JPH09512025A - Tricyclic derivatives as 5HT-lower 2C and 5HT-lower 2B antagonists - Google Patents

Abstract

(57) [Summary] Formula (I): [Wherein P represents a phenyl, quinoline or isoquinoline residue, or a 5- or 6-membered aromatic heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen or sulfur; J is a bicyclic aromatic Represents a group or partially saturated ring system; R ¹ and R ² are independently hydrogen, halogen, hydroxy, oxygen, or C _1- , optionally substituted by one or more halogen atoms _{. 6} alkyl; R ⁴ is hydrogen, C _1-6 alkyl, C _1-6 alkylthio, halogen, nitro, cyano, CF ₃ , NR ⁸ R ⁹ , CO ₂ R ¹² , CONR ¹² or OR ¹² , where R is ⁸ , R ⁹ and R ¹² are independently hydrogen, C _1-6 alkyl or aryl C _1-6 alkyl; R ⁵ is hydrogen or C _1-6 alkyl; n is 2 or 3; R ¹³ and R ¹⁴ Is hydrogen or C _{1 to 6} by standing, provided that the compound represented by] P of not a heterocyclic group when J forms a benzothiophene ring, their use as their preparation and CNS agents Is disclosed.

Description

Detailed Description of the Invention         5HT_2CAnd 5HT_2BTricyclic derivatives as antagonists   The present invention comprises compounds having pharmacological activity, a process for producing them, and those containing them. Compositions and their use in the treatment of mammals.   WO94 / 04533 (SmithKline Bee plm (SmithKline Bee cham plc)) describes indole and indole derivatives. 5HT_2CIt is described as having receptor antagonist activity. Structurally clear Finally, a new class of compounds has been found, which are 5HT_2CReceptor antagonist It was found to have activity. Some or all of the compounds of the invention are 5 HT_2BIt also has antagonist activity. 5HT_{2C / 2B}Receptor antagonists Anesthesia, depression, epilepsy, obsessive-compulsive disorder, migraine, Alzheimer's disease, sleep disorders, diet Anorexia and sensory disorders such as abnormal hunger, terror attacks, cocaine, ethanol, Escape from substance abuse such as nicotine and benzodiazepines, schizophrenia, In addition, diseases associated with head injury such as spinal cord trauma and / or hydrocephalus It is considered to be potentially useful in treating CNS disorders. The compound of the present invention is IBS Certain GI disorders such as, or also microscopic such as macular edema and retinopathy It is also expected to be useful in the treatment of vascular disease.   Therefore, in a first aspect, the invention provides a compound of formula (I): [Wherein P is a phenyl, quinoline or isoquinoline residue, or 5 member containing up to 3 heteroatoms selected from elemental, oxygen or sulfur or Represents a 6-membered aromatic heterocycle;   J represents a bicyclic aromatic or partially saturated aromatic ring system;   R¹And R²Are independently hydrogen, halogen, hydroxy, oxygen, or C optionally substituted by one or more halogen atoms_{1 ~ 6} Alkyl;   R^FourIs hydrogen, C_{1 to 6}Alkyl, C_{1 to 6}Alkylthio, halogen, nitro, sia No, CF_Three, NR⁸R⁹, CO₂R¹², CONR¹²Or OR¹²Where R⁸ , R⁹And R¹²Is independently hydrogen, C_{1 to 6}Alkyl or aryl C_{1 to 6}Archi Is;   R^FiveIs hydrogen or C_{1 to 6}Alkyl;   n is 2 or 3;   Group R¹³And R¹⁴Is independently hydrogen or C_{1 to 6}However,   P is not a heterocyclic group when J forms a benzothiophene ring] Or a salt thereof.   C_{1 to 6}The alkyl group may be alone or as part of another group. May be linear or branched, preferably methyl, ethyl, C such as n- and iso-propyl_{1 to 3}Alkyl.   Suitably R¹And R²Are independently hydrogen, halogen, hydroxy, oxygen Or optionally substituted by one or more halogen atoms Good C_{1 to 6}Alkyl. Preferably R¹And R²Are both hydrogen .   Suitably R^FourIs hydrogen, C_{1 to 6}Alkyl, C_{1 to 6}Alkylthio, halogen, C F_Three, NR⁸R⁹Or OR¹²And here, R⁸, R⁹And R¹²Is independently water Elementary, C_{1 to 6}Alkyl or aryl C_{1 to 6}Alkyl. Preferably R^FourIs Hydrogen.   Suitably R^FiveIs hydrogen or C_{1 to 6}Alkyl. Preferably R^FiveIs hydrogen is there.   Suitably, P is a phenylenequinoline or isoquinoline residue, or a nitrogen, 5- or 6-membered containing up to 3 heteroatoms selected from oxygen or sulfur Represents an aromatic heterocycle. When Ring P is a 5-membered aromatic heterocycle, a suitable moiety ( moiety) is, for example, isothiazolyl, isoxazolyl, thiadiazolyl and And triazolyl. When Ring P is a 6-membered aromatic heterocycle, suitable Moieties include, for example, pyridyl, pyrimidyl or pyrazinyl. P is kino When it is a phosphorus or isoquinoline residue, the urea moiety is at any position on the ring. Although it can also be bonded, it is preferably bonded at the 4-position. Preferably P is a 6-membered heterocycle And most preferably a 3-pyridyl group.   The urea moiety may be attached to a carbon atom of ring P or any available nitrogen atom. , Preferably attached to a carbon atom.   Suitably J represents a bicyclic aromatic or partially saturated ring system. Preferred Specifically, J is quinoline, tetrahydroquinoline, indazole, benzothiophene. Amine, dihydrobenzothiophene, indene, indane, benzothiazole, benzene Represents a zofuran or dihydrobenzofuran ring. Preferably, J is quinoline, te Trahydroquinoline, benzothiophene, benzofuran or indane.   Suitably, the group-(CR¹³R¹⁴)_n-Forms ethylene or propylene, which Each is C_{1 to 6}It may be substituted with alkyl. J is quinoline or tetra When it is hydroquinoline, the group-(CR¹³R¹⁴)_n-Attached to the 5th or 7th position of ring J And the urea bond is attached to the 6-position. When J is quinoline, the group-(CR¹³ R¹⁴)_n-Can also be bonded to the 2- or 4-position of ring J, and the urea bond is bonded to the 3-position. When J is a 6 or 5 membered ring system, for example a benzofuran ring, the group-(CR^{1 Three} R¹⁴)_n-Can be attached at the 4- or 6-position, the urea bond at the 5-position, or Is-(CR¹³R¹⁴)_n-Can be attached to the 5th or 7th position, and the urea bond can be attached to the 6th position. You. Preferably, the group-(CR¹³R¹⁴)_n− Is ethylene.   Particularly preferred compounds of formula (I) are 1- (3-pyridylcarbamoyl) -2,3-dihydro-1H-pyrrolo [2,3- g] quinoline, 2-Methyl-6,7-dihydro-5- (3-pyridylcarbamoyl) -furo [2, 3-f] Indore, 1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo- [2,3-f]- Inden, 2,3-Dihydro-1- (3-pyridylcarbamoyl) -pyrrolo [3,2-b] ki Norin, 5,6-dihydro-3-methyl-N- (3-pyridyl) -furo [3,2-f] yne Dole-7-carboxamide, 2,2-Dimethyl-2,3,6,7-tetrahydro-N- (3-pyridyl) furo [2 , 3-f] indole-5-carboxamide, 2,3,6,7-Tetrahydro-5- (3-pyridylcarbamoyl) -5H-thie No [2,3-f] indole, 5-methyl-N- (3-pyridyl) -2,3,5,6,7,8, -hexahydro-1H -Pyrrolo [2,3-g] quinoline-1-carboxamide, 2,3-dihydro-7-hydroxy-1- (3-pyridylcarbamoyl) pyrrolo -[2,3-f] indane, 2,3-Dihydro-7-oxo-1- (3-pyridylcarbamoyl) pyrrolo- [ 2,3-f] Indan, 2-Bromo-5,6-dihydro-N- (3-pyridyl) -thieno- [3,2-f] Indole-7-carboxamide, 5,6-Dihydro-N- (3-pyridyl) -thieno [3,2-f] -indole- 7-carboxamide, Alternatively, it includes pharmaceutically acceptable salts thereof.   