CA1105053A - No translation available - Google Patents
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- CA1105053A CA1105053A CA303,521A CA303521A CA1105053A CA 1105053 A CA1105053 A CA 1105053A CA 303521 A CA303521 A CA 303521A CA 1105053 A CA1105053 A CA 1105053A
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- Prior art keywords
- methoxy
- ethyl
- benzamide
- dimethyl
- amino
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
Abstract
P R E C I S
L'invention concerne de nouveaux composes chimiques utiles comme médicaments, leur préparation et des compositions pharmaceutiques. Les nouveaux composés chimiques répondent à
la formule générale:
R est un groupe alcoyle amino; X, qui se trouve en position 2, 3 ou 4 peut être un hydrogène, un halogène, un alcoxy infé-rieur; R1R2 sont des hydrogènes, des alcoyles inférieurs; R3 est un hydrogène ou alcoyle amino. L'invention s'applique également aux sels obtenus avec des acides minéraux ou organi-ques thérapeutiquement acceptables. Les médicaments contenant ces principes actifs sont utiles dans le traitement des trou-bles digestifs et psychosomatiques. SPECIFIC
The invention relates to new chemical compounds useful as medicaments, their preparation and compositions pharmaceutical. New chemical compounds respond to the general formula:
R is an amino alkyl group; X, which is in position 2, 3 or 4 may be hydrogen, halogen, lower alkoxy laughing; R1R2 are hydrogens, lower alkyls; R3 is hydrogen or amino alkyl. The invention applies also to salts obtained with mineral or organic acids therapeutically acceptable. Medicines containing these active ingredients are useful in the treatment of digestive and psychosomatic.
Description
J5~
La presente invention, se rapporte 3 des nouveaux derives sulfamido acetyleniques de methoxy benzamides, leur procede de preparation et leur application en therapeutique.
Ils sont utiles notamment dans le traitement de troubles digestifs psychosomatiques.
Les composes selon l'invention repondent à la formule generale I:
~ C - y - R
t~ ~ I
Rl S2 ~ I - Cl - C - C - R3 : :
dans laquelle: . :
R est un des groupes amino choisi parmi ceux ayant la formule:
~ / alcoyle - (A)n ~ N ¦ . ~ (A)n ~ N \
alcoyle :::
- CH2 ~ ou A est un alcoylid~ne en cha~ne droite ou ramifiee;
n est 2, 3 ou 4;
alcoyle est un alcoyle de 1 à 4 atomes de carbone;
X qui se trouve en position 2, 3 ou 4 est hydrog~ne, un halogene, ou un alcoxy inferieur de 1 3 4 atomes de carbone;
Rl et R2 sont des hydrogènes ou des alcoyles infe-rieurs de 1 a 4 atomes de carbone; ou 1 _ ~;
.. . .
~SC~i3 le groupe -CRlR2 peut former un cycle sature ayant de 3 à 6 atomes de carbone;
R3 est hydrogene ou un alcoyle amino de la formule:
CH2 N \
dans laquelle R4 et R5 sont des groupes alcoyles de 1 a 4 atomes de carbone; ou le groupe -NR4R5 peut former un heterocycle choisi parmi ceux ayant la formule: .
- N ~ 0 , - N ~ - CH3 et ~ : - benzyl L'invention s'applique egalement aux sels obtenus avec des acides mineraux ou organiques therapeutiquement accep-tables.
Par rapport aux derives connus de même orientation therapeutique, les nouveaux derives se caracterisent par le substituant acetylenique au niveau sulfamido, qui modifie leur s:pectre d'activite et introduit une voie de metabolisation : supplEmentaire.
:Les composes de la presente invention qui comprend - l'amidification ou la condensation d'un compose de la formule generale II:
: : o .
X~ 11 :
Rl II
` 502NH - C - C - C - R3 dans laquelle X, Rl, R2 et R3 son~ comme definis anterieurement D5 ~
The present invention relates to 3 of the new sulfamido acetylenic derivatives of methoxy benzamides, their preparation process and their application in therapy.
They are useful in particular in the treatment of disorders psychosomatic digestives.
The compounds according to the invention correspond to the formula general I:
~ C - y - R
t ~ ~ I
Rl S2 ~ I - Cl - C - C - R3::
in which: . :
R is one of the amino groups chosen from those having the formula:
~ / alkyl - (A) n ~ N ¦. ~ (A) n ~ N \
alkyl :::
- CH2 ~ or A is a straight or branched chain alkyl;
n is 2, 3 or 4;
alkyl is an alkyl of 1 to 4 carbon atoms;
X which is in position 2, 3 or 4 is hydrogen ~ ne, halogen, or alkoxy lower than 1 3 4 carbon atoms;
Rl and R2 are hydrogen or lower alkyl laughers of 1 to 4 carbon atoms; or 1 _ ~;
... .
~ SC ~ i3 the group -CRlR2 can form a saturated cycle having from 3 to 6 carbon atoms;
R3 is hydrogen or an amino alkyl of the formula:
CH2 N \
in which R4 and R5 are alkyl groups from 1 to 4 carbon atoms; or the group -NR4R5 can form a chosen heterocycle among those with the formula:.
- N ~ 0, - N ~ - CH3 and ~: - benzyl The invention also applies to the salts obtained with therapeutically acceptable mineral or organic acids tables.
Compared to known derivatives of the same orientation therapeutic, the new derivatives are characterized by substituting acetylenic at the sulfamido level, which modifies their s: pectre of activity and introduces a metabolization pathway : additional.
: The compounds of the present invention which comprises - the amidation or condensation of a compound of the formula General II:
:: o.
X ~ 11:
Rl II
`502NH - C - C - C - R3 in which X, Rl, R2 and R3 are ~ as defined previously
- 2 -, '' - . - . . .. .. . . . . . .
~IO5~S3 et Z represente les groupes - OCI - O - alcoyle, - O - alcoyle, halogene ou - OH, avec une amine de la formule RNH2, dans laquelle R est comme defini anterieurement.
Le compose de depart de la formule generale II peut être obtenu par la reaction d'un acide de la formule III: .
~ COOH
X ~ I I I
S02Cl ' ' ' avec une amine de la formule IV:
Rl N H 2 - f - C C - R3 IV
R2 , dans lesquelles X, Rl, R2 et R3 sont. comme definis anterieure-ment~
La presente invention sera maintenant illustree par quelques exemples. -Chlorhydrate de N(N' ethyl pyrrolidino-2' methyl) methoxy-2, (dimethyl-l"-l" propyny ~amino sulfonyl)-5 benzamide (F 1603) a) Preparation du N(dimethyl-l'-l' propyn-2' yl) carboxy-- 2 -, '' -. -. . .. ... . . . . .
~ IO5 ~ S3 and Z represents the groups - OCI - O - alkyl, - O - alkyl, halogen or - OH, with an amine of the formula RNH2, in which R is as previously defined.
The starting compound of general formula II can be obtained by the reaction of an acid of formula III:.
~ COOH
X ~ III
S02Cl ''' with an amine of formula IV:
Rl NH 2 - f - CC - R3 IV
R2, in which X, Rl, R2 and R3 are. as defined earlier-ment ~
The present invention will now be illustrated by some examples. -N (N 'ethyl pyrrolidino-2' methyl) methoxy-2 hydrochloride, (dimethyl-l "-l" propyny ~ amino sulfonyl) -5 benzamide (F 1603) a) Preparation of N (dimethyl-l'-l 'propyn-2' yl) carboxy-
3 methoxy-4 benzène sulfonamide Dans une solution de 106.5 g (1.28 mole) de methyl-2 butyn-3 amine-2 et 1250 cm3 d'eau, sous agitation sur un bain de glace, introduire par fractions de 100 g (0.4 mole) de chlorure de carboxy-3 m~thoxy-4 benzene sulfonyle. Maintenir une nuit sous agitation a temperature ambiante puis acidifier a pH 1 par une solution d'acide chlorhydrique 6N. Essorer, laver à l'eau et recristalliser dans l'acetate d'ethyle. On recupere , . :
i3 88 9 de produit de point de fusion 168C. Rendement 75%.
b) Preearation du F 1603:
_ _ _ Dans une solution de 74.5 9 de N(dimethyl-l'-l' propyn-2' yl) carboxy-3 methoxy-4 benzène sulfonamide 25.35 9 de triethylamine et 750 cm3 de tetrahydrofuranne, introduire goutte a goutte sous agitation ~ 0C une solution de 29.90 9 de chloroformiate d'ethyle dans 60 cm3 de tetrahydrofuranne pen-dant 2 heures à 0C et introduire goutte a goutte une solution de 32.11 9 de N-ethyl amino methyl-2 pyrrolidine dans 60 cm3 de tetrahydrofuranne. Maintenir sous agitation à temperature ambiante, puis distiller jusqu'à siccite. Reprendre par de l'eau et alcaliniser par C03K2. Essorer, laver à l'eau et secher. On recupere 80 9 de produit. Rendement 80% - Point de fusion : 136C.
