted alkoxy, halogen, nitro, NH-R 3 , C(0)-R 3 , or C(O)-NR 9 R 10 ;
  • R 3 is hydrogen, substituted or unsubstituted ⁇ C ⁇ alkyl, hydroxy, substituted or unsubstituted C 1-4 alkoxy, or substituted or unsubstituted c e -i 2 aryl; and
  • R 4 and R s are each independently hydrogen, substituted or unsubstituted C -C 2 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 - C 12 aralkyl, alkynyl, -C(0)-R 6 , -Y-
  • R 6 is hydrogen, hydroxy, substituted or unsubstituted C ⁇ - C 12 alkyl, substituted or unsubstituted C fi -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, or A-NR 9 R 10 , wherein A is substituted or unsubstituted C-.-C,.-, alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, and R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C 1 - C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, or indanyl; Y is substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 1 -
  • the subject is a human subject.
  • n is i. In another embodiment wherein n is 2.
  • R- and R 2 are each independently hydrogen, fluoro, hydroxy, methyl or methoxy.
  • R 3 is hydrogen or methyl .
  • This invention provides the above method wherein R 4 is propargyl .
  • This invention also provides the above method wherein R 5 is propargyl.
  • R 3 and NR 4 R 5 are in a cis spatial configuration. In another embodiment R 3 and NR 4 R 5 are in a trans spatial configuration.
  • the compound is an R enantiomer. In another embodiment the compound is an S enantiomer.
  • This invention provides the above method for treating epilepsy in a subject.
  • This invention also provides the above method for treating convulsions or seizures in a subject.
  • This invention provides a compound selected from the group consisting of 7-methyl-l-aminoindan, 5-methyl-l- aminoindan, (R) -6-hydroxy-l-aminoindan, 3,5,7-trimethyl- 1-aminoindan, 4,5-dimethoxy-l-aminoindan, (R)-4,5- dimethoxy-l-aminoindan, (S) - , 5-dimethoxy-l-aminoindan, -hydroxy-5-methoxy-l-aminoindan, 6-hydroxy-5-methoxy-1- aminoindan, N- (4-aminobutanoyl) -l-aminoindan, (R) -N- formyl-l-aminoindan, (S) -N-formyl-l-aminoindan, (R) -N- acetyl-1-aminoindan, N-acetyl-7-methyl-l-aminoindan, N- acet
  • this invention provides for the racemic mixture, the R enantiomer, and the S enantiomer.
  • the salt is a hydrochloride salt, a mesylate salt, an ethylsulfonate salt, or a sulfate salt.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-listed compounds and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a solid and the pharmaceutical composition is a tablet.
  • the therapeutically effective amount is from about 1 mg to about 1000 mg. In a more specific embodiment the therapeutically effective amount is from about 10 mg to about 100 mg.
  • the pharmaceutically acceptable carrier is a liquid and the pharmaceutical composition is an injectable solution.
  • the therapeutically effective amount is from about 1 mg/ml to about 1000 mg/ml . In a more specific embodiment the therapeutically effective amount is from about 10 mg/ml to about 100 mg/ml.
  • the carrier is a gel and the pharmaceutical composition is a suppository.
  • This invention further provides for the above pharmaceutical composition, further comprising a therapeutically effective amount of Levodopa.
  • This invention also provides for an embodiment of the pharmaceutical composition further comprising a therapeutically effective amount of a decarboxylase inhibitor.
  • the decarboxylase inhibitor is L-Carbidopa.
  • the effective amount of the compound is from about 1 mg to about 1000 mg, the therapeutically effective amount of Levodopa is from about 50 mg to about 250 mg, and the therapeutically effective amount of L-Carbidopa is from about 10 mg to about 25 mg.
  • the decarboxylase inhibitor is benserazide.
  • the therapeutically effective amount of the compound is from about 1 mg to about 1000 mg
  • the therapeutically effective amount of Levodopa is from about 50 mg to about 200 mg
  • the therapeutically effective amount of benserazide is from about 12.5 mg to about 50 mg.
  • the compounds of general formula 1 possess neuroprotective activity. Accordingly, this invention provides a method for treating acute neurological traumatic disorder or neurotrauma in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula:
  • Rj_ and R 2 are each independently hydrogen, hydroxy, substituted or unsubstituted Ci-C, alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, halogen, nitro, amino, NH-R 3 or C(0)-R 3 , or C (O) -NR 9 R 10 ;
  • R 3 is hydrogen, substituted or unsubstituted C-.-C, alkyl, hydroxy, substituted or unsubstituted C 1-4 alkoxy, or substituted or unsubstituted C € _ 12 aryl; and
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted C-.-C 12 alkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 7 -C 12 aralkyl, -C(0)-R 6 , -Y- C
  • the administering can be performed according to techniques well known to those of skill in the art.
  • the administering comprises administering orally, rectally, transdermally, or parenterally.
  • the therapeutically effective amount is from about 1 mg to about 1000 mg, preferably from about 10 mg to about 100 mg.
  • compositions are well known to those of skill in the art.
  • examples of pharmaceutically acceptable salts are a hydrochloride salt, a mesylate salt, an esylate salt, or a sulfate salt.
  • n is i. In another embodiment n is 2.
  • R x and R 2 are each independently hydrogen, fluoro, hydroxy, methyl or methoxy.
  • R x is 4-fluoro, 6- fluoro, 4-hydroxy, 6-hydroxy, 4-methyl, 6-methyl, 4- methoxy, or 6-methoxy.
  • R 2 is 4- fluoro, 6-fluoro, 4-hydroxy, 6-hydroxy, 4-methyl, 6- methyl, 4-methoxy, or 6-methoxy.
  • R 3 is hydrogen or methyl.
  • R 4 and R 5 are each independently hydrogen, or substituted or unsubstituted Ci-C- 2 alkyl.
  • R 4 is C j _-C 12 alkyl substituted with a lipophilic group, C 6 -C 12 aryl substituted with a lipophilic group, or C 7 -C 12 aralkyl substituted with a lipophilic group.
  • the lipophilic group is selected from the group consisting of piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, adamantyl, quinuclindyl, and substituted derivatives thereof.
  • R 5 is C ⁇ -C l2 alkyl substituted with a lipophilic group, C 6 -C 12 aryl substituted with a lipophilic group, or C 7 -C 12 aralkyl substituted with a lipophilic group.
