WO2003072055A2

WO2003072055A2 - Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective mao inhibitors

Info

Publication number: WO2003072055A2
Application number: PCT/US2003/005871
Authority: WO
Inventors: Eran Blaugrund; Yaacov Herzig; Jeffrey Sterling
Original assignee: Teva Pharmaceutical Industries, Ltd.; Teva Pharmaceuticals, Inc.
Priority date: 2002-02-27
Filing date: 2003-02-27
Publication date: 2003-09-04
Also published as: EP1490324A4; AU2003219913A8; WO2003072055A3; JP2005523289A; AU2003219913A1; EP1490324A2; CA2477218A1

Abstract

The subject invention provides derivatives of propargylamino indan (PAI) and propargylamino tetralin that selectively inhibit monoamine oxidase (MAO) in the brain, having the structure:, wherein R1 is OC (O) R9 and R2 is H, wherein R9 i s branched or unbranched C1 to C6 alkyl, aryl, or aralkyl, or R1 is OC (O) R4 and R2 is OC (O) R4, wherein R4 is branched or unbranched C1 to C6 alkyl, aryl, aralkyl or NR5R6, wherein R5 and R6 are each independently H, C1 to C8 alkyl, C6 to C12 aryl, C6 to C12 aralkyl or C6 to C12 cycloalkyl, each optionally substituted; wherein R3 is H or C1 to C6 alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof. Additionally, the subject invention provides methods of treating neurological disorders using these compounds, uses of these compounds for the manufacture of medicaments for treating neurological disorders and processes for synthesis of these compounds.

Description

PROPARGYLAMINO INDAN DERIVATIVES AND PROPARGYLAMINO TETRALIN DERIVATIVES AS BRAIN-SELECTIVE MAO INHIBITORS

This application claims the benefit of U.S. Serial No. 10/085,674, filed February 27, 2002, the contents of which are hereby incorporated by reference .

Throughout this application, various references are referenced by short citations within parenthesis. Full citations for these references may be found at the end of the specification, immediately preceding the claims. These references, in their entireties, are hereby incorporated by reference to more fully describe the state of the art to which this invention pertains.

Field of the Invention

The subject of this invention provides for derivatives of propargylaminoindans and propargylaminotetralins that are irreversible inhibitors of the enzyme monoamine oxidase A and/or B and also for prodrugs for the administration of these compounds . Such compounds may be useful in the treatment of Parkinson's disease, Alzheimer's disease, depression and other neurological disorders.

Background of the Invention

The enzyme monoamine oxidase (MAO) plays an essential role in the metabolic degradation of important amine neurotransmitters including dopamine, serotonin and noradrenaline . Thus, agents that inhibit MAO are of potential therapeutic benefit for a variety of neurological disease indications, including Parkinson's disease, Alzheimer's disease, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , etc. (Szelnyi, I.; Bentue-Ferrer et al . ; Loscher et al . ; White et al . ; U.S. Patent No. 5,744,500) . Other diseases and conditions which have been associated with toxic levels of monoamine oxidase-B are memory disorders (The interaction of L-deprenyl and scopolamine on spatial learning/memory in rats) , panic, post-traumatic stress disorder (PTSD) , sexual dysfunction, attention deficit and hyperactivity syndrome (ADHD) (Potential applications for monoamine oxidase B inhibitors) , attention deficit disorder (Kleywegt) , and Tourette'ε syndrome (Treatment of Tourette's: Overview) .

Many inhibitors of MAO are chiral molecules (U.S. Patent No. 5,744,500) . Although one enantiomer often shows some stereoselectivity in relative potency towards MAO-A and -B, a given enantiomeric configuration is not always more selective than its isomer in discriminating between MAO-A and -B (Hazelhoff et al . , Naunyn-Schmeideberg' s Arch. Pharmacol.).

MAO inhibitors can also be classified as reversible inhibitors which inhibit the enzyme by a competitive mechanism or as irreversible inhibitors which are generally mechanism based (suicide inhibitors) (Dostert) . For example, moclobemide is a reversible MAO-A- specific inhibitor (Fitton et al . ) developed as an anti-depreεsant . Likewise, rasagiline (U.S. Patent No. 5,744,500) and selegiline. (Chrisp et al . ) are MAO-B-selective irreversible inhibitors.

Irreversible inhibitors have the advantage of lower, less frequent dosing since their MAO inhibition is not based directly on the drugs' pharmacokinetic behavior, but rather on the de novo regeneration of the MAO enzyme.

MAO also plays an essential role in the oxidative deamination of biogenic and food-derived amines, both in the central nervous system and in peripheral tissues. MAO is found in two functional isoenzyme forms, MAO-A and MAO-B, each of which shows preferential affinity for substrates and specificity toward inhibitors. Thus, MAO-A preferentially oxidizes serotonin, noradrenaline and adrenaline, whereas MAO-B preferentially metabolizes phenylethylamine . Dopamine is a substrate for both forms of the enzyme (Szelenyi , I.).

N-Propargyl- (IR) -aminoindan is known to be a potent B-selective inhibitor of MAO (U.S. Patent No. 5,457,133). Various derivatives of this compound have been prepared and shown to have varying degrees of potency and selectivity for the inhibition of MAO-A and/or -B. There is no currently accepted theory explaining the effect of structure on the activity (SAR) of the various substituted propargylaminoindans .

The dopamine agonistic activity and MAO inhibitory properties of 7- (methyl-prop-2-ynylamino) -tetralin-2-ol and 7- (methyl-prop-2- ynylamino) -tetralin-2 , 3-diol have been reported (Hazelhoff et

• al . , Eur . J. Pharmacol.) . The details of the synthesis of these compounds have not been published, however.

6, 7-di-0-benzoyl-2-aminotetralin has been reported as a prodrug of the dopaminergic agonist 6, 7-di-hydroxy-2-aminotetralin (Horn et al.) . However, no N-propargyl derivatives were reported and the compounds were not shown to have MAO inhibitory or neuroprotective activities.

7- (propyl-prop-2-ynylamino) -tetralin-2-ol has been reported as an intermediate in the preparation _. of 7- [ (3-iodoallyl) - propylamino] -tetralin-2-ol . Only the latter has been pharmacologically characterized as D₃-dopamine receptor ligand' (Chumpradit et al . ) . No other N-alkyl substituents were described.

Florvall et al . report the preparation of amino acid-based prodrugs of amiflamine analogues. Amiflamine is a reversible MAO-A inhibitor. PCT International Application No. PCT/US97/24155 concerns carbamate aminoindan derivatives, including propargylamines, as inhibitors of MAO-A and MAO-B for the treatment of Alzheimer's disease and other neurological conditions. However, the compounds of PCT/US97/24155 are not selective for MAO over acetylcholinesterase ("AChE"). Thus, the compounds generally inhibit acetylcholinesterase along with MAO. Acetylcholinesterase inhibition is a route implicated in certain neurological disorders, but is a different route from the route of MAO inhibition.

U.S. Patent No. 6,303,650 discloses derivatives of 1-aminoindan as selective MAO B inhibitors that additionally inhibit acetylcholinesterase. The reference teaches that its compounds can be used to treat depression, Attention Deficit Disorder (ADC) , Attention Deficit and Hyperactivity Disorder (ADHD) , Tourette's Syndrome, Alzheimer's Disease and other dementias such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.

Many irreversible MAO inhibitors contain the propargyl amine functionality. This pharmacophore is responsible for the MAO inhibitory activity of such compounds. Some propargylamines have been shown to have neuroprotective/neurorescue properties independent of their MAO inhibition activity (U.S. Patent No. 4,844,033; Krageten et al . ) .

PCT International Application No. PCT/IL96/00115 relates to pharmaceutical compositions comprising racemic, (S) , and (R)-N- propargyl-1-aminoindan. (R) -N-propargyl-1-aminoindan selectively inhibits MAO-B in the treatment of Parkinson's disease and other neurological disorders (PCT/IL96/00115) .

Derivatives of 1-aminoindan, including propargyl aminoindan, and their salts are described in many U.S. patents (U.S. Patents No. 5,639,913, 5,877,221, 5,880,159, 5,877,218, 5,914,349, 5,994,408) and a PCT International Application (PCT/US95/00245) . These references disclose racemic, R and S enantiomers, of 1- aminoindan derivatives for the treatment of Parkinson's disease and other neurological conditions (U.S. Patents No. 5,639,913, 5,877,221, 5,880,159, 5,877,218, 5,914,349,^' 5,994,408, PCT/US95/00245) .

PCT International Application No. PCT/US97 /24155 concerns aminoindan derivatives, including propargyl aminoindan, as inhibitors of MAO-A and MAO-B for the treatment of Parkinson's disease and other neurological conditions. The publication reveals that the disclosed compounds exhibit a greater selectivity for MAO-A and MAO-B in the brain than in the liver or intestine.

U.S. Patent No. 6,316,504 discloses that the R(+) enantiomer of N-propargyl-1-aminoindan is a selective irreversible inhibitor of MAO-B. The patent indicates that (R) - N-propargyl-1-aminoindan is useful for the treatment of Parkinson's disease, a memory disorder, dementia, depression, hyperactive syndrome, an affective illness, a neurodegenerative disease, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, neurotrauma, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.

European Patent No. 436492 discloses the R enantiomer of N- propargyl-1-aminoindan as a selective irreversible inhibitor of MAO-B in the treatment of Parkinson's disease and other neurological conditions. Numerous U.S. patents also relate to the MAO B inhibition of (R) -N-propargyl-1-aminoindan and its use for treating patients suffering from Parkinson's Disease and other neurological disorders (U.S. Patents No. 5,387,612, 5,453,446, 5,457,133, 5,519,061, 5,532,415, 5,576,353, 5 , 668 , 181 , 5 , 744 , 500 , 5 , 786 , 390 and 5 , 891 , 923 ) .

PCT International Application No . PCT/IL.97/00205 disclpses S- (-) -N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder of neurotrauma or for improving memory. The compounds were found to be neuroprotective, but not inhibitory of MAO-A or MAO-B (PCT/IL97/00205) .

U.S. Patent No. 5,486,541 provides N-propargyl-1-amonoindan onofluorinated in the phenyl ring as selective inhibitors. of MAO-B. These compounds are presented as useful in the treatment of Parkinson's disease, memory disorders, dementia of the Alzheimer's type, depression and the hyperactive syndrome in children.

Among the many derivatives of propargyla inoindan mentioned in the prior art are hydroxy-propargylaminoindans . U.S. Patent No. 3,513,244 lists some racemic N-propargylamino indanols and tetralinolε for use as antihypertenεiveε . These compounds are not exemplified chemically and are not pharmacologically characterized (U.S. ^' Patent No. 3,513,244).

