Indian Patents. 235092:"A METHOD FOR PREPARING A STEROIDAL 17B-CARBOTHIOIC ACID OF FORMULA (IV)"

Title of Invention	"A METHOD FOR PREPARING A STEROIDAL 17B-CARBOTHIOIC ACID OF FORMULA (IV)"
Abstract	Method for preparing a steroidal carbothioic acid by reacting steroidal carboxylic acids or salts with carbodiimides alone or in conjunction with a coupling enhancer followed by reaction with a nucleophilic sulfur containing agent.

Full Text	The present invention relates to a novel process for the conversion of steroidal carboxylic acids to carbothioate derivatives such as fluticasone propionate via novel intermediates. Background of the Invention In the preparation of 17ß-carbothioic acids, salphur has generally been introduced under anhydrous conditions; either by the use of hydrogensulfide (US4335121, US4578221) or by employing the salt of hydrogensulfide, generated in situ from the reaction between sodium hydride and hydrogensulfide (US4188385, US4335121, US4578221). In US2002/0133032 Abbott claim a process towards fluticasone propionate starting from flumethasone. The process consists of 5 steps, of which the final two can be performed as a one-pot reaction, and the product is obtained in an overall yield of 51 %. Abbott also claims that a 6a-chloro-9a-fluoro-impurity present in commercial grade flumethasone necessitates an elaborate purification of flumethasone prior to use. In the preparation of fluticasone propionate, the introduction of the CH2F-moiety has been accomplished by the reaction of the carbothioic metal salt with a dihalomethane derivative, preferably a fluorohalomethane. Glaxo first made use of bromochloromethane, followed by halogen exchanges (US4335121). They later moved on to bromofluoromethane (W002088I67, W002100879, W00212265, W00212266), first mentioned by PhilUps etal. (J. Med. Chem., 1994, 37,3717-3729). The Israeli company Chemagis (IL109656) utilised both bromo- and chlorofluoromethane. Chlorofluoromethane was later used by Abbott as well (US2002/0133032). Summary of invention; The problem to be solved by the present invention is to provide a new method for the preparation of steroidal carbothioic acid and derivatives thereof such as fluticasone propionate, especially a method in which a number of the relevant method steps may be performed as a continuous one-pot synthesis. This denotes a method where relevant synthetic steps may be performed in situ without change of solvent or isolation of the individual intermediates. The present invention provides a method which comprises A) reacting a steroidal carboxylic acid or a salt thereof with a coupling agent alone or in conjunction with a coupling enhancer, and B) reacting the product of step A) with a nucleophilic agent comprising a sulfur atom. The solution is based on the identification by the present inventors that by employing novel in situ generated esters, such as 17ß-carboxy- imidazoryl-, succinimidyl- or triazolyl esters of formula (III), as intermediates, an increased threshold against competing hydrolysis reactions was achieved. The reduced level of hydrolysis further raises the efficiency regarding the formation of the end steroidal carbothioate product and removes the need to work under strictly anhydrous conditions. The preferred steroidal carbothioate end products are defined by formula (I) herein. When RIO of formula (I) is a fluoromethyl group this represents fluticasone propionate. The intermediate (such as an ester of formula (III)) is very suitable for use in a method for the conversion of a steroidal carboxylic acid to a steroidal carbothioic acid or a carbothioate. As explained above, an advantage of the method described herein relates to the possibility of performing relevant method steps in situ. The increased stability of the intermediates (such as compounds of formula (III)) against competing hydrolysis reactions, removes the need to work under anhydrous conditions. This makes it possible to avoid the use of hydrogensulfide gas, allowing instead the use of hydrosulfide salts, either as solids with crystal water or as solutions of the desired sulfide salt in water. Further it sets the stage for an in situ process where relevant steps may be performed in one-pot The present invention also discloses a novel process for the preparation of e.g. fluticasone propionate. By employing the method described herein, three out of five steps may be performed in one-pot, thus yielding fluticasone propionate in an overall yield of 89% (see example 3 herein). Coupling agents and enhancers have primarily been used in peptide chemistry where the need to activate carboxylic acids in order to facilitate peptide couplings has been recognized for decades (Handbook of Reagents for Organic Synthesis, Activating Agents and Protecting Groups, ed. A. J. Pearson and W.R. Roush, John Wiley & Sons, 1999). Within the field of steroids the use of coupling agents have also found use, especially in the preparation of carbothioic acids and esters of the androstane series (e.g. US4188385, US4198403, US4335121)). However, in these cases coupling enhancers were not used, and as a result some of the activated intermediates suffered the disadvantage of being prone to competing reactions, e.g. hydrolysis, resulting in a reduced yield of the final product. In US6197761, Glaxo made use of coupling enhancers. In example 16, a novel oxo-tetra-hydrofuranoyl amide was prepared by activating the androstane 17ß-carboxylic acid with 1-hydroxybenzotriazole (HOBt) in conjunction with l-ethyl-3-(3-dimethyl-amuiopropyl) carbodiimide hydrochloride (EDC). However, it is not disclosed in this reference that the carbothioic acid can be obtained by adding a nucleophilic agent to an activated carboxylic group. Embodiments of the present invention are described below, by way of examples only. The above mentioned references are incorporated by reference. Definitions: In the formulas, the substituents have the same meanings as in IUPAC Compendium of Chemical Terminology unless otherwise defined. When the substituent definition comprises a range (e.g. C6 to C22or Cl to C1O), me range is understood to comprise all integers in that range, i.e. 1,23,4, 5, 6,7, 8,9,10,11,12,13,14,15,16,17,18,19, 20,21,22 etc. The term "substituted" means that one or more (such as 1,2,3,4,5, or 6) hydrogen atoms are substituted with substituents independently selected from groups such as: halogen atoms, nitro groups, hydroxyl, mercapto, cyano, carbamoyl, optionally substituted amino, optionally substituted alkyl (e.g. perhalogenalkyl), optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalk(en/yn)yl, optionally substituted aryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted (hetero)aryl, optionally substituted (hetero)aryloxy or acyl groups. Two hydrogen atoms on the same carbon atom can be substituted with a divalent substituent, such as optionally substituted C1-C6 alkylene, O, NH, S. The term "halogen" represents fluoro, chloro, bromo, or iodo. The term "heteroatom" or "hetero" includes atoms such as 0, S, orN. The term "alkyl" includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Preferably, the alkyl group has 1-10 carbon atoms, and most preferred 1,2,3,4,5, or 6 carbon atoms. The alkyl groups may be interrupted by one or more heteroatoms, and may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. The term "alkoxy" stands for an -O-alkyl group. The term "cycloalkyl" includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings of preferably 3,4,5,6, or 7 ring members, which can be fused or isolated. The rings may be substituted, e.g. with groups as defined above, such, as halogen, hydroxyl, aryl, aryloxy, alkoxy, or alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyt and cyclohexyl. The term "alkenyl" includes straight or branched chain hydrocarbon groups having 2 to 15 carbon atoms (e.g. 2,3,4, 5,6 or 10 carbon atoms) with at least one carbon-carbon double bond, the chain being optionally interrupted by one or more heteroatoms. The chain hydrogens may be substituted, e.g. with groups as defined above, such as halogen. Preferred straight or branched alkenyl groups include vinyl, allyl, 1-butenyl,1-methyl propeayl and 4-peatenyl. The term "alkynyl" includes straight or branched chain hydrocarbon groups having 2 to 15 carbon atoms (e.g, 2,3,4,5,6 or 10 carbon atoms) with at least one carbon-carbon, triple bond, the chain being optionally interrupted by one or more heteroatoms. The chain hydrogens may be substituted, e.g with groups as defined above, such as halogen. Preferred straight or branched alkynyl groups include ethynyl, propynyl, 1-botynyl,1methyt propynyl and 4-pentynyl. The term "cycloalkenyl" includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings of preferably 3,4,5,6, or 7 ring members containing a carbon-carbon double bond, which can be fused or isolated. The rings may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, alkoxy, or alkyl. Preferred cycloalkenyl groups include cyclopentenyl and cyckthexenyl. The term "aryl" refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted, e.g. with groups as defined above, such as alkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc. Preferred aryl groups include phenyl, 3(trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl. The term "heteroaryl" refers to aromatic hydrocarbon rings (having such as 3,4, 5, 6, or 7 ring members) which contain at least one (e.g. 1,2,3,4, or 5) heteroatom(s) in the ring. Heteroaryl rings may be isolated, preferably with 5 to 6 ring atoms, or fused, preferably with 8,9 or 10 ring atoms. The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted, e.g. with groups as defined above, such as alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furane, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole. The term "aliphatic group" comprises both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. The term includes, but is not limited to, alkyl alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. It is presently preferred that alkyl or other aliphatic groups have 1-6 carbon atoms (which may be substituted or unsubstituted as specified). For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term "heteroaliphatic group" refers to aliphatic moieties (cf. the term aliphatic as defined above), which contain one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms,, e.g., in place of carbon atoms. Heteroaliphatic moieties may be substituted or unsubstituted, branched, unbranched, cyclic or acyclic, and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc The term "carbocyclic group/ring" includes a mono or bicyctic carbocyclic ring (e.g., cycloalkyl or cyoloalkenyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyolooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, and bicyclo[2.2.I]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyi, etc.); optionally containing 1-2 double bonds and optionally substituted by I to 3 suitable substituents as defined above. The term "heterocyclic group/ring" includes both heteroaryl as above defined as well as non-aromatio ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S, Examples of heterocyclic rings include 3-lH-benzimidazol-2-one, (l-substituted)-2-oxo-benzumidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,33-dioxalanyl, [l,3]-difliiolanyl, [l,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyI, 2-morphoIinyI, 3-raorpholinyl, 4-morpholinyl, 2-thiomorphollnyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyxrolidinyl, l-piperazinyl, 2-piperazbyl, 1-piperidinyl, 2-piperidinyJ, 3-piperidinyl, 4-piperidkyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, l-phthalimidinyl( benzoxanyl, benzopyrrolidiny], benzopipcridinyl, benzoxolanyl, benzothiolanyl, and beazothianyl. Also included within the scope of the term "heterocyclyl" or "heterocyclic", as it is used herein, is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, ortetrahydroquinoltnyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term "heterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted with substituents as above defined. The term "acyl" encompasses carboxylic acyl groups having the formula A-C(=O)-, in which formula A represents a substituent as defined above, such as an atkyl, alkenyl, aryl, heteroaryl or aralkyl group, the chain in said groups being optionally interrupted by one or more heteroatoms and the groups being optionally substituted, e.g. by one or more substituents as defined above. Examples on aoyl groups