NO169440B - ANALOGUE PROCEDURE FOR PREPARING A THERAPEUTIC ACTIVE 1,2,4-OXADIAZOL - Google Patents

Description

The present invention relates to an analogous process for the production of a therapeutically active 1,2,4-oxadiazole with structural formula I

or a salt or prodrug thereof, wherein

- R<2> stands for a substituent with low lipophilicity chosen from H, C^_4 alkyl or NR7R<8> in which R7 and R<8> independently stand for H or C]__2 alkyl, - the dashed line stands for a possible chemical bond, and - the substituents R<3> and R<4> are present in any position including the point of attachment to the oxadiazole ring, where R<3> stands for halogen, C]__4 alkoxy, C2-4 alkyl, cl-4 alkyl substituted with hydroxy or C1_4 alkoxy, or represents methyl or hydroxy in the 3-, 4- or 5-position, and R<4> represents hydrogen, C1_4<a>lkoxy, hydroxy, C1_4 alkyl, or R<3> and R<4> together stand for carbonyl, and the method is characterized in that a reactive derivative of a carboxylic acid with the formula Ra<->CO2H in which Ra is a 1-azabicyclo[2.2.1]heptane ring substituted with R<3> and R<4> having the indicated meanings, is subjected to cycloaddition with a compound of formula HIA or a salt thereof,

wherein R<b> is a group of low lipophilicity as indicated for R2.

These features of the invention appear in the patent claim. The invention thus relates to the production of a class of substituted oxadiazole compounds which stimulate central muscarinic acetylcholine receptors and which are therefore useful in the treatment of neurological and mental diseases whose clinical manifestations are due to cholinergic insufficiency. Such diseases include presenile and senile dementia

known as Alzheimer's disease and senile dementia of the Alzheimer type), Huntington's chorea, tardive dyskinesia, hyperkinesia, mania and Tourette's syndrome. Alzheimer's disease, which is the most common debilitating disease, is a slowly progressive neurological disease characterized by marked deficits in experiential functions including memory, attention, language and visual perception. The compounds produced by the invention are also usable analgesic agents and are therefore usable in the treatment of severe pain conditions such as rheumatism, arthritis and pain of death.

Compounds capable of increasing muscarinic cholinergic transmission in the cortex should be beneficial in reversing the cholinergic insufficiency in Alzheimer's disease and other diseases related to cholinergic dysfunction. However, most muscarinic agonists, including acetylcholine itself, are quaternary ammonium compounds that are unable to penetrate the blood-brain barrier to any clinically significant extent after peripheral (eg, oral) administration. Such agents fail to stimulate the desired central sites, but instead produce unwanted side effects mediated exclusively by peripherally located muscarinic acetylcholine receptors.

The oxadiazol compounds that can be produced by the invention are powerful muscarinic agonists, but as they are tertiary amines with physiochemical properties (lipophilicity and pKa) that agree with CNS permeability, they can stimulate these central sites that are implicated in the neurodegenerative diseases. It is believed that increase of cholinergic transmission of compounds obtained by the invention is achieved either directly by stimulation of postsynaptic receptors, or indirectly by potentiation of acetylcholine release.

EP-A-0261763, which was published on March 30, 1988, describes a class of compounds which include oxadiazoles bearing a certain unsubstituted exo-1-aza-bicyclo2,2,1]heptane substituent, and these compounds are stated to be of potential use in the treatment and/or prophylaxis of dementia in mammals. However, this publication does not describe exo-1-azabicyclo[2,2,1Jheptane-substituted oxadiazoles in which the azabicyclic substituent is itself substituted.

In addition, EP-A-0239309, which was published on September 30, 1987, describes a class of oxadiazole compounds which are said to be potent muscarinic agonists. These oxadiazoles are substituted on one of their ring carbon atoms with a non-aromatic azacyclic or azabicyclic ring system, and substituted on the other ring carbon atom with a substituent of low lipophilicity.

EP-A-0239309 specifically describes 3-[5-(3-amino-1,2,4-oxadiazol)-yl]-1-azabicyclo[2,2,1]heptane, but it should be noted that the azabicyclic group of the latter compound is unsubstituted. Furthermore, EP-A-0239309 describes generic oxadiazoles in which the azabicyclic ring system is a 1-azabicyclo[2,2,1Jheptane ring system, optionally substituted with methyl or hydroxy. Nevertheless, none of the oxadiazole compounds specifically disclosed in EP-A-0239309 exhibits a 1-azabicyclo[2,2,1]heptane substituent which is itself substituted.

In the following, comparative data are given between compounds previously known from EPA 261,763 (Becham) and EPA 239,309 (Merck, Sharp & Dohme) and the compounds that can be prepared by the present invention. Based on these, it can be seen that the previously known compounds have a ratio NMS/OXO-M greater than 100 0, while the compounds that can be prepared by the invention have a ratio below 600.

It is therefore a different biological profile in that instead of being potent muscarinic agonists, they display a strong antagonist activity in relation to partial or weak agonist activity, which is completely unexpected.

The compounds that can be prepared by the invention all have more than one asymmetric center and can therefore exist both as enantiomers and diastereoisomers. In particular, they can exist as exo- and endoisomers.

It is to be understood that salts of the compounds for use in medicine will be non-toxic, pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds of the invention or their non-toxic, pharmaceutically acceptable salts. Acid addition salts can e.g. is formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable, non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

Salts of amine groups can also include quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Such quaternary ammonium derivatives penetrate poorly into the central nervous system and are therefore useful as peripherally selective, muscarinic agents, agents to reduce gastric acid secretion, agents to block the muscarinic effects of acetylcholinesterase inhibitors in the treatment of myasthenia gravis, and as agents to be co-administered with muscarinic agonists in Alzheimer's disease.

It is believed that compounds obtained by the invention which directly stimulate postsynaptic receptors are particularly useful as analgesic agents.

Treatments made possible by the invention include a method of treating Alzheimer's disease, senile dementia of the Alzheimer type, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania or Tourette's syndrome by administering to a patient in need of such treatment an effective amount of one or several of the new compounds.

The invention further enables a method for the treatment of serious, painful conditions (e.g. rheumatism, arthritis and pain of death) which comprises administering to a patient in need of analgesic treatment an effective amount of one or more of the new compounds.

The compounds are prepared as previously indicated by reacting a reactive derivative of a carboxylic acid of the formula Ra<->CO2H, with a compound of the formula HIA or a salt thereof:

wherein Ra is a R<3> and R<4> substituted 1-azabicyclo[2,2,1]-heptane ring, and R<b> is a group of low lipophilicity.

Suitable reactive derivatives of the acid Ra<->CC>2H include esters, e.g. C 1-4 alkyl esters; thioesters, e.g. pyridyl thioesters; acid anhydrides, e.g. (R<a>C0)20; acid halogenides, e.g. acid chlorides, orthoesters and primary, secondary and tertiary amides.

When the compound of formula HIA is used, the reaction product is a 1,2,4-oxadiazole. It should be understood that the compound HIA can also be considered as the alternative

tautomeric form:

A 3-substituted 1,2,4-oxadiazol-5-yl compound is prepared when Ra denotes the azabicycloheptane group, and R° in formula HIA denotes the low lipophilicity substituent. In this case, a preferred reactive derivative of the acid R<a>CC>2H is a C]__4~ alkyl ester. The reaction is conveniently carried out in tetrahydrofuran, dimethylformamide or a lower alkanol, such as ethanol, propanol or isopropanol, at 20-100°C for 1-6 hours.

A 5-substituted 1,2,4-oxadiazol-3-yl compound is prepared by the method according to the invention when Ra denotes the substituent with low lipophilicity, and $ P denotes the azabicycloheptane group. For this reaction, a suitable reactive derivative is the acid chloride or the acid anhydride (R<a>C0)20. The reaction can be carried out by treating the compound HIA under cooling, e.g. from h-5 to +10°C, with the reactive derivative, followed by heating to 80-120°C for 1-6 hours.

In a possible use of a compound of formula IIIb or a salt thereof, the reaction product would be a 1,3,4-oxadiazole.

After the above reaction is completed, one low lipophilicity substituent can be converted to another. For example, an amino group can be converted to chlorine or hydrazo, -NHNH2, via the diazonium intermediate, -N^<+>. Similarly, a chloro substituent can be converted to methoxy by reaction with a nucleophile, such as methoxy; and an alkoxycarbonyl group can be converted via carboxy to an amino substituent, -NH2.

The reactive derivatives of the compound R<a>CO2H can e.g. is prepared by cyclization of a compound of formula IV:

wherein Rs, Rt, Ru and Rv denote hydrogen, carboxylic acid ester or a substituent R<3> or R<4> as defined above, or a group convertible thereto; wherein at least one of Rs, Rfc, Ru and Rv is different from hydrogen; and

R<c> and R^ are hydrocarbon groups, in particular C 1-6 alkyl, such as methyl or ethyl; while forming a compound of formula V:

or a ketal thereof; and optionally converting the carbonyl group in compound V or its ketal, or any of the groups Rs, Rfc, Ru and Rv into a

substituent group R<3> or R<4> or to a -CC^H group or a reactive derivative thereof.

The intermediate products of formula V are new compounds. They provide a valuable synthetic route to substituted 1-azabicyclo[2,2,1]heptanes used in the process according to the invention.

The cyclization of compound IV is carried out in the presence of a strong base, such as potassium t-butoxide, followed by acidification, e.g. with concentrated hydrochloric acid. This reaction causes condensation of the groups CC>2Ra and CO2R<b>. When one of the groups Rs, Rfc, Ru and Rv denotes an ester group, the reaction will release the free acid. To simplify the isolation, it is preferred to esterify the acid in situ, e.g. by treatment with methanol and hydrochloric acid.

The carboxylic acid group and its reactive derivative used to react with the oxadiazole moiety can be formed from any of the substituent groups Rs, Rt, Ru or Rv originally present in compound IV. By choosing such a group as an ester group, the point of attachment to the oxa-diazole can be determined in this way.

Alternatively, the ketone group formed in the intermediate product V can be converted into a carboxylic acid group, e.g. by reaction with an alkali metal cyanide, such as sodium cyanide, to form a compound VI:

The hydroxy group in compound VI can then be converted to a group R<3> or R<4> to form a substituent at the same position as the attachment point of the oxadiazole ring.

In any of the above reactions it may be necessary and/or desirable to protect any sensitive group in the compounds. If e.g. Ra and/or R<b>include amino, carboxy, hydroxy or thiol groups, these can be protected in a conventional manner. Suitable protecting groups for hydroxy groups thus include silyl groups, such as trimethylsilyl or t-butyldimethylsilyl and for ether groups, such as tetrahydropyranyl; and includes for amino groups benzyloxycarbonyl and t-butyloxycarbonyl. Carboxy groups are preferably protected in a reduced form, such as in the form of their corresponding protected alcohols, which can then be oxidized to form the desired carboxy group. Thiol groups can be protected by disulfide formation, either with the thiol itself or with another thiol to form a mixed disulfide. The protecting groups may be removed at any suitable step in the synthesis of the desired compound according to conventional techniques.

The following examples illustrate the preparation of compounds according to the invention. Each of the compounds set forth in the examples exhibits an affinity for the muscarinic receptor, with an IC50 (concentration required to displace 50% of specific [<3>H]-N-methylscopolamine binding from rat cortical membrane preparations) significantly lower than 100 µM. Agonism behavior and central nervous system permeability of the compounds of the examples were determined in a rat behavioral model by measuring the ability of the compound to elicit a mouth movement response and/or a hypothermic response characteristic of centrally acting muscarinic agonists (see Salamone et al., Psychopharm. , 1986 , 8_8 , 467. In this model, all compounds of the examples were active at doses of 10 mg/kg or less.

In the following examples, all temperatures are indicated in °C, THF is tetrahydrofuran, and ether is diethyl ether.

Example 1

Exo-3-[5-(3-methyl-1,2,4-oxadiazol)-yl]-1-azabicyclo-[2,2,1]heptan-3-ol hydrochloride

a) 1-benzyl-3-carbomethoxypyrrolidine

This compound was prepared from 1-benzyl-3-carbomethoxy-5-pyrrolidine by the procedure described by Korner et al., J. Org. Chem. , 1968, 3_3 , 3637.

b) 1-methoxycarbonylmethyl-3-methoxycarbonylpyrrolidine

A solution of 50 g (228 mmol) of 1-benzyl-3-carbomethoxypyrrolidine in 300 ml of methanol was subjected to hydrogenolysis over 6 g of Pd(OH) 2 on a Parr shaker for 7 hours. The suspension was filtered through celite and the solvent removed under vacuum to give 30 g of 3-carbomethoxypyrrolidine as a clear liquid. 29 g (225 mmol) of this amine was added to a rapidly stirred suspension of 64 g of potassium carbonate in 350 ml of xylene at 130°C. After 0.25 h, a solution of 35 g (230 mmol) methyl bromoacetate in 100 mL xylene was added dropwise, and the mixture was heated under reflux for 2 h. The xylene solution was decanted from the inorganic residue which was taken up in 200 ml of water and extracted with 3 x 250 ml of dichloromethane.

