HK1068792B - 5-halo-tryptamine derivatives used as ligands of the 5-ht6 and/or 5-ht7 serotonin receptors - Google Patents

Description

As 5-HT6And/or 5-HT75-halo-tryptamine derivatives of ligands of 5-hydroxytryptamine receptors

The invention described herein relates to the use as 5-HT₆And/or 5-HT₇5-halotryptamine derivatives of ligands of the 5-hydroxytryptamine receptor; processes for their preparation; their use as medicaments, in particular for the treatment of neurological pathologies associated with an insufficient level of 5-hydroxytryptamine, systemic pathologies involving the cardiovascular system, the gastrointestinal tract; and drugs containing themThe composition is prepared by mixing the above raw materials.

Background

Over the past 10 years, molecular cloning has revealed 14 subtypes of 5-hydroxytryptamine, which have been divided into 7 subfamilies. The diversity of 5-hydroxytryptamine receptors has been proposed as a direct result of the era of evolution of the 5-HT system. Except for 5-HT as ligand-gated ion channels₃All receptors, except receptors, are members of the 5-hydroxytryptamine receptor superfamily, and belong to a large group of receptors linked to their effector functions via G-proteins. (Gerhardt, C.C. et al Brain Res.746: 207-.

In 1994, 5-HT was found in the caudate nucleus and cerebellum₆5-hydroxytryptamine receptor. Since then, 5-HT was observed in the molecular layers of the olfactory tubercle, frontal lobe and entorhinal cortex, nucleus accumbens, striatum, hippocampus and cerebellum₆5-hydroxytryptamine receptor. 5-HT₆The 5-hydroxytryptamine receptors appear to be almost exclusively present in the brain and 5-HT projections, but not in the 5-HT neurons of the nucleus suturalis, suggesting that 5-HT₆The receptor may have a postsynaptic effect. 5-HT was also found₆Receptors are members of the G-protein superfamily, and they are positively coupled to the adenylate cyclase second messenger system.

5-hydroxytryptamine with 5-HT₆Receptor binding induces activation of adenylate cyclase, while increasing intracellular cAMP levels. More recently for 5-HT₆The discovery of 5-hydroxytryptamine receptors has stimulated penetration into 5-HT₆The study of selective ligands, to indicate the uniqueness of this new receptor sub-family and its exact clinical significance itself. It is known in fact that many psychotropic drugs (antidepressants, anti-psychotropic drugs) appear to be active against 5-HT₆High affinity, but not selective (Monsma, F.J. et al, Molecular Pharmacology 43.320-327, 1993; Roth, B.L. et al, J.Pharmacol. Exp. Ther. (J.Pharmacol. J.Exp. Ther.) (J.Pharmacol. therapeutic treatment) 268, 1403-1410; 1994), while 5-HT₆The receptor may modulate the central nervous systemCholinergic neurotransmission in (1). Furthermore, 5-HT has been proposed to occur in GABA-containing neurons in the striatum and in glutamate-containing neurons of the hippocampus₆The receptor mediates endogenous 5-hydroxytryptamine effects. Thus, 5-HT₆Ligands for the receptor may be useful in the treatment of: dyskinesia, depression, anxiety, mood disorders, memory disorders, huntington's chorea, parkinson's disease and alzheimer's disease (brain, t.a. and Blackburn, t.p., annu. rev. pharm. toxicol.40: 319-34, 2000).

Identification of 5-HT in several rodent and human tissues₇5-hydroxytryptamine receptor. In the rat brain, 5-HT₇Receptors appear and are particularly highly distributed in the hypothalamus, thalamus and hippocampus, whereas lower 5-HT is found in the cerebral cortex, striatum, olfactory bulb and olfactory tubercle₇Receptor RNAm levels. 5-HT₇The presence of the receptor RNAm is not limited to the brain but is also found in peripheral tissues (spleen, stomach, intestine, heart, coronary arteries). 5-HT₇The receptor is functionally coupled to an adenylate cyclase system. In vitro pharmacological evidence suggests that 5-HT is involved₇Following receptor stimulation, intracellular cAMP levels rise. 5-HT of the same type₆5-HT, like the 5-hydroxytryptamine receptor₇The clinical value of receptors is currently unknown (Sleight, a.j., Boess, f.g., Bourson, a., Sibley, d.r., Monsma, f.j., 1997 DN)&P; 10(4): 214-224). It has been suggested that the 5-HT7 receptor may be involved in the mechanism of regulating blood pressure. 5-HT₇The receptors are highly distributed in the blood vessels, and pharmacological data indicate that the receptors are in the 5-hydroxytryptamine and 5-HT₇The fact that vasodilation occurs after receptor binding suggests that 5-HT may be converted₇The ligands are useful as hypotensive agents (Martin, g.r. and Wilson, r., (1995) British j.pharmacol. (British pharmacology, will) 114: 383P). Furthermore, 5-HT, previously shown to be abundant in the hypothalamus₇The receptors are involved in the regulation of the circadian rhythm of spontaneous neuronal electrical activity in the central nervous system (Lowenberg, T.N. et al, Neuron (1993) 11: 449-58).

