AU4381800A - Ipratropium bromide enantiomer with a prolonged duration of action - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT(S): Boehringer Ingelheim International GmbH ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Ipratropium bromide enantiomer with a prolonged duration of action" The following statement is a full description of this invention, including the best method of performing it known to us: P:\OPERU(bmU2311237 di.doc-030700 -1A- Ipratropium salt enantiomer with prolonged duration of effect This application is a divisional of Australian Application No. 67397/96, the entire contents of which is incorporated herein by reference.

The invention relates to the use, by inhalation, of (endo;syn)-(-)-3-(3-hydroxy-l-oxo-2-phenylpropoxy)-8-methyl- 8-(1-methylethyl)-8-azoniabicyclo[3,2,1]octane salts as bronchospasmolytics with a powerful and particularly longlasting effect and the use of the salts in the manufacture of asthma preparations.

9*ooeo The racemate of the above-mentioned compound (in the form of 15 the bromide) is on sale under the name Ipratropium bromide as an active substance in anticholinergic drugs.

According to a first embodiment of the invention there is provided a pharmaceutical preparation for inhalation, comprising an (endo,syn)-(-)-3-(3-hydroxy-l-oxo-2phenylpropoxy)-8-methyl-8-(1-methylethyl)-8azoniabicyclo[3,2,1]octane salt with an enantiomeric purity of 90 to 100%, together with conventional excipients and/or carriers adapted for use in inhalation therapy and/or other 25 active substances.

According to a second embodiment of the invention there is provided a use of an (endo,syn)-(-)-3-(3-hydroxy-l-oxo-2phenylpropoxy)-8-methyl-8-(1-methylethyl)-8azoniabicyclo[3,2,1]octane salt with an enantiomeric purity of 90 to 100%, optionally combined with other active substances, in the preparation of medicament for treating respiratory tract diseases by inhalation; wherein the medicament has substantially prolonged duration of action relative to a medicament containing an equivalent amount of PAOPERUKbmU311237 div.doc-03 7 -2active ingredient present in a racemic mixture thereof.

According to a third embodiment of the invention there is provided a method of treatment of respiratory tract diseases in a subject, comprising the administration by inhalation to said subject of an effective dose of an active substance comprising an (endo,syn)-(-)-3-(3-hydroxy-l-oxo-2phenylpropoxy)-8-methyl-8-(l-methylethyl)-8azoniabicyclo[3,2,1]octane salt with an enantiomeric purity of 90 to 100%, or combinations of this active substance with other active substances used for respiratory tract therapy; wherein the active substance has a substantially prolonged duration of action relative to an active substance containing an equivalent amount of the octane compound 15 present in a racemic mixture thereof.

According to a fourth embodiment of the invention there is provided (endo,syn)-(-)-3-(3-hydroxy-l-oxo-2-phenylpropoxy)- 8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3,2,1]octane bromide with an enantiomeric purity of 90 to 100%.

It has now been found, surprisingly, that the conditions of activity of the racemate, laevorotatory and dextrorotatory enantiomers are significantly different and have major peculiarities which differ substantially from the norm. The eutomer the enantiomer having the desired or sought activity) is the L-(-)-enantiomer. Receptor binding studies on CHO-HM receptors have shown that the L-(-)-enantiomer has approximately twice as high an affinity as the racemate.

This ratio corresponds to observations which have frequently been made when comparing the effects of enantiomers and racemates.

However, what is surprising in the present case is that administration by inhalation to the (anaesthetised) dog in a comparison of the eutomer with the racemate in the weight P:\OPER\Kbm.2311237 div.doc-O3aO7 -3ratio 1:2 exhibits not only a higher potency but also a considerably longer duration of activity.

The diagram shown in Figure 1 gives the percentage inhibition of bronchospasm as a function of time. The dotted line (curve B) represents the pattern for the 4 (endo, 3 -hydr-oxy-oxo-2-phenylpropoxy)-8ethyl-methyl l-methylethyl)-8-azoniabicyclo[3,2,1]octane and the continuous line (curve A) gives the pattern for the corresponding racemate, the hydrobromides having been used. 5 pg of the pure L-(-)-enantiomer and, accordingly, 10 pg of the racemate were administered.

