DK164156B - Novel propane-1,3-diol ammonium compounds, their preparation and a pharmaceutical preparation which comprises the compounds - Google Patents

Description

DK 164156 B

in

The present invention relates to novel ammonium compounds of 2-methylenepropane-1,3-diol, processes for the preparation of the novel compounds, 5 pharmaceutical compositions containing said compounds.

A lipid chemical mediator has recently been identified which plays an important role in platelet aggregation and in allergic, asthmatic, inflammatory and hypotensive reactions. It is called the "platelet activating factor" (PAF), and has been found to be a mixture of two alkyl phospholipids: | -O (CH 2) nCH 3 O n = 15 or 17 H-ztr 2 O-CH, S in ©

Lo-P-O (CH7) 7-N-CH, tP CHj

Compounds that have PAF antagonistic activity (inhibitory effect on PAF activity) are potentially useful as platelet aggregation inhibitors, as agents for thrombosis, allergy, asthma, inflammation, hypotension, gastric ulcer, psoriasis, graft rejection, and / or as contraceptives. (cf. DJ Hanahan, Ann. Rev. Bi-ochem.f 55f (1986), 483-509. Summary of "Second Inter-20 National Conference on Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids", Gatlinburg,

Tennessee, U.S.A., October 26-29, 1986).

Thus, studies have been carried out to find compounds which in their chemical structure are equal to 2

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PAF and possessing a PAF antagonistic effect or having a hypotensive effect as PAF. The results of such studies are described in, for example, European Patent Publications Nos. 94586, 109255, 142333, 146258, 147768 and 157609 and in German Patent Application No. 3,307,925. All substances described in these applications are 1,2,3-trisubstituted propanes (derived from glycerol) with three sp3 hybridized carbon atoms (as PAF): CH 2 - (substituent) 10 CH - (substituent) CH 2 - (substituent)

All of the known compounds also have an asymmetric carbon atom at position 2 of the glycerol backbone (as is also found in natural PAF).

15 Surprisingly, it now turned out that it wanted to

PAF antagonist activity can be achieved with ammonium compounds of 2-methylene propane-1,3-diol of the general formula I

R2, CH20-A1-R1 / \ 20 R3 CH20-A2- (CH2) nB X- characterized in that O-A1 and O-A2, which may be the same or different, each represent 0, 0-C (0) , O-C (O) NH, O-C (S) NH or O-C (O) O, R1 represents an alkyl or alkenyl group of 10 to 22 carbon atoms, n is an integer from 1 to 11 , B + represents a quaternary ammonium group, either NR4R5R6, or N (Het) wherein R4, R5 and R6 are the same or different alkyl groups having 1-4 carbon atoms, or two or all of R4, R5 and R6 may be included in a monocyclic or bicyclic structure which may contain additional heteroato- 3

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more, such as 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethylene-iminyl, 1-imidazolidinyl, 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl, 4-morpholininyl, triethylenediamine-1- quinuclidinio and wherein -N (Het) means an aromatic heterocyclic ring substituent containing at least one nitrogen atom such as 1-pyridinio, 1-pyridazinio, 1-pyrimidinio, 1-pyrazinio, 3-oxazolio, 3-thiazolio, 1 -isoquinolinio, 1-quinolinio or 3-alkyl-1-imidazolio; X "means the anion of a pharmaceutically acceptable inorganic or organic acid, for example, the anion of an inorganic acid such as hydrochloric, hydrobromic, hydrochloric, sulfuric, phosphoric, nitric, or an anion of an organic acid such as acetic acid, lactic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, especially a halogen ion, for example chlorine, bromine or iodine ion, or the anions of methanesulfonic acid or p-toluenesulfonic acid; and R 2 and R 3 are the same or different and represent hydrogen or alkyl groups. with 1-4 carbon atoms.

Surprisingly, by replacing the previous tetrahedron configuration with a planar carbon configuration that seems to fit poorly with the receptors, substances which are potent PAF antagonists are obtained. Furthermore, a receptor can often distinguish between two enantiomeric forms of an optically active signal junction. Since natural PAF is also an optically active compound, one skilled in the art would have expected a total loss of biological activity when the asymmetric carbon atom was replaced, as has been the case in the present compounds.

Preliminary experiments seem to show that compounds of formula I wherein R 2 = R 3 = hydrogen and n is an integer from 4 to 9 have particularly interesting properties.

When the term "an alkyl group" or an "alkenyl group" is used in the definition of the various symbols of the present description and claims, they mean an alkyl or alkenyl group in a straight or branched chain.

Examples of an alkyl group of 10 to 22 carbon

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4 atoms represented by R 1 in formula I are the decyl, undecyl, dodedecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, henicosyl and docosyl groups and isomers thereof; an alkyl group 5 of 13 to 19 carbon atoms is preferred.

Examples of an alkyl group of 10 to 22 carbon atoms represented by R1 in formula I when A1 represents a single bond are groups having a double bond between two carbon atoms in the above-specified alkyl group and 10 when A1 is different from single bond, the groups are, which has a double bond between two carbon atoms, except for the carbon atom closest to A1, is in the above alkyl group.

The present compounds have been found to have a PAF antagonistic effect and an inhibitory effect on the growth of tumor cells, and are thus valuable in human and veterinary practice as platelet aggregation inhibitors as thrombosis, asthma, allergy agents , inflammation, hypotension, gastric ulcer, psoriasis, graft rejection, and as anti-conception and anti-tumor agents.

Some of these effects have been confirmed in animal experiments using standard laboratory tests. Thus, the antagonistic action against the platelet activating factor was tested by determining the inhibition of the PAF-induced 1) platelet aggregation in rabbit platelet rich plasma 2) bronchoconstriction in guinea pigs and 3) acute hypotensive activity in rats 1 2 3 Platelet rich plasma from rabbit blood, 2 was stabilized with 90 mM trisodium citrate in an amount of one-tenth of the 3 blood volume. Platelet aggregation was performed at 37 ° C for 4 an aggregometer. After a stabilization period of 2 minutes 5 hours, the test substances were added 2 minutes before the addition of 6 PAF to give a final concentration of 30 ng / ml.

5

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The result is given as 'EC50 values', ie the molar concentration of the tested substances where the inhibition of the aggregation is 50%. As the comparator, 'CV-3988', ie racemic 3- (N-n-octadecylcarbamoyloxy) -2-methoxypropyl-2-thiazolioethyl phosphate, was used. From these results and knowledge of the strength ratio between CV-3988 and ΌΝ0-6240 ', the compound selected from EP 142.333 and EP 146.258 for further development of 0N0 compound1 (cf. Z. Chustecka, Scrip, An Overview of R&D involving 10 Platelet Activating Factor (PAF), 1986, pages 51-52) - the NO substance is approx. 3 times as strong as CV-39881 2 - it could be shown that most of the present compounds exhibited an EC50 value of the same order or greater than CV-3988's (= 4.7) and ONO-6240's (= ca. 5.2). Some of the 15 compounds even gave ECS0 values <5x10 7M (see 'CRC Handbook of PAF and PAF Antagonists', ed. Pierre Braquet, CRC Press 1991 (ISBN 0-8493-3524-3) Chapter 6, page 135ff , in particular Table 2, page 140ff), see also the following table, which is an extract thereof, comprising the 20 substances exemplified later in the description: 1 (RS) -1-O-hexadecyl-2-0- ethyl 3-O- [7- (3-thiazolio) heptyl] glycerol chloride, cf. EP 146,258, page 48.

The formulas for CV-3988 and ONO-6240 are shown in Biochemical Pharmacology, Vol. 35, No. 24, page 4512

Table

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6

Compound No. Example No. - log EC50 _PAF

_1__62__4,8 5 2__36__5,3 _3__30__5,2 _4__37__5,3 _5__63__5,3 _6__64__5,1 10 7__12__6,0 _8__49__6,0 _9__13__7,0 _10__48__5,5 _11__60__6,1 * 15 12__58__6,1 _13__61__6,6 _14__59__5__ , 3 20 17__3__4,5 _18__4__4,3 _19__5__5,3 * _20__23__4,6 _21__20__4,1 25 23__21__5,0 _24__24__5,6 _25__22__4,3 _26__25__4,3

Table no

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7

Compound No. Example No. - log EC50 5 PAF

_27__27 __ <4 _28__29__4,4 _29__26__4,7 _30__28__5,1 10 35__69__5,5 * _36__70__5,1 _37__54__6,6 _38__33__6,7 _39__53__6,8 15 40__52__6,1 _41__50__6,0 _42__32__5,4

5.3 I

_44__68__5,3 20 45__51__6,3 * _46__71__5,7 _47__65__5,1 _48__66__5,0 _53__15__5,0 25 54__10__5,6 _55__7__5,6 _56__14__5,3 _59__9__6,4

_61__39__5.7 I

30 I 62 6 6.0 I

Table, continued

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8

Compound No. Example No. - log ECS0 5 _PAF

_63__44__5.6 _68__46__6.6 _69__45__6,0 * _75__11__6,5 10 _77__38__5,4 _78__8__6,1 _79__19__4,3 _80__17__5,0 81__18__5,1 15 _82__16__5,5 _83__43__7,0 * _84__41__6,6 _85__42__6,6 * _86__40__,6,6 * _86__40__,6,6 4 _88__34__6.4 _89__57__6.1 _90__55__6.0 * CV 3988 4.7 25 ONO-6240 ___ 5.2 * indicates proaggregating properties 2) The substances tested could be in doses of 1 - 20 mg / kg iv inhibit the bronchoconstriction of anesthetized guinea pigs by intravenous injection of PAF (100 ng / kg body weight. The β-adrenergic receptors in the animals were blocked during the trial by intravenous administration of propranolol (0.1 mg / kg) in the animals that were muscle depolarized with suxamethonum. (NFN) (1.2 mg / kg iv) Bronchoconstriction was measured by modum 35 Konzett-Rossler, H. Konzett and Rossler, Arch. Exp. Pathol.

Pharmacol., 195, (1940), 71-74). Respiratory pressure was 8 cm H2 O.

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3) Prior treatment of pentobarbital-anesthetized rats with the tested substances at doses of 0.1-20 mg / kg i.v. gave an inhibition of hypotensive blood pressure reactions caused by PAF i.v. (500 ng / kg body weight). Blood pressure 5 was measured by means of transducers connected to cannulas for

The present invention also relates to an analogous process for the preparation of the compounds of formula I. This process is characterized by a reaction of a compound of the general formula II

R2 CH20-A1-R1

\ _ / II

/ \

R3 CH20-A2 (CH2) n-Z

wherein A1, A2, R1, R2 and R3 and n are as defined above and Z20 is a suitable leaving group, such as chloride, bromide, iodide, benzenesulfonate, toluene sulfonate or methanesulfonate, with a trialkylamine NR4R5R6 wherein R4, R5 and R 6 is as defined above, or with a heterocyclic amine N (Het), as defined above, alone or dissolved in a suitable solvent such as methanol, ethanol, propanol, ethyl acetate, methylene chloride, chloroform, ether or tetrahydro furan or mixtures thereof. When Z is a halogen ion, the reaction can be carried out in the presence of a silver salt, AgX, where X "is different from a halogen ion. Any anion Z ~ can be replaced by another anion X" by known methods such as ion exchange chromatography.

The starting materials of formula II, wherein A2 is a single bond, can be prepared from a compound of formula III

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ίο Η2 Οί, Ο-Α1 -! * 1 \ _ / / \ 111

R3 CH2 OH

5 wherein A1, R1, R2 and R3 have the above meanings, by deprotonization with a strong base such as sodium hydride or potassium t-butoxide in a suitable solvent such as dimethylformamide, dioxane, 1,2-dimethoxyethane or tetrahydrofuran; followed by a reaction with Y (CH 2) n Z, where Z and n have the meanings set forth above and Y is another suitable leaving group such as chloride, bromide, iodide, benzene sulfonate, toluene sulfonate or methanesulfonate, Y being more reactive than Z or as reactive as Z.

The starting material of formula II, wherein A2 is a carbonyl group, can be prepared from a compound of formula III by reaction with either a) H00C (CH2) nZ and dicyclohexylcarbodiimide or b) C1C (O) (CH2) nZ wherein Z and n have the above meanings, both in the presence of a tertiary amine such as triethylamine, pyridine or 4-dimethylaminopyridine, alone or in an inert solvent such as ether, methylene chloride or chloroform.

The compounds of formula II wherein A2 is C (O) NH or C (S) NH can be prepared from a compound of formula III by reaction with 0CN (CH2) nZ or SCN (CH2) nZ, respectively, where n and Z have the above meanings, in the presence of a tertiary amine such as triethylamine, pyridine or 4-dimethylaminopyridine, alone or in an inert solvent such as ether, methylene chloride, chloroform or toluene.

The starting compounds of formula II, wherein A2 is 35 C (0) 0, can be prepared from a compound of formula III by reaction with ClC (0) 0 (CH2) nZ, where n and Z have the above meanings, in the presence of a tertiary amine such as

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11 triethylamine, pyridine or 4-dimethylaminopyridine, alone or in an inert solvent such as ether, methylene chloride, chloroform or toluene.

The starting materials of formula III wherein A1 is a single bond can be prepared from a compound of

formula IV

R2 CH, OH

10 X /, / \

R 3 CH 2 OH

by deprotonization with a strong base, such as sodium hydride or potassium t-butoxide, in an inert solvent such as dimethylformamide, dioxane, 1,2-dimethoxyethane or tetrahydrofuran, followed by reaction with RXY where R 1 and Y are as defined above.

The compounds of formula III wherein A1 is a carbonyl group can be prepared from a compound of formula IV by reaction with either a) HOOCR1 and dicyclohexylcarbodiimide or

b) C1C (0) RX

wherein R 1 has the above meanings, both in the presence of a tertiary amine such as triethylamine, pyridine or 4-dimethylaminopyridine alone or in an inert solvent such as ether, methylene chloride or chloroform.

The compounds of formula III wherein A1 is C (O) NH or C (S) NH can be prepared from a compound of formula IV by reaction with OCNR1 or SCNR1, respectively, where R1 has the meanings given above, in the presence of a tertiary amine such as triethylamine, pyridine or 4-dimethylaminopyridine alone or in an inert solvent such as ether, methylene chloride, chloroform or toluene.

The compounds of formula III, wherein A2 is C (O) 0, can be prepared from a compound of formula IV by reaction with CICiOJR1, wherein R

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compounds, in the presence of a tertiary amine such as triethylamine, pyridine or 4-dimethylaminopyridine, alone or in an inert solvent such as ether, methylene chloride, chloroform or toluene.

The starting materials of formula II wherein A2 is one

single bond, may also be prepared from a compound of formula V

10 R2 CH, 0-A1-R1 \ _ /, / \

R 3 CH 2 O (CH 2) NOH

Wherein A1, R1, R2, R3 and n have the above meanings, by reaction with a sulfonic acid chloride such as benzenesulfonyl chloride, toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine, alone or in an inert solvent, such as ether, methylene chloride or chloroform.

The starting materials of formula V can be prepared from a compound of formula VI

25 R2 CH, 0-A1-R1 x_y / \ vi

R3 CH2O (CH2) n0G

Wherein G1, R1, R2, R3 and n have the above meanings and G means a suitable alcohol protecting group, such as trifanylmethyl, tetrahydropyranyl or methoxymethyl, by removing the protecting group with a suitable compound such as toluene sulfonic acid , hydrochloric acid, sulfuric acid, acetic acid or acid ion exchange resin, in a suitable solvent such as water, methanol or ethanol, alone

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13 or mixed with an inert solvent such as ether, chloroform or methylene chloride.

The compounds of formula VI, wherein A1 is a single bond, can be prepared from a compound of formula VII

R2 CH, OH

\ _ / ./ \

R 3 CH 2 O (CH 2) nOG

wherein n and G have the above meanings, by removing the protecting group with a strong base such as sodium hydride or potassium t-butoxide, in a suitable solvent such as dimethyl formamide, dioxane, 1,2-dimethoxyethane or tetrahydrofuran , followed by reaction with RXY where R1 and Y are as defined above.

