MC2164A1 - STEROIDS - Google Patents

Description

STEROIDS

The present invention relates to new steroids of formula

"R

?

-N'

C m

~i A ■

- l r C

\

Or

R1 represents a hydrogen, lower alkyl or lower alkylidene,

2 3 4 /

R, R and R represent a hydrogen or a lower alkyl group or together form with the atom

2

nitrogen atoms, a heterocyclic aromatic or saturated ring with 5 or 6 members, to which a lower alkyl group may be attached,

n represents the number 2, 3, or 4,

5X represents a formula group

~(CH2)p-c(Q'Q')-(z)x or 0",

-CH2CH(Y)CH2-(Z)1 or 0",

-CH2CH(CH2Y)-(Z)1 or 0~ or -(CH2CH2O)g-CH2CH2-(Z)1 or 0~, 10 q represents the number 1 or 2,

Z represents a group of formula -C(0)-,

-0C(0)-, -0C(0)CH2-, -0CH2C(0)- or -N(T)C(0)-,

Q, Q' and T represent a lower hydrogen or 15-alkyl group,

p represents an integer between

1 and 9, and, if Z is a carbonyl, can also represent 0,

Y represents a hydroxy, lower alkoxy,

20 lower alkanoyloxy, carbamoyloxy or lower mono- or di-alcoyl-carbamoyloxy, the dotted C-C- bonds in positions 5(6)-, 7(8)-, 22(23)-, 24(25)- and 24(28)- are optional, the side chain 25 being either saturated or monounsaturated,

and their physiologically acceptable salts.

The hydrogen atoms bonded to the C atoms in positions 3 and 5 of the steroid fraction of compounds of formula I can independently of each other have the configuration a or 6.

3

The invention further relates to a method for preparing these steroids, drugs based on these steroids and these steroids as pharmaceutical active substances, as well as the application of these steroids to the preparation of drugs inhibiting intestinal cholesterol absorption and lowering plasma cholesterol.

The term "lower" means that the 10 radicals thus designated contain up to four carbon atoms and can be straight-chain or branched-chain. Examples of lower alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl. Examples of lower alkylidene radicals include methylene and ethylidene. Examples of lower alkanoyloxy radicals include acetoxy and propionyloxy.

Pharmaceutically acceptable salts of formula I steroids are inorganic salts,

such as hydrochlorides and sulfates; organic salts, such as trifluoroacetate, mesylate, and tosylate; and metallic salts, such as sodium salt. Compounds of formula I can exist as a hermaphroditic ion, and those of formula 2, 3, and 4

25 or at least one of the radicals R, R and R is a hydrogen can appear in the form of an acidic phosphate.

Among steroids of formula I, those where R"*" represents a hydrogen or an alkyl group are preferred.

30 lower, in particular an ethyl, or even

2

those where R is a hydrogen or a lower alkyl group,

.V,

4

and R and R represent a lower alkyl, in

2 3 4

in particular a methyl group, or where R, R and R together with the nitrogen atom form a pyridinium or 1-methylpyrrolidinium group. 5 Steroids of the formula

I where n is the number 2, as well as those which have a saturated or unsaturated steroid fraction in 5(6)— or 5(6) and 22(23).

Other preferred steroids of formula 10 I include those where X represents the group

-(ch2)2-, -(ch2)20(ch2)2-, -(ch2)20(ch2)20(ch2)2-, -ch2chohch2-,

-ch2ch(ococh3)ch2~, -ch2ch(oconhch3)ch2n[ch(ch3)2]co-, -(ch2)2nhco-, -(ch2)3nhco-, -ch2chohch2oco-, 15 -ch(ch3)co- or in particular -(ch2)2oco-, -(ch2)3oco-,

-(ch2)4oco-, -(ch2)8oco-, -(ch2)co-, -(ch2)2co-,

-(ch2)3co-, -(ch2)5co-, -ch2ch(ococh3)ch2oco-, -ch2c(ch3)2co- or -ch2ch(ch2oh)nhco-.

Examples of preferred compounds with the formula I 20 include the following:

Internal hydroxide salt of O-[[2-[[(cholest-5-ene-3 3-yloxy)carbonyljoxyj ethoxyli-hydroxyphosphinyl]-choline,

internal hydroxide salt of O-[hydroxy-[3-25 L(3 g-stigmastanyloxy)carbonyl]propoxy]phosphiny11-choline,

internal hydroxide salt of O-[ [.2-(cholest-5-ene-36-yloxy)ethoxy] hydroxyphosphinyl]-choline and

30 internal hydroxide salt of O-[hydroxy- [2-

11-(5a-stigmastan-3 B-yloxy)formamidoj-ethoxy]phosphiny1]choline.

Other examples of compounds with formula I include the following:

Internal hydroxide salt of O- [ [2-I I(5ot- stigmastan-3 3-yloxy)carbonyl]oxy]ethoxy]-hydroxyphosphinyl]choline,

Internal hydroxide salt of O-[hydroxy-[2-f l fE)-stigmasta-5,22-diene-3B-yloxy]carbonyl]-ethoxy]phosphiny1]choline,

internal hydroxide salt of O- [ [3-£.£(cholest-5-ene-3B-yloxy)carbonyl]oxy] propoxy]-hydroxyphosphinyl]-choline,

internal hydroxide salt of O-[ [4-1 f. (cholest-5-ene-3 B-yloxy)carbonyl]oxy]butoxy]-hydroxyphosphinyl] choline,

internal hydroxide salt of 0-1I[8-LC(cholest-5-ene-3 B-yloxy) carbonyl] oxy] octyl] oxyj -hydroxyphosphinyl]choline,

internal hydroxide salt of O-Lf [(cholest-5-ene-3 B-yloxy)carbonyl]methoxy]hydroxyphosphinyl]-choline,

internal hydroxide salt of O-J[2-[(cholest-5-ene-3B-yloxy)carbonyl]ethoxy]hydroxyphosphinyl]-choline,

internal hydroxide salt of O-[hydroxy-l2-l (3 B-stigmastanyloxy)carbonyl]ethoxy]-phosphiny-l1]-choline,

internal hydroxide salt of O-[hydroxy-[2-f(stigmasta-5,22-diene-33~yloxy)carbonyl]-ethoxy]-phosphiny1] choline,

internal hydroxide salt of O-f[3-l(cholest-5-ene-3 B-yloxy) carbonyl] propoxy] hydroxy-phosphinyl'J -choline,

internal hydroxide salt of O-[hydroxy-[3-l(E)-stigmasta-5,22-diene-33-yloxy)-carbonyl]propoxy]-phosphinyl]choline,

internal hydroxide salt of 0-[hydroxy-f[5-L (5a-stigmastan-3 3-yloxy)carbonyl]penty 1]oxy]phosphinyl]-choline,

internal hydroxide salt of 0-[hydroxy-1 f.5 — [ C(E)-stigmasta-5, 22-diene-33-yloxy )carbonyl] -pentyl1|oxy]phosphinyl]choline,

internal hydroxide salt of O-[hydroxy[L(33-stigmastanyl)oxy]carbonyl]methoxy]phosphinyl]choline,

internal hydroxide salt of 0-[hydroxy-1[[(E)-stigmasta-5,22-diene-3 3-yloxy] carbony1]methoxy]phosphinyl] choline,

internal hydroxide salt of O-[hydroxy-[2-(stigmasta-5,22-diene-3 3-yloxy)ethoxy1-phosphinyl]-choline,

internal hydroxide salt of O-[[2-[2-(cholest-5-ene-3^2-yloxy) ethoxy]-hydroxy-phosphinyl choline,

internal hydroxide salt of 0-[hydroxy-[2-[2-[(E)-stigmasta-5,22-diene-3 3-yloxy]ethoxy]ethoxy-phosphinyl] choline,

internal hydroxide salt of 0—L[2—[2—12 — (cholest-5-ene-33-yloxy)ethoxy]ethoxy]ethoxy]ethoxy]-hydroxyphosphinyl]choline,

internal hydroxide salt of O-I [2-L(5α-cholestan-3 3-yloxy ) carbonyloxy] ethoxy] hydroxyphosphinyl"] choline,

internal hydroxide salt of O-[hydroxy-j2-[2-(3 B-stigmastanyloxy)ethoxyj ethoxy]phosphinyl]-choline,

internal hydroxide salt of O-[hydroxy-[2-(33-stigmastanyloxy)ethoxylphosphinyl]choline,

internal hydroxide salt of 1-[2-[hydroxy-[2- [1-(5a-stigmastan-3 3-yloxy)-formamidolethoxy]-phosphinyl]oxyethyl]pyridinium,

internal hydroxide salt of 0-[hydroxy-12-[1- [(E)-stigmasta-5,22-diene-3 3-yloxy]formamido]-ethoxy "[phosphinyl]choline,

internal hydroxide salt of O-[hydroxy-[3-II-[(E)-stigmasta-5,22-diene-3 3-yloxy]formamido-propoxy]phosphinyl]choline,

internal hydroxide salt of O-[hydroxy-I(RS)-3-fN-isopropyl-l-[(E)-stigmasta-5,22-diene-3 3-yl]oxyformamido]-2-] (methylcarbamoyl)oxy]propoxy-phosphinyl]choline,

internal hydroxide salt of O-[[[2-tl-cholesterol 5-ene-3 3-yloxy) formamido] ethoxy! hydroxyphosphinyl]-choline,

internal hydroxide salt of O-II2-[1-(5 3-cholestan-3a-yloxy)formamido] ethoxy! hydroxyphosphinyl] choline,

internal hydroxide salt of 1-[2-1Lhydroxy-[3- [1-L(E)-stigmasta-5,22-diene-3 3-yloxy]-formamido]-propoxy]phosphinyl oxy]ethylpyridinium,

internal hydroxide salt of 0-Ihydroxy-[2-[l[(E)-stigmasta-5,22-diene-3 3-yloxy]-carbonyl-oxy]ethoxy]phosphinyl]choline,

internal hydroxide salt of 1-[2 — J" £ L~2-[1-Icholest-5-ene-3 3-yloxy]formamido]ethoxy]hydroxyphosphinyl] oxy]ethyl]-1-methylpyrrolidinium,