are formyj, C1-C6 alk(en/yij)ylcarbonyl, arylcarbonyl, aryl-Cl-C6 alk(en/yn)ylcarbonyl, cycloalkylcarbonyl, or cycIoalkyl-Cl-C6 alk(en/yn)ylcarboayl group. Also, the term acyl comprises any of the above groups in which the C(-O) group is replaced by C(=S) or C(N-R), R is H or a substituent as defined above. The terra "hydroxy-protecting group" is intended to mean any group used for the temporary protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as "silyl" groups), and alkoxyalkyl groups. Alkoxycarbonyl protecting groups are alkyl-O-CO-- groupings such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopiopoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxyoarbonyl, benzyloxyoarbonyl or allyloxycarbonyl. Alkoxyalkyl protecting groups are groups such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl-protecting groups are trimethylsilyl, trietnylsilyl, t-butyldimethylsilyl, dibutylmetttylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals. A "protected hydroxy" group is a hydroxy group derivatised or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl or alkoxycarbonyl groups, as previously defined The term "steroid" as used herein is intended to mean compounds having a cyclopenlanophcnanthrene nucleus. In these structures, the use of bold and dashed lines to denote particular conformation of groups again follows the IUPAC steroid-naming convention. The symbols "alpha" and "beta" indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn. Thus "alpha." denoted by a broken line, indicates that the group in question is below the general plane of the molecule as drawn, and "beta" denoted by a bold line, indicates that the group at the position in question is above the general plane of the molecule as drawn. The terms "steroidal carbothioate", "steroidal carbomioic acid" and "steroidal carboxylic acid" are intended to mean compounds in which a carbothioate group, carbothioic acid group or carboxylic acid group, respectively, is bound to the steroid nucleus, either directly or via linker, such as an optionally substituted C1-C6 alkylene group, in any position of the nucleus. Presently preferred are steroidal compound where the carbothioate group, carbothioic acid group or carboxylic acid group is bound to the carbon atom in position 17, more preferably directly to the nucleus without an intervening linker, and most preferably in beta configuration. The term "carbothioate" is intended to mean the substitnent -C(=O)-S-R, wherein R represents a substituent selected from: en aliphatic group, an heteroaliphatic group, a carbocyclic group, a heterocyclic group, a heteroaryl group, an aryt group, etc; all said groups are optionally substituted as above defined. Presently preferred R is substituted aliyl or substituted heterocyclyl. The term "nucleophilic agent" means a chemical compound capable of forming a covalent bond with an activated carboxylic acid group. The term "electrophilic agent" as used herein relates to a chemical compound capable of forming a covalent bond with a electron rich system such as e.g. a thioanion (-S'), Examples are compounds of the formula X-Y, where X is halogen and Y is aryl, a heterocyclic group or an aliphatic or heteroaliphatic group, said groups being optionally substituted. Presently, preferred agents are optionally substituted alkylhalogenides or optionally substituted heterocyclyliialides. The term "solvate" represents an aggregate that comprises one or more molecules of the compound of the invention, with one or more molecules of solvent. Solvents may be, by way of example, water, ethanol, acetone, THF, DMA, or DMF. Detailed description of the Invention A first aspect of the invention relates to a method for preparing a steroidal carbothioic acid or a salt thereof, said method comprises; A) reacting a steroidal carboxylic acid or a salt thereof with a coupling agent [such as a carbcdiimide derivative] alone or in conjunction with a coupling enhancer [such as a chemical entity comprising a saturated or unsaturated 5-6 membered heterocyclic ring in which the 5-6 membered heterocyclic ring contains one, two or three nitrogen atoms, said heterocyclic ring is optionally substituted on at least one nitrogen atom (such as by a hydroxy- or a cyano group) and/or optionally substituted on at least one carbon atom (such as by a keto group, a aulfonic acid or a salt thereof (i.e. the substituent is a sulftnate group, -S(=O)(=O)-O" wherein me single bonded oxygen is bond directly to hydrogen, or to a group LA. or HA light metal (such as sulfonic acid sodium salt) or to an optionally substituted ammonium), an aliphatic group (e.g. alkyl comprising 1 - 4 carbon atoms, such as a methyl group) or a betearoaliphatic group preferably comprising a sulfur atom (e.g. heteroalkyl with 1-4 carbon atoms, such as a thiomethyl group)) and, when me said heterocyclic/ ring contains two adjacent carbon atoms, the said ring is optionally fused with an aromatic- or a heteroaromatic ring which is optionally substituted (such as by a halogen atom e.g. a chloro atom)]; and B) reacting the product of step A) with a nucleophilic agent comprising a sulfur atom [such as hydrogen sulfide or a corresponding salt, optionally a hydrated salt thereof and preferably sodium hydrosulfide hydrate]. As coupling agent, it is presently preferred to use a carbodiimide derivative, represented by the following formula: Ra—N=C=N—Rb wherein Ra and Rb are the same or different, and each represent an aliphatic, heteroaliphatic, carbocyclic or a heterocyclic group [all said groups are optionally sustituted]; more preferably the coupling agent is 1-ethyl-3-(3-dimelhylaminopropyl) carbodiimide (EDC); and most preferably the hydrochloride salt of EDC. But the coupling agent can also be selected from the group consisting of: A) derivatives of guanidinium N-oxide salts (N-methyl mefhannminhim salts) of a unsaturated 5- membered heterocyclic ring fused to an optionally substituted aryl, heteroaryl, benzene- or pyridine ring, (such as compounds of formula (A)), (Formula Removed) X =* H, F, Cl, Br and Y « CH, N, O, S, W B) derivatives of uranium salts (O-hydronated ureas) of a unsauirated 5-membered heterocyclic ring fused to a optionally substituted aryl, heteroaryl, benzene- or pyridine ring, (such as compounds of formula (B)), (Formula Removed) X- H, F, Cl, Br and Y - CH, N, O, S, W"= PF6,BF4,SbCl6; and; C) derivatives of thiouronium salts (such as compounds of formula (C), preferably as the tetrafluoroborate salt), (Formula Removed) In an embodiment of the invention, the coupling enhancer is selected from the group consisting of: A) a heterocyclic ring containing one or two nitrogen atoms, said ring being optionally substituted [such as by a koto group, a hydroxy group, an aliphatic group, a heteroaliphatic group, a cyano group, a halogen atom]; such as a compound of formula (D) or formula (E), (Formula Removed) wherein R11 and R12 can be the same or different, and each represent a hydrogen atom or a cyano group (C=N); R13 represent a hydrogen atom or an alkyl group (such as methyl); and RM represent a hydrogen atom or a salt of a sulfonic acid such as sodium sulfonate [-S(=O)-O- Na+]; and B) an unsaturated 5-6 membered heterocyclic ring fused to an aromatic- or heteroaromatic ring in which the said heterocyclic ring contains three nitrogen atoms, said rings being optionally substituted [such as with a hydroxy group, a halogen atom, a keto group and/or an optionally substituted aliphatic- or heteroaliphatic group], such as a compound of formulas (F), (G) (Formula Removed) X=H F, Cl, Brand Y=CH.N, O, S preferably 6-chloro-hydroxybenzotriasole (6-Cl-HOBt), 7-aza-bydroxybenzotriasole (HOAt), or 3-hydroxy-4-axo-3,4-dihydro-l,2,3'-benziotciazine (Dbht-OH). In a further embodiment of the invention, the nucleophilic agent comprising a sulfur atom is selected from the group comprising: - compounds of formula \|M]+[SH]~ wherein M is a metal such as Li, Na or K; or [M]2+[S]2' wherein M is a metal such as Ca or Mg, the said sulfide salts being optionally hydrated (such as sodium hydrosulfide hydrate); and an in situ generated sulfide salt or a hydrated sulfide salt The nucleophilic agent can be added in fhe form of a solid salt or dissolved in a suitable solvent prior to addition to the reaction mixture, eg, as a solution of the salt in water and/or an organic solvent or a combination thereof. In a presently preferred embodiment, the invention relates to preparing a steroidal carbotbioic acid of formula (IV) or a salt thereof; (Formula Removed) The symbol == in the 1,2-position represent a single or a carbon-carbon double bond. R1 represents a hydrogen atom, a hydroxy- or an alkoxy group (such as optionally substituted C1-6 alkoxy) in the a-configuration, a group -O-C-(=O)-R6. where R6 is an alkyl group (such as optionally substituted Cl-6 alkyl) or an optionally substituted 5-6 membered heterocyclic ring containing either oxygen, nitrogen or sulfur as ring hetero atom [such as a furanyl-, pyrrolyl- or thiophenyl group]; R2 represents a hydrogen atom, a hydroxy group, an alkoxy group (such as optionally substituted C1-6 alkoxy) in the α-configuration, an alkyl group (such as optionally substituted C1-6 alkyl) which may be in either the α- or ß-configuration, an alkylene group (such as optionally substituted C1-6 alkylene having the two free valencies on the same carbon atom, preferably methylen) [the alkylene group is bound to the steroid nucleus via a double bond] or R1 and R2 together represent where R7 and R8are the same or different and each represent a hydrogen atom or an alkyl group (such as optionally substituted C1-6 alkyl); R3 represent hydrogen, hydroxy or a protected hydroxy group in either the α- or ß-configuration or an oxo group (in which case the bond between R3 and the steroid nucleus is a double bond); R4 represents a hydrogen atom or a halogen atom or R3 and R4 together represent a carbon-carbon bond or an epoxy group in the ß-configuration; and R5 represents a hydrogen atom or a halogen atom in either the α- or ß-configuration; R9 represents a hydrogen atom or Rg represent a metal ion [eg. the moiety -S-Rg represents a group of the formula [-S]-[M]+ wherein M is Li, Na or K]; the method comprising; A) reading a steroidal carboxylic acid of formula (II) (Formula Removed) in which the substiruents of formula (II) have the above defined meaning, or a salt thereof, with an coupling agent alone or in conjunction with an coupling enhancer, followed by the reaction with a nucleophilic agent comprising a sulfur atom; and optionally B) reacting the product from step A) with an acid. The sequence of addition of the coupling agent and the coupling enhancer is not considered to be very important, as the agent can be added before die enhancer, or vice versa. Lt is also possible to add a mixture of a steroidal carboxylic acid to a mixture of the agent and the enhancer or vice versa. Presently, it is preferred to add the agent and the enhancer, in succession, as solids to a steroidal carboxylic acid dissolved in a polar aprotic solvent, preferably DMF or DMA, optionally at a elevated temperature The carboihioic acid or a salt thereof can be used in a process for producing steroidal carbothioates, and therefore the invention in a second aspect relates to a method for preparing a steroidal carbothioate (i.e. the carbothioio ester of die steroid), or a salt thereof, the method comprising: reacting a steroidal carbothiolc acid or a salt thereof, which is prepared as defined in the first aspect of the invention, with an electrophilic agent [such as a di-or trihaloalkane]. Preferably the etectrophilic agent is selected from the group consisting of; C1-6 di- or trihaloalkanes, preferably a trihalo- or a dihalomethane, such as chlorobromomethane or bromofluororoethane. In a preferred embodiment, the invention relates to a method for preparing a steroidal carbothioate of formula (I) (Formula Removed) The symbol ==in the 1,2-position represent a single or a carbon-carbon double bond, wherein R1, R2, R3,R4, and R5 are defined aa above; and R10 represents a C1-6 haloalkyl [such as a fluoro-, chloro-, bromomethyl group, a difluoromethyl or a trifluoromethyl group, or a 2-fluoroethyl group] or a optionally substituted heterocyclic ring (Formula Removed) [such as a tetrahydrofuranyl group, preferably a 2-oxo-tetrahydrofuran-3-yl], the method comprising: A) reacting a steroidal carboxylic acid of formula (II) (Formula Removed) with a coupling agent [such