Title of Invention

SPIRO(2H-1-BENZOPYRAN-2,4'-PIPERIDINE) DERIVATES AS GLYCINE TRANSPORT INHIBITORS

Abstract The present invention relates to spiro[2H-1-benzopyran-2,4'-piperidine] derivatives having general formula (I), wherein the substituents R1, R2, X and Y are ase defined in the claims or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said derivatives, as well as to the use of these spiro[2H-1-benzopyran-2,4'-piperidine] derivatives in therapy, more specifically for the treatment of CNS disorders.
Full Text

The invention relates to spiro2H-1 -benzopyran-2,4'-piperidine] derivatives, to phamnaceutical compositions containing the same, as well as to the use of these spiro[2H-1-benzopyran-2,4'-piperidine] derivatives in therapy.
The simplest a-amino acid glycine has a number of important roles in the mammaifan central nervous system (CNS). Along with y-aminobutyric acid (GABA), it is a major post-synaptic inhibitory transmitter in the spinal cord and brainstem, acting through [igand gated ion channels. Interaction of glycine with these receptors can be antagonized by the alkaloid strychnine. These receptors are therefore referred to as 'strychnine sensitive' glycine receptors. Glycinergic neurotransmission is important in the processing and control of visual, auditory and motor signalling. Glycine is also an obligatory co-agonist along with glutamate at the N-methyl-D-aspartate (NMDA) receptor. Glycine therefore functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the CNS. In addition the amino acid plays a role in the metabolism of peptides and proteins, including the exchange of one-carbon units.
Control of the availability of glycine for any of the above processes will potentially influence their function and provide means of treating a number of diseases and conditions. Apart from metabolism, one of the major processes controlling the concentrations of free glycine in the proximity of strychnine-sensitive and strychnine-insensitive glycine receptors is the functioning of selective high affinity glycine transporters. These proteins can actively limit the spread of glycine beyond the immediate environs of receptors, thus maintaining both spatial and temporal fidelity of receptor activation. Rapid sequestering of transmitter into neuronal or glial cells via the transporter will also conserve glycine for future release.
Glycine transporters have been doned to reveal two major classes, GlyT-1 and GlyT-2. GlyT-1 is expressed throughout the brain with higher mRNA levels being detected in caudal areas and cellular localisation being predominantly glial.

Three isoforms of GlyT-1, la, 1b and 1c, arising from differential splicing and exon usage have been identified by Kim et al. (Molecular Phaim. 1994, 45, 608-617), The doning and expression of a further human isofomn GlyT-ld was recently disclosed in European Patent Application EP 951543 (Allelix Neuroscience, inc.).
GlyT-2 distribution, as indicated by immunochemistry studies, corresponds closely to that of inhibitory 'strychnine sensitive' glycine receptors, particulariy in the spinal cord.
By regulating the synaptic levels of glycine, the glycine transporters GlyT-1 and GlyT-2 are expected to selectively influence the activity at NMDA receptors and at strychnine-sensitive glycine receptors, respectively.
Compounds which alter the functional activity of glycine transporters may therefore result in changes in tissue glycine levels which can be useful in the treatment of a number of disease states. Such disease states include those associated with decreased or exaggerated function of NMDA receptors, namely psychosis, depression, dementia and other forms of impaired cognition, such as attention deficit disorders. NMDA receptors have further been implicated in conditions arising from neuronal cell death and neurodegeneration such as, for example, stroke (head trauma), Alzheimer's disease, Parkinson's disease and Huntington's disease. Enhanced inhibitory glycinergic transmission resulting from inhibition of GlyT-2 or GIyT-1 activity may be useful in the treatment of muscle hyperactivity associated with spasticity, myoclonus and epilepsy. Compounds elevating spinal glycine may also possess analgesic properties.
Compounds that inhibit glycine transport via the Gly-TI or GIy-T2 transporters are disclosed in WO 97/45115 (TROPHIX PHARM. INC.). in WO 97/45423 (TROPHIX PHARM. INC.). in WO 99/34790 (ALLELIX NEUROSCIENCE INC.) and in WO 00/07978 (AK20 NOBEL N.V.) as compounds useful in the treatment of the neurological and neuropsychiatric disonders discussed above. There exists a need for additional compounds suitable for the treatment of psychiatric and neurological disorders, especially for compounds having a selective pharmacological profile.



The term (C1-4)alkyl, as used in the definition of fomnula I, means a branched or straight chain alkyl group having 1-6 carbon atoms, like hexyl, pentyl, neopentyl (2,2-dimethyipropyI). butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. Likewise, the temi (C1-4)alkyl refers to an alkyl group having 1-4 carbon atoms,
In the term (C1-6)alkyloxy, (C1_6)alkyl means a branched or an unbranched alkyl group as previously defined. The (C3-6)alkyloxy group may be substituted with 1-3 halogens or with (C3-6)cycloalkyI. which means a cyclic alkyl group having 3-6 carbon atoms, like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples of such substituted (C1-4)alkyloxy groups are trifluoromethyloxy and cyclopropylmethyloxy, The term halogen means F, CI. Br, or I. When halogen is a substituent at an alkyl group, F is preferred. A preferred halogen substituted alkyl group is trifluoromethyl.
The term (C2-6)alkenyl, such as used in the term (C2-6)alkenyioxy, means a branched or straight chain aikenyl group having 2-6 carbon atoms, such as etheyl (vinyl), 2-propenyl (ailyl), isopropenyl and 2-butenyl.
The term(C1-4)alkynyl, such as used in the term (C2-6)alkynyloxy, means a branched or straight chain alkynyl group having 2-6 carbon atoms, such as propargyl.
In the term {C5-12)ary\oxy, as used in the definition of formula I, (C6-13)aryi means an aromatic hydrocarbon group having 6-12 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl or biphenyl. These aromatic groups may be substituted with halogen, or with (C1-4)alkyl or (C1-4)alkyloxy, wherein (C1-4)alkyl has the previously given meaning and may be substituted with halogen or (C1-4)alkyloxy.
The term (C7-15)arylalkyl, as used in the definition of Formula I, means an arylalkyi group having 7 to 15 carbon atoms, wherein the alkyl group is a (Ci^)alkyl group and the aryl group Is a (Ce.i2)aryl as previously defined. Phenyl(C-,^)aikyl groups are preferred arylalkyi groups, such as benzyl.
The term heteroaryl, such as used in the term heteroaryloxy, means a substituted or insubstituted aromatic group having 6-12 carbon atoms, including at least one leteroatom selected from N. O and S, like for example 'imdazolyl, thienyl.

