IE47789B1 - Thieno(3,2-c)and thieno(2,3-c)pyridines,process for their preparation and therapeutic composition containing them - Google Patents
Thieno(3,2-c)and thieno(2,3-c)pyridines,process for their preparation and therapeutic composition containing themInfo
- Publication number
- IE47789B1 IE47789B1 IE163/79A IE16379A IE47789B1 IE 47789 B1 IE47789 B1 IE 47789B1 IE 163/79 A IE163/79 A IE 163/79A IE 16379 A IE16379 A IE 16379A IE 47789 B1 IE47789 B1 IE 47789B1
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- Prior art keywords
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- derivative
- thieno
- alkyl
- pyridine
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
Compounds of the formula: in which R<1> and R<2> are independently: hydrogen; alkyl; cycloalkyl, alkenyl; alkynyl; aryl or aralkyl optionally substituted on a phenyl nucleus with one or more halogen atoms or alkyl, alkoxy, hydroxy or trifluoromethyl groups; heteroaryl or heteroaralkyl; or a group having the formula: in which n is 2 or 3, and R<3> and R<4> are independently C1-4 alkyl or, together with the nitrogen atom to which they are attached, form a heterocycle which may carry a second heteroatom selected from oxygen, sulfur and nitrogen, which nitrogen may carry a C1-4 alkyl radical; or, together with the nitrogen atom to which they are attached, R<1> and R<2> form a heterocycle which may carry a second heteroatom selected from oxygen, sulfur and nitrogen, which nitrogen may carry alkyl or phenyl optionally substituted with one or more halogen atoms or alkyl, alkoxy or trifluoromethyl groups; and their pharmaceutically acceptable acid addition salts have sedative, anticonvulsant and anti-inflammatory activity.
Description
This invention relates to new thieno/3,2-c/ and /2,3-c/pyrid.ines, to a process for their preparation and to their therapeutic applications.
The' new derivatives of this invention have one of the following formulae!
(i)
(II)
2 in which R and R represent independently: hydrogen; an alkyl group; a cycloalkyl group; an alkenyl group; an alkynyl group; an aryl or aralkyl group optionally substituted on a phenyl nucleus with one or more halogen atoms or lower alkyl, lower alkoxy, hydroxy or trifluoromethyl groups; a heteroaryl or heteroaralkyl group; or a group having the formula:
in which n is 2 or 3 and R and R4 are independently a alkyl radical or, together with the nitrogen atom to which they are attached, form a saturated heterocycle which nay contain a second hoteroatom selected from oxygen, sulfur and nitrogen,which nitrogen may carry a C . alkyl radi-1 2 cal; or R and R , together with the nitrogen atom to which they are attached, form a hcterocycle which may cnntain a'second heteroatom selected from oxygen, sulfur and nitrogen, which nitre-uen may carry a lower alkyl group, a benzyl radical or a phenyl radical which .may itself be-optionally·
477 substituted with one or more halogen atoms or lower alkyl, lower alkoxy or trifluoromethyl groups.
The invention includes also within its scope the jiharmaceutically acceptable acid addition salts of said derivatives with inorganic or organic acids.
2
Wien R and/or R represent an aralkyl group, the latter is typically a benzyl or phenethyl group; when they represent a hetcroaralkyl group, the latter is typical ly a (3-pyridylJmethyl or (4-pyridyl)methyl group.
By lower alkyl or lower alkoxy groups are meant groups having 1-6 carbon atoms and, particularly, 1-4 carbon atoms.
This invention relates also to a process for the preparation of compounds having above defined formula (I) or (XI), comprising reacting an amine having the formula:
HN„
0 ,C-O-’C-OR
-c-,„ “ O J
2 in which R end R are as previously defined, with a mixed anhydride of the formula (III) or (IV) in which R is a C,_.j alkyl group:
riG ^S' '^'^c-o-c >1 H
0 (III) (IV) to give the derivative of the formula (I) or (IX), respectively.
The starting compounds (III) and (IV) are in turn prepared by condensation, in the presence of triethylamine, of a thienopyridine of the formula .(V) or (VI) (V)
COOH
(VI)
COOH with an alkyl chloroformate of the formula CICCOR
47788 in which R has the previously defined meaning.
Both reactions are preferably effected sequentially in the same container: mixed anhydrides (III) and (IV) are first prepared at temperatures between -5° and +15°C within an inert solvent such as chloroform or inethylene xr1 cnloride; amino ΗΪΓ , pure or dissolved in a solvent
Rz such as benzene, toluene, chloroform or methylene chloride is then added at the same temperature, after which the mixture is left aside at room temperature.
Thier.opyridines (V) and (VI) used as starting materials may be prepared according to a process comprising reacting a compound of the formula:
OH (VII) (VIII) with nitrous acid, and dehydrating and removing the nitroso group of the resulting compounds by reaction with an alkali metal hydroxide and subsequent neutralization.
