AP874A - Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof. - Google Patents
Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof. Download PDFInfo
- Publication number
- AP874A AP874A APAP/P/1998/001180A AP9801180A AP874A AP 874 A AP874 A AP 874A AP 9801180 A AP9801180 A AP 9801180A AP 874 A AP874 A AP 874A
- Authority
- AP
- ARIPO
- Prior art keywords
- oil
- fatty acid
- iodinated
- derivatives
- process according
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Fats And Perfumes (AREA)
Abstract
Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof which are stable and are of a fluid pharmaceutical quality, are obtained by iodohydrination involving, in an organic medium, alkylsilylated derivatives of the trimethylsilyl chloride or trimethylchlorosilane type reacting with an alkaline iodide of the sodium iodide type, followed by the in-situ formation of hydroiodic acid by action of water, hydroiodic acid reacting, for example, with fatty acid esters and, in particular, with the fatty acid methyl esters of rapeseed oil recommended as biological fuel for petrol engines, yielding a product with advantageous low cost price and used in therapy, in particular in treatment of iodo-deprived goitre.
Description
Description
The invention relates to iodinated fatty acid esters and iodinated fatty acids and derivatives thereof obtained by iodohydrination involving the introduction of alkylsilylated derivatives with alkaline iodides used in the treatment of endemic goitre and pharmaceutical compositions containing them. They can also be used as contrast compounds in radiology and as a vehicle for chemiemboiisation.
Endemic goitre is a deficiency disease which constitutes one of the most serious public health problems faced by the World Health Organisation (WHO). According to official WHO records, 1,000 million individuals, meaning about 20 % of the world’s population, are affected by iodine deficiency, mainly in developing countries (Hetzel B.S., Potter B.J. and Dulberg E.M. The iodine deficiency disorders : nature, pathogenesis and epidemiology. World Rev. Nutr. Diet. 62 : 59-119 (1990)). Almost all of these countries manifest variable degrees of prevalence. In the most severely affected regions, up to 80 % of subjects may suffer from thyroid dysfunction : this is documented by the appearance of unattractive glandular hypertrophy which may undergo secondary hypothyroidism with neurological problems. Adolescent girls and women of child-bearing age constitute vulnerable groups and can give birth to a high proportion of up to 10 % of newborn babies suffering from a particular form of irreversible mental disability known as endemic cretinism and considered as the most threatening medical and social complication.
It is universally accepted that iodine dietary deficiency is the primary and predominant cause of this nutritional scourge. The geological nature and the geographical environment therefore appear to be the main factors determining this situation although some dietary compounds are incriminated as aggravating secondary causes. Appropriate treatment therefore implies the supplementation of deficient populations with additional amounts of iodine to cover physiological requirements.
8110/86 /d/dV
APO00874
Theoretically, this objective is easy to achieve. However, experience over recent decades has shown that the traditional means used for iodine supplementation (drinking water, table salt, bread-flour) encounter major spreading obstacles associated with transportation, storage and consumption conditions in (sub)tropical regions. Indeed, iodine is administered in the form of sodium or potassium iodide or iodate releasing the halogen in a non-storable form in adipose tissues. It is therefore necessary to ingest this form of iodinated vehicle on a daily basis during years. The nutritional benefits are irregular and slow to obtain, and this form of supplementation does not allow to overcome the emergency problems encountered in regions of high prevalence.
There exists also an iodinated oil characterized by long-lasting effects known as Lipiodol® (Societe Guerbet) which, administered in a single yearly oral or parenteral dose, demonstrated anti-goitrous preventive and therapeutic effects. This iodinated oil, originally designed as contrast product in radiology, is expressed from the rare and relatively expensive poppyseed oil (Somnifer papaverum). Although the good tolerance and curative properties of Lipiodol® are known for a long time, this product has not compelled recognition as a tool for massive eradication owing to its relatively high cost with respect to the huge requirements of the Third World.
