DD142053A5 - METHOD FOR THE PRODUCTION OF NEW THIENO SQUARE BRACKET ON 3,2-C SQUARE BRACKET AND THIENOOUS BRACKET ON 2,3-C CORNER BRACKET TO PYRIDINES - Google Patents

Description

2 I j 0

Process for the preparation of new thieno / "3,2-c / and thieno / 2,3- 7pyridines

Field of application of the invention , ...

The present invention relates to a process for the preparation of novel thieno / ~ 3,2-7- and thieno / ~ 2,3 ~ c7-pyridines of the general formulas (I) and (II) below.

The compounds prepared by the process according to the invention can be used as therapeutic agents.

Characteristics of the available technical solutions . Z. not possible. Object of the invention

The compounds prepared by the process according to the invention have in particular sedative, anticonvulsant and anti-inflammatory activities.

Explanation of the essence of the invention

The invention has for its object to provide a method for the preparation of new Thieno / ~ 3,2- £ 7 and Th ± eno / ~ * 2,3- £ 7-pyridines available.

18th-6th 1979 55 "008 12

The present invention relates to a process for the preparation of novel thieno / "" 3,2-c7- and - / ² "3-c7-pyridines of the general formulas

COF ^ and

(I) (II)

wherein R ¹ and R are each independently hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; Aryl or aralkyl, optionally on the phenyl ring one or more times with halogen, nied. Alkyl, low. Alkoxy, hydroxy or trifluoromethyl substituted; Heteroaryl, heteroaralkyl or a group of the formula

where η is 2 or 3 and R 1 and R 4 are each independently of the other C 1 -C 4 alkyl, or together with the nitrogen atom to which they are attached form a heterocyclic group which acts as a second heteroatom may have an oxygen, sulfur or nitrogen atom, which

the latter can carry a C 1 -4 -alkyl group, or R and R together with the nitrogen atom to which they are attached form a heterocyclic group which as a second heteroatom can carry an oxygen, sulfur or nitrogen atom, which in turn carries a may carry "alkyl group or a phenyl group, which may in turn optionally

18, 6, 1979 55 008 12

or several times by halogen, low. Alkyl, low. Alkoxy or trifluoromethyl can be substituted, and their acid addition salts with mineral acids or organic pharmaceutically acceptable acids.

1 2

When R and / or R is aralkyl, it is in particular benzyl or phenethyl; when they are heteroaralkyl, it is in particular (3-pyridyl) -methyl or (4-pyridyl) -methyl.

The term "lower," as used herein in connection with alkyl or alkoxy, means that the groups in question contain up to 6 C atoms, in particular 1 to 4 C atoms.

The process of the invention consists in that one is aiuin of the general formula

12

wherein R and R have the above meaning, with a mixed anhydride of the general formula

It

tt

or

C-O-C-OR tt tr

0 0

C-O-C-OR

(III)

S - 4 - 18. 6. 1979

55 008 12

wherein R is C - ^ - alkyl, allowed to react.

The starting compounds (III) and (IV) are in turn obtained by condensation of thienopyridines of the formulas

COOH

or · COOH

(V) (VI)

with an alkyl chloroformate of the formula ClCOOR, wherein R has the above meaning, prepared in the presence of triethylamine.

The two reactions are preferably carried out successively in the same vessel: the mixed anhydrides (III) and (IV) are first prepared at temperatures of -5 to + 15 C in an inert solvent such as chloroform or methylene chloride; then at the

, -ni

same temperature, the amine HrT - ^ _R 2 is added in pure form or diluted in a 'solvent,' such as benzene, toluene, chloroform or methylene chloride, and the mixture allowed to stand at ambient temperature.

The compounds (V) and (VI) can be prepared by reacting a compound of the formula

Berlin, d _e 29 55 1979 008/12 _οβ β

COOH

or

COOH

(VII) (VIII)

with nitric acid, followed by dehydration and removal of the nitroso group of the resulting compounds by reaction with an alkali metal hydroxide and subsequent neutralization,

Finally, the compounds of formula (VII) or (VIII) may be prepared by reacting a compound of formula

OH

or

0OH

0OH

with an aqueous solution of formaldehyde in the presence of a strong acid.

Execution; sbe i spjLeJLe

The following examples are intended to explain the present invention in more detail, without, however, being restricted thereto.

