JPS5993087A - Substituted aminoalkanol phosphatide and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel substituted aminoalkanol phospholipids and methods for their preparation.

The compounds of the present invention have the general formula (χV to "I"88 elementary sulfur atoms, and Y is a -Nft1R2 to 10R3 group, where R1 and B2 are the same or different from each other. can and 1
A saturated or unsaturated chain or branched alkyl group, benzyl group, phenyl group or hydrogen having ~20 carbon atoms, R'tj: phenyl, benzyl or 0
1-C4-alkyl, H4, R5 and R6 can be the same or different from each other and hydrogen or 1-C4-alkyl;
is a lower alkyl group having 4 carbon atoms, and t is 0
It is an integer of ~19, and m times an integer of 2 to 6, which corresponds to (2 is nl, ?It is 2 to 4).

Examples of compounds according to the present invention are as follows.

2-(3-hexadecyl-1-methylureido)-ethanol-phosphocholine, 2-(1-methyl-3-octadecylureido)-ethanol-phosphocholine, 2-(ro-eikonru-1-methylureido)-ethanol-phosphocholine , 2-(1-methyl-6-oleylureido)-ethanol-phosphocholine, 2-(3-methyl-1-undecylureido)-nithanol-phosphocholine, 2-(3-ethyl-1-undecylureido) -ethanol-phosphocholine, 2-(3,3-dimethyl-1-undecylureido)-
Ethanol-phosphocholine, 2-(3-methyl-1-undecylthimeureate)-phenol-phosphocholine, 2-(1-hexadecyl-6-Meg-Leuret)-
Ethanol-phosphocholine, 2-(3-ethyl-1-hexadecylureido)-ethanol-phosphocholine, 2-(1-hexadecyl-5-meg ruthiourate)
-ethanol-phosphocholine, 2-(5,5-dimethyl-1-hekiladecylureido)-ethanol-Σ, sulfocholine, 2-(5-methyl-1-octadecylureido)-ethanol-phosphocholine, 2-(3 -Ethyl-1-octadecylureido)-ethanol-phosphocholine, 2-(3,3-dimethyl-1-octadecylureido)-echnol-phospocholine, 2-(6-methyl-1
-Mectadecylthiourei 1-)-ethanol-phosphocholine, 2-(3-butyl-1-octadecylureido)-ethanol-phosphocholine, 2-(3-hexade/ru 1-71tadesolureido')- Ethanol-phosphocholine, 2-(3-benzyl-1-octadecylureido)-ethanol-phosphocholine, 6-(6-methyl-1-octadecylureido)-panol-(1)-phosphocholine, 3-(3
-ethyl-1-octadecylureido)-solr:jp/
'-Lu(1)-phosphocholine, 6-(ro,3-dinotyl-1-octadecylureido)-zololξnor-(
1) -Phosphocholine, 6-(3-nobru 1-octadesolthimeureido) -7J'lovanol-(1,)-
Phosphocholine, 4-(6-methyl-1-octadedyluyl/ido)-butanol...(1)-Phosphocholine, 4
-(ro-ethyl-1-octadecyl-1/id-di-butanol-(1)-phosphocholine, 4-(3,3-dimethyl-1-octadecylureido)-butanol-(
1) -Phosphocholine, 4-(3-methyl-1-octadecylthioureido)-butanol-(1,1-phosphocholine, 2-(1-ethyl-1-cosyl-6-methylureido)-
・Ethanol-phosphocholine, 2-[1-eicosyl-3-ethyl/ide]-ethanol-phosphocholine, 2,-(3,5-simejiru-1-eicosylureido)
-Ex/'-Roof 1-77I Choline, 2-(1-Eigosyl-3-Mediylthiol[/Il゛)-Ethanol-Phosocholine, 2-(3-)J, Nyl-1-Undecyl Ureido )-ethanol-osphocolin, 2-c3--: fujiru-1-undecylureido)
-etha,'-luposhocholine, 2-(1-undecylureido)-ethanol-phosphocholine, 2-(3-hexadecyl-1-undecylureido)-
F2norupospocorin, 2-C3-ylrail-
1-undecylureido)-ethanol-phosphocholine, [2-43-methyl-1-octadecylureido)-ethyl) -(2-)! J ethiammonium ethyl)
-phosphate, [2-(3-methyl-1-octadecylureitra-ethyl]-(2-dimethylammoniumethyl)-phosphate, )-phosphocholine, N-benzyloxycarbonyl-N-undeflu-2-amineethanol-(1)-phosphocholine, N-benzyloxycarbonyl-N-hexadene-2
-Amineethanol-(1)-phosphocholine, N-benzyloxycarbonyl-N-octadecyl-2
-Amineethanol-(1)-phosphocholine, -benzyloxycarbonyl-N-octadecyl-
3-aminopropano-(1)-phosphocholine, N-benzyloxycarbonyl-N-octadecyl-4
-aminobutanol-(1)-phosphocholine, N-penglumexycarbonyl-N-eicosyl-2-
Amine ethanol-(1)-phosphocholine, N-methoxycarbonyl-N-octadecyl-2-amineethanol-(1)-phosphocholine, and N-ethoxycarbonyl-N-octadecyl-2-amineethanol-(1)- Phosphocholine.

The compounds according to the invention are very biologically active and can be used, for example, in medicines and protectants. These new compounds exhibit strong dream synergistic effects. In particular, they exhibit depressant and immunomodulatory effects. They can therefore be used not only in the treatment of hypertension, but also in the treatment of inflammatory diseases and in the treatment of atherosclerosis and tumors.

311 made from ureido alkyl phospholipid that is one of the most common baths? To do this, the general formula II CFT37(CJT2)z-NH-(CH2), -O
Examples of N-alkylaminoalkanols having HII (where t and Tn have the same properties as in formula In a solvent, benzyl halide is substituted with an auxiliary base such as pyridine, dinotylaminopyridine, triethylamine, alkali metal hydroxide or alkaline earth metal oxide. General 2 CH3-(CH2)z-N-(CH2), rl-OHI by reacting with benzyl ester
ll! 7 (where t and m are as in Formula 1 and R
7Vi represents a group such as benzyl or -penzyloxycarbonyl) which can be separated by hydrogenation.

This reaction can also be carried out in two phases, optionally using a phase transfer catalyst. Compound 1 (where n7i Henssil and m2) is also prepared from fc N-benzyl alkylamine and ethylene oxide. Compound 2 can be prepared by reaction of an appropriate amino acid with ethylene oxide. Alternatively, it can be obtained from the reduced pressure of N-7 flue ω-aminoalkanol.

