BE889563A - Mild steroids with anti-inflammatory activity - Google Patents

Description

       

  "Mild steroids with anti-inflammatory activity" <EMI ID = 1.1>

  
mild exerting anti-inflammatory activity, pharmaceutical compositions containing these mild steroids, new intermediate chemicals useful in the preparation of these steroids, as well as methods of preparing these steroids and these intermediate products.

  
Happy predictions made on a basis

  
  <EMI ID = 2.1>

  
to new drugs, constitute the main objective of the researchers developing these drugs. To this end, a bioactive molecule known as a basis for structural modification is usually taken into account, either by the method of biofunctional groups or fractions, or by modifying the general physicochemical properties of the molecule. Consequently, the main objective has been to design, synthesize and carry out tests on new compounds with a structure analogous to that of the basic bioactive molecule, these compounds however having better therapeutic and / or pharmacokinetic properties.

   Although "vulnerable" fractions have been recognized as fractions whose role is the bioinactivation or metabolic elimination of the drug when it has played its role, during the drug development process, little or

  
no attention to the rational concept of metabolic elimination of drugs. This has been the case despite the fact that the toxicity of a number of bioactive molecules is due to their longer elimination half-life, their greater stability or to other factors involved in attempts to to increase their activity. Drugs and, in particular, their metabolic processes contribute to the manifestation of various toxic processes through the formation of active metabolites. The phenomenon of metabolic activation, manifested in reactive intermediates establishing a covalent bond with tissue macromolecules, constitutes the initial stage of cell deterioration.

   It is also evident that most toxic metabolites do not survive long enough to be excreted and identified; therefore, studies undertaken on stable metabolites may lead

  
to incorrect information.

  
It is clear that, to avoid and / or alleviate the toxicity problems posed by drugs, the metabolic elimination of these drugs must be taken into account.

  
from the early stages of the drug development process. This is especially true when you consider that the body can attack and chemically modify

  
very stable structures and that even if a drug is excreted 95% without being modified, the small remaining portion

  
can and will most likely be the cause of toxicity.

  
"Soft drugs" can be defined as chemical and biologically active compounds (drugs) which

  
the structure could resemble that of known active drugs (mild analogs) or which could be structures

  
of an entirely new type, however these drugs

  
are all characterized by predictable destruction in vivo
(metabolism) into non-toxic fractions after playing their therapeutic role. Metabolic elimination of drugs

  
soft takes place at an adjustable speed and predictably.

  
The Applicant has discovered five major classes of mild drugs. One of the most useful classes is that of "inactive metabolites" which can be advantageously used. <EMI ID = 3.1>

  
significant. This method starts with an inactive metabolite known to a drug or class of drugs, and then changes the metabolite so that its structure
(isosteric and / or isoelectronic) resembles that of the active drug (i.e. activation), after which we develop

  
the metabolism of the species activated to arrive at the initial inactive metabolite when the drug has played its desired therapeutic role, without or in which toxic intermediate products are formed (that is to say a predictable metabolism).

  
In addition, the inactive metabolite method allows the rate of metabolism and pharmacokinetic properties to be controlled by molecular manipulation at the activation stage. Of

  
even if no useful inactive metabolites are known,

  
one can be developed by introducing transporter groups into non-critical structural fractions.

  
The Applicant has now applied - its method

  
inactive metabolites in the case of glucocorticosteroids

  
  <EMI ID = 4.1>

  
hydrocortisone, one of its main inactive metabolites, namely cortienic acid, i.e. acid

  
  <EMI ID = 5.1>

  
used as a starting point and it was activated by the introduction of suitable non-toxic substituents in

  
  <EMI ID = 6.1>

  
have played their therapeutic role., an in vivo cleavage into an inactive starting metabolite and other non-toxic fractions.

  
  <EMI ID = 7.1>

  
structural formula:

  

  <EMI ID = 8.1>


  
in which :

  
  <EMI ID = 9.1>

  
  <EMI ID = 10.1>

  
carbon atoms, a cycloalkenyl group containing 3 to 8 carbon atoms or an alkenyl group containing 2 to 10 carbon atoms, these groups being able to be substituted or not and the

  
  <EMI ID = 11.1>

  
halogen, lower alkoxy group, lower alkyl-thio group, lower alkyl-sulfinyl rump, rump

  
  <EMI ID = 12.1>

  

  <EMI ID = 13.1>


  
(alkyl containing

  
1 to 10 carbon atoms) and a group
  <EMI ID = 14.1>
  <EMI ID = 15.1>
(alkyl containing

  
  <EMI ID = 16.1>

  
benzyl or .. a substituted or unsubstituted phenyl group, substituting them. being chosen from the group comprising a lower alkyl group, a lower alkoxy group, a halogen atom, <EMI ID = 17.1>

  
identical or different, each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group containing 3 to 8 carbon atoms, a phenyl group or a group

  
  <EMI ID = 18.1>

  
  <EMI ID = 19.1>

  
substituted or unsubstituted phenyl, the substituents being chosen from the group comprising the substituents defined above for

  
  <EMI ID = 20.1>

  
represents a group

  

  <EMI ID = 21.1>


  
(lower alkyl) in which Y

  
  <EMI ID = 22.1>

  
hydrogen, a lower alkyl group or a phenyl group,

  
  <EMI ID = 23.1>

  
combined so that R, is a cyclic system of

  
type

  

  <EMI ID = 24.1>


  
  <EMI ID = 25.1>

  
while the alkylene group contains 3 to 10 atoms. carbon including at least. -.1 and. to the maximum. 6 are atoms

  
cyclical; where he represents a group

  

  <EMI ID = 26.1>


  
in which

  
  <EMI ID = 27.1> <EMI ID = 28.1>

  
carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms or an alkenyl group containing 2 to 10 carbon atoms, these groups being substituted or unsubstituted and the substituents being chosen from the group comprising a halogen atom, a lower alkoxy group, a group

  
  <EMI ID = 29.1>

  
  <EMI ID = 30.1>

  

  <EMI ID = 31.1>


  
  <EMI ID = 32.1>

  
(alkyl

  
containing 1 to 10 carbon atoms) and a group
  <EMI ID = 33.1>
-----
(alkyl <EMI ID = 34.1>

  
benzyl or a substituted or unsubstituted phenyl group, the substituents being chosen from the group comprising a lower alkyl group, a lower alkoxy group, a halogen atom, a carbamoyl group, a lower alkoxy-carbonyl group,

  
  <EMI ID = 35.1>

  
lower-thio, a lower alkyl-tallow group and a lower alkyl-sulfonyl group;

  
  <EMI ID = 36.1>

  
  <EMI ID = 37.1>

  

  <EMI ID = 38.1>


  
  <EMI ID = 39.1>

  
where R2 is

  
  <EMI ID = 40.1>

  
  <EMI ID = 41.1>

  
fluorine or a chlorine atom;

  
R- represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group;

  
  <EMI ID = 42.1>

  
Z represents a carbonyl group or a group

  
  <EMI ID = 43.1>

  
while the dotted line of nucleus A indicates that the 1,2 bond is saturated or unsaturated.

  
  <EMI ID = 44.1>

  
those in which:

  
  <EMI ID = 45.1>

  
carbon; a (monohalo or polyhalo) -alkyl group containing 1 to 6 carbon atoms; a group -CH2COOR6 in which R6 is an alkyl group containing 1 to 6 carbon atoms; a

  
  <EMI ID = 46.1>

  

  <EMI ID = 47.1>


  
  <EMI ID = 48.1>

  
alkyl group containing 1 to 6 carbon atoms;

  
  <EMI ID = 49.1>

  
carbon, a cycloalkyl group containing 3 to 8 carbon atoms, a phenyl group, a benzyl group or a group
(monohalo or polyhalo) -alkyl containing 1 to 6 carbon atoms;

  
R3 represents a hydrogen atom, a group

  
  <EMI ID = 50.1>

  
group

  

  <EMI ID = 51.1>


  
  <EMI ID = 52.1>

  
  <EMI ID = 53.1>

  
defined above;

  
R4 represents a hydrogen atom or a fluorine atom;

  
  <EMI ID = 54.1>

  
fluorine;

  
  <EMI ID = 55.1>

  
X and the dotted line of nucleus A have the meanings defined above.

  
  <EMI ID = 56.1>

  
quaternary ammonium matrices of selected compounds of formula

  
(I) as will be described in more detail below. The invention also provides new intermediate products for

  
lead to the compounds of formula (I), for example, the compounds

  
  <EMI ID = 57.1>

  
  <EMI ID = 58.1>

  
  <EMI ID = 59.1>

  
extremely powerful premises; however, since their easy destruction in vivo only leads to the steroid metabolite

  
  <EMI ID = 60.1>

  
systemic activity far inferior to that of the known glucocortico-steroids from the inactive metabolites from which they are derived. In fact, many of the compounds of the present invention are completely devoid of systemic activity.

  
This minimal (or non-existent) systemic activity means that the compounds of the present invention can be used for the local treatment (eg, topical treatment) of inflammatory conditions without producing the serious systemic side effects resulting from the use of known glucocorticosteroids. .

  
With regard to the different groups encompassed by the generic terms used here and throughout this specification, the following definitions and explanations apply:

  
The alkyl, alkenyl and alkylene groups can. be straight or branched chain groups containing the aforementioned numbers of carbon atoms. Likewise, the alkyl fractions of the alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkanoyloxy, haloalkyl, monoalkylamino, dialkylamino, monoalkylcarbamoyl and dialkylcarbamoyl groups may each be straight or branched chain. The expression

  
  <EMI ID = 61.1>

  
of these groups or with an "alkyl" group indicates that

  
  <EMI ID = 62.1>

  
carbon atoms.

