US3172812A - Gamma-aminototyryl nicotinate for neurogenic vasospasm - Google Patents
Gamma-aminototyryl nicotinate for neurogenic vasospasm Download PDFInfo
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- US3172812A US3172812A US3172812DA US3172812A US 3172812 A US3172812 A US 3172812A US 3172812D A US3172812D A US 3172812DA US 3172812 A US3172812 A US 3172812A
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- US
- United States
- Prior art keywords
- nicotinate
- gamma
- aminobutyryl
- neurogenic
- vasospasm
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- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title claims description 66
- 235000001968 nicotinic acid Nutrition 0.000 title claims description 60
- 239000011664 nicotinic acid Substances 0.000 title claims description 60
- 230000001272 neurogenic Effects 0.000 title description 20
- 206010047163 Vasospasm Diseases 0.000 title description 18
- 239000003937 drug carrier Substances 0.000 claims description 10
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 16
- 230000001225 therapeutic Effects 0.000 description 16
- 239000003814 drug Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- BTCSSZJGUNDROE-UHFFFAOYSA-N GABA Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 12
- 229960003692 aminobutyric acid Drugs 0.000 description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drugs Drugs 0.000 description 12
- 229940013945 gamma-Aminobutyric Acid Drugs 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 206010013935 Dysmenorrhoea Diseases 0.000 description 10
- 230000017531 blood circulation Effects 0.000 description 10
- 239000000969 carrier Substances 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- UKHWJBVVWVYFEY-UHFFFAOYSA-M silver;hydroxide Chemical compound [OH-].[Ag+] UKHWJBVVWVYFEY-UHFFFAOYSA-M 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 230000005540 biological transmission Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000001537 neural Effects 0.000 description 6
- 229960003512 nicotinic acid Drugs 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000001575 pathological Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000007086 side reaction Methods 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 230000002195 synergetic Effects 0.000 description 6
- 230000000304 vasodilatating Effects 0.000 description 6
- 210000002565 Arterioles Anatomy 0.000 description 4
- 210000004204 Blood Vessels Anatomy 0.000 description 4
- 210000001736 Capillaries Anatomy 0.000 description 4
- 210000003169 Central Nervous System Anatomy 0.000 description 4
- 210000003205 Muscles Anatomy 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000000202 analgesic Effects 0.000 description 4
- -1 as for example Chemical compound 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 210000000038 chest Anatomy 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000008024 pharmaceutical diluent Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000003071 vasodilator agent Substances 0.000 description 4
- 229940035676 ANALGESICS Drugs 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 210000001367 Arteries Anatomy 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 210000004958 Brain cells Anatomy 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N Epinephrine Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 206010017711 Gangrene Diseases 0.000 description 2
- 229940088597 Hormone Drugs 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- 206010033372 Pain and discomfort Diseases 0.000 description 2
- 241001272996 Polyphylla fullo Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010042772 Syncope Diseases 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive Effects 0.000 description 2
- 230000001476 alcoholic Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000002921 anti-spasmodic Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000903 blocking Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 230000000994 depressed Effects 0.000 description 2
- 230000000881 depressing Effects 0.000 description 2
- 230000000916 dilatatory Effects 0.000 description 2
- 230000003292 diminished Effects 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 229960005139 epinephrine Drugs 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 239000003457 ganglion blocking agent Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 230000036543 hypotension Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 230000001473 noxious Effects 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- 230000000624 ovulatory Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 230000001624 sedative Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- KFLRWGSAMLBHBV-UHFFFAOYSA-M sodium;pyridine-3-carboxylate Chemical compound [Na+].[O-]C(=O)C1=CC=CN=C1 KFLRWGSAMLBHBV-UHFFFAOYSA-M 0.000 description 2
- 230000002048 spasmolytic Effects 0.000 description 2
- 230000001148 spastic Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000004936 stimulating Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- 230000000261 vasodilator Effects 0.000 description 2
- 230000002455 vasospastic Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000036642 wellbeing Effects 0.000 description 2
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
- vasodilating agents which are capable of causing an increased blood flow.