Compounds of the general formula II (in which t and mIi have the same meanings as in formula I and B7 represents a group which can be separated off by hydrogenation, such as for example benzyl or benzylox7carbonyl) are known per se. Depending on the method, the general formula ■ (in the formula B4, B5, R6, L, m and n
has the same meaning as in formula l and R7←v formula II
phospholipids with the same meaning as in +). Compounds of the formula (1), in which P7 is xendylox7carbonyl, correspond to compounds of the formula 1, in which R3 is benzyl. For example, compound III Iri in an inert organic solvent optionally using an auxiliary base can be prepared by formula ■ t (where n has the same meaning as in formula I and Hal
is a chlorine or odor atom)
The product can be phosphorylated using an ω-alkyl halide ester, and the product can then be phosphorylated in an inert organic solvent, optionally under pressure. [ rAngew, chem, J
fP, Vol. 91, No. 550-560 (1979) and “
Chem, analPhye. of Lipj, 6th, Vol. 26, pp. 405-429 (1980)].

A compound of formula (1) is reacted with phosphorus/trichloride and then optionally an auxiliary base such as triethylamine is introduced (2) and an inert solvent (1) such as, for example, tetrahydrofuran is used. is reacted with -rlucanediol having the formula ■ HO-(CH2)n-OHVll [in the formula ntJ has the same meaning as in the formula ■] to form the formula ■ (in the formula 1. m
, n and R7 have the same meaning as in formula ■)
It is also produced by forming a cyclic intermediate with
pid, 5yntheeiθJ (1981) No. 19
~See pages 50].

The intermediate product of formula
II, in which an auxiliary base is added to form the formula IX (wherein 11 is the formula ■
It can also be prepared by reacting with a winged phosphorus-containing compound having the same meaning as (r' T
etrahedron Lett. ” Volume 23, No. 104
3-46 negative (1982) and [io-chim, l
31ophys, Acta J Vol. 711 No. 357-3
See page 60 (1982)].

Intermediate product (1) can be converted into a compound of formula (1) by simple methods, such as treatment with an amine of formula (1) in an organic solvent, optionally under pressure (1-B+u1°Soc,C)1
1m, F'r, J 1974, pp. 667-671].

A compound of formula (II) is separated off from the benzyl group in a suitable organic solvent such as methanol, ethanol, ether, dioxane or a mixture thereof with water in the presence of a conventional hydrogenation catalyst such as palladium/activated carbon. Upon concomitant hydrogenation with hydrogen, a compound having the general formula

A compound of formula Addition of a catalyst such as aminopyridine or an ia group such as pyridine or triethylamine to form
Compounds of formula 1 of the invention are formed when reacting with carboxylic acid derivatives having the same meaning as in formula 1.

The compound of formula 1 (wherein R1=F (2=H) is converted into V from the compound of formula
Hllget; written by ag rOrg, Chem, Expe
rimentierkunet J1970 No. 420
[see page], suitably using an alkaline anate in an aqueous or aqueous-organic medium, such as water/dimegizane, optionally with the addition of an organic acid or an Id inorganic acid, preferably acetic acid. It's coming.

Compounds having the formula I (wherein R2 is hydrogen and X is oxygen) may also be prepared in a suitable organic solvent such as methanol, ethanol, ether, a mixture of these with water, etc. In the presence of conventional hydrogenation catalysts, such as palladium/activated carbon, with separation of the benzyl group, compounds of formula 9 can be hydrogenated with hydrogen, in which R1=R2=H. It is formed.

To prepare the novel (aryl]alkylox7carponylaminoalkanol phospholipids of formula 1, N-alkyl-amino alcohols of formula Chloro M, ji% in an inert organic solvent, preferably in the presence of an auxiliary base such as pyridine, dimethylaminopyridine, triethylamine, alkali hydroxide, alkaline earth oglylide.
Benzyl ester, chlorooFj (acid 7-r:= /l'
x/(tilt fr-tti React with a chloroformic acid alkyl ester to form a compound having the general formula (1) B3-0ln3-0-C-1=J(CH2).

Compounds of the formula XI[l in which T1.5, t and m have the same XI'' as in formula 1; U'+- are converted into phospholipids of the general formula I by methods known per se. .

Compounds of formula λ111 can be phosphorylated, for example, with a dichlorophosphoric acid-ω-alkyl halide nisder of formula (I) in an inert organic solvent, optionally using an auxiliary base, and then optionally added in an inert organic solvent. 7' under pressure
can be converted into compounds of formula I by reaction with amine.

Compounds of formula I can also be prepared by phosphorylation of compounds of formula It can also be prepared by converting an alkanediol of the formula (1) into a cyclic intermediate having the formula XIV (where B3, L, m and n have the same meanings as in formula 1).

Intermediate XIV can be converted into a compound of formula (1) in a simple manner, for example by treatment with an amine of formula (1) in an organic solvent, optionally under pressure. Compounds of formula I may also include compounds of formula X, such as chloropol 1. in an inert solvent such as dimethylformamide, optionally with the addition of an auxiliary base such as pyridine or triethylamine (
- It can also be produced by reacting with chloroformic acid ester.

Suitable examples of starting compounds having formula (1) are as follows. i.e. 2-methylamino-ethanol,
2-ethylamino-ethanol, 2-propylamino-
Ethanol, 2-butylamino-ethanol, 2-pentylamino-ethanol, 2-hexylamino-ethanol, 2-heptylamino-ethanol, 2-octylamino-ethanol, 2-nonylamino-ethanol,
2-decylamino-ethanol, 2-undecylamino-ethanol, 2-dodecylamino-ethanol, 2-
tri/ruamino-ethanol, 2-tetradecylamino-ethanol, 2-antadecylamino-ethanol, 2-hexadecylamino-ethanol, 2-heptadecylamino-ethanol, 2-octadecylamino-ethanol, 2-nonadecylamino-ethanol Ethanol, 2-eicosylamino-ethanol, 3-methylamino-zolopanol, 6-airamino-propanol, 3-propylamino-propanol, 3-butylamino-propanol, 6-pentylamino-pro/senol, 3-to Xylamino-propanol, 3-hebutylamino-propanol, 3-octylamino-propanol, 5-
Nonylamino-zolopanol, 6-zosylamino-zolopanol, 6-unzosylamino-propanol, 3
-dodecylamino-propanol, 3-tridecylamino-pro/senol, 3-tetradecylamino-propanol, 3-pentadenylamino-propanol, 3
-Hexadefluoraminopropanol, 6-hezotadecylaminopropanol, 3-octadecylamino-
Propanol, 3-nonadecylamino-propanol,
3-eicosylamino-propanol, 4-methylamino-butanol, 4-ethylamino-butanol, 4-
Propylamino-butanol, 4-butylamino-butanol, 4-27tylamino-butanol, 4-hexylamino-butanol, 4-hekylamino-butanol, 4-octylamino-butanol, 4-nonylamino-butanol Tutanol, 4-decylamino-butanol,
4-Undecylamino-butanol, 4-1'decylamino-butanol, 4-tridecylamino-butanol, 4-tetradecylamino-butanol, 4-pentadecylamino-butanol, 4-hexadecylamino-butanol, 4- Hezotadecylaminobutanol, 4-
Octadecylamino-butanol, 4-nophthelenebutanol, 4-eicosylamino-butanol, 5-methylamino-butanol, 5-airamino-pentanol, 5-propyl minol, 5-phthylamino - is tutanol, 5-duntylamino is tutanol, 5-hegisolaminone is tutanol, 5-hebutylamino is tutanol, 5-octylamino is tutanol, 5-nonylamino-pantanol, 5-decylamino-takuntanol , 5-undecylaminopentanol, 5-dodecylaminosontanol, 5-tria/ruamino- is montanol, 5-tetradecylamino- is montanol, 5-undecylamino- is montanol, 5-hekylydecyl/ l, 7
minortanol, 5-hephtatecylaminopenknol, 5-octadecylaminotanol, 5
-nonadecylaminosontanol, 5-eicosylamino-pentanol, 6-medylaminohexanol, 6-nityl-f-hexanol, 6-propylamino-hegizanol, 6-butylaminohexanol /
-) L-,6-hentylamino'-hegizanol, 6-
Hegylylaminohexanol, 6-heptylami2-, hexa,nol, 6-octylminorquinanol, 6-tunylaminohexanol, 6-dedylaminohexanol, 6-landinylaminohexanol, 6-dobuzolamino -hexanol, 6-driven ruamino-hexanol, 6-tetradecylaminohexanol, 6-ntadecylaminohexanol, 6-octazosylaminohexanol, 6-hexdecylaminohexanol, 6 -Heptadecylamino-hexanol, 6-nonazosylamino-hexanol and 6-nicosylamino-hexanol.

