AU619731B2

AU619731B2 - Enantiomers of absolute configurations of amide derivatives of 3-aminoquinuclidine, the process for preparing them and their application in therapy

Info

Publication number: AU619731B2
Application number: AU11230/88A
Authority: AU
Inventors: Nicole Dorme; Michel Langlois; Alain Renaud
Original assignee: Delalande SA
Current assignee: Synthelabo SA
Priority date: 1987-02-04
Filing date: 1988-02-03
Publication date: 1992-02-06
Anticipated expiration: 2008-02-03
Also published as: AU1123088A; DE280603T1; JPH0681754B2; EP0280603A1; JPS63196583A; FR2610323B1; ES2009718A4; ZA88723B; FR2610323A1

Description

I

61973or1o COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPI IFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name of Applicant: Ad ss Applicant Address of Applicant: DELALANDE S.A.

Actual Inventor: Address for Service: 32, rue Henri Regnault, 92400 Courbevoie, France NICOLE DORME, ALAIN RENAUD and MICHEL LANGLOIS EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

V Complete Specification for the invention entitled: ENANTIOMERS OF ABSOLUTE CONFIGURATION S OF AMIDE DERIVATIVES OF 3-AMINOQUINUCLIDINE, THE PROCESS FOR PREPARING FOR PREPARING THEM AND THEIR APPLICATION IN

THERAPY

The following statement is a full description of this invention, including the best method of performing it known to us Enantiomers of absolute configuration S of amide derivatives of 3-aminoquinuclidine, the process for preparing them and their application in therapy The subject of the present invention is the enantiomers of absolute configuration S of amide derivatives of 3-aminoquinuclidine, the process for'preparing them and their application in therapy.

Amide derivatives of 3-aminoquinuclidine, corresponding to the formula:

(I)

Sin which: X denotes an oxygen or sulphur atom; and Ar has one of the following meanings: a phenyl ring substituted with one, two or three C 1

-C

4 alkoxy groups; a phenyl ring of structure: R t C, t CH 3 tt 3 Where R 1 denotes a halogen atom or an alkylcarbonyl group in which the alkyl group contains from 1 to 4 carbon atoms; a phenyl group of structure:

R

i 2 3CH 3 where R 2 denotes a halogen atom and R 3 is a hydrogen atom or an alkylcarbonyl group in which the alkyl residue contains 1 to 4 carbon atoms; a 3-fluoro-2-methoxyphenyl group; or a 5-pyrimidinyl group of structure: i I-i *Q6.

o *a c *o

H

2 N/

OR

4 where R 4 denotes a C1-C4 alkyl group or a phenyl ring, the addition salts of these derivatives with an organic or inorganic acid, as well as the hydrates of these derivatives and salts, are already known from EP-A-O,099,789.

The above derivatives of formula salts and hydrates have, however, been described, in EP-A-O,099,789, only in the form of their racernic mixture. In the course of studying the racemic mixture of these compounds, the applicant endeavoured to synthesize the two enantiomers corresponding to each racemic mixture. After overcoming the problem presented by this synthesis, he studied the pharmacological 1 0 properties of these enantiomers and was thus able to observe that, altogether unexpectedly, the enantiomers of absolute configuration S had a pharmacological behaviour that was very different both from that of the corresponding racemic mixtures and from that of antipodes of absolute configuration R.

Consequently, the subject of the present invention is the enantiomers of absolute 1 5 configuration S of N-(3-quinuclidinyl)-4-amino-5-chloro-2-methoxybenzamide and acid saltsor hydrates thereof. Its subject is, in addition, the processes for preparing these enantiomers, as well as the application of these enantiomers in therapy.

The enantiomers according to the invention may be obtained by the resolution of racemic mixtures or by stereospecific synthesis.