Example 1 6-Methylaminocarbonylthieno [3 "2-clipyridine

(I; IiR ¹ R ² = IiHCK ₃ , derivative no. 1)

To a maintained at 10 ⁰ C solution of 10 g (0 050 mol _s) 6 ™ Carboxythieno £ 3.2 ~ c7pyridin and 5.6 g (0.057 mol) rriäthyl "- AMLN in 500 ml of dry chloroform is added slowly with vigorous stirring 6 , 2 g (O _P O57 mol) of ethyl chloroformate added «

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55 008/12

After completion of the addition, stirring is continued for 40 minutes at ambient temperature followed by the dropwise addition of a solution of 2 g (0.064 mole) of methylamine in 50 ml of benzene. The mixture is allowed to stand at ambient temperature for 4 hours and then evaporated to dryness Residue is taken up in ether »

The ethereal phase is washed with a saturated aqueous solution of matrium bicarbonate, dried over sodium sulfate and evaporated to dryness

The solid residue is recrystallised from a mixture of benzene and diisopropyl ether. The title compound is obtained in pinkish crystalline form, Pp ₀ 99 ⁰ C, yield 79 %.

Example 2: Oss-dimethylaminoethylaminocarbonylthieno- '

£ 3,2-cT | «pyridine (I; In ¹ R ² = NH (CH ₂₎ gN (CH _{3) 2,} derivative Hr" 2) ^ To a maintained at 10 ⁰ C solution of 10 g (0.056 mol 6 "Carboxythieno [3.2" c] pyridine and 5.6 g (0.057 mol) of triethylamine in 300 ml of dry chloroform are slowly added with vigorous stirring 6.2 g (0.057 mol) of ethyl chloroformate. "After completion of the addition, stirring is begun 5.4 g (0.061 mol) of β-Diniethylaminoäthylamin be added dropwise at ambient temperature for 40 min. "The mixture is allowed to stand for 3 1/2 h at ambient temperature and then evaporated to dryness, and the residue is taken up in η hydrochloric acid Aqueous acid phase is washed with ether and then made alkaline with 6N sodium hydroxide, followed by extraction with methylene chloride. The extracts of chloromethylene are dried over dry sodium sulphate and evaporated to dryness. The oily residue

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55 008/12

is purified via its dichlorohydrate intermediate "The title compound is obtained in the form of beige crystals, mp * 170 ^° C. (isopropanol-methanol), yield 75% *

Example. 3: 5 «(4-P ~ chlorophenyl-1-piperazinyl ^ carbonylthieno £ 2, 3 ~ e] pyridine

(II; NR ¹ R ² = IT Ii- / θ / -Cl, derivative

No. ₀ 3)

To a held at 10 ⁰ C solution of 12 g (0.067 mol) of 5 ~ Carboxythieno [2,3-c] pyridine and 6.9 g (0.068 mol) of triethylamine in 250 ml of dry chloroform are slowly with vigorous stirring 7.3 g (0.068 mole) of ethyl chloroformate added. Stirring is continued at ambient temperature for 50 minutes followed by the dropwise addition of 13.2 g (0.067 mole) of p-chlorophenylpiperazine dissolved in 50 ml of chloroform. The mixture is allowed to stand at ambient temperature for 5 hours then, evaporated to dryness and the residue is taken up in methylene chloride. The chlorinethylene phase is washed first with an aqueous saturated sodium bicarbonate solution, dried over dry sodium sulphate and evaporated to dryness. The obtained crystals are purified by chromatography on a silica column (eluent ethyl acetate). the title compound is obtained in the form of white K _r istalle, 170 ⁰ C (isopropanol-diisopropyl ether) Yield 41 % o

Example 4: 6-ethylaminocarbonylthieno / 3,2-cJpyridine

(I; NR ¹ R ² = UlC ₂ II ₅₉ derivative Hr ₉ 4)

The procedure is as in Example 1, starting from 6-carboxythieno | 3,2-c] pyridine and ethylamine. The title compound is obtained in the form of beige K _r , mp ₀ 110 ⁰ C (diisopropyl ether) ₉ Yield 87 % *

Berlin, d _e 29 _β β 0Ί9 79 55 008/12

Example 5: 5 ~ isopropylaminocarbonylthienol2,3 ~ c}

pyridine (II; ISIR ¹ R ² = HHO ₃ H ₇₂ derivative.