Our invention is intended to overcome this handicap : a new iodinated drug is proposed which is formed from iodinated fatty acid esters or iodinated fatty acids and derivatives thereof which are of pharmaceutical purity, stable, free of toxic contaminants, totally iodinated, with no double bonds, and obtained by action of an alkylsilylated reagent and an alkaline iodide on fatty acid esters or fatty acids, revealing therapeutic properties.
For example, it is possible to produce low cost iodinated fatty acid esters from iodinated fatty acid methyl esters obtained by original synthesis from rapeseed oil (Brassica campestris) used as very low cost price biological fuel in car engines, allowing to undertake mass campaigns. The new product is characterized by higher bioavailability and extended therapeutic effects because the iodine is bound to three fatty acids (oleic acid n-9, linoleic acid n-6 and α-linolenic acid n-3), of which the last two are essentia! fatty acids and which are precursors of the three main fatty acid metabolic pathways. Our iodinated product is exclusively proposed for oral administration in order to avoid the risks of blood viral contamination (hepatitis B and C, HIV).
AP/P/ 9 8/01 180
APO 0 0 8 7 4
Several methods have already been described for the transformation of unsaturated fatty acids or of unsaturated fatty acid esters into iodinated saturated derivatives. Oleic acid can be submitted to hydrobromation followed by nucleophilic substitution via potassium iodide after action of hydrobromic acid (J. F. Lane and H. W. Heine : On cyclic Intermediates in Substitution Reactions. I. The Alkaline Hydrolysis of Some Aliphatic Rromoanids. ,J. Am. Chem. Soc. 1951, 73. 1348-1350). Olive oil cooled to the region of the setting point is saturated directly with hydroiodic acid. Other fatty acids have been considered. (A. Guerbet, A. Gibaud, G. Tilly, R. Joussot, V. Loth and M. Guerbet ; Monoiodostearate d'ethyle. Preparation et caractbres analytiques. Ann. pharm. fr., 1965, 23, No. 11, 663-671). Direct iodination with hydroiodic acid is also carried out using dehydrating substances such as polyphosphoric acids, phosphorus pentoxide (W. Kuhn, H. Hartner, F. Schindler, I. Sandner and K. Hering ; German patent P 35 13 322.6/C 07 C 69/62, 1985). Hydroiodination can also be carried out with iodine in the presence of alumina generating hydroiodic acid (L. J. Stewart, D. Gray, R. M. Pagni and G. W. Kabalka; A convenient Method for the addition of HI to unsaturated hydrocarbons using l2 on AI2O3, Tetrahedron Lett, 1987, Vol. 28, No 39, 4497-4498). Hydroiodination has also been carried out using the boron-N, N-diethylamine complex involving boron triiodide. (Ch. Kishan Reddy and M. Periasamy ; A new simple procedure for the generation and addition of HI to alkenes and alkynes using BI3 : N, N-diethylaniline complex and acetic acid. Tetrahedron Lett. , 1990, Vol. 31, No 13, 1919-1920). Hydroiodination with potassium iodide in orthophosphoric acid can also be envisaged (Organic Synthesis, Vol. 9, 66).
The document JP-A 53119817 is also known, which discloses the synthesis of glyceryl tri-(2-iodohexadecanoate) in two stages. In a first stage, 2-bromopalmitoyl chloride reacts with glycerine in a water-free benzene/pyridine solvent to obtain 36 % of glyceryl tri-(2bromohexadecanoate) after purification. This product then reacts with Nal in acetone to yield 74 % of glyceryl tri-(2-iodohexadecanoate) after treatment with Na2S2O3, purification, drying, etc.
As specified, among others, in German patent No. C07 C69/62/P 3513 323.8 dated
13.4.1985 and belonging to W. Kuhn et al. , the methods for the preparation of iodinated compounds lead to products containing toxic impurities, products which are unstable in air and light during the preparation and storage thereof. Our method of preparation leads, in particular, to a product characterized by various constituents and devoid of
ΛΡ/Ρ/ 0 ft / ft 1 1 8 0
AP Ο Ο Ο 8 7 4 double bonds which are a source of instability, in particular in the presence of oxidation derivatives and free radicals.
