JPH06503331A - pharmaceuticals - 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] pharmaceuticals The present invention provides novel compounds with pharmacological activity, methods for their production and their Concerning use as a medicine.

British Patent No. 1571447 [Société Detude Scientific] Engineering Industrinil de Liroudeau France (Societe D'Et udes Scientific et I industryelles de France) has dopamine antagonist activity. A group of benzamide derivatives are disclosed.

Here, a group of new compounds were discovered, and these compounds It is a tar antagonist.

Therefore, the present invention provides a compound having the formula (1):R having 5-HT3 receptor antagonistic activity. , is hydrogen, halo, nitro, amino, self alkyl or C1,6 alkoxy: R 2 is halo, C1-6 alkyl or Cl-6 alkoxy; A is 1 or has 1 to 3 carbon atoms optionally substituted by two 01-6 alkyl groups (Poly)methylene, L is ○ or NH: Z is a di-azacyclic or azanicyclic side chain] or its Provided are pharmaceutically acceptable salts.

Suitable examples of alkyl moieties in R3 and R7 and A include methyl, ethyl, chill, n- and 1so-propyl, n-1iso-1sec- and tert -butyl.

Suitable examples of halo include fluoro, chloro and bromo, preferably is chloro or bromo.

Often R1 is hydrogen and R4 is chloro or bromo.

A is an unsubstituted polymethylene of 1 or 2 carbon atoms (i.e. ○-A- (〇 is methylenedioxy or ethylenedioxy) is preferred.

Preferred examples of Z include those disclosed in the technical field regarding 5-HT3 receptor antagonists. It is. That is, as follows: i) GB 2125398A [ Sandoz Limited CB 215 2049A [Sand Limited] tit) EP-A-215545 [B Cham Group Public Limited and Company (Beacham) Group p, 1. c, )] tv) EP-A-214772 [B Cham Group Public Limited Company Co., Ltd. V) EP-A-377967 [Beacham Group Public Limited Company] vi) PCT/GB91101629 (Beacham Group Public ・Limited Company Co. n) EP-A-358903 [Dianippon] especially The side chains of interest are:

granatan isotropane [In the formula, R is hydrogen or methyl; X is oxygen, sulfur, or optionally Cl-6alk; Kyl, C34 cycloalkyl, C3-*cycloalkyl C3-4 alkyl, phenylene nyl, naphthyl, phenyl Cl-4 alkyl or naphthyl Cl-4 alkyl ( Here, the [enyl or naphthyl moiety] optionally has one or more halo, C1-6 atom, optionally substituted by lucoquine or c+-g alkyl) Nitrogen may be present.

Particularly important side chains Z include tropane, oxagranacune, and and azagranatan. Preferred for N-substituent when X is N The meaning is disclosed in PCT/GB91101629, for example, 1so-propylene. Lopyl or ethyl.

Preferably, L is NH.

Alternatively, COL in formula C'D is the bioisostere (b ioisostere), such as 1,2,4-oxadiazole and other E P-A-377967 (Beacham Group Public Limited Kan may also be substituted by a group of structure h) as disclosed in Panney).

Pharmaceutically acceptable salts of the compound represented by formula (I) include hydrochloric acid, hydrobromic acid, , conventional acids such as boric, phosphoric, and sulfuric acids, as well as acetic, tartaric, and maleic acids. , citric acid, succinic acid, benzoic acid, ascorbic acid, methanesulfonic acid, Pharmaceuticals such as toglutarate, alpha-glycerophosphate and glucose-1-phosphate and acid addition salts with organic acids that are legally acceptable.

Pharmaceutically acceptable salts of the compound represented by formula (1) are usually prepared using hydrochloric acid or 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 RX-T [where Rx is C1-6 alkyl, phenyl-01-6 alkyl or C3-7 cycloalkyl, T is acid is a group corresponding to the anion of formula (I), such as a compound quaternized by Examples include quaternary derivatives of compounds represented by: A suitable example of R is methoxy ethyl, ethyl and n- and 1so-propyl: and benzyl and phenyl Chill is an example. Suitable examples of T include chloride, bromide and iosito Examples include halides such as

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

Compounds of formula (I), pharmaceutically acceptable salts thereof (quaternary derivatives and and N-oxides) to form pharmaceutically acceptable solvates such as hydrates. and whenever it refers to a compound of formula (I) or a salt thereof included.

