Use of tricyclic compounds for producing topical pharmaceuticals

(42) Date of commencement of the patent: 15. 6.1991 (45) Date of issue: 25. 3. 1996 (56) Documentation:

EP 0184162A2

PSCHYREMBEL, 251. EDITION, (1972), pp. 349 AND 1218 EP 0090378A1 EP 0127426A1 EP 0147476A1 WEIR DM HANDB00K OF EXPERIMENTAL IMMJNOLOGY IN FOLLOW VDLUMES, BAM) 2, 4. EDITION, 1986, BLACKWELL SCIENTIFIC PUBLICATIONS, OXFORD 1986, PAGE 7701 TORO KINO ET AL. "FK 506, A NOVEL IMMUNOSUPPRESSANT ISOLATED FROM A STREPTOMYCES", THE JOURNAL OF ANTIBIOTICS (SEPTEMBER 1987), XL (9), p. 1249 BIS 1255 WOLF R. ET AL. "A NEW CONCEPT IN THE PATHOGENESIS OF ORGAN IMXICED PSORIASIS", MEDICAL HYPOTHESES (1986), (3), PAGE 277

NAJBAUER J. ET AL. AERERCE OF CELLS TO MYELIN BASIC PROTEIN ", ACTA NEUROL SCAMC., (1987) 76, PAGE 172

RESEARCH RA ET AL. "A NEW ONE-STEP SYNTHESIS OF LECICOVORIN FROM FOLIC ACID ...", ORG. CHEM. (1985)

50, PAGES 2582 TO 2583

BAKER BS ET AL. "EPIDERMAL TLYMPHOCYTES AND HLA-OR EXPRESSION IN PSORIASIS", BRITISH JOURNAL OF DERMATX0GY (1984) 110, PAGES 555 TO 564

BAKER BS ET AL. T-CELL SUBPOPULATIONS IN THE BLOOD AND SKIN OF PATIENTS WITH PSORIASIS ", BRITISH JOURNAL OF DERMATOLOGY (1984) 110, PAGES 37 TO 44 VALDIMARSSON H. ET AL. PSORIASIS: A DISEASE OF ABNORMAL KERATINOCYTE PROLIFERATION INDUCED BY TLYMPHOCYTES ", IMMJNOLOGY TODAY (1986) 7 (9), PAGES 256 TO 258

TERUI T. ET AL. "HLA-OR ANTIGEN EXPRESSION ON KERATINOCYTES IN HIGHLY INFLAMED PARTS OF PSORIATIC LESIONS", BRITISH JOURNAL OF DERMATOLOGY (1987) 116, PAGES 87 TO 93

MORHENN VB PSORIASIS ", CUTIS (1984), 34, PAGES 223 TO 224

BOS JD ET AL. "IMUNOCOMPETENT CELLS IN PSORIASIS" AROf. DERMATOL RES. (1983), 275, pp. 181-189 ALDRIDGE RD ET AL. IMHIBITION OF CONTACT SENSITIVITY REACTIONS TO DNFB BY TOPICAL CYCLOSPORIN APPLICATION IN THE GUINEA-PIG ", CLIN. EXP. IMMJNOL. (1985), 59, pp. 23 to 28.

(73) Patent owner:

SAMXJ2-ERF INDUNGEN VERWALTUNGSGESELLSCHAFT MBH A-1235 VIENNA (AT).

(54) USE OF TRICYCLIC COMPOUNDS FOR PREPARING TOPICAL MEDICAMENTS (57) The use of compounds of the formula I

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AT 400 808 wherein Ri is an optionally protected hydroxy group, R₂ for hydrogen or an optionally protected hydroxy group, R₃ are methyl, ethyl, propyl or allyl and the dotted line represents a single or double bond, for the manufacture of topical medicines for the treatment of psoriasis.

kr eeraeca

AT 400 808 Β

The invention relates to a novel use of compounds of the formula

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wherein Rt is an optionally protected hydroxy group, R2 is hydrogen or an optionally protected hydroxy group, R3 is methyl, ethyl, propyl or allyl and the dotted line represents a single or double bond, for the preparation of topical medicaments for the treatment of psoriasis.

