AU675332B2 - 4-(4-fluorophenylmethyl)-piperidines having sigma and D2-receptor affinity - Google Patents

Description

WO 94/26712 PCT/EP94/01594 4-(4-FLUOROPHENYLMETHYL)-PIPERIDINES HAVING SIGMA AND D2-RECEPTOR AFFINITY The present invention relates to new 1,4-disubstituted piperidine derivatives having the general formula F S0

R

(I)

wherein X is hydroxymethylene or methoxymethylene, Y is a 3membered methylene sequence and R is a p-fluorophenyl group, as well as their pharmaceutically acceptable addition salts.

The compounds of the present invention are obtained according to Scheme I. In effect, the alkylation of 4- (p-fluorobenzoyl) piperidine with the halogen derivative Cl-Y-O-R, wherein Y and R are as previously defined, in the presence of an alkali and a non polar solvent, leads to 4-(p-fluorobenzoyl)-1-(3-pfluorophenoxy)propylpiperidine Subsequent reduction of this intermediate with sodium borohydride yields the final compound of formula X: CHOH, Y: (CH 2 3 R: p-F-C 6

H

4 In contrast, the compound of formula X: CH(OCH,), Y: (CH 2 R: p-F-C 6

H

4 requires first the protection of 4-(p-fluorobenzoyl)piperidine. For this purpose, this compound is conveniently reacted with di-tert-butyl dicarbonate in an organic basic medium. N-tert-butoxycarbonyl derivative (III) c WO 94/26712 WO 9/26 12PCTr/EP94/O 1594 0 CI-Y-0-R K 2 00 3 KI CH 3

-CN

F NH It-Bu-O-CO-O-CO-O-t-Bu/Et 3

N

t-8u (111)

NI

INoBH 4 EtOH x(n N. 0R X: CHOH, Y: (CH 2 3 R: p-F-C 6

H

4 FHF (IV) t-Bu MV JHCI DO0H 0-CH 3 F NH

ICI-Y-O-R

K 2 00 3 K! CH 3

CN

'N.

N' 0" X: CH(OCH 3 Y: (CH 2 3 R: p-F-C 6

H

4 Abbrevi ationc: t-Bu-0-CO-0-CO-0-i-Bu: Di-tert-butyl dicarbonate Et,N: Triathylamine EtOH: Ethanol THF: Tatrahydrofuran WO 94/26712 PCT/EIP94/O1594 3 is then formed, which enables to be handled safe from dialkylation in subsequent synthesis steps. The reduction of N-tert-butoxycarbonyl derivative with sodium borohydride in ethanol provides the corresponding secondary alcohol (IV).

Its methylation with iodomethane in the presence of a strong base in an ether-like solvent leads to the methoxy-derivative The strong base and the choice ether-like solvent are sodium hydride and tetrahydrofuran respectively. The following step is the unprotected reaction of in acid medium. This reaction occurs conveniently by dissolving hydrogen chloride in a mixture of water and ethanol. The piperidinyl-derivative (VI) is then susceptible co be alkylated under analogous conditions to those employed for the obtention of Thus, the final compound of the formula X: CH(OH 3 Y: (CH 2 3 R: p-F-C 6

H

4 is obtained.

US Patent No. 4588728 describes the treatment of psychosis with cis-9-[3-(3,5-dimethyl-piperazinyl)propyl]carbazole.

US

Patent No. 4709094 describes the preparation of 1,3disubstituted guanidines as well as their utility in the diagnosis and treatment of hallucinations associated with psychotic disorders c.d chronic mental depression. US Patent No. 4929734 describes the preparation of N-substituted 1- (l,2,3,6-tetrahydro-3-piridinyl)oximes and N-substituted 1- (1,2,3,6-tetrahydro-4-piridinyl)oximes and their use in treating depression, psychosis and/or inflammatory diseases.

