DE2820892A1 - NEW STRUCTURAL ANALOGS OF GLYVERIDES AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Description

DR. ING. F. WtTESTIIOFF DIt. E. ν. PECHMANN DR. ING. D. CONTRIBUTION DIPL ·. ING. It. GOKTZ PATENT LAWYERS

HOOO M UNO II HN .scmvi: i (u: n.sTiiAHSE S TKI.KION (080) OGSOOl τκΐ, κχ Ο 24-070

I KI.K (IIlAMME 1 ΡΚϋΤΚΟΤΓΑΤΚΝΤ ΜϋΝΟΠΕΧ

LA-50 922

Patent application

Applicant:

A. Nattermann & Cie. GmbH 5000 Cologne 30, Nattermannallee 1

Title:

New structural analogues of glycerides and Process for their manufacture

909847/0108

DIt. ING. F. "WUESTIIOΙΊ ' IRISHMAN. τ, ΡΚΙΊΙΜΑΝΝ

UK. IN (I. I). IJEIIRKNS DIPL ·. ING. Ii. C! OHTZ

PATENT LAWYERS

HOOO MÜNCIIKN OO SCIIWKl (IEIlSTIiASSI! S TELEFON (080) 00 20 01 TKLJCX ti 24 070

TELKGITAMMKt /. U Z U 0 J Z PHÜTKCTPATIäST M0NOnsv

LA-50 922

Description

The invention relates to new pharmacologically active substances structurally related, synthetic analogs of natural glycerides of the general formulas given in the claim. These new glyceride analogs In contrast to the naturally occurring glycerides described so far, they have at least one acid amide group instead of the usual acid ester groups in the molecule, this acid amide group on one or two of the three carbon atoms of the glycerol skeleton may be present.

For the preparation of the structural analogues of the glycerolipids according to the invention you can start from the corresponding aminopropanediols or diaminopropanols and thereby specifically in the desired fatty acid residues Introduce the molecule that you have the respective primary hydroxyl groups or the individual amino groups that are not or not yet with the fatty acid residue are to be substituted, blocked or masked by protective groups.

A suitable intermediate protective group for masking the amino groups is, for example, the phthalic acid group, which is formed by using phthalic anhydride can be introduced and which can easily be split off again later. With the help of hydrazine can in a known manner intermediately formed phthalimide group are cleaved. The triphenylmethoxy group, for example, can be used to mask the hydroxyl group, which can be easily introduced using triphenylchloromethane and then split off again by hydrolysis. But also for blocking the amino group can be triphenylchloromethane as well as z. B. the dichloroacetic acid ester be used because the triphenylmethyl group or the dichloroacetyl radical also differ from the respective amino group of the aminopropanol derivative can hydrolytically split off again after the fatty acid residues in question in the desired hydroxyl group or amino group of the glycerine-analogous compound have been introduced. ' This is shown in the reaction schemes below and in more detail in the examples explained. 909847/0108

Reaction scheme 1:

H ^ C-NH,

HC-OH

H ₂ C-OH

0 ° Il HC-CR,

H ₂ C- (M

0 Il

• «CO

H ₂ CN

Il

- H ₂ O

HC-OH

2. + Cl-C-Äj) - HCl H ₂ COC- (Q)

Acetic acid 75 % - (C _b H ₅ ) ₃ C-CH

a) 0
0
HC-OOR _-

+ Fatty acid chloride (ClCOR ₁ )

- HCl

H ₂ C-OH

b)

+ Fatty acid chloride

(ClCOOR ₂ ) - HCl

0 Il

HC-OCR ₁

H ₂ C-OH

0 Il

Il

Il

0 Il

HC-O-C-P.,

0 H ₂ COCR ₂

■ f +

H "C-NH ₂

0 HN

I! I.

