Carbazole derivatives for the treatment of NPY related diseases

Description

FIELD OF THE INVENTION

[0002] The invention relates to novel carbazole derivatives and their use for the preparation of pharmaceutical compositions for the treatment of eating and metabolic disorders such as obesity, bulimia nervosa, anorexia nervosa, of sleep disturbance, of morphine withdrawal and of epileptic seizures.

BACKGROUND OF THE INVENTION

[0003] Neuropeptide Y (NPY) is a 36 amino acid peptide discovered by Tatemoto in 1982 (Tatemoto, K. et al., Neuropeptide Y: complete amino acid sequence of the brain peptide. Proc. Natl. Acad. Sci. U.S.A. (1982), 79(18), 5485-9). Since its discovery, NPY has been found in the brain in concentrations higher than any other putative neurotransmitter. Hypothalamic regions are particularly rich in NPY-containing neurons, with the paraventricular nucleus containing perhaps the highest concentration of NPY in the brain.

[0004] Evidence suggests the existence of several NPY receptor subtypes among which hY1 (Larhammar et al., Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. J. Biol. Chem., 1992, 267(16), 10935-8.), hY2 (WO 95/21245), hY4 (WO 95/17906), hY5 (Gerald et al., Cloning and expression of a novel neuropeptide Y receptor. J. Biol. Chem. 271, 16435, 1996.; WO97/46250) and hY6 have been cloned (hY6: Weinberg et al., Cloning and expression of a novel neuropeptide Y receptor. J. Biol. Chem., 1996), 271(28), 16435-8). However, the Y6 receptor appears to be nonfunctional in humans. The NPY receptor subclassification is based mainly on the activity/affinity profile of NPY/PYY/PP and certain selective analogs/fragments (Michel M. C., et al., XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol. Rev. March 1998; 50(1):143-50).

[0005] NPY is the most potent stimulant of food intake. Chronic i.c.v. administration of NPY in rats results in a robust increase in food intake associated with an increase in body weight and body fat content (White, Neuropeptide Y: a central regulator of energy homeostasis. Regul. Pept. 1993, 49(2), 93-107). Because NPY does not only increase food intake but also reduces energy expenditure it has been hypothesized that NPY could be an important brain peptide regulating energy balance. Moreover, food deprivation in rats is associated with an increase in NPY concentrations in the hypothalamus (Frankish et al., Neuropeptide Y, the hypothalamus, and diabetes: Insights into the central control of metabolism. Peptides, 16, 4, 757-771, 1995). This fluctuation of NPY levels in the brain with different feeding states supports a physiological role for NPY in feeding. Antisera against NPY (Dube M. G. et al., Evidence that neuropeptide Y is a physiological signal for normal food intake. Brain Res. (1994), 646(2), 341-4) as well as peptide (Myers et al, Anorexic action of a new potential neuropeptide Y antagonist [D-Tyr27,36,D-Thr32]-NPY (27-36) infused into the hypothalamus of the rat. Brain Res. Bull. 1995, 37(3), 237-45) and nonpeptide antagonists attenuate the hyperphagia seen after food deprivation. In addition, hypothalamic concentrations of NPY as well as NPY mRNA, are increased in genetically obese animals, such as the fatty Zucker rat or the ob/ob mouse (Frankish et al., Neuropeptide Y, the hypothalamus, and diabetes: Insights into the central control of metabolism. Peptides, 16, 4, 757 -771, 1995).

[0006] Accordingly, NPY antagonists seem to be promising candidates for the treatment of obesity. The characterization of the NPY receptor subtype responsible for food intake in rats is mainly based on functional experiments. The agonist receptor binding profile suggests that the Y5 receptor is involved in the NPY induced feeding behavior. Thus Y5 antagonists inhibit NPY mediated feeding as well as food intake in 24 hours food deprived rats (Criscione, L. et al., Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor. J. Clin. Invest.1998, 102(12), 2136-2145; Kask et al. Neuropeptide Y Y5 receptor antagonist CGP71683A: the effects on food intake and anxiety-related behavior in the rat. Eur. J. Pharmacol., 2001, 414(2/3), 215-224) supporting the notion that the Y5 receptor is the “feeding” receptor. In addition, Hwa J. J. et al. (Activation of the NPY Y5 receptor regulates both feeding and energy expenditure. Am J Physiol 277(5 Pt 2), R1428-R1434, 1999) demonstrated a reduced oxygen consumption and energy expenditure in rats upon administration of a Y5 agonist, thereby further substantiating the role of the Y5 receptor in energy homeostasis. However, Y1 selective antagonists such as BIBO3304 and 1229U91 inhibit the NPY induced feeding in rodents and in primates (rhesus monkey experiments using 1229U91) too.

