NZ228999A

NZ228999A - Pharmaceutical compositions containing a compound with alphabalpha 2 -mimetic activity and a compound with platelet activating factor (paf) antagonist activity

Info

Publication number: NZ228999A
Application number: NZ228999A
Authority: NZ
Inventors: Hubert Heuer
Original assignee: Boehringer Ingelheim Int
Priority date: 1988-05-06
Filing date: 1989-05-04
Publication date: 1991-07-26
Also published as: HU205009B; IL90181A; IL90181A0; ZA893261B; EP0341559A3; DK220389A; JPH0211525A; AU3406389A; KR900017588A; AU614362B2; DE3815480A1; DK220389D0; EP0341559A2; HUT50291A

Description

<div id="description" class="application article clearfix"> 22 89 99 j Priority Oate(*): Conjptet* SotcHlcatlofi Filed: | Ow. {5)....Q rrjuttw" u&S)ctrtlof» Date: i P.O. Journal, No: Patents Form No. 5 «EW ZEALAND PATENTS ACT 1953 COMPLETE SPECIPICATI SYNERGISTIC COMBINATIONS THEIR USE AS THERAPEUTIC AGENTS j£/We, BOEHRINGER INGELHEIM INTERNATIONAL GMBH, A Body Corporate organised under the laws of the Federal Republic of Germany, of D-6507 Ingelheim am Rhein, FEDERAL REPUBLIC OF GERMANY hereby declare the invention, for which %/we pray that a patent may be granted to i^f/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 ~ (followed by page la) 22 8999 54155.03 Synergistic combinations and their use as therapeutic agents The invention relates to new combinations of active substances comprising /32-mimetics and PAF-antagonists, and their potential use in the treatment of bronchial asthma. It is known that /32-mimetic compounds are suitable for treating bronchial asthma and in particular for treating acute asthmatic reaction. Hcwever, /3-mimetics have little or no influence on PAF-inciuced bronchospasm or on the changes in the lung caused by PAF, such as microvascular leakage, late phase reaction, cell infiltration (eosinophily) or disorders of mucociliary clearance. It is also known that platelet activating factor (PAF) is of importance in the pathophysiology of bronchial asthma as a mediator; it is supposed to be able to induce and imitate many symptoms of bronchial asthma, particularly bronchial hyperreactivity, inflammation of the respiratory tract with the formation of oedema and infiltration of inflammation cells (eosinophily), disturbances in the secretion of mucous and mucociliary clearance and late phase reaction. As far as is known at p -ent however, PAF is not directly involved in the indv. tion of acute bronchospasm. According to one aspect of the invention, we have now found that a couiiination of one or more /32-mimetics and one or more PAF-antagonists have a synergistic effect when combined in asthma therapy. For the /32-mimetics, it is possible to use one or more compounds known from the literature with the above type of activity. For the PAF antagonists it is possible to use one or more compounds having such activity including, for example those described in European Patent Application (followed by page 2) •• ' i minimi ' HTfUBftWi'iyii ^28999 m Nos. 176 927, 176 928, 176 929, 194 416, 230 942, 240 899, 254 245 and 255 028. The PAF antagonists disclosed in the above applications are suitable for use according to the invention. Preferably, the PAF 5 antagonist is selected from one or more of the following: 4-(2-chlorophenyl)-9-raethyl-2-[3-(4-morpholiny1)-3-propanon-l-y1]-6H-thieno[3,2-f][l,2,4]-triazolo[4,3-a][l,4]-diazepine (WEB 2086), 6-(2-chlorophenyl)-3,9-dihydro-l-methyl-8-[(4-morpholinyl)-10 carbonyl]-4H,7H-cyclopenta[4,5]thieno[3,2-f][l,2,4]-triazolo-[4,3-a][l,4]diazepine (WEB 2170) or 6-(2-chlorophenyl)-8,9-dihydro-l-methyl-8-[dipropyl?jnino-carbonyl]-4H,7H-cyciopenta[4,5]thieno[3,2f][l,2,4]-triazolo[4,3-a][l,4]diazepine (WEB 2347) or the acid 15 addition salts thereof, and the compounds emphasised or referred to as preferred in the European Patent Applications mentioned above. Preferably, the /32-mimetics are selected from one or more 20 of the following: (a) l-(3,5-dihydroxylphenyl)-l-hydroxy-2-[(4- hydroxyphenyl)isopropylamino]ethane (Fenoterol) 25 (b) 4-amino-a-[tert.-butylamino)methyl]-3,5-dichloro-benzyl alcohol) (Clenbuterol) (c) 2-hydroxymethyl-3-hydroxy-6-(l-hydroxy-^-tert-butylaminoethyl) pyridine (Pirbuterol) 30 (d) 8-hydroxy-5-[l-hydroxy-2-[(1-methylethyl)-amino]butyl]-2(1H)-quinolinone (Procaterol) (e) 2-(tart.