JPH11180929A - Ester derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a methylene chain between functional groups and having ether bond and anionic ester group in long- chain alkyl chain part and having wide application range and excellent in general-purpose properties as a component of liposome, etc., or as drug delivery system agent for chemical modification. SOLUTION: This compound is represented by formula I [R<1> and R<2> are each an alkyl or a group obtained by substituting carbon-carbon single bond of an alkyl with carbon-carbon double bond; R<3> is a lower alkyl or hydrogen; (n) is >=2], e.g. 7,8-dioleyloxy octanoic acid. The compound is obtained by reacting, e.g. a compound of formula II with an alkylating agent such as an alkyl chloride to afford 1,2-dioldialkyl ether, hydroboronizing a terminal carbon of the terminal olefin thereof with a hydroboronizing agent such as diborane and subjecting the reaction product to oxidation reaction with preferably hydrogen peroxide to afford a terminal alcohol of formula III and subjecting the compound of formula III to oxidation reaction with e.g. Jones reagent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel ester derivative.

[0002]

2. Description of the Related Art Lipid (lipid) is a general term for substances which are generally hardly soluble in water and easily soluble in organic solvents, and most of them are derivatives of fatty acids. Lipids are broadly classified into the following compounds.

[0003] (1) neutral lipids such as fatty acid glycerides, and simple lipids such as esters of fatty acids and higher alcohols, esters of vitamin A and esters of vitamin D, (2) phospholipids containing phosphorus and nitrogen atoms, Complex lipids such as glycolipids having sugar as a component, (3) (1),
Derived lipids such as fatty acids and higher alcohols which are considered to be precursors and metabolites of (2).

[0004] In the natural world, lipids constitute a large part of biological components together with proteins and sugars.
There are also substances useful as energy sources, small and effective substances such as hormones or vitamins, and those present as complex lipids of lipoproteins in cellular components such as plasma membranes, mitochondria, microsomes, or chloroplasts.

[0005] On the other hand, liposomes that have attracted attention in recent years are vesicles prepared from lipid molecules such as phospholipids and cholesterol, and are widely used as biological membrane models.
Lipids constituting biological membranes are roughly classified into polar lipids and non-polar lipids. Non-polar lipids include cholesterol and tocopherol (vitamin E), and polar lipids include phospholipids and glycolipids. is there.

[0006] In recent years, liposomes have been converted to DDS of various drugs.
(Drug delivery system) Attempts have been made to apply it as an agent. In particular, DDS of polar compounds such as DNA
As for, another kind of derivative using natural lipid as a raw material or a parent compound has been synthesized, and there have been many attempts to apply this as a liposome component. For example, DNA
Of cationic lipids (N- [1
-(2,3-dioleyloxy) propyl] -N, N, N
-An example using trimethylammonium chloride and the like was reported (Felgner, Proc. Natl. Acad. Sci., 84, 7413-7417, 1987.)
Have been.

[0007] In addition, there are many examples in which lipid is derivatized using a DDS agent, that is, a chemical modifier for drugs, and various derivatives have been proposed for the purpose of imparting sustained release and site selectivity. The derivatives include 5′-phosphatidyl-5-fluorouridine (Matsuda et al., Drug Deliver).
y System, 11, 81-88, 1996. JP-A-4-364198),
Polar lipid-peptides (Tokuheihei 7-509227), (5
(3-dodecylmercapto-2-decyloxy) propyl ester of -fluorouridine) -5'-phosphate (W
O9532984) has been proposed.

[0008]

The lipid derivative is used as a component such as a liposome or as a DD for chemical modification.
Various derivatives have been synthesized as S agents, but they have been insufficient in the applicable range. An object of the present invention is to provide a lipid derivative which is widely used as a component such as a liposome or as a DDS agent for chemical modification and has excellent versatility.