as a carbodiimide] and a coupling enhancer [such as a compound of formula (D) or formula (B) (Formula Removed) wherein R11 and R12 independently represent a hydrogen atoms or a cyano group (Cs=N); R13 represent a hydrogen atom or an alkyl group (such as methyl); and R14 represent a hydrogen atom or & moiety of a sulfozdc acid, such as sodium sulfonate (eg. thegroup-S(=O)(=O)-O-Na+)] . B) reacting the product from step A) with a nucleophilic agent comprising sulfur; and C) reacting the product from step B) with an electrophilic agent [such as a C1-6 di- or trihaloalkane, preferably a trihalo- or a dihalomethane such, as chlorofluoromethane or bromofluoromethanc] or a compound of the following formula; (Formula Removed) wherein X=H, F, Cl, Br and; Y=CH2, NH, 0, S, preferably X=C1 and Y=O In this method it is preferred that formula (D) is MM (N-methylimidazole) or DCI (4,5-dicyanoinudazole), or formula (B) is NHS (N-hydroxysuccinimide) or suIfo-NHS (a N-hydroxysulfosuccinimidc salt). In 3 further embodiment, the invention relates to the above method wherein at least one of R11 and R12 is a cyano group (C=N), and/or R13 is a hydrogen atom, and/or R10 is a fluoromethyl group. In a third embodiment, step C) constitutes the in situ reaction of the product from stop B) with bromofluoromethane to form a compound of formula (I) wherein R10 is a fluoromethyl group, such as fluticasone propionate, It is presently preferred that the method is performed without unnecessary isolation of intermediates, and thus in a preferred embodiment, at least two subsequent steps of the method are performed in situ, i.e. without any change or removal of solvents, or isolation of the individual intermediates. Advantageously, the steps A), B) and C) are conducted as a one-pot synthesis without solvent changes and/or are performed at room or elevated temperature. Also, the method can be conducted as a continuous method. In an interesting embodiment, the invention relates to a method, wherein an androstano 17ß-carboxylic acid is converted to an androstane 17ß -carbothioate. In an other interesting embodiment, step B) provides an alkalimetal salt of the thioio acid, such as a compound of formula (IV), in which the moiety -S-R9 represent a group of the formula [-S]"[M]+ wherein M is Li, Na or K e.g. -S" Na+, and the other substituents have the same meaning as defined for formula (I). (Formula Removed) A third aspect of the invention relates to a method for producing a compound of the formula (Formula Removed) The symbol== in the 1,2-position represent a single or a carbon-carbon doable bond Wherein wherein R1, R2, R3,. R4and R5 are defined as above; Rc represents S, O, NH; and W represents hydrogen, an optionally substituted aliphatic- or heteroaliphatic group [such as a C1-6 alkyl group substituted with one or more halogens] or an optionally substituted [such as with =O] hetcrocyclic ring containing either O, N or S as ring hetero atom [such as a tetrahydrofuranyl-(lactono), tetrahydrothiopflenyl- (thiolaotone) or a pyrrolidinyl (lactame) group] which method comprises reacting a corresponding compound wherein Re represents 0 and W represents H or a salt thereof with a coupling agent alone or in conjunction with a coupling enhancer, (the agent aad enhacer defined in claim 1, step A); and reacting the resulting product with a nucleophilic agent having the formula: Rd-W, wherein W is defined as above and Rd represents OH, NH2 or SH, or a salt thereof. A fourth aspect of the invention relates to the novel products which can be obtained by the methods of the invention, or novel compounds which are intermedistes in the methods. Thus, the invention, relates to a compound of the formula (IB) and salts and solvates thereof (Formula Removed) The symbol = in the 1,2-position represent a single or a carbon-carbon double bond, wherein R1, R2, R3,R4and R5 are defined as above; and Z represent the structural moiety resulting from the reaction between the steroidal carboxylic acid of formula ( II) and a coupling agent (preferably EDC), followed by a coupling enhancer as defined above, such as a compound selected from the group consisting of the compounds of formulas (D); (E);(F);and(G): (Formula Removed) wherein R11 and R12 represent a hydrogen atom or a cyano group; R13 represent a hydrogen atom or a alkyl group (such as methyl); and R14 represent a hydrogen atom or a moiety of a sulfonic acid, such as sodium sulfouate [ie. the group -S(=O)(=O)ONa+] (Formula Removed) X-= H, F, Cl, Br and Y= CH, N, O, S with the proviso that l-[(9alpha-fluaro-l lbeta-hydroxy-16beta-methyl-3-oxo-17alpha-propionyIoxvandrosta-l,4-dien-17beta-yl)carbonyl]imidazole is disclaimed. This compound is mentioned in Phillips et al. (j. Med. Chem., 1994,37,3717-3729) The compounds of the invention also comprises salts and solvates of the above formulas, and the skilled person will know that the compounds exsist in several polymorph forms, which also is an aspect of the present invention. Also, the above methods lead to compounds in the form of free bases, salts and polymorphs. Interesting compounds of formula in are compounds wherein at least one of Rn and R^ is a cyano group (ON), and/or compounds, wherein R13 is a hydrogen atom, and/or compounds obtained using a coupling enhancer selected from the group consisting of: NMI (N-methylimidazole); DCI (4,5-cyanoimidazole); NHS (N-hydroxysuccinimide); and sulfo-NHS (N-hydroxysulfosuccinhnide sodium salt) and/or a compound having the formula: (Formula Removed) The symbol == in the 1,2-position represent a single or a carbon-carbon double bond. in which the substituents have the same meaning as defined above, and salts and solvateg thereof. The fifth aspect of the invention relates to a composition comprising a compound according to the invention, and, as a sixth aspect, the use of a compound of the invention as an intermediate in a method for preparing a steroidal carbothioatc or a steroidal carbothioic acid. In a very interesting embodiment, the invention relates to the use of a compound of the invention as an intermediate in a method for preparing fluticasone prapionate, especially in a method which comprises reaction with a nucleophilic agent comprising a sulfur atom [such as sodium hydrosulfide hydrate] and/or comprises reaction with an electrophilic agent [such as a C1-6 di- or trihaloalkane, preferably a trihalo- or a dihalomethane such as chlorofluoromethane or bromofluoromethane]. The method as described herein relates in a presently preferred embodiment to the conversion of androstane 17ß-carboxylic acids to 17ß-carbothioates such as e.g. fluticasone propionate via novel in situ activated 17ß-carboxylic acid intermediates. In a preferred embodiment of the method the 17ß-carbothioic esters are prepared by reacting an acid of formula (II) with a coupling agent in conjunction with a coupling enhancer. The terms "coupling agent' and "coupling enhancer" are herein used to refer to chemical reagents that facilitate the formation of a reactive intermediate of formula (III) where Z represent a group with the structural formula (D) or formula (E). Such intermediates may be formed between androstane I7ß-carboxylic acids and a carbodiimide derivative such as l-ethyl-3-ß-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (a preferred example of a coupling agent) in combination with suitable coupling enhancers. Suitable coupling enhancers as used herein can for example be represented by the structures of formula (D) and formula (E) as described above. The coupling agent and the optional coupling enhancers are preferably water-soluble so the reactions could be effected in aqueous solutions if preferred. Presently considered the best mode of the invention: Compounds of formula (III) as defined hereinbefore may be prepared by treating a compound of formula (II) with EDC in combination with a compound of formula (D). The resulting 17ß-carboxy tmidazolyl ester, which may be isolated if required, is treated with a nucleophilic agent (a sulfur source) that displaces the active ester group to form a compound of formula (IV), In one embodiment of the invention R9 may represent optionally substituted C1-6 alkyl groups like e.g. methyl, ethyl or a isopropyl group (preferably substituted with a halogen atom), or a 5-6 membered heterocyclic ring containing either oxygen, nitrogen or sulfur, the said heterocyclic ring being optionally substituted by a oxo group on either of the ring carbons. Compounds of formula (IV) may readily be isolated. la another embodiment of the mvention, R9 represent a hydrogen atom or a salt. Preferred examples of salts include alkali metal salts; e.g. Li, N~a or K, alkaline earth metal salts; e.g. Ca or Mg, tertiary amine salts; e.g. pyridurium, triethylammonium or diisopropylethylamine salt, or quaternary ammonium salts; e.g. tetrabutylammonium salt. Such compounds of formula (IV) may be isolated if necessary. Subsequent addition of an electrophilic agent leads to the formation of compounds of formula (I) as depicted hi scheme 1, wherein R10 is a C1-6 haloalkyl, a fluoro-, chloro-, or bromomethyl group, a diffuoromethyl or a trifluoromethyl group, or a 2-fluoroethyl group. Preferably the nucleophilio agent is a hydrogen sulfide or a salt thereof or more preferably a hydrated sulfide salt such as sodium hydrosulftde hydrate. Preferably the electrophilic agent is chlorofluoromethane or more preferably bromofluoromethane. In a preferred embodiment of the present method, compounds of formula (III) as defined hereinbefore may be prepared by treating a compound of formula (II) with EDC in combination with a compound of formula (E). The resulting l7ß-carboxy succmimidyl ester which may be isolated if required is treated with a nucleophilic agent that displaces the active ester group to form a. compound of formula (IV) as defined hereinbefore. Subsequent addition of a electrophilic agent conclude tine synthesis towards compounds of formula CO as depicted in scheme 1, wherein R10 is a C1-6 haloalkyl, a fluoro-, chloro-, or bromomethyl group, a difluoromethyl or a trifluorometliyl group, or a 2-fluoroetiiyl group. The formation of compounds of formula (I) may take place hi a one-pot reaction starting with compounds of formula (II) without isolation of the intermediates of formula (III) and (IV) if e.g. sodium hydrosulfide hydrate is used as the nucleophilic agent. The use of a coupling enhancer in combination with a carbodiimide forms an active ester intermediate of formula (III) with increased stability and reactivity. These intermediates have an increased threshold against competing hydrolysis reactions. The reduced level of hydrolysis raises the efficiency regarding the formation of products of formula (I) (scheme 1, see below) where RIO is defined as hereinbefore. Surprisingly, we have found that the use of these novel I7ß-carboxy succinimidyl- and 17)3-carboxy imidazolyl esters of formula (III) reduce the cycle time, increase the yield and enhance the purity of the final product of formula (I). Compound preparation The method of the disclosed invention will be better understood when related to the following synthetic scheme, which illustrates a preferred embodiment of the method as described herein. Moreover, persons skilled in the art will be aware of variations of, and alternatives to the method described hereinafter. The provided examples will demonstrate the synthesis and allow compounds defined by formula (I) to be obtained. In scheme 1, the substituents have the above-defined meaning. Scheme 1 (Formula Removed) The androstane 17ß-carboxylic acid starting materials employed in the present invention may be readily prepared by any means known in the art. Compounds of formula (II) can be prepared by oxidation of a suitable 21-hydroxy-20-keto pregnane of formula (V) as taught in e.g. US3636010 (example 1). (Formula Removed) Compounds of formula (V) which are commercially available include e.g. budesonide, desonide, triaraoinolone aoetonide, fluocinolone acetonide, betamethasone, dexamethasone, prednisolone, flumethasone, beclometbasone, icomethasone, diflorasone, hydrocortisone and fludrocortisone. The method as described herein will now be described in detail in connection with other particularly preferred embodiments of scheme 1. Thus, me following and not limiting examples will illustrate an especially preferred methodology. The examples are presented to provide what is believed to be the most useful and readily understood description of