-butylamino)-l-(4-hydroxy-3-hydroxy- j ^ 35 methylphenyl) ethanol (Salbutamol) (f) 1-(3,5-dihydroxyphenyl)-2-(tert.-butylamino)- ■ T-A- J a TiOOCQ * I ' ✓ ethanol (Terbutaline) (g) l-(2-fluoro-4-hydroxyIphenyl)-2-[4-(1-benzimidazolyl)-2«methyl-2-butylamino]-ethanol (h) erythro-5-hyJroxy-8-(l-hydroxy-2-isopropylamino-butyl)-2H-1,4-benzoxazin-3(4H)-one I v m (i) l-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-10 (tert.-butylaini.no) ethanol (k) l-(4-ethoxycarbonylamino-3~cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol 15 (1) N,N'-bis[2-(3,4-dihydroxyphenyl)-2-hydroxy-ethyljhexamethylenediamine (Hexoprenaline) (m) 7-[3-[[2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]-amino]propyl]-3,7-dihydro-l,3-dimethyl-lH-purin-20 2,6-dione (Reproterol) (n) [5—(2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxyphenyl]-urea (Carbuterol) 25 (o) 2-chloro-a-[[(1,l-dimethylethyl)-amino]-methyl]-benzyl alcohol (Tulobuterol) (p) 3-formylamino-4-hydroxy-o-[N-[l-methyl-2-p- methoxyphenyl)ethyl]-aminomethyl]benzyl alcohol 30 semifumarate (Formoterol) (Fumarate) 35 (q) 2-hydroxymethyl-3-hydroxy-6-[l-hydroxy-2- tert.butylaminoethy1)-pyridine dihydrcchloride ^ (Pirbuterol) (r) a[(tert.butylaroino)methyl]-4-hydroxy-3-(methyl sulphonyl)methyl]benzylalcohol hydrochloride ft I ?28999 (Sulfonterol) (s) dimethylcarbamic acid 5-[2-[(1,1-dimethylethyl)-amino]-1-hydroxyethyl]-1,3-phenylene ester 5 Bambuterol (t) a-(tert.butylaminomethyl)3,5-dihydroxybenzyl-alcohol-3,5-diisobutyrate (Ibuterol) 10 (u) a-[(tert.-butylaminomethyl]-3,4- dihydroxybenzylalcohol-3,4-di-p-toluate mesylate (Bitolterol) (v) 4-hydroxy-a[[(6-(4-phenylbutoxy)]hexylamino]-15 methyl-m-xylene-o,a'diol (Salmetrol) The surprising advantages of the new combinations include the iaCt that, compared with the use of 02-mimetics on their own, a lower dosage of each of these 20 active substances is sufficient in treatment, thus reducing any harmful side effects of j32-mimetics, and in addition a better response to the therapy is observed. The dosage of 02-miraetic and PAF-antagonist necessary for comparative treatment is found to be 25 between 20% and 95% of the dosage needed when the active substances are used on their own. In particular, a higher dosage of one component (within the scope of the above range) allows for a lower dosage of the other component. 30 According to a further aspect of the invention, the combinations can be administered in joint formulations or in the form of separate formulations with a short time interval between their respective ac'ainistrations. The combinations according to the invention provide 35 a method of treating bronchial asthma which(Comprises administering to a subject a combination of substa according to the invention. ^ 7 j 728999 5 Propranolol (0.1 mg/kg *! /.) increases the sensitivity of NMRI mice to PAF (30 ng/kg i.v.); the probability of a PAF-induced fatal shock increases from 0% to 93%. This effect ean be suppressed or prevented by £2-mimetics or PAF-antagonists, depending on the dosage. As can be seen from Figure 1, the probability of survival when Fenoterol, and WEB 2086 are administered simultaneously is virtually doubled, compared with the sum of the individual effects. According to a yet further aspect of the invention, we provide a pharmaceutical composition which comprises a combination of one or more /?-raimetics and PAF-antagonists together with a pharmaceutically acceptable carrier, diluent or excipient. Suitable forms for administration include tablets, either plain or coated, granules, capsules, injectable solutions, metering aerosols or powders for inhalation. The following Examples illustrate compositions which may be formed according to the invention: 1. Tablets 5 parts by weight of a combination of active substances according to the invention 1 part by weight of stearic acid 194 parts by weight of glucose The ingredients are compressed to form tablets weighing 200 mg. } I 22 899g 2. Inhalation aerpgQl 0.02 parts by weight of Fenoterol hydrobromide 0.10 parts by weight of WEB 2086 0.20 parts by weight of soya lecithin ad 100.00 parts by weight of propellant gas (Frigen 11, 12 and 114) . The mixture is transferred into aerosol containers with a metering valve and each actuation of the aerosol is designed to deliver a dose of 0.12 mg of the combination of active substances. </div>

