ZA200602436B - Benzimidazolone and quinazolinone derivatives as agonists on human ORL1 receptors - Google Patents

Description

BENZIMIDAZOLONE AND QUINAZOLINONE DERIVATIVES AS AGONISTS ON

HUMAN ORL1 RECEPTORS

The present invention relates to a group of novel benzimidazolone and quinazolinone derivatives which are agonists on human ORL1 (nociceptin) receptors. The invention also relates to the preparation of these compounds, to pharmaceutical compositions containing a pharmacologically active amount of at least one of these imidazolone and quinazolinone derivatives as an active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of disorders in which ORL1 receptors are involved.

The invention relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. A beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention specific compounds disclosed herein are used for the manufacture of a medicament.

The ‘Opoid Receptor-Like 1’ (ORL1) receptor was identified from a human cDNA library. It was established that this ‘orphan receptor’ has a close homology with p-, x- and 8-opoid receptors (Mollereau et al, FEBS Lett., 341, 33-38, 1994; Bunzow et a.,

FEBS Lett, 347, 284-288, 1994). Despite its close sequential and structural resemblance with opioid receptors, classical opioid receptor ligands do not interact with ORL1 receptors. In 1995 a 17-amino acid neuropeptide was purified from brain extracts, and subsequently shown to be the natural ligand of the G protein-coupled

ORL1 receptor (Reinscheid et al, Science, 270, 792-794, 1995; Meunier et al.

Nature, 377, 532-535, 1995). This peptide was named orphanin FQ or nociceptin. It does not bind to the three traditional opioid receptors. These findings triggered substantial research info the functional role of, and novel ligands for, the ORL1 receptor.

That resulted in several hundreds of publications, including several reviews (see e.g.

Grond et al., Anaesthesist, 51, 896-1005, 2002), and dozens of patent applications, describing both peptide and non-peptide ligands. The described compounds strongly vary in potency for ORL1 receptors, and also in selectivity (ORL1 versus p-opiate receptors). As p-opiate receptors are widely distributed throughout the body, a lack of selectivity might lead to a range of undesired opiate-like side-effects such as sedation, respiratory depression, tolerance and dependence (Drug News Perspect., 14, 335, 2001). The in vivo pharmacodynamic and pharmacokinetic properties of the described compounds are likewise strongly variable.

A number of the ORL1 related patent applications concem benzimidazolone derivatives: e.g. WO 98/54168, WO 99/36421, WO 00/006545, WO 00/08013, WO 01/39775 and US 20020128288. Of the latter, WO 01/39775 is closest to the present invention. However, the benzimidazolone derivatives described therein do not seem to meet the criteria generally acknowledged to be of importance for useful therapeutic agents. They are characterized by: (1) modest potency (affinities for ORL1 receptors in the range of 166 — 1252 nM); (2) little selectivity towards p-opiate receptors (affinities in the range of 19 — 457 nM); (3) no evidence for availability after oral administration, and (4) no evidence for CNS-availability.

The most potent ORL1 agonist described is Ro 64-6198. This compound does not contain a benzimidazolone moiety but has a spiro core instead (see: EP0856514;

Eur. J. Med. Chem, 35 (2000) 839-851 and Proc. Natl. Acad. Sci. USA, 2000, 97, 4938). Ro 64-6198 is cited as a potent and selective compound easily penetrating the

Blood Brain Barrier. However, in spite of its favourable in vitro binding data, the in vivo profile of this ligand shows some drawbacks: (1) it is less efficacious in anxiety models than predicted on basis of the in vitro data (2) the therapeutic window between the desired efficacy as an ORL1 agonist and the undesired opiate side-effects in vivo is less than predicted on basis of the in vitro data.

The teachings on the benzimidazolone derivatives and Ro 64-6198 quoted above do not indicate directions on how to improve the in vivo pharmacological profile of the best compounds described. in a review on the subject matter (“Characterisation of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors”, Eur. J.

