NOVEL CYCLIC LIPID DERIVATIVES AS POTENT PAF ANTAGONISTS

FIELD OF INVENTION

The present invention is to provide a series of novel cyclic diol derivatives having a potent antagonistic activity of the platelet activating factor(PAF), together with a process for their preparation. The invention also relates to their use in the treatment of the diseases in which PAF is involved.

BRIEF DESCRITION OF THE PRIOR ART

The platelet activating factor (PAF, 1- 0 -alkyl-2-acetyl-sπ -glyceryl -3-phosphocholine) is a potent endogenous phospholipid found in a variety of cells implicated in inflammatory process, including platelets, neutrophils, basophils, eosinophils, macrophages, mast cells and endothelial cells, and several tissues ( heart, lung, kidney) of organism [Venuti, M. C, in " Comprehensive Med. Chem .", Ed. Hansch C, Pergamon Press, Oxford, 1990, vol 3. P 715].

PAF was recognized for the first time as a potent platetet aggregating agent[Benveniste, J. et al., /. Exp. Med., 1972, .136 ] and it was found later to have a wide spectrum of biological activities such as constriction of smooth muscle, decrease of coronary blood flow, inhibition of cardiac effect, increase of vascular permeability or hypotension via interaction with specific receptors[Cooper, K. et al., Anπu. Rep. Med. Che . 1989, 24, 81]. Although the precise role of PAF in vivo is still not fully understood, PAF has been implicated as a potential mediator in a number of pathophysiological conditions such as asthma, inflammation, septic shock, thrombosis, gastric ulceration, transplant rejection, hypotension, and ischemic heart disease[Koltai et al., Dwgs , 1991, 42(21, 9 & 174 ].

These facts suggest that a specific potent PAF antagonist may prove useful in the treatment of these diseases related directly or indirectly with PAF. A number of potent, structurally diverse classes of PAF antagonists have been reported. In particular, natural PAF -like lipid compounds disclosed in patents JP 57/67589, JP 60/104066, EP 327962, EP 353474, USP 4851450, USP 4891363, USP 4940706, USP 4945098, and USP 4997843 are among them.

However, very few of these compounds are satisfactory due to some problems associated with selectivity, potency and bioavailability, the three properties which are essential for the clinical development of a PAF antagonist Under these circumstances, the inventors have long made intense investigations for the purpose of finding novel compounds which are better than the known PAF antagonists in these properties.

DETAILED DESCRITION OF THE INVENTION

The invention described and claimed herein encompasses compounds represented by the formula I or pharmaceutically acceptable salts thereof:

I in which:

Y represents a divalent group selected from the class consisting of O, S, SO, SO ₂ , (CH^ wherein m is zero or an integer of lto 5, and NR ^* group wherein R ^* is hydrogen, lower

_' alkyl, lower alkoxycarbonyl, aryl, arylalkyl, or acyl; R ¹ represents either an alkyl, alkenyl or alkynyl group, of 10 to 24 carbon atoms or a

CONR ³ R ⁴ group, wherein R ³ is hydrogen or lower alkyl and R ⁴ is an alkyl, alkenyl or alkynyl group, of 10 to 24 carbon atoms;

R ² represents a group having formula T-(CH ₂ ) _n -V (X ^" )q , wherein T refers a simple covale linkage, or a CO, PO ₃ ^" , C(O)O, or CONR ^b group wherein R ^b is hydrogen, lower alkyl or acyl; n refers to an integer of from 1 to 10;

V refers to either (i) the group indicated by formula - ⁺ NR ^S R ⁶ R ⁷ wherein R ^s , R ⁶ , and R ⁷ stand for identical or different lower alkyl group, or two or three of R ⁵ , R ⁶ and R ⁷ taken together with the adjacent nitrogen form heterocyclic ammonio group, 5 or ii) the group indicated by the formula

A Xn

wherein R ⁸ represents lower alkyl group; q is one or zero;

X ^" represents a pharmaceutically acceptable anion such as halide(chloride, bromide, or iodide), lower alkyl sulfonate, arylsulfonate, carboxylate, sulfate, nitrate, or phosphate.

The present invention is also to provide another class of cyclic glycol derivatives represented by the formula II or pharmaceutically acceptable salts thereof :

π

in which Y, R ¹ , and R ² are of same meanings as defined above in the formula I.

0 The following definitions are given for various terms used throughout this specification. The term "alkyl group" in the definition of R\ R ³ and R ⁴ refers to straight or branched -C^ alkyl which may have a double bond or triple bond. Preferably it refers to a C. _Q -C^alkyl group. Examples of such alkyl groups include the decyl, undecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nanodecyl, icosyl, henicosyl, dococyl, tricocyl 5 and tetracosyl groups.

The term "lower alkyl group" in the definition of R\ R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ refers to _ straight or branched C. to C ₆ alkyl. Examples of such alkyl groups include the methyl, ethyl, n - propyl, isopropyl, n -butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl groups, of which the methyl, ethyl, and propyl groups are preferred.

20 The term "lower alkoxycarbonyl group" in the definition of R ^* refers to lower carboalkoxy group derived from the lower alkoxy groups whose carbon number ranges from 1 to 4, such as methoxy, ethoxy, propoxy, or butoxy group.

The term "aryl group" in the definition of R* refers to substituted or unsubstituted phenyl or naphthyl group . Where they are substituted, the substituents include, for example, 25 halogen atoms, C C ₄ alkyl groups, such as methyl, ethyl, propyl and butyl, C.-Q alkoxy, and C--C ₄ haloalkyl.

The term "arylalkyl group" in the definition of R ^* refers to arylalkyl group derived from the above-described aryl group. The alkyl part is preferably a C _j to C ₄ alkyl group. Examples o such arylakyl groups include the benzyl, phenethyl, phenylpropyl, and 1- or 2- naphthylmethyl groups, of which the benzyl group is preferred. Such preferred groups may, if desired, be substituted as defined above.

The term "acyl group" in the definition of R* and R ^b refers to the residues of organic acids such as aliphatic saturated carboxylic acids, aliphatic unsaturated carboxylic acids, carbocyclic carboxylic acids and heterocyclic carboxylic acids. They include lower alkanoyl groups, aroyl groups, heteroaroyl groups, and lower cycloalkylcarbonyl groups. Examples of the lower alkanoyl groups include the formyl, acetyl , propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl groups. Examples of the aroyl groups include the benzoyl and naphthoyl groups which may contain one or more sustituents as defined above. Examples of the heteroaroyl groups include the furoyl, nicotinyl and isonicotinyl groups. Examples of the lower cycloalkylcarbonyl groups include cycloalkylcarbonyl groups in which number of carbon ranges from 4 to 7, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl. Among them, preferred are the lower alkanoyl groups such as acetyl, propionyl and butyryl , and the benzoyl group unsubstituted or substituted by one or more substituents as defined above .

The term "heterocyclic ammonio group" in the definition of - ⁺ NR ⁵ R ⁶ R ⁷ refers to 5 to 6 membered mono-, bi, tri- cyclic ammonio groups connected directly to the methylene group by the nitrogen atom of the ring , which may contain additional hetero atoms selected from sulfur, nitrogen and oxygen. They may be aromatic or partly or wholly saturated and may optionally be substituted by lower alkyl, -C ₄ alkoxy, halogen, or like. Examples of such heterocyclic ammonio group include N-methyl-1-pyrrolino, N-methyl-1-pyrrolidino, 3- oxazolino, 2-isoxazolino, 3-thiazolio, 4-methyl- 3-thiazolio, 1-pyridinio, N-methyl-1- piperidinio, N-methyl-4-morpholio, 1-pyridmidinio, 1-pyrazinio, 3-benzothiazolio, 3- benzoxazolio, 1-quinolinio, 5, 6, 7, 8 - tetrahydro-1-quinolinio, 2-isoquinolinio, etc. Among them, preferred are the aromatic heterocyclic ammonio groups such as 3-thiazolio, 4-methyl- 3-thiazolio, 1-pyridinio, 1-quinolinio, and 2-isoquinolinio.

If desired, the anion X ^" can be interchanged with another anion by ion exchange techniques, to afford other salts, all of which are considered part of the present invention.

The vast majority of the compounds of the present invention contain at least one asymmetric carbon atom so that they exist in various optical and diastereomeric stereoisomers. As a matter of course, all of individual isomer in pure form and in admixture, including racemic mixture, are within the scope of this invention.

The compounds of the formula I and II of this invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvate forms, with pharmaceutically acceptable solvents such as water, ethanol or the like are equivalent to the unsolvated forms for purpose of the invention.

Although the present invention covers all the compounds mentioned above, the following compounds are more preferred:

Referring to the compound of the foπnula I,

Those compounds in which Y is an oxygen or sulfur atom, a methylene or NR* group wherein R* is lower alkyl, arylalkyl or acyl;

Those compounds in which R ¹ is an alkyl group of C _]4 to C^ carbon atoms, and most preferably those in which R ¹ is an alkyl group of C ₁₆ to C, _g carbon atoms, that is, hexadecyl, heptadeyl, and octadecyl;

Those compounds in which R ¹ is a CONR ³ R ⁴ group wherein one of R ³ and R ⁴ is preferably hydrogen or methyl and the other group is an alkyl group of C_ to C^ carbon atoms, specially of C, ₆ to _g carbon atoms, that is, hexadecyl, heptadeyl, and octadecyl ;

Those compounds in which R ² is T-CCH^-V wherein T is a simple covalent bond or CO group, n is an integer from 4 to 8, and V is the group indicated by the formula (i) - ⁺ NR ^S R ⁶ R ⁷ which represents a heterocyclic ammonio group, especially an aromatic heterocyclic ammonio group selected from the class consisting of 3- thiazolio, 1- pyridinio, 1-quinolinio and 1-isoquinolinio group ;

Those compounds in which R ² is T-(CH ₂ ) _n -V wherein T is a -CONR ^b group, R ^b is an acetyl or benzoyl group unsubstituted or substituted by methoxy group, n is 1, V is the group indicated by the foπnula (ii) where R ⁸ is methyl, ethyl and propyl, and most desirable R ⁸ is ethyl.

Referring to the compound of the formula π, preferred examples of Y includes an oxygen or sulfur atom, a (CH^ group wherein m is zero or an integer of 1 to 4, or NR' group wherein R ^* is lower alkyl, arylalkyl or acyl. Preferred examples of other symbols are the same as described above in the preferred compounds having the formula I.

The purpose of the present invention is also to provide methods to prepare compounds of the formula I.

The title compound I in which T is CONR ^b (wherein R ^b is hydrogen or acyl), V is the grou of formula (i), and other symbols are of the same meanings as defined above, i.e. a compound of formula(IX), can be prepared from the starting compound (III), as shown in Scheme 1.

In step 1, one of the two hydroxyl groups present in the diol(III) is functionalized to provid the compound(IV) containing an alkyl or alkylcarbamoyl group represented by R ¹ . If an alkyl group as R ¹ is desired, the diol(III) is treated with a slight excess of an inorganic base such as sodium hydride, potassium hydride or potassium hydroxide followed by an alkylating reagent, such as alkyl halide or an alkyl-or arylsulfonate. The reaction can be carried out in an aprotic solvent compatible with reagents, such as tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or toluene at the temperature ranging from room temperature to 100°C. If an alkylcarbamoyl group as R ¹ is desired, the diol(III) is reacted with an equivalent of the n-alkylisocyanate. The reaction can be accelerated by adding 0.1 equivalent of dibutyltin oxide as a catalyst in an aprotic solvent which does not interfere with reaction, such as tetrahydrofuran or diethyl ether. The reaction can be performed at temperature ranging from 0°C to 60°C. Alternatively, this reaction can be carried out in the presence of a nitrogen - containing base such as pyridine or triethylamine, which can ^~ be used as solvent, if desired. The reaction temperature is suitably selected between room temperature and 100°C.

In step 2, A compound of the general formula(IV) is reacted with phenyl haloformate in th presence of a base to provide a compound of the general formula(V). As a suitable base, mention can be made of an inorganic base such as sodium hydride or potassium hydride an a nitrogen - containing organic base such as pyridine or triethylamine. The reaction is earned out without any solvent or with a solvent that does not interfere with the reaction,

Scheme 1

III IV

R ¹ = alkyl, alkylcarbamoyl

VIII VII

Quarternization R ⁸ - X

Scheme 1'

such as, for example, methylene chloride, chloroform, benzene, tetrahydrofuran, or dioxane. The reaction temperature is suitably selected between 0°C and the boiling point of the solvent, preferably between 0°C and 30° C.

In step 3, a compound of the general formula(V) is treated with one equivalent of a primary amine having the general formula(VI) to give a compound of the general formula (VII). The reaction is performed in a solvent that does not interfere with the reaction. Among the are the chlorocarbon solvents such as chloroform or dichloromethane, the ethers such as tetrahydrofuran, diethyl ether, or dioxane, and aromatic solvents such as benzene or toluene. The reaction temperature is suitably selected between room temperature and the boilng point of the solvent, preferably between 50° C and 90° C.

In step 4, a compound of general formula(VII) is acylated by a conventional method to provide a compound of the general formula(VII). This acylation step involves the use of a reactive derivative of a carboxylic acid having the formula R ^b OH, where R ^b is acyl group, such as anhydride(R ) ₂ O or acid chloride(R ^b Cl). The reaction is preferably conducted in the presence of an organic base such as pyridine or triethylamine, which can be used as solvent, if desired. The reaction can be done in a solvent selected from the chlorocarbon solvents such as chloroform and methylene chloride or the aromatic solvents such as benzene and toluene at the temperature selected in the rang of 0°C to the boiling point of the solvent used.

In step 5, a compound of the general formula(VIII) is reacted with R ⁸ -X(R ⁸ and X being as defined above) to obtain an intended product(IX) of the present invention. When X is a halide, R ⁸ -Hal can be used. The reaction can be performed without any solvent or with a solvent that does not interfere with the reaction, such as acetonitrile, toluene, dimethyl formamide, etc. The reaction temperature is suitably selected in the range of 50°C to 120°C It is desirable that the reaction is done under argon atmosphere, while protected from light.

The intented products(D ) obtained are salts wherein the anion X ^" comes from the reagent X. If desired, this anion can be interchanged with another anion using ion exchange methods.

The intermediate compound having the formula(VII) where R ¹ contains an alkylcarbamoyl group can be prepared by the alternative sequences , as shown in Scheme 1' . The reaction of (HI) -→ (X) can be conducted under conditions similar to the case of (IV) → (V), but using two equivalents of phenyl chloroformate and a base. The conversion of (X) to (VII) can then be readily achieved by reacting the dicarbonate compound(X) with an equivalent of amine (R'NH _j ) followed by an equivalent of the compound having the formula (V) in the same reaction flask. This one-pot reaction can be conducted in an aprotic solvent such as toluene, chloroform, or dimethylformamide at the temperature ranging from 50°C to 120°C.

The title compound of formula I in which T contains a CO group and V is the group indicated by the formula(ii) ⁺ NR ⁵ R ⁶ R ⁷ ( wherein R ⁵ , R ⁶ , R ⁷ and other symbols are of the same meanings as defined above) , i. e. a compound of formula(XII), can be prepared by following two step sequences starting from the compound(IV), as shown in Scheme 2.

In the first step, a compound of the general formula(IV) is acylated with a compound having the formula[(ClCO(CH ₂ ) _n X)] to obtain (XI) under conditions similar to that of (IV) → (V) .

The second step involves a quartemization reaction which can be done by allowing(XI) to react with an excess amount of the tertiary amine having formula NR ⁵ R ⁶ N ⁷ . The reaction can be done without any solvent or with a suitable solvent such as acetonitrile , benzene or toluene at the temperature ranging between 50°C and 120°C. It is desirable that the reaction is done under argon atmosphere, while shielded from light

Scheme 2

IV

NR ⁵ R ⁶ R ⁷

XII

The intended compound of formula I in which T contains a PO ₃ ^' group and V is the group indicated by the formula(ii) ⁺ NR ⁵ R ⁶ R ⁷ (wherein R ⁵ , R ⁶ , R ⁷ and other symbols are of the same meanings as defined above) , i. e. a compound of formula(XIV), can be prepared by following two step sequences starting from the compound(IV), as shown in Scheme 3.

The first step is a phosphorylation reaction. A compound of the general formula(IV) is reacted with bromoalkyl phosphorodichloridate(Cl ₂ P(=O)O(CH ₂ ) _ri Br), obtained by utilizing method of the literature[Hirt, R. et al., Pharm. Acta Helv ., 1958, 33, 349], This reaction ca be done in the presence of a base such as triethylamine or pyridine at the temperature rangin from 0° C to the boiling point of the solvent. As the preferable solvent, mention can be made of an aprotic solvent such as methylene chloride, chloroform, diethyl ether, tetrahydrofuran, benzene, or toluene. The compound (Xπi) can then be produced by hydrolysis using pyridine or sodium acetate as a base in water at the temperature ranging from 20°C to 70°C. A miscible co-solvent such as tetrahydrofuran or acetonitrile can be used, if desired.

The second step (XIII) ^→ (XIV) involves a quaternization reaction which can be done by allowing (XIII) to react with the compound having formula NR ⁵ R ⁶ N ⁷ under conditions similar to that of (XI ) → (XII). The intended quartemary ammonium salt(XIV) is then obtained in a zwitterionic form by treating with silver carbonate in a suitable solvent such a acetonitrile, methanol, or tetrahydrofuran. The reaction temperature is suitably selected in the range between room temperature and the boiling point of the solvent.

The intended compound of formula I in which T is a simple covalent bond and V is the group indicated by the formula(ii) ⁺ NR ⁵ R ⁶ R ⁷ (wherein R ⁵ , R ⁶ , R ⁷ and other symbols are of the same meanings as defined above) , i. e. a compound of formula(XVI), can be prepared by following two step sequences starting from the compound(IV), as shown in Scheme 4 .

Scheme 4

R ¹ 0 OH >c- (CH2) _n -X R ¹ 0 X O(CH2) _n -X

XV

NR ⁵ R ⁶ R ⁷

The first step involves a deprotonation reaction with a strong base, such as sodium hydride, followed by the alkylation reaction with X(CH ₂ ) _n X', where X and n have the above meanings and X' is another suitable leaving group, such as bromide, iodide, alkyl or arylsulfonate, X' being a leaving group better than or equal to X.

The second step (XV) ^→ (XVI) is a quarternization reaction which can be performed in a manner similar to (XI ) → (XII).

The compound of the general formula(III) used as the intermediate compound in the process of the present invention can be easily prepared by the process shown in Scheme 5, 6 and 7.

The compound (Ilia) in which Y of the formula (IH) is an oxygen atom can be readily synthesized starting from the compound (XVII), obtained by the methods of literature [Walkup, R.D. et al., TeL Lett., 1987, 28, 4019 ].

Scheme 5

mCPBA XVII XVIII XIX

n - Bu ₃ SnO

Ilia XX ( R = alkyl , - CH ₂ Ph

As shown in Scheme 5 , the starting compound (XVϋ)(wherein R denotes the above- defined alkyl group as R ¹ or a benzyl group) is allowed to react with an equivalent of allylic magnesium bromide in an aprotic solvent such as tetrahydrofuran or ethyl ether at the temperature ranging from 0°C to 50°C to obtain the secondary alcohol (XVTII). Epoxidation reaction of (XVIII) → (XIX) can be carried out with perbenzoic aicd such as m -chloroperbenzoic acid in a suitable solvent such as methylene chloride, chloroform or tetrahydrofuran at room temperature.

The ring-closure reaction of (XIX) → (XX) can then be performed by heating (XIX) in the presence of tributyltin methoxide in accordance with the methods described in the literature [Bats, J. P. et al., Tetrahedro , 1982, __&_, 2139]. The reaction can be done without any solvent or with a solvent that does not interfere with the reaction, such as toluene or benzene at the temperature ranging from 100°C to 250°C. Where the oxetane compound(XX) contains a benzyl group for R, the benzyl group present in (XX) can be reductively removed under the typical hydrogenolysis conditions to produce the intended diol compound (Ilia).

The palladium catalyst such as Pd(OH) ₂ or Pd C is used for this reduction under the pressure ranging from latm to 50 atm. The reaction proceeds at the temperature ranging from 20°C to 80°C in a polar solvent such as methanol, ethanol, or ethyl acetate.

As shown in Scheme 6, the starting material (I- b) in which Y of the formula (IH) is sulfur can be prepared starting from the dibromo ester (XXI), as reported in the literature[Baldwin, J. et al., /. Chem. Soc. Chem. Commun ., 1985, 194].

Scheme 6

Reduction

XXI XXII (trans) 1Mb (trans)

Reduction _ι

XXII (cis) lllb (cis)

The thietane ring-forming reaction of (XXI) with one equivalent of sodium sulfide proceeds rapidly in a polar solvent such as dimethyl sulfoxide, methanol, or methylene chloride alone, or a mixture thereof to afford the thietane compound(XXII). The reaction can be performed at the temperature ranging from -78°C to room temperature, preferably between -30° C to 20° C. The compound (XXII) exists in a diastereomeric mixture of the cis and trans isomers. If desired, each isomer can be separated in a pure form by a flash column chromatography. Reduction of the ester groups of (XXH) can be performed by a conventional method employing lithium aluminum hydride or lithium borohydride as a reducing agent in a suitable solvent such as tetrahydrofuran or ethyl ether to the diol compound (nib).

The starting material (Iϋc') in which Y of the formula (HI) is a NR ^* group(wherein R ^* is a lower alkyl, aryl or arylalkyl) can also be prepared from the dibromo ester compound(XXI) in two steps(Scheme 7).

Scheme 7

R ³ = tow alkyl, aryl, arylal

XXIIΓ _XXIV me-

R ^a = acyl The first reaction of (XXI) ^→ (XXIII) can be carried out bv subjecting the dibromo ester (XXI) to a primary amine(R ^* NH ₂ ). The reaction can be conducted in the presence of two equivalents of a base such as an inorganic base (e.g. sodium hydrogen carbonate, potassium carbonate) or a nitrogen-containing organic base such as pyridine or triethylamine. This reaction can also be performed conveniently without a base by using three equivalents of R'NH _j , which can serve as solvent, if desired. As the reaction solvent, a mention can be made of a polar solvent such as acetonitrile, dimethyl formamide, chloroform, tetrahydrofuran, or toluene. The reaction temperature ranges from 0° C to the boiling point o the solvent. If desired, the pure cis and trans isomers of the compound (XXIII) can be separated in pure forms by a flash chromatography.