die procedures and conceptual aspects of the method described herein. Examples General MS (ESI) refer to mass spectra obtained using electrospray ionisation techniques. Melting points were obtained using a Mettler FP8I MBC cell and are uncorrected. The purity of the products was determined by RP18-HPLC analysis using UV-detection at 239 run. Abbreviations; DMF (N,N-dimethyUbrmamide), DMA (N,N-dimethylacetamide), THF (tetrahydrofurane), EDC (l-ethyl-3-(3-dimethyl-iaininbpropyI)carbodiimide hydrochloride), NHS (N-hydrojcysucoinimide), NMI (N-methylimidazole) and DCI (4,5-dicyano-imidazole). Example 1 6α,9α-difluoro-l lß,17α-diydroxy-16α-meihyl- 3-oxoandrosta-l,4-diene-17ß-carboxylic acid 6α,9α-difluoro-llß-16α-21-trihydroxy-16α-methyl-pregpa-1,4-diene-3,20-dione(flumetasone) (525 g, 12.78 mmol) was dissolved in THF (25 ml) at 0 °C. To the stirred solution, periodic acid (2.0 eq., 5.83 g in 12 ml H2O) was added drop wise. The reaction flask was covered in aluminum foil after 75 minutes and left stirring at room temperature. The reaction was quenched after 4.5 hours by addition of water (120 ml) and left in a refrigerator over-night. The resulting precipitate was filtered, washed with water until the filtrate was neutral to pH-paper and dried under reduced pressure. The title compound was obtained as a white solid (4.96 g, 93%), with a purity of >99% byHPLC. Example 2 6α,9α-difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17 ß-carboxylic acid A suspension of 6α,9α-difluoro-11ß,17α-dihydroxy-16α-methyl-3-oxoandrosta-l,4-diene-17p-carboxylic acid (4.11 g, 10.38 mmol) in acetone (30 ml) was added Et3N (3.5 eq., 3,7 ml) under N2 and stirring. The resulting solution was cooled to 0 °C and propionyl chloride (4.5 eq., 43 ml) was added drop wise to a white suspension. After 85 minutes Et2NH (10.0 eq., 7.6 ml) was added and the resulting mixture was left stirring for 55 minutes at 0 °C, before the solvent was removed under reduced pressure. The resulting solid was dissolved in water (20 ml), and treated with IN HC1 to pH 2. The white precipitate thus formed was filtered, washed with ice cold water and dried under reduced pressure at 60°C, The title compound was obtained as a white solid (4.64 g, 99%) with a purity of 99% by HPLC. Example 3 S-fluorornethyl 6α,9α-difluoro-l lß-hydroxy-16α-methyI-3-oxo-17α-propionyloxyandrosta-l ,4- diene-17ß-carbothioate (fluticasone propionate) A flask charged with 6α,9α-difluoro-l lß-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-l,4-diene-17ß-carboxylic acid (0.30 g, 0.66 mmol) In DMA (30 ml) at-50 °C was added EDC (3.0 eq., 0.38 g) and NHS (3.1 eq., 0.24 g) and left stirring until the reaction was complete, as monitored by HPLC analysis. The oil bath was toned off and sodium hydrosulfide hydrate (20.0 eq., 0.74 g) was added in one portion at -35 °C. The addition Immediately resulted in a strongly blue colored reaction mixture. After 15 minutes the reaction was complete and gaseous bromoiluormefnane was added at room temperature. The initial blue color gradually changed to pale yellow during the additioa of bromofluoromethane. On completion of the reaction, after 15 minutes, as monitored by HPLC analysis, sodiumcarbonate (25 ml, 10% in water) followed by water (10 ml) was added to the cooled reaction mixture. The solid thus formed was filtered, dissolved in mctbanol (40 ml), heated to reflux and filtered. Temperated water (40 ml) was slowly added to the warm filtrate. The beginning suspension was left at room temperature for two hours before cooling in a refrigerator. The resulting precipitate was collected by filtration, washed with water (40 ml) and dried under reduced pressure. The title compound was obtained as a white amorphous solid (0.25 g, 92%) with a melting point of 267 °C and a purity of >98% by HPLC. Spiking of the product sample with the British Pharmacopoeia Standard (melting point: 265 °C) of fluticasoae propionate, showed one peak fay HPLC analysis. Example 4 6α,9α-difluoro-l 1 ß-hydroxy-16α-methyI-3-oxo-l 7α-propionyloxyandrosta-l,4-diene-17ß-carbomiotc acid A flask charged with 6α,9α-difluoro-11ß-hydroxy-16α-methyl-3-oxo-l7α-propionyl-oxyandrosta-l,4-diene-17ß-carboxylic aoid (0.30 g, 0.66 mmol) in DMA (30 ml) was heated to -50 °C. EDC (3.0 eq., 0.38 g) and NMl (3.1 eq., 162 µl) was added and the reaction mixture was left stirring until the reaction was complete, as monitored by HPLC analysis. The oil bath was turned off and sodium hydrosulfide hydrate (20.0 eq., 0.74 g) was added in one portion at ~35 °C. The addition immediately resulted in a strongly blue colored reaction mixture with some precipitation. After 15 minutes the reaction was complete and crushed ice followed by 2N HC1 (10 ml) to pH ~2 was added and the flask was left in a refrigerator. Ouring the addition of HCI, the initial bluish reaction mixture gradually became colorless. The solid thus formed was filtered and a minimum amount of acetone following temperated water was added to a beginning crystallisation. The refrigerated suspension was filtered, washed with water (30 ml) until the filtrate was neutral to pH-paper and dried under reduced pressure. The title compound was obtained as a white amorphous solid (0,10 g, 32%) with a purity of 98% by HPLC. Example 5 S-melhyl 6α,9α-difliioro-11ß-hydroxy-16α-methyl-3-oxo- 17α-propionyloxyandrosta-l,4-diene-17ß-carbothioate 6α,9α-difluoro-1lß-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-l,4-diene-l7ß-carboxylic acid (0.20 g, 0.43 mmol) was dissolved in DMF (10 ml). The reaction flask was immersed in an oil-bath and the temperature was raised to ~40 °C. EDC (~2 eq., 0.15 g) and NHS (~5 eq., 036 g) was added and the reaction mixture was left stirring at 40 °C for 19 hours. The temperature was raised to 50 °C and another portion of EDC (-4 eq., 0.29 g) was added. The mixture was left stirring at 50 °C for 3 hours. The flask was removed from the oil-bath and the reaction mixture was diluted by the addition of DMF (5 ml). Aqueous NaSMe (1,0 ml, 21% solution in water) was added in portions over a period of 30 minutes. The reaction mixture turned into a pale pink suspension. The reaction was quenched by the addition crushed ice and aqueous HCI (12 ml, 10%). The white precipitate was filtered, washed with water and dried. The crude product was dissolved in a minimum amount of acetone and water was added until a beginning precipitation. The resulting solid was collected by filtration, washed with water and dried under reduced pressure to yield the title compound as a white solid (0.11 g, 51%) with a purity of 90% by HPLC. Example 6 S-methyl 6α-9α-difluoro-lIß-hydroxy-16α-methyl-3-oxo- 17α-propionyloxyandrosta-l ,4-diene-I7ß-carbothioate Charge a flask with 6α,9α-difluoro-1 1ß-hydroxy-16α-methyl-3-oxo-17α-propionyl-oxyandrosta-l,4-diene-17ß-carboxylic acid (0.30 g, 0.66 mrnol) in DMA (30 ml), and heat the contents to ~50 °C. Add EDC (3.0 eq., 0.3 8 g) and NMI (3.1 eq., 162µ,l) and leave the mixture stirring until the reaction is complete, as monitored by HPLC analysis. Turn off /remove the oil bath and add aqueous NaSMe (1.5 ml, 21% solution in water) in one portion at ~35 °C. The reaction is quenched by the addition of crushed ice and aqueous HCI (12 ml, 10%). The white precipitate is filtered, washed with water and dried. The crude product is dissolved in a minimum amount of acetone and water is added to induce precipitation. The resulting solid is collected by filtration, washed with water and dried under reduced pressure to yield the title compound as a solid. Example7 S-fluoromethyl 6α,9α-difluoro-11 ß-hydroxy-16α-methyI-3-oxo-17α-propionyloxyandrosta-1,4- diene-17ß-carbothioate (fluticasone propionate) Charge a flask with 6α,9α-difluoro-l lß-hydroxy-16α-methyI-3-oxo-17α-propioiiyl-oxyandrosta-l,4-diene-17ß-carboxylio acid (0.30 g, 0.66 mmol) in DMA (30 ml) and heatthe contents to ~50 °C. Added EDC (3.0 eq., 0.38 g) and DCI (3.1 eq.) and leave the mixture stirring until the reaction is complete, as monitored by HPLC analysis. Turn off/remove the oil bath and add sodium bydrosulfide hydrate (20.0 eq., 0.74 g) in one portion at ~35 °C. After x minutes the reaction is complete and gaseous bromofluoromethene is added at room temperature. Upon completion of the reaction, as monitored by HPLC analysis, sodium carbonate (25 ml, 10% in water) and water (10 ml) is added to the refrigerated reaction mixture. The solid which forms is filtered and dissolved in methanol (40 ml). The methanolic solution is heated to reflux and filtered Temperate water (40 ml) is added slowly to the warm filtrate. The resulting suspension is left at room temperature for two hours before being transferred to a refrigerator. The precipitate which forms is collected by filtration, washed with water (40 ml) and dried under reduced pressure. The title compound is obtained as a solid. WE CLAIM: 1. A method for preparing a steroidal 17ß-carbothioic acid of formula (IV) or a salt thereof, (Formula Removed) wherein the symbol in the 1,2-position represent a single or a carbon-carbon double bond; R1 represents a hydrogen atom, a hydroxy- or an alkoxy group in the α- configuration, a group -O-C(=O)-R6, where R6 is an alkyl group or an optionally substituted 5-6 membered heterocyclic ring containing either oxygen, nitrogen or sulfur as ring hetero atom; R2 represents a hydrogen atom, a hydroxy group, an alkoxy group in the α- configuration, an alkyl group which may be in either the α- or ß- configuration, an alkylene group or R1 and R2 together represent (Formula Removed) where R7 and R8 are the same or different and each represent a hydrogen atom or an alkyl group; R3 represent a hydrogen atom, hydroxy- or a protected hydroxy group in either the α- or ß-configuration or an oxo group; R4 represents a hydrogen- or a halogen atom or R3 and R4 together represent a carbon-carbon bond or an epoxy group in the ß-configuration; and R5 represents a hydrogen- or a halogen atom in either the α- or ß- configuration; R9 represents a hydrogen atom or R9 represent a metal ion; the method comprising; step A) reacting a steroidal 17ß-carboxylic acid of formula (II) or a salt thereof (Formula Removed) in which the substituents of formula (II) have the above defined meaning with a coupling agent selected from the group consisting of carbodiimide derivatives represented by the following formula: (Formula Removed) wherein Ra and Rb are the same or different, and each represent an aliphatic, heteroaliphatic, carbocyclic or a heterocyclic group; alone or in conjunction with a coupling enhancer; step B) followed by the reaction with a nucleophilic agent comprising a sulfur atom; and optionally reacting the product of step B) with an acid such as herein described. 2. A method as claimed in claim 1, in which the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. 3. A method as claimed in claim 2, in which the coupling agent is the hydrochloride salt of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide. 4. A method as claimed in any of the preceding claims, in which the coupling enhancer is selected from the group consisting of: A) a heterocyclic ring containing one or two nitrogen atoms, said ring being optionally substituted; such as a compound of formula (D) or formula (E), (Formula Removed) wherein R11 and R12 are the same or different, and each represent a hydrogen atom or a cyano group; R13 represent a hydrogen atom or an alkyl group; and R14 represent a hydrogen atom or a salt of a sulfonic acid; and B) an unsaturated 5-6 membered heterocyclic ring fused to an aromatic- or heteroaromatic ring in which the said heterocyclic ring contains three nitrogen atoms, said rings being optionally substituted, such as a compound of formulas (F) or formula (G), (Formula Removed) preferably 6-chloro-hydroxybenzotriasole, 7-aza-hydroxybenzotriasole, or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine. 5. A method as claimed in any of the preceding claims, where the nucleophilic agent comprising a sulfur atom is selected from the group comprising: compounds of formula [M]+[SH]- wherein M is a metal, or [M]2+[S]2' wherein M is a metal, and an in situ generated sulfide salt of a hydrated sulfide salt. 6. A method as claimed in any of the preceding claims, wherein nucleophilic agent dissolved in a suitable solvent prior to addition to the reaction mixture, or wherein the nucleophilic agent is added in the form of a solid salt or as a solution of the salt in water and/or an organic solvent or a combination thereof.

