JPH06510990A - 3,9-diazabicyclo(3.3.1) nonane derivative having 5-HT3 receptor antagonistic activity - 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] 3,9-diazabicyclo(3,3,1) nona with 5-HT3 receptor antagonistic activity derivatives The present invention relates to a novel compound having pharmaceutical activity, a method for producing the same, and a method for producing the same. Concerning intermediates and their use as drugs.

EP-A-158265, EP-A-200444, EP-A-247266, EP-A-235878, EP-A-254584, EP-A-255297, EP-A-289170, EP-A-315390, Wo 91/17161, WO92/10494 (Beacham Group Public Limited Ka Company CBeecham Group p, 1. c, )), EP-A -158532 (A.H. Loving Company, I'/Corporate (A, H, Robins Company, I nc, )), EP-A -67770 (Merrell Tr. Company)), GB 2125398A and CB 2145416A (Sandoz Limited) , EP-A-322016 and EP-8-436245 (Duffer Inter -National Research Beth Roten 1 Phennote Shiny (Duphar) 1 international Re5 search B, V, ))%EP- A-307172 (Eli Lilly & Company) y and Company)), EP-A-323077, EP-A-306 148, CB 2208385A and WO91105738 (John Wyeth ・And Brother Limited (John Wyeth and Brot her Li+*1ted)), EP-A-234872 (Atria Laborato Leeds Incorporated (Adria Laboratories) c, )), EP-A-294292 (Azoia et Campagne (Adir et Compagnie), EP-A-339950 (Roller Inter -Nano-3Nal (Overnose) 1 Incorporated (Rarer I) r+national(overseas), Inc, )), EP -A-309423 (Instituto de Angeli Sonoeta Bell Azaoni (In5tituto de Angeli S, p, A,)), E P-A-313393 and EP-A-407137 (=ll Hitomi) 7? S Yoshitosi Phar mechanical industries Limited)), EP-A- 328200 and EP-A-337547 (Merck Nzebu & Dohme ・Limited (Merck 5harp and Do) u+e Li+*1t ed)), EP-A-329932 (Merrell Dow Pharmaceuticals ・Incophorated (Merrell Day Pharmaceutical als I nc, )), WO90106039 and UWO91104738 (0-lane=K line 9-su: zi+le c, t-burns), incoholite (Rorer I international (Overseas), I nc, )), EP-A-378111 (f Npon Group Soneta Bell ・Azaoni (Zambon Group S, p, A,), EP-A 43 0190 (Nontex (nee Nis A) Incoholated (Sy ntex (U, S, A,) I nc,) Nara U NiUS P492021 9 and 4920227 (Roller Pharmaceutical Corporation B (Roere Pharmaceutical Corp, )) A saturated azabicyclo ring group such as trovanyl, granatyl or quinuclidinyl A group of compounds that are 5-HT receptor antagonists are disclosed.

WO92105174 (Beacham Group Public Limited Kan Punny (Beecham Group p, 1.c, )) and EP A 469449 Ninnon Frauer Milling Company 2 Limited (Nicchin Flour Milling Co, L td,) ), the saturated azabincro ring group is endo-3,9-diazapinoclo[3,3 , 1] nonan-7-yl, 5-HT, receptor antagonists are disclosed.

Currently, endo-3,9-, in which a saturated azabincro ring group is substituted with an anol group, is Also found is a group of new compounds that are diazapinoclo[3,3,1,]nonan-7-yls. It is being issued. These compounds have 5-HT3 receptor antagonistic activity.

Therefore, the present invention provides 5-HT, having the receptor antagonistic activity, formula (1): (D [In the formula, X is phenyl or a 5- or 6-membered heteroaryl group, and either group is optionally fused with a saturated or unsaturated 5- to 7-membered carbocyclic or heterocyclic ring It's okay to stay.

A is a linking group; Z is a carboxylic acid acyl group.

R is hydrogen or methyl] The present invention provides a compound represented by: or a pharmaceutically acceptable salt thereof.

X is unsubstituted or usually halogen, 01-6 alkoxy/, C, - , alkylthio, Cl-6 alkyl, hydroxy, amino, C1-6 alkyl substituted by one or more substituents selected from C1-7 alkanoylamino, or the two substituents on X (if fused) may be taken together to form an optionally substituted saturated or unsaturated carbocyclic ring. It's okay.

Heteroatoms for heteroaryl and peterocyclic groups in X include oxygen, nitrogen and and sulfur.

Halo includes furomo, chloro and fluoro.

X by an aromatic carbon atom or (if X is fused) by a carbocyclic ring carbon atom bonded to eight by a child or by a heterocyclic ring carbon or nitrogen atom . When X is fused and A is bonded to an aromatic carbon atom, preferably "fused" bonded at the aromatic carbon adjacent to the carbon atom, which is the heterocyclic group in formula (1) Bonds to the heteroatom of the ring. Asagranatan side town joins A in “spiro” configuration do.