The second step involves the reduction of diester group of (XXIII) to afford the diol compound(IIIc'). As the preferable reducing agent, mentioned can be lithium aluminum hydride or liihium borohydride. As the solvent, use is made of methanol, tetrahydrofuran, ethyl ether, etc., and the reaction proceeds at the temperature ranging from 0°C to 50°C.

The starting compound (Die") in which Y of the formula(IE-) is a NR ^* group (wherein R' is acyl) can be derived from the compound (XXffl') containing a benzyl group for R ^* . The reductive removal of the N-benzyl group of (XXIIT) under similar conditions to those for (XX) → (ma) affords the compound(XXIV). The transformation of (XXIV) → (-fflc") involves an N-acylation reaction followed by a reduction. By allowing (XXIV) to react with one equivalent of a reactive derivative of a carboxylic acid R* OH ( wherein R ^* is acyl), such as acid chloride(R ^* Cl) or acid anhydride (R ^* ) ₂ O as an acylating agent in the presence of a base, such as pyridine or triethylamine, the N-acylation of the azetidine compound(XXIV) can be achieved. As the reaction solvent, an aprotic solvent such as methylene chloride, acetonitrile, tetrahydrofuran, benzene, or toluene can be employed. The reaction temperature ranges from -20°C to the boiling point of the solvent. The selective reduction of the ester functional group to the diol compound(IIIc") can then be performed by treatment with a reducing reagent such as lithium borohydride in ethyl ether at room temperature.

The starting material (Tlld) in which Y of the formula(III) is a methylene group can be readily prepared in a pure cis or trans form by lithium aluminum hydride reduction of its corresponding diester compound, which is disclosed in the literature[Allinger N. L. et al., /. Org . Chem ., 1965, 30 , 1945 ].

The purpose of this invention is also to provide the compound having the general formula II wherein Y, R ¹ , and R ² are of the same meanings as defined above. They can be easily produced by the same synthetic sequences employed for the preparation of the compound of formula I , but utilizing the compound (XXV) instead of the compound (HI) as the starting material.

The starting compounds (XXVa) and (XXVd), in which Y of the formula (XXV) is an oxygen atom and a (CH^ group respectively, can be synthesized by utilizing compounds

known in the literature or by modified methods of the following literature[e.g. Issidorides, C. H. et al., /. Am. Chem. Soc ., 1955, 77, 6382 ; Picard, P. et al., Synthesis, 1981, 551 ; Mariella, P., Org. Synthesis, 1966, Coll. vol 4. 288 ; Mandolini, L. et al., J. Org. Chem ., 1981, 46, 3127] , as shown in Scheme 8.

5 Scheme 8

LIAIH ₄ / AICI ₃

Deprotection

XXVa

lOThe starting compound (XXVb) in which Y of the formula (XXV) is sulfur can be prepared from 2, 2 - Bis - (bromomethyl) - 1, 3 -propanediol(XXVI) in three steps, as shown in Scheme 9.

Scheme 9

15 XXVI XXVII XXVIII XXVb

After protection of the diol functional group present in the compound(XXVI) as acetonide utilizing the conventional methods, the thietane ring-forming reaction of (XXVII) to (XXVTfl) can be done by treatment with sodium sufide in a polar sovent such as dimethyl sulfoxide or methanol at the temperature ranging from 0°C to 50°C. The desired diol compound (XXVb) is then obtained by deprotection of the acetonide protecting group under acidic conditions.

The starting compound (XXVc ¹ ) in which Y of the formula(XXV) is a NR* group (wherein R* is a lower alkyl, aryl or arylalkyl) can be prepared from (XXVH) in two steps, as shown in Scheme 10.

Scheme 10

H ₂ NR ^a

XXVII XXIX

Deprotection

XXIX' XXX

The first azetidine ring- forming reaction (XXVH) manner similar to that of (XXI) → (XXIII). The second step involves deprotection of the acetonide protecting group present in compound(XXIX) to produce the desired conpound (XXVc')

To prepare the starting compound (XXVc") in which Y of the formula(XXV) is a NR ^* group(wherein R ^* is acyl) , the compoundQOfl-X') having a benzyl group for R* is subjected to the catalytic hydrogenation conditions similar to those for (XXIH) → (XXIV). The N-acylation reaction of (XXX) under conditions similar to the case of (XXIV) → (HI") followed by the deprotection reaction of the acetonide protecting group affords the diol compound(XXVc").

As mentioned before, the starting compound having the general formula (XXV), i.e. (XXVa), (XXVb), (XXVc'), (XXVc"), (XXVd), can readily be converted to the tide compound having the general formula II by employing the same general synthetic sequence presented above in Scheme 1- 4. For the simplicity of the exposition, the preparation of the title compound II starting from the compound of formula(XXV) is not presented here but will be described in detail in Working Examples.

The title compounds I and II of the present invention exhibit exellent platelet activating factor(PAF) antagonistic activities , and are thus useful as prophylactic and therapeutic agents for circulatory disturbances due to PAF, for example, thrombosis, apoplexy (e.g. cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina pectoris, venus thrombosis, nephritis, diabetic nephritides, shock(e.g. endotoxin shock, observed after grav infectious diseases or surgical operation, intravascular hemagglutination syndrome caused b endotoxin, anaphylactic shock, hemorrhagic shock). The title compounds I and II are also useful for the treatment of diseases associated with allergy and inflammation(e.g. bronchial asthma, psoriasis), gastroentric diseases caused by PAF(e.g. gastric ulcer), pneumonia, rejection symptoms associated with increase in the amount of PAF produced in the case of internal organ transplantation, insufficiency of internal organ(e.g. heart, kidney, liver) in the case of internal organ operation, ischemic cerebral and cardiac diseases, and renal disorders.

The PAF antagonistic properties of the title compounds I and II can be demonstrated by their ability to displace [ ³ H]PAF from its binding sites in rabbit platelets and to inhibit PA -mediated effects, such as rabbit platelet aggregation and serotonin release. The following pharmacological test examples explain the effects of the present invention in a more concret manner.

TEST EXMAPLE I

Inhibitory action on PAF - induced [ ^>4 C}- serotonin release

Blood was collected from the hearts of conscious New Zealand white male rabbits weighing 2 to 3kg. The blood was immediately subjected to a centrifuge at 1400 rpm for 10 minutes to obtain platelet rich plasma(PRP). PRP was incubated with a trace amount of [ ¹⁴ C]-serotonin for 20 minutes at 22°C. Prelabelled platelets were prepared by centrifugation at 3500 rpm for 10 minutes. The test compound was added to 80 μl of [ ¹⁴ C] serotonin-labeled platelets in plastic test tubes, and the mixture was incubated for 2 minutes. PAF (1x10 ^'9 M) was then added to the reaction mixture and incubated for additional 2 minutes at which time 10 μl of cold formaldehyde was added to stop the reactions. The tubes were immediately cooled to 4°C and centrifuged at 12000 rpm for 2 minutes. The supematants (80 μl) were assayed for percentage of [ ¹⁴ C] serotonin release by the conventional methods of measuring ^I C counts. The test results are shown in Table 1.

Table 1.

TEST EXAMPLE II

Inhibitory action on PAF-induced platelet aggregation

Blood was collected from the hearts of conscious New .Zealand white male rabbits weighin 2 to 3kg using citric acid as an anticoagulant (one volume part of 3% citric acid relative to 9

5 volume parts of the whole blood). A platelet-rich plasma(PRP) was prepared by centrifugation at 1000 rpm for 10 minutes. The remaining blood after collecting the PRP w subjected to a centrifuge at 3000 rpm for 10 minutes to obtain platelet poor plasma(PPP). PRP was diluted with PPP to adjust the number of platelets to about 3 x 10 ^s / μl. Solution test compound (30 μl) was added to the PRP(270 μl), and after incubation for 2 minutes at

1037°C, 30 μl aliquot of PAF(5 xl0 ^'9 M) was added. Platelet aggregation was then examined by means of turbidimetry [Born, Nature, 194, 927(1962)] with dual channel aggregometer (Chrono-Log. Corp., Havertown, PA). As the the control, physiological saline without test sample was used. The platelet aggregation inhibiting activities of the test sample are expressed as IC ₅₀ , that is the concentration of the compound at which 50% of the aggregatio

15 is inhibited. The test results are shown in Table 2.

TEST EXAMPLE m

PAF Receptor Binding Assay

Citrated whole rabbit blood was obtained from Pel-Freez(Rogers, AR). Rabbit platelets we prepared by centrifugation and washing. The platelets were lysed by freeze-thawing and 0 sonification; Platelet membranes were prepared by centrifugation and washing. Final membrane preparation were stored frozen in 10 mM Tris 5 mM MgC 2 mM EDTA (TM buffer, pH 7.0) with 0.25 M sucrose added for membrane stabilization. The standard PAF receptor binding assay contained 10 μg platelet membrane protein, 0.6 nM [ ³ H]C- _g -PAF(from Amersham or New England Nuclear, specific activity 120 -180 Ci/

25 mmol), -a. test compound, in "binding buffer" consisting of TME with 0.25% bovine serume albumin added(Sigma, RIA grade). The final volume of the assay was lOOμl. The assay wa conducted in Millititre-GV™(Millipore Corp.) filtration plates; incubation time was for 60 minutes at room temperature (22-23°C).

"Specific binding" was operationally defined as the arithmetic difference between "total binding" of 0.6 nM [ ³ H]C. _g -PAF( in the absence of added PAF) and "nonspecific binding" (in the presence of 1 μM PAF). After the prescribed incubation, platelet membranes were filtered under vacumm, and washed with 1 ml of ice cold "binding buffer". The fiters were dried and removed. The bound radioactivity was quantitated with a Berthold TLC-Linear Analyzer model LB2842. Dose-response curves of inhibition of specific [ ³ H]C _lg -PAF binding by test compounds were conducted in duplicated, with at least four doses covering the active range. Experiments were repeated at least once. IC ₅₀ values (concentration producing 50% inhibition) were determined by linear regression evaluation . Ki values of inhibitory binding constants were calculated according to the methods of the literature[Cheng et al., Biochem. Pharmacol ., 1973, 22, 3099] whereby Ki = IC^l-i- ([ ³ H] PAF] / Kd[ ³ H] PAF) = IC ₅₀ / (1+ (0.6 nM/ 0.6 nM) = IC ₅₍ 2.

Table 2

Table 3

[WORKING EXAMPLES]

The following typical working examples will further illustrate the present invention, which by no means limit the invention.

EXAMPLE 1

cis-2-[[N-Acetyl - N - [[[2-[(hexadecyloxy)methyl] - 4 - oxetanyl]methoxy] carbonyl] amino]methyl]-l - ethyl -pyridinium iodide

(a) l-(hexadecyloxy)-4-penten-2-ol

To a cold(0°C) stirred solution of allyl magnesium bromide ( 10 ml, 1.0 M solution in diethyl ether) in dry ethyl ether(50ml) was added dropwise n- hexadecyloxy aldehyde(1.82g) in dry ethyl ether(5ml). The mixture was then heated at reflux for lh. The reaction was quenched by the addition of saturated ammonium chloride aqueous soution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 10) to afford 1.92g of the desired product as a white solid (92 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.97 (t, 3H, J = 6.5Hz), 1.20 -1.60 (m, 26H ), 2.22 -2.27(m,

2H), 2.30(d, IH, J = 3.5Hz), 3.27(dd, IH, J = 9.7Hz, J = 7.5Hz), 3.38-3.51 (m, 5H), 3.80 -3.85(m, IH), 5.05 -5.15 (m, 2H), 5.88(m, IH)

(b) l-(hexadecyloxy)-4, 5- epoxy -penten-2-ol

To a stirred solution of the compound prepared in example la (1.60g) in methylene chloride (50ml) was added 50 -60 % m -chloroperbenzoic acid (1.69g) at 0°C, and the mixture was stirred for 12 h at room temperature. The reaction mixture was then washed successively with brine, 10% sodium bicarbonate solution and water. The organic layer was dried, concentrated under reduced pressure, and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 5) to afford 1.4 lg of the desired product (84 % yield).

^■ R - NMR( 300 MHz, CDC1 ₃ ) : ^β 0.88 (t, 3H, J = 6.4Hz), 1.20 -1.90 (m, 29H), 2.59 -2.63 (m, 2H), 2.76 -2.83 (m, IH), 3.05 -3.15 (m, IH), 3.30 -3.5

(m, 5H), 3.95 - 4.05(m, IH)

(c) cis,trans-4-[(Hexadecyloxy)methyl] oxetane-2-methanol

A mixture of the compound prepared in example lb (316mg) and tri-n-butyltin methoxide (0.28ml) was heated at 120°C under reduced pressure (20 mmHg) for 1 h. The mixture was then heated at 220°C for 2h under argon atmosphere. After cooling to room temperature, the reaction mixture was poured into the saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried, concentrated under reduced pressure and the resultin residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 3) to afford lOlmg of the desired product as a ca. 1 : 1 mixture of the cis and trans isomers as a colorless solid(32 % yield).

mp : 34.6 - 35.2°C

Η - NMR( 300 MHz, CDC1 ₃ ) : ^β 0.88 (m, 3H), 1.20 - 1.65(m, 27H), 2.16 - 2.95(m, 2H),

3.42 - 3.81(m, 8H), 4.74 - 4.85(m, 2H) IR(KBr) : 3386, 2925, 2851, 1487, 1376, 1109, 899, 849, 721 cm ^"1 Mass (El, m z) : 343 (M ⁺ + 1)

(d) cis, trans- 2-[[ N-[[[ 4-[(Hexadecyloxy)methyl]-2-oxetanyl] methoxy] carbonyl] amino] methyl] pyridine

To a cold(0°C) stirred solution of the compound prepared in example lc (277mg) in methylene chloride(15ml) was added pyridine (0.13ml) and then phenyl chloroformate(0.12ml) . After stirring at room temperature for lh, the reaction mixture was poured into the saturated ammonium chloride(lθml). The organic phase was washed with 10% sodium bicarbonate, drie and concentrated under reduced pressure. The resulting residue was dissolved in benzene(5ml) containing 2-picolyl amine(104mg), and the mixture was heated at reflux overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed successively with IN- HCl solution and water. The organic layer was dried, concentrated und reduced pressure, and the resulting residue purified by flash chromatography on silica gel (eth acetate : hexane = 1 : 1) to afford 377mg of the desired product as a ca. 1 : 1 mixture of the ci and trans isomers as a colorless solid(85 % yield).

¹ H - NMR( 300 MHz, CDC1 ₃ ) : δ 0.85 - 0.94(m, 3H), 1.20 - 1.60(m, 26H), 2.30 - 2.60(m,

2H), 3.44 - 3.66(m, 4H), 4.25(d, IH, J = 4.7Hz), 4.29(d, IH, J = 4.4Hz), 4.50(d, 2H, J =5.5Hz), 4.60 - 4.90(m, 2H), 5.85 - 6.05(m, IH), 7.16 - 7.21(m, IH), 7.26 - 7.29( IH), 7.66(t IH, J = 7.7Hz), 8.53(d, IH, J = 4.7Hz) IR(KBr) : 3311, 2921, 2851, 1691, 1550, 1466, 1283, 1122, 1033, 992, 858, 753 cm ^"1

(e) cis - 2-[[ N- Acetyl - N-[[[ 4-[(hexadecyloxy)methyl]-2-oxetanyl] methoxy] carbonyl] amino]methyl] pyridine and its trans isomer

A mixture of the compound prepared in example Id (84mg) and acetic anhydride(0.25ml) was heated at 110°C in the presence of pyridine(0.35ml) for 4 h. The mixture was then diluted with methylene chloride(20ml), washed with IN- HCl solution and then 10 % sodium bicarbonate solution. The organic layer was dried, concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 3) to afford 36mg of the pure cis isomer and 38mg of the pure trans isomer(79 % overall yield).

cis isomer : 'H - NMR( 300 MHz. CDC1 ₃ ) : ^β 0.88 (t, 3H, J = 6.9Hz), 1.15 - 1.62(m, 28H), 2.18 - 2.27(m, IH), 2.40 - 2.55(m, IH), 2.62(s, 3H), 3.39 - 3.49(m, 4H), 4.24 - 4.37(m, 2H), 4.76 - 4.82(m, 2H), 5.11(s, 2H), 7.13(d, 2H, J = 7.3Hz), 7.61(t, IH, J=7.9Hz), 8.49(d, IH, J = 5.4Hz)

IR(KBr) : 2922, 2850, 1736, 1705, 1466, 1370, 1216, 1123, 970 cm ^"1

trans isomer : 'H - NMR( 300 MHz. CDC1 ₃ ) : δ 0.88 (t, 3H, J = 6.9Hz), 1.15 - 1.62(m, 28H), 2.23 - 2.30(m, IH), 2.40 - 2.50(m, IH), 2.64(s, 3H), 3.41 - 3.5 l(m, 4H), 4.24 - 4.37(m, 2H), 4.49 - 4.54(m, IH), 4.75 - 4.77(m, IH), 5.14(s, 2H), 7.12(d, 2H, J = 7.8Hz), 7.60(t IH, J=7.6Hz), 8.49(d, IH, J = 3.2Hz)

IR(KBr) : 2924, 2852, 1744, 1703, 1444, 1362, 1213, 1101, 981, 763 cm ^'1

(f) Preparation of the title compound of this example

A mixture of the cis compound isolated in example le (20mg) and ethyl iodide(0.25ml) was heated at reflux in acetonitrile(0.5ml) for 12 h under argon atmosphere, while shielded from light. The mixture was concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (methanol : methylene choride = 1 : 10) to afford 22mg of the title compound of this example as a yellow solid(85% yield).

mp : 35.1 - 37.5°C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88 (t, 3H, J = 6.5Hz), 1.20 - 1.62(m, 28H), 1.73(t, 3H, J =6.5Hz), 2.29 - 2.36(m, IH), 2.60 - 2.73(m, 4H), 3.39 -

3.53(m, 4H), 4.30 - 4.35(m, IH), 4.54 - 4.61(m, 1H), 4.82- 4.90(m, 2H), 5.03(q, 2H, J = 7.3Hz), 5.29 - 5.49(m, 2H), 7.75(d, IH, J = 8.1Hz), 8.07(t IH, J=7.3Hz), 8.46(t, IH, J=8.0Hz), 9.67(d, lH, J = 6.1Hz) IR (KBr) : 3450, 2921, 2851, 1748, 1683, 1507, 1218, 770cm ¹ Mass(FAB, m/z) : 547(M ⁺ - 1)

EXAMPLE 2

trans-2-[[N- Acetyl - N - [[[ 4-[(hexadecyloxy)methyl] - 2 - oxetanyl] methoxy] carbonyl]amino]methyl]-l - ethyl -pyridinium iodide

Following the procedure described in example If, the trans compound obtained in example le (32mg) was reacted with ethyl iodide (0.8ml) in acetonitrile(0.5ml) to afford 35mg of the title compound of this example as a yellow solid( 80% yield).

mp : 39.7 - 42.5°C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88 (t, 3H, J = 6.5Hz), 1.20 - 1.62(m, 28H), 1.73(t, 3H, J =7.4Hz), 2.42 - 2.47(m, IH), 2.50 - 2.60(m, IH), 2.67(s,

3H), 3.43 - 3.60(m, 4H), 4.43 - 4.57(m, 2H), 4.68 - 4.78(m, IH), 4.85 - 4.95(m, IH), 5.10(q, 2H, J = 7.4Hz), 5.44(s, 2H), 7.82(d, IH, J = 8.0Hz), 8.05(t, IH, J = 7.1Hz), 8.46 (t IH, J = 7.8Hz), 9.57(d, IH, J = 6.3Hz) IR (KBr) : 3446, 2920, 2851, 1743, 1684, 1508, 1218, 774cm ^"1 Mass(FAB, m/z) : 547 (M ⁺ - 1)

EXAMPLE 3

cis-2-[[N- Acetyl - N - [[[ 4-[[(octadecylcarbamoyl)oxy]methyl] - 2 - oxetanyljmethoxy] carbonyl]amino]methyl]-l - ethyl -pyridinium iodide

,

(a) l-(benzyloxy)-4-penten-2-ol

Following the procedure described in example la, but replacing n-hexadecyloxy aldehyde with benzyloxy aldehyde, the desired product was obtained as a colorless oil (83 % yield).

'H - NMR( 300 MHz, CDC1 ₃ ) : a 2.26(t, 2H, J = 6.9Hz), 2.44(d, IH, J = 3.4Hz), 3.37(dd,

IH, J=9.4Hz, J=3.5Hz), 3.51(dd, IH, J = 9.4Hz, J = 7.3Hz), 3.86 - 3.90(m, IH), 4.55(s, 2H), 5.07 - 5.14(m, 2H), 5.78 - 5.87(m, IH), 7.26 - 7.38(m, 5H)

(b) l-(benzyloxy)-4, 5- epoxy -pentan-2-ol

Following the procedure described in example lb, but replacing the compound prepared in example la with the compound prepared in example 3a , the desired product was obtained as a colorless oil (94 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 1.48 - 1.87(m, 2H), 2.50 - 2.55(m, 2H), 2.75 - 2.83(m, IH), 3.09 - 3.13(m, IH), 3.36 - 3.59(m, 2H), 4.02 - 4.08(m, IH),

4.56(s, 2H), 7.25 - 7.39(m, 5H)

(c) cis, trans-4-[(benzyloxy)methyl] oxetane-2-methanol

Following the procedure described in example lc, but replacing the compound prepared in example lb with the compound prepared in example 3b , the desired product was obtained as a mixture of cis and trans isomer (32 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : « 1.73-2.88(m, 2H), 3.49 - 3.58(m, 4H), 4.51- 4.67 (m, 3H),

4.81- 4.88(m, 2H), 7.25-7.37(m, 5H), Mass (El, m z) : 208(M ⁺ )

(d) cis, trans- 4-[[(N-octadecylcarbamoyl)oxy]methyl] -2- [(benzyloxy)methyl] oxetane

To a stirred solution of die compound prepared in example 3c (120mg) in benzene (5ml) was added pyridine (0.5ml) followed by octadecyl isocyanate(208mg) , and the mixture was heated 65°C for 5h. After cooling, the reaction mixture was diluted with methylene chloride(20ml), w washed with 1N-HC1 solution and water. The organic layer was dried, concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (ethy acetate : hexane = 1 : 3) to afford 220mg of the desired product as a white solid(75 % yield).