HC-CR ₁ + HN

Il

H ₂ CCR ₂

909847/0108

Reaction scheme 2a):

H ₂ C-NH ₂ fatty acid chloride

HC-OH

H ₂ C-OH

- HCl

0 u

HC-OH

H ₂ C-OH

-C-

-HCl

2. + fatty acid chloride (ClOC-R ₂ ) -HCl

0 H ₂ C-NH-CR ₁

0 HC-OCR _n

H ₂ CO- (

Acetic acid 75 %

/ / -ι TT \ / -ι / ΛΤ_Ι

H ₂ C-NH-CR ₁ 0

HC-OCR _n

H ₂ C-OH

- HCl N ^

+ Fatty acid chloride (ClOC-R ₃ )

HC-OCR ₂

0 U

H ₂ COCR ₃

909847/0108

. , ir -

Reaction scheme 2b) :

H _n C-NH,

HC-OH

H ₂ C-OH

Fatty acid chloride

(ClOC-R.) -HCl

OH ₂ C-NH-CR,

HC-OH

H ₂ C-OH

Ph

1. + Cl-C-Ph ι

Ph

2. ß-Benzoylpropionic acid chloride

0 H ₂ C-NH-CR

0

HC-OC-CH ₂ -CH ₂ -C- (g> acetic acid 75 %

-HO-C (Cz-H ₁ -), ο 5 j

H ₂ C-NH-CR

0

Ii Il

HC-OC-CH ₂ -CH ₂ -C-

H ₂ C-OH

I!

Cl-C-Rj

- HCl 0 H _n C-NH-CR,

Il

HC-OC-CH ₂ -CH ₂ -C- I

I ii

H ₂ COCR

H ₂ N-NH ₂

N NH

CH ₂ -CH ₂

0 H ₂ C-NH-CR ₁

HC-OH

0 H ₂ COCR ₁

909847/0108

Reaction scheme 3:

H ₂ C-OH

HC-NH,

H ₂ C-OH

+ Fatty acid chloride (ClOC-R ₁ )

- HCl H ₂ C-OH

0 κ

HC-NH-C-R.

H ₂ C-OH

+ 2 fatty acid chloride (2 ClOC-R ₂ )

- 2 HCl

H _n COCR ₂ 0 HC-O-NH-CR ₁

0
H ₂ COCR ₂

909847/0108

Reaction scheme

HC-NH.

O = COC ₀ Hf-

1. + CI-C

2. LiAlH ₁

- HCl

H ₂ C-NH- (

HC-NH.

H ₀ C-OH

+ Fatty acid chloride

- HCl

H ₂ C-NH-C

HC-NH-C-R. Il 0

H ₂ C-OH

Acetic acid 75 %

+ Fatty acid chloride

(ClOC-R ₂ ), - HCl H ^ C-NH,

HC-NH-C-R.

H ₂ C-OH

+ Fatty acid chloride

(ClCC-R ₂ ) - HCl

0 Il HC-NH-C-Rh

0.

H ₂ COCR ₂ H ₂ C-NH-CR ₂ O

HC-NH-C-R. Il 1 O

H ₂ C-OH

Acetic acid 75 %

H ₃ C-NH ₂

HC-NH-CR ₃

0 11

H ₃ COCR ₂

+ Fatty acid chloride

(ClOC-R ₃ ) - HCl

0 H ₂ C-NH-CR ₃

I °

HC-NH-CR ₁

0
H ₂ COCR ₂

909847/0108

Reaction scheme

H ₀ C-NH, HC-NH,

O = COC ₀ H ₁ -2

1. + C1-C- <Ö> - HCl

2. LiAlH,

H ₂ C-NH-

HC-NH,

H ₂ C-OH

Methyl dichloroacetate

- Methanol HC-NH-C-CHCl ₀
ti 2

0
H ₂ C-OH

75 ί acetic acid

H ₀ C-NH.

Il

HC-NH-C-CHCl,

H ₂ C-OH 0
Cl-CR ₁

- HCl

H ₂ C-NH-CR ,,

HC-NH-C-CHCl,

H ₂ C-OH

, 0
H ₀ C-NH-CR

OH"

- Cl ₀ CH-C

^N 0H HC-NH,

H ₂ C-OH

909847/0108

AX

In the new structural analogues of mono-, di- or triglycerides are the fatty acids, instead of the usual ester bond, are partially or completely bound in an acid amide-like manner, which gives them special physiological effects demonstrate.

