JP2003522178A - Pyrroloisoquinoline and tetrahydropyrroloisoquinoline derivatives and their use as mediators of the 5-HT7 receptor - Google Patents

Abstract

(57) Summary The compounds of formula (1) are useful in treating anxiety, depression and related disorders of the central nervous system and other conditions such as schizophrenia, sleep disorders (including in the case of circadian rhythms), etc. Useful for treatment, treatment of alcohol and drug withdrawal symptoms and sexual dysfunction. Embedded image

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION The recently identified human 5-hydroxytryptamine-7 (5-HT7) receptor subtype has been cloned and a widespread distribution of its mRNA has been reported. Highest levels of 5-HT7 receptor mRNA have been observed in the hypothalamus, thalamus, brainstem and hippocampus, while low levels are 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 been found in peripheral tissues: spleen, stomach, ileum, intestine, coronary arteries, descending colon, smooth muscle cells and heart.

Distribution and pharmacological studies suggest that the 5-HT7 receptor is involved in vasodilation and therefore may play a role in cardiovascular manifestations. The 5-HT7 receptor also plays a role in controlling the circadian rhythm of spontaneous electrical activity in the suprachiasmatic nucleus. The high affinity of many antipsychotics for the 5-HT7 receptor suggests that this receptor may help mediate the therapeutic effects of these compounds.

[0003]   formula:

[0004]

[Chemical 4]

Octahydro-pyrrolo-isoquinoline derivatives having [wherein R ² is hydrogen, alkyl, cycloalkyl, alkenyl, acyl, aryl or aralkyl] are disclosed in EP 10661 as antipsychotic neuroleptic agents. .

[0006]   formula:

[0007]

[Chemical 5]

Wherein R is phenyl or heterocycle; R ¹ , R ² are alkyl, carboxyalkyl, phenyl; and R ³ , R ⁴ contain 1 to 3 S, O or N atoms. Good 5 or 6
Anilated indole derivative having a member ring] is used as an anti-inflammatory drug according to DE 77-2
740836.

Treatment of anxiety, depression and related CNS disorders and other conditions such as schizophrenia, sleep disorders (including circadian rhythms), alcohol and drug withdrawal and sexual dysfunction A series of novel 3- (2-aminoethyl) pyrrolo [2,3-g] isoquinolin-5-one derivatives, which are therapeutically active pharmaceutical agents, are claimed.

SUMMARY OF THE INVENTION The present invention provides novel 3- (2-aminoethyl) pyrrolo [2,3-g] isoquinolin-5-one derivatives, processes for their preparation, pharmaceutical compositions containing them, and Regarding their use in therapy. Due to their ability to bind to the 5-HT7 receptor subtype, these compounds are associated with CNS disorders such as anxiety, depression and other conditions such as schizophrenia, sleep disorders (including circadian rhythm). It is thought to be useful for the treatment of migraine, alcohol and drug withdrawal and sexual dysfunction. The compounds of the invention may also find utility in the treatment of cardiovascular and septic shock, hypotension, renal failure, diarrhea and spastic colon.

[0011]   The compound of the present invention has the general formula (1)

[0012]

[Chemical 6]

[0013] [In the formula, R₁Is hydrogen, alkyl having 1 to 8 carbons, cycloalkyl having 3 to 8 carbons
3-8 membered heterocycloalkyl, alkylcycloalkyl having 4-9 carbon atoms,
4- to 9-membered alkylheterocycloalkyl or (CH_Two)_mAr or (CH_Two) _m Het;   R_TwoIs hydrogen, alkyl having 1 to 8 carbons, (CH_Two)_nAr or (CH_Two)_nHe
t;   R_ThreeIs hydrogen, alkyl having 1 to 8 carbons, alkylcycloalkyl having 4 to 9 carbons
4- to 9-membered alkylheterocycloalkyl, (CH_Two)_nAr or (CH_Two) _n Het;   R_FourIs hydrogen or alkyl having 1 to 8 carbon atoms;   R is hydrogen or alkyl having 1 to 4 carbon atoms;   X is [(CH = CH) R]_n, (CH_Two)_n, [(C≡C) R]_n, CHR (CH_Two)_nWell
Or CR_Two(CH_Two)_n;   Dotted lines represent optional double bonds;   m is an integer selected from 1 or 2; and   n is an integer selected from 0, 1 or 2] Or a pharmaceutically acceptable salt thereof.

