CH632161A5 - PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ASTHMA. - Google Patents
PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ASTHMA. Download PDFInfo
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- CH632161A5 CH632161A5 CH48478A CH48478A CH632161A5 CH 632161 A5 CH632161 A5 CH 632161A5 CH 48478 A CH48478 A CH 48478A CH 48478 A CH48478 A CH 48478A CH 632161 A5 CH632161 A5 CH 632161A5
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- CH
- Switzerland
- Prior art keywords
- pharmaceutical composition
- composition according
- active ingredient
- asthma
- administration
- Prior art date
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Classifications
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
La presente invenzione concerne una composizione farmaceutica contenente una sostanza appartenente alla classe delle 2-aloergoline-8ß-sostituite, utile per il trattamento terapeutico dell'asma. The present invention relates to a pharmaceutical composition containing a substance belonging to the class of 2-haloergoline-8ß-substitutes, useful for the therapeutic treatment of asthma.
La sostanza sunnominata è la D-2-bromo-6-metil-8ß--(morfolinocarbonilossimetil)ergolina di per sé o sotto forma di suoi sali specialmente adatti per le composizioni farmaceutiche. The substance named is D-2-bromo-6-methyl-8ß - (morpholinocarbonyloxymethyl) ergoline per se or in the form of its salts especially suitable for pharmaceutical compositions.
Nel brevetto svizzero 619 709 è descritta la preparazione delle 2-aloergoline-8ß-sostituite. Queste sostanze sono dal punto di vista chimico degli esteri carbammici variamente sostituiti del 2-bromo, o cloro o iodio lisergolo e dei corrispondenti composti idrogenati. In the Swiss patent 619 709 the preparation of the 2-haloergoline-8ß-substituted is described. From the chemical point of view, these substances are variously substituted carbamic esters of 2-bromine, or chlorine or iodine lysergol and the corresponding hydrogenated compounds.
Le sostanze di questa serie, come descritto, posseggono singolari e importanti proprietà farmacologiche specialmente per alcuni composti dotati di proprietà adrenolitiche estremamente potenti. The substances of this series, as described, have singular and important pharmacological properties especially for some compounds with extremely powerful adrenolytic properties.
La composizione farmaceutica secondo l'invenzione è caratterizzata nella rivendicazione 1 precedente. The pharmaceutical composition according to the invention is characterized in claim 1 above.
Il composto di cui alla formula I risponde alla formula bruta C21H2GN303Br, P.M. 448,38. The compound of formula I responds to the brute formula C21H2GN303Br, P.M. 448.38.
Esso fornisce dei sali con acidi minerali e con acidi organici non tossici e accettabili per l'impiego terapeutico. Questi sali sono solubili in acqua e nelle soluzioni fisiologiche come ad es. il maleato C25H30N3O7Br p.f. 213-16°C o il metansulfonato C22H30N3O6BrS p.f. 265-6°C e si possono preparare secondo i metodi convenzionali per trattamento di I con le quantità equivalenti dell'acido in mezzo acquoso o in appropriati solventi organici o in miscele di solventi organici, come gli alcoli, gli eteri, i chetoni alifatici a basso peso molecolare ecc. presi singolarmente o in miscele opportune fra di loro, come verrà dettagliatamente specificato negli esempi. It supplies salts with mineral acids and with non-toxic organic acids which are acceptable for therapeutic use. These salts are soluble in water and in physiological solutions such as e.g. the maleate C25H30N3O7Br m.p. 213-16 ° C or the methanesulfonate C22H30N3O6BrS m.p. 265-6 ° C and can be prepared according to conventional methods for the treatment of I with the equivalent quantities of the acid in aqueous medium or in appropriate organic solvents or in mixtures of organic solvents, such as alcohols, ethers, aliphatic ketones low molecular weight etc. taken individually or in appropriate mixtures with each other, as will be specified in detail in the examples.
L'attività farmacologica del composto di formula 1 si manifesta in saggi opportuni, condotti sull'animale da esperimento ed è specialmente evidente nei seguenti test: The pharmacological activity of the compound of formula 1 is manifested in appropriate tests, conducted on the experimental animal and is especially evident in the following tests:
attività antiasma anti-asthma activity
I THE
EDioo EDioo
0,25 0.25
mg/kg/p.o. mg / kg / P.O.