Suitable starting compounds of formula (1) include, for example: Namely, dichlorophosphoric acid-2-bromoethyl ester, dichloroFi acid-2-chloroethyl ester, dichloro(M m -3-7' rimbrovir ester and dichloro tl'4 acid-4-chromium butyl ester).

The secondary and tertiary amines i+ are used as starting compounds for the formula (2). For example, dimethylamine, diethylamine, dipropylaone, dibutylamine, trimethylamine, triethylamine, tripropylamine, tributylamine, ethylmethylamine, methylpropylamine, ethylzolobylamine, butylmethylamine, butylethylamine, butylpropylamine, dimethylethylamine, dimethyl Zorobylamine, butyldimethylamine, diethylmethylamine, diethylpropylamine, butyldiegulamine, diethylmethylamine, diethylmethylamine, butyldipropylamine, diethylmethylamine, dibutylethylamine, dibutylpropylamine, ethylmethyl They are worobilamine, butylmethylpropylamine, butylethylmethylamine and butylethylmethylamine.

Suitable starting compounds of formula X include, for example: Namely, methyl isocyanate, methyl isothiocyanate, ethyl isocyanate, ethyl isothimecyanate, zorobyl isocyanate, propyl inthiocyanate, isopropyl incyanate, isopropyl inthionanate, butylisonaoate, butylisothymesoanate, allyl isocyanate, allyl isothiocyanate. auto, hexyl isocyanate, hexyl isodiozoanate, octyl isocyanate, octyl inthiocyanate, decyl isonanate, decyl isofmenanate, undecyl isocyanate, undecyl inthiophanate, dodecyl isocyanate],
Dodenruinthiocyanate, Tetradecyl Isocyanate, Tetradecyl Inthionanate, Hexadecyl Isocyanate, Hecadecyl Isothiocyanate, Octadecyl Isocyanate, Octadesol Isothiocyanate, Oleyl Isocyanate, Oleyl Isothionanate, Eikon Ruinocyanate, Eikon Ruinocyanate Dionane-1., phenylisonanate, benzyl isocyanate, phenyl isodiocyanate and benzyl inthionanate.

The starting compounds of the formula J Lupamic acid chloride, diethylcarbamic acid chloride, dibrovir carbamic acid chloride, dibutylcarbamic acid chloride, methylethylcarbamic acid chloride, methylpropylcarbamic acid chloride, methylbutylcarbamic acid chloride, ethylcarbamic acid chloride, butyl Propylcarbamate chloride, butylethylcarbamate chloride, dimethylthiocarbamate chloride, diethylthiocarbamate chloride, dipropylthiocarbamate chloride, diethylthiocarbamate chloride, methylethylthiocarbamate chloride, methylpropylthiocarbamate chloride , methyl ethylthiocarbamic acid chloride, ethylprobinotodiocarbamic acid chloride, butyltulovylcarbamic acid chloride and butyl ethylthiocarbamic acid chloride 1.

The novel substituted aminoalkanol phospholipids can be formulated into pharmaceutical formulations, for example. These pharmaceutical preparations are suitable for enteral and oral or rectal and parenteral administration and contain the pharmaceutically active agent alone or in combination with conventional pharmaceutically applicable carrier materials. Pharmaceutical preparations of active agents include tablets, coated tablets, capsules, herbal medicines, granules, solutions, milk7
Preferably, it is in the form of eight individual doses adapted to the desired administration, such as a liquid solution or a suspension.

For compound drugs, HL is usually 1 to 1000 ml per drug dose, and how many times 1. < is 1 to 10■ and once or several times,
tI74 can be administered 2-3 times a day.

RII! of the compounds of the invention according to the examples below. The product manufactured by I will be explained in detail.

Production example of alcohol A, 2) 1 N-benzyloxycarbonyl-N-7'thyl-2-
Amine ethanol 2-Methylamine ethanol 75F and triethylamine 101y mixed with anhydrous chloroform 10100O-
do. Chloroformic acid benzyl ester 1711 is added dropwise to this solution at about 20°C. The mixture was stirred at moderate temperature for 1 hour, washed with water, dilute hydrochloric acid and again with water and sulfuric acid).
The solvent was evaporated under vacuum to form an oil.
73v remains. IR (film): 1695tM-
1゜Example 2 N-benzyloxi7carbonyl-N-undecyl-2-
2-Undenyamin-ethanol 1 in the same manner as in Aminoethanol Example 1
247, triethylamine 58f1 chloroform 5 [
10- and chloroformic acid hensyl ester 97.

Column chromatography (7Lica gel/'Hejiang Zhan/
Purify by ethyl acetate (ethyl acetate).

Oily content 1113f, IR (film): 168
3crn-1゜Example 3 N-penzyl mexocarbonyl-N-hexatecyl-
2-Amine ethanol In the same manner as in Example 1, 71 2-hexadefluamino-ethanol, 252 triethylamine, and 250 chloroporm were prepared.
-Oyohi Chloro Mre 'y Shi/1 Nisdel 437
obtained from.