The compounds of formula VI, wherein A1 is a carbonyl group, can be prepared from a compound of formula VII by reaction with either a) HOOCR1 and dicyclohexylcarbodiimide or b) ClCiOjR1 where R1 has the above meanings, both in the near 25 room of a tertiary amine, eg triethylamine, pyridine or 4-dimethylaminopyridine, alone or in an inert solvent such as ether, methylene chloride, chloroform or toluene.

The compounds of formula VI wherein A1 is C (O) NH 30 or C (S) NH can be prepared from a compound of formula VII by reaction with OCNR1 or SCNR1, respectively, where R1 has the meanings given above, in the presence of a tertiary amine, for example, triethylamine, pyridine or 4-dimethylaminopyridine, alone or in an inert solvent such as ether, methylene chloride, chloroform or toluene.

The compounds of formula VI wherein A1 is C (O) 0 can be prepared from a compound of formula VII by

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in which R 1 has the above meanings, in the presence of a tertiary amine such as triethylamine, pyridine or 4-dimethylaminopyridine alone or in an inert solvent such as ether, methylene chloride, chloroform or toluene.

The starting materials of formula VII can be prepared from a compound of formula IV, by deprotonization with a strong base such as sodium hydride or potassium t-butoxide, in a suitable solvent, for example, dimethyl formamide, dioxane, 1,2-dimethoxyethane or tetrahydrofuran. followed by reaction with Y (CH2) nG, where Y, n and G are as defined above.

The preparation of the compounds of formula IV is described in the chemical literature. When R 2 and R 3 are different, the final products of Formula I can be prepared as mixtures of, or, by a suitable separation method known to those skilled in the art, as the pure double bond isomers (E and Z).

It is a further object of the present invention to provide pharmaceutical compositions useful in human and veterinary practice that can be used enterally, parenterally or topically.

The compositions of the invention are characterized by containing as active ingredient at least one or more of the compounds of formula I, together with pharmaceutically acceptable, non-toxic carriers and / or excipients.

The compositions may further contain other therapeutically active ingredients such as glucocorticoids, anti-histamines, anticholinergics, methylxanthines, β-adrenergic agents, salicylates, indomethacin, flufenamate, naproxen, timegadine, gold salts, penicillamine, serum cholesterol reducing agents. retinoids, zinc salts and anti-neoplastic agents suitable for administration with the present compounds in the treatment of hypertension, cancer, psoriasis and other proliferative skin disorders, asthma, allergy, inflammatory conditions, endotoxin shock, angina pectoris and thrombosis .

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In said compositions, the therapeutically active material is usually between 1% and 95% by weight. The compositions may be worked up into various pharmaceutical administration forms such as tablets, pills, drugs, suppositories, capsules, delayed release tablets, solutions, suspensions and the like containing the compounds of formula I as non-toxic salts, as defined above, mixed with carriers and / or diluents.

Pharmaceutically acceptable, non-toxic, organic or inorganic, solid or liquid carriers and / or diluents may be used in the preparation of the present compositions. Gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, rubber, polyalkylene glycol, buffers and other known carriers, excipients and / or diluents in medicaments are all suitable.

Compositions of the present invention suitable for oral administration may be in the form of separate units such as capsules, letters, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granule; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus (suppository), light guard or paste.

A tablet may be prepared by pressing or forming the active ingredient, if desired, together with one or more excipients. Pressed tablets can be prepared by compressing the active ingredient in a free-flowing form, for example as a powder or granule, if desired mixed with a binder, lubricant, inert solvent, surfactant or dispersant. Molded tablets may be prepared by forming in a suitable machine a mixture of the active substance in powder form and a suitable carrier moistened with an inert liquid solvent.

Liquid preparations for oral administration include 16

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pharmaceutically acceptable emulsions, solutions, suspensions, juices and mixtures containing the inert diluents commonly used in the art, such as distilled water or ethanol. In addition to inert solvents, such compositions may also comprise auxiliaries such as wetting and suspending agents, and sweetening, flavoring, perfuming and preservative agents.

Rectal administration preparations may be in the form of a suppository containing the active ingredient in a carrier such as cocoa butter, or in the form of an enema.

Suitable formulations for administration to the nose or sinuses include powders, self-propelled or spray preparations such as aerosols or nebulizers. Preferably, when dispersed, the compositions should have a particle size of from 10 to 100 µm.

Such compositions are preferably in the form of a finely divided powder for pulmonary administration from a powder inhaler or self-propelled powder dispensing compositions, the active ingredient, such as a finely divided powder, being up to 20.9% by weight (wt. for weight / weight%) of the composition. In the case of a self-propelled solution and atomizing preparations, the effect can be obtained either by selecting a valve with the desired spray characteristics (e.g., capable of producing a spray of the desired particle size) or by incorporating the active ingredient as a suspended powder with controlled particle size. These self-propelled preparations may be either powder dispensing preparations or preparations which dispense the active ingredient as drops of a solution or suspension.

Self-propelled powder-dispensing compositions preferably contain solid active ingredient particles and a liquid propellant having a boiling point below 18 ° C at atmospheric pressure. The liquid propellant may be any propellant suitable for medical use and may comprise one or more lower alkyl hydrocarbons or halogenated lower alkyl hydrocarbons or mixtures thereof; 17

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chlorinated and fluorinated lower alkyl hydrocarbons are particularly preferred. Generally, the propellant constitutes 50 to 99.9% by weight of the composition, while the active ingredient constitutes 0.1 to 20% by weight, e.g., 2% by weight of the composition.

The pharmaceutically acceptable carrier in such self-propelled compositions may contain, in addition to the propellant, other ingredients, in particular a surfactant or solid diluent or both. Surfactants are desirable as they prevent clumping of the particles of the active ingredient and keep the active ingredient in suspension. Particularly valuable are liquid nonionic and solid anionic surfactants or mixtures thereof. Suitable liquid nonionic surfactants are esters and partial esters of fatty acids with aliphatic polyhydric alcohols, for example sorbitan monooleate and sorbitan trioleate, known commercially as respectively. "Span 80" (trademark) and "Span 85" (trademark). The liquid nonionic surfactant may comprise from 0.01% to 20% by weight of the composition, but preferably below 1% by weight of the composition.

Suitable solid surfactants include alkali metal, ammonium and amine salts of dialkyl sulfosuccinates (wherein the alkyl groups have 4 to 12 carbon atoms). The solid anionic surfactants may comprise from 0.01% to 20% by weight of the composition, but preferably below 1% by weight of the composition. However, it is preferred to include solid diluents in such self-propelled preparations where the density of the active ingredient differs significantly from the density of the propellant; these also help keep the active ingredient in suspension. The solid diluent is in the form of a fine powder, and preferably has a particle size of the same order as the particles of the active ingredient. Suitable solid diluents include sodium chloride, sodium sulfate and sugars.

Compositions of the present invention may also be in the form of a self-propelled composition wherein the active ingredient is in solution. Such self-propelled preparations may comprise the active ingredient, propellant and

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18 auxiliary solvent, and advantageously an antioxidant stabilizer. The propellant is one or more of the aforementioned. Auxiliary solvents are selected according to their solubility in the propellant, their ability to dissolve the active ingredient, and according to which have the lowest boiling point and at the same time have the above properties. Suitable auxiliary solvents are lower alkyl alcohols and ethers and mixtures thereof. The auxiliary solvents may comprise from 5 to 40% by weight of the composition, but preferably 10 less than 20% by weight of the composition. Antioxidant stabilizers may be incorporated into such solutions / compositions to inhibit the degradation of the active ingredient and are suitably alkali metal ascorbates or bisulfites. They are preferably present in an amount of up to 0.25% by weight of the composition.

Such self-propelled compositions may be prepared by any method known to those skilled in the art. For example, the active ingredient (either as particles as defined above in suspension in a suitable liquid or in up to 20% by weight solution in an acceptable solvent) is mixed with any other component of a pharmaceutically acceptable carrier. The resulting mixture is cooled, placed in a suitably cooled container, and the propellant is added in liquid form, after which the container is sealed. Alternatively, such a self-propelled preparation may be prepared by mixing the active ingredient, either as particles as defined above or in a 2 to 20% by weight alcoholic or aqueous solution, with the other portions of the pharmaceutically acceptable carrier, other than the propellant. ? then the resulting mixture is optionally placed with some propellant in a suitable container, and the propellant is injected under pressure into the container at room temperature through a valve which is part of the container and used to control the preparation discharge therefrom. If desired, the container may be purified by removing air from it at an appropriate stage during the preparation of the self-propelled preparation.

A suitable container for a self-propelled preparation is provided with a manually operated valve and is made of

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19 aluminum, stainless steel or reinforced glass. The valve must, of course, have the desired atomization characteristics for a particle size as defined above.

The valve is advantageously of a type which gives a predetermined amount of preparation at each operation of the valve, for example 50 to 100 μΐ.

Compositions of the present invention may also be in the form of an aqueous or dilute alcoholic solution, preferably a sterile solution, of the active ingredient for use in a spray or atomizer wherein an accelerated flow of air is used to produce a fine mist consisting of small drops of the solution. A buffer and a surfactant may also be included in such a composition which should further contain a preservative, such as, for example, methyl hydroxybenzoate.

further suitable nasal administration compositions include a fine powder having a particle size of 10 to 100µ which is administered in the same way as snuff is ingested, i.e. by rapid inhalation through the nose of powder from a container held close to the nose.

In addition to the above ingredients, the compositions of the invention may contain one or more additives such as diluents, buffers, flavors, binders, surfactants, thickeners, lubricants, preservatives, e.g., methyl hydroxybenzoate (including antioxidants), emulsifiers and the like.

Preparations of the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples 30 of aqueous solvents or suspensions are distilled water for injection and a physiological saline solution. Examples of non-aqueous solvents or suspensions are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (registered trademark). These compositions may also contain adjuvants, such as preservatives, wetting, emulsifying and dispersing agents. They can for example 20

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is sterilized by filtration through a bacteria-retaining filter, by admixture of sterilizers in the compositions or by irradiation. They may also be prepared in the form of sterile solid preparations which may be dissolved in sterile water or other sterile injectable carrier immediately prior to use.

Suitable compositions for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient. Liposomal preparations or biodegradable polymeric systems can also be used for both intramuscular and ophthalmic administration of the active ingredient.

Suitable topical compositions include liquid or semi-liquid compositions, e.g., liniments, lotions, lubricants; oil-in-water or water-in-oil emulsions, e.g., creams, ointments or pastes; or solutions or suspensions, such as drops. For example, the active ingredient for ophthalmic administration may be in the form of aqueous eye drops, for example a 0.1-1.0% solution.

In the human treatment, the present 20 compounds are suitably administered (for adults) in dosage units of the preparation. By the term "dosage units" is meant a unit, i.e. a single dose which can be administered to a patient and which can be easily handled and packaged, remaining a physically stable unit dose and containing either the active material as such or a mixture thereof with solid or liquid pharmaceutical diluents or carriers; solvents and / or excipients.

For example, the dose of the present compounds depends on age, body weight, symptoms, desired therapeutic effect, route of administration and duration of treatment.

For adult patients, the doses per a person between 1 mg and 2 g, preferably between 20 and 500 mg by oral administration, and between 100 pg and 200 mg, preferably between 1 and 100 mg by parenteral administration and may be administered up to several times daily, the amounts indicating the content of one or more of the present compounds.

21

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As mentioned above, the doses used depend on different circumstances. Therefore, there may be cases where doses higher or lower than the above limits are used. The compounds of formula I-5 are typically administered in amounts of from 0.1 to 100 mg / kg body weight per day. day.

In the form of dosage units, the present compounds may be administered once or several times daily at appropriate intervals, always depending on the condition of the patient and the physician's prescriptions.

Thus, the daily dose will preferably be an amount of from 0.005 to 5 g of a compound of formula I, conveniently divided into several single doses.

In the continuing treatment of patients suffering from 15 chronic diseases, tablets or capsules are the preferred mode of administration, if desired, as delayed-release preparations.

In veterinary practice, the aforementioned pharmaceutical compositions may also be used, preferably in the form of 20 dosage units containing from 5 mg to 25 g of the compound of formula I.

In the treatment of patients, the present compounds may be administered either alone or together with other therapeutically active compounds. Such combination therapy may be performed with compositions containing several or all of the therapeutically active compounds, or these may be administered in separate preparations either simultaneously or at appropriate intervals.

In the treatment of patients, the daily dose 30 may be administered either at once or in separate doses, e.g., two, three or four times daily.

In the following "Preparations", the methods for preparing new starting materials and intermediates are to be described in more detail and these Preparations are followed by Examples.

In the preparations and examples described below, the following abbreviations are used:

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22 TLC: Thin layer chromatography on silica gel 60.

The compounds are traced by spraying with 2M sulfuric acid and 10% phosphomolybdic acid in ethanol, followed by heating to 150 ° C.

IR: Infrared absorption spectrum (5% in chloroform).

NMR: Nuclear magnetic resonance spectrum measured at 100 MHz in deuterochloroform (CDC13) with tetramethylsilane (TMS) as internal reference (6 = 0.00).

Ether: Diethyl ether.

10

Preparation 1 3-Hexadecyloxy-2-methylenopropan-1-ol 61.1 g of 1-Bromohexadecane, 200 ml of diethylformamide and 17.7 g of 2-methylenepropan-1,3-diol were mixed. 21.8 g of sodium-15 hydride dispersion (55-60% in oil) was added over 10 minutes and the mixture was stirred at 55 ° C for 1 hour. The reaction mixture was cooled to room temperature and gently poured with 400 ml of water, extracted with 2 x 200 ml of ether and the ether extracts washed with 200 ml of water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo. The product was purified through a silica gel 60 column (70-230 mesh, 30 g) eluting with ether / pentane 1: 3. Further purification was obtained by chromatography on a Waters PrepLC / System 500A using a prepPAK -500 / SILICA cartridge with ether / pentane 1: 4 followed by ether as the eluent.

Mp. 38-40eC.

Elemental analysis: calculated: C 76.86%, H 12.90%, found: C 76.82%, H 12.85% TLC (ether / pentane 1: 1) R £ 0.4.

NMR: δ = 0.9 (t, 3H), 1.0-1.8 (m, 28H), 2.21 (t, 1H), 3.42 (t, 2H), 4.03 (s, 2H) , 4.16 (d, 2H), 5.12 (m, 2H).

Preparation 2 3-Hexadecanoyloxy-2-methylpropan-1-ol 3.0 g of 2-Methylene propane-1,3-diol was dissolved in 40 ml of methylene chloride. 8.7 g of dicyclohexylcarbodiimide, 0.4 g of 4-di-

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23 methylaminopyridine and 8.7 g of hexadecanoic acid were added. The mixture was stirred for 24 hours, filtered and the filtrate purified through a silica gel-60 column (70-230 mesh, 30 g) eluting with ether / chloroform / pentane 1: 1: 1. The eluate 5 was washed with 3 x 70 ml of saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. Further purification was obtained (6) by chromatography on a Waters PrepLC / System 500A using a prepPAK -500 / SILICA cartridge with ether / -10 chloroform / pentane 1: 1: 3 as eluent.

NMR: δ = 0.88 (t, 3H), 1.0-1.8 (m, 26H), 2.10 (t, 1H), 2.34 (t, 2H), 4.13 (d, 2H), 4.64 (s, 2H), 5.20 (m, 2H).

Preparation 3 3 Octadecylaminocarbonyloxy-2-methylpropan-1-ol 59.1 g of octadecyl isocyanate and 17.7 g of 2-methylene propane-1,3-diol were dissolved and stirred in 100 ml of pyridine for 24 hours at 22 ° C. 200 ml of water was added and the mixture was extracted with 3 x 200 ml of chloroform. The chloroform extracts 20 were washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo. The mixture was purified through a silica gel-60 column (70-230 mesh, 100 g) eluting with chloroform / ether 1: 1. Further purification was obtained by chromatography on a Waters PrepLC / SY-25 STEM 500A using a prepPAK-500 / SILICA cartridge with chloroform / ether / pentane 1: 1: 3 as eluent. The product was recrystallized from acetone.

Mp. 71-73 ° C.

Elemental analysis: calculated: C 71.99%, H 11.82%, 30 N 3.65%.

Found: C 71.93%, H 11.93%, N 3.64%.

TLC (chloroform / ether 1: 1) Rf 0.5.

IR (CHCl3): 3450, 2925, 2850, 1710, 1518 cm -1.

NMR: δ - 0.9 (t, 3H), 1.1-1.7 (m, 32H), 2.4 (t, 1H), 3.17 (m, 2H), 4.12 (d , 2H), 4.64 (s, 2H), 4.75 (m, 1H), 5.17 (m, 2H).

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Preparation 4 3-Pentadecylaminocarbonyloxy-2-methylenepropan-1-ol

Following the procedure described in Preparation 2, replacing octadecyl isocyanate with pentadecyl isocyanate, the desired product is obtained.

Mp. 60-62 ° C.

NMR: δ = 0.88 (t, 3H), 1.0-1.7 (m, 26H), 2.63 (t, 1H), 3.16 (m, 2H), 4.11 (d, 2H), 4.63 (s, 2H), 4.8 (m, 1H), 5.16 (m, 2H).

10

Preparation 5 3-Hexadecylaminothiocarbonyloxy-2-methylenepropan-1-ol 9.65 g Hexadecylisothiocyanate and 3.0 g 2-methylene-propan-1,3-diol were heated with 17 ml of pyridine and 0.8 g of 4-dimethylaminopyridine to 104 ° C for 6.5 hours. The mixture was evaporated to dryness in vacuo and chromatographed on a Waters PrepLC / System 500A using a prep-PAK -500 / SILICA cartridge with ether / chloroform / hexane 2: 2: 9 as eluent.

20

Preparation 6 3-Hexadecyloxycarbonyloxy-2-methylenepropan-1-ol 5.0 g of 2-Methylenepropan-1,3-diol, 17.4 g of hexadecyloxycarbonyl chloride and 4.4 g of pyridine were dissolved in 60 ml of methylene chloride. The mixture was stirred for 2.5 hours at 22 ° C. The mixture was purified through a silica gel-60 column (70-230 mesh, 30 g) eluting with ether / chloroform 1: 1. Further purification was obtained by chromatography on a Waters Prep-LC / System 500A using a prepPAK - 500 / SILI-30 CA cartridge with ether / chloroform / pentane 1: 1: 3 as eluent.

NMR: δ = 0.88 (t, 3H), 1.1-1.8 (m, 28H), 1.94 (bt, 1H), 4.14 (m, 4H), 4.68 (bs, 2H), 5.24 (m, 2H).

35 25

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Preparation 7 1-Hexadecyloxy-3-Γ 4- (methanesulfonyloxy) butoxyl-2-methylene propane 5.0 g 3-Hexadecyloxy-2-methylene propan-1-ol (from Preparation 1), 1.55 g sodium hydride dispersion (55-60% in oil) and 12.5 g of 1,4-dimethanesulfonyloxybutane were mixed in 25 ml of dry dimethylformamide and stirred at 50 ° C for 1 hour. The mixture was cooled to room temperature and 100 ml of ether was added. The mixture was gently poured with 100 ml of water, the aqueous phase was separated and extracted with 100 ml of ether. The combined ether extracts were washed with 100 ml of water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo. The product was purified by chromatography on silica gel 60 (70-230 mesh, 50 g) eluting with ether-pentane 1: 2.

Glementary analysis: calculated C 64.88%, H 10.89%, S 6.95%.

found: C 64.86%, H 10.82%, S 6.76%.

TLC (ether / pentane 1: 1) Rf 0.3.

NMR: δ = 0.9 (t, 3H), 1.1-2.0 (m, 32H), 2.99 (s, 3H), 3.35 (m, 4H), 3.95 (bs, 4H), 4.26 (t, 2H), 5.15 (bs, 2H).

Preparation 8 25 L-Hexadecyloxy-3- [5- (methanesulfonyloxy) oentoxy] -2-methylenepropane 4.45 g 3-Hexadecyloxy-2-methylenepropan-1-ol (from Preparation 1), 1.4 g of sodium hydride dispersion (55-60% in oil) and 10.9 g of 1.5 dimethanesulfonyloxypentane were mixed in 33 ml of dimethylformamide and stirred at 54 ° C for 20 hours. Following the reprocessing procedure described in Preparation 7, the desired compound was obtained.

Preparation 9 1-Octadecylaminocarbonyloxy-3- (6-bromohexanovloxy) -2-methylenepropane 1.62 g 3-Octadecylaminocarbonyloxy-2-methylene

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26 propan-1-ol (from Preparation 3), 1.08 g of dicyclohexylcarbo-diimide, 52 mg of 4-dimethylaminopyridine and 0.91 g of 6-bromohexanoic acid were shaken in 50 ml of ether for 20 hours at 22 ° C. Chloroform (50 ml) was added and the mixture was filtered. The filtrate 5 was purified through a silica gel-60 column (70-230 mesh, 40 g) eluting with chloroform / ether 1: 1. Further cleaning

was obtained by chromatography on a Waters PrepLC / System 500A

(§) using a prepPAK -500 / SILICA cartridge with chloroform / ether / pentane 1: 1: 3 as eluent.

TLC (chloroform / ether / pentane 1: 1: 1) Rf 0.75.

NMR: δ = 0.9 (t, 3H), 1.2-2.0 (m, 38H), 2.37 (t, 2H), 3.17 (m, 2H), 3.40 (t, 2H), 4.60 (s, 4H), 4.7 (m, 1H), 5.24 (bs, 2H).

Preparation 10 1-Octadecylaminocarbonyloxy-3- (5-bromopentanoyloxy-2-methylenepropane)

Following the procedure described in Preparation 9, replacing 6-bromohexanoic acid with 5-bromo-pentanoic acid, gave the desired product.

NMR: δ = 0.9 (t, 3H), 1.1-1.65 (m, 32H), 1.7-2.0 (m, 4H), 2.39 (t, 2H), δ , 17 (m, 2H), 3.41 (t, 2H), 4.60 (s, 4H), 4.7 (m, 1H), 5.24 (bs, 2H).

Preparation 11 1-Octadecylaminocarbonylloxy-3- (8-bromooctanoyloxy) -2-methylenepropane

Following the procedure described in Preparation 9, replacing 6-bromohexanoic acid with 8-bromo-octanoic acid, gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.0-2.0 (m, 42H), 2.34 (t, 2H), 3.16 (m, 2H), 3.40 (t , 2H), 4.60 (bs, 4H), 4.65 (m, 1H), 5.24 (bs, 2H).

Preparation 12 1-Pentadecylaminocarbonyloxy-3- (6-bromohexanoyl) -2-methylene propane

By following the procedure described in Preparation 9

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procedure, replacing 3-octadecylaminocarbonyl-oxy-2-methylenopropan-1-ol with 3-pentadecylaminocarbonyl-oxy-2-methylenopropan-1-ol (from Preparation 4) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.0-2.0 (m, 32H), 2.30 (t, 2H), 3.16 (m, 2H), 3.40 (t, 2H) ), 4.60 (bs, 4H), 4.65 (m, 1H), 5.25 (bs, 2H).

Preparation 13 10-Pentadecylaminocarbonyloxy-3- (8-bromooctanoyloxy) -2-methylenoropane

Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-oxy-2-methylenepropan-1-ol with 3-pentadecylaminocarbonyl-15-oxy-2-methylenepropan-1-ol (from Preparation 4) and replacing 6- bromohexanoic acid with 8-bromooctanoic acid gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.0-2.0 (m, 36H), 2.34 (t, 2H), 3.16 (m, 2H), 3.39 (t, 2H) , 4.59 (bs, 4H), 4.65 (m, 1H), 5.24 (bs, 2H).

Preparation of 14.1-Octadecylaminocarbonyloxy-3- (4-bromobutylaminocarbonyl-oxy-2-methylene propane) 2.0 g of 3-Octadecylaminocarbonyloxy-2-methylene-propan-1-ol (from Preparation 3) was dissolved in 40 ml of methylene chloride. 0.13 g of 4-Dimethylaminopyridine and 1.30 g of 4-bromo-butyl isocyanate were added and the mixture was stirred for 22 hours at 22 ° C. 40 ml of ether was added and the mixture was purified through a silica gel-60 column (70-230 mesh, 20 g) eluting with ether / chloroform 1: 1. Further purification was obtained by chromatography on a Waters PrepLC / System 500A using a prepPAK -500 / SILICA cartridge with ether / chloroform / pentane 1: 1: 2 as eluent.

NMR: δ = 0.9 (t, 3H), 1.1-2.0 (m, 36H), 3.2 (m, 4H), 3.42 (t, 2H), 4.59 (s , 4H), 5.22 (s, 2H).

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Preparation 1-Octadecylaminocarbonyloxy-3- (2-bromethylaminocarbonyl-oxy) -2-methylene propane

Following the procedure described in Preparation 14, replacing 4-bromobutyl isocyanate with 2-bromomethyl isocyanate, the desired product was obtained.

NMR: δ = 0.9 (t, 3H), 1.1-1.6 (m, 32H), 3.16 (m, 2H), 3.3-3.7 (m, 4H), 4, 61 (s, 4H), 5.24 (s, 2H).

Preparation 16 1-Hexadecyloxy-3- (4-bromobutylaminocarbonyloxy) -2-methylenepropane 2.0 g of 3-Hexadecyloxy-2-methylenepropan-1-ol (from Preparation 1) was dissolved in 40 ml of ether. 0.16 g of 4-Dimethyl-15-aminopyridine and 1.6 g of 4-bromobutyl isocyanate were added and the mixture was stirred for 22 hours at 22 ° C. 40 ml of chloroform was added and the mixture was purified through a silica gel-60 column (70-230 mesh, 20 g) eluting with ether / chloroform 1: 1. Further purification was obtained by chromatography on a Waters PrepLC / System 500A using a prepPAK -500 / SILICA cartridge with ether / chloroform 1: 1 as eluent.

NMR: δ = 0.88 (t, 3H), 1.26 (bs, 26H), 1.3-2.0 (m, 6H), 3.21 (q, 2H), 3.35 (t, 2H) , 3.39 (t, 2H), 3.97 (bs, 2H), 4.58 (bs, 2H), 4.60 (bs, 1H), 5.18 (bs, 2H).

Preparation 17 1- Hexadecyloxy-3- (2-bromomethylaminocarbonyloxy) -2-methylene-propane 30 Following the procedure described in Preparation 16, replacing 4-bromobutyl isocyanate with 2-bromomethyl isocyanate gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (bs, 26H), 1.50 (m, 2H), 3.42 (q, 2H), 3.50 (m, 4H), 3.97 (bs, 2H), 4.61 (bs, 2H), 5.00 (bs, 1H), 5.19 (bs, 2H).

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Preparation 18 1-Hexadecyloxy-3- (6-bromohexanoyloxy) -2-methylene propane 1.8 g of 3-Hexadecyloxy-2-methylene propan-1-ol (from Preparation 1) was dissolved in 35 ml of ether. 1.5 g of dicyclohexyl-5 carbodiimide, 0.07 g of 4-dimethylaminopyridine and 1.2 g of 6-bromohexanoic acid were added and the mixture was stirred at 22 ° C for 18 hours. The reaction mixture was filtered and the filtrate washed with 35 ml of water, 35 ml of 5% acetic acid in water and 35 ml of water. The ether solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by chromatography on a Waters PrepLC / System 500A using a prepPAK -500 / SILICA cartridge first with ether / pentane 1: 4 and then with methylene chloride / hexane 1: 4 as eluent.

NMR: δ = 0.9 (t, 3H), 1.1-2.0 (m, 34H), 2.36 (t, 2H), 3.40 (t, 4H), 3.97 (bs, 2H) ), 4.60 (bs, 2H), 5.20 (m, 2H).

Preparation 19 1-Hexadecyloxy-3-bromoacetoxy-2-roethylene propane 20 Following the procedure described in Preparation 18, replacing 6-bromohexanoic acid with bromoacetic acid gave the desired product.

NMR: δ = 0.9 (t, 3H), 1.1-2.0 (m, 28H), 3.40 (t, 2H), 3.85 (S, 2H), 3.98 (bs, 2H) , 4.70 (bs, 2H), 5.24 (bs, 2H).

25

Preparation 20 1-Hexadecyloxy-3- (4-bromobutanovloxy) -2-methylene propane

Following the procedure described in Preparation 18, replacing 6-bromohexanoic acid with 4-bromo-butanoic acid, gave the desired product.

Preparation 21 .1 -H.exa.dfigylQsyr3 ^ (.. U -J3r.Qjn.un.deca.noy ioxy) -2-rroethy laapropane By following the procedure described in Preparation 18, substituting 6-bromohexanoic acid with 11-bromodecanoic acid, the desired product was obtained.

NMR: δ = 0.9 (t, 3H), 1-2 (m, 44H), 2.34 (t, 2H), 3.40

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(t, 4H), 3.97 (bs, 2H), 4.59 (bs, 4H), 5.20 (m, 2H).

Preparation 22 1-Hexadecanoyloxy-3- (6-bromohexanoyloxy) -2-methylene propane 5 Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-oxy-2-methylenepropan-1-ol with 3-hexadecanoyloxy 2-methylpropan-1-ol (from Preparation 2) afforded the desired product.

NMR: δ = 0.88 (t, 3H), 1.1-2.0 (m, 32H), 2.3 (m, 4H), 3.40 (t, 2H), 4.60 (bs , 4H), 5.26 (bs, 2H).

Preparation 23 1-Hexadecanoyloxy-3- (4-bromobutylaminocarbonyloxy) -2-methyl-15 enopropane

Following the procedure described in Preparation 14, replacing 3-octadecylaminocarbonyl-oxy-2-methylenepropan-1-ol with 3-hexadecanoyloxy-2-methylpropan-1-ol (from Preparation 2) 20 product.

Preparation 24 1-Hexadecylaminothiocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane -nyloxy-2-methylenepropan-1-ol (from Preparation 5) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 28H), 1.1-2.0 (m, 6H), 2.38 (t, 2H), 3.1-3 , 5 (m, 4H), 4.62 (bs, 2H), 4.98 (m, 2H), 5.28 (bs, 2H), 6.2-6.8 (m, 1H).

Preparation.25 1-Hexadecyloxycarbonyloxy-3- (6-bromohexanoyloxy) -2-methylenepropane

By following the procedure described in Preparation 9

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Procedure Replacing 3-octadecylaminocarbonyl-oxy-2-methylenopropan-1-ol with 3-hexadecyloxycarbonyloxy-2-methylenopropan-1-ol (from Preparation 6) afforded the desired product.

NMR: δ = 0.88 (s, 3H), 1.25 (s, 28H), 1.2-2.0 (m, 6H), 2.33 (t, 2H), 3.40 (t , 2H), 4.13 (t, 2H), 4.63 (bs, 4H), 5.31 (s, 2H).

Preparation 2.6 10 3-Octadecylaminocarbonyloxy-2-isopropylidene propane

Following the procedure described in Preparation 3, replacing 2-methylenepropane-1,3-diol with 2-isopropylidene-propane-1,3-diol, gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (bs, 32H), 1.81 (bs, 1H), 2.60 (bs, 1H), 3.14 (q, 2H), 4.17 (s, 2H), 4.70 (s, 3H).

Preparation, 27 L - Oct adecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-isopropyl ideopT-Opaa

Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-oxy-2-methylenepropan-1-ol with 3-octadecylaminocarbonyloxy-2-isopropylidene propan-1-ol (from Preparation 26), the desired compound was obtained. .

NMR: δ - 0.86 (t, 3H), 1.26 (s, 32H), 1.1-1.9 (m, 6H), 1.82 (s, 3H), 1.84 (s, 3H), 2.32 (t, 2H), 3.14 (q, 2H), 3.40 (t, 2H), 4.6 (bs, 1H), 4.68 (bs, 4H). 1 2 3 4 5 6

Preparation 28 2 3-Octadecylaminocarbonyloxy-2-ethylidene propan-1-ol 3

Following the procedure described in Preparation 3, replacing 2-methylenepropane-1,3-diol 5 with 2-ethylidene-propane-1,3-diol gave an approx. 1: 1 mixture 6 of the E and z isomers of the desired compound.

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Preparation 29 1-Octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-ethylidene propane

Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-oxy-2-methylenepropan-1-ol with a ca. A 1: 1 mixture of the E and Z isomers of 3-octadecylaminocarbonyloxy-2-ethylidene-propan-1-ol (from Preparation 28) afforded a ca. 1: 1 mixture of the E and Z isomers of the desired compound.

10

Preparation 30 l-Hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-oxy-2-methylene propan-1-ol with 3-hexadecanoyloxy-2 Methylpropan-1-ol (from Preparation 2) and replacing 6-bromo-hexanoic acid with 8-bromooctanoic acid gave the desired compound.

NMR: δ = 0.88 (s, 3H), 1.26 (s, 28H), 1.2-1.9 (m, 8H), 2.34 (t, 4H), 3.39 (t , 2H), 4.59 (s, 4H), 5.25 (s, 2H).

Preparation 31 1-Octadecylaminocarbonyloxy-3- (7-bromoheptanovloxy) -2-methylene propane 25 Following the procedure described in Preparation 9, replacing 6-bromohexanoic acid with 7-bromoheptanoic acid gave the desired compound.

Mp. 49 ° C (from methanol).

Elemental analysis: Calculated: C 62.70%, H 9.82%, N 2.44%

Found: C 62.83%, H 9.79%, N 2.56%.

NMR: δ = 0.87 (t, 3H), 1.26 (s, 34H), 1.1-2.0 (m, 6H), 2.35 (t, 2H), 3.14 (q, 2H), 3.40 (t, 2H), 4.60 (s, 4H), 4.65 (m, 1H), 5.24 (m, 2H).

33 33

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Preparation 32 1 -Octadecylaminocarbonyloxy-3- [7- (methanesulfonylloxy) heptane-oyloxyl-2-methylene propane

Following the procedure described in Preparation 9, replacing 6-bromohexanoic acid with 7- (methanesulf onyloxy) heptanoic acid gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 8H), 2.32 (t, 2H), 2.99 (s, 3H), 3.16 (q, 2H), 4.22 (t, 2H), 4.59 (S, 4H), 4.70 (m, 1H), 5.23 (bs, 2H).

10

Preparation 33 1 -Oct adecylaminocarhony 1xyr-3.- T_8 -A. 1-Imidazolyl) octanoyl oxyl-2-methylene propane 1.18 g of 1-Octadecylaminocarbonyloxy-3- (8-bromo-octanoyloxy) -2-methylene propane (from Preparation 11) and 0.68 g of imidazole are stirred in 20 ml of toluene. 1046C for 14 hours. The mixture was cooled and evaporated in vacuo. The residue was chromatographed on silica gel 60 (70-230 mesh, 40 g) with ether / chloroform / triethylamine (1: 1: 0.04) as the eluent to give the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 36H), 1.2-1.8 (m, 6H), 2.33 (t, 2H), 3.16 (q, 2H), 3.91 (t, 2H), 4.59 (s, 4H), 4.95 (bt, 1H), 5.22 (s, 2H), 6.89 (s, 1H), 7, 04 (s, 1H), 7.40 (s, 1H).

25

Preparation [34 1-Octadecylaminocarbonyloxy-3-6- (1-imidazolyl) hexanoyl-oxyl-2-methylene propane

Following the procedure described in Preparation 33, replacing 1-octadecylaminocarbonyl-oxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-octadecyl-aminocarbonyloxy-3- (6-bromohexanoyloxy) -2- methylene propane (from Preparation 9) afforded the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 32H), 1.0-2.0 (m, 6H), 2.34 (t, 2H), 4.16 (q , 2H), 3.93 (t, 2H), 4.58 (s, 4H), 5.06 (m, 1H), 5.23 (s, 2H), 6.89 (s, 1H), 7 , 03 (s, 1H), 7.45 (s, 1H).

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Preparation 35 1-Octadecylaminocarbonyloxy-3- (5-bromopentylaminocarbonyl-oxy) -2-methylpropane

Following the procedure described in Preparation 14, replacing 4-bromobutyl isocyanate with 5-bromopentyl isocyanate, the desired compound was obtained.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 32H), 1.0-2.0 (m, 6H), 3.15 (m, 4H), 3.40 (t, 2H), 4.59 (s, 4H), 4.65 (m, 2H), 5.22 (s, 2H), 10

Preparation 36 1-Octadecylaminocarbonyloxy-3- (7-bromoheptylaminocarbonyl-oxy) -2-methylene propane

Following the procedure described in Preparation 14, replacing 4-bromobutyl isocyanate with 7-bromoheptyl isocyanate, the desired compound was obtained.

NMR: δ = 0.88 (t, 3H,), 1.26 (s, 32H), 1.0-2.0 (m, 10H), 3.16 (q, 4H), 3.40 (t , 2H), 4.59 (s, 3H), 4.70 (bs, 2H), 5.22 (s, 2H).

20

Preparation 37 1-Octadecyloxycarbonyloxy-2-methylenepropan-1-ol

Following the procedure described in Preparation 6, replacing hexadecyloxycarbonyl chloride 25 with octadecyloxycarbonyl chloride, the desired compound was obtained.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 32H), 2.0 (ts, 1H), 4.13 (t, 2H), 4.16 (s, 2H), δ , 68 (s, 2H), 5.23 (m, 2H). 1 2 3 4 5 6

Preparation 38 2-Octadecyloxycarbonyloxy-3- (7-bromoheptanoyloxy) -2-methyl-3-enopropane 4

Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-6-oxy-2-methylenepropan-1-ol with 3-octadecyloxycarbonyloxy-2-methylenepropan-1-ol and 6-bromohexanoic acid with 7-bromoheptane acid, one got the desired product.

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NMR: δ = 0.88 (t, 3H), 1.26 (s, 32H), 1.2-2.0 (m, 8H), 2.35 (t, 2H), 3.40 (t , 2H), 4.13 (t, 2H), 4.63 (s, 4H), 5.31 (s, 2H).

Preparation 39 1-Hexadecylxycarbonyloxy-3- (8-bromooctanoyloxy) -2-methylene-propane

Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-10-oxy-2-methylenepropan-1-ol with 3-hexadecyloxycarbonyloxy-2-methylenepropan-1-ol and 6-bromohexanoic acid with 8-bromooctanoic acid , you got the desired product.

NMR: δ = 0.88 (s, 3H), 1.25 (bs, 28H), 1.2-1.9 (m, 10H), 2.30 (t, 2H), 3.40 (t, 2H), 4.13 (t, 2H), 4.64 (bs, 4H), 5.31 (m, 2H).

Preparation 40 1- Octadecylaminocarbonyloxy-3- (8-bromooctanovloxy) -2-isopropylene preparation Q. 20 Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-oxy-2-methylene propane-1-one. ol with 3-octadecylaminocarbonyloxy-2-isopropylidene propan-1-ol (from Preparation 26) and 6-bromohexanoic acid with 8-bromooctanoic acid gave the desired product.

NMR: δ = 0.88 (s, 3H), 1.25 (bs, 30H), 1.1-1.8 (m, 12H), 1.83 (s, 3H), 1.85 (s , 3H), 2.30 (t, 2H), 3.14 (q, 2H), 3.39 (t, 2H), 4.55 (bs, 1H), 4.67 (bs, 4H).

Preparation .Jl 30 3-Pentadecylaminocarbonyloxy-2-isopropylidene propan-1-ol

Following the procedure described in Preparation 3, replacing octadecyl isocyanate with pentadecyl isocyanate and 2-methylenepropane-1,3-diol with 2-iso-propylidene propane-1,3-diol, the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.25 (bs, 26H), 1.81 (s, 6H), 2.65 (bs, 1H), 3.15 (q, 2H), 4.17 (s, 2H), 4.70 (bs, 2H).

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36

Preparation 42 1-Pentadecylaminocarbonyloxy-3- (8-bromooctanoyloxy) -2-iso-propylidene propane

Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-oxy-2-methylenepropan-1-ol with 3-pentadecylaminocarbonyl-oxy-2-isopropylidene propan-1-ol (from Preparation 41) and 6 -bromohexanoic acid with 8-bromooctanoic acid gave the desired compound.

NMR: δ = 0.88 (t, 3H), 1.25 (bs, 26H), 1.1-1.8 (m, 10H), 1.82 (s, 3H), 1.84 (s , 3H), 2.30 (t, 2H), 3.10 (q, 2H), 3.39 (t, 2H), 4.60 (bs, 1H), 4.66 (bs, 4H).

Preparation 43 1-Pentadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-isopropylidene propane

Following the procedure described in Preparation 9, replacing 3-octadecylaminocarbonyl-oxy-2-methylenopropan-1-ol with 3-pentadecylaminocarbonyl-20-oxy-2-isopropylidene propan-1-ol (from Preparation 41), desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (bs, 26H), 1.1-1.9 (m, 6H), 1.82 (s, 3H), 1.84 (s, 3H), 2.32 (t, 2H), 3.14 (q, 2H), 3.40 (t, 2H), 4.67 (bs, 5H).

25

Preparation 44 3- (6-Bromohexanoyloxy) -2-methylenepropan-1-ol 5.0 g of 2-Methylene propane-1,3-diol, 11.1 g of 6-bromohexanoic acid, 0.7 g of 4-dimethylaminopyridine and 14 5 g of dicyclohexylcarbodiimide were mixed in 60 ml of methylene chloride. After stirring for 4 hours at 22 ° C, ether was added, the mixture was filtered and the filtrate was purified through a silica gel 60 column (70-230 mesh, 30 g) eluting with ether / chloroform 1: 1. Further purification was obtained by chromatography on 35 Waters PrepLC / System 500A using a prepPAK -500 / SILICA cartridge with ether / chloroform / pentane 1: 1: 3 as eluent.

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NMR: δ - 1.3-2.0 (m, 6H), 2.33 (m, 3H), 3.41 (t, 2H), 4.13 (d, 2H), 4.65 (s, 2H), 5.20 (m, 2H).

Preparation 45 1-Tridecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylone propane 0.58 g of 3- (6-bromohexanoyloxy) -2-methylene propan-1-ol (from Preparation 44), 0.5 g of tridecyl isocyanate and 0.05 g of 4-dimethylaminopyridine were mixed in 3 ml of methylene chloride.

After stirring for 23 hours at 22 ° C, the mixture was filtered and the filtrate was purified through a silica gel-60 column (70-230 mesh, 4 g) eluting with ether / chloroform. Further purification was obtained by chromatography on a Waters

PrepLC / System 500A using a prep (E> 15 PAK -500 / SILICA cartridge with ether / chloroform / pentane 1: 1: 4 as the eluant.

NMR: δ = 0.88 (s, 3H), 1.25 (s, 22H), 1.1-2.0 (m, 6H), 2.37 (t, 2H), 3.16 (q, 2H), 3.40 (t, 2H), 4.60 (s, 4H), 4.70 (bs, 1H), 5.25 (bs, 2H).

20

Preparation 46 3- [6- (Triphenylmethoxy) hexoxyloxy] -2-methylenepropan-1-ol

Sodium hydride (from 0.52 g of 55-60% oil dispersion washed with 3 x 3 ml of pentane), 20 ml of dry dimethyl formamide and 1.0 g of 2-methylene propane-1,3-diol were mixed. After 1 hour, when H2 development had ceased, 4.2 g of 1-chloro-6- (triphenylmethoxy) hexane was added and the mixture was stirred for 3 hours at 85 ° C. After cooling, 20 ml of water was added cautiously and the mixture extracted with 2 x 100 ml of ether. The ether-30 extracts were washed with 100 ml of water, dried over magnesium sulfate and evaporated to dryness in vacuo. The product was purified through a silica gel-60 column (70-230 mesh, 40 g) eluting with ether. Further purification was obtained by chromatography on a Waters PrepLC / System 500A using a prepPAK -500-SIL1CA cartridge with ether / pentane 1: 2, followed by ether / pentane 1: 1 as eluent.

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NMR: δ = 1.1-1.8 (m, 8H), 2.10 (bs, 1H), 3.05 (t, 2H), 3.39 (t, 2H), 4.00 (s, 2H), 4.12 (s, 2H), 5.10 (bd, 2H), 7.0-7.5 (m, 15H).

Preparation 47 3-Pentadecylaminocarbonyloxy-1- [6- (triphenylmethoxy) hexyl-oxyl-2-methylene propane

A mixture of 1.2 g of 3- [6- (triphenylmethoxy) hexyl-oxy] -2-methylenepropan-1-ol (from Preparation 46), 0.78 g of pentadecyl isocyanate and 0.07 g of 4-dimethylaminopyridine in 5 ml methylene chloride was stirred for 5 hours at 22 ° C. The mixture was evaporated to dryness in vacuo and the residue was extracted with ether (2 x 20 ml). The ether extracts were evaporated to dryness in vacuo and the product purified through a silica gel-60 column (70-230 mesh, 15 g) eluting with ether / methylene chloride 1: 1. Further purification was obtained by chromatography on a Waters PrepLC / System 500A using a prepPAK -500 / SILICA cartridge with ether / methylene chloride / pentane 1: 1: 3 as eluent.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 26H), 1.2-1.8 (m, 8H), 3.15 (m, 4H), 3.38 (t , 2H), 3.95 (s, 2H), 4.57 (.S, 2H), 4.70 (m, 1H), 5.16 (s, 2H), 7.2-7.5 (m , 15H).

Preparation 48 3-Octadecylaminocarbonyloxy-1-6-(triphenylmethoxy) hexyl-oxyl-2-methylene propane

Following the procedure described in Preparation 47, replacing pentadecyl isocyanate with octadecyl isocyanate, the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 32H), 1.1-1.7 (m, 8H), 3.10 (m, 4H), 3.38 (t , 2H), 3.95 (s, 2H), 4.57 (s, 2H), 4.60 (m, 1H), 5.17 (s, 2H), 7.1-7.4 (m, 15H).

Preparation 49 3-Octadecyloxycarbonyloxy-1-6-(triphenylmethoxy) hexoxyloxyl-2-methylene propane

A mixture of 1.5 g of 3- [6- (triphenylmethoxy) hexyl

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39 oxy] -2-methylenepropan-1-ol (from Preparation 46) and 4.5 ml of pyridine in 15 ml of methylene chloride were cooled in an ice / water bath and 1.3 g of octadecyloxycarbonyl chloride was added. After stirring for 10 minutes at 0 ° C, the temperature was raised to 22 ° C for 5 hours. 15 ml of ether was added and the mixture was filtered. The filtrate was evaporated to dryness in vacuo and the residue was purified through a silica gel-60 column (70-230 mesh, 15 g) eluting with ether / methylene chloride 1: 1. Further purification was obtained by chromatography on a Waters Prep-LC / System 500A using a prepackaged PAK-500 / SILICA cartridge with ether / methylene chloride / pentane 1: 1: 3 as eluent.