In animal experiments, the analogs accumulate after oral and / or intravenous routes Application in the lipids of cellular membrane structures and in the lipids of plasma lipoproteins. The analogs can in vitro partly convert into each other. Thus, in the rat, monoglyceride analogs are made Metabolized to lecithin and cephalin analogues. The distribution of the analogues to the individual organs, subcellular Structures and lipoproteins are not only determined by the basic structure, but mostly also by the amide-like bound fatty acids certainly. The analogues show metabolic properties of the corresponding natural phosphatides. Due to the relatively metabolically stable amide group, the metabolism of the analogues but modified in a defined way. This allows the special pharmacokinetic-pharmacodynamic effects of the invention Explain connections.

The pharmacological effects are due to the basic structure and fatty acid component as well as for some of the substances also determined by the type of application. They are therefore differently pronounced. The individual effects are as follows:

Anti-lipemic

Antiatherosclerotic

Inhibits tumor growth

Tissue, draining or edema-inhibiting

Immunosuppressive

Antiprostaglandin inhibitory to platelet aggregation

The classes of compounds listed below are examples for the structural analogues of glycerides according to the invention.

- 9 " 909847/0108

Monoglyceride analogs

Form1

yield

Fp Rf value (running system)

Molecular formula

[MG]

CH ₀ -NH ₀ ι <- <- CH-OR,

CH ₂ -OH

70 %

57 0.5 CHCl./CIUOH/HgO

[355]

25th

CH ₂ -OH CH-NH-R,

CH ₂ -OH

78 t

87 ° C 0.24

CHCl ₃ / CH ₃ OH 15: 1 ■

C ₂₁ H ₃₉ O ₃ N

[353]

CH ₂ -OH CH-NH-R.

CH ₂ -NH ₂ C ₂₁ H ₃₈ O ₂ N ₂

80 % CHCl ₃ / CH ₃ OHZH ₂ O 65:25:

CH ₂ -OH CH-NH.

75 Ϊ

65 ⁰ C 0.45 CHCl ₃ / CH ₃ OH / H ₂ O

C ₁₉ H ₃₉ O ₂ N ₂

(328]

65 25

^R l = R ₂ = R ₃ = Ri, =

Oleyl-Linolyl-Linolenyl-Palmltyl-

909847/0108 - 10 -

Diglyceride analopa

Form1 yield Fp Pf value
(Running system) Sum formula
[MGJ (
(
( 85 % 62 ° C 0.75
CHCl ₃ ZCH ₃ OH
15: 1 C ₃₇ H ₇₁ O ₁₁ N
[593] (
₍
( 78 % 69 ⁰ C 0.75
CHCl ₃ ZCH ₃ OH
15: 1 C ₂₇ H ₅₃ O ₄ N
& 55] (
(
C. 65 % 58 ⁰ C 0.43
CHCl ₃ ZCH ₃ OH
15: 1 C ₂₉ H ₅₃ O ₁₁ N
579] (
(
( 73 % 67 ⁰ C 0.25
CHCl ₃ ZCH ₃ OH
15: 1 C ₃₉ H ₇₂ O ₃ N ₂
[616] (
(
C. 85 % 55 ⁰ C 0.65
CHCl ₃ ZCH ₃ OH
15: 1 C ₂₉ H ₅₂ O ₃ N ₂
| 47β] 3H ₂ -NH-R ₂
JH-OR ₁
JH ₂ - OH 3H ₂ -NH-R ₂
IH-OH
3H ₂ -OR ₃ 3H ₂ -NH ₂
! HOR ₄
3H ₂ -OR ₃ 3H ₂ -OR ₆
: h-nh-r ₅
3H ₂ -NH ₂ 3H ₂ -OH
IH-NH-R ₅
3H ₂ -NH-R ₃

R ₁ = oleyl R ₃ = caprylic R ₂ = palmityl R ₄ = linolyl

909847/0108

= Linolenyl- = stearyl-

- 11 -

Triglyceride analogs

formula yield Fp Rf value
(Running system) Molecular formula
[mg] (
(
₍ 85 % 72 ⁰ C 0.30
Petroleum ether / ether
70:30 C ₅₅ H ₁₀₅ O ₅ N
[859] C.
C.
_{ 75 %
j 57 ° C 0.28
Petroleum ether / ether
70:30 C ₅₅ H ₁₀₃ O ₅ N
[857] C.
(
C. 67 % 0.20
Petroleum ether / ether
70:30 JH ₀ -NH-R.
£ 5
IH-OR ₁ IH-NH-R ₂
JH ₀ -OR ₁ - JH ₂ -OR ₆
JH-NH-R,
JH ₂ -NH-R ₁ ,

R ₁ = oleyl-R ₂ = linolyl-R, = linolenyl-R ₁ ^ = palmityl-R ^ = stearyl-R ^ = caprylic

909847/0108

- 12 -

Example 1;

(Reaction scheme la)

I ¹ *, 8 g (0.1 mol) of phthalic anhydride and 9.1 g (0.1 mol) of 1-Aminopropandiol- (2,3) are in an oil bath slowly heated up to 170 ⁰ C and at this temperature 2 Held for 3 hours. After cooling to room temperature, 80 ml of ethanol are added and left to stand overnight. The crystallized N-phthalimidyll-amino-propanediol- (2,3) is filtered off with suction and recrystallized from ethanol.

6, ^ g (30 mmol) of this substance in 30 ml of abs. Tetrahydrofuran and 10 ml of abs. Pyridine dissolved. After addition of 9.3 g (33 mmol) of triphenylchloromethane, the reaction mixture is heated overnight at 70 ^0C. After cooling to room temperature, it is extracted three times with ether and N-phthalimidyl-3-0-trityl-1-aminopropanediol- (2,3) is isolated by column chromatography over silica.

2.3 g (5 mmol) of this are in 30 ml of abs. Chloroform and 10 ml of abs. Pyridine dissolved, 2 g of linoleic acid chloride in 10 ml of abs. Chloroform at 0 ⁰ C were slowly added dropwise, and then 3 - J ¹ further stirred for 40 hours at 50 ⁰ C. After the end of the reaction (thin-layer chromatographic test), N-phthalimidyl ^ -O-nolyl-S-trityl ^ -aminopropanediol- (2,3) is extracted from ether and purified by column chromatography over silica. 2.2 g (3 mmol) of this substance is dissolved in Ί0 ml of 75% acetic acid and refluxed. After the trityl group has been completely cleaved, the solution is poured into water, extracted with ether and N-phthalimidyl-2-O-linolylamino-propanediol (2,3) is isolated by column chromatography. 1.2 g (2.5 mmol) of the product are dissolved in 30 ml of warm ethanol, 250 mg (5 mmol) of hydrazine hydrate are added and the mixture is left to stand overnight at room temperature. It is acidified with dilute hydrochloric acid, and phthalic acid hydrazide is suctioned off as a precipitate, the ethanolic solution is neutralized with ammonia and extracted three times with chloroform.

Yield: 660 mg = 75 % of theory 2-0-Linolyl-1-aminopropanediol- (2.3) Rf value: 0.50

CHCl ₃ / CH ₃ OHVH ₂ O
65/25: ¹ I.

