JPS63152320A - Teststerone-5 alpha-reductase inhibitor composition containing 4-aza-17-substituted 5 alpha-androstane-3-one - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Testosterone-5a- and stan-3ones and their A-ring and D-ring congeners, and the testosterone-5a-
Regarding its use as a reductase inhibitor.

Some unfavorable physiological symptoms, such as acne vulgaris, seborrhea, female baldness, male pattern baldness, and benign prostatic hypertrophy, are due to the metabolic system's dependence on testosterone or similar androgene systems. It is a well-known fact in the art that this is due to hyper-androgien stimulation caused by excessive accumulation of hormones. Several steroidal anti-androgiens have been developed in an initial attempt to provide chemotherapeutic agents against these unfavorable consequences of hyperandrogenism;
These themselves have undesirable hormone-like activities. For example, nystrodiene not only counteracts the effects of androdiene, but also has feminizing effects. Non-steroidal anti-androgiens have also been developed. For example, fdl:4'm:tro3'-trifluoromethylbutylanilide. Neri et al. , ,h'? L. (Vol. 1691, No. 2, 1972) However, these compounds do not have hormone-like effects, but are active in the periphery, competing with androgiens in the receptor, and therefore being administered. It has a tendency to feminize fetuses in male and female wombs.

Recently, the major mediator of androgien activity in several target organs is 5α-dihydrotestosterone, which is locally administered to testosterone-5a-
It has become well known that it is produced by reductase. It was therefore hypothesized, and has been shown, that inhibitors of testosterone-5a-reductase would reduce or prevent the symptoms of hyperandrogen stimulation. Nayfeh Others are in vitro Cin
(in vitro) K, methyl 4-andosten-3-one-17β monocarpoxylate was converted to testosterone-5a.
-reductase inhibitor (8-t-
e-roidg, vol. 14. 269, 1969). Additionally, Boyd (VOlit) and Fusia (H, iα) have shown that the above-mentioned ester and its free acid, i.e., 4-andosten-3-one-17β-carboxylic acid, are inhibitors of testosterone-5α-reductase in vitro. CEtLdocrino −
Jogy+ Volume 92, Page 1216, 1973M, Canadian Patent No. 970692). They further showed that topical administration of testosterone or 5α-dihydrotestosterone increases androgen-derived adipose structures in the flank organs of female hamsters. However, co-administration of 4-androsten-3-one-17β monocarboxylic acid or its methyl ester has been shown to inhibit testosterone-induced responses (no changes made) or to inhibit responses induced by 5α-dihydrotestosterone. response is not inhibited. These results are explained by the fact that these compounds have anti-anthrosene activity due to their ability to inhibit testosterone-5α-reductase.

The new compounds of the present invention are therefore selective antianthrodiene substances capable of specifically inhibiting testosterone-5α-reductase.

Until now, the use of 4-aza-17-substituted-5α-antrostan-3-ones for the treatment of hyperandrogien stimulation was unknown. However, Seri (Se
In Belgian patent no. agent (Ca1.al.o
xic agent).

A number of 4-aza steroid compounds are known. For example, U.S. Pat.
64,301, 3,285,918, French Patent No. 1,465,544, Doorenbos
bos) and Solomon (8o1omons) J.

Phar, 8ct, Vol. 62, No. 4, pp. 638-6
40 pages% 1973, Doorenbos CD Dooranb
os) and Brown CErown) J, Phar
.

8ci, Vol. 60, No. 8, pp. 1.234-1235, 1971. However, no known compounds suggest the 4-aza compounds of the present invention or their use in hyperandrodiene conditions.

The present invention provides a novel anti-androdiene, 4-aza-17β
-Substituted-5α-antrostan-3ones, their analogues, some isoesters and derivatives thereof, processes for the preparation of these compounds, pharmaceutical formulations and novelties containing these new compounds as active ingredients The present invention relates to a method for treating hyperanthrodiene symptoms by inhibiting 5a-Redac (content unchanged) by using compounds or their pharmaceutical formulations.

The present invention particularly relates to novel compounds represented by the following formula.

(II) (In set IID 1, structural formula (I) is a partial structural formula (II)
and/or (IIIr), where A is (1) CH2CH2- (2) -CH=CH- CH3 (3) -CH-CH2- CH2 (4) -CH-'CH- , B is here R1 is (8) hydrogen (b) methyl or ethyl (C) ethynyl (d) ethynyl (e) NR2R' where R2 and R3 are hydrogen or methyl (f) cyano θ where X is various is an anion and R4 is (a) OR5 where R5 is c, -4 alkyl; or (b) NR6R7 where R6 and R7 are hydrogen or methyl; R' is hydrogen or methyl and R'' is hydrogen or β -methyl, R″′ is β-methyl or hydroxy, and Z is (1)
Oxo (2) β-hydrogen and α-hydroxy; or α-hydrogen or α-hydroxyl (3) (Y)nQ where n is 0 or 1, and Y is a straight chain or branched carbon atom 1 to 12 hydrocarbons Q is O (a) C-R8 where R8 is (i) hydrogen (ii) hydroxy (i) Cl-4 alkyl (to) N R9RIo where R9 and R'' are Hydrogen C
independently selected from 1-4 straight chain or branched alkyl, C3-6 cycloalkyl and phenyl. Alternatively, R9 and R'', together with the nitrogen to which they are attached, are shown as a 5- to 6-membered saturated ring containing up to one further heteroatom (chosen from oxygen or nitrogen atoms).

(v)OR "R" here is M, here M is hydrogen or an alkali metal, or Or straight chain or branched Cl-18 Alkyl or benzyl Ru.

(b) 0R12 (If it is 17α-OH, n must be l.) Here, R12 is (■) hydrogen (ii) alkylcarbonyl Gi of Cl-20)
phenyl C1-6 alkylcarbonyl) C5-8゜cycloalkylcarbonyl (v) benzoyl, or 6/D C1-a alkoxycarbonyl group is replaced.

(b) NR9R10 (6) cyano; or (7) a pharmaceutically acceptable compound of the above-mentioned compounds; It is salt.

Unless otherwise indicated, various substituent configurations α and β were tried.

A preferred form of the new compound has the following structural formula.

R' Here, R1 is hydrogen, methyl or amino, and ■ is C-OCH:l.

The most preferred structure of this new compound is R1 or methylteT.
C,t CON HCH2CH3 or CON (C
H2CH,)2.

