CH398562A - Process for the preparation of 1-ketocyclododecyl-2-acetic acid and its salts - Google Patents
Process for the preparation of 1-ketocyclododecyl-2-acetic acid and its saltsInfo
- Publication number
- CH398562A CH398562A CH360761A CH360761A CH398562A CH 398562 A CH398562 A CH 398562A CH 360761 A CH360761 A CH 360761A CH 360761 A CH360761 A CH 360761A CH 398562 A CH398562 A CH 398562A
- Authority
- CH
- Switzerland
- Prior art keywords
- ketocyclododecyl
- acetic acid
- carried out
- salt
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 150000003839 salts Chemical class 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 5
- SXVPOSFURRDKBO-UHFFFAOYSA-N Cyclododecanone Chemical compound O=C1CCCCCCCCCCC1 SXVPOSFURRDKBO-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- 150000001447 alkali salts Chemical class 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical group C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- 238000005956 quaternization reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims 2
- 125000002147 dimethylamino group Chemical class [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 230000001989 choleretic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- -1 sodium cyanide Chemical compound 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000035603 choleresis Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- KPJPHPFMCOKUMW-UHFFFAOYSA-N iodomethane Chemical compound I[CH2] KPJPHPFMCOKUMW-UHFFFAOYSA-N 0.000 description 1
- ADDQUOLYROTOKS-UHFFFAOYSA-N iodomethanol Chemical class OCI ADDQUOLYROTOKS-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000021962 pH elevation Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/18—Saturated compounds containing keto groups
- C07C62/24—Saturated compounds containing keto groups the keto group being part of a ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Procédé de préparation de l'acide 1-cétocyclododécyl-2-acétique et de ses sels
L'invention vise la préparation de composés nou veaux: l'acide 1 'acide l-cétocyclododécyl-2-acétique répon- dant à la formule:
EMI1.1
ainsi que ses sels thérapeutiquement administrables.
I1 a en effet été découvert selon l'invention que ces composés présentent une activité cholérétique marquée s'exerçant de manière durable, sont bien tolérés par l'organisme et ont une faible toxicité.
C'est ainsi que la dose léthale 50 o/o (DL 50) du sel de sodium de l'acide (I) chez le rat est comprise entre les limites suivantes pour les trois voies d'administration
voie orale: entre 0,625 et 1,250g/kg
voie sous-cutanée: entre 0, 625 et 1,250g/kg
voie intraveineuse: entre 0,156 et 0,312g/kg
Grâce à ces diverses propriétés, les composés précités sont des agents thérapeutiques intéressants pour activer la cholérèse, leur action étant en général plus durable que celle des cholérétiques connus.
Dans ce but, ils peuvent être administrés sous diverses formes, parmi lesquelles on peut citer les suivantes - Comprimés de 0,50 g dosés à 0,25 ou 0,35 g de
principe actif, le reste étant constitué par les
excipients usuels: 1 à 4 de ces comprimés peu
vent être administrés par jour; - ampoules injectables de 1 cm3 contenant 0,80 g
à 1,20 g de principe actif en solution dans l'eau
ou autre véhicule liquide injectable ; 1 à 2 de ces
ampoules peuvent être administrées par jour par
voie intraveineuse.
L'invention a ainsi pour objet un procédé de préparation de l'acide l-cétocyclododécyl-2-acétique et de ses sels. Ce procédé est caractérisé en ce qu'il comporte la suite des réactions suivantes: conversion de la cyclododécanone en 2-diméthylaminométhylcyclododécanone-l par traitement au moyen de diméthylamine et de formaldéhyde, quaternisation de l'amine tertiaire ainsi obtenue, cyanuration du sel d'ammonium quaternaire résultant en 2-cyanométhylcyclododécanone-1 par traitement au moyen d'un agent cyanurant, hydrolyse du nitrile ainsi obtenu par une base alcaline avec obtention d'un sel alcalin de l'acide l-cétocyclododécyl-2-acétique, à partir duquel on libère l'acide, qui peut être ensuite salifié par toute base désirée.
La suite de ces réactions est illustrée par la figure unique du dessin annexé, dans une forme d'exécution particulière du procédé.
Le premier stade du procédé ou stade (a) est réalisé en chauffant à reflux au sein d'un solvant, tel que l'alcool, la cyclododécanone (Il) avec un sel de diméthylamine (en particulier le chlorhydrate) et du formaldéhyde sous forme de trioxyméthylène.
On obtient ainsi, après alcalinisation, la 2-diméthylaminométhylcyclododécanone-l (III) qui est quaternisée dans le stade (b). Cette quaternisation est opérée avantageusement à l'aide d'iodure de méthyle et aboutit à l'iodométhylate (in).