N-propargylamino indanol also appears in E.P. 267024 as a hydrofluorene derivative, i.e., 3-amino-4-indanol (7-OH fluorene) . The hydrofluorene derivatives and salts in E.P. 267024 are employed as cerebral activators in the treatment of anoxe ia and hypoxemia. In addition, such derivatives help prevent arrhythmia and heart failure caused by lack of oxygen (E.P. 267024). The derivatives also act as antioxidants and cholinergic nerve system activating agents (E.P. 267024). Smπmary of the Invention

The subject invention provides a compound having the structure:

wherein R₃ is OC(0)R₉ and R₂ is H, wherein R₉ is branched or unbranched C₁ to C₆ alkyl, aryl, or aralkyl, or R is OC(0)R₄ and R₂ is OC(0)R₄, wherein R₄ is branched or unbranched C₁ to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_α to C_B alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C₁ to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.

The subject invention also provides a compound having the structure:

wherein R_x is OH; wherein R₂ is H or OC(0)R₄ when R₂ is attached to the "a" carbon or the "d" carbon, or

R₂ is OC(0)R₄ when R_x is attached to the "b" carbon or the "c" carbon; wherein R₄ is C_a to C₆ branched or unbranched alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_α to C_B alkyl, C₆ to C₁₂ aryl, C₆ to C_i2 aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein n is 0 or 1, and m is 1 or 2 ; and wherein R₃ is H or Me when n is 1 and m is 1, or R₃ is H or C_x to C₆ alkyl when n is 0 or m is 2, or a pharmaceutically acceptable salt thereof.

In addition, the subject invention provides a compound having the structure:

wherein the compound is an optically pure enantiomer; wherein R_α is OH; wherein R₂ is H; wherein R₃ is H or C_τ to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.

The subject invention further provides a compound having the structure:

wherein R-, is H, C₂ to C₆ alkyl, aryl, aralkyl or C(0)R₄, wherein R₄ is branched or unbranched C_x to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C₂ to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C_x to C₆ alkyl; wherein R₈ is H or t-butoxycarbonyl (Boc) . The subject invention also provides a method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure:

wherein R_α is- OH or OC(0)R₉, and wherein R₉ is branched or unbranched C_α to C₆ alkyl, aryl, or aralkyl;

R₂ is H or OC(0)R₄, or both R_a and R₂ are OC(0)R₄, wherein R₄ is branched or unbranched C_a to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈' alkyl, C₅ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C_x to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological diεease in the subject.

Furthermore, the subject invention provides a method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure:

wherein Rj is OH or OC(0)R,; wherein R₂ is H or OC(0)R₄,

•wherein R₄ is branched or unbranched C_x to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to' C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C₂ to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological disease in the subject.

Th e subj ect invention additionally provides a process for preparing a compound having the structure :

wherein n is 0 or 1, and ra is 1 or 2 ; wherein R₃ iε H or C_α to C₆ alkyl; and wherein R_s is branched or unbranched C_y to C₆ alkyl, .aryl, or aralkyl; comprising the step of reacting

or

R, with

in the presence of -an acid or 4-dimethylaminopyridine (DMAP) to form the compound. T U 03/05871

-13- The subject invention also provides a process for preparing a compound having the structure:

wherein R₄ is branched or unbranched C_Ύ to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_α to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; which process comprises:

03 05871

^■14-

[a) reacting a compound having the structure:

with AlCl₃ or BBr₃ in the presence of toluene to produce a compound having the structure:

(b) reacting the product formed in εtep (a) with benzyl chloride and K₂C0₃ in the presence of dimethyl formamide (DMF) to produce a compound having the structure: .

(c) reacting the product formed in step (b) with MeNH₂ΗCl, NaCNBH₃ in tetrahydrofuran (THF) /MeOH to produce a compound having the structure:

(d) reacting the product formed in step (c) with H₂, Pd/C and MeOH to produce a compound having the structure:

(e) reacting the product formed in step (d) with Boc₂0, dioxane/H₂0 and NaHC0₃ to produce a compound having the structure:

(f) reacting the product formed in step (e) with R₄C0C1, Et₃N in CH₂C1₂ in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:

boc

(g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the structure:

(h) reacting the product formed in step (g) with propargyl bromide, K₂C0₃ in CH₃CN and then with HCl/ether and MeOH to produce a compound having the structure:

The subject invention also provides the use of a compound or a prodrug of a compound which becomeε the compound having the structure:

wherein R_α is OH or OC(0)R₄; 'wherein R₂ iε H, OH or OC(0)R₄, wherein R₄ iε branched or unbranched C₁ to C₆ alkyl, aryl, aralkyl . or NR₅R₆, wherein R₅ and R₆ are each independently H, Ci to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C_α to C₆ alkyl; wherein n iε 0 or 1 ; and wherein m iε 1. or 2, or a pharmaceutically acceptable εalt thereof, for the manufacture of a medicament for treating a subject afflicted with a neurological diseaεe, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.

Additionally, the subject invention provides the use of a compound or a prodrug of a compound which becomes the compound having the structure:

wherein R_α is OH or 0C(0)R₉, and wherein R₉ is branched or unbranched C_λ to C₆ alkyl, aryl, or aralkyl; R₂ is H or OC(0)R₄, or both R₂ and R₂ are OC(0)R₄, wherein R₄ is C_a to C₅ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, Ci to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to • C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C_α to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable εalt thereof, for the manufacture of a medicament for treating neurological disease in a subject, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose. Description of the Drawings

Figure 1 presents routes for the manufacture of compounds with the following structures:

and

Figure 2 displays routes for the manufacture of a compound with the following structure:

In Figure 2, the letterε a) - i) are used to designate the following: a) A1C1₃, toluene; b) BnCl, K₂C0₃, DMF; c) R₃-NH₂, HCl, NaCNBH₃, THF/MeOH; d) H₂₍ Pd/C, MeOH; e) Boc₂0, dioxane/H₂0, NaHC0₃; f) R₄-COCl, Et₃N, DMAP, CH₂Cl₂; g) HCl/dioxane; h) propargyl bromide, K₂C0₃, CH₃CN; and i) HCl/ether, MeOH.

Figure 3 depicts routes for the manufacture of compounds with the structures:

and

In Figure 3, the letters g) - 1) are uεed to designate the following: g) NaCNBH₃, NH₄0Ac; h) propargyl bromide, ACN, K₂C0₃; i) NaCNBH₃, paraformaldehyde; j) N-methylpropargylamine, NaCNBH₃; k) BBr₃; and 1) R₄COCl, TFA or DMAP.

03 05871

-23-

Detailed Description of the Invention

The subject invention provides a compound having the structure:

wherein R_x is 0C(0)R₉ and R₂ is H, wherein R₉ is branched or unbranched Cj to C₆ alkyl, aryl, or aralkyl, or R-i is OC(0)R₄ and R₂ is 0C(0)R₄, wherein R₄ iε branched or unbranched C_x to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R_E and R₆ are each independently H, C_: to C_B alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C₁ to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2 , or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutically acceptable salt is the acetate salt, mesylate εalt, esylate, tartarate salt, hydrogen tartarate salt, benzoate εalt, phenylbutyrate salt, phosphate εalt, citrate salt, ascorbate εalt, mandelate εalt, adipate εalt, octanoate salt, the myristate εalt, the succinate salt, or fumarate εalt. In another embodiment, the compound has the structure:

In a further embodiment, the compound has the structure:

In yet another embodiment, the compound has the structure:

In one embodiment, n iε 1 In a further embodiment, the compound has the structure:

In an added embodiment, n is 0.

In yet another embodiment, the compound has the structure:

In still another embodiment, the compound has the structure:

In one embodiment, R₉ is Me and R₃ is H.

In another embodiment, R₉ is tBu and R₃ iε H.

In a further embodiment, R_g is nBu and R₃ iε H.

In yet another embodiment, R₉ is CHPh and R₃ is H.

In an additional embodiment, R₉ is Ph and R₃ is H. In still another embodiment, wherein R₉ is Me and R₃ is Me. .

In a further embodiment, R₉ iε nBu and R₃ is Me.

In one embodiment, R₉ is Ph and R₃ is Me.

In an added embodiment, R₉ is tBu and R₃ is Me.

In another embodiment, R₉ iε Ph(Me) and R₃ iε Me. In still another embodiment, R₉ lε Ph(OMe)₂ and R₃ is Me.

In a further embodiment, R₀ iε Ph(OMe)₂ and R₃ is H.

In one embodiment, the compound has the structure:

In an additional embodiment, R₃ is Me and R₉ is Me.

In a further embodiment, R₃ iε Me and R₉ iε Ph In another embodiment, R₃ is Me and R₉ iε Ph(OMe)₂.

In yet another embodiment, the compound haε the structure:

In an added embodiment, R₃ is Me and R₉ is Me.

In still another embodiment, R₃ is H and R₉ is Ph.

In one embodiment _r R₃ iε H and R₉ is Ph(OMe)₂. 5871

-28-

In another embodiment, the compound has the structure:

In a further embodiment, n iε 0

In yet another embodiment, R₄ is Ph and R₃ is Me.

In one embodiment, n iε 1

In still another embodiment, R₃ is Me.

In an added embodiment, the compound has the structure:

The subject invention also provides a compound having the structure:

wherein R_a iε OH; wherein R₂ iε H or OC(0)R₄ when R_x iε attached to the "a" carbon or the "d" carbon, or

R₂ iε OC(0)R₄ when R_a iε attached to the "b" carbon or the ^vc" carbon; wherein R₄ iε C_x to C₆ branched or unbranched alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R_e are each independently H, Ci to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein n is 0 or 1, and m iε 1 or 2; and wherein R₃ is H or Me when n iε 1 and m is 1, or R₃ is H or Ci to C₆ alkyl when n iε 0 or m is 2, or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutically acceptable salt is the acetate salt, mesylate salt, esylate, tartarate εalt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate salt, ascorbate salt, mandelate salt, adipate salt, octanoate salt, the myristate salt, the εuccinate salt, or fumarate salt. In another embodiment, the compound has the structure:

In an additional embodiment, R₃ is H.

In a ' further embodiment, R₃ is Me,

In yet another embodiment, the compound haε the structure:

In still another embodiment, R₃ is H.

In one embodiment, R₃ iε Me

In a further embodiment, n iε 0 Additionally, the subject invention provides a compound having the structure:

wherein the compound is an optically pure enantiomer; wherein R₂ is OH; wherein R₂ is H; wherein R₃ iε H or C₃ to C₆ alkyl; wherein n is 0 or 1 ; and wherein m iε 1 or 2 , or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutically acceptable salt is the acetate salt, mesylate εalt, esylate, tartarate salt, hydrogen tartarate εalt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate εalt, aεcorbate salt, mandelate εalt, adipate salt, octanoate salt, the myristate salt, the succinate salt, or fumarate salt.

In a further embodiment, the compound has the structure:

In another embodiment, the compound haε the structure:

In an added embodiment, R₃ is H.

In yet another embodiment, R₃ is Me.

In a further embodiment, the compound haε the structure

In one embodiment, R₃ iε H.

