Mono-fluorinated derivatives of n-propargyl-1-aminoindan, their preparation and pharmaceutical compositions containing them

FIELD OF THE INVENTION

The present invention is in the field of selective irreversible inhibitors of the enzyme monoamine oxidase (hereinafter MAO) and relates to to novel propargylamine compounds which are selective irreversible inhibitors of the B-form of the monoamine oxidase enzyme (hereinafter, MAO-B). The invention also relates to pharmaceutical compositions containing these propargylamine compounds which are particularly useful for the treatment of Parkinson's disease, memory disorders and dementia of the Alzheimer type (DAT), depression, and hyperactive syndrome in children.

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BACKGROUND OF THE INVENTION AND PRIOR ART

Parkinson's disease is widely considered to be the result of degradation of the pre-synaptic dopaminergic neurons in the brain, with a subsequent decrease in the amount of the neurotransmitter dopamine, that is being released. Inadequate dopamine release, therefore, leads to the onset of voluntary muscle control disturbances symptomatic of Parkinson's disease.

Various procedures for treating Parkinson's disease have been established and are currently in widespread use, for example, the administration of L-Dopa, which is a precursor of dopamine, together with a decarboxylase inhibitor, such as L-carbidopa or benzerazide. The decarboxylase inhibitor protects the L-Dopa molecule from peripheral decarboxylation and thus ensures L-Dopa uptake by the remaining dopaminergic neurons in the striatum of the brain. Here the L-Dopa is converted into dopamine resulting in increased levels of dopamine in these neurons. In response to physiological impulses these neurons are therefore capable of releasing larger amounts of dopamine, the quantity of which approximates the normal required levels. This treatment therefore alleviates the symptoms of the disease and contributes to the well-being of the patients.

However, this L-Dopa treatment has its drawbacks, the main one being that its effectiveness is optimal only in the first few years following the onset of treatment. After this initial period the clinical response is diminished and is accompanied by adverse side effects which include dyskinesia, fluctuation in efficacy throughout the day (onoff effect) and psychiatric symptoms such as confusional states, paranoia and hallucinations. This fall-off in the effect of L-Dopa treatment is attributed to a number of factors, including the natural progression of the disease, alteration in dopamine receptors as a consequence of increased dopamine production or increased levels of dopamine metabolites, and pharmacokinetic problems of L-Dopa absorption (reviewed by Youdim et al., Progress in Medicinal Chemistry, Vol. 21, Chapter 4, pp. 138-167 (1984), Eds. Ellis and West, Elsevier, Amsterdam).

In order to overcome the drawbacks of the L-Dopa treatment, various treatments have been devised in which L-Dopa is combined with MAO inhibitors, with the aim of reducing the metabolic breakdown of the newly formed dopamine (see for example, U.S. 4,826,875).

MAO exists in two forms known as MAO-A and MAO-B which have selectivity for different substrates and inhibitors. For example, MAO-B metabolises more efficiently substrates such as 2-phenylethylamine and is selectively and irreversibly inhibited by (-)-deprenyl (as described below).

It should be noted, however, that combining LDopa with an inhibitor of both MAO-A and MAO-B is undesirable leading to adverse side effects related to an increased level of catecholamines throughout the neuraxis. Furthermore, complete inhibition of MAO is also undesirable as it potentiates the action of sympathomimetic amines such as tyramine leading to the so-called cheese effect (reviewed by Youdim et al., Handbook of Experimental Pharmacology, Vol. 90, Chap. 3 (1988) Eds, Trendelenburg and Weiner, Springer-Verlag). As MAO-B was shown to be the predominant form of MAO in the brain, selective inhibitors for this form were thus considered to be a possible way for achieving a decrease in dopamine breakdown on the one hand, together with a minimization of the systemic effects of total MAO inhibition, on the other.

One of these selective MAO-B inhibitors, (-)deprenyl, has been extensively studied and has been used as an MAO-B inhibitor to augment L-Dopa treatment. This treatment with (-)-deprenyl is generally favourable, not causing the cheese effect at doses causing nearly complete inhibition of MAO-B (Elsworth et al., Physchopharmacology, 57, 33 (1978). Furthermore, addition of (-)-deprenyl to a combination of L-Dopa and decarboxylase inhibitor to Parkinson's patients leads to improvements in akinesia and overall functional capacity as well as the elimination of on-off type fluctuations (reviewed by Birkmayer & Riederer in Parkinson's Disease pp. 138-149, Springer-Verlag (1983)).

Thus, (-)-deprenyl enhances and prolongs the effect of L-Dopa and permits a lowering of the dosage of LDopa whereby the adverse effects of L-Dopa treatment are limited.

