CA1088542A - 5-mercaptopyridoxine alkanesulfonates - Google Patents
5-mercaptopyridoxine alkanesulfonatesInfo
- Publication number
- CA1088542A CA1088542A CA251,741A CA251741A CA1088542A CA 1088542 A CA1088542 A CA 1088542A CA 251741 A CA251741 A CA 251741A CA 1088542 A CA1088542 A CA 1088542A
- Authority
- CA
- Canada
- Prior art keywords
- ethane
- mercaptopyridoxine
- bis
- disulfonate
- treated
- 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
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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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
- C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Abstract of the Disclosure 5-Mercaptopyridoxine C1-4 alkane sulfonates, par-ticularly the ethane-1,2-disulfonate, is a superior pharma-ceutically acceptable form of the previously preferred 5-mercaptopysidoxine hydrochloride and hydrobromide.
Description
f~- ` 1088S4Z
This invention is concerned with pharmaceutically acceptable alkanesulfonic acid addition salts of 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridine, a physi-cally, chemically, and pharmaceutically improved form of the known pharmacologically active 2-methyl-3-hydroxy-4-hydroxy-methyl-5-mercaptomethylpyridine (5-mercaptopyridoxine or 5-MP).
In particular, this invention is concerned with Cl 4 alkanesulfonic and Cl 4 alkanedisulfonic acid addition salts ::
10 of 5-mercaptopyridoxine of formula: .
HO~CH2SH .' s CH ~ N ~ _ ( 03S)XC1 4 alkane where X is 1 or 2, and Cl 4 alkane is either straight or branched chain; a process for their preparation, a method of treating rheumatoid arthritis and pharmaceutical compositions :--comprising a novel compound. Even more particularly, it is .-concerned with the ethane-1,2-disulfonic acid addition salt (edisylate) of 5-mercaptopyridoxine, a process for its prepa-rationj a method of treating rheumatoid arthritis with it, -and pharmaceutical compositions. .:
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1 The compound, 5-mercaptopyridoxine, has been re-
This invention is concerned with pharmaceutically acceptable alkanesulfonic acid addition salts of 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridine, a physi-cally, chemically, and pharmaceutically improved form of the known pharmacologically active 2-methyl-3-hydroxy-4-hydroxy-methyl-5-mercaptomethylpyridine (5-mercaptopyridoxine or 5-MP).
In particular, this invention is concerned with Cl 4 alkanesulfonic and Cl 4 alkanedisulfonic acid addition salts ::
10 of 5-mercaptopyridoxine of formula: .
HO~CH2SH .' s CH ~ N ~ _ ( 03S)XC1 4 alkane where X is 1 or 2, and Cl 4 alkane is either straight or branched chain; a process for their preparation, a method of treating rheumatoid arthritis and pharmaceutical compositions :--comprising a novel compound. Even more particularly, it is .-concerned with the ethane-1,2-disulfonic acid addition salt (edisylate) of 5-mercaptopyridoxine, a process for its prepa-rationj a method of treating rheumatoid arthritis with it, -and pharmaceutical compositions. .:
,,,~ - .
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1 The compound, 5-mercaptopyridoxine, has been re-
2 ported to be pharmacologically active as a radiation
3 protective agent and an anti-rheumatoid arthritic agent,
4 preferrably in the form of a salt with a pharmaceutically acceptable acid. The preferred salt i8 stated to be the 6 hydrochloride or hydrobromide.
7 It has been found that most, if not all, of the 8 salts specifically reported in the prior art, and certainly 9 the hydrochloride, the previously preferred salt, suffer serious physical, chemical andtor pharmaceutical disadvan-11 tages by virtue of their chemical instability and other un-12 desirable properties. Surprisingly, it has now been found 13 that the Cl_~ alkanesulfonate and Cl_4 alkanedisulfonate 14 salts of 5-mercaptopyridoxine, and particularly the ethane-1,2-disulfonate salt (edisylate) are substantially free of 16 this defect and are, therefore, much superior to the pre-17 viou~ly preferred salts for formulation into pharmaceutical 18 unit dosage forms. The superior chemical stability of the 19 salts o~ this invention has been confirmed by actual com-parative test.
21 Thus, in order to evaluate the relative stability 22 of several salts of 5-mercaptopyridoxine~ the test salts 23 selected (i.e., the ethane-1,2-disulfonate, the phosphate, 24 the sulfamate, the nitrate and the hydrochloride) were sub-jected to accelerated conditions of high temperature as 26 the pure, unformulated, compound. The high temperature 27 date obtained at 80C. and at 105C. i8 conventionally used 28 in the pharmaceutical industry to screen compounds in as 29 short a time as possible. Where a number of derivatives ` 15771IA
~08854;~
1 or salts are available, comparative data can be obtained 2 and the test compounds can be ranked in an expected order 3 of stability. The thermally stressed salts were assayed 4 colorimetrically for intact thiol group. The ethane~
disulfonate, hydrochloride and sulfamate salts also were 6 subjected to NMR analysis to confirm the chemical analy-7 sis. The NMR data supports the chemical data. The accumu-8 lated data obtained is shown in Table 1 below.
g TABLE 1 10Comparison of Thermal Stability of 5-MP Salts 11Thermal Stability % Remaining 12 Salt of 5-MP 105C 80C ~-13 3 days 7 day~1 week 3 weeks 14 Ethanedisulfonate - 97.3 99.4 101.0 100.2 ~ydrochlorlde 57.3 __ 70.5 57 3 16 Sulfamate 13.0 8.8 94.0 75.7 '~
17 Phosphate 93.0 58.0 __ __ I , .
IB ~ ~ 87-2¦
19 The data clearly ~hows that the ethanedisulfonate salt is the most stable salt at the temperatures employed. Based on 21 the thermal stability advantages obviously shown by the :
22 data, the ethanedisulfate is the salt of choice.
