AU675060B2 - 2,6-methano-2H-quinolizin derivative as 5-HT3-receptor antagonist - Google Patents

Description

OPI DATE 13/09/93 AOJP DATE 25/11/93 APPLN. ID 36034/93 v PCT NUMBER PCT/US93/00880 1111 I Il illll lllllilll l Il II ll llII III llI AU9336034 S. EATY(PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 93/17019 C07D 471/18 A61K 31/435 (C07D 471/18, 221:00, 221:00 Al (43) International Publication Date: 2 September 1993 (02,09.93) C07D 221:00) (21) International Application Number: PCT/US93/00880 (74) Agent: MOON, Carolyn, Merrell Dow Pharmaceuticals Inc., 2110 East Galbraith Road, P.O. Box 156300, (22) International Filing Date: 3 February 1993 (03.02.93) Cincinnati, OH 45215-6300 (US).

Priority data: (81) Designated States: AU, CA, FI, HU, JP, KR, NO, NZ, US, 92400474.0 24 February 1992 (24.02.92) EP European patent (AT, BE, CH, DE, DK, ES, FR, GB, (34) Countries for which the regional GR, IE, IT, LU, MC, NL, PT, SE).

or international application wasfiled: FR et al.

Published With international search report.

(71) Applicant (for all designated States except US): MERRELL DOW PHARMACEUTICALS INC. [US/US]; 2110 East Galbraith Road, P.O. Box 156300, Cincinnati, OH 45215-6300 (US).

(72) Inventor; and Inventor/Applicant (for US only) GITTOS, Maurice, W.

[GB/FR]; 16, rue Andr6-Malraux, F-67115 Plobsheim

(FR).

(54)Title: 2,6-METHANO-2H-UINO ZIN DERIVATIVE AS 5-T3-RECEPTOR ANTAGONST (54)Title: 2,6-METHANO-2H-QUINOLIZIN DERIVATIVE AS 5-HT3-RECEPTOR ANTAGONIST HO 3 a

H

3

C

(57) Abstract This invention relates to 5-chloro-2, 3-dihydro-2;2-dimethylbenzofuran-7-carboxylic acid-octahydro-3-hydroxy-2,6-methano-2H-quinolizin-8-yl ester a novel 5-HT 3 -receptor antagonist, its method of preparation, and to its end-use application in the treatment of radio- and chemo-therapeutically-induced nausea and vomiting, in the treatment of pain associated with migraine, in the treatment of cognitive disorders, in treating hallucinatory endogenous psychoses of the type manifested in patients suffering from schizophrenia and mania, for irritable bowel syndrome, and to combat drug abuse.

WO 93/17019 PCT/US93/00880 1 2,6-Methano-2H-quinolizin derivative as 5-HT3-receptor antagonist This invention relates to 5-chloro-2,3-dihydro-2,2dimethylbenzofuran-7-carboxylic acid-octahydro-3-hydroxy- 2,6-methano-2H-quinolizin-8-yl ester, a novel 5-HT 3 -receptor antagonist, its method of preparation, and to its end-use application in the treatment of conditions responsive to 3 receptor antagonism such as radio- and chemo-therapeutically-induced nausea and vomiting, ~in the treatment of pain associated with migraine, in the treatment of cognitive disorders such as Alzheimer's Disease, the treatment of hallucinatory endogenous psychoses of the type manifested in patients suffering from schizophrenia and mania, the treatment of irritable or inflammatory bowel syndrome, or to combat drug abuse.

More specifically this invention relates to compounds of the formula

H

-HO r0

H

3 C-

H

3

C

HC

:1711 C WO 93/17019 PCT/US93/00880 2 its tautomers, stereo- and geometrical isomers, and mixtures thereof, and to the pharmaceutically acceptable salts thereof.

As used herein, the wavy line bonding the oxygen atom of the ester moiety to the 8-position of the octahydro-2,6-methano- 2H-quinolizin moiety (hereinafter sometimes referred to as the methano bridged quinolizinyl moiety) indicates that the bonding may be in the endo (trans) or the exo (cis) configuration. The preferred configuration is endo.