NMR: δ - 0.88 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 8H), 3.05 (t, 2H), 3.38 (t, 2H), 3.97 (s, 2H), 4.12 (t, 2H), 4.63 (s, 2H), 5.25 (s, 2H), 7.1-7.5 (m, 15H).

Preparation 5Q

3-Hexadecyloxycarbonylloxy-1 - Γ 6- (triphenylmethoxy) hexoxyloxyl-2-methylene propane 20 Following the procedure described in Preparation 49, replacing octadecyloxycarbonyl chloride with hexadecyloxycarbonyl chloride gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.2-1.8 (m, 8H), 1.26 (s, 28H), 3.05 (t, 2H), 3.38 (t , 2H), 3.97 (s, 2H), 4.12 (t, 2H), 4.63 (s, 2H), 5.25 (s, 2H), 7.1-7.5 (m, 15H).

Preparation 51 3-Hexadecyloxycarbonylloxy-1- (6-hydroxyhexyloxy) -2-methylene propane 1.95 g 3-Hexadecyloxycarbonyloxy-1- [6- (triphenylmethoxy) hexoxyloxy] -2-methylene propane (from Preparation 50) 4-toluenesulfonic acid monohydrate and 0.15 ml of water were shaken in 30 ml of methylene chloride for 24 hours at 22 ° C. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. It was cleaned at 40

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(S) chromatography on a Waters PrepLC / System 500A using a prepPAK -500 cartridge with ether / chloroform / pentane 1: 1: 10 followed by ether / chloroform 1: 1 as eluents.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 30H), 1.2-1.8 (m, 7H), 3.41 (t, 2H), 3.63 (t, 2H), 3.98 (s, 2H), 4.13 (t, 2H), 4.64 (s, 2H), 5.23 (s, 2H).

Preparation 52 3-Octadecyloxycarbonylloxy-1- (6-hydroxyhexyloxy) -2- methyl-enp-r.pp.sn

Following the procedure described in Preparation 51, replacing 3-hexadecyloxycarbonyl-oxy-1- [6- (triphenylmethoxy) hexyloxy] -2-methylene propane with 3-octadecyloxycarbonyloxy-1- [6- (triphenylmethoxy) hexoxy] - -2-methylene propane (from Preparation 49) to give the desired product.

NMR: 6 - 0.87 (t, 3H), 1.25 (s, 32H), 1.2-1.8 (m, 9H), 3.41 (t, 2H), 3.63 (t , 2H), 4.07 (s, 2H), 4.13 (t, 2H), 4.64 (s, 2H), 5.23 (s, 2H).

Preparation 53 3-Octadecylaminocarbonyloxy-1- (6-hydroxyhexyloxy) -2-methylene propane

Following the procedure described in Preparation 51, replacing 3-hexadecyloxycarbonyl-oxy-1- [6- (triphenylmethoxy) hexyloxy] -2-methylene propane with 3-octadecylaminocarbonyloxy-1- [6- (triphenylethoxy) hexyl-30xy ] -2-methylene propane (from Preparation 48) to give the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 8H), 3.14 (m, 3H), 3.40 (t, 2H), 3.62 (t, 2H), 3.95 (s, 2H), 4.56 (s, 2H), 4.60 (bs, 1H), 5.16 (s, 2H).

35 41

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Preparation., 5.4 3-Pentadeoylaminocarbonyloxy-1- (6-hydroxyhexyloxy) -2-methylene propane

Following the procedure described in Preparation 51, replacing 3-hexadecyloxycarbonyloxy-1- [6- (triphenylmethoxy) hexoxyloxy] -2-methylene propane with 3-pentadecylaminocarbonyloxy-1- [6- (triphenylmethoxy) -hexyloxy] - 2-methylene propane to give the desired product.

NMR: δ 0.87 (t, 3H), 1.25 (s, 26H), 1.2-1.7 (m, 8H), 1.86 (S, 1H), 3.14 (q, 2H), 3.41 (t, 2H), 3.62 (t, 2H), 3.96 (S, 2H), 4.58 (s, 2H), 4.70 (m, 1H), 17 (s, 2H).

Preparation 55 3- Hexadecyloxycarbonylloxy-1- [6- (methanesulfonyloxy) hexyl-oxoxy-2-methylene propane 0.54 g of 3-Hexadecyloxycarbonyloxy-1- (6-hydroxyhexyloxy) -2-methylene propane (from Preparation 51) and 0.20 g of methanesulfonyl chloride was stirred in methylene chloride at 0 ° C.

6 ml of Pyridine was added and stirring was continued for 15 minutes at 0 ° C and for 2.5 hours at 22 ° C. 10 ml of methylene chloride was added and the organic phase was washed with 3 x 15 ml of water, dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. Purification was obtained by chromatography on silica gel 60 (70-230 mesh, 15 g) eluting with chloroform / ether / pentane 1: 1: 10, followed by chloroform / ether 1: 1.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 28H), 1.0-1.8 (m, 8H), 2.99 (s, 3H), 3.41 (t, 2H), 3.98 (s, 2H), 4.12 (t, 2H), 4.22 (t, 2H), 4.64 (s, 2H), 5.23 (s, 2H).

30

Preparation-SS-3-Octadecyloxycarbonylloxy-1- [6- (methanesulfonyloxy) hexyl-oxy-2-methylpropane

Following the procedure described in Preparation 55, replacing 3-hexadecyloxycarbonyloxy-1- (6-hydroxyhexyloxy) -2-methylene propane with 3-octadecyloxy-carbonyloxy-1- (6-hydroxyhexyloxy) -2-methylene propane (from

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42

Preparation 52) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 32H), 1.0-2.0 (m, 8H), 3.00 (s, 3H), 3.41 (t, 2H), 3.98 (s, 2H), 4.13 (t, 2H), 4.22 (t, 2H), 4.64 (s, 2H), 5.23 (s, 2H).

5

Preparation 52 3-Pentadecylaminocarbonyloxy-1-6- (methanesulfonyloxy) -hexyloxy-2-methylenepropane

Following the procedure described in Preparation 55, replacing 3-hexadecyloxycarbonyloxy-1- (6-hydroxyhexyloxy) -2-methylene propane with 3-pentadecylamycarbonyloxy-1- (6-hydroxyhexyloxy) -2-methylene propane (from Preparation 54), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 26H), 1.1-1.9 (m, 8H), 3.00 (s, 3H), 3.16 (q , 2H), 3.41 (t, 2H), 3.96 (s, 2H), 4.22 (t, 2H), 4.58 (s, 2H), 4.70 (m, 1H), δ , 18 (s, 2H).

Preparation 58 3-Octadecylaminocarbonyloxy-1- [6- (methanesulfonyloxy) hexyl-oxyl-2-methylene propane

Following the procedure described in Preparation 55, replacing 3-hexadecyloxycarbonyl-oxy-1- (6-hydroxyhexyloxy) -2-methylene propane with 3-octadecylaminocarbonyloxy-1- (6-hydroxyhexyloxy) -2-methylene propane 25 (from Preparation 53), the desired product was obtained.

NMR: δ = 0.87 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 8H), 2.99 (s, 3H), 3.12 (q, 2H), 3.40 (t, 2H), 3.96 (s, 2H), 4.22 (t, 2H), 4.57 (s, 2H), 4.70 (bs, 1H), 18 (bs, 2H). 1 2 3 4 5 6

Example 1 2 1-Hexadecyloxy-3- [4- (trimethylammonio) butoxy] -2-methylene-3-propane methanesulfonate 4 1.77 g of 1-Hexadecyloxy-3- [4- (methanesulfonyloxy) butoxy] -2-methylene propane ( from Preparation 7) was refluxed under 6% with 33% trimethylamine in ethanol at 50 ° C for 4 hours. Excess trimethylamine and ethanol were removed in vacuo. The product was recrystallized from chloroform / acetone.

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Mp. 125-131 ° C.

Elemental analysis: calculated: C 64.44%, H 11.40%, N 2.68%, S 6.15% found: C 64.39%, H 11.37%, 5 N 2.72%, S 6 , 05%.

NMR: δ = 0.9 (t, 3H), 1-2 (m, 32H), 2.71 (s, 3H), 3.32 (s, 9H), 3.2-3.7 (m, 6H), 3; 94 (bs, 4H), 5.14 (bs, 2H).

EXAMPLE 2 1-Hexadecyloxy-3- [4- (3-thiazolio) butyl] -2-methylene propylate methanesulfonate 2.5 g of 1-Hexadecyloxy-3- [4- (methanesulfonyloxy) butoxy] -2-methylene propane (from Preparation 7) was heated with 2 ml of thiazole to 60 ° C for 4 days. Excess thiazole was removed in vacuo.

NMR: δ = 0.9 (t, 3H), 1-1.8 (m, 30H), 1.9-2.3 (m, 2H), 2.76 (s, 3H), 3.2 3.5 (m, 4H), 3.94 (bs, 4H), 4.76 (t, 2H), 5.14 (bs, 2H), 8.4 (m, 2H), 10.7 (bs) , H).

Example 3 1-Hexadecyloxy-3- (4- [5- (2-hydroxyethyl] -4-methyl-3-thiazoliol butoxy) -2-methylene propane methanesulfonate 0.30 g of 1-Hexadecyloxy-3- [4- (methanesulfonyloxy) ) but-oxy] -2-methylene propane (from Preparation 7) was heated with 5- (2-hydroxyethyl) -4-methylthiazole to 56 ° C for 5 days.

Excess 5- (2-hydroxyethyl) -4-methylthiazole was removed. vacuo.

NMR: δ = 0.9 (t, 3H), 1-2.2 (m, 32H), 2.50 (s, 3H), 2.69 (s, 3H), 3.05 (t, 2H) , 3.2-3.5 (m, 4H), 3.85 (m, 2H), 3.94 (s, 4H), 4.5 (t, 2H), 5.14 (bs, 2H), 10 , 29 (s, 1H).

Example 4 4-Hexadecyloxy-3- [4- (1-pyridinio) butoxyl-2-methylpropane methanesulfonate 1.6 g of 1-Hexadecyloxy-3- [4-methanesulfonyloxy) -butoxy] -2-methylene propane (from Preparation 7) was heated. with 50 ml of dry pyridine to 50 ° C for 28 hours. Excess pyridine

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44 was removed in vacuo. The product was recrystallized from chloroform / acetone.

NMR: δ = 0.9 (t, 3H), 1.1-1.8 (m, 32H), 1.95-2.3 (m, 2H), 2.75 (s, 3H), 25-3.55 (m, 4H), 3.93 (bs, 4H), 4.89 (t, 2H), 5.14 (bs, 2H), 8.1 (t, 2H), 8, Δ (t, 1H), 9.3 (d, 2H).

Example 5 1-Hexadecyloxy-3- [5- (1-pyridinio) pentyloxy] -2-methylene-propane methanesulfonate 10 Following the procedure described in Example 4, replacing 1-hexadecyloxy-3- [4- (methanesulphonyloxy) ) butoxy] -2-methylene propane with 1-hexadecyloxy-3- [5- (methanesulfonyloxy) pentyloxy] -2-methylene propane (from Preparation 8) to give the desired product.

NMR: δ = 0.9 (t, 3H), 1-1.8 (m, 32H), 1.85-2.3 (m, 2H), 2.75 s, 3H), 3.39 ( m, 4H), 3.92 (bs, 4H), 4.83 (t, 2H), 5.13 (m, 2H), 8.10 (t, 2H), 8.5 (t, 1H), 9.3 (d, 2H).

Example 6 6-Oct-adecylaminocarbonyloxy-3- [6- (1-pyridinio) hexanovloxyl-2-methylene propane bromide 0.84 g of 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 9) was dissolved in 20 ml of dry pyridine and heated to 60 ° C for 22 hours. Excess pyridine was removed in vacuo.

NMR: δ = 0.9 (t, 3H), 1.1-1.9 (m, 36H), 1.9-2.25 (m, 2H), 2.36 (t, 2H), 3, 16 (m, 2H), 4.57 (s, 4H), 5.03 (t, 3H), 5.23 (m, 2H), 8.17 (t, 2H), 8.57 (t, 1H) ), 9.61 (d, 2H).

Example 7 1- Octadecylaminocarbonyloxy-3- [5- (1-pyridinio) pent anoyl

Oxy.1- 2 -methy lenp.r.OP.9Pb.r.omi.d.

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-35- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (5-bromopentanoyloxy) -2-methylene propane (from Preparation 10) gave the desired product.

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NMR: δ = 0.9 (t, 3H), 1.1-2.2 (m, 36H), 2.46 (t, 2H), 3.15 (m, 2H), 4.57 (bs) , 4H), 5.1 (m, 2H), 5.23 (m, 2H), 8.1 (t, 2H), 8.5 (t, 1H), 9.6 (d, 2H).

Example 8 1- 1-Octadecylaminocarbonyloxy-3- [8- (1-ovridinio) octanovloxy] -2-methylene propane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-10 -3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy) -3- (8-bromooctanoyloxy) -2-methylene propane ( from Preparation 11), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.1-1.8 (m, 40H), 1.8-2.2 (m, 2H), 2.32 (t, 2H), 15 (m, 2H), 4.58 (b, 4H), 4.9 (m, 1H), 5.03 (t, 2H), 5.24 (bs, 2H), 8.15 (t, 2H), 8.54 (t, 1H), 9.55 (d, 2H).

Example 9 1-Octadecylaminocarbonyloxy-3- [6- (3-thlazolio) hexanoyloxy] -20 -2-methylene propane bromide 0.55 g of 1-Octadecylaminocarbonyloxy-3- (6-bromohexane oyloxy) -2-methylene propane (from Preparation 9) 2.5 ml of thiazole was heated to 110 ° C for 4 hours. The reaction mixture was evaporated to dryness in vacuo.

NMR: δ = 0.88 (t, 3H), 1.0-1.8 (m, 36H), 1.8-2.2 (m, 2H), 2.37 (t, 2H), 3.15 (m, 2H), 4.58 (b, 4H), 4.88 (t, 2H), 5.0 (m, 1H), 5.23 (bs, 2H), 8.37 (bs, 1H) , 8.63 (bs, 1H), 11.15 (bs, 1H). 1 2 3 4 5 6

Example 10 2 1-Octadecylaminocarbonyloxy-3-Γ 5- (3-thiazolio) pentanoyl-3-oxyl-2-methylene propane bromide 4

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-6 -3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (5-bromopentanoyloxy) -2-methylene propane (from Preparation 11), the desired product was obtained.

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NMR: δ = 0.88 (t, 3H), 1.0-1.9 (m, 34H), 1.9-2.3 (m, 2H), 2.46 (t, 2H), (M, 2H), 4.58 (bs, 4H), 4.7-5.1 (m, 3H), 5.24 (bs, 2H), 8.35 (m, 1H), 8.66 (m, 1H), 11.15 (bs, 1H).

5

Example 11 1-Octadecylaminocarbonyloxy-3-8- (3-thiazolio) octanoyl-oxyl-2-methylene propane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (8-bromooctanoyloxy) -2-methylene propane (from Preparation 11), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1-1.75 (m, 40H), 1.75-2.2 (m, 2H), 2.33 (t, 2H), 3.15 (m, 2H), 4.58 (bs, 4H), 4.87 (t, 2H), 4.9 (m, 1H), 5.24 (bs, 2H), 8.41 (bs, 1H) , 8.61 (bs, 1H), 11.18 (bs, 1H).

Sfes-emp-el 1,2 1,2-Pentadecylaminocarbonyloxy-3- [6- (3-thiazolio) hexanoyl oxyl-2-methylpropane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-pentadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 12), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.1-2.0 (m, 30H), 2.1 (m, 2H), 2.37 (t, 2H), 3.15 (q, 2H), 4.58 (bs, 3H), 4.85 (t, 2H), 4.9 (m, 1H), 5.28 (bs, 2H), 8.36 (m, 1H), 8, 63 (d, 1H), 10.84 (bs, 1H).