Representative compounds of the present invention are as follows.

17β-N,N-diethylcarbamoyl-4-methyl-
4-aza-5α-antrostan-3-one 17β-N,N-diethylcarbamoyl-4-aza-5
α-Anthrostan-3-one 17β-N,N-diethylcarbamoyl-4-amino-4-aza-5α-Anthrostan-3-one 17β-acetoxy-4-aza-5α-Anthrostan-3-one 4 -aza-20-spiroxy-5α-an-3-one 4-methyl-4-aza-5α-20-spiroxane-3
-one 17β-N-ethylcarbamoyl-4-methyl-4-aza-5α-anthrost-3-one 4-methyl-4-aza-5α-plecnan-3.20-
Dione 4-ethyl-4-aza-5α-20-spiroxane-3
-one 17β-carbomethoxy-4-methyl-4-aza-5α
-Anthrostan-3-one The novel compound of the present invention having the structural formula (1) and the structural formula (I) having a partial structure of the structural formula (2) is produced by a method including the following steps.

A compound having the structural formula shown in the following formula (in the following formula, A is -C
(1) By treating with an oxidizing agent at low temperature, the corresponding 5-oxo-3,5-seco-antrostane-3-
Obtain the compound of oic acid.

(2) A compound of 4-aza-5-androsten-3-one in which the 4-position is substituted with R' by treating the product of step (1) with an amine having the structural formula C of R' NH2 get.

(3) Compound B is obtained by reacting the product of step (2) with hydrogen in the presence of a catalyst.

Thus, the final step of the process is hydrogenation to introduce 5α-hydrogen.

The reactions described above are described in detail in Examples 1 to 8 below and illustrated schematically in the Tables below.

CVrl) (VI)
When producing a compound, the product produced by the above method is further reacted in the following steps.

(,1) By reacting the lactim carbonyl with trialkyloxonium tetrafluoroforate and alkylating the lactim carbonyl, the corresponding alkyliminium ether, i.e., structural formula 1B or R as described above, can be prepared.
A compound that is 4 OR' is obtained.

(2) By reacting the product of step (1) with an amine having the structural formula (NR6R') and subsequently reacting with a mineral acid, the product of the structural formula Obtain a certain compound.

When it is desired to produce a compound having the structural formula (A) or -CH═CH-, the product produced by the method described on pages 37 to 39 is further reacted by the following steps.

(1) (1) A corresponding erulate is prepared by reacting a disaturated compound with lithium diisopropylamide.

(2) L-1 in step (1) is treated with diphenyl disulfide in situ to obtain the corresponding α-phenylthio compound.

(3) Oxidize the product of step (2) to obtain the corresponding sulfoxide compound.

(4) The product of step (3) is heated and the structural formula 1 is A-
A compound of CH=CH- is obtained.

A typical method for preparing this type of compound is described in Example 10 below.

A preferred method for producing 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-antrostan-3-one, a particularly preferred compound of the present invention, includes the following method. (a) Pregnenolone (V), which is an available starting material, is subjected to a haloform King reaction with iodine and pyridine to obtain a 20-iodide pyridinium derivative (Vl) of pregnenolone. (1)) This pyridinium iodide derivative (Vl) is subjected to metatolysis to methylnisder (■) of 17-carboxyanthrostenol using helium methoxide and methanol. The ester type is convenient for the subsequent Otzbennauer reaction. (c
) reacting the methyl ester of 17-carboxyanthrostenol (■) with aluminum isopropoxide and cyclohexanone in a suitable solvent such as toluene;
Thimeru-4-androsten-3-one-17-carboxylate (■) is obtained. (d) Methyl-4-androsten-3-one-17 carboxylate 1 to (■) thus obtained in a solvent of about 4:l methanol:water;
Hydrolysis under acidic conditions yields 17-acid (IX). (e) The 17-acid chloride is obtained by reacting the 17-acid (IX) with a complex of about 11 oxalyl chloride:pyridine in a suitable solvent such as toluene or xylene. (f) This 17-acid chloride (X) and an excess amount of diethylamine are reacted on the spot to 17β-N,N
-Diethylcarbamoyl-4-androsten-3-one (X[) is obtained. (g) The thus produced 4-androsten-3-one (X[) is oxidized with sodium periodate and potassium permanganate in t-tutanol and water as a solvent to give the corresponding 5-oxo-3,5- Secoantrostane-3-oic acid (■) is obtained. (h
) This secoantrostanic acid Off[) was dissolved in ethylene glycol for 1 minute while maintaining the temperature from 0.5 to 5 minutes.
The temperature was raised from 40° to 180°C, and the mixture was reacted with methylamine for about 1 hour to convert to the corresponding 4-aza compound (Xl). (1) The obtained 17β-N,N-diethyl-carbamoyl-4-methyl-4-methyl-4-aza-5-androsten-3-one (Xi[) was heated from room temperature to 6,000 yen using platinum oxide as a catalyst. , or more, to perform hydrogenation by reacting with hydrogen to obtain 17β-N,N-ethylcarhamoyl-4-methyl-4-aza-5α-antrostan-3-one (011V) as the final product, This is separated and purified.

1- The reaction described is detailed in Example 12 and is represented diagrammatically in the figures below.

(?H.

■) @) Flash) (XI) ((XV) L of , manufactured.

(1) Testosterone is reacted with ethanedithiol in the presence of 37 boron fluoride esterate
- Obtaining a dithioketal derivative. (2) Reacting the product obtained in step (1) with metallic sodium and liquid ammonia to remove the 3-dithioketal substituent. (3) The product of step (2) is reacted with dihydrobilane in the presence of p-1-luenesulfonyl chloride to obtain a 17-titrahydrobilanyl derivative. (4).

The product of step (3) is reacted with poran, and then reacted with sodium hydride and hydrogen peroxide to form 4-hydroxy-5α.
~Obtain a hydrogen compound. (5).

The product of step (4) is reacted with chromium trioxide to obtain a 4-keto compound. (6), by reacting the product of step (5) with an acid to remove the 17-titrahydrobilanyl protecting group;
A hydrochloric acid compound is obtained.

(7) The product of step (6) is reacted with acetic anhydride to obtain a 17-acetochloride compound. (8) The product of step (7) is reacted with hydroxyamine hydrochloride to obtain a 4-oxime compound. (9) The reaction product of step (8) is reacted with thionyl chloride and further treated with potassium hydroxide to obtain a compound represented by structural formula I having a partial structure Il,
That is, an A-homo-4α-aza compound is obtained.