Thus, 5-HT₇The ligand may be a modulator of a variety of processes regulated by circadian rhythms, particularly the sleep cycle, whose dysregulation leads to sleep disorders.Additional evidence suggests 5-HT₇The receptors may be involved in the pathogenesis and treatment of depression. 5-HT in rat hypothalamus₇The observation that receptor binding sites determine downregulation following long-term treatment with the antidepressant fluoxetine supports this therapeutic indication (Sleight, a.j. et al, mol. pharm. (molecular pharmacology) (1996), 47: 99-103). The strict classical view of the hypothesis of neurotransmitter dysregulation, which has recently been extended to include disorders of biological rhythm regulation, correlates depression with a deficiency in available neurotransmitters or a low reactivity of mainly the noradrenergic and/or 5-hydroxytryptamine receptor systems. Many have suggested that impairment of rhythm maintenance efficacy or dysrhythmia leads to mental fatigue and depression (Goodwin F.K., Wirz-Jupitce A., Wehr T.A., 1982.In Costar (eds.), Typical and nutritional antidepressants: Clinical practice).

Although melatonin is generally considered to be a major regulator of circadian function, 5-hydroxytryptamine also plays a key role, particularly in 5-HT in the suprachiasmatic nucleus of the hypothalamus_1a、5-HT_1b、5-HT_2a、5-HT₇Subtype (Van Den Pol, A.N., Dudek, F.E., (1993) neurosciences 56: 793. sup. 811; Mullins, U.L. et al, (1999) Neuropsychopharmacology 21, (3) 352. sup. 367).

5-HT₆And 5-HT₇The receptor sites are simultaneously localized in brain regions (hippocampus, frontal cortex) functionally involved in attention and learning processes, albeit at different distribution densities, and the same ability of both receptors to increase intracellular cAMP levels after stimulation suggests itself in 5-HT₆And 5-HT₇Receptor-bound substances may modulate neuronal plasticity mechanisms underlying individual learning and subsequent learning processes.

For 5-HT₆And 5-HT₇Ligands with simultaneous affinity for receptors may have therapeutic applications in conditions where improvement of cognitive processes is desired (Menese, a., (1999) neurosci. biotehav. rev., 23 (8)):1111-25)。

recent evidence suggests 5-HT₇Possible uses of the ligands in the treatment of irritable bowel disease. Gastric hypomotility is considered to be a potential mechanism in the pathophysiological mechanisms of this syndrome and remains an attractive therapeutic target. Indeed, a new generation of prokinetic drugs includes 5-HT₄Receptor ligands (tegaserod, procapril). Preliminary evidence has led to the targeting of 5-HT to the above therapeutic targets₇Of interest for receptor ligand studies (De Ponti, F., Tonnii, M., (2001) Drugs, 61 (3): 317-. Indeed, with respect to 5-HT₇Receptor mediated smooth muscle relaxation and 5-HT₇The observation that the binding site is located on intestinal tissue should indicate 5-HT₇Therapeutic use of ligands for receptors.

At present, p-5-HT has been identified₆Compounds with affinity for receptors belong to different chemical classes. For example, EP 0815861 and EP 0930302, Hoffmann-La Roche, describe sulfonamide and benzenesulfonate derivatives as selective ligands for the above receptors; WO 98/27058, SmithKline Beecham describes carboxyamide indole derivatives as 5-HT₆Receptor antagonists, whereas WO 98/27081 and WO 99/42465, SmithKline Beecham and US 6,187, 805, Merck Sharp and Dohme describe in particular sulfonamide derivatives; WO 00/12623, SmithKline Beecham describes sulfonate and sulfonamide derivatives; WO 00/37452, Merck Patent, describes sulfonyl oxazolamines; WO 00/63203 and US 6,133,287, Allelix Bio-pharmaceutical Inc. describe the use of piperidinoindoles as 5-HT₆An antagonist.

Tryptamine derivatives are known for several pharmacological applications. WO 97/06140 describes their use for the treatment of pathological conditions associated with melatonin disorders; WO 97/46525 and WO98/23587 describe them as 5-HT_1DSelective ligands for receptors and their use in the treatment of migraine; WO 97/48680 describes a treatment for vasospasm; WO 98/06695 describes use in the treatment of skin diseases; WO 98/47868 describes as diverse 5-HT₁Combined activity of antagonists of the receptor subtypes; WO 00/11619 describesSaid compounds are selective 5-HT_2AA selective antagonist of a receptor; WO 99/51576 describes the use for the treatment of neurological disorders associated with the 5-hydroxytryptamine energy system; WO 99/54301 describes them as antibacterial agents; WO 00/37441 describes treatments for cardiovascular, ischemic, parasitic, inflammatory, neurodegenerative diseases, myopathy and sickle cell anemia; WO 00/78716 and WO 00/44721 describe them as active agents acting on the adrenergic system.

Note that other tryptamine derivative pairs differ from 5-HT₆The 5-hydroxytryptamine receptor of (1) for example WO 95/14004, WO 95/24200, WO 96/26922, WO 96/26923, WO 97/13512, WO 99/51576, EP 1023898 and WO 00/52002.

