JPS6145637B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 17β-esters of testosterone and 5α-dihydrotestosterone. Testosterone (17β-hydroxy-△ ⁴ -17
-androstenone) and 5α-dihydrotestosterone (17β-hydroxy-5αH-17-androstenone) (hereinafter abbreviated as T and DHT, respectively) are known. In the medical community, these androgen substances are used, for example, in men who are deficient in endogenous androgenic hormones. Esters of T or DHT are usually administered parenterally, ie, dissolved or suspended in a suitable liquid carrier and injected. T and DHT exhibit very little activity when administered orally. T and
Administration of DHT in the presence of oil enhances the effects of oral administration, especially when T and DHT are in their ester states derived from aliphatic carboxylic acids such as decanoate and undecanoate. It is known. Surprisingly, new T-esters and DHT-esters derived from certain branched chain aliphatic monocarboxylic acids having 8 to 16 C atoms have very interesting androgenic effects, especially It has now been found that it has this effect when administered orally in the presence of pharmaceutically usable riboids. Therefore, the present invention provides the formula [In the formula, n is 0 or 1; R ₁ is alkyl (1 to
5C); R ₂ is alkyl (3-10C), provided that when R ₁ = alkyl (1-2C), R ₂ is not alkyl (3-6C), and when R ₁ = alkyl (3-5C), preferably
When R ₂ = R ₁ , R ₁ = alkyl (1-2C), R ₂ = alkyl (7-8C), or R ₂ is a cycloaliphatic group having 6 to 10 C atoms, and the cycloaliphatic The group group has a 6-membered ring; or R ₁ +R ₂ together with the C atoms to which they are attached form a cycloalkyl group with 7 to 12 C atoms, preferably 8 to 10 C atoms; This cycloalkyl group is an alkyl (1
~3C); however, the total number of C atoms in the ester group is 8 to 16, preferably 8 to 12) Concerning 17β-ester. The novel esters are prepared by methods known to those skilled in the art, for example by adding T or DHT to the monocarboxylic acid, or a functional compound of the monocarboxylic acid, such as an acid halide (acid chloride or acid bromide) or an acid anhydride. Manufactured by reacting with derivatives. The reaction of T or DHT with a monocarboxylic acid as described above can be accomplished, for example, by melting the two reactants together or by combining the two reactants in a solvent such as acetonitrile via a water binder such as dicyclohexylcarbodiimide. It is carried out by reacting. The reaction of T or DHT with an acid halide such as chloride is usually carried out in a solvent such as acetone, hexane, toluene, pyridine in the presence of a base such as pyridine or dimethylaniline. The reaction between T or DHT and an acid anhydride is usually carried out in a solvent such as hexane, pentane, or toluene in the presence of a base such as pyridine or an acid catalyst such as P-trienesulfonic acid, dinitrobenzenesulfonic acid, or sulfosalicylic acid. It will be implemented with As particular examples of branched aliphatic monocarboxylic acids which can be used to prepare the novel esters according to the invention:
2'-methyl-decanoic acid, 3'-methyl-decanoic acid,
2'-Methyl-3'-cyclohexyl-propionic acid, 2'-cyclohexyl-butyric acid, cycloheptyl-acetic acid, cyclo-octyl-acetic acid, cyclo-
Examples include octane-carboxylic acid, cyclodecanecarboxylic acid, cyclododecanecarboxylic acid, 3'-butyl-heptanoic acid, 2'-propyl-pentaic acid, and 2'-butyl-hexanoic acid. Anhydrides or acid chlorides or bromides of these acids may also be used as described above. The novel ester according to the present invention can be administered internally and parenterally in the form of tablets, powders, capsules, granules, pills, large pills, sugar coatings, granules, microcapsules, suppositories, solutions, and dispersions. It can be administered in the usual dosage forms for. The novel T- and DHT-esters are particularly useful as androgen substances for oral administration, and are particularly effective when administered orally in the presence of lipoidal substances, preferably non-steroidal lipoids which can be used as drugs. Nonsteroidal lipoids that can be used as drugs include vegetable and animal fats and oils that consist of or contain mono-, di-, and triglycerides of various fatty acids; fatty acid esters of alcohols; higher aliphatic alcohols. (containing 6 or more C atoms); saturated and unsaturated fatty acids; commercially available synthetic and semisynthetic mono-, di-, and triglyceride oils and glycerol ethers; certain types of waxes and two or more means a mixture of the above substances. The lipoidal material may be liquid at normal temperatures, ie, temperatures of about 10<0>C to about 35<0>C.
