WO2003070712A1

WO2003070712A1 - Thioibotenic acid and derivatives thereof

Info

Publication number: WO2003070712A1
Application number: PCT/DK2003/000104
Authority: WO
Inventors: Lennart Bunch; Ulf Madsen; Hans BRÄUNER-OSBORNE; Povl Krogsgaard-Larsen; Charlotte GRUBE JØRGENSEN
Original assignee: H. Lundbeck A/S
Priority date: 2002-02-19
Filing date: 2003-02-17
Publication date: 2003-08-28
Also published as: AU2003205558A1

Abstract

The present invention relates to novel compounds of formula Ia or Ib; wherein the variable groups are as defined in the claims or a pharmaceutically acceptable addition salt thereof.The compounds of the invention are agonists at the metabotropic glutamic acid Group II and III receptors.

Description

Thioibotenic acid and derivatives thereof

Field of the invention

The present invention relates to thioibotenic acid, systematic name 2-amino- 2-(3-hydroxy-5-isothiazolyl)acetic acid, and derivatives thereof. These compounds are agonists at the metabotropic glutamic acid Group II and Group III receptors.

Background of the invention

Receptors for central excitatory arnino acids are divided into two main families, ionotropic (iGluRs) and metabotropic glutamic acid receptors (mGluRs). The iGluRs consist of three types named N-methyl-D-aspartic acid (NMDA), 2-amino- 3-(3-hydroxy-5-methyl-4-isoxazolyl)proρionic acid (AMPA) and kainic acid receptors, and the mGluRs consist of three types named Group I comprising mGluRl and mGluR5, Group II comprising mGluR2 and mGluR3, and Group III comprising mGluR4, mGluR.6, mGluR7 and mGluR8.

The naturally occurring compound ibotenic acid has been isolated from the fly agaric mushroom, Amanita muscaria, and has been used as a pharmacological tool at iGluRs and mGluRs. Ibotenic acid shows potent neurotoxic properties and interacts potently with NMDA receptors and mGluRs, and to a lesser extent with other iGluRs (P. Krogsgaard-Larsen, T. Honore, JJ. Hansen, D.R. Curtis and D. Lodge, Nature 1980, 284, 64-66; U. Madsen, M.A. Dumpis, H. Brauner-Osborne and L.B. Piotrovsky, Bioorg. Med. Chem. Lett. 1998, 8, 1563-1568). The neurotoxic properties are primarily related to the activity at NMDA receptors.

In contrast to the agonist activity at the NMDA receptors, the agonist activity at the metabotropic Group II and Group III receptors such as subtypes mGluR2 and mGluR4 will lead to neuroprotective properties. mGluR2 and mGluR4 agonists have, on the basis of animal models, been proposed to have therapeutic potential for treatment of the neurodegeneration observed in Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS dementia and epilepsy. Furthermore the neuroprotective properties of mGluR Group II and III agonists may be beneficial in relation to the central neurodegeneration observed after stroke and brain injury and, finally, therapeutic applications for schizophrenia, pain and anxiety have been proposed for such compounds (H. Brauner-Osborne, J. Egebjerg, E.0. Nielsen, U. Madsen and P. Krogsgaard-Larsen, J. Med. Chem. 2000, (43), 2609-2645).

Hence, there is a desire for novel compounds that are agonists at the metabotropic glutamic acid Group II and III receptors.

Summary of the invention

The objective of the present invention is to provide compounds that are agonists at the metabotropic glutamic acid Group II and III receptors.

A further objective of the present invention is to provide compounds with such activities which have an improved pharmacological profile with respect to the activity at the metabotropic glutamic acid Group II and III receptors relative to the activity at the NMDA receptors as compared to ibotenic acid.

Accordingly, the present invention relates to novel isothiazole derivatives of formula la or lb;

wherein R¹ is hydrogen, C_1-18-alkyl, C_2-18-alkenyl, C_2-ιg-alkynyl, C_3-8-cycloalkyl, C_3-g-cycloalkyl-C_1-6-alkyl or aryl-C_1-6-alkyl; R² is hydrogen, C_1-6-alkyl, C _-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl- C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl or heteroaryl-C_1-6-alkyl;

R³ and R⁴ independently are selected from hydrogen, C_1-6-alkyl, C_2-6-alkenyl, C _-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl-C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl, heteroaryl-Cι_-6-alkyl, C_1-6-alkylcarbonyl, trifluoromethylsulfonyl and C i _-6-alkylsulfonyl;

