JPS61275276A - Novel compound, manufacture and medicinal composition - 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 OBJECTS OF THE INVENTION Industrial Application The present invention relates to novel compounds having useful pharmacological properties, to pharmaceutical compositions containing them, to processes and intermediates for their production. Concerning their use in the body and as medicine.

Prior Art British Patent Application Nos. 2100259A and 21253
No. 98A has an azabicyclo side chain and 5-HT (5
Benzoates and benzamides with antagonistic activity (-hydroxytryptamine) are described.

SUMMARY OF THE INVENTION In the present invention, a group of novel structurally different compounds have been invented. These compounds have 5-HT antagonistic activity and/or
or has gastric motility-enhancing activity.

[Structure of the invention]

Means for Solving the Problem Accordingly, the present invention provides the formula (1) in which X is Co and Y is NH or 0, or X is Nu and Y is CO. 2 is CI (2, 0, 8 or NRa, here R3
is hydrogen, C troalkyl, C3-γalkenyl-methyl, phenyl or phenylC1-4 alkyl, and either phenyl moiety is substituted by 1 or 2 of halogen, CF3, C1-6 alkoxy or Cl-6 alkyl. and Ra is absent or 2 is CH or N and Ra has the same meaning as above and Rb when X-Y-Rz is attached to the phenyl field
exists, hydrogen, halogen, CE'3, hydroxy, Cl
-6 alkoxy or C1-6 alkyl,
R1 is hydrogen, halogen, CFs, Cl-s alkyl,
Cl-s alkoxy, Cl-8 alkylthio, CI-?
Acyl, C1-7 acylamino, Cl-6 furkylsulfonylamino, N -(Cl-a alkylsulfonyl)
-N -Cl-4 alkylamino, Cl-6 alkylsulfinyl, hydroxy, nitrot tahcl-8 alkyl, cs-8 cycloalkyl, Cs-5 cycloalkyl Cl-4 alkyl, phenyl or phenyl C1
Amino, aminocarbonyl, aminosulfonyl, aminosulfonylamino or (aminosulfonyl) -Cl-4 alkylaminodecha, R is of formula (a), ■ or (c) (wherein n is 2 or 3, p and q are independently 1
~3, and R4 or R6 is the group (CH2)tRa, where t is 1 or 2, R6 is Cl-6 alkyl1. Ct-1s7
p:=r is chenyl, pyrrolyl or furyl optionally substituted with one or two substituents selected from xy, trifluoromethyl or halogen;
or C1 optionally substituted with C1-4 flukoxy, trifluoromethyl, halogen, nitrocarboxy, esterified carboxy and hydroxy, C1-4 alkoxy, carboxy, esterified carboxy or acyloxy which can be hydrolyzed in vivo. -4 alkyl optionally substituted with one or two substituents) or a pharmaceutically suitable salt thereof is provided.

Preferably, X is CO and Y is NH or O
It is.

2 is correspondingly NRs, and Ra does not exist,
Alternatively 2 is N - and Ra has the same meaning as for R3.

Preferred values for R3 or Ra include hydrogen, methyl, ethyl, n- and isopropyl; stereoisomers, if any, of their E and di-forms prop-2-ale, boudo-2-enyl, boudo-3-enyl; , l-methyleneglobin and 1-methylprop-2-yl: chlor, bromo, CF3, methoxy, ethoxy, n- and iso-propoxy, methyl, ethyl, n- and iso-propyl, by two prongs. , optionally substituted phenyl and benzyl. Preferably, Rs/Ra is hydrogen or methyl, most preferably methyl O. When present, preferred values for Rb include hydrogen, chloro, bromo, CF3, methoxy, ethoxy, n- and iso-propoxy, Includes methyl, ethyl, n- and iso-propyl.

Optionally, the X-Y-Rs side chain is attached to the 6-position, preferably the 3-position as depicted in formula (1).

Values for R1 include hydrogen, fluoro, chloro, bromine,
CF3, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, acetyl, glopionyl, acetylamino, methylsulfonylamino, methylsulfinyl, hydroxy, nitro and substituted by one or two methyl groups or by cyclopentyl or cyclohexyl groups Included are amino, aminocarbonyl, aminocarbonyl, aminosulfonylamino or N-(aminosulfonyl)-methylamino, which may be substituted with C4t or Cs polymethylene. R+ is optionally hydrogen or 5-halo, such as 5-fluoro or 5-chloro.

Preferably p and q are It or 2.

Preferably, R4/R11 is Cl-7 alkyl,
Preferred groups include Cl-3 alkyl such as methyl, ethyl and n- and in-propyl. Among the Cl-7 alkyls, Ca-t alkyls are also advantageous, especially those of the formula (C&)uRe (where U is 1 or 2,
and R9 is a dai- or tert C5-a alkyl group). Examples of C4-7 alkyl include n-1 and tert-butyl, n-pentyl, n-hebutyl and iso-butyl, 3-methylbutyl and tert-butylmethyl. R4/Rs is preferably methyl or ethyl, most preferably methyl.

Examples of R4/R8 when it is C5-5cycloalkyl-01-2alkyl are particularly those in which the cycloalkyl moiety is cyclohexyl or cyclopropyl.

Examples of R4/Rs include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, tart-
Includes butylmethyl, in-propylmethyl, iso-propylethyl and -monobutylethyl.

R4/R8 are particularly preferably cyclopropylmethyl, cyclohexylmethyl, iso-propylmethyl, tert-butylmethyl or isopropylmethyl.

Alternatively, tart-butylmethyl may be used.

