EP0000301B1 - Process for the preparation of thieno(2,3-c) and thieno(3,2-c) pyridines - Google Patents

Process for the preparation of thieno(2,3-c) and thieno(3,2-c) pyridines Download PDF

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EP0000301B1
EP0000301B1 EP78400018A EP78400018A EP0000301B1 EP 0000301 B1 EP0000301 B1 EP 0000301B1 EP 78400018 A EP78400018 A EP 78400018A EP 78400018 A EP78400018 A EP 78400018A EP 0000301 B1 EP0000301 B1 EP 0000301B1
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acid
formula
thieno
derivatives
carboxy
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EP0000301A1 (en
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Jean-Pierre Maffrand
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Sanofi SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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  • the present invention relates to a new process for the preparation of thieno [2,3-c] and thieno [3,2-c] pyridines of formulas: in which R represents hydrogen or the carboxy group.
  • R represents hydrogen or the carboxy group.
  • the object of the present invention is to provide an inexpensive synthesis process making it possible to obtain, with good yields, the compounds (I) and (II) which are important intermediates in the chemical and pharmaceutical industry, in particular for the preparation of thienopyridine derivatives having various therapeutic activities, for example anti-inflammatory, anti-platelet aggregation, anti-arrhythmic, etc. (see for example the patents and published French patent applications No. 2 215 948, 2 257,271, 2,315,274 and 2,345,150.
  • the process of the invention is characterized in that a compound of formula is reacted with nitrous acid, thus obtaining compounds of formula and reacting the compounds of formula (V) or (VI) respectively with an acid, thereby obtaining the derivatives of formula (I) and (II) respectively in which R is hydrogen, or with an alkali metal hydroxide and subsequent neutralization, thereby obtaining the derivatives of formula (I) and (II) respectively in which R is the carboxy group.
  • nitrous acid is formed in situ by reacting an alkali metal nitrite in aqueous solution with an acid.
  • the reaction is carried out in particular by slowly adding an aqueous solution of alkali metal nitrite, in particular sodium, to a hydrochloric solution, maintained at 0 ° -15 ° C., of the derivative of formula (III) or (IV) then leaving for several hours at room temperature.
  • alkali metal nitrite in particular sodium
  • a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, preferably hydrochloric acid
  • an organic acid such as trifluoroacetic acid or trichloroacetic acid, preferably trifluoroacetic acid
  • the starting compounds of formula (III) or (IV) can be prepared by reaction of a compound of formula with formaldehyde in aqueous solution, in the presence of a strong acid.
  • Example 3 By operating as in Example 3, starting from the nitrose compound obtained in Example 1, thieno [2,3-c] pyridine is obtained. F ⁇ 50 ° C, yield: 47%.

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Description

La présente invention est relative à un nouveau procédé de préparation de thiéno[2,3-c] et thiéno[3,2-c]pyridines de formules:

Figure imgb0001
dans lesquelles R représente l'hydrogène ou le groupe carboxy. Plusieurs méthodes conduisant aux dérivés de formules I et II (R = H) ont été décrites dans la littérature, mais elles sont difficilement transposables à l'échelle industrielle et/ou sont trop onéreuses. Ainsi, les voies d'accès mentionnées par W. HERTZ et L. TSAI (J. Amer. Chem. Soc., 1953, 75, 5122) ou par C. HANSCH, W. CARPENTER et J. TODD (J. Org. Chem. 1958, 23, 1924) ou par L. H. KLEMM, J. SHABTOY, D. R. McCOY et W. K. KRIANG (J. Het. Chem., 1968,5883 et ibid. 1969,6813) ou par S. GRONOWITZ et E. SANDBERG (Ark. Kemi., 1970, 32, 217) présentent les deux inconvénients cités plus haut.The present invention relates to a new process for the preparation of thieno [2,3-c] and thieno [3,2-c] pyridines of formulas:
Figure imgb0001
 in which R represents hydrogen or the carboxy group. Several methods leading to the derivatives of formulas I and II (R = H) have been described in the literature, but they are difficult to transpose on an industrial scale and / or are too expensive. Thus, the access routes mentioned by W. HERTZ and L. TSAI (J. Amer. Chem. Soc., 1953, 75, 5122) or by C. HANSCH, W. CARPENTER and J. TODD (J. Org. Chem. 1958, 23, 1924) or by LH KLEMM, J. SHABTOY, DR McCOY and WK KRIANG (J. Het. Chem., 1968,5883 and ibid. 1969,6813) or by S. GRONOWITZ and E. SANDBERG ( Ark. Kemi., 1970, 32, 217) have the two disadvantages mentioned above.

