SUBSTITUTED UREA COMPOUNDS AND THEIR PREPARATION AND USE

Use . The present invention relates to therapeutically ac¬ tive substituted urea compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds, and a method of treating therewith.

EP-A-323 077 describes aryl or aroyT ureas and carbamic aci-d deriva¬ tives of formula A-X-NHCW-Y-8, wherein A is an aromatic radical including optionally substituted phenyl, X is a direct bond or CO, W is 0 or S, Y is NH or S and B is a spiecified saturated azacyclic ring, e.g. tropan-S-yl or quinuclidin-3-yl. The compounds possess 5-HT3-raceptor antagonist activity.

EP158265 and EP 235878 describes benzamides and sub¬ stituted urea compounds having an- azabicyclic side chain and possesing 5-HT antagonist activity.

A class of novel, structurally distinct compounds with higher 5KT3 - antagonist activity has now been dis¬ covered. These compounds have 5-HT„-receptor antago¬ nist activity, anti-emetic activity and/or gastric mo¬ tility enhancing activity- The" present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof:

R O ff-vX NH-5-NH-R1 (I) wherein R is a group of formula II ot 111 T*.",***"?* S" f E SHSEt t )' '* - _•> I Replacement sheet (twice amended) PCT/'K9C/00232 tCB-)n">0«4 (II) (III ) where n is 2 or 3, p is 1 or 2, q is 1 to 3, and R is H, C,, alkyl or C3_5 cycloalkyl; and wherein R is l,2,4-oxadia2ol-5-yl substi¬ tuted with C, g alkyl, C-.g alkenyl, C2_g alkynyl, C3_7 cycloalkyl, benzyl, phenyl, G. - alkoxy, C,_g alkylthio, or amino; or wherein R is -C-R -N-Q--R wherein R is hydrogen or methyl and R is C, g alkyl which may be substituted with C,. cycloalkyl; and wherein R is hydrogen, halogen, nitro, trifluorotnethyl, Cg alkyl or Cj_g alkoxy, The invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutic SUBSTITUTE SHEET WO 91/03475 PCT/DK90/00232 ally acceptable salt thereof, which process comprises reacting a compound of formula V:

,Cy (V) with a compound of formula VI J-K1 where R , R , R are as defined above.

R is COQ, where Q is a group displaceable by a nu- cleophile, R and R together *C*0, or R is hydrogen (when R is hydrogen); and when R is COQ, or R -N~R is N=C=0, J is NH0, or a reactive derivative thereof or when R is hydrogen, J is a group containing an activated carbonyl group capable of forming a CO-N- linkage with the compound of formula (V).

Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The acid addition salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceu- tically acceptable organic or inorganic acid.

Compounds of formula (I), whic » antagonise the effect of 5-HT at 5-HT3 receptors, are useful in the treat¬ ment Of conditions such as psychotic disorders (e,g.

schizophrenia and mania); anxiety; and nausea and vo¬ miting, particularly that associated with cancer che¬ motherapy and radiotherapy. Compounds of formula (I) SUeSTITUTH SHSST WO 91/03475 PCT/DK90/00232 are also useful in the treatment of gastric stasis; symptoms of gastrointestinal dysfunction such as occur with dyspepsia, peptic ulcer, reflux oesophagitis, flatulence and irritable bowel syndrome; migraine; and pain. Compounds of formula (I) may also be used in the treatment of dependency on drugs and substan¬ ces of abuse, depression, and dementia and other cog¬ nitive disorders.

Unlike existing drug treatments for certain of the above conditions, the compounds of the invention, be¬ cause of their high selectivity for 5-HT- receptors, would not be expected to produce undesirable side effects. Thus, for example, neuroleptic drugs may cause extrapyramidal effects, such as tardive dyski¬ nesia, and benzodiazepines may cause dependence.

According to another aspect, the invention provides a method of treatment of a human or animal subject suf- fering from a psychotic disorder such as schizophre¬ nia or mania; or from, anxiety; nausea or vomiting, particularly that associated with cancer chemotherapy and radiotherapy; gastric stasis; symptoms of gastro¬ intestinal dysfunction such as dyspepsia, reflux oeso- phagitis, peptic ulcer, flatulence and irritable bowel syndrome; migraine; pain; dependency on drugs or sub¬ stances of abuse; depression; or dementia and other cognitive disorders which comprises administering an effective amount of a compound Of formula (I) or a physiologically acceptable salt or solvate thereof.