- 13 909847/0108

Example 2;

(Reaction scheme Ib)

2, ^ g (5 mHol) N-Phthalmidyl-2-0-linolyl-l-amino-propanediol- (2,3), prepared by reacting l-amino-propanediol- (2,3) with phthalic anhydride, triphenylchloromethane and Linoleic acid chloride as described in Example 1, abs in 50 ml. Chloroform and 10 ml of abs. Pyridine dissolved and 1.65 g (6 mmol) of palmitic acid chloride in 10 ml of abs. Chloroform was slowly added dropwise ^{at 0 ° C.} Stirring is continued for 3-4 hours at 40-50 ^° C., after the end of the reaction (TLC test) the mixture is extracted with ether and the reaction product is isolated by means of column chromatography. 1.4 g (2 mmol) of N-phthalimidyl-2-0-linolyl-3-0-palmityl-l-amino-propanediol- (2,3) are dissolved in 30 ml of warm ethanol, with 200 mg (4 mmol) Added hydrazine hydrate and, as described in Example 1, the protective group is removed. The result: 0.9 g = 78 % of theory 2-0-linolyl-3-0-palmityl-l-

Amino-propanediol (2,3) Rf value: 0.46
CHCl ₃ ZCH ₃ OH

15: 1

Example 3:

(Reaction scheme 2a)

0.92 g (10 mmol) of 1-amino-propanediol- (2,3) are in 50 ml of water and 5o ml of tetrahydrofuran suspended with 0.5 g of magnesium oxide. After the addition of 1.95 g (12 mmol) of caprylic acid chloride, 30 minutes shaken vigorously. The solution is then weakly acidified and extracted with ether. The extract is then extracted three times with dilute ammonia to remove the unreacted caprylic acid. The ether phase is washed neutral and the solvent is stripped off in vacuo. 1.74 g (B mmol) of the resulting N-caprylic-amino-propanediol- (2,3) are in 50 ml abs. Tetrahydrofuran and 10 ml of abs. Dissolved pyridine and after adding 2.8 g (10 mmol) of chlorotriphenylmethane the reaction mixture is stirred at 70 ° C. overnight. After cooling to room temperature, three times with ether extracted and the extract purified by column chromatography. 3.8 g (6 mmol) of the resulting N-capryl-3-O-trityl-l-amino-propanediol-

909847/0108

(2,3) are abs in 6O ml. Chloroform and 10 ml of abs. Pyrldln dissolved, 3.6 g (12 mmol) of linoleic acid chloride in 10 ml of abs. Chloroform at 0 ⁰ C were slowly added dropwise and 3 - further stirred 50 ⁰ C - 4 hours at 40th After the reaction has ended (TLC test), the ether extract is purified by column chromatography. 3.6 g (5 mmol) of the N-capryl-2-0-linolyl-3-0-trityl-1-aminopropanediol (2,3) obtained are dissolved in 60 ml of 75% acetic acid and heated under reflux . After the trityl group has been completely split off, the solution is poured into water and extracted with ether. After purification by column chromatography, 2.1 g = 89 % of theory are obtained. N-capryl-2-0-linolyl-1-amino-propanediol- (2 »3) obtained. Rf value: 0.73
CHCl ₃ ZCH ₃ OH

15: 1

example H:

(Reaction scheme 2a)

0.96 g (2 mmol) of N-capryl-2-0-linolyl-1-amino-propanediol- (2,3), prepared as described in Example 3, are in 50 ml of abs. Chloroform and 10 ml of abs. Pyridine dissolved, 0.66 g (2.4 mmol) of palmitic acid chloride in 10 ml of abs. Chloroform was ^{slowly added dropwise at 0 °} C. and the mixture was stirred at 40 ^° C. for a further two hours. After the end of the reaction, extraction is carried out with ether and, after purification by column chromatography, 1.17 g = 81 % of theory are obtained. N-Capryl ^ -O-nolyl-SO-palmltyll-amino-propanediol- (2,3) obtained.
Rf value: 0.30

Petroleum ether / ether
70:30

Example 5:

(Reaction scheme 3)

0.92 g (10 mmol) of 2-amino-propanediol- (l, 3) are suspended in 50 ml of water and 50 ml of tetrahydrofuran with 0.5 g of magnesium oxide. To Addition of 3.6 g (12 mmol) of oleic acid chloride is shaken vigorously for 30 minutes. The solution is made weakly acidic and extracted with ether. The extract is then treated three times with dilute ammonia to remove the unreacted oleic acid. The ether

909847/0108 _ ₁₅ .

