WO1996015100A1

WO1996015100A1 - Heterocyclic compounds, their preparation and use

Info

Publication number: WO1996015100A1
Application number: PCT/DK1995/000444
Authority: WO
Inventors: Roberto Pellicciari; Roberto Luneia; Grazia Lombardi; Flavio Moroni
Original assignee: Novo Nordisk AS
Current assignee: Novo Nordisk AS
Priority date: 1994-11-09
Filing date: 1995-11-08
Publication date: 1996-05-23
Anticipated expiration: 1997-05-09
Also published as: WO1996015099A1; AU3839895A; AU1106195A

Abstract

The present invention relates to therapeutically active heterocyclic compounds of formula (I), wherein n is 0, 1 or 2; and X is -O-, -S, -N(R5)- or -CH¿2?-; and R?1¿ is H, NH¿2, NHR?5 or OH; and R?2 and R3¿ independently are H, COOH; COOR5, CONH¿2?, CONHR?5, CON(R5)¿2, CONHSO2R5 or tetrazole; and R4 is H, OH, NH¿2?, NHR?5; CF¿3, C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, C3-6-cycloalkyl, phenyl or C1-4-alkoxy; and R5 is H, C¿1-8?-alkyl, C2-8-alkenyl, C2-8-alkynyl, phenyl or C3-6-cycloalkyl; and ring A can be partly or completely saturated or aromatic, or a salt thereof with a pharmaceutically acceptable acid or base, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating diseases in the central nervous system related to the metabotropic glutamate receptor system.

Description

Heterocvclic compounds, their preparation and use

The present invention relates to therapeutic active amino acids, a method for preparing the same, pharmaceutical compositions comprising the compounds and a method of treating therewith.

Recent molecular biological studies have clearly established the existence of two major types of glutamate receptors in the central nervous system namely the ionotropic and the metabotropic glutamate receptors. The latter is characterised by being G-protein-linked to changes in second messenger formation and modulation of ion channel function, (Meldrum,

B. (1991 ) Epilepsy Res. 10, 55-61 , Chapman, A. (1991 ) in Excitatory Amino Acids p. 265-286, Blackwell scientific publ. ltd., Oxford).

At present 6 different subtypes of the metabotropic glutamate receptors are described (MGIuR₁ to MGIuR_β) and in addition some spliced variants of the subtypes are reported.

The Metabotropic glutamate receptor subtypes MGIuR, and MGIuR₅ are coupled to phosphoinositide hydrolysis (Johnson, G. and Bigge, C.F. (1991 ) Annu. Rep. Med. Chem. 26, 11-22, Hansen, J.J. and

KrogsgaardLarsen, P. Med. Res. Rev. 10,55-94, Thomsen, C. and Suzdak, P. (1993) Eur. J. Pharmacol. 245 ,299), while the others are coupled to cyclic AMP formation (Schoepp, D.D., Johnson, B.G. and Monn, J.A. (1992) J. Neurochem. 58, 1184-1186, Cartmell et al. (1992) J. Neurochem. 58, 1964-1966, Manzoni, O. et al. (1992) Eur. J.

Pharmacol. 225, 357-358).

Compounds such as L-glutamate, quisqualate and ibotenate are known to act as non-selective agonists on the metabotropic glutamate receptors, while selective ionotropic glutamate receptor agonists such as NMDA, AMPA and kainate do have little effect on these receptors.

Recently a few compounds without activity at the ionotropic glutamate receptors but with activity at the metabotropic receptors have been identified.

These comprise trans-ACPD (trans 1 S,3R-1-aminocyclopentane-1 ,3- dicarboxylic acid), the partial agonist L-AP3 (L-2-amino-3-phosphono- propionic acid) (Palmer, E., Monaghan, D.T. and Cotman, C.W. (1989) Eur. J. Pharmacol. 166, 585-587, Desai, M.A. and Conn, P.J. (1990) Neurosci. Lett. 109, 157-162, Schoepp, D.D. et al. (1991 ), J. Neurochem. 56, 1789-1796, Schoepp D.D. and Johnson B.G. (1989), J. Neurochem. 53,1865-1613), L-AP4 (L-2-amino-4-phosphonobutyrate) which is an agonist at the MGIuR₄ receptor (Thomsen C. et al. (1992), Eur. J. Pharmacol. 227, 361-362) and some of the isomers of CCG (2-(carboxγcyclopropyl)giγcines) especially L-CCG-I and L-CCG-II (Hayashi, Y. et al. (1992), Br. J. Pharmacol. 107, 539- 543).

Very few selective antagonists at the metabotropic glutamate receptors have been reported, however some phenylglγcine derivatives S-CPG

(S-4-carboxyphenyl glycine), S-4C3HPG (S-4-carboxy-3-hydroxy phenyl glycine) and S-MCPG ( S-alpha methyl-4-carboxyphenyl glycine) have been reported to antagonise trans ACPD stimulated phosphoinositide hydrolysis and thus possibly acting as antagonists at the metabotropic glutamate receptors at the subtypes MGIuR, and MGIuR_s (Thomsen, C. and Suzdak, P, (1993) Eur. J. Pharmacol. 245, 299).

Literature evidence suggests that compounds selective for the meta¬ botropic glutamate receptors either as agonists or antagonists are useful in the treatment of different neurological diseases. The use of compounds active at the metabotropic glutamate receptors for the treatment of epilepsy is corroborated by investigations of the influence of trans-ACPD in the formation of convulsions (Sacaan and Schoepp, (1992), Neurosci. lett. 139, 77) and that phosphoinositide hydrolysis mediated via MGIuR is increased after kindling experiments in rats (Akiyama et al. (1992), Brain Res. 569, 71 ).

Trans-ACPD has been shown to increase release of dopamine in the rat brain which indicates that compounds acting on the metabotropic glutamate receptors might be usable for the treatment of Parkinson's disease and Huntington's Chorea (Sacaan et al. (1992), J. Neurochem. 59, 245).

The use of compounds active at the metabotropic glutamate receptors for treatment of neurological diseases such as senile dementia has been indicated by the findings of Zheng and Gallagher ((1992), Neuron 9, 163) and Bashir et al. ((1993), Nature 363, 347) who demonstrated that activation of metabotropic glutamate receptors are necessary for the induction of long term potentiation (LTP) in nerve cells (septal nucleus, hippocampus) and the finding that long term depression is induced after activation of metabotropic glutamate receptors in cerebellar granule cells (Linden et al. (1991), Neuron 7,81 ).

Investigations also show that in the treatment of deficiencies of mental and motoric performance seen after conditions of brain ischemia the metabotropic glutamate receptor active compounds may prove usable.

Trans-ACPD has been shown to be a neuroprotective agent in an MCAO model in mice (Chiamulera et al. (1992), Eur. J. Pharmacol. 215, 353), and it has been shown to inhibit NMDA induced neurotoxicity in nerve cell cultures (Koh et al., (1991 ), Proc. Natl. Acad. Sci. USA 88, 9431 ). Also in the treatment of pain the metabotropic glutamate receptor active compounds seem of interest, proved by the fact that antagonists at the metabotropic glutamate receptors antagonises sensory synaptic response to noxious stimuli of thalamic neurons (Eaton, S.A. et al. (1993), Eur. J. Neurosci. 5, 186).

The above findings support that compounds acting on the metabotropic glutamate receptors are useful for the treatment of epilepsy, neurological diseases such as senile dementia, Parkinson's disease, Huntington's

Chorea, pain and deficiencies of mental and motoric performance seen after conditions of brain ischemia.

We have now discovered a series of new amino acids which are potent antagonists at the metabotropic glutamate receptors.