20 The stereospecific synthesis consists in: either condensing laevorotatory 3-aminoquinuclidine of configuration S with, respectively, acids or thioacids of formula: HO Ar

(II)

Gon a 0 a a: 00 40404 0* 0 0 *0*000 0 where X and Ar have the same meaning as in formula 1 3 in particular in the presence of dicyclohexylcarbodiimide, (ii) or condensing laevorotatory 3-aminoquinuclidine of configuration S with the chloride of, respectively, acids or thioacids of formula: HO Ar'

(III)

X

where X has the same meaning as in the formula and Ar' assumes one of the following meanings: a phenyl ring substituted with one, two or three C 1

-C

4 alkoxy groups; a phenyl ring of structure: S*

H

OCH

3 where R 1 denotes a halogen atom or an alkylcarbonyl group in which the alkyl group contains from 1 to 4 carbon atoms; a phenyl group of structure: 0

C

3 8 where R 2 denotes a halogen atom and R 5 is an alkylcarbonyl group in which the alkyl residue contains 1 to 4 carbon atoms; a 3-fluoro-2-methoxyphenyl group; or a 5-pyrimidinyl group of structure:

N

R-NH

N=

R

4 where R 4 denotes a C 1

-C

4 alkyl group or a Oee-y I phenyl ring and R 6 denotes an eetmid group, which leads to the enantiomers of absolute con- I figuration S of formula: I A4} m 4

NH

where X and Ar' have the same meaning as in the formula (III), and then, if required, subjecting the enantiomers of the formula (Ia) and having the particular structures: R 0 4 CH O

H

4nH NH H 2 where R 2 and R 4 have the same meaning as in the o* formula to a deacetylation reaction, preferably by the action of a strong base such as potassium hydroxide.

Laevorotatory 3-aminoquinuclidine of absoLute 004E4O configuration S is also a new compound, since only the racemic mixture of 3-aminoquinucidine is known from EP-A-0,099,789. It hence falls within the scope of the present invention. It may be prepared by two different routes, namely: the action of D-tartaric acid on N-(3-quinuclidinyl)-3-chlorobenzamide, resolution by crystallization of the diastereo isomeric salts thereby formed to obtain laevorotatory N-(3-quinuclidinyl)-3-chorobenzamide D-tartrate, and the action of a base such as an alkali metal hydroxide on this tartrate to obtain (S)-(-)-N-(3-quinucLidinyl)-3-chlorobenzamide, followed by the acid hydroLysis of this amide, or (ii) the reaction of quinucidinone with methylbenrylamine to obtain (R)-N-(a-methyLbenzyLI)- 3-quinucidinimine, and reduction of this imine with an alkali metal borohydride to obtain CS)-N-C(R)a-methyLbenzyL]-3-aminoquinucL idine, foL Lowed by hydrogenolysis of the latter in acid medium.

It wiLL be noted that dextrorotatory r p .0 09 0 0 01 *0 00 0Q o 0 C *O 0* *0 0 1~1 _A 7 5 3 -aminoquinucidine of absolute configuration R may be obtained by route above, but using L-tartaric acid in place of D-tartaric acid, or by route (ii) above, but using (S)-a-methylbenzylamine in place of (R)-a-methyLbenzyamine., The preparations below are given by way of exampLe in order to illustrate the invention.

Example 1: Preparation of (S)-(-)-3-aminoquinuclidine A/ First synthetic route (resolution of the diastereoisomeric salts): 1st stage: Preparation of (S)-(-)-N-(3-quinuclidinyl)-3-chlorobenzamide N-(3-Quinuclidinyl)-3-chorobenzamide (52.5 g) dissolved in methanol is added to a solution of D-tartaric 15 acid (29.7 g) in methanol. The preciOjitate obtained is collected by filtration and treated twice with methanol under reflux. The salt thus purified (20 g) is decomposed with aqueous sodium hydroxide solution and the product extracted with chloroform. After the organic phase has 20 been dried and evaporated, the base obtained is treated in acetone with ethanolic hydrogen chloride solution. The hydrochloride which precipitates is collected by filtration and recrystallized in ethanol. 9.4 g of optically pure (S)-(-)-N-(3-quinucidinyL)-3-chorobenzamide hydrochloride are obtained.

