IE42788B1 - Esters of theophyllinylacetic acid - Google Patents
Esters of theophyllinylacetic acidInfo
- Publication number
- IE42788B1 IE42788B1 IE601/76A IE60176A IE42788B1 IE 42788 B1 IE42788 B1 IE 42788B1 IE 601/76 A IE601/76 A IE 601/76A IE 60176 A IE60176 A IE 60176A IE 42788 B1 IE42788 B1 IE 42788B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- acyl
- carbonyl
- group
- Prior art date
Links
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (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)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
1496298 Esters of theophyllinylacetic acid J A WULFING 18 March 1976 [24 March 1975] 10871/76 Heading C2C Novel compounds of the Formula I wherein R is hydrogen or methyl, n is 1 to 4 and Acyl is nicotinoyl, 3-methylpyrazole-5- carbonyl, 3 - methylisoxazolyl - 5 - carbonyl, 5 - n - butylpyridin - 2 - carbonyl, 2 - (4- chlorophenoxy) - 2 - methyl - propionyl, 2- acetoxybenzoyl or theophyllinyl - 7 - acetyl, may be prepared by (a) reacting a compound III with HO-Acyl or an acylating derivative thereof or (b) reacting a compound with theophyllinylacetic acid or an acylating derivative thereof where in both processes X is hydroxyl or a group displaceable on esterification. Pharmaceutical compositions of the compounds I with the usual excipients may be administered orally or parenterally in the treatment of adverse hyperlipedemic states.
Description
Ihe present invention relates to pharmaceutically active compounds, to their preparation and to compositions containing them.
A common problem encountered when administering medicaments is that they sometimes tend to become less effective than expected in bringing about the desired pharmacoldgical effect because of the so called ’Rebound Effect’. It has been discovered that this problem can be reduced for certain acidic medicaments if they are administered in the form of certain esters. Furthermore use’ of certain of these esters can also prolong the effective period after administration.
LO Accordingly the present invention provides compounds of the formula (l):
wherein R is a hydrogen atom or a methyl group; n is a number from 1 to 4 and 'Acyl' is a nicotinoyl, 3-methylpyrazole-5-carbonyl,. 3-methylisoxasolyl-5-carbonyl, 5-n-butylpyridin-2-carbonyl, 2-(4-chlorophenoxy)-2-methyl-propionyl, 2-acetoxybenzoyl or theophyllinyl7-acetyl group.
-2 42788
Suitably 'Acyl' is a nicotinoyl, J-methylpyrazole-5-carbonyl, 5-n-butylpyridin-2-carbonyl, 2-(4-chlorophenoxy)-2-methyl-propionyl, 2-acetoxybenzoyl or theophyllinyl-7-acetyl group.
Particularly suitable compounds of the formula (i) which have 5 improved pharmacodynamic properties include those of the formula (ll):
(Π) wherein n and R are as defined in relation to formula (I).
Most suitably B in the compounds of the formulae (I) and (ll) represents a hydrogen atom.
Most suitably n in the compounds of the formulae (i) and (ll) is or 2.
A particularly favoured -CHR-(CK2)n- residue in the compounds of formulae (i) and (ll) is the -CHg-CSg- group.
A preferred compound of this invention is l-(theophyllinyl-715 methylenecarbonyloxy)-2-(nicotinoyloxy)ethane which has particularly acceptable pharmacological effects on serum lipids.
- 3 42788
The present invention also provides a process for the preparation of the compounds of the formula (i) which process comprises:
(a) The reaction of a compound of the formula (ill):
(in) with a compound of fhe formula (IT):
HO.Aeyl (IT) or an acylating derivative thereof, wherein R, n and Acyl are as defined in relation to formula (I) end X is a hydroxyl group or a group readily displaceable in an esterification reaction; or 10 (h) The reaction of a compound of the formula (V):
X - CHR - (CE2)n - 0 - Acyl (V) with theophyllinylaoetic acid or an acylating derivative thereof; wherein R, n and Acyl are as defined in relation to formula (I) and X is a hydroxyl group or a group readily displaceable in an esterification reaction.