benzthienyl. quinolinyi and indolyL The heteroaryl group may carry substituents as listed for the aryl group.
Heteroaryialkyl groups are analogs of the (7-15)arylalkyI groups, including at least one heteroatom selected from N, O and S.
In the definition of formula I, Y can represent a fused (C5-6)afyl group, which means that Y is a 5 or 6-membered aromatic ring fused to the benzene ring to which X is attached to form a (C11-12)aromatic ring system, like a naphthalene or an in^ene ring.
In addition to the definition of R1, the O-R1 group in Formula I may be any other group from which the free acid (R-, is hydrogen) can be generated (in vivo). Such alternative acid precursors or prodnjgs, such as further ester or amide derivatives, are known in the art, and are within the scope of the present invention.
The spiro[2H-1-benzopyran-2,4'-piperidine] derivatives of formula I and their salts may contain one or more stereogenic centres and may exist therefore as stereoisomers. The present invention includes these stereoisomers within its scope, as well as enantiomers of the compounds of fonmula I and their salts, substantially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer, and mixtures of such stereoisomers in any proportions including the racemic mixtures containing substantially equal amounts of the two enantiomers.
Preferred are the spiro[2H-1-ben2opyran-2,4-piperidine] derivatives of formula I wherein the dotted line represents a bond, while those compounds wherein in addition R^ and R2 Bve both hydrogen are more preferred.
Especially preferred 5piro[2H-1 -ben2opyran-2.4'-piperidine] derivatives of the invention, and of salts thereof, correspond to compounds of formula 1 wherein the dotted line is a bond, R^ and R2 are hydrogen, and wherein Y represent a para-substituent selected from chlono, bromo, (C^^)aikyloxy, (C^^)alkenytoxy, (C,^)-alkynyioxy and NR3R4, and 1 or 2 meta-substituents selected among the halogens, the preferred selection being fluoro. Specific examples of prefeoed substitution patterns Y are: 3-fluon>4-methyl; 3-fluoro-4-ditoro; 3-fluoro-4-dimethyiamino and

3,5-diriuoro-4-dimethylannino. Especially preferred are compounds according to formula I wherein Y represents 3-fluoro-4-aIkyloxy, in particular 3-fluoro-4-n-propoxy and 3-fluoro-4-n-butoxy, and 3,5-difluoro-4-alkyloxy.
Spiro[2H-1-benzopyran-2,4'-piperidine] derivatives of general formula I may be prepared using a sequence of reactions in which 2'-hydroxyacetophenone derivatives of Formula II, wherein X has the meanings as previously defined, are utilized as starting materials which are readily available either commercially or using synthesis methods known to the person skilled in the art of synthetic organic chemistry. The 2'-hydroxyacetophenone derivatives II are condensed with 1-methyl-4-piperidone [R is methyl; as an alternative 1-benzyl-4-piperidone (R is benzyl) may be used, the benzyl group being often more easily removed than the methyl group (see Scheme C)] in methanol solution in the presence of pyrrolidine to provide A(-methyl-5piro[2H-1 -benzopyran-2,4'-piperidinel-4(3H)-one derivatives having Formula III as shown in Scheme A,

Scheme A, The spiro-keto derivatives of Formula Hi are subsequently treated, as shown in Scheme B. with a Grignard reagent having formula IV, wherein Y has the meaning as previously defined, in a suitable solvent, like tetrahydrofuran, to give the 4-ar^-N-methyl- or N-benzyl-spiro[2H-1-benzopyran-2.4'-piperidine] derivatives of formula V after treatment with acid.


Scheme B, Alternatively, compounds according to Fomnula V can be prepared by conversion of a spiro-keto derivative of Formula 111, wherein R is H, methyl or benzyl, to the enoltrifiate derivative 111", and subsequent Suzuki coupling reaction with a phenylboronic acid derivative IV" (Scheme B").

Scheme B". N-Dealkylation of the compounds according to formula V using 1-chloroethyl chlorofornate in a chlorinated solvent such as 1,3-dichlonopropane or dichloromethane yields the intermediate 4-aryi-spiro[2H-1-benzopyran-2,4'-piperidine] derivatives of Fomnula VI. which are subsequently alkylated on reaction with HalCH2R2-COOR1. wherein R1 may be (C1-4)cdkyl or (C6-i2)aryl and Rj has the meaning as previously defined and Hal means halogen, preferably bronro, to give the 4-aryl-spiro[2H-1-benzopyran-2,4*-piperidine] derivatives of Formula 1, as shown in Scheme C. the ester function of whic^ may be hydrcrfysed to the compounds of formula I wherein R^ is hydrogen.


Scheme C. Where the required Grignard reagent according to Fonnula IV is not connmercially available it is prepared fronn the relevant bromoarene using a standard procedure {The Handbook of Grignard Reagents, ed. G. S. Silverman and P. E. Rakita, 1996, Marcel Dekker, New York),
The compounds of the invention can be used in the treatment of schizophrenia, depression, dementia and other forms of impaired cognition, for the treatment or prevention of neurodegeneration follov/ing stroke or head trauma, for the treatment of neurodegenerative diseases like Alzheimer's-, Parkinson's- and Huntington's disease, for the treatment of muscle hyperactivity associated with spasticity, myoclonus and epilepsy, for the treatment or prevention of pain, mood disorders or learning disorders.
The compounds of this invention may possess one or more stereogenic centres and can therefore be obtained as pure stereoisomers, or as a mixture of stereoisomers. Methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, enantioseiective enzymatic ester hydrolysis, crystallization of salts which are obtained from opticaliy active acids and the racemic mixture, separation of stereoisomers or enantiomers using chromatography on chiral media, or on straight phase or reversed phase chromatography media. Such methods are for example described in Chirality in Industry (edited by A. N. Collins, G, N, Sheldrake and J. Crosby, 1992; John Wiley).