The procedure is as in Example 1, wherein of 5-Carboxythieno [2 _? 3- »ο] pyridine and isopropylamine is obtained.» The title compound is obtained in the form of shiny chestnut-colored crystals, mp 102 ⁰ C (diisopropyl ether) _s yield 80 % _m

Example 6: 6-n-butylaminocarbonylthieno [3.2 ~ cJ

pyridine (I; IJR ¹ R ² HHG ₄ Hg, derivative Hr _e 6)

The procedure is as in Example 2, starting from 6 "Carbosythieno | 3g2" c] pyridine and n-butylamine. "The title in the title compound is obtained as a chlorohydrate in the form of yellow-orange crystals, Fp _e IO4 ⁰ C (acetonitrile ), Yield 55 % «

Example 7: O-Octylaminocarbonyltliieno [3,2-c3-pyridine

(Ij HR ¹ R ² B-KHC ₈ H ₁₇ , derivative No ₀ 7)

The procedure is as in Example 1, starting from 6-Carbozythieno [_3> 2-cJ pyridine and octylanine. The title compound is obtained in the form of white crystals, 3 .p _e 63 ⁰ C (diisopropyl ether), yield 54 %.

Example 8ϊ 6-Dimethylsminocarbonylthieno [3 »2« cU pyridine

, din (I; HR ¹ R ² = H (CH ₃ ) ₂ , derivative Hr _e 8)

The procedure is as in Example 1, starting from 6-carboxy-thieno [3,2-c] pyridine and dimethylamine. The title compound is obtained in the form of white crystals, mp ₀ 93 ⁰ O (diisopropyl ether) , Yield 55% ·

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Example 9i 6 «Diethylaminocarbonylthieno Jj3» 2-cy-pyri ~

din (I; NR ¹ R ² = H (C ₂ HJ ₂ , derivative Hr, '9)

The procedure is as in Example T, starting with 6- carboxy-thieno-3-pyridine and diethylamine. The title compound is obtained in the form of beige crystals, mp 119.degree. C. (diisopropyl ether), Yield 80%,

Be i s ρ i e 1 10: 6 - (1-pyrrolidinyl) -carbonylthieno [3j2-cJ

-pyridine (I; HR ¹ R ² _ 10)

, Derivative lir »

The procedure is as in Example 1, starting from 6-carboxy ~> thieno [3? 2-c] pyridine and pyrrolidine * The title compound is obtained in the form of off-white crystals, mp ₄ IO5 ⁰ C (diisopropyl ether ), Yield 52 % »

Example 11: 6-piperidinocarbonylthieno ^ 3 _? 2 ~ c] pyridine

(I; HR ¹ R ² β ® J 9 derivative Hr, 11)

The procedure is as in Example 1, 6-Carboxythieno [3? 2 ~ c] is assumed pyridine and piperidine "The title compound is obtained in the form of a shiny maroon powder, m.p. _e 145 ⁰ C (diisopropyl ether), yield 9 * 6% ·

Example 12: 6-morpholinocarbonylthieno [3j2-c] pyridine

(I; HR ¹ R ² = \ _JP 9 derivative Ur ₉ 12)

The procedure is as in Example 1, starting from 6-Carboxythieno [3y 2-cj pyridine and morpholine, "The title compound is obtained in F _o rm of white crystals, Pp, .136 ⁰ C (benzene-diisopropyl ether ), Yield 79 %

Example 13: 5-Benzylaminocai'bonylthieno £ 2,3- ^c7pyricin

(II, NR ¹ R ² = ITHCH ₂ C ₆ H ₅ , derivative Hr, 13)

45 Q 45 ~ ¹⁰ "-Berlin, June 29, 1979 • *". 55 008/12

The procedure is as in Example 1, wherein of 5 ~ Carbo: sy · - thieno [2 _? 3-c3 pyridine and benzylamine is assumed, "The. the title compound is obtained in the form of beige K _r , Pp * 113 ⁰ O (isopropanol), yield 75%

Example 14: 6 ~ o ~ Chlorobenzylaminocarbonylthieno [3.2 ~

^{12 C1} *

MCH

y -pyridine (I; NR ¹ R ² = ^C1

^A 2

: Derivative Kr. 14)

The procedure is as in Example 1, wherein of 6-carboxy. Thieno [3,2-Cj pyridine and o ~ chlorobenzylamine is assumed. The title compound is obtained in the form of a beige powder, mp ₆ I69 ⁰ C (methanol), yield 58%).

