KR860000452B1 - Soft steroide having anti-inflammatory activity - Google Patents

Abstract

Androstenones (I) and (II) [ R = alkyl, hydroxyalkyl, haloalkyl, alkoxycarbonylmethyl, (un)substd. carbamoylmethyl, alkylthioethyl, alkylsulfonylmethyl, ect.; X = O, S; R1 = aliph. alkyl carbamoyl, alkoxycarbonyl, ect.; R2 = H, HO, Me, alkoxy carbonyloxy; R3 = H, Cl, F; R4 = H, F, Cl, Me; Z = O, HO, H were prepd. Thus, hydrocortisone was reacted with INaO4 in THF to give 96 % 11 β , 17α - dihydroxy-3- oxoandrost-4-ene-3-one-17β . -carboxylic acid, which was acylated by ClCO2Me in TEA and then esterified by ClCH2I, and crystallized with THF/hexane solvent system to give I ( R = ClCH2 ; R1 = Me; R2=R3=R4 = H; X = O; Z = . α-OH, β-H). I and II is used as antiinflammatory.

Description

Method for preparing a soft steroid with anti-inflammatory action

The present invention relates to a method for producing a novel soft steroid with anti-inflammatory action.

The main goal of drug designers is to create new drugs by making good predictions about the theoretical basis of the biological action of compounds.

This can be accomplished on the basis of structural alteration of known biologically active molecules by the approach of groups or biologically active moieties or by alteration of all physicochemical properties of the molecule. Therefore, the main objective is to design, synthesize and test novel compounds that are structurally similar to basic biological molecules but have improved therapeutic effects and pharmaceutical properties. Although the vulnerable part is identified as a molecule with a biological deactivation or metabolism role after performing its role, little or no attention is focused on the theoretical planning of the metabolic degradation of the drug in the drug planning process. have. This ignores the fact that the toxicity of many biologically active molecules is due to their increased release half-life, stability, or other factors introduced in the scheme of increasing their activity. Drugs and especially their metabolic processes cause various toxic processes by the formation of active metabolites. Metabolic activation of reactive intermediates covalently bound to the polymer of the tissue is an early stage of cell damage. Also, since the most toxic metabolites do not remain sufficiently to be excreted and identified, studies on stable metabolites may clearly provide false information.

Metabolism of the drug should be considered at an early stage of the drug planning process to prevent or reduce toxicity associated with the drug. This is especially true given the fact that it can attack the body and alter chemically very stable structures, and that small amounts that are not calculated can cause toxicity even if the drug is excreted 95% without change. There is no

A "flexible drug" can be defined as a biologically active chemical compound (drug) that may be structurally similar to a known active drug (soft analog) or an entirely new type of structure, but after their therapeutic role ends, It is characterized in that it is destroyed in vivo and all become nontoxic molecules. Metabolism of flexible drugs occurs at an adjustable rate in the expected manner.

The inventors have found five main classes of flexible drugs. One of the most useful classes is called the "active metabolite" approach, which can be advantageously used in particular to plan valuable "soft drugs". This approach starts with a known inert metabolite of the drug or class of drugs, and structurally changes the metabolite to the active drug (ie, activation) (stereomeric arrangement and / or isoelectronics) and achieves the desired therapeutic role. It is planned to induce the activated type of metabolism into a starting inactive metabolite, without forming a toxic intermediate (ie, predicted metabolism). The "inactive metabolite" approach also makes it possible to regulate the rate and pharmacodynamic properties of metabolism by molecular manipulation in the activation stage. In addition, if no useful inert metabolite is known at all, it can be planned by introducing a transporter into the non-critical structure part.

The inventors have applied their inactive metabolite approach to natural and synthetic glucocorticosteroids, and have planned the soft steroidal anti-inflammatory bodies of the present invention derived from known natural metabolites of glucocorticosteroids. For example, in the case of hydrocortisone, one of its main metabolites, corticic acid, i.e., 11β, 17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid, is used as a starting point and is suitable for nontoxicity. It is activated by the introduction of the 17α- and 17β-substituents of the activated derivatives, which are degraded in vivo into starting inactive metabolites and other nontoxic molecules after their therapeutic role ends.

In accordance with the foregoing, the present invention provides a novel method for producing a flexible steroid having the following structural formula and having an anti-inflammatory action.

In the above formula:

(C₁~C₁₀알킬) 또는

(C₁~C₁₀알킬)로 이루어진 기중에서 선택되고, 또는 R₆는 치환 또는 비치환 페닐 또는 벤질인데, 치환체는 저급알킬, 저급알콕시, 할로, 카르바모일, 저급 알콕시카르보닐, 저급 카노일옥시, 저급 할로알킬, 모노(저급알킬)아미노, 디(저급알킬)아미노, 모노(저급알킬)카르바모일, 디(저급알킬)카르바모일, 저급 알킬티오, 저급 알킬술피닐 및 저급알킬술포닐로 이루어진 기중에서 선택됨〕이거나 또는 R₁은 -CH₂CONR₇R₈(여기서, R₇및 R₈은 서로 동일 또는 상이할 수 있으며, 각각 수소, 저급알킬, C₃~C₈시클로알킬, 페닐 또는 벤질이거나, 또는 R₇및 R₈이 서로 결합하여 -NR₇R₈이 포화모노사이클릭 2차 아민의 잔기를 나타냄)이거나 ; 또는R ₁ is C ₁ -C ₁₀ alkyl: C ₂ -C ₁₀ (monohydroxy or polyhydroxy) alkyl: C ₁ -C ₁₀ (monohalo or polyhalo) alkyl: or -CH ₂ COOR ₆ [where , R ₆ is unsubstituted or substituted C ₁ to C ₁₀ alkyl, C ₃ to C ₈ cycloalkyl, C ₃ to C ₈ cycloalkenyl or C ₂ to C ₁₀ alkenyl, the substituents being halo, lower alkoxy, lower alkyl Thio, lower alkylsulfinyl, lower alkylsulfonyl,

(C ₁ to C ₁₀ alkyl) or

Is selected from the group consisting of (C ₁ -C ₁₀ alkyl), or R ₆ is substituted or unsubstituted phenyl or benzyl, the substituent being lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower carbonyl jade Lower haloalkyl, mono (lower alkyl) amino, di (lower alkyl) amino, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulphur Or R ₁ is —CH ₂ CONR ₇ R ₈ , wherein R ₇ and R ₈ may be the same or different from each other, and each hydrogen, lower alkyl, C ₃ to C ₈ cycloalkyl, Phenyl or benzyl, or R ₇ and R ₈ are bonded to each other and —NR ₇ R ₈ represents a residue of a saturated monocyclic secondary amine); or

R ₁ represents unsubstituted or substituted phenyl or benzyl, wherein the substituent is selected from phenyl and benzyl substituent (the same as previously defined in R ₆ ); or

(저급알킬)〔여기서 Y는 -S-, -SO-, -SO₂- 또는 -O-이고, R₉는 수소, 저급알킬 또는 페닐이고, 또는 R₉와 Y에 인접한 저급알킬기는 결합하여 R₁은

형태 고리화합물인데, 여기서 Y는 전기 정의한 바와 동일하며, 알킬렌기는 3내지 10개의 탄소원자를 포함하며, 이들 중에서 적어도 3~6개는 고리원자임〕을 나타내거나 ; 또는R ₁ is

(Lower alkyl) [where Y is -S-, -SO-, -SO ₂ -or -O-, R ₉ is hydrogen, lower alkyl or phenyl, or a lower alkyl group adjacent to R ₉ and Y is bonded to R ₁ is

Wherein the Y is the same as previously defined and the alkylene group contains 3 to 10 carbon atoms, at least 3 to 6 of which are ring atoms; or

이며(여기서, R₆는 상기 정의한바이며, R₁₀은 수소, 저급알킬, 페닐 또는 할로알킬임)R ₁ is

Where R ₆ is as defined above and R ₁₀ is hydrogen, lower alkyl, phenyl or haloalkyl

(C₁~C₁₀알킬) 및

(C₁~C₁₀알킬)기들 중에서 선택됨〕; 또는R ₂ is unsubstituted or substituted C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl or C ₂ -C ₁₀ alkenyl [The substituent is halo, lower alkoxy, lower alkylthio Lower alkylsulfinyl, lower alkylsulfonyl,

(C ₁ to C ₁₀ alkyl) and

Selected from (C ₁ -C ₁₀ alkyl) groups]; or

R ₂ is unsubstituted or substituted phenyl or benzyl [substituents are lower alkyl, lower alkoxy, halo, carbyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono (lower alkyl) amino, di (lower alkyl) ) Amino, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl];

R is R ″ ₃ , R ′ or R ₃ ,

이며 (여기서, R₂는 상기 정의한 R₂와 동일함) ;R ″ ₃ is hydrogen, α-methyl, β-methyl, = CH ₂ , or

Where R ₂ is the same as defined above for R ₂ ;

(여기서 R₂는 상기에 정의한 것과 같다) ;R 'is R ₃ "' or R ₃ ", where R ₃ "'is as defined above and R ₃ "' is hydrogen, α-methyl, βmethyl, = CH ₂ , α-OCOC1 or β-OCOC1 )ego ; R ₃ is hydrogen, α-hydroxy, β-hydroxy, α-methyl, β-methyl, = CH ₂ , or α- or

(Wherein R ₂ is as defined above);

R ₄ is hydrogen, fluoro or chloro;

R ₅ is hydrogen, fluoro, chloro or methyl;

Z is carbonyl or β-hydroxymethylene; And dashed lines in ring A indicate that the 1, 2-bond is saturated or unsaturated.

