WO2004026301A1 - 1h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1 receptor ligands - Google Patents

1h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1 receptor ligands Download PDF

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WO2004026301A1
WO2004026301A1 PCT/EP2003/050628 EP0350628W WO2004026301A1 WO 2004026301 A1 WO2004026301 A1 WO 2004026301A1 EP 0350628 W EP0350628 W EP 0350628W WO 2004026301 A1 WO2004026301 A1 WO 2004026301A1
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group
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substituted
heteroatoms
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Josephus H.M. Lange
Cornelis G. Kruse
Andrew C. Mccreary
Herman H. Van Stuivenberg
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Solvay Pharmaceuticals B.V.
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Priority to UAA200503704A priority Critical patent/UA80298C2/en
Priority to SI200331803T priority patent/SI1542678T1/en
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Priority to MXPA05002862A priority patent/MXPA05002862A/en
Priority to EP03797318A priority patent/EP1542678B1/en
Priority to DK03797318.7T priority patent/DK1542678T3/en
Priority to CA2491394A priority patent/CA2491394C/en
Priority to AT03797318T priority patent/ATE458479T1/en
Priority to DE60331444T priority patent/DE60331444D1/en
Priority to AU2003299024A priority patent/AU2003299024B2/en
Priority to JP2004537155A priority patent/JP2006501275A/en
Priority to BR0312020-1A priority patent/BR0312020A/en
Publication of WO2004026301A1 publication Critical patent/WO2004026301A1/en
Priority to IL165611A priority patent/IL165611A/en
Priority to HR20050053A priority patent/HRP20050053A2/en
Priority to NO20051870A priority patent/NO20051870L/en
Priority to HK05110963A priority patent/HK1078796A1/en

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Abstract

The present invention relates to a group of 1H-1,2,4-triazole-3-carboxamide derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing at least one of these compounds as an active ingredient. These 1H-1,2,4-triazole-3-carboxamide derivatives are potent cannabinoid-CB1 receptor agonists, partial agonists, inverse agonists or antagonists, useful for the treatment of disorders involving cannabinoid neurotransmission. The compounds have the general formula (I), wherein R and R1-R3 have the meanings given in the specification.

Description

1H-1 , 2 , 4- TRIAZO Ξ-3- CARBOXAMIDE DERIVATIVES AS CANNABINOID-CBl RECEPTOR LIGANDS
The present invention relates to a group of 1H-1,2,4-triazoie derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active ingredient.
These 1H-1,2,4-triazo!e-carboxamide derivatives are potent cannabinoid-CBi receptor agonists, partial agonists, inverse agonists or antagonists, useful for the treatment of psychiatric and neurological disorders, as well as other diseases involving cannabinoid-CBi neurotransmission.
1 ,5-Diaryl-1 H-1 ,2,4-triazole-3-carboxamide derivatives have been described in EP 0346620 and GB 2120665 as herbicides. Recently 1 ,2,4-triazoles were described as potential agonists and antagonists of cannabinoid-CB1 and -CB2 receptors (Jagerovic, N. et al„ Drugs Fut. 2002, 27(Suppl. A): XVIIth Int. Symp. on Medicinal Chemistry, P284)
It has now surprisingly been found that known and new 1 ,5-diaryl-1 H-1,2,4-triazole-3- carboxamide derivatives of the formula (I), as well as prodrugs, salts, and stereo- isomers thereof, are potent antagonists, agonists, inverse agonists or partial agonists of the cannabinoid CBi receptor:
Figure imgf000002_0001
(I)
wherein
- R and R independently represent a phenyl, naphtyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl group, which groups may be substituted with 1-4 substituents X, which can be the same or different, from the group branched or unbranched (C -3)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C1-2)-amino, mono- or dialkyl (Cι-2)-amido, (C^-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, (C^-alkylsul-fonyl, carboxyl, cyano, carbamoyl, (Cι-3)-dialkylaminosulfonyl, (C1-3)- monoalkylamino-suifonyl and acetyl,
- R2 represents a hydrogen atom or a branched or unbranched C1-B alkyl or C-|8 cycloalkyl-alkyl group or a phenyl, benzyl or phenethyl group which aromatic rings may be substituted with 1-4 substituents X, wherein X hasthe meaning as indicated above, or R2 represents a pyridyl or thienyl group,
- R3 represents branched or unbranched Cι.8 alkyl, Cι-8aIkoxy, C3-8 cycloalkyl, C5-ιo bicycloalkyl, C6_ι0 tricycloalkyl, C^s alkenyl, C5.8 cycloalkenyl, which groups may optionally contain one or more heteroatoms from the group (O, N,
S), which groups may be substituted with a hydroxy group, an ethynyl group or 1-3 fluoro atoms, or R3 represents a phenyl, benzyl or phenethyl group which aromatic rings may be substituted with 1-4 substituents X, wherein X has the meaning as indicated above, or Rs represents a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or thienyl group which heteroaromatic rings may be substituted with 1-2 substituents X, wherein X has the meaning as indicated above, or R3 represents a group NR R5 wherein R4 and R5, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic group contains one or two heteroatoms from the group N, O or S, which heteroatoms can be the same or different, which heterocyclic moiety may be substituted with a branched or unbranched C1-3 alkyl, hydroxy or trifluoromethyl group or a fluoro atom, or
R2 and R3, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic group contains one or two heteroatoms from the group N, O or S, which heteroatoms can be the same or different, which heterocyclic moiety may be substituted with a branched or unbranched C1-3 alkyl, hydroxy, piperidinyl or trifluoromethyl group or a fluoro atom.