Pharmaceutically acceptable salts of the compounds of formula 1 may be obtained by treating the free base of the compounds according to formula I with a mineral acid such as hydrochloric add, phosphoric acid, sulphuric acid, preferably hydrochloric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulphonic acid and the like. Pharmaceutically acceptable salts of compounds of fonnula 1 wherein R, is hydrogen, may be obtained by treating the acid or zwitterionic form of those compounds with an organic base or a mineral base, like sodium, potassium or lithium hydroxide.
The invention provides in a further aspect pharmaceutical compositions comprising a spiro[2H-1-benzopyran-2,4-piperidine] derivative having general formula I, or a pharmaceutically acceptable salt thereof, in admbcture with phanmaceutically acceptable auxiliaries.
The pharmaceutical compositions for use according to the invention comprise a spiro[2H-1-benzopyran-2,4'-piperidine] derivative having formula 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The term "acceptable" means being compatible with the other Ingredients of the composition and not deleterious to the recipients thereof. The compositions can be prepared in accordance with standard techniques such as for example are described in the standard reference, Gennaro et al, Remington's Phannaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture).
Compositions include e.g. those suitable for oral, sublingual, intranasal, subcutaneous, intravenous, intramuscular, local, or rectal administration, and the like, all in unit dosage forms for administration.
For oral administration, the active ingredient may be presented as distrete units, such as tablets, capsules, powders, granulates, solutions, and suspensions.

For parenteral administration, the phamiaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophillzed) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
The compounds of the invention may be administered for humans in a dosage of 0.001-50 mg per kg body weight, preferably in a dosage of 0.01-20 mg per kg body weight.
The invention furt:her includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
The invention is illustrated by the following examples.
General:
All mass spectrometry was carried out on either a PE SCIEX API 150EX or a ?E SCIEX API 365 machine. Melting points are uncorrected and were determined jsing either a Leica Galen 111 instrument or a Leica VMHB System Kofler.
Example 1
r-Carboxvmethvl-7-methoxv-4-phenvlspiror2H-1-benzopvran-2,4'-Diperidine1 ivdrochloride
Step A: 7-mef/TOxy-/V-mef/7v/sp/ror2H-f-benzopyran-2.4-p/penc//ne/-4r3H)-one
To a stirred solution of 2-hydroxy-4Hnethoxyacetophenone (4.08 g, 24.58 nmol) in anhydrous methyl alcohol (60 cm3) under an atmosphere of dry nitrogen was added 1-methyl-4-piperidinone (3 cm3, 24.58 mmol) followed by pyrrolidine (4 :m^, 47.92 mmoi) and the solution was heated to reflux. After 7 h. a further portion if 1-methyl-4-piperidinone (0.6 cm3. 4.76 mmol) was added and the mixture was leated to reflux for a further 4.5 h. It was then allowed to axA to room temperature efore the volatile fractions were removed under reduced pressure. The resulting oil

was treated with dichloromethane (100 cm2), washed with water (5 x 100 cm2), dried over anhydrous sodium sulfate to afford a dark viscous oil (6.33 g, 24.25 mmol) which partially crystallised on standing over a long period of time.
Step B: 7-methoxv-N-methvl'4-ohenvl'SDirof2H-1-benzoDvmn'2A'-poeridinel
To a stirred solution of 7-methoxy-A/-methylspiro[2H-1-benzopyran-2,4*-piperidine]-4(3H}-one (6.19 g, 23.72 mmol), in anhydrous tetrahydrofuran (80 cm2) under an atmosphere of anhydrous nitrogen was added drop-wise a solution of phenylmagnesium bromide in tetrahydrofuran (40 cm2, 1.0 M, 40 mmol) maintaining the reaction temperature below 30 C. When the addition was complete the reaction was stirred at room temperature for 2.5 h at which time the reaction was incomplete but no Grignard reagent was present. A further portion of phenylmagnesium bromide (13.3 cm2) was carefully added to the reaction and it was allowed to stir overnight. Water (30 cm2) was added followed by saturated aqueous ammonium chloride solution (30 cm2). The volatiies were removed in vacuo before the resulting material was treated with diethyl ether (100 cm2) and water (100 cm2). The organic layer was separated before the aqueous portion was extracted further with diethyl ether (2 x 100 cm2). The combined extracts were washed with water (3 x 100 cm2), dried over sodium sulfate and the ether was removed in vacuo. The residue was triturated with a little diethyl ether and the resulting crystals were isolated by vacuum filtration (4.57 g. 12.15 mmol, 51 %). This solid was then taken up into ethyl alcohol (75 cm2) and treated with hydrochloric acid (75 cm2, 2 N) before being heated to reflux for 1.5 h. The solution was concentrated under reduced pressure until a solid began to crystallise. The mixture was then cooled and the solid was isolated by vacuum filtration. This was then treated with a mixture of water (300 cm2), saturated aqueous potassium bicarbonate solution (50 cm2) and diethyl ether (650 cm2) and shaken. The aqueous layer was separated and extracted with diethyl ether (2 x 100 cm2) before the combined extracts were washed with water (3 x 250 cnr), dried over sodium sulfate and the volatiies were removed in vacuo to afford the title compound (3.91 g, 12.18 mmol, 51 % from ketone).

step Cv7-methoxV'4-DhenvlsDirol2H'lTbenzoDvran'2A'-Dmendmel
To a stirred solution of 7-methoxy-N-methyl-4-phenylsplro[2H-1"ben2opyran-2,4'-piperidine] (3.76 g, 11.71 mmol) in anhydrous 1,2-dichloropropane (150 orr?) was added potassium carbonate (4.04 g, 29.23 mmol) and the resulting suspension was cooled in an ice-bath before being treated drop-wise with 1-chloroethyl chloro-formate (1.58 cm2, 14.64 mmol). The reaction mixture was heated to reflux overnight and a further portion of 1-chloroethyl chioroformate (0.8 cm2. 7.4 mmol) was added before it was heated to reflux for a further 24 h. Upon cooling, the reactbn mixture was filtered through cotton wool which was subsequently washed with dichloro-methane (50 cm2) and the volatiles were removed in vacuo. The resulting intermediate was treated with methyl alcohol (200 cm2) and the mixture was heated to reflux overnight. Upon cooiing, the voiatiies where removed In vacuo before the resulting solid was dissolved in a mixture of dichloromethane (150 cm2) and aqueous sodium carbonate solution (5 %, 30 cm2). The organic layer was separated, washed with water (2 x 50 cm2), dried over sodium sulfate and the solvent was removed in vacuo to afford the title compound as a gum (3.93 g).
Step D: ethyl 7-mBtiioxv-4-DhenvlsDirof2H' 1 -benzoovran-Z.4'-Piperidinel-1 -aoetate
To a solution of 7-methQxy-4-phenyispiro[2H-1-ben2opyran-2,4'-pfperidine] (3.85 g, 12.54 mmol} in anhydrous N,N--dimethylformamide (75 cm2) was added potassium carbonate (4.32 g, 31.30 mmol) followed by ethyl bromoacetate (1.39 cm2, 12.53 mmol) and the mixture was heated to 100 °C under nitrogen for 2 h. The resulting mixture was poured into water (600 cm2) and extracted with ethyl acetate (3 X 150 cm2). The combined organic extracts were washed with water (3 x 300 cm3 dried over sodium sulfate and the volatiles were removed in vacuo. This cmde product was purified by column chromatography (silica, eluting with dichloromethane-ethyl acetate-9:1 through to 4:1) resulting in the pure ethyl ester (3.51 g, 71 %).

