US3106562A - Esters of nicotinic acid - Google Patents
Esters of nicotinic acid Download PDFInfo
- Publication number
- US3106562A US3106562A US127158A US12715861A US3106562A US 3106562 A US3106562 A US 3106562A US 127158 A US127158 A US 127158A US 12715861 A US12715861 A US 12715861A US 3106562 A US3106562 A US 3106562A
- Authority
- US
- United States
- Prior art keywords
- esters
- nicotinic acid
- addition salts
- acid addition
- oil
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000002148 esters Chemical class 0.000 title claims description 17
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title claims description 15
- 229960003512 nicotinic acid Drugs 0.000 title description 6
- 235000001968 nicotinic acid Nutrition 0.000 title description 6
- 239000011664 nicotinic acid Substances 0.000 title description 6
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- OZICRFXCUVKDRG-UHFFFAOYSA-N 2-[2-hydroxyethyl(propyl)amino]ethanol Chemical compound CCCN(CCO)CCO OZICRFXCUVKDRG-UHFFFAOYSA-N 0.000 description 2
- 241000698776 Duma Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- -1 amino alcohol esters Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- AKNUHUCEWALCOI-UHFFFAOYSA-N N-ethyldiethanolamine Chemical compound OCCN(CC)CCO AKNUHUCEWALCOI-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Definitions
- n have a minimum value of 2 and a maximum value of 4 and R designates hydrogen or an alkyl group having a maximum of 4 carbon atoms.
- esters of simple alcohols with both straight, branched and cyclic hydrocarbon chains have previously been produced.
- a number of amino alcohol esters are also known in literature.
- esters have a comparatively short time of onset and an intensive effect combined with the disadvantage that they give the same side effects as the nicotinic acid, prickling of the skin and sometimes itching. These esters moreover give too short a duration, as the intensive vasodilating effect also rapidly diminishes.
- nicotinic acid esters of the above Formula I have extremely good therapeutic properties.
- the new compounds have an approximate time of onset of 5-10 minutes and a duration of 5-6 hours.
- the new esters are manufactured according to usual and known esterification methods.
- dial-cohols of the formula wherein: m, n, and R have the same si ificance as in Formula I can be made to react with nicotinic acid, nicotinic acid chloride or with a lower nicotinic acid ester.
- the esters obtained have the character of an oil and are suitable for the production of ointments with a hyperaemic effect.
- esters of this invention should be transformed into salts soluble in water, which a human being can stand. It is then appropriate to treat the esters with an inorganic acid such as phosphoric acid, sulfuric acid, hydrochloric acid or some other appropriate acid which forms a pharmaceutically acceptable acid addition salt with the ester.
- an inorganic acid such as phosphoric acid, sulfuric acid, hydrochloric acid or some other appropriate acid which forms a pharmaceutically acceptable acid addition salt with the ester.
- Example 1 1275 g. of nicotinic chloride hydrochloride, divided up into small portions, is placed in a round flask with a reflux cooler, stirrer and thermometer. The flask is arranged in such a way that both cooling and heating can take place. The flask has previously been charged with 500 g. of propyl diethanol amine and 1000 g. of pyridine. While adding the nicotinic acid chloride hydro chloride the flask is cooled with water around it, so that the temperature does not exceed C. Thereafter the reaction mixture is heated for 1 hour at 100- C.
- the mixture is finally digested twice with 100 g. of anhydrous sodium sulphate and once with active carbon. After the carbon has been filtered off, the benzene is distilled off, as well as the pyridine which has not been Washed out. If there is an odor of pyridine from the residue in the distillation flask, 100 ml. of xylene is added, which is distilled olf in vacuum. This operation is followed by the same operation with 100 ml. of benzene. The lightly opalescent residue, an oil, consisting of propyl-diethanol-amino dinicotinate is filtered through infusorial :earth. A yield of approximately 950 g.
- Ethyldiethanol-amino-dinicotin'ate remains in the form of a brown oil 'with a low viscosity, when the other has evaporated. Approximately 900 g. corresponding to a yield of approximately 80% is obtained. Nitrogen content according to Dumas 12.18% (theoretically 12.28%). Refnactive index, N 1.5394.