Chlorhydratation:
_ _ _ _ _ _ _ _ Dissoudre le produit dans 4 volumes de methanol et ajouter en tiedissant une solution ~thanolique saturee d'HCl jusqu'à pH 1. Concentrer et ajouter de l'ether ethylique jusqu'à fin de precipitation. On recupere avec un rendement de 90% le produit de formule:
~ C - RH - CH
S2 ~ NH - IC - C _ C - H
CH
Formule brute : C20 H30 Cl N3 04 S -~
Masse moleculaire : 444 Point de fusion : 205C
Cristaux blancs Spectre IR : vNH à 3370 cm 1 (libre) et 3140 cm 1 (lie); 3-methoxy-4 benzene sulfonamide In a solution of 106.5 g (1.28 mole) of methyl-2 butyn-3 amine-2 and 1250 cm3 of water, with stirring on a bath of ice, introduce in fractions of 100 g (0.4 mole) of 3-carboxy chloride ~ 4-thoxy benzene sulfonyl. Maintain overnight with stirring at room temperature then acidify to pH 1 with a 6N hydrochloric acid solution. Spin, wash with water and recrystallize from ethyl acetate. We recover ,. :
i3 88 9 of product of melting point 168C. Yield 75%.
b) Preearation of the F 1603:
_ _ _ In a solution of 74.5 9 of N (dimethyl-l'-l ' propyn-2 'yl) carboxy-3 methoxy-4 benzene sulfonamide 25.35 9 of triethylamine and 750 cm3 of tetrahydrofuran, introduce drip with stirring ~ 0C a solution of 29.90 9 of ethyl chloroformate in 60 cm3 of tetrahydrofuran pen-for 2 hours at 0C and introduce a solution drop by drop of 32.11 9 of N-ethyl amino methyl-2 pyrrolidine in 60 cm3 of tetrahydrofuran. Keep stirring at temperature ambient, then distill until dry. Resume with water and basify with C03K2. Spin, wash with water and to dry. 80% of product is recovered. Yield 80% - Point of fusion: 136C.
Hydrochlorination:
_ _ _ _ _ _ _ _ Dissolve the product in 4 volumes of methanol and adding a saturated solution of HCl up to pH 1. Concentrate and add ethyl ether until the end of precipitation. We recover with a yield of 90% the product of formula:
~ C - RH - CH
S2 ~ NH - IC - C _ C - H
CH
Gross formula: C20 H30 Cl N3 04 S - ~
Molecular mass: 444 Melting point: 205C
White crystals IR spectrum: vNH at 3370 cm 1 (free) and 3140 cm 1 (lie);
- 4 -- .
)S~53 VC - C ~ 1600 cm~l et VS - O a 1300-1350 cm~l et 1150 cm~l -1200 cm~
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck ~
- solvant : butanol - acide acetique - eau 6/2/2 - revelation : UV et iode - Rf : 0 45 Solubilite : soluble dans l'eau.
Chlorhydrate de N(N'-N' diethyl amino-2' ethyl) methoxy-2 (dimêthyl-l"-l" propynyl-2" amino sulfonyl)-5 benzamide (F 1744) On opere comme dans l'exemple 1 mais en utilisant de la di~thyl amino ethyl amine, on obtient le produit de formule:
Z l\Et CH3 Cl- ~: -SO - N - C - C ~ CH
Formule brute : Clg:H30 Cl N3 04 S
Masse moleculaire : 431.98 ; Cristaux blancs - -Point de fusion : 195C ~-.
Chromatographie sur plaque: ~.
- support : silice 60 F 254 Merck - solvant : chloroforme ~ m~thanol - eau 65/25/4 - r~velation : UV et iode - Rf : 0.45 Solubilites : Soluble à 25% dans l'eau. Soluble ~ 4% dans l'ethanol a 95GL et a 8% dans le dimethyl :
-~ acetamide.
*~1~r~e ~ ~O~er~e 5 ~
- , . . - .
. .. . , . ~. . -1S~53 Maleate du N(N'-N' diethyl amino-2' propyl) methoxy-2 (dimethyl-l"-l" propynyl-2" amino sulfonyl)-5 benzamide (F 1737) On opere comme dans l'exemple 1 mais en utilisant la diethyl amino-2 propylamine, puis la base libre est traitee par l'acide malelque, on obtient le produit de formule:
OCH3 0 H \ / Et H3 02C ~
S2 - NH - f - C _ CH J
Formule brute : C24 H3s N3 8 S
Masse moleculaire : 525.63 Cristaux blancs Point de fusion : 146C
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : chloroforme - me-thanol - eau 65/25/4 - revelation : UV et iode - Rf : 0.62 Solubilites : soluble dans l'eau a 10% et dans l'ethanol a -95GL.
. N(N'-N' diethyl amino-3' propyl) methoxy-2 (dimethyl-l"-l"
propynyl-2" amino sul~onyl)-5 benzamide :
On opère comme dans l'exemple 1 mais en utilisant la diethyl amino propylamine, on obtient le produit de formule:
~, . ..... .. .
.. ., . . , .................. ~ .- . ~- .:
..
~Q50S3 CH30 0~ /Et - N:; CH2 ~ CH2 2 \Et Formule brute: C20 H31 N3 04 S
Masse moleculaire : 409.55 Cristaux blancs -Point de fusion: 110C .
Chromatographie sur plaque:
- support: gel de silice 60 F 254 Merck - solvant: ethanol a 95GL - ammoniaque 95/5 - revelation : UV et iode - Rf: 0.45 . : :
Spectre IR : VC - O 1635 cm EXEMPLE 5 .
N(N'-N' diethylamino-4' butyl) mathoxy-2 (dimethyl-l"-l" .
prop~yl-2" amino sulfonyl)-5 benzamide On opere selon l'exemple 1 mais en utilisant la diethyl amino butylamine, on obtient le produit de formule:
CH31 O . /Et ~C - NH - CH2 - CH2 - CH2 - CH2 N\
\/ ICH3 : -S2 - NH - I - C _ CH
Formule brute: C21 H33 N3 04 S
Masse moleculaire : 423.58 20 Cristaux blancs Point de fusion: 129C
. ' .' . - ~ ~ :
. . . . .
S~i3 Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : ethanol ~ 95GL - ammoniaque 95/5 - r~velation UV et iode - Rf : 0.42 Chlorhydrate du N(N' ethyl piperidino-3') methoxy-2 (dimethyl-1"-1" propynyl-2" amino sulfonyl)-5 benzamide, monohydrate (F 1740) On opere comme dans l'exemple 1 mais en utilisant la N-ethyl amino-3 piperidine, on obtient le produit de formule:
OCH~ O
~ ~ - N~ 3 ~ ~
CH3 H/ \Et Cl ; H20 52 ~ NH - f - C - C - H
CH3 ::~
Forlnule brute C20 H30 Cl N3 04 S~ H20 Masse moleculaire : 462 Cristaux blancs Point de fusion : 203C
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck : - solvant : butanol - acide acetique - eau 6/2/2 .
- r~Yelation : UV et iode - Rf : 0.23 Solubil;t~s : soluble dans l'eau a 25%, dans l'ethanol a 95GL
a 5% et a 50% dans le dimethyl acetamide.
Chlorhydrate du N(pyrrolidino-2 ethyl) methoxy-2 (dimethyl-1'-1' propynyl amino sulfonyl)-5 benzamide (F 1529) :~ .
V5~S3 On opere comme dans l'exemple 1 mais en utilisant la N(amino-2 ethyl) pyrrolidine, on obtient le produit de formule:
OCH3 ~ :
Cl - NH ~ CH2 ~ CH2 -82 - NH - C - C _ CH
Formule brute : Cl9 H28 Cl N3 04 S
Masse moleculaire : 429.97 Cristaux beige clair Point de fusion : 220C
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : butanol - acide acetique - eau 6/2/2 - revelation : UV et iode - Rf : 0 45 Spectre IR : vN ~l a 3400 cm 1 ; v_c H a 3280 cm 1 VC O a 1660 cm~l ; VC - C a 1595 cm~l ;
vS = O a 1300-1350 cm~l et 1150-1200 cm~
Chlorhydrate de N(pyrrolidino-2 ethyl) (dimethyl-l'-l' propynyl-2' amlno sulfonyl)-3 benzamide (F 1528) a) Preparation du N(dimethyl-l'-l' propynyl-2') carboxy-3 benzène sulfonamide _ _ _ Dans une solution de 133 g de methyl-2 butyn-3 amine-2 et 1300 cm3 d'eau3 on introduit sous agitation a 0C 110 g de chlorure de carboxy-3 benzene sulfonyle. Maintenir l'agitation a temperature ambiante pendant 10 heures. Acidifier par une solution d'acide chlorhydrique 6 N, laver a l'eau. Extraire par de l'acetate d'ethyle, secher. On recupere 72% de produit.