The combined organics were dried (sodium sulfate) and evaporated to give 43 g of the title compound as a yellow liquid, 6 (60 MHz, CDCl 3 ), 2.10-3.30 (7 H, m, 3 x CH 2 and 1 x CH); 3.37 (2 H, s, CH2-CO2<M>e) and 3.72

(6 H, s, 2 x CO 2 Me).

c) 1-azabicyclo[2,2,1]heptan-3-one

A solution of 5 g (24.9 mmol) of 1-methoxycarbonylmethyl-3-methoxycarbonylpyrrolidine in 75 ml of toluene was added dropwise over 3 hours to a rapidly stirred solution of 8 g (71 mmol) of potassium t-butoxide in 250 ml toluene at 130°C. The mixture was heated under reflux for 4 hours, was cooled to room temperature, and 75 ml of concentrated hydrochloric acid was added dropwise, and the mixture was stirred for 0.25 hour. The separated toluene solution was extracted with 3 x 50 mL of concentrated hydrochloric acid, and the combined aqueous extracts were heated under reflux for 16 hours. The solvent was reduced to half volume under vacuum, basified to pH above 10 with potassium carbonate and extracted with 6 x 100 ml chloroform. The material isolated from the organic extracts was chromatographed on silica in dichloromethane-methanol (90:10) to give 1.2 g of 1-azabicyclo [2,2,1]heptan-3-one as a yellow oil, 6 (360 MHz , CDCl 3 ), 1.75-1.80 (1 H, m, 0.5 x CH 2 ); 2.06-2.12 (1 H, m, 0.5 x CH 2 ); 2.70-2.81 (4 H, m, 2 x CH2-N), and 3.00-3.12

(3 H, m, CH2-N and CH) .

d) exo-3-carbomethoxy-l-azabicyclo[2,2,1]heptan-3-ol

The hydrochloride salt of 1-azabicyclo[2,2,1]heptan-3-one

was prepared by adding ethereal hydrogen chloride to a solution of the compound in methanol. A solution of 0.7 g (14.3 mmol) of sodium cyanide in 4 ml of water was added dropwise to a solution of 1.7 g (11.5 mmol) of 1-azabicyclo[2,2,1]-heptane-3- on hydrochloride in 5 ml of water at -h5°C. The mixture was stirred at 0°C for 1 hour, and the precipitated cyanohydrin was filtered and washed with cold water. The solid material was taken up in 15 ml of concentrated hydrochloric acid and was stirred for 24 hours at room temperature. The residue obtained after removal of the solvent and drying was dissolved in a saturated solution of hydrogen chloride in methanol (100 ml) and was stirred at room temperature for 16 hours. The solvent was removed under

vacuum, the residue was taken up in 25 ml of water, basified to pH 10 with potassium carbonate and extracted with 8 x 50 ml of dichloromethane. The combined extracts were dried and evaporated to give 1.3 g of the title compound, m/e 171 (M<+>); 6 (360 MHz, CDCl 3 ), 1.39-1.48 (1 H, m, 0.5 x CH 2 ); 2.16-2.21 (1 H, m, 0.5 x CH 2 ); 2.40-2.50 (2H, m, CH2-N); 2.66-2.72 (2 H, m, CH and 0.5 x CH 2 -N); 3.22-3.26 (1 H, m, 0.5 x CH 2 -N); 3.8 3 (3 H, s, CO 2<M>e).

e) exo-3-[5-(3-methyl-1,2,4-oxadiazol)-yl]-1-azabicyclo[2,2,13heptan-3-ol hydrochloride

0.5 g of activated molecular sieves (type 4 A) was added to a stirred solution of 0.4 g (5.4 mmol) of acetamidoxime in 50 ml of anhydrous tetrahydrofuran under nitrogen. After half an hour, sodium hydride (0.14 g of an 80% dispersion in oil, 4.6 mmol) was added and the solution was stirred for another half hour. A solution of 0.4 g (2.34 mmol) of exo-3-carbomethoxy-1-azabicyclo[2,2,1]heptan-3-ol in 20 mL of tetrahydrofuran was then added, and the mixture was stirred under reflux for 2 hours. The mixture was cooled to room temperature, 20 ml of water was added and extracted with 5 x 100 ml of dichloromethane. The combined extracts were dried (sodium sulfate), the solvent was evaporated and the residue chromatographed through alumina using dichloromethane-methanol (95:5) as eluent to give 0.2 g of the title oxadiazole as a crystalline solid. The product was further purified as the hydrochloride salt, m.p. 225-227°C (isopropanol). (Found: C, 46.33; H, 6.07; N, 17.81, CgH^^C^. HCl requires C, 46.65; H, 6.05; N, 18.14%); m/e 195 (M<+> for free base); 6 (360 MHz, CDCl 3 ), 1.46-1.56 (1 H, m, 0.5 x CH 2 ); 2.12-2.24 (1 H, m, 0.5 x CH 2 ); 2.45 (3H, s, Me); 3.26-3.34 (1 H, m, 0.5 x CH 2 -N); 3.35 (1 H, d, J = 4.75 Hz, CH bridgehead); 3.44-3.60 (2H, m, 2 x 0.5 x CH 2 -N); 3.75 (1 H, dd, J = 2.8 and 13 Hz, 0.5 x CH 2 -N); 3.88-3.90 (1 H, m, 0.5 x CH 2 -N); 4.1 (1 H, dd, J = 2.48 and 13 Hz, 0.5 x CH2~N).

Example 2

3-[ 5-( 3- methyl- 1, 2, 4- oxadiazol)-yl]- 1- azabicyclo[ 2, 2, 1]-heptan- 5-ols

a) trans-3,4-dicarbomethoxypyrrolidine

This compound was prepared from glycine by the procedure described by Joucla et al. (J. Chem. Soc., Chem. Commun., 1985, 1566).

b) 1-methoxycarbonylmethyl-trans-3,4-dicarbomethoxypyrrolidine

A solution of 4.1 g (22 mmol) of trans-3,4-dicarbomethoxypyrrolidine in 30 ml of xylene was added to a rapidly stirred suspension of 7 g of potassium carbonate in 150 ml of xylene at 120°C. After 0.25 h, a solution of 3.45 g (22.5 mmol) methyl bromoacetate in 30 mL xylene was added dropwise, and the mixture was stirred and heated under reflux for 2 h. The solution was then decanted from the inorganic residue which was taken up in 100 ml of water and extracted with 3 x 150 ml of dichloromethane. The combined organic extracts were dried (sodium sulfate) and evaporated to give the title compound as 6 g of a yellow liquid; 6 (3 60 MHz, CDCl 3 ), 2.96-3.11 (4 H, m, 2 x CH 2 -N); 3.34 (2 H, ABg, J = 16.5 Hz, CH 2 -CO 2 Me); 3.46-3.52 (2H, m, 2xCH) and 3.74

