JPH06503332A - Azabicyclic amides or esters of halogenated benzoic acids - 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] Azanicyclic amides or esters of halogenated benzoic acids The present invention provides pharmacologically active New compounds with do.

EP-A-220011 (Beecham Group PLC) ham Group p, 1. c, )) is a benzamide derivative of 5- Use as an HT3 receptor antagonist has been described.

Here, a group of new compounds were discovered, and these compounds - Antagonist.

Therefore, the present invention provides formula (1): [In the formula, R1 is hydrogen or C1-6 alkoxy; L is O or NH, and Z is a di-azacyclic or azanicyclic side chain], and 5-HT! receipt Provides a compound with target antagonist activity, or a pharmaceutically acceptable salt thereof. provide

Suitable examples of alkyl moieties in R1 include methyl, ethyl, dan- and = Tarpropyl, Tan -1 plot, ≦ and bold ■ -Buchil are listed.

Suitable examples of halo moieties include fluoro, chloro and bromo.

In particular, RI is hydrogen, R, is chloro and R3 is chloro; or %R, is methoxy R1 is fluoro or chloro and R3 is chloro.

A suitable example of Z is 5-HT, as reported in the art regarding receptor antagonists. It has been tell. That is, as follows: 1) GB 2125398A ( Sandoz Limited) ii) GB 215 2049A (Santos) iii) EP-A-215545 (Beacham Gu Loop PLC) iv) EP-A-214772 (Beacham Group Loop PLC) v) EP-A-377967 (Beacham Guru vi) PCT/GB91101629 (Beacham ・Group PLC) vii) EP-A-358903 (Diani The specific side chains of importance are represented as follows: Quinuclidine [In the formula, R is hydrogen or methyl; X is oxygen, sulfur, or optionally Cl-6 alk Kyl, C, cycloalkyl, C3-1 cycloalkyl, Cl-4 alkyl, Nyl, naphthyl, phenylCl-4alkyl or naphthylCl-4alkyl ( wherein the phenyl or naphthyl moiety is optionally substituted with one or more moieties. Cl-6 alkoxy or C3-6 alkyl) [Nitrogen]

Particularly important side chains Z include tropane, oxagranatane and azagranatane. (where R is methyl). When X is N, the N-substituent Appropriate meanings are similar to those described in PCT/GB91101629, for example, 1 so-propyl or ethyl.

L is preferably NH.

Alternatively, COL in formula (I) is stere), for example 1,2,4-oxadiazole and EP-A-377 967 (Beacham Group PLC) having structure h) as described in May be replaced by other groups.

Pharmaceutically acceptable salts of the compound of formula (I) include hydrochloric acid, hydrobromic acid, boric acid, Phosphoric acid, sulfuric acid, and pharmaceutically acceptable organic acids such as acetic acid, tartaric acid, phosphoric acid Golic acid, citric acid, succinic acid, benzoic acid, ascorbic acid, methanesulfonic acid, α - Ketoglutaric acid, α-glycerophosphate, and glucose-1-phosphate, etc. Acid addition salts with conventional acids may be mentioned.

Examples of pharmaceutically acceptable salts include compounds R, -T (where R8 is C1-6 alkyl, phenyl-01-6 alkyl or C3-7 cycloalkyl, T is acid of formula (I), such as a compound quaternized by a group corresponding to the anion of Quaternary derivatives of the compounds may be mentioned. Suitable examples of R include methyl, ethyl and n- and yuzu-propyl; additionally benzyl and phenethyl. It will be done. Suitable examples of T include halides such as chloride, promide and yoshito. One example is de.

Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.

Compounds of formula (I) and their pharmaceutically acceptable salts (quaternary derivatives and N- (including oxides) may form pharmaceutically acceptable solvates such as hydrates. (, is included whenever it means a compound of formula (1) or a salt thereof.

Of course, some compounds of formula (I) have chiral or brochiral centers. It is therefore understood that numerous stereoisomers, including enantiomers, can exist. It will be done. The present invention covers each of these stereoisomers (including enantiomers) and mixtures thereof. Compounds (including racemic compounds). The various stereoisomers can be obtained by conventional methods. , can be distinguished and separated from each other.