A group of four 1 ,5-diaryl-1H-1,2,4-triazole-3-carboxamide derivatives in which the amide N-atom is part of an unsubstituted piperidinyl or morpholinyl group is described by D. Clerin and J.P. Fleury in Bull. Soc. Chim. Fr., 1974, 1-2, Pt.2, 211- 217.
1 -(4-Methylphenyl)-5-phenyl-N-(2-pyridyl)-1 H-1 ,2,4-triazole-3-carboxamide is described by M. H. Elnagdi et al. in Heteroatom Chem., 1995, 6, 589-592.
A group of four 1 ,5-diary!-N-(2-pyridyl)-1 H-1 ,2,4-triazole-3-carboxamides is described by A. H. Harhash et al. in Indian J. Chem., 1976, 14B, 268-272. Due to the potent cannabinoid-CB! receptor agonistic, partial agonistic, inverse agonistic or antagonistic activity the compounds of the invention are suitable for use in the treatment of psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovascular disorders.
The affinity of the compounds of the invention for cannabinoid CB-i receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB., receptor is stably transfected in conjunction with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [3H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.
The cannabinoid CB., receptor antagonistic, agonistic or partial agonistic activity of compounds of the invention was determined by functional studies using the human CB., receptor cloned in Chinese hamster ovary (CHO) cells. CHO cells were grown in a DMEM culture medium, supplemented with 10% heat-inactivated fetal calf serum. Medium was aspirated and replaced by DMEM, without fetal calf serum, but containing [3H]-Arachidonic acid and incubated overnight in a cell culture stove (5% C02/95% air; 37 °C; water-saturated atmosphere). During this period [3H]- Arachidonic acid was incorporated in membrane phospholipids. On the test day, medium was aspirated and cells were washed three times using 0.5 ml phosphate- buffered saline, containing 0.2% bovine serum albumin. Stimulation of the CB| receptor by WIN 55,212-2 led to activation of PLA2 followed by release of [3H]- Arachidonic acid into the medium. This WIN 55,212-2-induced release was concentration-dependently antagonized by CB, receptor antagonists.
Cannabinoid agonistic or partial agonistic activity of compounds of the invention can be determined according to published methods, such as assessment of /n vivo cannabimimetic effects (Wiley, J. L; Jefferson, R. G; Grier, M. C; Mahadevan, A.; Razdan, R. K.; Martin, B. R. J. Pharmacol. Exp. Ther. 2001, 29Q 1013). The invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (I). Also prodrugs, i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (I), belong to the invention. 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 (I) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamiπe, a Mannich base, a hydroxy nethylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.A pro-drug 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. 216).
The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.
Suitable synthetic routes for the compounds of the invention are the following:
Synthetic route A
Step 1: Ester hydrolysis of a compound having formula (II) wherein Re represents a branched or unbranched (C14)-alkyl group or a benzyl group,
Figure imgf000005_0001
yields a compound having formula (III)
Figure imgf000005_0002
wherein R and R^ have the meanings as described above. The compounds of the invention having formula (II), wherein R6 represents a branched or unbranched alkyl group (CM) or benzyl group can be obtained according to methods known, for example:
a) Sawdey, G.W. J. Am. Chem. Soc 1957, 79, 1955 b) Czollner, L. et al., Arch. Pharm. (Weinhβim) 1990, 323, 225 c) Eicher, T. and Hauptmann, S. The Chemistry of Heterocycles, Thieme Verlag, Stuttgart, 1995 (ISBN 313 100511 4), p. 208-212.