-(CH2)tR6, an example of R4/R11 is one where t is 1. R6 is Cl-4 alkyl, C-4
Alkoxy, trifluoromethyl or halogen
It may be 2- or 3-chenyl, 2- or 3-pyrrolyl or 2- or 3-furyl, optionally substituted by h, Cl-4
By one of flukoxy, trifluoromethyl, halogen, carboxy, esterified carboxy and hydroxy, C4 alkoxy, carboxy, esterified carboxy or C1-4 alkoxy which may be substituted with acyloxy which can be hydrolyzed in vivo. It is phenyl which may be substituted.

Suitable substituents for the R6 group will be described in the following five paragraphs.

Examples of C]-4 alkoxy substituents include methoxy, ethoxy and n- and iso-propoxy, especially methoxy.

Examples of halogen substituents include fluoro, chloro and bromo,
The 3rd or 4th position, as appropriate, is included, especially chlor.

[In the optionally substituted C1-4 alkyl substituents, examples of CI-a alkyl include methyl, ethyl, n- and iso-propyl and n- and iso- and tert-butyl, with methyl being preferred. . Examples of substituents for such alkyl groups include hydroxy, methoxy, ethoxy,
Included are n- and iso-propoxy, carboxy, esterified carboxy and in vivo hydrolyzable acyloxy. Substitution preferably occurs on the terminal carbon atom of the alkyl group. Examples of esterified carboxy groups include Cl-4 alkoxycarbonyl, such as methyl-, ethoxy-1n- and iso-propoxycarbonyl, or Cl- on the phenyl ring.
Included are phenoxy or benzyloxycarbonyl optionally substituted with one or two substituents selected from 4-alkyl, Cl-4-alkoxy, trifluoromethyl, halogen or nitro.

Examples of acyloxy groups that can be hydrolyzed in vivo include C1
-6 alkanoyloxy, such as acetoxy, propionoxy, n- and iso-butyroxy, and 2,3-
Dimethylpropanoyloxy, C1-4 on the phenyl ring
benzoyloxy or benzenesulfonyloxy, optionally substituted with one or two substituents selected from alkyl, Cl-4alkoxy, trifluoro)k-methyl, halogen or nitro, or a sulfonyloxy group, e.g. methanesulfonyloxy. Like Cl-6
Contains a flucansulfonyloxy group.

-(CH2)t Re, &/RsO example has t
is 1, and R6 is unsubstituted phenyl or monosubstituted phenyl. Examples of substituents include methyl,
Includes trifluoromethyl, fluoro, chlor and brome.

Pharmaceutically suitable salts of the compound represented by formula (1) include common acids such as hydrochloric acid, hydrobromic acid, boric acid, phosphoric acid, sulfuric acid, etc., and acetic acid, tartaric acid, maleic acid, citric acid, succinic acid, etc. Acid addition salts with pharmaceutically suitable organic acids such as benzoic acid, ascorbic acid, methanesulfonic acid, alpha-ketoglutaric acid, alpha-glycerophosphoric acid and glucose-1-phosphoric acid are included.

Pharmaceutically suitable salts of the compound represented by formula (1) are usually hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid,
It is an acid addition salt with lactic acid and acetic acid.

Preferably the acid addition salt is a hydrochloride.

Examples of pharmaceutically suitable acids include Rho-T (wherein R
ho C1-a furkyl, phenyl-CI-6 alkyl or cs,y cycloalkyl, and T is a radical corresponding to the anion of the acid) Quaternary derivatives of the compound represented by formula (I) are included.

Suitable examples of Rho include methyl, ethyl and n- and iso-propyl, and benzyl and phenethyl.

Suitable examples of T include halides such as chloride, bromide and iodide.

Pharmaceutically acceptable salts of compounds of formula (1) also form internal salts such as pharmaceutically acceptable N-oxides.

Compounds of formula (1) and their pharmaceutically suitable salts (including quaternary derivatives and N-oxides) are also included whenever such compounds and salts are mentioned. Pharmaceutically suitable solvates can also be formed.

Of course, the compound represented by formula (1) is chiral (Chi
ral) and glochiral (Prochiral)
It will be appreciated that the compound has a central center and thus can exist as a number of stereoisomers, including the 1-enantiomer.

The invention extends to each of these stereoisomeric forms (including enantiomers) and mixtures thereof (including racemates). The different stereoisomeric forms can be separated from each other by conventional methods.

The compound represented by formula (1) in which R3 is hydrogen has two tautomeric forms, namely, one in which R3 is hydrogen and Ra is absent, and one in which Ra is hydrogen and 2 is N It will also be understood that it can exist as something that is. The invention extends to each of these forms and to mixtures thereof. The predominant tautomeric form is usually one in which R3 is hydrogen.

A group of compounds encompassed by formula (1) are of the formula (It) Ra (where nl is 2 or 3, Yl is NHt and O, and the remaining variables are of the formula (It) have the same meaning).

Examples of variables and preferred variables are as described for the corresponding variables with respect to formula (1).

Another group of compounds encompassed by formula (1) is the formula (lit)
(wherein pl is 1 or 2, and the remaining variables have the same meanings as in formulas (1) and (fl) K-) The corresponding variable groups in formula (1) are as described above.

Furthermore, formula (IV) encompassed by formula (1), in which ql is 1 or 2, and the remaining variables have the same meanings as in formulas (1) and (It); There are compounds represented.

Examples of variables and preferred variables are the conventions described for the corresponding variables in formula (1).

The present invention also provides a method for producing a compound represented by formula (1), which comprises reacting a compound represented by formula (V) with a compound represented by formula (M) 'LRm (■), In the above formula, G is C0Q1 (wherein Ql is a group that can be substituted with a nucleophilic group), and L is NH
*t or OH or a reactive derivative thereof, and the remaining variables have the same meanings as above, then any RIe Rs e R* Rs if desired
# Other R from Ra and Rb groups) e Rs # R4
t Rs p Ra t or Rb groups, respectively, and, if desired, forming a pharmaceutically suitable salt of the resulting compound of formula (1).

