BE601394A - - Google Patents
Info
- Publication number
- BE601394A BE601394A BE601394DA BE601394A BE 601394 A BE601394 A BE 601394A BE 601394D A BE601394D A BE 601394DA BE 601394 A BE601394 A BE 601394A
- Authority
- BE
- Belgium
- Prior art keywords
- sep
- piperazine derivatives
- preparation
- chlorophenyl
- cough
- Prior art date
Links
- 238000000034 method Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 150000004885 piperazines Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims 3
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 206010011224 Cough Diseases 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229960004415 codeine phosphate Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- -1 2,3-dihydroxypropyl Chemical group 0.000 description 1
- 241001633942 Dais Species 0.000 description 1
- 241001181114 Neta Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 210000003801 laryngeal nerve Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
<Desc/Clms Page number 1>
EMI1.1
?:!s¯Ltveaux de 1-: p.ipr=zine
Le brevet 569.407 concerne des dérives de la piperazine parmi lesquels une substance de formule
EMI1.2
Ce produit possède une activité antitoux considérable
EMI1.3
et uns trs faible toxicité. Toutefois, il présente l'inconve- nient de ne pas pouvoir être conditionné sous toutes les forces pharmaceutiques scuhaitables.
La présente invention se rapporte à de nouveaux
EMI1.4
dérives de 1:, piprazine répondant à 1. --on.ule générale
EMI1.5
EMI1.6
'la:-..3 Le.zaélle R représente un atcWe 2- 1 ::y:.rogène ou un atone i's>1:1.lr:e se :rouv3nt en pcsition crthj, neta Du para.
<Desc/Clms Page number 2>
EMI2.1
Elle se rapporte J,a==...<;:: à la préparation 1e ces drives ainsi que ie le3 : d'acides minéraux en organiques.
Selcn :. 1 ir:ve!lticr¯: en prépare les composés de l-' !"'H:J.10 (I) en :ais3:-:.t réagir une '::'-:.2.-';.:?:../::')-ril,'?razine avec le 1,2i Oxß l : .rxj-¯7r0= .:e , R à=:#:-.= 1::: . ::e 3i?;i.:'ication qU"2 p2.s ;-..; J. -:; .
Les dérives de î'¯:=-,r=.tor foss9den une activité aatitoux considérable, ils scn' tr3 peu toxiques et présentent l' ,sa:tae due ne pas provoquer toxicomanie.
Dans le tableau I, on compare l'activité antitoux des produits préparas dans les exemples 1 et 2 à celle d'un produit de référence, er. l'occurrence le phosphate de codéine, désigné par produit A. La réduction ie l'amplitude de la toux a été déterminée suivant la aéthode de ¯?. Cu.¯sJvZ (nrcr.exp.:ath.u.
Pnaroeakoàyn.215,(1952),19-2±). i=elon re ité méthode, on observe le réflexe de la toux chez '1.."l cliat endorcd. au Nusial et dont le nerf laryngé supérieur est s2is à une excitation électrique.
1..-..=-3ri.U
EMI2.2
<tb>
<tb> Produits <SEP> Dose <SEP> Réduction <SEP> de
<tb> (per <SEP> os <SEP> en <SEP> mg/kg) <SEP> l'aplitude <SEP> de <SEP> la <SEP> toux
<tb> Exemple <SEP> 1 <SEP> 6 <SEP> 48%
<tb> Exemple <SEP> 2 <SEP> 6 <SEP> 33%
<tb> 6 <SEP> 38%
<tb>
EMI2.3
Dans le tableau II. cr- compare la toxicité du proinit préparé dans l'exemple 1 à celle du phosphate de codéine, administrés chez le rat, par 7G= cuccal e (v .. ) ou intraveineuse (V.I.). Les chiffres indi1et la toxicité D.L.50, autr-seni dit le nombre Óe iillijrai.:-es administres par kilograi#e d' animal ui tuent 507 des animaux sc=is aux 8?sais.
?ÀlEa5 II
EMI2.4
<tb>
<tb> Produits <SEP> Toxicité
<tb>
EMI2.5
"Í . -z . 1J . 1.
