IE904210A1 - Steroids - Google Patents
SteroidsInfo
- Publication number
- IE904210A1 IE904210A1 IE421090A IE421090A IE904210A1 IE 904210 A1 IE904210 A1 IE 904210A1 IE 421090 A IE421090 A IE 421090A IE 421090 A IE421090 A IE 421090A IE 904210 A1 IE904210 A1 IE 904210A1
- Authority
- IE
- Ireland
- Prior art keywords
- yloxy
- internal salt
- hydroxy
- hydroxide internal
- ethoxy
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Steroids of the formula in which R<1> to R<4>, X and n have the meaning indicated in the description, have activity reducing the intestinal absorption of cholesterol and the plasma cholesterol. They are prepared starting from corresponding steroids with an alcohol residue of the formula -O-X-OH in position 3.
Description
R is hydrogen, lower-alkyl or lower-alkylidene,
3 4
R . R and R 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(C.0')-(Z)1 or
-CH2CH(Y)CH2-(Z)1 oi θ-,
-CH2CH(CH2Y)-(Z)1 or 0- or
-(CH-CH,O) -CH CH,-(Z), .-.
2 q 2 2 1 or O q is the number 1 or 2.
Z is a group of the formula -C(O)-. -OC(O)-,
-0C(0)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
Me/11.9.90
90421ο carbonyl, can also be O,
Y is hydroxy, lower-alkoxy, lower-alkanoyloxy.
carbamoyloxy or mono- or di-lower alkyl-carbamoyloxy.
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 mono10
-unsaturated, and physiologically compatible salts thereof.
The hydrogen atoms attached to the C atoms in position and 5 of the steroid part of the compounds of formula I . . .
can each independently have the a- or β-configuration.
The invention is also concerned with a process for the manufacture of these steroids, medicaments based on the latter and these steroids as pharmaceutically active substances, as well as the use of these steroids in the manufacture of medicaments which inhibit the intestinal resorption of cholesterol and which lower the plasma cholesterol.
The term lower signifies that the residues denoted thereby contain up to 4 carbon atoms and can be straight-chain or branched. Methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl are examples of lower-alkyl residues. Methylene and ethylidene are examples of lower-alkylidene 30 residues. Acetoxy and propionyloxy are examples of lower-alkanoyloxy residues.
Pharmaceutically acceptable salts of the steroids of formula I are inorganic salts such as hydrochlorides and sulphates: organic salts such as trifluoroacetates.
mesylates and tosylates; and metal salts such as sodium salts. The compounds of formula I can be present in the form of a zwitterion and those in which at least one of
3 4 the residues R . R and R is hydrogen can be present in the form of a hydrogen phosphate.
Among the steroids of formula I there are preferred those in which R1 is hydrogen or lower-alkyl, especially 2 ethyl, further those in which R is hydrogen or 3 4 lower-alkyl and R and R are lower-alkyl, especially 2 3 4 methyl, or in which R . R and R together with the
N atom form a pyridinium or 1-methylpyrrolidinium group.
Further, the eteroids of formula I in which n is the number 2 as well as those having a saturated or 5(6)15 -unsaturated or 5(6)- and 22(23)-unsaturated steroid part are preferred.
Further preferred steroids of formula I are those in which X represents the group -(CH2)2~.
-(CH ) O(CH ) -. -(CH ) O(CH ) O(CH ) -.
-ch2?hShch2 . -ch2ch(ococh3)?h2-.
-CH2CH(OCONHCH3)CH2N[CH(CH3) ]co-.
-(CH ) NHCO-. - (CH ) NHCO-. -CH CHOHCH OCO-.
A A Aw A A
-(CH(CH3)CO- or especially -(CH2)2OCO-.
-(^2½000-° -2)4°CO-. -(CH2)bOCO-.
-(CH2)CO-. -(ch2)2co-. -(ch2)3co-.
- (CH )_CO-. -CH.CH(OCOCH.)CH OCO-.
b 2 4 2
-CH2C(CH3>2CO- or -CH2CH(CH2OH)NHCO-.
The following are examples of preferred compounds of formula I:
O-[[2-[[(Cholest-5-en-3H-yloxy)carbonyl]oxy]ethoxy]hydroxyphosphinyl]choline hydroxide internal salt,
0-[hydroxy-[3-[(3H-stigmastanyloxy)carbonyl]propoxy] phosphinyljcholine hydroxide internal salt.
- 4 O-[[2-(cholest-5-en-3fi-yloxy)ethoxy]hydroxyphosphinyl] choline hydroxide internal salt and
O-[hydroxy-[2-[1-(5a-stigmastan-3fl-yloxy)formamidojethoxyjphosphinylJcholine hydroxide internal salt.
The following are further examples of compounds of formula I:
O-[[2-[[(5a-Stigmastan-3fl-yloxy)carbonylJoxyJethoxyJhydroxyphosphinyl]choline hydroxide internal salt.
O-[hydroxy-[2-[[[E)-stigmasta-5.22-dien-3flyloxyjcarbonylJ ethoxyJphosphinylJcholine hydroxide internal salt,
O-[[3-[[(cholest-5-en-3fl-yloxy)carbonyl]oxyJpropoxyJ20 hydroxyphosphinyl]choline hydroxide internal salt,
O-[[4-[[(cholest-5-en-3fl-yloxy)carbonyl]oxy]butoxyJhydroxyphosphinylJcholine hydroxide internal salt,
O-[[[8-[[(cholest-5-en-3fl-yloxy)carbonylJoxyJoctylJoxyjhydroxyphosphinylJcholine hydroxide internal salt.
0-[[[(cholest-5-en-3B-yloxy)carbonyl]methoxyJhydroxyphosphinylJcholine hydroxide internal salt,
0-[[2-[(cholest-5-en-3fl-yloxy)carbonyl JethoxyJhydroxyphosphinylJcholine hydroxide internal salt,
0-[hydroxy-[2-[(3B-stigmastanyloxy) carbony1J ethoxy]35 phosphinylJcholine hydroxide internal salt.
0-[hydroxy-[2-[(6tigmasta-5,22-dien-3B-yloxy)carbonyl J ethoxyjphosphinylJcholine hydroxide internal salt.
- 5 Ο-[[3-[(cholest-5-en-3B-yloxy)carbonyl]propoxy]hydroxy phosphinyl]choline hydroxide internal salt,
O-[hydroxy-[3-[(E)-stigmasta-5.22-dien-3B-yloxy)carbonyl]propoxy]phosphinyl]choline hydroxide internal salt.
O-[hydroxy-[[5-[(5a-stigmastan-3B-yloxy)carbonyl]pentyl]oxy]phosphinyl]choline hydroxide internal salt.
O-[hydroxy-[[5-[((E)-stigmasta-5.22-dien-3fl-yloxy)carbonyl]pentyl]oxy]phosphinyl]choline hydroxide internal salt,
O-[hydroxy-[[[(3fl-stigmastanyl)oxy]carbonyl]methoxy]phosphinylJcholine hydroxide internal salt.
O-[hydroxy-[[[(E)-stigmasta-5.22-dien-3fl-yloxy]carbonyl]methoxy]phosphinyl]choline hydroxide internal salt,
O-[hydroxy-[2-(stigmasta-5.22-dien-3B-yloxy)ethoxy]phosphinylJcholine hydroxide internal salt.
O-[[2-[2-(cholest-5-en-3fl-yloxy)ethoxy]ethoxy]hydroxyphosphinylJcholine hydroxide internal salt.
O-[hydroxy-[2-[2-[(E)-stigmasta-5.22-dien-3flyloxy)ethoxy]ethoxy]phosphinyl]choline hydroxide internal salt,
0-[[2-[2-[2-(cholest-5-en-3B-yloxy)ethoxy]ethoxy]35 ethoxy]hydroxyphosphinyl]choline hydroxide internal salt.
0-[[2-[(5a-cholestan-3fl-yloxy) carbonyloxy]ethoxy]hydroxyphosphinyl]choline hydroxide internal salt.
0-[hydroxy-[2-[2-(3β_stigmastanyloxy)ethoxy]ethoxy]phosphinyl]choline hydroxide internal salt.
- 6 0- [hydroxy- [2- (SB-stigmastanyloxyJethoxyjphosphinylJcholine hydroxide internal salt,
1-[2-[[hydroxy-[2-[1-(5a-stigmastan-3B-yloxy)formamido]ethoxy]phosphinyl]oxy]ethylJpyridinium hydroxide internal salt.
0-[hydroxy-[2-[l-[(E)-stigmasta-5,22-dien-3flyloxyJformamidoJethoxy]phosphinylJ choline hydroxide internal salt.
0-[hydroxy-[3-[1-[(E)-stigmasta-5,22-dien-3fi15 yloxyjformamidoJpropoxyJphosphinylJcholine hydroxide internal salt.
0-[hydroxy-[(RS)-3-[N-isopropyl-1-[(E)-stigmasta-5,22 -dien-3fl-ylJoxyformamidoJ-2-[(methylcarbamoyl)oxy]propoxyJ
2o phosphinyljcholine hydroxide internal 6alt,
0-[[[2-[1-cholest-5-en-3fi-yloxyJformamidoJ ethoxyJhydroxyphosphinylJcholine hydroxide internal salt.
0-[[2-[1-(5fl-cholestan-3a-yloxy)formamidoJethoxyJhydroxyphosphinylJcholine hydroxide internal salt,
1-[2-[[hydroxy-[3-[1-[(E)-stigmasta-5,22-dien-3fl-yloxyJformamido]propoxy]phosphinyl]oxyJethylJpyridinium 30 hydroxide internal salt.
0-[hydroxy-[2-[[[(E)-stigmasta-5.22-dien-3fl-yloxyJcarbonyljoxyjethoxyjphosphinyljcholine hydroxide internal salt.
l-[2-[[[2-[l-[cholest-5-en-3B-yloxy]formamidoJethoxyJ hydroxyphosphinyl]oxyJethylJ-l-methylpyrrolidinium hydroxide internal salt.
- 7 l-O- (3a,B-6tigmaBtanyl )-3-0- (RSJ-glyceryl-phosphorylcholine.