Preferred groups of the compound of formula (I) are as follows;

이며(여기서, R₆'는 C₁~C₆알킬 또는 페닐임) ;R ₁ is C ₁ -C ₆ alkyl; C ₁ -C ₆ (monohalo or polyhalo) alkyl; -CH ₂ COOR ₆ wherein R ₆ is C ₁ -C ₆ alkyl; -CH ₂ -Y- (C ₁ -C ₆ alkyl), wherein Y is -S-, -SO-, -SO ₂ or -O-; or

Where R ₆ ′ is C ₁ -C ₆ alkyl or phenyl;

R ₂ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, phenyl, benzyl or C ₁ -C ₆ (monohalo or polyhalo) alkyl;

이며(여기서, R₂는 전기 정의한 R₂와 동일함) ;R is hydrogen, α-methyl, β-methyl or

Where R ₂ is identical to the previously defined R ₂ ;

R ₄ is hydrogen or fluoro;

R ₅ is hydrogen or fluoro;

Z is β-hydroxymethylene; And

The dashed line of the ring A is as defined above.

The present invention also provides an anti-inflammatory quaternary ammonium salt of selected compounds of formula (I), which will be discussed in more detail below. Also provided as compounds of formula (I) are new intermediates, for example corresponding compounds in which R ₁ is hydrogen. Soft steroids of formula (I) and quaternary ammonium salts thereof are very effective topical anti-inflammatory agents; Because of its easy destruction in vivo and eventually to an inactive steroidal metabolite, the present compound has less systemic effect than its inactive metabolite derived from known glucocortisone.

Certainly, many of the compounds of the present invention have no systemic side effects. With such a slight or no systemic effect, that is, the compounds of the present invention can be used to treat topical inflammation without the severe systemic side effects associated with the use of known glucocorticosteroids.

Throughout this specification, the following definitions and descriptions may be applied to various groups including general terms used herein.

Alkyl, alkenyl and alkylene groups may be straight or branched chain groups containing any of the aforementioned carbon atoms. Likewise, the alkyl portion of the alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, alkoxycarbonyl, alkanoyloxy, haloalkyl, monoalkylamino, dialkylamino, monoalkylcarbamoyl and dialkylcarbamoyl groups Each may be straight or branched.

The term "lower" as used in connection with any of the crowds or in connection with "alkyl" means that each alkyl moiety in it may contain 1 to 8 carbon atoms.

Particular examples of alkyl radicals contained by formula (I), whether as specific values for R ₁ or R ₂ , or as part of an R ₁ .R ₂ or R ₃ "group, are methyl, ethyl, propyl, butyl, pentyl , Hexyl, heptyl and octyl and side chain isomers thereof, as well as straight and branched chain homologs when the "alkyl" comprises 8 or more carbon atoms, etc. Examples of alkenyl radicals include vinyl, propenyl and butenyl, etc. Cycloalkyl and cycloalkenyl radicals are cyclopentyl, cyclohexyl, cyclopentynyl, cyclohexenyl, etc. Representative alkylene molecules are trimethylene, tetramethylene and the like.

The alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, alcoholcicarbonyl, alkanoyloxy, monoalkylamino, dialkylamino, mono alkylcarbamoyl and dialkylcarbamoyl groups are each in the following forms.

Wherein alkyl is as defined and exemplified above.

With regard to the structural variables included by the group of the preferred compound of formula (I), identical to the above, the term “C ₁ to C ₆ alkyl” means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, It is referred to as straight or branched chain alkyl of 1 to 6 carbon atoms such as sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like groups. Furthermore, the term "C ₁ to C ₆ (monohalo or polyhalo) alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, and the term "halogen" as used herein includes chlorine. Atoms, bromine atoms, iodine atoms or fluoro atoms belong to the group. Specific examples of predicted monohaloalkyl and polyhaloalkyl groups include chloromethyl, dichloromethyl, 1-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 2, 2, 2-trichloroethyl, 2, 2 , 2-trifluoroethyl, 1, 2-dichloroethyl, 1-chloropropyl, 3-chloropropyl, 1-chlorobutyl, 1-chloropentyl, 1-chlorohexyl, 4-chlorobutyl and the like. The term "C ₃ to C ₈ cycloalkyl" also refers to cycloalkyl radicals having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

When R _{1 in} formula (I) is —CH ₂ CONR ₇ R ₈ , wherein —NR ₇ R ₈ represents a residue of a saturated monocyclic secondary amine, such monocycle is a hetero atom other than the nitrogen atom indicated. It is preferred to have 5 to 7 ring atoms optionally comprising -O-, -S- or -N-) and optionally having one or more substituents such as phenyl, benzyl and methyl.

N) 또는 불포화아민(

N)과 쉽게 반응할 수 있다. 반응물들은 일반적으로 동몰량의 비율로 사용되고, 반응은 불활성 용매(예, 에테르, 아세토니트릴, CH₂Cl₂등) 존재하, 실온 내지 용매의 환류 온도에서, 대략 2내지 24시간 동안 행한다. 다른 방법으로, 반응은 두 반응물을 함께 혼합하고 이것을 실온 또는 20°내지 70℃사이의 온도에서 2내기 24시간 동안 유지함으로써 용매 없이 행할 수 있다. 각 경우에 있어 형성된 결정질 염은 에테르-에탄올의 혼합액 등으로 결정화함으로써 정제할 수 있다.Examples of the residues of saturated monocyclic secondary amines included by -NR ₇ R ₈ are morpholino, 1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydro-1, 2, 4-oxa Thiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino, hexamethyleneimino, 4-phenylpiperidino, 2-methyl-1-pyrazoli Diyl, 1- or 2-pyrazolidinyl, 3-methyl-1-imidazolidinyl, 1- or 3-imidazolidinyl, 4-benzylpiperidino and 4-phenyl-1-piperazinyl, and the like. have. For example, selected compounds of formula (I) wherein R ₁ is α-haloalkyl readily form corresponding soft quaternary ammonium salts useful as soft anti-inflammatory agents. Thus, for example, selected halo alkyl derivatives of formula (I) may be used to produce tertiary amines to produce the corresponding quaternary ammonium salts.

N) or unsaturated amine (

Can easily react with N). The reactants are generally used in equimolar proportions and the reaction is carried out at room temperature to reflux of the solvent for approximately 2 to 24 hours in the presence of an inert solvent (eg ether, acetonitrile, CH ₂ Cl _2, etc.). Alternatively, the reaction can be done without solvent by mixing the two reactants together and holding it for 24 hours at room temperature or between 20 ° and 70 ° C. In each case, the crystalline salt formed can be purified by crystallization with a mixture of ether-ethanol and the like.

The expression "unsaturated amine" as used above denotes an N-heterocyclic unsaturated system having 3 to 10 members in the ring and its substituted derivative, the unsaturation being consistent with the maximum number of discontinuously doubled bonds, and hydrogen as a substituent. It provides a nitrogen atom that contains no atoms at all. By the following examples, the scope of the defined terms will be fully explained.

Substitution derivatives of unsaturated amines include groups as indicated above that include one or more alkyl, -COO (alkyl) or -COO (alkyl) substituents.

With respect to the expression "tertiary amine", this term refers to an amine that does not belong to the N-heterocyclic unsaturated system contained in the "unsaturated amine" defined above without having a hydrogen atom attached to the nitrogen atom. Typically, the term "tertiary amine" includes an alkyl group the same as or different from each other, and preferably, trialkylamines each having 1 to 8 carbon atoms; Trialkoxyamines each having an alkoxy moiety of 1 to 8 carbon atoms; Tertiary saturated cyclic amines such as quinuclidin or substituted quinuclidin (eg, 3-acetoxyquinuclidin); And N-substituted derivatives of secondary saturated cyclic amines, optionally including additional substituents such as methyl [eg, N-substituted derivatives of morpholine, pyrrolidine, imidazolidine, pyrazolidine, piperidine or piperazine , Wherein the N-substituent may be a group such as (C ₁ -C ₈ ) alkyl].

Preferred quaternary ammonium salts include those derived from 1, 2-dimethylpyrrolidine, 3-acetoxyquinuclidin, 1-methylpyrrodine, triethylamine and N-methylimidazole. Particular preference is given to quaternary ammonium salts derived from the reaction of the aforementioned amines with compounds of formula (I) in which Z is β-hydroxymethylene and R ₁ is chloromethyl and R ₂ is lower alkyl.

While all compounds contained in the above formula (I) inherently meet the object of the present invention, compounds having a certain group are more preferred. "Most preferred groups" of the preferred compounds of formula (I) are described in the description of the groups for formula (I) above.