Compounds of formula (I) were tested for their 5HT3- antagonist activity using the following method:

Principle 5-Hf produces contractions of the guinea pig ileum SUBSTITL'TS C?-:»! WO 91/03475 PCT/T:K90/00232 via 2 different receptors. 1) direct contractions via 5-HT2 receptors on the muscle, 2) indirect contracti¬ ons via 5-HT3 receptors on intrinsic gut neurones, producing acetylcholine release. By administering 5- HT to lengths of ileum in the presence of methysergi- de (to block 5-HT2 receptors) you can assay 5-HT3 re¬ ceptor activity.

Method Guinea pigs were killed by means of cervical disloca¬ tion the terminal 15 cm of ileum removed, and 1.5 - 2.0 cm lengths prepared and mounted in 10 ml organ baths containing calcium deficient tyrodes of the fol- lowing composition (mM) NaCl (136.9); KC1 (2.68); CaCl2 (0.9); MgCl2 (1.05); NaC03 (11.9); NaH2P0.(0.42); glucose (5.55) and containing methysergide (10~ M) maintained at 370C and gassed with 95% 02 and 5% C02, The mechanical activity of the muscle was measured by a HSE 351 isometric transducer connected via a HSE bridge amplifier to a potentiometric pen recorder.

Resting tension was 1 g and the tissue left to equi¬ librate for 1 hour.

First a dose response curve is obtained to acetylcho¬ line on each tissue. Then one tissue is incubated for min with tyrode and three with tyrode plus the pu¬ tative 5-HT3 antagonist. After this incubation dose response Curves to 5-HT are constructed to 5-HT in all 4 tissues (one control 3 + test drug). Contact time for 5-HT 30 sec.

Results The maximum response to acetylcholine for each tissue is fltaasured and the responses to 5-HT calculated as percentage tnaximum of the acetylcholine (Ach) maximum SUBSTITUTE SHSET Replacement sheet (twice amended) PCT/D;O0/CC232 response in that tissue. The peak of the 5-HT response is measured.

For each tissue the concentration of 5-HT giving 100% of the maximum acetylcholine response (measured at 30 sec) is quoted.

The effect of a drug is quantified as the ratio of the concentration of 5-HT producing a 100% maximal Ach response in the presence and absence of the antagonist (dose ratio). The figure quoted is the concentration of the antagonist giving a dose ratio of 2, (A2).

Test results obtained by testing some compounds of the invention appear from table I Table I EXAMPLE NO A2 /jg/ml 1 0.016 2 0.1 14 0.012 4 0r0013 6 0.1 7 0.01 3 0.005 11 0.0018 12 0.012 The compound of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically-acceptable acid ad- SUBSTiTUTE SH£ET WO 91/03475 PCT/DK90/00232 dition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solu- tions, suspensions, emulsions, elixirs, or capsules filled with the same, all tor oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical com- positions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or prin¬ ciples, and such unit dosage forms may contain any suitable effective central nervous system ailment al- leviating amount of the active ingredient commensurate with the intended daily dosage range to be employed.

Tablets containing one (1) milligram of active ingre¬ dient or, more broadly, one (1) to thirty (30) milli¬ grams, per tablet, are accordingly suitable represen- tative unit dosage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g., for oral and parenteral administration to mammals in- eluding humans, in accordance with conventional me¬ thods of galenic pharmacy.

Conventional excipients are such pharmaceutically ac¬ ceptable organic or inorganic carrier substances suit- able for parenteral or oral application which do not delteriously react with the active compound.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylat- ed castor oil, gelatin, lactose, amylose, magnesium • Steafate, talc, silicic acid, fatty acid monoglyfceri- d&S &ftdi diglycerides, pentaeiythritol fatty acid es WO 91/03475 PCT/DK90/00232 ters, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxilliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compound.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqu¬ eous solutions with the active compound dissolved in polyhydroxylated castor oil.

Ampoules are convenient unit dosage forms.

For oral application, particularly suitable are tab¬ lets, dragees, or capsules having talc and/or a car¬ bohydrate carrier or binder ow the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A feyrup, elixir or like can be used when a sweetened vehicle can be employed. Generally, as to broader ranges, the dompound of the invention is dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically-acceptable carrier per unit dosage.