Example 15: 6-Phenethylaminocarbonylthieno [^ 3> 2-c

pyridine (I; ITR ¹ R ² = HHCH ₂ CHpCgH ₅ ,. derivative 15)

The procedure is as in Example 1, starting from 6 "Carboxy ~ thieno J3§ 2-cl pyridine and phenethylamine" The title compound is obtained in the form of beige crystals ^ Fp "127 ⁰ C (isopropanol-diisopropyl ether), Yield 66 % »

Example 16: 6-Allylaminocarbonylthieno [3 * 2-c3 pyridine

(I; HR ¹ R ² = HHCH ₂ -CH = CH ₂ , derivative Wr. 16)

The procedure is as in Example 1, starting from 6 ~ Carbo: xy ~ thieno [3f2-c} pyridine and allylamine. The title compound is obtained as an oxalate in the form of white crystals, mp _Q 131 ⁰ C (ethyl acetate), yield 54 % +

piel 17: 6-Propargylaminocarbonylthieno / _3 _s 2-cJ pyridine (I; HR ¹ R ² = IHCH ₂ C ^ CH ₉ derivative irr «17) ... -

211 04§ ~ ¹¹ "Berlin, d, 29. 6," 1979

55 008/12

The procedure is as in Example 1, starting from 6-carboxythieno [3,2-cTj pyridine and propargylamine _o The title compound is obtained in the form of rose-colored crystals, mp. "134. ⁰ C (isopropanol-diisopropyl ether), yield 60% »

Example 18: 6β-diethylaminoethyl8-amino carbonylthieno *

[3,2-clpyridine (I; IR ¹ R ² = UH (CH ₂ ) ^ (C ₂ Hc) ₂ , derivative Nf ₀ 18)

The procedure is as in Example 2, starting from 6-Carboxythieno [3s2-cJpyridin and ß-diethylaminoethylamine. The title compound is obtained as Diohlorhydrat in the form of beige K _r rall, Pp 145 ⁰ C (isopropanol -Ethanol), yield 81% «

Example 19: ββ-morpholinoethylaminocarbonylthieno

[3j2-c3 pyridin-

(I; ITR ¹ R ² = ITH (CH ₂ ) ₂ N ^ p _s Derivative Ur *: .19)

The procedure is as in Example 2, starting from 6-carboxythieno [3,2'c] pyridine and U- (2-aminoethyl) morpholine. The title compound is obtained in the form of white crystals. Fp _e IO4 ⁰ C (isopropanol-diisopropyl ether) _? Yield 71 % o

Example 20 6-Dimethylaminopropylaminocarbonyl

thieno - ["3,2-CJ pyridine (I; HR ¹ R ² " UH

(CH ₂ ) ₃ U (CHO) ₂ , derivative Ur. 20)

The procedure is as in Example 2, wherein of 6-Carbozythieno £ 3? The title compound is obtained as a dichlorohydrate in the form of beige crystals, mp * I46 ⁰ C (ethanol), Yield 77 % *.

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Example 21: 5- (4-Pyridylmethyl) aminocarbonylthienoyl

£ 2,3-c] pyridine (II; NR ¹ R ² s HHCH,

-. Derivative Ur, 21) "

The procedure is as in Example 3, starting from 5-Carboxythieno £ 2,3 ~ c3 pyridine and 4-aminomethylpyridine, the title compound is obtained in the form of inon shiny maroon crystals, mp. 167 ⁰ C (isopropanol-diisopropyl ether ), Yield 78 % ₉

Example 22: 6 ~ (4-pyridylmethyl) aminocarbonyl thieno

[3,2-e] pyridine (I; HR ¹ R ² = NHCH ₂

Derivative No. ♦ 22) 'The procedure is as in Example 3, starting from 6-Carboxythieno [3s2-cj pyridine and 4 ~ aminomethylpyridine, "The title compound is obtained in the form of orange-* gefarbenen crystals, m.p. _e 046 ⁰ C (ethyl acetate), yield 98 % ₀

Example 23: 5- (3-Pyridylmethyl) aminocarbonylthieno

[2,3-3ppridine (H; ^ ¹ R ² = NHCH ₂ ^ Q), -: derivative ITr. 23) '/ ^^

The procedure is as in Example 3 ^ starting from 5 ~ Carboxy ~ thieno [2 _s 3-c] pyridine and 3-Aminometh.ylpyriain «The title compound is obtained in the form of beige crystals, mp _e 143 ⁰ C. (Isopropanol-diisopropyl ether) _s yield 73%

Example 24: 6- (3-Pyridylmethyl) aminocarbonylthieno

[3 $ 2 «<3pyridine (I; HR ¹ R ² = ..: derivative Kr ₀ 24) '

The procedure is as in Example 3, starting from 6 "thienor3" 2 "o7pyridine and 3-aminomethylpyridine

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The title compound is obtained as beige crystals, mp, 137 ⁰ C (ethyl acetate), yield 55 %.