P C A P C A
Goose, Immuno- Goose, Immuno-
sodio sodium
logy, 16, 149, 1969 logy, 16, 149, 1969
cromoglicato cromolyn
EDioo EDioo
5 5
mg/kv/i.v. mg / kv / i.v.
attività antide antide activity
I THE
ED100 ED100
5 5
mg/kv/os pressiva imipramina mg / kv / os pressurized imipramine
EDioo EDioo
25 25
mg/kv/os azione muscolo mg / kv / os muscle action
I THE
EDi00 EDi00
100 100
mg/kg rilassante phénobarbital mg / kg relaxing phénobarbital
EDioo EDioo
100 100
mg/kg tossicità mg / kg toxicity
DL50 topo os DL50 mouse os
180 180
mg/kg mg / kg
DL50 topo iv DL50 mouse iv
18-22 mg/kg 18-22 mg / kg
L'esame comparato con sostanze di confronto universalmente note per le loro proprietà farmacologiche ha messo in evidenza come il composto I possa esercitare una selettiva e potente attività antiasma. La pluripotenzialità del composto I si manifesta anche nell'esercitare una potente attività adrenergica in vitro come è stato messo in evidenza nel brevetto svizzero 619 709 una notevole attività antidepressiva comparabile alla imipramina ed una notevole azione miorilassante comparabile al fenobarbital come è stato qui dimostrato. Tutte queste attività accessorie che si manifestano a dosi notevolmente più alte di quelle che provocano l'effetto antiasma sono da considerarsi favorevoli nel senso di migliorare il profilo farmacologico del prodotto e di preconizzarne un eventuale uso terapeutico dello stesso come alleviante per i sofferenti di asma. Comparative examination with comparator substances universally known for their pharmacological properties has shown how compound I can exert a selective and powerful antiasthma activity. The pluripotency of compound I also manifests itself in exercising a potent adrenergic activity in vitro as it has been highlighted in the Swiss patent 619 709 a remarkable antidepressant activity comparable to imipramine and a remarkable muscle relaxant action comparable to phenobarbital as has been demonstrated here. All these accessory activities that occur at considerably higher doses than those that cause the antiasthma effect are to be considered favorable in the sense of improving the pharmacological profile of the product and of recommending its possible therapeutic use as a reliever for asthma sufferers.
L'esame della tossicità mostra poi un notevole margine di sicurezza del prodotto i cui effetti tossici si manifestano ad oltre 1000 volte la dose terapeutica. The toxicity test then shows a considerable safety margin of the product whose toxic effects occur at over 1000 times the therapeutic dose.
Risulta poi evidente il progresso tecnico realizzato nel campo dei prodotti antiasma il cui termine di confronto universalmente accettato è il sodio cromoglicato la cui attività farmacologica si manifesta solo per via parenterale, venosa e nell'uomo per inalazione come polvere dispersa. The technical progress made in the field of anti-asthma products, the universally accepted comparison term of which is sodium cromoglycate, whose pharmacological activity occurs only parenterally, venously and in man by inhalation as a dispersed powder, is evident.
Nel caso del composto I essa si manifesta però non solo a livelli di dose notevolmente inferiori ma, ciò che è molto significativo e importante, per via orale. In the case of compound I, however, it occurs not only at significantly lower dose levels but, what is very significant and important, orally.
Per l'utilizzazione a scopo terapeutico il composto può essere formulato sotto forma di sale adatto, secondo le indicazioni sopra riportate, in varie composizioni farmaceutiche per uso orale, parenterale o rettale. Tali composizioni possono essere sotto forma di compresse, confetti oppure soluzioni tal quali o capsule in gelatina molle, capsule in gelatina dura per la somministrazione per via orale. Per tale via il composto di formula I può essere anche formulato in forma a cessione protratta. Gli eccipienti, i disperdenti, i lubrificanti, le sostanze ausiliarie e i solventi per le preparazioni farmaceutiche sono quelli che risultano noti all'uomo For use for therapeutic purposes, the compound can be formulated in the form of a suitable salt, according to the indications above, in various pharmaceutical compositions for oral, parenteral or rectal use. These compositions can be in the form of tablets, sugared almonds or solutions as such or soft gelatin capsules, hard gelatin capsules for oral administration. By this way the compound of formula I can also be formulated in protracted release form. The excipients, dispersants, lubricants, auxiliary substances and solvents for pharmaceutical preparations are those which are known to man
5 5
io I
15 15
20 20
25 25
30 30
35 35
40 40
45 45
50 50
55 55
60 60
65 65
3 3
632161 632161
di mestiere, adatti per ottenere una biodisponibilità soddisfacente per il principio attivo. by trade, suitable for obtaining satisfactory bioavailability for the active ingredient.