Examples of leaving groups Q1 that can be substituted by nucleophilic groups include halogens such as chloro and bromo, hydroxy, C-4
Included are alkanoyloxy or carboxyl-based acyloxy such as Ct4acoxycarbonyloxy and activated hydrocarbyloxy such as pentachlorophenoxy. Alternatively, in formula (V), G is CO
Q> and when 2 is NH, the nitrogen heterocycle is a leaving group, i.e. represented by formula (V), where G is C
When a compound in which O*H and 2 is NH is reacted with thionyl chloride, it can act as a compound obtained from K,
gives diindazoloC2e3-&, 2'#3'-dlpyrazone-7°14-dione.

When group Q is a halide, the reaction is preferably carried out at non-extreme temperatures in an inert, non-hydroxyl solvent, such as benzene, dichloromethane, toluene, diethyl ether, T
It is carried out in HF (tetrahydroctane) or DMF' (dimethylformamide). It is preferably carried out in the presence of an acid acceptor, such as an organic base, especially a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which also serve as solvent. Alternatively, the acid acceptor may be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. Temperatures of 0 to 100°C, especially 10 to 80°C are preferred.

When group Q1 is hydroxy, the reaction is generally carried out in an inert non-hydroxy solvent such as dichloromethane, T'H
F' or IIVIF in the presence of a dehydration catalyst such as dicyclohexylcarbodiimide. When Y is CO, the compound of formula (IV) is preferably in the form of an acid addition salt, for example a hydrohalide salt such as a hydrochloride. The reaction may be carried out at any extreme temperature, e.g. -10 to ZoooC, e.g. 0 to 80C.
It can be done with Generally, higher reaction temperatures are used with less active compounds, and lower temperatures are generally used with more active compounds.

When the group Q+ is carboxyl acyloxy,
The reaction is preferably carried out in substantially the same manner as when Ql is a halide. Suitable examples of acyloxy leaving groups include CI+ 4.1 alkanoyloxy and C
1-4 alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent such as methylene chloride at non-extreme temperatures such as ambient temperature and in the presence of an acid acceptor such as triethylamine. It will be done. C1-
The 4-alkoxycarbonyloxy leaving group is generated in situ by treatment of C1-4 alkyl chloroformate with the corresponding compound where Ql is hydroxy.

When the group Q+ is activated hydrocarbyloxy,
The reaction is preferably carried out in an inert polar solvent, such as dimethylformamide. It is also preferred that the activated hydrocarbyloxy group is a pentachlorphenyl ester and that the reaction is carried out at ambient temperature.

When the leaving group Qr is a nitrogen heterocycle having the same meaning as above, the reaction is carried out in the same way as when Ql is a halide.

When L is OH or a reactive derivative thereof, the reactive derivative is accordingly a salt, for example a lithium salt.

Pharmaceutically suitable salts of the compounds of this invention can be formed by conventional methods.

The salt can be formed, for example, by reacting the basic compound represented by formula (1) with an organic or inorganic acid suitable as a pharmaceutical.

Other R+ + Rs e R4* Rs r Ra
or R+ # Rse R4 # which can be converted to Rb group
It will be apparent that compounds of formula (1) containing Rse Ra or Rb groups are useful new intermediates. A large number of such transformations are possible not only to the target compounds of formula (1) but also to their intermediates as described below.

(1) Hydrogen substituents can be converted to nitro substituents by nitration.

(il) Nitro substituents can be converted to amino substituents by reduction.

(lil) C1-t acylamino substituents can be converted to amino substituents by deacylation.

(1) Amine substituents can be converted to Cl-4 acylamino substituents by acylation with carboxylic acid derivatives.

(V) Is the hydrogen substituent due to halogenation?・Can be converted into a substituent such as Rogge.

(Vj) A Cl-s alkylthio or C1-6 alkylsulfinyl substituent can be converted by oxidation to a Cl-6 alkylsulfinyl t Tatri C1-a alkylsulfonyl substituent, respectively.

(v+i) amino, aminocarbonyl, aminosulfonyl, aminosulfonylamino or N-(aminosulfonyl) -N -Cl-4 alkylamino substituent is N-
By alkylation, Cl-4 alkyl, cs-a cycloalkyl, and Ct-a alkylating agents are converted to phenyl Cl-4 alkyl groups (however, diphenyl groups are all halogen, trifluoromethyl, Cl-s furkyl, cs-s alkoxy and nitro, or optionally di-substituted and di-substituted by C4-8 polymethylene). can be converted into a substituent.

(The VIID amine substituent may be KNf substituted as defined by acylation with C1-6 alkylsulfonyl chloride or di-tm aminosulfonyl chloride.
The Cl-4 alkylamino substituent may be converted to an alkylsulfonylamino group or an aminosulfonylamino group.
N-(Cl-salkylsulfonyl) N which may be substituted with N as defined by acylation with 6-alkylsulfonyl or disubstituted aminosulfonyl chloride
It can be converted to a -C1-4 alkylamino group or a N-(aminosulfonyl) N -Cl-4 furkylamino group.

The conversions (+) to (ix) are merely examples and do not exclude possibilities.

Regarding (1), nitration is carried out according to known methods.

Regarding (11), the reduction of nitroanisole to aminoanisole is carried out using a suitable reagent.

Regarding (ii+), deacylation is carried out by treatment with a base, for example an alkali metal hydroxide.