O-[[(RS)-2-acetoxy-3-[5a-stigmastan-3a.B-yloxy]propoxyjhydroxyphosphonyljcholine hydroxide internal salt.
O-[[(RS)-3-[(cholest-5-en-3B-yloxy)carbonyloxy]-210
-hydroxypropoxy]hydroxyphosphinylJcholme hydroxide internal salt.
O-[hydroxy-(RS)-2-hydroxy-3-[[5a-stigmastan-3B-yloxy)carbonyloxy]propoxyJphosphinyl]choline hydroxide
internal salt
0-[hydroxy-[(RS)-2-hydroxy-3-[[(E)-stigmasta-5.22-dien-3B-yloxy]carbonyloxy]propoxy]phosphinyljcholine hydroxide internal salt,
O-[hydroxy-[2-[[(stigmast-5-en-3B-yloxy) carbonyl]oxy] ethoxy]phosphinyl]choline hydroxide internal salt.
0-[hydroxy-[3-[(stigraast-5-en-3B-yloxy)carbonyl]25 propoxy]phosphinyl]choline hydroxide internal salt,
0-[hydroxy-[2-(stigmast-5-en-3B-yloxy)ethoxyJphosphinyl]choline hydroxide internal salt, 30 cholest-5-en-3B-yl 2-[[[2-(dimethylamino)ethoxyjhydroxyphosphinyl]oxy]ethylcarbonate,
0-[hydroxy-[2-[1-(stigmast-5-en-3B-yloxy)formamido]ethoxy]phosphinyl]choline hydroxide internal salt,
0-[[(RS)-2-acetoxy-3-[[(cholest-5-en-3B-yloxy)carbonyl]oxy]propoxyJhydroxyphosphinyl]choline hydroxide internal salt.
O-[[2-[cholest-5-en-3B-yloxy)carbonyl]-2-methylpropoxy ] hydr oxyphosphinyl] -choline hydroxide internal salt and
O-[[(RS)-2-[l-(cholest-5-en-3B-yloxy)formamido]-3hydroxypropoxy]hydroxyphosphinyl]choline hydroxide internal salt.
The steroids of formula I and the salts thereof can be manufactured by
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
- I ® 0
R -N-iCH?) -0P>4 1© (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.
These reactions can be carried out in a manner known per se.
Thus, a carbonate of formula II in which X is a group of the formula -(CH_) -OCO- is reacted in a solvent 2 p .
such as methylene chloride or chloroform in the presence of a base such as quinoline or pyridine firstly with a halide of the formula PO(Hal)3. e.g. phosphorus oxychloride, at room temperature and the compound obtained can be treated with a salt of the formula
wherein W is lower-alkylsulphonyloxy or arylsulphonyloxy. e.g. with choline tosylate, in the presence of a base such as pyridine in a solvent such as methylene chloride at room temperature.
A carbamate of formula II in which X is a group of the formula -(CH ) N(T)C(O)- can be reacted firstly with a 2 p halide of the formula
- 10 IV
e.g. with 2-chloro-2-oxo-l.3.2-dioxaphospholane. in a solvent such as tetrahydrofuran (THF) while cooling to temperatures to 0°C in the presence of a base such as triethylamine and the phosphate obtained can be reacted in 2 3 4 the same solvent with an amine of the formula N(R ,R ,R ) while heating, e.g. to 50 to 100°C.
An ester of formula II in which X is a group of the formula -CH(CH3)CO- can firstly be reacted with a halide such as β-bromoethylphosphoric acid dichloride (Pharm.
2o Acta Helv. 33. 1958» 349) in a solvent such as methylene chloride in the presence of a base such as triethylamine and the compound obtained can then be treated in a solvent such as toluene with an amine of the formula
3 4
N(R ,R ,R ).
As described in Example 11 hereinafter, a benzyl group can be used to protect a hydroxy residue Y present in the group X of a compound of formula II. Thus, a glycerol derivative of formula II in which X is a group of the 30 formula -CH2CH(OH)CH2~ can be reacted with trityl chloride in pyridine to give the corresponding trityl ether. This ether can be converted by means of sodium hydride in THF and benzyl chloride in dimethylformamide (DMF) at a temperature up to 100°C into the corresponding 35 trityl benzyl diether in which X stands for
-CH„CH(OCH„C.Hc)CHO-. After cleavage of the ζ ζ o b z trityl group from the diether, e.g. by means of hydroIE 904210
- 11 chloric acid in dioxan while heating, the benzyl ether obtained is treated as described above with an agent which introduces the group
(G).
By cleavage of the benzyl group, e.g. by hydrogenation in the presence of palladium-charcoal (Pd/C) in methanol and
THF or (in order to avoid the simultaneous hydrogenation of double bonds present in the steroid part of the ether) in the presence of palladium oxide (PdO) in acetic acid, there is obtained the glycine derivative of formula 1 in which X is -CH2CH(OH)CH2-. which corresponds to the starting compound of formula II.
A benzyl-protected steroid alcohol of formula II in which X stands for -CH2CH(OCH2C6H5)CH2- can also be prepared by reacting the corresponding steroid
3-chloroformate with O-benzylglycerol in methylene chloride.
As described in Example 22 hereinafter, a phenoxycarbonyl group can also be used for the protection of a hydroxy residue Y present in the group X of a compound of formula II. Thus, a compound of formula II in which X is a group -CH2CH(CH2OH)NHCO- can be reacted with phenyl chloroformate in methylene chloride, THF and pyridine. The resulting compound containing a phenoxycarbonyloxy group is then reacted, e.g. in toluene and triethylamine, with an agent which introduces the group of formula G above,
e.g. with 2-chloro-2-oxo-l.3.2-dioxaphospholane. and then •Ε 904210
- 12 with trimethylamine in toluene and acetonitrile. The compound of formula 1 in which X is the group
-CH2CH(CH2OH)NHCO- is then obtained by cleaving off the phenoxycarbonyl group, e.g. using aqueous sodium hydroxide.
The hydrogenation of an unsaturated steroid of 10 formula I can be carried out in the presence of Pd/C in a solvent such as methanol at a temperature up to 100°C.
The alkanoylation of a hydroxy group Y can be mentioned as a functional modification of a reactive residue present in the group X of a steroid of formula I. Thus, a glycerol derivative of formula I in which X is the group -CH2CH(OH)CH2- can be reacted at room temperature in a solvent such as chloroform in the presence of a base such as pyridine and a catalyst such as
dimethylaminopyridine (DMAP) with the carboxylic acid anhydride corresponding to the alkanoyl group to be introduced.
The starting alcohols of formula II in which X is a group of the formula -(CH2)p-C(Q,Q')-Z',
-CH2CH(Y)CH2-Z'-, -CH2CH(CH2Y)-Z·- or
-(CHCH.O) -CHCH-Z1-, Z' is a group of the
2 g 2 2 formula -0C(0)-. -OC(O)CH -. -OCH C(0)- or -N(T)C(O)1 2 2 . . . and R . Q, Q', p. q, y and T have the significance given 3Q above are novel and as such are an object of the invention
The alcohols of formula II can be prepared in a manner known per se, e.g. as described in Examples A to M hereinafter .
Thus, an alcohol ether of formula II in which X is
e.g. a group -(CH ) - can be prepared by reacting the 2 p corresponding steroid-3-tosylate with the glycol
- 13 HO-(CH ) -OH in dioxan at about 120°C.
p
An alcohol ester of formula II in which X is e.g. a group -(CH_) -CO- can be prepared by reacting the z p corresponding steroid-3-ol in methylene chloride with the corresponding halide of the formula Hal-(CH ) -COCI at z p about 5°C in the presence of pyridine and converting the 10 halide obtained into the desired alcohol of formula II by means of potassium trifluoroacetate in methylene chloride, DMF and water at about 80°C.
An alcohol ester of formula II in which X is e.g. a 15 group -CH(CH3)CO- can be prepared by reacting the corresponding steroid-3-ol with lactic acid in toluene in the presence of catalytic amounts of p-toluenesulphonic acid.
An alcohol carbonate of formula II in which X is e.g.
a group -(CH_) -0C(0)- can be prepared by reacting the z p corresponding steroid-3-ol in methylene chloride at about -10°C with a solution of phosgene in toluene and reacting the steroid-3-chloroformate obtained in chloroform or methylene chloride with a diol of the formula
HO-(CH-) -OH in the presence of pyridine or triethylz p amine at about 5°C.
An alcohol carbamate of formula II in which X is e.g. a group -(CH_) -N(T)C(O)- can be prepared by reacting έ P the corresponding steroid-3-ol in chloroform and THF with phenyl chloroformate in the presence of pyridine and reacting the phenylcarbonate obtained in chloroform with the amine of the formula HO-(CH)-N(T)-H.
p
A compound of formula II in which X is a group of the formula -CH-CHfOCONHiT1)]CH_N(T2)C(O)- and T1 and T are hydrogen or lower-alkyl can be prepared by
- 11 reacting the corresponding l-deoxy-l-amino-3-O-tritylglycerol of the formula T2NHCH2CHOHCH2OC(C6H5)3 with a steroid-3-chloroformate in methylene chloride in the presence of potassium hydroxide, reacting the product obtained in methylene chloride with the isocyanate of the formula O=C=N(T1) at 80°C and cleaving off the trityl group from the product obtained in dioxan by means of hydrochloric acid at 95°C.
A glycerol derivative of formula II in which X is a group -CH2CH(OH)CH2- is obtained by reacting the corresponding 3-0-tosylsteroid in dioxan with glycerol at 15 100°C.
An alcohol of formula II which has a double bond in the steroid part can be hydrogenated to the corresponding saturated alcohol, e.g. in the presence of Pd/C in THF.
The preparation of some compounds of formula II is described in detail in Examples A to M hereinafter.