Compounds of formula (I) are conventional pharmaceutically acceptable acids such as maleic acid, salts. Acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mann Forming acid addition salts with acids such as delineic acid, tartaric acid and methanesulfonic acid Can be.   Certain compounds of formula (I) may also be solvates such as N-oxides or hydrates. Can be formed and the present invention also includes these forms. In such a case, Honmei It is understood that the term “compound of formula (I)” in the text encompasses these forms as well.   Certain compounds of formula (I), eg, P is pyridyl, R^FourIs hydroxy Or NR⁸R⁹And R⁸And R⁹A compound in which at least one of the is hydrogen An entity may exist as one or more forms of tautomers. The present invention , Or any other tautomer and mixtures thereof.   Certain compounds of formula (I) exist as stereoisomers, including enantiomers. The present invention is directed to each of these stereoisomers, and those containing racemates. Of mixtures. Separation of different stereoisomers from each other by a useful method Or any stereoisomer by stereospecific or asymmetric synthesis. Can also be obtained.   The present invention further provides a method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof. And formula (II): A compound represented by the formula (III) Wherein A and R⁶Is a partial -NR when bound^Five'Necessary to form CO A suitable functional group, wherein R^Five'Is R defined in formula (I)^FiveIs Or R^FiveAnd n, J and P are defined in formula (I). Is the same as what was meant, and the variable R^{1 '}, R^{2 '}, R^Four', R^Five', R^13'And R^14'Haso R defined in formula (I) respectively¹, R², R^Four, R^Five, R¹³And R¹⁴Is Or a group convertible to them] And then optionally and optionally Can be in the order^{1 '}, R^{2 '}, R^Four', R^Five', R^13'And R^{1 Four'} Is R¹, R², R^Four, R^Five, R¹³And R¹⁴If they are other than R¹, R² , R^Four, R^Five, R¹³And R¹⁴Converted to R¹, R², R^Four, R^Five, R¹³And R¹⁴To Providing a method consisting of mutual exchange and then forming a pharmaceutically acceptable salt thereof. Offer.   Groups A and R⁶Suitable examples of include:   (i) A is -N = C = O and R⁶Is -H,   (ii) A is -NR^Five'R at COL⁶Is -H,   (iii) A is -NHR^Five'And R⁶Is COL, or   (iv) A is halogen and R⁶Is -CONHR^Five'   Where R^Five'Is the same as defined above, and L is a leaving group. Of a suitable leaving group L Examples are halogens such as imidazole, chloro or bromo or optionally Include, for example, phenoxy or phenylthio which may be substituted with halogen. Including.   A is -N = C = O and R⁶Is H, suitably an inert solvent such as The reaction is carried out at ambient temperature in dichloromethane or toluene.   A is -NR^Five'COL and R⁶Is H, or A is -NHR^Five'Is R⁶Is COL, suitably in an inert solvent such as zirlomethane, Reaction at ambient temperature, optionally in the presence of a base such as triethylamine. Reaction or in dimethylformamide at ambient or elevated temperature And react.   A is halogen and R⁶Is CONHR^Five'If it is Then, the temperature is raised in an inert solvent, and the reaction is carried out in the presence of a base if desired.   R^FourRadical R convertible to alkyl group^Four'Suitable examples of are conventionally introduced acyl Conventional reduction involving groups, such as the use of sodium borohydride in an inert solvent , Then converted to the corresponding alkyl group by hydrogenolysis in an inert solvent. it can. Alkoxycarbonyl that can be converted to hydrogen by hydrolysis and decarboxylation Base May obtain a hydrogen substituent. R^FourWhen is hydroxy, preferably In the compound of formula (II) it is And protect.   R^FiveGroup R convertible to^Five'Suitable examples of are alkoxycarbonyl and benzyl Or para-methoxybenzyl, R which is hydrogen using conventional conditions.^FiveStrange Will be replaced.   R by selective halogenation of ring P or J respectively using conventional conditions^FourHalo And R¹/ R²A halo group may be introduced.   By treating the compound of formula (II) below as follows, A is -N = C = O. A compound of formula (II) may be obtained: i) When A is amino, phosgene or in the presence of excess base in an inert solvent. Or treated with phosgene equivalent ii) A is an acyl azide (ie CON_Three), Conventional conditions (d L.S.Trifonov and others, Helve Kimi Actor (Helv.Chi m.Acta), 1987, 70, 262). Via Ren iii) A is CONH₂If is then via nitrene using conventional conditions   A is NR^Five'From the corresponding amine, which is H, a phosgene equivalent, such as chloroformate When treated with nil, A is NR^Five'To obtain a compound of formula (II) which is COL Can be. A is halogen and R^Four'A compound of formula (II) in which is hydrogen is commercially available ing.   Methods well known in the art, eg similar to WO94 / 04533 The method may be used to obtain compounds of formula (III).   The novel intermediates of formula (III) also form part of the invention.   Reaction with a suitable acid or acid derivative affords a conventionally pharmaceutically acceptable salt. Good. N-oxides are conventionally converted to N-oxides by reaction with hydrogen peroxide or percarboxylic acids. You may get it.   The compounds of formula (I) and their pharmaceutically acceptable salts are 5HT_2CReceptor you Has gonist activity, some compounds are 5HT_2BShows antagonist activity. So Therefore, the compounds of formula (I) are suitable for the treatment of anxiety, depression, epilepsy, obsessive-compulsive disorder, migraine, Alzheimer's disease, sleep disorders, loss of appetite and sensory disorders such as abnormal hunger, fear Drugs such as seizures, cocaine, ethanol, nicotine and benzodiazepines Escape from substance abuse, schizophrenia, and even spinal cord trauma and / or hydrocephalus Considered to be potentially useful in the treatment of CNS disorders such as those associated with head injury Can be The compounds of the invention are useful in the treatment of certain GI disorders such as IBS. Can also be considered. Therefore, the present invention specifically relates to the treatment or prevention of the above-mentioned diseases. Of the formula (I) or a pharmaceutically acceptable compound thereof for use as a therapeutic substance in Ru salt is also provided.   The invention further provides a method of treating or preventing the above diseases, wherein a therapeutically effective amount of the formula A method comprising administering a compound of (I) or a pharmaceutically acceptable salt thereof to a patient Provide the law.   In another aspect, the present invention provides a medicament for treating or preventing the above-mentioned diseases. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of You.   The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a medicament. There is provided a pharmaceutical composition comprising the above acceptable carrier.   