  
Whether specific identifications for

  
  <EMI ID = 63.1>

  
  <EMI ID = 64.1>

  
ethyl, the propyl group, the butyl group, the pentyl group, the hexyl group, the heptyl group and the octyl group, their branched chain isomers., as well as their higher straight and branched chain counterparts in cases where the group " alkyl "may contain more than 8 carbon atoms. The "alkenyl" groups can be, for example, the vinyl group, the propenyl group and the butenyl group. Among

  
cycloalkyl and cycloalkenyl groups, there is, for example, the cyclopentyl group, the cyclohexyl group &#65533; the cyclopentenyl group and the cyclohexenyl group. The alkylene groups are specifically the trimethylene group, the tetramethylene group and the like.

  
The alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkanoyloxy, monoalkylamino, dialkylamino, monoalkylcarbamoyl and dialkylcarbamoyl groups are of the type:

  

  <EMI ID = 65.1>
 

  

  <EMI ID = 66.1>


  
respectively, where "alkyl" meets the definition and examples given above.

  
With regard to the structural variables belonging to the group of preferred compounds of formula (I) which have been identified above, the expression "group

  
alkyl containing 1 to 6 carbon atoms "is used to denote a straight or branched chain alkyl group containing 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, the n-butyl group, the isobutyl group, the sec-butyl group,

  
  <EMI ID = 67.1>

  
and the like. In addition, the expression "(monohalo or polyhalo) -alkyl group containing 1 to 6 carbon atoms" is used to denote a straight or branched chain alkyl group containing 1 to 6 carbon atoms and substituted by 1 to 3 carbon atoms. 'halogens, the expression "halogen atom" used in this case, including a chlorine atom, a bromine atom,

  
\ an iodine atom or a fluorine atom. Among the specific monohaloalkyl and polyhaloalkyl groups contemplated, there are,

  
e.g. chloromethyl group, dichloromethyl group,

  
  <EMI ID = 68.1>

  
fluoromethyl, the difluoromethyl group, the trifluoro group <EMI ID = 69.1>

  
even the expression "cycloalkyl group containing 3 to 8 carbon atoms" is used to denote a cycloalkyl group containing 3 to 8 carbon atoms, for example, the cyclopropyl group, the cyclobutyl group, the cyclopentyl group, the cyclohexyl group, the cycloheptyl group and the cyclo-octyl group.

  
  <EMI ID = 70.1> <EMI ID = 71.1> saturated monocyclic secondary amine, these monocyclic structures preferably contain 5 to 7 cyclic atoms

  
  <EMI ID = 72.1>
-N-) in addition to the nitrogen atom indicated and optionally one or more substituents such as a phenyl group, a group <EMI ID = 73.1>

  
saturated monocyclic secondaries included in the group <EMI ID = 74.1>

  
  <EMI ID = 75.1>

  
  <EMI ID = 76.1>

  
readily form the corresponding mild quaternary ammonium salts which are also useful as mild anti-inflammatory agents. Thus, for example, one can simply react the chosen haloalkyl derivative of formula

  
(I) with a tertiary amine

  

  <EMI ID = 77.1>


  
or an unsaturated amine

  

  <EMI ID = 78.1>


  
to give the corresponding quaternary ammonium salt.

  
Reagents are generally used in approximately equimolecular proportions and the reaction is carried out in the presence of an inert solvent (eg, ether, acetonitrile, CHCl2 or the like) at a temperature between room temperature and the reflux temperature of the solvent for a period of about 2 to 24 hours. Alternatively,

  
the reaction can be carried out in the absence of a solvent by mixing the two reagents together and keeping them

  
at room temperature or at a temperature between
20 and 70 [deg.] C for a period of 2 to 24 hours. In either case, the crystal salt formed can be purified

  
  <EMI ID = 79.1>

  
denotes N-heterocyclic unsaturated systems containing 3 to 10 members in the nucleus, as well as their sub-

  
  <EMI ID = 80.1>

  
non-cumulative double bonds, provided that the nitrogen atom does not contain any hydrogen atom as a substituent. The following examples suffice to illustrate the framework of the defined expression:

  

  <EMI ID = 81.1>
 

  

  <EMI ID = 82.1>


  
Substituted derivatives of the unsaturated amines include groups such as those indicated above and containing one or more alkyl, -COO (alkyl) or -OCO (alkyl) substituents.

  
  <EMI ID = 83.1>

  
in which no hydrogen atom is attached to the nitrogen atom and which are not part of the unsaturated systems

  
  <EMI ID = 84.1>

  
defined above. Specifically, the expression "tertiary amine" includes trialkylamines in which the alkyl groups, which may be the same or different, each preferably contains 1 to 8 carbon atoms;

  
trialcoxysmines in which the alkoxy fractions each contain 1 to 8 carbon atoms; saturated cyclic tertiary amines such as quinuclidine or

  
substituted quinuclidine (for example, 3-acetoxyquinuclidine); as well as the N-substituted derivatives of saturated cyclic secondary amines [for example, an N-substituted derivative of morpholine, pyrrolidine, imidazolidine, pyrazolidine, piperidine or piperazine, the N-substituent possibly being a group such as an alkyl group containing 1 to 8 carbon atoms], optionally containing additional substituents such as a methyl group.

  
Among the preferred quaternary ammonium salts,

  
There are those derived from 1,2-dimethylpyrrolidine, 3-acetoxyquinuclidine, 1-methylpyrrolidine, triethylamine and N-methylimidazole. Particularly preferred are the quaternary ammonium salts derived from the reaction of the above-mentioned amines with compounds of formula

  
  <EMI ID = 85.1>

  
  <EMI ID = 86.1>

  
  <EMI ID = 87.1>

  
  <EMI ID = 88.1>

  
above essentially meet the objectives of the present invention, certain groups of compounds nevertheless remain preferred. A "first" group of preferred compounds of formula (I) has been described above.

  
Another preferred group of compounds includes those

  
  <EMI ID = 89.1>

  
the meanings defined above, the other structural variations being identical to that of hydrocortisone

  
  <EMI ID = 90.1>

  
  <EMI ID = 91.1>

  
each a hydrogen atom and that the 1,2 bond is unsaturated), more particularly when R 1 and R 2 have the meanings defined with regard to the "first" group of preferred compounds indicated above.

  
Another preferred group of compounds includes

  
  <EMI ID = 92.1>

  
compounds indicated in the previous paragraph. Among this

  
  <EMI ID = 93.1>

  
meanings defined above, while the other structural variables are identical to those of fludrocortisone, betamethasone and dexamethasone, are

  
  <EMI ID = 94.1>

  
have the meanings defined in connection with the "first" group of preferred compounds indicated above. Other particularly interesting compounds belonging to this group

  
  <EMI ID = 95.1>

  
defined above, while the other structural variables are identical to those of triamcinolone, flumethasone &#65533; fluprednisolone or paramethasone, in particular, when R 1 and R 2 have the meanings defined with respect to the "first" group of preferred compounds indicated above.

  
Still other interesting compounds are those in which

  
  <EMI ID = 96.1>

  
structural are identical to those of triamcinolone,

  
  <EMI ID = 97.1>

  
defined in connection with the "first" group of preferred compounds indicated above.

  
In each of the groups of compounds indicated in the three preceding paragraphs, the compounds in which X is an oxygen atom are particularly preferred.

  
More particularly preferred, the compounds belonging to the groups indicated above in which Z is a

  
  <EMI ID = 98.1>

  
an alkyl group containing 1 to 6 carbon atoms (in particular, a methyl group, an ethyl group, a propyl group

  
  <EMI ID = 99.1>

  
1 to 6 carbon atoms, a (monohalo) alkyl group containing 1 to 6 carbon atoms (in particular, a chloro-

  
  <EMI ID = 100.1>

  
carbon), Y having the meaning defined above (in particular, when the alkyl group containing 1 to 6 carbon atoms is a methyl group).

  
In general, the compounds of formula (I) can be prepared by known methods, the choice of the method depending on the identity of the different substituents of the desired final product.

  
According to a generally useful method for the preparation of the compounds of formula (I) in which Z represents a p-hydroxymethylene group, while X represents an oxygen atom, steranic starting materials of formula are used:

  

  <EMI ID = 101.1>


  
  <EMI ID = 102.1>

  
  <EMI ID = 103.1>

  
represents a hydrogen atom, an a-methyl group, a

  
  <EMI ID = 104.1>

  
formula :

  

  <EMI ID = 105.1>


  
  <EMI ID = 106.1>

  
suitable organic solvent, at room temperature or at elevated temperature). According to this process of the invention, a starting material of formula (II) is reacted with

  
  <EMI ID = 107.1> <EMI ID = 108.1>

  
suitable such as dichloromethane, chloroform or tetrahydrofuran, preferably in the presence of an appropriate acid acceptor (for example, triethylamine, pyridine, calcium carbonate or other suitable base). Duration and temperature are not critical factors; however, the reaction is advantageously carried out

  
  <EMI ID = 109.1>

  
  <EMI ID = 110.1>

  
17p-carboxylic acid carbonate obtained corresponds to the formula:

  

  <EMI ID = 111.1>


  
  <EMI ID = 112.1>

  
R20COBr in sufficient quantity to provide training

  
  <EMI ID = 113.1>

  
  <EMI ID = 114.1>

  
  <EMI ID = 115.1>

  
  <EMI ID = 116.1> Sometimes, when it is desired to obtain a compound of

  
  <EMI ID = 117.1>

  
  <EMI ID = 118.1>

  
later stage of the synthesis, as will be described below in more detail.

