MXPA02007521A

MXPA02007521A - Pyrrolo isoquinoline and tetrahydropyrrolo isoquinoline derivatives and their use as mediators of the 5 ht7 receptor.

Info

Publication number: MXPA02007521A
Application number: MXPA02007521A
Authority: MX
Inventors: Michael Gerard Kelly
Original assignee: Wyeth Corp
Priority date: 2000-02-04
Filing date: 2001-02-02
Publication date: 2002-12-13
Also published as: CN1396921A; BR0108007A; AU2001231287A1; CA2399545A1; WO2001057039A1; CN1168728C; JP2003522178A; EP1252161A1

Abstract

Compounds of the formula (1) are useful in the treatment of anxiety, depression and related disorders of the central nervous system and other conditions such as schizophrenia, sleep disorders, including instances of circadian rhythm, the treatment of alcohol and drug withdrawal and sexual dysfunction.

Description

PS OF PIRRÓLO-ISOQUJNOLINA AND TETRAHIfiROPIRROLO- ISOQUINOLINE AND ITS USE AS MEDIATORS OF THE RECEIVER OF 5-HIDROXITRIPTAMINA-7 (5-HT7) Background of the Invention The recently identified human 5-hydroxytryptamine-7 (5-HT7) receptor subtype has been cloned / and the extensive distribution of its mRNA has been reported. The highest levels of 5-HT7 mRNA have been observed in the hypothalamus, thalamus, the portion of the brain that is continuous with the spinal cord and the hippocampus, while lower levels have been found in the cerebral cortex, striatum, olfactory bulb and olfactory tubercle. The presence of 5-HT7 mRNA is not limited to the brain, it has also been found in peripheral tissues, especially the spleen, stomach, ileum, intestine, coronary artery, descending colon, smooth muscle and heart cells. Distribution and pharmacological studies have suggested that the 5-HT7 receptor may be involved in the vasodilation of blood vessels, and therefore may play a role in cardiovascular indications. 5-HT7 receptors also play a role in the control of circadian rhythms of spontaneous electrical activity in the suprachiasmatic nucleus. Affinity REF 140594 Elevation of a number of antipsychotic agents towards the 5-HT7 receptor suggests that this receptor can help mediate the therapeutic actions of these compounds. The octahydro-pyrrolo-isoquinoline derivatives, as antipsychotic neuroleptic agents are described in EP 10661 having the formula: wherein R2 is hydrogen, alkyl, cycloalkyl, alkenyl, acyl, aryl or aralkyl. Auxiliary indole derivatives are described as antiphlogistic agents in DE 77-2740836 having the formula: wherein: R is phenyl or heterocycle, carboxyalkyl, phenyl, and R 3, R 4 is a 5 or 6 element ring optionally containing 1-3, 5, 0 or N atoms. A series of 3- (2-aminoethyl) -5 pyrrolo derivatives [2, 3 -g] isoquinolin-5-one are claimed, which are effective pharmaceutical substances for the treatment of anxiety, depression and related CNS disorders and other conditions such as schizophrenia, sleep disorders, including cases of the circadian rhythm, treatment of the 10 withdrawal of alcohol and drugs and sexual dysfunction.

BRIEF DESCRIPTION OF THE PRESENT INVENTION This invention relates to novel derivatives of 3- (2-aminoethyl) -pyrrolo [2, 3-g] isoquinolin-5-one, to processes for their preparation, to pharmaceutical compositions which they already contain their use in therapy. The compounds are believed to be useful for the treatment of CNS disorders such as anxiety, depression and related CNS conditions and other conditions such as schizophrenia, sleep disorders, including cases of circadian rhythm, migraine headaches, treatment of alcohol and drug withdrawal and sexual dysfunction, by virtue of their ability to bind to the 5-HT7 receptor subtype. The compounds of the present invention can also find the treatment of cardiovascular and septic shocks, hypotension, kidney disorders, diarrhea and spastic colon. The compounds of the present intention are represented by the general formula (1), (i) wherein: R 1 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 3 to 8 members, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 members or ( CH2) mAr or (CH2) mHet; R2 is hydrogen, alkyl of 1 to 8 carbon atoms, (CH2) nAr or (CH2) nHet; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, alkylcycloalkyl of 4 to 9 carbon atoms, 4- to 9-membered alkylheterocycloalkyl, (CH2) nAr or (CH2) nHet; R 4 is hydrogen or alkyl of 1 to 8 carbon atoms; R is hydrogen or alkyl of 1 to 4 carbon atoms; 5 X is t (CH = CH) R] n, (CH2) n, [(C = C) R] n, CHR (CH2) n, or CR2 (CH2) n; a dotted line represents an optional double bond; m is a selected integer of 1 or 2; and n is an integer selected from 0, 1 or 2; or a pharmaceutically acceptable salt thereof. In some preferred aspects of the present invention R1 is hydrogen, alkyl of 1 to 8 carbon atoms, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 elements, (CH2) nAr or (CH2) nHet. In other embodiments of the present invention R2 is hydrogen or alkyl of 1 to 8 carbon atoms. X is preferably (CH2) n, and the optional double bond is preferably absent. R3 and R4 are preferably hydrogen or alkyl. "Alkyl" refers to straight or branched chain alkyl. Cycloalkyl refers to a saturated ring of 3 to 8 carbon atoms and preferably 5 to 6 carbon atoms such as cyclopentyl and cyclohexyl.