. .
9 -;
. . . . .
~5C~53 b) Chlorhydrate de N(pyrrolidino-2 ethyl) (dimethyl-l'-l' proeynyl-2' amino sulfonyl2-3 benzamide Dans une solution de 32 9 de N(dimethyl-l'-l' propynyl-2') carboxy-3 benzène sulfonamide dans 250 cm3 de benzène et 12.7 9 de triethylamine, on additionne goutte à
goutte sous forte agitation 14.3 g de chloro~ormiate d'ethyle en solution dans 15 cm3 de benzène. Maintenir 4 heures sous agita~ion à temperature ambiante. Essorer le chlorhydrate de triethylamine forme, laver au benzène puis introduire goutte à
10 goutte sous agitation 13.7 g de N(amino-2 ethyl) pyrrolidine. -Laisser sous forte agitation une nuit a temperatur~ ambiante, glacer, filtrer et chlorhydrater. On recupère 71% de produit de formule:
C - RH - CH2 - CH2 -/N ~
CH3 -.
S2 ~ NH - C - C - C - H ~
.
Formule brute : C18 H26 Cl N3 03 S
Masse moleculaire : 399.94 Cristaux blancs Point de fusion : 186-187C
Chromatographie sur plaque:
20- support : gel de silice 60 F 254 Merck - solvant : butanol - acide acetique - eau 6/2/2 - revelation : UV et iode - Rf : 0-55 Spectre IR : V-C H a 3280 cm 1 ; vN H à 3160 cm 1 et 1660 cm~
Solubilites : soluble dans l'eau a 50%, soluble dans l'ethanol à 95GL à 5% et a 25% dans le dimethylformamide.
- 10 - '' .- . - , . .......... . . . . ..
,, ,, , ,, . . ., .,~ , .: , Chlorhydrate de N(N' ethyl pyrrolidino-2' m~thyl) (dimethyl-1"-1" propynyl-2" amino sulfonyl)-3 benzamide (F 1634) On opere comme dans l'exemple 8, mais en utilisant la . .
N-ethyl (amino methyl)-2 pyrrolidine, on obtient le produit de formule:
~ NH - CH2 ~/ ~ IN
\~ CH3 Formule brute : Cl9 H28 Cl N3 03 S
10 Masse moleculaire : 414 Cristaux blancs Point de fusion: 195C
Chromatographie sur plaque:
- support: gel de silice 60 F 254 Merck - solvant : butanol - acide acetique - eau 6/2/2 - revelation: UV et iode - Rf: 0~55 Spectre IR : vNH a 3300 cm i VC _ C
VC - O à 1665 cm 20 Solubilite: tr~s soluble dans 1'eau.
NtN' ethyl pyrrolidino-2' methyl) (dimethyl-l"-l" propynyl-2"
amino sulfonyl)-4 benzamide, maleate (F 1738) ::
a) Preparation de l'acide p(N-dimethyl-l'-l' propynyl-2' :
amino sulfonyl) benzoïgue _ Dans une solution de 27.2 9 de methyl-2 butyn-3 ~
1 1 :
.. . , . ,, ~ ,, , , : :
15~
amine-2 dans 250 cm3 d'eau, introduire goutte a goutte a 0C
sous forte agitation 24 9 de chlorure de p-carboxy benzène sulfonyle. Laisser une nuit sous agitation a température ambiante. ~cidifier, filtrer, laver a l'eau et dissoudre les cristaux dans l'acetate d'ethyle apres sechage. On recupere avec un rendement de 70% le produit de point de fusion 204-205C.
b) Preparation du N(N' ethyl pyrrolidino-2' methyl) (dimethyl~ l" propynyl-2" sulfonyl)-4 benzamide _________________________________________________ Dans une solution de 20 9 de p-carboxy N(dimethyl-1'-1' propynyl-2 amino sulfonyl benzoique dans 200 cm3 de tetrahydrofuranne, introduire 10.5 cm de triethylamine puis une solution de 8.96 g de chloroformiate d'ethyle dans 20 cm3 de tetrahydrofuranne. Mainten;r une heure sous agitation a oc puis additionner une solution de 9.65 9 de N-ethyl pyrrolidino-2 methyl amine dans 20 cm3 de tetrahydrofuranne. Laisser une nuit a temperature ambiante sous agitation et distiller jusqu'a siccite. Traiter par une solution bicarbonatee, extraire a l'acetate d'ethyle, laver a l'eau et secher. Apres recupera-tion de la base libre, on traite par une solution ethanolique d'acide male~que, on recup@re avec un rendement de 80% un produit de formule:
O
C - NH - C~l2 ~ J
N
H3 ;C02/
82 ~ NH - IC - C - C - H
Formule brute : C23 H31 N3 07 S
Masse moleculaire : 493.58 , .,. . ~.
1~5VS3 Cristaux blancs Point de fusion : 145C
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : chloroforme - methanol - eau 65/25/4 ; - revelation : UV et iode - Rf : 0.36 Solubilites : soluble dans l'eau a 2% et dans l'ethanol a 95GL
â 3%
Chlorhydrate de N(pyrrolidino-2' ethyl) (dimethyl-l"-l"
propynyl-2" amino sulfonyl)-3 chloro-4 benzamide (F 1530) a) Preparation du N(dimethyl-l-l propynyl-2) chloro-2 carboxy-5 benzene sulfonamide Dans une solution de 80 9 de methyl-2 butyne-3 amino-2 dans 800 cm3 d'eau, introduire à 0C sous agitation 76.5 g de chlorure de chloro-2 carboxy-5 benzene sulfonyle. Mainten;r l'agitation pendant 8 heures ~ temperature ambiante. Acidi-fier, essorer et dissoudre les cristaux obtenus dans l'acetated'~thyle. Decanter, s~cher, filtrer et cristalliser. On recu-pere avec un rendement de 92% un produit fondant a 210C.
b) Preparation du chlorhydrate du N(pyrrolidino-2' ethyl) (dimêthyl-l"-l" propynyl-2" amino sulfonyl)-3 chloro-4 benzamide _ _ ___ ____ _ ___ Dans une solution de 26.97 g de N(dimethyl-l-l propynyl-2) chloro-2 carboxy-5 benzene sulfonamide dans 270 cm3 de tetrahydrofuranne, ajouter a 5 cm3 de triethylamine et 12 g ;~
de chloroformiate d'ethyle en solution dans 15 cm3 de tetra-` 30 hydrofuranne. Laisser 4 heures sous agitation et introduire goutte a goutte a 0C sous forte agitation une solution de 11.42 g de N(amino-2 ethyl) pyrrolidine dans 15 cm3 de tetra-hydrofuranne. Maintenir l'agitation a temperature ambiante . - ' .
' ' - 4 --.
) S ~ 53 VC - C ~ 1600 cm ~ l and VS - O a 1300-1350 cm ~ l and 1150 cm ~ l -1200 cm ~
Plate chromatography:
- support: silica gel 60 F 254 Merck ~
- solvent: butanol - acetic acid - water 6/2/2 - revelation: UV and iodine - Rf: 0 45 Solubility: soluble in water.
N (N'-N 'diethyl amino-2' ethyl) methoxy-2 hydrochloride (dimethyl-1 "-l" propynyl-2 "amino sulfonyl) -5 benzamide (F 1744) We operate as in Example 1 but using di ~ thyl amino ethyl amine, we obtain the product of formula:
Z l \ Et CH3 Cl- ~: -SO - N - C - C ~ CH
Gross formula: Clg: H30 Cl N3 04 S
Molecular mass: 431.98 ; White crystals - -Melting point: 195C ~ -.
Plate chromatography: ~.
- support: silica 60 F 254 Merck - solvent: chloroform ~ m ~ thanol - water 65/25/4 - reformation: UV and iodine - Rf: 0.45 Solubilities: 25% soluble in water. Soluble ~ 4% in ethanol at 95GL and 8% in dimethyl:
- ~ acetamide.
* ~ 1 ~ r ~ e ~ ~ O ~ er ~ e 5 ~
-,. . -.