For the pair 5-HT₆Compounds having specific activity on receptors, WO 99/47516, Slassi et al describe the use of 5-HT₆1-acyl or 1-sulfonylindoles substituted with alkylpyrrolidine at the 3-position with affinity for the receptor. WO 99/65906, Allelix Biopharmaceutical Inc. discloses bicyclic piperidines and piperazines linked to indole residues as 5-HT₆An inhibitor of a receptor.

Patent application WO 00/34242, Virginia Commonwelth University, discloses having an increased para-5-HT₆5-hydroxytryptamine derivatives with affinity and selectivity for receptors. Patent application WO 00/63203, Allelix Biopharmaceuticals Inc. discloses the para-5-HT₆1-acyl or 1-sulfonylindoles substituted with piperidine at position 3 with an affinity for the receptor.

With respect to 5-HT₇The receptor, WO 00/37082, SmithKline Beecham discloses the 5-HT described in WO 97/29097, WO 98/48681 and WO 97/49695₇Use of a receptor antagonist for the treatment of neuronal degeneration caused by an ischemic event; EP 0998923, BASF, discloses 5-HT₇Use of a receptor antagonist for the prevention of ischemia, particularly infarction; WO 99/54303 and WO 98/00400, Meiji disclose tetrahydrobenzindole for the treatment of psychiatric and circulatory disorders.

Summary of The Invention

The present invention relates to p-5-HT₆And/or 5-HT₇A tryptamine-based ligand having affinity for the 5-hydroxytryptamine receptor. From a therapeutical point of view, these substances can be used for the treatment of neurological pathologies associated with an insufficient level of 5-hydroxytryptamine, systemic pathologies involving the cardio-circulatory system (hypertension) and the gastrointestinal tract (irritable bowel disease).

It is known that many diseases of the central nervous system are effectively treated by using drugs which specifically interact with 5-hydroxytryptamine receptors and for this reason are clinically approved for the treatment of migraine, depression, hypertension, psychosis and mental fatigue, sleep disorders and other effects caused by dysrhythmias.

It has been found that the compound of formula (I) is para-5-HT₆And/or 5-HT₇The receptors have an affinity for the protein(s),

wherein:

R₁and R₂Identical or different, is H or C₁-C₆A linear or branched alkyl group;

R₃＝C₁-C₆a linear or branched alkyl group;

R₄halogen.

Accordingly, it is an object of the present invention the use of compounds of formula (I) above and pharmaceutically acceptable salts thereof for the preparation of a medicament for use as 5-HT₆And/or 5-HT₇Use of a ligand for a 5-hydroxytryptamine receptor, in particular for the treatment of a neurological pathology associated with an insufficient level of 5-hydroxytryptamine, a systemic pathology involving the circulatory system of the heart (in particular hypertension), the gastrointestinal tract (in particular irritable bowel disease).

Further objects of the present invention are novel compounds of formula (I), excluding from formula (I): wherein R is₄Is fluorine, chlorine or bromine, R₃Is methyl or ethyl, R₁And R₂Identical or different, are hydrogen and methyl; a process for the preparation of the novel compounds of formula (I); their use as medicaments, in particular for the treatment of neurological pathologies associated with an insufficient level of 5-hydroxytryptamine, systemic pathologies involving the cardiovascular system (in particular hypertension), the gastrointestinal tract (in particular irritable bowel disease); and a pharmaceutical composition comprising the compound as an active ingredient.

Detailed Description

In the compounds of formula (I), the term C₁-C₆Alkyl means methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl and all possible isomers, preferably methyl and ethyl.

Halogen means fluorine, chlorine, bromine and iodine, preferably chlorine and bromine.

In the compounds of formula (I), a first preferred subgroup comprises R therein₁And R₂Compounds of the same, in particular methyl.

A second preferred subgroup comprises compounds of formula (I) wherein R is₃Is alkyl as defined above, in particular methyl or ethyl, and R₄Is chlorine.

Wherein R is₄para-5-HT of compounds of formula (I) which are chlorine₆5-hydroxytryptamine receptors having selective affinity and useful for the preparation of compounds useful as 5-HT₆For example for the treatment of depression, mood disorders, psychosis, schizophrenia, dyskinesias, cognitive disorders, parkinson's disease, alzheimer's disease, huntington's chorea.

A third preferred subgroup comprises compounds of formula (I) wherein R is₃Is alkyl as defined above, especially methylGroup, and R₄Is bromine.

In particular, when R₄In the case of bromine, the molecule also acquires para-5-HT₇Affinity of receptor subtypes.

Due to this property, the compounds are indicated for the treatment of depression, migraine, hypertension, in particular for improving the learning process of individuals, against biorhythm disturbances and many of the changes resulting therefrom (mental fatigue, depression, sleep disorders).

Particularly preferred compounds are 5-bromo-2-methyl-N, N-dimethyltryptamine (ST1938), 5-chloro-2-ethyl-N, N-dimethyltryptamine (ST2253) and 5-chloro-2-methyl-N, N-dimethyltryptamine (ST 1936).