US Patent No. 5061728 describes the use of 4-phenyl-l,2,3,4tetrahydro-1-naphthalenamine derivatives in treating WO 94/26712 PCTIEP94/01594 4 psychosis and inflammation and their use as immunosupressants. US Patent No. 5086054 describes the preparation of arylcycloalkylpolyalkyl-amines and their use as antipsychotic, anti-ischemic, anti-apoplectic, antidementia agents and anticonvulsants. US Patent No. 5162341 describes the use of various compounds for combating amphetamine and analogous drug abuse. US Patent No. 5175174 describes the preparation of N-phenyl-piperidyl-4-amine derivatives and their use as Class III antiarryhthmic agents, potassium channel blockers, antipsychotics, anticonvulsants and neuroprotectors. US Patent No. 5158947 describes the preparation of N-piperidyl-alkyl-benzazepine derivatives and their utility for the treatment of psychoneurosis. US Patent No. 5116995 describes the preparation of 4-(aminoalkyl)carbazole and their use as antipsychotics. US Patent No.

5149817 describes the preparation of 4-phenyl- and 4-thienyltetrahydropyridine and their use for treating depression, mania, schizophrenia and cerebral ischemia. US Patent No.

5109002 discloses l-cyclo-alkyl-piperidine derivatives and their use as antipsychotics and for treating dyskinesia.

The compounds disclosed :n all these patents share their affinity as ligands for sigma receptors of Nervous System. To this regard, literature reviews by B.L. Largent et al ("Eur. J. Pharmacol.", 155, 345-7, 1988), S.I. Deutsch et al ("Clinical Neuropharmacology", 11(2), 105-119, 1988) and T.P. Su ("Eur. J. Biochem.", 200, 633-642, 1991) are illustrative of the biochemical, pharmacological and clinical WO 94/26712 PC'T/EP9)4/01594 aspects of sigma-receptor ligands.

Applicants have found out that although the compounds of the present invention are chemically very different from those of the above prior art patents, they show a high affinity as ligands for sigma receptors. Due to such an activity, they are potentially useful in the treatment of some sigma receptor-related mental disorders, mainly psychosis and schizophrenia.

Moreover, and from a chemical viewpoint, the closest compound to the compounds of this invention is 4-(p-fluorobenzoyl)-1- (3-p-fluorophenoxy)propylpiperidine which is described in US Patent No. 3576810 (1971). In accordance with this patent, the compounds generically disclosed therein are claimed to be useful as tranquilizers, and as such, they show antianxiety activity. Obviously, no indication of a possible effect on sigma-receptors is given in this patent, insomuch as this term was introduced later on. However, applicants have found out that 4-(p-fluorobenzoyl)-l-(3-p-fluorophenoxy)propylpiperidine (II) is effectively bound to sigmareceptors, but also bound to D 2 receptors to a great extent.

In contrast, the compounds of the present invention show as a major advantage over the compound of the formula (II) their high selectivity on sigma receptors versus D 2 receptors, which results in a lesser possibility of developing extrapyramidal effects on account of the interaction with D, receptors (Table Furthermore, the lower incidence of WO 94/26712 PCT/EP94/01594 6 side-effects in the compounds of this invention with regard to the compound of the formula (II) has been made evident by means of the stereotypy inhibition test (Table 2) and Irwin test (Table 3).

Specific binding to a and D, receptors has been tested as follows: a receptors: A 2-nM solution of radioactive 3-PPP 3 H]3-[3-hydroxyphenyl]-N- (1-propyl) -piperidine), which acts as a specific ligand, was incubated with the membrane corresponding to 40 mg of guinea-pig total brain for 90 min at 25°C buffered at pH 8.5 with Tris.HCl. Thus, total binding of ligand to membranes was attained. Non-specific binding was then determined by adding a micromolar concentration of unlabelled 3-PPP. IC, 0 values (inhibitory concentration were calculated from the inhibition rate of the specific binding obtained by adding eleven different concentrations of the compounds to be tested. After the incubation was completed, the samples were filtered through a glass fiber filter and then washed three times with Tris.HCl buffer. The amount of receptor-bound radioactivity was retained on the membrane and determined by liquid scintillation counting.

D2 receptors: A 2-nM solution of radioactive spiperone 3 H]spiperone), which acts as a specific ligand, was incubated with the membrane corresponding to 20 mg of rat striatum for 20 min at 35°C buffered at pH 7.4 with Tris.HCl.

