JPH05507071A - new compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] new compound The present invention relates to a novel compound having useful pharmacological effects, a pharmaceutical composition containing the same, and a manufacturing method thereof. The present invention relates to manufacturing methods and intermediates for manufacturing, and their use as pharmaceuticals.

GB 2145416A (Sandra) is 5-HT!　Receptor Anta Naphthylenes, chromenes and chimerates with saturated azanicyclic side chains exhibiting agonist activity. Disclosing Norin's group.

A group of structurally distinct compounds containing isoquinoline moieties has now been developed. this Their compound exhibits 5-HT receptor antagonist activity.

Therefore, the present invention is based on the formula (1). [During the ceremony, E is NH or 0; R1 is hydrogen, halogen, auto-, alkyl, 01-4 alkoxy, hydroxy or Nitro 2 is the formula (a), (b) or (C): (in each formula, p is 1 or 2, q is 1-3, r is l-3: R3 or R4 is hydrogen or Cl-4 alkyl and Y is a group -CH2-X-CH2-, where X is -CH2- , oxygen, sulfur, or where X is a bond) an azanicyclic side chain; and i) the group C0-E-Z is in the l-position and R3 is in the 3-position and is hydrogen, CI-S alkyl or CI-s alkoxy , or R1 is in the 4-position, hydrogen, halogen, CF, C,, alkyl , CI-v acyl, C1-, acylamino, (1 or 2 CI-S alkyl phenyl (optionally substituted with C11 alkoxy or halogen), (1 or 2 01-, alkyl or C5-5 cycloalkyl, or C a-5 (Optionally substituted with polymethylene or phenyl) amino, atom Minocarbonyl or aminosulfonyl, CI-S alkylsulfonyl, CI- s-alkylsulfinyl, Cl-4 alkoxy, Cl-4 alkylthisu, hydro is oxy or nitro: or ii) The group C0-E-Z is in the 3-position and R2 is in the l-position, hydrogen, C I-II alkyl or Cl-4 alkoxy, or R1 is in the 4-position and is hydrogen or C1-6 alkoxy] A compound or compound that exhibits 5-HTs receptor antagonist activity represented by provides pharmaceutically acceptable salts thereof.

Suitable examples of radicals R1 include hydrogen, bromo, chloro, methyl, ethyl, n- and and-2propyl, n-, iso-1see- and tert-butyl, methoxy , ethoxy, n- and iso-propoxy, n-, iso-1Sec- and te Includes rt-butoxy.

Suitable examples of Z include the literature on 5-HT, receptor antagonists such as: It is described in· i) GB2125398A C Sand 7 companies) ii) GB 2152049A (Sandra Corporation) iii) EP-A-215545 (Beacham Group) i v) EP-A-214772 (Beacham Group) v) EP-A-377 967 (Beacham Group) vi) EP-A-358903 (Dainippon Pharmaceutical) Thus, we will indicate the specific side chain of interest. Quinuclidine [In each formula, R is hydrogen or methyl: and X is oxygen or sulfur. ] The side ff1Z of particular interest is tropane and oxagranatane where R is methyl. be.

E is preferably NH.

When the group C0-E-Z is in the 1-position, suitable examples of the group R2 in the 4-position are: are: hydrogen, chloro, bromo, methyl, ethyl, amine, methylamino , dimethylamine phenyl, C3-. Alkanoylamino (e.g. formylamino) mino, acetylamino, propionylamino, n- and iso-butyrylamino ), aminosulfonyl, (1 or 2 methyl, ethyl, n- or iso -propyl, n-1sec-, iso- or tert-butyl or phenyl (optionally substituted with) amino and aminosulfonyl, nitro, methoxy, Ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and Iso-pro and ruthys, hydroxy, methylsulfonyl and ethylsulfonyl.

Also, when R2 is in the 3-position, suitable examples are: hydrogen, metal thyl, ethyl, n- or iso-propyl, methoxy and ethoxy.