Of course, compounds of formula (I) may have chiral or brochiral centers. Therefore, it is possible that multiple stereoisomers, including enantiomers, may exist. It is understood that The present invention provides that each of these stereoisomers (including enantiomers) and mixtures thereof (including racemates). Various stereogenic forms are normal Depending on the method, they can be distinguished and separated from each other.

The present invention is based on the formula (■): The compound represented by the formula (■): HL Z’ (I[[) or when L is ○, its reactive derivative Rlo, R2' and/or Zo are R,, R2 and R2, respectively. and/or Z, or a group or atom convertible thereto; Q is a leaving group, a residue The variables R are as defined above]; then, if desired, Rlo, R2° and and/or converting Zo into another group or atom R1, R2, R3 or Z: then and, if desired, a pharmaceutically acceptable salt of the obtained compound represented by formula (I). A compound of formula (I) or its pharmaceutically acceptable The present invention provides a method for producing salt.

Examples of leaving groups Q, which can be displaced by nucleophiles, include chloro and pro-like. halogen, CH, ○ and C1-4 alkoxy such as C2H50-, ph Activated hydrocarbyloxy such as o-1C1sCs○- or C/3C○- , or a nitrogen-bonded heterocycle such as imidazole.

When group Q1 is a halide, the reaction is performed with benzene, dichloromethane, toluene, Diethyl ether, tetrahydrofuran (THF) or dimethylformamide in an inert, non-hydroxyl solvent such as (DMF) at non-extreme temperatures. Uno is preferable. Organic bases, especially triethylamine, trimethylamine, pyridine or picoline (some of which can also function as a solvent) It is also preferable to carry out the reaction in the presence of an acid acceptor such as (a). Alternatively, acid receptors is an inorganic substance such as calcium carbonate, sodium carbonate or potassium carbonate. obtain. Temperatures of 0'' to 100°C, especially 10 to 80°C are preferred.

Group Q1 is Cl-4 alkoxy, phenoxy or activated hydrocarbyloxy In some cases, the reaction is carried out using an inert polar solution such as toluene or dimethylformamide. Preferably, it is carried out in a solvent. Group Q1 is C13CQ-, the reaction is carried out at reflux temperature, Preferably it is carried out in toluene.

When L is 0, the compound of formula (III) is in the form of its reactive derivative This is often a lithium, sodium or potassium salt. It is like salt.

Compounds of formula (I) containing an R9 or R2 group that is convertible into another group appears to be a useful new intermediate. That is, the hydrogen substituent is a conventional halogen can be converted to a halogen substituent by halogenation using a chlorinating agent.

When Zo is other than Z, R is optionally halo, C31 alkoxy or C1-, even if substituted by one or two groups selected from alkyl substituted with R', a hydrogenolyzable protecting group that is a good benzyl Good too. Such a benzyl group is, for example, when R, /R, is not a halogen, removed by conventional transition metal catalyzed hydrogenolysis to form the formula ( A compound represented by I) is obtained.

The present invention provides N-methylation of a compound represented by formula (I) in which R is hydrogen, and optionally to form a pharmaceutically acceptable salt of the compound represented by formula (I) obtained. A compound of formula (I), in which R is methyl, or a pharmaceutically acceptable compound thereof, consisting of The present invention also provides a method for producing a salt containing the same. In this further method of the invention , "N-methylation" is a reaction with a compound CHsQs in which C3 is a leaving group. can be achieved.

Preferred variables for Q include CI, Br, I, 03OICH, or by nuclear reagents such as O20, C, H, pCH, preferably C1, Br or I. Examples include groups substituted with .

The reaction is carried out under conventional alkylation conditions, e.g. in the presence of an acid acceptor such as potassium carbonate. In the presence of dimethylformamide in an inert solvent such as dimethylformamide. In general, the reaction is carried out at non-extreme temperatures, such as room temperature or slightly higher. Ru.