The present invention relates to compounds of formula I

wherein n is 0, 1 or 2; and X is -O-, -S, -N(R⁵)- or -CH₂-; and

R¹ is H, NH₂, NHR⁵ or OH; and

R² and R³ independently are H, COOH, COOR⁵, CONH₂, CONHR⁵,

CON(R^B)₂, CONHSOjR⁵ or tetrazole; and

R* is H, OH, NH₂, NHR⁵, CF₃, C^-alkyl, C₂.₈-alkenyl, C₂.₈-alkynyl, C₃._β- cycloalkyl, phenyl or C^-alkoxy; and

R⁵ is H, C^-alkyl, C₂.₈-alkenyl, C₂.₈-alkynyl, phenyl or C₃._β-cycloalkyl; and ring A can be partly or completely saturated or aromatic, or a salt thereof with a pharmaceutically acceptable acid or base.

These salts include pharmaceutically acceptable acid addition salts, phar- maceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hγdrobromic, hydroiodic, phosphoric, sulfu- ric, trifluoroacetic, trichloroacetic, oxalic, maleic, pγruvic, malonic, succinic, citric, mandelic, benzoic, cinnamic, methanesulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceuti- cally acceptable salts listed in Journal of Pharmaceutical Science, 6J 2 (1977) and incorporated herein by reference, or lithium, sodium, potas¬ sium, magnesium and the like.

The term "C ₈-alkyr as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 8 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. butyl, isobutyl, tert. butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4- methylpentyl, neopentyl, n-hexyl, 2,2-dimethylpropyl and the like.

The term "C₂.₈-alkenyr as used herein refers to an unsaturated hydrocar¬ bon chain having from 2 to 8 carbon atoms and at least one double bond such as vinyl, 1-propenyl, allyl, isopropenγl, n-butenyl, n-pentenyl and n- hexenyl and the like.

The term"C₂-₈-alkynyP as used herein refers to an unsaturated hydrocar¬ bon chain having from 2 to 8 carbon atoms and at least one triple bond such as -C_≡.CH, -C_≡.CCH₃, -CH₂C_≡.CH, -CH₂-CH₂-C_≡_CH, -CH(CH₃)C_≡.CH and the like.

The term "C_j-_β-cycloalkyP as used herein refers to a radical of a satu¬ rated cyclic hydrocarbon having from 3 to 6 carbon atoms such as cγclopropyl, cyclobutyl, cyclopentyl or cγclohexyl and the like.

The term "C^-alkoxy" as used herein, alone or in combination, refers to a monovalent substituent comprising a lower alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 4 carbon atoms e.g. methoxy, ethoxy, propoxy, butoxy and the like.

It is to be understood that the invention extends to each of the stereo- isomeric forms of the compounds of formula I as well as the racemates.

The invention also relates to a method of preparing the above mentioned compounds. These methods comprise

a) reacting a compound of the formula II

prepared by well known methods, wherein X, n, R³, R⁴ have the mean¬ ings defined above with reagents well known for converting oxo groups to amino acids or hydroxy acids either through hydantoin formation, through hydroxy nitrile or through aminonitrile formation, or

b) reacting a compound of the formula III

wherein X, n, R\ R³ and R* have the meanings defined above with reagents known to transform a cyano group into a R² group wherein R² has the meaning defined above provided that R² must not be H.

Examples of the compounds of formula I are the following:

3-Amino-2,3-dihydrobenzo[b]furane-3,6-dicarboxylic acid,

3-Amino-2,3-dihγdrobenzo[b]furane-3,7-dicarboxylic acid,

3-Amino-2,3-dihydroindole-3,6-dicarboxylic acid, 3-Amino-2,3-dihydroindole-3,7-dicarboxylic acid,

3-Amino-1 -methyl-2,3-dihydroindole-3,6-dicarboxylic acid,

3-Amino-1 -propyl-2,3-dihydroindole-3,7-dicarboxylic acid,

3-Methylamino-1 -ethyl-2,3-dihydroindole-3,6-dicarboxylic acid,

3-Amino-2,3-dihydrobenzo[b]thiophene-3,6-dicarboxylic acid, 3-Hydroxy-2,3-dihydrobenzo[b]thiophene-3,7-dicarboxylic acid,

1 -Amino- 1-(5-tetrazolyl)indane-5-carboxylic acid,

Methyl 1 -amino-1 -(5-tetrazolyl)indane-6-carboxylate,

1-Aminoindan-1 ,5-dicarboxylic acid,

1-Aminoindan-1 ,6-dicarboxylic acid, 1 -Aminoindan-1 ,4-dicarboxylic acid,

1 -Amino-1 ,2,3,4-tetrahγdronaphtaiene-1 ,6-dicarboxylic acid,

1 -Amino-1, 2,3,4-tetrahydronaphtalene-1 ,7-dicarboxylic acid,

1 -Amino-6-methoxyindane-1 -carboxylic acid,

1 -Amino-6-hydroxyindane-1 -carboxylic acid, 1-Amino-5-methoxyindane-1 ,6-dicarboxylic acid,

1 -Amino-5-hydroxyindane-1 ,6-dicarboxylic acid,

1-Amino-5-methoxyindane-1 ,5-dicarboxylic acid,

1 -Amino-5-hydroxyindane-1 -carboxylic acid,

1-Amino-5-methoxyindane-1 -carboxylic acid. The pharmacological properties of the compounds of the invention can be illustrated by determining their effects in different conventional radioligand binding assays or in functional in vitro assays.

The compounds of the invention were studied in an in vitro assay for measuring inhibition of Pl-hydrolysis in BHK 570 cells expressing mGluR,σ receptors.

Principle

The metabotropic glutamate receptor (mGluR) is selectively activated by trans-aminocyclopentane dicarboxylic acid and is coupled to the hydroly- sis of inositol phosphates via a GTP-binding protein. At the molecular level, cDNAs encoding six subtypes of the mGluR family have been isolated. The first subtype isolated (Houamed et al., 1991 , Science 252, 1318), termed the mGluRlσ, has been shown to be coupled to Pl- hydrolysis when expressed in baby hamster kidney cells (BHK) (Thomsen et al., Brain Res. (in press)). In these cells no stimulation by 1 mM quisqualate or glutamate was observed with control BHK cells whereas a 6-8 fold increase over basal Pl-hydrolysis was seen with BHK cells expressing mGluRlσ.

Cell culture

BHK570 cells expressing mGluRlσ are cultured in DMEM (4.5 g/l glu¬ cose, 2mM glutamin); 5% foetal calf serum; 0.10 mg/ml neomycin; 0.5 mg/ml G418; 1 μM methotrexate; 50 //g/ml gentamycin. Cells are subcultured every 5 days using 0.05% trypsin/EDTA in PBS.

Inositol phosphate formation

The protocol for Pl-hydrolysis was measured using a modification of a method previously described (Berridge et al., 1982, Biochem. J. 206,587). Cells were plated in 16 mm wells (24 well multidish, Costar) with 1 confluent 100 mm dish per multidish. Replace the medium 24 h before the experiment with 500 μ\ fresh growth medium containing 4 Ci/ml myo-[2-³H]inositol (specific activity 18 Ci/mmol, Amersham). The cells were washed twice with Krebs-Henseleit buffer (Sigma cat. # 3753: glucose 2.0 g/l, MgSO₄ 0.141 g/l, KHPO₄ 0.16 g/l, KCI 0.35 g/l, NaCI 6.90 g/l and NaHCO₃ 2.1 g/l) supplemented with 10 mM LiCI and 2.5 mM CaCI₂. The buffer was equilibrated with 5% CO₂, 95% air to pH 7.5 at 37°C. Following 5 min of preincubation in the above buffer, buffer or test compounds were added and cells were incubated for 30 min at 37°C. In antagonist studies, add test compounds 5 min prior to agonist stimulation. Pl-formation was stopped by placing the cells on ice and quickly aspirating the media. The wells were washed once with ice- cold Krebs-Henseleit buffer and subsequently 1 ml ice-cold 10% perchloric acid was added to each well. Place the cells on ice for 20 min. In Nunc minisorp test tubes (75 x 12 mm, cat. # 443990): add 250 μ\ of 10 mM EDTA, pH 7.0 + 5% Universal Indicator (Merck). Transfer the PCA extract to each tube containing the pH-indicator. Neutralize the samples with 1.5 M KOH + 60 mM HEPES to pH 7.5 ( ~ 1100-1200 μ\). Centrifugate (6.000 rpm, 5 min, 0°C). They can be stored frozen at this point. Fractions of inositolphosphates were separated using ion- exchange columns (Amersham, RPN 1908) according to the method provided by Amersham.