In another embodiment, R₃ is Me

The εubject invention further provides a compound having the structure:

wherein R₇ is H, C_α to C₆ alkyl, aryl, aralkyl or C(0)R₄, wherein R₄ iε branched or unbranched C to C₆ alkyl, aryl, aralkyl or NR_£R₆, wherein R₅ and R_f are each independently H, C_: to C_e alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally subεtituted; wherein R₃ is H or C₁ to C₆ alkyl; wherein R₈ iε H or t-butoxycarbonyl (Boc) .

In one embodiment , the compound has the structure:

In another embodiment, the compound haε the εtructure:

In still another embodiment, the compound has the structure;

In an added embodiment, the compound has the structure:

In yet another embodiment, R₄ iε Ph.

In one embodiment, the compound haε the structure:

In a further embodiment, R₄ is Ph.

The subject invention additionally provides a pharmaceutical composition comprising a compound having the structure:

wherein R_x is OC(0)R₉ and R₂ iε H, wherein R₉ is branched or unbranched Ci to C₆ alkyl, aryl, or aralkyl, or R_: iε OC(0)R₄ and R₂ iε OC(0)R₄, wherein R₄ iε branched or unbranched C_r to C₅ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C₂ to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ iε H or C_α to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2 , or a pharmaceutically acceptable εalt thereof.

The εubject invention further provides a pharmaceutical compoεition compriεing a compound having the εtructure:

wherein Rj iε OH; wherein R₂ iε H or 0C(0)R₄ when _α iε attached to the "a" carbon or the "d" carbon, or

R₂ is 0C(0)R₄ when R_x iε attached to the "b" carbon or the "c" carbon; wherein R₄ is C₁ to C₆ branched or unbranched alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_α to C₈ alkyl, C_e to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein n iε 0 or 1, and iε 1 or 2; and wherein Rj is H or Me when n iε 1 and m is 1, or R₃ is H or C₁ to C₆ alkyl when n is 0 or m iε 2, or a pharmaceutically • acceptable εalt thereof.

The subject invention alεo provides a pharmaceutical composition comprising a compound having the εtructure:

wherein the compound is an optically pure enantiomer; wherein R_α is OH; wherein R₂ iε H; wherein R₃ iε H or C to C₆ alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable εalt thereof.

The εubject invention alεo provides a method of treating a subject afflicted with a neurological disease comprising administering to the εubject a compound having the structure:

wherein R_λ is OH or OC(0)R₄; wherein R₂ is H, OH or 0C(0)R₄, wherein R₄ is branched or unbranched C_α to C₆. alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ iε H or C_α to C₆ alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomeε the compound in the εubject, εo as to thereby treat the neurological diεeaεe in the subject.

Additionally, the subject invention provides a method of treating a subject afflicted with a neurological disease comprising administering to the εubject a compound having the structure :

wherein R_α is OH or OC(0)R₉, and R₂ iε H or 0C(0)R₄, or both R-_L and R₂ are 0C(0)R₄, wherein R₉ is branched or unbranched C₂ to C₆ alkyl, aryl, or aralkyl; wherein R₄ iε branched or unbranched C_λ to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈ alkyl, C₆ to C_l2 aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ iε H or C_α to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable εalt thereof, or a prodrug which becomeε the compound in the subject, εo as to thereby treat the neurological disease in the subject.

In one embodiment of the method, the compound has the εtructure:

wherein ₂ iε 0C(0)R₉ and R₂ iε H, wherein R_s iε branched or unbranched Cx to C₆ alkyl,^' aryl, or aralkyl, or R_x is OC(0)R₄ and R₂ iε OC(0)R₄, wherein R₄ iε branched or unbranched C_α to C₆ alkyl, aryl, aralkyl or NR₅R₆,

. wherein R₅ and R₆ are each independently H, Cj to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally subεtituted; wherein R₃ is H or Cj to C₆ alkyl; wherein n is 0 or 1; and wherein m iε 1 or 2.

In another embodiment of the method, the compound haε the structure :

wherein R_τ is OH; wherein R₂ is H or OC(0)R₄ when R_λ is attached to the "a" carbon or the "d" carbon, or

R₂ is 0C(0)R₄ when R iε attached to the "b" carbon or the "c" carbon; wherein R₄ is C_a to C₆ branched or unbranched alkyl, ■ aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C-_. to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally εubεtituted; wherein R₃ iε H or C_α to C₆ alkyl; wherein n is 0 or 1; and wherein m iε 1 or 2.

In a further embodiment of the method, the compound has the structure:

wherein the compound iε an optically pure enantiomer; wherein _x iε OH; wherein R₂ iε H; wherein R₃ is H or C₁ to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2. 03 05871

-41-

In one embodiment, the εubject iε human.

In a further embodiment, the adminiεtration comprises oral, parenteral, intravenous, tranεdermal, or rectal adminiεtration.

In one embodiment, the effective amount iε from about 0.01 mg per day to about 100.0 mg per day.

In yet another embodiment, the effective amount iε from about 0.01 mg per day to about 50.0 mg per day.

In still another embodiment, the effective amount is from about 0.1 mg per day to about 100.0 mg per day.

In an added embodiment, the effective amount is from about 0.1 mg per day to about 10.0 mg per day.

In yet another embodiment, the effective amount is from about 0.01 mg to about 100.0 mg .

In one embodiment, the effective amount is from about 0.01 mg to about 50.0 mg .

In a further embodiment, the effective amount is from about 0.1 mg to about 100.0 mg.

In another embodiment, the effective amount is from about 0.1 mg to about 10.0 mg .

In an additional embodiment, the neurological disease is Parkinson's disease, Alzheimer's disease, depreεsion, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , memory disorderε, panic, poεt-traumatic εtreεs disorder (PTSD), εexual dyεfunction, attention deficit and hyperactivity syndrome (ADHD), attention deficit diεorder, or Tourette's syndrome. The diεease may also be neuropathy, hyperactive syndrome, neurotrauma, stroke, Parkinson' ε diεease, Huntington'ε diεease, and other dementia such as senile dementia, dementia .of the vascular dementia or Lewy body dementia.

In still another embodiment, the neurological disease iε depression.

In still another embodiment, the compound has the structure:

5871

-43-

The subject invention further provides a proceεs for preparing a compound having the εtructure:

wherein n iε 0 or 1, and m is 1 or 2 ; wherein R₃ is H or C_α to C_ε alkyl; and wherein R₉ is branched or unbranched C_x to C₆ alkyl, aryl , or aralkyl ; comprising the step of reacting

or

with

in the presence of an acid or 4-dimethylaminopyridine (DMAP) to form the compound. 5871

-44- The εubject invention alεo provideε a process for preparing a compound having the εtructure:

wherein R₉ is branched or unbranched Cj_, to C₆ alkyl, aryl, or aralkyl ; which process comprises:

(a) reacting a compound having the structure:

with a compound having the εtructure:

wherein X iε a leaving group, to produce a compound having the εtructure:

(b) reacting the compound formed in εtep (a) with a compound having the εtructure:

in the preεence of trifluoroacetic acid (TFA) and an aprotic solvent to produce a compound having the structure:

In one embodiment, the leaving group in step (a) is selected from the group consiεting of a halogen and benzene sulfonate and the aprotic solvent in step (b) is CHC1₃. T U 03/05871

-46- The subject invention further provides a process for preparing a compound having the structure:

which comprises

(a) reacting a compound having the structure:

with a compound having the structure:

wherein X iε a leaving group, to produce a compound- having the εtructure:

(b) N-protecting the compound formed in εtep (a) with tert- butoxycarbonyl .(Boc) to -produce a compound having the εtructure: 03 05871

-47-

(c) reacting the compound formed in εtep (b) with a compound having the εtructure:

in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:

(d) deprotecting the compound formed in step (c) with HCl to produce a compound having the εtructure:

In one embodiment, the leaving group in step (a) is selected from the group consisting of a halogen and benzene sulfonate and the aprotic solvent in step (b) is CHC1₃. The subject invention additionally provides a process for preparing a compound having the structure:

wherein R₉ iε branched or unbranched _τ to C₆ alkyl, aryl, or aralkyl; which process comprises:

(a) reacting a compound having the structure:

with a compound having the structure:

wherein X is a leaving group, to produce a compound having the structure:

(b) reacting the compound formed in εtep (a) with NaCNBH₃ and paraformaldehyde to produce a compound having the structure:

( c : reacting the compound formed in step (b) with a compound having the structure:

in the presence of trifluoroacetic acid (TFA) and an aprotic εolvent to form a compound having the structure:

In one embodiment, the leaving group in εtep (a) is εelected from the group consisting of a halogen and benzene sulfonate and the aprotic εolvent in step (c) is CHC1₃. 03 05871

-50-

The subject invention provides another process for preparing a compound having the structure:

wherein R₉ iε branched or unbranched C_x to C₆ alkyl, aryl, or aralkyl ; which process comprises:

[a) reacting a compound having the structure;

with ethyl formate to produce a compound having the structure:

(b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the structure :

(c) reacting the compound formed in step (b) with a compound having the εtructure:

wherein X iε a leaving group, to form a compound having the εtructure:

reacting the compound formed in εtep (c) with a compound having the εtructure:

in the presence of trifluoroacetic acid (TFA) and an aprotic εolvent to form a compound having the εtructure:

In one embodiment, the aprotic solvent in step (c) is CHC1₃ The subject invention provides yet another process for preparing a compound having the structure:

wherein R₉ is branched or unbranched C_±- to C₆ alkyl, aryl, or aralkyl ; which process comprises:

reacting a compound having the structure:

with NaCNBH₃/paraformaldehyde to produce a compound having the εtructure:

(b) reacting the compound formed in εtep (a) with a compound having the structure:

wherein X iε a leaving group, to form a compound having the εtructure:

!c) reacting the compound formed in step (b) with a compound having the structure:

in the presence of trifluoroacetic acid (TFA) and an aprotic solvent to form a compound having the structure:

In one embodiment, the aprotic solvent in step (d) is CHC1₃

5871

-56-

Additionally, the subject invention provides a process for preparing a compound having the structure:

which comprises:

(a) reacting a compound having the structure:

with a compound having the structure

wherein X is a leaving group, to produce a compound having the structure:

(b) reacting the compound formed in step (a) with NaCNBH₃ and paraformaldehyde to produce a compound having the structure :

Ic) reacting the compound formed in step (b) with a compound having the structure:

in the preεence of 4-dimethylaminopyridine (DMAP) and an aprotic εolvent to form a compound having the structure:

In one embodiment, the leaving group in step (a) is selected from the group consisting of a halogen and benzene sulfonate and the aprotic εolvent in step (c) is CHC1₃. The εubject invention provides another process for preparing a compound having the structure:

which comprises:

(a) reacting a compound having the structure:

,

with ethyl formate to produce a compound having the structure :

(b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the structure:

(c) reacting the compound formed in εtep (b) with a compound having the structure:

wherein X is a leaving group, to form a compound having the structure:

(d) reacting the compound f ormed in εtep ( c) with a compound having the structure :

in the presence of 4-dimethylaminopyridine (DMAP) and an aprotic solvent to form a compound having the structure:

In one embodiment, the aprotic solvent in step (c) iε CHCl, The subject invention provideε yet another process for preparing a compound having the structure:

which comprises:

(a) reacting a compound having the εtructure:

.

with NaCNBH₃/para ormaldehyde to produce a compound having the εtructure:

(b) reacting the compound formed in step (a) with a compound having the structure:

wherein X is a leaving group, to form a compound having the structure:

[c) reacting the compound formed in step (b) ^' with a compound having the εtructure:

in the presence of 4-dimethylaminopyridine (DMAP) and an aprotic εolvent to form a compound having the structure:

In one embodiment, the aprotic εolvent in step (d) iε CHC1₃.