Pharmacol., 428, 29-36, 2001) Zaveri et al., conclude: “In the absence of a model of a small molecule in the active site, or a crystal structure of the small-molecule-bound

ORL1 receptor, one must be very careful in evaluating SAR's among different classes of ORL1 receptor ligands, even those with very close structural similarities”

Surprisingly, it has now been found that in a series of benzimidazolone and quinazolinone derivatives with novel combinations of substituents, a group of compounds was shown to have a high affinity for human ORL1 receptors. Moreover, these compounds show an excellent selectivity br ORL1 receptors relative to p- opiate receptors, are readily available after oral administration and do penetrate the blood-brain-barrier. The in vitro and in vivo pharmacological profile of several of these compounds are superior to that of Ro 64-6198, nh particular with respect to the therapeutic window between the desired efficacy as an ORL1 agonist and the undesired opiate side-effects in vivo. The invention relates to compounds of the general formula (1):

Ri\ 0) Rs R, 4

IL N— Ld N (1) 294

Ra R, (Ra), R; wherein:

R, represents H, alkyl(1-6C), alkyl(1-3C)cycdloalkyl(3-6C), carbalkoxy(2-7C) or acyl(2-7C), [lm symbolizes (CH), wherein mis either O or 1,

Ra represents halogen, CF3, alkyl(1-6C), alkyl(1-3C)cycloalkyl(3-6C), phenyl, amino, aminoalkyl(1-3C), alkyl(1-3C)amino, dialkyl(1-3C)amino, cyano, cyanoalkyl(1-3C), hydroxy, hydroxyalkyl(1-3C), (1-3C)alkoxy, OCF, acyl(2-7C), trifiuoroacetyl, aminocarboxyl, (1-3C)alkyisutfonyl or ftrifiuoro- methylsulphonyl, and n is an integer from 0 - 4, with the proviso that when n is 2,3 or 4, the R; substituents may be either the same or different,

A is a saturated or partially unsaturated ring [ b and [ | represent {CHz)o- and —(CHy)p- respectively, with the proviso that also the meaning —CH- is possible when A is a partially unsaturated ring, and o and p independently are either 0, 1 or 2,

Rs, Ri, Rs and Rs independently represent hydrogen, alkyl(1-3C), alkyl(1-3C)cyclo- alkyl(3-6C), CH,OH or (R; and Rs) or (Rs and Re) or (Rs and Rs) or (Rs an

Rs) together can form an alkylene bridge of 1 © 3 carbon atoms, with the proviso that when o is 2, Rj is hydrogen, and when pis 2, Rs is hydrogen,

R; represents H, halogen, CFs, alkyl(1-6C), alkyl(1-3C)cycloalky3-6C), amino, aminoalkyl(1-3C), alkyl(1-3C)amino, dialkyl(1-3C)amino, hydroxy, hydroxyalkyl(1-3C), (1-3C)alkoxy, OCF, acyl(2-7C), aminocarboxyl or (1-3C) alkylsulfonyi, and pharmacologically acceptable salts and prodrugs thereof.

To the invention belong all compounds having formula (1), racemates, mixtures of diastereomers and the individual stereoisomers. Thus compounds in which the substituents on potentially asymmetrical carbon atoms are in either the R- configuration or the S-configuration belong to the invention. Also prodrugs, i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (1), belong to the invention. Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (J.

Stella, “Prodrugs as therapeutics’, Expert Opin. Ther. Patents, 14(3), 277-280, 2004).

In particular this relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can be reacted with organic acids to yield compounds having formula (1) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. A prodrug is an inactive compound, which when absorbed is converted into an active form (Medicinal

Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed. F. D. King, p.

The invention particularly relates to compounds having formula (1) wherein: Ais a 5 saturated ring, R, represents hydrogen, alkyi(1-3C), or acyl(2-4C), Rs, Rs, Rs and Re independently represent hydrogen or alkyl(1-3C) or (Rs; and Rs) or (Ra and Re) or (R4 and Rs) or (Rs an Re) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, Rj is hydrogen, and when p is 2, Rs is hydrogen, R; represents H, halogen, CFs, alkyl(1-3C), amino, aminoalkyi(1-3C),alkyi(1-3C)amino, dialkyi(1-3C)amino, hydroxy, (1-3C)alkoxy or OCF3, and Rz, m, n, 0 and p have the meanings as given above.