Separation of inositol phosphates on ion-exchanαe columns Prepare columns with 5 ml 1 M KHCO₃ and wash with 15 ml dist. water. Adjust vacuum so that the flow-rate does not exceed 5 ml/min. Add 4 ml dist. water and subsequently 1 ml [³H]lnsP sample. Wash with 5 ml dist. water. IP1 to IP4 fractions may be collected with 5 ml 0.05; 0.10; 0.17 and 0.25 M KHCO₃, respectively. Usually IP1 and IP2 frac¬ tions are collected simultaneously. Scintillation liquid: use 12-15 ml Ultima Gold (Packard).

Testprocedure Testcompounds are dissolved in DMSO, DMSO and Pluronic F-127 or ethanol and diluted in assay buffer. Glutamate (10 μM and 1000 μM) and buffer alone are included as a control.

Results

The stimulation by 10 M shall represent a submaximal stimulation. The response by 10 μM glutamate should exceed 3-fold the basal level and should be below maximal stimulation (glutamate at 1 mM). The results are calculated relative to be stimulation by 10 μM glutamate and a dose response curve is generated.

Examples of test results obtained by testing some compounds of the present invention in the above mentioned assay appear from the follow¬ ing Table 1.

Table i

Compound No. IC₅₀ (uM)

7 10

25 50

The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 10 mg to about 70 mg per day. In choosing a regimen for patients suffering from a disease in the central nervous system related to the metabotropic glutamate receptor system it may frequently be necessary to begin with a dosage of from about 30 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 1 to about 10 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.

The route of administration may be any route, which effectively trans- ports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intra¬ venous, intramuscular or intranasal, the oral route being preferred.

Typical compositions include a compound of formula I or a pharmaceuti- cally acceptable acid addition salt thereof, associated with a pharma¬ ceutically acceptable carrier. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.

When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxy- ethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaery¬ thritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteri- ously react with the active compounds.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

Generally, the compounds are dispensed in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.

A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:

Active compound 5.0 mg

Lactosum 67.8 mg Ph. Eur.

Avicel^® 31.4 mg

Amberlite^® 1.0 mg Magnesii stearas 0.25 mg Ph. Eur.

The invention will now be described in further detail with reference to the following examples.

General Procedure for the Synthesis of Hydantoins.

NaCN (2 mmol) and (NH₄)₂CO₃ (4 mmol) were added to a solution of ketone (1 mmol) in DMF (2 ml) and water (0.2 ml) and the resulting mixture was heated at 120°C in a bomb for 3 h. After cooling, the reaction mixture was diluted with AcOEt (20 ml), washed with saturated NaHCO₃ (5x10 ml), brine (10 ml) and dried over anhydrous Na₂SO₄. After evaporation of the solvent, the residue was submitted to flash chromatography and elution with CHCI₃-MeOH (98:2).

General procedure for Hydrolysis of the Hydantoins.

A mixture of hydantoin (1 mmol), NaOH (15 mmol) and water (15 ml) was refluxed for 3-4 h. After cooling, the reaction mixture was diluted with water (10 ml) and extracted with CH₂CI₂ (2x10 ml). The aqueous layer was neutralized with 3N HCI and submitted to ion exchange chromatography on Dowex 50x2-200; elution with 10% pyridine gave a residue which was further purified by reversed phase chromatography (RP-8 Lobar column).

General Procedure for the Methyl-Ether Cleavage of the Amino Acid Derivatives.

A mixture of methyl ether (1 mmol), 48% HBr (100 mmol) and Nal (2.2 mmol) was heated at 90-94 °C in a flask tightly sealed with a septum fastened by rubber rings for 8 h. After cooling, the evaporation of the solvent gave a residue which was neutralized with NH₄OH 30% and then submitted to ion exchange resin chromatography on Dowex 50x2-200 and elution with 10% pyridine. The residue was further purified by reversed-phase medium pressure chromatography.

EXAMPLE 1

5-Acetylindan (1 )

AICI₃ (1.706 g, 12.8 mmol) was added portionwise in 20 min to a solution of indan (1.50 g, 12.7 mmol) and AcCI (0.996 g, 12.7 mmol) in benzene (7.6 ml) kept under vigorous magnetic stirring at 0°C in an argon atmosphere. The resulting mixture was reacted at room tempera¬ ture for 2 h after which cold (0°C) water was added (30 ml). The reaction mixture was then acidified with 3N HCI and extracted with AcOEt (3x20 ml). The combined organic phases were washed with brine (20 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent yielded 1 as a yellow oil (2 g) which was used in the next step without any further purification; ^-NMR (CDCI₃) δ 2.10 (2H, q, J = 7.2 Hz, 2- CH₂), 2.56 (3H, s, Mc), 2.93 (4H, t, J = 7.2 Hz, 1-CH₂ and 3-CH₂), 7.26 (I H, d, J = 8.3 Hz, 7-CH), 7.80 (1 H, d. J = 8.3 Hz, 6-CH), 7.85 (I H, s, 4-CH).

lndan-5-carboxylic acid (2)

Br₂ (5.89 g, 36.85 mmol) was added to a cold (0°C), magnetically stirred solution of KOH (6.9 g, 123.2 mmol) in water (25 ml). 1 (1.50 g, 9.36 mmol) was added dropwise in 5 min to this solution and the resulting mixture was heated at 40°C under stirring for 2 h. The reaction mixture was then diluted with ether (20 ml), the aqueous layer separ- ated, added with MeOH (100 ml) and, after acidification with 6N HCI, extracted with CHCI₃ (3x30 ml). The combined organic phases were washed with water (30 ml), brine (30 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent yielded 2 as a white-yellow solid (1.0 g, 66%), mp 165-8°C; ¹H-NMR (CDCI₃) δ 2.13 (2H, q, J = 7.4 Hz, 2-CH₂), 3.00 (4H, t, J = 7.4 Hz, 1-CH₂ and 3-CH₂), 7.32 (1H, d, J = 8.5 Hz, 7-CH), 7.90 (1 H, d, J = 7.8 Hz, 6-CH), 7.95 (1H, s, 4-CH).

Methyl indan-5-carboxylate (3)

An etheral solution of diazomethane (90 ml, from 16 g of Diazald™) was added to a cold (0°C) solution of 2 (3.0 g, 18.5 mmol) in ether (50 ml) and the resulting solution was magnetically stirred at room temperature for 30 min. Acetic acid (20 ml) was then added and the resulting mixture was washed with water (2x30 ml). Evaporation of the solvent gave a residue (3.2 mg) which was submitted to flash chromatography: elution with light petroleum-AcOEt 9:1 afforded 3 (3.0 g, 92%) as a yellow oil; ¹H-NMR (CDCI₃) δ 2.15 (2H, q, J = 7.5 Hz, 2-CH₂), 2.95 and 3.00 (4H,

2t, J = 7.5 Hz, 1-CH₂ and 3-CH₂), 3.90 (3H, s, Mc), 7.25 (1 H, d, J = 7.8 Hz, 7-CH), 7.85 (1H, d, J= 7.8 Hz, 6-CH), 7.90 (1 H, s, 4-CH).

