HK1055974B - 9.alpha.-chloro-6.alpha.-fluoro-17.alpha.-hydroxy-16-methyl-17-beta-methoxycarbonyl-androst-1,4-dienes esterified in position17.alpha.by a cyclic acyl group - Google Patents

Description

9 alpha-chloro-6 alpha-fluoro-17 alpha-hydroxy-16-methyl-17 beta-methoxycarbonyl-androst-1, 4-dienes esterified at the 17 alpha position by a cyclic acyl group

The present invention relates to organic compounds, their preparation and their use as pharmaceuticals.

In one aspect, the invention provides a compound of the formula

Wherein R is a monovalent cyclic organic group having 3 to 15 atoms in the ring system.

The terms used in the specification have the following meanings:

“C₁-C₄by alkyl is meant a straight or branched chain C₁-C₄-alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

“C₁-C₄-alkylamino "means C as defined above₁-C₄-alkyl substituted amino.

"(di-C)₁-C₄-alkyl) amino "means C as defined above₁-C₄-alkyl disubstituted amino.

“C₁-C₄-alkylsulfonyl "means C as defined above₁-C₄-alkyl substituted sulfonyl.

"halo-C₁-C₄-alkyl "means C as defined above substituted by one or more, preferably two or three halogen atoms, preferably fluorine or chlorine atoms₁-C₄-an alkyl group.

"hydroxy-C₁-C₄-alkyl "means C as defined above substituted by one or more, preferably 1, 2 or 3, hydroxy groups₁-C₄-an alkyl group.

“C₁-C₄By alkoxy is meant a straight or branched chain C₁-C₄-alkoxy and can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

“C₁-C₄-alkoxycarbonyl "means a radical C as defined above₁-C₄-alkoxy-substituted carbonyl and can be methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl.

“C₁-C₄Alkylthio is understood to mean a straight-chain or branched C₁-C₄Alkylthio, and can be methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio.

“C₁-C₄-acyl "means C as defined above₁-C₄-alkoxy-substituted carbonyl.

“C₁-C₄-acyloxy "means C as defined above₁-C₄-alkoxy-substituted carbonyloxy.

“C₁-C₄By acylamino "is meant a formyl group or C as defined above₁-C₄Acyl-substituted amino.

R may be a carbocyclic group or a heterocyclic group having one or more heteroatoms selected from nitrogen, oxygen and sulfur. In one embodiment, R is a cycloaliphatic radical having from 3 to 8 carbon atoms, e.g., C₃-C₈Cycloalkyl radicals such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl or cycloheptyl, preferably C₃-C₆-a cycloalkyl group.

In another embodiment, R is an at least partially saturated heterocyclic group having 5 to 10 ring atoms, wherein one or more ring atoms are a ring heteroatom selected from nitrogen, oxygen and sulfur, said heterocyclic group preferably having 5 to 7 ring atoms, wherein one or two ring atoms are heteroatoms selected from nitrogen and oxygen, especially a 5-membered heterocyclic group having one ring heteroatom, such as tetrahydrofuranyl or oxotetrahydrofuranyl.

In another embodiment, R is a carbocyclic or heterocyclic aryl group having 5 to 15 atoms in the ring system. For example, R may be an aryl group wherein the ring system is unsubstituted or substituted with one or more substituents selected from: halogen, cyano, C₁-C₄-alkyl, halo-C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄Alkylthio, hydroxy, C₁-C₄-acyl group, C₁-C₄-acyloxy, amino, C₁-C₄Alkylamino, di- (C)₁-C₄-alkyl) amino, C₁-C₄-acylamino, C₁-C₄-acyl (C)₁-C₄-alkyl) amino, C₁-C₄-alkylsulfonyl (C)₁-C₄-alkyl) amino, C₁-C₄-alkoxycarbonyl, or a 5-membered heterocyclic group, typically an N-heterocyclic group having one or two nitrogen atoms. One preferred class of such heterocyclyl groups is phenyl or naphthyl optionally substituted with one or more, preferably 1, 2 or 3 substituents selected from: cyano radicals, C₁-C₄-alkyl, halo-C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen, hydroxy, C₁-C₄-acyloxy, amino, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino radical, C₁-C₄-acylamino, C₁-C₄-acyl (C)₁-C₄Alkyl) amino, C₁-C₄Alkylsulfonyl (C)₁-C₄Alkyl) amino or C₁-C₄Alkoxycarbonyl, particularly preferred such aryl groups include phenyl, cyanophenyl, tolyl, dimethylphenyl, ethylphenyl, (trifluoromethyl) phenyl, dimethoxyphenyl, diethoxyphenyl, hydroxyphenyl, (methylamino) phenyl, (methylsulfonylmethylamino) phenyl and (methoxycarbonyl) phenyl.