[0007] Other fields for the use of NPY Y5 receptor ligands have been demonstrated for the treatment of morphine withdrawal (Woldbye D. P. et al., Neuropeptide Y attenuates naloxone-precipitated morphine withdrawal via Y5-like receptors. J Pharmacol Exp Ther 284(2), 633-636, 1998), based on the attenuation of these effect upon i.c.v. administration of Y5 selective agonists, and for seizures, based on the reduced exhibition of spontaneous seizures in Y5 knock out mice (Marsh D. J. et al., Role of the Y5 neuropeptide Y receptor in limbic seizures. Proc Natl Acad Sci USA 96(23), 13518-13523, 1999) as well as administration of Y5 selective agonists (Woldbye D. P. et al., Powerful inhibition of kainic acid seizures by neuropeptide Y via Y5-like receptors. Nature Medicine, 1997, 3(7), 761-4) in seizure models. Influence of the Y5 receptors in the hypothalamic suprachiasmatic nucleus on the circadian rhythm have been reported by Gribkoff V. K. et al (Phase shifting of circadian rhythms and depression of neuronal activity in the rat suprachiasmatic nucleus by neuropeptide Y: mediation by different receptor subtypes. J. Neurosci. 18(8), 3014-3022, 1998).

SUMMARY OF THE INVENTION

[0008] This invention is directed to novel carbazole compounds which bind selectively to and modulate, i.e. inhibit or stimulate, the activity of the human Y5 receptor. The invention relates to new compounds as listed in Table 1, or a salt thereof, to pharmaceutical compositions containing them, and to the manufacture of new compounds as listed in Table 1 and salts thereof. The invention furthermore relates to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5, such as eating and metabolic disorders, of sleep disturbance, of morphine withdrawal and of epileptic seizures and to the use of the compounds according to the invention for the preparation of a pharmaceutical composition for treating said disorders and diseases.

DETAILED DESCRIPTION OF THE INVENTION

[0009] It has now been found that the new compounds as listed in Table 1 and the diastereomers, enantiomers, mixtures and salts thereof, and in particular the physiologically acceptable salts thereof, are useful for the treatment of eating and metabolic disorders such as obesity, bulimia nervosa, anorexia nervosa, of sleep disturbance, of morphine withdrawal symptoms and of epileptic seizures.

1TABLE 1New compounds useful for the treatment of NPY related diseasesNo.Chemical nameChemical formula26-1N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2- oxo-2,3-dihydro-benzoimidazol-1-yl)- piperidin-1-yl]-acetamide

26-2N-(9-Ethyl-9H-carbazol-3-yl)-succinamic acid

26-3Tetrahydro-furan-3-carboxylic acid (9- ethyl-9H-carbazol-3-yl)-amide

26-4N-(9-Ethyl-9H-carbazol-3-yl)-2-(2- methoxy-ethoxy)-acetamide

26-5N-(9-Ethyl-9H-carbazol-3-yl)-isonicotin- amide

26-6N-(9-Ethyl-9H-carbazol-3-yl)- nicotinamide

26-7Pyridine-2-carboxylic acid (9-ethyl-9H- carbazol-3-yl)-amide

26-8N-(9-Ethyl-9H-carbazol-3-yl)-2-phenyl- acetamide

26-9N-(9-Ethyl-9H-carbazol-3-yl)-4-fluoro- benzamide

26-104-Chloro-N-(9-ethyl-9H-carbazol-3-yl)- benzamide

26-124-Dimethylamino-N-(9-ethyl-9H- carbazol-3-yl)-benzamide

26-13N-(9-Ethyl-9H-carbazol-3-yl)-4-nitro- benzamide

26-143-Chloro-N-(9-ethyl-9H-carbazol-3-yl)- benzamide

26-15(E)-N-(9-Ethyl-9H-carbazol-3-yl)-3- phenyl-acrylamide

26-16N-(9-Ethyl-9H-carbazol-3-yl)-2,2- dimethyl-propionamide

26-17N-(9-Ethyl-9H-carbazol-3-yl)-4-oxo-4- phenyl-butyramide

26-194-Methyl-[1,2,3]thiadiazole-5-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide

26-205-tert-Butyl-2-methyl-2H-pyrazole-3- carboxylic acid (9-ethyl-9H-carbazol-3- yl)-amide