-VS-

phase is washed neutral and the solvent is stripped off in vacuo .

Yield: 2.4 g = 68 % of theory N-01eyl-2-aminopropandol- (1,3) Rf value: 0.24
CHCl ₃ ZCH ₃ OH

15: 1

Example 6:

(Reaction scheme 3)

0.71 g (2 mmol) of 2-N-01eyl-2-aminopropanediol- (1,3), as described in Example 5, are prepared in 30 ml of abs. Chloroform and 10 ml of abs. Dissolved pyridine and 1.3 g (4.8 mmol) of palmitic acid chloride in 10 ml of abs. Chloroform was slowly added dropwise ^{at 0 ° C.} The mixture is then stirred at 40-50 ^° C. for a further 2-3 hours. After the reaction has ended, the mixture is extracted with ether and, after purification by column chromatography, 1.25 g = 75 % of theory result. 2-N-01eyl-1,3-0-dipalmityl-2-aminopropanediol- (1,3) . Rf value: 0.30

Petroleum ether / ether
70:30

Example 7:

(Reaction scheme 4a)

2.6 g (20 mmol) of ethyl 2,3-diamino-propionate are dissolved in 100 ml Water / tetrahydrofuran 1: 1 suspended with 1 g of magnesium oxide. The solution should be alkaline. 5.6 g (20.mol) triphenylchloromethane in 100 ml of benzene are added and shaken vigorously. The resulting 3-N-trityl-2,3-diamino-propionic acid ethyl ester is purified by chromatography on a silica column and 3.0 g (8 mmol) in abs. Tetrahydrofuran dissolved. This solution becomes several times LiAlHj. added in small amounts (50-100 mg). The reduction is completed by heating, by careful addition of water the reaction is interrupted and the lithium and Aluminum hydroxide precipitates are centrifuged off, the water-containing one Tetrahydrofuran is evaporated. 3.0 g (8 mmol) of the

- 16 909847/0108

hold 3-N-Trityl ~ 2,3-diamino-propanol- (l) in 30 ml of abs. Chloroform and 10 ml of pyridine dissolved, 2.7 g (9 mmol) of linoleic acid chloride in 10 ml of abs. Chloroform was ^{slowly added dropwise at 0 °} C. and the reaction was completed ^{within 3-1 1} hours by stirring at room temperature. The solvent is drawn off, the O-acyl group is split off with 30 ml of 0.5 N methanolic KOH, the reaction product is extracted with ether after the addition of water, washed neutral and the ether is stripped off in vacuo.

0.6 g (1 mmol) of 3-N-trityl-2-N-linolyl-3,2-diamino-propanol- (l) are refluxed in 50 ml of 75% acetic acid. After the trityl group has been completely split off, the product is extracted with chloroform and 2-N-linolyl-2,3-diamino-propanol- (I) is isolated by column chromatography.
Yield: 270 mg = 76 % of theory
Rf value: 0.15

65:25

Example 8:

(Reaction scheme ¹ Ia)

0.7 g (2 mmol) of 2-N-linolyl-2,3-diamino-propanol- (l), prepared as described in Example 7, are in 30 ml of abs. Chloroform and 10 ml of abs. Pyridine dissolved, 0.6 g (2.2 mmol) of palmitic acid chloride in 10 ml of abs. Chloroform was ^{slowly added dropwise at 0 °} C. and then stirred for a further 3 hours at room temperature. After the reaction has ended, the solvent is drawn off, the O-acyl group is split off with 30 ml of 0.5 N methanolic KOH, the reaction product is extracted with ether after the addition of water, and the ether phase is washed neutral. After removing the solvent in vacuo, 1.01 g = 88 % of theory remain. 3-N-Palmltyl-2-N-linolyl-2 ₁ 3-diamino-propanol- (l).
Rf value: 0.65
CHCl ₃ ZCH ₃ OH

15: 1

909847/0108

Example 9:

(Reaction scheme 4a)