The present invention provides a method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. This method also provides a method for converting a compound of formula (■): into a compound of formula (I[[) :%formula%() or, when L is 0, its reactive derivative (where R1', R1', R1' and/or Zo are each R,, R,, R8 and/or Zl or a group or atom that can be converted thereto Child: R4 is hydrogen or N-protecting group; Ql is leaving group; remaining variables are as above. ); then, as desired, R8', R1', R3' and/or Zo into another group or atom R, %R1, R8 or Z; and, if desired, forming a pharmaceutically acceptable salt of the compound of formula (I) obtained.

Examples of R4 include Cl-1@ such as cl-7 alkanoyl when it is other than hydrogen. Acyl (where alkyl may be as listed for R1); Preferably it is acetyl. R4 is usually hydrogen.

Examples of leaving groups Q1 that can be substituted with nucleophiles include halo such as chloro and bromo. C1-4 alkoxy, such as gen, hydroxy, CH, O and C2H50-, P Activated hydrorubyloxy such as hOPho-1c1sc or C1,CO- , or form a mixed anhydride and therefore Q+ is carboxylic acyloxy. or a nitrogen-bonded heterocycle such as imidazole.

If the group Q1 is a halide or COQ+ forming a mixed anhydride , the reaction is preferably carried out using benzene, dichloromethane, toluene, diethyl ethyl ether, tetrahydrofuran (THF) or dimethylformamide (DMF) at non-extreme temperatures in an inert, non-hydroxyl solvent such as. So It is also preferably an organic base, especially triethylamine, trimethylamine, It is carried out in the presence of an acid acceptor for a tertiary amine such as pyridine or picoline.

Some of these can function as solvents. Or acid Receptors are inorganic substances such as calcium carbonate, sodium carbonate or potassium carbonate. can be done. A temperature of 06-100°C, especially a temperature of 10-80°C is suitable. .

Group Q is C1-4 alkoxy, phenoxy or activated hydrocarbyloxy In some cases, the reaction is preferably carried out using toluene or dimethylformamide, etc. in an inert polar solvent. Group Q1 is C13CO-, and the reaction Preference is given to carrying out in toluene at reflux temperature.

When the group Q, is hydroxy, the reaction generally involves dichloromethane, T optionally in an inert non-hydroxyl solvent such as HF or DMF. In the presence of a dehydrating agent such as bodiimide, e.g. dicyclohexylcarbodiimide Implemented. The reaction may be carried out at non-extreme temperatures, such as -10 to 100°C, e.g. , what is necessary is just to carry out at 0-80 degreeC. In general, compounds with low reactivity have high reactivity. temperature is used, whereas lower temperatures are used for highly reactive compounds.

When the group Q1 is carboxylic acyloxy, the reaction is preferably carried out when Q1 is The reaction is carried out in substantially the same manner as in the case of a halide. acyloxy leaving group Suitable examples include C6-4 alkanoyloxy and C1-4 alkoxycar Bonyloxy, in which case the reaction is preferably carried out in dichloromethane triethyl acetate in an inert solvent such as at non-extreme temperatures, e.g. It is carried out in the presence of acid acceptors such as min. C1-4 alkoxy carbonyl oxy The si leaving group converts the corresponding compound (where Ql is hydroxy) into chloroformic acid It may also be generated in situ by treatment with C1-4 alkyl.

When the group QI is activated hydrocarbyloxy, the reaction preferably It is carried out in an inert polar solvent such as methylformamide. In addition, activated hydro The carbyloxy group is a pentachlorophenyl ester, and the reaction is carried out at ambient temperature. It is preferable to carry out.

When Y is O, the compound of formula (II[) may be in the form of a reactive derivative thereof. It is often a salt such as a lithium, sodium or potassium salt.

As the R1' or R3° group which is convertible R2 or R3, conventional halogen Hydrogen substituents that can be converted to halogen substituents by halogenation using a chlorinating agent are listed. can be lost.

When Z' is other than Z, R is optionally halo, Cl-4 alkoxy and benzene substituted with 1 or 2 groups selected from may be substituted with R, which is a hydrogenolyzable protecting group. child For example, when R1/R2 are not halogen, a benzyl group such as It is removed by hydrogenolysis using a transfer metal as a catalyst, and with the formula (1) [wherein R is hydrogen] The compound shown can be obtained.

The present invention also provides a compound represented by formula (1) [wherein R is methyl] or a pharmaceutical thereof. Provided is another method for producing a pharmaceutically acceptable salt, which method comprises: R is hydrogen] is N-methylated, and if desired, the obtained formula (1) forming a pharmaceutically acceptable salt of the compound. In this alternative method of the invention "N-methylation" refers to the reaction with the compound CH302 [wherein C2 is a leaving group] Therefore, it should be achieved.