. ... ,. ~. . -1S ~ 53 N (N'-N 'diethyl amino-2' propyl) methoxy-2 maleate (dimethyl-l "-l" propynyl-2 "amino sulfonyl) -5 benzamide (F 1737) We operate as in Example 1 but using the diethyl amino-2 propylamine, then the free base is treated with malelque acid, the product of formula is obtained:
OCH3 0 H \ / And H3 02C ~
S2 - NH - f - C _ CH J
Gross formula: C24 H3s N3 8 S
Molecular mass: 525.63 White crystals Melting point: 146C
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: chloroform - me-thanol - water 65/25/4 - revelation: UV and iodine - Rf: 0.62 Solubilities: soluble in water at 10% and in ethanol at -95GL.
. N (N'-N 'diethyl amino-3' propyl) methoxy-2 (dimethyl-l "-l"
propynyl-2 "amino sul ~ onyl) -5 benzamide :
We operate as in Example 1 but using the diethyl amino propylamine, we obtain the product of formula:
~,. ..... ...
...,. . , .................. ~ .-. ~ -.:
..
~ Q50S3 CH30 0 ~ / And - NOT:; CH2 ~ CH2 2 \ And Gross formula: C20 H31 N3 04 S
Molecular mass: 409.55 White crystals -Melting point: 110C.
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: ethanol at 95GL - ammonia 95/5 - revelation: UV and iodine - Rf: 0.45. ::
IR spectrum: VC - O 1635 cm EXAMPLE 5.
N (N'-N 'diethylamino-4' butyl) mathoxy-2 (dimethyl-l "-l".
prop ~ yl-2 "amino sulfonyl) -5 benzamide We operate according to example 1 but using the diethyl amino butylamine, the product of formula is obtained:
CH31 O. /And ~ C - NH - CH2 - CH2 - CH2 - CH2 N \
\ / ICH3: -S2 - NH - I - C _ CH
Gross formula: C21 H33 N3 04 S
Molecular mass: 423.58 20 White crystals Melting point: 129C
. '.' . - ~ ~:
. . . . .
S ~ i3 Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: ethanol ~ 95GL - ammonia 95/5 - UV and iodine development - Rf: 0.42 N (N 'ethyl piperidino-3') methoxy-2 (dimethyl-) hydrochloride 1 "-1" propynyl-2 "amino sulfonyl) -5 benzamide, monohydrate (F 1740) We operate as in Example 1 but using the N-ethyl amino-3 piperidine, the product of formula is obtained:
OCH ~ O
~ ~ - N ~ 3 ~ ~
CH3 H / \ Et Cl; H20 52 ~ NH - f - C - C - H
CH3 :: ~
Gross formula C20 H30 Cl N3 04 S ~ H20 Molecular mass: 462 White crystals Melting point: 203C
Plate chromatography:
- support: silica gel 60 F 254 Merck : - solvent: butanol - acetic acid - water 6/2/2.
- r ~ Yelation: UV and iodine - Rf: 0.23 Solubil; t ~ s: soluble in water at 25%, in ethanol at 95GL
5% and 50% in dimethyl acetamide.
N (2-pyrrolidino-ethyl) methoxy-2 (dimethyl-) hydrochloride 1'-1 'propynyl amino sulfonyl) -5 benzamide (F 1529) : ~.
V5 ~ S3 We operate as in Example 1 but using the N (2-amino-ethyl) pyrrolidine, the product of formula is obtained:
OCH3 ~:
Cl - NH ~ CH2 ~ CH2 -82 - NH - C - C _ CH
Gross formula: Cl9 H28 Cl N3 04 S
Molecular mass: 429.97 Light beige crystals Melting point: 220C
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: butanol - acetic acid - water 6/2/2 - revelation: UV and iodine - Rf: 0 45 IR spectrum: vN ~ la 3400 cm 1; v_c H at 3280 cm 1 VC O at 1660 cm ~ l; VC - C at 1595 cm ~ l;
vS = O at 1300-1350 cm ~ l and 1150-1200 cm ~
N (2-pyrrolidino ethyl) hydrochloride (dimethyl-l'-l ' propynyl-2 'amlno sulfonyl) -3 benzamide (F 1528) a) Preparation of N (dimethyl-l'-l 'propynyl-2') carboxy-3 benzene sulfonamide _ _ _ In a solution of 133 g of methyl-2 butyn-3 amine-2 and 1,300 cm3 of water3 are introduced with stirring at 0C 110 g of 3-carboxybenzene sulfonyl chloride. Maintain agitation at room temperature for 10 hours. Acidify with a 6N hydrochloric acid solution, wash with water. Extract with ethyl acetate, dry. 72% of product is recovered.
. .
9 -;
. . . . .
~ 5C ~ 53 b) N (2-pyrrolidino ethyl) hydrochloride (dimethyl-l'-l ' proeynyl-2 'amino sulfonyl2-3 benzamide In a solution of 32 9 of N (dimethyl-l'-l ' propynyl-2 ') carboxy-3 benzene sulfonamide in 250 cm3 of benzene and 12.7 9 of triethylamine, added dropwise to drop with strong stirring 14.3 g of chloro ~ ethyl ormiate dissolved in 15 cm3 of benzene. Maintain 4 hours under stirred at room temperature. Wring out the hydrochloride triethylamine form, wash with benzene then add drop to 10 drop with stirring 13.7 g of N (2-amino-ethyl) pyrrolidine. -Leave under vigorous stirring overnight at ambient temperature, glaze, filter and hydrochloride. We recover 71% of product of formula:
C - RH - CH2 - CH2 - / N ~
CH3 -.
S2 ~ NH - C - C - C - H ~
.
Gross formula: C18 H26 Cl N3 03 S
Molecular mass: 399.94 White crystals Melting point: 186-187C
Plate chromatography:
20- support: silica gel 60 F 254 Merck - solvent: butanol - acetic acid - water 6/2/2 - revelation: UV and iodine - Rf: 0-55 IR spectrum: VC H at 3280 cm 1; vN H at 3160 cm 1 and 1660 cm ~
Solubilities: 50% water soluble, ethanol soluble at 95GL at 5% and at 25% in dimethylformamide.
- 10 - '' .-. -,. ........... . . . ..
,, ,,, ,,. . .,., ~,.:, N (N 'ethyl pyrrolidino-2' m ~ thyl) hydrochloride (dimethyl-1 "-1" propynyl-2 "amino sulfonyl) -3 benzamide (F 1634) We operate as in Example 8, but using the. .
N-ethyl (amino methyl) -2 pyrrolidine, the product of formula:
~ NH - CH2 ~ / ~ IN
Gross formula: Cl9 H28 Cl N3 03 S
10 Molecular Weight: 414 White crystals Melting point: 195C
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: butanol - acetic acid - water 6/2/2 - revelation: UV and iodine - Rf: 0 ~ 55 IR spectrum: vNH at 3300 cm i VC _ C
VC - O at 1665 cm 20 Solubility: very soluble in water.
NtN 'ethyl pyrrolidino-2' methyl) (dimethyl-l "-l" propynyl-2 "
amino sulfonyl) -4 benzamide, maleate (F 1738) ::
a) Preparation of the acid p (N-dimethyl-l'-l 'propynyl-2':
amino sulfonyl) benzoïgue _ In a solution of 27.2 9 of methyl-2 butyn-3 ~
1 1:
... ,. ,, ~ ,,,,::
15 ~
amine-2 in 250 cm3 of water, introduce dropwise at 0C
with vigorous stirring 24 9 of p-carboxy benzene chloride sulfonyl. Leave overnight with stirring at temperature ambient. ~ acidify, filter, wash with water and dissolve crystals in ethyl acetate after drying. We recover with a yield of 70% the product of melting point 204-205C.
b) Preparation of N (N 'ethyl pyrrolidino-2' methyl) (dimethyl ~ l "propynyl-2" sulfonyl) -4 benzamide _________________________________________________ In a solution of 20 9 p-carboxy N (dimethyl-1'-1 'propynyl-2 amino sulfonyl benzoique in 200 cm3 of tetrahydrofuran, introduce 10.5 cm of triethylamine then a solution of 8.96 g of ethyl chloroformate in 20 cm3 of tetrahydrofuran. Now; r for one hour with stirring at oc then add a solution of 9.65 9 of N-ethyl pyrrolidino-2 methyl amine in 20 cm3 of tetrahydrofuran. Leave a overnight at room temperature with stirring and distill until siccite. Treat with a bicarbonate solution, extract at ethyl acetate, wash with water and dry. After recovering-tion of the free base, treatment with an ethanolic solution of male acid that is recovered with a yield of 80% a formula product:
O
C - NH - C ~ l2 ~ J
NOT
H3; C02 /
82 ~ NH - IC - C - C - H
Gross formula: C23 H31 N3 07 S
Molecular mass: 493.58 , .,. . ~.