In some preferred embodiments of the present invention, R ₁ is hydrogen, alkyl having 1 to 8 carbons, alkylcycloalkyl having 4 to 9 carbons, alkylheterocycloalkyl having 4 to 9 members, (CH ₂ ). _n Ar or (CH ₂ ) _n Het.

In another embodiment of the present invention, R ₂ is hydrogen or alkyl having 1 to 8 carbons. X is preferably (CH ₂ ) _n , and the optional double bond is preferably absent. R ₃ and R ₄ are preferably hydrogen or alkyl. Alkyl means straight or branched chain alkyl. Cycloalkyl means a saturated ring having 3 to 8 carbon atoms, preferably 5 to 6 carbon atoms (for example, cyclopentyl and cyclohexyl). Heterocycloalkyl means a saturated ring having 3 to 8 carbon atoms having 1 or 2 heteroatoms selected from N, O and S. Preferably, heterocycloalkyl is a 5- or 6-membered ring having at least one nitrogen heteroatom (eg,
Piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl and pyrazolidinyl).

Ar is aryl, preferably phenyl or naphthyl, fluorine, chlorine,
It may be substituted with one or more groups selected from bromine, iodine, hydroxy, alkyl having 1 to 6 carbons, trifluoromethyl, cyano and amino. Het means heteroaryl, which means a monocyclic 5- or 6-membered heteroaryl group or a bicyclic 9- or 10-membered heteroaryl group. Preferred heteroaryls have 1 or 2 heteroatoms selected from N, O and S,
When two heteroatoms are present, it is preferred that at least one heteroatom is nitrogen. Exemplary monocyclic heteroaryl groups include pyridinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, indolyl. Exemplary bicyclic heteroaryl groups include benzodioxanyl or quinolyl. The heteroaryl group may be substituted with one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, alkyl having 1 to 6 carbons, trifluoromethyl, cyano and amino.

The pharmaceutically acceptable salt is a compound represented by the above general formula and a pharmaceutically acceptable acid.
(For example, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, fumaric acid, acetic acid, lactic acid or methanesulfonic acid).

The compounds of the present invention contain a chiral center and give rise to various stereoisomers (eg racemic mixtures and optical isomers). The individual optical isomers can be prepared directly, or by asymmetric or stereospecific synthetic methods, or by conventional methods of separating optical isomers from racemic mixtures.

DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention may be made by one of ordinary skill in the art of organic synthesis using conventional methods, utilizing readily available reagents and starting materials. For example, an acidic solution of 5-fluoroindanone (eg, methanesulfonic acid) is reacted with sodium azide to give the required Schmidt rearrangement product. It can be alkylated with alkyl halides, alkylaryl halides or alkylheteroaryl halides under the influence of a base (e.g. sodium hydride) and the product treated with hydrazine hydrate to give the required product. Arylhydrazines can be obtained. The 1-aryl substituted hydrazine is reacted with a substituted aldehyde derivative or a protected derivative thereof (eg, enol ether or dioxolane protecting group) under Fisher's indole synthesis conditions to give 3-substituted-pyrrolo [2,3-g ] To obtain the isoquinolin-5-one compound. 2- (3-chloropropyl) -1,3-dioxolane is
An example of a suitably substituted and protected aldehyde derivative, dilute sulfuric acid or hydrochloric acid is a suitable catalyst or cosolvent for this reaction. The basic amine may be directly alkylated under the influence of a base (e.g. sodium hydride), for example by reaction with an alkyl halide or an alkylaryl halide, or the basic amine may be reacted with a carboxylic acid halide. The following amide can be reduced by the action of lithium aluminum hydride. These steps may be repeated to obtain the bis-alkylated derivative. The pyrrole nitrogen may be alkylated with an alkyl halide or an alkylaryl halide or an alkylheteroaryl halide under the influence of a base (eg sodium hydride). The optional double bond can be introduced by known conventional methods. For example, reacting 3-substituted-1,6,7,8-tetrahydropyrrolo [2,3-g] isoquinolin-5-one with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to give The required 3-substituted-pyrrolo [2,3-g] isoquinolin-5-one compounds of the invention are obtained.