The εubject invention further provides a process for preparing a compound having the structure:

which comprises

(a) reacting a compound having the structure:

with A1C1₃ or BBr₃ in the presence of toluene to produce a compound having the structure:

(b) reacting the product formed in εtep (a) with benzyl chloride and K₂C0₃ in the presence of dimethyl for amide (DMF) to produce a compound having the structure: .

(c) reacting the product formed in εtep (b) with MeNH₂ΗCl, NaCNBH₃ in tetrahydrofuran (THF) /MeOH to produce a compound having the structure:

(e) reacting the product formed in εtep (d) with Boc₂0, dioxane/H₂0 and NaHC0₃ to produce a compound having the εtructure :

(f) reacting the product formed in step (e) with R₄COCl, Et₃N in CH₂C1₂ in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:

(g) reacting the product formed in εtep (f) with HCl/dioxane to produce a compound having the structure:

(h) reacting the product formed in εtep (g) with propargyl bromide, K₂C0₃ in CH₃CN and then with HCl/ether and MeOH to produce a compound having the εtructure:

Also, the εubject invention provides a process for preparing a compound having the εtructure:

which comprises

(a) reacting a compound having the structure:

with AlClj or BBr₃ in the presence of toluene to produce a compound having the structure:

03 05871

-67-

(b) reacting the product formed in step (a) with benzyl chloride and K₂C0₃ in the presence of dimethyl formamide (DMF) to produce a compound having the structure: .

(c) reacting the product formed in εtep (b) with MeNH₂ΗCl, NaCNBH₃ in tetrahydrofuran (THF) /MeOH to produce a compound having the εtructure:

(d) reacting the product formed in εtep (c) with H₂, Pd/C and MeOH to produce a compound having the εtructure:

(f) reacting the product formed in step (e) with PhCOCl, Et₃N in CH₂C1₂ in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the structure:

boc

(h) 'reacting the product formed in step (g) with propargyl bromide, K₂C0₃ in CH₃CN and then with HCl/ether and MeOH to produce a compound having the εtructure:

The εubject invention further provides the use of a compound or a prodrug of a compound which becomeε the compound having the structure:

wherein R_a is OH or OC(0)R₄; wherein R₂ is H, OH or OC(0)R₄, wherein R₄ iε branched or unbranched C₁ to C_€ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C_α2 aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ iε H or C_α to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a εubject afflicted with a neurological disease, wherein the compound is to be periodically administered to the subject in a therapeutically effective doεe.

The subject invention alεo provides the use of a compound or a prodrug of a compound which becomeε the compound having the structure:

wherein R iε OH or OC(0)R₉, and wherein R₉ iε branched or unbranched C_x to C₆ alkyl, aryl, or aralkyl; R₂ iε H or 0C(0)R₄, or both R and R₂ are OC(0)R₄, wherein R₄ iε branched or unbranched CT_, to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C₁ to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ iε H or C_a to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating neurological diεease in a εubject, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose. e embodiment of the use, the compound has the structure:

wherein R_x is OC(0)R₉ and R₂ is H, wherein R₉ is branched or unbranched C_: to C_£ alkyl, aryl, or aralkyl, or Ri is OC(0)R₄ and R₂ is OC(0)R₄, wherein R₄ iε branched or unbranched C_: to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_α to C_s alkyl, C₆ to C₁₂ aryl, C₅ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally εubstituted; wherein R, is H or Cj to C₆ alkyl; wherein n is 0 or 1; and wherein iε 1 or 2.

In another embodiment of the use, the compound haε the structure :

wherein Rj is OH; wherein R₂ is H or OC(0)R₄ when R is attached to the "a" carbon or the "d" carbon, or

R₂ is OC(0)R₄ when R_: is attached to the "b" carbon or the "c" carbon; wherein R₄ is Cj_, to C₆ branched or unbranched alkyl, ^• aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, Ci to C_ε alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C₁ to C₅ alkyl; wherein n is 0 or 1; and wherein m iε 1 or 2

In an additional embodiment of the use, the compound .has the structure:

wherein the compound iε an optically pure enantiomer; wherein R₁ iε OH; wherein R₂ is H; wherein R₃ is H or Cj to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.

In a further embodiment of the use, the sub ect is human.

In yet another embodiment of the use, the medicament is formulated for oral, parenteral, intravenous, transdermal, or rectal administration.

In an embodiment of the use, the therapeutically effective amount is from about 0.01 mg per day to about 50.0 mg per day.

In an added embodiment of the use, the therapeutically effective amount is from about 0.1 mg per day to about 100.0 mg per day.

In -still another embodiment of the use, the therapeutically effective amount is from about 0.1 mg per day to about 10.0 mg per day . In an embodiment of the use, the neurological disease is Parkinson's disease, Alzheimer's diεeaεe, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis (ALS) , . memory disorders, panic, poεt-traumatic εtreεε diεorder (PTSD), εexual dysfunction, attention deficit and hyperactivity εyndrome (ADHD), attention deficit disorder, or Tourette's εyndrome.

In a further embodiment of the use, the neurological disease iε depresεion. In one embodiment, the compound haε the structure:

The εubject invention thuε discloεeε various derivatives and isomers of hydroxylated propargylamino indan and tetralin which have surpriεingly varied potency and εelectivity for MAO inhibition. The εubject invention also provideε modificationε of the hydroxy compoundε which have surprisingly varied MAO inhibitory propertieε depending upon the substitution pattern, however, the hydroxy compound iε alwayε a more potent inhibitor than the modified verεion. Thuε, the modified version may be considered a prodrug of the more active hydroxy compound into which it will be metabolized in vivo .

In one embodiment of the invention, the prodrug compound iε a carboxylic acid eεter of the hydroxy compound. In another embodiment, the parent is a carbamate derivative of the hydroxy compound.

As discusεed above, carbamate propargylamino indans and tetralinε have been reported in PCT International Application No. PCT/US97/24155 aε both MAO inhibitorε and AchE inhibitors. However, it is a further embodiment of this invention that such a prodrug compound will not be a potent inhibitor of AchE (IC_5C. >500 micromolar) , and the IC₅₀ for MAO-A inhibition of the corresponding hydroxy metabolite be at least 100 times more potent than the prodrug.

In one embodiment, the compoundε are dihydroxy derivativeε of propargylamino indan or tetralin. These derivativeε are expected to be antioxidants, as well aε MAO inhibitorε. In another embodiment, the subject invention provideε ester prodrugε .

Thuε, the εubject invention provideε esters or carbamates of propargylamino indanols, propargylamino indandiolε, propargylamino tetralinolε or propargylamino tetralindiolε , and may be prepared by methodε of esterification or carbamoylation of hydroxy compounds. Ester derivatives (Figur.e 1) when R₂ equals hydrogen were prepared by reacting the propargylamino indanolε with acyl chlorideε in the presence of a εtrong organic acid such aε trifluoroacetic acid or an acylation catalyεt εuch aε 4-dimethylaminopyridine (DMAP) , with or without an inert organic εolvent εuch aε chloroform. Compounds when R₃ equals hydrogen were prepared either by direct acylation as described above, or by firεt N-protecting the amine moiety, e.g., by a tert-butoxycarbonyl (Boc) group, followed by acylation as above, and finally removing the protecting group. The preparation of compounds of the εubject invention which are carbamates iε deεcribed in PCT/US97/24155.

Propargylamino indanols may ..be prepared by reacting amino indanols with propargyl bromide in a polar organic solvent such as N,N-dimethylacetamide or acetonitrile in the presence of a base such as potassium carbonate. N-Methyl, N-propargylamino indanolε may be prepared by reductive alkylation of propargylamino indanolε by methodε known to thoεe εkilled in the art, e.g., with NaCNBH₃ and paraformaldehyde . Alternatively, N- methyl, N-propargylamino indanolε were prepared by firεt methylating amino indanols either by NaCNBH₃/paraformaldehyde or by ethyl formate followed by LiAlH₄ reduction, and then reacting the N-methylamino indanols thus obtained with propargyl bromide aε described above.

The N-propargyl derivatives of, inter alia , 3-amino-indan-4-ol, l-amino-indan-4-ol, 3-amino-indan-5-ol and 7-amino-5, 6, 7 , 8- tetrahydro-naphthalen-2-ol were prepared.

Compounds of the subject invention with both R_x and R₂ equal to OCOR₄ (see Figure 2, compound numbered 9) were prepared by propargylation of 5 , 6-di-0-benzoyl-l-methylamino-l-indan (Figure 2, compound numbered 8), as described above. 5 , 6-Di-O-benzoyl- 1-methylamino-l-indan (Figure 2, compound numbered 8) waε prepared from 5 ; 6-bis-benzyloxy-l-indanone 3 aε follows:

1) reductive amination of the compound numbered 3 in Figure 2 aε described above gave 5 , 6-biε-benzyloxy-l- indanyl )methylamine (Figure 2, compound numbered 4);

2) the compound numbered 4 in Figure 2 was debenzylated by catalytic hydrogenation and protected by the Boc group to give N-Boc-l-methylamino-indan-5 , 6-diol (Figure 2, compound numbered 6) ; and

3) Compound 6 in Figure 2 waε esterified as described above and the protecting group removed as previously described to give 5 , 6-di-O-benzoyl-l-methylamino-l-indan (Figure 2, compound numbered 8) .

The diester tetralin derivative numbered 12 (Figure 3) was prepared by esterification of the dihydroxy tetralin numbered 11 (Figure 3) . Table 1. Chemical Data

P T/US03/05871

-78-

ster = stereochemistry pos = position mesylate salts wide range, hygroscopic

U 03/05871

-79-

Table 3. ^αH-NMR Data (R₁ = H, R₃ = Me) (300 MHz,D₂0)

Table 3. ¹H- MR Data (F^ - H, R₃ = Me) (300 MHz,D₂0) cont.

* DM80-d6

Table 5. MAO in vitro Data

Table 5. MAO in vitro Data cont. 1

Table 5. MAO in vitro Data cont. 2

Table 5. MAO in vitro Data cont. 3

Table 5. MAO in vitro Data cont. 4

Table 5. MAO in vitro Data cont. 5

Table 5. MAO in vitro Data cont. 6

Table 5. MAO in vitro Dala cont. 7

•

Table 5. MAO in vitro Data cont. 8

Table 6. MAO in vivo Dala

Table 6. MAO in vjvo Dala cont 1.

