<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">230406 <br><br>
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Patents Form No. 5 <br><br>
NEW ZEALAND <br><br>
PATENTS ACT 1953 <br><br>
COMPLETE SPECIFICATION <br><br>
!i 2 "AUG/989 <br><br>
\„/ ./ XffivtS. <br><br>
USE OF PAF-ANTAGONISTS FOR TREATING AUTOIMMUNE DISEASES <br><br>
JtyWe, BOEHRINGER INGELHEIM INTERNATIONAL GMBH, A Body <br><br>
Corporate organised under the laws of the Federal Republic of Germany, of D-6507 Ingelheim am Rhein, <br><br>
FEDERAL REPUBLIC OF GEMRNAY hereby declare the invention, for which 3(/we pray that a patent may be granted to i^/us, and the method by which it is to be performed, to be particularly described in and by the following statement: <br><br>
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54570001.26 <br><br>
"Use of PAF-antagonists for treating autoimmune diseases" <br><br>
This invention relates to the use of PAF-antagonists for treating autoimmune diseases. <br><br>
In idiopathic thrombocytopenic purpura (ITP), a disorder of the immune mechanism causes massive 5 destruction of the body's own thrombocytes, which are finally eliminated in the spleen. The thrombocyte survival time, instead of being 10 days, is frequently only a few hours and the megacariocytes in the bone marrow which form the thrombocytes are multiplied in 10 compensation. <br><br>
Previously, this disease was fatal in 60-80% of cases. Since therapy with steroids, particularly prednisolon, the prognosis for ITP has improved significantly. <br><br>
15 With this syndrome it is essential in many cases for the therapy, i.e. the drug treatment, to be maintained throughout the patient's life. The disadvantages of long-term cortisone therapy are well known to those skilled in the art. <br><br>
20 We have found that surprisingly, PAF-antagonists <br><br>
(PAF-acether antagonists) may be used successfully in therapy for treating autoimmune diseases, particularly idiopathic thrombocytopenic purpura, without giving rise to the known side effects of steroid treatment. 25 Many of the compounds which are used as PAF- <br><br>
antagonists (PAF = platelet activating factor) which may be used according to the invention are known from the patent literature and the specialist literature, e.g. in Prostaglandins 3.5, 781 (1988). Examples of known PAF-30 antagonists include the tetrahydrofuran derivatives SDZ 63-441, SDZ 63-675, L 659.886. BN 52 111, thiazole <br><br>
•> <br><br>
t h j y* o derivatives of the type RP 59 227, iraidazo[2,1-a]iso- ;•z ;\ 2 <5N0Vjoor ;230406 ;quinolines of the type SDZ 64412 and SDZ 63135, dihydropyridines, compounds of type SRI 63441, RO 19-3704, CV 6209 and hetrazepine compounds such as thienodiazepines and benzodiazepines, as claimed in 5 European Patent Applications 176 928, 176 927, 176 929, 268 242, 320 922, 315 698 and 316 456. Preferably, PAF-antagonists according to European Patent Applications 230 942, 240 899, 194 416, 254 245, 268 242 and 255 028 may be used according to the invention. The compounds 10 listed below are particularly preferred. ;[4-(2-chlorophenyl)-l-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a](1,4]diazepin-2-yl]-carboxylic acid morpholide ;15 ;[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-carboxylic acid amide ;2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-20 triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid diethylamide ;2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic 25 acid N,N-di-(2-hydroxyethyl)amide ;2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid methylamide ;30 ;2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid isopropylamide ;3 5 2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid dimethylamide ;23 0406 ;3 ;2-[4-(2-chlorophenyl)-9-raethyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid N'-methyl-piperazide ;2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolof 4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid pyrrolidide ;10 2-[4-(2-chlorophenyl)-9-raethyl-6H-thieno[3,2-f][l,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid piperidide ;2-[4-(2-chlorophenyl)-6H-thieno[3,2-f][1,2,4]triazolo-15 [4 , 3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid morpholide ;2-[4-(2-chlorophenyl)-9-bromo-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic 20 