GB2311991A - Compounds produced by reacting a long chain aliphatic carboxylic chloride with an amino or hydroxy group of an alkyl phosphonic acid derivative - Google Patents
Compounds produced by reacting a long chain aliphatic carboxylic chloride with an amino or hydroxy group of an alkyl phosphonic acid derivative Download PDFInfo
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- GB2311991A GB2311991A GB9617729A GB9617729A GB2311991A GB 2311991 A GB2311991 A GB 2311991A GB 9617729 A GB9617729 A GB 9617729A GB 9617729 A GB9617729 A GB 9617729A GB 2311991 A GB2311991 A GB 2311991A
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- phosphonic acid
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- organo phosphonic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/105—Aliphatic or alicyclic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/179—Colouring agents, e.g. pigmenting or dyeing agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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- Organic Chemistry (AREA)
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- Pharmacology & Pharmacy (AREA)
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Abstract
Disclosed are organo phosphonic acids having the formula: where:- n = 0 or 1 R 1 = H or R 3 = an alkyl group containing > 10 carbon atoms R 4 = H or CH 3 that provide improved bio-availability of drugs and nutrients by permiabilising cell membranes. They may also be used for nanoencapsulation of drugs and for improving pigment absorption in aqua-cultures. Also disclosed is a method for preparing organo phosphonic compounds comprising reacting an acid chloride of long chain aliphatic acid (eg having 10-20 carbon atoms) with an alkyl phosphonic acid derivative containing an active amino or hydroxy group in a non-aqueous medium at low temperatures (eg in chloroform at temperatures below 5{C). Especially useful are the reaction products of palmitoyl or lauroyl chloride with ethane-1-hydroxy-1,1-diphosphonic acid, 2-amino-ethyl phosphonic acid or 1 amino-ethyl phosphonic acid.
Description
ORGANO PHOSPHOROUS COMPOUNDS
The present invention relates to organo phosphorous compounds that provide improved bioavailability of drugs and nutrients by permiabilising cell membranes. In particular the compounds may be used as animal feed additives to increase nutrient uptake, pigment absorption in aqua-cultures and for the nanoencapsulation of drugs for drug delivery in vivo, in a way similar to lysophospholipids and phospholipids. A suggested mechanism for the improvement in bio-availability is given in the paper by David Garnett and Robin Jones in The Genetic Engineer and Biotechnologist, Vol.13,
No.2, 1993 and in International Application
W094/22324.
Compounds of the type referred to above are available as purified natural compounds and as a result are substantially impure. There is, therefore, a need for compounds of higher purity, such as may be obtained by chemical synthesis, which will have improved thermal stability and resistance to enzymatic attack, when compared to phospholipids.
The organo-phosphorous compounds of the present invention are phosphonolipids prepared by the reaction of a long chain alkyl acid chloride with an organophosphonic acid derivative preferably including a reactive hydroxy or amino residue.
From one aspect the present invention provides an organo phosphonic acid compound having the formula:
where: - n = O or 1
R3 = an alkyl group containing
> 10 carbon atoms
R4 = H or CH3
Preferably R4 is a methyl group.
The alkyl acid chlorides have a chain length of 10 or more carbon atoms and preferably not more than about 20 carbon atoms; particularly suitable are the acid chlorides of palmitic and lauric acids.
Particularly suitable phosphonic acid derivatives are ethane-1 -hydroxy-1, 1-diphosphonic acid (Etidronic acid) and 1 and 2 amino-ethyl phosphonic acids.
From another aspect, therefore, the present invention provides a method for preparing organo phosphorous compounds suitable for use as animal feed additives, pigment absorption in aqua-culture and nanoencapsulation drugs for drug delivery in vivo, comprising reacting an acid chloride of a long chain aliphatic acid with an alkyl phosphonic acid derivative containing an active amino or hydroxy group in a non-aqueous medium, preferably chloroform, at low temperatures, washing with cold water and subsequently drying.
Preferably the reaction temperature is kept below Soc and most preferably in the range 3-50C.
Preferably also the reactants are employed in stoichiometric proportions.