A more potent selective inhibitor of MAO-B than the racemic mixture is the optical isomer R-(+)-Npropargyl-l-aminodan. HC1 [R-(+)-PAI.HCl] which is more selective in vivo and in vitro as described in our copending Israel Patent Application No. 92952.

However it is highly desirable to further increase the selectivity of MAO inhibitor, inhibiting preferably MAOB and not MAO-A, thus minimizing the side effects caused by the inhibition of MAO-A.

The compounds of the present invention were found to have a surprisingly high degree of selectivity in vitro, inhibiting preferably MAO-B over MAO-A.

The compounds of the present invention are mono-fluoro derivatives of N-propargyl-l-aminoindan stereoisomers and salts thereof.

US 3,513,244 claims generically and specifically a large number of secondary and tertiary aminoindans which are stated to have hypotensive activity. There is no disclosure of the specific compounds of the present invention, and there is no evidence that the monofluorinated derivatives of 1-propargylaminoindan of the present invention have ever been synthesised and characterised. Furthermore, the secondary and tertiary aminoindans of US 3,513,244 are stated to have hypotensive activity and there is no teaching that any components of the group have any as MAO-B inhibitor activity.

GB 1,003,686 discloses a group of benzocycloalkane compounds in which the cycloalkane has from five to seven ring members and is substituted by an N-(alkynylalkyl)amino group. This patent mentioned the possibility of substituting the aromatic portion of the benzo-cycloalkane ring system by one or more halogen atoms. Although the compounds of the present invention are generically included in the group, they are not specifically disclosed. The compounds claimed in GB 1,003,683 are stated to be as monoamine oxidase inhibitors in general, but there is no disclosure of any activity by which MAO-B is inhibited, selectively in preference over MAO-A.

The mono-fluorinated N-propargyl-1-aminoindans of the present invention are surprisingly more potent selective MAO-B inhibitors than any of the other species of the groups disclosed in both US 3,513,244 and GB 1,003,686, enabling the inhibition of MAO-B at lower concentrations. This high potency and selectivity in vivo is a unique and surprising property of the mono-fluorinated N-propargyl-1aminoindan compounds and their salts according to the invention, not shared by other halogenated N-propargyl-1aminoindans.

The MAO-3 inhibitors of the present invention can also be used for the treatment of patients with dementia of the Alzheimer type (DAT), ana. the treatment of patients wxth depression and for treatment of hyperactive syndrome in children. Other MXo-3 inhibitors have been usea an me case for the treatment of patients suffering from these diseases (Tarior et al.,' Psychopharmacology, 91, 489-495, 1937), J. Mendlewich ana M.3.H. Ycudim (Brit. J. Psychiat., 142, 08ה511, 1983, Perenyi A., et al., PCT/HU89/00044, 17 August 1988).

DETAILED DESCRIPTION ^of THE INVENTION

The present invention provides a compound selected from the group consisting of 4-fluoro-N-propargyl-1aminoindan, 5-fluoro-N-propargyl-l-aminoindan, 6-fluoroN-propargyl-l-aminoindan, or its optically pure enantiomer, and pharmaceutically acceptable addition salts thereof.

A preferred compound of the invention is 6-fluoro-Npropargyl-l-aminoindan and particularly preferred compound is the enantiomer (+)-6-fluoro-N-propargyl-1aminoindan.

The present invention also relates to pharmaceutical compositions comprising compounds selected from the group consisting of 4-fluoro-N-propargyl-l-aminoindan, 5fluoro-N-propargyl-l-aminoindan,6-fluoro-N-propargyl-1aminoindan, or its optically pure enantiomer together with pharmaceutically acceptable carriers and/or excipients and/or diluents. The pharmaceutical compositions may be adapted for oral, rectal, parenteral, topical or transdermal administration. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or soft gelating capsules, syrups and suspensions. Suitable forms for parenteral administration include ampoules or vials which additionally contain an aqueous or nonaqueous solution or emulsion. Compositions adapted for rectal administration include suppositories with hydrophilic and/or hydrophobic vehicles.

The pharmaceutical compositions may be in dosage unit forms preferably containing 1-20 mg of the compound according to formula (I). The pharmaceutical compositions may additionally comprise levodopa and a decarboxylase inhibitor, such as L-carbidopa or benserazide. Preferably the pharmaceutical composition will comprise 2-10 mg of the compound selected from the group consisting of 4-fluoroN-propargy1-1-aminoindan, 5-fluoro-N-propargyl-l-aminoindan, 6-fluoro-N-propargyl-l-aminoindan, or its optically pure enantiomer, 50-250 mg levodopa and 10-25 mg of Lcarbidopa. Another preferable pharmaceutical composition will comprise 2-10 mg of the compound selected from the group consisting of 4-fluoro-N-propargyl-l-aminoindan, 5fluoro-N-propargyl-l-aminoindan,6-fluoro-N-propargyl-1aminoindan, or its optically pure enantiomer, 10-250 mg levodopa and 12.5-50 mg benserazide.