Iodinated fatty acid esters prepared by iodohydrination involving alkysilylated derivatives and an alkaline iodide forming the substrate of the invention exhibit the form of a pharmaceutically pure, stable, light yellow, fluid, oily liquid having a relatively low cost price. The fatty acid esters used for the preparation of iodinated derivatives involving an alkylsilylated compound and an alkaline iodide can be, for example, fatty acid triglycerides originating from vegetable oils of the rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil and palm oil type and from oils of animal origin.
The fatty acid esters used can also be mixtures of fatty acid methyl esters or ethyl esters originating form vegetable oils of the rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil and palm oil type and oils of animal origin.
It is of particular interest for large-scale production to use as raw material the fatty acid methyl esters originating from rapeseed oil used as low cost price biological fuel for car engines. Fatty acids of the oleic acid, linoleic acid, α-linolenic acid, erucic acid, arachidonic acid and ricinoleic acid type can also be used as raw substrates.
The process for obtaining iodinated fatty acid esters or iodinated fatty acids implies the reaction of an alkaline iodide with an alkylsilylated halide in an organic medium yielding in situ, in the presence of water, hydroiodic acid reacting either with the fatty acid ester(s) or with the fatty acids.
To obtain iodinated fatty acid esters or iodinated fatty acids, for example, sodium iodide is reacted with trimethylsilyl chloride or trimethylchlorosilane in acetonitrile followed by the action of water and the addition either of unsaturated fatty acid esters or of unsaturated fatty acids.
The iodohydrination of fatty acid esters can be carried out according to the following reaction :
CH3CN H2O (1)
Nal + SiMe3CI-----> NaCl + SiMe3l-------> SiMe30H + HI-----> iodohydrin (1) fatty acid esters or fatty acids
AP/P/ 9 8/01180
ΑΡΰυθ874
The mode of operation, for example, for unsaturated fatty acid esters is as follows : 89.25 ml of trimethychlorosilane (or trimethylsilyl chloride) are added to a solution of 107.1 g of sodium iodide in 550 ml of acetonitrile in a nitrogen atmosphere and at 0°C. 6.65 ml of water are added dropwise after total addition of the trimethylchlorosilane. A solution of 70 g of unsaturated fatty acid methyl or ethyl esters of rapeseed oil is then added. After 24 hours of reaction with stirring, the reaction is then stopped with 700 ml of water. The mixture is extracted using ether. The organic phase is washed several times with a 10 % solution of sodium thiosulphate then several times with water. It is dried over anhydrous sodium sulphate and the ether is evaporated at a temperature of 90eC over 16 mm of Hg (2133 Pa) in order to eliminate the romaine of cilicoous ether. The residue is brown. The iodinated ratty acid esters dissolved in etner are then Pleached over coal then filtered over alumina to eliminate the peroxides. The ether is evapored and the traces of solvent are eliminated using a vane pump. The mixture of iodinated fatty acid esters obtained is golden yellow and has good fluidity. This mixture can be identified by 1H NMR and 13C NMR spectrometry. This method of synthesis of iodinated fatty acid esters was carried out over larger quantities. Other water-immiscible solvents can be used. The insolubility of sodium chloride in acetonitrile allows the total displacement of the reaction toward the formation of trimethylsilyl iodide. This reaction is exothermic and allows the generation of hydroiodic acid and hydroxylated trimethylsilyl. The secondary product βίΜθβΟΗ is c eliminated after the iodohydrination reaction by simple evaporation under reduced β pressure and washing in water. The iodohydrination reaction is visually followed by the bleaching of the solution. The sodium thiosulphate allows the elimination of the iodine c present in oxidized form. The final product is free of ethylenic bonds as shown by the ·* absence of any NMR proton signal and 13C signal. On the other hand, no degradation product appears in the NMR of the proton.