A typical tablet which may be prepared by conventio¬ nal tabletting techniques contains:

Active compound 1.0 mg Lactosum 67.9 mg ph.Eur Avicel ® 31.4 mg Amberlite * IRP 88 1.0 mg Magnesii stearas 0.25 rtig Ph. Eur The invention will now be deSCJtibed in further detail with reference to the following examples:

Production of starting materials 5- (2-Aniinophenyl) -3-cyclopropyl -1,2, 4-oxadiazole Methyl 2-amino-ben2oate' (6 g# 40 mmol) and cyclopfop- ylcarboxamid oxime (5 g, 50 mmol) was refluxed for h in dry ethanol containing 0,25 g sodium and 2 g mo¬ lecular sieves. The mixture was filtered while hot, and cooled precipitating 2.8 g of the desired product as white needles. Upon addition of water to the .fil¬ ls trate, a further amount of 3.2 g white crystals could be isolated. M.p. 84.4-84.90C.

By a similar procedure wers prepared:

5-(2-aminophenyl)-3-methyl-l,2,4-6xadiazol. M.p.

118.2- 119.80C, 5-(2-aminophenyl)-3-phenyl-l,2,4-oxadiazol. M.p.

128-1290C, 5-(2-aminophenyl -3-butyl-l, 2, 4-oxad.iazol. M.p.

36.4-36.60C, 5-(2-amino-6-chlorophenyl)-3-cyclopropyl-1,2,4-oxa- diazol. M.p. lOS-lOS, 5-(2'-aminos-4-chlorophenyl)-3-cyclopropyl-1, 2, 4-oxa- diazpl.- M,p. 135-1360C and 5-(2-aminp-3-methylf>hfenyD-3-cyclopropyl-l, 2( 4-oxa diazol. M.p. IST-ISS0 SUSSTJTUtESHE f" .C**3l£<.k«2i'*«i*n\Sfc.wC>..«\SU. iA/.-v/v-lv"- 2-(2-Aininophenyl)-5-inethyl-l,3,4-oxadiazol A mixture of isatoic anhydride {16.3 g, 0.1 tnol), p- toluenesulfonic acid (0.2 g, 1.1 mmol), glacial ace¬ tic acid (10 ml), acethydrazide (7.4 g, 0.1 mol) and dry toluene (90 ml) was stirred at 120oC for 4 h, cooled to room temperature and poured into ice water.

Toluene (500 ml) was added, and the phases were sepa¬ rated. The aqueous phase was extracted with CH-Cl- (2x100 ml).

The combined organic phases were dried and concentrat¬ ed in vacuo. The resulting oil was dissolved in warm ethylacetate. By cooling and addition of ether the desired product precipitated, 3.4 g. M.p. 152-1580C.

By similar procedures were prepared:

2-(2-aminophenyl)-l,3,4-oxadiazol. M.p. 206-209oC* 2-(2-aminophenyl)-5-butyl-l,3,4-oxadiazol. M.p. 89- 920C.

2-(.2aminophenyL)-5-phenyl-l, 3, 4-oxadiazt>l. M.p, 163-170OC.

EXAMPLE 1 (endo-8-nietftyl-8-az&biqyclo[3;2.l]oct--yl)urea. HC1 35.

1?®! a solution of phosgene in toluene (8.5 ml, 2.6 M) SftitTftd under N- at 0 C was added dropwise 5-(2«amino< SUBSTITUTE SHEET phenyl)-3-cyclopropyl-l,2,4-oxadiazoXe (3.0 g, mmol) in 175 ml dry methylene chloride. After 100 ml of the solution was added 6.5 ml of dry triethylamine was added. Upon addition the mixture was stirred at 0OC for 15 min. whereupon a solution of (endo)-8-me- thyl-8-azabicyclo[3.2.1]octan-3-amine (2.8 g, mmol) in 10 ml GH2C12 was added. This mixture was stirred at room temperature for 3 h and washed with 150 ml.saturated sodium bicarbonate. The organic pha- se was dried with magnesium sulphate and concentrated in vacuo. The resulting oil was recrystallized three times from ethyl acetate to give 1.3 g of the desired product as white crystals. This product was dissolved in ethanol and precipitated as the hydrochloride by addition of dry hydrochloric acid in ether, giving 1.'3 g.. M.p.. 178-8'0OC.

EXAMPLE 2 N-CEndo-S-methyl-S-aiabicyclota.lloct-S-yD-N1- (2(3-methyl-l,2,4-Qxadiazol-5-yl)-phenyl)urea,. HC1 To a solution of phosgene in toluene (4 ml, 2.6 M) stirred under N- at 0 C was added dropwise 5-(2--amino- phenyl)-3methyl-1,2,4-oxadiazol (1.4 g, 8 mmol) in 100 ml dry methylene chloride. After 50 ml of the so¬ lution was-added, 2.8 ml of dry ttiethylamine was ad- .

ded. Upon addition the mixture was stirred at 0oC for min. whereupon a solution of (ehdo)-8-methyl-8-aza- bicyclo[3.2.1]octan-3*amine (1.1 g, 8 mmol) in 10 ml CH-Gl, was added. This mixture was stirred at room temperature for 3 h and washed with 150 ml saturated sodium bicarbonate, the organic, phase was dried with magnesium sulphate and concentrated in vacuo. The ire- suiting oil was recrystallized three times from ethyl- acetate to give 1.0 g of the desired product as white crystals, this product was dissolved in ethanol and SUSSTSTUTS SHEET XJ precipitated as the hydrochloride by addition of dry hydrochloric acid in ether, giving 0.76 g. M.p. 156- 160oC.