R⁵ is hydrogen, halogen, cyano, nitro, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl-C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl, heteroaryl- C_1-6-alkyl, amino, C_1-6-alkylamino, di-(C_1-6-alkyl)amino, C_1-6-alkylcarbonyl, aminocarbonyl, C_1-6-alkylaminocarbonyl, di-(C_1-6-alkyl)aminocarbonyl, Cι_₆-alkoxy, C_1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl or C_1-6-alkylsulfonyl; or

R² and R⁵ together are -CR⁷=CR⁸- or -CR⁷R^7'-CR⁸R^8'-, wherein R⁷, R^7', R⁸ and R^8' independently are selected from hydrogen, Cμe-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C _-8-cycloalkyl, C_3-8-cycloalkyl-C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl and heteroaryl-C_1-6-alkyl; and

R⁶ is hydrogen, C_1-6-alkyl, C_2-6-alkenyl, C₂.₆-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl- C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl, heteroaryl-C_1-6-alkyl C_1-6-alkylcarbonyl, trifluoromethylsulfonyl or Cι_-6-alkylsulfonyl; and

each aryl and heteroaryl present in the molecule may be substituted with one or more substituents independently selected from the group comprising hydrogen, halogen, cyano, nitro, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl- C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl, heteroaryl-C_1-6-alkyl, amino, C_1-6-alkylamino, di-(C_1-6-alkyl)amino, C_1-6-alkylcarbonyl, aminocarbonyl, C_1-6-allcylaminocarbonyl, di-(C_1-6-alkyl)aminocarbonyl, -β-alkoxy, C_1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl or C_1-6-alkylsulfonyl;

or pharmaceutically acceptable addition salts thereof. Detailed description of the invention

Throughout the description and the claims, the term C_1-6-alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-l- propyl. Similarly, C_1-18-alkyl refers to a branched or unbranched alkyl group having from one to eighteen carbon atoms inclusive.

Similarly, C_2-6-alkenyl and C_2-6-alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond, respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

Similarly, C_2-1s-alkenyl and C _-18-alkynyl, respectively, designate such groups having from two to eighteen carbon atoms, including one double bond and one triple bond, respectively.

The term C_3-8-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.

As used herein, the term acyl refers to a formyl, C_1-6-alkylcarbonyl, arylcarbonyl, aryl-C_1-6-alkylcarbonyl, C_3-8-cycloalkylcarbonyl or a C_3-8-cycloalkyl-C_1-6-alkyl- carbonyl group.

The terms C_1-6-alkoxy, C_3-8-cycloalkyl-C_1-6-alkyl, C_1-6-alkylsulfonyl, C_1-6-alkylamino, C_1-6-alkylcarbonyl, and the like, designate such groups in which the C_1-6-alkyl and the C_3-8-cycloalkyl group are as defined above.

The term aryl refers to a carbocyclic aromatic group, such as phenyl or naphthyl, in particular phenyl.

