GB2096138A - 7-(2-diethylaminoethyl)theophylline acetylsalicylate and a process for the preparation thereof - Google Patents
7-(2-diethylaminoethyl)theophylline acetylsalicylate and a process for the preparation thereof Download PDFInfo
- Publication number
- GB2096138A GB2096138A GB8207789A GB8207789A GB2096138A GB 2096138 A GB2096138 A GB 2096138A GB 8207789 A GB8207789 A GB 8207789A GB 8207789 A GB8207789 A GB 8207789A GB 2096138 A GB2096138 A GB 2096138A
- Authority
- GB
- United Kingdom
- Prior art keywords
- process according
- theophylline
- solvent
- diethylaminoethyl
- acetylsalicylate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title claims abstract description 21
- AWKLBIOQCIORSB-UHFFFAOYSA-N etamiphylline Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CCN(CC)CC AWKLBIOQCIORSB-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229940068372 acetyl salicylate Drugs 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 21
- 230000008569 process Effects 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 4
- 229960004592 isopropanol Drugs 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 230000000694 effects Effects 0.000 description 8
- 230000009471 action Effects 0.000 description 6
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229960000278 theophylline Drugs 0.000 description 3
- 230000024883 vasodilation Effects 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 230000002744 anti-aggregatory effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- ANEXTOPWMYHSDQ-UHFFFAOYSA-N 2-methoxy-9,10-dihydrophenanthren-4-ol Chemical compound COC1=CC=2CCC3=CC=CC=C3C2C(=C1)O ANEXTOPWMYHSDQ-UHFFFAOYSA-N 0.000 description 1
- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical compound C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 241000157855 Cinchona Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 229950006790 adenosine phosphate Drugs 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000007883 bronchodilation Effects 0.000 description 1
- 230000002802 cardiorespiratory effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229940009979 dehydrocholate Drugs 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 229960000505 etamiphylline Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- KPJPHPFMCOKUMW-UHFFFAOYSA-N iodomethane Chemical compound I[CH2] KPJPHPFMCOKUMW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 description 1
- 150000003872 salicylic acid derivatives Chemical class 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
Classifications
-
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
7-(2-diethylaminoethyl)theophylline acetylsalicylate is a new compound having pharmaceutical applications. The compound can be prepared by reacting 7-(2-diethylaminoethyl)-theophylline with acetylsalicylic acid.
Description
SPECIFICATION 7-(2-diethylaminoethyl)-theophyl line acetylsalicylate and a process for the preparation thereof
This invention relates to a new compound 7 (2-diethylaminoethyl)-theophylline acetylsalicylate, and to a process for the preparation thereof.
Since the introduction of theophylline into therapeutical treatment, with the recognition of its action on the blood and respiratory stystems, it has held a leading place amongst similarly indicated drugs. At the same time, in view of the need to have theophylline derivatives having a greater pharmacological activity and devoid, as far as possible, of the side effects and physico-chemical drawbacks of the alkaloid per se, there has been offered a number of more or less manageable and active theophylline salts which have been accepted to a greater or lesser extent, the culmination of this acceptance being the preparation, in 1946, of 7-(2-diethylaminoethyl)-theophylline (Etamiphylline) which, being a chemical base, with facility for forming salts, offers optimum pharmacological characteristics.During thirty years of use this theophylline derivative has shown its qualities by being converted into a number of salts with different therapeutic activities (iodomethylate, hydrochloride, camphosulphonate and dehydrocho late). The therapeutic actions referred to above may be summed up as: an increase in the cardio-respiratory action with general vasodilation and bronchodilation, spasmolytic action and promotion of diuresis.
Acetylsalicylic acid, in spite of its being introduced almost a century ago, is still widely used in modern pharmacology, occupying a leading role not only within its pharmacological group, but also in the overall range of drugs integrating the present day therapeutical arsenal.
This reputation has been promoted and maintained by its pharmaco-therapeutic activity in a number of different areas which appear alone or in combination in very many clinical pictures. Its activity is developed against such frequent symptoms as pain (analgesic/antialgic action), inflammation (antiphlogistic antiinflammatory and antirheumatic action) and fever (antipyretic), against which acetylsalicylic acid has always acted effectively.
The general effect of the salicylic acid derivatives is a depression of the central nervous system, the point of action being located in the subcortical space.
The antialgic action is probably due to its acting on the stria terminalis, on which it may have a depressive action. Its activity is manifested especially on pain derived from an inflammatory process in organs of a tegumentary, rather than visceral structure, such as headaches, neuralgias and particularly arthralgias.