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

A compound of formula (I[[) before coupling with a compound of formula (II) It is also possible to convert R in objects. Such a conversion is performed under the conditions mentioned above. It is convenient to be exposed. Acid addition such as 02-, alkanoyl group before R/Z conversion It is desirable to protect any amine functionality with a group that is easily removable by water lysis. Delicious.

Produce the corresponding compounds in which the methyl group is replaced by an alkoxycarbonyl It is often convenient in the preparation of compounds of formula (III) to Ru.

Such compounds are then treated with strong reducing agents such as lithium aluminum hydride. can be reduced to the corresponding compound of formula (n) using a compound of formula (n).

The compound of formula (n) is known or has been disclosed in UK 1571278. Similarly to known compounds as shown or from the known compounds according to conventional methods. Manufacturable.

Compounds of formula (III) generally employ substituted piperidines. From the corresponding exocyclic keto derivatives of azanicyclic side chains prepared by the condensation method Manufactured.

They can be prepared by the methods disclosed in the above-mentioned patent documents relating to the significance of the side chain Z. can be manufactured.

Formulas with tropane, granatan or oxa/thia/aza-granatan side chains ( In the compound represented by 1), the -COL- bond is the bicyclic moiety to which it is bonded. It is understood that it takes an end configuration with respect to the ring. of the compound represented by formula (I) Mixtures of endo and exo isomers can be synthesized non-stereospecifically to achieve the desired isomerism. bodies are conventionally separated from them, e.g. by chromatography. .

Alternatively, the endo isomer is optionally a compound of formula (n). can be synthesized from the corresponding endoforms. The corresponding pairs of geometric isomers are isoquinucleic Side of Gin, Isogranatan, Oxa/Thia-Isogranatan and Isotropane Possible about chains.

Pharmaceutically acceptable salts of compounds of the invention may be formed conventionally.

The salt is, for example, a basic compound represented by formula (I) combined with a pharmaceutically acceptable organic acid. or may be formed by reacting with an inorganic acid.

Compounds of the invention are 5-HT3 receptor antagonists and thus generally May be used in the treatment or prevention of pain, vomiting, CNS disorders and gastrointestinal disorders Seem. Pain includes migraines, cluster headaches, trigeminal neuralgia, and visceral pain. Examples include: vomiting, especially those to prevent vomiting and nausea associated with cancer treatment; , postoperative vomiting, and nausea associated with migraine. Examples of such cancer treatment and Platinum complexes, including cisplatin, as well as doxorubicin and cyclophos methods using cytotoxic agents such as Sphamide, especially cisplatin, and radiation Radiotherapy is an example. CNS disorders include anxiety, psychosis, senile dementia, and age. Cognitive disorders such as memory-associated memory impairment (AAMI), and drug dependence include It will be done. Gastrointestinal disorders include irritable bowel syndrome and diarrhea.

5-HT3 receptor antagonists may be associated with obesity, arrhythmia, and/or myocardial instability. It may be used to treat associated disorders.

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. Also provided are pharmaceutical compositions comprising 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 rosé. powders, reconstituted powders, solutions or suspensions for injection and infusion, or It may be in the form of a full row. Orally administrable compositions may be This is preferred because it is convenient.

Tablets and capsules for oral administration are usually given in unit doses and may contain binders, fillers, etc. such as fillers, diluents, tabletting 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. Thus, for example, it may be coated with an enteric coating.

Fillers suitable for use include cellulose, mannitol, lactose and and other similar drugs. Suitable disintegrants include starch, polyvinyl Starch derivatives such as polypyrrolidone and sodium starch glycolate can be mentioned. Suitable lubricants include, for example, magnesium stearate. can be lost.

Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate. Ru. Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, and sprays.

It may be in the form of a cream or elixir, or it may be mixed with water or water before use. may be provided as a dry product for reconstitution with other suitable excipients. like this Liquid preparations include, for example, sorbitol, syrup, methylcellulose, gelatin, human Droxyethylcellulose, carboxymethylcellulose, aluminum stearate Suspending agents such as gels or hydrogenated edible fats, e.g. lecithin, monooleic conventional additives such as emulsifiers such as sorbitan phosphate or gum arabic; e.g. oil esters, such as almond oil, fractionated coconut oil, glycerin esters, Non-aqueous excipients such as pyrene glycol or ethyl alcohol (including edible oils) for example methyl p-hydroxybenzoate or p-hydroxybenzoic acid); Preservatives such as propyl acid or sorbic acid, and optionally conventional flavoring agents Or it may contain a coloring agent.