The starting materials of the formula (VII) or (VIII) may in turn be prepared by reacting a compound of the formula
with an aqueous formaldehyde solution, in the presence of a strong acid.
'Pile following non-limiting Examples are given to illustrate this invention.
Example 1
G-Kethylaminocarbonyl-thisno/S,2-c/pyridine Formula (I): NRXR2 = NHCH-j. Derivative n°l
To a solution of 6-carboxy-thieno/3,2-c/pyridine (10 gf 0.050 mole) and triethylamine (5.6 g; O.C57 mole) in dry chloroform (500 cc) maintained at 10°C, is slowly added ethyl chlorcformate (6.2 g; 0.057 mole), with vigorous stirring. When addition is complete, stirring is continued at room temperature for a further 40 minutes, after which a solution of methyiamine (2 g; 0.064 mole) in benzene (50 cc) is added dropwise thereto. The reaction mixture is then left aside at room temperature for 4 hours, evaporated to dryness, and the residue is taken up into ether. The ether phase is washed with a saturated aqueous sodium carbonate solution, dried over sodium sulfate and evaporated to dryness.
The solid residue is recrystnllized from benzenerii isopropyl ether. Pinkish crystals; m.p. = 99°C.
Yield: 79%.
Rxamplo 2
6-ft-Dir.igi-hvlamineethylaminocarbonyl-thieno/3,2-c/pyrldlne Formula (I): Nr1r2 = NH(CH2)2N(CH3)2· Derivative n°2
To a solution of 6-cnrboxy-thieno/3,2-c/pyridine (10 g; 0.056 mole) and triethylamine (5.6 y; 0,057 mole) in dry chloroform (300 cc) maintained nt 10°C, is slowly added ethyl chloroformate (6.2 g; 0.057 mole) with vigorous stirring. On completion of the addition, stirring is continued at room temperature for a further 40 minutes, after which /i-dimethylaminoethylamine (5.4 gt 0.061 mole) is added dropwise. The reaction mixture is left aside at room temperature for 3.5 hours; it is then evaporated to dryness and the residue is taken up into N hydrochloric acid. The acid aqueous phase is washed with ether and is then made alkaline with 6K sodium hydroxide and extracted with methylene chloride. The methylene chloride extracts are dried over dry sodium sulfate and evaporated to dry»» ness. The oily residue is purified via its dihydrochloride. Beige crystals; K.p. = 170°C (isopropanol-methanol).
Yield: 75%.
Example 3
-(4-p.Chlprophenyl-l-piperazinyl)carbonyl-thieno22,3-c/pyridine
i-Cl . Derivative n°3.
To a solution of 5-carboxy-thieno/2,3-c/pyridine (12 g; 0.067 mole) and triethylamine (6.9 g; 0.068 mole) in dry chloroform (250 cc) maintained at 10°C, is slowly added ethyl chlororormate (7.3 g; 0.068 mole), with vigorous stirring. Stirring is then continued at room tempera ture for 50 minutes and p-chlorophenyl piperazine (13.2 g; 0.067 mole) dissolved in chloroform (50 cc) is then added dropwise. The reaction mixture is left aside at room temperature for 5 hours, after which it is evaporated to dryness and the residue is taken up into methylene chloride. The methylene chloride phase is washed with a saturated aqueous sodium bicarbonate solution, dried over dry sodium sulfate and evaporated to dryness. The resulting crystals are purified by column chromatography through silica (eluent: ethyl acetate).
White crystals, M.p. = 170°C (isopropanol-diisopropyl ether). Yield: 41%.
Example 4
Γ,-?? hvlaminocarbonyl-thieno/3,2-c/pyridine
Formula (I): NR^R2 = NHC^ilg. Derivative n°4.
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno/3,2-c/pyridine and ethylamino, Beige crystals; M.p. = 110°C (diisopropyl ether); Yield: 8 7%.
Example 5
-Isopro; -ylarainoe·'.rbonyl-thiuno/2,3-c/pyridine Formula (II): NR^·;2 — 7JH CgHy Derivative n°5.
This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno/2,3-e/pyridine and isopropylamine. Light brown crystals, M.p. = 102°C (diisopropyl ether). Yield: 80%.
Example 6
G-n.Butylaminocarbonyl-thieno/3,2-c/pyridine formula (I): NR^-R2 - NIIC^H . Derivative n°6.
This compound is prepared according to the procedure of Example 2, from 6-carboxv-thieno/3,2-c/pyridine and n--butylamine. Hydrochloride: orange-yellow crystals, m.p. 104°C (acetonitrile). Yield: 55%.
Example 7
6-0ctyla«inocnrbonyl-thieno/3,2-c/pyridine Formula (I): NR-'-R2 = ΝΗΟθΗ^ . Derivative n°7.
This compound is prepared according to the procedure of Example 1, from 6-carbo::y-thieno^3,2-c/pyridine and octylamine. White crystals, M.p. = 63°C (diisopropyl ether). Yield: 54%.