step E: a mixture of ethyl 7-methoxy-4-phenylspiro[2H-1-benzopyran-2,4'-piperidine]-1'-acetate (3.38 g, 8.60 mmol), ethyl alcohol (250 cm2) and aqueous lithium hydroxide solution (2 N, 6.44 cm2 12.88 mmol) was heated to reflux for 3.5 h. Upon cooling, the mixture was treated with hydrochloric acid (5 N, 70 cm2) and some of the ethyl alcohol was removed until precipitation began. The mixture was then cooled to 4 °C until crystallisation was complete. The solid was removed by vacuum filtration to afford the title product as a white solid, m.p. 195-230 ^C. positive ion ESI (M+H)+ 366,4.
The following compounds were prepared in a similar manner using the appropriate
2*-hydroxyacetophenone derivative of Formula II (Scheme A) and Grignard reagent
of formula IV (Scheme B): _ _
Example 2: 1 '-carboxymethyl-4-(4-chlorophenyI)spiro[2H"1-benzopyran-2,4'-piperidine] hydrochloride: m. p. 259-265 °C; positive ion ESI (M+H)* 370.0. Example 3: lithium 4-(4-fluorophenyI)spiro[2H-1-benzopyran-2,4-plperidine}-1'-acetate:
This lithium salt was prepared analogous to the procedure as described in Example 1 (Step E) except that the hydrolysis of the ethyl ester was carried out using 1.02 mole equivalents of aqueous lithium hydroxide solution (2.0 N) and when the reaction was complete the volatiies were removed in vacuo, m. p. 285-291 °C (decomp.); positive ion ESI (M+H)* 354.2. Example 4: 1 '-carboxymethyl-4-(4-methylphenyl)spiro[2H-1-ben2opyran-2.4'-piperidine] hydrochloride; m. p. 247-249 °C; positive ion ESI (M+H)" 352.2. Example 5: lithium 6-fluoro-4-phenylspiro[2H-1-ben2opyran-2,4'-piperidine]-1 '-acetate: m. p. 293-298 = °C (decomp.); negative ion ESI (M+Hf 354.2. Example 6: 1 '-carboxymethyl-6-methyl-4-phenylspiro[2H-1 -ben2opyran-2,4'-piperidine] hydrochloride: m. p. 240-244 °C; positive ion ESI (M+H)+ 350.2. Example 7: 1 '-carboxymethyl-7-fluoro-4-phenylspiro{2H-1-benzopyran"2,4'-piperidine] hydrochloride: m. p. 237-242 °C; positive ion ESI (M+H)+ 354.2. Example 8: 1 '-carboxymethyl-4-(4-chloro-3-fluorophenyl)spiro[2H-1-benzopyran-2,4'-piperidine] hydrochloride: m. p. 263-274 °C; positive km ESI (M+H)+ 388.2





Example 36: 1 '-carboxymethyl-4-(3,5-difluoro-4-methoxyphenyl)spiro[2H-1 -ben2opyran-2,4'-piperidine] hydrochloride: positive ion ESI (M+H)+ 402.2.
4-Bromo-2,6-difluoroanlsole, the starting material for the preparation of the Grignard reagent according to Formula IV (Scheme B), was prepared from 4-bromo-2.6-difluorophenol. To a solution of the phenol (49.0 g, 234 mmol) in anhydrous acetone (980 cm2) was added methyl iodide (29.4 cm2, 468 mmo) followed by potassium carbonate (80.85 g, 585 mmoi). The stirred mixture was heated to reflux for 2 h before being allowed to cool. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was taken up into diethyl ether (1000 cm2) and the solution was washed with water (3 x 300 cm2), dried (Na2S04) and the ether was removed in vacuo to afford the crude product which was used to prepare the desired Grignard reagent without further purification (49.4 g, 222 mmol, 95 %). Example 37: 1 -cariboxymethyl-4-(4-dimethylamino-3-fluorophenyl)spiro[2H-1-benzopyran-2,4'-piperidine] hydrochloride: m. p. 231-239 °C; positive ion ESI
(M+H)+ 397.4.
Example 38: 1 '-carboxymethyl-4-{3,5-difluoro-4-dimethylaminophenyl)spiro[2H-1-
benzopyran-2.4'-piperidine] hydrochloride; m. p. 231-242 °C; positive ion ESI
(M+H)+415.0.
Example 39: 4-(4-bromo-3-fluorophenyl)-1 *-carboxymethylspiro[2H-1 -benzopyran-
2,4'-piperidine] hydrochloride; positive ion ESI (M+Hf 432.5.
Example 40: 1 '-carboxymethyl-4-(3-bromo-4-methoxyphenyl)spiro[2H-1 -
benzopyran-2,4*-piperidine] hydrochloride; positive ion ESI (M+H)" 444.1.
Example 41:1 '-carboxymethyl-4-(3,5-difluorophenyl)spiro[2H-1-benzopyran-2.4'-
piperidine] hydrochloride; m. p, 230-264 °C; positive ion ESI (M+H)* 372.2.
Example 42:
V-carboxymethyl-4-(3.5-difluoro-4-ethoxyphenyi)spiro[2H-1-benzopyran-2,4'-
piperidine] hydrochloride:

step A: 1 -carboxvmethvl'4'(3,5-dlf1uorO'44ivdrox\mhenvl}spirof2H'1'ben ZA'-oiperidine] hvdrobromide
A mixture of the methyl ether (2,35 g) in acetic acid (15 cm2) and 47 % hydrobromic acid was stinted at 120 °C for 40 h. The resulting suspension was cooled in an ice-bath before water (30 cm2) was added. The solid was removed by filtration, washed with acetic acid then water before being dried in vacuo. Step B: ethyl [3.5-difluoro-4'hvdroxvohenyl)sDimf21^-1-benzoDvran-2A'-DiDeridineh V-aoetate
1-carboxymethyl-4-(3,5-difluoro-4-hydroxyphenyl)spiro[2H-1-benzopyran-2,4'-piperidine] hydrobromide (1.7 g; prepared as described in Step A) was suspended in a solution of hydrogen chloride in ethyl alcohol (120 cm2) and the mixture was heated to reflux for 16 h. Upon cooling the volatile materials were removed in vacuo to afford a solid residue which was partitioned between ethyl acetate (100 cm2) and a combination of water (100 cm2) and saturated aqueous potassium bicariDonate (30 cm2). The aqueous layer was extracted into ethyl acetate (2 X 50 cm2) before the combined extracts were washed with water (2 x 50 cm2} and dried (Na2S04). The crude material was then filtered through silica using ethyl acetate as the eluent which was then evaporated to afford the solid product (1.54 g) Step C: ethyl (3.5-difluoro-4'ethoxvphenvl)SDirof2H'1'benzopvran'2A'-Dipehdine]' V-acetate
To ethyl (3,5-difluoro-4-hydroxyphenyl)sp!ro[2H-1-benzopyran-2,4'-piperi-dine]-V-acetate (350 mg), cesium carbonate (412 mg) and sodium iodide (13 mg) was added A/,A/-dimethylformamide (9 cm2) followed by iodoethane (1.7 mole equiv.). The resulting mixtures were heated to 65 °C with stirring for 3 h. Upon cooling, the reaction was diluted with ethyl acetate (90 cm2) then washed with water (5 X 35 cm2) and dried (Na2S04). This solution of crude material was then filtered through a pad of silica before the solvent was removed in vacuo to afford the product in a homogeneous state.
Step D: Prepared from ethyl (3,5-difluoro-4-ethoxyphenyl)spiro[2H-1-benzopyran-2.4'-piperidine]-1'-acetate according to the procedure described in Example 1. V-carboxymethyl-4-(3,5-difluoro-4-ethoxy phenyl )spiro|2H-1-benzopyran-2,^ piperidine] hydrochloride: positive ion ESI (M+H)+ 416-5.







evaporated to give the product as a gum which solidified on standing. This was broken up with a spatula, filtered off and washed with water (20 em3). The cake was sucked almost dry and then finally dried in vacuo at 65 °C to gfve the product (300 mg), (M+H)+ = 534.2 m/z.
This ester was hydrolysed according to the procedure described in Example 1 except that the hydrolysis was carried out in n-butanol: positive ion ESI (M+H)"" 506.2.
Example 70: 1 '-carboxymethyl-8-fluoro-4-phenylspiro[2H-1-benzopyran-2,4*-piperidine] hydrochloride.
When the required starting 2'"hydroxyacetophenone was not commercially available it could be prepared as described below: Step A: (2'fluoroDhenvl) acetate
Acetic anhydride (81 cm2, 856 mmol) was added dropwise to a stirred mixture of 2-fluorophenol (60.0 g. 535 mmol) and aqueous sodium hydroxide (4 N, 214 cm2 856 mmol) at 0 °C. After the reaction had been stirred for 30 min the aqueous layer was separated from the organic portion and washed with dichloromethane (150 cm2). The combined organic extracts were washed with aqueous sodium hydroxide solution (4 N, 150 cm2) and then brine (100 cm2). The organic phase was dried (Na2S04) and the solvent was evaporated in vacuo to afford the title compound (84.9g, >100%). Step B: 2-hvdroxv-3'-fluoro acetoohenone
Finely powdered aluminium trichloride (32.0 g, 239 mmol) was added to (2-fluorophenyl) acetate (23.0 g. 149 mmol) and the mixture was heated to 180 °C for 1 h. Upon cooling to room temperature, the reaction mixture was carefully poured onto ice/water and the product was extracted into dichloromethane (150_cm2). The organic layer was separated, washed with brine (150 cm2), dried (Na2SO4 and the solvent was removed in vacuo. The crude reaction mixture was purified by column chromatography (silca gel, dichloromethane-methyi alcohol 99:1) to afford the title compound (3.1 g. 14 %).
From this point on the acetophenone was converted through to the final compound according to the procedures described in Example 1: m. p. 180-182 'C; positive ion ESI (M+H)+ 354.0.

Also prepared according to this route was:
Example 71: 1 -carboxymethyl-7-chloro-6-fluorD-4-phenylspiro[2H-1-ben2opyran-
2,4'-piperidine] hydrochloride; m. p. 275-293 °C; positive ion ESI (M+H)* 387,7.
Example 72: 1 -carboxymethyi-5-fluoro-4-phenylspiro[2H-1-benzopyran-2,4'-
piperidine] hydrochloride.
The required starting 2'-hydroxyacetophenone was not commercially available and
therefore had to be prepared as described below:
Step A: 2'-f!uoro-6'-methoxvacBtoDhenone
A mixture of 2-fluoro-6-methoxybenzonitrile (15.94 g, 105.5 mmoi) and a solution of methyl magnesium iodide in diethyl ether (3 M, 46.0 cm2, 137 mmol) was heated to 100 °C for 18 h. Upon cooling to room temperature, aqueous hydrochloric acid (3 M, 94 cm2) was added and the mixture was heated to reflux to for 4 h. When the reaction had cooled to room temperature the organic layer was separated and the aqueous phase was extracted with ethyl acetate (100 cm2). The combined organic extracts were washed with brine (100 cm2) before being dried (NajSO^), The solvent was removed in vacuo to afford the title compound as an oil (117.7 g, 100%). Step B: 2'-ffuorO'6'hvdoxvacetoDhenone
A solution of boron tribromide in dichloromethane (69.0 cm2. 69.6 mmo!) was added dropwise over a period of 25 min to a solution of 2'"fluoro-6'-methoxyaceto-phenone (17,72 g, 105.5 mmol) in dichlonDmethane (150 cm2) at - 78 'C. After allowing the reaction to warm to 0 ""C it was quenched with water (100 cm2) and the product was extracted into dichloromethane (100 cm2). The organic solution was washed with water (100 cm2), brine (150 cm2) and then dried (Na2S04). Evaporation of the solvent in vacuo afforded the crude product which was taken forward without purification.
From this point on the acetophenone was converted through to Wie final compound according to the procedures described in Example 1: m. p. 252-254 °C; posftrve ion ESI (M+H)+ 354.2.
Example 73: 1 '-carboxymethyl-4-[4-(2-ethoxymorpholino)pheny!3spiro[2i-/-1 -benzopyran-2,4'-piperidine] hydrochloride. Prepared according to the mettxxis