WO 94/26712 PCT/EP94/01594 7 The non-specific binding was then determined by addition of a micromolar concentration of unlabelled spiperone. (inhibitory concentration 50%) was calculated from the inhibition rate of the specific binding obtained by addition of eleven different concentrations of the compounds to be tested. After the incubation was completed, the sample was filtered through a glass fiber filter and then washed three times with Tris.HCl buffer. The amount of receptor-bound radioactivity was retained on the membrane and determined by liquid scintillation counting.

Stereotvpy inhibition test: Male Sprague-Dawley rats, weighing 200-300 g were used. The animals were weighed and then placed in individual transparent boxes. At time 0 the compounds to be tested were administered intraperitoneally.

0.25% agar was used as vehicle. After 30 min, apomorphine was injected subcutaneously at a dose of 1.5 mg/kg in a concentration of 0.6 mg/ml. At 40, 50, 60, 90 and 120 min, stereotypy was scored from to according to the following criteria: absence of stereotypy or any abnormal movement; presence of slight stereotyped movements of the head and intermittent sniffing; intense movements of the head, mild licking interspersed with sniffing; and intense licking and/or gnawing. Results are expressed as ED 50 in mg/kg for a better quantification.

Irwin test: It consists in a package of tests intended to find out the properties of a compound as well as the WO 94/26712 PCTIEP94/01594 8 magnitude of such properties which are completely unknown.

Assessment begins with general observations until reaching gradually more detailed observations. Changes are arbitrarily scored from the observations of control animals.

On the basis of animals' behaviour, the following parameters were assessed: a) General examination: sex, weight, age, b) Behavioural examination: alertness, locomotor activity, mood.

c) Neurological examination: central nervous system excitation, autonomic nervous system study, body carriage, motor incoordination, muscular tone, reflexes and general signs.

The results have been expressed as the first dose causing behavioural and neurological undesirable effects. Under the experimental conditions described, IC 50 values on a and D, receptors expressed in nanomolar concentrations (nM) are shown in Table 1. This table also contains the D 2 /a ratio of selectivity and the D,/a ratio of relative selectivity to compound (II) (Compound II, Example 6, D 2 /a Preferred compounds are those whose D 2 /a ratio of selectivity is higher. Compound Ex. 6, is less selective.

WO 94/26712 PCT/EP94/01594 9 Table 1 Compound IC 50 (nM) Selectivity Relative selectivity 2 D D 2 /a D 2 II, Ex. 6 60.9 155 2.5 1 Ex. 5 75.2 631 8.4 3.4 Ex. 7 9.44 1430 151.5 60.6 In Table 2, the results on stereotypy, expressed as ED 50 (mg/Kg), show that the ED 5 of the compounds of the present application was higher than that for reference compound (II).

This indicates that the compounds of the invention are less potent as inductors of undesirable abnormal movements attributed to D 2 receptors. This finding is, in addition, consistent with the biochemical results shown in Table 1.

Moreover, the results of Irwin test (Table 3) show that no undesirable effects were observed for the compounds of the invention until doses were several times higher than those for reference compound Furthermore, among the side effects of the compounds of the invention, unlike reference compound neither decreased muscular tone nor catalepsy were found.

WO 94/26712 PCT/EP94/01594 Table 2 Compound EDs 5 (mg/Kg) II, Ex. 6 Ex. 5 Ex. 7 Tabla 3 Compound First dose (mg/kg) Side effects II, Ex. 6 Ex. 5 10 100 40 Inhibition of motor activity, motor incoordina ion, hypothermia, decreased muscular tone and catalepsy Inhibition of motor activity, motor incoordination and hypothermia Inhibition of motor activity, motor incoordination and hypothermia Ex. 7 WO 94/26712 1 1/!",194/01$901 11 The experimental results obtained suggest that the compounds of the invention can be useful in the treatment of sigma receptor-related nervous system diseases, and especially in anoxia, anxiety, convulsions, dyskinesia, drug addiction, schizophrenia, hypoxia, cerebral ischemia, mania, psychosis and stress. The compounds can be administered in combination with suitable vehicles via the oral, rectal or parenteral routes. These compounds are administered in doses ranging from 0.5 up to 100 mg per day, more preferably from 1 up to 30 mg per day.