23 The novel compounds of this invention are pre-24 pared by the novel proce8s which comprises mixing 2 molar parts of 5-mercaptopyridoxine or soluble acid additior.
26 salt therof, preferable the hydrochloride, and 2 molar 27 parts of Cl 4 alkanesulfonic acid or 1 molar part of ~ 15771IA
-1~88S4Z
1 Cl_4 alkanedisulfonic acid or alkali metal or alkaline 2 earth metal salt thereof, preferably the sodium salt in 3 a liquid medium capable of dissolving to some degree the 4 two starting materials at a temperature between ambient and reflux temperature. The product is isolated by cry-6 stallization from the liquid medium by cooling and/or 7 concentration, if necessary. In a preferred embodiment a 8 5-mercaptopyridoxine hydrohalide, preferably the hydro-9 chloride, and an alkali metal or alkali earth metal salt of a Cl_4 alkanesulfonate or disulfonate, preferably the 11 sodium salt, in the above-stated molar ratio, are dissolved 12 in a minimum amount of water at ambient temperature and 13 cooled.
14 Alternatively, the novel compounds of this inven-tion may be prepared by treating bis(2,2,8-trimethyl-4-H-m-1~ dioxino~4,5-c]pyridyl-5-methyl)disulfide with a mixture of 17 z~nc or tin dust and the desired Cl_4 alkanesulfonic acid 18 or Cl_4 alkanedisulfonic acid in water or a suitable organic 19 solvent. The reaction conveniently i8 carried out by the reaction mixture on a steam bath for about 3 to about 10 21 hours, preferably under an inert atmosphere. The reaction 22 mixture is then cooled, filtered and concentrated in vacuo.
23 The residue is extracted into refluxing organic solvent and 2~ ~the filtrate is filtered and cooled to precipitate the de-sired salt.
26 SLmilarly, the novel compounds of this invention 27 may be prepared by treating bis(2-methyl-3-hydroxy-4- hy-28 droxymethylpyridyl-5-methyl)disulfide with a mixture of 29 zinc or tin dust and the desired Cl 4 alkanesulfonic acid or Cl_4 alkanedisulfonic acid in water or a suitable organic 31 solvent. The reaction is run as described above and the de-32 sired salt is similarly recovered.
^ 15771IA
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1 ~he novel compounds of this invention also may be 2 prepared by treating 5-mercaptomethyl-2,2-8trimethyl-4-H-m 3 -dioxino[4,5-c]pyridine with the desired Cl 4 alkanesulfonic 4 acid or Cl_4 alkanedisulfonic acid in water or a suitable organic solvent. In this case, the reaction mixture is 6 usually heated on a steam bath for about 2 to about 10 hours, 7 preferably under an inert atmosphere. The reaction is then 8 concentrated to obtain the desired salt.
9 To practice the novel method of treatment of this invention, the active compounds may be administered orally, 11 parenterally, by inhalation or rectally in dosage unit formu-12 lations containing conventional non-toxic pharmaceutically 13 acceptable carriers, adjuvants, and vehicles. The term 14 parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or in-16 fusion techniques. In addition to the treatment of warm-17 blooded animals such as mice, rats, horses, dogs, cats, etc., 18 it is effective in the treatment of humans.
19 The pharmaceutical compositions containing the active ingredient are preferably in a form suitable for 21 oral use, for example, as tablets, troche--, lozenges, 22 aqueous or oily suspensions, dispersible powders, or granu-23 les, emulsions, hard or soft capsules, or syrups or elixirs.
24 Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharma-26 ceutical compositions and such compositions may contain one 27 or more agents sel~cted from the group consisting of sweeten-28 ing agents, flavoring agents, coloring agents, coating agents 29 and preserving agents such as &ntioxidants in order to provide 3~ a pharmaceutically elegant and palatable preparation.
-- ^ 15771IA
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1 The amount of active ingredient, alone or com-2 bined with the carrier materials, to produce a single 3 dosage form will vary depending upon the host treated 4 and the particular mode of administration. For example, a formulation intended for the oral administration to 6 humans may contain from 5 mg. to 5 gm. of active agent 7 either alone or compounded with an appropriate and con-8 venient amount of carrier material which may vary from g about 0 to about 95 percent of the total composition.
Dosage unit forms will generally contain between about 11 50 mg. to about 1 gm. of active ingredient and preferably 12 500 mg.
13 In practicing the novel method of treatment of 14 this invention, a formulation such as described above is administered at such a rate as to provide 1 mg. to 16 100 mg. per kilogram of body weight per day and preferably 17 about 1-3 grams per human patient per day. After a latent 18 period the benefits of treatment are realized by significant 19 improvement in clinical and serological symptoms such as a lowering of circulating rheumatoid factor (RF) titer.
21 It will be understood, however, that the specific 22 dose level for any particular patient will depend upon a -~ 15771IA
, 1088s4Z
1 variety of factors including the age, body weight, general 2 health, sex, diet, time of administration, route of admin~
3 istration, rate of excretion, drug combination, previous ~
4 therapy, and the severity of the particular disease under- -going therapy.
7 Example 1 ~-i, .
8 Bis(2-methYl-3-hydroxy-4-hYdroxYmethYl-s-mercaptomethyl- '~
9 pyridinium~ ethane-1,2-disulfonate `~
10 A solution of 11.1 g. (0.05 mole) 5-mercapto- -~
11 pyridoxine hydrochloride in 40 ml. of water was mixed with a : ! ' .`
`. :
12 solution of 5.85 g. (0.025 mole) of disodium ethane-1,2-13 disulfonate in 40 ml. of water at room temperature. The 14 mixture was cooled in an ice-bath until precipitation was !' substantially complete. The precipitate (1) was collected 16 on a filter and the filtrate was concentrated to about 40 17 ml. and again cooled in an ice-bath until precipitation was 18 substantially complete. The precipitate (2) was collected ~-19 on a fllter and the filtrate was concentrated to about 20 -20 ml. and cooled in an ice-bath until precipitation was ~; '!
21 substantially complete. The precipitate ~3) was collected 22 on a filter. Precipitates (1), (2), and (3) were combined , 23 and recrystallized from methanol to give 6.5 g. of bis(2-24 methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium ethane-1,2-di~ulfonate, m.p. 178-180C.
26 Employing the procedure substantially as de-27 scribed in Example 1, but substituting for the disodium 28 ethane-1,2-disulfonic acid used therein, an equimolar 29 amount of the di(metal) alkanedisulfonates, or two equimalar amounts of the metal alkane sulfonates depicted ~; ~
,; ~ .
1 in Table I, there are produced the corresponding acid 2 addition salts of 5-mercaptopyridoxine, also depicted in 3 Table I, in accordance with E~uation I.
4 Equation I
CH20H ~
HO ~ CH2S + Cl 4 alkane ~S03M)X
CH3 H ~3A
_ CH2H ~ . .
> H ~ CH2SH
~ 3 ~ Q ~ ( ~ 53)XC1-4 alkane X . :
wherein X is 1 or 2, and 6 A ~ is an acid anion, and 7 M is an alkali metal or alkaline earth metal.
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'' ~
''"' ' Table I
~ . .
2 A (~) M X Cl 4 alkane .:
3 Cl K 2 2 H2 -:~
4 Cl Na 2 -CH2-Cl Na 2 - (CH2 ) 3~ ` ~
6 Br .Na 2 - (CH2) 4- --. -7 Cl K 1 CH3-8 Br K 1 3CH2 :
9 Cl Na 1 CH3CH2CH2-Br Ca 2 -CH-. 12 Cl Ca 2 -CH-CH2-14 . CH3 Br Na 2 -C-.
.
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1 Example 2 2 ~i~(2-meth 1-3-hYdrox -4-hydroxymethyl-5-mercaptomethyl-3 ~yrid$nium~ ethane-l,~-disulfonate 4 A mixture of 9.25 gm. ~0.05 m) 5-mercaptopyri-doxine, 4.75 gm. (0.025 m) of ethane-1,2-disulfonic acid, 6 and 40 ml. of water is heated briefly until solution 7 occurs. The solution is cooled and the precipitate col-8 lected by filtration. Recrystallization from methanol 9 gives bis(2-methyl-3-hydroxy-4-hydroxymethyl-5-mercapto-methylpyridinium) ethane-1,2-disulfonate.
11 Employing the procedure substantially as de-12 scribed in Example 2, but substituting for the ethane-1,2-13 disulfonic acid used therein, an equimolar amount of the 14 alkanedisulfonic acids or two equimolar amounts of the alkanesulfonic acids depicted in Table II, there are 16 produced the corresponding acid addition salts also de-17 picted in Table II, in accordance with Equation II.
18 Equation II
HO~CH2SH
CH ~ N + Cl 4 alkane (SO3H)x HO ~ CH2SH ~ i -CH ~ ~ ( O3S)xCl_4 alkane _ X
~ 15771IA
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Table II
2 X Cl 4 alkane . ~
3 2 -CH2- ~ ;
4 2 ~CH2) 3 ~ -2 ~CH2) 4 9 2 -CH- :
. ' S~H3 13 fH3 ~.
,, -.
' .,.~ I ,, .. .
.
'~CJ'' ~ , ~'~ ' ' .
~' ' ' ",., . ~ , `. ~
~ .
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1 Example 3 2 Bis(2-methyl-3-hYdroxY-4-hydroxymethyl-5-mercaptometh 3 pyrldln~um)ethane-1,2- iSU onate 4 Heat a mixture of 0.1 mole of bis(2,2,8-trimethyl-4H-m-dioxino[4,5-c]-pyLidyl-5-methyl)disulfide, 0.2 mole 6 of zinc dust, 0.35 mole of ethane-1,2-disulfonic acid and 7 200 ml. of water on a steam bath for about 5 hours under an 8 atmosphere of nitrogen. Cool the reaction mixture, filter 9 and concentrate in vacuo. ~xtract the residue with 100 ml.
of boiling methanol, filter and cool the filtrate to obtain 11 the title product.
12 Example 4 13 Bis ~
14 ~ `
lS Heat a mixture of 0.1 mole of 5~mercaptomethyl-16 2,2-8-trimethyl-4H-m-dioxino~4,5-clpyridine and 0.055 mole 17 of ethane-1,2-disulfonic acid in 100 ml. of water on a 18 steam bath under an atmosphere of nitrogen for about 3 hours.
1~ Concentrate the reaction to obtain the title product.
"
20 Example 5 ~
. . . .
21 Bis(2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-22 pyridinium)ethane-1,2-disul onate 23 Heat a mixture of 0.1 mole of bis(2-methyl-3-24 hydroxy-4-hydroxymethylpyridyl-5-methyl)disulfide, 0.2 mole of zinc dust, 0.35 mole of ethane-1,2-disulfonic acid and 26 200 ml. of water on a steam bath fo~ about 6 hours under a 27 nitrogen atmosphere. Cool the reaction mixture, filter and 2~ concentrate in vacuo. Extract the residue with 100 ml. of 29 boiling methanol, filter and cool the filtrate to obtain the title product.
'~ 15771IA
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1 Employing the procedure substantially as described 2 in Examples 3, 4, or 5, but substituting for the ethane~
3 2-disulfonic acid used therein, an equimolar amount of the 4 alkanedisulfonic acids or two equimolar amounts of the alkanesulfonic acids depicted in Table II above, there are 6 produced the corresponding acid addition salts as depicted , 7 in Table II in accordance with Equation II. -. .
.. ~ .
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1 Example 6 2 (1) Tablets - 10,000 scored tablets for oral 3 use, each containing 500 mg. of active ingredient are 4 prepared from the following ingredients:
Gm.
6 bis(5-mercaptopyridoxine) ethane-1,2-7 disulfonate 5000 8 Starch, U.S.P. 350 9 Talc, U.S.P. 250 10 Calcium ~tearate 35 11 The powdered bis(5-mercaptopyridoxine) ethane-1,2-12 disulfonate is granulated with a 4% w./v. aqueous solution 13 of methylcellulose U.S.P. (1500 cps.). To the dried 14 granules is added a mixture of the remainder of the in-gredients and the final mixture compressed into tablets of 16 proper weight. -17 (2) Capsule~ - 10,000 two-piece hard gelatine 18 capsules for oral use, each containing 250 mg. of bis(5-19 mercaptopyridoxine) ethane-1,2-disulfonate are prepared from the following ingredients:
21 Gm.
22 bis(5-mercaptopyridoxine) ethane-1,2-23 disulfonate 2500 24 Lactose, U.S.P. 1000 25 Starch, U.S.P. 300 26 Talc, U.S.P. 65 27 Calcium stearate 25 28 The powdered bis(5-mercaptopyridoxine) ethané-1,2-29 disulfonate is mixed with the starch-lactose mixture followed by the talc and calcium stearate. The final .
^ 15771IA
l mixture is then encapsulated in the usual manner. Cap-2 sules containing l0, 25, 50, and 100 mg. of 5-mercapto-3 pyridoxine ethane-1,2-disulfonate are also prepared by 4 substituting 100, 250, 500, and 1000 gm. for 2500 gm. in the above formulation.
6 (3) Soft elastic capsules - One-piece soft 7 elastic capsules for oral use, each containing 500 mg. of 8 bis(5-mercaptopyridoxine) ethane-1,2-disulfonate are pre-9 pared in the usual manner by first dispersing the powdered active material in sufficient corn oil to render the ma-ll terial capsulatable.
12 (4) Aqueous suspension - An aqueous suspension 13 for oral use containing in each 5 ml., 1 gm. of bis(5-14 mercaptopyridoxine) ethane-1,2-disulfonate is prepared from 15 the following ingredients:
16 bis~5-mercaptopyridoxine) ethane-17 1,2-disulfonate gm. 2000 18 Methylparaben, U.S.P. gm. 7.5 19 Propylparaben, U.S.P. gm. 2.5 20 Saccharin sodium gm. 12.5 21 Glycerin ml. 3000 22 ~ragacanth powder gm. 10 23 Orange oil flavor gm. 10 24 F.D.&C. orange dye gm. 7.5 Deionized water, g.s. to 10 liters
7 It has been found that most, if not all, of the 8 salts specifically reported in the prior art, and certainly 9 the hydrochloride, the previously preferred salt, suffer serious physical, chemical andtor pharmaceutical disadvan-11 tages by virtue of their chemical instability and other un-12 desirable properties. Surprisingly, it has now been found 13 that the Cl_~ alkanesulfonate and Cl_4 alkanedisulfonate 14 salts of 5-mercaptopyridoxine, and particularly the ethane-1,2-disulfonate salt (edisylate) are substantially free of 16 this defect and are, therefore, much superior to the pre-17 viou~ly preferred salts for formulation into pharmaceutical 18 unit dosage forms. The superior chemical stability of the 19 salts o~ this invention has been confirmed by actual com-parative test.
21 Thus, in order to evaluate the relative stability 22 of several salts of 5-mercaptopyridoxine~ the test salts 23 selected (i.e., the ethane-1,2-disulfonate, the phosphate, 24 the sulfamate, the nitrate and the hydrochloride) were sub-jected to accelerated conditions of high temperature as 26 the pure, unformulated, compound. The high temperature 27 date obtained at 80C. and at 105C. i8 conventionally used 28 in the pharmaceutical industry to screen compounds in as 29 short a time as possible. Where a number of derivatives ` 15771IA
~08854;~
1 or salts are available, comparative data can be obtained 2 and the test compounds can be ranked in an expected order 3 of stability. The thermally stressed salts were assayed 4 colorimetrically for intact thiol group. The ethane~
disulfonate, hydrochloride and sulfamate salts also were 6 subjected to NMR analysis to confirm the chemical analy-7 sis. The NMR data supports the chemical data. The accumu-8 lated data obtained is shown in Table 1 below.
g TABLE 1 10Comparison of Thermal Stability of 5-MP Salts 11Thermal Stability % Remaining 12 Salt of 5-MP 105C 80C ~-13 3 days 7 day~1 week 3 weeks 14 Ethanedisulfonate - 97.3 99.4 101.0 100.2 ~ydrochlorlde 57.3 __ 70.5 57 3 16 Sulfamate 13.0 8.8 94.0 75.7 '~
17 Phosphate 93.0 58.0 __ __ I , .
IB ~ ~ 87-2¦
19 The data clearly ~hows that the ethanedisulfonate salt is the most stable salt at the temperatures employed. Based on 21 the thermal stability advantages obviously shown by the :
22 data, the ethanedisulfate is the salt of choice.