The present invention further relates to the use of a compound selected from the group consisting of 4fluoro-N-propargyl-l-aminoindan,5-fluoro-N-propargyl-1aminoindan, 6-fluoro-N-propargyl-l-aminoindan, or its optically pure enantiomer for manufacturing a pharmaceutical composition for the treatment of human patients suffering from Parkinson's disease, memory disorders, dementia of the Alzheimer type and hyperactive syndrome in children.

_ g

The invention also relates to processes for the preparation of the compound of formula (I).

ch₂-c=ch־hn.

The racemic mixture of the compound of formula (I) can be prepared by reacting aryl fluorinated 1-chloro or 1bromoindans, with propargylamine. Alternatively, these racemates may be prepared by reacting propargylamine with substituted 1-indanones to form the corresponding imines, followed by reduction of the carbon-nitrogen double bond of the imine with a suitable agent, such as sodium borohydride.

Another method of preparation of the racemic mixture of the compound of formula (I) comprises the reaction of a racemic fluorinated 1-aminoindan of the formula:

nh₂ with propargyl bromide or propargyl chloride in the presence of an organic or inorganic base, optionally in the presence of a suitable solvent and, if desired, converting the resulting free base of formula I into a pharmaceutically acceptable acid addition salt thereof.

The racemic mixture of (+) and (-) enantiomers of fluorinated 1-aminoindan may be prepared by chemical reduction of corresponding fluorinated oximes, e.g., with Zn in acetic acid or by catalytic hydrogenation. Fluorinated indan-l-one may be prepared, e.g., by Friedel-Crafts cyclization of fluorinated dihydrocinnamic chloride using aluminium chloride or other Lewis acids as condensing agents. Fluorinated dihydrocinnamic chlorides may be prepared.

The enantiomers of the compounds of formula (I) may be obtained by optical resolution of racemic mixtures of ( + ) and (-) enantiomers of compounds of formula (I). Such a resolution can be accomplished by conventional resolution methods, well known to a person skilled in the art, such as those described in Enantiomers, Racemates and Resolutions by J. Jacques, A. Collet and S. Willen, Pub. John Wiley & Sons, NY 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column. Another suitable resolution method is the formation of diastereomeric salts with a chiral acid such as tartaric, maleic, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine, followed by recrystallization to isolate the diastereomeric salt of the desired enantiomer.

In accordance with this invention, the ( + ) enantiomers of the compounds formula (I) can be prepared directly from the optically active (-)-enantiomers of fluorinated 1-aminoindans of the formula

<img file="IL99759A_D0001.tif" />

by reaction with propargyl bromide or propargyl chloride in the presence of an organic or inorganic base and optionally in the presence of a suitable solvent and if desired converting the resulting (-) enantiomeric free base of formula I into a pharmaceutically acceptable acid salt thereof.

Suitable organic or inorganic bases for use in the above reaction are, e.g., triethylamine, pyridine, alkali metal carbonates or bicarbonates etc. If the reaction is conducted in the presence of a solvent, this may be chosen from, e.g., toluene, methylene chloride and acetonitrile. A preferred method of preparation of the aforementioned compounds is the reaction between fluorinated (-)-1aminoindans with propargyl chloride using potassium carbonate as a base and acetonitrile as solvent.

The above described reaction between fluorinated 1-aminoindans generally results in a mixture of unreacted primary amines, the desired secondary amines and tertiary amines, namely the Ν,Ν-bispropargylamino products. The desired secondary amines, i.e. fluorinated N-propargyl-1aminoindans, can be separated by conventional separation methods including but not limited to chromatography, distillation and selective extraction.

Alternatively, the fluorinated (-)-1-aminoindans may be prepared by reacting fluorinated 1-indanone with an optically active amine, followed by reduction of the carbonnitrogen double bond of the resulting imine by hydrogenation over a suitable catalyst such as platinum oxide, Raney nickel, or by chemical reduction, for example, with sodium borohydride. Suitable optically active amines are, for example, one of the antipodes of alphaphenylethylamine or an ester of an amino acid, such as phenylalanine. The benzylic N-C bond may be cleaved by hydrogenolysis.

Halogenated (-) aminoindans may also be prepared by enzyme mediated selective acylation of a racemic mixture of a compound of the formula:

<img file="IL99759A_D0002.tif" />

(III) preferably using the enzyme subtilisin A isolated from Bacillus licheniformis in 3-methyl-3-pentanol with trifluoroethyl butyrate as the acylating agent thereby forming a mixture comprising an acylated (+) enantiomer fluoro-l-aminoindan and a non-acylated (-) enantiomer of fluoro-l-aminoindan than the resulting halogenated (-)-1aminoindan may be readily separated from the corresponding (+)-amide by chromatography, distillation, selective extraction, or conversion of the free base into a suitable acid addition salt and its recrystallisation.