In Chapman, N.B et al, j.chem.soc. (journal of the chemical society) 1965; 1424-1428 describes compounds of formula (I) wherein R₃Is methyl, R₁And R₂Identical or different, are hydrogen and methyl.

The compounds according to the invention can be prepared by methods exemplified by the following schemes, according to procedures reported in the literature for analogous compounds (Spadoni, G. et al, J.Med.chem. (J.Med. chem., 1993; 36 (25): 4069-74).

The skilled person will be able to select the correct starting compounds and corresponding reagents and reaction conditions for the target end product in connection with formula (I) above.

The process of the present invention is carried out according to scheme 1 reported below.

The starting compound 5-halo-2-alkyl-indoles are commercially available or can be prepared by methods similar to those described in J.Med.chem.1993, 36, 4069, but see also JOC 1994, 59, 6372-6377.

The compound of formula (I) is reacted with commercially available 1-dimethylamino-2-nitroethylene. The molar ratio is not critical, for example it is convenient to react the compounds in equimolar amounts, even though the presence of an excess of one or the other reactant may be taken into account in relation to the different final products of formula (I). The reaction is carried out in trifluoroacetic acid and at a temperature and for a time which can be chosen according to the reactants used, their concentration and the solvent. Suitably, the reaction may be carried out at low temperatures, for example 0 ℃, up to a temperature compatible with the reaction conditions, in the absence or presence of reduced amounts of secondary products or degradation, for a period of minutes to hours.

If desired, compound (2) is isolated from the reaction medium using conventional methods known to those skilled in the art, and the ethyl double bond adjacent to the nitro group is then reduced to give the corresponding saturated derivative (3). The skilled person can derive considerations regarding the reaction conditions from the preceding paragraphs.

The final step is used in R₁And R₃The groups given in the definition of (a) functionalize the primary amino group. This is done by conventional methods as described in the literature, e.g., J.org.chem. (organic chemistry, J.) 37, 1673-.

The following examples further illustrate the invention.

Example 1

(E) -5-bromo-2-methyl-3- (2-nitrovinyl) -1H-indole

A solution of 0.58g1- (dimethylamino) -2-nitroethylene (5mmol) in 5mL trifluoroacetic acid was stirred and cooled to 0 deg.C, 1.05g (5mmol) 5-bromo-2-methyl-indole was added and the resulting mixture was allowed to react at room temperature under nitrogen for 30 min. The reaction mixture was then placed in an ice-water bath. The aqueous solution was extracted with ethyl acetate, and the organic phases were combined, then washed with a saturated bicarbonate solution, then with water, and finally dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure leaving a solid, orange residue, which was then suspended in an ethyl acetate-ether mixture and filtered.

Yield: 89 percent

R_f0.3 (cyclohexane/EtOAc: 1)

M.p.: 196 Inflatting 198 deg.C (decomposition)

¹H-NMR(200MHz)(DMSO-d₆)：δ 2.59(s，3H)，7.34(m，2H)，7.97(d，1H，J＝13.2Hz)，8.06(m，1H)，8.26(d，1H，J＝13.2Hz)

EIMS：m/z280,282(M⁺)，154(100)

5-bromo-2-methyltryptamine hydrochloride

A solution of nitrovinylindole (2) (1.7g, 6mmol) in 25mL of anhydrous THF was added dropwise to LiAlH under nitrogen at 0 deg.C₄(1.2g, 36mmol) in THF (6.5mL) and the resulting mixture was stirred at room temperature for 5 hours. After cooling to 0 ℃ the excess LiAlH was destroyed by careful addition of water₄And the resulting suspension was filtered through celite. The solvent was evaporated in vacuo and the residue was acidified with 2N HCl and then partitioned with water and ethyl acetate. The aqueous phase was subsequently basified with 6N NaOH and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting free amine was then converted to the hydrochloride salt by addition of a solution of HCl in anhydrous methanol. The salt was subsequently purified by crystallization from ethyl acetate.

Yield: and 69 percent.

¹H NMR(200MHz，(DMSO-d₆): δ 2, 33(s, 3H), 7.09(dd, 1H, J ═ 1, 9, and J ═ 8, 3Hz), 7.21(d, 1H, J ═ 8, 3Hz), 7.65(d, 1H, J ═ 1, 5Hz), 7.94(br, s, 3H), 11, 15(s, 1H), 7.94(br, s, 3H), 11.15(s, 1H).

5-bromo-2-methyl-N, N-dimethyltryptamine (ST1938)

A40% HCHO solution in 16mL MeOH (0.95mL) was added dropwise to a stirred solution of 5-bromo-2-methyltryptamine (0.8g, 3.16mmol), AcOH (0.47mL), and NaCNBH₄(0.35g) of a solution. The solution was allowed to react for 2.5 hours at room temperature with stirring; then 5mLK was added₂CO₃A saturated aqueous solution; methanol was evaporated under vacuum and the aqueous phase was extracted with ethyl acetate.