Another preferred class of such aryl groups are 6-membered heterocyclic aryl groups having 1, 2 or 3 ring heteroatoms, preferably nitrogen, which heterocycles are unsubstituted or substituted by one or more, preferably 1, 2 or 3 substituents selected from the group consisting of: halogen, cyano, hydroxy, C₁-C₄-acyloxy, amino, C₁-C₄Alkylamino, di- (C)₁-C₄-alkyl) amino, C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, halo-C₁-C₄Alkyl radical, C₁-C₄-alkoxy, or C₁-C₄-alkylthio, and said heterocycle is optionally fused to a benzene ring. Preferred such heterocyclic aryl groups include those in which the heterocyclic group has one or two nitrogen atoms in the ring, especially a pyridine, pyrimidine, pyrazine or pyridazine ring. Particularly preferred heterocyclic aryl groups are pyridyl, pyrimidinyl and pyrazinyl, said heterocyclic aryl groups being optionally substituted with one or two substituents selected from the group consisting of: halogen (especially chlorine) or C₁-C₄-alkyl (especially methyl or n-butyl).

Another preferred class of such aryl groups are heterocycloaryl groups having a 5-membered heterocycle with 1, 2 or 3 ring heteroatoms selected from nitrogen, oxygen and sulfur, which heterocycle is unsubstituted or substituted with one or two substituents selected from: halogen, C₁-C₄-alkyl, halo-C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄Alkylthio, cyano and hydroxy-C₁-C₄-an alkyl group, and the heterocyclic ring is optionally fused with a benzene ring. Preferred such heterocyclic aryl groups include those in which the heterocyclic ring has one nitrogen, oxygen or sulfur atom in the ring, or one oxygen atom and one or two nitrogen atoms in the ring, or one sulfur atom and one or two nitrogen atoms in the ring, especially pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, furazan, thiazole or thiadiazole rings. Particularly preferred heterocyclic aryl groups are pyrrolyl, furanyl and thienyl, said heterocyclic aryl groups being optionally substituted with one or two substituents selected from the group consisting of: halogen (especially chlorine or bromine), C₁-C₄Alkyl (especially methyl or ethyl), halo-C₁-C₄Alkyl (especially trifluoromethyl), C₁-C₄Alkoxy (especially methoxy), C₁-C₄Alkylthio (especially methylthio), cyano or hydroxy-C₁-C₄-alkyl (in particular hydroxymethyl); isoxazolyl, imidazolyl, pyrazolyl, thiazolyl or thiadiazolyl, said heterocyclic aryl optionally being substituted by one or two C₁-C₄-alkyl substitution; and benzeneFuryl, benzothienyl and benzofurazanyl.

In the compounds of formula I, the methyl group at position 16 of the corticosteroid ring system may be in the α or β conformation. 16-alpha-methyl compounds are preferred.

Compounds of formula I wherein R contains a basic group are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compounds of formula I include the salts of the following acids: inorganic acids, for example hydrohalic acids, such as hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts can be prepared from the compounds of formula I by known salt-forming methods.

Particularly preferred compounds of formula I include the compounds described in the examples below, in particular the compounds of examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101.

In another aspect, the present invention provides a process for the preparation of a compound of formula I, said process comprising

(A) Reacting a carboxylic acid of formula II

Wherein R is as defined above, and wherein,

or an ester-forming functional derivative thereof to its methyl ester; or

(B) Hydrochlorinating a compound of formula III

Wherein R is as defined above.

Process (A) may be carried out by known methods for converting a carboxylic acid or ester-forming functional derivative thereof, for example an acid halide thereof, to the corresponding methyl ester. Conveniently, the carboxylic acid is reacted with a methyl ester of a strong acid, preferably dimethyl sulfate, in the presence of an aprotic organic base such as 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU). The reaction is generally carried out in an inert organic solvent such as an amide, for example dimethylformamide, an ester, for example tetrahydrofuran or a mixture thereof. Conveniently, the reaction temperature is from room temperature to 100 ℃.

Process (B) may be carried out by known hydrochlorination methods, for example by passing HCl gas through a solution of the compound of formula III in an inert organic solvent, for example a hydrocarbon such as toluene. Conveniently, the reaction temperature is from room temperature to 60 ℃.

The compounds of formula II are novel and can be prepared by suitable acylation of the corresponding 17-hydroxy compound, i.e. the compound of formula IV

The acylation may be carried out by known methods, for example by reacting a compound of formula IV with an acid halide of formula RCOX wherein R is as defined above and X is halogen, for example bromine, or preferably chlorine. The reaction is generally carried out in the presence of a base, preferably a tertiary organic base such as pyridine. Suitable reaction temperatures are from room temperature to 50 ℃. The acylation may also be carried out by reacting a compound of formula IV with a compound of formula RCO₂The H carboxylic acid is carried out in the presence of an activating agent such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and a base, preferably a tertiary organic base such as N, N-diisopropylethylamine. The reaction can be carried out in a dipolar aprotic solvent such as N, N-Dimethylformamide (DMF) or a chlorocarbon solvent such as Dichloromethane (DCM). Suitable reaction temperatures are from room temperature to 60 ℃. The compounds of formula IV can be prepared by hydrochlorination of compounds using known hydrochlorinationsProcesses such as the hydrochlorination of the corresponding epoxy compound of the formula V9, 11

Compounds of formula V wherein the 16-methyl group has the alpha conformation can be prepared by the methods described by Aigbirrho et al, J.Labelled Compd.radiopharm. (1997), 39(7), 567-584. Compounds of formula V wherein the 16-methyl group has the beta conformation can be prepared by the method described in US 4607028.