Example A
A solution of 10 g of cholesterol tosylate and 25.3 g of ethylene glycol in 180 ml of dioxan is heated to 120°C while stirring. The mixture is then treated with 200 ml of water and extracted with ether. The ethereal phase is 30 washed firstly with 10% sodium carbonate solution and then with water. The organic phase is dried and evaporated. The residue is chromatographed on silica gel while eluting with ether/hexane. There are obtained 5.6 g of 2-(cholest-5-en-3B-yloxy)-l-ethanol. m.p. 92-95°C, the starting material in Example 2q.
- 15 Example B
Analogously to Example A there are obtained:
a) 2-[[(E)-Stigmasta-5.2-dien-3fl-yl]oxy]-l-ethanol. MS: 456 (M+H+).
b) 2-[2-[(E)-stigmasta-5,22-dien-3B-yloxy]ethoxy]-1-ethanol. MS: 501 (M+H+).
c) 2-[2-(cholest-5-en-3B-yloxy)ethoxy]-l-ethanol. MS: 474 (M+H+),
d) 2-[2-[2-(cholest-5-en-3B-yloxy)ethoxy]ethoxy]ethanol. MS: 519 (M+H+).
Example C
1. A solution of 20 g of stigmastanol in 200 ml of methylene chloride and 4 ml of pyridine is added dropwise at 5°C to a solution of 12.5 g of 3-bromopropionyl chloride (obtained from 11.1 g of bromopropionic acid and 25 9.77 ml of oxalyl chloride in 55 ml of methylene chloride and 3 drops of DMF) in 44 ml of methylene chloride. The mixture is evaporated, 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 30 evaporated. The residue is chromatographed on silica gel while eluting with ether-hexane. There is obtained 3B-stigmastanyl 3-bromopropionate of melting point 150-152°C.
2. Analogously there are prepared:
a) Stigmasta-5.22-dien-3fl-yl 3-bromopropionate.
- 16 b) 5a-stigmastan-3B-yl bromoacetate.
c) cholest-5-en-3B-yl bromoacetate.
d) cholest-5-en-3B-yl bromopropionate.
e) 5a-stigmastan-3B-yl 4-bromobutyrate.
f) cholest-5-en-3B-yl 4-chlorobutyrate.
g) 3B-stigmastanyl 4-chlorobutyrate, !5 h) 3B-stigmastanyl 4-iodobutyrate,
i) (E)-stigmasta-5.22-dien-3B-yl 4-chlorobutyrate,
j) (E)-stigmasta-5.22-dien-3B-yl 4-iodobutyrate.
k) cholest-5-en-3B-yl 4-iodobutyrate.
l) (E)-stigmasta-5.22-dien-3B-yl 6-bromohexanoate,
m) 5a-stigmastan-3B-yl 6-bromohexanoate.
n) stigmast-5-en-3B-yl 4-bromobutyrate.
3. A solution of 23.1 g of 3B-stigmastanyl 3-bromo30 propionate in 400 ml of methylene chloride and 200 ml of DMF is treated with 63.3 g of potassium trifluoroacetate and heated at 80°C over 72 hours. After adding 30 ml of water the solution is heated at 8O°C for a further l hour The solution is evaporated and the residue is chromato35 graphed on silica gel using ether-hexane. There is obtained 3B-stigmastanyl 3-hydroxypropionate of melting point 152-153°C. the starting material of Example 2o.
. - 17 Example D
Analogously to Example C there are prepared:
a) Cholest-5-en-3fl-yl glycolate, MS: 369 (M-HOCH2COOH).
b) 3B-stigmastanyl glycolate. MS: 399 (M-HOCH2COOH).
c) cholest-5-en-3fl-yl 3-hydroxypropionate, MS: 368 (M-HOCH CH COOH). z z
d) stigmasta-5.22-dien-3fl-yl 3-hydroxypropionate. MS: 394 15 (M-HOCH2CH2COOH).
e) cholest-5-en-3fl-yl 4-hydroxybutyrate. m.p. 98°C,
f) 3fi-stigmastanyl 4-hydroxybutyrate. m.p. 149°C.
g) (E)-stigmasta-5.22-dien-3B-yl 4-hydroxybutyrate. m.p. 147°C.
h) 5a-stigmastan-3B-yl 6-hydroxyhexanoate, m.p. 130°C.
i) (E)-stigmasta-5.22-dien-3B-yl 6-hydroxyhexanoate. m.p. 133°C,
j) stigmast-5-en-3B-yl 4-hydroxybutyrate. m.p. 125-126°C.
Example E
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 to a solution of 13.8 g of ethylene glycol in 200 ml of methylene chloride. The solution is then treated with 300 ml of water and extracted with methylene chloride. The organic phase is washed with
- 18 water, dried and evaporated. The residue is recrystallized in methylene chloride-ethanol. There are obtained 6.4 g of cholest-5-en-3B-yl 2-hydroxyethylcarbonate of melting point 139-14O°C. the alcohol starting material of
Example 1.
Example F
Analogously to Example E there are prepared:
a) 5a-Stigmastan-3B-yl 2-hydroxyethylcarbonate, m.p.
184°C,
b) 2-hydroxyethyl (E)-stigmasta-5.22-dien-3fl-ylcarbonate. m.p. 172°C.
c) cholest-5-en-3fl-yl 3-hydroxypropylcarbonate. m.p. 96°C,
d) cholest-5-en-3B-yl 4-hydroxybutylcarbonate. m.p. 107°C,
e) cholest-5-en-3B-yl 8-hydroxyoctylcarbonate, m.p. 79°C,
f) 2-hydroxyethyl stigmast-5-en-3B-ylcarbonate. m.p.
160»C.
Example G
1. A solution of 1.71 g of phenyl chloroformate in 5 ml of CHClj is added dropwise to a suspension, cooled to
-50°C, of 4.16 g of etigmastanol in 25 ml of CHC13<
12.5 ml of THF and 0.75 ml of pyridine. A further 0.25 ml of pyridine is then added. The mixture is reacted at a low temperature for 30 minutes and at room temperature for a further 1 hour. The reaction solution is poured into a solution of pyridine and agueous KHCO3· After the evolution of CO has finished the mixture is evaporated z
- 19 to dryness. The residue is partitioned between CH2C12 and HO. After crystallization from CH Cl -pentane
A A A there are obtained 4.75 g of 3-stigmastanyl phenylcarbonate. M.p. 96°C.
2. 0.3 ml of ethanolamine is added to a solution of 1.07 g of the above phenylcarbonate in 3 ml of CHC13·
The mixture is reacted at room temperature for 2 days. The excess reagent is distilled off and the phenol which results in the reaction is separated as Na phenolate. The compound is crystallized from CH2C12· There is obtained 0.9 g of 3B-stigmastanyl (2-hydroxyethyl)25 carbamate. M.p. 206°C, the starting material in Example 5.
Example H
Analogously to Example G,
1. from stigmasterol via (E)-stigmasta-5.22-dien-3B-yl phenylcarbonate. m.p. 156-157°C, there are obtained
a) (E)-stigmasta-5.22-dien-3fl-yl (2-hydroxyethyl)carbamate. m.p. 187°C. and
b) (E)-stigmasta-5.22-dien-3fl-yl (3-hydroxypropyl)carbamate. m.p. 172-173°C,· 3Q 2. from cholesterol via 3B-cholesteryl phenylcarbonate there is obtained 3fl-cholesteryl (2-hydroxyethyl) carbamate, m.p. 168-170oC;
3. from epicoprostanol via epicoprostanyl phenylcarbamate there is obtained epicoprostanyl (2-hydroxyethyl)35 carbamate, m.p. 98°C;
4. from β-sitosterol via stigmast-5-en-3-yl phenylIE 904210
- 20 carbonate, m.p. 108-109°C, there is obtained stigmast-5-en-3fl-yl (2-hydroxyethyl)carbamate. m.p. 198-199°C, the starting material in Example 19.
Example I
1. 10 ml of a 20% phosgene solution in toluene are added to a solution, cooled to -10°C, of 4.12 g of stigmasterol in 40 ml of methylene chloride. The mixture is reacted overnight and then cooled to -10°C. After adding 0.7 ml of triethylamine in 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 the (E)-stigmasta-5.22-dien-3B-yl chloroformate is isolated.
2. A solution of 2.3 g of the above chloroformate in
2o Ιθ ml of chloroform is added dropwise 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 is poured on to ice and a sodium bicarbonate solution. The mixture is extracted with methylene chloride, chromatographed on silica gel with toluene/ chloroform/ethyl acetate (4/2/1 vol.). After crystallization from methylene chloride-methanol there are obtained 1.86 g of (E)-stigmasta-5,22-dien-3fl-yl (2-hydroxyethyl)carbamate, m.p. 172-173°C. the alcohol 30 starting material of Example 9.
Example J
1. A solution of 1.45 g of 3-O-tosylstigmasterol in 20 ml 35 of dioxan is reacted with 2.5 g of glycerol for 2 hours at
100°C while stirring. After distillation of the solvent, dilution of the residue with water, extraction with diethyl ether and crystallization from methylene chlorideIE 904210
- 21 -methanol there is obtained 1 g of O-3a,fi-stigmasteryl-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 catalyst, distillation of the solvent and crystallization from THF-methanol there is obtained in quantitative yield O-3a,B-stigmastanyl-(RS)-glycerol. the starting material of Example ll.
Example K
1. 0.74 g of (RS)-glycidol and 2.8 g of trityl chloride in 5 ml of pyridine are reacted overnight. A solution of 2 g of potassium bicarbonate is then added while stirring. After evaporation, partition of the residue between' water and methylene chloride and chromatography on silica gel
2o with toluene there are obtained 2.25 g of (RS)-epoxy-l-O-tritylglycerol.
2. 3 g of this product are reacted with 5 ml of isopropylamine in a bomb tube at 100°C for 2 hours. After distilling off the excess isopropylamine 4.4 g of (RS)-l-deoxy-l-isopropylamino-3-O-tritylglycerol. m.p. 128-130°C, are crystallized from methylene chloride-hexane
3. 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 to a solution, cooled to -10°C. of 1.1 g of stigmasteryl chloroformate in 4 ml of methylene chloride. After reaction at room temperature for 2 hours, phase separation in a separating funnel.