^] H - NMR( 300 MHz, CDC1 ₃ ) : δ 0.86(t, 3H, J = 6.4Hz), 1.20 - 1.60(m, 32H), 2.32-2.50(m,

IH), 2.55 - 2.60(m, IH), 3.06 - 3.16(m, 2H), 3.57(dd, 2H, J = 4.2Hz, J = 4.1Hz), 4.17 -4.24 (m, 2H), 4.53 - 4.63(m, 2H 7.24 - 7.36(m, 5H)

Mass(FAB, m/z) : 504 (M ⁺ +l)

(e) cis, trans- 4-[[(N-octadecylcarbamoyl)oxy]methyl] oxetane - 2 - methanol

A mixture of the compound prepared in example 3d (2(X>mg) and palladium hydroxide on carb ( 80mg) was stirred in methanol(20ml) at room temperature for 12 h under hydrogen . atmospheιe(latm). The mixture was filtered and the filtrate concentrated under reduced pressure to afford 154mg of the desired compound as a white solid(95 % yield).

mp : 79.6 - 80.3°C

'H - NMR( 300 MHz, CDC1 ₃ ) : ^β 0.87(t, 3H, J = 6.4Hz), 1.20 - 1.60(m, 32H), 1.60 - 2.05

(m, IH), 2.40 - 2.68(m, 2H), 3.14 - 3.22(m, 2H), 3.53 - 3.82 (m, 2H), 4.08 - 4.40(m, 2H), 4.76 - 4.87(m, 3H) IR (KBr) : 3346, 2920, 2848, 1687, 1532, 1470, 1252, 1140, 1024, 720cm ^"1

Mass(EI, m/z) : 413 (M ⁺ )

(f) cis - [4 -[[(N -octadecylcarbamoyl)oxy] methyl] - 2- oxetanyl] methyl phenyl carbonate and its trans isomer

To a stirred solution of the compound prepared in example 3e (277mg) in chloroform(15ml) was added pyridine (0.13ml) followed by phenyl chloroformate(0.12ml) at 0°C. After stirring at room temperature for 1 h, the reaction mixture was poured into the saturated ammonium chloride(lθml). The organic layer was washed with 10 % sodium bicarbonate solution and water, dried, concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 2 ) to afford 120mg of the cis isomer and 125 mg of trans isomer (overall yield 82 %).

cis isomer ; mp : 69.8 - 70.2°C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.4Hz), 1.12 - 1.55(m, 32H), 2.50 - 2.70

(m, 2H), 3.11-3.18(m, 2H), 4.22(d, 2H, 3.7Hz), 4.32(dd, IH, J = 12.2Hz, J ---- 2.9Hz), 4.41 (dd, IH, J = 12.2Hz, J =

4.5Hz), 4.92 - 5.02(m, 3H), 7.12 - 7.42(m, 5H) IR (KBr) : 3338, 2922, 2851, 1767, 1686, 1534, 1471, 1267, 1026, 958, 862, 774 cm ^"1 Mass(FAB, m/z) : 534 (M ⁺ +l)

trans isomer ; mp : 76.2 - 76.8°C Η - NMR( 300 MHz, CDC1 ₃ ) : « 0.87(t, 3H, J = 6.4Hz), 1.20 - 1.60(m, 32H), 2.52 -2.69(m,

2H), 3.15 - 3.22(m, 2H), 4.27(d, 2H, J = 4.9 Hz), 4.43 - 4.49(m, 2H), 4.75(br s, IH) 4.88 - 4.94(m, 2H), 7.17 - 7.41 (m, 5H)

IR (KBr) : 3353, 2922, 2848, 1762, 1686, 1530, 1469, 1263, 1025, 957, 858, 776, 720 cm ^"1 Mass(FAB, m/z) : 534 (MM)

(g) cis - 2-[[N -[[[4 -[[(octadecylcarbamoyl)oxy]methyl] - 2- oxetanyl] methoxy] carbonyl] amino] methyl] pyridine

A mixture of the cis compound prepared in example 3f (309mg) and 2-picolyl amine(0.11ml) was heated at reflux in toluene(2ml) . After cooling, the mixture was diluted with methylene chloride(20ml), washed with IN- HCl sotution followed by water. The organic layer was dried, concentrated under reduced pressure and d e resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane - 4 : 1) to afford 250mg of the desired product as white solid(80% yield).

mp : 104.6 - 106.0 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88 (t, 3H, J = 6.5Hz), 1.20 - 1.60(m, 32H), 2.25-2.38(m,

IH), 2.55 - 2.70(m, IH), 3.12 - 3.19(m, 2H), 4.19(s, 2H), 4.24(d, 2H, J = 3.5Hz), 4.50(d, 2H, J = 5.4Hz), 4.88 - 4.92

(m, 2H), 5.05(br s, IH), 5.95(br s, IH), 7.15 - 7.20(m, IH), 7.27(d, IH, J =6.5Hz), 7.65(t, IH, J = 7.6Hz), 8.53(d, IH, J = 4.4Hz) IR (KBr) : 3317, 2920, 2847, 1692, 1544, 1470, 1435, 1268, 1152, 1033, 919, 864 cm ^"1 Mass(EI, m/z) : 547 (M ⁺ )

(h) cis - 2-[[N -Acetyl -N-[[[4 -[[(octadecylcarbamoyl)oxy]methyl] - 2- oxetanyl] methoxyjcarbonyl] amino] methyl] pyridine

Following the procedure described in example le, but replacing the compound prepared in example Id with the compound prepared in example 3g , the desired product was obtained (90 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : s 0.89(t, 3H, J = 6.5Hz), 1.15 - 1.56(m, 32H), 2.15 -2.25(m, 2H), 2.45 - 2.55(m, IH), 2.62(s, 3H), 3.13 - 3.20(m, 2H),

4.03 - 4.14(m, 2H), 4.28(d, 2H, J = 4.7Hz), 4.80 -4.84(m, 2H), 5.12(d, 2H, J = 3.3Hz), 7.13(d, 2H, J = 7.7Hz), 7.62(t, IH, J = 5.9Hz), 8.5 l(d, IH, J = 3.8Hz)

(i) Preparation of the title compound of this example

Following the procedure described in example If, but replacing the compound prepared in example le with the compound prepared in example 3h , the title compound of this example was obtained as a yellow solid (88 % yield).

mp : 53.7 - 56.5°C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.6Hz), 1.17 - 1.59(m, 32H), 1.73(t, 3H, J = 7.3Hz), 2.20 - 2.72(m, 5H), 3.12 - 3.20(m, 2H),

4.07(d, 2H, J = 4.4Hz), 4.15-4.30(m, 2H), 4.85 - 4.95(m, 2H) 4.95 - 5.10(q, 2H, J = 5.9Hz), 5.31(br s, IH), 5.47(s, 2H), 7.80(d, IH), 8.02(t lH, J =6.3Hz ), 8.44(t, lH, J = 7.5Hz), 9.45(d, IH, J = 6,0Hz) IR (KBr) : 3375, 2919, 2850, 1746, 1686, 1630, 1528. 1358, 1227, 1160, 985, 774cm ^"1 Mass(FAB,m/z) : 618 (M ⁺ - 1)

EXAMPLE 4

cis-2-[[N- Acetyl - N - [[[ 4-[[(octadecylcarbamoyl)oxy]methyl] - 2 - oxetanyl]methoxy] carbonyl]amino]methyl]-l - ethyl -pyridinium chloride

The compound obtained in example 3i (128mg) dissolved in 70% methanol (0.5ml) was eluted through the column packed with IRA -410 resin (5g, Cl ^" form) using the eluent ( methanol : water = 7 : 3) to afford 105 mg of the title compound of this example(94% yield). Mass (FAB, m/z) : 618 (M ⁺ - Cl)

EXAMPLE 5

trans-2-[[N- Acetyl - N - [[[ 4-[[(octadecylcarbamoyl)oxy]methyl] - 2 - oxetanyl] methoxy] carbonyl]amino]methyl]-l - ethyl -pyridinium iodide

(a) trans - 2-[[N -[[[4 -[[(octadecylcarbamoyl)oxy]methyl] - 2- oxetanyl] methoxyjcarbonyl] amino] methyl] pyridine

Following the procedure described in example 3g, but replacing the cis compound separated in example 3f with the trans compound separated in example 3f , the desired compound was obtained (93 % yield).

mp : 97.0 - 98.6 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : s 0.88(t, 3H, J = 6.5Hz), 1.20 - 1.56(m, 32H), 2.52(br t,

2H), 3.13 - 3.21 (m, 2H), 4.24(d, 2H, J=4.1Hz), 4.29(d, 2H, J = 4.5Hz), 4.50(d, 2H, J = 5.5Hz), 4.80 - 4.88(m, 3H), 5.99 (br s, IH), 7.18(d, IH, J = 7.4Hz), 7.27(d, IH, J = 5.4Hz), 7.65(t, IH, J = 7.7Hz), 8.53(d, IH, J = 4.4Hz)

IR(KBr) : 3342, 2917, 2849, 1690, 1544, 1470, 1438, 1276, 1151, 1029, 993, 867, 749cm ^"1 Mass (El, m/z) : 547 (M ⁺ )

(b) trans - 2-[[N -Acetyl -N-[[[4 -[[(octadecylcarbamoyl)oxy]methyl] - 2- oxetanyl] methoxy] carbonyl] amino] methyl] pyridine

Following the procedure described in example le, but replacing the compound prepared in example Id wid the compound prepared in example 5a , the desired compound was obtained as a white solid (93 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.5Hz), 1.15 - 1.56(m, 32H), 2.20 - 2.40

(m, 2H), 2.64(s, 3H), 3.13 - 3.20(m, 2H), 4.16(d, 2H, J = 4.3Hz) , 4.24 - 4.40(m, 2H), 4.51- 4.60(m, IH), 4.75 - 4.86 (m, 2H), 5.14(d, 2H, J = 2.5Hz), 7.14(d, 2H, J = 7.4Hz),

7.61(t, IH, J =6.0Hz), 8.48(d, IH, J = 4.6Hz)

(c) Preparation of the title compound of this example

Following the procedure described in example If, but replacing the compound prepared in example le with the compound prepared in example 5b , the title compound of this example was obtained as a yellow solid (90 % yield).

mp : 56.9 - 60.3 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88 (t, 3H, J = 6.6Hz), 1.20 - 1.65(m, 32H), 1.73(t, 3H,

J = 7.3Hz), 2.36 - 2.54(m, IH), 2.54 - 2.65(m, IH), 2.68(s, 3H), 3.14-3.21(m, 2H), 4.18(d, 2H, J = 4.8Hz), 4.35 - 4.55 (m, 2H), 4.75(br s, IH), 4.80 - 4.92(m, 2H), 5.02(q, 2H, J

= 7.4Hz), 5.46(s, 2H), 7.78(d, IH, J = 8.1Hz), 8.01(t, 1H, J = 6.0Hz), 8.45(t, lH, J = 7.7Hz), 9.44(d, IH, J = 6.7Hz)

IR(Kbr) : 3343, 2919, 2850, 1743, 1701; 1630, 1528, 1358, 1227, 1159, 985, 773cm ^"1

Mass (FAB, m z) : 618 (M ⁺ - I)

EXAMPLE 6

2-[[N-Acetyl - N - [[[ 3-[[(octadecylcarbamoyl)oxy]methyl] - 3 - oxetanyl]methoxy] carbonyl]amino]methyl]-l - ethyl -pyridinium iodide

(a) 3, 3 - bis- (benzyloxymethyl) oxetane

To a cold (0°C )stirred solution of pentaerythritol dibenzyl etiιer(420mg) in dry tetrahydrofuran(20ml) was added slowly n-butyllithium (0.86ml, 2.73M in hexane) via a syringe, and the resulting solution was stirred for 10 min under argon atmosphere. A solution of p - toluene sulfonyl chloride (261mg) in dry tetrahydrofuran(5ml) was then added over 20min. After stirring for lh at 0°C , an equivalent of n- butyllithium(0.86ml) was added over 10 min and the reaction mixture allowed to warm to 60°C. After 2h the reaction mixture was poured into an ice-cold water and extracted with ethyl acetate. The organic layer was dried, concentrated under reduced pressure, and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = ϊ : 4) to afford 293 mg of the desired product as a colorless oil(74 % yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : ^β 3.70(s, 4 H), 4.47(s, 4 H), 4.54 (s, 4 H), 7.30 (br s, 10 H)

(b) 3, 3 - bis- (hydroxymethyl) oxetane

A mixture of the above-described compound (283mg) and palladium hydroxide on carbon (130mg) was stirred at room temperature overnight under hydrogen atmosphere(l atm). The reaction mixture was filtered and the filtrate concentrated to afford 112 mg of the desired product as a colorless oil (quantitative yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : δ 2.60(br s, 2H), 4.12(s, 4 H), 4.46(s, 4 H)

(c) 3-[[N-(Octadecylcarbamoyl)oxy]methyl] oxetane - 3 - methanol

To a cold (0° stirred solution of 3, 3 - bis- (hydroxymethyl) oxetane(222mg) in dry tetrahydrofuran (20ml) was added octadecyl isocyanate(584mg) and d en dibutyltin oxide (35mg) as the catalyst. After stirring at room temperature for 2h, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 2) to afford 554mg of the desired product as a white solid (71 % yield).

mp : 66.8 - 67.9° C

Η - NMR( 300 MHZ, CDC1 ₃ ) : ^~ 0.88 (t, 3H, J = 6.8Hz), 1.25(br s, 30H), 1.46(m, 2H),

3.03(brs, IH),3.17(q, 2H,J=6.6Hz), 3.79(s, 2H), 4.40(s, 2H), 4.45(brs,4H), 4.82(brs, IH) IR(KBr) : 3400,2921,2849, 1692, 1523, 1240, 1048,966cm ^"1

Mass (El,m/z) : 414(M ⁺ + 1 )

(d) 2-[[N -[[[3 -[[(Octadecylcarbamoyl)oxy]methyl] - 3- oxetanyl] methoxyjcarbonyl] amino] methyl] pyridine

Following the procedure described in example Id, but replacing the compound prepared in example lc with the compound prepared in example 6c , the desired compound was obtained as a light yellow solid (87 % yield).

mp : 62.7 - 63.3° C

Η - NMR( 300 MHz, CDC1 ₃ ) : 0.88(t, 3H, J = 6.8Hz), 1.25(br s, 30H), 1.48(m, 2H), 3.15

(q, 2H, J = 6.3Hz), 4.29(s, 2H), 4.33(s, 2H), 4.50(br s, 6H) 4.90(br s, IH), 6.03(br s, IH), 7.17 - 7.28(m, 2H), 7.63 -

7.69(m, IH), 8.53(d, IH, J = 4.2Hz) IR(KBr) : 3363, 2920, 2850, 1703, 1530, 1470, 1255, 1148, 1043, 770 cm ^"1

(e) 2-[[N -Acetyl -N-[[[3 -[[(octadecylcarbamoyl)oxy]methyl] - 3- oxetanyl] methoxy] carbonyl] amino] methyl] pyridine

Following the procedure described in example le, but replacing the compound prepared in example Id with the compound prepared in example 6d , the desired compound was obtained a a white solid (84 % yield).

mp : 57.5 - 58.3° C ¹ H - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.8Hz), 1.25(br s, 30H), 1.49(m, 2H), 2.64(

3H), 3.15(q, 2H, J = 6.3Hz), 4.12(s, 2H), 4.17(d, 2H, J = 6.4 Hz), 4.28(d, 2H, J = 6.4Hz), 4.37(s, 2H), 5. 8(s, 2H), 5.10(br s, IH), 7.10 - 7.16(m, 2H), 7.62(m, IH), 8.47(d, I J = 4.5Hz) IR(KBr) : 3311,2919,2849, 1740, 1695, 1535, 1352, 1214, 1078,980cm ^"1

(f) Preparation of the title compound of this example

Following the procedure described in example If, but replacing the compound prepared in example le with d e compound prepared in example 6e , the title compound of this example was obtained as a yellow solid (75 % yield).

5 mp : 48.2 - 51.1° C

Η - NMR( 300 MHz, CDC1 ₃ ) : s 0.88(t, 3H, J = 6.8Hz), 1.25 - 1.48(m, 32H), 1.73(t, 3H, J

= 7.3Hz), 2.66(s, 3H), 3.12(q, 2H, J = 6.3Hz), 4.24(s, 2H), 4.43(d, 2H, J = 6.7Hz), 4.49(d, 2H, J = 6.7Hz), 4.57(s, 2H), 5.02(q, 2H, J = 7.2Hz), 5.03(br s, IH) 5.51(s, 2H), 7.89(d, iσ, IH, J = 6.8Hz), 8.00(t, IH, J = 6.3Hz), 8.45(t, IH, J =

7.8Hz), 9.39(d, IH, J = 5.7Hz) IR(KBr) : 3361, 2919, 2849, 1717, 1527, 1467, 1353, 1226, 1155, 1085, 981, 772, 595 cm ^"1 Mass (FAB, m/z) : 746 (M ⁺ + 1 )

EXAMPLE 7

15 2-[[N- Acetyl - N - [[[ 3-[[(octadecylcarbamoyl)oxy]methyl] - 3 - oxetanyl]methoxy] carbonyl] amino]methyl]-l - ethyl -pyridinium chloride

The title compound obtained in example 6f (128mg) dissolved in 70% medianol (0.5ml) was passed through the column packed widi IRA -410 resin (5g, Cl ^" form) using the eluent ( methanol 20 : water = 7 : 3) to afford 105 mg of the title compound of this example(94% yield).

IR(KBr) : 3358, 2921, 2850, 1717, 1630, 1527, 1462, 1354, 1226, 1156, 1086, 982, 773,

598 cm ^"1 Mass (FAB, m z) : 618 (M ⁺ - Cl)

EXAMPLE 8

2-[[N- Acetyl - N - [[[ 3-[[(hexadecylcarbamoyl)oxy]methyl] - 3 - oxetanyl]methoxy] carbonyl]amino]methyl]-l - ethyl -pyridinium iodide

(a) 3, 3-Bis[[(phenoxycarbonyl)oxy]methyl] oxetane

To a cold(0°C) stirred solution of the compound prepared in example 6b (200mg) in methylene chloride(15ml) was added pyridine (0.33ml) and then phenyl chloroformate(0.47ml) . After stirring at room temperature for lh, the reaction mixture was diluted with methylene chloride, washed with water. The organic layer was dried, concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (etiiyl acetate : hexane = 1 : 3) to afford 420 mg of the desired product (78 % yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : δ 4.50( br s, 8H), 7.00-7.30 (m, 10H)

(b) 2-[[N -[[[3 -[[(Hexadecylcarbamoyl)oxy]methyl] - 3- oxetanyl] methoxy] carbonyl] amino] methyl] pyridine

A mixture of the compound prepared in example 8a(300mg) and n-hexadecyl amine (240mg) was heated in toluene (2ml) at 80° C for 6h. 2- Picolyl amine (0.2ml) was then added, and the mixture was heated at 80°C overnight. After cooling, the reaction mixture was diluted with ethyl acetate(30ml) and washed successively with 0.1N- HCl solution and water. The organic layer was dried, concentrated under reduced pressure, and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 1) to afford 160 mg of the desired product (37 % yield).

mp : 53.1 - 53.9° C

¹ H - NMR( 300 MHz, CDC1 ₃ ) : s 0.87(t, 3H, J = 6.4Hz), 1.25(br s, 26H), 1.48(br s, 2H), 3.15(q, 2H, J =6.4Hz), 4.29(s, 2H), 4.33(s, 2H), 4.50(s,

4H), 4.79(br s, IH), 5.92(br s, IH), 7.17 -7.27(m, 2H), 7.63 - 7.69(m, IH), 8.53(d, IH, J = 4.8Hz) IR(KBr) : 3362, 2920, 2850, 1702, 1530, 1256, 1042, 769 cm ^"1

(c) 2-[[N -Acetyl -N-[[[3 -[[(hexadecylcarbamoyl)oxy]methyl] - 3- oxetanyl] methoxy]carbonyl] amino] methyl] pyridine

Following the procedure described in example le, but replacing the compound prepared in example Id with the compound prepared in example 8b , the desired compound was obtained as a white solid (79 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : ^' 0.87(t, 3H, J = 6.4Hz), 1.25(br s, 26H), 1.47(br s, 2H),

2.64(s, 3H), 3.14(q, 2H, J = 6.4Hz), 4.11(s, 2H), 4.17(d, 2H, J = 6.4Hz), 4.28(d, 2H, J = 6.4Hz), 4.36(s, 2H), 5.07(s, 2H), 5.13(br s, lH), 7.10 - 7.16(m, 2H), 7.59 - 7.65(m, IH), 8.46(d, lH, J = 4.6Hz) IR(KBr) : 3310, 2920,2850, 1741, 1694, 1536, 1353, 1220, 1078,979, 774, 589cm ^"1

(d) Preparation of the tide compound of this example

Following the procedure described in example If, but replacing the compound prepared in example le with the compound prepared in example 8c , the title compound of this example was obtained as a yellow solid (37 % yield).

mp : 41.0 - 45.5° C

Η - NMR( 300 MHz, CDC1 ₃ ) : β 0.87(t, 3H, J = 6.4Hz), 1.25(br s, 26H), 1.48(br s, 2H),

1.73(t, 3H, J = 7.4Hz), 2.66(s, 3H), 3.11(q, 2H, J = 6.4Hz), 4.24(s, 2H), 4.43(d, 2H, J =6.7Hz), 4.5 l(d, 2H, J = 6.7Hz), 4.57(s, 2H), 5.02(q, 2H, J = 7.4Hz), 5.5 l(s, 2H), 7.91- 8.03(m, 2H), 8.46(t, IH, J = 7.9Hz), 9.48(d, IH, J =

5.6Hz) IR(KBr) : 3358, 2921, 2850, 1717, 1630, 1527, 1462, 1354, 1226, 1156, 1086, 982, 773 cm ^"1 Mass (FAB, m/z) : 718 (M ⁺ + 1), 590 (M ⁺ - 1)

EXAMPLE 9

2-[[N-Acetyl - N - [[[ 3-[(hexadecyloxy)methyl] - 3 - oxetanyl] methoxy] carbonyl]amino]methyl]-l - ethyl -pyridinium iodide

(a) 3-[(hexadecyloxy)methyl] oxetane -3 - methanol

To a cold(0 ^G C) 60% sodium hydride(640mg, washed previously, with hexane) suspension in dry dimethylformamide(lθml) was added 3, 3 -bis -(hydroxymethyl) oxetane (1.18g) in dry

dimethylfoπnamide(lθml). After the evoution of hydrogen gas subsided, n-hexadecyl bromide (0.65ml) in dry dimeti ylformamide(lml) was added, and the mixture was then heated at 60° C for 7h. After cooling, the reaction mixture was poured into an ice- cold water, neutralized with IN- HCl solution, and extracted with ethyl acetate. The organic layer was dried, concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 2) to afford 313 mg of the desired product as a white solid(50 % yield).

mp : 46.7 - 48.3° C

Η - NMR( 300 MHz, CDC1 ₃ ) : ^~ 0.88(t, 3H, J = 6.8Hz), 1.26(br s, 26H), 1.57(q, 2H, J = 6.7Hz), 2.47(t IH, J = 5.7Hz), 3.47(t, 2H, J = 6.4Hz), 3 .78

(s, 2H), 3.93(d, 2H, J = 5.4Hz), 4.41(d, 2H, J = 6.4Hz), 4.47

(d, 2H, J=6.0Hz) IR(KBr) : 3397, 2919, 2852, 1473, 1121, 1063, 963, 716 cm ^"1

(b) 2-[[ N-[[ 3-[(hexadecyloxy)methyl] 3-oxetanyl] methoxy] carbonyl] amino]methyl] pyridine

Following the procedure described in example Id, but replacing the compound prepared in example lc with the compound prepared in example 9a , the desired compound was obtained as a white solid( 72 % yield).

mp : 42.2 - 43.0 °C Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.8Hz), 1.26(br s, 26H), 1.55(m, 2H),

3.43(t, 2H, J = 6.4Hz), 3. 61(s, 2H), 4.31(s, 2H), 4.44 - 4.51(m, 6H), 5.94(br s, IH), 7.18(m, lH), 7.27(m, 1H), 7.65 (m, IH), 8.53(d, IH, J=4.9Hz) IR(KBr) : 3265, 2924, 2851, 1721, 1550, 1469, 1259, 981, 769 cm ^"1

(c) 2-[[ N- Acetyl - N-[[[ 3-[(hexadecyloxy)methyl] 3-oxetanyl] methoxy] carbonyl] aminojmethyl] pyridine

Following the procedure described in example le, but replacing the compound prepared in example Id with the compound prepared in example 9b , die desired compound was obtained as a light yellow oil( 94% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : ^~ 0.87(t, 3H, J = 6.9Hz), 1.25(br s, 26H), 1.49(m, 2H),

2.65(s, 3H), 3.31(t, 2H, J = 6.7Hz), 3. 39(s, 2H), 4.21(d, 2H, J =6.2Hz), 4.27 (d, 2H, J = 6.4Hz), 4.35(s, 2H), 5.08(s, 2H), 7.08 - 7.15(m, 2H), 7.58 - 7.64(m, IH), 8.48

(d, IH, J=4.4Hz)

(d) Preparation of the tide compound of this example

Following the procedure described in example If, but replacing the compound prepared in example le widi the compound prepared in example 9c , the tide compound of this example was obtained as a yellow solid ( 38% yield).

mp : 37.1 - 41.4°C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.87(t, 3H, J = 6.8Hz), 1.26(br s, 26H), 1.50(br s, 2H),

1.71- 1.77(m, 3H), 2.67(s, 3H), 3.35 - 3.45(m, 2H), 3. 63(s, 2H), 4.40(d, 2H, J = 4.0Hz), 4.42(d, 2H, J = 6.5Hz), 4.55(s, 2H), 4.99 - 5.08(m, 2H), 5.50(s, 2H), 7.85(d, IH, J = 8.1Hz),

8.02 - 8.08(m, IH), 8.46 - 8.49(m, IH), 9.53(d, IH, J =4.9Hz)

IR(KBr) : 2919, 2850, 1749, 1685, 1629, 1462, 1371, 1217, 1166, 981, 772 cm ^"1

Mass (FAB, m/z) : - 575 (M ⁺ )

EXAMPLE 10

N- [5 - [[[3-[(Hexadecyloxy)meώyl] - 3 - oxetanyl] methoxy] carbonyl] pentyl]pyridinium bromide

(a)[3-[(Hexadecyloxy) methyl]-3-oxetanyl] methyl 6-bromohexanoate

To a cold (0°C ) stirred solution of the compound prepared in example 9a (600 mg) in methylene chloride(10 ml) was added pyridine(0.2ml) and then 6-bromo hexanoyl chloride (0.32ml) , and die mixture was allowed to warm to room temperature. After stirring at room temperature for 3hrs, the reaction mixture was diluted with ethyl acetate, washed with water. The organic layer was concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 3 ) to afford 720 mg of the desired product as a light yellow solid( 79 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : s 0.88(t, 3H, J = 6.8Hz), 1.25(br s, 26H), 1.50 - 1.55(m, 4H), 1.65(m, 2H), 1.88(m, 2H), 2.37(t, 2H, J = 7.5Hz),

3.38 - 3.46(m, 4H), 3.61(s, 2H), 4.29(s, 2H), 4.45 - 4.50(m, 4H) IR (KBr) : 2925, 2856, 1739, 1461, 1249, 1116, 986, 839, 727cm ^"1

(b) Preparation of the tide compound of this example

The above-described compound (200mg) was dissolved in dry pyridine (2ml) and heated at 100° C for 3 h. After removal of excess pyridine under reduced pressure, die residue obtained was purified by flash chromatography -on silica gel (chloroform : methanol = 20 : 1) to afford 204 mg of d e tide compound (89 % yield).

mp : 46.8 - 47.4° C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.6Hz), 1.26(br s, 26H), 1.34 -1.58(m, 4H),

1.68 -1.75(m, 2H), 2.05 - 2.10(m, 2H), 2.37(t, 2H, J = 7.2Hz), 3.46(t, 2H, J = 6.5Hz) , 3.61 (s, 2H), 4.27(s, 2H), 4.49 (s, 4H), 4.74(m, 2H), 8.13(t, 2H, J = 6.8Hz), 8.54(t, IH, J = 7.8Hz), 9.12(t, 2H, J = 4.8Hz)

IR(KBr) : 3412, 2918, 2849, 1732, 1634, 1487, 1369, 1176, 1115, 974, 777, 719 cm ^"1

Mass (FAB, m/z) : 598 (M ⁺ ), 518 (M ⁺ - Br)

EXAMPLE 11

N- [5 - [[[3-[(Hexadecyloxy)methyl] - 3 - oxetanyl] methoxy] carbonyl] pentyl]thiazolium bromide

Br ^"

The compound prepared in example 10a(300mg) was dissolved in thiazole (1ml) and heated at 100°C for 3 h. After removal of excess thiazole under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (chloroform : methanol = 20 : 1) to afford 116mg of the tide compound (33% yield).

m.p. : 48.2 - 52.9° C

Η - NMR( 300 MHz, CDC1 ₃ ) : ^β 0.88(t, 3H, J = 6.7Hz), 1.25(br s, 26H), 1.43 -1.55(m,

4H), 1.66 - 1.74(m, 2H), 2.03 - 2.13(m, 2H), 2.38(t 2H, J ^; 6.6Hz), 3.44(t, 2H, J = 6.9Hz), 3.60(s, 2H), 4.26(s, 2H),

4.46(s, 4H), 4.90( t, 2H, J = 7.4Hz), 8.27(m, IH), 8.46(d,

IH, J=3.7Hz), 11.30(s,lH) IR(KBr): 3400,2919,2850, 1731, 1550, 1466, 1143,976, 839,720cm ^"1 Mass(FAB,mz) : 604(M ⁺ ), 524(M ⁺ -Br)

EXAMPLE 12

N-[ 5 - [[[ 3 -[[(Octadecylcarbamoyl)oxy]methyl] - 3 - oxetanyljmethoxy] carbonyl] pentyl] pyridinium bromide

(a)[3-[[( N -Octadecylcarbamoyl)oxy]methyl] - 3 - oxetanyl] methyl - 6- bromo hexanoate

Following the procedure described in example 10a, but replacing the compound prepared in example 9a with the compound prepared in example 6c, the compound prepared in example 6c was reacted wid 6- bromohexanoyl chloride to afford the desired compound as a white solid (76% yield).

mp :44.7-46.5°C

Η-NMR(300MHz, CDC1 ₃ ) : δ0.85(t, 3H,J=6.9Hz), 1.23(brs,30H), 1.41 - 1.53(m,4H),

1.65(m, 2H), 1.85(m, 2H), 2.34(t, 2H, J=4.5Hz), 3.15(q, 2H,J=6.4Hz), 3.37(m, 2H), 4.25(d, 4H, J= 5.4Hz), 4.43(d, 2H,J=6.4Hz), 4.48(d, 2H,J=6.4Hz),

4.70(brs, IH)

IR(KBr): 3267,2919,2850, 1732, 1690, 1557, 1407, 1265, 1170,995,721 cm ^"1

(b) Preparation of the tide compound of this example

The compound prepared in example 12a(600 mg) was dissolved in pyridine ( 2 ml) and heated at 100° C for 12 h. After removal of excess pyridine under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (chloroform : methanol = 20 : 1) to afford 600 mg of the tide compound of this example ( 88% yield).

mp : 52.1 - 59.3° C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.89(t, 3H, J = 6.8Hz), 1.27(br s, 30H), 1.43 - 1.50(m,

4H), 1.68 - 1.75(m, 2H), 2.05 - 2.10(m, 2H), 2.43(t, 2H, J= 6.9Hz), 3.12(t 2H, J = 6.9Hz), 4.25 - 4.57(m, 8H), 4.70(t, 2H, J = 7.8Hz), 8.14(t, 2H, J =6.8Hz), 8.59(t IH, J =

7.5Hz), 9.06(t 2H, J = 6.0Hz)

IR(KBr) : 3379, 2918, 2849, 1718, 1634, 1538, 1467, 1254, 1164, 982, 775, 684 cm ^"1

Mass (FAB, m/z) : 589 (M ⁺ - Br)

EXAMPLE 13

3- [5 - [[[3-[[ (Octadecylcarbamoyl)oxy] methyl] - 3 - oxetanyl] methoxy] carbonyl] pentyl] thiazolium bromide

Br ^"

The compound prepared in example 12a( 300 mg) was dissolved in thiazole ( 0. 8 ml) and heated at 100 °C for 8h. After removal of excess pyridine under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (chloroform : methanol : water = 100 :15 : 2) to afford 154 mg of die tide compound ( 45 % yield).

mp : 42.3 - 46.0° C

Η - NMR( 300 MHz, CDC1 ₃ ) : 0.88(t 3H, J = 6.7Hz), 1.25(br s, 30H), 1.35 - 1.50(m,

4H), 1.65 - 1.72(m, 2H), 2.04 - 2.09(m, 2H), 2.38(t, 2H, J= 6.6Hz), 3.15(m, 2H), 3.47(s, 2H), 3.55(s, 2H), 4.1 l(s, 4H), 4.86(t, 2H, J = 6.8Hz), 5.25(br s, IH), 8.33(d, IH, J = 2.5Hz), 8.57(d, IH, J = 2.5Hz), 10.95(br s, IH)

IR(KBr) : 3347, 2918, 2849, 1713, 1541, 1466, 1256, 1049 cm ^"1

Mass (FAB, m/z) : 675 (M ⁺ ), 595 (M ⁺ - Br)

(g) preparation of die tide compound of this example

Following the procedure described in example 11 , but replacing the compound prepared in example 10a widi die compound prepared in example 12a, the tide compound of this example was obtained as a light yellow solid(50% yield).

mp : 48.3 - 52.1°C

Η - NMR( 300 MHz, CDC1 ₃ ) : d 0.87(t, 3H, J = 6.3Hz), 1.25(s, 26H), 1.48(br s, 2H), 1.71 (t 2H, J = 3.8Hz), 1.63(s, 3H), 2.64(s, 3H), 3.11(br s,

2H), 3.73(s, 2H), 3.99 - 4.21 (m, 4H), 4.47(s, 2H), 5.12(br s, 2H), 5.35(br s, lH), 5.59(s, 2H), 7.79(d, IH, J = 7.1Hz), 7.97(br s, IH), 8.39(t, IH, J = 7.7Hz), 9.43(br s, IH)

IR(KBr) : 3410, 2924, 2853, 1706, 1635, 1526, 1460, 1363, 1226, 1160, 1087, 984, 772, 596cm ^"1

EXAMPLE 14

2-[[N-Acetyl - N - [[[ l-[[(octadecylcarbamoyl)oxy] methyl] - 1 - cyclobutyl] methoxy] carbonyl] amino] methyl] -1 - ethyl -pyridinium iodide

(a) l-[[(N-Octadecylcarbamoyl)oxy]methyl] cyclobutane - 1 - medianol

To a cold (0°C ) stirred solution of 1,1 - bis- (hydroxymethyl) cyclobutane( 167mg) in dry tetrahydrofuran (10ml) was added octadecyl isocyanate( 425 mg) and then dibutyitin oxide( 35 mg) as the catalyst After stirring at room temperature for 4 h, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 5) to afford 580mg of the desired product as a colorless solid ( 98 % yield).

mp : 46.2 -46.5°C 'H - NMR( 300 MHz, CDC1 ₃ ) : « 0.88(t, 3H, J = 6.4Hz), 1.15 - 1.75(m, 33H), 1.76 - 1.89(m,

4H), 1.89 - 1.96(m, 2H), 3.10 - 3.20(m, 2H), 3.51(s, 2H),

4.16(s, 2H), 4.72(br s, IH) IR(KBr) : 3327, 2919, 2859, 1692, 1541, 1468, 1269 cm ^"1 Mass (El, m z) : 411 (M ⁺ )

(b) 2-[[N -[[[1 -[[(Octadecylcarbamoyl)oxy]methyl] - 1-cyclobutyl] methoxy]carbonyl] amino] methyl] pyridine

Following the procedure described in example Id, but replacing the compound prepared in example lc wid die compound prepared in example 14a , the desired compound was obtained as a white solid( 90 % yield).

¹ H - NMR( 300 MHz, CDC1 ₃ ) : β 0.88(t, 3H, J = 6.3Hz), 1.10-1.55(m, 32H), 1.73 - 2.00(m,

6H), 3.12 - 3.19(m, 2H) 4.09(s, 2H), 4.12(s, 2H), 4.50(d, 2H, J = 5.3Hz), 4.72(br s, IH), 5.80(br s, lH), 7.19(d, IH, J = 7.4Hz), 7.26(d, IH, J =7.0Hz), 7.67(t, IH, J = 7.9Hz), 8.54(d, IH, J= 4.5Hz)

IR(KBr) :3346,2919,2849, 1693, 1543, 1467, 1263cm ^"1

Mass(FAB,m/z) : 546(M ⁺ + 1)

(c) 2-[[N -Acetyl -N-[[[l -[[(octadecylcarbamoyl)oxy]methyl] - 1-cyclobutyl ] methoxy] carbonyl] amino] methyl pyridine

Following the procedure described in example le, but replacing the compound prepared in example Id with the compound prepared in example 14b , the desired compound was obtained. ( 85 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88 (t, 3H, J = 6.5Hz), 1.20 - 1.60(m, 32H), 1.60-1.70 (m, 4H), 1.70 - 1.90(m, 2H), 2.65(s, 3H), 3.12 - 3.17(m,

2H), 3.90(s, 2H), 4.12(s, 2H), 5.10(s, 2H), 5.19(br t IH), 7.10(d, IH, J = 8.4Hz), 7.13(d, IH, J=5.3Hz), 7.62(t, IH, J =7.7Hz), 8.48(d, IH, J = 4.5Hz)

Mass(FAB, m/z) : 588 (M ⁺ + 1)

(d) Preparation of the tide compound of this example

Following the procedure described in example If, but replacing the compound prepared in example le with the compound prepared in example 14c , the tide compound of this example was obtained as a yellow solid ( 80 % yield).

mp : 41.8 -43.6 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.8Hz), 1.25 - 1.55(m, 32H), 1.73(t, 3H, J =

7.3Hz), 1.85(d, 4H, J = 5.6Hz), 1.96 - 2.15(m, 2H), 2.65(s, 3H), 3.07 - 3.14(m, 2H), 3.97(s, 2H), 4.33(s, 2H), 4.94(br IH), 5.06(q, 2H, J = 7.2Hz), 5.45(s, 2H), 7.89(d, IH, J = 7.8Hz), 8.07(t IH, J=6.2Hz), 8.52(t, IH, J=7.9Hz), 9.84 (d, IH, J = 6.1Hz)

IR (KBr) : 3349, 2920, 2850, 1745, 1689, 1630, 1525, 1342, 1222, 773cm ^"1

Mass (FAB, m/z) : 616(M ⁺ - I)

EXAMPLE 15 -18

Following the same procedure as described in Example 13, but replacing 1,1 - bis- (hydroxymet-hyl) cyclobutane as die starting compound with 1,1 - bis- (hydroxymethyl) cycloproane(Example 15), 1,1 - bis- (hydroxymethyl) cyclopentane(Example 16), 1,1 - bis- (hydroxymethyl) cyclohexaneQExample 17), and 1, 1 - bis- (hydroxymethyl) cycloheptane (Example 18), the corresponding tide compounds were obtained in similar overall yields.

EXAMPLE 15

2-[[N-Acetyl - N - [[[ l-[[(octadecylcarbamoyl)oxy] methyl] - 1 - cyclopropyl] methoxy] carbonyl] amino] methyl] -1 - ethyl -pyridinium iodide

mp : 38.5 - 45.5 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ0.67(s,4H), 0.88(t, 3H, J = 6.9), 1.20-1.35(m, 30H), 1.35

-1.55(m,2H), 1.75(t, 3H, J = 7.32Hz), 2.67(s,3H), 3.1 l(q, 2H, J = 6.7Hz), 3.84(s,2H), 4.20(s,2H),4.95-5.10(m, IH), 5.10(q, 2H, J = 7.3Hz), 5.46(s,2H), 7.80(d, 1H, J = 7.8hz), 8.07(t IH, J = 7.1Hz), 8.54(t, IH, J = 7.9Hz), 9.65(d, IH, J = 6.0Hz)

IR(KBr) : 3334, 2922, 2852, 1744, 1695, 1530, 1326, 1227, 1152, 1013, 768, cm ^"1

Mass (FAB, m/z) : 602(M ⁺ - I)

EXAMPLE 16

2-[[N-Acetyl - N - [[[ l-[[(octadecylcarbamoyl)oxy] methyl] - 1 - cyclopentyl] methoxy] carbonyl] amino] methyl] -1 - ethyl -pyridinium iodide

mp : 45.1 - 55.8 °C

Η - NMR( 300 MHz, CDC1 ₃ ) δ 0.88(t, 3H, J = 6.9Hz), 1.20 - 1.35(m, 30H), 1.35 - 1.50(m, 6H), 1.50 - 1.68(m, 4H), 1.75(t, 3H, J = 7.3Hz), 2.66(s, 3H), 3.05 - 3.20 (m , 2H), 3.60 (S, 2H), 4.17(s, 2H), 4.90 - 5.01(m, IH), 5.05(q, 2H, J = 7.1Hz), 5.44(s, 2H), 7.92(d, IH J = 7.8Hz), 8.09(t IH, J = 6.5Hz), 8.54(t, IH, J =

7.6Hz), 9.65(d, IH, J = 5.5Hz)

IR (KBr) : 3401, 2920, 2851, 1720, 1701, 1629, 1526, 1462, 1344, 1226, 1159, 774, cm ^"1

Mass(FAB, m/z) : 630(M ⁺ - 1)

EXAMPLE 17

2-[[N-Acetyl - N - [[[ l-[[(octadecylcarbamoyl)oxy] methyl] - 1 - cyclohexyl] methoxy] carbonyl] amino] methyl] -1 - ethyl -pyridinium iodide

mp : 74.5 - 78.5 °C

Η - NMR( 300 MHz, CDC1 ₃ ) δ 0.88(t, 3H, J = 6.9Hz), 1.20 - 1.35(m, 30H), 1.35 - 1.50(m, 8H), 1.50 - 1.68(m, 4H), 1.75(t, 3H, J = 7.3Hz), 2.66(s, 3H), 3.05 - 3.20 (m , 2H), 3.60 (s, 2H), 4.17(s, 2H), 4.90 - 5.01(m, IH), 5.05(q, 2H, J = 7.1Hz), 5.44(s, 2H), 7.92(d, IH, J = 7.8Hz), 8.09(t IH, J = 6.5Hz), 8.54(t, IH, J = 7.6Hz), 9.65(d, I H, J = 5.5Hz)

IR (KBr) : 3401, 2920, 2851, 1720, 1701, 1629, 1526, 1462, 1344, 1226, 1159, 774, cm ^"1 Mass(FAB,m/z) : 644(M ⁺ - I)

EXAMPLE 18

2-[[N-Acetyl - N - [[[ l-[[(octadecylcarbamoyl)oxy] methyl] - 1 - cycloheptyl] methoxy] carbonyl] amino] methyl] -1 - ethyl -pyridinium iodide

mp : 93.7 - 99.8 °C

¹ H - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.9Hz), 1.19 - 1.65(m, 44H), 1.75(t, 3H, J

= 7.3Hz), 2.65(s, 3H), 3.07 - 3.09(m, 2H), 4.09(s, 2H), 5.00 - 5.10(m, 3H), 5.42(s, 2H), 7.89(d, IH, J = 7.8Hz), 8.08(t,

IH, J = 6.6Hz), 8.50(t, IH, J = 7.8Hz), 9.67(d, IH, J = 6.1Hz)

IR (KBr) : 3311, 2922, 2853, 1747, 1705, 1630, 1524, 1457, 1364, 1230, 1167, 1088, 977cm ^"1

Mass(FAB, m/z) : 658(M ⁺ - 1)

EXAMPLE 19

trans-2-[[N- Acetyl - N - [[[ 3-[[(octadecylcarbamoyl)oxy] methyl] - 1 - cyclobutyl] methoxy] carbonyl] amino] methyl] -1 - ethyl -pyridinium iodide

Following the same procedure as described in Example 13, but replacing 1,1 - bis- (hydroxymethyl) cyclobutane as the starting compound with trans- 1, 3 - bis- (hydroxymethyl) cyclobutane, the tide compound of this example was obtained as a light yellow solid in a similar overall yield.

mp : 50.4 - 58.8 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.18 - 1.60(m, 32H), 1.74(t, 3H, J =

7.3Hz), 1.81 - 1.98(m, 4H), 2.50 - 2.74(m, 5H), 3.14(q, 2H, J = 6.0Hz), 4.05(d, 2H, J = 6.5Hz), 4.35(d, 2H, J = 7.5Hz), 4.88(br s, IH), 5.07(q, 2H, J = 7.4Hz), 5.42(s, 2H), 7.70(d, IH, J = 8.0Hz), 8.03 - 8.08(m, IH), 8.46(t, IH, J =

8.0Hz), 9.66(d, lH J = 5.8Hz) IR (KBr) : 3365, 2919, 2850, 1739, 1696, 1528, 1358, 1220, 775 cm ^"1 Mass(FAB, m/z) : 616(M ⁺ - 1)

EXAMPLE 20

2-[[N- Acetyl - N - [[[ l-[[(hexadecylcarbamoyl)oxy] methyl] - 1 - cyclopentyl] methoxy] carbonyl] amino] methyl] -1 - ethyl -pyridinium iodide

(a) 1 , 1 -Bis- [[(phenoxycarbonyl)oxy] methyl] cyclobutane

Following the procedure described in example 8a, but replacing the compound prepared in example 6b with 1,1 -bis- (hydroxy methyl) cyclopentane , the desired compound was obtained as a white solid ( 95 % yield). Η - NMR( 80 MHz, CDC1 ₃ ) : δ 1.32 - 1.67(m, 8H), 3.9(s, 4H), 7.25 - 7.43(m, 10H)

(b) 2-[[N -[[[1 -[[(Hexadecylcarbamoyl)oxy]methyl] - 1-cyclopentanyl] methoxy]carbonyl] amino] methyl] pyridine

Following the procedure described in example 8b, but replacing the compound prepared in example 8a with the compound prepared in example 20a , the desired compound was obtained as a white solid (35 % yield).

mp : 54.7 - 56.2°C

Η - NMR( 80 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.8Hz), 1.10 - 1.80(m, 36H), 3.00 - 3.25(m,

2H), 3.93(s, 2H), 3.98(s, 2H), 4.47(d, 2H, J=5.5Hz), 4.75 - 5.00(m, IH), 5.90 - 6.10(m, IH), 7.05 - 7.30(m, 2H), 7.50 ^■

7.68(m, IH), 8.52(d, IH, J = 4.8Hz) IR(KBr) : 3338, 2919, 2851, 1691, 1547, 1468, 1434, 1258, 1155, 1033, 996cm ^"1

(c) 2-[[N -Acetyl -N-[[[l -[[(hexadecylcarbamoyl)oxy]methyl] - 1-cyclopentanyl ] methoxy] carbonyl] amino] methyl] pyridine

Following the procedure described in example 8c, but replacing the compound prepared in example 8b widi the compound prepared in example 20b , d e desired compound was obtained as a light yellow oil. ( 80% yield).