X is further expressed in the following formula CIA) when )“-RI　O is N-B=N. (may be combined with A)

Preferred examples of X are disclosed in the said patent publications on 5-HT3 receptor antagonists. There is.

Suitable examples of A include CONH (amide), Coo (ester), NHCO NH (tsuri, i)'), C0NHCONH (extended ureido), l is the structural formula [formula Inside, the dotted circles represent two double bonds at any position in the five-membered ring: G, Two of H and I are selected from oxygen, sulfur, nitrogen and carbon, the remainder being , oxygen, sulfur or nitrogen, E is a bond or optionally phenyl or Cl-3 alkylene optionally substituted by hydroxy, or is E when G is nitrogen, H is methylene, and I is oxygen or sulfur. does not exist, and the petro ring in the structural formula ('') is azagranata in the “spiro” configuration. ] Examples include groups represented by.

For the avoidance of doubt, formula (I) as disclosed in the cited patent publications The preferred definitions of X include a saturated azapinoclocyclic group and 1) is the part of the structure that remains if we ignore it.

Z is often halo, C1-6 alkoxy or is a C1-7 alkyl which may be substituted by one or more of C1-6 alkyls. Lukanoyl or benzyl. Z is often acetyl.

R is preferably methyl.

C3-6 atom, where Z may be optionally substituted as defined in formula (1); of a compound within formula (I) which is alkyl, phenyl or phenylC1-4 alkyl. There is a group.

In certain embodiments, the present invention provides that formula (IA)) is NH or ).

X is (a), (b), (c), (d), (e), (f) or (g) or (h):(a) ('b) (c) (d) (e) (D (h) R1-R1 and R, ~R1 are selected from hydrogen, halogen or hydroxy .

R8 is hydrogen and R1 is hydrogen or C1-4 alkyl: or R 1 and R6 together represent a bond; R8-R7 independently represent hydrogen or C1 -6 alkyl.

When R, is hydrogen, R4 together with R2 is Ct-t polymethylene or or Ct-S polymethylene interrupted by a series of linking groups: R8 and and R, are independently selected from hydrogen or c+-S alkyl; Alternatively, R8 and R, taken together, are 02-6 polymethylene or 10 series. C4-5 polymethylene interrupted by groups.

R5° is hydrogen, Cl-6alcokyne, CI, chloroalkyloxy or C3 -, nochloroalkyl, C7-, alkyl-containing group, or C1° is Y and combine, so that Y-R, , is N-B=N, where B is N or C It is H: R1+ is hydrogen, halo, CI-S alkoxy or CI-S alkyl, Madekoha RIO and R11 combine to form -0CH(R+sR+a)E-, Here, E is (CH2) or NRBCO(CH2)-, where n is 1 or 2, m is 0 or 1, R15, R16 and R17 are independently selected from hydrogen or C1-6 alkyl.

R12 is hydrogen, C0-6 alkokene, or optionally C1-, alkyl group Therefore, R12 is an optionally substituted amino, or R12 is an alkanoyl alkanoyl group. It's Mino.

R33 is halo, C3-6 alkyl, C1-6 alkokino or C1-6 alkyl It's Lucio R11 is hydrogen or C1-6 alkyl.

In formula (h), Co-Y is at the 1st position +: present, R15 is at the 3rd position, hydrogen, CI-@furkyl or or C1-6 alkoxy, or R11 is in the 4-position, hydrogen, Rogen, CF3, C1-6 alkyl, cl-? acyl, auto-7 acylamino, place optionally 1 or 2 01-6 alkyl, C troalkoxy or halogen phenyl optionally substituted by 1 or 2 C by l-6alkyl or Cm-8-chloroalkyl groups or by C44 poly by methylene or phenyl, C5-6alkylsulfonyl, C1-6a Rukylsulfinyl, Cl-8 alkoxy, CI-@alkylthio, hydroxy or amino, aminocarbonyl or amino which may be replaced by nitro Minosulfonyl or co-y- is in the 3rd position, RIB is in the 1st position, hydrogen, CI-S alkyl or or Cl-6 alkoxy, or R1, in the 4-position, is hydrogen or is C1-6 alcoquine, L is CH or N) It is a group represented by .

Z and R are the same as defined in formula (I)] or a compound thereof The present invention provides pharmaceutically acceptable salts of.

Examples of alkyl or alkyl-containing groups in Z or R1-R15 include thyl, ethyl, n- and 1so-propyl, n-1ISO-1sec- and Mention may be made of tert-butyl, preferably methyl. Socroalkyl group Examples include C8, C4, C6, C6, C7 and C8 nocroalkyl.

Halo groups include fluoro, chloro, bromo and iodo.

When bonded, preferred examples of R2 and R1 or Rs and R1 include C2 , C3, C1, C5 or C6 polymethylene, preferably C2, C 8, C4 or C5 polymethylene.