_c chromatography on silica gel with methylene chlorideJo
-diethyl ether (2/1) there are obtained 1.63 g of (E)-stigmasta-5.22-dien-3fl-yl isopropyl-[(RS)-2-hydroxy-3-trityloxypropyl]-carbamate. m.p. 75-76°C.
- 22 4. A solution of 2 g of the above product in 10 ml of methylene chloride is reacted with 2 ml of methyl isocyanate in a bomb tube at 80°C for 40 hours and there is obtained in quantitative yield (E)-stigmasta-5.22-dien -3B-yl isopropyl-[(RS)-2-methylcarbamoyl-3-trityloxypropylj-carbamate, m.p. 92-93°C.
- By cleaving off the trityl group analogously to
Example 11c there are obtained from 2.5 g of the above trityl ether 1.7 g of (E)-stigmasta-5,22-dien-3B-yl [(RS)-3-hydroxy-2-[(methylcarbamoyl)oxy]propyl]-isopropyl carbamate, m.p. 240°C. the starting material in Example 7
Example L
A solution of 10.2 g of cholesteryl chloroformate in 130 ml of methylene chloride is treated under argon while 2Q stirring with 4.6 g of 2-O-benzylglycerol in 120 ml of methylene chloride and 2 ml of pyridine, taken up in 500 ml of water and 50 ml of IN HCl after 1 hour and extracted with methylene chloride. The organic phase is dried and concentrated at 50°C. After chromatography over 25si°2 with n-hexane:ether (1:1) there are obtained 6.17 g of (RS)-2-(benzyloxy)-3-hydroxypropyl chloride 5-en-3B-ylcarbonate, MS: 595 (M+H+). the starting material of Example 13.
Example M
A solution of 3.86 g of cholesterol and 0.85 ml of L-(+)-lactic acid (90% in water) in 80 ml of toluene is boiled for 1 hour. The water is separated, the cooled reaction mixture is treated with 0.3 g of p-toluene35 sulphonic acid and boiled for a further 4 hours. The reaction mixture is treated with 30 ml of water and extracted with ether. The organic phase is dried over
- 23 sodium sulphate and concentrated. The residue is purified on silica gel (elution agent petroleum ether/ether 4:1).
There are obtained 1.5 g of cholest-5-en-3B-yl (S)-2-hydroxypropionate, m.p. 120-122°C.
The steroids of formula I and the 6alts thereof inhibit the intestinal resorption of cholesterol.
The inhibition of the intestinal resorption of cholesterol can be demonstrated as follows in an animal experiment:
Squirrel monkeys are orally administered the substances to be investigated together with a test feed 14 containing a protein, starch, triolein and [26- C]-cholesterol. Thereafter, the faeces is collected for
2.5 days. The difference between the administered and the
2q collected radioactive cholesterol determined in the faeces is taken as the measurement of resorbed cholesterol. The cholesterol resorption (CHORES) is expressed in percentages of the control values determined prior to the medication.
The results which have been obtained with some representative products in accordance with the invention are reproduced in the Table hereinafter. There are given for each of the compounds indicated therein the 30 cholesterol resorption, determined at a dosage of 100 vimol/kg p.o., in percentages of that in the pre-period. Moreover, the Table contains data concerning the acute toxicity of the compounds investigated (LD^0 in mg/kg in the case of single oral or intravenous administration to mice).
- 24 Table
Compound of formula I of Example No. 2a 2k 2q 2r 4a CHORES in % of the pre-period: 3Θ 39 16 37 30 LD5o in mg/kg p.o. 4000 4000 4000 4000 i.v. 250 250 250 500
Compound of formula I of Example No. 5 6 7a 16 CHORES in % of the pre-period: 40 31 35 40 LD__ in mg/kg p.o. b v 4000
The products in accordance with the invention can be used as medicaments. 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 and soft gelatine capsules, solutions, emulsions or suspensions.
For the manufacture of pharmaceutical preparations, the products in accordance with the invention can be mixed
- 25 with pharmaceutically inert, inorganic or organic carriers. Lactose, maize starch, talc, stearic acid or its salts can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatine capsules. Vegetable oils, waxes, fats or semi-solid and liquid polyols are, for example, suitable carriers for soft gelatine capsules; depending on the nature of the active substance no carrier is. however, generally required in the case of soft gelatine capsules. Water, polyols, saccharose, invert sugar and glucose are, for example, suitable carriers for the manufacture of solutions and syrups.
The pharmaceutical preparations can, moreover, contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the
osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, medicaments containing a steroid of formula I or a pharmaceutically acceptable salt thereof
are also an object of the present invention, furthermore also a process for the manufacture of such medicaments which comprises bringing one or more products in accordance with the invention and. if desired, one or more 3Q other therapeutically valuable substances into a galenical administration form. As mentioned earlier, the products in accordance with the invention can be used in the control or prevention of illnesses.
They can be used especially in the control or prevention of hypercholesterolemia and of atherosclerosis. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each
- 26 particular case. In general, in the case of oral administration a daily dosage of about 50 mg to about 3 g, preferably of about 200 mg to about 1 g. should be appropriate.
The manufacture of compounds of formula I is described in the Examples hereinafter.
Example 1
A solution of 48.7 g of cholest-5-en-3B-yl 2-hydroxyethylcarbonate and 10 ml of quinoline in 500 ml of methylene chloride is added dropwise at room temperature to a solution of 12.5 ml of phosphorus oxychloride. The solution is treated at room temperature while stirring with 60 ml of pyridine and 77 g of choline tosylate in 500 ml of methylene chloride, whereupon the reaction mixture is stirred at room temperature overnight. The mixture is treated with 125 ml of water and 34 g of sodium bicarbonate and then with 3000 ml of acetone. The precipitated product is filtered off under suction, dissolved in 1000 ml of chloroform-methanol 1:1 and stirred with 500 g of ion exchanger (Amberlite MB-3). The latter is filtered off under suction and the solution is evaporated. The resulting residue is recrystallized in a mixture of methylene chloride-methanol 1:1 and dioxan. There are obtained 39 g of O-[[2-[[(cholest-5-en-3B-yloxy)car bony1]oxy]ethoxy]hydroxyphosphinyl]choline hydroxide internal salt of melting point 224°C, MS: 640 (M+H)+.
Example 2
Analogously to Example 1,
a) starting from 5a-stigmastan-3B-yl 2-hydroxyethylIE 904210
- 27 carbonate there is obtained O-[[2-[[(5a-stigmastan-3fl-yloxy)carbonyl]oxy]ethoxyJhydroxyphosphinylJcholine hydroxide internal salt. m.p. 220°C
b) starting from 2-hydroxyethyl (E)-stigmasta-5,22-dien-3fl-ylcarbonate there is obtained O-[hydroxy-[2-[[[E)-stigmasta-5.22-dien-3fl-yloxy]carbonyl]ethoxy]phosphinyl] 10 choline hydroxide internal salt, m.p. 220°c
c) starting from cholest-5-en-3fl-yl 3-hydroxypropylcarbonate there is obtained 0-[[3-[[(cholest-5-en-3B-yloxy) carbony1]oxy]propoxy]hydroxyphosphinyl]choline hydroxide internal salt. m.p. 23O°C
d) starting from cholest-5-en-3fl-yl 4-hydroxybutylcarbonate there is obtained 0-[[4-[[(cholest-5-en-3fl-yloxy) carbonyl]oxy]butoxy]hydroxyphosphinylJcholine
hydroxide internal salt, m.p. 232°C
e) starting from cholest-5-en-3fl-yl 8-hydroxyoctylcarbonate there is obtained O-[[[8-[[(cholest-5-en-3B-yloxy)carbonyl]oxy]octyl]oxy]hydroxyphosphiny1]choline hydroxide internal salt. m.p. 235°C
f) starting from cholest-5-en-3fl-yl glycolate there is obtained O-[[[(cholest-5-en-3B-yloxy)carbonylJmethoxyJhydroxyphosphinylJcholine hydroxide internal salt. m.p.
226°C
g) starting from cholest-5-en-3B-yl 3-hydroxypropionate there is obtained 0-[[2-[(cholest-5-en-3B-yloxy)carbonyl] ethoxyJhydroxyphosphinylJcholine hydroxide internal salt,
m.p. 180°C
h) starting from 3B-stigmastanyl hydroxypropionate there is obtained 0-[hydroxy-[2-[(3B-stigmastanyloxy)carbonylJIE 904210
- 28 ethoxyjphosphinylJcholine hydroxide internal salt, m.p. 187°C
i) starting from stigmasta-5.22-dien-3B-yl 3-hydroxypropionate there is obtained O-[hydroxy-[2-[(stigmasta-5,22-dien-3B-yloxy)carbonyl]ethoxyJphosphinylJcholine hydroxide internal salt. m.p. 199°C
j) starting from cholest-5-en-3B-yl 4-hydroxybutyrate there is obtained O-[[3-[(cholest-5-en-3B-yloxy)carbonylJpropoxyjhydroxyphosphinylJcholine hydroxide internal salt, m.p. 255°C
k) starting from 3B-stigmastanyl 4-hydroxybutyrate there is obtained O-[hydroxy-[3-[(3B-stigmastanyloxy)carbonylJpropoxyjphosphinylJcholine hydroxide internal salt, m.p. 250°C
l) starting from (E)-stigmasta-5,22-dien-3B-yl
4-hydroxidebutyrate there is obtained O-[hydroxy-[3-[(E)-stigmasta-5,22-dien-3B-yloxy)carbonylJpropoxyJphosphinylJ choline hydroxide internal salt. m.p. 225°C
m) starting from 5a-stigmastan-3B-yl 6-hydroxyhexanoate there is obtained O-[hydroxy-[[5-[(5a-stigmastan-3B-yloxy)carbonyl J pentyl JoxyJphosphinylJcholine hydroxide internal salt. m.p. 254eC
n) starting from (E)-stigmasta-5.22-dien-3B-yl 6-hydroxyhexanoate there ie obtained O-[hydroxy-[[5-[((E)-stigmasta-5.22-dien-3B-yloxy)carbonyl J pentyl JoxyJphosphinyljcholine hydroxide internal salt. m.p. 215°C
o) starting from 3B-stigmastanyl glycolate there is obtained O-[hydroxy-[[[(3B-stigmastanyl)oxy]carbonylJmethoxy]phosphinylJcholine hydroxide internal salt. m.p.