Other preferred groups for compounds of formula (I) are as defined previously by Z, R ₁ and R ₂ , and the remaining variable structures are hydrocortisone (eg, R, R ₄ and R ₅ are each hydrogen atoms, 1, 2-bond is saturated) or prednisolone (e.g. R, R ₄ and R ₅ are each hydrogen atom and 1, 2-bond is unsaturated), in particular R ₁ and R are the " When the same as defined in the "preferred" group.

이고 남아 있는 가변구조가 트리암시놀론의 그것과 동일한 화합물인데, 특히R₁및 R₂가 상술한 바람직한 화합물의 "가장 바람직한"기에 관하여 정의한 바와 동일한 경우이다. 상기 화합물의 각기에 있어, X가 산소인 화합물이 특히 바람직하다. 특히 가장 바람직한 화합물은 Z가 β-히드록시메틸렌이고, X가 산소이고, R₂가 C_1~6알킬(특히, 메틸, 에틸, 프로필 또는 이소프로필)이고, 그리고 R₁이 C_1~6알킬, C_1~6(모노할로)알킬 (특히 클로로메틸) 또는 Y가 상기 정의한 바와 같은 CH₂-Y-(C_1~6알킬)(특히 C_1~6알킬기가 메틸인 경우)인 상술한 기들에 포함되는 화합물들이다.Another preferred group of compounds consists of the 6α- and / or 9α-fluoro and 16α- or 16β-methyl congeners of the compounds indicated in the preceding paragraphs. Within this group, compounds in which Z, R ₁ and R ₂ are defined as above and the remaining variable structures are particularly preferred are the same as those of fludrocortisone, betamethasone and dexamethasone, with R ₁ and R ₂ being the preferred compounds Particular preference is given when it is the same as defined with respect to the "most preferred" group. Other compounds of particular interest in this group are those in which Z, X, R ₁ and R ₂ are as defined above and the remaining variable structures are the same as triamcinolone, flumethasone, fluprednisolone, or paramethasone, in particular R ₁ and R _{When 2} is as defined with respect to the "most preferred" group of the preferred compounds described above. Other compounds of further interest are those in which Z, X, R ₁ and R ₂ are as defined above and R is

And the remaining variable structure is the same compound as that of triamcinolone, in particular when R ₁ and R ₂ are as defined for the "most preferred" group of the preferred compounds described above. In each of the above compounds, compounds in which X is oxygen are particularly preferred. Particularly most preferred compounds are Z is β-hydroxymethylene, X is oxygen, R ₂ is C _1-6 alkyl (especially methyl, ethyl, propyl or isopropyl), and R ₁ is C _1-6 alkyl , Wherein C _1-6 (monohalo) alkyl (particularly chloromethyl) or Y is CH ₂ -Y- (C _1-6 alkyl) as defined above, especially when the C _1-6 alkyl group is methyl Compounds included in the groups.

Compounds of formula (I) may generally be prepared by known methods, which may be selected according to the type of various substituents of the desired end product.

One commonly useful method of preparing compounds of formula (I) wherein Z is β-hydroxymethylene and X is oxygen is to use a steroidal starting material having the structure

Where

The dashed lines of R ₄ , R ₅ and ring A are as defined above,

R is hydrogen, α-methyl, β-methyl, α-OH, β-OH, or = CH ₂ (NaIO _{4 by} heating or warming the corresponding 21-hydroxypregnenolone of the formula It can be conveniently prepared by treating with.

Where

The dashed lines of R ₄ , R ₅ , R and ring A are as defined above. )to be.

According to the process of the invention, the starting material of formula (II) is reacted with R ₂ OCOCl or R ₂ OCOBr (R ₂ OH and COCl ₂ or COBr ₂ where R ₂ is as defined above) In an inert organic solvent such as dichloromethane, chloroform, or tetrahydrofuran, the reaction is preferably carried out in the presence of a suitable acid acceptor (eg triethylamine, pyridine, calcium carbonate or other suitable base). Time and temperature are not decisive; The reaction is conveniently carried out at a temperature of 0 ° C. to room temperature for about 1 to 6 hours. The resulting novel 17β-carboxylic acid 17α-carbonate has the following structural formula.

Wherein the dashed lines of R ₂ , R ₄ , R ₅ and A are as defined above,

R is H, α-CH ₃ , β-CH ₃ , α-OCOOR ₂ , β-OCOOR ₂ or = CH ₂ . When R in the starting material of formula (II) is α-OH or β-OH, generally not only the 16-position but also the 17-position [ie, R in formula (II) is α-OH or β-OH, Sufficient amount of R ₂ OCOCl or R ₂ OCOBr is used to assure the formation of carbonate in the case where R of the intermediate of formula (III) is α- or β-OCOOR.

Occasionally, when a compound of formula (I) wherein R ₂ comprises a sulfinyl or sulfonyl group is desired, such a group is not introduced via the R ₂ OCOCl / R ₂ OCOBr reaction, but as described in detail below, Prepared from the corresponding thiocomprising R ₂ derivative in the final step of the synthesis process.

Possible methods of preparing the compounds of the present invention can be used to prepare compounds of formula (I) wherein Z is β-hydroxymethylene and X is oxygen or sulfur, wherein 17β-carboxyl of formula (III) Acid 17α-carbonate intermediate is used. According to this method, the intermediate of formula (III) is first reacted with a mild acyl chloride (e.g. diethyl chlorophosphate or oxalyl chloride) to produce the corresponding novel acid chloride of formula (VI) Next, in order to produce the compound of Formula (I), the compound of Formula (VI) and the compound of Formula (V) are reacted.

Where

(R₂는 상기에 정의함), 및 R₁₁가 R₃"(R₃"는 상기에 정의함)이거나 ; 또는P is -COCl, Q is

(R ₂ is defined above), and R ₁₁ is R ₃ ″ (R ₃ ″ defined above); or

P is -COOR ₁ (R ₁ is defined above), Q is -OCOCl and R ₁₁ is R ₃ "'(R ₃ "' is defined above); or

P is -COOR ₁ (R ₁ is defined above), Q is -OH and R ₁₁ is R ₃ '(R ₃ ' is defined above).

R ₁₂ XR ₁₃ ... … (V)

Where

이고, R₁₁이 R₃"일때, R₁₂는 R₁(R₁은 상기에 정의함)이고, X는 -O- 또는 -S-이고, R₁₃은 수소, 또는 알칼리금속, 알칼리토금속/2, 탈륨 또는 NH₄이고 ;P is -COCl and Q is

When R ₁₁ is R ₃ ", R ₁₂ is R ₁ (R ₁ is defined above), X is -O- or -S-, and R ₁₃ is hydrogen, or an alkali metal, an alkaline earth metal / 2 , Thallium or NH ₄ ;

When P is -COOR ₁ , Q is -OCOCl and R ₁₁ is R ₃ ", R ₁₂ is R ₂ (R ₂ is defined above), X is -O- and R ₁₃ is defined above Same as;

일 수 있다.When P is -COOR ₁ , Q is -OH, R ₁₁ is R ₃ ', R ₁₂ is R ₂ , X is -O-, R ₁₃ is -COX (X' is chlorine or bromine) or R ₁₃ is

Can be.

To produce a compound of formula (I), R ₁₂ and the same as X defined electrical, R ₁₃ is an R ₁₂ XR _13, and an inert solvent hydrogen or M is an alkali metal (eg sodium or potassium) (e.g., CHCl ₃ , THF, acetonitrile or DMF) at a temperature between 0 ° C. and the boiling point of the solvent, in order for 1 to 6 hours.

Where

Dotted lines of R ₂ , R, R ₄ , R ₅ and ring A are as defined above).

When using a compound of the formula R ₁ XR _{13 wherein} R ₁₃ is hydrogen, an acid scavenger such as triethylamine is preferably present in the reaction system. Two steps of this process can be carried out very conveniently in the same solvent without separating the acid chloride of formula (VI) produced in the first step. This method is also particularly valuable when a compound of formula (I) wherein X is S is desired.

Another preferred method of preparing the compound of formula (I) wherein Z is β-hydroxymethylene and X is oxygen uses the following 17α-hydroxy-17β-carboxylate.

Where

The dashed lines of R ₁ , R, R ₄ , R ₅ and ring A are as defined above. According to this method, the intermediate of formula (I) is subjected to about 2 hours in a suitable organic solvent (e.g., toluene, benzene, CH ₂ Cl ₂ or acetonitrile) at low temperature (-20 ° C to room temperature, e.g. 0 ° C). Or phosgene) until the reaction is complete. Evaporation and excess use of phosgene to remove the solvent yields the novel 17α-chlorocarbonyloxy-17β-carboxylate intermediate of the desired formula.