Dxa inpl e 8
6-Bimethylafninocarbonyl-thieno/3,2-c/pyridine
Formula (I): NR-'-R2 = N(CH3)2 . Derivative n°8.
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno^3,2-c/pyridine and dimuthylamine. White crystals; M.p. = 93°C (diisopropyl ether). Yield: 55%.
Byvifiple 9 g-Dicthvlaminocorbonyl-thieno/1?,2-g/pyridine Formula (I): NR^R2 ~ N(C2K,-)2 ' Uerivative n°9·
This compound is prepared according to the procedure 30 of Example 1, from 6-carboxy-thieno/3,2-c/pyridine and diethylaraine. Beige crystals; m.p. = 119°C (diisopropyl ether). Yield: 8Cr/°
Example 1C
6-(l-Py»r )l3dinyl)-carbcny1-thicro/3,2-c/pyridine 35 Formula (I): NR-'-R2 - if j Derivative nu10.
This compound is prepared according to the procedure of Example 1, from G-carboxy-thieno^T,2-c/pyridine and pyrrolidine. Off-white crystals; M.p. = 105°C (diisopropyl ether). Yield: 52%.
Example 11
6-l?iperidinocarbonyl-thieno/3,2-c/pyridine formula (I): NR-'-R2 = Derivative n°ll.
This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno/3,2-c/pyridine and piperidine. Light brown powder; M.p. = 145°C (diisopropyl ether). Yield: 96%.
Example 12
6-Eorpholinocarbonyl-thieito/3,2-c/pyridine i o
Formula (I): KRtR2 = _p Derivative n°12
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno/3,2-c/pyridine and morpholine. White crystals; M.p. = 136°C (benzene-diisopropyl ether). Yi°ld: 79%.
Example 13
-Bengylaminocarbonyl-thleno/2,3-c/pyridine
Formula (XI): NR!R2 = ΝΗΟΙΙ^Ο^ΕΙ^ Derivative n°13
This compound is prepared according to the procedure of Example 1, from '5-carboxy-thieno/?.,3-c/pyridine and benzylamine. Beige crystals; M.p. = 113°C (isopropanol);
Yield: 75%.
This compound is prepared according to the procedure of Example 1, from 6-carbo.xy-thieno/3,2-c/pyridine and
o.chlorobenzylamin.e. Beige povzder; M.p.= 16ScC (methanol).
Yield: 5:)%.
Example 15
6-Phcnethylaminoc3rbonyl-thisne/3,2-c/pyridine Formula (I): NR^R2 _ NficH^CH^GgHg. Derivative n°15.
This compound is prepared according to the procedure 5 of Example 1, from 6-carboxy-thieno^3,2-c/pyridine and phenethylamine. Beige crystals; m.p. = 127°C (isopropanoldiiscpropyl ether). Yield; 66%.
Example 16
C-Allylaminocarbonyl-thieno/3,2-c/py ridins 10 Formula (X): NRlR2 = NHCH2-CH=CK2. Derivative n°16
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno/3,2-c/pyridine and allylamine. Oxalate: white crystals; M.p. = 131°G (ethyl acetate). Yield: 54%.
Example 17 g-Pronargylaminocarbonyl-thieno/3,2-c/pyridine
Formula (I); NRlR2 = NHCU2C3CH Derivative n°17
This compound is prepared according to the procedure of Example 1, from 6-C£irboxy-thieno/3, ?~c,7pyridine and propargylamine. Pinkish crystals, m.p. = 134°C (isopropanol-diisopropyl ether). Yield: 60%.
Example 18
6-#-Diethylamlnoethylamlnocarbonyl-thieno/3.2-c/pyridine Formula (I): i.'R-'-R2 = ^er^vatIve n°i3
This compound is prepared according to the procedure of Example 2, from 6-carboxy-thieno/3,2-c/pyridine and /?diethylaminoethylamine. Dihydi'ochloride; beige crystals;
1-3.p. =- 145°G (iscpropanol-mfethanol). Yield: 81%.
Example 19
6-19-’3or pbol inoethylaminoca χ-bony 1-th i eno/3,2-c/pyridine
Formula (I): NRiR2 = NH(GH^) N p Derivative n°19
This compound is prepared according to the procedure of Example 2, from 6-carboxy-thier.o/3,2-c/pyridine and N-(2-ami.n'aethyl)-morpholine. Vihite crystals; ί·ϊ.ρ.= 1O‘1°C
I isopi’opanol-diisopropyl ether). Yield: 71%.
Example 20
6-Y-Dimethylaminopropylaminocarbonyl-thienq/3,2-c/pyri dine Formula (I): NrIr2 = NH(CH2)3N(CH3)2 . Derivative n°20
This compound is prepared according to the procedure of Example 2, from 6-carboxy-thieno/3,2-c/pyridine and jf -dimethylaminopropyiamine. Dihydrochlorides beige crystals. 14.p. - 146°C (ethanol). Yield: 77%.
