IE45276B1 - 11 -amino-3 hydroxy steroids - Google Patents

11 -amino-3 hydroxy steroids

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Publication number
IE45276B1
IE45276B1 IE712/77A IE71277A IE45276B1 IE 45276 B1 IE45276 B1 IE 45276B1 IE 712/77 A IE712/77 A IE 712/77A IE 71277 A IE71277 A IE 71277A IE 45276 B1 IE45276 B1 IE 45276B1
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Ireland
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group
compound
compounds
hydroxy
preparation
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IE712/77A
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IE45276L (en
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Glaxo Lab Ltd
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Publication of IE45276B1 publication Critical patent/IE45276B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J21/005—Ketals
    • C07J21/008—Ketals at position 17
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0011—Unsubstituted amino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0016—Oximes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Anesthesiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

STEROID OF THE FORMULA: (SEE PHOSETYL) WHEREIN R IS A GROUP - NHR, WHEREIN R IS A HYDROGEN ATOM OR AN ALKYL GROUP ALKYLSULPHONATE, ARYLSULPHONATE CYCLOALKYL OR BENZYL OR AN ALKENYL IN THE REQUEST. [FR2485020A1]

Description

This invention relates to anaesthetic steroids.
Many steroids possessing anaesthetic activity are 4 now known, these mostly being 3a-hydroxy 5 a or Δ compounds in the 17a-unsubstituted 20-oxo-pregna.ne and androstane series, the best compounds often having an 11-oxo group. These compounds are mostly insufficiently soluble in water, and it has been necessary to formulate them for administration in aqueous solutions of parenterally acceptable non-ionic surface active agents as for example described in our Patent Specification No. . 35204 with regard to the important anaesthetic 3ahydroxy-5a-pregnane-ll,20-dione. Anaesthetic steroids are also known which possess water-solubilising groups at various positions on the steroid nucleus, for example at the 2β- or 3a-position or the 21-position in a pregnane or the 17p-position in an androstane, but the introduction of the water-solubilising group has frequently resulted in a fall in activity or stability.
He have now found very interesting anaesthetic activity in a group of 3a-hydroxy 5α-, 5β- or to Δ^ pregnanes and androstanes and their DhonQ analogues possessing an amino group, di-substituted by aliphatis or araliphatic - 2 /: zo 7G gseup.3, heturccyci aixi.u'. grcuy at the ilopoeit-ios, particularly 5u the vv uolubis cults of fcaese compounds Λλ *:’- i_.C... λί'. ·:·.....; uu-'iucusu :::-.- p:: steroids ox tka SosEulat ,10 ΚΟΚ5 (1) I .- f'. K' whei-oin . is a i+cnp -'•ϊΰ'Ί?.-, ir. which R aud R (which Bay be the sate ex different) era C._ alkyl. G,_, alkenyl, or b cycl-’-slkyl .rcu;v (provided that and R together contain 2-7 earbor. atoms and that, when Ra and/or Rb is sa :.7:.:-:.. the carbon atoj. cr stems adjacent to tr.c Td.trogen :λ& group "M8aRb is or are saturated), :: i« which one of Re and Rb is a benzyl cr phsu&thy1 grcup, the other group being a methyl group, or in which Rfi and Ru (together with the nitrogen atom) represent an asitidino, pyrrolidine, piperidino, hesMmethyierimino -or raorphol tno group, which - 3 45276 groups may optionally be substituted by one or two methyl groups; R is a hydrogen atom or a alkyl group: R^ is a hydrogen atom or a alkyl, alkoxy (which may ba optionally substituted by a halogen atom, e. g„ chlorine), benzyloxy, C2_g alkanoyloxy, or thiocyanate group or a halogen atom; R is a hydrogen atom or a methyl group; is a hydrogen atom or a methyl group; 8 R represents a hydrogen atom or (except when R is a group (c) as defined below) a chlorine atom; and 9 9 R is (a) a cyano group; (b) a group -COR where R is a methyl group or such a group substituted by a fluorine atom^ a alkoxy, hydroxy, alkyl, methoxymethyl, ethoxymethyl, alkanoyloxy, benzoyloxy, or &2-5 g alkoxycarbonyloxy group; or where R is a alkoxy or cyclopropyl group; or where R$ is the group -ΝϊΛΐ^ where SX and r7 (which may he the same or different) are methyl or ethyl groups; or (c) a vinyl group or together with R^ a Z-substituted methylene group in which the substituent is a methyl or cyano group; - 4 45276 R^w is r. hydro^ar; f.tom (:::-sopt wfei-. Re and Κ^θ together represent & Ξύ:ε·ί:.ζαί^ά methylene group); the broken lines iadi^te the optianal prsssnee of double bonds at She positions shown; .-.,3 4 provided that at leacf one of '? and S' is a hydrogen ate®; s,i:i - ' and ' togs&er raprejeaf a hydrogen atom wneaa 1,2-doublc bond is present} and that the 2*>position is saturated man a 4,5-double bond is present; end _A that R is a hydrogen ate®;, u' io a hydrogen atess or a methyl group and P? is o. hydrogen afcca or optionally (when K" is a hydrf. . = atom) a methyl group when a 5phydrogen atom is r«;--?3at; δ and the D-he:?.o ar.iiiogues thereof carrying R at the 17a6"positoi\ ; D1-'' at the 'i/'aa-pasit^on and R at the 17-posifcian; and the acid addition salts thereof.
In the tests we nave carried out, the compounds of the invention have been shown generally to bo good anaesthetics, usually· giving rapiz induction of anaesthesia when administered intravenously. The wafer soluble salts are particularly important in that they can ba formalafcsc in aqueous solution and in general comparison to known water soluble anaesthetic steroids they are superior as regards their potency and/or quality of anaesthesia and/or freedom from side effects such as thrombophlebitis. The aqueous solutions of the water soluble salts have also in general been found to be Very stable. The compounds of the invention are of use for inducing anaesthesia which is to be maintained for example by an inhalation anaesthetic, such as ether, halothane, nitrous oxide or trichloroethylene. The compounds may also be capable of maintaining , anaesthesia to a sufficient degree to enable surgical operations to be conducted without the aid of an inhalation anaesthetic, the anaesthesia being maintained if necessary by repeated or continuous administration. The compounds may have other useful central nervous system depressant activities, for example they may be of use as sedatives.
As indicated above, the R and R groups may be alkyl groups, which may be straight or branched, such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, pentyl, iso-pentyl or 1,3-dimethylbutyl groups; or Q T·» ^3=6 alkenyL groups such as allyl groups. When R or R is a cycloalkyl group, it may be for example a cyclopentyl or cyclohexyl group. - 6 ¢5276 Whsa me cf if'1 and ii a C3-6 alkeayl group there is preferably only yea double bond present, e.g, as in an allyl group, and the other group is preferably an ulkyl group; 6.. χ, ε cuthyl group.
’Ibm eR^T-y .mras mc m.-moeyeiic group, it is prefer.:!) w a pyrrolidine group.
Preferably one of S and S is a methyl group, the other gems being a methyl, athyl, propyl, iso-propyl or butyl group. Cgbsh.·. ''herein both ya and Se are , methyl groups are er.»scisliy preferred. tfiisn e za'E ? is present, it is preferably & sethy'. group. i'Jtiers ?' rs a nisthyl group tbs 6-position is preferably saturated, Gonspornds having & 2S(R^}-substituent are particularly important in 3 Compounds in the 5c;- and 58-hydrogen series are generally preferred, as are compounds in which the tetracyclic steroid system is saturated and in which Rb and R? are both hydrogen atoms; R5 is also preferably a hydrogen atom, When the steroid rings are unsaturated, Δ8-compounds are preferred.
One group or compounds of the invention is compounds in which RS and Rb are other than benzyl or phenethyl groups; 9 9...R is other than the group -COR where R is a metnyi group substituted by a C2-4 a^kyl group; and in which R^and R^ are all hydrogen atoms when a 50-hydrogen atom, is present.
A preferred group of compounds are those of formula wherein: R1 is a group -WRaRb, in which one of Ra end Rb is a methyl group, the other group being a methyl, ethyl, propyl, iso-propyl, butyl or allyl group, or in which both R and R are ethyl groups, or in which Ra and Rb (together tiifch the nitrogen atom) represent a pyrrolidino group; - 8 45276 R is a hydrogen atom or a methyl group; R^ is a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, acetoxy or thiocyanate group or & fluorine, chlorine or bromine atom; S 9 R is (a) a cyano group; (b) a group-COR where g R is a methyl group or such a group substituted by a 9 methyl, hydroxy or acetoxy group, or R is a cyclopropyl group; or (c) a vinyl group or, together with R^, a Z-ethylidene group; and R^ is a hydrogen atom (except when and R^ together represent an ethylidene group); the broken lines indicate the optional presence of a double bond ' at the 1,2-position; provided that at least one of RJ and R4 is a hydrogen atom; that R^ and R^ together represent a hydrogen atom when a 1,2-double bond is present; and A that RJ is a hydrogen atom and R* is a hydrogen atom or a methyl group when a 5β- hydrogen atom is present; and the D-homo analogues carrying R at the 17af310 position and R at the 17a - 9 45276 9 R is preferably a cyano group or a group -COS g where R is a methyl group (optionally substituted by a hydroxy, methyl or acetoxy group) or a cyclopropyl group. The 1,2-position is preferably saturated, θ In the compounds of formulae (l) and (II) R is preferably an acetyl or cyano group; R^ is preferably a hydrogen atom when a 5p-hydrogen atom is present, or is a hydrogen atom or an alkoxy group, advantageously an ethoxy group, when a 3a-hydrogen atom is present; and R is preferably a hydrogen atom. It is 8 especially preferred for R to be an acetyl group, slag D to have 5 members and for -WRaR^ to be a dimethylamino group. 5a-Goiflpounds are most preferred.
As indicated above, the ability of the bases of the invention to form water soluble acid addition salts is particularly Important. Thus, the compounds of the invention in the form of their bases can be formulated simply in aqueous acidic solution.
Examples of suitable salts are hydrochlorides, hydrobromides, phosphates, sulphates, g-toluenesulphonates, methanesulphqnutes, citrates, tartrates, acetates, ascorbates, lactates, maleates, succinates, tricarballylates, ¢5276 glutarates, aconitates - citraccnates, mesaconates, salicylates «ad glutcor vser, 1.-.-= citrate cad hydrochloric-¾ l=-Its ars purticulo.·.·!·.·· preferred for use as anaesthetics.
When these saifcc ars used as anaesthetics they should be physiologically acceptable at the dosage at which they are adKiui*;:c..Ίύ. Other salts may, however, be of use in for steeple. isolation of the product from a synthetic reactiv.·. frefarrod compounds are: 1. Ila·. 1.: •ii«seshyi.cjaino-3u-h7-roxy-5a-pregnan-20-one} 2. liK-K,K-aimethy'i.amiriC’>2C-eth&xy-3a-hydrosy-5apregnaa"20--:-i.as 3. nahsf:Gim9thyi£®ir'?"£K-iiydroxy"26~ms£hyi-5a15 pregMai-ZO-one; 4. lla-ii,r'- ) - 11 .. . lla"N5N-dimethylamino-3a-hydroxy-5p-pregnan-20one; 6. lla-N,N-dimethylaffiino-3a-hydroxy-5a-androsfcane17p-carbonitrile . 7. lla-N»butyl"N-methylamino-3a-hydroxy"5a-pregnan20-one; 8. 2p-chloro-lla-N ,N-dimethylantino-3a-hydroxy-5apregnan-20-one; 9. lla-N ,N-dimethylamino-2p-£luoro-3a-hydroxy-5a1θ pregnan-20-one; . lla-N,N-dimethylamino~3a-hydroxy-2p-methoxy-5apregnan-20-one; 11. 2p»ethoxy"lla-N-ethyl"N-methylamino-3a-hydroxy~5a pregnsn-20-one; 12. lla-N-ethyl-N-methylamino-3a-hydroxy"5a-pregnan20-one; 13. 3 a=hy dro xy-11 a-N-methyl -N-propy lami.no - 5 a-pr egnan20-one; - 12 45276 & >y,KgE„n"£C-»oc; , 3-47-1:-:7- ':.. .: ' 3:.:.-2--. ?i,-i"Siihy.!.£ffi.^t.iw=2S" xach'.:r.· -2-. p_/://..//1^/0==///=2 ib, ’,li2-.«-n.'i;-l"N«-.aei;.hyi£aino"23"3i;hoxy-3«-hydzo35y5^-//·56//ε/ι-24» -·<··.;«, 17. 2----.:1/ :/-y :,/-4 ΐ. "pyrroliiiao«5G-p?cgnas20» r-y.} IS. /.Is-ZI / 5s-pr^/;;'a//«2C-.··.. = 19, « λ/;=- / 7- ·'/ .asi.hyj awi/i;?-’? -oay-2 > i so-propory5-x-f/-/3://.. -. /- -on?. 5 ρϊβ£:///-·"20='ί;-Κί 21 SS-aieto?:/-//K-n"S//i;'/.=’N-mefcisylsalno»3e:"Ey'dSOj3i'"’ Sk»c reii/?/2»-/0-=‘vis = 21, 20--s-;.-./.‘)?.y-3;>N«icc"propyl-il-inafcliy'l·· aii-iao-*3a'"-jregaaa-?.0 ·(: = 22, 33K^/'i"s2uyl*'i?-niei:;i'\:-aminG-20«=fluoro"3K-hydroiiy20 5a-pregn«.i-2u-one; 24. 2g-fluoro-3a:-hydi:oxy-ll(t-N-iso-propyl-K"Ptethylamino-5a-pregnan"20=one; . 2p"chloro-lla->K-efchyI-N"iaathylamii3O"3a;-hydroxy" 5a-pregnan-20-one ; 26. 2gchloro-3g-hydroxy°llo:°ii"iso-pro'pyl-H-niethyl asnino-5a-pregnan-20-one s 27. 2p"bromo"lla"N,W"dimethylamino-3g-hydroxy-5Kpregnan-20-one; 28. lla-N,N-dimethylarainO"3a"hydroxy"2P"thiocyanato 5 α-pregnan-20-one; 29. lla-N,N-dimethylamino"3a"hydro3cy"5a"pregn"l-en20-one; . llrc-K 5N"dimafchylamino"3K"bydroxy-D"homo"5a" pregnan-20-ones 31. lla-N,R-dimethylamino"2p~ethoxy-3a-hydroxy-Dhomo-5a-pregnan"20~one; 32. lla-N,K"dimethylamino=21,21-ethylene-3a-hydroxy 5a-pregnan-20-one; 33. ila-N ,K"dimethylainino-3£i-hydroxy"21-methyl-5apregnan-20-one; j6,. i'i-x-L' ;-c'=-di^y"5:3=prsgS£.»"2O" ΰΐ.:: ΐ /. 2: -hγ:; :. ~γ - λ ic- '. - -Τ-~ y’-kwte thyl&vdffio- 3β-·20·ΌΤ.5 ; 3€ - 2 λε--·>7·--eth·/1 - .,'--KsstJ::.<,.C3ino=3c:"hyGix;:»y"36"prsg£K;a...0 ?·'·.,,· ·„. ::. ; ::4-- .7' :4::~/^il::4· : .- 2G-®®; TO. : , Ί - .ii:-,c..3a«»hy&ro:ry«50 prSii. . . t; = li::-: j: :. >aridro£fcans" - .7--ciimefhylamiiiO"2S -:4:::^--4:: =170^-3:3^-50 .,~ : -... i?_ -; : -.4: ::ie; 4 77,- 77 ~-e77-7;e:.ei'.y/i:..:7.nO"3i=hy&i.:3r5a-presr. 17(20)>0 S. :.- 45276 44, methyl lla-N,N-dimethylamino-26-ethoxy-3a-hydroxy5a-androstane-17f!=carbQxylate$ , 1Ια-N, N-dimethy lamino-3ct:- hydroxy- 5 α-pregn- 20( 21) -ene; 46, 2j3"'butoxy-lla-N,N-ditnethylamino-3ff"hydroxy"5o;" pregnan-20-one; 47, 1 l All of the above compounds have shorn good activity ' in our tests in the form of their citrate salts in aqueous solutions (sometimes in the presence of sodium and chloride ions). Good activity has similarly been shown in our tests for the tricarballylate, hydrochloride, phosphate and methanesulphonate of compound Wo, 1; the acetate, methanesulphonate, lactate, phosphate, tartrate, tricarballylate, hydrochloride, succinate, citraconate, aeonitate and mesaconate of compound No. 2; the acetate, hydrochloride, tartrate, lactate, tricarballylate, phosphate, methanesulphonate and succinate of compound No. 55 and the acetate salt of compound No. 10.
Of the above-mentioned compo;«ds, compound Nos. 1, 2, 5,6,8,9,31,36-38,41 and 42 and their salts are particularly preferred. 2:::2 Γί. ma citrate; 1, . . . 2 ¢: ·. 2:, «hyaio- .,0):'’. ’· J --2...... yymticylariy ' -. .· . -i‘ » ·.. : :::: <: ..„:. .., · ;: · :.1, • ·. .. : i -' ,,:.- .: 2 ..: :. . ,-1. m:.. 20 : . :: :::. :::-. ,: .::, . ::: . :-2- OK :..-. 22 2.2 0:.12.2.:: 11.1 --.I . ......J Ol·.* ..::2.-. '·. . . .· . : - . :2: ts glim :/ -:: /. 2:: -. . . ... :: ::::: in/miim comprises , -.: .: ::::: :: mmion comprising Ϊ3 om. v. ::.....,. : . .:. . . · . ...·· Ihs ::.-::.-:.-.2,: 22. : . .2-: mify :'..I £ i.X ,/ ..:. _. .,2.. 2..- ... : :. 2.· — , - :, prassnts-i in uqrimuo , , - . ,- ,:, Ot diO J-ti I--’-. :1.- :,- ,-.1/ ,:: '.I.:-·., bases into ://. -:.:.,.::: ml. 1 mm ..2::1 bales». ?or induction ,//,-2.///2-//. :- .:: ::.1, mimiy contain 0.1-4.0½ / //./ ώ.'.. , 1 1-222 -../-.- ,, :,.. :.:::iva COffipOUJldj but ?'//·.:,/./ ./,. η: :.: -: ί:,. I:. / :::/, :::. lien she r/ore soluble 25 mil., 21 : :72--.-:1. :2: 2.::2 2,:: ml cm acid required fcr 5:22 ' . :-.:,: ::./ .,: nt .,1 : in two-pack £θϊώ fc-i* ·. .2:2,21:: 2: . ,.-, Alternatively the steroid salt and the aqueous injection vehicle may be packed separately in two'-pack form.
Although the compounds of the invention are preferably formulated as simple aqueous solutions of their salts, the free bases or salts may also be formulated in an aqueous solution of a parenterally acceptable non-ionic surface active agent in the same way (and using the same proportions of materials) as described in our Patent Specification No. 35204, 3a-hydroxy=5a-pregnane-ll,20-dione. The simple aqueous solutions have the advantage for example of avoiding anaphylactoid responses in surfactant-sensitive subjects The aqueous solutions may be adjusted in tonicity, for example with sodium chloride.
The anaesthetic solutions according to the invention are generally administered by intravenous injection although in certain cases (e.g. with children or animals) intramuscular injection might be preferred.
The simple aqueous solutions of the salts may also be administered subcutaneously. For intramuscular injection hydrochloride salts may be particularly suitable. - 18 . ¢5276 :.s is usual ii. the ease *,-f unaesthytios <, the xu.niii, '7 cusroid :::.: £:. induce snaesshscia depends up’-il·. :. -.: .- .:..:- cr :::. ss :-: cl··.
Si<: i:.::-. ..-- : s ηΐν..::. in the utetege man ε dose of feaa 0.1 t.-. 6-C g/ij sill in general es fcuad to fee eati t&tt jl : ·:: iiideis ; :u_j tthesia; the preferred dose feeing tit-·:.; teoa:? ..,? 3:::.-, :,2 to 4.6 fflg/hg. She dost till i.ifei.'iil 7 : :.:/ to -,:.: extent, depsndsnfc upon She .-ivstee.·. tf ths pncient and She degree XO tni ....I..;.... ii is - : So matneain prolonged anaesthesia, :.. irf :-?. the above ..·ο3ν£ϊοϋ3 may be used, such repeat ;-d doses being generally either of the same order or the c-igrasl ies+. Alternatively coafciau1S sus udyiu-t x.rssion a»ny be undertaken using solutions •.r^neabteng ίΧ ϋ1-ό=4Κ (yreferabl;· 3.02-C.2) w/v of the active tosyoena at 2s: s.xsffipit a rate of 0.0125-0.2 (+.tp 3:3:2-3,2^ e-g/hg/min. Continuous administration may «Iso 1-: used to produce sedation for prolonged periods. ciiers c...t anaesthetic solutions are a«&iiaistered intramuscularly or subcutaneously, higher doses are generally secsscary, COMPOUND PREPARATION The compounds of the invention may be prepared by a number of different methods, using generally known techniques. Suitable methods are described below. 1. Conversion of an unsubstituted or mono$ubstituted llct-amine into a di-substituted amine.
This reaction may be performed by reacting a corresponding compound of formula (I) in v/hich a b either or both of R and R is hydrogen with a compound of the formula RaX where X is a readily displaceable group such as halide (e.g. iodide), a hydrocarbylsulphonyloxy group (e.g. toluene-p-sulphonyloxy), hydrocarbyloxysulphonyloxy (G.g. methoxysulphonyloxy) or a dialkoxyphosphonyloxy group (e.g. dimethoxyphosphonyloxy). The reaction is preferably carried out in the presence of a base (e.g. potassium carbonate or silver oxide) in solution at any suitable temperature from ambient to reflux, conveniently at ambient temperature. An excess of the compound RaX, e.g. methyl iodide, may be used as the reaction solvent, but there are many other alternative solvents such as halogenated hydrocarbon solvents (e.g. methylene chloride), alkanols (e.g, ethanol or methanol) or acetonitrile. - 20 45276 Vihes a H-mono-sufcstituted starting material is used, the reaction can produce h,N-di-substxfcuted coEpounds the invention ia wbich Iia and S° are either the seme or differeat groups. 2he v'-mcno-suhstit^ted scart-.ng materials «ay be prepared in .-.xailar as-naer by reu<.riug a compound of formula I ia which booh S’* and Ea are hydrogen atoms with a compound of formula RaX as described above.