[0009]

Means for Solving the Problems The present inventors have conducted various searches for compounds in order to achieve the above object, and as a result, have found that a spacer (methylene chain) having an appropriate length is provided between appropriate functional groups. However, a derivative having an ether bond in the long alkyl chain portion and having an anionic ester group has been developed. That is, the present invention provides an ester derivative represented by the following formula 1.

[0010]

Embedded image R ¹ OCH ₂ CH (OR ² ) (CH ₂ ) _n COOR ³ Formula 1

However, the symbols in the formula 1 have the following meanings. R ¹ and R ² may be the same or different, and each represents an alkyl group or a group in which at least one carbon-carbon single bond of an alkyl group is substituted with a carbon-carbon double bond. R ³ : lower alkyl group or hydrogen atom. n: an integer of 2 or more.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the formula 1, R ¹ and R ² may be the same or different and each represents an alkyl group,
Or a group in which at least one carbon-carbon single bond of an alkyl group is substituted with a carbon-carbon double bond.

The number of carbon atoms of the alkyl group in R ¹ and R ² is preferably 5 or more, more preferably 5 to 20, and particularly preferably 5 to 18. Further, the alkyl group may have either a straight-chain structure or a branched structure, and a straight-chain structure is preferable. In the case of a branched structure, it is preferable that the branched portion is a methyl group, an ethyl group, or the like. The alkyl group for R ¹ and R ² is preferably a long-chain alkyl group, for example, an n-pentyl group, an n-hexyl group, an n-hexyl group,
-Octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl or octadecyl is preferred.

In R ¹ and R ² , a group in which at least one carbon-carbon single bond of an alkyl group has been substituted by a carbon-carbon double bond (hereinafter referred to as an unsaturated group) has a carbon number of one. A group in which one or more carbon-carbon bonds of two or more alkyl groups are substituted with a carbon-carbon double bond. The unsaturated group preferably has 2 to 20 carbon atoms, and particularly preferably 6 to 18 carbon atoms.
Further, the number of double bonds in the unsaturated group is preferably 1 to 3. The unsaturated group may have a straight-chain structure or a branched structure. In the case of a branched structure, the branched portion is preferably a methyl group or an ethyl group. Specific examples of the unsaturated group include an oleyl group, a 1,3-butadienyl group, a 3-methyl-2-butenyl group, a 9,12-octadecadienyl group, a 9,12,15-octadecatrienyl group and the like. Is mentioned.

R ¹ and R ² in the formula 1 may be the same or different and are preferably the same.
^It is preferred that both ¹ and R ² are oleyl groups.

R ^{3 in} Formula 1 is a lower alkyl group or a hydrogen atom, preferably a hydrogen atom. The lower alkyl group in the present specification refers to an alkyl group having 1 to 5 carbon atoms.
When R ³ is lower alkyl, an alkyl group having 1 to 4 carbon atoms is preferable, and a methyl group, an ethyl group, an n-propyl group, a butyl group, and an iso-butyl group are preferable.

N is an integer of 2 or more, preferably an integer of 2 to 10.

Specific examples of the ester derivative (formula 1) of the present invention include the following compounds. 7,8-Dioleyloxyoctanoic acid, methyl 7,8-dioleyloxyoctanoate, 11,12-dioleyloxylaurate, 6-
Decyloxy-7-dodecyloxyheptanoic acid, 14,
15-dihexadecyloxypentadecanoic acid, 13,1
Ethyl 4-dioctadecyloxytetradecanoate.

The ester derivative (formula 1) of the present invention can be synthesized by combining known synthesis means. Although the synthesis route is not necessarily limited, the following routes are exemplified. However, R ¹ in the following formula,
R ² , R ³ and n have the same meanings as in Formula 1, and R ³⁰ represents a lower alkyl group.