Table 6. MAO in vivo Dala cont 2.

U 03/05871

-96-

Experimental Details

EXAMPLE 1: GENERAL PROCEDURE FOR PROPYN-2-YLAMINO (PROPARGYLAMINO) INDANOLS (R, = H)

A mixture of amino indanol(35 mmol) , propargyl bromide (35 mmol) and potassium carbonate (35 mmol) in DMA (100 ml) was stirred at room temperature (RT) for 24 hours. The reaction mixture was filtered, diluted with water (200 ml) and extracted with toluene (4 x 100 ml) . The organic extracts were combined, dried and evaporated to dryness under reduced pressure. The residue waε then subjected to flash column chromatography (hexane : EtOAc, 1:1) .^' The free base was optionally converted to an acid addition εalt.

Alternatively, the' propargylation reaction was run in acetonitrile at elevated temperature, e.g., 60°C for 4 hours. The reaction mixture was then filtered, and the cake washed with acetonitrile. The combined layers were evaporated, to dryness, and the residue (brown oil) subjected to flash column chromatography (hexane : EtOAc, 2:1). The product (white solid) waε thuε obtained in 40 - 55 % yield.

Thuε were prepared: (R) -3-prop-2-ynylamino-5-indanol mesylate, (S) -3-prop-2-ynylamino-5-indanol mesylate, l-prop-2-ynylamino-4- indanol HCl, and 3-prop-2-ynylamino-4-indanol HCl.

EXAMPLE 2: GENERAL PROCEDURES FOR N-METHYL-PROP-2-YNYLAMINO INDANOLS (R,=Me) , EXEMPLIFIED BY 3- (METHYL-PROP-2-YNYL AMINO) -5- INDANOL

Experiment 2A

A mixture of (S) -3-prop-2-ynylamino-5-indanol (5.0 g, 26.7 mmol), paraformaldehyde (3.6 g, 30 mmol) and NaCNBH₃ (1.96 g, 31.2 mmol) in abs MeOH (90 ml) was refluxed under argon for 4 hours. The crude product obtained after evaporation of the solvent was purified by flash chromatography (hexane: EtOAc, 70:30) and was converted to its HCl salt (etheral HCl: 4.2g(17.6 mmol, 66%)). H NMR (DMSO-d₆) : 11.7 (br d,NH) , 9.62 (br s, OH), 6.8-7.3(3H), 4.98(m,lH), 3.98 (ABq, 2H) , 3.0 (m, IH) . 2.90(m,lH), 2.77(s,Me), 2.48(mlH), 2.40 (m, lH)ppm. αH NMR(D₂0) :7.29 (d,lH) , 6.95-7.02 (2H) ,5.09(m,lH) ,4.0(AB q, 2H) , 3.0 ( , IH) ,2.90 ( , IH) , 2.77 (s,Me) ,2.48 (m, IH) , 2.40 (m, lH)ppm.

Thus were prepared (R) 3- (methyl-prop-2-ynylamino) -5-indanol and 1- (methyl-prop-2-ynylamino) -4-indanol .

Example 2B: 3- (methyl-prop-2-ynylamino) -4-indanol

Experiment 2B1

3-amino-4-indanol (3.70 g, 24.8 mmol) in ethylformate (200 ml) was refluxed for 18 hr . The solvent was then removed under reduced pressure, and the residue was purifed by flash chromatography to give 4.10 g (93%) of N- (7-hydroxy-indan-1-yl) - formamide as a yellow solid.

Experiment 2B2

Lithium aluminium hydride (4.5 g) was added portionwise to stirred and cooled dry THF (100 ml) at 0°C. A solution of N-(7- hydroxy-indan-1-yl) -formamide (4.1 g) in dry THF (70 ml) waε added while maintaining the temperature at 5-10°C The reaction mixture waε stirred at ambient temperature for 9 hr, cooled and treated with water (100 ml) . The pH was adjusted to 8-9, water (200 ml) waε added, and the mixture was extracted with ether (6 X 300 ml) . The etheral extract waε evaporated to dryness to give 3.2 g (94%) .

Experiment 2B3

3-Methylamino-4-indanol was reacted- with propargyl bromide in acetonitrile as described in Example 1.

Example 2C

7- (methyl-prop-2-ynylamino) -2-tetralinol and 6- (methyl-prop-2- ynyla ino) -2 , 3-tetralindiol were prepared according to Chumpradit et al . and Horn et al .

EXAMPLE 3: GENERAL PROCEDURE FOR ESTERIFICATION OF PROP-2-YNYL AMINO INDANOLS AND TERALINOLS , EXEMPLIFIED BY PENTANOIC ACID (R)-3-PROP-2-YNYLAMINO-INDAN-5-YL ESTER HCL (Cmpd # 107)

To a solution of (R) 3-prop-2-ynylamino-5-indanol (2.5 g, 13.4 mmol) in CHCl₃(30ml) and TFA (5 ml), was added valeryl chloride (2.03 g, 2.0 ml, 16.7 mmol) . The solution was heated at 60° for 8 hours and cooled to RT. Water (250 ml) was added, and the pH adjusted to 7 by means of concentrated aqueous ammonia. Extracted with methylene chloride (4x100 ml) , dried and evaporated to dryness under reduced pressure. The residue (brown oil, 3.65 g) was purified by flash chromatography (Si0₂, CH₂Cl₂:MeOH 99:1). The free base thus obtained (3.25 g) waε diεεolved in dry ether (80 ml), and 20% etheral HCl was added. The resulting suspension waε stirred for 2 hours at RT, the solid product was collected by filtration and washed with ether (20 ml) and dried at 60° to give 3.45 g (11.2 mmol, 85%) of the ester HCl .

EXAMPLE 4: ALTERNATIVE PROCEDURE, EXEMPLIFIED BY BENZOIC ACID (R)-3-PROP-2-YNYLAMINO-INDAN-5-YL ESTER (Cmpd # 111)

(R) 3-prop-2-ynylamino-5-indanol (3.0 g, 16 mmol) was dissolved in dry THF (75 ml), and triethylamine^' (3.15 ml, 22.6 mmol) followed by Boc₂0(4.5 g, 20.6 mmol) was added. The solution was stirred at RT for 24 hours and evaporated to dryness. The residue waε taken up in water (200 ml) and extracted with CH₂Cl₂(4xl00 ml). The organic layers were combined, dried and evaporated to dryness. The crude product was purified by flash column chromatography (hexane: EtOAc 3:1) to give 3.75 g (81.5%) of a white solid.

*H NMR (DMSO-d6) (a 1:1 mixture of 2 rotamers): 9.17 (ε, OH), 7.0 (d,lH), 6.62 (dd, IH) , 6.5(br ε, IH) , 5.51 & 5.22 (brε, IH) , 4.05, 3.72, 3.60, 3.38(m,2H), 3.06(br ε, IH) , 2.83 (m,lH), 2.64 (m,lH) ,2.30 (br ε, IH, 2.10(br ε, IH) , 1.4 & 1.27 (2s, 9H)ppm.

(R) N-Boc 3-prop-2-ynylamino-5-indanol (2.65 g, 9.23 mmol) waε dissolved in dry methylene chloride (20 ml) , and triethylamine (2.65 ml, 18.5, mmol), DMAP (0.11 g, 0.9 mmol) and benzoyl chloride (1.7 ml, 18.5 mmol) was added. The solution was stirred at RT for 3 hours, water (100 ml) -was added and acidified to pH 4 (aq HCl) . The organic layer was separated and washed with 10% HCl. The aqueous layer was washed with methylene chloride (100 ml) , and the combined organic phases were dried and evaporated to dryness in vacuo. The crude product (5.2 g brown oil) was purified .by flash column chromatography (hexane: EtOAc 3:1) to give 4.1 g (90%) of a white solid.

(R) N-Boc-3-prop-2-ynylamino-5-benzoyloxy indan (2.55 g, 6.5 mmol) was dissolved in dioxan --(25 ml), and HCl/dioxan (25 ml) was added. The mixture was stirred at RT for 4 hours and the solvent was evaporated to dryness in vacuo. Ether (50 ml) was added, the suspension was then εtirred at RT for 2 hours. The εolid was collected by filtration, washed with ether and dried (1.5 g) . The crude product was crystallized from iPrOH (90 ml) to give 1.3 g (3.96 mmol, 61%), mp 210-2°C.

EXAMPLE 5: PREPARATION OF BENZOIC ACID (S) -3- (METHYL-PROP-2- YNYL-AMINO)-INDAN-5-YL ESTER HCL Cmpd # 127

(S) 3- (methyl-prop-2-ynylamino) -5-indanol (1.5 g, 7.46 mmol) was dissolved in dry methylene chloride (15 ml), and triethylamine (2.15 ml, 15.5 mmol), DMAP (0.08 g, 0.66 mmol) and benzoyl chloride (2.1 ml, 18.1 mmol) was added. The solution waε stirred at RT for 2 hours, water (100 ml) was added and acidified to pH 4 (aq HCl) . The organic layer was separated, washed with 10% HCl. The aqueous layer waε washed wit methylene chloride (4x100 ml) , and the combined organic phases were dried evaporated to dryness in vacuo. The crude product (3.78 g brown oil) waε purified by flash column chromatography (hexane: EtOAc 4:1) to give 1.6 g (5.3 mmol, 71%) of a yellow oil. The free base was converted to the HCl salt (etheral HCl, 2 hours, RT) , 1.39g (4.07 mmol, 77%, 55% from the hydroxy compound) .

By the same proce^'dure was prepared 7-0-benzoyl-2- (methyl-prop-2- ynyla ino) -tetralin Hcl, ^αHNMR (D₂0): 7.20, 6.98, 6.95 (3H, ArOCO), 8.05, 7.71, 7.53 (5H, PhCOO), 4.15 (m, 2H, CH₂CCH) , 3.80 (m, IH, C₇-H) , 3.15 (t, IH, CH₂CCH) , 3.14, 3.01 (m, 2H, C₈-H) , 2.8-3.0 ( , 2H, C₅-H) , 2.31, 1.87 (m, 2H, C₆-H) , 3.0 (S, 3H, Me) pp .