Full Text

The present invention relates to a novel process for the conversion of steroidal carboxylic acids to carbothioate derivatives such as fluticasone propionate via novel intermediates.
Background of the Invention
In the preparation of 17ß-carbothioic acids, salphur has generally been introduced under anhydrous conditions; either by the use of hydrogensulfide (US4335121, US4578221) or by employing the salt of hydrogensulfide, generated in situ from the reaction between sodium hydride and hydrogensulfide (US4188385, US4335121, US4578221).
In US2002/0133032 Abbott claim a process towards fluticasone propionate starting from flumethasone. The process consists of 5 steps, of which the final two can be performed as a one-pot reaction, and the product is obtained in an overall yield of 51 %. Abbott also claims that a 6a-chloro-9a-fluoro-impurity present in commercial grade flumethasone necessitates an elaborate purification of flumethasone prior to use.
In the preparation of fluticasone propionate, the introduction of the CH2F-moiety has been accomplished by the reaction of the carbothioic metal salt with a dihalomethane derivative, preferably a fluorohalomethane. Glaxo first made use of bromochloromethane, followed by halogen exchanges (US4335121). They later moved on to bromofluoromethane (W002088I67, W002100879, W00212265, W00212266), first mentioned by PhilUps etal. (J. Med. Chem., 1994, 37,3717-3729). The Israeli company Chemagis (IL109656) utilised both bromo- and chlorofluoromethane. Chlorofluoromethane was later used by Abbott as well (US2002/0133032).
Summary of invention;
The problem to be solved by the present invention is to provide a new method for the preparation of steroidal carbothioic acid and derivatives thereof such as fluticasone propionate, especially a method in which a number of the relevant method steps may be performed as a continuous one-pot synthesis. This denotes a method where relevant synthetic steps may be performed in situ without change of solvent or isolation of the individual intermediates.
The present invention provides a method which comprises A) reacting a steroidal carboxylic acid or a salt thereof with a coupling agent alone or in conjunction with a coupling enhancer, and B) reacting the product of step A) with a nucleophilic agent comprising a sulfur atom.

