AU627763B2

AU627763B2 - Use of PAF-antagonists for treating autoimmune diseases

Info

Publication number: AU627763B2
Application number: AU40173/89A
Authority: AU
Inventors: Helmet Lohmann
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1988-08-24
Filing date: 1989-08-24
Publication date: 1992-09-03
Anticipated expiration: 2009-08-24
Also published as: EP0361077A2; DK95890A; NZ230406A; ZA896422B; WO1990001927A2; HU896004D0; DK95890D0; AU4017389A; IL91386A0; HUT59604A; PH26996A; EP0361077A3; KR900701276A; JPH03500898A; WO1990001927A3

Description

AUSTRALIA

PATENTS ACT 1952 Form COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE 627763 Short Title: Int. Cl: Application Number: Lodged: C t omplete Specification Lodged: Accepted: t e Lapsed: Published: 'Priority: Related Art: i TO BE COMPLETED BY APPLICANT 'Name of Applicant: Address of Applicant: St A Actual Inventors: tt BOEHRINGER INGELHEIM INTERNATIONAL GMBH D-6507 Ingelheim am Rhein, Federal Republic of Germany HELMET LOHMANN, of Ludwig-Richter-Strasse, Ingelheim an Rhein, Federal Republic of Germany.

6507 Address for Service: CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.

Complete Specification for the invention entitled: USE OF PAF-ANTAGONISTS FOR TREATING AUTOIMMUNE DISEASES The following statement is a full description of this invention, including the best method of performing it known to us:la "Use of PAF-antagonists for treating autoimmune diseases" This invention relates to the use of PAFantagonists for treating autoimmune diseases.

In idiopathic thrombocytopenic purpura (ITP), a disorder of the immune mechanism causes massive 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 compensation.

Previously, this disease was fatal in 60-80% of cases. Since therapy with steroids, particularly prednisolon, the prognosis for ITP has improved significantly.

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 Sdisadvantages of long-term cortisone therapy are well known to those skilled in the art.

20 We have found that surprisingly, PAF-antagonists (PAF-acether antagonists) may be used successfully in therapy for treating autoimmune diseases, particularly idiopathic thrombocytopenic purpura, without giving rise Sto the known side effects of steroid treatment.

25 Many of the compounds which are used as PAFantagonists (PAF platejet activating factor) which may be used according to the invention are known from the S.patent literature and the specialist literature, e.g. in Prostaglandins 35, 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 derivatives of the type RP 59 227, imidazo[2,1-a]iso- 2 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 European Patent Applications 176 928, 176 927, 176 929, 268 242, 320 922, 315 698 and 316 456. Preferably, PAFantagonists 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 V ,10 listed below are particularly preferred.