When the group CD-E-Z is in the 3-position, suitable examples of the group R2 in the l-position are: i.e. hydrogen, methyl, ethyl, n- or iso-propyl, methoxy and Nidoxi. Also, when R2 is in the 4-position, a suitable example is: namely hydrogen, methoxy and ethoxy.

Preferred R1 groups in any of the above specified positions are hydrogen, methyl and methoxy. Ru. Preferably, R2 is present in the l-position.

For the avoidance of doubt, all alkyl and alkyl-containing groups may be straight or branched. It is branched.

Examples of R□/R when alkyl are methyl, ethyl, n- and iso-propylene. pyru, rho, iso-1sec- and tert-butyl, with methyl being preferred. stomach.

Preferably p, q and r are 1 or 2.

Pharmaceutically acceptable salts of compounds of formula (D) include hydrochloric acid, hydrobromic acid, boric acid, phosphoric acid. , common acids such as sulfuric acid and acetic acid, tartaric acid, lactic acid, maleic acid, citric acid, Huccinic acid, benzoic acid, ascorbic acid, methanesulfonic acid, α-ketoglutaric acid, Pharmaceutically acceptable organic compounds such as α-glycerophosphate and glucose-1-phosphate Includes acid addition salts with acids.

Pharmaceutically acceptable salts of the compound of formula (1) are usually prepared using hydrochloric acid, hydrobromic acid, phosphorus sulfate, etc. acid, acid addition salts with acids such as citric acid, tartaric acid, lactic acid, and acetic acid.

Examples of pharmaceutically acceptable salts include compounds R, -T (where R1 is C'+- + anol, phenyl-014 alkyl or C6-7 cycloalkyl, T is the radical corresponding to the anion of the acid). There are quaternary derivatives of Q compounds of formula (]). Suitable examples of R1 are methyl, ethyl, rho and and isopropyl, benzyl, phenethyl, with methyl being preferred. T suitability Examples are halides such as chloride, bromide, and yoshito.

Examples of pharmaceutically acceptable salts of the compound of formula (1) include pharmaceutically acceptable salts. Also included are internal salts such as oxides.

Compounds of formula (1), their pharmaceutically acceptable salts (quaternary derivatives and N-oxides) ) may also form pharmaceutically acceptable solvates such as hydrates.

Whenever a compound of formula (1) or a salt thereof is referred to herein, It shall include a solvate.

Of course, some of the compounds of formula (1) have chiral or brochiral centers; It is understood that the present invention can exist as many stereoisomers (including enantiomers). represents each of these stereoisomers (including enantiomers) and their mixtures (labeled (including semi-forms). The individual stereoisomers can be separated from each other by conventional methods. Can be separated.

Furthermore, the isoquinoline nucleus in the compound of formula (1) has an endo or exo configuration with respect to Z. It is understood that it is possible to take a different position. End placement is preferred.

One group of compounds included in formula (]) is defined by formula (ID: [wherein each symbol represents formula C As defined in D].

Examples of symbols and suitable symbols are given in the series given for the corresponding symbols with respect to formula (1). Another group of compounds included in composition (1) has the formula (IID+ [wherein ql is 1 or is 2, and the remaining symbols are as defined in formulas D and (II). It will be done.

Examples of symbols and suitable symbols are as described for the corresponding symbols in formula CD. .

Yet another group of compounds included in formula (1) is formula ([V): [where rl is 1 or 2, and the remaining symbols are as defined in formulas CI) and (II) ].

Examples of symbols and suitable symbols are as described for the corresponding symbols in formula CI). Ru.

The present invention also provides formula (V): A compound of the formula At-Z' is reacted with a compound of the formula At-Z' [where Z' is the formula (defined in D street Z, R5 and R4 are replaced by R1゛ and R4゛, and A + and A2 are groups that react together to form an amide or ester bond; And R1゛ and R4゛ are R2 and R2 as defined in formula (1), respectively. or a hydrogenolyzable protecting group], then optionally or If necessary, replace R1 or R1゛ or R4゛ other than R1 with R3 or R4, respectively. and R4 and optionally a pharmaceutically acceptable salt of the compound of formula (1). A method of making a compound of formula CD is provided, comprising forming a compound of formula CD.