Purified by column chromatography (silica gel 7'chloroformo). Oily yield i: 40.2r, engineering R
(Film): 1690 cm-1° Example 4 1q-benzyl-N-,4tadecyl-2-amineethanol Ethylene oxide F40 me cooled with dry ice in a mixture of N-benzyl-octadecylamine 6597 and methanol 200 Room? ! Drop within 2 hours at +R. The mixture was stirred for a further 5 hours, the solvent was removed and the residue was purified by column chromatography (silica gel/chromatography 1 Polmura. Yield 737, melting point 31 l).

Example 5 N-benzitoo last 7 carbonyl N-, 4tadecyl-
6-Aminopropanol It is obtained analogously to Example 1 from 34.2 f of 3-octadecylamino-propanol, 10.57 f of triethylamine, 100 mg of chloroform and 17.7 f of chlorotv+mhensyl ester.

Purified by column chromatography (silica gel 7 chloroform). Yield of oil 33.12, IR (film CICl68O').

Example 6 -benzyloxycarbonyl-N-octadecyl-
4-Aminobutanol As in Example 1, 24.8 g of 4-octadenyl aminobutanol, 7.4 f of ethylamine.

Chloroform 200+++/and chloroformic acid hensyl ester 12. ! Obtained from M.

Calano, V purification by chromatography (silica gel 7 chlorol). Yield of oil: 182, film: 1690 cPn-1° Example 7 N-benzyloxocarbonyl-N-eicosyl-2
-amine ethanol 2-eicosylamino-ethanol 6 as in Example 1
2,8, triethylamine 9.7 f, chloroform 200 and benzylnisder chloroformate 16
．． Obtained from 3F.

Purified by column chromatography (silica gel/hexane/ethyl acetate). Yield 14.67, melting point 5
3 to 54°C, IR (Firno, ): 1690 cm-1° B1 Example of manufacturing phospholipid of formula (8) :) Chlorom acid-2-bromoethyl ester 10
5f, pyridine 53vre and anhydrous chloroform.
220ml of chloroform in the 800-liter mixture! N-penzyloxy/carbonyl-N-methyl- dissolved in
Add 46f of 2-aminoethanol dropwise while cooling with ice. The reaction mixture is stirred for 1 hour while cooling with ice and, after addition of ice water, stirred for a further 1 hour at room temperature. The organic phase is separated off, washed with water until neutral, dried over sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel/chloroform/methanol). (N-benzyloxycarbonyl-N-methyl-2-
Amount of 28 grams of (amine ethyl)-2-bromoedyl phosphate (oil).

b) (N-benzyloxycarbonyl-N-methyl-2
-aminoethyl)-2--yromuethyl phosphate 2
8 f completely dry) Lul 7300m7! Dissolve medium KFI, 53% ethanolic trimethylamine solution 30/
and stirred the mixture for 4 hours at 60° C. in an autoclave. The solvent was then removed using a rotary evaporator (Rotava).
por) and the residue is purified by chromatography (silica gel/chloroporum/methanol/water). Yield a5q, melting point 75-78°C
.

Example 9 N--<endyloxocarbonyl-N-unphyl-2-amineethanol-phosphocholine a) Dichlorophosphoric acid-2-bromoethyl ester 75f in the same manner as in Example 8
, Bill J Jin 51m! , 600 mg of chloroporm and 150 rnl of chloroporm yielded 54.21 ethanol of J-benzyloxycarbonyl-1(-undecyl-2-aminoethyl).(N-benzyloxycarbonyl-N-undecyl-2-aminoethyl) -2--
10 Collection of Muedzyl Phosphate (Oil) Jj 4
ZB y.

1')) N-Penglumexycarbonyl-N-undecyl-2-aminoethyl]-2-bromoethyl-phosphate-1-47,6f, toluene 5 in the same manner as in Example 8
00ml and a 33% ethanolic trimethylamine solution 30-. Yield 29.9 ml, melting point 224-
226°C, IR (in Knr): 1692rn-10 Example 10 1=1-benzyloxycarbonyl-N-hexadecyl-2-amineethanolphosphocholine a) Dichlorophosphoric acid-2-bromoethyl ester 469 as in Example 8;
Biljgin'2"rm, e, chloroform 400+++
/ and N-benzyloxycarbonyl-N-hexadecyl-2-amine ethanol 407 in chloroform 95 me. (1.I-benzyloxi7carbonyl-N-?vzadesol-2-aminoethyl)-
2-f, Ethyl-phosphate (oil) Yield f21.50 b) (N-Benzylox7carbonyl-N-hexadecyl-2-aminoethyl)-2-bromoethyl-phosphate 21. 41, obtained from 100 in toluene and 10 in a 36% ethanolic trimethylamine solution. Revenue Q7? , melting point 226-228℃, engineering R (
(in KBr): 16916n-'.

Example 11 ■-Benzyl-N-ntadesol-2-aminoethanol-phosphocholine FV) N-benzyl-11-octadeclue-2-amino-ethanol IQf, dichlorophosphoric acid-
2-, 'Romuethylestermi 3r is added dropwise. The reaction mixture is stirred for a further 3 hours at room temperature, ice water is added and then stirred again for 1 hour. The organic phase is separated, washed with water until neutral, dried over sodium sulfate and concentrated.

The residue is purified by Calano chromatography (silica gel/chloroform/methanol). (N-benzyl-N-octadecyl-2-abanoethyl)-2-7
'Yield of romuethyl phosphate (oil) 9.2
f.

b) N-Benzyl-N-octadecyl-2-aminoethanol-phosphocholine was prepared analogously to Example 8b (N-
Benzyl-N-octadecy/L-2-aminoethyl)-
2-bromoethyl phosphate) 9.21i', obtained from 30 m/m of toluene and 5.2 m of a 53% ethanolic trimethylamine solution. Yield 6.4? , melting point 2
15-217°C.

Example 12 N-benzyloxycarbonyl-N-octadecyl-3
-Aminopropanol-(1)-phosphocholine 8) Dichloroformic acid-2-bromoethyl ester 34.3F, pyridine 140ml. Chloroform, 140ml! and in chloroform 100m/)
J--<ndyloxycarbonyl-N-octadecyl-3-aminopropatol 32.7F is thus obtained. (
N-benzyloxycarbonyl-N-octadecyl-
Yield of 3-Fuminoprovir)-2-broth, ediluphosphate (oil) 96F.