¹ H - NMR( 80 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.9Hz), 1.10 - 1.70(m, 36H), 2.65(s, 3H), 3.00 - 3.20(m, 2H), 3.73(s, 2H), 4.00(s, 2H), 5.1 l(s, 2H),

5.1Q-5.20(m, IH), 7.05 - 7.25(m, 2H), 7.52 - 7.70(m,lH),

8.5l(d, IH, J=4.5Hz) IR(neat) : 3343,2927, 2853, 1740, 1710, 1629, 1521, 1457, 1374, 1294, 1224, 1162, 981cm ^"1

(d) Preparation of the tide compound of this example

Following the procedure described in example If, but replacing the compound prepared in example le with the compound prepared in example 20c , the title compound of this example was obtained as a yellow solid (70% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.3Hz), 1.26-1.64(m, 36H), 1.77(t, 3H, J =

7.2Hz), 2.66(s, 3H), 3.06 - 3.13(m, 2H), 3.81(s, 2H), 4.17 (s, 2H), 4.93(br s, IH), 5.08(q, 2H, J = 7.5Hz), 5.44(s, 2H), 7.88 - 7.95(m, IH), 8.10(t, IH, J = 7.7Hz), 8.53(t, IH, J = 7.9Hz), 9.71(d. 1H, J = 6.1Hz) IR(KBr) : 3346, 2926, 2853, 1743, 1712, 1593, 1529, 1465, 1354, 1289, 1213,1153, 1078cm ^"1

EXAMPLE 21

N-[4-[[[l-[[(Octadecylcarbamoyl)oxy]methyl]l-cyclopentyl] methoxy]carbonyl]butyl] pyridinium bromide

(a) l-[[(N-Octadecylcarbamoyl)oxy]methyl] cyclopentane - 1 - methanol

Following the procedure described in example 14a , but replacing l,l-bis(hydroxy methyl)cyclobutane with l,l-bis(hydroxy methyl)cyclopentane , the desired compound was obtained as a white solid ( 89% yi ld).

mp : 60.4 - 61.7°C

Η - NMR( 80 MHz, CDC1 ₃ ) : a 0.77(t, 3H, J = 7.0Hz), 1.01 - 1.24(m, 32H), 1.39 - 1.71(m,

8H), 2.96 - 3.17(m, 2H), 3.26(s, 2H), 3.98(s, 2H), 4.50-

4.80(m, IH) 5 IR(KBr) : 3318(br), 2920, 2850, 1684, 1552, 1468, 1272, 1151, 1045, 718cm ^"1 Mass ( FAB, m/z) : 426 (M ⁺ + 1)

(b)[l-[[(N-Octadecylcarbamoyl)oxy]methyl]-l-cyclopentyl] methyl - 5 - bromopentanoate

To a cold (0°C ) stirred solution of the compound prepared in example 21a (425 mg) in 10 methylene chloride(15 ml) was added pyridine(0.097ml) and tiien 5-bromo pentanoyl chloride (0.166ml) , and die mixture was allowed to warm to room temperature. After stirring for 3hrs, the reaction mixture was diluted with ethyl acetate, washed with water. The organic layer was concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 5 ) to afford 525 mg of the desired product as a white 15 solid (89 % yield).

mp _: 44.8 - 45.7°C

Η - NMR( 80 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.9Hz), 1.10 - 1.70(m, 40H), 1.71 - 2.00(m,

4H), 2.05 - 2.45(m, 2H), 3.02 - 3.20(m, 2H), 3.20 - 3.49(m, 2H), 3.95(s, 4H), 4.40 - 4.60 (m, IH) 20 IR(KBr) : 3384, 2919, 2849, 1731, 1699, 1521, 1468, 1392, 1276, 1176, 1028, 779cm ^"1

(c) Preparation of the tide compound of this example

The above-described compound (100 mg) was dissolved in dry pyridine (0.5 ml) and heated at 100°C for 16hrs. After removal of excess pyridine under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (chloroform : methanol = 10 : 1 ) to afford 25 80 mg of die tide compound as a yellow solid (71% yield).

p : 54.5 - 56.2 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.86(t, 3H, J = 6.3Hz), 1.23 - 1.78(m, 42H), 2.07 - 2.14(m,

2H), 2.40(t, 2H, J = 6.9Hz), 3.07 - 3.14(m, 2H), 3.88(s, 2H), 3.91(s, 2H), 4.77(br s, lH), 5.06(t, 2H, J=7.2Hz), 8.07(t, 2H, J=6.6Hz), 8.45(t, IH, J = 7.5Hz), 9.55(d, 2H, J= 5.1Hz)

IR (KBr) : 3326, 2919, 2851, 1726, 1700, 1547, 1473, 1260, 1171, 1048, 780, 681cm ^"1

Mass (FAB, m/z) : 587 (M ⁺ - Br)

EXAMPLE 22

3-[ 4 - [[[l-[[(Octadecylcarbamoyl)oxy]methyl]-l-cyclopentyl]methoxy ] carbonyl] butyl] thiazolium bromide

Br ^"

The compound prepared in example 21b(200mg) was dissolved in thiazole (0.5ml) and heated at 100°C for 18 hrs. After removal of excess thiazole under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (chloroform : methanol = 10 : 1) to afford 189 mg of the title compound as a yellow solid. ( 83% yield).

mp : 54.2 - 56.5°C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.7Hz), 1.25 - 1.78(m, 42H), 2.07 - 2.14(m

2H), 2.42(t, 2H, J = 6.9Hz), 3.10 - 3.16(m, 2H), 3.92(s, 2H), 3.94(s, 2H), 4.82(br s, IH), 4.85 - 4.95(m, 2H), 8.23

(br s, IH), 8.58(br s, IH), 11.36(br s, IH) IR(KBr) : 3325, 2919, 2850, 1724, 1692, 1541, 1465, 1385, 1260, 1163, 1036, 834, 722, 635cm ^" Mass (FAB, m/z) : 593 (M ⁺ - Br)

EXAMPLE 23

N-[ 4 - [[[l-[[(Octadecylcarbamoyl)oxy]methyl]l-cyclopentyl]methoxy] carbonyl] butyl]- quinolinium bromide

The compound prepared in example 10a( lOOmg) was dissolved in quinoline ( 1ml) and heated at 50°C for 8hrs. After removal of excess quinoline under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (chloroform : methanol = 10 : 1 ) to afford 72 mg of the tide compound as a purple solid. ( 60% yield).

mp : 56.2 - 59.2°C Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.84(t, 3H, J = 6.7Hz), 1.25 - 1.88(m, 42H), 2.15 - 2.22

(m, 2H), 2.41(t 2H, J = 6.9Hz), 3.05 - 3.16(m, 2H), 3.85(s, 2H), 3.87(s, 2H), 4.82(br s, IH), 5.44(m, 2H), 7.93( lH, J = 7.6Hz), 8.15 - 8.23(m, 2H), 8.37(d, IH, J = 7.5Hz), 8.48 (d, IH, J = 8.7Hz), 9.14(d, IH, J = 8.4Hz), 10.45(br s, IH) IR(KBr) : 3326, 2918, 2850, 1724, 1693, 1533, 1465, 1379, 1256, 1168, 1038, 819, 777, 722cm ^"1 Mass (FAB, m/z) : 637 (M ⁺ - Br)

EXAMPLE 24

l-[[(N-Octadecylcarbamoyloxy)methyl] cyclopentan-1-yl] metiiyl 2-pyridinioethyl phosphate (Inner salt)

(a)l-[[(N-Octadecylcarbamoyloxy)medιyl] cyclopentan-lyl] methyl 2- bromoethyl phosphate

To a cold (0°C ) stirred solution of the compound prepared in example 21a ( 150mg) in dry methylene chloride(2 ml) was added slowly dry triethyl amine( 0.1 ml) and tiien a freshly prepared 2 - bromoethyl phosphodichloridate (127 mg) , and die mixture was allowed to warm to room temperature. After stirring for 12h, the reaction mixture was diluted with methylene chloride and washed with water. The organic layer was dried, concentrated under reduced pressure and die resulting residue purified by flash chromatography on silica gel (chloroform : methanol = 8 : 1 ) to afford 214 mg of the desired product as a white solid( 85 % yield).

mp : 108.0 - 110.9 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.9Hz), 1.10 - 1.71(m, 40H), 2.95 -3.15(m,

2H), 3.53(t, 2H, J = 6.0Hz), 3.60 - 4.25(m, 6H), 5.20 - 5.40 (m, IH), 6.70 - 6.80(m, IH) IR (KBr) : 3329, 2925, 2583, 2696, 1526, 1461, 1237, 1068, 909, 803 cm ^"1 Mass (FAB, m/z) : 612 (M ⁺ )

(b) Preparation of the tide compound of tiiis example

A mixture of the above-described compound ( 154mg) and dry pyridine(0.2ml) was heated at 80° C overnight. The reaction mixture was then treated with methanol(5ml) solution of siver carbonate(250mg) and stirred for 2h at room temperature. After Alteration and concentration of the filtrate under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (chloroform : methanol : water = 65 : 25 : 4 ) to afford 82 mg of the desired product ( 54 % yield).

mp : 105.5 - 115.8 °C

^] H-NMR( 300 MHz, CD ₃ OD) : δ 0.89(t, 3H, J = 6.9Hz), 1.20 -1.65(m, 40H), 3.09(t, 2H, J =7.2Hz), 3.67(d, 2H, J = 4.3Hz), 3.89(s, 2H), 4.20 - 4.30

(m, 2H), 4.80(m, 2H), 8.07(t 2H, J = 6.9Hz), 8.54(t, IH,

J = 7.9Hz), 8.9ό(d, 2H, J = 6.0Hz)

IR (KBr) : 3375, 2918, 2851, 1694, 1526, 1473, 1239, 1085, 1052, 925, 850, 750, 681, cm ^"1 Mass (FAB, m z) : 611 (M ^* + 1)

EXAMPLE 25

l-[[(N-Octadecylcarbamoyloxy)methyl] cyclopentan-lyl] methyl 2-thiazolioethyl phosphate (Inner salt)

Following the procedure described in example 24b, the compound obtained in example 24a was reacted with thiazole to afford the title compound of this example(54% yield).

mp : 69.3 - 75.5 °C Η - NMR( 300 MHz, CDC1 ₃ + trace OMSO-d ₆ ) : a 0.88(t, 3H, J = 6.9Hz), 1.20 - 1.70(m,

40H), 3.01 - 3.09(m, 2H), 3.67(d, 2H, J = 4.2Hz), 3.91(s, 2H), 4.20 - 4.30(m, 2H), 4.93(s, 2H), 6.20 - 6.30(m, IH), 8.23(s, IH), 8.64(s, IH), 10.7 l(s, IH) IR (KBr) : 3329, 2920, 2851, 1701, 1540, 1468, 1244, 1063, 945, 846, 533 cm ^"1 Mass (FAB, m/z) : 618 (M ⁺ + 2)

EXAMPLE 26

1-[[(N-Octadecylcarbamoyloxy)methyl] cyclopentan-lyl] methyl 2-quinolinioethyl phosphate (Inner salt)

Following the procedure described in example 24b, the compound obtained in in example 24a was reacted widi quinoline to afford the tide compound of this example(50% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.89(t, 3H, J=6.9Hz), 1.20 - 1.70(m, 40H), 3.01 - 3.09(m,

2H), 3.57(d, 2H, J = 4.3Hz), 3.80(s, 2H), 4.38 - 4.45(m, 2H), 5.35(t, 2H, J = 4.8Hz), 8.03(t, 2H, J =7.5Hz), 8.15(dd,

IH, J = 8.4Hz, J = 5.9Hz), 8.27(t, IH, J = 7.0Hz), 8.38(d,

IH, J =8.0Hz), 8.57(d, 1H, J = 9.0Hz), 9.15(d, IH, J =

8.3Hz), 9.45(d, J = 5.6Hz)

EXAMPLE 27

trans-2-[[N-Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methy l]-2-thietanyl]methoxy]carbonyl]- amino]methyl]- 1-ethyl-pyridinium chloride

(a) trans- 2, 4 - Bis[(carbomethoxy)methyl] thietane and its cis isomer

To a stirred solution of 2,4-dibromoglutarate(15.30g)in methylene chloride( 120ml) was added slowly sodium sulfide (11.50g) in dry dimethyl sulfoxide(80ml) at - 30°C. The mixture was stirred for lh, and concentrated under reduced pressure, diluted widi ethyl acetate and washed with an ice-cold water. The organic layer was dried, concentrated under reduced pressure and die resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 9 ) to afford 2.50g of trans isomer and 2.40g of cis isomer as a colorless oil ( 51 % yield).

trans isomer : ^! H - NMR( 300 MHz, CDC1 ₃ ) : a 3.31(t, 2H, J = 7.3Hz), 3.77(s, 6H), 4.13(t,

2H, J = 7.4Hz) Mass(EI, m/z) : 190( M ⁺ )

cis is er : Η - NMR( 300 MHz, CDC1 ₃ ) : δ 3.05 (dt, IH, J=12.9Hz, J = 8.7Hz), 3.61(dt,

IH, J =12.9Hz, J = 7.5Hz), 3.75(s, 6H), 4.13(t, 2H, J = 7.9Hz)

Mass(EI, m/z) : 190( M ⁺ )

O ) trans -2, 4 -Bis-(hydroxymethyl) diietane

To a stirred soution of the above-described compound(1.50g) in dry ethyl ether(50ml) was added lithium borohydride(0.35g), and the mixture was stirred at room temperature overnight. The reaction was quenched by adding an ice- cold water(5ml), and the aqueous layer was extracted widi ethyl acetate. The combined organic layer was dried, concentrated under reduced pressure, and die resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 2 : 1) to afford 0.93g of the desired product as a white solid(88 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 2.13(br s, 2H), 2.77(t, 2H), 3.7 l(m, 6H) IR(KBr): 3220, 2940, 2830, 1462, 1309, 1242, 1040, 981, 701 cm ^"1

(c) trans -2, 4 -Bis-[[(phenoxycarbonyl)oxy]methyl] thietane

Following the procedure described in example 8a , the diol compound prepared in example 27 (0.81g) in methylene chloride(20ml) was reacted with two equivalents of phenyl chloro formate(l.70ml) in the presence of pyridine( 1.3ml) to afford 2.0g of die desired compound as a white solid( 88% yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : a 2.88 (t, 2H,J = 7.2Hz), 3.86(q, 2H, J = 6.8Hz), 4.42 (dd,

2H, J = 11.0Hz, J = 6.1Hz), 4.53(dd, 2H, J = 11.3Hz, J = 6.9Hz), 7.17 - 7.41 (m, 10H)

IR(KBr): 2952, 1761, 1492, 1386, 1232, 1061, 964, 772cm ^"1

(d) trans-2-[[N-[[[4-[[(Octadecylcarbamoyl)oxy]methyl]-2-thietan yl]methoxy]carbonyl]- amino]methyl]pyridine

Following the procedure described in example 8b , but replacing the compound prepared in example 8a with die compound prepared in example 27c , the desired compound was obtained as a white solid( 46% yield).

mp : 121.3 -122.1 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.20 - 1.40(m, 30H), 1.40 - 1.60(m,

2H), 2.71(app t, 2H, J = 7.0Hz), 3.15 (q, 2H, J = 6.4Hz),

3.67 - 3.76(m, 2H), 4.16 - 4.26(m, 2H), 4.28 -4.43(m, 2H), 4.49(d, 2H, J = 5.2Hz), 4.69(br s, IH), 5.85(br s, IH),

7.17 - 7.28(m, 2H), 7.66(t IH, J = 7.7Hz), 8.53(d, IH, J

= 5.0Hz) IR(KBr) : 3324, 2921, 2851, 1686, 1539, 1463, 1258, 1144, 1050, 647 cm ^"1

(e)trans-2-[[N-Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]me thyl]-2- thietanyl]methoxy]carbonyl]-amino]metiιyl]pyridine

Following the procedure described in example le , but replacing the compound prepared in example Id with the compound prepared in example 27d , die desired compound was obtained as a white solid( 88% yield).

'H - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.4Hz), 1.20 - 1.40(m, 30H), 1.40 - 1.60(m, 2H), 2.47 - 2.55(m, 2H), 2.62(s, 3H), 3.13(q, 2H, J =

6.4Hz), 3.54 - 3.61(m, 2H), 4.12 - 4.43(m, 4H), 4.80(br s, IH), 5.08(s, 2H), 7.09 - 7.15(m, 2H), 7.60(app t IH, J = 7.7Hz), 8.49(d, IH, J = 4.9Hz)

( preparation of the title compound of this example

A mixture of the compound prepared in example 27e (109mg) and ethyl iodide(0.5ml) was heated at 80 °C in acetonitrile(0.5ml) for 10 h , while shielded from light. The mixture was concentrated under reduced pressure, and the resulting crude was eluted dirough the column packed with IRA -410 resin (5g, Cl ^' form) using die eluent ( methanol : water = 7 : 3). The residue obtained after evaporation of the solvent was then purified by flash chromatography on silica gel (methanol : methylene chloride = 1 : 10) to afford 94mg of the title compound of this example as a light yellow solid( 78% yield).

mp : 51.9 - 54.7 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.5Hz), 1.20 - 1.60(m, 32H), 1.73(t, 3H, J =

7.2Hz), 2.66 - 2.72(m, 5H), 3.10 - 3.22(m, 2H), 3.50 - 3.80 (m, 2H), 4.12 - 4.56(m, 4H), 5,10 - 5.40(m, 3H), 5.48(s,

2H), 7.65(d, IH, J = 8.0Hz), 8.00 - 8.15(m, IH), 8.39(t, IH, J

=8.3Hz), 9.99(d, IH,J=4.8Hz) IR(KBr) : 3385,2920,2851, 1744, 1694, 1631, 1530, 1357, 1226,988,775 cm ^"1 Mass(FAB, m/z) : 634(M ⁺ - Cl )

EXAMPLE 28

cis-2-[[N-Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl] -2-thietanyl]methoxy]carbonyl]- amino]methyl]-l-edιyl-pyridinium chloride

(a) cis -2, 4 -Bis-(hydroxymethyl) thietane

Following the procedure described in example 27b, but replacing the compound prepared in example trans-27a with the compound prepared in example cis-27a , the desired compound was obtained as a white solid (70 % yield).

^] H - NMR( 80 MHz, CDC1 ₃ ) : a 2.45 - 3.08(m, 4H), 3.44 - 3.94(m, 6H) IR(KBr) : 3346(br), 2925, 2858, 1648, 1461, 1357, 1060, 1016, 838cm ^"1

(b) cis -2, 4 -Bis-[[(phenoxycarbonyl)oxy]methyl] thietane

Following the procedure described in example 27c, but replacing die compound prepared in example 27b widi the compound prepared in example 28a , the desired compound was obtained as a white solid (82% yield).