Suitable A and A2 are as described, for example, in the above-mentioned patent publications. example For example, A is an active compound such as an acid chloride or an N-hydroxysuccinimide ester. type carbonyl functional group, and when ε or NH in formula (1), A2 is an amino It can be a base.

4. Intermediates of formula (V) are generally known or can be prepared from structurally related known compounds. Manufactured using a method similar to that of

The 2Ax-Z' intermediate is often substituted with a substituted pipette, as described in the above patent literature. Exocyclic keto derivatives of the corresponding azani cyclic side chains prepared by condensation methods using lysine. Can be manufactured from conductors.

In certain aspects, the invention also provides a compound of formula (VD: or when J is oxygen, react with its active derivative [here, J is an acid or NH, Q is a leaving group, and Rlo and R1 are each defined as R3 and R4 as defined above, or are hydrogenolyzable protecting groups; and the remaining symbols are as defined above], then R1 or R4 as the case may be. Convert R8゛ or R4゛ to R1 and R4 respectively, and if forming a pharmaceutically acceptable salt of a compound of formula CD by ) is provided.

Examples of leaving groups Q that can be displaced by nucleophiles include halogens such as chloro and bromo. Cl-4 alkoxy, Ph0-1 or has an activated hydrocarbyloxy such as C1,C,O-, and Q is a carboxylic acid. As an acyloxy acid, COQ forms a mixed acid anhydride.

If the group Q is a halide or COQ forms a mixed acid anhydride, this reaction The reaction is carried out at moderate temperatures in an inert, non-hydroxyl solvent such as benzene, dichloromethane, etc. lomethane, tonohan, diethyl ether, tetrahydrofuran (THF) or i Preferably, this is carried out using dimethylformamide (DMF). Also, preferably , organic bases, especially tertiary amines such as triethylamine, trimethylamine, It is carried out in the presence of acid acceptors such as lysine or picoline, some of which are Also functions as a solvent. Apart from this, acid receptors include calcium carbonate and sodium carbonate. It may be inorganic such as aluminum or potassium carbonate. Temperatures from 0-100℃, especially 1 Suitable for 0-80°C.

Group Q is Cl-4 alkoxy, phenoxy, activated hydrocarbyloxy, or In the case of activated esters (e.g. N-hydroxysuccinimide), this reaction is preferably carried out in an inert polar solvent such as toluene or dimethylformamide. stomach.

Alternatively, when the group Q is CtzCO-, the reaction is carried out in toluene at reflux temperature. It is suitable to carry out.

When the group Q is hydroxy, this reaction is generally performed with dichloromethane, THF, optionally the carbodiimide in an inert non-hydroxyl solvent such as DMF. (e.g. dicyclohexylcarbodiimide), optionally in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. This is carried out in the presence of N-hydroxysuccinimide. This reaction is -10℃ It can be carried out at non-extreme temperatures from to 100"C, e.g. 0-80"C. Ru. In general, relatively high temperatures are used for less active compounds; For chemical compounds, lower temperatures are used.

When the group Q is an acyloxy of a carboxylic acid, this reaction occurs when Q is a halide. It is preferable to carry out the reaction in substantially the same manner as in the above case. Acyloxy leaving group Suitable examples include C1-4 alkanoyloxy and Cl-4 alkoxycar Bonyloxy, in which case the reaction is carried out in an inert solvent such as dichloromethane. , at non-extreme temperatures, e.g. ambient temperature, and the presence of acid acceptors such as triethylamine. It is preferable to do it while the person is present. CI-a alkoxycarbonyloxy leaving group is Q The corresponding compound where is hydroxy is treated with 01-4 alkyl chloroformate This allows it to be formed on the spot.