(tv), (van) and (IX) Ic g L
, 7'/k is carried out with a haphsylating agent, such as the corresponding acid or acid chloride. Formylation is carried out using free acid.

Regarding (V), oxidation is carried out using customary halogenating agents.

Regarding (■1), the oxidation is carried out at sub-ambient temperature in a non-aqueous solvent, e.g. a chlorinated hydrocarbon, in the presence of an organic peracid, e.g. 3-chloroperbenzoic acid, or in the presence of a water-soluble strong inorganic oxidizing agent, e.g. It is carried out in the presence of an alkali metal permanganate or in an aqueous hydrogen peroxide solution. This method also allows the N portion of the side chain (!L), (b) or (c) to be N#
It will be appreciated that those skilled in the art will routinely take appropriate precautions.

(For ViD K, the alkylation is carried out under customary conditions using the corresponding alkylating agent such as chloride or bromide.

R4/Rs, which is an optionally substituted benzyl having the same meaning as above, may be replaced with other R4/R1+. For example, when R+ or Rb is not a halogen, such a benzyl group can be removed by conventional transition metal catalyzed hydrogenolysis to form to give a compound represented by (the variables have the same meanings as in formula (1)).

The present invention is also represented by the formula (1), where Rz is the formula (a)
or (c), which process comprises N-alkylating a compound of formula (■) and, if desired, rendering the resulting compound of formula (Xia) suitable as a pharmaceutical. Consists of forming salt.

In this alternative method of the invention, "N-alkylation" includes replacing the N atom depicted in formula (■) by any group R4/R5 having the same definition as above. This means that the compound represented by the formula (■) is the compound Ra Qz
This is achieved by reacting with Rs(h, where R4 and R6 have the same meanings as above and (h has a leaving group).

Suitable values for C2 include CI r B e I t 08
Included are groups substituted with nucleophilic groups such as 0zCHs or 08OzCaH4P-CHs.

Preferred values for C2 include CItBrt and O. The reaction is carried out under conventional alkylation conditions, for example in the presence of an acid acceptor such as potassium carbonate in an inert solvent such as dimethylformamide. Generally, the reaction is carried out at non-extreme temperatures such as ambient or slightly elevated temperatures.

Alternatively, "N-alkylation" is achieved when the group R4 or R in the compound represented by formula (1) contains a methylene group adjacent to the N atom in the bicyclic ring - achieved by normal reductive alkylation conditions. It can be done.

R4 or R in the compound represented by formula (■).

It is also possible to interconvert them before coupling them with the compound of formula (V). Such interconversions are conveniently carried out under the conditions described above.

Prior to Ra/Rs interconversion, it is desirable to protect any amine functionality with a group that is easily decomposed by acidolysis, such as a C-door alkanoyl group.

In the compound represented by formula (1), when 84 and R5 are benzyl, the substituent on the phenyl ring, especially the substituted C1-
The 4 substituents are interconvertible. A large number of such interconversions are possible not only to the final compounds of formula (1), but also to their intermediates as described below.

(1) Carboxy Cl-4 alkyl substituents can be converted to esterified carboxy Cl-4 alkyl substituents by esterification. - (il) The esterified carboxy C1-4 alkyl substituent can be converted to a carboxy C1-a alkyl substituent by deesterification.

(iti) Cl-4 alkoxy C1-4 alkyl f%
A group or an in vivo hydrolyzable C-to-4 acyloxy C1-4 alkyl substituent can be converted to a dihydroxy CI-a alkyl substituent by deesterification.

(iv) Carboxy or carboxyC+-s alkyl substituents which may be esterified may be converted to hydroxymethyl or hydroxyCt4alkyl substituents by reduction. and (V) the hydroxy Cl-4 alkyl substituent can be hydrolyzed in vivo by O-alkylation to C1-4 alkoxyCl-4 alkyl or by O-acylation to C1-4 acyloxy C1-4 Can be converted to alkyl.

Conversions (1) to (V) are merely examples and do not represent all possibilities.

Regarding (1) and (:lI), the esterification and deesterification reactions can be carried out in a conventional manner. , for example by heating with aqueous hydrobromic acid or by treatment with pyridine hydrochloride, boron tribromide, boron triiodide or iodotrimethylsilane.

cz-4 acyloxyCl- which can be hydrolyzed in vivo
4 alkyl substituents can be converted to dihydroxy C1-a alkyl substituents by acid or base hydrolysis.

Regarding formula (1v), the reduction is carried out under customary conditions using a selective metal hydride complex, such as lithium aluminum hydride.

With respect to formula (V), O-alkylation is carried out under conventional conditions in an inert solvent at non-extreme temperatures such as ambient or slightly elevated temperatures, or at reflux temperature. C3-4
The alkylating agent has a leaving group that can be easily replaced by a nucleophilic group. Examples of leaving groups include halides, such as chloride, bromide or iodide, or labile acyloxy groups, such as mesyl and tosyl.

O-acylation is carried out under conventional conditions using hydrogen and an acylating agent having an acyl group capable of forming an acyloxy group that can be hydrolyzed in vivo and a leaving group, such as a halide such as chloride and bromide. When a halide is the leaving group, the reaction is generally carried out in the presence of a base. When hydroxy is the leaving group, the reaction is generally carried out in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide, in an inert solvent at non-extreme temperatures, such as ambient or slightly elevated temperatures, or at reflux temperature.

Before performing any of these transformations, the effect on other substituents, if any, must be considered and appropriate such reagents must be selected with the adoption of necessary such precautions. For example, O-alkylation and O
-Acylation is also possible unless the nitrogen atom is previously protected.
-alkylated and N-acylated products respectively.

