CA2028759A1 - Steroids - Google Patents

Abstract

Abstract Steroids of the formula I

wherein R1 to R4. X and n have the significance given in the description, have activity which lowers the intestinal resorption of cholesterol and plasma cholesterol. They are manufactured starting from corresponding steroids having an alcohol residue of the formula -O-X-OH in the 3-position.

Description

RAN 4104~180 The invention i~ concerned with novel 6teroid~ of the formula C H ;3 f `~C H 3 C H 3 l ~ CH3 15 '~

R3 N (C!~ ) -OP0~ ~0 1 4 1~3 wherein R is hydrogen. lower-alkyl or lower-alkylidene, R2. R and R4 a~e hydrogen or lower-alkyl or together with the N atom form a 5- o~ 6-membered aromatic or ~aturated heterocyclic residue which may be lower-alkylated, n is the number 2, 3 OI ~, X i~ a group of the foImula -(CH2)p-c~Q~Q )-(Z)l. o~ O ' -CH2cH(Y)cH2-(z)l or O
-CH2cH(c~2Y)-(z~l or O
-(CH2CH~O~q-~H2cH2-(z)l or O
q i~ the number 1 or 2, Z i5 a grou~ of the fo~mula -C(O)-~ -OC(O)-, -OC~O)CH2-, -OCH~C(O)- or -N(T)C(O)-, Q, Q' and T are hydrogen or lower-alkyl, p is a whole nu~ber between 1 and 9 and, ~here Z i6 Mé/ll.9.90 s~

carbonyl, can alfio be 0, Y i~ hyd~oxy, lower-al~oxy, lower-alkanoyloxy, carbamoyloxy or mono- or di-lower alkyl-carbamoyl-oxy,the dotted C-C bond6 in ~he 5(6)-, 7(8)-, 22(23)-, 24(253- and 24(2~-position are optional, whereby the side-chain i~ either ~aturated or mono--un6aturated, and ~hy~iologically compatible ~alts ~hereof.

The hydrogen atoms attached to the C a~om~ in po6ition 3 and 5 of the ~teroid part of the compound~ of formula I
can each independently have the a- or B-configuration.

The invention i8 al~o concerned with a process for ~he manufacture of these ~teroids, medicament ba~ed on the latter and the~e ~teroid~ a~ phar~aceutically active substance6, as well as the usa of ~hese steroid~ in the - manufacture of medicaments which inhibit the in~e~inal re60rption of ~hole~terol and which lowe~ the plasma cholesterol.

The te~m "lower" signifie that the residues denoted thereby contain up to ~ carbon atom6 and can be ~traight--chain or branched. ~ethyl, ethyl, n-propyl, i~opropyl, n-butyl ~nd t-butyl are examplefi of lower-alkyl re6idues.
Methylene and ethylidene are examples of lower-alkylidene re6idue6. Acetoxy and propionyloxy are examples of lower--alkanoyloxy residue~.

PhaLmaceutically acceptable ~alt~ of the steroids of formula I are inorgan;c 6alt8 ~uch a~ hydrochloride~ and 6ulphate6; organic ~altG ~uch a~ trifluoroaceta~e~, mesylate~ and to~ylate6; and metal sal~ ~uch a8 sodium salt~. The compoundfi of for~ula I can be pre~*nt in the form of a zwitterion and tho~e in which at lea~t one of : , ,; ~ ~ .. . .

r~

the residues R2, R3 and R4 i~ hydrogen can be present in the form of a hydrogen phosphate.
Among the steroids of formllla I therç are preferred those in which Rl i~ hyd~ogen or lower-alkyl, e~pecially ethyl, further ~hose in which E12 i~ hydrogen or lower-alkyl and R3 and R4 are lower-alkyl. especially methyl, or in which R2, R3 and ~4 ~ogetheL with the N atom for~ a pyridinium or l-~ethylpyrrolidinium group.

Further, the steroids of for~ula I in which n i6 the number 2 as well as those having a satu~ated or 5~6)--unsaturated or 5(6)- and 22(23)-unsaturated steroid part are preferred.

Further preferred s~eroid6 of formula I are tho~e in which X represents the group -(CH2)2-, -(cH2)zo(c~2)2-~ -(CH2)20(CH2)2 ( 2 2 -CH2CHOHCH2-. -CH2CH(OCOCH3)CH2-.
-cH2cH(ocoNHcH3)cH2N[cH(cH3)2]co-~
-(CH2)2N~CO-, -(CH2)3NHCO-, -CH2CHOHCH20CO-, -(CH(CH3)CO- or especially -(CHz)20CO-, ( 2)3 ' ( 234 ' ( H2)8 -(CH2)~0-, -(C~2~2C-- -(CH2)3C

2 ) 5CO , -CE12CH ( OCOCH3 ) CH20CO-, -CH2C(CH3~2CO- or -CH2CH(CH20H)NHCO-.

The following are examples of pr~ferred compounds of formula I:

O-~t2-~t(chole~t-5-en-3~-yloxy)carbonyl]oxy]çth hydroxyphosphinyl]choline hydroxide internal 6alt, O-[hydroxy-[3-r(3~-stigmastanyloxy)carbonyl]p~opoxy]-pho~phinyl~choline hydroxide internal ~alt, - -: . .

. ~ . ,. . .. - :

. :.., ~J '~ J ~ 7 ~ ~

-~12-(chole6t-5-en-3J~-yls)xy)ethoxy]hydLoxyphosphinyl]-choline hydroxide internal 6al1: and O-rhydro~cy-r2-~l-(5a-~eigrlafitan-3J~-yloxy)formamido]
e~hoxy]phosphinyl]choline hydroxide internal ~alt.

The following are further example~ of compound6 o ~o~ula I:

O-[r2-[t(5a-stigma~tan-3~-yloxy)carbonyl~oxy]ethoxy]
hydcoxyphosphinyl]choline hydcoxide in~ernal ~alt, 0-~hydroxy-~2- r r rE) -~ti~ma8ta-5.22-dien-3B-yloxy]carhonyl]ethoxy]pho6phinyl]choline hydroxide inte~nal ~alt, 0-[r3-[t(chole~t-5-en-3~-yloxyjcarbonyl]oxy]pr hydroxyphosphinyl]choline hydroxide internal ~alt, O-lr4-l[(cholest-5-en-3B-yloxy)carbonyl]sxy]butoxy]
hydroxyphosphinyl]choline hydroxide internal ~alt, 0-[[[8-rt(cholest-5-en-3~-yloxy~carbonyl]o~y30ctyl]-oxy]hyd~oxypho~phinyl3choline hydroxide internal salt, 0-r~l(chole6t-5-en-3~-yloxy)carbonyl]methoxy3hydr phosphinyl~choline hydroxide internal ~alt, 0-[[Z-~(chole6t-5-en-3~-yloxy)carbonylJethoxy]hydroxy-pho~phinyl~choline hyd~oxide internal ~alt, 0-[hydroxy-~2-t(3~-~tigma~tanyloxy)carbonrl]ethoxy3 pho~phinyl]choline hydroxide internal salt.

thydroxy-[2-[(~tigma8ta-5~22-dien-3~-yloxy)carbonyl3 ethoxy3pho~phinyl~choline hydroxide internal salt, - - , , , ~, , ' ', ".,~. , i: , ; .
,., '~'. '` ' .' ~
, , , 2 ~,~ r~

o-tr3-~(chole~t-5-en-3~-yloxy)carbonyl]plo~oxy]hydr pho~phinylJcholine hyd~oxide internal salt, 0 rhydroxy-r3- r tE)-~tigmasta-5,22-dien-3~-YloxY)-carbonyl]propoxy]phosphinyl]choline hydroxide internal ~alt, o- rhYd~oxY- r t5-t(5a-stigmastan-3~-yloxy)carbonyl]-pentyl~oxy]pho6phinyl~choline hydroxide internal 6alt, 0-~hydloxy-[~5-~((E)-stigmasta-5,22-dien-3~-yloxy)car-bonyl]pentyl]oxy~phosphinyl]choline hydroxide internal 5alt, O-thYdroxY-~[[(3B-stigmastanyl)oxy~carbonyl~methoxy]-phosphinyl]choline hydroxide internal salt, 0-[hydroxy [[[(E)-~tigmasta-5,22-dien-3~-yloxy]-carbonyl]methoxy]phosphinyl]choline hydroxi-de internal ~alt, 0-[hydroxy-[2-(stigmasta-5,22-dien-3fl-yloxy)ethoxy]-phosphinyl~holine hydroxide internal ~alt, 0-t[Z-[2-~holest-5-en-3~-yloxy)ethoxy]ethoxy]hydroxy-pho~phinyl]~holine hydroxide inte~nal sal~, O-thyd~oxy-t2-r2-~tE)-6tig~asta-5~22-dien-3~-yloxy]ethoxy3ethoxy]ehosphinyl]choline hydroxide internal salt, 0-[~2-[2-t2-(chole~t-5-en 3~-yloxy)ethoxy~ethoxy]-ethoxy~hydroxyphosphinyl]choline hydroxide internal salt, 0-[~2-1(5-chole~tan-3~-yloxy)carbonyloxy]e~hoxy]-hydroxyphosphinyl~choline hyd~oxide internal salt, O-rhydroxy-t2-[2-(3~-~tigma6t~nyloxy)ethoxy]ethoxy]
phosphinyl]eholine hydroxide internal 6alt, , , ' ., ~ :; , :.

~, . . . .
:~, . : :

5.~

0-[hydroxy-~2-(3~-6ti~ma~tanyloxy)ethoxy~pho~phinyl]-choline hydroxide internal ~alt, l-t2-t[hydroxy-[2-[1-(5~-fitigmas~can-3~-yloxy)-formamido]ethoxy]pho6phinyl]0xy]ethyl]pyridinium hydroxide internal salt, 0-[hydroxy-E2 [1-t(E~-~tigmasta-5,22-dien-3B-yloxy3forma~ido]ethoxy]phosphinyl]choline hydroxide internal 6alt, 0-~hydroxy-r3-[l-[(E~-6tigmasta-5,22-dien-3B-yloxy]formamido3propoxy3pho~phinyl]choline hydLoxideinternal ~alt, O-[hydroxy-[(RS)-3-rN-i~opropyl-l-[(E~-stigma~ta-5,22--dien-3B-yl]oxyformamido]-2-[(methylcarbamoyl~oxy]~ropoxy3-pho~phinyl]choline hydroxide internal salt, -t r r2-~l-chOle~t-s-en-3~-YlOxY]~ormamido~ethoxy]-hydroxyphosphinyl]choline hydroxide internal salt, 0-tt2-rl-(5B-chole~tan-3a-yloxy)formamido]ethoxy]-hydroxyphosphinyl3cho~ine hydroxide internal ~alt, 1-[2-t[hydroxy-r3-[1-[(2)-stigma6ta-$,22-dien-3B--yloxy]formamido]p~opoxy]pho6phinyl]0xy]ethylJpyridinium hydroxide internal 6alt, 0-[hydroxy-t2-t r t (E)-8tigma8ta-5~22-dien-3~-yloxy]-carbonyl]oxy]ethoxy]phosphinylJcholine hydroxide internal 6alt, l-t2-[[[2-[1-~chole~t-5-en-3~-yloxy3foLmamido~ethoxy~-hydroxyphosphinyl~oxy3ethyl~ methylpyrrolidinium hydroxide internal 6alt, - : .