Methyl 1-oxoindane-5-carboxylate (4) and methyl 1-oxoindane-6-car- boxylate (5)

A solution of Cr₂O₃ (7.0 g, 70 mmol) in glacial AcOH (27 ml) and water (11.6 ml) was added dropwise in 30 min. to a magnetically stirred solution of 3 (5.0 g, 28.4 mmol) in glacial AcOH (13.5 ml) at room temperature. Stirring was continued for 36 h after which the reaction mixture was diluted with water (60 ml) and extracted with AcOEt (4x50 ml). The combined organic phases were washed with 10% K₂CO₃ (3x30 ml), brine (30 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent gave a residue (4.8 mg) which upon flash filtration on silica gel allowed the recovery of starting material 3 (0.5 g) and of a mixture of 4 and 5 (4 g). This mixture was then submitted to medium pressure chromatography: elution with light petroleum- AcOEt 85:15 yielded 4 (1.4 g, 26%) as a white solid, mp 110.8°C; 'H-NMR (CDCI₃) δ 2.78 (2H, t, J = 6 Hz, 2-CH₂), 3.22 (2H, t, J = 6 Hz, 3-CH₂), 3.97 (3H, s,

Mc), 7.82 (1 H, d, J = 8 Hz, 7-CH), 8.05 (1 H, d, J = 8 Hz, 6-CH), 8.18 (1 H, s, 4-CH). Further elution with the same solvent gave 5 (1.6 g, 30%) as a white solid, mp 111.9°C;¹H-NMR (CDCI₃) δ 2.75 (2H, t, J = 6.3 Hz, 2-CH₂), 3.22 (2H, t, J = 6.3 Hz, 3-CH₂), 3.95 (3H, s, Me), 7.55 (1 H, d, J = 7.6 Hz, 7-CH), 8.25 (1 H, d, J = 7.6 Hz, 6-CH), 8.42 (1 H, s, 4-CH). Hydantoin of 4 (6)

KCN (0.424 g, 6.5 mmol) and (NH₄)₂CO₃ (1.35 g, 14.0 mmol) were added to a solution of 4 (0.620 g, 3.26 mmol) in DMF (6.2 ml) and water (0.5 ml) and the resulting mixture was heated at 120°C in a bomb for 3 h. After cooling, the reaction mixture was diluted with AcOEt (30 ml), washed with saturated Na₂CO₃ (5x20 ml), brine (20 ml) and dried over anhydrous Na₂SO₄. After evaporation of the solvent, the residue (0.62 g) was submitted to flash chromatography: elution with CHCI₃- McOH 96:4 yielded 6 (0.490 g, 58%) as a pale yellow solid, mp I

(CDCI₃) δ 2.25 (1 H, m, 2-CHa), 2.70 (1 H, m, 2-CHb), 2.95-3.30 (2H, m, 3-CH₂), 3.90 (3H, s, Me), 7.22 (1 H, d, J = 7.8 Hz, 7- CH), 7.88 (1 H, d, J = 7.8 Hz, 6-CH), 7.90 (1 H, s, 4-CH).

1-Aminoindan-1 ,5-dicarboxylic acid (7)

A mixture of 6 (0.650 g, 2.5 mmol), Ba(OH)₂ octahydrate (0.520 g, 1.7 mmol) and water (9.5 ml) was heated at 120°C in a bomb for 3 h. After cooling, the reaction mixture was diluted with water (20 ml) and extracted with CH₂CI₂ (3x15 ml). CO₂ was then bubbled into the aque¬ ous layer, the resulting precipitate was centrifuged and the supernatant was neutralized with 3N HCI. The neutral solution was submitted to ion exchange resin chromatography on Dowex 50x2 200 and elution with 10% pyridine to give a solid which was further purified by reversed phase medium pressure chromatography: elution with McOH-water 6:4 afforded 7 (0240 g, 43%) as a white solid, mp> 300°C; ¹H-NMR (D₂O) δ 2.20 (1 H, m, 2-CHa), 2.50 (1 H, m, 2-CHb), 2.95 (2H, t,J = 7.8 Hz, 3- CH₂), 7.05 (1 H, d, J = 7.8 Hz, 7-CH), 7.55 (1 H, d, J = 7.8 Hz, 6-CH),

7.60 (1 H, s, 4-CH); ¹³C-NMR (D₂O) δ 30.42, 35.50, 68.70, 123.00, 127.20, 129.50, 132.50, 142.90, 146.00, 169.90, 172.70. Hydantoin of 5 (8)

NaCN (0.695 g, 14,18 mmol) and (NH₄)₂CO₃ (2.94 g, 30.4 mmol) were added to a solution of 5 (1.35 g, 7.10 mmol) in DMF (13.5 ml) and water (1.2 ml) and the resulting mixture was heated at 120°C in a bomb for 3 h. After cooling, the reaction mixture was diluted with AcOEt (50 ml), washed with saturated Na₂CO₃ (5x30 ml), brine (30 ml) and dried over anhydrous Na₂SO₄. After evaporation of the solvent, the residue (90 g) was submitted to flash chromatography: elution with CHCI₃-MeOH 96:4 yielded 8 (0.790 g, 43%) as a pale yellow solid, mp 112°C; 'H- NMR (CDCI₃ + CD₃OD) <5 2.35 (1H, m, 2-CHa), 2.70 (1 H, m, 2-CHb), 2.95-3.30 (2H, m, 3-CH₂), 3.90 (3H, s, Mc), 7.40 (1 H, d, J = 8 Hz, 4- CH), 7.82 (1 H, s, 7-CH), 7.98 (1H, d, J = 8 Hz, 5-CH).

1-Aminoindan-1 ,6-dicarboxylic acid (9)

A mixture of 8 (0.790 g, 3.04 mmol), Ba(OH)₂ octahγdrate (0.632 g, 2.07 mmol) and water (11.5 ml) was heated at 120°C in a bomb for 3 h. After cooling, the reaction mixture was diluted with water (30 ml) and extracted with CH₂CI₂ (3x20 ml). CO₂ was then bubbled into the aque¬ ous layer, the resulting precipitate was centrifuged and the supernatant was neutralized with 3N HCI. The neutral solution was submitted to ion exchange resin chromatography on Dowex 50x2 200 and elution with 10% pyridine to give a solid which was further purified by reversed phase medium pressure chromatography: elution with MeOH-water 6:4 afforded 9 (0.210 g, 30%) as a white solid, mp >300°C; ¹H-NMR (D₂O) δ 2.28 (1 H, m, 2-CHa), 2.72 (1 H, m, 2-CHb), 3.08 (2H, t, J = 6 Hz, 3- CH₂), 7.35 (1 H, d, J = 8 Hz, 4-CH), 7.82 (1 H, s, 7-CH), 7.85 (1 H, d,

J = 8 Hz, 5-CH); ¹³C-NMR (D₂O) -530.30, 35.00, 68.54, 124.67, 125.93, 129.26, 131.90, 138.55, 151.10, 169.60, 173.32. EXAMPLE 2

4- and 5-Chloromethyl-indan (10)

Concentrated H₂SO₄ (90 ml) was added dropwise during 4 h to a warm (60°C), mechanically stirred solution of indan (77.2 g, 0.65 mol), formaldehyde (81 ml of a 40% solution) and 12N HCI (138 ml). After addition completion, stirring was continued for 6 h after which the reaction mixture was poured into water (1.5 I) and extracted with ether (4x300 ml). The combined organic phases were washed with water (3x50 ml) and dried over anhydrous Na₂SO₄. After filtration and evapor¬ ation of the solvent, the residue (80 g) was distilled in high vacuum to afford 10 (68.0 g, 63%), bp 75-80°C/0.3 mmHg; ¹H-NMR (CDCI₃) δ 2.10 (2H, m, 2-CH₂), 2.92 (4H, t, 1 - and 3-CH₂), 4.56 (2H, s, CH₂CI),

7.18 (3H, m, aromatic's).