26-211-Methyl-1H-pyrrole-2-carboxylic acid (9-ethyl-9H-carbazol-3-yl)-amide

26-22Isoxazole-5-carboxylicacid (9-ethyl-9H- carbazol-3-yl)-amide

26-241H-Indole-2-carboxylic acid (9-ethyl-9H- carbazol-3-yl)-amide

26-25N-(9-Ethyl-9H-carbazol-3-yl)-2-phenoxy- acetamide

27-11-(9-Ethyl-9H-carbazol-3-yl)-3-isopropyl- urea

27-21-tert-Butyl-3-(9-ethyl-9H-carbazol-3-yl)- urea

27-31-(9-Ethyl-9H-carbazol-3-yl)-3-(2- hydroxy-ethyl)-urea

28-19-Ethyl-9H-carbazole-3-carboxylic acid phenylamide

28-29-Ethyl-9H-carbazole-3-carboxylic acid isopropylamide

28-39-Ethyl-9H-carbazole-3-carboxylic acid tert-butylamide

28-49-Ethyl-9H-carbazole-3-carboxylic acid diethylamide

28-59-Ethyl-9H-carbazole-3-carboxylic acid cyclopropylamide

28-69-Ethyl-9H-carbazole-3-carboxylic acid (3-imidazol-1-yl-propyl)-amide

29-1N-(9-Methyl-9H-carbazol-3-yl)- benzamide

29-22-Dimethylamino-N-(9-methyl-9H- carbazol-3-yl)-acetamide

29-32-Methoxy-N-(9-methyl-9H-carbazol-3- yl)-acetamide

29-4N-(9-Methyl-9H-carbazol-3-yl)- succinamic acid

29-5N-(9-Methyl-9H-carbazol-3-yl)-2-phenyl- acetamide

29-6N-(9-Methyl-9H-carbazol-3-yl)- |isobutyramide|

29-72,2-Dimethyl-N-(9-methyl-9H-carbazol- 3-yl)-propionamide

29-8Cyclohexanecarboxylic acid (9-methyl- 9H-carbazol-3-yl)-amide

29-9Cyclopropanecarboxylic acid (9-methyl- 9H-carbazol-3-yl)-amide

29-10N-(9-Methyl-9H-carbazol-3-yl)- isonicotinamide

30-1N-(9-Benzyl-9H-carbazol-3-yl)- benzamide

30-2N-(9-Benzyl-9H-carbazol-3-yl)-2- dimethylamino-acetamide

30-3N-(9-Benzyl-9H-carbazol-3-yl)-2- methoxy-acetamide

30-4N-(9-Benzyl-9H-carbazol-3-yl)- succinamic acid

30-5N-(9-Benzyl-9H-carbazol-3-yl)-2-phenyl- acetamide

30-6N-(9-Benzyl-9H-carbazol-3-yl)-isobutyr- amide

30-7N-(9-Benzyl-9H-carbazol-3-yl)-acetamide

30-8Cyclohexanecarboxylic acid (9-benzyl- 9H-carbazol-3-yl)-amide

30-9Cyclopropanecarboxylic acid (9-benzyl- 9H-carbazol-3-yl)-amide

30-10N-(9-Benzyl-9H-carbazol-3-yl)- isonicotinamide

31-1N-(9H-Carbazol-3-yl)-2-dimethylamino- acetamide

31-2N-(9H-Carbazol-3-yl)-2-methoxy- acetamide

31-3N-(9H-Carbazol-3-yl)-succinamic acid

31-4N-(9H-Carbazol-3-yl)-2-phenyl- acetamide

31-5N-(9H-Carbazol-3-yl)-isobutyramide

31-6Cyclohexanecarboxylic acid (9H- carbazol-3-yl)-amide

31-7Cyclopropanecarboxylic acid (9H- carbazol-3-yl)-amide

31-8N-(9H-Carbazol-3-yl)-isonicotinamide

[0010] The present invention relates to the new compounds mentioned above, the diastereomers, enantiomers, mixtures and salts thereof, particularly to the pharmaceutically acceptable salts thereof, to their use for the treatment of eating and metabolic disorders such as obesity, bulimia nervosa, anorexia nervosa, of sleep disturbance, of morphine withdrawal symptoms and of epileptic seizures, to their use for the preparation of apharmaceutical composition for treating said disorders and diseases, pharmaceutical compositions containing them and processes for preparing them.

[0011] Preferred compounds are:

[0012] (a) tetrahydro-furan-3-carboxylic acid(9-ethyl-9H-carbazol-3-yl)-amide

[0013] (b) N-(9-ethyl-9H-carbazol-3-yl)-2-(2-methoxy-ethoxy)-acetamide

[0014] (c) N-(9-ethyl-9H-carbazol-3-yl)-nicotinamide

[0015] (d) N-(9-ethyl-9H-carbazol-3-yl)-2-phenyl-acetamide

[0016] (e) N-(9-ethyl-9H-carbazol-3-yl)-2,2-dimethyl-propionamide

[0017] (f) N-(9-ethyl-9H-carbazol-3-yl)-4-oxo4-phenyl-butyramide

[0018] (g) 2-chloro-N-(9-ethyl-9H-carbazol-3-yl)-benzamide

[0019] (h) 1-(9-ethyl-9H-carbazol-3-yl)-3-isopropyl-urea

[0020] (i) 1-(9-ethyl-9H-carbazol-3-yl)-3-(2-hydroxy-ethyl)-urea

[0021] (j) N-(9-methyl-9H-carbazol-3-yl)-isobutyramide

[0022] (k) 2,2-dimethyl-N-(9-methyl-9H-carbazol-3-yl)-propionamide

[0023] (l) cyclopropanecarboxylic acid(9-methyl-9H-carbazol-3-yl)-amide

[0024] and the diastereomers, enantiomers, mixtures and salts thereof, particularly to the pharmaceutically acceptable salts thereof.

[0025] The compounds according to the invention, if they contain a basic group, may be converted into their salts, particularly, for pharmaceutical use, into their physiologically acceptable salts, with inorganic or organic acids. Suitable acids for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

[0026] Furthermore, the compounds according to the invention, if they contain a carboxy group, may, if desired, be converted subsequently into their salts with inorganic or organic bases, particularly, for pharmaceutical use, into their physiologically acceptable salts. Examples for suitable bases include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

[0027] As already mentioned hereinbefore, the new compounds as listed in Table 1 and the salts thereof have valuable pharmacological properties and are useful for the treatment of eating and metabolic disorders such as obesity, bulimia nervosa, anorexia nervosa, of morphine withdrawal symptoms, of epileptic seizures or of sleep disturbance, particularly for the treatment of obesity.