Step 2: Reaction of a compound having formula (II!) with a compound having formula R2R3NH wherein R2 and R3 have the meanings as described above via activating and coupling methods such as formation of an active ester, or in the presence of a coupling reagent such as DCC, HBTU, BOP, CIP (2-chIor 1 ,3- dimethylimidazolinium hexafluorophosphate) or PyAOP (7-azabenzotriazol-1- yloxytris(pyrrolidino)phosphonium hexafluorophosphate). Activating and coupling methods of this type are described in
a) M. Bodanszky and A. Bodanszky: The Practice ofPeptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akaji et al., Tetrahedron Lett. (1994), 35, 3315-3318); c) F. Albericio et al., Tetrahedron Lett. (1997), 38, 4853-4856).
This reaction gives a 1 H-1 ,2,4-triazole derivative having formula (I).
Synthetic route B
A compound having formula (111) is reacted with a halogenating agent such as thionyl chloride (SOCI ) or oxaly! chloride. This reaction yields the corresponding carbonyl chloride (acid chloride) (IV).
Figure imgf000006_0001
Reaction of a compound having formula (IV) with a compound having formula R2R3NH wherein wherein R2 and R3 have the meanings as described above gives a 1H-1,2,4-triazole derivative having formula (I). Synthetic route C
A compound having formula (II) is reacted in an amidation reaction with a compound having formula R2R3NH wherein R2 and R3 have the meanings as described hereinabove to give a 1 H-1 ,2,4-triazole derivative having formula (I). Such amidation reactions can be promoted by the use of trimethylaluminum AI(CI-fe)3 (For more information on aluminum-mediated conversion of esters to amides, see: J. I. Levin, E. Turos, S. M. Weinreb, Synth Commun. (1982), 12, 989-993.)
Example l
Part A: To a stirred solution of dimethyl aminomaloπate hydrochloride (25 gram, 0.136 mol) in dichloromethane (200 ml_) triethylamine (41.4 mL, 2.2 molar equivalent) is added at 0 °C. 4-ChIorobenzoyl chloride (23.8 gram, 0.136 mol) is slowly added and the resulting solution is allowed to stand at room temperature overnight. Water is added and the organic layer is separated. The water layer is extracted twice with dichloromethane. The collected organic layers are washed with water, dried over MgS04, filtered and concentrated in vacuo. The residue is recrystallised from methanol (400 mL) to give dimethyl 2-(4- chlorobenzoylamino)malonate (30.5 gram, 79 % yield). Melting point: 146-148°C. 1H- NMR (200 MHz, CDCI3): δ 3.86 (s, 6H), 5.38 (d, J = 6 Hz, 1H), 7.15 (br d, J ~ 6 Hz, 1H), 7.43 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H).
Part B: To a stirred suspension of 2,4-dichloroaniline (19.44 gram, 0.12 mol) in concentrated HCI (25 L) and acetic acid ( 75 mL) at 0 °C is added a solution of NaN02 (9.0 gram, 0.13 mol) in water (50 mL) and the resulting solution is stirred for 15 minutes. A solution of dimethyl 2-(4-chlorobenzoylamino)-malonate (28.55 gram, 0.10 mol) in acetone (200 mL) is slowly added while keeping the temperature below 0 °C. A solution of K2C03 (120 gram) in water (200 mL) is slowly added and the resulting black mixture is stirred for 30 minutes at 0°C. The mixture is extracted three times with EtOAc. The collected organics are washed with water, aqueous NaHCQ and water, respectively, dried over MgS0 , filtered and concentrated in vacuo. The residue is dissolved in methanol (500 mL) and a solution of sodium (1 gram) in methanol (75 mL) is added. The resulting stirred mixture is allowed to stand overnight at room temperature and cooled in a refrigerator. The formed precipitate is collected by filtration and washed with methanol to give methyl 5-(4-chlorophenyl)-1-(2,4- dichlorophenyI)-1 H-1,2,4-triazoIe-3-carboxylate (11.4 gram, 30 % yield). Melting point: 153-154 °C. 1H-NMR (200 MHz, CDCI3): δ 4.07 (s, 3H), 7.28-7.60 (m, 7H). Part C: To a stirred suspension of methyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 1 H-1,2,4-triazole-3-carboxylate (11.3 gram, 0.0295 mol) in methanol (100 mL) is added KOH (45 % aqueous solution, 7.5 mL) and the resulting mixture is heated at reflux temperature for 4 hours. The mixture is concentrated in vacuo and water (150 L) and concentrated HCI are added. The yellow precipitate is collected by filtration, washed with water and dried in vacuo to give 5-(4-chlorophenyI)-1-{2,4- dichlorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (10.0 gram, 92 % yield). Melting point: 141-144 °C (decomposition).