(9 H, s, 3 x CO 2 Me).

c) 3-carbomethoxy-5,5-dimethoxy-1-azabicyclo[2,2,1]-heptane

A solution of 5 g (19.31 mmol) of 1-methoxycarbonylmethyl-trans-3,4-dicarbomethoxypyrrolidine in 75 ml of toluene was added dropwise over 3 hours to a rapidly stirred solution of 9 g (80 mmol) of potassium t- butoxide in 250 ml of toluene at 130°C. The mixture was heated under reflux for 4 hours, was cooled to room temperature, and 75 ml of concentrated hydrochloric acid was added dropwise, and the mixture was stirred for 0.25 hour. The separated organic phase was extracted with 3 x 50 ml of concentrated hydrochloric acid, and the combined aqueous extracts were heated under reflux for 16 hours. The solvent was removed in vacuo, the residue was dried and taken up in 150 ml of a saturated solution of sodium chloride in methanol. The mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, 50 mL of water was added, and the solution was basified to pH 10 with potassium carbonate. The solution was extracted with 5 x 150 mL of dichloromethane, and the combined organic extracts were dried (sodium sulfate) and evaporated. The residue was purified by chromatography on silica gel in dichloromethane-methanol (93:7) to give 0.5 g of the title azanorborane as a yellow liquid, and as a single isomer, 6 (360 MHz, CDCl 3 ), 2.44

(1 H, dd, J = 9.8, 3 Hz, 0.5 x CH 2 ); 2.63 (1 H, dd, J = 12.7, 3 Hz, 0.5 x CH 2 ); 2.77 (1 H, d, J = 12.7 Hz, 0.5 x CH 2 ); 2.80-3.10 (5 H, m, 2 x CH and 1.5 x CH 2 ); 3.11 (3H, s, OMe); 3.2 4 (3 H, s, OMe); 3.71 (3H, s, CO 2 Me).

d) 3-[5-(3-methyl-1,2,4-oxadiazol)-yl]-5,5-dimethoxy-1-azabicyclo[2,2,1]heptane 1 g activated molecular sieves (type 4 A) was added to a stirred solution of 0.6 g (8.1 mmol) of acetamidoxime in 50 ml of anhydrous tetrahydrofuran under nitrogen. After half an hour sodium hydride (0.2 g of an 80% dispersion in oil, 6.7 mmol) was added and the solution was stirred for another half hour. A solution of 0.5 g (2.3 mmol) of exo-3-carbomethoxy-5,5-dimethoxy-1-azabicyclo[2,2,1]heptane in 20 mL of tetrahydrofuran was then added, and the mixture was heated under reflux for 6 hours. The mixture was cooled to room temperature, diluted with 15 ml of water and extracted with 5 x 100 ml of dichloromethane. The combined extracts were dried (sodium sulfate), the solvent was evaporated and the residue chromatographed through silica gel using dichloromethane-methanol (95:5) as eluent to give 0.26 g of a clear oil, 6 (360 MHz, CDCl 3 ), 2.38 (3H, s, Me); 2.43 (1 H, dd, J = 12.7, 3 Hz, 0.5 x CH 2 ); 2.73 (1 H, dd, J = 10, 3.2 Hz, 0.5 x CH 2 ); 2.95 (1 H, d, J = 12.8 Hz, 0.5 x CH 2 ); 2.99 (1H, s, CH); 3.10 (1 H, d, J = 12.8 Hz, 0.5 x CH 2 ); 3.07-3.22 (2H, m, CH2); 3.22 (3H, s, OMe); 3.27 (3H, s, OMe); 3.47-3.50 (1H, m, CH).

Example 3

Exo-3-[5-(3-amino-1,2,4-oxadiazol)-yl]-1-azabicyclo[2,2,1]-heptan-5-ol

a) 3-[5-(3-amino-1,2,4-oxadiazol)-yl]-5,5-dimethoxy-1-azabicyclo[2,2,1]heptane

0.75 g (32.6 mmol) of sodium was divided into small pieces and added to a stirred mixture of 2.47 g (9.30 mmol) of hydroxyguanidine sulfate in 60 ml of methanol (dried over molecular sieves). After 0.25 h, a solution of 1 g (4.65 mmol) of 3-carbomethoxy-5,5-dimethoxy-1-azabicyclo[2,2,1]heptane in 5 ml of methanol was added, and the solution was heated to 80 °C i

2 hours.

The reaction mixture was decanted from the molecular sieves, the solvent was removed under vacuum, and the residue was taken up in 10 ml of water. Extraction in 4 x 100 ml dichloromethane, drying (Na 2 SO 4 ) and removal of the solvent under vacuum was followed by chromatography through alumina (grade II/III) using dichloromethane/methanol (98:2) as eluent to give 0.26 g of the aminooxadiazole title product; m/e 240 (M<+>)<+>, 225 (<+>M-CH 3 ); 6 (360 MHz, CDCl 3 ), 2.41 (1 H, dd, J = 13 Hz and 3.2 Hz, CH of CH 2 ); 2.73 (1 H, dd, J = 10 Hz and 3.3 Hz, CH of CH 2 ); 2.91-3.19 (5 H, m, 2 x CH 2 and CH); 3.21 (3H, s, OMe); 3.26 (3H, s, OMe); 3.35-3.68 (1 H, m, CH-oxadiazole); 4.36 (2 H, br s, NH 2 ).

Example 5

Exo- 5-[( 3- methyl- 1, 2, 4- oxadiazol)- yl]- 3- methoxymethyl- 1-azabicyclo[ 2, 2, 1] heptanesesquioxalate

a) 3- hydroxymethyl- 5, 5- dimethoxy- 1- azabicyclo[ 2, 2, 1]-heptane

A solution of 4.19 g (19.5 mmol) of 3-carbomethoxy-5,5-dimethoxy-1-azabicyclo[2,2,1]heptane in 40 ml of anhydrous THF was added dropwise with stirring to a solution of lithium aluminum hydride ( 19.5 mL of a 1 M solution in THF, 19.5 mmol) in 50 mL THF at 5°C. Stirring at 5°C for 1 hour was followed by stirring at room temperature for 1 hour. 3 ml of water and 1 ml of 2 N sodium hydroxide were added and the reaction mixture was filtered through hyflo filter aid. The filter pad was washed with 200 ml of dichloromethane, the combined organics were dried (Na 2 SO 4 ) and evaporated to give 2.83 g of 3-hydroxymethyl-5,5-dimethoxy-1-azabicyclo[2,2,1]heptane, m.p. p. 151-153°C (ethyl acetate).