EXAMPLE · 1,1,3 l-Pentadecylaminocarbonyloxy-3- 3 8- (3-thiazolio) octanoyl-oxyl-2-methylenepropane bromide Following the procedure described in Example 9, replacing l-octadecylaminocarbonyloxy-3- (6) (bromohexanoyloxy) -2-methylene propane with 1-pentanoy 1-47

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aminocarbonyloxy-3- (8-bromooctanoyloxy) -2-methylpropane (from Preparation 13) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.1-2.2 (m, 36H), 2.33 (t, 2H), 3.15 (m, 2H), 4.58 (bs, 4H) , 4.86 (t, 2H), 4.8 (m, 1H), 5.24 (bs, 2H), 8.37 (m, 1H), 8.53 (d, 1H), 10.83 (bs, H).

Example 14 1-Octadecylaminocarbonyloxy-3- [6- (trimethylammonio) hexanoyloxyl-2-methylene propyl bromide 0.84 g of 1-Octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 9) dissolved in 33% trimethylamine in 30 ml of ethanol and heated to 60 ° C in a sealed flask for 5 hours. Excess trimethylamine and ethanol were removed in vacuo.

NMR: δ - 0.9 (t, 3H), 1.1-2.0 (m, 38H), 2.39 (t, 2H), 3.15 (m, 2H), 3.46 (s, 9H) ), 3.5-3.8 (m, 2H), 4.59 (bs, 4H), 4.9 (m, 1H), 5.25 (bs, 2H).

EXAMPLE 15 1-Octadecylaminocarbonylloxy-3- [5- (trimethylammonio) pentanoic acid

Ylo «y .1 ~ 3 -methylene propane bromide

Following the procedure described in Example 14, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (5-bromopentanoyloxy) -2-methylene propane (from Preparation 10) gave the desired product.

NMR: δ - 0.9 (t, 3H), 1.1-2.0 (m, 36H), 2.48 (t, 2H), 3.15 (m, 2H), 3.45 (s, 9H) , 3.75 (m, 2H), 4.6 (m, 4H), 4.9 (m, 1H), 5.25 (bs, 2H).

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Example 16 1- Octadecylaminocarbonyloxy-3- [4- (1-pyridinio) butylamino] carbonyloxyl-2-methylene propane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy--3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (4-bromobutylaminocarbonyloxy) -2-me -

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48 thylenepropane (from Preparation 14), obtained the desired product.

NMR: δ = 0.9 (t, 3H), 1.1-1.9 (m, 34H), 1.9-2.3 (m, 2H), 3-3; 4 (m, 4H), 4.53 (bs, 4H), 5.0 (m, 2H), 5.17 (bs, 2H), 5.3 (m, 1H), 6.35 (m, 1H), 8.1 ( t, 2H), 8.54 (t, 1H), 9.63 (d, 2H).

Example 17 1-Octadecylaminocarbonyloxy-3- [2- (1-pyridinio) ethylamino-carbonyloxy] -2-methylene propane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (2-bromethylaminocarbonyl-oxy) -2-methyl 15 lenpropane (from Preparation 15), obtained the desired product.

NMR: δ = 0.9 (t, 3H), 1.1-1.7 (m, 32H), 3.13 (m, 2H), 3.8 (m, 2H), 4.45 (m, 4H), 5.15 (m, 4H), 5.45 (t, 1H), 7.1 (m, 1H), 8.1 (t, 2H), 8.5 (t, 1H), 9, 38 (d, 2H).

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Example 18 1- Octadecylaminocarbonyloxy-3- [4- (trimethylammonio) butylaminocarbonyloxyl -2-methylpropane bromide

Following the procedure described in Example 14, replacing 1-octadecylaminocarbonyloxy--3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (4-bromobutylaminocarbonyloxy) -2-methyl -lenpropane (from Preparation 14), obtained the desired product.

NMR: δ = 0.9 (t, 3H), 1-2 (m, 36H), 3.2 (m, 4H), 3.40 (bs, 9H), 3.74 (m, 2H), 4.56 (bs, 4H), 5.22 (m, 3H), 6.3 (t, 1H).

Example 19 1 -Oct adeny laminocarbonyloxy-3- [2- (trimethylammonio) ethylaminocarbonyloxyl-2-methylene propane bromide

Following the procedure described in Example 14,

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49 substituting 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylamycarbonyloxy-3- (2-bromethyl aminocarbonyloxy) -2-methylpropane (from Preparation 15) the desired product.

NMR: δ 0.9 (t, 3H), 1.1-1.5 (m, 32H), 3.1 (m, 2H), 3.46 (bs, 9H), 3.79 (m, 4H), 4.58 (m, 4H), 5.23 (bs, 2H), 5.25 (m, 1H), 7.1 (m, 1H).

Example 20 10 -Hexadecyloxy-3- [4- (trimethylammonio) butanovloxy] -2- methylene propane bromide

Following the procedure described in Example 14, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecyl-oxy-3- (4-bromobutanoyloxy) -2-methylene propane (from Preparation 20) gave the desired product.

NMR: δ = 0.9 (t, 3H), 1.1-1.8 (m, 28H), 2.1 (m, 2H), 2.57 (t, 2H), 3.39 (m, 2H), 3.49 (bs, 9H), 3.75 (m, 2H), 3.96 (bs, 2H), 4.61 (bs, 2H), 5.20 (m, 2H).

20

Example 21 1-Hexadecyloxy-3- [6- (trimethylammonio) hexanovloxy] -2-methylpropane 25 Following the procedure described in Example 14, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2- methylene propane with 1-hexadecyl-oxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 18) afforded the desired product.

NMR: δ = 0.9 (t, 3H), 1.1-2.0 (m, 34H), 2.38 (t, 2H), 3.3-3.7 (m, 4H), δ , 46 (bs, 9H), 3.96 (bs, 2H), 4.58 (bs, 2H), 5.19 (m, 2H).

Example · - [35 - 1-Hexadecyloxy-3- [11-Γ trimethylammonio] undecanoyloxy] -2- methylenoropane bromide

Following the procedure described in Example 14,

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By replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylpropane with 1-hexadecyl-oxy-3- (11-bromoundecanoyloxy) -2-methylene propane from Preparation 21) product.

NMR: δ = 0.88 (t, 3H), 1.25 (bs, 38H), 1.3-1.8 (m, 6H), 2.34 (t, 2H), 3.3-3 , 6 (m, 4H), 3.47 (s, 9H), 3.97 (bs, 2H), 4.59 (bs, 2H), 5.19 (bs, 2H).

Example 23 10-Hexadecyloxy-3- (1-pyridinioacetoxy) -2-methylene propane bromide 0.65 g of 1-Hexadecyloxy-3-bromoacetoxy-2-methylene propane (from Preparation 19) was dissolved in 20 ml of dry pyridine. .

After 1.5 hours at 22 ° C, the mixture was evaporated to dryness 15 in vacuo.

NMR: δ - 0.87 (t, 3H), 1.25 (bs, 26H), 1.45 (m, 2H), 3.45 (t, 2H), 3.97 (bs, 2H), δ , 74 (bs, 2H), 5.25 (bs, 2H), 6.28 (bs, 2H), 8.11 (t, 2H), 8.57 (t, 1H), 9.40 (d, 2H).

Example 24 1-Hexadecyloxy-3- [6- (1-pyridinio) hexanoyloxyl -2-methylene-propane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-25- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecyl oxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 18) gave the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (bs, 28H), 1.3-1.5 (m, 4H), 2.1 (m, 2H), 2.36 (m, 2H), 3.39 (m, 2H), 3.95 (bs, 2H), 4.56 (bs, 2H), 5.01 (t, 2H), 5.17 (bd, 2H), δ , 16 (m, 2H), 8.56 (m, 1H), 9.50 (d, 2H).

Example 25 1-Hexadecyloxy-3- [11- (1-pyridinio) undecanoyloxy] -2-methyl-enopropane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy

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-3- (6-bromohexanoyloxy) -2-methylenepropane with 1-hexadecyl-oxy-3- (11-bromoundecanoyloxy) -2-methylenepropane (from Preparation 21) gave the desired product.

NMR: 6 - 0.87 (t, 3H), 1.2-1.7 (bs, 42H), 2.05 (m, 2H), 2.33 (t, 2H), 3.40 (t , 2H), 3.96 (bs, 2H), 4.59 (bs, 2H), 4.99 (t, 2H), 5.19 (bs, 2H), 8.17 (t, 2H), 8 , 55 (m, 1H), 9.50 (d, 2H).

Example · · .26 10 1 -Hexadecyloxy-3- [4- (trimethylammonio) butylaminocarbonyl] oxyl-2-methylene propane bromide

Following the procedure described in Example 14, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-propane with 1-hexadecyloxy-3 (4-15 bromobutylaminocarbonyloxy) -2-methylene propane (from Preparation 16 ), you got the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (bs, 28H), 1.70 (m, 4H), 3.30 (m, 4H), 3.41 (m, 9H), δ , 73 (t, 2H), 3.96 (bs, 2H), 4.55 (bs, 2H), 5.18 (bs, 2H), 6.00 (bt, 1H).

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Example 27 1-Hexadecyloxy-3- 3- 2- (trimethylammonioethylaminocarbonyl)

Qkyl -2-methylenep.EQpent> r.Qinid

Following the procedure described in Example 14, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecyl oxy-3- (2-bromethylaminocarbonyloxy) -2-methylene propane (from Preparation 17), the desired product was obtained.

NMR: 6 - 0.88 (t, 3H), 1.25 (bs, 26H), 1.50 (m, 2H), 3.38 (t, 2H), 3.46 (s, 9H), 3.69 (q, 2H), 3.80 (bm, 2H), 3.95 (bs, 2H), 4.57 (bs, 2H), 5.17 (bs, 2H), 6.95 (bt , H).

Example 28 1-Hexadecyloxy-3- [4- (1-pyridinio) butylaminocarbonyloxy] -2-methylene propane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy

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52 -3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecyl-oxy-3- (4-bromobutylaminocarbonyloxy) -2-methylene propane (from Preparation 16) afforded the desired product.

NMR: δ = 0.88 (t, 3H), 1.2-1.9 (m, 32H), 3.20 (q, 2H), δ 3.38 (t, 2H), 3.95 (bs) , 2H), 4.54 (bs, 2H), 5.10 (t, 2H), 5.16 (bs, 2H), 5.90 (bt, 1H).

Example · 29 1 -Hp.xadecyloxy-3- [2- (1-pyridinio) ethylaminocarbonyloxy] -2-methylene propane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecyl oxy-3- (2-bromethylaminocarbonyloxy) -2-methylene propane (from 15 Preparation 17) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.1-1.7 (m, 28H), 3.36 (t, 2H), 3.85 (q, 2H), 3.89 (bs, 2H), 4.40 (bs, 2H), 5.11 (bs, 2H), 5.22 (t, 2H), 6.85 (bt, 1H), 8.0 (m, 2H), 8, 46 (m, 1H) / 9.40 (bd, 2H).

20

Example 30 1-Hexadecanoyloxy-3- [6- (1-pyridinio) -hexanoyloxyl-2-methyl-enopropane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecanoyloxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 22), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.1-2 (m, 30H), 2.12 (m, 2H), 2.35 (m, 4H), 4.58 (bs, 4H) ), 5.05 (t, 2H), 5.25 (bs, 2H), 8.15 (t, 2H), 8.55 (t, 1H), 9.58 (d, 2H).

Example 31 1-Hexadecanoyloxy-3- [4- (1-pyridinio) butylaminocarbonyloxy-35-2-methylene propane bromide

Following the procedure described in Example 6, substituting 1-octadecylamino corbonyloxy

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53 -3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecanoyl-oxy-3- (4-bromobutylaminocarbonyloxy) -2-methylene propane (from Preparation 23) afforded the desired product.

Example ...... 32 1-Hexadecylamino_thiocarbonyloxy-3-16 .- =. 11-P.yridiniQ) heKanQ =. yloxyl-2-methylenpropanbromid

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-10 -3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecylaminothiocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylpropane ( from Preparation 24), the desired product was obtained.

NMR: δ - 0.88 (t, 3H), 1.25 (s, 28H), 0.9-2.0 (m, 4H), 2.05 (m, 2H), 2.37 (t, 2H), 3.2-3.6 (m, 2H), 4.60 (m, 2H), 4.92 (m, 2H), 4.99 (t, 2H), 5.26 (m, 2H), 6.8-7.6 (m, 1H), 8.16 (t, 2H), 8.56 (t, 1H), 9.57 (d, 2H).

Example 33 1-Hexadecyloxycarbonyloxy-3- [6- (1-pyridinio) hexanovloxy] -20 -2-methylene propane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylpropane with 1-hexadecyloxy-carbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane (from 25 Preparation 25) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 28H), 1.0-2.3 (m, 6H), 2.36 (t, 2H), 4.13 (t, 2H), 4.59 (s, 2H), 4.63 (s, 2H), 5.05 (t, 2H), 5.29 (s, 2H), 8.16 (t, 2H), 8, 56 (t, 1H), 9.57 (d, 2H). 1 2 3 4 5 6

Example 34 2 1 -Octadecylaminocarbonyloxy-3- [6- (1-pyridinio) hexanoyl] Xyl] -3-2-isopropylidene propane bromide 4

Following the procedure described in Example 6, replacing the 1-octadecylaminocarbonyloxy-6 -3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-isopropylidene -propane (from Preparation 27), obtained the desired product.

54

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NMR: δ = 0.87 (t, 3H), 1.25 (s, 32H), 1.0-2.2 (m, 6H), 1.82 (s, 3H), 1.84 (s, 3H), 2.32 (t, 2H), 3.13 (q, 2H), 4.62 (bs, 2H), 4.64 (bs, 2H), 4.70 (m, 1H), 05 (t, 2H), 8.12 (t, 2H), 8.52 (t, 1H), 9.57 (d, 2H).

5

Example 35 1-Octadecylaminocarbonyloxy-3- [6- (1-pyridinyl) hexanovloxy] -2-ethylidene propane bromide

Following the procedure described in Example 6, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with a ca. A 1: 1 mixture of the E and Z isomers of 1-octadecylamino-carbynyloxy-3- (6-bromohexanoyloxy) -2-ethylidene propane (from Preparation 29) yielded a ca. 1: 1 mixture of the E and Z isomers of the desired compound.

Example 36 1-Hexadecanoyloxy-3- [6- (3-thiazolio) hexanoyloxy] -2-methyl-enopropane bromide Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) 2-Methylene propane with 1-hexadecanoyloxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 22) gave the desired products.

NMR: δ = 0.88 (s, 3H), 1.25 (s, 24H), 1.1-2.1 (m, 8H), 2.34 (m, 4H), 4.58 (s , 4H), 4.90 (m, 2H), 5.25 (s, 2H), 8.40 (bs, 1H), 8.64 (bs, 1H), 11.18 (bs, 1H).

Example 37 1-Hexadecanoyloxy-3- [8- (1-pyridinio) octanoyloxy] -2-methylenepropane bromide 0.80 g of 1-Hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane (from Preparation 30) was dissolved in 20 ml of dry pyridine and heated to 100 ° C for 8 hours. Excess 35 pyridine was removed in vacuo.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 30H), 1.1-2.2 (m, 6H), 2.32 (t, 4H), 4.58 (s, 4H), 5.02 (t, 2H), 5.25 (s, 2H), 8.23

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(t, 2H), 8.57 (t, 1H), 9.38 (d, 2H).