23 The novel compounds of this invention are pre-24 pared by the novel proce8s which comprises mixing 2 molar parts of 5-mercaptopyridoxine or soluble acid additior.
26 salt therof, preferable the hydrochloride, and 2 molar 27 parts of Cl 4 alkanesulfonic acid or 1 molar part of ~ 15771IA
-1~88S4Z
1 Cl_4 alkanedisulfonic acid or alkali metal or alkaline 2 earth metal salt thereof, preferably the sodium salt in 3 a liquid medium capable of dissolving to some degree the 4 two starting materials at a temperature between ambient and reflux temperature. The product is isolated by cry-6 stallization from the liquid medium by cooling and/or 7 concentration, if necessary. In a preferred embodiment a 8 5-mercaptopyridoxine hydrohalide, preferably the hydro-9 chloride, and an alkali metal or alkali earth metal salt of a Cl_4 alkanesulfonate or disulfonate, preferably the 11 sodium salt, in the above-stated molar ratio, are dissolved 12 in a minimum amount of water at ambient temperature and 13 cooled.
14 Alternatively, the novel compounds of this inven-tion may be prepared by treating bis(2,2,8-trimethyl-4-H-m-1~ dioxino~4,5-c]pyridyl-5-methyl)disulfide with a mixture of 17 z~nc or tin dust and the desired Cl_4 alkanesulfonic acid 18 or Cl_4 alkanedisulfonic acid in water or a suitable organic 19 solvent. The reaction conveniently i8 carried out by the reaction mixture on a steam bath for about 3 to about 10 21 hours, preferably under an inert atmosphere. The reaction 22 mixture is then cooled, filtered and concentrated in vacuo.
23 The residue is extracted into refluxing organic solvent and 2~ ~the filtrate is filtered and cooled to precipitate the de-sired salt.
26 SLmilarly, the novel compounds of this invention 27 may be prepared by treating bis(2-methyl-3-hydroxy-4- hy-28 droxymethylpyridyl-5-methyl)disulfide with a mixture of 29 zinc or tin dust and the desired Cl 4 alkanesulfonic acid or Cl_4 alkanedisulfonic acid in water or a suitable organic 31 solvent. The reaction is run as described above and the de-32 sired salt is similarly recovered.
^ 15771IA
108854'~
1 ~he novel compounds of this invention also may be 2 prepared by treating 5-mercaptomethyl-2,2-8trimethyl-4-H-m 3 -dioxino[4,5-c]pyridine with the desired Cl 4 alkanesulfonic 4 acid or Cl_4 alkanedisulfonic acid in water or a suitable organic solvent. In this case, the reaction mixture is 6 usually heated on a steam bath for about 2 to about 10 hours, 7 preferably under an inert atmosphere. The reaction is then 8 concentrated to obtain the desired salt.
9 To practice the novel method of treatment of this invention, the active compounds may be administered orally, 11 parenterally, by inhalation or rectally in dosage unit formu-12 lations containing conventional non-toxic pharmaceutically 13 acceptable carriers, adjuvants, and vehicles. The term 14 parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or in-16 fusion techniques. In addition to the treatment of warm-17 blooded animals such as mice, rats, horses, dogs, cats, etc., 18 it is effective in the treatment of humans.
19 The pharmaceutical compositions containing the active ingredient are preferably in a form suitable for 21 oral use, for example, as tablets, troche--, lozenges, 22 aqueous or oily suspensions, dispersible powders, or granu-23 les, emulsions, hard or soft capsules, or syrups or elixirs.
24 Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharma-26 ceutical compositions and such compositions may contain one 27 or more agents sel~cted from the group consisting of sweeten-28 ing agents, flavoring agents, coloring agents, coating agents 29 and preserving agents such as &ntioxidants in order to provide 3~ a pharmaceutically elegant and palatable preparation.
-- ^ 15771IA
1088S4~
1 The amount of active ingredient, alone or com-2 bined with the carrier materials, to produce a single 3 dosage form will vary depending upon the host treated 4 and the particular mode of administration. For example, a formulation intended for the oral administration to 6 humans may contain from 5 mg. to 5 gm. of active agent 7 either alone or compounded with an appropriate and con-8 venient amount of carrier material which may vary from g about 0 to about 95 percent of the total composition.
Dosage unit forms will generally contain between about 11 50 mg. to about 1 gm. of active ingredient and preferably 12 500 mg.
13 In practicing the novel method of treatment of 14 this invention, a formulation such as described above is administered at such a rate as to provide 1 mg. to 16 100 mg. per kilogram of body weight per day and preferably 17 about 1-3 grams per human patient per day. After a latent 18 period the benefits of treatment are realized by significant 19 improvement in clinical and serological symptoms such as a lowering of circulating rheumatoid factor (RF) titer.
21 It will be understood, however, that the specific 22 dose level for any particular patient will depend upon a -~ 15771IA
, 1088s4Z
1 variety of factors including the age, body weight, general 2 health, sex, diet, time of administration, route of admin~
3 istration, rate of excretion, drug combination, previous ~
4 therapy, and the severity of the particular disease under- -going therapy.