- * V- "Heterocycloalkyl" refers to a saturated ring of 3 to 8 carbon atoms having 1 or 2 heteroatoms selected from N, 0 and S. Preferably, heterocycloalkyl refers to rings of 5 or 6 elements having at least one nitrogen heteroatom such as piperidinyl, piperazinyl, pyrrolidinyl, 1-idazolidinyl, morpholinyl, thiomorpholinyl, and pyrazolidinyl Ar is aryl and preferably is phenyl or naphthyl which may be optionally substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, alkyl of 1 to 6 carbon atoms, trifluoromethyl, cyano and amino Het refers to heteroaryl and refers to a heteroaryl group of 5 or 6 elements, monocyclic, or a bicyclic heteroaryl group of 9 or 10. The preferred heteroaryls have 1 or 2 heteroatoms selected from N, O and S, and, when 2 heteroatoms are present, it is preferred that at least one heteroatom be nitrogen.The monocyclic heteroaryl groups Mplares include pyridinyl, pyridinyl, pyrazinyl, furyl, thienyl, pyrrolyl, indolyl. Exemplary bicyclic heteroaryl groups include benzodioxanyl or quinolyl. Heteroaryl groups may be optionally substituted with one or more groups selected from fluorine, * t. i. -1 - "f • Chloroxy, iodo, hydroxy, alkyl of 1 to 6 carbon atoms, trifluoromethyl, cyano and amino The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, fumaric, acetic, lactic or methanesulphonic acid The compounds of this invention contain a chiral center, providing various stereoisomeric forms such as racemic mixtures as well as optical isomers The individual optical isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of the optical isomers from the racemic mixture.

Detailed Description of the Invention The compounds of the present invention can be prepared by those skilled in the art of organic synthesis employing conventional methods which utilize reagents and readily available raw materials. For example, the reaction of an acid solution (for example methanesulfonic acid) of 5-fluoromdanone with sodium azide yields the required Schmidt rearrangement product. East ,? "A" is substituted with alkyl halides, alkylaryl halides or alkylheteroaryl halides under the influence of a base such as sodium hydride, and the product can be treated with hydrazine hydrate to give the 5-aryl hydrazine required. The reaction of substituted 1-aryl hydrazine with a substituted aldehyde derivative or protected derivative thereof (for example enol ether or dioxolane protecting group) under the condition of Fisher indole synthesis produces the pyrrolo compound [2, 3-g ] substituted isoquinolin-5-one 3-10. 2- (3-Chloropropyl) -1,3-dioxolane is an example of the suitably protected and substituted aldehyde derivative, and dilute sulfuric acid or dilute hydrochloric acid are suitable or cosolvent catalysts for the reaction. The basic amine can be directly alkylated for example by the reaction of an alkyl halide or alkylaryl halide under the influence of a base such as sodium hydride, or alternatively the basic amine can be acylated directly by the action of the carboxylic acid halides, and the subsequent amine can be reduced by the action of lithium aluminum hydride. These steps can be repeated to provide the bis-alkylated derivatives. The nitrogen of the pyrrole can be alkylated with alkyl halides and alkylaryl halides or alkylheteroalkyl halides or the influence of a Y* ... | F fease tai as sodium hydride. The optional double bond can be introduced by known and conventional methods. For example, the reaction of a 1, 6, 1, 8-tetrahydropyrrolo [2, 3-g] isoquinolin-5-one 3-substituted with 2,3,5-dichloro-5,6-dicyanobenzoquinone (DDQ) produces the 3-substituted pyrrolo [2, 3-g] isoquinolin-5-one compound of the present invention. > e ^ jg * ' } The compounds of the present invention bind with a very high affinity to the 5-HT7 receptor and consequently, they are useful for exerting a mediating action on the 5-HT7 receptor in mammals. The compounds of the present invention are useful in the treatment of central nervous system disorders associated with 5-HT7 receptor dysfunction such as conditions of anxiety, depression and related conditions (eg GAD) and other conditions such as schizophrenia. , sleep disorders, including cases of circadian rhythm, migraine headaches, treatment of alcohol and drug withdrawal and sexual dysfunction, by virtue of their ability to bind to the 5-HT7 receptor subtype. Similarly, the compounds of the present invention may also find utility in the treatment of cardiovascular and septic shock, hypotension, renal disorders, diarrhea and spastic colon.