Preparation of such geometric isomers may be effected by the processes and techniques of U.S. Patent 4,906,755 which is incorporated herein by reference. A chirality exists at the 3-position of the methano-bridged quinolizinyl moiety presenting d- or 1-isomers and racemate mixtures thereof.

When desired resolution of said racemates may be effected by standard procedures and techniques well known in the art.

The enantiomer is preferred.

The pharmaceutically acceptable acid addition salts referred to above can be non-toxic salts with suitable acids such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids; or with organic acids such as organic carboxylic acids, for example, acetic, propionic, glycolic, maleic, hydroxymaleic, malic, tartaric, citric, salicylic, 2-acetyloxybenzoic, nicotinic or isonicotinic; or organic sulfonic acids, for example, methanesulfonic, ethanesulfonic, 2hydroxyethanesulfonic, 4-toluenesulfonic or 2-naphthalenesulfonic.

The preparation of the compounds of the present invention may be illustrated by the following example.

WO 93/17019 PCT/US93/00880 3

EXAMPLE

5-CHLORO-2,3-DIHYDRO-2,2-DIMETHYLBENZOFURAN-7-CARBOXYLIC ACID TRANS-OCTAHYDRO-3-HYDROXY-2,6-METHANO-2H-QUINOLIZIN-8- YL ESTER STEP A: Using triphosgene 5-Chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester A solution of triethylamine (1.79 4-dimethylaminopyridine (1.09 g) and 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid (3.8 g) in dichloromethane (75 ml) was slowly added to a stirred solution of triphosgene (5.28 g) in dichloromethane (100 ml) at 0°C, nitrogen being continuously bubbled through the mixture.

After the addition, the mixture was stirred at room temperature overnight under nitrogen, filtered and evaporated.

A suspension of the residue in anhydrous toluene was refluxed with a stirred suspension of hexahydro-8-hydroxy- 2,6-methano-2H-quinolizin-3(4H)-one (3.25 g) overnight. The cooled solution was filtered, the toluene washed with aqueous potassium carbonate, dried over magnesium sulphate and evaporated to give a residue (4.8 g) containing the title compound. It was then purified by partitioning between ethyl acetate (200 ml) and IN methanesulphonic acid (40 ml).

Basification of the separated methanesulphonic acid solution with a saturated aqueous solution of potassium carbonate gave a crystalline solid which was further purified by crystallization, from aqueous methanol or by silica gel chromatography to give a pure sample of the title compound.

WO 93/17019 WO 931709PCT/ US93/00880 -4 Step A' (Alternate to Step Using trichioromethyl chioroformate 5-Chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid trans-octahydro-3-oxo--2,6-methano-2H-auinolizin-8-yl ester A solution of trichioromethyl chioroformate (1.76 g, 1.08 ml) in dichloromethane (10 ml) was added to a stirred solution of 5-chloro-2 ,3-dihydro-2, 2-dimethylbenzofuran-7carboxylic acid (2 g) and triethylamine (1.4 ml) in dichloromethane (30 ml) at 0 0 C. The mixture was stirred overnight at room temperature, washed with an ice cold saturated aqueous solution of ammonium chloride, dried over magnesium sulphate and evaporated to give an oi'l (2.2 g).

A stirred mixture of the oil hexahydro-8-hydroxy- 2,6-methano-2H-quinolizin-3(4H)-one (1.6 g) and toluene ml) was refluxed overnight. The cooled mixture was washed with a saturated aqueous solution of potassium carbonate and then four times with water to remove any unreacted hexahydroquinolizine one. Evaporation of the dried toluene solution (MgS0 4 gave a solid residue which was recrystallized from ethyl acetate/hexane to give the title compound (0.35 g).