More particular the invention relates to compounds of formula (I) wherein: A is a saturated ring, m=0, n=0 or 1, 0=1, p=1, R; =H or acetyl, Rz represents halogen, CF, alkyl(1-3C), amino, cyano, OCH, or OCF3, Ra, Rs, Rs and Re independently represent hydrogen or alkyl(1-2C) or (Rs and Rg) together can form an alkylene bridge of 1 to 2 carbon atoms and Ry is H, halogen, CF3, akyl(1-3C), amino, hydroxy or OCF.

Even more preferred is the compound having formula @) and its stereoisomers.

Below, this compound will be referred to as ‘example 1'.

X

=O y @

The compounds of the invention can be brought into forms suitable for administration by usual processes using auxiliary substances and/or liquid or solid carrier materials.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid. Suitable acid addition salts can be formed with inorganic acids such as hydrochloric acid or with organic acids such as fumaric acid.

The compounds of the invention of the general formula (1), as well as the salts thereof, have ORL1 agonistic activity. They are useful in the treatment of disorders in which ORL1 receptors are involved, or that can be treated via manipulation of those receptors. For instance in acute and chronic pain conditions, central nervous system disorders, especially, but not limited to amelioration of symptoms of anxiety and stress disorders, depression, various forms of epilepsy, stroke, disorders characterized by impairment of cognition and memory such as Alzheimer's disease,

Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (posttraumatic brain lesions); acute brain or spinal cord injury, substance related disorders, including substance use disorders (like dependence and abuse) and substance induced disorders (like substance withdrawal), eating disorders like anorexia nervosa and bulimia nervosa, obesity; gastro-intestinal disorders in particular irritable bowel syndrome, inflammatory bowel disease (Crohn's disease) and ulcerative colitis, urinary tract inflammation, renal disorders characterized by imbalances of water retention/excretion or salt excretion; cardiovascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma, respiratory disorders including chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; diseases of the immune system, and viral infections.

Compounds of the present invention are generally administered as pharmaceutical compositions which are important and novel embodiments of the invention because of the presence of the compounds, more particularly specific compounds disclosed herein. Types of pharmaceutical compositions that may be used include but are not limited fo tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art.

In embodiments of the invention, a pharmaceutical pack or kit is provided comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.

GENERAL ASPECTS OF SYNTHESES

The compounds of the invention and their salts can be obtained according to the general route outlined below in scheme 1: aN 0 RR, oN, fy oO Rs BR,

N 1.~< N= 1. heat Nn (4 [ln N—{ A NH _— (lh N— A jg" + 2. NaBH(OAc)3 ( 1<

Rs Ry R, Rs R, (R)n (Ry), R; k 0) (ii) k (1 scheme 1

Starting compounds for this general route are obtained as follows: benzimidazolones [(i), when m=0] can be synthesized according to the methods described in J. Med. Chem. 30, 814-819, 1987 and WO 99/36421. Quinazolinones [(i), when m=1] can be synthesized according to Chem. Pharm. Bulil., 33, 1116-1128, 1985. N-nitro-oximes of (substituted) 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one (ii) are prepared from the corresponding ketones. These ketones in tum are prepared from the corresponding (substituted) tetralones as described in Eur. J. Med .Chem,, 35, 839-851, 2000.

SPECIFIC EXAMPLES OF SYNTHESES

Synthesis of example 1:

A detailed overview of the synthesis of example 1 is given in Scheme 2

OH

CO Et £ COH 1. Diethylsuccinaat AcOH —————— ———— 0) = COC 1* step 1 step 2 3 - 2 -

Lo]

GOH

H,/Pd(C) PPA HN—OH HCI > Be —d —— eee step 3 step 4 step 5 4* 5°

HO—N ON—NG

NaNO, 4 — step 6 7° CC =—=0 ~N 6’ + NaBH(OAc),

Oo step 7 N we se a 8

Example 1

Scheme 2

The first four steps from scheme 2 were performed according to Eur. J. Med. Chem, 35, 839-851, 2000. Starting with the intermediate compound 5° (see scheme 2), the synthesis is as follows:

Step 5 (scheme 2): A mixture of 52 g (0.28 mole) 2,3,3a,4,5,6-hexahydro-1H- phenalen-1-one (compound 5°), 28.1 g (0.40 mole) hydroxylamine. HCI and 55 g (0.40 mole) sodiumacetate.3H,0 in 500 ml 96% ethanol was stirred at 80°C for 4 hours and for an additional 16 hours at room temperature. The resulting mixture was concentrated in vacuo and 750 mil dichloromethane and 300 ml of a §% aqueous solution of NaHCO; were added. The aqueous layer was washed twice with 100 ml dichloromethane, the combined organic layers were washed with 100 ml brine, dried over MgSO, and concentrated in vacuo.

Step 6 (scheme 2): 58.8 g (representing a quantitative yield) of the resulting off-white solid oxime (compound 6*) was suspended in 600 ml f-butylmethyl ether. At room temperature, D this suspension 230 ml of a solution 41.4 g (0.6 mole) of sodium nitrite in water was added, followed by 290 ml of a solution of 2N sulfuric acid. After stirring at 40°C for 16 hours, the mixture was cooled to room temperature and 300 ml of a saturated aqueous NaHCO, solution was added. The aqueous layer was extracted twice with 300 ml t-butyimethy! ether and the combined organic layers were washed with 150 ml brine, dried over MgSO, and concentrated in vacuo. The resulting brown oil was purified by column chromatography (silicagel) with dichloromethane as eluent. The oily product obtained after concentration in vacuo was triturated with cyciochexane and the resulting precipitate was collected by filtration and dried. The pure NO.-imine (compound 77) was obtained (34 g, 0.148 mole, 52% yield) as an off-white solid with a melting point of 64-69°C.

Step 7 (scheme 2): a mixture of 6.51 g (30 mmole) 4-(1-benzimidazolone) piperidine (compound 8%, ACROS), 6.9 g (30 mmole) of the NO-imine (compound 7°) and 5.25 ml di-isopropylethylamine in 450 ml 1,2-dichloro-ethane was heated at 50°C and stirred under N\; for 16 hours. After cooling to room temperature 12.7 g (60 mmole)

NaBH(OAc); was added and the resulting mixture was stirred at room temperature under No for 24 hours. After concentration of the reaction mixture in vacuo, 500 mi dichloromethane and 500 mi of an aqueous 5% NaHCO, solution were added under stirring. The aqueous layer was washed twice with 100 mi dichloromethane, the combined organic layers were washed with 100 mi brine, dried over MgSOs and concentrated in vacuo. The crude product was purified by column chromatography (silicagel) with a mixture of dchloromethane-methanol-ammonia (92 : 7.5 : 0.5) as eluent. The pure product was obtained by concentration in vacuo (8.09 g, 21 mmole, 70% yield, melting point 155-158°C). To 8.08 g (21 mmole) of the pure product, 60 mi ethanol and 2.44 g (21 mmole) fumaric acid were added. Concentration in vacuo of the resulting solution afforded the fumarate salt of example 1 (10.53 g, 21 mmole, quantitative yield) as a white foam with a M of 358 m/z and a melting point of 232- 234°C.

Synthesis of example 2:

A mixture of 2.31 g (10 mmole) 4-(1-quinazolinone) piperidine and 2.3 g (10 mmole) ot the NO,-imine (compound 7%) in 100 ml 1,2-dichloroethane under nitrogen was heated and stirred at 50°C for 7 hours and for an additional 16 hours at room temperature. Subsequently 4.2 g (20 mmole) NaBH(OAC); was added and the resulting mixture was stirred at room temperature under Nz for 24 hours. After concentration of the reaction mixture in vacuo, 200 ml dichloromethane and 200 ml of a 5% aqueous NaHCO; solution were added under stirring. The aqueous layer was washed twice with 40 mi dichloromethane, the combined organic layers were washed with 40 ml brine, dried over MgSO, and concentrated in vacuo. The crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane : methanol : ammonia (94.5 : 5 : 0.5) as eluent. The pure product resulting after concentration in vacuo (2.5 g, 6.2 mmole) was dissolved in 50 ml of a solution of HCI in ethanol. Concentration in vacuo yielded the HCI salt of example 2 (2.05 g, 4.7 mmole, 47% yield) as a white amorphous solid with a M' of 402 m/z and a melting point of 172-180°C.