EXAMPLE 3 N-(2-(3-Butyl-l,2,4-oxadiazol-5-yl)phenyl)-N1-(endo- 8-methyl-8-azabicyclo[3-2.1]oct-3-yl)urea, (CCuH)_ To a solution of phosgene in toluene (6.5 ml, 1.93 M) stirred under N- at 6 C was added dropwise 5-(2-aniino- phenyl)-3-butyl-l,2,4-oxadia2ol (1.3 g, 6 mnvol) in ml dry methylene chloride. After 25 ml of the so¬ lution was added, 1.7 ml of dry triethylamine was ad- ded. Upon addition the mixture was stirred at 0oC for min. whereupon a solution of '(endo)-8-inethy 1-8-aza¬ bicyclo [3.2.l]octan-3-amine (1.0 g, 7 mmol) in 5 ml £H_C12 was added. This mixture was stirred at room temperature, for 20. h and yashed with, 50 ml. saturated.

sodium bicarbonate, 50 ml water, and 50 ml saturated sodium chloride. The organic phase was dried with mag¬ nesium sulphate and concentrated in vacuo. The resul¬ ting oil dissolved in acetone (5 ml) and treated with oxalic acid (0.6 g) in 5 ml acetone to give 0.6 g of the desired product as white crystals. M.p. 180-181oC.

EXAMPLE 4 N-(2-(3-Cyclopropyl-l,2,4-oxadiazol"-5-yl)-phenyl )•- N -(endo-9-methyl-9-a2abicyclo[3.3.1]non-3-yl)urea, HC1 To a solution of phosgene in toluene (4.7•ml; 1.93 M) stirred under M* at 0 C was added dropwise 5-(2-amino- phenyl)-3-cyclo-propyl-l,2,4-oxadiazol (1.6 g, 8 iranol) in 100 ml dry methylene chloride. After 50 ml Of the solution was added, 2.5 ml of dry triethylami- SUSSTITUTE SHEET -r """ - ne was added. Upon addition tha mixture was stirred at 0oC for 15 rain, whereupon a solution of (endo)-9- methyl-9-azabicyclo[3.3.linonan-3-amine (1 g, 6.4 nunol) in 10 ml CH2C12 was added, this mixture was stirred at room temperature for 3 h and washed with ml saturated sodium bicarbonate. The organic phase was dried with magnesium sulphate and concentrated in vacuo. The resulting oil was dissolved in methanol.

Addition of ether gave 1.8 g of the desired product as white crystals. This product was dissolved in etha- ndl and precipitated as the hydrochloride by addition of dry hydrochloric acid in ether, giving 1.4 g of the desired product. M.p. 145-147,50C.

EXAMPLE N-CEndo-S-methyl-e-azabicycloCa.a.ljoct-S-ylJ-N1- ( 2-(3-phens'l-l,,2,,4-oxadiazo!-5-yl )-phenyl Jurea, HC1 To a solution of phosgene in toluene (8.5 ml, 1.9 M) stirred under N- at 0 C was added dropwise 5-(2-amino- phenyl )-3-phenyl-l, 2,4-oxadiazal (1.9 g, 8 nunol) in ml dry methylene chloride. After 25 ml of the solu¬ tion was added, 3.5 ml of dry triethylamine was added.

Upon addition the mixture was stirred at 0oC for min. whereupon a Solution of (endo)-8-methyl-8-aza- bi<syclot3.2..1]octan-3-amine {14.g, 10 inmol y in 10 .ml CH-Cl, was added. This mixture was stirred at room, temperature for 20 h and washed with 50 ml saturated sodium bicarbonate, 50 ml water and 50 ml saturated sodium chloride. The organic phase was dried with mag- nesium sulphate And concentrated in vacuo. The resul¬ ting product was washed with ace-tone; dissolved in ethanol and precipitated as the hydrochloride by addi- tion of dry hydrochloric acid in ether. Recrystalliza- tion from ethanol and methanol gave 0.9 g of the de¬ sired product* M.p. 281i-2820C.