7 Example 1 ~-i, .
8 Bis(2-methYl-3-hydroxy-4-hYdroxYmethYl-s-mercaptomethyl- '~
9 pyridinium~ ethane-1,2-disulfonate `~
10 A solution of 11.1 g. (0.05 mole) 5-mercapto- -~
11 pyridoxine hydrochloride in 40 ml. of water was mixed with a : ! ' .`
`. :
12 solution of 5.85 g. (0.025 mole) of disodium ethane-1,2-13 disulfonate in 40 ml. of water at room temperature. The 14 mixture was cooled in an ice-bath until precipitation was !' substantially complete. The precipitate (1) was collected 16 on a filter and the filtrate was concentrated to about 40 17 ml. and again cooled in an ice-bath until precipitation was 18 substantially complete. The precipitate (2) was collected ~-19 on a fllter and the filtrate was concentrated to about 20 -20 ml. and cooled in an ice-bath until precipitation was ~; '!
21 substantially complete. The precipitate ~3) was collected 22 on a filter. Precipitates (1), (2), and (3) were combined , 23 and recrystallized from methanol to give 6.5 g. of bis(2-24 methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium ethane-1,2-di~ulfonate, m.p. 178-180C.
26 Employing the procedure substantially as de-27 scribed in Example 1, but substituting for the disodium 28 ethane-1,2-disulfonic acid used therein, an equimolar 29 amount of the di(metal) alkanedisulfonates, or two equimalar amounts of the metal alkane sulfonates depicted ~; ~
,; ~ .
1 in Table I, there are produced the corresponding acid 2 addition salts of 5-mercaptopyridoxine, also depicted in 3 Table I, in accordance with E~uation I.
4 Equation I
CH20H ~
HO ~ CH2S + Cl 4 alkane ~S03M)X
CH3 H ~3A
_ CH2H ~ . .
> H ~ CH2SH
~ 3 ~ Q ~ ( ~ 53)XC1-4 alkane X . :
wherein X is 1 or 2, and 6 A ~ is an acid anion, and 7 M is an alkali metal or alkaline earth metal.
.~ . , .
_ ~ _ -- ~~ 15771 IA
.
" . '`.
1088S4~ ~
'' ~
''"' ' Table I
~ . .
2 A (~) M X Cl 4 alkane .:
3 Cl K 2 2 H2 -:~
4 Cl Na 2 -CH2-Cl Na 2 - (CH2 ) 3~ ` ~
6 Br .Na 2 - (CH2) 4- --. -7 Cl K 1 CH3-8 Br K 1 3CH2 :
9 Cl Na 1 CH3CH2CH2-Br Ca 2 -CH-. 12 Cl Ca 2 -CH-CH2-14 . CH3 Br Na 2 -C-.
.
_ 9 _ ~ 15771 IA
1(~88~4Z
1 Example 2 2 ~i~(2-meth 1-3-hYdrox -4-hydroxymethyl-5-mercaptomethyl-3 ~yrid$nium~ ethane-l,~-disulfonate 4 A mixture of 9.25 gm. ~0.05 m) 5-mercaptopyri-doxine, 4.75 gm. (0.025 m) of ethane-1,2-disulfonic acid, 6 and 40 ml. of water is heated briefly until solution 7 occurs. The solution is cooled and the precipitate col-8 lected by filtration. Recrystallization from methanol 9 gives bis(2-methyl-3-hydroxy-4-hydroxymethyl-5-mercapto-methylpyridinium) ethane-1,2-disulfonate.
11 Employing the procedure substantially as de-12 scribed in Example 2, but substituting for the ethane-1,2-13 disulfonic acid used therein, an equimolar amount of the 14 alkanedisulfonic acids or two equimolar amounts of the alkanesulfonic acids depicted in Table II, there are 16 produced the corresponding acid addition salts also de-17 picted in Table II, in accordance with Equation II.
18 Equation II
HO~CH2SH
CH ~ N + Cl 4 alkane (SO3H)x HO ~ CH2SH ~ i -CH ~ ~ ( O3S)xCl_4 alkane _ X
~ 15771IA
~08854;~ ~
Table II
2 X Cl 4 alkane . ~
3 2 -CH2- ~ ;
4 2 ~CH2) 3 ~ -2 ~CH2) 4 9 2 -CH- :
. ' S~H3 13 fH3 ~.
,, -.
' .,.~ I ,, .. .
.
'~CJ'' ~ , ~'~ ' ' .
~' ' ' ",., . ~ , `. ~
~ .
~ ~ 15771IA
108854;~
1 Example 3 2 Bis(2-methyl-3-hYdroxY-4-hydroxymethyl-5-mercaptometh 3 pyrldln~um)ethane-1,2- iSU onate 4 Heat a mixture of 0.1 mole of bis(2,2,8-trimethyl-4H-m-dioxino[4,5-c]-pyLidyl-5-methyl)disulfide, 0.2 mole 6 of zinc dust, 0.35 mole of ethane-1,2-disulfonic acid and 7 200 ml. of water on a steam bath for about 5 hours under an 8 atmosphere of nitrogen. Cool the reaction mixture, filter 9 and concentrate in vacuo. ~xtract the residue with 100 ml.
of boiling methanol, filter and cool the filtrate to obtain 11 the title product.
12 Example 4 13 Bis ~
14 ~ `
lS Heat a mixture of 0.1 mole of 5~mercaptomethyl-16 2,2-8-trimethyl-4H-m-dioxino~4,5-clpyridine and 0.055 mole 17 of ethane-1,2-disulfonic acid in 100 ml. of water on a 18 steam bath under an atmosphere of nitrogen for about 3 hours.
1~ Concentrate the reaction to obtain the title product.
"
20 Example 5 ~
. . . .