2.4 g (4 mmol) of 3-N-trityl-2-N-linolyl-2,3-diamino-propanol- (l), prepared as described in Example 7, are in 50 ml of abs. Chloroform and 10 ml of abs. Pyridine dissolved, 1.2 g (4.5 mmol) of palmitic acid chloride in 10 ml of abs. Chloroform at 0 ⁰ C were slowly added dropwise and 3-4 hours at 40 - 50 ⁰ C stirred further. After the end of the reaction (TLC determination) the product is extracted from ether and purified by column chromatography. 2.5 g (3 mmol) of 3-N-trityl-2-N-linolyl-l-0-palmityl-2,3-diamino-propanol- (l) are refluxed in 50 ml of 75% acetic acid until the trityl group is totally split off. The product is extracted with chloroform and, after purification by column chromatography, 1.3 g = 73 % of theory are obtained. 2-N-linolyl-l-0-palmltyl-2 ₁ 3-diamino-propanol- (l) obtained.
Rf value: 0.25
CHCl ₃ ZCH ₃ OH

15: 1

Example 10:

(Reaction scheme 4a)

1.2 g (2 mmol) of 2-N-linolyl-l-palmityl-2,3-diamino-propanol- (l) as described in Example 9 are in 50 ml of abs. Chloroform and 10 ml of abs. Pyridine dissolved, 0.66 g (2.4 mmol) of palmitic acid chloride in 10 ml of abs. Chloroform at 0 ⁰ C slowly dripped in and another 2-3 hours at 40 - 50 ^0C further stirred. After the reaction has ended, the mixture is extracted with ether and 1.4 g of 2-N-Llnolyl-3-N-palmityl-l-0-palmltyl-2,3-diamino-propanol- (l) = 85 % of theory. obtained after purification by column chromatography. Rf value: 0.23

Petroleum ether / ether
70:30

- 18 -

909847/0108

Example 11;

(Reaction scheme 2b)

5.7 g (10 mmol) of N-palmityl-3-0-trityl-1-amino-propanediol- (2,3), prepared as described in Example 3, are in 60 ml of abs. Tetrahydrofuran and 10 ml of abs. Pyridine dissolved. 2.4 g (12 mmol) of 3-Benzylpropionsäurechlorid in 10 ml of tetrahydrofuran are slowly added dropwise at 0 ⁰ C and 3-4 hours at 40 - 50 ⁰ C stirred further. After the end of the reaction (TLC test) the crude product is extracted with ether. After purification by column chromatography, 6.5 g = 88.6 % of theory are obtained. N-palmityl-3-O-trityl-2-O-β-benzylpropionyl-1-amino-propanediol- (2,3) was obtained.

6.5 g of the obtained palmityl-3-0-trityl-2-0-ß-benzylpropionyl-amino-propanediol- (2,3) are refluxed in 60 ml of 75% acetic acid. After cleavage of the trityl group (DC test) the product is extracted with ether and isolated by silica chromatography. The result is: 3.9 g (8 mmol) of N-palmityl-2-O-β-benzylpropionyl-1-aminopropanediol (2,3).

3.9 g (8 mmol) of N-palmityl-2-O-ß-benzylpropionyl-1-amino-propanediol- (2,3) are dissolved in 50 ml of abs. Chloroform and 10 ml of abs. Pyridine dissolved. To the solution is slowly dripped into 10 ml of chloroform at 0 ⁰ C 3.8 g (12 mmol) of palmitoyl chloride. The mixture is then stirred for a further 3-4 hours at room temperature. After the end of the reaction (TLC test), the reaction product is extracted with ether and isolated by silica chromatography. The result:

5.8 g (8 mmoles) of N-palmityl ^ -O-palmityl ^ -O-ß-benzylpropionyl-laminopropanediol- (2,3).

5.8 g (8 mmol) N-palmityl-S-O-palmityl ^ -O-ß-benzylpropionyl-lamino-propanediol- (2,3) are stirred with 0.8 g (16 mmol) of hydrazine hydrate in 20 ml of pyridine - 80> 6 glacial acetic acid (4: 1) overnight. That Solvent is stripped off in vacuo and the reaction product is purified by silica chromatography.

