CH651043A5 - 3(4-fenil-1-piperazinio-1-il)-1,2-propandiolo 3(teofillin-7-il)-1-propansolfonato e relativo procedimento di fabbricazione e farmaco comprendente questo composto. - Google Patents
3(4-fenil-1-piperazinio-1-il)-1,2-propandiolo 3(teofillin-7-il)-1-propansolfonato e relativo procedimento di fabbricazione e farmaco comprendente questo composto. Download PDFInfo
- Publication number
- CH651043A5 CH651043A5 CH1167/82A CH116782A CH651043A5 CH 651043 A5 CH651043 A5 CH 651043A5 CH 1167/82 A CH1167/82 A CH 1167/82A CH 116782 A CH116782 A CH 116782A CH 651043 A5 CH651043 A5 CH 651043A5
- Authority
- CH
- Switzerland
- Prior art keywords
- compound
- propanediol
- phenyl
- phenylpiperazin
- piperazinium
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims 13
- 229940079593 drug Drugs 0.000 title claims 5
- 239000003814 drug Substances 0.000 title claims 5
- 238000004519 manufacturing process Methods 0.000 title claims 2
- 229960004063 propylene glycol Drugs 0.000 claims 14
- 230000000954 anitussive effect Effects 0.000 claims 7
- 239000002904 solvent Substances 0.000 claims 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 4
- 230000000694 effects Effects 0.000 claims 4
- 238000000034 method Methods 0.000 claims 4
- 230000001988 toxicity Effects 0.000 claims 4
- 231100000419 toxicity Toxicity 0.000 claims 4
- 239000000443 aerosol Substances 0.000 claims 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- 239000002244 precipitate Substances 0.000 claims 3
- 239000007864 aqueous solution Substances 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 230000037396 body weight Effects 0.000 claims 2
- 239000002775 capsule Substances 0.000 claims 2
- 210000000748 cardiovascular system Anatomy 0.000 claims 2
- 239000006196 drop Substances 0.000 claims 2
- 230000008030 elimination Effects 0.000 claims 2
- 238000003379 elimination reaction Methods 0.000 claims 2
- 235000019441 ethanol Nutrition 0.000 claims 2
- 230000000144 pharmacologic effect Effects 0.000 claims 2
- 238000001953 recrystallisation Methods 0.000 claims 2
- 239000000829 suppository Substances 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 claims 2
- 239000003826 tablet Substances 0.000 claims 2
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- 241000700199 Cavia porcellus Species 0.000 claims 1
- 206010022998 Irritability Diseases 0.000 claims 1
- 241000699670 Mus sp. Species 0.000 claims 1
- 241000700159 Rattus Species 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 230000007059 acute toxicity Effects 0.000 claims 1
- 231100000403 acute toxicity Toxicity 0.000 claims 1
- 229940124584 antitussives Drugs 0.000 claims 1
- 238000009835 boiling Methods 0.000 claims 1
- 230000002425 cardiocirculatory effect Effects 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- 230000035487 diastolic blood pressure Effects 0.000 claims 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims 1
- 230000002349 favourable effect Effects 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000007920 subcutaneous administration Methods 0.000 claims 1
- 230000035488 systolic blood pressure Effects 0.000 claims 1
- 231100001274 therapeutic index Toxicity 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
651043
2
Claims (6)
1
ch,
2. Procedimento di sintesi del composto secondo la rivendicazione 1, comportante il trattamento di acido 3(teofil-lin-7-il)-l-propansolfonico con 3(4-fenilpiperazin-l-il)-l,2--propandiolo in. un solvente.
3. Procedimento di sintesi secondo la rivendicazione 2, comprendente la eliminazione almeno parziale del solvente impiegato, la raccolta del precipitato ottenuto, e la eventuale ricristallizzazione da un solvente.