- esters having the formula 0 0 II II C0 ⁇ /OC it (I) wherein: m and n each have a minimum value of 2 and a maximum value of 4 and R is a member of the group consisting of hydrogen and an alkyl group having a maximum of 4 carbon atoms.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Description
Patented Oct. 8, 1963 ESTERS F NICOTINIC ACID Bo Thuresson at Ekenstam and Fritz Henn, Bofors, and
Nils Evald Natanael Johansson, Karlskoga, Sweden,
assignors to Aktiebolaget Bofors, Bofors, Sweden, a
corporation of Sweden No Drawing. Filed July 27, 1961, Ser. No. 127,158 9 Claims. (Cl. 260-2955) O the O I Oilon); r
t R (I) wherein: m and n have a minimum value of 2 and a maximum value of 4 and R designates hydrogen or an alkyl group having a maximum of 4 carbon atoms.
It has been known for a long time that nicotinic acid and some of its esters have :a hyperaemic elfect on skin. This effect occurs after a certain latency time with different intensity and duration, depending upon the individual configuration of the esters and according to a physiological mechanism which has not yet been completely elucidated.
A number of esters of simple alcohols with both straight, branched and cyclic hydrocarbon chains have previously been produced. A number of amino alcohol esters are also known in literature.
Many of the last mentioned esters have a comparatively short time of onset and an intensive effect combined with the disadvantage that they give the same side effects as the nicotinic acid, prickling of the skin and sometimes itching. These esters moreover give too short a duration, as the intensive vasodilating effect also rapidly diminishes.
Tests have been made with nicotinic acid esters of high molecule polyols. These esters almost without exception show too slight an effect in the blood vessels of the skin, and for this reason, cannot be used.
Extensive scientific investigations leading to the present invention have resulted in the discovery that nicotinic acid esters of the above Formula I have extremely good therapeutic properties. The new compounds have an approximate time of onset of 5-10 minutes and a duration of 5-6 hours.
The new esters are manufactured according to usual and known esterification methods. Thus, dial-cohols of the formula wherein: m, n, and R have the same si ificance as in Formula I, can be made to react with nicotinic acid, nicotinic acid chloride or with a lower nicotinic acid ester. The esters obtained have the character of an oil and are suitable for the production of ointments with a hyperaemic effect.
If it is desired to inject the esters of this invention, the esters should be transformed into salts soluble in water, which a human being can stand. It is then appropriate to treat the esters with an inorganic acid such as phosphoric acid, sulfuric acid, hydrochloric acid or some other appropriate acid which forms a pharmaceutically acceptable acid addition salt with the ester.
The amino alcohol nitrogen facilitates the salt formation to the highest possible degree. These novel esters when injected produce vasodilation.
The present inventionwil-l be described in more detail in connection with the following examples.
Example 1 1275 g. of nicotinic chloride hydrochloride, divided up into small portions, is placed in a round flask with a reflux cooler, stirrer and thermometer. The flask is arranged in such a way that both cooling and heating can take place. The flask has previously been charged with 500 g. of propyl diethanol amine and 1000 g. of pyridine. While adding the nicotinic acid chloride hydro chloride the flask is cooled with water around it, so that the temperature does not exceed C. Thereafter the reaction mixture is heated for 1 hour at 100- C. After the mixture has cooled somewhat, it is poured out into 5 litres of ice water, and a sulhcient quantity of ice is used so that the temperature does not exceed 20 C. A yellowish brown solution is obtained from which the color is removed by treating it with active carbon after the pH has been raised to approximately 5 with 40% sodium hydroxide solution with simultaneous cooling. Under continued stirring the pH is raised after filtering to 11-12. The precipitated oil is separated and the water phase is extracted twice with 500 of benzene. The benzene layeris mixed with the oil and the mixture is thereafter washed first twice with 5% sodium hydroxide and thereafter twice with Water.
The mixture is finally digested twice with 100 g. of anhydrous sodium sulphate and once with active carbon. After the carbon has been filtered off, the benzene is distilled off, as well as the pyridine which has not been Washed out. If there is an odor of pyridine from the residue in the distillation flask, 100 ml. of xylene is added, which is distilled olf in vacuum. This operation is followed by the same operation with 100 ml. of benzene. The lightly opalescent residue, an oil, consisting of propyl-diethanol-amino dinicotinate is filtered through infusorial :earth. A yield of approximately 950 g. is obtained, or approximately Nitrogen content ac- ;cording to Dumas 11.86% (theoretically 11.76%). Spe- If the propyl-diethanol amine according to Example 1 is replaced by ethyl-diethanol amine, after a reaction time of 4 hours at 110 C. ethyl-diethanol-amino dinicotinate is obtained as a final product. After the end of the reaction time the reaction substance is poured out into 8 liters of ice water and the temperature is then not allowed to exceed 20" C. At a pH of approximately 1, the solution is treated with -200 g. of active carbon and filtered. Thereafter 40% sodium hydroxide solution is added to the solution to pH 12 and the oil thereby obtained is separated and the residue is extracted several times with ether. The ether extract is mixed with the oil, and the mixture is washed twice with 1000 ml. of 5% sodium hydroxide and rfinally several times with water. The ether extract is dried with sodium sulphate and the ether is distilled off. The residue is mixed with 250 ml. of xylene, which is distilled off in vacuum. The same operation is repeated with benzene. The distillation residue is dissolved in 2500 ml. of ether and the solution is treated with active carbon and filtered. Ethyldiethanol-amino-dinicotin'ate remains in the form of a brown oil 'with a low viscosity, when the other has evaporated. Approximately 900 g. corresponding to a yield of approximately 80% is obtained. Nitrogen content according to Dumas 12.18% (theoretically 12.28%). Refnactive index, N 1.5394.
It will be understood that the foregoing description of the invention and the examples set forth are merely illustrative of the principles thereof. Accordingly, the
3 appended claims are to be construed as defining the invention within the spirit and scope thereof.
We claim:
1. A member of the group consisting of nicotinic acid esters and the pharmaceutically acceptable acid addition salts thereof, said esters having the formula 0 0 II II C0\ /OC it (I) wherein: m and n each have a minimum value of 2 and a maximum value of 4 and R is a member of the group consisting of hydrogen and an alkyl group having a maximum of 4 carbon atoms.
2. Propyl-diethanol-amino dinicotinate.
3. Ethyl-diethanol-amino dinicotinate.
4. The phosphoric acid addition salts of the compound of claim 2.
5. The sulfuric acid addition salts of the compound of claim 2.
6. The hydrochloric acid addition salts of the compound of claim :2.
7. The phosphoric acid addition salts of the compound of claim 3.
8. The sulfuric acid addition salts of the compound of claim 3.
9. The hydrochloric acid addition salts of the compound of claim 3.
References Cited in the file of this patent UNITED STATES PATENTS 2,766,252 Schlesinger Oct. 9, 1956 2,863,873 Ekeustam et a1. Dec. 9, 1958 OTHER REFERENCES
Claims (1)
1. A MEMBER OF THE GROUP CONSISTING OF NICOTINIC ACID ESTERS AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, SAID ESTERS HAVING THE FORMULA
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US127158A US3106562A (en) | 1961-07-27 | 1961-07-27 | Esters of nicotinic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US127158A US3106562A (en) | 1961-07-27 | 1961-07-27 | Esters of nicotinic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3106562A true US3106562A (en) | 1963-10-08 |
Family
ID=22428609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US127158A Expired - Lifetime US3106562A (en) | 1961-07-27 | 1961-07-27 | Esters of nicotinic acid |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3106562A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3996234A (en) * | 1972-04-18 | 1976-12-07 | Bayer Aktiengesellschaft | 1,4-Dihydropyridine carboxylic acid esters |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2766252A (en) * | 1955-01-24 | 1956-10-09 | Endo Lab | Esters of nicotinic acid |
| US2863873A (en) * | 1956-08-29 | 1958-12-09 | Bofors Ab | Esters of nicotinic acid |
-
1961
- 1961-07-27 US US127158A patent/US3106562A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2766252A (en) * | 1955-01-24 | 1956-10-09 | Endo Lab | Esters of nicotinic acid |
| US2863873A (en) * | 1956-08-29 | 1958-12-09 | Bofors Ab | Esters of nicotinic acid |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3996234A (en) * | 1972-04-18 | 1976-12-07 | Bayer Aktiengesellschaft | 1,4-Dihydropyridine carboxylic acid esters |
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