The antiinflammatory action, not fully described in view of its variety according to the originiating causes, may be generalised with a
PGs synthesis inhibiting activity, suppressing their participation in the inflammation, vasodilation, increase of permeability, etc. It may also block certain reactions in which quinines and SRS-A participate.
The antipyretic action is due to its activity on the central nervous system, particularly on the hypothalamus where the body temperature thermoregulating centre is located, either directly or by prior reiease of prostaglandins.
As a result of the hypothalmic action, the well known effects of acetylsalicyclic acid, such as sweating and vasodilation, are stimulated.
More recently a new activity, that of platelet antiaggregant, has been discovered. Sufficient experience has been obtained of this activity to add it to the other actions.
The interference by acetylsalicylic on the platelet function, based on the inhibition of platelet release and subsequent aggregation caused by adrenaline, adenosine phosphate and small amounts of collagen and thrombin has been confirmed. Thus acetylsalicylic acid makes the formation of the thrombus, induced by the platelets, difficult, thereby hindering the clinical derivations that this has.
It has, unexpectedly been found that it is possible to produce the acetylsalicylate salt of 7-(2-diethylaminoehtyl)-theophylline and that the properties of the compound are the combined properties of the two constituent parts.
The combination of the anti-aggregant and, therefore, anti-thrombotic activity of acetylsalicylic acid with the vasodilating activity of 7 (2-diethylaminoethyl)-theophylline offers excellent therapeutical advantages in the treatment of thromboembolic disease.
The compound of the invention offers the advantage of an excellent solubility, which allows suitable concentrations for quickly obtaining high blood levels by parenteral and oral administration.
The formula of the compound is CgH80 413H21N5O2, the molecular weight is 459.50 and the pH of a 5% solution is 6.02.
The process for preparing the compound according to the invention comprises reacting 7-(2-diethylaminoethyl)-theophylline in a solvent medium with acetylsalicylic acid.
The solvent medium may for example, be a ketone, such as acetone or methylethyl ketone, an alcohol, such as ethanol, isopropanol, n-propanol or tert-butanol or a chlorinated solvent such as chloroform or methylene chloride.
The following Example illustrates the invention.
EXAMPLE 1 80.1 9 (1 mole) of acetylsalicylic acid were dissolved in 360 ml of acetone. There was added to this solution a previously prepared solution of 279.3 g (1 mole) of 7-(2 diethylaminoethyl)--:heophylline base in 300 ml of acetone.
The solution thus obtained was stirred for 8 hours at room temperature. Thereafter the resulting white precipitate was filtered off and washed once with 500 ml of acetone.
The new substance thus obtained, after drying for 4 hours at 1 50 C, had a m.p. 109 to 111 C. The yield was 390 g (85%).
CLAli\nS 1. 7-(2-diethylaminoethyl)-theophylline acetylsalicylate.
2. A process for the preparation of 7-(2diethylaminoethyl)-theophylline acetylsalicylate, wherein 7-(2-diethylaminoethyl)-theophylline is reacted in a solvent medium with acetylsalicylic acid.
3. A process according to claim 2, wherein the solvent medium is a ketone.
4. A process according to claim 3, wherein the solvent is acetone or methylethyl ketone.
5. A process according to claim 2, wherein the solvent rriedium is an alcohol.
6. A process according to claim 5, wherein the solvent is ethanol, iso-propanol, npropanol or tert-butanol.
7. A process according to claim 2, wherein the solvent medium is a chlorinated solvent.
8. A process according to claim 7, wherein the solvent is chloroform or methylene chloride.
9. A process according to claim 2, substantially as described in the Example.
1 0. 7-(2-diethylaminoethyl)-theophylline acetylsalicylate whenever produced by a process according to any of claims 2 to 9.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (9)
1. 7-(2-diethylaminoethyl)-theophylline acetylsalicylate.
2. A process for the preparation of 7-(2diethylaminoethyl)-theophylline acetylsalicylate, wherein 7-(2-diethylaminoethyl)-theophylline is reacted in a solvent medium with acetylsalicylic acid.
