Amidine derivatives and drug carriers comprising the same

Details Amidine derivatives and drug carriers comprising the same Amidine derivatives and drug carriers comprising the same

1998-12-10

2001-05-08

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C424S001210, C424S009321, C424S009510, C424S094300, C564S225000, C564S244000

Reexamination Certificate

active

06228391

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel amidine derivative and a drug carrier comprising it.
BACKGROUND ART
Recently, studies have been actively made for applications of closed vesicles such as liposome, emulsion, and lipid microsphere as drug carriers have been activity made for drug delivery system (hereinafter referred to as DDS). These closed vesicles are usually prepared using phospholipids or their derivatives, sterols, or lipids except phospholipids as basic membrane-constituting materials. However, the closed vesicles composed of only these basic materials could not overcome various problems occurring in the practical use, such as mutual aggregation of closed vesicles and shortened retention time in circulation. Furthermore, it was practically difficult for them to drive drugs to their target sites.
In order to improve a drug-loading and cell binding ability of the closed vesicles, an attempt has been made to charge the surface of the closed vesicles to cationic at physiological pH range by charging a small amount of a cationic lipid such as stearylamine. In particular, cationic liposomes containing DNA are well known to promote transfer of the DNA into cells, that is, transfection, and those liposomes having higher introduction efficiency, higher expression level, and higher safety level are strongly required. But, there are limited kinds of lipid available to use for cationic liposome, then it has been desired to develop cationic lipids usable for a drug carrier that are highly safe and exhibit high performance. Such cationic lipids have been reported so far in U.S. Pat. Nos. 4,897,355, 5,334,761, JP-A 2-292246, and JP-A 4-108391. However, their effects are not satisfactory.
Therefore, it has been eagerly desired to develop a drug carrier that can transfect a DNA into cells efficiently and safely. And regarding other purpose in addition to the transfection of a DNA, the effective and safety carriers are also required for effective DDS therein to enable accurate, efficient, and safe targeting of a drug to such as injured sites in vascular endothelium and affected sites caused by nephritis, kidney cancer, pneumonia, lung cancer, hepatitis, hepatoma, pancreatic cancer, lymphoma, etc.
DISCLOSURE OF THE INVENTION
An objective of the present invention is to provide a drug carrier that enables transfection of nucleic acids, polynucleotides, genes, and their analogues into cells efficiently and safely, and to provide a cationic lipid capable of forming such drug carrier. Another objective of the present invention is to provide a drug carrier that effectively delivers a desired drug, peptide, or protein to target sites, and to provide a cationic lipid capable of forming such drug carrier.
The above objectives are achieved by the present invention as described below.
(1) An amidine derivative represented by the formula 1 or a salt thereof:
wherein A is an aromatic ring, R
1
and R
2
are the same or different and independently represent an alkyl group having any one of 10 to 25 carbon atoms, and an alkenyl group having any one of 10 to 25 carbon atoms, X and Y are the same or different and independently represent —O—, —S—, —COO—, —OCO—, —CONH—, or —NHCO—, m is 0 or 1, and n is 0 or a natural number of 1 to 6.
(2) A drug carrier comprising the amidine derivative as described in (1) as a constituent.
(3) The drug carrier as described in (2), wherein said carrier encloses a drug for diagnosis and/or therapy.
(4) The drug carrier as described in (2) or (3), wherein said carrier has an external diameter of 0.02 to 250 &mgr;m.
(5) The drug carrier as described in (2) to (4), wherein said carrier is constituted by at least one of liposomes, emulsions, macromolecules, fine aggregates, fine particles, microspheres, and nanospheres.
(6) The drug carrier as described in (2) to (5), wherein said carrier contains phospholipids or their derivatives, and/or lipids other than phospholipids or their derivatives, and/or a stabilizer, and/or an antioxidant, and/or the other surface modifier.
(7) The drug carrier as described in (2) to (6), wherein said drug for diagnosis and/or therapy is a nucleic acid, a polynucleotide, a gene, or their analogues.
(8) The drug carrier as described in (2) to (6), wherein said drug for diagnosis and/or therapy is an antiinflammatory agent, a steroid agent, an anticancer agent, an enzyme agent, an enzyme inhibitor, an antibiotic, an antioxidant, a lipid-intake inhibitor, a hormone agent, an angiotensinase inhibitor, an angiotensin receptor antagonist, an inhibitor of proliferation and migration of smooth muscle cells, a platelet-aggregation inhibitor, an inhibitor of releasing a chemical mediator, an enhancer or inhibitor of proliferation of vascular endothelial cells, an aldose reductase inhibitor, a mesangial cell-proliferation inhibitor, a lipoxygenase inhibitor, an immunosuppressant, an immunpotentiator, an antiviral agent, or a radical scavenger.
(9) The drug carrier as described in (2) to (6), wherein said drug for diagnosis and/or therapy is a glycosaminoglycan or its derivative.
(10) The drug carrier as described in (2) to (6), wherein said drug for diagnosis and/or therapy is an oligo- and/or poly-saccharide or their derivatives.
(11) The drug carrier as described in (2) to (6), wherein said drug for diagnosis and/or therapy is a protein or a peptide.
(12) The drug carrier as described in (2) to (6), wherein said drug for diagnosis and/or therapy is an endogenous diagnostic agent including an X ray contrast medium, a radioisotopically labeled nuclear medical diagnostic agent, and an agent for diagnosis by nuclear magnetic resonance.
The compounds of the present invention represented by the formula 1 are all novel. An example of their synthetic process is shown below. However, the present invention is not construed to be limited thereto.
For example, the compounds can be produced by introducing thiourea to the moiety of Z of the compound represented by the following formula 2 when Z is a halogen atom or by converting Z to an amidino group when Z is —CN.
In the formula 2, A is an aromatic ring, R
1
and R
2
are the same or different and independently represent an alkyl group having 10 to 25 carbon atoms, an alkenyl group having 10 to 25 carbon atoms, X and Y are the same or different and independently represent —O—, —S—, —COO—, —OCO—, —CONH—, or —NHCO—, and n is 0 or a natural number of 1 to 6. Z is a halogen atom or —CN.
The thus-produced amidine derivatives represented by the formula 1 can be isolated and recovered by per se known separation and purification methods (for example, chromatography and recrystallization).
The carrier of the present invention preferably has a particle diameter of 0.02 to 250 &mgr;m, more preferably 0.05 to 0.4 &mgr;m.
Its structure can take various forms and does not have to be limited. The carrier is most preferably formed by at least one of macromolecules, fine aggregates, fine particles, microspheres, nanospheres, liposomes, and emulsions, which can potentially function to load drugs in a high concentration.
In the present invention, compositions of the drug carrier are not particularly limited as long as they can take the above-described forms. In view of safety, in vivo stability, the compositions preferably contain phospholipids, their derivatives, lipids other than phospholipids, their derivatives, a stabilizer, an antioxidant, and some other surface modifier.
Examples of phospholipids are natural or synthetic phospholipids including phosphatidylcholine (lecithin), phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cardiolipin, and their hydrogenated products obtained by usual methods.
Examples of the stabilizers include sterols, such as cholesterol, which reduce membrane fluidity, glycerol, or saccharides such as sucrose.
The antioxidants include tocopherol homologues, namely vitamin E. There are four tocopherol isomers, &agr;, &bgr;, &ggr;, and &dgr;. Any of them can be used in the present invention.
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