8

internal hydroxide salt of 1-O-(3a,3-stigmastanyl)-3-O-(RS)-glyceryl-phosphoryl-choline,

internal salt of 0-I[(RS)-2-acetoxy-3-[5a-stigmastan-3a,3-yloxy! propoxy]hydroxyphosphonyl]choline,

internal hydroxide salt of O-[[(RS)-3-[(cholest-5-ene-33-yloxy)carbonyloxy]-2-hydroxy-propoxy|hydroxyphosphinyl]choline,

internal hydroxide salt of 0-[hydroxy-(RS)-2-hydroxy-3-[[5a-stigmastan-3 3-yloxy)carbonyloxy] propoxy]phosphinyl]choline,

internal hydroxide salt of O-[hydroxy-l (RS)-2-hydroxy-3-1[ ( E )-stigmasta-5,22-diene-3 3-yloxy]carbonyloxylpropoxy]phosphinyl]choline,

internal salt of O-[hydroxy-L2-ε[(stigmast-5-ene-3 3-yloxy)carbonyl]oxy]ethoxy]phosphinyl]choline,

internal hydroxide salt of O-[hydroxy-[3-[ (stigmast-5-ene-33-yloxy)carbonyl]propoxy]phosphinyl]choline,

internal hydroxide salt of O-[hydroxy-[2-(stigmast-5-ene-3 3-yloxy)ethoxy]phosphinyl]-choline,

Cholest-5-ene-33~yl-2-[I[2-(dimethyl-amino)ethoxy]hydroxyphosphinyl]oxy]ethylcarbonate,

internal hydroxide salt of O- [Lhydroxy-[%- [1-(stigmast-5-ene-3 3-yloxy)formamido]-ethoxy|phosphinyl]choline,

internal hydroxide salt of O-[[(RS)-2-acetoxy-3-[[(cholest-5-ene-3 3-yloxy)carbonyl]oxy]-propoxy]hydroxyphosphinyl] choline,

9

internal hydroxide salt of 0-[[2-[cholest-5-ene-3 6-yloxy)carbonyl]-2-methylpropoxy]hydroxyphosphinyl]choline and internal hydroxide salt of 0-[[(RS)-2-5 [1-(cholest-5-ene-3 6-yloxy)formamido]-3-hydroxypropoxy]hydroxyphosphinyl]choline.

Steroids of formula I and their salts can be prepared a) by treating an alcohol of formula with intermediate protection from a hydroxyl radical Y present in a group X, with an agent introducing the group of formula

3 "®

RJ-N-(CH2)n-0P(G)

9

and b) if desired, by hydrogenating an unsaturated steroid of formula I to give the saturated steroid,

c) if desired, by performing a functional transformation of a reactive radical contained in group X of a steroid of formula I,

d) if desired, by transforming a steroid of formula I into a salt.

These reactions can be controlled in a known way.

We can thus react a carbonate of formula II, where X represents a group of formula

— (CH₂)₂CO₃ in a solvent, such as methylene chloride or chloroform, in the presence of a base such as quinoline or pyridine, first with a halide of formula PO(H₂)₃, e.g., phosphorus oxychloride, at room temperature, and mix the resulting compound at room temperature with a salt of formula

*2

©

W

©

R -N-(CH,) -OH

III

11

where W is a lower alkyl-sulfonyloxy or aryl-sulfonyloxy, e.g. with choline tosylate, in the presence of a base, such as pyridine, in a solvent, such as methylene chloride.

We can first react a carbonate of formula II where X is a group of formula

-(CH„) N(T)C(0)- with a halide of formula P

/ \

0.0

X py IV

/■ \

0 Ha 1

e.g. with 2-chloro-2-oxo-l,3,2-dioxaphospholane in a solvent such as tetrahydrofuran (THF)

by cooling to temperatures as low as

0°C in the presence of a base, such as triethylamine,

then react the phosphate obtained in the same solvent by heating, e.g., to 50 to 100°C with a

2 3 4

amine of formula N(R ,R ,R' ).

We can first react an ester of formula II where X is a group of formula -CHfCH^JCO-

with a halide, such as acid dichloride

B-bromoethylphosphoric (Pharm. Acta Helv. 33, 1958,

349) in a solvent such as methylene chloride,

in the presence of a base such as triethylamine and mix the resulting compound in a solvent, such as

2 3 4

toluene with an amine of formula N(R ,R ,R ).

To protect the hydroxyl radical Y present in group X of a compound of formula II, one can, as shown in example 11 below, use

12

a benzyl group. For example, a glycerin derivative of formula II, where X is a group of formula -CI^CH (OH) C1^-, can be reacted with trityl chloride in pyridine to give the corresponding triethyl ether. This ether can be transformed using sodium hydride in THF and benzyl chloride in dimethylformamide (DMF) at a temperature up to 100°C to give the corresponding tritylbenzyl diether, where X represents -CH2CH(OCH2CgH^)CH2-. After separation of the trityl group from the diether, for example by heating hydrochloric acid in dioxane, the resulting benzyl ether is treated as described above with an agent introducing the group.

|@ he

R3_N-(CH2)n-0P

©

(G)

By separation of the benzyl group, e.g. by hydrogenation in the presence of palladium-carbon (Pd/C) in methanol and THF or (to avoid simultaneous hydrogenation of the double bonds present in the steroidal part of the ether) in the presence of palladium oxide (PdO) in acetic acid, the glycerin derivative of formula I corresponding to the starting compound of formula II is obtained.

and where X represents -CH2CH(OH)CH2~.

V

13

A steroid alcohol of formula II protected by a benzyl where X represents -CH2CH(OCH2C6H5 )CH2- can be prepared, also by reacting the corresponding steroid 3-chloroformate 5 with O-benzylglycerin in methylene chloride.

To protect a hydroxyl radical Y present in group X of a compound of formula II, a phenoxycarbonyl group can also be used, as shown in Example 10 22 below. For example, a compound of formula II, where X is a -CH2CH(CH2OH)NH-CO- group in methylene chloride, THF, and pyridine, can be reacted with phenyl chloroformate. The resulting compound, containing a phenoxycarbonyl group, e.g., in toluene and triethylamine, is then reacted with an agent introducing the group of formula G above, e.g., with 2-chloro-2-oxo-1,3,2-dioxaphospholane and then with trimethylamine in toluene and acetonitrile. By separating the phenoxycarbonyl group, e.g. using aqueous sodium hydroxide, we obtain the compound of formula I where X is the group -CH2CH(CH2 OH)NHCO-.

The hydrogenation of an unsaturated steroid 25 of formula I can also be carried out in the presence of Pd/C in a solvent, such as methanol, at a temperature up to 100°C.

As a functional transformation of a reactive radical contained in group X of a steroid of formula I, we can mention the alkanoyl-

tion of a hydroxy group Y. This allows us to react

14

a glycerin derivative of formula I, where X is the -CH2CH(OH)CH2~ group in a solvent, such as chloroform, in the presence of a base, such as pyridine, and a catalyst, such as dimethyl-aminopyridine (DMAP), with the carboxylic acid anhydride corresponding to the alkanoyl group to be introduced, at room temperature.

Starting alcohols of formula II where X is a group of formula -^CH2)p-C(Q,Q' )-Z ' , -ch2ch(y)ch2~z'-, -ch2ch(ch2y)-z'- or

-(CH2CH20)q-CH2CH2-Z'-,

Z' is a group of formula -0C(0)-, -0C(0)CH2~, -0CH2C(0)- or -N(T)C(0)- and R1, Q, Q', p, q, y and T have the meaning given above, are new and as such objects of the invention.

Formula II alcohols can be prepared in a known manner, e.g. as described in examples A to M below.

We can thus prepare an alcohol ether of formula II where X represents, for example, a -(CH~) - group

A p by reaction of the corresponding steroid-3-tosylate with glycol HO-(CH„)-OH in dioxane at approximately

2. p

120 °c.

An alcohol ester can be prepared with the formula

II, where X is, for example, a group -(CH„) -CO-, by r P

reaction of the corresponding steroid-3-ol in methylene chloride with the corresponding halide of formula Hal-(CH„)₂COCl at approximately 5°C in the presence

2p of pyridine and by transformation of the halide obtained into the desired alcohol of formula II by means of potassium trifluoroacetate in methylene chloride, DMF and water at about 80°C.

15

An alcohol ester of the formula can be prepared

II where X is, for example, a -CHfCH^JCO- group by reaction of the corresponding 3-ol steroid with lactic acid in toluene, in the presence of catalytic amounts

_ p-toluenesulfonic acid.

5

We can prepare an alcohol carbonate of formula II, where X is, for example, a -(CH9)-0C(0)- group

^ P

by reaction of the corresponding steroid-3-ol in methylene chloride at about -10°C with a solution of phosgene in toluene and by reaction of the steroid-3-chloroformate obtained in chloroform or methylene chloride with a diol of formula HO-(CH2)p-OH in the presence of pyridine or triethylamine at about 5°C.

We can prepare an alcoholcarbamate of formula II where X is, for example, a -(CH„) -(T)C(O)- group

z p by reaction of the corresponding steroid-3-ol in chloroform and THF with phenyl chloroformate in the presence of pyridine and by reaction of the phenyl carbonate obtained in chloroform with the amine

20

formula H0-(CHo) -N(T)-H.