Characteristics of rapeseed oil iodinated fatty acid esters :
Nuclear magnetic resonance of the proton (NMR1H) and of the carbon 13 (NMR13C). An
NMR1H spectrum of the iodinated fatty acid esters of rapeseed oil allows to check the disappearance of the ethylene protons by comparison with the spectrum of the noniodinated fatty acid esters of rapeseed oil. Furthermore, this allows to check the absence of traces of solvent diethylether and of silica ether. Moreover, an NMR^C spectrum allows to check the disappearance of the carbons involved in the non-saturated double bounds.
ο υ /a/u*
ΑΡ ο υ ο 8 7 4
The NMR1 Η spectra obtained for several productions of iodinated fatty acid ethyl esters of rapeseed oil are identical. No spectrum reveals the presence of diethyiether or silica ether.
° NMR1H spectrum of iodinated fatty acid ethyl esters [NMR1H (CDCI3) over 200 MHz]: 0.89 ppm (3H, m, CH3), 1.20-2.00 ppm (m, CH2 of the chains and CH.sCHpQ). 2.3 ppm (2H, t. CH2-COOEt). 4.2 ppm (m, CHI, CH2-OOC).
0 NMR13C spectrum of iodinated fatty acid ethyl esters [NMR3C (CDCI3) over 200 MHz]: 14 ppm (QH3 at the chain end and CH3CH2O), 28-29 ppm (CHI) 22-24, 30-31, 34 ppm (GH2 of the chains), 39-41 ppm (CH2-CHI), 60 ppm (QH2-O), 173 ppm (COO).
The infrared absorption spectrum (NaCl) has the following characteristic bands : γ (C=O ester) at 1740 cm-1 ; γ (saturated CH) at 2850 end, γ (saturated CH) at 2950 cm'1.
0 NMR1H spectrum of iodinated fatty acid methyl esters [NMR1H (CDCI3) over 200MHz]: 0.89 ppm (3H, m, CH3), 1.25 -1.30 ppm (m, CH2 of the chains), 1,60-1.80 ppm (m, CH2I 2.3 ppm (2H, t, CH2-COO), 3.66 ppm (3H, s, CH3-OOC), 4.12 ppm (m, CHI).
e NMR13C spectrum of iodinated fatty acid methyl esters [NMR13C (CDCI3) over 200 MHz]; 14 ppm (£H3 at the chain end), 28-29 ppm (CHI), 22-24, 31-34 ppm (CH2 of the chains), 38-41 ppm (CH2-CHI), 51 ppm (ΩΗ3-Ο), 173 ppm (COO).
Stability : as most iodinated products are generally unstable substances, it is necessary to check the stability of the iodinated fatty acid esters and/or of the iodinated fatty acids. Stability is investigated by NMR1H, by thin film chromatography and by quantitative analysis of the iodine bound to the fatty acid esters or on the fatty acids.
NMR1H spectra were performed after 2 months, 3 months and 8 months storage at a temperature of 20-22°C, sheltered from the light. The three spectra are identical to that obtained during production. Thin film chromatography (silica gel plate GF 254 AP/T7 9 8/01180
APO 0 0 8 7 4 moving phase : diethylether/hexane 1 : 20 - examination in ultraviolet light at 254 nm and after atomization of a 10 % m/V solution of phosphomolybdenic acid R in alcohol and heating of the plate to 120°C for 5 min) reveals spots identical both in intensity and position to those found on freshly prepared products or in those stored for 8 months.