Example 38 1-Octedecylaminocarbonyloxy-3- Γ 8- (1-methyl-3-imidazolyl) octanoyloxyl-2-methylene propanoid 0.55 g of 1-Octadecylaminocarbonyloxy-3- [8- (1-imidazolyl) -octanoyloxy ] -2-Methylene propane (from Preparation 33) was dissolved in 10 ml of chloroform, 6 ml of methyl iodide was added and the mixture was stirred at 22 ° C for 24 h, and the mixture was evaporated to dryness in vacuo to give the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 34H), 1.0-1.8 (m, 6H), 1.90 (m, 2H), 2.34 (t, 2H), 3.14 (q, 2H), 4.11 (s, 3H), 4.33 (t, 2H), 4.58 (s, 4H), 4.70 (bt, 1H), 24 (bs, 2H), 7.45 (m, 1H), 7.52 (m, 1H), 9.96 (s, 1H).

Example 39 1-Octadecylaminocarbonyloxy-3-Γ 6- (1-methyl-3-imidazolio) -hexanoyloxy-2-methylene propane bromide 20 Following the procedure described in Example 38, replacing 1-octadecylaminocarbonyloxy-3- [ 8- (1-Imidazolyl) octanoyloxy] -2-methylene propane with 1-octadecylaminocarbonyloxy-3- [6- (1-imidazolyl) hexanoyl-oxy] -2-methylene propane (from Preparation 34) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 32H), 1.0-2.0 (m, 6H), 2.32 (t, 2H), 3.14 (q, 2H), 4.10 (s, 3H), 4.36 (t, 2H), 4.58 (s, 4H), 4.90 (bt, 1H), 5.24 (s, 2H), 7, 55 (m, 2H), 9.88 (bs, 1H).

30

Example 40 1-Octadecylaminocarbonyloxy-3- [7- (1-pyridinio) heptylamino-carbonyl] oxy] -2-methylene propane bromide

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (7-bromoheptylaminocarbonyloxy) -2-methylene propane ( from 56

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Preparation 36), obtained the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 6H), 2.10 (m, 4H), 3.13 (q, 4H) , 4.56 (s, 4H), 5.03 (t, 2H), 5.20 (S, 2H), 5.25 (bt, 2H), 8.13 (t, 2H), 8.54 ( t, 1H), 9.57 (d, 2H).

Example 41 1-Octadecylaminocarbonyloxy-3- [5- (1-pyridinio) pentylamino-carbonyloxyl-2-methylene propane bromide 10 Following the procedure described in Example 37, substituting 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) 3- ) -2-Methylene propane with 1-octanoyloxyaminocarbonyl-oxy-3- (5-bromopentylaminocarbonyloxy) -2-methylene propane (from Preparation 35) afforded the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 30H). 1.0-1.7 (m, 6H), 2.10 (m, 2H), 3.12 (m, 4H), 4.53 (s, 4H), 4.9-5.2 (m, 5H) , 5.85 (m, 1H), 8.10 (bt, 2H), 8.51 (bt, 1H), 9.60 (bd, 2H).

Example 42 1-Octadecylaminocarbonyloxy-3-7- (3-thiazolio) heptylaminocarbonyloxy 1-2 methylene propane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecyl-2-aminocarbonyloxy-3- (7-bromoheptylaminocarbonyloxy) -2-methyl lenpropane (from Preparation 36), obtained the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 34H), 1.0-1.8 (m, 6H), 2.0 (m, 2H), 3.16 (q, 4H), 4.56 (s, 4H), 4.85 (t, 2H), 5.15 (t, 1H), 5.20 (s, 2H), 5.45 (m, 1H), δ , 40 (s, 1H), 8.70 (s, 1H), 11.14 (s, 1H).

Example 43 1- Octadecylaminocarbonyloxy-3- 5- (3-thiazolio) pentylamino-carbonyloxy 1-2 methylpropane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy

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57 -3- (6-bromohexanoyloxy) -2-methylenepropane with 1-octadecylaminocarbonyloxy-3- (5-bromopentylaminocarbonyloxy) -2-methylpropane (from Preparation 35) afforded the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 32H), 1.1-1.8 (m, 4H), 2.05 (m, 2H), 3.14 (bq , 4H), 4.55 (s, 4H), 4.80 (t, 2H), 5.19 (s, 3H), 5.75 (bs, 1H), 8.30 (bs, 1H), 8 , 70 (bs, 1H), 11.10 (bs, 1H).

Example 44 1-Octadecylaminocarbonyloxy-3- [6- (1-Pyridaziniol hexanoyl-oxyl-2-methylenepropane bromide 0.28 g of 1-octadecylaminocarbonyloxy-3- (6-bromo-hexa-neyloxy) -2-methylene propane (from Preparation 9) Dissolve in 5 15 ml of toluene, 0.18 ml of Pyridazine is added and the mixture is stirred for 20 hours at 64 DEG C. The mixture is evaporated to dryness in vacuo to give the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 4H), 2.30 (m, 4H), 3.14 (q, 2H), 4.57 (bs, 4H), 4.8-5.3 (m, 5H), 8.80 (m, 1H), 8.90 (m, 1H), 9.50 (bs, 1H), 10.85 (m, 1H).

Example 45 1-Octadecylaminocarbonyloxy-3- [7- (11β-pyridinio) heptanol] -oxyl-2-methylene propane bromide

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromo-octanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyl-oxy-3- (7-bromoheptanoyloxy) -2-methylene propane (from Preparation 31) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 6H), 2.07 (m, 2H), 2.33 (t, 2H), 3.13 (q, 2H), 4.57 (s, 4H), 5.01 (t, 2H), 5.10 (bs, 1H), 5.22 (bs, 2H), 8, 15 (t, 2H), 8.54 (t, 1H), 9.56 (d, 2H).

35 58

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Example 46 1-Octadecylaminocarbonyloxy-3- [7- (3-thiazolio) heptanoyl-oxyl-2-methylene propane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (7-bromoheptanoyloxy) -2-methylene propane (from Preparation 31), the desired product was obtained.

Mp. 55-56 ° C (from acetone / ether).

Elemental Analysis: Calculated for C33H59BrN2O4S, H2O: C

58.47%, H 9.07%, Br 11.79%, N 4.13%, S 4.73%, H 2 O 2.65%.

Found C 58.31%, H 9.01%, Br 11.53%, N 4.18%, S 4.54%, H 2 O 2.74%. Hygroscopic.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 32H), 1.0-2.0 (m, 6H), 2.10 (m, 2H), 2.35 (t , 2H), 3.14 (q, 2H), 4.58 (s, 4H), 4.88 (t, 2H), 5.02 (m, 1H), 5.24 (s, 2H), δ , 43 (m, 1H), 8.69 (d, 1H), 11.15 (s, 1H).

Example 47 1-Octadecylaminocarbonyloxy-3- [7- (3-thiazolio) heptanoyloxy-2-methylene propane methanesulfate

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecyl-2-aminocarbonyloxy-3 - [7- (methanesulfonyloxy) heptanoyloxy] - -2-methylene propane (from Preparation 32) to give the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 6H), 2.0 (m, 2H), 2.35 (t, 2H), 2.76 (t, 3H), 3.16 (q, 2H), 4.58 (s, 4H), 4.70 (t, 2H), 5.0 (t, 1H), δ , 23 (s, 2H), 8.35 (m, 1H), 8.43 (m, 1H), 10.72 (bs, 1H).

Example _48 1-Pentadecylaminocarbonyloxy-3- [8- (1-pyridinio) octanoyl-oxy] -2-methylpropane bromide

Following the procedure described in Example 37, replacing l-hexadecanoyloxy-3- (8-bromo

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tanoyloxy-2-methylene propane with 1-pentadecylaminocarbonyl-oxy-3- (8-bromooctanoyloxy) -2-methylene propane (from Preparation 13) to give the desired product.

NMR: δ = 0.87 (s, 3H), 1.25 (s, 28H), 1.0-1.9 (m, 6H), δ 2.05 (m, 2H), 2.32 (m , 2H), 3.16 (q, 2H), 4.58 (s, 4H), 4.95 (m, 3H), 5.24 (s, 2H), 8.17 (m, 2H), δ , 57 (t, 1H), 9.60 (d, 2H).

Example 49 1-Pentadecylaminocarbonyloxy-3- [6- (1-pyridinio) hexanoyl-oxyl-2-methylene propane bromide

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-pentadecylaminocarbonyl-oxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 15 12), the desired product was obtained.

NMR: δ - 0.87 (s, 3H), 1.25 (s, 26H), 1.0-1.9 (m, 4H), 2.08 (m, 2H), 2.36 (t, 2H), 3.16 (q, 2H), 4.57 (s, 4H), 5.00 (m, 3H), 5.22 (s, 2H), 8.13 (t, 2H), 8, 52 (t, 1H), 9.55 (d, 2H).

Example ·. 50-Hexadecylaminothiocarbonyloxy-3- [6- (3-thiazolio) hexanoyloxy] -2-methylene propane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-25 -3 '- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecylaminothiocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane ( from Preparation 24), the desired product was obtained.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 26H), 1.0-2.2 (m, 8H), 2.38 (t, 2H), 3.2-3, 7 (m, 2H), 4.61 (bs, 2H), 4.8-5.1 (m, 4H), 5.30 (m, 2H>, 11.20 (bs, 1H)).

Example 51 1-Octadecyloxycarbonyloxy-3- [7- (3-thiazolio) heptoxy] oxoxy] -2- methylene propane bromide Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoxy) -methylene propane with 1-octadecyl-60

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oxycarbonyloxy-3- (7-bromoheptanoyloxy) - 2-methylene propane (from Preparation 38) to give the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 32H), 1.0-1.8 (m, 6H), 2.05 (m, 2H), 2.34 (t, 2H), 4.13 (t, 2H), 4.61 (s, 2H), 4.63 (S, 2H), 4.85 (t, 2H), 5.30 (s, 2H), δ , 40 (s, 1H), 8.64 (bd, 1H), 11.15 (bs, 21H).

Example 52 1 -Hexadecyloxycarbonylloxy-3- [8- (1-pyridinio) octanoyloxy] -1,2-methylene propane bromide

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-hexadecyloxycarbonyloxy-2- (8-bromooctanoyloxy) -2-methylene propane (from Preparation 15 39), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 28H), 1.0-2.0 (m, 8H), 2.10 (m, 2H), 2.33 (t, 2H), 4.13 (t, 2H), 4.60 (s, 2H), 4.63 (s, 2H), 5.03 (t, 2H), 5.29 (s, 2H), 8, 17 (t, 2H), 8.57 (t, 1H), 9.58 (d, 2H).

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Example 53 1- Hexadecyloxycarbonyloxy-3- [8- (3-thiazolio) octanoyloxy] -2-methylene propane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecyl oxycarbonyloxy-3- (8-bromooctanoyloxy) -2-methylene propane (from Preparation 39), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 28H), 1.0-2.0 (m, 8H), 2.10 (m, 2H), 2.33 (t , 2H), 4.13 (t, 2H), 4.61 (s, 2H), 4.64 (s, 2H), 4.88 (t, 2H), 5.31 (s, 2H), δ , 45 (bs, 1H), 8.65 (d, 1H), 11.20 (bs, 1H).

Example 54 1-Hexadecyloxycarbonylloxy-3- [6- (3-thiazolio) hexanoyloxy] -2-methylene propane bromide

Following the procedure described in Example 9

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by replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecyl-oxycarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 25) to give the desired product .

NMR: δ = 0.88 (t, 3H), 1.25 (s, 28H), 1.0-2.2 (m, 6H), 2.37 (t, 2H), 4.13 (t , 2H), 4.61 (bs, 4H), 4.90 (t, 2H), 5.31 (bs, 2H), 8.40 (m, 1H), 8.63 (m, 1H), 11 , 15 (bs, 1H).

Example 55 10-Octadecylaminocarbonyloxy-3- [8- (1-pyridinio) octanoyloxy] -2-isopropylidene propane bromide

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyl-oxy-3- (8-bromooctanoyloxy) -2-isopropylidene propane ( from Preparation 40), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 36H), 1.1-2.2 (m, 6H), 1.82 (s, 3H), 1.84 (s, 3H) , 2.27 (t, 2H), 3.13 (q, 2H), 4.63 (bs, 4H), 4.75 (bt, 1H), 5.03 (t, 2H), 8.15 ( m, 2H), 8.55 (m, 1H), 9.57 (bd, 2H).

Example 56 1- Octadecylaminocarbonylloxy-3- [6- (3-thiazolio) hexanoyloxy] -2-isopropylidene propane bromide Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -methylene propane with 1-octadecylamycarbonyloxy-3- (6-bromohexanoyloxy-2-isopropylidene propane (from Preparation 27)) gave the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 32H), 1.0-2.2 (m, 6H), 1.83 (bs, 6H), 2.33 (t, 2H) ), 3.13 (q, 2H), 4.63 (bs, 2H), 4.65 (bs, 2H), 4.89 (m, 3H), 8.40 (m, 1H), 8.65 (bd, 1H), 11.16 (bs, 1H). 1 62

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Example 57 1- Octadecylaminocarbonyloxy-3- [8- (3-thiazolio) octanoyloxy] -2-isopropylidene propane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- (8-bromooctanoyloxy) -2-isopropylidene -pan (from Preparation 40), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 36H), 1.0-2.1 (m, 6H), 1.83 (s, 3H), 1.84 (s , 3H), 2.28 (t, 2H), 3.13 (q, 2H), 4.64 (bs, 2H), 4.66 (bs, 2H), 4.87 (m, 3H), δ , 41 (m, 1H), 8.61 (m, 1H), 11.18 (bs, 1H).

Example 58 1-Pentadecylaminocarbonyloxy-3- [6- (1-pyridinio) hexanoyl-oxy] -2-isopropylidene propane bromide

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-pentadecylaminocarbonyl-oxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 43), the desired product was obtained.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 26H), 1.1-2.2 (m, 6H), 1.82 (s, 3H), 1.84 (s, 3H) , 2.32 (t, 2H), 3.15 (q, 2H), 4.63 (s, 2H), 4.65 (s, 2H), 4.8 (bs, 1H), 5.05 ( t, 2H), 8.12 (t, 2H), 8.50 (m, 1H), 9.57 (d, 2H).

Example 59 1 -Pentadecylaminocarbonyloxy-3- [8- (1-pyridinio) octano-vixy-2-isopropylidene propane bromide Following the procedure described in Example 37, substituting 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylenepropane with pentadecylaminocarbonyloxy-3- (8-bromooctanoyloxy) -2-isopropylidene propane (from Preparation 42) to give the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 30H), 1.2-2.1 (m, 6H), 1.82 (s, 3H), 1.84 (s, 3H) ), 2.28 (t, 2H), 3.13 (q, 2H), 4.65 (bs, 4H), 4.70 (m, 1H), 5.03 (t, 2H), 8.15 (t, 2H), 8.55 63

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(t, 1H), 9.55 (d, 2H).

Example fine lr.Entadecylaminocarbonyloxy-3- [6- (3-thiaZ-aliylhexanovl-5QXV1-3i sopropylidene nitrone bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-pentadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-isopropylidene-10 propane (from Preparation 43), the desired product was obtained.

NMR: δ * 0.88 (t, 3H), 1.26 (s, 26H), 1.1-2.2 (m, 6H), 1.82 (s, 3H), 1.84 (s, 3H) , 2.32 (t, 2H), 3.14 (q, 2H), 4.65 (S, 4H), 4.88 (m, 3H), 8.41 (m, 1H), 8.66 ( m, 1H), 11.16 (bs, 1H).

Example 61 1-Pentadecylaminocarbonyloxy-3- [8- (3-thiazolio) octanoyl-oxy] -2-isopropylidene propane bromide

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-20- (6-bromohexanoyloxy) -2-methylene propane with 1-pentadecylaminocarbonyloxy-3- (8-bromooctanoyloxy) -2-isopropylidene propane (from Preparation 42), the desired product was obtained.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 30H), 1.0-2.2 (m, 6H), 1.83 (s, 3H), 1.84 (s, 3H) , 2.32 (t, 2H), 3.14 (q, 2H), 4.65 (bs, 4H), 4.88 (m, 3H), 8.42 (m, 1H), 8.62 (m, 1H), 11.17 (bs, 1H).