4- and 5-Acetoxymethyl-indan (11 )

A suspension of 10 (68.0 g, 0.4 mol) and anhydrous AcONa (83.0 g, 0.6 mol) in glacial AcOH (200 ml) was heated at 150°C under vigorous mechanical stirring for 8 h. AcOH was then distilled off at reduced pressure (water pump) and the residue was taken up in water (200 ml) and extracted with AcOEt (2x100 ml). The combined organic phases were washed with water (2x50 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent gave 11 (72.0 g, 92%) which was used in the next step without any further purification.

4- and 5-lndanyl-methanol (12)

A solution of 11 (70.0 g, 0.37 mol) in 3.7N NaOH (120 ml) and MeOH (120 ml) was heated at 50°C under magnetic stirring for 0.5 H. MeOH was then partially removed at reduced pressure, the resulting mixture was poured into cold (0°C) water and the solid thus formed was filtered (54 g) and dissolved in boiling light petroleum (300 ml). After cooling, the precipitate was removed and the mother liquid was evaporated to give 12 (11.0 g, 20%) as a mixture enriched in the desired σ-isomer; 'H- NMR (CDCI₃) δ 2.10 (2H, m, 2-CH₂), 2.80 (4H, m, 1- and 3-CH₂), 3.20 (1 H, br, s, OH), 4.50 (2H, s, CH₂OH), 7.08 (3H, m, aromatic's).

lndan-4-carbaldehyde (13)

A solution of 12 (9.0 g, 61 mmol) in CH₂CI₂ (150 ml) was added drop- wise in 5 min to a mechanically stirred solution of pyridinium chloro- chromate (13.1 g, 61 mmol) in CH₂CI₂ (50 ml) in an argon atmosphere at room temperature. Stirring was continued for 2 h after which the reac¬ tion mixture was filtered with the aid of celite, the filtrate was washed with water (3x50 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent gave a residue which was submitted to flash chromatogra¬ phy: elution with cyclohexane-ether 95:5 afforded 13 (2.6 g, 29%); ¹H- NMR (CDCI₃) δ 2.13 (2H, m, 2-CH₂), 2.91 (2H, t, J = 7.4 Hz, 1-CH₂),

3.25 (2H, t, J = 7.4 Hz, 3-CH₂), 7.29 (1 H, 2d, J = 7.6 Hz, 6-CH), 7.45 (1 H, d, J = 7.6 Hz, 7-CH), 7.60 (1 H, d, J = 7.6 Hz, 5-CH), 10.14 (1 H, s, CHO). Further elution with the same solvent afforded a mixture of both formyl derivatives (6 g).

lndan-4-carboxylic acid (14)

Jones reagent (15 ml) was added dropwise in 15 min. to a magnetically stirred solution of 13 (1.1 g, 7.53 mmol) in acetone (50 ml) at room temperature. Stirring was continued for 1 h after which the reaction mixture was filtered and the solvent evaporated off. The residue was taken up in AcOEt (100 ml), washed with water (2x40 ml), brine (40 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent afforded 14 (1.0 g, 82%) which was used in the next step without any further purification.

Methyl indan-4-carboxylate (15)

An etheral solution of diazomethane (35 ml, from 6.3 g of Diazald) was added dropwise in 15 min. to a cold (0°C) solution of 14 (2.5 g, 15.4 mmol) in ether (15 ml). After addition completion, stirring was continued for 10 min. at room temperature. Evaporation of the solvent gave 15 (2.5 g, 92%) which was used in the next step without any further purification; ¹H-NMR (CDCI₃) δ 2.06 (2H, m, 2-CH₂), 2.89 (2H, t, J = 7.6 Hz, 1-CH₂), 3.24 (2H, t, J = 7.6 Hz, 3-CH₂), 3.83 (3H, s, Me), 7.20 (1 H, t, J = 7.6 Hz, 6-CH), 7.37 (1 H, d, J = 7.6 Hz, 7-CH), 7.83 (1 H, d, J = 7.6

Hz, 5-CH).

Methyl 1-oxoindan-4-carboxylate (16)

A solution of chromic anhydride (5.8 g, 58 mmol) in water (10 ml) was added dropwise in 10 min to a magnetically stirred solution of 15 (2.5 g, 14.2 mmol) in glacial AcOH (34 ml). Stirring was continued for 40 h after which the reaction mixture was poured into water (60 ml) and extracted with AcOEt (4x50 ml). The combined organic phases were washed with 10% K₂CO₃ (2x40 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent yielded a residue (1.5 g) which was submitted to flash chromatography: elution with light petroleum containing 5-15% AcOEt afforded 16 (0.3 g, 11 %), mp 102°C; ¹H-NMR (CDCI₃) δ 2.72 (2H, m, 2-CH₂), 3.50 (2H, m, 3-CH₂), 3.96 (3H, s, Me), 7.48 (1 H, 2d,

J = 7.6 Hz, 6-CH), 7.95 (1 H, d, J = 7.6 Hz, 7-CH), 8.28 (1 H, d, J = 7.6 Hz, 5-CH). Hydantoin of 16 (17)

NaCN (0.207 g, 4.22 mmol) and (NH₄)₂CO₃ (0.87 g, 9.0 mmol) were added to a solution of 16 (0.40 g, 2.1 mmol) in DMF (4 ml) and water (0.4 ml) and the resulting mixture was heated at 120°C in a bomb for 3 h. After cooling, the reaction mixture was poured into water (50 ml) and extracted with ether (5x20 ml). The combined organic phases were washed with water (2x20 ml) and dried over anhydrous Na₂SO₄. Evapor- ation of the solvent gave a residue (0.3 g) which was submitted to flash chromatography: elution with AcOEt-light petroleum 7:3 afforded 17 (0.20 g, 37%), mp 170-2°C (H₂O); ¹H-NMR (CDCI₃ + CD₃OD) δ 2.30 (1H, m, 2-CHa), 2.72 (1 H, m, 2-CHb), 3.47 (2H, m, 3-CH₂), 3.92 (3H, s, Me), 4.00 (2H, br s, 2xNH), 7.38 (2H, m, 6- and 7-CH), 7.98 (1H, m, 5- CH).

1-Aminoindan-1 ,4-dicarboxylic acid (18)

A suspension of 17 (0.15 g, 0.58 mmol) and Ba(OH)₂.8H₂O (0.11 g, 0.35 mmol) in water (4 ml) was heated in a bomb at 120°C for 2.5 h. After cooling, the reaction mixture was filtered, the solid washed with CH₂CI₂ (10 ml) and the filtrate evaporated to dryness in vacuo. The residue thus obtained (0.12 g) was submitted to ion exchange resin chromatography on Dowex 1x8 200: elution with 0.3N AcOH afforded 18 (0.040 g, 31 %); H-NMR (D₂O + HCI) δ 2.27 (1H, m, 2-CHa), 2.72 (1H, m, 2-CHb), 3.32 (2H, t, J = 7.2 Hz, 3-CH₂), 7.30 (1 H, 2d, J = 7.7 Hz, 6-CH), 7.48 (1 H, d, J = 7.7 Hz, 7-CH), 7.87 (1 H, d, J = 7.7 Hz, 5- CH). EXAMPLE 3

6-Acetyl-1 ,2,3,4-tetrahydronaphtalene (19) AICI₃ (15.3 g, 114.8 mmol) was added portionwise in 40 min. to a solution of 1 ,2,3,4-tetrahydronaphthalene (15.0 g, 113.5 mmol) and AcCI (8.9 g, 113.5 mmol) in benzene (45 ml) kept under vigorous magnetic stirring at 0°C in an argon atmosphere. The resulting mixture was reacted at room temperature for 30 min. after which cold (0°C) water was added (100 ml). The reaction mixture was then acidified with 3N HCI and extracted with AcOEt (3x50 ml). The combined organic phases were washed with brine (60 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent yielded 19 as a yellow oil (20 g) which was used in the next step without any further purification.