Part D: To a stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichIorophenyl)-1H-1,2,4- triazole-3-carboxylic acid (1.48 gram, 4.0 mmol) in acetonitrile (20 L) is successively added diisopropylethylamine (DIPEA) (1.5 mL, 2.1 molar equivalent), O- benzotriazol-1-yl-N,N,N',N'-tetramethy!uronium hexafluorophos-phate (HBTU) (1.66 gram, 1.1 molar equivalent) and 1-aminopiperidine (0.44 gram, 1.1 molar equivalent). After stirring overnight an aqueous NaHC03 solution is added. The resulting mixture is three times extracted with dichloromethane. The combined organic layers are washed with water, dried over Na2S04, filtered and concentrated in vacuo to give a crude oil (3.6 gram). This oil is further purified by flash chromatography (silica gel; EtOAc / petroleum ether (40-60 °C) = 7/3 (v/v)). The purified material is treated with ethanolic HCI (1M solution) to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N- (piperidin-1-yl)-1H-1,2,4-triazole-3-carboxamide hydrochloride (1.50 gram, 77 % yield). Melting point: 238-240 °C (decomposition). 1H-NMR (400 MHz, DMSO-d6): δ 1.46-1.54 (m, 2H), 1.78-1.85 (m, 4H), 3.22-3.28 (m, 4H), 7.50 (s, 4H), 7.70 (dd, J = 8 and 2 Hz, 1H), 7.85-7.87 (m, 1H), 7.91 (d, J = 8 Hz, 1H), (NH not visible). Analogously were prepared the examples 2-18:
2. 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1H-1,2,4- triazole-3-carboxamide hydrochloride. Melting point: 248-255 °C
(decomposition). 3. 5-(4-Chlorophenyl)-N-cyclohexyl-1 -(2,4-dichlorophenyl)-1 H-1 ,2,4-triazole-3- carboxamide. Melting point: 186-188 °C. 4. N-t-Butoxy-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3- carboxamide. Melting point: 150-152 °C.
5. 5-(4-Chloropheny!)-1-(2,4-dich!orophenyl)-N-(n-pentyl)-1 H-1 ,2,4-triazole-3- carboxamide. 1H-NMR (400 MHz, CDCI3): δ 0.92 (t, J = 7 Hz, 3H), 1.35-1.44 (m, 4H), 1.62-1.70 (m, 2H), 3.48-3.56 (m, 2H), 7.20-7.25 (m, 1H), 7.34 (dt, J = 8 and 2 Hz, 2H), 7.42-7.50 (m, 4H), 7.54 (d, J = 2 Hz, 1 H).
6. 5-(4-Chlorophenyl)-1-(2,4-dichiorophenyl)-N-(morpholin-4-yl)~1H-1,2,4- triazole-3-carboxamide. Melting point: 184-186 °C.
7. 1-(4-ChIorophenyl)-5-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-1 ,2,4-triazole- 3-carboxamide hydrochloride. Melting point: 234-237 °C (decomposition). 8. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyI)-N-(pyrrolidin-1-yI)-1H-1,2,4- triazole-3-carboxamide hydrochloride. Melting point: 234-236 °C
(decomposition). 9. 1-(4-ChlorophenyI)-N-cyclohexyI-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3- carboxamide. 1H-NMR (400 MHz, CDCI3): δ 1.14-1.81 (m, 8H), 2.02-2.10 (m, 2H), 4.00-4.11 (m, 1H), 7.08 (br d, J ~ 7 Hz, 1H), 7.26 (br d, J ~ 8 Hz, 2H),
7.34 (br d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H). 10. N-t-Butoxy-1-(4-chlorophenyl)-5-(2,4-dichiorophenyI)-1 H-1 ,2,4-triazole-3- carboxamide. 1H-NMR (400 MHz, CDCI3): δ 1.38 (s, 9H), 7.25 (br d, J ~ 8 Hz, 2H), 7.35 (br d, J ~ 8 Hz, 2H), 7.41 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H), 9.18, br s, 1H). 11. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(n-pentyl)-1 H-1 ,2,4-triazole-3- carboxamide. 1H-NMR (400 MHz, CDCI3): δ 0.91 (t, J = 7 Hz, 3H), 1.35-1.41 (m, 4H), 1.60-1.70 (m, 2H), 3.48-3.56 (m, 2H), 7.21 (br t.J ~ 7 Hz, 1 H), 7.26 (br d, J ~ 8 Hz, 2H), 7.34 (br d, J ~ 8 Hz, 2H),7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H). 12. 1 -(4-ChlorophenyI)-5-(2,4-dichlorophenyl)-N-(morpholin-4-yl)-1 H-1 ,2,4- triazole-3-carboxamide hydrochloride. Melting point: 224-226 °C.