2 p

We can prepare a compound of formula II where X is a group of formula

-CH2CH[:0C0NH(T1)lCH2N(T2)C(0)- and T1 and T2 represent a hydrogen or a lower alkyl group, by reaction 25 of the corresponding l-deoxy-l-amino-3-O-tritylglycerin of formula T2NHCHoCH0HCH„C(C,Hc)_ with a

2. 2. 6 5 J

steroid-3-chloroformate in methylene chloride in the presence of potassium hydroxide, reaction of the product obtained in methylene chloride with 30 isocyanate of formula O=C=N (T"*") at 80 °C and separation of the trityl group from the product obtained in

T\

16

dioxane by means of hydrochloric acid at 95 °C.

A glycerin derivative of formula II is obtained where X is the -C^CHfOHjC^- group by reaction of the corresponding 5 3-O-tosylsteroid in dioxane with glycerin at 100°C.

An alcohol of formula II having a double bond in the steroid part can be hydrogenated to give the corresponding saturated alcohol, e.g. 10 in the presence of Pd/C in THF.

Examples A to M below describe in detail the preparation of some compounds of formula II.

Example A

15. A solution of 10 g of cholesterol tosylate and 25.3 g of ethylene glycol in 180 ml of dioxane is heated with stirring to 120°C. The mixture is then mixed with 200 ml of water and extracted with ether. The ether phase is washed first with a 10% sodium carbonate solution and then with water. The organic phase is dried and concentrated. The residue is chromatographed by eluting with ether-hexane on silica gel. 5.6 g of 2-(choles-5-ene-33-yloxy)-1-ethanol, 25 P^ 92-95°C, the starting material of Example 2q, is obtained.

Example B

Similar to example A, we obtain:

a) 2- [ [(E)-stigmasta-5,2-diene-3-8-yl]oxyl] -

30 1-ethanol, SM: 456 (M+H+).

b) 2-L2-1(E)-stigmasta-5,22-diene-3 6-yloxyH-

ethoxyj-1-ethanol, SM: 501 (M+H+).

17

c) 2-[2-(choiest-5-ene-3 3-yloxy)ethoxy-1-ethanol, SM: 474 (M+H+)

d) 2-12-[2-(cholest-5-ene-33-yloxy)ethoxy]-ethoxy]ethanol, SM: 519 (M+H+).

5 Example C

I. In a solution of 12.5 g of 3-bromopropionic acid chloride (obtained from

II.1 g of bromopropionic acid and 9.77 ml of oxalyl chloride in 55 ml of methylene chloride and

10 3 drops of DMF), in 44 ml of methylene chloride, a solution of 20 g of Stigmastanol in 200 ml of methylene chloride and 4 ml of pyridine is added dropwise at 5°C. The mixture is concentrated, the residue is dissolved in 500 ml of methylene chloride, and this solution is washed with dilute hydrochloric acid. The organic phase is dried and concentrated. The residue is chromatographed by eluting with 11-etherhexane on silica gel. 3-Stigmastanyl-3-bromopropionate is obtained at 150-152°C.

2. Similarly, we prepare:

a) stigmasta-5,22-diene-3 β-yl-3-bromopropionate b) 5α-stigmastan-3 3-ylbromoacetate c) cholest-5-ene-33-ylbromoacetate

25 d) cholest-5-en-33-yl-3-bromopropionate e) 5a-stigmastanyl-3 3-yl-4-bromobutyrate f) cholest-5-en-3 3-yl-4-chlorobutyrate g) '3B-stigmastanyl-4-chlorobutyrate h) 3 3-stigmastanyl-4-iodobutyrate

30 i) (E)-stigmasta-5,22-diene-3B-yl~4-

chlorobutyrate

1

18

j) (E)-stigmasta-5,22-diene-3 B-yl-4-iodo-butyrate k) cholest-5-ene-3 B-yl-4-iodobutyrate

1) (E)-stigmasta-5,22-diene-3 6-yl-6-bromohexanoate m) 5a-stigmastan-3 8-yl-bromohexanoate n) stigmast-5-ene-3 B-yl-4-bromobutyrate.

3. A solution of 23.1 g of 3 6- is mixed

stigmastanyl-3-bromopropionate is dissolved in 400 mL of methylene chloride and 200 mL of DMF with 63.3 g of potassium trifluoroacetate and heated for 72 hours at 80°C. After adding 30 mL of water, the solution is heated for another hour at 80°C. The solution is concentrated, and the residue is chromatographed using ether-hexane on silica gel. The resulting compound, 36-stigmastanyl-3-hydroxypropionate, is obtained at a boiling point of 152–153°C and is the starting material for Example 20.

Example D

Similar to example C, we prepare:

a) cholest-5-ene-36-ylglycolate, SM: 369

(m-hoch2cooh)

b) 36-stigmastanylglycolate, SM: 399

(m-hoch2cooh)

c) cholest-5-ene-3 6-yl-3-hydroxypropionate,

SM: 368 (M-HOCH2CH2COOH) d) stigmata-5,22-diene-3 8-yl-3-hydroxy-

propionate, SM: 394 (M-HOCH2CH2COOH) e) cholest-5-en-3 3-yl-4-hydroxybutyrate,

Pf 98°C

f) 3 6-stigmastanyl-4-hydroxybutyrate, m.p. 149°C

g) (E)-stigmasta-5,22-3-diene B-yl-4-hydroxy-butyrate, mp 147°C.

19

h) 5a-stigmastan-3 g-yl-6-hydroxyhexanoate, mp 130 °C

i) (E)-stigmasta-5,22-diene-3 8~yl-6-hydroxy-hexanoate, 133°C

5 j) stigmast-5-ene-3 8-yl-4-hydroxybutyrate,

Pf 125-126°C.

Example E

In a solution of 13.8 g of ethylene glycol in 200 mL of methylene chloride, a solution of 10 g of cholesteryl chloroformate in 100 mL of methylene chloride and 2.16 mL of pyridine is added dropwise at 5°C. The solution is mixed with 300 mL of water and extracted with methylene chloride. The organic phase is washed with water, dried, and concentrated. The residue is recrystallized from methylene chloride and ethanol. This yields 6.4 g of cholesteryl 5-ene-3-8-yl-2-hydroxyethyl carbonate at 139–140°C, the starting alcohol of Example 1.

20 Example F

Similar to example E, we prepare:

a) 5<=<-stigmastan-3 8-yl-2-hydroxyethylcarbonate

Pf 184 °C

25 b) 2-hydroxyethyl-(E)-stigmasta-5,22-diene-

38-ylcarbonate, P^ 172°C c) cholest-5-ene-3 B-yl-3-hydroxypropyl-

carbonate, Pf 96°C d) cholest-5-ene-3 B-yl-4-hydroxybutyl-

30 carbonate, P^ 107°C

e) cholest-5-ene-3 B-yl-8-hydroxyoctyl-

carbonate, P^ 79°C

T

20

f) 2-hydroxyethyl-stigmast-5-ene-3-8-yl-

carbonate, 160°C

Example G

1. In a suspension cooled to -50°C, 5 of 4.16 g of stigmastanol in 25 ml of CHCl^,

In 12.5 mL of THF and 0.75 mL of pyridine, a solution of 1.71 g of phenyl chloroformate is added dropwise to 5 mL of CHCl₂. Then, 0.25 mL of pyridine is added. The reaction is allowed to proceed for 30 x 0 minutes at low temperature and for another hour at room temperature. The reaction solution is poured into a solution of pyridine and aqueous KHCO₃. After the complete evolution of CO₂, the solution is concentrated to dryness. The residue is distributed between CH₂Cl₂ and CH₃O. After crystallization from CH₂Cl₂-pentane, 4.75 g of 3-stigmastanyl-phenyl-carbonate is obtained at 96°C.

2. In a solution of 1.07 g of phenyl carbonate dissolved in 3 ml of CHCl₂, add

20 0.3 ml of ethanolamine. Let it react for two days.

at room temperature. The excess reagent is removed by distillation, and the phenol formed during the reaction is separated as sodium phenolate. The compound is crystallized from CH2Cl2. 0.9 g of 3B-stigmastanyl-(2-hydroxyethyl)-carbamate, P^ 206°C, the starting product of Example 5, is obtained.

Example H

Similar to example G, we

30 results in:

■c i

21

1. from stigmasterol via (E)-stigmasta-5,22-diene-3-8-yl-phenylcarbonate, Pf 156-157 °C

a) (E)-stigmasta-5,22-diene-38-yl-(2-5 hydroxyethyl)-carbamate, P^ 187°C and b) (E)-stigmasta-5,22-diene-3B-yl-(3-hydroxypropyl)carbamate, P^ 172-173°C.

2. From cholesterol through the

36-cholesteryl-phenylcarbonate and 38-cholesteryl-10 (2-hydroxyethyl)carbamate, P^ 168-170°C.

3. From 1'Epicoprostanol via Epi-coprostanyl-phenylcarbamate 1'Epicoprostanyl-(2-hydroxy-ethyl)carbamate, P^ 98°C.

4. From 6-sitosterol via the

15 stigmast-5-ene-3-yl-phenyl-carbonate, P^ 108-109°C, stigmast-5-ene-3 g-yl-(2-hydroxyethyl)carbamate, P^ 198-199°C, starting product of example 19.

Example I

1. To a solution, cooled to -10°C of

2.0 4.12 g of stigmasterol in 40 mL of methylene chloride is added to 10 mL of a 20% phosgene in toluene solution. The reaction is allowed overnight and then cooled to -10°C. After adding 0.7 mL of triethylamine to 10 mL of methylene chloride, the reaction is continued for 24 hours. The mixture is neutralized with 0.7 mL of triethylamine in 10 mL of methylene chloride, and (E)-stigmasta-5,22-diene-3g-ylchloroformate is isolated.