When group Q is activated hydrocarbyloxy, this reaction Preferably, the reaction is carried out in an inert polar solvent such as chloride. In addition, activated hydrocarbyl or pentachlorophenyl ester, and this reaction is carried out at ambient temperature. It is also suitable to

When J is 0, the compound of formula HJ-Z' is a reactive derivative thereof, e.g. lithium It can be in the form of salts, such as salts, sodium salts, potassium salts.

When Rs' and R4' are other than R8 and R4, respectively, hydrogenolysis possible protecting groups, such as halo, C1-4 alkoxy and C1-4 alkyl benzyl optionally substituted with one or two groups selected from . Such benzyl groups can be removed, for example, by conventional transition metal catalyzed hydrogenolysis. and the formula% respectively): This provides a compound of the formula: where each symbol is as defined above.

The present invention further provides compounds of formula (VID or (VII)) with N-alkyl optionally to form a pharmaceutically acceptable salt of the resulting compound of formula ([)] A compound of formula ([) or a drug thereof, wherein Z is a) or C), Provided is a method for producing a chemically acceptable vine salt.

In this method of the invention, "N-alkylation" refers to formula (Vll) or (VTII) consisting of substituting the N-atom ・ with the group R2 or R4 defined above, respectively ing. This can be applied to the compound R=Qi or R-Qi (where R3 and and R6 are as defined above, and Q is a leaving group]. more achieved.

Appropriate Qs include CL Br, [, 0SOtCHs or 0SOzCJLpCH Groups substituted with coughing groups such as 2 are included.

Preferred Q's are C1, Br and ■.

This reaction is carried out under normal alkylation conditions, e.g. It can be carried out in an active solvent and in the presence of an acid acceptor such as potassium carbonate.

Generally, this reaction is carried out at non-extreme temperatures, such as ambient or slightly elevated temperatures. Do it with

Apart from this, "N-alkylation" may be carried out under normal reductive alkylation conditions. You can also do it.

Also, before coupling with the compound of formula (Vl), the formula (Vm or (VrrD) It is also possible to interconvert R3 and R4 in a compound. Such mutual conversion is It is advantageously carried out under the conditions mentioned above. Prior to interconversion of R8 or R4, the amine The functional group is a group that can be easily removed by acidolysis, such as a C2-y alkanoyl group. It is desirable to protect it.

In the production of such compounds of formula (Vl+) or CVIIH, methylene Corresponding compounds where the group is substituted with 100-, or where Rs or R4 is methyl If so, the corresponding compound whose methyl group is replaced with alkoxycarbonyl It is often advantageous to produce Compounds of this type were subsequently developed into hydrided aluminium. Using a strong reducing agent such as umlithium, the formula (V[D or (Vrl D can be reduced to the corresponding compound.

The compound of formula (■]) is known or similar to known isoquinoline compounds Alternatively, it can be produced by a conventional method from known isoquinoline compounds.

Formula (1) to grow tropane, granatan, or oxa/thia-granatan side chains In the compound, the -COE- bond or the ring of the attached bicyclic moiety is It will be understood that nurturing the code arrangement. End and E of compounds of formula (+) Mixtures of xoisomers can be synthesized non-stereospecifically, e.g. by chromatography. The desired isomers can be separated using conventional methods. Also, if desired, the formula ( Endo isomers can also be synthesized from the corresponding endo form of the compound [). versus The corresponding geometric isomer pairs are isoquinuclidine, isogranatane, oxa/thia-iso Possible in granatan and isotropane side chains.

Pharmaceutically acceptable salts of the compounds of this invention can be conventionally formed. acid addition A salt is, for example, a basic compound of the formula ([) and a pharmaceutically acceptable organic or inorganic acid. It is formed by the reaction of

The compounds of this invention are antagonists of 5-HT receptors and therefore generally It may be used to treat and prevent pain, vomiting, CNS disorders, and gastrointestinal disorders.