Where

The dotted lines of R ₁ , R ₄ , R _5, and A are the same as previously defined,

R is hydrogen, α-methyl, β-methyl, α-OCOCl, β-OCOCl or = CH ₂ . In the starting material of formula (V), when R is hydroxy, not only the 16-position but also the 17-position (that is, R 'of formula (VII) is α-OH or β-OH and the synthetic intermediate of formula (VII) When R is α- or β-OCOCl], a sufficient amount of phosgene is generally used to ensure the production of the chlorocarbonyloxy group. Intermediate Then, equation (Ⅷ) is to produce the corresponding compound of formula (I), preferably from Sans scavenger (e.g., triethylamine) present and, R ₂ and R ₁₃ is electrical in an inert solvent React with a compound of the formula R ₂ OR ₁₃ as defined. When R ₂ OR ₁₃ is an alcohol of the formula R ₂ OH, the reaction is carried out under the same conditions as the conversion reaction of compound (II) to compound (III). On the other hand, if a compound of formula R ₂ OM is used as R ₂ OR ₁₃ , the reaction conditions are the same as described above for the conversion of compound (VI) to compound (I). If R in formula V is OCOCl, a sufficient amount of R ₂ OR ₁₃ is generally used to ensure conversion of both 16- and 17α-substituents to the OCOOR ₂ group in the final product. And also formula (I) 16-hydroxy and sulfinyl- and sulfonyl-comprising compounds are most conveniently produced as the final step of the synthesis process.

As a variation of the method just described, the steroidal 17α-hydroxy-17β-carboxylic acid starting material of formula (II) produces a 17α-chlorocarbonyloxy-17β carboxylic acid intermediate of formula (II). To phosgene as described above, and then to R ₂ OR _{13 as} described above to produce the corresponding compound of formula (III).

Where

The dashed lines of R, R ₄ , R ₅ and ring A are as defined above. The new intermediate can then be synthesized with the corresponding compound of formula (I) as described above. Once again 16-hydroxy and sulfinyl and sulfonyl derivatives are best prepared as the final step.

(포스겐과 2당량의 R₂OH와의 반응으로 편리하게 제조될 수 있음)의 초과량의 탄산염과 반응한다. R₂군의 성질에 따라,

반응물은 또한 탄산염반응물의 비점에서 또는 상응하는 R₂OH(반응 혼합물로 부터 이런식으로 편리하게 제거될 수 있음)의 비등점에서 용매로서 작용할 수 있거나, 또는 반응물들은 적절한 불활성유기용매(예, 벤젠 또는 톨루엔 같은 방향족, 또는 디클로로메탄 또는 클로로포름 같은 할로겐화 히드로카르본)중 결합할 수 있다. 그리고, 또한 식( I )의 16-히드록시 및 술피닐 및 술포닐 화합물들은, 이 황원자를 포함하는 식(Ⅶ)의 중간물질이 첫째로 산화될수 있다 할지라도, 과정에 있어 최종 단계로서 편리하게 제조될 수 있고, 그런 다음 식(Ⅶ)의 합성 술피닐 또는 술포닐 화합물은

와 반응한다.Another method for preparing the compound of formula (I) wherein Z is β-hydroxymethylene and X is oxygen uses 17α hydroxy-17β-carboxylate of formula (VII). According to this method, the intermediate of formula (i) is present in the presence of an acid catalyst to produce the corresponding compound of formula (I),

React with an excess of carbonate (which can be conveniently prepared by reacting a posgen with 2 equivalents of R ₂ OH). Depending on the nature of the R ₂ group,

The reactant may also act as a solvent at the boiling point of the carbonate reactant or at the boiling point of the corresponding R ₂ OH (which may be conveniently removed from the reaction mixture in this way), or the reactants may be suitable inert organic solvents (eg benzene or Aromatics such as toluene, or halogenated hydrocarbons such as dichloromethane or chloroform). In addition, the 16-hydroxy and sulfinyl and sulfonyl compounds of formula (I) are convenient as final steps in the process, even if intermediates of formula (IV) containing these sulfur atoms can be oxidized first. Can be prepared, and then the synthetic sulfinyl or sulfonyl compounds of formula

React with

Other methods of preparing the selective compounds of formula (I) are clearly known by known techniques. According to an embodiment, a compound of formula (I) in which R ₁ or R ₂ is halo-substituted may be subjected to halogen exchange in order to replace halogen with another halogen according to the reactivity sequence Cl <Br <I. For example, when the chloroalkyl 17β-carboxylate of formula (I) is reacted with an alkali metal iodide (eg sodium iodide), the corresponding iodoalkyl 17β-carboxylate will be produced. As such, salts of bromide (eg lithium bromide) may be reacted with chloroalkyl 17β-carboxylate to produce the corresponding bromoalkyl 17β-carboxylate. Suitable solvents for these two reactions can be selected from hexamethylphosphoramide, acetone, ethanol, methylethylketone, dimethylacetamide, dimethylformamide and acetonitrile.

In the same way, halogen exchange reactions based on relative solubility can convert the chloroalkyl 17β-carboxylate or iodoalkyl 17β-carboxylate of formula (I) to the corresponding fluoroalkyl derivatives. Silver fluoride may be used in this reaction in a suitable organic solvent (eg acetonitrile), particularly useful in the preparation of compounds wherein R is fluoromethyl or fluoroethyl.

21-hydroxypregnenolone capable of preparing the steroidal starting material of formula (II) is either commercially available or prepared by known methods. Likewise the nonsteroidal starting materials used in the various methods discussed above can be used commercially or prepared by known chemical methods.

In addition, the starting material of formula (II) may react with a compound of formula R ₂ OCOCl or R ₂ OCOBr as defined by R ₂ , to produce an intermediate of formula (X).

In the above formula,

The dashed lines of R ₂ , R, R ₄ , R ₅ and ring A are as defined above, with the corresponding intermediates of formula (III) by partial hydrolysis with or without separating compounds of formula (X) Can be converted to a substance. Equation (Ⅱ), as the reaction of the starting material and R ₂ OCOCl or R ₂ OCOBr is described above in formula (Ⅱ) compound and R ₂ OCOCl or may be performed with the same conditions as reaction in the R ₂ OCOBr of The exception is that R ₂ OCOCl or R ₂ OCOBr is used in an amount of from 2 moles to more per mole of the compound of formula (II). Partial hydrolysis of the synthetic compound of formula (X) can be carried out in the presence of a catalyst in an inert solvent. Examples of suitable catalysts include tertiary alkylpyridine such as triethylamine, trimethylamine and the like, aromatic amines such as 4, 4-dimethylaminopyridine, quinoline and the like; Secondary alkylamines such as diethylamine and dimethylamine; And inorganic bases such as sodium hydroxide, potassium hydroxide, potassium hydrogencarbonate or the like. Preferably pyridine and potassium hydrogen carbonate are used. Examples of suitable inert solvents for use in hydrolysis include water; Lower alcohols such as ethanol and methanol; Ethers such as dimethyl ether, diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran and the like; Halogenated hydrocarbons such as dichloromethane and chloroform; Tertiary amines such as pyridine and triethylamine; Or mixtures of two or more of the solvents described above. The reaction is usually carried out at a temperature of about 0 ° C. to 100 ° C. for 1 to 48 hours, but preferably at room temperature to 50 ° C. for 2 to 5 hours.

As will be discussed in detail below, the results of various activity studies on a representative class of the invention clearly demonstrate the effective anti-inflammatory and minimal systemic effects / toxicity of the soft steroids of formula (I). Compounds of the present invention in that local and systemic effects can be separated as desired, known natural compounds such as cortisone, hydrocortisone, 17α-butyrate, betamethasone 17-valerate, triamcinolone, betamethasone dipropionate, and the like And for the treatment of local or other local inflammation without severe systemic side effects typically represented by synthetic glucocorticosteroids.

Thymus Retraction Test

Test animals are male Spragu / Dawly species, each weighing about 40-50 g.

One side of each ear of mice is treated with a solution containing the amounts indicated below (ethanol / isopropyl myristate or acetone / isopropyl myristate, 90/10) in a total amount of 25 μ. As a control, the test compound is removed and treated in the same manner. After 24 hours, all rats are sacrificed and weighed after their thymus is removed.

The results are summarized in Table 1, where the weight of the thymus is expressed as mg per 100 g of rat.

TABLE 1

Effect of topically administered soft steroids and reference steroids on intramuscular thymus weight

The change in weight in the thymus is a measure of the systemic effect and the toxicity that occurs here. As can be seen from the above data, even natural glucocorticoid hydrocortisone causes a significant reduction in thymus weight compared to the control. Diseases caused by the same amount of the representative class of the invention are much less severe, and these compounds have a much less systemic effect than hydrocortisone.

[Blanching Studies]

The blanching studies of McKenzie-type humans showed that chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxyl, a representative compound of the present invention, It was done to study the effect of rate blanking. It has been found that the action of a compound causing blanching in humans is closely related to its anti-inflammatory action.

Test compounds are dissolved in ethanol / isopropyl myristate (90/100 or 70/30) at concentrations of 0.03, 0.01, 0.003, 0.001 and 0.0003M. A 50 μl aliquot of each solution is used to separate the bandage-type gauze moiety commonly used for allergy testing, and the bandage is used for the forearm. After occlusion for 6 hours, remove the bandage. One to five hours after bandage removal, blanching is also observed in the most intelligent test compounds.

When the hydrocortisone is directly compared with the test compound according to the method described above, no blanching is observed at the hydrocortisone concentration of 0.03 M or less. In addition, 0.03 M of hydrocortisone is approximately equivalent to that of 0.001 M of chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate. Causes ranching.