[0028] In the Synthetic Section, the Following Abbreviations are Used:

[0029] Ac acetyl

[0030] aq. aqueous

[0031] DMSO dimethylsulfoxide

[0032] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimid

[0033] Hünig's base ethyl-diisopropyl-amine

[0034] min. minutes

[0035] org. organic

[0036] PyCloP chlorotripyrrolidinophosphonium hexafluorophosphate

[0037] sat. saturated

[0038] CAN ceric ammonium nitrate

[0039] SiO2 silica

[0040] Synthetic Methods

[0041] The syntheses of the key building blocks 18 and 22 to 24 are described in Scheme 1. Carbazol 25 was commercially available from Aldrich.

[0042] Procedure for the Synthesis of Acid 18:

[0043] To a stirred solution of 5.0 g Na2CO3 and 15.0 g KMnO4 in water (250 ml) was added 5.0 g (22.4 mmol) 9-ethyl-3-carbazole carboxaldehyde. The reaction mixture was refluxed for 5 h, then allowed to cool to room temperature and treated with 10% aq. NaH2PO4— solution until pH 6 was reached. The reaction mixture was extracted with EtOAc, the org. layer washed with sat. Brine, dried (MgSO4), evaporated and the residue dried under reduced pressure to yield 3.6 g of crude product, which after re-crystallization from EtOAc gave 1.49 g (27.8%) of acid 18.

[0044] 1H-NMR (300 MHz, DMSO-d6): 12.60 (br. S, 1H); 8.80 (m, 1H); 8.26 (dd, J=0.5, 7.2, 1H); 8.05 (dd, J=1.7, 8.7, 1H); 7.67-7.63 (m, 2H); 7.49 (dt, J=1.1, 7.1, 1H); 4.47 (q, J=7.1, 2H); 1.31 (t, J=7.1, 3H).

[0045] General Procedures for the Synthesis of Carbazoles 22 to 24:

[0046] Alkylation:

[0047] Was performed according to J Chem. Soc. Perkin Trans I, 1973, 499-500.

[0048] Nitration:

[0049] Was performed according to Synthetic Commun. 1994, 24, 1-10.

[0050] Reduction of the Nitro Group:

[0051] A mixture of 32% aq. HCI-solution (24 ml) and EtOH (24 ml) was added dropwise to a mixture of the corresponding 3-nitro-carbazole (11.3 mmol) and iron powder (6.31 g, 113 mmol) in EtOH (48 ml). The reaction mixture was stirred for 90 min. at 80° C., cooled and poured onto a mixture of 2N NaOH-solution (350 ml) and ice. The mixture was extracted with EtOAc, the org. layer washed with 2N aq. NaOH-solution and sat. Brine, dried (Na2SO4) and evaporated. The crude residue was suspended in Et2O, filtered and dried under reduced pressure.

[0052] Yields: 22 (93.7%); 23 (83%); 24 (67.1%). 22: 1H-NMR (300MHz, DMSO-d6): 9.91 (m, 1H); 7.44-7.25 (m, 4H); 7.05 (ddd, J=1.1, 6.9, 7.9, 1H); 6.81 (dd, J=2.0, 8.6, 1H); 4.71 (s, 2H); 3.74 (s, 3H). 23: 1H-NMR (300 MHz, DMSO-d6): 7.95 (br. D, J=7.7, 1H); 7.47 (d, J=8.2, 1H), 7.33-7.04 (m, 9H); 6.77 (m (dd), 1H); 5.51 (s, 2H); 4.73 (s, 2H). 24: 1H-NMR (300 MHz, DMSO-d6): 10.67 (br. S, 1H); 7.87 (m, 1H); 7.35-7.14 (m, 4H); 7.00 (ddd, J=1.1, 6.8, 8.8, 1H); 6.74 (dd, J=2.2, 8.4, 1H); 4.65 (br. S, 2H).

[0053] General Procedure for the Preparation of 26 and 29, 30 and 31:

[0054] From Acid Chlorides:

[0055] To a solution of 3-amino carbazoles 22 to 25 (0.25 mmol) in CH2Cl2 (1 ml) was added pyridine (1.25 mmol) and N,N-dimethylaminopyridine (0.05 mmol) and the corresponding acid chloride (0.3 mmol). The reaction mixture was stirred for 2-24 h at room temperature, evaporated to dryness and the residue was chromatographed on SiO2 using hexane/EtOAc.

[0056] From Carboxylic Acids:

[0057] To a solution of 3-amino carbazoles 22 to 25 (0.25 mmol) in CH2Cl2 (1 ml) was added the corresponding carboxylic acid (0.38 mmol) and EDCI (0.38 mmol) at room temperature. The reaction mixture was stirred for 24 h at room temperature and extracted with NaHCO3-solution and EtOAc. The org. layer was dried (MgSO4), evaporated and the residue chromatographed on SiO2 as described above.