acid morpholide ;25 ;2-[4-(2-chlorophenyl)-9-methoxy-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-2-yl]-ethane-l-carboxylic acid morpholide ;4-(morpholin-4-yl-carbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-[l]benzothieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine ;30 3-(morpholin-4-yl-carbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine ;35 ;3-(N,N-diethylaminocarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine ;23040 ;4 ;4-(N,N-diethylaminocarbonyl)-6-(2-chlorophenyl)-lime thy 1-2 ,3,4,5-tetrahydro-8H-[1)benzothieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine n ;5 4-(4-methylpiperazinylcarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-[l]benzothieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine ;4- (N-methyl-N-2-hydroxyethylaminocarbonyl) -6-(2-10 chlorophenyl)-ll-methyl-2,3,4,5-tetrahydro-8H-[1]- ;benzothieno[3,2-f][i,2,4]-triazolo[4,3-a][1,4]diazepine ;4-(N,N-dimethylaminocarbonyl)-5-(2-chlorophenyl)-10-methyl-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f]-15 [1,2,4]triazolo[4,3-a][1,4]diazepine ;3-(N,N-diethylaminocarbonyl)-5-(2-chlorophenyl)-10-methyl-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine ;20 ;3-(N,N-diethylaminocarbonyl-5-(2-chlorophenyl)-10-bromo-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]— triazolo[4,3-a][1,4]diazepine ;25 4-(morpholin-4-yl-carbonylmethylaminocarbonyl)-5-(2-chlorophenyl)-10-bromo-3,4-dihydro-2H,7H-cyclopenta-[4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine ;4-(morpholin-4-yl-carbonyl)-6-(2-chlorophenyl)-11-30 methyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f]-imidazo[1,2-a][1,4]diazepine ;4—(N,N-diethylamino)-6-(2-chlorophenyl)-ll-methyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f]imidazo-35 [1,2-a][1,4]diazepine ;3-(N-morpholinomethyl)-5-(2-chlorophenyl)-10-methyl-3,4- ;230406 ;dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine ;3-(acetoxymethyl)-5-(2-chlorophenyl)-10-methyl-3,4-5 dihydro-2H,7H-cyclopenta[4,5]thieno[ 3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine ;3-(1.2.4-triazolyl-l-yl-methyl)-5-(2-chlorophenyl)-10-methyl-3 , 4-dihydro-2H, 7H-cyclopenta [4,5] thieno [3,2-f]-10 [ 1,2,4]triazolo[4,3-a][1,4]diazepine ;3-(N-2.6-dimethylmorpholino-methyl)-5-(2-chlorophenyl)-10-methyl-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno-[3,2—f][1,2,4]triazolo[4,3-a][1,4]diazepine ;15 ;3-acetoxymethyl-5-(2-chlorophenyl)-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2~f][l,2,4]triazolo[4,3-a][1,4]-diazepine ;20 4-acetoxymethyl-6-(2-chlorophenyl)-ll-methyl-2,3,4,5- ;tetrahydro-8H-[1]benzothieno[3,2-f]imidazo[1,2-a][1,4]-diazepine ;^ 3-acetoxymethyl-5-(2-chlorophenyl)-10-methyl-3,4- ;25 dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f]imidazo-[1,2-a][1,4]diazepine c.'"\ 3-diethylaminomethyl-5- (2-chlorophenyl) -10-methyl-3 , 4- ;^ dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]- ;30 triazolo[4,3-a][1,4]diazepine ;4-hydroxymethyl-6-(2-chlorophenyl)-ll-methyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f][1,2,4]triazolo-[4,3-a][l,4]diazepine ;35 ;4-(N-morpholinomethyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3 ,2-f][1,2,4]- ;23040 ;triazolo[4,3-a][1,4]diazepine ;4-(pyrazolyl-l-yl-methyl)-6-(2-chlorophenyl)-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine ;4-[4,4-dimethyl-2-oxazolin-2-yl}-6-(2-chlorophenyl)-ll-methyl-2, 3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f ]-[l,2,4]triazolo[4,3-a][1,4]diazepine ;4-[4,4—dimethyl-2-imidazolin—2—yl]-6-(2-chlorophenyl)-ll-raethyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine ;15 4-[1,4,4-trimethyl-2-imidazolin-2-yl]-6-(2- ;chlorophenyl)-ll-methyl-2,3,4,5-tetrahydro-8H-[l]benzo-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine ;4-aminocarbonyl-6-(2-chlorophenyl)-ll-methyl-2,3,4,5-2 0 tetrahydro-8H-[1]benzothieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine ;"r,. 4-[morpholin-4-yl-carbonyl ] -6- (2-chlorophenyl) -2,3,4,5- ;tetrahydro-8H-[ 1]benzothieno[3 ,2-f ]imidazo[l, 5-a] [1,4]-25 diazepine ;4-[4,4-dimethyl-2-thiazolin-2-yl]-6-(2-chlorophenyl)-11 methyl-2 ,3,4, 5-tetrahydro-8H-[ 1 ] benzothieno[ 3 , 2-f ] -[1,2,4]triazolo[4,3-a][1,4]diazepine ;30 ;4-amino-6-(2-chlorophenyl)-ll-methyl-2,3,4,5-tetrahydro 8H-[1]benzothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine ;35 ;3-(N-morpholinyl-methyl)-5-(2-chlorophenyl)-10-methyl-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f]imidazo-[1,2-a][1,4]diazepine ;? 