The solution is based on the identification by the present inventors that by employing novel in situ generated esters, such as 17ß-carboxy- imidazoryl-, succinimidyl- or triazolyl esters of formula (III), as intermediates, an increased threshold against competing hydrolysis reactions was achieved. The reduced level of hydrolysis further raises the efficiency regarding the formation of the end steroidal carbothioate product and removes the need to work under strictly anhydrous conditions. The preferred steroidal carbothioate end products are defined by formula (I) herein. When RIO of formula (I) is a fluoromethyl group this represents fluticasone propionate.
The intermediate (such as an ester of formula (III)) is very suitable for use in a method for the conversion of a steroidal carboxylic acid to a steroidal carbothioic acid or a carbothioate. As explained above, an advantage of the method described herein relates to the possibility of performing relevant method steps in situ.
The increased stability of the intermediates (such as compounds of formula (III)) against competing hydrolysis reactions, removes the need to work under anhydrous conditions. This makes it possible to avoid the use of hydrogensulfide gas, allowing instead the use of hydrosulfide salts, either as solids with crystal water or as solutions of the desired sulfide salt in water. Further it sets the stage for an in situ process where relevant steps may be performed in one-pot The present invention also discloses a novel process for the preparation of e.g. fluticasone propionate. By employing the method described herein, three out of five steps may be performed in one-pot, thus yielding fluticasone propionate in an overall yield of 89% (see example 3 herein).
Coupling agents and enhancers have primarily been used in peptide chemistry where the need to activate carboxylic acids in order to facilitate peptide couplings has been recognized for decades (Handbook of Reagents for Organic Synthesis, Activating Agents and Protecting Groups, ed. A. J. Pearson and W.R. Roush, John Wiley & Sons, 1999).
Within the field of steroids the use of coupling agents have also found use, especially in the preparation of carbothioic acids and esters of the androstane series (e.g. US4188385, US4198403, US4335121)). However, in these cases coupling enhancers were not used, and as a result some of the activated intermediates suffered the disadvantage of being prone to competing reactions, e.g. hydrolysis, resulting in a reduced yield of the final product. In US6197761, Glaxo made use of coupling enhancers. In example 16, a novel oxo-tetra-hydrofuranoyl amide was prepared by activating the androstane 17ß-carboxylic acid with 1-hydroxybenzotriazole (HOBt) in conjunction with l-ethyl-3-(3-dimethyl-amuiopropyl) carbodiimide hydrochloride (EDC). However, it is not
disclosed in this reference that the carbothioic acid can be obtained by adding a nucleophilic agent to an activated carboxylic group.
Embodiments of the present invention are described below, by way of examples only. The above mentioned references are incorporated by reference.
Definitions:
In the formulas, the substituents have the same meanings as in IUPAC Compendium of Chemical Terminology unless otherwise defined. When the substituent definition comprises a range (e.g. C6 to C22or Cl to C1O), me range is understood to comprise all integers in that range, i.e. 1,23,4, 5, 6,7, 8,9,10,11,12,13,14,15,16,17,18,19, 20,21,22 etc.
The term "substituted" means that one or more (such as 1,2,3,4,5, or 6) hydrogen atoms are substituted with substituents independently selected from groups such as: halogen atoms, nitro groups, hydroxyl, mercapto, cyano, carbamoyl, optionally substituted amino, optionally substituted alkyl (e.g. perhalogenalkyl), optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalk(en/yn)yl, optionally substituted aryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted (hetero)aryl, optionally substituted (hetero)aryloxy or acyl groups. Two hydrogen atoms on the same carbon atom can be substituted with a divalent substituent, such as optionally substituted C1-C6 alkylene, O, NH, S.
The term "halogen" represents fluoro, chloro, bromo, or iodo.
The term "heteroatom" or "hetero" includes atoms such as 0, S, orN.
The term "alkyl" includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Preferably, the alkyl group has 1-10 carbon atoms, and most preferred 1,2,3,4,5, or 6 carbon atoms. The alkyl groups may be interrupted by one or more heteroatoms, and may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. The term "alkoxy" stands for an -O-alkyl group.
The term "cycloalkyl" includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings of preferably 3,4,5,6, or 7 ring members, which can be fused or isolated. The rings may be substituted, e.g. with groups as defined above, such, as halogen, hydroxyl, aryl, aryloxy, alkoxy, or alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyt and cyclohexyl.
The term "alkenyl" includes straight or branched chain hydrocarbon groups having 2 to 15 carbon atoms (e.g. 2,3,4, 5,6 or 10 carbon atoms) with at least one carbon-carbon double bond, the chain being optionally interrupted by one or more heteroatoms. The chain hydrogens may be substituted, e.g. with groups as defined above, such as halogen. Preferred straight or branched alkenyl groups include vinyl, allyl, 1-butenyl,1-methyl propeayl and 4-peatenyl.
The term "alkynyl" includes straight or branched chain hydrocarbon groups having 2 to 15 carbon atoms (e.g, 2,3,4,5,6 or 10 carbon atoms) with at least one carbon-carbon, triple bond, the chain being optionally interrupted by one or more heteroatoms. The chain hydrogens may be substituted, e.g with groups as defined above, such as halogen. Preferred straight or branched alkynyl groups include ethynyl, propynyl, 1-botynyl,1methyt propynyl and 4-pentynyl.
The term "cycloalkenyl" includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings of preferably 3,4,5,6, or 7 ring members containing a carbon-carbon double bond, which can be fused or isolated. The rings may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, alkoxy, or alkyl. Preferred cycloalkenyl groups include cyclopentenyl and cyckthexenyl.
The term "aryl" refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted, e.g. with groups as defined above, such as alkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc. Preferred aryl groups include phenyl, 3(trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl.
The term "heteroaryl" refers to aromatic hydrocarbon rings (having such as 3,4, 5, 6, or 7 ring members) which contain at least one (e.g. 1,2,3,4, or 5) heteroatom(s) in the ring. Heteroaryl rings may be isolated, preferably with 5 to 6 ring atoms, or fused, preferably with 8,9 or 10 ring atoms. The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted, e.g. with groups as defined above, such as alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furane, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
The term "aliphatic group" comprises both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. The term includes, but is not limited to, alkyl alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. It is presently preferred that alkyl or other aliphatic groups have 1-6 carbon atoms (which may be substituted or unsubstituted as specified). For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
The term "heteroaliphatic group" refers to aliphatic moieties (cf. the term aliphatic as defined above), which contain one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms,, e.g., in place of carbon atoms. Heteroaliphatic moieties may be substituted or unsubstituted, branched, unbranched, cyclic or acyclic, and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc
The term "carbocyclic group/ring" includes a mono or bicyctic carbocyclic ring (e.g., cycloalkyl or cyoloalkenyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyolooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, and bicyclo[2.2.I]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyi, etc.); optionally containing 1-2 double bonds and optionally substituted by I to 3 suitable substituents as defined above.
The term "heterocyclic group/ring" includes both heteroaryl as above defined as well as non-aromatio ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S, Examples of heterocyclic rings include 3-lH-benzimidazol-2-one, (l-substituted)-2-oxo-benzumidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,33-dioxalanyl, [l,3]-difliiolanyl, [l,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyI, 2-morphoIinyI, 3-raorpholinyl, 4-morpholinyl, 2-thiomorphollnyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyxrolidinyl, l-piperazinyl, 2-piperazbyl, 1-piperidinyl, 2-piperidinyJ, 3-piperidinyl, 4-piperidkyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, l-phthalimidinyl( benzoxanyl, benzopyrrolidiny], benzopipcridinyl, benzoxolanyl, benzothiolanyl, and beazothianyl. Also included within the scope of the term "heterocyclyl" or "heterocyclic", as it is used herein, is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, ortetrahydroquinoltnyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term "heterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted with substituents as above defined.
The term "acyl" encompasses carboxylic acyl groups having the formula A-C(=O)-, in which
formula A represents a substituent as defined above, such as an atkyl, alkenyl, aryl, heteroaryl or aralkyl group, the chain in said groups being optionally interrupted by one or more heteroatoms and the groups being optionally substituted, e.g. by one or more substituents as defined above. Examples on aoyl groups are formyj, C1-C6 alk(en/yij)ylcarbonyl, arylcarbonyl, aryl-Cl-C6 alk(en/yn)ylcarbonyl, cycloalkylcarbonyl, or cycIoalkyl-Cl-C6 alk(en/yn)ylcarboayl group. Also, the term acyl comprises any of the above groups in which the C(-O) group is replaced by C(=S) or C(N-R), R is H or a substituent as defined above.
The terra "hydroxy-protecting group" is intended to mean any group used for the temporary protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as "silyl" groups), and alkoxyalkyl groups. Alkoxycarbonyl protecting groups are alkyl-O-CO-- groupings such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopiopoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxyoarbonyl, benzyloxyoarbonyl or allyloxycarbonyl. Alkoxyalkyl protecting groups are groups such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl-protecting groups are trimethylsilyl, trietnylsilyl, t-butyldimethylsilyl, dibutylmetttylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals.
A "protected hydroxy" group is a hydroxy group derivatised or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl or alkoxycarbonyl groups, as previously defined
The term "steroid" as used herein is intended to mean compounds having a cyclopenlanophcnanthrene nucleus. In these structures, the use of bold and dashed lines to denote particular conformation of groups again follows the IUPAC steroid-naming convention. The symbols "alpha" and "beta" indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn. Thus "alpha." denoted by a broken line, indicates that the group in question is below the general plane of the molecule as drawn, and "beta" denoted by a bold line, indicates that the group at the position in question is above the general plane of the molecule as drawn.
The terms "steroidal carbothioate", "steroidal carbomioic acid" and "steroidal carboxylic acid" are intended to mean compounds in which a carbothioate group, carbothioic acid group or carboxylic acid group, respectively, is bound to the steroid nucleus, either directly or via linker, such as an optionally substituted C1-C6 alkylene group, in any position of the nucleus. Presently preferred are steroidal compound where the carbothioate group, carbothioic acid group or carboxylic acid group
is bound to the carbon atom in position 17, more preferably directly to the nucleus without an intervening linker, and most preferably in beta configuration.
The term "carbothioate" is intended to mean the substitnent -C(=O)-S-R, wherein R represents a substituent selected from: en aliphatic group, an heteroaliphatic group, a carbocyclic group, a heterocyclic group, a heteroaryl group, an aryt group, etc; all said groups are optionally substituted as above defined. Presently preferred R is substituted aliyl or substituted heterocyclyl.
The term "nucleophilic agent" means a chemical compound capable of forming a covalent bond with an activated carboxylic acid group.
The term "electrophilic agent" as used herein relates to a chemical compound capable of forming a covalent bond with a electron rich system such as e.g. a thioanion (-S'), Examples are compounds of the formula X-Y, where X is halogen and Y is aryl, a heterocyclic group or an aliphatic or heteroaliphatic group, said groups being optionally substituted. Presently, preferred agents are optionally substituted alkylhalogenides or optionally substituted heterocyclyliialides.
The term "solvate" represents an aggregate that comprises one or more molecules of the compound of the invention, with one or more molecules of solvent. Solvents may be, by way of example, water, ethanol, acetone, THF, DMA, or DMF.
Detailed description of the Invention
A first aspect of the invention relates to a method for preparing a steroidal carbothioic acid or a salt thereof, said method comprises;
A) reacting a steroidal carboxylic acid or a salt thereof with a coupling agent [such as a carbcdiimide derivative] alone or in conjunction with a coupling enhancer [such as a chemical entity comprising a saturated or unsaturated 5-6 membered heterocyclic ring in which the 5-6 membered heterocyclic ring contains one, two or three nitrogen atoms, said heterocyclic ring is optionally substituted on at least one nitrogen atom (such as by a hydroxy- or a cyano group) and/or optionally substituted on at least one carbon atom (such as by a keto group, a aulfonic acid or a salt thereof (i.e. the substituent is a sulftnate group, -S(=O)(=O)-O" wherein me single bonded oxygen is bond directly to hydrogen, or to a group LA. or HA light metal (such as sulfonic acid sodium salt) or to an optionally substituted ammonium), an aliphatic group (e.g. alkyl comprising 1 - 4 carbon atoms, such as a methyl group) or a betearoaliphatic group preferably comprising a sulfur atom (e.g. heteroalkyl with 1-4 carbon atoms, such as a thiomethyl group)) and, when me said heterocyclic/ ring contains two adjacent carbon atoms, the said ring is optionally fused with an
aromatic- or a heteroaromatic ring which is optionally substituted (such as by a halogen atom e.g. a chloro atom)]; and
B) reacting the product of step A) with a nucleophilic agent comprising a sulfur atom [such as hydrogen sulfide or a corresponding salt, optionally a hydrated salt thereof and preferably sodium hydrosulfide hydrate].
As coupling agent, it is presently preferred to use a carbodiimide derivative, represented by the
following formula: Ra—N=C=N—Rb
wherein Ra and Rb are the same or different, and each represent an aliphatic, heteroaliphatic,
carbocyclic or a heterocyclic group [all said groups are optionally sustituted]; more preferably the
coupling agent is 1-ethyl-3-(3-dimelhylaminopropyl) carbodiimide (EDC); and most preferably the
hydrochloride salt of EDC. But the coupling agent can also be selected from the group consisting
of:
A) derivatives of guanidinium N-oxide salts (N-methyl mefhannminhim salts) of a unsaturated 5-
membered heterocyclic ring fused to an optionally substituted aryl, heteroaryl, benzene- or pyridine
ring, (such as compounds of formula (A)),
(Formula Removed)
X =* H, F, Cl, Br and Y « CH, N, O, S, W
B) derivatives of uranium salts (O-hydronated ureas) of a unsauirated 5-membered heterocyclic ring fused to a optionally substituted aryl, heteroaryl, benzene- or pyridine ring, (such as compounds of formula (B)),
(Formula Removed)
X- H, F, Cl, Br and Y - CH, N, O, S, W"= PF6,BF4,SbCl6;
and;
C) derivatives of thiouronium salts (such as compounds of formula (C), preferably as the
tetrafluoroborate salt),
(Formula Removed)
In an embodiment of the invention, the coupling enhancer is selected from the group consisting of: A) a heterocyclic ring containing one or two nitrogen atoms, said ring being optionally substituted [such as by a koto group, a hydroxy group, an aliphatic group, a heteroaliphatic group, a cyano group, a halogen atom]; such as a compound of formula (D) or formula (E),
(Formula Removed)
wherein R11 and R12 can be the same or different, and each represent a hydrogen atom or a cyano group (C=N); R13 represent a hydrogen atom or an alkyl group (such as methyl); and RM represent a hydrogen atom or a salt of a sulfonic acid such as sodium sulfonate [-S(=O)-O- Na+]; and B) an unsaturated 5-6 membered heterocyclic ring fused to an aromatic- or heteroaromatic ring in which the said heterocyclic ring contains three nitrogen atoms, said rings being optionally substituted [such as with a hydroxy group, a halogen atom, a keto group and/or an optionally substituted aliphatic- or heteroaliphatic group], such as a compound of formulas (F), (G)
(Formula Removed)
X=H F, Cl, Brand Y=CH.N, O, S
preferably 6-chloro-hydroxybenzotriasole (6-Cl-HOBt), 7-aza-bydroxybenzotriasole (HOAt), or 3-hydroxy-4-axo-3,4-dihydro-l,2,3'-benziotciazine (Dbht-OH).
In a further embodiment of the invention, the nucleophilic agent comprising a sulfur atom is
selected from the group comprising:
- compounds of formula |M]+[SH]~ wherein M is a metal such as Li, Na or K; or [M]2+[S]2'
wherein M is a metal such as Ca or Mg, the said sulfide salts being optionally hydrated (such
as sodium hydrosulfide hydrate); and
an in situ generated sulfide salt or a hydrated sulfide salt
The nucleophilic agent can be added in fhe form of a solid salt or dissolved in a suitable solvent prior to addition to the reaction mixture, eg, as a solution of the salt in water and/or an organic solvent or a combination thereof.
In a presently preferred embodiment, the invention relates to preparing a steroidal carbotbioic acid of formula (IV) or a salt thereof;
(Formula Removed)
The symbol == in the 1,2-position represent a single or a carbon-carbon double bond.
R1 represents a hydrogen atom, a hydroxy- or an alkoxy group (such as optionally substituted C1-6 alkoxy) in the a-configuration, a group -O-C-(=O)-R6. where R6 is an alkyl group (such as optionally substituted Cl-6 alkyl) or an optionally substituted 5-6 membered heterocyclic ring containing either oxygen, nitrogen or sulfur as ring hetero atom [such as a furanyl-, pyrrolyl- or thiophenyl group];
R2 represents a hydrogen atom, a hydroxy group, an alkoxy group (such as optionally substituted C1-6 alkoxy) in the α-configuration, an alkyl group (such as optionally substituted C1-6 alkyl) which may be in either the α- or ß-configuration, an alkylene group (such as optionally substituted C1-6 alkylene having the two free valencies on the same carbon atom, preferably methylen) [the alkylene group is bound to the steroid nucleus via a double bond] or R1 and R2 together represent
where R7 and R8are the same or different and each represent a hydrogen atom or an alkyl group
(such as optionally substituted C1-6 alkyl);
R3 represent hydrogen, hydroxy or a protected hydroxy group in either the α- or ß-configuration or
an oxo group (in which case the bond between R3 and the steroid nucleus is a double bond);
R4 represents a hydrogen atom or a halogen atom or R3 and R4 together represent a carbon-carbon
bond or an epoxy group in the ß-configuration; and
R5 represents a hydrogen atom or a halogen atom in either the α- or ß-configuration;
R9 represents a hydrogen atom or Rg represent a metal ion [eg. the moiety -S-Rg represents a group
of the formula [-S]-[M]+ wherein M is Li, Na or K]; the method comprising;
A) reading a steroidal carboxylic acid of formula (II)
(Formula Removed)
in which the substiruents of formula (II) have the above defined meaning, or a salt thereof, with an coupling agent alone or in conjunction with an coupling enhancer, followed by the reaction with a nucleophilic agent comprising a sulfur atom; and optionally B) reacting the product from step A) with an acid.
The sequence of addition of the coupling agent and the coupling enhancer is not considered to be very important, as the agent can be added before die enhancer, or vice versa. Lt is also possible to add a mixture of a steroidal carboxylic acid to a mixture of the agent and the enhancer or vice versa. Presently, it is preferred to add the agent and the enhancer, in succession, as solids to a steroidal carboxylic acid dissolved in a polar aprotic solvent, preferably DMF or DMA, optionally at a elevated temperature
The carboihioic acid or a salt thereof can be used in a process for producing steroidal carbothioates, and therefore the invention in a second aspect relates to a method for preparing a steroidal carbothioate (i.e. the carbothioio ester of die steroid), or a salt thereof, the method comprising: reacting a steroidal carbothiolc acid or a salt thereof, which is prepared as defined in the first aspect of the invention, with an electrophilic agent [such as a di-or trihaloalkane]. Preferably the etectrophilic agent is selected from the group consisting of; C1-6 di- or trihaloalkanes, preferably a trihalo- or a dihalomethane, such as chlorobromomethane or bromofluororoethane.
In a preferred embodiment, the invention relates to a method for preparing a steroidal carbothioate of formula (I)
(Formula Removed)
The symbol ==in the 1,2-position represent a single or a carbon-carbon double bond, wherein R1, R2, R3,R4, and R5 are defined aa above; and
R10 represents a C1-6 haloalkyl [such as a fluoro-, chloro-, bromomethyl group, a difluoromethyl or a trifluoromethyl group, or a 2-fluoroethyl group] or a optionally substituted heterocyclic ring
(Formula Removed)
[such as a tetrahydrofuranyl group, preferably a 2-oxo-tetrahydrofuran-3-yl], the method
comprising:
A) reacting a steroidal carboxylic acid of formula (II)