Finally the (+)-fluoro-N-propargyl-l-aminoindan is prepared by reacting the separated (-) fluoro-l-aminoindan with propargyl bromide or propargyl chloride in the presence of an organic or inorganic base, optionally in the presence of a suitable solvent, and isolating the (+) fluoro-Npropargyl-1-aminoindan formed as the free base or a pharmaceutically acceptable acid addition salt thereof.

Additional methods for preparing fluorinated (-)1-aminoindans are the reduction, as described above, of indan-1-one oxime ethers, wherein the alkyl portions of the ether contains an optically pure chiral centre. Alternatively, a non-chiral derivative of fluorinated indan1-ones containing a carbon-nitrogen double bond, such as an imine or oxime, can be reduced with a chiral reducing agent, e.g., a complex of lithium aluminium hydride and ephedrine.

Pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared by reacting according to conventional methods the free base forms of the compounds of formula (I) with the desired acids in the presence of a suitable solvent. Similarly, an acid addition salt may be converted to the free base form or directly to another acid addition salt by methods well known to those skilled in the art.

Thus, the present invention also provides a method for the preparation of a (-) enantiomer of the formula (III) wherein X represents a halogen, comprising:

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a) selectively acylating a racemic mixture of a compound of the formula (III) wherein X represents a halogen, using the enzyme subtilisin A isolated from Bacillus licheniformis thereby forming a mixture comprising an acylated ( + ) enantiomer of halogenated-1-aminoindan and a non-acylated (-) enantiomer of halogenated-l-aminoindan,

b) separating the (-) halogenated-l-aminoindan from the acylated (+) halogenated-l-aminoindan by chromatography, distillation, selective extraction or conversion of the free base into a suitable acid addition salt and its recrystallisation.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The present invention will not be specifically described in the following Examples to which it is not limited.

Example 1: 5-Fluoro-1-aminoindan

A solution of 3-fluorobenzaldehyde (10g), malonic acid (15.6 g) and piperidine (0.7 ml) in pyridine (35 ml) was heated at reflux for 3.5 hours. After cooling to room temperature, the reaction mixture was added to a mixture of ice water (210 ml) and cone, hydrochloric acid (56 ml). The precipitate was isolated by filtration and recrystallised from methanol/water to give 3-fluorocinnamic acid (11.3 g).

A mixture of 3-fluorocinnamic acid (11 g), sodium hydroxide (2.7 g), 3% sodium amalgam (220 g) in 340 ml of water was heated overnight at 70-80°C. The aqueous solution was decanted from the mercury residue and acidified with cone, hydrochloric acid (35 ml) to pH 2, cooled at 0°C and the resulting precipitated 3-fluorohydrocinnamic acid (10 g) isolated by filtration.

A solution of 3-fluorohydrocinnamic acid (28 g) in thionyl chloride (90 ml) was heated at reflux for 3 hours. 3-Fluorohydrocinnamoyl chloride (27 g) was isolated by distillation (150-110’C @ ca 20 mm.Hg).

A solution of 3-fluorodihydrocinnamoyl chloride (15.4 g) in carbon disulfide (78 ml) was added dropwise to a cold (-5°C) mixture of aluminium chloride (13.9 g) in carbon disulfide (300 ml) for 30 minutes. During this time and for 30 minutes the mixture was allowed to warm to room temperature (1 hr), then it was heated to reflux (1 hr) and finally the volatiles were removed by distillation under reduced pressure. The residue was dissolved in methylene chloride (400 ml) and washed successively with 10% aqueous sodium hydroxide and water. After drying (magnesium sulfate) and solvent removal in vacuo, 5-fluoroindanone (2 g) was isolated by recrystallisation from hexane.

A solution of 5-fluoroindanone (10 g), hydroxylamine hydrochloride (9 g), potassium carbonate (23 g) and water (3.5 ml) in 96% ethanol (40 ml) was heated to

99759-8 reflux, cooled to ca 45 and additional hydroxylamine hydrochloride (4.5 g) and potassium carbonate (11.5 g) were added and refluxed for an additional 30 min. At this time the mixture was poured into cold water (300 ml) and stirred in an ice bath for one hour; 5-fluoroindanone oxime (9.8 g) was isolated by filtration.

Zinc powder (20.2 g) was added during three hours to the stirred solution of the above oxime (20.2 g) in acetic acid (200 ml) which maintains the temperature at 2535°C. The resulting mixture was stirred an additional 12 hours at room temperature. The solids were removed by filtration and the filtrate concentrated in vacuo. The concentrated filtrate was partitioned between water and toluene and the aqueous phase adjusted to pH 12 with ammonium hydroxide and extracted with toluene. Solvent removal in vacuo gave 5-fluoro-l-aminoindan (17.8 g) as a colored oil.

