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Publication numberUS3632806 A
Publication typeGrant
Publication dateJan 4, 1972
Filing dateOct 14, 1968
Priority dateOct 16, 1967
Also published asDE1802162A1
Publication numberUS 3632806 A, US 3632806A, US-A-3632806, US3632806 A, US3632806A
InventorsIchizo Inoue, Kazuhiko Kondo, Kentaro Okumura
Original AssigneeTanabe Seiyaku Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Novel n - pyridylmethylidene - homo-cysteine thiolactone compound and the preparation thereof
US 3632806 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent 3,632,806 NOVEL N PYRIDYLMETHYLIDENE HOMO- CYSTEINE THIOLACTONE COMPOUND AND THE PREPARATION THEREOF Kentaro Okumura, Kobe-shi, Hyogo-ken, Ichizo Inoue, Takarazuka-shi, Hyogo-ken, and Kazuhiko Kondo, Higashi-Osaka-shi, Osaka-fa, Japan, assignors to Tanabe Seiyaku Co., Ltd., Osaka, Japan No Drawing. Filed Oct. 14, 1968, Ser. No. 767,094 Claims priority, application Japan, Oct. 16, 1967, 42/66,416 Int. Cl. C07d 31/32 US. Cl. 260--240 2 Claims ABSTRACT OF THE DISCLOSURE A vitamin B compound for oral administration comprises N (2 methyl 3 hydroxy hydroxymethyl- 4 pyridylmethylidene) homocysteine thiolactone. A method is provided to produce this N-pyridylmethylidenehomocysteine thiolactone compound.

This invention relates to a novel N-pyridylmethylidenehomocysteine thiolactone compound and to the process for preparing the same. More particularly, it relates to N (2 methyl 3 hydroxy 5 hydroxymethyl 4- pyridylmethylidene)-homocysteine thiolactone.

The compound may be illustrated by the following formula:

on, he 1') (I) It has been well known that vitamin B compounds such as pyridoxine, pyridoxal and pyridoxamine, which are important for therapy and nutrition, have disadvantageous property in their low adsorption and short duration in the living body. Therefore, it has been desired to obtain vitamin B derivatives having higher absorbability and longer durability in the living body.

We have now found that the compound (I) of this invention has not only the activity of both vitamin B and homocysteine but also very high and durable pyridoxal level in the living body as compared with those known vitamin B compounds.

When administering the compound (I) of this invention orally, it is readily absorbed and resulted in increasing higher and more durable pyridoxal level in the living body than pyridoxal hydrochloride. This fact is clearly proved by the following experimental data shown in Table I, where vitamin B derivatives tabulated in Table I were administered orally to male white rabbits of 2.0-2.5 kg. body weight at equimolar doses to pyridoxal hydrochloride, and subsequent vitamin B level (-y/ml.) in the blood was measured for a period of time by the microbiological method (using Saccharomyces carlsbergensis).

On the other hand, LD of the compound (I) of this invention are illustrated in Table II.

3,632,806 Patented Jan. 4, 1972 There is observed acute toxic symptoms such as hyperventilation, clonus and sensitivity of sounds in the subcutaneous administration of pyridoxine hydrochloride or pyridoxal phosphate, but the aforementioned symptoms were not pronounced in the oral and subcutaneous administration of the compound (I).

From the foregoing fact, the compound (I) of this invention is more useful than vitamin B compound which are known heretofore for the treatment of vitamin B deficiency symptoms, particularly on its oral administration.

The compound of this invention is also useful, due to the synergetic activity of vitamin B and homocysteine, for prevention and treatment of various dermatitis such as seborrhoetic dermatitis, acne symplex or INAH (isonicotinic acid hydrazide) eruption.

According to the present invention, the compound (I) can be prepared by the method represented by the following formula:

wherein HX is an acid. The condensation reaction may be conveniently carried out by mixing pyridoxal and an acid addition salt of homocysteine thiolactone in a suitable solvent, and stirring the mixture for a few hours, preferably at room temperature. Methanol, ethanol or isopropanol, etc., may be used as the reaction solvent. Pyridoxal in the above reaction can be replaced with an acid addi tion salt of pyridoxal or (3-hydroxy-S-hydroxymethyl-2- methyl-4-pyridyl)-hydroxymethane sulfonic acid in the form of the betaine or its alkaline metal salt such as the sodium salt. The oxidation mixture of pyridoxine or the reaction mixture of pyridoxal oxime with nitrous acid, in which pyridoxal is being formed, can also be employed as the starting material. The final product (I) can be recovered from the reaction mixture conveniently in the form of an acid addition salt such as hydrochloride or sulfate. Alternatively, the final product (I) can be easily recovered in the form of a free base by adding metal alkoxide such as sodium methoxide to the reaction mixture. The precipitating crystals of the final product (I) may be collected and purified in conventional manners.