-443788
Por the reaction of a compound of the formulae (ill) or (V) wherein X is a hydroxyl group suitable oompounds of the formula (IT) or suitable derivatives of theophyllinylaoetic aoid include the free acid in the presence of a dehydrating agent such as dicyclohexyl carbodiimide, or derivatives of the free acid such as an acid halide such as the acid chloride or the acid anhydride or mixed anhydride.
Por the reaction of a compound of the formulae (ill) or (v) wherein X is a displaceable group such as a chlorine, bromine or iodine atom or an activated ester suoh as a methane sulphonyl or toluene sulphonyl ester, the preferred derivative of the compound of formula (IT) or of theophyllinylaoetic acid is a Balt such es an alkali metal, for example the sodium salt.
The preceding reactions can be brought about under conditions conventionally used for the preparation of esters.
Suitable solvents for such reactions include inert organic solvents such as dimethylformamide, benzene and pyridine.
The present invention also provides a pharmaceutical composition which comprises a compouncl of the formula (l) together with a pharmaceutically acceptable carrier.
The compositions of the invention are specially useful in treating adverse hyperlipedemie states in humans. Por such treatment, the compounds are generally administered orally although parenteral methods of administration may also be uaed.
- 5 43788
Typical, oral formulations will include tablets, pills, capsules, sachets, granules, powders, chewing gum, suspensions, emulsions and solutions, particularly preferred oral formulations are tablets and capsules. Where appropriate, the formulations may include conventional diluents, binding agents, dispersing agents, surface-active agente, lubricating agents, coating materials, flavouring agents, colouring agente, solvents, thickening agents, suspending agents, sweeteners or any other pharmaceutically acceptable additives, for example, gelatin, lactose, starch, talc, magnesium stearate, hydrogenated oils, polyglycols and syrups. Where the formulations are tablets or oapsules and the like, they Will represent pre-measured unit doses but in the case of granules, powders, suspensions and the like, the formulations may be presented as pre-measured unit doses or in multi-dose containers from which the appropriate unit dose may be withdrawn.
Injectable compositions may be as aqueous or non-aqueous solutions, suspensions or emulsions in a pharmaceutically acceptable liquid.
Preferred dosage forms of the composition will be conventional tablets or capsules containing a pre-measured dose for oral administration Such dosage forms will normally contain between 10 and 500 mgs of compound of formula (X) and preferably between 25 and 300 mgs. Such dosage forms will normally be’.taken from 1 to 6 times daily. The maximum daily dose for a 70 kg adult will not normally exceed 1500 mgs and, a daily dose of not more than 1000 mgs is generally preferred. Normally, the daily dose for a 70 kg adult will be at least 25 mgs and usually at least 50 mgs.
The compositions of the invention may be prepared by conventional methods of mixing, blending, tabletting.
The following Examples illustrate the invention:
- 6 42788
Example 1 l-(Theophyllin.vl-7-methylencarbonyloxy) -2- (nicotinoyloxy)ethane
Theophyllinyl-7-acetic acid β-hydroxyethyl ester (56.5 g), pyridine (32 ml) and chloroform (500 ml) were stirred together for an hour. To this was added nicotinoylchloride hydrochloride (42 g) in a mixture of chloroform (200 ml) and pyridine (32 ml). The reaction wa3 stirred for 24 hours at room temperature. The reaction mixture was diluted with water (500 ml) and the chloroform phase separated, dried and evaporated to yield a crystalline material (77-1 g). A sample of this material recrystallised from water yielded the desired compound (m.p. 187°C).
The title compound has an oral ΙΛ,-θ in rats of greater than lc/kg. When administered to 17 hour starved rats at 300 mg/kg the title compound produced a fall in serum triglyceride and cholesterol of about 3°% each at 1 hour post dose.
An analogous procedure may be used to prepare l~(theophyllinyl7-methylenecarbonyloxy)-4-(nicotinoyloxy)butane, m.p. 148 - 15O°C.
- 7 42788
Example 2
2-(Theophyllin.yl-7-methylencarbon.yloxy) -3- fnicotlnovloxv) propane
Nicotinic acid-2-hydroxypropyl ester (I5.O3 g) was dissolved, in pyridine (100 ml). To this was added dropwise over 1 hour theophyllinyl5 7-methylene-carbonyl chloride (21.33g) ih chloroform (250 ml). The reaction mixture was maintained at room temperature for 24 hours and then the solvent removed by evaporation. The residue was taken up in chloroform (400 ml) and washed with sodium carbonate solution (3 x 100 ml) and dried (sodium sulphate). The chloroform was removed by evaporation to yield a brownish crystalline material (28.1 g). The product was reerystallised from ethyl acetate to yield the desired compound m.p. 137°C.
Claims (6)
1. Claims:1. A compound of the formula (I): CH 3 (I) wherein R is a hydrogen atom or a methyl group; n is a number 5 from 1 to 4 and 'Acyl' is a nicotinoyl, 3-methylpyrazoie-5-carbonyl, 3-methyl-isoxazolyl-5-carbonyl, 5-n-butylpyridin-2- carbonyl, 2. -(4-chlorophenoxy)-2-methyl-propionyl, 2-acetoxybenzoyl or theophyllinyl-7-acetyl group.
2. A compound as claimed ln claim 1 wherein 'Acyl' is a 10 nicotinoyl, 3-methyl-pyrazole-5-carbonyl, 5-n-butylpyridin-2carbonyl, 2-(4-chloro-phenoxy)-2-methyl-propionyl, 2acetoxybenzoyl or theophyllinyl-7-acetyl group.
3. A compound as claimed in claim 2 wherein ’Acyl' is a nicotinoyl group. 15 4. A compound as claimed in any of claims 1 to 3 wherein n is 1. 5. A compound as claimed in any of claims 1 to 4 wherein R is a hydrogen atom. 6. A compound as claimed in any of claims 1 to 4 wherein the -CHR-(CH2) n -residue is a -CH2~CH2-group. 20 7. 1-(Theophyllinyl-7-methylenecarbonyloxy)-2-(nicotinoyloxy) ethane.
4. 8. A process for the preparation of a compound as claimed in claim 1 which process comprises: (a) The reaction of a compound of the formula (III): (III) 12788 oο CH 3 ch 2 -co-o-chr-(ch 2 ) η -χ with a compound of the formula (IV): HO.Aeyl (IV) or ati acylating derivative thereof, wherein R, n and 5 Acyl are defined in relation to formula (I) and X is a hydroxyl group or a group readily displaceable in an esterification reaction; or (b) The reaction of a compound of the formula (V)s X-CHR-(CH 2 ) n -O-Acyl (V)
5. 10 with theophyllinylacetic acid or an acylating derivative thereof; wherein R, n and Acyl are as defined in relation to formula (I) and X is *a hydroxyl group or a group readily displaceable in an esterification reaction. 10. A pharmaceutical composition which comprises a compound 15 of the formula (I) as defined in claim 1 together with a pharmaceutically acceptable carrier.