The organic phase was dried over anhydrous sodium sulfate and after evaporation of the solvent under vacuum an orange oil was obtained which was purified by filtration through silica gel and subsequent crystallization from dichloromethane-hexane.

Yield: 56 percent

M.p.：135-136℃

Rf＝0，52(CH₂Cl₂/MeOH/TEA 9：0，4：0，4)

¹H NMR(200MHz，(CDCl₃)：δ 2，35(s，6H)，2，37(s，3H)，2，44-2，52(m，2H)，2，78-2，86(m，2H)，7，11(d，1H，J＝8，5Hz)，7，18(dd，1H，J＝1，6eJ＝8，5Hz)，7，60(d，1H，J＝1，6Hz)，7，95(br s，1H)。

EIMS：m/z 280,282(M⁺)，222,224(100)。

Example 2

According to the process described, and according to the routes and examples above, the following compounds are prepared:

(E) -5-chloro-2-methyl-3- (2-nitrovinyl) -1H-indole

Orange solid

Yield: 85 percent;

M.p..191-193℃

¹h NMR (200MHz, (acetone-d)₆): δ 2, 68(s, 3H), 7, 21(dd, 1H, J-1, 95 and J-8, 5Hz), 7, 5(d, 1H, J-8 Hz), and8，5Hz)，7，85(d，1H，J＝13，3Hz)，7，86(d，1H，J＝1，95Hz)，8，30(d，1H，J＝13，3Hz)；EIMS：m/z236(M⁺)，154(100)。

5-chloro-2-methyltryptamine hydrochloride

From EtOH/Et₂O precipitated as a light brown solid.

Yield: 72 percent

¹H NMR(200MHz，(DMSO-d₆): δ 2, 33(s, 3H), 6, 97(dd, 1H, J-1, 9 and J-8, 3Hz), 7, 25(d, 1H, J-8, 3Hz), 7, 52(d, 1H, J-1, 5Hz), 8, 03(br, s, 3H), 11, 15(s, 1H).

5-chloro-2-methyl-N, N-dimethyltryptamine (ST 1936)

A white solid;

yield: 75 percent;

M.p.＝126-127℃

¹H NMR(200MHz，CDCl₃): δ 2, 35(s, 6H), 2, 38(s, 3H), 2, 44-2, 52(m, 2H), 2, 79-2, 87(m, 2H), 7, 05(d, 1H, J ═ 1, 9, and J ═ 8, 6Hz), 7, 17(d, 1H, J ═ 8, 2Hz), 7, 45(d, 1H, J ═ 1, 9Hz), 7, 86(br s, 1H)

EIMS：m/z 236(M⁺)，178(100)。

Example 3

The reactants are as follows: (a) t-BuLi, THF, -20 ℃; EtI, from-78 ℃ to room temperature, for 2 h; (b)2N NaOH and MEOH are refluxed for 40 hours; (c)1- (dimethylamino) -2 nitroethylene, TFA, 0 ℃, 0, 5 h; (d) LiAlH₄THF, room temperature, 6 h; (e) NaCNBH₃，40％，HCHO，MeOH，AcOH, room temperature, 2, 5 h.

N- (benzenesulfonyl) -5-chloro-2-ethylindole (2).

t-BuLi (3.7mL of a 1.7M solution in pentane) was added dropwise to a solution of N- (benzenesulfonyl) -5-chloroindole (1) (J.org.chem. (J.org. chem.) 1981, 46, 3859) (1.5g, 5.14mmol) in THF (35mL) at-70 ℃ under a nitrogen atmosphere. The mixture was stirred for 15 min, warmed to room temperature over 20 min, cooled to-70 ℃ and treated with a solution of iodoethane (0.84mL, 10.5mmol) in anhydrous THF (5 mL). The mixture was stirred at-78 ℃ for 1 hour, allowed to warm to room temperature, stirred for 2 hours, poured over ice (15g) and saturated NH₄Aqueous Cl solution, then extracted with ether (3X 20 mL). The combined organic extracts were washed with brine and dried (Na)₂SO₄) And evaporated in vacuo to give a residue which is purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 8:2) and crystallization from ethyl acetate/cyclohexane.

Yield: 80 percent of

M.p.: 108 deg.C (decomposition)

¹H-NMR(MHz，)(CDCl₃)：δ 1.33(τ，3H)，3.01(q，2H)，6.35(s，1H)，7.23(dd，1H)，7.39-7.74(m，6H)，8.11(d，1H)

EIMS：m/z319(M⁺)；178,143(100％)

5-chloro-2-ethylindole (3)

A mixture of 2(1.3g, 4.07mmol), 2N NaOH (12mL) and MeOH (62mL) was refluxed for 40 hours. The organic solvent was evaporated and the residue was extracted with EtOAc. The combined extracts were washed with brine and dried (Na)₂SO₄) And evaporated in vacuo to give a residue which is purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 8:2) and crystallization from diethyl ether/cyclohexane.