Le composizioni farmaceutiche per via parenterale a loro volta comprendono fiale contenenti una soluzione adatta per la somministrazione intramuscolare, endovenosa o per via transcutanea, preparate con soluzioni fisiologiche o con solventi adatti. Parenteral pharmaceutical compositions in turn comprise vials containing a solution suitable for intramuscular, intravenous or transcutaneous administration, prepared with physiological solutions or with suitable solvents.
Infine le composizioni farmaceutiche per via rettale sono rappresentate da suppositori formulati con le metodiche ben note all'uomo di mestiere. Finally, pharmaceutical compositions by rectal route are represented by suppositories formulated with the methods well known to the skilled man.
Le forme farmaceutiche menzionate contengono dosi di principio attivo comprese tra 0,1 e 25 mg per dose. Il principio attivo si intende somministrato tal quale o preferibilmente sotto forma di sale. Specialmente adatti risultano il maleato ed il metansulfonato che si prestano particolarmente bene sia per la stabilità fisica che chimica. The pharmaceutical forms mentioned contain active ingredient doses ranging from 0.1 to 25 mg per dose. The active ingredient is intended as it is or preferably in the form of salt. Maleate and methanesulfonate are particularly suitable and are particularly suitable for both physical and chemical stability.
Esempi dì sintesi Examples of synthesis
Sintesi 1 Synthesis 1
Maleato del D-2-bromo-6-metil-8ß(morfolino carbonilos-simetil)ergolina g 1 di D-2-bromo-6-metil-8ß(morfolino carbonilossimetil)-ergolina in 15 mi di EtOH assoluto bollente vengono trattati con una soluzione di 0,240 g di acido maleico nello stesso solvente. Dopo raffreddamento e diluizione con % volume di etere si filtra il precipitato e lo si cristallizza da EtOH 95% ottenendo g 1,1 di prodotto puro; p.f. 213-16°C [a]D20 = —54° (c = 0,5 metanolo), M+ 449,447. Analisi elementare: calcolato (per C25H30N3O7Br) C% 53,20; H% 5,36; N% 7,45; trovato: C% 53,13; H% 5,65; N% 7,29. U.V. X ™xOH 282 m|i (e 9300) 278 m[i (s 9400) 224 mu (s 35820); IR (KBr) 1695 cm-1. D-2-bromo-6-methyl-8ß (morpholino carbonilos-simetil) ergoline g 1 of D-2-bromo-6-methyl-8ß (morpholino carbonyloxymethyl) -ergoline maleate in 15 ml of boiling absolute EtOH are treated with a solution of 0.240 g of maleic acid in the same solvent. After cooling and dilution with% volume of ether, the precipitate is filtered and crystallized from 95% EtOH to obtain 1.1 g of pure product; mp 213-16 ° C [a] D20 = —54 ° (c = 0.5 methanol), M + 449.447. Elementary analysis: calculated (for C25H30N3O7Br) C% 53.20; H% 5.36; N% 7.45; found: C% 53.13; H% 5.65; N% 7.29. Ultraviolet X ™ xOH 282 m | i (e 9300) 278 m [i (s 9400) 224 mu (s 35820); IR (KBr) 1695 cm-1.