Synthesis of example 13:

A detailed overview of the synthesis of example 13 is given in scheme 3:

H

ON cl H aN K,CO, o a. Raney Ni ol ale oO or Cl 10° step 1 (of 11° step 2

H, i= col Loy CI-Et-Cl-formate

SoG.

H LO) ON"NS NaBH(OAc), OD oe + step 5 a

A qe Example 13

Scheme 3

Step 1 (scheme 3): a solution of 3.84 g (20 mmole) 2,4-dichloronitrobenzene (compound 9*, Aldrich), 4.1 ml (20 mmole) 4-amino-1-benzylpiperidine (compound 10°, Aldrich), 4.46 g (32 mmole) K.COs in 50 ml dimethylformamide was stirred at 95°C under N; for 18 hours. After cooling to room temperature the mixture was poored into water(150 mi)-dichloromethane (250 ml). The aqueous layer was extracted twice with 50 ml dichloromethane and the combined organic layers were washed twice with 50 mi water, dried over MgSO, and concentrated in vacuo. The resulting crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane : methanol (97 : 3) as eluent. After concentration in vacuo the pure product was obtained as a yellow oily substance (4.8 g, 13.8 mmole, 69% yield). :

Step 2 (scheme 3): a portion of Raney-Ni (Aldrich R 2800 [7440-02-0], ~ 500 mg) was washed twice with 10 ml 96% ethanol and subsequently added under No 0 a solution of 4.8 g (13.8 mmole) of compound 11° in 200 ml 96% ethanol. The solution was hydrated at room temperature and a pressure of 1 atmosphere for 2.5 hours.

The mixture was subsequently filtered over Hyflo, washed with 300 mi 96% ethanol and the filtrate concentrated in vacuo to give quantitative yield of compound 12° as a colored oily substance (4.36 g, 13.8 mmole, 100% yield).

Step 3 (scheme 3): to a solution of 4.36 g (13.8 mmole) of compound 12* the product from the previous step in 200 mi acetonitrile, stirred at room temperature under nitrogen, 3.36 g (20.7 mmole) 1,1'-carbonyldiimidazole CDI, ACROS) was added.

The precipitate, starting to form at 10 minutes and increasing up to 3 hours, was collected by filtration, washed with acetonitrile (200 ml) and dried in vacuo, giving an almost pure compound 13* (3,30 g, 9.7 mmole, 70% yield)

Step 4 (scheme 3): to a suspension of 3.30 g (3.7 mmole) of compound 13" in 80 ml 1,2-dichloroethane, stimed under N; and cooled to OC, a portion of 1-chloroethyl chioroformate (1.17 mi, 10.7 mmole) was added dropwise. After steering at 0°C for 30 minutes and at 80°C for 90 minutes, the mixture was cooled again to (°C and another portion of 1-chloroethyl chloroformate (1.17 ml, 10.7 mmole) was added dropwise. The mixture was stirred once more at 0°C for 30 minutes and at 80°C for 16 hours. After cooling to room temperature the mixture was concentrated in vacuo and 75 ml methanol was added to the residue. The resulting solution was stirred at 65°C for 1 hour and concentrated in vacuo. After addition of 75 mi dichioromethane to the resulting brown semi-solid it solidified under stirring for 1 hour. The precipitate was collected by filtration, washed with 100 ml dichloromethane and dried. The obtained crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane-methanol-ammonia (92 : 7.5 : 0.5) as eluent. After concentration in vacuo compound 14* was obtained as a white solid (1.61 g, 6.4 mmole, 66% yield).