Claims

<div id="claims" class="application article clearfix printTableText"> ?28999 % WHAT WE CwVIM IS:-

1. A pharmaceutical composition comprising in synergistic combination at least one compound with 0Z~ 5 mimetic activity and at least one compound with PAF-antagonist activity, or acid addition salts thereof.

2. A composition as claimed in claim 1, wherein the 02~ mimetic compound is Fenoterol, Clenbuterol, Pirbutarol, 10 ProcateroX, Salbutamol, Terbutaline, Hexoprenaline, Reproterol, Carbuterol, Tulobutarol, Formoterol, Pirbuterol, Sulfonterol, Bambuterol, Ibuterol, r': Bitolterol, Salmetrol, l-(2~fluoro-4-hydroxylphenyl)-2-[4-(l-benzimidazolyl)-2-methyl-2-butylamino]-ethanol, 15 arythro-5-hydroxy-8-(l-hydroxy-2-isopropylaminobutyl)-is 2H-l,4-benzoxazin-3(4H)-one, l-(4-amino-3-chloro-5- trifluoromethylphenyl)-2-(tart.butylamino)ethanol or l-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.butylamino)ethanol. ¥ 20

3. A composition as claimed in claim l or 2, wherein J the PAF-antagonist is WEB 2086, WEB 2170 or WEB 2347 (as defined herein) or acid addition salts thereof. 25

4. A pharmaceutical composition as claimed in any of claims 1 to 3 which includes a pharmaceutically acceptable carrier, excipient or diluent.

5. Use of a pharmaceutical composition as claimed in 30 any one of claims l to 4 for the treatment of bronchial asthma in an non-human animal subject.

6. Use of a pharmaceutical composition as claimed in claim 5 wherein the 02-mimetic is Fenoterol, Clenbuterol, 35 Pirbuterol, Procaterol, Salbutamol, Terbut&line, Hexoprenaline, Reproterol, Carbuterol, Tulobut^jEai^ ^ T £ Formoterol, Pirbutarol, Sul£jnterol, Bambutrfrol, 'T'^rV / I n..i» ■ Illiiiwwmriw^iiinn..,, 20 '28999 Ibuterol, Bitolterol, Salmetrol, l-(2-fluoro-4-hydroxylphenyl)-2-[4~(l-ben2imidazolyl)-2-methyl-2-butylamino]-ethanol. arythro-5-hydroxy-3-(L-hydroxy-2-isopropylaminobutyl)-'2H-l,4-benzoxazin-3(4H)-one, l-(4-5 amino-3-chloro-!5-trifluoromethylphenyl) -2-(tert.- butylamino)-ethanol or l-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tart.-butylamino)ethanol. ^

7. Use of a pharmaceutical composition as claimed in 10 claim 5 or claim 6, wherein the PAF-antagonist is WEB 2086, WEB 2170 or WEB 2347 (as defined herein) oc an acid addition salt thereof.

3. A. method of treating bronchial asthma in a non-15 human animal subject which comprises administering to said subject one or more j32-mimetics and one or more PAF-antagonists or physiologically acceptable acid addition salts thereof. BOEHRINGER INGELHEIM INTERNATIONAL GMBH byNAerr Attorneys BALDWIN SON & CAREY </div>