Pain includes migraines, cluster headaches, trigeminal neuralgia and visceral pain, and vomiting includes This includes vomiting, nausea, and motion sickness, especially those associated with cancer treatment. This kind of cancer treatment Examples include cytotoxic drugs such as cisplatin, doxorubicin, and cyclophosphamide. There are those that use substances and radiation therapy. CNS disorders include anxiety, psychosis, and aging. This includes dementia and drug addiction. Gastrointestinal disorders include irritable bowel syndrome and diarrhea. It will be done.

Antagonists of 5-HT* receptors may also be used to treat obesity and/or arrhythmia. It may also be effective in therapy.

The present invention further provides a compound of formula (1) or a pharmaceutically acceptable salt thereof, and Pharmaceutical compositions containing a pharmaceutically acceptable carrier are provided.

Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration. As such, it can be used as tablets, capsules, oral liquid preparations, powders, granules, Lozenges, ready-to-use powders, solutions or suspensions for injection and infusion, or may be in the form of suppositories. Compositions that can be administered orally because they are convenient for regular use Preferably.

Tablets and capsules for oral administration are generally presented in unit doses and include conventional excipients. , such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavoring agents. and a wetting agent. The tablets may be prepared by methods known in the art, e.g. with an enteric coating. Can be coated.

Suitable fillers for use include cellulose, mannitol, lactose, and other similar It is a substance. Suitable disintegrants include starch, polyvinylpolypyrrolidone, starch-derived conductor, such as sodium starch glycolate. Suitable lubricants include, for example, Magnesium tearate.

A suitable pharmaceutically acceptable ammonium agent is sodium lauryl sulfate. oral Liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups or It may be in the form of an elixir and may be prepared with water or other suitable vehicle before use. It can also be presented as a dried product. Such liquid formulations may contain conventional excipients, e.g. For example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl Cellulose, carboxymethylcellulose, aluminum stearate gel, water Suspending agents such as naturalized edible fats: lecithin, sorbitan monooleate, arabic Emulsifiers such as gums: almond oil, fractionated coconut oil, and glycerin esters non-aqueous vehicles such as oily esters, propylene glycol, and ethyl alcohol. (including edible oil); methyl or propyl p-hydroxybenzoate, sorbitol and optionally conventional flavoring or coloring agents. can.

Oral liquid preparations are usually aqueous or oil-based suspensions, solutions, emulsions, syrups or is in the form of an elixir and may be prepared with water or other suitable vehicle before use. Presented as a dried product. Such liquid formulations may contain customary additives such as suspending agents. agents, emulsifiers, non-aqueous vehicles (including edible oils), preservatives, and flavoring or coloring agents. It can contain a coloring agent.

Oral compositions are prepared by conventional methods of mixing, filling or tabletting. large amount of filler Repeated mixing operations are employed to homogeneously distribute the active agent in the composition used. Ru. Such operations are of course commonly used in the art.

For parenteral administration, liquid unit dosage forms containing a compound of the invention and a sterile vehicle are provided. or prepared. The compound can be suspended or dissolved depending on the vehicle and concentration. Ru. Parenteral solutions are typically prepared by dissolving the compound in a vehicle, filter sterilizing, and then applying the appropriate It is prepared by filling a suitable vial or ampoule and sealing it. advantageously Adjuvants such as local anesthetics, preservatives, and buffering agents are also dissolved in the vehicle. Stability In order to increase I can do it.

Parenteral suspensions are prepared in substantially the same manner or by dissolving the compound in the vehicle. It can be suspended instead of suspended in a sterile vehicle and sterilized by exposure to ethylene oxide before being suspended in a sterile vehicle. Bacteria. Advantageously, a surfactant is included in the composition to promote homogeneous distribution of the compounds of the invention. Add sex agents and humectants.

The present invention further provides an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof. pain, vomiting, CNS disorders in mammals (e.g. humans), and/or gastrointestinal disease.