[0020]

[Chemical 7]

The compounds of the present invention bind with very high affinity to the 5-HT7 receptor, so that they are useful in mediating the mammalian 5-HT7 receptor. The compounds of the present invention, due to their ability to bind to the 5-HT7 receptor subtype,
CNS disorders (eg, anxiety, depression) and related conditions (eg, GAD) as well as other conditions (eg, schizophrenia, sleep disorders (7)
It is useful for the treatment of circadian rhythms), migraine), alcohol and drug withdrawal and sexual dysfunction. Similarly, the compounds of the invention may find utility in the treatment of cardiovascular and septic shock, hypotension, renal failure, diarrhea and spastic colon.

5-HT7 Receptor Binding Assay High affinity for serotonin 5-HT7 receptor replaces [ ³ H] LSD binding in CHO cells stably transfected with human 5-HT7 receptor. It was established by testing the potency of the compounds described in. Human Cloned Receptor Membrane of Serotonin-7 Subtype, Expressed in Chinese Hamster Ovary (CHO) Cell Line, is Purchased from BioSignal Drug Discovery Technology (Montreal, Canada). Frozen ampoule of the receptor membrane was placed in 50.0 mM Tris.HCl buffer, p.
Reconstitute with H7.4 to obtain 15-20 μg tissue protein per 100.0 μl suspension. The diluted membranes are kept cold on ice and used immediately for the next binding experiment.

Binding experiments were performed in a 96-well microtiter plate format with a total volume of 200
Perform with μl. Prepare each well with 50 mM Tris.HCl buffer (pH 7.4),
80.0 μl incubation buffer containing 10.0 mM MgCl ₂ and 0.5 mM EDTA; 20 μl [ ³ H] LSD (SA, 86.0 Ci / mmol, Amersham Life Science) ) 5.0-6.
Add 0 nM. The dissociation constant K _D of [ ³ H] LSD at the human serotonin 5-HT7 receptor is 2.9 nM, as measured in saturation studies with increasing concentrations of [ ³ H] LSD. The reaction is started by the final addition of 100.0 μl tissue suspension. Non-specific binding is determined in the presence of 10.0 μM methiothepin added in a volume of 20.0 μl.

Test compounds are added in a volume of 20.0 μl when needed. The reaction proceeds in the dark at room temperature for 120 minutes. At this time, the bound ligand-receptor complex is filtered off on a 96-well unifilter using a Packard (registered trademark) Filtermate 196 Harvester. Filtermates were air dried, dried and 40.0 μl of Microscint®-20 scintillant added to each shallow well, followed by Packard (Packard) equipped with 6 photomultiplier detectors. Radioactivity is measured by Top Count®. Heat seal the unifilter plate and use Packard
Top Count® with a tritium efficiency of 31.0%.

Specific binding is defined as the total radioactivity bound less than the amount bound in the presence of 10.0 μM unlabeled methiothepin. Binding in the presence of varying concentrations of test drug is expressed as the percentage of specific binding in the absence of drug.
These results are then plotted as log (% binding) vs. log (concentration of test drug). Non-linear regression analysis of the data points is performed using the computer aided program Prism.TM. To obtain both _IC.sub.50 and _K.sub.i values for the test compound with 95% confidence limits. Alternatively, if a linear regression line with descending data points is plotted, then the IC ₅₀ value can be read and the K _i value can be determined by solving the following equation: K _i = IC ₅₀ / (1 + L / K _D ) where L is the concentration of the radioactive ligand used and K _D is the dissociation constant of the ligand for the receptor (both are expressed in nM).

