GB2143233A - Xanthine derivatives - Google Patents
Xanthine derivatives Download PDFInfo
- Publication number
- GB2143233A GB2143233A GB08417008A GB8417008A GB2143233A GB 2143233 A GB2143233 A GB 2143233A GB 08417008 A GB08417008 A GB 08417008A GB 8417008 A GB8417008 A GB 8417008A GB 2143233 A GB2143233 A GB 2143233A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- composition
- formula
- human
- animal body
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
-
- 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
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The compound of formula (I> <IMAGE> is useful as a brochodilator and mucolytic. It is produced by esterification of a reactive derivative of thiophene-2-carboxylic acid.
Description
SPECIFICATION
Xanthine derivative
THIS INVENTION relates to a new therapeutically useful xanthine derivative, to a process for its preparation and pharmaceutical compositions containing it.
The new compound of the present invention is the 7-2-(2-thenoyloxy)prnpyl] theophylline of the formula:
In contrast to theophylline and other xanthines where therapeutic effectiveness is limited by side-effects, the compound of formula I has useful bronchodilator and mucolytic activity unassociated with phenomena such as tachycardia and gastric irritation-induced nauseas and vomiting. It is therefore specially useful for the treatment of obstructive respiratory diseases such as chronic bronchitis. For humans, useful therapeutic doses of the compound are between 0.2 and 3 g daily.
According to a feature of the present invention 7-[2-(2-thenoyloxy)propyi] theophylline of formula I is prepared by the process which comprises reacting 7-(2-hydroxypropyl) theophylline of formula:
with a reactive derivative of 2-thiophenecarboxylic acid of the formula:
As reactive derivative of said carboxylic acid are used the chloride, bromide, an anhydride or the imidazolide, which may be prepared in situ without further isolation, or are prepared isolating them before reacting with compound II.
The reaction is preferably carried out at a temperature between 10 and 90"C in an inert organic solvent as acetone, dioxane, methylene chloride, benzene, toluene or pyridine and preferably in the presence of a tertiary amine as triethylamine.
Also included within the scope of the present invention are pharmaceutical compositions which comprise as active ingredient 7-[2-2-(thenoyloxy)propyl] theophylline in association with a pharmaceutically acceptable carrier or diluent. The compositions are preferably made in a form suitable for oral or rectal administration. The compositions for oral administration may take the form of tablets, suspension capsules or powders and such preparations may be made by methods well known in the art and using usual ingredients.
The following Examples illustrate the preparation of the compound of the present invention.
EXAMPLE 1
To a suspension of 7-(2-hydroxypropyl)theophylline (6.0 g; 0.025 mols) and triethylamine (2.5 g; 0.025 mols) in anhydrous benzene (100 ml) a solution of thenoyl chloride (3.7 g; 0.025 mols) in anhydrous benzene (20 ml) was slowly added. The mixture was bolted under reflux for 24 hours after which the solvent was removed in vacuo, the residue treated with water and extracted with methylene chloride. The organic solution was washed with an aqueous solution of sodium bicarbonate, dried, decolorized and the solvent removed in vacuo when a wax residue was obtained which solidifies by treating with diethyl ether. 7-[2-(2-thenoyloxy)propyl] theophylline (5.5 g) was obtained which melts at 142-144"C after recrystallization from ethanol.
EXAMPLE 2
A mixture of benzene (20 ml), N,N-dimethylformamide (3.6 ml) and thionyl chloride (3 ml) was stirred at room temperature for ten minutes (two layers are formed) and the resulting mixture was slowly added to a solution of 2-thiophenecarboxylic acid (5.12 g; 0.04 mols) in benzene (25 ml). After stirring at room temperature for 45 minutes, the solution was slowly added to a suspension of 7-(2-hydroxypropyl) theophylline (9.5 g; 0.04 moles) and triethylamine (4.04 g; 0.04 moles) in benzene (125 ml). The mixture was boiled under reflux for 24 hours after wihich the compound was isolated as described in Example 1.