1)) Analogously to Example 8 (N-pendylmegizocal) (N-mettadecyl-3-aminopropyl)-2-bromoethyl-phosphate 9.52 m, toluene 45 m
Obtained from 5 ml of 33% ethanolic trimethylamine solution. Yield 6.5 f, melting point 21
9-223'C, IR (in KBr): 1688ctn-
1゜Example 13 N-benzyloxy7carbonyl-N-octadecyl-4
-aminobutanol-(1)-phosphocholine FV) 2-bromoethylnisder dichlorophosphate 17.4fI, e"J syn72-,
Chloroporm 72- and Chloroform 40-resistant 1 size-penzyloxycarbonyl-N-octadecyl-4-
Aminobutanol 17f' is thus obtained. Yield of (N-benzyloxycarbonyl-N-octadecyl-4-aminobutyl)-2-bromoethyl-phosphate (oil) i6.10b) Analogously to Example 8 (N-benzyloxycarbonyl-N-octadecyl-4-aminobutyl)-2-bromoethyl-phosphate (oil) -aminobutyl)-2--
j Romuethyl-phosphate 6F, toluene 30 furnace e and 33% ethanolic trinotylamine solution 3 me
obtained from. Yield 5141° Melting point 220°C (decomposition), I
'R (in KBr): 1694tm-1゜Example 14 N-benzyloxycarbonyl-N-eicosyl-2-
Aminoethanol-phosphocholine a) Dichlorophosphoric acid-2-bromoethyl ester 14.52 as in Example 8;
Hyridine 7.5ml, Chloropho A. No., 12Dre deceased.
and N-eicosyl-2-amine ethanol 14 in chloroform and 3o furnace i
．． 51 is obtained. Yield of (N-pendyloxyluponyl-N-eicosyl-2-aminoethyl)-2-f romethyl phosphate (oil) 12.7 f.

b) Analogously to Example 8 (N-benzyloxycarbonyl-N-eicosyl-2-aminoethyl)-2-bromoethyl-phosphate 12.6F, Toluev 60 ml
and 20 m of 55% ethanolic trimethylamine solution
Obtained from 1. Yield - Jill, 4 ml, melting point 210C (
decomposition], H ((in KBr): 1694cn1'''1゜Example 15 (N-benzyl-N-octadecyl-2-aminoethyl)-2-toIJ ethyl ammonium ethyl poniferin (hy --: Njiru N.-octadecyl-2-aminoethyl)-2-bromoethyl phosphate 11.8 da, toluene 60 me.

Triethylamine 5 me and 2-propatool 10
It is obtained from m1. Yield Ql 1 [1,2f% Melting point 21
5-216℃.

Example 16 (N-benzyl-N-octadecyl-2-aminoethyl)-2-ammoniumethyl tenophate (N-benzyl-1\1-octaacyl-2-aminoethyl)-2 - Bromoethyl phosphate 11. +11. ) Luene 6Gml.

Obtained from 30 ml of 2-propertool and 40% aqueous dimethylamine solution 11]me. Yield 9.5fS Melting point 210°C.

Example of Preparation of Pseudolipid of C0 Formula .

This solution is mixed with 0.81% of 10% palladium on activated carbon and the reaction mixture is hydrogenated with hydrogen.

After the absorption of H2 has ended, the solution is filtered and the filtrate is evaporated to dryness under vacuum. Yield of wax-like material 5 r0 Example 18 3-Undenylamineethanolphosphocholine N-benzyloxycarbonyl-N-undecyl-2-aminoethanolphosphocholine 141 and dioxane/water (ratio 'f4:I V/V) Medium+
7) Obtained from Pd-activated carbon 1.47. Yield 9.27
, melting point 205-208°C.

Example 19 2-hexyloxycarbonyl-N prepared in the same manner as in Example 17
-hegizadecyl-2-amineethanolphosphocholine 6
．． 97 and dioxane/water (ratio 4:1, V/V
) in Pd-activated carbon 0.71 to 1Sf. Yield 5.2 f, melting point 2+]3-207°C (decomposition).

Example 20 2-:A Phtadecylaminoethanol Phosphorone Example 1
In the same manner as in 7, N-benzyl-N-octadecyl-2-
Obtained from 0.6 g of Pd-activated carbon in aminoethanol phosphocholine 6,/I and dioxane/water (ratio 4:1, V/V). Yield 51, melting point 211] ~ 21
2t:.

Example 21 8-occudecylaminodulopanol phosphocholine N-benzyloxycarbonylate J-71 ctadene-5-aminopropanol phosphocholine 6.29 and dioxane/water (H; ratio 4 : 1
, v7v) Nakano Pd-activated carbon 0.62 to i! ) can be done. Collection-Yu! : 4.4 v, melting point 227-229°C.

Example 22 4-Octadecylaminobutanol Phosphocholine Example 17
In the same manner as N-x-di-A-oxycarbonyl-N-octadecyl-4-aminobutanolphosphocholine 3.7
2 and T in dioxane/water (ratio 4:1, V/V)
Obtained from d-activated carbon 041. Yield 2.29, melting point 208-210°C.

Example 23 2-Ecosylamine ethanolphosphocholine Example 17
N-benzyloxycarbonyl-N-eicosyl-2-amine in ethanolphosphocholine 11F and dioxane/water (ratio 4:1, V/V) (7) in the same manner as
Obtained from 1.1v of Pd-activated carbon. Yield 7.41i'
, melting point 214-219°C.

Example 24 (N-octadecyl-2-aminoethyl)-2-triethylammonium ethyl phosphate full In the same manner as in 17 (N-benzyl-N-octaan-2-aminoethyl) -2-) IJ ethylammonium ethyl phosphate A+102 and dioxane/water (4:1,
V/V) from Pd-activated carbon 11. Yield a
1? , melting point 218-219°C.

Example 25 ()I-octadecyl-2-aminoethyl)-2-dimethylammonium ethyl phosphate (N-benzyl-N-octadecyl-2-aminoethyl)-2-dimethylammonium ethyl phosphate)
9.5 F and dioxane/water (4:1, V/V)
Obtained from Pd-activated carbon 0.92 in. Yield 7.5
f, melting point 220-226°C.

]] Production example of phospholipid of formula 00 26 2-(3-ethyl-1-octadecylureido-ethanolphosphocholine 2-octadecylamino-ethanolphosphocholine 0.
52 is dissolved in chloroform, and this solution is mixed with 0.14 f of ethyl isocyanate and a few drops of dimethylformamide and stirred at room temperature for about 4 hours.

The solution is concentrated under vacuum (- and the residue is purified by column chromatography (silica gel/chloroform/methanol/water). Yield: 0.43F, mp 21
4-215°C, IR (in KTFr): 1630.153
5 cm-'.

Example 27 2-(3-Methyl-1-octadenureido)-ethanolphosphocholine Same as Example 26 212-Octadecylamino-ethanolphosphocholine 05f1 Methyl isocyanate 0.1
Obtained from 1F and chloroform 10we. Yield 0
．． 35r, melting point to 219・220℃, 11E (J3!
Medium): 1625.1540 cm-1゜Example 28 2-(3-methyl-1-mectadeneruthiourayi)
- Ethanol phosphocholine 0.5/2-mekudecylaminoethanol phosphocholine in the same manner as in Example 26, nodyl isothionane-t
・0.15 f Obtained from 10 me of chloroformum. Expropriation 0.41 f/, melting point 215-217°C.