- this class of compounds has many inherent limitations which restricts their use.
- those agents which are derived from (or related to) epinephrine have a special etiect upon the heart, such serious side reactions sometimes resulting in death.
- Other members of this class of drugs which act by blocking the transmission of the nerve impulse as, for example, ganglionic blocking agents, affect the blood pressure as well and give rise to a state of hypotension which in turn may lead to fainting and weakness.
- the untoward effects of the conventional vasodilating drugs are by no means limited to the described symptoms, the common appearance of side reactions which require special care and dosage regulation during therapy, result in denial of the drugs to a large group of patients suifering from neurogenic vasospasm.
- the conventional vasodilating drugs have a limited order of activity which is essentially restricted to the larger trunk vessels and have little or no effect on the causative mechanism arising in the brain cell.
- the product of the present invention is capable of causing an increased blood-flow by counteracting excessive neuronal transmission and, at the same time, causing vasodilation without superimposing the noxious effects of the common vasodilating drugs.
- Gammaaminobutyryl nicotinate depresses neuronal transmission, thereby relaxing spastic contraction. At the same time it acts to dilate the smaller arterioles and capillary bed, thereby improving circulation through a muscle area.
- gamma-aminobutyryl nicotinate may be demonstrated by its effect in the relief of the symptoms of primary dysmenorrhea.
- Primary dysmenorrhea occurs without evident organic cause. The symptoms usually present themselves in ovulatory cycles, often ending with the first pregnancy.
- primary dysmenorrhea is generally considered to be functional, nevertheless, evidence of nerve pathology has been demonstrated, and the association between the symptoms of the disease and the psychologic well-being of the patient have been inter-related. While there has been considerable uncertainty and confusion concerning the etiology and pathogenesis of primary dysmenorrhea, its symptoms and therapeutic approaches have been studied in great detail.
- Analgesics and anti-spasmodics aizzgaiz Patented Mar. 9,1965
- Gamma-aminobutyryl nicotinate is prepared through the reaction between gamma-aminobutyric acid and nicotinic acid in anhydrous alcoholic media. Equimolar amounts of the reacting compounds are dissolved in an anhydrous alcohol as, for example, absolute isopropyl alcohol, and the mixture refluxed for four hours. The alcohol is then concentrated until a slurry forms, and the whole set aside to crystallize in an ice chest. The crystals of gamma-aminobutyryl nicotinate are then filtered and dried.
- the structural formula is:
- An alternate method of preparation of gamma-aminobutyryl nicotinate is to neutralize the solution of gammaaminobutyric acid in 0.1 N hydrochloric acid with a metallic salt of nicotinic acid, as for example, sodium, calcium, potassium, copper, magnesium or silver in the presence of freshly precipitated silver hydroxide or copper powder.
- a metallic salt of nicotinic acid as for example, sodium, calcium, potassium, copper, magnesium or silver in the presence of freshly precipitated silver hydroxide or copper powder.
- the compound is stable and may be formulated into pharmaceutical preparations which are both eiiicacious and safe for therapeutic purposes.
- the administration or" gamma-aminobutyryl nicotinate to humans does not cause the undesirable side reactions which have been reported for the group of compounds known as vasodilators; nor does it appear to act through the same pharmacologic mechanisms as do the principal members of this therapeutic group.
- Gamma-aminobutyryl nicotinate provides a dual at tack upon the problem of neurogenic vasospasm by exert ing a neuronal, depressant efiect upon synaptic transmission, at the same time that a local stimulatory action occurs at the end-organ site.
- a local stimulatory action occurs at the end-organ site.
- This synergism of the therapeutic activity of the component moieties which is superior to the mere additive enhancement of the specific and independent pharmacologic actions of the component fractions, may be demonstrated by the reduced dosage equivalence of the therapeutic agent required to produce the increased effect.