'H - NMR( 80 MHz, CDC1 ₃ ) : a 2.33 - 3.33(m, 2H), 3.72 - 4.65(m, 6H), 7.09 -7.51 (m, 10H)

(c)cis-2-[[N-[[[4-[[(Octadecylcarbamoyl)oxy]methyl]-2-thieta nyl]medιoxy]carbonyl]- amino]methyl]pyridine

Following the procedure described in example 27d, but replacing the compound prepared in example 27c with the compound prepared in example 28b , the desired compound was obtained as a light yellow solid ( 37% yield)

mp : 103.4 - 106.3°C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88 (t, 3H, J = 6.6Hz), 1.15 - 1.55(m, 32H), 2.40 - 2.44(m,

IH), 2.97 - 3.01(m, IH), 3.10 - 3.20(m, 2H), 3.75 - 3.79(m, 2H), 4.10 - 4.39(m, 4H), 4.49(d, 2H, J = 4.9Hz), 4.87( br s,

IH), 5.90(br s, IH), 7.16 - 7.28(m, 2H), 7.66(t, 1H, J =

7.6Hz), 8.53(d, IH, J = 4.5Hz) IR(KBr) : 3334, 2920, 2850, 1689, 1537, 1464, 1258, 1142, 1048, 990, 770, 639cm ^"1

(d) cis-2-[[N-Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl]-2- thietanyl]methoxy]carbonyl]- amino]methyl]pyridine

Following the procedure described in example 27e, but replacing the compound prepared in example 27d widi the compound prepared in example 28c , the desired compound was obtained as a white solid (89 % yield).

mp : 64.4 - 67.2°C

'H - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.6Hz), 1.21 - 1.55(m, 32H), 2.20 - 2.29(m,

IH), 2.62(s, 3H), 2.73 - 2.80(m, IH), 3.12 - 3.18(m, 2H), 3.63 - 3.75(m, 2H), 3.96 - 4.40(m, 4H), 4.87( br s, IH), 5.10(s, 2H), 7.09 - 7.16(m, 2H), 7.62(t, IH, J =7.6Hz), 8.50(d, IH, J =4.8Hz)

IR(KBr) : 3347, 2920, 2850, 1734, 1695, 1529, 1469, 1304, 1216, 1153, 1084, 1040, 981cm ^"1

(e) preparation of the title compound of this example

Following die procedure described in example 27f, but replacing the compound prepared in example 27e with the compound prepared in example 28d , the title compound of this example was obtained as a white solid (73 % yield).

Η-NMR( 300MHz, CDC1 ₃ ) : δ0.88(t, 3H,J=6.6Hz), 1.21 - 1.57(m, 32H), 1.72(t, 3H, J=

6.8Hz), 2.23 - 2.45(m, IH), 2.65(s, 3H), 2.93 - 3.20(m, 3H), 3.59 -4.05(m, 3H), 4.14-4.57(m, 3H), 5.10- 5.19(m, 2H), 5.47(s,2H), 7.66- 7.69(m, IH), 8.01 - 8.06(m, IH), 8.42(t, IH,J=7.8Hz), 9.78(d, IH,J=6.2Hz)

IR(KBr) : 3367,2919,2850, 1736, 1715, 1708, 1631, 1530, 1357, 1226, 988,774cm ^"1

Mass(FAB, m/z) : 634( M ⁺ - Cl )

EXAMPLE 29

U.'ans-2-[[N-Acetyl-N-[[[4-[[(hexadecylcarbamoyl)oxy]meth yl]-2-thietanyl]methoxy]carbonyl]- amino]methyl]-l-edιyl-pyridinium chloride

C16H33 CO— v

(a)trans-2-[[N-[[[4-[[(hexadecylcarbamoyl)oxy]methyl]-2-thie tanyl]methoxy]carbonyl]- amino]methyl]pyridine

Following the procedure described in example 27d , but replacing octadecyl amine with hexadecyl amine , the desired compound was obtained as a white solid (49% yield).

mp : 118.2 - 119.7 °C

^■ H - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.4Hz), 1.20 - 1.40(m, 26H), 1.40 - 1.55(m,

2H), 2.71(app t, 2H, J = 7.0Hz), 3.15(q, 2H, J = 6.4Hz),

3.66 - 3.76(m, 2H), 4.16 - 4.28(m, 2H), 4.32 - 4.43(m, 2H), 4.49(d, 2H, J = 5.2Hz), 4.71(br s, IH), 5.86(br s, IH), 7.17

7.27 (m, 2H), 7.66(app t, IH, J = 7.7Hz), 8.53(d, IH, J =

5.0Hz) IR(KBr) : 3324, 2922, 2852, 1686, 1539, 1463, 1258, 1144, 1050, 771, 648, cm ^"1

(b) trans-2-[[N-Acetyl-N-[[[4-[[(hexadecylcarbamoyl)oxy]methyl]- 2-thietanyl] methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example le , but replacing the compound prepared in example Id widi the compound prepared in example 29a , the desired compound was obtained as a white solid(80 % yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 0.65Hz), 1.18 - 1.40(m, 26H), 1.40 - 1.55(m,

2H), 2.46 - 2.55(m, 2H), 2.62(s, 3H), 3.11 - 3.15 (m, 2H), 3.54 - 3.61(m, 2H), 4.13 - 4.43(m, 4H), 4.77(br s, IH), 5.08 (s, 2H), 7.09 - 7.15 (m, 2H), 7.60(app t, IH, J = 7.8Hz), 8.49(d, IH, J = 4.5Hz)

IR(KBr) : 3358, 2921, 2851, 1740, 696, 1527, 1459, 1384, 1341, 1221, 1149, 1074, 985 cm ^"1

(c)preparation of the title compound of this example

Following the procedure described in example 27f , but replacing die compound prepared in example 27e with the compound prepared in example 29b , the title compound of this example was obtained as a white solid(75% yield).

mp : 45.6 -50.4°C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.8Hz), 1.20 - 1.55(m, 28H), 1.72(t, 3H, J =

7.2Hz), 2.64 - 2.75(m, 5H), 3.10 - 3.25(m, 2H), 3.50 - 3.90 (m, 2H), 4.10 - 4.60(m, 4H), 5.10 - 5.30(m, 3H), 5.48(s, 2H), 7.66(d, IH, J=7.9Hz), 8.02 - 8.06(m, IH), 8.38 - 8.44 (m,

IH), 9.97(d, IH, J=4.5Hz)

IR(KBr) : 3379, 2919, 2850, 1729, 1696, 1530, 1223, 774 cm ^"1 Mass(FAB, m/z) : 606( M ⁺ - Cl )

EXAMPLE 30

trans-2-[[N - ( 2-Methoxy)benzoyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl]-2 - thietanyl] methoxy] carbonyl] amino] -1-ethyl-pyridinium chloride

(a) trans-2-[[N - ( 2-methoxy)benzoyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl]-2 - thietanyl]methoxy] carbonyl]amino]methyl]pyridine

To a cold (0°C) stirred solution of the compound prepared in example 27d(220mg) in metiiylene chloride(3ml) was added triethylamine(56μi) and then o -methoxy benzoyl chloride (65μi) and die mixture was allowed to warm to room temperature . After stirring overnight, die reaction mixture was diluted widi methylene chloride, washed successively with IN- HCl solution and water. The organic layer was dried, concentrated under reduced pressure, and die resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 1) to afford 266mg of the desired product as a white solid(95 % yield).

'H - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.20 - 1.40(m, 30H), 1.40 - 1.55(m,

2H), 2.28 - 2.33(m, IH), 2.37 - 2.42(m, IH), 3.11 - 3.18(m, 2H), 3.25 - 3.30(m, IH), 3.84(s, 3H), 4.08 - 4.16(m, 2H), 4.20 - 4.27(d, IH, J = 8.2Hz), 7.00(t IH J = 7.5Hz), 7.13 - 7.18(m, IH), 7.33 - 7.47(m, 3H), 7.64(app t IH, J = 7.6Hz),

8.54(d, lH, J = 4.9Hz)

(b)Preparation of the tide compound of this example

Following the procedure described in example 27f , but replacing die compound prepared in example 27e widi die compound prepared in example 30a , die desired compound was obtained as a white solid(71% yield).

mp : 55.8 - 58.9 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.5Hz), 1.19 - 1.55(m, 32H), 1.79(t, 3H, J =

7.1Hz), 2.25 - 2.55(m, 2H), 3.10 - 3.25(m, 2H), 3.30 - 3.55 (m, 2H), 3.92(s, 3H), 3.93 - 4.34(m, 4H), 5.01(br s, IH), 5.25(q, 2H, J = 7.0Hz), 5.55(s, 2H), 6.95(d, IH, J = 8.4Hz), 7.04 - 7.09(m, IH), 7.44 - 7.53(m, 2H), 8.03 - 8.1 l(m, 2H), 8.41 - 8.47(m, IH), 10.24(d, IH, J = 5.8Hz)

IR(KBr) : 3357, 2923, 2852, 1731, 1695, 1630, 1525, 1458, 1344, 1233, 1151, 977, 768, cm ^"1

Mass(FAB,m/z) : 726(M ⁺ -Cl )

EXAMPLE 31

trans-2-[[N - ( 2-Methoxy)benzoyl-N-[[[4-[[(hexadecylcarbamoyl)oxy]methyl]-2 - thietanyl] methoxy] carbonyl] amino] methyl] 1-ethyl-pyridinium chloride

(a) trans-2-[[N - ( 2-Medιoxy)benzoyl-N-[[[4-[[(hexadecylcarbamoyl)oxy]methyl]- 2- dιietanyl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example 30a , but replacing the compound prepared in example 27d with the compound prepared in example 29a , the desired compound was obtained as a white solid(91% yield).

¹ H - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9hz), 1.20 - 1.40(m, 26H), 1.40 - 1.55(m,

2H), 2.27 - 2.33(m, IH), 2.39 - 2.43(m, IH), 3.11 - 3.15(m, 2H), 3.25 - 3.30(m, IH), 3.40 - 3.60(m, IH), 3.83(s, 3H), 4.07 - 4.26(m, 4H), 4.71(br s, IH), 5.22(s, 2H), 6.90(d, IH, J = 8.3Hz), 7.00(app t IH, J = 7.2Hz), 7.13 - 7.17(m, IH),

7.33 - 7.47(m, 3H), 7.65(app t IH, J =7.6Hz), 8.54(d, IH, J = 4.3Hz)

(b)Preparation of die title compound of this example

Following the procedure described in example 27f , but replacing the compound prepared in example 27e with die compound prepared in example 31a , the desired compound was obtained as a white solid(76% yield).

mp : 92.5 - 93.8 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.6Hz), 1.19 - 1.65(m, 28H), 1.79(t, 3H, J =

7.3Hz), 2.29 - 2.54(m, 2H), 3.05 - 3.20(m, 2H), 3.30 - 3.55 (m, 2H), 3.91(s, 3H), 4.02 - 4.34(m, 4H), 5.01(br s, IH), 5.24(q, 2H, J = 7.3Hz), 5.55(s, 2H), 6.95(d, IH, J = 8.4Hz), 7.04 - 7. 10(m, IH), 7.44 - 7.53(m, 2H), 8.03 - 8.1 l(m, 2H),

8.41 - 8.47 (m, IH), 10.19(d, IH, J=6.3Hz) IR(KBr) : 3370, 2920, 2851, 1729, 1696, 1601, 1527, 1461, 1343, 1234, 1151, 1017, 977 cm ^"1 Mass(FAB, m/z) : 698(M ⁺ - Cl)

EXAMPLE 32

trans- 2-[[N - Acetyl-N-[[[4-[(hexadecyloxy)methyl]-2-thietanyl]methoxy] carbonyl] amino] methyl] -1-ethyl-pyridinium chloride

(a) trans-4-[(Hexadexyloxy)methyl]thietane-2-methanol

To a stirred suspension of 60% sodium hydride( 230mg), washed previously widi pentane, in dry dimethyl formamide(10ml)was added slowly trans -2,4-bis(hydroxymethyl) thietane dissolved in dry dimethyl formamide(lml) at 0°C. After lOmin, l-bromohexadecane( 1.4ml) was added, and the reaction mixture was then allowed to warm to 50°C and stirred overnight.

The reaction was quenched by adding saturated ammonium chloride solution and extracted widi etiiyl acetate. The organic layer was dried, concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 2) to afford 617mg of die desired product as a white solid(51 % yield).

mp : 48.7 - 50.0°C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.6Hz), 1.21 - 1.39(m, 26H), 1.52 - 1.59(m,

2H), 2.21(br s, IH), 2.64 - 2.80(m, 2H), 3.46(t, 2H, J = 6.6Hz), 3.59 - 3.72(m, 6H) IR(KBr) : 3307(br), 2920, 2848, 1469, 1368, 1302, 1125, 1027, 965, 718cm ^"1

(b)trans-2-[[N-[[[4-[(Hexadecyloxy)methyl]-2-thietanyl] methoxy] carbonyl] amino] methyl] pyridine

Following the procedure described in example Id , but replacing the compound prepared in example lc widi die compound prepared in example 32a , die desired compound was obtained as a white solid(90% yield).

mp:76.1-77.8°C

Η-NMR(300MHz, CDC1 ₃ ) : a0.88(t,3H,J=6.6Hz), 1.16- 1.41(m,26H), 1.51 - 1.58(m,

2H), 2.69(t, 2H,J=6.3H), 3.45(t,2H,J= 6.9Hz), 3.58 - 3.72

(m,4H), 4.23-4.44(m,2H), 4.49(d,2H,J=5.1Hz), 5.79(br s, IH), 7.17-7.28(m,2H), 7.66(t, IH,J=7.8Hz), 8.53(d, IH,

J=4.8Hz)

IR(KBr) : 3346, 2918, 2850, 1681, 1558, 1542, 1508, 1457, 1261, 1121, 1054,766, 719cm ^"1

(c) trans-2-[[N - Acetyl-N-[[[4-[(hexadecyloxy)methyl]-2-dιietanyl]methoxy] carbonyl] amino] methyl]pyridine

Following the procedure described in example le , but replacing the compound prepared in example Id with the compound prepared in example 32b , the desired compound was obtained as a white solid(81% yield).

mp : 52.6 - 55.3°C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ0.88(t, 3H, J = 6.6Hz), 1.18 - 1.39(m, 26H), 1.52 - 1.56(m,

2H), 2.49 - 2.54(m, 2H), 2.62(s, 3H), 3.42(t, 2H, J = 6.6Hz), 3.52 - 3.63(m, 4H), 4.26 - 4.44(m, 2H), 5.08(s, 2H), 7.09 -

7.14(m, 2H), 7.60(t, IH, J = 7.8Hz), 8.49(d, IH, J = 4.6Hz) IR(KBr) : 2923, 2851, 1740, 1698, 1592, 1471, 1436, 1379, 1340, 1283, 1119, 1074, 981cm ^"1

(d) preparation of the title compound of this example

Following the procedure described in example 27f , but replacing the compound prepared in example 27e with the compound prepared in example 32c, the tide compound of this example was obtained as a white solid(75% yield)

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.6Hz), 1.19 - 1.32(m, 26H), 1.53 - 1.62(m,

2H), 1.73(t, 3H, J = 7.2Hz), 2.50 - 2.75(m, 5H), 3.40 - 3.67

(m, 6H), 4.44 - 4.57(m, 2H), 5.19(q, 2H, J = 7.2Hz), 5.45(s, 2H), 7.68 - 7.7 l(m, IH), 8.02 - 8.07 (m, IH), 8.36 - 8.47(m,

IH), 10.05(d, IH, J = 6.3Hz)

IR(KBr) : 2921, 2852, 1743, 1686, 1630, 1582, 1455, 1368, 1166, 1098, 982, 898cm ^"1

Mass(FAB, m/z) : 563(M ⁺ - Cl)

EXAMPLE 33

trans-2-[[N - (2-Methoxy)benzoyl-N-[[[4-[(hexadecyloxy)methyl]-2-thietanyl ]methoxy] carbonyl]amino]methyl]- 1 -ethyl-pyridinium chloride

(a)trans-2-[[N - (2-Medιoxy)benzoyl-N-[[[4-[(hexadecyloxy)methyl]-2-thietany l]methoxy] carbonyl] amino]methyl]pyridine

Following the procedure described in example 30a , but replacing the compound prepared in example 27d widi the compound prepared in example 32b , the desired compound was obtained as a light yellow oil (79% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.6Hz), 1.20 - 1.32(m, 26H), 1.51 - 1.56(m,

2H), 2.27 - 2.46(m, 2H), 3.24^ 3.58(m, 7H), 3.84(s, 3H), 4.11 - 4.27(m, 2H), 5.22(s, 2H), 6.89(d, IH, J = 8.3Hz), 7.00 (t, IH, J = 7.5Hz), 7.13 - 7.47(m, 3H), 7.64(t, IH, J = 7.8Hz), 8.55(d, lH, J = 4.5Hz)

IR(neat) : 2928,2854, 1714, 1671, 1598, 1463, 1437, 1390, 1346, 1249, 1112, 981, 908cm ^"1

(b)preparation of die title compound of this example

Following die procedure described in example 27f , but replacing the compound prepared in example 27e with the compound prepared in example 33a , the tide compound of mis example was obtained as a white solid(77% yield).

'H - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.6Hz), 1.21 - 1.35(m, 26H), 1.52 - 1.58(m,

2H), 1.78(t, 3H, J = 6.9Hz), 2.21 - 2.55(m, 2H), 3.29 - 3.59 (m, 6H), 3.92(s, 3H), 4.21 - 4.30(m, 2H), 5.25(q, 2H, J = 7.2Hz), 5.54(s, 2H), 6.94(d, IH, J = 8.4Hz), 7.06(t, IH, J = 7.4Hz), 7.44 - 7.5 l(m, 2H), 8.03 - 8.15(m, 2H), 8.46(t, IH, J = 7.5Hz), 10.23(d, IH, J = 5.9Hz)

IR(neat) : 2923, 2853, 1742, 1671, 1630, 1601, 1489, 1335, 1249, 1136, 1018, 977, 889cm ¹ Mass(FAB, m/z) : 655(M ⁺ - Cl)

EXAMPLE 34

trans-N-[4-[[[4-[[(Octadecylcarbamoyl)oxy]methyl]-2-thiet anyl]methoxy]carbonyl]butyl] quinolinium bromide

(a) trans-[4-[[Octadecylcarbamoyl)oxy]methyl]-2-thietanyl]methyl 5 - bromopentanoate

Following the procedure described in example 21b , but repl cing the compound prepared in example 21a with trans-4-[[N-Octadecylcarbamoyl)oxy]methyl]thietane-2-methano l , the desired compound was obtained as a white solid(97% yield).

mp : 80.7 - 81.8°C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.20 - 1.40(m, 30H), 1.45 - 1.55(m,

2H), 1.75 - 1.96(m, 4H), 2.37(t, 2H, J = 7.3Hz), 2.68 - 2.74(m, 2H), 3.15(q, 2H, J = 6.6Hz), 3.4 l(t 2H, J = 6.4H), 3.66 - 3.76 (m, 2H), 4.17 - 4.25(m, 2H), 4.33 - 4.42(m, 2H), 4.65(br s,

IH)

IR(KBr) : 3334, 2920, 2849, 1737, 1689, 1535, 1464, 1252, 1160, 1031, 777, 723, 641 cm ^"1

(b)preparation of the title compound of this example

Following the procedure described in example 23 , but replacing the compound prepared in 0 example 21b widi the compound prepared in example 34a , the title compound of this example - was obtained as a light purple solid(75% yield).

mp : 55.3 - 57.8 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.8Hz), 1.19 - 1.51 (m, 32H), 1.89 - 1.97(m,

2H), 2.17 - 1.25(m, 2H), 2.48(t, 2H, J = 6.9Hz), 2.66 - 2.72 5 (m, 2H), 3.11 - 3.18(m, 2H), 3.63 - 3.7 l(m, 2H), 4.14 - 4.36

(m, 4H), 4.85,(br s, IH), 5.5 l(t, 2H, J = 7.7Hz), 7.97(t, IH, J = 7.6Hz), 8.15 - 8.36(m, 2H), 8.30(d, IH J =7.4Hz), 8.46(d, lH, J=9.0Hz), 9.01(d, lH, J=8.4Hz), 10.72(d, IH, J=5.7Hz) IR(KBr) : 3370, 2920, 2850, 1729, 1690, 1530, 1466, 1375, 1250, 1161, 761cm ^"1 0 Mass(FAB, m/z) : 641(M ⁺ - Br)

EXAMPLE 35

trans-N- [4- [ [4- [[ (Octadecylcarbamoyl)oxy] methyl] -2-thietany 1] medioxy] butyl] quinolinium bromide

(a)trans-N-[4-[4-[[(Octadecylcarbamoyl)oxy]methyl]-2-dιieta nyl]methoxy] butyl bromide

To a cold (5°C) stirred solution of trans-4-[[N-Octadecylcarbamoyl)oxy]methyl]thietane-2- methanol (lOOmg) in dimediyl sulfoxide (2ml) was added potassium hydroxide(20mg) and then l,4-dibromobutane(0.036ml) at room temperature. After stirring for 12h, the reaction mixture was diluted with ethyl acetate , washed successively with IN- HCl solution and water. The organic layer was dried, concentrated under reduced pressure, and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 5) to afford 60mg of die desired product as a colorless oil(46 % yield).

¹ H - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.2Hz), 1.25(s, 30H), 1.55(m, 4H), 1.77(m,

4H), 2.67(m, 2H), 3.10(q, 2H, J = 6.4Hz), 3.43(q, 4H, J = 6.4Hz), 3.64(br s, 4H), 4.28(t 2H, J = 5.6Hz), 4.65(br s, IH).