Step 5 (scheme3): a mixture of 1.61 g (6.4 mmole) of compound 14" and 1.47 g (6.4 mmole) of NO,-imine (compound 7°) in 200 ml 1,2-dichioroethane under N, was heated and stirred at 50°C for 16 hours. After cooling to room temperature 2.76 g (13 mmole) NaBH(OAc); was added and the resulting mixture was stirred at room temperature under N for 24 hours. The slightly colored solution was poured on a mixture of 300 mi dichloromethane, 100 mi water and 50 ml aqueous 5% NaHCO; solution. The aqueous layer was washed twice with 70 ml dichloromethane, the combined organic layers were dried over MgSO, and concentrated in vacuo. The crude product was purified by column chromatography (silicagel) with a mixture of dichloromethane : methanol : ammonia (92 : 7.5 : 0.5) as eluent. The pure product was concentrated in vacuo and solidified upon subsequent co-evaporation with acetonitrile. After stirring in 100 ml di-isopropylether, the precipitate was collected by filtration and dried, leading to example 13 (1.35 g, 3.2 mmole, 50% yield) as a slightly colored pure solid with a M+ of 422 m/z and a melting point of 185-188°C.

By these and comparable methods the following specific examples were synthesized.

They are intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way. Structural information of these compounds, all represented by the general formula (1), is presented in the table below.

R, \ O Rs R, nN [1.~ (lh N— AN (1) , [ < a 4 : 9

Rs Rs \ (Ron 5 6 8 7 R, [Fr | Ramo Ri. THC AJolp] Bs | Ri] Re] Rs [Reig +r rr 11 rr 1 T° 1 "1 " 1 JH Jo] - Jofsatf|1[1] H | H | H [H | H (1 HJo] - Jojsat [1/1] H | H [HHI] H |] (1H Jo] - Jo satf1[1] H | H | H | HI] H (1~jHjo] - fofsati1][1] HI HI H|HIT] H ("| H [0] - jO sat [1{1] H | H [ H [ H | H 2 | H [1] - [0 sat |1)1] H | H | HH] H ] 3 CH [0] - [0 sat [1]1] H | H [| H | H]| H 4 [CH[1] - Jol sat [1]1] H | H | HH] H ] 5 | H [of 4F 1 sat [1]1] H [ H [HHI] H 6 [H]o] 5F Jt sat]1]1] H | H | HH | H 7 J Hlo] 6F 1 sat 1/1] H | H | H | H | H 8 | H [0] 7F [1 sat |1]1] H | H [| H | HJ] H 9 | H |O] 5CF, [1 sat 1/1] H | HH] HI] H 10] H J0] 6CF, 1 sat J1]1] H | H [| H JH | H 11 JH Jo] 4CI [1] sat [1]1] H | HH [| HI H (12 | H [0] 5CI [1 sat |1{1] H | H [HH] H (18 [Ho] 6Cl [1 sat]1]1] H | H [HH] H (14 |] HJ]o] 7c Ji sat [1]1] H [ H | HTH] H 5 | H Jo] acH, (1 sat|1][1] HH H|H] H 16 | H [0] &5CH, [1] sat [1[1] H [ H [HH | H (17 | H fo] 6CH, [teat [1/1] HH [HH] H

[18] H Jo] 7CH, Jisst[1J1] H | H | HJTHI H

Claims (9)