  • the lipophilic group is selected from the group consisting of piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, adamantyl, quinuclindyl, and substituted derivatives thereof.
  • This invention provides the above method wherein A is substituted or unsubstituted C-.-C 12 alkyl.
  • This invention provides the above method wherein Y is substituted or unsubstituted C-.-C 12 alkyl.
  • This invention provides the above method wherein R 7 is substituted or unsubstituted C-.-C 12 alkyl.
  • R 4 is -C(0)-R 6 , wherein R 6 is alkyl or ANR 9 R 10 , wherein A is alkyl, and R 9 and R 10 are each independently hydrogen, or substituted or unsubstituted C : -C 12 alkyl.
  • R 5 is -C(0)-R 6 , wherein R 6 is alkyl or ANR 9 R 10 , wherein A is alkyl, and R 9 and R 10 are each independently hydrogen, or substituted or unsubstituted C--C 12 alkyl.
  • R 4 is -Y- C ( 0 ) -R 7 , wherein Y is substituted or unsubstituted C 1 - C 12 alkyl and R 7 is NR 9 R- 0 .
  • R 5 is -Y-C(0)-R 7 , wherein Y is substituted or unsubstituted C -C ⁇ alkyl and R 7 is NR 9 R 10 .
  • R 3 and NR 4 R 5 are in a cis spatial configuration. In another specific embodiment R 3 and NR 4 R 5 are in a trans spatial configuration.
  • the compound may also be a mixture of the cis and trans isomers.
  • the compound is an R enantiomer. In another embodiment the compound is an S enantiomer.
  • the compound is selected from the group consisting of l-aminoindan, (R) - l-aminoindan, (S) -l-aminoindan, 1-aminotetralin, 1- aminobenzocyclobutane, 6-hydroxy-l-aminoindan, (R) -6- hydroxy-l-aminoindan, 6-fluoro-l-aminoindan, (R) -6- fluoro-l-aminoindan, (S) -6-fluoro-l-aminoindan, 5- methoxy-l-aminoindan, (S) -6-methoxy-l-aminoindan, 7- methyl-l-aminoindan, 5-methyl-l-aminoindan, 4,5- dimethoxy-l-aminoindan, (R) -4, 5-dimethoxy-l-aminoindan,
  • This invention provides the above method for treating acute neurological traumatic disorder in a subject.
  • This invention provides the above method for treating neurotrauma in a subject.
  • the neurotrauma is caused by a closed head injury.
  • the subject invention further provides a method of treating a subject afflicted with a memory disorder which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat the memory disorder in the subject.
  • the subject invention further provides a method of treating a subject afflicted with dementia which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat dementia in the subject.
  • the dementia is of the Alzheimer type (DAT) .
  • the subject invention further provides a method of treating a subject afflicted with depression which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat depression in the subject.
  • the subject invention further provides a method of treating a subject afflicted with hyperactive syndrome which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat hyperactive syndrome in the subject.
  • the administering may comprise orally administering, rectally administering, or parenterally administering.
  • the subject invention further provides a method of treating a subject afflicted with an affective illness which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat the affective illness in the subject.
  • the subject invention further provides a method of treating a subject afflicted with a neurodegenerative disease which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat the neurodegenerative disease in the subject.
  • the subject invention further provides a method of treating a subject afflicted with a neurotoxic injury which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat the neurotoxic injury in the subject.
  • the subject invention further provides a method of treating a subject afflicted with brain ischemia which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat brain ischemia in the subject.
  • the subject invention further provides a method of treating a subject afflicted with a head trauma injury which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat the head trauma injury in the subject.
  • the subject invention further provides a method of treating a subject afflicted with a spinal trauma injury which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat the spinal trauma injury in the subject . - 3 1 -
  • the subject invention further provides a method of treating a subject afflicted with schizophrenia which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat schizophrenia in the subject.
  • the subject invention further provides a method of treating a subject afflicted with an attention deficit disorder which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat the attention deficit disorder in the subject.
  • the subject invention further provides a method of treating a subject afflicted with multiple sclerosis which comprises administering to the subject an amount of a compound of general formula l or the pharmaceutically acceptable salt thereof of the subject invention effective to treat multiple sclerosis in the subject.
  • the subject invention further provides a method of preventing nerve damage in a subject which comprises administering to the subject an amount of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to prevent nerve damage in the subject.
  • the nerve damage is structural nerve damage. In another embodiment, the structural nerve damage is optic nerve damage.
  • the subject invention further provides a method of treating a subject suffering from symptoms of withdrawal from an addictive substance which comprises administering to the subject an amount of a compound of general formula 1 or the pharmaceutically acceptable salt thereof of the subject invention effective to treat the symptoms of withdrawal in the subject.
  • symptoms of withdrawal refers to physical and/or psychological symptoms, including drug craving, depression, irritability, anergia, amotivation, appetite change, nausea, shaking and sleep irregularity.
  • the term "addictive substance” includes, by way of example, (a) addictive opiates such as opium, heroin and morphine, (b) psychostimulants such as cocaine, amphetamines and methamphetamines, (c) alcohol, (d) nicotine, (e) barbiturates and (f) narcotics such as fentanyl, codeine, diphenoxylate and thebaine.
  • the addictive substance is cocaine. In another embodiment, the addictive substance is alcohol .
  • This invention provides a method for preparing an optically active enantiomer of a compound of the formula:
  • enantiomer is optically active at the C x position; n is 0, 1 or 2; R x and R 2 are each independently hydrogen, hydroxy, substituted or unsubstituted C--C 4 alkyl, substituted or unsubstituted C x - C 4 alkoxy, or halogen; and R 3 is hydrogen or unsubstituted C,.-C 4 alkyl; comprising incubating in a reaction mixture a racemic N- benzyl analog of the compound with an optically active enantiomer of mandelic acid; converting the optically active ammonium salt obtained to its corresponding optically active base; and reducing the base to the optically active enantiomer of the compound.
  • the racemic N-benzyl analog is reacted with the optically active enantiomer of mandelic acid in a solvent.
  • suitable solvents include ethanol; ethanol and acetone,* and ethanol and acetylacetate, as well as other solvents that can be identified by one of ordinary skill in the art. Most preferably, the solvent is ethanol.
  • the optically active salt is isolated prior to its conversion to its corresponding optically active base.
  • the reaction mixture of the mandelic acid and the racemic N-benzyl analog is heated prior to the isolation of the salt until complete dissolution of the reactants is observed, and then cooled.
  • the reaction mixture is heated to a temperature from about 68°C to about 78°C, preferably about 75°C, and then cooled over a period of several hours to a temperature from about 5°C to about 20°C, preferably about 10°C.
  • the isolated optically active salt is recrystallized prior to its conversion to its corresponding base.
  • the optically active salt is converted to its corresponding base by the addition of a basic reagent.
  • the basic reagent is an organic or inorganic base.
  • Suitable bases include sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate and triethylamine, as well as other suitable bases that can be identified by one of skill in the art .
  • the base is sodium hydroxide.
  • the optically active salt is suspended in a mixture of water and a water immiscible solvent, such as toluene, prior to the addition of the basic reagent.
  • a water immiscible solvent such as toluene
  • the toluene:water ratio is about 75:70.
  • the optically active base is isolated prior to its reduction to the optically active enantiomer of the compound. Any known system for performing reduction may be used.
  • the optically active base is reduced by reaction with hydrogen gas in the presence of a palladium/carbon catalyst, preferably under increased pressure.
  • n 1, and R-, R 2 and R 3 are hydrogen.
  • the optically active salt is R(+) or S (-) -N-benzyl-1-aminoindan -mandelate ethanolate and the optically active base is R- (+) or S-(- ) -N-benzyl-1-aminoindan.
  • the optically active enantiomer of mandelic acid is L- (+) -mandelic acid
  • the optically active salt is R- (+) -N-benzyl-1-aminoindan-mandelate ethanolate
  • the optically active base is R- ⁇ +) -N- benzy1-1-aminoindan.
  • the optically active enantiomer of mandelic acid is D- (-)mandelic acid
  • the optically active salt is S- (-) -N-benzyl-1-aminoindan-mandelate ethanolate
  • the optically active base is S- (-) -N-benzyl-1- aminoindan.
  • This invention provides method for preparing an optically active mandalate salt of a compound of the formula
  • n is 0, l, or 2;
  • R lf R 2 , and R 3 are each independently hydrogen, hydroxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C ⁇ -C 4 alkoxy, or halogen; and
  • R 3 is hydrogen, or unsubstituted C 1 -C 4 alkyl; comprising reacting a racemic mixture of the compound with an optically active enantiomer of mandelic acid, and recovering the optically active mandelate salt.
  • n is 1; and R l t R 2 and R 3 are hydrogen.
  • This invention further provides a method for preparing an optically active free base of the formula:
  • This invention also provides R- (+) -N benzyl-l-aminoindan and S- (-) -N-benzyl-1- aminoindan, when prepared in accordance with this method.
  • This invention provides R- (+) -N-benzyl-l-aminoindan, R- (+) -N-benzyl-1-aminoindan-L-mandelate ethanolate, and S- (-) -N-benzyl-1-aminoindan-D-mandelate ethanolate.
  • This invention provides a method for preparing racemic N- benzyl-1-aminoindan comprising reacting 1-chloroindane with benzylamine in an inert solvent.
  • the 1- chloroindane and benzylamine are combined at a temperature of about 90°C. It is also preferable that the temperature is raised to about 115°C for a period of about ten hours following the combining of the 1-chlorindane with the benzylamine.
  • This invention provides N-benzyl- l-aminoindan when prepared in accordance with the above- described method.
  • the R-1-aminoindan starting material can be prepared by methods known in the art which include, by way of example, the method of Lawson and Rao, Biochemistry, 19, 2133 (1980) , methods in references cited therein, and the method of European Patent No. 235,590.
  • R-1-aminoindan can also be prepared by resolution of a racemic mixture of the R and S enantiomers, which involves, for example, the formation of diastereomeric salts with chiral acids, or any other known method such as those reported in J. Jacques, et al. , ibid.
  • R-1-aminoindan may be prepared by reacting 1-indanone with an optically active amine, followed by reduction of the carbon nitrogen double bond of the resulting imine by hydrogenation over a suitable catalyst, such as palladium on carbon, platinum oxide or Raney nickel.
  • Suitable optically active amines include, for example, one of the antipodes of phenethylamine or an ester of an amino acid, such as valine or phenylalanine.
  • the benzylic N-C bond may be cleaved subsequently by hydrogenation under non-vigorous conditions.
  • R-1-aminoindan is the hydrogenation of indan-1-one oxime ethers as described above, wherein the alkyl portion of the ether contains an optically pure chiral center.
  • a non- chiral derivative of indan-1-one containing a carbon- nitrogen double bond such as an imine or oxime, can be reduced with a chiral reducing agent, e.g., a complex of lithium aluminum-hydride and ephedrine.
  • the R- and S- enantiomers of each compound may be obtained by optical resolution of the corresponding racemic mixtures.
  • a resolution can be accomplished by any conventional resolution method well known to a person skilled in the art, such as those described in U.S. Patent No. 4,833,273, issued May 23, 1989 (Goel) and in J. Jacques, A. Collet and S. Wilen, "Enantiomers, Racemates and Resolutions," Wiley, New York (1981) .
  • the resolution may be carried out by preparative chromatography on a chiral column.
  • Another example of a suitable resolution method is the formation of diastereomeric salts with a chiral acid such as tartaric, malic, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine, followed by recrystallization to isolate the diastereomeric salt of the desired R enantiomer.
  • a chiral acid such as tartaric, malic, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine
  • the racemic mixture of R and S enantiomers of N- propargyl-l-aminoindan may be prepared, for example, as described in GB 1,003,676 and GB 1,037,014.
  • the racemic mixture of PAI can also be prepared by reacting 1-chloroindan with propargylamine .
  • this racemate may be prepared by reacting propargylamine with l-indanone to form the corresponding imine, followed by reduction of the carbon-nitrogen double bond of the imine with a suitable agent, such as sodium borohydride.
  • the 1-aminoindans of general formula 1 where R- and R 2 are as indicated and R 4 and R 5 are hydrogen may be prepared by the chemical reduction of the relevant oximes, by means of zinc/acetic acid or by catalytic hydrogenation.
  • the oximes may be prepared by reaction of the corresponding indan-1-ones with hydroxylamine hydrochloride.