From another aspect the invention provides an animal feed additive prepared by the reaction of ethane-1-hydroxy-1, 1-diphosphonic acid and palmitoyl chloride in a non-aqueous medium at temperatures below Soc.
From a further aspect the invention provides a method for the manufacture of an organo-phosphonic acid derivative suitable for use in the nanoencapsulation of drugs for drug delivery in vivo by the reaction of 1 or 2-amino ethyl phosphonic acid and palmitoyl chloride in a non-aqueous medium at temperature below 50C.
The following examples are illustrative but non-limitative of the present invention.
Example 1
Preparation of Ethane-1-Palmitoyl-1,1 Diphosphonic Acid
A glass 5-litre 3 necked reacton flask equipped with a stirrer is charged through one neck with 206 grams of Etidonic acid (ethane-1-hydroxy-1, 1diphosphonic acid) dissolved in 1 litre of chloroform and the solution cooled to a temperature in the range 3 to 50C. 275 grams of palmitoyl chloride are added slowly through one neck with vigorous stirring whilst maintaining the temperature at 3-50C. Hydrochloric acid evolved in the reaction is withdrawn through the other neck and passed through a sodium hydroxide scrubber.
Stirring is continued for 60 minutes after the addition of the palmitoyl chloride is complete. At the end of the reaction the contents of the reaction flask are poured into cold water and the chloriform and unreacted palmitoyl chloride, in the form of palmitic acid (a wax) separated off. The resultant product is further washed with cold water to remove any trace of unreacted etidonic acid. After repeated washing the product is filtered off and dried under vacuum.
The product yield was 90% of theoretical.
The product is soluble in water at about 700C to provide a solution of pH 10.5 and is characterised by a Near Infra Red (NIR) spectra (measured on an
NIR Systems Seris 5000 spectrometer), shown in
Figure 1. It is believed that the product has the structure:
Example2
The process of Example 1 was repeated except that the etidonic acid was replaced by 125 grams of 2-amino-ethyl phosphonic acid.
The product yield was 90% of theoretical. The product dissolved in water at 600C to provide a solution having a pH of 3.33.
The product had a NIR spectra as shown in
Figure 2 and is believed to have the structure:
Example3
Example 2 was repeated using 1 amino ethyl phosphonic acid in place of 2 amino ethyl phosphonic acid. The product yield was 60% and had an NIR spectra as shown in Figure 3. The product was soluble in water at 600C to give a solution of pH 3.76 and is believed to have the structure shown below:
Example4
Example 1 was repeated except that the palmitoyl chloride was replaced by 219 grams of lauroyl chloride.
The product yield was 23.2% of theoretical and the product dissolved in water at 60 C to give a solution having a pH of 10.42. The product is identified by is NIR spectra shown in Figure 4 and is believed to have the structure shown below:
Example 5
Example 3 was repeated replacing palmitoyl chloride with 219 gram of lauroyl chloride. The product yield was 20% of theoretical.
The product is believed to have a structure as shown below:
The use of octanoyl chloride in place of palmitoyl chloride with either etidronic acid or 2 amino ethyl phosphonic acid did not produce any useful product.
The in vitro effect of the product of Example 1 on Inulin uptake in BHK cells is shown in Example 6 below.
Example6
Preparation of 1 -Palmitoylaminoethylphosphonic Acid
The preparation was conduced in three steps.
Step 1
Thiourea (9.89g.130 mmol) was added to a solution of acetaldhyde(18.57 ml.325 mmol)and triphenylphosphite (68.13 ml,325 mmol) in acetic acid (130 ml) and the resulting solution stirred and heated at 800C for 1hr to give an orange solution. Acetic anhydride (325 ml) was then added and the resulting solution refluxed for 2h to give a dark brown solution. 37%
Aqueous hydrogen bromide (325 ml) was then added very carefully dropwise, via the condenser, and the resulting solution refluxed for 8h then cooled and rotary evaporated. The dark residue was dissolved in ethanol (260 ml) and methyloxirane added slowly until pH6 was reached. This addition resulted in the immediate precipitation of the aminophosphonic acid A shown as the product of the reactions outlined below. The solid was allowed to settle and the liquid supernatant decanted. Fresh ethanol (250 ml) was added and the mixture briefly refluxed, then cooled and the ethanol decanted. This washing was repeated until most of the brown coloration was removed. The solid was finally dried under high vacuum to give the aminophosphonic acid A (8.23g,50.6%) as a slightly coloured solid, m.p. < 2900C(dec.).