- This synergistic attack upon the neurogenic vasospasm is not limited to any specific disease entity, but rather to the broader pathologic states in which this condition is found, whether as a symptom or etiologic factor.
- gamma-aminobutyryl nicotinate When it is desired to use gamma-aminobutyryl nicotinate for therapeutic purposes, it may be prescribed in the form of a tablet or capsule for oral administration or as a hydroalcoholic solution. Regardless of the dosage form utilized, the average dosage range of the active compound is from 20 mg. to 2 gm. per day, depending upon pound.
- Individual dosage forms whether solid or liquid consist of from to 300 mg. of gamma-aminobutyryl nico tinate in a compatible pharmaceutical diluent or carrier.
- such carrier may be lactose, starch, sucrose, mannitol, or any of the other compatible carriers.
- the carrier In the case of the liquid form, the carrier may be ethanol, soroitol, propylene glycol, glycerine or any other compatible carrier.
- Example 1 In a suitable round-bottom glass boiling flask, fitted with a dropping funnel, reflux condenser and stirrer, is placed one liter of a solution of one-tenth mol of gammaaminobutyric acid dissolved in absolute isopropyl alcohol. Hydrogen chloride gas is passed through the solution until one reacting-equivalent of hydrogen chloride has been absorbed by the solution. The flow of gas is then stopped and a solution of 1.3 mols of sodium nicotinate, dissolved in one liter of isopropanol is then added to the acidified solution of gamma-aminobutyric acid, followed by one-half gram of finely divided copper powder. The mixture is stirred at room temperature for ap proximately twenty minutes and then the temperature is gradually elevated to refluxing. The mixture is refluxed for one hour and then cooled to room temperature.
- Example 2 To a solution of 1 mol of gamma-aminobutyric acid, dissolved in two liters of methanol, is added 1.1 mols of nicotinic acid and the mixture refluxed for four hours. The solvent is then distilled and the residue crystallized from isopropyl alcohol, using a ratio of five parts of alcohol for every part of dried residue. The resulting crystals are gamma-aminobutyryl nicotinate, melting at 147-148 C., and conform, in every respect, to those obtained as a result of Example 1, above.
- Example 3 In place of the dry hydrogen chloride used in Example 1, may be substituted an equimolar amount of hydrochloric acid, or hydrogen bromide gas, or hydrobromic acid, or sulphuric acid, or nitric acid; although from the viewpoint of ease of synthetic procedure, hydrogen chloride is the preferred reagent.
- hydrochloric acid or hydrogen bromide gas, or hydrobromic acid, or sulphuric acid, or nitric acid
- hydrogen chloride is the preferred reagent.
- the reaction will proceed exactly as described above, with the other steps remaining the same.
- an organic acid for example, acetic, propionic, butyric, citric, or tartaric acid
- Example 4 In place of the isopropyl alcohol used as a solvent in Example 1, and the methanol used as the solvent in Example 2, there may be substituted any liquid alcohol of a class ROH, wherein R is either a straight or branched chain alkyl group from 1 to 6 carbon atoms in length. The other steps are carried out exactly as described in Examples 1 and 2.
- Example 5 In place of the copper powder used as a catalyst in Example 1, there may be substituted freshly precipitated silver hydroxide.
- the amounts which are to be used are from 0.1 to 0.5 gram of either copper powder or silver hydroxide for each 0.5 mol of gamma-aminobutyric acid obtained (calculated).
- Example 6 When it is desired to utilize gamma-aminobutyryl nicotinate in therapy it may be administered in the form of a tabelt or capsule or hydroalcoholic solution.
- the dos age range employed is from 20 mg. to 2 gm. per day, ad ministered in divided doses dependent upon the individual patients needs.
- each unit dose contain 200 mg. although greater or lesser amounts may be employed as indicated above, and as the condition of a particular user dictates.