  • the indan- l-ones may be prepared by Friedal-Crafts cyclization of substituted dihydrocinnamic acids or the corresponding chlorides using aluminum trichloride or other Lewis acids, such as polyphosphoric acid or methanesulphonic acid as condensing agents, for example according to procedures described in J. Org. Chem. .46., 2974 (1981) and in J. Chem. Soc. Perkin Trans, 1 , 151 (1972) .
  • N-methyl-l-aminoindan may be prepared from l-aminoindan according to the procedure described in J.Med.Chem.9_, 830 (1966) .
  • N,N-dimethyl-l-aminoindan may be prepared from 1- aminoindan according to the procedure described in Yakugaku Zasshi, 81 1597 (1962) - Chem. Abs. 59. 611f.
  • N-formyl and N-acyl derivatives of l-aminoindan and 1- aminotetralin may be prepared from the corresponding 1- aminoindan or 1-aminotetralin using the methods described in J.Med.Chem. 9_, 830 (1966), J.Chro atog. 502, 154 (1990) or Boll.Chim.Farm. 115. 489 (1976) .
  • R 4 is hydrogen or lower alkyl and R s is C(0)-R 6 , and R 6 is A-NR 9 R 10 are indanylamides of amino acids, and may be prepared by procedures known to those skilled in the art, for example, by reacting the aminoindan with an activated form of the amino acid in the presence or absence (as necessary) of acylation catalysts such as 4-N,N- dimethylaminopyridine.
  • acylation catalysts such as 4-N,N- dimethylaminopyridine.
  • aminoindan is reacted with an amino acid anhydride having the amino terminus protected by a suitable radical such as t-butoxycarbonyl (Boc) , in the presence of for example DMAP, in an aprotic organic solvent such as THF, at a temperature within the range of 0-50 C, preferably from 25-40 C, for a period of from l- 24 hours, preferably from 5-10 hours.
  • a suitable radical such as t-butoxycarbonyl (Boc)
  • the l-aminoindan may be reacted with an N- hydroxy succinimide ester of an amino acid having the terminal amino group protected as above, in an aprotic solvent such as 1, 2-dimethoxyethane (DME) , at a temperature within the range of 0-70 C, preferably from 25-50 C, for a period of from 12-48 hours, preferably from 24-36 hours.
  • DME 1, 2-dimethoxyethane
  • the product may be purified by column chromatography and/or by crystallization. Removal of the protecting group may be accomplished by subjecting said group to acidic conditions for example to hydrochloric acid or trifluoroacetic acid in a suitable organic solvent such as isopropanol or dioxane. The desired products are then obtained as their acid addition salts.
  • the compounds of general formula 1 wherein R : or R 2 are hydrogen or lower alkyl, R 4 is hydrogen and R 5 is Y-C(O) -R 7 and R 7 is NR9R10, are N-indanyl derivatives of amino acid amides, and may be prepared by reacting the relevant amino acid amide with a 1-halogeno-indan or with a 1- indanone. In the latter case, the resulting Schiff base is further reduced, by a suitable reducing agent such as sodium borohydride, to afford the desired amine.
  • these compounds may be prepared by reacting the l-aminoindan with an omega-halogeno derivative of the relevant amino acid amide, in an alcoholic solvent such as ethanol in the presence of a base such as potassium carbonate, at a temperature within the range of 50-100 C, preferably at the reflux temperature of the solvent, for a period of from 12-36 hours, preferably 24 hours.
  • the product may then be converted into its acid addition salt.
  • the R and S enantiomers of each of these compounds may be resolved using procedures known to those skilled in the art .
  • N,N-di- (2-acetamido) -l-aminoindan N,N-di- (2-acetamido) -l-aminoindan
  • EXAMPLE 56 N- (l-indanyl) -aminoacetonitrile
  • EXAMPLE 57 N-acetyl-6-nitro-l-aminoindan
  • EXAMPLE 58 6-amino-N-acetyl-l-aminoindan
  • EXAMPLE 59 6-acetamido-N-acetyl-l-aminoindan
  • EXAMPLE 60 6-cyano-N-acetyl-l-aminoindan
  • EXAMPLE 61 6-carboxamido-N-acetyl-l-aminoindan
  • EXAMPLE 62 6-carboxamido-N-acetyl-l-aminoindan
  • the title compound was prepared from (rac) -l-aminoindan in a manner analogous to that described in Example 1, m.p. : 201-2°C.
  • the free base melted at 131-3°C.
  • the title compound was prepared in 25% yield from 1- aminotetralin and 2-chloroacetamide according to the procedure described in Example 1.
  • the base was purified by filtration through silica with acetone as eluent, to give a white solid, m.p. : 139°-41°C.
  • IR (KBr) 3360, 3190, 3020, 2910, 2410, 1690, 1600, 1500, 1405 cm- 1 .
  • Boc-GABA anhydride (4.46 g, 11.5 mmole, prepared from Boc GABA and DCC in CH 2 C1 2 ) in dry THF (15 ml) was added to a solution of l-aminoindan (1.5 g, 11.2 mmole) in dry THF (15 ml) , and DMAP (1.5 g, 12.3 mmole) was then added in one portion.
  • the reaction mixture was stirred at RT for 6 hr, filtered and the filtrate was evaporated to dryness.
  • N- (4-aminobutanoyl) -l-aminoindan also called N- (4-aminobutanoyl) -l-aminoindan.HCl .
  • N- (N-Boc-4-aminobutyryl) -l-aminoindan (2.50 g, 7.8 mmole) was dissolved in dry dioxane (20 ml) , and 1.7N HCl in dioxane (20 ml) was added. The solution was stirred at ambient temperature for 4 hr, evaporated to dryness, and the residue taken up in CH 2 C1 2 :H 2 0 mixture (1:1, 160 ml) . The aqueous phase was separated, filtered through millipore and evaporated to dryness in vacuo. The crude product was crystallized from 40:60 EtOAc :ethanol to give 1.55 g (78%) white crystalline solid, m.p. : 168°C.
  • the title compound was prepared from (rac) -l-aminoindan, according to J.Med.Chem., 9, 830 (1963) , and crystallized from iPrOH/Et 2 0 (overall yield 25%) , m.p. : 147-9°C.
  • IR 3281, 2959, 2835, 1638, 1551, 1495, 1296, 1260, 1217 cm "1 .