30 2. In 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, add drop by drop to

%

22

Drop a 2.3 g solution of the above chloroformate into 10 mL of chloroform. Pour the reaction mixture onto ice and a sodium bicarbonate solution. Extract with methylene chloride and analyze by silica gel chromatography with toluene/chloroform/ethyl acetate (4:2:1 vol.). After crystallization from methylene chloride-methanol, 1.86 g of (E)-stigmasta-5,22-diene-38-yl-(2-hydroxyethyl)carbamate, Pf 172–173°C, the starting alcohol of Example 9, is obtained.

Example J

1. A solution of 1.45 g of

3-O-tosylstigmasterol was heated in 20 ml of dioxane for 2 hours at 100°C while stirring with 2.5 g of glycerin. After distillation of the solvent, dilution of the residue with water, extraction with diethyl ether, and crystallization from methylene-methanol chloride, 1 g of O-3-tosylstigmasterol-glycerin was obtained.

2. • A solution of 1.7 g of the above product is hydrogenated in 15 ml of THF over 0.5 g of 10% Pd/C at normal pressure. After removal of the catalyst, distillation of the solvent, and crystallization from THF-methanol, 0-3a,B-stigmastanyl-(RS)-glycerin, the starting product of Example 11, is obtained in quantitative yield.

Example K

1. 0.74 g of (RS)-glycidol and 2.8 g of trityl chloride are reacted in 5 ml of pyridine overnight. Then, while stirring, a 2 g potassium bicarbonate solution is added.

After concentration, distribution of the residue between water and methylene chloride and silica gel chromatography with toluene, 2.25 g of (RS)-epoxy-l-O-tritylglycerin is obtained.

2. In a sealed tube, 3 g of this product is reacted for 2 hours at 100°C with 5 ml of isopropylamine. After distillation of the excess isopropylamine, 4.4 g of (RS)-l-deoxy-l-isopropyl-amino-3-O-tritylglycerin is crystallized from methylene-hexane chloride at 128-130°C.

3. In a solution, cooled to -10°C, of 1.1 g of stigmasterylchloroformate in 4 ml of methylene chloride, 1.04 g of the above amine in 20 ml of methylene chloride and 0.2 g of potassium hydroxide in 2 ml of water are added dropwise while stirring. After 2 hours of reaction at room temperature, phase separation in a separatory funnel, silica gel chromatography with methyl chloride/diethyl ether (2:1) yields 1.63 g of (E)-stigmasta-5,22-diene-3 B-yl-isopropyl-Σ(RS)-2-hydroxy-3-trityloxy-propyl]-carbamate, Pf 75-76°C.

4. A solution of 2 g of the above product in 10 ml of methylene chloride is reacted with 2 ml of methyl isocyanate for 40 hours.

at 80°C in a sealed tube and we obtain with a quantitative yield the (E)-stigmasta-5,22-diene-3 B-yl-isopropyl-C(RS)-2-methylcarbamoyl-3-trityloxy-propyl]-carbamate, Pf 92-93°C.

24

5. By separating the trityl group in a manner analogous to Example 11c, 1.7 g of (E)-stigmasta-5,22-diene-3 O-yl-[(RS)-3-hydroxy-2-[(methylcarbamoyl) 5 oxypropyll-isopropylcarbamate, starting product of Example 7c, is obtained from 2.5 g of the tritylether above at 240°C.

Example L

A solution of 10.2 g of cholesterylchloroformate is mixed in 130 mL of methylene chloride under argon while stirring with 4.6 g of 2-O-benzylglycerin in 120 mL of methylene chloride and 2 mL of pyridine. After one hour, the mixture is absorbed into 500 mL of water and 50 mL of HCl and extracted with methylene chloride. The organic phase is dried and concentrated at 50°C. After chromatography on SiO2 with n-hexane ether (1:1), 6.17 g of (RS)-2-(benzyloxy)-3-hydroxypropylchloride-3-ene-3f3-ylcarbonate, SM: 595 (M+H+), is obtained, the starting material of Example 13. 2 0 Example M

A solution of 3.86 g of cholesterol and 0.85 mL of L-(+)-lactic acid (90% in water) is boiled in 80 mL of toluene for one hour. The water is separated, and the cooled reaction mixture is mixed with 0.3 g of p-toluenesulfonic acid and boiled for another 4 hours. The reaction mixture is mixed with 30 mL of water and extracted with ether. The organic phase is dried over sodium sulfate and concentrated. The residue is purified over silica gel (eluent).

petroleum ether/ether 4;1). 1.5 g of cholest-5-ene-3 B-yl-(S)-2-hydroxypropionate is obtained,

Pf 120-122 °C.

25

Formula I steroids and their salts inhibit intestinal cholesterol absorption.

Inhibition of intestinal cholesterol reabsorption can be demonstrated experimentally in animals as follows:

Death's-head monkeys are orally administered the substances to be examined with an experimental meal containing a protein, starch, triolein, and [26-β]-cholesterol. Then, feces are collected for 2 days. The difference between the administered radioactive cholesterol and the excreted cholesterol is measured as the difference in stool values between the administered cholesterol and the excreted cholesterol. Cholesterol reabsorption (CHORES) is expressed as a percentage of the control values determined before drug administration.

The table below summarizes the results obtained with some representative products according to the invention. For each of the compounds listed, the cholesterol absorption determined at a dose of 100 µmol/kg orally is given as a percentage of that found in the prior period. In addition, the table contains data on the acute toxicity of the compounds examined (LD5q at 25 mg/kg for oral or, as appropriate, intravenous administration to mice).

30

26

Painting

Formula I compound from example #2a

CHORES as a percentage of the previous period 38

2k 2q 2r 4a

39 16 37 30

LD5q in mg/kg p.o. 4000 4000 4000 4000 i.v. 250 250 250 250

Formula I compound

from example no. 5 6 7a 16

CHORES as a percentage of the previous period

DL^q in mg/kg p.o.

40 31 35 40

4000

The products according to the invention can be used as medicinal products, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations are administered orally, e.g. in the form of tablets, coated tablets, dragees, hard gelatin and soft gelatin capsules, solutions, emulsions or suspensions.

To prepare pharmaceutical preparations, the products can be mixed according to the invention.

27

with pharmaceutically inert inorganic or organic carriers. For tablets, coated tablets, dragees, and hard gelatin capsules, carriers may include, for example, lactose, corn starch, talc, stearic acid, or its salts. For soft gelatin capsules, carriers may include, for example, vegetable oils, waxes, fats, or semi-solid and liquid polyols; however, depending on the nature of the active substance, soft gelatin capsules may not require a carrier at all. For preparing solutions and syrups, carriers may include, for example, water, polyols, sucrose, invert sugar, and glucose. 15 Pharmaceutical preparations may also contain preservatives, third-party solvents, stabilizing agents, wetting agents, emulsifiers, softening agents, colorings, flavoring agents, 20 salts for modifying osmotic pressure, buffers, coating agents, or antioxidants. They may also contain other therapeutically useful substances.

As mentioned above, the 25 drugs containing a steroid of formula I or one of its pharmaceutically acceptable salts are also the subject of the invention, as well as a method for preparing these drugs characterized in that one or more products according to the invention, and optionally one or more other therapeutically useful substances, are placed in a galenic administration form 30. As it has

28

As mentioned above, the products according to the invention can be used to combat or prevent diseases.

They can be used in particular to combat or prevent hypercholesterolemia and atherosclerosis. The dosage can vary widely and must, of course, be adapted to each individual circumstance. Generally, for oral administration, a daily dose of approximately 50 mg can be used.

to about 3 g, preferably about 200 mg to about

1 g.

The examples below describe the preparation of compounds of formula I. Example 1

In a 12.5 mL solution of phosphorus oxychloride, a solution of 48.7 g of cholest-5-ene-3g-yl-2-hydroxyethyl carbonate and 10 mL of quino-20 lein in 500 mL of methylene chloride is added dropwise at room temperature. This solution is then mixed with 60 mL of pyridine and 77 g of choline tosylate in 500 mL of methylene chloride at room temperature, after which the reaction mixture is stirred overnight at 25°C. It is then mixed with 125 mL of water and 34 g of sodium bicarbonate, followed by 3 mL of acetone. The precipitate is filtered through a filter funnel, dissolved in 1000 mL of chloroform-methanol 1:1, and stirred with 500 g of ion-exchange resin 30 (Amberlite MB-3). The latter is filtered through a filtering funnel and the solution is evaporated. The residue that appears is recrystallized in a mixture of methylene chloride-

C

29

methanol 1:1 and dioxane. 39 g of internal hydroxide salt of O-[12-L[(cholest-5-ene-36-yloxy)carbonyl]oxy]ethoxy]hydroxyphosphinyl}choline is obtained at Pf 224°C, SM: 640 (M+H+) 5 Example 2

Similar to example 1, we obtain

from a) 5a-stigmastan-33-yl-2-hydroxyethyl-carbonate the internal hydroxide salt of 0-[L2-1[(5q-

10 stigmastan-3 6-yloxy)carbonyl]oxylethyl]hydroxyphosphinyl} choline, p^ 220°C.

b) of 2-hydroxyethyl (E)-stigmasta-5,22-diene-

36-yl-carbonate the internal hydroxide salt of O-[hydroxy-2-L1E)-stigmasta-5,22-diene-3 B-yloxylcarbony1J-15 ethoxy]phosphiny11choline, P^220°C

c) of cholest-5-ene-3 6-yl-3-hydroxypropyl-

carbonate, the internal hydroxide salt of O-[[3-L[(cholest-5-ene-3 6-yloxy)carbonyl} oxy} propoxy} hydroxy-phosphinylcholine, P^ 230°C 20 d) of cholest-5-ene-36-yl-4-hydroxybutylcarbonate, the internal hydroxide salt of O-T[4-l[(cholest-5-ene-36-yloxy)carbonyl]oxy}butoxy} hydroxy-phosphinylII] choline, P^ 232°C

e) of cholest 5-ene-3B-yl-8-hydroxyoctylcarbonate 25 the internal hydroxide salt of 0-[118-1L(cholest-5-

3-ene 6-yloxy) carbonyl] oxy] octyl}oxy} -hydroxyphosphinyU choline, P^ 235°C

f) of cholest-5-ene-36-ylglycolate the internal hydroxide salt of O-JXHcholest-5-ene-36-yloxy)carbonyl]-

30 methoxy]hydroxyphosphinyl]choline, mp 226°C.