The compounds of the formula III are novel and can be prepared by reacting the corresponding carboxylic acid compounds of the formula VI 17

Converted into its methyl ester. This transformation can be carried out by the method described above for the method (A). The compounds of formula VI can be prepared by appropriate acylation of the corresponding compounds of formula V17-hydroxy; this acylation may be carried out by known methods, for example, the method described above for acylating a compound of formula IV.

The compounds of formula I are useful as medicaments. Accordingly, the present invention also provides a compound of formula I for use as a medicament. The compounds of formula I have important pharmacological properties. For example, they have high anti-inflammatory activity, as demonstrated by their inhibition of TNF- α synthesis and release in human macrophage lines, as well as their inhibition of inflammatory disorders, particularly airway inflammatory disorders, for example inhibition of eosinophil activation in animal models such as mouse or rat airway inflammatory models, e.g., Szarka et al, j.immunol.methods (1997) 202: 49-57; renzi et al, am.rev.respir.dis, (1993) 148: 932-939; tsuyuuki et al, j.clin.invest, (1995) 96: 2924-2931; and cernadias et al (1999) am.j.respir.cell mol.biol.20: 1-8.

The compounds of formula I exhibit surprisingly low systemic side effects at therapeutically effective doses. The compounds of formula I have a long duration of action and can be administered once a day.

Inhibition of TNF- α synthesis and release from the human macrophage line U937 by compounds of formula I may be found, for example, in Sajjadi et al J.Immunol.1996; 156: 3435 and 3442. In this assay, the compounds of examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101 had IC's of 0.035, 0.025, 0.100, 0.05, 0.046, 0.024, 0.10, 0.102, 0.101, 0.048, 0.102, 0.159, 0.076, 0.106 and 0.208, respectively₅₀(nM) values.

The in vivo anti-inflammatory activity can be determined by inhibiting the pulmonary eosinophilia in rats using a modified form of the method of Szarka et al, referred to above. On day 1, male Brown Norway rats (approximately 200g) were sensitized by intraperitoneal injection of a mixture of 0.5ml ovalbumin (0.02mg/ml) and aluminum hydroxide (20mg/ml), followed by Acellula pertussis adsorbat vaccine (0.2ml of a 1: 4 dilution in 0.95 saline). This procedure was repeated on days 15 and 21. On day 28, test compound was administered intratracheally as a dry powder lactose cocktail under isoflurane anesthesia. After 24 hours, sensitized and dosed rats were exposed to ovalbumin aerosol (5mg/ml) for 60 minutes and after 24 hours the rats were sacrificed. Lungs were removed and after rinsing with Hank's solution (balanced salt solution, 100 ml; EDTA100mM, 100 ml; HEPES 1M, 10ml, water 1000ml), the number of eosinophils in the collected solution was directly determined using a Corbas Helios5Diff apparatus (Hoffman-LaRoche).

In this assay, the compounds of examples 14, 17, 26, 34, 37, 39, 51, 60, 73, 99 and 101 reduced eosinophil number by 65, 71, 63, 90, 61, 76, 69, 67, 43, 48 and 40%, respectively, compared to vehicle controls. The doses for examples 14, 26, 34 and 99 were 3mg/kg, the remainder 1 mg/kg.

Systemic side effects can be assessed by the reduction in thymus weight following chronic dosing of rats. Male Sprague-Dawley rats (approximately 250g) were treated once daily for 4 days with test compound at a dose of 1mg/kg (administered orally as a hydroxypropyl cellulose suspension or intratracheally as a dry powder lactose mix under isoflurane anesthesia). Rats were sacrificed on day 5, necropsy was performed, and thymus weight was determined. In this assay, the compounds of examples 17, 26, 34, 37, 73, 99 and 101 reduced thymus weight by 20, 2, 0, 19, 9, 0 and 2%, respectively, when administered orally, compared to vehicle controls. In this assay, the compounds of examples 17, 26, 73 and 99 reduced thymus weight by 78, 55, 31 and 70% respectively when administered intratracheally as compared to vehicle controls.

Due to their anti-inflammatory activity, the compounds of formula I are useful in the treatment of inflammatory conditions, in particular inflammatory or obstructive airways diseases. The treatment according to the invention may be a symptomatic or prophylactic treatment.

Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, asthma induced by exercise, occupational asthma and asthma induced following bacterial infection. It will be appreciated that asthma treatment also includes the treatment of individuals (e.g. individuals under the age of 4 or 5) who exhibit wheezing symptoms and are diagnosed as "asthmatic infants", an established major medical condition and are now often considered to be a patient category of incipient or early asthma (for convenience this particular asthmatic condition is referred to as "asthma-infant syndrome").

The prophylactic efficacy of asthma treatment may be evidenced by a reduction in the frequency or severity of symptomatic attack, e.g., acute asthma or bronchoconstrictor attack, improvement in lung function, or improvement in airway hypersensitivity. May further be evidenced by a reduced need for treatment of other symptoms, i.e. treatment that limits or halts the onset of symptoms when they occur, such as anti-inflammatory (e.g. corticosteroid) treatment or bronchodilatory treatment. In individuals who are prone to "morning sickness", the beneficial effects on asthma prevention are particularly pronounced. "morning urgency" is a recognizable asthma syndrome that is common in a large number of asthmatic patients and is characterized by asthma attacks occurring, for example, at about 4-6 am, i.e., at a time generally distant from any previously administered symptomatic treatment of asthma.