1-0-(3a,~-~tigma~tanyl~-3-0-(R5)-glyceryl-pho6pho~yl-choline, O-[[(RS)-Z-acetoxy-3-t5-stigmastan-3cl,~-yloxy~-propoxy]hydro~ypho~phonyl]choline hydroxide internal ~alt, 0-[~RS)-3-[(cholest 5-en-3~-yloxy)carbonyloxy]-Z-~hydroxypLopoxy]hydroxyphosphinyl]choline hydroxide internal 6alt.

O-rhydroxy-(Rs)-2-hydLoxy-3-rt5a-~tigmastan-3B--yloxy)carbonyloxyJpropoxy]phosphinyl]choline hydroxide int~rnal 8al~

0-[hydroxy-[(RS)-2-hydroxy-3-t~(E)-stigma~ta-5,22--dien-3B-yloxy]carbonyloxy]pLopoxy]phosphinyl~choline hydroxide internal ~ialt, O-~hydroxy-~2-~(stigmas~-5-en-3J3i-yloxy)carbonyl]oxy]-ethoxy]pho~phinyl]choline hydroxide in~ernal ~alt, 0-[hydroxy-[3-r(~tigma~t-5-en-3~-yloxy)carbonyl]-propoxy]phosphinrl~choline hydroxide internal salt.

O-rhydroxy-r2-(stigma~t-5-en-3~-yloxy)ethoxy]ph phinyl]choline hydroxide inte~nal ~alt, chole~t-5-en-3B-yl 2- r [ r2- (dimethylamino)ethoxy]-hydroxyphosphinyl30xy]ethylcarbonate, O-~hydroxy-r2-[1-(sti~ma~t-5-en-3B-yloxy)formamido]-ethoxy]pho~phinyl]choline hydroxide inte~nal ~alt, 0-~(RS)-2-acetoxy-3-~(chole~t-5-en-3~-yloxy)-carbonyl]oxy]p~opoxy]hyd~oxyphosphinyl~choline hydroxide internal ~alt, .
, : :. .

0-t[2-t~hvlest-5-en-3~-yloxy3carbonyl]-2-methylpro-poxy]hydroxyphosphinyl]-choline hydroxide inteLnal salt and O-[[(P~S)-2-[~-(chole~t-5-en-3~-yloxy)formamido3-~-hydroxypropoxy]hydro~yphosphinyl]choline hydroxide internal salt.

The s~eLoid6 of formula I and the ~alt6 the~eof can be manufactured by a) treating an alcohol of the formula Rl CH3 ~ 1'` / CH3 ~ CH3 ll HO~ ~O

with intermediary protection of a hydroxy Lesidue Y
pre6ent in the group X, with an agent which introduGe~ the group of the formula I ~ ~
R ~7-(CH2)n-01- (G), and . . ~.
; .
' ' -7 ~ ~

g b) if de~ired, hydrogenating an unsatu~a~ed ste~oid of formula I to the atu~ated steJ:oid, c) if desired, functionally modifying a reactive residue present i~ the group X of a steroid of formula I, d) if de~ired, converting a ~teroid of formula I into a ~al~.

These reactions can be carried out in a manner known per ~e. ;~

Thus, a carbonate of formula II in which X i~ a group of the formula -(CH2)p-OC0- i~ reacted in a solvent ~uch as me~hylene chloride or chloroform in the presence of a base such as quinoline or ~yridine firstly with a halide of the formula PO(Hal)3, e.g. phosphorus oxy-chloride, at room tempeLaSure and the compound obtained can be treated with a ~alt o~ the formula 3 I W III' R -N-(CHz)n-OH

wherein W i~ lower-alkylsulphonyloxy or aryl~ulphonyl-oxy, e.g. with choline to~ylate, in the pre~ence of a base ~uch a6 pyridine in a fiolvent ~uch as methylene chloride at room temperature.

A carbamate of formula II in which X is a group of the formula -(CH2)pN(T)C(0)- can be reacted fir~ely with a halide of the formula . ~ : - :.
., . . ~

~: . : ', . , ' ~

r~
'\ /
~ P`;~ 1 0 Hal e.g. with 2-chloro-2-oxo-1,3,Z-dioxapho~pholane, in a ~olvent ~uch a~ tetrahydrofuran (THF) while cooling to temperature to 0C in the pre~ence of a ba~e 6uch a~
triethylamine and the phosphate obtained can be reacted in 'che ~ame ~olvent ~ith an amine of ~che formula N~R ,R ,R ) while heating, e . g. to 50 ~o 100C.

An este~ oî formula II in which X i~ a g~oup of the formula -CH(CE13)C0- can firstly be reacted with a halide ~uch as ~-bromoethylphosphoric acid dichloride (Pharm.
Acta Helv. 33, 1958, 349) in a 601vent ~uch a~ methylene ~hloride in the presence of a ba~ ~uch a~ triethylamine and the ~ompound obtained can then be trea~ed in a ~olvent such a~ t~luene with an amin~ of the f ormula N(R2 R3 R43 As de~cribed in Example 11 hereinafter. a benzyl group can be u~ed to protect a hydroxy residue Y pre6ent in the group ~ of a compound of formula II. Thu~, a glycerol deriva~ive of formula II in which X i8 a group of the formuila -CH2CH(OH)CH2- can be reacted with tri~yl chloride in pyridine ~o give the corre~ponding trityl ether. Thi~ ether can be converted by mean~ of ~odium hydride in THF a~d benzyl chloride in dimethylformamide (DM~) at a tempe~ature up to 100C into the cQrresponding trityl benzyl diether in which X stands for -CH2C~(OCH2C6H5)CH2-. ~fter cleavage of the trityl group from the diether, e.g. by mean~ o~ hydro-,; :

: . ', ,; " . ~ . .
- , . . .......... .
,. .: ' , ,~ ~ 4,~ J ~

~hloric acid in dioxan while heating, ~he benzyl ether :
obtained i~ ~reated as described above with an agent which in~roduces the group 3 1 ~ D `
R -N-(CH2~n-0P- ~G).
l4 By cleavage of ~he benzyl g~oup, e.g. by hydrogenation in the presence of palladium-charcoal (Pd/C) in methanol and 15 T~F or ~in order to avoid the ~imul~aneou~ hydrogenation , of double bond~ present in the ~eroid part of the ether) in the pre~ence of palladium oxide (PdO~ in acetic acid, there i~ obtained the glycine derivative of for~ula I in which X i~ -CH2CH(OH)CHz-. which coLrespond6 to the ~tarting ~ompound of formula II.

A benzyl-protected steroid alcohol of formula II in which X stands for -C~2CH(OCH2C6~5)CH2- can al60 be prepa~ed by leacting the corresponding steroid 3-chloroformate ~ith O-benzylglycerol in methylene chloride.

As de~cribed in ~xample 22 hereinafter, a phenoxy-carbonyl group can al80 be used for the prote~tion of a hydroxy re~idue Y pre~ent in the group X of a compound of formula II. Thu~, a compound of focmula II in which ~ i~ a group -CH2CH(CH20H)N~CO- can be ~eacted with ~henyl chlo~ofo~mate in methylene chloride, THF and pyridine. The re~ulti~g compound containing a phenoxycarbonyloxy group i~ then reacted, e~g. in toluene and triethylamine, with an agent which introduce~ the group of formula G above, e.g. with 2-chlo~o-Z-oxo-1.3~2-dioxapho6pholane, and then ., : . . ., ;

.. : . . . . :
; ... . .

~, . . ..

2 ~ 3 ~

~ 12 -with trimethylamine in toluene and ace~onitrile. The compound of formula 1 in which ~ i8 the ~roup -CH2CH(CH20H)NHCo- i~ then ob~ained by cleaving off the pheno~ycarbonyl group, e.g. using aqueou6 sodium hydroxide.

The hyd~ogenation of an unsaturated ~teroid of formula I can be ca~ried out in the pre6ence of Pd/C in a solvent 6uch a~ methanol at a temperature up to 100C.

The alkanoylation of a hydroxy group Y can be mentioned as a functional modification of a reactive residue present in the gcoup X of a steroid of formula I.
Thus, a glycerol derivative of formula I in which ~ is the group -CH2CH(OH)CH2- can be reacted at room temperature in a ~olvent such as chloroorm in the presence of a ba6e ~uch a6 pyridine and a catalyst such as dimethylaminopyridine (D~AP) with ehe carboxylic acid anhydride corre6ponding ~o the alkanoyl group to be introduced.

The starting alcohol~ of for~ula II in which X is a group of the ~ormula -(CHz)p-C(Q,Q')-Z'.
-CH2CH(Y)CH2-Z'-, -CH2CH(CH2Y)-Z'- or - (CH2CH20)q~CH2CH2~Z ' -, Z ' i8 a group of ~he formula -OC(0)--. -OC(O)CH2-. -OCH2C(0)- or -N(T)C(0)-and R , Q, Q', p, q, y and T have the 6ignificance given above are novel and as such are an object of the invention.

The alcohol~ of formula II can be prepared in a manner known per 6e, e.g. as de~cribed in Examples A to ~ herein-after.

Thu~, a~ alcohol e~hec of formula II in which X i6 e.g. a group -(CH2)p- can be prepared by reacting the corre6ponding steroid-3-tosylate with the glycol . . . . . . .
.
.
:':

. .
.

`' ' ~ ' ' '' ` "

H0-(CH2)p-OH in dioxan at about 120~C.

An alcohol ester of foLmula II in which X i6 e.g. a group -(CH2)p-C0- can b~ prepared by reacting the corresponding ~teroid-3-ol in methylene ~hloride with the corresponding halide o the foLmula ~al-(CH2)p-COCl at about 5C in the pre~ence of pyl id ine and converting the halide obtained into the desired alcohol of formula II by mean~ of pota~sium tri~luoroa~e~ate in methylene chloride, DMF and water at about 80C.

An alcohol ester of formula II in which X i6 e.g. a group -CH(CH3)C0 can be prepared by reacting the corresponding ~tecoid-3-ol with lactic acid in toluene in the presence of catalytic amount6 of p-toluene~ulphonic acid.

An alcohol carbonate of formula II in which X is e.g.
a group -(C~z)p-~C(O)- can be prepared by r-eacting the corresponding ~teroid-3-ol in methylene chlo~ide at about -lODC with a ~olution of pho~gene in toluene and reacting the stecoid-3-~hloroformate obtained in chlorofocm oc 2~ methylene chloride with a diol of the formula H0-(CH2~p-0~ in the pre6ence of pyridine or trie~hyl-amine at about 5C.