Stability of iodinated fatty acid esters of rapeseed oil after therapeutic use in the field : the mixture of iodinated fatty acid esters of rapeseed oil was used for the treatment of people living in a region of endemic goitre in Africa. During these surveys, the iodinated esters were submitted to extreme environmental conditions (transportation, exposure to light for several hours and at temperatures of about 45°C). After two weeks of investigations, the iodinated fatty acid esters were analyzed : the NMR1H spectrum was found .to be identical to that of a freshly synthesized oil and thin layer chromatography yields spots identical to those of freshly synthesized iodinated fatty acid esters and does not reveal degradation products. , c
T
Test of tolerance on rats : Before administering the mixture of iodinated fatty acid * j* esters of rapeseed oil to goitrous subjects, the tolerance of the mixture of iodinated esters was tested on adult male rats weighing about 300 g. Each test group consists of 5 rats c submitted to an oral administration of 0.5 ml of mixture of iodinated fatty acid esters of < rapeseed oil. The rats were kept under observation. After one week, the behaviour and general state of the rats in each test group are normal arid identical to those of the control group. The iodinated products prepared by the above-described method are used as generally administered drugs, for example as anti-goitre drugs in the pure state or in combination with appropriate excipients in the form of a drinkable or ingestable liquid, capsules or ampoules for example. These iodinated products can also be used as generally or topically administered drugs, for example as contrast products or as antiinflammatory agents in rheumatoid therapies. These products can be used as drugs which are administered using general or local intravascular delivery for the treatment of certain cancers by chemiembolisation involving the prescription of an anti-cancer drug emulsified into iodinated fatty acid esters acting as carriers to target tumoral lipophilic cells.
Claims (15)
1. Process for obtaining at least one iodinated fatty acid or at least one iodinated fatty acid ester or iodinated derivatives thereof which have pharmaceutical purity, are stable and free from toxic impurities, characterized in that it involves reacting an alkaline iodide with an alkylsilylated reagent in an organic medium giving rise in situ, in the presence of water, to hydrolodic acid reacting with the fatty acid(s), the fatty acid ester(s) or derivatives thereof in such a way that all the double bonds initially present in the fatty acid(s) or fatty ester(s) or derivatives thereof are saturated in iodine in a proportion of one molecule of hydroiodic acid per double bond.
2. Process according to claim 1, characterized in that the alkaline iodide is sodium iodide.
3. Process according to claim 1, characterized in that the alkylsilylated reagent is an alkylsilylated halide.
o
4. Process according to claim 3, characterized in that the alkylsilylated halide^ is trimethylsiiyl chloride or trimethylchlorosilane.
5. Process according to claim 1, characterized in that the organic medium rcontains acetonitrile. ®
6. Process according to claim 1, characterized in that the fatty acid ester(s) consist(s) of fatty acid triglyceride(s) originating from vegetable oil(s) selected from the^ group formed by rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil,L> grapeseed oil, sunflower oil, linseed oil, com oil, olive oil, sesame oil, wheatgerm oil,££ coconut oil, palm oil and oils of animal origin.
7. Process according to claim 1, characterized in that the fatty acid ester(s) consist(s) of fatty acid methyl ester(s) originating from vegetable oil(s) selected from the group formed by rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil, palm oil and oils of animal origin.
8. Process according to claim 7, characterized in that the fatty acid ester(s) consist(s) of fatty acid methyl ester(s) originating from rapeseed oil, used as low cost price biological fuel for car engines.
9. Process according to claim 1, characterized in that the fatty acid ester(s) consist (s) of fatty acid ethyl ester(s) originating from vegetable oil(s) selected from the group formed by rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil, palm oil and oils of animal origin.
AP o ο υ 8 7 4
10. Process according to claim 1, characterized in that the fatty acid(s) is/are selected from the group formed by oleic acid, linoleic acid, α-Iinolenic acid, erucic acid, arachidonic acid and ricinoleic acid.
1.1. Iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof, obtained by the process according to any one of the claims 1 to 10 and not having the double bond, for use as a drug.
12. Use of the iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof according to claim 11, characterized in that the drug is intended for the preventive and/or therapeutic treatment of goitre and is used in the pure state or in combination with appropriate excipients in drinkable or ingestable form, in the form of capsules or ampoules, for example.