Other inflammatory or obstructive airways diseases to which the present invention is applicable include Acute Lung Injury (ALI), Adult Respiratory Distress Syndrome (ARDS), chronic obstructive pulmonary disease, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, and exacerbation of airways allergy following other drug therapy, particularly inhaled drug therapy. The invention may also be used to treat bronchitis of any type or origin, including, for example, acute, arachidic, catarrhal, fibrinous, chronic or tuberculous bronchitis. Inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, usually occupational, disease of the airways, frequently accompanied by chronic or acute airways obstruction and elicited by repeated inhalation of dust) of any type or genesis, including, for example, aluminosis, silicosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

Due to their anti-inflammatory activity, in particular associated with inhibition of eosinophil activation, the compounds of formula I may also be useful in the treatment of eosinophil-associated disorders, such as hypereosinophilia, in particular eosinophil-associated airway disorders (e.g., involving pathogenic eosinophil infiltration into pulmonary tissue), including hypereosinophilia, as it acts on the airway and/or lung and eosinophil-associated airway disorders such as those that occur following or are associated with: l * ffler's syndrome, eosinophilic pneumonia, parasitic (particularly metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-associated airway affecting conditions induced by drug response.

The compounds of formula I are also useful in the treatment of skin inflammatory disorders, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, and other skin inflammatory disorders.

The compounds of formula I may also be useful in the treatment of other diseases or conditions, particularly diseases or conditions having an inflammatory component, for example in the treatment of eye diseases and conditions such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose such as allergic rhinitis, joint diseases such as rheumatoid arthritis and inflammatory bowel diseases such as ulcerative colitis and crohn's disease.

The compounds of formula I may also be used as co-therapeutic agents in combination with other agents for the treatment of airway diseases, in particular bronchodilatory or anti-inflammatory agents, in particular for the treatment of obstructive or inflammatory airway diseases such as those mentioned above, for example as enhancers of the therapeutic activity of such agents or as means to reduce the required dose or possible side effects of such agents. The compound of formula I may be mixed with the other drug in a fixed pharmaceutical composition, or it may be administered alone, before, during or after administration of the other drug. Such other drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide and tiotropium bromide, LTB4 antagonists such as those described in US5451700, LTD4 antagonists such as montelukast and zafirlukast, dopamine receptor agonists such as cabergoline, bromocriptine, ropinirole and 4-hydroxy-7- [2- [ [2- [ [3- (2-phenylethoxy) propyl ] bromide, and]sulfonyl radical]Ethyl radical]Amino group]Ethyl radical]-2(3H) -benzothiazolone and pharmaceutically acceptable salts thereof (hydrochloride salt is Viozan)^*AstraZeneca), PDE4 inhibitors such as Ariflo^*(GlaxoSmith Kline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004(Bayer), SCH-351591(Schering-Plough), and PD189659(Parke-Davis), and beta-2 adrenergic receptor agonists such as albuterol, terbutaline, salmeterol, and formoterol, among others, and pharmaceutically acceptable salts thereof, and the compound of formula I (free or salt or solvate form) of PCT International publication No. WO00/75114, which is incorporated herein by reference, preferably in its practiceExemplary Compounds, especially in free form or in the form of a pharmaceutically acceptable salt or solvate

Combinations of a compound of formula I with a beta-2 agonist, a PDE4 inhibitor or an LTD4 antagonist may be useful, for example, in the treatment of COPD, or in particular asthma. Combinations of an active agent of the invention with an anticholinergic or antimuscarinic agent, a PDE4 inhibitor, an LTB4 antagonist or a dopamine agonist are useful, for example, in the treatment of asthma or, in particular, COPD.

In accordance with the above, the present invention also provides a method of treating an inflammatory condition, in particular an inflammatory or obstructive airways disease, which comprises administering to a subject, in particular a human subject, in need thereof an effective amount of a compound of formula I as described above. In another aspect, the present invention provides the use of a compound of formula I as described above in the manufacture of a medicament for the treatment of an inflammatory condition, in particular an inflammatory or obstructive airways disease.

The compound of formula I may be administered by any suitable route, for example orally, for example in the form of tablets or capsules; parenteral, e.g., intravenous administration; administration by inhalation, for example to treat inflammatory or obstructive airways diseases; intranasal administration, e.g., to treat allergic rhinitis; topical administration to the skin, for example to treat atopic dermatitis; or rectally, for example, to treat inflammatory bowel disease.

In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula I as an active ingredient, optionally together with a pharmaceutically acceptable diluent or carrier therefor. The compositions of the present invention may contain a combination of therapeutic agents such as the bronchodilators or anti-inflammatory drugs described above. Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets and capsules. Topical formulations may be in the form of creams, ointments, gels, or transdermal delivery systems such as patches. The inhalation composition may comprise an aerosol or other spray formulation or a dry powder formulation.

The present invention includes (a) a compound of formula I in inhaled form, for example in an aerosol or other spray composition or inhalation particles, for example particles in micronized form; (B) an inhalation pharmaceutical comprising a compound of formula I in inhaled form; (C) a medicament comprising a compound of formula I in inhaled form and an inhalation device; and (D) an inhalation device comprising a compound of formula I in inhaled form.

