NL8502571A - Steroidal immuno-modulators - comprising 4-oestrene derivs. - Google Patents

Abstract

4-Oestrene derivs. of formula (I) are claimed for use as immunomodulators. R1 = (H,H) or O; R2 = (alpha-R5,beta-OR6) or O; R3 = 1-2C alkylidene or (H,beta-R7); R4 = Me or Et; R5 = H or 1-4C hydrocarbyl; R6 = H or 1-18C acyl; R7 = 1-4C hydrocarbyl opt. substd. by Cl, OMe or OEt. Pref. R3 = CH2 or (H,beta-R7); R4 = Me; R5 = H or ethynyl; R6 = H; R7 = Me, Et, vinyl, ethynyl, CH2Cl or CH2OMe.

Description

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OA / 8993-184 H. van 't Holt Afczo 2f.V. , Arnhem

Steroids with immunomodulatory properties

The invention relates to steroids of the estrogen series, in particular Δ * -estrogenic derivatives with an optionally substituted hydrocarbon suspendant in position 11, for use as immunodulators and pharmaceutical preparations containing these steroids as active ingredient.

Estrene derivatives with a double bond between carbon atoms 4 and 5 and an optionally substituted hydrocarbon substituent in position 11 are known. See, for example, U.S. patents 3 325 520, 3 465 010, 3 652 606, 3 927 046, 10 3 972 906, 3 983 144 and 4 292 251.

The estrogen derivatives disclosed in the literature to which the present patent application relates are reported to have hormonal properties, in particular androgenic, anabolic, estrogenic, progestative and / or ovulation inhibiting properties.

Surprisingly, it has now been found that a particular group of Δ * estrene derivatives with an optionally substituted hydrocarbon group in position 11 have immunomodulatory properties.

The present invention therefore relates to estrene derivatives of the general formula I.

20 r3 λ, R2 ν / \ ϊ_γ 25 / xAA /

Ri / vV

1502 5 7 1 30 2 in which

R 1 * Hg or 0; R2 = (aR5) (BOR6; or O; R3 = alkylidene (1-2 C) or H (8R7); 5 Row = methyl or ethyl;

Rs = H or hydrocarbyl (1-4C);

Re * H or acyl (1-18 C); and R7 * hydrocarby K1-4 C), optionally substituted by Cl or alkoxy (1-2C), for use as immunoniodulators.

The invention also relates to pharmaceutical preparations with immunomodulatory properties, which contain at least one of the compounds of the formula I.

By alkylidene (1-2 C) is meant methylene and ethylidene (E and Z form). The alkylidene group is preferably methylene. R 1 * is preferably methyl.

Acyl (1-18 C), as the addition (1-18 C) already indicates, is derived from an organic carboxylic acid with 1-18 carbon atoms.

As examples of this can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, trimethyl acetic acid, valeric acid, caproic acid, capric acid, pelargonic acid, undecylene acid, lauric acid, palmitic acid, oleic acid, phenyl acetic acid, phenyl propionic acid, cyclopentyl propionic acid, cyclohexic acid octylacetic acid, benzoic acid, fumaric acid, maleic acid, succinic acid, citric acid.

By hydrocarbyl (1-4C) is meant methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl or an unsaturated variant thereof with 2-4 carbon atoms, such as vinyl, ethinyl, allyl, propargyl isopropenyl, butynyl or butadienyl .

R5 is preferably H or ethinyl, wherein R6 is then preferably H. R7 is preferably hydrocarbyl (1-2 C), optionally substituted by chlorine or methoxy. Examples for R7 are methyl, ethyl, vinyl, ethinyl, chloromethyl and methoxymethyl.

85 0 2 5 7 1 3

The compounds of the formula I and the pharmaceutical preparations based thereon have, as mentioned, immunomodulatory properties, ie they are capable of beneficially influencing the immune system. They are particularly suitable for use in the treatment. from autoimmune diseases, such as SLE (systemic lupus erythematosus), rheumatoid arthritis, autoimmune thyroiditis, Sjpgrens syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis and haemolytic anemia.