Reference compounds tested using the above method: K _i value and 95% confidence interval Compound 5-HT7 binding Ki (nM) Clozapine 6.3 (2.6-11.0) nM Loxapine 43.0 ( 26.0-68.0) nM The compounds of the present invention showed activity in the above test. For example: Compound 5-HT7 bound Ki (nM) Compound 1 14

The following non-limiting specific examples are included to illustrate the synthetic methods used to make compounds of Formula 1. In these examples, all chemicals and intermediates are either commercially available or can be prepared by standard methods found in the literature, or are known to those skilled in the art of organic synthesis. Several preferred embodiments have been described to illustrate the invention. However, it should be understood that the invention is not limited to particular embodiments.

Intermediate 1 6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one While maintaining the temperature at 22 ° -29 ° C, sodium azide (7.8 g, 120 mmol) was added to methanesulfonic acid. To a stirred solution of 5-fluoroindanone (9 g, 60 mmol) in (35 mL) and dichloromethane (35 mL) was added portionwise. Once the addition was complete, the mixture was stirred at room temperature for 16 hours. This mixture at 0 ° C
The mixture was cooled to room temperature, neutralized by adding a 5N NaOH solution, and the organic layer was separated.
Wash the aqueous layer with dichloromethane (3 x 50 mL) and combine the organics with water (50 mL).
, Washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filter and concentrate to give a light oil (7.8 g). This was purified by flash silica gel chromatography (eluting with ethyl ether) to give the title compound as a white solid. Mp 107-108 ° C. M ⁺ 165 Elemental analysis (as _C 9 _H 8 FNO): 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-1-one 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (3.6 g, 0.02
A solution of 2 mol) and hydrazine (17.3 mL, 0.55 mol) was stirred under nitrogen in dioxane (150 mL) at reflux for 48 hours. The reaction mixture was concentrated under vacuum, water (150 mL) was added and the product was isolated by filtration. The product was washed extensively with diethyl ether to give the title compound quantitatively as a white solid. Melting point 158-160 ° C MS (EI) m / e 177 (M ⁺ ) Elemental analysis results (as C ₉ H ₁₁ N ₃ O.0.75H ₂ O): Calculated value : C, 56.68; H, 6. 61; N, 22.03 Found: C, 56.69; H, 6.11 ; N, 22.23

Compound 1 3- (2-Aminoethyl) -1,6,7,8-tetrahydropyrrolo [2,3-g] isoquino
Phosphorus-5-one 6-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (0.5 g, 2.3
Mmol) and 2- (3-chloropropyl) -1,3-dioxolane (0.31 mL, 2
A solution of 0.3 mmol) was stirred under nitrogen in degassed EtOH / H ₂ O (5/1, 90 mL) at reflux for 24 hours. The reaction mixture was partitioned between saturated aqueous NaHCO ₃ solution and isopropyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column with a CH ₂ Cl ₂ / MeOH / NH ₄ OH (9.0 / 1.0 / 0.1) solution. To give an oil. This oil, containing two isomers, was treated with Primesphere C-5 reversible preparative HP.
It was separated by _{LC (90% CH 3 CN /} H 2 O + 0.1% TFA), and lyophilized under vacuum the desired product was obtained the title compound as a yellow solid. Melting point 82-86 ° C MS (ESI) m / e 230 (M + H) ⁺ Elemental analysis result (as C ₁₃ H ₁₅ N ₃ O.C ₂ HF ₃ O ₂ · H ₂ O): Calculated value : C, 49.86 ; H, 4.60; N, 11.24 Found: C, 49.98; H, 4.65 ; N, 11.39