EXAMPLE 1: 1-(tert-butoxycarbonyl)-4-(p-fluorobenzoyl) piperidine A mixture of 4-(p-fluorobenzoyl)piperidine (10 g, 48 mmole), di-tert-butyl dicarbonate (10.5 g, 48 mmole) and triethylamine (10 mL) in 50 mL of tetrahydrofuran was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue was dissolved in benzene. The solution thus obtained was poured into water and ice, acidified with hydrochloric acid, stirred for 10 min and decanted. The benzene extract was washed with two further portions of water, dried over anhydrous sodium sulfate and evaporated in vacuo. There were obtained 12 g (83 of 1-(tert-butoxycarbonyl)-4-(p-fluorobenzoyl)piperidine in the form of a colourless oil that solidifies slowly. NMR (CDC1 3 1.47 (s, 9 1.6-1.8 2 1.8-1.9 2 Hi; 2.9 (ta, 2 3.4 (t t, 1 4.2 (da, 2 7.15 2 7.98 (d d, 2 H).

WO 94/26712 PCTI/EP94/01594 12 EXAMPLE 2: 1-(tert-butoxycarbonyl)-4-(1-(p-fluorophenyl)-1hydroxymethyl) piperidine To a solution of 1-(tert-butoxycarbonyl)-4-(pfluorobenzoyl)piperidine (10 g, 33 mmole) in ethanol (100 mL), 2 g of sodium borohydride were added. After stirring for 2 h at room temperature, the solution was evaporated in vacuo, the residue was dissolved in benzene, poured into water and ice, and then added hydrocnloric acid to provide pH 5-6. The organic extract was dried over anhydrous sodium sulfate and evaporated to give 5.9 g (59 of 1-(tertbutoxycarbonyl) -4-(1-(p-fluorophenyl)-1-hydroxymethyl) piperidine. NMR (CDC13): 1.0-1.2 1 1.2-1.3 2 H); 1.43 9 1.6-1.8 1 1.9-2.0 (da, 1 2.5-2.7 2 4.0-4.2 2 4.36 1 7.02 2 H); 7.26 (d d, 2 H).

EXAMPLE 3: 1-(tert-butoxycarbonyl)-4-(1-(p-fluorophenyl)-1methoxymethyl)piperidine 0.8 g of sodium hydride (dispersion in 80% paraffin), previously washed with hexane, were suspended in 25 mL of anhydrous tetrahydrofuran. To the suspension, a solution of 1- (tert-butoxycarbonyl)-4-(1-(p-fluorophenyl)hydroxymehyl)piperidine (5 g, 16 mmole) in 25 mL of tetrahydrofuran was added. The mixture was stirred for min at room temperature and then 2 mL of iodomethane were added. After further stirring for 16 h, the mixture was WO 94/26712 PCTIEl9)4/01594 13 evaporated in vacuo and the residue was dissolved in chloroform. The solution was poured into water and ic.e and neutralized by addition of hydrochloric acid. The chloroform extract was dried over anydrous sodium sulfate and evaporated to give 5 g of 1- (tert-butoxycarbonyl)-4- (p-fluorophenyl) 1-methoxymethyl)piperidine in the form of an oil which can be employed without further purification. NMR (CDC1 3 1.0-1.3 3 1.44 9 1.6-1.8 1 2.0 (da, 1 H) 2.5-2.7 2 3.16 3 4.78 1 4.0-4.2 (m, 2 7.03 2 7.20 (d d, 2 H).

EXAMPLE 4: (p-fluorophenyl) -l-methoxymethyl)piperidine To a solution of 1-(tert-butoxycarbonyl)-4-(1-(pfluorophenyl)-1-methoxymethyl)piperidine (5 g, 15 mmole) in mL of ethanol, 35 mL de HC1 4 M solution were added. After stirring for 1 h at room temperature, the mixture was concentrated in vacuo until removal of ethanol, and the resulting aqueous solution was washed with benzene and added to NaOH to provide pH 14. The aqueous solution was next extracted with chloroform three times, and the chloroform extracts were dried over sodium sulfate and evaporated to give 2.4 g (69 of 4-(1-(p-fluorophenyl)-1-methoxymethyl) piperidine in the form of an oil which solidifies slowly. Melting point: 73- 76°C. IR (KBr, 3270,1610,1510, 1230, 1090. NMR (CDCl 3 1.0-1.3 3 1.6-1.7 1 2.0 (da, 1 2.2 (sa, 1 2.4-2.6 2 3.0 (da, 1 3.12 (da, 1 3.16 3 3.78 1 7.02 2 7.20 (dd, 2 H).

WO 94/2671.2 PCT/EP94/01594 14 EXAMPLE 5: 4-(1-(p-fluorophenyl)-1-methoxy)methyl-1-( 3 -pfluorophenoxy)propylpiperidine hydrochloride To a solution of 4-(1-(p-fluorophenyl)-1-methoxymethyl) piperidine (2.2 g, 10 mmole) and 3-(p-fluorophenoxy)propyl chloride (1.9 g, 10 mmole) in 40 mL of acetonitrile, 1.5 g of anhydrous potassium carbonate and 0.2 g of potassium iodide were added. After heating under reflux overnight, the mixture was allowed to cool and evaporated to dryness. The residue was added to water and extracted with ethyl ether. The ethereal extracts were dried over sodium sulfate and evaporated. The oil thus obtained was dissolved in acetoneether and precipitated by addition of an ethereal solution of HC1 to give 2 g of 4-(1-(p-fluorophenyl)-1methoxy)methyl-1-(3-p-fluorophenoxy)propylpiperidine hydrochloride. Melting point: 109-111'C. Elemental analysis calculated for C 2

,HF

2

NO

2 .HC1: C, 64.15; H, 6.85; N, 3.40; Cl 8.61; Found: C, 64.10; H, 6.67; N, 3.56; Cl, 8.60.

IR (KBr, 3200-3700, 2300-2900, 1510, 1230. NMR (CDC13): 1.3 (da, 1H); 1.8 1H); 2.0 1 2.2 1 2.4- 2.8 6 3.1-3.2 (s m, 5 3.5 1 3.7 1 3.8 1 4.1 2 6.9-7,0 4 7.15 2 7.4 (dd, 2 H).

EXAMPLE 6: 4-(p-fluorobenzoyl)-1-(3-p-fluorophenoxy)propyl piperidine hydrochloride A mixture of 4- (p-fluorobenzoyl)piperidine hydrochloride WO 94/26712 PCT/EP94/01594 (8.8 g; 36 mmole), 3-(p-fluorophenoxy)propyl chloride (7 g, 36 mmole), anhydrous potassium carbonate (10 g, 71 mmole) and potassium iodide (0.5 g) in 75 mL of acetonitrile were heated under reflux for 16 h. The reaction mixture was allowed to cool, filtered and evaporated to dryness. To the residue thus obtained, 150 mL of water were added, and then extracted with 3 portions of 100 mL of ethyl ether. The ethereal extracts were evaporated to dryness, the product was redissolved in isopropanol (50 mL) y precipitated by addition of a solution of HC1 in isopropanol. The product was filtered and dried in vacuo to give 6 g of 4-(p-fluorobenzoyl)-1-(3-pfluorophenoxy)propylpiperidine hydrochloride. Melting point: 190-192°C. Elemental analysis calculated for C 21 H2F 2 NO,.HC1: C, 63.71; H, 6.11; N, 3.54; Cl, 8.96. Found: C, 63.72; H, 6.10; N, 3.62; Cl, 8.91. IR (KBr, 3300-3700, 2400-2800, 1690, 1600, 1510, 1230. NMR (ds-DMSO): 2.0 4 2.2 2 H); 3.15 2 3.20 2 3.6 (da, 2 3.75 1 H); 4.05 2 H);6.98 2 7.14 2 7.4 2 H); 8.15 (dd, 2 H).