An alcohol carbamate of formula II in which X i~ e.g.
a group -(CH2)p-N(T)C(0)- can be prepa~ed by reacting the corresponding steroid-3-ol in chloroform and THF with phenyl chloroformate in the pre~ence of pyridine and reacting the phenyl~arbonate obtained in chloroform with the amin2 of the fo~mula H0-(CH2)p-N(T)-H~

A compound of fo~mula II in which X is a group of the ~ocmula -CH~CHEOCONH(T )]CH2N(T )CtO)- and T
and T are hydrogen or lo~er-alkyl Gan be prepaced by ,. . ~
.: . , , .1. .:
, , ' , ' ', ~ . , ' ,:

37~

reacting the corresponding l-de!oxy-l-amino-3-0-trityl-glycerol of the for~ula T NHCH2CHOHCHzOC(C6H5)3 with a steroid-3-chlorofolmate in ~ethylene chloride in the presen~e of pota6sium hydroxide, reacting the product obtained in methylene ~hloride with the i~ocyanate of the formula 0=C=N(T ) at 80C and cleaving off the trityl group f~om the p~oduct obtained in dioxan by mean~ of hydrochloric acid a~ 95C.

A glycerol deri~ative of formula II in which X i8 a group -CH2CH~OH)CH~- is obtained by reacting the co~esponding 3-0-tosyl~teroid in dioxan wi~h glycerol at 100c, An alcohol of formula II whi~h has a double bond i~
~he ~teroid part can be hydrogena~ed to the ~orre~ponding ~aturated alcohol. e.g. in the pre~ence of Pd/C in THF.

The pre~aration of some compounds of formula II i6 described in detail in Example6 A to M hereinafter.

Exam~le_A

A ~olution of 10 g of cholesterol tosylate and 25.3 g of ethylene glycol in 180 ~1 of dio~an i6 hea~ed to 120C
while ~tirring. The mixture is then treated with 200 ~1 of water and e~tracted with ether. The ethereal phase is washed fi~tly with 10% sodium caIbonate solution and then with wa~er. The organic pha6e is dried and evapo~ated. The residue i~ chromatographed on 6ilica ~el while eluting with ether/hexane. There are obtained 5.6 g of 2-(cholest--5-en-3~-yloxy)-1-ethanol, ~.p. 92-95C. the 6tarting material in Example 2q.

.. , ~ , p~ ~ ~

- lS -Exam~le B

Analogou61y to Example A theLe are obtained:

a) 2-[[(E)-Stigma~ta-5~2-dien-3~-yl]oxy]-1-ethanol, MS:
456 (M+H ).

10 b) 2-r2-r(E~ ~tigma~ta-5,22-dien-3B-yloxy]ethoxy~-l--ethanol, MS: 501 (M~H ), c) 2-[2-(cholest-S-en-3B-yloxy~ethoxyJ-l~ethanol, MS: 474 (M~H ~, d) 2-r2-[2-~holest-5-en-3B-yloxy)ethoxy]ethoxy]ethanol, MS: 519 (M~H ). -Example C
1. A solution f ? g f stigma6ta~01 in 200 ml of methylene chloride and 4 ml of pyridine i8 added dropwise at 5C to a solution of 12.S g of 3-bromopropionyl chloride (obta1ned from 11.1 g of bromopropionic a~id and 9~77 ~1 of oxalyl chloride in 55 ml of methylene chloride and 3 drop~ of DMF) in 44 ml of ~e~hylene chloride. The mixture i8 evaporated, the re~idue i6 dis~olved in 500 ml of methylene chloride and thi~ 601ution i~ wa~hed with dilute hydxochloric a~id. The organic pha6e is dried and evaporated. Th~ residue i8 chro~atogLaphed on ~ilica gel while eluting with ether hexane. There is obtained 3~-stigma~tanyl 3-bromopropionate of melting point 150-152~C.

2. Analogou~ly there are prepa~ed:

a) 5tigmasta-5,22-dien-3~-yl 3-bromopropionate, 2 -g 7 ~' r~

b) 5a-s~ig~astan-3~-yl bromoa~etate, c) cholest-5-en-3B-yl bromoa~etate, d~ cholest-5-en-3B-yl b~omopropionate, e) 5a-stigmagtan-3~-yl ~-bromobutyrate~

f) chole6t-S-en-3B-yl 4-chlorobutyrate, g) 3B-sti~mas~anyl 4-chlorobutyrate, h) 3~-6tigmastanyl 4-iodobutyrate, i) (E)-stigmas~a-5,22-dien-3~-yl 4-chlorobutyrate, j) (E)-~tigma~ta-5,22-dien-3B-yl 4-iodobutyrate, k) ~holest-5-en-3~-yl 4-iodobutyrate, 1) (E)-stigmasta-5,22-dien-3fl-yl 6-bromohexanoate, m) 5a-stigma~tan-3~-yl 6-bromohexanoa~e, n) ~tigmast-5-en-3~-yl 4-bromobutyrate.

3~ A ~olution of 23.1 g of 3B-~tigma~tanyl 3-bromo-propionate in 400 ml of methylene chloride and 200 ~1 of DMF is treated with 63.3 g of potassium trifluoroacetate and heated a~ 80C over 72 hours. After adding 30 ml of water the solution i~ heated at 80~C for a further 1 hour.
The solution i8 evaporated and the residue is chromato-graphed on ~ilica gel u6ing ether-hexane. There i~
obtained 3~-~tigmastanyl 3-hydroxypropionate of mel~ing poin~ 152-153C, the ~ta~ting matecial of ~xample 20.

. . . . : .,. , ., .

: :
, :: :

.- 17 -ExamP 1_ Analogou~ly to Example C there are prepared:

a) Chole~t-5-en-3B-yl glycolat:e, MS: 369 (M-HOCH~COOH), b) 3~-~tigma~tanyl glycolate, ~S: 399 (M-HOCH2COOH), c) cholest-5-en-3~-yl ~-hydroxypropionate, ~S: 368 (M-HOCH2CH2COOH), d) ~tigmasta-5,22-dien-3~-yl 3~hydroxypropionate, MS: 394 (M-HOCH2CH2cooH~, e) chole~t-5-en-3~-yl 4-hydeoxybutyrate, m.p. 98C, f) 3~-~tig~astanyl 4-hydroxybutylate, m.p. 149C, g) (E)-stigmasta-5,22-dien-3B-yl 4-hydroxybutyrate, m.p.
147C, h) 5a-~tigmastan-3~-yl 6-hydroxyhexanoate, m.p. 130C, i) (E)-stigmasta-5,22-dien-3B-yl 6-hydroxyhexanoate, m.p.
133C, j) 6tigmast-5-en-3R-yl 4-hydroxybuty~ate, m.p. 125-126C.

ExamPle E

A 601ution of 10 g of cholesteryl chloroforma~e in 100 ml of methylene chloride and 2.16 ml of pyridine i8 added dropwi~e at 5C to a 601u~ion of 1~.8 g of e~hylene glycol in ZOO ~1 of methylene chloride. The 601ution i~
then ~rea~ed with 300 ml of water and extracted with methylene chloride. The organic phase i6 washed with ,, 7 .~ ~

water, dEied and evapocated. The re~idue i6 recry~tallized in methylene chloride-ethanol. There are obtained 6.4 g of chole6t-5-en-3~-yl 2-hydroxyethylcarbonate of melting point 139-140C, the alcohol 6t:arting material of Example 1.

Exam~le F

Analogously ~o Example E there are prepared:.

a) 5a-Stigma~tan-3~-yl 2-hydroxyethylcaLbonate, m.p.
184C, b) 2-hydroxyethyl (E)-~tigma~ta-5,22-dien-3B-ylcarbonate.
m.p. 172C, c) cholest-5-en-3~-yl 3-hydroxypropylcarbonate, m.p. 96C, ~0 d) cholest-5-en-3B-yl 4-hydroxybutylca~bonate, m.p. lQ7C, e) chole~t-5-en-3~-yl 8-hydroxyoctylca~bonate, m.p. 79C, f) 2-hydroxyethyl ~tigma~t-5-en-3~-ylcarbona~e, m.p.
160C.

ExamPle G

1. A solu~ion of 1.7I g of phenyl chlorsf OEmate in 5 ml of C~C13 i6 added dropwi6e to a fiu~een6ion~ cooled to -50C, of 4.16 g of ~tigma~tanol in 25 ml of CHC13, 12.5 ml of THF and 0.75 ml of pyridine. A further 0.25 ml of pyridi~e îs ~hen added. The mix~ure i~ reacted at a low temperature for 30 minutes and at ~oom temperature for a furthec 1 hour. The reaction ~olution i6 poured into a solution of pyridine and aqueou6 RHC03. After the evolution of C02 has finished the ~ixture is evaporated ., , : ~, . ; . .

~2~

-- 19 ~

to dryne~. The re6idue is partitioned between CH2C12 and ~2 After cry~tallization from CH2C12-pentane there are obtained ~.75 g of 3-~tigmastanyl phenyl-carbonate. M.p. 96C.

2. 0.3 ml of ethanolamine i~ add2d to a ~olution of 1.07 g of the above phenylcarbonaSe in 3 ml of CHC13.
The mixture is r0acted at room temperature for 2 day~. The exces~ reagent i8 di~tilled off and the phenol which result6 in ~he reaction i~ separated a~ Na phenolate. The compound i6 crystalli~ed~from CH2C12. There is obtained 0.9 g of 3A-s~igmastanyl (2-hydroxyethyl)-carbamate. ~.p. 206C, the starting ~ateLial in Example 5.

ExamPle Analogou61y to ~xample G, 201. from ~tigma~te~ol via (E)-~tigmasta-5,2-2-dien-3~-yl phenylcaEbonate, m.p. 156-157~C, there are obtained a) (E)-~Sigma~ta-5,22-dien-3B-yl (2-hydroxyethyl~-carbamate, m.p. 187C, and b~ (E)-~tig~a6ta-S,Z2-dien-3~-yl (3-hydroxypro~yl)-carbamate, m.p. 172-173C;

2. from chole~terol via 3~-chole6teryl ph~nylcarbonate there i8 obtained 3~-chole~teryl t2-hydroxyethyl) carbamate, ~.p. 168-170C;
;
3. from epicop~ostanol via epicoprostanyl phenylcarbamate there is obtained epicopro6tanyl (2-hydroxy~thyl)-carbamate, m.p. 98C;

~. from B-~ito~terol via ~tigma~S 5-en-3-yl phe~yl-, ~ , , .

,. ~J~?.,~i3~

carbonate, m.p. 108-109C, there i6 obtained 6tigma6t-5--en-3~-yl (2-hydroxyethyl3carbamate, m.p. 198-199C, the starting ma~erial in E~ample 19.