Cet iodométhylate est traité à chaud dans un solvant par un cyanure alcalin, tel le cyanure de sodium, dans le stade (c). ll est ainsi converti en 2-cyanométhylcyclododécanone-1 (V).
Ce nitrile (V) est hydrolysé dans le stade (d) par chauffage avec une base alcaline en solution aqueuse, telle la potasse, ce qui donne le sel alcalin correspondant (VI) de l'acide 1 -cétocyclododécyl-2-acéti- que.
I1 suffit alors de libérer-cet acide (I) dans le stade (e) par action d'un acide minéral, lorsqu'on désire obtenir l'acide (I) sous forme libre ou sous forme d'un autre sel que le sel alcalin (VI).
Les composés intermédiaires III, IV et V sont des composés nouveaux.
Exemple a) 2 -diméthylaminométhylcyclodoçiécanone-1 (III)
18,2 g de cyclododécanone, 9 g de chlorhydrate de diméthylamine, 2,5 g de trioxyméthylène et 50 cm3 d'alcool absolu, sont chauffés à reflux pendant une heure. On rajoute alors 2 g de trioxyméthylène, puis 10 gouttes d'acide chlorhydrique concentré. Le trioxyméthylène passe en solution. On chauffe encore une heure à reflux puis place en glacière. Les cristaux de chlorhydrate de la base sont séparés, dissous dans 120 cm3 d'eau et additionnés de carbonate de potassium solide jusqu'à alcalinité. La base est séparée et séchée sous vide.
Poids: 14,5 g; F: 580C. b) lodométhylate de 2-diméthylaminométhylcyclo-
dodécanone-l (IV)
22 g de 2-diméthylaminométhylcyclododécanone1 sont dissous dans 50cm3 d'acétate d'éthyle. On ajoute 21 g d'iodure de méthyle et chauffe au bainmarie. n y a prise en masse. On essore et cristallise dans le méthanol.
Poids: 33g; F: 2520C (tube). c) 2-cyanométhylcyclododécanone-1 (V)
170 cm8 d'eau, 170 cm3 d'alcool à 95O, 17 g de cyanure de sodium et 41 g d'iodométhylate de 2-di méthylaminométhylcyclododécanone-1 sont chauffés à 700 sous agitation pendant une heure et demie.
Tout se dissout et par refroidissement, le nitrile cristallise.
Poids: 21g; F: 880C. d) I-cétocyclododécyl-2-acétate de potassium (VI)
18 g de 2-cyanométhylcyclododécanone-1, 25 g de potasse et 100 g d'eau sont chauffés 6 heures à reflux sous agitation. Le sel de potassium de l'acide se sépare peu à peu. e) Acide l-cétocyclododécyl-2-acétique (I)
Après refroidissement, le sel (VI) est recueilli, dissous dans l'eau et l'acide est libéré par addition d'acide chlorhydrique dilué. Il est ensuite cristallisé dans le benzène.
Poids: 10 g ; F: 1290 C.
Process for the preparation of 1-ketocyclododecyl-2-acetic acid and its salts
The invention relates to the preparation of new compounds: 1-ketocyclododecyl-2-acetic acid corresponding to the formula:
EMI1.1
as well as its therapeutically administrable salts.
It has in fact been discovered according to the invention that these compounds exhibit a marked choleretic activity which is exerted in a lasting manner, are well tolerated by the organism and have low toxicity.
Thus, the lethal 50 o / o (LD 50) dose of the sodium salt of acid (I) in rats is between the following limits for the three routes of administration
oral route: between 0.625 and 1.250g / kg
subcutaneous route: between 0.625 and 1.250g / kg
intravenous route: between 0.156 and 0.312g / kg
Thanks to these various properties, the abovementioned compounds are useful therapeutic agents for activating choleresis, their action being generally more durable than that of known choleretics.
For this purpose, they can be administered in various forms, among which may be mentioned the following - Tablets of 0.50 g dosed at 0.25 or 0.35 g of
active principle, the remainder being constituted by
usual excipients: 1 to 4 of these tablets
can be administered daily; - injectable ampoules of 1 cm3 containing 0.80 g
to 1.20 g of active ingredient in solution in water
or other injectable liquid vehicle; 1 to 2 of these
ampoules can be administered daily by
intravenous route.
The subject of the invention is thus a process for the preparation of 1-ketocyclododecyl-2-acetic acid and its salts. This process is characterized in that it comprises the sequence of the following reactions: conversion of cyclododecanone to 2-dimethylaminomethylcyclododecanone-1 by treatment with dimethylamine and formaldehyde, quaternization of the tertiary amine thus obtained, cyanidation of the salt of quaternary ammonium resulting in 2-cyanomethylcyclododecanone-1 by treatment with a cyanating agent, hydrolysis of the nitrile thus obtained with an alkaline base with obtaining an alkali salt of l-ketocyclododecyl-2-acetic acid, from which the acid is released, which can then be salified with any desired base.