described in Example 42 by alkylating the appropriate phenol with 4-(2-chioro-
ethyl)morpholine hydrochloride; positive ion ESI (M+2H)* 465.2.
Example 74: 1 '-cartDOxymethyl-6-hydroxy-4-phenylspiro[2H-1 -benzopyran-2,4'-
piperidine] hydrochloride. Prepared according to the methods described in
Examples 1 and 42; positive ion ESI (M+H)* 352,2.
Example 75: 1 '-cart30xymethyl-7-methylthio-4-phenylspiro[2H-1 -benzopyran-2,4'-
piperidine] hydrochloride.
Step A: 7'fluorO'N-methvlsDiro[2H'1'benzopvran'2A'-DiDeridineh4{3H)-one
fK stin-ed solution of 4'-fluoro-2'-hydroxyacetophenone (15.97 g), 1-methyl-4-piperidone (12.74 cm2) and pyn-olidine (4.325 cm2) in methyl alcohol (250 cm2) was heated to reflux under nitrogen. After 0.5 h. further pyrrolidine (4.33 cm2) was added and, after another 0.5 h, the solution was allowed to cool. The reaction mixture was then evaporated under reduced pressure to give an oil, which was dissolved in dichloromethane (400 cm2). This solution was washed with water (3 x 400 cm2), dried (Na2SO4) and evaporated to give an oil (25.7 g). Flash chromatography on silica (eluting with dichloromethane-methyl aicohol-33% aqueous ammonia = 380:20:1) gave the purified product as an oil (14.41 g). Step B: 7'methvlthio-N-methvlso}mf2H'1-benzopvmn-2A'-oioendinel-4f3H}n
To a stirred solution of 7-fluoro-/V"methylspiro[2H-1-benzopyran-2,4'-piperidine]-4(3/-/)-one (4.54 g) in dimethylformamide (20 cm2) under nitrogen was added sodium thiomethoxide (1.40 g). The mixture was stirred at room temperature for 1.25 h, at 60 °C for 4.5 h and then was allowed to cool and to stand ovemight at room temperature. It was stirred and heated at 130 °C for 2.5 h then was allowed to cool and to stand ovemight at room temperature before being poured into stirred water (140 cm2). The solid product was filtered off, washed with water and dissolved in dichloromethane. The solution was dried (Na2S04) and evaporated to give the product as a gum (4.44 g).
From this point on the 7-methylthio-/V-metiiylspiro[2H-1-benzopyran-2.4'-piperid!ne]-4(3H)-one was converted through to the final compound according to the procedure described in Example 1 with the follov^ng excefrtion: in the work-up of the demethylation step the required secondary amine vras converted unexpectedly into a less polar compound which was treated with aqueous potassium hydroxide (10 A/)

in methyl alcohol at reflux to regenerate the required annine; (M+H)" = 382.0,
Example 76: 1 -carbDxymethyI-4-(4-trifluorometho>cyphenyl)spiro[2H-1 -benzopyran-2,4-piperidine] hydrochloride.
Step A: Trifluromethanesulfonic acid-4-f1 'Dhenvlmethvl-SDiro(2H-1-benzoDvran' ZA'-oiperidme)! ester.
To a cooled stinted solution (-78 °C) of the A/-benzylspiro[2H-1-benzopyran-2,4'-piperidine}-4(3H)-one (1.54 g, 5 mmol; prepared as in Example 1) in dry tetrahydrofuran (40 cm2) was added lithium hexamethyidisilazide (1 M solution in hexane, 7.5 cm2, 7.5 mmol) dropwise over a period of ca. 5 min. After stirring at that temperature for 1 h the N-phenyltrifluoromethane sulfonamide (2.68 g, 7.5 mmol) was added in one portion and the resulting reaction mixture was left to stir and warm up slowly overnight. The reaction was quenched with water (10 cm2) and extracted into ethyl acetate (2 x 50 cm2). The organic portion was washed with saturated aqueous ammonium chloride (50 cm2), saturated aqueous sodium chloride (50 cm2) and water (50 cm2) before being dried (Na2S0) and concentrated. The product was purified by column chromatography on silica (3:1 heptane-ethyl acetate) to afford the desired material (1.75 g, 80 %) which was either used immediately or stored under an inert atmosphere at - 20 "^C.
Step B: N'benzvl-4'(44nfluoromethoxvphenvl)sDiro[2H' 1 -benzoDvran-2,4 -DiperidineMOhDone
A mixture of {N-benzylspiro[2A7-1-benzopyran-2.4'-piperidine]}-4-(phenyl-4-trifluoromethylsulfonate) (1.69g. 3,86 mmol), 4-trifluoromethoxybenzene boronic acid (1.25 equiv.), dimethoxyethane (40 cm2). lithium chloride (2.5 equiv.), tetrakis(triphenylphosphine)palladium (0) (2.5 mol%) and aqueous 2 N sodium carbonate solution (2 equiv.) was heated to reflux for 12 h. Upon cooling, the mixture was treated with water (75 cm2) and ethyl acetate (75 cm2). After shaking the organic layer was separated and washed with water (2 x 100 cm2). dried (NajSO^) and tiie solvent was removed to yield the desired product (96 %) which was used in the next step without further purification.
From this point on the N-benzyl-4-{4-trifluoroniethoxyphenyi^piropH-1-Denzopyran-2,4-piperid!ne}4-(3H>one was converted through to the fmal conpound