•Ε 904210
- 29 260°C
p) starting from (E)-stigmasta-5,22-dien-3flyl-yl glycolate (not isolated) there is obtained O-[hydroxy-([f(E)-stigraasta-5.22-dien-3B-yloxy]carbonyl]methoxyJphosphinylJcholine hydroxide internal salt, m.p. 215°C
q) starting from 2-(cholest-5-en-3B-yloxy)-l-ethanol there is obtained O-[[2-(cholest-5-en-3fl-yloxy)ethoxy]hydroxyphosphinyljcholine hydroxide internal salt. MS: 596 (M+H+)
r) starting from 2-([(E)-stigmasta-5,22-dien-3fl-yl]oxyJ-1-ethanol there is obtained O-[hydroxy-[2-(stigmasta-5,22-dien-3B-yloxy)ethoxy]phosphinyljcholine hydroxide internal salt. m.p. 230°C
2o s) starting from 2-[2-(cholest-5-en-3B-yloxy)ethoxy]-l-ethanol there is obtained 0-([2-[2-(cholest-5-en-3fl-yloxy)ethoxy]ethoxy]hydroxyphosphinyl]cho1ine hydroxide internal salt, MS: 640 (M+H+)
t) starting from 2-(2-((E)-stigraasta-5,22-dien-3fl-yloxy]ethoxy]-l-ethanol there is obtained O-[hydroxy-[2-[2-[(E)-stigmasta-5.22-dien-3fi-yloxy]ethoxy]ethoxy]phosphinyl]choline hydroxide internal salt, MS: 666 (M+H+) 3Q u) starting from 2-[2-[2-(cholest-5-en-3fl-yloxy)ethoxy]ethoxyj-ethanol there is obtained O-[[2-[2-[2-(cholest-5-en-3B-yloxy)ethoxy]ethoxy]ethoxy]hydroxyphosphinylJcholine hydroxide internal salt, MS: 684 (M+H+).
Example 3 g of 0-([2-[(cholest-5-en-3fl-yloxy)carbonyloxy]ethoxy]hydroxyphosphinylJcholine hydroxide internal salt
- 30 is hydrogenated in 100 ml of methanol with 1 g of Pd/C 5% under 30 bar of H2 at 80°C. After filtration the solution is evaporated and the residue is dissolved in chloroform-methanol-dioxan. By adding ether there is obtained 0.6 g of O-[[2-[(5a-cholestan-3B-yloxy)carbony loxy]ethoxy]hydroxyphosphinyljcholine hydroxide internal salt as a hygroscopic powder, m.p. 225°C.
Example 4
In an analogous manner to Example 3,
a) using 0-[hydroxy-[2-[2-[(E)-stigmasta-5.22-dien-3B-yloxy]ethoxy]ethoxy]phosphinylJcholine hydroxide internal salt there is obtained O-[hydroxy-[2-[2-(3B-stigmastanyloxy)ethoxyjethoxyjphosphinylJcholine hydroxide internal salt. MS: 670 (M+H+)
b) using 0-[hydroxy-[2-(stigmasta-5,22-dien-3B-yloxy)20 ethoxyjphosphinylJcholine hydroxide internal salt there is obtained O-[hydroxy-[2-(3β-stigmastanyloxy)ethoxy]phosphinyljcholine hydroxide internal salt. m.p. 200°C.
Example 5 g of 3B-stigmastanyl (2-hydroxyethyl)carbamate and 0.35 ml of Et^N are dissolved in 5 ml of THF. A solution of 315 mg of 2-chloro-2-oxo-1,3.2-dioxaphospholane in 3 ml of THF is added dropwise to the solution, which is cooled in an ice bath. The suspension obtained is stirred at room temperature for 5 hours. The Et3N*HCl precipitate is then filtered off and the solution remaining behind is evaporated .
The phosphate obtained is dissolved in 10 ml of THF. the solution is treated in a pressure flask with 1 g of
- 31 (CH3)3N in 10 ml of THF. The mixture is reacted at 70°C for 24 hours. After distillation of the excess reagent and of the solvent the residue is taken up in 20 ml of MeOH-CHCl3 and the solution is percolated through an ion exchanger (Amberlite MB3). The product is chromatographed on silica gel with CHCl3-MeOH-H2O (60/35/5 in vol.). There is obtained 0.6 g of O-[hydroxy10 -[2- [1-(5a-6tigmastan-3B-yloxy)formamido]ethoxy]phosphinyljcholine hydroxide internal salt. MS: 669 (M+H+).
Example 6
The preparation of the phosphate is repeated as described in Example 5. The material obtained from 2 mmol of starting carbamate is dissolved in 5 ml of dry pyridine and reacted at 80°C for 24 hours. The product is isolated
and purified analogously to Example 5. There is obtained 0.95 g of l-[2-[[hydroxy-[2-[l-(5a-stigraastan-3B-yloxy)formamido]ethoxy]phosphinyl]oxy]ethyl]pyridinium hydroxide internal salt. MS: 689 (M+H+).
Example 7
Analogously to Example 5.
a) starting from (E)-stigmasta-5,22-dien-3fl-yl 3Q (2-hydroxyethyl)carbamate there is obtained O-[hydroxy-[2-[1-[(E)-stigmasta-5.22-dien-3B-yloxy]formamido]ethoxy]phosphinyljcholine hydroxide internal salt, MS: 665 (M+H+)
b) starting from (E)-stigmasta-5.22-dien-3B-yl (3-hydroxypropyl)carbamate there is obtained O-[hydroxy-[3-[1-[(E)-stigmasta-5.22-dien-3fl-yloxy]formamido]propoxy]phosphinyl]choline hydroxide internal salt. MS:
- 32 679 (M+H+)
c) starting from (E)-stigmasta-5.22-dien-3fi-yl [(RS)-3-hydroxy-2-((methylcarbamoyl)oxy]propyl]-isopropylcarbamate there is obtained O-[hydroxy-[(RS)-3-[N-isopropyl-l-[(E)-stigmasta-5,22-dien-3B-ylJoxyformamido]-2-[(methylcar bamoyl )oxyJ propoxy]phosphinylJcholine hydroxide internal salt. MS: 794 (M+H+)
d) starting from 3B-cholesteryl (2-hydroxyethyl)carbamate there is obtained O~[[[2-[l-cholest-5-en-3B-yloxy]formamido]ethoxyJhydroxyphosphinyl]choline hydroxide 15 internal salt. MS: 639 (M+H+)
e) starting from epicoprostanyl (2-hydroxyethyl)carbamate there is obtained O-[[2-[l-(5fl-cholestan-3a-yloxy)formamido]ethoxyJhydroxyphosphinylJcholine hydroxide 2o internal salt. MS: 641 (M+H+).
Example 8
Analogously to Example 6. starting from (E)-stigmasta25 -5.22-dien-3B-yl (3-hydroxypropyl)carbamate there is obtained 1-(2-([hydroxy-[3-[1-[(E)-stigmasta-5.22-dien-3B-yloxyjformamido]propoxy]phosphinyl]oxy]ethyl]pyridinium hydroxide internal salt. MS: 699 (M+H+).
Example 9
A solution of 2.22 g of (E)-stigmasta-5.22-dien-3B-yl (2-hydroxyethyl)carbonate and 1.1 ml of pyridine in 10 ml of chloroform is added dropwise to a solution, cooled to 35 0°C. of 0.75 g of phosphorus oxychloride in 3 ml of chloroform. The mixture is reacted at room temperature for hour. Then. 1.6 g of choline tosylate in 15 ml of pyridine are added. The mixture is stirred overnight, then
- 33 a solution of 2 g of potassium bicarbonate is added. The mixture is evaporated to dryness and the residue is taken up in 100 ml of THF/methanol/chloroform (l/l/l). The solids are filtered off. The solution remaining behind is percolated over an ion exchanger (Amberlite MB-3). After chromatography on silica gel with chloroform/methanol/ water (60/35/5 vol) and crystallization from methylene chloride/acetone there are obtained 1.6 g of O-[hydroxy-[2-[[[(E)-stigmasta-5.22-dien-3B-yloxy]carbonyl]oxy]ethoxy]phosphinyl]choline hydroxide internal salt. MS: 666 (M+H+).
Example 10
4.75 g of 3fi-cholesteryl (2-hydroxyethyl)carbamate are reacted with 2-chloro-2-oxo-l.3.2-dioxaphospholane. The phosphate obtained is treated with N-methylpyrrolidine at
2o 70°C for 24 hours. After chromatography on silica gel with chloroform/methanol/water (30/62.5/7.5 vol.) there are obtained 1.2 g of l-[2-[([2-[l-[cholest-5-en-3B-yloxy]formamido]ethoxy]hydroxyphosphinyl]oxy]ethyl]-1-methylpyrrolidinium hydroxide internal salt, MS: 665 (M+H+).