EXAMPLE 7: 4-(1-(p-fluorophenyl)-l-hydroxy)methyl-l-(3-pfluorophenoxy)propylpiperidine To a solution of 4-(p-fluorobenzoil)-1-(3-pfluorophenoxy)propylpiperidine hydrochloride (10 g, 25 mmole) in ethanol (150 mL), 6 g of NaBH4 were added and then stirred at room temperature for 2 hours. The solvent was evaporated in vacuo, water was added and the product was extracted with WO 94/2671.2 WO 94/6712 C'I'/Etg94/01594 16 t 41 acetate. The extracts were dried over Na2SO4 and evaporated to give 7 g of 4-(1-(p-fluorophenyl)-1-hydroxy) methyl-i- (3-p-f luorophenoxy)propylpiperidine in the form of an oil which solidifies slowly. Elemental analysis calculated for C 21 H25F 2

NO

2 C, 69.79; H, 7.25; N, 3.88. Found: C, 69.57; H, 7.17; N, 4.04. IR (KBr, 3000-3200, 1510, 1220. RIM (CD3OD): 1.22 (mn, 2 1.4 (in, 1 1.6 (mn, 1 1.8-2.0 mn, 4 2. 5 (mn, 2 2. 9 (da, 1 H) 3. 02 (da, 1 H) 3. 94 2H); 4. 35 1 6. 8 1 (mn, 6 7.38 (dd, 2 H).

Claims (3)

17- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:- 1. A compound which is a 1,4-Disubstituted piperidine derivative of the general formula F X" N YO'R (I) wherein X is hydroxymethylene or methoxymethylene, Y is a 3-membered methylene sequence and R is a p-fluorophenyl group, and their pharmaceutically acceptable addition salts. 2. A compound according to claim 1, which is: 4-(1 -(p-fluorophenyl)-1 -methyoxy)methyl-1 -(3-p-fluorophenoxy)propylpiperidine. 3. A compound according to claim 1, which is 4-(1 -(p-fluorophenyl)- -hydroxy)methyl-1 -(3-p-fluorophenoxy)propylpiperidine. 4. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3, in combination with pharmaceutically acceptable carriers and/or adjuvants. 15 5. A method for treating sigma receptor-related nervous system diseases which comprises administering at least one compound according to any one of claims 1 to 3 or a composition according to claim 4 to a mammalian host in need of such treatment. 6. A process for preparing a compound according to any one of claims 1 to 3 which comprises alkylating a compound of the formula: with a halogen derivative of the formula Hal-Y-O-R wherein Y and R are as defined in claim 1 and Hal is halogen, to obtain a compound of formula (II): formula (II):

177.00 l)On/n/mt F N-Y-O-R (II) and reducing the carbonyl group in the compound of formula (II) to obtain a compound of formula wherein X is hydroxymethylene. 7. A process according to claim 6, further comprising methylating the compound of formu with a suitable methylating agent to obtain a compound of formula wherein X is methoxymethylene, and/or converting the so-obtained compound of formula into a pharmaceutically acceptable addition salt. 8. A process for preparing a pharmaceutical composition according to claim 4 which comprises providing at least one compound according to any one of claims 1 to 3 in a form suitable for administration, in combination with pharmaceutically acceptable carriers and/or adjuvants. DATED this 21st day of November, 1996 o FERRER INERNACIONAL SA Attorney: IAN T. ERNST Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS e