13. 1 -(2,4-Dich!orophenyl)-5-(pyridin-2-yl)-N-(piperidin-1 -yl)-1 H-1 ,2,4-triazole-3- carboxamide. Melting point: 191-193 °C.
14. 5-(2,4-DichIorophenyl)-N-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H- 1 ,2,4-triazole-3-carboxamide. Melting point: 159-161 °C.
15. 1 '-[5-(2,4-dich!orophenyl)-1-(4-(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazo!-3- yl)carbonyl]piperidine. Melting point: 155-156 °C.
16. 1-(2,4-Dichlorophenyl)-N-(piperidin-1-yl)-5-(pyridin-3-yI)-1 H-1,2,4-triazole-3- carboxamide. Melting point: 219 °C. 17. 1-(4-Chloroρhenyl)-5-(2,4-dichlorophenyl)-N-(5,5,5-trifluoropentyI)-1H-1,2,4- triazole-3-carboxamide. 1H-NMR (400 MHz, CDC!3): 5 1.63-1.80 ( , 4H), 2.06-2.22 (m, 2H), 3.54 (q, J ~ 7 Hz, 2H), 7.26 (m, 3H), 7.34 (br d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H). 18. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(5-fluoropentyl)-1 H-1 ,2,4- triazole-3-carboxamide. 1H-NMR (400 MHz, CDCI3): 5 1.63-1.80 (m, 4H),
2.06-2.22 ( , 2H), 3.54 (q, J ~ 7 Hz, 2H), 7.22-7.28 (m, 3H), 7.34 (br d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H).
Example 9 Part A: 1-(Chlorophenyl)-5-(2,4-dichIorophenyl)-1H-1 ,2,4-triazole-3-carboxylic acid was prepared analogously to the procedure as described in Example 1 , Part A-C by using dimethyl aminomalonate hydrochloride, 2,4-dichlorobenzoyl chloride and 4- chloroaniline as starting materials, respectively. Melting point: 102-104 °C. 1 H-NMR (400 MHz, DMSO-de): δ 7.36 (br d, J - 8 Hz, 2H), 7.50 (br d, J ~ 8 Hz, 2H), 7.59 (dd, J = 8 and 2 Hz, 1H), 7.70 (d, J = 2 Hz, 1H), 7.75 (d, J = 8 Hz, 1 H), OH proton is part of water peak at δ 3.4.
Analogously was 1 -(chlorophenyl)-5-(2,5-dichlorophenyl)-1 H-1 ,2,4-triazole-3- carboxylic acid prepared by using dimethyl aminomalonate hydrochloride, 2,5- dichlorobenzoyl chloride and 4-chIoroaniline as starting materials, respectively. Melting point: 183-188 °C. 1H-NMR (400 MHz, DMSO-dB): δ 7.41 (br d, J ~ 8 Hz, 2H)i 7.52 (br d, J ~ 8 Hz, 2H), 7.56 (d, J = 8 Hz, 1H), 7.65 (dd, J = 8 and 2 Hz, 1 H), 7.88 (d, J = 2 Hz, 1H), OH proton is part of water peak at δ3.5. Part B: To a stirred solution of 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1 H-1,2,4- triazole-3-carboxylic acid (0.37 g, 1.00 mmol) in dichloromethane (10 mL) is added oxalyl chloride (0.254 g, 2.00 mmol). The resulting mixture is concentrated in vacuo to give crude 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-carbonyl chloride.
Part C: The crude 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1 ,2,4-triazole-3- carbonyl chloride is dissolved in tetrahydrofuran (THF) (10 mL). 2,3-Dihydro-1H- inden-2-ylamine (0.40 g, 3.00 mmol) is added and the resulting solution is stirred for 42 hours at 25 °C. The mixture is concentrated in vacuo and the residue is purified by preparative liquid chromatography to give pure 1-(4-chIorophenyI)-5-(2,4- dichlorophenyl)-N-(2,3-dihydro-1 H-inden-2-yl)-1 H-1 ,2,4-triazole-3-carboxamide (393 mg, 81 % yield). MS (ESI+) 485.6. 1H-NMR (400 MHz, DMSO-d6): 3.06 (dd, J = 16 and 8 Hz, 2H), 3.21 (dd, J = 16 and 8 Hz, 2H), 4.71-4.82 (m, 1H), 7.12-7.16 (m, 2H), 7.19-7.24 (m. 2H), 7.39 (br d, J ~ 8 Hz, 2H), 7.52 (br d, J ~ 8 Hz, 2H), 7.60 (dd, J = 8 and 2 Hz, 1H), 7.71 (d, J = 2 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 8.93-8.97 (m, 1H, NH). Analogously were prepared the examples 20-43:
20. 1-(4-Chloropheny!)-5-(2,4-dichlorophenyl)-N-(1-ethynylcyclohexyl)-1 H-1 ,2,4- triazo!e-3-carboxamide. MS (ESO 473.3. 21. 1-(4-Ch!orophenyl)-5-(2,4-dichlorophenyl)-N-(2-methylcycIohexyl)-1 H-1 ,2,4- triazo!e-3-carboxamide. MS (ESI+) 465.5.
22. 1 -(4-Chloropheny!)-5-(2,4-dichlorophenyl)-N-(4-methylcyclohexyl)-1 H-1 ,2,4- triazo!e-3-carboxamide. MS (ESI+) 465.5.
23. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-cyclooctyl-1H-1,2,4-triazole-3- carboxamide. MS (ESI+) 477.3.
24. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(azepan-1-yI)-1 H-1,2,4-triazole- 3-carboxamide. MS (ESI+) 466.4.
25. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-cyclohepty!-1 H-1 ,2,4-triazole-3- carboxamide. MS (ESI+) 465.5. 26. N-t-Butyl-1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1 ,2,4-triazole-3- carboxamide. MS (ESI+) 425.4.
27. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(1 ,1-diethylprop-2-yn-1-yI)-1H- 1 ,2,4-triazole-3-carboxamide. MS (ESI+) 461.5.
28. 1 -(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(2,2,2-trifluoroethyl)-1 H-1 ,2,4- triazole-3-carboxamide. MS (ESI+) 451.3.
29. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(exo-bicyclo[2.2.1]hept-2-yl)-1H- 1 ,2,4-triazole-3-carboxamide. MS (ESI+) 461.5.
30. 1 -(4-Ch!orophenyl)-5-(2,4-dichlorophenyl)-N-(4-(2-propyl)piperazin-1 -yl)-1 H- 1 ,2,4-triazole-3-carboxamide. MS (ESI*) 480.3. 1H-NMR (400 MHz, DMSO- d6): 1.00 (d, J = 7 Hz, 6H), 2.46-2.56 (m, 4H), 2.72 (septet, J = 7 Hz, 1H),
3.66-3.74 (m, 4H), 7.36 (br d, J = 8 Hz, 2H), 7.51 (br d, J = 8 Hz, 2H), 7.59 (dd, J = 8 and 2 Hz, 1H), 7.72 (d, J = 2 Hz, 1H), 7.75 (d, J = 8 Hz, 1H). 31. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(hexahydrocyclopenta[c]pyrrol-
2(1H)-yl)-1 H-1,2,4-triazole-3-carboxamide. MS (ESi+) 476.4.
32. 1 -(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-pentyI-1 H-1 ,2,4-triazole-3- carboxamide. MS (ESI+) 435.5.
33. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(2,2-dimethylpropyI)-1H-1,2,4- triazole-3-carboxamide. MS (ESP) 439.6.
34. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(3-(trifluoromethy!)phenyl)-1H-
1,2,4-triazole-3-carboxamide. MS (EST) 511.7.
35. 1 '-[1 -(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-1 H-1 ,2,4-triazol-3-yl)carbonyl]-
1,4'-bipiperidine. MS (ESI+) 520.5.
36. 1-(4-Chlorophenyl)-N-(4-chlorophenyl)-5-(2,5-dichlorophenyl)-N-methyl-1H-
1,2,4-triazole-3-carboxamide. MS (ESI+) 491.4.
37. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-(1-ethynylcyclohexyl)- H-1 ,2,4- triazole-3-carboxamide. MS (ESP) 473.4.
38. 1 -(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-(2-methylcyclohexyl)-1 H-1 ,2,4- triazole-3-carboxamide. MS (ESI+) 465.5.
39. 1 -(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-(4-methylcyclohexyl)-1 H-1 ,2,4- triazole-3-carboxamide. MS (ESI+) 465.6.
40. 1 -(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-cyclooctyl-1 H- ,2,4-triazole-3- carboxa ide. MS (ESI4-) 477.3.
41. 1 -(4-Chlorophenyl)-5-(2,5-dichloropheny!)-N-cydoheptyl-1 H-1 ,2,4-triazoIe-3- carboxamide. MS (ESI+) 465.6.