1 ~ 5VS3 White crystals Melting point: 145C
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: chloroform - methanol - water 65/25/4 ; - revelation: UV and iodine - Rf: 0.36 Solubilities: soluble in water at 2% and in ethanol at 95GL
â 3%
N (2-pyrrolidino-ethyl) hydrochloride (dimethyl-l "-l"
2-propynyl "amino sulfonyl) -3 4-chloro benzamide (F 1530) a) Preparation of N (dimethyl-ll propynyl-2) chloro-2 5-carboxybenzene sulfonamide In a solution of 80 9 of methyl-2 butyne-3 amino-2 in 800 cm3 of water, introduce at 0C with stirring 76.5 g of 2-chloro-5-carboxybenzene sulfonyl chloride. Now; r stirring for 8 hours at room temperature. Acidi-proud, wring and dissolve the crystals obtained in the acetated '~ thyle. Decant, dry, filter and crystallize. We received-father with a yield of 92% a product melting at 210C.
b) Preparation of N hydrochloride (pyrrolidino-2 'ethyl) (dimethyl-1 "-l" propynyl-2 "amino sulfonyl) -3 chloro-4 benzamide _ _ ___ ____ _ ___ In a solution of 26.97 g of N (dimethyl-ll 2-propynyl) 2-chloro-5-carboxybenzene sulfonamide in 270 cm3 of tetrahydrofuran, add to 5 cm3 of triethylamine and 12 g; ~
of ethyl chloroformate in solution in 15 cm3 of tetra-`30 hydrofuran. Leave for 4 hours with stirring and introduce drop by drop at 0C with vigorous stirring a solution of 11.42 g of N (2-amino-ethyl) pyrrolidine in 15 cm3 of tetra-hydrofuran. Maintain agitation at room temperature . - '.
''
5~3~
pendant une nuit. Distiller jusqu'a siccite, traiter avec une solution bicarbonatee. Laver a l'eau les cristaux obtenus, dissoudre dans l'acetate d'ethyle, decanter, secher. Puis chlorhydrater par addition d'une solution ethanolique saturee d'acide chlorhydrique. On recupere avec un rendement de 70% le --produit de formule:
1l /~
l CH3 S2 ~ NH - f _ C - H
Formule brute : C18 H25 C12 N3 03 S
Masse moleculaire : 434.38 Cristaux beiges Point de ~usion : 211C
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : butanol - acide acetique - eau 6/2/2 - revelation : UV et iode - R~ : 0.51 Spectre IR : vN H a 3310 cm 1 ; V-C H à 3300 cm 1 VC ~ C a 2120 cm ; VC _ O a 1660 cm VC - C a 1600 cm~l et VS - O a 1150 - 1200 cm~l et 1300 - 1350 cm~l Solubilites : soluble dans l'eau a 4% - soluble a 2% dans l'ethanol a 95GL et a 5% dans le dimethyl-formamide.
Chlorhydrate de N(N' ethyl pyrrolidino-2' methyl) (dim~thyl-1"-1" propynyl-2" amino sul~onyl)-3 chloro-4 benzamide _ ;~
- (F 1635) .. . .
On opere comme dans l'exemple 11, mais en utilisant la N-ethyl amino-2 methyl pyrrolidine, on obtient le produit de formule:
8 ~ CH2 ~
H ~t Cl H3 Formule brute : Cl9 H27 C12 N3 03 S ~.
Masse moleculaire : 448.42 Cristaux blancs : . .
Point de fusion : 172C . .
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : butanol - acide acetique - eau 6/2/2 - rev~lation : UV et iode : - Rf : 0.59 Spectre IR : vN H a 3290 cm 1 ; v_c H a 3280 cm 1 ; ~:
VC - O a 1660 cm~l et VC = C ~ 1600 cm~
Solubilites : tres soluble dans l'eau. Soluble 3 1% dans : : l'ethanol. :::
... .
~ EXEMPLE 13 .~ Chlorhydrate du N(N' ethyl pyrrolidino-2' methyl) methoxy-2 : 20 (ethynyl-l" cyclohexyl am;no sulfonyl)-5 benzamide (F 1742) ~.
' a) Preparation de l'acide methoxy-2 (éthynyl-l' cyclo-hexylamino sul~fonyl)-S benzamide Dans une solution de 25.8 9 d'ethynyl-l cyclohexyl .~:~
amine dans 300 cm3 d'eau, introduire en gl.açant et sous forte agitation 17.5 g de carboxy-3 methoxy-4 benzene sulfochlorure.
Maintenir sous agitation 3 temperature ambiante pendant une :.
`, . ,, ~- . . ~ . , ~ .
~50S;~
nuit. Acidifier, essorer et secher. On recupere avec un rendement de 75~ un produit fondant a 195C.
b) Preparation du chlorhydrate du N(N' ethyl pyrrolidino-2' ethyl) methoxy-2 (ethynyl-l" cyclohexyl amino sulfonyl)-5 benzamide ___ _ _ __ ___ _ _ __ _____ Dans une solution de 15.6 g d'acide methoxy-2 (ethynyl-l' cyclohexyl amino sulfonyl)-5 benzamide dans 160 cm3 de tetrahydrofuranne et 7 cm de triethylamine, ajouter sous forte agitation en glac~ant une solution de 5.55 g de chloro-10 formiate d'ethyle dans 10 cm3 de tetrahydrofuranne. Maintenir une heure sous agitation à 0C et introduire goutte a goutte ~-une solution de 5.95 g de N-ethyl pyrrolidino-2' methylamine dans 10 cm3 de tetrahydrofuranne. Laisser sous agitation a temperature ambiante pendant une nuit. Distiller jusqu'a siccite et traiter par une solution bicarbonatee a 10%. Les cristaux obtenus sont traites par une solution methanolique saturee d'acide chlorhydrique. On recupere avec un rendement de 85% le produit de formule:
[~C - NH - CH2~
82 ~ NH -/C - C ~ C - H
V
Formule brute : C23 H34 Cl N2 4 Masse moleculaire: 484.06 Cristaux blancs Point de fusion: 208C
Chromatographie sur plaque:
~3S~S3 - support : silice 60 F 254 Merck - solvant : chloroforme - methanol - eau 65/25/4 - re~elation : UV et iode - Rf : 0.6 Solubilites : soluble dans l'eau et dans l'ethanol a 95GL a 2%
et a 10% dans le dimethyl acetamide.
D'une façon similaire aux produits precedents, nous avons prepare:
Chlorhydrate du N(N' ethyl pyrrolidino-2' ethyl) methoxy-2 (diethyl-l"-l" propynyl amino sulfonyl)-5 benzamide de formule:
C - NH - CH ~ Cl~
Formule brute : C22 H34 04 Cl N3 S
.~ Masse moleculaire : 472.05 : :
:-Cristaux blancs :
. ~ . . .
. Point de fusion : 218C
;~ Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck -- solvant : chloroforme - mêthanol - eau 65/25/4 :
- revelation : UV et iode ~: - Rf : 0.47 Spectre IR : VC - 0 ~ 1645 cm l : EXEMPLE 15 : - .
N(N' ethyl pyrrolidino-2' ~thyl) methoxy-2 (propynyl amino sulfonyl)-S benzamide de formule:
: ' - 17 - :-~
.
, .. . . . . . . . . .
.. . . ..
9 ~ 3 NH - CH2 ~ ~
S2 ~ NH - CH2 - C - C - H
Formule brute : Clg H25 N3 04 S
Masse moleculaire : 407.53 Cristaux blancs Point de fusion : 128C
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : chloroforme - methanol - eau 65/25/4 - revelation : UV et iode : 10 - Rf : 0.37 , Spectre IR : VC O ~ 1640 cm ' N(N' ethyl pyrrolidino-2' methyl) mathoxy-2 (pyrrolidino-4"
dimethyl-l"-l" butynyl-2" amino sulfonyl)-5 benzamide (F 1735) de formule:
..
~0 2 ~ ~:
Formule brute : C2s H38 N4 04 S
Masse moleculaire : 490.67 -~
20~ Cristaux beiges Point de fusion : 115C ~ .
Chromatographie sur plaque:
.~ ~ , . .
.:, .