Compound 2 3- (2-Aminoethyl) -6-benzyl-1,6,7,8-tetrahydropyrrolo [2,3- g] isoquinolin-5-one 6-Fluoro- in acetonitrile (100 mL) 3,4-Dihydro-2H-isoquinolin-1-one (1.5 g, 9.1 mmol) and cesium carbonate (3.3 g, 1
(9 mmol) solution was stirred at room temperature under nitrogen. Benzyl bromide (1.2 mL)
10 mmol) was added and the mixture was refluxed for 15 hours. The reaction mixture is concentrated and chromatographed on a silica gel column with EtOAc / hexane (9/1) to give the expected product 2-N-benzyl-6-fluoro-3,4-dihydro- 2H-isoquinolin-1-one was obtained as an oil (2.2 g, 95%). 2-N-benzyl-6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (2
A solution of .2 g, 8.6 mmol) and hydrazine (6.7 mL, 0.215 mol) was stirred under reflux in dioxane (150 mL) under nitrogen for 48 hours. The reaction mixture was concentrated and chromatographed on a silica gel column with EtOAc / MeOH (9/1) to give the expected product 2-N-benzyl-6-hydrazino.
-3,4-Dihydro-2H-isoquinolin-1-one was quantitatively obtained as an oil. 2-N-benzyl-6-hydrazino-3,4-dihydro-2H-isoquinolin-1-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) under reflux in a degassed EtOH / H ₂ O (5/1, 200 mL) solution under reflux.
Stir for 4 hours. The reaction mixture was partitioned between saturated aqueous NaHCO ₃ solution and isopropyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and subjected to multiple chromatography on a silica gel column with CH ₂ Cl ₂ / MeOH / NH ₄ OH (9.0 / 1.0 / 0.1) solution. Chromatography gave the free base of the desired product as an off-white solid (0.35 g, 1.1 mmol, 27%). The product in methanol was treated with 1.0 M ethereal HCl (1.1 mL, 1.1 mmol) and recrystallized from CH ₂ Cl ₂ / MeOH (1/1) to give the title compound as an off-white color. Obtained as a solid. Mp 262~263 ℃ MS (ESI) m / e320 (M + H) + Elemental analysis (as _{C 20 H 21 N 3 O ·} HCl · H 2 O): Calculated: C, 64.25; H, 6 . 47; N, 11.24 Found: C, 64.31; H, 6.09 ; N, 11.09

Compound 3 3- (2-Aminoethyl) -6-benzylpyrrolo [2,3-g] isoquinolin-5-one 3- (2-aminoethyl) -6-benzyl-1 in chlorobenzene (15 mL) ,
A solution of 6,7,8-tetrahydropyrrolo [2,3-g] isoquinolin-5-one (1 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (2 mmol) was refluxed under nitrogen for 24 hours. To give the title compound as a yellow solid. MS (ESI) m / e 228 (M + H) ⁺ Elemental analysis result (as C ₁₃ H ₁₃ N ₃ O): Calculated value : C, 68.70; H, 5.70; N, 18.49 Found value : C , 68.51; H, 5.59; N, 18.29

Compound 4 3- (2-N-benzylaminoethyl) -1,6,7,8-tetrahydropyrrolo [2,3-
g] Isoquinolin-5-one 3- (2-aminoethyl) -1,6,7,8-tetrahydropyrrolo [2,3-g] isoquinolin-5-one (0. 0) in CH ₂ Cl ₂ (15 mL). A solution of 229 g, 1 mmol, compound 1) above and triethylamine (1 mmol) was treated with benzoyl chloride (1 eq) at 0 ° C. and the mixture was stirred at room temperature for 16 hours. Water (25 mL) was added and the organics separated, washed with water (15 mL), brine (15 mL) and (MgSO ₄ ).
Dried. Filter and concentrate in vacuo to remove the required amide as a yellow oil (
Obtained as 0.26 g, yield 78%). A solution of this amide in THF (15 mL) was cooled to 0 ° C. under N ₂ atmosphere, and lithium aluminum hydride (1M THF, 1 mL) was added.
Was added dropwise for treatment. The mixture was refluxed for 30 minutes, cooled to 0 ° C., and excess hydride reagent treated with saturated NH ₄ Cl solution. The mixture was 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. Filtered and concentrated in vacuo to give the title amine as a yellow oil. MS (ESI) m / e 320 (M + H) ⁺ Elemental analysis result (as C ₂₀ H ₂₁ N ₃ O): Calculated value : C, 75.21; H, 6.63; N, 13.16 Measured value : C , 75.03; H, 6.59; N, 13.29.