42. 1 -(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-cycIopentyl-1 H-1 ,2,4-triazole-3- carboxamide. MS (ESf) 435.5.
43. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-(2,2-dimethylpropyl)-1H-1,2,4- triazole-3-carboxamide. MS (ESI+) 439.6.
Pharmacological test results of a subset of the compounds of the invention, obtained with the assays described above, are given in the table below:
Figure imgf000011_0001

Claims

Claims
1. A method of treating disorders involving CB-i cannabinoid neurotransmission such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebra! trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovascular disorders, characterized in that for the preparation of a pharmaceutical composition for the treatment of said disorders a compound of formula (I) is used
Figure imgf000012_0001
wherein
- R and Ri independently represent a phenyl, naphtyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl group, which groups may be substituted with 1-4 substituents X, which can be the same or different, from the group branched or unbranched (C1-3)-a!kyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C1-2)-amino, mono- or dialkyl (C1-2)-amido,
(C1-3)-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, (d.3)-alkylsul-fonyl, carboxyl, cyano, carbamoyl, (Cι.3)-dialkylaminosulfσnyl, (CM)- monoalkylamino-sulfonyl and acetyl, - R2 represents a hydrogen atom or a branched or unbranched C1-8 alkyl or C1β cycloalkyl-alkyl group or a phenyl, benzyl or phenethyl group which aromatic rings may be substituted with 1-4 substituents X, wherein X hasthe meaning as indicated above, or R2 represents a pyridyl or thienyl group,
- R3 represents branched or unbranched C1-8 alkyl, Cι.8alkoxy,C3.8 cyclo- alkyl, C5.10 bicycloalkyl, Cβ.ι0 tricycloalkyl, C^s alkenyl, C5.8 cycloalkenyl, which groups may optionally contain one or more heteroatoms from the group (O, N, S), which groups may be substituted with a hydroxy group, an ethynyl group or 1-3 fluoro atoms, or R3 represents a phenyl, benzyl or phenethyl group which aromatic rings may be substituted with 1 -4 substituents X, wherein X has the meaning as indicated above, or R3 represents a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or thienyl group which heteroaromatic rings may be substituted with 1-2 substituents X, wherein X has the meaning as indicated above, or R3 represents a group NR1R5 wherein R4 and R5, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic group contains one or two heteroatoms from the group N, O or S, which heteroatoms can be the same or different, which heterocyclic moiety may be substituted with a branched or unbranched C1-3 alkyl, hydroxy or trifluoromethyl group or a fluoro atom, or R2 and R3, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic group contains one or two heteroatoms from the group N, O or S, which heteroatoms can be the same or different, which heterocyclic moiety may be substituted with a branched or unbranched C1.3 alkyl, hydroxy, piperidinyl or trifluoromethyl group or a fluoro atom,
■ and prodrugs, stereoisomers and salts thereof.
2. Compounds of the general formula (I)
Figure imgf000013_0001
wherein
- R and R, have the meanings as given in claim 1 , - R2 represents a hydrogen atom or a branched or unbranched Ci-8 alkyl group
- R3 represents branched or unbranched C2^ alkoxy, C3.8 cycloalkyl, C^o bicycloalkyl, C6-ιo tricycloalkyl, C^a alkenyl, C5.8 cycloalkenyl, which groups may optionally contain one or more heteroatoms from the group (O, N, S), which groups may optionally be substituted with a hydroxy group or 1-3 fluoro atoms, or R3 represents a C3.8 trifluoroalkyl or C2-a fluoroalkyl group, or R3 represents a benzyl or phenethyl group which aromatic rings may be substituted with 1-4 substituents X, wherein X has the meaning as given in claim 1, or R3 represents a 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or thienyl group which heteroaromatic rings may be substituted with 1-2 substituents X, wherein X has the meaning as given in claim 1 , or R3 represents a group NR^R5 wherein R4 and R5 together with the nitrogen atom to which they are bonded form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic group contains one or two heteroatoms from the group N, O or S, which heteroatoms can be the same or different, which heterocyclic moiety may be substituted with a branched or unbranched C1-3 alkyl, hydroxy or trifluoromethyl group or a fluoro atom, or
R2 and R3, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated, monocycic or bicyclic, heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic group contains one or two heteroatoms from the group N, O or S, which heteroatoms can be the same or different, which heterocyclic moiety may be substituted with a branched or unbranched C1-3 alkyl, hydroxy, piperidinyl or trifluoromethyl group or a fluoro atom, with the proviso that this heterocyclic moiety is not an unsubstituted piperidinyl or unsubstituted morpholinyl group or 2,2,6, 6-tetraalkylpiperidinyl group, and prodrugs, stereoisomers and salts thereof.