4. Farmaco ad azione antitussiva, comprendente come sostanza attiva il composto di cui alla rivendicazione 1.
5. Farmaco secondo la rivendicazione 4 a dosi comprese fra 10 mg e 500 mg.
6. Farmaco, secondo la rivendicazione 4, presentato in fiale, gocce, compresse, capsule, supposte, aerosol.
Del 3(4-fenilpiperazin-l-il)-l,2-propandiolo è documentata l'azione antitussiva (P.R.B. Noël, ARZN. FORSCH. 19 (8) [1969]; Cartwrigh T.K., Paterson J.L., J. PHARM. PHARMACOL. 23 (Suppl.) 247 S [1971]). Tuttavia il suo uso è limitato, particolarmente nel caso di somministrazione parenterale, a causa della tossicità e degli effetti collaterali che esso provoca sull'apparato cardiocircolatorio.
Il compito della presente invenzione è la messa a disposizione di un composto, che può essere utilizzato in un farmaco ad azione antitussiva che presenta un'attività uguale o superiore, unitamente ad una minor tossicità e minori effetti a carico dell'apparato cardiocircolatorio, di quella presentata dal 3(4-fenilpiperazin-l-il)-l,2-propandiolo.
È oggetto dell'invenzione, il composto 3(4-fenil-l-pipe-razinio-1 -il)-1,2-propandiolo 3 (teofiIlin-7-il)-1 -propansolfo-nato, che corrisponde alla seguente formula di struttura (I):
,©
/qN— / ^A:h,-ch-ch,
\w/ \ /\ 2 I I 2
w\,
I I
oh oh
Ni i
ch
1 z
X)
(I)
Il composto I si presenta sotto forma di una polvere bianca, cristallina con p.f. 160-162°C, molto solubile in acqua (> 20%) e stabile in soluzione acquosa.
L'invenzione si riferisce anche ad un procedimento per la preparazione del composto I, per trattamento dell'acido 3(teofillin-7-il)-l-propansolfonico con 3(4-fenilpiperazin-l--il)-l,2-propandiolo in solvente appropriato. Il procedimento comprende anche la almeno parziale eliminazione del solvente impiegato, la raccolta del precipitato ottenuto e la eventuale ricristallizzazione da un solvente appropriato.
Si riporta, a titolo di esempio, il seguente metodo di preparazione:
A g 23,7 (0,1 moli) di 3(4-fenilpiperazin-l-il)-l,2-propan-diolo in 2500 mi di alcool etilico, si aggiungono sotto agitazione g 30,1 (0,1 moli) di acido 3(teofillin-7-il)-l-propan-solfonico. Si scalda la miscela fino alla ebollizione, si filtra la soluzione a caldo e si lascia freddare. Il precipitato ottenuto, filtrato e cristallizzato ripetutamente da etanolo, pre-s senta un p.f. 160-162°C.
Massimi di assorbimento in soluzione acquosa a 233 nm (e = 21 000) e a 274 nm (e = 28 000).
Il 3(4-fenil-l-piperazinio-l-il)-l,2-propandiolo 3(teofil-lin-7-il)-l-propansolfonato (I) può essere applicato in tera-10 pia umana, essendo questo prodotto dotato di attività antitussiva. È stato dimostrato infatti, in sede farmacologica, che il 3(4-fenil-l-piperazinio-l-il)-l,2-propandiolo 3(teofil-lin-7-il)-l-propansolfonato (I) presenta, a parità di dose, una tossicità nettamente inferiore a quella del 3(4-fenilpipe-'5razin-l-il)-l,2-propandiolo, ed una'attività farmacologica in senso antitussivo uguale o superiore.
La sperimentazione farmaco-tossicologica ha portato alle conclusioni seguenti.
La tossicità acuta per via orale e sottocutanea nel topo 20 maschio e femmina del 3(4-fenil-l-piperazinio-l-il)-l,2-pro-pandiolo 3(teofillin-7-il)-l-propansolfonato (I), in confronto a quelle del 3(4-fenilpiperazin-l-il)-l,2-propandiolo (I) è riportata in tabella I.