~LQ5i~S3 - support : gel de silice 60 F 254 Merck - solvant : chloroforme - methanol - eau 65/25/4 - revelation : UV et iode - Rf : 0.20 Solubilites : insoluble dans l'eau - soluble a 50% dans l'ethanol et dans le dimethyl acetamide N(N' ethyl pyrrolidino-2' methyl) methoxy-2 (morpholino-4"
dimethyl-l"-l" butynyl-2" amino sulfonyl)-5 benzamide -de formule:
~ C - hH - CH
f H3 A
Formule brute : C2s H38 N4 05 S
Masse moleculaire : 506.59 Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : ethanol - ammoniaque 95/5 - revelation : UV et iode - Rf : 0.52 : ~ :
N(N' ethyl pyrrolidino-2' methyl) methoxy-2 (N" methyl pipera-zine-4'' dimethyl-1"-l"~butynyl-2" amino sulfonyl)-5 benzamide de formule: ~-OCH3 ~ ~; -0 It IH3 ~
S02 ~ NH - C - C _ C - CH2 - N N - CH3 19 : :
9.~ 5i3 Formule brute : C26 H41 N5 04 S
Masse moleculaire : 519.13 Cristaux blancs Poi nt de fus i on : 105C
Chromatographie sur plaque:
- support : gel de si1ice 60 F 254 Merck - solvant : ethanol - ammoniaque 95/5 - revelation : UV et iode - Rf : 0-34 N(N' ethyl pyrrolidino-2' methyl) methoxy-2 (N" benzyl pipera-zine-4" dimethyl 1"-1" butynyl amino sulfonyl)-5 benzamide -.
de formule: -0CH3 1l NH _ CH2 Et S02 ~ NH - C - C - C - CH2 - N 3 - CH
Formule brute C32 H45 N5 04 S
Masse molêculaire : 595.80 Cristaux blancs Point de fusion : 135C
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck solvant : chloroforme - methanol - eau 65/25/4 , - revelation : UV et iode - Rf : 0-5 Spectre IR : Vc _ 0 a 1645 cm ` N(N' ethyl pyrrolidino-2' methyl) methoxy-2 (N"N" diethyl-4"
; dimethyl-l"-l" butynyl-2" amino sulfonyl )-5 benzamide . : . ~ ~ . . .....
Soei3 de formule:
OCH3 1l R CH2 ~
H3 / Et S2 - NH - I - C _ C - CH2 - N\
CH3 Et Formule brute : C25 H40 N4 S 04 Masse moleculaire : 492.68 Cristaux blancs Point de fusion : 95C
Chromatographie sur plaque:
- support : gel de silice 60 F 254 Merck - solvant : chloroforme - methanol - eau 65/25/4 - revelation : UV et iode - Rf : 0.26 Spectre IR : VC - O a 1640 cm EXPERIMENTATIONS: -Les composes chimiques, precedemment decrits ont fait l'objet d'experimentations toxicologiques, pharmacologiques et Cl l niques en vue de determiner les possibilites d'application ; ~ dans le domaine therapeutique.
!~ A) Toxicologie:
Les composes chlmiques ont ete soumis à des contrôles 1 20 de toxicite. La toxicite aiguë de certains composes determinee I par la dose latale 50 est rapportee dans le tableau suivant.
E11e a ~te recherchee sur des lots de 10 souris par voie orale et intra-peritoneale calculee selon la methode de Miller et :
Tainter. .
., .
, ' . ' ' .
"
.. ~ , . . ~: .
58~3 ComposesDL 50 voie i.p.DL 50 voie orale F 1603 > 500 > 1000 ..
F 1744 400 > 1000 _ ; 10 F 1735 > 500 > 1000 F 1737 > 500 > 1000 F 1738 400 > 1000 . .
Sulpiride 320 800 _ _ Metoclopramide 150 600 ~' Les derives dont la chatne sulfamido est polyazotee sont très peu toxiques et les DL 50 par voie orale sont supe-rieures a 1 g/kg (exemples 19, 189 17, 16 et 20).
B~ Pharmacodynamie:
Il a ete mis en evidence une propriete antiemetique par antagonisme de l'apomorphine selon Burkman - Arch. Int.
Pharmacodyn. 1962, 137, 396.
. . .
~:' ; - 22 -35~S3 A titre d'exemple, quelques resultats sont rapportes dans le tableau ci-dessous:
ComposesDoses en ~g/kg % inhibition par .
I .
_ ., , L'activite varie en fonction de la nature de l'amide.
Certains composes ont une activite sur ce test egale ou supe-rieure a celle du sulpiride ou du metoclopramide. Les effets visceraux ont ete egalement etudies e~ plus specialement ~ -l'activite sur le transit intestinal selon Janssen - J. Pharm.
pharmacol. 1957, 9, 381.
.~. .... .. .
` 20 Les composes F 1603, F 1744, F 1737, F 1735, ainsi que . .
~ les produits des exemples 4, 5, 19, 20 manifestent une accele-. .
ration du transit intestinal comparativement aux temoins.
Ces derives diminuent le nombre d'ulceres chez le rat , .
apres ligature du pylore, ce qui peut être reli~ aux effets sur le systeme nerveux central.
~` C) Applications therapeutiques:
Il a ete procede a des essais cliniques pour certains ,, , :-. . .
3SC~S3 `-composes objet de l'invention, plus particulièrement les F 1603, F 1744, F 1735 et les composes des exemples 4, 5, 18, 19. Ils ont ete appliques dans le traitement des troubles digestifs psychosomatiques chez les sujets anxieux ou surmenes, les vomissements et malaises digestifs de la femme enceinte et les intolerances medicamenteuses. Ces composes peuvent egalement être utilises en psychopathologie de pratique courante.
Les preparations pharmaceutiques contenant ces prin-cipes actifs peuvent être administrees par voie orale ou paren-terale. Pour l'administration par voie orale, il est possibled'utiliser des comprimes ou des gelules. Ces compositions pharmaceutiques peuvent egalement contenir d'autres principes actifs therapeutiquement acceptables.
A titre d'exemples, nous citons quelques preparations pharmaceutiques contenant des principes actifs objet de l'in-vention:
1) Gelules:
_ _ F 1603 ...................... 50 mg 2) Comerimes:
_ _ F 1744 ...................... 10 mg Cellulose microcristalline Stearate de Mg 3) Solute inJectable:
F 1735 ...................... S0 mg par ampoule de 2 ml.
- . : . - . .- :. . , . ~ . . .:
.. . . .- : . :., : , . ~ . . .: 5 ~ 3 ~
overnight. Distill until dry, treat with a bicarbonate solution. Wash the crystals obtained with water, dissolve in ethyl acetate, decant, dry. Then hydrochloride by adding a saturated ethanolic solution hydrochloric acid. We recover with a yield of 70% the -formula product:
1l / ~
l CH3 S2 ~ NH - f _ C - H
Gross formula: C18 H25 C12 N3 03 S
Molecular mass: 434.38 Beige crystals Usion point: 211C
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: butanol - acetic acid - water 6/2/2 - revelation: UV and iodine - R ~: 0.51 IR spectrum: vN H at 3310 cm 1; VC H at 3300 cm 1 VC ~ C at 2120 cm; VC _ O at 1660 cm VC - C at 1600 cm ~ l and VS - O at 1150 - 1200 cm ~ l and 1300 - 1350 cm ~ l Solubilities: 4% water soluble - 2% soluble in ethanol at 95GL and 5% in dimethyl-formamide.
N hydrochloride (N 'ethyl pyrrolidino-2' methyl) (dim ~ thyl-1 "-1" propynyl-2 "amino sul ~ onyl) -3 chloro-4 benzamide _; ~
- (F 1635) ... .
We operate as in Example 11, but using N-ethyl amino-2 methyl pyrrolidine, we get the product of formula:
8 ~ CH2 ~
H ~ t Cl H3 Gross formula: Cl9 H27 C12 N3 03 S ~.
Molecular mass: 448.42 White crystals:. .
Melting point: 172C. .
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: butanol - acetic acid - water 6/2/2 - revelation: UV and iodine : - Rf: 0.59 IR spectrum: vN H at 3290 cm 1; v_c H a 3280 cm 1; ~:
VC - O at 1660 cm ~ l and VC = C ~ 1600 cm ~
Solubilities: very soluble in water. Soluble 3 1% in :: ethanol. :::
...
~ EXAMPLE 13 . ~ N hydrochloride (N 'ethyl pyrrolidino-2' methyl) methoxy-2 : 20 (ethynyl-1 "cyclohexyl am; no sulfonyl) -5 benzamide (F 1742) ~.
'a) Preparation of 2-methoxy acid (ethynyl-cyclo-hexylamino sul ~ fonyl) -S benzamide In a solution of 25.8 9 of ethynyl-1 cyclohexyl. ~: ~
amine in 300 cm3 of water, introduce in ice and under strong stirring 17.5 g of 3-carboxy-4-methoxy-benzene sulfochloride.