Examl~le I

1. 10 ml of a 20% phosgene ~olution in toluene are added to a 801ution, cooled to -10C, of 4.12 ~ of fitigma6ter in 40 ml of methylene chloride. The mixture i8 reacted overnight and then cooled to -10C. After adding 0.7 ml of triethylamine in 10 ml of methylene chloride the reaction i6 continued for 24 hours. The mixture i6 neutralized with 0-7 ml of triethylamine in 10 ml of methylene chloride and the (E~-stigma~ta-5,22-dien-3~-yl chloroformate i8 isolated.

2. A solution of 2.3 g of the above chloroformate in 10 ml of chlorofocm i~ added dropwi~e to a solution, cooled in an ice bath, of 1.6 g of ethylene glycol and 0.5 ml of pyridine in 10 ml of chloroform. The reaction mixture ifi poured on to ice and a ~odium bicarbonate solution. The mixture is e~tracted with ~ethylene chloride, chromatographed on silica gel with toluene~
chloroform/ethyl acetate (4/2~1 volO). Af~er cry~tal-: lization from methylene chloride-~ethanol there are obtained 1.86 g of t~)-s~igmasta-5DZ2-dien-3~-yl l2-hydroxyethyl)carbamate, m.p. 172-173C, the alcohol ~tartin~ ~aterial of E~ample 9.

ExamPle J

1. A ~olutio~ o~ 1.45 g of 3-0-to6yl~tigma~t~rol in 20 ml of dioxan i reacted with 2.5 g of glycerol for ~ hou~ at 100C while ~irring. After di6tillation of the ~ol~ent, dilution of the residue wi~h water, extraction with diethyl ether and cry~alliza~ion from methylene chloride-. ... ..

'~.: . .

': .

~ 21 ~

-methanol there i~ obtained 1 g of 0-3,B-stiqmasteryl--glycerol .

2. A solution of 1.7 g of the above product in 15 ml of THF is hydrogenated over 0.5 g of 10% Pd/C under normal pressure. After removal of the cataly~t, dis~illation of the solvent and crystallization from THF-methanol there is obtained in quantita~ive yield 0-3a,~-stigmastanyl-(RS)--glycerol, the starting material of Example 11.

~xample_K

1. 0.74 g of (RS)-glycidol and Z.R g of tcityl chloride in 5 ml of pyridine are reacted overnight. A ~olution of 2 g of potassium bica~bonate i8 then added while sti~riny.
After evaporation, partition of ~he cesidue between water and methylene ~hloride and chcomatography on 6ilica gel 2~ with toluene there are obtained 2.25 g of (RS)-epoxy-l-0--tcitylglycerol.

2. 3 g of this product are reacted with 5 ml of isopropylamine in a bomb tube at 100C fo~ 2 hours. Af~er distilling off the excess ifiopropylamine 4.4 g of (RS)-l deoxy-l-isopropylamino-3-0-tritylglyceeol, m.p. , 128-130C, are ccystallized from methylene chloride-hexane.

3. 1.04 g of the above amine in 20 ml of me~hylene chloride and 0.2 g of potassium hydroxide in 2 ml of water are added dropwise while stirring to a solution, cooled to -10C, of 1.1 g of stigmasteryl chloroformate in 4 ml of methylene chloride. After reaction at room ~emperature for Z hours, pha~e sepaLation in a ~eparating funnel, chromatography on silica gel with methylene chloride--diethyl ether (2/1) there ace obtained 1.63 g af (E)-stigmasta-5,22-dien-3~-yl isopropyl-[(RS)-~-hydroxy--3-trityloxypropyl]-carbamate, m.p. 75-75vc.

.. .~ ., .

, ,' '' , . : ~ , , ''' .. '' ' ~ ,73 .... - ~2 -4. A solution of 2 g of the above product in 10 ml of methylene chloride i6 ~eacted with 2 ml o~ methyl iRocyanate in a bomb tube at 80C for 40 hour6 and there i~ obtained in quantita~ive yield (E)-~tigma~ta-5,22-dien--3~-yl i60pcopyl-[(RS)-2-methylcarba~oyl-3-trityloxy-propyl]-carbamate, m.p. 92-93C.

lo 5- By cleaving off the tLityl group analogously to Example llc there are obtained from 2.5 g of the above trityl ether 1.7 g of (E)-stigmata-5,22-dien-3~-yl [~RS)-3-hydroxy-2-[(methylcarbamoyl)oxy]pLopyl]-isopropyl-carbamate, m.p. 240C, the 6tarting material in Example 7c.

~m~ . .

A solution of 10.2 g of chole~teryl chloroforma~e in 130 ml of methylene chloride i8 treated under argon while ~tirring with 4.6 g of 2-0-benzylglycerol in 120 ml of methylene chloride and 2 ml of pyriidine, ~a-ken up in 500 ml of water and ~0 ml of lN HCl after 1 hour and extracted with methylene chloride. The organic pha6e is dried and concentrated at 50C. ~fter chromatography over SiO2 with n-hexanie:ether (1:1) there are obtained 6.17 g of (RS)-2-(benzyloxy)-3-hydroxypropyl chloride 5-en-3B--ylcarbona~e, MS: 595 (M~H ), the ~tartin~ material of Exampls 13.

~a~
A ~olution of 3.~6 g of cholesterol and 0.~5 ~1 of L-(~)-lactic acid (90% in water) in ao ml of toluene i6 boiled ~or 1 hour. The water i~ separated, the cooled reaction mixture i~ treated with 0.3 g of p-toluene-iulphonic acid ~nd boiled for a Purther 4 hour6. The reaction mixture i~ treated with 30 ml of water and extracted with ether. The organic pha6e i~ dried over .

2~2$7~9 ~odium ~ulphate and concen~rated. The residue i~ purified on silica gel (elution agent petroleum ether/ether 4~
The~e are ob~ained 1.5 g of choles~-5-en-3~-yl (S)-2--hydroxyeropionate, m.p. 1~0-122~C.

The ~teroid~ of formula I and the 6alt~ thereof inhibit ~he intestinal re~orption of cholesterol.

The inhibition of the intestinal reso~ption of cholesterol can be demonstrated a~ follow~ in an animal experiment:

Squirrel monkey~ are orally administered the substances to be investiga~ed together with a te6t feed containing a protein, stacch, triolein and ~26_14C]_ -cholesterol. Thereafter, the faece~ i~ collected for 2.5 days. The difference between the administered and the collected radioactive chole6terol determined ln the faece~
i~ taken as the measurement of resorbed cholesterol. The cholesterol resorption (CHORES~ i~ expres~ed in eercentages of the control ~alue~ determined prior to the medication.

The resul~s which have been ob~ained with ~ome representative eroduct~ in accordance with the invention are reproduced in ~he Table hereinafter. There are given for each of the compounds indicated the~ein the chole~tecol ce~orption, determined at a dosage of 100 ~mol/kg p.o., in percentage~ of that in the pre-period. Moreove~, the Table contains data concerning the acute toxicity of the compound~ investigated ~LD50 in mg/kg in the ca~e of ~ingle oral or intravenou~
admini~tration to mice).

,. "
, Tabl~

.. _ __ _ _ _ _ Compound of formula I
of Example No. 2a 2k 2q 2r 4a 10 CHORES in % of the pre-period: 38 39 16 37 30 ._ _ .. __ _____ _ __ T--------LD~o in mg/kg p.o. 4000 4000 4000 4000 --- __ i.v. 250 25~ 250 500 Compound of formula I
of Example No. 5 6 7a 16 CHORES in % of the pre-period:40 31 3~ 40 -LD50 in mg/kg p.o. 4000 _ _ . _ _ . _ .

The products in accordance with the invention ean be u6ed a6 medicamen~s. e.g. in the form of pharmaceutical preparations. The pharmaceutical ereParation~ are administered orally, e.g. in the form of tablet6, coated - tablet6, dragee~, hard and soft gelatine cap6ules, 35 601utions, emul6ion~ or 6uspen6ion~.

For the manufacture of pharmaceutical preparation6, the products in accordance with the invention can be mixed ' t ~ . ;"1:, ",, , ~ " ,~ ." .
, ~
; : :
- , ~. . . ~.. . :., -:. . : .. ,.i.:

~ 3;i) ~J

with pharmaceutically inert, inorganic or organic carriers. Lactose, maize starch, talc, ~tearic acid or it6 ~alts can be u~ed, for example, as carrier~ for tablet6, coated tablets, dragee~ and hacd gelatine cap~ule~.
Vegetable oil~, waxe~, fats or semi-solia and liquid polyols are, for example, ~uitable carriers for soft gelatine capsules; depending on the nature of the active 8ub6tance no carrier i8, however, generally required in the ca~e of soft gelatine cap~ules. Water, polyol~, ~accharo~e, i~vert ~ugar and gluco6e are, for exam~le, ~uitable cacrier~ for ~he manufacture of solution~ and ~yrup6.

The pharmaceutical erepara~ions can, moreover, con~ain pre6erving agen~ olubilizer6, ~tabilizing agen~s, wetting agent~, emulsifying agents, 6weetening agent~
colouring agents, flavouring agent~, ~alts for varying the osmotic pressure, buffer6, coating agents or antioxidant~.
They can also con~ain still other therapeutically valuable substances.

As mentioned eaLlier, medicaments containing a steroid o foLmula I or a pharmaceutically acceptable ~alt thereof are al~o an object of the pre6ent invention, furthermore also a proce6~ for the manufacture of ~uch medicaments which compri~es bringing one or more product6 in accordance with the invention and, if de6ired~ one or more o~her therapeutically valuable sub~tance into a galenical admini~tration form. As mentioned earlier, the product~ in accordance with ~he invention can be used in the control or prevention o illnes6e~.

5They can be used e~pecially in the control or prevention of hypelchole6terolemia and of athero6clero6i~.
The dosage can vary within wide limit6 and will, of course, be fitted to the individual requirements in each .
' ~ .

particular case. ln general, in the ca6e of oral admini~tration a daily do~age of about 50 mg to about 3 g, pref~Lably of about 20Q mg to about 1 ~, ~hould be appropriate.

The manufacture of compound~ of formula I i~ described in the Examples hereinafter.

Example 1 A fiolution of 48.7 g of chole~t-5-en-3~-yl 2-hydroxy-ethylcarbonate and 10 ml of quinoline in 500 ml of methylene chloride i~ added dropwi6e at room t~mpera~ure to a 601ution of lZ.5 ml of phosphoru6 oxychloride. ~he solution i~ treated at room tempe~a~ure while stirring with 60 ml of pyridine and 77 g of choline to~ylate in 500 ml of methylene chloride, whereupon the reaction mixtuce is stirred at roo~ temperatuce overnigh~. The mixture i~ treated with lZ5 ml of water and 34 g of ~odium bicarbonate and then with 3000 ml of acetone. The precipi~a~ed product i~ filtered off under ~uction, dissolved in 1000 ml of chloroform~methanol 1:1 and ~tirred with 500 g of ion excha~ger (Amberlite ~B-3~. The latter is filtered off under suction and the solution is evaporated. The re~ultinq re6idue i~ recrystallized in a mixture of ~ethylene chlorid~-methanol 1:1 and dioxan.
There are obtained 39 g of 0-t~2-trtcholest-5-en-3~--yloxy)carbonyl]oxy]ethoxy~hydroxypho~phinyl]choline hydroxide internal ~alt of melting poin~ 224C, MS: 640 (M~H) .