25 TABELLA I
DL 50 espresse in g/kg di peso corporeo e limiti fiduciali al 95%
Composto Maschi
OS
Femmine
SOTTOCUTE Maschi Femmine
I
1,43
(1,00-1,87)
1,59
(1,11-2,29)
superiore a 1,5
II
0,67
(0,65-0,69)
0,62
(0,43-0,90)
0,76 0,72 (0,40-1,43) (0,42-1,22)
^ I: 3(4-fenil-l-piperazinio-l-il)-l,2-propandiolo 3(teofillin-7-il)
1-propansolfonato II : 3(4-fenilpiperazin-l-il)-l,2-propandiolo
L'azione antitussiva è stata valutata col test dell'aerosol da acido citrico nella cavia (Iolanpaan-Hekkila J.E. Jalo-« nen, K. Vartiainen, A. Acta Pharmac. 25, 333 [1967]). Per somministrazioni a dosi equiponderali per via orale e per via sottocutanea, l'attività antitussiva del composto I è rispettivamente uguale ed 1,5 volte superiore a quella del composto II.
so Data la sua minor tossicità acuta, il composto I quindi presenta un indice terapeutico molto più favorevole del composto II.
Gli effetti collaterali a carico dell'apparato cardiocircolatorio del composto I, rispetto a quelli del composto II, ss sono stati studiati sul ratto anestetizzato dopo somministrazione per via endovenosa della dose di 2,5 mg/kg di peso corporeo: a 15' dalla somministrazione, il composto II provoca una diminuzione significativa del 20-30% dei valori di pressione sistolica, diastolica e della frequenza cardiaca, 60 mentre il composto I alla stessa dose ed allo stesso tempo non determina variazioni significative rispetto ai controlli.
Il composto conforme all'invenzione viene usato in terapia umana a dosi comprese fra 10 mg e 500 mg e presentato sotto forma di fiale, gocce, compresse, capsule, suppo-65 ste, aerosol.
v
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT8109343A IT1210639B (it) | 1981-02-25 | 1981-02-25 | Prodotto: 3(4-fenil1piperazinio-1-il)-1,2-propandiolo 3(teofillin-7-il)-1propansolfonato,utilizzabile in terapia,e relativo procedimento di fabbricazione |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH651043A5 true CH651043A5 (it) | 1985-08-30 |
Family
ID=11128724
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1167/82A CH651043A5 (it) | 1981-02-25 | 1982-02-25 | 3(4-fenil-1-piperazinio-1-il)-1,2-propandiolo 3(teofillin-7-il)-1-propansolfonato e relativo procedimento di fabbricazione e farmaco comprendente questo composto. |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4372958A (it) |
| JP (1) | JPS57188589A (it) |
| AT (1) | AT380881B (it) |
| BE (1) | BE892271A (it) |
| CA (1) | CA1192549A (it) |
| CH (1) | CH651043A5 (it) |
| DE (1) | DE3205149A1 (it) |
| DK (1) | DK148687C (it) |
| ES (1) | ES509850A0 (it) |
| FR (1) | FR2500455A1 (it) |
| GB (1) | GB2093445B (it) |
| GR (1) | GR76060B (it) |
| IT (1) | IT1210639B (it) |
| LU (1) | LU83962A1 (it) |
| NL (1) | NL8200746A (it) |
| PT (1) | PT74463B (it) |
| SE (1) | SE440503B (it) |
| YU (1) | YU44007B (it) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1203721B (it) * | 1983-12-29 | 1989-02-23 | Dompe Farmaceutici Spa | Composti otticamente attivi ad attivita' antitosse e sedativa centrale,procedimento per la preparazione e composizioni che li contengono |