EXAMPLE 3
To a suspension of 7-(2-hydroxypropyl)theophylline (11.9 g; 0.05 moles) in dioxane (100 ml), a solution of 2-thiophenecarboxylic anhydride (13.1 g; 0.055 moles) in dioxane (20 ml) was added. The resulting mixture was stirred at 80"C for 6 hours after which was cooled and poured onto cold water. While stirring, a saturated aqueous solution of sodium bicarbonate was added until alkaline pH, and the insoluble solid was filtered and washed with water. 7-[2-(2 thenoyloxy)prnpyl theophylline (13.4 g) was obtained which melts at 133"-144"C.
EXAMPLE 4
To a solution of imidazole (7.7 g; 0.113 moles) in methylene chloride (80 ml), 2thiophenecarboxylic acid (3.84 g; 0.03 moles) was added. Thionyl chloride (3.33 g; 0.028 moles) was added at a temperature below 10"C and then the resulting mixture was boiled under reflux for 2.5 hours. After cooling at 15 C, 7-(2-hydroxypropyl) theophylline (5.48 g; 0.023 moles) was added and the mixture was boiled under reflux for 3 hours, poured onto an aqueous solution of sodium bicarbonate and decanted. The organic solution was washed with water and the solvent removed in vacuo to give a residue which was treated with diethyl ether. 7-[2-(2thenoyloxy)propyl theophylline] (6.9 9) was obtained melting point 143"-144"C.
EXAMPLE 5
To a coid solution of 7-(2-hydroxypropyl) theophylline (4980 g; 20.9 moles) in pyridine (10.5 litres), thenoyl chloride (3063 g; 20.9 moles) was slowly added. After stirring for 1 5 hours to room temperature the mixture was poured onto water (100 litres) and the precipitated solid was filtered, washed thoroughly with water and dried. 7-[2-(2-thenoyloxy)propyl] theophilline (7684 g) was obtained which melts at 143"-144"C after recrystallization from isopropanol.
The following Examples illustrate pharmaceutical compositions according to the invention.
EXAMPLE 6
1000 litres of a suspension containing 450 mg of 7-2-(2-thenoyloxy)prnpyl] theophylline per 5 ml were prepared from the following formulation: 7-2-(2-thenoy1oxy)prnpyl] theophylline (as coated granules) 90kg microcrystalline cellulose 1 Okg methylcellulose 4kg sorbitol solution (70%) 300kg sodium saccharin 1kg flavouring 2kg purified water, a suficient quantity to make 10001.
The microcrystalline cellulose and methylcellulose was dispersed in 1 50 1. of water, the suspension passed through a colloidal mill and an aqueous solution of sodium sacharine, flavouring substance and sorbitol was added. Then the 7-[2-(2-thenoyloxy)propyl] theophiline line coated granules were added and the mixture made up to 1000 1. with deionized water.
EXAMPLE 7 7-[2-(2-thenoyloxy)propylj theophylline coated granules were prepared as follows:
One par of 7-L2-(2-thenoyloxy)prnpyl] theophylline and four parts of lactose were granulated in a ultrrapid mixer using polyvinylpryrrolidone as agglutinating and water as mixing agents. The dried granules were passed through a screen with an opening of 40 mesh and microcoated by spray drying at a temperature of 75"C and a pressure of 6 kg/cm2. Finally the resulting granules were dried at SOC and sieved through a 60 mesh sieve.
As coating agent was used the following suspension: hydroxypropylcellulose phthalate 60g triacetin 10g polysorbate 80 49 talc 209 isopropanol 700ml deionized water q.s. 1000ml EXAMPLE 8
1000 tablets, each containing 450 mg of 7-[2-(2-thenoyloxy)propyl] theophylline, were prepared from the following formulation: 7-[2-(2-thenoyloxy)propyl) theophylline 4509 corn starch 2009 lactose monohydrate 1009 polyvinylpyrrolidone 5% aqueous solution 459 carboxymethyl starch 409 sodium stearyl fumarate 89 7-(2-(2-thenoyloxy)propyl] theophylline, corn starch, lactose monohydrate and polyvinylpyrrolidone were mixed and the resulting granulated passed through a screen with an opening of 2 mm and dried at 60"C. Then it was passed again through a screen with an opening of 0.84 mm, and carboxymethyl starch and sodium stearyl fumarate, added. The resulting mixture compressed in 810 mg tablets.
