Linear or cyclic aminophosphonates as pH markers in...

Details Linear or cyclic aminophosphonates as pH markers in... Linear or cyclic aminophosphonates as pH markers in...

2000-11-16

2003-03-04

Powers, Fiona T. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C558S166000, C436S163000

Reexamination Certificate

active

06528656

ABSTRACT:

The invention relates to novel linear or cyclic aminophosphonates and to their use as pH markers in phosphorus-31 NMR spectroscopy, More generally, the A invention relates to the use of aminophosphonate derivatives as pH markers in NMR spectroscopy. Phosphorus-31 NMR spectroscopy has been found to be an effective means for measuring extracellular and intracellular pH in vivo.
The advantage of this method is that it does not at all disrupt the medium on which the measurement is taken, which is an essential condition for an in vivo measurement.
A compound can be used as a pH marker when the numerical value of the chemical shift of the resonance peak obtained by
31
P NMR varies as a function of the pH of the medium into which the compound has been introduced. The difficulty consists in developing the ideal, non-toxic compound which will be able to function as a pH marker in a broad pH range, with good sensitivity. An additional requirement is that the measurement should be little, if at all, affected by the other constituents of the physiological medium and that it should only react to a pH variation, even a very small one.
A certain number of markers are commonly proposed in the art. The one most commonly used is inorganic phosphate Pi, which has the advantage of being an endogenous compound present in all cells. However, this marker has two major drawbacks which may prevent the production of precise measurements (R. J. Gillies et al. (1986) Proc. Soc. Magn. Reson. Med. 5, 153-154):
the Pi content is generally relatively low in the cell and varies with the metabolic state of the cell;
the lack of sensitivity of this compound does not make it possible to distinguish between extra-cellular and intracellular pH.
2-Deoxyglucose 6-phosphate and methyl phosphonate have also been tested (M. DeFronzo et al., (1987) J. Biol. Chem. 262, 11032-11037). The results of these studies show that methyl phosphonate is a much more sensitive marker than 2-deoxyglucose 6-phosphate. Furthermore, although the latter compound is not metabolized, it is found to be toxic to the cell. On the other hand, despite its low toxicity, methyl phosphonate has the major drawback of total permeability with respect to cell membranes in the case of the tumour cell line studied.
Phenyl phosphonate is another extracellular pH marker (cf. Circulation Research, vol. 60, No. 4, 1987, 472-477). The drawback of this compound is that the
31
P chemical shift is influenced by the presence of specific ions in the measuring medium. The American Physiological Society, 1994, C195-C203 moreover reports the possibility of using 3-aminopropyl phosphonate as an extracellular pH indicator.
The present inventors have discovered a family of molecules, namely linear or cyclic aminophosphonates, which are particularly advantageous since they lead to improved sensitivity in measuring pH and since they make it possible to cover a whole range of different pH values depending on the substituents, thus allowing high precision as regards measurement at more acidic or more basic pH values. These molecules are moreover relatively non-toxic.
Only some of these aminophosphonates are novel. These novel compounds have the formula (I.1) or (I.2):
Formula (I.1)
in which:
R represents a (C
1
-C
18
)alkyl or (C
6
-C
10
)aryl group;
R
1
and R
2
independently represent a deuterium atom; a halogen atom; a (C
1
-C
18
)alkyl group optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkoxy, (C
3
-C
11
)cycloalkyl, halogen, (C
6
-C
10
)aryl and nitro; a (C
6
-C
10
)aryl group optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, halogen, nitro and (C
3
-C
11
)cycloalkyl; (C
1
-C
8
)alkoxy optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkoxy, halogen, nitro, (C
3
-C
11
)cycloalkyl and (C
6
-C
10
)aryl; a nitro group; or a (C
3
-C