Compounds where »NF"h^ is a heterocyclic amino group may also he prepared -y th.y· method, by use cf a reagent X-R£-R^-X where X is as defined above (e.g. a 2,2’-dihaioethyl si:isr or a. yih'ieslkana, such as 1,4-diiodobufcane), Wien a group is present in the starting material, thus may be protected as described below as a 30-kefcal group, Such protection is net necessary in the S-i-ufcstituticr. mactica, but a 20-ketal group is often present as a result of the earlier stages in the preparative sequence. Isolation of the product of the N-subsfcitution reaction frequently involves acidic conditions which also serve to regenerate the desired -oxo g.’OUp. ~ 21 " The lla-amino starting materials required for this reaction may for example be prepared by stereo-selectively reducing the corresponding ll-oxime, This- reduction may be effected with an alkali or alkaline earth metal reducing agent in an alcohol and/or an amine and/or ammonia, e.g. sodium in n-propanol, if desired in the presence of a suitable solvent, e.g. tetrahydrofuran, at any suitable temperature up to and preferably at reflux.
The 11-oximes may themselves be prepared from the corresponding 11-oxo compounds in which the 20-oxo group (if present) is protected as a ketal group. The 11-oxo compound may for example be reacted with hydroxylamine under strongly alkaline conditions in aqueous alcohol (e.g. ethanol), preferably at reflux. When other oxo groups are absent, the reaction may be carried out under acidic conditions (ca. pH 4), e.g. in buffered pyridine.
The severe conditions used in the reduction of the ll-oxime make it necessary or desirable that certain of the optional substituents should be introduced after the formation of the lla-amino group, examples of such - 224S37 groups being Up-eycao and -alkoxycarbonyl, Zl-alkanoyl''» and -halo, 2p-halo, -alkanoyloxy and -thiocyanate, end lbS"cb.icri,. In ntrodtsing c<.r ,·.'.In of chess cubsfcxfcuenfcs (by the ti'.-chods described bslcw, e.g. in acylation or esterification reactions) it can be desirable to protect the ilce-amino group. Conventional amine protection methods way h& used, e.g. acylation (e.g, with fcrlfluorofecefcic or fcrrcic acid or a reactive derivative thereof) or eiiylafclsn. 2. A correspoali.ng lla-aeylataine steroid (i.e. in whieh one of R6 ε:.;ν. s is as defined above and the other is an acyl group) may be reduced, fcr example with lithium aluminiufrt hydride in an ether solvent (e.g. tetrahydro.cnran or diwethoxyethsne) at any suitable tempera15 ture up to reflux. The starting material .may possess a 20-ketal group, which should subsequently be converted into a 20-oxo group, or a Ja-esterified hydroxy group, which will be converted Into a 3a-hydroxy group in the reaction.
The acylamino starting materials may be prepared by acylation of an appropriate lln-mono-substituted amino compound (or a 20-tetal. or 20-hydroxy derivative thereof), for example with, the appropriate carboxylic <513270 acid (or a reactive derivative thereof, e.g. an acid halide, ester or anhydride), if desired in the presence of an acid binding agent (e.g. pyridine). The 3 group, this may then be reduced to form the desired 3a-hydroxy group. 3. Opening of a corresponding 2a,3a-epoxide.
This reaction may be used to prepare ring Asaturated 20-substituted 5a-compounds, and it is the preferred way of making the 2p-halo, alkoxy, alkanoyloxy and thiocyanate· compounds, The general method of preparing 20-compounds by this route is described in our British Patent Specification 1376892. Thus In general the reaction comprises treating the corresponding 2a,3a-epoxide with a compound HR under acidic conditions (if necessary in th e.y. suipr.-.-ric , or a C'.mocand id presence of an added acid catalyst, id, perchloric c.cid o? boron trifluoride) 4.- 4 ch produces tne anion \R‘> (were R is as defined above, other than hydrogen), and then (when tha initial product possesses a deprotonated 3a-hydroxy group) treating the product with a source of protons (e.g. aqueous ammonium chloride) to form the 3a-hydroxy group. .Examples of HR* reagents are alcohols, carboxylie acids/ihiocyanic acid and hydrogen halides (HE may be used in the form of the HF-urea complex, conveniently in the absence of a solvent); examples of reagents which produce (S > anions are metal alkyls such as lithium dimethyl cuprate, alkali metal or ammonium salts of HR^ acids and alkali metal alkoxides.
The reaction is preferably carried out under anhydrous conditions in a suitable solvent (e.g. a hydrocarbon or an ether) at any suitable temperature up to reflux. 2β-Halo and thiocyanato compounds may also be prepared in aqueous media.
The starting materials required for this reaction may for example be prepared by first introducing the ~ 21 desired ίΐα-substituted amino group (e, g„ by the method of reaction 1 above) using a Λ - starting material, then forming a salt (e.g, with toluene-g-sulphonic acid) and then epoMdising the Λ - compound with a peracid, finally 2 regenerating the free base, Λ '«-Compounds may be prepared by formation of the 3-raethanesulphoante and subsequent elimination c£ methanesulphonic acid. 4. A corresponding liir-amino or lla-msno-substituted amino compound (or a 20-ketal thereof) can be reductively alkylated with an appropriate mono- or di-earbonyl compound in the presence of a reducing agent, for example, with lla-amino compounds the use of mono-carbonyl compounds, such as formaldehyde or acetaldehyde, can provide the lla-dimethyl or -diethyl amines, whereas a dicarbonyl compound can provide compound in which -NRil is a heterocyclic amino group (e.g, glutardialdehyde may be used to form a piperidino group). When an lla-N-mono-substituted starting material is used, a mono-carbonyl compound should be used. The reducing agents which may be used are those generally known for the reduction of imines, examples being formic acid (e.g, at any suitable temperature up to 100120°C, for example from room temperature up to 100l>, and using the carbonyl compound as the reaction solvent, in the presence or absence of water), an alkali metal borohydride or cyancborokydride (e.g. sodium borohydride or cyauoborohydride, using an alcohol such as ethanol as solvent, suitably at room temperature), iron pentacarbonyl or an alkali metal hydrogen iron carbonylate (e.g. Fe(GO)g or MHFe(CO)^ where M is sodium or potassium, at any suitable temperature up to reflux using an ether such as tetrahydrofuran or an alcohol or aqueous alcohol as solvent), hydrogen in the preface of a metal catalyst (using an alcohol, e.g, ethanol, an ether, e.g, dioxan or an ester, e.g. ethyl acetate, as reaction solvent, conveniently at room temperature), or aluminium amalgam in the presence of water (conveniently at room temperature, and in the presence of an ether solvent such as tetrahydrofuren).
The metal catalyst may, for example, be a noble metal catalyst such as platinum, platinum oxide, palladium or rhodium. The catalyst may be supported, e.g. on charcoal or kieselguhr. A homogeneous catalyst such as tristriphenyl phosphine rhodium chloride may also be used. If desired the intermediate imino compound may be isolated.
«S27S ο>Ν-$ιοησ-substituted amino starting materials can be prepared in similar manner by reacting the corresponding lla-araino compound with an appropriate aldehyde or ketone in the presence of a reducing agent as described above. Thus, for example, the use of formaldehyde, acetaldehyde or acetone can provide the lla-N-raethyl-,Ν-ethyl or N-isp-propyl amines respectively. Whether an lla-N-mono- or Ν,Ν-disubstituted compound is obtained is dependent partly on the proportion of ketone or aldehyde used.
. Ring A-saturated 2p-unsubstituted 5a-sceroids of the invention may be prepared from appropriate 3-oxo compounds by stereospecific reduction, e.g. by the method of Browne and Kirk (J. Chem. Soc. C, 1969, 1653) or by the method of our British Patent Specification 1409239. The latter method preferably uses a pre-formed iridium catalyst reduction system. For example, a reduction system may be prepared from an iridium acid or salt (e.g. chloroiridlc acid), atrivalenL phosphorus compound such as a phosphorous acid ester (e.g. trimethyl phosphite), water and an organic reaction medium (e.g. an alcohol such as isopropanol). The reduction system ia then neutralised (e.g. to --- pH of ό to 8.5) with an organic base such as a secondary or tertiary amine (e.g. triethyiamine) and reacted with the steroid. When the cacaly;,; system is preformec by heating at reflux, e.g. for It· to 72 hours, the reduction can ba accomplished for example in 2-3 hours at reflux; longer times may be necessary at room temperature. 6. Reduction of a corresponding 3-oxo 5p-compound. 3a-Hydroxy 5i3-steroids may be prepared by hydride reduction of the corresponding 3-oxg compound (in which a 29-oxo group, if present, is optionally protected), for example with sodium borchydride using an alcohol (e.g. ethanol) or pyridine as solvent. 7. Inversion of derivatives of the corresponding •15 3p-hydroxy. compounds.
This preparative method is suitable for the preparation of compounds which are unsubstituted at the 3P-position and do not possess a 5,6-double bond. The starting material may be a corresponding compound possessing a readily displaceable 3p-group such as a hydrocarhylsulphonyloxy (e.g, p-toluenesulphonyloxy or mesyloxy) group, and the 3p-group may be displaced by hydrolysis _ 29 (e.g, in acid conditions) to give the desired 3ghydroxy compounds. Methods forpreparing compounds by this route are described in our British Patent Specification 1372175. 8. Reduction of the corresponding Δ~ compound. s Compounds in which R is a group (a) or (b) as defined above may be prepared by hydrogenating the corresponding Δ compound in the presence of a hydro genatisn catalyst (e.g. a palladium catalyst) in a suitable solvent (e.g. an alcohol, ether or ester). The reaction may be effected conveniently at or about room temperature and atmospheric pressure in the presence of a tertiary base, e.g. triethylamine, (except where an easily displaceable substituent (e.g. bromo) is at the 2β15 position) and/or an acid, e.g. acetic acid, 9. Hydrochlorination of the corresponding Δ^θ compound. Ιδα-Chloro compounds may be prepared by reacting 16 the corresponding Δ - compound with hydrogen chloride 20 in an anhydrous solvent (e.g. an ether) at a temperature of for example 15-40°C0 as generally described in our British Patent Specification 1380248.
, Dehydration of a corresponding 170-carbamoyl compound or the oxime of s. corresponding 17g-formyl compound. 17.3-Gyauo compotrods may be prepared by dehydrating the - yproprie.··.· ox.bos for example with acetic anhydride nt reflux, H-ts 3'<-hydroxy group will generally be esterified in this reaction and has to be regenerated by deesterification. The oxime starting material for thia re- action say be prepared from the corresponding-170-ronByl compound/?; ith NH.,.OH.),itsalf prepared by periodate cleavage of the corresponding 20,21-dihydroxy pregnane.
Alternatively. the corresponding 170-(unsubstituted carbamoyl) ceryouad can be dehydrated, e.g. using polyphosphate ethyl ester, as described in our British Patent Specification 1380246, 11. Esterification of a corresponding 170-carboxylic acid, 17s-Alkoxycarfconyl compounds may bs prepared by reacting the corresponding 17(5-carboxylic acid or a reac20 tive derivative thereof (e.g. an acid halide or anhydride or a salt) with the appropriate alcohol or alkyl halide.
This reaction is preferably carried out at temperatures of dS27S -20eC to llO’C, as is described for sxnrapla in our British Patent Specification 1380246.
The 17p-carboxylic acid can conveniently be formed by oxidising tha corresponding 178-acetyl compound , using for example NaOBr in an.aqueous inert solvent (e.g., dioxas). The acids -re conveniently obtained in the form of their triethylammonium salts by neutralisation and addition of trietnylamine, followed by extraction into a suitable solvent (e.g. chloroform). These salts may be converted into their alkali metal salts by treatment with an alkali metal alkoxide (e.g. lithium methoxide). 12. Reaction of the corresponding 17p-carboxylic acid with an amine. 17β-(Substituted carbamoyl) compounds may be prepared by reacting the corresponding 17p-earboxylic acid or a reactive derivative thereof (e.g. an acid halide or ester) with an amine HNRXR^, where Rx and R^ are as defined above. The reaction is again preferably carried out in the presence of an acid binding agent, as is described generally in our British Patent Specification 1380246. 13. Acyloxylation of a corresponding 21-unsubstituted compound. - 32 21-A-,kcoyloxy and bensoyloxy compounds may be prepared by treating the corresponding 21-unsubstituted compound (in which the 3&-hydroxy group is optionally protected) wwch ae appropriate load tetraacylate, preferably in the presence of a Lewis acid (e.g. boron trifluoride) in a hydrocarbon/alcohol solvent. This reaction is generally described in our Patent Specification no. 35202, 14. Displacement of a 21-iodine atom by fluoride. 21-i?Iucrides may be prepared from the corresponding 21-iodo compound* by treatment with a source of fluoride ions (e.g. a- alkan metal or silver fluoride), as described generally ia oar Patent Specification No, 37597.
. Deacylation of a corresponding 21-acyloxy compound, 21-HydroA-y compound5 may be prepared by hydrolysing a corresponding 21-acyloxy compound (e.g. a 21-acetoxy compound) under basic conditions, as generally described in our British Patent Specification No. 1,377,608. 16. Etherification of a corresponding 21-hydroxy or ?l-halo compound. 35276 21-Alkoxy compounds may be prepared by etherifying a corresponding compound having a 21-hydroxy group or a displaceable substituent at the 21-position (e„g. a 21-haloj such as a 21-bromo, compound) with for example an appropriate alkanol, diazealkane or alkali metal alkoxide, these methods being again generally described in our British Patent Specification 1377608. The 3a-hydroxy group is desirably protected in these reactions. 17, Acyloxylation of a corresponding 21-substituted compound. 21-Alkanoyloxy and benzoyloxy compounds may be prepared by reacting a corresponding compound having a readily displaceable substituent at the 21-position (e.g. a bromine, chlorine or iodine atom or a hydrocarbyl sulphonyloxy group) with a salt of the appropriate carboxylic acid. This reaction is generally described in our Patent Specification No. 35203. 18. Acylation of the corresponding 21-alcohol. 21-Alkanoyloxy and benzoyloxy compounds may also be prepared by acylating the corresponding 21-alcohol, again as described generally in our British Patent Specification 1317185. 21-Garbonate esters may similarly be prepared by using for example the appropriate alkylchloroformate, 19. Oehydrohalogenation of a corresponding 2p-kalc compound, J r- „ £ -aa-CompounGS may be prepared by dehydrohalogenatin a corresponding 23-halo compound (preferably a 2fi-brorao compouna) using ror example a nitrogen-containing Lewis b-^ve, s.g. uimethylformaraide or dimethylacetamide. The starting materia I may have a protected 3oc-hydroxy group, and the reaction is advantageously carried out in the presence of an alkali metal or alkaline earth metal io carbonate or halide (e.g. a mixture of calcium carbonate and lithium bromide) at a temperature of 80-170%.
This reaction is described generally in our British Patent Specification 1389243.
, A lTp-^'inyl group may for example be introduced IS by partial hydrogenation of an appropriate 17p-efchynyl coinpound.
The 170-ethynyl compounds required in this prepara fcion may themselves be prepared from a 170-acetyl steroid by first forming the corresponding 20-hydrazone, iodinating the hydrazone (e.g. with iodine and triethylamine), and then dehydroiodinating the iodide (e.g, with ethanolic potassium hydroxide). - 35 3 5 2 7 6 The 17p-ethynyl compounds may also he prepared by treating an appropriate 21-mathanesulphonyloxy-2Q‘*oxo steroid with toluene-p-sulphonylhydrazide and then a base. 21« A 17,S-vinyl group may also be introduced by treating an appropriate 20,21-epoxide with ε,η alkali metal (e.g. potassium) selenocyanate, for example in an alcoholic solvent. The epoxides may be prepared as generally described in our British Patent Specification 1377608, 22, A Z-ethylidene or Z-cyancraethylsne .group may ba introduced by a Wittig reaction, by reacting a 17-oxo steroid with for example a suitable organophosphorus reagent, such as (i) a substituted or unsubstituted methylenephosphorane (e.g. ethylidenetriphenyl phosphorane), which is conveniently prepared in situ using a base (e.g, sodium hydride) in a solvent (such as dimethylsulphoxide or tetrahydrofuran) and a substituted or unsubsfcituted methyl phosphonium salt (e.g. an ethyl triphenylphosphonium halide e.g. bromide or chloride), or (ii) a substituted methyl dialkylphosphon&te (e.g. diethyl cyanomethylphosphonate), - 36 4 5 2 7 6 23, Compounds in which Sa is a methyl or cyclopxopyl group or a methyl group substituted by a alkyl group may be prepared by reacting the 17p-carboxylic acid or more preferably a salt (e.g. a lithium or feriethylaminc salt) with the appropriate lithium alkyl (e.g. using 2-4 mols: of the lithium alkyl per mole of the carboxylic acid or salt). Examples of suitable reaction solvents include ethers and hydrocarbons (e.g. diethyl ether and hexane)| the reaction is conveniently effected at room tem10 perature and is followed by protonation (e.g. by addition of water), 24, Deketalisation of a corresponding 20-ketal.
As indicated above, it is frequently necessary or desirable to protect a 20-oxo group during the preparation of the pregnanes of the invention, for example by ketaiisation, The 20-cxo group may then be regenerated as the final step in the preparation. The ketal is preferably the corresponding 20,20ethylenedioxy compound, and the 20-oxo group may be regenerated for example by hydrolysis in the presence of - 37 «5276 an acid (e.g. hydrochloric, sulphuric or acetic acid), or by exchange reaction with a ketone e.g. acetone in the presence of an acid catalyst, e.g. p-toluenesulphonic acid, at a temperature of 0=100°C.
, Deprotection of a corresponding compound having a protected 3a-hydroxy group.
This method is sometimes a necessary last stage in the preparation of the compounds of the invention in that the 3a-hydroxy group is often either deliberately protected or is formed in the esterified state by inversion from a 3β-hydroxy compound (for example by treating the 30-alcohol with diethyl azodicarboxylate in the presence of an acid such as formic or benzoic acid and a phosphine such as triphenylphosphine). The group present at the 3a-position in the starting materials in this reaction may thus be an ester group, e.g. an alkanoyloxy group, and such esters may be hydrolysed to give the desired 3a-hydroxy compounds under mild acidic or basic conditions. Weakly basic conditions are generally most convenient (using for example an alkali metal bicarbonate in aqueous methanol at any suitable temperature up to reflux). Dilute mineral acids (e.g. perchloric acid in aqueous methanol) - 38 Λ ζ| Λ λ "* Μ < g ^may also be used.. Strong bases (e.g, alkali metal hydroxides) V j. 'say be used if the reaction is carried out briefly. Alternatively, the starting material in this reaction may bn & protected 3a-hydra: IQ 2(,, Salt formation.
Compound* of the invention are desirably used in the form, of a salt, and thus salt formation by reaction of the base with an acid is particularly important.
A generally convenient method of forming the salts is to mix appropriate quantities of tha free base and tha acid in a mixture of water and a solvent for the bass (e.g. an alcohol such as ethanol), removing the solvent (e.g. by evaporation) and then if desired dissolving the residue in water.
In some cases solid salts can be formed by treating the free base with acid (e.g. citric acid, HG1) in an anhydrous solvent, such as diethyl ether. In most cases it is possible te 327 8 form an aqueous solution of the salt by simply mixing the free base with an aqueous acid. If desired one or more steroid bases and/or one or more acids may be used.
In these preparations, the base and the acid are not necessarily used in equivalent quantities. When the acid is a weak acid, an excess of the acid is sometimes desirable. In the preparation of aqueous solutions, in some cases for example it is found that an excess of the base may be used, implying that the free base is dissolved to some extent in the solution of the salt.
If desired the pH of the salt solution may subsequently be adjusted by addition of a base, e.g. sodium hydroxide and/ or disodium hydrogen citrate.
The methods indicated above for preparing the compounds of the invention can be used as the last main step in a preparative sequence. The same general methods can be used for the introduction of the desired groups or unsaturation at an intermediate stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in many different ways in such multi-stage processes, as will be apparent from the Examples below. Thus for example the desired lla-substituted amino group may _ 40<28376 be formed either before or after the reduction of a 3-oxo group or 16,17-double bond, and either before or after the introduction of an optional substituent at the 16,173 or 21-positions or the formation of a double bond at the 1,2-position. The sequence of the reactions ia multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product, Other structural features which may be present in the compounds of the invention may be introduced by the following methods.
Methods generally suitable for introducing substituents at the and 33 positions are. described in our British Patent Specification 1330248.
Z4-Steroids may be obtained by the methods described in cur British Patent Specification 1372175.
Compounds having an alkyl or substituted alkyl group at the 21-position or a cyclopropyl group at the -position may be prepared by the methods generally described in our Patent Specification do. 38863. - 41 ¢5376 Compounds having a δβ-methyl group may be prepared by hydrogenating a corresponding S-methyl 3-oxo 4,6-diens, followed by reduction of the δβ-ιηεΙί^Ι-Β-οχσ-οοιηρο'αηά formed e.g, using chloroiridic acid in the 5c,-series as described above. 1 The D-homo, and 4 -compounds and Δ s5@«compaundg may be prepared by choice of starting materials of appropriate structure. - 42 <5 The following example? illvscrafce the invention.