6. 11. An orally administrable pharmaceutical composition which comprises 1-(theophyllinyl-7-methylenecarbonyloxy)-2(nicotinoyloxy)ethane together with a pharmaceutically 20 acceptable carrier.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19752512886 DE2512886A1 (en) | 1975-03-24 | 1975-03-24 | NEW ESTERS OF THEOPHYLLINYL-7-ACETIC ACID, PROCESS FOR THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
Publications (2)
Publication Number | Publication Date |
---|---|
IE42788L IE42788L (en) | 1976-09-24 |
IE42788B1 true IE42788B1 (en) | 1980-10-22 |
Family
ID=5942253
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE601/76A IE42788B1 (en) | 1975-03-24 | 1976-03-22 | Esters of theophyllinylacetic acid |
Country Status (16)
Country | Link |
---|---|
JP (1) | JPS6043352B2 (en) |
AR (2) | AR211336A1 (en) |
AT (1) | AT344191B (en) |
BE (1) | BE839890A (en) |
CA (1) | CA1051890A (en) |
CH (1) | CH605950A5 (en) |
DK (1) | DK140843B (en) |
ES (2) | ES446321A1 (en) |
FI (1) | FI760755A (en) |
FR (1) | FR2305184A1 (en) |
GB (1) | GB1496298A (en) |
HU (1) | HU174879B (en) |
IE (1) | IE42788B1 (en) |
NL (1) | NL7603103A (en) |
SE (2) | SE419864B (en) |
ZA (1) | ZA761801B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2714883A1 (en) * | 1977-04-02 | 1978-10-12 | Basf Ag | NON-GLYCOSIDIC THEOPHYLLIN SUGAR DERIVATIVES |
-
1976
- 1976-03-18 GB GB10871/76A patent/GB1496298A/en not_active Expired
- 1976-03-19 FR FR7608048A patent/FR2305184A1/en active Granted
- 1976-03-22 BE BE165447A patent/BE839890A/en not_active IP Right Cessation
- 1976-03-22 FI FI760755A patent/FI760755A/fi not_active Application Discontinuation
- 1976-03-22 IE IE601/76A patent/IE42788B1/en unknown
- 1976-03-22 AT AT209376A patent/AT344191B/en not_active IP Right Cessation
- 1976-03-23 JP JP51031891A patent/JPS6043352B2/en not_active Expired
- 1976-03-23 SE SE7603564A patent/SE419864B/en unknown
- 1976-03-23 DK DK128076AA patent/DK140843B/en not_active IP Right Cessation
- 1976-03-23 CA CA248,568A patent/CA1051890A/en not_active Expired
- 1976-03-24 CH CH365876A patent/CH605950A5/xx not_active IP Right Cessation
- 1976-03-24 HU HU76WU24A patent/HU174879B/en unknown
- 1976-03-24 ZA ZA761801A patent/ZA761801B/en unknown
- 1976-03-24 NL NL7603103A patent/NL7603103A/en not_active Application Discontinuation
- 1976-03-24 ES ES446321A patent/ES446321A1/en not_active Expired
- 1976-03-26 AR AR262675A patent/AR211336A1/en active
- 1976-11-08 AR AR265378A patent/AR217246A1/en active
-
1977
- 1977-06-14 ES ES459777A patent/ES459777A1/en not_active Expired
-
1979
- 1979-03-19 SE SE7902463A patent/SE7902463L/en unknown
Also Published As
Publication number | Publication date |
---|---|
HU174879B (en) | 1980-03-28 |
BE839890A (en) | 1976-09-22 |
AT344191B (en) | 1978-07-10 |
ZA761801B (en) | 1977-03-30 |
CA1051890A (en) | 1979-04-03 |
GB1496298A (en) | 1977-12-30 |
FR2305184B1 (en) | 1979-09-21 |
FR2305184A1 (en) | 1976-10-22 |
SE7902463L (en) | 1979-03-19 |
ATA209376A (en) | 1977-11-15 |
DK140843B (en) | 1979-11-26 |
NL7603103A (en) | 1976-09-28 |
DK140843C (en) | 1980-04-28 |
JPS51118794A (en) | 1976-10-18 |
DK128076A (en) | 1976-09-25 |
AR211336A1 (en) | 1977-11-30 |
JPS6043352B2 (en) | 1985-09-27 |
SE7603564L (en) | 1976-09-25 |
AR217246A1 (en) | 1980-03-14 |
ES446321A1 (en) | 1977-10-01 |
SE419864B (en) | 1981-08-31 |
IE42788L (en) | 1976-09-24 |
ES459777A1 (en) | 1978-04-01 |
FI760755A (en) | 1976-09-25 |
CH605950A5 (en) | 1978-10-13 |
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