Example 25: 6- (3-trifluoromethyl-phenyl) -aminocarbonyl

thieno / 3f 2-ό] pyridine

/ ^{C: P} 3

(I; HR ¹ R ² "MH- ((J) , derivative Hr. 25)

The procedure is as in Example 1, starting from 6-Carboxythieno f3,2-cj pyridine and m-trifluoromethylaniline. The title compound is obtained in form of white crystals, m.p. * 151 ⁰ C (isopropanol-diisopropyl ether), yield 62%. ₉

For example, 26: 6 ~ (4-p-tolyl-1-piperazinyl) -carbonyl

thieno [3 »2 ~ o] pyridine (

(I; UR ¹ R ² =] / "~ ^ Γ - ^ Q) -CH ₃ , derivative

Ur ₀ 26)

The procedure is as in Example 3, starting from 6-carboxythieno [3,2 ^ c] pyridine and 1-p- »tolylpiperazine. The title compound is obtained in the form of beige crystals, mp. 150 ⁰ C (isopropanol, "Dii8opropyläther), yield 82%,

Example 27: 6 «(4-o ~ chlorophenyl ~ 1-piperazine $: l)« car <~

Bonyl-thieno ^, 2-oJ pyridine

(I; IIR ¹ R ² = nQ-O ^{'derivative Hi% 27)} where £ _3 »2-Oj of 6-Carboxythieno The procedure is as in Example 3, | pyridine and io ^ chlorophenylpiperazine is assumed * The compound of the title is obtained in the form of crystals, mp ₀ 140 ⁰ G ₉ (isopropanol ~ diisopropyl-

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55 008/12

ether), yield 52% »

Example 28: 6- (4 ™ m -chlorophenyl-1'-piperazine 3 ' ^r l) - car-

bonyl thieno [3s2 "c] pyridine

(I; HR ¹ R ² = KN- <QJ), derivative No.28)

The procedure is as in Example 3, wherein of 6-Carboxythieno Π? 2 «c] pyridine and 1 ~ m-" chlorophenylpiperazine is considered "The title compound is in the form of" egg Ben obtained crystals of v / mp "157 ⁰ C (ethyl acetate), yield 52%. .,.

Example 29: 6- (4- * p-Methoxyphenyl-1-piperazinyl)

, carbonylthieno ^ [3,2-c3 pyridine

(I; HR ¹ R ² =

Mr _ft 29) '

The procedure is as in Example 3, wirdo starting from 6 «Garboxy""thieno £ 3j2 ~ c] pyridine and 1-p-methoxyphenylpiperazine The title compound is obtained in form of white crystals, m.p.« 152 ⁰ C (ethyl acetate Diisopropyl ether) ₉ Yield 72% »

Example 3Oi 5- (4-o-methoxyphenyl-> 1-piperazinyl) ^

carbonylthieno [2,3 ~ oJ pyridine

s HRR iQrC / ' ^derivative 30)

The procedure is as in Example 3., Starting from 5-Carboxythieno £ 2,3 ~ c] P ^{vr: i} - ^ ⁿ ^ ¹¹¹ ^ 1-oK ^e '^ o2cyphenylpiperazin6 The compound mentioned in the title is in the form of beige crystals, mp ₀ 171 ⁰ C (isopropanol), yield 62% o *

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Example 31: 6-Carbamoylthieno [3.2 ~ cJ pyridine

(I; UR ¹ R ² = IJH ₂ , derivative no. 31)

The procedure is as in Example 1, starting from 6'Carboxythieno [3 »2-c] pyridine and ammonia _o The title compound is obtained in the form of white crystals, mp 172 ⁰ C (acetonitrile), yield 68 %.

Example 32: 5-Qarbamoylthieno / 2,3-c] pyridine

(II; HR ¹ R ² = ITH ₂ , derivative 3Jr. 32)

The procedure is as in Example 1, starting from 5-carboxythieno [_2,3 "-c] pyridine and ammonia» The title compound is obtained in the form of white crystals, mp. 200 ⁰ C (acetonitrile), yield 76 % *

Example 33: 5-Phenethylaminocarbonylthieno £ 2,3-c]

pyridine (II; IiR ¹ R ² = NHCH ₂ C ₆ H ₅ , derivative

₂₆₅ No, 33) "

The procedure is as in Example 1, starting from 5- * carbonylthieno ^ 2,3-c] pyridine and Phenäthylamin is assumed. The title compound is obtained in the form of beige crystals, mp. I30 ⁰ C (isopropanol-diisopropyl ether), yield 79%. ".