An effective amount to treat the above symptoms depends on the relative potency of the compounds of the invention, It depends on the nature and severity of the symptoms and the body weight of the mammal. however , a unit dose for a 70 kg adult is generally 0.05-100001 g, e.g. It will contain 1-500 mg of a compound of the invention. The unit dose is once a day or or more, for example 2.3 or 4 times a day, more commonly 1-3 times a day. , about 0.0001-50 mg/kg/s, more typically 0.0002-2 The range is 5 mg/kg/day.

Within the above dosage range, no toxicological side effects appear.

The present invention also provides a non-toxic and effective amount of a compound of formula (1) or a pharmaceutically acceptable amount thereof. Pain, emesis, CNS disorders and Pharmaceutical compositions for the treatment and/or prevention of gastrointestinal diseases are provided.

The present invention further provides for use as an active therapeutic substance, particularly in the treatment of pain, emesis, and CNS. Compounds of formula () or the like for use in the treatment of disorders and/or gastrointestinal diseases Provided are pharmaceutically acceptable vine salts of.

The invention further provides for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders. and/or the compound of formula (D) or its pharmaceutically acceptable Provides a method for using vine salt.

The examples below show how to make compounds of formula ([), and the reference examples below show how to make intermediates. show.

1,4-dimethylisoquinoline (9,4 6g) (K,C.

Agrawal, P. D., Mooney and A. C., 5artorell. i, J. Med, Chew, 1976, 19. 970j Selenium dioxide (6.65 g) was added to the solution and the mixture was heated for 4 hours under nitrogen atmosphere. The mixture was heated to reflux for a while. After cooling the reaction mixture to room temperature, the precipitated selenium was removed by filtration. The filtrate was concentrated to dryness. Flash chromatograph the residue on silica gel light petroleum ether (boiling point 60-80°C) and diethyl as eluents. Purified using ether (up to 20% V/V) and purified with aldehyde (DI) (3,7 8 g) was obtained as a tan solid. Melting point 61-63°C.

M, S, M" 171 n, m, r, (CDCIs, 250 BJHz) 6 2.74 (s, 3 8) 7.71-7.87 (a+, 2H) 8.05 (d, 1B) 8.63 (S, IH) 9.38 (d, IH) 10.35 (s, IH) Aqueous solution of silver oxide (stirred solution of sodium hydroxide (2,40 g) in water (10 ml) (prepared by adding a solution of silver nitrate (5 g) in water (10 ml)) to 0 °C. So, 4-methyl-1-isoquinolinecarboxaldehyde (Di) (2,50g ) was added little by little. The reaction mixture was stirred at ambient temperature overnight. Filter the silver suspension Filtered and washed with warm water (3 x 5 ml). Combine the filtrate and washing liquid and add concentrated hydrochloric acid. Acidified and extracted with chloroform (3×50 ml). Dry the organic phase with Mg 5Os) and concentrated in vacuo to give the title compound (D2) (980mg) as a beige solid. I got it as a body. Melting point 155-57°C0M, S, M" 188 n, m, r, (CDC1,, 250MHz) 6 2.75 (S, 3H) 7.79-7.92 (m, 2H) 8.07 (d, IH) 8.43 (s, IH) 9.67 (d, IH) 10.58 (BS, IH) Example 1 Isoquinoline-1-carboxylic acid (2 g) in dry DMP (50 ml), N- Hydroxysuccinimide (1,5 g) and 1-ethyl-3-(3-dimethyl A solution of (aminopropyl)carbodiimide (2.6 g) was stirred at room temperature for 4 hours.

The reaction mixture was cooled to 0°C and endo-N-( Addition of 9-methyl-9-azabicyclo[3,3,11 nonan-3-amine (2 g) The mixture was stirred at room temperature overnight. The solvent was removed, the residue was dissolved in cH, cL, and saturated Na Washed with aqueous HCO*, dried and concentrated. The residue was diluted with ethyl acetate and betrol ( Recrystallization from a boiling point range of 60-80°C gave the title compound (2.4g).

Melting point 155-157°C0 Example 2-6 The following compounds are prepared analogously to Example 1 or as previously described.

