CA1246066A - Method for the preparation of a pharmaceutically usable benzothiazine dioxide, and an intermediate for use in the method - Google Patents
Method for the preparation of a pharmaceutically usable benzothiazine dioxide, and an intermediate for use in the methodInfo
- Publication number
- CA1246066A CA1246066A CA000464861A CA464861A CA1246066A CA 1246066 A CA1246066 A CA 1246066A CA 000464861 A CA000464861 A CA 000464861A CA 464861 A CA464861 A CA 464861A CA 1246066 A CA1246066 A CA 1246066A
- Authority
- CA
- Canada
- Prior art keywords
- carboxylic acid
- dioxide
- methyl
- benzothiazine
- dimethylacetamide
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
ABSTRACT
This invention relates to a method for the preparation of a pharmaceutically usable 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide with formula I
I
In accordance with the invention 2-methyl-4-mesyloxy-2H,1,2-benzothiazine-1,1-dioxide-3-carboxylic acid with formula II
II
is reacted with 2-aminopyridine in the presence of thionyl chloride in an inert solvent. The invention relates also to the intermediate with formula II which can be used in the method.
This invention relates to a method for the preparation of a pharmaceutically usable 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide with formula I
I
In accordance with the invention 2-methyl-4-mesyloxy-2H,1,2-benzothiazine-1,1-dioxide-3-carboxylic acid with formula II
II
is reacted with 2-aminopyridine in the presence of thionyl chloride in an inert solvent. The invention relates also to the intermediate with formula II which can be used in the method.
Description
A method for the preparation oE a pharmac0utically usable benzothiazine dioxide, and an intermediate for use in the method The present invention relates to a method for the preparation of a pharmaceutically useful 2-methyl-4-hydroxy-2H-1,2-benzothiazine-l,l-dioxide-3-(N-2-pyridyl)-carboxamide, i.e.
piroxicam, having the formula OH
~-CH 3 and to a new intermediate, 2-methyl~4-mesyloxy-2H-1,2-benzothiazine-l,l~dioxide-3-carboxylic acid, for carrying out the said reaction. The formula of the intermediate is COOH
J S,N-CH3 II
Piroxicam has proved to be a highly usable anti-inflammatory and analgesic agent which does not have the harmful effects steroids usually have. Methods for the preparation of piroxicam have been presented in numerous Finnish and foreign patent specifications, of which can be mentioned Finnish Patents 51189, 59592, 62297 and 63573.
The best method with respect of yield is presented in Finnish Patent 51189. In the method of Patent 51189, the 3-carboxylic acid ester of 3,4-dihydro-4-oxo-2H-1,2-benzothia~ine-carboxamide-l,l-dioxide is allowed to react with an at least equimolar amount of an amine which contains the desired aromatic part, which in the case of piroxicam is pyridyl. The yield obtained using the '; J
~2~ 6~;
piroxicam, having the formula OH
~-CH 3 and to a new intermediate, 2-methyl~4-mesyloxy-2H-1,2-benzothiazine-l,l~dioxide-3-carboxylic acid, for carrying out the said reaction. The formula of the intermediate is COOH
J S,N-CH3 II
Piroxicam has proved to be a highly usable anti-inflammatory and analgesic agent which does not have the harmful effects steroids usually have. Methods for the preparation of piroxicam have been presented in numerous Finnish and foreign patent specifications, of which can be mentioned Finnish Patents 51189, 59592, 62297 and 63573.
The best method with respect of yield is presented in Finnish Patent 51189. In the method of Patent 51189, the 3-carboxylic acid ester of 3,4-dihydro-4-oxo-2H-1,2-benzothia~ine-carboxamide-l,l-dioxide is allowed to react with an at least equimolar amount of an amine which contains the desired aromatic part, which in the case of piroxicam is pyridyl. The yield obtained using the '; J
~2~ 6~;
-2- 72222-77 ~ethod in question is about 70%.
A somewhat better yield is obtained by a similar to but different from the method according to Finnish Pate~ 51189 only with respect to the esterized group. Thus, in Pate~t 51189, methyl ester is used as the ester of the carboxylic acid in the 3-position, and in the other method methoxyethyl ester is used instead.