[Ear Edema Test]

Test animals are Sprag / Duli rats, each weighing approximately 150 g. In the treatment group, a selective amount of the test compound is dissolved in acetone containing 5% croton oil, and 50 µl of the solution is applied to the inner surface of the rat right ear. The control group is treated the same with excipients, 5% croton oil in acetone. After 6 hours of croton oil treatment, a portion of each ear is removed by anesthesia. Then, 48 hours after steroid treatment, when the animal is sacrificed, the thymus and adrenal glands are removed and weighed. Test results showing the inhibitory effect of topically used steroids on ear swelling caused by croton oil are summarized in Table 2 below.

TABLE 2

Effect of topically used soft steroids and reference steroids on ear swelling caused by croton oil

a: Calculation based on using 50 μl of steroid solution

b: 50 μl of 5% croton oil / acetone and 5% croton oil / acetone are applied to the right ear.

Ear weight is measured after 6 hours of topical use.

^* : p <0.05; ^{* *} p <0.01: Severe Difference from Control

Table 2 continued

^* : P <0.05; ^{* *} P <0.01: Severe Difference from Control

As can be seen from Table 2 above, a representative type of the invention, namely chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate, is Substantially inhibits swelling of the ear (and thus weight) caused by a compound that exhibits anti-inflammatory action, ie croton oil. On the other hand, in contrast to the effects caused by betamethasone 17-valerate, the representative compounds of the present invention show that the weight of the thymus does not decrease significantly when compared to the control, ie the degree of systemic effect is not severe.

[Granuloma Formation Test]

Test compounds are dissolved in acetone and aliquots of varying concentrations are injected into cotton pallets. The globules are dried and one of them is transplanted under the skin of each test rat. After 6 days, when the animal is sacrificed, granulation tissues (granulomas) formed in and around the transplanted globules are removed, dried and weighed.

The thymus and adrenal glands are also removed and weighed. The efficacy of compounds that inhibit granulomatous formation in this test is a direct indication of local anti-inflammatory activity; therefore, the smaller the granulation tissue weight, the better the anti-inflammatory activity. On the other hand, a severe decrease in thymus weight indicates a severe systemic effect, on the contrary, when the test compound does not significantly reduce the weight of the aspirate compared to the control, it indicates a lack (or minimal) of systemic side effects.

The results are shown in Table 3, 4 and 5 ^-a and ^-b 5 of.

TABLE 3

Effect of Topically Administered Softsteroids and Reference Steroids on Body Weight, Thymus Weight, and Granulation Tissue Formation Caused by Transplantation of Cotton Balls in Rats

^{* * *} , P <0.001.

Table 3 Continued

Effect of topically administered soft steroids and reference steroids on body weight, thymus weight, and granulation tissue formation caused by transplantation of cotton globules in rats

^* , P <0.05, ^{* *} , P <0.01, ^{* * *} , P <0.001. (Mean ± standard error)

TABLE 4

Effect of topically administered soft steroids and reference steroids on body weight, thymus weight, and granulation tissue formation caused by transplantation of cotton globules in rats

^* , p <0.05, ^{* *} , p <0.01, ^{* * *} , p <0.001. (Mean ± standard error)

TABLE 4

Effect of topically administered soft steroids and reference steroids on body weight, thymus weight, and granulation tissue formation caused by transplantation of cotton globules in rats

^* , p 0.05, ^{* *} , p 0.01, ^{* * *} , p 0.001. (Mean ± standard error)

Table 5-a

Effect of topically administered soft steroids and reference steroids on body weight, thymus weight, and granulation tissue formation caused by transplantation of cotton globules in rats

^* , p <0.05, ^{* *} , p <0.01, ^{* * *} , p <0.01. (Mean ± standard error)

Table 5-a (continued)

Effect of topically administered soft steroids and reference steroids on body weight, thymus weight, and granulation tissue formation caused by transplantation of cotton globules in rats

^* , p <0.05, ^{* *} , p <0.01, ^{* * *} , p <0.001. (Mean ± standard error)

Table 5-b

Effect of Topically Administered Soft Steroids on Body Weight, Thymus Weight, and Granulation Tissue Formation Caused by Transplantation of Cotton Balls in Rats

^* , p 0.05, ^{* *} , p 0.01, ^{* * *} , p 0.001. (Mean ± standard error)

Male Sprague / Dolly rats weighing 152 to 183 g (mean body weight 71 g) were used.

Cotton ball weight is 30.1 + 0.3mg (the number of test animals is 30)

From the data in Tables 3, 4 and 5-a and 5-b above, the representative compounds of the present invention exhibit significant anti-inflammatory action in smaller amounts than prior art steroids such as hydrocortisone 17-butyrate and betamethasone 17-valerate. It can be seen that. On the other hand, while representative compounds of the present invention do not significantly reduce the weight of the thymus or only slightly reduce the weight of the thymus to a minimum, all steroids of the prior art are very effective as they significantly reduce the weight of the thymus. Show systemic effect Thus, the compounds have a much larger therapeutic effect than the steroidal anti-inflammatory agents of the prior art, that is, the separation of local anti-inflammatory activity from systemic effects.

In addition, from the above Table 5-b, it can be seen that the representative compounds of the present invention exhibit significant local anti-inflammatory activity.

From the results in Tables 4 and 5-b, representative of the present invention were measured in ED ₄₀ 's, ED ₅₀ ' s and ED ₆₀ 's and the relative titers of the compounds are shown in Table 6 below. Among the compounds of the present invention

TABLE 6

Relative Potency of Soft Steroids by Topical Sampling of Granulocytes

1. One dose that causes 40% inhibition of granulation tissue increase.

2. Two doses causing 50% inhibition of granulation tissue mass. () = 95% confidence limit

3. 3 doses causing 60% inhibition of granulation tissue increase.

Nine chloromethyl 11-hydroxy-17-isopropoxycarbonyloxyandrost-4-ene-3-silver-17-carboxylate assigns a titer of 1 at each ED level and the titers of other compounds Relative to. ED ₄₀ 's, ED ₅₀ 's and ED ₆₀ 's are the dosages required to reduce the weight of granulation tissue by 40%, 50% and 60%, respectively.

[Thymus Suppression Test]

When the drug was administered systemically, several further studies were conducted to determine the effect of selected compounds of the invention on the thymus weight of rats. In each study, male Sprague-Dawley mice were used (see the following table for the average weight of mice for each study). The test compound is subcutaneously injected once a day for 3 days in 0.5% CMC (carboxymethylcellulose). On the 15th day (48 hours after the last treatment) the animal is sacrificed and the thymus weight is recorded. Weight gain is measured 24 hours after the last treatment. The test results are shown in the following Tables 7, 8 and 9. The TED ₄₀ 's, TED ₅₀ 's (the thymolytic effective dose or the dose required to inhibit the weight of the thymus 40% and 50%, respectively) and relative titers of the representative compounds and reference steroids of the invention are shown in Table 10 below. . In Table 10, TED ₄₀ and TED ₅₀ for the reference steroid betamethasone 17-valerate were assigned 1 and the titers of the other compounds were shown relative thereto. Obviously, the less thymic action at a given dose, the more toxic the compound is.

TABLE 7

Effects of Systemically Administered (s · c) Soft and Reference Steroids on Body Weight and Thymus Weight in Rats

^* P <0.05, ^** , P <0.01, ^*** , P <0.001 (mean ± standard error)

Male Sprague-Dawley rats weighing between 149 and 168 g are used.

TABLE 8

Effect of systemically administered (s. C.) Soft steroids and reference steroids on body weight and thymus weight in rats

^* , P <0.05, ^** P <0.01, ^*** , P <0.001 (mean ± standard error)

Male Sprague-Dawley rats weighing about 185g (162-202g) are used.

TABLE 9

Effect of Systemically Administered (s. C) Soft Steroids on Body Weight and Chest Weight in Rats

^* , P 0.05, ^** , P 0.01, ^*** , P 0.001 (mean ± standard error)

Male Sprague-Dawley rats weighing 91-112 g are used.

TABLE 10

Timol Degradation of Subcutaneously Administered Soft Steroids in Rats

Even at a dose level of 100 mg / kg / day, a 50% reduction in thymus weight cannot be achieved.

Blank Cotton Ball Granuloma Analysis

Compared to betamethasone 17-valerate, further tests were conducted to determine the thymol degradation of a representative class of the invention. In this test, the drug was administered intravenously to rats while using the blank glomerulosarcoma assay. Male Sprague-Dawley rats weighing about 185 g (166-196 g) each were used. Two cotton tools each weighing 30 mg and containing no test compound were sterilized and subcutaneously implanted at the constant velocity of the test animals. This day is considered the day when the transplant is zero. The test compound suspended in 0.8% polysorbate 80 is administered intravenously once daily for three consecutive days from day 1. On day 5, the animals are sacrificed and their cotton granules are removed along with their respective granulomas, dried overnight in an oven at 50 ° C. and weighed (dry granuloma weight). Thymus and final weight are also recorded. The results are shown in Table 11.