The pharmaceutical composition of the present invention, which may be prepared by mixing, suitably at ambient temperature and pressure The article is usually adapted for oral, parenteral or rectal administration, and as such, Tablets, capsules, oral liquid preparations, powders, granules, sweetened tablets, reconstitutable powders , Injectable or infusible solutions or suspensions, or in the form of suppositories Good. Orally administrable compositions are generally preferred.   Tablets and capsules for oral administration may be in unit dosage form, including binders, fillers, Contains conventional excipients such as tabletting lubricants, disintegrants and acceptable wetting agents. May be. The tablets are coated by methods well known in normal pharmaceutical practice. You may sing.   Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, May be syrup or elixir, or with water or other suitable carrier It may be in the form of a dry product that is reconstituted before use. Such liquid preparations are suspensions Agents, emulsifiers, non-aqueous carriers (including edible oils), preservatives and, if desired, conventional It may also contain conventional additives such as aromatics or colours.   For parenteral administration, the compound of the present invention or a pharmaceutically acceptable salt thereof and sterile A liquid unit dosage form is prepared using a solid carrier. Depending on the carrier used and the concentration used, The compound is suspended or dissolved in the carrier. When preparing the solution, dissolve the compound in water for injection. Sterilize, filter sterilize, fill into a suitable vial or ampoule, then It can be sealed. Advantageously, an adjuvant such as a local anesthetic, preservation The drug and buffer are dissolved in the carrier. In order to improve stability, the composition should be It can be frozen after being filled in aluminum and removing water under reduced pressure. Compound Suspend instead of dissolving in the body, but not sterilizing by filtration A parenteral suspension is prepared by the method described in. Ethyleneoxy before suspension in sterile carrier The compound can be sterilized by exposure to a solvent. Advantageously, Or wetting agents may be included in the composition to facilitate uniform distribution of the compound.   Depending on the mode of administration, the composition may range from 0.1% to 99% by weight, preferably 10%. It may contain 60% by weight of active substance.   The dose of the compound used to treat the above-mentioned diseases depends on the severity of the disease, the weight of the patient, and other factors. Will be modified in the usual way by similar factors in. However, As a general guide, a suitable unit dose is 0.05 to 1000 mg, more appropriate Is in the range of 0.05 to 70.0 mg, such as 0.2 to 5 mg, such units Dosage may be administered once or more times daily, for example 2 or 3 times daily with a total daily dose of about 0. It may be in the range of 0.01 to 100 mg. How many weeks Or for months.   Unacceptable toxicological effects when administered in accordance with the invention are associated with compounds of the invention. I can't think of it.   The following examples illustrate the preparation of pharmacologically active compounds of this invention. Description example 1 6-nitro-1-trifluoroacetylindoline (D1)   While adding trifluoroacetic anhydride (6.6 ml, 47 mmol) dropwise, Troindoline (6.50 g, 40 mmol) and triethylamine (6.6 m 1, 47 mmol) was stirred in dichloromethane (65 ml). This mixture Stir 0.75 h and add water (100 ml). Stir for 10 minutes, then mix The material was acidified with 5M HCl and separated. Wash the organic portion with brine and dry (Na₂SO_Four) And evaporated to give the title compound (9.64 g, 93%) as a tan solid. Got as. NMR (CDCl_Three) Δ: 3.4 (2H, t, J 8), 4.4 (2H, t, J 8), 7.4 (1H, d, J 8), 8.1 (1H, dd, J 8,2), 9.05 (1H, d, J)  2). Description example 2 6-amino-1-trifluoroacetylindoline (D2)   6-Nitro-1-trifluoroacetylindoline (D1) (4.10 g, 1 6 mmol) to 5% palladium (60% aqueous paste, 1.0 g) on activated carbon. More, it was hydrogenated in ethanol (200 ml) for 4 hours. The catalyst is filtered off and the filtrate is Evaporation gave the title compound (3.60 g, 99%) as a pale brown solid. NMR (CDCl_Three) Δ: 3.15 (2H, t, J 8), 3.35 (2H, b), 4. 25 (2H, t, J 8), 6.5 (1H, dd, J 8,2), 7.0 (1H, d, J 8) ), 7.65 (1H, d, J 2). Description example 3 6-Hydroxy-1-trifluoroacetylindoline (D3)   Dark H₂SO_FourWhile adding (3 ml) dropwise, 6-amino-1-trifluoroacetyl Stir Ruindoline (D2) (2.98 g, 13 mmol) in water (30 ml) did. The solution was cooled to 0 ° C., in water (10 ml) maintaining the temperature ≦ 0 ° C. NaNO₂(0.98 g, 14 mmol) was added dropwise. The mixture is stirred for 5 minutes , Then CuSO 4 in water (50 ml)_Four・ 5H₂O (13.0 g, 5 mmol) Transferred to boiling solution. The mixture is boiled for 5 minutes, then cooled and the black solid filtered off. And air-dried. Silica gel chromatograph eluting with 0-5% methanol in chloroform To give the title compound (1.01 g, 67%) as a dark brown solid by topography. Was. NMR (DMSO-d₆) Δ: 3.1 (2H, t, J 8), 4.25 (2H, t, J) 8), 6.6 (1H dd, J 8,2), 7.1 (1H, d, J 8), 7.6 (1H, d, 2), 9.05 (1H, s). Description example 4 6- (2-oxopropoxy) -1-trifluoroacetylindoline (D4)   6-Hydroxy-1-trifluoroacetylindoline (D3) (2.00 g , 8.7 mmol), anhydrous K₂CO_Three(1.79 g, 13.0 mmol) and black Roacetone (0.84 ml, 10.4 mmol) in dry DMF (20 ml) 64 Stirred for hours. The mixture was diluted with ethyl acetate (200 ml), water, then brine. Washed in and dried (Na₂SO_Four) And then evaporated to give the title compound (2.4 2 g, 97%) was obtained as a brown oil.   Silica gel chromatography eluting with 0-10% ethyl acetate in chloroform Purify a portion of it to give the title compound as a slightly off-white solid. Was. NMR (CDCl_Three) Δ: 2.3 (3H, s), 3.2 (2H, t, J 8), 4.3 ( 2H, t, J 8), 4.6 (2H, s), 6.75 (1H, dd, J 8,2), 7.1 5 (1H, d, J8), 7.85 (1H, d, J2). Description example 5 5,6-dihydro-3-methyl-7-trifluoroacetylfuro [3,2-f] ii Ndor (D5)   Dark H₂SO_Four(25 ml) at 0 ° C. in 6- (2-oxopropoxy) -1- Added to trifluoroacetyl indoline (D4) (2.42 g, 8.4 mmol) did. The dark mixture was then stirred at ambient temperature for 15 minutes and poured onto ice. Crude generation The product was extracted into ethyl acetate and the extract washed with water then brine and dried (N a₂SO_Four) And then evaporated to give a brown gum. Elute with chloroform Silica gel chromatography to give the title compound (0.47g, 21%) Was obtained as a yellow solid. NMR (CDCl_Three) Δ: 2.25 (3H, s), 3.35 (2H, t, J 8), 4. 