The above-mentioned methods based on an aminolysis reaction of the respective ester of 1,2 benzothiazine-3-carboxylic acid ln and 2-aminopyridine are, it is true, suitable for industrial production owing to their yield and also to their other properties, but their disadvantages include the use of a high temperature, involving temperatures of boiling xylene, and a very long reaction time, which is usually more than 20 hours. Both the temperature and the long reaction time tend to have a decomposing effect on the product, in which case -the purification of the product is difficult and the yield tends to decrease owing to decomposition. Purification is further complicated especially because the methods in question produce colored byproducts which require numerous leachings and recrystallizations, and also other steps, in order to yield an acceptable final product.
Another method for the preparation of piroxicam that is worth mentioning is presented in Finnish Patent 63573. In the said specification the starting material is a compound having the formula ~ CONHR2 ~ S,~-CH3 b2 ~2~
wherein Z is isopropoxy and R2 is 2-pyridyl when the product desired is piroxicam, The compound is contacted with an inor~anic acid, whereby ~he isopropoxy group is caused to break off. The total yleld ob~alned by thls method 1~ very poor, for before the breaking off of the isopropoxy group the preparation also includes ~he llnking of an aminopyridyl group to the benzothiazine, which is preceded by the conversion of the 3-acetyl compound to the respective 3 carboxylic acid Thus the total yield o~tained is only about 2 ~. The dis-advantages of the said method are not limited to the poor yield, for the method includes several steps using detrimental solvents such as benzene and strong acid such as 32 %
hydrobromic acid, by means of which the isopropyl group is broken off. The method is not suitable for industrial production.
The object of the present invention is to provide a method by which piroxicam can be produced with a very good yield and by using reaction steps which are both easy to carry out and rapid to complete. It is also an object to obtain as pure a final product as possible.
The method of the invention for the preparation of piroxicam, 2~methyl-4-hydroxy-2H-1,2-benzcthiazine-l,l~dioxide-3 (N-2-pyridyl) carboxamide, OH
~-HN~3 I
b2 is characterized in that 2-methyl-4-mesyloxy-2H-l,l-benzothiazine-l,l-dioxide-3-carboxylic acid or its solvate with dimethyl acetamide CH3~SO2-O /CH3 ~
,C0~N (C 3 \ ) II
(n is O or 1) is reacted with 2-aminopyridine of the formula H2N - ~ III
in ~he presence o~ thionyl chloride in an inert solvent.
The starting material II and 2-aminopyridine are used in approximately equimolar amounts, whereas thionyl chloride can be used in excess, for example about a double amount.
Inert solvents suitable for use include chlorinated hydro-carbons such as dichloromethane (boiling point about 40C), or1,2-dichlorethane (boiling point 83-84C), acetonitrile ~boiling point about 82C), etc. The reaction is conveniently carxied out at a temperature of about 40 to 85C, particularly by reflux at a boiling point of the solvent. The reaction usually reaches completion within 2-3 hours. When desired, it is also possible to use in the reaction a tertiary amine such as 2,6-dimethyl pyridine, a]though it has very little effect on the reaction.
When the method of the invention is used for the preparation of piroxicam, the entire reaction takes place under quite mild conditions. Thus the reaction with 2-aminopyridine occurs at a moderate temperature and rapidly. Likewise, the mesyl group can be removed under very mild conditions, for the breaking off takes place immediately after the acylation reaction, by using a dilute NaOH solution.
Owing to the low temperature, the short reaction time, and the mild conditions the piroxicam obtained as the final product is very pure, whereupon several of the steps used for purification in known methods can be eliminated. Likewise, owing to the factors mentioned above, the yield is high, on average 86~. The method of the invention further includes one surprising feature, namely that an acid acceptor is not necessarily needed in the method at all. Evidently the N,N-dimethyl acetamide used, which forms a solvate with the starting material, being an aprotic solvent, effectively catalyses the acylation reaction of 2-aminopyridine, whereupon the acid acceptor becomes unnecessary.