The sequence of these reactions is illustrated by the single figure of the appended drawing, in a particular embodiment of the process.
The first stage of the process or stage (a) is carried out by heating under reflux in a solvent, such as alcohol, cyclododecanone (II) with a salt of dimethylamine (in particular the hydrochloride) and formaldehyde in the form of trioxymethylene.
In this way, after alkalinization, 2-dimethylaminomethylcyclododecanone-1 (III) is obtained which is quaternized in stage (b). This quaternization is advantageously carried out using methyl iodide and results in iodomethylate (in).
This iodomethoxide is treated hot in a solvent with an alkali cyanide, such as sodium cyanide, in stage (c). It is thus converted to 2-cyanomethylcyclododecanone-1 (V).
This nitrile (V) is hydrolyzed in step (d) by heating with an alkaline base in aqueous solution, such as potassium hydroxide, which gives the corresponding alkali salt (VI) of 1-ketocyclododecyl-2-acetic acid. .
It is then sufficient to release this acid (I) in stage (e) by the action of a mineral acid, when it is desired to obtain the acid (I) in free form or in the form of a salt other than the salt. alkaline (VI).
Intermediate compounds III, IV and V are new compounds.
Example a) 2 -dimethylaminomethylcyclodoçiecanone-1 (III)
18.2 g of cyclododecanone, 9 g of dimethylamine hydrochloride, 2.5 g of trioxymethylene and 50 cm3 of absolute alcohol are heated at reflux for one hour. Then 2 g of trioxymethylene are added, then 10 drops of concentrated hydrochloric acid. The trioxymethylene goes into solution. Heat for another hour at reflux then place in a cooler. The hydrochloride crystals of the base are separated, dissolved in 120 cm3 of water and added with solid potassium carbonate until alkalinity. The base is separated and dried under vacuum.
Weight: 14.5 g; F: 580C. b) 2-dimethylaminomethylcyclo- lodomethoxide
dodecanone-l (IV)
22 g of 2-dimethylaminomethylcyclododecanone1 are dissolved in 50cm3 of ethyl acetate. 21 g of methyl iodide are added and heated in a water bath. There is solidification. It is filtered off and crystallized from methanol.
Weight: 33g; F: 2520C (tube). c) 2-cyanomethylcyclododecanone-1 (V)
170 cm8 of water, 170 cm3 of 95O alcohol, 17 g of sodium cyanide and 41 g of 2-di-methylaminomethylcyclododecanone-1 iodomethoxide are heated at 700 with stirring for one and a half hours.
Everything dissolves and on cooling the nitrile crystallizes.
Weight: 21g; F: 880C. d) Potassium I-ketocyclododecyl-2-acetate (VI)
18 g of 2-cyanomethylcyclododecanone-1, 25 g of potassium hydroxide and 100 g of water are heated for 6 hours at reflux with stirring. The potassium salt of the acid gradually separates out. e) 1-Ketocyclododecyl-2-acetic acid (I)
After cooling, the salt (VI) is collected, dissolved in water and the acid is released by addition of dilute hydrochloric acid. It is then crystallized from benzene.
Weight: 10 g; F: 1290 C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR823192A FR1466205A (en) | 1960-04-01 | 1960-04-01 | 1-Ketocyclododecyl-2-acetic acid, its salts and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH398562A true CH398562A (en) | 1966-03-15 |
Family
ID=8728479
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH360761A CH398562A (en) | 1960-04-01 | 1961-03-27 | Process for the preparation of 1-ketocyclododecyl-2-acetic acid and its salts |
Country Status (4)
| Country | Link |
|---|---|
| BE (1) | BE601671A (en) |
| CH (1) | CH398562A (en) |
| ES (1) | ES266158A1 (en) |
| FR (2) | FR1466205A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3040994A1 (en) * | 1980-10-31 | 1982-06-09 | Henkel KGaA, 4000 Düsseldorf | METHOD FOR PRODUCING 13-OXABICYCLO 10.3.0 -PENTADECAN |
| HUP0500844A2 (en) * | 2002-12-09 | 2007-08-28 | Univ Texas | Methods for selectively inhibiting janus tyrosine kinase 3(jak3) |
-
1960
- 1960-04-01 FR FR823192A patent/FR1466205A/en not_active Expired
- 1960-08-02 FR FR834804A patent/FR100M/en active Active
-
1961
- 1961-03-22 BE BE601671A patent/BE601671A/en unknown
- 1961-03-27 CH CH360761A patent/CH398562A/en unknown
- 1961-03-29 ES ES0266158A patent/ES266158A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES266158A1 (en) | 1961-09-01 |
| FR100M (en) | 1961-01-09 |
| BE601671A (en) | 1961-07-17 |
| FR1466205A (en) | 1967-01-20 |
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