Exemule 1 75= 20J
EMI2.6
<tb>
<tb> A <SEP> 85 <SEP> 54
<tb>
<Desc/Clms Page number 3>
EMI3.1
Lè3 hv;"' :.5 3ivants illustrent l'invention, ils ne
EMI3.2
la limitent en aucune façon.
EMI3.3
Exemple 1. Fr :û: ru tior de la 1-phn;rl-4-(2,3-dih,yàrox;ywrop,rl)- 1ÜD2razir:e. une solution de 64)u g de 1-pineniJlpipôrazin1e dans 00 c3 d'0tlLi':0:", on ajoute une solution de 34 g de 1,2-4};::oxy- 3-hy.roxy-propane dans 50 c3 d'eau, en tsaintenani la température en dessous de 502'-. On laisse reposer la solution pendant une nuit, on l'évapore à sec sous vide et on cristallise le residu sirupeux dais.-10C, ca3 d'acétone.
On obtient 60 g de 1-ph4nyl-4-(2,3-àihy-lroxypropyi)pip?r3zine fondant à 1C5 C et bouillant à 2059C/1 ma Hg.
Le onochlorhydrate correspondant préparé en milieu alcoolique a ur. point de fusion de 142QC.
Exemple 2. Préparation de la 1-p-chloronhényl-4-(Z,3-dih,yârox -
EMI3.4
propyl)-pipérazine.
EMI3.5
On opsre comme dans l'exemple 1, m:::is en utilisant la 1-p--ihlorqJh4nj,lpipérazine au lieu de la I-phénylpip'3L zine .
EMI3.6
On obtient la 1-p-chlorophényl-4-(2,3-dihydroxypropyl)-
EMI3.7
pipsrazine qui, cristallisée dans l'isopropanol, fond à 142±C.
Exemple 3 . Préparation de la 1-o-cnlorophén,yl-4-( Z , 3-:îih,ydrox,yprop.vl) -r;:i.p.jrazine .
On opère comme dans l'exemple 1, 3is en utilisant la 1-o-chlorophé :3>lpipérazine au lieu de la 1-phénylpipérazine.
On obtient la 1-c-chlorophényl-4-(2,3-dihydrcxypropyl)pipérazine qui bout à lîC/0,02 me: Hg.
<Desc / Clms Page number 1>
EMI1.1
?:! s¯ Levels of 1-: p.ipr = zine
Patent 569,407 relates to derivatives of piperazine, including a substance of formula
EMI1.2
This product has considerable anti-cough activity
EMI1.3
and a few very low toxicity. However, it has the disadvantage of not being able to be packaged under all the scuhaitable pharmaceutical forces.
The present invention relates to new
EMI1.4
drifts of 1 :, piprazine responding to 1. --on.ule general
EMI1.5
EMI1.6
'la: - .. 3 Le.zaélle R represents an atcWe 2- 1 :: y: .rogen or an atone i's> 1: 1.lr: e se: rouv3nt en pcsition crthj, neta Du para.
<Desc / Clms Page number 2>
EMI2.1
It relates J, a == ... <; :: to the preparation of these drives as well as the 3: of mineral acids in organic.
Selcn:. 1 ir: ve! Lticr¯: by preparing the compounds of l- '! "' H: J.10 (I) in: ais3: - :. t react a '::' - :. 2.- ';. :?: ../ :: ') - ril,'? razine with 1,2i Oxß l: .rxj-¯7r0 =.: e, R at =: #: -. = 1 :::. :: e 3i?; i.: 'ication qU "2 p2.s; - ..; J. - :; .
The drifts of î'¯: = -, r = .tor foss9den a considerable aatitoux activity, they scn 'very little toxic and present the, its: tae due not to cause drug addiction.
In Table I, the anti-cough activity of the products prepared in Examples 1 and 2 is compared with that of a reference product, er. the occurrence codeine phosphate, designated by product A. The reduction ie the amplitude of the cough was determined according to the method of ¯ ?. Cu.¯sJvZ (nrcr.exp.:ath.u.
Pnaroeakoàyn. 215, (1952), 19-2 ±). According to the method, the cough reflex is observed in '1 .. "the endorced cliat at the Nusial and whose superior laryngeal nerve is subjected to electrical excitation.