Oral liquid preparations are usually aqueous or oil-based suspensions, solutions, emulsions, and syrups. , or in the form of an elixir, or with water or other suitable excipients before use. Provided as a dry product for reconstitution with formulations. Such liquid formulations Clouding agents, emulsifiers, non-aqueous excipients (which may include edible oils), preservatives, and flavoring agents. or may contain conventional additives such as colorants.

Oral compositions may be prepared by conventional compounding, filling or tabletting methods. Repetitive Using a compounding operation, large amounts of filler can be used throughout these compositions. distribution of the active ingredient.

For parenteral administration, a unit dose of liquid containing the compound of the invention and a sterile vehicle is prepared. A dosage form is prepared. The compound may be suspended or dissolved depending on the excipient and concentration. can be understood. Parenteral solutions are usually prepared by dissolving the compound in an excipient and sterilizing it by filtration. and then filling and sealing a suitable vial. local anesthetic Adjuvants, such as preservatives and buffers, are also conveniently dissolved in the excipient. . To increase stability, the composition may be frozen after filling into vials. , moisture can be removed under vacuum.

Parenteral suspensions are made by suspending the compound in a sterile vehicle instead of dissolving it in the vehicle. Virtually all other than sterilized by exposure to ethylene oxide prior to suspension. prepared in a similar manner. Including a surfactant or wetting agent in the composition, It is advantageous to facilitate uniform distribution of the compounds of the invention.

The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof pain, emesis, C. A method for treating or preventing NS disorders and/or gastrointestinal disorders is provided.

An amount effective to treat said disorder depends on the relative potency of the compounds of the invention to treat said disorder. Depends on the nature and severity of the disorder and the body weight of the mammal. However, 7 A unit dose for an adult weighing 0 kg usually contains a compound of the invention in the range 05-1000-9. , for example, will contain between 0.5 and 500 leaves. The unit dose is - once a day or more than once per - day, such as 2.3 or 4 times per - day, more commonly on - days. Can be administered 1-3 times, which is about 0.0001-50u/ky7 days, more commonly ranges from 0.0002 to 25 km/kg/day.

No toxicological side effects are shown within the above dosage range.

The present invention provides an active compound of formula (I) or a pharmaceutically acceptable salt thereof. Use as a therapeutic substance, in particular pain, emesis, CNS disorders and/or gastrointestinal disorders It also provides therapeutic use.

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

Example 1 Endo-N-(9-methyl-9-azabinclo[3,3,1]nonan-3-yl )-7-chloro-1,4-benzonoxane-5-carboxylic acid [British Patent No. 1. No. 571.278, Sonete Detudes Scientifique Inc. Anda Strineil de Liroude de France (Societe D’Etudes) 5cientifiques et Industryelles de L' l1e-de-France)] (0,25g) S　Ocr2　(Oll ) solution was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness and diluted with xylene (2X2 0 ml> was reevaporated. Dissolve the residue in CHtClt (20ml) , endo-9-methyl-9-azabicyclo[3,3,1cononan-3-amine ( 0.29) in CH2Cl2 (10w1). Stir overnight at room temperature. After washing, the reaction mixture was washed with saturated NaHCO3 (50I11>) and dried with K2C. O3) was evaporated to dryness. The residue was subjected to column chromatography (AJ20., CH , C12) to give the title compound, which was purified by ethanol It was converted to its HCj salt with HCl and precipitated with Et,O (0.319).