Suitable values for C2 are C1, Br, I, ○5O2CH3 or 03OzCaH4 pCHi, preferably a group redeemed by a nuclear reagent such as C1, Br or 1 included.

The reaction is carried out under conventional alkylation conditions, e.g. This may be carried out in an inert solvent in the presence of an acid acceptor such as potassium carbonate.

Generally, the reaction is carried out at extreme temperature, such as at ambient temperature or slightly above. Perform at a temperature that is not at the edge.

Alternatively, "N-methylation" may be carried out under conventional reductive alkylation conditions.

In the compound of formula (I[[) before coupling with the compound of formula (I[) It is also possible to exchange R. Such exchange may be conveniently made under the conditions mentioned above. Do it.

Prior to R/Z exchange, the amine functionality is acid-hydrolyzed like the C2-1 alkanoyl group. It is desirable to protect with a group that is easily removable by solution.

In preparing such compounds of formula (I[I), the corresponding compound ( where the methyl group is substituted with alkoxycarbonyl) is prepared by Often convenient. Such compounds are then treated with lithium aluminum hydride. When reduced to the corresponding compound represented by formula (n) using a strong reducing agent such as The benzoic acid-derived intermediate of formula (n) is known or is a known compound. or from known compounds according to conventional methods. R When 2 is fluoro, this intermediate is a hypofluorofluoride as described in Explanation 1 above. Using a suitable fluorination catalyst such as trifluoromethyl chloride, the corresponding R2 is It may be prepared by fluorinating a hydrogen compound.

Compounds of formula (m) are generally prepared by condensation, often using substituted piperidines. from the corresponding exocyclic keto derivatives with azanicyclic side chains prepared by the synthesis method. prepared. They are the methods described in the above-mentioned patent publications regarding the significance of the side chain Z. It may be made by tA.

Formulas with tropane, granatan or oxa/thia/aza-granatan side chains ( In compounds of I), the -COL- bond is related to the ring of the bicyclic moiety to which it is attached. It is understood that the end arrangement can be taken as follows. Endo or end of the compound represented by formula (1) Mixtures of and exo isomers can be synthesized non-stereospecifically, with the desired isomer , and then separated according to conventional methods, e.g. by chromatography: Alternatively, the endo isomer may optionally be the corresponding endoisomer of the compound of formula (II). It can be synthesized from the indexed form. The corresponding pairs of geometric isomers are isoquinuclidine, i. Regarding the side chains of sogranatan, oxa/thia-isogranacune, and isotropane. It is possible.

Pharmaceutically acceptable salts of the compounds of the present invention may be formed according to conventional methods.

These salts are, for example, a combination of a basic compound of formula (I) and a pharmaceutically acceptable organic acid or may be formed by reaction with an inorganic acid.

The compounds of the invention are 5-HTs receptor antagonists and therefore Commonly used to treat or prevent pain, vomiting, CNS disorders, and gastrointestinal disorders it is conceivable that. Pain includes migraines, cluster headaches, trigeminal neuralgia and visceral pain. Rare: Vomiting may be caused by vomiting, especially those to prevent vomiting and nausea associated with cancer treatment or after surgery. vomiting, and nausea associated with migraine. Examples of such cancer treatments include: Platinum complexes, including cisplatin, and also doxorubicin and cyclophosphamide cytotoxic agents, especially cisplatin; and radiation therapy. It also includes treatment. CN5H harm includes anxiety, psychosis, and senile dementia. ,! ! ! Includes disability and age-related memory impairment (AAMI), and drug dependence. Ru. Gastrointestinal disorders include intestinal hypersensitivity syndrome and diarrhea.

5-HT, a receptor antagonist, may also be used to treat obesity, arrhythmias, and/or It may be used to treat disorders involving myocardial instability or myocardial instability.

The present invention also provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are usually suitable for oral or parenteral administration. As such, it is available in tablets, capsules, oral liquid preparations, powders, granules, and troches. formulations, renewable powders, solutions or suspensions for injections and infusions, or suppositories. It is a form. Orally administrable compositions are more convenient for general use; ,preferable.