STEP B: 5-Chloro-2, 3-dihydro-2 ,2-dimethylbenzofuran-7-carboxylic acid trans-octahydro-3-hydroxy-2,6-methano-2H-guinolizin-8yl ester Sodium borohydride (1.52 g) was slowly added to a stirred solution of 5-chloro-2, 3-dihydro-2, 2-dimethylbenzofuran-7-c~irboxylic acid trans-octahydro-3-oxo-2,6-methano-2Hquinolizin-8-yl ester (3.9 g) in ethanol (75 ml) at room WO 93/17019 PCI'/US93/00880 5 temperature and the mixture stirred at room temperature overnight. The ethanol was evaporated, the residue dissolved in a mixture of water (20 ml) and 2N hydrochloric acid ml), and the acidic solution almost immediately basified by the addition of an excess of a saturated solution of aqueous potassium carbonate. Extraction with a mixture of tetrahydrofuran-ethyl acetate and evaporation of the dried extract gave the title compound. 192-193 0

C.

Conversion to the methane sulphonate salt was effected by the addition of one equivalent of an alcoholic solution of methanesulphonic acid and evaporation of the solvent.

The racemic mixture can be separated into its separate enantiomers by standard techniques.

WO 93/17019 PCT/US93/00880 6 The compounds of the present invention block the M receptors for 5-hydroxytryptamine (5HT) on afferent sensory neurons otherwise known as 5HT 3 -receptors. The activity of the compounds of this invention against the 5HT 3 -receptor can be assessed by determining their pA 2 values in the isolated rabbit heart as described by J. R. Fozard et al., Eur. J. Pharmacol. 59, 195-210 (1979). The invivo 3 -receptor antagonist activity can be assessed by measurement of the effect of the compound on the Von Bezold- Jarisch reflex induced by 5HT injected intravenously into the rat (see Paintal A. Physiol. Rev. 53, 159-227 (1973); J. R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol.

326, 36-44 (1984).

Using the foregoing standard procedures, as well as other standard procedures recognized to illustrate 3 -receptor antagonist activity for the above-stated enduse applications, as well as by comparison with other 3 -receptor antagonists known to be useful for such purposes, the compounds of this invention may be utilized in a variety of treatments.

Generally, the compounds of the present invention are useful in treating conditions responsive to 5-HT 3 receptor antagonism. Examples of conditions responsive to 5-HT 3 receptor antagonism are well known to those skilled in the art. Some examples of these conditions are treating anxiety, psychosis, glaucoma and for stimulating gastric motility Patent No. 5,011,846), treatment of panic disorders and/or agoraphobia or obsessive compulsive disorders (Patent No. EP 422,154); treatment of autism or other disorder originating in childhood in which there is mental retardation (Patent No. EP 450,757); treatment of cognitive disorders such as Alzheimer's Disease Patent Application Serial No. 806,987); production of orexiogenic WO 93/17019 PCT/US93/00880 7 effect Patent Application Serial No. 742,951.); serotonin-induced nasal disorders, rhinitis or impaired approach-oriented behavior in stressful situations or for increasing vigilance Patent No. GB 2,193,633); relief or prevention of withdrawal syndrome resulting from addiction to and/or for the suppression of dependence on a drug or substance (Patent No. EP 279,114 and GB 2,206,788); treatment of lung embolism (Patent No. GB 2,231,265); treatment of cough and/or bronchoconstriction (Patent No. EP 340,270); treatment of nausea, bradycardia, and/or hypotension associated with myocardial instability (Patent No. W091/09593); treatment of urinary incontinence (Patent No. EP 467,365); and combination therapy with ACE inhibitors (Patent No. EP 477,625 and EP 477,624), with 3-[2methanesulphonamide (Patent No. EP 433,043); and histamine

H

2 -receptor antagonist (Patent No. EP 275,669). All of the foregoing are incorporated herein by reference.

Preferred uses for the compounds of the present invention include the treatment of nauseas and vomiting, particularly radio- and chemo-therapeutically induced in those patients being treated for cancer, in the treatment of pain associated with migraine and neuralgia, in the treatment of cognitive dysfunctions such as memory and learning disorders as well as dysfunctions in selective attention, in the treatment of hallucinatory endogenous psychoses of the type manifested in patients suffering from schizophrenia and mania, for the treatment of irritable or inflammatory bowel syndrome, as well as to be useful in combating drug abuse.