Par ailleurs, la méthode de F. ELOY et A. DERYCKERE (Bull. Soc. Chim. Belges, 1970, 79, 301) fait intervenir un azide qui présente des risques d'explosion. Enfin, les procédés décrits par J. P. MAFFRAND et F. ELOY (J. Het. Chem., 1976, 13,, 1347) et par A. HEYMES et J. P. MAFFRAND (Demande de brevet français publiée N° 2 312 498) sont plus coûteux que celui de la présente invention.Furthermore, the method of F. ELOY and A. DERYCKERE (Bull. Soc. Chim. Belges, 1970, 79, 301) involves an azide which presents risks of explosion. Finally, the processes described by JP MAFFRAND and F. ELOY (J. Het. Chem., 1976, 13 ,, 1347) and by A. HEYMES and JP MAFFRAND (French published patent application No. 2 312 498) are more expensive than that of the present invention.

Les dérivés de formules (I) et (II) dans lesquelles R =COOH n'ont été décrits qu'une fois dans la littérature par M. FARNIER, S. SOTH et P. FOURNARI (Can. J. Chem., 1976, 54, 1067), mais le procédé utilisé pour les préparer ne permet pas d'obtenir ces produits en grandes quantités.The derivatives of formulas (I) and (II) in which R = COOH have only been described once in the literature by M. FARNIER, S. SOTH and P. FOURNARI (Can. J. Chem., 1976, 54, 1067), but the process used to prepare them does not allow these products to be obtained in large quantities.

La présente invention a pour but de fournir un procédé de synthèse peu onéreux permettant d'obtenir, avec de bons rendements, les composés (I) et (II) qui sont des intermédiaires importants dans l'industrie chimique et pharmaceutique, en particulier pour la préparation de dérivés de thiéno-pyridines présentant diverses activités thérapeutiques, par exemple anti-inflammatoire, anti-agrégation plaquettaire, anti-arythmique, etc... (voir par exemple les brevets et demandes de brevet français publiées N° 2 215 948, 2 257 271, 2 315 274 et 2345 150.The object of the present invention is to provide an inexpensive synthesis process making it possible to obtain, with good yields, the compounds (I) and (II) which are important intermediates in the chemical and pharmaceutical industry, in particular for the preparation of thienopyridine derivatives having various therapeutic activities, for example anti-inflammatory, anti-platelet aggregation, anti-arrhythmic, etc. (see for example the patents and published French patent applications No. 2 215 948, 2 257,271, 2,315,274 and 2,345,150.

Le procédé de l'invention est caractérisé en ce qu'on fait réagir un composé de formule

Figure imgb0002
avec de l'acide nitreux, obtenant ainsi des composés de formule
Figure imgb0003
et on fait réagir les composés de formule (V) ou (VI) respectivement soit avec un acide, obtenant ainsi les dérivés de formule (I) et (II) respectivement dans lesquels R est l'hydrogène, soit avec un hydroxyde de métal alcalin et neutralisation subséquent, obtenant ainsi les dérivés de formule (I) et (II) respectivement dans lesquels R est le groupe carboxy.The process of the invention is characterized in that a compound of formula is reacted
Figure imgb0002
 with nitrous acid, thus obtaining compounds of formula
Figure imgb0003
 and reacting the compounds of formula (V) or (VI) respectively with an acid, thereby obtaining the derivatives of formula (I) and (II) respectively in which R is hydrogen, or with an alkali metal hydroxide and subsequent neutralization, thereby obtaining the derivatives of formula (I) and (II) respectively in which R is the carboxy group.

On forme de préférence l'acide nitreux in situ par réaction d'un nitrite de métal alcalin en solution aqueuse avec un acide.Preferably nitrous acid is formed in situ by reacting an alkali metal nitrite in aqueous solution with an acid.

La réaction est effectuée notamment en ajoutant lentement une solution aqueuse de nitrite de métal alcalin, notamment de sodium, à une solution chlorhydrique, maintenue à 0°-15°C, du dérivé de formule (III) ou (IV) puis en abandonnant plusieurs heures à température ambiante.The reaction is carried out in particular by slowly adding an aqueous solution of alkali metal nitrite, in particular sodium, to a hydrochloric solution, maintained at 0 ° -15 ° C., of the derivative of formula (III) or (IV) then leaving for several hours at room temperature.

Le traitement de la nitrosoamine de formule (V) ou (VI) est effectué à l'aide d'un acide minéral tel que l'acide chlorhydrique, l'acide bromhydrique ou l'acide sulfurique, de préférence l'acide chlorhydrique, ou d'un acide organique, tel que l'acide trifluoroacétique ou l'acide trichloroacétique, de préférence l'acide trifluoroacétique, pour aboutir à la thiénopyridine de formule (la) ou (Ila) dans laquelle R=H.The treatment of the nitrosoamine of formula (V) or (VI) is carried out using a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, preferably hydrochloric acid, or an organic acid, such as trifluoroacetic acid or trichloroacetic acid, preferably trifluoroacetic acid, to result in the thienopyridine of formula (la) or (Ila) in which R = H.

Avec l'acide trifluoroacétique pur, la réaction est très exothermique, alors qu'il est nécessaire de chauffer avec l'acide chlorhydrique pour réaliser la transformation.With pure trifluoroacetic acid, the reaction is very exothermic, while it is necessary to heat with hydrochloric acid to carry out the transformation.

Le chauffage à reflux des mêmes dérivés de formule (III) ou (IV) dans une solution aqueuse d'un hydroxyde de métal alcalin, la soude de préférence conduit après neutralisation respectivement aux acides de formule (lb) ou (Ilb) (R = COOH). Si on le désire, ces acides peuvent d'ailleurs être décarboxylés au moyen de poudre de cuivre en présence de quinoléine, selon M. FARNIER, S. SOTH et P. FOURNARI (Can. J. Chem. 1976, 54, 1067) pour donner les composés de formule (la) ou (Ila) (R = H).The reflux heating of the same derivatives of formula (III) or (IV) in an aqueous solution of an alkali metal hydroxide, the soda preferably leads after neutralization respectively to the acids of formula (lb) or (Ilb) (R = COOH). If desired, these acids can also be decarboxylated using copper powder in the presence of quinoline, according to M. FARNIER, S. SOTH and P. FOURNARI (Can. J. Chem. 1976, 54, 1067) to give the compounds of formula (la) or (Ila) (R = H).

Ce procédé peut être représenté par le schéma réactionnel suivant:

Figure imgb0004
This process can be represented by the following reaction scheme:
Figure imgb0004

Les composés de départ de formule (III) ou (IV) peuvent être préparés par réaction d'un composé de formule

Figure imgb0005
avec du formaldéhyde en solution aqueuse, en présence d'un acide fort.The starting compounds of formula (III) or (IV) can be prepared by reaction of a compound of formula
Figure imgb0005
 with formaldehyde in aqueous solution, in the presence of a strong acid.

Les sérines de formule (VII) ou (VIII) peuvent être obtenues comme suit:

  • -la β-(thiényl-2) sérine peut être préparée selon G. Weitnauer, Gazz. Chim. Ital. 1951,81, 162
  • -la β-(thiényl-3) sérine peut être préparée à partir du thiénaldéhyde-3 en adoptant le procédé de Weitnauer ci-dessus - chlorhydrate cristaux blancs, F = 241 °C.
The serines of formula (VII) or (VIII) can be obtained as follows:
  • β- (2-thienyl) serine can be prepared according to G. Weitnauer, Gazz. Chim. Ital. 1951.81, 162
  • -the β- (3-thienyl) serine can be prepared from 3-thienaldehyde by adopting the Weitnauer method above - white crystal hydrochloride, mp = 241 ° C.

Les exemples non limitatifs suivants sont donnés à titre d'illustration de l'invention.The following nonlimiting examples are given by way of illustration of the invention.

Exemple 1.Example 1.

Préparation de la carboxy-5 hydroxy-4 nitroso-6 tétrahydro-4,5,6,7 thiéno[2,3-c]pyridinePreparation of 5-carboxy-4-hydroxy-6-nitroso-4,5,6,7 thieno [2,3-c] pyridine

A une suspension agitée magnétiquement et maintenue à 10°C de 20 g (0,1 mole) de carboxy-5 hydroxy-4 tétrahydro-4,5,6,7 thiéno-[2,3-c]pyridine dans 200 cm3 d'acide chlorhydrique 3N, on ajoute, goutte à goutte, 200 cm3 d'une solution aqueuse à 10% de nitrite de sodium (2,9 équivalents) et on agite à température ambiante pendant 3 heures. Le milieu reste hétérogène pendant toute la durée de l'opération et on observe un dégagement de vapeurs nitreuses. Le précipité obtenu est filtré, lavé à l'eau et séché sous vide: Cristaux beiges, fusion pâteuse à partir de 100°C (21,3 g, 93%).To a suspension stirred magnetically and maintained at 10 ° C of 20 g (0.1 mole) of 5-carboxy-4-hydroxy-4,5,6,7-tetrahydro thieno [2,3-c] pyridine in 200 cm 3 of 3N hydrochloric acid, 200 cm 3 of a 10% aqueous solution of sodium nitrite (2.9 equivalents) are added dropwise and the mixture is stirred at room temperature for 3 hours. The medium remains heterogeneous throughout the duration of the operation and a release of nitrous vapors is observed. The precipitate obtained is filtered, washed with water and dried under vacuum: beige crystals, pasty melting from 100 ° C. (21.3 g, 93%).

Exemple 2.Example 2.

En opérant comme à l'exemple 1, on obtient la carboxy-6 hydroxy-7 nitroso-5 tétrahydro-4,5,6,7 thiéno[3,2-c]pyridine. Fusion pâteuse à partir de 60°C, rendement: 97%.By operating as in Example 1, 6-carboxy-7-hydroxy-5-nitroso-4,5,6,7 thieno [3,2-c] pyridine is obtained. Pasty fusion from 60 ° C, yield: 97%.

Exemple 3.Example 3. Préparation de la thiéno[3,2-c'pyridinePreparation of thieno [3,2-c'pyridine

On chauffe à 60°C pendant 2 heures une solution de 24 g du dérivé nitrosé obtenu à l'Exemple 2 dans 200 cm3 d'acide chlorhydrique 6N. On observe un dégagement gazeux et la formation de vapeurs rousses. Après refroidissement, le milieu réactionnel brun est basifié avec de la lessive de soude et extrait au chlorure de méthylène. Les extraits organiques sont lavés à l'eau, séchés sur sulfate de sodium, décolorés au noir, filtrés sur talc, et évaporés à sec. La distillation sous vide du résidu fournit 6,5 g (rendement global à partir du produit de départ de formule (IV); 43%) de thiéno[3,2-c]pyridine qui cristallise au refroidissement. F < 50°C.A solution of 24 g of the nitrose derivative obtained in Example 2 in 200 cm 3 of 6N hydrochloric acid is heated at 60 ° C. for 2 hours. A gas evolution and the formation of red vapors are observed. After cooling, the brown reaction medium is basified with sodium hydroxide solution and extracted with methylene chloride. The organic extracts are washed with water, dried over sodium sulfate, discolored in black, filtered through talc, and evaporated to dryness. The vacuum distillation of the residue provides 6.5 g (overall yield from the starting product of formula (IV); 43%) of thieno [3,2-c] pyridine which crystallizes on cooling. F <50 ° C.

Exemple 4.Example 4.

En opérant comme à l'exemple 3 en partant du composé nitrosé obtenu à l'Exemple 1, on obtient la thiéno[2,3-c]pyridine. F < 50°C, rendement: 47%.By operating as in Example 3, starting from the nitrose compound obtained in Example 1, thieno [2,3-c] pyridine is obtained. F <50 ° C, yield: 47%.

Exemple 5.Example 5. Préparation de la carboxy-5 thiéno[2,3-c]pyridinePreparation of 5-carboxy thieno [2,3-c] pyridine

On chauffe à reflux pendant 2 heures une solution initialement homogène de 10 g (0,044 mole) du dérivé nitrosé obtenu à l'exemple 1, 20 cm3 d'éthanol et 60 cm3 d'hydroxyde de sodium à 20%. Après refroidissement et addition d'éthanol, le précipité obtenu est filtré, lavé à l'éthanol puis à l'éther et séché. Le sel sodique obtenu (F = 2600, 4,7 g, 60%) est traité par 23 cm3 (1 équivalent) d'acide chlorhydrique N. On observe une dissolution puis une reprécipitation. On recristallise directement après avoir ajouté 27 cm3 d'eau. On obtient 2,5 g (32%) de cristaux rosés, F = 246°C.An initially homogeneous solution of 10 g (0.044 mole) of the nitrose derivative obtained in Example 1 is heated at reflux for 2 hours, 20 cm 3 of ethanol and 60 cm 3 of 20% sodium hydroxide. After cooling and addition of ethanol, the precipitate obtained is filtered, washed with ethanol then with ether and dried. The sodium salt obtained (F = 2600, 4.7 g, 60%) is treated with 23 cm 3 (1 equivalent) of hydrochloric acid N. A dissolution is observed then a reprecipitation. Recrystallized directly after adding 27 cm 3 of water. 2.5 g (32%) of pink crystals are obtained, mp = 246 ° C.

Exemple 6.Example 6.

En opérant comme à l'Exemple 5 en partant du dérivé nitrosé de l'Exemple 2, on obtient la carboxy-6 thiéno[3,2-c]pyridine. Cristaux rosés, F = 212°C, rendement: 84%.By operating as in Example 5 starting from the nitrose derivative of Example 2, 6-carboxy-thieno [3,2-c] pyridine is obtained. Pink crystals, M = 212 ° C, yield: 84%.

Exemple 7.Example 7. Préparation de la thiéno[3,2-c]pyridinePreparation of thieno [3,2-c] pyridine

On ajoute, par portions, 11,4 g du dérivé de formule VI de l'exemple 2 à 55 cm3 d'acide trifluoroacétique agités à température ambiante. La température passe de 19°C à 34°C et il y a dégagement de vapeurs rousses. On laisse revenir à température ambiante, verse le mélange réactionnel sur de la glace, basifie par addition d'ammoniaque concentrée et extrait à l'éther diisopropylique. Les extraits organiques sont lavés à l'eau, séchés sur sulfate de sodium et évaporés à sec. La distillation sous vide du résidu fournit 3,8 g (rendement 56%) de thiéno[3,2-c]pyridine.11.4 g of the derivative of formula VI of Example 2 are added in portions to 55 cm 3 of trifluoroacetic acid stirred at room temperature. The temperature rises from 19 ° C to 34 ° C and there is release of red fumes. The mixture is left to return to ambient temperature, the reaction mixture is poured onto ice, basified by the addition of concentrated ammonia and extracted with diisopropyl ether. The organic extracts are washed with water, dried over sodium sulfate and evaporated to dryness. The vacuum distillation of the residue provides 3.8 g (yield 56%) of thieno [3,2-c] pyridine.

Claims (9)

1. Process for the preparation of derivatives having the formula
Figure imgb0009
wherein R is hydrogen or carboxy, characterized in that a compound of the formula
Figure imgb0010
is reacted with nitrous acid, to give compounds of the formula
Figure imgb0011
and the compounds of the formula (V) or (VI) are reacted either with an acid, to give the derivatives of the formulae (1) and (II), respectively, in which R is hydrogen, or with an alkali metal hydroxide with subsequent neutralization, to give the derivatives of the formulae (I) and (II), respectively, in which R is the carboxy group.
2. Process as claimed in claim 1, wherein the nitrous acid is formed in situ, by reaction of an aqueous solution of an alkali metal nitrite with an acid.
3. Process as claimed in claim 2, wherein said acid is hydrochloric acid.
4. Process as claimed in claim 1, wherein said denitrosation with the acid is effected with an inorganic or organic acid.
5. Process as claimed in claim 4, wherein said inorganic acid is hydrochloric acid.
6. Process as claimed in claim 4, wherein said organic acid is trifluoroacetic acid.
7. Process as claimed in claim 1, wherein said denitrosation with said alkali metal hydroxide is effected in aqueous solution at the reflux temperature.
8. Process as claimed in claim 1, wherein a compound selected from the compounds of the formulae (1) and (II) in which R is carboxy is decarboxylated to give the corresponding compound of the formula (I) or (II) in which R is hydrogen.
9. Process as claimed in claim 8, wherein said decarboxylation is effected with copper powder in the presence of quinoline.
EP78400018A 1977-06-21 1978-06-13 Process for the preparation of thieno(2,3-c) and thieno(3,2-c) pyridines Expired EP0000301B1 (en)

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BE816390A (en) * 1973-06-15 1974-12-16 Vinyl or ethynyl-substd. mercapto-methyl pyridines - for treatment of rheumatoid arthritis and inflammatory troubles
JPS6171830A (en) * 1984-09-17 1986-04-12 Dainippon Ink & Chem Inc Cationic surfactant
US5962490A (en) 1987-09-25 1999-10-05 Texas Biotechnology Corporation Thienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
HUT74685A (en) * 1994-02-02 1997-01-28 Lilly Co Eli Hiv protease inhibitors and intermediates piperidine derivatives condensed with heterocycles as intermediates for hiv protease inhibitors
US5958905A (en) * 1996-03-26 1999-09-28 Texas Biotechnology Corporation Phosphoramidates, phosphinic amides and related compounds and the use thereof to modulate the activity of endothelin
US5804585A (en) * 1996-04-15 1998-09-08 Texas Biotechnology Corporation Thieno-pyridine sulfonamides derivatives thereof and related compounds that modulate the activity of endothelin
FR2797874B1 (en) * 1999-08-27 2002-03-29 Adir NOVEL PYRIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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FR2345150A2 (en) * 1975-08-06 1977-10-21 Centre Etd Ind Pharma NEW DERIVATIVES OF THIENOPYRIDINE, AND THEIR APPLICATION
US3997545A (en) * 1973-07-23 1976-12-14 Takeda Chemical Industries, Ltd. Thienopyridine-carboxylic acid derivatives
FR2263745B1 (en) * 1974-03-12 1977-12-02 Roussel Uclaf
FR2278683A1 (en) * 1974-07-16 1976-02-13 Parcor PROCESS FOR THE PREPARATION OF THIENO (3,2-C) PYRIDINE AND THIENO (2,3-C) PYRIDINE
FR2312247A1 (en) * 1975-05-30 1976-12-24 Parcor THIENO-PYRIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS
FR2312498A1 (en) * 1975-05-30 1976-12-24 Parcor PROCESS FOR THE PREPARATION OF THIENO (3,2-C) PYRIDINE AND DERIVATIVES THEREOF
FR2315274A1 (en) * 1975-06-27 1977-01-21 Parcor NEW DERIVATIVES OF THIENO (2,3-C) PYRIDINE, THEIR PREPARATION AND THEIR APPLICATIONS

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NO149315C (en) 1984-03-28
HU178316B (en) 1982-04-28
PT68182A (en) 1978-07-01
CA1074800A (en) 1980-04-01
FR2395271B1 (en) 1980-04-04
SU728717A3 (en) 1980-04-15
MX5020E (en) 1983-02-22
NO149315B (en) 1983-12-19
US4161599A (en) 1979-07-17
ATA337978A (en) 1980-10-15
DK147827C (en) 1985-06-10
AU3725578A (en) 1980-01-03
FI781900A (en) 1978-12-22
FR2395271A1 (en) 1979-01-19
IT1105427B (en) 1985-11-04
JPS6230192B2 (en) 1987-07-01
YU135878A (en) 1982-10-31
ES469703A1 (en) 1978-12-16
BE868272A (en) 1978-12-20
IT7849919A0 (en) 1978-06-19
DD135492A5 (en) 1979-05-09
PL113510B1 (en) 1980-12-31
YU40709B (en) 1986-04-30
IL54780A (en) 1981-01-30
FI63236C (en) 1983-05-10
GB1584143A (en) 1981-02-04
PH17024A (en) 1984-05-11
IL54780A0 (en) 1978-07-31
AR216515A1 (en) 1979-12-28
DK266978A (en) 1978-12-22
FI63236B (en) 1983-01-31
AU515505B2 (en) 1981-04-09
IE47055B1 (en) 1983-12-14
IE781023L (en) 1978-12-21
EP0000301A1 (en) 1979-01-10
ZA783051B (en) 1979-06-27

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