Pharmaceutical compositions Applicable solid carriers also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow agents, compression aids, binders or tablet disintegrating agents. There may be mentioned one or more possible substances or encapsulating materials. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% of active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. Liquid carriers include solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents,
Other suitable pharmaceutical additives such as suspending agents, thickening agents, coloring agents, viscosity adjusting agents, stabilizers or osmotic pressure adjusting agents may be included. Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing the above-mentioned additives (e.g., cellulose derivative, preferably sodium carboxymethylcellulose solution)), alcohol (
Mention may be made of monohydric and polyhydric alcohols (eg glycols) and their derivatives, as well as oils (eg 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 sterile liquid form compositions for parenteral administration.

The liquid pharmaceutical composition which is a sterile solution or suspension can be used by, for example, intramuscular, intraperitoneal or subcutaneous injection. The sterile solution can also be administered intravenously. Oral administration may be either liquid or solid composition form.

The pharmaceutical composition is preferably in unit dosage form, for example a tablet or capsule. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; The unit dosage form can be a packaged composition, for example, a packaged powder, a vial, an ampoule, a prefilled syringe or a liquid-containing sachet. The unit dosage form is
For example, it may be a capsule or tablet itself, or the composition may be in a suitable number of package forms.

The therapeutically effective amount to be used for treating a particular disease must be subjectively determined by the attending physician. A novel method of the present invention for treating a condition associated with or affected by the 5-HT7 receptor is to provide warm-blooded animals, including humans, with an effective amount of at least one of the formula (1) It consists of administering the compound or a non-toxic pharmaceutically acceptable addition salt thereof. These compounds may be administered orally, rectally, parenterally or topically to the skin and mucous membranes. A typical daily dose will depend on the particular compound, the method of treatment and the condition being treated. The usual daily dose is 0 for oral administration.
The dose is 01 to 1000 mg / Kg, preferably 0.5 to 500 mg / Kg, and 0.1 to 100 mg / Kg, preferably 0.5 to 50 mg / Kg for parenteral administration.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 25/18 A61P 25/18 25/20 25/20 25/22 25/22 25/24 25/24 25 / 32 25/32 25/36 25/36 43/00 111 43/00 111 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, A, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR , HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA , ZW (72) Inventor Yang Hee Kang United States 08691 Andover Place, No. 324 F Term, Robinsville, NJ 4C065 AA05 AA19 BB04 DD02 EE02 JJ04 KK05 PP01 4C086 AA01 AA02 AA03 CB05 MA02 MA05 NA14 ZA18 ZA05 ZA12 ZA12 ZA12 ZA43 ZA81 ZC10 ZC39

Claims (17)