35 (2H, t, J 8), 7.35 (1H, s), 7.45 (1H, s), 8.35 (1H, s). Description example 6 5,6-Dihydro-3-methylfuro [3,2-f] indole (D6)   5,6-dihydro-3 while adding 2.5 M sodium hydroxide (1 ml) -Methyl-7-trifluoroacetylfuro [3,2-f] indole (D5) (0.49 g, 1.8 mmol) was stirred in ethanol (10 ml). mixture Was stirred for 15 minutes, diluted with water and extracted with ethyl acetate. Wash the extract with brine Clean and dry (Na₂SO_Four) And then evaporated to give the title compound (0.29 g, 9 6%) as a brown oil. NMR (CDCl_Three) Δ: 2.2 (3H, s), 3.1 (2H, t, J 8), 3.3 ( 1H, vb), 3.6 (2H, t, J8), 6.7 (1H, s), 7.2 (2H, m). Description example 7 5-benzyloxyindoline (D7)   Sodium cyanoborohydride (11.9g, 189mmol) over 1 hour While adding dropwise, 5-benzyloxindole (14.0 g, 63 mmol) Was stirred in glacial acetic acid at 15 ° C. The mixture was stirred for an additional hour and water (50 0 ml) and made basic by adding potassium hydroxide. This mixture The mixture was extracted with ethyl acetate and the extract was dried (Na₂SO_Four) And let it evaporate The title compound (14.09 g, 100%) was obtained as a cloudy oil.¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 2.99 (2H, t, J 8), 3. 0 (1H, b), 3.54 (2H, t, J8), 4.98 (2H, s), 6.55-6 .7 (2H, m), 6.85 (1H, m), 7.3 to 7.5 (5H, m). Description example 8 5-benzyloxy-1-trifluoroacetylindoline (D8)   Carefully add trifluoroacetic anhydride (10.5 ml, 75 mmol). 5-benzyloxyindoline (D7, 14.09 g, 63 mmol) and And triethylamine (10.5 ml, 75 mmol) in dichloromethane (250 ml). After stirring for 1 hour, water (200 ml) was added and the mixture was added to 15 Stir vigorously for min, acidify (5M HCl) and separate. Diclosure the aqueous part Extract with dichloromethane and wash the combined organic portions with brine and dry (Na₂SO_Four ) And evaporated to give the title compound (22.5 g) as a brown solid.¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 3.22 (2H, t, J 8), 4. 29 (2H, t, J 8), 5.07 (2H, s), 6.8 to 6.95 (2H, m), 7 .3 to 7.5 (5H, m), 8.12 (1H, d, J8). Description example 9 5-hydroxy-1-trifluoroacetylindoline (D9)   5-benzyloxy-1-trifluoroacetylindoline (D8, 22.5 g, nominally 70 mmol) and 5% palladium on activated carbon (60% aqueous paste 5.0 g) was hydrogenated in ethanol (400 ml) for 18 hours. Further catalyst Was added and hydrogenation was continued for another 18 hours. Then, the catalyst is on kieselguhr) and the filtrate was evaporated to give a gummy solid. Ethyl acetate Dissolved in dilute HCl, diluted HCl, water, NaHCO_ThreeWash with saturated solution, then brine Clean and dry (Na₂SO_Four) And evaporated to give the title compound (14.37 g, 88%). Was obtained as a pale yellow solid.¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 2.97 (2H, t, J 8), 4. 01 (2H, t, J 8), 6.4 to 6.6 (2H, m), 7.74 (1H, d, J 8) , 8.8 (1H, b). Description example 10 5- (2-Methyl-1-propen-3-yloxy) -1-trifluoroacetyl Ruindoline (D10)   5-hydroxy-1-trifluoroacetylindoline (D9, 4.56 g, 20 mmol), anhydrous potassium carbonate (4.1 g, 30 mmol) and meta chloride. Ril (3.9 mg, 40 mmol) was stirred in dry DMF at 60 ° C. for 16 hours. Next Then add more potassium carbonate and methallyl chloride and react for another 24 hours. Continued. It was then partitioned between ethyl acetate and water and separated. Water the organic part Then washed with brine and dried (Na₂SO_Four) And evaporated to give the title compound (5.00 g, 89%) was obtained as a brown oil.¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 1.73 (3H, s), 3.32 ( 2H, t, J 8), 4.26 (2H, t, J 8), 4.43 (2H, s), 5.00 ( 1H, s), 5.09 (1H, s), 6.8 (2H, m), 8.10 (1H, d, J 8 ). Description example 11 2,2-Dimethyl-2,3,6,7-tetrahydro-5-trifluoroacetylfuro [2,3-f] Indole (D11)   5- (2-methyl-1-propen-3-yloxy) -1-trifluoroacetate Cylindolin (D10, 5.00 g, 18 mmol) was added to N, N-diene under Ar. Stir in chillaniline (25 ml) at 215 ° C. for 5.5 hours. Then the mixture Was cooled, diluted with ethyl acetate, washed with 5M HCl, then brine and dried. Dry (Na₂SO_Four) And evaporated to give a brown gum. Silica gel chromatography Raffy (0 → 100% CH₂Cl₂/ CHCl_Three, Gradient) The compound (2.1 g, 42%) was obtained as a pale yellow waxy solid.¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 1.48 (6H, s), 3.00 ( 2H, s), 3.19 (2H, t, J 8), 4.25 (2H, t, J 8), 6.63 ( 1H, s), 8.03 (1H, s). Description example 12 2,2-Dimethyl-2,3,6,7-tetrahydrofuro [2,3-f] indole ( D12)   2,2-dimethyl-2,3,6,7-tetrahydro-5-trifluoroacetyl B) [2,3-f] indole (D11, 0.26 g, 0.91 mmol) was added to 10% Stir for 2 hours in ethanol (10 ml) containing sodium hydroxide (1 ml) did. The mixture was then partitioned between ethyl acetate and water and separated. Organic part Washed with brine and dried (Na₂SO_Four) And evaporated to give the title compound (0.15 g, 85%) as a yellow-green oil.¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 1.46 (6H, s), 2.92 ( 2H, s), 2.95 (1H, t, J 8), 3.4 (1H, b), 3.50 (2H, t, J 8), 6.49 (1H, s), 6.56 (1H, s). Description example 13 2,3,6,7-Tetrahydro-5H-thieno [2,3-f] indole (D13)   Trifluoroacetic acid (4 ml) was added to 6,7-dihydro-5- (3-pyridylcarboxyl). Vamoyl) -5H-thieno [2,3-f] indole (see WO94 / 22871) 50) in a mixture consisting of lantern (1.0 g) and triethylsilane (1.63 ml). Added while heating to ° C. After 140 hours, the cooled mixture was washed with aqueous sodium carbonate. The solution was neutralized, and the aqueous layer was extracted with diethyl ether. Dry the organic phase (Na₂SO_Four And concentrated under reduced pressure. The residue is eluted with 1% ethanol and chloroform. It was subjected to kagel chromatography to obtain the title compound (340 mg).¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 2.95 (t, 2H), 3.12 ( t, 2H), 3.33 (t, 2H), 3.55 (t, 2H), 6.58 (s, IH) , 6.96 (s, 1H). Description example 14 2,3-Dihydro-1H-pyrrolo [3,2-b] quinoline (D14)   3-oxopyrrolidine-1-carboxylic acid (1. 0 g), 2-aminobenzaldehyde (1.0 g) and 85% sodium hydroxide A solution consisting of an aqueous solution of water (2.8 ml) was stirred for 20 hours under an inert atmosphere. Ethanol was concentrated under reduced pressure and the residue was partitioned between chloroform and water. Acid water layer The mixture was returned to the sex side, adjusted to pH 8, and extracted with chloroform. Dry the organic phase (Na₂ SO_Four) And concentrated to give the product (950 mg).¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 3.50 (t, 2H), 3.95 (t , 2H), 7.15 (s, 1H), 7.51 to 7.60 (m, 2H), 7.71 to 7.7 8 (m, 1H), 8.04 to 8.10 (m, 1H). Description example 15 6-trifluoroacetamide-1,2,3,4-tetrahydroquinoline (D15 )   6-trifluoroacetamidoquinoline (16 ml) in methanol (250 ml) 0.5 g, 69 mmoles) to nickel chloride hexahydrate (3.3 g, 14 mmol) es) and sodium borohydride (13.4 g, 350 mmoles) slowly. Each was added and treated. After 1 1/2 hours, the mixture was concentrated under reduced pressure and the residue was diluted with hydrochloric acid. (500 ml). Basify, extract with dichloromethane, silica gel Chromatography gave the title compound (D15) (6.5 g, 39%). NMR (CDCl_Three) Δ: 1.85 to 2.02 (2H, m), 2.71 to 2.85 (2 H, m), 3.25 to 3.39 (2H, m), 3.80 to 4.02 (1H, brs), 6.45 (1H, d, J = 11Hz), 7.03 to 7.12 (1H, m), 7.15 ( 1H, s), 7.55 to 7.85 (1H, brs). Description example 16 1-ethoxycarbonyl-6-trifluoroacetamide-1,2,3,4-teto Lahydroquinoline (D16)   6-trifluoroacetamide-1,2,3,4-tetrahydroquinoline (D1 5) (5.2 g, 21 mmoles) was added to ethyl chloroformate and triethylamido. Treatment with hexane afforded the title compound (D16) (6.5 g, 96%). NMR (CDCl_Three) Δ: 1.33 (3H, t, J = 9Hz), 1.95 (2H, t, J = 7Hz), 2.78 (2H, t, J = 7Hz), 3.75 (2H, t, J = 7Hz) 4.25 (2H, q, J = 7Hz), 7.15 to 7.22 (1H, m), 7.45 ( 1H, s), 7,75 (1H, d, J = 12Hz), 7.80 to 8.00 (1H, br s). Description example 17 6-amino-1-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline (D17)   1-Ethoxycarbonyl with 1.2 equivalents of sodium hydroxide in ethanol Le-6-trifluoroacetamide-1,2,3,4-tetrahydroquinoline (D 16) (6.5 g, 20 mmoles) by hydrolysis to give the title compound (D17) (3.6 g, 80%) was obtained. NMR (CDCl_Three) Δ: 1.30 (3H, t, J = 7Hz), 1.83-1.99 ( 2H, m), 2.70 (2H, t, J = 7Hz), 3.40 to 3.60 (2H, brs) ), 3.71 (2H, t, J = 7Hz), 4.21 (2H, q, J = 7Hz), 6.3 8 to 6.57 (2H, m), 7.45 (1H, d, J = 10Hz). Description example 18 6- (2,2-dimethoxyethyl) amino-1-ethoxycarbonyl-1,2,3, 4-tetrahydroquinoline (D18)   6-amino-1-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline (D17) (3.6 g, 16 mmoles) was added to dimethoxyethanal-methyl. In the presence of a 41% solution in t-butyl ether (6.7 g, 27 mmoles), Hydrogenate on activated carbon over 10% palladium catalyst (0.5 g) for 4 hours. Then touch The medium was filtered off and the filtrate was evaporated to dryness. Dissolve with 0-2% methanol / dichloromethane By silica gel chromatography, the title compound (D18) (4.5 g, 90%). NMR (CDCl_Three) Δ: 1.30 (3H, t, J = 8Hz), 1.83-1.99 ( 2H, m), 2.70 (2H, t, J = 7Hz), 3.20 (2H, d, J = 7Hz) 3.39 (6H, s), 3.72 (2H, t, J = 7Hz), 4.21 (2H, q, J = 8 Hz), 4.55 (1 H, t, J = 6 Hz), 6.33 to 6.51 (2 H, m), 7.42 (1H, d, J = 8Hz). Description example 19 5-ethoxycarbonyl-1-trifluoroacetyl-5,6,7,8-tetrahi Doro-1H-pyrrolo [2,3-g] quinoline (D19)   6- (2,2-dimethoxyethyl) amino-1-ethoxycarbonyl-1,2, 3,4-Tetrahydroquinoline (D18) (4.5 g, 15 mmoles) was added to 60 in Lifluoroacetic acid (50 ml) and Trifluoroacetic anhydride (20 ml) Heated to reflux for an hour. The mixture was then evaporated to dryness. 0-1% methanol / di The title compound by silica gel column chromatography eluting with chloromethane. (D19) (1.65 g, 33%) was obtained. NMR (CDCl_Three) Δ: 1.32 (3H, t, J = 8), 1.92 to 2.12 (2H , m), 2.92 (2H, t, J = 7Hz), 3.79 (2H, t, J = 7Hz), 4. 25 (2H, q, J = 8Hz), 6.70 (1H, d, J = 5Hz), 7.35 7.42 (1H, m), 7.92 (1H, s), 8.13 (1H, s). Description example 20 5-ethoxycarbonyl-5,6,7,8-tetrahydro-1H-pyrrolo [2,3- g] quinoline (D20)   5-Ethoxycarbonyl-1-trifluoroacetyl in methanol (50 m) Le-5,6,7,8-tetrahydro-1H-pyrrolo [2,3-g] quinoline (D19 ) (1.65 g, 5 mmoles) with potassium carbonate (0.9 g, 7 mmoles) At ambient temperature for 2 hours. The mixture was evaporated to dryness and the residue was washed with 2% methanol. Partition / dichloromethane and water. Dry the organic portion (Na₂SO_Four) Then, it was evaporated to dryness to obtain the title compound (D20) (1.05 g, 88%). NMR (CDCl_Three) Δ: 1.35 (3H, t, J = 8Hz), 1.91 to 2.12 ( 2H, m), 2.81 (2H, t, J = 7Hz), 3.80 (2H, t, J = 7Hz) 4.25 (2H, q, J = 8Hz), 6.45 to 6,50 (1H, m), 7.05 7.15 (2H, m), 7.80 (1H, s), 8.10 to 8.15 (1H, brs) . Description example 21 5-ethoxycarbonyl-2,3,5,6,7,8-hexahydro-1H-pyrrolo [ 2,3-g] quinoline (D21)   5-Ethoxycarbonyl-5,6,7,8-tetrahydr in glacial acetic acid (25 ml) B-1H-pyrrolo [2,3-g] quinoline (D20) (1.05 g, 4 mmole s) with sodium cyanoborohydride (1.25 g, 20 mmoles). It was treated at ambient temperature for 1 hour. Dilute the mixture with water and base with sodium hydroxide. The mixture was rendered sexual and extracted with dichloromethane. Dry the organic portion (Na₂SO_Four) And evaporate to dryness Hardened. Silica gel chromatography eluting with 0-2% methanol / dichloromethane Ruffy gave the title compound (D21) (0.84 g, 79%). NMR (CDCl_Three): 1.32 (3H, t, J = 8Hz), 1.85 to 1.98 (2 H, m), 2.68 (2H, t, J = 7Hz), 2.99 (2H, t, J = 9Hz), 3.51 (2H, t, J = 9Hz), 3.68 (2H, t, J = 7Hz), 4.20 ( 2H, q, J = 8Hz), 6.33 (1H, s), 7.21 (1H, s), 7.30 ~ 7.42 (1H, brs). Description example 22 5-methyl-2,3,5,6,7,8-hexahydro-1H-pyrrolo [2,3-g] ki Norrin (D22)   5-ethoxycarbonyl-2,3,5, in dry tetrahydrofuran (50 ml) 6,7,8-Hexahydro-1H-pyrrolo [2,3-g] quinoline (D21) (0. 84 g, 3 mmoles) to lithium aluminum hydride (0.27 g, 7 m) moles) at ambient temperature for 1 hour. Normal finish and mark The compound (D22) (0.64 g, 100%) was obtained. NMR (CDCl_Three) Δ: 1.95 to 2.05 (2H, m), 2.71 (2H, t, J = 7 Hz), 2.80 (3 H, s), 2.95 (2 H, t, J = 9 Hz), 3.15 ( 2H, t, J = 7Hz), 3.45 (2H, t, J = 9Hz), 6.40 (2H, s) , 6.55 (1 H, s). Description example 23 1-Acetyl-6-nitroindoline (D23)   Dichloromethane (200 ml) and pyridine (14.7 ml, 0.18 mol) A) stirred solution of 6-nitroindoline (25 g, 0.15 mmol) in Acetyl chloride (13 ml, 0.18 mol) was added dropwise to (0 ° C.). Mixture 0 Stirred at 1 ° C. for 1 hour, treated with water (100 ml) and stirred for an additional 1/2 hour. phase Separate and wash organic portion (5N HCl, H₂O, then brine), Dry and concentrate to give the title compound (31.5 g, 100%) as a pale green solid. Was.¹ 1 H NMR (250 MHz CDCl_Three) Δ: 2.28 (s, 3H), 3.30 ( t, 2H), 4.2 (t, 2H), 7.26 (m, 1H), 7.89 (m, 1H), 8.9 5 (s, 1H). Description example 24 1-Acetyl-6-aminoindoline (D24)   D23 (31 g, 150 mmol) and 10 in ethanol (700 ml) A suspension consisting of% Pd / C (2 g) was hydrogenated for 1 hour (50 psi, 45 ° C). The catalyst is filtered and washed (50% CH₂Cl₂/ MeOH). Concentrate the filtrate Thus, the title compound (26.3 g, 99%) was obtained as a brown oily substance.¹ 1 H NMR (250 MHz CDCl_Three) Δ: 2.20 (s, 3H), 3.05 (t , 2H), 3.66 (br, 2H), 4.00 (t, 2H), 6.35 (m, 1H), 6 .92 (m, 1H), 7.68 (s, 1H). Description example 25 1-Acetyl-6-iodoindoline (D25)   Prepare the title compound in 76% yield using modified Sandmeyer conditions. I made it.¹ 1 H NMR (250 MHz) δ: 2.20 (s, 3H), 3.14 (t, 2H), 4.04 (t, 2H), 6.90 (d, 1H), 7.82 (dd. 1H), 8.59 (s , 1H). Description example 26 (1-Acetyl-5-indolyl) propenoic acid benzyl ester (D26)   Heck conditions¹From D25 and benzyl acrylate using The compound was produced with a yield of 70%.¹ 1 H NMR (250 MHz CDCl_Three) Δ: 2.22 (s, 3H), 3.20 (t , 2H), 4.10 (t, 2H), 5.24 (s, 2H), 6.39 (d, 1H), 7. 37 (m, 7H), 7.68 (d, 1H), 8.20 (d. 1H).