Melting point: 244-247 0

C

Ca] 2 0 -16.80 (c 1, CH 3 0H)

D

2nd stage: Preparation of (S)-(-)-3-aminoquinucLidine dihydrochloride The hydrochloride obtained in the preceding stage (9 g) is treated under reflux for 3 hours 30 minutes with concentrated hydrochloric acid. The reaction medium is cooled, filtered and concentrated to dryness. The residue is treated with absolute ethanoL and the quinuclidine dihydrochloride which crystallizes is collected by filtration.

Melting point: 260 0

C

E0J -24.90 (c 1, H 2 0).

The R antipode is obtained under the same conditions, using The R antipode is obtained under the same conditions, using -6 L-tartaric acid as resolving agent.

Melting point 260 0

C

+24.80 (c 1, H 2 0).

B/ Asymmetric synthesis: 1st stage: Preparation of (R)-N-(a-methylbenzyl)- 3-quinucLidinimine Quinuclidinone (80 g) in 800 ml of toluene is brought to reflux in the presence of (R)-a-methylbenzyLamine (77.4 g) for 24 h, the water formed being removed with a Dean Stark apparatus. The reaction medium is then concentrated to dryness and the imine formed (130 g) is distilled.

Yield: 89% Boiling point: 140-150 0 C (0.05 mm Hg) 12 0 +97.20 (c 1, CHCL 3 2nd stage: Preparation of (S)-N-C(R)-a-methyLt benzyl3-3-aminoquinuclidine dihydrochloride t E t t E The imine (129.5 g) obtained in the preceding stage is dissolved in methanol and potassium borohydride (30.6 g) is added in small portions at between 10 and 0 C. After one hour, the medium is evaporated to dryness under reduced pressure. The residue is dissolved in a mixture of acetone and isopropyl alcohol The expected amine is precipitated in the form of the dihydrochloride by adding ethanolic hydrogen chloride solution.

The product is recrystallized twice in an ethanol/methanol mixture to obtain optically pure (S)-N-E(R)-a-methylbenzyl3-3-aminoquinuclidine dihydrochloride (81 g).

Yield: 47% Melting point: 260 C (c 2, H 2 0).

3rd stage: Preparation of (S)-(-)-3-aminoquinuclidine dihydrochloride The product obtained in the preceding stage (64.4 g) is dissolved in ethanol with 2 equivalents of 1N hydrochloric acid solution and palladium on charcoal,

H

2 0 (12.8 The reaction medium is stirred for 18 h under a hydrogen atmosphere, filtered, and then evaporated to dryness under reduced pressure.

(S)-(-)-3-aminoquinuclidine dihydrochLoride is crystallized in an ethanol/ether mixture.

-24.20 (c 1, The antipode is obtained by the same sequence of reactions, starting with (S)-a-methylbenzylamine.

Example 2: Stereospecific synthesis of N-(3-quinuclidinyL)- 4-amino-5-chloro-2-methoxybenzamide hydrochLoride, isomer [code MD 200054] and isomer [code MD 200051] 1st variant: (S)-(-)-3-Aminoquinuclidine dihydrochLoride (40 g; 0.2 mole) is dissolved in 80 ml of 2.5 N aqueous sodium ii hydroxide solution. 4-Amino-5-chloro-2-methoxybenzoic acid (44.5 g) dissolved in 300 ml of pyridine is added to t3 15 this solution, cooled in an ice bath. DicyclohexyLtarbodiimide (85 g) is added in two portions. The mixture is stirred vigorously for 18 h at room temperature. The medium is then diluted with 150 ml of water. The insoluble material is removed by filtration and washed with water. The aqueous phase is brought to pH 10 with 10 N sodium hydroxide solution and extracted with chloroform.

After the organic phase has been dried (over Na 2

SO

4 and evaporated, the residue is crystallized in isopropyL ether.

The solid obtained (56 g) is dissolved in 280 mL of isopropyl alcohol and the solution acidified with HCL. The hydrochloride which precipitates is collected by filtration and recrystallized in 99% pure ethanol.

The desired product (MD 200054) is obtained in a yield..

Melting point: 233-235 0

C

-3.9o (c 1, H 2 0).

The dextrorotatory antipode (MD 200051) is obtained under the same conditions, starting with (R)-(+)-3-aminoquinuclidine dihydrochloride.

Melting point: 232-234 0

C

+3.80 (c 1, H 2 0).