The above reaction is detailed in Example 9 below and is illustrated schematically in the figures below.

H (XXXVI I) 13ρ The novel compound of the present invention having the partial structure X and represented by the structural formula (2), ie, the D-homologue, can be made by various methods well known in the art. They are described by Alig et al.
Staroid Biockam, Volume 5, Issue 4, 29
8, June 1974 and the method reported by Goldbgrg and Mannigr.
) by He1r, Chim, Acta, vol. 23,
376-384, 840j)-845.

1.2 The novel compounds of the invention are such that the α-methylene substituent is cg*-cg-c'g-
Chtm, and In by Leeb (Logv) et al.
d.

1710, October 1964, according to methods well known in the art.

A novel compound of the present invention in which Δ1, ie, A is 101l-CH, and the nitrogen at the 4-position has a substituent other than hydrogen, is produced according to the method shown in Example 10 below.

When the nitrogen at the 4-position is replaced only with hydrogen, it is produced according to the method shown in Example 11, which will be described later.

The compound of the present invention produced by the above-mentioned method is a specific inhibitor of testosterone-5α-reductase, as mentioned above, and is therefore a potent anti-androgien agent.

Therefore, the present invention provides a method for administering the novel compound of the present invention to the hyperandrogenic symptoms of prurigo vulgaris, seborrhea, male pattern baldness, and baldness in women by topical administration, and to treat the above-mentioned conditions by parenteral administration. , and administration methods for benign prostatic hyperplasia, breast cancer, and prostate cancer are particularly relevant. Breast cancer and prostate cancer are androdiene-related conditions or diseases that are exacerbated by the presence of androgene in the metabolic system, both normal and in higher than normal amounts.

The present invention also relates to suitable topical and parenteral pharmaceutical formulations in the new administration method of the present invention.

Compositions containing a compound of the invention as an active ingredient for use in the treatment of benign prostatic hyperplasia can be prepared using conventional excipients for tissue administration (e.g., oral administration in the form of tablets, capsules, solutions, or intravenous administration). It can be administered in a wide range of clinical dosages (suspensions for injection). The daily dosage of the compound varies over a wide range from 250 to 2000 mg.

The composition should be adjusted according to the symptoms of the patient being treated.5.10.25.5
It is preferably supplied in the form of tablets numbered containing 0.100.150.250 and 500 milligrams of active ingredient.

An effective amount of the drug is generally provided at a dosage of about 1 to 501 v per 1 body weight per - day.

The preferred range is Img to 7mg per body weight IKf per day.
It is. These doses will be significantly less than harmful amounts of the compound. Capsules containing the compound of the invention contain the active substance of the invention and lactose, magnesium stearate,
It is prepared by mixing calcium stearate, starch, talc, and other excipients and filling the mixture into gelatin capsules. Tablets are prepared by mixing the active substance with excipients such as calcium phosphate, lactose, corn starch, or magnesium stearate. Solutions are prepared in suspension or dispersion with suitable flavours, such as synthetic and natural gums, such as tragacanth, acacia, and methylcellulose. Other dispersants that may be used include glycerin. For parenteral administration,
Sterile suspensions and solutions are preferred. If intravenous administration is desired, iso-osmotic drugs usually containing appropriate preservatives are used.

For the treatment of spasm vulgaris, seborrhea, baldness in women, and baldness in men, the compounds of the invention may be administered in a form containing the active substance together with a pharmaceutically acceptable excipient suitable for topical administration. be done. These topical pharmaceutical compositions take the form of creams, ointments, gels, or aerosols for application to the skin. Their pharmaceutical composition for topical administration is
generally containing from 0.1 to 15 units of a compound of the invention;
Preferably 3.s contains about 5% active ingredient and about 95% excipients.

The preparation of the novel compounds of the invention as already described in general form is further illustrated in the following examples.

Example 1 Sodium 3-oxo-4-ethchenate i3 of -3-one etchenamide 202
Suspend in 60° of dry benzene and 0.13° of pyridine and cool to 14C.

This suspension was treated with 20d of oxalyl chloride.
5 Stir for 20 minutes. The suspension is evaporated to dryness and then suspended in 125d of dry tetrahydrofuran. This suspension is then added to a solution of 1251 in tetrahydrofuran and 251 in diethylamine and stirred for 1 hour at room temperature, after which the mixture is poured into 4t of ice, 3Z water. A semi-crystalline precipitate forms which is extracted with ethyl acetate, washed with water and then with saturated brine, dried and evaporated to give the product 25.72. The product is recrystallized from ethyl ether; the first 10.05' product has a melting point of 127-129C and the second a12 product has a melting point of 114C.
-119C.

Step A product 152 was dissolved in 150 IIJ of methylene chloride and 75 tl of methanol, cooled to -780;
This solution is then bubbled with ozone until a blue color remains.

The reaction solution is then returned to room temperature, sparged with nitrogen, and then evaporated to dryness at 35C. Dissolve the residue in benzene 2.
Extract three times with 5N A' a OH. Combine these basic washing solutions, acidify with concentrated hydrochloric acid, extract with benzene, wash,
When dried and evaporated, Mi7 11,5? A white crystalline solid is obtained. Recrystallization of this product from ethyl acetate gives a material with a melting point of 205-208C.

Add 26.32 grams of the product from Step B to 190 grams of ethanol to make a solution. The solution is cooled in a water bath to saturate the methylamine and then heated at 180C for 8 hours. The reaction mixture was then cooled to room temperature and evaporated to give 22
32 yellow solids are obtained. Chromatography and reconsolidation from ethyl acetate gives the final product, melting point 120-122U.

36.5 F of the product of Step C is brought into solution in 1 t of glacial acetic acid. This solution is then treated with a platinum oxide catalyst of 3.5 r and hydrogenated for 8 hours at room temperature under a pressure of 40 p, t, i. The reaction mixture is then filtered and evaporated to dryness. The residue is dissolved in chloroform and washed with bicarbonate solution, salt, then dried and evaporated to dryness.

This product, when reconstituted from ethyl acetate, has a melting point of 168-1.
The final product 30.659 of white crystals with 70C is served.