R1-R1 and R1-R7 are preferably hydrogen, fluoro, chloro and hydrogen. selected from droxy, most preferably hydrogen. R, is 5-16- or is 7-chloro or fluoro.

When X is a group represented by sub-formula (a), one of R7 and R8 is preferably is hydrogen, and one or both (most preferably both) of R2 and R4 are , an alkyl group, e.g. methyl, or linked to Ct-t polymethylene or if one of R2 and R1 is hydrogen, the other is , preferably ethyl or n- or 1so-propyl.

When X is a group represented by sub-formula (b), R5 is preferably hydrogen or methyl. or ethyl group.

When X is a group represented by the lower formula (C), one of Co-Y and R6 is the lower R6 is preferably methyl or or ethyl.

When X is a group represented by sub-formula (d), R7 is preferably methyl.

When X is a group represented by sub-formula (e), R8 and Ro are preferably covalent. is a methyl group.

X is a group represented by the sub-formula (f), and RIG is a Cl-6 alkokene, or when bonded to Y, R12 is preferably amino, and RI3 is Preferably it is chloro or bromo, most preferably chloro. R.I. When O is C1-6 alkoxy/, it is preferably methokino.

When X is a group represented by sub-formula (f) and R8 is hydrogen, R8 and R l + is preferably chloro or methyl, RIG is preferably hydrogen It is.

Other interesting definitions of X within sub-formula (f) are found in EP-A-307172 ( Eli Lily Ant Cumber 1- (Eli Li1ly and C company)) and EP-A-313393 (Yonotomi Farmanonite Technical Industries ° Limited (Yoshitomi Pharwac eutical I industries Li, m1ted)) It is something.

When X is a group represented by sub-formula (g), R,,t;1. , preferably hydrogen Or methyl.

When X is a group represented by the subformula (h) and co-y is at the 1st position, it is at the 4th position Suitable examples of Rl 5 in this case include the following groups: hydrogen, chloro, bromo, methyl , ethyl, amino, methylamino, dimethylamino, phenyl, Cl-4 alkali noylamino, e.g. formylamino, acetylamino, propionylamino n- and 1so-butyrinogenomino, aminosulfonyl, and optionally 1 or 2 methyl, ethyl, n- or 1so-propyl, n-1sec-1 iso- or tert-butyl or phenyl groups, nitro, n- and lso -propoxy, methylthio, ethylthio, n- and 1so-propylthio, Even if substituted by droxy, methylsulfonyl and ethylsulfonyl Good amino and aminosulfonyl are mentioned, preferred when RI3 is in the 3-position Examples include the following groups: hydrogen, methyl, ethyl, n- or 1so-propyl , metquin and ethoxy.

If X is represented by sub-formula (h) and co-y is in the 3rd position, then Suitable examples of R15 include hydrogen, methyl, ethyl, n- or 1so -propyl and when RI5 is in the 4-position, suitable examples include the following groups: , hydrogen, methquino and ethoquino.

RI5 in any of the above specific positions is preferably hydrogen, methyl and metokino. Preferably, co-y is in the 1st position.

Preferably, Y is NH.

In another aspect, the carbonyl group of co-y is WO92/1 when Y is NH ．． 4733 (Beacham Group Public Limited Company (B eecham Group p, 1. c,) as disclosed in It can be replaced by bioisostere.

Pharmaceutically acceptable salts of the compound represented by formula (I) include hydrochloric acid, hydrobromic acid, , conventional acids such as boric acid, phosphoric acid, sulfuric acid, and acetic acid, tartaric acid, maleic acid, Citric acid, succinic acid, cheap aromatic acid, ascorbic acid, methanesulfonic acid, α-keto Pharmaceutical drugs such as glutaric acid, alpha-glypeptolophosphate and glucose-1-phosphate and acid addition salts with acceptable organic acids.

Pharmaceutically acceptable salts of the compound represented by formula (1) include hydrochloric acid, hydrobromic acid, Acid addition salts with acids such as , phosphoric acid, sulfuric acid, citric acid, tartaric acid, lactic acid and acetic acid It is.

Preferably, the acid addition salt is a hydrochloride.

Examples of pharmaceutically acceptable salts include the compound R, -T (where Ro is 01 -6 alkyl, phenyl-Cl-S alkyl or C5-t-chloroalkyl. (T is a group corresponding to the anion of the acid) Examples include quaternized derivatives of the compound represented by formula (I). A suitable example of R8 Examples include methyl, ethyl and n- and 1so-propyl, benzyl and Examples include phenethyl. Suitable examples of T include chloride, bromide and iodine. - Examples include halides such as Cito.

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

Mono-salt or di-salt depends on the presence of two chlorinable nitrogens in the azagranakun side chain. Therefore, it is thought to be formed.