3 0 4 0 6 ;7 ;4-(1,2,4-triazol-1-yl-methyl)-6-(2-chlorophenyl)-ll-methyl-2 ,3,4,5-tetrahydro-8H-[1]benzothieno[3 , 2-f]-[l,2,4]triazol[4,3-a][l,4]diazepine ;4-(1,2,4-triazol-1-yl-methyl)-6-(2-chlorophenyl)-ll-methyl-2 ,3,4,5-tetrahydro-8H-[1]benzothieno[3 , 2-f]-imidazo[1,2-a][l,4]diazepine. ;The following are more particularly preferred: ;6-(2-chlorophenyl)-8,9-dihydro-l-methyl-8-[(4-raorpholinyl)carbonyl]-4H,7H-cyclopenta[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Web 2170) ;4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl) -3-propanon-l-yl]-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine (Web 2086) ;6-(2-chlorophenyl)-8,9-dihydro-l-methyl-8-[dipropyl-aminocarbonyl]-4H,7H-cyclopenta[4,5]thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine (Web 2347). ;Any reference herein to PAF antagonists includes within its scope all pharmaceutical^ acceptable acid addition salts thereof, and any and all isomers and tautomers thereof having similar activity. ;By way of Example of the application of the invention, a 52 year old male patient with ITP was treated with the PAF-antagonist Web 2086 {4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-l-yl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a]-[1,4]diazepine) in a dosage of 4 x 20 mg a day, by oral route, instead of prednisolon. There was a rapid increase in the thrombocytes which had previously not been observed in the patient in question in the 3 years he had had the disease, reliably diagnosed, during his treatment with steroids. The treatment with Web 2086 ;? 3 0 ' C C ;8 ;was discontinued after 10 days, and there was a corresponding fall in the thrombocyte count, as expected. This is illustrated graphically in Fig. 1, as described below. ;The advantage of treatment with PAF-antagonists consists in the total absence of side effects, as far as is currently known in humans, compared with the therapeutic agents hitherto used for this treatment, which have been shown to have considerable side effects, and the rapid increase in the thrombocytes. For a single dose, a dosage range of between 5 and 50 mg for oral administration appears to be acceptable whilst for intravenous administration single doses of between 2.5 and 30 mg are advisable. ;The PAF-antagonist may also be used in conjunction with a cofactor in a low-dose form. Examples of possible cofactors include substances with an immune suppressant effect as well as steroids in low concentrations. ;It is known from prior art that immunosuppressive substances, for example cyclosporin, are recommended for the treatment of idiopathic thrombocytopenic purpura. As is known, cyclosporins give rise to strong side effects. The use of a compound according to the invention has been found to lead to a considerable reduction of these side effects. In this connection, special note has to be taken of the pharmaceutical compositions consisting of a PAF-antagonist, selected from European Patent Applications 176 928, 268 242, 230 942, 240 899, 194 416, 254 245, and 255 028, and a cyclosporin, in particular cyclosporin A, azathioprin or prednisolon. The European Patent Applications listed above contain, as their central structural element, a thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4jdiazepine or a [1,2,4]triazolo[4,3-a][1,4]-benzodiazepine. Agents containing the PAF-antagonists Web 2086, Web 2170 or Web 2347 and a cyclosporin, particularly cyclosporin A, ;230406 ;j ;"2 S NOx are of special significance. ;Because of the aetiology of ITP (Werlhof disease) as an autoimmune disease, treatment with PAF-antagonists, particularly 4-(2-chlorophenyl)-9-methyl-2-5 [3-(4-morpholinyl)-3-propanon-l-yl]-6H-thieno[3,2 — f] — [1,2,4]triazolo[4,3-a](1,4Jdiazepine (Web 2086), may also be advisable in the following autoimmune diseases: autoimmune haemolytic anaemia, autoimmunologically caused glomerulonephritis, thyreoidis Hashimoto, primary 10 myxoedema, pernicious anaemia, autoimmune atrophic gastritis, Addison's disease, juvenile diabetes, Goodpasture syndrome, idiopathic leucopenia, primary biliary cirrhosis, active or chronically aggressive hepatitis (HBsAg-neg.), ulcerative colitis, chronic 15 polyarthritis