SUBSTITUTE SHSET EXAMPLE 6 N-(2-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-phenyl)- N -(3-quinuclidinyl)urea To a solution of phosgene in toluene (K.5 ml,, 1.9 M) stirred under N- at 0oC was added dropwise 5-(2-amino- phenyD-a-cyclopropyl-l-oxadiazol (0.5 g, 2.5 mmol) in 30 ml dry methylene chloride and then 0.8 ml of dry triethylamine. Upon addition the mixture was stirred at 0 C for 15 min. whereupon a solution of 3- aminoquinuclidine (0.18 g, 1.4 mmol) in 10 ml CH-Cl,, was added. This mixture was stirred at room tempera¬ ture for 4 h and washed with 25 ml saturated sodium bicarbonate.. The organic phase was dried with magne¬ sium sulphate and concentrated in vacuo. The result¬ ing oil dissolved in methanol. Addition of ether pre¬ cipitated 0.38 g of the desired product as white crys- talsi This- .product was ."dissolved- in. ethanol and : pre- cipitaised as the hydrochloride by addition of dry hy¬ drochloric acid in ether, giving 0.3 g. M.p. 229-2330C, EXAMPLE ? -(Endo-9-methyl-9-azabiGyclo[3.3.l]non-3-yli-N1- (2-(3-phenyl-l,2,4-oxadiazol-5-yl)phenyl ).urea To a solutiori of phosgene in toluene (17 ml, 1.9 M) stirred under N2 at 0 C was added dropwise 5-(2-amino- phenyl)-3-phenyl-1,2,4-oxadiazol (3.8 g, 16 mmol) in 100 ml dry methylene phloride. After 50 ml of the so¬ lution w&$ added, 7 ml ©f dry triethylamine was added.

Upon addition the mi-jiture was stirred' at 'fr0C for min. whereupon a solution oi (endo)-9-methyl-9-eizabi- cyclQ[3.3.i]nonanj*3~amine (1.5 g, 10 mmol) in 10 ml CH-Cl- was added. This rtixture was stirred at room temperature for 24 h and washed with 50 ml saturated SUBSTJTUTE SHEET sodium bicarbonate, 50 ml H-Oand 50 ml saturated so¬ dium chloride. The product was triturated with metha¬ nol to give 1.0 g of the desired compound. M.p. 182- 1850C.

EXAMPLE £ N-(2-(3-Butyl-l,2,4-oxadiazol-5-yl)phenyl)-N -(endo- 9-methyl-9-azabicyclo[3.3.13non-3-yl)urea,. HC1 To a solution of phosgene in toluene (6.5 ml, 1.9 M) stirred under N- at 0 C was added dropwise 5-(2-amino- phenyl)-3-butyl-l,2,4-oxadiazol (1.43g, 6 mmol) in ml dry methylene chloride. After 25 ml of the so- lution was added,, 1.7 ml of dry triethylamine was ad¬ ded. Upon addition the mixture was stirred at 0oC for¬ is min. whereupon a solution of (endo)- 9-methyl-9- azabicyclo[3.3.l]hohan-3-amine (1.1 g, 7 mmol) in ml- GJUClU was added.'1 This-mixture was stirred at room temperature for 24 h and washed with 50 ml saturated sodium bicarbonate and 50 ml water. The organic phase was dried with magnesium sulphate and concentrated in vacuo. This product was dissolved in ethanol and pre¬ cipitated as the hydrochloride by addition of dry hy- drochloric acid in. ether. Recrystallization from etha¬ nol gave 1.7 g of the desired: product as white crys¬ tals. M.p- 217-2180C EXAMPLE 9 N-CS-Chloro-Z-O-cyclopropyl-lyl, 4-oxadiazol-5-yl )• phenyl)-N -(endo-9-methyl-9-azabicyclo[3,3.1)non-3- ylJurea To a solution of phosgene in toluene (9 ml, 1.9 M) stirred under N* at 0oC was added dtbpwise 5-(2-am S-*chiorophenyl) -3-cyclepropyi-l, 2,4-oxadiaiOl (2.0 J**1 g, 8.5 nunol) in 60 ml dry methylene chloride. After ml of the solution was added, 4.8 ml of dry tri- ethylamine was added. Upon addition the mixture was stirred at 0 C for 15 min. whereupon a solution of (endo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (0.9 g, 6.2 mmol) in 10 ml CH2C12 was-added. This mixture was stirred at room temperature for 24 h and washed with 150 ml saturated sodium bicarbonate. The organic phase was dried with magnesium sulphate and concehtrat- ed in vacuo. The resulting oil was treated with ace¬ tone to give 1.3 g of the desired product as white crystals. M.p. 199-203OC.