Example 62

Iron Tridecylamino Carbonyloxy- (3- (¢ - (1-pyridiniophenesanoylogyl) -2-methylpropane bromide

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-tridecylaminocarbonyl-oxy-3- (6-bromohexanoyloxy) -2-methylene propane (from Preparation 35 45), obtained the desired product.

NMR: δ = 0.88 (t, 3H), 1.25 (s, 20H), 1.0-2.0 (m, 6H), 2.15 (bt, 2H), 2.36 (t, 2H), 3.16 (q, 2H), 4.57 (s, 4H), 5.04 64

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(m, 3H), 5.23 (bs, 2H), 8.17 (t, 2H), 8.58 (t, 1H), 9.65 (d, 2H).

Example 63 '5 1-Pentadecylaminocarbonyloxy-3- [6- (3-thiazolio) hexoxyloxy] -2-methylpropane methanesulfonate

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-pentadecyl-10-aminocarbonyloxy-3- [6- (methanesulfonyloxy) hexoxy] -2- methylene propane (from Preparation 57) gave the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (, 26H), 1.1-1.7 (m, 6H), 2.0 (m, 2H), 2.77 (bs, 3H) ), 3.15 (q, 2H), 3.38 (t, 2H), 3.94 (s, 2H), 4.56 (s, 2H), 4.70 (t, 2H), 5, 07 (s, 1H), 5.17 (s, 2H), 8.45 (m, 2H), 10.80 (bs, 1H).

Example 64 1-Pentadecylaminocarbonyloxy-3- [6- (1-pyridinio) hexoxyloxy] -2-methylene propane methanesulfonate

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-pentadecylaminocarbonyl-oxy-3- [6- (methanesulfonyloxy) hexoxy] -2- methylene propane (from Preparation 57) afforded the desired product. .

NMR: δ = 0.87 (t, 3H), 1.25 (bs, 26H), 1.0-1.8 (m, 6H), 2.0 (m, 2H), 2.73 (s, 3H), 3.14 (q, 2H), 3.38 (t, 2H), 3.94 (s, 2H), 4.55 (s, 2H), 4.79 (t, 2H), 05 (bs, 1H), 5.15 (s, 2H), 8.11 (t, 2H), 8.49 (t, 1H), 9.20 (d, 2H).

30

Example 65 1-Octadecylaminocarbonyloxy-3- [6- (3-thiazolio) hexoxyloxy] -2-methylene propane methanesulfonate

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy--3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyloxy-3- [6- (methanesulfonyloxy) hexoxy] -2-methyl-65

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lenpropane (from Preparation 58), obtained the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (bs, 38H), 2.0 (bm, 2H), 2.77 (s, 3H), 3.15 (q, 2H), δ , 38 (t, 2H), 3.95 (s, 2H), 4.57 (s, 2H), 4.70 (t, 2H), 5.10 (s, 1H), 5.16 (s) , 2H), 8.40 (m, 2H), 10.76 (bs, 1H).

Example 66 1- Octadecylaminocarbonyl-3- [6- (1-pyridinio) hexyloxy] -2- [10m] sibglenpEapaniB.ethanesulphate

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-octadecylaminocarbonyl-oxy-3- [6- (methanesulfonyloxy) hexoxy] -2- methylene propane (from Preparation 58) gave the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 32H), 1.1-1.7 (m, 6H), 2.0 (m, 2H), 2.75 (bs, 2H), 3.15 (q, 2H), 3.38 (t, 2H), 3.9 (s, 2H), 4.56 (s, 2H), 4.80 (t, 2H), 05 (bs, 1H), 5.16 (s, 2H), 8.08 (t, 2H), 8.45 (t, 1H), 9.22 (d, 2H).

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Example 67 1-Octadecyloxycarbonylloxy-3- [6- (3-thiazolyl) hexyloxy] -2-methylpropane methanesulfonate

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-octadecyl-oxycarbonyloxy-3- [6- (methanesulfonyloxy) hexoxy] -2-methylene propane (from Preparation 56) to give the desired product.

NMR: δ = 0.87 (s, 3H), 1.26 (s, 32H), 1.0-2.1 (m, 8H), 2.76 (bs, 3H), 3.38 (t, 2H) ), 3.96 (s, 2H), 4.13 (t, 2H), 4.62 (s, 2H), 4.70 (t, 2H), 5.22 (s, 2H), 8.35 (bs, 2H), 10.80 (s, 1H). 1

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66

Example 68 1 -Octadecyloxy carbonyloxy-3 -methylenpropanmethansulfonat

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-octadecyloxycarbonyl-oxy-3- [6- (methanesulfonyloxy) hexoxy] -2-methylene propane (from Preparation 56) to give the desired product.

NMR: δ = 0.87 (s, 3H), 1.26 (s, 32H), 1.1-2.1 (m, 8H), 2.75 (s, 3H), 3.37 (t , 2H), 3.95 (s, 2H), 4.12 (t, 2H), 4.62 (s, 2H), 4.80 (t, 2H), 5.21 (s, 2H), δ , 10 (m, 2H), 8.50 (m, 1H), 9.31 (d, 2H).

Example 69 1-Hexadecyloxycarbonyloxy-3- [6- (3-thiazolio) hexoxy] -2-methylene propane methanesulfonate

Following the procedure described in Example 9, replacing 1-octadecylaminocarbonyloxy-3- (6-bromohexanoyloxy) -2-methylene propane with 1-hexadecyl-oxycarbonyloxy-3- [6- (methanesulfonyloxy) hexoxy] -2- methylpropane (from Preparation 55), obtained the desired product.

NMR: δ = 0.88 (t, 3H), 1.26 (s, 28H), 1.1-2.0 (m, 8H), 2.77 (s, 3H), 3.39 (t, 2H) , 3.96 (s, 2H), 4.13 (t, 2H), 4.63 (S, 2H), 4.70 (t, 2H), 5.22 (s, 2H), 8.31 (s, 2H), 10.82 (S, 1H).

Example 70 1 -Hexadecyloxycarbonyloxy-3- [6- (1-pyridinylhexyloxy) -2-30-methylene propane methanesulfonate

Following the procedure described in Example 37, replacing 1-hexadecanoyloxy-3- (8-bromooctanoyloxy) -2-methylene propane with 1-hexadecyloxycarbonyloxy-3- [6- (methanesulfonyloxy) hexyloxy] -2-methylene propane ( from 35 Preparation 55), obtained the desired product.

NMR: δ = 0.87 (t, 3H), 1.25 (s, 28H), 1.1-1.9 (m, 6H), 2.05 (m, 2H), 2.75 (s, 3H), 3.37 (t, 2H), 3.95 (s, 2H), 4.12

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67 (t, 2H), 4.62 (s, 2H), 4.82 (t, 2H), 5.22 (s, 2H), 8.09 (t, 2H), 8.47 (t, 1H) ), 9.25 (d, 2H).

Example. 1-Octadecyloxycarbonyloxy-3- [1- (pyridinio) heptanovlosyl] -2-methylpropane bromide

Following the procedure described in Preparation 37, replacing 1-hexadecanoyloxy-3- (8-bromo-octanoyloxy) -2-methylene propane with 1-octadecyloxycarbonyl-10-oxy-3- (7-bromoheptanoyloxy) -2-methylene propane ( from Preparation 38), the desired product was obtained.

NMR: δ * 0.88 (t, 3H), 1.25 (s, 32H), 1.0-1.8 (m, 6H), 2.10 (m, 2H), 2.33 (t, 2H), 4.13 (t, 2H), 4.60 (s, 2H), 4.63 (s, 2H), 5.04 (t, 2H), 5.29 (, 2H), 8.15 (m, 2H), 8.55 (m, 1H), 9.57 (d, 2H).

Example 72 Aerosol 20-Octadecylaminocarbonyloxy-3- [7- (3-thiazolio) heptanoyloxy] -2-methylene propane bromide (GS-1160-180) (active substance) 1,000 mg

Water for injection up to 1,000 ml 25 The active substance is dissolved in a suitable amount of water for injection by gentle heating. Water for injection is added until a final volume of 1,000 ml is reached.

The solution is filtered through a 0.2 µm sterile membrane filter and aseptically loaded into appropriate unit dose containers, each containing 5 ml. A dose of 5 ml (corresponding to 5 mg of active substance) is inhaled by a suitable nebulizer.

Example 73 Capsule GS-1160-180 (active substance) 50 g

Fine crystalline lactose 300 g 68

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Magnesium stearate 3 g

The active substance is mixed in a suitable lactose mixer until homogeneity is achieved. The magnesium stearate is added and the mixture is continued for a few minutes. Using a suitable capsule filling machine, size 0 hard gelatin capsules are filled, each containing 353 mg of the mixture.

Example 74 Tablet GS-1160-180 (active substance) 100 g

Lactose 200 g

Starch 100 g

Methyl cellulose 4 g Magnesium stearate 4 g

The active substance, lactose and starch are homogeneously mixed in a suitable mixer and wetted with a 5% aqueous solution of 15 cps methylcellulose. Mixing is continued until grain is formed. If necessary, the wet granulate is sieved through a suitable screen tissue and dried to a water content of less than 2.5% in a suitable dryer, for example, fluid bed or oven. The dried granules are passed through a 1 mm sieve tissue. Magnesium stearate is added and the mixing process is continued for a short time.

25 Tablets weighing 408 mg are prepared from the granulate by a suitable tablet machine.

Example 75

Suppository 30 GS-1160-180 200 g

Suppository base, Witepsol W-35 1,900 g

Cocoa butter is slowly heated until a melting mass is formed with a temperature not exceeding 60 ° C hot.

The active substance is kneaded in the melt and the suppositories 35 are cast to a weight of 2.1 g.

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Example 76 Topical Composition I GS-1160-180 (active substance) 20 g

Cetostearyl alcohol 100 g 5 Liquid paraffin 100 g

White soft paraffin 50 g

Polyoxyethylene sorbitan monostearate 50 g II Methylparaben 2 g

Glycerol 100 g 10 Water up to 1,000 g

The components of I are fused and heated to 70 ° C in a vessel equipped with a stirrer and homogenizer. In another vessel, the aqueous phase (II) is prepared by heating to 70 ° C. The aqueous phase is slowly added to the oil phase 15 with constant stirring and homogenization.

The active substance is added and the temperature is maintained for 15 minutes at 70 ° C. The vessel is cooled to 40 ° C with constant stirring and homogenization. Cooling is continued with slow stirring to a temperature below 25 ° C.

20

Example-Z? -

Injection preparation GS-1160-180 (active substance) 10 g Ethanol 100 g

Propylene glycol 200 g

Water for injection up to 1,000 ml

The active substance is dissolved in a mixture of ethanol and propylene glycol under gentle heating. Water for injection 30 is added until a final volume of 1,000 ml is reached.

The injection mixture is filtered through a sterile 0.2 µm membrane filter and aseptically filled into vials, each containing 5 ml.

Example 78 Eye preparation GS-1160-180 (active substance) 2 g 70

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Mannitol 50 g

Hydroxyethyl cellulose 5 g

Phenylethyl alcohol 5 g

Water for injection up to 1,000 g 5 A 2% concentrate of hydroxyethyl cellulose in water for injection containing phenylethyl alcohol is prepared by slowly spreading the cellulose on the water surface. Concentrate is recommended until the cellulose is completely swollen.

10 The active substance and mannitol dissolve in that residue the amount of water for injection.

The solutions are mixed thoroughly and sterilized. The solutions are filled into suitable sterile containers under aseptic conditions.

15

Claims (11)

5 DK 164156B 71 1. Propane-1,3-diol-ammonium compounds of the general formula I R1 CH, O-A1-R1 10 \ _ / I / \, R3 CH2 O-A1- (CH2) nB + X- A1 and O-A1, which may be the same or different, each represent O, OC (O), 0-C- (0) NH, 0-C (S) NH or 0-C (0) 0, R1 represents a alkyl or alkenyl group of 10 to 22 carbon atoms, n is an integer from 20 to 11, B + represents a quaternary ammonium group, either N * R 4 R 5 R 6, where R 4, R 5 and R 6 are the same or different alkyl groups of 1 to 4 carbon atoms , or two or all or all of R4, R5 and R6 may be included in a monocyclic or bicyclic structure selected from the group consisting of 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethylene-iminyl, 1-imidazo lidinyl, 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl, 4-morpholinyl, triethylenediamin-1-io and 1-quinuclidinio, or B + represents N + (Het), where N * (Het) means 1-pyridinio, 1 -pyridazinio, 1-pyrimidinio, 1-pyrazinio, 3-oxazolio, 3-thiazolio, 1-isoquinolinio, 1-quinolinio, or 3-alky 1-l-imidazolio, X "means the anion of a pharmaceutically acceptable inorganic or organic acid; and R 1 and R 3 are the same or different, and represent hydrogen or alkyl groups of 1-4 carbon atoms. A compound according to claim 1 in crystalline form. 72 DK 164156 B A compound according to claim 1, characterized in that X "means the anion of an inorganic acid selected from the group consisting of hydrochloric, hydrobromic, hydrochloric, sulfuric, phosphoric and nitric, or an anion of an organic acid selected from the group consisting of acetic acid, lactic acid, tartaric acid, benzoic acid, citric acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene sulfonic acid and isethionic acid, with X * especially meaning chloride, bromide, iodide or anions of methanesulfonic acid 10 or p-toluenesulfonic acid. A compound according to claim 1, characterized in that R 2 and R 3 are both hydrogen and n is an even number from 4 to 9. 15 A compound according to claim 1, selected from the group consisting of 1-octadecylaminocarbonyloxy-3- [7- (3-thiazolio) -heptanoyloxy] -2-methylene propane bromide, 1-octadecylamino-carbonyloxy-3- [6- ( 1-pyridinio) hexanoyl-oxy] -2-methylene-propane bromide, 1-pentadecylaminocarbonyl-oxy-3- [8- (3-thiazolio) -octanoyloxy] -2-methylene-propane bromide, 1-hexadecyl-oxycarbonyloxy-3- [8- (3-thiazolio) octanoyloxy] -2-methylene propane bromide, 1-pentadecylaminocarbonyloxy-3- [8- (3-thiazolio) octanoyloxy] -2-isopropylidene propane bromide, 1-octadecylaminocarbonyloxy-3- [5- (1-Pyridinio) -pentylamino-carbonyloxy] -2-methylenepropane bromide, 1-octadecylamino-carbonyloxy-3- [6- (3-thiazolio) -hexyloxy] -2-methylene-propane-methanesulfonate. An analogous process for the preparation of a compound according to claim 1, characterized in that a compound of formula II R2 / CH, O-A1-R1, R3 CH20-A2 (CH2) nZ 73 wherein O-A1, O-A2, R1, R2, R3 and n are as defined in claim 1, and Z is an appropriate leaving group such as chloride, bromide, iodide, benzenesulfonate, toluene sulfonate or methanesulfonate. trialkylamine NR4R5R6 wherein R4, R5, R6 are as defined in claim 1, or with a heterocyclic amine N (Het) as defined in claim 1, alone or dissolved in a suitable solvent such as methanol, ethanol, propanol, ethyl acetate , methylene chloride, chloroform, ether or tetrahydrofuran or a mixture thereof, in the presence of a silver salt when Z 1 is a halide, and / or if desired by replacing the anion Z "with another anion X by known methods, after recovering the compound of formula I. A pharmaceutical composition containing an effective amount of at least one or more of the compounds of claim 1, together with pharmaceutically acceptable, non-toxic carriers and / or excipients. A pharmaceutical composition according to claim 7 in parenteral form. A pharmaceutical composition according to claim 7 in topical form. 25 A pharmaceutical composition according to claim 7 in enteral form. The use of a compound according to any one of claims 1-5 for the manufacture of a pharmaceutical composition for the treatment of patients suffering from cancer or of diseases in which PAF plays a role. 35