- each teaspoonful contains 200 mg. gamma-aminobutyryl nicotinate
- the vehicle used is 20 to 30 percent ethanol and the active ingredient is dissolved in the solvent to form a solution which may then be flavored to taste.
- a pharmaceutical preparation comprising gammaaminobutyryl nicotinate and a compatible pharmaceutical carrier.
- a pharamaceutical preparation comprising in unit dosage form, from 5 to 300 mg. of gamma-.aminobutyryl nicotinate and a compatible pharmaceutical carrier.
- the method of treating an animal suffering from neurogenic vasospasm which comprises administering to said animal from 20 mg. to 2 gm. of gamma-aminobutyryl nicotinate per day.
- the method of treating an animal suffering from neurogenic vasospasm which comprises administering to said animal in unit dosage form from 5 to 300 mg. of gamma'aminobutyryl nicotinate in a compatible pharmaceutical diluent.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent 3,172,812 GAMMA-AMINOBUTYRYL NICOTINATE FOR NEURGGENEQ VASUSPASM Alfred Halpern, Great Neck, N.Y., assignor to Synergistics, Inc, New York, N.Y., a corporation of New York No Drawing. Filed Nov. 7, 1962, Ser. No. 236,132 6 Claims. (Cl. 16765) This invention is concerned with new compositions of matter comprising gamma-aminobutyryl nicotinate and a pharmaceutically acceptable carrier, which are useful in the therapy of neurogenic vasospasm, and the methods for achieving a spasmolytic action.
This application is a continuation-in-part of applicants co-pending application Serial No. 64,282, filed October 24, 1960, now US. Patent No. 3,108,113.
It has been known that the reduction of blood flow through an organ may result from excessive central nervous system activity. Such reduced blood flow may be caused by a narrowing of the blood vessels, especially the arteries, arterioles and capillaries, because of an increase in muscle tonus. The diminished blood flow may give rise to distressing symptoms of pain and discomfort as well as result in more severe pathologic states which involve thromboembolism from blood stasis and eventually gangrene.
These pathologic states have been treated in the past With vasodilating agents which are capable of causing an increased blood flow. However, this class of compounds has many inherent limitations which restricts their use. Thus, for example, those agents which are derived from (or related to) epinephrine have a special etiect upon the heart, such serious side reactions sometimes resulting in death. Other members of this class of drugs, which act by blocking the transmission of the nerve impulse as, for example, ganglionic blocking agents, affect the blood pressure as well and give rise to a state of hypotension which in turn may lead to fainting and weakness.
While the untoward effects of the conventional vasodilating drugs are by no means limited to the described symptoms, the common appearance of side reactions which require special care and dosage regulation during therapy, result in denial of the drugs to a large group of patients suifering from neurogenic vasospasm. Furthermore, the conventional vasodilating drugs have a limited order of activity which is essentially restricted to the larger trunk vessels and have little or no effect on the causative mechanism arising in the brain cell. In contrast to this, the product of the present invention is capable of causing an increased blood-flow by counteracting excessive neuronal transmission and, at the same time, causing vasodilation without superimposing the noxious effects of the common vasodilating drugs. Gammaaminobutyryl nicotinate depresses neuronal transmission, thereby relaxing spastic contraction. At the same time it acts to dilate the smaller arterioles and capillary bed, thereby improving circulation through a muscle area.