The term heteroaryl refers to 5-membered monocyclic rings such as IH-tetrazolyl, 3H-l,2,3-oxathiazolyl, 3H-l,2,4-oxathiazolyl, 3H-l,2,5-oxathiazolyl, 1,3,2-oxa- thiazolyl, 1,3,4-oxathiazolyl, 1,4,2-oxathiazolyl, 3H-l,2,4-dioxazolyl, 1,3,2-dioxa- zolyl, 1,4,2-dioxazolyl, 3H-l,2,3-dithiazolyl, 3H-l,2,4-dithiazolyl, 1,3,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyL 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thia- diazolyl, lH-l,2,3-triazolyl, lH-l,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, lH-imidazolyl, lH-pyrazolyl, lH-pyrrolyl, furanyl, thienyl, lH-pentazolyl; 6-membered monocyclic rings such as 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, 4H-l,3,5-oxathiazinyl, 1,4,2-oxathiazinyl, 1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl, 4H-l,3,2-dioxazinyl, 4H-l,3,5-dioxazinyl, 1,4,2-dioxazinyl, 2H-l,5,2-dioxazinyl, 1,2,3-dithiazinyl, 1,2,4-dithiazinyl, 4H-l,3,2-dithiazinyl, 4H-l,3,5-ditl iazinyl, 1,4,2-dithiazinyl, 2H-l,5,2-dithiazinyl, 2H-l,2,3-oxadiazinyl, 2H~l,2,4-oxadiazinyl, 2H-l,2,5-oxadiazinyl, 2H-l,2,6-oxa- diazinyl, 2H-l,3,4-oxadiazinyl, 2H-l,3,5-oxadiazinyl, 2H-l,2,3-thiadiazinyl, 2H-l,2,4-thiadiazinyl, 2H-l,2,5-thiadiazinyl, 2H-l,2,6-thiadiazinyl, 2H-l,3,4-thia~ diazinyl, 2H-l,3,5-thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-l,2-oxazinyl, 2H- 1,3 -oxazinyl, 2H-l,4-oxazinyl, 2H-l,2-thiazinyl, 2H-l,3-thia- zinyl, 2H-l,4-thiazinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, 2H-pyranyl, 2H-thiinyl; and to bicyclic rings such as 3H-l,2,3-benzoxathiazolyl, 1,3,2-benzodioxazolyl, 3H-l,2,3-benzodithiazolyl, 1,3,2-benzodithiazolyl, benz- furazanyl, 1,2,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, lH-benzotriazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzoxazolyl, 1,2-benz- isothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, IH-benzimidazolyl, lH-indazolyl, 3H-l,2-benzoxathiolyl, 1,3-benzoxathiolyl, 3H-2,l-benzoxathiolyl, 3H-l,2-benzo- dioxolyl, 1,3-benzodioxolyl 3H-l,2-benzodithiolyl, 1,3-benzodithiolyl, lH-indolyl, 2H-isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl, 2-benzothienyl, lH-2,l-benzoxazinyl, lH-2,3-benzoxazinyl, 2H-l,2-benzoxazinyl, 2H-l,3-benz- oxazinyl, 2H-l,4-benzoxazinyl, 2H-3,l-benzoxazinyl, lH-2,l-benzothiazinyl, lH-2,3-benzothiazinyl, 2H-l,2-benzothiazinyl, 2H-l,3-benzothiazinyl, 2H-l,4-benzo- thiazinyl, 2H-3,l-benzothiazinyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl, quinolyl, lH-2-benzopyranyl, 2H-l-benzopyranyl, lH-2-benzo- thiopyranyl or 2H-l-benzothiopyranyl.

Halogen means fluoro, chloro, bromo or iodo.

The term BOC means the well-known protecting group tert-butyloxycarbonyl. In one embodiment, the present invention relates to such compounds wherein R¹ is hydrogen.

In another embodiment, the present invention relates to such compounds wherein R² is hydrogen or C_1-6-alkyl.

In yet another embodiment, the present invention relates to such compounds wherein R³ and R⁴ are hydrogen.

In yet another embodiment, the present invention relates to such compounds wherein R⁵ is hydrogen or C_1-6-alkyl.

In yet another embodiment, the present invention relates to such compounds wherein R⁶ is hydrogen.

In yet another embodiment, the present invention relates to compounds of formula la.

In yet another embodiment, the present invention relates to compounds of formula lb.

In yet another embodiment, the present invention relates to thioibotenic acid.

The compounds of the general formulas la and lb may exist as optical isomers thereof and such optical isomers are also embraced by the invention.

The compounds of the invention are agonists at the metabotropic Group II and III receptors having an activity (EC₅₀) of 500 μM or less, typically of 200 μM or less, and preferably of 100 μM or less.

Accordingly, the compounds of the invention are considered useful in treating a variety of disorders in the central nervous system (CNS) such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS dementia, epilepsy, central neurodegeneration observed after stroke or brain injury, schizophrenia, pain and anxiety. The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The pharmaceutical compositions of this invention, or those which are manufactured in accordance with this invention, may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any phaπnaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.

Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.05 to 1000 mg.

The total daily dose is usually in the range of about 0.1 mg - 5 g, and most preferably about 0.5 to 1000 mg of the active compound of the invention.

The compounds of the invention may be prepared as follows:

Synthesis of 3-hydroxyisothiazole can be achieved in two steps from commercially available 3,3'-dithianedipiOpionic acid according to procedures described in J Chem. Soc. Perlύn Trans. I 1994, 2245-2251 and references therein. Benzylation with benzylbromide provides an easily separable mixture of 3-(benzyloxy)isothiazole II and 2-benzylisothiazol-3-one, respectively (90% yield, ratio 2:1), which is in agreement with results described in Tetrahedron 1970, 26, 2497-2506. 3-(benzyloxy)isothiazole II may be used as starting material for the synthesis of the compounds of the invention. This is exemplified by the syntheses outlined in scheme 1-3 below:

Scheme 1 : Thioibotenic acid

V VI

Reagents and reaction conditions: a) 1.1 equiv LDA, -78 °C, Et₂O, then 1.1 equiv imine III (56%); b) LiOH, H₂O/THF, rt, 4h (76%); c) 10 % HBr / AcOH, room temperature, 2 h (60%).