according to the procedure described in Example 1; m.p. 233-237 °C; (M+Hf = 420.2.
Example 77: 1 'Kiarboxymethyl-4-(4-methylthbphenyl)spiro[2H-1-benzopyran-2,4'-
piperidinej hydrochloride. Prepared according to the methods described in
Examples and 76; positive ion ESI (M+H)" 352.2.
Example 78: 1 '"Carboxymethyl-4-[4-(A/-methyl-A/-methylsulfonamido)phenyl]-
spiro[2H-1 -benzopyran-2,4'-piperidine] hydrochloride.
Step A: ethyl 4-f4'hvdmxvphenvl}spiror2H-1-benzoDvran-2A-DiDeridinel'V-acetate
To a mixture of .l-Carboxymethyl-4-(4"hydroxyphenyl)spiro[2H"1-benzopyran-2,4'-piperidine]-V-acetate (432 mg, 1 mmoi., prepared according to Example 42), sodium hydrogen carbonate (176 mg, 2.1 mmol) in dry N,N-dimethylformamide (25 cm2) was added ethyl iodide (0.088 cm2 1.1 mmol) and the mixture was heated to 80 °C for 2 h. Upon cooling, it was diluted with ethyl acetate (100 cm2) and washed with water (5 x 100 cm2). The organic solution was then dried over sodium sulfate before the solvent was removed in vacuo. The crude material was then passed through a short pad of silica first with dichloromethane (which was discarded) and then with ethyl acetate. The solvent was removed to afford the desired product (194 mg, 51 %).
Step B: Trifluoromethanesulfonic acid-{1'-carboxvmethvl-4'Phenvlspirof2H-1' benzopyran-ZA'-pioeridinel ethyl ester}
To a cooled (-20 °C) stirred suspension of ethyl 4-(4-hydroxypheny!)spiro[2H-1-ben2opyran-2,4'-piperidine]-1'-acetate (158 mg, 4.16 x 10-4 mol) in anhydrous dichloromethane (10 cm2) under an inert atmosphere was added triethylamine (0.065 cm2, 4.6 x 10^ mol). After 10 min a solution of trifluoromethanesulfonic anhydride (0.077 cm2 4.6 x 10"^ mol) in dichloromethane (7.7 cm2) was added dropwise over a period of ca. 5 min. During the next ca. 20 min the solid material disappeared. However, analysis by thin layer chromatography revealed that the reaction was incomplete so a further portion of the trifluoromethanesutfonic anhydride was added (0.25 equiv.). After a further ca. 20 min, the reaction mixture was diluted with ethyl acetate (50 cm2) and then washed with water (3 x 60 cm2) before being dried (Na2S04) and the solvent removed in vacuo. The crude product

was puinted vy column cnromatography on silica {3:1 dichloromethane-ethyl
acetate) to afford the desired material (154 mg, 75 %).
Step C: 4~f4'(diphenvl!mino)Dhenvnspirof2H-1enzoovran'2A'-Diperidm
acid ethvl esten
The title compound was prepared by a modification of the procedure of Buchwald et a/.. Tetrahedron Letters, 1997, 38, 6367.
To a solution of trifiuoromethanesulfonic acid-{1'-carboxymethyl-4-phenylspiro[2H-1-benzopyran"2,4'-piperidine] ethyl ester} (421 mg, 8.43 x 10-4 mo!) in dry tetrahydrofuran (25 cm2). being stirred at room temperature under an atmosphere of dry nitrogen, was added benzophenone imine (1.2 equiv., 0.283 cm2). This was followed by the addition of palladium acetate (1.25 mol%), (RH+)-2,2-bis(diphenylphosphino)-1,V-binaphthyl (3.75 mol%) and cesium carbonate (1.40 equiv., 385 mg). The mixture was heated to reflux for 24 h before being allowed to cool to room temperature. It was then diluted with (non-dry) diethyl ether (250 cm2), filtered through a pad of filter aid and then the volatiles were removed in vacuo. The residue was purified by column chromatography on silica (1:1 heptane-ethyl acetate) to afford the desired material (547 mg; contaminated with benzophenone imine). Step P: ethvl 4'(4-aminoohenvl)sDirof2H'1'benzopvran-Z4'-pipendinel-1'-acetate
The title compound was prepared according to the procedure of Buchwald et 3/., Tetrahedron Letters, 1997, 38, 6367.
To a stirred solution of ethyl 4-(4-benzophenoneiminophenyl)spiro[2H-1 -penzopyran-2,4'-piperidine]-1'-acetate (542 mg, 1 mmol) in methyl alcohol (25 cm2) was added sodium acetate (198 mg. 2.4 mmol) followed by hydroxylamine lydrochloride (125 mg, 1.8 equiv.) and the reaction was allowed to stir at room emperature for 30 min. The methyl alcohol was removed in vacuo before the asidue was partitioned between dichloromethane (25 cm2) and aqueous sodium ydroxide solution (0.1 M, 25 cm2). The organic layer was isolated and the volatiles were removed in vacuo before the product was purified by column chromatography silica, ethyl acetate) (220 mg. 69 % from trillate).

step E: ethvl 4-(methvl 4-Dhenvlsulfonamide)spiror2H'1'benzoDvran-2,4'-p'loeridlne h 1 '-acetate
The title compound was prepared according to the procedure of R. J. Sundberg et a/., Journal of Organic chemistry, 1984, 49, 249.
A flask containing a mixture of ethyl 4-(4-aminophenyI)spiro[2H-1"benzo-pyran-2,4'-piperidine]-1'-acetate (214 mg. 0.566 mmol), pyridine (3 equiv., 0.137 cm2) and anhydrous dichioromethane (10 cm2) was allowed to stir in an ice/methyl alcohol bath. After 10 min at this temperature a solution of methanesulfonyl chloride (1.5 equiv., 0.066 cm2) in dry dichioromethane (0.66 cm2) was added dropwise over a period of ca. 5 min. After stirring for 2 h, the reaction mixture was poured onto a saturated aqueous solution of potassium hydrogen carbonate (10 cm2). The organic layer was washed with water (3 x 50 cm2) and the solvent removed in vacuo. Toluene (30 cm2) was added and then removed in vacuo (this was repeated until the smell of pyridine ceased) and then methyl alcohol was added (30 cm2) and removed. The remaining material was homogeneous (234 mg, 91 %). Step F: ethvl 4-(nietfivl 4-Dlienvl-N-methvlsulfonamide)sDirof2H'1'benzoDvran-2,4' pipendinel-1 '-acetate
To a solution of ethyl 4-(methyl 4-phenylsutfonamide)spiro[2H-1-benzopyran-2,4*-piperidine]-1'-acetate (108 mg, 0.236 mmol) in methyl alcohol (10 cm2) was added a solution of trimethylsilyl diazomethane (2 M in hexanes, 5 cm2) in the absence of stirring. Immediately upon the addition evolution of nitrogen was observed. After standing for 1 h at room temperature the volatiles were removed in vacuo before the residue was purified by column chromatography (silica, ethyl acetate) to afford the homogeneous product (74 mg, 67 %). 1 '-carboxvmethvl 4-(N-methvl 4-phenvl-N-methvlsulfonamide)soirof2H'1-benzoDvran'2A'-piperidinel hydrochloride
From this point on the synthesis proceeded according to the method described in Example 1; positive ion ESI (M+H) = 443.2.
Example 80: 1 '-carboxymethyl-4-(4-amino-3,5-difluorophenyl)spiro[2H-1-benzopyran-2,4'-piperidine] dihydrochloride.
(4-Bromo-2,5-difluorophenyl)-2,5-dimethylpyrrole was prepared according to the procedure of Bruekelmann et a/., J. Chem, Soc, Peridn Trans. 1, 1984, 2801.