(Formula Removed)

with a coupling agent [such as a carbodiimide] and a coupling enhancer [such as a compound of formula (D) or formula (B)

(Formula Removed)

wherein R11 and R12 independently represent a hydrogen atoms or a cyano group (Cs=N);
R13 represent a hydrogen atom or an alkyl group (such as methyl); and
R14 represent a hydrogen atom or & moiety of a sulfozdc acid, such as sodium sulfonate (eg. thegroup-S(=O)(=O)-O-Na+)]
.
B) reacting the product from step A) with a nucleophilic agent comprising sulfur; and
C) reacting the product from step B) with an electrophilic agent [such as a C1-6 di- or trihaloalkane,
preferably a trihalo- or a dihalomethane such, as chlorofluoromethane or bromofluoromethanc] or a
compound of the following formula;

(Formula Removed)
wherein X=H, F, Cl, Br and; Y=CH2, NH, 0, S, preferably X=C1 and Y=O
In this method it is preferred that formula (D) is MM (N-methylimidazole) or DCI (4,5-dicyanoinudazole), or formula (B) is NHS (N-hydroxysuccinimide) or suIfo-NHS (a N-hydroxysulfosuccinimidc salt).
In 3 further embodiment, the invention relates to the above method wherein at least one of R11 and R12 is a cyano group (C=N), and/or R13 is a hydrogen atom, and/or R10 is a fluoromethyl group.
In a third embodiment, step C) constitutes the in situ reaction of the product from stop B) with bromofluoromethane to form a compound of formula (I) wherein R10 is a fluoromethyl group, such as fluticasone propionate,
It is presently preferred that the method is performed without unnecessary isolation of intermediates, and thus in a preferred embodiment, at least two subsequent steps of the method are performed in situ, i.e. without any change or removal of solvents, or isolation of the individual intermediates. Advantageously, the steps A), B) and C) are conducted as a one-pot synthesis without solvent changes and/or are performed at room or elevated temperature. Also, the method can be conducted as a continuous method.
In an interesting embodiment, the invention relates to a method, wherein an androstano 17ß-carboxylic acid is converted to an androstane 17ß -carbothioate. In an other interesting embodiment, step B) provides an alkalimetal salt of the thioio acid, such as a compound of formula (IV), in which the moiety -S-R9 represent a group of the formula [-S]"[M]+ wherein M is Li, Na or K e.g. -S" Na+, and the other substituents have the same meaning as defined for formula (I).
(Formula Removed)
A third aspect of the invention relates to a method for producing a compound of the formula
(Formula Removed)
The symbol== in the 1,2-position represent a single or a carbon-carbon doable bond Wherein wherein R1, R2, R3,. R4and R5 are defined as above; Rc represents S, O, NH; and
W represents hydrogen, an optionally substituted aliphatic- or heteroaliphatic group [such as a C1-6 alkyl group substituted with one or more halogens] or an optionally substituted [such as with =O] hetcrocyclic ring containing either O, N or S as ring hetero atom [such as a tetrahydrofuranyl-(lactono), tetrahydrothiopflenyl- (thiolaotone) or a pyrrolidinyl (lactame) group] which method comprises reacting a corresponding compound wherein Re represents 0 and W represents H or a salt thereof with a coupling agent alone or in conjunction with a coupling enhancer, (the agent aad enhacer defined in claim 1, step A); and reacting the resulting product with a nucleophilic agent having the formula: Rd-W, wherein W is defined as above and Rd represents OH, NH2 or SH, or a salt thereof.
A fourth aspect of the invention relates to the novel products which can be obtained by the methods of the invention, or novel compounds which are intermedistes in the methods. Thus, the invention, relates to a compound of the formula (IB) and salts and solvates thereof
(Formula Removed)
The symbol = in the 1,2-position represent a single or a carbon-carbon double bond, wherein R1, R2, R3,R4and R5 are defined as above; and
Z represent the structural moiety resulting from the reaction between the steroidal carboxylic acid of formula ( II) and a coupling agent (preferably EDC), followed by a coupling enhancer as defined above, such as a compound selected from the group consisting of the compounds of formulas (D); (E);(F);and(G):
(Formula Removed)
wherein R11 and R12 represent a hydrogen atom or a cyano group; R13 represent a hydrogen atom or a alkyl group (such as methyl); and R14 represent a hydrogen atom or a moiety of a sulfonic acid, such as sodium sulfouate [ie. the group -S(=O)(=O)ONa+]
(Formula Removed)
X-= H, F, Cl, Br and Y= CH, N, O, S
with the proviso that l-[(9alpha-fluaro-l lbeta-hydroxy-16beta-methyl-3-oxo-17alpha-propionyIoxvandrosta-l,4-dien-17beta-yl)carbonyl]imidazole is disclaimed. This compound is mentioned in Phillips et al. (j. Med. Chem., 1994,37,3717-3729)
The compounds of the invention also comprises salts and solvates of the above formulas, and the skilled person will know that the compounds exsist in several polymorph forms, which also is an aspect of the present invention. Also, the above methods lead to compounds in the form of free bases, salts and polymorphs.
Interesting compounds of formula in are compounds wherein at least one of Rn and R^ is a cyano group (ON), and/or compounds, wherein R13 is a hydrogen atom, and/or
compounds obtained using a coupling enhancer selected from the group consisting of: NMI (N-methylimidazole); DCI (4,5-cyanoimidazole); NHS (N-hydroxysuccinimide); and sulfo-NHS (N-hydroxysulfosuccinhnide sodium salt) and/or a compound having the formula:
(Formula Removed)
The symbol == in the 1,2-position represent a single or a carbon-carbon double bond.
in which the substituents have the same meaning as defined above, and salts and solvateg thereof.
The fifth aspect of the invention relates to a composition comprising a compound according to the invention, and, as a sixth aspect, the use of a compound of the invention as an intermediate in a method for preparing a steroidal carbothioatc or a steroidal carbothioic acid.
In a very interesting embodiment, the invention relates to the use of a compound of the invention as an intermediate in a method for preparing fluticasone prapionate, especially in a method which comprises reaction with a nucleophilic agent comprising a sulfur atom [such as sodium hydrosulfide hydrate] and/or comprises reaction with an electrophilic agent [such as a C1-6 di- or trihaloalkane, preferably a trihalo- or a dihalomethane such as chlorofluoromethane or bromofluoromethane].
The method as described herein relates in a presently preferred embodiment to the conversion of androstane 17ß-carboxylic acids to 17ß-carbothioates such as e.g. fluticasone propionate via novel in situ activated 17ß-carboxylic acid intermediates. In a preferred embodiment of the method the 17ß-carbothioic esters are prepared by reacting an acid of formula (II) with a coupling agent in conjunction with a coupling enhancer. The terms "coupling agent' and "coupling enhancer" are herein used to refer to chemical reagents that facilitate the formation of a reactive intermediate of
formula (III) where Z represent a group with the structural formula (D) or formula (E). Such intermediates may be formed between androstane I7ß-carboxylic acids and a carbodiimide derivative such as l-ethyl-3-ß-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (a preferred example of a coupling agent) in combination with suitable coupling enhancers. Suitable coupling enhancers as used herein can for example be represented by the structures of formula (D) and formula (E) as described above.
The coupling agent and the optional coupling enhancers are preferably water-soluble so the reactions could be effected in aqueous solutions if preferred.
Presently considered the best mode of the invention:
Compounds of formula (III) as defined hereinbefore may be prepared by treating a compound of formula (II) with EDC in combination with a compound of formula (D). The resulting 17ß-carboxy tmidazolyl ester, which may be isolated if required, is treated with a nucleophilic agent (a sulfur source) that displaces the active ester group to form a compound of formula (IV), In one embodiment of the invention R9 may represent optionally substituted C1-6 alkyl groups like e.g. methyl, ethyl or a isopropyl group (preferably substituted with a halogen atom), or a 5-6 membered heterocyclic ring containing either oxygen, nitrogen or sulfur, the said heterocyclic ring being optionally substituted by a oxo group on either of the ring carbons. Compounds of formula (IV) may readily be isolated. la another embodiment of the mvention, R9 represent a hydrogen atom or a salt. Preferred examples of salts include alkali metal salts; e.g. Li, N~a or K, alkaline earth metal salts; e.g. Ca or Mg, tertiary amine salts; e.g. pyridurium, triethylammonium or diisopropylethylamine salt, or quaternary ammonium salts; e.g. tetrabutylammonium salt. Such compounds of formula (IV) may be isolated if necessary. Subsequent addition of an electrophilic agent leads to the formation of compounds of formula (I) as depicted hi scheme 1, wherein R10 is a C1-6 haloalkyl, a fluoro-, chloro-, or bromomethyl group, a diffuoromethyl or a trifluoromethyl group, or a 2-fluoroethyl group.
Preferably the nucleophilio agent is a hydrogen sulfide or a salt thereof or more preferably a hydrated sulfide salt such as sodium hydrosulftde hydrate.
Preferably the electrophilic agent is chlorofluoromethane or more preferably bromofluoromethane.
In a preferred embodiment of the present method, compounds of formula (III) as defined hereinbefore may be prepared by treating a compound of formula (II) with EDC in combination with a compound of formula (E). The resulting l7ß-carboxy succmimidyl ester which may be
isolated if required is treated with a nucleophilic agent that displaces the active ester group to form a. compound of formula (IV) as defined hereinbefore. Subsequent addition of a electrophilic agent conclude tine synthesis towards compounds of formula CO as depicted in scheme 1, wherein R10 is a C1-6 haloalkyl, a fluoro-, chloro-, or bromomethyl group, a difluoromethyl or a trifluorometliyl group, or a 2-fluoroetiiyl group. The formation of compounds of formula (I) may take place hi a one-pot reaction starting with compounds of formula (II) without isolation of the intermediates of formula (III) and (IV) if e.g. sodium hydrosulfide hydrate is used as the nucleophilic agent.
The use of a coupling enhancer in combination with a carbodiimide forms an active ester intermediate of formula (III) with increased stability and reactivity. These intermediates have an increased threshold against competing hydrolysis reactions. The reduced level of hydrolysis raises the efficiency regarding the formation of products of formula (I) (scheme 1, see below) where RIO is defined as hereinbefore.
Surprisingly, we have found that the use of these novel I7ß-carboxy succinimidyl- and 17)3-carboxy imidazolyl esters of formula (III) reduce the cycle time, increase the yield and enhance the purity of the final product of formula (I).
Compound preparation
The method of the disclosed invention will be better understood when related to the following
synthetic scheme, which illustrates a preferred embodiment of the method as described herein.
Moreover, persons skilled in the art will be aware of variations of, and alternatives to the method
described hereinafter. The provided examples will demonstrate the synthesis and allow compounds
defined by formula (I) to be obtained. In scheme 1, the substituents have the above-defined
meaning.
Scheme 1
(Formula Removed)
The androstane 17ß-carboxylic acid starting materials employed in the present invention may be readily prepared by any means known in the art. Compounds of formula (II) can be prepared by oxidation of a suitable 21-hydroxy-20-keto pregnane of formula (V) as taught in e.g. US3636010 (example 1).
(Formula Removed)
Compounds of formula (V) which are commercially available include e.g. budesonide, desonide, triaraoinolone aoetonide, fluocinolone acetonide, betamethasone, dexamethasone, prednisolone, flumethasone, beclometbasone, icomethasone, diflorasone, hydrocortisone and fludrocortisone.
The method as described herein will now be described in detail in connection with other particularly preferred embodiments of scheme 1. Thus, me following and not limiting examples will illustrate an especially preferred methodology. The examples are presented to provide what is believed to be the most useful and readily understood description of die procedures and conceptual aspects of the method described herein.
Examples
General
MS (ESI) refer to mass spectra obtained using electrospray ionisation techniques. Melting points
were obtained using a Mettler FP8I MBC cell and are uncorrected. The purity of the products was
determined by RP18-HPLC analysis using UV-detection at 239 run.
Abbreviations; DMF (N,N-dimethyUbrmamide), DMA (N,N-dimethylacetamide),
THF (tetrahydrofurane), EDC (l-ethyl-3-(3-dimethyl-iaininbpropyI)carbodiimide
hydrochloride), NHS (N-hydrojcysucoinimide), NMI (N-methylimidazole) and DCI
(4,5-dicyano-imidazole).
Example 1
6α,9α-difluoro-l lß,17α-diydroxy-16α-meihyl-
3-oxoandrosta-l,4-diene-17ß-carboxylic acid 6α,9α-difluoro-llß-16α-21-trihydroxy-16α-methyl-pregpa-1,4-diene-3,20-dione(flumetasone)
(525 g, 12.78 mmol) was dissolved in THF (25 ml) at 0 °C. To the stirred solution, periodic acid (2.0 eq., 5.83 g in 12 ml H2O) was added drop wise. The reaction flask was covered in aluminum foil after 75 minutes and left stirring at room temperature. The reaction was quenched after 4.5 hours by addition of water (120 ml) and left in a refrigerator over-night. The resulting precipitate was filtered, washed with water until the filtrate was neutral to pH-paper and dried under reduced pressure. The title compound was obtained as a white solid (4.96 g, 93%), with a purity of >99% byHPLC.
Example 2
6α,9α-difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17 ß-carboxylic acid
A suspension of 6α,9α-difluoro-11ß,17α-dihydroxy-16α-methyl-3-oxoandrosta-l,4-diene-17p-carboxylic acid (4.11 g, 10.38 mmol) in acetone (30 ml) was added Et3N (3.5 eq., 3,7 ml) under N2 and stirring. The resulting solution was cooled to 0 °C and propionyl chloride (4.5 eq., 43 ml) was added drop wise to a white suspension. After 85 minutes Et2NH (10.0 eq., 7.6 ml) was added and the resulting mixture was left stirring for 55 minutes at 0 °C, before the solvent was removed under reduced pressure. The resulting solid was dissolved in water (20 ml), and treated with IN HC1 to pH 2. The white precipitate thus formed was filtered, washed with ice cold water and dried under reduced pressure at 60°C, The title compound was obtained as a white solid (4.64 g, 99%) with a purity of 99% by HPLC.
Example 3 S-fluorornethyl 6α,9α-difluoro-l lß-hydroxy-16α-methyI-3-oxo-17α-propionyloxyandrosta-l ,4-
diene-17ß-carbothioate (fluticasone propionate)
A flask charged with 6α,9α-difluoro-l lß-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-l,4-diene-17ß-carboxylic acid (0.30 g, 0.66 mmol) In DMA (30 ml) at-50 °C was added EDC (3.0 eq., 0.38 g) and NHS (3.1 eq., 0.24 g) and left stirring until the reaction was complete, as monitored by HPLC analysis. The oil bath was toned off and sodium hydrosulfide hydrate (20.0 eq., 0.74 g) was added in one portion at -35 °C. The addition Immediately resulted in a strongly blue colored reaction mixture. After 15 minutes the reaction was complete and gaseous bromoiluormefnane was added at room temperature. The initial blue color gradually changed to pale yellow during the additioa of bromofluoromethane. On completion of the reaction, after 15 minutes, as monitored by HPLC analysis, sodiumcarbonate (25 ml, 10% in water) followed by water (10 ml) was added to the cooled reaction mixture. The solid thus formed was filtered, dissolved in mctbanol (40 ml), heated to reflux and filtered. Temperated water (40 ml) was slowly added to the warm filtrate. The beginning suspension was left at room temperature for two hours before cooling in a refrigerator. The resulting precipitate was collected by filtration, washed with water (40 ml) and dried under reduced pressure. The title compound was obtained as a white amorphous solid (0.25 g, 92%) with a melting point of 267 °C and a purity of >98% by HPLC. Spiking of the product sample with the British Pharmacopoeia Standard (melting point: 265 °C) of fluticasoae propionate, showed one peak fay HPLC analysis.
Example 4
6α,9α-difluoro-l 1 ß-hydroxy-16α-methyI-3-oxo-l 7α-propionyloxyandrosta-l,4-diene-17ß-carbomiotc acid
A flask charged with 6α,9α-difluoro-11ß-hydroxy-16α-methyl-3-oxo-l7α-propionyl-oxyandrosta-l,4-diene-17ß-carboxylic aoid (0.30 g, 0.66 mmol) in DMA (30 ml) was heated to -50 °C. EDC (3.0 eq., 0.38 g) and NMl (3.1 eq., 162 µl) was added and the reaction mixture was left stirring until the reaction was complete, as monitored by HPLC analysis. The oil bath was turned off and sodium hydrosulfide hydrate (20.0 eq., 0.74 g) was added in one portion at ~35 °C. The addition immediately resulted in a strongly blue colored reaction mixture with some precipitation. After 15 minutes the reaction was complete and crushed ice followed by 2N HC1 (10 ml) to pH ~2 was
added and the flask was left in a refrigerator. Ouring the addition of HCI, the initial bluish reaction mixture gradually became colorless. The solid thus formed was filtered and a minimum amount of acetone following temperated water was added to a beginning crystallisation. The refrigerated suspension was filtered, washed with water (30 ml) until the filtrate was neutral to pH-paper and dried under reduced pressure. The title compound was obtained as a white amorphous solid (0,10 g, 32%) with a purity of 98% by HPLC.
Example 5
S-melhyl 6α,9α-difliioro-11ß-hydroxy-16α-methyl-3-oxo-
17α-propionyloxyandrosta-l,4-diene-17ß-carbothioate
6α,9α-difluoro-1lß-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-l,4-diene-l7ß-carboxylic acid (0.20 g, 0.43 mmol) was dissolved in DMF (10 ml). The reaction flask was immersed in an oil-bath and the temperature was raised to ~40 °C. EDC (~2 eq., 0.15 g) and NHS (~5 eq., 036 g) was added and the reaction mixture was left stirring at 40 °C for 19 hours. The temperature was raised to 50 °C and another portion of EDC (-4 eq., 0.29 g) was added. The mixture was left stirring at 50 °C for 3 hours. The flask was removed from the oil-bath and the reaction mixture was diluted by the addition of DMF (5 ml). Aqueous NaSMe (1,0 ml, 21% solution in water) was added in portions over a period of 30 minutes. The reaction mixture turned into a pale pink suspension. The reaction was quenched by the addition crushed ice and aqueous HCI (12 ml, 10%). The white precipitate was filtered, washed with water and dried. The crude product was dissolved in a minimum amount of acetone and water was added until a beginning precipitation. The resulting solid was collected by filtration, washed with water and dried under reduced pressure to yield the title compound as a white solid (0.11 g, 51%) with a purity of 90% by HPLC.
Example 6
S-methyl 6α-9α-difluoro-lIß-hydroxy-16α-methyl-3-oxo-
17α-propionyloxyandrosta-l ,4-diene-I7ß-carbothioate
Charge a flask with 6α,9α-difluoro-1 1ß-hydroxy-16α-methyl-3-oxo-17α-propionyl-oxyandrosta-l,4-diene-17ß-carboxylic acid (0.30 g, 0.66 mrnol) in DMA (30 ml), and heat the contents to ~50 °C. Add EDC (3.0 eq., 0.3 8 g) and NMI (3.1 eq., 162µ,l) and leave the mixture stirring until the reaction is complete, as monitored by HPLC analysis. Turn off /remove the oil bath and add aqueous NaSMe (1.5 ml, 21% solution in water) in one portion at ~35 °C. The reaction is quenched by the addition of crushed ice and aqueous HCI (12 ml, 10%). The white precipitate is filtered, washed with water and dried. The crude product is dissolved in a minimum amount of acetone and
water is added to induce precipitation. The resulting solid is collected by filtration, washed with water and dried under reduced pressure to yield the title compound as a solid.
Example7 S-fluoromethyl 6α,9α-difluoro-11 ß-hydroxy-16α-methyI-3-oxo-17α-propionyloxyandrosta-1,4-
diene-17ß-carbothioate (fluticasone propionate)
Charge a flask with 6α,9α-difluoro-l lß-hydroxy-16α-methyI-3-oxo-17α-propioiiyl-oxyandrosta-l,4-diene-17ß-carboxylio acid (0.30 g, 0.66 mmol) in DMA (30 ml) and heatthe contents to ~50 °C. Added EDC (3.0 eq., 0.38 g) and DCI (3.1 eq.) and leave the mixture stirring until the reaction is complete, as monitored by HPLC analysis. Turn off/remove the oil bath and add sodium bydrosulfide hydrate (20.0 eq., 0.74 g) in one portion at ~35 °C. After x minutes the reaction is complete and gaseous bromofluoromethene is added at room temperature. Upon completion of the reaction, as monitored by HPLC analysis, sodium carbonate (25 ml, 10% in water) and water (10 ml) is added to the refrigerated reaction mixture. The solid which forms is filtered and dissolved in methanol (40 ml). The methanolic solution is heated to reflux and filtered Temperate water (40 ml) is added slowly to the warm filtrate. The resulting suspension is left at room temperature for two hours before being transferred to a refrigerator. The precipitate which forms is collected by filtration, washed with water (40 ml) and dried under reduced pressure. The title compound is obtained as a solid.