3. Compounds of the general formula (I)
Figure imgf000014_0001
wherein
- R and R, independently represent a phenyl, naphtyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl group, which groups are substituted with 1-4 substituents X, wherein X has the meaning as given in claim 1,
- R2 and R3 have the meanings as given in claim 2, and prodrugs, stereoisomers and salts thereof.
4. Compounds of the general formula (I)
Figure imgf000015_0001
wherein
R and R, independently represent a phenyl group which phenyl groups are substituted with 1-4 substituents which can be the same or different, from the group methyl, methoxy, halogen, trifluoromethyl or cyano or R and R-, independently represent a phenyl, thienyl or pyridyl group, which phenyl group is substituted with 1-4 substituents, which can be the same or different, from the group methyl, methoxy, halogen, trifluoromethyl or cyano,
- R2 has the meaning as given in claim 2,
- R3 represents a group NR4R5 wherein
R4 and R5 together with the nitrogen atom to which they are bonded form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic group contains one or two heteroatoms from the group N, O or S, which heteroatoms can be the same or different, which heterocyclic moiety may be substituted with a branched or unbranched C1-3 alkyl, hydroxy or trifluoromethyl group or a fluoro atom, and prodrugs, stereoisomers and salts thereof.
5. Pharmaceutical compositions containing a pharmacologically active amount of at least one compound of one of the claims 1-4 as an active ingredient.
6. Use of a compound of one of the claims 1-4 for the preparation of a pharmaceutical composition for the treatment of disorders involving cannabinoid neurotransmission.
7. Use as in claim 6 characterised in that said disorders are: psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington'ε disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, septic shock, glaucoma, diabetes, cancer, emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovascular disorders.
PCT/EP2003/050628 2002-09-19 2003-09-17 1h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1 receptor ligands WO2004026301A1 (en)

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AU2003299024A AU2003299024B2 (en) 2002-09-19 2003-09-17 1H-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-CB1 receptor ligands
DE60331444T DE60331444D1 (en) 2002-09-19 2003-09-17 1H-1,2,4-TRIAZOL-3-CARBOXAMIDE DERIVATIVES AS CANNABINOID-CB1 RECEPTOR LIGANDS
MXPA05002862A MXPA05002862A (en) 2002-09-19 2003-09-17 1h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1.
SI200331803T SI1542678T1 (en) 2002-09-19 2003-09-17 1H-1,2,4-TRIAZOLE-3-CARBOXAMIDE DERIVATIVES AS CANNABINOID-CB sb 1 /sb RECEPTOR LIGANDS
DK03797318.7T DK1542678T3 (en) 2002-09-19 2003-09-17 1H-1,2,4-triazole-3-carboxamide derivatives as cannabinoid CB sb 1- / sb receptor ligands
CA2491394A CA2491394C (en) 2002-09-19 2003-09-17 1h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1 receptor ligands
JP2004537155A JP2006501275A (en) 2002-09-19 2003-09-17 1H-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-CB1 receptor ligands
UAA200503704A UA80298C2 (en) 2002-09-19 2003-09-17 1h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1 receptor ligands
EP03797318A EP1542678B1 (en) 2002-09-19 2003-09-17 1H-1,2,4-TRIAZOLE-3-CARBOXAMIDE DERIVATIVES AS CANNABINOID-CB sb 1 /sb RECEPTOR LIGANDS
AT03797318T ATE458479T1 (en) 2002-09-19 2003-09-17 1H-1,2,4-TRIAZOLE-3-CARBOXAMIDE DERIVATIVES AS CANNABINOID-CB1 RECEPTOR LIGANDS
BR0312020-1A BR0312020A (en) 2002-09-19 2003-09-17 Method of treating disorders, compounds, pharmaceutical compositions, and use of a compound
IL165611A IL165611A (en) 2002-09-19 2004-12-07 1h - 1,2,4 - triazole - 3 - carboxamide derivatives and pharmaceutical composotions comprising them
HR20050053A HRP20050053A2 (en) 2002-09-19 2005-01-19 1 h-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1 receptor ligands
NO20051870A NO20051870L (en) 2002-09-19 2005-04-18 1H-1,2,4-triazole-3-carboxamide derivatives as cannabinoid CB1 receptor ligands
HK05110963A HK1078796A1 (en) 2002-09-19 2005-12-01 1H-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-cb1- receptor ligands

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