Example 34: 6- (4-Benzyl-1-piperapinyl) -carbonyl

thi.eno- / 3j2 ~ c] pyridine

1 ? ^Λ

(I; NR ¹ R 1 = Nv 1 MH ₂ CgH ₅ , derivative no.

  34)

The procedure is as in Example 3, starting from 6-Carboxythieno [3 »2« cü pyridine and 1-benzylpiperazine. The title compound is obtained as a dihydrochloride in the form of white K _r istallen, mp. 187 ⁰ C (Isopropptälol- • ethanol), yield 49%, '' "'..'

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Example 35s 6- (3,4-Diraethoxy- »phenethyl) -aminocarbo-

nyl-thieno [3> 2-c] pyridine

(I; UR ¹ R ² β NHCH ₂ CH ₂ -

Derivative ITr. 35).

The procedure is as in Example 1, starting from 6 <-Caryboxythieno [3s 2-c] pyridine and (3 ₉ 4 »Dimetho3cyphenäthyl) amine * The title compound is obtained in the form of white crystals, mp" 125 ⁰ C (isopropanol-di-isopropyl ether) _s yield 77% «

Example 36: 5 "- (3i4-di-ethoxyphenethyl) -aminocarbo-

nyl-thieno [2 _? 3 «ο] pyridine

(II; UR ¹ R ² β ImGE ₂ GE? - ((γ> -OCH

Derivative Hr _e 36)

The procedure is as in Example 1, starting from 5'-carboxy thieno (^ 2,3-pyrridine and (3,4-dimethoxyphenethyl) -amine. The title compound is obtained in the form of white crystals. Mp> 125 ^° C (isopropanol, diisopropyl ether) ₉ Yield 73%.

Example 37: 6 (4-methyl-1-piperazinyl) -carbonyl

2 "cJ pyridine

(I; HR ¹ R ² = HH - CH ₃ , derivative Ur * 37)

The procedure is as in Example 1, starting from 6-Carboxythieno [3,2-cj pyridine and 1-Methylpipersszin, ..The the titled compound is obtained in the form of a chestnut-colored powder as leat M _a, mp "16S ⁰ C (isopropanol), yield 83% ·;

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The results of pharmacological and toxicological investigations illustrate the properties of the compounds (I) and (II) obtainable according to the invention with regard to toxicity and tolerability as well as their efficacies, in particular sedative, anticonvulsive and anti-inflammatory efficacies *

I * Toxicological examination

The compounds of formulas (I) and (II) are excellent in compatibility and low in toxicity.

, In terms of acute toxicity, the LD, -Q / 24h / kg body mass, determined in the mouse according to the method of Miller and Tainter, when administered orally, is higher than 400 mg for all compounds. »

By the same method, the LDj-q / 24 h / kg body mass when administered intravenously, for example, was 154 mg for the No. ₁ derivative No. _{1, and the 0 0} 2 derivative was used

89 mg, for the derivative No. 10 with 184 mg, for the derivative 3Tr. 11 with 130 mg, for the derivative no. 12 with 350 mg, for the derivative no. 18 with 65 mg, for the derivative no. 22 with

90 mg, 96 mg derivative no. 24 and 105 mg derivative no.

Furthermore, experiments to determine the acute, chronic, subchronic and delayed toxicity in various animal species did not reveal any local or general response and no interference or anomaly in biochemical, microscopic or macroscopic investigations during this experiment.

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Let Pajarmakogische investigation

A) study of behavior

This experiment was carried out according to the method of Samuel Irwin (Ph. D * Animal and Clinicyl Pharmacology Technics in Drug Evaluation). The compounds of formulas (I) and (II) were orally administered to mice at a dose of 100 mg / kg treated animals were 4 hours were observed after administration of the drug "Their behavior was studied, and the various physiological parameters (temperature ₉ speed of the heartbeat and respiration) were measured © In the treated animals, a significant reduction in the Motrizität and muscle _tone} was d _e h «, an impairment of the state of waking and of the reactions to sounds and to the environment.