[0020]

HOCH ₂ CH (OH) (CH ₂ ) _n-1 CH = CH ₂ formula a → R ¹ OCH ₂ CH (OR ² ) (CH ₂ ) _n-1 CH = CH _2. Formula b → R ¹ OCH ₂ CH (OR ² ) (CH ₂ ) _n CH ₂ OH Formula c → R ¹ OCH ₂ CH (OR ² ) (CH ₂ ) _n COOH Formula 1a → R ¹ OCH ₂ CH (OR ² ) (CH ₂ ) _n COOR ³⁰ Formula 1b

That is, with respect to the 1,2-diol of an alkene having a carbon-carbon double bond at the terminal (formula a), p
Reacting with one or more compounds selected from alkyl toluene esters, alkyl iodides, alkyl bromides and alkyl chlorides to obtain 1,2-diol dialkyl ethers (formula b).

Next, the terminal carbon of the terminal olefin of the 1,2-diol dialkyl ether (formula b) is hydroborated with a hydroborating agent. Next, an oxidation reaction is performed to introduce a hydroxyl group, thereby obtaining a terminal alcohol (formula c). As the hydroborating agent, a known or well-known hydroborating agent is employed, and for example, borane-dimethyl sulfide complex, diborane, texyl borane and the like can be employed.
The amount of the hydroborating agent is preferably 0.4 to 10 mol based on the 1,2-diol dialkyl ether (formula b).
The reaction temperature is preferably -20 to 50C, and the reaction time is preferably 0.1 to 48 hours. As the oxidizing agent used for the oxidation reaction, a known or well-known oxidizing agent can be employed, and hydrogen peroxide is preferable. The amount of the oxidizing agent is 0.4 to 30 with respect to the 1,2-diol dialkyl ether (formula b).
Molar is preferred. The reaction temperature of the oxidation reaction is -20 to 50 ° C.
The reaction time is preferably 0.1 to 48 hours.

Next, the terminal alcohol (Formula c) is subjected to an oxidation reaction to obtain a terminal carboxylic acid (Formula 1a) corresponding to the case where R ³ in Formula 1 is a hydrogen atom. As a method of oxidizing the terminal alcohol (formula c), there is a method of first oxidizing to an aldehyde and then converting to a carboxylic acid, or a method of converting to a carboxylic acid by a one-step reaction, and either method may be used. . When the latter method is employed, it can be carried out by using a Jones reagent used in ordinary organic synthesis. The amount of the Jones reagent is preferably 0.5 to 100 mol based on the terminal alcohol (formula c). When the reaction is carried out by the latter method, the reaction temperature is 0 to 50 ° C.
The reaction time is preferably 0.5 to 48 hours.

Further, when it is desired to obtain the ester derivative of the present invention (formula 1b) where R ^{3 in} formula 1 is a lower alkyl group, the terminal carboxylic acid (formula 1a) is esterified by a usual esterification method. I just need.

Further, in the method for producing the above ester derivatives (Formula 1a and Formula 1b), a reaction solvent may be used.

Although the use of the ester derivative of the present invention is not particularly limited, various derivatives can be synthesized by using the ester derivative as a DDS agent, that is, a chemical modifier for a drug.

[0027]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Synthesis Example 1 1,2-Dioleoxy-7
-Octene Synthesis Example 7-octene-1,2-diol (1.9 ml, 12 m
mol) was dissolved in xylene (60 ml), and potassium-
t-butoxide (3.6 g, 35 mmol), p-toluenesulfonic acid oleyl ester (14.7 g, 35 m
mol), and the mixture was stirred at 160 ° C for 5 hours. After cooling, water was added and extracted with ethyl acetate. The organic layer was washed with saturated saline and then purified by column chromatography to obtain 7.0 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90 (t, J = 7 Hz, 3
H), 1.2-1.6 (m, 52H), 1.9-2.1 (m, 10H), 3.3-3.6 (m, 7H), 4.9
-5.05 (m, 2H), 5.3-5.4 (m, 4H), 5.7-5.9 (m, 1H).