In the previous test, the deactivation of a representative class of the present soft steroids administered intravenously in rats is measured. The ratio between test steroid and betamethasone 17-valerate titer for topical anti-inflammatory is 283: 0.7 as can be seen in Table 6. This means that the test compound exhibits about 400 times higher activity than that of betamethasone 17-valerate. Test compounds are administered intravenously to test for test compounds for systemic anti-inflammatory activity as compared to betamethasone 17-valerate. It can be seen that the test compound has lower granulation tissue suppression and thymic contraction action than betamethasone 17-valerate. From the test results, it can be presumed that a compound whose metabolism (deactivation) is not easy to have systemic anti-inflammatory action, as in the case of betamethasone 17- valerate.

TABLE 11

Timol Degradation Activity of Test Steroids Administered Intravenously in Mice by the Analysis of Blank Sosomosphere Granulomas

^* , P <0.05, ^** P <0.01, ^*** , P <0.001. (Mean ± standard error)

Calculated based on ED ₅₀ 's and thymus suppression tests (e.g., as shown in Table 10, above) calculated for local cotton tool granulomas analysis (e.g., as shown in Table 6 above) TED ₄₀ 's are used to reach the relative potency and therapeutic index for a representative class of the invention compared to steroids of the prior art. See Table 12 below, which clearly shows the potent anti-inflammatory and minimal systemic toxicity of the compounds of the present invention.

TABLE 12

Therapeutic Indexes of Representative Types of the Invention Compared to Previous Steroids

a Number (µg / bullet) for the anti-inflammatory effect in SOM granuloma

b Levels of thymic inhibitory effect required subcutaneously (mg / kg)

c Ratio of relative potency to ED ₅₀ and relative potency to TED ₄₀ ; Assigned the value of hydrocortisone 17-butyrate to 1.

Compounds of formula (I) may be combined with suitable pharmaceutically acceptable non-toxic carriers to provide pharmaceutical compositions for topical or other topical treatment. In view of the absence of systemic effects, it is evident that the compounds of the present invention will not be used to treat conditions requiring systemic adrenal cortex treatment such as adrenal insufficiency. Examples of inflammatory conditions that can be treated with a pharmaceutical composition comprising at least one of the compounds of the invention and one or more pharmaceutical carriers include, ie; Dermatological diseases such as atopic dermatitis, acne, psoriasis or contact dermatitis; Eye and otic diseases with acute and chronic allergic and inflammatory reactions; Respiratory system name; Ulcerative gastroenteritis; Proctitis, pruritus and analgesia associated with hemorrhoids, proctitis, fever, fever, fissures, postoperative analgesia and anal pruritus.

Such compositions can also be used topically as a preventive measure against inflammatory and tissue rejection reactions associated with transplantation.

Clearly, the choice of carrier and pharmaceutical form will vary depending on the particular conditions under which the composition is to be administered. Examples of various dosage forms for topical administration include ointments, lotions, creams, powders, drops (eg eye or ear drops), suppositories, retention enemas, chewable or washable tablets or pellets (eg aphthaic) For the treatment of ulcers) and aerosols. For example, ointments and creams may be prepared as aqueous or oily medicines by the addition of suitable thickening and / or gelling agents and / or glycols. Thus, for example, such medicines include oils such as water and / or liquid paraffin or vegetable oils such as peanut oil or castor oil, or glycolic solvents such as propylene glycol or 1,3-butanediol. Thickening agents that can be used according to the nature of the drug include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, dehydrated lanolin, hydrogenated lanolin and beeswax and / or glyceryl monostearate, and / or nonionic emulsions. have.

The solubility of ointments or cream steroids can be improved by blending aromatic alcohols such as benzyl alcohol, phenylethyl alcohol or phenoxyethyl alcohol.

Lotions can be prepared as aqueous or oily agents, and generally include one or more of emulsifiers, dispersants, suspending agents, thickening agents, solvents, colorants and flavoring agents. Powders may be prepared with the aid of suitable powder injections such as talc, lactose or starch. Drops may also be prepared in aqueous formulations containing one or more dispersants, suspending agents, or solubilizing agents. Spray compositions can be prepared as aerosol using, for example, a suitable propane such as dichlorodifluoromethane or trichlorofluoromethane.

The proportion of active ingredient in the composition according to the invention varies depending on the very compound used, the form of the preparation form and the particular conditions under which the composition is to be administered. Formulation forms generally comprise from about 0.0001 to about 5.0% by weight of the compound of formula (I). Topical preparations generally contain 0.0001 to 2.5%, preferably 0.01 to 0.5%, and may be administered once a day or as needed. Generally speaking, the compounds of the present invention are also approximately the same (or proportionally more if they are the most potent compounds of the present invention) compared to known high active agents such as methylprednisolone acetate and beclomethasone dipropionate. Low) at a dosage level or substantially lower dosage level compared to known hypoactive agents such as hydrocoptisone, such as compositions of the presently available forms, including known glucocorticostades It can be mixed into lodging and other local compositions.

Thus, for example, aspirated formulations suitably used for the treatment of asthma, according to methods well known in conventional pharmaceutical formulations, are chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4 It may be prepared as a metered-dose aerosol unit comprising a representative class of the invention such as -en-3-one-17β-carboxylate.

Such aerosol units may comprise a microcrystalline suspension in which the above-mentioned compounds together with oleic acid or other suitable dispersant are suspended in suitable sprays (eg trichlorofluoromethane and dichlorodifluoromethane). Each unit typically comprises 10 mg of the active ingredient described above, about 50 μg released in each operation. One effective class of the present invention such as chloromethyl 17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrostar-1, 4-diene-3-silver-17β-carboxylate When used or more, each unit typically contains 1 mg of active ingredient, with about 5 μg released in each operation. Another example of a pharmaceutical composition according to the invention is a formula of 0.1% such as chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-ene-3-silver-17β-carboxylate together with an inert body. Compound of I) and propylene glycol, ethoxylated stearyl alcohol, polyoxyethylene-10-stearyl ether, cetyl alcohol. In the mucoadhesive foam base of methylparaben, propylparaben and triethanolamine, consisting of 1% such as pramoxin hydrochloride and local anesthetics, it is used to treat a wide range of rectal inflammatory diseases that can be applied to the anus or perianal region. Suitable foam formulations.

When more potent compounds of the invention are used, for example, generally 0.05% of chloromethyl-9a-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16αmethylandrostar-1, 4 Less active ingredients such as -diene-3- and -17β-carboxylate are used.

Another pharmaceutical formulation according to the present invention is typically the present invention, such as chloromethyl17α-ethoxycarbonyloxy--11β-hydroxyandrost-4-ene-3-silver-17β-carboxylate together with sodium chloride. Compound 40 mg (or chloromethyl 9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrostar-1, 4-diene-3-silver-17β-carboxylate or chloromethyl 9α-fluoro-11β-hydroxy-16α-methyl-17α-propoxycarbonyloxyandrosta-1, 4-diene-3- is a more potent compound of the invention such as 17β-carboxylate 20 mg), poly A solution or suspension suitable for use as a one-time retention enema comprising sorbate 80 and 1 to 6 ounces of water (water added in a short time before use). Suspensions can be administered as retention enema or by drip several times per week in the treatment of ulcerative gastroenteritis.

Other pharmaceutical formulation names according to the invention are described in the following examples.

Without further assimilation, one of the conventional techniques in the technique using the above-described technique can fully utilize the present invention. Therefore, the following embodiments should be construed as illustrative only and do not limit the scope of the specification and claims in any sense.

Example 1

To a solution of hydrocortisone (15 g, 0.04) dissolved in 120 ml of tetrahydrofuran and 30 ml of methanol at room temperature, a warm solution in which sodium metaperiodate (25.7 g, 0.12 mol) was dissolved in 100 ml of water was added. The reaction mixture is stirred at room temperature for 2 hours and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. The solid is ground with 50 ml of water, washed with water and vacuum dried at 50 ° C. for 3 hours. A product having the following structure, 11β, 17α-dihydroxyandrost-4-ene-3-silver-17β-carboxylic acid (ie, cortenoic acid) was obtained in a yield of 96% (melting point 231-234 ° C). .

Example 2

Dichloromethane in a cold solution of 11β, 17α-dihydroxyandro-4-ene-3-17β-carboxylic acid (5% weight / vol. 1 mol) and triethylamine (4 mol) dissolved in dichloromethane To this is added 50% (weight / volume) solution of methylchloroformate (3.9 mol) dissolved. The reaction mixture is kept at room temperature for 2 hours. The resulting triethylamine hydrochloride precipitate is filtered off and the filtrate is subsequently washed with 3% sodium hydrogen carbonate, dilute (1%) hydrochloric acid and water, the organic layer is separated, dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo until foamy. The foam is used in the next step (eg Example 3) or is chromatographed and crystallized for analysis, the product 11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β The carboxylic acid is chromatographed and crystallized and then melted at 198 to 204 ° C. ir (KBr) 3000-2800 (C = H), 1750, 1735, 1720 (C = O), 1650, 1640 (C = CCO) cm ^-1 . The product can be represented by the following structural formula.