The compound represented by formula (1), its pharmaceutically acceptable salts (quaternary derivatives and N- (including oxides) also form pharmaceutically acceptable solvates such as hydrates; This is where the compound represented by formula (1) or a salt thereof is mentioned in this specification. Also included.

Of course, some of the compounds of formula (I') may be chiral or brochiral. It has a central center and, as a result, exists in multiple stereoisomeric forms, including enantiomers. It is clearly understood that it is possible to The present invention relates to these stereoisomeric forms (mirror forms). (including enantiomers) and mixtures thereof (including ceramicompounds).

The various stereoisomeric forms are separated from each other by conventional methods.

The present invention provides compound X'-A, having the formula (II) (II) [In the formula, A1 and A! usually through an amide or ester bond, or - reacting together by condensation to form the same heterocycle (j) as defined above is a group forming A as defined above, and Xo is X or a group convertible thereto; ,R.

and Zo are R and Z as defined above or a hydrogenolyzable protecting group] react with the indicated compound, then optionally convert Xo to X, and R'/Z' is other than R/Z, convert R"/Z" to R/Z, and then optionally characterized by forming a pharmaceutically acceptable salt of a compound of formula (I) , also provides a method for producing a compound represented by formula (I).

Suitable definitions of A1 and A2 are the same as described in the aforementioned patent publications.

Intermediates of formula X'-AI are generally known from the said patent publications/literature. or similar to those used for structurally related known compounds. Manufactured by law.

The intermediate represented by formula (11) is generally prepared using a suitable compound as described in the following description. Formula (m) prepared by condensation/cyclization of 2゜6-disubstituted piperazine derivatives: ( III) Manufactured from the compound shown in

In a specific aspect, the present invention provides the formula (■): X+' COQ+ (rV) The compound represented by formula (V) Leap [In the formula, X1' is Xl or a group convertible thereto, Q is a leaving group, and R' is R or a hydrogenolyzable protecting group as defined above; the remaining variables are: Same as above definition] When the compound represented by or Y is O, it is reacted with its reactive derivative, and the following Then, if desired, convert X, ゛ to 1, R7 or Ro. , R11, R12, R13, R14 or RIM group to another (including conversion into such groups), when R'/Z' is other than R/Z, R' /Z' to R/Z, and if desired, the compound of formula (IA) can be used pharmaceutically. A compound of formula (IA) or It also provides a method for producing pharmaceutically acceptable salts thereof.

Examples of leaving groups Q1 that can be displaced by nucleophiles include chloro and pro such halogens, CHIO and C3-4 alcoynes such as C,H,O-, Ph0 - or active hydrocarbons such as cf, c6o- or C13C○- 0 group Q including activated hydrocarbyloxy When 1 is a halide, the reaction is performed with benzene, dichloromethane, toluene, diene Tyl ether, tetrahydrofuran (THF) or trimethylformamide (D Preferably carried out at non-extreme temperatures in an inert non-hydroxyl solvent such as MF) . In the presence of acid acceptors such as organic bases, especially triethylamine, trimethylamine It is also preferred to carry out in the presence of tertiary amines such as amines, bilins or picolines. Additionally, some of these acid acceptors can also function as solvents.

Alternatively, the acid receptor may be calcium carbonate, sodium carbonate or potassium carbonate. It can be an inorganic substance such as aluminum. Temperatures from 0° to 100°C, especially from 10 to 80°C suitable.

Group Q1 is 01,4 alkokino, phenoquino or active hydrocarbyloxy If the reaction is carried out in an inert polar solvent such as toluene or trimethylformamide, It is preferable to do it inside. The group Q, is C13CO-, and the reaction is carried out in toluene at reflux temperature. It is also preferable that the process be carried out in a chamber.

When Y is O, the compound of formula (V) is a reactive derivative thereof. It is often a salt such as a lithium, sodium or potassium salt. Ru.

Usually Xo1 is XI, but when R1° is bonded to Y, formula CIA) and Xo is the subformula (f) [where RIO is nitro or amino] ], which is then disclosed in EP-A-315390 It is connected to Y so that

R1-R1, R1, R5 or R1゜~RIS group convertible to other such groups The compound of formula (IA,) containing appears to be a useful new intermediate . That is, hydrogen substituents can be removed by halogenation using conventional halogenating agents. is converted to a halogen substituent, or a C3-, alkanoylamino substituent is , can be converted to amino by conventional hydrolysis.

When other than R/Z, R'/Z' may optionally be halo, Cl-4 alkoxy or and C1-4 alkyl substituted with one or two groups selected from Benzyl is a hydrogenolyzable protecting group. Such a benzyl group can be For example, if R1-R1, R1, Rh, R+ l-R+ s are other than halogen, is removed by conventional transition metal catalyzed hydrogenolysis to give The corresponding compound which is hydrogen is obtained.