1. Compounds of the general formula (1) Ri\ 0) Rs Rs NC (1, N—( LA N (1) 294 Rs Re (Ro), R, wherein: R4 represents H, alkyl(1-6C), alkyk1-3C)cydoalkyl(3-6C), carbalkoxy(2-7C) or acyl(2-7C), [ln symbolizes {CHz),- wherein mis either OQ or 1, R: represents halogen, CFj, alkyl(1-6C), alkyl(1-3C)cycloalkyl(3-6C), phenyl, amino. aminoalkyl(1-3C), alkyl(1-3C)amino, diakyi(1-3C)amino, cyano, cyanoalkyl(1-3C), hydroxy, hydroxyalkyl(1-3C), (1-3C)alkoxy, OCF3, acyl(2- 7C), trifluoroacetyl, aminocarboxyl, (1-3C)alkylsulfonyt or trifluoromethyi- sulphonyl, and n is an integer from 0 - 4, with the proviso that when nis 2,3 or 4, the R; substituents may be either the same or different, A is a saturated or partially unsaturated ring [ b and [ L represent {CH.),- and —(CH),- respectively, with the proviso that also the meaning -CH- is possible when A is a partially unsaturated ring, and 0 and p independently are either 0, 1 or 2, Ra, Ry, Rs and Re independently represent hydrogen, alkyl(1-3C), alkyl(1-3C)cyclo- alkyl(3-6C), CH,OH or (Rs and Res) or (Ra and Rs) or (Rs and Re) or (Rs an Re) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, Rj is hydrogen, and when p is 2, Rs is hydrogen, R; represents H, halogen, CF, alkyl(1-6C), alkyl(1-3C)cycloalkyl(3-6C), amino, aminoalkyl(1-3C), alkyl(1-3C)amino, dialkyl(1-3C)amino, hydroxy, hydroxyalkyl(1-3C), (1-3C)alkoxy, OCF, acyl(2-7C), aminocarboxyl or (1-3C) alkyisulfonyl, all stereoisomers, as well as pharmacologically acceptable salts and prodrugs, which are derivatives of the compounds having formula (1) wherein a group is present which is easily removed after administration, such as amidine, enamine, a Mannich base, a hydroxyl-methylene derivative, an O- (acyloxymethylene carbamate) derivative, carbamate or enaminone.

2 Compounds as claimed in claim 1 of the general formula (1) wherein Ais a saturated ring, R, represents hydrogen, alkyl(1-3C), or acyl(2-4C), Rs, Rs, Rs and Rg independently represent hydrogen or alkyl(1-3C) or (R; and Rs) or (Rs and Rg) or (R¢ and Rs) or (Rs an Rs) together can form an alkylene bridge of 1 to 3 carbon atoms, with the proviso that when o is 2, R; is hydrogen, and when p is 2, Rs is hydrogen, R; represents H, halogen, CFs, alkyl(1-3C), amino, aminoalkyl(1-3C), alkyl(1-3C)amino, dialkyl(1-3C)-amino, hydroxy, (1-3C)alkoxy or OCF3, and R;, m, n, 0 and p have the meanings as given above.

3 Compounds as claimed in claim 1 of the general formula (1) wherein: A is a saturated ring, m=0, n=0 ori, o=1, p=1, Ry =H or acetyl, R. represents halogen, CF,, alkyl(1-3C), amino, cyano, OCH; or OCF;, Ry, Rs, Rs and Rg independently represent hydrogen or alkyl(1-2C) or (R« and Rs) together can form an alkylene bridge of 1 to 2 carbon atoms and Ry represents H, halogen, CF3, alkyl(1-3C), amino, hydroxy or OCF,

4, Compound as claimed in claim 1 having formula (2) and stereoisomers thereof: x p FD (2)

5. Compounds of the general formula (3): ON—Ny (3) R, wherein R; has the meaning as given in claim 1, useful in the synthesis of compounds with the general formula (1).

6. A compound as claimed in any of the claims 1-4, or a salt thereof, for use as a medicament

7. Pharmaceutical compositions containing a pharmacologically active amount of at least one of the compounds as claimed in any of the claims 1-4 as an active ingredient.

8. Use of a compound as claimed in any of the claims 1-4 for the preparation of a pharmaceutical composition for the treatment of disorders in which ORL1 receptors are involved, or that can be treated via manipulation of those receptors,

9. Use as claimed in claim 8 characterized in that said disorders are acute and chronic pain conditions, central nervous system disorders, especially, but not limited to amelioration of symptoms of anxiety and stress disorders, depression, various forms of epilepsy, stroke, disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury, substance related disorders, including substance use disorders (like dependence and abuse) and substance induced disorders (like substance withdrawal); eating disorders like anorexia nervosa and bulimia nervosa, obesity; gastro-intestinal disorders in particular irritable bowel syndrome, inflammatory bowel disease (Crohn's disease) and ulcerative colitis, urinary tract inflammation, renal disorders characterized by imbalances of water retention/excretion or salt excretion; cardiovascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma, respiratory disorders including chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; diseases of the immune system, and viral infections.