The experiment was carried out on five test animals using the pure L-enantiomer (BIIH 150 BR) whilst the racemate was administered to seven test animals.

Figure 1 shows that the inhibition of acetylcholineinduced bronchospasm in the dog by the administration of the Ipratropium bromide aerosol (curve A) has reached a peak of about 55% after about 10 minutes and has fallen K back to its initial level after 60 minutes. The same quantity of eutomer (curve as contained in the racemate, achieves a 60% inhibition after about minutes and does not fall back to its starting level for 180 minutes.

The half-lives measured show that the eutomer BIIH 150 BR has a duration of activity which is approximately four times longer.

The eutomer is obtained in substantially pure form from the racemate by combined application of high pressure liquid chromatography and recrystallisation.- The term "eutomer" for the purposes of the present invention also includes strongly concentrated products (over about preferably containing more than 95, and particularly more than 97% of the L-(-)-enantiomer. The anion corresponds to the one in the starting compound.

If desired, an exchange may be carried out. Therefore the salts preferably comprise Br e Cle or CH3SO3 as anion.

The Example which follows is intended to illustrate the preparation of the and D-(+)-enantiomer:.- 18 grams of Ipratropium bromide are separated by highpressure liquid chromatography over a Chiralcel OD column (250x20 mm) with a mobile phase composed of 600 hexane, 250 methanol, 150 ethanol and 1 saturated alcoholic NaBr solution throughflow rate 6 ml/min., wavelength 254 nm; sensitivity 0.5 A.U.F.S, solution containing 1 g Ipratropium bromide/5 ml ethanol 5 ml mobile phase 2.5 ml conc. acetic acid).

By repeated chromatography and recrystallisation from ethanol, the L-(-)-enantiomer, white crystals, m.p.

239-40 0 C (decomp.), specific rotation [0]20 -24.06° (c 1.014; H 2 enantiomeric purity 97.4% (HPLC) and the D-(+)-enantiomer, white crystals, m.p. 238-39 0

C

(decomp.), specific rotation [a] 2 0 +24.260 (c 1.018;

H

2 enantiomeric purity 98.9% (HPLC), are obtained.

Elemental analyses and spectra indicate that these compounds are present.

The L- (-)-eutomer in the form of the various salts is suitable, by virtue of being an anticholinergic, for treating chronic obstructive bronchitis and asthma by inhalation, whilst side effects are largely excluded.

For use, the active substance is processed with known excipients and/or carriers to form conventional galenic preparations, e.g. solutions for inhalation, suspensions in liquefied propellant gases, preparations containing liposomes or proliposomes, powders for inhalation (optionally in capsules) for use in conventional inhalers.

Examples of formulations (amounts given in percent by weight): 6 1. Metering aerosols Active substance according to the invention 0.005 Sorbitan trioleate 0.1 Monofluorotrichloromethane and difluorodichloromethane 2:3 ad 100 The suspension is transferred into a conventional aerosol container with metering valve. 50 tl of suspension, for example, are released on each actuation.

If desired, the active substance may also be present in higher doses 0.02 Instead of the chlorinated propellant gases, alternative propellant gases such as TG 134a (1,1,1,2-tetrafluoroethane) and/or TG 227 (1,1,1,2,3,3,3-hepta- Sfluoropropane) may also be used.

2. Powder for inhalation Micronised powdered active substance (particle size to 7 Am) is mixed with micronised lactose and packed into hard gelatine capsules, optionally with other additives. For example, 0.01 mg of active substance and mg of lactose are packed into each capsule. The powder may be inhaled using conventional inhalers, e.g.

as in DE-A 3345772.

3. Solutions for inhalation Aqueous solutions of the active substance may also be used, the aerosol being produced, for example, by a device according to W091/14468. 0.005 mg of active substance may be administered per spray dose, for example.

The active substance which may be used according to the -7 invention may advantageously also be used in conjunction with other active substances for respiratory tract therapy. j 2 -mimetics may be mentioned in particular; these are used in combinations with 50 1 000-- of the dose for individual use.