Example 21
-(4-Pyridyl-methyl)aminocarbonyl-thienp/2,3-c/pyridine Formula (II): NR-^-R2 =
NHCH
Derivative n°21
This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno/2,3-c/pyridine and 4amincmethyl-pyridine. Light brown crystals. M.p. = 167°C (isopropanol-diisopropylether). Yield: 78%.
Example 22 ό-(4-Pyridyl-methyl)aminocarbonyl-thieno/3,2-c/pyridine
Formula (I): NRAR
1r2 =
NHCH,
Derivative n°22
This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno/3,2-c/pyridine and
4-aminomethyl-pyridine. Orange crystals; M.p. = 146°C (ethyl acetate); Yield: 9814.
Exainole 23
-( 3-l]vriQvl-m,.''thvl )aminocarbonyl-thieno/2,3-c/pyridine Formula (III): NR1R2 = NKGH2 \(Zv Derivativa n°23
This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno/2,3-c/pyridine and 3amincmethyl-pyridine. Beige crystals; M.p. = 143°C (isopropanol diisopropyl ether). Yield: 73%.
Example 24
6-(3-Pyridvl-methvl)aminocarbonvl-thleno/3,2-c/pyridine /— N
Formula (I): NRXR2 = ΝΗΟΗ,,-υ^Λ Derivative n°24.
This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno/3,2-c/pyridine and
3-aminomethyl-pyridine. Beige crystals; M.p. = 137°C (ethyl acetate). Yield: 55%.
Example 25
6-(3-Trifluorotnethyl-phenyl)aminocarbonyl-thieno/3,2 -c/pyridine _CF3
Formula (I): MR-'-R2 -. Derivative n°25
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno/3,2-c/pyridine and m-trifluoromethylaniline. White crystals; M.p. - 151°C (isopropanol-diisopropyl ether). Yield: 62%.
Example 26
6~(4-p,Tolyl-l-piperaxinyl)carbonyl-thieno/3, 2-c/pyridine
Formula (I): NR1R2
Derivative n°26
This compound is prepared according to the procedure of Example 3, from 6-earboxy-thieno/3,2-c/pyridine and 1-p-tolyl-piperazine. Beige crystals. M.p. = 150°C (isopropanol-diisopropyl ether). Yield: 8254.
Example 27
6-(4-o.chlorophanyl-l-piperazinyl)carbonyl-thieno/3,2-c/~ pyridine. C1v_.
Formula (I): NR^R2 = NDerivative n°27
This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno/3,2-c/pyridine and l-o.chloro;.henyl-piperazine. Beige crystals. M.p. = 140°C (isopropanol-diisopropyl ether). Yield: 52%.
Example 28
6-(4-m.chlnroPhenyl~l-piperazinyl)carbonyl-thieno/3,2-c7pyridlne Formula (I)
NRlR2 =
Derivative n°28
This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno/.'7-2-c7pyridine and
1-m.chloro.ihenyl-pipsrazine. 'White crystals; M.p. = 157°C (ethyl acetate). Yield: 52%
47788
Example 29
6-(4-p.Hethoxypheny1-1-pipera giny 1)-thieno/^3, 2-c/pyridine
Formula (X)
NR1!!2
Derivative n°29
This compound is obtained according to the procedure of Example 3, from 6-carboxy-thieno/3,2-c/pyridine and 1-p.methoxyphenyl-piperazine. White crystals. M.p.=152°C (ethyl acetate-diisopropyl ether). Yield: 72%.
Example 30
- (4-o.Methoxyphenyl-l-piperazinyl)carbonyl-thieno/2,3-c/· pyridine $CH3
Formula (II): NR1R2 = Derivative n°30
This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno,/2,3-c/pyridina and l-o.methoxyphenyl- piperazine. Beige crystals. M.p.=171°C (isopropanol). Yield: 62%.
Example 31
6- Carbrtmoyi~thieno/3,2-c/pyridine.
Formula (I): NR1R2 = NH^ · Derivative n°31
This compound is prepared according to the procedure of Example 1, frora 6-carboxy-thieno/3,2-c/pvridine and ammonia. White crystals.K.p.= 172°C (acetonitrile).
Yield: 6S%.
Example 32 ?-Carbamoyl-thieno/2,3-c/pyridine
Formula (II): NR^-R2 = - Derivative n°32
This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno/2,3-c/pyricline and ammonia. White crystals. M.p. = 200°C (acetonitrile). Yield: 76%.
Example 33
-Phenethylaminocnrbonyl-thieno/2,3-c/pyridine
Formula (II).- NR1?;2 = NHCl^CI^CgHj . Derivative n°33
This compound is prepared according to the procedure of Example 1, from 5-carbonyl-thieno/2,3-c/pyridine and phcnethylainine. Beige crystals. M.p. = 130°C (isopropanol47789 diisopropyl ether). Yield: 79%.