Tablets and capsules for oral administration are usually given in unit doses; agents, excipients, diluents, tabletting agents, lubricants, disintegrants, colorants, flavoring agents, and moisturizing agents. Contains conventional additives such as lubricants. The tablets are prepared according to methods known in the art. For example, it may be coated with an enteric coating.

Suitable excipients for use include cellulose, mannitol, lactose and other Contains similar drugs. Suitable disintegrants include starch, polyvinylpolypyrrolid and starch derivatives such as sodium starch glycolate.

Suitable lubricants include, for example, magnesium stearate.

Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate. oral Liquid preparations for use include, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or or in the form of an elixir, reconstituted with water or other suitable vehicle before use. It may also be provided as a dried product. Such liquid formulations may contain suspending agents, e.g. For example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl Cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats and oils, emulsifiers such as lecithin, sorbitan monooleate, and conventional additives such as gum arabic; non-aqueous media (including edible oils), e.g. , almond oil, fractionated coconut oil, oily esters such as glycerin esters, Ropylene glycol, or ethyl alcohol: preservatives, e.g. p-hydroxy Methyl or propyl benzoate or sorbic acid and, if necessary, conventional It may also contain flavoring agents and coloring agents.

Oral liquid preparations typically include aqueous or oily suspensions, solutions, emulsions, syrups, or in the form of an elixir and reconstituted with water or other suitable vehicle before use. It is offered as a dried product for fresh consumption. Such liquid preparations contain suspending agents, emulsifying agents, agents, non-aqueous vehicles (which may include edible oils), preservatives, and additives such as flavorings and colorants. It may also contain conventional additives.

Oral compositions may be prepared by conventional methods of compounding, filling, or tabletting. stomach. These compositions with large amounts of excipients can be formulated using repeated compounding operations. All you have to do is distribute the drug. Such operations are, of course, conventional in the field. It is the law.

For parenteral administration, a unit dose of a liquid containing a compound of the invention and a sterile vehicle. A form is prepared. The compound may be suspended or dissolved depending on the medium and concentration. can do. Parenteral solutions are usually prepared by dissolving the compound in a vehicle and sterilizing it by filtration. Prepared by filling a suitable vial or ampoule and sealing it after sterilization. be done. Additionally, adjuvants such as local anesthetics, preservatives and buffering agents may be dissolved in the vehicle. It is convenient. To increase stability, the composition can be It can be frozen and the moisture removed under vacuum.

Parenteral suspensions are made by suspending the compound in a sterile vehicle instead of dissolving it in a vehicle. Prepared in substantially the same manner, except for exposure to ethylene oxide prior to suspension in Manufactured. Surfactants and wetting agents may be included in the composition to achieve uniform distribution of the compounds of the invention. It is advantageous to facilitate this.

The present invention further relates to pain, vomiting, CNS disorders and/or or a method of treating or preventing gastrointestinal disorders, which method comprises formula (I) from administering an effective amount of a compound represented by or a pharmaceutically acceptable salt thereof. Ru.

Amounts effective to treat the disorders described below are based on the relative potency of the compounds of the invention. , depending on the nature and severity of the disorder being treated and the body weight of the mammal. but However, a unit dose for a 70 kg adult will typically contain a compound of the invention at 0.0 5 to 1000+ag, for example, 0.5 to 500 mg. The unit dose is −day once or more every day, such as 2.3 or 4 times a day, more usually on a day It may be administered 1 to 3 times, which is about 0.0001 to 50 mg/kg/day, and It is usually within the range of 0,0002 to 25 mg/kg/day.

Within the above dosage range, no toxicological side effects are observed.

The present invention also provides the activity of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Use as a sexual therapeutic agent, especially for pain, vomiting, CNS disorders and/or gastrointestinal disorders Provides for use in the treatment of disorders.

The following examples illustrate the preparation of compounds of formula (I).

! Twisted Ex, No, R, R2R3L Z I HCI CI NHNmT 2 HCI CI NHQ 3　0CHJCI　CI　NHNmT 4 0CHs CI CI NHNl1105 0CHs F CI NHNm T N+*T=N-methyltropane Q=quinuclidin-3-yl NtaO=N-methyloxagranatanmethyl-4-acetamido-5-chloro -2-Methoxybendoate (10.9g) dissolved in chloroform (40ml) The mixture was cooled to -10°C under a nitrogen atmosphere. 3 molar excess of trifluorohypofluorite The lomethyl was slowly bubbled through the stirred cooled solution for 6 hours. slow positive pressure A nitrogen flow was maintained throughout the reaction. Warmed to room temperature and purged thoroughly with nitrogen. Afterwards, chloroform was removed in vacuo.

The residue was purified using silica gel using chloroform containing increasing amounts of methanol as eluent. chromatography on a column. the product as an off-white solid isolated.

'HNMR (CDCIs) 250MHz δ: 7.64 (d, IH), 7. 37 (BS, LH), 3.98 (BS, 3H), 3.9 (s.

3H), 2.2 (s, 3H) b) 4-Amino-5-chloro-3-fluoro-2-methoxybenzoic acid ethanol Methyl-4-acetamido-5-chloro-3-fluoro-2-meth in 25ml Xybenzoate (1,89 g) was dissolved in sodium hydroxide (1,1 5g) solution. The mixture was heated under reflux for 16 hours and then cooled. .

The solvent was removed in vacuo and the residue was acidified. Collect the precipitated solids by filtration 1.48 g of product was obtained.

'HNMR (DMSO) 250MH2 δ: 7.49 (d, IH), 6.19 (bs, LH), 3.80 (s, 3H) Example 1 Endo-N-(8-methyl-8-azabicyclo[3,2,11octane-3-y )-4-Amino-3,5-dichlorobenzamide (El) 0°C CHzClz (50ml) and 4-amino-3°5 in EtsN (0,8+1) -To a stirred solution of dichlorobenzoic acid (1.1 g) was added EtOtCCI (0.48 g). l) was added. After stirring for 1 hour to room temperature, the solution in CHzCb (10 ml) nd-8-methyl-8-azabicyclo[3,2,13octan-3-amine (0 , 7g) was added and the whole was stirred overnight. The reaction mixture was purified with saturated NaHC. Washed with Os solution, dried and evaporated. The residue (EtOAc/vetro The title compound (0.35 g) was obtained by recrystallization (from 100 g of filtrate). Melting point 192-193 ℃.

'HNMR (CDCIs) 67.55 (s, 2H) 6.25 (brd IH ), 4.76 (brs, 2H) 4.22 (Q, IH) 3, 21 (brs, 2H) 2.33 (s, 3H) 2,35~2.10 (m, 4H) 1,88~1.68 (m, 4H) Similarly, it was manufactured by Example 2 N-(1-azabicycloC2,2,21octan-3-yl)-4-amino-3 ,5-dichlorobenzamide (E2) Melting point 233-235℃ Example 3 Endo-N-(8-methyl-8-azabicyclo[3,2,1cooctane-3-y )-4-amino-3,5-dichloro-2-methoxybenzamide (E3)CH Endo-N-(8-methyl-8-azabicyclo[3 ゜2.1]octan-3-yl)-4-amino-5-chloro-2-methoxyben A solution of zuamide (0°8 g) in CH, Co○H (5 mL) (Dell 2) (0.18g) (Solution D was treated with TI. After standing overnight at room temperature, the solvent was removed by rotary evaporation. It was removed by extraction and the residue was partitioned between EtOAc and aqueous NaHCOs. Yes The machine extract was separated, dried (over KtCOs), evaporated and the residue was filtrated. Rush chromatography (SiOz, 5-10% MeOH/CHC 1g) 1 Accordingly, purified title compound (0,065 g) was obtained. Melting point 148-151℃ .

Similarly manufactured were: Example 4 endo-N-(9-methyl-9-aza-3-azabicyclo[3,3,1 cononane -7-yl)-4-amino-3,5-dichloro-2-methoxybenzamide (E 4) Melting point 170-172°C.

Example 5 endo-4-amino-5-chloro-3-fluoro-2-methoxy-N-(8-methoxy) Thyl-8-azabicyclo[3,2,1]octan-3-yl)benzamide (E 5) 4-Amino-5-chloro by a procedure similar to that described in Example 1 Prepared from -3-fluoro-2-methoxybenzoic acid.

The product was isolated as the hydrochloride salt. Melting point: 202-203°C.

'HNMR (free base), (CDCIs), 250MHz endo-4-amino 5-chloro-3-fluoro-2-methoxy-N-(8-methyl-8-azabicic b[3,2,1]octan-3-yl)benzamide (E5) as described in Example 1. 4-Amino-5-chloro-3-fluoro-2- Prepared from methoxybenzoic acid.

The product was isolated as the hydrochloride salt. Melting point: 202-203°C.

IHNMR (free base), (CDCI, ), 250MHz δ: 8.61 (b d, IH), 7.81 (d, LH), 4.34 (BS, 2H), 4.2 0 (dd, IH), 3.98 (d, 3H), 3.10 (b, 2H), 1 ．． 53-2.21 (m, 11 Hinc, s, 2.21.3H).

A 5-HT receptor antagonist active compound is anesthetized according to the following method. 5-HT-evoked phono-belorto-yarisi in mice The antagonism of the won Bezold-Jarisch reflex was evaluated. .

Male rats weighing 250-350 g were anesthetized with urethane (1.25 g/kg, i.p.). , blood pressure and heart rate were measured using Fozard J.R. o) et al. Journal of Cardiovascular Pharmacology (J, Ca rdiovasc, Pharmacol,) vol. 2, pp. 229-245 (198 Record as described in Year 0). submaximal dose (usually 6 μg/kg) 5-HT is given repeatedly by intravenous route and changes in heart rate are measured. compound intravenously After administration by the intravenous route, the response evoked by 5-HT was reduced to 50% of that of the control. The concentration required to reduce (EDso) was determined.

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Claims (19)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is hydrogen or C1-6 alkoxy; R2 is halo; R3 is halo; L is O or NH; and Z is a di-azacyclic or azabicyclic side chain], and the 5-HT3 receptor A compound having anti-antagonist activity, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R1 is hydrogen, R2 is chloro and R3 is chloro. . 3. R1 is methoxy, R2 is fluoro or chloro and R3 is chloro. A compound according to claim 1. 4. Side chain Z is tropane, granatan, oxa/thia/aza-granatan, quinuc -Lysine, Isoquinuclidine, Isogranatan, Oxa/Thia isogranatan or intropane, the compound according to any one of claims 1 to 3. 5. Claim 4, wherein Z is tropane, oxagranatan or azagranatan. compound. 6. 6. A compound according to any one of claims 1 to 5, wherein L is NH. 7. Endo-N-(8-methyl-8-azabicyclo[3.2.1]octane-3 -yl)-4-amino-3,5-dichlorobenzamide. 8. N-(1-azabicyclo[2.2.2]octan-3-yl)-4-amino -3,5-dichlorobenzamide. 9. Endo-N-(8-methyl-8-azabicyclo[3.2.1]octane-3 -yl)-4-amino-3,5-dichloro-2-methoxybenzamide. 10. Endo-N-(9-methyl-9-aza-3-azabicyclo[3.3.1] nonan-7-yl)-4-amino-3,5-dichloro-2-methoxybenzami Do. 11. Endo-4-amino-5-chloro-3-fluoro-2-methoxy-N-( 8-Methyl-8-azabicyclo [3.2.1. ] octane-3-yl) benzua Mid. 12. A pharmaceutically acceptable salt of a compound according to any one of claims 7 to 11. 13. Compounds according to claim 1, substantially specified by reference to the examples. . 14. A method for producing the compound according to claim 1, wherein formula (II): ▲ mathematical formula, chemical formula , tables, etc. ▼ The compound represented by (II) is expressed as formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼Do you want to react with the compound shown in (III)? , or when L is O, react with its reactive derivative (here, R1', R 2', R3' and/or Z' are respectively R1, R2, R3 and/or Z or a group or atom convertible thereto; R4 is hydrogen or an N-protecting group ; Q1 is a leaving group; the remaining variables have the same meanings as in claim 1); then, as desired , R1', R2', R3' and/or Z' are replaced by another group or atom R1, R 2, R3 or Z; and, optionally, of the resulting compound of formula (I). A manufacturing method comprising forming a pharmaceutically acceptable salt. 15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 16. Pain, vomiting, CNS disorders and/or gastrointestinal disorders in mammals such as humans A method of treating or preventing harm, comprising administering an effective amount of a compound according to claim 1. A method consisting of: 17. According to any one of claims 1 to 13 for use as an active therapeutic substance. compound. 18. For use in the treatment of pain, vomiting, CNS disorders and/or gastrointestinal disorders A compound according to any one of claims 1 to 13. 19. Treat and/or prevent pain, vomiting, CNS disorders and/or gastrointestinal disorders A compound according to any one of claims 1 to 13 in the manufacture of a medicament for preventing Use of.