  • the title compound was prepared in 72% from 6-methoxy-1- indanone in a manner analogous to that described in Ex. 24, except that 6-methoxy-l-oximinoindan was reduced by hydrogen over Pd on charcoal; m.p. : 244-5°C.
  • the NMR, MS and IR data are identical to those described in Ex. 24.
  • IR (KBr) 2900, 1602, 1509, 1500, 1300, 1252 cm" 1 .
  • 2-Methyl-1-indanone was prepared from benzene and ⁇ - bromoisobutyryl bromide, as in Polish J. Chem. 5_2., 2059 (1978) , and converted to the oximino derivative, from which the title compound was obtained by reduction with Zn/HOAc. The overall yield was 14%, m.p. : >275°C (dec.) .
  • the aqueous layer was separated, extracted with CH 2 C1 2 (50 ml) , and the combined organic layer was dried (Na 2 S0 4 ) and evaporated to dryness.
  • the crude product was purified by flash column chromatography (silica, hexane:ET0Ac 80:20) , to give 5.4 g (36%) of the free base, which was converted to its HCl salt by dissolving it in Et 2 0 (60 ml) and adding to it an Et 2 0 solution saturated with HCl gas (75 ml) .
  • the title compound was prepared in 77% from (rac)-l- aminoindan (1.0 g, 7.5 mmole) and benzoyl chloride (2.1 g, 15 mmole) , under the Schotten-Bauman conditions, according to J.Chem.Soc 2 ⁇ > 25 (1897) and J.Org.Chem. 27, 4465 (1962) , m.p.: 140-2°C.
  • 1-Acetylamino-6-aminoindan (Ex. 59, 11.42 g, 0.060 mole) was mechanically stirred with water (15.5 ml) in an ice- salt bath and treated with cone hydrochloric acid (15.5 ml, 0.16 mole) to give a uniform thick suspension which was allowed to cool to ca 0°C. It was then treated dropwise with a solution of sodium nitrite (4.46 g, 0.063 mole) in water (9 ml) so that the temperature stayed below 5°C. After complete addition, the mixture was neutralized by the portionwise addition of sodium carbonate (3.1 g) .
  • reaction mixture was stirred at ambient temperature for 2 hrs; the solid was collected by filtration, washed with toluene (10 ml) , dried and crystallized from hexane:EtOAc, to give 1.85 g (9.8 mmole, 78%) , mp: 146- 7°C.
  • Racemic l-aminoindan (5.7g, 43mmole) in ether (20ml) stirred in ice, was treated dropwise with adipoyl chloride (1.83g, lOmmole) in ether (10ml) . After 30min. the solid was filtered and slurried with water for 45min. The insoluble solid was collected, air dried (2.82g) and crystallized from HOAc/H 2 0, washed with acetic acid/water (1:1) , ethanol and ether and then dried to give 2.26g (60% title compound. Melting point: 227°C.
  • N.N* -Bis- ( (R) -1-indanyl)adipamide This was prepared by the same procedure as in Example 73 starting from (R) -l-aminoindan (5.32g, 40mmole) , with an additional recrystallization from ethanol (20ml) and acetic acid (15ml) to give the white product (2.37g, 62.9%) . Melting point: 244-7°C.
  • Examples 76 to 82 exemplify the preparation of compounds of Formulas 2 and 3.
  • a mixture of 272ml of toluene and 199.5g benzylamine was prepared and heated to 90°C.
  • the chlorindan was added dropwise to the mixture over a 30 minute period.
  • the reaction mixture was heated to 115°C for ten hours.
  • the reaction mixture was cooled to ambient temperature and 300ml of water was added.
  • the resulting heterogeneous mixt ⁇ re was then brought to pH2.2 by the addition of 33% H 2 S0 4 .
  • the phases were separated and the organic layer discarded.
  • the pH of the aqueous layer was adjusted to pH6.0 prior to extraction with 300ml of toluene. A further 100ml of toluene was then added and the aqueous phase discarded.
  • Example 77 (57.7g), prepared as in Example 77, was suspended in a mixture of 70ml water and 75ml toluene. The mixture was stirred vigorously and adjusted to pH13-14 by the addition of 40%NaOH solution. The extraction was repeated with further 50ml of toluene. The toluene was removed in vacuo from the combined organic layers to provide the title compound as a colorless oil (99.5% yield) .
  • the pH of the aqueous phase was adjusted to pH2.3 by adding 10% NaOH solution and the phases were then separated.
  • Toluene (50ml) was added to the aqueous phase and the pH increased to 12.5 with 45% NaOH.
  • the organic phase was separated and the aqueous phase re-extracted with 30ml toluene.
  • the combined toluene phases were evaporated in vacuo and the crude compound purified by distillation, (20mmHg/ll7.5-119°C) to give 2.57g R- (-) -l-aminoindan (72% yield) .
  • the title compound was prepared by the process of Example 81, except that (S) -N-benzyl-l-aminoindan was used as the starting material.
  • EXAMPLE 1 EFFECT OF 1-AMINOINDANS IN AN EXPERIMENTAL MODEL OF DOPAMINERGIC HYPOFUNCTION Experiments 1A and IB. Alpha-MpT- induced hypokinesia in hypoxic rat
  • Experiment 1A Wistar male rats, 15-19 month-old, were exposed to a single hypoxic episode which is assumed to decrease the level of dopamine in the brain.
  • Four to five rats were kept for six hours in a glass chamber equipped with an inlet and outlet tubes for the admission of an atmosphere of premixed nitrogen (92%) and oxygen (8%) at a flow rate of 3L/min.
  • Control rats received room air from a compressed tank under similar conditions.
  • 1-R-aminoindan HCl (hereinafter R-AI) or deprenyl (an MAO B inhibitor) were administered to the rats immediately following the conclusion of the hypoxic episode at the standard dose of 0.5mg/kg/Day for 70-80 days.
  • the dose of free amine (the active species) corresponding to 0.5 mg/kg salt is actually 0.39mg/kg for R-AI and 0.42 mg/kg for deprenyl .
  • the drugs were administered by gavage, using a special syringe equipped with rounded tip that could be directed into the stomach. The dose was contained in 0.3-0.5 mL of distilled water.
  • the rats were pretreated for 70-80 days with daily doses of the test drugs and received intra-peritoneal (i.p.) or-MpT ( ⁇ -methyl-p-tyrosine) at a dose of lOOmg/kg in 0.3-0.5 mL saline. Controls received saline.