1 ..- .. = - 3ri.U
EMI2.2
<tb>
<tb> Products <SEP> Dose <SEP> Reduction <SEP> of
<tb> (per <SEP> os <SEP> in <SEP> mg / kg) <SEP> the amplitude <SEP> of <SEP> the <SEP> cough
<tb> Example <SEP> 1 <SEP> 6 <SEP> 48%
<tb> Example <SEP> 2 <SEP> 6 <SEP> 33%
<tb> 6 <SEP> 38%
<tb>
EMI2.3
In Table II. cr- compares the toxicity of the proinit prepared in Example 1 to that of codeine phosphate, administered in rats, by 7G = cuccal e (v ..) or intravenously (V.I.). The figures indi1et the toxicity D.L.50, other says the number Óe iillijrai.:- administered per kilogram of animal that kill 507 of the animals sc = is to 8 know.
? ATlEa5 II
EMI2.4
<tb>
<tb> Products <SEP> Toxicity
<tb>
EMI2.5
"Í. -Z. 1J. 1.
Example 1 75 = 20J
EMI2.6
<tb>
<tb> A <SEP> 85 <SEP> 54
<tb>
<Desc / Clms Page number 3>
EMI3.1
Lè3 hv; "': .5 3ivants illustrate the invention, they do not
EMI3.2
limit it in any way.
EMI3.3
Example 1. Fr: û: ru tior of 1-phn; rl-4- (2,3-dih, yàrox; ywrop, rl) - 1ÜD2razir: e. a solution of 64) µg of 1-pineniJlpipôrazin1e in 00 c3 of 0tlLi ': 0: ", a solution of 34 g of 1,2-4}; :: oxy-3-hy.roxy-propane in 50 c3 of water, with the temperature below 502 ° C. The solution is left to stand overnight, it is evaporated to dryness in vacuo and the syrupy residue is crystallized in dais.-10 ° C., ca3 of acetone.
60 g of 1-ph4nyl-4- (2,3-aihy-lroxypropyi) pipr3zine are obtained, melting at 1C5 C and boiling at 2059C / 1 ma Hg.
The corresponding onochlorhydrate prepared in an alcoholic medium has ur. melting point of 142QC.
Example 2. Preparation of 1-p-chloronhenyl-4- (Z, 3-dih, yârox -
EMI3.4
propyl) -piperazine.
EMI3.5
The procedure is as in Example 1, m ::: is using 1-p - ihlorqJh4nj, lpiperazine instead of I-phenylpip'3L zine.
EMI3.6
We obtain 1-p-chlorophenyl-4- (2,3-dihydroxypropyl) -
EMI3.7
pipsrazine which, crystallized from isopropanol, melts at 142 ± C.
Example 3. Preparation of 1-o-chlorophen, yl-4- (Z, 3-: ilh, ydrox, yprop.vl) -r;: i.p.jrazine.
The procedure is as in Example 1, 3is using 1-o-chlorophy: 3> lpiperazine instead of 1-phenylpiperazine.
1-c-chlorophenyl-4- (2,3-dihydrcxypropyl) piperazine is obtained which boils at 1 C / 0.02 me: Hg.
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BE601394A true BE601394A (en) |
Family
ID=192580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BE601394D BE601394A (en) |
Country Status (1)
| Country | Link |
|---|---|
| BE (1) | BE601394A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4699911A (en) * | 1983-12-29 | 1987-10-13 | Dompe' Farmaceutici S.P.A. | Levo and dextro dropropizine having antitussive activity |
| EP0349066A1 (en) * | 1988-06-25 | 1990-01-03 | Dsm N.V. | Preparation of enantiomers of dropropizine |
| EP0409044A3 (en) * | 1989-07-20 | 1991-05-29 | Dompe' Farmaceutici S.P.A. | A process for the optical resolution of dropropizine |
-
0
- BE BE601394D patent/BE601394A/fr unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4699911A (en) * | 1983-12-29 | 1987-10-13 | Dompe' Farmaceutici S.P.A. | Levo and dextro dropropizine having antitussive activity |
| EP0349066A1 (en) * | 1988-06-25 | 1990-01-03 | Dsm N.V. | Preparation of enantiomers of dropropizine |
| EP0409044A3 (en) * | 1989-07-20 | 1991-05-29 | Dompe' Farmaceutici S.P.A. | A process for the optical resolution of dropropizine |
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