1 ,2,3,4-Tetrahydronaphtalene-6-carboxylic acid (20)

Br₂ (71.8 g, 449 mmol) was added to a cold (0°C), magnetically stirred solution of KOH (84.43 g, 1.507 mol) in water (200 ml). 19 (20 g) was added dropwise in 15 min. to this solution and the resulting mixture was heated at 40°C under stirring for 3 h. The reaction mixture was then washed with ether (3x60 ml), the aqueous layer was acidified with 6N HCI and extracted with CHCI₃ (5x50 ml). The combined organic phases were washed with water (100 ml), brine (100 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent yielded 20 as an oil (13.5 g) which was used in the next step without any further purification.

Methyl- 1 , 2,3, 4-tetrahydronaphtalene-6-carboxylate (21)

An etheral solution of diazomethane (250 ml, from 44.5 g of Diazald ™) was added to a cold (0°C) solution of 20 (13.5 g) in ether (50 ml) and the resulting solution was magnetically stirred at room temperature for 30 min. Acetic acid (50 ml) was then added and the resulting mixture was washed with water (2x50 ml). Evaporation of the solvent gave a residue (13.5 g) which was submitted to flash chromatography: elution with light petroleum-AcOEt 9:1 afforded 21 (9.1 g) as a yellow oil; ¹H- NMR (CDCI₃) δ 1.80 (4H, m, 2-CH₂ and 3-CH₂), 2.80 (4H, m, 1-CH₂ and 4-CH₂), 3.90 (3H, s, Me), 7.08 (1H, d, J = 9 Hz, 8-CH), 7.72 (1H, d, J = 9 Hz, 7-CH), 7.75 (1 H, s, 5-CH).

Methyl 1-oxo-1 ,2,3,4-tetrahydronaphtalene-6-carboxylate (22) and methyl 1-oxo-1 ,2,3,4-tetrahydronaphtalene-7-carboxylate (23)

A solution of Cr₂O₃ (14.9 g, 149 mmol) in glacial AcOH (43 ml) and water (13.5 ml) was added dropwise in 30 min. to a magnetically stirred solution of 21 (9.1 g, 47.9 mmol) in glacial AcOH (21.6 ml) at room temperature. Stirring was continued for 36 h after which the reaction mixture was diluted with water (100 ml) and extracted with AcOEt (4x50 ml). The combined organic phases were washed with 10% K₂CO₃ (2x50 ml), brine (50 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent gave a residue (8.5 g) which upon flash filtration on silica gel allowed the recovery of starting material 21 (1 g) and of a mixture of 22 and 23 (7 g). This mixture was then submitted to medium pressure chromatography: elution with light petroleum- AcOEt 85:15 yielded 22 (2.0 g, 20.5%); 'H-NMR (CDCI₃) δ 2.13 (2H, m, 3-CH₂), 2.65 (2H, t, J = 7.5 Hz, 2-CH₂), 3.00 (2H, t, J = 7.5 Hz, 4-CH₂), 3.90 (3H, s, Me), 7.85 (1 H, d, J = 8 Hz, 8-CH), 7.90 (1 H, s, 5-CH), 8.02 (1 H, d, J = 8 Hz, 7-CH). Further elution with the same solvent gave 23 (2.3 g, 23.5%); ¹H-NMR (CDCI₃) δ 2.15 (2H, m, 3-CH₂), 2.68 (2H, t, J = 7.5 Hz, 2-CH₂),

3.02 (2H, t, J = 7.5 Hz, 4-CH₂), 3.92 (3H, s, Me), 7.33 (1 H, d, J = 8 Hz, 5-CH), 8.10 (1 H, 2d, J = 8 Hz, J = 2 Hz, 6-CH), 8.66 (1 H, d, J = 2 Hz, 8- CH).

Hydantoin of (22) (24)

NaCN (0.231 g, 4.7 mmol) and (NH₄)₂CO₃ (0.971 g, 10.07 mmol) were added to a solution of 22 (0.479 g, 2.35 mmol) in DMF (4.5 ml) and water (0.5 ml) and the resulting mixture was heated at 120°C in a bomb for 3 h. After cooling, the reaction mixture was diluted with AcOEt (30 ml), washed with saturated Na₂CO₃ (5x20 ml), brine (20 ml) and dried over anhydrous Na₂SO₄. After evaporation of the solvent, the residue (0.5 g) was submitted to flash chromatography: elution with CHCI₃- MeOH 98:2 yielded 24 (0.360 g, 59%); ¹H-NMR (CDCI₃) δ 1.80 and 2.10 (2H, 2m, 3-CH₂), 2.35 (2H, m, 2-CH₂), 2.90 (2H, m, 4-CH₂), 3.90 (3H, s, Me), 7.24 (1H, s, 5-CH), 7.27 (1 H, m, 8-CH), 7.82 (1 H, m, 7- CH).

1 -Amino-1 ,2,3,4-tetrahydronaphtalene-1 ,6-dicarboxylic acid (25)

A mixture of 24 (0.360 g, 1.39 mmol), Ba(OH)₂ octahydrate (0.413 g,

1.35 mmol) and water (5 ml) was heated at 120°C in a bomb for 3 h. After cooling, the reaction mixture was diluted with water (20 ml) and extracted with CH₂CI₂ (3x15 ml). CO₂ was then bubbled into the aque¬ ous layer, the resulting precipitate was centrifuged and the supernatant was neutralized with 3N HCI. The neutral solution was submitted to ion exchange resin chromatography on Dowex 50x2 200 and elution with 10% pyridine to give a solid which was further purified by preparative t.l.c: elution with nBuOH-AcOH-H₂O (68:16:16) afforded 25 (0.100 g, 33%); ¹H-NMR (D₂O) δ 1.75 and 1.90 (2H, m, 3-CH₂), 2.10 and 2.30 (2H, m, 2-CH₂), 2.70 (2H, m, 4-CH₂), 7.20 (1H, d, 8-CH), 7.55 (2H, m,

5- and 7-CH); "C-NMR (D₂O) δ 18.67, 28.97, 32.44, 61.81 , 128.20, 128.71 , 131.64, 132.32, 135.90, 139.88, 170.38, 174.55.

Hydantoin of (23) (26)

The above compound was prepared by the general hydantoin preparation procedure described above. 61 % yield; m.p. 188-190^*C (H₂O); ^-NMR (CDCI₃) δ 1.70 and 2.00 (2H, 2m, 3-CH₂), 2.30 (2H, m, 2-CH₂), 2.80 (2H, m, 4-CH₂), 3.90 (3H, s, Me), 7.20 (1H, d, J = 8 Hz, 5-CH), 7.70- 7.80 (2H, m, 6-CH and 8-CH).

1 -Amino-1 , 7-dicarboxy-1 ,2,3,4-tetrahydronaphtalene (27)

MeOH-water (8:2); 43% yield; m.p. >300 ^*C; 'H-NMR (D₂O) δ 1.75 and 1.90 (2H, 2m, 3-CH₂), 2.10 and 2.30 (2H, m, 2-CH₂), 2.80 (2H, m, 4-CH₂), 7.25 (1H, d, J = 8 Hz, 5-CH), 7.75 (2H, m, 6-CH and 8-CH), ¹³C-NMR (D₂O + CD₃OD) δ 17.72, 28.52, 31.76, 61.43, 128.45, 128.65, 130.32, 130.74, 131.23, 144.58, 169.58, 174.68.