EXAMPLE 9
10,000 suppositories each containing 650 mg of 7-2-(-thenoyloxy)propyl] theophylline were prepared as follows: 7-[2-(2-thenoyloxy)propyl] theophilline 6. 500g theobroma oil 13.500g
The theobroma oil was melted and the active compound suspended in it. The mixture was then poured into appropriate suppository mould to make 2.0 g suppositories.
Claims (20)
1. The compound of formula (I)
2. A process for producing the compound of claim 1 comprising reacting the compound of formula (II)
with a reactive derivative of the compound of formula (III)
3. A process as claimed in claim 2 wherein the reactive derivatives is the carboxylic acid chloride, bromide, imidazolinyl amide or an anhydride.
4. A process as claimed in claim 2 or claim 3 which is conducted at a temperature of between 10 and 90"C.
5. A process as claimed in any one of claims 2 to 4 which is conducted in the presence of an inert solvent.
6. A process as claimed in claim 5 wherein the solvent is acetone, dioxane, methylene chloride, benzene, toluene or pyridine.
7. A process as claimed in any one of claims 2 to 6 which is conducted in the presence of a tertiary amine.
8. A process as claimed in claim 7 wherein the amine is triethylamine.
9. A process as claimed in any one of claims 2 to 9 wherein the reactive derivative of the compound of formula (III) is produced and used in situ without isolation.
10. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier or diluent therefor.
11. A composition as claimed in claim 10 in unit dosage form.
1 2. A composition as claimed in claim 11 wherein each unit dose comprises from 0.2 to 3.0 g of the active ingredient.
1 3. A composition as claimed in any one of claims 10 to 1 2 in the form of tablets, capsules, powders, granules, suspensions of suppositories.
14. The compound of claim 1 for use in a method of treatment of the human or animal body by surgery or therapy or diagnosis practised on the human or animal body.
1 5. A composition as claimed in any one of claims 10 to 1 3 for use in a method of treatment of the human or animal body by surgery or therapy, or of diagnosis practised on the human or animal body.
1 6. The compound as claimed in claim 14 or a composition as claimed in claim 1 5 for use as a bronchodilator.
1 7. The compound as claimed in claim 14 or a composition as claimed in claim 1 5 for use as a mucolytic.
1 8. The compound of claim 1 substantially as herein described with reference to Examples 1 to 5.
1 9. A process as claimed in claim 2 and substantially as herein described with reference to
Examples 1 to 5.
20. A pharmaceutical composition as claimed in claim 10 and substantially as herein described with reference to Examples 6 to 9.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES523854A ES523854A0 (en) | 1983-07-05 | 1983-07-05 | PROCEDURE FOR THE PREPARATION OF A XANTHINIC DERIVATIVE. |
Publications (2)
Publication Number | Publication Date |
---|---|
GB8417008D0 GB8417008D0 (en) | 1984-08-08 |
GB2143233A true GB2143233A (en) | 1985-02-06 |
Family
ID=8485967
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08417008A Withdrawn GB2143233A (en) | 1983-07-05 | 1984-07-04 | Xanthine derivatives |
Country Status (7)
Country | Link |
---|---|
JP (1) | JPS6084290A (en) |
KR (1) | KR850001197A (en) |
DE (1) | DE3424620A1 (en) |
ES (1) | ES523854A0 (en) |
FR (1) | FR2554449A1 (en) |
GB (1) | GB2143233A (en) |