In place of 3-oxo-4-ethchenate in Step A, an equimolar amount of other available or easily prepared 3-oxo-Δ4 compound, or in place of diethylamine, an equimolar amount of another suitable Following the method described in Example 1 above using the following amines, the Formula I compounds of the invention listed in the table below are prepared.

2 HC0N(CH2CFIs)t 2
63'-2655E C0CHs
272-2756 CHs CO
Cll5 218 2207
CHx C0NHCHHzCIIs 249
2518 HC00CHs
300-302 Example 9 Ten-3-thioketal A solution consisting of 7.52 Lt of testosterone, 37.511 Lt of glacial acetic acid, 4.5 d of ethanedithiol, and add 3.0 d of borous trifluoride etherate is prepared in OC. . Raise the temperature of this mixture to ft temperature, then continue
Keep time.

The mixture is then diluted with water, extracted with chloroform, washed with 5% aqueous sodium bicarbonate, then several times with water, and then with saturated saline. The mixture was then dried and evaporated to give a white solid, which was reconstituted from methanol to give the final product (95% yield) with a melting point of 160-162C.
9. Of is obtained.

Add 1.22 g of sodium metal to 60 g of anhydrous liquid ammonia. To this solution is added 1.02 parts of thioketal in 101 parts of dry tetrahydrofuran and the solution is refluxed for 20 minutes.

The reaction is stopped by adding several 1 portions of ethanol, and the mixture is dried at room temperature. The solution is then diluted with water, extracted with methylene chloride, washed with water, Hα, then water, dried and evaporated to give a white solid with a melting point of 149-152C (609~, yield 81).

Dihydrobilane 301 containing p-toluenesulfonyl chloride 450~! Product of Step B to Lt6. Ori
and stir the solution for 1 hour at room temperature. This solution was then diluted with ethyl acetate and diluted with 20% pyridine water mixture.
Washing twice, then with water and then with brine, drying and evaporation gives a pale yellow oil. This is crystalline 8.
sy) has a melting point of 92-96c.

D, 17β-tetrahydrobilanyl salt 2, 7. To a cooled solution of 5 ttl of IM borane (in tetrahydrofuran) in dry tetrahydrofuran (OC) of 2.d. 500 μm (1.4 mmol) of the product of step C in 1.0 ml of dry tetrahydrofuran are added. The clear solution is stirred at room temperature for 1 hour, then cooled and treated with 2.5N sodium hydroxide solution and then 30% hydrogen peroxide solution. The solution is stirred at room temperature for 1 hour, diluted with water, extracted with ethyl acetate, washed with water, brine, dried and evaporated to give an oily crystalline material.

The product is washed with cold methanol and pump dried to give the final product 175~, mp 167-170C.

0.421 Lt of dry pyridine 6.31 Lt of dry dichloromethane to 0.264 ? Gradually add chromium trioxide of
The mixture is stirred for 15 minutes at room temperature. This mixture contains 0
, 7d dissolved in methylene chloride 175
A solution of ~ is added and the resulting mixture is stirred at room temperature for 20 minutes. This mixture was diluted with water and extracted with ethyl acetate.
Wash with 2.5N sodium hydroxide, water and saline. The mixture is then dried and evaporated to give a clear oil.

Product 2.322 of Step E is added to a solution in 75°C ethanol, which is subsequently treated with 51°C 2.5N hydrochloric acid and heated on a steam bath for 40 minutes to give the crystalline product Zlf with a melting point of 123-126C. is obtained.

121 of dry pyridine and 61 of acetic anhydride to the product of Step F2. , Of is added to form a solution, which is heated on a steam bath for 30 minutes, then poured into a 175 mm column of ice water and stirred to destroy excess acetic anhydride. The reaction mixture is filtered, washed with water and pump dried under high vacuum at 50C to give the final product 1. with a melting point of 160-163C.
72 is obtained.

The product of step G, 2=Of, was added to 1251 L of tan-4-oxime in ethanol and 30 cod dry pyridine to form a solution, and this was dissolved in 4
Treat with hydroxylamine hydrochloride from 20°C and stir at room temperature. The reaction mixture was developed overnight on silica gel thin layer chromatography (20% ethyl acetate/benzene) and ffff. The product is concentrated to a small volume under high vacuum at 30-40 g and slowly diluted with water to form a white crystalline material. It is filtered, washed with water, dissolved in ethyl ether, dried and reconstituted from ethyl ether. The final product has a melting point of 222-224C.

I. 17β to 7 sets 4a aza-5α-distilled thionyl chloride 3.3 mJ to 78c product of step 50
Add 01Iv and stir the resulting solution for 1-2 minutes, then slowly add 501 to 4N sodium hydroxide solution at 20C. A solid precipitate forms, which is filtered and washed thoroughly with water and then with ethyl ether. This product is recrystallized from ethyl acetate, washed with ethyl acetate, ethyl ether and dried to give the final product 210.mu.

Example 10 A solution of 0.2 Of anhydrous diisopropylamine in anhydrous tetrahydrofuran at 5.0° C. is treated with 91° C. of 2.2 M butyllithium under nitrogen. After 20 min at -78C, a solution of 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-antrostan-3-one of 3885′ in tetrahydrofuran of 311Le was added to the reaction mixture. do. -78
After stirring for 30 minutes at C, a solution of 440q of phenyl disulfide in 1d of tetrahydrofuran is slowly added into the reaction mixture. After stirring for 10 minutes at ~78C, the reaction mixture is brought to room temperature. Water is then added to the mixture and the product is extracted into ethyl acetate. The organic solvent layer is washed with a sodium hydroxide solution, then with water, then with diluted hydrochloric acid, and finally with saturated saline. The solution is dried over calcium sulfate and then concentrated to give a crude solid product. Elution from silica gel 302 by increasing the proportion of ethyl acetate in the solution gives the 2-phenylthio derivative as a mixture of two distinct isomers.

This material, suspended in 20% aqueous methanol, is treated with a solution of 225 ml of sodium metaperiodate in water. After stirring for 16 hours, the reaction mixture was diluted with water and extracted with methylene chloride. The organic solvent layer is washed with water, dried and concentrated to yield the crude sulfoxide. A solution of this material in 5d of toluene is refluxed for 30 minutes. The solvent is removed and the residue 'c209 is chromatographed on silica gel by elution with increasing amounts of ethyl acetate in ether. The final product crystallizes when treated with ether.

Example 11 17β-N, #- of 291 in 3 ml of methylene chloride
Diethylcarbamoyl-4-aza-5α-antrostane-3-one Ti liquid ft.

