CA2061197C - Salicyloyl carnitine and process for its preparation - Google Patents
Salicyloyl carnitine and process for its preparation Download PDFInfo
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- CA2061197C CA2061197C CA 2061197 CA2061197A CA2061197C CA 2061197 C CA2061197 C CA 2061197C CA 2061197 CA2061197 CA 2061197 CA 2061197 A CA2061197 A CA 2061197A CA 2061197 C CA2061197 C CA 2061197C
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- Prior art keywords
- trimethylammonio
- butyric acid
- acid betaine
- hydroxybenzoyloxy
- pharmaceutically acceptable
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- 238000000034 method Methods 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title claims description 4
- 229960004203 carnitine Drugs 0.000 title description 8
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 title 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229960003237 betaine Drugs 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 230000002496 gastric effect Effects 0.000 claims abstract description 8
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 11
- 230000000202 analgesic effect Effects 0.000 claims description 9
- IVKTUTOOZFCEQC-UHFFFAOYSA-N C[N+](C)(C)CC(CC([O-])=O)OC(=O)C1=CC=CC=C1O Chemical compound C[N+](C)(C)CC(CC([O-])=O)OC(=O)C1=CC=CC=C1O IVKTUTOOZFCEQC-UHFFFAOYSA-N 0.000 claims description 7
- IVKTUTOOZFCEQC-SNVBAGLBSA-N (3r)-3-(2-hydroxybenzoyl)oxy-4-(trimethylazaniumyl)butanoate Chemical compound C[N+](C)(C)C[C@@H](CC([O-])=O)OC(=O)C1=CC=CC=C1O IVKTUTOOZFCEQC-SNVBAGLBSA-N 0.000 claims description 6
- -1 2-methoxybenzoyl halide Chemical class 0.000 claims description 6
- 210000004400 mucous membrane Anatomy 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- AIBYQZDTCMYHGF-UHFFFAOYSA-N COC1=CC=CC=C1C(=O)OC(CC([O-])=O)C[N+](C)(C)C Chemical compound COC1=CC=CC=C1C(=O)OC(CC([O-])=O)C[N+](C)(C)C AIBYQZDTCMYHGF-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- ZCCXZMHMPCCJIG-UHFFFAOYSA-N 2-(trimethylazaniumyl)acetate;hydrobromide Chemical compound [Br-].C[N+](C)(C)CC(O)=O ZCCXZMHMPCCJIG-UHFFFAOYSA-N 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- AIBYQZDTCMYHGF-LLVKDONJSA-N C[N+](C)(C)C[C@@H](CC([O-])=O)OC(C1=CC=CC=C1OC)=O Chemical compound C[N+](C)(C)C[C@@H](CC([O-])=O)OC(C1=CC=CC=C1OC)=O AIBYQZDTCMYHGF-LLVKDONJSA-N 0.000 claims description 2
- IVKTUTOOZFCEQC-JTQLQIEISA-N C[N+](C)(C)C[C@H](CC([O-])=O)OC(C1=CC=CC=C1O)=O Chemical compound C[N+](C)(C)C[C@H](CC([O-])=O)OC(C1=CC=CC=C1O)=O IVKTUTOOZFCEQC-JTQLQIEISA-N 0.000 claims 3
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 claims 2
- AIBYQZDTCMYHGF-NSHDSACASA-N COC1=C(C(=O)O[C@@H](CC(=O)[O-])C[N+](C)(C)C)C=CC=C1 Chemical compound COC1=C(C(=O)O[C@@H](CC(=O)[O-])C[N+](C)(C)C)C=CC=C1 AIBYQZDTCMYHGF-NSHDSACASA-N 0.000 claims 1
- 230000001335 demethylating effect Effects 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 229960001138 acetylsalicylic acid Drugs 0.000 abstract description 9
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 3
- RZNHSEZOLFEFGB-UHFFFAOYSA-N 2-methoxybenzoyl chloride Chemical compound COC1=CC=CC=C1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- JXXCENBLGFBQJM-FYZOBXCZSA-N [(2r)-3-carboxy-2-hydroxypropyl]-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)C[C@H](O)CC(O)=O JXXCENBLGFBQJM-FYZOBXCZSA-N 0.000 abstract 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 229960004889 salicylic acid Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- WREGFMQRDKANCE-FYZOBXCZSA-N (3r)-3-hydroxy-4-(trimethylazaniumyl)butanoate;hydrobromide Chemical compound Br.C[N+](C)(C)C[C@H](O)CC([O-])=O WREGFMQRDKANCE-FYZOBXCZSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000003463 organelle Anatomy 0.000 description 2
- 230000009103 reabsorption Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003872 salicylic acid derivatives Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- JXXCENBLGFBQJM-UHFFFAOYSA-N (3-carboxy-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CC(O)=O JXXCENBLGFBQJM-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002337 anti-port Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960003403 betaine hydrochloride Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- HOPSCVCBEOCPJZ-UHFFFAOYSA-N carboxymethyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)=O HOPSCVCBEOCPJZ-UHFFFAOYSA-N 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Novel 3-(2-hydroxybenzoyloxy)-4-(trimethylarnmonio)-butyric acid betaine and its pharmaceutically acceptable salts are disclosed. The compounds are distinguished by high water solubility, minimum toxicity, and good gastric tolerance vis-a-vis acetylsalicylic acid and can be prepared from carnitine hydrochloride and o-methoxybenzoyl chloride.