B) Action against hypnotics

The compounds of formulas (I) and (II) enhance the effect of hypnotics very clearly. "In fact, when administered orally to mice at 100 mg / kg 30 minutes prior to intraperitoneal administration, they enhance an infrahypnoic amount of sodium pentobabital as compared to untreated Control the effect of the barbiturate considerably «

In fact, the number of hunted animals, the mean time to fall asleep and the duration of sleep are significantly higher in the treated animals * The results with the most potent compounds are given in the following Table I,

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treatment

Table I % sleeped mean time animals until falling asleep

mean sleep time

0 (control 'group) derivative 1 derivative 5 derivative 6 derivative 10 derivative 15 derivative 16 derivative 18 derivative 22 derivative 23 derivative 25 derivative 26 derivative 28 derivative 29

70 80 80 90 90 70 80 70 80 90 90 80 90

8 min min min min

min

min

min

min

min

min

s

s s s s

s s s

1 h 30

1 h 45

1 h 48

1 h 35

1 h 50

1 h 42

1 h 38

1 h 45

1 h 50

1 h 38

1 h 35

1 h 40

1 h 47

mm min min min min min min min min min min

2 # Anticonvulsant effect;

This effect was studied by means of electric shocks. "Application in the rat elicits experimental convulsions in response to an electrical stimulus above the stimulus threshold. Then the presence and the duration of each convulsive phase and the intensity of the convulsive phase are determined in the control animals and in the treated animals Cramps compared in the totality

For each compound to be tested, a group of 10 rats is taken and each animal is orally administered with 100 mg / kg of the compound in question. "

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An electrode is applied to each side of the tail of each rat and, 30 minutes after treatment, is passed through the animal placed in a glass cage for 50 ms alternating current at 50 Hz and 120V *.

The current drift triggers a convulsive spasm whose phases (tonic, clinical, muscular relaxation) are recorded in time. The intensity of the spasm is then rated 0 to 4 according to the presence of each phase and its duration. Compounds obtained according to the invention are tested in comparison with phenobarbital. which has a marked anticonvulsant effect (intensity of the spasm = 2), whereas in the non-treated control animals the maximum intensity obtained is 4,

In this way it was found that all the compounds of formulas (I) and (II) confer important protection against electroshock, since the average intensity values of the convulsions in each group 2 ₉ 5 for the derivative Ur »1,3 for the derivative no , &, 2, 5 for the derivative Hrβ 5, 2.5 for the derivative Ur « S ₉ 3 for the derivative Ur. .13, 2.5 for the derivative no. 19, 2.5 for the derivative Hr ₀ 25, 2.5v for the derivative no ₄ , 30 and 2.5 for the derivative Ur * 31 «,

• 3 ». Anti-inflammatory effect a) Mejthj5dj3j | ^

0 ₉ 1 ml of a 1% carrageenin solution is injected into the muscles of the metatarsus of the right hind paw

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Rat injected at time 0 "The animals of the treated group also received orally 100 mg / kg of the compound to be tested 1 h before and simultaneously with the injection of the phlogistic agent and then 1 h and 2 h after the injection ROOH micrometer at time-i), 1 h, 2 h _f 3 h, and 5 h after administration of carrageenin make it possible to determine, as a function of time, the percentage of anti-inflammatory activity by comparison with the control group _e >

The results for some compounds of formulas (I) and (II) are shown in the following Table II *

Table II

Derivative Hr «Percent anti-inflammatory effect 2o h oh h 5 * h 1 · h 42 46 47 1 35 46 50 58 4 41 49 54 56 5 43 42 46 51 10 37 40 45 51 13 34 45 49 53 15 38 46 50 55 18 41 48 51   54 21 40 47 51 55 22 41 46 49 52 25 39 49 52 54 27 41 45 49 53 30 38 41 45 47 32 34 of chicken egg whites generalized b) Method edema

ml of egg white and 0.5 ml of an aqueous 1% solution

•. -22-

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In addition, 100 mg / kg of the compound to be tested are orally administered to the animals of the treated group 1 h before and at the same time as the egg white. ranges ₀ The intensity of the phenomenon produced in this way is evaluated by a number from 1 to 5 according to the progression of the inflammatory syndrome. This will be the mean edematous intensity and the percentage reduction of the edematous reaction in comparison to the control as a function of time

The percentage of anti-inflammatory activity of some of the compounds of formulas (1) and (II) obtained according to the invention obtained 2 h and 3 h after the injection of egg white is given in Table III.