EXAMPLE N-(5-Chloro-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)- phenyl)-N -(endo-9-methyl-9-azabicyclo[3.3.llnon-3- yl)urea To a solution of phosgene in toluene (4.2 ml, 1.9 M) stirred under N- at 0 C was added dropwise 5-(2-aniino- 4-chiorophenyl)-3-cyclopropyl-l,2,4-oxadiazol (1 g, 4 mmol) in 40 ml dry methylene chloride. After 20 ml of the solution was added, 2.4 ml of dry triethylamine was added. Upon addition the mixture was stirred at 0od for 15 min. whereupon a solution of (endo)-9-me- thyl-9-azabicyclo(3.3.l)nonan-3-amine (1 g, 6.5 nunol) in 10 ml CH2Cl2 was added. This mixture was stirred at room temperature for 3 h and washed with 150 ml saturated sodium bicarbonate. The organic phase was dried with magnesium sulphate and concentrated in vacuo. The resulting oil was recrystailized from etha- nol to give 0.9 g of the desired product as white cry- stals. M.p. 196*1970C.

SUSST'.TUTS SHEET N-(Endo-S-methyl-S-azabicycio[3,2.1 ]oct:-3-yl J-N1 - EXAMPLE 1].

cyclo[3,2.1 (2-(N-cyclopropylmethoxyiminomethyl)phenyl)urea, HC1 To a solution of phosgene in toluene (3 ml, 1.9 M) stirred under at 0oG was added drbpwise 2-amino-N- cyclopropylmethoKyiminbtnethylbenzene (0.47 g, 2.5 mmol) in 25 ml dry methylene chloride and then 0.8 ml of dry triethylamine. Upon addition the mixture was stirred at 0 C for 15 min. whereupon a solution of (endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (0.2 g, 1.4 mmol) in 5 ml CH-Cl- was added. This mixture was stirred at 40oG for 30 h and washed with 150 ml saturated sodium bicarbonate. The organic phase was dried with magnesium sulphate and concentrated in vacuo. The resulting oil was purified by column chro¬ matography (silicagel; methanol, triethylamine (100:1)). This product was dissolved'-in ethanol and precipitated as the hydrochloride by addition of dry hydrochloric acid in- ether, giving 0.1 g. M.p. 1270C (dec.).

EXAMPLE 12 N-(Endo-8-methyl-8-azabicyclo[3.2.1)oct-3-yl)-N1- (2-(N-ethoxyiminomethyl)phenyl)urea, HCl To a solution of phosgene in toluene (3 ml, 1.9 M) stirred under N2 at 0oC was added dropwise 2-amino- N-ethoxyiminomethylbenzefte (0.41 g, 2.5 nunoi) in »1 dry methylene chloride and then 0.8 ml of dry tri¬ ethylamine; Upon addition -the mixture was stirred at 0oC for 15 min. whereupon a solution of (endo)-S-me- thyl-8-a*aMeyclo|*3.2.13octan-3-amine (0.2 g, 1,4 mmol) in 5 ml CJCl* was added. This mixture was stir- f-ed at 40oC 30 h and washed with 150 ml saturated so- suBStmns**** jtMSiaCeilnsii u a..w«t *»*/•-'»->>/ v w » ».« dium bicarbonate. The organic phase was dried with magnesium sulphate and concentrated in vacuo. The re¬ sulting oil was purified by column chromatography (silicagel; methanol, triethylamine (100:1)). This product was dissolved in ethanol and precipitated as the hydrochloride by addition of dry hydrochloric acid in ether, giving 0.23 g. M.p. 165-1780C (dec).

N-(2-(N-Methoxyiminomethyl)phenyl)-N -(endo-8-methyl- EXAMPLE 13 lyl)phenyl )- 8-azabicyclo[3.2.1]oct-3-yl)urea, HC1 To a solution of phosgene in toluene (4 ml, 2.6 M) stirred under N_ at 0 C was added dropwise 2-amino-N- methoxyiminomethylbenzene (1.4 g, 9.3 nunol) in 90 ml dry methylene chloride. After 45 ml of the soluti¬ on was added,, 3 ml of dry triethylamine was added.