Therefore, further use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The production method is to N-acylate a compound represented by formula (1) in which Z is hydrogen, Then, if desired, a pharmaceutically acceptable compound of the obtained formula (1) is added. Consists of forming salt. In this further production method of the present invention, “N-acyl ''consists of substitution of an azabicyclo ring N-atom by a Z group as defined above.

This is the compound ZQ3 [wherein Z is the same as defined above and Q is a leaving group. is carried out by a reaction with A suitable definition for Q is the halo ZQs can be substituted by a nucleating agent such as acetic anhydride or It is an acid anhydride such as. The reaction is carried out under conventional anolization conditions, e.g. triethyl performed in an inert solvent such as dichloromethane in the presence of an acid acceptor such as an amine It will be done.

Generally, the reaction is carried out at non-extreme temperatures, such as at or slightly above room temperature.

R in the compound represented by formula (V) before bonding with the compound represented by formula (IV) Alternatively, Z conversion is also possible. Such transformations can be carried out using appropriate protection of the amine functionality. It is conveniently carried out under conventional conditions.

The compound represented by formula (IV) is known or similar to a known compound. , or can be conventionally produced from known compounds.

Compounds of formula (I) can be prepared in a manner similar to that disclosed in the European patent publication mentioned above. It is also manufactured by the method of

In the compound represented by formula (1), the -A series linking group is of the bicyclo ring to be bonded. It is clearly understood that the group has an endo orientation with respect to the ring. Expression (1) shows A mixture of endo and exo isomers of a compound is synthesized non-stereospecifically. , from which the desired isomer is conventionally isolated, e.g. by chromatography. Alternatively, the endo isomers are optionally separated with the formula (n) is synthesized from the corresponding endo form of the compound.

Pharmaceutically acceptable salts of the compounds of this invention are conventionally formed.

Salts include, for example, pharmaceutically acceptable organic acids or salts of the basic compound represented by formula (I). or by reaction with inorganic acids.

The compounds of the present invention are 5-HT3 receptor antagonists and are thus generally associated with pain, nausea and Possible use in the treatment or prevention of vomiting, CNS disorders and gastrointestinal disorders .

Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain, and vomiting These include, among others, vomiting and nausea related to cancer treatment, postoperative migraines and migraines. Nausea associated with Examples of such cancer treatments include sosbratin. cytotoxic substances such as platinum complexes, and doxorbinone and ncrophospha Treatments using drugs, particularly nosblatin, may be mentioned, and may also include radiotherapy. C NS disorders include anxiety, psychosis, senile dementia, and age-related memory impairment (AAMI). ), and drug dependence. As a gastrointestinal disorder, hypersensitivity Includes intestinal syndrome and diarrhea.

5-HT3 receptor antagonists are also useful in treating obesity and/or arrhythmia .

Some of the compounds of the present invention, for example, when R14 is Cl-11 alkyl, Gastric prokinetic activity is also useful in treating gastrointestinal disorders. have

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier. There is also.

Such compositions are prepared by mixing 11'' and are usually suitable for oral or parenteral administration. For example, tablets, capsules, oral liquid preparations, powders 1. Granules, lo Zenno preparations, reconstitution powders, injectable and infusible solutions or suspensions, or in the form of suppositories. Orally administrable compositions are more suitable for general use. This is preferred because it is convenient.

Tablets and capsules for oral administration are usually presented in unit doses and contain binders, fillers, etc. , diluents, tableting agents, lubricants, disintegrants, colorants, flavoring agents and wetting agents. Contains conventional excipients such as. Tablets can be prepared by methods well known in the art. Accordingly, for example, it is coated with an enteric coating.

Suitable fillers for use include cellulose, mannitol, lactose and others. Similar drugs include: Suitable disintegrants include starch, polyvinyl polyester, Starch derivatives such as pyrrolidone and sodium starch glycolate are mentioned. can be lost. Suitable lubricants include, for example, magnesium stearate. It will be done.

Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate. Ru. Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups, etc. may be in the form of a cup or elixir, or may be diluted with water or other suitable liquid before use. Provided as a dry product for reconstitution with excipients. Kagar liquid preparations are Suspending agents, such as sorbitol, chlorine, methylcellulose, gelatin, human Doroquinoethylcellulose, carboquinomethylcellulose, aluminum stearate gel or hydrogenated vegetable fat, emulsifiers such as lentin, monoolein acid sorbitan or gum arabic, non-aqueous excipients (including vegetable oils), e.g. coconut oil, fractionated coconut oil, glycerin, propylene glycol, or Oily esters such as esters of chill alcohol; preservatives, e.g. p-hydro Ammonium chloride, methyl or propyl carbonate or sorbic acid, and optionally conventional Other suitable excipients may be included, such as flavoring or coloring agents.