Temper afcures are ία °C.
Melting-points ware determined on a Kofler block ana are uncorrected. Optical rotations ware determined at room temperacure on solutions in chloroform (ca· 1% w/v) ci..}xbit·is C·'.·--.- oΰ,',,ί.ιίζ’« Preparative TLC (thin lay·'.·-· chromatography) and CC (column chromatography) were carried out over silica· Cnloroiridic acid reagent was prepared by refluxing a mixture of cnloroiridic acid (50 mg)· isopropanol (94 ml), water (δ .'.I) and trimethyl phosphite (8 ml) for 24 hours and adjusting to pH 7 by the addition of triethylemino immediately prior to use.
Msth . r.. chloride (dichloromethaua)-.Was redistilled and dried.
Solutions were dried either azeotropically or by use of mpgacsium or sodium sulphate.
In the Examples and Preparations which follow reagents and rclvants which occur frequently have been abbreviated for simplicity. Thus» ethyl acetate = EA; petroleum ether (b.p. 60-803C) - PE; acetonitrile = AN; chloroform " CH; dichloromethsne = DM; diethylfefher = DE; dimethylsulphoxide = DMSO; pyridine =PY; THF»tetrahydrofuran; q5S7S water = W; bensene = B; toluene-4-sulphonic acid = PTSAj methyl acetate = MA; ethanol = ΕΪ; industrial methylated spirits e IMS; propan-i-ol .«.PR; 1,2-diehioroethane =BC; dioxan ~ B; petroleum ether (b.p. 40-60°0) = PT; dimediylfoanamide = DMF; acetone = AC,· methanol = MSj and room temperature = RT;. ' In the Preparations and Examples, 58-100% formic acid was used and formaldehyde was used as a 37-40% v?/v aqueous solution, iq In the Preparations the following known starting materials were used: ,2Q-ethylenedioxy"3a~hydroxy-5c4-pregnan-ll"one (I) Sa-hydroxy-Sp-methoxy-Sa-pregnane-ll, 20-dione (IJ.) 2d-butQxy»3o:"hydroxy«5a"pregnane-llp20-dione (III) 20p20-efchylenadioxy-2u,3a-epoxy-5a-pregnan-il-one (IV) 3p-hydroxy-20,20"ethylenedioxy-5(Z"pregnan"ll-one oxime (V) 20J20-ethyXenedicx5'"5a-pregn=2°en"ll-one (VI) 2p=ethoxy-3 6-methylpregna-4,6-diene-3pllp20-trione (X) 3a-hydroxy-21-methyl-5o:-pregnane-lls 20-dione (XI) 21521-ethylene-3a-hydroxy"5a"pregnane-llp20-dione (XII) 3a-hydroxy-21»methoxy-5«-pregnane-ll,20-dione (XIII) 2p-ethoxy-3a-hydroxy"5a-pregnane-ll,20-dione (XIV) - 44 4 s a y θ 3a-fcydroxy-D-homo-5e-pregaane-ll,20-diooe (XV) 2p-ethoxy-3«-hydroxy-D"hon:o-5a:-pregnaiie-ll,20-dione (XVI) 20 β, 21-epoxv- h-'ayir. Ζ ‘J 5a-pragna-<-._ I€-diene-ll,20"dior.0 (Χ7ΠΙ) 3a-hydrcxy-5a-aadrostane-ll,17-dione (XIX) 3+,200,21-trihydroxy-5a-pr2gnan-Il-one (XX) ,20-efchylenedioxy-3a-hydro:iy-5c-pregnan-ll-one (XXI) 3a, 23;?, 21-fcrihydroxy·» op-pragnan-ll-one (XXII) Preparation I (Z)-1Ig-Amino-5;. pregn-17.(20)- fe-3a-ol· (XL!) A solution :7 (Z)-3a-hydroxy-5a«pragn-17(20)-en-llone oxl&B (9_638g) in PS (200 ml) was refluxed under Ng whilst Na (9.6 g„) was added portionwise. When all of the Na had reacted, about 90 ml PR was distilled and then the residue was poured into W, ice was added and the crystalline solid (9.19 g) was collected by filtration.
A portion (6.1? g) was crystallised from ET-W to afford title compound (3.6 g), m.p. 118-125°, My + 3,46.
Preparation 2 6g-Methyl-5K-pregnane-3.il.20-trione (XXIII) /3 3 37© X (1.7g) in SA (lOOml) was hydrogenated at atmospheric pressure using 10% palladium on charcoal (Pd-G) (500mg) as catalyst. The catalyst.was filtered off and the filtrate evaporated.. 'Crystallisetion of the residue from AC-PE gave the.title compound (72Gmg)t m.op.174-176°5 [α]Ώ +106°. . 20-dione XXIII (600mg) was heated under reflux with chloro10 iridic acid reagent (35ml) for a total of 8,5h, The reaction mixture was diluted with W and extracted with EA. Evaporation of the extract gave a foam which was purified by preparative TLC in EA-PE (1:1) to give the title compound (440mg) as a foam, [a]Q -+88°. Preparation 4 21-N„N"Dimsfchylaminomethyl-2 6-ethoxy-3a-hydroxy-5 aXIV (10,0 g) was dissolved in dry AN (50 ml) and N,N-diniethyl(methylene)ammonium chloride (5.0 g) was added. Tire mixture was heated under reflux for 2h.s cooled and partitioned between 2N-hydrochloric acid and = 46 2S370 SA ana the acidic extract was basified with KaOH solution and extracted with CH (2x). The extract was erred (aa,./ ano evupor&Cco so give the cxtle coni— ροκηο (10.7 as a fcaat, Preparation 5 2Q-Ethoxy-3a-hydrox;f"21-aethylsne-0e-pv3iraane-ll,20dione. (XXV) KW.i· . XXIV (’0,5 g) was dissolved in ME (105 ml) and iodomethane (10,5 mi) was added, The mixture was main10 tained at 20" for 20k, and was then evaporated under reduced pressure, The residue was dissolved in W. (200ml) and stirred vigorously with 5% NaHCCL solution (100 ml) for l,5h. The layers ware separated and the organic phase was dried (NajSO,) and evaporated to give a foam.
CC using EA-PE (l.sl) gave the title compound (3.48 g), m.p. 181-184°, Fa]^ +112°.
'Preparation 6 23-Ethoxy53g-hvdroxy-2i-methyl-5a-pregnanQ"11.20-dione. XXV (3,37 g) was hydrogenated at atmospheric pres20 sure and 234 in EA (150 ml) over 5% Pd»G, The catalyst was removed by filtration and the filtrate was evapora- 47 4δ37 δ ted to give the title compound as a foam (3.27 g), m.p. 147-149% [α]β +92°; Preparation 7 3α-Ην4ηοχν·=5ΰί-ρτ£§η~20^βη-11~|θη£ X7II (330 mg) in W-ME (Is 10; 11ml) was treated with potassium selenceyanate and the solution heated at GO°C for 20 hours. The solution was filtered through kieselguhr and the filtrate evaporated to dryness under reduced pressui*e. The residue was dissolved in EM and purified by CO eluting with EA-PE (Isl) to give, a foam which was crystallised from DS-PE to give the title compound as a pale yellow solid (80 mg), m.p, 137.5-139*5°, Preparation 8 (Z>3K4ivdroxy-5tt-pregn-17(20)-en-ll-one Sodium hydride (80% dispersion in oil; l.Og) was washed with PE and heated with dry DMSO at 70-80° until a green solution was obtained. The solution was cooled to RT and then treated with ethyl triphenylphosphonium iodide (13.3g) in DMSO (50ml), XIX (2.0g) in distilled DMSO (40ml) was added in one go and the mixture was heated to 40-60°. After six hours the reaction mixture - 48 : 7 6 was poured into W and extracted into DS. Evaporation of the washed and dried extract afforded an oil which was purified by CC using 2A-5E (1:1) and crystallisatic-B from EA-7E to give titla...compound (824mg), r„1 rX Co a l«jd .
Preparation 9 -Oxlmino-5a-pragna-2 ,16-dien-ll-ona. (XXVI) A mixture of XVIII (60 g), hydroxylammoniuai chloride (21 g) and anhydrous ?Y (240 ml) was left to stand at RT overnight before diluting with ice and W, The precipitate obtained was collected by filtration, washed with W and dried in vacuo at 80°, (62 g). Crystallisation from EA afforded the title compound, m.p. 168-182°. [aJD. +137°.
Preparation 10 5a-Ar;drost-2-ene-ll ,17-dione (XXVII) A solution of XXVI (60 g) in anhydrous PY (250 ml) was treated with 22.5 ml of a solution prepared from phosphorus oxychloride (55 ml) in anhydrous PY (250 ml) whilst maintaining the reaction temperature at ¢5° during addition of the reagent. The reaction mixture - 49 4527 6 was then added to a solution of concentrated HG1 (350ml) in W (3 1), This mixture was stirred for 60 hours before collecting the precipitate by filtration. The precipitate was washed with W, dissolved in hot IMS and treated with 214 HC1 (50 ml) at ST. After one hour,, the reaction mixture was diluted with W and the precipitate obtained was collected by filtration,, washed with H and dried. (38«4g). Crystallisation from ME afforded the title compound, m.p. 188-192°, +-207°.
Preparation 11 ι_ι. i .rtiuimiTTCTMaMMEPEBgacsa» H(KAtnino-28-ethoxy-3ix-hydroxy-21"tKethyl-5tt-pr6gnan-20cna, (1ΧΠ) 2p-Ethoxy-20,20-ethylenedioxy-3a-hydroxy-21-methyl5a-pregnan"ll"one oxime (2.8 g) was dissolved in PR IS (150 ml) and heated to reflux. Na (12.6 g) was added and refluxing continued until all the Na had dissolved. The PS was removed by distillation with simultaneous addition of W. The resulting mixture was extracted with EA (2x) and the washed organic layer was re-extracted with 2N-HC1. The acidic extract was basified to pH 11 with 40% NaOH solution, extracted with EA (2x) dried - 50 «133 7 6 (NagSO/) and evaporated to give the title compound as a foam (1.,94 g) , Preparation 12 S pregi,an-20-aae (XXVIIIJ A solution of llx-N^N-dimsthylamino^-ethoxy-Sah.ydroxy~5a-pregnan-20-one hydrochloride (450 mg) in dry ME (50 mi) was treated drcpwise with a solution of bromine (0.1 ml) in ML (5 mi) at 0°C with stirring. Each subsaQuetii drop of reagent solution was added when the colour from prior additions was discharged. When the addition war· complete 10% K.CG„ solution (150 ml) was added and the mixture stirred for 15 minutes. The precipitate was filtered off and washed with W and dried.
Purification by preparative TLC in EA-PE (1:1) gave title compound (230 mg).
Preparation 13 11g-N,H-Dimethylamino-2p-athoxy-3«-hydroxy-5 g-androstane 17p-car boxy lie acid lithium salt (LXJiV) Bromine (4.3 ml) was added to a stirred solution of NaOH (12.1 g) in W (90 ml) at -S to 0°. D (42 ml) was added and this mixture was added to a stirred solution of lla-N,N-dimethylamino-2p-ethoxy-3a-hydroxy-5a-pregnan20-one (10.0 g) in & (316 ml) and V (90 ml) at 8°. The mixture was stirred at 5 to 10° for 3.5 h. A'solution of sodium sulphite heptahydrate (4.66 g) in ff (20 ml) was added and the mixture was boiled for 15 min. The solution was filtered hot and the cooled filtrate was extracted with CH. The GH extract was washed with W and the combined aqueous fractions were acidified 10 with concentrated HC1 to pH 3. Triethylamine (50 ml) was added and the solution was extracted with CH. The extract was dried (MgSO^) and evaporated to dryness to give the crude triethylammonium salt, which was dissolved in MS (20 ml) and treated with a solution of lithium methoxide (20.4 mmoles) in ME (35.7 ml). The resulting solution was evaporated to dryness and the residue was crystallised from a mixture of ME (36 ml), PT (36 ml,) and DE (354 ml) to give the title compound (7.03 g) , m.p. >300°, [a]D + 9.1. - 52 4SS76 A solution of ΧΧΣΧ (2,8 kj in ME (100 ml) was treated at ST with 10% Κ,.ΰΟ, solution (15 ml) for 15minutes. ?hi aixcure was diluted with W to 700 ml and the oily TOecipitScii.·.. excreted iTiio DE 5,. 3 x./c Ths Gxtr&cUs wexs washed with w, dried (Ne23O^) and evaporated to a foam (2.5 g), A sample (300 mg) was purified by preparative T!.C in Ea-PE (1:1) to give title compound (160 mg), as a foam, [r]r + 65°.
Preparation 15 r-N.ii-aimethylaaaso-2gethoxy-5«-pregnane-3g,208,21triol (ΧΧλ'Ι) A solution of XXX (2,2 g) in ME (50 ml) was treated with sodium borohydride (230 mg). After 10 minutes the mixture was diluted with 10% solution (80 ml) and H to 300 ml. The mixture was extracted with DE (x3) and the extracts were washed with W, dried (NagSO^) and evaporated to a foam which was purified by GG eluting with DM-AG (1:1) to give title compound (700 mg) as a f qo Lujd " J , Preparation 16 .20-Ethylenetiioxy-3g-hydroxy-2|i-methyl^5«-pregnan"llone &5S7 δ A stirred suspension of dried cuprous iodide (19.6 g) in dry xylene (350 ml) under nitrogen was cooled to -10° and 1,9 M methyl lithium in DE (108 ml) was added until the initial yellow precipitate redissolved to give an almost clear colourless solution. A solution of IV (12.9 g) in xylene (430 ml) was added dropwise at -10° to "5°. After the addition, the mixture v?as stirred overnight at RT, and then poured into 25% NH^Cl solution (1200 ml). The mixture was extracted with DE and the extract was washed with 25% NH^Cl solution and W. Evaporation of the DE left an oily solid which from TLC was a 2:1 mixture of the starting material and the title compound. This solid was recycled using the same quantities of reagents, temperatures and times. The resulting solid was crystallised from EA-PE to give the title compound (7.22 g), m,p. 167-168°, [α]β +68.1°. -pregnan-11one (XXXII) A solution of VII (8„2g) in B (300ml) and ethylene glycol (40ml) was treated with PTSA (200mg) at reflux under a Dean & Stark water trap using vigorous stirring. - 5420 After 5 hours solid NaHCG, (5C0mg) was added to the cooled mixture, Aqueous saturated NaKCO, solution (iOOail) and ΐί (iOnil) were acaed and the organic phase wa.. wv;hs;i with W (x3), dried (ha^SO^,) and evaporated to a foe» ?>hich was purified by CC slating with EA-PE (1:2) to give 6g of product, 5'J0ng of which was crystallised from MA»?E to give tha tide compound (210mg), m.ps 124»127°G, i j... +53% Table 1 sursaarises the preparation of 20-kefcals by the following method.
A sour Lon of the appropriate 20-ketone in B and ethylene glycol was refluxed under a Dean and Stark water trap in the presence of PT3A for the time indicated.
The cooled mixture was than worked-up by one of the following methods: A, The mixture was treated with sciid NaHCOj and diluted with (i) DE-W or (ii) B, The organic phase was separated, v?ashed, dried and evaporated.
B. The mixture was diluted with aqueous NaHGO^ solution and extracted with (i) ΞΑ or (ii) DM, The extract was washed, dried and evaporated. - 55 sBSTS C„ The mixture was poured into aqueous KaKCO^ solution, the layers separated and the aqueous layer ex» traeted with S. The combined organic extracts were washed, dried and evaporated.
The material obtained by one of these procedures was purified by chromatography (CC or TLG) and/or crystallisation* - 56 ΰ,ΐ27( ά S3 2 7 S „20-Ethylanedioxy~5a-pre2n-2-en-ll-one 11-oxime nt Qaa—on»»eig=— ι'.···~·ιπι u-i^rfciaaa»Mar -Mimr-r-n rign -:«^.\r»3a=a (mm) A solution of VI (5g ) in ET (150 ml ) was treated with a mixture of hydroxylamine hydrochloride (10 g ) and 50% NaOH solution (40 ml ) at pH 11. The mixture was refluxed for 3 days, diluted v?ith W and the precipitate was filtered off, washed with W and dried. The residue (5.5 g ) was crystallised from ΜΑ-PE (x2) to give the product (2.2 g ), A portion (200 mg.) was further crystallised to give the title compound (150 mg.), m.p. 174-179°C, [α]β+Ι44°.
Preparation 28 ,20-Ethylenedioxy-28°ethoxy-3K-hydroxy-5a-pregnan-llone 11-oxime (XXXIV) A solution of XXXII (5g) in ET (200ml) was treated with a mixture of hydroxylamine hydrochloride (15g) and 40% NaOH solution (60ml) at reflux for 18 hours at ca. pH 11. The mixture was diluted with W to 2 1. and the precipitate was filtered off, washed with W and dried in vacuo to give 4.5g. of product, a sample of which (SOOmg) -.-5865S7S was crystallises from ΏΆ-ΡΞ tc give the title compound (150mg,), m.p. softens >17C-C, [α]Γι +-83.3°.
Pronara.tion <0 xxb/t. ii? -¾¾^ hhivt-t t-hydroxy-' G ;· -pregnan-ll-one 11-oxime (XXXV) A solution of XXI (11 g.) in ET (130 ml.) was treated with a mixture of hydroxylamine hydrochloride (15 g.) and 50% NaO’I (50 ml.,, Tha mixture was refluxed for 24 hours at pH 11, then diluted to 2 1. with W, The precipitate (11 gj war filtered off, washed with water and dried, A portion (500 mg,) x?as purified by preparative TLC and rut tallised from DE-PE to give the title compound (100 mg.), m.p, 224-228°C, (α^ΉΟΟ Preparations 30-46 Tabie 2 summarises the Preparation of ll-oximes by the following method.
A solution of tha corresponding 11-ketone in ET was refluxed with a mixture of hydroxylamine hydrochloride and aqueous NaOH at £ pH 11 for the time indicated. The cooled mixture was diluted with W, and the precipitate was filtered off, washed and dried. The material obtained was purified by chromatography (GC or TLC) and/or crystallisation. _ <4 5 27 8 ΰ ΰ 3 ? 6 Φ ε β Φ δ « 23 t'j co 42 S2 10 φ Α- Χ5 β 3 3 Φ 2:; Λ-Χ 3 4J σ «;'3 ε ·> ο\ ή χ> φ *«·' £- 42 «5 φ Π . «Η 05 ΙΛ Μ 42 Ζ·Ή η Φ • Μ ΟΆ . m »Η ιη r* • β κ—-' « €S3 W Φ *Φ Σϊ 42 k _ β S3 0 ·γ1 0 Ο 23 52 β α 0 Ό κ φ t-J Ο οο £2 <Μ 0 A 0 0 Id Φ Ο £ Ή ’Ό Ό Ο κ*Ί ΰ ·ι2 X 42 β Φ S3 0 φ β 2η γΗ Ή Ο Φ •Μ £ J ’ CO ri ξ?* Η U. r~1 • »Η Φ >Ί ¢5 4η 23 ί4 Ε 42 ζ~\ 0 < Φ Ή 00 ;η >3 <3 $ a in X) CM β co X) · -j Γ*-Ι φ φ cH Μ φ φ £ 23 42 \»z 0J 05 42 42 Φ Φ ,1^ Φ ?u xj 42 22 Jm 42 Ή μ 0 Φ <-J -4 fa O ς-ί β pH • ♦Η 42 CO 23 ϋ3 β C cs ϋ 42 Μ Q Φ a 0 β β •ί-! #>© μ φ ο 42 «ί 42 ·« > 23 •Η φ 0 £» Γί 42 Μ 3 21 Ο ιΗ hi X ω d UM Ο Φ w hi α. ο hl β β*·Η β Φ X co 42 22 Φ φ 1 Τ3 M-J •Η Ό Η Φ Φ 0*42 Ρ ω 3 «Η C χ 3 Ό 1 42 ϋ ο Φ 24 β hl 00 Ό Μ Φ Φ X β Ό p d 23 ί>% w <4 J2 &1 6·* 23 θ © 11κ-Amino-28-ethoxy-3a-hydroxy-D-honio-5g-pregnan-20-ong (LXIV) Na (8g) was added portionwise to a refluxing 5 solution of 2p-ethoxy-20,20-ethylenedioxy-3ft" hydroxy-D=homo-5a-pregnan-ll-one 11-oxime (4.0g) in PR (200 ml)o Refluxing was continued for 4hr. then ME (10 ml) was added. The alcohol solvents were removed by distillation whilst adding W. The cooled aqueous suspension was extracted with EA (3x) and the combined extracts washed with saturated brine solution (2x)s dried and evaporated to a foam. This was dissolved in EA and extracted with 2N-HCl(3x). The combined aqueous extracts were basified with. 0.88 ammonia solution and extracted with EA. The combined EA extracts were washed with saturated brine solution, dried and evaporated to give the title compound as a foam (2.43g), [α]β +40°. .208.21-Trihvdroxy-56°pregnan°ll-one ll-oxime (XXXVI) 504 KOH solution (32 ml) was added to a solution of hydroxylamine hydrochloride (l6g) in W (32 ml) with cooling and the resulting mixture added to a solution of XXII (8g) in ET (256 ml). The reaction mixture was refluxed for 4 days, - 62 3jme ET was distiiied off and the mixture poured into iced 2N-HCI, The steroid was extracted with EA and crystallised from I.A to give title compound (6.7g) m.p. 226229°,[a]p + 82° (£ 8.7 □).