Melting point 87-88℃ 'H-NIJR (CDCIs) 6 9.67 (d, IH) 8.75 (d, IH) 8.48 (d, IH) 7.9-7.6 (m, 48) 4.42-4.28 (all) 3.25 (brs, 2H) 2.42-1.70 (m, 2.35.s, IIH including 3H) Melting point 13 3-136℃ 'H-NIJR (CDCIs) 6 9.19 (s, IH) 8.85 (brd, IH) 8.60 (S, IH) 8, 10-7.95 (m, 2H) 7.80-7.65 (m, 2H) 4.36 (dt, IH) 3.25 (brs, 2H) 2.44-1.95 (m, 2.36.s, 9H including 3H) 1°85 (brd, 2H) Melting point 115-117℃ 'H-NMR (CDC12) 6 9.62 (d, 1h) 8.51-8.40 (m, 2h) 7.9-7.62 (m, 4h) 4.35-4.15 (m, 1h) 3.58-3.41 (m, 1h) 3.10-2.82 (m, 4h) 2.75 (dd, 1h) 2.41-1.5 (m, 5h) Example 5 Endo-N-(9-methyl-9-aza-3-oxabicyclo[3,3,11 nona (7-yl)isoquinoline-1-carboxamide (E5) Melting point 148-150 ℃ 'H-NMR (CDC1*) δ 10.03 (brd, IH) 9.42 (d, LH) 8.50 (d, 18) 7.9-7.62 (1,4H) 4.88-4.72 (1,1H) 4.10 (d, 2H) 3.68 (d, 2Ji’) 2.75 (brs, 2H) 2, 67-2゜50 (a 2-60.s, 5H including 3H) 1.60 ( d, 2) l') Example 6 Endo-N-(8-methyl-8-azabicyclo[3,2,1]octane-3-y )-4-Methyl-■-isoquinoline-1-carboxamide hydrochloride (E6) drying 4-Methyl-1-isoquinolinecarboxylic acid (500ml) in DMF (15ml) g) and N~hydroxysuccinimide (368 mg) under nitrogen atmosphere. and stirred at ambient temperature for 30 minutes. 1-ethyl-3-(3-dimethylaminopropyl) ) Carbodiimide (768 mg) was added in one portion and stirring continued for 1 hour. This anti The reaction mixture was cooled to 0°C and dissolved in endo-8-methyl-8-alcohol in DMF (5 ml). Add dropwise solution of Zabishik O[3,2,1]octan-3-amine (374 mg) and stirred at ambient temperature for 20 hours. The solvent was removed under vacuum and the residue was dissolved in chloroform. (50 ml) and 10% aqueous NaOH solution (5 ml). Dry the remaining organic phase Mg5O,) was evaporated under reduced pressure. Flash chroma the residue on silica gel chloroform and ethanol (10% V/V or less) as eluents. ) to obtain oil. Treatment with ethanolic MCI gave the title compound (2 00 mg) was obtained as a pale yellow solid. Melting point 140-43°C.

M, S, M"309 (free base)') ("NMR (d4-MeOH, 25 0MHz) 6 2.33-2.52 (a+, 58) 2.59-2.65 (m , 2H) 2.84 (s, 3H) 2.92 (S, 3) 1) 3.02 (d, IH) 3.89-4.06 (+a, 2H) 4.40-4.53 (a+, IH) 8.10 (t, IH) 8.30 (t, IH) 8.44-8.60 (a3H) 5-HT　s　receptor antagonist activity This compound shows no activity in anesthetized rats. Antagonism of Betuorto-Yarisch reflex induced by 5-HT It is evaluated according to the following method: male rats (250-350 g) are anaesthetized with urethane ( 1,25 g/kg (intraperitoneal) was applied, and the blood pressure and heart rate were measured by Fozard J, R, et al. al,, J, Cardiovasc, Pharmacol, 2.22 9-245 (1980) ■L Record it so that it will be posted. Intravenous administration of less than the equivalent amount of 5-HT (usually 6 μg/kg) Repeat administration via route and measure changes in heart rate. The compound is administered intravenously and then The concentrations (EDs) required to reduce the 5-HT-induced response to 50% of the control response are Melt.