-HT7 Receptor Binding Assay The high affinity to serotonin 5-HT7 receptor was established by testing the ability of the claimed compound to displace the [3 H] LSD that binds in stably transfected CHO cells with the receptor of human 5-HT7. The membranes of the human cloned receptor of subtype 7 of serotonin, expressed in a cell line of the Chinese Hamster Ovaries (CHO), are purchased from BioSignal Drug Discovery Technology, Montreal, Canada. The frozen vials of the receptor membranes are reconstituted in 50.0 mM Tris.HCl buffer, at pH 7.4 to give 15-20 μg of the tissue protein per 100.0 μl of suspension. The diluted membranes are kept cool on ice and used immediately in subsequent binding experiments. The binding experiments are carried out in a 96-well microtiter plate format, in a total volume of 200 μl. To each cavity are added: 80.0 μl of incubation buffer made in 50 mM Tris.HCl buffer, pH 7.4 and containing 10.0 mM MgC12 and 0.5 mM EDTA; 20 μl of [3 H] LSD (S.A., 86.0 Ci / mmol, Amersham Life Science), 5.0 - 6.0 nM. The dissociation constant, KD of [3H] LSD at the 5-HT7 receptor of human serotonin is 2.9 nM, as determined in saturation studies with increasing concentrations of [3H] LSD. The reaction is initiated by the final addition of 100.0 μl of the tissue suspension. The non-specific binding is measured in the presence of 10.0 μM methiothepin, added in a volume of 20 μl. % * > r 1% '^ 1? s The test compounds when necessary, are added in a volume of 20.0 μl. The reaction proceeds in the dark for 120 minutes at room temperature, during which time, the bound ligand receptor complex is removed by filtration on a 96-well unifilter with a Packard® Filtermate 196 Harvester. The Filtermate is air-dried and the radioactivity is measured in a Packard TopCount® apparatus equipped with six photomultiplier detectors, after drying and addition of 40.0 μl Microscint® scintillation substance to each shallow cavity. The unifiltro plate is thermally sealed and counted in a Packard TopCount® device with a tritium efficiency of 31.0%. The specific binding is defined as the total bound radioactivity minus the bound amount in the presence of 10.0 μM unlabeled methiothepin. The binding in the presence of varying concentrations of the test drugs is expressed as the percentage of specific binding in the absence of the drug. These results are plotted - then as the% bound log against the log concentration of the test drug. The non-linear regression analysis of data points with a computer aided with a Prism® program produces the values of both IC5o and Ki of the "test compounds with 95% confidence limits." Alternatively, the line of linear regression of the declination of the data points is plotted, from which the value IC5o can be read completely and the value of Kx determined by solving the following equation: K, = IC50 / d + L / KD) wherein L is the concentration of the radioactive ligand used and KD is the ligand dissociation constant for the receptor, both expressed in nM. Reference compounds were tested using the above procedure: Kx value and 95% confidence interval.