- Preparation 49 ,20-Ethyleqdl>xy-5'X"rresn-2-3n-* Ir-aaAne (XXXVII) A tclnwioa of XXZ'ill (1.85 g ) in PR (250 ml) was treated at reflux with Na (20 g ) added over 1,5 hours. When the Na had been consumed ME (20 ml) was IQ added and the mixture w-/· diluted to 2 1 with W. The mixture was extracted with DE and the extract was washed with W, dried (ha^SO, rud evaporated to leave title compound as aa cil (2 g ·Preparation 50 I5 ilK-Affllro· l'~-, <0-cthylenedloxy-2g-ethoxy-5c-pregnan-3«-ol A solution of XXXIV (4g) in FS (500ml) was treated at reflux with Na f'AOg) over i hour. When all the Na had dissolved. ME (20ml) was added. The mixture was then distilled with the constant addition of W until all the PR had been remo/ee. The product was extracted intp i)E (x2) and the extract was washed with W (x2) dried (NaoSO^> end evaporated to leave a foam (3.7g), which was <8 8 27 6 purified by CC, eluting with ME, to give the title compound as a foam (2.5g), [0^+13.7°.
A solution of XXXV (2 g.) in PR (250 ml) at reflux was treated with Na (20 g.) over 1 hour. When all the Na had dissolved, ME was added. The PR was removed by distillation during the cautious addition of W. The residue was extracted with DE and the extract was washed with W, dried (Na2S0^) and evaporated to leave a solid which was purified by CC, eluted with ME and crystallised from MA to give the title compound (220 mg.), 153=155°C, [ct]D+5n (c 0.65) Preparations 52-63 Table 3 summarises the preparation of lla-amines by the following method: A solution of the corresponding 11-oxime in PR was treated at reflux with sodium. When all the sodium had reacted the PR was distilled and simultaneously replaced with W.
The residual mixture was worked-up by one of the following methods: A. The mixture was extracted with (i) DE or (ii) EA and the extract washed, dried and evaporated. - 64 37ο S, The r-rsci; itsts for+sd was filtered off, washed and dr'5-i. nw. if Purified by CC eluting with ME ME added prior to additon of W, Prensyacion ji £ 2) /11::-Amtac-2:· tbhoxy··Γΐϋ2."· (£»?//TrHliSfii ( LX7 ΙΑ i/fluwing solution (uar’er nitrogen? of <Ζ)-2βe thoxy- 3«- hydroxy- 3 α-pregn- i 7 ( 20) - en- 11- oat 11- oxime 5 «'^50 .eg) in PS (13 «?.) was treated with places of Na (4S<« iag), r :.;.· v7u& no yy: of Na left the mixture was added fcc chilled V/ tc a fine precipitate which was collected by filtration.
The solid was dissolved in EA, dried (Na^SO*) and evaporated to a froth which was partitioned between 2N ilCl and BE, The in::.·.·.;..ole material which separated was collected by fiitra;- '.on and partitioned between EA and 2N NaOH solution, Ta organic phase was isolated, washed with V dried ·' y,.,2(·/> ana evaporated to give a froth which was crystallised from PE to afford the title compound (110 mg), m„p. 65-79°. raJD + 1Q°.
Preparation 65 llct-Si-Mthyiaaino-5S-pregnfanfe* 3g,20S,21.-tr:lol (LIXX) XhZ‘-’I (5.75g) was dissolved in ?P. (500 ml)and Na (6g) was added oortionwise under nitrogen. The excess PR was removed In^'-ccnc· and Ea (IL) was added to the cooled reaction mixture, The solution was washed with W (x4), dried (MgSO.) and evaporated. The crude amine was dissolved in λ HCHO (60sl) and HCOOH (1,2ml), The solution was heated co 100s for j minutes and poured onto ice, basified with - 67 45270 50% NaOH solution and the steroid extracted with EA. The resulting gum was redissolved in ME (80 ml) and 25% aqueous NaOK (20 ml) was added. The solution was allowed to stand at RT for 45 minutes, and then acidified with HG1, The solution was washed with SA and basified with 50% NaOH solution. Extraction witn EA afforded material which was triturated with pentane, and crystallised from MA-pentane to give title compound (1.8g), 124-128°. llffi°Amino"3a-hydroxy"D-homo°5a-'pregnan-20-one (LXIII) ,20"Ethylenedioxy"3oc"hydroxy-D-homo"5a-pregnan11-one 11-oxime (l,87g) in PR (200 ml) was treated with Na (10 g) and worked-up as described in Preparation 47„ Crystallisation from EA-PE gave the title compound (128 mg), M.P. 154-157°, [a]D+36.1°.
Preparation 67 lla°Amino°3g-hydroxy-5«-pregnan-20-one (XLIV) To a solution (under nitrogen) of V (7,0 g) in refluxing PR (700 ml) was added small pieces of Na metal (14 g)„ When all the Na metal had been consumed, the reaction mixture was evaporated to ca.200 ml and cold W was added. Overnight refrigeration afforded a precipitate which was collected by filtration and then partitioned between 2N-HCI and DE. The aqueous phase was basified - 68 »ifch fN-haOV !3 The ...rys tall ire nats-l-.l whir:. separated was collected by filtration and crystallised fra DE to give the f title cc.r.ce%:c 2:..0.. 1.·'-.'.%: , <.£-,3°. 2l.X.o 2 f 2£2 -- -¾¾ %Li - h/droxy-5 j-py tgnan-gjjpone ΧΧΧΣΧ (lg) was dissolved in ET (30ml)s and K^CO^ D +43°.
Fregarat-? on 69 j:lgNy3ucyj.Eyiia-3'7-hyci»/gxy-5y‘pi;egnap-20-ane (LXVII) A soidt-ion cf llc-amino- 0,20-sfchylenedioxy-5a"pregnan20 3«"ί.ά (XL) (i,3g) in 1-iodobutane (Shall) was treated at 80°C with 5-.sCG„ (3g) and stirred for 3 hours. The mixture was partitioned between DE and W and tha organic layer was extracted with 2N-HG1s The extract was basified with 4N"’’i.0H solution and the oily deposit was extracted - 69 ¢027 6 into DE. The extract was washed with W, dried (I^SO^) and evaporated to leave a foam (i.5g). A portion (500mg) was purified by preparative TLC in AC to give the title compound (350mg) as an oil, [α]^ +60°. 3aHydroxy-llo’.-N-propyl^iaino-5o;-pregnan-20one (LXVI) A solution of XL (Ig) in l-iodopropane (10ml) was stirred at reflux with KgCOg (3g) for 40 minutes and the mixture was worked-up as in Preparation 69. CC using Me and removal of solvent from later fractions left a residue which was crystallised from PE to give the title compound (450mg),m.p0138-141'', [al^ 4-32°.
Preparation 71 · llg-N-Ethylamino-3a-hydroxy-5K-pregnan-20-one (LXVIII) A solution of XL (4g) in ethyliodide was stirred with AggO (12g) at RT for 2 hours. AggO was removed by filtration and the filtrate xrorked-up as in Preparation 69. CC and TLC yielded the title compound (400mg). Preparation 72 xy-5-i-pregnan-20-one A solution of XXXVIII (750mg) in ET (10ml) was treated with allylbromide (2ml) and KgCOg (lg) at 80° for 3 hours. The reaction mixture, after filtration, was evaporated to dryness and the residue partitioned between EA and brine (adjusted to ca. pH9 by addition - 70 of IN-NayXg). The aq-.;tcu? _ayer wa~ extracted with further EA are combined extracts washed with brine, dried (Ec„SC ) and evaporated: Preparative TLC yielded the title,c&mpound as a gum (107mg). iTGparatict 73 ' : '5->-~:regn-z» Le-2G-or::- _(XLII) ZXhTII (1¾) was mixed with acetaldehyde (0,4ml) in ET (ICiiil) at 21 and sodium cyanoborohydride (400mg) was added, After 15 mins, the clear solution was made alkali,ie with NaKCO- fcixticn, Brine was added and the c mixture :< ·· ezctracted with ΞΑ (3 x). The combined organic solutions ware washed with brine (3 x) and then were shaken with 2N-AA!. Excoi-i 40% aoueous SaGri solution was added and tha layezi separated. The organic solution was wasned with brine (2 x) and evaporated to dryness. The resulting oil zas chromatographed in EA-PE to give the title ciwuccjnd as a crystalliue solid (774mg). A sample was '^crystallised from ET-V and showed m.p, 1.05-103% [a] + 59,5 .
Preparation 74 lla-N-Cyclche2glaisino-2P-cthoxy-3-.-.-hydroxy-5a-pregnan-20-one XXZVIli (0.5g) was mixed with cyclohexanone <£ml) in ET (20ml) at RT and NaBi^CN (250mg) and acetic acid (0.1ml) added. After 20 hours the mixture was worlted- 71 10 up as in Preparation 73 and purified by TLC to yield title compound (268mg) as a foam. [+-1^+26.6°.
Preparation 75 11g-H-Bertzylamino-28-ethoxy-3 g-hydroxy-5g-pregnan-20-one XXXVIII (0.5g) vzas mixed with benaaldehyde (1ml) in ET (10ml) at RT and NaBH^CN (250mg) and acetic acid (0,1ml) added. After 1 hour the mixture was worked-up as in Preparation 73 and purified by CG and TLG to yield title compound (205mg) as a foam, [oc]D +34.1".
Preparation 76 llg-Isopropylamino-5;]c-pregn-2-en-20-one(XLIII) XXXVII (200mg) was mixed with AC (0.2ml) in ET (5ml) containing NaBH^.GN (200mg)„ After 3¾ hours the mixture was worked-up as in Preparation 73 and purified by CG in EA-PE followed by recrystallisation from ET-W to give title compound (55mg). m.p. 99-101°. [g]_ +80.6° (c 0.52). u — Preparation 77 3g-Hydroxy-N-isopropylamino-5i3-pregnan-20-one XXXIX (920mg) was dissolved in ET (40ml) and added to NaBH^CN (450mg). AC (4ml) was added, followed by acetic acid (0.2ml) and the reaction mixture was kept at RT for 17 hours. The reaction mixture was divided - 72 20 inco two pi-rts fox extraction, (a) The solution was partitioned between EA and solution and the organic layer was washed well with W. dried G-igSO,) and evaporated to drvness. The residue R was dissolved in MS (lOmi) and 2ii«r!C.i (10ml) was added, The mixture .~?.s allowed co stand at ST for 30 minutes and then ossified with NagGOg solution and the steroid extracted with EA, (b) The second part of the reaction mixture was iU partitioned between ,ni iia,.€0, solution as z 3 in (a) above and the organic layer was then shaken with 2N-HC1 and left fc* 3C miaucos. The reaction mixture was then basified with NaHcC., and extracted with SA. The combined EA extracts v-ve washed with water, dried (MgSO^) and evaporated, (a) and (b> were combined and subjected to thick plate chromatography using EA as solvent and the steroid w'·' eluted with EA-ME to yield title .compsund (590mg), E«]d +38°.
Preparation 78 i/hing^^yLaminp; 5u-pregn-.17i2Q )-ea-3flsfll.
NaBHgCN <.398mg) was added to a solution of XLI (l.O27g) in ET (30ml) and when dissolution was complete acetaldehyde (9ml) ws added. After 35 minutes the - 75 solution was diluted with 2N-HC1 and W and washed with EA, basified with 2N-NaOH and the precipitated material extracted into EA. The washed organic extract was evaporated in vacuo to yield an oil. Purification by preparative TLC (ME-EA 1:1) gave an oil which crystallized on trituration with a little AN. Recrystallization from W-AN afforded title compound (287mg), m.p. 106-109 [a]D -19.9% (Z)-llarlsopropylamino-5g-pregn-17(20)-en-3g-ol A solution of XLI (422mg) in IMS (6ml) containing AC (1ml) was treated with NaBH^GN and the resulting mixture worked-up as described in Preparation 78. Purification by TLC (ET-CH 1:1) gave title compound (180mg) as a froth. 2g-Ethoxy~20!20"ethylenedioxylla-(4-methylpent-2-ylamlno)5a-pregnan-3a-ol Isomers A (L) & B (LI).
XXXVIII (1.06 g) was refluxed with 4-methylpentan-220 one (2 ml) in PR (40 ml) under nitrogen for 20 hours.
Reflux under nitrogen was maintained and Na (4 g) was added over 3 hours. W (ca 50 ml) was added and the PR was evaporated at reduced pressure. The aqueous - 74 = .•-•.Αλ,·; was extraauad wit? £-, The combined extracts were wasiisc with -'riaa, cried (N«,30,.‘, and evaporated to a ga i,£ais vr purified by preparative TLC developed • .·', '.··.·.· :. . . J separata ;: · ot title compound j giving iior-er Λ (3j5 mg) (gum) and isomer B (322 mg) tv;.
Prepsrar. tSELdl JLt:::~3· _ J.'kt-lii: j:-pragn"2-en-20-oae (XLVI) XII1 (655 ..J, r?s heated nt 100° for 5 mins, with iq formic id·: (0,32 tu.? in aqueous HCHO solution (37% so kt ion, 2, 5 t’ ). Tr.e niixcure was cooled to 21° and excess acu-s? selutica added. The mixture was extracted with EA and the combined organic layers were sashvi with saturated brine, dried and evaporated to dryness. 2:.-. regional gum was filtered through silica gel 1ι» ΕΑ-5Ξ (i. 3,, Evaporation of the eluate gave the title copipo'ryy (·?? my.), ;cj ·► 111°.
Prepsr?ti;gn :2 UH*·1scpycnyl-N-ae&nyjataino-5u"pregn-2-ea-2Q-one (XLVII) Reaction of Xt-IXI (333 mg) with 37% aqueous HCHO (3.3 ml) containing formic acid (0.43 ml) in a similar manner to that described in Preparation 81 and recrystalli- 75 sation from ET-W gave title compound (643 mg), m.p. 88-99°, [ffijjj +113.5°, Preparation 83 lla-NtN-Ditnethylamino-5a.-prsgn-2-en-20-one (XLV) XXXVII (8.2 g) was heated at 95eto 110° in HCHO (37% aqueous solution, 32 ml) and formic acid (4 ml) for 6 minutes. The mixture was cooled rapidly and partitioned between EA and 2N-Na2CO~ solution. The aqueous layer was extracted with EA and the combined organic solutions were washed with brine before evaporation to leave a solid, which was dissolved in EA and filtered through silica gel. The eluate was evaporated and the residue was recrystallised from ME to give the title compound (4.0 g), m.p, 123-126°, + 110°.
Preparation 84 lla-Amino-5a-pregnane-3a,20p,21-triol (950 mg) v/as dissolved in ME (20 ml) and methyl iodide (10 ml) and stirred at RT with i^CO^ (3 g) for 4 hours.
Work-up as in Preparation 69 and purification by TLC in AC and crystallisation from DE gave title compound - 76 16.7% (16C ml)t m.p. 121-125°, Preparation z 1 ltd.hHIfiL?h echoxyy 2()..20-ethylenedioxySct- cve^- -s-n-l -..-ol ·.. Lxj.) XXX'/IIT (5,0 g) was dissolved in a mixture of 40% aqueous HCHO (60 ml) and 96-100% formic acid (2.1 ml) and the resulting solution was lieated on a steam bath for 15 Kd'iiVte&. 1:·... solution was cooled, diluccd with W (190 ml) end 3//111.%% aq/soua NaHGOg (25 ml) and the pH brought to 11 by the addition of NaOH (0.3 g) dissolved in 57 (30 ml,, .%& resultant precipitate was collected by filtratl;-.., washed with W and dried to give the title compsuni (5.41 g), icjn + 57.5°, m.p. 70% il«-jUimefchyl-aaiinp-3l-hydrpxy-5a-pregnan-20-one ( LVI I) A mixture of XLIV (0,5 g), 37% HCHO solution (3 ml) and 98% formic acid (-,-, 3 -&d, was kept at 100° for 3 minutes before pouring into aqueous NaHCOg solution.
The precipitate obtained was collected by filtration and partitioned between EA and 2N-HC1. The acidic phase was basified with 2N NaOH solution, extracted with EA, washed with W and evaporated to a froth. CC (EA-PE 1:2) - 77 and crystallisation from EA-PE afforded the title compound (300 mg), m.p. 119-121°, + 68.0°.
XLV (1.9 g) and PTSA (1.0 g) were dissolved in DG (150 ml) and m-chloroperbenzoic acid (1.24 g) was added. After stirring the mixture at 20° for 15 hours, the organic solution was washed successively with dilute aqueous NSgSgO^ solution, NaKCOg solution and W. Each time the organic layer was back extracted with DC. The combined organic solutions were dried (MgSO^) and evaporated The residue was filtered through silica gel In 1:3 EA-PE and the eluate evaporated to give crystals which on recrystallisation from PE gave the title compound (0.51 g), m.p. 154-157°, [a]D -J- 80.0°.
Preparation 88 2K,3g°Epoxy"llg°Nethyl-N-methylamino°5o:-preRnan-20-one XLVI (6.0g) and PTSA (3.21g) were dissolved in DG (300 ml) and m-chloroperbensoic acid (4.4g) was added.
After 1 hour the mixture was worked up as in Preparation 87 (except that DM was used in place of DC). Purification by CC using EA-PE yielded title compound (4.49g) [a]D+79.5°. - 78 Preparati on 8¾ Sa^a-Epoxy-Ilc- K-isopropy] -K-methylsmiii’.i-5a-prsgnan--2G-one XLVji (300.:/,: and PTSA (154mgj wore dissolved in DC .r.c m· chlorcperbencoic acid (210riig* was added, s After SO alias, further oxidant (60mg) was added. After a further 30 sainutes the mixture was worked up as in preparation 87. Purification by preparative TLC (EA-PE) and recrystallisation from «-ΕΤ yielded title compound (I14mg), m.p. 114-116% id.. -r 84.5% I* Preparati on 90 2g.37-Epoxy-.5r-.ar--:.joatane-ll,17-dione (XLV1II) A mix’ - !r< of XXVII ¢.77,2g), m-chloroperben2oic acid (30s) and CH (60uial) was allowed co stand for 0.5 hour at RT before partitioning between CH and saturated aqueous NaHCO.- solution. The organic phase was isolated and washed with w. dried and evaporated tc a low volume. Addition of PE followed by refrigeration overnight afforded crystalline material (27.5g). Escryscallisation from ,EA-PE afforsed the title compound m.p. 166-167° [α)^ + 126°. '20 Preparation 31 2p-Ethcxy-3tt-hydroxy-5g-aadgostane-ll,17-dione (XLIX) A solution of XLVXIl (5,9¾) in absolute ET (250ml) was treated with eight drops of fuming at RT. After minutes the reaction mixture was treated with aqueous NaHCO^ and evaporated to low volume. W was added to the mixture which was then refrigerated overnight. The precipitate was collected by filtration, washed with W and dried. Recrystallisation from V-ET afforded the title sound (2.1g), m.p. 164-167°, j>]D +- 114°. 3roxy-5o;-pregn-l7(20)-en-ll-one A mixture of XLIX (l,742g), ethyl triphenylphosphonium iodide (6.27g), sodium hydride (360mg) and Na- dried tetrahydrofuran (100ml) was stirred and refluxed under nitrogen. After 4.5 hours the reaction mixture was partitioned between EA and W. The organic phase was isolated, washed with dried (Na^SO^) and evaporated to give an oil (4.0g)„ CC (EA-PE 1:2) followed by preparative TLC (EA-PE 1:1 x 2) and crystallisation from EA-PE afforded the title compound 0.10 mg), m.p. 172-178°, + 25°. -ethoXy-3a-hydroxy-5t)i-pregnan-20-one (LIX) - 80 Ε®ΰΐΙ (ibg; wts suspended in W (38 ml) snd treated with concentrated dCi (12 mi). The insoluble material was j-'eviovad by filtration and wr-shed with a small portion of λ, ' Siaterial was resuspend.-.d in W (50 ml) and treated with iN-davE to pH S, The mixture was stirred at 0° for 10 slrutes and then the solid was collected by filtration and washed with L to give the title compound. Ί,ρ. 105-166 = , L'7-]?} >9,2° Trepanation 11««tejino-5-jt-hydn-oxy-5g-pregnan-20-one (LX) -ffiKX (2g? was dissolved in ME (20 ml) and 2N-HC1 (20 ml) ..adsd, The. reaction mixture was kept at RT for 15 minutes, basified with iced NaOH solution and the white solid collected by filtration. Crystallisation 15 fro;s &£··« gave title compound (1.13 g), m.p. 128-130°. - 81 dS876 Preparation 95 Zg-Sthoxy-SK-hydroxy-lla: - U-raethylpent-2-ylami.no) -5a-pregnan10 -one isomer A L (330 mg) was dissolved in ME (20 ml) and 2N HC1 (0.5 ml) added. After 15 minutes at 21°, the mixture was neutralised with 2N~Na2COg solution and evaporated to small volume. The residue was partitioned between EA and brine The aqueous layer was extracted with further EA and the combined organic solutions were washed with brine (2X), dried (Ife, ^0^) and evaporated to dryness (310 mg). This was purified by preparative TLG developed in 5% c ME in EA and EA to give title compound as a white foam, ion 96 -one isomer B llg-(4-niethylpent-2-vlamino)-5Q:-pregnaii20 LI (322 mg) was treated as described in preparation 95 to give the title compound (170 mg) as a white foam, [D + 2.1° (c 0.36). limethylamino-3 g-hydroxy-5 oc-andro s tane-17 g-carbalde(LV) A solution of LII (250 mg) in D (15 ml) and W (3 ml) - 82 SBS7S treated with period4·-· ncid (1 g) for 30 minutes. Aqueous '•h/if? solution ;’2N; 10 ml) and V (2C0 ml) were added and the oily precipitate extracted into DE. The extract was washer with ;··. driei fra,30,) and evaoorated to leave Z ig li.a -N »M—iXf••s.-inylasuino-S-e· k.y«roxy-5s~androstane-17p-carbaldehyde as n foam (IS 3 mg).