Doses administered to patients are within the range of about 0.01 to about 10 mg per kilogram of body weight, with 0.01 to 1 mg per kilogram of body weight being preferred for WO 93/17019 PCT/US93/00880 -8 parenteral administration and 0.25 to 1 mg per kilogram of body weight upon enteral administration. Of course, the dosage required for the treatment of the foregoing disease states will depend upon such factors as the severity and stage of the particular disease, the age and condition of the patients as such other normal factors taken into consideration by the attending diagnostician.

The term "patient" means warm-blooded animals such as rats, mice, dogs, cats, guinea pigs, primates and humans.

The term "treat" means to prevent or alleviate the patient's disease or condition.

The compounds of Formula can be administered in various manners to achieve the desired effect. For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compounds of Formula can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or algenic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or nonaqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.

For parenteral administration, the compounds may be dissolved in a physiologically acceptable pharmaceutical WO 93/17019 PCT/US93/00880 9 carrier and administered as either a solution or a suspension. Illustrativeof suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin.

The pharmaceutical carrier may also contain preservatives, buffers, etc. as are known in the art.

The compounds of this invention can also be administered topically. This can be accomplished by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.

Some suitable transdermal devices are described in U.S.

Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894 incorporated herein. These devices generally contain a backing member which defines one of its face surfaces, an active agent permeable adhesive layer defining the other face surface and at least one reservoir containing the active agent interposed between the face surfaces.

Alternatively, the active agent may be contained in a plurality of microcapsules distributed throughout the permeable adhesive layer. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.

WO 93/17019 PCTIUS93/00880 10 In another device for transdermally administering the compounds in accordance with the present invention, the pharmaceutically active compound is contained in a matrix from which it is delivered in the desired gradual, constant and controlled rate. The matrix is permeable to the release of the compound through diffusion or microporous flow. The release is rate controlling. Such a system, which requires no membrane is described in U.S. Pat. No. 3,921,636 incorporated herein. At least two types of release are possible in these systems. Release by diffusion occurs when the matrix is non-porous. The pharmaceutically effective compound dissolves in and diffuses through the matrix itself. Release by microporous flow occurs when the pharmaceutically effective compound is transported through a liquid phase in the pores of the matrix.

Specific formulations of the present invention are prepared in a manner well known perse in the pharmaceutical art and usually corprise one or more active compounds of the invention in admixture or otherwise in association with a pharmaceutically acceptable carrier or diluent therefor. The active ingredient will usually be mixed with a carrier, or diluted by a diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other container. A carrier or diluent may be solid, semisolid or liquid material which serves as a vehicle, excipient or medium for the active ingredient. Suitable carriers or diluents are well known per se. See Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, incorporated herein, for a description of the preparation of such formulations.

Claims (6)