WE CLAIM:
1. A method for preparing a steroidal 17ß-carbothioic acid of formula (IV) or a salt thereof,
(Formula Removed)
wherein the symbol in the 1,2-position represent a single or a carbon-carbon
double bond;
R1 represents a hydrogen atom, a hydroxy- or an alkoxy group in the α-
configuration, a group -O-C(=O)-R6, where R6 is an alkyl group or an
optionally substituted 5-6 membered heterocyclic ring containing either
oxygen, nitrogen or sulfur as ring hetero atom;
R2 represents a hydrogen atom, a hydroxy group, an alkoxy group in the α-
configuration, an alkyl group which may be in either the α- or ß-
configuration, an alkylene group or R1 and R2 together represent
(Formula Removed)
where R7 and R8 are the same or different and each represent a hydrogen
atom or an alkyl group;
R3 represent a hydrogen atom, hydroxy- or a protected hydroxy group in
either the α- or ß-configuration or an oxo group;
R4 represents a hydrogen- or a halogen atom or R3 and R4 together represent
a carbon-carbon bond or an epoxy group in the ß-configuration; and
R5 represents a hydrogen- or a halogen atom in either the α- or ß-
configuration;
R9 represents a hydrogen atom or R9 represent a metal ion; the method
comprising;
step A) reacting a steroidal 17ß-carboxylic acid of formula (II) or a salt
thereof
(Formula Removed)
in which the substituents of formula (II) have the above defined meaning with a coupling agent selected from the group consisting of carbodiimide
derivatives represented by the following formula:
(Formula Removed)
wherein Ra and Rb are the same or different, and each represent an
aliphatic, heteroaliphatic, carbocyclic or a heterocyclic group; alone or in
conjunction with a coupling enhancer;
step B) followed by the reaction with a nucleophilic agent comprising a
sulfur atom; and optionally
reacting the product of step B) with an acid such as herein described.
2. A method as claimed in claim 1, in which the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.
3. A method as claimed in claim 2, in which the coupling agent is the
hydrochloride salt of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide.
4. A method as claimed in any of the preceding claims, in which the
coupling enhancer is selected from the group consisting of:
A) a heterocyclic ring containing one or two nitrogen atoms, said ring being
optionally substituted; such as a compound of formula (D) or formula (E),
(Formula Removed)
wherein R11 and R12 are the same or different, and each represent a hydrogen atom or a cyano group; R13 represent a hydrogen atom or an alkyl group; and R14 represent a hydrogen atom or a salt of a sulfonic acid; and
B) an unsaturated 5-6 membered heterocyclic ring fused to an aromatic- or
heteroaromatic ring in which the said heterocyclic ring contains three
nitrogen atoms, said rings being optionally substituted, such as a compound
of formulas (F) or formula (G),
(Formula Removed)
preferably 6-chloro-hydroxybenzotriasole, 7-aza-hydroxybenzotriasole, or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine.
5. A method as claimed in any of the preceding claims, where the
nucleophilic agent comprising a sulfur atom is selected from the group
comprising:
compounds of formula [M]+[SH]- wherein M is a metal, or [M]2+[S]2'
wherein M is a metal, and
an in situ generated sulfide salt of a hydrated sulfide salt.
6. A method as claimed in any of the preceding claims, wherein
nucleophilic agent dissolved in a suitable solvent prior to addition to the
reaction mixture, or wherein the nucleophilic agent is added in the form of a
solid salt or as a solution of the salt in water and/or an organic solvent or a
combination thereof.

Documents:

4538-DELNP-2005-Abstract-(03-11-2008).pdf

4538-DELNP-2005-Abstract-(09-06-2009).pdf

4538-delnp-2005-abstract.pdf

4538-DELNP-2005-Claims-(03-11-2008).pdf

4538-DELNP-2005-Claims-(05-05-2009).pdf

4538-DELNP-2005-Claims-(09-06-2009).pdf

4538-delnp-2005-claims.pdf

4538-DELNP-2005-Correspondence-Others-(03-11-2008).pdf

4538-DELNP-2005-Correspondence-Others-(05-05-2009).pdf

4538-DELNP-2005-Correspondence-Others-(06-05-2009).pdf

4538-delnp-2005-correspondence-others.pdf

4538-DELNP-2005-Correspondence-Otners-05-12-2008.pdf

4538-DELNP-2005-Description (Complete)-(03-11-2008).pdf

4538-DELNP-2005-Description (Complete)-(09-06-2009).pdf

4538-delnp-2005-description (complete).pdf

4538-DELNP-2005-Form-1-(05-05-2009).pdf

4538-DELNP-2005-Form-1-(09-06-2009).pdf

4538-delnp-2005-form-1.pdf

4538-delnp-2005-form-13-(05-05-2009).pdf

4538-delnp-2005-form-18.pdf

4538-DELNP-2005-Form-2-(03-11-2008).pdf

4538-DELNP-2005-Form-2-(05-05-2009).pdf

4538-DELNP-2005-Form-2-(09-06-2009).pdf

4538-delnp-2005-form-2.pdf

4538-DELNP-2005-Form-3-(03-11-2008).pdf

4538-delnp-2005-form-3.pdf

4538-DELNP-2005-Form-5-(05-05-2009).pdf

4538-delnp-2005-form-5.pdf

4538-DELNP-2005-GPA-(03-11-2008).pdf

4538-delnp-2005-gpa.pdf

4538-DELNP-2005-Others-Document-(05-05-2009).pdf

4538-delnp-2005-pct-210.pdf

4538-delnp-2005-pct-220.pdf

4538-delnp-2005-pct-237.pdf

4538-delnp-2005-pct-409.pdf

4538-delnp-2005-pct-416.pdf

4538-DELNP-2005-Petition-137-(03-11-2008).pdf

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Patent Number

235092

Indian Patent Application Number

4538/DELNP/2005

PG Journal Number

31/2009

Publication Date

31-Jul-2009

Grant Date

24-Jun-2009

Date of Filing

06-Oct-2005

Name of Patentee

AXELLIA PHARMACEUTICALS APS

Applicant Address

11 DALSLANDSGADE, P.O.BOX 1736,DK-2300 COPENHAGEN S,DENMARK

Inventors:

#	Inventor's Name	Inventor's Address
1	BJOERN REITSTOEN	EKELYVELEN 4B,NO 0374 OSLO, NORWAY
2	MAGNY FIVELSTAD	SOGNSVEIEN 131B, NO-0855 OSLO,NORWAY
3	TROND LOEVLI	WELHAVENS VEI 2,NO-1412 SOFIEMYR, NORWAY
4	ANNE-METTE NYGAARD	HARALD HAARFAGRES GATES 10B,NO-0363 OSLO,NORWAY

PCT International Classification Number

CO7J 3/00

PCT International Application Number

PCT/DK2004/000242

PCT International Filing date

2004-04-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2004 00449	2004-03-19	EPO
2	03007756.4	2003-04-04	EPO