Compound of 5-HT7 Ki (nM) Clozapma 6.3 (2.6 - 11.0) nM Loxapina 43.0 (26.0 - 68.0) nM The compounds of the present invention showed activity in the above test, for example: Compound 1 14 The following specific non-limiting examples are included to illustrate the synthetic procedures used to prepare the compounds of formula 1. In these examples, all chemical substances and intermediates are either commercially available or can be prepared by the standard procedures found in Literature or are known by those experts in the art of organic synthesis. Several preferred embodiments are described to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments. stir at room temperature for 16 hours. The mixture is cooled to 0 ° C and neutralized by the addition of a 5N NaOH solution and the organic layer is separated. The aqueous layer is washed with dichloromethane (3 x 50 ml) and the combined organic substances are washed with water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. Filtration and concentration gave a light oil (7.8 g) which was purified by flash silica gel chromatography (eluted with diethyl ether) to give the title compound as a white solid. P.f. 107-108 ° C. M + 165 Elemental Analysis for: C9H8FNO Calculated: C, 65.45; H, 4.88; N, 8.48 Found: C, 65.01; H, 5.10; N, 8.33 Intermediate 2 6-Hydrazino-3,4-dihydro-2H-isoquinolin-l-one A solution of 6-fluoro-3, -dihydro-2H-isoquinolin-1-one (3.6 g, 0.022 mol) and hydrazine (17.3 ml, 0.55 mol) is stirred at reflux in dioxane (150 ml) under nitrogen for 48 hours. The reaction mixture is concentrated under vacuum, water (150 ml) is added, and the product is isolated by filtration. The product was completely washed With, < diethyl ether to give the title compound quantitatively as a white solid. P.f. 158-160 ° C. BM (IIE) m / e 177 (M +) Elemental Analysis for: C9H11N30 0.75H2O Calculated: C, 56.68; H, 6.61; N, 22.03 Found: C, 56.69; H, 6.11, N, 22.23 Compound 1 3- (2-Amino-ethyl) -1,6,7,8-tetrahydro-pyrrolo [2, 3-g] isoquinolin-5-one A solution of 6-hydrazino-3,4-dihydro-2H- isoquinoline-1-one (0.5 g, 2.3 mmol) and 2- (3-chloropropyl) -1,3-d-oxolane (0.31 ml, 2.3 mmol) is stirred at reflux in degassed EtOH / H20 solution (5/1). , 90 ml) under nitrogen for 24 hours. The reaction mixture is partitioned between saturated aqueous NaHC03 and isopropyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to perform chromatography on a column filled with silica gel using a solution of CH2Cl2 / MeOH / NH4OH (9.0 / 1.0 / 0.1) to give an oil. The oil containing two isomers was separated by reversible preparative HPLC C-5 Primesphere (90% CH3CN / H20 + 0.1% TFA) and the desired product it was dried by freezing under vacuum to give the title compound as a yellow solid. P.f. 82-86 ° C MS (IIE) m / e 230 (M + H) + Elemental Analysis for: C13H15N30.C2HF302.H2O Calculated: C, 49.86, H, 4.60; N, 11.24 Found: C, 49.98, H, 4.65, N, 11.39 Compound 2 3- (2-Amino-ethyl) -6-benzyl-l, 6,7,8-tetrahydro-pyrrolo [2,3- g] isoquinolin-5-one A solution of 6-fluoro-3, -dihydro -2H-isoquinolin-1-one (1.5 g, 9.1 mmol) and cesium carbonate (3.3 g, 10 mmol) in acetonitrile (100 ml) is stirred at room temperature under nitrogen. To this is added benzyl bromide (1.2 ml, 10 mmol) and the mixture is refluxed for 15 hours. The reaction mixture is concentrated to chromatograph on a column filled with silica gel using EtOAc / hexane (9/1) to give the expected product, 2-N-benzyl-6-fluoro-3,4-dihydro-2H -isoquinolin-1-one, as an oil (2.2 g, 95%). A solution of 2-N-benzyl-6-fluoro-3, -dihydro-2H-isoquinolm-1-one (2.2 g, 8.6 mmol) and hydrazine (6.7 ml, 0.215 mol) is stirred under reflux in dioxane (150 ml. ) low li nitrogen for 48 hours. The reaction mixture is concentrated to chromatograph on a column filled with silica gel using EtOAc / MeOH (9/1) to give the expected product, 2-N-benzyl-6-hydrazino-3, -dihydro-2H- isoquinolin-2-one, quantitatively, as an oil. A solution of 2-N-benzyl-6-hydrazino-3,4-dihydro-2H-isoquinolin-l-one (1.1 g, 4.1 mmol), 2- (3-chloropropyl) -1, 3-dioxolane (0.6 ml) , 4.1 mmol) and 1.0 M ethereal HCl (4.1 mL) is stirred at reflux in a degassed EtOH / HS0 solution (5/1, 200 mL) under nitrogen for 24 hours. The reaction mixture is partitioned between saturated aqueous NaHCO3 and isopropyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to perform multiple chromatography on a column filled with silica gel using a solution of CH2Cl2 / MeOH / NH4OH (9.0 / 1.0 / 0.1) to give a free base of the product desired as a matt white solid (0.35 g, 1.1 mmol, 27%). The product in methanol is treated with 1.0 M ethereal HCl (1.1 ml, 1.1 mmol) and recrystallized from CH2Cl2 / MeOH (1/1) to give the title compound as a white off-white solid. P.f. 262-263 ° C EM (IIE) m / e 320 (M + H) + A lis s -Elemental for: C20H21N30.HC1.H2O Calculated: C, 64.25, H, 6.47; N, 11.24 Found: C, 64.31, H, 6.09, N, 11.09 Compound 3 3- (2-Amino-ethyl) -6-benzylpyrrolo [2,3-g] isoquinolin-5-one A solution of 3- (2-amino-ethyl) -6-benzyl-l, 6, 7, 8-tetrahydro-pyrrolo [2, 3-g] isoquinolin-5-one (1 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (2 mmol) in chlorobenzene (15 ml) at reflux under nitrogen for 24 hours provides the title compound as a yellow solid. MS (IIE) m / e 228 (M + H) + Elemental Analysis for: C13H13N30 Calculated: C, 68.70, H, 5.70; N, 18.49 Found: C, 68.51, H, 5.59, N, 18.29 Compound 4 3- (2-N-benzylamino-ethyl) -1,6,7,8-tetrahydro-pyrrolo [2, 3-g] isoquinolin-5-one A solution of 3- (2-amino-ethyl) - 1, 6, 7, 8-tetrahydro-pyrrolo [2, 3-g] isoquinolin-5-one (0.229 g, 1 mmol, compound 1 above) and triethylamine (1 mmol) in CH2C12 (15 ml) is treated with chloride of benzoyl (1 equivalent) at 0 ° C and the mixture is stirred at room temperature for 16 hours.