[0058] General Procedure for the Preparation of 27:

[0059] To 0.3 mmol of the corresponding amine or aniline in CH3CN were added 0.11 mmol triphosgene and 0.9 mmol Hünig's base at 4° C. to give a clear solution, which was stirred at room temperature (30 min.) and for 2 h at 75° C. The reaction mixture was cooled to room temperature followed by addition of 25 (0.25 mmol). The reaction mixture was heated for 3 h at 75° C., evaporated to dryness and the residue was chromatographed on SiO2 with hexane/EtOAc.

[0060] General Procedure for the Preparation of 28:

[0061] To a mixture of acid 18 (0.25 mmol) and the corresponding aniline or amine (0.28 mmol) in CH2Cl2 (1 ml) was added chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP) (0.28 mmol) and Hünig's base (1.05 mmol). The reaction mixture was stirred for 15 h at room temperature, extracted with water and EtOAc, the org. layer was dried (MgSO4), evaporated and the residue chromatographed on SiO2 with hexane/EtOAc.

2TABLE 2aExamples for compounds of general formula 26:No.Chemical nameChemical formulaExample 26-10N-(9-Ethyl-9H-carbazol-3-yl)-2- [4-(2-oxo-2,3-dihydro- benzoimidazol-1-yl)-piperidin-1- yl]-acetamide

Example 26-2N-(9-Ethyl-9H-carbazol-3-yl)- succinamic acid

Example 26-3Tetrahydro-furan-3-carboxylic acid (9-ethyl-9H-carbazol-3-yl)- amide

Example 26-4N-(9-Ethyl-9H-carbazol-3-yl)-2- (2-methoxy-ethoxy)-acetamide

Example 26-5N-(9-Ethyl-9H-carbazol-3-yl)- isonicotinamide

Example 26-6N-(9-Ethyl-9H-carbazol-3-yl)- nicotinamide

Example 26-7Pyridine-2-carboxylic acid (9- ethyl-9H-carbazol-3-yl)-amide

Example 26-8N-(9-Ethyl-9H-carbazol-3-yl)-2- phenyl-acetamide

Example 26-9N-(9-Ethyl-9H-carbazol-3-yl)-4- fluoro-benzamide

Example 26-104-Chloro-N-(9-ethyl-9H- carbazol-3-yl)-benzamide

Example 26-11N-(9-Ethyl-9H-carbazol-3-yl)-4- methoxy-benzamide

Example 26-124-Dimethylamino-N-(9-ethyl- 9H-carbazol-3-yl)-benzamide

Example 26-13N-(9-Ethyl-9H-carbazol-3-yl)-4- nitro-benzamide

Example 26-143-Chloro-N-(9-ethyl-9H- carbazol-3-yl)-benzamide

Example 26-15(E)-N-(9-Ethyl-9H-carbazol-3- yl)-3-phenyl-acrylamide

Example 26-16N-(9-Ethyl-9H-carbazol-3-yl)- 2,2-dimethyl-propionamide

Example 26-17N-(9-Ethyl-9H-carbazol-3-yl)-4- oxo-4-phenyl-butyramide

Example 26-182-Chloro-N-(9-ethyl-9H- carbazol-3-yl)-benzamide

Example 26-194-Methyl-[1,2,3]thiadiazole-5- carboxylic acid (9-ethyl-9H- carbazol-3-yl)-amide

Example 26-205-tert-Butyl-2-methyl-2H- pyrazole-3-carboxylic acid (9- ethyl-9H-carbazol-3-yl)-amide

Example 26-211-Methyl-1H-pyrrole-2- carboxylic acid (9-ethyl-9H- carbazol-3-yl)-amide

Example 26-22Isoxazole-5-carboxylic acid (9- ethyl-9H-carbazol-3-yl)-amide

Example 26-23Thiophene-2-carboxylic acid (9- ethyl-9H-carbazol-3-yl)-amide

Example 26-241H-Indole-2-carboxylic acid (9- ethyl-9H-carbazol-3-yl)-amide

Example 26-25N-(9-Ethyl-9H-carbazol-3-yl)-2- phenoxy-acetamide

[0062]

3

TABLE 2b

Experimental data of the compounds listed in table 2a

1H NMR(300MHz)
Mass Spectrum

Solvent
signals
calculated
(M+H)+
(M−H)+

Example 26-1
—
467,5756
468.5
466.5

Example 26-2
DMSO-d6
1.28(t, 3H); 2.55(2t, 4H);
310,3558
311.6
309.2

4.39(q, 2H); 7.12(t, 1H); 7.41

(t, 1H); 7.52(m, 3H); 8.01(d,

1H); 8.40(s, 1H); 9.98(s,

1H); 12.3(s, 1H)

Example 26-3

308,3835
309.2
307.5

Example 26-4
DMSO-d6
1.28(t, 3H); 3.30(s, 3H); 3.45
326,3988
327.4
325.6

(q, 2H); 3.68(q, 2H); 4.09(s,

2H); 4.40(q, 2H); 7.16(t,

1H); 7.42(t, 1H); 7.68(m,

3H); 8.04(d, 1H); 8.40(d,

1H); 9.60(s, 1H)