The special therapeutic advantages of gamma-aminobutyryl nicotinate may be demonstrated by its effect in the relief of the symptoms of primary dysmenorrhea. Primary dysmenorrhea occurs without evident organic cause. The symptoms usually present themselves in ovulatory cycles, often ending with the first pregnancy. Although primary dysmenorrhea is generally considered to be functional, nevertheless, evidence of nerve pathology has been demonstrated, and the association between the symptoms of the disease and the psychologic well-being of the patient have been inter-related. While there has been considerable uncertainty and confusion concerning the etiology and pathogenesis of primary dysmenorrhea, its symptoms and therapeutic approaches have been studied in great detail. Analgesics and anti-spasmodics aizzgaiz Patented Mar. 9,1965
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appear to be of only moderate value. The use of hormones has been cautiously employed because of the dangers from adverse reactions arising from a disturbance of the endocrine balance. This condition, which has been related to a neurogenic vasospastic origin, is presently treated with a wide variety of drugs, with little therapeutic success. However, the distressing symptoms of primary dysmenorrhea may be successfully combatted by the administration of gamma-aminobutyryl nicotinate in spite of the fact that it has no analgesic or sedative properties.
Gamma-aminobutyryl nicotinate is prepared through the reaction between gamma-aminobutyric acid and nicotinic acid in anhydrous alcoholic media. Equimolar amounts of the reacting compounds are dissolved in an anhydrous alcohol as, for example, absolute isopropyl alcohol, and the mixture refluxed for four hours. The alcohol is then concentrated until a slurry forms, and the whole set aside to crystallize in an ice chest. The crystals of gamma-aminobutyryl nicotinate are then filtered and dried. The structural formula is:
N ..HOOC
An alternate method of preparation of gamma-aminobutyryl nicotinate is to neutralize the solution of gammaaminobutyric acid in 0.1 N hydrochloric acid with a metallic salt of nicotinic acid, as for example, sodium, calcium, potassium, copper, magnesium or silver in the presence of freshly precipitated silver hydroxide or copper powder. The yield of a compound by either of these methods is excellent, and the resulting product may be used in therapy without further purification.
The compound is stable and may be formulated into pharmaceutical preparations which are both eiiicacious and safe for therapeutic purposes. The administration or" gamma-aminobutyryl nicotinate to humans does not cause the undesirable side reactions which have been reported for the group of compounds known as vasodilators; nor does it appear to act through the same pharmacologic mechanisms as do the principal members of this therapeutic group.
Gamma-aminobutyryl nicotinate provides a dual at tack upon the problem of neurogenic vasospasm by exert ing a neuronal, depressant efiect upon synaptic transmission, at the same time that a local stimulatory action occurs at the end-organ site. Thus, by depressing the level of excessive stimulae originating in the central nervous system (which tend to cause the local vasoconstrictions) at the same time that the dilatory mechanism of the blood vessels is stimulated, an elfective synergistic therapeutic action results. This synergism of the therapeutic activity of the component moieties, which is superior to the mere additive enhancement of the specific and independent pharmacologic actions of the component fractions, may be demonstrated by the reduced dosage equivalence of the therapeutic agent required to produce the increased effect. This synergistic attack upon the neurogenic vasospasm, furthermore, is not limited to any specific disease entity, but rather to the broader pathologic states in which this condition is found, whether as a symptom or etiologic factor.
When it is desired to use gamma-aminobutyryl nicotinate for therapeutic purposes, it may be prescribed in the form of a tablet or capsule for oral administration or as a hydroalcoholic solution. Regardless of the dosage form utilized, the average dosage range of the active compound is from 20 mg. to 2 gm. per day, depending upon pound. Individual dosage forms whether solid or liquid consist of from to 300 mg. of gamma-aminobutyryl nico tinate in a compatible pharmaceutical diluent or carrier. In the case of solid forms such carrier may be lactose, starch, sucrose, mannitol, or any of the other compatible carriers. In the case of the liquid form, the carrier may be ethanol, soroitol, propylene glycol, glycerine or any other compatible carrier.
The following examples illustrate our invention:
Example 1 In a suitable round-bottom glass boiling flask, fitted with a dropping funnel, reflux condenser and stirrer, is placed one liter of a solution of one-tenth mol of gammaaminobutyric acid dissolved in absolute isopropyl alcohol. Hydrogen chloride gas is passed through the solution until one reacting-equivalent of hydrogen chloride has been absorbed by the solution. The flow of gas is then stopped and a solution of 1.3 mols of sodium nicotinate, dissolved in one liter of isopropanol is then added to the acidified solution of gamma-aminobutyric acid, followed by one-half gram of finely divided copper powder. The mixture is stirred at room temperature for ap proximately twenty minutes and then the temperature is gradually elevated to refluxing. The mixture is refluxed for one hour and then cooled to room temperature.