3. A process according to claim 2, wherein the solvent medium is a ketone.
4. A process according to claim 3, wherein the solvent is acetone or methylethyl ketone.
5. A process according to claim 2, wherein the solvent rriedium is an alcohol.
6. A process according to claim 5, wherein the solvent is ethanol, iso-propanol, npropanol or tert-butanol.
7. A process according to claim 2, wherein the solvent medium is a chlorinated solvent.
8. A process according to claim 7, wherein the solvent is chloroform or methylene chloride.
9. A process according to claim 2, substantially as described in the Example.
1 0. 7-(2-diethylaminoethyl)-theophylline acetylsalicylate whenever produced by a process according to any of claims 2 to 9.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES501162A ES8202009A1 (en) | 1981-04-07 | 1981-04-07 | 7-(2-diethylaminoethyl)theophylline acetylsalicylate and a process for the preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2096138A true GB2096138A (en) | 1982-10-13 |
| GB2096138B GB2096138B (en) | 1984-08-01 |
Family
ID=8482205
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8207789A Expired GB2096138B (en) | 1981-04-07 | 1982-03-17 | 7-(2-diethylaminoethyl)-theophylline acetylsalicylate and a process for the preparation thereof |
Country Status (6)
| Country | Link |
|---|---|
| CH (1) | CH647780A5 (en) |
| DE (1) | DE3212909A1 (en) |
| ES (1) | ES8202009A1 (en) |
| GB (1) | GB2096138B (en) |
| IT (1) | IT1153967B (en) |
| PT (1) | PT74716B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0169466A3 (en) * | 1984-07-21 | 1986-05-21 | Hoechst Aktiengesellschaft | Mixture of xanthin derivatives and o-acetyl-salicylic acid, or their pharmacologically acceptable salts, and its use |
| FR2631030A1 (en) * | 1988-05-05 | 1989-11-10 | Coma Julia Concepcion | PROCESS FOR OBTAINING 7- (2-DIETHYLAMINO-ETHYL) -THOPHYLLIN ACETYL-SALICYLATE AND ITS APPLICATION TO THE PREPARATION OF ANTI-AGGLUTINANT AND ANTI-THROMBOTIC AGENTS |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU144902S (en) | 2001-03-02 | 2001-08-15 | Nokia Mobile Phones Ltd | A handset |
| AU144901S (en) | 2001-03-02 | 2001-08-15 | Nokia Mobile Phones Ltd | A handset |
| CA97021S (en) | 2001-03-02 | 2003-06-25 | Nokia Mobile Phones Ltd | Handset |
| AU144906S (en) | 2001-03-02 | 2001-08-15 | Nokia Mobile Phones Ltd | A handset |
-
1981
- 1981-04-07 ES ES501162A patent/ES8202009A1/en not_active Expired
-
1982
- 1982-03-17 GB GB8207789A patent/GB2096138B/en not_active Expired
- 1982-03-22 CH CH1743/82A patent/CH647780A5/en not_active IP Right Cessation
- 1982-03-30 IT IT20487/82A patent/IT1153967B/en active
- 1982-04-06 DE DE19823212909 patent/DE3212909A1/en active Granted
- 1982-04-06 PT PT74716A patent/PT74716B/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0169466A3 (en) * | 1984-07-21 | 1986-05-21 | Hoechst Aktiengesellschaft | Mixture of xanthin derivatives and o-acetyl-salicylic acid, or their pharmacologically acceptable salts, and its use |
| US4880791A (en) * | 1984-07-21 | 1989-11-14 | Hoechst Aktiengesellschaft | Combination product composed of xanthine derivatives and O-acetylsalicylic acid or its pharmacologically tolerated salts, and its use |
| FR2631030A1 (en) * | 1988-05-05 | 1989-11-10 | Coma Julia Concepcion | PROCESS FOR OBTAINING 7- (2-DIETHYLAMINO-ETHYL) -THOPHYLLIN ACETYL-SALICYLATE AND ITS APPLICATION TO THE PREPARATION OF ANTI-AGGLUTINANT AND ANTI-THROMBOTIC AGENTS |
| US4908111A (en) * | 1988-05-05 | 1990-03-13 | Laboratories Boi, S.A. | Process for the preparation of 7-(2-diethylaminoethyl)-theophylline acetyl salicylate and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ES501162A0 (en) | 1982-02-01 |
| IT8220487A0 (en) | 1982-03-30 |
| IT1153967B (en) | 1987-01-21 |
| PT74716B (en) | 1983-11-14 |
| CH647780A5 (en) | 1985-02-15 |
| DE3212909C2 (en) | 1990-07-26 |
| ES8202009A1 (en) | 1982-02-01 |
| GB2096138B (en) | 1984-08-01 |
| DE3212909A1 (en) | 1982-11-18 |
| PT74716A (en) | 1982-05-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930317 |