Add to a solution of 117 gv of trimethyloxonium fluoroborate in methylene chloride at C.

The mixture was then stirred at OC for 6 hours and then at 125
1.5-diazabicyclo[5゜4.0]undec-
Treat with 5-ene. After continued stirring for 2 hours, the reaction mixture was diluted with anhydrous ether. The organic solvent layer is separated from the residue and concentrated under reduced pressure to leave crude cutim ether. This material is then converted to a compatible Δl compound by the method described in Example 10 above.

Example 12 -3-Onridinium IKg (3.16 mol) of pregnenolone was added to 2t of pyridine, and the mixture was stirred gently until 90%
When heated to -951:' all pregnenolone dissolves. A total of 866.1 f (3.41 moles) of iodine fc is carefully added to this mixture over a period of 15-20 minutes. The temperature of the reaction mixture is observed to rise to 120C. This mixture was heated to 100C or higher for 1 hour.
Stir for an hour, then cool slowly over an hour, then place in a cold water bath to cool to room temperature. The product was collected on a silica gel funnel with medium porosity and found to be rubbery and gel-like. Aid the filtration by adding pyridine and reduce the filtered product to 300
Wash 6 times with ml of pyridine and then 6 times with 300 at/ml of ether and then air dry. Melting point 228-230
The product with C is obtained in 99% yield (1635,82).

In a flask was added Z7h (5,177 mol) of iodide (3β-hydroxypregnated 5-en-20-one-21-ylumpyridium, 13,5 t of methanol and 9oo9
of sodium methylate. The mixture was refluxed for 1 hour, then cooled to about 53C, then quenched by adding 241 g of ice and 2 tons of water, and the temperature of the reaction solution was reduced to 53 C.
Make it c. The mixture is then neutralized to pHf 6-7 by adding a 1:1 solution of 2100-hydrochloric acid and water. The mixture is aged for 45 minutes, then collected on a lap funnel and washed with cold water until most of the color is washed out. The product is briefly dried on a funnel, then transferred onto two glass trays and dried in an air oven at 50C overnight. Product yield is 83.6% (1440 g).

160.0 y of methyl 5-androsten-3β-ol-17β-carboxylate in flask, 2.4
Add toluene and 680 mJ of cyclohexanone dried using a molecular sieve. Heat this mixture to reflux and remove any water present for 15 minutes (i.e. until the distillate is clear).
Remove by azeotroping. Then 320-881-81-g of aluminum isopropoxide in dry toluene is added all at once as a slurry. Reprint of the specification (no changes in content) The reaction mixture was allowed to flow at a rapid rate, during which time
Remove 0mM toluene. The mixture is then cooled to 25° C. and 409 g of diatomaceous earth is added followed by 80 nlj of water. The mixture is stirred for 10 minutes, filtered through diatomaceous earth, and then washed three times with 110 ml of I toluene. The liquid is concentrated to dryness and then cooled in a water bath.

The crystallized product is aged at 0-5°C, collected, washed with cold hexane, and then dried under reduced pressure. The yield of product is 83.6% (13319)C, melting point is 130-13
It is 2°C.

24.6 To 2.462 Kg of methyl 4-androsten-3-one-17β-carboxylate in methanol are added +r potassium hydroxide to 4.9 kg of 1,23 dissolved in water. The reaction mixture is refluxed under nitrogen for 6 hours, then cooled overnight at room temperature. Add this mixture to 3200
Acidify with ml of 6N hydrochloric acid. Most of the product precipitates as thin crystals. 14 tons of water are then allowed to flow down over 30 minutes, causing all of the product to precipitate out. The mixture is aged for 4 hours at 30C with stirring. This mixture is filtered through a funnel with a lid and washed with water until the washings become neutral. The product is dried in an oven at 50C overnight. A product with a melting point of 245-248C is obtained in a yield of 98% (2, axar).

7002 of 4-androsten-3-one-17β-carboxylic acid and 11.61 of azeotropically dried benzene are placed in a flask.

Pyridine dried through 2261 molecular sieves is added to this mixture, followed by the careful addition of oxalyl chloride 2501 in 250 ml of dry toluene over a period of 20 minutes. The reaction mixture is aged for 1 hour at room temperature and then cooled to 10C. Then, diethylamine' dried over molecular sieves mixed with an equal amount of dry truviene
f. Add enough until the pH is permanently alkaline. Approximately 2.4 t of solution is required. The reaction mixture is aged for 30 minutes and then 16 tons of ice water is added to stop the reaction. The mixture is separated into two layers, and the aqueous layer is extracted three times with 4 tons of ethyl acetate. The organic solvent layers are combined and washed with 8 tons of water and hydrochloric acid to make the liquid acidic (pH 3), then washed with 8 tons of water alone, and finally with 8 tons of saturated saline solution. The solution is dried over sodium imilate and then concentrated to a small volume (3-4 t) in a large rotary evaporator. Next, 4 tons of hexane was added to this liquid, and the mixture was cooled at 0-5C for 1 hour. The product is collected and washed three times with a small amount of cold soap and then dried overnight at 40-50C in an air oven. Melting point 119-12
175% yield of product with IC (616,52
) can be obtained.

5≠ F, 17β-N, N-diethylcarbamoyl 6002 in flask
-Androsten-3-one and 1st tertiary butanol are added to form a solution. Then 1200! Add a solution of 2582 sodium carbonate in ILe water.

Next, 2.4Kt of sodium periodate dissolved in 18T of water was added over 1.5 hours, during which time
Maintain the color of the reaction mixture while adding 340d of 2% potassium permanganate.

The temperature is maintained between 25° and 40C during the addition. The mixture is aged for 2 hours, filtered and the cake washed with water. Concentrate until only the aqueous solution remains to remove the tertiary butanol, then cool to 10C and acidify (p) 13) with 50% sulfuric acid 1101. This aqueous solution f6t is extracted three times with ethyl acetate. Combine the ethyl acetate washes and wash with 4 t of 5-t sodium bisulfate solution and then twice with 4 t of saturated brine. Combine the extracts and dry with sodium sulfate.
, 5t, then boiled and then aged at 5-10C for 2 hours. Filter this liquid and wash the filter cake with ethyl acetate. 77% product with melting point 205°-208C
(488f).