(b)Preparation of the tide compound of this example

Following the procedure described in example 23 , but replacing the compound prepared in example 21b with die compound prepared in example 35a , the desired compound was obtained as a yellow solid(76% yield).

mp : 46.3 - 48.1°C

H - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.2Hz), 1.25(br s, 30H), 1.48(br s, 2H), 1.88

(m, 2H), 2.27(m, 2H), 2.67(t 2H, J = 6.8Hz), 3.13(q, 2H, J = 6.3Hz), 3.61 - 3.75(m, 6H), 4.20 - 4.36(m, 4H), 4.85(br s,

IH), 5.48(t, 2H, J = 8.0Hz), 7.96(t, IH, J = 7.6Hz), 8.15 - 8.29 (m, 3H), 8.41(d, IH, J = 9.0Hz), 8.95(d, IH, J = 8.4Hz), 10.71 (d, IH, J = 5.4Hz). IR(KBr) : 3401, 2919, 2850, 1707, 1530, 1463, 1377, 1266, 1121, 775cm ^"1 Mass(FAB, m z) : 613(M ⁺ - Br)

EXAMPLE 36

2-[[N - Acetyl-N-[[[3-[[(octadecylcarbamoyl)oxy]methyl]-3-thietanyl] methoxy] carbonyl] amino] methy 1] - 1 -ethyl -pyridinium iodide

(a) Isopropylidene ketal of 3, 3 - bis-(hydroxymethyl)thietane

To a stirred solution of 5, 5 - bis(bromomethyl)-2, 2 -dimethyl - 1, 3 - dioxane(5.00g) in dimethyl sulfoxide (30ml) was added sodium sulfideO^S ' 9H ₂ 0, 0.32g) at room temperature. After stirring for 3h, the reaction mixture was diluted with ethyl acetate , washed with brine and water. The organic layer was dried, concentrated under reduced pressure and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 5) to afford 2.50g of the desired product as a viscous solid (87 % yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : a 1.37(s, 6H), 2.95(s, 4H), 3.86(s, 4H)

IR(KBr) : 2997, 2937, 2860, 1445, 1379, 1185, 1114, 1050, 929, 824, 730, 660, 516cm ^"1

(b) 3, 3 - Bis-(hydroxymethyl)dιietane

<X

The above-described acetonide compound(0.50g) dissolved in ethyl acetate(20ml) containing water(O.lml) and trace 1N-HC1 was stirred at room temperature for lh. The reaction mixture was diluted with ethyl acetate , washed with 10 % sodium bicarbonate solution and brine.

The organic layer was dried, concentrated under reduced pressure, and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 5) to afford 0.30g of the desired product as a white solid (98 % yield).

mp : 69.1 - 69.8°C ¹ H - NMR( 80 MHz, CDC1 ₃ + trace DMSO- d6) : a 2.89(s, 4H), 3.63(d, 4H, J = 5.6Hz),

4.32(t, 2H, J = 5.6Hz) IR(KBr) : 3247, 2931, 1452, 1356, 1100, 1123, 1023, 690, 586cm ^"1

(c) 3-[[(N-Octadecylcarbamoyl)oxy]methyl]thietane -3 -methanol

Following the procedure described in example 14a , but replacing 1,1-bis-

(hydroxymethyl)cyclobutane with die compound prepared in example 36b , the desired compound was obtained as a white solid(84% yield).

mp : 55.9 - 57.3 °C

^! H - NMR( 80 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 5.6Hz), 1.25(s, 32H), 2.91 (s, 4H), 3.12(q, 2H, J = 7.2Hz), 3.61 (d, 2H, J = 5.4Hz), 4.30(s, 2H), 4.78(m, IH)

IR(KBr) : 3400, 2922, 2851, 1710, 1538, 1464, 1255, 1044, 721cm ^"1

(d) 2-[[N-[[[3-[[(Octadecylcarbamoyl)oxy]methyl]-3-thietanyl]met hoxy]carbonyl]amino]- methyl]pyridine

Following the procedure described in example Id , but replacing the compound prepared in example lc widi the compound prepared in example 36c , the desired compound was obtained as a white solid(89% yield).

mp : 54.1 - 56.5 °C

H - NMR( 80 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 5.6Hz), 1.25(s, 32H), 2.99(s, 4H), 3.11(q, 2H,

J = 7.2Hz), 4.20(s, 2H), 4.24(s, 2H), 4.45(d, 2H, J = 5.6Hz), 4.75(m, IH), 5.89(m, IH), 7.10 - 7.34(m, 2H), 7.56 - 7.67(m, IH), 8.52(d, IH, J = 3.2Hz)

IR(KBr) : 3389, 3290, 2918, 2850, 1724, 1687, 1545, 1510, 1263, 1205, 1145, 1029, 761cm ^"1

(e)2-[[N-Acetyl-N-[[[3-[[(octadecylcarbamoyl)oxy]methyl]- 3- thietanyl]methoxy]carbonyl]amino]-medιyl]pyridine

Following the procedure described in example le , but replacing the compound prepared in example Id widi die compound prepared in example 36d , the desired compound was obtained as a white solid(88 yield).

mp : 57.3 - 58.5 °C

Η - NMR( 80 MHz, CDC1 ₃ ) : a 0.86(t, 3H, J = 4.8Hz), 1.24(s, 32H), 2.63(s, 3H), 2.69(s, 2H), 2.74(s, 2H), 3.16(q, 2H, J = 5.6Hz), 4.00(s, 2H), 4.25(s, 2H),

5.08(s, 2H), 5.20(m, IH), 7.07 - 7.16(m, 2H), 7.52 - 7.67(m, IH), 8.46(d, IH, J = 3.2Hz) Mass (FAB, m/z) : 606(M ⁺ + 1)

(f) Preparation of the tide compound of this example

Following the procedure described in example If , but replacing the compound prepared in example le with the compound prepared in example 36e , the desired compound was obtained as a yellow solid(12% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.9Hz), 1.25(s, 30H), 1.48(m, 2H), 1.73(t 3H,

J = 5.1Hz), 2.64(s, 3H), 2.66(q, 4H, J = 5.1Hz), 3.13(q, 2H, J = 5.6Hz), 4.06(s, 2H), 4.29(d, 2H, J = 4.8Hz), 5.04(q, 2H, J =

7.2Hz), 5.08(br s, IH), 5.47(s, 2H), 7.88 - 8.03(m, 2H), 8.44 (m, IH), 9.51(d, 1H, J = 6.0Hz) Mass (FAB, m z) : 762(M ⁺ + 1), 634(M ⁺ - I)

EXAMPLE 37

2-[[N - Acetyl-N-[[[3-[[(octadecylcarbamoyl)oxy]methyl] thietane l-oxide-3-yl]methoxy] carbonyl]amino]methyl]-l-ethyl-pyridinium iodide

(a) 2-[[N-Acetyl-N-[[[3-[[(octadecylcarbamoyl)oxy]medιyl]thieta ne-l-oxide-3-yl]methoxy] carbonyl] aminojmethyl] pyridine

To a stirred solution of the compound prepared in example 36d (lOOmg) in methylene chloride (10ml) was added m-chloroperbenzoic acid(50-60%, 48mg) at -78°C. After stirring at -78°C for lh, the reaction mixture was diluted with methylene chloride , washed successively with 10% sodium bicarbonate solution and water. The organic layer was dried, concentrated under 5 reduced pressure and die resulting residue purified by flash chromatography on sUica gel (methanol : methylene chloride = 1 : 15) to afford 102mg of the desired product as a light yellow solid(99 % yield).

mp : 37.4 - 39.0 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.26(s, 30H), 1.50(m, 2H), 2.62(s, 0 3H), 3.01 - 3.17(m, 4H), 3.15(q, 2H, J = 6.0Hz), 3.92(d, 2H,

J = 4.2Hz), 4.10 and 4.17(s, 2H), 5.02(br s, IH), 5.09(s, 2H), 7.16 - 7.19(m, 2H), 7.65(m, IH), 8.49(br s, IH)

Mass (FAB, m/z) : 622(M ⁺ + 1)

(b) preparation of die tide compound of this example

Following the procedure described in example If , but replacing the compound prepared in example le with the compound prepared in example 37a , the desired compound was obtained as a light yellow solid(76% yield).

mp : 67.8 - 73.3 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.9Hz), 1.25(br s, 30H), 1.49(t 2H, J =

6.9Hz), 1.74(t 3H, J = 7.2Hz), 2.67 and 2.69(s, 3H), 3.09- 3.20(m, 4H), 3.66 and 3.88(d, 2H, J = 13.7Hz), 4.03(d, 2H, J=15Hz ), 4.38(d, 2H, J = 12.3Hz), 4.98 - 5.05(m, 2H), 5.25 and 5.35(br s, IH), 5.58(d, 2H, 12.3Hz), 7.98 - 8.05(m, 2H), 8.05 - 8.56(m, IH), 9.18 and 9.26 (d, IH, J = 6.0Hz)

IR(KBr) : 3366, 2920, 2850, 1718, 1630, 1525, 1456, 1359, 1225, 1156, 1069, 771cm ^"1

EXAMPLE 38

2-[[N - Acetyl-N-[[[3-[[(octadecylcarbamoyl)oxy]methyl] thietane 1,1- dioxide-3-yl]methoxy] carbonyl]amino]methyl]-l-ethyl-pyridinium iodide

(a) [3-[[(Octadecylcarbamoyl)oxy]medιyl]-3-thietanyl]methyl phenyl carbonate

Following the procedure described in exampl 3f, but replacing the compound prepared in example with 3e the compound prepared in example 36c, the desired compound was obtained as a white solid(72% yield).

mp : 56.3 - 58.7 °C ¹ H - NMR( 80 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.2Hz), 1.25(br s, 30H), 1.55(m, 2H), 3.05(s,

4H), 3.12(q, 2H, J = 6.3Hz), 4.28(s, 2H), 4.41(s, 2H), 4.75 (br s, lH), 7 .14 - 7.31(m, 5H)

(b) [3-[[(Octadecylcarbamoyl)oxy]methyl] thietane 1, 1- dioxide-3-yl]methyl phenyl carbonate

0 To a stirred solution of the compound prepared in example 38a(240mg) in methylene chloride (10ml) was added two equivalents of m-chloroperbenzoic acid(50-60%, 276mg) at -78°C, and the mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was diluted widi metiiylene chloride , washed successively widi 10% sodium bicarbonate solution and water. The organic layer was dried, concentrated under reduced 5 pressure, and die resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 5) to afford 190mg of the desired product as a white solid (75 % yield).

- mp : 65.9 - 67.4 °C

Η - NMR( 80 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.2Hz), 1.25(br s, 32H), 3.13(q, 2H, J = 6.2Hz),

3.98(s, 4H), 4.35(s, 2H), 4.46(s, 2H), 4.88(br s, IH), 7.10 - 7.52 0 (m, 5H)

IR(KBr) : 3350,2919,2851, 1763, 1704, 1537, 1322, 1252, 1064,773cm ^"1

(c) 2-[[N-[[[3-[[(Octadecylcarbamoyl)oxy]methyl]thietane 1, l-dioxide-3-yl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example 3g , but replacing die compound prepared in example 3f with the compound prepared in example 38b , the desired compound was obtained as a white solid(87% yield).

mp : 79.1 - 80.3 °C

Η - NMR( 80 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.2Hz), 1.25(br s, 32H), 3.12(q, 2H, J = 6.2Hz),

4.02(s, 4H), 4.27(s, 2H), 4.31(s, 2H), 4.46(d, 2H, J = 5.6Hz), 4.85(br s, IH), 6.01(br s, IH), 7.20 - 7.28(m, 2H), 7.57 - 7.78 (m, lH), 8.51(d, lH, J = 4.8Hz) IR(KBr) : 3340, 2919, 2850, 1715, 1536, 1321, 1249, 1191, 1042, 770cm ^"1

(d) 2-[[N-Acetyl-N-[[[3-[[(octadecylcarbamoyl)oxy]methyl]thietan e 1, l-dioxide-3-yl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example le , but replacing the compound prepared in example Id widi the compound prepared in example 38c , die desired compound was obtained as a yellow solid(90% yield).

mp : 79.6 - 81.6 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.25(br s, 30H), 1.48(m, 2H), 2.63(s,

3H), 3.15(q, 2H, J = 6.6Hz), 3.73(q, 4H, J = 13.8Hz), 4.10(s, 2H), 4.32(s, 2H), 5.08(s, 2H), 5.27(br s, IH), 7.15 - 7.19(m,

2H), 7.62 - 7.68(m, IH), 8.46(d, IH, J = 4.5Hz)

IR(KBr) : 3352, 2920, 2851, 1720, 1536, 1328, 1210, 1103, 985, 771cm ^"1

Mass (FAB, m/z) : 638(M ⁺ + 1)

(e) prepation of die tide compound of this example

Following die procedure described in example If , but replacing the compound prepared in example le with the compound prepared in example 38d , die desired compound was obtained as a light yellow solid(75% yield).

mp : 53.2 - 56.4 °C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.25(br s, 30H), 1.48(br s, 2H), 1.75

(t, 3H, J = 7.2Hz), 2.69(s, 3H), 3.13(q, 2H, J = 6.6Hz), 4.05(d, 2H, J = 14.4Hz), 4.23(s, 2H), 4.26(d, 2H, J = 15.3Hz), 4.55(s, 2H), 4.91 (q, 2H, J = 7.2Hz), 5.10(br s, 2H), 5.36(t, 1H, J = 5.7Hz), 5.57(s, 2H), 7.99(t, IH, J = 6.6Hz), 8.10(d, IH, J =

8.4Hz), 8.53(t, IH, J = 7.8Hz), 9.14(d, IH, J = 6.0Hz) IR(KBr) : 3355, 2919, 2850, 1724, 1630, 1526, 1459, 1330, 1224, 1175, 1085, 981, 772 cm ^"1 Mass(FAB, m/z) : 666(M ⁺ - 1)

EXAMPLE 39

N-[5-[[[3-[[(Octadecylcarbamoyl)oxy]methyl]-3-thietanyl]m ethoxy]carbonyl]pentyl] pyridinium bromide

(a) [3-[[(N-Octadecylcarbamoyl)oxy]-3-thietanyl] methyl-6-bromohexanoate

To a stirred solution of the compound prepared in example 36c(800mg) in methylene chloride (10ml) was added dry pyridine(0.18ml) and then 6-bromohexanoyl chloride(523mg) at 0°C, and d e mixture was allowed to warm to room temperature.

After stirring for 3h, the reaction mixture was diluted with metiiylene chloride , washed successively with IN-HCl solution and water. The organic layer was dried, concentrated under reduced pressure and die resulting residue purified by flash chromatography on sdica gel (ethyl acetate : hexane = 1 : 3) to afford 980mg of the desired product as a white solid (87 % yield).

mp : 56.7 - 57.8 °C

Η - NMR( 80 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.4Hz), 1.26(br s, 30H), 1.50 - 1.95(m, 8H),

2.37(t 2H, J = 6.4Hz), 2.99(s, 2H), 3.01(s, 2H), 3.13(q, 2H, J = 5.6Hz), 3.40(t, 2H, J = 6.4Hz), 4.20(s, 2H), 4.22(s, 2H), 4.75 (m, IH) IR(KBr) : 3282, 2919, 2850, 1731, 1690, 1551, 1264, 1153, 1023, 721cm ^"1

(b) Prepation of the title compound of this example

The compound prepared in example 39a( 100 mg) was dissolved in dry pyridine ( 1.0 ml) and heated at 80 ° C overnight. After removal of excess pyridine under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (methanol : methylene chloride = 1 : 20) to afford 100 mg of the tide compound as a white solid ( 88 % yield).

mp : 66.4 - 67.8 °C

^! H - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t. 3H, J = 6.9Hz), 1.25(br s, 30H), 1.49(m, 4H), 1.70

(m, 2H), 2.09(m, 2H), 2.37(t, 2H, J = 7.2Hz), 2.92(d, 2H, J =

9.9Hz), 3.03(d, 2H, J = 9.9Hz), 3.14(q, 2H, J = 6.3Hz), 4.16 (s, 2H), 4.2 l(s, 2H), 4.96(br s, IH), 5.03(t, 2H, J = 7.2Hz),

8.14(t, 2H, J = 7.5Hz), 8.51(t, IH, J = 7.8Hz), 9.53(d, 2H, J

= 6.0Hz) IR(KBr) : 3385, 2918, 2849, 1727, 1691, 1548, 1467, 1260, 1170, 1027, 776cm ^"1 Mass (FAB, m/z) : 605(M ⁺ - Br)

EXAMPLE 40

3-[5-[[[3-[[(Octadecylcarbamoyl)oxy]methyl]-3-thietanyl]m edιoxy]carbonyl]pentyl] thiazolium bromide

The compound prepared in example 39a (200mg) was dissolved in thiazole ( 0. 5 ml) and heated at 100 ° C for 15hrs. After removal of excess thiazole under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (methanol : methylene chloride = 1 : 10) to afford 152mg of the title compound as a white solid ( 67 % yield).

mp 60.9 - 61.4 °C Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.6Hz), 1.25(br s, 30H), 1.46(m, 4H), 1.70(m,

2H), 2.07(m, 2H), 2.37(t, 2H, J = 7.2Hz), 2.92(d, 2H, J = 9.9Hz), 3.04(d, 2H, J = 9.9Hz), 3.14(q, 2H, J = 6.3Hz), 4.16(s, 2H), 4.22(s, 2H), 4.89(t, 2H, J = 7.2Hz), 4.92(br s, IH), 8.31 (t, IH, J = 3.0Hz), 8.56(d, IH, J = 3.3Hz), 11.23(s, IH) IR(KBr) : 3384, 2918, 2849, 1727, 1693, 1544, 1465, 1260, 1161, 1027, 721cm ^"1 Mass (FAB, m/z) : 611(M ⁺ - Br)

EXAMPLE 41

N-[5-[[[3-[[(Octadecylcarbamoyl)oxy]methyl]-3-thietanyl]m ethoxy]carbonyl]pentyl] quinolinium bromide

The compound prepared in example 39a( 130 mg) was dissolved in quinoline ( 0. 5 ml) and heated at 70 ° C for 24hrs. After removal of excess quinoline under reduced pressure, the residue obtained was purified by flash chromatography on silica gel (methanol : methylene chloride = 1 : 10) to afford 120 mg of the title compound as a light yellow solid (76 % yield).

mp : 50.7 - 52.6 °C Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.9Hz), 1.25(br s, 30H), 1.50(br s, 2H),

1.61 - 1.76(m, 4H), 2.16(t, 2H, J = 6.6Hz), 2.37(t, 2H, J = 6.0Hz), 2.9 l(d, 2H, J = 9.6Hz), 3.01(d, 2H, J = 9.3Hz), 3.11 (q, 2H, J = 6.6Hz), 4.17(s, 2H), 4.20(s, 2H), 4.89(br s, IH), 5.48(t 2H, J = 6.9Hz), 7.96(t,lH, J = 7.5Hz), 8.17(m, 2H), 8.24(d, IH, J = 8.9Hz), 8.43(d, IH, J = 8.9Hz), 9.02(d, IH, J

= 8.1Hz), 10.68(d, IH, J = 3.9Hz)

IR(KBr) : 3388,2918,2849, 1715, 1530, 1463, 1376, 1250,775,721cm ^"1

Mass(FAB, m/z) : 655(M ⁺ - Br)

EXAMPLE 42

N-[4-[[[3-[(Hexadecyoxy)methyl]-3-d ietanyl]methoxy]carbonyl]butyl] quinolinium bromide

(a) 3-[(Hexadecyloxy)methyl] thietane -3-methanol

To a stirred solution of 3,3-bis-(hydroxymethyl) thietane (lOOmg) in dimethyl sulfoxide (3ml) was added potassium hydroxide(50mg) and then 1-bromohexadecane (0.23ml) at room temperature. After stirring for 12h, the reaction mixture was diluted with ethyl acetate , washed successively with IN- HCl solution and water. The organic layer was dried, concentrated under reduced pressure, and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 5) to afford 130mg of the desired product as a light yellow solid(50 % yield).

mp : 31.1 - 33.2 °C

*H - NMR( 80 MHz, CDC1 ₃ ) : a0.87(t, 3H, J = 5.6Hz), 1.25(br s, 28H), 2.27(br s, IH), 2.93(s,

2H), 2.95(s, 2H), 3.46(t, 2H, J = 6.0Hz), 3.66(s, 2H), 3.80(s, 2H) IR(KBr) : 3387, 2924, 2852, 1462, 1109, 1042cm ^"1

(b) 3-[[(Hexadecyloxy)methyl]-3-oxetanyl]methyl 5-bromopentanoate

Following the procedure described in example 21b , but replacing the compound prepared in example 21a widi die compound prepared in example 42a , die desired compound was obtained as a colorless oil(89% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.26(br s, 26H), 1.54(br s, 2H), 1.80 -

1.92(m, 4H), 2.39(t, 2H, J = 6.9Hz), 2.97(d, 4H, J = 2.4Hz), 3.39 - 3.46(m, 4H), 3.52(s, 2H), 4.20(s, 2H)

(c) preparation of the title compound of this example

Following the procedure described in example 23 , but replacing die compound prepared in example 21b widi the compound prepared in example 42b , the title compound of this example was obtained as a light yellow solid(73% yield).

mp : 33.7 - 35.3 °C ^■ H - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 3.4Hz), 1.26(s, 26H), 1.53(br s, 2H), 1.95(m,

2H), 2.24(m, 2H), 2.50(m, 2H), 2.90(m, 4H), 3.42(m, 2H), 3.48(d, 2H, J = 4.0Hz), 4.14(d, 2H, J = 5.4Hz), 5.54(m, 2H), 7.95(m, IH), 8.22(m, 2H), 8.33(t, IH, J = 6.8Hz), 8.50 _ (t, IH, J = 7.5Hz), 9.07(dd, lH, J = 8.4Hz, 8.2Hz), 10.73(d,

IH, J = 5.7Hz) IR(KBr) : 3414, 2919, 2850, 1731, 1624, 1593, 1528, 1464, 1376, 1250, 1170, 1112 776 cm ^"1 Mass(FAB, m/z) : 570(M ⁺ - Br)

EXAMPLE 43

2-[[N - Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl]-l- acetyl azetidine-2-yl]methoxγ] carbonyl]amino]methyl]-l-ethyl-pyridinium chloride

(a) trans-N-benzyl-2,4-Bis-(carbomethoxy)azetidine and its cis isomer

To a stirred solution of dimethyl 2,4-dibromo-glutarate(41.0g) in acetonitrile(lθθml) was added 3 equivalent of benzylamine( 14.9ml) at room temperature. The reaction mixture was stirred for lh at room temperature and at 80°C for 12h. After removal of die solvent, the mixture was partitioned between ethyl acetate and water. The organic layer was dried, concentrated under reduced pressure, and die resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 1 : 4) to afford 3.2g(30%) of the trans isomer and 5.12g(45%) of the cis isomer.

trans isomer : Η - NMR(80 MHz, CDC1 ₃ ) : a 2.50(t, 2H, J = 6.8hz), 3.65(s, 6H), 3.87(s,

2H), 4.21(t, 2H, J=6.7Hz), 7.26(s, 5H)

cis isomer : Η - NMR( 80 MHz, CDC1 ₃ ) : a 2.25 - 2.65(m, 2H), 3.34 - 3.75(m, 2H), 3.63(s,

6H), 3.88(s, 2H), 7.29(s, 5H)

(b) trans-2, 4 - Bis-(carbomethoxy)azetidine

A mixture of trans-N-benzyl-2,4-Bis-(carbomethoxy)azetidine(250mg) and palladium hydroxide on carbon(130mg) in methanol(20ml) was stirred in a Parr hydrogenator at 50 psi for 5hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate : hexane = 2 : 1) to afford l lOmg of the desired compound(67% yield)

Η - NMR(300MHz, CDC1 ₃ ) : δ 2.72 (t, 2H, J = 7.6Hz), 2.79(s, IH), 3.78(s, 6H), 4.32(t, 2H, J = 7.5Hz)

(c )trans-N- Acetyl -2,4-bis-(carbomethoxy) azetidine

To a stirred solution of the compound obtained in example 43b (1.95g) in methylene chloride (30ml) at 0°C was added dry triethylamine (3.3ml) and then acetyl chloride(0.96ml) . The reaction mixture was stirred for 5h at room temperature. After removal of the volatiles, the residue was partitioned between etiiyl acetate and water. The organic layer was dried, 5 concentrated under reduced pressure and die resulting residue purified by flash chromatography on silica gel (methanol : methylene chloride = 1 : 20) to afford 2.25g of die desired compound (67% yield).