Example 34
6-(4-Eenzyl-l-piperazinyl)cafbonyl“thieno/3,2-c/pyridine
Formula (I): NRXR2 νΛεΗ2°6Η5 *
Derivative n°34
This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno/3,2-c/pyridine and 1-benzyl-piperazine. Dihydrochloride: white crystals; m.p. = 187°C (isopropanol-ethanol). Yields 49%.
Example 35
6-(3,4-Dimethoxy-phenethy1)-aminocarbonyl-thieno/3,2-c/pyridine OCH3
Formula (I): NR1?/ = UHCH2CH2-(^--OCH.J.Derivative^35
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno^3,2-c/pyridine and (3,4-dimethoxv-phenethyl)amine. White crystals; M.p. = · 125°C (isopropanol-diisopropyl ether). Yield: 77%.
Example 36
-(3,4-Dimethoxy-phenethyl)aminocarbonyl-thieno/2,3-c/pyridine OCH„
NR1!!2 = NHCH2CH2
-oOCH,
Formula (XI):
Derivative n°36
This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno/2,3-c/pyridine and (3,4-dimethoxy-phenethyl)amine. White crystals; M.p. =
125°C (isopropanol-diisopropyl ether). Yield: 73%.
Example 37
6-(4-Fcthyl-l-piPerazinyl)-carbonyl~thieno/3,2-c7pyrldine i 9 I—\
Formula (I): NR R - N- CH3 . Derivative n“37.
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno/J,2-c/pyridine and l-metliyl-piperazine. Maleate: brown powder, M.p. ~ 168°C (isopropanol). Yield: 83%.
The pharmacological and toxicological data reported below demonstrate the properties of the derivatives of this invention with respect both to their toxicity and their tolerance and to their activities, typically their sedative, anti-convulsant and anti-inflammatory activities .
Thus, this invention includes also within its scope a therapeutic composition having, in particular, sedative, anti-convulsant and anti-inflammatory activities, comprising, as active ingredient, a derivative of the formula ¢) or (II) or a pharmaceutically acceptable acid addition salt thereof, together with a therapeutically administratis carrier.
I - TOXICOLOGICAL I’TZESTIC-ATION
The compounds of the formulae (I) and (II) benefit from an excellent tolerance and a low toxicity.
With respect to acute toxicity, the LD_Q/24 hrs/kg body weight, determined in mice according to the method disclosed by Killer and Tainter, by the oral route, is in excess of 400 mg for all derivatives.
According to the same method, t'ne ΟΙ,^θ/^ hrs/kg body weight, determined by the intravenous route, is, for example, 154 mg for derivative n°l, 89 mg for derivative n°2, 184 mg for derivative n°10, 130 mg for derivative n° 11, 350 mg for derivative n°12, 65 mg for derivative n°
18, 90 mg for derivative n° 22, 96 mg for derivative n°24 and 105 mg for derivative n°31.
In addition, the tests effected on acute, chronic, sub-chronic and delayed toxicity, in different animal species failed to evidence any local or systemic reaction, any perturbation or anomaly in the biochemical, microscopical or macroscopical examinations effected in the course of said experimentation.
11 PHARMACOLOGICAL INVESTIGATION 1/ Sedative action
A) Study of the behavior
This investigation was effected according to the method disclosed by Samuel IRWIN (Ph. D. Animal and Clinical Pharmacology Technics in Drug Evaluation). The derivatives of the formulae (I) and (II) are orally administered to mice at a dosage of 100 rng/kg. The treated animals are observed during the 4 hours that follow administration of the active compound. Their behavior is studied and, in addition, the different physiological parameters (temperature, cardiac and respiratory rate) are determined. A marked decrease of motor activity and muscular tone, together with a decrease of the alertness and of the reactions to noise and to environment are noted in the treated animals.
B) Action on hypnotic drugs
The compounds of the formulae (I) and (IX) potentiate most markedly the action of hypnotic drugs. Indeed, on oral administration to different groups of mice, at a dosage of 100 mgAg» 3° minutes prior to intra peritoneal injection of an infra-hypnotic dosage of sodium pentobarbital, they produce, with respect to the untreated reference animals, a marked potentiation of the action of the barbiturate.
Indeed, the number of sleeping mice, the average time to sleep and the duration of sleep are markedly increased in the treated groups. The results obtained with the more active compounds are tabulated in following Table I.
TABLE I
Treatment Percent sleeping animals Ayerage time to sleep Average sleeping time 0 (reference group 0 0 0 ' Derivative n°l 70 8 mn 30 s 1 hr 30 mn Derivative n°5 80 9 mn 15 s 1 hr 45 mn Derivative n°6 SO 8 mn 40 s 1 hr 48 mn Derivative n°10 90 8 mn 25 s 1 hr 35 mn Derivative n°l5 90 8 mn 10 s 1 hr 50 mn Derivative n°16 70 7 mn 50 s 1 hr 42 mn Derivative n°18 80 9 mn 45 3 1 hr 38 mn Derivative n°22 70 9 mn 20 s 1 hr 45 mn Derivative n°23 80 7 mn 55 s 1 hr 50 mn Derivative n°25 90 8 mn 10 s 1 hr 38 mn Derivative n°26 SO 8 mn 50 s 1 hr 35 mn Derivative n°28 80 7 mn 45 s 1 hr 40 mn Derivative n°29 90 8 mn 15 s 1 hr 47 mn
2/ Anti-convulsent action
This action was studied with respect to electroshocks.