  
  <EMI ID = 119.1>

  
described above, the new intermediate product obtained of formula (III) is transformed into its corresponding metal salt of formula:

  

  <EMI ID = 120.1>


  
  <EMI ID = 121.1>

  
core A have the meanings defined above, while

  
  <EMI ID = 122.1>

  
(such as sodium or potassium), an alkaline metal

  
  <EMI ID = 123.1>

  
  <EMI ID = 124.1>

  
in a suitable organic solvent such as ethyl ether or tetrahydrofuran, at a temperature between

  
  <EMI ID = 125.1>

  
at 4 o'clock. Then, the salt of formula (IV) is reacted

  
  <EMI ID = 126.1> fication defined above and W represents a halogen atom,

  
  <EMI ID = 127.1>

  
step of the reaction sequence can advantageously be carried out at room temperature for a period

  
  <EMI ID = 128.1>

  
  <EMI ID = 129.1>

  
desires to obtain a compound of formula (I) in which IL is a chloromethyl group, it has been found that the reaction proceeds suitably using hexamethylphospho #

  
  <EMI ID = 130.1>

  
which halogen atom, preferably a chlorine atom or

  
a bromine atom while, in place of hexamethyl &#65533; phosphoramide, solvents can optionally be used

  
  <EMI ID = 131.1>

  
methane, acetonitrile, tetrahydrofuran or chloroform. When it is desired to obtain a compound of formula (I) in which

  
  <EMI ID = 132.1>

  
group is generally not introduced by the reaction with i R.-W, but it is subsequently prepared from the corresponding thio-sterord as described below.

  
  <EMI ID = 133.1>

  
t

  
  <EMI ID = 134.1> <EMI ID = 135.1>

  
a compound of formula (I) can be reacted in which <EMI ID = 136.1>
  <EMI ID = 137.1>
  <EMI ID = 138.1>

  
has a hydrogen atom, a lower alkyl group or is combined with the lower alkyl group adjacent to S to form a ring system as described above] with 1 equivalent of m-chloroperoxybenzofque acid at a temperature of 0-2SDC for a period of 1 to 24 hours, in an appropriate solvent such as chloroform, to obtain the corresponding compound of formula (I) in which IL is a

  
group

  

  <EMI ID = 139.1>


  
(lower alkyl), or with 2 equivalents

  
  <EMI ID = 140.1>

  

  <EMI ID = 141.1>


  
(lower alkyl). We can also adopt this type

  
  <EMI ID = 142.1>

  
  <EMI ID = 143.1>

  
alkyl, cycloalkyl group, cycloalkenyl group, alkenyl group, phenyl group or benzyl group subs-

  
  <EMI ID = 144.1>

  
  <EMI ID = 145.1>

  
lower-thio; as well as to prepare compounds of

  
  <EMI ID = 146.1>

  
cycloalkyl, a cycloalkenyl group, an alkenyl group, a phenyl group or a substituted benzyl group, the substituent being a lower alkyl-sulfinyl group or an alkyl group

  
  <EMI ID = 147.1>

  
  <EMI ID = 148.1>

  
  <EMI ID = 149.1>

  
in which R3 is an a- or p-hydroxy group, these compounds can be prepared by partial acid hydrolysis of the compounds

  
  <EMI ID = 150.1>

  
  <EMI ID = 151.1>

  
desirable to use a moderate reagent, for example, oxalic acid in methanol. Alternatively, the hydrolysis of 16carbonate to the 16-hydroxy compound could be carried out at a first stage of any synthesis described in this specification after introduction of the 16,17carbonate groups, for example, after selective hydrolysis of a product

  
  <EMI ID = 152.1>

  
  <EMI ID = 153.1>

  
laying, to then transform into a

  
  <EMI ID = 154.1>

  
In another process for preparing the compounds

  
  <EMI ID = 155.1>

  
methylene, while X is an oxygen atom, we use

  
  <EMI ID = 156.1>

  
essentially uses the same reaction conditions, the same non-steranic reagents, etc. than those described above. CI is how we react first

  
  <EMI ID = 157.1>

  
form the corresponding intermediate product of formula:

  

  <EMI ID = 158.1>


  
  <EMI ID = 159.1>

  
nucleus A tillés have the meanings given above, this intermediate product then being reacted with a

  
  <EMI ID = 160.1>

  
formula :

  

  <EMI ID = 161.1>


  
  <EMI ID = 162.1>

  
  <EMI ID = 163.1>

  
  <EMI ID = 164.1>

  
  <EMI ID = 165.1>

  
compound (V) are the same as those described in detail above <EMI ID = 166.1>

  
(IV). Likewise, the parameters of the transformation process

  
  <EMI ID = 167.1>

  
described in detail above in connection with the transformation process

  
  <EMI ID = 168.1>

  
way the parameters of the transformation process of a

  
  <EMI ID = 169.1>

  
then optionally selectively hydrolyze to 16-hydroxy-
17-corresponding carbonate of formula (1). Likewise, we can

  
again advantageously prepare the compounds of formula

  
  <EMI ID = 170.1>

  
a sulfinyl group or a sulfonyl group., by oxidation of the corresponding compounds of formula (I) containing a thio group as described in detail above. Alternatively,

  
  <EMI ID = 171.1>

  
  <EMI ID = 172.1>

  
sulfonyl group [for example, when IL is a group

  

  <EMI ID = 173.1>


  
(lower alkyl) or a group

  

  <EMI ID = 174.1>


  
(lower alkyl)].,

  
1 'i

  
by oxidation (preferably with m-chloroperoxy-

  
  <EMI ID = 175.1>

  
sulfinyl or sulfonyl obtained.

  
In another process which can be envisaged for preparing the compounds of the present invention, which

  
can be used to prepare compounds of formula

  
  <EMI ID = 176.1> an oxygen or sulfur atom, we use the products

  
  <EMI ID = 177.1>

  
of formula (III) above. According to this process, an intermediate compound of formula (III) is successively treated first with a moderate agent forming acyl chloride, for example, diethyl chlorophosphate or oxalyl chloride, to form the new chloride d 'acid

  

  <EMI ID = 178.1>


  
  <EMI ID = 179.1>

  
  <EMI ID = 180.1>

  
period of 1 to 6 hours., to obtain the corresponding compound

  
  <EMI ID = 181.1>

  
  <EMI ID = 182.1>

  
  <EMI ID = 183.1>

  
  <EMI ID = 184.1>

  
  <EMI ID = 185.1>

  
  <EMI ID = 186.1>

  
  <EMI ID = 187.1>

  
the first step * This process is particularly useful when it is desired to obtain a compound of formula (I) in which X represents S.

  
In yet another desirable process for preparing the compounds of formula (I) wherein Z is a

  
  <EMI ID = 188.1>

  
above. According to this process, an intermediate product of formula (VI) is reacted with phosgene in an appropriate organic solvent (for example, toluene, benzene,

  
  <EMI ID = 189.1>

  
2 hours (or until the reaction is complete). By evaporation to remove the solvent and

  
  <EMI ID = 190.1>

  

  <EMI ID = 191.1>


  
  <EMI ID = 192.1> <EMI ID = 193.1>

  
sufficient quantity to ensure the formation of the chlorocarbonyloxy group in position 16, as well as in position 17

  
  <EMI ID = 194.1>

  
defined above, in an inert solvent, preferably,

  
in the presence of an acid fixative (for example, triethyla-

  
  <EMI ID = 195.1>

  
  <EMI ID = 196.1>

  
reaction under the same conditions as during -The reaction of transformation of the compound (II) into a compound (III).

  
  <EMI ID = 197.1>

  
in the final product. Likewise, the 16-hydroxy compounds and the compounds of formula (I) containing sufinyl and sulfonyl groups are most advantageously formed as the final stage of the synthesis.

  
As an alternative to the process described immediately above, a steranic acid starting material can be reacted

  
  <EMI ID = 198.1>

  

  <EMI ID = 199.1>


  
  <EMI ID = 200.1>

  
nucleus A have the meanings defined above, this compound

  
  <EMI ID = 201.1>

  
new intermediate product into a corresponding compound of

  
  <EMI ID = 202.1>

  
  <EMI ID = 203.1>

  
same as derivatives containing sulfinyl and sulfonyl groups as a final step.

  
In yet another process for the preparation of

  
  <EMI ID = 204.1> <EMI ID = 205.1>

  
(VI) with an excess of a carbonate of formula

  

  <EMI ID = 206.1>


  
(that we

  
can advantageously prepare by reacting phosgene

  
  <EMI ID = 207.1>

  
  <EMI ID = 208.1>
  <EMI ID = 209.1>
  <EMI ID = 210.1> can also

  
act as solvent at the boiling point of the carbon reagent

  
  <EMI ID = 211.1> reactional * thus bringing the reaction to an end), or we

  
can combine the reagents in a suitable inert organic solvent (for example, an aromatic hydrocarbon such as benzene or toluene, or a halogenated hydrocarbon

  
such as dichloromethane or chloroform). Once again, the 16-hydroxy compounds, as well as the compounds containing sulfinyl and sulfonyl groups of formula (I) can

  
be advantageously prepared as a final step in the process,

  
  <EMI ID = 212.1>

  
which R. contains a sulfur atom; may be everything

  
  <EMI ID = 213.1>

  
react with

  

  <EMI ID = 214.1>


  
Other methods of preparing selected compounds

  
  <EMI ID = 215.1>

  
  <EMI ID = 216.1>

  
halogen exchange reaction to replace the halogen atom with a different halogen atom in order

  
  <EMI ID = 217.1>

  
a chloralkyl 170-carboxylate of formula (T) with an iodide

  
  <EMI ID = 218.1>

  
the corresponding iodalkyl 17p-carboxylate. Likewise, a bromide salt can be reacted (for example,

  
  <EMI ID = 219.1>

  
A suitable solvent for either reaction can

  
  <EMI ID = 220.1>

  
  <EMI ID = 221.1>

  
way we can adopt a halogen exchange reaction

  
  <EMI ID = 222.1>

  
chloralkyl carboxylate or an iodalkyl 17p-carboxylate of formula (I) to a corresponding fluoralkyl derivative. Silver fluoride can be used in this reaction which is carried out in a suitable organic solvent (eg acetonitrile) and which is particularly useful for the

  
  <EMI ID = 223.1>

  
methyl or a fluorethyl group.

