Process to prepare 2-aminoindan derivatives

Details Process to prepare 2-aminoindan derivatives Process to prepare 2-aminoindan derivatives

2001-02-14

2002-06-25

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S163000, C564S164000, C514S619000

Reexamination Certificate

active

06410787

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to (2S)-enantiomers of 2-aminoindan derivatives and a novel process for the preparation of them.
BACKGROUND OF THE INVENTION
Schizophrenia is a common and devastating mental disorder which is currently an unmet medical need. It is characterized by so-called positive (hallucinations, delusions) and negative (blunted affect, poverty of speech, social & emotional withdrawal) symptoms, as well as cognitive deficits (working memory impairment). About 1% of the world population is affected, men and women equally, with typical onset between ages 15 and 25. Antagonists of the neurotransmitter dopamine are known to block psychosis. The present invention provides compounds of formula I (wherein each R is independently C
1-8
alkyl), a highly selective D
3
receptor antagonist, for the treatment of Schizophrenia and other CNS diseases.
Racemic forms of formula I and their preparations have been disclosed in PCT publication WO 97/45403. The present invention has discovered that the (2S)-enantiomer of formula I is the form that possesses the superior desirable bioactivity. The present invention also provides a process for the synthesis, in a large scale, of said (2S)-enantiomer in a highly enantiomerically enriched form, which solved an extremely challenging problem of a long period of time.
INFORMATION DISCLOSURE
PCT International Publication No. WO 97/45403 discloses aryl substituted cyclic amines as selective dopamine D3 ligands.
U.S. Pat. No. 5,708,018 discloses 2-aminoindans as selective dopamine D3 ligands.
SUMMARY OF THE INVENTION
The present invention provides compounds of formula I:
or a pharmaceutically acceptable salt thereof wherein each R is independently C
1-8
alkyl.
More preferably, a compound of formula I of the present invention is (2S)-(+)-2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention also provides:
a process for the preparation of (2S)-enantiomers of formulas I in a highly enantiomerically enriched form;
novel intermediates in a highly enantiomerically enriched form useful for preparing compounds of formula I;
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (the composition preferably comprises a therapeutically effective amount of the compound or salt),
a method for treating a disease or condition in a mammal wherein a D
3
receptor is implicated and modulation of a D
3
receptor function is desired comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal;
a method for treating or preventing anxiety, obesity, depression, schizophrenia, a stress related disease (e.g. general anxiety disorder), panic disorder, sleep disorders, a phobia, mania, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the gastrointestinal or cardiovascular system, or sexual dysfunction in a mammal comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal;
a method for treating or preventing ADHD (attention deficit hyperactivity disorder), migraine, substance abuse (including smoking cessation), cognitive deficits, memory impairment, alzheimer's disease, movement disorders including choreatic movements in huntington's disease or motor complications such as dystonias and dyskinesias in Parkinson's disease, extrapyramidal side effects related to the use of neuroleptics, and “Tics” including Tourette's syndrome in a mammal comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described.
The term alkyl refer to both straight and branched groups, but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C
i-j
indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, C
1-8
alkyl refers to alkyl of one to eight carbon atoms, inclusive.
Mammal refers to human or animals.
Pharmaceutically acceptable salts refer to organic acid addition salts such as tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, &agr;-ketoglutarate, &agr;-glycerophosphate, or suitable inorganic salts including hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, and carbonate salts, etc.
The term “chiral salt” refers to a salt containing a chiral acid. The term “chiral acids” refers to the acids having one or more chiral centers. Examples of chiral acids are tartaric acid, di-benzoyltartaric acid, di-para-toluoyltartaric acid, camphorsulfonic acid, and mandelic acid. The preferred chiral acid is mandelic acid.
All temperatures are in degrees Centigrade.
[&agr;]
D
25 refers to the angle of rotation of plane polarized light (specific optical rotation) at 25° C. with the sodium D line (589 A).
The compounds of formula I are active orally or parenterally. Orally the formula I compounds can be given in solid dosage forms such as tablets or capsules, or can be given in liquid dosage forms such as elixirs, syrups or suspensions as is known to those skilled in the art. It is preferred that the formula I compounds be given in solid dosage form and that it be a tablet.
Typically, the compounds of formula I can be given in the amount of about 0.5 mg to about 250 mg/person, one to three times a day. Preferably, about 5 to about 50 mg/day in divided doses.
The exact dosage and frequency of administration depends on the particular compound of formula I used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the active compound in the patient's blood and/or the patient's response to the particular condition being treated.
Thus, the subject compounds, along with a pharmaceutically-acceptable carrier, diluent or buffer, can be administrated in a therapeutic or pharmacological amount effective to alleviate the central nervous system disorder with respect to the physiological condition diagnosed. The compounds can be administered intravenously, intramuscularly, topically, transdermally such as by skin patches, buccally or orally to man or other vertebrates.
The compositions of the present invention can be presented for administration to humans and other vertebrates in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, oil in water and water in oil emulsions containing suitable quantities of the compound, suppositories and in fluid suspensions or solutions.
For oral administration, either solid or fluid unit dosage forms can be prepared. For preparing solid compositions such as tablets, the compound can be mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar pharmaceutical diluent or carrier materials. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsula

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