M.p.＝89℃

Yield: 90 percent of

¹H NMR(CDCl₃)δ 1.35(t，3H)，2.79(q，2H)，6.19(s，1H)，7.06(dd，1H)，7.21(d，1H)，7.49(s，1H)，7.92(br s，1H)

EIMS：m/z 179(M⁺)；164(100)

(E) -5-chloro-2-ethyl-3- (2-nitrovinyl) -1H-indole (4)

Indole 3(5mmol) was added to a stirred ice-cold solution of 1- (dimethylamino) -2-nitroethylene (0.58g, 5mmol) in trifluoroacetic acid (5 mL). The mixture was cooled to room temperature and N₂Stirred under an atmosphere for 0.5 hour and then poured into ice water. The aqueous solution was extracted with ethyl acetate and saturated NaHCO₃The combined organic layers were washed with the solution and then with water. With Na₂SO₄After drying, the solvent was evaporated under reduced pressure to give a crude orange solid, which was suspended in EtOAc-Et₂O and filtered or chromatographed on silica gel (cyclohexane/EtOAc, 1:1 as eluent).

Yield: 89 percent

M.p.: decomposing at 188 ℃.

¹H(CDCl₃)δ 1，42(t，3H)，3，02(q，2H)，7，21-7，34(m，2H)，7，68(m，1H)，7，72(d，1H)，8，3(d，1H)，8，68(br s，1H)

EIMS：m/z 250(M⁺)，203,188(100)

5-chloro-2-ethyltryptamine (5)

A solution of nitrovinylindole 4(6mmol) in anhydrous THF (25mL) was added dropwise to a stirred ice-cold LiAlH under nitrogen₄(1.2g, 36mmol) in dry THF (65mL) and the mixture was stirred at room temperature for 5 h. After cooling to 0 ℃ the unreacted LiAlH was destroyed by careful addition of water₄. By usingThe resulting mixture was filtered through a pad, and the filtrate was concentrated under vacuum, then acidified with 2N HCl and partitioned with water and ethyl acetate. The aqueous phase was made basic with 6N NaOH, then extracted with EtOAc (3X), the combined organic layers were washed with brine and dried (Na)₂SO₄) And concentrated under reduced pressure to give the amine as a crude oil.

(oil); EIMS: m/z 222 (M)⁺)；192(100)，177

5-chloro-2-ethyl-N, N-dimethyltryptamine (6) (ST2253)

40% HCHO (0.95mL) in MeOH (16mL) was added dropwise to a stirred, cooled (0 deg.C.) (5) (3.16mmol), AcOH (0.47mL), and sodium cyanoborohydride (0.35g) solution. The resulting mixture was stirred at 25 ℃ for 2.5 hours. Addition of saturated K₂CO₃Aqueous solution (5 mL). MeOH was removed under vacuum and the aqueous phase was extracted with EtOAc. With Na₂SO₄After drying, the solvent was evaporated under reduced pressure to give a crude residue, which was purified by filtration over silica gel.

(amorphous solid);¹H NMR(CDCl₃)δ 1.3(t，3H)；2.42(s，6H)；2.55(m，2H)，2.83(m，4H)，7.06(dd，1H)，7.19(d，1H)，7.45(m，1H)，7.88(br s，1H)

EIMS：m/z 250(M⁺)；192,177，58(100)

the compound according to the invention is 5-HT₆And/or 5-HT₇A ligand for a 5-hydroxytryptamine-capable receptor; they are therefore useful as medicaments, in particular for the treatment of pathologies of the nervous system associated with an insufficient level of 5-hydroxytryptamine, and of pathologies of the system involving the circulatory system of the heart (hypertension), the gastrointestinal tract (irritable bowel disease).

Pathological conditions treated with the compounds of the invention are: migraine, depression, hypertension, psychosis and other processes involving functional changes, resulting from a loss and/or malfunction of circadian rhythms (wake/sleep cycles, melatonin synthesis).

About a groupPreferred compounds of formula (I) wherein R₃Is methyl and R₄Is bromine or chlorine, especially when R₄In the case of bromine, the molecule acquires para-5-HT₇Affinity of receptor subtypes. Due to this property, a compound called ST1938 is indicated for the treatment of depression, migraine and hypertension, in particular to promote and improve the learning process of individuals, and to combat the dysrhythmias of humans that lead to mental fatigue, depression and sleep disorders.

Determination of binding to 5-HT according to published methods₆Inhibition of the receptor (Monsma, F.J. et al, Molecular Pharm. (Molecular pharmacology), 1993, 43: 320-327). Rat 5-HT stably transfected into HEK293 (human embryonic Kidney cells)₆Combination of³H]LSD (lysergic acid diethylamide) as radioligand was tested for binding. Each compound was first dissolved in DMSO to prepare a 10mM stock solution, which was then dissolved in H₂O reached a final concentration of 0.1 mM. After serial dilution, competition curves were obtained using duplicate 8 different concentrations (from 10. mu.M to 0.001nM), from which each test compound was evaluated for 5-HT₆Binding affinity of the receptor. The experimental conditions were: 2nM [ 2 ]³H]LSD, 100. mu.M 5-hydroxytryptamine creatinine sulfate to define nonspecific binding, and 60 minutes, at 37 ℃ for incubation of each sample. After incubation, the membrane was rapidly filtered through a glass fiber filter (GF/B, Packard) under vacuum. Bound radioactivity was determined using a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint0, Packard). IC was determined for each compound using non-linear regression analysis of competition curves using the Hill equation curve fitting method₅₀. These values were then used to calculate the inhibition constant (K)_i) Value, thereby representing the 5-HT of each test compound₆The affinity of the receptor. Ki values are defined by the Cheng Prusoff equation: k_i＝IC₅₀/1+([L]/Kd), wherein IC₅₀Values are the concentration of test compound (nM) with 50% of the specific radioligand displaced from the receptor, L is the concentration of specific radioligand in the assay, and K_dIs the affinity of the radioligand for the receptor.