1. 2. The compound according to claim 1 when used as a pharmaceutically active compound for treatment of diseases responsive to 5-HT3-receptor antagonist.
2. 3. The compound according to claim 1 when used in the treatment of nausea and vomiting, treatment of migraine, treatment of cognitive disorders, treatment tJ schizophrenia and mania, treatment of irritable or inflammatory bowel syndrome, or treatment of drug abuse.
3. 4. A pharmaceutical composition including the compound according to claim 1 in combination with a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 4 when used in the treatment of nausea and vomiting, treatment of migraine, treatment of cognitive disorders, treatment of schizophrenia and mania, treatment of irritable or inflammatory bowel syndrome, or treatment of drug abuse. J C \WINWORDUACKIE\NODELETEI6034N93.DOC WO 93/17019 9 I SC/ US93/0088() 12
4. 6. Use of a compound according to Claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of nausea and vomiting, treatment of migraine, treatment of cognitive disorders, treatment of schizophrenia and mania, treatment of irritable or inflammatory bowel syndrome, or treatment of drug abuse.
5. 7. A method of treating a patient in need of 9 therapy with an effective amount of the com according to Claim 1 for treating nausea aj ting, treating migraine, treating c ve disorders, treating schizo h and mania, treating irritable or inflammatory 1 Wtel syndrei i.-or treating drug a'buse.---- 7. The method of making a compound having the formula: H 3 C by reacting the oxoderivative O I I O-C Cl -Cl H 3 C 3i 1i 13 with an appropriate reducing agent temperature until the alcohol at about room H 3 C is produced; and optionally producing a pharmaceutically acceptable salt thereof. #e A method according to claim 8 substantially as hereinbefore described with reference to the Example. 25 DATED: 1 FEBRUARY, 1995 a a o *o a a *o a. a oo oo.. o a PHILLIPS ORMONDE FITZPATRICK Attorneys for: MERRELL DOW PHARMACEUTICALS INC. a 39 95631 IN'II.ChN A'1'1ONA1, [E1AI0111I 1P1011 Internationali Application No PCT/US 93/00880 I. CLASSIFICATrION OF~SUBJECT MATT7ER (if Severe! classification symbols apply, Indicate aui)G Accordling to International Pmetat Classification (IPC) or to both National Classification and II'C Int.C1. 5 C07D471/18; //A6lK31/435,(C07D471/18,221:OO,221:OO, 221: 00) ff. FIEWS SEARCHED Minimum Documentation Searched7 Classification System Classification Symbols Int.C1. 5 C07D ;A61K Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searchedl 1I. DOCUMENTS CONSIDERD TO BE RELEVANT 9 Category' Citation of Document, It with indication, where appropriate, of the relevant r.asages L2 Relevant to Claim No.L3 YEP,A,0 329 932 (MERRELL DOW) 1,4 August 1989 claim 1 and page 5, line 56 to page 6, line 2* Y JOURNAL OF MEDICINAL CHEMISTRY 1,4 vol. 35, no. 2, 24 January 1992, WASHINGTON US pages 310 319 D.W. ROBERTSON 'Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships' page 312, table III P,A EP,A,O 517 984 (MERRELL DOW) 1,4 16 December 1992 see page 11, line 18 page 15, line 9; claim 1 0 Spedial categories of cited documents t 'T later document published after the International filing date the oal ofth h~chor prIoritydate and not In conflict with the application but document defining tegenea state ofte z hihI not cited to uneand the principle or theory unJ'eriying the considered to be of particular relevance invention 'El earlier document but published on or after the international -V document of partIcular relevance; the clted Invention filing date cannot be considered novel or cannot be considered to LV document which may throw doubts on priority claim(s) or involva an inventive step which is cited to establish the publication date of another IV document of particular relevance; the claimed Invention citation or other special reason (as specified) cannot be considered to Involve an inventive step when the O0 document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other mean ments, such combination being obvious to a person skilled P document published prior to the international filing date but In the art. later than the priority date claimed 0&1 document member of the same patent family IV. CERTIFICATION Date of the Actual Complerlon of the Internationa Search Date of Milling of this International Search Report 12 MAY 199325.0.q3 Intezzuational Searching Authority Signature of Authorzed Officer EUROPEAN PATENT OFFICE ALFARO FAUS I. Pamu PC17MWJZI twcad MkAW tJOUN07 InI S4 7 7 7 77' 2L L INTERNATIONAL SEARCH REI'ORT mri4Lionil olhPtlonu~ No, PCT/ US 93/ 00880 I Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. D Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Although claim 7 is directed to a method of treatment of(diagnostic method practised on) the human/animal body the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. O Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. D As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. D As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest D The additional search fees were accompanied by the applicant's protest. No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (continuation of first sheet (July 1992) A S S ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. 9300880 69869 This annex fists dhe patent family members relating to the patent documents cited in the above-mentioned international searc report. The members are as contained in the European Patent Office EDP file on The European Patent Office is in no way Liable for these particulars which are merely given for the purpose of information. 12/05/93 Patent document Publication Patent family Publication cited in search report date member(s) d t e EP-A-0329932 30-08-89 EP-A- EP-A- EP-A- EP-A- AU-A- JP-A- US-A- US-A- 0329902 0329903 0329904 0329905 3021489 2288880 5011846 4906755
6. 30-08-89 30-08-89 30-08-89 30-08-89 24-08-89 28-11-90 30-04-91 06-03-90 EP-A-0517984 16-12-92 AU-A- 1803792 24-12-92 EP-A- 0518767 16-12-92 0 '6 For more details about this annex: wee Official Journal of the European Patent Office, No. 12182