and systemic lupus erythematodes (SLE). ;The synthesis of 4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-l-yl]-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4Jdiazepine (Web 2086) and the production of galenic preparations is known from German 20 Offenlegungsschrift DE A1 35 02 392 (Example 1). The synthesis of Web 2170 and Web 2347 is known from European Patent Application 254 245. The active substances may be used in the form of conventional galenic preparations such as tablets, suppositories or 25 injectable solutions. Details of the preparation thereof are disclosed in European Patent Applications 194 416 and 254 245, to which reference is hereby made. ;According to one aspect of this invention, we provide pharmaceutical preparations containing a PAF-30 antagonist and a substance having an immune suppressant effect, generally containing up to 40% by weight of the immunosuppressive substance relative to the total amount of the active substance. The amount of the PAF-antagonist in such a preparation must be such that the 35 side effects of the immune suppressant are reduced. ;Such a preparation may be in association with a pharmaceutically acceptable carrier, diluent or ;230406 ;10 ;O ;5 ;o ;15 ;20 2 5 ;excipient. A proportion of between 10 and 20% by weight is preferred. The amount of the PAF-antagonist in a preparation per single dose amounts to between 5 and 50 mg, when administered orally, and between 2 and 30 mg, when administered intravenously. ;The effective compositions according to the invention may be used in the form of the conventional galenic preparations, for instance ;1. Tablets ;5 parts by weight of effective component according to the invention 1 part by weight of stearic acid 194 parts by weight of glucose ;The components are compressed to form tablets of 2 00 mg. ;2. Ampoule solutions ;5 mg of effective component 45 mg of sodium chloride ad 5 ml Aqua pro inj ;In Figure I, the number of thrombocytes is shown in thousands against the time in days. The treatment starts on day 0 and as expected, because of a certain latency, the number of thrombocytes drops again on the next day, to rise very rapidly to approximately normal levels of about 150,000 in the course of the treatment. After the treatment ends on the eleventh day, the number c ;2;UM0G ;11 ;of thrombocytes also falls again, as expected. ;The thrombocytes were counted by known methods using a Coultex Counter* Model S-Plus II. <br><br>
An important side-effect cf cyclosporin in man is nephrotoxicity (Mihatsch MJ, Thiel G, Spichtin HP, Oberholzer M, Brunner FP, <br><br>
Harder P et al. Transplant Proc (1983) 15:2821-2835). <br><br>
The treatment of male spontaneously hypertensive (SH) rats with cyclosporin causes damage to the kidneys which has been used as a model for cyclosporin nephrotoxicity (Reference: Ryffel B, <br><br>
Siegel H, Mueller AM, Hauser R, Mihatsch MJ transplant Proc (1985) JL711430—1431). <br><br>
This nephrotoxicity can be monitored by measurenients of serum creatinine. Elevation of serum creatinine provides evidence of renal damage. Groups of 8 SH rats were dosed orally for 28 days either with 2, 25 or 50 mg/kg cyclosporin; 2, 25 or 50 mg/kg cyclosporin plus 13 mg/kg WEB 2170; 13 mg/kg WEB 2170 alone or vehicles (olive oil arid water alone). Blood was removed before ar.d 4,13, 22 and 29 days after ocnmenceinent of treatment. The rrean level of serum creatinine in rats treated with cyclosporin plus WEB 2170 was lower than that for rats treated with cyclosporin alone. The effect was statistically significant (0.05>p). As an example, at 29 days, mean creatinine levels in micronoles per litre serum were: <br><br>
Vehicle <br><br>
13 mg/kg WEB 2170 alone <br><br>
2 mg/kg cyclosporin alone <br><br>
25/mg/kg cyclosporin alone <br><br>
50 mg/kg cyclosporin alone <br><br>
13 mg/kg WEB 2170 plus 2 mg/kg cyclosporin <br><br>
13 mg/kg WEB 2170 plus 25 mg/kg cyclosporin <br><br>
13 mg/kg WEB 2170 plus 50 mg/kg cyclosporin <br><br>
65 <br><br>
53 <br><br>
71 <br><br>
67 <br><br>
93 <br><br>
56 55 59 <br><br>
22 J An 799 2 <br><br>
v <br><br>
Based on these results it appears that the combination cyclosporin/WEB 2170 may be associated with reduced nephrotoxicity in comparison with cyclosporin alone. <br><br></p>
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