t [4-(2-chlorophenyl)-l-methyl-6H-thieno[3,2-f1[1,2,4]triazolo[4,3-a] [l,4]diazepin-2-yl]-carboxylic acid Ails' morpholide [4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] triazolo[14,3-a] [l,4]diazepin-2-yl]-carboxylic acid amide 2-[4-(2-chlorophenyl)-9-methy1-6H-thienoI13,2-f1 triazolo[4,3-a] [l,4]diazepin-2-yl]-ethane-l-carboxylic acid diethylamide 2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,41triazolo[4,3-a] (l,4]diazepin-2-yl]-ethane-l-carboxylic acid N,N-di- (2-hydroxyethyl) amide 2-[4-(2-chlorophenyl)-9-methyl-6H-thienoll3,2-f] j triazolo[4,3-a] [l,4]diazepin-2-yl]-ethane-l-carboxylic acid methylamide 2-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] 11,2,4]triazolo[4,3-a] [l,4]diazepin-2-yl]-ethane-l-carboxylic acid isopropylamide 2-[4-(2-chlorophenyl)-9-methyl-6H-thienoll3,2-f] triazolo[4,3-a] [1,4]diazepin-2-yl]-ethane-l-carboxylic acid dimethylamide 3 2-[4-(2-chloroPhenyl)-9-methy1-6H-thieflo[3,2-f] triazolo[4,3-a] [1,4]diazepin-2-yl]-ethafle-l-carboxylic acid N' -methyl-piperazide 2-l4-(2-chlorophefyly)-9methyl16H-thielo[3,2-f] triazolo[4, 3-a] [1,4]diazepin-2-y1]-ethafle-l-carboxyliC acid pyrrolidide 2-[4-(2-chlorophefl)-9-methy16H-thieloI3,2-f] 11,2,4]triazolo[4, 3-a] [1,4]diazepin-2-yl]-ethafle-l-carboxylic Its acid piperidide 2-[4-(2-chlorophenyl)-6H-thielol3,2-f] [1,2,4]triazolo- 14,3-a] [1,4]di~azepin-2-y1]-ethafle-1-carboxylic acid morphol ide 2-14-(2-chlorophenyl)-9-bromo-6H-thieflo[3,2-f] triazolo[4,3-a] [1,4]diazepin-2-y1]-ethafle-1-carboxylic 20 acid morpholide 2-[4-(2-chlorophelyl)-9--methoxy-6H-thielo[3,2-f] triazolo[4,3-a] [1,4]diazepin-2-yl]-ethafle-1-carboxylic acid morpholide 4-(morpholin-4-yl-carbonyl)-6-(2-chlorophelyl) -11methyl-2, 3,4, 5-tetrahydro-8H-11] benzothielo 3,2-f] [1,2,4]triazolo[4, 3-a] [1,4]diazepine 3-(morpholin-4-yl-carboflyl)-6-(2-chlorophelyl) -11methyl-2, 3, 4,5-tetrahydro-8H- [1]benzothieno13 2-f] [1,2,4]triazolo[4, 3-a] [1,4]diazepine 3- (N,N-diethylaminocarbonyl) (2-chlorophenyl) -11methyl-2,3,4,5-tetrahydro-8H-[]belzothielo[3 [1,2,4]triazolo[4, 3-a] [1,4]diazepine 4 4-(N,N-diethylaminocarbonyl) -6-(2-chlorophenyl) -11methyl-2,3,4,5-tetrahydro-8H-[l]benzothieno[3,2-f]- [1,2,4]triazolo[4,3-a] [1,4]diazepine 4-(4-methylpiperazinylcarbonyl) -6-(2-chJlorophenyl) -11methyl-2, 3 5-tetrahydro-8H- [1]benzothieno [1,2,*4]triazolo[4, 3-a] [1,4]diazepine 4- (N-methyl-N-2-hydroxyeth-ylaminocarbonyl) (2chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f][1,2,4]-triaz ,lo[4,3-a]iI1,4]diazepine 4-(N,N-dimethylaminocarbonyl) -5-(2-chJlorophenyl) methyl-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f]- 3-(N,N-diethylaninocarbonyl) -5-(2-chlorophenyl) methyl-3 ,4-dihydro-2H, 7H-cyclopenta[4, 5]thieno[3 [1,2 ,4]triazolo[4 4]diazepine (2-chlorophenyl) 3,4-dihydro-2H,7H-cyclopenta[4,5]thierlo[3,2-f][1,2,4]d triazolo[4,3-a][1,4]diazepine 4- (morpholin-4-yl-carbonylmethylaminocarbonyl) (2chiorophenyl) -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) (2-chiorophenyl) -11- Li 30 methyi-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f]imidazo[1,2-a] [1,4]diazepine 4- (N,N-diethylamino) (2-chiorophenyl) -11-methyl- 2, 3,4, 5-tetrahydro-8H- [1]benzothieno imidazo- [1,2-a][1,4]diazepine 3- (N-morpholinomethyl) (2-chiorophenyl) -l0-methyl-3 ,4dihydro-2H,7H-cyclopefta4,5]thieflo[3,2f][1,2,4]triazolo(4,3-a] [1,4 ]diazepine 3- (acetoxymethyl) (2-chlorophenyl) -10-methyl-3 ,4dihydro-2H,7H-cyclopefta[4,5]thieflo[3,2f][1,2,4]triazolo[4 [1,4]diazepine 3- 4-triazolyl-1-yl-methyl) (2-chiorophenyl) methyl-3 ,4-dihydro-2H, 7H-cyclopenta[4, 5] thieno 2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine -dimethylmorpholino-methyl) -5-(2-chlorophenyl) 10-methyl-3 ,4-dihydro-2H,7H-cyclopelta[4 44fl[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine 4 4 3 -acetoxymethyl-5-(2-chlorophenlyl) 3, 4-dihydro-2H,7Hcyclopenta[4,5]thieno[3,2-f] 2,4]triazolo[4,3-a] diazepine 4-acetoxymethyl-6-(2-chloropheflyl)-11-methyl-2,3,4,5- 4,14,tetrahydro-8H-[1]benzothieno[3,2-f]imidazo[1,2-a] II diazepine (2-chloropheiyl) -10-methyl-3 ,4dihydro-2H,7H-cyclopenta[4 ,5]thieno[3 imidazo- [1,4]diazepine (2-chiorophenyl) -10-methyl-3 ,4dihydro-2H,7H-cyclopenta[4,5]thieno[3 triazolo[4,3-a] [1,4]diazepine 4-hydroxymethyl-6-(2-chlorophenyl) -11-methyl-2,3,4, tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo- [1,4]diazepine 4- (N-morpholinomethyl) (2-chiorophenyl) -Il-methyl- 2,3,4, 5-tetrahydro-SH-[1]benzothieno[3 6 triazolo[4,3-a] [1,4]diazepine 4- (pyrazolyl-1-yl-methyl) (2-chJlorophenyl) -2,3 tetrahydro-8H-[l1benzoEhienoI3,2-f]1[2,2,4]triazolo- [4,3-a](l,4]diazepine 4-[4,4-dimethyl-2-oxazolin-2-ylJ-6-(2-chlorophenyl)-.1methyl-2,3,4, 5-tetrahydro-8--[1]benzothieno [1,2,4]triazolo[4,3-afl2.,4]diazepine 4-[4,4-dimethyl-2-imidazolin-2-yl]-6-(2-chlorophenyl)- 444 11-methyl-2,3,4,5-tetrahydro-8H-[l]benzothieno[3,2-f]- [1,2,4]triazolo[4,3-a] [1,4]diazepine 4-[1,4,4-trimethyl-2-imidazolih-2-yl]-6-(2chiorophenyl) -11-methyl-2, 3,4, 5-tetrahydro-8H-[1]benzothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-aininocarbonyl-6- (2-chiorophenyl) -11-methyl-2 ,3,4,5tetrahydro-8H-[l]benzothieno[3,2-f] [1,2,4]triazolo- 4 4 [4,3-a][l,4]diazepine 4 t4 4-[morpholin-4-yl-carbonyl]-6-(2-chlorophenyl)-2,3,4,5tetrahydro-8H-[ljbenzothieno[3,2-f]imidazo[1,5-a] diazepine 4-[4,4-dimethyl-2-thiazolin-2-yl]-6-(2-chlorophenyl)-11methyl-2,3,4, 5-tetrahydro-BH-[ljbenzothieno[3 4]triazolo[4, 3-a] 4]diazepine Li 4-amino-6- (2-chiorophenyl) -11-methyl-2, 3,4, 8H-[l]benzothieno[3,2-f][1,2,4]triazolo[4,3-a]ll,4]diazepine 3-(N-morpholinyl-methyl) (2-chiorophenyl) 3, 4-dihydro-2H, 7H-cyclopenta thieno 2-f] imidazo- [1,4]diazepine 7 4- 2 ,4-triazol-l-yl-methyl) -6-(2-chiorophenyl) -11methyl -2 ,3 5-tetrahydro-8H- [1]benzothieno [3 ,2 [1,2,4]triazol[4,3-a][l,4]diazepine 4-(1,2,4-triazol-l-yl-methyl)-6-(2-chlorophenyl)-llmethyl-2 ,3 5-tetrahydro-8H- 1] benzothieno [3 imiclazo[l,2-a] [l,4]diazepine.