Exam~le 2 Analogou~ly to Example 1, a) starting from 5a-stig~a~tan-3~-yl 2-hydro~yethyl-.... ~ .,.. . .. .

.. . . , . ~ , ~ .
, . . : ,~.. ;~: :::
.: . ~

~ ~ ~ 7 ~

carbonate there i6 obtained 0-l[~2-[[(5a-~tigmastan-3~--yloxy)carbonyl~oxy~ethoxy]hydroxypho6phinyl]choline hydroxide internal ~alt, m.p. ;220C

b) 6tarting from Z-hydroxyethyl (E)-~tigmasta-5,2Z-dien--3~-ylcarbonate there is obtained 0-thydroxy-[2-[[tE3--~tigma~ta-5,22-dien-3~-yloxy]carbonyl~ethoxy~phosphinyl]-choline hydroxide internal ~alt, m.p. 220~C

c) ~tarting fro~ cholest-5-en-3~-yl 3-hydroxypropyl-carbonate there is obtained 0-rr3-~[(cholest-5-en-3B--yloxy)ca~bonyl]oxy]propoxy~hydroxypho~phinyl]choline hydroxide internal ~alt, m.p. 230C

d) 6tarting from cholest-5-en-3A-yl 4-hydroxybutyl-ca~bonate there i~ obtained 0-rr4-~[(cholest-5-en-3~--yloxy)carbonyl]oxy]butoxy~hyd~oxypho6phinyl~choline hydroxide internal 6alt, ~.p. 232C

e~ starting from cholest-5-en-3~-yl 8-hydroxyoctyl-carbonate there i~ obtained 0-[[[B-[~(cholest-5-en-3B- ~ --yloxy)carbonyl~oxy~octyl]oxy]hydroxypho~phinyl~choline hydroxide internal 6alt, m.p. 235C

f) starting from chole~t-5-en-3~-yl glycolate there i6 obtained 0-[[[~holest-5-en-3~-yloxy)carbonylJmethoxy]-hydroxypho~phinyl~choline hydroxide internal salt, m.p.

g) starting from cholest-5-en-3~-yl 3-hydroxypLopionate there i~ obtained O-rr2-ttcholest-5-en-3~-yloxy)carbonyl~-e~hoxy]hydloxyphosphinyllcholine hydroxide inte~nal ~alt, m.p. 180C

h) staLting from 3~-~tigmastanyl hydroxypropionate the~e is obtained O-thydroxy-[Z-t(3~-sti~ma~tanyloxy)carbonyl]-'` ~' ' ` .
, , .. . . . .

7~

éthoxy]phoEphînyl]cholin2 hydroxide inteLnal 6alt, m.p.

i3 starting from stigmasta-5,;22-dien-3~-yl 3-hydroxy-propionate there i~ obtained O-[hydroxy-[2-[(~tigmasta--5,22-dien-3~-yloxy)carbonyl~ethoxy]pho6phinyl~choline hydroxide internal ~alt, m.p. 199C
j) 6tarting from chole~t-5-en-3~-yl 4-hydcoxybutyrate there i~ obtained O-rt3-rtcholest-5-en-3~-yloxy)carbonyl]-propoxy]hydloxypho6phinyl~choline hydroxide internal 6alt, m.p. 255C

k) 6tarting from 3~-stigma~tanyl 4-hydroxybutyrate there i~ obtained 0-thydroxy-~3-t(3~-6tigma6tanyloxy)ca~bonyl]-propoxy]phosphinyl]choline hydroxide internal salt, m.p.

1) ~tar~ing from (E)-6tigmasta-5,Z2-dien-3~-yl 4-hydroxidebutyrate there i& obtained 0-~hydroxy-[3-r(E)--~tigma~ta-5,22-dien-3~-yloxy)carbonyl]propoxy]pho6phinyl~-choline hydroxide internal salt, m.p. 2Z5C
~5 m) starting ~rom 5a-~tigma~an-3~-yl 6-hydroxyhexanoate there is obtained 0-~hydroxy-[[5-~(5a-6tigma~an-3~--yloxy)carbonyl~pentyl]oxy]phosphinyl]choline hydroxide internal 6al~, m.p. 254C

n~ ~tarting from ~E)-~tigma~ta-5,22-dien-3~-yl 6-hydroxy-hexanoate there i6 obtained 0-rhydroxy-~5-[((E)--~tigma6~a-5,2Z-dien-3~-yloxy)carbonyl~pentyl]oxy]-phosphinyl]choline hydroxide internal 6alt, m.p. 215C

o) s~arting rom 3~-~tigma~tanyl glycolate ~he~e is obtained 0-[hydroxy-r[~3B-6tigma~anyl)oxy]carbonyl3-methoxy]phosphinyl]choline hydroxide internal ~alt, m.p.

,.,. ~,,, :

. . ::.. :.
- ,~. ~ .
"~;.' :,, :

2~2~7~

Zg 260C .

p) starting from ~)-stigmasta-5,22-dien-3~yl-yl glycolate (not i~olated) there is obtained 0-~hydroxy--r tt(E)-stigma6ta-5,Z2-dien-3~-yloxy]carbonyl]me~hoxyJ-phosphinyl]~holine hydcoxide im~ernal salt, m.p. 215C

9) star~ing f~om Z-(cholest-5-en-3~-yloxy)-1-ethanol there is obtained 0-rr2-(cholest-5-en-3~-yloxy)ethoxy]-hydroxyphosphinyl]choline hydroxide internal salt, MS: 595 (M~H ) r) startin~ from 2-[t(E)-stigmasta-5,22-dien-3~-yl]oxy]--l-ethanol there is obtained 0-~hydroxy-~2-(stigmasta--5,22-dien-3~-yloxy)ethoxy]phosphinyl~choline hydroxide internal sal~, ~.p. 230C

5) starting ~rom 2-r2-(chole6t-5-en-3~-yloxy)ethoxy~
-ethanol there is obtained 0-rr2-[2-(cholest-5-en-3~--yloxy)ethoxy]ethoxy]hyd~oxyphosphinyl]choline hydroxide intecnal salt, MS: 640 (M~H ) t) starting from 2-[2-[(E)-stigmasta-5,22-dien-3~-yloxy]-ethoxy]-l-e~hanol there i8 obtained 0-thydroxy-[2-r2-r~E)--stigmasta-5,22-dien-3~-yloxy]ethoxy]ethoxy~phosphinyl]-choline hyd~oxide internal ~alt, MS: 666 (M+H j u~ sta~ting from 2-t2-rZ-(chole t-5-en-3~-yloxy~e~hoxy]-ethoxy]-ethanol thece i8 obtained 0-~[2-~2-r2-(cholest-5--en-3~-yloxy)ethoxy]ethoxy]ethoxy]hydroxyphosphinyl]choline hydroxide int~rnal salt, ~S: ~84 (~+H ).

_a~
1 g of 0-[~2-[~cholest-5-en-3~-yloxy)carbonyloxy]-ethoxy~hydcoxyphosphinyl]choline hydroxide internal salt :

,, ~ '3~5'J~
-is hydrogenated in 100 ml of methanol with 1 g of Pd/C 5%
under 30 bar of H2 at 80C. After filtration the solution i8 evaporated and the residue is dis601ved in chloroform-methanol-dioxan. By aclding ether there i6 obtained 0.6 g of 0-r~Z-[(5-chol,estan-3~-yloxy)car-bonyloxy]ethoxy]hydroxyphosphinyl]choline hydroxide internal salt as a hygroscopic powder, m.p. 2250C.

Example,~
In an analDgous manner to Example 3, a) using 0-[hydroxy-[2-[2-r(E)-stigmasta-5,22-dien-3~--yloxy]ethoxy]ethoxy]phosphinyl]choline hydroxide internal salt there is obtained 0-[hydroxy-[Z-[2-(3~-~tigmastanyl-oxy)ethoxy]ethoxy]phosphinyl]choline hydroxide internal salt, MS: 670 (M+H ) b) using 0-~hydroxy-r2-(stigmasta-5,22-dien-3~-yloxy)-ethoxy]phosphinyl]choline hydroxide internal salt there is obtained 0-[hydroxy-~2-(3~-stigmastanyloxy)ethoxy]-phosphinyl]choline hydroxide internal salt, m.p. 200C.

Example_5 1 g of 3~-stigma~tanyl (2-hydroxyethyl)carbama~e and 0.35 ml of Et3N are dissolved in 5 ml of THF. A solution of 315 mg of 2-chloro-2-oxo-1,3,2-dioxaphoseholane in 3 ml of THF is added dropwise to the solution, which is cooled 30 in an ice bath. The suspen6ion obtained i6 stirred at room temperature for 5 hours. The Et3N~HCl precipitate is then filtered off and the solution remaining behind i6 evaporated.

The phosphate obtained i6 dissolved in 10 ml of THF, the ~olution is treated in a pressure flask with 1 g of ,:
, ..

.
,: .. ~ , :, . : .
.. . . ..
... .

(CH3)3N in 10 ml of THF. The mixture i~ reacted at 70C for 2~ hour~. After di6ti~Llation o~ the exce~6 reagent and of the ~olven~ the residue is taken up in 20 ml of ~eOH-CHC13 and the ~olu~ion i6 percolated through an ion exchangee (Ambe~lite MB3). The ~roduct i~
chromatographed on æilica gel with CHC13-MeOH-H20 (S0/35/5 in vol.). Ther~ i8 obtained 0.6 g of 0-[hydroxy-10 -r2-[l-(5a-~tigmastan-3B-yloxy)formamido]ethoxy]-phosphinyl]choline hydroxide internal sal~, MS: 669 (M~H ).

Example 6 The preparation of the phosphate i8 repeated as de~cribed in Example 5. The material obtained from 2 mmol of ~tarting carbamate i~ di~solved in 5 ml of dry pyridine and reacted at B0C for 24 hour~. The produ~t is i~olated and purified analogously to Example 5. There i8 obtained 0.95 g of 1-[2-~[hydroxy-~2~ 5-s~igma~tan-3~-yloxy)-formamido]ethoxy]pho~phinyl~oxy]ethyl]pyridinium hydroxide internal salt, ~S: 689 (~+H ).