(Found: C, 57.54; H, 9.04; N, 7.30, C9<H>17<N>03 requires C, 57.73; H, 9.15; N, 7.48%) ; 6 (360 MHz, CDCl 3 ), 2.20-2.27

(1 H, m, CH of CH2); 2.38 (1 H, dd, J = 9 Hz and 2.4 Hz, CH of CH 2 ); 2.39-2.45 (1 H, m, CH of CH 2 ); 2.48 (1 H, dd, J = 13 Hz and 3.2 Hz, CH of CH 2 ); 2.78 (1 H, d, J = 4.0 Hz, CH bridgehead); 2.87 (1 H, dd, J = 13 Hz and 1.7 Hz, CH of CH 2 ); 2.95 (1 H, dd, J = 9.6 Hz and 2.3 Hz, CH of CH 2 ); 3.02-3.09 (1H, m, CH); 3.24 (3H, s, OMe); 3.26 (3H, s, OMe); 3.65-3.82 (2H, m, CH2-OH).

b) 3-Methoxymethyl-l-azabicyclo[2,2,1]heptan-5-one

0.69 g (4.3 mmol) of diethylaminosulfur trifluoride was

added dropwise to a stirred solution of 0.80 g (4.3 mmol) of 3-hydroxymethyl-5,5~dimethoxy-1-azabicyclo[2,2,1Jheptane in 40 ml of dichloromethane at +-78°C. After 1 hour, the reaction mixture was warmed to room temperature and stirred

16 hours. 10 ml of water and 100 ml of dichloromethane were added and the aqueous layer was made basic with potassium carbonate. Extraction into 3 x 100 ml dichloromethane, drying (Na 2 SO 4 ) and evaporation of the solvent was followed by chromatography of the residue through silica gel using dichloromethane/methanol (93:7) as eluent to give 0.23 g of the title ketone as an orange oil; 6 (360 MHz, CDCl 3 ) 2.38-2.46 (1 H, m, CH of CH 2 ); 2.64-3.02 (6 H, m, 2 x CH 2 , CH of CH 2 and CH bridgehead); 3.30 (3H, s, OMe); 3.2 6-3.66 (3 H, m, CH 2 -OMe and CH). c) 5 - ( 1, 3- dithian- 2- ylidene)- 3- methoxymethyl- l-aza bicyclo[ 2, 2, 1jheptane n-Butyllithium (2.03 mL of a 1.6 M solution in hexane, 3.25 mmol) was added to a solution of 0.68 g (3.54 mmol) of 2-trimethylsilyl-1,3-propanedithiane in 50 ml of anhydrous THF at +35°C, and the solution was stirred for 2 hours. A solution of 0.42 g (2.71 mmol) of 3-methoxymethyl-1-azabicyclo[2,2,1]-heptan-5-one in 5 mL of THF was added, and the reaction mixture was warmed to room temperature and stirred in 1 hour. 6 ml of water was added, followed by 100 ml of dichloromethane, and the mixture was stirred for 0.1 hour. Chromatography of the residue after extraction into 3 x 100 ml dichloromethane, drying (Na2-SO4) and evaporation of the solvent through silica gel, using dichloromethane/methanol (91:9) as eluent, gave 5-(1,3-dithian-2 -ylidene)-3-methoxymethyl-1-azabicyclo[2,2,1]heptane (0.53 g); m/e 157 (M<+>); 6 (360 MHz, CDCl 3 ), 1.96-2.20 (4 H, m, 2 x CH 2 ); 2.30-3.20 (10 H, m, 4 x CH2 and 2 x CH); 3.32 (3H, s, OMe); 3.40-3.54 (2H, m, CH 2 -OMe).

d) 5-carbomethoxy-3-methoxymethyl-1-azabicyclo[2,2,1]-heptane

0.53 g (2.06 mmol) of the preceding dithioketene acetal was dissolved in methanol (saturated with hydrogen chloride) (45 ml) and was stirred at 55°C for 24 hours. The solvent was removed under vacuum, the residue was taken up in 6 ml of water and basified with potassium carbonate. The aqueous layer was extracted into 4 x 70 mL dichloromethane, dried (Na 2 SO 4 ), and the solvents were removed in vacuo. The resulting residue was purified by chromatography through alumina (grade II/III) using dichloromethane/methanol (99:1) as eluent to give 0.26 g of the title ester as an orange oil, m/e 199 (M<+ >); 6 (360 MHz, CDCl 3 ), 1.92-1.98 (1 H, m, CH); 2.29-2.86 (5 H, m, 2 x CH 2 and CH); 2.87 (1 H, d, J = 4 Hz, CH bridgehead); 2.95-3.08 (2H, m, CH2); 3.35 (3H, s, OMe); 3.29-3.42 (2H, m, CH 2 -OMe); 3.68 (3H, s, CO 2 Me).

e) exo-5-[5-(3-methyl-1,2,4-oxadiazol)-yl]-3-methoxymethyl-1-azabicyclo[2,2,1]heptanesesquioxalate

Sodium hydride (78.4 mg of an 80% dispersion in oil, 2.61 mmol) was added to a stirred solution of 0.22 g (2.90 mmol) of methylamidoxime in 70 mL of anhydrous THF in the presence of 1 g of molecular sieves. The reaction mixture was stirred at 75°C i

0.25 hour before adding a solution of 0.26 g (1.31 mmol) of 5-carbomethoxy-3-methoxymethyl-1-azabicyclo[2,2,1jheptane in 5 ml of THF and refluxing for 1, 5 hours. The reaction mixture was cooled to room temperature and 15 ml of water and 100 ml of dichloromethane were added. The aqueous layer was extracted with 4 x 100 mL dichloromethane, the combined extracts were dried (Na 2 SO 4 ) and evaporated, and the residue was chromatographed through alumina using dichloromethane-methanol (99:1) as eluent to form the title oxadiazole. The compound was further purified as the sesqui-oxalate salt, m.p. 122.5-124.5°C (dichloromethane/ether).

(Found: C, 46.65 ; H, 5.67; N, 11.14, C11<H>17N302•1.6 (C02H)2 requires C, 46.41; H, 5.56; N, 11 .44%); 6 (360 MHz, D 2 O), 2.38 (3 H, s, Me); 2.75-3.10 (2H, m, CH2); 3.20-3.30 (2 H, rn, 2 x CH); 3.40 (3H, s, OMe); 3.53-3.91 (6 H, m, 3 x CH 2 );

3, 90-3, 96 (1H, m, CH-oxadiazole).