Description
This invention relates to the novel 3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine of the general formula:
~ Ho /, p Ca3 0 (I) CH3.~. N' I ~z in racemic and optically active form and pharmaceutically acceptable salts thereof, as well as a new process for its preparation. As an ester of salicylic acid with carnitine (salicyloyl carnitine), 3-(2-hydroxybenzoyloxy)-~-(trimethylammonio)-butyric acid betaine is a salicylic acid derivative with promising therapeutic properties.
Salicylic acid is used. to a great extent as an analgetic in the form of its acetyl derivative. Although this acetyl derivative (known, inter alia, as Aspirin') was originally developed to reduce undesirable side-effects of the previously known salicylic acid, it is nevertheless burdened with some properties which limit its use. Among these disadvantageous properties is, above all, its low water solubility, especially in an acidic environment, such as in gastric juice. The low solubility can lead to precipitation of the active component in the stomach when aqueous solutions are orally administered. This effect is undesirable not only in persons having a sensitive or already damaged gastric mucous membrane, as it may lead to serious side-effects in these persons, but it also generally delays reabsorption, and thus postpones the onset of the analgetic effect.
* Trade-mark Moreover, acetylsalicylic acid can virtually only be administered orally, and not parenterally (e. g.
intravenously intraperitoneally) or topically. It is for facilitating a quick response while protecting the gastrointestinal tract that a parenteral application would often be desirable.
Thus, the object of this invention is to provide a salicylic acid derivative which has good water solubility in an acidic environment, a high reabsorption rate and minim;~m toxicity, and which can be administered both enterally and parenterally or topically and exhibits a quick analgetic effect in all forms of administration.
Accordingly, the invention provides 3-(2 hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine of formula I above. This compound has an asymmetric carbon atom and can therefore occur in two mirror-inverted optically active forms and as a racemic mixture. All forms constitute a part of the invention;
however, the enantiomer with (R) configuration, which is derived from the naturally occurring L-carnitine, is preferred.
The advantageous physical and chemical properties, such as high water solubility and a good pH
value of the solution, are of course, also attained by the (S) enantiomer and the racemate. However, L-carnitine is known as an acyl-group transmitter in fat metabolism. It is actively absorbed in most of the organs of the body via high affinity transport systems and in cellular organelles (mitochondria etc.) via antiport transporters. There is reason to assume that salicyloyl L-carnitine also reaches the cells and organelles via these transport systems and that the onset of the analgetic effect is thus accelerated.
Acyl L-carnitines continue to be easily dissociated by enzymes of the individual cells, so that one can expect a quick release of the salicylate radical.
~ Ho /, p Ca3 0 (I) CH3.~. N' I ~z in racemic and optically active form and pharmaceutically acceptable salts thereof, as well as a new process for its preparation. As an ester of salicylic acid with carnitine (salicyloyl carnitine), 3-(2-hydroxybenzoyloxy)-~-(trimethylammonio)-butyric acid betaine is a salicylic acid derivative with promising therapeutic properties.
Salicylic acid is used. to a great extent as an analgetic in the form of its acetyl derivative. Although this acetyl derivative (known, inter alia, as Aspirin') was originally developed to reduce undesirable side-effects of the previously known salicylic acid, it is nevertheless burdened with some properties which limit its use. Among these disadvantageous properties is, above all, its low water solubility, especially in an acidic environment, such as in gastric juice. The low solubility can lead to precipitation of the active component in the stomach when aqueous solutions are orally administered. This effect is undesirable not only in persons having a sensitive or already damaged gastric mucous membrane, as it may lead to serious side-effects in these persons, but it also generally delays reabsorption, and thus postpones the onset of the analgetic effect.