The synthesis of thioibotenic acid VI is described in detail in the experimental section. The protected thioibotenic acid IV may be N-deprotonated with a base and reacted with an electrophile R³-L wherein L is a leaving group thereby introducing an N-substiuent R³ prior to deprotection.

Scheme 2: Synthesis of thioibotenic acid derivatives with substituents in the 4-position of the isothiazole

VII VIII

X

Reagents and reaction conditions: a) IC1, K₂CO₃, CHC1₃; b) j-PrMgBr, then R⁵-L or Pd(0)/R⁵-L/ Zn, wherein R⁵ is alkyl, alkenyl, cycloalkyl, cycloalkylallcyl, aryl or arylalkyl and L is a leaving group according to methods described in (Negishi, E., King, AO., Okukado, N. J. Org. Chem. 1977, 42, 1821; Negishi, E., Valente, LF, Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298; Lauk, UH., Skrabal, P., Zollinger, H. Helv. Chem. Ada. 1985, 68, 1406); c) 1.1 equiv LDA, -78 °C, Et₂O, then 1.1 equiv imine; d) LiOH, H₂O/THF, room temperature; c) 10% HBr / AcOH, room temperature.

Exemplary for the reagents R -L in the reaction step b) in scheme 2 for the reaction without palladium are alkylhalides which introduce alkyl groups as R⁵ and N-brom succinimide and N-chlor succinimide which introduce bromide and chloride as R⁵. Exemplary for the reagents R⁵-L in the reaction step b) in scheme 2 for the reaction with palladium catalyst are alkylhalides and arylhalides which introduce alkyl and aryl groups as R .

The protected thioibotenic acid derivative IX may be N-deprotonated with a base and reacted with an electrophile R³-L wherein L is a leaving group thereby introducing an N-substiuent R³ prior to deprotection. Scheme 3: Synthesis of thioibotenic acid derivatives with N-substituents and/or substituents at the α-carbon

EtOOC. -FT

II XI

XII

XIV Reagents and reaction conditions: a) 1.1 equiv LDA, -78 °C, Et₂O, then ICl; b) Pd(0)/K₂CO₃/protected α-amino acid according to method described in (Lee S, Beare NA, Hartwig JF. J. Am. Chem. Soc. 2001, 123, 8410-8411); c) LiOH, H₂O/THF, room temperature; d) 10% HBr / AcOH, room temperature.

Experimental section

All reagents were obtained from commercial suppliers and used without further purification. Tetrahydrofuran (THF) was distilled from sodium/benzophenone and Et O was dried over sodium. NMR (300 MHz) spectra were recorded in CDC1₃ using CHC1₃ as reference. Merck kieselgel (35 - 70 mesh) was used for flash chromatography.

3-(Benzyloxy)isothiazole II

To a solution of 3-hydroxyisothiazole (2.02 g, 20 mmol) in dimethylformamide

(DMF) (20 mL) at 0 °C was added K₂CO₃ (5.53 g, 40 mmol) followed by benzyl bromide (2.74 mL, 20 mmol). The reaction mixture was allowed to stir for 48 h at room temperature, then diluted with H₂O (200 mL) and extracted with Et₂O. The organic layer was washed with brine, dried (Na SO₄) and evaporated to give crude product (2:1 O/N-mixture based on 1H NMR) which was purified by short column flash chromatography (heptane/EtOAc 4:1) followed by submission to high vacuum for 72 h to give II as a clear oil (2.29 g, 60%). 1H NMR δ 8.46 (d, 1H, J = 5 Hz), 7.49-7.30 (m, 5H), 6.65 (d, 1H, J= 5 Hz), 5.42 (s, 2H); ¹³C NMR δ 169.61, 149.00, 136.66, 128.65, 128.29, 128.25, 112.05, 70.49. Anal, calcd. for C₁₀H₉NOS: C, 62.80; H, 4.74; N, 7.32. Found: C, 63.05; H, 4.45; N, 7.17.