Example 6

Exo-5-[5-(3-methyl-1,2,4-oxadiazol)-yl 3-3-methyl-1-azabicyclo[2,2,1]heptane hydrochloride

a) 3-methyl-5,5-dimethoxy-l-azabicyclo[2,2,1]heptane n-butyllithium (2.21 ml of a 2.5 M solution in

hexane, 5.53 mmol) was added to a solution of 0.94 g (5.03 mmol) of 3-hydroxymethyl-5,5-dimethoxy-1-azabicyclo-[2,2,1]-heptane in 50 mL of THF at 0°C and was stirred for 1 hour. 1.53 ml (10.05 mmol) of tetramethylphosphoramidine acid chloride was added to the reaction mixture, and this was stirred at room temperature for 1.5 hours. Removal of the solvent under vacuum was followed by chromatography through alumina using dichloromethane/methanol (99:1) as eluent, under

formation of 1.4 g of the desired 3-tetramethylphosphoramidate, 6 (360 MHz, CDCl 3 ), 2.25-2.73 (6 H, m, 2 x CH 2 and 2 x CH);

2.62 (6H, s, NMe); 2.66 (6H, s, NMe); 2.89-3.00 (1 H, m, 0.5 x CH 2 ); 3.18 (6H, s, OMe); 3.20-3.27 (1H, m, 0.5 x C<H>2)<;> 4.05-4.30 (2H, rn, CH2-O) .

0.31 g (43.6 mmol) of lithium metal was added to 50 ml of freshly distilled ethylamine and stirred at 0°C until the metal had dissolved. A solution of 0.97 g (13.1 mmol) of t-butyl alcohol and 1.4 g (4.36 mmol) of the preceding phosphoramidate in 10 mL of anhydrous THF was added to the reaction mixture at such a rate that the blue color was maintained . After stirring for half an hour, the reaction was quenched by careful addition of 50 mL of water, the mixture was extracted into 4 x 100 mL of dichloromethane, dried (Na 2 SO 4 ), and the solvent was evaporated. Chromatography through alumina (grade II/III) and elution with dichloromethane/methanol (97.5:2.5) gave 0.55 g of 3-methyl-5,5-dimethoxy-1-azabicyclo[2,2,1]heptane as a colorless oil;

m/e 171 (M<+>); 6 (360 MHz, CDCl 3 ), 1.30 (3 H, d, J = 7.3 Hz, MeCH); 1.98-2.04 (1H, m, CH); 2.37 (1 H, dd, J = 12.5 Hz and 3.3 Hz, 0.5 x CH 2 ); 2.4 3 (1 H, dd, J = 9.3 Hz and 3.7 Hz, 0.5 x CH 2 ); 2.49 (1 H, d, J = 3.7 Hz, CH bridgehead); 2.63-2.70

(2H, m, CH2); 2.91 (1 H, dd, J = 9.4 Hz and 2 Hz, 0.5 x CH 2 ); 2.95 (1 H, d, J = 11 Hz, 0.5 x CH 2 ); 3.18 (3H, s, OMe); 3.20 (3H, s, OMe).

b) 3-methyl-l-azabicyclo[2,2,1]heptan-5-one A solution of 0.55 g (3.22 mmol) 3-methyl-5,5-dimethoxy-l-azabicyclo[2, 2.1 Jheptane in 3 ml of perchloric acid was stirred for 1 hour at room temperature. 40 mL of dichloromethane was added, followed by 10 mL of water, and the aqueous layer was basified with sodium carbonate. The aqueous layer was extracted with 4 x 40 mL of dichloromethane, the combined extracts were dried (Na 2 SO 4 ), and the solvent was removed in vacuo to give 0.35 g of the title ketone, m/e

125 (M<+>); 6 (360 MHz, CDCl 3 ), 1.05 (3 H, d, J = 7 Hz, Me-CH); 2.13-2.18 (1H, m, CH); 2.60-2.70 (2 H, m, CH and 0.5 x CH 2 ); 2.74 (1 H, dd, J = 17.5 and 4.3 Hz, 0.5 x CH 2 ); 2.87

(1 H, dd, J = 10.4 and 4.3 Hz, 0.5 x CH 2 ); 3.03 (1 H, dd, J = 10.4 and 2.6 Hz, 0.5 x CH 2 ); 3.09 (1 H, d, J = 17.5 Hz, 0.5 x CH 2 ); 3.33-3.39 (1 H, m, 0.5 x CH 2 ).

c) 3- methyl- 5-( 1, 3- dithian- 2- ylidene)- 1- azabicyclo-[ 2, 2, 1] heptane

This compound was prepared by the procedure described in Example 5, part c. A solution of 0.35 g (2.80 mmol) of 3-methyl-1-azabicyclo[2,2,1]heptan-5-one in THF gave treatment with 2-trimethylsilyl-2-lithio-1,3-propane-dithiane 0.44 g of the title product after chromatography through alumina using dichloromethane/methanol (97:3) as eluent; m/e 227 (M<+>); 6 (360 MHz, CDCl3), 0.96

(3 H, d, J = 7 Hz, Me-CH); 2.12-2.70 (4 H, m, 1.5 x CH2 and CH); 2.50-3.50 (10 H, m, CH and 4.5 x CH2) .

d) 3-methyl-5-carbomethoxy-1-azabicyclo[2,2,1jheptane

This compound was produced by the procedure

described in Example 5, part d. Treatment of 0.44 g (4.41 mmol) of the preceding dithioketene acetal with methanol (saturated with hydrogen chloride) (30 ml) gave, after chromatography over alumina and elution with dichloromethane, 0.14 g of the title ester as a light yellow liquid, m/e 169 (M<+>); 6 (360 MHz, CDCl 3 ), 0.93 (3 H, d, J = 7 Hz, He-CH); 1.75-1.80 (2 H, m, CH and 0.5 x CH 2 ); 2.48-3.06 (7 H, m, 2 x CH and 2.5 x CH 2 ); 3.68 (3H, s, Me).

e) exo-5-[5-(3-methyl-1,2,4-oxadiazol)-yl]-3-methyl-1-azabicyclo[2,2,1]heptane hydrochloride

This compound was prepared by the procedure described in Example 5, part e. 0.14 g (0.83 mmol) of 3-methyl-5-carbomethoxy-1-azabicyclo[2,2,1jheptane gave 40 g of the title oxadiazole after chromatography through silica gel using dichloromethane/methanol (93:7) as eluent and after treatment with ethereal hydrogen chloride, m.p. 175-177°C (isopropyl alcohol). (Found: C, 51.81; H, 6.99; N, 17.73, <C>10<H>15N3O.HCl.0.15 H20 requires C, 51.68; H, 7.02; N , 18.09%); m/e 193 (M+ of free base); 6 (360 MHz, CDCl 3 ), 1.25 (3 H, d, J = 6.7 Hz, Me-CH); 2.41 (3H, s, Me); 2.75-2.84 (2 H, m, CH and 0.5 x CH 2 ); 3.24 (1 H, bd, J =

3.5 Hz, CH bridgehead); 3.42 (1 H, d, J = 10 Hz, 0.5 x CH 2 ); 3.46 (1 H, d, J = 10 Hz, 0.5 x CH 2 ); 3.70-3.88 (3 H, m, CH 2 and 0.5 x CH 2 ); 4.04 (1 H, dd, J = 8.5 and 5.5 Hz, CH-oxadiazole).