The following are more particularly preferred: 6-(2-chlorophenyl) -8 ,9-dihydro-l-methyl-8-[ (4morpholinyl) carbonyl] -4H, 7H-cyclopenta 5] thieno- [3,2-f][1,2,4]triazolo[4,3-a]ll,4]diazepine (Web 2170) 4-(2-chlorophenyl) -9-methyl-2-[3-(4-morpholinyl) -3propanon-l-yl]-6H-thieno[3,2-f] [l,2,4]triazolo- [4,3-a][l,4]diazepine (Web 2086) 6-(.2-chlorophenyl) -8 ,9-dihydro-l-methyl-8--[dipropylaminocarbonyl-4H-,7H-cyclopenta[4, 5]thieno[3 [l,2,4]triazolo[4,3-a][l,4]diazepine (Web 2347).

Any reference herein to PAF antagonists includes within its scope all pharmaceutically 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 chlorophenyl) -9-methyl-2-[3-'(4-morpholinyl) -3-propanon- [l,4]diazepine) in a dosa'ge 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, duting his treatment with steroids. The treatment with Web 2086 was discontinued after 10 days, and there was a 8 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 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 25 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 Europeah Patent Applications listed above contain, as their central structural element, a thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine 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, are of special significance.

kl.- MMMMMM I ~_~*r-~-N~LibrrUNLI-~-il ~sll -9- Therefore, according to a further aspect of the present invention we provide a method of reducing any undesired side effects caused by the therapeutic use of a substance having an immune suppressant effect whereby the immunosuppressant substance is not a PAF-antagonist in a human or animal subject which comprises administering to the said subject an effective amount of a PAF-antagonist.