The aldehyde was dissolved in ET (50 ml) and a mixture ex NH^OH.hCl (300 mg) and haOH solution (2Nj 5 ml) to pH 11 v?as added, After 15 minutes the mixture was diluted with ’0 W and tne pracipltacs rat extracted into DE. The extract was washed with K dried (:\a,50^) and evaporated to leave a ie-am whic.h was crystallised from PE-DE to give the title compouK·. (A3G mg) m.p. i07.5-110’G, [κ]β +4°. f Preparation 9« Ϊ 5 lls-N Ehrethylsaino-2S-ethoxy- 3 a - hydro y.y- 5 a- and r j?tane-17 β carba:ldt-lyre oxime '..L, i) XXXI (650 mg) was treated as described in preparation 97 and erysta<.lie-c.d from hnuaue - DE tc give title compound (330 mg), m.p. 99-102% [ujn -.- 12°.
Preparation ϊ/,. l«-DiBiethvl^mino-3ft-hy0roxy-5p-androstane -17g-ca,rbaldehyda (LIV) LU* (I.3g) was dissolved in D (65 ml) and periodic acid (1.3g) in W (6.5 ml) was added. The reaction mixture - «3 037 6 was kept at RT for 15 minutes, poured into aqueous NaHCO^ and the steroid was extracted with EA. A portion of the steroid (300 mg) was subjected to preparative thick plate chromatography using EA - PT 1:3. Elution with ME gave title compound as a foam (150 mg), taJjj + 24° (c 0.5) Preparation 100 3g°Acetoxy-lla-dimsthylamino-5g-androstane°17g-c5rbQnitrile (LXXII) 50% Aqueous KOH (4 ml) was added to a solution of Nt^OH.HCl (2g) in W (4 ml) with cooling. This solution was then added to LIV (860 mg) in ET (32 ml) and the mixture was kept at RT for 10 minutes. Dilution with W and extraction with EA gave the 17p-oxime (890 mg) This material was dissolved in acetic anhydride (20 ml) and refluxed for . ig nn'nutes. After dilution with iced aqueous NaHCO3 solution the mixture was stirred for a further 30 minutes. The steroid was extracted with EA and subjected to preparative TLC using EA-PT 1:3 as solvent. Elution with ME and crystallization from EA-ME gave tide compound (560 mg) m.p. 148-152°. 3g°Acetoxy-llg°M,N-dimethylamino-5g-androstane-17p-carbonitrile (LXX) A solution of’LV (1.30 g) in acetic anhydride (20 ml) was refluxed for 1 hour. The mixture was poured into iced -84 it ΰ % 7 ·: saturated NahCO., ·?-: ;3GG ··;·.} sod the precipitate was entra.·i,.=tc DE·. '..ce ext·,·?5 washed with W, dried (Ka-Xlb ) arc evapar.At-.id to leave a foara which was purified ay preparative %% in > ΓΧ» pH 9*4 4J <5 © p> ft » Φ SS CM • k V pH CM 4J «s o o o O Λ $ 42 % B <0 o Γχ 00 © CM ?H £ S' £ Φ 10 in in in © \£ XI W --— M © pH 'CM s © r- co C\ pH «Η pH 102 TABLE 4 (confc) 2 — Z~s «rl \-z PQ o « z—X •H *r! cq 03 .«'"X »ri Ή x«z ffl & x^z •H « 2 /~X 03 r^X •ri x-*» PQ Q r—1 b L_J 0 en in + 0 p*» co + o in • CM kO + -Π Q o o s + L Q CO m + • ZH. 0.0 Β-ϊζ . O' v 1 »"4 O r-I r* in r-i 'ί in 00 ό co1 CO CM r-i 1 »—1 CM »—ί 1 Crystallisation solvent u < 1........ -- w Pk 1 jy o i 1 .. — ¢. 1 ω Q f. 1 1 s . §£ O A h ci d 60 Eh Hi ! Q < < y w w o < u w r-........J M a ύ g< a H a 2 a O l i« y y a O H • w a 2 y O i u a y eh 2 0 s-\ Ή bO en CM • o -——. co « o in iM O V. -m o vD O i—i kO o Reaction Time 3» k M-f ,£ Φ P3 co js en w X C £} ·Η r-l B U4 Φ o P5 < W o k O ,£ < r-i CM CO k JC in co £ m c5 φ ω 4J !' s bO F-1 d t§\ O rH S Ο Μ « m \ (§ bO «i cc oCr-i \ΰ Io 3 M 00 > bO cm m < δΰ C •H 4J 4 if < CM a* Cl V) u o r—) O en X.O 5—i u Φ CM ί-η pij Λ K CM tc o cm tc CO O O en o tC CM o & CM Z~X EC* cm en *^O H Q en *\O H V V CM rM «3 •rl k 4) •U .03 z-s 60 U & in F-J in r-l r-i r-i in r-i cn Starting M o’ 2 Ck 41 Jm Cj r-Ί in $ on kO en VO σι in en m £ en rM 2 in kO F-l r- r-i co r-l 103 TABLE 4 cent NCO a aa a CO 5 co *O P"< S * ¢3 w a nco ό · CI €0 tJ 43 ¢5 U4 O O r-1 W =* 43 CO O s»z r-l Q\ •H e J4 CO 4J O CO - »1 Is* O * CM /~>a COQ a o a i CM 321 Ο N OK 5 P· Ό i-3 £ *· SiM K-Z S tn i oo ex ♦ > 3 a rM r-4 γ·Μ Cj ο o u i wrap •H » w cn 2 (β (B z-'.s^ COr~ τ3 ό ri · Π i-l 1-3 b Ctf I > ax 2Ε-< ·-ι O Cd μ Μ 104 4837s lloc-Diethylam3.no-3g-hydroxy-5S-pregnan-20-one XXXIX (0.5 g) was dissolved in ET (25 ml) and acetaldehyde (5 ml) and NaBH^CN (250 mg) was added.
The reaction :.....: kepi at RT for 15 minutes and was then acidified with 2N-HC1· After a further 15 minutes the. solution xias basified with KOH and extracted with EA. Crystallisation from ME-W gave the title compound (354 mg), m.p. 123-125°, + 36°.
. Example 25 ll«-I>iethylamino-3a-hydroxy-5p-pregnan-20-one XXXIX (50 mg) was dissolved in ET (2.5 ml) and acetaldehyde (0 25; ti) and NaBH^ (25 mg) were added. The reaction was kept at RT for 30 minutes and then worked up as in Example 24 to give title compound, which by gas chromatography was identical to the product from Example 24.
Example 25 2|3-,Bthoxy-3g-hydroxy-li«-piperidino-5g-pregnan-20-one XXXVIII (0.5 g) was mixed with 25% aq. glutaric dialdehyde solution (2ml) in ET (10ml) at RT and NaBH^CN (250mg) and acetic acid (0.1 ml.) added. After 6 hours the mixture was worked-up as in Preparation 73 and purified by CC and 1045 TLC to yield title compound (211 mg) as a foam· [aJD + 35.2°.
Example 27 3g-Hydroxy-llg-piperidino-58-pregnan-20-one 5 XXXIX (1 g) was mixed with NaBH^ CN (500 mg) and 25% aqueous solution of glutaric dialdehyde (5 ml) in ET (10 ml) at RT and acetic acid (0.2ml) added. After 3 hours· the mixture was partitioned between EA and NaHCO^ solution. The organic solution was yO washed with 2N-HC1 and the combined acidic extract was washed with EA. basified using 50% NaOH solution, extracted with EA. washed with W. dried (MgSO^) and evaporated to give a foam.
This material was purified by preparative TLC eluting with ME containing ca 1% W and the solution evaporated.
The product was then dissolved in DE filtered and evaporated giving title compound (318 mg), [a]D + 58.5°.
Example 28 llK"5imethylamlno-28-ethoxy-3cc-hydroxy-5g-pregnan-20-one (a) LIX •(200mg) heated to ca 100° with HCHO (4ml) and formic acid (0.08 ml) for 10 minutes. The reaction mixture was then poured into NaHCO^ solution and the 106 4537 steroid extracted with EA. Preparative TLC using AC-PT (3:7) and crystallisation from DE-PT gave title compound <50 mg), m.p. 140-143°. (by LIX (230 ng) was dissolved in ΞΑ (25 ml) and 37% aqueous ECHO (0.5 ml). 10% Palladium on charcoal » (250 mg) was added and the solution hydrogenated for 17 hours. The catalyst was removed by filtration through kieselguhr. and the solution was washed with W. dried (MgSO.) and evaporated to dryness. Preparative TLC using CK-MA-ME (49:49:2) followed by crystallisation from AC--W gave the title compound (100 mg)> m.p. 129-134°. (c) LIX (100 mg) was dissolved in EA (10 ml) and HCHO (0.2 mi). Tris(triphenylphosphine)chloro rhodium (50 rag) was added and the solution was hydrogenated for 17 hours. It was then washed with W and the organic layer was dried (MgSO^) and evaporated to dryness. Chromatography on thick plates using MA-PT-ME (33:65:2) as solvent gave the title compound (30 mg) identical by TLC and gas phase chromatography to the product of part (a).
Example 29 llg-N.N-Dimethylamino-3tt-hydroxy-5g-pregnan-20-one (LXXIII) (a) LX (50 mg) was stirred at RT with HCHO 107 4S276 (1 ml) and formic acid (0,02 ml) for 23 hours to give the title compound similar to product of Example 3 by TLC. (b) LX (50 mg) was dissolved in EA (10 ml) and paraformaldehyde (lOOmg), and 10% platinum on carbon (50 mg) added. The reaction mixture was stirred for 17 hours under hydrogen to give the title compound identical with the product of Example 3 by TLC. (c) LX (100 mg) was dissolved in EA (10 ml) and HCHO.(1 ml) and 10% Pd/C (100 mg) was added. The reaction mixture was hydrogenated for 17 hours and the catalyst removed by filtration through kieselguhr. The solution was washed with W, dried (MgSO^) and evaporated to dryness to give the title compound (110 mg)> which resembled the product of Example 3 by TLC and p.m.r. spectroscopy. (d) A solution of HCHO in EA (20 ml; prepared by heating paraformaldehyde at 200° and bubbling the HCHO gas into the EA for 5 minutes) was added to LX (100 mg) and 10% Pd/C (100 mg) in EA (5 ml). The reaction mixture was stirred with hydrogen for 30 minutes to give the title compound identical by TLC to the product of Example 3. 108 6 Example 30 lla-N.N-Dimethyla.?.ino-26-ethoxy-3u:-hydroxy-2i-methyl-5ttpregnan-20-one LXII (I.00 g) was heated for 10 mins at ca 100" in a mixture of HCHO solution (20 ml) and formic acid (0·'' ml). I he cooled reaction mixture was diluted with 5% NaHCO^ solution (50 ml) and extracted with EA. The organic extracts were extracted with 2NHCli basified to pH 11 with 40% NaOH solution and re-extracted with DM. The extract was dried (Na^SO^) and evaporated tc give a foam which was purified by CC using EA as eluent to give the title compound as a foam (828 mg), [g] + 72.
Example 31 l'ia-Dimethylaminc-3-<-hydroxy-D-homo-5K-pregnan"20-one A suspension of LXXII (656 mg) in HCHO ( 5 ml) was treated with formic acid (0.21 mg) and the mixture heated to ca 100° for 5 mins.
The cooled solution was partitioned between EA and 2N^a2^3‘ The organic portion was washed with saturated brine solution, dried and evaporated to give a foam (704 mg). This was purified by preparative TLC (ME) 109 4B270 and crystallization from ME to afford the title compound m.p. 116-118°, [a] + 41.5°.
Example 32 lla-Simethylamino"28-ethoxy-3a"hydroxy-’D-homo5KFormic acid (0.29 ml) was added to a suspension of LXIV (1 g) in HCHO. The mixture was heated on a steam bath for 20 mins, cooled and partitioned between EA and 5% aqueous NaHCO^. The organic extract was washed with saturated brine solution dried and evaporated to a foam. This was purified by preparative TLC (ME), and crystallization from AN to affdrd the title compound (469 mg), m.p. 132.5-133.5°, 03 46.8°.
A mixture of LXV (1.8 g) , HCHO (12'ml) and formic acid (1.2 ml) was kept at ca 100° for minutes before pouring into aqueous NaHCO^ solution. The precipitated solid was collected by filtration, washed with W and dissolved in EA. Evaporation afforded a froth which was filtered through a plug of 110 silica in SA-PE 1:1. Recrystailisation from ME-W then afforded the title compound, m.p. 63-78°» WD - 2°· Example 34 (Z)-lla:-Dig.eth vlaainc-5«-pregn-17 (20 )-en-3«-ol 5 A suspension of XLI (550 mg) fn HCHO (4 ml) was treated with formic acid (0.3 ml) and the mixture was agitated until the steroid had dissolved· The solution was heated to ca 100° for 10 minutes, cooled and diluted with excess NaOH solution, The precipitated material was extracted into EA, the extract was washed with W and then 2NHC1. The acid extract was washed with EA, basified with NaOH and re-extracted with EA. Evaporation of the washed organic extract afforded crystalline material which was purified by preparative TLC (5% ME-CH) and crystallization from ME-W to afford title compound (309 mg), m.p. 39-61°. [a]& - 8.1°. Example 35 (2)-ll't-Diethyl^nino-5,x-pregn-17(20)-en-3«-ol A solution of XLI (608 mg) in ET (20 ml) was treated with acetic acid (0.1 ml) and NaBH^CN (231 mg).
Ill The mixture was kept at RT for 27 minutes and then acetaldehyde (3ml) was added. After a further 15 minutes the mixture was worked-up as in Example 24 and purified by preparative TLC (EA) and crystallization from AN-W to yield title compound (333mg), m.p. 89-90°, [α]^ -38,1°, Example 36 Lg°Piperidino-5g-pregn-17(20)-en-3g-ol A solution of XLI (795mg) in IMS (10ml) was treated with NaBH^CN (395 mg), 25% aqueous glutaric dialdehyde (2ml) and acetic acid (0,1ml). The mixture was kept at RT for 1 hour and then worked up as in Example 24. Purification by preparative TLC using 10% ME-EA yielded the title compound as a froth (410mg), Coc}D -15.3°.
Example 37 g-Dimethy lamino-5 g-pregn-20-en-3g-ol lia-Aminop5a-pregn-20-en-3a-ol (650mg) in methyl iodide (15ml) was stirred with K2C03 s^x hours, The reaction mixture was evaporated to dryness under reduced pressure and the residue was partitioned between EA and W. The organic layer was washed with W and then extracted with dilute HC1, The acidic extract was washed with EA, Π2 ΰ2?β basified with concentrated ammonia solution and extracted with EA, The organic extract was washed with W, dried (MgSO^) and evaporated to give a foam. This was purified by preparative TLC (EA-PE 1:1) to give the title compound as a crystalline solid (270mg), m.p, 131-133°, Example 38-46 Table summarises the preparation of Ιΐα-Ν,Νdisubstitutsd amines from the appropriate lla-N-monosubstituted amines by the following method:10 The amine was dissolved in HCHO solution ' containing formic acid and the mixture heated to ca 100°.
The mixture was then worked up by one of the following methods:15 A, The mixture was partitioned between EA and aqueous NaHCO^ and the EA extract washed with brine, dried and evaporated, B. The mixture was diluted with W and extracted in EA, The aqueous layer was basified with NaOH, extracted with EA, and evaporated. The original EA washings were washed with NaOH and W and evaporated. The residues were combined. 113 C. The mixture was neutralised with NaOii and extracted with EA, The washed extract was evaporated.
D, The mixture was diluted with saturated NaHCO^ solution and the precipitate collected.
The material from one of these procedure was purified by CG or preparative TLC and/or crystallisation.
The foilwing compounds were prepared: 38, lla-N-Cyclohexyl~N-methylamino-2|3-ethoxy-3ahydroxy-5 α-pregnan-20-one 39, 28-Efhoxy-3a-hydroxy-lla-(N-methyl-N-4-methylpent 2-ylamino)-5a-pregnan-20-one, isomer A 40, 2p-Ethoxy-3o:-hydroxy-lla-(N-methyl"N-4"methylpent 2-ylamino)-5a-pregnan-20-one, isomer B 41, 11α-N-Benzyl-N-methylamino-2β-ethoxy-3a-hydroxy» a-pregnan-20-one 42, lla-N-Allyl-N-methylamino-2p-ethoxy-3a-hydroxy5 a-pregnan-20-one 43, (Z)-lla-N-Ethyl-N-methylamino-5a-pregn-17(20)-en3a-ol 44, (2)-lla-N-Isopropyl-N-methylamino-5a-pregn-17(20)· en-3a-ol 45, lla-N-Ethyl-N-methylaminO"3a-hydroxy-58-pregnan20-one 46, 3a-Hydroxy-lla-N-is£-propyl»N-methylaminO"5ppregnan-20-one 114 *i>376 Example 47 3g°Hydroxy-1la-N-methyl-N-propylamino-5g°pregnan-20-one A solution of LXVI (380mg) in methyl iodide (10ml) was stirred with I^COg ^g) for 4 hours. The mixture was diluted with DE and W and the organic phase was extracted into 2N-HCI, The extract was basified with SN-NaOK and the oily precipitate extracted into DE. The extracts were washed with W, dried (f^SO^) and evaporated to leave a foam which was purified by preparative TLC and crystallisation from PE to give the title compound (210mg), m.p, 149-152°C, [α]^ +90°.
Example 48 lla:-N-Bufcyl"H-methylaminQ~3K-hydroxy-5g-pregnan-20-one A solution of LXVII (Ig) in methyl iodide (40ml) was stirred with K^CO^ (3g) for 3 hours. Workup as in Example 47 and purification by preparative TLC in AC-PE (1:3) gave title compound (680mg), +83°, Example 49 llffi-N-Ethyl-N-methylamino-3g-hydroxy-5K-pregnan"20-one A solution of LXVIII (370mg) in methyl iodide (2ml) and DM (40ml) was stirred with ^g) for 3 hours, DE and W were added and the organic phase was 116 «S2?s washed with W, dried (Na„SO, ) and evaporated to leave a foam which was purified by preparative TLC in AC-PE (1:3) to give the title compound (350mg) as a foam, [c]D +83.7% Example 50 llc-N, K-Diroeth? amino-2j>atho?y-3 y.-hydroxy-5g-pregna.P" -one LXIX (560mg) was stirred with boron trifluoride etherate (0,5ml) in ET (25ml) at 20° for 4 days. The mixture was concentrated by evaporation and partitioned between EA and 2N-NaoC0, solution. The aqueous layer was extracted with further EA and the combined organic solutions were washed with saturated brine, dried (MgSO^) and evaporated to leave an oil. This oil was purified by preparative TLC and recrystallisation from PE to give the title compound (46mg), m.p. 131-137.5°, [o:]_ +83.3°. u Example 51 llq-N,N-Dimethylamino2g-gbhoxy-3g-hydroxy-5g-pregnan20 20-one 50% Aqueous perchloric acid (2ml) was added to a stirred solution of LXIX (lg) in ET (100ml) at 20°. 117 After 2 hours NazCOg solution was added to raise the mixture to pH 9 and most of the ET was evaporated. The residue was partitioned between EA and W. The aqueous layer was extracted with further EA and the combined organic solutions were washed with saturated brine, dried (Na„S0.) and evaporated to a gum. This gum was Z * purified by preparative TLC and recrystallisation from ET-W to give the title compound (5Q4mg), m.p. 119-123°, [dD +83°.
Examples 52-70 % Table 6 summarises the preparation of 2βsubstituted-lla-di-substituted amines from the corresponding 2a,3a-epoxide by the following method:The 2a,3a-epoxide was treated with the appropriate 15 alcohol or acid in the presence of a catalyst( where necessary) at RT (or 100°C in the case of 2p-acetoxy compounds) for the time indicated. The mixture was diluted with aqueous ^£00, solution (or aqueous NaOH in the case of 2p-fluoro compounds) and worked-up by one of the following methods:A, The mixture was extracted with EA and the extract washed with brine, dried and evaporated. 118 B, The solid which precipitated was collected by filtration, washed and dried.
C, The alcohol was evaporated and the aqueous residue extracted as in A above.
The material from one of these procedures was further purified by CC and/or preparative TLC and/or crystallation The following 2p-substituted derivativesof 3ahydroxy-lla-N,N-dimethylamino-5a-pregnan-20-one were prepared:- (Example Nos. are given in brackets) 2p-fluoro (66),-chloro (61),-bromo (65), -thiocyanato (64),racetoxy (69),-propoxy (54),. -benzyloxy (59),-chloroethoxy (60), and-isopropoxy (52); and of lla-N-c;.hyl-N-methyla!Tiino~3a-hydroxy-5a-pregnan20-one:2S-fluoro (68),-chloro (62),-methoxy (55), -ethoxy (53) and-acetoxy (70); and of 3a-hydroxy-lla-N-iso-propyl -N-methyl-5a-pregnan20-one:2,e-fluoro (67),-chloro (63),-methoxy (56), -ethoxy (57) and-acetoxy (58).