A displacement experiment was carried out to determine the identity of the substance to 5-HT 18204 according to published methods (Shen, Y. et al, (1993) Journal of Biologicalchemistry 268: 18220-₇The affinity of the receptor. For the performance of the assay, human 5-HT stably transfected into CHO cells (human ovarian cells) was used₇A receptor, and [ 2 ]³H]LSD (4nM) as radioligand. Further experimental conditions were: 10 μ M5-hydroxytryptamine as a non-specific ligand, and 120 ℃ at 22 ℃ for each sample incubation. At 8 different concentrations in duplicate (10)^-5M to 10^-12M) various test compounds were studied to obtain a complete competition curve. Each compound was first dissolved in DMSO to obtain 10^-3Stock solution of M, which is then dissolved in H₂O to a final concentration of 10^-5And M. The binding reaction of each test compound was interrupted by rapid filtration through a glass fiber filter (GF/B, Packard) under vacuum. The filter was then washed several times with ice-cold buffer. Bound radioactivity was determined using a liquid scintillation cocktail (Microscint0, Packard) using a scintillation counter (Topcount, Packard). IC was determined by non-linear regression analysis of each competition curve as described above₅₀Value and is given by the Chen Prusoff equation (K)_i＝IC₅₀/(1+ L/Kd) calculation of K_iThe value is obtained.

In Table 1, the 5-HT of each test compound is reported₆And 5-HT₇Binding affinity value.

TABLE 1

For 5-HT ₆ e5-HT ₇ Affinity of (2)

5-HT 5-HT
	Compound IC(nM) Ki(nM) IC(nM) Ki(nM)
ST 1936 62 31 527 168
	ST 1938 62 32 158 47
ST 2253 52 26 >1000nM >1000nM
	5-hydroxytryptamine 171870.640.19

ST1936, ST1938, ST2253 showed recombinant 5-HT in rats₆High affinity of the receptor. In addition, their binding affinity is greater than that observed for 5-hydroxytryptamine.

Among these compounds, the compound named ST1938 also showed recombinant 5-HT in humans₇The highest affinity of the receptors, whereas ST1936 and ST2253 exhibit moderate and negligible affinity, respectively.

Examining selected compounds to determine their association with 5-HT₆Specificity of receptor binding. Binding affinity to other 5-hydroxytryptamine sites was previously assessed.

In table 2, the affinity values (Ki, nM) of the selected compounds for various 5-hydroxytryptamine subtypes are shown.

TABLE 2

This table shows that compounds ST1936 and ST2253 are capable of selectively binding to the 5-HT6 receptor. But also in the evaluation of the binding affinity to some receptors involved in other neurotransmittersThereafter, ST1936 and ST2253 were tested for 5-HT₆The binding specificity of the receptor.

ST1936 and ST2253 were tested at 23 sites. In most of these receptors, the selected compounds exhibit negligible affinity. Specifically, the affinity values of ST1936 and ST2253 for the following receptors were similar or greater than 1000 nM: alpha is alpha_1aAnd beta₁(ii) adrenergic; d₁、D₂、D₃、D_4，4、D₅Dopaminergic; NMDA, muscarinic (non-selective); n neurons (α -BGTX-sens.), N neurons (α -BGTX-ins.) nicotine, H₁Histamine, opiate (nonselective), vasopressin V_1a、V_1b、V₂ML of melatonin₁And ML₂NA transporters, DA transporters. Furthermore the compounds show a-alpha_1bThe intermediate avidity of adrenergic receptors was 53nM and 69nM for ST1936 and ST2253, respectively. However, the selected compounds are related to alpha_1bReceptor interaction Capacity alignment 5-HT₆The evaluation values for receptors were approximately 2-fold and 3-fold lower. All data indicate that compounds ST1936 and ST2253 are on 5-HT₆The receptor has selective affinity.

Relative to the expression of the pair 5-HT₆And 5-HT₇Selected compounds known as ST1938, which are active as a mixture of 5-hydroxytryptamine receptors, show negligible affinity for these sites (Ki)>1000nM)：H₁(ii) a NMDA; a PCP; a muscarinic receptor; nicotinic receptors, opiates; vasopressin V₁And V₂；D₁、D₂、D₃、D₄，₄、D₅(ii) a DA transporter, NA transporter.