There is an immediate separation of sodium chloride which is filtered from the solvent and the clear filtrate concentrated to one-tenth its original volume and then set aside to crystallize in an ice chest. The crystals are filtered, Washed with two portions of cold isopropyl alcohol and then dried. The dried white crystals of gammaaminobutyryl nicotinate melt at 147148 C., and an alyze for carbon, hydrogen and nitrogen in good agreement with the theoretical values.
Theory: Carbon, 53.33; hydrogen, 5.77; nitrogen, 12.44. Found: Carbon, 53.16; hydrogen, 6.47; nitrogen, 12.60.
It is soluble in organic polar solvents such as alcohol, acetone and chloroform. It is insoluble in water, petroleum ether and benzene. The molecular weight of the compound is 225.23.
Example 2 To a solution of 1 mol of gamma-aminobutyric acid, dissolved in two liters of methanol, is added 1.1 mols of nicotinic acid and the mixture refluxed for four hours. The solvent is then distilled and the residue crystallized from isopropyl alcohol, using a ratio of five parts of alcohol for every part of dried residue. The resulting crystals are gamma-aminobutyryl nicotinate, melting at 147-148 C., and conform, in every respect, to those obtained as a result of Example 1, above.
Example 3 In place of the dry hydrogen chloride used in Example 1, may be substituted an equimolar amount of hydrochloric acid, or hydrogen bromide gas, or hydrobromic acid, or sulphuric acid, or nitric acid; although from the viewpoint of ease of synthetic procedure, hydrogen chloride is the preferred reagent. When any of the other inorganic acids are used, the reaction will proceed exactly as described above, with the other steps remaining the same. Should it be desired to utilize an organic acid, for example, acetic, propionic, butyric, citric, or tartaric acid, in place of the hydrogen chloride as described in Example 1, then the procedure must be modified inorder to separate the formed sodium acid salt from the mother liquor. This is accomplished through the use of fractional crystallization techniques which are wellknown to the organic chemist. An example of such a technique is to add an equal volume of acetone to the concentrated alcohol solution of gamma-aminobutyryl nicotinate. On standing, a fiocculent precipitate of the sodium acid salt forms which is filtered, and the filtrate concentrated to one-half the volume and then set aside to crystallize. The remaining steps are carried out as described in Example 1.
It is recognized that the use of an organic acid, as a means of facilitating the synthesis of gamma-aminobutyryl nicotinate, will appreciably increase the cost of the final product. In addition, the yield of the final compound might not be comparable to those obtained after the use of the inorganic acids.
Example 4 In place of the isopropyl alcohol used as a solvent in Example 1, and the methanol used as the solvent in Example 2, there may be substituted any liquid alcohol of a class ROH, wherein R is either a straight or branched chain alkyl group from 1 to 6 carbon atoms in length. The other steps are carried out exactly as described in Examples 1 and 2.
Example 5 In place of the copper powder used as a catalyst in Example 1, there may be substituted freshly precipitated silver hydroxide. When copper powder or silver hydroxide is used as a catalyst for this reaction, the amounts which are to be used are from 0.1 to 0.5 gram of either copper powder or silver hydroxide for each 0.5 mol of gamma-aminobutyric acid obtained (calculated).
Example 6 When it is desired to utilize gamma-aminobutyryl nicotinate in therapy it may be administered in the form of a tabelt or capsule or hydroalcoholic solution. The dos age range employed is from 20 mg. to 2 gm. per day, ad ministered in divided doses dependent upon the individual patients needs. For optimal flexibility in dosage administration it is preferred that each unit dose contain 200 mg. although greater or lesser amounts may be employed as indicated above, and as the condition of a particular user dictates.
