BE749984A - N-alkyl indenopyridines therapeutics - Google Patents
N-alkyl indenopyridines therapeuticsInfo
- Publication number
- BE749984A BE749984A BE749984DA BE749984A BE 749984 A BE749984 A BE 749984A BE 749984D A BE749984D A BE 749984DA BE 749984 A BE749984 A BE 749984A
- Authority
- BE
- Belgium
- Prior art keywords
- emi
- alkyl
- addition salts
- formula
- action
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims 2
- 239000002253 acid Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 230000001741 anti-phlogistic effect Effects 0.000 claims abstract description 3
- 230000000767 anti-ulcer Effects 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract 3
- 150000007513 acids Chemical class 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 150000004694 iodide salts Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 239000001257 hydrogen Substances 0.000 claims 3
- PFWJFKBTIBAASX-UHFFFAOYSA-N 9h-indeno[2,1-b]pyridine Chemical class C1=CN=C2CC3=CC=CC=C3C2=C1 PFWJFKBTIBAASX-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 230000001539 anorectic effect Effects 0.000 claims 1
- 150000003842 bromide salts Chemical class 0.000 claims 1
- 150000003841 chloride salts Chemical class 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 239000012024 dehydrating agents Substances 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 230000001077 hypotensive effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 239000002220 antihypertensive agent Substances 0.000 abstract description 2
- 150000004820 halides Chemical class 0.000 abstract description 2
- 208000001953 Hypotension Diseases 0.000 abstract 1
- 229940124332 anorexigenic agent Drugs 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- -1 anti-ulcerous Substances 0.000 abstract 1
- 239000002830 appetite depressant Substances 0.000 abstract 1
- 208000021822 hypotensive Diseases 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PFVFXDVOCHMQDU-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-4-carboxylic acid Chemical compound OC(=O)C1CCNC=C1 PFVFXDVOCHMQDU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- UORJNBVJVRLXMQ-UHFFFAOYSA-N aprobarbital Chemical compound C=CCC1(C(C)C)C(=O)NC(=O)NC1=O UORJNBVJVRLXMQ-UHFFFAOYSA-N 0.000 description 1
- 229960003153 aprobarbital Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Acid-addition salts of cpds. of formula : (where R1 is H, Cl, Br, F or alkyl; R2 is CN, COOR5 or CONR5R6; R3 is H or alkyl; R4 is H or alkyl; R5 is H or alkyl; R6 is H or alkyl; in CONR5R6, R5 and R6 may form a 5- or 6-membered ring; n is 0-3) are prepd. by treating a 5-hydroxy-1,3,4,4a,5,9b-hexahydroindeno-1,2-c/-pyridine with Hal-CHR3-CHR4-/CH2/n-R2 (where Hal is Cl, Br or I) in the presence of base, and then dehydrating the product with a strong acid or acid halide. The products are antiphlogistic, anti-ulcerous, hypotensive and anorexigenic agents.
Description
<EMI ID=1.1>
<EMI ID=2.1>
<EMI ID=3.1>
<EMI ID=4.1> .1 <EMI ID=5.1>
<EMI ID=6.1>
dans lequel
<EMI ID=7.1>
<EMI ID=8.1>
<EMI ID=9.1>
<EMI ID=10.1>
<EMI ID=11.1>
données, on déshydrate un cocposé de formule lift
<EMI ID=12.1>
<EMI ID=13.1>
groupe
<EMI ID=14.1>
<EMI ID=15.1>
déjà données, et, simultanéoent ou ultérieurement, on trans-
<EMI ID=16.1>
ou <EMI ID=17.1>
<EMI ID=18.1>
<EMI ID=19.1>
drate un composé de formule IIb
<EMI ID=20.1>
<EMI ID=21.1>
<EMI ID=22.1>
<EMI ID=23.1>
ou un grcupe
<EMI ID=24.1>
<EMI ID=25.1>
<EMI ID=26.1>
estérifie les composés ainsi obtenus.
Les composés de formule I sont stables lorsqu'ils sont
<EMI ID=27.1>
bases libres ils subissent une transposition avec migration de la
<EMI ID=28.1> pourquoi il est préférable d'utiliser, pour la déshydratation,
<EMI ID=29.1>
de formule I.
Les chlorures, bromures ou iodures d'acides forts ne peuvent être utilisés pour la déshydratation que dans le cas ou R2 signifie autre chose que le groupe COOH, étant donné que les halcsénures d'acides forts transforment le groupe carboxylique en halcgenures d'acides correspondants.
Coc=e exemples d'acides forts appropriés pour la déshy-
<EMI ID=30.1>
ou aqueuse, tels que l'acide chlorhydrique, l'acide bromhydrique, l'acide iodhydrique, l'acide sulfurique, ou des acides organiques
<EMI ID=31.1> sous forme d'un sel d'addition d'acide, par exemple sous forme de chlorhydrate, par un acioe fort ou un chlorure, un bromure ou
<EMI ID=32.1>
<EMI ID=33.1>
température comprise entre la température ambiante et la température d'ébullition du mélange réactionnel, le cas échéant dans un solvant inerte. On évapore ensuite le mélange réactionnel à siccité et, le cas échéant, on purifie selon les méthodes habituelles le sel d'addition d'acide du composé de formule I qui s'est formé.
Selon les conditions sous lesquelles on opère pour
<EMI ID=34.1>
intact ou être transformé. C'est ainsi par exemple que l'on peut obtenir les composés de formule la non seulement à partir des
<EMI ID=35.1>
<EMI ID=36.1>
<EMI ID=37.1>
<EMI ID=38.1>
<EMI ID=39.1>
<EMI ID=40.1>
<EMI ID=41.1>
<EMI ID=42.1>
déjà données.
Si l'on désire obtenir, comme produits finals, les
<EMI ID=43.1>
<EMI ID=44.1>
d'acides forts, avantageusement en milieu anhydre, par exemple dans l'alcool anhydre correspondant. Dans ce cas, un groupe amide ou cyano éventuellement présent peut d'abord être transformé par hydrolyse en groupe carboxylique et être ensuite esterifié. Cependant, l'estérification du groupe amide, cyano ou
<EMI ID=45.1>
déshydratation.
Le procédé de l'invention peut être réalisé par exemple de la manière suivante:
On chauffe à l'ébullition au reflux pendant environ une demie heure un composé hydroxylique de formule II avec un
<EMI ID=46.1> <EMI ID=47.1>
<EMI ID=48.1>
<EMI ID=49.1>
composés de formule IV
<EMI ID=50.1>
<EMI ID=51.1>
formule V
<EMI ID=52.1>
<EMI ID=53.1>
<EMI ID=54.1>
<EMI ID=55.1>
<EMI ID=56.1>
mentionnées.
<EMI ID=57.1>
<EMI ID=58.1>
d'environ 2 heures, la réaction est terminée. Comme agent de condensation basique, on peut utiliser par exemple un carbonate alcalin tel que le carbonate de sodium ou de potassium, cu un
excès d'un équivalent du composé de formule III. Le produit de la réaction peut être purifié selon les méthodes connues ou également être utilisé directement, sans autre purification, pour la réaction suivante.