Example 7 Analogou61y to Example 5, a) ~tarting from (E)-~ti~ma~ta-5,22-dien-3~-yl 52-hydroxyethyl)carbamate there i6 obtained 0-rhydroxy-~2--rl-[(E)-~tigmasta-5,22 dien-3~-yloxy]~ormamido]ethoxy~_ pho~phinyl]~ho].ine hydroxide internal 6alt, ~S: 665 (M+H ) b) ~ta~ting ~rom (~)-stigmasta-5,22-dien-3~-yl ~3-hydroxypl~pyl)carbamate there i6 obtained C-~hydroxy--t3- rl-r (E~-8tigma~ta-s~22-dien-3A-yloxy]foLmamido]-propoxy]pho~phinyl~choline hydroxide internal saltJ MS:

'` : . : .

: ;

3 l ~ ~

679 (~H~) c~ ~tar~ing from (E~-stigmasta-~,Z2-dien-3~-yl ~(RS)-3--hydroxy-2-r(methylcarbamoyl~oxy~propyl]-i~opropylcarbamate there i~ obtained 0-rhydroxy-rRS)-3-~N-i~opropyl-l-~(E)--~tigma6ta-5,22-dien-3B-rl]oxyformamido]-2-r(methyl-carbamoyl)oxy]propoxy]phophinylJcholine hydroxide internal 6alt, MS: 794 (M~H ) d) star~ing from 3~-chole~teryl (2-hydroxyethyl)carbamate there i~ obtained 0-[[[Z-rl-chole~t-5-en-3~-yloxy3-formamido]ethoxy]hydLoxypho~phinyl]choline hydroxide internal ~alt, MS: 63g (M~H ) e) starting from epicopro6tanyl (2-hydroxyethyl)carbamate there i~ ob~ained 0-t~2-tl-(5~-chole~an-3-yloxy)-formamido]ethoxy~hydroxyphosphinyl]choline hydroxide internal salt, ~S: ~41 (M+H ~.

Example 8 Analogou~ly to Example S, ~tarting from (E)-stigmas~a--5,22-dien-3~-yl (3-hydroxypropyl)carbamate there i~
obtained 1-~2-~thydroxy- r 3-tl-t(E)-~tigma6ta-5,22-dien-3B--yloxy]formamido]propoxy]phogphinyl]oxy]ethyl]pyridinium hydroxide internal ~alt, ~S: 699 (M+H ).

Example 9 A solution of 2.22 g of (E)-stigma6ta-5,22-dien-3B-yl (2-hydroxyethyl)carbonate and 1.1 ml of pyridine in 10 ml of chloroform i~ added dropwise to a solutio~0 cooled to 0C, of 0.75 g of pho~phoru~ oxychloride in 3 ml of chlorofoem. The mixture i6 reacted at room ~emperature for 1 hour. Then, 1.6 g of choline tosylate in 15 ml of pyridine are added. The mixture is stirred o~ernigh~, then .

~ ~t f S'.~

a ~olution of 2 g of pota~sium bicarbonate i6 added. The mixture i~ evaporated to dryne~s6 and ehe re~idue i6 taken up in 100 ml of THF/methanol/chloro~orm (1/1/1). The solids are filtered oEf. The ~olution remaining behind i8 percolated over an ion exchang,er ~Ambe~lite MB 3). After chromatography on silica gel with chloroform/methanol/
water ~60/35/5 vol) and cry~tallization from methylene chloride/acetone there are obtained 1.6 g of 0- rhydroxy--[2-~[~(E)-~tigma~ta-5,22-dien-3B-yloxy]carbonyl]oxy]-ethoxy~phosphinyl]choline hydroxide internal ~alt, MS: 666 (M~H ).

Example 10 4.75 g of 3~-chol~stelyl (2-hydroxyethyl)carbamate are reacted with 2-chloro-2-oxo-1,3,2-dioxaphospholane. The phosphate obtained i6 treated wi~h N-methylpyrrolidine at 70C for 24 hour~. After chromatography on ~ilica gel with ~hlorofoLm/me~hanol/water t30/62.5f7.5 vol.) there are obtained 1.2 g of 1-r2-~tr2-~l-rcholest-5-en-3~-yloxy]-formamido]ethoxy]hydroxypho~phinyl]oxy~ethyl]-l-methyl-pyrrolidinium hydroxide internal ~alt, MS: 665 ~M+H ).

ExamPle 11 a) 1.41 g of trityl chloride are added to a 601ution of 2.49 ~ of 0-3a,~-~itigmaRtanyl-(RS)-glycerol in 10 ml of pyridine. After reaction for 48 hours a potafi~ium bicarbona~e ~olution is added while stirring. The mixture i8 evaporated to drynes~. The residue i~ partitioned between ~ethylenie chloride and water. After chLomato~raphy on ~ilica gel with methylene chloride there i6 obtairLed l-0-trityl-3-0-(3a,B-~tigmastanyl)-~RS)-glycerol.

b) Z.4 g of the above trityl ether in 10 ml of THF and then 0.46 ml of benzyl chloride in 5 ml of DMF are added :

rJ

dropwi6e to a 6u~pen~ion of 96 ~g of ~odium hydride in 5 ml of THF. After reaction at 80C for 2 hours, distil-lation of the solvent and partition of the residue between methylene chloride and water ~he~e is obtained l-0-trityl--2-0-benzyl-3-0-~3a,~-stigma6tanyl)-(RS)-glycerol.

c) 2 ml of lN hydrochloric acid are added to a 601ution, heated to 95~C, of 2.4 g of the above benzyl ethe~ in 20 ml of dioxan. After reaction a~ 95~C for Z hourfi the solvent is distilled off, the residue i~ taken up in hexane and the precipitated triehenylme~hanol i&
~eparated. Afte~ ch~omatog~aphy on ~ilica ~el with toluene/ethyl acetate (9/1) there are obtained 1.5 g of 1-0-(3a,B-6~ig~astanyl)-Z-0-benzyl-(RS)-glycerol.

d) Analogously to Example 5, from 1.4 g of the above glycerol de~ivative fir6tly by reaction with 2-chloro-2--oxo-1,3,2-diox2pho pholane and then reaction of the re~ulting phosphate with trimeehylamine there is obtained :~
0.8 g of 1-0-(3,~-stigmastanyl)-2-0-benzyl-3-0-(RS)--glyceryl-pho6phorylcholine, MS: 7~6 (M~H ).

e) A solution of 0.77 g of the above benzyl ether in 10 ml of methanol and 5 ml of THF i~ hydro~enated under normal pressure in the presence of 10% Pd/C. There is obtained in quantitative yield 1-0-(3a,B-stigmastanyl)--3-0-(RS)-glyceryl-phosphorylcholine, MS: ~56 (M+H ).

Exam~le 12 50 mg of DM~P and 0.5 ~1 of acetic anhydride are added to a solution of 0.5 g of the glycecol derivative of Example 11 in 3 ~1 of chloroform and 1 ml of ~yridine.
AfteL reaction for 1 hour the mixture is concentrated to dryness. The ~olution of the residue in Z0 ml of methanol i6 percolated over ion ~xchanger ~Ambellite ~B-3). There -, ,. - ; ~ . ~

- ~ ' : , :: ::

, ~, ~$3~

is obtained 0.51 g of O-~r(RS)-2-acetoxy-3-[5a--~tigmastan-3a,~-yloxy]propoxy]hydroxypho~phonyl]choline hydroxide internal salt, MS: 698 (~H ).

Examp]e 13 a) 1.15 ml of phosphoru~ oxychloride are treated under argon and while stirring with 6.1 g of (RS)-2-(benzyloxy)--3-hydroxypropylchole~t-5-en-3~-yl carbonate and 1.5 ml of quinoline in 80 ~1 of methylene chloride. There ace added thereto after 4 hours 7.4 g of choline to~ylate and 6 ml of py~idine and after 24 hours 15 ml of water and 4 g of NaHCO3. Afte~ 30 minutes the mixture i~ poured into 500 ml of water and 50 ml of lN HCl and extracted wi~h chlorofo~m. The organic pha~e is concentrated. The product i~ dis~olved in 150 ~1 of MeOH-CHC13 (2:1) and tceated with 100 g of ion exchanger (A~be~lit MB3). Af~er stirring for 16 hou~ the ion exchanger iB filtered off under ~uction. The solution obtained is concentrated at 60C, distilled with toluene and d~ied. The residue i6 purified over ~ilica gel with CHC13-MeOH (1:1) and CHC13-MeOH-H2O
(60:35-5). After drying there are obtained ~.9 g of O-r[(RS)-2-benzyloxy-3-[(cholest-5-en-3B-yloxy~carbonyl_ oxy]propoxy]hydroxypho~phinyl]choline hydroxide internal ~al~, yield: 63~. MS: 760 (M~H ).

b) 4.65 g of the product of a) and 1.~ g of PdO in 200 ml of CH3COOH are stiLr~d under H2 undec normal pre~sure for 20 minute6. After f;ltLation of the cataly~t the solution i~ concentrated at 60C. The residue i6 washed in 200 ml of ether, filtered and dried. The re~idue is dissolved i~ 40 ml of CHC13-MeOH (1:1) and treated with 25 ml of dio~can and 200 ml of ether. The separated cly~tal~ a~e filtered off under ~uction, washed wi~h ether and dried at 50C. There are obtained 3.25 g o~ o-r ~ (RS)--3-t(chole~t-5-en-3~-yloxy~arbonyloxy]-2-hyd~oxyproeoxy]-.
.

2~7~ ~3 hydroxyphosphinyl]choli~e hydroxide internal salt (strongly hygroscopic), yield: 793, MS: 670 (M~H ~.

xamP:Le 14 Analogou~ly to Example 13 there can be manufactured:

a) 0-~Hydroxy-~RS)-2-hydroxy-3-~r5-~tigmastan-3~--yloxy)carbunyloxy]p~opoxy]pho phinyl]choline hydroxide internal ~alt ~epimer6 1~ S: 700 (N~H ) b~ 0-rhydroxy-[(RS~-2-hydroxy-3-[t(E)-stigma~ta-5,22- -15 -dien-3~-yloxy]carbon~loxy]plopoxy~pho~phinrl]choline ~, hydroxide internal salt (epimel~ 1:1), MS: 696 (~H )0 xam~e~l5 a~ A Bolution of 1 g of chole~t-5-en-3~yl (S)-2-hydroxy-propionate and 0.37 ~1 of triethylamine i~-5 ml of methylene chloride i~ added dro~wise to a solution of 1 g of ~-bromoethyl-phosphoric acid d7chloride in 10 ml of methylene chloride. ~he mixture i~ stirred firstly at room temperature for 4 hours. then under ~eflux for 1 hour.
Aftel adding 5 ml of water the mi~tule i~ boiled at reflux for 2 hours. The mixture is diluted with methylene chloride, the aqueous phase is ~eparated, the organic phase i~ wahed with water, d ied over odium sulphate and concen~rated. The ~e~idue i~ dis~olved in ether and treated with a ~olution of 5 g o~ barium a~etate in 20 ml of water. The ~ixture iB ~tir~ed at ~oom ~emperature for 20 hour~, the re~ulting barium ~alt i~ fil~ered off and i~
treated with a mixSure of Z0 ml o~ 3N hydro~hloric acid and 20 ml of methylene chloride. The mixture i~ stirred at room temperature for 1 hour, the organic phaQe i~
~eparated, dried over ~odium sulphate and ~o~centrated.
There is obtained 0.7 g of chole~-5-en-3~-yl ~S)-2-~[(2-" ~ ~

:, ~

-~ 7 -bromoe~hoxy)hydroxyphosphinyl]oxy]propionate, MS: 643 (M-H) .

b) A ~olution of 0.7 g of cholest-5-en-3~-yl SS)-2-t~(2--bromoethoxy)hydroxyphosphinyl]oxy]propionate in 15 ml of toluene i6 treated with 15 ml o~ trimethylamine in a dry-ice bath. The mixture i8 heated to 60C ~or 30 hour6.
After cooling the reac~ion ~ix~ure i~ taken up in toluene and concentrated. The residue i~ taken up in 30 ml of me~hanol, treated with 2 g o~ silver carbonate and stirred at 50C for 0.5 hour. ~he precipita~e is filter~d off, concentrated and there i~ obtained 0.6 g o~ 0-~[(S)-l--~(choles~-5-en-3~-yloxy)carbonyl]ethb~y]hydroxy-phosphinyl]choline hydroxide internal sal~, MS: 624 (M+H ).