Example 26-5
DMSO-d6
1.29(t, 3H); 4.42(q, 2H); 7.20
315,378
316.4
—

(t, 1H); 7.46(t, 1H); 7.62(t,

2H); 7.79(dd, 1H); 8.07(d,

1H); 8.30(m, 2H); 8.60(s,

1H); 8.97(m, 2H); 10.91(s,

1H)

Example 26-6
DMSO-d6
1.31(t, 3H); 4.43(q, 2H); 7.13
315,378
316.3
—

(t, 1H); 7.44(t, 1H); 7.58(m,

3H); 7.73(dd, 1H); 8.08(d,

1H); 8.30(dd, 1H); 8.52(s,

1H); 8.74(d, 1H); 9.16(s,

1H); 10.48(s, 1H)

Example 26-7
—
315,378
316.3
—

Example 26-8
—
328,4175
329.2
—

Example 26-9
DMSO-d6
1.30(t, 3H); 4.43(q, 2H); 7.17
332,3808
333.4
—

(t, 1H); 7.30-7.46(m, 3H);

7.58(d, 2H); 8.08(m, 3H);

8.31(s, 1H); 10.30(s, 1H)

Example 26-10
DMSO-d6
1.28(t, 3H); 4.41(q, 2H); 7.17
348,8354
349.2
—

(t, 1H); 7.23(t, 1H); 7.60(m,

3H); 7.73(d, 1H); 8.04(m,

3H); 8.51(s, 1H); 10.34(s,

1H)

Example 26-11
—
344,4169
345.2
343.4

Example 26-12
—
357,4593
358.4
—

Example 26-13
DMSO-d6
1.30(t, 3H); 4.44(q, 2H); 7.18
359,3879
360.5
—

(t, 1H); 7.44(t, 1H); 7.60(m,

2H); 7.75(dd, 1H); 8.08(d,

1H); 8.24(d, 2H); 8.37(d,

2H); 8.55(s, 1H); 10.61(s,

1H)

Example 26-14
—
348,8354
349.3
348.3

Example 26-15
—
340,4287
341.2
—

Example 26-16
DMSO-d6
1.2-1.3(t + s; 12H); 4.39(q,
294,4
295.2
—

2H); 7.15(t, 1H); 7.41(t, 1H);

7.5-7.6(m, 3H); 8.04(d, 1H);

8.32(d, 1H); 9.21(s, 1H)

Example 26-17
—
370,4551
371.5
369.5

Example 26-18
—
348,8354
349.2
—

Example 26-19
—
336,4184
337.6
335.7

Example 26-20
—
374,4899
375.2
373.2

Example 26-21
—
317,3939
318.2
—

Example 26-22
—
305,3392
306.4
304.2

Example 26-23
DMSO-d6
1.30(t, 3H); 4.42(q, 2H); 7.20
320,4162
321.1
—

(m, 2H); 7.45(t, 1H); 7.57(d,

2H); 7.71(dd, 1H); 7.83(d,

1H); 8.05(m, 2H); 1.45(s,

1H); 10.38(s, 1H)

Example 26-24
—
353,4274
354.3
352.5

Example 26-25
—
344,4169
345.2
—

[0063]

4

TABLE 3a

Examples for compounds of general formula 27

No.
Chemical name
Chemical formula

Example 27-1
1-(9-Ethyl-9H-carbazol-3-yl)-3-isopropyl-urea

Example 27-2
1-tert-Butyl-3-(9-ethyl-9H-carbazol-3-yl)-urea

Example 27-3
1-(9-Ethyl-9H-carbazol-3-yl)-3-(2-hydroxy-ethyl)-urea

[0064]

5

TABLE 3b

Experimental data of the compounds listed in table 3a

1H NMR(300MHz)
Mass Spectrum

solvent
signals
calculated
(M+H)+
(M−H)+

Example
—
295,3876
296.1
—

27-1

Example
—
309,4147
310.6
—

27-2

Example
DMSO-
1.26(t, 3H); 2.80(t,
297,3599
—
297.6

27-3
d6
1H); 3.16(q, 2H);

3.45(m, 2H);

4.36(q, 2H);

4.73(m, 1H);

6.13(t, 1H);

7.12(t, 1H);

7.30-7.54

(m, 5H); 8.01(d,

1H); 8.15(d, 1H);

8.47(s, 1H)

[0065]

6

TABLE 4a

Examples for compounds of general formula 28

No.
Chemical name
Chemical formula

Example 28-1
9-Ethyl-9H-carbazole-3-carboxylic acid phenylamide

Example 28-2
9-Ethyl-9H-carbazole-3-carboxylic acid isopropylamide

Example 28-3
9-Ethyl-9H-carbazole-3-carboxylic acid tert-butylamide

Example 28-4
9-Ethyl-9H-carbazole-3-carboxylic acid diethylamide

Example 28-5
9-Ethyl-9H-carbazole-3-carboxylic acid cyclopropylamide

Example 28-6
9-Ethyl-9H-carbazole-3-carboxylic acid (3-imidazol-1-yl-propyl)-amide