Oral liquid preparations usually include aqueous or oily suspensions, solutions, emulsions, syrups, etc. It may be in the form of a cream or eliquin, or it may be mixed with water or other suitable liquid before use. Present as a dry product for reconstitution with suitable excipients. Such liquid preparations contains suspending agents, emulsifying agents, non-aqueous excipients (including food oils), preservatives and flavoring agents. It may also contain conventional additives such as additives or colorants.

Oral compositions are prepared by conventional methods of mixing, filling or tablet forming.

Repeated mixing operations can be used throughout these compositions that use large amounts of filler. The active agent may also be distributed. Such operations are, of course, within the technical field. It is idiomatic.

For parenteral administration, flowable unit dosages containing a compound of the invention and a sterile excipient may be used. Prepare a dosage form. Depending on the excipient and concentration, the compound may be suspended. or can be dissolved. Parenteral solutions typically involve dissolving the compound in an excipient. , then fill into suitable vials or ampoules after #oversterilization, and then , prepared by sealing. Conveniently local anesthesia, preservatives and buffers Adjuvants such as oxidizing agents may also be dissolved in the excipient. In order to enhance stability, the composition The product can be filled into vials and then frozen after removing the moisture under vacuum. can.

Parenteral suspensions are made by suspending the compound in a vehicle instead of dissolving it, and then adding it to a sterile vehicle. No practical use other than sterilization by exposure to ethylene oxide prior to suspension. Prepared in a qualitatively identical manner. Conveniently a surfactant or wetting agent is included in the composition. to facilitate homogeneous distribution of the compound of the present invention.

Furthermore, the present invention provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. pain, vomiting, and CNS disorders in mammals, characterized by administering an effective amount of and/or methods for treating or preventing gastrointestinal disorders.

An effective amount for the treatment of said disorder will depend on the relative efficacy of the compounds of the invention to be treated. It depends on the nature and severity of the disorder and the weight of the mammal. However, 7 A unit dose for adults of 0 to 9 will usually contain 0.05 to 1000 - 9, for example, 0.5 to 500 m+9. Unit administration is once or more a day, e.g. For example, 2.3 or 4 times a day, more usually 1 to 3 times a day, i.e. , about 0°0001 to 50 sy/by/day, more usually 0,000 to 25 m The range is y/by' days.

None of the above dosage ranges exhibit any toxic side effects.

The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. a non-toxic effective amount and a pharmaceutically acceptable carrier; Useful in the treatment and/or prevention of vomiting, CN5IIW and/or gastrointestinal disorders. The present invention also provides a pharmaceutical composition for use.

The present invention is particularly useful as an active therapeutic agent for pain, emesis, CNS disorders and/or or a compound of formula (I) or its pharmaceutically useful compound for the treatment of gastrointestinal disorders. It also provides acceptable salts.

The following examples illustrate methods for preparing compounds of formula (I); , a method for producing the intermediate will be explained.

explanation a) Methyl 4-bromocrotonate in diethyl ether (500@l) at 0°C (509) to diethyl ether (20m, benzylamine in Q (22m+ri) dripped. The reaction mixture was stirred at room temperature for 72 hours. + precipitation! ! removed due to The filtrate was washed with water (75,/). Dry the organic phase (MgSO4), The solvent was evaporated under reduced pressure and the residue was dissolved in light petrol. Flash chromatography on Norica eluting with ol) and diethyl ether. dimethyl-4,4°-benzyliminotran s-2-butitur) (17,19) was obtained.

b) Dimethyl-4,4'-benzyl in methanol (2501ff) at 0°C. Methylamine (7,5 11! , 33% W/W in IMS) was added dropwise. The reaction mixture was stirred at room temperature overnight. . The solvent was evaporated under reduced pressure and the residue was evaporated with lightvetrol and dichloromethane as eluent. Chromatography on silica using ethyl ether dimethyl-1-benzyl-4-methylpipe as a mixture of and trans isomers. Radinyl-3,5-diacetate was obtained (9.29v).

C) Potassium tcrt-bu in toluene (350 ml) at room temperature under nitrogen atmosphere. Dimethyl-4-benzene (9,679) l in toluene (150 l) Addition of diacetyl-1-methylpiperazinyl-2,6-diacetate (9,269) did. The reaction mixture was heated to reflux for 3 hours. Cool the reaction mixture and add 5N HCI (4X 75i/). The combined aqueous extracts were heated to reflux for 13 hours.