In rats, application of an electrical stimulation in excess of the eleetro-convulsant threshold, produces experimental convulsions. The presence and duration of each convulsive phase and also the intensity of the overall seizure are compared in the reference animals and in the treated animals.
Groups of 10 rats are used per test material, and each animal is orally administered 100 tng/kg of said test material.
An electrode is positioned on either side of the basis of the tail of each animal and, 30 minutes after treatment, the animal, placed in a glass enclosure, is administered for 50 milliseconds a sinusoidal current of 50 periods/ seconds of 120 volts.
Passage of the current induces a convulsive seizure
47788 each phase of which (tonic, clonic, muscular relaxation) is timed. The intensity of the seizure is then rated according to a scale from 0 to 4, depending on the presence .of each one of the phases and their duration. The derivatives of the formulae (I) and (II) are tested comparatively with phenobarbital which possesses a marked anticonvulsant action (intensity of the seizure = 2), whereas in the untreated reference animals a maximum intensity of 4 is obtained.
It is thus determined that all the compounds of the formulae (I) and (II) produce substantial protection against electroshock since the mean values of the intensity of the seizures within each group are 2.5 for derivative n°l, 3 for derivative n°4, 2.5 for derivative n°5, 2.5 for derivative n°9, 3 for derivative n°13, 2.5 for derivative n°19, 2.5 for derivative N°25, 2.5 for derivative n°3O and 2.5 for derivative n°31.
3° Anti-inflammatory action
a) Method of the localized carracecm'.n-indnced edema
A 1% carrageenin solution (0.1 ml) is injected at time 0 in the metatarsal flexor muscles of the right rear limb of rats. The animals of the treated group are additionally orally administered 100 mg/kg of the test material, respectively 1 hour prior to, simultaneously with, and then 1 hour and 2.5 hours after injection of the phlegogenic agent. The percent anti-inflammatory activity is determined as a function of time, with respect to the reference group, by the determinations effected with a ROCII micrometer at times Ο, 1 hr, 2 hrs, 3 hrs and 5 hrs after carrageenin administration.
The results obtained with derivatives of the formula (I) or (II) are set forth in following Table II.
47783
TABLE II
Derivative n° Percent anti-inflammatory activity after 1 hour 2 hours 3 hours 5 hours 1 35 42 46 47 4 41 46 50 58 5 43 49 54 56 10 37 42 46 51 13 34 40 45 51 15 33 45 49 53 18 41 46 50 55 21 40 48 51 54 22 41 47 51 55 25 39 46 49 52 27 41 49 52 54 30 3Θ 45 49 53 32 34 41 45 47
b) Method of the ovalbumin-induced systemic edema
A simultaneous intraperitoneal injection of 1 ml ovalbumin and of 0.5 ml of a 1% Evans blue solution is effected in rats. On the other hand, the animals of the treated group are orally administered 100 mg/kg of the test derivative one hour prior'to and simultaneously with the ovalbumin administration. The intensity of the phenomenon thus induced is rated according to a scale from 1 to 5, depending on the progress of the inflammatory syndrome. The mean edematous intensity and the percent decrease of the edematous reaction, with respect to the controls, are thus determined as a function of time.
The percent anti-inflammatory activity obtained 2 and 3 hours after ovalbumin injection is . set forth in following Table III for some derivatives of the formula (I) or (II).
TABLE III
Derivative n° Percent anti-inflammatory activity after 2 hours 3 hours 1 48 56 4 47 56 3 52 60 10 47 55 13 50 56 15 53 60 18 49 58 21 45 52 22 51 58 25 51 59 27 47 56 30 48 56 32 52 60
The results of said investigations provide evidence of the low toxicity and good tolerance, and also of the useful sedative, anti-convulsant and anti-inflammatory properties of the derivatives of the formula (I) or (31) that make them most valuable in human and veterinary medicine.
The composition of this invention may be formulated, for oral administration, as tablets, coated tablets, capsules, drops and syrups. It may also be formulated.: for rectal administration, as suppositories and, for parenteral administration, as .injectable solutions.
Each unit dose will advantageously contain from 0.050 g to 0.500 g active ingredient. The daily dosage regimen may vary from 0.030 g to 1.50 g active ingredient, depending on the age of the patient and on the condition treated.
47788
Non-limiting Examples of pharmaceutical formulations of the therapeutic composition of this invention are given below.