HCIO^ was used as a 60% aqueous solution. 119 4S276 61 cn © Gn © 58 57 56 55 UI 53 52 F3 κ 87 co xj CO 00 © 00 © CO ·& CO co co -4 CD co co *4 g « 2! © 4 Ar-___„ Starting Material 300 go 00 co > £ Go © o > o o GO o o GH O O --4 Gn O Gn O O *4 in O si rt * Z-\ a 00 \z ' 1 ο § P s o 1-. TO NJ |s> a h* 0 © Η K o & Benzyl alcohol Acetic acid 1 g ►d w t-J Hd K © ‘d § 8 NJ 8 © £ Η» CX O Hi > !—1 0. O s i—3 M £> O Ul gj GO © GO O Gn O © © Gn O r* un < © w z*s 3 Η» D 4>° X © >° X e p-° X © w X © Η» ¢.° X a l·-4 >° X © -?·σ X NJ CO O s Β-» to rt* 1 © « co © 00 p Gn © © en H1 t-4 Gn © t K NJ << 0 K z*\ & %✓ H4 Gn & •S· o B S' co Ui 3 S’ (0 ω ί?1 Κ M S' nj GFI 3 S’ ω GO •v! 3 s° co t-1 S' GO S' (0 ¢- S' co Reaction Time < 101 to © NJ & H3 t4 •xj GO f-4 *4 09 ho Go Gj $ © Gn NJ NJ GJ cn GJ3 £ B-3 iX a l·1 β o M > £ g M r s A tr* O ? hd FJ £ a w =r hd F3 i-3 f a H > 1 Π3 H 1-3 O M =r hd W £ o M 3 <4 d r* © n« Hd W 00 9 S g W § S' P >< rf o 1 ad Ϊ • B 1 1 5 Crystallisation solvent •HH , ^Gd .* 3 0 { 1 1 1 ! i o g r> * Ό + oo Φ oo Ψ © Gj o ·+ cn 0 + -*4 00 Gn 0 —¥" •4 Gn 0 .L •*4 © 0 + 00 © Gn 0 + Gj oo 0 + 00 NJ o z-s + 0 00 © NJ » 0 CN x-z R I I o « ► ► © > a o © © > > IS g O ID «Off s' l-h S' V (X TABLE 6 120 TABLE 6 cont 0276 hi σ © κ ii Η» X ο Φ CO ft Η> Ό CO 0 0 o P Η t-} f-* o g © < ft ω CL ro cl Pa i£ & ο O* H* co 0 *< a 3 σ* Ό Φ ct P Μ X O co Φ cv W kJ r» w z-s l-ft P H· Ο p o Φ 3 CL rt H* a u· S Η O p. Φ a ft Ρ a* o /-ν hh tn P 09 P o \-Z CC 3 S3 H· P a a CL r- rt CL 32 H K m fi> § ft a- w St P 09 H rt H* a a © b JQ S P i.! ft ! U? r? φ O © Η» P 3 ro 1-» £5 > Ο Ο Η- Π> G. ft ft’ σ» ό ti (ΰ *ϋ CL Κι w ο w § Η· Π* & Μ > Η» W Ο Ο» CF* α Η· « W ο Η» <; Η· Ρ Η* Ρ . Μ > ro w ·>, 45* a1 Η ω ο OQ S3 CO rr* Ρ ο ·5 & a* P * Φ a X CL CL rr K K *a H· P a* Φ 0 o CL co ft Ό P h· a* a w o CL 09 K H· Η» 0 <3 a P Π- P Ό ο 0 0 H* a -ffl CL P o r? z-s f& » CL CP· 09 d s>z a1 (D Ί22 333 Yield (ng) $ o PJ T hd Pi Q w σ’ 8 g 1 Ϊ Crystallisation solvent 1 /***< O° .3 T3 - λ -l· CO 1 r~j 8 sa i » -1 Method of workup Example 71 tt-N,N-Dlmethylanino-3 a-hydroxy-5 g-aadrostar e-17 gcarbonitrile A solution of LXX (500mg) in ME (150ml) was treated with saturated NaHC0„ solucion (20ml) at reflux o for 24 hours.. The mixture was diluted with W to 1 1, and the precipitate was filtered off, washed with W and dried. The solid (340mg) was purified by preparative TLC in EA-PE (l:2) and crystallisation from DE-PE to give the title compound (i70mg) m.p. 183-186°C, La]„ +47.5° I) Example 72 llg-N,N-Dimethylaminoj 26-ethoxy-3g-hydroxy-5a-a.ndrostane175-carbonitrile A solution of LXXI (320mg) in ME (80ml) was treated 15 at reflux with saturated NaHCO^ solution (8ml), After hours the mixture was diluted to 600ml with W and the precipitate was extracted into DE, The extracts were washed with V, dried (Ka^SC·^) and evaporated to a foam (300mg) which was purified by preparative TLC in 7C-PE (1:3) to give title compound <250mg) as a foam, [a] +46°. 123 43376 Example 73 llg-Dimethyl£mino-3g-hydroxy-5p-andros't:ane-17g-carbonitrile KHCOg (Ig) in W (20ml) was added to a solution of LXXII (500mg) in ME (50ml) and the mixture was refluxed under nitrogen for 2 hours. Dilution with W and extraction with EA gave crude product which was crystallized from DE-PE and ME-W to afford title compound (170mg), m.p. 137139°, [dD+67°.
Example 74 21°Acetoxy-llo:-N,N-dimethylamino-3g-hydroxy-5g-pregnan20°one (LXXIV) Lead tetra-acetate (l.Og) was added to a solution of LXXIII (b,5g) in benzene (18ml) and ME (1.15ml). The solution was cooled to 10° and boron trifluoride etharate (2.85ml) was added; the reaction mixture was stirred at 10° for 5 hours and then was poured into aqueous NaHCOg solution. The steroid was extracted into DE and subjected to preparative TLC in 2:1 EA-PT. Elution with EA followed by crystallisation from DE gave the title compound (iOOmg), m.p. 150-152°. 124 2 7 6 Example 75 3g,21-Dihydroxy*llg-C'imethylamino-5i3-pregnan-20-one LXXIV (SQOmg) was dissolved in ME (20ml) and aqueous KHCO^ (5ml, 20 £) was added. The solution was refluxed under nitrogen fcr 2 hours, and was then poured into W and the steroid extracted with EA.
Preparative TLC using AC--PT 1:2 as solvent and elution with AG gave title compound as a white froth (310mg), [trip +47% Example 76 lla-Dimethylamino-3a-hydroxy-5g-pregnan-20-one LV1XI (110lag ) was treated with a refluxing solution of chloroiridie acid reagent (3al) for one hour before partitioning between £A and aqueous NaHCO, solution.
The organic phase was isolated, washed with W and evaporated to a froth. Crystallisation from PE afforded the titla compound (78mg), m.p, 119-122°, [aj^ +76.0°, Example 77 llg-Dimethylamlno-3r-hydroxy-5r-pregnan-20-or.e To a mixture of LVII (362mg), formic acid .. (0.11ml), triphenylphosphine (787mg) and tetrahydrofuran (15ml) was added a solution of diethylazodicarboxylate 725 f dried (ifegSO^) and evaporated, to give a froth, CC (eluting with DM) afforded a froth which was dissolved in ME (10ml) and treated with 10 drops of perchloric acid. After 0,5 hour, the reaction mixture was worked up as in Example 76, Crystallisation from PE afforded the title compound (106mg), m.p. 119-123°, [a]D+76.7°.
Example 78 q-Dimethylamino- 2g - ethoxy-3q-hydroxy- 5q-pregnan- 20- one XLV (IOOmg) was stirred with PTSA (61mg) in DC (10ml) and ET (5ml) for 5 minutes. m-Chloroperbenzoic acid (75mg) was added and after 24 hours at 20° TLC showed formation of the title compound , Example 79 lla-N,N-Dimethylamino- 2p.°ethoxy-3q-hydroxy-5a-pregnan20-one LXI (3,0g) was dissolved in DM (20ml) and the solution was extracted with a solution of cone H„SO, 4 (1,8ml) in W (25ml) and then with W (15ml). The combined 126 2 7 6 aqueous extracts were kept at RT for 10 minutes and then brought to pH 11 by the addition of NaOH solution. The precipitate was extracted into DM and the extracts were washed with W. The dried (MgSO^) solution was subjected to CC eluting with DM-MA (9:1). The eluats was evaporated to give a feat; h' ich was crystallised from AC-W (4:1) to give the title compound (1,65s), , +74°, m.p. 135143°, Example 80 Methyl llx-N,N-diniethyiamino-2E-ethqxy-3a-hydroxy-5aandros cane -17 3-carboxylate Iodomethane (8,4ml) was added to a solution of LXXV (3,5g) in dimethyIfarmamide (30ml) and triethylamine (25ml), After stirring for 20 h, the mixture was poured into 5% NaliCO^ solution (50ml) ana was extracted with CH. The combined extracts are dried (MgSO.) and evaporated.
The residue was purified by CC using 1:4 EA-PE as eluent to give the title compound as a foam (965mg), [a]p +35°. Example 81 1ίζ-Ν<Ν-Ρίπΐ3Ηιγΐ3Π'.1ηο-26-£ίΗοχγ-3κ-ΗγΰΓοχγ-21-ρΓορνΊ-5«pregnan-20-one Butyl lithium in hexane (8.6ml, 1,7M) was added 127 42276 to a suspension of LXXV (2.0g) in DE (12ml) under nitrogen with cooling in ice-W. The mixture was stirred vigorously at 20° for 31 h, and was then diluted with W (25ml). The mixture was extracted with EA and the combined extracts were washed with 0.1 N-NaOH, The dried (MgSO^) extract was evaporated to give a foam which was purified by preparative TLC on alumina using 1:2 EA-PE as eluent to give the title compound (146mg) as a foam, [α]^ +75°. Example 82 11K-Dimethylamlno-3 «-hydroxy-5g-pregn-1-en-20-one 2p-Bromo-11g-N,N-dimethylamino-3a-hydroxy-5apregnan-20-one (2.76g) was stirred with, dihydropyran (7ral) and PTSA (1.30g) in B (150ml) at 21°, After one hour, the clear solution was washed with excess 2NNa^CO^ solution, brine and dried (Na^SO^). The B was evaporated to an oil which was then dissolved in DMF (75 ml) and heated at 105° to 115° with CaCO^ (7.5g) and LiBr (lOg) for 19 hours. The mixture was diluted with ME. and insoluble solids were separated by filtration. The residue was washed with further ME and the combined ME solutions were diluted to ca 300ml. 128 u ίι3 2 7 6 This solution was adjusted to pH 1 with 2N-HC1 and after 1 hour at 21'', 2N-LiaydOg solution was added to raise the mixture to pH 9,0 and the ME was evaporated at reduced pressure. The residue was extracted twice with EA and the comoined extracts were washed with brine, dried (Na^SO^), and evaporated to an oil. Residual DM? was evaporated using an oil pump leaving a gum. This was dissolved in 1:1, EA-PE and filtered through silica gel (30g) to give the crude product. This was purified by prep10 arative TLC (EA-PE) to give title compound (6'ilmg), [α]_> +1,5% Example 83-157 Preparation of salts Table / summarises the properties and preparation 15 of aqueous solutions of salts of the invention by one of the following methods:A. The lla-amine was added to a solution of the acid in W and the mixture stirred or shaken until a clear solution was obtained. The solution was 20 xiade up with W to the weight indicated, filtered through a membrane and the pH determined.
B. As A above except that prior to making up with W 129 3 276 the solution was filtered and treated dropwise with 0.1M NaOH solution until the precipitate initially formed did not quite redissolve on stirring.
C, A solution of the lla-amine in ET was treated with a solution of the acid in W. The. mixture was evaporated in vacuo and dried to constant weight.
The residue was dissolved in a little W and any material which then remained undissolved collected in a weighed funnel and the weight of the dissolved free base calculated. The solution was made up with W to the weight indicated and its pH measured, D. The lla-amine was added to a solution of the acid in W and the mixture stirred or shaken. As free base remained undissolved, further acid was added and the mixture agitated again. The solution was made up with V and any material which then remained undissolved was collected in a weighed funnel and the weight of dissolved free base calculated and the pH of the solution measured, Έ, The lla-amine was added to a solution of the acid in W and the mixture stirred or shaken. The solution was made up with W to the weight indicated. The material remaining undissolved was collected in a weighed funnel and the weight of dissolved free base calculated and the pH of the solution measured.
The solid citric acid used was its monohydrate. 130 table 7 <· Ϊ3 87 6 Ex Free Base Ex. No. Salt Method DissoLvec 1 la-amine (mg) ij Molarity of acid solution Acid J 1 Wt of j solution ig) pH 83 6 citrateB 120.5 ί 0. i 3,4ml 24 6.5 84 6 ft C 120 0.1 3.34ml 12 3.6 85 6 hydro- chloride8 120 0..1 3,4ml 12 4.85 86 6 phos- phate B 120 ! 0.1 5 ! 3„4ml 10 5.7 87 6 mesy- late 3 1 120 i ! 0.1 3,4ml 10 3.3 8S 6 triear- ballylat B 2 120 0.1 2.3ml 12 6.05 89 7 citrate B 100 - 54mg 10 5.0 j 90 8 If A 102 - 55mg 10 3.7 !» 9 15 A 101 56mg 10 3,8 92 , 10 It A 103 ! i 55mg 10 3.7 93 11 II A 101 - 57mg 10 3.7 94 12 V A 102 - 57mg 10,06 3.7 95 12 acetate E 34 0.5 1,59ml 10 4.4 95 14 citrate B 100 0,1 2.6ml 10 4.8 97 14 acetate J5 100 0.5 1,5ml 10 3,9 98 15 citrate B 100 0.1 2.5ml 10 3.5 99 16 II c 100 0,1 4.5ml 16.5 3.0 100 17 II B 350 0.1 9.0ml 35 5.1 101 18 II B 100 0.1 2.5ml 10 4.0 L02 19 .. 3 16 - 48mg 5 2.45 103 20 11 E QO i s - 24.5mg 5 5.26 L04 21 If E 45 - 25,5mg 5 5.58 LOS 23 II £ ί 130 0.1 3.3ml 13 5.3 L06 24 it B ! 100 - 54mg 10 4.5 L07 26 II E 41 { - 23.5mg 5 3.4 LOS 27 n D100 1 - 104.2mg 12 |3.0 L09 30 It A 100 - 50mg 10 3.7 L10 3L II E 94 - 60mg 10 3.8 Lll 32 If4 I 100 . 50mg 10 3.7 L12 37 If D* j 96 f - 121.6mg 20 3.1 731 Q 2 *7 6 TABLE 7 cont ' --------- w M Free Base Ex. No, Salt Method ---- Dissolved! Molarity lla-amineI of acid Ϊ Acid Wt of solution (s) (mg) solution 1L334 citrate A 100 52mg~ J.0 3.65 11435 69 D 103 - 74mg 10.29 3.45 115 36 If D 102 - 114mg 10.21 3.0 116 33 II A 78 - 63mg 7.8 3.16 117 38 go E 17 - 22mg 5 2.85 118 ί 39 u D 25 - 44mg 5 2.65 119 ί 40 u D 41 - 44mg 5 2.8 120 42 ! ft D 43 48mg 5 2.9 121 43 II A 87 51mg 8,7 3.75 122 44 II D 99 - 105mg 10. 28 3.1 123 45 II A 100 - 55.9mg 10 3.75 124 46 H A 100 54mg 10 3.75 125 47 et B 100 0,1 2.6ml 10 4.9 12S 48 It B 101 0.1 2.5ml 10.1 3.6 127 49 if B 125 0.1 3. 2ml 12.5 6.0 128 52 19 E 48 25mg 5 3.65 129 53 99 - A 50 25mg 5 3.6 130 54 91 D 48 - 50mg 5 3.0 131 55 II A 50 26mg 5 3.75 132 56 It T7> 43 - 26mg 5 3.5 133 57 II E 48 - 24mg 5 3.45 134 58 91 E 41 - 24mg 5 3.5 135 61 1.1 E • 47 - 53mg 5 2.97 136 62 It E 50 - 38.5mg 5 3.18 137 63 II D 33 - 50mg 5 2,8 138 64 11 D 43 -- 50mg 5 2.82 139 65 If D 21 - 48mg 5 2.55 140 66 i: E 49 - 27mg 5 3.58 141 67 19 D 45 - 52mg 5 2.95 142 68 II A 50 - 27mg 5 3.6 143 69 55 E 49 - 25,5ms 5 3,52 144 70 II E 49 24mg 5 3.6 145 71 II B 100 61mg 10 5.4 132 I TABLE 7 As material remained urZissolved after second addition of acid, ET was added dropwise until complete solution was attained and the resulting solution was evaporated to dryness under reduced pressure. The residue ras dried and dissolved in XL) 133 4S276 Example 158-171 Preparation of salts of lla-N,N-Dimethylamino-2β-ethoxy-5a~pregnan 20-one (Table 8) The amine was added to a solution of the acid in W 5 and the mixture stirred or shaken until a clear solution was obtained. The solution was then either: (A) treated dropwise with 0.ΙΜ-NaOH until the precipitate initially formed just redissolved, made up to the weight indicated with W, filtered through a membrane and the pH determined; or (b) made up with W to the weight indicated, filtered through a membrane and the pH determined.
TABLE 8 L Salt Method . Dissolved | lla-amine (mg) Molarity of acid solution Acid Mt of solution (g) PH 158 citrate A 500 0,1 12.4ml 50 4.4 159 acetate B 50 0.5 0.75ml 5 4.0 160 lactate A 101 0,5 1,5ml 10 4,2 161 mesylate A 100 0.1 2,5ml 10 4.05 162 phosphate A 100 0.525 0,5ml 10 3.6 163 (+)»tartrate A 101 37.5mg 10 4.5 164 tricarbally- late A 101 - 46mg 10 4.9 165 hydrochloric a A 101 0,1 2.5ml 10 3,55 166 sulphate B 100 0.05 2,5ml 10 3,3 167 citraconate A 100 36mg 10 3.8 168 mesaconate B 81 52mg 8.1 3.02 169 aconitafce B 81 - 35mg 8.1 3.38 170 succinate B 100 58mg . 10 3.7 171 salicylate B 81 • 27.6mg 8.1 4.48 —--------· 134 Examples 172-180 Preparation of salts of llg-N,N-dlmethylamino-3«-hydroxy56-pregnan-20-one (Table 9) The amine was added to a solution of the acid in W and the mixture stirred or shaken until a clear solution was obtained. The solucion was made up with W to the weighc indicated, filtered through a membrane and the pH determined.
TABLE 9 Salt Dissolved 1la-amine (’···; Molarity of acid solution Acid Wt of solution (g) PH citrate 120 0.1 4.0ml 12 3.2 hydrochloride 50 0,1 1,4ml 5,06 2.9 acetate 50 C.5 0.55ml 5 4.5 succinate 50 - 16.3mg 5 4.5 mesylate 50 0,1 1.4ml 5 3.85 phosphate 50 0. 52 O.4ml 5 2.5 tricarballylate 50 - 24.4mg 5 4.15 lactate 50 0,5 0,14ml 5 4.1 (+)-tartrate 50 - 20.7 mg 5 3,65 ‘135 413 27 3 Example 181 lla-N/N°Dimethylamino-2g-ethpxy°3g-hydroxy-5g-pregnan-20-one hydrochloride salt A solutian of lla-NsN-dimethylamino-2p-ethoxy-3a5 hydroxy-Sa-pregnan-20-one (10,5g) in dry DE (80ml) was stirred while a stream of HC1 was passed through.
The precipitated solid was collected by filtration under pressure of a nitrogen atmosphere and washed well with dry DE and dried to give title compound (11.5g) m.p. dec. 200°C, [a]D +35° (ME) Example 182 ilg-N,,N-Dimethyiamino--28ethoxy°3g-hydroxy-5g-pregnan·· 20one citrate salt A solution of lia-N,N-dimethylamino-2p-ethoxy15 3g-hydroxy-5a-pregnan~20-one (Ig) in DE (20ml) was added to a stirred solution of citric acid monohydrate (1.05g) in DE (60ml). An immediate precipitate was formed which ' was collected by filtration under nitrogen pressure to give title compound containing 1 mole of citric acid in excess.
The filtrate was evaporated to half volume and the precipitate collected by filtration to give further 136 title compound containing 1 mole of citric acid in excess -^values (ϊ^θ) include 9,35 (s, 18-K), 8,87 (s, 19-H), 8.84 (t, J 7Hz, -9CH2CH3), 7.78 (s, 21-H), 7.67 (triplet of doublet, J 12 and 5 Hz, U|3-H), 7,02 and 7.24 (ABq, J 16 Hz, -CH2- of citric acid), 6,97 and 7,09 (2 singlets, 11aW(CH-)-), 6.2-r·, 5 (m, -GGibCH,, 2a-H and Ιβ-H) and 6.05 (m, 3β-Η), Example 183 21-Acetoxy-lla-N,N-diniethylafflin,O"20-ethoxy-3a"hydroxy·· 5a»pregnan-20-one (XXIX) A solution of £' ϊϊI (200 mg) in AC (10 ml) was stirred at RT with anhydrous potassium acetate (200 mg) for 4 hours. The mixture was diluted with W to 100 ml and the precipitate extracted into DE.