1

30

g) of cholest-5-ene-3B~yl-3-hydroxypropionate the internal hydroxide salt of O-[I2-Kcholest-5-ene-

3 B-yloxy)carbonyllethoxyj hydroxyphosphinylj-choline Mp 180 °C

h) of 3B-stigmastanylhydroxypropionate the internal hydroxide salt of O-[hydroxy-[2-[(3B-stigmastanyl-oxy)carbonyl]ethoxyphosphinylcholine, P^ 187°C

i) of stigmasta-5,22-diene-3B-yl-3-hydroxypropionate the internal hydroxide salt O-[hydroxy-[2-[(stigmasta-5,22-diene-3B-yloxy)carbonyllethoxy1-phosphinyl!

choline, P^ 19 9°C

j) of cholest-5-ene-3B-yl-4-hydroxybutyrate the internal hydroxide salt of O-1β3-T(cholest-5-ene-3B-yloxy)carbonyl propoxylhydroxyphosphinyl choline,

Pf 255°C

k) 3'B-stigmastanyl-4-hydroxybutyrate the internal salt of 0-[hydroxy-[3-t(3B-stigmastanyloxy)carbonyll-propoxy]phosphiny11choline hydroxide, p^ 250°C

1) of (E)-stigmasta-5,22-diene-3B-yl-4-hydroxybutyrate the internal hydroxide salt of O-Chydroxy-[3-H(E)-stigmasta-5,22-diene-3B-yloxy)carbonylpropoxyphosphinylcholine, P^ 225°C

m) 5a-stigmastan-3B-yl-6-hydroxyhexanoate the internal hydroxide salt of 0-hydroxy-[[5-[(5a-stigmastan-3 B-yloxy)carbonyllpentylloxyj phosphinylj choline Mp 254°C

n) of (E)-stigmasta-5,22-diene-3B-yl-6-hydroxyhexanoate the internal hydroxide salt of 0-[hydroxy-[[5-[(E)-stigmasta-5,22-diene-3 B-yloxy)carbonylj pentyljoxyj-phosphinyl]choline, P^ 215°C.

o) of 3B-stigmastanyl glycolate, the internal hydroxide salt of O-[hydroxy-[[[3 B-stigmastanyl)oxycarbonyl]-methoxyphosphinylcholine, P^ 260°C

31

p) of (E)-stigmasta-5,22-diene-33-yl-yl-glycolate, the internal hydroxide salt of O-[hydroxy-[t(E)-stigmasta-5,22-diene-3B-yloxy]carbonyl]methoxylphosphinyl]choline, P^ 215°C 5 q) of 2-(cholest-5-3B-yloxy)-1-ethanol, the internal hydroxide salt of O-t[2-(cholest-5-ene-3B-yloxy)-ethoxy]hydroxyphosphinyl]choline, SM: 59 6 (M+H+) r) of 2-[[(E)-stigmasta-5,22-diene-3B-yl]oxy]-1-ethanol, the internal hydroxide salt of O-[hydroxy-[2-(stigmasta-10 5,22-diene-3B-yloxy)ethoxy]phosphinyU choline,

Pf 230°C

s) of 2-[2-(cholest-5-ene-3B-yloxy)ethoxy]-1-ethanol the internal hydroxide salt of 0-L[2-T_2-(cholest-5-

3-ene B-yloxy)ethoxy]ethoxy]hydroxyphosphinyl]-

15 choline, SM: 640 (M+H+)

t) 2-[2-I_(E)-stigmasta-5, 22-diene-3 B-yloxylethoxy]-

1-ethanol the internal hydroxide salt of O-[hydroxy-

[2-C2-L(E)-stigmasta-5,22-diene-3 B-yloxy] ethoxy] ethoxy! -

"f"

phosphinyl]choline, SM: 6 66 (M+H ) 20 u) of 2-[2-C2-(cholest-5-ene-3B-yloxy)ethoxylethoxy]ethanol the internal hydroxide salt of 0-1[2-Q2-[2-(cholest-5-ene-3B-yloxy)ethoxy]ethoxy]ethoxy]hydroxy-

-f phosphinyl]choline, SM: 684 (M+H)

Example 3

25 On hydrogen 1 g of internal hydroxide salt of 0-[\2~[(cholest-5-ene-3B-yloxy)carbonyloxylethoxyl-hydroxyphosphinyl]choline in 10 0 ml of methanol with 1 g of Pd/C at 5% under 30 bars of H^ at 8 0°C.

After filtration, solution 30 is evaporated and the residue is dissolved in chloroform-methanol-dioxane. By addition of ether, 0.6 g of the internal hydroxide salt of 0-L [2-T(5α-cholestan-3β-yloxy)carbonyloxy]ethoxy]hydroxyphosphinyl]choline is obtained.

1

32

in the form of a hydroscopic powder, P^ 225 C.

Example 4

Similar to example 3, we obtain by using

5 a) the internal hydroxide salt of O- [hydroxy- [2- [2-

I(E)-stigmasta-5,22-diene-3B-yloxy]ethoxy]ethoxyl-phosphinyl]choline, the internal hydroxide salt of O-[hydroxy-[2-[2-(3g-stigmastanyloxy)ethoxy]ethoxy]phosphinyl]choline, SM: 670 (M+H+)

10 b) the internal hydroxide salt of O-[hydroxy~r2-(stigmasta-5,22-diene-3 6-yloxy)-ethoxylphosphinyl]choline, the internal hydroxide salt of O-thydroxy-[2-(36-stigmastanyloxy)ethoxy]phosphinyl]choline,

Pf 200°C.

15 Example 5

1 g of 36-stigmastanyl-(2-hydroxyethyl)-carbamate and 0.35 ml of Et^N are dissolved in 5 ml of THF.

In the solution cooled in an ice bath, a solution of 315 mg of 20 2-chloro-2-oxo-l,3,2-dioxaphospholane is added dropwise to 3 ml of

THF. The resulting suspension is stirred for 5 hours at room temperature. The Et^N.HCl precipitate is then separated by filtration, and the remaining solution is concentrated.

25 The phosphate obtained is dissolved in 10

In a pressurized flask, 1 g of (CH-^^N) is mixed with 10 ml of THF. The reaction is allowed to proceed for 24 hours at 70°C. After distillation of the excess reagent and solvent, the residue is absorbed into 20 ml of MeOH-CHCl.

and the solution is passed through an ion exchanger (Amberlite MB3). The product is then chromatographed.

33

on silica gel with CHCl^-MeOH-H^O (60/35/5 by volume). We obtain 0.6 g of internal hydroxide salt of O-Lhydroxy-[2-Cl-(5a-stigmastan-36-yloxy)formamido]-ethoxy]phosphinyl11choline, SM: 669 (M+H ).

Example 6

The phosphate preparation is repeated as described in Example 5. The material obtained from... is dissolved in 5 ml of dry pyridine.

2 mM of starting carbamate is reacted at 80°C for 24 hours. The product is isolated and purified in a manner analogous to Example 5. 0.95 g of internal hydroxide salt of 1-[2-f Hhydroxy-

[2- ri-(5a-stigmastan-36-yloxy)-formamido]ethoxy]phosphinyl]-oxy]ethyl]pyridinium, MS: 68 9 (M+H+).

Example 7

In a manner analogous to example 5, starting from a) (E)-stigmasta-5,22-diene-3B-yl-(2-hydroxyethyl)-carbamate, we obtain the internal hydroxide salt of O-Lhydroxy-[2-[I-(E)-stigmasta-5,22-diene-3 6-yloxy1formamido}-ethoxy]phosphinyl]choline, SM 665 (M+HH).

b) of (E)-stigmasta-5,22-diene-36-yl-(3-hydroxypropyl) carbamate the internal hydroxide salt of O-[hydroxy-[3-tl-[(E)-stigmasta-5,22-diene-3 6-yloxy} formamido-propoxy]phosphinyl]choline, SM 679 (M+H+)

c) of (E)-stigmasta-5,22-diene-36-yl-I(RS)-3-hydroxy-2-[(methylcarbamoyl)oxy|propyl]-isopropylcarbamate the internal hydroxide salt of O-Ihydroxy-T(RS)-3-[N-isopropyl-1-[(E)-stigmasta-5,22-diene-36-yl]-oxyformamido]-2-](methylcarbamoyl)oxy|propoxy]phosphinyl]choline, SM: 794 (M+H+)

d) of 3B-cholesteryl-(2-hydroxyethyl)carbamate, the internal hydroxyl salt of O-T L£2-[l-cholesteryl-5-ene-

3 6-yloxy]formamido]ethoxyhydroxyphosphinyl}choline SM 639 (MMH+)

34

e) of epicoprostanyl-(2-hydroxyethyl)carbamate the internal hydroxide salt of O-LL2~Hl-(5 8-cholestan-3a-yloxy)formamido]ethoxy]hydroxy-phosphinyl]choline SM: 641 (M+H+)

5 Example 8

In a manner analogous to example 6, starting from (E)-stigmasta-5,22-diene-3 S-yl-(3-hydroxypropyl)carbamate, we obtain the internal hydroxide salt of l-l2-Ifhydroxy-X3-ri-r(E)-stigmasta~5,22-10 diene-3 6-yloxy] f ormamido] propoxy} phosphinyl"] oxylethyl] -pyridinium, SM : 699 (m+H+)

Example 9

A solution of 2.22 g of (E)-stigmasta-5,22-diene-36-yl~(2-hydroxyethyl)carbonate and 1.1 mL of pyridine in 10 to 15 mL of chloroform is added dropwise to a solution of 0.75 g of phosphorus oxychloride in 3 mL of chloroform, cooled to 0°C. The reaction is allowed to proceed for one hour at room temperature. Then, 1.6 g of choline tosylate in 15 mL of pyridine is added. The mixture is stirred overnight, and then a solution of 2 g of potassium bicarbonate is added. The mixture is concentrated to dryness, and the residue is absorbed into 100 mL of THF/methanol/chloroform (1:1:1). The solids are then separated by filtration. The remaining oil is passed through an ion exchanger (Amberlite MB-3). After silica gel chromatography with chloroform/methanol/water (60/35/5 vol.) and crystallization with methylene chloride/acetone, 1.6 g of internal salt 30 of O-[hydroxy-L2-rCL(E)-stigmasta-5,22-] is obtained.