The dosage of the compounds of formula I used in the practice of this invention will, of course, vary with, for example, the particular condition being treated, the desired effect and the mode of administration. For inhalation administration, suitable daily dosages are generally from 0.005 to 10mg, whereas for oral administration, suitable daily dosages are generally from 0.05 to 100 mg.

The invention is illustrated by the following examples.

Examples 1 to 101

Compounds of formula I and their preparation are shown in the following table, wherein Et means ethyl and n-Bu means n-butyl, and the procedure is described below. In examples 34 and 45, the methyl group at position 16 is in the beta conformation; in all other embodiments, it is in the alpha conformation.

Method A

Step 1

Reacting (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3. H ] -cyclopenta [ a ]]Phenanthrene-17-carboxylic acid (50g) was dissolved in dioxane (500 mL). HCl gas was bubbled through the solution for 15 minutes, and the reaction mixture was stirred at room temperature. After 4 hours, the precipitate formed was collected by filtration and washed with methanol. The crude product was boiled in methanol and filtered hot. The filtrate was evaporated to give (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-Cyclopentano [ a ]]Phenanthrene-17-carboxylic acid. Selected of¹H-NMR Signal (d)₆-DMSO)δ6.10(1H，d)，6.30(1H，dd)，7.25(1H，d)

Step 2

The product of step 1 (250mg) was dissolved in pyridine (1.5mL) and added to 4-methyl-1, 2, 3-thiadiazole-5-carbonyl chloride (108 mg). The reaction mixture was stirred at room temperature for 2 hours and then added dropwise to 6N HCl. The precipitate formed was collected by filtration and dried to obtain 4-methyl- [1, 2, 3] thiadiazole-5-carboxylic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -17-carboxy-9-chloro-6-fluoro-11-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester. HPLC retention time 0.849 mins; HPLC conditions: zorbax high resolution column, a 0.1% trifluoroacetic acid (TFA) in water, B0.1% TFA in acetonitrile, gradient 30-95% B in a mixture, eluting at 4 mL/min for 1 min, 50 ℃.

Step 3

The product of step 2 (326mg) was dissolved in dimethylformamide (DMF, 0.5mL) and tetrahydrofuran (THF, 1 mL). 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU, 101mg) was added followed by dimethyl sulfate (84 mg). The reaction mixture was stirred at room temperature for 2 hours and then partitioned between water and Dichloromethane (DCM). The organic layer was dried over magnesium sulfate and evaporated. This compound was purified by flash chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) to give 4-methyl- [1, 2, 3] thiadiazole-5-carboxylic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester.

Method B1

Step 1

The process of (6S, 9S, 10S,11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ]]Phenanthrene-17-carboxylic acid (5g) was dissolved in pyridine (15mL) and cooled to 0 ℃. 2-Furanoyl chloride (1.82g) was added to the solution, and the reaction mixture was stirred at room temperature. After 2 hours, the reaction mixture was added dropwise to a vigorously stirred solution of 6M HCl. DCM was added and the phases separated and the organic phase washed with water and brine. After drying over magnesium sulfate and evaporation, furan-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-carboxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] is obtained]Phenanthren-17-yl ester. Selected of¹H-NMR Signal (CDCl)₃)δ6.30(1H，dd)，6.5(2H，m)，6.55(1H，d)，7.20-7.65(m，2H)。

Step 2

The product of step 1 (6.20g) was dissolved in ethyl acetate (100mL) and DBU (2.20g) and dimethyl sulfate (1.83g) were added in that order. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated. Crystallization from methanol gave furan-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a []Phenanthren-17-yl ester. Selected of¹H-NMR Signal (CDCl)₃)δ3.75(3H，s)，6.30(1H，dd)，6.45(1H，d)，6.55(2H，m)，7.15(1H，d)，7.60(1H，d)。

Step 3

The product of step 2 (4.5g) was dissolved in toluene (150 mL). HCl gas was bubbled through the solution for 15 minutes, and the reaction mixture was stirred at room temperature for 6 hours. The solvent was evaporated and the crude product was crystallized from isopropanol to yield furan-2-carboxylic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester.

Method B2

Step 1

Reacting (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] a]Phenanthrene-17-carboxylic acid (20g) was dissolved in pyridine (50mL) and cooled to 0 ℃. 3-methylthiophene-2-carbonyl chloride (9.39g) was added, and the reaction was stirred at room temperature. After 2 hours, the reaction mixture was added dropwise to a vigorously stirred solution of 6 MHCl. DCM was added and the phases separated and the organic phase washed with water and brine. After drying over magnesium sulfate, evaporation and subsequent purification by column chromatography on silica gel eluting with DCM-methanol (25: 1), 3-methylthiophene-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-carboxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] is obtained]Phenanthren-17-yl ester. Selected of¹H-NMR Signal (CDCl)₃)δ0.90(3H，d)，0.95(3H，s)，1.40(3H，s)，2.40(3H，s)。

Step 2

The product of step 1 (11.1g) was dissolved in ethyl acetate (200 mL). DBU (4.05g) and dimethyl sulfate (3.36g) were added sequentially and the reaction mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated crystallization from methanol gave 3-methylthiophene-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] o [ a]Phenanthren-17-yl ester. Selected of¹H-NMR Signal (CDCl)₃)δ0.90(3H，d)，0.92(3H，s)，1.40(3H，s)，2.40(3H，s)，3.65(3H，s)。

Step 3

The product of step 2 (16g) was dissolved in toluene (250 mL). HCl gas was bubbled through the solution for 15 minutes, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the crude product was crystallized from acetonitrile and isopropanol in sequence to give 3-methylthiophene-2-carboxylic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester.