Examples of steroids of the formula X which can be used according to the invention are: 11-methylene-Uct-ethinyl-A * -estren-17B-ol; 11-methylene-17a-ethiny1-17β-hydroxy-Δ * -oe strren-3-one; U-methylene-1 / a-ethyl-A * -estren-17β-ο1; 11-methylene-1Z-ethinyl-1S-methyl-A1 * -estren-17β-ο1; 11 -methylene-17α-ethiny 1-17 β-hydroxy-18-methyl-A't-estren-3-one; 11- {Z) -ethylidene-17a-ethinyl-A, f-estren-17S-ol; 21- (E) -ethylidene-17a-ethinyl-17B-hydroxy-atestones-3-one; 11-methylene-Ua-allyl-A * -estren-17β-ο1; 11-raethylene-1 7B-hydroxy-A-1-esters-3-one; 11-methylene-17 α-butyl-17B-hydroxy-Aif-esters-3-one; 11-methylene-1-methyl-A * -sotren-17-one; 11B-methyl-17ct-ethiny1-Δ4-oestren-17β-οΐ; HB-methyl-1Za-isopropyl-A1 * -estren-17β-ο1; 11B-raethyl-17B-hydroxy-d * -estren-3-one; 25 118.17a-diethyl - & * - oestren-17β-ο1; 11β-vinyl-1 7a-e thiny 1-17B-hydroxy-A * -oes tren-3-one; 11B-vinyl-A * -s treen-3,17-dione; 18-vinyl-178-hydroxy-Ait-estren-3-one; 11β, 17a-diethinyl-1 7B-hydroxy-Atestren-3-one; 11β, 17a-di-ethiny1-Δ * -estren-17B-ol; 11β-ethiny1-17β-hydroxy-A + -oestren-3-one; 11B-chloromethyl-17a-ethinyl-17B-hydroxy-d * -estren-3-one; II B-chloromethy 1-17a-ethiny 1- / 1-oestren-17β-ο1; 11β-methoxymethyl-1Ja-allyl-d * -estren-17B-ol; 3502571 35 4

Uf} -methoxymethyl-17-ethyl-vinyl-17 (3-hydroxy-A'f-estren-3-one; 118-methoxymethyl-17 &-hydroxy-A't-esters-3-one; and esters thereof, for example the acetate , the decanoate or the cyclooctyl acetate.

The pharmaceutical preparations according to the invention can be prepared according to known galenic techniques, for example by molding the respective steroid compound of the formula I suitable for enteral (eg oral or rectal), parenteral (eg intravenous, subcutaneous or intra -10 muscular) or local (through the skin or mucous membranes) application. For this purpose, the steroid compound is mixed with or dissolved in a pharmaceutically acceptable carrier.

Examples of such preparations are tablets, pills, dragees, lozenges, suppositories, powders, (micro) capsules, emulsions, suspensions, solutions, implants, ointments, creams and lotions.

The amount of active substance (Al-estrene derivative of the formula I) in the moldings and powders to be administered entralally is 0.01-25.0 mg and usually 0.1-5.0 mg. The daily dose is usually 1-3 dosage units. In the liquid and semi-soft dosage forms, which are injected or applied to the skin or mucous membranes, the active substance concentration is about 0.005 to 20% by weight, usually 0.01 to 5% by weight. Injections are usually performed with 1 ml dose units.

The pharmaceutically acceptable carriers may be composed of one or more of the following ingredients: starch (eg potato starch, corn starch), sugars (eg lactose), lubricants (magnesium stearate, stearic acid), binders (eg amylopectin, polyvinylpyrrolidone), water, alcohol, glycerol and its derivatives, vegetable, animal and mineral oils and fats, fatty alcohols, silicones, lanolins, polyalkylene glycols, cellulose derivatives, silica, dispersants, emulsifiers, surfactants, antioxidants, preservatives, etc.

8502 57 1 5

The immunomodulatory properties of compounds of formula I were demonstrated by a test representative of the said action, the Bursa model.

In this model, the influence of the substance to be investigated on the development of the Bursa of Fabricius is investigated in chickens. The substance is administered at the embryonic stage by immersing incubated eggs in an ethanolic solution of the test substance for three days. The eggs are then incubated further and ten days after hatching the chicks are killed and the body weight and weight of the Bursa of Fabricius determined.

The Bursa of Fabricius is an organ located near the cloaca and responsible for the maturation of the B cell system, which ensures the production of antibodies. The inhibitory effect on the development of said organ of the test substance is determined, using nandrolone (19-nor-testosterone) as a reference.

The use of nandrolone as a reference is based on the fact that nandrolone in another model, the so-called NZB / W model, has a beneficial effect on lupus in NZB / W mice (murine lupus), which is an indication for a beneficial effect of this substance on autoimmune diseases. See in this regard Clin. Exp. Immunol. 44 (1981), p.

11-17.

A drawback of the NZB / W model is that the tests in this model take so long (1 to a year). The Bursa model is preferable for the screening of a large number of substances.

The results of the tests in the Bursa model are summarized in the following table.