21 Bis(2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-22 pyridinium)ethane-1,2-disul onate 23 Heat a mixture of 0.1 mole of bis(2-methyl-3-24 hydroxy-4-hydroxymethylpyridyl-5-methyl)disulfide, 0.2 mole of zinc dust, 0.35 mole of ethane-1,2-disulfonic acid and 26 200 ml. of water on a steam bath fo~ about 6 hours under a 27 nitrogen atmosphere. Cool the reaction mixture, filter and 2~ concentrate in vacuo. Extract the residue with 100 ml. of 29 boiling methanol, filter and cool the filtrate to obtain the title product.
'~ 15771IA
108854;~ ~
1 Employing the procedure substantially as described 2 in Examples 3, 4, or 5, but substituting for the ethane~
3 2-disulfonic acid used therein, an equimolar amount of the 4 alkanedisulfonic acids or two equimolar amounts of the alkanesulfonic acids depicted in Table II above, there are 6 produced the corresponding acid addition salts as depicted , 7 in Table II in accordance with Equation II. -. .
.. ~ .
':~
;, ~' ' ~ . '',.
' ~ ~ 15771 IA
1 Example 6 2 (1) Tablets - 10,000 scored tablets for oral 3 use, each containing 500 mg. of active ingredient are 4 prepared from the following ingredients:
Gm.
6 bis(5-mercaptopyridoxine) ethane-1,2-7 disulfonate 5000 8 Starch, U.S.P. 350 9 Talc, U.S.P. 250 10 Calcium ~tearate 35 11 The powdered bis(5-mercaptopyridoxine) ethane-1,2-12 disulfonate is granulated with a 4% w./v. aqueous solution 13 of methylcellulose U.S.P. (1500 cps.). To the dried 14 granules is added a mixture of the remainder of the in-gredients and the final mixture compressed into tablets of 16 proper weight. -17 (2) Capsule~ - 10,000 two-piece hard gelatine 18 capsules for oral use, each containing 250 mg. of bis(5-19 mercaptopyridoxine) ethane-1,2-disulfonate are prepared from the following ingredients:
21 Gm.
22 bis(5-mercaptopyridoxine) ethane-1,2-23 disulfonate 2500 24 Lactose, U.S.P. 1000 25 Starch, U.S.P. 300 26 Talc, U.S.P. 65 27 Calcium stearate 25 28 The powdered bis(5-mercaptopyridoxine) ethané-1,2-29 disulfonate is mixed with the starch-lactose mixture followed by the talc and calcium stearate. The final .
^ 15771IA
l mixture is then encapsulated in the usual manner. Cap-2 sules containing l0, 25, 50, and 100 mg. of 5-mercapto-3 pyridoxine ethane-1,2-disulfonate are also prepared by 4 substituting 100, 250, 500, and 1000 gm. for 2500 gm. in the above formulation.
6 (3) Soft elastic capsules - One-piece soft 7 elastic capsules for oral use, each containing 500 mg. of 8 bis(5-mercaptopyridoxine) ethane-1,2-disulfonate are pre-9 pared in the usual manner by first dispersing the powdered active material in sufficient corn oil to render the ma-ll terial capsulatable.
12 (4) Aqueous suspension - An aqueous suspension 13 for oral use containing in each 5 ml., 1 gm. of bis(5-14 mercaptopyridoxine) ethane-1,2-disulfonate is prepared from 15 the following ingredients:
16 bis~5-mercaptopyridoxine) ethane-17 1,2-disulfonate gm. 2000 18 Methylparaben, U.S.P. gm. 7.5 19 Propylparaben, U.S.P. gm. 2.5 20 Saccharin sodium gm. 12.5 21 Glycerin ml. 3000 22 ~ragacanth powder gm. 10 23 Orange oil flavor gm. 10 24 F.D.&C. orange dye gm. 7.5 Deionized water, g.s. to 10 liters
Claims (8)
1. A process for the preparation of a compound of structural formula:
wherein X is 2, and C1-4 alkane is straight or branched chain; characterized in that a compound of structural formula:
wherein R1, is -CH2OH, R2 is -OH, or taken together, R1 and R2 are A is -H or or an acid addition salt thereof where R1 is -CH2OH, R2 is -OH and A is -H; is treated with a compound of structural formula:
C1-4 alkane (SO3H)X
or an alkali metal or alkaline earth metal salt thereof when R1 is -CH2OH, R2 is -OH and A is -H; or is treated with a compound of structural formula:
C1-4 alkane (SO3H)X
in the presence of zinc dust when A is or is treated with a compound of structural formula:
C1-4 alkane (SO3H)X
when R1 and R2, taken together, are and A is -H.
wherein X is 2, and C1-4 alkane is straight or branched chain; characterized in that a compound of structural formula:
wherein R1, is -CH2OH, R2 is -OH, or taken together, R1 and R2 are A is -H or or an acid addition salt thereof where R1 is -CH2OH, R2 is -OH and A is -H; is treated with a compound of structural formula:
C1-4 alkane (SO3H)X
or an alkali metal or alkaline earth metal salt thereof when R1 is -CH2OH, R2 is -OH and A is -H; or is treated with a compound of structural formula:
C1-4 alkane (SO3H)X
in the presence of zinc dust when A is or is treated with a compound of structural formula:
C1-4 alkane (SO3H)X
when R1 and R2, taken together, are and A is -H.
2. The process of Claim 1 for the preparation of bis(5-mercaptopyridoxine)ethane-1,2-disulfonate characterized in that 5-mercaptopyridoxine hydrogen halide is treated with a di-(alkali metal)ethane-1,2-disulfonate.
3. The process of Claim 1 for the preparation of bis(5-mercaptopyridoxine)ethane-1,2-disulfonate characterized in that bis(2,2,8trimethyl-4H-m-dioxino[4,5-c]-pyridyl-5-methyl)disulfide is treated with ethane-1,2-disulfonic acid in the presence of zinc dust.
4. The process of Claim 1 for the preparation of bis(5-mercaptopyridoxine)ethane-1,2-disulfonate characterized in that 5-mercaptomethyl-2,2,8-trimethyl-4H-m-dioxino[4,5-c]
pyridine is treated with ethane-1,2-disulfonic acid.
pyridine is treated with ethane-1,2-disulfonic acid.
5. The process of Claim 1 for the preparation of bis(5-mercaptopyridoxine)ethane-1,2-disulfonate characteriz-ed in that bis(2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-5-methyl)disulfide is treated with ethane-1,2-disulfonic acid in the presence of zinc dust.
6. A compound of formula:
wherein X is 2, and C1-4 alkane is straight or branched chain, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
wherein X is 2, and C1-4 alkane is straight or branched chain, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
7. The bis(5-mercaptopyridoxine) ethane-1,2-disulfonate, when prepared by the process defined in Claim 2, 3 or 4 or by an obvious chemical equivalent.
8. The bis(5-mercaptopyridoxine) ethane-1,2-disulfonate, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57605575A | 1975-05-09 | 1975-05-09 | |
| US576,055 | 1975-05-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1088542A true CA1088542A (en) | 1980-10-28 |
Family
ID=24302783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA251,741A Expired CA1088542A (en) | 1975-05-09 | 1976-05-04 | 5-mercaptopyridoxine alkanesulfonates |
Country Status (29)
| Country | Link |
|---|---|
| JP (1) | JPS51138684A (en) |
| AR (1) | AR210883A1 (en) |
| AT (1) | AT348691B (en) |
| AU (1) | AU1342876A (en) |
| BE (1) | BE841593A (en) |
| BG (1) | BG25218A3 (en) |
| CA (1) | CA1088542A (en) |
| CH (1) | CH625222A5 (en) |
| CS (1) | CS189003B2 (en) |
| DD (1) | DD125482A5 (en) |
| DE (1) | DE2620325C3 (en) |
| DK (1) | DK143335C (en) |
| ES (1) | ES447717A1 (en) |
| FI (1) | FI61881C (en) |
| FR (1) | FR2310130A1 (en) |
| GB (1) | GB1490688A (en) |
| GR (1) | GR59817B (en) |
| HU (1) | HU172048B (en) |
| IE (1) | IE43030B1 (en) |
| IL (1) | IL49466A (en) |
| LU (1) | LU74892A1 (en) |
| NL (1) | NL7604285A (en) |
| NO (1) | NO144925C (en) |
| NZ (1) | NZ180691A (en) |
| PL (1) | PL100306B1 (en) |
| PT (1) | PT65061B (en) |
| RO (1) | RO68526A (en) |
| SE (1) | SE427033B (en) |
| ZA (1) | ZA762750B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1695428C3 (en) * | 1967-06-08 | 1978-10-05 | Merck Patent Gmbh, 6100 Darmstadt | Derivatives of 5-mercaptopyridoxine and process for their preparation |
| US3852454A (en) * | 1973-06-15 | 1974-12-03 | Merck & Co Inc | Treatment of rheumatoid arthritis |
-
1976
- 1976-04-21 DK DK179376A patent/DK143335C/en not_active IP Right Cessation
- 1976-04-21 SE SE7604580A patent/SE427033B/en not_active IP Right Cessation
- 1976-04-21 FI FI761084A patent/FI61881C/en not_active IP Right Cessation
- 1976-04-22 NO NO761367A patent/NO144925C/en unknown
- 1976-04-22 NL NL7604285A patent/NL7604285A/en not_active Application Discontinuation
- 1976-04-24 RO RO7685792A patent/RO68526A/en unknown
- 1976-04-26 CH CH521976A patent/CH625222A5/en not_active IP Right Cessation
- 1976-04-26 NZ NZ180691A patent/NZ180691A/en unknown
- 1976-04-26 IL IL49466A patent/IL49466A/en unknown
- 1976-04-27 AR AR263046A patent/AR210883A1/en active
- 1976-04-28 AU AU13428/76A patent/AU1342876A/en not_active Expired
- 1976-04-29 GR GR50620A patent/GR59817B/en unknown
- 1976-04-30 PT PT65061A patent/PT65061B/en unknown
- 1976-05-04 GB GB18196/76A patent/GB1490688A/en not_active Expired
- 1976-05-04 CA CA251,741A patent/CA1088542A/en not_active Expired
- 1976-05-04 BG BG7600033100A patent/BG25218A3/en unknown
- 1976-05-05 FR FR7613351A patent/FR2310130A1/en active Granted
- 1976-05-06 PL PL1976189342A patent/PL100306B1/en unknown
- 1976-05-06 DD DD192709A patent/DD125482A5/xx unknown
- 1976-05-06 LU LU74892A patent/LU74892A1/xx unknown
- 1976-05-07 BE BE166849A patent/BE841593A/en unknown
- 1976-05-07 IE IE990/76A patent/IE43030B1/en unknown
- 1976-05-07 ES ES447717A patent/ES447717A1/en not_active Expired
- 1976-05-07 AT AT335676A patent/AT348691B/en not_active IP Right Cessation
- 1976-05-07 ZA ZA762750A patent/ZA762750B/en unknown
- 1976-05-07 DE DE2620325A patent/DE2620325C3/en not_active Expired
- 1976-05-07 CS CS763063A patent/CS189003B2/en unknown
- 1976-05-07 HU HU76ME00001974A patent/HU172048B/en unknown
- 1976-05-08 JP JP51051720A patent/JPS51138684A/en active Pending
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