- TABLETS
Derivative n°l .......... 0.250 g
Excipient: corn starch, magnesium stearate, stearic acid
- COATED TABLETS
Derivative n°5 .......... 0.150 g
Excipient: magnesium stearate, corn starch, gum arabic, shellac, sugar, glucose, white wax, carnauba wax; lactose, castor oil, alcohol, tartrazine-aluminum lacquer.
- CAPSULES
Derivative n° 13..........0.100 g
Excipient: magnesium stearate, corn starch, lactose.
- SUPPOSITORIES
Derivative n°24.......... 0.150 g
Semi-synthetic triglycerides, sufficient to make 1 suppository.
- INJECTABLE SOLUTION
Derivative n°31 .......... 0.100 g
Isotonic solvent, sufficient to make 5 ml
Due to their sedative and anti-convulsant action, the derivatives of the formula (I) or (II) reduce personality and behavioral disorders and facilitate personal contacts because of improved mental equilibrium. They are applicable in children and adults in cases of aggressiveness, irritability, instability, excitation, and psychomotor agitation, and also in all manifestations of excitability .
Due to their anti-inflammatory action, when administered for short or extended treatments, they act efficiently on the inflammatory reaction to control edema, hypersecretion and exudation in the course of the different stages of inflammation. They are indicated in cases of chronic inflammatory rheumatism, degenerative rheumatism, ab-articular conditions, acute gout, in post-operative plastic surgery, in traumatology and in oto-rhinolaryngology.
Claims (9)
1. Compounds having the formula: (I) 1 2 in which R and R are independently: hydrogen; an alkyl group; a cycloalkyl group; an alkenyl group; an alkynyl group; an aryl or aralkyl group optionally substituted on a phenyl nucleus with one or more halogen atoms or lower alkyl, lower alkoxy, hydroxy or trifluoromethyl groups; a heteroaryl or heteroaralkyl group; or a group having the formula: -(CH) . 2. 'n \ r 4 in which n is 2 or 3, and R 2 and R^ are independently a C^ alkyl radical or, together with the nitrogen atom to which they are attached, form a saturated heterocycle which may contain a second heteroatom selected from oxygen, sulfur and nitrogen, which nitrogen may carry a C^ 4 alkyl radical; or, together with the nitrogen atom to which they are attached, 1 2 R and R form a hefcerocycle which may contain a second heteroatom selected from oxygen, sulfur and nitrogen,which nitrogen may carry a lower alkyl grow, a benzyl radical or a phenyl radical optionally substituted with one or more halogen atoms or lower alkyl, lower alkoxy or trifluoromethyl groups; and their pharmaceutically acceptable acid addition salts.
2. Process for the preparation of compounds as claimed in claim 1, comprising reacting an amine having the formula : „1 1 2 5 in which R and R are as claimed in claim 1, with a mixed anhydride having the formula (III) or (IV) in which R is a alkyl group: η n 0 0 (III) (IV) to give a derivative of the formula (I) or (II), respecti10 vely.
3. Process as claimed in claim 2, wherein thienopyridines of the formula (V) or (VI) are condensed, in the presence of triethylamine, with an 15 alkyl chlorcformate having the formula C1C00R in which R has the meaning given in claim 2, to give the compounds of the formula (III) or (IV), respectively.
4. Process as claimed in claim 2, wherein the reaction is effected within an inert solvent at a temperature 20 between -5°C and +15°C.
5. Process as claimed in claim 3, wherein the reaction is effected within an inert solvent, at a temperature between -5°C and +15°C.
6. Therapeutic composition having, in particular, sedative, anti-convulEant and anti-inflammatory activities, comprising, as active irgredient, a derivative of the formula (I) or (II) as claimed in claim 1 or a pharmaceutically acceptable acid 5 addition salt thereof, together with a therapeutically administrable carrier.
7. Therapeutic composition as claimed in claim 6, in unit dosage form.
8. Therapeutic composition as claimed in claim 7, wherein 10 each unit dose contains from 0.050 g to 0.500 g active ingredient.