'HNMR (d'-DMSO) δ8.40.8.20 (2-a, IH) 7, 1 0 (s, 2H) 4.65-4.15 (4, 30, brs, m including 4H, 5H) 3, 65-3.45 (m, 2H) 2.81.2.79 (2-s, 3H) 2.55-2.30 (m, 4H) 2.20-1.95 (m, 2H) 1.82-1.53 (m, 2H) 1.55-1.35 (m, 2H) The following were manufactured in the same way. Example 2 Endo-N-(9-methyl-9-azabinclo[3,3,1cononan-3-yl )-6-chloro-1,3-benzoneoxole-4-carboxamide (E2) 'HNMR (CDC1s) 67, 51 (d, IH) 6.88 (d, LH) 6. 72 (brci, IH) 6.13 (s, 2H) 4.58-4.38 (m, IH) 3.09 (brs, 2H) 2.60-2.40 (2,50s, m including 3H, 5H) 1.98 (brd 　3H) 1.59-1.42 (m, LH) 1.31 (dt, 2H) 1.03 (brd, 2H) 5-HT, receptor antagonist activity In anesthetized rats, the 5-HT-evoked phase was determined according to the following method. Compounds are evaluated for antagonism of the Ono-Bezoltoyarisch reflex.

Male rats aged 250-3509 were injected with urethane (1.25g/J+g, i.p.). Drunk, Fozard, J.R., et al. [Journal ・Off Cardiopathic Pharmacology (J, Cardiova sc, Pharmacol, ) 2.229-245 (1980)] Blood pressure and heart rate were recorded as indicated. Submaximal dose by intra-arterial route (usually 6 μq/he) of 5-HT is administered repeatedly and changes in heart rate are quantified. Compound was administered by the intra-arterial route, and the 5-HT-evoked response was then 50% lower than that of the control. Determine the concentration (ED, .) required to reduce the concentration by .

Both example compounds are active at a dose of 10μ9/J19i,v.

international search report Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number CO7D 453102 8829-4C4531068829-4C 4711088829-4C 4981088415-4C 5131088415-4C I

Claims (16)

[Claims] 1.5-HT3 receptor antagonist activity, formula (I); ▲ mathematical formula, chemical formula, table etc.▼(I) [In the formula, R1 is hydrogen, halo, nitro, amino, C1-6 alkyl or C1-6 alkoxy C; R2 is halo, C1-6 alkyl or C1-6 alkoxy; A is optional 1 to 3 carbon atoms optionally substituted with 1 or 2 C1-6 alkyl groups (poly)methylene; L is O or NH; Z is a side chain of a di-aza ring or aza-bicycle] or a pharmaceutical thereof acceptable salt. 2. The compound according to claim 1, wherein R1 is hydrogen and R2 is chloro or bromo. . 3. Claim 1 or 2, wherein O-A-O is methylenedioxy or ethylenedioxy. is the compound described in 2. 4. Side chain Z is tropane, granatan, oxa/thia/aza-granatan, quinuc Lysine, isoquinuclidine, isogranatan, oxa/thiaisogranatan or 4. The compound according to any one of claims 1 to 3, which is intropan. 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-(9-methyl-9-azabicyclo[3.3.1]nonane-3- yl)-7-chloro-1,4-benzodioxane-5-carboxamide. 8. Endo-N-(9-methyl-9-azabicyclo[3.3.1]nonane-3- yl)-6-chloro-1,3-benzodioxole-4-carboxamide. 9. A pharmaceutically acceptable salt of a compound according to claim 7 or 8. 10. A compound according to claim 1 substantially as cited in the Examples. 11. Formula (II); ▲There are mathematical formulas, chemical formulas, 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' and/or Z' are each R1, R2 and/or Z, or a group or atom that can be converted into; Q1 is a leaving group; the remaining variables are the same as defined above; ]; then, if desired, R1', R2', and/or Z' are replaced with another group or or atoms R1, R2, R3 or Z; then, if desired, the resulting formula A claim consisting of forming a pharmaceutically acceptable salt of a compound represented by (I) 1. A method for producing the compound described in 1 or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. . 13. A mammal, such as a human, comprising administering an effective amount of a compound according to claim 1. Treatment or prevention of pain, vomiting, CNS disorders and/or gastrointestinal disorders in Law. 14. According to any one of claims 1 to 11 for use as an active therapeutic substance. compound. 15. Claims 1-1 for the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders 1. The compound according to any one of 1. 16. Treatment and/or prevention of pain, vomiting, CNS disorders and/or gastrointestinal disorders Use of a compound according to any one of claims 1 to 11 in the formulation of a medicament for prophylaxis. .