E~ample 16 Analogously to Example 1, starting from 6tigmast-5--en-3~-yl 2-hydroxyethylcarbonate there i8 obtained 0--~hydroxy-t2~[(~tigmast-5-en-3B-yloxy~carbonyl]oxy]ethoxy]-pho~phinyl]choline hydroxide internal ~alt, m.p. 207C
~decompo6ition~.
Example 17 Analogously to Example 2k) and Example 2q), there are Obtained a3 0-rhydroxy-t3-t~stigmast-5-en-3~-yloxy)carbonyl]-propoxy]phozphinyl]choline h~droxide internal salt, m.p.
220C (decompo6ition), and, respectively, b) 0-~hydroxy-[2-(6tigmast-5-en-3~-yloxy)ethoxy]phofi-phinyl]choline hydroxide internal salt, m.p~ 197C
~decomposition).

.
. :

:

7J~Jf37~

- 3~ -~3~ ]e 18 Analogously to Example 5, but using dimethylamine in place of triethylamine, there i6 obtained cholest-5-en-3~--yl 2-[~2-(dimethylamino)ethoxy]hydrsxyphosphinyl]oxy]-ethylcarbonate, m.p. 150C (decomposition).

Example 19 Analogou~ly to Example 5, there i6 obtained O-thYdLoxy-[2-rl-~stig~ast-5-en-3~-yloxy)formamido]-ethoxy]pho phinyl]choline hydroxide internal 6alt, m.p.
lS 225C (de~omposition).

Exam~le 20 A~alogously to Example 12, there is obtained O-[t~RS~--2-acetoxy-3-[t(cholest-5-en-3~-yloxy)carbonyl~oxy]propoxy]-hydroxyphosphinyl3choline hydLoxide interna-l ~alt.
130C [decompo6ition).

Example 21 a~ A solution of 11.6 g of chole~terol and 3.5 g of hydroxypivalic acid i~ R0 ml of toluene i8 ~reated with 1 g of p-toluenesulphonic acid and boiled for 4 hour~. The reaction mixture is treated with water and extracted with ether. The organic pha6e is dried and concentrated and the re6idue i6 purified ove~ 6ilica gel ~ith petroleum ether/
ether $4:1). There are obtained 1.9 g of chole6t 5-en-3~--yl 3-hydroxy-2,2-dimethyl-propionate. ~.p. 174-176C.

b) To a ~olution of 1.9 ~ of the produ~t of a) in 60 ml of methylene chloride are added dropwise fir~tly 1.1 ml of triethylamine and then a 601ution of 1.42 g of ~-bromo-ethyl-pho~phoric acid di~hloride in 30 ml of methylene .

, ..
.:

3 ~ j ~

chloride. The mixture i6 boiled under reflux for 18 hour~, and, after the addition sf watler, boiled under reflux for 1 hour. The aqueou~ phase i~ ~eparated and the organic phase is wa~hea wi~h water, dried and concent~ated. The residue i8 di~olved in ether and trea~ed with a ~olution of 15 g of barium acetate in 30 ml of water. The mixture is ~tirred for 20 hours, the resul~ing barium ~alt i~
filtered off and treated wi~h a mixture of ~0 ml of ~N
hydrochlo~ic acid and 50 ml of me~hylene chloride. The mixture i8 ~irred at ~oom temperature for 1 hour and the organic phase i8 separa~ed, dried and concent~ated. There are obtained 1.6 g of chole~t-S-en-3~-yl 3-t[(2-bromo-ethoxy)hydLoxy-phosphinyl]oxy]-2,2~dime~hylpropionate, m.p. 98C.

c) A ~olution of 1.6 g of the product of b) in 15 ~1 of ~oluene is trea~ed with 15 ml of trimethylamine while cooling i~ a dry-ice bath. The mixture i6 heated to 60C
for 2 day~. After cooling in a dry-ice bath the reaction mixture i6 taken up in toluene and concentrated. The residue is taken up in methanol, treated with 3 g of silver carbonate and stirred at 50C for 0.5 hour. The precipitate i8 filtered off and the filtrate i~ con-centlated. By recry~allization of the refiidue from ethee there is obtained 0.8 g (5Z~) of 0-rtZ-~chole6t~5-en-3B--yloxy~carbonyl]-2-methylp~opoxy~hydro~yphosphinyl~choline hydroxide inte~nal ~alt, m.p. 210C.

Example 2?

a) A ~olution of 5.00 g of cholesteryl chloroformate i~
20 ml of methylene Ghloride i8 added d~opwi~e to a mixture of 1.4 g of DL-~erinol~HCl and 3.1 ml of triethylamine in 30 ml o~ methylene choride. After 6tirring for 45 hour~
the mixture is taken up in ayueous methanol and extrac~ed with chloroform. The organic phase i6 dried and con-, ,:

- ~J~2~37 centrated. ~fte~ chromatography over SiO2 with chloro-form and then with ether ~here are obtained 4.3 g of cholest-5-en-3B-yl [2-hydroxy-:L-(hydroxymethyl)ethyl]car-bamate. m.p. 158C ~decomposition~.

b) A solution of 3.7 g of the product of a) in 30 ml of methylene chloride, 10 ml of ~HF and Ou6 ml of pyridine i8 treated under argon with 1 ml of phenyl chlo~oformate in 15 ml of methylene chloride. A~ter stirring for 1 hour the solution is taken up in 200 ml of water and 50 ml of O.lN
HCl and extracted with lSO ml of methylene chloride. The organi~ pha~e i~ dried and concentrated. After chroma-tography over SiOz with n-hexane/ether (1:1) and ether there are obtained 2.1 g of chole~t-S-en-3B-yl [(RS)-2--hydroxy-l-~(phenoxycarbonyl)oxymethyl]ethyl~carbamate.

c) 0.05 ml of 2-chloco-2-oxo-1,3,Z-dioxapho~pholane is added to ~ mixture of 320 mg of the product of b) in 20 ml of toluene and 0008 ml of ~riethylamine under argon while ~tirring at room temperaeure. The (Et)3N:HCl is filtered off under 6uc~ion afte~ 16 hour~O The solution obtained i~
concentrated and the residue i6 di~olved in a solution of 2 g of ~rimethyla~ine in 20 ml of toluene and 5 ml o~
acetonitrile and held at 80C. Ths ~olution is concen-trated after 6 hours. The product, O-[r(RS)-2-rl--(cholest-5-en-~-yloxy)focmamido~-3-(phenoxycarbonyloxy)-propoxy]hydroxyphosphinyl]choline hydroxide internal ~alt, is u6ed in the next step without purification.

d) The product of c) i~ dissolved in 20 ml of methanol--chloroform ~1:1) and t~eated with 2 ml of lN NaOH at room temperature ~while ~Sirring. AfteL adding 10 g o~ ion exchanyer (Ambellite MB-3) and tirring for 4 hours the ~olution i8 concentrated, azeotropically distilled with toluene and then dried. The re~idue is chro~atoqraphed on ~ilica gel with CHC13-MeOH-H20 (60/35/5 by vol.).

.. : : ....................... . . . :

.

Aftel drying there are obtained 200 mg Of O-t~RS)-2-[1--(cholest-S-en-3~-yloxy)formamido]-3-hydroxypropoxy]-hydroxyphosphinyl]choline hydLoxide internal salt, m.p.
220C (decomposition).

Tablets and capsule~ of the following composition are manufactuced in a mann2l known pe~ se:

ExamPle a Tablets 1 tablet contains 15 Compound of formula I200 mg Mic~ocrystalline cellulose 155 my Maize starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 m~
425 mg -Example b Capsules 1 capsule contains Compound of formula I100.0 mg Maize starch 20.0 mg '`
Lactose 95.0 mg Talc 4.5 mg 30 Magnesium steara~e 0.5 m~
200.0 mg ..
. ~ ' ' :
. : .. : .
, , ' : ' ' : ' :
,: :
. :
,............................................ . : ..

Claims (17)

1. Steroids of the formula wherein R1 is hydrogen, lower-alkyl or lower-alkylidene, R2, R3 and R4 are hydrogen or lower-alkyl or together with the N atom form a 5- or 6-membered aromatic or saturated heterocyclic residue which may be lower alkylated, n is the number 2, 3 or 4, X is a group of the formula -(CH2)p-C(Q,Q')-(Z)1 or 0-, -CH2CH(Y)CH2-(Z)1 or 0--CH2CH(CH2Y)-(Z)1 or 2.
-(CH2CH2O)q-CH2CH2-(Z)1or 0-q is the number 1 or 2, Z is a group of the formula -C(O)-, -OC(O)-, -OC(O)CH2-, -OCH2C(O)- or -N(T)C(O)-.
Q, Q' and T are hydrogen or lower-alkyl.
p is a whole number between 1 and 9 and, where Z is carbonyl, can also be O, Y is hydroxy, lower-alkoxy, lower-alkanoyloxy, carbamoyloxy or mono- or di-lower alkyl-carbamoyl-oxy, the dotted C-C bonds in the 5(6)-, 7(8)-, 22(23)-, 24(25)- and 24(28)-position are optional, whereby the side-chain is either saturated or mono--unsaturated.
and physiologically compatible salts thereof.

2. Steroids according to claim 1, wherein R1 is hydrogen or lower-alkyl, especially ethyl.

3. Steroids according to claim 1 or 2, wherein R2 is hydrogen or lower-alkyl and R3 and R4 are lower-alkyl.

4. Steroids according to claim 1 or 2, wherein R2, R3 and R4 are methyl.

5. Steroids according to claim 1 or 2, wherein R2, R3 and R4 together with the N atom form a pyridinium or l-methylpyrrolidinium group.