This is conveniently accomplished by carrying out the alkylation or acylation reaction in a strong acid, such as trifluoroacetic acid, which protonates and thereby protects the nitrogen atom.

When R4 and Rs in the compound represented by formula (M) contain a methylene group adjacent to the N atom in the bicyclic ring,
In the preparation of such compounds of IV),
The methylene group is substituted by 100-, or R
When 4 or Rg is methyl, it is convenient in some cases to prepare the corresponding compounds in which the methyl is replaced by an esterified carboxyl. Such compounds can then be reduced to the corresponding compounds of formula (V) using strong reducing agents such as lyticum aluminum hydride.

The compounds of formula (V) and (Vl) are known or can be customarily prepared by or from methods analogous to known compounds.

Compounds of formula (Vl) in which R2 is of formula (e) can be prepared as described in European Patent Publication EP-A-115933 or by methods analogous thereto.

The compound represented by the formula (helmet) is novel and constitutes one aspect of the present invention.

It will be appreciated that in compounds of formula (1), the -X-Y- bond may have an endo or exo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of a compound of formula (I) can be synthesized non-stereospecifically and the desired isomer separated therefrom in a conventional manner, e.g. by chromatography;
Alternatively, if desired, the endo and exo isomers can be of the formula (
can be synthesized from the corresponding isomer represented by Vl).

The compounds of the present invention are 5-HT antagonists and thus for the treatment or prevention of migraines, complex headaches and trigeminal neuralgia, and also antiemetics, particularly for preventing vomiting and nausea and motion sickness associated with cancer treatment. It is considered that it can be generally used as Examples of such cancer treatments include cytotoxic agents such as cisplatin, doxorubicin and cyclophosphamide;
This includes in particular those using cisplatin and radiation therapy. Compounds that are 5-HT antagonists also have potential value in the treatment of CNS disorders such as anxiety and psychosis, arrhythmias, obesity, and irritable belly syndrome.

The compounds of the present invention also have gastric promotility activity and are useful in treating disorders such as delayed blue sky, dyspepsia, bloating, esophageal reflux, and peptic ulcers.

The compounds of the present invention also provide pharmaceutical compositions comprising a compound of formula (1) or a pharmaceutically suitable salt thereof and a pharmaceutically suitable carrier.

Such compositions can be prepared by mixing, are suitable for oral or parenteral administration, and can be prepared as tablets, capsules, oral liquid preparations, powders, granules, lozenges, etc.
They may take the form of liquid preparations, powders, injection and infusible solutions or suspensions, or suppositories. Orally administrable compositions are preferred because they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in unit dosage form and contain binders, fillers, diluents, tabletting agents, lubricants,
Contains the usual excipients such as disintegrants, colorants, flavors and wetting agents. Tablets may be coated according to methods well known in the art, for example using enteric coating agents.

Fillers suitable for use include cellulose, mannitol, lactose, and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as starch glycolate. Suitable disintegrants include, for example, magnesium stearate.

A suitable pharmaceutically suitable humectant includes sodium lauryl sulfate. Oral liquid preparations may take the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be mixed with water or other suitable vehicle to prepare the liquid before use. It may be provided as a dry product. Such liquid formulations may contain the usual additives, e.g. tld'sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, suspending agents such as aluminum stearate gels and hydrogenated edible fats, lecithin, sorbitan. emulsifiers such as monooleate or gum arabic; non-aqueous (and may also include edible oils) such as almond oil, rectified coconut oil, oily esters (esters of glycerin), phlopylene gellicol, and ethyl alcohol; The vehicle may contain preservatives such as methyl or ethyl p-hydroxybenzoate or sorbic acid, and conventional flavoring or coloring agents, if desired.

Oral liquid preparations usually take the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or are presented as a dry product for liquid preparation with water or other suitable vehicle before use. It can be done. Such liquid formulations contain the usual additives, such as suspending agents, emulsifiers,
It may contain a non-aqueous medium (which may include an edible oil), a preservative, and flavoring or coloring agents.

Oral compositions are manufactured by conventional compounding, filling or tableting methods. Iterative compounding operations can be used to distribute the active agent in these compositions using large amounts of fillers. Of course, such operations are common in this field.

For parenteral administration, liquid unit dose dispensers are prepared containing a compound of the invention and a sterile vehicle.

Depending on the vehicle and concentration, the compound may be suspended or dissolved. Parenteral solutions are conventionally prepared by dissolving the compound in a vehicle, filter sterilizing, filling the compound into a suitable vial or ampoule, and sealing. Advantageously,
Adjuvants such as local anesthetics, preservatives and buffering agents are also dissolved in the vehicle. To increase stability, the composition can be frozen and then filled into vials and the water removed under vacuum.

° Oral suspensions can be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and is sterilized by exposure to ethylene oxide and then suspended in the sterile vehicle. . Advantageously, surfactants or wetting agents are included to promote homogeneous distribution of the compounds of the invention.

The present invention further relates to the administration of a compound represented by formula (1) or a pharmaceutically suitable salt thereof to a mammal, such as a human, for migraine, complex headache, trigeminal neuralgia, etc. and/or provide a method for treating or preventing emesis.

Amounts effective to treat the disorders described above will vary depending on the relative potency of the compounds of the invention, the nature and extent of the disorder being treated, and the body weight of the mammal. However, a unit dose for an adult of 70V4 is usually 0.5 to x, o
ooIIIPs will contain, for example, 1 to 500 capes. The unit dosage is one or more times per day, e.g. 2, 3 or 4 times per day.
times, more usually 1 to 3 times a day, about 0.001 to 50
/ kg-/day, usually 0.002-25w1I
/9/day.