IR: 690, 748, 815, 864, 929, 1126, 1244, 1315, 1377, 1433, 1454, 1485, 1595, 1614, 2800, 3000, 3300 cm¹־.

NMR: 1.81, 2.4, 2.8, 6.8, 7.2; m/e 151.0786 C_gH₁₀NF;

Example 2: 4-fluoro-l-aminoindan

The title compound was prepared in 47% overall yield according to the procedure of Example 1 except that 2fluorobenzaldehyde was used instead of 3-fluorobenzaldehyde.

IR: 708, 780, 1170, 1242, 1290, 1377, 1472, 1587, 1624, 2800, 2950, 3200 an¹־;

NMR: 1.7, 2.1, 2.7, 2.9, 3.1, 4.3, 6.8, 7.0, 7.1;

m/e: 151.0782 (C_gH₁₀NF)

Example 3: 6-fluoro-l-aminoindan

The title compound was prepared in 29% overall yield according to the procedure of Example 1 except that 4fluorobenzaldehyde was used instead of 3-fluorobenzaldehyde.

IR: 694, 740, 770, 812, 844, 870, 912, 1130, 1163, 1253, 1441, 1483, 1597, 1612, 2800, 3000, 3300 an¹־;

NMR: 1.5, 2.1, 2.8, 6.8, 7.1; m/e 151.0774 C_gH_1QNF

Example 4; (-)-6-Fluoro-l-aminoindan

A solution of 6-fluoro-l-aminoindan (4,2 g) in methanol (10 ml) was added to a heated clear solution of LN-acetyl-methyl-3,4-dimethoxyphenylalanine (7,8 g) in methanol (30 ml). The mixture was stirred with cooling. The product was crystallised from methanol with carbon black (0.5 g) two times and checked by HPLC (chiral column).

The title compound obtained by extraction from aqueous 10% sodium hydroxide with methylene chloride, drying and evaporation.

[a]_D.9^e (c 2%, EtOH).

The spectral properties were identical to the compound of Example 3.

Example 5: (+)-6-Fluoro-l-aminoindan

The title compound was crystallised from mother liquors after separation of (-)-antipode by the procedure of Example 4, and repeated crystallisation from the same solvent. The title compound was obtained by extraction from aqueous 10% sodium hydroxide with methylene chloride, drying and evaporation. The spectral properties were identical to the compound of Example 3.

Example 6: (-)-4-Fluoro-l-aminoindan

The title compound was prepared in 50% yield according to the procedure of Example 4 except that 4fluoro-l-aminoindan was used instead of 6-fluoro-laminoindan. The spectral properties were identical to the compound of Example 2.

Example 7: (-)-5-Fluoro-l-aminoindan:

The title compound was prepared in 25% yield according to the procedure of Example 4 except that 5fluoro-l-aminoindan was used instead of 6-fluoro-laminoindan. The spectral properties were identical to the compound of Example 1.

Example 8: (-)-6-Fluoro-l-aminoindan

A solution of 20 grams of racemic 6-fluoro-laminoindan and 60 ml of tri fluoroethyl butyrate in 400 ml of

3-methyl-3-pentanol was treated with 2 g of subtilisin A. The resulting suspension was shaken on an orbital shaker at 200 rpm at 40’C for 72 hours at which time the enzyme was removed by filtration, and the filtrate was extracted with IM aqueous hydrochloric acid. The aqueous layer was back extracted with methylene chloride and freeze dried to yield 10 grams of the title compound as the HC1 salt. The free base was obtained by suspending the HC1 salt in aqueous 10% sodium hydroxide, extracting with methylene chloride, drying and evaporation. The free base so obtained was of 99% optical purity with spectroscopic properties identical to those of the compound from Example 4.

Example 9; (-)-5-Fluoro-1-aminoindan

The title compound was obtained in 99% optical purity by the method of Example 8 using racemic 5-fluoro-laminoindan instead of 6-fluoro-l-aminoindan.

Example 10: (-)-4-Fluoro-l-aminoindan

The title compound was obtained in 99% optical purity by the method of Example 8 using racemic 4-fluoro-laminoindan instead of 6-fluoro-l-aminoindan.

Example 11; 5-Fluoro-N-propargyl-l-aminoindan hydrochloride A mixture of 5-fluoro-l-aminoindan (6.2 g), potassium carbonate (7.4 g) and acetonitrile (54 ml) were heated under nitrogen to 60^eC. Propargyl chloride (3.3 g) was added and heating was continued overnight. Acetonitrile was evaporated and products were distributed between methylene chloride and 10% sodium hydroxide in water.