* Trade-mark Moreover, acetylsalicylic acid can virtually only be administered orally, and not parenterally (e. g.
intravenously intraperitoneally) or topically. It is for facilitating a quick response while protecting the gastrointestinal tract that a parenteral application would often be desirable.
Thus, the object of this invention is to provide a salicylic acid derivative which has good water solubility in an acidic environment, a high reabsorption rate and minim;~m toxicity, and which can be administered both enterally and parenterally or topically and exhibits a quick analgetic effect in all forms of administration.
Accordingly, the invention provides 3-(2 hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine of formula I above. This compound has an asymmetric carbon atom and can therefore occur in two mirror-inverted optically active forms and as a racemic mixture. All forms constitute a part of the invention;
however, the enantiomer with (R) configuration, which is derived from the naturally occurring L-carnitine, is preferred.
The advantageous physical and chemical properties, such as high water solubility and a good pH
value of the solution, are of course, also attained by the (S) enantiomer and the racemate. However, L-carnitine is known as an acyl-group transmitter in fat metabolism. It is actively absorbed in most of the organs of the body via high affinity transport systems and in cellular organelles (mitochondria etc.) via antiport transporters. There is reason to assume that salicyloyl L-carnitine also reaches the cells and organelles via these transport systems and that the onset of the analgetic effect is thus accelerated.
Acyl L-carnitines continue to be easily dissociated by enzymes of the individual cells, so that one can expect a quick release of the salicylate radical.
Studies on rats have already shown an extremely slight acute toxicity of salicyloyl L-carnitine. However, dosages of up to 1000 mg/kg body weight were easily tolerated orally. Furthermore, there were no harmful side-s effects observed with intravenous and intraperitoneal administration of therapeutic amounts.
In a first study, the analgetic effect of salicyloyl L-carnitine was compared with that of Aspirin after being orally, intraperitoneally and intravenously administered to rats.
With the oral application, salicyloyl L-carnitine showed a retarded effect by 1.5 hour vis-a-vis acetylsalicylic acid. With intraperitoneal and intravenous applications, a clear analgetic effect readily set in after 10 to 15 minutes. The invention also provides salts of the salicyloyl carnitine with pharmaceutically acceptable acids.
According to the invention, salicyloyl carnitine is prepared by esterifying a carnitine hydrohalide, preferably hydrochloride, with a 2-methoxybenzoyl halide (o-anisoylhalide), preferably with acid chloride, to form the corresponding 3-(2-methoxy benzoyloxy)-4-(trimethylammonio)-butyric acid betaine hydrohalide (o-anisoyl carnitine hydrohalide).
A polar erotic solvent which is inert to hydrochloric acid is preferably used as the solvent.
Advantageously, lower aliphatic carboxylic acids are used, such as acetic acid or formic acid. Trichloroacetic acid is preferred.
The reaction temperature in this process is advantageously from 50 to 90°C, and the reaction time from 1 to 4 hours.
By subsequently treating the o-amisoylcarnitine hydrohalide with an excess of hydrogen bromide in glacial acetic acid, it is possible to convert the methoxy group to a hydroxy group. The conversion with hydrogen bromide is preferably carried out at 20 to 80°C. Due to an excess of hydrogen bromide, the target compound is obtained in the form of the hydrobromide, which can then be isolated in crystalline form.
For pharmaceutical applications, the hydrobromide is suitably converted with a base to the free betaine.
Enhanced solubility is advantageously attained by treating the free betaine with a slightly basic anion exchanger.
Such slightly basic anion exchanger carries primary, l0 secondary and tertiary amino groups as functional groups, and has a further advantage in that it neither hydrolyzes the ester group of the product nor binds it over the slightly acidic phenol function. If a dissolved base is used for the free betaine conversion, a salt would result which has solubility behaviour similar to the betaine and would, therefore, not be easy to separate.
Depending on the basic material, the process described above is equally suitable for the preparation of racemic as well as optically active salicyloyl carnitine.
It is also within the scope of the process of the invention to subsequently convert the betaine to a corresponding salt by the addition of a pharmaceutically acceptable acid.