¹ Organic reactions, Volume 27, 345-3 90 pages. Description example 27 (1-Acetyl-5-indolinyl) propionic acid (D27)   Yield 9% of the title compound as a white solid from D26 using standard hydrogenation conditions. Obtained at 2%. Description example 28 1-Acetyl-2,3-dihydro-7-oxopyrrolo [2,3-f] indane (D 28)   Dissolution of D27 (6.2 g, 26.6 mmol) in dichloromethane (100 ml) The liquid was mixed with oxalyl chloride (2.48 ml, 29 mmol) and dimethylforma. Treated with amide (2 ml, drop) and stirred for 20 minutes. The solvent was removed under reduced pressure and the residue was It was dissolved in dichloromethane (100 ml) and cooled to 0 ° C. In this solution, chloride Aluminum (10.6 g, 79 mmol) was added in small portions and the mixture was left to stand. To room temperature and stirred for 12 hours. The mixture was poured onto ice and 5N HCl (50 ml) was added. Extract the aqueous portion (with dichloromethane) and dry the organic portion. And concentrated. Flush eluting with 50% ethyl acetate / 60 ° C-80 ° C petroleum ether Chromatography gave the title compound (4.1 g, 72%) as a white solid. I got it.¹ 1 H NMR (250 MHz CDCl_Three) Δ: 2.24 (s, 3H), 2.70 (m , 2H), 3.07 (m, 2H), 3.25 (t, 2H), 4.12 (t, 2H), 7. 24 (s, 1H), 8.49 (s, 1H). Description example 29 Acetyl-2,3-dihydro-7-hydroxy-pyrrolo- [2,3-f] inda (D29)   Stirred of D28 (2.9 g, 13 mmol) in ethanol (100 ml) To the suspension in place under argon, sodium borohydride (0.6 g, 15 mmo l) was added in small portions. The suspension was stirred at room temperature for 4 days and the solvent was removed under reduced pressure. The residue was triturated with water. The solid was filtered and dried to give the title compound (2.6g, 92%). Obtained as a white solid.¹ 1 H NMR (250 MHz CDCl_Three) Δ: 1.9 (m, 1H), 2.48 (m, 1H), 2.71 (m, 1H), 2.95 (m, 3H), 3.52 (t, 2H), 4. 82 (br, 1H), 5.10 (t, 1H), 6.68 (s, 1H), 6.99 (s, 1) H). Description example 30 2,3-Dihydro-7-hydroxy-pyrrolo- [2,3-f] -indane (D30 )   A suspension of D29 (1 g, 4.6 mmol) in ethanol (30 ml) was added to 1 0% N sodium hydroxide solution (20 ml) and sodium hydroxide pellets (1 0.1 g, 27.5 mmol). Reflux the mixture under argon for 12 hours, Cooled and partitioned between dichloromethane and water. Dry the organic phase, concentrate and label The compound (0.29 g, 37%) was obtained as a yellow solid.¹ 1 H NMR (250 MHz CDCl_Three) Δ: 1.9 (m, 1H), 2.45 (m, 2H), 2.70 (m, 1H), 2.94 (m, 3H), 3.53 (t, 2H), 5. 11 (t, 1H), 6.68 (s, 1H), 7.0 (s, 1H). Description example 31 1,1'-diacetyl- (6-indolyl) -disulfide (D31)   Olah et al.²N-methyl-6- (chlorosulfonyl) using the method of Indoline¹Was converted to the title compound in 50% yield. Literature 1. Carlier, R.R., Rock Thin, MP (Lockshin, M.P.), Philosa, M.P., Journal of ・ Organic Chemistry (J.Org.Chem.), 1994, Volume 59, 32 32 pages. 2. Olah, G.A., Navang, S.C., Field, L.A., Salem, G.F., Journal of Organic Chemistry (J.Org.Chem.), 1980 45, 4792. Description example 32 1-Acetyl-6-mercaptoindoline (D32)   (1,1′-diacetyl- (6--in dioxane / water (100 ml / 10 ml) Indolyl) -disulfide) (2.76 g, 7.2 mmol), triphenylpho Mixture consisting of sphing (2.8 g, 10.8 mmol) and concentrated hydrochloric acid (20 drops) Was heated to reflux under argon for 2 hours. The mixture was evaporated to dryness and redissolved in ethyl acetate. Then, the mixture was extracted twice with a 1% aqueous sodium hydroxide solution. Wash the aqueous extract with ethyl acetate Purified, then acidified with 1M aqueous hydrochloric acid and extracted twice with ethyl acetate. Dry ( Sodium sulfate) and evaporation gave the product as a white solid (1.36 g, 49%). NMR (CDCl_Three): 2.20 (3H, s), 3.15 (2H, t, J 8Hz), 3.50 (1H, s), 4.05 (2H, t, J 8Hz), 6.90 (1H, dd, J 6Hz), 7.05 (1H, d, J 6Hz) and 8.15 (1H, d, J 1Hz) . Description example 33 1-Acetyl-6- (2,2-diethoxyethylthio) -indoline (D33)   1-acetyl-6-mercaptoindoline (4.25) in DMF (30 ml). g, 22 mmol) (under argon, 0 ° C.) in sodium hydride ( 0.7 g, 80% dispersion, 0.55 g NaH, 23 mmol) and then After 0.75 hours, bromoacetaldehyde diethyl acetal (4 ml, 5.1 g, 26.4 mmol). The mixture is heated at 50 ° C. for 1 hour, then Aqueous ammonium chloride solution (10 ml) was added and the mixture was evaporated to dryness. The residue Dissolve in ethyl acetate and wash 3 times with dilute brine, then once with brine, then Dry (Na₂SO_Four) And evaporated. 0-2% methanol in dichloromethane The product was colorless oil by silica gel chromatography eluting with a gradient. Obtained as a quality (4.4 g, 65%). Description example 34 7-Acetyl-5,6-dihydro-7H-thieno [3,2-f] indole (D3 4)   1-Acetyl-6- (2,2-diethoxyethylthio) in toluene (8 ml) ) A solution of indoline (0.42 g, 1.35 mmol) was added to a solution of trichlorotetrachloride in toluene. Treated with tan solution (1M; 1.6ml, 1.6mmol) and heated at 50 ° C for 10 minutes did. Partition the cooled reaction mixture between ethyl acetate and aqueous sodium bicarbonate. did. Dry the organic extract (Na₂SO_Four) And evaporated to a brown oil (0.24). g) was obtained. 50%, 70%, then 100% acetic acid in 60/80 petroleum ether Chromatography eluting with ethyl gave the title compound as a white solid ( 100 mg, 33%). NMR (CDCl_Three) Δ: 2.25 (3H, s), 3.30 (2H, t, J 8Hz) 4.10 (2H, t, J 8Hz), 7.30 (1H, d, J 5Hz), 7.45 ( 1H, d, J 5Hz), 7.60 (1H, s), 8.65 (1H, s). Description example 35 7-Acetyl-2-bromo-5,6-dihydro-7H-thieno [3,2-f] yne Doll (D35)   7-Acetyl-5,6-dihydro-7H-thieno in chloroform (6 ml) A solution of [3,2-f] indole (90 mg, 0.41 mmol) was added to chloroform. Treated with a bromine solution (100 mg, 0.62 mmol) in (1 ml). 0.75 After hours, dilute the reaction mixture with chloroform (20 ml) and dilute sodium sulfite. Wash with aqueous solution, then half saturated brine. Dry (Na₂SO_Four) Evaporation gave a white solid (130 mg). 0/10 in 60/80 petroleum ether Chromatography eluting with 0% ethyl acetate gave the product as a white crystalline solid. Obtained (108 mg, 83%). NMR (CDCl_Three) Δ: 2.25 (3H, s), 3.25 (2H, q, J 8Hz), 4.10 (2H, q, J 8Hz), 7.15 (1H, s), 7.40 (1H, s), 8 .60 (1H, s). Description example 36 2-Bromo-5,6-dihydro-7H-thieno [3,2-f] indole (D36 )   Prepare the title compound material from D35 using a method similar to that for D12. , White solid (125 mg, 67%). NMR (CDCl_Three) Δ: 3.10 (2H, t, J 8Hz), 3.60 (2H, t, J  8Hz), 3.90 (1H, bs), 6.85 (1H, s), 7.10 (1H, s) 7.45 (1 H, s). Description example 37 5,6-dihydro-7H-thieno [3,2-f] indole (D37)   This material was prepared from D34 using a method similar to that for D12 to give a white solid The title compound was obtained as (40 mg, 60%). NMR (CDCl_Three) Δ: 3.10 (2H, t, J 8Hz), 3.60 (2H, t, J  8 Hz), 3.90 (H, bs), 7.05 (1 H, s), 7.10 (d, J 5 Hz ), 7.15 (d, J 5 Hz), 7.50 (1 H, s). Example 1 1- (3-pyridylcarbamoyl) -2,3-dihydro-1H-pyrrolo [2,3- g] quinoline (E1)   Of nicotinoyl azide (90 mg, 0.6 mmol) in toluene (4 ml) The solution was refluxed and heated for 1.75 hours. After cooling, 2,3-dihydroxide in dichloromethane Dissolution of Doro-1H-pyrrolo [2,3-g] quinoline (0.1 g, 0.59 mmol) Liquid was added and the mixture was stirred overnight. The precipitate was filtered off and washed with petrol. The The title compound (0.09 g, 53% by recrystallization from chloromethane / petrol) )Obtained. Melting point 215-216 [deg.] C. NMR (d₆-DMSO) δ: 3.43 (2H, t, J = 7), 4.27 (2H, t, J = 7), 7.39 (2H, m), 7.80 (1H, s), 8.04 (1H, d, J = 8), 8.23 (1H, d, J = 8), 8.28 (2H, s), 