Keep stirring at 3 room temperature for one :.
`,. ,, ~ -. . ~. , ~.
~ 50S; ~
night. Acidify, wring and dry. We recover with a yield of 75 ~ a product melting at 195C.
b) Preparation of N hydrochloride (N 'ethyl pyrrolidino-2 'ethyl) methoxy-2 (ethynyl-1 "cyclohexyl amino sulfonyl) -5 benzamide ___ _ _ __ ___ _ _ __ _____ In a solution of 15.6 g of methoxy-2 acid (ethynyl-l cyclohexyl amino sulfonyl) -5 benzamide in 160 cm3 tetrahydrofuran and 7 cm of triethylamine, add under strong agitation in ice ~ ant a solution of 5.55 g of chloro-10 ethyl formate in 10 cm3 of tetrahydrofuran. Maintain one hour with stirring at 0C and introduce drop by drop ~ -a solution of 5.95 g of N-ethyl pyrrolidino-2 'methylamine in 10 cm3 of tetrahydrofuran. Leave to stir room temperature overnight. Distill until dry and treat with a 10% bicarbonate solution. The crystals obtained are treated with a methanolic solution saturated with hydrochloric acid. We recover with a yield of 85% the product of formula:
[~ C - NH - CH2 ~
82 ~ NH - / C - C ~ C - H
V
Gross formula: C23 H34 Cl N2 4 Molecular mass: 484.06 White crystals Melting point: 208C
Plate chromatography:
~ 3S ~ S3 - support: silica 60 F 254 Merck - solvent: chloroform - methanol - water 65/25/4 - re ~ elation: UV and iodine - Rf: 0.6 Solubilities: soluble in water and in ethanol at 95GL at 2%
and 10% in dimethyl acetamide.
In a similar way to the previous products, we have prepared:
N (N 'ethyl pyrrolidino-2' ethyl) methoxy-2 hydrochloride (diethyl-l "-l" propynyl amino sulfonyl) -5 benzamide of formula:
C - NH - CH ~ Cl ~
Gross formula: C22 H34 04 Cl N3 S
. ~ Molecular mass: 472.05::
: -White crystals:
. ~. . .
. Melting point: 218C
; ~ Plate chromatography:
- support: silica gel 60 F 254 Merck -- solvent: chloroform - methanol - water 65/25/4:
- revelation: UV and iodine ~: - Rf: 0.47 IR spectrum: VC - 0 ~ 1645 cm l : EXAMPLE 15: -.
N (N 'ethyl pyrrolidino-2' ~ thyl) methoxy-2 (propynyl amino sulfonyl) -S benzamide of formula:
: ' - 17 -: - ~
.
, ... . . . . . . . .
... . ..
9 ~ 3 NH - CH2 ~ ~
S2 ~ NH - CH2 - C - C - H
Gross formula: Clg H25 N3 04 S
Molecular mass: 407.53 White crystals Melting point: 128C
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: chloroform - methanol - water 65/25/4 - revelation: UV and iodine : 10 - Rf: 0.37 , IR spectrum: VC O ~ 1640 cm ' N (N 'ethyl pyrrolidino-2' methyl) mathoxy-2 (pyrrolidino-4 "
dimethyl-l "-l" butynyl-2 "amino sulfonyl) -5 benzamide (F 1735) of formula:
..
~ 0 2 ~ ~:
Gross formula: C2s H38 N4 04 S
Molecular mass: 490.67 - ~
20 ~ Beige crystals Melting point: 115C ~.
Plate chromatography:
. ~ ~,. .
.:,.
~ LQ5i ~ S3 - support: silica gel 60 F 254 Merck - solvent: chloroform - methanol - water 65/25/4 - revelation: UV and iodine - Rf: 0.20 Solubilities: insoluble in water - soluble at 50% in ethanol and in dimethyl acetamide N (N 'ethyl pyrrolidino-2' methyl) methoxy-2 (morpholino-4 "
dimethyl-l "-l" butynyl-2 "amino sulfonyl) -5 benzamide -of formula:
~ C - hH - CH
f H3 A
Gross formula: C2s H38 N4 05 S
Molecular mass: 506.59 Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: ethanol - ammonia 95/5 - revelation: UV and iodine - Rf: 0.52 : ~:
N (N 'ethyl pyrrolidino-2' methyl) methoxy-2 (N "methyl pipera-zine-4 '' dimethyl-1 "-l" ~ butynyl-2 "amino sulfonyl) -5 benzamide of formula: ~ -OCH3 ~ ~; -0 It IH3 ~
S02 ~ NH - C - C _ C - CH2 - NN - CH3 19::
9. ~ 5i3 Gross formula: C26 H41 N5 04 S
Molecular mass: 519.13 White crystals Fus i on point: 105C
Plate chromatography:
- support: Merck 60 F 254 si1ice gel - solvent: ethanol - ammonia 95/5 - revelation: UV and iodine - Rf: 0-34 N (N 'ethyl pyrrolidino-2' methyl) methoxy-2 (N "benzyl pipera-zine-4 "dimethyl 1" -1 "butynyl amino sulfonyl) -5 benzamide -.
of formula: -0CH3 1l NH _ CH2 And S02 ~ NH - C - C - C - CH2 - N 3 - CH
Gross formula C32 H45 N5 04 S
Molecular mass: 595.80 White crystals Melting point: 135C
Plate chromatography:
- support: silica gel 60 F 254 Merck solvent: chloroform - methanol - water 65/25/4 , - revelation: UV and iodine - Rf: 0-5 IR spectrum: Vc _ 0 to 1645 cm `N (N 'ethyl pyrrolidino-2' methyl) methoxy-2 (N" N "diethyl-4"
; dimethyl-l "-l" butynyl-2 "amino sulfonyl) -5 benzamide . :. ~ ~. . .....
Soei3 of formula:
OCH3 1l R CH2 ~
H3 / And S2 - NH - I - C _ C - CH2 - N \
CH3 And Gross formula: C25 H40 N4 S 04 Molecular mass: 492.68 White crystals Melting point: 95C
Plate chromatography:
- support: silica gel 60 F 254 Merck - solvent: chloroform - methanol - water 65/25/4 - revelation: UV and iodine - Rf: 0.26 IR spectrum: VC - O at 1640 cm EXPERIMENTATIONS: -The chemical compounds previously described have made subject to toxicological, pharmacological and Clinics to determine application possibilities ; ~ in the therapeutic field.
! ~ A) Toxicology:
Chemical compounds have been subjected to controls 1 20 of toxicity. The acute toxicity of certain compounds determined I by the lateral dose 50 is reported in the following table.
E11e was researched on lots of 10 mice orally and intra-peritoneal calculated according to the Miller method and:
Tainter. .
.,.
, '. '' "
.. ~,. . ~:.
58 ~ 3 ComposesDL 50 ipDL 50 oral F 1603>500> 1000 ..
F 1744 400> 1000 _ ; 10 F 1735>500> 1000 F 1737>500> 1000 F 1738 400> 1000 . .
Sulpiride 320 800 _ _ Metoclopramide 150,600 ~ ' Derivatives with a sulfonated polyamid are very slightly toxic and the oral LD 50 are higher less than 1 g / kg (examples 19, 189 17, 16 and 20).
B ~ Pharmacodynamics:
It has been demonstrated an antiemetic property by apomorphine antagonism according to Burkman - Arch. Int.
Pharmacodyn. 1962, 137, 396.
. . .
~: ' ; - 22 -35 ~ S3 As an example, some results are reported in the table below:
Composes Doses in ~ g / kg% inhibition by .
I.
_., , The activity varies according to the nature of the amide.
Certain compounds have activity on this equal or superior test.
lower than that of sulpiride or metoclopramide. The effects visceral have also been studied ~ more specifically ~ -activity on intestinal transit according to Janssen - J. Pharm.
pharmacol. 1957, 9, 381.
. ~. .... ...
`` 20 Compounds F 1603, F 1744, F 1737, F 1735, as well as . .
~ The products of Examples 4, 5, 19, 20 show an acceleration-. .
intestinal transit ration compared to witnesses.
These derivatives reduce the number of ulcers in rats ,.
after ligation of the pylorus, which can be related to the effects on the central nervous system.
~ `C) Therapeutic applications:
Clinical trials have been carried out for some ,,, : -. . .
3SC ~ S3 `-compounds object of the invention, more particularly F 1603, F 1744, F 1735 and the compounds of Examples 4, 5, 18, 19. They have been applied in the treatment of digestive disorders psychosomatic in anxious or overworked subjects, vomiting and digestive discomfort in pregnant women and drug intolerances. These compounds can also be used in everyday psychopathology.