The reaction mixture was cooled, the solvent was concentrated under reduced pressure, and the residue was saturated with solid potassium carbonate. I let it happen. The product was extracted into chloroform (4X75m6) and the organic phase was dried. Mg5O4), then the solvent was evaporated under reduced pressure. Increased ethanol capacity (up to 10%) on silica using chloroform eluent. 3-Benzyl-9-methyl-3,9-diazavinchlor [3,3,1]nonan-7-one was obtained (1.89).

d) Adding hydrogen to a stirred solution of pre-εe ketone ( ], , 809) in ethanol (501f). Roxylamine hydrochloride (0,549) was added. The reaction mixture was then heated for 2 hours. The mixture was heated to reflux for a while. Reaction M8 was cooled 5 and I'8@ was evaporated under reduced pressure. residual The product was triturated with diethyl ether to give 3-benzene-9-methyl-3,9- Diazavinclo[3,3,1]nonane-7-one oxim hydrochloride (],,,8 79) was obtained.

e) [Dry THF (30+1, Lithium aluminum hydride (0,889 ) produced by the action of concentrated H2SO1 (0,93 m1') on [3-benzyl-9-methyl-3,9-/azabinc Treatment of b[3,3,],1-nonane-7-onoxime hydrochloride with potassium carbonate 3-bentrue-9-methyl-3,9-diazabi/chloro[3, 3,1]nonane-7-one oxide was added. The reaction mixture is then subjected to nitrogen Heat to reflux under atmosphere overnight. The reaction mixture was then cooled and diluted with 40% NaOH. Aqueous solution (2 mff) and water (1 ml) were added dropwise. diethyl ether (5ml ) was added and the mixture was stirred for 1 hour.

The resulting precipitate was removed by filtration through diatomaceous earth and the filtrate was concentrated under reduced pressure. and endo-3-benzyl-9-methyl-3,9-diazabicyclo[3, 3,11 nonan-7-amine (0,909) was obtained.

Example 1 endo-N-3,3-)methylindolin-1-yl(3-acetyl-9- Methyl-3,9-diazabi/chloro[3,3,11nonan-7-yl)carboxa mido(El)a) 3,3-dimethylindoline (1,59) and triethyla A solution of amine (1,42 ml) in CHxClx (15 m++) was mixed with phosgene (9 ml) in CHxClx (15 m++). ++/, 12.5% W/W in toluene) cooled in CH2C/4 (1517') Dropwise into the stirred solution. The reaction mixture was stirred at 0 °C for 1 h, then pentane (1 00+, /) and washed with 5N sulfuric acid (5 ml) and brine (5d>).

The organic phase was dried (Mg5O+) and the solvent was then evaporated under reduced pressure to give the crude 1- (2,3-dihydro-3,3-dimethyl)indolylcarbonyl chloride (1, 7g) was obtained.

b) At room temperature, 1-(2,3-dihydro-3,3-dimethyl)indolylcarbonyl CH2CH2C12 (CH2CH2C12) (CH,C endo-3-penn-9-methyl-3,9-diaza in C12(15/) Bicyclo[3,3,1]nonan-7-amine (902-9) and triethyla Min (512 μl) was added.

The reaction mixture was stirred at room temperature overnight. Wash the resulting solution with NaHCOs aqueous solution (Mg5O4) and then the solvent was removed by rotary evaporation. elution Furanoyuchroma on silica using chloroform and ethanol as solutions The endo-N-3,3-dimethylindolin-1-yl ( 3-Benzyl-9-methyl-3,9-diazavinchlo[3,3,1]nonane-7 -yl)carboquinamide (360-9) was obtained. 188-191°C.

'HNMR (CDC63) 250MHz; 61.29 (s, 6H), 1.48 ( d, 2H), 2.40-2.57 (m, 5H), 262-2.78 (m, 4 H), 2.83-2.90 (m, 2H), 3.53 (s, 2H), 3.70 ( s, 2H), 4.39-4.42 (m, IH), 6.90 (t, IH), 7.0 5-7.46 (m, 8H), 7.81 (d, IH), 8.78 (d, IH).

C) End with 5% Pd/C catalyst in methanol (50 ml) for 4 hours at atmospheric pressure. o -N-3,3-tumethylindolin-1-yl (3-benzyl-9-methyl -3,9-diazabinoclo[3,3,],]nonan-7-yl)carboxamide (El3) (350-9) was hydrogenated. Catalyst II! removed by fl, Evaporate the filtrate and end.

-N-3,3-dimethylindolin-1-yl (9-methyl-3,9-diazabi Cyclo[3,3,11nonan-7-yl)carboxamide (14919) was obtained .

Help 248-251℃ Summer HN MR (CD (Js) 250MHz+61, 35 (s, 6H), 1.6 8 (d, 2H), 2.50-2.67 (m, 3H), 2.75 (s, 3H) , 2.99 (d, 2H), 3.17-3.26 (m, 2H), 3.58 (s, 2H) H), 3.61-3.71 (m, 2H), 4.37-4.49 (m, IH), 6.89-697 (m, IH), 7.06-7.20 (m, 2H), 7.8 8 (m, IH).