8.69 (1H, m) , 8.81 (1H, s), 8.92 (1H, s). Example 2 2-Methyl-6,7-dihydro-5- (3-pyridylcarbamoyl) -furo [2, 3-f] indole (E2)   Following the procedure of Example 1, 2-methyl-6,7-dihydrofuro [2,3-f] yl Ndol (0.18 g, 1.0 mmol) and nicotinoyl azide (0.17 g) This material was prepared from 1.1 mmol). The reaction mixture was evaporated to dryness, 0-4 Subject to silica gel chromatography using% methanol / chloroform. The product was triturated with toluene and dried under reduced pressure to give the title compound (0.18 g, 59%). Obtained as a white powder. Melting point 230-20.5 ° C. NMR (DMSO-d₆) Δ: 2.4 (3H, s), 3.25 (2H, t, J = 8), 4.2 (2H, t, J = 8), 6.5 (1H, s), 7.3 (2H, m), 8.0 (2H , m), 8.2 (1H, d, J = 4), 8.7 (1H, s), 8.75 (1H, s). m .s. (m / z): measured value M + 1 = 294, C₁₇H_FifteenN_ThreeO₂As M + 1 = 29 4. Elemental analysis: Found C, 69.5; H, 5.3; N, 14.3%. C₁₇H_FifteenN_ThreeO₂As C, 69.6; H, 5.2; N, 14.3%. Example 3 1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo- [2,3-f]- Inden (E3)   3-pyridylisocyanate in toluene (0.32 g of nicotinoyl azide ( 2.1 mmol) prepared by heating 2) in dichloromethane. Of 3-dihydropyrrolo- [2,3-f] indene (0.31 g, 1.9 mmol) Add to stirred solution. After stirring for 24 hours, the solid is filtered and chromatographed. Perform the feeding to obtain the title compound (0.42 g, 80%) as an ocher powder. NMR (250 MHz, DMSO) δ = 8.85 (m, 1H Ar): 8.77 (s , 1H, Ar), 8.31 (d, 1H, J = 5, Ar), 8.10 (m, 2H, Ar), 7.38 (m, 2H, Ar), 6.95 (dd, 1H, J = 5, alkene), 6.61 ( dd, 1H, J = 5, alkene), 4.28 (t, 2H, J = 7, indoline), 3.3 (T, 2H, J = 7.5, indoline). Melting point = 180-182 ° C (decomposition). Example 4 2,3-Dihydro-1- (3-pyridylcarbamoyl) -pyrrolo [3,2-b] ki Norin (E4)   A solution of nicotinoyl azide (218 mg) in dry toluene (5 ml) for 5 minutes. Heat to reflux, cool to room temperature, then 2,3- in dichloromethane (5 ml). Poured into a solution of dihydro-pyrrolo [3,2-b] quinoline (250 mg). Mixed The mixture was cooled for 2 hours and the product was collected by filtration. Chloroform and ethanol Column using silica gel (increasing volume up to 20%) as eluent By chromatography, followed by recrystallization from ethanol-diethyl ether. The title compound was obtained as a beige solid (50 mg).¹ 1 H NMR (d₆-DMSO, 270 MHz) δ: 3.44 (t, 2H), 4.28 (T, 2H), 7.38 (dd, 1H), 7.41 to 7.59 (m, 2H), 7.85 (D, 2H), 7.99 to 8.08 (m, 1H), 8.27 (dd, 1H), 8.41 (S, 1H), 8.81 (d, 1H), 8.99 (bs, 1H). Melting point 205-208 [deg.] C. M⁺(EI) 290. Example 5 5,6-dihydro-3-methyl-N- (3-pyridyl) -furo [3,2-f] yne Dole-7-carboxamide (E5)   Nicotinoyl azide (0.14 g, 0.94 mmol) in dry toluene (5 ml) Was heated to reflux under Ar for 0.75 hours and cooled to ambient temperature. Then this Filtration through absorbent cotton, 5,6-dihydride in stirred dichloromethane (5 ml) Rho-3-methylfuro [3,2-f] indole (D6) (0.15g, 0.86m) mol). After stirring for 15 minutes, the suspension was ice-cooled, the precipitate was filtered off and dried. . This gave the title compound (0.15g, 59%) as an ocher powder. NMR (DMSO-d₆) Δ: 2.17 (3H, s), 3.27 (2H, t, J 8) 4.24 (2H, t, J 8), 7.35 (2H, m), 7.62 (1H, d, J 2) , 8.01 (2H, m), 8.24 (1H, m), 8.76 (2H, s). MS (C.I.) (m / z) [M + H]⁺= 294, C₁₇H_FifteenN_ThreeO₂As [M + H]⁺= 294. Example 6 2,2-Dimethyl-2,3,6,7-tetrahydro-N- (3-pyridyl) furo [2 , 3-f] Indole-5-carboxamide (E6)   Following the procedure of Example 1, 2,2-dimethyl-2,3,6,7-tetrahydrofuro From [2,3-f] indole (D12, 0.147 g, 0.77 mmol) this The material was produced. This gave the title compound (0.147 g, 61%) as a white powder. I got it.¹ 1 H NMR (250 MHz, CDCl_Three) Δ: 1.48 (6H, s), 2.99 (2 H, s), 3.18 (2H, t, J 8), 4.11 (2H, t, J 8), 6.60 (2 H, s), 7.15 to 7.30 (2H, m), 7.76 (1H, s), 8.08 (1H, m), 8.30 (1H, d, J4), 8.50 (1H, d, J2). Example 7 2,3,6,7-Tetrahydro-5- (3-pyridylcarbamoyl) -5H-thie No [2,3-f] indole (E7)   Add a solution of nicotinoyl azide (309 mg) in toluene (5 ml) for 5 minutes. Heat to reflux, then cool to room temperature, CH₂Cl₂2,3,6,7 in (20ml) -Tetrahydro-5H-thieno [2,3-f] indole (D13, 340 mg ) Was poured into the solution. After 2 hours at 0 ° C, the product was collected by suction filtration and filtered with ethanol. Le / CH₂Cl₂Recrystallized from to give the title compound as a white powder (280 mg) . Melting point 185-189 [deg.] C. H NMR (CDCl_Three, 250 MHz) δ: 3.16 to 3.30 (4 H, m), 3. 40 (t, 2H), 4.12 (t, 2H), 6.44 (s, 1H), 7.02 (s, 1) H), 7.23 to 7.30 (m, 1H), 7.82 (s, 1H), 8.10 (dd, 1) H), 8.35 (d, 1H), 8.50 (d, 1H). Example 8 5-methyl-N- (3-pyridyl) -2,3,5,6,7,8-hexahydro-1H -Pyrrolo [2,3-g] quinoline-1-carboxamide oxalate (E8)   5-methyl-2,3,5,6,7,8-hexahydro-1H-pyrrolo- [2,3-g ] Quinoline (D22) (0.64 g, 3 mmoles) and 3-pyridyliso Prepare the title compound from cyanate (0.4 g, 3 mmoles) in the usual manner. Then treated with oxalic acid and recrystallized from methanol / diethyl ether . This gave E8 (0.42 g, 31%). Melting point 193-194 [deg.] C. NMR (DMSO-d₆) Δ: 1.80 to 1.95 (2H, m), 2.68 (2H, t) , J = 7 Hz), 2.79 (3H, s), 3.05 to 3.19 (4H, m), 4.05 ( 2H, t, J = 9Hz), 6.52 (1H, s), 7.30 to 7.38 (1H, m), 7.49 (1H, s), 7.97 to 8.03 (1H, s), 8.15 to 8.25 (1H , brs), 8.59 (1H, s), 8.71 to 8.83 (1H, brs). Example 9 2,3-dihydro-7-hydroxy-1- (3-pyridylcarbamoyl) pyrrolo -[2,3-f] Indane (E9)   3-Pyridylacyl azide (0.25 g, 1.6 mm) in toluene (10 ml) solution) was refluxed under argon for ˜1 / 2 hour and then cooled. Dichloro To a solution of D30 (0.27 g, 1.6 mmol) in methane (10 ml) was added fresh. The resulting 3-pyridyl isocyanate solution was added. The precipitated solid is filtered and dried did. Recrystallize from dichloromethane / ethanol to give the title compound (0.33 g , 70%) as a white solid.¹ 1 H NMR (250 MHz d₆  DMSO) δ: 1.78 (m, 1H), 2.3 1 (m, 1H), 2.61 (m, 1H), 2.82 (m, 1H), 3.14 (t, 2H) ), 4.12 (t, 2H), 4.95 (t, 1H), 5.2 (d, 1H), 7.01 ( s, 1H), 7.32 (m, 1H), 7.89 (s, 1H), 7.98 (dd, 1H), 8.20 (m, 1H), 8.66 (s, 1H), 8.75 (m, 1H). Melting point 200 ~ 201 ° C C₁₇H₁₇N_ThreeO₂As C, 69.14; H, 5.80; N, 14.23, Found C, 68.85: H, 5.94; N, 14.34. Example 10 2,3-Dihydro-7-oxo-1- (3-pyridylcarbamoyl) pyrrolo- [ 2,3-f] Intan (E10)   Stirred of E9 (0.5 g, 1.7 mmol) in dichloromethane (20 ml) Dioxane (1.03 g, 11.9 mmol) was added to the suspension and the mixture was Stir under argon for 36 hours. Filter the mixture through Kieselguhr and wash the pad. Purified (5% methanol / dichloromethane) and concentrated the filtrate. 2% methanol The title compound ( 0.23 g, 46%) was obtained as a white solid. Melting point> 250 ° C.