Sintesi 2 Synthesis 2
Metansulfonato del D-2-bromo-6-metil-8ß(morfolinocar-bonilossimetil)ergolina g 1 di D-2-bromo-6-metil-8ß(morfolinocarbonilossimetil)-ergolina in 30 mi di acetone bollente sono trattati con 0,236 g di acido metansolfonico. Si ha immediata precipitazione del sale che viene filtrato e cristallizzato da metanolo ottenendo g 1 di prodotto puro; p.f. 265-66°C [a]D20 = —54 (c = 0,5 C5H5N) M+ 449,447. Analisi elementare: calcolato C% 48,53; H% 5,55; N% 7,72; trovato C% 48,56; H% 5,38; N% 7,76. N.V. X 276 m|i (e 9350) 226 mp, D-2-bromo-6-methyl-8ß (morpholinocar-bonyloxymethyl) ergoline g 1 of D-2-bromo-6-methyl-8ß (morpholinocarbonyloxymethyl) -ergoline in 30 ml of boiling acetone are treated with 0.236 g of methanesulfonic acid. There is immediate precipitation of the salt which is filtered and crystallized from methanol obtaining 1 g of pure product; mp 265-66 ° C [a] D20 = —54 (c = 0.5 C5H5N) M + 449.447. Elementary analysis: calculated C% 48.53; H% 5.55; N% 7.72; found C% 48.56; H% 5.38; N% 7.76. N.V. X 276 m | i (e 9350) 226 mp,
(e 34000) 210 m|x (e 21600). (e 34000) 210 m | x (e 21600).
Gli esempi che seguono sono unicamente illustrativi e non limitano l'ambito della presente invenzione. The following examples are only illustrative and do not limit the scope of the present invention.
Esempi di forme galeniche Examples of Galenic forms
5 5
Esempio 1 Example 1
Preparazione compresse Preparation of tablets
50 g di D-2-bromo-6-metil-8ß(morfoIinocarboniIossimetil)-ergolina maleato si mescolano con 810 g di amido di mais, io 1050 g di cellulosa microcristallina e 85 g di talco. La mistura si introduce in un mescolatore per polveri e si fa girare fino a omogenea distribuzione del principio attivo negli eccipienti. 50 g of D-2-bromo-6-methyl-8ß (morphineinocarbonsIoxymethyl) -ergoline maleate mix with 810 g of corn starch, 1050 g of microcrystalline cellulose and 85 g of talc. The mixture is introduced into a powder mixer and made to turn until a homogeneous distribution of the active principle in the excipients.
Successivamente la polvere viene direttamente com-ìs pressa in una comprimitrice in forma di compresse del diametro di 2 cm e peso di 2 g. Subsequently the powder is directly compressed in a tablet press in the form of tablets with a diameter of 2 cm and weight of 2 g.
Le compresse così ottenute vengono passate al granulatore. II granulato viene addizionato di 5 g di stearato di magnesio e quindi sottoposto a nuova compressione definitiva 20 per ottenere 10 000 compresse del peso di mg 200 e contenenti ciascuna 5 mg di principio attivo. The tablets thus obtained are passed to the granulator. The granulate is added with 5 g of magnesium stearate and then subjected to a new definitive compression 20 to obtain 10 000 tablets weighing 200 mg and each containing 5 mg of active principle.
Esempio 2 Example 2
Preparazione fiale 25 2,5 g di D-2-bromo-6-metil-8ß(morfolinocarbonilossi-metil)ergolina metansulfonato vengono sciolti in una miscela di mi 10 di EtOH 95% e mi 20 di acqua distillata esente da pirogeni. La soluzione viene poi diluita con 20 mi di glicerina bidistillata ed infine portata a 2000 mi con acqua 30 distillata esente da pirogeni. Si filtra sterile, poi si infiala sotto atmosfera di azoto in 1000 ampolle da 2 mi, ottenendo in questo modo fiale contenenti ciascuna 2,5 mg di principio attivo. Preparation ampoules 25 2.5 g of D-2-bromo-6-methyl-8ß (morpholinocarbonyloxy-methyl) ergoline methanesulfonate are dissolved in a mixture of 10 ml of 95% EtOH and 20 ml of distilled water without pyrogen. The solution is then diluted with 20 ml of bidistilled glycerin and finally brought to 2000 ml with distilled 30 pyrogen-free water. It is filtered sterile, then infia under a nitrogen atmosphere in 1000 ampoules of 2 ml, thus obtaining ampoules each containing 2.5 mg of active principle.