[Claims] 1. Formula 1 [Chemical 1] [In the formula, R₁Is hydrogen, alkyl having 1 to 8 carbons, cycloalkyl having 3 to 8 carbons
3-8 membered heterocycloalkyl, alkylcycloalkyl having 4-9 carbon atoms,
4- to 9-membered alkylheterocycloalkyl or (CH_Two)_mAr or (CH_Two) _m Het;   R_TwoIs hydrogen, alkyl having 1 to 8 carbons, (CH_Two)_nAr or (CH_Two)_nHe
t;   R_ThreeIs hydrogen, alkyl having 1 to 8 carbons, alkylcycloalkyl having 4 to 9 carbons
4- to 9-membered alkylheterocycloalkyl, (CH_Two)_nAr or (CH_Two) _n Het;   R_FourIs hydrogen or alkyl having 1 to 8 carbon atoms;   R is hydrogen or alkyl having 1 to 4 carbon atoms;   X is [(CH = CH) R]_n, (CH_Two)_n, [(C≡C) R]_n, CHR (CH_Two)_nWell
Or CR_Two(CH_Two)_n;   Dotted lines represent optional double bonds;   m is an integer selected from 1 or 2; and   n is an integer selected from 0, 1 or 2] Or a pharmaceutically acceptable salt thereof. 2. A compound according to claim ₁ , wherein R ₁ , R ₂ , R ₃ and R ₄ are independently selected from hydrogen or alkyl. 3. 3- (2-Aminoethyl) -1,6,7,8-tetrahydropyrrolo- [
The compound of claim 1, which is 2,3-g] isoquinolin-5-one. 4. The compound according to claim 1, which is 3- (2-aminoethyl) -6-benzyl-1,6,7,8-tetrahydropyrrolo [2,3-g] isoquinolin-5-one. 5. The compound according to claim 1, which is 3- (2-aminoethyl) -6-benzylpyrrolo [2,3-g] isoquinolin-5-one. 6. The compound according to claim 1, which is 3- (2-N-benzylaminoethyl) -1,6,7,8-tetrahydropyrrolo [2,3-g] isoquinolin-5-one. 7. Formula I [Chemical 2] [In the formula, R₁Is hydrogen, alkyl having 1 to 8 carbons, cycloalkyl having 3 to 8 carbons
3-8 membered heterocycloalkyl, alkylcycloalkyl having 4-9 carbon atoms,
4- to 9-membered alkylheterocycloalkyl or (CH_Two)_mAr or (CH_Two) _m Het;   R_TwoIs hydrogen, alkyl having 1 to 8 carbons, (CH_Two)_nAr or (CH_Two)_nHe
t;   R_ThreeIs hydrogen, alkyl having 1 to 8 carbons, alkylcycloalkyl having 4 to 9 carbons
4- to 9-membered alkylheterocycloalkyl, (CH_Two)_nAr or (CH_Two) _n Het;   R_FourIs hydrogen or alkyl having 1 to 8 carbon atoms;   R is hydrogen or alkyl having 1 to 4 carbon atoms;   X is [(CH = CH) R]_n, (CH_Two)_n, [(C≡C) R]_n, CHR (CH_Two)_nWell
Or CR_Two(CH_Two)_n;   Dotted lines represent optional double bonds;   m is an integer selected from 1 or 2; and   n is an integer selected from 0, 1 or 2] Or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier or excipient,
A pharmaceutical composition comprising. 8. The function of 5-HT7 receptor in mammals in need thereof
A method of treating a condition associated with insufficiency, wherein the condition is alleviated in the mammal
An effective amount of Formula I [Chemical 3] [In the formula, R₁Is hydrogen, alkyl having 1 to 8 carbons, cycloalkyl having 3 to 8 carbons
3-8 membered heterocycloalkyl, alkylcycloalkyl having 4-9 carbon atoms,
4- to 9-membered alkylheterocycloalkyl or (CH_Two)_mAr or (CH_Two) _m Het;   R_TwoIs hydrogen, alkyl having 1 to 8 carbons, (CH_Two)_nAr or (CH_Two)_nHe
t;   R_ThreeIs hydrogen, alkyl having 1 to 8 carbons, alkylcycloalkyl having 4 to 9 carbons
4- to 9-membered alkylheterocycloalkyl, (CH_Two)_nAr or (CH_Two) _n Het;   R_FourIs hydrogen or alkyl having 1 to 8 carbon atoms;   R is hydrogen or alkyl having 1 to 4 carbon atoms;   X is [(CH = CH) R]_n, (CH_Two)_n, [(C≡C) R]_n, CHR (CH_Two)_nWell
Or CR_Two(CH_Two)_n;   Dotted lines represent optional double bonds;   m is an integer selected from 1 or 2; and   n is an integer selected from 0, 1 or 2] And a pharmaceutically acceptable salt thereof. 9. The method of claim 7, wherein the condition is a disorder of the central nervous system. 10. The central nervous system disorder is anxiety or depression.
The method described. 11. The method of claim 7, wherein the disorder of the central nervous system is schizophrenia, sleep disorders, migraine, alcohol and drug addiction, or sexual dysfunction. 12. The method of claim 7, wherein the condition is cardiovascular disorder. 13. The method of claim 7, wherein the condition is hypotension. 14. The method of claim 7, wherein the condition is renal failure. 15. The method of claim 7, wherein the condition is septic shock. 16. The method of claim 7, wherein the condition is a disorder of the digestive tract. 17. The method of claim 7, wherein the disorder is diarrhea or spastic colon.