¹ 1 H NMR (250 MHz d₆-DMSO) δ: 2.63 (m, 2H), 3.0 1 (m, 2H, m), 3.28 (t, 2H), 4.21 (t, 2H), 7.35 (m, 2) H), 8.00 (m, 2H), 8.24 (m, 1H), 8.74 (d, 1H), 8.8 0 (s, 1H). MS m / z = 293 (28%). C₁₇H_FifteenN_ThreeO₂・ H₂O as C, 65.56; H, 5.50; N, 13.96, Found: C, 65.55; H, 5.01; N, 13.59. Example 11 2-Bromo-5,6-dihydro-N- (3-pyridyl) -thieno- [3,2-f] Indole-7-carboxamide (E11)   This was prepared from D36 by the general method as in Example 1 and the title compound was prepared in white. Obtained as a colored solid (158 mg, 86%). Melting point> 200 ° C. δ (DMSO): 3.30 (2H, t, J 8Hz), 4.20 (2H, J 8Hz) , 7.35 (1H, m), 7.45 (1H, s), 7.60 (1H, s), 8.00 ( 1H, m), 8.25 (1H, m), 8.35 (1H, s), 8.75 (1H, m), 8.80 (1H, s). m / e 375. M⁺  C₁₆H₁₂N_Three375 for BrOS. Example 12 5,6-Dihydro-N- (3-pyridyl) -thieno [3,2-f] -indole- 7-Carboxamide (E12)   This was prepared from D37 by the general method as in Example 1 and the title compound was isolated on white. Obtained as a colored solid (15 mg, 44%). Melting point 218-222 [deg.] C. NMR (DMSO) δ: 3.30 (2H, t, J 8Hz), 4.25 (2H, t, J) 8Hz), 7.30 (1H, d, J 5Hz), 7.35 (1H, m), 7.55 (1 H, d, J 5Hz), 7.70 (1H, s), 8.25 (1H, m), 8.40 (1H , s), 8.80 (2H, m). m / e 295. M⁺  C₁₆H₁₃N_Three295 as OS. Pharmacological data Rat or human 5-HT expressed in 293 cells in vitro_2CKu To loan [^Three[H] -Methrazine binding   5-HT according to literature evidence_2CAntagonists are anxiety, migraine, depression, Eating disorders and obsessive-compulsive disorders (Curzon and Kennett) , 1990; Fozaed and Gray, 1989) and And Alzheimer's disease (Lawlor, 1989, Journal of A Includes J.Arch.Gen.Psychiat. Vol.46, p.542. It has been shown to have many therapeutic examples, including.   5-expressed in 293 cells (Julius et al., 1988) HT_2Cfrom[^ThreeBy evaluating the substitution ability of [H] -mesulazine, 5-HT_{2 C} The affinity of the test agent for the binding site can be measured. The method used is The method of Pazos et al., 1984 was similar.   Cell suspension (400 ml) in Tris HCl buffer (pH 7.4) , At 37 ° C^ThreeH] -Mesulazine (0.5 nM) for 30 minutes Cubated. Non-specific binding to mianserin (10^-6M) in the presence of did. Ten concentrations of test drug were added in a volume of 50 ml (final concentration 3 x 10^-9 Through 10^-FourM). The total assay volume was 500 ml. Brandel Selja -Beth Incubation by rapid filtration using a (Brandel cell harvester) It was stopped and radioactivity was measured by scintillation counting. 4 parameters Four-parameter logistic program IC using DeLean (1978)₅₀Determine the value, pK_i(Negative inhibition constant The logarithm of was calculated from the Cheng Prusoff equation: In the formula, K_i= Inhibition constant C = [^ThreeH] -Methrazine concentration K_d= 5-HT_2CAffinity of mesulazine for the binding site.   Curzon, G.A. and Kennett, G.A. G.A.) (1990) TIPS Vol. 11, 181-182.   Fozard, J.R. And Gray, J.A. y, J.A) (1989) TIPS 10: 307-309.   Pazos, A. et al. (1984) European Journal of * Pharmacology (Eur.J.Pharmacol.) 106, 531-538.   Julius et al. (1988) Science, Volume 241, 558-564.   DeLean, A., Manson, Munson P.J., Rod Baud, D. (1978) American Journal of Physiology (Am. J. Physiol.) Volume 235, E97-E102.   The compounds of Examples 1-12 have a pK in the range of 6.43-8.58._iHad.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI A61K 31/44 AAM 9454-4C A61K 31/44 AAM AAN 9454-4C AAN ADR 9454-4C ADR C07D 471/04 101 9283-4C C07D 471/04 101 491/048 9271-4C 491/048 495/04 103 9053-4C 495/04 103 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB , GR, IE, IT, LU, MC, NL, PT, SE), JP, US (72) Inventor Ham, Peter England, CM 19.5 Adie, Essex, Harlow, The Pinnacles, Cord Harbor・ Road (No street address) From Smithkline Beecham Pharmaceuticals (72) Tomorrow Forbes, Ian Thomson United Kingdom, CM 19.5 Adie, Essex, Harlow, The Pinnacles, Cold Harbor Road (No street number) SmithKline Beecham Pharmaceuticals (72) Inventor Jones, Graham Elgin United Kingdom, CM 19.5 Adie, Essex, Harlow, The Pinnacles, Cold Harbor Road (no street number shown) SmithKline Beecham Pharma Ceuticals

Claims (1)

[Claims]   1. Formula (I): [Wherein P is a phenyl, quinoline or isoquinoline residue, or 5 or 6 member containing up to 3 heteroatoms selected from elemental, oxygen or sulfur Represents a membered aromatic heterocycle;   J represents a bicyclic aromatic or partially saturated ring system;   R¹And R²Are independently hydrogen, halogen, hydroxy, oxygen, or C optionally substituted by one or more halogen atoms_{1 ~ 6} Alkyl;   R^FourIs hydrogen, C_{1 to 6}Alkyl, C_{1 to 6}Alkylthio, halogen, nitro, sia No, CF_Three, NR⁸R⁹, CO₂R¹², CONR¹²Or OR¹²Where R⁸ , R⁹And R¹²Is independently hydrogen, C_{1 to 6}Alkyl or aryl C_{1 to 6}Archi Is;   R^FiveIs hydrogen or C_{1 to 6}Alkyl;   n is 2 or 3;   Group R¹³And R¹⁴Is independently hydrogen or C_{1 to 6}However,   P is not a heterocyclic group when J forms a benzothiophene ring] Or a salt thereof.   2. The compound according to claim 1, wherein P is pyridyl.   3. J is quinoline, tetrahydroquinoline, benzofuran, benzothiophene Or a compound of claim 2 which is indane.   4. R¹And R²Are both hydrogen. Listed compounds.   5. R^FourAnd R^FiveAre both hydrogen. Listed compounds.   6. (CHR¹³)_n6. An ethylene group according to any one of claims 1 to 5. Compound.   7. 1- (3-pyridylcarbamoyl) -2,3-dihydro-1H-pyrrolo [2,3-g] quinoline, 2-Methyl-6,7-dihydro-5- (3-pyridylcarbamoyl) -furo [2, 3-f] Indore, 1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo- [2,3-f]- Inden, 2,3-Dihydro-1- (3-pyridylcarbamoyl) -pyrrolo [3,2-b] ki Norin, 5,6-dihydro-3-methyl-N- (3-pyridyl) -furo [3,2-f] yne Dole-7-carboxamide, 2,2-Dimethyl-2,3,6,7-tetrahydro-N- (3-pyridyl) furo [2 , 3-f] indole-5-carboxamide, 2,3,6,7-Tetrahydro-5- (3-pyridylcarbamoyl) -5H-thie No [2,3-f] indole, 5-methyl-N- (3-pyridyl) -2,3,5,6,7,8, -hexahydro-1H -Pyrrolo [2,3-g] quinoline-1-carboxamide, 2,3-dihydro-7-hydroxy-1- (3-pyridylcarbamoyl) pyrrolo -[2,3-f] indane, 2,3-Dihydro-7-oxo-1- (3-pyridylcarbamoyl) pyrrolo- [ 2,3-f] Indan, 2-Bromo-5,6-dihydro-N- (3-pyridyl) -thieno- [3,2-f] Indole-7-carboxamide, 5,6-Dihydro-N- (3-pyridyl) -thieno [3,2-f] -indole- 7-carboxamide, Alternatively, the compound of claim 1 selected from pharmaceutically acceptable salts thereof.   8. A compound according to any one of claims 1 to 7 for use in therapy.   9. A compound according to any one of claims 1 to 7 and a pharmaceutically acceptable compound. A pharmaceutical composition comprising a carrier or an excipient.   10. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising: Formula (II): With a compound of formula (III): Wherein A and R⁶Is a partial -NR when bound^Five'Necessary to form CO A suitable functional group, wherein R^Five'Is R defined in formula (I)^FiveIs Or R^FiveAnd n, J and P are defined in formula (I). Is the same as what was meant, and the variable R^{1 '}, R^{2 '}, R^Four', R^Five', R^13'And R^14'Haso R defined in formula (I) respectively¹, R², R^Four, R^Five, R¹³And R¹⁴Is Or a group convertible to them] And then optionally and optionally Can be in the order^{1 '}, R^{2 '}, R^Four', R^Five', R^13'And R^{1 Four'} Is R¹, R², R^Four, R^Five, R¹³And R¹⁴If they are other than R¹, R², R^Four, R^Five, R¹³And R¹⁴Converted to R¹, R², R^Four, R^Five, R¹³And R^{1 Four} And then forming a pharmaceutically acceptable salt thereof. .