EXAMPLE 4

5-Methoxy-6-Acetylindane (28)

AICI₃ (3.94 g, 29.5 mmol) was added portionwise in 20 min to a solution of 5-methoxyindane ( 2.04 g, 13.8 mmol) and AcCI (1.36 g, 17.3 mmol) in benzene (9 ml) kept under vigorous magnetic stirring at 0 "C in an argon atmosphere. The resulting mixture was reacted at room tempera¬ ture for 2 h after which cold (0 ^*C) water was added (30 ml). The reaction mixture was then acidified with 3N HCI and extracted with

AcOEt (3x20 ml). The combined organic phases were washed with brine (20 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent gave a yellow oil (3 g) which was submitted to flash-chromatography; elution with light petroleum/AcOEt (8:2) gave pure 28 (1.5 g, 61 %); ¹H- NMR (CDCI₃) δ 1.90-2.10 (2H, m, 2-CH₂), 2.5 (3H, s, Me), 2.70-2.90

(4H, m, 1-CH₂and 3-CH₂), 6.80 (1H, s, 4-CH), 7.50 (1 H, s, 7-CH). Methyl 5-methoxγindane-6-carboxγlate (29)

Br₂ (18.21 g, 113.93 mmol) was added to a cold (0 ^*C) magnetically stirred solution of KOH (21.3 g, 380 mmol) in water (100 ml). 28 (5.50 g, 28.94 mmol) was added dropwise in 15 min to this solution and the resulting mixture was heated at 40 ^*C under stirring for 8 h. The reac¬ tion mixture was then diluted with ether (50 ml), the aqueous layer separated, added with MeOH (100 ml) and, after acidification with 6N HCI, extracted with CHCI₃ (3x30 ml). The combined organic phases were washed with water (30 ml), brine (30 ml) and dried over anhydrous Na₂SO₄. Evaporation of the solvent gave a yellow oil (3.7 g), which was dissolved in ether (50 ml). An ethereal solution of diazomethane (120 ml, from 21.3 g of Diazald™) was added to this cold (0 ^*C) solution and the reaction mixture was magnetically stirred at room temperature for 30 min. Acetic acid (15 ml) was then added and the resulting mixture was washed with water (2x30 ml). Evaporation of the solvent gave a residue (4.2 g) which was submitted to flash chromatography: elution with light petroleum-AcOEt 9:1 afforded 29 (3.90 g, 70%) as a yellow oil: ¹H-NMR (CDCI₃) δ 2.00-2.15 (2H, m, 2-CH₂), 2.80-3.00 (4H, m, 1-CH₂and 3-

CH₂), 3.85 (6H, s, 2-Me), 6.85 (1 H, s, 4-CH), 7.65 (1H, s, 7-CH).

Methyl 1-oxo-5-methoxyindan-6-carboxylate (30)

A solution of Cr₂O₃ (1.53 g, 15.3 mmol) in glacial AcOH (7.8 ml) and water (5 ml) was added dropwise in 30 min to a magnetically stirred solution of 29 (1.0 g, 4.8 mmol) in glacial AcOH (2.7 ml) at room temperature. Stirring was continued for 12 h after which the reaction mixture was diluted with water (40 ml) and extracted with AcOEt (4x50 ml). The combined organic phases were washed with 10% K₂CO₃ (3x20 ml), brine (20 ml) and dried over anhydrous Na₂SO₄. Evaporation of the - 27 - solvent gave a residue (1.1 g) which upon flash filtration on silica gel allowed the separation of starting material 29 (0.2 g) and of pure 30 (0.8 g 26%) as a white solid, m.p. 122-124 ^*C; ¹H-NMR (CDCI₃) δ 2.65- 2.75 (2H, t, J = 6.5 Hz, 2-CH₂), 3.10-3.20 (2H, t, J = 6.5 Hz, 3-CH₂), 3.90 and 4.00 (6H, s, 2-Me), 7.00 (1 H, s, 4-CH), 8.20 (1 H, s, 7-CH).

Hydantoin of 30 (31 )

The above compound was prepared by the general hydantoin preparation procedure described above. 30% yield; m.p. 176-178^*C (H₂O); ¹H-NMR (CDCI₃) δ 2.00-2.55 (2H, m, 2-CH₂), 2.75-3.35 (2H, m, 3-CH₂), 3.90- 3.95 (6H, 2s, Me), 5.85 (1 H, s, NH), 6.95 (1 H, s, 4-CH), 7.65 (1 H, s, 7-CH), 7.90 (1 H, s, NH).

1-Amino-5-methoxy-1 ,6-dicarboxyindane (32)

The above compound was prepared by the general hydantoin hydrolysis procedure described above. MeOH-water (9:1 ); 40% yield; m.p. >300 ^*C; ¹H-NMR (CD₃OD) δ 2.50-2.70 (1 H, m, 2-CH.), 2.90-3.10 (1 H, m, 2- CH_b), 3.30-3.45 (2H, t, J = 6.6 Hz, 3-CH₂), 4.10 (3H, s, Me), 7.35 (1 H, s, 4-CH) 7.95 (1 H, s, 7-CH), "C-NMR (CD₃OD) δ 30.81 , 35.41 , 56.20, 69.47, 109.30, 116.15, 126.16, 127.31 , 132.10, 152.24, 160.02, 175,56.

1 -Amino-5-hydroxy-1 ,6-dicarboxyindane (33)

Prepared by the general demethylation procedure described above.

RP-8 Lobar column (MeOH-water 7:3); 27% yield; m.p. >300 ^*C; ¹H- NMR (CD₃OD) δ 2.15-2.35 (1H, m, 2-CH , 2.60-2.75 (1 H, m, 2-CH_b), 3.15 (2H, m, 3-CH₂), 6.80 (1 H, s, 4-CH), 7.65 (1 H, s, 7-CH), ¹³C-NMR (CD₃OD) δ 30.53, 35.48, 69.56, 1 13.03, 116.14, 125.47, 127.52, 131.05, 152.09, 161.72, 174.32.

EXAMPLE 5

Hydantoin of 6-Methoxyindan-1-one (34)

The above compound was prepared by the general hydantoin preparation procedure described above. 85% yield; m.p. 152-154" C (H₂O); H-NMR (CDCI₃) δ 2.20-2.40 (1 H, m, 2-CH , 2.70-2.85 (1 H, m, 2-CH_b), 2.95-

3.25 (2H, m, 3-CH₂), 3.80 (3H, s, Me), 5.85 (1H, s, NH), 6.70 (1 H, d, J = 3 Hz, 7-CH), 6.90 (1H, dd, J = 3 Hz, J = 8 Hz, 5-CH), 7.20 (1 H, d, J = 8 Hz, 4-CH) 8.05 (1 H, s, NH).

1-Amino-6-methoxy-1-carboxyindane (35)

The above compound was prepared by the general hydantoin hydrolysis procedure described above. MeOH-water (9:1 ); 49% yield; m.p. 216- 218 ^*C; 'H-NMR (D₂O) δ 2.05-2.25 (1H, m, 2-CH_a), 2.40-2.65 (1 H, m,

2-CH_b), 2.70-2.95 (2H, m, 3-CH₂), 3.60 (3H, s, Me), 6.65-6.85 (2H, m, 5-CH and 7-CH), 7.05-7.15 (1 H, d, J = 8 Hz, 4-CH), ¹³C-NMR (D₂O + CD₃OD) δ 29.34, 35.40, 55.82, 68.75, 108.20, 1 17.48, 126.66, 137.36, 138.53, 158.88, 172.82.