The same procedure was also used to prepare 6, 7-di-0-benzoyl-2- (methyl-prop-2-ynylamino) -tetralin HCl, ¹HNMR (DM80-d₆) : 7.91 (dd, 4H) , 7.65 (t,2H), 7.46 (t,4H), 7.28 (s, 2H) , 4.24 (br s, 2H) , 3.87 (br s, IH) , 3.74 (m, IH) , 3.35-2.90 ( , 4H) , 2.87 (s, 3H) , 2.39 (m, IH) , 1.90 (m, IH) ppm. EXAMPLE 6: PREPARATION OF 5.6-DI-O-BENZOYL-l- (METHYL-PROP-2- YNYL-AMINO) -INDAN HCL Cmpd # 137) :

Experiment 6A: (5, 6-Bis-benzyloxy-l-indan-l-yl) -methylamine HCl (Figure 2, Compound 4) ■

A mixture of 5, 6-dibenzyloxy-l-indanone (10.0 g, 29 mmol), 8M ethanolic methylamine (30 ml, 240 mmol), methylamine HCl (7.15 g, 106 mmol), and NaCNBH₃ (2.95 g, 47 mmol) in dry THF (750 ml) and methanol (250 ml) was refluxed under nitrogen for 4 hours. The reaction mixture waε cooled to 5°C, acidified with concentrated HCl to pH 1.5, and evaporated to dryness. The solid residue was treated with a mixture of methylene chloride (600 ml) and water (400 ml) . The aqueous layer was separated, extracted with methylene chloride (4x100 ml) , and the combined organic layers were evaporated to dryness. The crude product thus obtained was slurried in EtOAc (80 ml) for 30 min at RT, filtered and purified by flash column chromatography (CH₂C1₂ : MeOH, 80:20), to give 6.3 g (54.8 %) , mp: 180-182°C.

Experiment 6B: 1- Methylamino -1-indan- 5,6-diol HCl (Figure 2, Compound 5)

A solution of (5 , 6-biε-ben^'zyloxy-l-indan-l-yl) -methylamine HCl (3.15 g, 7.96 mmol) in MeOH (250 ml) was hydrogenated (44 psi) over 10% Pd/C (1.05 g) at RT for 3 hours. The mixture was filtered (Filteraid) , and the filtrate evaporated to dryness. The residue waε treated with charcoal in boiling MeOH, filtered and evaporated to dryness, to give 1.6 g of a light grey solid, mp : 153-5°C lHNMR (DM80-d₆) : 9.3-8.8 (3H, br , OH, NH₂) , 7.02 (s, IH, Ar) , ^•6.08 (s, IH, Ar) , 4.7 (dd, IH, C₃-H) , 2.92 (m, IH, C_x-H) , 2.66 ( , IH, Cj-H) , 2.44 (s, 3H, Me), 2.33 (m, IH, C₂-H) , 2.11 (m, IH, C₂-H') ppm. Experiment 6C: N-Boc-1- methylamino -1-indan- 5,6-diol (Figure 2 , Compound 6)

To a solution of l-methylamino-l-indan-5, 6-diol HCl (0.5 g, 2.32 mmol) in water (30 ml) was added dioxane (30 ml), NaHC0₃ (0.6 g) and Boc₂0 (0.6 g) . The reaction mixture waε stirred at RT for 4 hours under nitrogen, evaporated to dryness, and the solid residue taken up in a mixture of water (100 ml) and methylene chloride (100 ml) . The aqueous layer waε εeparated and extracted with methylene chloride (5x50 ml) . The latter waε filtered, washed with water, dried and evaporated to dryneεε to give a viscous oil which waε purified by flaεh column chromatography (CH₂C1₂ : MeOH, 95:5) to give 0.35 g (54 %) of a viscouε oil which soon solidified.

Experiment 6D: N-Boc- ( 5, 6-di-O-benzoyl-l-indan-l-yl) -methylamine (Figure 2, Compound 7)

To a solution of N-Boc-l-methylamino-l-indan-5 , 6-diol (0.34 g, 1.22 mmol) in methylene chloride (15 ml) was added triethylamine (0.49 g, 4.88 mmol), DMAP (0.03 g, 0.244 mmol) and benzoyl chloride (0.69 g, 4.88 mmol), and the εolution was stirred at RT for 4.5 hours. Water (100 ml) was added, acidified to pH 4 with dilute HCl. The organic layer was separated and washed with 10% HCl. The aqueous layer was extracted with methylene chloride (2x75 ml.), and the latter was washed with 10% HCl. The combined organic layers were dried, evaporated to dryness, and the residue purified by flash column chromatography (hexane : EtOAc, 50:50) to give 0.50 g (40%) of a yellow oil. 5871

-105-

Experiment 6Es (5, 6-di-O-Benzoyl-l-indan-l-yl) -methylamine HCl (Figure 2 , Compound 8)

To a εolution of N-Boc- (5 , 6-di-O-benzoyl-l-indan-l-yl) - methylamine (0.29 g, 0.59 mmol) in dioxane (5 ml) was added 20% HCl, in dioxane (5 ml) , and the mixture stirred at RT for 4 hours under nitrogen. The solvent was removed and ether (40 ml) was added to the reεidue, and the suspension stirred at RT for 1 hour. The εolvent waε removed^' to give 0.11 g (89 %) of a white solid, mp : 192-3°C. lE NMR (CDC1₃) : 8.1-7.2 (12H, Ar) , 4.79 (br s, IH, C₃-H) , 3.40 (m, IH, Ci-H) , 3.01 ( , lH.Ci-H) , 2.60 (s, 3H, Me), 2.50 ( , IH, C₂-H) , 1.83 (m, IH, C_a-H') ppm.

Experiment 6F: 5 , 6-di-O-Benzoyl-l- (methyl-prop-2-ynyl-amino) - indan HCl (Figure 2, Compound 9 (Cmpd # 137))

To a εolution of (5 , 6-di-O-benzoyl-l-indan-l-yl) -methylamine HCl (-0.2 g, 0.48 mmol) in acetonitrile (100 ml) was added K₂C0₃ (130 mg, 0.96 mmol), followed after 15 min by a εolution of propargyl bromide (56 mg, 0.48 mmol) in acetonitrile (10 ml). The reaction mixture waε εtirred under nitrogen at RT for 20 hours, filtered and evaporated to dryness. The crude product waε purified by flash column chromatography (hexane : EtOAc, 50:50) to give 0.15 g (0.35 mmol, 75 %) of a viscous light tan oil.

The free base . was disεolved in MeOH (30 ml), and saturated etheral HCl (4 ml) waε added. The solution was stirred at RT^' for 30 min and evaporated to dryness. The oily residue was triturated three times in ether, to give 120 mg (0.26 mmol, 74%) • of a light tan solid. NMR (CDC1₃) : 8.1 - 7.2 (m, 12H, Ar) , 5.1 (br d, IH, Cl-H) , 3.91 (br s, 2H, CH₂CCH) , 3.6 - 2.5 ( , 8H, indan CH₂'s, Me, CH,CCH) . EXAMPLE 7 : INHIBITION OF MAO ACTIVITY IN VITRO EXPERIMENTAL PROTOCOL

The MAO enzyme source was a homogenate of rat brain in 0.3 M sucrose 1:20 w/v. The homogenate was pre-incubated with serial dilutions of the test compounds (Table 5) for 60 minutes at 37°C. ¹⁴C-labeled substrates (2-phenylethylamine, hereinafter PEA; 5-hydroxytryptamine, hereinafter 5-HT) were then added, and the incubation continued for a further 20 minutes (PEA) , or 30- 45 minutes (5-HT) . In the case of PEA, the enzyme concentration waε chosen so that not more than 10% of the εubεtrate was metabolized during the course of the reaction. The reaction was then¹ stopped by addition of citric acid. Radioactivity indicates the production of 5-HT and PEA metabolites formed aε a result of MAO activity. Activity of MAO in the sample waε expressed aε a percentage of control activity in the absence of test compounds after subtraction of appropriate blank values. The activity determined using PEA as substrate is referred to aε MAO-B, and that determined using 5-HT as MAO-A.

1

-107-

EXAMPLE 8 : INHIBITION OF MAO ACTIVITY IN VIVO : CHRONIC TREATMENT EXPERIMENTAL PROTOCOL

Ratε were treated with the teεt compounds (Table 5) at several dose levels by oral adminiεtration, one dose daily for 7-21 days, and decapitated 2 hourε after the laεt dose. The activities of MAO-A and MAO-B were determined in the brain, liver and intestine aε described in the previous example. Inhibition of MAO activity waε calculated by dividing MAO activity in the treated rats by MAO activity in the control ratέ (saline treated, MAO activity in these rats was taken as 100%) .

A mixture of toluene: ethyl acetate (1:1) waε added to the reaction and mixed for 10 minutes, followed by 5 minutes of centrifugation at 1760 g. The upper phase was taken for radioactive determination by liquid scintillation εpectrometry .

Ref erences

U.S. Patent No. 3,513,244, Gittos et al.^', issued May 19., 1970.

U.S. Patent No. 4,844,033, Abinett et al., isεued July 4, 1989.

U.S. Patent No. 5,387,612, Youdim et al . , isεued February 7, 1995.

U.S. Patent No. 5,453,446, Youdim et al . , iεεued September 26,

1995.

U.S. Patent No. 5,457,133, Youdim et al . , issued October 10,

1995'. U.S. Patent No. 5,519,061, Youdim et al., issued May 21, 1996.

U.S. Patent No. 5,532,415, Youdim et al., issued July 2, 1996.

U.S. 'Patent No. 5,576,353, Youdim et al . issued November 19,

1996.

U.S. Patent No. 5,649,913, Cohen, issued July 22, 1997. U.S. Patent No. 5,668,181, Youdim et al . , issued September 16,

1997.

U.S. Patent No. 5,744,500, Youdim et al . , isεued April 28 , 1998.

U.S. Patent No. 5,786,390, Youdim et al . , isεued July 28, 1998.

U.S. Patent No. 5,844,003, Tatton, issued December 1, 1998. U.S. Patent No. 5,877,221, Cohen et al . , issued March 2, 1999.

U.S. Patent No. 5,877,218, Herzig et al . issued March 2, 1999.

U.S. Patent No. 5,880,159, Herzig et al . issued March 9, 1999.

U.S. Patent No. 5, 891, 923 ,^• Youdim et al . issued April 6, 1999.

U.S. Patent No. 5,914,349, Cohen et al . isεued June 22, 1999. U.S. Patent No. 5,994,408, Cohen et al . , iεsued November 30,

1999.

U.S. Patent No. 6,303,650, Chorev et al ^•isεued October 16,

2001.

U.S. Patent No. 6,316,504, Youdim et al . , issued November 13, 2001.

.PCT International Application No. PCT/IL96/00115, Berger et al., published April 10, 1997.

PCT International Application No. PCT/US95/00245 , Cohen et al., published July 13, 1995. PCT International Application No. PCT/US97/24155, Chorev et al . , published June 25, 1998.

European Patent No. 0 436 492, Youdim et al . , issued June 8,

1994.

Bentue-Ferrer et al., CNS Drugs 6, 217, 1996. Chrisp et al . , Drugs & Aging, 1, 228., 1991.

Chumpradit, S. et al., J. Med. Chem., 36/ 4308, 1993.

Dostert, J.. Neurol. Tranεm. Suppl 41, 269, 1994.^'

Fitton et al., Drugs, 43, 561, 1992.

