Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-11-06
2001-11-13
LeGuyader, John L. (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S450000, C264S004100, C264S004300, C554S001000, C560S001000, C435S006120, C435S325000
Reexamination Certificate
active
06316422
ABSTRACT:
The present invention relates to new compounds related to the amidinium family, including in particular the guanidiniums, pharmaceutical compositions containing them and their applications.
More precisely, the present invention relates to compounds of general formula I and their salts
in which:
R1 represents a cholesterol derivative or an alkylamino —NR′R″ group with R′ and R″ representing, independently of each other, a saturated or unsaturated, linear or branched C
12
to C
22
aliphatic radical.
R2 and R3 represent, independently of each other, a hydrogen atom or a group of general formula II with at least one of them being different from a hydrogen atom.
in which;
n and m represent, independently of each other and distinctly between the groups R2 and R3, an integer between 0 and 4,
R4 and R5 represent, independently of each other, a hydrogen atom or a group of formula III:
in which
p and q represent, independently of each other, an integer between 0 and 4 and r is equal to 0 or 1, with the condition that when r is equal to 1
X represents an NH group and x is equal to 1 or
X represents a nitrogen atom and x is equal to 2 and
it being possible for p, q and r to vary independently between the groups R4 to R5.
By way of preferred subfamily, there may be mentioned more particularly within the framework of the present invention the compounds of general formula I in which R2 or R3 represent, independently of each other, a hydrogen atom or a group of formula IV:
in which
n, m and p are as defined above and R4 represents a hydrogen atom or a group of formula V:
with q and r as defined above,
and it being possible for m, n, p, q and r to vary independently between the different groups R2 and R3.
These new products of general formula (I) may be provided in the form of nontoxic and pharmaceutically acceptable salts. These nontoxic salts comprise the salts with inorganic acids (hydrochloric, sulphuric, hydrobromic, phosphoric or nitric acids) or with organic acids (acetic, propionic, succinic, maleic, hydroxymaleic, benzoic, fumaric, methane-sulphonic or oxalic acids) or with inorganic bases (sodium hydroxide, potassium hydroxide, lithium hydroxide or calcium hydroxide) or organic bases (tertiary amines such as triethylamine, piperidine or benzylamine).
As representatives of the compounds according to the invention, there may be mentioned more particularly the compounds of the following general subformulae:
(H
2
N)
2
+
C—NH—(CH
2
)
2
—NH—COO—R1 VI
[(H
2
N)
2
+
C—NH—(CH
2
)
3
][(H
2
N)
2
C
−
—NH—(CH
2
)
4
]—N—COO—R1 VII
[(H
2
N)
2
+
C—NH—(CH
2
)
2
]
2
—N—(CH
2
)
2
—NH—COO—R1 VIII
[(H
2
N)
2
+
C—(CH
2
)
2
]
2
N—COO—R1 IX
[[(H
2
N)
2
+
C—(CH
2
)
2
]
2
—N—(CH
2
)
2
]
2
N—COO—R1 X
in which R1 has the above meaning.
As representatives of the claimed guanidiniums and amidiniums, there may be mentioned more particularly the compounds of the above subformulae VII, VIII and IX with R1 representing therein a cholesteryl group. The three compounds will be respectively identified hereinafter by the name BGSC (Bis Guanidino Spermidine Cholesterol) and BGTC (Bis Guanidino Tren Cholesterol) and BADC (Bis Amidinium Diethylenetriamine Cholesterol bishydrochloride).
The claimed compounds are most particularly advantageous from the therapeutic point of view for their nontoxic characteristics and their amphiphilic properties. Given these qualities, they may in particular be used for complexing nucleic acids in the perspective of cellular transfection thereof. These compounds may therefore be advantageously used in gene therapy.
Compounds VII (BGSC) and VIII (BGTC) are most particularly advantageous for in vivo gene transfer. These two compounds form a complex with DNA and protect it against degradation due to pH variations during transport to the cell to be treated.
The invention therefore relates to a pharmaceutical composition which comprises at least one compound according to the invention. In a preferred embodiment of the invention, the compound is Bis Guanidino Spermidine Cholesterol (BGSC) and in another preferred embodiment, the compound is Bis Guanidino Tren Cholesterol (BGTC).
The principal objective of gene therapy is to correct genetic diseases associated with a defect in expression and/or an abnormal, that is to say a deficient or excessive, expression of one or more nucleic acids. Efforts are being made to correct this type of genetic abnormality through cellular expression in vivo or in vitro of cloned genes.
Nowadays, several methods are proposed for the intracellular delivery of this type of genetic information. One of the technologies currently used is based precisely on the use of chemical or biochemical vectors. These synthetic vectors have two principal functions: compacting the DNA to be transfected and promoting its cellular attachment as well as its passage across the plasma membrane and, where appropriate, across the two nuclear membranes. Positively charged cationic lipids such as N-[1-(2,3-dioleyloxy)propryl]-N,N,N-trimethylammonium chloride (DOTMA) have thus been proposed. Advantageously, they interact, in the form of liposomes or of small vesicles, spontaneously with DNA, which is for its part negatively charged, to form lipid-DNA complexes capable of fusing with the cell membranes, and thus allowing the intracellular delivery of the DNA. However, in the specific case of DOTMA, its good efficiency in transfection unfortunately remains associated with a defect in biodegradability and a toxic character towards cells.
Since DOTMA, other cationic lipids have been developed on this model of structure: lipophilic group combined with an amino group via a so-called “spacer” arm. Among these, there may be mentioned more particularly those comprising, as lipophilic group, two fatty acids or a cholesterol derivative, and comprising, in addition, where appropriate, as amino group, a quaternary ammonium group. DOTAP, DOET or ChOTB may be mentioned in particular as representatives of this category of cationic lipids.
By virtue of their chemical structure and their biodegradable character, the claimed compounds meet precisely the requirements needed for a nucleic acid transfection vector.
The present invention therefore also relates to any application of these new compounds in the in vitro, ex vivo and/or in vivo transfection of cells and in particular for the vectorization of nucleic acids. It relates in particular to any pharmaceutical composition comprising a nucleic acid in addition to at least one compound according to the invention.
In the compositions of the present invention, the nucleic acid combined with at least one claimed compound may be either a deoxyribonucleic acid or a ribonucleic acid. These may be oligonucleotide or polynucleotide sequences of natural or artificial origin, and in particular genomic DNA, cDNA, mRNA, tRNA, rRNA, hybrid sequences or synthetic or semisynthetic sequences. These nucleic acids may be of human, animal, plant, bacterial or viral origin and the like. They preferably comprise a therapeutic gene.
Another object of the invention therefore relates to a pharmaceutical composition containing, in addition, a nucleic acid. Preferably, this nucleic acid is either a deoxyribonucleic acid or a ribonucleic acid. In a preferred embodiment of the invention, the nucleic acid comprises a therapeutic gene.
For the purposes of the invention, therapeutic gene is understood to mean in particular any gene encoding a protein product having a therapeutic effect. The protein product thus encoded may be a protein, a peptide or the like. This protein product may be homologous with respect to the target cell (that is to say a product which is normally expressed in the target cell when the latter exhibits no pathology). In this case, the expression of a protein makes it possible, for example, to compensate for an insufficient expression in the cell or for the expression of a protein whi
Lehn Jean-Marie
Lehn Pierre
Vigneron Jean-Pierre
Centre National de la Recherche Scientifique
Epps Janet L.
LeGuyader John L.
Synnestvedt & Lechner LLP
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