13. Use of the iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinatedQ derivatives thereof according to claim 11, characterized in that the drug is intended forQQ anti-inflammatory treatment in rheumatoid therapies, administered by general or topical methods. * β
14. Iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof, obtained by the process according to any one of the claims 1 to 10 for the use in oc the treatment of certain cancers by chemiemboiization.
15. Iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof, obtained by the process according to claim 14 for the use as carrier(s) for anticancer drug emulsified in said iodinated fatty acid(s), iodinated fatty acid ester(s) Or derivatives thereof, for tumoral lipophilic cells.
16. Iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof, obtained by the process according to any one of the claims 1 to 10 for the use as a contrast product.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9508582A FR2736549B1 (en) | 1995-07-11 | 1995-07-11 | ESTERS OF IODINE FATTY ACIDS, IODINE FATTY ACIDS AND DERIVATIVES THEREOF, OBTAINED BY IODOHYDRINATION USING ALKYLSILYL DERIVATIVES WITH ALKALINE IODIDES AND THEIR PHARMACOLOGICAL ACTIVITIES |
| PCT/FR1996/001075 WO1997003038A1 (en) | 1995-07-11 | 1996-07-10 | Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkylsilylated derivatives and alkaline iodides, and pharmacological activities thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AP874A true AP874A (en) | 2000-09-13 |
Family
ID=9481022
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1998/001180A AP874A (en) | 1995-07-11 | 1996-07-10 | Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof. |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6124357A (en) |
| EP (1) | EP0840720B1 (en) |
| CN (1) | CN1077880C (en) |
| AP (1) | AP874A (en) |
| AT (1) | ATE249414T1 (en) |
| AU (1) | AU6523496A (en) |
| BG (1) | BG63802B1 (en) |
| BR (1) | BR9609610A (en) |
| DE (1) | DE69629928T2 (en) |
| EA (1) | EA001719B1 (en) |
| FR (1) | FR2736549B1 (en) |
| GE (1) | GEP20002238B (en) |
| HU (1) | HUP9901340A3 (en) |
| IN (1) | IN185195B (en) |
| MA (1) | MA23935A1 (en) |
| OA (1) | OA10650A (en) |
| PL (1) | PL185807B1 (en) |
| RO (1) | RO120337B1 (en) |
| TR (1) | TR199800031T1 (en) |
| UA (1) | UA56142C2 (en) |
| WO (1) | WO1997003038A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6426367B1 (en) * | 1999-09-09 | 2002-07-30 | Efa Sciences Llc | Methods for selectively occluding blood supplies to neoplasias |
| FR2891461B1 (en) * | 2005-09-30 | 2010-09-03 | Jacques Theron | INJECTABLE VISCOUS MEDICINAL PREPARATION COMPRISING ETHANOL AND X-RAY OPAQUE LIPOSOLUBLE COMPOUND |
| CN101245007B (en) * | 2008-03-13 | 2011-03-23 | 武汉工程大学 | Process for producing iodination vegetable oil fatty acid ethyl ester |
| FR2976491B1 (en) * | 2011-06-14 | 2015-07-10 | R I P H | IODIZED FATTY ACID ESTERS CONTAINING AT LEAST 50 PER CENT OF MONOIODO STEARIC ACID ESTERS OR DERIVATIVES IN THE FORM OF A SOFT CAPSULE OR GELULE, USEFUL IN A NUCLEAR ACCIDENT. |
| CN107287029B (en) * | 2016-05-30 | 2021-04-06 | 江苏恒瑞医药股份有限公司 | Preparation method of iodized vegetable oil fatty acid ethyl ester |
| CN109251144B (en) * | 2017-07-12 | 2021-06-18 | 财团法人食品工业发展研究所 | Preparation method of iodized fatty acid ethyl ester |