3-diene 6-yloxy]carbonyl]oxylethoxy}phosphinyl]choline, SM: 666 (M+H+).

O

35

Example 10

4.75 g of 3B-cholesteryl-(2-hydroxyethyl)carbamate is reacted with 2-chloro-2-oxo-1,3,2-dioxaphospholane. The resulting phosphate is mixed at 70°C for 24 hours with N-methylpyrrolidine. After silica gel chromatography with chloroform/methanol/water (30/62.5/7.5 vol.), 1.2 g of the internal hydroxide salt of 1—[2—LEC2— £2—[choiest-5-ene-3 B-yloxylformamidolethoxyl-10-hydroxyphosphinyl] oxy]ethyl]-] methylpyrrolidinium SM: 665 (M+H+) is obtained.

Example 11

a) To a solution of 2.49 g of 0-3α,8-stigmastanyl-(RS)-glycerol in 10 ml of pyridine, 1.41 g is added

15 of trityl chloride. After 48 hours of reaction, a potassium bicarbonate solution is added while stirring. The mixture is concentrated to dryness. The residue is divided between methylene chloride and water. 20 silica gel chromatography with methylene chloride yields 1-O-trityl-3-O-(3a,8-stigmastanyl)-(RS)-glycerin;

b) To a suspension of 96 mg of sodium hydride in 5 ml of THF, 2.4 g of the above triethyl ether is added dropwise to 10 ml of THF, then

25 0.46 ml of benzoyl chloride in 5 ml of DMF. After 2 hours of reaction at 80°C, distillation of the solvent and distribution of the residue between

•w methylene chloride and water we obtain l-0-trityl-2-0-benzyl-3-0-(3a,8-stigmastanyl)-3 0 (RS)-glycerin.

36

c) To a solution of 2.4 g of the above benzyl ether in 20 ml of dioxane, heated to 95°C, 2 ml of hydrochloric acid (IN) is added. After 2 hours of reaction at 95°C, solvent 5 is removed by distillation, the residue is absorbed in hexane, and the prepared triphenylmethanol is separated. After silica gel chromatography with toluene/ethyl acetate (9:1), 1.5 g of 1-O-(3a,B-stigmastanyl)-2,O-benzyl-(RS)-glycerin is obtained. 10 d) In a manner analogous to example 5, from 1.4 g of the glycerol derivative above, first by reaction with 2-chloro-2-oxo-1,3,2-dioxaphospholane and then reaction of the phosphate obtained with trimethylamine, 0.8 g of 1-0-15 (3a,3-stigmastanyl)-2-0-benzyl-3-0-(RS)-glyceryl-phosphorylcholine, SM: 746 (M+H+)

e) A solution of 0.77 g of the above benzylether is hydrogenated in 10 ml of methanol and 5 ml of THF at normal pressure in the presence of 10% Pd. A quantitative yield of 1-0- is obtained.

(3a,8-stigmastanyl)-3-0-(RS)-glyceryl-phosphoryl-choline, SM: (M+H+)

Example 12

To a solution of 0.5 g of the gly-25 cerine derivative from Example 11 in 3 ml of chloroform and 1 ml of pyridine, 50 mg of DMAP and 0.5 ml of acetic acid anhydride are added. After one hour of reaction, the solution is concentrated to dryness. The residue solution is then passed through 20 ml of methanol 30 on an ion exchanger (Amberlite MB-3). 0.51 g of the internal hydroxide salt of O-[f(RS)-2-acetoxy-3-[5a-stigmastan-3a,8-yloxylpropoxy]hydroxyphosphonyloicholin, SM: 698 (M+H+)

37

Example 13

a) 1.15 ml of phosphorus oxychloride is mixed under argon while stirring with 6.1 g of

(RS)-2-(benzyloxy)-3-hydroxypropylcholest-5-ene-3g-ylcarbonate and 1.5 mL of guinoline are dissolved in 80 mL of methylene chloride. After 4 hours, 7.4 g of choline tosylate and 6 mL of pyridine are added, and after 24 hours, 15 mL of water and 4 g of NaHCO3- are added. After 30 minutes, the mixture is poured into 50 mL of water and 50 mL of HCl and extracted with chloroform. The organic phase is concentrated. The product is dissolved in 150 mL of MeOH-CHCl (2:1) and mixed with 100 g of ion exchanger (Amberlite MB3). After stirring for 16 hours, the ion exchanger is filtered through a filtering ion exchanger. The resulting solution is concentrated at 60°C, distilled with toluene, and dried. The residue is purified on silica gel with CHCl₂-MeOH (1:1) and CHCl₂-MeOH-O₂ (60:35:5). After drying, 4.9 g of the internal hydroxide salt of O-[C(RS)-2-benzyl-oxy-3-[(cholest-5-ene-3-8-yloxy)carbonyloxylpropoxy]-hydroxyphosphinylcholine is obtained. Yield: 63% SM: 760 (M+H+)

b) 4.65 g of the product from a) and 1.4 g of PdO are stirred under normal pressure for 20 minutes in 200 mL of CH₃COOH. After filtering out the catalyst, the solution is concentrated at 60°C. The residue is washed in 200 mL of ether, filtered, and dried. The residue is dissolved in 40 mL of CHCl₃-MeOH (1:1).

and mix it with 25 ml of dioxane and 200 ml of ether. Filter with a filtering funnel

38

precipitated crystals, they are washed with ether and dried at 50°C. 3.25 g of internal hydroxide salt of O-[£(RS)-3-C(cholest-5-ene-30-yloxy)carbonyl-oxyj-2-hydroxypropoxy}hydroxyphosphinyl} choline is obtained, (strongly hygroscopic, yield: 79%, SM: 670 (M+H+).

Example 14 Similar to example 13, we can prepare:

a) the internal hydroxide salt of O-[hydroxy-(RS)-2-hydroxy-3-[ [5 -stigmasta.n-3-ylaxyy ) carbonyloxy] -propoxy]phosphinyl} choline, (Epimer 1:1) SM: 700 ,{M+H+)

b) the internal hydroxide salt of O-[hydroxy-L(RS)-2-hydroxy-3-[[(E)-stigmasta-5,22-diene-3 B-yloxy}-carbonyloxy} propoxyphosphinylcholine (Epimer 1:1) SM: 696 (M+H+)

Example 15

a) In a solution of 1 g of β-bromoethylphosphoric acid dichloride in 10 mL of methylene chloride, a solution of 1 g of cholest-5-ene-3β-yl-(S)-2-hydroxypropionate and 0.37 mL of triethylamine in 5 mL of methylene chloride is added dropwise. The mixture is stirred first for 4 hours at room temperature, then for 1 hour under reflux. After adding 5 mL of water, the mixture is boiled under reflux for 2 hours. It is diluted with methylene chloride, the aqueous phase is separated, the organic phase is washed with water, dried over sodium sulfate, and concentrated. The residue is dissolved in ether and mixed with a solution of 5 g of barium acetate in

39

20 ml of water. The mixture is stirred for 20 hours at room temperature. The barium salt that forms is separated by filtration and mixed with 20 ml of 3N hydrochloric acid and 20 ml of methylene chloride. The mixture is stirred for one hour at room temperature, the organic phase is separated, dried over sodium sulfate, and concentrated. 0.7 g of cholest-5-ene-38-yl-(S)-2-[L(2-bromoethoxy)-hydroxyphosphinyl}oxy}propionate is obtained. SM: 643 (M+H) b) A solution of 0.7 g of cholest-5-ene-38-yl-(S)-1L(2'-bromoethoxy)-hydroxyphosphinyl}oxy}propionate in 15 ml of toluene is mixed in a dry ice bath with 15 ml of trimethylamine. The mixture is heated for 30 hours at 60°C. After cooling, the reaction mixture is absorbed into toluene and concentrated. The residue is absorbed into 30 ml of methanol, mixed with 2 g of silver carbonate, and stirred for 1 hour at 50°C. The precipitate is separated by filtration, concentrated, and yields 0.6 g of the internal hydroxide salt of O-It(S)-Q-L(cholest-5-ene-3 6-yloxy)carbonyl11ethoxyl-hydroxyphosphinyl11choline, SM: (M+H+).

Example 16

In a manner analogous to example 1, starting from stigmast-5-ene-3Σ-yl-2~hydroxyethylcarbonate, we obtain the internal hydroxide salt of O- [hydroxy-[_2-[ Σ( stig-mast-5-ene-3 3-yloxy)carbonylloxy} ethoxy]phosphinyl} choline, P^ 207°C (decomposition).

Example 17

Similar to example 2k or, as the case may be, example 2q, we obtain

40

a) the internal salt of O-[hydroxy-[3-~[( stigmast-5-ene-3 6-yloxy)carbonyl11propoxylphosphinylUcholine, Pf 220°C (decomposition) or as the case may be b) the internal hydroxide salt of O-fhydroxy-[2-(stigmat-5-ene-36-yloxy)ethoxylphosphinyl]choline, Pf 197°C (decomposition).