Water (25 ml) is added, the organic substances are separated and washed with water (15 ml) and dried (MgSO4). Filtration and concentration in vacuo gives the required amide as a yellow oil (0.26 g, 78% yield). A THF solution (15 ml) of the amide was cooled to 0 ° C under an N2 atmosphere and treated by the dropwise addition of lithium aluminum hydride (1M THF, 1 ml). The mixture is refluxed for 30 minutes, cooled to 0 ° C and the excess hydride reagent is treated with saturated NH 4 Cl solution. The mixture is filtered, concentrated in vacuo, dissolved in ethyl acetate (15 ml), washed with water (2 x 20 ml), brine (15 ml), and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded the title amine as a yellow oil. MS (IIE) m / e 320 (M + H) + Elemental Analysis for: C20H21N30 Calculated: C, 75.21, H, 6.63; N, 13.16 Found: C, 75.03, H, 6.59, N, 13.29 Pharmaceutical Composition Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, slip agents, «,« «- * t AdjuBit compression, agglutination or tablet disintegrating agents or an encapsulation material. In the powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, low melting point waxes and exchange resins. ionic. The liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention may be diammony or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, a * flavoring agents, suspending agents, thickeners, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, for example cellulose derivatives, preferably a solution of carboxymethyl cellulose sodium), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, and oils (for example fractionated coconut oil and peanut oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in the compositions of the sterile liquid form for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration can be in the form of either liquid or solid composition. Preferably, the pharmaceutical composition is in the unit dosage form, for example as " -. i tablets or capsules). In such form, the composition is subdivided into unit doses containing appropriate amounts of the active ingredient; the unit dosage forms may be packaged compositions, for example packaged powders, ampoules, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, itself a capsule or tablet, or it can be the appropriate number of any such compositions in the packaged form. The therapeutically effective dosage that is to be used in the treatment of a specific disease must be determined subjectively by the attending physician. The novel method of the invention for the treatment of conditions related to or affected by the 5-HT7 receptor, comprises administering to the warm-blooded animals, including humans, an effective amount of at least one compound of the invention. Formula (1) and its pharmaceutically acceptable, non-toxic addition salts. The compounds can be administered orally, rectally, parenterally or topically to the skin and mucosa. The usual daily dose depends on the specific compound, method of treatment and condition treated. The usual daily dose is 0.01 - 1000 mg / kg for oral application, preferably 0.5 - 500 mg / kg and 0.1 - 100 ? .s mg / kg < f- > for pSenteal application, preferably 0.5-50 mg / kg.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. ? '£ i > * -asM? ^

Claims

TOUCHINGS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula I (1) characterized in that: R1 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 3 to 8 members, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 members or (CH2) ) mAr or (CH2) mHet; R2 is hydrogen, alkyl of 1 to 8 carbon atoms, (CH2) nAr or (CH2) nHet; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocyclic < • 4- to 9-membered alkyl, (CH2) nAr or (CH2) nHet; R 4 is hydrogen or alkyl of 1 to 8 carbon atoms; R is hydrogen or alkyl of 1 to 4 carbon atoms; X is [(CH = CH) R] n, (CH2) n, [(C = C) R] n, CHR (CH2) n, or CR2 (CH2) n; a dotted line represents an optional double bond; m is a selected integer of 1 or 2; and n is an integer selected from 0, 1 or 2; or pharmaceutically acceptable salts thereof.
2. A compound of claim 1, characterized in that R1, R2, R3 and R4 are independently selected from hydrogen or alkyl.
3. A compound of claim 1, characterized in that it is 3- (2-amino-ethyl) -1,6,7,8-tetrahydro-pyrrolo- [2, 3-g] isoquinolin-5-one.
4. A compound of claim 1, characterized in that it is 3- (2-amino-ethyl) -6-benzyl-l, 6, 7, 8-tetrahydro-pyrrolo- [2, 3-g] isoquinolin-5- ona
5. A compound of claim 1, characterized in that it is 3- (2-ammo-ethyl) -6-benzylpyrrolo- [2, 3-g] isoquinolin-5-one.
6. A compound of claim 1, characterized in that it is 3- (2-N-benzylamino-ethyl) -1,6,7,8-tetrahydro-pyrrolo- [2, 3-g]? Soquinolin-5-one. . Al- * í 4-
7. A pharmaceutical composition, characterized in that it comprises a compound of Formula I (i) wherein: R 1 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 3 to 8 members, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 members or (CH 2) ) mAr or (CH2) mHet; R2 is hydrogen, alkyl of 1 to 8 carbon atoms, (CH2) nAr or (CH2) nHet; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 elements, (CH2) nAr or (CH2) nHet; R 4 is hydrogen or alkyl of 1 to 8 carbon atoms; R is hydrogen or alkyl of 1 to 4 carbon atoms; v i is [(CH = CH) R] n, (CH2) n, ffC = C) R] n, CHR (CH2) n, or CR2 (CH2) n; a dotted line represents an optional double bond; m is a selected integer of 1 or 2; and n is a whole number selected from 0, 1 or 2, or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier or excipient, or a pharmaceutically acceptable salt thereof.
8. A method for treating conditions associated with 5-HT7 receptor dysfunction in a mammal in need thereof, characterized in that it comprises administering to the mammal an amount of the compound having Formula I (I) wherein: R 1 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocycloalkyl of 3 to 8 members, alkylcycloalkyl of 4 to 9 carbon atoms, alkyheterocyclohexamethylene from 4 to 9 elements or (CH2) mAr or (CH2) mHet; R2 is hydrogen, alkyl of 1 to 8 carbon atoms, (CH2)? IAr or (CH2) nHet; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, alkylcycloalkyl of 4 to 9 carbon atoms, alkylheterocycloalkyl of 4 to 9 elements, (CH2) nAr or (CH2) nHet; R 4 is hydrogen or alkyl of 1 to 8 carbon atoms; R is hydrogen or alkyl of 1 to 4 carbon atoms; X is [(CH = CH) R] n, (CH2) n, [(C = C) R] n, CHR (CH2) n, or CR2 (CH2) n; a dotted line represents an optional double bond; m is a selected integer of 1 or 2; and n is an integer selected from 0, 1 or 2; or a pharmaceutically acceptable salt thereof to alleviate the aforementioned condition. The method of claim 7, characterized in that the condition is a disorder of the central nervous system. The method of claim 7, characterized in that the disorder of the central nervous system is anxiety or depression. The method of claim 7, characterized in that the nervous system disorder It is schizophrenia, sleep disorders, migraine headaches, addiction to alcohol and drugs or sexual dysfunction. 12. A method of claim 7, characterized in that the condition is a cardiovascular disorder. 13. The method of claim 7, characterized in that the condition is hypotension. 14. A method of claim 7, characterized in that the condition is renal disorders. 15. A method of claim 7, characterized in that the condition is septic shock. 16. A method of claim 7, characterized in that the condition is a disorder of the gastrointestinal tract. 17. The method of claim 7, characterized in that the disorder is diarrhea or spastic colon. RESEFIT BE THE INVENTION The present invention relates to compounds of the formula (1) which are useful in the treatment of anxiety, depression and related disorders of the central nervous system and other conditions such as schizophrenia, sleep disorders, including cases of circadian rhythm, the treatment of alcohol and drug withdrawal and sexual dysfunctions. (i)