  • ⁇ -MpT is assumed to inhibit the formation of L-Dopa from tyrosine and, consequently the formation of dopamine itself. Lack of central dopamine is expressed as hypokinesia. Following the injection of ⁇ -MpT, motor activity was recorded for the duration of 10 hours. Locomotion scores were taken in seven fully-computerized cages (26x25cm) having a grid of infra-red beams at 4 cm-intervals.
  • Crossing of a beam initiated an electric signal which was fed into a computer.
  • the number of crossings over a given period provided a measure of locomotion.
  • the records gave two data categories: (a) "small movements” originating in stationary activities such as grooming and scratching and (b) "big movements” originating in ambulation and recorded as the simultaneous crossing of more than two beams. "Total movements” include both categories.
  • Counts of motor activity in the presence of ⁇ -MpT were related as percent with respect to counts in its absence in the corresponding control group (unlesioned or hypoxia-lesioned) .
  • Motor activity counts of drug-treated rats were related to the hypoxia saline-treated as 100%. All behavioral tests were performed 90-120 min. after administration of the last dose of the test compound.
  • Figures 1 and 2 In Figures 1 and 2, hours after alpha- methyl-p-tyrosine injection are given on the x-axis and percent response as compared to the relevant control is given on the y-axis. Figure 1 shows the effect the hypoxic episode had as compared to the control animals, whereas Figure 2 shows the effect the drug treated group compared to the untreated hypoxic group. TABLE 1: Locomotor activity after ⁇ -MpT treatment, recorded as total movements.
  • Control rats underwent two phases of hypokinesia. The first at hour 1-2 after ⁇ -MpT followed by full recovery and rebound at hour 3. Then, another phase of hypokinesia at hours 6-7 followed by full recovery to control level at hours 7-8. In the hypoxic group, the decrease in motor activity was more pronounced during the first phase at hours 1-2, with some recovery at hour 4, followed by a second phase of hypokinesia which lasted till hour 10 with no signs of recovery. Hypoxic rats that had been pretreated with R-AI or deprenyl behaved similarly ( Figure 2) . In either case the two-phase cyclic pattern of depression-rebound-depression found for ⁇ -MpT-treated hypoxic controls could be observed.
  • N 7 - 10 in a group.
  • ⁇ -MpT produced a paradoxical effect in control rats, with outbursts of hyperkinesia which lasted for as long as ten hours after an initial small decrease in activity which may not be significant.
  • hypoxia-lesioned rats were hypokinetic for as long as ten hours with no signs of recovery.
  • R-AI corrected the hypokinetic syndrome in the hypoxia group, bringing the level of activity almost to /21640
  • Experiment IB The procedure of Experiment 1A was repeated with the following changes : (1) Animal: 11-14 month-old rats. (2) Drug treatment: R-AI and deprenyl at a daily dose of 0.3 mg/Kg in 0.2 mL. The drugs were given i.p.
  • Total movements after ⁇ -MpT are given in Table 3 and Figure 5.
  • the score of big movements is given in Table 4 and Figure 6.
  • Figures 5 and 6 hours after alpha-methyl-p- tyrosine injection are given on the x-axis and percent response as compared to the relevant control is given on the y-axis.
  • Figure 5 shows the fate of the groups treated with R-AI or deprenyl as compared to the hypoxic group over the first four hours, with respect to total movements.
  • Figure 6 shows the same data with respect to big movements.
  • Antagonism to ⁇ -MpT by R-AI and deprenyl is best perceived within the 2-4 hours after the ⁇ -MpT injection as shown in Figures 5 and 6.
  • N 4 - 7 in a group.
  • Experiment 1A demonstrates the ability of R-AI to correct a syndrome of dopaminergic hypofunction associated with Parkinson's Disease to an extent at least comparable, or in some instances better than that of deprenyl. This effect was also evident in the first 2-4 hours of Experiment IB. This experiment was carried out over a shorter period than Experiment 1A, using a lower dosage of R-AI on a separate population of animals Both these experiments indicate that 1-ammomdans of formula 1 have a role in the treatment of Parkinson's Disease.
  • Experiment 1C The procedure of Experiment 1A was repeated with the following changes: (1) Animal. 11-14 month-old rats. (2) Drug treatment: Test compounds were administered at the dosages indicated, as a single i.p. dose 1 hour prior to ⁇ -MpT (150mg/kg) .
  • EXAMPLE 2 EFFECT OF 1-AMINOINDANS ON AMPHETAMINE-INDUCED STEREOTYPE BEHAVIOR IN HYPOXIC RAT Procedure
  • Experiment 2A Wistar male rats, 15-19 month-old, were exposed to a single hypoxic episode as described above. R-AI or deprenyl were administered to the rats at the same dose and method used in Example 1A. Rats pretreated for 29 days with daily doses of the test drugs (0.5mg/kg) , received a sub-cutaneous (s.e) injection of D-amphetamine sulfate at a dose of 0.5mg/kg. D-amphetamine is known to cause an enhancement of the effects of CNS dopamine by a mechanism involving dopamine release, and blockage of its uptake and its metabolism by MAO. The behavioral manifestation of amphetamine action is a stereotypic pattern of lateral head movements. Counts of lateral head movements were taken over two successive intervals of 1 min each, 45-60 min after the injection of amphetamine and then averaged.
  • Test compounds were administered as a single treatment, at a dose of 1.2mg/kg (base equivalents) 60 minutes prior to
  • Table 5 shows the total number of lateral head movements per minute for each of the experimental groups .
  • Stereotypic behavior is not caused by amphetamine itself, but by the enhancement of the effect of released dopamine through a combination of effects: release, uptake inhibition and MAO inhibition.
  • Experiment 3A Wistar male rats, 15-19 month-old, were exposed to a single hypoxic episode as described above. R-AI or deprenyl were administered o the rats at the same dose and method used in the ⁇ -MpT mode]
  • the passive avoidance test was performed on day 13 afcer initiation the drug treatment.
  • the apparatus consisted of a lit chamber that can be separated from a dark chamber by a sliding door. At training, a rat is placed in the lit chamber for 30 seconds, then the door is opened. The rat moves to the dark chamber after a short delay - the latency, that is recorded.
  • a Grass S-88 stimulator Upon entry into the dark chamber, the door is shut closed and a 0.3-mA footshock is delivered for 3 seconds by a Grass S-88 stimulator. Retention of the experience is determined after 48 hours by repeating the test and recording the latency to an arbitrary maximum of 300 seconds. Longer latencies are ascribed to retention of memory and improved cognition.
  • Results are latency of response expressed in seconds as Mean ⁇ SEM.
  • n 11-13 rats in a group.
  • the apparatus used consists of a circular water tank 160cm in diameter filled with water to a depth of 38cm.
  • the water was made cloudy by the addition of milk powder.
  • a clear Plexiglass 15cm platform, supported by a movable stand rest on the bottom of the tank was submerged to a depth of 2cm from the water surface.
  • Normally a swimming rat cannot perceive the location of the platform but it may recall it from a previous experience and training, unless it suffers from some memory impairment .
  • the time taken to locate the platform is measured in seconds and referred to as the latency.
  • all orientational cues such as ceiling lights etc. remained unchanged. Longer latencies are observed with rats with some impairment to their memory.
  • each rat was given two trails a day for four days, entering the pool from the same point of entry each day. The position of the platform was changed daily to one of four predetermined positions. Each rat was tested twice each day over the four days, referred to as runs 1 and 2 on sessions I-IV. Initially the rat was placed on the platform for 60 seconds. It was then removed and placed at the point of entry and allowed a maximum of 120 seconds to locate the platform (run 1) . The second run for that day followed 60 seconds later (run 2) . In the second run the rat is expected to find the platform much sooner, having benefitted from its earlier experience.
  • Performance is assumed to represent the rate of acquisition from the more recent experience, hence this is termed working memory.
  • the average latency of run 1 in four sessions on four different days was then related to the corresponding parameter of run 2.
  • R-AI can correct a syndrome of cognitive dysfunction and loss of memory which are prevalent in dementia's such as senile dementia, Parkinson-type dementia and dementia of the Alzheimer's type.
  • NSS Neurological Severity Status
  • RAI 1-R-aminoindan
  • Experiment 4B The method of Experiment 1A was repeated with RAI and 1-S-aminoindan (SAI) being administered at a 0. lmg/kg dosage once a day for a period of 14 days . NSS assessment was performed at 1 hour, 24 hours, 7 days and 14 days. The results are shown in Table 10 below from which it can be seen that aminoindans have an improved effect on post trauma motor function when administered over a prolonged period and that RAI can restore almost complete motor function to a traumatized rat.
  • SAI 1-S-aminoindan
  • Experiment 4E In order to obtain an idea as to the effective "therapeutic window" during which RAI can be given and still be effective, Experiment 4A was repeated giving RAI at lmg/kg 1, 2 or 3 hours post induction of head trauma. As shown in Table 13 below RAI was still effective even if given 3 hours after the induction of head trauma.
  • the standard electrically induced test model is the Maximal electroshock (MES) model. This model is used to show efficacy for antiepileptic agents against generalized and partial seizures.
  • the standard model for chemically induced seizures is the subcutaneous pentylenetetrazol (s.c.Met) seizure threshold test model. This model is used to show efficacy for agents against absence seizures.
  • convulsions were administration in rats after oral (p.o.) administration, and/or in mice after intraperitoneal (i.p.) administration of the compound. Both the MES and s.c.Met models are described in E.A. Swinyard et al . , in "-Antiepileptic Drugs" E.R.H. Levy et al . , Raven Press, New York (1985) . The methods described therein were followed in the present examples.
  • results of the MES model are shown in Table 15 and where relevant the results of scMet in Table 16. All results in the Tables are in mg/kg. Compounds are deemed to be within the scope of the invention if they displayed an ED50 of less than 200mg/kg in at least one of the models.
  • the racemic and individual enantiomers of l-aminoindan showed activity in the MES model, indicating an activity in generalized and partial seizures. Surprisingly, there were significant differences between the activities of the (R) and (S) enantiomers.
  • the racemic compound A had an median effective dose of 36mg/kg
  • the (R) enantiomer B had an ED50 of 184.
  • the ED50 of the (S) enantiomer C was 17. This difference was also observed in mice.
  • the (R) isomer had an ED50 of 80
  • the (S) isomer had an ED50 of 18.
  • Compound 19 (S) -N-acetylaminoindan) had an ED50 of 24 in MES test in rats, and 40 in mice. These compounds also showed activity in the s.c Met model in mice, which is representative of absence seizures. Compound 18 had an ED50 of 66, whereas Compound 19 had an ED50 of 86.
  • Fluorinated analogs of l-aminoindan also had activity in the MES test. "I” has approximately the same efficacy. J had a better efficacy profile. The ED50 was less than 50 in rats, 3 times more efficacious than that observed for B. K also showed activity in the MES model in mice. Compound 5 also showed activity in mice in the MES model. L also showed activity in mice in this model.
  • Hydroxylated analogs of l-aminoindan also show activity in the MES model.
  • Compound 34 (6-hydroxy analog of 1- aminoindan) showed activity in the MES test in mice.
  • amino tetralins also showed activity in the MES mode.
  • M (1-amino tetralin) had an ED50 of less than 50 in rats and less than 100 in mice.
  • Substitution on the 1- amino group with glycinamide also showed activity in mice.
  • Neurotoxicity of the claimed agents was also assessed in mice (i.p. administration) by the rotorod ataxia test and/or in rats (p.o. administration) by positional sense test and gait stance test. See E.A. Swinyard, et al . , in Antiepileptic Drugs," ed. by R.H. Levy, et al . , Raven Press, New York, at 85-200 (1989) .
  • the term quantitating the neurotoxicity is the medial neurological toxic dose (TD50) , was determined in the above tests. The results obtained in mg/kg are shown in the relevant positions of Tables 15 and 16. In some of the species, the TD50 was only determined to be above a certain level, indicating a lower neurotoxicity than specified.
  • the PI is used to show a useful separation between neurotoxicity and antiepileptic activity. The larger the PI, the better the separation between the neurotoxic and efficacious doses.
  • the preferred embodiment of this application is therefore those compounds in which we have already demonstrated a PI > 1 in the MES model of one of the species tested. Where the TD50 is only listed as greater than a particular value, the PI will represent a minimum value, and therefore a better index.
  • the racemic l-aminoindan analog A and the individual enantiomers B and C had PI values in rats of >4.7, 2.7 and >29.4, respectively.
  • the PI values of the N-acetyl analogs Compound 17 and Compound 16 was > 20.8, and > 35.7 respectively.