-4-Methyl-4-aza-5-andro Condensate 200- of graduated cylinders of methylamine maintained in a drying water bath and then add 1250 ml of methylamine to it at room temperature with stirring.
Add ethylene glycol (d). Capacity increases by 16 inches. 3t of this methylamine/ethylene glycol solution
of 17β-N,N-diethylgarhamoyl-5-oic acid in a flask of 3.5-secoantrostane-3-oic acid. It becomes a solution in a few minutes. The reaction mixture is heated to 110 GK for 40 minutes and heating is continued at a rate of 2 C per minute until the temperature reaches 180 C. Then stop heating. Total heating time is 70 minutes. When the reaction mixture is poured into 10 tons of water to stop the reaction, a milky solution is obtained, which is diluted with 2
Extract 5 times with methylene chloride. Combine the organic solvent layers,
Wash with 4 t of water acidified with concentrated hydrochloric acid, 4 t of sodium bicarbonate solution and 3 times with 4 t of water. The combined organic solvent layers are then dried over sodium sulfate, treated with 502 silicon dioxide, and then concentrated to dryness. The residue was dissolved in 750 wIg of cyclohexanone normal solution (75 oy).
K dissolved and then aged overnight at room temperature with stirring. The product was filtered, washed with normal soap and dried under reduced pressure. The final yield of product with melting point 115-118C is 9
1% (226f).

,S7〃,17β-N,N-diethylcarbamoyl-4 in 1502 in a 17β-N,N-diethylcarbamoyl flask
- Methyl-4-aza-5-androsten-3-one and 750-proof glacial acetic acid were added, and the mixture was mixed with 45p, t, i
.

Heat to 60C under nitrogen for 4 hours. The product is filtered, the filter cake is washed with methylene chloride, and the p-liquid is concentrated to dryness.

The residue was dissolved in 750 d of methylene chloride and 500 d of I
Wash twice with N sulfuric acid, once with 500 IILt water, once with saturated sodium bicarbonate solution and once with saturated saline solution.

The solution was dried over magnesium sulfate, treated with 152 charcoal, and passed through a 752 silicon dioxide sieve with E.
treat The filter cake is washed with 1 t of methylene chloride and concentrated to dryness.

The residue was dissolved in 450 ml of ethyl acetate and then diluted with 1 ml of ethyl acetate at room temperature.
Aging in a water bath for 1 hour.

The product was filtered with 501 ethyl acetate, then l;? Wash and dry with Misan to 100-normal. Solution F was concentrated to dryness, dissolved in 1,001 ml of ethyl acetate, and diluted with 2.0 ml of ethyl acetate at room temperature.
Time aged, filtered, 15d ethyl acetate and 1001
Wash with normal hexane. Melting point 172-174t:'
The yield of product is 7a6ti (115f).

Example 13 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-antrostane-3 at 375 mV in 31 methylene chloride with OC in a mixture of 160 Mj trimethyloxonium fluoroborate and 31 methylene chloride.
−Add on. After stirring for 6 hours at 0°-50, the mixture is left overnight at room temperature. diazabicyclo[5,4,
Add 03 undec-5-ene (160 μl) and dilute the organic solvent layer with anhydrous ether. The solid residue is removed by centrifugation, and the organic solvent layer is concentrated to dryness, leaving Δ2-lactiminomethyl ether. A mixture of this material and 1.02 parts methylamine in 5d toluene was heated at 100C in a sealed tube.
, heat for 24 hours. After cooling, the tube is opened and the solution is concentrated to dryness under a nitrogen stream. The residue is dissolved in 81 mL of ethyl acetate and anhydrous hydrogen chloride gas is bubbled through with OC. The precipitated product was removed by centrifugation, washed twice with ether, and dried under reduced pressure to give N-methyl-N-C17β-(N',N'-diethylcarbamoyl)-4-aza-4-methyl-5α. -Anthrostan-3-en-3-yl]amine hydrochloride is obtained.

In addition, embodiments of the present invention include the following; 1
Formula: % formula % () Engraving of specification (no change in content) ~10, slope [Formula (I)
may also have partial structures (n) and/or (III); where A is (1) CH2CH2; (2) -CH= CH-.H3 (3) -aH-C)12-; or,(,
R2 (4) -C' Hl-c H-te; B is h (wherein, R1 is (a) hydrogen, (b) methyl group or ethyl group, (C) ethynyl group, (d) ethynyl group , (e) R
NR2R3, (where 2 and R3 are hydrogen or methyl groups)
f) a cyano group) or R' ○ (wherein X is an anion; R4 is (a) R5 or an alkyl group having 1 to 4 carbon atoms;
b) NR6R where R6 and R7 are hydrogen or methyl groups
7); R' is hydrogen or a methyl group:
R″ is hydrogen or β-methyl group; R″ is β-methyl group or hydroxy group; Z is (1) oxo: (
2) β-hydrogen and α-hydroxy group, or α-hydrogen or α-hydroxyl group and (3)(Y)nQ (in the formula, n
is 0 or 1, Y is a straight or branched hydrocarbon chain consisting of 1 to 12 carbon atoms, and Q is (
a) R” or (i) hydrogen, ■ hydroxyl group, (iocl
-4 alkyl group, to) R9 and R'' or hydrogen, C1-4 straight or branched chain alkyl group, C, cycloalkyl group,
5 each independently selected from the phenyl group, or together with the nitrogen to which R9 and R'' are attached, further comprising up to one other hederoatom selected from oxygen or nitrogen;
-NR9R” (v) R eyes are M
(M is hydrogen or an alkali metal), or CI-
1゜O which is a straight chain or branched chain alkyl group, benzyl group
C-R8 represented by R+ 1, or (b) 17α-
If it is a hydroxy group, n is 1 and R12 is (i)C
I-28 alkylcarbonyl group, ω phenyl c1-6 argylcarbonyl group, Oi+') C5-+o cycloalkylcarbonyl group, 0 benzoyl group or (V) CI-
(5) NHC-R'3 If it is a 17α-OH group, n is l (in the formula, R'' is (
a) Cl-127 alkyl group* is (b) NR9RI
G), (6) a cyano group, or (7) a tetrazolyl group), and pharmaceutically acceptable salts of the above compounds.

2nd formula: [wherein R1 is hydrogen, a methyl group or an amino group;
The compound according to item 1 above, wherein T is C0NHCH2CH3.OCH3 0CCH3 or OCH3.