  
The 21-hydroxy-pregnenolones from which the steranic starting materials of formula (II) are prepared, can be obtained commercially or they can be prepared by known methods. Likewise, the non-steranic starting materials used in the various methods described above are commercially available or can be prepared by known chemical methods.

  
Similarly, we can react with a starting material

  
  <EMI ID = 224.1>

  
  <EMI ID = 225.1>

  
intermediate product of formula:

  

  <EMI ID = 226.1>
 

  
  <EMI ID = 227.1>

  
core A have the meanings defined above, this product

  
  <EMI ID = 228.1>

  
correspondent of formula (III) above by partial hydrolysis, with or without isolation of the compound of formula (XI). This reaction

  
  <EMI ID = 229.1>

  
R20COBr is used in an amount of 2 moles or more to

  
1 mole of the compound of formula (II). The partial hydrolysis of the compound obtained of formula (XI) can be carried out in an inert solvent in the presence of a catalyst. Among the suitable catalysts are, for example, tertiary alkylamines such as triethylamine, trimethylamine or the like;

  
aromatic amines such as pyridine, 4,4-dimethylamino-pyridine, quinoline or the like; secondary alkylamines such as diethylamines dimethylamine or the like; as well as inorganic bases such as sodium hydroxide, potassium hydroxide, potassium bicarbonate or the like. Preferably, pyridine and potassium bicarbonate are used. Among the inert solvents which can be used during hydrolysis, there are,

  
for example, water; lower alcohols such as ethanol, methanol or the like; ethers such as dimethyl ether, diethyl ether, dimethoxyethane, dioxane,

  
tetrahydrofuran or the like; halogenated hydrocarbons such as dichloromethane, chloroform or the like;

  
tertiary amines such as pyridine, triethylamine or the like; or a mixture of two or more of the above solvents. The reaction is usually carried out at a temperature

  
  <EMI ID = 230.1> at a temperature between room temperature and

  
  <EMI ID = 231.1>

  
for a period of 2 to 5 hours.

  
In yet another aspect, the present invention provides new compounds of formula:

  

  <EMI ID = 232.1>


  
  <EMI ID = 233.1>

  
of the nucleus A have the meanings defined about the

  
  <EMI ID = 234.1>

  
of formula (IX) by the methods described above for the

  
  <EMI ID = 235.1>

  
comprising an 11-keto group, this intermediate product is then transformed into its metal salt corresponding to the

  
  <EMI ID = 236.1>

  
instead of a group 11--hydroxy; , then we react

  
  <EMI ID = 237.1>

  
of formula (IX). All the reaction conditions are those described above with regard to the corresponding processes for the preparation of the corresponding compounds of <EMI ID = 238.1>

  
  <EMI ID = 239.1>

  
sulfinyl or a sulfonyl group or in which R3 is a hydroxy group, generally takes place as a final stage during the synthesis in a manner analogous to that adopted

  
  <EMI ID = 240.1>

  
all the operating variants described above for the

  
  <EMI ID = 241.1>

  
applicable to the preparation of the compounds of formula (IX) in

  
  <EMI ID = 242.1>

  
  <EMI ID = 243.1>

  
example, replacing the 11-hydroxy group of the formulas
(V), (VI), (VII), (VIII), (X) and (XI) by an 11-oxo group and also proceeding as described above for the

  
  <EMI ID = 244.1>

  
Likewise, the compounds of formula can be prepared
(IX) by reacting the corresponding compounds of formula

  
  <EMI ID = 245.1>

  
  <EMI ID = 246.1>

  
into a corresponding compound of formula (IX), using an oxidizing agent in an appropriate solvent. This solvent can be any conventional solvent, for example, water, an organic acid (e.g., formic acid, acetic acid, trifluoroacetic acid), an alcohol (e.g.

  
  <EMI ID = 247.1>

  
example, chloroform or dichloromethane) or the like. The oxidizing agent can also be any conventional agent effectively oxidizing a hydroxy group to a carbonyl group, for example, pyridinium chlorochromate, <EMI ID = 248.1>

-II

  
  <EMI ID = 249.1>

  
dichromic acid, dichromates (for example, sodium dichromate or potassium dichromate), permanganic acid, permanganates (for example, sodium permanganate or potassium permanganate) or the like. Usually the oxidizing agent is used in an amount of 1 mole or more,

  
preferably in an amount of 1 to 3 moles per mole of the

  
  <EMI ID = 250.1>

  
  <EMI ID = 251.1>

  
close to room temperature for a period of approximately 6 to 30 hours.

  
The new compounds of formula (IX) are useful

  
  <EMI ID = 252.1>

  
as in vivo or in vitro precursors of the corresponding llp-hydroxy compounds. Thus, the compounds of formula (IX) can be reduced in vitro to give the corresponding compounds of formula (I) using a reducing agent known for its ability to reduce the 11-oxo group to an llphydroxy group without modifying the rest of the sterile starting material

  
  <EMI ID = 253.1>

  
tagger to carry out the desired transformation, although chemical reduction is also possible. In addition, the compounds of formula (IX) can be formulated in forms

  
appropriate dosages (for example, retention clysters) for the treatment of conditions such as ulcerative colitis. In these dosage forms, it is believed that the compounds of formula (IX) undergo microbiological reduction by bacteria

  
of the body (for example, in the colon) to be transformed

  
  <EMI ID = 254.1>

  
desired anti-inflammatory response,

S

  
  <EMI ID = 255.1>

  
  <EMI ID = 256.1>

  
Z is a p-hydroxymethylene group, in particular the compounds
11-keto corresponding of formula (IX). A particularly preferred group of compounds of formula (IX) includes those in

  
  <EMI ID = 257.1>

  
about formula (I) and in which also the other structural variations are identical to those of

  
  <EMI ID = 258.1>

  
  <EMI ID = 259.1>

  
defined in connection with the "first" group of preferred compounds indicated above. Are more particularly preferred among

  
  <EMI ID = 260.1>

  
  <EMI ID = 261.1>

  
is an alkyl group containing 1 to 6 carbon atoms, a

  
(monohalo) alkyl group containing 1 to 6 carbon atoms

  
[in particular, the chloromethyl group] or a group <EMI ID = 262.1>

  
The results of various studies relating to the activity of representative species of the invention and which will be described in detail below, clearly indicate the

  
  <EMI ID = 263.1>

  
in view of this desirable separation between local activity and systemic activity, the compounds of the invention can be used for the treatment of topical inflammatory conditions or other localized inflammatory conditions without causing the serious systemic side effects that exercise specific

  
  <EMI ID = 264.1>

  
d <1> hydrocortisone, betamethasone 17-valerate, triamcinolone, betamethasone dipropionate and the like.

  
  <EMI ID = 265.1>

  
The test animals are female rats of the Sprague / Dawley family weighing approximately 40-45 g each. One side of each ear of each rat is treated with a total amount of 25 micro liters of a solution (90:10

  
  <EMI ID = 266.1>

  
test compound. The animals having undergone identical treatment, but with omission of the test compound, act as controls. After 24 hours, we sacrifice all

  
  <EMI ID = 267.1>

  
and we weigh these. The results obtained are shown in Table I below., The weights of the thymuses being expressed in mg / 100 g of the body weight of each rat.

  

  <EMI ID = 268.1>
 

  
The change in thymus weight is a measure of systemic activity and therefore of toxicity. The lower the weight of the thymus, the stronger the systemic activity As seen from the results below

  
  <EMI ID = 269.1>

  
natural, causes a strong reduction in the weight of the thymus

  
  <EMI ID = 270.1>

  
equal doses of representative species of the invention are much less, thus indicating that these compounds exert a systemic activity clearly less strong than hydrocortisone.

MONEY LAUNDERING STUDIES

  
McKenzie-type bleaching studies are undertaken in humans to study the bleaching effects of a representative test compound of the invention,

  
  <EMI ID = 271.1>

  
The study of a compound that causes bleaching in humans is closely correlated with its anti-inflammatory activity.

  
Dissolve the test compound in a 90:10 mixture

  
  <EMI ID = 272.1>

  
50 microliters aliquots of each solution on

  
separate pieces of gauze with a bandage of the type usually used for allergy testing and the bandage is applied to the forearm. After 6 hours of occlusion, the bandage is removed. One to five hours after removing the bandage,

  
bleaching is observed even at minimum concentrations

  
of the test compound.

  
When hydrocortisone is tested in accordance with the above method by direct comparison with the test compound, no bleaching is observed at hydrocortisone concentrations below 0.03 M.

  
In addition, it is observed that the 0.03M hydrocortisone causes roughly the same degree of whitening as that resulting

  
  <EMI ID = 273.1>

EAR edema test

  
Test animals are family rats

  
  <EMI ID = 274.1>

  
of treatment, selected quantities of the test compound are dissolved in acetone containing 5% crotonic oil

  
and 50 microliters of the solution are applied to the inner surface of the right ear of the rats. A control group is subjected to an identical treatment only with the vehicle, that is to say crotonic oil at 5% in acetone. Six hours after the crotonic oil test, a constant area of each ear is removed by dissection under anesthesia. Then, 48 hours after the steroid treatment, the animals are sacrificed, the ablation is carried out

  
thymus and adrenal glands, and then weigh these. Table II below summarizes the results of the tests demonstrating the inhibitory effect exerted by the topical application of steroids on the swelling of the ear caused by crotonic oil.

  

  <EMI ID = 275.1>
 

  

  <EMI ID = 276.1>
 

  
As can be seen from Table II above, the representative species of the present invention,

  
  <EMI ID = 277.1>

  
swelling (and therefore weight gain) of the ear caused by crotonic oil, that is to say that the compound exerts a strong anti-inflammatory activity. On the other hand, unlike

  
  <EMI ID = 278.1>

  
Compound representative of the invention does not greatly reduce the weight of the thymus compared to the control, that is to say that it does not exert a systemic activity to a significant degree.