The free base of the title compound was isolated by flash column chromatography on silica gel.

An ethereal solution of this base was treated with hydrogen chloride gas and the title compound (2.8 g) was isolated by filtration.

M.p. 178.4’C (decomp.); IR (KBr) 899, 1216, 1437, 1491, 2359, 2928, 3287 cm¹־. Anal, calcd. for C₁₂H₁₅C1FN: % C 63.86, H 5.81, N 6.21, Cl 15.71; found % C 63.38, H. 5.69, N 6.33, Cl 15.00.

Example 12; 4-Fluoro-N-propargyl-l-aminoindan hydrochloride

The title compound was prepared in 29% yield according to the procedure of Example 11 except that 4fluoro-l-aminoindan was used instead of 5-fluoro-laminoindan.

M.p. 191.3^eC (decomp.); IR (KBr) 771, 1045, 1248 1473, 1586, 2400, 2653, 2719, 2949, 3200 cm¹־; m/e 190. Anal, calcd. for C₁₂H₁₅C1FN; % C 63.86, H 5.81, N 6.21, Cl 15.71; found % C 63.66, H.58, N 6.15, Cl 15.54.

Example 13: 6-Fluoro-l-propargylaminoindan

The title compound was prepared in 44% yield according to the procedure of Example 11 except that 6fluoro-1-aminoindan was used instead of 5-fluoro-laminoindan. The spectral properties were identical to the compound of Example 16.

Example 14; (+)-4-Fluoro-N-propargyl-l־aminoindan hydrochloride

The title compound was prepared in 70% yield according to the procedure of Example 11 except that (-)-4fluoro-l-aminoindan was used instead of 5-fluoro-laminoindan.

M.p. 218.9°C (decomp.); [a]D + 10.7 (c, 0.4%, H₂0); NMR (D₂0) 2.35 m, 2.65 m, 3.00 m, 3.93 s, 4.8 s, 5.00 m, 7.15 m, 7.33 m ppm; m/e 189.09;

IR (KBr) 771, 1248, 1583, 2438, 2655, 2718, 2849, 2945, 3239 cm־l; Anal, calcd. for C-^HisClFN: % C 63.86, H. 5.81, N. 6.21, Cl 15.71; found % C 64.01, H 5.74, N 6.05, Cl 15.80.

Example 15: (+)-5-Fluoro־N־propargyl-l-aminoindan hydrochloride

The title compound was prepared in 50% yield according to the procedure of Example 11 except that (-)-5fluoro-l-aminoindan was used instead of 5-fluoro-laminoindan.

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NMR (CDCI3) 2.35 m, 2.8 m, 3.3 m, 3.6 s, 4.6 d, 6.8 m, 7.6 m ppm; m/e 189.09; IR (KBr) 690, 713, 833, 945, 1016, 1238, 1252, 1420, 1444, 1487, 1600, 1625, 2100, 2400, 2500, 2900, 3250 cm¹־; [a]_D +23.5° (c, 0.2%, ¾0),- M.p. 192°C (decomp.); Anal, calcd. for C₁₂H₁₅C1FN; % C 63.86, H 5.81, N 6.21, Cl 15.71;

found % C 64.52, H. 5.68, N 6.35, Cl 15.47.

Example 16: (+)-6-Fluoro־N-propargyl-l-aminoindan hydrochloride

The title compound was prepared in 46% yield according to the procedure of Example 11 except that (-)-6fluoro-l-aminoindan was used instead of 5-fluoro-laminoindan.

M.p. 220.8°C (decomp.); [a]D=+18.1° (c, 0.3%, H₂0);

IR (KBr) 694, 735, 820, 880, 1042, 1131, 1173, 1228, 1246, 1256, 1365, 1460, 1492, 1584, 1599, 2128, 2438, 2946, 3064, 3224 cm. Anal, calcd. for C!2^H15^(11FN: % C 63.86, H. 5.81, N 6.21, Cl 15.71;

found % C 64.39, H 5.54, N. 6.21, Cl 15.71.

Example 17: (6-(־-Fluoro-N-propargyl-l-aminoindan hydrochloride

The title compound was prepared in 61% yield according to the procedure of Example 11, except that ( + )-6 fluoro-1-aminoindan was used instead of 5-fluoro-laminoindan.

M.p. 220°C; [a]D=-17.7^e; IRJKBr) 828, 1130, 1228, 1493, 1597, 2440, 2633, 2945, 3229 cm¹־.

Example 18: 6-Chloro־N-propargyl-l-aminoindan hydrochloride

The title compound was prepared in 33.1% yield according to the procedure of Example 11 except that 6chloro-1-aminoindan was used instead of 5-fluoro-laminoindan.