Another object of the present invention relates to pharmaceutical compositions comprising as active principle at least one compound of formula (I), alone or in combination with one or more other compounds of formula (I), or with other active principle examples for the treatment of the pathological conditions described hereinE.g. other pairs of 5-HT₆And/or 5-HT₇Combinations of products in which the 5-hydroxytryptamine receptor is active, said compositions being present as individual doses or in a form suitable for combination therapy. The active ingredients according to the invention are mixed with suitable carriers and/or excipients which are customary in pharmaceutical technology, for example as described in Remington's pharmaceutical sciences Handbook, latest edition. The compositions of the present invention comprise a therapeutically effective amount of the active ingredient. The dosage will be determined by a person skilled in the art, e.g. a clinical worker or a physician, on the basis of the pathological condition to be treated and the general condition of the patient or on the basis of the administration of other active ingredients.

Examples of pharmaceutical compositions are those which allow oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal administration.

Pharmaceutical compositions suitable for this purpose are pills, hard or soft capsules, powders, solutions, suspensions, syrups, solid dosage forms for the extemporaneous preparation of liquids. For example, compositions for parenteral administration are in all injectable forms, whether intramuscular, intravenous, subcutaneous, in the form of solutions, suspensions and emulsions. Liposomal formulations are also mentioned. Controlled release dosage forms of the active ingredient for oral administration, e.g. coated with a suitable coating material, microencapsulated powders, cyclodextrin complexes, and long acting dosage forms, e.g. for subcutaneous or as implants, are also included.

Claims (21)

1. Use of compounds of formula (I) and pharmaceutically acceptable salts thereof for the preparation of a medicament for use as 5-HT₆And/or 5-HT₇Use of a ligand of the 5-hydroxytryptamine receptor for the treatment of pathological conditions of the nervous system, related to insufficient levels of 5-hydroxytryptamine, and of drugs for treating pathological conditions of the system involving the cardiovascular system and the gastrointestinal tract

Wherein

R₁And R₂Identical or different, is H or C₁-C₆A linear or branched alkyl group;

R₃＝C₁-C₆a linear or branched alkyl group;

R₄halogen.

2. Use according to claim 1, wherein the medicament is for the treatment of hypertension.

3. Use according to claim 1, wherein the medicament is for the treatment of irritable bowel disease.

4. Use according to claim 1, wherein the medicament is for the treatment of migraine, depression, hypertension, psychosis and symptoms caused by dysrhythmia and/or loss of circadian rhythm.

5. The use according to claim 1, wherein the medicament is 5-HT₆Ligands of the 5-hydroxytryptamine receptor and for the treatment of depression, mood disorders, psychosis, schizophrenia, dyskinesias, cognitive disorders, parkinson's disease, alzheimer's disease and huntington's chorea.

6. Use according to claim 1, wherein in the compound of formula (I), R₁Is equal to R₂。

7. Use according to claim 1 or 3, wherein in the compound of formula (I), R₃Is methyl, and R₄Is bromine or chlorine.

8. Use according to claim 1 or 4, wherein in the compound of formula (I), R₄Is bromine.

9. Use according to claim 8, wherein the compound of formula (I) is 5-bromo-2-methyl-N, N-dimethyltryptamine.

10. Use according to claim 1 or 5, wherein in the compound of formula (I), R₄Is chlorine.

11. Use according to claim 10, wherein the compound of formula (I) is 5-chloro-2-methyl-N, N-dimethyltryptamine or 5-chloro-2-ethyl-N, N-dimethyltryptamine.

12. Use according to claim 8, wherein the medicament is for use as 5-HT₇A ligand for a 5-hydroxytryptamine energy receptor.

13. Use according to claim 10 or 11, wherein the medicament is for use as 5-HT₆A ligand for a 5-hydroxytryptamine energy receptor.

14. Use according to claim 12 for the preparation of a medicament for the treatment of depression, migraine and hypertension.

15. Use according to claim 13 for the preparation of a medicament for the treatment of depression, mood disorders, psychosis, schizophrenia, movement disorders, cognitive disorders, parkinson's disease, alzheimer's disease and huntington's chorea.

16. Compounds of formula (I) and pharmaceutically acceptable salts thereof,

wherein:

R₁and R₂Identical or different, is H or C₁-C₆An alkyl group;

R₃＝C₁-C₆an alkyl group;

R₄halogen;

with the proviso that when R₄Is fluorine, chlorine or bromine, R₃When it is methyl, R₁And R₂Identical or different and is not H or methyl.

17. A process for the preparation of a compound according to claim 16, which follows the following route:

18. the use of a compound according to claim 16 for the preparation of a medicament.

19. A pharmaceutical composition comprising as active ingredient at least one compound according to claim 16, in admixture with pharmaceutically acceptable carriers and/or excipients.

20. The use of claim 4, wherein the circadian rhythm is the wake/sleep cycle and melatonin synthesis.

21. The use according to claim 12, wherein the medicament is for assisting or improving the learning process and counteracting circadian rhythms in humans that lead to mental fatigue, depression and sleep disorders.