M’329 d) endo-N-3,3-tumethylindolin-1-yl (9-methyl-3 ,9-diazabi/chloro[3,3,1]nonan-7-yl)carboxamide (50 -9) in CH2CH2 (6f) with triethylamine (23 μl) and Hydroacetic acid (16μf) was added. The reaction mixture was stirred at room temperature for 2 hours. Reduce solvent Evaporate under pressure and partition the residue between water (5%) and chloroform (10%). did. The organic phase was dried ~IgSO+), the solvent was removed by rotary evaporation, and The crude title compound was obtained. Elution method for Nio1 with chloroform and ethanol Furano/Uchromatography on a force gel was performed. Light the resulting product Trituration with Betrol (boiling point 60-80'C) gave the title compound (29 -9).

Melt<], 165~168° 'HNhlR (CDC/+) 250MHz: δ 1. , 36(s, 6t]), ],, ]58-1.71m, IH), 2.10(s, 3H), 244-2.6 0m, 51(), 2.95-3 10(m, 2H), 3.14-3.28(m , 1) 1), 3.37-3.68 (m, 4H), 4.14-4.25 (m, 2 H), 4.779-488 (, IH), 6.93 (t, IH), 7.05-7. 21 (m, 2H), 7.93 (d.

IH).

MH”371 Example 2 endo-N-3,3-tumethylindolin-1-yl (3-benzoyl-9- Methyl-3,9-diazavinchlo[3,3,11nonan-7-yl)carboxa Endo-N (E2) according to the manufacturing method outlined in Example 1(d) -3,3-dimethylindolin-1-yl (9-methyl-3,9-diazabisic) [3,3,1]nonan-7-yl)carboxamide (40 g) was added to benzene chloride. (15 μl) and triethylamine (18 μl) to give the title compound. Product (E2) was obtained (35++v).

Melting point 182-185° 'HNMR (CDCrs) 250MHz+61, 31 (s, 6H), 1.43 -1.60 (m, LH), 2.44-2.70 (m, 5H), 2.88-2. 98 (m, LH), 3.09-3.13 (m, 'lH), 3.35-3゜80 ( m, 5H), 4.20-4.35 (m, LH), 4.38-4.52 (m, LH ), 481-4.93 (m, LH), 6.94 (t, IH), 7.06 (d, IH), 7.17 (t.

IH), 7.28-7.48 (m, 5H), 7.92 (a, IH).

Eight IH”433 5-HT3 receptor antagonist activity palpitations 5-HT-induced photosynthesis was performed in an anesthetized patient according to the following method. von Bezold - J arisc Evaluate compounds for antagonism of h reflex) Male rats 250-3509 were anesthetized with urethane (intraperitoneal 1, 25 v/hg) Fozard J, R, et al. Cardiovascular Pharmacoronau (J, Cardi ovas, Pharmacol, ), 2.229-245 (1980) According to the disclosed method, blood pressure and heart rate are recorded. 5- The best of HT A large dose (administered, 6μ9/&9) was administered by intravenous route, and Stylize changes in numbers. Compounds are administered intravenously and 5-HT-induced responses are then controlled. The concentration required to reduce the response by 50% (EDso) is determined.

international search report Continuation of front page (72) Inventor Rahman, Shashi Catherine Essex City, UK -M19.5Aday, Barlow, The Pinnacles, Coldharbour Lo (No address displayed) SmithKline Beecham Pharmaceutica Luz

Claims (8)

[Claims] 1.5-HT3 receptor antagonistic activity, formula (I): ▲ Numerical formula, chemical formula, table, etc. ▼(I) [In the formula, X is a phenyl group or a monocyclic 5- or 6-membered heteroaryl group, and Both groups may optionally be fused with a saturated or unsaturated 5- to 7-membered carbocyclic or heterocyclic ring. may match; A is a linking group; Z is a carboxylic acid acyl group; R is hydrogen or methyl] A compound represented by or a pharmaceutically acceptable salt thereof. 2. Formula (IA): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IA) [In the formula, Y is NH or O (or attached to R10 as defined below); X1 is Formulas (a), (b), (c), (d), (e), (f), or or a group represented by (g) or (h)] or its pharmaceutical 2. A compound according to claim 1 which is an acceptable salt. 3. X is a group represented by sub-formula (a), and one of R1 and R3 is hydrogen and R2 and R4 are both C1-6 alkyl groups, or are combined to form C 3. A compound according to claim 2 which forms a 2-7 polymethylene. 4. endo-N-3,3-dimethylindolin-1-yl (3-acetyl-9 -methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)carboxy Samid and endo-N-3,3-dimethylindolin-1-yl (3-benzoyl-9- Methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)carboxa 4. A compound according to claim 3, selected from the group consisting of: 5. characterized by comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition. 6. 5. Compounds according to any one of claims 1 to 4 useful as therapeutically active substances. 7. Claims 1-1 useful for treating pain, emesis, CNS disorders and/or gastrointestinal disorders 4. The compound according to any one of 4. 8. Treatment and/or prevention of pain, vomiting, CNS disorders and/or gastrointestinal disorders 5. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for use.