Ethyl 2-tert-butyloxycarbonylamino-2-ethoxycarbonyl-2-(3-benzyloxy-5-isothiazolyl)- acetate IV

3-(Benzyloxy)isothiazole II (100 mg, 0.52 mmol) dissolved in Et₂O (0.3 mL) was added drop wise to freshly prepared LDA (0.58 mmol) in Et₂O (4.5 mL) at -78 °C under N . After 15 min the imine III (Call, P.; Begtrup, M. Synthesis 2002, 63-66) (0.58 mmol) dissolved in Et₂O (0.2 mL) was added and stirring continued at -78 °C for 15 min. The reaction mixture was quenched with saturated aqueous NH C1 and extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄) and evaporated to give the crude product. Isolation by flash chromatography (heptane/EtOAc 4:1, R/ = 0.25) gave crude IV as a clear oil (135 mg, 56%), which was not purified further. 1H NMR δ 7.47-7.30 (m, 5H), 6.75 (s, 1H), 6.50 (br s, ³Λ H), 6.30 (br s, V H), 5.35 (s, 2H), 4.40-4.20 (m, 4H), 1.43 (br s, 9H), 1.26 (t, 6H, J = 7 Hz).

2-Amino-2-(3-hydroxy-5-isothiazolyl)acetic acid (thioibotenic acid) VI

LiOH (aq) (50 mL, 2.5 M) was added to a solution of IV (1.87 g, 4.02 mmol) in THF (50 mL) at room temperature and stirred for 4 h. The reaction mixture was then cooled to 0 °C and pH adjusted to 2 with 1 M HC1 (aq). The aqueous phase was extracted with EtOAc and the collective organic layers washed with brine, dried (Na₂SO₄) and evaporated to give the crude product. Isolation by flash chromatography (CH₂C1₂, MeOH, AcOH 100:5:2, R = 0.28) gave crude V as a clear oil (1.25 g, 76%), which was used without further purification. 10% HBr/AcOH (15 mL) was added to a solution of V (1.25 g, 3.06 mmol) in glacial AcOH (15 mL) and the reaction mixture was stirred at room temperature for 2h. After evaporation, the crude product was trituated with Et₂O, then H O (20 mL) was added and the crystals formed filtered off. The crystals were washed with H₂O then dried to give VI as a yellow semi-crystalline solid (360 mg, 60%). 1H NMR (DMSO) δ 9.05 (br s, 3H), 6.84 (s, 1H), 5.62 (br s, 1H); ¹³C NMR (DMSO/OH) δ 178.84, 176.08, 167.05, 127.45, 113.19. Recrystallization of a sample from H₂O: Anal, calcd. for C₅H₆N₂O₃S: C, 34.48; H, 3.47; N, 16.08. Found: C, 34.45; H, 3.32; N, 15.80. Mp = 178-180 °C.

Pharmacological testing

Thioibotenic acid, which is a compound of the invention, was tested in well- recognised and reliable tests and compared to ibotenic acid as a reference compound. The tests were as follows: NMDA activity (IC₅₀ in the [³H]CGP39653 binding assay (M.A. Sills, G. Fagg, M. Pozza, C. Angst, D.E. Brandish, S.D. Hurt, EJ. ilusz and M. Williams, Eur. J. Pharmacol. 1991, 192, 19-24) and EC₅₀ in the electrophysiological model (NX. Harrison and M.A. Simmonds, Br. J. Pharmacol. 1985, 84, 381-391)), and activity at mGluR receptors (EC₅₀) (H. Brauner-Osborne, B. Nielsen and P. Krogsgaard-Larsen, Eur. J. Pharmacol. 1998, 350, 311-316). The tests were performed according to procedures described in the references. The results show that thioibotenic acid has a reduced agonist effect at the NMDA receptor as compared to ibotenic acid and an increased agonist effect at nιGluR2 relative to ibotenic acid as well as agonist activity in the μM range at mGluR4.

In vivo experiments performed by intravenous administration to mice at a very high dose of thioibotenic acid (53 mg/kg) have shown no toxic or behavioral effects of thioibotenic acid.

Formulation examples

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.