La réaction du composé de formule III avec le composé de formule V, selon le procédé décrit sous b'), peut être effec-
<EMI ID=59.1>
température d'ébullition du mélange réactionnel, le cas échéant dans un solvant: inerte, par exemple dans un alcool inférieur tel que le méthane! ou l'éthanol. La réaction dure approximativement
<EMI ID=60.1>
méthodes confies et être purifié par exemple par cristallisation
<EMI ID=61.1>
Les corps de départ nécessaires à la préparation des composés de formule II sont en partis connus; ils peuvent être préparés de la façon suivante:
<EMI ID=62.1>
réagir un ester de l'acide tétrahydroisonicotinique de formule VI
<EMI ID=63.1>
<EMI ID=64.1>
<EMI ID=65.1>
<EMI ID=66.1>
le VIII
<EMI ID=67.1>
<EMI ID=68.1>
<EMI ID=69.1>
<EMI ID=70.1>
<EMI ID=71.1> <EMI ID=72.1>
<EMI ID=73.1>
<EMI ID=74.1>
demande.
Les exemples suivants illustrent la présente Invention
<EMI ID=75.1>
décomposition).
En procédant de manière analogue, on obtient la composé de forçai* I suivant:
<EMI ID=76.1>
décomposition).
<EMI ID=77.1>
<EMI ID=78.1>
tion).
<EMI ID=79.1>
<EMI ID=80.1>
<EMI ID=81.1>
ensuite sous pression réduite, on évapore ensuite avec de l'étha-
<EMI ID=82.1>
<EMI ID=83.1>
décomposition..
<EMI ID=84.1>
<EMI ID=85.1>
d'éthyle. Len extraits d'acétate d'éthyle sont lavés avec une solution saturée de chlorure de sodium, séchés sur sulfate de magnésium et évaporés. On dissout le résidu dans l'acétone et on ajoute une solution éthérée d'acide chlorhydrique jusqu'à-
<EMI ID=86.1>
décomposition).
<EMI ID=87.1>
<EMI ID=88.1> EXEMPLE_9:
<EMI ID=89.1>
<EMI ID=90.1>
<EMI ID=91.1>
<EMI ID=92.1>
<EMI ID=93.1>
<EMI ID=94.1>
décomposition).
En procédant de manière analogue, on obtient le composé de formule I salvant:
<EMI ID=95.1> <EMI ID=96.1>
<EMI ID=97.1>
<EMI ID=98.1>
<EMI ID=99.1>
<EMI ID=100.1>
<EMI ID=101.1>
<EMI ID=102.1>
<EMI ID=103.1>
<EMI ID=104.1>
<EMI ID=105.1>
ultérieure.
En procédant de manière analogue, on obtient les
<EMI ID=106.1>
avec décomposition (utilisé comme produit de départ
<EMI ID=107.1>
<EMI ID=108.1>
<EMI ID=109.1>
décomposition (utilisé comme produit de départ aux exemples 3 et 24 sans autre purification)
<EMI ID=110.1>
corme produit de départ à l'exemple 11 sans autre purification)
<EMI ID=111.1>
<EMI ID=112.1>
tion) <EMI ID=113.1> <EMI ID=114.1>
<EMI ID=115.1>
évapore ensuite la solution sous pression réduite, on reprend le résidu par de l'eau et on l'extrait à 3 reprises avec du
<EMI ID=116.1>
pesant 3 heures, on filtre une faible quantité de précipité qui s'est formé, on agite le filtrat d'abord avec de l'eau
puis avec de l'acide chlorhydrique 1 8 et ensuite avec une solu-
<EMI ID=117.1>
au bout d'un certain temps.
<EMI ID=118.1>
<EMI ID=119.1>
<EMI ID=120.1>
de sodium, on extrait à 3 reprises avec du chloroforme, on
<EMI ID=121.1>
l'évaporé. Après cristallisation du résidu d'évaporation dans <EMI ID=122.1>
<EMI ID=123.1>
pyridine-5-ol fondant à 168-170[deg.] (utilisé comme produit de départ à l'exemple 32)
<EMI ID=124.1>
l'exemple 33.