Derivative ITr _β percent 2OH 1 48 4 47 5 52 10 47 13 50 ¹ 5 53 18 49 21 45 22 51 25 51 27 47 30 48 32 52

Percent anti-inflammatory activity

3 ". h 56

56 60

55 56 60

, 58 52 58 59 56 56 60

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The results of these experiments illustrate the low toxicity and the good tolerability as well as the interesting sedative, anticonvulsive and antiinflammatory properties of the compounds obtainable according to the invention, which are extremely useful in both human and veterinary medicine. "

The compounds of formulas (I) and (II) obtainable according to the invention are formulated for oral administration as tablets, dragees, capsules, drops or syrups. For rectal administration they may be formulated as suppositories and for parenteral administration as injectable solutions.

Each unit dose advantageously contains 0.050 to 0.500 g active ingredient, the daily administrable doses from 0.050 to 1.50 g of active ingredient 3e after the age of the patient and to be treated Z _u article may vary "

The following are some examples of pharmaceutical formulations *

1 * (tablets

Derivative no. ₀ 1 0.250 g

Excipients corn starch, magnesium stearate, stearic acid

2 »dragees

Derivative Hr _β 5 0.150 g

Excipient: M _a stearate, gum arabic, corn starch, gum,

Lac, sugar, glucose, white wax, carnauba wax, lactose, castor oil, alcohol, tar trasinaluminium lacquer »

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3o capsules

Derivative No. 13 0.100 g

Excipient: magnesium stearate, corn starch, lactose

, 'se »

4 © Suppo sit orien _n .

Derivative Hr ₀ 24. 0.150 g

semisynthetic triglycerides q _e s _e p _e 1 suppo sitium

Derivative Hr. 31 0.100 g

isotonic solution q.s.po · - 5

Due to their sedative and anticonvulsant properties, the compounds (I) and (II) according to the invention reduce character and behavioral disorders and improve the reactions to the unxwells thanks to a better psychic balance. They are in the pail of aggressiveness and irritability, childlessness , Arousal and psychomotor restlessness as well as all signs of irritability indicated *

Through their anti-inflammatory action, which can be administered for short or long term treatment, they effectively influence the inflammatory response in the treatment of edema hypersecretion and exudation during various stages of inflammation © They are for the treatment of chronic, inflammatory rheumatism, degenerative rheumatism , abarticular effects, acute gout, after traumatic and plastic surgery, and in traumatology and in ear, rabbit and ear diseases *

Claims (4)

\ Oi ^ -25- Berlin, ά. 29 o6o 1979 -55 008/12 claim for invention 1 9 wherein R and R have the above meaning, with a ge mixed anhydride of the general formula or -O-C-OR S C-O-C-OR wherein R represents C, -A -alkyl, converts * 1 2 wherein R and R are each independently hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; Aryl or aralkyl, ^ optionally on the phenyl ring one or more times by halogen, nied. Substituted alkyl, lower alkoxy, hydroxy or trifluoromethyl; heteroaryl; Heteroaralkyl or a group of the formula where η is 2 or 3 and R and R are independently. each represents C 1 -C 4 alkyl or, together with the nitrogen atom to which they are bonded, form a heterocyclic group which may carry, as a second heteroatom, an oxygen, sulfur or nitrogen atom, the latter optionally being replaced by C 1 -C 4. Alkyl are substituted; R and R together with the nitrogen atom to which they are attached, form a heterocyclic group which may have as the second heteroatom is an oxygen, sulfur or nitrogen atom, which latter may be substituted by nied _e alkyl or phenyl, which for its part is optionally substituted by at least one halogen atom or - 26 - Ber Iin, d.29 »6, '799 55 008/12 a nied _e alkyl, niedoAlkosy- or trifluoromethyl group is substituted, and their acid addition salts with pharmaceutically acceptable acids »characterized by .Daß that an amine of the general formula HH 1 "Process for the preparation of new thieno [3 _> 2 ^ cj" and hT2,3 ~ c] pyridines of the general formulas (I). (ID 2 © "Method according to item 1, characterized in that Compounds (III) or (IV), which by condensing. of thienopyridines of the formulas or 0OH (V) COOH with an alkyl chloroformate of the formula GlCOOR, wherein R has the meaning given in point 1, were obtained in the presence of triethylamine » 45 ~ 27 - Berlin, d _ö 29 »6.1979 55 008/12 3. The method according to item 1, characterized in that one carries out the reaction in an inert solvent at a temperature of "5 to +15 ⁰ G · .4 · Process according to item 2 _5, characterized in that the reaction was carried out in an inert solvent at a temperature of -5 to +15 ⁰ C.