[0066]

7

TABLE 4b

Experimental data of the compounds listed in table 4a

1H NMR(300MHz)
Mass Spectrum

solvent
signals
calculated
(M+H)+
(M−H)+

Example 28-1
—
314,3904
315.5
313.3

Example 28-2
—
280,3729
218.5
—

Example 28-3
—
294,4
295.5
—

Example 28-4
CDCl3
1.23(t, 6H); 1.40(t, 3H);
294,4
295.4
—

3.49(m, 4H); 4.37(q,

2H); 7.20-7.60(m, 4H);

8.08(d, 1H); 8.16(s, 1H)

Example 28-5
—
278,357
279.7
—

Example 28-6
CDCl3
1.42(t, 3H); 2.20(p, 2H);
346,436
347.4
345.1

3.55(q, 2H); 4.13(t, 2H);

4.35(q, 2H)6.71(t, 1H);

7.07(d, 2H); 7.20-7.55

(m, 4H); 7.90(m, 2H); 8.15(d,

1H); 8.55(s, 1H)

[0067]

8

TABLE 5a

Examples for compounds of general formula 29

No.
Chemical name
Chemical formula

Example 29-1
N-(9-Methyl-9H-carbazol-3-yl)- benzamide

Example 29-2
2-Dimethylamino-N-(9-methyl-9H- carbazol-3-yl)-acetamide

Example 29-3
2-Methoxy-N-(9-methyl-9H-carbazol- 3-yl)-acetamide

Example 29-4
N-(9-Methyl-9H-carbazol-3-yl)- succinamic acid

Example 29-5
N-(9-Methyl-9H-carbazol-3-yl)-2- phenyl-acetamide

100

Example 29-6
N-(9-Methyl-9H-carbazol-3-yl)- isobutyramide

101

Example 29-7
2,2-Dimethyl-N-(9-methyl-9H- carbazol-3-yl)-propionamide

102

Example 29-8
Cyclohexanecarboxylic acid (9- methyl-9H-carbazol-3-yl)-amide

103

Example 29-9
Cyclopropanecarboxylic acid (9- methyl-9H-carbazol-3-yl)-amide

104

Example 29-10
N-(9-Methyl-9H-carbazol-3-yl)-iso- nicotinamide

105

[0068]

9

TABLE 5b

Experimental data of the compounds listed in table 5a

1H NMR(300MHz)
Mass Spectrum

solvent
signals
calculated
(M+H)+
(M−H)+

Example
—
300,3633
301.6
299.2

29-1

Example
—
281,3605
282.3
—

29-2

Example
—
268,3181
269.6
—

29-3

Example
—
296,3287
297.4
295.3

29-4

Example
—
314,3904
315.1
312.6

29-5

Example
—
266,3458
267.6
366.6

29-6

Example
—
280,3729
281.5

29-7

Example
—
306,4111
307.4
305.4

29-8

Example
CDCl3
0.78(m, 2H);
264,3299
265.5
—

29-9

1.06(q, 2H);

1.47(q, 1H); 3.73(s,

3H); 7.07-7.48(m,

5H); 7.96(d, 1H);

8.26(s, 1H)

Example
—
301,3509
302.6
300.0

29-10

[0069]

10

TABLE 6a

Examples for compounds of general formula 30

No.
Chemical name
Chemical formula

Example 30-1
N-(9-Benzyl-9H-carbazol-3-yl)- benzamide

106

Example 30-2
N-(9-Benzyl-9H-carbazol-3-yl)-2- dimethylamino-acetamide

107

Example 30-3
N-(9-Benzyl-9H-carbazol-3-yl)-2- methoxy-acetamide

108

Example 30-4
N-(9-Benzyl-9H-carbazol-3-yl)- succinamic acid

109

Example 30-5
N-(9-Benzyl-9H-carbazol-3-yl)-2- phenyl-acetamide

110

Example 30-6
N-(9-Benzyl-9H-carbazol-3-yl)- isobutyramide

111

Example 30-7
N-(9-Benzyl-9H-carbazol-3-yl)- acetamide

112

Example 30-8
Cyclohexanecarboxylic acid (9- benzyl-9H-carbazol-3-yl)-amide

113

Example 30-9
Cyclopropanecarboxylic acid (9- benzyl-9H-carbazol-3-yl)-amide

114

Example 30-10
N-(9-Benzyl-9H-carbazol-3-yl)- isonicotinamide

115

[0070]

11

TABLE 6b

Experimental data of the compounds listed in table 6a

1H NMR(300MHz)
Mass Spectrum

solvent
signals
calculated
(M+H)+
(M−H)+

Example 30-1
—
376,4621
377.4
375.2

Example 30-2
—
357,4593
358.3
—

Example 30-3
CDCl3
3.53(s, 3H); 4.09(s, 2H);
344,4169
345.3
343.4

5.51(s, 2H); 7.08-7.55(m, 10H);

8.11(d, 1H); 8.40(m, 2H)