Les sels acceptables du point de vue pharmaceutique
<EMI ID=125.1>
dans la littérature. Dans les essais effectués sur les animaux de laboratoire, ils se signalent par d'intéressantes propriétés
<EMI ID=126.1>
composés de l'invention exercent une action antiphlogistique. Ils peuvent, par conséquent, être utilisés en thérapeutique pour le traitement des inflammations d'origines diverses ainsi que pour le traitement des oedèmes consécutifs à des contusions, des
<EMI ID=127.1>
<EMI ID=128.1>
ministrée en 2 à 3 fractions ou sous forme d'une préparation retard.
Les sels d'addition d'acides des composés de formule 1 exercent, chez le rat, une action protectrice contre les ulcères. Ils peuvent être utilisés en thérapeutique comme anti-ulcéreux pour le traitement des ulcères gastriques. Ils seront administrés à des doses quotidiennes comprises entre 10 et 50 mg, dose quipeut être administrée en 2 à 3 fractions ou sous forme d'une préparation retard.
Sur le système circulatoire du chien narcotisé à l'aprobarbital, les composés de formule I provoquent une baisse de la pression sanguine et ils peuvent par conséquent être utilisés en thérapeutique comme agents hypotenseurs pour le traitassent de l'hypertension d'origines diverses. Ils seront administrés dans ce cas à des doses quotidiennes comprises
<EMI ID=129.1>
fractions ou sous forme d'une préparation retard.
Les sels d'addition d'acides des composés de formule I
<EMI ID=130.1>
anoreifants. Ils seront alors prescrits à des doses quotidiennes comprises entre 10 et 50 mg, dose qui peut être administrée en
2 à 3 fractions ou sous forme d'une préparation retard.
Les sels acceptables du point de vue que
<EMI ID=131.1>
<EMI ID=132.1>
<EMI ID=133.1>
<EMI ID=134.1>
<EMI ID=135.1> <EMI ID=136.1>
soit apte à la granulation. On granule, on sèche le granulé, on le brise et on en fait des comprimes.
<EMI ID=137.1>
<EMI ID=138.1>
<EMI ID=139.1>
libre).
<EMI ID = 1.1>
<EMI ID = 2.1>
<EMI ID = 3.1>
<EMI ID = 4.1> .1 <EMI ID = 5.1>
<EMI ID = 6.1>
in which
<EMI ID = 7.1>
<EMI ID = 8.1>
<EMI ID = 9.1>
<EMI ID = 10.1>
<EMI ID = 11.1>
given, we dehydrate a cocpose of formula lift
<EMI ID = 12.1>
<EMI ID = 13.1>
group
<EMI ID = 14.1>
<EMI ID = 15.1>
already given, and, simultaneously or subsequently, we trans-
<EMI ID = 16.1>
or <EMI ID = 17.1>
<EMI ID = 18.1>
<EMI ID = 19.1>
drate a compound of formula IIb
<EMI ID = 20.1>
<EMI ID = 21.1>
<EMI ID = 22.1>
<EMI ID = 23.1>
or a group
<EMI ID = 24.1>
<EMI ID = 25.1>
<EMI ID = 26.1>
esterifies the compounds thus obtained.
The compounds of formula I are stable when they are
<EMI ID = 27.1>
free bases they undergo a transposition with migration of the
<EMI ID = 28.1> why it is better to use, for dehydration,
<EMI ID = 29.1>
of formula I.
Chlorides, bromides or iodides of strong acids can only be used for dehydration when R2 means something other than the COOH group, since the halcenides of strong acids convert the carboxylic group into the corresponding acid halides. .
Coc = e examples of strong acids suitable for dehydration
<EMI ID = 30.1>
or aqueous, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, or organic acids
<EMI ID = 31.1> in the form of an acid addition salt, for example in the form of the hydrochloride, with a strong acioe or a chloride, a bromide or
<EMI ID = 32.1>
<EMI ID = 33.1>
temperature between room temperature and the boiling point of the reaction mixture, where appropriate in an inert solvent. The reaction mixture is then evaporated to dryness and, if necessary, the acid addition salt of the compound of formula I which has formed is purified according to the usual methods.