9. A compound as claimed in claim 1, said compound being the product of any one of Examples 1 to 37.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7804561A FR2417512A1 (en) | 1978-02-17 | 1978-02-17 | THIENO (3,2-C) AND THIENO (2,3-C) PYRIDINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE790163L IE790163L (en) | 1979-08-17 |
| IE47789B1 true IE47789B1 (en) | 1984-06-13 |
Family
ID=9204729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE163/79A IE47789B1 (en) | 1978-02-17 | 1979-01-30 | Thieno(3,2-c)and thieno(2,3-c)pyridines,process for their preparation and therapeutic composition containing them |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP0003920B1 (en) |
| JP (1) | JPS54157599A (en) |
| AR (1) | AR227623A1 (en) |
| AT (1) | AT369369B (en) |
| AU (1) | AU519318B2 (en) |
| BE (1) | BE874228A (en) |
| CA (1) | CA1126732A (en) |
| CH (1) | CH635844A5 (en) |
| DD (1) | DD142053A5 (en) |
| DE (1) | DE2960109D1 (en) |
| DK (1) | DK146046C (en) |
| ES (1) | ES477401A1 (en) |
| FI (1) | FI66872C (en) |
| FR (1) | FR2417512A1 (en) |
| GB (1) | GB2014576B (en) |
| GR (1) | GR66844B (en) |
| HU (1) | HU178075B (en) |
| IE (1) | IE47789B1 (en) |
| IL (1) | IL56541A (en) |
| IT (1) | IT1115001B (en) |
| LU (1) | LU80861A1 (en) |
| MX (1) | MX5588E (en) |
| NO (1) | NO150483C (en) |
| NZ (1) | NZ189638A (en) |
| PH (1) | PH15171A (en) |
| PL (1) | PL117264B1 (en) |
| PT (1) | PT69220A (en) |
| RO (1) | RO76642A (en) |
| SU (1) | SU810081A3 (en) |
| YU (1) | YU26879A (en) |
| ZA (1) | ZA79513B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2525595A1 (en) * | 1982-04-27 | 1983-10-28 | Pharmuka Lab | NOVEL ARENE AND HETEROARENECARBOXAMIDE DERIVATIVES AND THEIR USE AS MEDICAMENTS |
| DE3621413A1 (en) * | 1986-06-26 | 1988-01-07 | Boehringer Ingelheim Kg | USE OF CARBOCYCLIC AND HETEROCYCLICALLY FURNISHED DIHYDROPYRIDINE AS A CARDIOPROTECTIVE AGENT AND NEW HETEROCYCLIC AND CARBOCYCLICALLY FURNISHED DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND ITS ADDITIONAL PRODUCTS |
| DE3752373T2 (en) * | 1986-10-13 | 2004-03-25 | Asahi Kasei Kogyo K.K. | PYRIDINE DERIVATIVES |
| CN101815718A (en) * | 2007-08-10 | 2010-08-25 | 克里斯捷诺米有限公司 | Pyridine derivate and using method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3845065A (en) * | 1972-02-18 | 1974-10-29 | Merck & Co Inc | 4-oxo-4,5-dihydrothieno(3,2-c)pyridines |
-
1978
- 1978-02-17 FR FR7804561A patent/FR2417512A1/en active Granted
-
1979
- 1979-01-26 EP EP79400053A patent/EP0003920B1/en not_active Expired
- 1979-01-26 DE DE7979400053T patent/DE2960109D1/en not_active Expired
- 1979-01-29 CH CH84479A patent/CH635844A5/en not_active IP Right Cessation
- 1979-01-30 IE IE163/79A patent/IE47789B1/en not_active IP Right Cessation
- 1979-01-30 IL IL56541A patent/IL56541A/en unknown
- 1979-01-30 GR GR58210A patent/GR66844B/el unknown
- 1979-01-31 LU LU80861A patent/LU80861A1/en unknown
- 1979-02-02 AU AU43897/79A patent/AU519318B2/en not_active Ceased
- 1979-02-02 ES ES477401A patent/ES477401A1/en not_active Expired
- 1979-02-06 ZA ZA79513A patent/ZA79513B/en unknown
- 1979-02-07 YU YU00268/79A patent/YU26879A/en unknown
- 1979-02-07 DK DK50279A patent/DK146046C/en not_active IP Right Cessation
- 1979-02-07 AR AR275419A patent/AR227623A1/en active
- 1979-02-09 AT AT0098679A patent/AT369369B/en not_active IP Right Cessation
- 1979-02-09 RO RO7996565A patent/RO76642A/en unknown
- 1979-02-12 FI FI790460A patent/FI66872C/en not_active IP Right Cessation
- 1979-02-13 CA CA321,393A patent/CA1126732A/en not_active Expired
- 1979-02-13 PT PT7969220A patent/PT69220A/en unknown
- 1979-02-13 NZ NZ189638A patent/NZ189638A/en unknown
- 1979-02-14 HU HU79PA1342A patent/HU178075B/en not_active IP Right Cessation
- 1979-02-15 IT IT48023/79A patent/IT1115001B/en active
- 1979-02-15 DD DD79211045A patent/DD142053A5/en not_active IP Right Cessation
- 1979-02-15 MX MX797720U patent/MX5588E/en unknown
- 1979-02-16 SU SU792728455A patent/SU810081A3/en active
- 1979-02-16 GB GB7905508A patent/GB2014576B/en not_active Expired
- 1979-02-16 NO NO790515A patent/NO150483C/en unknown
- 1979-02-16 PL PL1979213472A patent/PL117264B1/en unknown
- 1979-02-16 PH PH22206A patent/PH15171A/en unknown
- 1979-02-16 BE BE0/193507A patent/BE874228A/en not_active IP Right Cessation
- 1979-02-17 JP JP1778479A patent/JPS54157599A/en active Granted
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| MM4A | Patent lapsed |