Example 11
a) 1.41 g of trityl chloride are added to a solution of 2.49 g of O-3a.B-stigmastanyl-(RS)-glycerol in 10 ml of pyridine. After reaction for 48 hours a potassium bicarbonate solution is added while stirring. The mixture is evaporated to dryness. The residue is partitioned between methylene chloride and water. After chromatography on silica gel with methylene chloride there is obtained
1-0-trity1-3-0-(3a.β-stigmastanyl)-(RS)-glycerol.
b) 2.4 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
- 34 dropwise to a suspension of 96 mg of sodium hydride in 5 ml of THF. After reaction at 80°C for 2 hours, distil5 lation of the solvent and partition of the residue between methylene chloride and water there is obtained 1-O-trityl-2-0-benzyl-3-0-(3a.B-stigmastanyl)-(RS)-glycerol.
c) 2 ml of IN hydrochloric acid are added to a solution. ]_0 heated to 95°C, of 2.4 g of the above benzyl ether in ml of dioxan. After reaction at 95°C for 2 hours the solvent is distilled off. the residue is taken up in hexane and the precipitated triphenylmethanol is separated. After chromatography on silica gel with toluene/ethyl acetate (9/1) there are obtained 1.5 g of 1-0-(3α,B-stigmastanyl)-2-0-benzyl-(RS)-glycerol.
d) Analogously to Example 5. from 1.4 g of the above glycerol derivative firstly by reaction with 2-chloro-220 -oxo-1.3.2-dioxaphospholane and then reaction of the resulting phosphate with trimethylamine there is obtained 0.8 g of 1-0-(3a.B-stigmastanyl)-2-O-benzyl-3-O-(RS)-glyceryl-phosphorylcholine, MS: 746 (M+H+).
e) A solution of 0.77 g of the above benzyl ether in ml of methanol and 5 ml of THF is hydrogenated under normal pressure in the presence of 10% Pd/C. There is obtained in quantitative yield l-O-(3a.B-stigmastanyl)-3-0-(RS)-glyceryl-phosphorylcholine, MS: 656 (M+H+).
Example 12 mg of DMAP and 0.5 ml of acetic anhydride are added to a solution of 0.5 g of the glycerol derivative of
Example 11 in 3 ml of chloroform and 1 ml of pyridine.
. ..,
After reaction for 1 hour the mixture is concentrated to dryness. The solution of the residue in 20 ml of methanol is percolated over ion exchanger (Amberlite MB-3). There
- 35 is obtained 0.51 g of O-[[(RS)-2-acetoxy-3-[5a-stigmastan-3a,B-yloxy]propoxy]hydroxyphosphony1Jcholine hydroxide internal salt, MS: 698 (M+H+).
Example 13
a) 1.15 ml of phosphorus oxychloride are treated under argon and while stirring with 6.1 g of (RS)-2-(benzyloxy)-3-hydroxypropylcholest-5-en-3B-yl carbonate and 1.5 ml of quinoline in 80 ml of methylene chloride. There are added thereto after 4 hours 7.4 g of choline tosylate and 6 ml of pyridine and after 24 hours 15 ml of water and 4 g of NaHCO3. After 30 minutes the mixture is poured into 500 ml of water and 50 ml of IN HCl and extracted with chloroform. The organic phase is concentrated. The product is dissolved in 150 ml of MeOH-CHCl3 (2:1) and treated with 100 g of ion exchanger (Amberlit MB3). After stirring
for 16 hours the ion exchanger is filtered off under suction. The solution obtained is concentrated at 60°C, distilled with toluene and dried. The residue is purified over silica gel with CHClg-MeOH (1:1) and CHCl3-MeOH-H2O (60:35:5). After drying there are obtained 4.9 g of
O-[[(RS)-2-benzyloxy-3-[(cholest-5-en-3B-yloxy)carbonyl25 . .
oxy]propoxy]hydroxyphosphmyl]choline hydroxide internal salt, yield: 63*. MS: 760 (M+H+).
b) 4.65 g of the product of a) and 1.4 g of PdO in 200 ml 3O of CHjCOOH are stirred under H2 under normal pressure for 20 minutes. After filtration of 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 treated with ml of dioxan and 200 ml of ether. The separated crystals are filtered off under suction, washed with ether and dried at 50°C. There are obtained 3.25 g of O-[f(RS)-3-[(cholest-5-en-3B-yloxy) carbonyloxy]-2-hydroxypropoxy]IE 904210
- 36 hydroxyphosphinyl]choline hydroxide internal salt (strongly hygroscopic), yield: 79*. MS: 670 (M+H+).
Example 14
Analogously to Example 13 there can be manufactured:
a) O-[Hydroxy-(RS)-2-hydroxy-3-[[5a-stigmastan-3fl-yloxy)carbonyloxy]propoxy]phosphinylJcholine hydroxide internal salt (epimers 1:1), MS: 700 (M+H+)
b) O-[hydroxy-[(RS)-2-hydroxy-3-[[(E)-stigmasta-5,2215 -dien-3B-yloxy]carbonyloxy]propoxy]phosphinylJcholine hydroxide internal salt (epimers 1:1), MS: 696 (M+H+).
Example 15
2o a) A solution of 1 g of cholest-5-en-3fi-yl (S)-2-hydroxypropionate and 0.37 ml of triethylamine in 5 ml of methylene chloride is added dropwise to a solution of 1 g of β-bromoethyl-phosphoric acid dichloride in 10 ml of methylene chloride. The mixture is stirred firstly at room temperature for 4 hours, then under reflux for 1 hour.
After adding 5 ml of water the mixture is boiled at reflux for 2 hours. The mixture is diluted with methylene chloride, the aqueous phase is separated, the organic phase is washed with water, dried over sodium sulphate and
concentrated. The residue is dissolved in ether and treated with a solution of 5 g of barium acetate in 20 ml of water. The mixture is stirred at room temperature for 20 hours, the resulting barium salt is filtered off and is treated with a mixture of 20 ml of 3N hydrochloric acid 35 and 20 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour, the organic phase is separated, dried over sodium sulphate and concentrated.
There is obtained 0.7 g of cholest-5-en-3B-yl (S)-2-[[(2IE904210
- 37 -bromoethoxy)hydroxyphosphinyl]oxy]propionate. MS: 643 (M-H)~.
b) A solution of 0.7 g of cholest-5-en-3fl-yl (S)-2-[[(2-bromoethoxy)hydroxyphosphinyl]oxy]propionate in 15 ml of toluene is treated with 15 ml of trimethylamine in a dry-ice bath. The mixture is heated to 60°C for 30 hours.
After cooling the reaction mixture is taken up in toluene and concentrated. The residue is taken up in 30 ml of methanol, treated with 2 g of silver carbonate and stirred at 50°C for 0.5 hour. The precipitate is filtered off. concentrated and there is obtained 0.6 g of O-[[(S)-115 -((cholest-5-en-3fl-yloxy)carbonyl]ethoxy]hydroxyphosphinyljcholine hydroxide internal salt, MS: 624 (M+H+).
Example 16
Analogously to Example 1. starting from stigmast-5-en-3B-yl 2-hydroxyethylcarbonate there is obtained O-[hydroxy-[2-[[(stigmast-5-en-3fl-yloxy)carbonyl]oxy]ethoxy] phosphinyljcholine hydroxide internal salt. m.p. 207°C (decomposition).
Example 17
Analogously to Example 2k) and Example 2g), there are 30 obtained
a) O-[hydroxy-[3-[(stigmast-5-en-3B-yloxy) carbonyl]propoxy]phosphinyl]choline hydroxide internal salt. m.p. 220°C (decomposition), and. respectively.
b) O-[hydroxy-[2-(stigmast-5-en-3fl-yloxy)ethoxy]phosphinyljcholine hydroxide internal salt. m.p. 197°C (decomposition).
- 38 Example 18
Analogously to Example 5, but using dimethylamine in place of triethylamine. there is obtained cholest-5-en-3B-yl 2-[[[2-(dimethylamino)ethoxy]hydroxyphosphinyl]oxy]ethylcarbonate. m.p. 150°C (decomposition).
Example 19
Analogously to Example 5, there is obtained O-[hydroxy-[2-[1-(stigmast-5-en-3B-yloxy)formamido]ethoxy]phosphinyl]choline hydroxide internal salt. m.p.
225°C (decomposition).
Example 20
Analogously to Example 12. there is obtained O-[[(RS)2o -2-acetoxy-3-[[(cholest-5-en-3B-yloxy)carbonyl]oxy]propoxy] hydroxyphosphinyljcholine hydroxide internal salt, m.p. 130°C (decomposition).
Example 21
a) A solution of 11.6 g of cholesterol and 3.6 g of hydroxypivalic acid in 80 ml of toluene is treated with g of p-toluenesulphonic acid and boiled for 4 hours. The reaction mixture is treated with water and extracted with 30 ether. The organic phase is dried and concentrated and the residue is purified over silica gel with petroleum ether/ ether (4:1). There are obtained 1.9 g of cholest-5-en-3fl-yl 3-hydroxy-2.2-dimethyl-propionate, m.p. 174-176°C.
b) To a solution of 1.9 g of the product of a) in 60 ml of methylene chloride are added dropwise firstly 1.1 ml of triethylamine and then a solution of 1.42 g of B-bromoethyl-phosphoric acid dichloride in 30 ml of methylene
- 39 chloride. The mixture is boiled under reflux for 18 hours, and. after the addition of water, boiled under reflux for
1 hour. The aqueous phase is separated and the organic phase is washed with water, dried and concentrated. The residue is dissolved in ether and treated with a solution of 15 q of barium acetate in 30 ml of water. The mixture is stirred for 20 hours, the resulting barium salt is filtered off and treated with a mixture of 50 ml of 3N hydrochloric acid and 50 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour and the organic phase is separated, dried and concentrated. There are obtained 1.6 g of cholest-5-en-3fl-yl 3-[[(2-bromo25 ethoxy)hydroxy-phosphinyl]oxy]-2,2-dimethylpropionate.
m.p. 98°C.
c) A solution of 1.6 g of the product of b) in 15 Ini of toluene is treated with 15 ml of trimethylamine while cooling is a dry-ice bath. The mixture is heated to 60°C for 2 days. After cooling in a dry-ice bath the reaction mixture is taken up in toluene and concentrated. The residue is taken up in methanol, treated with 3 g of silver carbonate and stirred at 50°C for 0.5 hour. The precipitate is filtered off and the filtrate is concentrated. By recrystallization of the residue from ether there is obtained 0.8 g (52%) of O-[[2-[cholest-5-en-3fl-yloxy)carbonyl]-2-methylpropoxy]hydroxyphosphinylJcholine hydroxide internal salt, m.p. 210°C.