In this case, the T- or DHT-ester is dissolved in the lipoidal material and the solution is incorporated into the preparation or optionally converted into drug form. At normal temperatures, a portion of the ester may be present as a suspension in the liquid lipoid, in which case the amounts of ester and lipoid material are such that the ester is completely dissolved in the lipoid material at body temperature. mutually adjusted to the amount. Examples of lipoidal substances that can be used in the preparations according to the invention include peanut oil, castor oil, sesame oil, linseed oil, soybean oil, sunflower seed oil, olive oil, fish liver oil, ethyl oleate, oleyl oleate, glyceryl trioleate, glyceryl dioleate. ate, glyceryl monooleate, cetyl alcohol, stearyl alcohol, capric acid, udecenoic acid, undecanoic acid, lauric acid, oleic acid,
synthetic glycerides of saturated fatty acids having 8 to 10 or 8 to 12 C atoms, such as the commercial products under the trade names "Syndermin GTC" and "Miglyol 812";
Mention may be made of polyoxyethylene derivatives of glycerol, such as the commercial product under the trade name "Labrafil 1944", beeswax and mixtures of two or more of these substances. The combination of novel T- or DHT-esters and lipoids in liquid or semi-liquid state may also be processed into solid oral dosage forms such as pills or tablets. For this purpose, the oily solution of the steroid ester is absorbed, for example in calcium phosphate, lactose or cellulose derivatives, and then processed into tablets or pills in the usual manner. The combination of T- or DHT-esters and lipoids that are solid or semi-solid at room temperature but liquid at body temperature, such as glyceryl monooleate or capric acid, can be granulated and processed to form coated pills or tablets. You may. Medicaments made into dosage forms for internal and parenteral administration can be prepared, for example, by benzyl alcohol, water or thickening agents such as gelatin or agar, polyethylene glycol, lactose starch, to improve the solubility of the active substance in the oil component. It may also contain one or more conventional adjuvants such as talc or magnesium stearate. Other additives may also optionally be included, such as preservatives, emulsifiers, stabilizers, wetting agents, perfumes, dyes, fillers, binders, and/or encapsulating agents. As mentioned above, the T- or DHT-esters according to the invention may be administered dissolved in lipoidal materials that are liquid at normal temperatures. The oral dosage form of choice for this liquid state preparation according to the invention is a soft gelatin capsule or microcapsule. By methods conventional in the art, the oily solution containing the active ingredient and optionally other ingredients is encapsulated as soft gelatin capsules or microcapsules of the desired size and containing the desired amount of the active ingredient. be done. The microcapsules can be further processed into tablets or pills by well-known dosage formulation techniques. The concentration of the androgenic ester in the lipoid-containing preparation formed into a dosage form is T- or DHT-
The weight of the ester does not exceed the weight of the lipoid material, in other words the concentration of the androgen ester in the preparation is 50% by weight or less, usually in the range of 1 to 40% by weight, It can be varied within considerable limits. As mentioned above, the weight of the lipoid being prepared according to the invention is equal to or greater than the weight of the androgen ester. Depending on the other ingredients present in the preparation (adjuvants, capsule shells, coatings), the amount of lipoidal material per dosage unit may be 25
It varies between ~95% by weight and is usually in the range of 40-80% by weight. 1 such as 1 capsule or 1 tablet
The amount of androgenic ester per dosage unit also varies within a wide range, for example between 0.5 mg and 400 mg, preferably between 1 mg and 200 mg. The useful androgenic properties of the novel T- and DHT-esters of the present invention are demonstrated by the Hershberger test [L.G. Hershberger et al., Proceedings of the Society for
Experimental Biology and Medicine; Vol.83,
p175-180 (1953)] and is measured as follows. First, male rats (21st age) of the Holtzman-Rolfsmeyer strain are castrated and treated with the active substance of the present invention and a control substance (T-decanoate) once or twice a day.
After oral administration for 7 days, the weight increase between the spermatozoa and the ventral prostate was measured. The results are shown in the following table as a ratio to the control substance.