-! -Tonoichi 5-HT, an isoquinoline derivative that develops receptor antagonist activity; methods for their preparation and their use as medicaments.

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Claims (19)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, E is NH or O; R1 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy or or nitro; Z is an azacyclic or azabicyclic side chain; and i) the group CO-E-Z is in the I-position and R2 is in the 3-position, hydrogen, C1-6 alkyl or C1-6 alkoxy, or R2 is in the 4-position, hydrogen, halogen, CF3 , C1-6 alkyl, C1-7 acyl, C1-7 acylamino, (1 or 2 even if substituted with C1-6 alkyl, C1-6 alkoxy or halogen phenyl, (1 or 2 C1-6 alkyl or C2-6 cyclo substituted with alkyl, or with C4-5 polymethylene, or with phenyl optional) amino, aminocarbonyl or aminosulfonyl, C1-6 alkyl rusulfonyl, C1-6 alkylsulfinyl, C1-6 alkoxy, C1-6 or ii) the group CO-E-Z is alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position, and R2 in the 1-position, hydrogen, C1-4 alkyl or C 1-4 alkoxy, or R2 is in the 4-position and hydrogen or C1- 4 alkoxy] A compound having 5-HT3 receptor antagonist activity or is a pharmaceutically acceptable salt thereof. 2. 2. A compound according to claim 1, wherein E is NH. 3. 3. A compound according to claim 1 or 2, wherein CO-E-Z is in the 1-position. 4. 4. A compound according to any one of claims 1-3, wherein R1 is hydrogen. 5. Z is tropane, granatan, oxa/thiagranatan, quinuclidine, i Soquinuclidine, isogranatane, oxa/thiaisogranatan or isotho 5. A compound according to any one of claims 1-4, which is lopane. 6. Endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane-3- Isoquinoline-1-carboxamide. 7. Endo-N-(8-methyl-8-azabicyclo[3.2.1]octane-3 -yl)inquinoline-1-carboxamide. 8. Endo-N-(8-methyl-8-azabicyclo[3.2.1]octane-3 -yl) isoquinoline-3-carboxamide. 9. N-(quinuclidin-3-yl)inquinoline-1-carboxamide. 10. Endo-N-(9-methyl-9-aza-3-oxabicyclo[3.3.1 ] nonan-7-yl)isoquinoline-1-carboxamide. 11. Endo-N-(8-methyl-8-azabicyclo[3,2.1]octane- 3-yl)-4-methyl-1-inquinolin-1-carboxamide. 12. 12. A pharmaceutically acceptable salt of a compound according to any one of claims 6-11. 13. A compound according to claim 1, substantially as defined herein in connection with the examples. . 14. A method for producing a compound according to claim 1, comprising formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Compound (V) and compound of formula A2-Z' react [where Z' is Z as defined in claim 1, and R3 and R4 are R3' and R4' are substituted and A1 and A2 react together to form an amide or or a group forming an ester bond, and R3' and R4' are each R3 and R4 as defined in claim 1, or a hydrogenolyzable protecting group ], then as desired or necessary, R3' other than R3 or R4 or converting R4' to R3 and R4, respectively, and optionally of formula (I) The above method comprising forming a pharmaceutically acceptable salt of the compound. 15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. A product. 16. comprising administering an effective amount of a compound according to claim 1 to a mammal, e.g. for the treatment of pain, vomiting, CNS disorders and/or gastrointestinal disorders (in humans) or Prevention methods. 17. According to any one of claims 1-13 for use as an active therapeutic substance compound. 18. For use in the treatment of pain, vomiting, CNS disorders and/or gastrointestinal disorders 14. A compound according to any one of claims 1-13. 19. For the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders and/or of a compound according to any one of claims 1-13 for the manufacture of a medicament for prophylaxis. use.