11
)cycloalkyl group optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, halogen and nitro;
R
3
represents a hydrogen or deuterium atom; an n-propyl group or a linear (C
5
-C
18
)alkyl group, optionally substituted with one or more radicals chosen from: nitro, halogen, (C
1
-C
6
)alkoxy and (C
3
-C
11
)cycloalkyl; a (C
3
-C
11
)cycloalkyl group optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, halogen and nitro;
and the salts thereof with a pharmaceutically acceptable acid.
Formula (I.2)
in which
R′ represents a hydrogen atom or a (C
1
-C
18
)alkyl or (C
6
-C
10
)aryl group;
R′
1
represents a hydrogen atom; a deuterium atom; a halogen atom; a (C
1
-C
18
)alkyl group optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkoxy, (C
3
-C
11
)cycloalkyl, halogen, (C
6
-C
10
)aryl and nitro; a (C
6
-C
10
)aryl group optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, halogen, nitro and (C
3
-C
11
)cycloalkyl; (C
1
-C
18
)alkoxy optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkoxy, halogen, nitro, (C
3
-C
11
)cycloalkyl and (C
6
-C
10
)aryl; a nitro group; or a (C
3
-C
11
)cycloalkyl group optionally substituted with one or more radicals chosen from (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, halogen and nitro;
R′
2
and R′
3
together form a divalent radical:
in which the group —C(L
1
)(L
2
)— is directly linked to the carbon bearing R′
1
,
and in which L
1
, L
2
, L
3
and L
4
represent, independently of each other, a hydrogen atom, a deuterium atom or a (C
1
-C
18
)alkyl or (C
6
-C
10
)aryl group;
L
5
and L
6
being defined as follows:
when R′
1
represents a hydrogen, halogen or deuterium atom, an optionally substituted (C
1
-C
18
)alkoxy group, a nitro group or an optionally substituted (C
3
-C
11
)cycloalkyl group, L
5
and L
6
represent, independently of each other, a hydrogen atom, a deuterium atom, a (C
1
-C
18
)alkyl group, a (C
6
-C
10
)aryl group or a group —P(O)(OR′)
2
;
when R′
1
represents an optionally substituted (C
1
-C
18
)alkyl or optionally substituted (C
6
-C
10
)aryl, either L
5
or L
6
represents a hydrogen atom, and the other represents (C
2
-C
18
)alkyl or (C
6
-C
10
)aryl;
when R′
1
represents methyl, L
1
, L
2
, L
3
, L
4
and L
5
represent a hydrogen atom and R′ represents ethyl, then L
6
is not isopropyl;
and the salts thereof with a pharmaceutically acceptable acid.
The compounds of formula (I.1) are linear phosphonates.
The compounds of formula (I.2) are cyclic phosphonates.
In the context of the invention, the expression “alkyl” means a linear or branched saturated hydrocarbon radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl or 1-methyl-1-ethylpropyl.
The alkyl radical preferably contains 1 to 10 and better still 1 to 6 carbon atoms.
The term “alkoxy” denotes the —O-alkyl radical in which alkyl is as defined above.
“Halogen” denotes a chlorine, bromine, fluorine or iodine atom, fluorine and chlorine being preferred.
According to the invention, the term “cycloalkyl” denotes saturated, monocyclic or polycyclic, preferably monocyclic or bicyclic, carbocycles.
Cycloalkyls containing 3 to 8 endocyclic carbon atoms are more particularly preferred.
Cycloalkyls which may be mentioned are cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, cyclopentyl and cyclohexyl being preferred.
The term “aryl” means a monocyclic or polycyclic, preferably monocyclic or bicyclic, aromatic hydrocarbon radical containing from 6 to 10 endocyclic carbon atoms, such as phenyl and naphthyl.
Among the linear compounds of formula (I.1), the ones which are preferred are those corresponding to one or more of the following conditions:
1) R
3
is other than a hydrogen atom.
2) R
1
and R
2
are both other than a hydrogen atom.
3) R
3
represents n-propyl or a linear (C
5
-C
6
)alkyl group, optionally s

Affiliated with

Also associated with

Rating

Linear or cyclic aminophosphonates as pH markers in... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Linear or cyclic aminophosphonates as pH markers in..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Linear or cyclic aminophosphonates as pH markers in... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3018873