Depending on the conditions under which one operates for
<EMI ID = 34.1>
intact or be transformed. Thus, for example, it is possible to obtain the compounds of formula la not only from
<EMI ID = 35.1>
<EMI ID = 36.1>
<EMI ID = 37.1>
<EMI ID = 38.1>
<EMI ID = 39.1>
<EMI ID = 40.1>
<EMI ID = 41.1>
<EMI ID = 42.1>
already given.
If it is desired to obtain, as final products, the
<EMI ID = 43.1>
<EMI ID = 44.1>
strong acids, advantageously in anhydrous medium, for example in the corresponding anhydrous alcohol. In this case, an amide or cyano group optionally present can first be transformed by hydrolysis into a carboxylic group and then be esterified. However, esterification of the amide, cyano or
<EMI ID = 45.1>
dehydration.
The process of the invention can be carried out, for example, as follows:
A hydroxylic compound of formula II is heated to boiling under reflux for about half an hour with a
<EMI ID = 46.1> <EMI ID = 47.1>
<EMI ID = 48.1>
<EMI ID = 49.1>
compounds of formula IV
<EMI ID = 50.1>
<EMI ID = 51.1>
formula V
<EMI ID = 52.1>
<EMI ID = 53.1>
<EMI ID = 54.1>
<EMI ID = 55.1>
<EMI ID = 56.1>
mentioned.
<EMI ID = 57.1>
<EMI ID = 58.1>
approximately 2 hours, the reaction is complete. As the basic condensing agent, an alkaline carbonate such as sodium or potassium carbonate, or a
excess of one equivalent of the compound of formula III. The reaction product can be purified according to known methods or also be used directly, without further purification, for the next reaction.
The reaction of the compound of formula III with the compound of formula V, according to the process described under b '), can be carried out.
<EMI ID = 59.1>
boiling point of the reaction mixture, optionally in a solvent: inert, for example in a lower alcohol such as methane! or ethanol. The reaction lasts approximately
<EMI ID = 60.1>
methods entrusted and be purified for example by crystallization
<EMI ID = 61.1>
The starting materials necessary for the preparation of the compounds of formula II are in part known; they can be prepared as follows:
<EMI ID = 62.1>
reacting an ester of tetrahydroisonicotinic acid of formula VI
<EMI ID = 63.1>
<EMI ID = 64.1>
<EMI ID = 65.1>
<EMI ID = 66.1>
the VIII
<EMI ID = 67.1>
<EMI ID = 68.1>
<EMI ID = 69.1>
<EMI ID = 70.1>
<EMI ID = 71.1> <EMI ID = 72.1>
<EMI ID = 73.1>
<EMI ID = 74.1>
request.
The following examples illustrate the present invention
<EMI ID = 75.1>
decomposition).
Proceeding in a similar manner, we obtain the following compound of forcai * I:
<EMI ID = 76.1>
decomposition).
<EMI ID = 77.1>
<EMI ID = 78.1>
tion).
<EMI ID = 79.1>
<EMI ID = 80.1>
<EMI ID = 81.1>
then under reduced pressure, the mixture is then evaporated off with ethanol.
<EMI ID = 82.1>
<EMI ID = 83.1>
decomposition..
<EMI ID = 84.1>
<EMI ID = 85.1>
ethyl. The ethyl acetate extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is dissolved in acetone and an ethereal solution of hydrochloric acid is added until
<EMI ID = 86.1>
decomposition).
<EMI ID = 87.1>
<EMI ID = 88.1> EXAMPLE_9:
<EMI ID = 89.1>
<EMI ID = 90.1>
<EMI ID = 91.1>
<EMI ID = 92.1>
<EMI ID = 93.1>
<EMI ID = 94.1>
decomposition).