The following Examples illustrate the process according to the invention.
Examgle 1 (R)-(-)-3-(2-methoxybenzoyloxy)-4-(trimethylammonio)-butyric-acid betaine-hydrochloride (o-anisoyl L-carnitine hydrochloride) 61.8 g of L-carnitine hydrochloride were dissolved in 152.0 g of trichloroacetic acid at 80°C> 80.0 g of 2-methoxybenzoyl chloride was added dropwise over 30 minutes at 80°C. The reaction mixture was stirred for an additional 90 minutes at the same temperature, then cooled to 30°C and, while being stirred, mixed with 500 ml diethyl 2~~~.~.~'~
ether and 200 ml ethyl acetate. The mixture was heated to reflux for 30 minutes, whereby the product crystallized.
The raw product was filtered off and dried (raw yield: 112.6 g), and subsequently suspended in 200 ml 5 isopropanol at 80°C, then filtered and rinsed twice with 50 ml isopropanol in each case.
Yield: 75.7 g (73.0%) colourless crystals Melting point: 186-190°C.
[a] DO - -28.8° (c = 1, water) ~H-NMR (DMSO-db, 300 MHz) 8 7.02 - 7.75 (m, 4H) 5.67 - 5.75 (m, 1H) 3.78 - 4.02 (m, 2H) 3.84 (s, 3H) 3.22 (s, 9H) 2.80 - 2.90 (m, 2H) Example 2 (R)-(-)-3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine-hydrobromide (salicyloyl L-carnitine hydrobromide) 24.0 g of o-anisoyl L-carnitine hydrochloride (prepared as per Example 1) were dissolved in 200 ml of a 30% solution of hydrogen bromide in glacial acetic acid and stirred for 6 hours at 60 ° C. The reaction mixture was then evaporated under vacuum and the residue suspended and filtered with 200 ml diethyl ether. The crystalline raw product was recrystallized twice from 110 ml hot isopropanol in each case.
Yield: 14.0 g (50.2%) colourless crystals Melting point: 173-175°C
[a]DO - -27.2° (c = 1, water) Example 3 (R)-(-)-3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine (salicyloyl L-carnitine) 13.0 g of salicyloyl L-carnitine hydrobromide (prepared as per Example 2) were dissolved in 130 m1 water.
The solution was filtered over a column with 58 g of a slightly basic anion exchanger (Amberlite* IRA-93) and concentrated under vacuum. The product was precipitated by the addition of 60 ml of acetone. The crystalline product was filtered off and dried under vacuum at 40°C.
Yield: 10.0 g (quantitatively) colourless crystals Melting point: 120-122°C
[a] DO - -25.0° (c = 1, water) Elementary Analysis Reported: C 59.5 H 6.9 N 4.9 Br - C1 -Found: C 59,8 H 6.8 N 5.0 Br <0.1 C1 <0.1 Gastric Tolerance Test on Rats (Ulcer Index The (R)-(-)-3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric-acid betaine (salicoyl L-carnitine = SC) was tested on male rats in comparison to acetylsalicylic acid (ASA) by inducing gastric mucous membrane changes based on the method of Okabe et al., Japan. J. Pharmacol. 1974, 24, 363 ff.
The test substances were administered p.o. to the test rats in a 1% carboxymethyl cellulose suspension (1%
CMC). The gastric mucous membrane changes were measured by the Ulcer Index according to Chaumontet et al., Arzneimittelforschung [Pharmacological Research] 1978, 28, 2047-2178.
* Trade-mark 2~~~1~~
The results are shown in Table 1 Table 1 Substance Ulcer Index Number of (U. I.) Rats Tested Comparison 1% CMC 1 ml/250 63.00 10 g ComparisonASA200 mgkg-~ 300.00 20 Invention SC 200 mgkg~ 144.00 10 Invention SC 500 mgkg~ 200.00 10 Invention SC 1000mg>kg~ 200.00 10 CMC - carboxymethyl cellulose ASA - acetylsalicylic acid SC - salicoyl L-carnitine
In a first study, the analgetic effect of salicyloyl L-carnitine was compared with that of Aspirin after being orally, intraperitoneally and intravenously administered to rats.
With the oral application, salicyloyl L-carnitine showed a retarded effect by 1.5 hour vis-a-vis acetylsalicylic acid. With intraperitoneal and intravenous applications, a clear analgetic effect readily set in after 10 to 15 minutes. The invention also provides salts of the salicyloyl carnitine with pharmaceutically acceptable acids.