M.p. 191.7°C (decomp.); NMR (D₂0) 2.3 m, 2.5 m, 3.1 m, 3.93 s, 4.9 d, 5m ppm; m/e 205.0658 and 207.0640.

IR (KBr) 760, 812, 1091, 1259, 1472, 1578, 1599, 1651, 1700, 2900, 3300 cm; Anal, calcd. for Cj2H!3NC12: % C 59.52, H 5.41, N 5.78, Cl 29.28; found % C 59.80, H 5.33, N 5.61, Cl 29.11.

Example 19: 4,6-Difluoro-N־propargyl-l-aminoindan hydrochloride

The title compound was prepared in 61.8% yield according to the procedure of Example 11 except that 4,6difluoro-l-aminoindan was used instead of 5-fluoro-laminoindan.

M.P. 218.8°C (decomp.); NMR (D₂0) 1.16, 2.36 m, 2.63 m, 3.02 m, 3.98 s, 7.01 s, 7.18 d; m/e 207.0817;

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IR (KBr) 851, 872, 980, 995, 1055, 1113, 1335, 1447, 1462, 1487, 1584, 1601, 1630, 2400, 2700, 2950,3200 an¹־;

Anal, calcd. for C-_L2H₁₂^NC1F2^{; % C 59}.¹⁵׳ ^{H 4}.⁹⁵׳ ^{N 5}.⁷⁵׳ ^C114.55;

found % C 59.41, H 5.19, N 5.61, Cl 13.98.

Example 20; Pharmaceutical formulation

A typical pharmaceutical preparation can be prepared as follows:

Each tablet contains:

<td> 6-fluoro-N-propargylaminoindan hydrochloride</td><td> 3.0 mg</td>

<td> Pregelatinized starch</td><td> 11.0 mg</td>

<td> Starch</td><td> 48.5 mg</td>

<td> Microcrystalline cellulose</td><td> 80.0 mg</td>

<td> Ethylcellulose</td><td> 1.0 mg</td>

<td> Talc</td><td> 1.5 mg</td>

<td> Tablet weight:</td><td> 145.0 mg</td>

Blend the excipients and the active granulate with Isopropyl alcohol. Dry the mixture, blend with the talc and compress into tablets.

<td> Similar formulations can be prepared</td><td> by one</td>

<td> skilled in the art for each of the compounds</td><td> of the</td>

invention.

Example 21; Tablet Composition

Each tablet contains:

6-fluoro-N-propargyl-l-aminoindan-hydrochloride 5.0 mg

<td> Levodopa</td><td> 100.0 mg</td>

<td> Carbidopa</td><td> 25.0 mg</td>

<td> Pregelatinised starch</td><td> 24.0 mg</td>

<td> Starch</td><td> 40.0 mg</td>

<td> Microcrystalline cellulose</td><td> 49.5 mg</td>

Alcohol USP added as required to granulation.

Similar formulations can be prepared by one skilled in the art for each of the compounds of the invention.

Example 22; Inhibition of MAO Activity In-Vitro Experimental Protocol:

These experiments were performed essentially according to the protocol of K.F. Tipton and M.B.H. Youdim in CIBA Symposium No. 39, Editors: G.E.W. Wolstenholme and J. Knight, Elsevier, Amsterdam, 1976, pp. 393-403. The MAO enzyme source was a homogenate of rat brain in 0.3 M sucrose which was centrifuged at 600 g for 15 minutes. The supernatant was diluted appropriately in 0.05M phosphate buffer and preincubated with serial dilutions of compounds of interest which are listed below for 20 minutes at 37^eC. ¹ -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). Substrate concentrations used were 20 μΜ (PEA) or ImM (5-HT). In the case of PEA the enzyme concentration was chosen so that not more than 10% of the substrate was metabolised during the course of the reaction. The reaction was then stopped by the addition of tranylcypromine (to final concentration of 1 mM) and the incubate filtered over a small column of Amberlite CG-50; buffered to pH 6.3. The column was washed with 1.5 ml water, ־ 28 the eluates pooled and the radioactive content determined by liquid scintillation spectrometry. Since the amine substrates are totally retained on the column, radioactivity in the eluate indicates the production of neutral and acidic metabolites formed as a result of MAO activity. Activity of MAO in the sample was expressed as a percentage of control activity in the absence of inhibitors after subtraction of appropriate blank values. The activity determined using PEA as a substrate is referred to as MAO B activity, and that determined using 5-HT as a substrate is referred to as MAO A activity. The inhibitory activity of each of the compounds was examined separately in vitro and is shown in Table 1.

The results shown in Table 1 demonstrate that the fluorinated propargylaminoindans of the invention are surprisingly more selective MAO-B inhibitors than the nonhalogenated parent compound. The preferred compound of the invention, (+ )-6-F-propargyl-N-aminoindan is much more selective than the parent non-fluorinated compound and more selective than the other fluorinated derivatives.