Synthesis Example 2 1,2-Dioleoxy-8
Synthesis Example of -Hydroxyoctane The compound obtained in Synthesis Example 1 (1.4 g, 2.2 mmol) was dissolved in tetrahydrofuran (5 ml), cooled to 0 ° C, and borane dimethylsulfide complex (0.078 ml,
0.82 mmol) and reacted for 2 hours. 2N-Sodium hydroxide (0.51 ml) and 30% -hydrogen peroxide solution (0.22 ml) were added, the mixture was stirred for 10 minutes, water was added, and the mixture was extracted with ethyl acetate. Purification by column chromatography gave 0.42 g of the title compound.

Thin layer chromatography (TLC) (developing solvent: hexane-ethyl acetate = 3: 1) Development coefficient (Rf)
= 0.5. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90 (t, J = 7H
z, 3H), 1.2-1.6 (m, 58H), 1.95
−2.1 (m, 8H), 3.3-3.7 (m, 9H),
4.9-5.05 (m, 2H), 5.3-5.4 (m, 2H)
4H).

Example 1 Synthesis Example of 7,8-Dioleoxyoctanoic Acid The compound obtained in Synthesis Example 2 (0.42 g, 0.63 mmol)
l) was dissolved in acetone (10 ml), and at 0 ° C Jones' reagent (New Laboratory Chemistry, Oxidation and Reduction I-1, p.151)
, Maruzensha) was added and stirred. After confirming the disappearance of the raw materials, the reaction solution was concentrated, water was added, and the pH was adjusted with 2N hydrochloric acid.
Was adjusted to about 1 and extracted with chloroform. Purification by column chromatography gave 0.34 g of the title compound.

TLC (developing solvent: toluene-ethyl acetate = 1: 1) Rf = 0.7. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90 (t, J = 7 Hz, 3H), 1.2-1.6 (m, 5
8H), 1.9-2.05 (m, 9H), 2.35 (t, J = 7Hz, 2H), 3.3-3.6 (m, 7H),
5.3-5.4 (m, 4H).

Reference Example 1 Synthesis Example of N- (7,8-Doleyloxyoctanoyl) -3'-fluoroadenosine 7,8-Doleyloxyoctanoic acid obtained in Example 1 (0.2 g, 0.29 mmol), 1,3-dicyclohexylcarbodiimide (72 mg, 0.35 mmol)
Is dissolved in dichloromethane (10 ml), and 2 ′,
Add 5'-di-O-benzoyl-3'-fluoroadenosine (0.12 g, 0.26 mmol) and add 12
Stirred for hours. After completion of the reaction, the precipitate was filtered and the solvent was evaporated to dryness. Methanol (10 ml) was added and dissolved therein, 1N-sodium hydroxide (0.5 ml)) was added, and the mixture was stirred at 0 ° C for 1 hour. After evaporating the solvent, the residue was purified by column chromatography to obtain the title compound (0.18 g). ¹⁹ F-NMR (CCl ₃ F standard, CDCl ₃ ) δ (ppm): -20.

[0035]

Industrial Applicability The ester derivative of the present invention is useful as a component of liposome or as a DDS agent for various chemical modifications. Since the structure of the derivative contains a higher alkyl ether moiety and a methylene chain serving as a spacer suitable as a liposome or a DDS agent, it has a wide application range as a DDS agent for chemical modification, and is excellent in versatility. Compound.

Claims (2)

[Claims] 1. An ester derivative represented by the following formula 1. Embedded image R ¹ OCH ₂ CH (OR ² ) (CH ₂ ) _n COOR ³ Formula 1 where the symbols in the formula 1 have the following meanings. R ¹ , R
² : a group in which one or more carbon-carbon single bonds of an alkyl group, which may be the same or different, are substituted with a carbon-carbon double bond. R ³ : lower alkyl group or hydrogen atom. n: an integer of 2 or more. 2. The ester derivative according to claim 1, wherein R ¹ and R ² are oleyl groups.