Substituting the above-mentioned methylchloroformate with an equivalent amount of ethylchloroformate and substantially repeating the above-described method, 17α-ethoxycarbonyloxy-11β-hydrate which melts at 192-195 ° C. after chromatography and crystallization A loxyandro-4-en-3-one-17β-carboxylic acid is produced. ir (KBr) 3500 (11β -OH), 3000-2800 (C = H), 1740 (C = O), 1630 (C = CC = O) ^-1 ; nmr (CDCl 3) δ 6.4 (1, b, COOH), 5.67 (1, S, C-CH), 4.43 (1, b, CHOH), 4.13 (2, q, J = 7.5 Hz, OCH ₂ CH ₃ ) ; Analytical calcd. For C ₂₃ H ₃₂ O ₇ : C, 65.69: H, 7.67. Found C, 65.76; H, 7.74.

In a similar manner, the methylcroformate used in the first paragraph of this example is replaced by the equivalent of butyl chloroformate and the process described therein is substantially repeated, yielding 17α-butoxycarbonyloxy-11β-hydroxyandro Str-4-en-one-17β-carboxylic acid is produced. The final product is determined by tetrahydrofuran-hexane and then melted at 164 to 166 ° C.

Likewise, the methylchloroformate used in the first paragraph of this example is substituted with the equivalent of isopropylchloropurmate and described in detail therein (repeat the method, 11β-hydroxy-17α-isopropoxycarbonyloxyandrost 4-ene-3-silver-17β-carboxylic acid is produced The final product is crystallized with tetrahydrofuran-hexane and then melted at 144.5-146.5 ° C.

Example 3A

Substituting the hydrocortisone used in Example 1 with one of the equivalents of starting material listed below and substantially repeating the method described therein yields the material indicated below:

Example 3B

Substituting the hydrocortisone used in Example 1 with one of the equivalents of starting material listed below and substantially repeating the method described therein yields the material indicated below:

Example 4A

Following the general method of Example 2 and substituting the appropriate reactants therein results in the novel intermediates of the present invention as follows:

The compounds of 4A-1 to 4A-15 are named as follows:

4A-1: 17α-benzyloxycarbonyloxy-11β-hydroxyandmist-4-en-3-one-17β-carboxylic acid

4A-2: 17α-ethoxycarbonyloxy-9α-fluorom-11β-hydroxyandmist-4-en-3-one-17β-carboxylic acid

4A-3: 17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16β-methylandrostar-1, 4-dien-3-one 17β-carboxylic acid

4A-4: 17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrostar-1, 4-dien-3-one 17β-carboxylic acid

4A-5: 9a-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16α-methylandrostar-1, 4-dien-3-one-17α-carboxylic acid

4A-6: 11β-hydroxy-17α-isobutoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic acid

4A-7: 9a-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrostar-1, 4-dien-3-one-17α-carboxylic acid

4A-8: 11β-hydroxy-17α-phemoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic acid

4A-9: 9α-fluoro-11β-hydroxy-16α-menyl-17α-propoxycarbonyloxyandrostar-1, 4-dien-3-one-17β-carboxylic acid

4A-10: 17α-cyclohexyloxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acid

4A-11: 9α-fluoro-11β hydroxy-17α-methoxycarbonyloxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxylic acid

4A-12: 17α-n-pentyloxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxylic acid

4A-13: 17α-ethoxycarbonyloxy-6α, 9α-difluorom-11β-hydroxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxylic acid

4A-14: 17α-phenoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxylic acid

4A-15: 17α- (2-chloroethoxycarbonyloxy) -9α-fluoro--11β-hydroxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxylic acid

Example 4B

Following the general method of Example 2 and substituting the appropriate reactants therein results in the novel intermediates of the present invention as follows:

^* Prepared by continuing the reaction with m- chloroperbenzoic acid from a 4A-20,

Example 5A

Example 2 The method of each paragraph is substantially repeated and the steroids used therein are substituted with the equivalents of each of the following starting materials: chloromethyl 11β, 17α-dihydroxyandmist-4-ene-3- On-17β-carboxylate; And methylthiomethyl 11β, 17α-dihydroxyandro-4-en-3-one-17β-carboxylate, the following soft anti-inflammatory formula (I) is obtained:

^{* Use} isobutyl chloroformate as alkylchloroformate reactant.

Example 2 The method of each paragraph is substantially repeated and the steroids used therein are replaced by the equivalents of each of the following starting materials; Methylthiomethyl 11β, 17α-dihydroxyandrost-4-en-3-one-17β-carboxylate and methylsulfonylmethyl 11β, 17α-dihydroxyandro-4--4--3-one-17β Carboxylates. The following soft anti-inflammatory agents [formula (I)] are obtained:

Other representative types (e.g., compounds of Examples 7A and 7B) can likewise be prepared according to the methods of Examples 8-10.

Example 6

The products of Examples 2 and 6A-4 are first reacted with diethylchlorophosphate and then with chloroform increase HB ₃ SNa for approximately 6 hours, respectively.

The following intermediates are obtained in the first step:

Then the next compound of formula (I) is obtained in the second step.

When the remaining product of Example 6A and Example 6B is treated according to the above method, the corresponding compound of the following structural formula is obtained.

In the above formula,

Various structural variables and dashed lines represented by R ₂ , R ₃ , R ₄ , R ₅ , Z are the same as those of compound 6A1-6A3, 6A5-6A11 and 6B1-6B25 of Examples 6A and 6B.

Example 7

Chloromethyl 11β, 17α-dihydroxyandro-4-en-3-one-17β-carboxylate (0.01 mol) is dissolved in toluene (100 ml) and the solution is cooled to approximately 0 ° C., then The phosgene is bubbled into the solution, keeping the reaction mixture at low temperature until the reaction is complete (about 2 hours). When the solvent and excess phosgene are evaporated, the crude 17α-chlorocarbonyloxy compound of the following formula remains.

The intermediate (0.01 mol) obtained above was combined with ethanol (0.02 mol) containing 2.6-dimethylpyridine (0.01 mol) and reacted for 6 hours at room temperature. At the end the desired chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate is separated from the reaction mixture. After crystallization, the compound is melted at 197 to 200 ° C.

Chloromethyl 11β, 17α-dihydroxyandrost-4-ene-3-silver-17-carboxylate, used in the above equivalent of methylthiomethyl 11β, 17α-dihydroxyandrost-4-ene-3 Substituting with -on-17β-carboxylate and substantially repeating the above-described method, methylthiomethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-ene melting at 133-136 ° C after crystallization 3-one-17β-carboxylate is produced. If desired, the compound can then be converted to the corresponding sulfonyl or sulfinyl compound as described in Example 4.

Other representative classes, such as the compounds of paragraphs 1, 3, 4 and 5 of Example 3, and the compounds of Examples 7A and 7B, are carried out as appropriate from the corresponding 17α-hydroxy 17β-carboxylate with appropriate alcohols. It can be prepared in a similar manner by continuing treatment with m-chloroperoxybenzoic acid as in Example 4.

Example 8

Chloromethyl 11β, 17α-dihydroxyandrost-4-en-3-one-17β-carboxylate, instead of the equivalent of 11β, 17α-dihydroxyandrost-4-en-3-one-17β-carbox The procedure of the first paragraph of Example 12 is repeated except using an acid. Then, an intermediate material having the following formula is obtained.

The intermediate was then subjected to the method of paragraph 2 of Example 12 to produce 17α-ethoxycarbonyloxy-11β, 17α-hydroxyandrost-4-en-3-one-17β-carboxylic acid. Applies, the same as the product of paragraph 2 of Example 2.

Other compounds of Examples 2, 6A and 6B can be prepared using the same general method.

Example 9

Chloromethyl 11β, 17α-dihydroxyandro-4-en-3-one-17β-carboxylate (0.02 mol) is combined with diethylcarbonate (0.2 mol) containing 20 mg of p-toluene sulfonic acid. . The reaction mixture is kept at room temperature for 4 hours and then heated to about 80-85 ° C .: The resulting residual ethanol is removed by distillation under reduced pressure. After crystallization, crude chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate is obtained as a residue which melts at 197 to 200 ° C.

Chloromethyl 11β, 17α-dihydroxyandrost-4-en-3-one-17β-carboxylate, used in the above equivalents of methylthiomethyl 11β, 17α-dihydroxyandrost-4-ene-3 Substituting with on-17β-carboxylate and substantially repeating the above-described method, methylthiomethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-ene-3 melted at 133-135 ° C -On-17β-carboxylate is produced. If desired, the compound can then be converted to the corresponding sulfonyl or sulfinyl compound as described in Example 4.

Other representative classes, such as the compounds of paragraphs 1, 3, 4 and 5 of Example 3 and the compounds of Examples 7A and 7B, result from the reaction of the corresponding 17α-hydroxy-17β-carboxylate with the appropriate t25 carbonate It can be prepared in the same manner (if appropriate, continue treatment with m-chloroperoxybenzoic acid as in Example 4).