The following may be mentioned: Bambuterol Bitol terol Carbuterol Clenbuterol Fenoterol Formoterol Hexoprenalime Ibuterol Pirbuterol *0 Procaterol Reproterol Salbutamol Salmeterol Sulfonterol 00.0.0Terbutalime Tulobuterol :00001- 2 -fluoro-4-hydroxyphenyl) (l-benzimidazolyl) -2methyl -2 -butylaminol ethanol -hydroxy-8' (l-hydroxy-2-isopropylaminobutyl) 2H-l, 4-benzoxazin-3- (4H) -one 1- 4 -amino- 3- chloro- 5- trif luoromethylphenyl) 2 -tert. butylarnino) ethanol 1- (4-ethoxycarbonylamino-3 -cyano-5-fluorophenyl) -2- (tert. -butylamino) ethanol.

Inhalable steroids such as Budesonide, Beclomethasone (or the 17, 21-dipropionate) dexamethasone-21isonicotinate, Flunisolide and antiallergics such as disodiun cromoglycate, Nedocromil, Epinastine may also be used as ingredients in the combination. These combination ingredients may also be administered in the same or smaller doses than when they are used on their 8 own.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

oooe *ooo

Claims (20)

1. A pharmaceutical preparation for inhalation, comprising an (endo, syn)-(-)-3-(3-hydroxy-l-oxo-2- phenylpropoxy)-8-methyl-8- (-methylethyl) -8- azoniabicyclo[3,2,1]octane salt with an enantiomeric purity of 90 to 100%, together with conventional excipients and/or carriers adapted for use in inhalation therapy and/or other active substances.

2. A pharmaceutical preparation according to claim 1 wherein the enantiomeric purity is 95 to 100%. S 15

3. A pharmaceutical preparation according to claim 1 or claim 2 wherein the salt comprises Cle or CH 3 SO, as anion.

4. A pharmaceutical preparation according to claim 1 or claim 2 wherein the salt comprises Br 8 as anion.

Pharmaceutical preparations for inhalation according to any of claims 1 to 4, also comprising an effective dose of a p,-mimetic, an inhalable steroid or an inhalable antiallergic agent.

6. Inhalable pharmaceutical preparations according to claim 5, wherein the J-mimetic used is Bambuterol Bitolterol Carbuterol Clenbuterol Fenoterol Formoterol Hexoprenaline Ibuterol Pirbuterol PAMIKMN7397.W .s3*C.MR 10 Procaterol Reproterol Salbutamol Salmeterol Sulfonterol Terbutalime Tulobuterol 1- (2-fluoro-4-hydroxyphenyl) (1-benzimidazolyl) -2- methyl-2 -butylamino) ethanol erythro-5 I -hydroxy-8'1 (1.-hydroxy-2-isopropylaminobutyl) -2H- 1, 4-benzoxazin-3- (4H) -one 1- (4 -amino- 3 -chloro- 5 trif uoromethyphenyl)2.tert. butylamino) ethanol or 1- 4 -ethoxycarbonylamino3cyano-5...fluorophenyl) (tert. 15 butylamino)ethanol; the steroid used is Budesonide, Beclomethasone (or the 17, 21-diproprionate) dexamethasone-21-isonicotinate, or Flunisolide; and the antiallergic agent used is Disodium cromoglycate, Nedocronil or Epinastine.

Use of an *(endo, syn) (3-hydroxy-l-oxo.2- phenyipropoxy)

8-methyl -B8- (1 -methylethyl) -8 azoniabicyclo[3, 2,l1] octane salt with an enantiomeric purity of 90 to l00%, optionally combined with other active substances, in the preparation of medicament for treating respiratory tract diseases by inhalation, wherein the medicament has substantially prolonged duration of action relative to a medicament containing an equivalent amount of active ingredient present in a racemic mixture thereof. 8. A use according to claim 7 wherein the enantiomeric purity is 95-100k. PMROMUKbaw976 Wsp.d ^Awwo 11

9. A use according to claim 7 or claim 8 wherein the salt comprises Cl" or CH 3 SO 3 as anion.

A use according to claim 7 or claim 8 wherein the salt comprises Br- as anion.