D

f -7 r ft ft t c t I I t 8 2nd variant: (S)-(-)-3-Aminoquinuclidine (1.9 g) is dissolved in 33.5 ml of IN aqueous sodium hydroxide solution.

4-Acetamido-5-chloro-2-methoxybenzoyl chloride (3.75 g) dissolved in 70 mL of dioxane is added dropwise to this solution. After 15 minutes' stirring, the medium is acidified, washed with chloroform and alkalinized with concentrated aqueous sodium hydroxide solution, and the product extracted with chloroform. The organic phase is dried (over Na2SO 4 and then evaporated. The oily residue is dissolved in ethanol and ethanolic hydrogen chloride is added until an acid pH is obtained. The N-(3-quinuclidinyl)-4-acetamido-5-chLoro-2-methoxybenzamide hydrochloride thereby formed precipitates (quantitative yield), 15 and the latter is collected by filtration.

The product is then deacetylated by treating it under reflux for 30 minutes in a 5% strength solution of potassium hydroxide in ethanol.

The reaction medium is then dissolved in water and extracted with chloroform. After the organic phase has been dried and evaporated, the hydrochloride MD 200054 is prepared and isolated as above.

-3.70 (c 1, H 2 0).

D

The other enantiomers according to the invention are obtained by procedures similar to those of Example 2, but using appropriate starting reactants.

The compounds according to the invention were studied in laboratory animals and were shown to have activity with respect to the digestive system and, in particular, activity with respect to gastric movements and antiemetic activity.

By way of example, the antiemetic activity of N-(3-quinuclidinyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride, administered orally in the form of the racemic mixture (code MD 780209), of the laevorotatory enantiomer of configuration S (code MD 200054) and of the dextrorotatory enantiomer of configuration R (code MD 200051), was studied in relation to cisplatin-induced vomiting in dogs.

41 I 4 'i I- 9 1/ Method: The method is derived from that described by J.A. GYLYS et aL (Res. Commun. Chem. Pathol. Pharmacol.

1979, 23, no. 1, p.61-68). Vomiting is induced by the intravenous injection of cispLatin (INN) at a dose of 3 mg/kg in a random sample of male and female dogs weighing between 10 and 16 kg, which have been maintained on a fluid diet (hydric diet) for 24 hours.

The test compounds are administered orally minutes after the injection of cisplatin.

The animals are fed 1 h 30 min after the treatment. The observation period is 6 hours following the injection of cisplatin.

II 2/ Results (4 dogs per treatment): S 15 TREATMENT DOSE VOMITING Ag/kg AVERAGE DECREASE NUMBER IN NUMBER AS ALL SOR NONE

CONTROL

(distilled water) 0 10.8 MD 780209 (racemic) 15 2 81.4 MD 200054 7.5 0.5 95.3 MD 200051 30 7 34.9 0 The results collated in the table above clearly demonstrate that the laevorotatory enantiomer of configuration S(code MD 200054) is, surprisingly, much more active in inhibiting vomiting induced by anticancer drugs such as cisplatin than its antipode (code MD 200051) and the corresponding racemate. Furthermore, the a.^ 10 laevorotatory enantiomer exhibits fewer side effects than the dextrorotatory enantiomer.

The compounds according to the invention do not exhibit significant toxicity at the active doses shown in the table above; they find their application as medicinal products in the field of the digestive system, in particular as antiemetic agents.

The present invention finally encompasses the pharmaceutical compositions containing, by way of active principaL, at least one compound chosen from the enantiomers of absolute configuration S of the derivatives of formula their addition salts with a pharmaceuticalLy acceptable organic or inorganic acid and the hydrates of these enantiomers and salts, in combination with a suitable vehicle. These compositions may be administered orally in the form of gelatin capsules, tablets, dragees and the Like, at dosages which can reach 500 mg of active principal per day (in one or more doses), or parenterally in the form of injectable solutions, at dosages which can reach 200 mg of active principal per day (in one or more daily doses).