The invention also relates to an intermediate of the formula COOH II
N-CH
which is a new compound. Especially for the method according to the present invention it is advantageous that the said intermediate forms a solvate with dimethyl acetamide.
The preparation of the intermediate~starting material) is best carried out by hydrogenating benzyl 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate o~ the formula C ~ COOCH2 ~ IV
in the presence of a hydrogenation catalyst in an inert solvent ~or example N,N-dimethylacetamide. The starting material i~
~6f~6~i - 5a - 4680-325 benzyl-2-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate, for its part can be prepared, with an almost ~"
i6 theoretical yield, by m~sylat$on by conventlonal ~rocedures from the respectlve 4-hydroxy compound.
Benzyl-2~methyl-4~hydroxy-1,2-benzothiaz~ne~ dloxlde-3-carboxylate is a known compound which has been presented ln, for example,EP Patent Application 82303978.9, publication number 77 603.
The following examples illustrate the invention without confining it in any way.
Example 1 2-methyl-3-carboxy-4-mesyloxy-2H-1/2-benzothiazine~
dioxide-N,N-dimethylacetamide solvate A solution which contained 42.3 g (0.1 mole) of benzyl-2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate ~m.p. 110-112 C), 8.7 g (0.1 mole) of N,N-dimethyl acetamiae, and 2 g of 10 % palladium charcoal catalyst was hydrogenated for 3 hours at normal pressure and room temperature. The catalyst was filtered off and the solvent was distilled off at a lowered pressure, whereby 41.8 ~ (99.5 % of the theoretical amount) of the desired product ~m.p. 102-104 C) was obtained.
Example 2 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1l1-dioxide-3-(N-2-pyridyl)-carboxamide (piroxicam3 To a solution which contained 16.8 g (0.040 mole) of the intermediate prepared in Example 1 and 4.0 g ~0.043 mole) of 2-aminopyridine in 200 ml of boiling 1,2-dichlorethane, and possibly 4.3 g (0.40 mole) of 2,6-dimethylpyridine, was added 9.5 9 (0.08 mole) thionyl chloride whlle stirring, ln the course of 0.5 hours. The mixture was refluxed for 2 hours, whereafter the mixture was cooled to about 40 C, and about 500 ml of 0,5 N NaOH solution was added to it gradually while stirring. The stirring was continued for another 0.5 hour at a temperature of 40 C. ~hereafter the aqueous layer was separated, and it was washed with methylPne chloride, filtered and made mildly acidic by means of acetic acid, whereupon the desired product crystallized. The product was filtered and dried, whereby 11.4 g (86 % of the theoretical amount) of the desired product, m.p. 198-200 C
(purity > 98 %), was obtained.
A somewhat better yield is obtained by a similar to but different from the method according to Finnish Pate~ 51189 only with respect to the esterized group. Thus, in Pate~t 51189, methyl ester is used as the ester of the carboxylic acid in the 3-position, and in the other method methoxyethyl ester is used instead.
The above-mentioned methods based on an aminolysis reaction of the respective ester of 1,2 benzothiazine-3-carboxylic acid ln and 2-aminopyridine are, it is true, suitable for industrial production owing to their yield and also to their other properties, but their disadvantages include the use of a high temperature, involving temperatures of boiling xylene, and a very long reaction time, which is usually more than 20 hours. Both the temperature and the long reaction time tend to have a decomposing effect on the product, in which case -the purification of the product is difficult and the yield tends to decrease owing to decomposition. Purification is further complicated especially because the methods in question produce colored byproducts which require numerous leachings and recrystallizations, and also other steps, in order to yield an acceptable final product.
Another method for the preparation of piroxicam that is worth mentioning is presented in Finnish Patent 63573. In the said specification the starting material is a compound having the formula ~ CONHR2 ~ S,~-CH3 b2 ~2~
wherein Z is isopropoxy and R2 is 2-pyridyl when the product desired is piroxicam, The compound is contacted with an inor~anic acid, whereby ~he isopropoxy group is caused to break off. The total yleld ob~alned by thls method 1~ very poor, for before the breaking off of the isopropoxy group the preparation also includes ~he llnking of an aminopyridyl group to the benzothiazine, which is preceded by the conversion of the 3-acetyl compound to the respective 3 carboxylic acid Thus the total yield o~tained is only about 2 ~. The dis-advantages of the said method are not limited to the poor yield, for the method includes several steps using detrimental solvents such as benzene and strong acid such as 32 %
hydrobromic acid, by means of which the isopropyl group is broken off. The method is not suitable for industrial production.
The object of the present invention is to provide a method by which piroxicam can be produced with a very good yield and by using reaction steps which are both easy to carry out and rapid to complete. It is also an object to obtain as pure a final product as possible.
The method of the invention for the preparation of piroxicam, 2~methyl-4-hydroxy-2H-1,2-benzcthiazine-l,l~dioxide-3 (N-2-pyridyl) carboxamide, OH
~-HN~3 I
b2 is characterized in that 2-methyl-4-mesyloxy-2H-l,l-benzothiazine-l,l-dioxide-3-carboxylic acid or its solvate with dimethyl acetamide CH3~SO2-O /CH3 ~
,C0~N (C 3 \ ) II
(n is O or 1) is reacted with 2-aminopyridine of the formula H2N - ~ III
in ~he presence o~ thionyl chloride in an inert solvent.
The starting material II and 2-aminopyridine are used in approximately equimolar amounts, whereas thionyl chloride can be used in excess, for example about a double amount.
Inert solvents suitable for use include chlorinated hydro-carbons such as dichloromethane (boiling point about 40C), or1,2-dichlorethane (boiling point 83-84C), acetonitrile ~boiling point about 82C), etc. The reaction is conveniently carxied out at a temperature of about 40 to 85C, particularly by reflux at a boiling point of the solvent. The reaction usually reaches completion within 2-3 hours. When desired, it is also possible to use in the reaction a tertiary amine such as 2,6-dimethyl pyridine, a]though it has very little effect on the reaction.
When the method of the invention is used for the preparation of piroxicam, the entire reaction takes place under quite mild conditions. Thus the reaction with 2-aminopyridine occurs at a moderate temperature and rapidly. Likewise, the mesyl group can be removed under very mild conditions, for the breaking off takes place immediately after the acylation reaction, by using a dilute NaOH solution.
Owing to the low temperature, the short reaction time, and the mild conditions the piroxicam obtained as the final product is very pure, whereupon several of the steps used for purification in known methods can be eliminated. Likewise, owing to the factors mentioned above, the yield is high, on average 86~. The method of the invention further includes one surprising feature, namely that an acid acceptor is not necessarily needed in the method at all. Evidently the N,N-dimethyl acetamide used, which forms a solvate with the starting material, being an aprotic solvent, effectively catalyses the acylation reaction of 2-aminopyridine, whereupon the acid acceptor becomes unnecessary.
The invention also relates to an intermediate of the formula COOH II
N-CH
which is a new compound. Especially for the method according to the present invention it is advantageous that the said intermediate forms a solvate with dimethyl acetamide.
The preparation of the intermediate~starting material) is best carried out by hydrogenating benzyl 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate o~ the formula C ~ COOCH2 ~ IV
in the presence of a hydrogenation catalyst in an inert solvent ~or example N,N-dimethylacetamide. The starting material i~
~6f~6~i - 5a - 4680-325 benzyl-2-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate, for its part can be prepared, with an almost ~"
i6 theoretical yield, by m~sylat$on by conventlonal ~rocedures from the respectlve 4-hydroxy compound.
Benzyl-2~methyl-4~hydroxy-1,2-benzothiaz~ne~ dloxlde-3-carboxylate is a known compound which has been presented ln, for example,EP Patent Application 82303978.9, publication number 77 603.
The following examples illustrate the invention without confining it in any way.
Example 1 2-methyl-3-carboxy-4-mesyloxy-2H-1/2-benzothiazine~
dioxide-N,N-dimethylacetamide solvate A solution which contained 42.3 g (0.1 mole) of benzyl-2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate ~m.p. 110-112 C), 8.7 g (0.1 mole) of N,N-dimethyl acetamiae, and 2 g of 10 % palladium charcoal catalyst was hydrogenated for 3 hours at normal pressure and room temperature. The catalyst was filtered off and the solvent was distilled off at a lowered pressure, whereby 41.8 ~ (99.5 % of the theoretical amount) of the desired product ~m.p. 102-104 C) was obtained.
Example 2 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1l1-dioxide-3-(N-2-pyridyl)-carboxamide (piroxicam3 To a solution which contained 16.8 g (0.040 mole) of the intermediate prepared in Example 1 and 4.0 g ~0.043 mole) of 2-aminopyridine in 200 ml of boiling 1,2-dichlorethane, and possibly 4.3 g (0.40 mole) of 2,6-dimethylpyridine, was added 9.5 9 (0.08 mole) thionyl chloride whlle stirring, ln the course of 0.5 hours. The mixture was refluxed for 2 hours, whereafter the mixture was cooled to about 40 C, and about 500 ml of 0,5 N NaOH solution was added to it gradually while stirring. The stirring was continued for another 0.5 hour at a temperature of 40 C. ~hereafter the aqueous layer was separated, and it was washed with methylPne chloride, filtered and made mildly acidic by means of acetic acid, whereupon the desired product crystallized. The product was filtered and dried, whereby 11.4 g (86 % of the theoretical amount) of the desired product, m.p. 198-200 C
(purity > 98 %), was obtained.
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for the preparation of pharmaceutically useful 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3-(N-2-pyridyl)carboxamide of the formula:
(I) which comprises reacting 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid of the formula:
(II) or its dimethylacetamide solvate, with 2-aminopyridine in the presence of thionyl chloride in an inert solvent.
(I) which comprises reacting 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid of the formula:
(II) or its dimethylacetamide solvate, with 2-aminopyridine in the presence of thionyl chloride in an inert solvent.
2. A method according to claim 1, wherein the reaction is carried out at a temperature of 40 to 85°C, and after the amidation, the reaction product is treated with a dilute aqueous NaOH solution to remove the mesyl group.
3. A method according to claim 2, wherein also a tertiary amine is used in the reaction.
4. A method according to claim 3, wherein the tertiary amine is 2,6-dimethylpyridine.
5. A process according to claim 1, wherein the carboxylic acid (II) or its dimethylacetamide solvate is reacted with an approximately equimolar amount of 2-aminopyridine.
6. A process according to claim 1, 2 or 3, wherein the carboxylic acid (II) or its dimethylacetamide solvate is reacted with an approximately equimolar amount of 2-aminopyridine in the presence of an excessive molar amount (per mole of the carboxylic acid (II)) of thionyl chloride.
7. A process according to claim 1, 2 or 3, wherein the carboxylic acid (II) is prepared by hydrogenating benzyl 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate in the presence of a hydrogenation catalyst.
3. A process according to claim 2 or 3, wherein the carboxylic acid (II) or its dimethylacetamide solvate is reacted with an approximately equimolar amount of 2-aminopyridine.
9. A process for producing 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3-(N-2-pyridyl)carboxylate which comprises:
hydrogenating benzyl 2-methyl-4-mesyloxy-1,2-benzo-thiazine-1,1-dioxide-3-carboxylate in the presence of a hydrogenation catalyst in N,N-dimethylacetamide solvent to produce 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid N,N-dimethylacetamide solvate, and reacting the carboxylic acid solvate produced in the preceeding step with an approximately equimolar amount of 2-aminopyridine at a temperature of 40 to 85°C in the presence of an excessive molar amount of thionyl chloride in a reaction inert solvent, followed by the treatment of the amidation product with a dilute aqueous NaOH solution to remove the mesyl group.
hydrogenating benzyl 2-methyl-4-mesyloxy-1,2-benzo-thiazine-1,1-dioxide-3-carboxylate in the presence of a hydrogenation catalyst in N,N-dimethylacetamide solvent to produce 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid N,N-dimethylacetamide solvate, and reacting the carboxylic acid solvate produced in the preceeding step with an approximately equimolar amount of 2-aminopyridine at a temperature of 40 to 85°C in the presence of an excessive molar amount of thionyl chloride in a reaction inert solvent, followed by the treatment of the amidation product with a dilute aqueous NaOH solution to remove the mesyl group.
10. A process of claim 9, wherein the amidation reaction is carried out in 1,2-dichloroethane solvent at a reflux temperature of the solvent.
11. An intermediate 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid of the formula (II) or its solvate with N,N-dimethylacetamide.
12. A process for producing the carboxylic acid of formula (II) as defined in claim 11, which comprises hydrogenating benzyl 2-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate in the presence of a hydrogenation catalyst in an inert solvent.
13. A process according to claim 12, wherein N,N-dimethylacetamide is used as the solvent and N,N-dimethylacetamide solvate of the carboxylic acid (II) is produced.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI833628 | 1983-10-06 | ||
| FI833628A FI72317C (en) | 1983-10-06 | 1983-10-06 | PROCEDURE FOR THE FRAMEWORK OF PHARMACEUTICALS 2-METHYL-4-HYDROXY-2H-1,2-BENZOTHIAZINE-1,1-DIOXIDE -3- (N-2-PYRIDYL)-CARBOXAMIDE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1246066A true CA1246066A (en) | 1988-12-06 |
Family
ID=8517867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000464861A Expired CA1246066A (en) | 1983-10-06 | 1984-10-05 | Method for the preparation of a pharmaceutically usable benzothiazine dioxide, and an intermediate for use in the method |
Country Status (16)
| Country | Link |
|---|---|
| AT (1) | AT387775B (en) |
| BE (1) | BE900758A (en) |
| CA (1) | CA1246066A (en) |
| CS (1) | CS253593B2 (en) |
| DD (1) | DD224594A5 (en) |
| DK (1) | DK154504C (en) |
| ES (1) | ES536544A0 (en) |
| FI (1) | FI72317C (en) |
| HU (2) | HU195493B (en) |
| IT (1) | IT1218850B (en) |
| NO (1) | NO159275C (en) |
| PL (1) | PL143957B1 (en) |
| PT (1) | PT79326B (en) |
| SE (2) | SE460789B (en) |
| SU (1) | SU1405703A3 (en) |
| YU (2) | YU43381B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4289879A (en) * | 1980-09-29 | 1981-09-15 | Pfizer Inc. | Synthetic method and intermediate for piroxicam |
| JPH08270888A (en) * | 1995-03-30 | 1996-10-15 | Nec Eng Ltd | Heat insulating engagement mechanism |
-
1983
- 1983-10-06 FI FI833628A patent/FI72317C/en not_active IP Right Cessation
-
1984
- 1984-10-01 NO NO843949A patent/NO159275C/en not_active IP Right Cessation
- 1984-10-02 DK DK471284A patent/DK154504C/en not_active IP Right Cessation
- 1984-10-03 HU HU844649A patent/HU195493B/en unknown
- 1984-10-03 HU HU843746A patent/HU194559B/en unknown
- 1984-10-03 CS CS847493A patent/CS253593B2/en unknown
- 1984-10-04 YU YU1708/84A patent/YU43381B/en unknown
- 1984-10-04 PT PT79326A patent/PT79326B/en not_active IP Right Cessation
- 1984-10-04 IT IT22981/84A patent/IT1218850B/en active
- 1984-10-05 ES ES536544A patent/ES536544A0/en active Granted
- 1984-10-05 SE SE8405002A patent/SE460789B/en not_active IP Right Cessation
- 1984-10-05 PL PL1984249918A patent/PL143957B1/en unknown
- 1984-10-05 DD DD84268074A patent/DD224594A5/en not_active IP Right Cessation
- 1984-10-05 AT AT0316384A patent/AT387775B/en active
- 1984-10-05 BE BE0/213782A patent/BE900758A/en not_active IP Right Cessation
- 1984-10-05 SU SU843805901A patent/SU1405703A3/en active
- 1984-10-05 CA CA000464861A patent/CA1246066A/en not_active Expired
-
1986
- 1986-08-27 YU YU1496/86A patent/YU43603B/en unknown
-
1989
- 1989-01-24 SE SE8900248A patent/SE464411B/en not_active IP Right Cessation
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