11. Use according to any of claims 7 to 10, in which mimetics, steroids or antiallergics are used as the combination partners.

12. A method of treatment of respiratory tract diseases in a subject, comprising the administration by inhalation to said subject of an effective dose of an active substance comprising an (endo, syn) (3-hydroxy-l-oxo-2- phenylpropoxy)-8-methyl-8-(1-methylethyl)-8- azoniabicyclo[3,2,1]octane salt with an enantiomeric purity of 90 to 100%, or combinations of this active substance with other active substances used for respiratory tract therapy; wherein the active substance has a substantially prolonged duration of action relative to an active substance containing an equivalent amount of the octane compound present in a racemic mixture thereof.

13. A method of treatment according to claim 13 wherein the enantiomeric purity is 95 to 100%.

14. A method of treatment according to claim 13 or claim 14 wherein the salt comprises Cl- or CH 3 SO0 3 as anion.

A method of treatment according to claim 13 or claim 14 wherein the salt comprises Br" as anion.

16. A pharmaceutical preparation according to any one of claims 1 to 6, substantially as hereinbefore described.

17. The use according to any of claims 7 to 11, substantially as hereinbefore described. M-E~gUMA6fl9146 .3.dA-2MWM -12

18. A method of treatment according to any of claims 12 to 16, substantially as hereinbefore described.

19. (endo, syn) 3 3 -hydroxy-l-oxo-2-phenylpropoxy) -8- methyl-8- (1-methylethyl) -8-azoniabicyclo [3,2,11 octane bromide with an enantiomeric purity of 90 to 1001. 13 1. (endo, syn)-(-)-3-(3-Hydroxy-l-oxo- 2 phenylpropoxy)-8-methyl-8-(l-methylethyl)-8- azoniabicyclo[3,2,1]octane salts with an enantiomeric purity of 90 to 100%. 2. Salts according to claim 1 with an enantiomeric purity of 95 to 100%. 3. Salts according to claim 1 or claim 2 comprising Bre, Cle or CH3CO3 as anion. 15 4. Pharmaceutical preparations for inhalation, comprising a compound according to any one of claims 1 to 3, together with conventional excipients and/or carriers and/or other active substances.

.20 5. Pharmaceutical preparations for inhalation according to claim 4, comprising a compound according to any one of claims 1 to 3, and an effective dose of a p 2 -mimetic, an inhalable steroid or an inhalable antiallergic agent. 6. Inhalable pharmaceutical preparations according to claim 5, wherein the P 2 -mimetic used is Bambuterol Bitolterol Carbuterol Clenbuterol Fenoterol Formoterol Hexoprenaline Ibuterol Pirbuterol -14 Procaterol Reproterol Salbutamol Salmeterol Sulfonterol Terbutaline Tulobuterol 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(l-benzimidazolyl)-2- methyl-2-butylamino]ethanol erythro-5'-hydroxy-8'-(l-hydroxy-2-isopropylaminobutyl)- 2H-1,4-benzoxazin-3-(4H)-one 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.- butylamino)ethanol or 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2- 15 (tert.-butylamino)ethanol; the steroid used is Budesonide, Beclomethasone (or the 17,21-dipropionate), dexamethasone-21-isonicotinate, or Flunisolide; and the antiallergic agent used is Disodium cromoglycate, Nedocromil or Epinastine. o 7. Use of compounds according to any one of claims 1 to 3, optionally combined with other active substances, in the preparation of medicament for treating Srespiratory tract diseases. 8. Use according to claim 7, in which P 2 -mimetics, steroids or antiallergics are used as the combination partners. 9. A method of treatment of respiratory tract diseases in a subject, comprising the administration to said subject of an effective dose of an active substance according to any one of claims 1 to 3 or combinations of these active substances with other active substances 15 used for respiratory tract therapy. A salt according to any one of claims 1 to 3, substantially as hereinbefore described. 11. A pharmaceutical preparation according to any one of claims 4 to 6, substantially as hereinbefore described. 12. The use according to claim 7 or claim 8, substantially as hereinbefore described. 13. A method of treatment according to claim 9, substantially as hereinbefore described. 555* 9 S