Pharmaceutical preparations containing these principles active cipes can be administered orally or parentally terale. For oral administration, it is possible to use tablets or capsules. These compositions pharmaceuticals may also contain other principles therapeutically acceptable active ingredients.
As examples, we cite some preparations pharmaceuticals containing active ingredients covered by the note:
1) Capsules:
_ _ F 1603 ...................... 50 mg 2) Comerimes:
_ _ F 1744 ...................... 10 mg Microcrystalline cellulose Mg stearate 3) InJectable solution:
F 1735 ...................... S0 mg per 2 ml vial.
-. :. -. .-:. . ,. ~. . .:
... . .-:. :.,:,. ~. . .:
Claims (23)
I
dans laquelle:
R est un des groupes amino choisi parmi ceux ayant la formule:
, , ou A est un alcoylidène en chaîne droite ou ramifiée;
n est 2, 3 ou 4;
alcoyle est un alcoyle de 1 à 4 atomes de carbone;
X qui se trouve en position 2, 3 ou 4 est hydrogène, un halogène, ou un alcoxy inférieur de 1 à 4 atomes de carbone;
R1 et R2 sont des hydrogènes ou des alcoyles infé-rieurs de 1 à 4 atomes de carbone; ou le groupe -CR1R2 peut former un cycle saturé ayant de 3 à 6 atomes de carbone;
R3 est hydrogène ou un alcoyle amino de la formule:
dans laquelle R4 et R5 sont des groupes alcoyles de 1 à 4 atomes de carbone; ou le groupe -NR4R5 peut former un hétérocycle choisi parmi ceux ayant la formule:
, et et de leurs sels d'addition avec des acides minéraux ou organi-ques compatibles, caractérisé en ce que l'on condense une amine de la formule RNH2 avec un dérivé de la formule II:
II
dans laquelle X, R1, R2 et R3 sont comme définis antérieurement et Z représente les groupes -O? - O - alcoyle, - O - alcoyle, halogène ou - OH, et si on le désire, on traite les dérivés ainsi obtenus avec des acides minéraux ou organiques compati-bles pour donner les sels d'addition acides correspondants. 1. Process for the preparation of sulfamido derivatives methoxy benzamide acetylenics of the general formula (I):
I
in which:
R is one of the amino groups chosen from those having the formula:
, , or A is a straight or branched chain alkyl;
n is 2, 3 or 4;
alkyl is an alkyl of 1 to 4 carbon atoms;
X which is in position 2, 3 or 4 is hydrogen, halogen, or lower alkoxy from 1 to 4 carbon atoms;
R1 and R2 are hydrogens or lower alkyls laughers of 1 to 4 carbon atoms; or the group -CR1R2 can form a saturated cycle having from 3 to 6 carbon atoms;
R3 is hydrogen or an amino alkyl of the formula:
in which R4 and R5 are alkyl groups from 1 to 4 carbon atoms; or the group -NR4R5 can form a chosen heterocycle among those with the formula:
, and and their addition salts with mineral or organic acids compatible characterized in that an amine of the formula is condensed RNH2 with a derivative of formula II:
II
in which X, R1, R2 and R3 are as defined previously and Z represents the groups -O? - O - alkyl, - O - alkyl, halogen or - OH, and if desired, process the derivatives thus obtained with compatible mineral or organic acids to give the corresponding acid addition salts.
avec une amine de la formule IV:
IV
dans lesquelles X, R1, R2 et R3 sont comme définis dans la revendication 1. 2. Method according to claim 1, in which the starting compound of formula II is obtained by the reaction of an acid of formula III:
with an amine of formula IV:
IV
in which X, R1, R2 and R3 are as defined in the claim 1.
propynyl-2" amino sulfonyl)-5 benzamide. 9. The method of claim 1 wherein one reacts N (dimethyl-1'-1 'propyn-2 yl) carboxy-3 methoxy-4 benzene sulfonamide with N (2-amino-ethyl) pyrrolidine for obtain N (2-pyrrolidino ethyl) 2-methoxy (1-dimethyl "-1") 2-propynyl "amino sulfonyl) -5 benzamide.
I
dans laquelle:
R est un des groupes amino choisi parmi ceux ayant la formule:
, , ou A est un alcoylidène en chaîne droite ou ramifiée, n est 2, 3 ou 4;
alcoyle est un alcoyle de 1 à 4 atomes de carbone;
X qui se trouve en position 2, 3 ou 4 est hydrogène, un halogène, ou un alcoxy inférieur de 1 à 4 atomes de carbone;
R1 et R2 sont des hydrogènes ou des alcoyles infé-rieurs de 1 à 4 atomes ce carbone; ou le groupe -CR1R2 peut former un cycle saturé ayant de 3 à 6 atomes de carbone;
R3 est hydrogène ou un alcoyle amino de la formule:
dans laquelle R4 et R5 sont des groupes alcoyles de 1 à 4 atomes de carbone; ou le groupe -NR4R5 peut former un hétérocycle choisi parmi ceux ayant la formule:
, et et de leurs sels d'addition avec des acides minéraux ou organi-ques compatibles, lorsque préparés par le procédé de la reven-dication 1 ou par un procédé chimique équivalent. 13. Acetylenic sulfamido derivatives of methoxy benzamides of the general formula (I):
I
in which:
R is one of the amino groups chosen from those having the formula:
, , or A is a straight or branched chain alkylidene, n is 2, 3 or 4;
alkyl is an alkyl of 1 to 4 carbon atoms;
X which is in position 2, 3 or 4 is hydrogen, halogen, or lower alkoxy from 1 to 4 carbon atoms;
R1 and R2 are hydrogens or lower alkyls laughers from 1 to 4 atoms this carbon; or the group -CR1R2 can form a saturated cycle having 3 to 6 carbon atoms;
R3 is hydrogen or an amino alkyl of the formula:
in which R4 and R5 are alkyl groups from 1 to 4 carbon atoms; or the group -NR4R5 can form a chosen heterocycle among those with the formula:
, and and their addition salts with mineral or organic acids compatible, when prepared by the resale process dication 1 or by an equivalent chemical process.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR77.15205 | 1977-05-16 | ||
| FR7715205A FR2391195A1 (en) | 1977-05-16 | 1977-05-16 | BENZAMIDE ACETYLENIC SULFAMIDO FOR THERAPEUTIC USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105053A true CA1105053A (en) | 1981-07-14 |
Family
ID=9190977
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA303,521A Expired CA1105053A (en) | 1977-05-16 | 1978-05-16 | No translation available |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS53144542A (en) |
| BE (1) | BE867097A (en) |
| CA (1) | CA1105053A (en) |
| CH (1) | CH620674A5 (en) |
| DE (1) | DE2818323A1 (en) |
| ES (2) | ES469708A1 (en) |
| FR (1) | FR2391195A1 (en) |
| GB (1) | GB1591770A (en) |
| IT (1) | IT1159672B (en) |
| NL (1) | NL7805235A (en) |
-
1977
- 1977-05-16 FR FR7715205A patent/FR2391195A1/en active Granted
-
1978
- 1978-04-26 DE DE19782818323 patent/DE2818323A1/en not_active Withdrawn
- 1978-05-11 ES ES469708A patent/ES469708A1/en not_active Expired
- 1978-05-12 CH CH524478A patent/CH620674A5/en not_active IP Right Cessation
- 1978-05-15 IT IT68111/78A patent/IT1159672B/en active
- 1978-05-16 JP JP5812578A patent/JPS53144542A/en active Pending
- 1978-05-16 NL NL7805235A patent/NL7805235A/en not_active Application Discontinuation
- 1978-05-16 BE BE187713A patent/BE867097A/en unknown
- 1978-05-16 GB GB19809/78A patent/GB1591770A/en not_active Expired
- 1978-05-16 CA CA303,521A patent/CA1105053A/en not_active Expired
-
1979
- 1979-02-16 ES ES477786A patent/ES477786A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2391195A1 (en) | 1978-12-15 |
| IT1159672B (en) | 1987-03-04 |
| BE867097A (en) | 1978-09-18 |
| NL7805235A (en) | 1978-11-20 |
| JPS53144542A (en) | 1978-12-15 |
| GB1591770A (en) | 1981-06-24 |
| DE2818323A1 (en) | 1978-11-30 |
| IT7868111A0 (en) | 1978-05-15 |
| CH620674A5 (en) | 1980-12-15 |
| FR2391195B1 (en) | 1982-09-17 |
| ES477786A1 (en) | 1979-10-16 |
| ES469708A1 (en) | 1979-09-16 |
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