Example 18 Analogously to example 5, but using dimethylamine instead of triethylamine, we obtain cholest-5-ene-33-yl-2-[L[2-(dimethylamino)ethoxylhydroxyphosphinylloxyl-ethylcarbonate, P^ 150°C (decomposition)

Example 19

In a manner analogous to example 5, the internal hydroxide salt of O-[hydroxy-[2-11-(stig-mast-5-ene-3 8-yloxy)formamido] ethoxy phosphinylcholine is obtained, P^ 225°C (decomposition)

Example 20 In a manner analogous to example 12, the internal hydroxide salt of 0-[[(RS)-2-acetoxy-3-[[(cholest-5-ene-3 B-yloxy)carbonylloxyipropoxy] • hydroxyphosphinyllcholine is obtained, Pf 130°C (decomposition).

Example 21

a) A solution of 1.6 g of cholesterol and 3.6 g of hydroxypivalic acid in 80 ml of toluene with 1 g of p-toluenesulfonic acid is mixed and boiled for 4 hours. The reaction mixture is mixed with water and extracted with ether. The organic phase is dried and concentrated,

The residue is then purified on silica gel with petroleum ether/ether (4:1). 1.9 g is obtained.

41

of cholest-5-ene-3 g-yl-3-hydroxy-2, 2-dimethyl-propionate, P^ 174-176°C.

b) In a solution of 1.9 g of product from a) in 60 mL of methylene chloride, 1 mL of triethylamine is added dropwise, followed by a solution of 1.42 g of γ-bromoethylphosphoric acid dichloride in 30 mL of methylene chloride. The mixture is boiled for 18 hours and, after the addition of water, refluxed for one hour. The aqueous phase is separated, the organic phase is washed with water, dried, and concentrated. The residue is dissolved in ether and mixed with a solution of 15 g of barium acetate in 30 mL of water. The mixture is stirred for 20 hours, the barium oxide that forms is separated by filtration, and mixed with a mixture of 50 mL of 3N hydrochloric acid and 50 mL of methylene chloride. The mixture is stirred for one hour at room temperature, the organic phase is separated, dried, and concentrated. We obtain 1.6 g of cholest-5-ene-3g-yl-3-tL2-bromo-ethoxy)hydroxy-phosphinylloxy]-2,2-dimethylpropionate, Pf 98°C.

c) A solution of 1.6 g of the product from b) is mixed with 15 mL of toluene and cooled in a dry ice bath with 15 mL of trimethylamine. The mixture is heated for 2 days at 60°C. After cooling in a dry ice bath, the reaction mixture is absorbed with toluene and concentrated. The residue is absorbed into methanol, mixed with 3 g of silver carbonate, and stirred for 1 hour at 50°C. The precipitate is separated by filtration and concentrated. By recrystallization

42

Sation of the residue from the ether yields 0.8 g (52%) of the internal hydroxide salt of O-It2-L-cholest-5-ene-3-6-yloxy)carbonyl-2-methylpropoxy-hydroxyphosphinyl-choline, Pf 210°C

Example 22

a) A solution of 5.00 g of cholesterylchloroformate in 20 mL of methylene chloride is added dropwise to a mixture of 1.4 g of DL-Serinol HCl and 3.1 mL of triethylamine in 30 mL of methylene chloride. After 4-5 hours of stirring, the mixture is absorbed into aqueous methanol and extracted with chloroform. The organic phase is dried and concentrated. After chromatography on SiO2 with chloroform and then with ether, 4.3 g of cholesterylchloroformate is obtained. (Decomposition at 158°C).

b) A solution of 3.7 g of the product from a) is mixed in 30 mL of methylene chloride, 10 mL of THF, and 0.6 mL of pyridine under argon with 1 mL of phenyl chloroformate in 15 mL of methylene chloride. After one hour, the solution is absorbed into 200 mL of water and 50 mL of 0.1 N HCl and extracted with 150 mL of methylene chloride. The organic phase is dried and concentrated. After chromatography on SiO2 with n-hexane/

ether (1:1) and from the ether we obtain 2.1 g of cholest-5-ene-3 3-yl-t(RS)-2-hydroxy-l-[(phenoxycarbonyl)oxy-methyl-ethyl} carbamate.

c) Add to a mixture of 320 g of the product from b) in 20 ml of toluene and 0.08 ml of triethylamine, under argon and while stirring at temperature

43

At room temperature, 0.05 mL of 2-chloro-2-oxo-l,3,2-dioxa-phospholane is prepared. After 16 hours, the (EtJ^NrHCl) solution is filtered using a filtering funnel. The resulting solution is concentrated, and the residue is dissolved in a solution of 2 g of trimethylamine in 20 mL of toluene and 5 mL of acetonitrile, maintained at 80°C. After 6 hours, the solution is concentrated. The product, the internal hydroxide salt of O-[[(RS)-2-[l-(cholest-5-ene-38-10 yloxy)formamido-3-(phenoxycarbonyloxy)propoxy]hydroxyphosphinyl]choline, is used without purification in the next step.

d) The product from c) is dissolved in 20 ml of methanol-chloroform (1:1) and, while stirring at room temperature, is mixed with 2 ml of

NaOH IN. After adding 10 g of ion exchanger (Amberlite MB-3) and stirring for 4 hours, the solution is concentrated, distilled azeotropically with toluene, and then dried. The residue is chromatographed on silica gel with CHCl₃-MeOH-O (60/35/5 by volume). After drying, 200 mg of the internal hydroxide salt of O-t[(RS)-2-Cl-(choiest-5-ene-3 8-yloxy)formamido-3-hydroxypropoxyhydroxyphosphinyl-choline is obtained, P₅: 25 220°C (decomposition).

Tablets and capsules with the following composition are known to be prepared:

44

Example a

10

15

Tablets composed of formula I: microcrystalline cellulose, corn starch, talc, hydroxypropylmethylcellulose

1

Example b

Capsules composed of formula I: corn starch, lactose, talc, magnesium stearate

Each tablet contains 200 mg, 155 mg, 25 mg, 25 mg, and 20 mg.

425 mg

1 capsule contains 100.0 mg 20.0 mg 95.0 mg 4.5 mg 0.5 mg

200.0 mg

20

(

45

DV 4104/180

Claims (6)