Method C

Step 1

Reacting (6S, 9S, 10S, 11S, 13S, 16S, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] a]Phenanthrene-17-carboxylic acid (1g) was dissolved in pyridine (5 mL). Cyclopropylcarbonyl chloride (330mg) was added to the solution, and the reaction mixture was stirred at room temperature. After 2 hours, the solution was added dropwise to a vigorously stirred solution of 6M HCl. The formed precipitate was collected by filtration and dried to obtain (6S, 9S, 10S, 11S, 13S, 16S, 17R) -9, 11-epoxy-17-cyclopropanecarbonyloxy-6-fluoro-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] a]Phenanthrene-17-carboxylic acid. Selected of¹H-NMR Signal (CDCl)₃)d 6.25(1H，dd)，6.45(1H，d)，6.55(1H，d)。

Step 2

The product of step 1 (1.1g) was dissolved in ethyl acetate (25 mL). DBU (450mg) was added followed by dimethyl sulfate (370 mg). The reaction was stirred at room temperature for 2 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated. The crude product was crystallized from methanol to yield (6S, 9S, 10S, 11S)13S, 16S, 17R) -9, 11-epoxy-17-cyclopropanecarbonyloxy-6-fluoro-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ]]Phenanthrene-17-carboxylic acid methyl ester. Selected H-NMR signals (CDCl)₃)δ3.65(3H，s)，6.25(1H，dd)，6.45(1H，d)，6.55(1H，d)。

Step 3

The product of step 2 (500mg) was dissolved in toluene (20 mL). HCl gas was bubbled through the solution for 5 minutes, and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the crude product was crystallized from isopropanol-methanol to obtain methyl (6S, 9R, 10S, 11S, 13S, 16S, 17R) -9-chloro-17-cyclopropanecarbonyloxy-6-fluoro-11-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthrene-17-carboxylate.

Method D

Step 1

N, N-diisopropylethylamine (2.3mL) was added to a cold (0 ℃) solution of 5-methyl-pyrazine-2-carboxylic acid (736mg) in DMF (7mL) followed by O- (7-azabenzotriazol-1-yl) -N, N, N, N' -tetramethyluronium hexafluorophosphate (HATU, 2.26 g). The suspension was stirred at room temperature for 10 minutes, then (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] was added]A solution of phenanthrene-17-carboxylic acid (2g) in DMF (7 ml). After 2 hours, the reaction mixture was added dropwise to a 1M HCl solution. The product was collected by filtration, washed repeatedly with water, and dried to obtain 5-methyl-pyrazine-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-carboxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ]]Phenanthren-17-yl ester. Selected H-NMR signals (CDCl)₃)δ0.95(3H，d)，1.10(3H，s)1.40(3H，s)，2.65(3H，s)。

Step 2

The product of step 1 (2.50g) was dissolved in DMF (11mL) and cooled to 0 ℃. DBU (1.68g) was added and after 10 minutes dimethyl sulfate (953mg) was added. The reaction was stirred at room temperature for 2 hours, poured into water, and extracted with ethyl acetate. The combined organic phases were washed with water and brine and then dried over sodium sulfate. Evaporation gave 5-methylpyrazine-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester. Measured mass (M + H) 511.

Step 3

The product of step 2 (1.92g) was dissolved in toluene (100 mL). HCl gas was bubbled through the solution for 90 minutes, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, the crude product was triturated with hot ethanol and dried to give 5-methylpyrazine-2-carboxylic acid 6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester.

Method E

Step 1

N, N-diisopropylethylamine (0.508mL) was added to a cold (0 ℃) solution of 5-acetoxyfuran-2-carboxylic acid (258mg) in DMF (1mL) followed by HATU (556 mg). The suspension was stirred at room temperature for 10 minutes, then (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] was added]A solution of phenanthrene-17-carboxylic acid (500mg) in DMF (1 mL). After 2 hours, the reaction mixture was slowly added to 0.2M HCl solution and extracted with DCM. An organic layer is formedWashed with water and brine, then dried over magnesium sulfate and evaporated to give 5-acetoxyfuran-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-carboxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ]]Phenanthren-17-yl ester. TLC R_f0.5 (10: 1 DCM-methanol elution)

Step 2

The product of step 1 (721mg) was dissolved in ethyl acetate (25 mL). DBU (242mg) was added followed by dimethyl sulfate (201mg), and the reaction was stirred at room temperature for 2 hours and then diluted with 0.2M HCl. The organic layer was washed with water and brine, then dried over magnesium sulfate and evaporated. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (2: 1) gave 5-acetoxyfuran-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ]]Phenanthren-17-yl ester. Selected NMR signals (CDCl)₃)δ0.96(3H，d)，0.98(3H，s)，1.40(3H，s)，2.18(3H，s)，2.76(3H，s)。

Step 3

The product of step 2 (555mg) was dissolved in methanol (10mL) and 2M sodium hydroxide in methanol (1mL) was added. After 1 hour, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated. Purification by flash chromatography eluting with hexane-ethyl acetate (1: 1) gave 5-hydroxyfuran-2-carboxylic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ]]Phenanthren-17-yl ester. TLC R_f0.25 (1: 1 hexane-ethyl acetate elution).