17768-00 DOc/mtm INTEBRNA/ ONAL SEARCH RlE'ORT INI RNATI ONAL SEARCHI 1I(PORVT Intornational appllcaton No, PCT/EP 94/01594 A. CIASSIFICATION OF SU IBJUCr MA'TIItR IPC 5 C07D211/22 A61K31/445 According to Intemaional Patent la.nification (IPIC) or to both national classification and IPC H. lIEI)DS SIEARCIIHHD Minimum documentation searched (classfication system followed by classification symbols) IPC 5 C07D Documcntauon searched other than minimum documentaton to the extent that such documents arc included in the fields searched Electronic data base consulted during the intemauonal ,carch (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO 1IF IaEI.EVANT Category' Citation of document, with indication, where appropnate, of the relevant p issages Relevant to claim No. X EP,A,O 229 391 (EISAI) 22 July 1987 1-7 see claim 1 see example 14 see page see page 12, line 3 page 13, line 1 see page 15, line 1 page 17, line A FR,A,2 681 319 (SYNTHELABO) 19 March 1993 1-7 see the whole document P,A EP,A,0 572 952 (FERRER INT. SA) 8 December 1-7 1993 see the whole document Further documents are listed in the contnuaton of box C. l I'atent family members are listed in annex. Special categories of cited documents: T later document published after the international filing date or priority date and not in conflict with the application but A' document defining the general state of the art which is not ted to understand the principle or theory underlying the considered to he of partcular relevance invention "F earlier document but published on or after the international document of particular relevance; the claimed inventon filing date cannot he considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot he considered to involve an inventive step when the document referrng to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combinaton being obvious to a person skilled document published prior to the international filing date hut in the art. later than the pnonty date claimed document member of the same patent family Date of the actual completion of the intenational search Date of mailing of the international search report 22 September 1994 1, Name and mailing address of the ISA Authorized officer European Patent Office, 5818 Patentlaan 2 Nt. 2280 [IV Ripwilk Tel. 31.70) 340-2040, Tx. 31 651 epo nl, K issler, Vax: (4 31.70) 340.3016 Form PCTidSA/210 I(econd sheet) (July 1992) page 1 of 2 lNTrlMNATION Al. SIKARlClI IMPORT)~'l Interndtional a~pplicaltion No. PCT/EP 94/01594 (:.(Conunuabton) DOCUMEiNTS CONSIDIPRHI TO0 fll RUIXiVANT Category 'Citation of doctimcnt, with indication, where appropriate, or the relevant pamuagcS Relevant to claim No. A US,A,3 576 810 L. DUNCAN ET. AL.) 27 1-7 April 1971 cited in the application see claims 1,7 see example 8 tiorm PCTISNj21O (continuation or 'emdO il et (July 1992) page 2 of 2 International application No. PCT/EP 94/01594 INTERNATIONAL SEARCH REPORT Box I Observations where certain claims were found unsearchable (Continuation of item I or first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. O Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely. Although claim 4 is directed to a method of treatment of (diagnostic method practised on) the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. C Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, spectfically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. D As all required additional search fees were timely paid by the applicant, this international search report covers ll searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authorty did not invite payment of any additional fee. 3. O As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. D No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest SThe additional search fees were accompanied by the applicant's protest. O No protest accompanied the payment of additional search fees. Form PCT/ISAi210 (conunuation of first snecet (July 1992) INIMINATIONAI, SICARCII RECP()HI intornational application No. In,~ ,Iatiofl on p4LCL (lnily nictrr PCT/EP 94/01594 Patent document I Publication IPatent family Publication cited in search report d ate member(s) date EP-A-0229391 22-07-87 AU-A- 6690686 02-07-87 CA-A- 1279317 22-01-91 0E-A- 3686248 03-09-92 ES-T- 2044836 16-01-94 jP-A- 62234065 14-10-87 US-A- 4942169 17-07-90 US-A- 5039681 13-08-91 US-A- 5118684 02-06-92 US-A- 5306720 26-04-94 US-A- 4849431 18-07-89 FR-A-2681319 19-03-93 NONE EP-A-0572952 08-12-93 ES-A- 2043557 16-12-93 JP-A- 6172308 21-06-94 US-A-3576810 27-OA-71 AT-A- 291258 15-06-71 BE-A- 734755 01-12-69 CA-A- 991642 22-06-76 CH-A- 555335 31-10-74 CH-A- 555334 31-10-74 DE-A,B,C 1930818 08-01-70 FR-A- 2011339 27-02-70 GB-A- 1268909 29-03-72 NL-A- 6909384 23-12-69 SE-B- 377118 23-06-75 Form PCT!15&N210 (pattnt family annex) (July 1992)