DEMANDS 1. Process for preparing steroids of formula î2® R -N-(CH-) -0P0 N0 i 4 n i ,0 Or R^" represents a hydrogen, lower alkyl or lower alkylidene, 2 3 4 R and R represent a hydrogen or a lower alkyl group, or together they form with the atom 46 nitrogen atoms, a heterocyclic aromatic or saturated ring with 5 or 6 members, to which a lower alkyl group may be attached, n represents the number 2, 3, or 4, X represents a formula group -(CH2)p-C{Q/Q.)-{z)l or 0", -CH2CH(Y)CH2-(Z)x or 0", -CH2CH(CH2Y)-(Z)1 or 0" or -(CH2CH2O) -CH2CH2-(Z)1 or 0", q represents the number 1 or 2, Z represents a group with the formula -C(O)-, -0C(0)-, -0v.(0)CH2-, -0CH2C(0)- OR -N(T)C(0)-, Q, Q' and T represent a hydrogen or a lower alkyl group. p represents an integer between 1 and 9, and, if Z is a carbonyl, can also represent 0, Y represents a hydroxy, lower alkoxy, lower alkanoyloxy, carbamoyloxy, or lower mono- or di-alkoyl-carbamoyloxy, the dotted C-C- bonds at positions 5(6)-, 7(8)-, 22(23)-, 24(25)-, and 24(28)- are optional, the side chain being either saturated or monounsaturated, and their physiologically acceptable salts characterized in that one proceeds 47 a) by treating an alcohol of formula with intermediate protection of a hydroxy radical Y present in a group X, with an agent introducing the group of formula * r\ u i © i N-(CH2!n-0P- J4 J.3 (G) 48 b) if desired, by hydrogenating an unsaturated steroid of formula I to give the saturated steroid# c) sx, if desired, by performing a functional transformation of a reactive radical contained in group X of a steroid of formula I, d) if desired, by transforming a steroid of formula I into a salt. 2. Method according to claim 1, 10 where R"*" is a hydrogen or a lower alkyl, in particular an ethyl. 3. Method according to claim 1 or 2 2, where R is a hydrogen or a lower alkyl group, 3 4 and R and R represent a lower alkyl. 15 4. Method according to claim 1 or 2 3 4 2, where R, R and R represent a methyl. 5. Method according to claim 1 or 2, 3, 4 2, where R, R, and R form a pyridinium or 1-meuhylpyrrolidinium group with the N atom. 20 6. Method according to any one of claims 1-5 where n is the number 2. 7. A process according to any one of claims 1-6, characterized in that compounds are prepared with saturated or unsaturated steroid fraction in 25 5(6) or unsaturated in 5(6) and 22(23). 8. A method according to any one of claims 1-7, where X represents the group C 49 ~ ^ ^2 ^ 2 ~ ' ~ ' CH2 ^ ^ ^"^2 ^ 2 ~ ' ~ ^ 2^ ^ ^"^2 ^ 2^ ^^2 ^ 2~ ' -ch2chohch2-, -ch2ch(ococh3)ch2-, -ch2ch(oconhch3)ch2nich(ch3)2|co- -(ch2)2nhco-, -(c'h2)3nhco-, -ch2chohch2oco-, -ch(ch3jco- or in particular -(ch^oco-, -(ch^oco-, -(ch2)4oco-, -(ch2)qoco-, -(ch2)co-, -(ch2)2co-f -(ch2)3co-, -(ch2)5co-, -ch2ch(ococh3)ch2oco-, -(CH2)3CO- or -CH2-(CH2)5CO-. 9. Method according to any one of claims 1-7, where x represents -ch2ch(ococh3)ch2oco-, -ch2c(ch3)2co- or -ch2ch(ch2oh)nhco-. 10. A process according to claim 1, characterized in that a compound from the group of the following compounds is prepared: Internal hydroxide salt of O-C[-[L(cholest-5-ene-38-yloxy)carbonyl]oxy]ethoxy]-hydroxyphosphinyl]-choline, internal hydroxide salt of O-[hydroxy-T3-[(3 8-stigmastanyloxy)carbonyl]propoxy]phosphinyl]-choline, internal hydroxide salt of O-[ [2-(cholest-5-ene-3 6-yloxy)ethoxy]hydroxyphosphinylj-choline and internal hydroxide salt of O-[hydroxy-E2-[l-(5a-stigmastan-36-yloxy)formamido]-ethoxy]phosphinyl choline. 50 10. A method according to claim 1, characterized in that a compound of the group is prepared: Internal hydroxide salt of O-I[2-l[(5a-stigmastan-38-yloxy)carbonyl]oxy]ethoxy]-hydroxyphosphinyl]choline, Internal hydroxide salt of O-Chydroxy-l3-L TIE) - stigmasta-5, 22-diene -3 8-yloxy*J carbonyl] -ethoxy]phosphinyl] choline, internal hydroxide salt of 0-[L3-1[(cholest-5-ene-3 B-yloxy)carbonyl]oxy]propoxy]-hydroxyphosphinyl-choline, internal hydroxide salt of O-[[4-[[(cholest-5-ene-3 B-yloxy) carbonyl] oxy] butoxy'J -hydroxyphosphinyl] choline, Internal hydroxide salt of O-C C [8-[["(cholesth-5-ene-3 B-ylox/)carbonyl]oxy]octyl]oxy]-hydroxyphosphinyl]choline, internal hydroxide salt of O-[[[(cholest-5-ene-3 S-yloxy)carbonyl]methoxy]hydroxyphosphinyl]-choline, internal hydroxide salt of 0-1[2-L(cholest-5-ene-3B-yloxy)carbonyljethoxy]hydroxyphosphinyl-choline, internal hydroxide salt of O-[hydroxy-12-[(38-stigmastanyloxy)carbonyl]ethoxy]-phosphinyl]-choline, internal hydroxide salt of O-[hydroxy-[2-(stigmasta-5,22-diene-3B-yloxycarbonyl]-ethoxy]-phosphinyl]choline, internal hydroxide salt of 0-tL3-[(cholest-5-ene-3B-yloxycarbonyl]propoxy]hydroxy-phosphinyl-choline, 51 internal hydroxide salt of O-[hydroxy-[3-[(E)-stigmasta-5,22-diene-3 rf-yloxy)-carbonyl]propoxy]- phosphinylcholine, internal hydroxide salt of 0-[hydroxy-[[5-5 I (5a-stigmastan-3.---yloxy) carbonyl] pentyl] oxy]phosphinyll -choline, internal hydroxide salt of 0-[hydroxy-[ [5-[((E)-stigmasta-5,22-diene-38-yloxy)carbonyl-pentylj oxyj phsophinylj choline, 10 internal hydroxide salt of O-ILhydroxy [[U 38- stigmastany1)oxyjcarbonyl]methoxy]phosphinylcholine, internal hydroxide salt of O-[hydroxy-CCL(E)-stigmasta-5,22-diene-36-yloxy] carbonyl]methoxy]phosphiny 14choline, 15 internal hydroxide salt of O-[hydroxy-[2- {stigmasta-5,22-diene-3d-yloxy)ethoxy]phosphinyl]-choline, internal hydroxide salt of O-1 [2-[2-(cholest-5-3b-yloxy)ethoxyl hydroxy-phosphiny1]choline, 20 internal hydroxide salt of O- Lhydroxy-"[2- [2-[(E)-stigmasta-5,22-diene-3 6-yloxy]ethoxylethoxy]-phosphinyl]choline, internal hydroxide salt of O-[C2-C2-L2-(cholest-5-ene-3c-yloxy)ethoxy]ethoxy]ethoxy]-25-hydroxyphosphinyl]choline, internal hydroxide salt of O-[[2-I(5α-cholestan-36-yloxy)carbonyloxy] ethoxyl hydroxyphosphinyl] choline, internal hydroxide salt of O-[hydroxy-[2-30 [2-(38-stigmastanyloxy)ethoxy]ethoxyj phosphinyl~ choline 52 internal hydroxide salt of O-[hydroxy-[2-(38-stigmastanyloxy)ethoxy phosphinyl choline, internal hydroxide salt of 1-[2-1[hydroxy-L2 — C1 — (5u-stigmastan-3 6-yloxy)-formamido]ethoxy]-phosphinylj oxy] ethyl"] pyridinium, internal hydroxide salt of 0-[hydroxy-[2-r1 — L(E)-stigmasta-5, 22-diene-3 6-yloxy]formamido-ethoxy phosphinyl choline, internal hydroxide salt of O-[hydroxy-[3-[l-[(E)-stigmasta-5,22-diene-3 6-yloxy]formamido-propoxy phosphinyl choline, internal hydroxide salt of O-Lhydroxy-[(RS)-3-[N-isopropyl-1-L(E)-stigmasta-5,22-diene-38-yl]oxyformamido]-2-J(methylcarbamoyl)oxypropoxy-phosphinyl choline, internal hydroxide salt of O-II[2-Cl-cholesterol 5-ene-3 b-yloxy)formamido ethoxy]hydroxyphosphinyl-choline, internal hydroxide salt of O-f C2-"[l-( 58-cholestan-3a-yloxy)formamido ethoxyl hydroxyphosphinyl^ choline, internal hydroxide salt of 1-[2-i[hydroxy-[3—Fl — L(E)-stigmasta-5,22-diene-3 6-yloxy-formamido-propoxy phosphinyl oxy]ethyl]pyridinium, internal hydroxide salt of O-Chydroxy-[2-1EC(E)-stigmasta-5,22-diene-3 8-yloxyl-carbonyl-oxyJ ethoxyj phosphinylj choline, internal hydroxide salt of 1-[2-[112-11-Lcholest-5~ene-3B-yloxyJ formamidoj ethoxyj hydroxyphosphinyl] ox.yj ethy lj -1 -methyl lpyr rolidinium, 53 internal hydroxide salt of l-O-(3a,S-stigmastanyl)-3-O-(RS)-glyceryl-phosphoryl-choline, internal salt of O-ji(RS)-2-acetoxy-3-[5a-stigmastan-3a, s-yloxy] propoxy] hydroxyphosphonyl] choline internal hydroxide salt of 0-tC(RS)-3-[(cholest-5-ene-3 S-yloxy)carbonyloxy]-2-hydroxy-propoxy]hydroxyphosphinyl]choline, internal hydroxide salt of O-[hydroxy-(RS)-2-hydroxy-3-115-α-stigmastan-36-yloxy)carbonyloxy]-propoxyl phosphinyll choline, internal hydroxide salt of O-[hydroxy-l(RS)-2-hydroxy-3-L C(E)-stigmasta-5,22-diene-3 8-yloxy]carbonyloxy]propoxyl phosphinyll choline, 11. A process according to claim 1, characterized in that a compound from the group of the following compounds is prepared: internal salt of O-Lhydroxy-f2-rC(stigmast-5-ene-3£S-yioxy) carbonyl oxy] ethoxy phosphinyl] -choline, internal hydroxide salt of O-Qihydroxy-C3-L(stigmast-5-ene-3B-yloxy)carbonylpropoxyl phosphinyll-choline, internal hydroxide salt of O-[hydroxy-C2-(stigmast-5-ene-36-yloxy)ethoxy]phosphinyl]-choline, Cholest-5-ene-38-yl-2-lf[2-(dimethyl-amino)ethoxyhydroxyphosphinyl]oxy'J ethyl carbonate, internal hydroxide salt of O-Lhydroxy-^ Cl-f1-(stigmast-5-ene-3 6-yloxy)formamido]-ethoxy]phosphinylj choline, internal hydroxide salt of O— C C(RS acetoxy-3-[C(cholest-5-ene-3 6-yloxy)carbonylloxyl-propoxy]hydroxyphosphinyl]choline, 54 salt incerne d'hydroxide de 0-J" L~2-Echolest-5-ene-3a-yloxy)carbonyl-2-methylpropoxy]hydroxy- internal hydroxide salt of 0-LC(RS)-2-1- (choles-5-ene-J S-yloxy)formamidoj-3-hydroxypropoxy | hydroxyphosphinylcholine. 12. Method for preparing a pharmaceutical preparation based on a steroid of formula I according to claim 1 or one of its salts, characterized in that a compound of this type is put into galenic form with a pharmaceutical support. 13. Application of a compound of formula I according to claim 1 or of one of its salts to the preparation of drugs that inhibit intestinal cholesterol absorption and lower plasma cholesterol. 14. Alcohols with the formula phosphinylcholine and R' IL.ch 55 or represents a formula group -(CH2)p-c(Q,Q')-(ZV) -ch2ch(y)ch2-(z'i -ch2ch(ch2y)-(z') -(ch~cho0) -ch0ch0-(z*) 2 2 q 2 2 Z1 is a formula group -OC(0)-, -0c(0)ch2-, -0ch~c(0)- or -n(t)c(0)- and 1 R » Q/ Q1/ p» q» ï and T have the meaning given above. original , cos me* s « ©n _— nierssnt References ïyi'é rno! crossed out null José CURAU Industrial Property Council 26blsf BOUT~Princes3e.^CKar[otte MO^TE-CARi " r f -01 0 luraiiofi ds IJ-OULUMRotin /Uy~. 1 <3 •