The extract was washed with W, dried (Na^ S0^) and evaporated to a foam (180 mg) which was purified by preparative TLC in EA-PE (lil) to give title compound (114 mg) as a foam, [alp + 90, 5°, Example 184 lla-Dlmethylamino-3g-hydroxy-5g-pregnan-20-one llcc-Amino-5 p-pregnane-3a, 20p-diol (44 mg) in 37% aqueous HCHO (1 ml) and HC02H (0,01 ml) was heated on a steam bath for 5 minutes. The cooled solution was 137 5376 diluted with NaHCOg solution and extracted with EA. Evaporation of the washed and dried (MgSO^) organic extract afforded a gum which was purified by preparative TLG in AC-PE (2:3) to give lla=dimethylamino-53-'pregnane-3a, 20β5 diol, This latter compound (40 mg) in AC (4 ml) was treated at 0° with Jones reagent (0,24 ml). After 15 minutes the mixture was poured into iced NaHCOg solution and extracted with EA, The washed and dried (MgSO^) extract was IS evaporated to give a solid ’which was purified by filtration through silica gel in AC-PE (1:10) and crystallization from ME-W to yield lla-dime'chylatnino-^-pregnane-3,20dione (10 mg), A solution of the latter compound (250 mg) in ET (17 ml) was stirred at RT for 15 minutes with NaBH^ (125 mg). Excess NaBH^ was decomposed by the addition of a little acetic acid and the mixture was then diluted with NaHCOg solution and extracted with EA, Evaporation of the washed and dried (MgSO.) . . „ . ... e 4 extract gave a foam which was purified by preparative TLC using AC-PE (1:5) to afford the title compoundί ctl + 66, 2°, 138 β S 3 7 6 Example 185 lla-N,N-Dimethyiamino-2ll-ethoxy-3ghydroxy"5g-pregnan20-one LXXV triethylammonium salt (500 mg) was dissolved in 5 dry THF (5 ml). Mechyl lithium (7,2 mi, 1,7M solution in DE) was added a.!'. the mixture was stirred at 20° under nitrogen for 2Gh, W (25 ml) was added and the mixture was extracted with EA (3X), The combined extract was dried (MgSO^) and evaporated to give title compound (372 mg) similar to the product of Example 1 by the chromatography, Example 186 (Z)-17-Cyanomet;iylene-ftg-dimethylainina-2p-ethoxy-5gandrostari-3g-Ql To a mixture of NaH (500 mg), diethyl cyanomethyl phosphonate (4ml) and cry THF (16 ml) was added a solution of LXXIX (1,2 g) in dry THF (12 mi). The reaction mixture was stirred at RT overnight before being partitioned between EA and W, The organic phase was washed with W, dried (Na^SO^) and evaporated to an oil. Purification by CC (EA-PE)and crystallisation from ME-W afforded the title compound, (833 mg). ;m,p. 128-146°,, [α]β-10»8° shown by n.in. r. to contain the corresponding E-isomer. 139 376 Example 187 llg-Dimethylamino-3a-hydroxy-5 tr-pr egnan-20-one LXXXITI (IOOmg) in EA (10ml) containing a few drops of acetic acid was hydrogenated at atmospheric 5 pressure using 5% Pd-C as the catalyst. After 24 hours, the catalyst was removed by filtration through kieselguhr and the filtrate evaporated to give the title compound (70mg) similar to the product of Example 6 by P.M.R.
G.L, C, and T.L, C, 140 3 2 7 0 Example 188 ll«-Dimsthylaiaino-3o:-hyd£Oxyprega-4-en-20-one A solution of Ha3H^ (117mg) in W (5ml) was added to a stirred solution of LXXX7 (500mg) in THF (20ml).
The solution was stirred for 5L/b hr at ca +21° and then glacial acetic acid wac added dropwise until effervescence ceased. The solution was partitioned between W and EA and the organic extract was washed with saturated brine solution and dried. Evaporation gave Ila-dimethylamino10 pregn-4-ene-30,2Oi. -diol (513iiig).
A solutinn of diethyl azodiearboxylate (343mg) in dry THE (2ml) was added dropwise over ca 5 min to a stirred solution of the above, diol (361mg) in dry THF (12ml) containingtriphenylphosphine (787mg) and chloroacetic acid (283mg), The solution was stirred at ca +21u for 1 hr. and then partitioned between 5%aqueous NaHCO, and EA, The organic extract was washed with saturated brine solution, dried and evaporated to give a solid (1,58g). This was purified by preparative TLC (EA-PE) to give 3a-chloroacetoxy"lla-dimethylaminopregn-4-er.-20$ -ol.
A solution of the above compound (438mg) in AC 141 (10ml) was cooled to 0 to 5° with stirring and Jones reagent (0,3ml) was added dropwise over ca 3 min. After a further 20 min at 0 to 5° the mixture was partitioned between 2^-aqueous NaHCOg,and EA, The organic extract was washed with saturated brine solution, dried and evaporated to give a foam. This was purified by ; preparative TLC (EA-PE) to give 3a-chloroacetoxy-lladimefchylaminopregn-4-en-20-one, A solution of this compound (469mg) in ME (15ml) was brought to reflux and a solution of NaHCOg (181mg) in W (2,5ml) was added. The mixture was refluxed for 30 min.j then cooled and partitioned between V and EA.
The organic extract was washed with saturated brine solution (100ml), dried and evaporated to give liquid.
This was purified by preparative TLC (EA-PE) to give a liquid (123mg), The PMR spectrum showed the material to contain the title compound and lla-dimethylamino-3phydroxypregn-4-en-20-one.
The above epimeric mixture (121mg) was mixed With similarly derived material (158mg) and resubjected to TLC purification (EA-PE), The more polar band was eluted with AC and evaporated to give the title compound as a foam (123mg), [a]^ +170°, 142 αΰ376 EXAMPLE 139 a-Di methyl ami no-2g-ethoxy-21-fluoro-3«-hydroxy -5a-prsg?ic n-20-one ar.d its citrate salt A mixture of XXVill (4.9 g), sodium iodide (5 g) and AC (300 ML) was refluxed for 30 minutes before evaporating to low volume and partitioning between DE and W. The organic phase was washed with W, dried and evaporated to a froth. This froth was dissolved in AN (350 ml) and treated with a solution of silver fluoride (3 g) in W (15 nil) at. 45° for 2* hours. The reaction mixture was partitioned between DE and potassium carbonate solution.
The organic phase was washed with W, dried and evaporated to a froth. Purification by preparative TLC (EA-PE 1/1) gave the title compound as a froth (240 ra9)’/<^r,+ 69.8°.
The latter free base (85 mg) was stirred with a solution of citric acid (82 mg) in W (8 ml). The solution was made up to 8.5 g with yi and an insoluble residue removed by filtration to give a solution of concentration 8.2 mg/ml and nH 2.9.
The above compound and its salt is a preferred compound of the invention Thus an additional preferred group of compounds are those of the formula (I) or (II) in which R9 is a fluororaethyl group. 143 3527S Examples A - F Formulations of lla-N,N-dinfcthylamino-2p-ethoxy3 g-hydroxy- 5 κ-pregnan- 20- one, A, Single dose injection, 5mg/ml % w/v steroid 0,50 citric acid 0, 26 sodium chloride 0,80 sodium hydroxide to pH4.5 water for Injections to 100,00 Citric acid was dissolved in most of the water and the steroid added with stirring under a nitrogen blanket.
Once the steroid was in solution, the sodium chloride was added and dissolved. Then the pH was adjusted with sodium hydroxide solution and the product made up to volume, . The solution was clarified by membrane filtration and filled under nitrogen into clean glass ampoules. The sealed Containers were sterilised by moist heat, B, Single dose injection, 5mg/ml % w/v steroid 0.50 hydrochloric acid (pure) 0,11 sodium chloride 0.62 disodium hydrogen citrate 0.32? sodium hydroxide to pH4,5 Water for Injections to 100.00 The steroid was added to a dilute solution of the hydrochloric acid and dissolved by stirring under a nitrogen blanket. Disodium hydrogen citrate and sodium chloride were added and dissolved, the pH adjusted with sodium hydroxide solution and the product made up to volume, The solution was clarified by membrane filtration and filled under nitrogen into glass ampoules. The sealed containers were sterilised by moist heat. 144 a 3 8 ? β C, Solution for intravenous infusion % w/v steroid citric acid sodium chloride sodium hydroxide Water for Injections to 0.050 0.026 0. 89 to pH4,5 100. CO Dissolve the citric acid in most of tha water and add the steroid with stirring under a nitrogen blanket. Once the steroid is in solution, add the sodium chloride and dissolve. Adjust the pH with sodium hydroxide solution and make the product up to volume. Clarify the solution by membrane filtration and fill into clean glass bottles under nitrogen. Close the bottles with rubber plugs holding them in position by aluminium sealitig rings and sterilise by moist heat, D, Solution for intravenous infusion % w/v steroid hydrochloric, acid (pure) disodium hydrogen citrate sodium chloride sodium hydroxide Water for Injections to 0.050 0.011 0.032 0.87 to pH4,5 100.00 Add the steroid to a dilute solution of hydrochloric acid and dissolve by stirring under a nitrogen blanket. Add and dissolve disodium hydrogen citrate and sodium chloride, adjust the pH with sodium hydroxide solution and make the product up to volume. Clarify the solution by membrane filtration and fill into clean glass bottles under nitrogen. Close the bottles with rubber plugs,holding them in position by aluminium sealing rings and sterilise by moist heat. E, Multidose injection % w/v steroid citric acid sodium chloride benzyl alcohol sodium hydroxide Water for Injections to 1,00 0.52 0. 50 1.00 v/v to pH4.5 100.00 145 4-3 2 7 0 Dissolve benzyl alcohol in most of the water and add and dissolve citric acid. Add and dissolve the steroid by stirring under a nitrogen blanket. Then dissolve sodium chloride and adjust the pH with sodium hydroxide solution. Make up the product to volume and sterilise by membrane filtration. Then fill the solution asepticaHy under nitrogen into sterile glass vials and close them with sterile rubber plugs or seals, holding them in position by aluminium sealing rings.
Multidose injection % w/y steroid 1.00 hydrochloric acid (pure) 0. 22 disodium hydrogen citrate 0,65 sodium chloride 0.15 benzyl alcohol 1.00 v/v sodium hydroxide to pH4.5 Water for Injections to 100,00 Dissolve benzyl alcohol in a dilute solution of hydrochloric acid and then dissolve the steroid with stirring under a nitrogen blanket. Add and dissolve disodium hydrogen citrate and sodium chloride. Adjust the pH with sodium hydroxide solution, make the product up to volume and sterilise by membrane filtration. Fill the solution as&p£icany under nitrogen into sterile glass vials and close the vials with sterile rubber plugs or seals, holding them in position with aluminium sealing rings.
Similar formulations wherein lla-N, N-dimethy lamino-2f3•ethoxy"3a"hydroxy-5cf-pregnan-20-one' is replaced by llct*N, N-dimethylaraino-3a-hydroxy-5$"pregnan-20-one may also be prepared.

Claims (12)

1. Steroids of tie formula: wherein: ; '· R‘ is a group -NR Cs % in which R a and R u (which may be the same or different) are Cj_g alkyl Co s alkeryl (conc-v. η”.5 one or two double bends), or cycloalkyl v“v groups (provided that R° and R b together contain 2-7 carbon atoms and that, when R G and/or R b is an alkenyl group, the carbon atom a K 10 or atoms adjacent to the nitrogen atom in the group -NR R is or are saturated)· or in which one of R a and R b is a benzyl or phenethyl group, the other group being a methyl group; or in which a. H R and R 7 (together with the nitrogen atom) represent an azetidino, pyrrolidino, pi peri dino, he/amethylenimino or 15 morpholine group, which groups may optionally be substituted by one or two methyl groups; 147 a « 7 6 R is a hydrogen atom or a C. , alkyl group; p5 is a hydrogen atom or. a C|_ g alkyl, C-j_ g alkoxy (which may be optionally substituted by a halogen atom), benzyloxy, C ? _ & alkanoyloxy or thiocyanate group or a halogen 5 atom; S\5 1= a hydrogen atom or a methyl group; R is a hydrogen atom or a methyl group; 7 8 R' represents a hydrogen atom or (except when R is a . group (c) as defined below) a chlorine atom; and 10 R 8 is (a) a cyano group; (b) a group -COR® where Q R is a methyl group or such a group substituted by a fluorine atom, or by a alkoxy, hydroxy, alkyl, methexymethyl, ethoxymethyl, C 2 _ 5 alkanoyloxy, benzoyloxy, or Cg_ 5 alkoxycarbonyloxy Q group; or where R is a C-._ 5 alkoxy or cyclopropyl group; 15 or where R 8 is the group -KrV where R x and p/ (which may be the same or different) are methyl or ethyl groups; or (c) a vinyl 10 group or together with R a substituted methylene group in which the substituent is in the Z-configuration and is a methyl or cyano group; 10 8 10 20 R is a hydrogen atom (except when R and R together represent a substituted methylene group); the broken lines indicate the optional presence of double bonds at the positions shown; 3 A provided that at least one of R and R is a hydrogen atom; and 25 R and R ’ together represent a hydrogen atom when a 1,2-double bond is present; and that a 1,2-double bond is not present when 3 a 4,5-double bond is present; and that R is a hydrogen atom; is a hydrogen atom or a methyl group and R 6 is a hydrogen atom or optionally (when R^ is a hydrogen atom) a methyl group 30 when a 5g-hydrogen atom is present; 148 and the n-hcmo analogues thereof carrying R 0 at the 17a8-pMSition, R 1J ac the Pea-position, and R' at the 17-positicn; and the acid addition salts the -eof. 5 2. Compounds ss claimed in claim ΐ, wherein R a and S' 3 are other than -:,-/7 or :>=·ιε;.'ΐ’.·; groups; R v is other than tne group -CP? wicre R J is a methyl group substituted by a 3 r c ^2-4 “’'kyl S’-ups and wnerein R , R and P? are all hydrogen atoms when a 53-hydrcgon atom is present. 10 3. Compounds as claimed in claim 2 which possess a 5a- or Sp-hyd'Oger. atom. 4. Comsouiids as 15 £. Compounds as skimes in any one of claims 2 to 4 wherein R is j nydrogen atom or a methyl group, a. Compounds as claimed in any one of claims 2 to 5 wherein ring Q is a 5-me-sbered ring. 7. Compounds as claimed in any one of claims 2 to 6 which 20 possess a Sn-hydrogen atom. 8. Compounds as claimed in any one of clcims 2 to 7 Q Q wherein R~ is (a) a cyano group or (d) a group -COR g where R is a methyl group or such a group substituted by a □ hydroxy, methyl or acetoxy group, or where R is a 25 cyclopropyl group. p 9. Compounds as claimed in claim 8 wherein R is an acetyl group. p 10. Compounds as claimed in claim 8 wherein R is a cyano group. 149 Li 2» / Ls 11. 5a-compounds as claimed in any-one of claims 2 ¢0 70 a wherein R' is a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, isa-propoxy, butoxy, acetoxy or thio-cyanato group or a chlorine, bromine or fluorine atom. 5 12. Compounds as claimed in claim 11 ·,-/herein R*- is a hydrogen atom or an ethoxy group. 13. - Compounds as.claimed in any one of claims 2 to 12 wherein R and fT are methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, iso-pentyl, 1,3-diraethylbutyl, 10 allyl, cyclopentyl or cyclohexyl groups, or wherein -i'iR a R J represents a pyrrolidino group. 14. Compounds as claimed in claim 13 wherein one of R and R is a methyl group and the other is a methyl, ethyl, propyl, iso-propyl, butyl or allyl group. 15 15. Compounds as claimed in claim 13 wherein both R a and R b are methyl groups. 16. Compounds as claimed in claim 1 of the formula: 150 wherein: R’ is s group -SR“R‘', in which one of ί: δ and R^ is a methyl group, the other gmp being a metnyl, ethyl, propyl, iso-propyl, butyl or allyl group, or in which Poth R d and 3 b are ethyl groups, or in which R a and R b (together with the nitrogen atom) represents a pyrrolidino group; ft* is a hyd-,gen atom or a ruetnyl group; R 4 is ?. hy-rogen atom or a methyl, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, acetoxy or thiocyanato group or a fluorine, chlorine or bromine atom; R 8 is ft) a cyano group; (b) a group -COR® where R 9 is a methyl group or such a group substituted by a methyl, hydroxy or □ acetoxy group, or R is a eye;opropyl group; or (c) a vinyl group or, together with P' 8 , a Z-ethylidene group; and R 10 is a hydrogeri atom (except when R 8 and R^° together represent an e:hy lie,or group;; the broken 1 :=·« indicates the optional presence of a double bond at the 1.Z-pusition; provided that at least one of R 3 and R 4 is a hydrogen atom; that R J s»>d ft* together represent a hydrogen atom when a 1,2-double bond is present; ana that R‘ is a hydrogen atom and R* is a hydrogen atcic or a methyl group when a 5e-hydrogen atom is present; β arc the D-homo analogues carrying R at the Vas-position and R^ J at the 17aa-pcsition; and the acid addition salts thereof. 17. Compounds as claimed in claim 16 wherein R 1 is a dimethyl3 4 amino group, R is a hydrogen atom, R is a hydrogen atom or an alkoxy group, R 3 is an acetyl or cyano group and ring D has 5 members. 151 4 3 3 ϊ Q 18. Cumpounds as claimed, ia claim 2 in the form of trials* hydrochloride, hydrobromide, phosphate, sulphate, -ji-toluenesulphonate, raethanesulphenate, citrate, tartrate, -acetate, ascorbate, lactate, maleate, .succinate, tricarballylate, gluterate or 5 glutaconate salts. IS. Compounds as claimed in any one of claims I to 17 in the form of their aconitafce, citraconate, mesaconate or salicylate salts. 20. Compounds as claimed in claim 2 in.the form of their citrate 10 or hydrochloride salts. - 21. . Compounds as claimed in claim 2. said compounds being lla-N,fi-dimethylamino-2e-etho,\y-3a-hydi : o;;y-5ci-pregnan-20-one and the physiologically acceptable acid addition salts thereof. 22. Compounds as claimed in claim 2, said compounds being: 15 1 la-R.R-dimethy 1 amino-2s-ethcxy-3ci-hydroxy-£a-pregnan-20-one and its citrate, acetate, methanesulphonate, lactate, phosphate, tartrate, tricarballylate, hydrochloride, and succinate salts. 23. Compounds as claimed in claim 2, said compounds being: the citraconate, acenitate and mesaconate salts of 20 Πα-ϊΐ,ίΐ-dimethyl ami no-2s-et'noxy-3a-hydroxy-5E-pregnan-20-one. 24. lla-fl s! , i-diffiethylamino-2e-ethcxy-3cs-hydroxy-5H-pregnan“20one citrate. 25. Compounds as claimed in claim 2, said compounds being lla-fl-diraethylamino-3ci-hydro.'!y-5g-pregnan-20-one and the 25 physiologically acceptable acid addition salts thereof. 26. Compounds as claimed in claim 1, said compounds being: lla-il,N-dimethylamino-3a-hydroxy-5g-pregnan-20-one and its citrate, acetate, hydrochloride, tartrate, lactate, tricarballylate, phosphate, methanesulphonate and succinate salts. 152 27, Compounds as claimed in claim 2. sand compounds being: 11a-N,N-dimetfy1amiro-3a-hydroxy-5u-pregnan-20-one; llu-!i,N«di.’iethylaa:ino-3u-hydraxy-5oi-aiid«)Stane-176“carbonitrile; 2s-chloro-l b-N,N-diinetfcy]6mii»-3<»-iiydiOxy-5s-pregnan-20-one; 5 11a-N l h--dimet. 1 iyl3.Bino-23-fiaoro-36-hydroxy-5a-pregnan-2 ! J-one; and 1 Ιύ-Ν,Ν-ιϊatny: aaino-Sc-nyd-’C-c'-ie-pregnaii-ZO-one; and the prysiologicc-Cy acceptable ac?d addiccc.-. salts thereof.