Step S 2. :00-'r1iir7 2.(PhO + 2. J + A X sox 8iC ss ss ii)Acl0.nfltn2h aq. HBr rcnts 8h; rtf'4ra8J Br H0;pt 0 H0tO OH > ) HOs 1 A 2 [HOw R
Step 2
A mixture of the aminophosphonic acid
A (8.23g.65.8 mmol) and hexamethyldisilazane (55.5ml,263 mmol) was heated on an oil bath at 1501600C until all the solid dissolved (2-5h). Excess hexamethyldisilazane was evaporated and the residue was distilled to give the N,0,0-trisily derivative,B (17.50g,86%), as a colourless oil, b.p.1400C at 15mm
Hg, the structure of which is outlined in the reaction illustrated below.
Step 2
Step 3
A solution of palmitic acid (13.18g,51.4 mmol) in dry ethyl acetate (80ml) was stirred at -5 C then treated sequentially with triethylamine (17.lSml,S.4mmol) and ethyl chloroformate (5.57g,51.
4mmol), the latter added dropwise. The resulting cloudy mixture was stirred at -50C for 0.5h, then a solution of tris-silyl derivative B in ethyl acetate (35ml) was added dropwise and the resulting mixture stirred at the same temperature for 2h, then for 2h without cooling and finally for 3h at 80 C. The volatiles were removed from the cooled mixture by rotary evaporation. The residue was dissolved in saturated aqueous sodium bicarbonate and the resulting solution acidified to pH 2 using 10% hydrochloric acid and the precipitated acylaminoacid C filtered off. The crude solid was washed with methanol to rmeove residual palmitic acid then dried under high vacuum to leave the 1
Palmitoylaminoethylphosphonic acid C (16.0g,868) as a white solid.
Step 3 ClCO2Et, EqN R OH EtOAc, -5iCX O.5h I R O OEt R = CHCH31, Me,SiC, SC. 2h; 20eC, 2h;2h ,P C, 2h; 20, MclSiO' II d(rC. 3h 03 'PI;OH aq. q. NiH to iiOS1Mc, H ii OH aq. MeJSi pH 2 0 Mei0 C The NMR spectra for the resultant lysophosphonolipid is shown in Fig.5.
Example7
BHK 21 (clonel3)cells were cultured in thenormal way using G-MEM (Sigma G5154) supplemented with 10% FBS (Sigma F2442) 1Oml/L of 200mM L-Glutamine (Sigma
G7513) 5% TSB (Sigma T8159) and 10 ml/L antibiotic/antimycotic solution (Sigma A9909). The cells were cultured at 37 0C with 5*C02. The cell line was sourced from the European Collection of
Animal Cell Cultures at the Centre for Applied
Microbiology and Research at Porton Down.
These cells were cultured in 24 well plates (Sigma M9655). All experiments were performed in triplicate.
Cells in the wells were exposed to 1pCi of C-14 Inulin (Sigma 30,480-8) prepared in Hanks Balanced
Salt Solution (Sigma H9394) from a 75pCi stock solution. These were co-exposed to varying concentrations of the product of Example 1. The cultures were left for 1 hr and then the media was removed by aspiration. The adhered cells were then washed twice in Hanks' solution and then the cells were trypsinised using Trypsin-EDTA solution (Sigma
T5775) and centrifuged to a pellet at 1000rpm in pre-weighed Eppendorf tubes. The cell pellet was then lysed using distilled water. The Eppendorfs are then re-spun and aliquots of the D-water (100cm) were then removed and mixed with SigmaFluor
Scintillation cocktail (Sigma S4398) and read in a scintillation counter. Results are converted into DPM per mg/cell weight after the Eppendorfs are reweighed.