9 4 I t t It *49 41 4 O

Claims

1. A method of treatment of emesis, comprising administering to a patient in need of such treatment an anti-emetically effective amount of the enantiomer of absolute configuration S of N-(3-quinuclidinyl)-4-amino-5-chloro-2-methoxybenzamide, and acid addition salt or the hydrate thereof, said enantiomer being free of enantiomer of absolute configuration R.

2. The method of claim 1, comprising oral administration of said compound.

3. The method of claim 2, wherein the oral administration is in the form of gelatin capsules, tablets, dragees or the like. r

4. The method of claim 2 or 3, wherein the compound is administered at a dosage rate of up to 500 mg per day. a 4o a The method of claim 1, comprising parenteral administration of said compound in the form of an injectable solution.

6. The method of claim 5, wherein the compound is administered at a dosage rate of up to 200 mg per day.

7. Process for preparing the enantiomer of absolute configuration S substantially free of the enantiomer of absolute configuration R, according to claim 1, characterised in that it comprises the condensation of laevorotatory 3-aminoquinuclidine of absolute configuration S with 4-amino-5-chloro-2-methoxybenzoic acid, in the presence of dicyclohexylcarbodimide.

8. Process for preparing the enantiomer of absolute configuration S substantially free of the enantiomer of absolute configuration R, according to claim 1, characterised in that it comprises the stages of condensing laevorotatory 3-aminoquinuclidine of absolute configuration S with 4-acetamido-5-chloro-2-methoxybenzoyl chloride, which leads to the enantiomer of absolute configuration S of N-(3-aminoquinuclidinyl)-4- acetamido-5-chloro-2-methoxybenzamide, and then, (ii) subjecting the latter to a deacetylation reaction. 12

9. Laevorotatory 3-aminoquinuclidine of absolute configuration S, substantially free of the other enantiomer. Process for preparing Laevorotatory 3-aminoquinuclidine of absolute configuration S substantially free of the other enantiomer characterised in that it comprises the stages of: reacting D-tartaric acid with N-(3-quinuclidinyl)-3-chlorobenzamide, (ii) resolving by crystallization the diastereo isomeric salts thereby formed to obtain Laevorotatory N-(3-quinuclidinyl)-3-chlorobenzamide D-tartrate, (iii) reacting a base with this tartrate to obtain quinuclidinyl)-3-chlorobenzamide, and then (iv) subjecting this amide to an acid hydrolysis.

11. Process for preparing Laevorotatory 3-aminoquinuclidine of absolute configuration S, substantially free of the other enantiomer, characterised in that it comprises the stages of: S(i) reacting quinuclidinone with (R)-a-methylbenzyl)-3-quinuclidinimine, (ii) reducing this imine with an alkali metal borohydride to obtain [(R)-a-methylbenzyl]-3-aminoquinuclidine, and then (iii) subjecting the latter to a hydrogenolysis in acid medium. t t

12. Dextrorotatory 3-aminoquinuclidine of absolute configuration R, substantially free of the other enantiomer. t p 13. Process for preparing the dextrorotatory 3-aminoquinuclidine of absolute configuration R, substantially free of the other enantiomer, characterised in that it I comprises: o reacting L-tartaric acid with N-(3-quinuclidinyl)-3-chlorobenzamide, (ii) resolving by crystallization the diastereoisomeric salts thereby formed to obtain dextrorotatory N-(3-quinuclidinyl)-3-chlorobenzamide L-tartrate (iii) reacting a base with this tartrate to obtain quinuclidinyl)-3-chlorobenzamide, and then (iv) subjecting this amide to an acid hydrolysis. j 13

14. Process for preparing dextrorotatory 3-aminoquinuclidine of absolute configuration R, substantially free of the other enantiomer, characterised in that it comprises: reacting quinuclidinone with -methylbenzylamine to obtain (a-methylbenzyl)-3-quinuclidinimine, (ii) reducing this imine with an alkali metal borohydride to obtain [(R)-ax-methylbenzyl]-3-aminoquinuclidine, and then (iii) subjecting the latter to a hydrogenolysis in acid medium. DATED this 18th day of November, 1991 DELALANDE S.A. WATERMARK PATENT TRADEMARK ATTORNEYS I THEATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA *:Otte ICPr tCC t Icirr