Upon addition the mixture was • strirred. at 0oC--for min. whereupon a solution of (endo)-8-methyl-8-aza- bicyclo[3.2.l]octan-3-amine (2.8 g, 20 mmol) in 10 ml CH-Cl, was added. This mixture was stirred at room temperature for 20 h and washed with 150 ml saturated sodium bicarbonate. The organic phase was dried with magnesium sulphate and concentrated in vacuo. The re- suiting oil was purified by columfi chromatography (silicagel; methanol, triethylamine (100:1)). This product was dissolved in acetone and precipitated as the hydrochloride by addition of dry hydrochloric acid in ether, giving 0.14 g. M.p. 152- 1530C.

EXAMPLE 14 N-(2-(N-Methojcyiminomethyl)phenyl) -N - (endo-9-me- thyl-9-azabicyclo[3.3.llnon-Syl)urea To a solution of phosgene in toluene (4 ml, 2.6 M) stirred under N2 at 0oC was added dropwise 2-amino-N-* methoxyiminomethylbenzene (1.4 g, 9.3 mmol) in 90 ml dry methylene chloride. After 45 ml of the soluti¬ on was added, 3 ml of dry triethylamine was added.

Upon addition the mixture was stirred at 0oC for min. whereupon a solution of (endo)-9-methyl-9-aza- bicyclo[3.3.1]nonan-3-amine (3.1 g, 20 nunol) in 10 ml CH-Cl- was added. This mixture was stirred at room temperature for 24 h and washed with 150 ml saturated sodium bicarbonate. The organic phase was dried with magnesium sulphate and concentrated in vacuo. The re¬ sulting oil was recrystallized from ethylacetate to give 0.4 g of the desired product as white crystals.

M.p. 150-151oC.

EXAMFLC N-(Endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-N1- (2-(2-methyl-l,3,4-oxadiazdl-5-yl)-phenyl)urea, HC1 To a solution of phosgeqe in toluene (2.4 ml, 1.93 M) stirred under N, at 0oC was added dropwe 2-(2-amino- phenyl)-5-methyl-l,3,4-oxadiazol 10.71 g, 4.1 mmol) in 50 ml dry methylene chloride. ATter the solution was added, 1.3 ml of dry trietjaylamine was added. Up¬ on addition the mixture was/stirred at 0oC for 15 min.

-whereupon a solution of &/endo)r'9-methyl-9-azabicyclo- [3i3.1]nonan-3-amine £0.52 g, 3.4 mmol) in 10 ml CH-Cl- was added* This mixture was stirred at room temperature for/3 h and washed with 150 ml saturated sodium bicarbonate. The organic phase was dried with magnesium/sulphate and concentrated in vacuo. The re- suiting oil was purified by column chromatography (methanol; triethylamine (100:1)) to give 0.54 g of the desired product as white crystals. This product was dissolved in methanol and precipitated as the hy- droohlorido by addition of dry hydroohlorio aoid in—- SUBSTITUTE SHEET Replacement sheet (twice amended) PCT/OKO/00232 EXAMPLE Ig" N-(Endo-9-methyl-9-azabicyclo[3.3.13r»on-3-y1)-N -(2-(3 cyclopropyl- l,2.4-oxadia2ol-5-v1)6-methvlDhenv1)area To a solution of phosgene in toluettfc (5.2 ml, 1.9M) stirred under N2 at 0oC was added dropwise a mixture of 5-(2-amino-3-methylphenyl)-3- cyclopropyl-l,2,4-oxadiazol (1-1 g, 5 mmol) and 1.4 ml of dry triethyl amine in 25 ml dry methylene chloride. Upon addition the mixture was stirred at 00C for 1 hour and at room temperature for 2 hours. The mixture was then concentrated in vacuo and redissolved in ml dry methylene chloride and 1.4 ml dry triethyl amine whereupon a t-Z*' Replacement sheet (twice amended) PCT/D'rGO/00232 22.

solution of (endo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine(l.l g, 7 mmol) in 10 ml methylene chloride was added. This mixture was stirred at room temperature for 20 hours and washed with saturated sodium bicarbonate, water, and saturated sodium chloride. Evapora¬ tion of the solvent gave after trituration witn acetone 1.5 g of the desired product. M.p. 189-1920C.

r T" '' ' Oar**" —ip <K. — Replacement sheet (twice amended) PCT/0;(30/G0232 EXAMPIE 16 N-(2-(3-Cyclopropy1-l,2,4-oxadiazol-5-yl)-4-nitropheny1)-N -(endo-9- methvl-9-azabicvcloTS.3.11 non-3»v1)urea To a solution of phosgene in toluene (5.2 ml, 1.94 M) and methylene chloride (25 ml) stirred under N- at 0oC was added dropwise 5-(2-annno-4-nitrophenyl)-3-cyclopropyl-l,2,4-oxadiazol (1.5 g, 16 mmol) in 25 ml dry methylene chloride upon addition of 10 ml of the solution, 1.4 ml triethyl amine (10 mmol) was added. After addition was completed the mixture was stirred ''v Replacement sheet (twice amended) PCT/D:O0/C0232 phate and concentrated vn vacuo. The resulting oil was dissolved in acetone and treated with oxalic acid (0.5 g) in 2 ml acetone to precipitate the desired product. Yield 1.3 g, m.p. 110-113oC.