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TABLE 1

IC50 Values (pM) for Inhibition of MAO-A and MAO-B in Brain Homogenates

<img file="IL99759A_D0003.tif" />

hn-ch₂-c=ch

<td> Compound Substituent</td><td> MAO-B</td><td> MAO-A</td><td> Selectivity MAO-A/MAO-B</td>

<td> 4-F</td><td> 0.0058</td><td> 0.5</td><td> 86</td>

<td> (+)-4-F</td><td> 0.0052</td><td> 0.34</td><td> 65</td>

<td> 5-F</td><td> 0.006</td><td> 0.7</td><td> 116</td>

<td> (+)-5-F</td><td> 0.0057</td><td> 0.14</td><td> 24</td>

<td> 6-F</td><td> 0.0062</td><td> 4.00</td><td> 645</td>

<td> (+)-6-F</td><td> __ 0.0022</td><td> 2.8</td><td> 1244</td>

<td> (-)-6-F</td><td> ~12</td><td> 40</td><td> 3</td>

<td> 6-Cl</td><td> 0.0077</td><td> 6.9</td><td> 896</td>

<td colspan="2"> (+)-4,6-Difluoro 0,5</td><td> 0.8</td><td> 2</td>

<td> H</td><td> 0.003</td><td> 0.073</td><td> 24</td>

ICgQ the concentration that caused 50% inhibition in MAO activity

Example 23: Inhibition of MAO Activity Ex-vivo: Acute Treatment Experimental Protocol:

Rats (male Sprague-Dawley derived) weighing 250±20 g were treated with the desired compound by intraperitoneal injection (ip) or oral gavage (po) and decapitated 2 hours later. Groups of three rats were used for each dose level of the compound and MAO activity was determined in the brain and liver using the general technique described above. The amount of protein in each incubation was determined using the Folin-Lowry method, and enzyme activity was calculated as nmol substrate metabolised per hour incubation for each mg protein. Activity of MAO in tissues from animals treated with inhibitors was expressed as a percentage of the enzyme activity in a group of control animals which were administered the vehicle alone (water in the case of oral gavage, or 0.9% saline in the case of intraperitoneal injection) and killed as above. The results are presented in Table 2.

The ex-vivo experiment demonstrates that the monofluorinated derivates of 1-propargylaminoindan of the present invention are more potent and selective in the inhibition of MAO-B as compared to MAO-A than the 6chloro derivates.

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TABLE 2

EX-VIVO HAO INHIBITORY ACTIVITY

<img file="IL99759A_D0004.tif" />

hn-ch₂-csch

<td colspan="5"> ED-50 BRAIN (mg/kg)</td><td colspan="2"> ED-50 LIVER (mg/kg)</td>

<td> !Compound Substituent R</td><td> HAO-B</td><td> MAO-A</td><td> MAO-A/MAO-B</td><td> MAO-B</td><td> MAO-A</td><td> MAO-A/MAO-B</td>

<td> 4-F</td><td> 0.22</td><td> 1.4</td><td> 6 </td><td> 0.13</td><td> 2.4</td><td> 18.5</td>

<td> (+)-4-F</td><td> 0.33</td><td> &gt;1.0</td><td> &gt;3</td><td> 0.17</td><td> &gt;1.0</td><td> &gt;5.9</td>

<td> 5-F</td><td> 0.4</td><td> 2.3</td><td> 6</td><td> 0.06</td><td> 2.2</td><td> 36.7</td>

<td> (+)-5-F</td><td> 0.07 </td><td> &gt;0.1</td><td> &gt;1.4</td><td> 0.07</td><td> &gt;0.1</td><td> &gt;1.4</td>

<td> 6-F</td><td> 0.13</td><td> 22</td><td> 170</td><td> ND ־</td><td> ND</td><td> ND</td>

<td> (+)-6-F</td><td> 0.14</td><td> 21.3</td><td> 152</td><td> 0.13</td><td> 5.2</td><td> 40</td>

<td> (-)6־-F</td><td> 0.45</td><td> 23</td><td> 51</td><td> &lt;0.5</td><td> ND</td><td> ND</td>

<td> 6-C1</td><td> 1.7</td><td> 10</td><td> 5.8</td><td> NO</td><td> ND</td><td> ND</td>

<td> (+)4,6-Difluoro</td><td> 3.7</td><td> 2.9 —</td><td> 1</td><td> ND .</td><td> ND</td><td> ND</td>

<td> H</td><td> 0.07</td><td> 1.2</td><td> 17.</td><td> 0.06</td><td> 5</td><td> 83</td>

ND ^:- Not determined

Rn-RO - The effective (mg/kg) that caused 50% inhibition in MAO activity

MAO - A/MAO-B - This is a measure of selectivity