Example 29 2-(3,3-dimethyl-1-octadecylurei 1
)-ethanolphosphocholine 2-mectadenylamino-ethanolphosphocholine 0.
Dissolve 51$ in 10me of chloroform and add this (
7. Dimedylcarbamic acid 0.21 F and charcoal 1
'Se2*l, io, mixed with 14 V perilla (7, stirred at room temperature for about 12 hours). The solution was concentrated under vacuum and the residue was purified by column chromatography (silica gel l chloroporum/methanol/ water).

Expropriation 0.31f, melting point 215-216℃, XB (KB
r): 1634crn-'.

Example 30 2-(3-Butyl-1-octadecylureido]-ethanolphosphocholine 2-octadecylamino-ethanolphosphocholine 057, butylison-anate 0.2
f and chloroform 10-. Yield [1
, 389, melting point 208-210°C, IR (in K, Br)
: 1625.1530 cm-1゜Example 31 2-(3-hegizadecyl-1-mectadecylureido)
-Ethanolphosphocholine 0.5 f, hexadecylino7ane) 0.6 F and chloroform 10 me to i(
I get caught. Yield Jt0.63r, melting point 220-230℃
, In(T(Br medium 7) 2 1625, 1
5 3 5cy+++-'.

Example 32 2-(3-benzyl-1-octadecylureido)-ethanolphosphocholineff! l In the same manner as 26, 2-octadecylamino-
Obtained from 0.5 r of ethanol phosphocholine, 0.277 g of pendylinane) and 10 mg of chloroform. Yield 0.42F, melting point 221-222℃ 0 cases
33 2-(3-Methyl-1-undecylureido)-ethanolphosphocholine Example 26 and four 2-unte'cylamino-ethanolphospocholine 0.5 f, methyl isocyanate)
0.15S' and chloroform 10-.

Yield of wax-like material with temperature ~185 °C 0.3 f, n (in KBr): 1629.1
540crn'''1゜Example 34 2-(3-ethyl-1-undecylureido)-ethanolphosphocholine In the same manner as in Example 26, 2-undecylaminoethanolphosphocholine 0.5F, ethyl isocyanate 0.18F
and chloroform 10-. il'lv Several wax-like substances with a clearing temperature of about 180°C to 183°C, IR (in KBr): 1626.153
6cm-1゜Example 35 2- (3,3-dimethyl-1-undecylureido)
-Ethanol Phosphocholine Obtained analogously to Example 29 from 2-undecylamino-ethanol-phosphocholine IJ, 5f, 0.2'8f of dimethylcarbamic acid chloride, 0.18f of silver carbonate and 10rne of chloroform. Clarifying temperature 203
Yield of wax-like material with ~204°C (], 32
r, It ((in KBr): 1634m-1゜Example
36 2-(3-Methyl-1-undecyldimeureate)-ethanol phosphocholine 0.5 f of 2-undecylamino-ethanol phosphocholine, methyl thionane-
10,19F and chloroform 10rn/! obtained from. Yield of wax-like material with fining temperature ~165°C 0.33 °C.

Example 37 2-(5-phenyl-1-undecylure (12-ethanolphosphocholine) Same as Example 26, 2-undecylamino-ethanolphosphocholine IJ, 5f, phenyl isocyanate 10.
31? and chloroporum 10me. Yield of wax-like material Jj0.611i', IH (in KBr) = 1649.15386n-'.

Example 38 2-(3-benzyl-1-undecylureido)-ethanolphosphocholine 2-undecylamino-ethanolphosphocholine 1.5F, benzyl incyanate 1.1
? and chloroform 3C1m)! obtained from. Collection of wax-like substances-3! : 1.79% IR(R,
F3r): 1533.1628 cm-1゜Example 3
9 2-(3-hexadecyl-1-undecylureido)-
Ethanolphosphocholine is obtained in the same manner as in Example 26 from 0.5Ii+ of 2-undenylamino-ethanolphosphocholine, 0.7t of hexadecyl isocyanate and 10ml of chloroform.

Yield [L69 f, melting point 196-199 °C, IR (K,
(in Br): 1622.1533 cm-'.

Example 40 2-(3-oleyl-1-undecylureido)-ethanolphosphocholine In the same manner as in Example 26, 2-undecylamino-ethanolphosphocholine o, 5 r , oleyl isocyanate 0.8 f and under a nitrogen stream Chloroform 1 []
+n/! obtained from. Yield of wax-like substance: 0.6
1f.

Example 41 2-(1-hexadecyl-3-notyl-1/ido)-ethanolphosphocholine 2-hexadecyl-amino-ethanolphosphocholine 0.3f,j-1-0 was prepared in the same manner as in Example 26.
,085' and chloroform 5me. Yield 0.22 f, melting point 215-218°C, IR(K
Br)+1635.1540cry+-'.

Example 42 2-(3-ethyl-1-hexadecylureido)-ethanolphosphocholine 0.5 f 2-hexadecylamino-ethanolphosphocholine, 0 ethyl isocyanate
．． 15y and chloroform 10-. Yield 0.45r, melting point 213-217°C.

Example 43 2-(1-hexadecyl-3-methylthioureido)-
Ethanolphosphocholine is obtained in the same manner as in Example 26 from 2-hexadecylamino-ethanolphosphocholine 0.5f, methylisothiocyanate) 0.16f and chloroform 10-.

Yield: 0.2 r, melting point: 210-212°C.

Example 44 2-(3,3-dinotyl-1-hexadecylureido)-ethanolphosphocholine 2-hexadecylamino-ethanolphospocholine 0.3f, dimethylcarbamic acid 11
Obtained from 0.241 i', charcoal pa 0.1 F and chloroform 5 trd2. Yield in, 157, melting point 20B-211°C, H (in KBr): 1635crn
.

Example 45 3-(3-knob-ru 1-octadenruurei 1')-
6-octazosylaminopropanol (1) in the same manner as in Example 26.
-Phosphocholine 0,52, Mebulisocyanate 0,
11 and chloroform 10rnI are obtained. Collection I
No, s3r, melting point 221-224], ], R(
KBr Medium): 1 628, 1 5 4
0z-”.

1s11 46 6-(3-Nige'-1-octadenureido)-[1panol-(1)-phosphocholine Example 26 Wash as in Example 26 to obtain 3-octadecylamino-propanol-(1)-phosphocholine0. 5 f.

Obtained from 0.14 f ethyl isocyanate and 10 fne chloroform. Collection 1jt: o, 3 f,
Melting point 215-218°C, IR (in KBr): 162
6.1535 cm-'.

Example 47 3-(3,3-dimethyl-1-octadecylure-f
) -furopanol-(1)-phosphocholine 3-octadecylamino-propano-
Lu(1)-phosphocholine 0.5 f.

Dimethylcarbamic acid chloride 0.1+11. Obtained from carbonated steel 0.14 S' and chloroform 10-. Yield gfi: 0.28F, melting point 224-225℃, IR
(in KBr): 1635crn-'.