GRANULOMS FORMATION TEST

  
  <EMI ID = 279.1>

  
aliquots of varying concentrations are injected into cotton pellets. The pellets are dried, then a tablet is implanted under the skin of each test rat.

  
Six days later, the animals are sacrificed, the granulation tissue (granuloma) which has formed in and around the implanted pellet is removed, then dried.

  
  <EMI ID = 280.1>

  
and weighing the thymus and adrenal glands. The ability of a compound to inhibit the formation of a granuloma during this test is a direct indication of local anti-inflammatory activity; therefore, the lower the weight of the granulation tissue, the better the anti-inflammatory activity. On the other hand, a strong reduction in weight

  
thymus is indicative of strong systemic activity; on the other hand, if a test compound does not significantly reduce the weight of the thymus compared to the control, this is the index of the absence of systemic side effects or the index of very minimal systemic side effects.

  
The results obtained are shown in the tables

  
  <EMI ID = 281.1>

  

  <EMI ID = 282.1>
 

  

  <EMI ID = 283.1>
 

  

  <EMI ID = 284.1>
 

  

  <EMI ID = 285.1>
 

  

  <EMI ID = 286.1>
 

  

  <EMI ID = 287.1>
 

  

  <EMI ID = 288.1>
 

  
The test results shown in Tables III,

  
  <EMI ID = 289.1>

  
representative of the present invention produce a strong anti-inflammatory response at dosages lower than those

  
  <EMI ID = 290.1>

  
hydrocortisone butyrate and betamethasone 17-valerate.

  
On the other hand, all the sterols of the prior art greatly reduce the weight of the thymus and, therefore, they exert a very powerful systemic activity, while the representative compounds of the invention do not strongly reduce or only reduce to a minimum extent the

  
  <EMI ID = 291.1>

  
ration between local anti-inflammatory activity and systemic activity) significantly higher than the steran anti-inflammatory agents of the prior art.

  
Similarly, the test results included in the

  
  <EMI ID = 292.1>

  
According to the results of Tables IV and V-b, we

  
  <EMI ID = 293.1>

  
the relative powers of the representative compounds of the invention; these values are listed in table VI below. For each effective dose, a power value of 1 has been assigned to one of the compounds of the invention, to

  
  <EMI ID = 294.1>

  
other compounds were expressed relative to this value.

  
  <EMI ID = 295.1>

  
  <EMI ID = 296.1>

  
60% of the weight of the granulation fabric,
  <EMI ID = 297.1>
   <EMI ID = 298.1>

  
Various additional studies were undertaken to determine the effects of selected compounds of the invention on the weights of the thymus of rats by administering the drugs systemically. In each of these studies, male rats of the Sprague-Dawley family were used. (Regarding the average weight of rats for each study, see the

  
  <EMI ID = 299.1>

  
  <EMI ID = 300.1>

  
suspensions thus obtained subcutaneously once a day for 3 days. On the fifth day (48 hours after the last treatment), the animals were sacrificed and

  
  <EMI ID = 301.1>

  
  <EMI ID = 302.1>

  
and IX below. Table X below shows the values

  
  <EMI ID = 303.1>

  
to get 40% and 50% inhibition respectively

  
  <EMI ID = 304.1>

  
  <EMI ID = 305.1>

  
  <EMI ID = 306.1>

  
reference, namely betamethasone 17-valerate, while the powers of the other compounds are expressed relative to this value. It is evident that the higher the inhibition of thymus activity at a given dose, the more toxic the compound.

  

  <EMI ID = 307.1>
 

  

  <EMI ID = 308.1>
 

  

  <EMI ID = 309.1>
 

  

  <EMI ID = 310.1>
 

  
  <EMI ID = 311.1>

COTTON

  
A complementary test was carried out in order to determine the thymolytic activity of a species representative of the invention compared to betamethasone 17-valerate.

  
In this trial, the drugs were administered to rats intravenously using a control training trial

  
of granulomas by cotton pellets. We used

  
  <EMI ID = 312.1>

  
185 g (166-196 g). Two cotton pellets each weighing 30 mg and containing no test compound were sterilized and then implanted subcutaneously in the back

  
of each test animal. This day was considered as day 0 of establishment. Beginning with day 1, for three consecutive days, intravenous injections of test compounds suspended in poly-

  
  <EMI ID = 313.1>

  
animals, the two pellets with their respective granulomas were removed and dried overnight in a
50 [deg.] C and weighed (dry weight of granulomas). The weights of the thymus and the final weights of the bodies of the rats were also recorded. The results are shown in Table XI below.

  
  <EMI ID = 314.1>

  
vation of representative species of the mild steroids of the present invention administered intravenously to rats. As can be seen from Table VI, 'the

  
  <EMI ID = 315.1>

  
Betamethasone 17-valerate against local inflammation

  
  <EMI ID = 316.1>

  
exercise a local anti-inflammatory activity about 400 <EMI ID = 317.1>

  
Test compounds were administered intravenously

  
to rats in order to also control these compounds concerning their systemic anti-inflammatory activity compared to betamethasone 17-valerate. The test compounds were found to be inferior to betamethasone 17-valerate in terms of inhibition of the formation of granulation tissue and also in terms of thymus involution activity. Based on test results, it is assumed that compounds that are not readily metabolized
(deactivation), exert a systemic anti-inflammatory activity, as is the case for betamethasone 17-valerate.

  

  <EMI ID = 318.1>
 

  
  <EMI ID = 319.1>

  
of local granuloma formation by cotton pellets
(as indicated, for example, in Table VI above),

  
  <EMI ID = 320.1>

  
inhibition of the thymus (as indicated, for example, in Table X above) to achieve a relative potency and a therapeutic index for representative species of

  
  <EMI ID = 321.1>

  
anterior. (See Table XII below which clearly shows the potent anti-inflammatory activity and the minimum systemic toxicity of the compounds of the present invention).

  

  <EMI ID = 322.1>
 

  
  <EMI ID = 323.1>

  
suitable, non-toxic and pharmaceutically acceptable carriers in order to obtain pharmaceutical compositions which can be used for the treatment of topical inflammations or other localized inflammations. Of course, since they exercise no systemic activity, the compounds of the present invention are not intended for the treatment of conditions in which systemic adrenocortical therapy is indicated, for example, in the event of adrenocortical insufficiency.

   Among. inflammatory conditions which can be treated with pharmaceutical compositions containing at least one compound of the invention, as well as one or more pharmaceutical carriers, there may be mentioned: dermatological disorders such as atopic dermatitis, acne, psoriasis or contact dermatitis; allergic conditions such as bronchial asthma; ophthalmic and otic disorders, including acute and chronic inflammatory and allergic reactions; respiratory disorders; ulcerative colitis; as well as anorectal inflammation, pruritus and pain associated with hemorrhoids, proctitis, cryptitis, cracks, post-operative pain and anal pruritus.

   These compositions can also be the subject of a local application as a prophylactic against inflammation and rejection of the tissues resulting from transplantations,

  
Of course, the choice of the support (s) and dosage forms varies according to the particular state for which the composition is to be administered,

  
  <EMI ID = 324.1>

  
topical / local administration, there are, for example, ointments, lotions, creams, powders, drops (for example, eye or ear drops), sprays
(for example, for the nose or throat), suppositories, retention cysts, tablets or lozenges

  
  <EMI ID = 325.1>

  
aphthous) and aerosols. Ointments and creams can be formulated, for example, with an aqueous or oily base by adding thickening agents and / or gelling agents

  
  <EMI ID = 326.1>

  
type can contain, for example, water and / or an oil such type can contain, for example, water and / or an oil such as a liquid paraffin or a vegetable oil such as peanut or castor oil, or a solvent

  
  <EMI ID = 327.1>

  
Among the thickening agents which can be used according to

  
the nature of the base used, there are soft paraffins,

  
aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool grease, hydrogenated lanolin

  
and beeswax and / or glyceryl monostearate and / or

  
non-ionic emulsifiers.

  
The solubility of the steroid in the ointment or cream can be increased by incorporating an aromatic alcohol

  
such as benzyl alcohol, phenylethyl alcohol or

  
1 phenoxyethyl alcohol.

  
.., lotions can be formulated with an aqueous or oily base and, as a general rule, these lotions; also hold one or more of the following products, including:

  
emulsifying agents, dispersing agents, agents

  
suspension, thickening agents, solvents,

  
coloring agents and perfumes. We can train

  
powders using any base suitable for powders, for example, talc, lactose or starch. We

  
all formulate drops with an aqueous base also comprising one or more dispersing agents, setting agents

  
  <EMI ID = 328.1>

  
compositions for spraying, for example, in the form of aerosols, using an appropriate propellant, for example

  
  <EMI ID = 329.1>

  
methane.

  
The proportion of active ingredient in the compositions

  
used, the type of formulation prepared and the particular condition for which the composition is to be administered. In ;

  
as a general rule, the formulation will contain approximately 0.0001 to

  
  <EMI ID = 330.1>

  
general, topical preparations contain 0.0001 to 2.5%, preferably 0.01 to 0.5% of this compound and they are administered once a day or as needed. Likewise, <generally speaking, the compounds of the invention can be

  
  <EMI ID = 331.1>

  
local statements formulated in much the same way as

  
currently available compositions containing gluco &#65533; known corticosteroids, at approximately identical dosages

  
(or proportionally lower in the case of compounds

  
the most potent of the invention) to those of known highly active agents such as methyl prednisolone acetate and beclomethasone dipropionate or at dosages much

  
lower than those adopted for known less active agents; such as hydrocortisone.

  
Thus, for example, one can prepare a formulation for inhalation which can be used for the

  
  <EMI ID = 332.1>

  
measured dose containing a species representative of the invention,

  
  <EMI ID = 333.1> <EMI ID = 334.1>

  
well known to those skilled in the art of pharmaceutical formulations. Such an aerosol unit may contain a microcrystalline suspension of the above compound in suitable propellants (e.g., trichlorofluoromethane and dichlorodifluoromethane) with oleic acid

  
or other suitable dispersing agents. Each unit

  
  <EMI ID = 335.1>

  
of which approximately 50 micrograms are released with each intervention.

  
  <EMI ID = 336.1>

  
chloromethyl, each unit specifically contains 1 mg of the active ingredient, releasing approximately 5 micrograms for each intervention.

  
  <EMI ID = 337.1>

  
according to the invention is a foam suitable for the treatment of a wide variety of inflammatory anorectal disorders by anal or perianal application &#65533; this foam comprising

  
  <EMI ID = 338.1>

  
polyoxyethylene-10-stearyl, cetyl alcohol &#65533; of

  
i methyl-paraben., propyl-paraben &#65533; of triethanolamine and water with inert propellants. When using one! more powerful compound of the invention, generally used

  
  <EMI ID = 339.1>

  
Yet another pharmaceutical formulation according to the invention is a solution or suspension which can be used as a retention clyster and in which a single dose specifically contains 40 mg of a compound of the invention such

  
  <EMI ID = 340.1>

  
chloromethyl carboxylate) together with sodium chloride, polysorbate 80 and 28 to 170 g of water (water being

  
  <EMI ID = 341.1>

  
as a retention or continuous drip clyster several times a week when treating ulcerative colitis.

  
Other pharmaceutical formulations according to the invention are illustrated in the examples below

  
Without further elaboration, we think that at the

  
  <EMI ID = 342.1>

  
ter the present invention. Consequently, the. The following examples should be considered for illustration only without limiting the rest of the specification and claims below.

  
EXAMPLE 1

  
At room temperature, 15 g solution
(0 04 04 mole) of hydrocortisone in 120 ml of tetrahydrofuran and 30 ml of methanol, a hot solution (approximately
50 [deg.] C) 25.7 g (0.12 mol) of sodium metaperiodate in
100 ml of water. The reaction mixture is stirred at room temperature for 2 hours, then concentrated under pressure <EMI ID = 343.1>

  
  <EMI ID = 344.1>

  
tration &#65533; it is washed with water and dried under vacuum at

  
  <EMI ID = 345.1>

  
  <EMI ID = 346.1>

  
say cortienic acid) with a melting point of 231-234 [deg.] C with a yield of about 96% (13.76 g), this product can be represented by the following structural formula:

  

  <EMI ID = 347.1>


  
EXAMPLE 2

  
  <EMI ID = 348.1>

  
1 mole) and triethylamine (4 moles) in dichloromethane,

  
  <EMI ID = 349.1>

  
of methyl chloroformate in dichloromethane. The reaction mixture is allowed to warm to room temperature for a period of 2 hours ". By filtration, the precipitate of triethylamine hydrochloride which forms is removed and the filtrate is washed successively with

  
  <EMI ID = 350.1>

  
  <EMI ID = 351.1>

  
dried with magnesium sulfate and filtered. The filtrate is concentrated in vacuo to form a foam. This foam is used in the next step (e.g., Example 3 below) or subjected to chromatography and crystallized for analysis. After .chromatography and crystallization, the product obtained, namely the acid II? -

  
  <EMI ID = 352.1>

  
represented by the following structural formula:

  

  <EMI ID = 353.1>


  
By substituting an equivalent amount of ethyl chloroformate for the methyl chloroformate used above and practically repeating the above process,

  
  <EMI ID = 354.1>

  
calculated: C 65.69; H 7.67

  
  <EMI ID = 355.1>

  
In an analogous manner by substituting an equivalent amount of butyl chloroformate for the methyl chloroformate used in the first paragraph of this example and

  
  <EMI ID = 356.1>

  
mixture of tetrahydrofuran and hexane, the final product has

  
  <EMI ID = 357.1>

  
Similarly, by substituting an equivalent amount of isopropyl chloroformate for the methyl chloroformate used in the first paragraph of this example and by repeating the process described above in detail,

  
  <EMI ID = 358.1>

  
slow sodium hydroxide IN in methanol and dilute this solution to 100 times its original volume with ethyl ether. The suspension obtained is subjected to cooling for 1 hour, then, by filtration., The crystals formed are removed, they are dried in a desiccator under vacuum.

  
  <EMI ID = 359.1>

  
sodium, with 4 moles of chloromethyl iodide, The reaction mixture is kept at room temperature for 3 hours, then it is diluted to 10 times its initial volume with ethyl acetate. The mixture is washed successively

  
  <EMI ID = 360.1>

  
3% sodium bicarbonate and water. The organic layer is separated, dried with magnesium sulfate and filtered. The filtrate is concentrated under vacuum to obtain a foam. This foam is purified by crystallization

  
  <EMI ID = 361.1>

  
chloromethyl carboxylate d: a melting point of 171-173 [deg.] C after crystallization; ray absorption spectrum

  
  <EMI ID = 362.1>

  
J = 5, SHz, 2, OCH2C1), 4.47 (broad, 1, CHOH);

  
  <EMI ID = 363.1>

  
  <EMI ID = 364.1>

  
  <EMI ID = 365.1>

  
The product obtained is characterized by the following structural formula:

  

  <EMI ID = 366.1>
 

  
By substituting an equivalent amount of acid

  
  <EMI ID = 367.1>

  
steranic acid carboxylic acid used above and by practically repeating the above process,

  
  <EMI ID = 368.1>

  
chloromethyl carboxylate with a melting point of 19 7-200 [deg.] C after crystallization; infrared ray absorption spectrum

  
  <EMI ID = 369.1>

  
calculated: C 61.46; H 7.09

  
found: C 61.58; H 7.08.

  
Similarly, by substituting a quantity

  
  <EMI ID = 370.1>

  
the first paragraph of this example and by practically repeating the process described in detail above, we obtain, as salt

  
  <EMI ID = 371.1>

  
  <EMI ID = 372.1>

  
after crystallization; infrared ray absorption spectrum

  
  <EMI ID = 373.1>

  
  <EMI ID = 374.1>

  
  <EMI ID = 375.1>

  
found: C 62.88; H 7.23; Cl 7.30.

  
Similarly, by substituting a quantity

  
  <EMI ID = 376.1>

  
androst-4-en-3-one-17p-carboxylic acid steranic used in the first paragraph of this example and practically repeating the process described in detail above, we obtain,

  
  <EMI ID = 377.1>

  
a mixture of tetrahydrofuran and hexane.

  
In an analogous way, we substitute a quantity

  
  <EMI ID = 378.1>

  
equivalent amount of butyl chloride to the chloromethyl iodide used in the first paragraph of this example and the process described in detail above is practically repeated, with the exception that the step of washing with thiosulfate is omitted 5% sodium. In this way, we obtain,

  
  <EMI ID = 379.1>

  
17-butyl carboxylate. After crystallization from acetone, the final product has a melting point of 148-149 [deg.] C; after chromatography and crystallization, absorption spectrum

  
  <EMI ID = 380.1>

  
  <EMI ID = 381.1>

  
  <EMI ID = 382.1>

  
  <EMI ID = 383.1>

  
EXAMPLE 4

  
  <EMI ID = 384.1>

  
  <EMI ID = 385.1>

  
  <EMI ID = 386.1>

  
perform precipitation. The precipitate is separated by filtration and dried in a vacuum desiccator

  
  <EMI ID = 387.1>

  
of a yellow powder. This salt is dissolved in 40 ml of hexamethylphosphoramide and 2.36 g (24.5 millimoles) of methyl chloromethyl sulfide are added slowly. Within a minute, a precipitate of sodium chloride is formed in the reaction mixture. This reaction mixture is stirred at room temperature for 1 hour, then diluted with

  
  <EMI ID = 388.1>

  
after which it is washed successively with 3% sodium bicarbonate and water. We separate the organic layer.

  
dry it with magnesium sulfate and filter it. The filtrate is concentrated under vacuum to obtain an oil which is subjected to chromatography in silica gel using

  
  <EMI ID = 389.1>

  
as electors. The chromatography product is crystallized from a mixture of ethyl ether and hexane to obtain

  
  <EMI ID = 390.1>

  
melting point of 133-136 [deg.] C. This product is characterized by the following structural formula:

  

  <EMI ID = 391.1>


  
  <EMI ID = 392.1>

  
  <EMI ID = 393.1>

  
mique which quickly calms down. The reaction mixture is stirred at room temperature for one hour. By filtration, the precipitate formed is removed and the filtrate is concentrated under

  
  <EMI ID = 394.1>

  
white foam * This product meets the structural formula:

  

  <EMI ID = 395.1>


  
  <EMI ID = 396.1>

  
By repeating the process described in the previous paragraph, but using only 1 millimole of acid

  
  <EMI ID = 397.1>

  
methyl.

  
EXAMPLE 5A

  
By substituting an equivalent quantity of one of the starting materials listed below for the hydrocortisone used in Example 1 and practically repeating the process described in detail in this example, the products indicated are obtained:

STARTING MATERIAL

  
  <EMI ID = 398.1>

  
17P-carboxylic, melting point:
248-249 [deg.] C

  
  <EMI ID = 399.1>

  
carboxylic melting point:

  
  <EMI ID = 400.1>

  
  <EMI ID = 401.1>

  
By substituting an equivalent quantity of one of the starting materials listed below for the hydrocortisone used in Example 1 and by practically repeating the process described in detail in this example, the products indicated are obtained:

STARTING MATERIAL

  
  <EMI ID = 402.1>

  
carboxylic <EMI ID = 403.1>

  
EXAMPLE 6A

  
By following the general process of Example 2 and by

  
substituting for it the appropriate reagents, the following new intermediate products of the present invention are obtained:

  

  <EMI ID = 404.1>
 

  

  <EMI ID = 405.1>
 

  

  <EMI ID = 406.1>
 

  
The compounds 6A-1 to 6A-15 above can be named as follows:

  
  <EMI ID = 407.1>

  
carboxylic.

  
EXAMPLE 6B

  
By following the general process of Example 2 and by

  
substituting for it the appropriate reagents, the following new intermediate products of the present invention are obtained:

  

  <EMI ID = 408.1>
 

  

  <EMI ID = 409.1>


  
  <EMI ID = 410.1>

  
  <EMI ID = 411.1>

  
  <EMI ID = 412.1>

  
Following the general process of Example 3 and substituting the appropriate reagents. the following compounds are obtained:

  

  <EMI ID = 413.1>
 

  

  <EMI ID = 414.1>
 

  

  <EMI ID = 415.1>
 

  

  <EMI ID = 416.1>
 

  
The above compounds can be named as follows:

  
  <EMI ID = 417.1> <EMI ID = 418.1>

  
chloromethyl

  
7A-20: 9a-fluoro-17a-isopropoxycarbonyloxy-16a-methyl-

  
  <EMI ID = 419.1>

  
en-3-one-17p-2-chloroethyl carboxylate.

  
EXAMPLE 7B

  
By following the general process of Example 3 or Example 4 and by replacing the appropriate reagents, the following compounds are obtained:

  

  <EMI ID = 420.1>
 

  

  <EMI ID = 421.1>
 

  

  <EMI ID = 422.1>
 

  

  <EMI ID = 423.1>
 

  

  <EMI ID = 424.1>
 

  

  <EMI ID = 425.1>


  
* prepared from compounds 6B-24 and 6B-25

  
  <EMI ID = 426.1>

  
  <EMI ID = 427.1>

  
perbenzorque.

  
EXAMPLE 8

  
  <EMI ID = 428.1>

  
  <EMI ID = 429.1>

  
practically repeats the process described in the first paragraph of this example. In this way, we obtain, as salt

  
  <EMI ID = 430.1>

  
  <EMI ID = 431.1>

  
chloromethyl dihydroxyandrost-4-en-3-one-17p-carboxylate with a melting point of 184-186 [deg.] C (recrystallization from a mixture of tetrahydrofuran, ether and hexane).

  
EXAMPLE 9

  
  <EMI ID = 432.1>

  
used as starting material in Example 4 and the process described in the first paragraph of this example is practically repeated. In this way, we obtain, as an intermediate salt

  
  <EMI ID = 433.1>

  
Methylthiomethyl 4-en-3-one-17p-carboxylate.

  
  <EMI ID = 434.1>

  
second paragraph of example 4 and by practically repeating the process described in detail in this example, one obtains

  
  <EMI ID = 435.1>

  
methylsulfonylmethyl.

  
EXAMPLE 10A

  
The process described in each paragraph of Example 2 is practically repeated, substituting an equivalent amount of each of the starting materials below for the steroids

  
  <EMI ID = 436.1>

  
obtains the following mild anti-inflammatory agents of formula
(I):

  

  <EMI ID = 437.1>
 

  

  <EMI ID = 438.1>


  
THF = tetrahydrofuran

  
  <EMI ID = 439.1>

  
of alkyl chloroformate.

  
EXAMPLE 10B

  
The process described in each paragraph of Example 2 is practically repeated, substituting an equivalent amount of each of the starting materials below for the steroids

  
  <EMI ID = 440.1>

  
dihydroxyandrost-4-en-3-one-17p-methylsulfonylmethyl carboxylate. The following mild anti-inflammatory agents of formula (I) are obtained:

  

  <EMI ID = 441.1>
 

  

  <EMI ID = 442.1>


  
Likewise, in accordance with the methods of Examples 8-10, other representative species can be prepared, for example, the compounds of Examples 7A and 7B.

  
EXAMPLE 11

  
Each of the products of Example 2 and of Example 6A-4 is reacted firstly with diethyl chlorophosphate, then with CH3SNa in chloroform for approximately 6 hours. During the first stage, the following intermediate products are obtained:

  

  <EMI ID = 443.1>
 

  

  <EMI ID = 444.1>


  
In the second step, the following compounds are obtained

  
of formula (I):

  

  <EMI ID = 445.1>


  
When the other products of Example 6A and those of Example 6B are treated in accordance with the above process, the corresponding compounds of formula are obtained:

  

  <EMI ID = 446.1>


  
in which the different structural parameters represent

  
  <EMI ID = 447.1>

  
toluene and the solution is cooled to a temperature of about 0 [deg.] C. Then phosgene is bubbled through the solution while keeping the reaction mixture at low temperature until the reaction is complete (about 2 hours). The excess phosgene and the solvent are removed by

  
  <EMI ID = 448.1>

  
gross formula:

  

  <EMI ID = 449.1>
 

  
Then combined mole of the intermediate product obtained above with 0.02 mole of ethanol containing 0.01 mole

  
  <EMI ID = 450.1>

  
  <EMI ID = 451.1>

  
crystallization.

  
  <EMI ID = 452.1>

  
  <EMI ID = 453.1>

  
methyl with a melting point of 133-136 [deg.] C after crystallization. Then, this compound can optionally be transformed into a corresponding sulfonyl or sulfinyl compound as described in Example 4.

  
In the same way, we can prepare other species

  
  <EMI ID = 454.1>

  
corresponding with the appropriate alcohols and also, when

  
  <EMI ID = 455.1>

  
  <EMI ID = 456.1>

  
in example 4.

  
EXAMPLE 13

  
We repeat the process of the first paragraph of the example
12, with the exception that an equal quantity is used

  
  <EMI ID = 457.1> thus obtained corresponds to the formula:

  

  <EMI ID = 458.1>


  
This intermediate product is then subjected to the process of the second paragraph of Example 12 to obtain the acid.

  
  <EMI ID = 459.1>

  
xylic identical to the product of Example 2, paragraph 2.

  
The other compounds of Examples 2, 6A and 6B can be prepared by adopting the same general process.

  
EXAMPLE 14

  
  <EMI ID = 460.1>

  
of diethyl carbonate containing 20 mg of p-toluenesulfonic acid. The reaction mixture is kept at room temperature for 4 hours and then heated to

  
  <EMI ID = 461.1>

  
  <EMI ID = 462.1>

  
  <EMI ID = 463.1>

  
  <EMI ID = 464.1>

  
  <EMI ID = 465.1> <EMI ID = 466.1>

  
ment transform this compound into a corresponding sulfonyl or sulfinyl compound as described in Example 4.

  
Similarly, other representative species can be prepared, for example, the compounds of Example 3,

  
  <EMI ID = 467.1>

  
  <EMI ID = 468.1>

  
  <EMI ID = 469.1>

  
(and also, when the conditions are suitable, by carrying out a subsequent treatment with m-chloroperoxybenzoic acid as described in Example 4).

  
EXAMPLE 15

  
  <EMI ID = 470.1>

  
  <EMI ID = 471.1>

  
and from 9.6 ml of triethylamine in 100 ml of dry dichloromethane, 10 g of ethyl chloroformate are added dropwise. The reaction mixture is allowed to gradually warm up to room temperature and the insoluble material is removed by filtration. The filtrate is washed successively

  
  <EMI ID = 472.1>

  
dric 1% and water, then dried over anhydrous magnesium sulfate. The solvent is concentrated under pressure

  
  <EMI ID = 473.1>

  
  <EMI ID = 474.1>

  
  <EMI ID = 475.1>

  
EXAMPLE 16

  
By following the general process described in Example 15, and by replacing the appropriate reagents, the following additional compounds are obtained:

  

  <EMI ID = 476.1>


  
THF = tetrahydrofuran.

EXAMPLE 17

  
To a solution of 9.8 g of 17a-ethoxycarbonyloxy-

  
  <EMI ID = 477.1>

  
in 100 ml of tetrahydrofuran and 120 ml of ethanol,

  
  <EMI ID = 478.1>

  
mix at room temperature for about 30 hours and adjust the pH to 2-3 by adding hydrochloric acid

  
  <EMI ID = 479.1>

  
crystallization from a mixture of tetrahydrofuran and

  
  <EMI ID = 480.1>

  
merger of 192-195 [deg.] C.

  
  <EMI ID = 481.1>

  
first paragraph, as well as the compounds of Example 6A by following the same process as that described above and by replacing the appropriate reagents.

  
EXAMPLE 18

  
By following the general process described in Example 17 and by replacing the appropriate reagents, the following compounds are obtained:

  

  <EMI ID = 482.1>


  
1 1 1 THF = tetrahydrofuran.

  
EXAMPLE 19

  
While cooling with ice, over a period of 1 to 1.5 hours, to a solution of 8.7 g of acid

  
  <EMI ID = 483.1>

  
10 g of triethylamine in 100 ml of dichloromethane, a solution of 13.2 g of n-propyl chloroformate in 20 ml of dichloromethane is added dropwise. The reaction mixture is allowed to warm to room temperature over a period of 2 hours, then washed successively with

  
  <EMI ID = 484.1>

  
  <EMI ID = 485.1> anhydrous &#65533; The solvent is concentrated under reduced pressure. By crystallization from a mixture of ether and n-hexane,

  
  <EMI ID = 486.1>

  
in 40 ml of pyridine. To this solution, add drop

  
drop 300 ml of water over a period of 1 to 1.5 hours.

  
The mixture is stirred for one hour and the pH is adjusted to

  
  <EMI ID = 487.1>

  
ice cooling. The mixture is then extracted with chloroform, washed successively with IN hydrochloric acid and water, then dried over sodium sulfate. The solvent is concentrated under reduced pressure and the residue is recrystallized from a mixture of acetone and

  
  <EMI ID = 488.1>

  
  <EMI ID = 489.1>

  
EXAMPLE 20

  
Following the general process described in detail in Example 19, but using the appropriate starting materials and reaction conditions, the other compounds of Example 6A are obtained.

  
EXAMPLE 21

  
  <EMI ID = 490.1>

  
chloromethyl in 200 ml of anhydrous dichloromethane. and 3.5 g of pyridinium chlorochromate are added at room temperature and while stirring. The mixture obtained is stirred for

  
24 hours, then the solvent is concentrated under reduced pressure

  
at a temperature of about 10 to 20 [deg.] C. The residue is subjected

  
chromatography in a column of silica gel

  
(Kiesel gel 60) using chloroform as elution solvent, then recrystallized from a mixture of tetrahy-

  
  <EMI ID = 491.1>

  
  <EMI ID = 492.1>

  
EXAMPLE 22

  
By a process analogous to that described in the example

  
  <EMI ID = 493.1>

  
methyl with a melting point of 200-201 [deg.] C.

  
EXAMPLE 23

  
Using the general method of Example 3 &#65533; but by substituting the appropriate reagents, the 17a-

  
  <EMI ID = 494.1>

  
recrystallization from isopropanol, this product has a melting point of 223-227 [deg.] C.

  
EXAMPLE 24

  
Following the same general process as that described

  
  <EMI ID = 495.1>

  
of 2-chlorethyl. After recrystallization from a mixture of tetrahydrofuran and hexane, this product has a melting point of 243-245 [deg.] C.

  
EXAMPLE 25

  
  <EMI ID = 496.1>

  
chloromethyl hydroxyandrost-4-en-3-one-17p-carboxylate and 0.01 mole of 1,2-dimethylpyrrolidine in 80 ml of acetonitrile and the mixture is heated to reflux temperature. The reaction mixture is maintained at this temperature while stirring for approximately 4 hours. About 65 ml of acetonitrile are removed;

  
then the mixture is cooled to room temperature and an excess of ethyl ether is added to cause precipitation. The precipitate is separated by filtration and washed

  
and it is dried under vacuum to thus obtain the desired quaternary ammonium salt of formula:

  

  <EMI ID = 497.1>


  
In an analogous manner, by using the steranic and amine starting materials suitable in the general process described above, the following additional quaternary ammonium salts of the invention are obtained:

  

  <EMI ID = 498.1>
 

  

  <EMI ID = 499.1>


  
EXAMPLE 26
  <EMI ID = 500.1>
 
  <EMI ID = 501.1>
 
  <EMI ID = 502.1>
 
  <EMI ID = 503.1>
 From the above description, those skilled in the art with current knowledge can readily determine the essential features of the present invention and, without departing from the spirit and the scope thereof. he can

  
make changes and / or modifications to it to adapt it to different uses and conditions. As such,

  
it is understood that these changes and / or modifications fall adequately and fairly within the whole range of equivalences of the claims below.


    

Claims (1)

1. Compound chosen from the group comprising: (a) a compound of formula:  <EMI ID = 504.1> where: <EMI ID = 505.1> carbon atoms; an (monohydroxy or polyhydroxy) alkyl group containing 2 to 10 carbon atoms; a (monohalo or polyhalo) alkyl group containing 1 to 10 carbon atoms; or one  <EMI ID = 506.1> 1 to 10 carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms, a cycloalkenyl group containing 3 to 8 carbon atoms or an alkenyl group containing 2 to 10 carbon atoms, these groups being substituted or unsubstituted and the substituents being chosen from the group comprising a halogen atom, a group lower alkoxy, a lower alkyl-thio group, a lower alkyl-sulfinyl group, a group o lower alkyl-sulfonyl, a group -NHC- (alkyl containing 0  <EMI ID = 507.1>  <EMI ID = 508.1> or a substituted or unsubstituted phenyl group, the substituents being chosen from the group comprising a lower alkyl group, a lower alkoxy group, a halogen atom, a carbamoyl group, a lower alkoxy-carbonyl group, a group <EMI ID = 509.1 > di (lower alkyl) -carbamoyl, a lower alkyl-thio group, a lower alkyl-sulfinyl group and a lower alkyl group-  <EMI ID = 510.1> cycloalkyl group containing 3 to 8 carbon atoms, a group  <EMI ID = 511.1>  <EMI ID = 512.1>  <EMI ID = 513.1> benzyl or a substituted or unsubstituted phenyl group, the substituents being chosen from the group comprising the substituents defined above for the phenyl and benzyl groups  <EMI ID = 514.1>  <EMI ID = 515.1> (lower alkyl)  <EMI ID = 516.1> hydrogen atom, lower alkyl group or phenyl group, or R9 and the lower alkyl group adjacent to Y are  <EMI ID = 517.1> type  <EMI ID = 518.1> where Y has the meaning defined above, while the alkylene group contains 3 to 10 carbon atoms  <EMI ID = 519.1> <EMI ID = 520.1> where R. represents a group  <EMI ID = 521.1>  <EMI ID = 522.1> where R6 has the meaning  <EMI ID = 523.1> lower alkyl group, phenyl group or halophenyl group;  <EMI ID = 524.1> carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms, a cycloalkenyl group containing 3 to 8 carbon atoms or an alkenyl group containing 2 to 10 carbon atoms, these groups being able to be substituted or not and the substituents being chosen from the group comprising a halogen atom, a lower alkoxy group, a lower alkyl group  <EMI ID = 525.1>  <EMI ID = 526.1>  <EMI ID = 527.1> 1  <EMI ID = 528.1> 1 to 10 carbon atoms) and a group  <EMI ID = 529.1> (alkyl containing  <EMI ID = 530.1> or a substituted or unsubstituted phenyl group, the substituents being chosen from the group comprising a lower alkyl group, a lower alkoxy group, a halogen atom, a carbamoyl group, a lower alkoxy-carbonyl group, a lower alkanoyl-oxy group, a lower haloalkyl group, a mono (lower alkyl) amino group, a di (lower alkyl) group  <EMI ID = 531.1> rieur-thio, a lower alkyl-sulfinyl group and a lower alkyl-sulfonyl group;  <EMI ID = 532.1> xy. a B-hydroxy rump, an a-methyl rump. a group  <EMI ID = 533.1>  <EMI ID = 534.1> in  <EMI ID = 535.1> R represents a hydrogen atom, a fluorine atom or a chlorine atom;  <EMI ID = 536.1> fluorine, a chlorine atom or a methyl group  <EMI ID = 537.1> Z represents a carbonyl group or a group  <EMI ID = 538.1> and the dotted line of nucleus A indicates that bond 1,2 is saturated or unsaturated; as well as a quaternary ammonium salt of the compound corresponding to the above formula in which at least one  <EMI ID = 539.1> halogen atom, and (b) a compound of formula:  <EMI ID = 540.1> in which :  <EMI ID = 541.1> have the meanings defined above; R represents a hydroxy group; a chlorine atom; an OM group in which M represents an alkali metal, a  <EMI ID = 542.1> GOLD. wherein IL has the meaning defined above;  <EMI ID = 543.1>  <EMI ID = 544.1> and  <EMI ID = 545.1>  <EMI ID = 546.1>  <EMI ID = 547.1>  <EMI ID = 548.1>  <EMI ID = 549.1>  <EMI ID = 550.1> hydrogen atom, an a-methyl group, an 0-methyl group,  <EMI ID = 551.1>  <EMI ID = 552.1>  <EMI ID = 553.1>  <EMI ID = 554.1> 2. Compound according to claim 1, characterized in that it corresponds to the structural formula described sub (a). 3. Compound according to claim 2, characterized  <EMI ID = 555.1> carbon atoms; a (monohalo or polyhalo) alkyl group  <EMI ID = 556.1> or a group  <EMI ID = 557.1>  <EMI ID = 558.1>  <EMI ID = 559.1> alkyl containing 1 to 6 carbon atoms or a phenyl group;  <EMI ID = 560.1>  <EMI ID = 561.1> carbon; a phenyl group; a benzyl group or a group (monohalo or polyhalo) alkyl containing 1 to 6 carbon atoms;  <EMI ID = 562.1> an a-methyl group - an 0-methyl group or a group  <EMI ID = 563.1>  <EMI ID = 564.1>  <EMI ID = 565.1>  <EMI ID = 566.1>  <EMI ID = 567.1> in that 2 is a p-hydroxymethylene group. 5. Compound according to claim 4, characterized  <EMI ID = 568.1> 1 to 6 carbon atoms.  <EMI ID = 569.1>  <EMI ID = 570.1> carbon.  <EMI ID = 571.1>  <EMI ID = 572.1> carbon, a phenyl group, a benzyl group or a (monohalo or polyhalo) alkyl group containing 1 to 6 carbon atoms. 8. Compound according to any one of the claims  <EMI ID = 573.1>  <EMI ID = 574.1>  <EMI ID = 575.1> 10. Compound according to claim 8, characterized  <EMI ID = 576.1> hydrogen atom. 11. Compound according to claim 10, characterized in that R3 represents an a-methyl group or a P-methyl group.  <EMI ID = 577.1>  <EMI ID = 578.1> 13. Compound according to claim 4, characterized  <EMI ID = 579.1> chloromethyl carboxylate.  <EMI ID = 580.1>  <EMI ID = 581.1>  <EMI ID = 582.1> <EMI ID = 583.1> 15. A pharmaceutical composition comprising, in an anti-inflammatory effective amount.  <EMI ID = 584.1>  <EMI ID = 585.1>  <EMI ID = 586.1> The nuclei of nucleus A have the meanings defined in claim 1, (a), in combination with a non-toxic and pharmaceutically acceptable carrier for this compound, this composition being suitable for topical or other local application. 16.- Mild steroids exerting anti-inflammatory activity, substantially as described above.