Florvall et al . , Eur . J. Med. Chem. 34, 137, 1999. Kleywegt, Monoamine oxidase, 1999 (http://alpha2.bmc.uu.se/ gerard/mao.html) .

Krageten et al., J. Biol. Chem., 273, 5821, 1998.

Hazelhoff et al . , Naunyn-Schmeideberg' s Arch. Pharmacol.,

1985, 330, 50. Hazelhoff, B. et al, Eur. J. Pharmacol., 109, 229, 1985.

Horn, A.S. et al . , J. Med. Chem., 25, 993, 1982.

Lidor et al., 1997, Organic Preparationε and Procedures

International (OPPI) 29,701.

Loscher et al., J. Pharmacol and Expt. Therap. 288, 984, 1999. Palfreyman et al . , J. Neurochemistry, 45, 1850, 1985.

Szelenyi, I., Inhibitors of Monoamine Oxidase B: Pharmacology and Clinical Use in Neurodegenerative Disorders, 1992,

Bierkhauser Berlag, Switzerland.

White et al . , Drug Development Research, 25, 191, 1992. Youdim et al . , Handbook of Experimental Pharmacology,

Trendelenburg and Weiner, eds. Springer-Verlag, 1988, 90, ch.3.

The interaction of' L-deprenyl and εcopolamine on spatial

^■learning/memory in rats, J. Neural Trans . Parkinson ' s Dis.

Dementia Sect . , 1993, 6(3): 189-197. Potential applications for monoamine oxidase B inhibitorε,

Dementia, 1990, 1(6): 323-348.

Treatment of Tourette's: An Overview, (http: //www. haverford. edu/psych/biopsych217b/tourettes/TSwebtreat . caf .html) . ^•

Claims

What is claimed is;

1. A compound having the structure:

wherein R_α is OC(0)R₉ and R₂ is H, wherein R₉ is branched or unbranched C to C₆ alkyl, aryl, or aralkyl, or Rj_. iε 0C(0)R₄ and R₂ iε OC(0)R₄, wherein R₄ iε branched or unbranched C_α to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ iε H or C_x to C₆ alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable salt thereof.

The compound of claim 1, wherein the pharmaceutically acceptable salt iε the acetate salt,_, mesylate salt, esylate, tartarate salt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate εalt, citrate salt, ascorbate εalt, mandelate salt, adipate salt, octanoate salt, the myristate salt, the succinate salt, or fumarate salt. The compound of claim 1 having the structure:

The compound of claim 1 having the structure:

The compound of claim 1 having the structure:

The compound of claim 5, wherein n is 1.

7. The compound of claim 6 having the structure:

8. The compound of claim.5, wherein n is 0

9. The compound of claim 8 having the structure:

10. The compound of claim 8 having the structure:

RQ V ^s^

he compound of claim 8, wherein R₉ iε Me and R₃ is H.

The compound of claim 8, wherein R₉ is tBu and R₃ i.s H.

The compound of claim 8, wherein R₉ is nBu and R₃ is H.

The compound of claim 8, wherein R₉ is CH₂Ph and R₃ is H.

The compound of claim 8, wherein R₉ is Ph and R₃ is H.

The compound of claim 8, wherein R₉ is Me and R₃ is Me..

The compound of claim 8, wherein R₉ is nBu and R₃ is Me.

The compound of claim 8, wherein R₉ iε Ph and R₃ is Me.

The compound of claim 8, wherein R₉ is tBu and R₃ is Me.

The compound of claim 8, wherein R₉ is Ph(Me) and R₃ is Me.

The compound of claim 8, wherein R₉ is Ph(0Me)₂ and R₃ is Me.

The compound of claim 8, wherein R₉ is Ph(0Me)₂ and R₃ is H.

he compound of claim 1 having the structure:

The compound of claim 23, wherein R₃ is Me and R₉ is Me.

The compound of claim 23, wherein R₃ is Me and R₉ iε Ph.

The compound of claim 23, wherein R₃ iε Me and R₉ iε Ph (OMe) ₂.

The compound of claim 1 having the structure:

The compound of claim 27, wherein R₃ is Me and R₉ is Me.

The compound of claim 27, •^•wherein R₃ is H and R₉ is Ph.

The compound, of claim 27, wherein R₃ is H and R₉ is Ph(OMe)₂.

31. The compound of claim 1 having the structure:

32. The compound of claim 31, wherein n i-s 0

33. The compound of claim 32, wherein R₄ is Ph and R₃ is Me,

34. The compound of claim 31, wherein n iε 1

35. The compound of claim 34, wherein R₃ is Me.

36. The compound of claim 31 having the structure;

5871

-116- A compound having the εtructure:

wherein R₂ is OH; wherein R₂ is H or OC(0)R₄ when R₃ is attached to the "a" carbon or the "d" carbon, or

R₂ is 0C(0)R₄ when R_x iε attached to the "b" carbon or the "c" carbon; wherein R₄ is C_x to C₆ branched or unbranched alkyl, aryl , aralkyl or NR₅R₆ , wherein R₅ and R₆ are each independently H, C₁ to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein n is 0 or 1, and m iε 1 or 2; and wherein R₃ is H or Me when n is 1 and m is 1, or R₃ is H or C_l to C₆ alkyl when n is 0 or m iε 2, or a pharmaceutically acceptable εalt thereof.

The compound of claim 37, wherein the pharmaceutically acceptable salt is the acetate salt, mesylate εalt, esylate, tartarate salt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate salt, ascorbate salt, mandelate salt, adipate salt, octanoate salt, the myristate εalt, the εuccinate salt, or fu arate salt .

39. The compound of claim 37 having the structure:

40. The compound of claim 39, wherein R₃ is H. .

41. The compound of claim 39, wherein R₃ is Me.

42. The compound of claim 37 having the εtructure:

OH

N

F

43. The compound of claim 42, wherein R₃ iε H.

44. The compound of claim 42, wherein R₃ iε Me,

A compound having the structure:

wherein the compound is an optically pure enantiomer; wherein R_x is OH; wherein R is H; wherein R₃ is H or Cj to C₆ alkyl; wherein n is 0 or 1; .and wherein m is 1 or 2, • or a pharmaceutically acceptable salt thereof.

The compound of claim 45, wherein the pharmaceutically acceptable salt is the acetate salt, mesylate salt, esylate, tartarate εalt, hydrogen tartarate salt, benzoate salt, phenylbutyrate salt, phosphate salt, citrate salt, ascorbate salt, mandelate salt, adipate salt, octanoate salt, the myristate εalt, the εuccinate εalt, or fumarate salt.

The^" compound of claim 45 having the structure:

48. The compound of claim 47 having the εtructure:

49. The compound of claim 48, wherein R₃ is H.

50. The compound of claim 48, wherein R₃ is Me,

51. The compound of claim 47 having the structure:

52. The compound of claim 51, wherein R₃ iε H.

53. The compound of claim 51, wherein R₃ iε Me,

P T/US03/05871

-120- A compound having the structure:

wherein R₇ iε H, C₂ to C₆ alkyl, aryl, aralkyl or C(0)R₄, wherein R₄ iε branched or unbranched Cj to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_: to C_s alkyl, C₆ to C₁₂ aryl, C₆ to C₁ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally εubεtituted; wherein R₃ iε H or C_Ύ to C₆ alkyl; wherein R₈ is H or t-butoxycarbonyl (Boc) .

The compound of claim 54 having the structure:

The compound of claim 54 having the structure:

57. The compound of claim 54 having the structure:

58. The compound of claim 54 having the structure:

59. The compound of claim 58, wherein R₄ is Ph,

60. The compound of claim 54 having the structure:

61. The compound of claim 60, wherein R₄ is Ph. 5871

-122- A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising the compound of claim 37 or a pharmaceutically acceptable εalt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising the compound of claim 45 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A method of treating a εubject afflicted with a neurological disease comprising administering to the subject a compound having the εtructure:

wherein R₁ iε OH or OC(0)R₄; wherein R₂ is H, OH or OC (0) R₄, wherein R₄ iε branched or unbranched C₁ to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C₁ to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the sub ect, so as to thereby treat the neurological diseaεe in the subject. A method of treating a subject afflicted with a neurological disease comprising administering to the subject a compound having the structure :

wherein _x iε OH or OC(0)R₉, and wherein R₉ is branched or unbranched C_α to C₆ alkyl, aryl, or aralkyl;

R₂ iε H or OC(0)R₄, or both R_r and R₂ are OC(0)R₄, wherein R₄ is branched or unbranched C_x to C_€ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C_€ to C₁₂ cycloalkyl, each optionally εubstituted; wherein R₃ iε H or Cj_. to C₆ alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable salt thereof, or a prodrug which becomes the compound in the subject, so as to thereby treat the neurological diseaεe in the subject.

The method of claim 66, wherein the compound has the εtructure:

P T/US03/05871

-124- wherein R₂ is OC(0)R₉ and R₂ is H, wherein R₉ is branched or unbranched C_α to C₆ alkyl, aryl, or aralkyl, or R₁ is OC(0)R₄ and R₂ is OC(0)R₄, wherein R₄ is branched or unbranched C_x to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C₂ to C_B alkyl, C₆ to C₁₂ aryl, C₆ to C₁ aralkyl or C₅ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ iε H or C_α to C₆ alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2.

The method of claim 66, wherein the compound has the structure:

wherein Rj is OH; wherein R₂ is H or OC(0)R₄ when R_x is attached to the "a" carbon or the "d" carbon, or

R₂ is OC(0)R₄ when R₃ iε attached to the "b" carbon or the "c" carbon; wherein R₄ is C₂ to C₆ branched or unbranched alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C_x to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2. T U 03/05871

-125-

69. The method of claim 66, wherein the compound has the structure:

wherein the compound is an optically pure enantiomer; wherein R_α is OH; wherein R₂ is H; wherein R₃ is H or C_x to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.

70. The method of claim 66, wherein the subject is human.

71. The method of claim 66, wherein the administration comprises oral, parenteral, intravenous, transdermal, or rectal administration.

72. The method of claim 66, wherein the effective amount is from about 0.01 mg per day to about 50.0 mg per day.

73. The method of claim 66, wherein the effective amount is from about 0.1 mg per day to about 100.0 mg per day. T U 03/05871

-126-

74. The method of claim 73, wherein the effective amount is from about 0.1 mg per day to about 10.0 mg per day.

75. The method of claim 66, wherein the neurological diεeaεe is Parkinεon'ε . diεease, Alzheimer's disease, depreεεion, epilepεy, narcolepsy, amyotrophic lateral sclerosis (ALS) , memory disorders, panic, post-traumatic streεε diεorder

(PTSD) , sexual dysfunction, attention deficit and hyperactivity syndrome (ADHD) , attention deficit disorder, or Tourette's syndrome.