We have assumed that the compound of this invention has the structure of the following tautomeric form (II), because the signal (1', in DMSO d :3.90, 1H (Triplet, 1:3 c./s.)) of the proton of olephone was observed in the spectrum of the nuclear magnetic resonance of said compound instead of the proton of azometine, and the spectrum of the ultraviolet absorption of said compound has a strong resemblance to that of pyridoxamine.

H OH (11) EXAMPLE 1 2.0 g. of pyridoxal was suspended in 60 ml. of methanol. To the solution was added gradually 1.9 g. of homocysteine thiolactone hydrochloride under stirring at room temperature. The solution was then allowed to stand in a refrigerator. The precipitating crystals were collected by filtration and dried, whereby yellow prisms of N-(Z- methyl 3 hydroxy 5 hydroxymethyl 4 pyridylmethylidene) homocysteine thiolactone hydrochloride were obtained. Yield: 2.2 g. (61%). M.P. ISO-182 C. (decomp.).

Analysis.Calculated for C H O N SHCl (percent): C, 47.61; H, 4.99; N, 9.26. Found (percent): C, 47.42; H, 5.17; N, 9.08.

EXAMPLE 2 10.0 g. of pyridoxal was suspended in 200 ml. of methanol. To the solution was added gradually 9.2 g. of homocysteine thiolactone hydrochloride under stirring. The solution was stirred for additional one and one-half hours. Then, sodium methoxide prepared by 1.38 g. of sodium and 50 ml. of methanol was added to the solution. While crystals were precipitating, the mixture was allowed to 4 stand in a refrigerator for a night. Precipitated crystals water and a small amountef acetone successively. The crystals were recrystallized 'from methanol, whereby yellow prisms of N (2 methyl 3 hydroxy 5 hydroxymethyl 4 pyridylmethylidene) homocysteinethiolactone were obtained. Yield: 8.5 g. M.P. 172-175 C. (decomp.). I

Analysis.--Calculated for C H O N S (percent): C, 54.13; H, 5.30; N, 10.52; S, 12.04. Found (percent): C, 54.32; H, 5.40; N, 10.28; S, 11.98.

What is claimed is: 7

1. N (Z methyl 3 hydroxy 5 hydroxymethyl- 4 pyridylmethylidene) homocysteine th'iolactone' or a pharmaceutically acceptable acid addition salt thereof.

2. N (2 methyl 3 hydroxy 5 hydroxymethyl: 4 pyridylmethylidene) homocysteine thiolactone hydrochloride.

' References Cited UNITED STATES PATENTS 3,313,822 4/1967 Meltzer 260- 240 2,703,323 3/1955 Karrer et a1. 260 240 HENRY R. JILES, Primary Examiner H. I. MOATZ, Assistant Examiner US. Cl. X.R.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4125616 *Jan 21, 1977Nov 14, 1978Zambeletti Espana, S.A.Pyridoxylidine amino benzoate compounds
US7459468Oct 28, 2004Dec 2, 2008Medicure International, Inc.Aryl sulfonic pyridoxines as antiplatelet agents
US7812037Oct 28, 2005Oct 12, 2010Medicure International, Inc.Dual antiplatelet/anticoagulant pyridoxine analogs
US20060019929 *Jul 7, 2005Jan 26, 2006Albert FriesenCombination therapies employing platelet aggregation drugs
US20060094748 *Oct 28, 2004May 4, 2006Medicure International Inc.Aryl sulfonic pyridoxines as antiplatelet agents
US20060094749 *Oct 28, 2004May 4, 2006Medicure International Inc.Substituted pyridoxines as anti-platelet agents
US20060094761 *Oct 28, 2005May 4, 2006Wasimul HaqueDual antiplatelet/anticoagulant pyridoxine analogs
US20070142270 *Feb 7, 2007Jun 21, 2007Wasimul HaqueAryl Sulfonic Pyridoxines as Antiplatelet Agents
US20070149485 *Nov 28, 2006Jun 28, 2007Medicure International, Inc.Selected dosage for the treatment of cardiovascular and related pathologies
US20080306108 *Jun 6, 2008Dec 11, 2008Medicure International Inc.Substituted Pyridoxines As Anti-Platelet Agents
U.S. Classification546/281.4
International ClassificationC07D409/12, C07D409/00
Cooperative ClassificationC07D409/12
European ClassificationC07D409/12