Because of the aetiology of ITP (Werlhof disease) as an autoimmune disease, treatment with PAF-antagonists, particularly 4-(2-chlorophenyl)-9-methyl-2-[3-(4morpholinyl)-3-propanon-1-yl]-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine (Web 2086), may also be advisable in the following autoimmune diseases: autoimmune haemolytic anaemia, autoimmunologically caused glomerulonephritis, thyreoidis Hashimoto, primary 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 polyarthritis and systemic lupus erythematodes (SLE).

The synthesis of 4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3propanon-l-yl]-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine (Web 2086) and S the production of galenic preparations is known from German Offenlegungsschrift DE Al 35 02 392 (Example 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 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-antagonist and a substance having an immune suppressant effect, whereby the immunosuppressant substance is not a PAFantagonist, generally containing up to 40% by weight of the I immunosuppressive substance relative to the total amount of the active substance. The amount of the PAFantagonist in such a preparation must be such that the side-effects of the immunosuppressant are reduced. Such a preparation may be in association with a pharmaceutically acceptable carrier, diluent or 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 mg, when administered intravenously.

The effective compositions according to the invention may be used in the form of the conventional galenic preparations, for instance j 1. Tablets #4 *144 a, .4r 44 4 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 200 mg.

2. Ampoule solutions 5 mg of effective component 45 mg of sodium chloride 30 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.

V After the treatment ends on the eleventh day, the number P jig *1,dl

.L

f 11 of thrombocytes also falls again, as expected.

The thrombocytes were counted by known methods using a Coultex Counter® Model S-Plus II.

Figure I Cr 150- 140- 130- 0 120.

110 S100- tort finish 4j I I I -1 0 1 2 3 4 5 6 7 8 9 1011 1213 1415 1617 days I; 1 i .I dYDIX...M~. lla An important side effect of cyclosporin in man is nephrotoxicity (Mihatsch MJ, Thiel G, Spichtin HP, Oberholzer M, Brunner FP, Harder F et al. Transplant Proc (1983) 15:2821- 2835).

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, Siegel H, Mueller AM, Hauser R, Mihatsch MJ, Transplant Proc (1985) 17:1430-1431).

This nephrotoxicity can be monitored by measurements 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 and water alone). Blood was removed before and 4, 13, 22 and 29 days after commencement of treatment. The mean 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 As an example, at 29 days, mean creatinine levels in micromoles per litre serum were: Vehicle 56 13 mg/kg WEB 2170 alone 25 2 mg/kg cyclosporin alone 59 25 mg/kg cyclosporin alone 93 mg/kg cyclosporin alone 71 13 mg/kg WEB 2170 plus 2 mg/kg cyclosporin 53 13 mg/kg WEB 2170 plus mg/kg cyclosporin 13 mg/kg WEB 2170 plus 50 mg/kg cyclosporin 67 Based on these results it appears that the combination cyclosporin/WEB 2170 may be associated with reduced nephrotoxicity in comparison with cyclosporin alone,

Claims

1. A pharmaceutical preparation comprising a PAF-antagonist and a substance with an immune suppressant effect whereby the immunosuppressant substance is not a PAF-antagonist, the proportion of the PAF-antagonist present being such that the side effects of the immunosuppressant are reduced.

2. A pharmaceutical preparation according to claim 1, wherein the PAP- antagonist is a derivative of a thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine or a derivative of [1,2,4]triazolo[4,3-a][1,4]benzodiazepine.

3. A pharmaceutical preparation according to claim 1 or claim 2, wherein the PAF-antagonist is Web 2086, Web 2170 or Web 2347 (as herein defined).

4. A pharmaceutical preparation according to any one of claims 1 to 3, wherein the substance having an immune suppressant effect is a cyclosporin.

A pharmaceutical preparation according to any one of claims 1 to 4 which additionally includes a pharmaceutically acceptable carrier, diluent or excipient.

6. A method of reducing any undesired 3ide effects caused by the therapeutic use of a substance having an immune suppressant effect, whereby the immunosuppressant substance is not a PAF-antagonist, in a human or animal subject which comprises administering to the said subject an effective amount of a PAF-antagonist.

7. A method as claimed in claim 6, wherein the substance having an immune S' suppressant effect is a cyclosporin.

8. A method as claimed in claim 6 or claim 7, wherein the PAF-antagonist is as defined in claim 2 or claim 3. DATED this 5th day of June 1992. BOEHRINGER INGELHEIM INTERNATIONAL GmbH By their Patent Attorneys: CALLINAN LAWRIE L