76. The method of claim 75, wherein the neurological diseaεe iε Qepreεεion.

77. The method of claim 75, wherein the compound has" the structure:

P T/US03/05871

-127-

78 A process for preparing a compound having the structure:

wherein n is 0 or 1, and m is 1 or 2; wherein^' R₃ iε H or C_x to C₆ alkyl; and wherein R₉ iε branched or unbranched C₃ to C₆ alkyl, aryl, or aralkyl; compriεing the εtep of reacting

or

with

in the presence of an acid or 4-dimethylaminopyridine (DMAP) to form the compound. P T/US03/05871

-128-

79. The proceεs of claim 78 for preparing a compound having the εtructure:

wherein R₉ iε branched or unbranched Ci to C₆ alkyl, aryl, or aralkyl; which proceεε compriεeε:

(a) reacting a compound having the εtructure:

,

with a compound having the structure:

wherein X is a leaving group, to produce a compound having the structure:

(b) reacting the compound formed in step (a) with a compound having_ι the structure:

in the presence of trifluoroacetic acid (TFA) and an aprotic solvent to produce a compound having the structure:

80. The process of claim 79, wherein the leaving group in step (a) is εelected from the group consiεting of a halogen and benzene εulfonate and the aprotic solvent in step (b) is CHC1₃.

T U 03/05871

-130-

81. The process of claim 78 for preparing a compound having the structure:

which comprises

[a) reacting a compound haying the structure:

with a compound having the εtructure:

wherein X is a leaving group, to produce a compound having the structure:

(b) N-protecting the compound formed in εtep (a) with tert- butoxycarbonyl (Boc) to produce a compound having the structure: P T/US03/05871

-131-

(c) reacting the compound formed in step (b) with a compound having the structure:

in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the εtructure:

(d) deprotecting the compound formed in εtep (c) with HCl to produce a compound having the εtructure :

82. The process of claim 81, wherein the leaving group in step (a) is εelected from the group conεiεting of a halogen and benzene sulfonate and the aprotic εolvent in step (b) is CHCl,. The process of claim 78 for preparing a compound having the structure:

wherein R₉ is branched or unbranched C_x to C₆ alkyl, aryl , or aralkyl; which process comprises:

reacting a compound having the structure:

,

with a compound having the structure:

wherein X is a leaving group, to produce a compound having the εtructure:

(b) reacting the compound formed in εtep (a) with NaCNBH₃ and paraformaldehyde to produce a compound having the εtructure:

84. The procesε of claim 83, wherein the leaving group in εtep (a) is selected from the group conεiεting of a halogen and benzene sulfonate and the aprotic solvent in step (c) iε CHC1₃.

55. The process of claim 78 for preparing a compound having the structure:

wherein R₉ is branched or unbranched C_α to C₆ alkyl, aryl, aralkyl^' or NR₅R₆; which process compriεeε:

(a) reacting a compound having the structure:

with ethyl formate to produce a compound ■ having the structure:

(b) reacting the compound formed in εtep (a), with lithium aluminum hydride to produce a compound having the structure:

5871

-135-

!c) reacting the compound formed in εtep (b) with a compound having the εtructure:

wherein X iε a leaving group, to form a compound having the structure:

(d) reacting the compound formed in step (c) with a compound having the εtructure:

l

in the presence of trifluoroacetic acid (TFA) and an aprotic solvent to form a compound having the εtructure:

56. The process of claim 85, wherein the aprotic solvent in step (c) is CHC1₃.

87. The process of claim 78 for preparing a compound having the structure:

wherein R₉ is branched or unbranched C_x to C₆ alkyl, aryl, or aralkyl; which procesε compriεes:

(a) reacting a compound having the structure:

with NaCNBH₃/paraformaldehyde to produce a compound having the structure:

wherein X is a leaving group, to form a compound having 'the structure:

88. The process of claim 87, wherein the aprotic solvent in step (d) is CHC1₃.

03 05871

-138- 9. The process of claim 78 for preparing a compound having the structure:

which compriseε;

(a) reacting a compound having the εtructure:

with a compound having the structure:

wherein X is a leaving group, to produce a compound having the structure:

T U 03/05871

-139-

(b) ^■ reacting the compound formed in step (a) with NaCNBH₃ and paraformaldehyde to produce a compound having the structure:

90. The method of claim 89, wherein the leaving group in step (a) iε selected from the group consisting of a halogen and benzene sulfonate and the aprotic solvent in step (c) is CHC1₃.

91. The process of claim 78 for preparing a compound having the structure:

which comprises:

(a) reacting a compound having the structure:

with ethyl formate to produce a compound having the structure:

(b) reacting the compound formed in step (a) with lithium aluminum hydride to produce a compound having the εtructure :

-Wife) reacting the compound formed in εtep (b) with a compound having the εtructure:

wherein X is a leaving group, to form a compound having the structure:

(d) reacting the compound formed in step (c) with a compound having the structure:

92. The process of claim 91, wherein the aprotic solvent in step (c) is CHC1₃.

93. The proceεε of claim 78 for preparing a compound having the εtructure:

which compriεes:

(a) reacting a compound having the structure:

with NaCNBH₃/paraformaldehyde to produce a compound having the structure:

wherein X is a leaving group, to form a compound having the structure:

(c) reacting the compound formed in step (b) with a compound having, the structure:

in the presence of 4-dimethylaminopyridine ^' (DMAP) and an aprotic solvent to form a compound having the structure:

94. The procesε of claim 93, wherein the aprotic solvent in step (d) is CHC1₃.

95. A procesε for preparing a compound having the structure:

wherein R₄ is branched or unbranched C₃ to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_λ to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally subεtituted; which proceεε comprises:

(a) reacting a compound having the structure:

(b) reacting the product formed in εtep (a) with benzyl chloride and K₂C0₃ in the presence of dimethyl formamide (DMF) to produce a compound having the structure:

(c) reacting the product formed in εtep (b) with MeNH₂"HCl, NaCNBH₃ in tetrahydrofuran (THF) /MeOH to produce a compound having the εtructure:

(d) reacting the product formed in εtep (c) with H₂, Pd/C and MeOH to produce a compound having the structure:

(e) reacting the product formed in εtep (d) with Boc₂0, dioxane/H₂0 and NaHC0₃ to produce a compound having the εtructure:

(f) reacting the product formed in εtep (e) with R^COCl, Et₃N in CH₂C1₂ in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the εtructure:

(g) reacting the product formed in step (f) with HCl/dioxane to produce a compound having the εtructure:

96. The process of claim 95 for preparing a compound having the structure:

which comprises:

(a) reacting a compound having the εtructure:

(e) reacting the product formed in step (d) with Boc₂0, dioxane/H₂0 and NaHC0₃ to produce a compound having the structure :

reacting the product formed in step (e) with PhCOCl, Et₃N in CH₂C1₂ in the presence of 4-dimethylaminopyridine (DMAP) to produce a compound having the εtructure:

(g) reacting the product formed in εtep (f) with HCl/dioxane to produce a -compound having the εtructure:

(h) reacting the product formed in step (g) with propargyl bromide, K₂C0₃ in CH₃CN and then with HCl/ether and MeOH to produce a compound having the εtructure:

97. Uεe of a compound or a prodrug of a compound which becomeε the compound having the structure:

wherein R_α is OH or OC(0)R₄; wherein R₂ is H, OH or OC(0)R₄, wherein R₄ is branched or unbranched C_α to C₆ alkyl, aryl, aralkyl or NR₅R₅, wherein R₅ and R₆ are each independently H, C_α to C₈ alkyl, C_s to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally substituted; wherein R₃ is H or C_x to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a subject afflicted with a neurological diseaεe, wherein the compound is to be periodically administered to the subject in a therapeutically effective dose.

98. Uεe of a compound or a prodrug of a compound which becomeε the compound having the εtructure:

wherein R₁ is OH or OC(0)R₉, and wherein R₉ is branched or unbranched C₁ to C₆ alkyl, aryl, or aralkyl; R₂ is H or OC(0)R₄, or both Rj_. and R₂ are OC(0)R₄, wherein R₄ iε branched or unbranched C_: to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_x to C₈ alkyl, C_s to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally εubεtituted; wherein R₃ iε H or C_x to C₆ alkyl; wherein n iε 0 or 1; and wherein m iε 1 or 2, or a pharmaceutically acceptable εalt thereof, for the manufacture of a medicament for treating neurological diεease in a εubject, wherein the compound is to be periodically adminiεtered to the εubject in a therapeutically effective doεe.

99. The uεe of claim 98, wherein the compound haε the εtructure:

wherein R_x is OC(0)Rg and R₂ is H, wherein R₉ is branched or unbranched C_x to C₆ alkyl, aryl, or aralkyl, or R_x is OC(0)R₄ and R₂ is 0C(0)R₄, wherein R₄ is branched or unbranched C_x to C₆ alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C₂ to C₈ alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₅ to C₁₂ cycloalkyl, each optionally subεtituted; wherein R₃ is H or C_α to C₆ alkyl; wherein n iε 0 or 1; and wherein iε 1 or 2.

The use of claim 98, wherein the compound has the εtructure:

wherein R₃ iε OH; wherein R₂ iε H or OC(0)R₄ when R_α is attached to the "a" carbon or the "d" carbon, or

R₂ is 0C(0)R₄ when R_λ iε attached to the "b" carbon or the "c" carbon; wherein R₄ iε 0χ to C₆ branched or unbranched alkyl, aryl, aralkyl or NR₅R₆, wherein R₅ and R₆ are each independently H, C_λ to C_B alkyl, C₆ to C₁₂ aryl, C₆ to C₁₂ aralkyl or C₆ to C₁₂ cycloalkyl, each optionally εubεtituted; wherein R₃ iε H or C_x to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.

101. The use of claim 98, wherein the compound has the structure:

wherein the compound is an optically pure enantiomer; wherein R₁ is OH; wherein R₂ iε H; wherein R₃ iε H or C_x to C₆ alkyl; wherein n is 0 or 1; and wherein m is 1 or 2.

102. The use of claim 98, wherein the εubject is human.

103. The use of claim 98, wherein the medicament is formulated for oral, parenteral, intravenous, transdermal, or rectal administration.

104. The uεe of claim 98, wherein the therapeutically effective amount iε from about 0.01 mg per day to about 50.0 mg per day.

105. The uεe of claim 98, wherein the therapeutically effective amount iε from about 0.1 mg per day to about 100.0 mg per day.

106.. The use of claim 105, wherein the therapeutically effective amount is from about 0.1 mg per day to about 10.0 mg per day.

107. The uεe of claim 98, wherein the neurological diεease iε Parkinson' ε disease, Alzheimer's disease, depression, epilepsy, narcolepsy, amyotrophic lateral sclerosis . (ALS) , memory disorderε, panic, post-traumatic stress disorder

(PTSD) , εexual dyεfunction, attention deficit and hyperactivity syndrome (ADHD) , attention deficit disorder, or Tourette's syndrome.

108. The use of claim 107, wherein the neurological diεease iε depression.

109. The use of claim 108, wherein the compound has the structure: