FIELD OF THE INVENTION The present invention relates to certain novel 17α and 17β substituted aromatic A ring steroidal compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5-α-reductase.

DESCRIPTION OF RELATED ART The class of steroidal hormones known as androgens is responsible for the physical characteristics that differentiate males from females. Of the several organs that produce androgens, the testes produce these hormones in the greatest amounts. Centers in the brain exert primary control over the level of androgen production. Numerous physical manifestations and disease states result when ineffective control results in excessive androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, male pattern baldness and prostate diseases such as benign prostatic hypertropy are correlated with elevated androgen levels. Additionally, the reduction of androgen levels has been shown to have a therapeutic effect on prostate cancer. Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5-α-reduced androgens are the active hormones in some tissues such as the prostate and sebaceous gland. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5-α-reduced analogue, in these tissues but not in others such as muscle and testes. Steroid 5-α-reductase is a nicotinamide adenine dinucleotide phosphate (NADPH) dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development was dramatically underscored by the discovery of a genetic steroid 5-α-reductase deficiency in male pseudohermaphrodites. Imperato-McGinley, J., el al., (1979), J. Steroid Biochem. 11:637-648.

Recognition of the importance of elevated DHT levels in various disease states has stimulated many efforts to synthesize inhibitors of this enzyme. Among the most potent inhibitors identified to date are 3- carboxy-estra-l,3,5(10) triene steroidal derivatives.

A number of 5-α-reductase inhibiting compounds are known in the art. For example,

1. J. Steroid Biochem.. Vol. 34, Nos. 1-6 pp. 571-575(1989), by M.A. Levy, et al., describes the interaction mechanism between rat prostatic steroid 5-alpha reductase and 3-carboxy-17β-substituted steroids;

2. J. Med. Chem. (1990) Vol. 33, pp. 937-942, by D.A. Holt, et al., describes the new steroid class of A ring aryl carboxylic acids; 3. TIPS (December 1989) Vol. 10, pp. 491-495, by B.W.

Metcalf, et al., describes the effect of inhibitors of steroid 5α-reductase in benign prostatic hyperplasia, male pattern baldness and acne; and

4. EPQ Publn, No, Q 343 954 A3, to D. A. Holt, et al., (SmithKUne Beckmann) describes steroidal 3-carboxylic acid derivatives as useful 5-α-reductase inhibitors.

However, none of the above references specifically suggests that any of the novel steroidal 17α or 17β-substituted estra 1,3,5(10) triene compounds of the present invention would have utility as potent testosterone 5-α-reductase inhibitors.

SUMMARY OF THE TNVENTTON This invention relates to a compound of Formula (I).

CONR ¹ R ²

wherein:

Rl represents: a hydrogen atom; an alkyl group having from 1 to 6 carbon atoms; or a substituted alkyl group having from 1 to 6 carbon atoms and having at least one substituent selected from aryl groups as defined below and aromatic heterocyclic groups as defined below; R2 represents:

a substituted alkyl group having from 1 to 6 carbon atoms and having at least one substituent selected from aryl groups as defined below and aromatic heterocyclic groups as defined below, and said alkyl group further optionally having a single hydroxy or carboxy substituent; adamantyl; or a ό arylamino group in which the two aryl parts are the same or different and each is as defined below;

R3 represents a carboxy group or a group of formula - CONHSθ2 ^ wherein R^ represents an alkyl group having from 1 to 6 carbon atoms; said aryl groups are carbocyclic aromatic groups having from 6 to 14 ring carbon atoms and which are unsubstituted or are substituted by at least one substituent selected from substituents A, defined below; said aromatic heterocyclic groups have 5 or 6 ring atoms of which from 1 to 3 are hetero-atoms selected from nitrogen, oxygen and sulphur hetero- atoms and the remainder are carbon atoms, said group being unsubstituted or being substituted by at least one substituent selected from substituents B, defined below; said substituents A are selected from: alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; alkoxycarbonyl groups having from 2 to 7 carbon atoms; hydroxy groups; halogen atoms; amino groups; alkylamino groups having from 1 to 6 carbon atoms; di- kylamino groups in which each alkyl part has from 1 to 6 carbon atoms; aliphatic acylamino groups having from 1 to 6 carbon atoms; aromatic acylamino groups in which the aromatic part is a carbocyclic aryl group which has from 6 to 10 ring carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from substituents C, defined below; cyano groups; nitro groups; and carboxy groups; said substituents B are selected from: alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; hydroxy groups; halogen atoms; carbocyclic aryl groups which have from 6 to 10 ring carbon atoms and which are unsubstituted or are substituted by at least one substituent selected from substituents C, defined below: amino groups; alkylamino groups having from 1 to 6 carbon atoms; dialkylamino groups in which each alkyl part has from 1 to 6 carbon

atoms; aliphatic acylamino groups having from 1 to 6 carbon atoms; aromatic acylamino groups in which the aromatic part is a carbocyclic aryl group which has from 6 to 10 ring carbon atoms and which is τmβubstituted or is substituted by at least one substituent selected from substituents C, defined below; nitro groups; and carboxy groups; said substituents C are selected from: alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; hydroxy groups; halogen atoms; amino groups; alkylamino groups having from 1 to 6 carbon atoms; dialkylamino groups in which each alkyl part has from 1 to 6 carbon atoms; aliphatic acylamino groups having from 1 to 6 carbon atoms; cyano groups; nitro groups; and carboxy groups; and pharmaceutically acceptable salts and esters thereof.

Also included within the scope of this invention are compounds in which the 17 position substituent is in the α position.

The invention also is a method for inhibiting 5-α-reductase activity in mammals, including humans, that comprises administering to a subject an effective amount of a presently invented 5-α-reductase inhibiting compound. Included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention. Also included in the present invention are methods of co-administering the presently invented 5-α-reductase inhibiting compounds with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention that inhibit 5-α-reductase have the following Formula (I):

wherein:

Rl represents: a hydrogen atom; an alkyl group having from 1 to 6 carbon atoms; or a substituted alkyl group having from 1 to 6 carbon atoms and having at least on substituent selected from aryl groups as defined below and aromatic heterocyclic groups as defined below; 2 represents: a substituted alkyl group having from 1 to 6 carbon atoms and having at least one substituent selected from aryl groups as defined below and aromatic heterocyclic groups as designed below, and said alkyl group further optionally having a single hydroxy or carboxy substituent; adamantyl; or a diarylamino group in which the two aryl parts are the same or different and each is as defined below;

R3 represents a carboxy group or a group of formula - CONHS02R wherein R^ represents an alkyl group having from 1 to 6 carbon atoms; said aryl groups are carbocyclic aromatic groups having from 6 to 14 ring carbon atoms and which are unsubstituted or are substituted by at least one substituent selected from substituents A, defined below; said aromatic heterocyclic groups have 5 or 6 ring atoms of which from 1 to 3 are hetero-atoms selected from nitrogen, oxygen a nd sulphur hetero-atoms and the remainder are carbon atoms, said group being unsubstituted or being substituted by at least one substituent selected from substituents B, defined below; said substituents A are selected from: alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; alkoxycarbonyl groups having from 2 to 7 carbon atoms; hydroxy groups; halogen atoms; amino groups alkylamino groups having from 1 to 6 carbon atoms; dialkylamino groups in which each alkyl part has from 1 to 6 carbon atoms; aliphatic acylamino groups having from 1 to 6 carbon atoms; aromatic acylamino groups i n which the aromatic part is a carbocyclic aryl group which has from 6 to 10 ring carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from substituents C, defined below; cyano groups; nitro groups; and carboxy groups; said substituents B are selected from: alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; hydroxy

groups; halogen atoms; carbocyclic aryl groups which have from 6 to 10 ring carbon atoms and which are unsubstituted or are substituted by at least one substituent selected from substituents C, defined below: amino groups; alkylamino groups having from 1 to 6 carbon atoms; dialkylamino groups in which each alkyl part has from 1 to 6 carbon atoms; aliphatic acylamino groups having from 1 to 6 carbon atoms; aromatic acylamino groups in which the aromatic part is a carbocyclic aryl group which has from 6 to 10 ring carbon atoms and which is unsubstituted or is substituted by at least one substituent selected from substituents C, defined below; nitro groups; and carboxy groups; said substituents C are selected from: alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; hydroxy groups; halogen atoms; amino groups; alkylamino groups having from 1 to 6 carbon atoms; dialkylamino groups in which each alkyl part has from 1 to 6 carbon atoms; aliphatic acylamino groups having from 1 to 6 carbon atoms; cyano groups; nitro groups; and carboxy groups; and pharmaceutically acceptable salts and esters thereof and other physiologically functional derivatives of said compounds of formula (I) which are capable of conversion in the mammalian body to said compounds of formula (I).

The invention also provides a pharmaceutical composition for the treatment of prophylaxis of disorders arising from high levels of 5-α- reductase, notably prostatic hypertrophy, which composition comprises an effective amount of an active compound in admixture with a pharmaceutically acceptable carrier or diluent; wherein said active compound is selected from compounds of formula (I), defined above, and pharmaceutically acceptable salts and esters thereof.

The invention still further provides the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt or ester thereof, as a pharmaceutical.

The invention also provides processes for the preparation of the compounds of the present invention, which processes are described in more detail hereafter.

In the compounds of the present invention, where R* represents an alkyl group having from 1 to 6 carbon atoms, this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl,

isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1- methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups, especially the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl groups. Of these, we prefer those alkyl groups having from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, the methyl, ethyl isopropyl and isobutyl groups being more preferred, and the methyl group being most preferred. Where R* and R^ represents a substituted alkyl group, this may be a straight or branched chain group as defined and exemplified above in relation to the unsubstituted alkyl groups which may be represented by Rl, such as the methyl, ethyl, propyl, isopropyl, t-butyl and 1- methylpentyl groups. Particularly preferred alkyl groups which may be represented by R* and R2 include the alkyl groups having from 1 to 4 carbon atoms, more preferably alkyl groups having from 1 to 3 carbon atoms, and most preferably the methyl, ethyl and isopropyl groups.

In the case of the substituted alkyl groups represented by R* and R2, there may be one or more substituents selected from aryl groups and aromatic heterocyclic groups, defined above and exemplified in more detail below. In the case of R^ only, there may optionally be a further substituent selected from hydroxy groups and carboxy groups. There is no particular limitation on the number of such substituents except such as may be imposed by the number of substitutable positions or by steric constraints. In general, however, from 1 to 3 such substituents are preferred, 1 or 2 being more preferred and 1 being most preferred. Where there are two or more substituents, these may be the same as each other or they may be different from each other.

Where the substituent on the substituted alkyl groups represented by Rl and R^ is an aryl group, this is a carboxcyclic aromatic group (i.e. an aromatic group containing one or more rings, in which all ring atoms are carbon atoms) having from 6 to 14 ring carbon atoms, preferably from 6 to 10 carbon atoms, and more preferably 6 to 10 carbon atoms. Examples of such groups include the phenyl, indeyl, 1-naphthyl, 2- naphthyl, biphenylenyl, acenaphthylenyl, fluoroenyl, phenanthryl and anthryl groups, of which the phenyl and naphthyl groups are preferred, the phenyl group being most preferred. Such aryl groups may be

unsubstituted or they may be substituted by one or more of substituents A, defined above and exemplified below. In the case of the substituted groups, there is no particular limitation on the number of such substituents A except such as may be imposed by the number of substitutable positions or possibly by steric constraints. In general, however, from 1 to 4 such substituents are preferred, from 1 to 3 being more preferred and 1 or 2 being most preferred. Where there are two or more substituents, these may be the same as each other or they may be different from each other. Examples of such substituents A include: alkyl groups having from 1 to 6 carbon atoms, such as those exemplified above in relation to the unsubstituted groups which may be represented by R ¹ ; alkoxy groups having from 1 to 6 carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopehtyloxy, neopentyloxy, 2-methoxypentyloxy, 3,3- dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2- dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, hexyloxy and isohexyloxy groups, of which the methoxy and ethoxy groups are preferred; alkoxycarbonyl groups having from 2 to 7 carbon atoms, that is the alkoxy part has from 1 to 6 carbon atoms, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, noepentyloxycarbonyl, 2- methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, 4- methoxypentyloxycarbonyl, 3-methoxypentyloxycarbonyl, 2- methoxypentyloxycarbonyl, 1-methoxypentyloxycarbonyl, 3,3- dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1- dimethylbutoxycarbonyl, 1,2-dimethylbotoxycarbonyl, 1,2- dimethylbutoxycarbonyl, 2,3-dimethylbuotyxcarbonyl, 2- ethylbutoxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups, of which the methoxycarbonyl, 2-ethylbutoxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups, of which the methoxycarbonyl and ethoxycarbonyl groups are preferred; hydroxy groups;

halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms, of which the fluorine, chlorine and bromine atoms are preferred, the fluorine and chlorine atoms being most preferred amino groups; alkylamino groups having from 1 to 6 carbon atoms, such as the methylamino, ethylamino, proplylamino, butylamino, isobutylamino, pentylamino and hexylamino groups; of these, we prefer the groups in which the alkyl part has from 1 to 4, more preferably 1 or 2, carbon atoms; dialkylamino groups in which each alkyl part has from 1 to 6 carbon atoms, such as the dimethylamino, diethylamino, methylethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, methylbutylamino and ethylpropylamino groups; of these, we prefer the groups in which each alkyl part has from 1 to 4, more preferably 1 or 2, carbon atoms; aUphatic acylamino groups having from 1 to 6 carbon atoms, such as the formylamino, acetylamino, propionylamino, butyrylamino, valerylamino, isovalerylamino, piraloylamino and hexanoylamino groups, of which those groups having from 1 to 5 carbon atoms are preferred, groups having 1 or 3 carbon atoms being most preferred; aromatic acylamino groups in which the aromatic part is a carbocyclic aryl group which has from 6 to 10, preferably 6 or 10, ring carbon atoms (for example the phenyl or naphthyl groups), and which is unsubstituted or is substituted by at least one substituent selected from substituents C, defined above, such as the benzoyl or naphthoyl groups and substituted derivatives thereof; cyano groups; nitro groups and carboxy groups;

Examples of the groups and atoms included in substituents C are the same as the corresponding groups and atoms included in substituents A and given above. Of these substituents A, we prefer alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups having 2 or 3 carbon atoms, hydroxy groups, halogen atoms, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups in which each alkyl part has from 1 to 4 carbon atoms, and aUphatic acylamino groups having from 1 to 3 carbon atoms, more preferably the methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, hydroxy, amino, methylamino,

ethylamino, dimethylamino, diethylamino, methylethylamino, formylamino and acetylamino groups, and the fluorine, chlorine and bromine atoms, and most preferably the methyl, methoxy, ethoxy and hydroxy groups, and the fluorine and chlorine atoms. Where the substituent on the substituted alkyl groups represented by Rl or R2 is an aromatic heterocycUc group, this is a heterocycUc group having 5 or 6 ring atoms in an aromatic ring. The group also has from 1 to 3 hetero-atoms selected from nitrogen atoms, oxygen atoms and sulphur atoms, the remaining ring atoms being carbon atoms. In general, where there are three hetero-atoms, we prefer that 1, 2 or 3, preferably 2 or 3, are nitrogen atoms and, correspondingly, 2, 1 or 0, preferably 1 or 0, are oxygen and/or sulphur atoms. Where there are 1 or 2 hetero-atoms, they may be freely selected from nitrogen, oxygen and sulphur atoms. Examples of such groups include the furyl, thienyl, pyridyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups. Of these, we prefer the furyl, thienyl and pyridyl groups, more preferably the furyl and thienyl groups, and most preferably the thienyl group. Such aromatic heterocycUc groups may be unsubstituted or they may be substituted by one or more substituents B, defined above. In the case of the substituted groups, there is no particular limitation on the umber of such substituents B except such as may be imposed by the number of substitutable positions or possibly by steric constraints. In general, however, from 1 to 3 such substituents are preferred, 1 or 2 being most preferred. Where there are two or more substituents, these may be the same as each other or they may be different from each other. Examples of such substituents B include the corresponding groups and atoms exemplified above in relation to substituents A and aryl groups having from 6 to 10 ring carbon atoms such as those exemplified above and included in the aryl groups which may be represented by R*. In particular, preferred substituents include alkyl groups having from 1 to 6 carbon atoms (such as those exemplified above in relation to R*) and halogen atoms (such as the fluorine, chlorine, bromine and iodine atoms). More preferred substituents are alkyl groups having from 1 to 4 carbon atoms, fluorine atoms and chlorine atoms, still more preferably a methyl or ethyl group, and most preferably a methyl group.

3 and possibly substituents A, B or C may represent carboxy groups, and the group represented by R2 may include a carboxy group, and the compounds of the present invention may therefore form salts and esters as weU as other derivatives, which are well known in the art, such as amides. There is no restriction on the nature of such salts, esters and other derivatives, provided that, where they are to be used for therapeutic purposes, they are pharmaceutically acceptable, that is they are not less active (or unacceptably less active) pr more toxic (or unacceptably more toxic) than the parent compound. However, where the compounds are to be used for other purposes, for example as intermediates in the preparation of other compounds, even this restriction may not apply.

Preferred ester groups are those that can be converted to a carboxy group in vivo. Examples of such ester groups include: alkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms, such as those exemplified above in relation to R*; haloalkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms, such as the trifluoromethyl, 2,2,-trifluoroethyl, 2,2,2- trichloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-iodoethyl, 3-chloropropyl, 40fluorobutyl and 6-iodohyxyl groups, preferably the 2,2,2-trichloroethyl and 2-chloroethyl groups; hydroxyalkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms, such as the 2-hydroxyethyl, 2,3-dihydroxypropyl, 3- hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl groups, preferably the 2-hydroxyethyl group; alkoxyalkyl and alkoxyalkoxyalkyl groups in which the alkyl and alkoxy groups each have from 1 to 6, preferably from 1 to 4, carbon atoms, such as the methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 2- methoxyethoxymethyl groups, preferably the methoxymethyl group; the phenacyl group; alkoxycarbonylalkyl groups in which the alkyl and alkoyx groups each have fom 1 to 6, preferably from 1 to 4, carbon atoms, such as the methoxycarbonylmethyl group; cyanoalkyl groups in which the alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms, such as the cyanomethyl and 2-cyanoethyl groups;

alkylthiomethyl groups in which the alkyl part has from ^" ! to 6, ^• preferably from 1 to 4, carbon atoms, such as the methylthiomethyl and ethylthiomethyl groups; arylthiomethyl groups in which the aryl part has from 6 to 10 ring carbon atoms and may be unsubstituted or may be substituted by at least one substituent selectedd from substituents C, defined and exemplified above, such as the phenylthiomethyl and naphthylthiomethyl groups; alkylsulphonylalkyl groups in which each alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms, and in which the alkylsulphonyl part may be unsubstituted or may be substituted by at least one halogen atom, such as th e2-methanesulphonylethyl and 2- trifluoromethanesulphonylethyl groups; arylsulphonylalkyl groups in which the aryl part has from 6 to 10 ring carbon atoms and may be unsubstituted or may be substituted by at least one substituent selected from substituents C, defined and exemplified above, and the alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms, such as the 2-benzenesulphonylethyl and 2- toluenesulphonylethyl groups; aralkyl groups in which the aryl part has from 6 to 10 ring carbon atoms and may be unsubstituted or may be substituted by at least one substituent selected from substituents C, defined and exemplified above, and the aklyl part has from 1 to 6, preferabyl from 1 to 3, carbon atoms, such as the benzyl, naphthylmethyl, diphenylmethyl, trityl, 6- phenylhexyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5- trimethylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl and 4-bromobenzyl groups, preferably those aralkyl groups in which the aryl part is a phenyl group and the alkyl part has from 1 to 6, preferably from 1 to 3, carbon atoms, more preferably the benzyl, 4-methyl-benzyl, 4- chlorobenzyl and 4-bromobenzyl groups; aryl groups, such as those defined and exemplified above in relation to the aryl groups which may be substituents on the substituted alkyl groups represented by R ¹ and R2; silyl groups of formula -SiR ^a R^R ^c , wherein 1, 2 or 3 or R ^a , R^ and R ^c , whcih may be the same or different from each other, each represents an alkyl group having from 1 to 6 carbon atoms (such ss those exemplified above in relation to R*), and correspondingly 2, 1 or 0 of R ^a , R^ and R ^c

represents an aryl group, such as those defined and exemplified above in relation to the aryl groups whcih may be substituents on the substituted alkyl groups represented by R* and R^; examples of such silyl groups include the trimethylsilyl, triethylsilyl, isopropyldimethylsil l, t- butylkimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl and phenyldiisopropylislyl groups, preferably the trimethylsilyl, t-butyldimethylsilyl and methyldiphenylsilyl groups; alkanoyloxyalkyl groups in which the alkanoyl and alkyl groups each have from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms in the case of alkyl groups or from 1 to 5 carbon atoms in the case of alkanoyl groups, such as the formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1- formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1- hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2- isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1- acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1- pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1- hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1- butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1- propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1- pivaloyloxyhexyl groups, preferably the formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1- formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl and 1-pivaloyloxyethyl groups, more preferably the acetoxymethyl, propiopnyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1- acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl and 1- pivaloyloxyethyl groups, most preferably the pivaloyloxymethyl and 1- pivaloyloxyethyl groups; cydoalkanecatbonyloxyalkyl groups in which the cycloalkane part has from 5 to 7, preferably 5 or 6, carbon atoms and the alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms (such as those exemplified above in relateion to R ), such as the cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, l-(cyclopentanecarbonyloxy)ethyl, 1-

(cyclohexanecarbonyloxy)ethyl, l-(cyclopentanecarbonyloxy)propyl, 1- (cyclohexanecarbonyloxy)propyl, l-(cyclopentanecarbonyloxy)butyl, 1- (cyclohexanecarbonyloxy)butyl, cycloheptanecarbonyloxymethyl, 1- (cydoheptanecarbonyloxy)ethyl, l-(cycloheptanecarbonyloxy)propyl and (l-cycloheptanecarbonyloxy)butyl groups, preferably cydopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, 1-

(cydopentanecarbonyloxy)ethyl and l-(cyclohexanecarbonyloxy)ethyl groups; alkoxycarbonyloxyalkyl groups in which the alkyl and alkoxy groups each have from 1 to 6, preferably from 1 to 4, carbon atoms, such as the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propocarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloycarbonyloxymethyl, 1- methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1- propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1- butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1- ethoxycarbonyloxypropyl, 1-propoxycarbonyloxypropyl, 1- isopropoxycarbonyloxypropyl- 1-butoxycarbonyloxypropyl, 1- isobutoxycarbonyloxypropyl, 1-pentyloxycarbonyloxypropyl, 1- hexyloxycarbonyloxypropyl, 1-methoxycarbonyloxybutyl, 1- ethoxycarbonyloxybutyl, 1-propoxycarbonyloxybutyl, 1- isopropoxycarbonyloxyutyl, 1-butoxycarbonyloxybutyl, 1- isobutoxycarbonyloxybutyl, 1-methoxycarbonyloxypentyl, 1- ethoxycarbonyloxypentyl, 1-methoxycarbonyloxyhexyl and 1- ethoxycarbonyloxyhexyl groups, preferably the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1- methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1- propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1- butoxycarbonyloxybutyl, 1-butoxycarbonyloxyethyl, 1- methoxycarbonyloxypropyl, 1-ethoxycarbonyloxypropyl, 1- propoxycarbonyloxypropyl, 1-isopropoxycarbonyloxypropyl, 1- butoxycarbonyloxypropyl, 1-isobutoxycarbonyloxypropyl, 1- methoxycarbonyloxybutyl, 1-ethoxycarbonyloxybutyl, 1- propoxycarbonyloxybutyl, 1-isoproxycarbonyloxybutyl, 1-

butoxycarbonyloxybutyl and 1-isobutoxycarbonyloxybutyl groups, more preferably the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycaronyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1- methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1- propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1- butoxycarbonyloxyethyl and 1-isobutoxycarbonyloxyethyl groups, and most preferably the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, 1- methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl and 1- isopropoxycarbonyloxyethyl groups; cydoalkyloxycarbonyloxyalkyl groups in which the cycloalkyl part has from 5 to 7, preferably 5 or 6, carbon atoms and the alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms (such as those exemplified above in relation to Rl), such as the cyclopentyloxycarbonyloxymethyl, cydohexyloxycarbonyloxymethyl, l-(cyclopentyloxycarbonyloxy)ethyl, 1- (cydohexyloxycarbonyloxy)ethyl, l-(cyclopentyloxycarbonyloxy)propyl, 1- (cydohexyloxycarbonyloxy)propyl, l-(cyclopentyloxyarbonyloxy)butyl, 1- (cyclohexyloxycarbonyloxy)butyl, cycloheptyloxycarbonyloxymethyl, 1- (cydoheptyloxycarbonyloxy)ethyl, l-(cycloheptyloxycarbonyloxy)propyl and l-(cydoheptyloxycarbonyloxy)butyl groups, preferably the cydopentyloxycarbonyloxymethyl, cydohexyloxycarbonyloxymethyl, 1- (cydopentyloxycarbonyloxy)ethyl and l-(cyclohexyloxycarbonylooxy)ethyl groups;(5-aryl- or 5-alkyl-2-oxo-l,3-dioxolen-4-yl)methyl groups in which the aryl part has from 6 to 10 ring carbon atoms and may be unsubstituted or may be substituted by at least one sustituent selected from substituents C, defined and exemplified above, and the alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms (such as those exemplified above in relation to R ), such as the (5-phenyl-2-oxo-l,3- dioxolen-4-yl)methyl, [5-(4-methylhenyl)-2-oxo- l,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-l,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyD- 2-oxo- l,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-l,3-dioxolen-4- yl]methyl,[5-(4-2-oxo-l,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-l,3- dioxolen-4-yl)methyl, (5-propyl-2-oxo- l,3-dioxolen-4-yl)methyl, (5- isopropyl-2-oxo-l,3-dioxolen-4-yl)methyl and (5-butyl-2-oxo-l,3-dioxolen- 4-yl)methyl groups, preferably the (5-phenyl-2-oxo-l,3-dioxolen-4- yl)methyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl and (5-ethyl-2-oxo-

l,3-dioxolen-4-yl)methyl groups, and most preferably the (5-methyl-2- oxo-l,3-dioxolen-4-yl)methyl group; and the phthaUdyl group

Of these, we esperially prefer: alkyl groups having from 1 to 4 carbon atoms; benzyl groups; substituted benzyl groups having from 1 to 3 substituents selected from methyl, ethyl, methoxy and ehtoxy groups and fluorine and chlorine atoms; the diphenylmethyl group; the naphthylmethyl groups; alkanoyloxylalkyl groups in which the alkanoyl part has from 1 to 5 carbon atoms and the alkyl part has from 1 to 4 carbon atoms; cycloalkanecarbonyloxyalkyl groups in which the cycloalkyl part has from 5 to 7 ring carbon atoms and the alkyl part has from 1 to 4 carbon atoms; alkoxycarbonyloxyalkyl groups in which the alkoxy and alkyl parts each have from 1 to 4 carbon atoms; cylcoalkyloxycarbonyloxyalkyl groups in which the cycloalkyl part has from 5 to 7 ring carbon atoms and the alkyl part has from 1 to 4 carbon atoms; (5-phenyl- or 5-alkyl-2-oxo-l,3-dioxolen-4-yl)methyl groups in which the alkyl part has from 1 to 4 carbon atoms; and the phthaUdyl group.

More preferred ester groups include: alkyl groups having from 1 to 4 carbon atoms; benzyl groups; alkanoyloxyalkyl groups in which the alkanoyl part has from 1 to 5 carbon atoms and the alkyl part has 1 or 2 carbon atoms; cycloalkanecarbonyloxyalkyl groupsi n which teh cydoalkyl part has from 5 to 7 ring carbon atoms and the alkyl part has 1 or 2 carbon atoms; alkoxycarbonyloxyalkyl groups in which the alkoxy part has from 1 to 4 carbon atoms and the alkyl part has 1 or 2 carbon atoms; cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl part has from 5 to 7 ring carbon atoms and the alkyl part has 1 or 2 carbon atoms; [5-phenyl-, 5-methyl- or 5-ehtyl-2-oxo-l,3-dioxolen-4-yl)methyl groups; and the phthaUdyl group. The most preferred ester groups include methyl groups, ethyl groups, pivaloyloxymethyl groups, ethoxycarbonyloxymethyl groups, 1- (ethoxycarbonyloxy)ethyl groups, isopropoxycarbonyloxymethyl groups, l-(isopropoxycarbonyloxy)ethyl groups, (5-methyl-2-oxo- l,3-dioxolen-4- yl)methyl group and phthaUdyl groups. The most preferred ester groups include methyl groups, ethyl groups, pivaloyloxymethyl groups, ethoxycarbonyloxymethyl groups, 1- (ethoxycarbonyloxy)ethyl groups, isopropoxycarbonyloxymethyl groups,

l-(isopropoxycarbonyloxy)ethyl groups, (5-methyl-2-oxo-l,3-dioxolen-4- yl)methyl group and phthaUdyl groups.

Those compounds of the present invention which contain a carboxy group can also form salts. Examples of such salts indude: salts with an alkaU metal, such as sodium, potassium or lithium; salts with an alkaline earth metal, such as barium or calrium; salts with another metal, such as magnesium or aluminium; ammonium salts; organic base salts, such as a salt with triethylamine, diisopropylamine, cydohexylamine, dicydohexylamine and guanidine; and salts with a basic amino add, such as lysine or arginine. Also, where the compound o the present invention contains a basic group, such as an amino group, in its molecule, it can form add addition salts. Examples of such add addition salts include: salts with mineral adds, espedally hydrohalic adds (such as hydrofluoric add, hydrobromic add, hydroiodic add or hydrochloric add), nitric add, carbonic add, sulphuric add or phosphoric add; salts with lower alkylsulphonic adds, such as methanesulphonic add triffuoromethanesulphonic add or ethanesulphonic add; salts with arylsulphonic adds, such as benzenesulphonic add or p- toluenesulphonic add; salts with organic carboxylic adds, such as acetic add, fumaric add, tartaric add,oxalic add, maleic add, malic add, sucdnic add, benzoic add, mandelic add, ascorbic add, lactic add, gluconic add or ritric add; and salts with amino adds, such as glutamic add or aspartic add.

Examples of alkyl groups which may be represented by R^ indude the alkyl groups exemplified above in relation to R , espedally the methyl and ethyl groups.

In general, in the compounds of the present invention, we prefer that R1 represents a hydrogen atom and R^ is as defined above.

Preferred groups of formula -NR^R^ include: the benzylamino, (2-, 3- or 4-methylbenzyl)amino, (2-, 3- or 4-methoxybenzyl)amino, (2-, 3- or 4-fluorobenzyl)amino, (2, 3- or 4-chlorobenzyl)amino, phenethylamino, (2-, 3- or 4-methylphenethyl)amino, (2-, 3- or 4- methoxyphenethyDamino, (2-, 3- or 4-fluorophenethyl)amino, (2-, 3- or 4- chlorophenethyl)-unino, (3-phenylpropyl)amino, (1-methyl-l- phenylethyDamino, [l-methyl-l-(2-, 3- or 4- methylphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4-methoxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4-fluorophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4-

dιlorphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- hydroxyphenyl)ethyl]amino, [l-methy-l-(2-, 3- or 4- aminophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- methylaminophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- ethylammophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- dimethylaminophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- acetamidophenyl)ethyllamino, [l-methyl-l-(2, 3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,50 or 3,6-cUmethoxyphenyl)ethyl]amino, (l,l-dimethyl-2- phenylethyDamino, [l,l-dimethyl-2-(2-, 3- or 4- methylphenyl)ethyl]amino, [l,l-dimethyl-2-(2-, 3- or 4- methoxyphenyl)ethyl]amino, [l,l-dimethyl-2-(2-, 3- or 4- fluorophenyl)ethyl]amino, [l,l-dimethyl-2-(2-, 3- or 4- chlorophenyl)ethyl]amino, benzhydrylamino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)dimethylbenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- [cUmethoxybenzhydι l]a_mino, [(2-,3- or 4-), (2'-, 3'- or 4'-)difluorobenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- 4'-)- dihydroxybenzhydryl]amino,[(2-, 3- or 4-), (2'-, 3'-, or 4'-)- cUaminobenzhydryl]amino,[2-, 3- or 4-), (2'-, 3'- or 4'-) (dimethylamino)benzhydryl]amino, (2-, 3- or 4- methylbenzhydryDamino, (2-, 3- or 4-methoxybenzhydryl)amine, (2-, 3- or 4-fluoroben-dιyldryl)amino, (2-, 3- or 4-chlorobenzhydryl)amino, (2-, 3- or 4-hydroxybenzhyd- Damino, (2-, 3- or 4-aminobenzhydryl)amino, (2-, 3- or 4-dimethylaminobenzhydryl)amino, (l,l-diphenylethyl)amino, (1,2- diphenylethyl)amino,[2-(2-, 3- or 4-methylphenyl)-l- phenylethyl]amino,[2-(2-, 3- or 4-methoxyphenyl)-l-phenylethyl]amino, [2-(2-, 3- or 4-cMorophenyl)-l-phenylethyl]amino,[l-(2-,3-or4- fluorophenyl)-2-(2-, 3- or 4-fluorophenyl)ethyl]amino, [l-(2-, 3- or 4- chlorophenyl)-2-(2-, 3- or 4-chlorophenyl)ethyl]amino, [l-(2-, 3- or 4- chlorophenyl)-2(2-, 3- or 4-methoxyphenyl)ethyl]amino,[l-(2-, 3- or 4- methylphenyl)-2-(2-, 3- or 4-methylphenyl)ethyl]amino,[l-(2-, 3- or 4- methylphenyl)ethyl]amino,[l-(2-, 3- or 4-hydroxyphenyl)-2-(2-, 3- or 4- hyc oxyphenyl)ethyl]amino,[l-(2-, 3- or 4-aminophenyl)-2-(2-, 3- or 4- aminophenyl)ethyl]amino,[l-(2-, 3- or 4-dimethylaminophenyl)-2-(2-, 3- or 4-ό methylaminophenyl)ethyl]amino, [2-(2-, 3- or 4-fluophenyl)-l-(2-, 3- or 4-methylphenyl)ethyl]amino, [2-(2-, 3- or 4-fluophenyl)-l-(2-, 3- or 4-methoxyphenyl)ethyl]amino, [2-(2-, 3- or 4-hydroxyphenyl)-l- phenyethyl]amino, [2-(2-, 3- or 4-aminophenyo)-l-phenylethyl]amino, [2-

(2-, 3- or 4-dimethylaminophenyl)-l-phenylethyl]amino, [l-(2-, 3- or 4- methoxyphenyl)-2-phenylethyl)amino, (l-methyl-1,2- diphenylethyDamino, (2,2-diphenylethyl)amino, [2-(2-, 3-or 4- methylphenyl-2-(2-, 3- or 4-methylphenyl)ethyl]amino, [l-benzyl-4- phenylbutyl)-unino, (l,l-dephenylethyl)amino, [l-(2-, 3- or 4- fluorophenyl)-l-(2-, 3- or 4-fluorophenyl)ethyl]amino, [l-(2-, 3- or 4- methylphenyl)-l-(2-, 3- or 4-methylphenyl)ethyl]amino, [l-(2-, 3- or 4- methoxyphenyl)-l-(2-, 3- or 4-)-methylphenyl)eι^yl]amino,[l-(2-, 3- or 4- hydroxyphenyl)-l-phenylethyl]amino, [l-(2, 3- 4-aminophenyl)-l- phenylethyl]-unino, [l-(2-, 3- or 4-dimethylaminophenyl)-l- phenylethylamino, tritylamino, [2-, 3- or 4-), (2'- 3' or 4'-), (2"-, 3"- or 4"-)trimethyltrity]amino, [(2-, 3- or 4-), (2'-, 3 ^* - or 4 ^* -), (2"-, 3"- or 4"-)trifluorotrityl]amino, (l-benzyl-2phenylethyl)amino, [l-(2-, 3- or 4- fluorobenzyl)-2-(2-, 3- or 4-fluorophenyl)ethyl]amino, (1-benzyl-l-methyl- 2-phenylethyl)amino, [l-(2-, 3- or 4-chlorobenzyl)-2-(2-, 3- or 4- chlorophenyl)ethyl]amino, [l-(2-, 3- or 4-fluorobenzyl)-2-(2-, 3- or 4- fluorophenyl)-l-methylethyl]amino, [l-methyl-2-(2-, 3- or 4- methylphenyl)-3-(2-, 3- or 4-methylphenyl)propyl]amino, [2-,(2-, 3- or 4- fluoroyphenyl)-3-(2-, 3- or 4-fluoroyphenyl)-l-methylpropyl]amino, (1,3- cUphenylpropyl)amino, [l-(2-, 3- or 4-methylphenyl)-3-(2-, 3- or 4- methylphenyl)propyl]amino, [l-(2-, 3- or 4-methoxyphenyl)-3-(2-, 3- or 4- methoxyphenyl)propyl]amino, (l,4-diphenylbutly)amino, [l-(2-, 3- 4- chlorophenyl)4-(2-, 3- or 4-chlorophenyl)butyl]amino, [l-(2-, 3- or 4- methoxyphenyl)-4-(2-, 3- or 4-methoxyphenyl)butyl]amino, (1-methyl- 3,3-diphenylpropyl)amino, [3-(2-, 3- or 4-fluorophenyl)-3-(2-, 3- or 4- fluorophenyl)-l-methylpropyl]amino, [l-methyl-3-(2-, 3- or 4- methylphenyl)-3-(2-, 3- or 4-methylphenyl)propyl]amino, M-benzyl-ϋ- methylamino, M-benzyl-H-ethylamino, N-benzyl-M-isopropylamino, H- benzyl-M-isobutylamino, N-benzyl-JS-t-butylamino, N-(2-, 3- or 4- fluorobenzyl)-M-isopropylamino, H-(2-, 3- or 4-chlorobenzyl)-N.- isopropylamino, N-(2-, 3- or 4-methylbenzyl)-M-isopropylamino, M-(2-, 3- or 4-methoxybeιιzyl)-N.-isopropylamino, H-(2-, 3- or 4-hydroxybenzyl)-N_- isopropylamino, K^i-dibenzylamino, M-benzyl-H-(2-, 3- or 4- methoxybenzyDamino, N-(2-, 3- or 4-fluorobenzyl)-H-(2-, 3- or 4- fluorobenzyl)amino, H-(2-, 3- or 4-methylbenzyl)-]N[-(2-, 3- or 4- methylbenzyDamino, M-(2-, 3- or 4-methoxybenzyl)-H-(2-, 3- or 4- methoxybenzyDamino, H-(2-, 3- or 4-hydroxybenzyl)-N.-(2-, 3- or 4-

hydroxyben-zyl)amino, N.-(2-, 3- or 4-aminobenzyl)-£H2-, 3- or 4- aπύnoben-yl)amino, N.-(2-, 3- or 4-dimethylaminobenzyl)-M-(2-, 3- or 4- dimethylam oben∑y amino, M-benzyl-M-phenylethylamino, N.-benzyl- M-(l-phenylethyl)amino, N.-benzyl-N.-(l-methyl-l phenylethyDamino, N. S-diphenylethylamino, N.,M-bis(l-phenylethyl)amino, N.-benzyl-N.-(3- phenylpropyDamino, (2-or 3-furylmethyl)amino, (2- or 3- tMenylmethyl)amino, (2-, 3- or 4-pyridylmethyl)amino, (2- or 5-methyl-2- or 3- furylmethyl)amino, (2- or 5-methyl-2- or 3-thienylmethyl)amino, [2- (2- or 3-furyl)et-hyl]amino, [2-(2- or 3-thienyl)ethyl]amino, [3-(2- or 3- furyl)propyl]amino, [3-(2- or 3-thienyl)propyl]amino, [bis(2- or 3- furyl)methyl]amino, [bis(2- or 3-thienyl)methyl]amino, [l,l-bis(2- or 3- furyl)ethyl]amino, [l,l-bis(2- or 3-thienyl)ethyl]amino, [(2- or 5-methyl- 2- or 3-furylmethyl),(2- or 5-methyl-2- or 3-furylmethyl]amino, [2 or 5- methyl-2- or 3-thienylmethyl),(2- or 5-methyl-2- or 3- thienylmethyl]amino, [l-(2- or 3-furyl)-l-methylethyl]amino, [l-(2- or 3- thienyl)-l-methylethyl]amino, [l-(2- or 5-methyl-2- or 3-thienyl)-l- methylethyl]amino, [l-(2- or 3-furyl)-2-(2- or 3-furyl)ethyl]amino, [l-(2- or 5-methyl-2- or 3-furyl^l-methylethyl]amino, [l-(2- or 3-thienyl)-2-(2- or 3-thienyl)ethyl]-3cmino, [l-(2- or 3-furyl)-2-phenylethyl]amino, [l-(2- or 3-furyl>2-(2-, 3- or 4-methylphenyl)ethyl]amino,[2-phenyl-l-(2- or 3- thienyl)ethyl]amino, [2-)2-, 3- or 4-methylphenyl)-l-(2- or 3- thienyl)et-hyl]amino, [2-(2-, 3- or 4-chlorophenyl)l-(2- or 3- thienyl)ethyl]amino, [2-(2-, 3- or 4-fluorophenyl)-l-(2- or 3- thienyl)ethyl]amino, [2-(2-, 3- or 4-methoxyphenyl)-l-(2- or 3- thienyl)ethyl]amino, N-(2- or 3-furylmethyl)-N 2- or 3- furylmethyl)amino, H-(2- or 3-furylmet^yl)amino, N.-(2- or 3- thienylmethyl)-N.-(2- or 3-thienylmethyl)amino, [l-(2-, 3- or 4- fluorophenyl)-2-(2- or 3-thienyl)ethyl]amino, N.-benzyl-N.-(2- or 3- fuιybnethyl)amino, N.-benzyl-N-(2- or 3-thienylmethyl)amino, (2- hydroxy-l,2-cUphenylethyl)amino, N ,H'-diphenymydrazino, N_'-(2-, 3- or 4-methylphenyl)-ϋ'-phenylhydrazino, ϋ'-(2-, 3- or 4-methoxyphenyl)- H'phenylhydrazino, N (2-, 3- or 4-chlorophenyl)-N.'-phenylhydrazino, N_'- (2-, 3- or 4-fluorophenyl)-N phenymydrazino, N_'-(2-, 3- or 4- dydroxyphenyl)-H'-phenylhydrazino, M'-(2-, 3- or 4-aminophenyl)-N.'- phenylhydrazino, N (2-, 3- or 4-cUmethylaminophenyl)-H _. - phenylhydrazino, N.'-(2-, 3- or 4-acetamidophenyl)-N.'-phenylhydrazmo, N (2-, 3- or 4-methylphenyl)-N (2-, 3- or 4-methylphenyl)hydrazino and

N (2-, 3- or 4-methoxyphenyl)-H'-(2-, 3- or 4-methoxyphenyl)hydrazino groups.

More preferred groups of formula -NR1R2 include: the (1-methyl- l-phenylethyl)amino, [l-methyl-l-(2-, 3- or 4-methylphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4-methoxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4-fluorophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- chlorophenyl)ethyl]amino, [-methyl-l-(2-, 3- or 4- hydroxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- aminophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- dimethylaminophenyl)ethyl]amino, [l-methyl-l-(2-, 3- or -4- acetamidophenyl)ethyl]amino, [l-methyl-l-(2,3-2,4-2,5-2,6-3,4-3,5-or 3,6- dimethoxyphenyl)ethyl]amino, (l,l-dimethyl-2-phenylethyl)amino, benzhydrylamino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- dimethylbenzhydryllamino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- dimethoxybenzhyrdyljamino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- difluorobenzhydryllamino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- dihydroxybeιιzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- diammobenzhydryllamino, [2-, 3- or 4-), (2'-, 3'- or 4'-)- cU(dimethylamino)benzhydryl]amino, (2-, 3- or 4- methylbenzhydry)amino, (2-, 3- 4-methoxybenzhydryl)amino, (2-, 3- or 4- fluorobenzhydryl)amino, (2-, 3- or 4-dιlorobenzhydryl)amino, (2-, 3- or 4- hydroxybenzhydryl)amino, (2-, 3- or 4-aminobenzhydryl)amino, (2-, 3- or 4-dimethylaminobenzhydryl)amino, (l,l-diphenylethyl)amino, (1,2- diphenylethyDamino, [2-(2-, 3- or 4-chlorophenyl)-l-phenylethyl]amino, [2-(2-, 3- or 4-fluorophenyl)-l-phenylethyl]amino, [2-(2-, 3- or 4- methylphenyl)-l-phenylethyl]amino, [2-(2-, 3- or 4-methoxyphenyl)-l- phenylethyljamino, [l-(2-, 3- or 4-fluorophenyl)-2-(2-, 3- or 4- fluorophenyl)ethyl]amino, [l-(2-, 3- or 4-chlorophenyl)-2-(2-, 3- or 4- chlorophenylethyl]amino, [l-(2-, 3- or 4-chlorophenyl)-2-(2-, 3- or 4- methoxyphenyl)ethyl]amino, [l-(2-, 3- or 4-methylphenyl)-2-(2-, 3- or 4- methylphenyl)ethyl]amino, [l-(2-, 3- or 4-hydroxyphenyl)-2-(2-, 3- or 4- hydroxyphenyl)ethyl]amino, [l-(2-, 3- or 4-aminophenyl)-2-(2-, 3- or 4- aminophenyl)ethyl]amino, [l-(2-, 3- or 4-dimethylaminophenyl)-2-(2-, 3- or 4-dimeι^yl- ιinophenyl)ethyl]amino, [2-(2-, 3- or 4-fluorophenyl)-l- (2-, 3- or 4-methylphenyl(ethyl]amino, [2-(2-, 3- or 4-fluorophenyl)-l-(2-, 3- or 4-methoxyphenyl)ethyl]amino, [2-(2-, 3- or 4-hydroxyphenyl)-l-

phenylethyljamino, [2-(2-, 3- or 4-aminophenyl)-phenylethyl]amino, [2- (2-, 3- or 4-dimethylammophenyl)-l-phenylethyl]amino, [l-(2-, 3- or 4- metiιoxyphenyl)-2-phenylethyl]amino, (l-methyl-1,2- diphenylethyDamino, (2,2-diphenylethyl)amino, (1,1- diphenylethyDamino, [l-(2-, 3- or 4-fluorophenyl)-l-(2-, 3- or 4- fluorophenyl)ethyl]amino, [l-(2-, 3- or 4-methylphenyl)ethyl]amino, [1- (2-, 3- or 4-methoxyphenyl)-l(2-, or 4-methoxyphenyl)amino, [l-(2-, 3- or 4-hydroxyphenyl)-l-phenylethyl]-m-ιino, [l-(2-, 3- or 4-aminophenyl)-l- phenylethyljamino, [l-(2-, 3- or 4-dimethylaminopheny)-l- phenylethyl]amino, tritylamino, (l-benzyl-2-phenylethyl)amino, (1- benzyl- l-methyl-2-phenylethyl)aminoH-benzyl-H-nιethylamino, N.- benzyl-N.-ethylamino, NOben-yl-N.-isopropyla_mino, N.-benzyl-N_- isobutylamino, N.-benzy-N.-t-butylamino, N.-(2-, 3- or 4-fluorobenzyD-ϋ- isopropylamino, _fcϊ-(2-, 3- or 4-chlorobenzyl)-M-isopropylamino, N.-(2-, 3- or 4-methylbenzyl)-ϋ-isopropylamino, H-(23- or 4-methoxybenzyl-N.- isopropylamino, H-(2-, 3- or 4-hydroxybenzyl)-H-isopr-, opylamino, M _» H- dibenzylamino, M-benzyl-N-(2-, 3- or 4-methoxybenzyl)amino, H-(2-, 3- or 4-fluorobenzyl)-N.-(2-, 3- or 4-fluorobenzyl)amino, H-(2-, 3- or 4- methylbenzyl)-H-(2-, 3- or 4-methylbenzyl)amino, M-(2-, 3- or 4- methoxybenzyl)-M-(2-, 3- or 4-methoxybenzyl)amino, H-(2-, 3- or 4- hydroxybenzyl)-H-(2-, 3- or 4-hydroxybenzyl)amino, ϋ-(2-, 3- or 4- -3Lminobenzyl)-M-(2-, 3- or 4-aιm^obenzyDamino, H-(2-, 3- or 4- d-Lmethylε-minobenzyl)-Ii-(2-, 3- or 4-dimethylammobenzyl(amino, [bis(2- or 3-fuτyl)methyl]amino, [bis(2-or3-thienyl)methyl]amino, [l,l-bis(2- or 3-tJ ienyDethyl]amino, [(2or5-methyl-2 or 3-thienyl),(2- or 5-methyl-2- or 3-tlιienyDmethyl]amino, [l-(2- or 3-thienyl)-l-methylethyl]amino, [l-(2- or 5-methyl-2 or 3-thienyl)-l-methylethyl]amino, [l-(2- or 3-furyl)-l- methylethyl]-amino, [l-(2- or 5-methyl-2- or 3-furyl)-l-methylethyl]- amino, [l-(2- or 3-furyl)-2-(2- or 3-furyl)ethyl]amino, [l-(2- or 3-furyl)-l- methylethyl]ειmino, [l-(2- or 3-thienyl)-2-(2- or 3-thienyl)ethyl]amino, [1- (2- or 3-furyl)-2-phenylethyl]amino, [2-phenyl-l-(2- or 3- tMenyl)ethyl]amino, [l-phenyl-2-(2- or 3-thienyl)ethyl]amino, [2-(2-, 3- or 4-methylphenyl)-l-(2- or 3-thienyl)ethyl]amino, [2-(2-, 3- or 4- chlorophenyl)-l(2- or 3-thienyl)ethyl]amino, [2-(2-, 3- or 4-fluorophenyl)- l-(2- or 3-thienyl)ethyl]amino, [2-(2-, 3- or 4-methoxyphenyl)-l-(2- or 3- thienly)ethyl]-mιino, H-(2- or 3-thienylmethyl)-H-(2- or 3- thienylmethyDamino, [l-(2-, 3- or 4-fluorophenyl)-2-(2- or 3-

thienyl)ethyl]anubim M'^ϊ'-diphenylhydrazino, N (2-, 3- or4- methylphenyD-ϋ'-phenylhydrazino, N. '-(2-, 3- or 4-methoxyphenyD-N.'- phenylhydrazino, N (2-, 3- or 4-chlorophenyl)-H'-pheήylhydrazino, N'-(2- , 3- or 4-fluorophenyl)-N phenylhyc azino, N (2-, 3- or 4- hydroxyphenyl)-NJ-phenymydrazino, NJ-(2-, 3- or 4-aminophenyD-N.'- phenylhydrazino, N (2-, 3- or 4-d-unethylaminophenyl)-NJ- phenylhydrazino, N.'-(2-, 3- or 4-acetamidophenyl)-N. ^l -phenylhydrazino, N (2-, 3- or 4-methylphenyl)-N (2-, 3- or 4-methylphenyl)hydrazino and N (2-, 3- or 4-methoxyphenyl)-H-(2-, 3- or 4-methoxyphenyl)hydrazino groups.

Still more preferred groups of formula -NR1R2 include: the (1- methyl-l-phenylethyl)amino, [l-methyl-l-(2-, 3- or 4- methylphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- methoxyphenyl)ethyl]amino, [l-methyl-l-(3,4- or 3,5- dimethoxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- fluorophenyl)ethyl]amino, [l-methyl-l(2-, 3- or 4- chlorophenyl)ethyl]amino,[l-methyl-l(2-, 3- or 4- hydroxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- cnmethylammophenyl)ethyl]amino, (l,l-dimethyl-2-phenylethyl)amino, benzhydrylamino, [(2-, 3- or 4-), (2 ^* -, 3'- or 4'-)- dimethylbenzhydryl]amino, [(2-, 3- or 4-), 2'-, 3'- or 4'-)- (Umethoxybenzhydryl]amino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- difluorobenzhydryllamino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- dichlorobenzhydryl]amino, (2-, 3- or 4-), (2'-, 3'- or 4'-)- dicMorobenzhydryl]amino, (2-, 3- or 4-methylbenzhydryl)amino, (2-, 3- or 4-methoxybenzhydryl)amino, (2-, 3- or 4-fluorobenzhydryl)amino, (2-, 3- or 4-chlorobenzhydryl)amino, (2-, 3- or 4-hydroxybenzhydryl)amino, (2-, 3- or 4-dimethylaminobenzhydryl)amino, (l,l-diphenylethyl)amino, (1,2- diphenylethyDamino, [2-(2-, 3- or 4-chlorophenyl)-l-phenylethyl]amino, [2-(2-, 3- or 4-fluorophenyl)-l-phenylethyl]amino, [2-(2-, 3- or 4- methylphenyl)-l-phenylethyl]amino, [2-(2-, 3- or 4-methoxyphenyl)-l- phenylethyl]amino, N^ϊ-dibenzylamino, H-(2-, 3- or 4-fluorobenzyl)-ϋ- (2-, 3- or 4-fluorobenzyl)amino, H-(2-, 3- or 4-methylbenzyl)-M-(2-, 3- or 4-methylbenzyl)amino, ϋ-(2-, 3- or 4-methoxybenzyl)-H-(2-, 3- or 4- metiioxybenzyDamino, [l-(2- or 3-thienyl)-l-(2- or 3- thienyl)methyl]amino, [2-phenyl-l-(2- or 3-thienyl)ethyl]amino, [1-

methyl-l-(2- or 3-thienyl)ethyl]amino, [l-methyl-l-(2- or 5-methyl-2- or 3-thienyl)ethyl]amino, [l-methyl-l-(2- or 3-furylethyl]amino, [1-methyl- l-(2- or 5-methyl-2-furyl)ethyl]amino, N ,N diphenylhydrazino, N'-(2-, 3- or 4-methoxyphenyl)-H-phenylhydrazino, N-(2-, 3- or 4-fluorophenyD-N.'- phenylhydrazino and N.'-(2-, 3- or 4-methoxyphenyl)-N. ^, -(2-, 3- or 4- methoxyphenyDhydrazino.

The most preferred groups of formula -NR1R2 include: the (1- methyl-l-phenylethyl)amino, [l-methyl-l-(2-, 3- or 4- methylphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- methoxyphenyl)ethyl]amino, [l-methyl-l-(3,4-or 3,5- dimethoxyphenyl)etiιyl]amino, [l-mehyl-l-(2-, 3- or 4- fluorophenyl)ethyl]amino, [l-methyl-l-(2-,3- or 4- chlorophenyl)ethyl]aιnino, [l-methyl-l-(2-, 3- or 4- hydroxyphenyl)ethyl]amino, [l-methyl-l-(2-, 3- or 4- cUmethylaminophenyl)ethyl]amino, (l,l-dimethyl-2-phenylethyl)amino, benzylamino, N-methyl-N-benzylamino, 1,1-diphenylmethyl amino, N- adamantylamino, benzyhydrylamino, [(2-, 3- or 4-), (2'-, 3'- or 4'-)- dimethylbenzylhydryl]amino,[(2-, 3- or 4-), (2'-, 3'- or 4'-)- dimethoxybenzhydryl]amino, [(2-, 3- or 4-), 2'-, 3'- or 4'-)- difluorobenzhydryl]amino,[(2-, 3- or 4-), (2'-, 3'- or 4'- dicMorobenzhydryl]amino, (2-, 3- or 4-methylbenzhydryl)amino, (2-, 3- or 4-methoxybenzhydryl)amino, (2-, 3- or 4-hydroxybenzhydryl)amino, (1,1- diphenylethyDamino, [l-methyl-l-(2- or 3-thienyl)ethyl]amino, [1- methyl-l-(2- or 5-methyl-2- or 3-thienyl)ethyl]amino, [l-methyl-l-(2- or 3-furylethyl]amino and [l-methyl-l-(2- or 5-methyl-2- or 3- furyl)ethyl]amino groups.

The compounds of the present invention may, depending upon the nature of the substituent groups, contain one or more asymmetric carbon atoms in their molecules, and in this case can form optical isomers. Although these are all represented herein by a single molecular formula, the present invention includes both the individual, isolated isomers and mixtures, including racemates thereof. Where stero spedfic synthesis techniques are employed or optically active compounds are employed as starting materials, individual isomers may be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques.

Also induded within the scope of this invention are compounds in which the 17 position substituent is in the α position.

Preferred classes of compounds of the present invention are those compounds of formula (I) and salts, esters and other functional derivatives thereof, in which:

(A) Rl represents: a hydrogen atom; an alkyl group having 3 carbon atoms; a benzyl group; a substituted benzyl group having at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups in which each alkyl part has from 1 to 4 carbon atoms, hydroxy groups, alkoxy carbonyl groups having from 2 to 5 carbon atoms and aliphatic acylamino groups having from 1 to 5 carbon atoms; a furylmethyl group; or a thienylmethyl group;

(B) R2 represents; a substituted alkyl group having from 1 to 4 carbon atoms and substituted by 1 or 2 substituents selected from phenyl groups, substituted phenyl groups, thienyl groups, furyl groups, substituted thienyl groups and substituted furyl groups, wherein the substituent or substituents on the phenyl group are selected from: alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, hydroxy groups, amino groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups in which each alkyl part has from 1 to 4 carbon atoms, alkoxycarbonyl groups having from 2 to 5 carbon atoms and aliphatic acylamino groups having from 1 to 5 carbon atoms; and the substituent or substituents on the thienyl and furyl groups are selected from alkyl groups having from 1 to 4 carbon atoms; or a diarylamino group, in which each aryl part is a carbocydic aromatic group which has from 6 to 10 ring carbon atoms and which is imsubstituted or is substituted by at least one substituent selected from alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, hydroxy groups, amino

groups, alkylamino groups having from 1 to 4 carbon atoms, dialkylamino groups in which each alkyl part has from 1 to 4 carbon atoms, alkoxycarbonyl groups having from 2 to 5 carbon atoms and aUphatic acylamino groups having from 1 to 5 carbon atoms; (C) R3 represents: a carboxy group; an alkoxycarbonyl group having from 2 to 5 carbon atoms; a substituted benzyloxycarbonyl group at least one substituent selected from methyl, ethyl, methoxy and ethoxy groups and fluorine and chlorine atoms; a naphthylmethoxycarbonyl group; a diphenylmethoxycarbonyl group; an alkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from

1 to 5 carbon atoms and the alkoxy part has from 1 to 4 carbon atoms; a cydoalkanecarbonyloxyalkoxycarbonyl group in which the cycloalkane part has from 5 to 7 carbon atoms and the alkoxy part has from 1 to 4 carbon atoms; and alkoxycarbonyloxyalkoxycarbonyl group in which each alkoxy part has from 1 to 4 carbon atoms; a cydoalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloalkyl part has from 5 to 7 carbon atoms and the alkoxy part has from 1 to 4 carbon atoms; a (5-phenyl- or 5-alkyl- 2-oxo-l,3-dioxolen-4-yl)-methoxycarbonyl group in which the alkyl part has from 1 to 4 carbon atoms; a phthalidyloxycarbonyl group; or a group of formula -CONHSθ2R^, wherein R^ represents an alkyl group having from 1 to 4 carbon atoms.

More preferred compounds of the present invention are those compounds of formula (I) and salts, esters and other functional derivatives thereof, in which:

(D) R! represents: a hydrogen atom; an isopropyl group; a benzyl group; a substituted benzyl group having at least one sustituent selected from methyl, ethyl, methoxy, ethoxy, hydroxy, ethoxycarbonyl, methoxycarbonyl, amino, methylamino, ethylamino, dimethylamino,

/3

diethylamino, formamido and acetamido groups and fluorine, chlorine and bromine atoms; or a thienylmethyl group; a substituted benzyl group having at least one substituent selected from methyl, ethyl, methoxy, ehtoxy, hydroxy, ethoxycarbonyl, methoxycarbonyl, amino, methylamino, ethylamino, diemthylamino, diethylamino, formamido and acetamido groups and fluorine, chlorine and bromie atoms; or a thienylmethyl group;

(E) R represents: a substituted alkyl group having from 1 to 4 carbon atoms and having 1 or 2 substituents selected from: phenyl groups; substituted pehnyl groups having at least one substituent selected from methyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, cUmethylamino, diethylamino, formamido and acetamido groups and fluorine, chlorine and bromine atoms; furyl groups; methyl-substituted furyl groups thienyl groups; and a diphenylamino group; or a substituted diphenylamino group having at least one substituent selected from methyl, ethyl, methoxy, ethoxy, hydroxy, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, ethylamino, dimethylamino,diethylamino, formamido and acetamido groups and fluorine, chlorine and bromine atoms;

(F) R3 represents: a carboxy group; an alkoxycarbonyl group having from 2 to 5 carbon atoms; a benzyloxycarbonyl group; an alkanoyloxyalkoxycarbonyl group in which the alkanoyl part has from

1 to 5 carbon atoms and the alkoxy part has 1 or 2 carbon atoms; a methoxycarbonyl or ethoxycarbonyl group which is substituted by an alkoxycarbonloxy group having from 2 to 5 carbon atoms; a cycloalkyloxycarbonyloxyalkoxycarbonyl group in which the cycloaklyl part has from 5 to 7 carbon atoms and the alkoxy part has 1 or 2 carbon atoms;

a (5-phenyl-, 5-methyl- or 5-ethyl-2-oxo-l,3-dioxolen-4- yDmethoxycarbonyl group; a phthaUdyloxycarbonyl group; or a group of formula -CONHS02R^, wherein R^ represents a methyl group or an ethyl group.

StiU more preferred compounds of the present invention are those compounds of formuls (I) and salts, esters and other functional derivatives thereof, in which:

(G)Rl and 2 are independently selected from benzyl groups and substituted benzyl geroups having at least one substituent selected from methyl, methoxy, hydroxy and acetamido groups and fluorine and chlorine atoms; or

(H) R! represents a hydrogen atom, and R2 represents: a substituted alkyl group having from 1 to 4 carbon atoms and having 1 or 2 substituents selected from: phenyl groups; substituted phenyl groups having at least one substituent selected from methyl, methoxy, hydroxy, dimethylamino and acetamido groups and fluorine and chlorine atoms; furyl groups and thienyl groups; a diphenylamino group; or a substituted diphenylamino group having at least one substitutent selected from methyl, methyoxy, hydroxy, dimethylamino and acetamido anf fluorine and chlorine atoms.

(I) R representa a carboxy group, a methoxycarbonyl group, an ethyxycarbonyl group, a pivaloyloxymethoxycarbonyl group, an ethyoxycarbonyl group, a l-(ethoxycarbonyloxy)ethoxycarbonyl group, an isopropoxycarbonyloxymethoxycarbonyl group, a 1- (isopropoxycarbonyloxy)ethoxycarbonyl group, a (5-methyl-2-oxo-l,3- dioxolen-4-yl)methoxycarbonyl group, a phthaUdyloxycarbonyl group or a group of formula -CONHSθ2R^, wherein R^ represents a methyl group.

The most preferred copounds of the present invention are those compounds of formula (I) and salts, esters and other functional derivatives thereof, in which:

(J) Rl represents a hydrogen atom, R2 represents adamantyl or an alkyl group having from 1 to 3 carbon atoms and substituted with 1 or 2 substituents selected from: phenyl, benzyl, substituted phenyl groups having at least one substituent selected from methyl, methoxy ad hydroxy groups and fluorine and chlorine atoms; furyl groups and thienyl groups;

(K) R represents a carboxy group, a methoxycarbonyl group or an ethoxycarbonyl group; (L) R represents a 2-hydroxyisopropyl group or a 1-carboxyethyl group having at least one substituent selected from aryl groups as defined above and aromatic heterocyclic groups as defined above. Specific examples of the compounds of the present invention include those of formula (I) in which Rl, and R3 are as shown in the foUowing Table 1. In the Table, the following abbreviations are used:

Ac acetyl

Bu butyl

Bz benzyl

Bzhy benzhydryl Et ethyl

Fur furyl

Me methyl

Mod (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl

Ph phenyl Phth phthaUdyl

Piv pivaloyl

Pr propyl iPr isopropyl

Thi thienyl

TABLE 1

Cpd. R ¹ R ² R3

No.

1 H 1,2-diPhEt COOH

2 H Bzhy COOH

3 H 1,1-diPhEt COOH

4 Bz Bz COOH

5 H l,2-di(2-Thi)Et COOH

6 H l,2-bis(4-FPh)Et COOH

7 H l,2-bis(4-MePh)Et COOH

8 H l,2-bis(4MeOPh)Et COOH

9 H l,2-bis(4-ClPh)Et COOH

10 H di(2-Thi)Ch- COOH

11 H l,2-di(2-Thi)Et COOMe

12 H bis(4-FPh)-CH- COOH

13 H bis(4-MePh)CH- COOH

14 H bis(4-MeOPh)CH- COOH

15 H 2-(4-MeOPH)-l-(2-Thi)Et COOH

16 H 2-(4-FPh)-l-(2-Thi)Et COOH

17 H 2-(4-MePh)-l-(2-Thi)Et COOH

18 H 2-(4-ClPh)-l-(2-Thi)Et COOH

19 H l-(2-Fur)-2-PhEt COOH

20 H 2-Ph-l-(2-Thi)Et COOH

21 H di(3-Thi)CH- COOH

22 H 2-(4-MePh l-PhEt COOH

23 H 2-(4-FPh)-l-(4-MePh)Et COOH

24 H 2-(4-MeOh)-l-PhEt COOH

25 H 2-(4-MeOPh)-l-(4-MeOPh)Et COOH

26 H l-Bz-4-PhBu COOH

27 H 4-ClBzhy COOH

28 H 4-MeOBzhy COOH

197 H l-Me-l-(3,4,5-triMeOPh)Et COOMe

198 H l-HOMe-l-(4-MeOPh)Et COOH

199 H l-HOOC-l-(4-MeOPh)Et COOH

200 H l-Me-l-(3,4,5-triMeOPh)Et COOH

201 H l-Me-l-(3,5-diNMe ₂ Ph)Et COOH

202 H Bz COOH

203 H 1,1-diPhMe COOH

204 H adamantyl COOH

205 H BzMe COOH

Of these, preferred compounds are Compounds No. 1, 2, 4, 5, 8, 9, 12, 14, 17, 19, 22, 27, 28, 29, 31, 33, 45, 48, 50, 64, 66, 67, 69, 73, 76, 78, 79, 82, 86, 88, 127, 130, 140, 142, 149, 152, 157, 159, 166, 168, 178, 180, 182, 190, 191, 192, 193, 194, 195, 196, 197, 200, 201, 202, 203, 204 and 205 and more preferred compounds are Compounds No. 1, 2, 4, 5„ 12, 14, 22, 27, 28, 31, 64, 66, 67, 76, 78, 127, 142, 145, 149, 159, 166, 178, 190, 192, 194, 195, 197, 200, 201, 202, 203, 204 and 205.

The most preferred compounds are Compounds No.

1. 17-[N-(l,2-Diphenylethyl)carbamoyl]estra-l,3,5(10)-triene- carboxyUc add;

2. 17-[N-(Diphenylmethyl)carbamoyl]estra-l,3,5(10)-triene- carboxylic add

14. 17-[N-(4,4 ^, -Dimethoxybenzhydryl)carbamoyl]estra-l,3,5(10)- triene-carboxyUc add 66. 17-[N-(l-Methyl-l-phenylethyl)carbamoyl]estra-l,3,5(10)-trie ne- carboxylic add

67. 17-{N-[l-Methyl-l-(2-thienyl)ethyl]carbamoyl}estra-l,3,5(10) - triene-carboxylic add

78. 17-{N-[l-(4-Fluorophenyl)-l-methylethyl]carbamoyl}estra- l,3,5(10)-triene-carboxylic add

127. 17B-[N-(4-Hydroxybenzhydryl)carbamoyl]estra-l,3,5(10)-triene - carboxyUc add

149. 17-{N-[l-(3,5-Dimethoxyphenyl)-l-methylehtyl]carbamoyl}estra - l,3,5(10)-triene-carboxyUc add 159. 17-CN-(Diphenylamino)carbamoyl]estra-l,3,5(10)-triene-carbox ylic add

166. 17-{N-[l-(3-Methoxyphenyl)-l(methylethyl]carbamoyl}estra- l,3,5(10)-triene-carboxylic add

168. 17-{N-[l-(2-Methoxyphenyl)-l-methylethyl]carbamoyl}estra- l,3,5(10)-triene-carboxylic add

178. 17-|^-(α,α-Dmethylfurfuryl)carbamoyl]estra-l,3,5(10)-trien e- carboxylic add

190. 17-{N-[l-(4-N,N-Dimethylaminophenyl)-l- methylethyl]carbamoyl}estra-l,3,5(10)-triene-carboxylic add 192. 17-{N-[l-(3,4-Dimethoxyphenyl)-l-methylethyl]carbamoyl}estra - l,3,5(10)-triene-carboxylic add

_M „, 33761

194. 17-{N-[M4-Ethoxyphenyl)-l-methylethyl]carbamoyl)estra- l,3,5(10)-triene-carboxyUc add

200. 17-{N-[l-Methyl-l-(3,4,5-trimethoxyphenyl)ethyl3carbamoyl}es tra- l,3,5(10)-triene-carboxyUc add

202. 17J3-(T^-Benzylcarbomoyl)-estra-l,3,5(10)-triene-3-carboxyUc add

203. 17β-(N-diPhenylmethylcarbomoyl)-estra- l,3,5(10)-triene-3- carboxyUc add

204. 17B-(N-Adamantylcarbamoyl)-estra-l,3,5(10)-triene-3-carboxyU c add

205. 17 ^β -(N-methyl-N-benzylcarbamoyl)-estra-l,3,5(10)-triene-3 - carboxyUc add and pharmaceutically acceptable salts and esters thereof.

The term "α-receptor antagonist", as used herein, refers to a known dass of alpha-andrenergic receptor antagonist comounds, such as described in Lafferty, et al. U.S. Patent No.4,963,547, which are utilized in treating vascular disorders such as diabetes, cardiovascular disease, benign prostatic hypertrophy and ocular hypertension.

Preferred alpha-andrenergic receptor antagonists for use in the compositions and methods of the invention indude amsulosin, terazosin, doxazosin, alfuzosin, indoramin, prazosin, 7-chloro-2-ethyl-3,4,5,6- tetrahydro^-methylthieno[4,3,2-efJ[3]-benzazepine and 8-{3-[4-(2- methoxyphenyl)-l-piperazinyl]-propylcarbamoyl}-3-methyl-4-ox o-2- phenyl-4H-l-benzopyran.

By the term "amsulosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically, amsulosin is designated as (-)-(R)-5-[2-[[2-(0- ethoxyphenoxy)ethyl]am o]propyl]-2-methoxybenzenesuffonamide.

Amsulosin is disdosed in U.S. Patent Number 4,703,063 and daimed in U.S. Patent Number 4,987,152 as being useful in treating lower urinary tract dysfunction.

By the term "terazosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically, terazosin is designated as l-(4-amino-6,7-dimethoxy- 2 qu-Lnazolinyl)-4-[(tetrahydro-2-furoyl)carbonyl]piperazine. Terazosin is disdosed in U.S. Patent Number 4,251,532.

By the term doxazosin as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically "doxazosin" is designated as l-(4-amino-6,7- dimethoxy-2-quinazolinyl)-4-[(2,3-cUhydro-l,4-benzoόioxin-2 - yl)carbonyl]-piperazine.

Doxazosin is disdosed in U.S. Patent Number 4,188,390.

By the term "alfuzosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

ChemicaUy alfuzosin is designated as N-[3-[(4-amino-6,7- dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2- furancarboxamide.

Alfuzosin is disclosed in U.S. Patent Number 4,315,007.

By the term "indoramin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically indoramin as designated N-[[l-[2-(lH-indol-3- yl)ethyll-4-piperidinyl]benzamine.

Indoramin is disclosed in U.S. Patent Number 3,527,761.

By the term "prazosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically prazosin is designated as l-(4-amino-6,7-dimethoxy-2- qumazolinyl)-4-(2-furanylcarbonyl)piperazine.

Prazosin is disclosed in U.S. Patent Number 3,511,836.

"7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2 -efl- [3]benzazepine" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2- efJ- [3]benzazepine is disclosed in U.S. Patent No. 5,006,521. Additionally, all compounds disdosed in U.S. Patent No. 5,006,521 as alpha- adrenergic receptor antagonist are preferred alpha-adrenergic receptor antagonist as used herein.

"8-{3-[4-(2-methoxyphenyl)-l-piperazinyl]-propylcarbamoyl }-3- methyl-4-oxo-2-phenyl-4H-l-benzopyran" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

8-{3-[4-(2-methoxyphenyl)-l-piperazinyl]-propylcarbamoyl} -3- methyl-4-oxo-2-phenyl-4H-l-benzopyran is disdosed in EPO Publn. No. 0558245 Al, to Leonardi, et al., (Recordati S.A.).

Additionally all compopunds disclosed in EPO Publn. No. 0558245 Al, as alpha-adrenergic receptor antagonists are preferred alpha- adrenergic receptor antagonists as used herein.

Persons skiUed in the art can readily determine if a compound other than one specifically referred to herein is a alpha-andrenergic receptor antagonist by utiUzing the assay described in Lafferty I. Thus, aU such compounds are included within the scope of the term "alpha- andrenergic receptor antagonist" as used herein.

By the term "minoxidir as used herein is meant the compound of the structure:

O

chemically minoxidil is designated as 2,4-pyrimidineadiamine, 6-(l- piperidinyl)-,3-oxide. Minoxidil is the active ingredient in Rogaine® which is sold as topical solution for stimulating hair growth by the Upjohn Company, Kalamazoo, Michigan.

The term "aromatase inhibitor", as used herein, refers to a known dass of compounds, steroidal and non-steroidal, which prevent the conversion of androgens to estrogens, such as described in Gormley et al.

International Publication Number WO 92 18132. Aromatase inhibitors are disdosed in Gormley et al. as having utility in treating benign prostatic hyperplasia when used in combination with a 5-α-reductase inhibitor. A preferred aromatase inhibitor for use in the compositions and methods of the invention 4-(5,6,7,8-tetrahydroimidazo-[l,5-α]pyridin-5- yDbenzonitrile (fadrazole). Fadrazole is disclosed in U.S. Patent No. 4,728,645. Additionally, all compounds disclosed in Gormley, et al. International Publication No. WO 92/18132 as having aromatase inhibiting activity are preferred aromatase inhibitors as used herein. As used herein, when a 5-α-reductase inhibitor, as described herein and a further active ingredient or ingredients are utilized together, said 5-α-reductase inhibitor can be co-administered with said further active ingredient or ingredients. By the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a 5-α-reductase inhibiting compound, as described herein, and a further active ingredient or ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocardnoma or compounds known to have utiUty when used in combination with 5-α-reductase inhibitors. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

The compounds of the present invention may be prepared by a variety of methods well known for the preparation of known compounds of this type. For example, formula (I) compounds can be prepared as shown in Schemes I through IV. As used herein Bβ is N 1R or moieties which can be converted to those of NR1R2 by chemical reactions readily is known to those of skill in the art, such as described in Derek Barton and U.D. Ollis, Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds. Pub: Pergamon Press (1979), provided that R * does not include any such moieties that

render inoperative the Schemes I through IV processes. As demonstrated in the foUowing Examples, reactions to convert Bβ to

NR1R2 are performed on products of the synthetic pathways of Schemes

I through TV or where appropriate or preferable, on certain intermediates in these synthetic pathways. For example, methylthio substituents can be converted to the methylsulfonyl by oxidation.

Methoxy substituents can be converted to the hydroxy by treatment with boron tribromide. Hydroxy substituents can be converted to the carboxy by reaction with a trihaloalkylsulfonic anhydride, such as trifluoromethanesulfonic anhydride, foUowed by a metal catalyzed coupling reaction.

The novel compounds of Formula (I) of the present invention can be prepared by methods outlined in schemes 1-4 below and in the

Examples from known and readily available estrone which has the formula:

or from the 17β-carboxylic add analogue of estrone, which is known and readily available.

(a)

(c)

(e)

(f)

Scheme I outlines formation of Formula I compounds. As used in scheme I compound (b) is prepared from compound (a) according to the procedure of Baldwin, et al., J. Chem. Soc. (c), 1968, 2283-2289.

Compound (b) is then stirred in an appropriate organic solvent, preferably methanol, with a base, preferably sodium hydroxide, and then addified to yield compound (c). Compound (c) is next treated with a Grignard reagent, described hereinbelow, in an appropriate organic solvent, preferably tetrahydrofuran or diethylether solvent, preferably at reflux temperature to yield formula (d) compounds.

A formula (d) compound and a base, preferably 2,5-di-t-butyl-3- methyl-pyridine in an appropriate organic solvent, preferably dichloromethane, is cooled to -20°C to 20°C, preferably 0°C, and reacted with a trihaloalkyl sulfonic anhydride, preferably trifluoromethanesulfonic anhydride to form compounds (e).

Formula (f) compounds are prepared by reacting a formula(e) compound in a metal catalyzed coupling reaction. Preferably a formula (e) compound dissolved in dimethylformide (DMF) an organic base preferably, triethylamine, a phosphine, preferably bis(diphenylphosphino)propane, a palladium(II) compound, preferably, palladium(π) acetate, and a Ci.galkyl alcohol (Ci.galkOH), foUowed by addition of carbon monoxide (CO). Compounds (f) next are reacted with a suitable base, preferably potassium carbonate, and addified to yield compounds (g).

As used herein the sulphonylamidation reaction may be carried out by reacting the corresponding carboxylic add, compounds of formula (g) in each of Schemes (I)-(IV), with an active esterifying agent to prepare an active ester, and then reacting this active ester with a compound of formula (LX):

MHNS0 R ⁴ (DC)

wherein R ⁴ represents an alkyl group in which the alkyl part has 1 to 4 carbons; and M represents an alkali metal, such as sodium or potassium. The compound of formula (IX) may be prepared by conventional procedures, for example by reacting the corresponding sulphonamide with an alkali metal alkoxide, such as sodium methoxide, sodium ethoxide or potassium t-butoxide, at a suitable temperature, e.g. at a bout room temperature, for an appropriate period, e.g. from 10 minutes to 3 hours, normally in an inert solvent, such as one of those

suggested hereafter for the reaction between the active ester and the compound of formula (IX).

The reaction between the active ester and the compound of formula (IX) may be carried out by reactin these compounds in an inert solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction and that it can dissolve the reagents, at least to some extet. Examples of suitable solvents include: amides, such as N.,H-dimetiιytformamide, H^-dimethylacetamide or hexamethylphosphoric tramide; sulphoxides, such as dimethyl sulphoxide; and ethers, such as tetrahydrofuran and dioxane.

The reaction will take place over a wide range of temperatures, and the predse reaction temperature chosed is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature in the range of from -20 to 100°C, more preferably from 0 to 50°C. The time required for the reaction may likewise vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, in most cases, a period of from 5 minutes to 10 hours, more preferably from 10 minutes to 3 hours, will normally suffice. After completion of the reaction, the desired compound can be coUected from the reaction mixture by conventional means. For example, one suitable recovery procedure comprises; removing the solvent by distillation under reduced pressure; adding water to the residue; and extracting the resulting mixture with a water-immisphate, the solvent may be distilled off, to give the desired compound. If necessary, the resulting compounds can be further purified by conventional means, such as recrystallisation or the various chromatography techniques, notably column chromatography.

SCHEME π

(d)

(h) palladium(ll)acetate ».

CO

Scheme II outlines formation of Formula I compounds. The starting materials in Scheme II are formula (d) compounds prepared as described in Scheme I.

As used in Scheme - , a formula (d) compound and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in an appropriate organic solvent, preferably dichloromethane, is cooled to -20°C to 20°C, preferably 0°, and reacted with fluorosuUbnic anhydride to form compounds (h). Formula (f) compounds are prepared by reacting a Formula (h) compound in a metal-catalyzed coupling reaction. Preferably a Formula (h) compound is dissolved in dimethylformide (DMF) an organic base preferably triethylamine, a phosphine preferably bis (diphenylphospine)propane, a palladium(II) compound, preferably, palladium(II) acetate, and a Ci.galkyl alcohol (C^galkOH), foUowed by addition of carbon monoxide (CO). Compounds (f) next are reacted with a suitable base, preferably potassium carbonate, and addified to yield compounds (g).

Scheme TTT

Scheme III outlines formation of Formula I compounds. As used in Scheme HI R ⁸ are as described above R ⁵ is CF3O2SO- or FO2SO-. As used in scheme III in the alkylation process (step C), the pyridylthio ester is reacted with an Ii-R^ or an XMgR ⁸ (X=C1, Br) Grignard reagent (as described hereinbelow).

In Route 1, the 3-hydroxyl add (i) is converted to the 3- trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (j) (step A)

by treating (i) with trifluoromethylsulfonyl anhydride or fluorosulfonic anhydride and an amine base, such as pyridine, preferably 2,5 di-t- butyl-3-methyl-pyridine, in an appropriate organic solvent, preferably dichloromethane at about -20°C to 20°C, preferably 0°. The activated ester (k) is produced (step B) by treating (j) with

2,2-dithiopyridyl and triphenylphosphine in an appropriate organic solvent solution preferably, tetrahydrofuran/toluene at room temperature for about 8-14 hours.

The 17-acyl derivative (1) is produced (step C) by treating (k) with a Grignard reagent, described hereinbelow, in tetrahydrofuran or diethyl ether solvent, at a temperature of about -50 to -70°C, for 1-16 hours.

The 3-alkyl ester (f) is produced (step D) by treating G) under carbonylation conditions, preferably by bubbling carbon monoxide gas through a solution of G) in an appropriate organic solvent, preferably methanol, containing palladium acetate catalyst, triphenylphosphine, and a tertiary organic amine preferably triethylamine at about room temperature for 1-16 hours. Compound (f) next are reacted with a suitable base, preferably potassium carbonate and addified to yield compounds (g).

Compounds (g) can also be produced (step G) by treating G) under carboxylation conditions, preferably by bubbling carbon monoxide gas through a solution of G) in an an appropriate non-alcoholic solvent, preferably DMSO, containing a paUadium catalyst, preferably paUadium (II) diacetate and l,l-Bis(diphenylphosphino)ferrocene (DPPF); and a base, preferably potassium acetate, preferably at increased temperatures.

Route 2 involves converting the starting steroidal add (i) to the 3- trifluoromethylsulfonylate or the 3-fluorosulfonylate derivative (j) by the above-described step A; carbonylating (j) to (m) by step D; forming the activated 2-pyridylthio ester (n) by step B; forming the 17-acyl compound (f) by step C; and hydrolyzing the 3-ester to the 3 add final product (g) by step F.

Route 3 involves converting the starting add (i) to the activated ester (o) by the above-described step B; forming the 17-acyl compound (d) by reacting (o) by the above described step C; converting (d) to the 3- trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (1) by the

above-described step A; and converting (1) to the final product (g) by the above described step G or by the above-described step D followed by the above described step F.

Scheme IV

Trifluoromethanesulfonic anhydride

(c)

hosphino)propane

acetate

(P)

iBugAIH

(q)

(Grignard Reagent)

(0

Oxidation

(s)

(9)

Scheme IV outlines formation of Formula I compounds.

As used in Scheme IV in the alkylation process (to prepare compounds of Formula (s)), the carboxaldehyde is reacted with an Li-R^ or an XMgRβ (x=Cl, Br) Grignard reagent (as described hereinbelow), The starting material in Scheme IV is Formula (c) compound prepared as in Scheme I.

As used in Scheme IV, a Formula (c) compound and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in an appropriate organic solvent, preferably dichloromethane, is cooled to -20°C to 20°C, preferably 0°C, and reacted with a trihaloalkyl sulfonic anhydride, preferably trifluoromethanesulfonic anhydride to form compounds (p). Formula (q) compounds are prepared by reacting a Formula (p) compound in a metal catalyzed coupling reaction. Preferably a Formula (p) compound dissolved in dήnethylfoπnide (DMF) and organic base preferably, triethylamine, a phosphine, preferably bis(diphenylphosphino)propane, a palladium(Ω) compound, preferably, paUadium(π) acetate, and a Cj-Cgalkyl alcohol (Ci-CgalkOH), followed by addition of carbon monoxide (CO). Formula (q) compounds are reacted with a redudng agent, preferably dnβobutylaluminum hydride, to yield Formula (r) compounds.

Formula (s) compounds are produced by treating Formula (r) compounds with a Grignard Reagent (as described in Scheme HI) in tetrahydrofuran or diethylether solvent, at a temperature of about -50° to -70°C, for 1-16 hours. Formula (g) compounds are prepared by oxidation of Formula (s) compounds. Preferably said oxidation will utilize a Jones reagent or tetrapropylamonium perruthenate followed by sodium chlorite.

Grignard reagents of the type, XMgR ⁸ , for aU of the spedes included within the scope of this invention, are available or can be made readily by one skilled in the art.

Formula I compounds in which the 17 position substitutent is in the α position are prepared from compounds which contain the corresponding β substituent by the General Method below.

General Method A

To a stirrred solution of a substituent 17β steroidal 5α-reductase inhibiting compound of Formula (I) in an appropriate solvent, preferably ethylene glycol or dimethyl sulfoxide, is added a base such as a hydroxide or alkoxide base, preferably sodium hydroxide, potassium hydroxide or sodium methoxide, at a temperature over 100°C preferably at reflux temperatures to yield the corresponding α epimer, after isolation and work up.

In determining the appropriate solvent for conducting the epimerization, dimethyl sulfoxide or other non-reactive high boiling solvents are preferred when the starting 17B 5α-reductase inhibiting steroidal compound contains reactive substituents or reactive unsaturated bonds that are, for example, subject to nucleophilic attack and ethylene glycol, or other reactive high boiling solvents can be used when the reactivity of the substituents or any unsaturated bonds of the starting 17B 5α-reductase inhibiting steroidal compound is not a consideration.

By the term "solvent" or "appropriate solvent" as used herein and the in the claims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, hexane, dimethylsulfoxide (DMSO), N,N'-dimethyl-N,N'-propylene urea, N-

methyl-2-pyrroUdinone, methanol, isopropylalcohol, dimethylformamide

(DMF), water, pyridine, quinoUne or ethanol.

Pharmaceutically acceptable salts, hydrates and solvates of

Formula (I) compounds are formed, where appropriate, by methods well known to those of sk-LU in the art.

Because the presently invented pharmaceutically active compounds inhibit steroid 5-α-reductase activity, they have therapeutic utiUty in treating diseases and conditions wherein decreases in DHT activity produces the desired therapeutic effect. Such diseases and conditions include acne vulgaris, seborrhea, female hirsutism, male pattern baldness, prostate diseases such as benign prostatic hypertrophy, and prostatic adenocardnoma.

In determining potency in inhibiting the human 5α-reductase enzyme, the following procedure is employed:

Preparation of membrane particulates used as source for recombinant steroid 5α-reductase isozvme 1.

Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5α-reductase isoenzyme 1 (Andersson, S., Berman, D.M., Jenkins, E.P., and Russell, D.W. (1991) Nature 354

159-161) are homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol, and 50 μM

NADPH (buffer A) using a Dounce glass-to-glass hand homogenizer

(Kontes Glass Co., Vineland, N.J.). Membrane particulates are isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol, and 50 uM NADPH (buffer B). The suspended particulate solution is stored at -80°C.

Preparation of prostatic membrane particulates used as source for steroid 5α-reductase isozvme 2.

Frozen human prostates are thawed and minced into small pieces ( Brinkmann Polytron (Sybron Corp., Westbury, New York). The solution is sonicated for 3 to 5 minutes with a Sonifier (Branson Sonic Power Co.) followed by hand homogenization in a Dounce hand homogenizer. Prostatic particles are obtained by differential centrifugation at 600 or 1000 x g for 20 minutes and 140,000 x g for 60

minutes at 4°C. The peUet obtained from the 140,000 x g centrifugation was washed with 5 to 10 tissue volumes of the buffer described above and centrifuged at 140,000 x g. The resulting pellet is suspended in buffer B and the particulate suspension was stored at -80°C.

Preparation of membrane particulates used as source for recombinant steroid 5-α-reductase isozvme 2.

Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5-α-reductase isozyme 2 are homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, ImM dithiothreitol, and 50 μM NADPH (buffer A) using a Douce hand homogenizer. Membrane particulates containing the recombinant human enzyme are isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, ImM dithiothreitol, and 50 uM NADPH (buffer B). The suspended particulate solution is stored at -80°C until used.

Assay for enzvmes activities and inhibitors potency.

A constant amount of [ C]testosterone (50 to 55 mCi/mmol) in ethanol and varying amounts of potential inhibitor in ethanol are deposited in test tubes and concentrated to dryness in vacuo. To each tube is added buffer, 10 uL (recombinant isoenzyme 1 or isoenzyme 2) or 20 uL (isoenzyme 2 from human prostate tissue) of 10 mM NADPH and an aliquot of a steroid 5α-reductase preparation to a final volume of 0.5 mL. Assays for human steroid 5α-reductase isoenzyme 1 are conducted with a sample of the recombinant protein expressed in CHO cells in 50 mM phosphate buffer, pH 7.5 while assays of isoenzyme 2 are conducted with a suspension of human prostatic particulates and/or recombinant protein expressed in CHO cells in 50 mM ritrate buffer at pH 5.0. After incubating the solution at 37°C for 20 or 30 minutes the reaction is quenched by the addition of 4 mL ethyl acetate and 0.25 umol each of testosterone, 5α-dihydrotestosterone, androstanediol, and androstanedione as carriers. The organic layer is removed to a second test tube and evaporated to dryness in a Speed Vac. The residue is dissolved in 40 uL chloroform, spotted on an individual lane of a 20 x 20 cm prechannelled siUca gel TLC plate (Si 250F-PA, Baker Chemical) and developed twice with acetonexhloroform (1:9). The radiochemical

content in the bands of the substrate and the products are determined with a BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C.). The percent of recovered radiolabel converted to product is calculated, from which enzyme activity is determined. All incubations are conducted such that no more than 20% of the substrate (testosterone) is consumed.

The experimentaUy obtained data is computer fit to a linear function by plotting the redprocal of the enzyme activity (1/velodty) against the variable inhibitor concentration; apparent inhibition constants (Kj _a pp) are determined by the Dixon analysis (Dixon, M. (1953).

The value for the inhibition constant Ki) is calculated from known procedures (Levy, M. (1989), Biochemistry.22:2815-2824).

All of the compounds within the scope of this invention are useful in inhibiting steroid 5-α-reductase in a mammal, including humans, in need thereof.

Compounds within the scope of this invention have been tested and have shown an activity of from 25-30 Ki(nM) to 400 Ki(nM) against isozyme 1 and an activity of from 0.5 Ki(nM) to 1-2 Ki(nM) against isozyme 2.

Particularly preferred among the compounds of the invention and the compounds used in the invented pharmaceutical compositions and invented methods are

17B-(N-Benzylcarbomoyl)-estra-l,3,5(10)-triene-3-carboxyl ic add 17B-(N-di Phenylmethylcarbomoyl)-estra-l,3,5(10)-triene-3- carboxyUc add

17 ^β -(N-Adamantylcarbamoyl)-estra-l,3,5(10)-triene-3-carbo xylic add

17 ^β -(N-methyl-N-benzylcarbamoyl)-estra-l,3,5(10)-triene-3 - carboxyUc add

The pharmaceutically active compounds of the present invention are preferably incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calrium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acada, magnesium stearate, and stearic add. Liquid carriers

include syrup, peanut oil, oUve oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of soUd carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation wfll preferably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous Uquid suspension.

The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingreidents, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficadous, nontoxic quantity preferably selected from the range of 0.01 - 1000 mg/kg of active compound, preferably 0.1 - 100 mg/kg. When treating a human patient in need of steroid 5-α-reductase inhibition, the selected dose is administered preferably from 1-6 times daily, orally or parenteraUy. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.1 to 500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

The method of this invention of inhibiting steroid 5-α-reductase activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective steroid 5-α-reductase inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in the inhibition of steroid 5-α-reductase. The invention also provides for a pharmaceutical composition for use in the treatment of benign prostate hypertrophy which comprises a compound of Formula I and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of prostatic adenocarcinoma which comprises a compound of Formula I and a pharmaceutically acceptable carrier.

The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises bringing the compound of Formula I into assodation with the pharmaceutically acceptable carrier or diluent.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocardnoma or compounds known to have utility when used in combination with 5-α-reductase inhibitors. Particularly preferred is the co-administration of a 5-α-reductase inhibitor, as disclosed herein, and minoxidil for use in the treatment of male pattern baldness. Particularly preferred is the co-administration of a 5α-reductase inhibitor, as disclosed herein, and a α-receptor antagonist for use in the treatment of benign prostatic hypertrophy. Preferred is the co-administration of a 5-α-reductase inhibitor, as disdosed herein, and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy. Preferred is the co-administration of a 5- α-reductase inhibitor, as disclosed herein, a α -receptor antagonist and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.

Without further elaboration, it is believed that one skiUed in the art can, using the preceding description, utilize the present invention to its fuUest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Example 1

Preparation ofl7β-(chlorocarboxvlVestra-1.3.5fl0)-3-(acetoxvmethvn trisns.

a) 17β-(formyl)-estra-l,3,5(10)-3-(acetoxymethyl) triene 4-dimethylamino pyridine (8.8 mg, 0.072 mmol) and triethylamine

(293 mg, 2.89 mmol) were added to a solution of 17β-(formyD-estra- l,3,5(10)-3-(hydroxymethyl) triene (431.8 mg, 1.45 mmol) in CH2CI2 (20 mL) at room temperature under argon. Next a solution of acetic anhydride (295 mg, 2.89 mmol) in CH2CI2 (5 mL) was added dropwise and the reacton mixture was stirred for 2.0 h at room temperature. The reaction mixture was washed with 5% HC1, H2O, brine, dried (magnesium sulfate), and concentrated in vacuo to afford the title compound as a slightly yellow solid (480 mg, 97%); ^Ϊ H NMR (CDCI3, 400 MHz): δ 0.8 (s, 3H), 2.1 (s, 3H), 5.05 (s, 2H), 7.1 (s, 1H), 7.16 (d, 2H), 7.3 (d, 1H), 9.82 (d, 1H); MS (ES/NH3) m/e 358 [M+NH4J+. b) 17β-(carboxyl)-estra-l,3,5(10)-3-(acetoxymethyl) triene To a stirred mixture of 17β-(formyl)-estra-l,3,5(10>3- (acetoxymethyl) triene (474 mg, 1.39 mmol), tert- butyl alcohol (15 mL), and 2-methyl-2-butene (976 mg, 13.92 mmol, 7.0 mL of 2.0 M solution) at 0°C was added a solution of sodium chlorite (1.26 g, 13.9 mmol) and sodium phospate monobasic monohydrate (1.92 g, 13.92 mmol) in H2O (5.0 mL). The mixture was warmed to room temperature and stirred for 5.0 h. HOAc (1.0 mL) and saturated NaCl were added and the mixture was extracted with EtOAc (2x50 mL), dried (sodium sulfate), concentrated in vacuo, and flash chromatographed (silica gel, 99:1 CHCI3 HOAC) to afford the title compound as a white soUd (400 mg, 81%); !H NMR (CDCI3, 400 MHz): δ 0.78 (s, 3H), 2.1 (s, 3H), 5.05 (s, 2H), 7.1 (s, 1H), 7.15 (d, 1H), 7.32 (d, 1H); MS (ES) m/e 355 [M-HJ+. c) 17β-(chlorocarboxyl)-estra-l,3,5(10)-3-(acetoxymethyl) triene

Oxalyl chloride (1.42 g, 11.22 mmol) was added to a solution of 17β-(carboxyl)-estra-l,3,5(10)-3-(acetoxymethyl) triene (400 mg, 1.12 mmol) in CH2CI2 at 0°C. The reaction was warmed to room temperature over 1 h and concentrated in vacuo to afford the title compound as a yeUow solid (380.7 mg, 915); *H NMR (CDCI3, 400 MHz): δ 0.83 (s, 3H), 2.1 (s, 3H), 2.98 (t, 1H 17αH), 5.05 (s, 2H), 7.1 (s, 1H), 7.15 (d, 1H), 7.3 (d, 1H); IR (thin film) 1790 cm" ¹ .

Example 2

Preparation of 17(V(N-nHflmantvlcarbamovD-estra-1.3.5(10)-triene-3- carboxylic add a) 17β-(N-adamantylcarbamoyl)-estra-l,3,5(10)-3- (acetoxymethyl) triene 1-aminoadamantane hydrochloride (93.9 mg, 0.5 mmol), triethylamine (101.2 mg, 1.0 mL), and 4-dimethylaminopyridine (3 mg, 0.025 mmo) were added to a solution of 17β-(chlorocarboxyl)-estra- l,3,5(10 3-(acetoxymethyl) triene ( 189.7 mg, 0.5 mmol) in CH2CI2 (15 mL) at room temperature under argon. The reaction was stirred for 4.5 h at ambient tempreature. The mixture was washed with 5% HCl, H2O, brine, dried (magnesium sulfate), concentrated in vacuo and flash chromatographed (silica gel, 2:1 hexane/EtOAc) to afford the title compound as a white foam (153 mg, 63%); !H NMR (CDCI3, 400 MHz): δ 0.72 (s, 3H), 2.1 (s, 3H), 5.0 (br s, 1H, NH), 5.05 (s, 2H), 7.1 (s, 1H), 7.15 (d, 1H), 7.3 (d, 1H); MS (ES) m/e 490 [M+H]+- b) 17β-(N-adamantylcarbamoyl)-estra-l,3,5(10)-triene-3- (hydroxymethyl) triene

To a suspension of 17β-(N-adamantylcarbamoyl)-estra-l,3,5(10)- triene-3-(acetoxymethyl) triene (153 mg, 0.31 mmol) in 10 mL of 9:1 CH3θH:H2θ was added l.ON NaOH (13.7 mg, 0.343 mmol, 0.343 mL) and the reaction was stirred at ambient temperature for 2.0 h. The reaction was addified to pH 3.0 using l.ON HCl and the solvent was removed in vacuo. The reaction was dissolved in CH2CI2, washed with H2O, dried (magnesium sulfate), concentrated in vacuo, and flashed chromatographed (silic gel, 2:1 hexane EtOAc) to afford the title compound as a white soUd (65 mg, 46%). *H NMR (CDCI3, 400 MHz): δ 0.72 (s, 3H), 4.63 (d, 2H), 5.0 (br s, 1H, NH), 7.1 (s, 1H), 7.15 (d, 1H), 7.28 (d, 1H); MS (ES) m/e 448 [M+H]+. c) 17p^(N-adamantylcarbamoyl)-estra-l,3,5(10)-triene-3- carboxylic add

Jones reagent was added to a solution of 17β-(N- adamantylcarbamoyl)-estra-l,3,5(10)-triene-3-(hydroxymethyl) triene (65 mg, 0.145 mmol) in acetone at 0°C until an orange color persisted and the reaction was allowed to warm to room temperature over 1.5 h. Isopropanol was added until green color persisted. The reacton mixture was filtered through celite, concentrated in vacuo, and flash chromatographed (silica gel, 1:2:97 HOAC CH3OH/CHCI3) to affor dthe

title compound as a white soUd (46.5 mg, 70%). *H NMR (CDCI3, 400 MHz): δ 0.75 (s, 3H), 5.0 (br s, IH, NH), 7.37 (d, IH), 7.82 (s, IH), 7.86 (d, IH); MS (ES) m/e 462 [M+H]+; mp: >260°C; Anal. (C30H30NO3) calcd: C, 78.05; H, 8.52; N, 3.03. found: C, 75.45: H, 8.32: N, 2.76.

Example 3

Preparation of 17β-(N-diPhenvlmethvlcarbomovl)-estra-1.3.5(10)-triene-

3-carboxvlic add a) 17β-(N-diPhenylmethylcarbomoyl)-estra-l,3,5(10)-3- (acetoxymethyl) triene

Following the procedure of Example 2(a), except substituting aminodiphenylmethane hydrochloride, the title compound was prepared as a white soUd (110 mg, 41%). H NMR (CDCI3, 400 MHz): δ 0.70 (s, 3H), 5.04 (s, 2H), 5.95 (d, IH), 6.31 (d, IH); MS (ES) m/e 522 [M+HJ+. ^b ) 17β-(N-diPhenylmethylcarbomoyl)-estra-l,3,5(10)-3-

(hydroxymethyl) triene

FoUowing the procedure of Example 2(b), the title compound was prepared as a white soUd (61.3 mg, 61.3%). *H NMR (CDCI3, 400 MHz): δ 0.70 (s, 3H), 2.88 (m, 2H), 4.62 (s, 2H), 5.97 (d, IH), 6.31 (d, IH), 7.09 (s, IH); MS (ES) m/e 480 [M+H]+. c) 17p^(N ^{^} -diPhenylmethylcarbomoyl)-estra-l,3,5(10)-triene-3- carboxylic add

FoUowing procedure of Example 2(c) the title compound was prepared as a white soUd (15 mg, 40% ). *H NMR (CDCI3, 400 MHz): δ 0.71 (s, 3H), 5.96 (d, IH), 6.31 (d, IH), 7.27 (m, 5H), 7.34 (m, 5H), 7.37 (d, IH), 7.82 (s, IH), 7.86 (d, IH); MS (ES) m/e 494 [M+H]+; mp: 170-172°C; Anal. (C33, H35, N, O3) calcd: C, 80.29: H, 7.15; N, 2.84. found C, 77.11; H, 6.93; N, 2.55.

Example 4

Preparation of 17B-(carboxvl)-estra-1.3.5(10)-3-ftert-butyl dimethyl silvloxvmethvl) triene a) 17β-(formyl)]-estra-l,3,5(10)-3-(tert-butyl dimethyl silyloxymethyl) triene Tert-butyl-dimethylsilyl chloride (167 mg, 1.11 mmol), triethylamine (112 mg, 1.11 mmol), and 4-dimethylamino pyridine (12.2 mg, 0.1 mmol) was added to a solution of 17β-(formyl)]estra-l,3,5(10)-3-

(hydroxymethyl) triene (300 mg, 1.0 mmol) in CH2CI2 (15 mL) at room temperature under argon and the mixture was stirred for 24 h. The reaction was concentrated in vacuo and flash chromatographed (silica gel, 100% CHCI3) to afford the title compound as a white soUd (335 mg, 77%); !H NMR (CDCI3, 400 MHz): δ 0.1 (s, 6H), 0.8 (s, 3H), 0.95 (s, 9H), 4.69 (s, 2H), 7.03 (s, IH), 7.1 (d, IH), 7.25 (d, IH), 9.80 (d, IH); MS (ES) m/e 411 [M-H]+. b) 17β-(carboxyl)-estra-l,3,5(10)-3-(tert-butyl dimethyl silyloxymethyl) triene To a stirred mixture of 17β-(formyl)-estra-l,3,5(10)-3-(tert-butyl dimethyl silyloxymethyl) triene (235.1 mg, 0.57 mmol), tert-butyl alcohol (9mL), and 2-methyl-2-butene (400 mg, 0.57 mmol, 2.85 mL of 2.0M solution) at 0°C was added to a solution of sodium chlorite (516 mg, 5.7 mmol) and sodium phospate monobasic monohydrate (787 mg, 5.7 mmol) in H2O (3.0 mL). The mixture was warmed to room temperature and stirred overnight. HO Ac (1.0 mL) and saturated NaCl were added and the mixture was extracted with EtOAc (2x30 mL), dried (sodium sulfate), concentrated in vacuo, and triturated with hexane to afford the title compound as a white soUd (155 mg, 64%). H NMR (CDCI3, 400 MHz): δ 0.1 (s, 6H), 0.18 (s, 3H), 0.91 (s, 9H), 4.67 (s, 2H), 7.03 (s, IH), 7.1 (d, IH), 7.25 (d, IH); MS (DCI NH3) m e 446 [M+NH41+.

Example 5 Preparation of 17B-(N-benzvlcarbamovl)-estra-1.3.5(10Vtriene-3- carboxvlic add a) 17β-(benzylcarbamoyl)-estra-l,3,5(10)-3-(tert-butyl dimethyl silyloxymethyl) triene

1,3-dicyclohexylcarbodiimide (20.9 mg, 0.1 mmol), 1- hydroxybenzotriazole (13.7 mg, 0.1 mmol), and benzylamine (10.8 mg, 0.1 mmol) were added to a solution of 17β-(carboxyl)-estra-l,3,5(10)-3- (tert-butyl dimethyl silyloxymethyl) triene (39.3 mg, 0.029 mmol) in CH2CI2 (10 mL) and stirred at ambient temperature for 24 h under argon. The reaction was filtered through a glass fritted funnel, concentrated in vacuo, and flash chromatographed (silica gel, 100% CHCI3) to afford the title compound as a white solid (35.5 mg, 75%). H NMR (CDCI3, 400 MHz): δ 0.1 (s, 6H), 0.77 (s, 3H), 0.95 (s, 9H), 4.4-4.55

(ddd, 2H), 4.69 (s, 2H), 5.68 (t, IH, NH). 7.05 (s, IH), 7.1 (d, IH), 7.25 (d, lH)7.27-7.4 (m, 5H); MS (DCIZNΗ3) m/e 518 [M+H]+. b) 17β-G>enzylcarbamoyD-estra-l,3,5(10)-3-(hydroxymethyD triene To 17β-(benzylcarbamoyl)-estra-l,3,5(10)-3-(tert-butyl dimethyl silyloxymethyl) triene (33.3 mg, 0.064 mmol) in THF (3.0 mL) was added tetrabutyl ammonium fluoride (8.4 mg, 0.32 mmol, 0.32 mL of 1.0M solution in THF). The reaction mixture was stirred at ambient temperature for 5.0 h under argon. The reaction was concentrated in vacuo, and the residue was dissolved in EtOAc, washed with H2O, brine, dried (magnesiun sulfate), concentrated in vacuo, and flash chromatographed (silica gel 9:1 CHCI3/CH3OH) to afford the title compound as a white solid (18 mg, 70%); *H NMR (CDCI3, 400 MHz), δ 0.75 (s, 3H), 4.4-4.55 (ddd, 2H), 4.62 (s, 2H), 5.67 (t, IH). 7.1 (d, IH), 7.12 (d, IH), 7.28-7.4 (m, 6H); MS (DCI/NH3) m/e 404 [M+H]+ c) 17β-(N-benzylcarbamoyl)-estra-l,3,5(10)-triene-3- carboxcylic add

FoUowing the procedure of Example 2(c) the title compound was prepared as a white soUd (14.5 mg, 84%). !H NMR (CDCI3, 400 MHz): δ 0.75 (s, 3H), 4.4-4.55 (ddd, 2H), 5.67 (t, IH), 7.28-7.4 (m, 6H), 7.82 (s, IH), 7.85 (d, IH); MS (DCI NH3) m/e 418 [M+H]+; mp: 123-125°C; Anal. (C27H31NO3) calcd: C, 77.67; H, 7.48; N, 3.35. found: C, 72.80; H, 7.06; N, 2.90.

Example 6

Preparation of 17β-(n-benzvlmethvlcarbamovl)-estra-1.3.5(10)-triene-3- carboxvlic add

a) 17β-(N-benzylmethylcarbamoyl)-estra-l,3,5(10)-3-(tertbutyl dimethylsilyloxymethylHriene

FoUowing the procedure of Example 5a), except substituting N- benzylmetiiylamine for benzylamine, the title compound was prepared

(33.0 mg, 35% ). *H NMR (CDCI3, 400 MHz): δ 0.85 (s, 3H), 0.93 (s, 3H), 4.67 (s, 2H), 7.03 (d, IH), 7.09 (d, IH), 7.15 (d, IH), 7.27 (mm, 3H), 7.35

(mm, 2H); MS (PCI/NH3) m/e 532 [M+H]+.

b) 17β-(N-benzylmethylcarbamoyl)-estra-l,3,5(10)-3- (hydroxymethyDtriene

FoUowing the procedure of Example 5b),the title compound was prepared as a white soUd (22.3mg, 88%). *H NMR (CDCI3, 400 MHz): δ 0.83 (s, 3H), 2.94 (minor rotamer, s, 3H, 35%), 3.00 (major rotamer, s, 3H, 65%), 4.32 (d, d IH), 4.62 (s, 2H), 5.00 (d, d 1H)7.09 (d, IH), 7.13 (m, 2H), 7.27 (m, 3H), 7.35 (mm, 2H); MS (OCI/NH3) m/e 418 [M+H]+. c) 17β-(N-benzylmethylcarbamoyl)-estra- l,3,5(10)-triene-3- carboxcyUc add FoUowing the procedure of Example 2c) the title compound was prepared as a white solid (6.9 mg, 32% overall); H NMR (CDCI3, 400 MHz): δ 0.87 (s, 3H), 2.95 (N-CH3, minor rotamer, 35%, s, 3H), 3.02 (N- CH3, major rotamer, 65%, s, 3H), 4.35(d, d, IH), 5.02 (d, d, IH), 7.28-7.4 (m, 5H), 7.86 (m, 2H); MS ΦCI/MΗ3) m/e 432 [M+H]+; mp: 127-129°C;.

FORMULATION Scored tablets for oral use, eachcontaining 250 mg of the active substance, are manufactured as follows:

Composition (for 10,000 tablets)

17β-[N-(l,2-Diphenylethyl)carbomoyl] 2500 g -estra-l,3,5,( 10)-triene-3-carboxyUc add corn starch 275 g talc powder 187 g caldum stearate 38 g

The active substance is granulated with a 4%w/v aqueous solution of methyl ceUulose.

To the dried granules a mixture of the remainder of the ingredients is added and the final mixture compressed into tablets of proper weight.

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the predse instructions herein disclosed and that the right to all modifications coming within the scope of the foUowing claims is reserved.