Example 7

Exo-3-[5-(3-methyl-1,2,4-oxadiazol)-yl]-4-methyl-1-azabicyclo[2,2,1jheptane. Hydrochloride and endo-3-[5-(3-methyl-1,2,4-oxadiazol)-yl]-4-methyl-1-azabicyclo[2,2,1]heptane. Hydrochloride

a) 4-methyl-1-azabicyclo[2,2,1]heptan-3-one'

A solution of 14 g (65 mmol) of 1-carbomethoxymethyl-3-methyl-3-carbomethoxypyrrolidine in 150 ml of toluene was added over 0.75 hour to a rapidly stirred solution of 24 g (21 mmol) of potassium t-butoxide in 750 ml of toluene at 140°C for 4 hours, was cooled to room temperature, and 250 ml of concentrated hydrochloric acid was added. The aqueous layer was separated and the organic extracted with three additional portions of hydrochloric acid (3 x 150 mL). The combined aqueous layers were heated to 110°C for 8 hours, the water was removed to half volume, basified with potassium carbonate and extracted with 4 x 250 mL of dichloromethane. The combined extracts were dried (Na 2 SO 4 ), evaporated and the residue chromatographed through alumina using dichloromethane/methanol (98:2) as eluent to give 4 g of the title ketone as a colorless oil. The product was characterized as the hydrochloride salt, m.p. 243-245°C (isopropyl alcohol). (Found: C, 51.87; H, 7.24; N, 8.68, C7H11NO.HCl requires C, 52.02; H, 7.48; N, 8.67%); m/e 126 (M + H)<+>; 6 (360 MHz, CDCl 3 ), 1.35 (3 H, s, Me); 1.98-2.06 (1 H, m, CH of CH 2 ); 2.29-2.38 (1 H, m, CH of CH 2 ); 3.18-3.62 (3 H, m, CH 2 and CH of CH 2 ); 3.7 9-3.92 (2H, m, CH2); 4.06 (1 H, dd, J = 2.7 and 17 Hz, CH of CH2).

b) 3-(1,3-dithian-2-ylidene-)-4-methyl-i-azabicyclo-[2,2,1]heptane

n-Butyllithium (20 mL of a 1.6 M solution in hexane, 32.2 mmol) was added to a stirred solution of 4.69 g (24.3 mmol) of 2-trimethylsilyl-1,3-dithiane in 150 mL anhydrous THF at -r50°C. After 2 hours a solution of 2.54 g

(20 mmol) of 4-methyl-1-azabicyclo[2,2,1]heptan-3-one in 10 mL of THF was added, and the reaction mixture was warmed to room temperature. Aqueous work-up and extraction into dichloromethane gave the crude product which was chromatographed through silica gel using dichloromethane/methanol (93:7) as eluent to give 1.06 g of the title compound as a low melting solid, m.p. 48-49°C, m/e 227 (M<+>); 6 (360 MHz, CDCl 3 ), 1.64 (3 H, s, Me);

1.64-1.91 (2H, m, CH2); 2.08-2.15 (2H, m, CH2); 2.38 (1 H, dd, J.= 3.45 and 9.2 Hz, CH of CH 2 ); 2.58-3.20 (7 H, m, 3 of CH 2 and CH of CH 2 ); 3.24 (1 H, dd, J = 3.5 and 16 Hz, CH of CH 2 ); 3.57 (1 H, d, J = 16 Hz, CH of CH2).

c) 3-carbomethoxy-4-methyl-1-azabicyclo[2,2,1Heptane

1.7 g (7.5 mmol) of the preceding dithioketene acetal

was dissolved in methanol (saturated with hydrogen chloride, 100 ml) and was stirred at 65°C for 4 hours. The solvent was removed under vacuum, 20 mL of water was added, and the solution was basified to pH 10 with potassium carbonate. The aqueous layer was extracted into 4 x 150 ml of dichloromethane, was dried (Na 2 SO 4 ), and the remaining residue, after removal of the solvents under vacuum, was chromatographed through alumina using dichloromethane/methanol (99:1) as eluent, giving 0.82 g of the title ester as a pale yellow oil; 6 (360 MHz, CDCl 3 ), 1.22 (3 H, s, Me); 1.23-1.27 (1 H, m, CH of CH 2 ); 1.43-1.52 (1 H, m, CH of CH 2 ); 2.12-2.15 (1 H, m, CH of CH 2 ); 2.23-2.26 (1 H, m, CH of CH 2 ); 2.72-2.82 (2H, m, CH2); 2.93-3.07 (2H, m, CH2); 3.16-3.21 (1 H, m, CH of CH 2 ); 3.68 (3H, s, CO 2 Me).

d) exo-3-[5-(3-methyl-1,2,4-oxadiazol)-yl]-4-methyl-1-azabicyclo[2,2,1]heptane. Hydrochloride and endo-3-[5-(3-methyl-1,2,4-oxadiazol)-yl 3-4-methyl-1-azabicyclo[2,2,1]heptane. Hydrochloride

Sodium hydride (0.36 g of an 80% dispersion in oil, 12.1 mmol) was added to a stirred solution of 50 mL of methylamidoxime in THF, in the presence of molecular sieves (4 A), and the reaction mixture was heated to 70°C in 0.25 hour. A solution of 0.82 g (4.85 mmol) of 3-carbomethoxy-4-methyl-1-azabicyclo[2,2,1]heptane in 15 mL of THF was then added, and the mixture was heated to 70°C for 1 .5 hours. 15 mL of water was added, followed by 150 mL of dichloromethane, and the aqueous layer was separated and extracted with 4.75 mL of dichloromethane. The combined extracts were dried (Na2SO4) and evaporated and the residue chromatographed through alumina using dichloromethane/methanol (100-99:1) as eluent to give the title compounds. The mixture of products was further chromatographed through silica gel using dichloromethane/methanol (95:5) as eluent to form two separated components.