Because of the stability of gamma-aminobutyryl nicotinate, no special techniques are necessary for the compounding of pharmaceutically useful tablets and capsules.
For the preparation of a liquid solution, so that each teaspoonful contains 200 mg. gamma-aminobutyryl nicotinate, the vehicle used is 20 to 30 percent ethanol and the active ingredient is dissolved in the solvent to form a solution which may then be flavored to taste.
What is claimed is:
1. A pharmaceutical preparation comprising gammaaminobutyryl nicotinate and a compatible pharmaceutical carrier.
2. A pharamaceutical preparation comprising in unit dosage form, from 5 to 300 mg. of gamma-.aminobutyryl nicotinate and a compatible pharmaceutical carrier.
3. The method of treating an animal suffering from neurogenic vasospasm which comprises administering to said animal an effective quantity ofgamma-aminobutyryl nicotinate.
4. The method of treating an animal suffering from neurogenic vasospasm which comprises administering to said animal an effective quantity of gamma-aminobutyryl nicotinate and a pharamaceutical carrier.
5. The method of treating an animal suffering from neurogenic vasospasm which comprises administering to said animal from 20 mg. to 2 gm. of gamma-aminobutyryl nicotinate per day.
6. The method of treating an animal suffering from neurogenic vasospasm which comprises administering to said animal in unit dosage form from 5 to 300 mg. of gamma'aminobutyryl nicotinate in a compatible pharmaceutical diluent.
References Cited in the file of this patent UNITED STATES PATENTS 2,477,505 Weisberg 'July 26, 1949 2,519,487 Macek Aug. 22, 1950 2,834,786 Mueller May 13, 1958 2,916,494 OBrochta Dec. 8, 1958
Claims (1)
1. A PHARMACEUTICAL PREPARATION COMPRISING GAMMAAMINOBUTYRYL NICOTINATE AND A COMPATIBLE PHARMACEUTICAL CARRIER.
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| Publication Number | Publication Date |
|---|---|
| US3172812A true US3172812A (en) | 1965-03-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| US3172812D Expired - Lifetime US3172812A (en) | Gamma-aminototyryl nicotinate for neurogenic vasospasm |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3973027A (en) * | 1974-03-07 | 1976-08-03 | Roemmers Sociedad Anonima Industrial, Comercial Y Financiera | Analgesic method containing Lysine 2-(2-methyl-3-chloro-anilino)-3-nicotinate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2477505A (en) * | 1945-10-18 | 1949-07-26 | Nat Dairy Res Lab Inc | Production of devitaminized casein by solvent extraction |
| US2519487A (en) * | 1947-07-02 | 1950-08-22 | Merck & Co Inc | Multivitamin preparation |
| US2834786A (en) * | 1955-09-01 | 1958-05-13 | Allied Chem & Dye Corp | Process for preparing nicotinic acid |
| US2916494A (en) * | 1959-12-08 | Purification of j-pyridine carboxylic acid |
-
0
- US US3172812D patent/US3172812A/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2916494A (en) * | 1959-12-08 | Purification of j-pyridine carboxylic acid | ||
| US2477505A (en) * | 1945-10-18 | 1949-07-26 | Nat Dairy Res Lab Inc | Production of devitaminized casein by solvent extraction |
| US2519487A (en) * | 1947-07-02 | 1950-08-22 | Merck & Co Inc | Multivitamin preparation |
| US2834786A (en) * | 1955-09-01 | 1958-05-13 | Allied Chem & Dye Corp | Process for preparing nicotinic acid |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3973027A (en) * | 1974-03-07 | 1976-08-03 | Roemmers Sociedad Anonima Industrial, Comercial Y Financiera | Analgesic method containing Lysine 2-(2-methyl-3-chloro-anilino)-3-nicotinate |
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