Yield: 4.2 g (7.5 mmol) = 94 % of theory N-palmityl-3-O-palmltyl-

1-amino propanediol (2,3)

Rf value: 0.75
CHCl ₃ ZCH ₃ OH

15: 1

Example 12:

(Reaction scheme
3 g (9 mmol) of 3-N-trityl-2,3-diamino ~ propanol- (l), prepared as described in Example 7, are dissolved in 15 ml of methyl dichloroacetate and the solution is heated at 100 ° C. in an oil bath for 2 hours ( DC test). 50 ml of petroleum ether are added to the cooled reaction mixture. The reaction product which has crystallized out is filtered off with suction, washed with petroleum ether and extracted from metha-,.

Tr, i'i ' -'- ^{/ l} ' ^P >

nol recrystallized. The result is: 2.7 g (6.1 mmol) of 3-N-dichloroacetyl-2,3-diamino-propanol- (l).

2.7 g (6.1 mmol) of the obtained 3-N-trityl-2-N-dichloroacetyl-2,3-diamino-propanol- (l) are dissolved in 50 ml of 75 Ziger acetic acid and heated under reflux. After the cleavage of the trityl group (TLC test) the reaction product is extracted with ether, isolated by silica chromatography and gives a 100 iige Yield: 1.2 g (6.1 mmol) of 2-N-dichloroacetyl-2,3-diaminopropanol- (l).

1.2 g (6.1 mmol) of 2-N-dichloroacetyl-2,3-diamino-propanol- (l) become in 30 ml abs. Chloroform and 5 ml of abs. Pyridine dissolved. To the solution 1.6 g (10 mmol) of caproic acid chloride in 10 ml of abs. Chloroform dripped slowly. After 3 hours, by adding 1 ml Water terminates the reaction. The solvent is then stripped off in vacuo and the residue is taken up in 50 ml of methanol. After adding 10 ml of 1 η NaOH, the N-dichloroacetyl group becomes and any O-acyl group cleaved in 3-4 hours.

After neutralization with dilute hydrochloric acid, the reaction product is extracted with chloroform and purified by silica chromatography.
Yield: 1.15 g (5.5 mmol) = 90 % of theory 3-N-Capryl-2,3-dlamino-

propanol (l) Rf value: 0.47

CHCl ₃ ZCH ₃ OH / H ₂ O

65: 25: 4

Starting from 1N-dichloroacetyl-1 3-diaminopropanol- (2), the ^ N-CapryL-1, H-diaminopropanol- (2) can be obtained in an analogous manner by acylation with the caproic acid chloride and subsequent cleavage.

9 Q ¹ Vi>;' ^T / 0 1 0 8

Claims (4)

Claims 1.) Structural analogues of natural glycerides with the general ones Formulas 1) H ₀ C-NH-R ₁ ² I. HC-OR ₁ , H C-O-R 2) H COR ₉ ² I ² HC-NH-R H ₂ COR ₂ 3) H ₀ C-NH-R ₁ HC-NH-R, H ₂ COR ₂ 4) H C-NH-R, HC-O-R, H C-NH-R ₁ Lt ± wherein the radicals R ₁ and R are either hydrogen and / or saturated or unsaturated straight-chain or branched acyl radicals having 2-24 carbon atoms, at least one of these substituents being an acyl radical. 2. Structure analogs according to claim I _5, characterized in that the acyl radical or radicals are caprylic, palmitic, stearic, oleic, linoleic, linolenic or arachidonic acid radicals. 909847/0108 3. Process for the preparation of the structural analogs according to claim 1, characterized in that the corresponding aminopropanediols or diaminopropanediols are optionally used after the reaction an amino or hydroxyl group with suitable protective groups with fatty acid chlorides in the presence of an inert base lets react. 4. Medicaments, characterized in that they contain one or more structural analogues according to claim 1 or 909847/0108