Step 4

The product of step 3 (250mg) was dissolved in toluene (10mL) and dioxane (10 mL). HCl gas was bubbled through the solution for 10 minutes, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the crude product was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) and then triturated with ether to give 5-hydroxyfuran-2-carboxylic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester.

Method F

Step 1

(6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl is converted to 3-acetoxy-benzoic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-carboxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] -phenanthren-17-yl ester by a method analogous to method D, step 1. HPLC retention time 0.762 min, same conditions as method a.

Step 2

The product of step 1 is converted to 3-acetoxybenzoic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester by a method analogous to method D, step 2. Measured mass 552(M +).

Step 3

The product of step 2 was converted to 3-hydroxybenzoic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester by a method analogous to method E, step 3. Measured mass 510(M +).

Step 4

The product of step 3 was converted to 3-hydroxybenzoic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester by a method analogous to method E, step 4.

Method G

Step 1

(6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthrene-17-carboxylic acid is converted to 4-methylaminobenzoic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-carboxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester. HPLC retention time 0.728 min, Max RP high resolution column conditions, a 0.05% TFA in water, B0.105% TFA in acetonitrile, gradient 30-95% B in a mixture, elution 4 mL/min for 1 min, 50 ℃.

Step 2

The product of step 1 is converted to 4-methylaminobenzoic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester by a method analogous to method D, step 2. Measured mass 523(M +).

Step 3

The product of step 2 (42mg) was dissolved in DCM (1mL), DBU (66mg) was added, and methanesulfonyl chloride (114mg) was added after 5 min. The reaction was heated to reflux overnight, then the solvent was evaporated and the residue taken up in DMF. The solution was added dropwise to 1M HCl, and the formed solid was collected by filtration and dried to obtain 4- (methanesulfonylmethylamino) benzoic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester. Measured mass 601(M +).

Step 4

The product of step 3 (35mg) was dissolved in toluene (10mL), and HCl gas was bubbled through the solution for 5 minutes, followed by stirring at room temperature for 16 hours. The solid formed was collected by filtration and dried to give 4- (methanesulfonylmethylamino) -benzoic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester.

Method H

Step 1

Sodium hydride (60% suspension in mineral oil, 241mg) was added to a suspension of terephthalic acid (1g) in DMF (5mL) and after 5 minutes 2- (trimethylsilyl) ethoxy-methyl chloride (0.998g) was added. After 2 hours, the reaction was added dropwise to water and the solid formed was collected by filtration and dried. Purification by column chromatography on silica eluting with ethyl acetate afforded mono- (2-trimethylsilylethoxymethyl) terephthalate. HPLC retention time 0.879 mins, conditions same as method G.

Step 2

(6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthrene-17-carboxylic acid is converted to the mono- (2-trimethylsilylethoxymethyl) terephthalate (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-carboxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester. HPLC retention time 1.046 min, same conditions as method G.

Step 3

The product of step 2 was converted to trimethylsilylethoxymethyl) ester (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester by a method analogous to step 2 of Process D. HPLC retention time 1.055 min, under the same conditions as method G.

Step 4

The product of step 3 (320mg) was dissolved in toluene (10mL), and HCl gas was bubbled through the solution for 5 minutes, followed by stirring at room temperature for 16 hours. The solid formed was collected by filtration, triturated with DCM and dried to give terephthalic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl monoester. Measured mass 575.1(M +).

Step 5

The product of step 4 (24mg) was dissolved in DMF (0.5 mL). DBU (8mg) was added followed by DMS (7mg), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to 1M HCl, and the formed solid was collected by filtration and dried to obtain 1-methyl-4- [ (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ] terephthalate.

Method I

Step 1

(6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-hydroxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3. H. -cyclopenta [ a ] phenanthrene-17-carboxylic acid is converted to 4- (tert-butoxycarbonylamino) benzoic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-carboxy-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester. HPLC retention time 0.873 min, under the same conditions as method G.

Step 2

The product of step 1 was converted to 4- (tert-butoxycarbonylamino) benzoic acid (6S, 9S, 10S, 11S, 13S, 16R, 17R) -9, 11-epoxy-6-fluoro-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl ester by a method analogous to method D, step 2. Measured mass 609.7(M +).

Step 3

The product of step 2 (510mg) was dissolved in 150mL of toluene, and HCl gas was bubbled through the solution for 5 minutes, followed by stirring at room temperature for 48 hours. The solvent was evaporated and the crude product was crystallized from ethyl acetate-cyclohexane to give 4-aminobenzoic acid (6S, 9R, 10S, 11S, 13S, 16R, 17R) -9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13, 16-trimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl monoester.