IT (1) | IT1180197B (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2097015A1 (en) * | 1970-07-27 | 1972-03-03 | Investigations Sci Pharm | Esters of 7-(2,3-dihydroxypropyl)theophylline - cardiovascular and respiratory system active |
DE3037391A1 (en) * | 1980-10-03 | 1982-05-19 | King Consult GmbH, 5000 Köln | ESTERS OF 7-HYDROXYALKYL-1,3-DIMETHYLXANTHINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A LIPID-REDUCING AGENT |
-
1983
- 1983-07-05 ES ES523854A patent/ES523854A0/en active Granted
-
1984
- 1984-07-04 DE DE19843424620 patent/DE3424620A1/en not_active Withdrawn
- 1984-07-04 JP JP59137377A patent/JPS6084290A/en active Pending
- 1984-07-04 KR KR1019840003861A patent/KR850001197A/en not_active Application Discontinuation
- 1984-07-04 GB GB08417008A patent/GB2143233A/en not_active Withdrawn
- 1984-07-04 IT IT21743/84A patent/IT1180197B/en active
- 1984-07-04 FR FR8410593A patent/FR2554449A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
IT8421743A1 (en) | 1986-01-04 |
KR850001197A (en) | 1985-03-16 |
IT8421743A0 (en) | 1984-07-04 |
DE3424620A1 (en) | 1985-01-17 |
GB8417008D0 (en) | 1984-08-08 |
ES8502113A1 (en) | 1984-12-16 |
FR2554449A1 (en) | 1985-05-10 |
IT1180197B (en) | 1987-09-23 |
JPS6084290A (en) | 1985-05-13 |
ES523854A0 (en) | 1984-12-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR870001982B1 (en) | Process for preparing 1,1-dioxopenicillanoyl-oxymethyl 6-(d-alpha-amino-alpha-phenylacetamido)penicillanate tosylate hydrate | |
AU666704B2 (en) | Anthraquinone compounds and pharmaceutical compositions containing them | |
WO2005044793A2 (en) | Nitrogen-containing fused heterocyclic compounds | |
RU2125571C1 (en) | 7-([-([1α,5α,6α]]-6-AMINO-3-AZABICYCLO-[3,1,0]-HEX-3-YL)-6-FLUORO-1- -(2,4-DIFLUOROPHENYL)-1,4-DIHYDRO-4-OXO-1,8-NAPHTHYRIDINE-3- -CARBOXYLIC AND METHANESULFONIC ACIDS SALT AND A METHOD OF ITS SYNTHESIS | |
HRP20000669A2 (en) | Novel crystalline forms of an antiviral benzimidazole compound | |
JPS6084221A (en) | Benzothiophene derivative as antiasthmatic | |
US4452800A (en) | Salts of 3(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridine-2(1H)-one and their use in treating chronic obstructive lung diseases | |
US3910955A (en) | Benzothiophene-ethylamines | |
JPH0655739B2 (en) | Novel 8α-acylaminoergolines | |
US4168380A (en) | 7-Methoxy-5-oxo-5H-thiazolo[2,3-b]quinazoline-2-carboxylic acid | |
EP0075607B1 (en) | 1-azaxanthone for use as therapeutic agent, processes for its production and pharmaceutical compositions | |
JPH0548234B2 (en) | ||
US4376121A (en) | Antiallerigically-active imidazothienopyrimidine derivatives | |
GB2143233A (en) | Xanthine derivatives | |
US3268406A (en) | Compositions and method of using (3-amino-pyrazinoyl) guanidines | |
US5708024A (en) | Salts of 2- (2,6-dichlorophenyl)amine!phenylacetoxyacetic acid with organic basic cations | |
JPS6222993B2 (en) | ||
JP2003508542A (en) | Novel C13-substituted estra-1,3,5 (10) -trien-3-yl-sulphamate, process for producing the same and pharmaceutical composition containing the compound | |
US3882127A (en) | 17-alkenyl-6{62 -azido-4,5{60 -epoxymorphinan-3-ols | |
US4188482A (en) | Thiazino indole compounds | |
HRP20030653A2 (en) | Novel benzoylguanidine salt | |
JPH07179426A (en) | Quinoline compound | |
JPH02275882A (en) | Pyrrolo(3,2-e)pyrazolo(1,5-a)pyrimidine derivative and pharmaceutical containing the same | |
KR890004662B1 (en) | 1,8-naphthyridine and 1,5,8-azanaphthyridine derivative and process for preparation thereof | |
CS276842B6 (en) | Pharmaceutical |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |