United States Patent
`Maffr and
`
`[»]
`
`[54] THIENO [2, 3-c]PYRIDINE
`DERIVATIVES AND THERAPEUTIC
`COMPOSITION CONTAINING SAME
`[75] Inventor:
`Jean-Pierre Maffrand, Toulouse,
`France
`
`Parcor, Paris, France
`[73] Assignee:
`[21] Appl. No. : 692, 186
`[22] Filed:
`June 2, 1976
`
`[30]
`
`Foreign Application Priority Data
`France . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 20241
`June 27, 1975
`[51] Int. Cl. i . . . . . . . . . . . . . . . . . . . . . A61K 31/S4; C07D 417/04
`[52] U. S. Cl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424/2S6; 260/294. 8 C
`[58] Field of Search . . . . . . . . . . . . . . . . . . 260/294. 8 C; 424/256
`References Cited
`[56]
`PUBLICATIONS
`Karrer, Organic Chemistry, 4th Eng. Edition, Elsevier
`Pub. Co. , (N. Y. ), p. 928, 1950.
`Chemical & Engineering News, vol. 50 p. 18, Apr. 3,
`1972.
`Burger, Medicinal Chemistry, Sec. Edition,
`1960.
`Elderfleld, Heterocyclic Compounds,
`Pub. , p. 485, (1950).
`its Derivatives, Part Two,
`Klingsberg, Pyridine and
`Interscience Pub. , pp. 50-51, (1961).
`Descamps et al. , Chem. Abstracts, vol. 59, (2), pp.
`1605-1607, July 22, 1963.
`Primary Examiner — Alan L. Rotman
`Attorney, Agent, or Firm — Young & Thompson
`ABSTRACT
`[57]
`This invention relates to derivatives having the formula:
`
`'p. 497,
`
`vol. I, Wiley
`
`[11]
`
`[45]
`
`4, 075, 340
`Feb. 21, 1978
`
`N — X
`
`Ri
`
`or
`
`taN X H, le
`
`s
`
`R,
`
`1tv)
`
`in which R, is hydrogen or alkyl having 1-6 carbon
`atoms; X is (CHR2)
`in which m is, an integer from 2 to
`15, or (CHR, )„R3 in which n is an integer from 1 to 15,
`Rz is hydrogen, or a hydroxy, acyloxy or alkyl group
`having 1-6 carbon atoms, and the various symbols Ri
`may have different meanings
`in each radical (CHRIS)
`when several radicals (CHRa) are present, R3 is a tri-
`carboxy or alkoxycarbonyl
`chloromethyl,
`acetyl,
`group, or a phenyl, phenoxy, benzoyl,
`thienyl or pyri-
`dyl radical optionally substituted with at least a halogen
`atom, or a hydroxy, nitro, amino, cyano, carboxy, al-
`alkyl having 1-6 carbon atoms, alkoxy
`kyloxycarbonyl,
`having 1-6 carbon atoms or methylenedioxy group, and
`to the acid addition salts of the derivatives of the for-
`mula (I).
`Said derivatives have useful anti-inflammatory
`and anti-
`arrhythmic activities and an inhibiting action on blood
`platelet aggregation.
`
`5 Claims, No Draped'iigs
`
`MYLAN - EXHIBIT 1025
`
`

`
`1
`
`4, 075, 340
`
`2
`salts of the formula (IV) are new
`The pyridinium
`compounds and also possess useful
`therapeutic activi-
`ties. They constitute a further feature of this invention.
`The compounds of the formula (I) may also be pre-
`pared by treatment of a 4, 5, 6, 7-tetrahydro-thieno[2, 3-
`c]pyridine with a halide of the formula (III), according
`to the following reaction scheme:
`
`THIENO [2, 8-c] PYRIDINE DERIVATIVES AND
`THERAPEUTIC COMPOSITION CONTAINING
`SAME
`
`to new
`This invention
`relates
`thieno[2, 3-c]pyridine
`derivatives and to their applications
`in human and vet-
`erinary medicine.
`The new compounds of this invention have the fol-
`lowing formula:
`
`N — X
`
`R,
`
`in which Ri represents hydrogen or an alkyl radical
`having 1-6 carbon atoms; X represents
`(CHR, ) H in
`which m is an integer from 2 to 15, or (CHRIS)„Ri in
`which n is an integer from 1 to 15, Rz represents hydro-.
`gen, or a hydroxy, acyloxy or alkyl group having 1-6
`carbon atoms, and the various symbols R, may have
`different meanings
`in each radical (CHRIS) when several
`radicals (CHRIS) are present, R, represents a trichloro-
`methyl, acetyl, carboxy or alkoxycarbonyl group, or a
`thienyl or pyridyl
`phenyl, phenoxy, benzoyl,
`radical
`optionally substituted with at least a halogen atom, or a
`hydroxy group, a nitro group, and amino group, a
`cyano group, a carboxy group, an alkyloxycarbonyl
`group, an alkyl group having 1-6 carbon atoms, an
`alkoxy group having 1-6 carbon atoms or a methylene-
`dioxy group.
`The invention
`includes also within
`its scope the acid
`inorganic or organic acids of the
`addition salts with
`derivatives of the formula (I).
`A process for the preparation of compounds of the
`formula (I) comprises condensing a compound of the
`formula:
`
`s
`
`N
`
`R,
`
`in which Ri has the above-defined meaning, with a
`halide having
`the formula:
`Hal — X
`
`in which Hal represents a halogen atom and X has the
`above-defined meaning,
`to give a pyridinium
`salt having
`the formula:
`
`(Iv)
`
`eN X H, le
`
`s
`
`Rl
`
`and subsequently
`the resulting pyridin-
`hydrogenating
`ium salt, to give the desired derivative of the formula
`(I)
`
`NH + Hal — X~derivative
`
`15
`
`Rl
`
`The resulting derivatives of the formula (I) may be
`isolated as such or in salt form.
`The condensation
`reaction
`is preferably conducted
`within a medium consisting of an inert solvent such as
`2o acetonitrile, for example.
`A reducing derivative such as an alkali metal borohy-
`for example,
`dride, sodium borohydride,
`is advanta-
`geously used as hydrogenating
`agent. Said reduction
`is
`normally effected at room temperature.
`According to a modification,
`the compounds of the
`formula (I) in which 14 is an acyloxy group may be
`prepared from the corresponding compounds
`in which
`Ra is a hydroxy group, by reaction with an acid anhy-
`as acetic
`dride,
`such
`for
`anhydride,
`example.
`The starting thieno[2, 3-c]pyridines of the formula (II)
`are known compounds which have been described
`in
`the literature.
`The purification. of the compounds obtained accord-
`ing to the above process is preferably effected by ex-
`traction with an organic solvent such as ether, after
`addition of a base (e. g. , ammonia), evaporating off the
`solvent and taking up the residue into an acid (HCI, for
`example) which causes precipitation as crystals which
`may be recrystallized, after filtration,
`from ethanol.
`The salts and the quaternary
`ammonium derivatives
`of the compounds of the formula (I) may be prepared by
`methods well known by those expert in the art.
`The following non limiting Examples are given to
`the preparation of compounds of this inven-
`illustrate
`tion.
`
`EXAMPLE 1
`Preparation of
`6-n-dodecy1-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine
`(Derivative No. 1)
`(a) A mixture of thieno[2, 3-c]pyridine
`(7 g; 0. 052
`(13 g; 0. 052 mole) and acetoni-
`mole), 1-bromododecane
`trile (100 cc) is refluxed during 4 hours. The solution is
`55 then concentrated
`in vacuo and the residue is triturated
`to give, after filtration and drying, 12 g
`with ether
`(Yield: 60%; m. p. = 95-100' C) 6-dodecyl-thieno[2, 3-
`c]pyridinium bromide (derivative of the formula (IV)).
`(b) The salt obtained
`in (a) (11. 5 g; 0. 030 mole) is
`in water (50 cc) and ethanol
`(200 cc) and
`60 dissolved
`sodium borohydride
`(2. 3 g)
`is added portionwise
`thereto. After stirring overnight at room temperature,
`is destroyed by addition of acetone.
`excess borohydride
`The mixture
`is concentrated
`in vacuo and the residual
`65 oil is dissolved
`chloride. The resulting
`in methylene
`solution
`is washed with water, dried over sodium sul-
`fate and concentrated
`in vacuo. 'The oily residue (9. 6 g)
`is converted to the maleate which is recrystallized
`from
`
`

`
`isopropyl ether-isopropanol
`yield: 80. 5%).
`
`5
`
`10
`
`15
`
`EXAMPLE 2
`Preparation of
`6-dodecy1-7-methyl-4, 5, 6, 7-tetrahydro-thieno[2, 3-
`iodide (Derivative No. 2)
`c]pyridinium
`A mixture of 6-dodecy1-4, 5, 6, 7-tetrahydro-thieno[2, 3-
`c]pyridine (2. 4g; 7. 17 mmoles), methyl
`iodide (0. 9 cc)
`and acetonitrile (30 cc) is refluxed during 2 hours. The
`reaction mixture
`is concentrated
`in vacuo and the resi-
`from ether. The resulting crystals are
`due is crystallized
`filtered off, washed with ether, dried in vacuo and re-
`from ethanol (M. p. = 120' C; Yield: 95%).
`crystallized
`EXAMPLE 3
`Preparation of
`7-methyl-6-(3, 4, 5-trimethoxy-benzyl)-4, 5, 6, 7-tetrahy-
`dro-thieno[2, 3-c]pyridine (Derivative No. 3)
`(a) A mixture of 7-methyl-thieno[2, 3-c]pyridine (3. 90
`g; 26. 2 mmoles), 3, 4, 5-trimethoxy-benzyl
`chloride (5. 67
`g; 26. 2 mmoles) and acetonitrile (40 cc) is refluxed dur-
`ing 5 hours. The mixture
`is then concentrated
`in vacuo
`from acetone. The result-
`and the residue is crystallized
`ing crystals are filtered off, washed with ether and dried
`in vacuo (M. p. = 203'-204' C; Yield: 37%).
`in (a) (3. 5 g; 9. 58 mmoles) is
`(b) The product obtained
`in water (24 cc) and ethanol (72 cc), and so-
`dissolved
`thereto.
`dium borohydride
`(3 g) is added portionwise
`the reac-
`After stirring overnight at room temperature,
`is made acidic with 2N hydrochloric acid,
`tion medium
`made basic with 2N sodium hydroxide and extracted
`chloride. The organic extracts are
`with methylene
`washed with water, dried over sodium sulfate and con-
`to the 35
`in vacuo. The residue
`centrated
`is converted
`from ethyl ace-
`hydrochloride which
`is recrystallized
`(M. p. = 180'-186' C. Reduction yield:
`tate-ethanol
`54%).
`
`340
`4, 075,
`3
`(M. p. = 146' C. Reduction
`lye (d = 1. 38; 20 cc) and ethanol (200 cc) is refluxed
`during one hour. The solution-is exactly neutralized
`in vacuo, and:
`with 6N hydrochloric acid, concentrated
`is extracted with methylene chloride. The
`the residue
`organic extracts are dried over sodium sulfate and con-
`in vacuo. The resulting crystals are recrystal-
`centrated
`lized from benzene (M. p. = 151' C. Yield: 52%).
`EXAMPLE 6
`Preparation of
`5, 6, 7-tetrahydro-
`6-[2-(S-chloro-thienyl)-methyl]-4,
`thieno[2, 3-c]pyridine (Derivative No. 6)
`(a) A mixture of thieno[2, 3-c]pyridine
`(10 g; 0. 074
`(13. 95 g;
`mole), and 5-chloro-2-chloromethyl-thiophene
`0. 083 mole) in acetonitrile
`(80 cc) is refluxed during 4
`hours. After cooling, the resulting crystals are filtered
`off, washed with ether and dried in vacuo (M. p. = 158'
`C. Yield = 88. 5%).
`(b) The salt obtained above in (a) (19. 8 g; 0. 066 mole)
`in water (100 cc) and ethanol (400 cc), after
`is dissolved
`(5 g ) is added portionwise
`which sodium borohydride
`thereto, with cooling. After stirring overnight at room
`the solution
`is concentrated
`in vacuo,
`temperature,
`made acidic with 3N hydrochloric
`th'en made
`acid,
`basic with concentrated
`ammonia and extiacted with
`chloride. The organic extracts are' washed
`methylene
`with water, dried over sodium sulfate and concentrated
`in vacuo. The residual oil (16. 3 g) is converted
`to the
`from 95%
`hydrochloride which
`is then recrystallized
`ethanol (M. p. = 200 C. Yield = 35%).
`EXAMPLE 7
`Preparation of
`5, 6, 7-tetrahy-
`6-(2-hydroxy-2-phenyl-ethyl)-7-methyl-4,
`dro-thieno[2, 3-c]pyridine (Derivative No. 7)
`(a) A mixture of 7-methyl-thieno[2, 3-c]pyridine (6 g;
`40. 2 mmoles), . phenacyl bromide (8. 08 g; 40. 6 mmoles)
`and acetone (30 cc) is stirred at room temperature dur-
`ing 6 hours. The solvent is then evaporated off in vacuo,
`3- "
`the
`after which
`7-methyl-6-phenacyl-thieno[2,
`from diethyl ether,
`c]pyridinium bromide is precipitated
`filtered, washed with ether and dried in vacuo (M. p. =
`255'-260' C. Yield = 71%).
`(b) The above product (10 g; 29 mmoles) is dissolved
`in water (35 cc) and ethanol (140 cc), after which so-
`(2. 2 g) is added portionwise
`dium borohydride
`thereto.
`After stirring overnight at room temperature,
`the excess
`is destroyed by addition of acetone. The
`borohydride
`is concentrated
`in vacuo and extracted with
`solution
`chloride. The organic extracts are washed
`methylene
`with water, dried over sodium sulfate and concentrated
`in vacuo. The oily residue
`to the hydro-
`is converted
`chloride which is recrystallized
`from acetonitrile (M. p.
`= 212' C. Yield = 41%).
`EXAMPLE 8
`Preparation of
`6-(2-acetoxy-2-p-chlorophenyl-ethyl)-4,
`5, 6, 7-tetrahy-
`dro-thieno[2, 3-c]pyridine (Derivative No. 8) .
`A solution of 6-(2-p-chlorophenyl-2-hydroxy-ethyl)-
`(6 g; 20. 4
`4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine
`mmoles) in acetic anhydride (12 cc) and pyridine (30 cc)
`during 4 hours. After
`is stirred at room temperature
`concentrating
`in vacuo,
`the residue
`the mixture
`is
`poured over ice, made' basic with ammonia'and
`ex-
`tracted with ether. The organic extracts are washed
`
`20
`
`25
`
`50
`
`EXAMPLE 4
`Preparation of
`6-o-methoxycarbonylbenzy1-4,
`5, 6, 7-tetrahydro-
`thieno[2, 3-c]pyridine (Derivative No. 4)
`(a) A mixture of thieno[2, 3-c]pyridine (15 g; 0. 111 45
`(26. 7 g; 0. 116
`mole), methyl 2-bromomethylbenzoate
`(150 cc) is refluxed during 2
`mole) and acetonitrile
`hours. After cooling, the resulting crystals are filtered
`off, washed with ether and dried in vacuo (M. p. = 170'
`C. Yield: 93%).
`(b) The compound obtained in (a) above (37. 6 g; 0. 103
`in water (100 cc) and ethanol (400
`mole) is dissolved
`cc), after which sodium borohydride
`(7. 85 g) is added
`thereto portionwise, while cooling in an ice-bath. After
`stirring overnight at room temperature,
`the excess boro- 55
`is destroyed by addition of acetone, the result-
`hydride
`ing material is concentrated
`in vacuo and extracted with
`ether. The organic extracts are washed with water,
`dried over sodium sulfate and concentrated
`in vacuo.
`The residual oil is then converted
`to the maleate (M. p. 60
`= 144' C. Reduction yield = 73. 5%).
`EXAMPLE 5
`Preparation of
`6-o-carboxybenzy1-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyri- 65
`dine (Derivative No. 5)
`A mixture of 6-o-methoxycarbonylbenzy1-4,
`5, 6, 7-tet-
`rahydro-thieno[2, 3-c]pyridine (19 g; 0. 066 mole), soda
`
`

`
`with water, dried over sodium sulfate and concentrated
`in vacuo. The resulting crystals are recrystallized
`from
`(M. p. = 92' C. Yield = 80%).
`isopropanol
`Using analogous procedures,
`the following deriva-
`tives were prepared:
`derivative No. 9: 6-(2-hydroxy-propyl)-4, 5, 6, 7-tetrahy-
`dro-thieno[2, 3-c]pyridine, hydrochloride; white crys-
`tals, m. p. = 212' C.
`derivative No. 10: 6-(2-acetoxy-2m. methoxyphenyl-
`ethyl)-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine; white
`crystals; m. p. = 80' C.
`derivative No. 11: 6-o-nitrobenzy1-4, 5, 6, 7-tetrahydro-
`thieno[2, 3-c]pyridine, hydrochloride; white crystals;
`m. p. = 100' C (decomposition).
`derivative No. 12: 6-p-nitrobenzy1-4, 5, 6, 7-tetrahydro-
`thieno[2, 3-c]pyridine;
`brown
`crystals; m. p.
`116'-118' C
`derivative No. 13: 6-o-cyanobenzy1-4, 5, 6, 7-tetrahydro-
`thieno[2, 3-c]pyridine, maleate; pale green crystals;
`m. p. = 168' C.
`derivative No. 14: 6-(2-p. chloropheny1-2-hydroxy-
`ethyl)-7-methyl-4, 5, 6, 7-tetrahydro-thieno[2, 3-cjpyri-
`hydrochloride;
`dine,
`white
`crystals; m. p.
`201'-203' C.
`derivative No. 15: 6-o-chlorobenzy1-7-methyl-4,
`5, 6, 7-
`tetrahydro-thieno[2, 3-c]pyridine,
`oxalate; off-white
`crystals; m. p. = 142' C.
`derivative No. 16: 6-(2-chloro-benzyl)-4, 5, 6, 7-tetrahy-
`dro-thieno[2, 3-c]pyridine, maleate; white
`crystals;
`m. p. = 187' C.
`derivative No. 17: 6-(3, 4, 5-trimethoxy-benzyl)-4, 5, 6, 7-
`' maleate;
`tetrahydro-thieno[2, 3-c]pyridine,
`white
`crystals; m. p. = 168' C.
`derivative No. 18: 6-p. methoxybenzy1-4, 5, 6, 7-tetrahy-
`dro-thieno[2, 3-c]pyridine, hydrochloride;
`yellowish-
`white material; m. p. = 198'-200' C.
`derivative No. 19: 6-P-phenethy1-4, 5, 6, 7-tetrahydro-
`thieno[2, 3-c]pyridine, hydrochloride; white crystals;
`m. p. 238' C.
`derivative No. 20: 6-m. methoxybenzy1-4, 5, 6, 7-tetrahy-
`dro-thieno-[2, 3-c]pyridine,
`hydrochloride;
`white
`crystals; m. p. = 208' C.
`derivative No. 21: 6-p. chlorobenzy1-4, 5, 6, 7-tetrahydro-
`thieno[2, 3-c]pyridine, hydrochloride; white crystals;
`m. p. = 235' C (decomposition)
`derivative No. 22: 6-m. chlorobenzy1-4, 5, 6, 7-tetrahy-
`dro-thieno[2, 3-c]pyridine, hydrochloride;
`yellowish-
`white crystals; m. p. & 240' C.
`derivative No. 23: 6-(2-hydroxy-2-phenyl-ethyl)-
`4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine,
`hydrochlo-
`ride; white crystals; m. p. = 210'-212' C.
`derivative No. 24: 6-p. methylbenzy1-4, 5, 6, 7-tetrahy-
`dro-thieno[2, 3-c]pyridine, hydrochloride; white crys-
`tals; m. p. = 240' C (decomposition).
`derivative No. 25: 6-(3, 4-dimethoxy-benzyl)-4, 5, 6, 7-tet-
`rahydro-thieno[2, 3-c]pyridine, hydrochloride, white
`crystals; m. p. = 216' C.
`derivative No. 26: 6-o. fluorobenzy1-4, 5, 6, 7-tetrahydro-
`thieno[2, 3-c]pyridine,
`fumarate; white crystals; m. p.
`= 173' C.
`derivative No. 27: 6-(2-hydroxy-2-p. chlorophenyl-
`ethyl)-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine; white
`crystals; m. p. = 122' C.
`derivative No. 28: 6-(2, 3, 4-trimethoxy-benzyl)-4,
`5, 6, 7-
`tetrahydro-thieno[2, 3-c]pyridine, oxalate; white crys-
`tals; m. p. = 175' C.
`
`4, 075, 340
`derivative No. 29: 6-(2-hydroxy-2-p. fluorophenyl-
`ethyl)-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine; white
`crystals, m. p. = 102' C.
`derivative No. 30: 6-(2-hydroxy-2-p. methoxyphenyl-
`ethyl)-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine; white
`crystals; m. p. = 106' C.
`derivative No. 31: 7-methyl-6-i3-phenethy1-4,
`5, 6, 7-tet-
`rahydro-thieno[2, 3-c]pyridine, maleate; white crys-
`tals; m. p. = 162' C.
`1P derivative No. 32: 6-(2-hydroxy-2-p. methoxyphenyl-
`ethyl)-7-methyl-4, 5, 6, 7-tetrahydro-thieno[2, 3-cjpyri-
`dine; off-white crystals; m. p. = 169'-171' C.
`derivative No. 33: 6-(2-hydroxy-2-m. methoxyphenyl-
`ethyl)-7-methyl-4, 5, 6, 7, -tetrahydro-thieno[2, 3-c]pyri-
`crystals; m. p. = 143' — 145' C.
`dine; creamy-white
`derivative No. 34: 6-[2-(2, 5-dimethoxy-phenyl)-2-
`hydroxy-ethyl]-7-methyl-4,
`5, 6, 7-tetrahydro-
`thieno[2, 3-c]pyridine;
`white
`crystals; m. p.
`207 -209' C.
`derivative No. 35: 6-(2-hydroxy-3-p. methoxyphenoxy-
`propyl)-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine,
`hy-
`drochloride; white crystals; m. p. = 152' C.
`derivative No. 36: 6-(3-oxo-butyl)-4, 5, 6, 7-tetrahydro-
`thieno[2, 3-c]-pyridine, maleate;. white crystals; m. p.
`= 131' C.
`derivative No. 37: 6-(2-hydroxy-3, 3, 3-trichloro-
`propyl)-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine;
`white crystals; m. p. = 150' C.
`30 derivative No. 38: 6-(3, 4-dimethoxy-benzyl)-4, 5, 6, 7-tet-
`rahydro-thieno[2, 3-c]pyridine; white crystals; m. p. =
`216' C.
`The following derivatives of the formula (IV) were
`also prepared:
`derivative No. 39: 7-methyl-6-phenacyl-thieno[2,
`3-
`c]pyridinium bromide; m. p. = 255'-260' C. Interme-
`the preparation of which
`diate compound,
`is de-
`scribed in step (a) of Example 7.
`4P derivative No. 40: 6-phenacyl-thieno[2, 3-c]pyridinium
`bromide; white crystals; m. p. = 248' C; intermediate
`of derivative No. 23
`derivative No. 41: 6-p-chlorophenacyl-thieno[2,
`3-
`c]pyridinium bromide, semi-hydrate; white crystals;
`45 m. p. = 243' C; intermediate of derivative No. 27.
`derivative No. 42: 6-p-fluorophenacyl-thieno[2,
`3-
`bromide,
`c]pyridinium
`pale cream
`semi-hydrate;
`crystals; m. p. = 210' C; intermediate of derivative
`No. 29.
`derivative No. 43: 6-p-methoxyphenacyl-thieno[2,
`3-
`cjpyridinium bromide; white crys'tais; m. p. & 260' C;
`intermediate of derivative No. 30.
`derivative No. 44: 7-methyl-6-p-methoxyphenacyl-
`thieno[2, 3-c]pyridinium bromide; white crystals; m. p.
`& 260' C; intermediate of derivative No. 32.
`derivative No. 45: 6-o-methoxyphenacyl-7-methyl-
`thieno[2, 3c-]pyridinium bromide; white crystals; m. p.
`= 243' C.
`60 derivative No. 46: 6-(2, 4-dichloro-phenacyl)-7-methyl-
`thieno[2, 3-c]pyridinium
`iodide; yellow crystals; m. p.
`= 194' C.
`derivative No. 47: 6-p-chlorophenacyl-7-methyl-
`thieno[2, 3-c]pyridinium bromide; white crystals; m. p.
`65 & 260' C.
`derivative No. 48: 6-(2-picolyl-N-oxide)-thieno[2, 3-
`chloride; white crystals; m. p. 230' C
`c]pyridinium
`(decomp. ).
`
`35
`
`

`
`INVESTIGATION
`
`II. PHARMACOLOGICAL
`1. Anti-inflammatory Action
`Edema Method
`a) Localized Carrageenin-induced
`0. 1 ml of a 1% carrageenin solution
`is injected at time
`flexor muscles of the right hind limb
`0 in the metatarsal
`of rats. The animals of the treated group are adminis-
`tered orally, additionally, 100 mg/kg of the test deriva-
`tive, respectively one hour prior to and then simulta-
`neously with the phlogogenic agent, and then one hour
`and 2. 5 hours
`thereafter. The determinations
`effected
`with a ROCH micrometer at times 0, 1 hour, 2 hrs, 3 hrs
`and Shrs after carrageenin administration, make it possi-
`ble to determine
`activity,
`the percent anti-inflammatory
`as a function of time. The results obtained are tabulated
`in following Table I:
`
`10
`
`Derivative n'
`
`20
`
`TABLE I
`Percent anti-inflammator
`after I hour
`after 2 hours
`46
`38
`44
`52
`40
`49
`50
`43
`40
`46
`37
`42
`39
`51
`43
`52
`38
`44
`37
`48
`
`activit
`after 5 hours
`54
`60
`59
`56
`52
`49
`58
`61
`51
`58
`
`1
`5
`8
`10
`14
`15
`23
`28
`30
`34
`
`4, 075, 340
`derivative No. 49: 6-p-fluorophenacyl-7-methyl-
`iodide; pale yellow crystals;
`thieno[2, 3-c]pyridinium
`m. p. = 220' C.
`No. 50: 6-2, 5-dimethoxy)-7-methyl-
`derivative
`thieno[2, 3-c]pyridinium bromide; white crystals; m. p.
`252' C. Intermediate of derivative No. 34,
`derivative No. 51: 6-m-methoxyphenacyl-7-methyl-
`thieno[2, 3-c]pyridinium bromide; white crystals; m. p.
`= 245' C; intermediate of derivative No. 33.
`derivative No. 52: 6-(3, 4-dihydroxy-phenacyl)-7-meth-
`iodide; brown
`crystals;
`yl-thieno[2, 3-c]pyridinium
`m. p. & 260' C.
`derivative No. 53: 7-methyl-6-p-methylphenacyl-
`thieno[2, 3-c]pyridinium bromide; white crystals; m. p.
`& 260' C.
`derivative No. 54: 6-p-hydroxyphenacyl-7-methyl-
`brown
`crystals;
`bromide;
`thieno[2, 3-c]pyridinium
`m. p. & 260' C.
`derivative No. 55: 6-ethoxycarbonylmethyl-thieno[2,
`3-
`c]pyridinium bromide; white crystals; m. p. & 260' C.
`derivative No. 56: 6-acetonyl-thieno[2, 3-c]pyridinium
`chloride; white crystals; m. p. & 260' C.
`derivative No. 57: 6-(2-carboxy-ethyl)-thieno[2, 3-
`crystals; m. p.
`chloride; white
`c]pyridinium
`246'-248' C.
`derivative No. 58: 6-carboxymethyl-thieno[2, 3-c]-
`chloride; pale pink crystals; m. p. = 170'
`pyridinium
`C.
`The results of toxicological
`and pharmacological
`the good toler-
`tests reported hereinafter demonstrate
`ance and the activities of the derivatives of this inven-
`anti-arrhyth-
`tion, particularly
`their anti-inflammatory,
`activity on blood
`mic activities and
`their
`inhibiting
`platelet aggregation.
`Thus, this invention relates also to a therapeutic com-
`anti-
`in particular
`position having
`anti-inflammatory,
`arrhythmic activities and an inhibiting activity on blood
`platelet aggregation, comprising as active ingredient, a
`derivative of the formula (I) or a derivative of the for- 40
`mula (IV) or a pharmaceutically
`acceptable acid addi-
`tion salt of a derivative of the formula (I), together with
`a pharmaceutically
`acceptable carrier.
`I. TOXICOLOGICAL INVESTIGATION
`the low toxicity of
`Said investigation
`demonstrates
`the derivatives of this invention.
`For indicative purposes,
`the LD, o/24 hrs/kg body
`route by the
`by the intravenous
`weight, determined
`method according to Miller and Tainter,
`is 135 mg for
`derivative No. 6, 120 mg for derivative No. 9, 80 mg for
`derivative No. 10, 160 mg for derivative No. 11, 80 mg
`for derivative No. 17, 60 mg for derivative No. 18, 48
`mg for derivative No. 19, 63 mg for derivative No. 20,
`55 mg for derivative No. 21, 67 mg for derivative No.
`23, 45 mg for derivative No. 24, 90 mg for derivative
`No. 25, 87 mg for derivative No. 26, 45 mg for deriva-
`tive No. 27, 60 mg for derivative No. 29, 53 mg for
`derivative No. 31, 84 mg for derivative No. 34, 19 mg
`for derivative No. 35, 16 mg for derivative No. 36, 18
`mg for derivative No. 37, 22 mg for derivative No. 38,
`35 mg for derivative No. 39 and 51 mg for derivative
`No. 44.
`that the derivatives of
`Experimentation
`has shown
`this invention were well tolerated throughout
`the acute,
`chronic or delayed
`toxicity tests and that no anomaly
`could be found on autopsy of the sacrificed animals.
`
`30
`
`35
`
`Systemic Edema Method
`b) Ovalbumin-induced
`Rats are administered
`a simultaneous
`intraperitoneal
`injection of 1 ml ovalbumin and 0. 5 ml of a 1% aqueous
`Evans Blue solution. The animals of the treated group
`administered orally 100 mg/kg of the
`are additionally
`test derivative, one hour prior to ovalbumin administra-
`ad-
`tion and then simultaneously with said ovalbumin
`ministration. The intensity of the phenomenon
`thus
`to a scale from 1 to 5, ac-
`is rated according
`induced
`cording to the progress of the inflammatory
`syndrome.
`The measurements are effected after 2 hours and after 3
`the mean intensity of the
`hours. Thus are determined
`edema and the percent decrease of the edema reaction.
`The results obtained are set forth in following Table II:
`
`45
`
`50
`
`55
`
`Derivative n'
`1
`5
`8
`10
`14
`15
`23
`28
`30
`34
`
`TABLE II
`Percent decrease
`After 2 hours
`After 3 hours
`36
`51
`61
`42
`45
`58
`48
`55
`41
`48
`46
`55
`50
`61
`63
`45
`59
`39
`61
`45
`
`60
`
`2. Anti-arrhythmic Action
`a) Against Adrenalin
`The test is effected in chloralosed dogs administered
`route. Three
`5 p, g/kg adrenalin, by the intravenous
`minutes prior to said administration,
`the treated dogs
`were given 10 mg/kg of the test derivative. While se-
`is found to occur in the reference
`vere tachyarrhythmia
`65 dogs, the treated dogs, in contrast, are found to be effi-
`ciently protected against the arrhythmic effects induced
`by injection of high dosages of adrenalin.
`b) Against Ouabaine
`
`

`
`4, 075, 340
`
`5
`
`10
`EXAMPLE 9-continued
`Tablets
`
`0. 025 g
`
`sugar
`
`Core
`
`coating
`
`EXAMPLE 10
`Coated tablets
`derivative n' 44
`Levilite
`magnesium
`starch
`
`stearate
`
`E
`
`gum tragacanth
`shellac
`gum arabic
`glucose
`talc
`Blue
`sugar, suflicient for 1
`
`coated tablet
`
`0. 050 g
`0. 010 g
`0. 010 g
`0. 005 g
`0. 003 g
`0. 002 g
`0. 002 g
`0. 010 g
`0. 001 g
`traces
`
`EXAMPLE 11
`CAPSULES
`
`derivative n' 24
`lactose
`magnesium
`starch
`colloidal sdica
`
`stearate
`
`EXAMPLE 12
`SYRUP
`
`derivative n' 27
`sweetened
`flavoured
`excipient, sufficient to make
`
`0. 150 g
`0. 005 g
`0. 005 g
`0. 005 g
`0. 010 g
`
`2. 50 g
`
`100 ml
`
`EXAMPLE 13
`INJECTABLE SOLUTION
`derivative n' 36
`isotonic solution,
`sufficient to make
`
`0. 125 g
`2
`
`ml
`
`20
`
`25
`
`35
`
`In view of its anti-inflammatory
`and antiarrhythmic
`properties and of its inhibiting effect on blood platelet
`the composition of this invention
`40 aggregation,
`is use-
`in the treatment of the various stages of
`fully applicable
`It is applicable
`in chronic inflammatory
`inflammation.
`degenerative
`rheumatism,
`in abarticular
`rheumatism,
`conditions,
`in oto-rhino-laryngology,
`in stomatology,
`in
`45 post-opertive
`surgery and in traumatology.
`In view of its anti-arrhythmic
`action and of its inhibit-
`ing action on blood platelet aggregation,
`the composi-
`tion of this invention
`in the treatment of
`is applicable
`disorders of the cardiac rhythm such as sinus tachycar-
`5o dia, fibrillation and auricular
`flutter, supra-ventricular
`tachycardia, extrasystoles and also of disorders of the
`cerebral and peripheral circulatory system.
`Having now described my invention what I claim as
`new and desire to secure by Letters Patent is:
`1. A compound having
`the following structure:
`
`9
`Chloralosed dogs are administered
`ouabaine, by the
`route, at a dosage of 80 p, g/kg. Highly
`intraveneous
`severe arrhythmia
`to occur in the animals,
`is found
`15-20 minutes after said injection. As soon as the ar-
`sets in, the animals are administered
`rhythmia
`intrave-
`nously 10 mg/kg of the test derivative. Both the sinus
`rhythm and the perturbed electric activity of the heart
`are found to be restored very rapidly by the derivatives
`of this invention.
`c) Disorders of the cardiac rhythm appear also in
`dogs after ligation of the coronary artery. On injection
`at a dosage of 10 mg/kg,
`the derivatives of this inven-
`tion are found caPable of raPidly
`restoring a normal
`cardiac activity.
`activity was 15
`On the average,
`the anti-arrhythmic
`found to be greater with the derivatives of the formula
`(IV) than with the derivatives of the formula (I).
`3. Inhibiting Activity On Blood Platelet Aggregation
`Rat plasma, prepared
`to contain 600, 000+20, 000
`blood platelets per mm3 is normally cloudy. Addition of
`adenosine diphosphate
`induces blood platelet aggrega-
`thus an increase of the light
`tion and,
`transmission.
`When the same test is effected with a plasma prepared
`from the blood of an animal which has been adminis-
`tered 100 mg/kg of a derivative having an inhibiting
`effect on blood platelet aggregation,
`there is no aggre-
`gation of the blood platelets and the serum
`remains
`cloudy. The turbidimetric assay effected with a spectro-
`photometer provides a measure of the inhibiting activi-
`ties of the test derivatives on blood platelet aggregation.
`The tests carried out with groups of five rats (three
`controls and two treated animals) show that the com-
`pounds of this invention
`induce a substantial percent
`inhibition on blood platelet aggregation,
`said percent
`inhibition being respectively 91% for derivative No. 3,
`85% for derivative No. 7, 89% for derivative No. 9,
`75% for derivative No. 12, 78% for derivative No. 18,
`91% for derivative No. 21, 78% for derivative No. 24,
`86% for derivative No. 27, 89% for derivative No. 29
`and 74% for derivative No. 33.
`The toxicological and pharmacological
`investigations
`reported above show that the derivatives of this inven-
`tion are endowed with a good tolerance and possess
`valuable anti-inflammatory
`activi-
`and anti-arrhythmic
`ties together with an inhibiting action on blood platelet
`aggregation.
`For oral administration,
`the composition of this in-
`vention may be formulated
`as tablets, coated tablets,
`capsules, drops or syrups. It may also be formulated
`for
`rectal administration,
`as suppositories
`and, for paren-
`teral administration,
`as injectable solutions.
`Each unit dose contains advantageously
`from 0. 010 g
`to 0. 300 g active ingredient,
`the daily dosage regimen
`varying within a range from 0. 010 g to 0. 900 g active
`ingredient, depending on the age of the patient and the
`severity of the condition
`to be treated.
`Non-limiting Examples of pharmaceutical
`tions of the composition of this invention
`below.
`
`formula-
`are given
`
`N — X
`
`Ri
`
`EXAMPLE 9
`Tablets
`
`derivative n' 1
`potato starch
`talc
`magnesium
`stearic acid
`
`stearate
`
`0. 100 g
`0. 010 g
`0. 005 g
`0. 005 g
`0. 010 g
`
`in which Ri is a member selected from the group con-
`65 sisting of hydrogen
`and methyl, with a proviso
`that
`when Ri is hydrogen, X is a member selected from the
`group consisting of
`n-dodecyl,
`
`

`
`o-methoxycarbonylbenzyl
`
`o-carboxybenzyl
`2-(5-chloro-thienyl)-methyl
`
`2-acetoxy-2-p-chlorophenyl-ethyl
`
`2-hydroxy-propyl
`2-acetoxy-2-m. methoxy phenyl-ethyl
`o-nitrobenzyl
`
`yl
`
`yl
`
`p-nitrobenzyl
`o-cyanobenzyl
`2-chloro-benzyl
`3, 4, 5-trimethoxy-benz
`P-phenethyl
`m. methoxybenzyl
`p. chlorobenzyl
`m. chlorobenzyl
`2-hydroxy-2-phenyl-ethyl
`p. methylbenzyl
`3, 4-dimethoxy-benz
`- o. fluorobenzyl
`2-hydroxy-2- p. chlorophenyl-ethyl
`2, 3, 4-trimethoxy-benz yl
`2-hydroxy-2-p. fluorophenyl-ethyl
`2-hydroxy-2-p. methoxyphenyl-ethyl
`2-hydroxy-3-p. methoxyphenoxy-propyl
`3-oxo-butyl
`2-hydroxy-3, 3, 3-trichloro-propyl
`3, 4dimethoxy-benzyl
`and when Rl is methyl, X is a member selecte
`d from the
`group consisting of
`3, 4, 5-trimethoxy-benzyl
`2-hydroxy-2-phenyl-ethyl
`2-p. chlorophenyl-2-hydroxy-ethyl
`o-chlorobenzyl
`2-hydroxy-2-p. methoxyphenyl-ethyl
`2-hydroxy-2-m. methoxyphenyl-ethyl
`2-(2, 4-dimethoxy-phenyl)-2'-hydroxyethyl.
`2. A compound having
`the following stru
`
`4, 075, 340
`
`12
`
`N — X, Hale
`
`s
`
`R|
`
`in which R, is a member selected from the group con-
`sisting of hydrogen
`and methyl, with a proviso
`that
`when R, is hydrogen, X is a member selected from the
`group consisting of
`dodecyl
`phenacyl
`p-chlorophenacyl
`p-fluorophenacyl
`p-methoxyphenacyl
`2-pic olyl-N-oxide
`ethoxycarbonylmethyl
`acetonyl
`2-carboxy-ethyl
`carboxymethyl
`and when R, is methyl, X is a member selected from the
`group consisting of
`phenacyl
`p-methoxyphenacyl
`o-methoxyphenacyl
`2, 4-dichloro-phenacyl
`p-chio rophenacyl
`p-fluorophenacyl
`2, 5-dimethoxy
`m-methoxyphenacyl
`3, 4-dihydroxy-phenacyl
`p-methylphenacyl
`p-hydroxyphenacyl.
`3. Therapeutic composition having an anti-inflamma-
`tory activity, comprising, as active ingredient, a com-
`pound according to claim 1 together with a pharmaceu-
`tically acceptable carrier, in unit dosage form, each unit
`dose containing 0. 010-0. 300 g active ingredient.
`4. Therapeutic composition having an inhibiting. ac-
`tivity on blood platelet aggregation,
`as
`comprising,
`to claim 1
`ingredient, a compound
`active
`according
`together w'ith a pharmaceutically
`acceptable carrier, in
`unit dosage form, each unit dose containing 0. 010-0. 300
`g active ingredient. '
`5. Therapeutic compos