The less polar compound was identified as exoisomers. (0.29 g) and was further purified as hydrochloride salts, m.p. 226-227°C (isopropyl alcohol). (Found: C, 52.15; H, 6.89; N, 18.08, C10H15<N>3O.HCl requires C, 52.29; H, 7.02; N, 18.29%); 5 (360 MHz, D 2 O), 1.13 (3 H, s, Me); 2.09-2.18 (2H, m, CH2); 2.42 (3H, s, Me); 3.23 (1 H, d, J = 10 Hz, CH of CH 2 ); 3.45-3.52 (2H, m, CH2); 3.62-3.70

(1 H, m, CH of CH2); 3.75-3.79 (1 H, m, CH of CH 2 ); 3.82-3.89 (1 H, CH of CH 2 ); 3.91-3.97 (1 H, m, CH-oxadiazole).

The more polar compound was identified as the second title compound and was characterized as the hydrochloride salt, m.p. 196-197°C (isopropyl alcohol). (Found: C, 51.51; K, 7.18; N, 17.96, C10<H>15<N>3O.HCl.0.2 H20 requires C, 51.48; H, 7.09; N, 18.01%)'; 6 (360 MHz, D 2 O), 1.50 (3 H, s, Me); 1.67-1.76 (1 H, m, CH of CH 2 ); 1.86-1.95 (1 H, m, CH of CH 2 ); 2.43 (3H, s, Me); 3.35 (1 H, dd, J = 2.5 and 9.2 Hz, CH of CH 2 ); 3.45-3.53 (2H, m, CH2); 3.62-3.67 (1 H, m, CH of CH 2 ); 3.30-3.84 (1 H, m, CH-oxadiazole); 3.91-4.06 (2H, m, CH2).

Example 8

Sxo-3-[5-(3-dimethylamino-1,2,4-oxadiazol)-yl]-1-azabicyclo[2,2,1]heptan-5-ol

a) exo-3-[5-(3-dimethylamino-1,2,4-oxadiazol)-yl]-5,5-dimethoxy-1-azabicyclo[2,2,1]heptane

Exo-3-[5-(3-dimethylamino-1,2,4-oxadiazol)-yl]-5,5-dimethoxy-1-azabicyclo[2,2,1jheptane was prepared from 2.73 g (13 mmol) 3-carbomethoxy-5,5-dimethoxy-1-azabicyclo[2,2,1]-heptane and 4.35 g (31 mmol) of dimethylhydroxyguanidine hydrochloride by the procedure described in Example 2, part d. The impure product was chromatographed through silica gel and eluted with dichloromethane/methanol (95:5) to give the dimethyl-aminocoxadiazole title product as 2.94 g of a water-melting solid, 6 (250 MHz, CDCl 3 ), 2.40 (1 H, dd , J = 3 and 18 Hz, CH of CH2); 2.75 (1 H, dd, J = 3 and 10 Hz, CH of CH 2 ); 2.93 (1 H, d, J = 18 Hz, CH of CH 2 ); 2.9 6 (1 H, s, bridgehead-H); 2.97 (1 H, d, J = 13 Hz, CH of CH 2 ); 2.99 (6H, s, NMe); 3.04-3.15 (2H, m, CH2); 3.21 (3H, s, OMe); 3.26 (3H, s, OMe); 3.32-3.37 (1 H, m, CH-oxadiazole).

b) exo-3-[5-(3-dimethylamino-1,2,4-oxadiazol)-yl]-1-azabicyclo[2,2,1]heptan-5-one

Deketalization of 0.5 g (1.87 mmol) of the preceding ketal was obtained using 17 mL of perchloric acid using the procedure described in Example 2, part e. The crude product was chromatographed through silica gel using dichloromethane/methanol (95:5) as eluent, yielding 0.37 g of the title ketone; 6 (250 MHz, CDCl 3 ), 2.88 (1 H, dd, J = 4.1 and 17.9 Hz, CH of CH 2 ); 3.00 (6H, s, NMe); 3.09-3.46 (7 H, m, 2 of CH 2 , CH of CH 2 CH-oxadiazole and CH bridgehead).

c) exo-3-[5-(3-dimethylamino-1,2,4-oxadiazol)-yl]-1-azabicyclo[2,2,1]heptan-5-ol

0.035 g (0.92 mmol) of sodium borohydride was added to a solution of 0.11 g (0.046 mmol) of the preceding ketone in 10 ml of ethanol at 0°C and stirred for 0.20 h. The reaction mixture was warmed to room temperature, stirred for 0.1 h, 0.2 g (3.7 mmol) of sodium methoxide was added, and the solution was stirred for 1.5 h. The solvent was removed under vacuum, 20 mL of water was added, and the solution was extracted with 5 x 50 mL of ethyl acetate. The combined extracts were dried (Na 2 SO 4 ) and evaporated to give the crude product which was recrystallized from ethyl acetate to give 55 mg of the title compound as a white crystalline solid, m.p. 149-150°C; 6 (360 MHz, CDCl 3 ), 1.88 (1 H, br s, OH); 2.12-2.17 (1 H, m, CH of CH 2 ); 2.63 (1 H, d, J = 10.3 Hz, CH of CH 2 ); 2.81 (1 H, dd, J = 3.5 and 10.3 Hz, CH of CH 2 ); 2.91 (1 H, d, J = 4.1 Hz, CH bridgehead); 3.00 (6H, s, NMe); 3.07-3.25 (3 H, m, CH 2 and CH of CH 2 ); 3.74 (1 H, dd, J = 5.3 and 8.3 Hz, CH-oxadiazole); 4.47-4.52 (1H, m, CH-OH).

Claims (1)

Analogous process for the preparation of a therapeutically active 1,2,4-oxadiazole with structural formula (I): or a salt or prodrug thereof, wherein - R represents a low lipophilicity substituent selected from H, <C>x_4 alkyl or NR<7>R<8> wherein R<7> and R<8> independently represent H or C1_ 2 alkyl, - the dashed line represents a possible chemical bond, and - the substituents R<3> and R<4> are present in any position including the point of attachment to the oxadiazole ring, with R<3> standing for halogen, Ci_4 alkoxy, C2-4 alkyl, Cl-4 alkyl substituted by hydroxy or C]__4 alkoxy, or represents methyl or hydroxy in the 3-, 4- or 5-position, and R<4> represents hydrogen, C]__4 Alkoxy, hydroxy, C]__4 alkyl, or R<3> and R<4> together stand for carbonyl, characterized in that a reactive derivative of a carboxylic acid with the formula Ra-CC>2H in which Ra is a 1-azabicyclo [2. 2 .1] heptane substituted with R<3> and R<4> with the indicated meanings, is subjected to cycloaddition with a compound of formula HIA or a salt thereof, wherein R<b> is a group of low lipophilicity as indicated for R2 .