2. S. Compounds as claimed in claim 1-, said compounds being: lIa-li,ii-diniethylaniino-2p-pthoxy-3ct-hydro/yD-hOinG-5a-pregnan-20-one; 10 3a-hydrc 1 Ια-N Jf-sthy 1 -h-methyl ami r.o-3a-r.yaroxy-56-pregnan-20-one; Ί Ια- N ,Ν-dimethyl amino-3ct-ivdroxy-5e-androstane-l 76- carbonitri 1 a; lla-N s N-dimethylai!iino--2G- ethoxy-3a-hydroxy-5a-androstane-l7gcarbonitrile: IS and tne physiologically acceptable acid addition thereof. 29. Compounds as claimed in claim 2, said compounds being: 11u-N,N-di»®t.'iyiaraii’0-3a-hydiw-26-iiiethyl-5e“pregnan-20-one5 n 20 lla-diraethylamino-3ci-hydroxy-26-iaethoxy-5a-pregnan-20-ones 2«-ethoxy-lla-N”ethyl-fi-m6thylamino-3a-hydroxy-5a-pregnan-20 - one; Πα-Ν-ethyl-^-methyl amir,o-3a-hydroxy-56-pregnan-20-one} 3a-hydroxy-lla-fi-me yiyl -N-propyl ami no -5ct-pregnan-20-one; lla-N,N-dimethylamino-3a-hydroxy-2B-propoxy-5a-pregnan-20-one; 25 na-N,N-d- i mothy1anilni)-3c i -hydroxy-26-iso-propoxy-5a-pregnan-20-one; 23-acetoxy-lla-N,N-dimethyl ami no-3a-hydro\y-5a-pregnan-20-one; Zs-bromo-1Ια-N,N-dimethyl ami no-3a-hydroxy-5a-pregnan-20-one; ΙΙα-Ν,Ν-dimethyiamino-3a-hydroxy-26-thiocyanato-5a-pregnan-20-one; 153 21 -acetoxy-1 la-fl s P5-dimethyl amino-3a-hydroxy-5g-pregn3S-20-one; lla-N 5 N-Qiffl3thylamino-3a-byd?Oxy-5a-pr3gn-2S(2i>”Sne; ’and the physiologically acceptable acid addition salts thereof. 30. Compounds as claimed in claim 1, said compounds being: 5 1ls-N-ethyl-N-methylami no-3a-hydrcxy-23-methoxy-5a-pregnan-20-one;
3. A-igd3:oxy-lls-K-i.so-propyl -H-methyl ami no-ZS-mathoxy-Sa-pregnan20-one; 11 -ct-K-al 1 yl -PJ-raethyl amint»-2e-ethoxy-3e-hy0roxy-5e-pragnan-20-one; 2g~ethoxy-3a-hydroxy-lla-pyrrolidino-5a-pregnan-20-one; 10 2g-acetoxy-lla-f>i-ethyl-W-ffiethylamino-3a- hydroxy-5a-pragnan20-one; 2g-acetoxy-3a-hydroxy-l ia-N-jso-propyl-?;-methylamino-5o!“pregnan20-one; Πα-Π-ethyl-Pi-methylamino-2S-fluoro-3a-hydroxy-5 s -pregnan-20-ones 15 2g-f 1 uoro-3a-hydroxy-lla-P-l-iso-prop.yl-Pi-ni5th.yl amino-5a-pregnan -20-one; 2g-chlora-lla-N-ethyl-K-methylamino-3a-hydroxy-5a-pregnan-20-one; 2e-chloro-So-hydroxy-lla-W-lso-propyl-W-methylami no-5a-pregnan20-one; 20 ll&-N-N-dimethylamino~33-hydroxy-5£s-pregn-l-en-20-one; lla-Pl s P!-diraethylamino-3a-hydroj:y“D“homo-5a-pregnan-20-one; Πα-Ν, Pi-dimethyl ami no-21 ,21-ethylene-3a-hydroxy-5ct-pregnan-20-one; 1Ια-Ν,Ν-dimetbylami no-3a-hydroxy-21-methyl-5a-pregnan-20-one; na-N,N-dimethylamino-2g-ethoxy-3a-hydroxy-21-methyl-5a-pregnan-20-one; 25 21-acetoxy-lla-Pi,P)-dimethylamino-23-ethoxy-3a-hydroxy-5ci-pregnan20-one; 3« ,21 -di hydroxy-1 la-N,Pi-dimethyl ami no-5s-pregnan-20-one; (Z)-lla-N,N-dimathylamino-3a-hydroxy-5a-pregn-17(20)-ene; methyl lla-N,N-dimethylamino-2g-ethoxy-3a-hydroxy-5a-androstane30 17g-carboxylate; 2g-butoxy-na-ii s ii-dimethy1amino-3s-hydroxy-5a-pregnan-20-one; na-Pi,Pi-dimethylamino-2s-ethoxy-3a-hydroxy-21-propyl-5a-pregnan-20one; and the physiologically acceptable acid addition salts thereof. 154 £0 31. Compounds as claimed in claim 27 or claim 29 wherein said salts are citrates, 32. Compounds as claimed in claim 23 or claim 30 wherein said sales are citrates. 33. A Dharmaceutical composition comprising Gne or more compounds as claimed in any one of the preceding claims, together srith one or more poor c?c:i;oi c-.rrisrc or excipier.ts. 3
4. A coxa- : ,icn as ci aimed in claim 33 ή the form of a solution of said compound or compounds in a parenterally acceptable venicle. 3
5. A composition as claimed in claim 24 in the form of a simple aqueous acidic solution of saiti compound or compounds. 35. A composition as caimed in any one of claims 33 to 35 wherein the said compound i? a compound as claimed in claim 2. 37. A composition a claimed in claim 35 wherein said compound is a compound in ary one of claims 21, 22, 25 or 2
6. 38. A compos:cion as claimed in claim 35 wherein said compound is the compound claimed in claim 24. 39. A process fcr the preparation of a compound as claimed in claim 1, which process comprises reacting a corresponding steroid in which either or both of R a anu R* 3 is a hydrogen atom with a compound of the formula R S X or (in the preparation of a compound in which R ; is a heterocyclic amino group) a compound of the formula X-^-R'-X (where X is a readily displaceable substituent). 40. A process for the preparation of a compound as claimed in claim 1 which comprises reducing a corresponding lla-acylamino steroid. 41. A process for the preparation of a ring A-saturated 2s- substituted 5a-steroids as claimed in claim 1 which comprises 155 treating corresponding 2o,3a-epoxlde with a compound HR^ under acidic conditions or with a compound which produces the anion (R^) (where R^ is as defined in claim 1, other than hydrogen), ahd then, when the initial product possess a deprotonated 3a-hydroxy & group, treating the product with a-source of protons. 42. A process for the preparation of a compound as claimed in claim 1 which comprises reductive alkylation of a corresponding Πα-amino or llo-mono-substituted amino steroid. 43. A process for the preparation of 5g-steroids or ring 10 A-saturated 2g-unsubstituted Sa-steroids as claimed in claim 1 which' comprises reducing the corresponding 3-oxo steroid. 44. A process for the preparation of 3p-unsubstituted compounds as claimed in claim 1 which do not possess a 5,6-double bond, which comprises inversion of the 3-hydroxy group of a derivative of a 15 corresponding 3g-hydroxy compound. 45. A process for the preparation of compounds in which o R is a group (a) or (b) as defined in claim 1 which comprises reducing the corresponding Δ compound. 46. A process for the preparation of l6a-chloro compounds as 20 claimed in claim 1, which comprising hydrochlorinating the •jg corresponding Δ compound. 4
7. A process for the preparation of 176-cyano compounds as claimed in claim 1 which comprises dehydrating the corresponding 17p-carbamoyl compound or the oxime of the corresponding 25 17g-formyl compound 4
8. A process for the preparation of 176-alkoxy-carbonyl compounds as claimed in claim 1 which comprises esterifying the corresponding 17&-carboxylic acid. 156 4
9. A process for the preparation of 17β- (substituted carbamoyl) compounds as claimed in claim 1 which comprises reacting the corresponding 17a-carbcxylic. acid with an amine. 50. A process for the preparation of 21-alkanoyloxy or 5 21-benzoyloxy compounds as claimed in claim 1 which comprises acyloxyation of the corresponding 21-unsubstitiited compound. 51. A process for tne preparation of 21-fluoro compounds as claimed in claim 1 which comprises displacement of the iodine atom of the corresponding 21-iode compound by fluoride. 10 52. A process for the preparation of 21-hydroxy compounds as claimed in claim 1 which comprises deacylating a corresponding 21-acyloxy compound. 53. A process fur the preparation of 21-alkoxy compounds as claimed in claim 1 which comprises etherifying a corresponding 15 compound having a 21-hydroxy group or a displaceable 21-substituent. 54. A process for the preparation of 21-alkanoyloxy or 21-benzoyloxy compounds as claimed in claim 1 which comprises acyloxylation of a corresponding compound having a readily displaceable 21-substituent. 20 55. A process for tne preparation of 21-alkanoyloxy or 21-benzoyloxy compounds as claimed in claim 1 which comprises acylating the corresponding 21-alcohol. 56. A process for the preparation of z?-5a-compounds as claimed in claim 1 which comprises dehydrohalogenating a corresponding 25 26-halo compound. 57. A process for the preparation of 20-oxo compounds as claimed in claim 1 which comprises deketalising a corresponding 20-ketal. 58. A process for the preparation of a compound as claimed in claim 1 which comprises deprotecting a corresponding compound 30 having a protected 3«-hydroxy group. 157 59. A process for the preparation of a salt as claimed in claim 1 which comprises treating the appropriate free base with an acid. 60. A process for the preparation of 17g-;vinyl compounds as claimed in claim 1 which comprises partially hydrogenating the correspond 5 ing 17g-ethynyl compound. 61. A process for the preparation of 17g-vinyl compounds as claimed in claim 1 which comprises treating the corresponding 20,21-epoxide with an alkali metal selenocyanate. 62. A process for the preparation of 17-(Z)-ethylidene or 10 17-(Z)-cyanomethylene compounds as claimed in claim 1 which comprises reacting the corresponding 17-oxo steroid with an organophosphorus reagent. 63. A process for the preparation of compounds as claimed in a claim 1 in which R is a methyl or cyclopropyl group or a 15 methyl group substituted by a C, .alkyl group, which comprises ~+ reacting a 17g-carboxylic acid or salt thereof with an appropriate lithium alkyl. 64. A process as claimed in any one of claims 39 to 62 wherein the compound prepared is a compound as claimed in claim 2. 20 65. A process for the preparation of Πα-Ν,Ν-dimethylamino2g-ethoxy-3a-hydroxy-5a-pregnan-20-one or an acid addition salt thereof» which comprises reductive alkylation of the corresponding Πα-ami no-20-ketal, followed, where a salt is required, by treatment with an acid. 25 66. A pharmaceutical composition substantially as described therein in any one of Examples A to F. 67. A compound as claimed in claim 1, said compound being the product of any one Examples 7, 12, 15, 16, 23 and 48, or a physiologically acceptable salt thereof. 158 ί 5J! 68. A compound as claimed ir claim 1, said compound being t’ne product of any one of Examples 10, 13, 19, 21, 22, 26, 27, 33, 35, 36, 38-41, 43-46, 57, 59, 60, 185 and 183, or a physiologically acceptable salt thereof. 65. Steroids of the formula; wherein: R 1 k c group -NHR a , in which R a is a hydrogen atom or a C,_g alkyl, C 3 _, cycloalkyl, benzyl or phenethyl group, 10 or a Cg.g alkenyl group having one or two double bonds in which the carbon atom adjacent to the nitrogen atom of the -NHR a group is saturated; R 3 is a hydrogen atom or a 0^_ 3 alkyl group; is a hydrogen atom cr a C^g alkyl, C^g alkoxy (which 15 may be optionally substituted by a halogen atom), benzyloxy, C 2 _g alkanoyloxy or thiocyanato group or a halogen atom; 159 R is a hydrogen atom or a methyl-group; R is a hydrogen atom or a methyl group; 7 8 R is a hydrogen atom cr {except when R is a group (c) as defined below) a chlorine atom; and o 99 5 R is (a) a cyano group; (b) a group -COR where- R is a methyl group cr such a group substituted by a fluorine atom, or by a alkoxy, hydroxy, alkyl, methoxymsthyl, ethoxymethyl, C 2 _ g alkandyloxy, benzcy.loxy, or C 2 _ 5 alkoxycarbonyloxy group; g or where R is a C^g alkoxy or cyclopropyl group; or where 10 R 9 is the group -NR X R^ where R x and p/ (which may be the same or different) are methyl or ethyl groups; or (c) a vinyl group or together with R 10 a methylene group substituted by a methyl or cyano group in the Z-configuration. R^ is a hydrogen atom except when R 8 and together represent 15 a substituted methylene group; the broken lines indicate the optional presence of double bonds at the positions shown; 3 4 provided that at least one of R and R is a hydrogen atom, and r3 and R^ together represent a hydrogen atom when a 1,2-double 20 bond is present; and that a 1,2-double bond is not present 3 when a 4,5-double bond is present; and that R is s hydrogen 4. 5 atom, R is a hydrogen atom or a methyl group and R is a hydrogen atom or optionally (when R^ is a hydrogen atom) a methyl group when a 5g-hydrogen atom is present; Q 25 and the D-homo analogues thereof carrying R at the 10 7 17ag~position, R at the 17aa-position, and R at the 17-positior.; and the 20-ketals of compounds having a 20-keto group; and the acid addition salts thereof; 160 ϋ ϊί 2 'ί ΰ but excluding compounds of the formula (wherein R y is a methyl group or a methyl group substituted by a hydroxy or C,_ 5 alkanoyloxy group) and the 2O-ketals thereof. 5. 70, Compounds as claimed in claim 69, wherein R a is other than a benzyl or phener.iyi group; R® is other than the group 9 3 -COR whore R ~ .-.athyl group substituted by a alkyl, bensoxy or alkoxycarbonyioxy group; and '4 5 wherein IT', R and R are all hydrogen atoms when a 5s-hydrogen 10 atom is present. 71. Compounds as claimed in claim 70, which possess a δα- or 5s-hydrogen atom. 72. Compounds as claimed in claim 70 or claim 71 wherein the tetracyclic steroid system is saturated and R 5 , R 5 and R 7 are all IS hydrogen atoms. 73. Compounds as claimed in any one of claims 70 to 72 wherein R“ is a hydrogen atom or a methyl group. 74. Compounds as claimed in any one of claims 70 to 73 wherein ring D is a 5-mambered ring. 161 ϊΐ 2 ? Ο 75. Compounds as claimed in any one of claims 70 to 7“ which possess a 5a-hydrogen atom. 76. Compounds as claimed in any one of claims 70 to 75 wherein n Q Q R is (a) a cyano group or (b) a group -COR where R is a methyl group or such a group substituted by a hydroxy, methyl or acetoxy g group, or where R is a cyclopropyl group. 77. - Compounds as claimed in claim 73 wherein R s is an acetyl group. 78. Compounds as claimed in claim 76 wherein R is a cyano group. 79. 5a-compounds as claimed in any one of claims 70 to 78 wherein R 4 is a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, acetoxy or thiocyanato group or a chlorine, bromine or fluorine atom. 80. Compounds as claimed in claim 73 wnerein R 4 is a hydrogen atom or an ethoxy group. 81. Compounds as claimed in ahy one of claims 70 to .80 wherein R a is a methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, iso-pentyl, 1,3-dimethylbutyl, allyl, cyclopentyl or cyclohexyl group, or a hydrogen atom. 82. Compounds as claimed in claim 69 of the formula 162 t·.- ο · > ‘itUf* ί Ο wherein: 1 · a R is a group -ί«« α , in which R is a hydrogen or a methyl, ethyl, propyl, iso-propyl, butyl or allyl group; R is a hydrogen or a methyl group: A R is a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, acetcxy cr thiocyanato group or a fluorine, chlorine or src..;?. - i -a t Oil· i R ' is (a) -: cyar.c group; (b) a group -COR 9 where R 9 is a methyl group or sucli a group substituted by a methyl, hydroxy or acetoxy group, 9 or R is a cyclopropyl group; or (c) a vinyl group or, together with R^, a Z-ethylidene group; and R^° is a hydrogsn ator.. (except when R 8 and P. 10 together represent an ethylidene group) the broken line indicates the options! presence of a double bond 0 ft at the 1,2-position; provided that at least one of R and R is -: Λ a hydrogen atom; that R' ano R together represent a hydrogen atom when a 1,2-double ..··.d is present; and that R is a hydrogen atom and R is a hydrogen atom or a methyl group when a 58-hydrogen atom is present; o and the D-homo analogues carrying R at the 17ae-position and at the !7aa-position; and the 20-ketals of compounds having a 20-keto group; and the acid addition salts thereof, 83. (Z)-lla-Annno-5a-pregn-17(20)-en-3a-ol. 84. 11a-Amino-2e-ethoxy-3a-hydroxy-21-methyl-5a-pregnan-20-one. 85. 11α-Ami no-2g-ethoxy-3a-hydroxy-D-homo-5a-pregnan-20-one 86. 1 la - Ami no-2g-ethoxy-3a-hydroxy-5«-pregnan-20-one. 87. (Z)-llG-Amino-28-ethoxy-5a-pregn-17(20)-en-3a-ol. 88. lla-Amino-3a-hydroxy-D-homo-5a-pregnan-20-one. 163 89. Πα-Κ-Al lyl amino-2p-ethoxy-3a-hydroxy-5a-pregnan-20-one. 90. 11 a-N-Gycl ohexyl ami nc-2p-3thoxy-3a-r.ydroxy-5;/,pre3nan-20-oris. 31. 11 α-Ν-Benzyl ami no-2g-ethoxy-3a-hydi’<3xy-5a-‘p!'’egs’.an-20-one. 92. (Z)-na-fi-Ethylsiiiino-5c;-pregn~17(20)-en-3a-ol. 93. (Zl“lIa-N~iSORropy1annno-5a-iVf’£gn-l7(20)-en-3a-ol. 94. Zs-Ethoxy-Sa-hydroxy-l 1c.- (4-methy' pent-2-yl ami no j-5a-pregnan20-ΌΪ19. 95. lla-Aminc-5a-pregn-2G-en-3a-ol. 96. lla-i1-Ethylanrino-3<;;-hydroxy-5e~pregnan-20-one. 97. na-N-3utylamino-3a'hyd!-oxy-5ci-pregnai!-20-one. 98. Sa-Hydroxy-lla-N-prepylamiRo-Sa-pregnan-ZQ-one. 99. lla-W-Ethylanrino-Sa-hydroxy-Sa-pregnan-ZQ-one. 100. 3a-Hydroxy-na-N~isopropylamino-5s-pregnan-20-one. 101. A process for the preparation cf a compound as claimed in claim 69 in which R a is other than a hydrogen atom, which process comprises reacting a corresponding steroid in which R a is a hydrogen atom with a compound of the formula R a X where X is a readily displaceable substituent. 102. A process for the preparation of a compound as claimed in claim 69 in which R a is other than a hydrogen atom, which comprises reducing a corresponding 11a-acyl amino steroid. 103. A process for the preparation of a ring A-saturated 2e-substituted 5a-steroid as claimed in claim 69, which comprises opening the epoxide ring of a corresponding 2a,3a-epoxide by treatment Λ with a compound HR* under acidic conditions or with a compound which produces the anion (R^) (where R 4 is as defined in claim 1, other than hydrogen), and then (when the initial product possesses a deprotonated 3a-hydroxy group) treating the product with a source of protons. 164 'J· ΰ 2 β 104. A process for the preparation of a compound as claimed in claim 69 in which R : is other than a hydrogen atom, which comprises reductive alkylation of a corresponding lla-amino steroid. 105. A process for the preparation of a 58-steroid or ring 5 A-saturated 2s-unsucstituted 5a-steroid as claimed in claim 69, which comprises reccing the corresponding 3-cxo steroid. 106. A orocess for the preparation of a compound as claimed in claim 69 in which R is a hydrogen atom, which comprises reducing the corresponding ll-oxime. 6. 10 107. A process for the preparation of a compound as claimed in c claim 69 in which R is a group (?.) or (b) as defined in claim 1, 1 F which comprises reducing the corresuonding Δ compound. IOS. A process fur the preparation of a 16a-chloro compound as claimed in claim 69, which comprises hydrochlorinating the 7. 15 corresponding compound. 109. A process Ter tne preparation of a 17g-cyano compound as claimed in claim 6S ; which comprises, dehydrating the corresponding 178-carbamoyl compound or tne oxime of tne corresponding 178-formyl compound. 8. 20 1
10. A process for the preparation of a 17e-alkoxycarbonyl compound as claimed in claim 59, which comprises esterifying the corresponding 170-carboxylic acid. 1
11. A process for the preparation of a 17(3-(substituted carbamoyl) compound as claimed in claim 69, which comprises reacting the 25 corresponding 17g-carboxylic acid or a reactive derivative thereof with an amine. 1
12. A process for the preparation of a 21-alkanoyloxy or 21-benzoyloxy compound as claimed in claim 69, which comprises acyloxylation of the corresponding 21-unsubstituted compound. 165 Λ3 ? *Θ Π3. A process for the preparation of a 21 -fluoro compound as claimed in claim 69, which comprises, displacement of the iodine atom of the corresponding 21-iodo compound by fluoride. 114. A process for the preparation of a 2]-hydroxy compound as 5 claimed in claim 69, which comprises deacylating a corresponding 9. 21-acyloxy compound. 115. A process for the preparation of a 21-alko.\y compound as claimed in claim 69, which comprises etherifyi ng a corresponding compound having a 21-hydroxy group or a displaceable 21-substituent. 10 116. A process for the preparation of a 21-alkanoyloxy or 21-benzoyloxy compound as claimed in claim 69, v/hich comprises acyloxylation of a corresponding compound having a readily displaceable 21-substituent. 117. A process for the preparation of a 21-alkanoyloxy or 15 21-benzoyloxy compound as claimed in claim 69, which comprises acylating the corresponding 21-aicohol. 118. A process for the preparation of a Δ -5a-compound as claimed in claim 69, which comprises dehydrohalogenating a corresponding 28-halo compound. 20 119. A process for the preparation of a 20-oxo compound as claimed in claim 69, which comprises deketalising a corresponding 20-ketal. 120, A.process for the preparation of a compound as claimed in Claim 69, which comprises deprotecting a corresponding compound having a protected 3a-hydroxy group. 10. 25 121, A process for the preparation of a salt of a compound as claimed in claim 69, which comprises, treating the appropriate free base with an acid. 122. A process for the preparation of a 17g-vinyl compound as claimed in claim 69, which comprises partially hydrogenating the 11. 30 corresponding 17g-ethynyl compound. 165 723. A process for the preparation of a 173-vinyl compound as claimed in claim 69, which comprises treating the corresponding 20,21-epoxide with an alkali matai selenocyanate. 124. A process for the preparation of a 17-(Z)-ethylidene5 or 17-{Z)-cyanomei.hylene compound as claimed in claim 69, which comprises reacting the corresponding 17-oxo steroid with an organophosphorus reagent. 125. A process for the preparation of a compound as claimed Q in claim 69, in which R is a methyl or cyclopropyl group or a 10 methyl group substituted by a C-j_^ alkyl group, which comprises reacting a 178-carboxylic acid or salt thereof with the appropriate lithium alkyl. 126. A process as claimed in any one of claims 101 to 124 in which the compound proauccc is a compound as claimed in claim 70. 15 127. A compound as claimed in claim 69 when prepared by a process as claimed ά? ,·^/ one of claims 101 to 126. 128. Compoun d as claimed in claim 69, said compounds being the products of any one of Preparations 50, 52, 53, 54, 58-62 and 80.
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FR2485020A1 (en) 1981-12-24
IT1073232B (en) 1985-04-13
IL51816A (en) 1981-09-13
GB1581234A (en) 1980-12-10
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NL7703667A (en) 1977-10-07
SE7703929L (en) 1978-10-27
FR2347382A1 (en) 1977-11-04
ES457507A1 (en) 1978-03-16
PL197186A1 (en) 1979-06-18
AU517206B2 (en) 1981-07-16
BE853227A (en) 1977-10-04
NZ183775A (en) 1979-12-11
IE45276L (en) 1977-10-05
JPS52142056A (en) 1977-11-26
FR2347382B1 (en) 1982-01-08
IL51816A0 (en) 1977-06-30
NO771197L (en) 1977-10-06
LU77064A1 (en) 1979-01-18
FI771046A (en) 1977-10-06
AU2394277A (en) 1978-10-12
ZA772029B (en) 1978-11-29
DK148677A (en) 1977-10-06

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