Claims (17)

1. A compound of formula I

Wherein R is C₃-C₈A cycloalkyl group; a monovalent heterocyclic group having 5 to 10 atoms in the ring system, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur; or phenyl or naphthyl optionally substituted with one or more substituents selected from: halogen, hydroxy, C₁-C₄Acyloxy, cyano, C₁-C₄Alkyl, halo-C₁-C₄Alkyl radical, C₁-C₄Alkoxy, amino, C₁-C₄Alkylamino, di-C₁-C₄Alkylamino radical, C₁-C₄Amido, C₁-C₄Acyl radical C₁-C₄Alkylamino radical, C₁-C₄Alkylsulfonyl radical C₁-C₄Alkylamino radical, C₁-C₄Alkoxycarbonyl group, C₁-C₄Alkylthio, or a 5-membered N-heterocyclyl.

2. The compound of claim 1, wherein R is C₃-C₆-a cycloalkyl group.

3. The compound of claim 1, wherein R is an at least partially saturated heterocyclyl having 5-10 ring atoms with one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.

4. The compound of claim 3, wherein R is a 5-membered heterocyclyl having one ring heteroatom.

5. The compound of claim 1, wherein R is phenyl or naphthyl optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C₁-C₄-acyloxy, cyano, C₁-C₄-alkyl, halo-C₁-C₄Alkyl radical, C₁-C₄Alkoxy, amino, C₁-C₄Alkylamino, di- (C)₁-C₄-alkyl) amino, C₁-C₄-acylamino, C₁-C₄-acyl (C)₁-C₄Alkyl) amino, C₁-C₄Alkylsulfonyl (C)₁-C₄-alkyl) amino, C₁-C₄Alkoxycarbonyl group, C₁-C₄Alkylthio, or 5-membered N-heterocyclyl.

6. The compound of claim 1Wherein R is a heterocyclic aromatic group having a 5-membered heterocyclic ring having 1, 2 or 3 ring heteroatoms selected from nitrogen, oxygen and sulfur, said heterocyclic ring being unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, C₁-C₄-alkyl, halo-C₁-C₄Alkyl radical, C₁-C₄-alkoxy, C₁-C₄-alkylthio, cyano or hydroxy-C₁-C₄-an alkyl group, and the heterocyclic ring is optionally fused with a benzene ring.

7. The compound of claim 1, wherein R is a heterocyclic aryl group having a 6-membered heterocyclic ring having 1 or 2 ring nitrogen atoms, said heterocyclic ring being unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, cyano, hydroxy, C₁-C₄-acyloxy, amino, C₁-C₄Alkylamino, di- (C)₁-C₄-alkyl) amino, C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, halo-C₁-C₄Alkyl radical C₁-C₄-alkoxy, or C₁-C₄-alkylthio, and said heterocycle is optionally fused to a benzene ring.

Compounds of formula I

Wherein the 16-methyl group shown has an alpha conformation and R is 5-methyl-2-thienyl, N-methyl-2-pyrrolyl, cyclopropyl, 2-furyl, 3-methyl-2-thienyl, 5-methyl-3-isoxazolyl, 3, 5-dimethyl-2-thienyl, 2, 5-dimethyl-3-furyl, 4-methyl-2-furyl, 4- (dimethylamino) phenyl, 4-methylphenyl, 4-ethylphenyl, 2-pyridyl, 4-pyrimidinyl, or 5-methyl-2-pyrazinyl, or the 16-methyl group shown has the beta conformation, and R is cyclopropyl.

9. The compound of any one of claims 1-8, wherein R contains a basic group and the compound is in the form of an acid addition salt.

10. Use of a compound according to any one of claims 1 to 9 in combination with another agent in the manufacture of a medicament for the treatment of an inflammatory disease, wherein the other agent is a bronchodilator or an anti-inflammatory agent.

11. The use of claim 10, wherein the other agent is a β -2 adrenergic receptor agonist.

12. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment of an inflammatory disorder.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 as active ingredient, optionally together with a pharmaceutically acceptable diluent or carrier therefor.

14. The pharmaceutical composition of claim 13, further comprising another agent that is a bronchodilator or an anti-inflammatory agent.

15. The pharmaceutical composition of claim 14, wherein the other drug is a beta-2 adrenergic receptor agonist.

16. A process for preparing a compound of formula I comprising

(A) Reacting a carboxylic acid of formula II

Wherein R is C₃-C₈A cycloalkyl group; a monovalent heterocyclic group having 5 to 10 atoms in the ring system, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur; or phenyl optionally substituted with one or more substituents selected fromOr naphthyl: halogen, hydroxy, C₁-C₄Acyloxy, cyano, C₁-C₄Alkyl, halo-C₁-C₄Alkyl radical, C₁-C₄Alkoxy, amino, C₁-C₄Alkylamino, di-C₁-C₄Alkylamino radical, C₁-C₄Amido, C₁-C₄Acyl radical C₁-C₄Alkylamino radical, C₁-C₄Alkylsulfonyl radical C₁-C₄Alkylamino radical, C₁-C₄Alkoxycarbonyl group, C₁-C₄Alkylthio, or a 5-membered N-heterocyclyl, or an ester-forming functional derivative thereof,

conversion to its methyl ester; or

(B) Hydrochlorinating a compound of formula III

Wherein R is as defined in claim 1.

17. A compound of formula II or III as defined in claim 16.