According to the invention, salicyloyl carnitine is prepared by esterifying a carnitine hydrohalide, preferably hydrochloride, with a 2-methoxybenzoyl halide (o-anisoylhalide), preferably with acid chloride, to form the corresponding 3-(2-methoxy benzoyloxy)-4-(trimethylammonio)-butyric acid betaine hydrohalide (o-anisoyl carnitine hydrohalide).
A polar erotic solvent which is inert to hydrochloric acid is preferably used as the solvent.
Advantageously, lower aliphatic carboxylic acids are used, such as acetic acid or formic acid. Trichloroacetic acid is preferred.
The reaction temperature in this process is advantageously from 50 to 90°C, and the reaction time from 1 to 4 hours.
By subsequently treating the o-amisoylcarnitine hydrohalide with an excess of hydrogen bromide in glacial acetic acid, it is possible to convert the methoxy group to a hydroxy group. The conversion with hydrogen bromide is preferably carried out at 20 to 80°C. Due to an excess of hydrogen bromide, the target compound is obtained in the form of the hydrobromide, which can then be isolated in crystalline form.
For pharmaceutical applications, the hydrobromide is suitably converted with a base to the free betaine.
Enhanced solubility is advantageously attained by treating the free betaine with a slightly basic anion exchanger.
Such slightly basic anion exchanger carries primary, l0 secondary and tertiary amino groups as functional groups, and has a further advantage in that it neither hydrolyzes the ester group of the product nor binds it over the slightly acidic phenol function. If a dissolved base is used for the free betaine conversion, a salt would result which has solubility behaviour similar to the betaine and would, therefore, not be easy to separate.
Depending on the basic material, the process described above is equally suitable for the preparation of racemic as well as optically active salicyloyl carnitine.
It is also within the scope of the process of the invention to subsequently convert the betaine to a corresponding salt by the addition of a pharmaceutically acceptable acid.
The following Examples illustrate the process according to the invention.
Examgle 1 (R)-(-)-3-(2-methoxybenzoyloxy)-4-(trimethylammonio)-butyric-acid betaine-hydrochloride (o-anisoyl L-carnitine hydrochloride) 61.8 g of L-carnitine hydrochloride were dissolved in 152.0 g of trichloroacetic acid at 80°C> 80.0 g of 2-methoxybenzoyl chloride was added dropwise over 30 minutes at 80°C. The reaction mixture was stirred for an additional 90 minutes at the same temperature, then cooled to 30°C and, while being stirred, mixed with 500 ml diethyl 2~~~.~.~'~
ether and 200 ml ethyl acetate. The mixture was heated to reflux for 30 minutes, whereby the product crystallized.
The raw product was filtered off and dried (raw yield: 112.6 g), and subsequently suspended in 200 ml 5 isopropanol at 80°C, then filtered and rinsed twice with 50 ml isopropanol in each case.
Yield: 75.7 g (73.0%) colourless crystals Melting point: 186-190°C.
[a] DO - -28.8° (c = 1, water) ~H-NMR (DMSO-db, 300 MHz) 8 7.02 - 7.75 (m, 4H) 5.67 - 5.75 (m, 1H) 3.78 - 4.02 (m, 2H) 3.84 (s, 3H) 3.22 (s, 9H) 2.80 - 2.90 (m, 2H) Example 2 (R)-(-)-3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine-hydrobromide (salicyloyl L-carnitine hydrobromide) 24.0 g of o-anisoyl L-carnitine hydrochloride (prepared as per Example 1) were dissolved in 200 ml of a 30% solution of hydrogen bromide in glacial acetic acid and stirred for 6 hours at 60 ° C. The reaction mixture was then evaporated under vacuum and the residue suspended and filtered with 200 ml diethyl ether. The crystalline raw product was recrystallized twice from 110 ml hot isopropanol in each case.
Yield: 14.0 g (50.2%) colourless crystals Melting point: 173-175°C
[a]DO - -27.2° (c = 1, water) Example 3 (R)-(-)-3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine (salicyloyl L-carnitine) 13.0 g of salicyloyl L-carnitine hydrobromide (prepared as per Example 2) were dissolved in 130 m1 water.