6. Steroids according to any one of claims 1-5, wherein n is the number 2.

7. Steroids according to any one of claims 1-6 having a 5(6)-unsaturated or 5(6)-and 22(23)-unsaturated steroid part.

8. Steroids according to any one of claims 1-7, wherein X represents the group (CH2)2-, -(CH2)2O)CH2)2-, -(CH2)2O(CH2)(2O2)2-, -CH2CHOHCH2-. -CH2CH(OCOCH3)CH2-.
-CH2CH(OCONHCH3)CH2N[CH(CH3)2]CO-, -(CH2)2NHCO-, -(CH2)3NHCO-, -CH2CHOHCH2OCO-, -(CH(CH3)CO- or esecially -(CH2)2OCO-.
(CH2)3OCO-, -(CH2)4OCO-, -(CH2)8OCO-, -(CH2)CO-, -(CH2)2CO-. -(CH2)3CO-, -(CH2)5CO-,-CH2-CH(OCOCH3)CH2OCO-, -CH2C(CH3)2CO- or -CH2CH(CH2OH)NHCO-,

9. A compound according to claim 1 from the following group O-[[Z-[[(Cholest-5en-3.beta.-yloxy)carbonyl]oxy]ethoxy]-.
hydroxyphosphinyl]choline hydroxide internal salt, O-[hydroxy-[3-[(3.beta.-stigmastanyloxy)carbonyl]propoxy]-phosphinyl]choline hydroxide internal salt, O-[[2-(cholest-5-en-3.beta.-yloxy)ethoxy]hydroxyphosphinyl]-choline hydroxide internal salt and O-[hydroxy-[2-[l-(5a-stigmastan-3.beta.-yloxy)formamido]-ethoxy]phosphinyl]choline hydroxide internal salt.

10. A compound according to claim 1 from the following group O-[[2-[[(5.alpha.-Stigmastan-3.beta.-yloxy)carbonyl]oxy]ethoxy]-hydroxyphosphinyl]choline hydroxide internal salt, O-[hydroxy-[2-[[[E]-stigmasta-5,22-dien-3.beta.--yloxy]carbonyl]ethoxy]phosphinyl]choline hydroxide internal salt, O-[(3[[(cholest-5-en-3.beta.-yloxy)carbonyl]oxy]propoxy]-hydroxyphospiphinyl]choline hydroxide internal salt, O-[[4-[[(cholest-5-en-3.beta.-yloxy)carbonyl]oxy]butoxy]-hydroxyphosphinyl]choline hydroxide internal salt.

O-[[[8-[[(cholest-5-en-3.beta.-yloxy)carbonyl]oxy]octyl-oxy]hydroxyphosphinyl]choline hydroxide internal salt, O-[[[(cholest-5-en-3.beta.-yloxy)carbonyl]methoxy]hydtoxy-phosphinyl]choline hydroxide internal salt, O-[[2-[(cholest-5-en-3.beta.-yloxy)carbonyl]ethoxy]hydroxy-phosphinyl]choline hydroxide internal salt, O-[hydroxy-[2-[(3.beta.-stigmastanyloxy)carbonyl]ethoxy]
phosphinyl]choline hydroxide internal salt, O-[hydroxy-[2-[(stigmasta-5.22-dien-3.beta.-yloxy)carbonyl]
ethoxy]phosphinyl]choline hydroxide internal salt, O-[[3-[(cholest-5-en-3.beta.-yloxy)carbonyl]propoxy]hydroxy-phosphinyl]choline hydroxide internal salt, O-{hydroxy-[3-[(E)-stigmasta-5.22-dien-3.beta.-yloxy)-carbonyl]propoxy]phosphinyl]choline hydroxide internal salt, O-[hydroxy-[[5-[(5.alpha.-stigmastan-3.beta.-yloxy)carbonyl]-pentyl]oxy]phosphinyl]choline hydroxide internal salt, O-[hydroxy-[[5-[((E)-stigmasta-5,22-dien-3.beta.-yloxy)car-bonyl]pentyl]oxy]phosphinyl]choline hydroxide internal salt, O-[hydroxy-[[[(E)(3B-stigmastanyl)oxy]carbonyl]methoxy]-phosphinyl]choline hydroxide internal salt.

O-[hydroxy-[[[(E)-stigmasta-5,22-dien-3.beta.-yloxy]-carbonyl]methoxy]phosphinyl]choline hydroxide internal salt, O-[hydroxy-[2-(stigmasta-5.22-dien-3.beta.-yloxy)ethoxy]-phosphinyl]choline hydroxide internal salt, O-[[2-[2-(cholest-5-en-3.beta.-yloxy)ethoxy]ethoxy]hydroxy-phosphinyl]choline hydroxide internal salt, O-[hydroxy-[2-[2-[(E)-stigmasta-5,22-dien-3.beta.--yloxy]ethoxy)ethoxy]phosphinyl]choline hydroxide internal salt, O-[[2-[2-[2-(cholest-5-en-3.beta.-yloxy)ethoxy]ethoxy]-ethoxy]hydroxyphosphinyl]choline hydroxide internal salt, O-[[2-[(5.alpha.-cholestan-3.beta.-yloxy)carbonyloxy]ethoxy]-hydroxyphosphinyl]choline hydroxide internal salt.

O-[hydroxy-[2-[2-(3.beta.-stigmastanyloxy)ethoxy]ethoxy]-phosphinyl]choline hydroxide internal salt, O-[hydroxy-[2-(3.beta.-stigmastanyloxy)ethoxy]phosphinyl]-choline hydroxide internal salt, 1-[2-[hydroxy-[2-[1-(5.alpha.-stigmastan-3.beta.-yloxy)-formamido]ethoxy]phosphinyl]oxy]ethyl]pyridiniumhydroxide internal salt, O-[hydroxy-[2-[1-[(E)-stigmasta-5.22-dien-3.beta.--yloxy]formamido]ethoxy]phosphinyl]choline hydroxide internal salt, O-[hydroxy-[3-[1-[(E]-stigmasta-5.22-dien-3.beta.--yloxy[formamido]propoxy]phosphinyl]choline hydroxide internal salt.

O- [hydroxy-[(RS)-3-[N-isopropyl-1-[(E)-stigmasta-5.22--dien-3.beta.-yl]oxyformamido]-2-[(methylcarbamoyl)oxy]propoxy]-phosphinyl]choline hydroxide internal salt, O-[[[2-[l-cholest-5-en-3.beta.-yloxy]formamido]ethoxy]-hydroxyphosphinyl]choline hydroxide internal salt, O-[[2-[1-(5.beta.-cholestan-3.alpha.-yloxy)formamido]ethoxy]-hydroxyphosphinyl]choline hydroxide internal salt.

1-[2-[[hydroxy-[3-[1-[(E)-stigmasta-5.22-dien;3.beta.--yloxy]formamido]propoxy]phosphinyl]oxy]ethyl]pyridinium hydroxide internal salt.

O-[hydroxy-[2-[[[(E)-stigmasta-5.22-dien-3.beta.-yloxy]-carbonyl]oxy]ethoxy]phosphinyl]choline hydroxide internal salt, l-[2-[[[2-[1-[cholest-5-en-3.beta.-yloxy]formamido]ethoxy]-hydroxyphodphinyl]oxy]ethyl]-l-methylpyrrolidinium hydroxide internal salt, 1-0-(3.alpha.,.beta.-stigmastanyl)-3-O-(RS)-glyceryl-phosphoryl-choline, O-[[(RS)-2-acetoxy-3-[5.alpha.-stigmastan-3.alpha.,.beta.-yloxy]-propoxy]hydroxyphosphonyl]choline hydroxide internal salt, O-[[(RS)-3-[(cholest-5-en-3.beta.-yloxy)carbonyloxy]-2 -hydroxypropoxy]hydeoxyphosphinyl]choline hydroxide internal salt.

O-[hydroxy-(RS)-2-hydroxy-3-[[5.alpha.-stigmasta-3.beta.-yloxy)carbonyloxy]propoxy]phosphinyl]choline hydroxide internal salt O-[hydroxy-[(Rs)-2-hydroxy-3-[[(E)-stigmasta 5,22--dien-3.beta.-yloxy]carbonyloxy]propoxy]phosphinyl]choline hydroxide internal salt, O-{hydroxy-[2-[[(stigmast-5 en-3.beta.-yloxy)carbonyl]oxy]-ethoxy]phosphinyl]choline hydroxide internal salt, O-[hydroxy-[3-[(stigmast-5-en-3.beta.-yloxy)carbonyl]pro-poxy]-phosphinyl]choline hydroxide internal salt.

O-[hydroxy-[2-(stigmast-5 en-3.beta.-yloxy)ethoxy]phos-phinyl]choline hydroxide internal salt, cholest-5-en-3.beta.-yl 2[[[2-(dimethylamino)ethoxy]-hydroxyphosphinyl]oxy]ethylcarbonate, O-[hydroxy-[2-[1-(stigmast-5-en-3.beta.-yloxy)formamido]
ethoxy]phosphinyl]choline hydroxide internal salt.

O-[[(RS)-2-acetoxy-3-[[(cholest-5-en-3.beta.-yloxy)-carbonyl]oxy]propoxy]hydroxyphosphinyl]choline hydroxide internal salt, O-[[2-[cholest-5-en-3.beta.-yloxy)carbonyl]-2-methylpro-poxy]hydroxyphosphinyl]-choline hydroxide internal salt and O-[[(RS)-2-[1-(cholest-5-en-3.beta.-yloxy)formamido]-3 hydroxypropoxy]hydroxyphosphinyl]choline hydroxide internal salt.

11. Alcohols of the formula II

wherein X' is a group of the formula -(CH2)p-C(Q.Q')-Z'-, -CH CH(Y)CH2-Z'-, -CH2CH(CH2Y)-Z'- or -(CH2CH2O)q-CH2CH2-Z'-, Z' is a group of the formula -OC(O)-, -OC(O)CH2-, -OCH2C(O)- or -N(T)C(O)-and R1, Q, Q', p, q. Y and T have the significance given above.

12. Compounds according to claim 1 for use as pharmaceutically active substances.

13. A process for the manufacture of the compounds according to claim 1. which process comprises a) treating an alcohol of the formula II

with intermediary protection of a hydroxy residue Y
present in the group X, with an agent which introduces the group of the formula (G).
and b) if desired, hydrogenating an unsaturated steroid of formula I to the saturated steroid, c) if desired, functionally modifying a reactive residue present in the group X of a steroid of formula I, d) if desired. converting a steroid of formula I into a salt.

14. Pharmaceutical preparations based on a compound according to claim 1.

15. The use of a compound according to claim 1 in the manufacture of medicaments which inhibit the intestinal resorption of cholesterol and which lower plasma cholesterol.

16. Compounds according to claim 1, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

17. Compounds, preparations, uses and processes as hereinbefore described, particularly with reference to the Examples.