By proceeding in an analogous manner, we obtain the compound of formula I saving:
<EMI ID = 95.1> <EMI ID = 96.1>
<EMI ID = 97.1>
<EMI ID = 98.1>
<EMI ID = 99.1>
<EMI ID = 100.1>
<EMI ID = 101.1>
<EMI ID = 102.1>
<EMI ID = 103.1>
<EMI ID = 104.1>
<EMI ID = 105.1>
later.
By proceeding in a similar manner, we obtain the
<EMI ID = 106.1>
with decomposition (used as starting material
<EMI ID = 107.1>
<EMI ID = 108.1>
<EMI ID = 109.1>
decomposition (used as starting material in Examples 3 and 24 without further purification)
<EMI ID = 110.1>
as starting material in Example 11 without further purification)
<EMI ID = 111.1>
<EMI ID = 112.1>
tion) <EMI ID = 113.1> <EMI ID = 114.1>
<EMI ID = 115.1>
the solution is then evaporated off under reduced pressure, the residue is taken up in water and it is extracted 3 times with
<EMI ID = 116.1>
weighing 3 hours, a small amount of precipitate which has formed is filtered off, the filtrate is stirred first with water
then with hydrochloric acid 1 8 and then with a solution
<EMI ID = 117.1>
after a certain time.
<EMI ID = 118.1>
<EMI ID = 119.1>
<EMI ID = 120.1>
sodium, extracted 3 times with chloroform,
<EMI ID = 121.1>
evaporated. After crystallization of the evaporation residue in <EMI ID = 122.1>
<EMI ID = 123.1>
pyridin-5-ol melting at 168-170 [deg.] (used as starting material in Example 32)
<EMI ID = 124.1>
example 33.
Pharmaceutically acceptable salts
<EMI ID = 125.1>
in the litterature. In tests carried out on laboratory animals, they are distinguished by interesting properties
<EMI ID = 126.1>
compounds of the invention exert an antiphlogistic action. They can therefore be used therapeutically for the treatment of inflammations of various origins as well as for the treatment of edemas resulting from contusions,
<EMI ID = 127.1>
<EMI ID = 128.1>
ministrée in 2 to 3 fractions or in the form of a delayed preparation.
The acid addition salts of compounds of formula I exert a protective action against ulcers in rats. They can be used therapeutically as an anti-ulcer for the treatment of gastric ulcers. They will be administered in daily doses of between 10 and 50 mg, a dose which can be administered in 2 to 3 fractions or as a depot preparation.
On the circulatory system of the dog narcotized with aprobarbital, the compounds of formula I cause a drop in blood pressure and they can therefore be used therapeutically as hypotensive agents to treat hypertension of various origins. They will be administered in this case at daily doses included
<EMI ID = 129.1>
fractions or as a depot preparation.
Acid addition salts of compounds of formula I
<EMI ID = 130.1>
anoreifants. They will then be prescribed in daily doses of between 10 and 50 mg, a dose which can be administered in
2 to 3 fractions or in the form of a depot preparation.
Salts acceptable from the point of view of
<EMI ID = 131.1>
<EMI ID = 132.1>
<EMI ID = 133.1>
<EMI ID = 134.1>
<EMI ID = 135.1> <EMI ID = 136.1>
is suitable for granulation. Granulate, dry the granule, break it up and make tablets out of it.
<EMI ID = 137.1>
<EMI ID = 138.1>
<EMI ID = 139.1>
free).
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH696769A CH516558A (en) | 1969-05-07 | 1969-05-07 | N-alkyl indenopyridines therapeutics |
| CH1842469 | 1969-12-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BE749984A true BE749984A (en) | 1970-11-05 |
Family
ID=25700501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BE749984D BE749984A (en) | 1969-05-07 | 1970-05-05 | N-alkyl indenopyridines therapeutics |
Country Status (1)
| Country | Link |
|---|---|
| BE (1) | BE749984A (en) |
-
1970
- 1970-05-05 BE BE749984D patent/BE749984A/en unknown
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