Example 22
a) A solution of 5.00 g of cholesteryl chloroformate 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 choride. After stirring for 45 hours the mixture is taken up in aqueous methanol and extracted with chloroform. The organic phase is dried and conIE 904210
- 40 centrated. After chromatography over SiO2 with chloroform and then with ether there are obtained 4.3 g of cholest-5-en-3B-yl [2-hydroxy-l-(hydroxymethyl)ethyl]carbamate. m.p. 158°C (decomposition).
b) A solution of 3.7 g of the product of a) in 30 ml of methylene chloride, 10 ml of THF and 0.6 ml of pyridine is treated under argon with 1 ml of phenyl chloroformate in 15 ml of methylene chloride. After stirring for 1 hour the solution is taken up in 200 ml of water and 50 ml of O.1N HCl and extracted with 150 ml of methylene chloride. The organic phase is dried and concentrated. After chroma35 tography over SiO2 with n-hexane/ether (1:1) and ether there are obtained 2.1 g of cholest-5-en-3B-yl [(RS)-2-hydroxy-1-[(phenoxycarbonyl)oxymethyl]ethyl]carbamate.
c) 0.05 ml of 2-chloro-2-oxo-1.3.2-dioxaphospholane is 2q added to a mixture of 320 mg of the product of b) in 20 ml of toluene and 0.08 ml of triethylamine under argon while stirring at room temperature. The (Et)3N:HCl is filtered off under suction after 16 hours. The solution obtained 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 and held at 80°C. The solution is concentrated after 6 hours. The product. O-[[(RS)-2-[1-(cholest-5-en-3B-yloxy)formamido]-3-(phenoxycarbonyloxy)propoxy]hydroxyphosphinyl]choline hydroxide internal salt, 30 is used in the next step without purification.
d) The product of c) is dissolved in 20 ml of methanol-chloroform (1:1) and treated with 2 ml of IN NaOH at room temperature while stirring. After adding 10 g of ion exchanger (Amberlite MB-3) and stirring for 4 hours the solution is concentrated, azeotropically distilled with toluene and then dried. The residue is chromatographed on silica gel with CHCl3-MeOH-H2O (60/35/5 by vol.).
•Ε 904210
- 41 After drying there are obtained 200 mg of O-[[(RS)-2-[l-(cholest-5-en-3B-yloxy)formamido]-3-hydroxypropoxy]5 hydroxyphosphinylJcholine hydroxide internal salt. m.p. 220°C (decomposition).
Tablets and capsules of the following composition are manufactured in a manner known per se:
Example a
Tablets 1 tablet contains
Compound of formula I 200 mg Microcrystalline cellulose 155 mg Maize starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 425 mq mg
Example b
Capsules capsule contains
Compound of formula I 100.0 mg Maize starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mq
200.0 mg •Ε 904210 . - 42 Claims
wherein 1 is hydrogen, lower-alkyl or lower-alkylidene,
4
R and R 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.
is the number 2. 3 or 4.
is a group of the formula
-(CH2)p-C(Q.Q')-(Z)1 or 0-.
-CH2CH(Y)CH2-(Z)1 or 0-.
-CH CH(CH Y)-(Z) - or
2 1 or 0
-(CHCHO) -CH CH -(Z), -.
2 q 2 2 1 or 0 is the number 1 or 2, is a group of the formula -C(0)-. -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-carbamoylIE 904210
- 43 oxy, the dotted C-C bonds in the 5(6)-. 7(8)-. 22(23)-, 5 24(25)- and 24(28)-position are optional, whereby the side-chain is either saturated or mono-unsaturated.
and physiologically compatible salts thereof.
Claims (23)
1. 0
2. Steroids according to claim 1. wherein R 1 is hydrogen or lower-alkyl, especially ethyl.
3. Steroids according to claim 1 or 2. wherein R 3 4 is hydrogen or lower-alkyl and R and R are 15 lower-alkyl.
4. Steroids according to claim 1 or 2. wherein R . 3 4 R and R are methyl. 20
5. Steroids according to claim 1 or 2. wherein R . 3 4 R and R together with the N atom form a pyridinium or 1-methylpyrrolidinium group.
6. Steroids according to any one of wherein n is the number 2. claims 1-5,
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 -(CH 2 ) 2 -. -(CH ) O(CH ) -. -(CH ) O(CH ) O(CH ) -, -ch 2 chohch 2 -. -ch 2 ch(ococh 3 )ch 2 -. -CH 2 CH(OCONHCH 3 )CH 2 N[CH(CH 3 ) 2 )co-. -(CH ) NHCO-. -(CH ) NHCO-, -CH CHOHCH OCO-. A A A «3 A A -(CH(CH 3 )C0- or especially -(01^)^000-. -(ch 2 ) 3 oco-. -(ch 2 ) 4 oco-. -(ch 2 ) 8 oco-. - 44 -(ch 2 )co-. -(ch 2 ) 2 co-. -(ch 2 ) 3 co-. -(CH 2 ) & C0-. -CH 2 CH(OCOCH 3 )CH 2 OCO-. 5 -CH 2 C(CH 3 ) 2 CO- or -CH 2 CH(CH 2 OH)NHCO-.
9. A compound according to claim 1 from the following group 10 O-[[2-[[(Cholest-5-en-3B-yloxy) carbonyl Joxy]ethoxyJ-. hydroxyphosphiny1]cho1ine hydroxide internal salt. 0-[hydroxy-[3-[(3B-stigmastanyloxy) carbony1]propoxy]phosphinylJcholine hydroxide internal salt. 0-[[2-(cholest-5-en-3B-yloxy) ethoxy]hydroxyphosphinyl] choline hydroxide internal salt and 0-[hydroxy-[2-[1-(5a-stigmastan-3B-yloxy)formamidoJ 20 ethoxyjphosphinylJcholine hydroxide internal salt.
10. A compound according to claim 1 from the following group 25 0-[[2-[[(5a-Stigmastan-3B-yloxy)carbonyl]oxy]ethoxy]hydroxyphosphinylJcholine hydroxide internal salt. 0-[hydroxy-[2-[[[E)-stigmasta-5,22-dien-3B-yloxy]carbonyl]ethoxy]phosphinyl]choline hydroxide 30 internal salt, 0-[[3-[[(cholest-5-en-3B-yloxy)carbonyl]oxy]propoxyJhydroxyphosphinyl]choline hydroxide internal salt. 35 o-[[4-[[(cholest-5-en-3B-yloxy)carbonyl]oxy]butoxyJhydroxyphosphinylJcholine hydroxide internal salt. O—[[[8—[[(cholest-5-en-3B-yloxy)carbonyl]oxy]octylJIE 904210 - 45 oxyjhydroxyphosphinyljcholine hydroxide internal salt. 5 O- [ [ [(cholest-5-en-3fl-yloxy)carbonyl]methoxy]hydroxyphosphinylJcholine hydroxide internal salt, 0-[[2-[(cholest-5-en-3fi-yloxy)carbony1]ethoxy]hydroxyphosphinyljcholine hydroxide internal salt. 0-[hydroxy-[2-[(3fl-stigmastanyloxy)carbonyl]ethoxy]phosphinyljcholine hydroxide internal salt, 0-[hydroxy-[2-[(stigmasta-5,22-dien-3B-yloxy)carbonyl]5 ethoxyjphosphinylJcholine hydroxide internal salt, 0-[[3—[(cholest-5-en-3fi-yloxy)carbonyl]propoxy]hydroxyphosphinyljcholine hydroxide internal salt, j 0-[hydroxy-[3-[(E)-stigmasta-5,22-dien-3B-yloxy)carbonylJpropoxyJphosphinylJcholine hydroxide internal salt, 0-[hydroxy-[[5-[(5a-stigmastan-3fl-yloxy) carbonyl]pentylJoxyJphosphinylJcholine hydroxide internal salt. O-[hydroxy-[[5-[((E)-stigmasta-5,22-dien-3B-yloxy)carbonyljpentyl]oxy]phosphinyl]choline hydroxide internal salt. O-[hydroxy-[[[(3B-stigmastanyl)oxy]carbonyl]methoxy]phosphinylJcholine hydroxide internal salt, 0-[hydroxy-[[[(E)-stigmasta-5,22-dien-3fl-yloxy]carbonyl]methoxy]phosphinyl]choline hydroxide internal j salt. 0-[hydroxy-[2-(stigmasta-5,22-dien-3B-yloxy)ethoxy]phosphinyljcholine hydroxide internal salt. O-[[2-[2-(cholest-5-en-3fl-yloxy)ethoxy]ethoxy]hydroxyIE 904210 - 46 phosphinyljcholine hydroxide internal salt, 5 0-[hydroxy-[2-[2-[(E)-stigmasta-5,22-dien-3fl-yloxy]ethoxy]ethoxy]phosphinyl]choline hydroxide internal salt. O- [[2-[2-[2-(cholest-5-en-3fl-yloxy)ethoxy]ethoxy]10 ethoxy]hydroxyphosphinyl]choline hydroxide internal salt, O-[[2-[(5a-cholestan-3fl-yloxy)carbonyloxy]ethoxy]hydroxyphosphinylJcholine hydroxide internal salt. 15 O-[hydroxy-[2-[2-(3β-stigmastanyloxy)ethoxy]ethoxy]phosphinyljcholine hydroxide internal salt, O-[hydroxy-[2-(3β-stigmastanyloxy)ethoxy]phosphinyljcholine hydroxide internal salt, l-[2-[[hydroxy-[2-[l-(5a-stigmastan-3fl-yloxy)formamido]ethoxy]phosphinyl]oxy]ethyl]pyridiniurahydroxide internal salt. 25 0-[hydroxy-[2-[l-[(E)-stigmasta-5.22-dien-3fl-yloxy]formamido]ethoxy]phosphinylJcholine hydroxide internal salt. O-[hydroxy-[3-[1-[(E)-stigmasta-5.22-dien-3fi 30 -yloxyjformamido]propoxy]phosphinyl]choline hydroxide internal salt. 0-[hydroxy-[(RS)-3-[N-isopropyl-l-[(E)-stigmasta-5.22 -dien-3fl-yl]oxyformamido]-2-[(methylcarbamoyl)oxy]propoxy] 35 phosphinyljcholine hydroxide internal salt. 0-[[[2—[1-cholest-5-en-3fl-yloxy]formamido]ethoxy]hydroxyphosphinyljcholine hydroxide internal salt. - 47 θ- [[2-[1-(5fl-cholestan-3a-yloxy)formamidoJ ethoxy]hydroxyphosphinylJcholine hydroxide internal salt. l-[2-[[hydroxy-[3-[l-[(E)-stigmasta-5.22-dien-3fi-yloxyjformamidoJ propoxyJphosphinylJoxyJethyl Jpyridinium hydroxide internal salt. 10 O-[hydroxy-[2-[[[(E)-stigmasta-5.22-dien-3fl-yloxyJcarbonyljoxyjethoxyjphosphinylJcholine hydroxide internal salt. 1-[2-[[[2-[1-[cholest-5-en-3B-yloxy]formamidoJ ethoxyJ 15 hydroxyphosphinylJoxyJethyl]-1-methylpyrrol idinium hydroxide internal salt. l-O-(3a.B-stigmastanyl)-3-O-(RS)-glyceryl-phosphorylcholine. O-[[(RS)-2-acetoxy-3-[5a-stigmastan-3a.