No adverse effects have been demonstrated within the above dosage ranges.

The invention also provides a compound of formula (1) or a pharmaceutically suitable salt thereof for use as an active therapeutic substance, in particular for the treatment of migraine, compound headache, trigeminal neuralgia and/or emesis. 0 Hereinafter, the production of the compound represented by formula (1) will be illustrated by Examples.

The nomenclature is the American Chemical Society (Am
erican Chemical 5ociety)
Published by Chemical Abstract Index Working Guide
x Guide) 1977.

Example 1 3-indazolecarboxylic acid (endo-8-methyl-8
-Azabicyclo-(3,1]oct-3-yl)ester (El) Tropine (0,45!?) and KButO (0,36&
) in amine-free DMF' (50d) was stirred at room temperature for 30 min. The more volatile t-butanol was removed using a rotary evaporator and the remaining solution was purified by diindazolo (213-at2't3'-a).
- treated with pyrazine-7,14-dione (0.2 g). After heating to 120 °C for 2 h, the reaction mixture was cooled, evaporated to dryness, and the residue was dissolved in saturated NaHCOs solution (50 m
) Processed with nine. - is adjusted to about 8 with acetic acid to produce the product tcHc
Drawn in en (3X 100 d).

The organic extract was dried (NaOi 5Oi), evaporated to dryness, and the residue was purified by trituration with diethyl ether.
l(0,169), melting point 234-5°C (decomposed).

lHM (270■(z -d s-necessary O)δ13.
5 (IH, brs ) 8.18 (IH, d) 7.60 (IH, d) 7.39 (IH, t) 7.28 (IH, t) 5.31 (IH, t) 3.23 ( 2H,brs) 2.36(3H,s) 2.45-1.90(8H,m) Example 2 N-(endo-9-methyl-9-azabicyclo(3,1
]Non-3-yl)indazole-3-carboxamide (E2) diindazolo(213-a#2'#3'-d ]Pyrazine-7,14-dione (0,769) DME' (2
'0, d) suspension in endo-9-methyl-9-
Azabicyclo(3,3,13nonan-3-amine(0,
31ii+) at 100° C. for 2 hours. After evaporation to dryness, the residue was purified by column chromatography (TLC grade alumina, CH(Js)K) to give the title compound (E2) (0,121?), melting point 209-2.
12°C was obtained.

”HNFviR (270MHz, CIXJs) δ
13.01 (brs, IH) 8.30 (d, IH) 7.54 (d, IH) 7.35 (t, IH) 7.20 (t, IH) 7. to (a, 1a) 4.54 (dtt, IH) 3.12 (brd, 2H) 2.60-2.40 (m, including 5H, 2, 53 * s
e 3a) 2.10-1.90 (m, 3H) 1.60-1.35 (m, 3H) 1.15-1.
00 (m, 2H) Example 3 1-Methyl-3-intersolcarboxylic acid (endo-8
-Methyl-8-azabicyclo[3,1]oct-3-yl)ester-hydrochloride (E3) According to the method described in Example 1, the potassium salt of tropine (0,379) was
7-methyl-3-indazolecarboxylic acid chloride (0,
219) and treatment with ethanolic hydrogen chloride to obtain the title compound (E3) (0.21 g), melting point 257-260°C.

'HNMR (79,5MHz, CDCis) δ8
．． 30-8.10 (m, IH) 7.60-7.2
0 (m, 3H) 5.55-5.30 (m, IH) 4.18 (s, 3H) 4.00-3.70 (m, 2H) 3.40-2.00 (m, 11H, 5a containing 2,83
paa) Following the method described in Example 2, the following compounds were prepared.

Example 4 N-(x, nodo-9-methyl-9-azabicyclo(3
,1]Non-3-yl)-5-fluorindamazole-3-carboxamide (E4) Melting point 264-7℃ (decomposition) 'HNMR (79,5MHz, CDCe5+ (CDs
hSO) δ 13.30 (brs, IH) 7.9
2 (dd, IH) 7.53 (dd, IH) 7.30-6.95 (m, 2H) 4.80-4.20 (m, IH) 3.30-2.90 (m, 2H) 2.70-0.80 (m, ls including 13H, 2,52
#3H) Example 5 N-(endo-9-methyl-9-azabicyclo(3,3
, 1] Non-3-yl-5-chloroindazole-3-
Carboxamide (E5)” HNMR (79.5MHz, CDCl5+ (CDs)s
so) δ 13.50 (brs, IH)s,
2s (brssIK) 7.80-7°25 (m, 3H) 4.75-4.20 (m, IH) 3.50-2.80 (m, 2H) 2.65-0.80 (m, r containing 13H,2,49
s e aa) Example 6 N-(endo-9-methyl-9-azabicyclo(3,1
]Non-3-yl)-1-methyl-indazole-3-
Carboxamide-hydrochloride (E6)Me
(E6) 1-methylintersol-3-carboxylic acid chloride <0
．． A stirred solution of 779) in dichloromethane (50d) was mixed with endo-9-methyl-9-azabicyclo(3,3,13nonan-3-amine (0,79) and triethylamine (0,79)).
), 7d) in dichloromethane (30, v). After 2 h, the reaction mixture was washed with saturated aqueous NaHCOs (100 d) and then dried (K.
Os ). After evaporation of the solvent, the remaining oil was purified by column chromatography (TLC-alumina, CHCl5).
The title compound E6 was obtained by treatment with hydrogen chloride. Melting point: 290-292°C.