3 Compound 17β-N,N-diethylcarbamoyl-
The compound according to item 1 above, which is 4-methyl-4-aza-5α-antrostan-3-one.

4 Formula (I) can also have the substructure formula (II) and/or (m): where A is (1) -CH2-CH2-1(2) -CH=C1
1-1K (wherein R1 is (a) hydrogen, (b) methyl group or ethyl group, (C) ethynyl group, (d) ethynyl group, (e) R
NR2R3, (where 2 and R3 are hydrogen or methyl groups)
f) is a cyano group), or (where ρ is an anion: R" is (a) R5 or C1
-4 alkyl group OR5, or (b) R6 and R
7 is hydrogen or a methyl group; R' is hydrogen or a methyl group; R'' is hydrogen or a β-methyl group; RIII is a β-methyl group; is a hydroxy group; Z is (1) oxo; (2) β
-hydrogen and a-hydroxy group; or α-hydrogen or α
-hydroxyl group and <3) CY)nQc, where n is O or 1, Y is a linear or branched 1 carbon atom droxyl group, (t!i) (j t -a alkyl group,
l1lV) R9 and A'IO are each independently selected from hydrogen, CI-4 straight or branched alkyl group, C3-6 cycloalkyl group, phenyl group, or R9 and B
5- which together with the nitrogen to which 10 is attached further contains up to one other heteroatom selected from oxygen or nitrogen;
7vxeRto shown as a 6-membered saturated ring.

M R” is J (# is hydrogen or an alkali metal),
or '1-III straight-chain or branched alkyl group, benzyl group OR''; or (b) OR', but if it is a 17α-OH group For example, n is l, R'' or (i) hydrogen, ωC, -2.
Alkynylcarbonyl group, 6M) phenyl C, -, alkylcarbonyl group, (to) C,, o cycloargylcarbonyl group, (ν) benzoyl group or 6tD CI-
a Alkoxycarbonyl group: substituted with hydrogen), (5) NH-C-R'3 but 17
If it is an α-OH group, n=1 (wherein R13 is (a
) CI-12 alkyl group or (b) NR' R10
), (6) a cyano group, or (7) a tetrazolyl group), and a pharmaceutically acceptable salt of said compound, administered locally to a patient in need of treatment in a therapeutically effective amount. vulgaris zayari, seborrhea, characterized by
Treatment methods for hyperanthogen symptoms of male pattern baldness and female baldness.

5 Formula: [Formula (1) also has partial structural formula (II) and/or (
11D; where l is tg-cH, -
c R2-1 (2) -UH=OH-, Ul130H2 (3) -U-OH2- or (4) -(jH, -0
H2-; B is ■ R1 (in the formula, %A'l is (a) hydrogen, (b) methyl group or ethyl group, (1) ethynyl group, (d) ethynyl group, (g)
NR21 where E'' and R3 are hydrogen or methyl group
1", (f) is a cyano group), or (in the formula, X is an anion and 7
is hydrogen or methyl group); l? ' is hydrogen or a methyl group; R'' is hydrogen or a β-methyl group; A /// is a β-methyl group or a hydroxy group; Z is (11 oxo; (2) β
-hydrogen and a-hydroxy group, or a-hydrogen or a
-hydroxyl group, (3) (1'), (2 (in the formula, the outside is O or 1, Y is a straight chain or branched carbon atom 1 (11) hydroxyl group, (lfD C1-4 Alkyl groups, QJ ll 9 and 7210 are each independently selected from hydrogen, Cl-4 direct flA or branched chain alkyl groups kC3-6 cycloalkyl groups, phenyl groups, or the nitrogen to which R9 and Blo are bonded together with up to one other heteroatom chosen from oxygen or nitrogen.
! R10゜(v) ll l l is If (Jl is hydrogen or an alkali metal), or 07211 where Ul-ta is a straight-chain or branched alkyl group, a benzyl group; oplz, but 17a-0
If it is an H group, the edict is 1, and ztg is (1) hydrogen, (I
f) '1-to alkylcarbonyl group, (110 phenyl U1-6 alkylcarbonyl group, (iV105-1
0 cycloalkylcarbonyl group, (v) benzoyl group or (represented by VIJOx-m alkoxycarbonyl group); (substituted with hydrogen); (5) 5H-6! 77+3 However, if it is a 1712-hydroxy group, n can be 1.
(wherein R''B is (α) Cl-12 alkyl group or (b) Iil19Bso); (6-nocyano group;
A routine treatment consisting of parenteral administration of a therapeutically effective amount of a compound represented by (7) tetrazolyl group and a pharmaceutically acceptable salt of the above compound to a patient in need of treatment. , a method for treating hyperandrogen symptoms of seborrhea, male pattern baldness, female baldness, benign prostatic hyperplasia, androgen-attributable breast cancer and prostate cancer.

Printing of the specification (no change in content) 6 Formula: %Formula% ((Formula (I) may also have partial structural formula (II) and/or (III); Formula%Formula% R1 ( In the formula, %R1 is (,) hydrogen, (b) methyl group or ethyl/L group, (c) ethynyl group, (d) ethynyl group, (e
) NI in which A''' and N3 are hydrogen or methyl group
? 1R3, (1) Schiff/group theal): 4 kuI (wherein,
and NI? where R7 is hydrogen or a methyl group? 6B7
); R' is hydrogen or a methyl group; R
” is hydrogen or a β-methyl group; R″′ is a β-methyl group or a hydroxy group; Z is (1) oxo; (
2) β-hydrogen and a-hydroxy group; or α-hydrogen or a-hydroxyl group and (3)(1′)sQ (in the formula,
n is 0 or 1, Y is a straight or branched hydrocarbon chain having from 1 to 12 carbon atoms, Q is a convex a8, in the formula (
G) R' is (1) hydrogen; (11) hydroxy group; (
i+9 (/', -, alkyl group; 0φR9 and Boo
is hydrogen, C and 1 straight or branched alkyl group, (73-
, cycloalkyl group, phenyl group, or together with the nitrogen to which R9 and R10 are attached, further comprising up to one other heteroatom selected from oxygen or nitrogen. -N represented by a 6-membered saturated ring
1191110° (V) R11 is # (Jf is hydrogen or an alkali metal), or '1-18 straight or branched alkyl group, 0R11 is a benzyl group; or (b) OB 12, but If it is a 17a-hydroxy group, the outside is 1, and A'12 is (1) hydrogen, (II) Ot-to alkylcarbonyl group, (1
10 Phenyl C! -6 alkylcarbonyl group, 60Cs
-to cycloalkylcarbonyl group, (v) benzoyl group or (represented by %l C1-s 6 alkoxycarbonyl group);:1 replaced with hydrogen), (5L#H-c;-Rss where 17a-OH If it is a group, the outside is 1, and (in the formula 1.
/? 13 is (cL) C+ -1z alkyl group or (b) N ReB to ); (6) cyano group; or (7) tetrazolyl group] and pharmaceutically acceptable compounds of the above compounds. A method of inhibiting testosterone-5a-reductase in a patient in need of treatment that inhibits testosterone-5a-reductase, the method comprising administering to a patient in need of treatment that inhibits testosterone-5a-reductase a therapeutically effective amount of a salt of the present invention.