1 -Amino-6-hydroxy- 1 -carboxyindane (36)

Prepared by the general demethylation procedure described above RP-8 Lobar column (MeOH-water 9:1 ); 50% yield; m.p. > 300 "C; ¹H-

NMR (D₂O) δ 2.15-2.30 (1 H, m, 2-CH,), 2.55-2.75 (1 H, m, 2-CHJ, 2.95 (2H, t, J = 6.8 Hz, 3-CH₂), 6.70 (H, s, 7-CH), 6,80 (1 H, dd, J = 3 Hz and 8 Hz, 5-CH), 7.15 (1 H, d, J = 8 Hz, 4-CH), ¹³C-NMR (D₂O + CD₃OD) δ 29.50, 35.51 , 70.00, 109.79, 117.57, 126.48, 136.66, 141.12, 154.99, 172.95.

EXAMP15 6

Hydantoin of 5-Methoxyindan-1-one (37) ___-,

The above compound was prepared by the general hydantoin preparation procedure described above. 69% yield; m.p. 132-134^*C (H₂O); ¹H-NMR (CDCI₃) δ 2.25-2.45 (1H, m, 2-CH.), 2.70-2.85 (1H, m, 2-CH_b), 2.95- 3.30 (2H, m, 3-CH₂), 3.85 (3H, s, Me), 5.80 (1 H, s, NH), 6.75-6.85

(2H, m, 4-CH and 6-CH), 7.15 (1 H, d, J = 8 Hz, 7-CH), 8.00 (1 H, s, NH).

1 - Amino-5-methoxy- 1 -carboxyindane (38)

The above compound was prepared by the general hydantoin hydrolysis procedure described above. MeOH-water (9:1); 54% yield; m.p. 222- 224 ^#C; ¹H-NMR (D₂O) δ 2.15-2.30 (1H, m, 2-CH.), 2.60-2.75 (1H, m, 2-CH_b), 2.95-3.05 (2H, t, J = 6.6 Hz, 3-CH₂), 3.70 (3H, s. Me), 6.75

(1 H, d, J = 8 Hz, 6-CH), 6.85 (1 H, s, 4-CH), 7.15 (1H, d, J = 8 Hz, 7- CH), ¹³C-NMR (D₂O + CD₃OD) -5 30.36, 35.51 , 55.66, 69.98, 110.31 , 113.90, 124.44, 132.50, 147.14, 160.60, 173.00.

1-Amino-5-hydroxy-1 -carboxyindane (39)

Prepared by the general demethylation procedure described above RP-8 Lobar column (MeOH-water 9:1); 17% yield; m.p. >300 "C; ¹H- NMR (D₂O) δ 2.05-2.30 (1H, m, 2-CH.), 2.55-2.75 (1H, m, 2-CH_b),

2.90-3.00 (2H, t, J = 6.8 Hz, 3-CH₂), 6.65 (1 H, s, 4-CH), 6.75 (1 H, d, J = 8 Hz, 6-CH), 7.10 (1 H, d, J = 8 Hz, 7-CH), ³C-NMR (D₂O + CD₃OD) •5 29.33, 35.32, 70.50, 109.60, 117.38, 126.30, 137.00, 141.95, 151.50, 173.05.

Claims

1. A compound of formula I

wherein n is 0, 1 or 2; and

X is -O-, -S, -N(R⁵)- or -CH₂-; and

R¹ is H, NH₂, NHR⁵ or OH; and

R² and R³ independently are H, COOH, COOR⁶, CONH₂, CONHR⁶, CON(R⁵)₂, CONHSO₂R⁵ or tetrazole; and

R⁴ is H, OH, NH₂, NHR⁵, CF₃, C^-alkyl, C₂.₈-alkenyl, C₂.₈-alkynyl, C^- cycloalkyl, phenyl or C ₄-alkoxy; and

R⁵ is H,

C₂.₈-alkenyl, C₂.₈-alkynyl, phenyl or C₃-_β-cycloalkyl; and ring A can be partly or completely saturated or aromatic, or a salt thereof with a pharmaceutically acceptable acid or base.

2. A compound according to claim 1 wherein n is 0, 1 or 2; and

X is -O-, -S, -N(R⁶)- or -CH₂-; and

R¹ is NH₂, NHR⁵ or OH; and R² is COOH, COOR⁵, CONH₂, CONHR⁵, CON(R⁵)₂, CONHSO₂R⁵ or tetra¬ zole; and

R³ is H, COOH, COOR⁵, CONH₂, CONHR⁵, CON(R⁵)₂, CONHSO₂R⁵ or tetrazole; and

R⁴ is H, OH, NH₂, NHR⁵, CF₃, C^-alky!, C₂.₈-alkenyl, C₂-₈-alkγnyl, C₃._β- cycloalkyl, phenyl or C,.₄-alkoxy; and

R⁵ is H, C,._β-alkyl, C₂.₈-alkenγl, C₂.₈-alkynyl, phenyl or C₃._β-cycloalkyl; and ring A can be partly or completely saturated or aromatic, or a salt thereof with a pharmaceutically acceptable acid or base.

3. A compound according to anyone of the preceding claims wherein R¹ is NH₂.

4. A compound according to anyone of the preceding claims wherein X is -CH₂-.

5. A compound according to anyone of the preceding claims wherein R² is COOH or tetrazole.

6. A compound according to anyone of the preceding claims wherein R³ is H, COOH, CONH₂, CONHR⁵, CON(R^s)₂, CONHSO₂R⁵ or tetrazole.

7. A compound according to claim 1 selected from the following:

1 -Aminoindan-1 ,5-dicarboxylic acid,

1-Aminoindan-1 ,6-dicarboxylic acid, 1 -Aminoindan-1 ,4-dicarboxylic acid,

1-Amino-1 ,2,3,4-tetrahydronaphtalene-1 ,6-dicarboxylic acid,

1 -Amino-1 , 2, 3,4-tetrahydronaphtalene-1 ,7-dicarboxylic acid,

1-Amino-6-methoxyindane-1 -carboxylic acid,

1-Amino-6-hydroxyindane-1 -carboxylic acid, 1 -Amino-5-methoxyindane-1 ,6-dicarboxylic acid,

1 -Amino-5-hydroxyindane-1 ,6-dicarboxylic acid,

1-Amino-5-methoxyindane-1 ,5-dicarboxylic acid,

1-Amino-5-hydroxyindane-1 -carboxylic acid,

1-Amino-5-methoxyindane-1 -carboxylic acid, or a salt thereof with a pharmaceutically acceptable acid or base.

8. A method of preparing a compound according to claim 1 , CHARAC¬ TERIZED IN

a) reacting a compound of the formula II

prepared by well known methods, wherein X, n, R³, R* have the mean¬ ings defined above with reagents well known for converting oxo groups to amino acids or hydroxy acids either through hydantoin formation, through hydroxy nitrile or through aminonitrile formation, or

b) reacting a compound of the formula III

wherein X, n, R¹, R³ and R⁴ have the meanings defined above with reagents known to transform a cyano group into a R² group wherein R² has the meaning defined above provided that R² must not be H.

9. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition for use in treating a disease in the central nervous system related to the metabotropic glutamate receptor system comprising an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.

1 1. The pharmaceutical composition according to claim 9 or 10 in the form of an oral dosage unit or parenteral dosage unit.

12. The pharmaceutical composition according to claim 11 , wherein said dosage unit comprises from about 1 to about 100 mg of the compound according to claim 1.

13. A method of treating a disease in the central nervous system related to the metabotropic glutamate receptor system comprising administering to a subject in need thereof an effective amount of a compound accord¬ ing to claim 1.

14. A method of treating a disease in the central nervous system related to the metabotropic glutamate receptor system comprising administering to a subject in need thereof a pharmaceutical composition according to claim 10.

15. The use of a compound according to claim 1 for the preparation of a medicament for treatment of a disease in the central nervous system related to the metabotropic glutamate receptor system.