Typical examples of recipes for the formulation of the invention are as follows:

1) Tablets containing 5.0 mg of a compound of the invention calculated as the free base:

Compound VI 5.0 mg Lactose 60 mg

Maize starch 30 mg

Hydroxypropylcellulose 2.4 mg

Microcrystalline cellulose 19.2 mg

Croscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg

2) Tablets containing 0.5 mg of a compound of the invention calculated as the free base:

Compound VI 0.5 mg Lactose 46.9 mg

Maize starch 23.5 mg

Povidone 1.8 mg

Microcrystalline cellulose 14.4 mg Croscarmellose Sodium Type A 1.8 mg

Magnesium stearate 0.63 mg

3) Syrup containing per millilitre:

Compound VI 25 mg

Sorbitol 500 mg

Hydroxypropylcellulose 15 mg

Glycerol 50 mg

Methyl-paraben l mg

Propyl-paraben 0.1 mg

Ethanol 0.005 mL

Flavour 0.05 mg

Saccharin sodium 0.5 mg

Water ad 1 mL

4) Solution for injection containing per millilitre:

Compound VI 0.5 mg

Sorbitol 5.1 mg Acetic acid 0.05 mg

Saccharin sodium 0.5 mg

Water ad 1 mL

Claims

1. An isothiazole derivative of formula la or lb;

wherein R¹ is hydrogen, -is-alkyl, C_2-18-alkenyl, C_2-18-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl-C_1-6-alkyl or aryl-Cι_-6-alkyl;

R² is hydrogen, C_1-6-alkyl, C_2-6-alkenyl, C _-6-alkynyl, C_3-s-cycloalkyl,

C_3-8-cycloalkyl-C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl or heteroaryl-C_1-6-alkyl;

R and R independently are selected from hydrogen, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl-C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl, heteroaryl-C_1-6-alkyl, C_1-6-alkylcarbonyl, trifluoromethylsulfonyl and

C_1-6-alkylsulfonyl;

R⁵ is hydrogen, halogen, cyano, nitro, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl-C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl, heteroaryl-C_1-6-alkyl, amino, C_1-6-alkylamino, di-(C_1-6-alkyl)amino,

C_1-6-alkylcarbonyl, aminocarbonyl, C_1-6-alkylaminocarbonyl, di-

(C_1-6-alkyl)aminocarbonyl, Cι_₆-alkoxy, C_1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl or C_1-6-alkylsulfonyl; or

R² and R⁵ together are -CR⁷=CR⁸- or -CR⁷R^7'-CR⁸R^8'-, wherein R⁷, R^7', R⁸ and

R^8' independently are selected from hydrogen, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl-C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl and heteroaryl-C_1-6-alkyl; and R⁶ is hydrogen, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkyl-C_1-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl, heteroaryl-C_1-6-alkyl C_1-6-alkylcarbonyl, trifluoromethylsulfonyl or C_1-6-alkylsulfonyl; and

each aryl and heteroaryl present in the molecule may be substituted with one or more substituents independently selected from the group comprising hydrogen, halogen, cyano, nitro, C_1-6-alkyl, C_2-6-alkenyl, C_2-6-alkynyl, C_3-s-cycloalkyl, C_3-8-cycloalkyl-Cι_-6-alkyl, aryl, aryl-C_1-6-alkyl, heteroaryl, heteroaryl-C_1-6-alkyl, amino, Cι_-6-alkylamino, di-(C_1-6-alkyl)amino, C_1-6-alkylcarbonyl, aminocarbonyl, C_1-6-alkylaminocarbonyl, di-(C_1-6-alkyl)aminocarbonyl, -e-alkoxy,

C_1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl or C i _-6-alkylsulfonyl;

or a pharmaceutically acceptable addition salt thereof.

2. An isothiazole derivative according to claim 1, characterised in that R¹ is hydrogen.

3. An isothiazole derivative according to any of claims 1-2, characterised in that R is hydrogen or C_1-6-alkyl.

4. An isothiazole derivative according to claim 3, characterised in that R² is hydrogen.

5. An isothiazole derivative according to any of claims 1-4, characterised in that R and R⁴ are hydrogen.

6. An isothiazole derivative according to any of claims 1-5, characterised in that R⁵ is hydrogen or C_1-6-alkyl.

7. An isothiazole derivative according to any of claims 1-6, characterised in that R⁶ is hydrogen.

8. An isothiazole derivative according to any of claims 1-7, characterised in that it is a compound of formula la.

9. An isothiazole derivative according to any of claims 1-7, characterised in that it is a compound of formula lb.

10. An isothiazole derivative according to any of claims 1-9, characterised in that it is thioibotenic acid.

11. A phaπnaceutical composition comprising a compound of any of claims 1 to 10 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.

12. Use of a compound of any of claims 1 to 10 for the manufacture of a phaπnaceutical preparation for the treatment of a disorder in the central nervous system.

13. Use according to claim 12 characterised in that the disorder is selected from the group comprising Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, AIDS dementia, epilepsy, central neurodegeneration observed after stroke and brain injury, schizophrenia, pain and anxiety.