Exampte 83
Method for determination of qivcine uptake in CHO cells heterotooouslv expressing the human G1vT-1b transporter.
A: Cloning: cDNA was generated by PCR according to the method described by Kim, K.-M. et al. Mol. Phanmacol. 1994, 45, 608-617. Sequence was verified by dideoxy sequencing using the ALF DNA sequencer™ (Pharmacia) and cloned into the expression construct pcDNA3 (Invitrogen).
B: Transfection: Transfection of hGlyT-1b into CHO ceils was performed using a standard calcium phosphate technique as described by Sambrook, J. et a/. (1989) in Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
Ql Selection: Stably transfected cells were selected for 1 week in growth medium containing Img.cm'^ Geneticin. Individual clones were picked for further analysis and positives passaged routinely as described below.
D: Culture conditions: Cells stably expressing the hGlyT-1b gene were cultured at 37 °C in a 5 % CO2 atmosphere in DMEM - NUT.MIX. F12 with GIutamax-1 (Gibco) containing Geneticin (O.Smg.cm3, Gibco) and supplemented with 10 % Fetalcione II (Hyclone). Maintenance culture was carried out in standard 80cm2 ventilated flasks (2 X 10-6 m filter, Nunc) and cells were subcultured by trypsinisation (Sigma) when confluent
E: Assay Procedure; Cells for uptake studies were plated in 96 well plates (17,000 cells per well) in the absence of Geneticin and culturKi for 48 h before use. To measure glycine transport, cells were washed twice with Hanks* balanced saJt solution (HBSS) pre-warmed to 37 °C and excess flukl removed before addition of test compounds dissolved in 0.200 cm2 HBSS. Plates were incutiated at 37 K2 for 5 minutes before addition of [3H]glycine (0.050 cm2 150 x 10-6 M, 248 Bq.nmor\ NEN)

and incubation continued for a further 10 minutes. Uptake was terminated by washing cells with ice-cold HBSS before removal of excess fluid and addition of 0.200 cm2 scintillation cocktail to each well. Plates were sealed with adhesive film. shaken to ensure samples were homogenous before scintillation counting in a plate counter.
R Data Analysis: Data were analysed using standard curve fitting procedures to produce a plC50 value for active compounds (where pIC50 is the negative logarithm of the concentration of test compound causing 50 % inhibition of uptake).
& Results: The compounds of the invention selectively Inhibit the glycine transport by the human GlyT-1b transporter as compared to the human GlyT-2 transporter (the molecular cloning and functional expression of the human GlyT-2 transporter is described by Morrow, J.A. et al, FEBS letters 1998. 439. 334-340. The plC50 values for a number of compounds of the invention are given in Table L





R2, R3 and R4 are independently hydrogen or (C1-4)alkyl;
R5 is (C1-4)alkyl (optionally substituted with one or more halogens) or (C5-12) aryl
(optionally substituted with (C1-4)alky!); or a pharmaceutically acceptable sait
thereof.
2. The spiro[2H-1-benzopyran-2,4'-piperidine, dervative according to the general formula 1 of claim 1 wherein the dotted line represents a bond.

3. The spiro[2H-l-benzopyran-2,4'-piperidine] derivative of claim 2, wherein R1
and R2 are hydrogen.
4. The spiro[2H-l-benzopyran-2,4'-piperidine] derivative of claim 3, wherein Y
represents a para-substituent selected from chloro, bromo, (C1_4)alkyloxy, (C1-4)
alkenyloxy, (C1-4)alkynyloxy and NR3R4, and 1 or 2 meta-substituents selected among
the halogens.
5. The spiro[2H-l-benzopyran-2,4'-piperidine] derivative of claim 4, wherein the
meta-substituents are fluoro.
6. The spiro[2H-l-benzopyran-2,4'-piperidine] derivative of claim 5, wherein X
is hydrogen.
7. The spiro[2H-l-benzopyran-2,4'-piperidine] derivative of any one of claims 1-
6 for use in therapy.
8. A pharmaceutical composition comprising a spiro[2H-l-benzopyran-2,4'-
piperidine] derivative having general formula I, of a pharmaceutically acceptable sah
thereof, in admixture with pharmaceutically acceptable auxiliaries.
9. A spiro[2H-l-benzopyran-2,4'-piperidine] derivative substantially as herein
described and exemplified.


Documents:

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in-pct-2002-714-che-correspondence po.pdf

in-pct-2002-714-che-description complete duplicate.pdf

in-pct-2002-714-che-description complete original.pdf

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in-pct-2002-714-che-form 26.pdf

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Patent Number 209183
Indian Patent Application Number IN/PCT/2002/714/CHE
PG Journal Number 38/2007
Publication Date 21-Sep-2007
Grant Date 22-Aug-2007
Date of Filing 15-May-2002
Name of Patentee N.V. ORGANON
Applicant Address KLOOSTERSTRAAT 6, NL-5349 AB OSS,
Inventors:
# Inventor's Name Inventor's Address
1 GIBSON Samuel George 19 Ross Crescent Motherwell Lanarkshire ML1 3AU
2 MILLER David John 6 Castelhill Cresent Chaplehall North Lanarkshire ML6 8LG
PCT International Classification Number C07D 491/107
PCT International Application Number PCT/EP2000/011351
PCT International Filing date 2000-11-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 99309137.0 1999-11-17 EUROPEAN UNION