The compounds of formula I and their preparation and their immunosuppressive and antimicrobial activity are described in EP-A2-0184 162.

It has now been found that the compounds of the formula I possess further interesting pharmacological properties and can therefore be used as remedies. In particular, they have an action against psoriasis in topical application.

It is known and repeatedly reported in the literature that, for example, cyclosporin, a highly effective immunosuppressive agent, when applied topically against psoriasis virtually no effect (eg Lancet 1987, p. 806). Surprisingly, it has now been found that the compounds of the formula I have an excellent action when applied topically, as could be ascertained in the comparative study on animals (oxazolone skin test on the mouse). In the absence of psoriasis models on experimental animals, experimental pharmacology uses test systems based on psoriasis characteristics. One such model is the allergic delayed-type reaction (DTH response) to the skin, which has immunopathological similarities with the psoriatic disorder. In this model, sensitization is carried out by applying an oxazolone solution to the abdominal skin. After 8 days, the second antigen exposure is by epicutaneous treatment of another body site, which is followed by the delayed-type inflammatory response. To sensitize the mice, 10 μl of oxazolone solution (2%) is applied to the ventral abdominal skin with a micropipette and distributed with the pipette tip. Before, the ventral abdominal skin is approx. Shorn 2-3 cm tall, to which the animals are narcotized. 8th Days after sensitization, for second exposure, 10 μl of a 2% oxazolone solution is applied to the peripheral inner surface of the right auricle with a micropipette. The topical treatment is carried out by placing the test solution twice in the place of the second exposure (20 minutes and 2 hours after the second exposure).

The evaluation of the test substance takes place in comparison to an untreated group (solvent control). 24 Hours after the second exposure, the animals are killed in groups by cervical dislocation and processed immediately in the same order. The auricles (first the right, then the left) are discontinued and immediately weighed to 1 mg. The difference between the two OM weights is used for evaluation by statistically determining the individual differences of the test groups and the solvent control (variance analysis and Student's T-test or Kruskal-Wallis' H-Test and Wilcoxon-Mann-Witney's U-Test). The effect of the test substance is given in terms of the mean values ​​in%.

In Tables 1 and 2 are the experimental results in this model for Cyciosporin A (Table 1) and for the compound of Formula I wherein Rt and R2 are hydroxy, R3 is allyl and the dotted line for

AT 400 808 Β a single bond is indicated (= substance A). The solvent used in the test is ethanol.

Table 1

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'S // s

Cs A 0.4% (inhibition: Cs A 0.13% (inhibition Cs A 0.04% (inhibition Cs A 0.01% (inhibition CsA = cyclosporin A llll

71.2%): 55.8%): 27.7%): 15.0%)

AT 400 808 Β

Table 2

35-1

F

F

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R

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N

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I

N

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G

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LM control

Subst. A 0.13% (inhibition: 65.4%)

Subst. A 0.01% (inhibition: 64.8%) Subst. A 0.005% (inhibition: 52.4%) Subst. A 0.002% (inhibition: 38.4%) Subst. A 0.0005% (inhibition: 35.2%)

In the same test, the compound of formula I wherein Ri and R2 are hydroxy, R3 is ethyl, and the dotted line is a single bond, showed a 49% inhibition at a concentration of 0.01%.

The compounds of the formula I are therefore suitable for the topical treatment of psoriasis. For this application, the dose to be administered depends on the compound used and the mode of administration and the type of treatment. Satisfactory results are obtained in larger mammals with multiple daily local administration of 1-3% drug concentration.

The compounds of formula I can therefore be used for the preparation of medicaments for combating psoriatic-induced human diseases. Suitable galenic forms are lotion, gel or cream.

Preferred for this use is the compound of the formula

AT 400 808 Β

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