  • the PI values of the N-glycinamide analogs Compound 1 and Compound 2 is > 1, and > 23.
  • hypobaric hypoxic model is a well accepted model for assessing the activity of compounds believed to possess neuroprotective activity.
  • the model is based on that described in Nakanishi M et al . Life Sci. (1973) ,13., 467, Oshiro et al . , J. Med. Chem. (1991) 34, 2004-2013 and US Patent 4,788,130.
  • Desiccator B was disconnected and allowed to equilibrate with room air whilst desiccator A was evacuated to a pressure of lOOmmHg.
  • desiccator B was then closed to room air and connected to desiccator A.
  • the pressure inside desiccator B was monitored using a mercury manometer and at the point were the pressure in desiccator B reached 200mmHg (usually within 14 seconds) , the two desiccators were disconnected from the vacuum pump and the pump switched off.
  • the survival time from the moment of induction of hypoxia to the time of cessation of respiration was recorded for each mouse for a maximum of 15 minutes after which time room air was reintroduced to desiccator B. Survivors were monitored for signs of lethargy or vitality.
  • Control groups were run twice, before and after each experimental group and consisted of 12-16 mice in groups of 4 mice. Each experimental group always consisted of 4 mice to ensure a constant residual volume of oxygen in all tests. The effect of each dose of test drug was determined in duplicate i.e. two groups of 4 mice. The range of survival times of control mice was from 108-180 seconds.
  • All drugs were administered intra-peritoneally at the dose indicated one hour prior to exposure to hypoxia.
  • Reference drugs were administered as follows; sodium pentobarbital, 20 or 40 mg/kg given 0.5 hour prior to hypoxia, diazepam, 5 or lOmg/kg given 0.5 hour prior to hypoxia.
  • the cerebellum was aseptically dissociated from 6 or 7-day old rat pups and placed in a 15ml sterile plastic conical tube containing 3ml of Dulbecco's modified Eagle's medium
  • DMEM DMEM with a high glucose concentration (lg/ml) and 2mM
  • Cells were plated at a density of 200/mm 2 on poly-L-lysine coated surfaces.
  • Poly-L-lysine coated glass coverslips were prepared at least one hour in advance of plating by immersing sterile coverslips in sterile distilled water solution containing 15 microgram/ml poly-L-lysine, and washing in sterile water just prior to use.
  • the plated cells were covered with enriched medium and incubated at 37°C in an atmosphere of 5% C0 2 in air and 97% humidity. After three days in culture, the media was replaced with media containing the desired test compound. Each test compound was tested in duplicate. Toxic-dose response was determined for each compound.
  • Control consisting of enriched media alone
  • N-methyl-D-aspartate (NMDA, lmM for 3 hours) as the cytotoxic challenge
  • Test compound plus NMDA
  • Positive control spermine (0.01 micromoles) plus NMDA.
  • Nerve cell survival was evaluated by phase contrast microscopy and tryptan blue staining after 24 hours.
  • test compound or vehicle were injected intra-peritoneally (ip) in a volume of 50 microliters of solvent per lOg body weight.
  • the first injection was given two minutes after clamp removal, and thereafter daily for the next 2 post-operative days (total of 3 injections) .
  • the rat electrical kindling model of epilepsy has been known to show efficacy of antiepileptic agents against complex partial seizures that evolve into generalized motor seizures.
  • rats were electrically stimulated via corneal electrodes twice daily for approximately 5 days and then once daily for an additional 10 days .
  • the seizure criteria as described by R.J. Racine, et al . , Electroenceph. Clin. Neurophysiol . 32: 281- 294 (1972) , were met, the test substance was administered p.o. to rats, and the rat electrically stimulated, and observed for the presence or absence of a seizure.
  • the detailed procedure of this test model can be found in, E.A. Swinyard, et al . , in "Antiepileptic Drugs," ed. by R.H. Levy, et al . , Raven Press, New York, at 85-100 (1989) and Racine, Id.
  • compound 18 prevented seizures with an ED 50 of 24.6 Mg/kg; compound 17 with an ED 50 of ⁇ 75 mg/kg; and compound 19 with an ED 50 of >50 mg/kg.
  • the results are therefore indicative of these compounds having an efficacy against generalized seizures and complex partial seizures which evolve into generalized motor seizures.

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Abstract

L'invention se rapporte à de nouveaux dérivés de 1-aminoindane et à leurs sels. On effectue la préparation de ces dérivés de 1-aminoindane optiquement actif en faisant réagir un analogue de N-benzyle du composé désiré avec un énantiomère d'acide mandélique. On traite la maladie de Parkinson, la démence, l'épilepsie, les convulsions ou les attaques en administrant un composé de la formule (I).
PCT/US1996/000169 1995-01-12 1996-01-16 Derives d'aminoindane optiquement actifs et leur preparation WO1996021640A1 (fr)

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US8784782B2 (en) 2005-02-04 2014-07-22 Senomyx, Inc. Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions
US9072313B2 (en) 2006-04-21 2015-07-07 Senomyx, Inc. Comestible compositions comprising high potency savory flavorants, and processes for producing them
CN105001104A (zh) * 2015-08-26 2015-10-28 吴玲 一种制备s-6-甲氧基-1-氨基茚满的方法
CN105061218A (zh) * 2015-08-13 2015-11-18 陈永军 动态动力学拆分制备(s)-1-氨基茚满
CN105111095A (zh) * 2015-08-26 2015-12-02 吴玲 一种制备s-5,6-二甲氧基-1-氨基茚满的方法
CN105175272A (zh) * 2015-08-31 2015-12-23 吴玲 制备r-5-溴-1-氨基茚满的方法
CN105175273A (zh) * 2015-08-26 2015-12-23 吴玲 制备s-6-羟基-1-氨基茚满的方法
WO2018045464A1 (fr) * 2016-09-08 2018-03-15 University Of Saskatchewan Agents de liaison alpha-synucléine et leurs utilisations
CN108794339A (zh) * 2017-05-03 2018-11-13 上海朴颐化学科技有限公司 一种(1r,2s)-2,6-二甲基-1-胺基茚满的制备方法
CN113045456A (zh) * 2019-12-26 2021-06-29 上海奥博生物医药技术有限公司 一种新的雷沙吉兰杂质化合物及其制备方法和用途

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