Example 48 3-(3-phthyl-1-octadecylthiol 1/ite)
-Propanol (1) - 3-octadecylamino-dulopanol (1) - in the same manner as in Phosphocholine Example 26
Phosphocholine 0.5f.

Obtained from 0.15 f of megul isodioneanate and 10 ml of chloroform. Yield 0.36f, melting point 21
0-212℃.

Example 49 4-(6-Methyl-1-octadecylureido)-butanol-(1)-phosphocholine 4-octadecyl-anobutanol-(1)-phosphocholine 0.5 f, methyl isocyanate 0.119 and chloroform IDrf! obtained from. Yield 0.49, melting point 226-260°C,]
IR (in KBr): 1629.1541 m-'.

Example 50 4-(3-ethyl-1-octadeneurate)-tsuknol-(1)-phosphocholine Dosogenized with Example 26- and then 4-octadecylamino-butanol-(1)-phosphocholine O0 filter 2, ethyl incyanate Obtained from 0.1 g and 5 ml of chloroform. Yield o, 25f, melting point 215-216℃, l11(
(in KBr): 1625.1532 cm-'.

Example 51 4-(5,3-dimethyl-1-mectadecyl)-butanol-(1)-phosphocholine 4-octadecylamino-butanol-(1)-phosphocholine 0.3 f, dimethylcarbamic acid chloride 0 .13f, carbonated steel 0, 1 f i
- and chloroform 5-.

Yield 0.15 f, melting point 234-236°C, IR (KB
r): 1632 cm-1゜Example 52 4-(3-methyl-1-octadecylthioureido)-
Butanol-(1)-phosphocholine 4-octadecylamino-butanol-(1)-phosphocholine 0.3 f', methyl-1-sodimenanate 0
．． Obtained from 1 f and chloroform iQmg. Agree 0.21f, melting point 221-224°C.

Example 53 2-(1-eicosyl-3-methylureido)-ethanol-phosphocholine Same as Example 26 [, 0.5 r of 2-eikol-amino-ethanol-phosphocholine, 1-0 methyl isocyanate
．． 11F and chloroform 10m/! obtained from.

Sound collection 0.35F, melting point 222-224℃0 Example 54 2-(1-eiko through 3-ethyl ureate)-efnol-phosphocholine 0.5f, ethyl isocyanate [ 1,
11' and 10 m/chloroform. Collection
pJ 0.4 f, melting point 218-220°C.

Example 55 2-(3,3-umethyl-1-eicosylureido)-
Obtained similarly to ethanol-phosphocholine Example 29 from 2-eicosylami/-ethanol-phosphocholine o, 5f, dimethylcarbamic acid chloride 0.21F, steel carbonate 0.142 and chloroform 10me. Yield 0.32, melting point 21
5-217℃.

Example 56 2-(1-eicosyl-3-methylthiocyane-)-ethanol-phosphocholine 0.5f, methylthiocyane-)0
．． j5f and chloroporum 10me. Yield Q: 52, melting point: 210-211°C.

Example 57 2-(1-undecylureido)-ethanol-phosphocholine Similar to Example 17 [2-(3-benzyl-1-undecylureido)-ethano-exo-phosphocholine 1.21 and dioxane/water ( 4:1, T'd in V/'V)
-Activated carbon (added in 6 times within 20 hours) 0.72
Obtained from y. Yield of wax-like material 1-1it: 0
．． 5 f, I'R (in KBr): 1652.1597c
rn””.

Example 58 [2-(3-Methyl-1-occudecylureto)-ethyl:]-(2-triethylammonium-ebour)
- Bosphate (rll Same as 26 (N-octatenru 2-
(aminoethyl) -2-to IJ ethyl ammonium-ethyl phosphate 0.5 y, methyl isosyphne-1
- Obtained from [3,11F and 10rnl of chloroform]. Yield -jQ', 0.41 f, melting point 220~2
21℃.

Example 59 (2-(!l-methyl-1-octadecylureido)-
(N-octadecyl-2-aminoethyl)-2-'; methylammonium-ethyl-phosphate 0.5 f', methyl isosif, ? ,-10,
11F and chloroporum 10y++/.

Yield! i’! :0.35F, melting point 215-216C.

Example 60 2-(3-hexadecyl-1-methylureido]-ethanol-phosphocholine 2-methylamino-ethanol-phosphocholine 0.5
f is dissolved in N-meghol-heptamide 1o-.

This solution is mixed with 1.08 S' of bexabucyl isocyanate and stirred for 24 hours at room temperature. The solution is concentrated under reduced pressure and the residue is purified by Calano chromagraphy (silica gel/chloroform/methanol/water). Yield 0.3F, mp 210-213C.

The following compounds are prepared analogously to Example 60.

2-(1-methyl-3-octadecylureido)-ethanol-phosphocholine, 2-(3-eicosyl-1-methylureido)-ethanol-phosphocholine, 2-(1-phthyl-3-oleylureido)-etha/-
Ruphosphocholine.

Example 61 1-methquinecarbonyl-N-octadecyl-2-amineethanol-(1)-phosphocholine N-octadecyl-2-amineethanol-(1)-phosphocholine 5
0me' in chloroform 2me i', -'; +
Add 20 parts of chloroformic acid methyl ester and 5 drops of triethylamine.

The mixture was stirred at room temperature for 1 h, concentrated under vacuum and the residue was purified by column chromatography (silica gel 1).
f′i! with chloroform/methanol/water] / make Collection of wax-like substances - Jij41r9, IR (KB
r): 1692crn-'.

Example 62 N-ethquincarbonyl-I■-octadecyl-2-amineethanol-(1)-phosphocholine 3'll 6
Same as 1, 1-ri tl r, I po, Ay m'l m
N-mectadecyl-2-amine ethanol-(1
)・-Phosphocholine 50W, Chloro M? rr9. Obtained from 20 ml of ethyl ester and 5 drops of triethylamine. Expropriation of wax-like substances; 39 FV, IR
(in KBr): 1690α-1゜Example 63
-Amineethanol-(1)-Phosphocholine 5+-l 61 and the same IPA (2 m
N-octadecyl-2-amine ethanol-(1) in e
- Posoniline 50 hits, chloroformic acid Hensyl ester 341! 'Obtained from 5 drops of F and l-ethylamine. Yield M55■, melting point 211°C.