| IT1217950B (it) * | 1988-06-28 | 1990-03-30 | Dott Formenti Ind Chimica E Fa | Sali di (r,s) 3 (4 fenil 1 piperazinil) 1,2 propandtolo |
| IT1231158B (it) * | 1989-07-20 | 1991-11-19 | Dompe Farmaceutici Spa | Procedimento per la risoluzione ottica della dropropizina. |
| DE3938123A1 (de) * | 1989-11-16 | 1991-05-23 | Diehl Gmbh & Co | Treibladungsanzuender |
| IT1318651B1 (it) * | 2000-07-28 | 2003-08-27 | Dompe Spa | Sintesi di (+-)1,3-diossolani e loro risoluzione ottica. |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3163649A (en) * | 1964-12-29 | Substituteb phenyl-piperazine | ||
| GB938646A (en) * | 1961-03-16 | 1963-10-02 | Henri Morren | New piperazine derivatives |
| FR1384693A (fr) * | 1963-10-08 | 1965-01-08 | Electrochimie Soc | Procédé de préparation d'esters méthallyliques |
| FR1554628A (it) * | 1967-05-23 | 1969-01-24 |
-
1981
- 1981-02-25 IT IT8109343A patent/IT1210639B/it active
- 1981-05-22 GB GB8115803A patent/GB2093445B/en not_active Expired
- 1981-06-10 US US06/272,281 patent/US4372958A/en not_active Expired - Fee Related
-
1982
- 1982-02-13 DE DE19823205149 patent/DE3205149A1/de active Granted
- 1982-02-17 AT AT0059982A patent/AT380881B/de not_active IP Right Cessation
- 1982-02-19 PT PT74463A patent/PT74463B/pt unknown
- 1982-02-23 LU LU83962A patent/LU83962A1/fr unknown
- 1982-02-23 GR GR67396A patent/GR76060B/el unknown
- 1982-02-24 DK DK79982A patent/DK148687C/da active
- 1982-02-24 NL NL8200746A patent/NL8200746A/nl not_active Application Discontinuation
- 1982-02-24 JP JP57027570A patent/JPS57188589A/ja active Granted
- 1982-02-24 ES ES509850A patent/ES509850A0/es active Granted
- 1982-02-24 YU YU412/82A patent/YU44007B/xx unknown
- 1982-02-24 CA CA000397008A patent/CA1192549A/en not_active Expired
- 1982-02-25 BE BE0/207403A patent/BE892271A/fr not_active IP Right Cessation
- 1982-02-25 SE SE8201184A patent/SE440503B/sv not_active IP Right Cessation
- 1982-02-25 CH CH1167/82A patent/CH651043A5/it not_active IP Right Cessation
- 1982-02-25 FR FR8203164A patent/FR2500455A1/fr active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DE3205149A1 (de) | 1982-11-11 |
| DK79982A (da) | 1982-08-26 |
| IT8109343A0 (it) | 1981-02-25 |
| ES8302680A1 (es) | 1983-02-01 |
| ES509850A0 (es) | 1983-02-01 |
| JPS57188589A (en) | 1982-11-19 |
| AT380881B (de) | 1986-07-25 |
| DK148687B (da) | 1985-09-02 |
| PT74463B (en) | 1983-08-24 |
| DK148687C (da) | 1986-04-28 |
| NL8200746A (nl) | 1982-09-16 |
| FR2500455A1 (fr) | 1982-08-27 |
| LU83962A1 (fr) | 1982-07-08 |
| PT74463A (en) | 1982-03-01 |
| YU41282A (en) | 1987-10-31 |
| GR76060B (it) | 1984-08-03 |
| SE8201184L (sv) | 1982-08-26 |
| IT1210639B (it) | 1989-09-14 |
| GB2093445A (en) | 1982-09-02 |
| GB2093445B (en) | 1985-02-27 |
| ATA59982A (de) | 1985-12-15 |
| BE892271A (fr) | 1982-06-16 |
| JPH0333715B2 (it) | 1991-05-20 |
| SE440503B (sv) | 1985-08-05 |
| FR2500455B1 (it) | 1984-04-27 |
| YU44007B (en) | 1990-02-28 |
| US4372958A (en) | 1983-02-08 |
| DE3205149C2 (it) | 1991-04-18 |
| CA1192549A (en) | 1985-08-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased | ||
| PL | Patent ceased |