Example 10

10 g of ethylchloroformate in a solution of 8, 7 g of 11β, 17α-dihydroxyandro-4-en-3-one-17β-carboxylic acid and 9.6 ml of triethylamine in 100 ml of anhydrous dichloromethane Is added dropwise at 0? 5 占 폚. The reaction mixture is slowly warmed to room temperature and the insoluble material is filtered off. The filtrate is continuously washed with 3% aqueous sodium hydrogen carbonate solution, 1% hydrochloric acid and water, and then dried over anhydrous magnesium sulfate. When the solvent is concentrated under reduced pressure to crystallize the residue, ethoxycarbonyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carbon which is melted at 158-159 ° C 10.5 g of carboxylate are obtained.

Example 11

Following the general method described in Example 10 and substituting the appropriate reactants therein, the following additional compounds are produced:

Example 12

13.2 g of m-propylchloroform in a solution of 8.7 g of 11β, 17α-hydroxyandro-4-en-3-one-17β-carboxylic acid and 10 g of triethylamine in 100 ml of dichloromethane The solution of the mate dissolved in 10 ml of dichloromethane is added dropwise over 1-1.5 hours under ice-cooling, the reaction mixture is warmed at room temperature for 2 hours, then washed with 3% aqueous sodium hydrogen carbonate solution 1N hydrochloric acid and water, Dry over magnesium sulfate. The solvent is concentrated under reduced pressure.

Crystallization with a mixture of ether and n-hexane yields 10.5 g of propoxycarbonyl 11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate, 40 ml of Dissolve in pyridine. To this solution, 30 ml of water is added dropwise over 1 to 1.5 hours. The mixture is stirred for 1 hour and, under ice-cooling, the pH is adjusted to 2 to 5.5 by addition of concentrated hydrochloric acid. The mixture is then extracted with chloroform, washed continuously with 1N hydrochloric acid and water and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was recrystallized from a mixture of acetone and tetrahydrofuran to give 11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one- having a melting point of 156-157 ° C. 7.7 g of 17β-carboxylic acid are obtained.

Example 13

Except for using the appropriate starting materials and reaction conditions, the general method described in Example 19 gave the remaining compound of Example 6A.

Example 14

Chloromethyl 17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrostar-1,4-dien-3-one-17β-carboxylate (2 g) was anhydrous dichloromethane (200 mg ) And pyridinium chlorochromate (3.5 g) is added at room temperature under stirring. The reaction mixture is stirred for 24 hours and then the solvent is concentrated under reduced pressure at about 10-20 [deg.] C. The residue was chromatographed on silica gel (Kieselgel 60) column using chloroform as eluent, and then recrystallized from a mixture of tetrahydrofuran and isopropyl ether. 1.7 g of oxy-9α-fluoro-16α-methylandrostar-1, 4-diene-3, 11-dione-17β-carboxylate are obtained.

Example 15

Chloromethyl 9α-fluoro-17α-isopropoxycarbonyloxy-16β-methylandrostar-1, 4-diene-3, 11-dione-17β having a melting point of 200-201 占 폚 by a method similar to Example 14 -Carboxylate is obtained.

Example 16

Chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandro-4-en-3-one-17β-carboxylate (0.01 mol) and 1, 2-dimethylpyrrolidine (0.01 mol) were acetonitrile (800 ml) and heated to reflux. The reaction mixture is kept at that temperature for about 4 hours under stirring. After about 65 ml of acetonitrile are removed, the mixture is cooled to room temperature and excess ethyl ether is added to produce a precipitate. By separating the precipitate by filtration. Washing and drying in vacuo give the desired quaternary ammonium salt of the following formula.

Similarly, using the appropriate steroidal and amine starting materials in the general manner described above yields the following additional quaternary ammonium salts according to the invention.

Example 17

Ointment

Compound of Formula (II), 0.2% W / W

Eg, chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate or chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost 4-en-3-one-17β-carboxylate

Liquid Paraffin 10.0% W / W

White soft paraffin 89/9% W / W

Afta ulcer globules

Compound of Formula (I) as above, 0.25% mg

Lactose 69.90mg

Gum arabic 3.0mg

Magnesium stearate 0.75mg

Identity administration

Compound of Formula (I) as above, 0.001% W / V

Tween SO 0.05% W / V

Ethanol 0.015% W / V

Propylparaben 0.02% W / V

Methylparaben 0.08% W / V

100 volume of distilled water

Eye drop

0.1% W / V of the compound of formula (I) as described above

Tween 80 2.5% W / V

Ethanol 0.75% W / V

Benzalkonium Chloride 0.02% W / V

Phenylethanol 0.25% W / V

Sodium Chloride 0.60% W / V

Water volume for injection 100

Example 18

Ointment

Compound of Formula (I):

Eg, chlorometal 17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxylate or chloromethyl 9α-fluoro -11β-hydroxy-17α-methoxycarbonyloxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxylate

Liquid Paraffin 10.175% W / W

White soft paraffin 89.8% W / W

Afta ulcer globules

A compound of formula (I),

Eg in chloromethyl 9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrostar-1, 4-dien-3-one-17β-carboxylate or chloromethyl 17α- Methoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxyl

0.1mg rate

Lactose 69.90mg

Arabian Rubber 3.00mg

Magnesium stearate 0.75mg

Identity administration

A compound of formula (I),

Eg, chloromethyl 11β-hydroxy-17α-isopropoxycarbonyloxyandrostar-1, 4-dien-3-one-17β-carboxylate or chloromethyl 9α-fluoro-11-hydroxy-17α- Isopropoxycarbonyloxy-16β-methylandrostar-1, 4-diene-3-silver-17β-carboxylate

Twist 80 0.05% W / V

Ethanol 0.015% W / V

Propylparaben 0.02% W / V

Methylparaben 0.08% W / V

100 volumes of distilled water

Eye drop

A compound of formula (I),

Eg, chloromethyl 9α-fluoro-11β-hydroxy-16α-methyl-17α-propoxycarbonyloxyandrostar-1, 4-bornen-3-one-17β-carboxylate or chloromethyl 9α-fluoro -11β-hydroxy-17α-methoxycarbonyloxy-16α-methylandrostar-1, 4-dien-3-one-17β-carboxylate

Twist 80 2.5% W / V

Ethanol 0.75% W / V

Benzalkonium Chloride 0.02% W / V

Phenylethanol 0.25% W / V

Sodium Chloride 0.6% W / V

Water volume for injection 100

From the foregoing, one of the common techniques in this field can easily find out its important features without departing from the spirit and scope of the present invention, and various changes and / or modifications of the invention to apply it to various uses and conditions. Can be modified. As such, these changes and / or modifications are appropriate and fair and will be used within the full scope of the following claims.

Claims (1)

A process for preparing the compound of formula (I) and quaternary ammonium thereof, characterized by reacting a compound of formula (IV) with a compound of formula (V):

In the formula, R ₁ is C ₁ ~ C ₁₀ Alkyl; C ₁ -C ₁₀ alkyl substituted with 1 to 3 halogen atoms; Or -CH ₂ COOR ₆ (R ₆ is C ₁ -C ₁₀ alkyl) or R ₁ represents -CH ₂ -Y- (C ₁ -C ⁸ alkyl) or (Y is -S- or -O- Or R ₁ is

(R ₆ is C ₁ -C ₁₀ alkyl), and R ₂ is C ₁ -C ₁₀ alkyl; C ₃ -C ₈ cycloalkyl, benzyl or C ₁ -C ₁₀ alkyl substituted with 1 to 3 halogen atoms, R ₃ is hydrogen, α-methyl, β-methyl, or

(R ₂ is defined above), R ₄ is hydrogen or fluoro, R ₅ is hydrogen or fluoro, X is -0-, Z is carbonyl or β-hydroxymethylene; The dotted line in Ring A indicates that the 1, 2-bond is saturated or unsaturated.

Wherein P is -COCl, Q is

(R ₂ is defined above) and R ₁₁ is R ₃ (R ₃ is defined above); P is -COOR ₁ (R ₁ is defined above), Q is -OCOCl and R ₁₁ is R ₃ "'(R ₃ "' is hydrogen, α-methyl, β-methyl or α-OCOCl); P is -COOR ₁ (R ₁ is defined above) Q is -OH, and R ₁₁ is R ₃ '(R ₃ is hydrogen, α-methyl, β-methyl or α-hydroxy). R ₁₂ XR ₁₃ (V) Wherein P is -COCl and Q is

(R ₂ is defined above), when R ₁₁ is R ₃ (R ₃ is defined above), R ₁₂ is R ₁ (R ₁ is defined above), X is -O-, R ₁₃ is hydrogen or an alkali metal, alkaline earth metal / 2, thallium or NH ₄ ; When P is -COOR ₁ (R ₁ is defined above), Q is -OCOCl and R ₁₁ is R ₃ '"(R ₃ '" is defined above), R ₁₂ is R ₂ (R ₂ Is defined above, X is -O-, and R ₁₃ is as defined above; When P is -COOR ₁ (R ₁ is defined above), Q is -OH, and R ₁₁ is R ₃ '(R ₃ ' is defined above), R ₁₂ is R ₂ and X is- O- and R ₁₃ is -COX '(X' is chlorine or bromine) or R ₁₃ is

(R ₂ is defined above).