Esempio 3 Example 3
35 Preparazione di toste 35 Preparing toasts
70 g di poliossietilensorbitano monostearato, 40 g di sor-bitanstearato, 155 g di olio di paraffina, 130 g di alcool stearico sono fusi insieme. Alla massa fusa tenuta sui 50-60° si aggiunge una soluzione di D-2-bromo-6-metil-8ß(morfoli-40 nocarbonilossimetil)ergolina metansulfonato 5 g sciolto in 600 mi di acqua distillata e mantenuta a 50-60°. Si agita vigorosamente a 50° per emulsionare la miscela poi si raffredda a temperatura ambiente e si immette negli stampi ottenendo così 1000 supposte contenenti ciascuna 5 mg di 45 principio attivo. 70 g of polyoxyethylene sorbitan monostearate, 40 g of sur-bitanstearate, 155 g of paraffin oil, 130 g of stearic alcohol are melted together. A solution of D-2-bromo-6-methyl-8ß (morphols-40 nocarbonyloxymethyl) ergoline methanesulfonate 5 g dissolved in 600 ml of distilled water and kept at 50-60 ° is added to the molten mass kept at 50-60 °. It is stirred vigorously at 50 ° to emulsify the mixture then it is cooled to room temperature and is introduced into the molds thus obtaining 1000 suppositories each containing 5 mg of 45 active principle.
v v
Claims (7)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH48478A CH632161A5 (en) | 1978-01-17 | 1978-01-17 | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ASTHMA. |
GB7835598A GB2012166A (en) | 1978-01-17 | 1978-09-05 | Pharmaceutical composition for the treatment of asthma containing D-2-bromo-6-methyl- 8beta-(morpholinocarbonyloxymethyl) ergoline or its salts. |
FR7826151A FR2414333A2 (en) | 1978-01-17 | 1978-09-12 | PHARMACEUTICAL COMPOSITION CONTAINING AS ACTIVE INGREDIENT D-2-BROMO 6-METHYL-8B- (MORPHOLINOCARBONYOXYMETHYL) -ERGOLINE, USEFUL IN PARTICULAR FOR THE TREATMENT OF ASTHMA |
BE190429A BE870414R (en) | 1978-01-17 | 1978-09-12 | NEW CARBAMATES OF 2-HALOGENOERGOLINS AND 2-HALOGENOERGOLENES, USE IN PARTICULAR AS VASODILATORS, AND THEIR PREPARATION PROCESS |
JP11246178A JPS54100396A (en) | 1978-01-17 | 1978-09-14 | Medical compositionf for curing asthma |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH48478A CH632161A5 (en) | 1978-01-17 | 1978-01-17 | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ASTHMA. |
Publications (1)
Publication Number | Publication Date |
---|---|
CH632161A5 true CH632161A5 (en) | 1982-09-30 |
Family
ID=4188059
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH48478A CH632161A5 (en) | 1978-01-17 | 1978-01-17 | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ASTHMA. |
Country Status (5)
Country | Link |
---|---|
JP (1) | JPS54100396A (en) |
BE (1) | BE870414R (en) |
CH (1) | CH632161A5 (en) |
FR (1) | FR2414333A2 (en) |
GB (1) | GB2012166A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8602372D0 (en) * | 1986-01-31 | 1986-03-05 | Sandoz Ltd | Organic compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH619709A5 (en) * | 1975-03-14 | 1980-10-15 | Siphar Sa | Process for the preparation of carbamates of 2-halogenoergolines and 2-halogenoergolenes |
-
1978
- 1978-01-17 CH CH48478A patent/CH632161A5/en not_active IP Right Cessation
- 1978-09-05 GB GB7835598A patent/GB2012166A/en not_active Withdrawn
- 1978-09-12 BE BE190429A patent/BE870414R/en active
- 1978-09-12 FR FR7826151A patent/FR2414333A2/en active Pending
- 1978-09-14 JP JP11246178A patent/JPS54100396A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
JPS54100396A (en) | 1979-08-08 |
GB2012166A (en) | 1979-07-25 |
FR2414333A2 (en) | 1979-08-10 |
BE870414R (en) | 1979-01-02 |
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PL | Patent ceased |