EXAMPLE fg N-(2-(3-eycl opropyl-1,2,4-oxadi azol-5-yl)-3-methyl phenyl}- 9-tnethyl-9-azabicyclor3.3.nnon-3-vl Vurea To a solution of phosgene in toluene (5.2 ml, 1.9 M) stirred under N, at 0oC was added dropwise a mixture of 5-(l-amino-3-methyl-2- phenyl}-3-cyc,lopropyl-l,2,4-oxadiazoT (0.9 g, 4 irnnol) and 1.4 ml dry triethyVamin in 25 ml dry methylene chloride. Upon addition the mixture was stirred at 0QC for 1 h and at room temperature for 2 h.

The mixture was then dissolved in 25 ml dry methylene and 1,4 ml dry triethyl amine, whereupon a solution of (endo)-3-amino-9-methyl-9- azabicyclo[3.3.1]nonan (1,0 g, 6.5 mrnol) in 10 ml methylene chloride was added. This mixture was stirred at room temperature for 20 h and washed with saturated sodium bicarbonate, water and saturated sodium chloride. Evaporation of the solvent gave after trituration with acetone 1.5 g of the desired product. M.p. 191-1920C.

EXAMPLE N-(2-Isopropoxyiminomethyl)-phertyl)-N 4endo-9- r3.3.11non-3-yT)urea. oxalate .

To a solution of pfrosgene in tolaene (IQ.tml, 1.93 M) and methylene ehloride (50 ml) stirred uhder* N2 at x.

A Replacement sheet (twice amended) PCT/DK50/00232 0oC was added dropwise 2-an)ino-fMsopropoxyinvinoniethylbenzene (1.4 g, 8 mmol) in methylene chloride (50 ml). After addition of 25 ml of this solution 2.8 ml triethylamine was added. Upon addition the mixture was stirred at 00C for 2 h and concentrated in vacuo. The mixture was then dissoTcid in 50 ml dry methylene chloride and 2.8 ml triethyl amine, whereupon (eado)-J-.amino-9-methyT-9-aZabicyclo- [3.3.1]nonane (1.5 g, 10 mrnol) was added. After stirring for 24 h at room temperature the mixture was washed with saturatfed sodiumbicar- bonate, water and saturated sodium chloride, dried over magnesium sulphate and evaporated. After trituration with acetone 1.8 g white crystals was isolated. Some of this product was dissolved in acetone and oxalic acid added to precipitate the desired product. M.p.

133-1340C.

N -(2-Isopropdxyiminomethyl)-phenyl)-N -(endo-S-mstliyl-8-azabicyclb? r3.2.lioct-3v1)urea. oxalate To a solution of phosgene in toluene (10.5 ml, 1.93 M) ana methylene chloride (50 ml) stirred under hL at 00C was added dropwise 2-amtnb*N-isopropoxyiminomethylbenzene (1.4 g, 8 mmol) in methylene chloride (50 ml). After addition of 25 ml of this solution 2.8 ml triethylamine was added* Upon addition the mixture was stirred at 00G for 2 h and concentrated tji vacuo> The mixture was then dissolved in 50 ml dry methylene chl-oride and 2.8 ml triethyl amine, whereupon (endo)-3-amino-8-methyl-8-azabicyclo[3.2.l,]octane (1.4 g, mmol) was added. After stirring for 5 days at room temperature the mixture was washed with saturated sodiumbicarbonate, water and saturated sbdium chloride, dried over magnesium sulphate and evapo¬ rated. The resulting oil was purified by column chromatography (si- SUBSTfTUTE SHSST lica geX; methylene chloride, methanol, concentrated ammonium hydroxide? 80:20:0.5 (v/v/v/)). This product was dissolved in acetone and oxalic acid (300 mg) in ml acetone added to precipitate the desired product.

Yield 1.1 g. M.p. 117-1190C.

IS *3 3 SUBSTITUTE SHEET Beplaceraenc sccfct yl'/utupv/ovts.

2?