| CN109251142A (en) * | 2017-07-12 | 2019-01-22 | 财团法人食品工业发展研究所 | Preparation method of iodized fatty acid ethyl ester |
| EP3664855A1 (en) | 2017-08-07 | 2020-06-17 | University of Geneva | Nanoemulsion of iodinated fatty acids for ct imaging |
| CN110387286A (en) * | 2018-04-18 | 2019-10-29 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of iodized vegetable fatty acids ethyl ester |
| CN109438240B (en) * | 2018-09-10 | 2022-05-03 | 季珉 | Preparation method of stable iodized linoleate |
| CN114606055B (en) * | 2020-12-08 | 2024-02-13 | 成都西岭源药业有限公司 | Method for removing unstable iodine combined in iodized vegetable oil fatty acid ethyl ester |
| EP4380687A1 (en) * | 2021-08-02 | 2024-06-12 | Microvention, Inc. | Iodinated fatty acids for medical imaging |
| PL245039B1 (en) * | 2022-02-15 | 2024-04-22 | Centrum Badan I Rozwoju Tech Dla Przemyslu Spolka Akcyjna | Bioactive candle and method of producing bioactive candle |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3513323A1 (en) * | 1985-04-13 | 1986-10-23 | Merck Patent Gmbh, 6100 Darmstadt | STABILIZED IODINE FATS AND METHOD FOR THE PRODUCTION THEREOF |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53119817A (en) * | 1977-03-26 | 1978-10-19 | Sinloihi Co Ltd | Glycerilltri*22iodoohexadecanoate* and process for preparing same |
-
1995
- 1995-07-11 FR FR9508582A patent/FR2736549B1/en not_active Expired - Fee Related
-
1996
- 1996-07-10 RO RO98-00028A patent/RO120337B1/en unknown
- 1996-07-10 DE DE69629928T patent/DE69629928T2/en not_active Expired - Lifetime
- 1996-07-10 BR BR9609610-1A patent/BR9609610A/en active Search and Examination
- 1996-07-10 GE GEAP19964133A patent/GEP20002238B/en unknown
- 1996-07-10 AP APAP/P/1998/001180A patent/AP874A/en active
- 1996-07-10 TR TR1998/00031T patent/TR199800031T1/en unknown
- 1996-07-10 WO PCT/FR1996/001075 patent/WO1997003038A1/en active IP Right Grant
- 1996-07-10 EP EP96924964A patent/EP0840720B1/en not_active Expired - Lifetime
- 1996-07-10 PL PL96324383A patent/PL185807B1/en not_active IP Right Cessation
- 1996-07-10 EA EA199800120A patent/EA001719B1/en not_active IP Right Cessation
- 1996-07-10 AT AT96924964T patent/ATE249414T1/en not_active IP Right Cessation
- 1996-07-10 AU AU65234/96A patent/AU6523496A/en not_active Abandoned
- 1996-07-10 HU HU9901340A patent/HUP9901340A3/en unknown
- 1996-07-10 US US08/981,931 patent/US6124357A/en not_active Expired - Lifetime
- 1996-07-11 IN IN1552DE1996 patent/IN185195B/en unknown
- 1996-07-11 MA MA24310A patent/MA23935A1/en unknown
- 1996-07-11 CN CN96107188A patent/CN1077880C/en not_active Expired - Fee Related
- 1996-10-07 UA UA98020668A patent/UA56142C2/en unknown
-
1998
- 1998-01-09 OA OA9800001A patent/OA10650A/en unknown
- 1998-02-05 BG BG102234A patent/BG63802B1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3513323A1 (en) * | 1985-04-13 | 1986-10-23 | Merck Patent Gmbh, 6100 Darmstadt | STABILIZED IODINE FATS AND METHOD FOR THE PRODUCTION THEREOF |
Also Published As
| Publication number | Publication date |
|---|---|
| BG102234A (en) | 1998-09-30 |
| MA23935A1 (en) | 1997-04-01 |
| HUP9901340A3 (en) | 1999-11-29 |
| BG63802B1 (en) | 2003-01-31 |
| EA001719B1 (en) | 2001-08-27 |
| BR9609610A (en) | 2002-05-07 |
| DE69629928D1 (en) | 2003-10-16 |