3502577 6

FABRIC P

1 l -methylene-18-methyl-A'f -estren-17-one 40 5 UB-chloromethyl-na-ethinyl-nB-hydroxy-A-1 -stren-S-on 35 llB-vinyl-Δ1 * -estrene- 3,17-dione 35 lB-chloronethyl-Ua-ethinyl-A * -estrins-178-ol 25 I lfJ-vinyl-17B-hydroxy-A * -stars-3-one 24 ll-methylene-Ua-ethyl-A1 * oestren-17β-ο1 21 10 lB-methyl-HS-hydroxy-A1 * oest-3-one 19 118,17a-diethinyl-h1 * '- oestren-17β-ο1 17 11-methylene-l 7a -ethinyl-l 7B-hydroxy-A * -estren-3-one 17 11-methylene-1 la-ethinyl-A1 * -estren-17β-ο1 14 Ιΐβ-vinyl-l7oj-ethinyl-l7β-hydroxy-Δ * - oestren-3-one 10 15 lB-methoxymethyl-HB-hydroxy-A1 * -estren-3-one 10 11-methylene-1 7S-hydroxy-A * -estren-3-one 9 1IB, 17a-diethyl- A4-oestren-17 $ -ol 7.5 11β-methyl-l7a-ethinyl-A '* - oestren-17β-ο1 7 II β-methyl-l 7a-isopropyl-Ai * -estren-17β-ο1 6 20 11 -methylene-1 la-ethinyl-A1 * -estren-17β-ο1 5 llB-methoxymethyl-ncj-allyl-A1 * -estren-17B-ol 4 nandrolone (reference) 1

Column P shows the potency of the substance compared to that of nadrolone. The values found do not appear to correlate with the endocrinological action of these substances.

The invention is illustrated by the following examples.

In each of the examples, the active agent may be replaced, if desired, by an equivalent amount of another agent of formula I.

85025/1 7

Example X.

Tablets 5 a) Li-vinyl -t-estrene ~ 3,17-dione 2.0 mg potato starch 10.0 mg magnesium stearate 0.5 mg ascorbyl palmitate 0.2 mg amylopectin 2.0 mg 10 lactose to 100.0 mg b) 11S-methyl-17g-hydroxy-A'i'-esters-3-one 3.0 mg corn starch 10.0 mg stearic acid 1.0 mg silica ("Aerosil") 1.0 mg polyvinylpyrrolidone 3.0 mg dl-a-tocopherol 0.1 mg lactose to 100.0 mg 20 c) 11gj ^ a-diethinyl-A-estren-nB-ol 3.0 mg potato starch 25.0 mg magnesium stearate 4.0 mg dl-ct- tocQpherol 0.2 mg lactose to 100.0 mg 25 d) 11-methylene-1S-methyl-A * -estren-17-one 1.0 mg potato starch 25.0 mg magnesium stearate 4.0 mg dl-a-tocopherol 0 .2 mg of lactose to 100.0 mg of 8502571, »f» w8

Example 2

In j ection preparations 5 a) Suspension: 11-methylene-17a-ethinyl-A * -estren-17β-1-17-decanoate 1.0 mg carboxymethyl cellulose Na 5.0 mg sodium bisulfite 0.2 mg water to 1.0 ml 10 b) Oil solution: II & -chloromethyl-17a-ethinyl-Ai * -estren-17S-ol 2.0 mg BHA / BTA (1/1) 0.2 mg arachis oil to 1.0 ml 15

Example 3

Soft gelatin capsules for oral use. A sterile solution of 11B-methoxymethyl-Ug-hydroxy-A1 * -estre-3-on-178 "cyclooctyl acetate in peanut oil was prepared containing 12.5 g per liter. This solution was packaged in soft gelatin capsules according to standard encapsulation methods. The capsules had a content of 0.24 ml, so that they each contain 3.0 mg of active substance.

25 8502 5 7 1

Claims (8)

Steroids according to claim 1, wherein R 3 = * methylene or H (BR7). Steroids according to claim 1 or 2, wherein R 1 e methyl. Steroids according to claims 1-3, wherein Re * H. Steroids according to claims 1-4, wherein R 5 * H or ethinyl. Steroids according to claims 1-5, wherein R7 * hydrocarbyl (1-2C), optionally substituted by Cl or methoxy. Steroids according to claim 6, wherein R7 "is methyl, ethyl, vinyl, ethinyl, chloromethyl or methoxymethyl. Steroids according to claims 1-5, wherein R 3 * methylene or H (BR7) and R? * methyl, ethyl, vinyl, ethinyl, chloromethyl or methoxymethyl. A pharmaceutical composition with immunomodulatory properties, which contains a compound according to claims 1-8. 8502 57 1