7 Pharmaceutically acceptable carrier and the following formula: Copy of specification (no change in content) [Formula (I) may also have partial structural formula (II) and/or (m); formula % Formula % (wherein R1 is (a) hydrogen, (b) methyl group or ethyl group, (C) ethynyl group, (d) ethyl group, (e) R2 and R3 are hydrogen or methyl group, NR2R3, (f )
cyano group): or L O (wherein X is an anion; R4 is (G) B 5
ORB is a C1-4 alkyl group; or (b)
Nl16 where R6 and R7 are hydrogen or methyl groups
R' is hydrogen or a methyl group; R'' is hydrogen or a β-methyl group; R'' is β-
The methyl group is still a hydroxy group: Z is (1) oxo; (2) β-hydrogen and a-hydroxy group; or a-hydrogen or a-hydroxyl group and (3) (1') tLQ (
In the formula, the outside is 0 or 1, and Y is a straight or branched hydrocarbon chain consisting of 1 to 12 carbon atoms (
11) Hydroxyl group, (110G+ -4 alkyl group).

0V) R' and Elo are each independently selected from hydrogen, a C1-4 straight-chain or branched alkyl group, a C3-6 cycloalkyl group, a phenyl group, or the nitrogen to which R9 and Ilo are bonded l1R9 denoted by a 5-6 membered saturated ring which together further contains up to one other heteroatom selected from oxygen or nitrogen;
i
Tatri(b) OA' IJ However, 17a-O
If it is an H group, the outside is 1, and in the formula A12 is (1) hydrogen,
(It) C1-zoalkylcarbonyl group, (III
) phenylCl-6 alkylcarbonyl group, 0φ'5-
10 cycloalkylcarbonyl group, (v) benzoyl group, or (represented by VDC't-s alkoxycarbonyl group); substituted with element) -(5)NH-U-It□3However,
If it is a 17α-hydroxy group, the outside is 1 (in the formula, R
18 is (α) Ct-1z alkyl group or (b) #
119R1G); (6) cyano group; also F? 0 (7) A tetrazolyl group] and a pharmaceutically acceptable salt of the above compound.

8(1) Treating pregnenolone with iodine and pyridine,
the corresponding 20-pyridinium iodide derivative of pregnenolone; (2) subjecting the product of step (1) to metathurisis;
as the methyl ester of 7-carboxyandrostenol; (3) treating the product of step (2) with aluminum isopropoxide and cyclohexanone;

4-androsten-3-one-17-carboxylic acid methyl ester; (4) Hydrolyze the product of step (3) to obtain the corresponding 17
(5) treating the product of step (4) with an oxalyl chloride:pyridine complex to form the corresponding 17-acid chloride compound; (6) converting the product of step (5) to the corresponding 17-acid chloride compound; Treatment with diethylamine in situ gives 17β-N,N-diethylcarbamoyl-4-
Androsten-3-one: (7) The product of step (6) was oxidized with sodium periodate and potassium permanganate in a t-phthanol:water solvent system to give the corresponding 5-year-old xo-3. 5-secoantrostane-3-oic acid compound; (8) step (
The product of 7) was treated with methylamine in ethylene glycol to give 17β-N,N-diethylcarbamoyl-4-
Methyl-4-asa-5-androsten-3-one: (9) Hydrogen addition by treating the product of step (8) with hydrogen in the presence of a catalyst to give the final product 17β-N,N
-diethylcarbamoyl-4-methyl-4-aza-5α
-Anthrostan-3-one: A method for producing a compound represented by the following formula: N(C,,H,,)2, comprising each step.

9(1) Treating 4-androsten-3-one-17β-carphonic acid with an oxalyl chloride:pyridine complex to give the corresponding 17-acid chloride: (2) converting the product of step (1) to its 17β-N,N-diethylcarbamoyl-4-
Androsten-3-one: (3) The product of step (2) is oxidized with sodium periodate and potassium permanganate in a two-t-tutanol solvent system to give the corresponding 5-oxo-3, (4) Treat the product of step (3) with methylamine in ethylene glycol to obtain 17β-N,N-diethylcarbamoyl-4-methyl-4- Aza-5-androstene-3
- on: (5) Hydrogenate the product of step (4) by treating it with hydrogen in the presence of a catalyst to produce the final product, 17β-N,
N-diethylcarbamoyl-4-methyl-4-asa-5
A method for producing a compound represented by the following formula consisting of α-an1herostane-3one: %Formula %)

Claims (1)

[Claims] 1. Pharmaceutically acceptable carrier and formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A is -CH_2-CH_2- or -CH=CH
-, R^1 is hydrogen or alkyl, and X is ▲ has a mathematical formula, chemical formula, table, etc. ▼ or ▲ has a mathematical formula, chemical formula, table, etc. ▼ (provided that X is ▲ mathematical formula, chemical formula, table, etc. ▼, then the carbonyl carbon is bonded to the nitrogen atom), and Z is α-hydrogen and alkyl, N-alkyl or N,N-dialkylcarbamoyl, lower alkanoyl, lower alkanoyloxy and lower alkoxy carbonyl or Z is oxaspiro-lower alkyl, provided that if X is 1. A pharmaceutical composition comprising a compound represented by [1] and a pharmaceutically acceptable salt. 2. R^1 is hydrogen or methyl, Z is α-hydrogen and N
-ethylcarbamoyl, N,N-diethylcarbamoyl, acetyl, acetyloxy and methoxycarbonyl; thing. 3. The pharmaceutical composition according to claim 1, wherein R^1 is hydrogen and Z is α-hydrogen and N,N-diethylcarbamoyl.