Example 30-4
—
372,4275
373.0
371.2

Example 30-5
—
390,4892
391.8
388.8

Example 30-6
—
342,4446
343.3
—

Example 30-7
—
314,3904
315.0
—

Example 30-8
—
382,5099
383.3
382.0

Example 30-9
—
340,4287
341.2
—

Example 30-10
—
377,4497
378.3
376.1

[0071]

12

TABLE 7a

Examples for compounds of general formula 31

No.
Chemical name
Chemical formula

Example 31-1
N-(9H-Carbazol-3-yl)-2-dimethyl- amino-acetamide

116

Example 31-2
N-(9H-Carbazol-3-yl)-2-methoxy- acetamide

117

Example 31-3
N-(9H-Carbazol-3-yl)-succinamic acid

118

Example 31-4
N-(9H-Carbazol-3-yl)-2-phenyl- acetamide

119

Example 31-5
N-(9H-Carbazol-3-yl)-isobutyramide

120

Example 31-6
Cyclohexanecarboxylic acid (9H- carbazol-3-yl)-amide

121

Example 31-7
Cyclopropanecarboxylic acid (9H- carbazol-3-yl)-amide

122

Example 31-8
N-(9H-Carbazol-3-yl)-isonicotin- amide

123

[0072]

13

TABLE 7b

Experimental data of the compounds listed in table 7a

1H NMR(300MHz)
Mass Spectrum

solvent
signals
calculated
(M+H)+
(M−H)+

Example 31-1
DMSO-d6
2.28(s, 6H); 3.08(s,
267,3334
268.5
266.3

2H); 7.10(t, 1H); 7.30-7.46

(m, 3H); 7.56(dd,

1H); 8.00(d, 1H); 9.65

(s, 1H); 11.14(s, 1H)

Example 31-2
DMSO-d6
3.40(s, 3H); 4.00(s,
254,291
255.4
253.3

2H); 7.11(t, 1H); 7.30-7.50

(m, 3H); 7.56(dd,

1H); 8.00(d, 1H); 8.37

(s, 1H); 9.69(s, 1H);

11.16(s, 1H)

Example 31-3
—
282,3016
283.6
281.2

Example 31-4
—
300,3633
301.4
299.2

Example 31-5
—
252,3187
253.4
251.0

Example 31-6
—
292,3841
293.6
291.1

Example 31-7
—
250,3028
251.3
249.2

Example 31-8
—
287,3238
288.3
285.9

Claims

1. A compound selected from Table 1:
2. A compound according to claim 1 selected from the following compounds: (a) tetrahydro-furan-3-carboxylic acid(9-ethyl-9H-carbazol-3-yl)-amide; (b) N-(9-ethyl-9H-carbazol-3-yl)-2-(2-methoxy-ethoxy)-acetamide; (c) N-(9-ethyl-9H-carbazol-3-yl)-nicotinamide; (d) N-(9-ethyl-9H-carbazol-3-yl)-2-phenyl-acetamide; (e) N-(9-ethyl-9H-carbazol-3-yl)-2,2-dimethyl-propionamide; (f) N-(9-ethyl-9H-carbazol-3-yl)-4-oxo-4-phenyl-butyramide; (g) 2-chloro-N-(9-ethyl-9H-carbazol-3-yl)-benzamide; (h) 1-(9-ethyl-9H-carbazol-3-yl)-3-isopropyl-urea; (i) 1-(9-ethyl-9H-carbazol-3-yl)-3-(2-hydroxy-ethyl)-urea; (j) N-(9-methyl-9H-carbazol-3-yl)-isobutyramide; (k) 2,2-dimethyl-N-(9-methyl-9H-carbazol-3-yl)-propionamide; and (l) cyclopropanecarboxylic acid(9-methyl-9H-carbazol-3-yl)-amide; or a diastereomer, enantiomer, mixture or salt thereof.
3. A compound according to claim 1 in the form of a pharmaceutically acceptable salt.
4. A compound according to claim 2 in the form of a pharmaceutically acceptable salt.
5. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
7. A method for treating an eating or metabolic disorder which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
8. A method for treating an eating or metabolic disorder which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
9. A method according to claim 7, wherein the disorder is selected from obesity, bulimia nervosa and anorexia nervosa.
10. A method according to claim 8, wherein the disorder is selected from obesity, bulimia nervosa and anorexia nervosa.
11. A method for treating sleep disturbance, morphine withdrawal symptoms or epileptic seizures which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
12. A method for treating sleep disturbance, morphine withdrawal symptoms or epileptic seizures which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.

Priority Claims (1)

Number	Date	Country	Kind
101 25 961	May 2001	DE

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. Nonprovisional application Ser. No. 10/157,597, files May 29, 2002, which claims benefit of U.S. Provisional Application Serial No. 60/307,675, filed on Jul. 25, 2001, and said applications are herein incorporated by reference in their entirety.

Provisional Applications (1)

	Number	Date	Country
	60307675	Jul 2001	US

Continuations (1)

	Number	Date	Country
Parent	10157597	May 2002	US
Child	10753776	Jan 2004	US

Carbazole derivatives for the treatment of NPY related diseases

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

US Classifications

International Classifications