Results are plotted on the graph shown in
Figure 6 and clearly show a bi-phasic response, where at very low concentrations the flux of Inulin into the cells is reduced and at higher doses the influx is dramatically increased whilst Inulin is a large compound and is not particularly typical of compounds which one might wish to preferentailly absorb. The same effect can be observed with other sized molecules.
Inferences about the emulsion forming properties of phosphonolipids and phosphonolipid mixtures can be made from the determination of the emulsifying power of Lecithin formulations. An
Empirical method that determines the percentage of oil in water emulsion that is stable for an excess of 24 hours is as follows:
Measure 100 ml amounts of distilled water and vegetable oil into a beaker. Add the test sample of lecithins (normally 1 gram). Using the high speed rotor action blender homogenise the mixture for 1 minute at 250C. Immediately empty the container into a measuring flask and leave at 250C for 24 hours. At the end of 24 hours calculate the percentage oil-water emulsion remaining.
An assay carried out comparing lecithin with a 90% lecithin - 10% of example 1 product gave the following results:- Contol 0.0010
Lecithin 0.1948
90% Lecithin - 10% product Example 1 - 0.222
These results show a 12.3% improvement in the emulsifying power.
The improvement in stability of Miscelles formed the inclusion of the product of Example 2 is indicated in Example 8 below.
Example 8
Liposomes were created as follows:
An aqueous 1% V/v dispersion of the product of
Example 2 was prepared by homogenisation using an
Utra-Turrex T25 homogeniser operating at 14,000 rpm for approximately 30 seconds. Two sets of liposomes were created, the first test sample was formed using pure phosphatidylcholines and the second set made using 10% of the product of Example 2 in the formulation. Liposome concentration was determined spectro-photometrically using a Cecil Series 2
Machine at 500 NM wavelength. The liposome preparations were examined microscopically to ensure calibration of the spectrophotometer. The miscelle preparations were subject to a 300C heat regime for periods of 10 minutes and 3 hours and 600C for 30 minutes using a heated water bath. The results of the analysis are given below.
10 minutes 3 hours 600C-30 mins
Lecithin Lecithin+10% 1.31 1.288 0.975
Product of
Example 2 1.34 1.338 1.062
Net Increase 0.022% 3.88% 8.92%
The results indicate that there is a significant improvement in the stability of miscelles at elevated temperatures in the presence of phospholipids formed according to the present invention.
Claims (19)
1. An organo phosphonic acid compound having the formula:
where:
n = Oor1
R3 = an alkyl group containing > 10 carbon atoms
R4 = H or CH3
2. An organo phosphonic acid compound according to claim 1 wherein
R4 is a methyl group
3. An organo phosphonic acid according to claim 2 having the formula:
4. An organo phosphonic acid according to claim 2 having the formula:
5. An organo phosphonic acid according to claim 2 having the formula:
6. An organo phosphonic acid according to claim 1 having the formula:
7. An organo phosphonic acid according to claim 2 having the formula:
8. A method for preparing organo phosphoronic compounds comprising reacting an acid chloride of a long chain aliphatic acid with an alkyl phosphonic acid derivative containing an active amino or hydroxy group in a non-aqueous medium at low temperatures, washing with water and drying.
9. A method for preparing organo phosphonic acid compounds according to claim 9 wherein the non-aqueous medium is chloroform.
10. A method of preparing organo phosphonic acid compounds according to claims 10 or 11 wherein the temperature is kept below 50C.
11. A method of preparing organo phosphonic acid compounds according to claim 10 wherein the temperature is in the range of 3-50C.
12. A method of preparing organo phosphonic acid compounds according to any one of claims 8-11 wherein said long chain aliphatic acid chloride contains less than 20 carbon atoms in the chain.
13. A method for preparing organo phosphonic acid compounds ccording to claim 12 wherein the. acid chloride is palmitoyl or lauroyl chloride.