Η - NMR(80 MHz, CDC1 ₃ ) : a 1.98(s, 3H), 2.75(t 2H, J = 7.5Hz), 3.80(s, 6H), 4.75(t, 2H,

J = 7.6Hz) lθ IR(KBr) : 2968, 1752, 1655, 1424, 1358, 1202, 1031, 981, 903, 760, 704 cm ^"1

(d) trans-N-Acetyl- 2,4-bis-(hydroxymethyl) azetidine

To a stirred solution of the compound obtained in example 43c (2.20g) in dry ethyl ether(50ml) was added lithium borohydride(0.65g) at 0°C. The reaction mixture was then allowed to warm 15 to room temperature and stirred overnight. The reaction was quenched by adding a trace amount of cold water. After drying and concentration under reduced pressure, the resulting residue was purified by flash chromatography on silica gel (ethyl acetate : hexane = 2 : 1) to afford 0.83g of the desired compound as a light yellow solid(57% yield).

Η - NMR(300 MHz, CDC1 ₃ ) : a 1.91 - 2.04(m, 4H), 2.12 - 2.25(m, IH), 3.35(br s, IH), 20 3.64 - 3.99 (m, 4H), 4.31 - 4.60(m, 2H), 5.15(br s, IH)

IR(KBr) : 3303, 2918, 2850, 1615, 1458, 1363, 1087, 1060, 949, 623 cm ^"1

(e) trans-N-Acetyl-2,4-bis-[[(phenoxycarbony)oxy]methyl] azetidine

Following the procedure described in example 8a , but replacing the compound prepared in example 6b widi the compound prepared in example 43d , die desired compound was obtained as a white solid(79% yield).

Η - NMR(80 MHz, CDC1 ₃ ) : a 1.96(s, 3H), 2.20 - 2.55(m, 2H), 4.21 - 4.96(m, 6H), 6.85 -

7.55(m, 10H)

(f) 2-[[N -[[[4-[[(Octadecylcarbamoyl)oxy]methyl]-l- acetyl azetidine-2-yl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example 8b , but replacing the compound prepared in example 8a with die compound prepared in example 43e , the desired compound was obtained as a white solid(41% yield).

Η - NMR(300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.9Hz), 1.20 - 1.55 (m, 32H), 1.92(s, 3H),

2.10 - 2.35(m, 2H), 3.10 - 3.25(m, 2H), 4.21 - 4.58(m, 8H), 4.80 - 4.95(m, IH), 5.88 - 6.12(m, lh), 7.17 - 7.29(m, 2H), 7.67(t, IH, J = 7.7Hz), 8.54(d, IH, J = 4.6Hz)

(g) 2-[[N - Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl]-l- acetyl azetidine-2-yl]methoxy] carbonyl] amino]methyl]pyridine

Following the procedure described in example le , but replacing the compound prepared in example Id with the compound prepared in example 43f , the desired compound was obtained as a white solid(59% yield).

mp : 66.6 - 67.8°C Η - NMR(300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 7.1hz), 1.20 - 1.55 (m, 32H), 1.75(s, 3H),

1.95 _r 2.05(m, 2H), 2.65(s, 3H), 3.15 - 3.25(m, 2H), 4.05 - 4.50(m, 6H), 4.70 - 4.80(m, 2H), 5.00 - 5.20(m, 3H), 7.10 - 7.25(m, 2H), 7.15 - 7.20(m, IH), 8.50(d, 1H, J = 5.1Hz)

IR(KBr) : 3372, 3237, 2920, 2850, 1710, 1623, 1535, 1448, 126, 1146, 755, 723 cm ^"1

O Preparation of the tide compound of diis example

Following the procedure described in example 27f , but replacing the compound prepared in example 27e with the compound prepared in example 43g , the desired compound was obtained as a light yellow solid( 75% yield).

mp : 88.9 - 97.0°C Η - NMR(300 MHz, CDC1 ₃ ) : δ 0.86(t, 3H, J = 6.6Hz), 1.20 - 1.55(M, 32H), 1.67(t 3H, J =

7.2Hz), 1.84(s, 3H), 2.05 - 2.30(m, 2H), 2.63(s, 3H), 3.05 - 3.20(m, 2H), 4.10 - 4.75(m, 6H), 5.15(q, 2H, J = 7.2Hz), 5.51(d, 2H, J = 2.4Hz), 5.80 - 5.90(m, IH), 7.80 - 8.10(m, 2H), 8.42(app t, IH, J = 7.8Hz), 9.75(d, IH, J = 6.1Hz) IR(KBr) : 3404, 2920, 2851, 1741, 1695, 1633, 1532, 1438, 1227, 1160, 989, 774cm ^"1 Mass(FAB, m/z) : 659(M ⁺ - Cl)

EXAMPLE 44

2-[[N - Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl]-l- benzoyl azetidine-2-yl]methoxy] carbonyl]amino]methyl]-l-edιyl-pyridinium chloride

(a) trans-N-Benzoyl -2,4-bis-(carbomethoxy) azetidine

Following the procedure described in example 43c , but replacing acetyl chloride with benzoyl chloride, die desired compound was obtained as a white solid(70% yield).

mp : 81.6 - 83.6°C

Η - NMR( 80 MHz, CDC1 ₃ ) : a 2.52(q, 2H, J = 7.2Hz), 3.37(s, 3H), 3.67(s, 3H), 4.95(m, 2H),

7.18 - 7.56(m, 5H) IR(KBr) : 2957, 1747, 1631, 1578, 1420, 1285^ 1207, 1033, 887, 717cm ^"1

(b) trans-N-Benzoyl -2,4-bis-(hydroxymethylj azetidine

Following the procedure described in example 43d , but replacing the compound prepared in example 43c with the compound prepared in example 44a , die desired compound was obtained as a white solid(97% yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : δ l.97 - 2.16(m, 2H), 3.19(br s, 2H), 3.72(q, 3H, J = 4.8Hz),

4.37 - 4.88(m, 3H), 7.25 - 7.48(m, 5H)

(c)trans- N-Benzoyl- 2,4-bis-[[(phenoxycarbony)oxy]methyl] azetidine

Following the procedure described in example 8a , but replacing the compound prepared in example 6b widi die compound prepared in example 44b , die desired compound was obtained as a white solid(95% yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : a 2.12 - 2.53(m, 2H), 3.81 - 3.95(m, 3H), 4.55 - 4.87(m, 3H),

7.19 - 7.61(m, 15H)

(d)2-[[N -[[[4-[[(octadecylcarbamoyl)oxy]methyl]-l- benzoyl azetidine-2-yl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example 8b , but replacing the compound prepared in example 8a widi d e compound prepared in example 44c , the desired compound was obtained as a light yellow solid(40% yield).

mp:36.2-38.5°C Η-NMR( 300MHz, CDC1 ₃ ) : a0.88(t3H,J=6.6Hz), 1.15 - 1.56(m,32H), 2.12- 2.45(m,

2H), 3.05 - 3.19(m,2H), 3.62 - 3.75(m, IH), 3.90- 3.98(m, IH), 4.38 -5.10(m, 7H), 6.00(brs, IH),7.16-7.67(m, 8H), 8.54(d, IH, J=4.5Hz)

IR(KBr) : 3315,2919,2850, 1714, 1624, 1573, 1530, 1467, 1254, 1146, 1038,765cm ^"1

(e) 2-[[N - Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]medιyl]-l- benzoyl azetidine-2- yl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example 8c , but replacing the compound prepared in example 8b widi the compound prepared in example 44d , die desired compound was obtained as a light yellow oil (72% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.6Hz), 1.20 - 1.56(m, 32H), 2.02 - 2.10(m,

2H), 2.66(s, 3H), 3.04 - 3.06(m, 2H), 3.55 - 3.95(m, 2H), 4.32 - 4.52(m, 2H), 4.66 - 4.68(m, 2H), 5.12 - 5.36(m, 2H), ._ 7.13 - 7.62(m, 8H), 8.51(d, IH, J = 3.9Hz)

IR(neat) : 3335, 2924, 2853, 1738, 1710, 1633, 1593, 1530, 1389, 1344, 1212, 1153, 840cm ^"1

(f) Preparation of the title compound of this example

Following the procedure described in example 27f , but replacing the compound prepared in example 27e with the compound prepared in example 44e , die desired compound was obtained as a light yellow solid (64% yield).

mp : 103.2 - 105.7°C

Η - NMR( 300 MHz, CDC1 ₃ ) : δ 0.88(t, 3H, J = 6.6Hz), 1.20 - 1.46(m, 32H), 1.64(t, 3H, J =

7.2Hz), 2.16 - 2.29(m, 2H), 2.66(s, 3H), 3.06 - 3.06(m, 2H), 3.58 - 3.62(m, IH), 3.90 - 3.93(m, IH), 4.39 - 4.42(m, IH), 4.59 - 4.92(m, 3H), 5.17 - 5.19(m, 3H), 5.41 - 5.55(m, 2H),

7.38 - 8.07(m, 8H), 9.80(d, IH, J = 5.7Hz)

IR(KBr) : 3426,2922,2851, 1737, 1714, 1695, 1682, 1529, 1410, 1225,987,717cm ^"1

Mass(FAB,m/z) :721(M ⁺ -Cl)

EXAMPLE 45

2-[[N - Acetyl -N-[[[4-[[(octadecylcarbamoyl)oxy]methyl]-l- benzyl azetidine-2-yl]medιoxy] carbonyl]amino]methyl]-l-ethyl-pyτidinium chloride

(a) trans- N-Benzyl- 2,4-bis-(hydroxymethyl) azetidine

Following the procedure described in example 43d , but replacing the compound prepared in example 43c widi die compound prepared in example 43a , die desired compound was obtained as a white solid (89% yield).

0 Η - NMR( 80 MHz, CDC1 ₃ ) : a 2.03 - 2.89(m, 4H), 3.26 - 3.59(m, 2H), 3.96 - 4.46(m, 6H),

7.26 - 7.57(m, 5H)

(b) trans- N-Benzyl- 2,4-bis-[[(phenoxycarbony)oxy]methyl] azetidine

Following the procedure described in example 43e , but replacing die compound prepared in 15 example 43d widi the compound prepared in example 45a , d e desired compound was obtained , as a colorless oil (98% yield).

'H - NMR( 300 MHz, CDC1 ₃ ) : δ 2.12 - 2.47(m, 2H), 4.17 - 4.82(m, 8H), 7.09 - 7.40(m, 15H) IR(neat) : 3027, 2939, 1763, 1716, 1593, 1547, 1492, 1295, 1211, 1069, 1023, 779cm ^"1

(c) 2-[[N -[[[4-[[(octadecylcarbamoyl)oxy]methyl]-l- benzyl azetidine-2-yl]methoxy] carbonyl] amino]methyl]pyridine

Following the procedure described in example 8b , but replacing the compound prepared in example 8a with the compound prepared in example 45a , the desired compound was obtained as a white solid(41% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.9Hz), 1.17 - 1.51(m, 32H), 2.01 - 2.43(m, 2H), 3.05 - 3.10(m, 2H), 3.95 - 5.20(m, 1 IH), 6.09(br s, IH),

7.10 - 7.61(m, 8H), 8.50(d, IH, J = 4.5Hz)

(d) 2-[[N - Acetyl-N-[[[4-[[(octadecylcarbamoyl)oxy]medιyl]-l- benzyl azetidine-2-yl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example 8c , but replacing the compound prepared in example 8b widi the compound prepared in example 45b , die desired compound was obtained as a light yellow oU(82% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.5Hz), 1.15 - 1.57(m, 32H), 1.88 - 2.15(m,

2H), 2.56(s, 3H), 3.05 - 3.70(m, 4H), 4.22 - 5.05(m, 9H), 7.05 - 7.60(m, 8H), 8.48(d, IH, J = 4.2Hz)

IR(neat) : 3343, 2924, 2853, 1740, 1717, 1593, 1494, 1358, 1191, 1081, 980, 823, 773cm ^"1

(e) Preparation of the tide compound of this example

Following the procedure described in example 27f , but replacing the compound prepared in example 27e with the compound prepared in example 45c , the title compound of this example was obtained as a light yellow solid(90% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.6Hz), 1.15 - 1.58(m, 32H), 1.64(t, 3H, J = 7.2Hz), 2.15 - 2.30(m, 4H), 2.55(s, 3H), 3.03 - 3.70(m, 4H),

4.33 - 5.35(m, 9H), 7.03 - 7.97(m, 8H), 9.73(d, IH, J = 5.4Hz) IR(KBr) : 3438, 2924, 2853, 1738, 1715, 1708, 1455, 1371, 1213, 981, 756cm ^"1

EXAMPLE 46

2-[[N - (2-methoxy)benzoyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl]- l- benzyl azetidine- 2- yl]methoxy] carbonyl]__mino]methyl]-l-ethyl-pyridinium chloride

(a) 2-[[N -(2-methoxy)benzoyl-N-[[[4-[[(octadecylcarbamoyl)oxy]methyl] -l- benzyl azetidine- 2-yl] medioxy ] carbonyl] amino]methy 1] pyridine

Following the procedure described in example 30a , but replacing the compound prepared in example 27d wid the compound prepared in example 45b , the desired compound was obtained as a light yellow oil (74% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.8 8(t, 3H, J = 6.6Hz), 1.15 - 1.53(m, 32H), 1.87 - 2.09(m,

2H), 3.09 - 3.16(m, 2H), 3.77(s, 3H), 3.81 - 4.47(m, 8H), 5.10 - 5.23(m, 3H), 6.86 - 7.63(m, 12H), 8.53(d, 1H, J = 4.5Hz)

IR(neat) : 3366, 3018, 2920, 2853, 1713, 1681, 1596, 1526, 1491, 1352, 1173, 1024, 984 cm ^"1

(b) preparation of the title compound of tiiis example

Following die procedure described in example 27f, but replacing the compound prepared in example 27e with the compound prepared in example 46a , the title compound of this example was obtained as a yellow solid(87% yield).

mp : 81.3 - 82.7°C

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.88(t, 3H, J = 6.6Hz), 1.20 - 1.55(m, 32H), 1.72(t, 3H, J =

7.2Hz), 1.83 - 2.09(m, 2H), 3.10 - 3.17(m, 2H), 3.84(s, 3H), 3.87 - 4.55(m, 8H), 5.14 - 5.45(m, 5H), 6.89 - 8.30(m, 12H), 10.08(d, lH, J = 4.6Hz)

IR(KBr) : 3441,2924, 2853, 1735, 1715, 1705, 1521, 1459, 1219, 978, 756cm ^"1

EXAMPLE 47

2-[[N - Acetyl-N-[[[3-[[(octadecylcarbamoyl)oxy]medιyl]-l- acetyl azetidine-3-yl]methoxy] carbonyl] amino]methyl] - 1 -ethyl -pyridinium chloride

,

(a) Isopropylidene ketal of N-benzyl -3, 3-bis-(hydroxymedιyl) azetidine

Ph' OCX

To a stirred solution of 5, 5 - bis-(bromomethyl)-2, 2 -dimethyl - 1, 3 - dioxane(lθ.θg) in dimethyl sulfoxide (50ml) was added benzyl amine(12ml) at room temperature, and the mixture was allowed to warm to 80°C. After stirring for 12h, the reaction mixture was diluted with etiiyl acetate and washed with brine. The organic layer was dried, concentrated under reduced pressure, and the resulting residue purified by flash chromatography on silica gel (ethyl acetate : hexane = 2 : 3) to afford 6.5g of the desired product as a colorless oil (80 % yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : δ 1.37(s, 6H), 3.05(s, 4H), 3.61(s, 2H), 3.89(s, 4H), 7.26(s,

5H) lR(KBr) : 3277, 2886, 1653, 1535, 1454, 1386, 1154, 826, 698cm ^"1 Mass (El, m/z) : 247(M ⁺ )

(b) Isopropylidene ketal of 3, 3-bis-(hydroxymethyl) azetidine

-OCX

A mixture of the above-described compound(2.0g) and 10% palladium on carbon(0.5g) was stirred in methanol(30ml) at room temperature for 36h in a Parr hydrogenator(60 psi). After evaporation of the solvent, the residue was treated widi 30 ml of a mixture of ethyl acetate and hexane( 1 :1). The resulting insoluble solid was filtered off and die filtrate concentrated to afford 1.0g of the desired product as a colorless oil(80% yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : a l.39(s, 6H), 2.82(br s, IH), 3.44(s, 4H), 3.93(s, 4H) IR(KBr) : 3440, 2958, 1332, 1200, 1078, 937, 824, 519cm ^"1

(c) Isopropylidene ketal of N-Acetyl -3, 3-bis-(hydroxymethyl) azetidine

oc* To a stirred solution of the compound prepared in example (l.Og) in methylene chloride(15ml) at 0°C was added triethyl amine(1.77ml) and then acetic anhydride(0.72ml) , and the mixture was allowed to warm to room temperature. After stirring for 2 h, the reaction mixture was diluted widi methylene chloride, washed successively with water, 10% sodium bicarbonate soution, and brine. The organic layer was dried, concentrated under reduced pressure, and the resulting residue purified by flash chromatography on silica gel (methanol : methylene chloride = 1 : 50) to afford 0.98g of the desired product as a light yellow solid (77 % yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : a 1.38(s, 3H), 1.41 (s, 3H), 1.85(s, 3H), 3.64(s, 2H), 3.89(s, 4H),

3.91(s, 2H) IR(KBr) : 2996, 2946, 2871, 1649, 1451, 1388, 1371, 1204, 1154, 1086, 824 cm ^"1

(d)N-Acetyl -3, 3-bis-[[(phenoxycarbony)oxy]methyl] azetidine-

A mixture of die compound prepared in example 47c (0.36g) and trifluoroacetic acid(0.5ml) wa stirred at room temperature in methylene chloride(lθml) containing water(0.5ml) for 8h. After removal of the volatiles under reduced pressure, the residue obtained was dissolved in methylene chloride(lθml) and treated with pyridine(0.48ml) and pheny chloroformate(0.55ml). The mixture was stirred at room temperature for 2h and washed with brine. The organic layer was dried, concentrated under reduced pressure, and die resulting residue purified by flash chromatography on silica gel (methanol : methylene chloride = 1: 20) to afford 0.17g of the desired product as a colorless oil (24% overal yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : a l.87(s, 3H), 3.89(s, 2H), 4.02(s, 2H), 4.46(s, 4H), 7.19 - 7.30(m, 10H)

(e) 2-[[N-[[[3-[[(Octadecylcarbamoyl)oxy]methyl]-l- acetyl azetidine-3-yl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example 8b , but replacing the compound prepared in example 8a with the compound prepared in example 47d , the desired compound was obtained as a light yellow od(49% yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : δ 0.87(t, 3H, J = 6.2Hz), 1.25(br s, 28H), 1.84(s, 3H), 3.1 l(q,

2H, J = 6.0Hz), 3.79(s, 2H), 3.92(s, 2H), 4 .21(s, 2H), 4.25(s 2H), 4.45(d, 2H, J = 5.6Hz), 4.80(br s, IH), 6.01(br s, IH), 7.20 - 7.30(m, 2H), 7.58(m, IH), 8.52(d, IH, J = 3.2Hz)

IR(neat) : 3299,2922,2852, 1716, 1642, 1537, 1464, 1254, 1041,744cm ^"1

(f) 2-[[N - Acetyl-N-[[[3-[[(octadecylcarbamoyl)oxy]methyl]-l- acetyl azetidine-3-yl]methoxy] carbonyl]amino]methyl]pyridine

Following the procedure described in example le , but replacing the compound prepared in example Id widi die compound prepared in example 47e , die desired compound was obtained as a light yellow oil(74% yield).

Η - NMR( 80 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 5.6Hz), 1.25(s, 28H), 1.76(s, 3H), 2.63(s,

3H), 3.10(q, 2H, J = 6.0Hz), 3.58(s, 2H), 3.70(s, 2H), 4.04(s, 2H), 4.27(s, 2H), 5.07(s, 2H), 5.08(br s, IH), 7.08 - 7.23(m, 2H), 7.54 - 7.66(m, IH), 8.45(d, IH, J = 4.0Hz)

IR(neat) : 3315, 2925, 2853, 1724, 1650, 1449, 1352, 1221, 979, 768cm ^"1

(g) Preparation of the tide compound of this example

Following the procedure described in example 27f , but replacing the compound prepared in example 27e widi the compound prepared in example 47f , the title compound of tiiis example was obtained as a light yellow solid(50% yield).

Η - NMR( 300 MHz, CDC1 ₃ ) : a 0.87(t, 3H, J = 6.3Hz), 1.25(br s, 26H), 1.48(br s, 2H), 1.71(t,

3H, J = 3.8Hz), 1.63(s, 3H), 2.64(s, 3H), 3.1 l(br s, 2H), 3.73(s,

2H), 3.99 - 4.21(m, 4H), 4.47(s, 2H), 5.12(br s, 2H), 5.35(br s, IH), 5.59(s, 2H), 7.79(d, IH, J = 7.1Hz), 7.97 (br s, IH), 8.39(t,

IH, J = 7.7Hz), 9.43(br s, IH)

IR(KBr) : 3410, 2924, 2853, 1706, 1635, 1526, 1460, 1363, 1226, 1160, 1087, 984, 772, 596cm ^"1

Mass(FAB, m/z) : 631(M ⁺ - Cl)