β-yloxyJpropoxyjhydroxyphosphonylJcholine hydroxide internal salt. O-[[(RS)-3-[(cholest-5-en-3fl-yloxy)carbonyloxy]-225 -hydroxypropoxyjhydroxyphosphinylJcholine hydroxide internal salt. O-[hydroxy-(RS)-2-hydroxy-3-[[5a-stigmastan-3B-yloxy)carbonyloxy]propoxy]phosphinylJcholine hydroxide 30 internal salt O-[hydroxy-[(RS)-2-hydroxy-3-[[(E)-stigmasta-5.22-dien-3fi-yloxyJ carbonyloxyJpropoxy]phosphinylJcholine hydroxide internal salt, 0-[hydroxy-[2-[[(stigmast-5-en-3fi-yloxy)carbonyl]oxy] ethoxyjphosphinyljcholine hydroxide internal salt. Ε 904210 Ο- [hydroxy- [3 - [ (stigmas t-5-en-3/3-yloxy) car bonyl ]propoxy]-phosphinyl]choline hydroxide internal salt, 0-[hydroxy-[2-(stigmast-5-en-3B-yloxy) ethoxy]phosphinyljcholine hydroxide internal salt, cholest-5-en-3B-yl 2-[[[2-(dimethylamino)ethoxy]hydroxyphosphinyl]oxy]ethylcarbonate. 0-[hydroxy-[2-[1-(stigmast-5-en-3B-yloxy)formamido]ethoxy]phosphinyl]choline hydroxide internal salt, 0-[[(RS)-2-acetoxy-3-[[(cholest-5-en-3fl-yloxy)carbonyl]oxy]propoxy]hydroxyphosphinylJcholine hydroxide internal salt, 0-[[2-[cholest-5-en-3B-yloxy)carbonyl]-2-methylpropoxy]hydroxyphosphinyl]-choline hydroxide internal salt and 0-[[(RS)-2-[l-(cholest-5-en-3fi-yloxy)formamido]-3hydroxypropoxy]hydroxyphosphinylJcholine hydroxide internal salt.
11. Alcohols of the formula HO R II - 49 wherein X 1 is a group of the formula -(CH 2 ) p -C(Q.Q')-Z'-. 5 -CH 2 CH(Y)CH 2 -Z'-, -ch 2 ch(ch 2 y)-z'- or -(CHCHO) -CHCH-Z 1 -, 2. 2 q 2 2 Ζ' is a group of the formula -OC(O)-, -OC(O)CH 2 ~, -OCHC(O)- or -N(T)C(O)- and 1 2 .... R . Q. Q'. p. q. Y and T have the significance given 10 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 -n-(ch 2 (G). and 10 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 20 according to claim 1. - 51
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. - 52
16. Compounds according to claim 1, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof. Έ904210
17. Compounds, preparations, uses and processes as hereinbefore described, particularly with reference to the Examples.
18. A steroid of the formula I given and defined in claim 1 or a physiologically compatible salt thereof, substantially as hereinbefore described and exemplified.
19. A process for the manufacture of a steroid of the formula I given and defined in claim 1 or a physiologically compatible salt thereof, substantially as hereinbefore described and exemplified.
20. A steroid of the formula I given and defined in claim 1 or a physiologically compatible salt thereof, whenever manufactured by a process claimed in claim 19.
21. An alcohol of the formula II' given and defined in claim 11, substantially as hereinbefore described and exemplified.
22. A pharmaceutical preparation according to claim 14, substantially as hereinbefore described and exemplified.
23. Use according to claim 15, substantially as hereinbefore described. Dated this the 21st day of November, 1990 F. R. KELLY & CO.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH418389 | 1989-11-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE904210A1 true IE904210A1 (en) | 1991-05-22 |
Family
ID=4271339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE421090A IE904210A1 (en) | 1989-11-22 | 1990-11-21 | Steroids |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0430078A3 (en) |
| JP (1) | JPH03170497A (en) |
| KR (1) | KR910009726A (en) |
| AU (1) | AU6670190A (en) |
| CA (1) | CA2028759A1 (en) |
| FI (1) | FI905746A (en) |
| HU (1) | HUT56116A (en) |
| IE (1) | IE904210A1 (en) |
| IL (1) | IL96366A0 (en) |
| MC (1) | MC2164A1 (en) |
| NO (1) | NO905029L (en) |
| NZ (1) | NZ236110A (en) |
| PT (1) | PT95954A (en) |
| YU (1) | YU222590A (en) |
| ZA (1) | ZA909188B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EE9700073A (en) † | 1994-09-29 | 1997-10-15 | The University Of British Columbia | Sterile compositions derived from pulp soap |
| DE4442388C2 (en) * | 1994-11-29 | 1999-01-07 | Heraeus Elektrochemie | Electrode with plate-shaped electrode holder |
| FI974648A (en) * | 1997-09-09 | 1999-05-06 | Raisio Benecol Oy | Hydroxy acid, lactic acid and hydroxyalkanoate esters and their uses |
| FI115527B (en) * | 1998-10-16 | 2005-05-31 | Upm Kymmene Oyj | Use of plant sterol derivatives and products containing them |
| PT1189923E (en) * | 1999-06-21 | 2005-05-31 | Forbes Medi Tech Inc | AROMATIC AND HETEROCYCLIC DERIVATIVES OF PHYTOSTEROIS AND / OR FITOSTANES FOR USE IN THE TREATMENT OR PREVENTION OF CARDIOVASCULAR DISEASE |
| EP1189924B1 (en) * | 1999-06-23 | 2004-08-18 | Forbes Medi-Tech Inc. | Conjugates of phytosterol or phytostanol with ascorbic acid and use thereof in treating or preventing cardiovascular disease |
| AU7736300A (en) | 1999-09-30 | 2001-04-30 | Hollis-Eden Pharmaceuticals, Inc. | Therapeutic treatment of androgen receptor driven conditions |
| JP5657902B2 (en) * | 2010-03-17 | 2015-01-21 | 株式会社コスモステクニカルセンター | Polyoxyalkylene sterol ether derivative and / or polyoxyalkylene stanol ether derivative, and external preparation composition containing the same |
| CN102584926B (en) * | 2012-01-12 | 2014-10-15 | 浙江大学 | Method for preparing supermolecule hydrogel based on amphiphilic micromolecules (cholesterol and phosphorylcholine) |
| WO2023176821A1 (en) * | 2022-03-15 | 2023-09-21 | 富士フイルム株式会社 | Lipid composition |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2967329D1 (en) * | 1978-07-11 | 1985-01-24 | Merck & Co Inc | Cholesterol derivatives as intermediary products for the synthesis of immunologic adjuvants |
| CA1252778A (en) * | 1983-08-25 | 1989-04-18 | Hoffmann-La Roche Limited/Hoffmann-La Roche Limitee | Steroids |
-
1990
- 1990-10-29 CA CA002028759A patent/CA2028759A1/en not_active Abandoned
- 1990-11-15 ZA ZA909188A patent/ZA909188B/en unknown
- 1990-11-15 MC MC902156A patent/MC2164A1/en unknown
- 1990-11-16 IL IL96366A patent/IL96366A0/en unknown
- 1990-11-16 AU AU66701/90A patent/AU6670190A/en not_active Abandoned
- 1990-11-16 NZ NZ236110A patent/NZ236110A/en unknown
- 1990-11-16 JP JP2308946A patent/JPH03170497A/en active Pending
- 1990-11-19 HU HU907192A patent/HUT56116A/en unknown
- 1990-11-20 NO NO90905029A patent/NO905029L/en unknown
- 1990-11-21 PT PT95954A patent/PT95954A/en not_active Application Discontinuation
- 1990-11-21 KR KR1019900018857A patent/KR910009726A/en not_active Application Discontinuation
- 1990-11-21 IE IE421090A patent/IE904210A1/en unknown
- 1990-11-21 FI FI905746A patent/FI905746A/en not_active IP Right Cessation
- 1990-11-22 EP EP19900122333 patent/EP0430078A3/en not_active Withdrawn
- 1990-11-22 YU YU222590A patent/YU222590A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR910009726A (en) | 1991-06-28 |
| NO905029D0 (en) | 1990-11-20 |
| NO905029L (en) | 1991-05-23 |
| NZ236110A (en) | 1993-03-26 |
| HU907192D0 (en) | 1991-05-28 |
| JPH03170497A (en) | 1991-07-24 |
| HUT56116A (en) | 1991-07-29 |
| PT95954A (en) | 1991-09-13 |
| EP0430078A2 (en) | 1991-06-05 |
| EP0430078A3 (en) | 1991-11-13 |
| YU222590A (en) | 1993-10-20 |
| MC2164A1 (en) | 1992-04-09 |
| AU6670190A (en) | 1991-05-30 |
| IL96366A0 (en) | 1991-08-16 |
| ZA909188B (en) | 1991-07-31 |
| CA2028759A1 (en) | 1991-05-23 |
| FI905746A (en) | 1991-05-23 |
| FI905746A0 (en) | 1990-11-21 |
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