Continuing from page 1 of Beschrenchter Hannotsung Priority claim @ October 25, 1982 ■ West Germany (D
E) [Yes] P 3239390.3 @ Inventor Harald Borbe Day 5000 Cologne 40 Lübezkerstrasse 5 0 Inventor Gerrit Prop Day 5024 Pulheim Mohn Blumenv 25 0 Invention Date of the Federal Republic of Germany - 5024 Pulheim am Angelsdorn 9 0 Inventor Ile Stefanie Doperfuelt Day of the Federal Republic of Germany - 5010 Gretzsen im Prufuer @ Inventor Michael Jorn Barnham Federal Republic of Germany Day-5024 Pulheim Aurikelveeg 2 10

Claims (1)

[Claims] 1) General formula I (wherein
-NI+jR2 or -(Bd group, where 1(1
and R2 can be the same or different and have a saturated or unsaturated profile ψ with 1 to 20 carbon atoms.
a straight or branched alkyl group, benzyl group, phenyl group or hydrogen, B3 is phenyl, benzyl or 0
1-C4-alkyl, G, ■44, ■(5 and R
6 can be the same or different and hydrogen size or 1
a lower alkyl group having ~4 carbon atoms, tt
m is an integer from 0 to 19, m is an integer from 2 to 6, and n is an integer from 2 to 4). 2) X is oxygen, lc is a sulfur atom, and Y is a -NRIF+2 group, where B1 and H2Vi can be the same or different and have 1 to 20 carbon atoms, saturated or unsaturated straight A chain chain, a branched alkyl group, a benzyl group, a phenyl group or up to 7'jQ is hydrogen, H4, 15 and B6 can be three times or different, and hydrogen or 1 to 4 A lower alkyl group having a carbon atom, t is an integer of O to 19, and 1n
is an integer of 2 to 6, and (2 and n is an integer of 2 to 4)
A substituted aminoalkanol phospholipid having 3) If X is 192 times or a sulfur atom (-teY
is an NR11 group, where R1 and R2 can be the same or different and are an alkyl group having 1 to 20 carbon atoms, R", R" and R6 are each a methyl group, and t is A substituted aminoalkanol phosphocholine having the general formula 1 according to the scope of claim 1 of the patent Nll1, which is an integer of θ to 19, m is an integer of 2 to 6, and n is 2. 4) x is an oxygen atom and Y is a -013,3 group, where n't, J phenyl, benzyl or l-1
C1-CΔ-alkyl, R4, R5 and R6 can be the same or different and hydrogen or V''-1
The above-mentioned patent is a lower alkyl group having ~4 carbon atoms, t is an integer from 0 to 19, m is a number from 2 to O, and n is an integer from 2 to 4. A substituted aminoalkanol phospholipid having the general formula I according to claim 1. 5) x is an oxygen atom and Y is a 0R5 group, where B5 is benzyl or 01-04-alkyl, R4, FlB and rt6 are each a methyl group, and l is an integer from 0 to 19; , m is an integer from 2 to 6, and n is 2.
gii Substituted aminoalkanol phosphocholine having the general formula I as described in Section 1 of Box 7. 6) Compounds of formula In particular, depending on the case, 11%1. or by reacting with a carboxylic acid derivative of the formula A method for producing a compound having the general formula I according to any one of items 1 to 3 of the range of the above 'I': r v'r requirements. υ General formula ■ OH5-(CI+2,)z, -NI -1-(CH2)
A 1■-alkyl-aminoalkanol having rn-OHn is reacted with benzyl-ride or benzyl chloroformate to form a group which can be separated by hydrogenation, such as benzyl- or benzyloxycarbonyl. ) and this compound is phosphoborylated by reacting with dichlorophosphoric acid-ω-alkyl halide 1ζ ester in a manner known per se and then converted by reaction with the amine NR4R5R6. to form a compound having the formula (■), which is hydrogenated by methods known per se to form a compound of the formula X, and which is reacted with a carboxylic acid derivative of the formula A method for producing a compound having the general formula 1 described in any one of items 1 to 3 of the scope of the invention. 8) Hydrogenating a compound of formula 1 (wherein 11 is benzyl, 5.112 is hydrogen and X is oxygen) in an inert solvent in the presence of a conventional hydrogenation catalyst. Formula I as described in any one of paragraphs 1 to 3 of the above formula 4:
2=I] (where Xu is oxygen). 9) 2■ (wherein R4, B5, R6, tlm and n have the same meanings as in formula I and can be separated by hydrogenation, such as 1'17ij: besidyl"!!: benzyloxycarbonyl) 10) Preparation of a compound having the formula X by hydrogenating a compound having the group ] in an inert organic solvent using a conventional hydrogenation catalyst. N-((Ti2)m-(1
A N , r=l-disubstituted aminoalkanol with 11In (wherein l, m and R7 have the same meanings as in formula ■) is prepared by formula ■ t ( In the formula, n has the same meaning as in formula 1 and Ha is one chlorine or bromine atom), and then Preparation of compounds of formula (1) by reacting the product with an amine in an inert organic solvent, optionally under pressure \B6 (wherein 1, Ti5 and R6 have the same meanings as in formula (2)). 11) Phosphorylation of the surrogate compound using phosphorous oxytrichloride and then the product optionally with the introduction of an auxiliary base and an inert solvent (7) with the formula flO-(ct+2)n-
or+ ■ (in which ni has the same meaning as in formula I) and R7 has the same meaning as in formula IK and R7 has the same meaning as in formula IK and R7 has the same meaning as in formula IK. A cyclic phosphorous-containing compound having the same meaning I11; 12) A process for preparing a compound of formula II by adding an auxiliary base to a compound of formula II in an inert organic solvent to prepare a cyclic phosphorus having the formula IX (wherein n has the same meaning as in formula II). A method for producing a compound of formula (■) by reacting it with a containing compound. 13) Formula ■ CU, -(CH2)z-N-(CH2)m-OHII(
by reacting an N-alkyl-aminoalkanol having the formula (l and m have the same meanings as in formula I) with benzyl halide or chloroformic acid benzyl ester in an inert organic medium, optionally with the addition of an auxiliary base. Method for producing the compound of Naru 2■. 14) Disubstituted amino alcohols having the formula phosphorylation with a dichlorophosphoric acid-〇)-argyl halide ester of the formula ■ and then reacting the product with an amine of the formula ■ in an inert organic solvent, optionally under pressure. A method for producing a compound having the formula 1 according to any one of Ranges 1.4 and 53Q. 15) Compounds of formula R3, t, m and n have the same meanings as in formula I) and then reacting this compound 1 with an amine of formula 2 in an organic solvent optionally under pressure. [Formula I according to any one of claims 1.4 and 5]
A method for producing a compound having 16) according to any of the preceding claims 11.4 and 5, comprising reacting a compound of formula XlTl with a cyclic phosphorus-containing compound of formula IX in an inert organic solvent with the addition of an auxiliary base; Process for preparing compounds having formula I as described. 17) N-alkyl-amino-alkanol of formula n 70
Preparation of compounds of formula X■ by reaction with chloroformic esters in an inert organic medium, optionally with addition of an auxiliary base. 18) Any of claims 1.4 and 5, comprising reacting an aminoalkanol phospholipid of formula X with a chloroformate ester in an inert organic medium, optionally with the addition of an auxiliary base. A method for preparing a compound having formula I as described in section.