'HNMR (270MHz, CDCJs) δ
8.30 (d, 1H) 7.50-7.20 (m, 4
H) 4.80-4.50 (m, IH) 4.12 and 4.1'0 (2-a, 3H) 3.75-
3.55 (m, 2H) 2.99 and 2.91 (2-s, 3H) 2.82-2.
40 (m, 4H) 2.20-2.00 (m, 2H) 1.90-1.60 (m, 4H) According to the method described in Example 6, the following compounds were prepared.

Example 7 N-(endo-9-methyl-9-azabicyclo(3,3
,13non-3-yl)-2-methyl-indazole-
3-Carboxamide-hydrochloride (E7) (E7) Melting point 271-2°C lHNMR (270MHz, (CDs)zso) δ 1
1.25, 10.30 (2s, IH) 8.72, 8.
45 (2d, IH) 8.80 (d, IH) 8.68 (d, IH) 7.36-7.15 (m, 2H) 5.05-4.90 (m, 1) () 4. 70-4.55 4.39 (s, 3H) s, 67 (brd, zH) 2.99, 2.90 (2d, 3H) 2.80-2.50 (m, 3H) 2.40-1 .90 (me4H) 1.80-1.50 (m, 3H) Example 8 N-(endo-9-methyl-9-7zabicyclo(3,1
]Non-3-yl)-1-ethylindazole-3-carboxamide (E8) t t ”HNMR (79.5 MHz, CDCj?s) δ
8.42 (dm, IH) 7.55-7.10 (m, 3H) 6.80 (b
rd, IH) 4.80-4.20 (m, including 3H, 4, 42, q,
2H) 3.30-2.90 (m, 2H) 2.75-2.30 (m, including 5H, 2,55 l S
#3H) 2.20-0.90 (m-ilHel, 5
4, t, 3H) Example 9 N-(endo-9-methyl-9-azabicyclo(3,1
[Non-3-yl) -1,2-benzisoxazole-3-carboxamide (E9) Melting point 126-8°C IHNMR (79,5MHz-CDCes) 6 8.3
5 (drn, IH) 7.80-7.25 (m, 3H) 6.80 (brd, IH) 4.80-4.30 (m, IH) 3.35-3.00 (m, 2H) 2.80-2.25 (e B including m, 5H, 2,56
#3H) 2.20-0.90 (m, 8H) Example 10 5α-N-(2-methyl-2-azabicyclo(2,2,
2]] Octo-5-yl-1-methyl-indazole-
3-carboxant (EIO)' (E
lo) e 'HNMR (270MHz, CDCJs) δ 8.
36 (dm, IH) 7.50-7.49 (m, 2H) 7.33-7.
24 (m, IH) 7.05 (brd, IH) 4.48-4.35 (m, IK) 4.10 (s, 3H) 2.90 (br4'; 2H) 2.76-2.60 (m, 2H) 2.42) C11,3H) 2.15-2.00 (m, 2H) 1.95-1.80 (m, 2H) 1.71-1.55 (m, 2H) 1 .44-1.34(m, IH) Example 11 N-(exo-2-methyl-2-azabicyclo(2,1
]-hept-5-yl)-1-methylindazole-3
-Carboxamide-hydrochloride (El 1 )”HN!VE
R(270ME(z,■(Js)613.00-12.
50 (m, IH) 8.28 (d, IH) 7.50-7.20 (m, 3H) 6.82 (brs, IH) 5.10-4.60 (m, IH) 4.20- 3.70 (m, including 4H, 4,09, s
*3H) 3.30-1.70 (m, 10H) Example 12 N-(endo-2-methyl-2-azabicyclo(2,1
]Hept-5-yl)-1-methylindazole-3-
Carboxamide hydrochloride (El2)ee IHNMR (270ME(z, CDCJs) 612.4
0-12.10 (m, IH) 8.40-8.20 (m,
2) () 7.50-7.20 (m, 3H) 4.72-4.55 (rn, IH) 4.22 (d, IH) 4.13 (s, 3H) 3.80 (s, II () 3.21 (s, IH) 3.00- 2.85 (m, including 4H, 2,80 es
s+3a) 2.61 (d, IH) 2.26 (t, IH) 2.16- 1.80 (m, 2H) Pharmacology” 5-HT in anesthetized rats according to the following method:
Compounds were evaluated for their antagonism of the huon-besoltoyarisch reflex evoked by

Salt rat (250-3009) is treated with urethane (1.25g)
/m intraperitoneal) anesthesia, FozartJ, Ret.
a& +Cardiovaaa, Pharmaco1
．． 2.229-245 (1980), blood pressure and 6°C were recorded. 5- of submaximal doses
HT (usually 6μ9Ay) was administered repeatedly (by intravenous route) and changes in hepatic frequency were quantified. Compounds were administered intravenously and the concentration required to reduce the 5-HT-induced response to 501% of the control response was determined.

The results were as follows.

Compound style mouthpiece (Misaki/Yu) 1 0.005”2
0.00113 0
．． 00145 0.015 6 0.00078
0.000610 0
．． 001711 0.01 Agent Patent attorney Masamitsu Akizawa and 1 other person

Claims (28)