| GEP20002238B (en) | 2000-09-25 |
| OA10650A (en) | 2002-09-18 |
| US6124357A (en) | 2000-09-26 |
| FR2736549B1 (en) | 1997-10-10 |
| EP0840720A1 (en) | 1998-05-13 |
| AU6523496A (en) | 1997-02-10 |
| EA199800120A1 (en) | 1998-10-29 |
| MX9800322A (en) | 1998-09-30 |
| UA56142C2 (en) | 2003-05-15 |
| FR2736549A1 (en) | 1997-01-17 |
| CN1143067A (en) | 1997-02-19 |
| PL324383A1 (en) | 1998-05-25 |
| PL185807B1 (en) | 2003-08-29 |
| CN1077880C (en) | 2002-01-16 |
| ATE249414T1 (en) | 2003-09-15 |
| IN185195B (en) | 2000-12-02 |
| EP0840720B1 (en) | 2003-09-10 |
| HUP9901340A2 (en) | 1999-09-28 |
| DE69629928T2 (en) | 2004-07-22 |
| RO120337B1 (en) | 2005-12-30 |
| TR199800031T1 (en) | 1998-05-21 |
| WO1997003038A1 (en) | 1997-01-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2142468C1 (en) | Cholesterol and fatty acid esters, method of treatment and pharmaceutical or cosmetic composition | |
| AP874A (en) | Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof. | |
| DE4141746A1 (en) | 20-METHYL-SUBSTITUTED VITAMIN D DERIVATIVES | |
| CN1097735A (en) | Derivative of fatty acid and the pharmaceutical composition that contains derivative of fatty acid | |
| EP0823889A1 (en) | 1,3-propane diol derivatives as bioactive compounds | |
| JPH07179398A (en) | Triglyceride | |
| JP2010509204A (en) | Fatty acid alcohol | |
| US5202313A (en) | Bilobalide derivatives, their applications and formulations containing them | |
| WO1994010125A1 (en) | Glycerin derivatives and uses thereof | |
| JPS63104917A (en) | Oral administration composition | |
| UA61884C2 (en) | 1,3-propane diol derivatives as biologically active compounds | |
| WO1991012238A1 (en) | Side-chain-homologous vitamin d derivatives, process for producing them, pharmaceutical preparations containing these derivatives and their use as medicaments | |
| GB2203042A (en) | Compositions acting on the heart and cardio-vascular system | |
| MXPA98000322A (en) | Esters of iodine fatty acids, iodine fatty acids and derivatives thereof, produced by iodohidrination using alkilsililated derivatives and alkaline iodues, and their activities farmacologi | |
| JPH0667869B2 (en) | Pharmaceutical composition for treating adrenoleukodystrophy | |
| JPS62482A (en) | Prostacyclines | |
| CN115160399B (en) | Soap-skin acid compound, preparation method and medical application thereof | |
| US4758591A (en) | Dialkanoyloxybenzylidene dialkanoate | |
| DE4234382A1 (en) | New 25-carboxylic acid cpds., exhibiting vitamin=D, anti-proliferative and cell-differentiating activity - are useful for treatment of e.g., psoriasis, acne, malignant tumours and immune disorders e.g. diabetes | |
| OA20568A (en) | Micromolecule PI4Klllα inhibitor composition, preparation method therefor and use thereof. | |
| TW546138B (en) | Compounds with 1,3-propane diol linked structure and 1,3-propane diol derivatives | |
| DE1643508C3 (en) | Carbonic acid esters of salicylic acid and process for their preparation | |
| JPS61267571A (en) | 2-(4-chlorophenoxy)-2-methylpropionic acid ester and antilipemic agent containing said compound as active constituent | |
| KR100984213B1 (en) | A novel farnesyl transferase inhibitors | |
| JPH06192177A (en) | Glycerol derivative and platelet coagulation inhibitor and fat infusion agent containing the same |