14. A method for preparing organo phosphonic acid compounds according to any of claims 8-13 wherein the phosphonic acid derivative is ethane-1-hydroxy-1,1-diphosphonic acid (Etidonic acid) or 1 or 2 aminoethylphosphonic acid.
15. A method of preparing organo phosphonic compounds according to any of claims 8-14 wherein the reactants are employed in stoichiometric proportions.
16. An organo phosphonic acid compound according to claim 1 substantially as herein described with reference to Examples 1-6.
17. A method of preparing organo phosphonic acid compounds according to claim 8 substantially as described herein with reference to
Examples 1-5.
18. A method of preparing the organo phosphonic acid compound of claim 7 substantially as described with reference to Example 6.
19. The organo phosphonic acid compound of any one of claims 1-7, 16-18 when used as an animal feed additive, to improve pigment absorption in aqua culture or for the nanoencapsulation of drugs for drug delivery in vivo.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9726184A GB2323089B (en) | 1996-04-12 | 1996-08-23 | Method for preparing organo phosphonic compounds |
| CN97194522A CN1218477A (en) | 1996-04-12 | 1997-04-14 | Organo phosphorous compounds |
| BR9708660-6A BR9708660A (en) | 1996-04-12 | 1997-04-14 | Phosphorous organo compound |
| EP97916556A EP0892806A1 (en) | 1996-04-12 | 1997-04-14 | Organo phosphorous compounds |
| PCT/GB1997/001020 WO1997039004A1 (en) | 1996-04-12 | 1997-04-14 | Organo phosphorous compounds |
| NO984671A NO984671L (en) | 1996-04-12 | 1998-10-06 | Organofosforsammensetninger |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9607583.3A GB9607583D0 (en) | 1996-04-12 | 1996-04-12 | Organo phosphorous compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9617729D0 GB9617729D0 (en) | 1996-10-02 |
| GB2311991A true GB2311991A (en) | 1997-10-15 |
| GB2311991B GB2311991B (en) | 1999-02-10 |
Family
ID=10791938
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GBGB9607583.3A Pending GB9607583D0 (en) | 1996-04-12 | 1996-04-12 | Organo phosphorous compounds |
| GB9617729A Expired - Fee Related GB2311991B (en) | 1996-04-12 | 1996-08-23 | Organo phosphorus compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GBGB9607583.3A Pending GB9607583D0 (en) | 1996-04-12 | 1996-04-12 | Organo phosphorous compounds |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB9607583D0 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015089609A1 (en) * | 2013-12-19 | 2015-06-25 | Instituto De Pesquisas Tecnologicas Do Estado De São Paulo S/A - Ipt | Method for nanoencapsulating high concentrations of active ingredients and resulting products |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1584014A (en) * | 1976-11-09 | 1981-02-04 | Hoechst Ag | Aqueous dispersion paints and process for preparing them |
| US5266576A (en) * | 1991-02-11 | 1993-11-30 | Adir Et Compagnie | N-myristoyl transferase inhibitors |
-
1996
- 1996-04-12 GB GBGB9607583.3A patent/GB9607583D0/en active Pending
- 1996-08-23 GB GB9617729A patent/GB2311991B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1584014A (en) * | 1976-11-09 | 1981-02-04 | Hoechst Ag | Aqueous dispersion paints and process for preparing them |
| US5266576A (en) * | 1991-02-11 | 1993-11-30 | Adir Et Compagnie | N-myristoyl transferase inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| Arch. Biochem. Biophys. 1994, Vol. 311(2), pages 358-368 & Chemical Abstracts, abstr no 121:31838 * |
| Chemical Abstracts, Vol. 67, abstr no 82242 & Kogyo Kagaku Zasshi 1967, Vol. 70(4), page 604 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015089609A1 (en) * | 2013-12-19 | 2015-06-25 | Instituto De Pesquisas Tecnologicas Do Estado De São Paulo S/A - Ipt | Method for nanoencapsulating high concentrations of active ingredients and resulting products |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9617729D0 (en) | 1996-10-02 |
| GB9607583D0 (en) | 1996-06-12 |
| GB2311991B (en) | 1999-02-10 |
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Effective date: 20020823 |