[Claims] (1) Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X is CO and Y is NH or O, or X is NH and Y is CO; Z is CH_2, O, S or NR_3, where R
_3 is hydrogen, C_1_-_6 alkyl, C_3_-_7
Alkenyl-methyl, phenyl or phenyl C_1_
-_4 alkyl, and any of the phenyl moieties are halogen, CF_3, C_1_-_6 alkoxy or C_
may be substituted by 1 or 2 of 1_-_6 alkyl, and Ra is absent, or Z is CH or N, and Ra has the same meaning as R_3 above, X-Y -Rb is present when R_2 is bonded to the phenyl ring, hydrogen, halogen, CF_3, hydroxy, C_
selected from 1_-_6 alkoxy or C_1_-_6 alkyl, R1 is hydrogen, halogen, CF_3, C_1
____6 alkyl, C_1_-_6 alkoxy, C_1
____6 alkylthio, C_1_-_7 acyl, C_1
_-_7 acylamino, C_1_-_6 alkylsulfonylamino, N-(C_1_-_6 alkylsulfonyl)-N-C_1_-_4 alkylamino, C_1_-_
N by one or two groups selected from 6alkylsulfinyl, hydroxy, nitro, or C_1_-_6alkyl, C_3_-_8cycloalkyl, C_3_-_8cycloalkyl, C_1_-_4alkyl, phenyl or phenylC_1_-_4alkyl groups is amino, aminocarbonyl, aminosulfonyl, aminosulfonylamino or N-(aminosulfonyl)-C_1_-_4 alkylamino, which may be substituted or N-disubstituted by C_4_-_5 polymethylene, and R_2 is Formula (a), (b) or (c) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(a) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(b) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(c ) (where n is or 3, and p and q are independently 1 to 3)
3, and R_4 or R_5 is C_1_-_7 alkyl, C_3
___8 cycloalkyl, C_3_-_8 cycloalkyl-C_1_-_2 alkyl or group (CH_2)tR
_6, where is 1 or 2, and R_
6 is thienyl, pyrrolyl or furyl optionally substituted with one or two substituents selected from C_1_-_6 alkyl, C_1_-_6 alkoxy, trifluoromethyl or halogen, or C_l
____4 alkoxy, trifluoromethyl, halogen,
1 or 2 substitutions selected from nitro, carboxy, esterified carboxy and hydroxy, C_l_-_4 alkoxy, carboxy, esterified carboxy or C_l_-_4 alkyl optionally substituted by acyloxy which can be hydrolyzed in vivo phenyl which may be substituted by a group] or a pharmaceutically suitable salt thereof. (2) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, n^1 is 2 or 3, Y^1 is NH or 0) and the remaining variables are Claim No. (
The compound according to claim (1), which has the same meaning as in claim (1). (3) The compound according to claim (2), wherein n is 3. (4) Formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, q^1 is 1 or 2, and the remaining variables are defined in claims No. Claim No. 1 (having the same meaning as in Clause 2))
) Compounds described in section 2. (5) Z is NR_3 having the same meaning as in claim (1), and Ra is absent;
or Z is N and Ra has the same meaning as in claim (1) for R_3 as claimed in any one of claims (1) to (4). Compound. (6) The compound according to claim (5), wherein R_3/Ra is hydrogen or methyl. (7) The side chain of X-Y-R_2 is defined in Claim No. (1)
A compound according to any one of claims (1) to (6), wherein the compound is bonded in the 3-position as depicted in formula (I) in claim 1. (8) The compound according to any one of claims (1) to (7), wherein R_1 is hydrogen or 5-halo. (9) The compound according to any one of claims (1) to (8), wherein R_4 or R_5 is C_l_-_7 alkyl. (10) The compound according to claim (9), wherein R_4 or R_5 is methyl. (11) 3-indazolecarboxylic acid (endo-8-methyl-8-azabicyclo-[3,2,0]oct-3-
il) ester. (12) N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)indazole-3-carboxamide. (13) 1-Methyl-3-indazolecarboxylic acid (endo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl) ester. (14) N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-5-fluoro-indazole-3-carboxamide. (15) N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-5-chloro-indazole-3-carboxamide. (16) N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1-methyl-indazole-3-carboxamide. (17) N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-2-methyl-indazole-3-carboxamide. (18) N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1-ethyl-indazole-3-carboxamide. (19) N-(endo-9-methyl-9-azabicyclo[3,3,1]non-3-yl)-1,2-benz-isoxazole-3-carboxamide. (20) 5α-N-(2-methyl-2-azabicyclo[
2,2,2]oct-5-yl)-1-methyl-indazole-3-carboxamide. (21) N-(exo-2-methyl-2-azabicyclo[2,2,1]hept-5-yl-methylindazole-3-carboxamide. (22) N-(endo-2-methyl-2-asabicyclo[2,2,1]hept-5-yl)-1-methylindazole-3-carboxamide. (23) A salt suitable as a drug for the compound described in any one of claims (11) to (22). (24) A compound represented by formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) is reacted with a compound represented by formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI), In the above formula, G is CO
Q_1 (wherein Q_1 is a group which can be substituted by a nucleophilic group), and L is NH_2 or OH or a reactive derivative thereof, and the remaining variables are as defined in claim (1). and then any R_1, R_3, R_4, R_5, if desired
Other R_1, R_3, R_4, R_ from Ra and Rb groups
5. the same as in claim (1), comprising converting the Ra or Rb groups respectively and forming, if desired, a pharmaceutically suitable salt of the compound of formula (I) obtained. A method for producing a compound represented by formula (I) or a pharmaceutically suitable salt thereof. (25) Formula (VII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) (In the formula, R_(2^1) is formula (d) or (e) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( d) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (e) and the remaining variables are defined in claim No.
The compound represented by R_4Q_2 or R_5Q_2 (having the same meaning as in item 1) (in the formula, Q_2
is a leaving group and the remaining variables have the same meaning as in claim (1)).
A method for producing a compound represented by I), where R_2 is represented by formula (a) or (c). (26) A compound represented by formula (VII) having the same meaning as in claim (25). (27) A pharmaceutical composition comprising the compound according to any one of claims (1) to (23) or a pharmaceutically suitable salt thereof and a pharmaceutically suitable carrier. (28) A compound according to claim (1) substantially as described in the text with regard to Examples.