The solution was filtered over a column with 58 g of a slightly basic anion exchanger (Amberlite* IRA-93) and concentrated under vacuum. The product was precipitated by the addition of 60 ml of acetone. The crystalline product was filtered off and dried under vacuum at 40°C.
Yield: 10.0 g (quantitatively) colourless crystals Melting point: 120-122°C
[a] DO - -25.0° (c = 1, water) Elementary Analysis Reported: C 59.5 H 6.9 N 4.9 Br - C1 -Found: C 59,8 H 6.8 N 5.0 Br <0.1 C1 <0.1 Gastric Tolerance Test on Rats (Ulcer Index The (R)-(-)-3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric-acid betaine (salicoyl L-carnitine = SC) was tested on male rats in comparison to acetylsalicylic acid (ASA) by inducing gastric mucous membrane changes based on the method of Okabe et al., Japan. J. Pharmacol. 1974, 24, 363 ff.
The test substances were administered p.o. to the test rats in a 1% carboxymethyl cellulose suspension (1%
CMC). The gastric mucous membrane changes were measured by the Ulcer Index according to Chaumontet et al., Arzneimittelforschung [Pharmacological Research] 1978, 28, 2047-2178.
* Trade-mark 2~~~1~~
The results are shown in Table 1 Table 1 Substance Ulcer Index Number of (U. I.) Rats Tested Comparison 1% CMC 1 ml/250 63.00 10 g ComparisonASA200 mgkg-~ 300.00 20 Invention SC 200 mgkg~ 144.00 10 Invention SC 500 mgkg~ 200.00 10 Invention SC 1000mg>kg~ 200.00 10 CMC - carboxymethyl cellulose ASA - acetylsalicylic acid SC - salicoyl L-carnitine
Claims (17)
1. 3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine of the formula:
and pharmaceutically acceptable salts thereof.
and pharmaceutically acceptable salts thereof.
2. (R)-(-)-3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric-acid betaine of the formula:
and pharmaceutically acceptable salts thereof.
and pharmaceutically acceptable salts thereof.
3. (S)-(+)-3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine of the formula:
and pharmaceutically acceptable salts thereof.
and pharmaceutically acceptable salts thereof.
4. 3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine or a pharmaceutically acceptable salt thereof for use as an active therapeutic component.
5. (R)-(-)-3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine or a pharmaceutically acceptable salt thereof for use as an active therapeutic component.
6. (S)-(+)-3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine or a pharmaceutically acceptable salt thereof for use as an active therapeutic component.
7. 3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine or a pharmaceutically acceptable salt thereof for use as an analgetic for the protection of the gastric mucous membrane.
8. (R)-(-)-3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine or a pharmaceutically acceptable salt thereof for use as an analgetic for the protection of the gastric mucous membrane.
9. (S)-(+)-3-(2-Hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine or a pharmaceutically acceptable salt thereof for use as an analgetic for the protection of the gastric mucous membrane.
10. 3-(2-Methoxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine and salts thereof.
11. (R)-(-)-3-(2-Methoxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine and salts thereof.
12. (S)-(+)-3-(2-Methoxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine and salts thereof.
13. A process for the preparation of 3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine which comprises esterifying 3-hydroxy-4-(trimethylammonio)-butyric acid betaine hydrohalide with a 2-methoxybenzoyl halide to form 3-(2-methoxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine hydrohalide, demethylating the 3-(2-methoxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine hydrohalide, with hydrogen bromide in acetic acid to form 3-(2-hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid betaine hydrobromide, and deprotonating the latter with a base to form the desired betaine.
14. A process according to claim 13, wherein the 3-hydroxy-4-(trimethylammonio)-butyric acid betaine hydrohalide is the hydrochloride.
15. A process according to claim 13 or 14, wherein the 2-methoxybenzoylhalide is the acid chloride.
16. A process according to claim 13 or 14, wherein the base is a slightly basic anion exchanger.
17. A process according to claim 13 or 14, wherein the starting material is (R)-3-hydroxy-4-(trimethylammonio)-butyric acid betaine hydrohalide (L-carnitine hydrohalide).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2061197 CA2061197C (en) | 1992-02-13 | 1992-02-13 | Salicyloyl carnitine and process for its preparation |
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| CA 2061197 CA2061197C (en) | 1992-02-13 | 1992-02-13 | Salicyloyl carnitine and process for its preparation |
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| CA2061197C true CA2061197C (en) | 2002-04-30 |
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