[Table] Thus, in experiments such as those described above, if the daily dose is in the range of 2 x 0.5 mg to 2 x 2 mg in peanut oil, for example, testosterone 3'-cyclohexylbutyrate, testosterone 2'-methyl The androgenic effects of -3'-cyclohexylpropionate, testosterone 2'-methyl-decanoate, and testosterone cyclo-octyl-acetate are greater than those of the unbranched ester, testosterone decanoate.
It turned out to be five times larger. Similar results were obtained for DHT-ester. In clinical trials with the novel esters according to the invention, administration of T-esters in the range of 20 to 100 mg per day showed that men with normal plasma T levels and reduced endogenous T production were Plasma T levels were significantly elevated in both men and men with low plasma T levels. One soft gelatin capsule containing 25 mg of testosterone cyclo-octyl-acetate in 0.24 ml of oleic acid was administered orally per day to men with sexual dysfunction for 3 months.
Levels rose to normal values. Next, the present invention will be explained by examples. Example 2 in a mixture of 8 ml pyridine and 8 ml acetone
A solution of g testosterone was cooled to -10 DEG C., and a solution of 4 ml of 2'-methyl-decanoyl chloride dissolved in 12 ml of acetone was added dropwise thereto under a nitrogen atmosphere. This mixture at 0℃
After stirring for 16 hours, 4 ml of pyridine and 8 ml of water were added thereto. This mixture was heated at 0°C for 1 hour and at 45°C.
After stirring at °C for 2 hours, the mixture was poured into 200 ml of ice water. Extraction with diethyl ether, neutralization of the extract, evaporation of the diethyl ether and chromatography of the residue on silica gel with toluene/ethyl acetate 8/2 yielded 3.0 g of oily testosterone 2'-methyl- Decanoate was obtained, which had [α] ²⁰ _D =+77.0° (in methylene chloride) and εmol=16800 (λmax 240 mμ). The following 17β-esters were produced in the same manner. T-3'-methyl-decanoate, oil, [α] ²⁰
_D
= +80°; T-2'-methyl-3'-cyclohexyl-propionate, melting point 133-136°C, [α] ²⁰ _D = +68°; T-3'-cyclohexyl-butyrate, melting point 82-88°C, [α] ] ²⁰ _D = +80.7゜ T-cyclododecanecarboxylate, melting point
116-119°C, [α] ²⁰ _D = 84°; DHT-2'-methyl-decanoate, melting point 86-
87°C, [α] ²⁰ _D = +25°; T-cyclo-octyl-acetate, melting point 82-
83°C, [α] ²⁰ _D = +84°; T-2'-propyl-pentanoate, melting point 83-
85℃, [α] ²⁰ _D = +84°; T-3'-butyl-heptanoate, oily, [α] ²⁰ _D = +77.0°; T-2'-butyl-hexanoate, oily, [α] ²⁰ _D =+74.2°; (The above [α] ²⁰ _D was measured in methylene chloride.)

Claims (1)

[Claims] 1 formula [In the formula, n=0 or 1, R ₁ = alkyl (1-5C) R ₂ = alkyl (3-10C), provided that when R ¹ is alkyl (1-2C), R ₂ is alkyl ( 3 to 6C), or R ₂ is a cyclo-alkyl group having 6 to 10 C atoms, and the cyclo-alkyl group has a 6-membered ring, or
R ₁ + R ₂ together with the C atom to which they are bonded is 7
from aliphatic monocarboxylic acids with 8 to 16 C atoms forming a cyclo-alkyl group with ~12 C atoms, which group may be substituted by alkyl (1-3C)] Novel 17β-esters of derived testosterone and 5α-dihydrotestosterone. 2. The ester according to claim 1, wherein when _R1 = alkyl (3-5C), _R1 = _R2 . 3. The ester according to claim ₁ , wherein when R1 = alkyl (1-2C), _R2 = alkyl (7-8C). 4. Ester according to claim 1, characterized in that R ₂ = cyclohexyl and R ₁ = methyl. 5. Ester according to claim 1, characterized in that R ₁ +R ₂ together with the bonded C atom form cyclooctyl. 6. The ester according to any one of claims 1 to 5, wherein the total number of C atoms in the aliphatic monocarboxylic acid residue is within the range of 8 to 12.